In October 2016, researchers at the Aga Khan University’s microbiology laboratory spotted a number of unusual organisms in blood samples from Hyderabad. Blood culture tests from the city contained a novel strain of typhoid that had developed resistance to an unprecedented range of antibiotics.
Over the next few months, several similar cases were detected from the city pointing to an outbreak of a form of the disease that would be especially difficult to treat. 
The research team, led by Pofessor Rumina Hasan, acted quickly to alert local government, the National Institutes of Health and the World Health Organization to this development. They also contacted the UK-based Wellcome Sanger Institute to explore the genetic cause behind the emergence of this extensively drug-resistant (XDR) typhoid strain.
“This was the world’s first outbreak of XDR typhoid,” said Professor Zahra Hasan of the department of pathology and laboratory medicine. “Understanding this new threat required high-level genome sequencing which would enable us to analyse the molecular blueprint of this new form of typhoid.”
Over the next six months, the research team collaborated with experts at the Wellcome Sanger Institute to jointly analyse over 100 DNA samples which resulted in a striking finding. The typhoid bacteria had acquired a DNA molecule through a plasmid from a bacterium commonly found in contaminated water and food, making it resistant to the majority of available medications .  
“We used to think that we had a complete picture of the typhoid ‘puzzle’,” said Dr Sadia Shakoor, assistant professor in pathology and laboratory medicine at AKU. “Together with our partners, we’ve found a missing piece that affects how we diagnose and treat the most complex strains of the disease.”   
Since patients with XDR typhoid do not respond to commonly prescribed antibiotics, blood culture tests have become an even more important tool for physicians, according to Dr Shakoor. Not only do these tests enable early detection but they also highlight the type of typhoid being tackled that affects the choice of antibiotic.
“There are currently three antibiotics available to treat XDR typhoid,” Dr Shakoor stated. “These drugs are expensive and we must only prescribe them when needed. Otherwise, bacteria could develop resistance to the only medications we have left.”
Beyond resistance, researchers also warn of the risk of the disease spreading since every patient is a potential ‘disease carrier’. The likelihood of the proliferation of the disease is especially high in developing countries where poor sanitation facilities result in the contamination of drinking water with sewage containing the typhoid bacteria.
Aga Khan Universitywww.aku.edu/news/Pages/News_Details.aspx?nid=NEWS-001521

A high-sensitive blood test can aid concussed hockey players when it might be safe to return to play. In a study, researchers at Sahlgrenska Academy has identified a superior blood-based biomarker for assessing subtle brain injury.
"This could serve as an objective test a long side clinical evaluation to whether a player is fit to return to playing. Currently, we lack an objective test like this", says Dr. Pashtun Shahim, lead author of the article.
The study entails yet another step forward in the research that has been carried out in Gothenburg for several years, with focus on sports-related concussions. This time it included all Swedish ice hockey teams that played in the highest division on the men’s side, SHL, during three seasons 2012-2015. Hockey clubs from Luleå HF in the north of Sweden to Rögle BK in the south were involved in the work.
In total, 288 players were included, of which 105 suffered a concussion during the seasons in question. From 87 of these players, blood samples were taken 1, 12, 36 and 144 hours (six days) after the concussion. A fifth sample was taken at the time when the person was determined fit to return to unrestricted competition.
The purpose of the study was to compare concentrations in the blood of known biomarkers for concussion, both directly after the event and over a period of time. The results show that it was the levels of the protein neurofilament light (NfL) that had the clearest connection to the severity of concussion, measured as the number of days it took for players to return to play.
"The strength of this study is that we longitudinally followed how these biomarkers are released and cleared from the blood. What we observed was that NfL was released within an hour after the concussion, and then it increased over time in players who had prolonged symptoms", Pashtun Shahim explains.
The levels of the other biomarkers that were studied (tau, S100B and neuron-specific enolase, NSE) decreased quickly and could thereby not indicate how injured the players were after 7-10 days, a time point many players returned to play in the study.
"Currently the duration of players’ symptoms determines when it is safe to play again. The finding that serum NfL concentrations correlate with the duration of post-concussive symptoms or return to play, implicates that serum NfL might serve as an objective test of when it is safe to return to play. It is important to protect the players from developing long-term symptoms by avoiding premature return to play. Suffering additional concussion, especially when the current post-concussion symptoms are not fully resolved might have long-term consequences", says Pashtun Shahim.
"There is no need for a biomarker in order to make a diagnosis of concussion, it is a clinical diagnosis that is based on the patient’s symptoms", he continues. "What we are really after is a prognostic biomarker that helps the physicians determine which players or patients might be at increased risk of developing persistent post-concussive symptoms, and thereby adjust the level of rest and care for these players."

