KAIMRC Innovations Issue 4 by Nature Research Custom Media

JANUARY 2018 - Issue No.4

ISSN 7901-2398 innovations.kaimrc.med.sa

RISK FAC TORS FOR PA NCRE ATIC CA NCER Large gene studies are finding lifestyle risks for the disease P. 8

A SINGLEDOSE VACCINE FOR MERS Tweaking certain vaccines may protect camels from MERS P. 34

Y OUR GE NE T IC M A K E- UP M AY A F F E C T E V OL U T ION A ND T R E AT ME N T OF HE PAT I T I S C P. 62

HOW GENETICS FIGHTS VIRUS INFECTIONS

SAUDI GENOME PROJECT

The Saudi Human Genome Project (SHGP) is a national program that aims for the identification of disease-associated variants for rare and common disease in the Saudi population. The ultimate objective of this endeavor is to create a national database for genetic variants at King AbdulAziz City for Science and Technology (KACST) and to make this information available for the national and international scientific community. This program is considered one of the largest life sciences research programs in Saudi Arabia. EMAIL: KAIMRC_BGD@NGHA.MED.SA

TABLE OF CONTENTS

P. 6 NANOMEDICINE: A TWO-HEADED FORCE AGAINST LUNG CANCER

P. 8 ZEROING IN ON RISK FACTORS FOR PANCREATIC CANCER

Nanocarriers that can transport precise doses of two drugs may prove effective against lung tumours.

Large gene databases help researchers discern lifestyle traits that cause pancreatic cancer.

P. 10 EXERCISE HELPS CANCER PATIENTS LEAD HAPPIER LIVES

P. 12 A PERSONALIZED PRESCRIPTION FOR CANCER TREATMENT

One of the first quality-of-life studies into Saudi cancer sufferers shows exercise and family support help.

‘Mini organ’ technique provides insights into the molecular basis of bowel cancer, and hope for more effective treatment.

P. 14 TIMING TREATMENT PERFECTLY

P. 16 TUMOURS ACTIVATE NEURONS TO TRIGGER APPETITE

Understanding how leukaemia affects the body’s circadian clock may unlock ways to treat the disease.

Blocking a population of neurons in the brain could help treat anorexia and weight loss caused by cancer.

Issue No.4

TABLE OF CONTENTS

P. 18 EXERCISING YOUNG PROTECTS HEART LATER IN LIFE

P. 19 COPING WITH ADVERSITY

P. 20 MYRRH DETOXIFIES WHEN LIVER CANNOT

Exercising when young can greatly reduce the risk of developing ischaemic heart disease in adulthood.

A Saudi study finds that adverse childhood experiences affect men and women in different ways.

The resin of a native shrub from the Arabian Peninsula and Africa relieves the symptoms of ammonia excess.

P. 22 WEIGHT LOSS SURGERY MAY REDUCE HEART DISEASE RISK

P.24 LEARNING TO PREDICT DIABETES

P. 25 ANTIBODY COULD HAVE DUAL ROLE

Data suggests gastric bypass surgery reduces by half the risk of developing congestive heart failure.

Machine learning could be used to identify high-risk patients and improve healthcare services.

An antibody that blocks the effect of follicle stimulating hormone may simultaneously treat obesity and osteoporosis.

P. 26 HOME BRAIN TRAINING HELPS WITH DISEASE

P. 28 A CHEMICAL RISK FOR BABIES

Computer-based brain training at home can improve cognition in patients with multiple sclerosis

Maternal exposure to chemicals widely used in consumer products and industries disrupts steroid hormone levels in babies’ cord blood.

January 2018

TABLE OF CONTENTS

P. 30 ISCHEMIC STROKE: EXAMINING BRAIN INFLAMMATION

P.31 SAUDIS BUCK THE DIABETES TREND

P. 32 HOPE FOR HOLDING BACK HYPERGLYCAEMIA

A signalling pathway may provide a target for reducing inflammation in the brain following ischemic stroke

Type II diabetes and insulin resistance don’t go hand in hand among Saudis as frequently as they do in other populations.

A two-drug combination that preserves and stimulates pancreatic function could offer a new option for treating type I diabetes.

P. 34 COMBATING MERS IN CAMELS WITH A SINGLE-DOSE VACCINE

P. 36 INJURY PREVENTION COULD STEM OPIOID ABUSE

P. 37 PLAYING RNA VIRUSES AT THEIR OWN GAME

Anti-MERS vaccines for camels could be optimized by varying their viral and DNA content, and adjusting their administration.

People are 1.4 times more likely to become persistent users of opioid painkillers after suffering a traumatic injury.

Researchers in France turn viruses against themselves by exploiting their ability to mutate and evolve rapidly.

P. 38 IMPROVING STEM CELL DONATION

P. 40 A VIRAL VECTOR TO FALL BACK ON

P. 42 A STEP CLOSER TO STEM CELL THERAPIES FOR BONE DISEASE

Stem cells could be collected from donors more safely by using a less invasive catheter.

A carrier made from the protein coat of a virus could efficiently deliver genetic material to the spinal cord.

Controlling a protein’s levels could guide stem cell differentiation for treatment of bone disease. Issue No.4

TABLE OF CONTENTS

P. 44 MINING BIG DATA HIGHLIGHTS IMPORTANCE OF ‘JUNK DNA HERE AFTER

P.46 MANAGING SALIVARY GLAND DAMAGE

P. 47 HEALTHY CELLS FOR HEALTHY PREGNANCIES

What was once called ‘junk DNA’ may play a role in early embryonic development and species evolution.

Stimulating saliva production is the most effective treatment option for managing radiotherapy damage.

Activating a defence gene may reduce damage to cells involved in preeclampsia.

P. 48 FILLING IN THE MICROBIAL GAPS

P. 50 THE RARE MUTATION THAT CAUSED MISDIAGNOSIS

P. 51 SCREENING FOR AN ENZYME DEFECT IN NEWBORNS

A new survey of the microbiome offers insights into its diversity and the interplay between bacteria and their human hosts.

A mutation found in two Saudi brothers is believed to have led to misdiagnosing cerebellar ataxia as multiple sclerosis.

Study boosts argument for cord blood screening to detect an enzyme defect in infants.

P. 52 LOSS OF SYNAPTIC ‘CARETAKER’ LEADS TO FATAL INFANT BRAIN INJURY

P. 54 HIV RESISTANCE GENE UNCOMMON AMONG SAUDIS

P. 55 SINGLE GENE DEFECT FOUND FOR UNEXPLAINED DWARFISM

A rare genetic mutation could provide insight into Alzheimer’s and Parkinson’s diseases.

A mutation that could provide resistance to HIV/AIDS is too rare among Saudis to screen for.

Mutations in a DNA replication gene cause a rare developmental disorder seen in Saudi children.

January 2018

TABLE OF CONTENTS

P. 56 INVESTIGATING IMMUNE RESPONSES

P.58 ANTIBIOTIC RESISTANCE: TRACKING DRUG SENSITIVITY IN E. COLI

P. 60 WHEN LIVER DISEASE PATIENTS FALL OFF THE MEDICAL RADAR

A molecule produced by hepatitis B virus prompts the body’s immune cells to leap into action.

Analyses of E. coli samples from Saudi hospital patients indicate large increases in resistance to first-line antibiotics.

People with viral hepatitis often do not return for follow-up treatment, highlighting the need for more robust support strategies.

P. 62 GENETIC MAKE-UP AND ITS IMPACT ON VIRAL INFECTION

P. 64 IN SEARCH OF STRATEGIES TO DISRUPT VIRAL DOCKING

A fast and simple approach for analysing people’s genetic make-up and the viruses that infect them could improve prevention and treatment of disease.

Insights into how two viruses initiate the infection of host cells could guide development of countermeasures.

KAIMRC Innovations is published for the King Abdullah International Medical Research Center (KAIMRC) by Nature Research Custom Media. King Abdullah International Medical Research Center (KAIMRC) Ar Rimayah, Riyadh 14611, Saudi Arabia Email: kaimrc@ngha.med.sa Web: kaimrc.med.sa

KAIMRC innovations Phone: +966 11 429 4516 Email: innovations@ngha.med.sa Web: innovations.kaimrc.med.sa

Springer Nature The Campus – 4 Crinan Street – London, N1 9XY, UK Email: nature@nature.com Web: www.nature.com

The Researcher Newsletter Phone: +966 11 429 4516 Email: theresearcher@ngha.med.sa Web: innovations.kaimrc.med.sa/en/newsletter

Issue No.4

A novel nanocarrier developed by researchers in China can deliver optimised doses of combined drugs to lung tumours with high precision. 6

January 2018

Nanomedicine: A two-headed force against lung cancer

anocarriers are a useful means for transporting exact Han and Wu trialled the effects of various ratios of the two doses of drugs to specific points in the body, for drugs by carefully placing different quantities of each on a example to target tumours in cancer therapy. Now, macromolecule, which was joined to the inside of the NLC by researchers in China have developed a novel nanobreakable linker molecules. Upon reaching its target, the NLC carrier that can transport precise opens as the linker molecules break, ratios of two drugs to treat nonand the drugs are released. By creat“Future research should be small-cell lung cancer. ing multiple versions of their NLC, Non-small-cell lung cancer is encouraged to investigate a dose- the researchers were able to select an the most common form of lung optimised NLC that was more cytodependent response and optimal cancer, representing 85 per cent toxic against non-small-cell lung doses with maximal anticancer of cases, but it is relatively insencancer cells than any previous treatsitive to chemotherapy. Surgery ments. efficacy, but fewer side effects.” is often required, either preceded Han and Wu included a gluor followed by treatment with a cose receptor-targeting molecule, combination of two anticancer drugs, gemcitabine and paclN-acetyl-D-glucosamine, (NAG) within their NLC design. itaxel. A key goal in refining the delivery of these two drugs Tumours feed off glucose, and therefore express high levels of to tumour sites is ensuring that precise ratios of the drugs are glucose transporters on their surfaces. The NAG-NLC prepared released to optimise their combined effect. by the team used this mechanism to target non-small-cell lung The new nanocarrier, developed by a team led by Jingtian Han cancer cells with high accuracy. at Binzhou Medical University and Zimei Wu at Yantai UniverAs the researchers state in their paper published in the sity, differs from more traditional nanoparticle designs because International Journal of Nanomedicine (2017): “[The NAGit contains both solid and liquid lipids. These ‘nanostructured NLCs] we designed can be beneficial to tumour therapy. Future lipid carriers’ (NLCs) have improved loading capacity and staresearch should be encouraged to investigate a dose-dependbility, and can carry two drugs that have differing physical and ent response and optimal doses with maximal anticancer effichemical characteristics. cacy, but fewer side effects.” Gemcitabine and paclitaxel target different elements of the cancer cell cycle, interfering with DNA synthesis and microLiang, Y., Tian, B., Zhang, J., Li, K., Wang, L. et al. Tumor-targeted polymeric nanostructubule growth respectively. Varied ratios of the drugs used in tured lipid carriers with precise ratiometric control over dual-drug loading for combicombination have different effects, and the aim is to deliver the nation therapy in non-small-cell lung cancer. International Journal of Nanomedicine optimal amount of each drug to a tumour. 2017, 1699-1715 (2017). Issue No.4

DEC A DE3 D / A L A M Y S TOC K P H OTO

Nanocarriers that can transport precise doses of two drugs may prove effective against lung tumours.

Zeroing in on risk factors for pancreatic cancer Large gene databases help researchers discern lifestyle traits that cause pancreatic cancer.

ancreatic cancer is one of the world’s deadliest cancers, often diagnosed at a late stage due to its lack of early symptoms. The difficulty in treating the disease in its later stages means effective prevention is necessary. Progress has been made in identifying the risk factors that cause pancreatic cancer. Mattias Johansson is a physicist-turned-geneticist working for the International Agency for Research on Cancer in Lyon, France. With his colleagues, Johansson has been able to home

January 2018

in on specific causal risk factors by lookdiabetes progression means caution must ing at how genetic ‘markers’ correlate be exercised when interpreting its apparwith pancreatic cancer. ent lack of association. “The classic example is coffee drinkers Obesity and insulin, however, are a lithaving a higher risk of lung cancer. In realtle more clear-cut. “There are a number ity, that’s because coffee drinkers tend to of hypotheses as to how obesity leads to smoke more than non-drinkers and, of cancer. These include hormonal imbalcourse, it’s the smokances, inflammation, ing that is the real risk and the elevation of “For obesity, it was factor for the cancer. insulin levels. Insureally confirmatory— We call this phenomlin itself has various enon ‘confounding’,” tumour-stimulatthis is a risk factor explains Johansson. ing effects, and this that everyone thought a t l e a s t p a r t i a l ly Johansson and his team identified the explains why obese was causal, so it was DNA sequences assopeople have a higher reassuring to see that ciated with suspected risk of pancreatic risk factors for panhold up in this analysis.” cancer.” creatic cancer, such Johansson has as obesity, body shape, insulin resistance, worked in the field for almost 15 years, and type II diabetes. They then analysed but says it’s just now that these lines the genetics of more than 14,000 individof inquiry are really starting to pay off, uals to see how the ‘markers’ correlated thanks to the public genetic databases with pancreatic cancer. that allow for large-scale investigaObesity and high insulin levels were tions into how our DNA translates into shown to be causal factors for pancreatic our health in life. The benefits cannot cancer, while type II diabetes was among be overstated: “It directly informs our the confounded, non-causal traits. “For understanding of what causes a disease, obesity, it was really confirmatory—this which is essential in order to prevent it.” is a risk factor that everyone thought was causal, so it was reassuring to see Carreras-Torres, R., Johansson, M., Gaborieau, V., that hold up in this analysis,” Johansson Haycock, P. C., Wade, K. H. et al. Journal of the says. He explains that the complexity of National Cancer Institute 109 (2017). Issue No.4

@20 1 7 S C I EN C E P H OTO LI B R A RY / A L A M Y S TOC K P H OTO

Our genetic information may hold the key to deciphering which physical traits make us more likely to get pancreatic cancer.

Exercise helps cancer patients lead happier lives

Exercise helps cancer patients stay healthier and happier.

cancer diagnosis is a harrowing concept, and a daily reality for millions of people. The World Health Organization names the disease as the second leading cause of death worldwide. While cancer treatment remains a top priority, scientists and physicians also strive to ensure patients lead meaningful lives, regardless of prognosis. But there has been a lack of quality-of-life (QoL) studies into what helps or harms them.

January 2018

“We care about the quality of our patients’ lives as much as we care about their treatment,” says Anwar E. Ahmed, an associate professor in the College of Public Health & Health Informatics at King Saud bin Abdulaziz University for Health Sciences. The reason for the lack of studies, he explains, is that the term ‘quality of life’, especially as it relates to cancer patients, is a new concept in the kingdom and in other non-Western countries.

Ahmed’s research group, comprising students and staff from five Saudi institutions, published in 2017 the most comprehensive Saudi-focused QoL evaluation to-date. The team used a self-assessment questionnaire to gather patients’ subjective appraisals of their own physical and mental health. They then analyzed the relationships between those scores and an array of patient attributes, including age, gender, marital status, education and employment status, cancer disease presentation, and more. “We are seeing more and more people diagnosed with cancer, and we just don’t know what their quality of life is — especially just after diagnosis,” says Ahmed. The scientists revealed multiple trends, the most prevalent being the benefit of regular exercise on multiple facets of well-being. Patients who exercised reported better physical health, vitality, social functioning, and overall general welfare. Patients with family support reported higher levels of emotional well-being and general health. Those with diagnoses less than a year old exhibited significantly poor QoL metrics. Leukaemia was particularly implicated in poor QoL, in comparison to other forms of cancer. These data endorse further investigation into exercise and emotional support for improving the lives of cancer patients in Saudi Arabia. Ahmed recommends further research involving a mobile app that allows patients to report their daily feelings, whether they exercised, and what symptoms they are experiencing. This can help better monitor their well-being and inform their treatment options, he says. Ahmed, A. E., Almuzaini, A. S., Alsadhan, M. A., Alharbi, A. G., Almuzaini, H. S. et al. Health-related predictors of quality of life in cancer patients in Saudi Arabia.

Journal of Cancer Education, 1–9 (2017).

P H A N I E / A L A M Y S TOCK P HOTO

One of the first quality-of-life studies into Saudi cancer sufferers shows exercise and family support help.

National Center for Stem Cell Technology With research partnerships spanning the globe, KACST is at the heart of the drive to reach innovative therapies for different diseases prevalent in Saudi Arabia, such as diabetes, through stem cells research. By establishing the National Center for Stem Cell Technology in April 2014, KACST is driving advances applied research in regenerative medicine and promoting technology transfer and localization. www.kacst.edu.sa

Organoids are miniature organs produced from a small sample of living tissue. 12

January 2018

A personalized prescription for cancer treatment

olorectal, or bowel, cancer is a leading cause of death in adults. The condition is difficult to treat because the makeup and d e ve l o p m e n t o f b o we l tumours differs from patient to patient. A generic approach often fails. Scientists from the University of Utrecht in The Netherlands, and Oxford University in the United Kingdom, propose a more personalized approach to bowel cancer starting with the molecular composition of the tumour itself. Their research reveals features specific to each cancer patient, while also highlighting common molecular signatures of the disease. The study makes use of a new technology known as ‘organoids’, in which a small tissue sample can be grown in the lab into a long-lived, simplified, miniature organ, containing all the cell types of the original tissue. Co-author Hans Clevers explains that the bowel was “where we first worked out the procedure to establish organoids.” The researchers generated

organoids from tumours and healthy tissue in seven bowel cancer patients. They then examined the proteins found in each organoid— its ‘proteome’—comparing these between patients, and between cancerous and non-cancerous tissues. Of the thousands of proteins identified, around 400 differed between tumour and healthy organoids from each patient. This was far greater than the number of active genes differing between the same tissues, em pha s i z i n g t he u s e f u l additional perspective provided by the proteome. The team next identified proteins implicated in tumour development. For instance, one patient’s tumour organoid had diminished levels of a protein, MSH3, which is responsible for repairing mistakes in DNA. MSH3 deficiency can cause the genome to become unstable, and has already been associated with colorectal cancer. In fact, many proteins are implicated in genome stability, and deficiencies in any of these may cause cancer. The

type of instability —what part of the genome is affected— can be crucial to a patient’s response to treatment. Thus, knowing which proteins are diminished may help provide targeted treatments and improve chances of survival. The levels of other proteins, around 300, were varied in the tumour organoids of all patients, and may prove to be valuable markers for colorectal cancer. O vera l l , t he orga noid technology explored by the Utrecht-Oxford team represents a marked advance over previous methods for exploring treatment options, and is less intrusive than repeated testing on actual patients. Clevers reports that the technique is already being trialled in a range of other cancers including pancreatic, prostate, breast and ovarian cancers. Cristobal, A., van den Toom, H. W. P., van

de Wetering, M., Clevers, H., Heck, A. J. R. et al. Personalized proteome profiles of healthy and tumor colon organoids

reveal both individual diversity and basic features of colorectal cancer. Cell

Reports 18, 263—274 (2017).

Issue No.4

‘Mini organ’ technique provides insights into the molecular basis of bowel cancer, and hope for more effective treatment.

from 75 patients at different stages of treatment for leukaemia and from 30 healthy controls. They found that the majority of clock genes were suppressed in patients with acute myeloid leukaemia with the exception of Cry2, whose levels increased toward the end of treatment and during relapse.

Changes in the expression of circadian clock genes have been found in people with leukaemia.

Timing treatment perfectly Understanding how leukaemia affects the body’s circadian clock may unlock ways to treat the disease.

he circadian clock is the internal rhythm of the body that responds to night and day, typically following a 24-hour cycle. KAIMRC researchers have shown that many circadian clock genes are suppressed in leukaemia patients, aiding the disease’s progression. The team also suggests a role for one key protein in restoring the circadian clock in chronic myeloid leukaemia. The circadian clock controls many key processes, including metabolism, sleep-wake patterns and the regulation of genes. Circadian rhythms and clock

January 2018

genes are disrupted in various diseases, including cancer and diabetes. Leukaemia is a malignant blood cancer that manifests in both acute and chronic forms. Changes to circadian genes have been reported in leukaemia patients. Mohamed Boudjelal, at KAIMRC’s drug discovery unit, and co-workers used gene expression profiling to examine circadian clock genes in acute and chronic forms of leukaemia before, during and after treatment. The researchers analysed the expression of seven clock genes, including Cry2 and BMAL1, in blood samples collected

A similar story unfolded with chronic forms of the illness, with all analysed clock genes suppressed, except for Cry2, which was unaffected in the initial stages of the disease. The team also investigated the role of Sirt1, a protein known to regulate genes associated with the circadian clock. They found that inhibiting Sirt1 resulted in partial recovery of circadian rhythm in patients with chronic myeloid leukaemia by normalising the switching on and off of the BMAL1 clock gene. Therapies targeting Sirt1 could improve dysfunctional circadian rhythm and enhance the effectiveness of existing chemotherapeutic drugs. “A comprehensive understanding of how circadian genes behave in leukaemia will provide insights into how the molecular clock is impacted in this disease,” write the researchers in their paper published in the Journal of Circadian Rhythms. “Such an understanding could also be used to develop treatment strategies whereby drugs are administered to patients… in synchrony with their molecular clocks to facilitate greater effectiveness.” Rahman, S., Al-hallaj, A., Nedhi, A., Gmati, G., Abuel-

gasim, K.A., et al. Differential expression of circadian genes in leukemia and a possible role for Sirt1 in restoring the circadian clock in chronic myeloid leukemia. Jour-

nal of Circadian Rhythms 15 (1), 3 (2017).

IM AGE B R O K E R / A L A M Y S TO C K PH O TO

A comprehensive understanding of how circadian genes behave in leukaemia will provide insights into how the molecular clock is impacted in this disease.

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Tumours activate neurons to trigger appetite loss Blocking a population of neurons in the brain could help treat anorexia and weight loss caused by cancer.

January 2018

Mice with cancer have large numbers of CGRP-expressing neurons (stained red) in the brain’s parabrachial nucleus, which reduce their appetite.

Issue No.4

C A R LOS C A M P OS @ 2 0 1 7

he same neurons that help the for the treatment of migraines. According brain respond to painful stimuli to Campos, these same drugs might prove are also responsible for causing useful for restoring appetite in cancer a loss of appetite in people with patients. cancer. The discovery could lead to new To test the role of these CGRP-expresstreatments for people suffering from caning neurons in cancer-induced appetite cer-induced weight loss and anorexia. changes, Campos and his team implanted “It’s pretty clear that people with cancer lung cancer cells in one set of mice genetoften die, not necic a l ly a l tere d essarily because a no t her s e t o f “If you can treat the weight mice to spontathe tumour is loss that is a consequence c a u s i n g o rg a n neously develop malfunction, intestinal cancer. of the loss of appetite, but because they They showed that you improve the ability to lose a lot of body CGRP-expressprolong life and hopefully weight. Loss of ing neurons in the appetite is a large PBN were pathohave a longer time frame part of that,” says logically active in to treat the tumour.” Carlos Campos, response to the from the Univertumours in both sity of Washington in Seattle, US, who led sets of mice. the study. “If you can treat the weight loss The researchers also injected an engithat is a consequence of the loss of appeneered virus into the brains of all the mice, tite, you improve the ability to prolong life allowing them to selectively inactivate the and hopefully have a longer time frame to CGRP-expressing neurons at will. In this treat the tumour.” way, they showed they could prevent or The neurons behind cancer-related reverse signs and symptoms of anorexia anorexia are located at the junction of the and weight loss, depending on when they brain stem and the midbrain, in a small silenced the neurons. anatomical structure known as the lateral In addition to boosting appetite, blocking parabrachial nucleus (PBN). Campos and the CGRP-expressing neurons also reversed his colleagues decided to focus on these signs of lethargy, anxiety and malaise in the neurons after previously showing that mice. If the same could be done with a drug their activation in otherwise healthy mice in patients, “that would have huge implicacould make them lose their appetites. tions for quality of life,” says Campos. Notably, the PBN neurons express a small protein known as calcitonin Campos, C. A., Bowen, A. J., Han, S., Wisse, B. E., Palmiter, gene-related peptide (CGRP). This neuroR. D. & Schwartz, M. W. Cancer-induced anorexia and peptide is the target of several drugs curmalaise are mediated by CGRP neurons in the parabrarently in late-stage clinical development chial nucleus. Nature Neuroscience 20, 934-942 (2017).

Exercising young protects heart later in life

Exercising when young can greatly reduce the risk of developing ischaemic heart disease in adulthood.

esearchers studied the data of 1.5 million Swedish men examined over several decades. They found that 18-year-olds demonstrating a combination of low aerobic fitness, measured by the ability to sustain cycling on a stationary bike, and high body mass index (BMI), measured from weight and height calculations, were at greater risk of developing ischaemic heart disease later in life. Obesity and a sedentary lifestyle are two of the biggest enemies of human health, but their interactive effects on the body are not all that clear. Past studies have shown that regular physical activity

January 2018

can help reduce the risk of developing chronic diseases, but it hasn’t been clear if exercising early in life can have an impact in adulthood. Casey Crump at Icahn School of Medicine at Mount Sinai, New York, and co-workers examined the interactive effects of obesity and physical fitness on the risk of ischaemic heart disease (IHD). They examined the data of approximately 1.5 million Swedish men who underwent compulsory physical examinations prior to military conscription between 1969 and 1997, and checked whether their body height, body mass, muscular strength and aerobic fitness had any

influence on IHD risk later in life. After adjusting for family history and socioeconomic factors, they found that people who had low aerobic fitness and high BMI at age 18 were more likely to develop IHD in adulthood. Of the 1.5 million men in the cohort, approximately 2.5% were diagnosed with IHD by 2012. The researchers found that those with low aerobic fitness at 18 were 1.8 times more likely to develop IHD than those with high aerobic fitness. Also, men with high BMI when young were 1.8 times more likely to develop IHD than those with normal BMI. Surprisingly, muscular strength had no significant impact on IHD risks. The results show that aerobic fitness and BMI in late adolescence are the two biggest risk factors for IHD in adulthood. Exercising, eating well and keeping an eye on body weight early in life might offer long-term protection for the heart and longevity. Crump, C., Sundquist, J., Winkleby, M. A. & Sundquist, K. Interactive effects of obesity and physical fitness on risk

of ischemic heart disease. International Journal of Obe-

sity, 41, 255–261 (2017).

P H OTOA LTO / A L A M Y S TOC K P H OTO

The data of approximately 1.5 million Swedish men were analysed in the study, the largest of its kind.

Coping with adversity A Saudi study finds that adverse childhood experiences affect men and women in different ways.

Governments should implement gender-specific preventive strategies to address certain problems resulting from adverse childhood experiences. Eighty per cent of participants had encountered one or more adverse childhood experiences before the age of 18, 29% of whom had encountered four or more. The five most common adverse childhood experiences for men were

Adverse childhood experiences can have life-long consequences

domestic violence, lack of protection/ supervision, peer violence, collective violence and parental divorce. For women, they were domestic violence, lack of protection/supervision, parental divorce, emotional abuse and collective violence. The researchers found significant differences in how each gender coped with ACEs. Men with four or more adverse childhood experiences were more likely to use drugs and drink alcohol, whereas women were more likely to develop depression, anxiety and mental disorders. The results suggest that governments

should implement gender-specific preventive strategies to address certain problems resulting from adverse childhood experiences. The findings are timely given that Saudi Arabia is seeing a growing number of reported cases of people with adverse childhood experiences similar to other countries. Almuneef, M., ElChoueiry, N., Saleheen, H. N. & Al-Ei-

ssa, M. Gender-based disparities in the impact of adverse childhood experiences on adult health: Findings from a national study in the Kingdom of Saudi Arabia. International Journal for Equity in

Health 16, 90 (2017).