University of Gothenburgwww.gu.se/english/about_the_university/news-calendar/News_detail//a-high-sensitive-blood-test-when-it-is-safe-to-return-to-play-after-a-sports-related-concussion.cid1564034

Human sperm may hold the potential to serve as biomarkers of the future health of newborn infants, according to a new study by a Wayne State University School of Medicine research team.
The study, “Sperm RNA elements as markers of health,” from the lab of Stephen Krawetz, Ph.D., the Charlotte B. Failing Professor of Fetal Therapy and Diagnosis in the WSU Department of Obstetrics and Gynecology and Center for Molecular Medicine and Genetics, indicates that RNA found in male sperm not only shows promise as a determinant in successful live birth, it may also tell us more about the health of a child as it matures.
“We explored the opportunity of using sperm RNA elements as a predictor of human health, with applications at the fertility clinic that would go hand-in-hand with the new neonatal intensive care unit genome sequencing to better health outcomes,” said Dr. Krawetz, associate director of the C.S. Mott Center for Human Growth and Development. “This leaves the intriguing possibility that, while sperm RNAs delivered to the egg inform the success of live birth, they may also open a pathway to understanding the birth and potential health of each child.
At fertilization, sperm delivers a structurally distinct genome, along with a complement of ribonucleic acids, or RNAs, and proteins to the immature egg cell. To test the hypothesis, sperm RNA elements corresponding to specific genes were characterized as a function of disease association. Dr. Krawetz’s team surveyed a total of 278,605 sperm RNA elements called short exon-sized sequences, or SREs, associated with diseases. This functional association of SREs may indicate a future phenotype, providing improved understanding of the father’s contribution to the life course of the child as well as the current state of paternal health.
In the future, if those SREs that are mutated or modified can be identified, researchers and physicians may be able to not only forecast disease or conditions, but develop ways to prevent them.
Wayne State University
www.med.wayne.edu/news/2017/12/01/sperm-rna-may-serve-as-biomarkers-of-future-health-wsu-researchers-find/

Matching unique genetic information from cancer patients’ tumours with treatment options – an emerging area of precision medicine efforts – often fails to identify all patients who may respond to certain therapies. Other molecular information from patients may reveal these so-called “hidden responders,” according to a Penn Medicine.
“Targeted sequencing can find individuals with certain mutations that are thought to confer susceptibility to anti-cancer drugs,” said senior author Casey Greene, PhD, an assistant professor of Pharmacology in the Perelman School of Medicine at the University of Pennsylvania. “But many people may lack these mutations, and as machine learning approaches improve they may help guide these patients to appropriate therapies.
”Greene and first author and doctoral student Gregory P. Way used machine learning to classify abnormal protein activity in tumours. This branch of artificial intelligence develops computer programs that can use new data to learn and make predictions. The algorithm they devised to search TCGA integrates genetic data from 33 different cancer types. Greene and Way used information from the transcriptome, the grand total of all messenger RNAs expressed within an individual.
They specifically applied their model to the Ras pathway, a family of genes that make proteins that govern cell replication and death. Changes in the normal function of Ras proteins – mutations which are responsible for 30 percent of all cancers – can power cancer cells to grow and spread. These mutations are often referred to as the “undruggable Ras,” having beaten back a variety of investigational inhibitor drugs and vaccine-based therapies.
“This model was trained on genetic data from human tumours in The Cancer Genome Atlas and was able to predict response to certain inhibitors that affect cancers with overactive Ras signalling in an encyclopaedia of cancer cell lines,” Greene said. The upshot is that the transcriptome is underused in bringing precision to oncology, but when combined with machine learning it can aid in identifying potential hidden responders.
The Penn team collaborated with co-author Yolanda Sanchez, PhD, a cancer biologist from the Geisel School of Medicine at Dartmouth College. They are working together to mesh her identification of compounds that target tumors with runaway Ras activity and tumour data (analysed by machine learning) to find patients who could benefit from these potential cancer drugs.
“For precision medicine to benefit individuals in real time, we must develop robust models to efficiently test efficacy of potential therapies,” Sanchez said. “We can use this very powerful combined approach of machine learning-guided drug discovery using Avatars, which are mice carrying identical copies of a patient’s tumors. The Avatars allow our interdisciplinary team to identify the tumours with runaway Ras activity and evaluate and compare multiple therapies in real time.”
Penn Medicinewww.pennmedicine.org/news/news-releases/2018/april/seeking-hidden-responders-machine-learning