Issue No.4

R O B I N B E CK H A M / B E E PS TO C K / AL A M Y STO C K P HO TO

dverse childhood experiences are stressful or traumatic events that occur in early life, such as emotional neglect, domestic violence, sexual abuse, parental divorce and the death of a loved-one. They are known to have life-long consequences. Past studies have shown that adverse childhood experiences disrupt brain development, cause behavioural changes and increase the risk of physical or mental disorders. KAIMRC’s Maha Almuneef and co-workers examined how adverse childhood experiences affect Saudis. They found that men with four or more adverse childhood experiences are more likely to use drugs and drink alcohol, while women are more likely to develop depression, anxiety and mental disorders. The researchers invited 10,156 people — of which 52% were men and 48% were women — from all regions of Saudi Arabia to participate in an interview or complete a questionnaire that asks them a series of multiple-choice questions regarding their physical and mental health, living habits and adverse childhood experiences.

Myrrh detoxifies when liver cannot Myrrh, the resin from a shrub native to the Arabian Peninsula and Africa, relieves the symptoms of ammonia excess from liver disease.

Myrrh could help treat symptoms of a faulty liver.

January 2018

but were normal in the treated rats. Excessive ammonia is particularly dangerous because it provokes the over-production of nitrogen and oxygen free radicals. Free radicals ‘steal’ electrons from the lipids in cell membranes, leading to cell damage. The scientists found that myrrh induced the production of several antioxidant and detoxifying proteins in the liver, kidneys and cerebrum. In particular, the team suggests that the anti-inflammatory protein Nrf2 plays a key role in this defensive process. In healthy and treated hyperammonaemic rats, Nrf2 is activated by high concentrations of oxygen free radicals and triggers the production of antioxidants, which protect the cells against free radicals. Nrf2 and antioxidant levels were significantly lower in untreated hyperammonaemic rats. Beyond the rise in Nrf2, C. molmol resin treatment also reduced protein tumour necrosis factor-alpha (TNF-α), which is known to be high in the serum of cirrhotic patients, a condition in which the liver is hardened by fibrous tissue. Although the precise mechanism of the treatment is still unclear, it might help attenuate the effects of liver disease. Mahmoud, A. M., Alqahtani, S., Othman, S. I., Germoush, M. O., Hussein, O. E., et al. Commiphora mol-

mol modulates glutamate-nitric oxide-cGMP and

Nrf2/ARE/HO-1 pathways and attenuates oxidative stress and hematological alterations in hyperammonemic rats. Oxidative Medicine and Cellular Lon-

gevity 2017, 7369671 (2017).

Issue No.4

A N DR EW M C C ON N ELL / A L A M Y S TOC K P H OTO

nown for its multiple beneficial properties, the dried sap of Commiphora molmol, a native shrub in the Arabian Peninsula and Africa, has been used in traditional medicine for centuries. Recently, KAIMRC’s Sultan Alqahtani, in collaboration with Beni-Suef University in Egypt, found that this resin, known as myrrh, counteracts the damaging effects of ammonia excess, a common consequence of cirrhosis and other liver diseases. When the liver cannot remove harmful substances sufficiently, they build up in the bloodstream. For example, ammonia, a by-product of protein digestion, needs to be converted into urea in the liver and eliminated via the kidneys. Accumulation of ammonia in the blood, called hyperammonaemia, is toxic to nerves and can lead to a decline of brain functions known as hepatic encephalopathy. Since current therapies to reduce ammonia levels in the blood have had limited effects, the team looked for a remedy in myrrh, whose antibacterial, anti-inflammatory, antioxidant, sugar-reducing and liver-protective properties have been used traditionally for the treatment of several diseases. The researchers induced hyperammonaemia in rats and administered an oral dose of concentrated C. molmol resin powder for eight weeks. Body weight, blood ammonia levels and other major liver and blood physiological parameters worsened in hyperammonaemic rats not treated with myrrh,

Weight loss surgery may reduce heart disease risk Data suggests gastric bypass surgery reduces by half the risk of developing congestive heart failure.

January 2018

ne of the most popular surgical ensured that the surgery was the only facprocedures for treating obetor attributable for the results. sity, Roux-en-Y gastric bypass The researchers concluded that RYGB (RYGB), reduces by almost half provides long-term protection against the risk of developing severe cardiovasmajor cardiovascular diseases, and in cular diseases, in patients assessed eight particular on congestive heart failure, years following the operation. a condition where the heart is unable to RYGB alters the process of digestion pump blood efficiently. While previous by reducing the size of the stomach and studies have linked weight loss surgery to bypassing the upper portion of the small reduction of heart attack, this is the first intestine. As a result of the procedure, analysis to show the impact of RYGB on people feel full more quickly, while a congestive heart failure. smaller amount of food is absorbed. SurBased on data analyses of a subset of gery is indicated for people whose body almost 900 patients, the researchers sugmass index (BMI) — an estimate of corpugest that the cardiovascular protective lence calculated effects of RYGB as body weight may be the result While previous studies have of reductions in divided by square of the height — is blood pressure, linked weight loss surgery greater than 40 in HDL to reduction of heart attack, increases kg/m2, or whose (good) cholesterol this is the first analysis to BMI is between 35 levels, and recovand 40 but have ery of blood vesshow the impact of RYGB another conelasticity. The on congestive heart failure. sel dition, such as same subset also type II diabetes, demonstrated a hypertension, hyperlipidaemia or sleep significant increase in diabetes remisapnoea. Beyond the positive effects on sions. body weight, a long-term study by the The next challenge for the team will Geisinger Obesity Institute in the US be to explain these improvements at the found the procedure brings other health molecular level. benefits. “In the US, there are approximately 15 The team analysed data on more than million adults who are extremely obese, 1,700 people who underwent RYGB but less then 1% undergoes weight loss between 2002 and 2012. At the time, they surgery. I hope that suitable patients did not have pre-existing cardiovascular who are at risk of cardiovascular diseases conditions. This group was compared with and meet the eligibility criteria would be a control group of obese individuals who offered this type of treatment,” says Peter did not undergo the procedure. Follow-up N. Benotti, first author of the study. data collected up to 12 years after surgery was also analysed. The team made sure Benotti, P. N., Wood, G. C., Carey, D. J., Mehra, V. C., Mirthat individuals in the study and control shahi, T., et al. Gastric bypass surgery produces a duragroups could be matched with each other ble reduction in cardiovascular disease risk factors and for age, BMI, sex, ten-year cardiovascureduces the long-term risks of congestive heart failure. lar risk, smoking history, hypertension Journal of the American Heart Association 6(5), medication and diabetes. This approach e005126, (2017). Issue No.4

B EN EDI C T E DE S R U S / A L A M Y S TOCK P HOTO

Gastric bypass surgery is the best option to reduce risk of cardiac diseases in obese patients

Blocking FSH with an antibody produces a dramatic effect on body fat in mice.

Learning to predict diabetes Machine learning approaches can effectively identify patients who are likely to develop diseases such as diabetes, according to new research from KAIMRC. A team led by Sherif Sakr evaluated how well several machine learning methods predicted diabetes incidence in patients who had taken part in the Henry Ford Exercise Testing (FIT) project, which collected metabolic, medical and demographic data from thousands of patients undergoing exercise treadmill stress testing. Sherif’s team used data from more than 32,000 of the patients who had had a five-year follow-up and no previous heart conditions or coronary artery disease. About 5,000 of the patients had developed diabetes by the time of the follow-up. Sakr’s goal was to determine which machine learning algorithm could reliably predict a patient’s likelihood of developing diabetes with high accuracy. “If you can identify people who are at risk before they get sick, that would save a lot of money and resources and improve 24

January 2018

healthcare service. Treating people before they get sick is much more effective and efficient,” Sakr says. He believes machine learning can achieve that goal. The team identified 13 relevant clinical variables in the FIT data and tested several classification algorithms to determine how well they predicted a patient’s odds of developing diabetes. They aimed to use as few variables as possible to increase the model’s practicality. Initially, the algorithms had a performance of about 70%, with none emerging as a clear winner. However, the FIT data suffers from an imbalance common to most healthcare datasets, with many more representatives of one class than another — far more healthy patients than diseased patients, for example. Such an imbalance hampers the algorithms and posed a major challenge in this project. To rectify this, Sakr’s team evaluated two approaches. Removing data points from the larger class (healthy patients) to reduce the difference had little impact on

the outcome. However, increasing the size of the smaller class (diseased patients) by generating random new data with similar characteristics significantly improved performance, raising it to nearly 92%, significantly better than traditional statistical techniques. The study has clearly shown that machine learning can identify high-risk patients, improving efforts at disease prevention and guiding the management of hospital resources. “There’s a huge amount of data in the healthcare domain, but there hasn’t yet been effective use of it,” says Sakr, who plans to cross-validate these models with another cohort, and is developing models that can accurately predict the likelihood of several other significant diseases. Alghamdi, M., Al-Mallah, M., Keteyian, S., Brawner, C., Ehrman, J. et al. Predicting diabetes mellitus using SMOTE and ensemble machine learning approach: The Henry Ford ExercIse Testing project. PLOS ONE 12, e0179805 (2017).

B RA I N LI G H T / A L A M Y S TOC K P H OTO

Machine learning could be used to identify high-risk patients and improve healthcare services.

Antibody could have dual role An antibody that blocks the effect of follicle stimulating hormone may simultaneously treat obesity and osteoporosis.

“

Blocking FSH with an antibody produces a dramatic effect on body fat in mice.

Zaidi. This effect was at least partly due to increasing the activity of brown fat cells, which are adept at metabolizing fat to release their stored chemical energy as heat. This discovery led the researchers to explore the potential of their antibody in the treatment of both obesity and osteoporosis. “FSH has very little function in males,” says Zaidi. “So as far as we can tell our procedure is unlikely to have any adverse consequences in men or in post-menopausal women, although caution would be required with pre-menopausal women.” He points out that in tackling obesity, treatment with the antibody could also prevent many of its harmful

consequences, including cardiovascular disease, diabetes and cancer. All such hopes, however, depend on the initial findings in mice being translated into an effective and safe therapy for humans. This is the challenge that the new company has been set up to tackle. An antibody that is being structurally ‘humanized’ to be compatible with human biology will soon enter toxicology studies then hopefully progress into human clinical trials by 2020. Liu, P., Ji, Y., Yuen, T., Rendina-Ruedy, E., DeMambro,

V. E. et al. Blocking FSH induces thermogenic adipose tissue and reduces body fat. Nature 546, 107–112 (2017).

Issue No.4

A DAM GAU LT / O J O IM AGE S / G E T T Y I M AG E S

There is no drug for obesity that either works well or is without side-effects,” says US-based endocrinologist, Mone Zaidi, explaining his work on developing an antibody against follicle stimulating hormone (FSH) to treat obesity. Animal studies in mice have been sufficiently encouraging for Zaidi and colleagues to found a start-up company to move the research into human clinical trials. FSH is produced in males and females, but is most commonly known for its action in stimulating the production and release of the hormone oestrogen in females. A rise in FSH levels during menopause coincides with bone loss, which leads to osteoporosis. Treating osteoporosis is therefore one obvious potential application for anti-FSH antibody therapy. But the hormone’s effect on body fat suggests a possible much wider option to treat obesity in both men and women. Zaidi, at the Icahn School of Medicine at Mount Sinai, is the leader of an international research team that initially set out to explore the effects of FSH and other hormones on bone. They worked with an antibody that binds to FSH and specifically blocks its interaction with receptor molecules in cell membranes, discovering that treatment with this antibody increases bone mass in mice. “Quite serendipitously, we noticed that our data revealed the antibody also dramatically reduced fat levels,” says

Brain training at home helps multiple sclerosis

January 2018

Previous work has suggested that computer-based cognitive training benefits patients with MS. Charvet and colleagues had previously seen success in a small-scale test of their tele-rehabilitation approach: a variety of auditory and visual exercises designed to improve speed and accuracy of information processing. The training is done at home with remote monitoring and supervision. The new trial tested the same approach more rigorously. The trial involved 135 patients with MS and mild to moderate neurologic disability. Participants were selected at random to either use the computer-based cognitive training program for 12 weeks, or to play normal computer games over the same period. People who did the cognitive training program improved more on tests of cognitive function over the trial period than people who played games, even though those who played games spent longer doing so. The outcome reinforces the fact that

cognitive training helps people with MS, and validates the tele-rehabilitation approach, which enables all patients to benefit regardless of their ability to attend clinics. Charvet and Shaw say that the approach could be used to target specific cognitive impairments early, and that it could be applied more widely. “Our methodology is not confined to reaching people with MS,” says Charvet. “The remote protocols we have developed are widely applicable across disorders associated with cognitive impairment.” The team’s next steps are to determine the optimal amount of training and how to maintain the improvement beyond 12 weeks. Ultimately, they hope to develop the approach so it can be personalized to provide each individual with maximal benefit. Charvet, L., Yang, J., Shaw, M. T., Sherman, K., Haider, L.

et al. Cognitive function in multiple sclerosis improves with telerehabilitation: results from a randomized controlled trial. PLOS ONE 12(5), e0177177 (2017).

omputer-based brain training at home can improve cognition in patients with multiple sclerosis (MS), a new trial shows. A ‘tele-rehabilitation’ approach offers easy access to treatment for disabled patients, and could improve treatment for many diseases. Multiple sclerosis causes a gradual decline in neurologic function and is well established as a cause of physical disability, but up to 70% of patients also develop cognitive impairment. Options for treating this impairment are limited, and disability can make access to therapy difficult. “Traditional cognitive rehabilitation typically requires clinic visits spanning weeks or months, but people with multiple sclerosis face many obstacles to reach the clinic,” explain Leigh Charvet and Michael Shaw from the New York University School of Medicine in the United States. “The travel presents a barrier to patients most in need of cognitive remediation.”

An example of a task in the brain-training program that involves tracking movement of multiple objects.

GE T T Y I M AGE S /I S TO C KP HO TO T HI N KS TO CK I MAG ES

Cognitive impairment caused by multiple sclerosis can be improved with a computer-based brain-training system accessible at home.

Leading Reliable Healthcare An outstanding, timely and much awaited contribution to the healthcare sector in the Kingdom of Saudi Arabia and globally.

Edited by Bandar Al Knawy, MD, FRCPC CEO, Ministry of National Guard Health Affairs Foreword by Dr. Paul Rothman CEO, Johns Hopkins Medicine Published by CRC Press, 2017

FEATURES

Contains contributions from recognized healthcare leaders from the UK, USA, Canada and South Korea/Singapore.

Describes how leadership can ensure reliable standards of care for patients and how excellence can be achieved.

Focuses on a different aspect of building a reliable healthcare system.

Relevant to global healthcare systems with key themes such as effective clinical practice and crisis management being universal.

Exposure to ‘nonstick’ chemical risky for foetal health Maternal exposure to chemicals widely used in consumer products and industries disrupts steroid hormone levels in babies’ cord blood.

January 2018

The study recommends raising global awareness about risks related to PFCs on child health.

Issue No.4

A N DR EY UG A DC H I KOV / A L A M Y S TOCK P HOTO

anmade perfluorinated in controlling human metabPFCs with longer carbon chains chem ic a l s ( PFC s ) , olism and reproduction. were increasing. As these PFCs regarded for their oilThey found that foetal are known to have greater toxand water-repellent exposure to a common PFC icity and longer half-lives, the properties, have been used in a contaminant, called perfluoresearchers emphasise that wide range of products, such as rooctane sulfonate (PFOS), awareness of associated risks non-stick cookware and food was linked to lower levels of needs to be raised. packaging, since the 1950s. cortisol and cortisone in cord Recommendations for Increasingly, scientists warn blood. PFOS was also associexpectant mothers and those that PFCs can now be detected ated with higher levels of the who are now breastfeedeverywhere in the environandrogenic hormone dehying include avoiding foods ment and even in our bodies. droepiandrosterone (DHEA). packaged in materials conMost of us ingest small This “may have adverse taining PFCs (such as microamounts of PFCs through effects on the foetal endowave popcorn bags, fast food food and water. So far, anicrine system and steroid horcontainers and pizza boxes); mal studies have shown that mone homeostasis in later life minimising dust ingestion PFCs delay developmental resulting in abnormalities in and hand-to-mouth transgrowth but their effects fer, and avoiding the on human health have use of groundwater for Recommendations for been less clear. drinking or cooking. Researchers in Japan Kishi says that colexpectant mothers and have , for t he f i r s t laborating and intethose who are now time, established a grating existing birth breastfeeding include link between PFCs in cohort studies across maternal blood and avoiding foods packaged in borders will become levels of cord blood more important. To this materials containing PFCs. hormones at birth. end, she led the launch Their study is part of of the Birth Cohort a large-scale, ongoing progrowth, neurodevelopment Consortium of Asia (BiCCA) ject called the Hokkaido Birth and reproductive health,” in 2012, which aims to deepen Cohort Study on Environsays Reiko Kishi from the understanding of the health ment and Children’s Health, Center for Environmental impacts of a wide range of which monitors the health of and Health Sciences at Hokenvironmental chemicals and children born in this region of kaido University. “Therefore, to develop effective prevennorthern Japan. in utero PFC exposure may be tion strategies for children’s The team measured PFC a public health concern, and health. levels in the blood of 185 long-term observation of expectant mothers, and subthese effects is warranted.” Goudarzi, H., Araki, A., Itoh, S., Sasaki, sequently measured cord Although PFCs are being S, Miyashita, et al. The Association of blood levels of two groups phased out by certain indusprenatal exposure to perfluorinated of steroid hormones in their tries, they are still present in chemicals with glucocorticoid and newborn babies: glucocorolder products, and can accuandrogenic hormones in cord blood ticoids (cortisol and cortimulate in our bodies. A previsamples: The Hokkaido Study. Environsone) and androgens, both of ous study by the same research mental Health Perspectives 125, 111– which play an important role team warned that new types of 118 (2017).

Ischemic stroke: Examining brain inflammation

Scientists in Japan identify a signalling pathway that may provide a target for reducing inflammation in the brain following ischemic stroke.

January 2018

Researchers in Japan and pinpoint a key signalling pathway that could provide a novel target for treatment following ischemic stroke.

that deficiencies in one or more of these genes resulted in severe inflammation and exacerbated brain injury. Further analysis showed that MSR1 is controlled by a transcription factor called Mafb, and that levels of MSR1 increased in the days following stroke in response to rising Mafb expression. “If we can enhance MSR1 levels, we might be able to resolve inflammation,” says Shichita. “We conducted a trial using an existing neuroprotective agent called Am80, which has been used to treat acute leukaemia and is undergoing clinical trials against Crohn’s and Alzheimer’s disease.” By targeting the Mafb/MSR1 pathway,

Am80 increased Mafb expression and enhanced MSR1 levels as the researchers hoped. However, there was a drawback, as Shichita explains: “We had to use a relatively high dose of Am80 (2 mg per day) to sufficiently enhance the MSR1 expression and associated phagocyte behaviour. We decided not to conduct clinical trials with Am80 and are instead focusing on finding novel agents that will target the Mafb/MSR1 pathway.” Shichita, T., Ito, M., Morita, R., Komai, K., Noguchi, Y. et

al. MAFB prevents excess inflammation after ischemic stroke by accelerating clearance of damage signals through MSR1. Nature Medicine http://dx.doi. org/10.1038/mn.4312 (2017).

PU WAD O L J AT U R AW U T T H I C HA I / A L AM Y S TO C K P H O TO

Ischemic stroke occurs when a blockage or blood clot forms in one of the brain’s arteries. The resulting cerebral inflammation could be targeted by therapies to reduce its debilitating impact. Now, researchers in Japan have revealed how the body naturally resolves cerebral inflammation and hope to create a therapy that promotes this recovery process. Scientists know that a set of proteins released from dead cells known as ‘damage-associated molecular patterns’ (DAMPs) disrupt the blood-brain barrier after an ischemic stroke, triggering inflammation. However, it had not been clear how the body resolves such inflammation over the following days. “Strong anti-inflammatory agents like steroids do not improve the pathology of ischemic stroke,” explains Takashi Shichita, from Keio University in Tokyo, who worked on the project with a colleague, Akihiko Yoshimura, and others across Japan. “In fact, such agents may even inhibit the repair process after tissue injury. We wanted to clarify how the body resolves cerebral inflammation, and develop a therapeutic method to promote the repair process.” The team isolated cells taken from mice brains three days after ischemic stroke was induced. They found that DAMPs were taken up by two groups of phagocytes — immune system cells that consume and destroy dangerous or dead cells. They showed that one of these phagocyte types, MSR1, is a key mediator of DAMP destruction in mice brains. They identified three genes that play vital roles in the process, and showed

Saudis buck the diabetes trend

Type II diabetes and insulin resistance don’t go hand in hand among Saudis as frequently as they do in other populations.

nsulin resistance (IR) leads to high blood glucose levels due to an inability to use the hormone effectively, and is generally considered a hallmark of type II diabetes. A new study, however, shows that IR may not occur together with type II diabetes in Saudis as often as it does in other populations. Blood analyses of 107 Saudis with type II diabetes and 101 non-diabetic controls revealed that only 47% of the diabetic group had IR. A study published in 1994 examining more than 5,000 people in the UK with type II diabetes had reported a much higher prevalence of association in other populations: 81% for Asians of

Indian origin, 77% for Caucasians and 73% for Afro-Caribbeans. The analysis also confirmed an association between IR and the ‘hunger hormone’ ghrelin. Released mainly by the stomach, ghrelin influences appetite, body weight and glucose metabolism. High ghrelin levels decrease total body fat by raising the expression of insulin receptors in adipose tissue. As expected, Saudis with diabetes had significantly lower levels of plasma ghrelin than controls. But more specifically, ghrelin levels were significantly lower in people when type II diabetes was associated with IR. Despite the small sample size and the

possible influence of therapeutic treatment, which could have obscured the real IR rate, the study highlights the need to further investigate IR prevalence in Saudi Arabia and differentiate patients accordingly. “Some anti-diabetic drugs are used to overcome the effects of IR, but the management of type II diabetes with and without IR should vary. Therefore, to track the disease progress, we advise the parallel screening for IR, together with diabetes, after the age of 45,” says Hayder Giha of the Arabian Gulf University College of Medicine and Medical Sciences in Bahrain, who conducted the study in collaboration with colleagues at Saudi Arabia’s National Guard Health Affairs. 1. Qarni, A., Ahmed, A., Joatar, F. E., Das, N., Awad,

M., Eltayeb, M., ... & Gumaa, K. Association of plasma ghrelin levels with insulin resistance in type

2 diabetes mellitus among Saudi subjects. Endo-

crinology and Metabolism, 32, 230-240 (2017).

2. UK Prospective Diabetes Study Group. UK Prospective Diabetes Study. XII: Differences between Asian, Afro-Caribbean and white Caucasian type 2 diabetic

patients at diagnosis of diabetes. Diabet Med 1994; 11:670-7.

Issue No.4

ASISEEIT/ E+/GET T Y IMAGES

Low levels of the ‘hunger hormone’ ghrelin in Saudis with type II diabetes associated with insulin resistance could impact their appetite, body weight and glucose metabolism.

A combination oral therapy formed of sitagliptin and GABA could offer a new option for treating type I diabetes.

Hope for holding back hyperglycaemia A two-drug combination that preserves and stimulates pancreatic function could offer a new option for treating type I diabetes.

January 2018

atients with autoimmune diabetes, also known as type I, have a far narrower range of treatment options than those with the more common type II form. By combining two parallel treatments, Qinghua Wang, of the University of Toronto, and colleagues have now identified a regimen with the potential to bolster insulin production in these patients.

In type I diabetes, the ability to regulate blood glucose is destroyed as the immune system attacks and kills insulin-producing beta cells in the pancreas. Treatment involves dependence on carefully regulated, self-administered insulin doses to stay healthy. In previous work, Wang’s team learned that a neurotransmitter known as γ-aminobutyric acid (GABA) can help preserve beta cell function in mice engineered to have type I diabetes. They next wanted to bolster this effect by pairing GABA with another anti-diabetic drug. They focused on a class of agents in current clinical use that stimulate the effects of hormones known as

Liu, W., Son, D.O., Lau, H.K., Zhou, Y., Prud’homme, G.J.,

Jin, T. & Wang, Q. Combined oral administration of GABA and DPP-4 inhibitor prevents beta cell damage and promotes beta cell regeneration in mice. Front. Pharmacol. 8, 362 (2017).

M OL E KU U L .BE / A L A M Y S TOCK P HOTO

incretins, which regulate blood sugar levels by stimulating insulin release. These drugs have proven effective in type II diabetes, which is primarily a metabolic disorder, but offer little benefit on their own in type I. However, the combination of GABA and the incretin-boosting drug sitagliptin proved surprisingly effective. Wang and colleagues simulated type I diabetes by using a toxic compound that selectively eradicates pancreatic, insulin-producing beta cells in mice. Treatment with the two agents had an additive effect in these subjects in terms of sustaining insulin production and maintaining reasonable levels of circulating glucose. More strikingly, the researchers observed a clear rebound in beta cell populations. Either drug alone contributed to the preservation of some beta cells, but in combination the effect was doubled. Closer investigation of these cells revealed that the sitagliptin-GABA treatment simultaneously enhanced cell division while also turning off pathways that lead to cell death. Wang and colleagues note that previous studies have suggested intriguing parallel mechanisms for these two agents. Whereas incretins have previously been linked to beta cell proliferation, GABA can potentially induce the direct conversion of pancreatic alpha cells — which contribute to elevated blood sugar — into beta cells. Importantly, both drugs can be administered orally, making them a potentially appealing therapeutic combination. “Further pre-clinical and clinical trials are warranted to test the eﬃcacy and toxicity of combined use of GABA and sitagliptin in type I diabetes mouse models and type I diabetes human subjects,” the researchers conclude.