Researchers have found that UTY, a gene on the Y chromosome, protects male mice lacking the tumour-suppressing UTX gene on the X chromosome from developing acute myeloid leukaemia
Researchers at the Wellcome Sanger Institute and the University of Cambridge found that this Y-chromosome gene protects against the development of Acute Myeloid Leukaemia (AML) and other cancers.
The study investigated how loss of the X-chromosome gene UTX, which is known to be mutated in many tumours, hastens the development of AML. However, they found that UTY, a related gene on the Y chromosome, protected male mice lacking UTX from developing AML. The authors then show that in AML and in several other human cancers types, loss of UTX is accompanied by loss of UTY, confirming that the cancer-suppressing role of UTY extends beyond AML.
Acute myeloid leukaemia is an aggressive blood cancer that affects people of all ages. It develops in cells in the bone marrow and leads to life-threatening infections and bleeding. Mainstream AML treatments have remained unchanged for decades.
Women have two X chromosomes whereas men have one X and one Y chromosome. The X and Y chromosomes share many genes, but a small number of genes, including UTY, are only found on the Y chromosome. These Y-specific genes were thought to contain the genetic information required for male sexual characteristics, but were not known to have other roles. The discovery of this new role changes the way the Y chromosome is viewed and improves understanding of how AML and other cancers develop.

“This is the first Y chromosome-specific gene that protects against AML. Previously it had been suggested that the only function of the Y chromosome is in creating male sexual characteristics, but our results indicate that the Y chromosome could also protect against AML and other cancers.”
Dr Malgorzata Gozdecka, the first author on the study from the Wellcome Sanger Institute

“It is known that men often lose the Y chromosome from their cells as they age, however the significance of this was unclear. Our study strengthens the argument that loss of the Y chromosome can increase the risk of cancer and describes a mechanism for how this may happen.”
Professor Brian Huntly, joint project leader from the Wellcome-MRC Cambridge Stem Cell Institute, and Consultant Haematologist, at Cambridge University Hospitals NHS Trust

In their study, researchers studied the UTX gene in human cells and in mice to try to understand its role in AML. In addition to their discovery that UTY acts as a tumour suppressor gene, the scientists found a new mechanism for how loss of UTX leads to AML. They discovered that UTX acts as a common scaffold, bringing together a large number of regulatory proteins that control access to DNA and gene expression, a function that can also be carried out by UTY. When UTX/UTY are missing, these proteins can’t regulate gene expression correctly and cancer growth becomes more likely.

“Treatments for AML have not changed in decades and there is a large unmet need for new therapies. This study helps us understand the development of AML and gives us clues for developing new drug targets to disrupt leukaemia-causing processes. We hope this study will enable new lines of research for the development of previously unforeseen treatments and improve the lives of patients with AML.”
Dr George Vassiliou, joint project leader from the Wellcome Sanger Institute, Wellcome-MRC Cambridge Stem Cell Institute and Consultant Haematologist at Cambridge University Hospitals NHS Trust.

“Survival rates for AML remain tragically low, with current treatment that involves intensive chemotherapy, often combined with a stem cell transplant, only curing a small proportion of patients. This important research helps build a fuller picture of what goes wrong genetically as this highly aggressive leukaemia develops. Understanding this process is key to developing targeted drugs for AML, allowing us to move away from gruelling and often ineffective chemotherapy-based treatments.”

Wellcome Sanger Institutewww.sanger.ac.uk/news/view/leukaemia-protective-role-y-chromosone-gene-discovered