Medical

BIOTECHNOLOGY Park The Medical Biotechnology Park, a new company at KAIMRC/MNG-HA is a strategic project of MNG-HA to contribute to the Saudi Vision 2030 through:

The development and commercialization of biomedical R&D products, technologies and services

The contribution to economic and health improvement through science and innovations in medical and health sectors

EMAIL: KAIMRC-KMBP@NGHA.MED.SA PHONE NUMBER: +966-11-429-4516 TWITTER: @MEDICALBIOTECH

Researchers target the spike-like proteins that form a crown around the Middle East Respiratory Syndrome Coronavirus (MERS-CoV). 34

January 2018

Combating MERS in camels with a single-dose vaccine

esearchers designed and compared four vaccines against the potentially deadly Middle East respiratory syndrome (MERS) and found one that activates a strong immune response in mice after a single dose. In June 2012, a Saudi patient died from a severe respiratory condition caused by a previously unrecognized coronavirus. Since then, the MERS-CoV virus has been reported in 27 countries and has infected more than 1,900 people, mostly in Saudi Arabia. It is mainly transmitted to humans via dromedary camels and brings a range of clinical outcomes from asymptomatic to severe. Its 40% mortality rate is higher than that caused by severe acute respiratory syndrome (SARS), but no vaccines or therapies have been clinically approved for human or veterinary use. One approach to tackle MERS is to use vaccines made from unarmed viruses that are efficient in triggering the development of a strong immune response against other dangerous viruses. ‘Viral vector vaccines’ against Ebola, HIV, malaria, tuberculosis, and influenza are already under study. To date, the only anti-MERS vaccine to be tested in camels is derived from a innovations.kaimrc.med.sa

highly attenuated strain of vaccinia virus, called modified vaccinia Ankara (MVA). It requires two doses to provide partial protection. An ideal vaccine would yield complete, rapid and long-lasting immunity after a single dose. Researchers from KAIMRC, the UK, and Germany compared MVA with a different viral vector, known as chimpanzee adenovirus Oxford University #1 (ChAdOx1). Previous studies have shown that one dose of ChAdOx1-based vaccine is effective against Rift Valley fever in multiple species, including camels, making it a promising vaccine tool. The scientists tested two MVA and two ChAdOx1 MERS vaccines. All of them carried the DNA sequence encoding MERS-CoV’s characteristic spikeshaped surface proteins, which are produced once the viral vector enters host cells. These are then recognized by the host’s immune cells, triggering more defence mechanisms. The production of the spike proteins is dependent on a promoter sequence. The MVA MERS vaccines were designed with one of two promoters, either mH5 or F11, to test which allows the largest production of spike proteins, enhancing the strongest immunity. The two ChAdOx1 MERS vaccines differed for the presence or

One approach to tackle MERS is to use vaccines made from unarmed viruses that are efficient in triggering the devel opment of a strong immune response against other dangerous viruses. absence of tissue plasminogen activator (tPA), another strategy to optimize the vaccine’s performance. They found that all these vaccine candidates stimulated the mouse immune system and the type of promoter did not have a significant impact on the results. Strikingly, a single dose of ChAdOx1 MERS with tPA was as immunogenic as two doses of MVA MERS (also containing tPA). The team suggests testing it as a single dose vaccine in dromedary camels, followed by a booster dose of MVA MERS vaccine if needed. Alharbi, N. K., Padron-Regalado, E., Thompson, C. P., Kupke, A., Wells, D., Sloan, M. A. et al. ChAdOx1 and MVA based vaccine candidates against MERS-CoV elicit neu-

tralising antibodies and cellular immune responses in mice. Vaccine (2017).

Issue No.4

N AT IO N A L I N S T I T UT E OF A LLER GY A N D I N F EC T I OUS DI S EAS ES (N I A I D)

Anti-MERS vaccines for camels could be optimized by varying their viral and DNA content, and adjusting their administration.

Injury prevention could stem opioid abuse People are 1.4 times more likely to become persistent users of opioid painkillers after suffering a traumatic injury.

roken bones, sprains and other physical injuries are often a pathway to opioid abuse, a new study has found. Public health efforts promoting injury prevention might not only help reduce death and disability, but could also reduce addiction to prescription painkillers and illicit opiate drugs, a problem responsible for an estimated 70,000 deaths worldwide each year. “Primary injury prevention could facilitate reduction of persistent opioid use and thus improve population health and reduce health expenditures,” says Suliman Alghnam, a KAIMRC epidemiologist and public health researcher who also led the study. The United States has the

January 2018

most cases of opioid abuse and approximately 80% of the world’s opioid supply is consumed there. Doctors often prescribe opioids, such as hydrocodone and oxycodone, to treat pain stemming from car accidents, falls and other kinds of injuries. But the contribution of these debilitating accidents to the growing opioid epidemic in the country was not known. Alghnam, who now focuses on tracking the burden of traumatic injuries in Saudi Arabia, decided to investigate the link between injuries and persistent opioid abuse in the United States during a postdoctoral fellowship at Johns Hopkins University in Baltimore, Maryland. He and his advisor, Renan Castillo, pored over data from a large government survey that

tracks how Americans interact with the medical care system. They identified a population of trauma victims who took opioids at least once immediately after sustaining an injury. Among them, around one in six became repeat users over the course of the two years they were followed. Overall, injuries accounted for about 11% of Americans on long-term opioid treatment. Alghnam and Castillo then compared the rate of persistent opioid use among those who experienced an injury and those who didn’t. After accounting for socioeconomic variables and other known predictors of drug abuse, the researchers found that injured individuals were about 1.4 times more likely to become

chronic opioid users. Notably, that estimate includes people with fairly mild knocks and bruises. “We certainly feel the magnitude would be higher had we limited the sample to severe cases,” Alghnam says. So, what’s driving so many Americans to start popping opiate pills after an injury? “Clearly chronic pain is a factor — but so might be overprescribing by physicians,” says Alghnam. “I think it’s several reasons that would need further research to dismantle,” he says. Alghnam, S. & Castillo, R. Traumatic

injuries and persistent opioid use in the USA: Findings from a nationally representative survey. Injury Prevention 23, 87–92 (2017).

PE O P L E I MAG ES / E+ /G ET T Y I M AG ES

Chronic pain is driving many Americans to take painkillers after injury.

Viable A Wild type

Viable B Genetically engineered

Viable Virus Dead Virus

Days after infection

Virus A (wild type) and virus B (genetically engineered) were inoculated in mice. During infection, virus B produced a significantly higher progeny of dead viruses as a result of the introduction of detrimental mutations. Mice infected with virus B survived and developed immune protection whereas mice infected with virus A succumbed.

Playing RNA viruses at their own game

Researchers in France turn viruses against themselves by exploiting their ability to mutate and evolve rapidly.

t is particularly hard to develop vaccines for viruses that have RNA as their genetic material, such as those responsible for flu, Ebola and hepatitis C. Their average mutation rates are estimated to be about 100 times greater than those for DNA viruses, mainly due to the lack of genome repair mechanisms. This allows them to evolve rapidly, evade the immune system and become drug-resistant. It also explains why vaccines that are effective during one flu season might be ineffective the next. Marco Vignuzzi and his team at the Institut Pasteur in Paris have genetically engineered two very different viruses that are both one mutation away from generating a potentially lethal signal in the part of their genetic sequence that halts protein synthesis, thus preventing replication in the host cell. “We have devised a way to beat them at their own game,” explains Gonzalo Moratorio, lead author of the study published in Nature Microbiology. The authors designed a fully functional Coxsackie B3 enterovirus and

“We have devised a way to beat them at their own game.” When the viruses were tested in mice, not only were they less virulent, but they triggered the production of antibodies that protected the mice from infection with wild-type strains. The degree of virus attenuation was further increased when the authors engineered an error-prone version of the viral protein responsible for replicating the virus’ genetic code. Introducing this low-fidelity RNA polymerase accelerated the generation of detrimental mutations and further reduced virus infectivity. Mice infected with this ‘optimal suicidal virus’ developed neutralizing antibodies that were able to protect them against lethal challenges with the wild-type viruses. “We were very surprised by the finding that a virus that is more prone to mutate, can actually increase survival,” said Moratorio. Further work is under way to better understand the immune response that is triggered by these virus strains and determine how broadly this ground-breaking approach to antiviral vaccine development can be applied. Moratorio, G., Henningsson, R., Barbezange, C., Carrau, L., Borderia, A.V. et al. Attenuation of RNA viruses by

redirecting their evolution in sequence space. Nature

Microbiology 2, 17088 (2017).

Issue No.4

an influenza A virus, in which a single mutation in one of more than 100 key regions of their genetic sequence would severely compromise their survival. The attenuation of the viruses was first assessed in cells. Although the ability of the engineered strains to replicate was not significantly different from wild-type control strains, they were more sensitive to deleterious mutations when they were exposed to mutagenic conditions, and virus titres fell up to 100 fold.

Improving stem cell donation

OL A F DOE R I NG / A L A M Y S TOCK P HOTO

Stem cells could be collected from donors more safely by using a less invasive catheter.

Collecting stem cell donations using a peripheral venous catheter is safer and just as effective as using a central venous catheter.

safe, effective method for collecting stem cells from the blood of volunteer donors has been successfully trialled by scientists at KAIMRC and clinicians at King Abdulaziz Medical City in Riyadh (KAMC-R).

Donated stem cells provide a supply for patients with cancer, damaged bone marrow, or impaired immunity and help them generate new blood. Until recently, this process of ‘hematopoietic stem cell transplantation’ involved the use of a central line, or central venous catheter (CVC), placed into a major vein, often in the donor’s chest or thigh. A CVC was thought to be preferable because the blood needs to flow at high pressure through a filtering machine, which separates stem cells and then returns the blood to the donor’s body. Now, it is believed that the less invasive peripheral venous catheter (PVC), which taps into peripheral veins in the upper arm, is safer 38

January 2018

and may be just as effective. “The use of CVC is still common in some hospitals in the Middle East, regardless of the donor’s ability to provide enough blood from their peripheral veins,” says Samer Ghazi at KAMC-R, who led the project. “However, inserting a CVC carries a high risk of bleeding, infection, clotting, and even death. We wanted to prove that PVCs could potentially do the job just as well in most cases.” Ghazi’s team believes that the donation process should be guided by collaborations between different medical professionals; for example, anaesthetists, intravenous therapy specialists and haematologists. The researchers aimed to reduce CVC use at KAMC hospital to less than 20% by encouraging nurses and clinicians to work together and try to use PVCs on every adult donor. The study, conducted over 16 months and including 42 adult donors, reduced

CVC use from 72% to 0%. On the first cycle of the trial, one in four cases had to revert to CVC; this reduced to one in eight by the second cycle, and all 30 donors in the third cycle successfully provided enough blood and stem cells using PVCs without any complications. “The advantages of switching to PVC are multiple, not least because of safety and quality of care,” says Ghazi. “PVC is readily accessible and there is no need to admit donors to the hospital, saving US$3000-4000 per case. It also frees up inpatient services and the radiology department, which were previously used for CVC insertion. Hopefully, our study will encourage the wider use of PVCs for stem cell donation.” Ghazi, S., Alaskar, A., Alzahrani, M., Damlaj, M., Abeul-

gasim, K.A. et al. Reducing central venous catheter use in peripheral blood stem cell donation: Quality

improvement report. BMJ Quality Improvement 6, u211975.w4817 (2017).

Translational Research Unit Is the Hub for clinical Trials with additional unique feature, phase 1 clinical Trials.

EMAIL: TRU@NGHA.MED.SA PHONE NUMBER: +966-11-429-4516

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Reception Ward with 16 Beds Phlebotomy Room Volunteers Screening Room Volunteer Recreation Room Centrifuge and Freezer Room Chemistry Lab

Spinal muscular atrophy is a rare genetic disorder that affects babies and children. 40

January 2018

A viral vector to fall back on

hio State University researchers in the United States have found that a carrier made from the protein coat of a virus could efficiently deliver genetic material to the spinal cord. This could provide future therapy options for conditions like spinal muscular atrophy. Spinal muscular atrophy is the leading genetic cause of death for babies and toddlers. The condition causes the breakdown of nerves in the brain and spinal cord that are responsible for supplying muscles. This often leads to muscle weakness, wasting and breathing difficulties. There is no cure for the condition, but delivering genetic material that can promote the survival of motor neurons could be an option. Lei Cao and co-workers at Ohio State University previously studied a family of viral vectors made from protein coats of the adeno-associated virus in which the DNA sequences were shuffled to make variations of the vector. Adeno-associated virus is naturally occurring and infects humans but is not known to cause disease. It is widely believed to be a safe and powerful vehicle for delivering genetic material into a patient’s body. The researchers found that one of the variations, called Rec2, efficiently delivered genetic material to fatty tissues — a feat that was previously difficult to achieve by adeno-associated virus. They tested to see if Rec2 or other members in its family were equally efficient at delivering genetic material to the spinal cord. They injected Rec2, Rec3, Rec4 and AAV9 (a common adeno-associated viral vector used in clinical trials for diseases affecting the spinal cord)

expressing green fluorescent protein into the spinal cord of adult mice, and then measured the intensity of green fluorescence along the spinal cord three weeks after injection. Cao and her team found that Rec3 was most efficient in delivering genetic material to the spinal cord. At equal dosage, Rec3 elicited green fluorescence over a longer section of the spinal cord (up to 1.5 cm) than Rec2, Rec4 or AAV9. More importantly, an injection containing as little as 0.4 billion viral particles of Rec3 was enough to generate green fluorescence in 60–90% of cells near the injection site in the spinal cord. For the sake of comparison, AAV9 would require 40 billion viral particles to achieve the same. The results suggest that Rec3 might be an efficient and cost-effective vehicle vector, because it needs fewer viral particles, for delivering genetic material to the spinal cord. The viral vector may be used, for example, to carry genetic material that induces the secretion of proteins that promote the survival of motor neurons. Through this approach, scientists may one day develop a therapeutic treatment for spinal muscular atrophy. “One factor that may be prohibitive for patients receiving gene therapy is cost,” says Cao. “If we can design viral vectors that can target specific cell types more efficiently and at lower dosage, life-saving therapeutics will become more accessible.” Siu, J. J., Queen, N. J., Huang, W., Yin, F. Q., Liu, X. et al. Improved gene delivery to adult mouse spinal cord through the use of engineered hybrid

adeno-associated viral serotypes. Gene Therapy 24, 361–369 (2017). Issue No.4

A F R I C A M EDI A ON LI N E / A L A M Y S TOC K P H OTO

A highly efficient method for delivering genetic materials to the spinal cord may help in the treatment of an inherited muscle-wasting disease .

A step closer to stem cell therapies for bone disease Controlling a protein’s levels could guide stem cell differentiation for treatment of bone disease.

January 2018

Insights into how bone marrow stem cells differentiate into bone tissue cells could inform future regenerative therapies for age-related bone diseases.

Issue No.4

DAVI D M A R C H A L / A L A M Y S TOCK P HOTO

s we get older, our bodies can analysed the genetic differences between struggle to generate the right the clones to precisely determine the balance of stem cells that are genes and associated proteins involved in committed to maintaining the differentiation process. bone formation and bone structure. This They found that the enhanced clone can contribute to the development of exhibited much higher levels of LRP3 bone-related diseases. Now, researchers than the reduced potential clone. Furin Saudi Arabia have uncovered the molecther, they showed that the LRP3 protein ular mechanisms acts as a molecular behind bone marswitch determinUsing micro-RNA row stem cell differing the differentiaentiation into bone tion of hBMSCs into molecules in this way to tissue and fat cells. osteoblasts. LRP3 stimulate hBMSCs into Their insights could itself is regulated inform the develby a small molecule required cell types and opment of future called miR-4739, a boost bone cell numbers microRNA known regenerative therapies for age-related to play a key role in could prove invaluable bone diseases. bone biology. Furin the treatment of Stem cells located ther experiments on in the bone marrow, the stem cell lines bone-related diseases. known as human showed that the bone marrow stroover-expression of mal cells (hBMSCs), have potential for miR-4739 led to reduced levels of LRP3. use in multiple therapies. But scientists This prompted hBMSCs to change into fat must first understand what determines cells instead of bone cells. their differentiation into osteoblasts (bone “We propose the use of miR-4739 cells) or adipocytes (fat cells) so they can mimics or inhibitors to fine-tune the be guided to generate the correct type. commitment of hBMSCs to [bone or Amer Mahmood and co-workers at fat cells], with potential application King Saud University in Riyadh, together in regenerative medicine,” state the with researchers across Saudi Arabia and authors in their paper, recently pubDenmark, highlighted the role of the lished in Stem Cell Research. Using low-density lipoprotein receptor-related micro-RNA molecules in this way to protein 3, or LRP3, in hBMSC differenstimulate hBMSCs into required cell tiation. The LRP3 protein is involved in types and boost bone cell numbers multiple cellular processes in the body could prove invaluable in the treatment and is expressed in many human tissues, of bone-related diseases. especially skeletal muscles. Mahmood’s team generated two clones Elsafadi, M., Manikandan, M., Alajez, N.M., Hamam, R., derived from hBMSCs: one that exhibDawud, R.A., et al. Micro-RNA-4739 regulates osteoited enhanced osteoblast differentiation genic and adipocytic differentiation of immortalized potential and one with reduced potential. human bone marrow stromal cells via targeting LRP3. Using gene profiling techniques, the team Stem Cell Research 20, 94-104 (2017). 43

Mining big data highlights importance of ‘junk DNA’ An exploratory bioinformatics investigation suggests ‘junk DNA’ plays a critical role in early embryonic development and species evolution.

January 2018

An exploratory bioinformatics investigation suggests transposable elements, previously considered by some scientists to be ‘junk DNA’, are vital for genetic diversity and evolution.

of translating its genetic information— can directly influence the expression of neighbouring genes, thus influencing the dynamics of gene expression in early embryos. Ge also identified possible regulatory proteins that bind to DNA motifs provided by TEs. “Transposons are essential in shaping gene regulatory networks during evolution,” says Ge. “They provide a copyand-paste mechanism to re-use and re-shape genetic logic, similar to the way in which computer programmers copy and revise old codes. TEs can introduce harmful mutations, but they drastically enhance genetic diversity for the popu-

“For two years, I spent my free time using all available bioinformatics tools and data, especially single-cell RNA-sequencing data, to understand how early embryos develop from fertilized eggs.” lation, and may be necessary for adaptation and survival, especially for species that reproduce slowly.” Ge calls for new, targeted studies using the insights gained from bioinformatics. “Ultimately, my goal was to gain as many actionable insights as possible from existing data, so that scientists can build a more complete picture of early embryonic development.” Ge, S.X. Exploratory bioinformatics investigation

reveals importance of ‘junk’ DNA in early embryo development. BMC Genomics 18:200 http://dx.doi. org/10. BMC Genomics 18, 200 (2017).

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N OB EAS TS OF I ER C E S C I EN C E / A L A M Y S TOCK P HOTO

physicist-turned-bioinformatician from South Dakota State University in the United States has conducted a largescale, open-ended genomic data-mining study to gain insights into early embryonic development. His results suggest that genetic components called transposable elements, or TEs, play a crucial role in early development and should be further investigated. An organism’s genome contains all the information needed for its formation. Some genetic components, like TEs, use a copy-and-paste mechanism to duplicate themselves and move around within the genome. TEs make up just under 50 per cent of the human genome, but for many years, some scientists discounted them as ‘junk DNA’ that is only there to fill space. This study by Xijin Ge in South Dakota supports other recent investigations demonstrating the opposite is true: TEs are in fact vital for development and evolution. Ge conducted an exploratory bioinformatics investigation (EBI) into genomic big data from studies of early embryonic development. Specifically, he focused on gene regulation in pre-implantation mouse embryos. “For two years, I spent my free time using all available bioinformatics tools and data, especially single-cell RNA-sequencing data, to understand how early embryos develop from fertilized eggs,” says Ge. “With the massive amount of genomic data available, there is much to be gained from re-analysing it.” Unlike traditional hypothesis-driven research, EBI allows the data to tell its own story, helping scientists to frame future research questions. By examining multiple RNA-sequencing datasets, Ge found that TE transcription—the process

Radiotherapy treatment of head and neck cancers can cause irreversible damage to the salivary glands.

Managing salivary gland damage Drugs that stimulate saliva production are the most effective treatment option for managing damage caused by radiotherapy.

review of data from 20 independent studies suggests that saliva-stimulating drugs are better than other options for managing the effects of radiotherapy-induced salivary gland damage. Head and neck cancers can be successfully treated with radiotherapy, however it can cause irreversible damage in up to 93% of patients if the salivary glands are within the irradiated field. Salivary gland damage reduces secretion, which in turn can cause the unpleasant sensation of dry mouth, oral

January 2018

infections, dental disease, altered taste, as well as difficulties speaking and eating. Despite the high incidence of this radiotherapy-associated adverse effect, clinicians have no clear evidence-based guidelines to inform the management of reduced salivary gland function. Arwa Al Hamad, at King Abdulaziz Medical City in Riyadh, and colleagues in the UK conducted an extensive review of data from 20 independent studies to determine the effectiveness of acupuncture, low-level laser therapy, herbal remedies, salivary substitutes and drugs that stimulate saliva production in a total of

1,732 patients with head and neck cancer. Evidence supporting the use of salivary substitutes or mouth care systems that help moisten oral tissues and lessen discomfort caused by dry mouth was very weak. “Our results were surprising as these products are usually considered the first line of treatment in the clinic,” she says. Only long-term administration of pilocarpine and cevimeline, two drugs that stimulate the glands to produce more saliva, significantly relieved dry mouth. Both compounds activate cell receptors that promote fluid secretion. Cevimeline specifically targets receptors found on tear and salivary glands. Thus, it produces fewer side-effects than pilocarpine, which stimulates secretory cells throughout the body including sweat glands, causing excessive sweating in patients. The duration of increased salivary flow after taking the drugs is unclear. Although patients reported feeling better after taking them, the available data suggests their efficacy was short-lived. “These results have important practical implications as clinicians managing patients with post-radiotherapy salivary gland damage should consider prescribing long-term cevimeline or pilocarpine therapy to ameliorate some of the symptoms even if the improvements are likely to have a short duration,” explains Al Hamad. A new oral medicine clinic established at King Abdulaziz Medical City will enable further investigation into the treatment of salivary gland damage and other oral lesions. Mercadante, V., Al Hamad, A., Lodi, G., Porter, S. &

Fedele, S. Interventions for the management of radi-

otherapy-induced xerostomia and hyposalivation: A systematic review and meta-analysis. Oral Oncol. 66, 64-74 (2017).

PH A N IE / A L A M Y S TO C K PH O TO

“Our results were surprising as these products are usually considered the first line of treatment in the clinic.”

Healthy cells for healthy pregnancies Activating a defence gene may reduce damage to cells involved in preeclampsia.

Defective stem cells in preeclampsia fail to express adequate levels of a gene that protects against oxidative damage.

defects in stem cells from preeclamptic patients might result from increased oxidative damage, causing the cells to die or reducing their ability to support the neighbouring muscle and endothelium cells. To test this, the team inactivated ALDH in healthy stem cell cultures and then challenged the cells with hydrogen peroxide, which causes oxidative stress. The engineered cells were more sensitive to hydrogen peroxide than normal cells, confirming the importance of aldehyde dehydrogenase in protecting stem cells. The engineered stem cells may prove an effective model for studying these conditions and developing new treatments. One approach would be to stimulate ALDH in the defective cells. The team evaluated three known ALDH activators. They found that two increased the expression of aldehyde dehydrogenase in preeclamptic stem cells, reducing the

damage caused by hydrogen peroxide. “That was an exciting moment, because it gave us hope that a therapy targeting this pathway could be a viable treatment,” says Mohamed Abumaree of King Saud Bin Abdulaziz University for Health Services, who took part in the study. “Restoring the resistance to oxidative stress may reduce the maternal symptoms of preeclampsia, allowing the pregnancy to continue and reducing the need for premature delivery,” he continues, adding that “searching for new strategies to reduce oxidative stress may be effective in preventing atherosclerosis and thereby cardiovascular disease.” Kusuma, G. D., Abumaree, M. H., Perkins, A. V., Brennecke, S. P., & Kalionis, B. Reduced aldehyde dehydrogenase expression in preeclamptic decidual mes-

enchymal stem/stromal cells is restored by aldehyde dehydrogenase agonists. Scientific Reports 7, 42397 (2017).

Issue No.4

C ATC H LI G HT V I SUA L SE R V I C E S / A L A M Y S TOC K P H OTO

he capacity of key stem cells to respond to oxidative stress, an accumulation of oxygen metabolism by-products, is reduced in preeclampsia. This finding could lead to the development of new treatments for diseases associated with oxidative stress, such as Alzheimer’s disease, atherosclerosis and hypertension. Preeclampsia is a pregnancy complication that can cause hypertension and impair liver and kidney function. It is thought to affect 5 to 10% of all pregnancies, and can be life threatening if left untreated. Researchers in Australia and Saudi Arabia recovered mesenchymal stem cells (MSCs) from the maternal part of the placenta of preeclamptic women and from women whose pregnancies were healthy. MSCs are adult stem cells that can differentiate into cells found in skeletal tissues. They found that the MSCs from preeclamptic women had reduced expression of the gene ALDH. MSCs normally express high levels of ALDH, responsible for encoding the enzyme aldehyde dehydrogenase, which protects cells from oxidative stress. MSCs have successfully been used to reduce oxidative stress in several diseases. The researchers suspected that the

Researchers are trying to understand how the composition and function of bacterial communities in the mouth and other tissues contribute to health and disease. 48

January 2018

Filling in the microbial gaps

he body harbours many diverse communities of bacteria that play a prominent but poorly understood role in health and disease. A recent survey of samples from hundreds of volunteers offers a wealth of valuable insights into the composition, function and dynamics of this internal ecosystem. In 2012, the Human Microbiome Project (HMP) released its first dataset: a survey of bacteria collected from the mouth, gut, genitals and other tissues of 242 healthy volunteers. A follow-up study from HMP researchers led by Curtis Huttenhower of The Broad Institute in the United States delves even deeper. By drawing on improved analytical tools and samples collected from 265 North American donors at multiple time-points, Huttenhower’s team has obtained a more extensive and dynamic view of the microbiome. In total, they examined 1,630 ‘metagenomes’ derived from microbial populations isolated from six different body sites. The researchers found that people generally maintain relatively stable bacterial communities over time, with far greater differences seen between individuals. However, they did observe some dynamic scenarios. For example, there is apparently regular fluctuation among Bacteroidetes and Firmicutes bacterial populations dwelling in the intestine, indicating that levels of these species may prove less useful as indicators of microbiome-associated health.

Huttenhower and colleagues identified 54 additional species of bacteria in their dataset relative to the first HMP study. They were also able to identify microbes that preferentially dwell in certain parts of the body, and to home in on biological functions that tend to be broadly shared across species versus those that are more common in certain physiological environments. For example, bacteria living in the gut were far more likely than those dwelling elsewhere to produce enzymes that break down plant-derived sugars, and to release chemical compounds that protect the intestinal lining. By employing sophisticated new algorithms for DNA sequence analyses, the researchers were able to identify millions of bacterial genes present in each body site studied. However, their analyses indicate that the current HMP census is far from complete. The authors note that future microbiome surveys should strive for greater ethnic, geographic and environmental diversity, and be coupled with a deeper analysis of health and lifestyle factors that may shape our inner ecosystems. “To rationally repair a dysbiotic microbiome, it is necessary to deepen our understanding of the personalized microbiome in human health,” they conclude. Lloyd-Price, J., Mahurkar, A., Rahnavard, G., Crabtree, J., Orvis, J. et al. Strains, functions and dynamics in

the expanded Human Microbiome Project. Nature

550, 61-66 (2017).

Issue No.4

S C I EN C E P H OTO LI B R A RY / A L A M Y S TOC K P H OTO

A new survey of the microbiome offers insights into its diversity and the interplay between bacteria and their human hosts.

Copycat mutation masquerades as multiple sclerosis Researchers in Saudi Arabia have identified a previously unknown mutation causing a condition that had been mistaken for multiple sclerosis (MS). The discovery emphasizes the risk of genetic diseases being misdiagnosed as MS. “Our work demonstrates that neurologists must be made aware of the red flags that might suggest a diagnosis of MS is less likely,” says KAIMRC’s Hussein Algahtani, who led the research. Algahtani examined two brothers with a long-standing diagnosis of MS and found atypical clinical and radiological abnormalities, ‘red flags’ that suggested possible misdiagnosis. Spinal abnormalities found in MRI scans known as ‘patchy white matter’ had, ten years earlier, contributed to an MS diagnosis, but the KAIMRC researchers and colleagues elsewhere in Saudi Arabia suspected a different cause. The team had previously identified several genetic conditions mimicking many of the symptoms of MS. “That these two new patients were from the same family led us to investigate the possibility of a genetic disorder, rather than MS,” says Algahtani. DNA analysis of blood from the patients and their parents revealed that the patients carried a mutation in a gene known to be involved in maintaining normal nerve transmission. This ‘recessive’ mutation must be inherited from both parents to do its damage by causing a form of cerebellar ataxia: a locomotion disorder originating in the brain’s cerebellum. Algahtani cautions that the possibility of a chance association between the mutation and the brothers’ condition cannot yet be completely ruled out, but the indications are very strong. “We are planning to conduct further genetic studies in other patients,” he says. 50

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@2 0 1 6 K A I M R C

A mutation found in two Saudi brothers is believed to have led to misdiagnosing cerebellar ataxia as multiple sclerosis.

Spinal patchy white matter, visible in an MRI scan, led to a misdiagnosis of MS several years earlier.

He points out that the high incidence in the kingdom of marriages between relatives, including first cousins, makes Saudi Arabia an ideal place to search for such genetic conditions. Genetic diseases account for a large proportion of conditions seen in Algahtani’s neurology clinic. For the two brothers, the research means an end to years of treatment for the wrong disease, and the opportunity for

more appropriate care. This study should help contribute to wider awareness of the possibility of misdiagnosing MS. Algahtani, H., Marzouk, Y., Algahtani, R., Salman, S., & Shirah, B. Autosomal recessive cerebellar ataxia type 1 mimicking multiple sclerosis: A report of two siblings with a novel mutation in SYNE1 gene in a

Saudi family. Journal of the Neurological Sciences 372, 97–100 (2017).

Screening for an enzyme defect in newborns

Study boosts argument for cord blood screening to detect an enzyme defect in infants.

nown as the most common enzyme defect in humans, glucose-6-phosphate dehydrogenase (G6PD) deficiency is an inherited condition that affects more than 300 million people worldwide. Early detection of the disorder is vital, as newborns are vulnerable to its symptoms, including jaundice and anaemia, which can be life threatening. In Saudi Arabia, screening is typically done by taking blood samples fromthe arms or legs. But blood taken from the umbilical cord immediately after birth is increasingly viewed as a preferable option, as it is easier to collect and does not cause the child or mother unnecessary pain. However, since infants undergo many physiological changes that might affect G6PD activity soon after birth, it was

unclear how effective cord blood could be in detecting the disorder. A large-scale retrospective study of children born in Saudi Arabia from January to December 2008 sought to reveal an accurate picture of the validity of cord blood screening for G6PD deficiency. Two per cent of the 8,139 newborns from whom cord blood was taken had G6PD deficiency. Boys were significantly more affected than girls, at a ratio of almost 4:1. Just over one thousand of the newborns had samples taken both from the umbilical cord and from the arms or legs. Results from the samples were compared and suggest that cord blood is just as effective as peripheral blood in detecting G6PD deficiency. Cord blood sampling notably led to fewer false negative results, reducing the

risk of missing a G6PD deficiency diagnosis. The team of researchers, including KAIMRC senior research scientist, Mohammed Al Balwi, concludes that the study reinforces the practice of using cord blood for newborn screening. The fact that 79% of those affected in the study were males concurs with the consensus that they are more at risk of the condition. The defective gene is carried on the X chromosome. Since males have just one X chromosome, a single altered gene may cause G6PD deficiency. Females, who have two X chromosomes, usually become carriers without showing signs of the defect. The World Health Organization recommends neonatal screening in areas with a prevalence of over 3% in males. Although figures vary widely by region, the Middle East has one of the highest prevalence estimates of G6PD deficiency in the world at six per cent. For males alone this figure is 7.2%. As yet, there are no treatments for G6PD deficiency. It is a lifelong condition requiring avoidance of certain foods and medicines, such as fava beans and antimalarial drugs. The present study may serve as a basis for further surveys tracking G6PD enzyme levels in older children and adults. AlSaif, S., Ponferrada, M.B., AlKhairy, K., AlTawil, K., Sallam, A. et al. Screening for glucose-6-phos-

phate dehydrogenase deficiency in neonates: a

comparison between cord and peripheral blood samples. BMC Pediatrics 17, 159 (2017).

Issue No.4

P H A N I E / A L A M Y S TOC K P H OTO

Cord blood sampling offers a convenient, stress-free way of screening for hereditary disorders in newborns.

Loss of synaptic ‘caretaker’ leads to fatal infant brain injury A rare genetic mutation that impairs communication between neurons could provide insight into Alzheimer’s and Parkinson’s.

“Similar to baggage tags at the airport, the cell chemically tags proteins to ‘fast-track’ them to their correct destination. We think PLAA acts as the scanner of these tags.”

January 2018

“They can’t eat, they can’t walk, they can’t talk… It’s heart-breaking,” says the University of Edinburgh’s Emma Hall, who over the last seven years has worked with an international cohort to study a hereditary disease that has devastated four families from the UK and Saudi Arabia. PLAA-associated neurodevelopmental disorder (PLAAND), described for the first time in Hall’s paper, severely disrupts the infant brain and leads to seizures, impaired brain growth, optic nerve degeneration, and a progressive deterioration of muscle control. Affected children die before their sixth birthday.

“It’s an extremely rare disease. We managed to identify just three families in the UK and one in Saudi Arabia. Another study was able to identify two Israeli families with a milder form of the illness,” says Hall. Her group embarked on their project after a colleague identified seven children from three families who shared an unusual clinical presentation without a diagnosis. Publishing their findings in The American Journal of Human Genetics, the group sequenced the patients’ DNA and found a shared, near-identical mutation in their genetic code for the

protein ‘PLAA.’ Using the pioneering ‘genetic scissor’ technology CRISPR, the researchers designed mice with the exact mutation suffered by the children. Analyses of these mice elucidated PLAA’s critical role in maintaining the brain’s small, specialized gaps, called synapses, across which information flows from one neuron to the next. “Proteins involved in propagating synaptic signals need to be sorted to the right place so the synapse can re-fire,” explains Pleasantine Mill of the University of Edinburgh. “Similar to baggage tags at the airport, the cell chemically

tags proteins to ‘fast-track’ them to their correct destination. We think PLAA acts as the scanner of these tags.” In children with defective PLAA, trafficking at synapses breaks down, signalling and transport proteins accumulate, and brain cells are rendered unable to develop or communicate correctly. “As a result, some receive too much signal or for too long, others not enough or at the wrong time,” says Mill. The new insights into PLAA’s function may offer a window into more common conditions, such as Alzheimer’s and Parkinson’s, which also involve protein

accumulation at synapses. “In future, I think we will try to reroute the accumulation of proteins with drugs,” says Hall. “It’s exciting that our studies might be able to shed light on treatments for both this really rare disease, as well as much more common neurological diseases.” Hall, E. A., Nahorski, M. S., Murray, L. M., Shaheen, R., Perkins, E. et al. PLAA mutations cause a lethal infantile

epileptic encephalopathy by disrupting ubiquitin-medi-

ated endolysosomal degradation of synaptic proteins.

The American Journal of Human Genetics 100, 706 – 724 (2017).

Issue No.4

S TO C KT R E K I MAG ES , I N C. / A L A M Y S TO C K P HO TO

The inability of PLAAND sufferers to maintain synaptic junctions leads to a host of debilitating symptoms, culminating in death.

KAIMRC’s newly established cord blood bank and stem cell donor registry will not routinely test for a certain mutation linked to HIV/AIDS resistance because it’s so rare in Saudi Arabia.

HIV resistance gene uncommon among Saudis

Routine screening in stem cell registries for a mutation that could help treat HIV/AIDS is not warranted in Saudi Arabia because of its rarity in this population. A gene mutation known to confer resistance to HIV/AIDS is rarely seen among Saudi nationals, two KAIMRC-led studies have found. E l s ewhere , where t he mutation is more common, cord blood banks and stem cell registries are beginning to routinely test donated samples for variants in this gene, known as CCR5. It is thought that stem cell transplantations carrying the resistance mutation could help 54

January 2018

treat HIV-infected patients. But with CCR5 mutations observed at such a low frequency in Saudi Arabia, this strategy likely makes little sense in the country, the study authors conclude. In the first study1, a team led by KAIMRC molecular geneticist Mohammed Al Balwi sequenced all the protein-coding DNA of 321 healthy Saudis. Their longterm goal was to build a large database of normal genetic

variation in Saudi Arabia to serve as a reference for future disease-related research. As a first analysis, they chronicled all the variants found in CCR5, a gene that encodes a protein found on the surface of some immune cells. This protein acts as a co-receptor for HIV entry into the immune cells. Al Balwi and his colleagues identified 475 variants of the gene. Seven gene variations that had been previously

1. Al Balwi, M.A., Hadadi, A.I., Alharbi, W., Ballow, M., AlAsiri, A. et al. Analysis of CCR5 gene polymorphisms in

321 healthy Saudis using Next Generation Sequencing. Human Immu-

nology

78,

384–386

(2017).

2. Alarifi, M., Al-Amro, F., Alalwan, A., Al-Turki, A., Fakhoury, H. et al. The prevalence of CCR5-Δ32 mutation in a

cohort of Saudi stem cell donors. HLA 90, 292–294 (2017).

BS I P SA / A L A M Y S TOCK P HOTO

reported were detected at very low frequency, including the ‘delta32’ mutation that, when harboured in duplicate, renders people immune to most HIV strains. In the other study2, Al Balwi teamed up with Dunia Jawdat, lab director of KAIMRC’s cord blood bank, to test for delta32 mutations in samples collected from 2,625 healthy stem cell donors and 400 cord blood units. Although the blood bank samples contained the mutation at a slightly higher frequency than in the first Saudi cohort, the delta32 variant still only occurred in about 1% of the samples — which is at least ten times lower than the frequency seen in Europe and Western Asia. Al Balwi surmises that the environmental factors that could have led to people carrying CCR5 mutations in other parts of the world must be lacking in the Middle East. That’s why these mutations are rarely seen today in Saudi Arabia, which means there’s an incredibly low probability of finding CCR5 mutation carriers who could serve as stem cell donors for HIV-positive patients. Accordingly, these mutations will not be routinely screened for at KAIMRC’s newly established cord blood bank and stem cell donor registry, he says.

Single gene defect found for unexplained dwarfism Mutations in a DNA replication gene cause a rare developmental disorder seen in Saudi children.

Brain scans from children with normal (left) and mutated (right) versions of the DONSON gene.

microcephalic dwarfism. In total, they the mutations fell in a non-coding region found 29 affected individuals from 21 that altered how the genetic code got families who all had a small head and processed, leading to an aberrant and re d u c e d h e i g h t , less abundant proand who all carried tein product. “We’re pleased that these mutations in both Either way, the copies of the DONloss of a functional families were finally SON gene. Eight of DONSON gene the families were impaired the body’s able to have molecular from Saudi Arabia, ability to copy DNA diagnosis enabled by wh e re m a r r i a g e fast enough to keep between cousins is pace with the needs this discovery, so they common and leads of the early growto a high rate of can avoid recurrence.” ing brain and body, birth disorders. explaining how a Collaborators in single mutation the United Kingdom then characterized could have such a devastating effect. the consequence of these mutations on a cellular level. For some patients, the Reynolds, J. J., Bicknell, L. S., Carroll, P., Higgs, M.R., mutations altered the coding sequence Shaheen, R. et al. Mutations in DONSON disrupt repof the protein produced by DONSON. But lication fork stability and cause microcephalic dwarffor all of the patients from Saudi Arabia, ism. Nature Genetics 49, 537–549 (2017). Issue No.4

F O W Z A N A L KUR AYA @ 20 1 7

study co-led by researchers in Saudi Arabia and the United Kingdom has identified the faulty gene behind a developmental disorder that often causes shrunken heads and short stature in Saudis. Before this discovery, the study participants, from across Europe, North America, Africa and the Middle East, had no idea what was causing their family’s disease and clinicians had no way of preventing more children being born with this debilitating illness, known as microcephalic dwarfism. Now they can point to defects in a gene called DONSON, which is needed for DNA to be faithfully copied when cells divide and grow. “We’re pleased that these families were finally able to have molecular diagnosis enabled by this discovery, so they can avoid recurrence,” says Fowzan Alkuraya, a clinical geneticist at the King Faisal Specialist Hospital and Research Center (KFSHRC) in Riyadh and a lead investigator of the study. One of the participating families was evaluated at Riyadh’s King Abdulaziz Medical City (KAMC) by a team that included Mohammed Al Balwi, a molecular geneticist at KAIMRC and a co-author of the study. Both KAMC and KFSHRC, in addition to several other Saudi hospitals, now have prenatal screening programmes designed to target DONSON mutations in prospective parents so they can avoid passing the gene on to offspring. Alkuraya and his colleagues pinpointed the gene by sequencing the protein-coding DNA of children with unexplained

Researchers show how a hepatitis B viral protein affects monocytes and B-lymphocytes, triggering appropriate immune responses to tackle the infection. 56

January 2018

Investigating immune responses

small signalling protein produced by one type of immune cell activates and promotes the proliferation of another. This B-cell activating factor (BAFF) appears to play an important role in combating hepatitis B infection. Understanding how the body’s immune cells respond to hepatitis B virus (HBV) could lead to ways to combat it. Hepatitis B virus (HBV) is transmitted through contact with blood or bodily fluids of an infected person. It attacks the liver and can lead to cirrhosis and cancer. An estimated 257 million people have HBV infection. A vaccine that is 95% effective has been available since 1982. Although treatments aren’t available for the acute form of the disease, drugs can slow the progression of cirrhosis and reduce the incidence of liver cancer. The roles of two types of immune cells, monocytes and B-lymphocytes, in HBV infections are still not clear, says Yulian Jiao from Shandong University in Jinan, China. “We are very interested in the interaction between these immune cells and HBV; more specifically how a viral protein, the HBV e antigen or HBe, affects these two cell types. HBe is a known marker for HBV replication and is also reported to be a key immune regulator, particularly during chronic HBV infection.” Jiao and his team conducted a unique series

of experiments using a lentivirus (a ‘carrier’ virus harbouring the HBe gene) to express HBe in culture plates containing monocytes and B-lymphocytes. This allowed them to mimic the processes HBe triggers in the body during HBV infection. They found that HBe severely inhibited the monocytes’ ability to move quickly, which is needed at times of infection. They also discovered that HBe prompts monocytes to increase their production of pro-inflammatory proteins and to accelerate the expression of a factor, called BAFF, that activates B-lymphocytes and promotes their proliferation. BAFF levels in HBe-positive patient blood samples tend to be far higher than in HBe-negative patients. Jiao’s team also found that HBe directly triggered B lymphocyte activation. “As BAFF increases, the activation and proliferation of B-lymphocytes increases. In fact, it appears the B cells become ‘supercharged’ and in turn trigger strong and appropriate immune responses,” says Jiao. “In addition, the antibodies produced by B lymphocytes neutralize the virus, helping to clear infection.” Lu, B., Zhang, B., Wang, L., Ma, C., Liu, X. et al. Hepatitis B virus e antigen regulates monocyte function and promotes B lymphocyte activation. Viral Immunology 30, (2017).

Issue No.4

B S I P SA / A L A M Y S TOC K P H OTO

A molecule produced by hepatitis B virus prompts the body’s immune cells to leap into action.

E. coli is building resistance to some antibiotics, but others might still be effective at different times of the year and in different patients.

Antibiotic resistance: Tracking drug sensitivity in E. coli Analyses of E. coli samples from Saudi hospital patients indicate large increases in resistance to first-line antibiotics. Bacterial blood infections, many of which are contracted in hospitals, are a leading cause of disease and death worldwide. Gram-negative bacteria, such as pathogenic Escherichia coli (E. coli), are becoming increasingly resistant to first-line antibiotics, presenting significant challenges in tackling infections. Faisal AlMajed and co-workers at King Saud Bin Abdulaziz University for Health Sciences in Riyadh investigated E. coli susceptibility to different drugs over the course of a year. Their results have implications for the treatment of men 58

January 2018

and women of different ages through different seasons. “Information regarding bacterial infection, bacteraemia, and antimicrobial resistance in Saudi Arabia is scarce,” says AlMajed. “We wanted to find out more about E. coli in our hospital to improve understanding of currently circulating bacteria and potentially help tackle infections more successfully.” AlMajed’s team took blood samples from 181 E. coli-infected patients of all ages at King Abdulaziz Medical City’s King Fahd Hospital in the period from

AlMajed, F., Swailem, Y.B.S., AlJaser, F., Aqel, H.,

Al-Juhani, S. & Qureshi, S. Antimicrobial susceptibility of Escherichia coli isolates from blood in relation

to age, sex and months. International Educational

Scientific Research Journal http://dx.doi.org/doiaddress (2017).

DE CO I M AG E S I I / A L A M Y S TOCK P HOTO

January to December 2013. 174 of the isolates were from patients who contracted the infection in hospital. They found that the E. coli isolates were least sensitive to ampicillin, a widely used broad-spectrum antibiotic. The bacterial isolates were most sensitive to amikacin, with sensitivity to this drug peaking in June and September. AlMajed’s team found several other drugs that worked effectively in other months of the year. Patients’ ages impacted drug sensitivity, with 94.9% of patients over 70 responding well to the antibiotic amikacin. E. coli in younger patients, aged 20 to 45 years, proved highly susceptible to ciproflaxin. The researchers also observed differences in drug sensitivity dependant on the sex of the patient, with females responding better to ciproflaxin and tobramycin. Bacteria can evade antibiotics by producing enzymes known as extended-spectrum beta-lactamases (ESBLs). These enzymes break the internal structure of the antibiotic molecule, destroying its antibacterial properties and enabling bacteria to survive multiple drug types. Interestingly, despite other studies finding that ESBL-producing bacteria are on the rise, AlMajed’s team found that non-ESBL-producing E. coli species increased at the hospital by 12.2% over the course of the year, particularly in patients aged 46 to 76. They caution this result may not reflect patterns across the wider community, being a finding from a single hospital. The team’s insights could help authorities and clinicians manage patients with bacterial blood infection more carefully. Their results provide further evidence indicating a worrying trend of proliferating strains that are resistant to first-line antibiotics in the region.

KAIMRC Experimental Medicine

Three state of the art vivarium facilities are located in Riyadh, Jeddah and Al Hasa. The vivariums are planned and designed according to international standards. They aim to assist biomedical research by providing animals and veterinary expertise. Moreover, they offer training and education in animal use for research. The facilities also work on the development and implementation of institutional policy, animal care and use policy including animal husbandry and veterinary care.

The hepatitis B virus can be fatal if left untreated.

When liver disease patients fall off the medical radar

People with viral hepatitis often do not return for follow-up treatment, highlighting the need for more robust support strategies.

January 2018

Issue No.4

SC I E NCE P I CT U R E CO / A L A M Y S TOCK P HOTO

ust under a third of hepatitis patients 30%) were deemed lost to follow-up. Of surveyed at King Abdulaziz Medithose 98, the top reason given (by 69% of cal City in Riyadh did not attend a respondents) for not returning for treatfollow-up appointment with the ment was that they were unaware that a hospital. More than two-thirds of those follow-up appointment was scheduled. weren’t aware an appointment had been Other reasons given were that they were scheduled. Researchers urge better infornever informed about the need for folmation, education and communication to low-up (15%) or they had a personal belief help reduce the incidence of liver disease that follow-up was not necessary (9%). complications. The number of patients lost to folMinimising the number of patients who low-up was found to be higher among become unreachathose diagnosed ble — known in the with HBV (71.4%) medical field as compared with If left undiagnosed or ‘lost to follow-up’ HCV (28.6%). untreated, the burden of — during treatAs yet, the full ment programmes extent of the liver disease on hospitals is critical. For peoproblem nationand families will continue ple with hepatitis, wide is unknown. to increase and lead to a insufficient care Since the study can lead to serious wa s c onduc te d greater number of people complications such at just one large requiring transplants. as liver scarring NGHA-affili(cirrhosis), failure ated hospital, the and cancer. researchers point Close to 400 million people are affected out that “the reported 30% may underby the hepatitis B virus (HBV) and another estimate the magnitude of the problem at 170 million are living with hepatitis C virus primary care centres and at the commu(HCV) around the world. In Saudi Arabia, nity level, where many people have never despite a large-scale HBV vaccination inibeen diagnosed or referred.” tiative launched in 1989, the incidence of If left undiagnosed or untreated, the both types of the disease remains higher burden of liver disease on hospitals and than expected. families will continue to increase and To gain a better idea of the number of lead to a greater number of people requirhepatitis patients who drop out of treating transplants. ment, and to reveal the reasons behind The study calls for a greater focus on the lack of follow-up, a multi-institueducation, as well as more efficient and tional team surveyed people diagnosed flexible referral and scheduling systems. with HBV and HCV between 2009 and A dedicated health centre for hepatitis 2010 at King Abdulaziz Medical City patients may help achieve this goal. The (KAMC) in Riyadh. team suggests that sending reminders to The team was led by Hanan Balkhy, patients via text messaging and email will chairman of KAIMRC’s infectious disalso be important. ease section and executive director of the Infection Prevention and Control ProBalkhy, H. H., El-Saed, A., Sanai, F. M., Alqahtani, M., gram at the Ministry of National Guard– Alonaizi, M. et al. Magnitude and causes of loss to folHealth Affairs (NGHA). low-up among patients with viral hepatitis at a tertiary Of a total of 328 patients who comcare hospital in Saudi Arabia. Journal of Infection and pleted the telephone survey, 98 (around Public Health 10, 379—387 (2017).

Genetic make-up and its impact on viral infection A fast and simple approach for analysing people’s genetic make-up and the viruses that infect them could reveal molecular information that can be used to improve prevention and treatment of disease.

January 2018

esearchers developed a method that allowed them to analyse how hepatitis C virus (HCV) evolved differently in a large number of infected people. They found specific genetic variations related to the immune system that affect how HCV evolves and responds to attack and to therapy. The findings highlight the role that joint analyses of host and viral genomes can play in elucidating host-virus molecular interactions to improve prevention and treatment of viral infection. Hepatitis C is a chronic viral infection that affects more than 185 million people worldwide. Transmitted by blood-toblood contact during intravenous drug use and transfusions, it can progress to liver disease with potentially serious complications, such as hepatocellular cancer and liver failure. The team of researchers, led by Chris Spencer and Eleanor Barnes of the University of Oxford in the UK, found that changes in the HCV genome that help it elude immune attack and treatment are controlled by variations in two types of host genes. Human leukocyte antigen (HLA) is a protein found on the surfaces of most cells. When a cell is infected with HCV, HLA presents amino acids from the virus that are then recognized by killer immune cells. The team demonstrated that some variations in the gene that codes for HLA were associated with viral mutations

that allow them to avoid presentation of their amino acids by HLAs and thus evade immune attack. IFNL4 is a human gene that codes for a protein that is released by infected cells as part of the innate immune response to infection. Variations in this gene were found to significantly impact the ‘viral load’ (or how many viruses are present in the blood stream), and to change the genetic make-up of the virus. This is the first time that the innate immune system has been shown to shape the viral genome. The results demonstrate that individual differences in genetic make-up have an effect on how HCV evolves. This determines whether the immune system is adequately able to respond to and control infection over time. These new insights into the biological mechanisms and interactions between host and viral genomes that drive HCV evolution in the human body are relevant for future approaches to individualized treatment and vaccine development, the researchers conclude in their study published in the journal Nature Genetics. Ansari, M. A., Pedergnana, V., Ip, C. L. C., Magri, A., Von Delft, A., Bonsall, D. et al. Genome-to-genome

analysis highlights the effect of the human innate and adaptive immune systems on the hepatitis C virus. Nature Genetics 49, 666–673 (2017).

Issue No.4

S C I EN C E P H OTO LI B R A RY / A L A M Y S TOC K P H OTO

Interactions between hepatitis virus particles and host-cell DNA drive the evolution of the virus in the body.

A model of MERS-CoV S trimers bound to their receptors.

In search of strategies to disrupt viral docking

Insights into how two viruses initiate the infection of host cells could guide development of countermeasures. Most coronaviruses (CoV) preferentially target animals, but the recent emergence of pathogens from this family that cause potentially fatal disease in humans is the subject of much investigation. No medical treatments are available for severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS), but new findings from George Gao and colleagues at the Chinese Academy of Sciences have revealed vulnerabilities in these viruses. The SARS-CoV and MERSCoV viruses rely on a molecule called the S protein to penetrate host cells. In previous 64

January 2018

work, Gao’s team used X-ray — were poorly understood.” crystallography to obtain a Although crystallography ‘snapshot’ of how a segment of worked well for studying the this protein binds to its target S protein’s receptor binding receptor on domain cell surfaces. (RBD) in “We are trying to “This work isolation, the develop neutralizing full protein elucidated the mechproved too antibodies that anism of floppy and target S protein MERS-CoV dynamic to attachment study with for the treatment to its host t h i s te ch of emerging coro cell receptor, nique. As navirus infections.” a n a l t e r which is the first step of native, the virus entry,” explains Yi Shi, researchers used a method a researcher on Gao’s team. called cryo-electron micros“However, the subsequent copy, which enabled them to steps — viral particle trafstudy the MERS- and SARSficking and membrane fusion CoV S proteins in a way that

Yuan, Y., Cao, D., Zhang, Y., Ma, J., Qi, J. et

al. Cryo-EM structures of MERS-CoV and SARS-CoV spike glycoproteins reveal

the dynamic receptor binding domains.

Nat. Commun. 8, 15092 (2017).

captures their structural diversity. They focused specifically on the ‘pre-fusion’ form of the protein, which assembles into complexes of three molecules and mediates the earliest stages of virus-host interaction. “We noticed that both [MERS- and SARS-CoV S] proteins can be classified into several classes with different RBD conformations,” says Shi. In particular, they noticed two distinct RBD arrangements they termed ‘standing’ and ‘lying’ to reflect their orientation relative to the remainder of the S protein. By combining these data with their structural analysis of the interaction between RBD and host cell receptor proteins, they formulated a model for viruscell binding. Their data suggest that only ‘standing’ RBDs can bind to cellular receptors, an interaction that facilitates subsequent virus-cell fusion steps. This analysis offers valuable starting points for fully reconstructing the process of viral entry, and could help researchers fight future outbreaks. Because the standing RBD is highly exposed prior to receptor binding, it’s a promising drug target. “We are trying to develop neutralizing antibodies that target S protein for the treatment of emerging coronavirus infections,” says Shi. “Aided by structural analysis and functional characterization, we can identify the molecular basis of this neutralizing activity and improve their efficacy through molecular engineering.”

Shared Enabling Platforms Shared enabling platforms is a key element to create a culture of cooperation. This approach is deeply engraved in KAIMRC to encourage collaborative environment between KAIMRC scientists and others to accelerate research outcomes and outputs. The Cord Blood Bank (CBB) at KAIMRC is a national non-profit project, responsible for recruiting, processing, testing, cryopreserving, storing, thawing and infusing cord blood units that will be used for patients in need of cord blood stem cell transplantation. The CBB activities are carried out within a quality control system up to international standards.

kaimrc-cbb@ngha.med.sa

Target Audience King Abdullah International Medical Research Center (KAIMRC) in collaboration with The Deanship of Postgraduate Education, KSAU-HS is pleased to invite you to attend the 9th Annual Forum for Medical Research with the theme “Achieving the National Vision through Medical Research”.

WEBSITE: FORUM.KAIMRC.MED.SA E-MAIL: RESFORUM-GENERAL@NGHA.MED.SA

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