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

In a new study New York University College of Dentistry (NYU Dentistry) researchers investigating the catabolic effect of parathyroid hormone (PTH) in hyperparathyroidism (HPT) showed, for the first time, that monocyte chemoattractant protein-1 (MCP-1) is required for catabolic responses to PTH. HPT is a condition in which an abnormally high concentration of PTH in the blood accelerates bone loss.
The research team, led by Nicola C. Partridge, PhD, professor and chair of the Department of Basic Science and Craniofacial Biology at NYU Dentistry, had previously found that MCP-1 is important in producing an anabolic effect of PTH, in which bone formation is increased, and they wanted to know if it was also important in causing a catabolic effect, in which bone is broken down.
In the present study, the researchers focused on the role of MCP-1 in PTH-induced osteoclast formation. Osteoclasts are cells that break down the bone. Increased osteoclast formation causes bones to become thinner and weaker. The researchers recreated the hyperparathyroid state in mice by constantly elevating their hyperparathyroid levels. Over a two-week period, they continuously infused female wild-type and MCP-1 knockout mice with human PTH. They showed that the ability of PTH to increase osteoclast formation in vitro is markedly impaired in cells from MCP-1 knockout mice and concluded that MCP-1 is an important chemokine, or signalling protein, in PTH-induced osteoclast formation and bone resorption.
The findings support the possibility that MCP-1 could be a marker for how PTH works in humans with hyperparathyroidism, as elevated serum MCP-1 has been shown to be correlated with elevated serum PTH levels in women. Notably, within minutes after humans undergo parathyroid adenoma surgery, MCP-1 serum levels decrease.
Because high serum levels of MCP-1 cause the white cells and osteoclasts to be stimulated, this process could have systemic effects as well as effects on bone. “MCP-1 is a chemokine, which induces cells to move along a gradient recruiting white cells and osteoclasts in tissues,” says Dr. Partridge. “Accordingly, there could also be effects on adipose tissue, the heart, and inflammatory conditions.”
In the United States, about 1,000 people develop HPT each year, with osteoporosis the most common manifestation. According to the National Institutes of Health, there are approximately 1.5 million osteoporotic fractures in the U.S. each year that lead to half a million hospitalizations, over 800,000 emergency room encounters, more than 2,600,000 physician office visits, and the placement of nearly 180,000 individuals in nursing homes. Hip fractures are by far the most devastating type of fracture, accounting for about 300,000 hospitalizations each year. About one in five people sustaining a hip fracture ends up in a nursing home.  
NYU College of Dentistryhttps://tinyurl.com/y7nzipw9

Clearing a major hurdle in the field of microbiome research, Harvard Medical School scientists have designed and successfully used a method to tease out cause-and-effect relationships between gut bacteria and disease.
The team says the approach could propel research beyond mere microbiome-disease associations and elucidate true cause-effect relationships.
The experiments, conducted in mice, also identify a previously unknown gut microbe that tames intestinal inflammation and protects against severe colitis. The researchers say the finding makes a strong case for testing the newly identified gut bacterium as a probiotic therapy in people with inflammatory bowel disease, a constellation of conditions marked by chronic inflammation of the intestines and estimated to affect up to 1.3 million people in the United States, according to the Centers for Disease Control and Prevention.
The approach uses a sort of “microbial triangulation.” It mimics the principles of classic maritime navigation or, in more modern terms, tracking the location of a mobile phone by verifying data from multiple sources—but instead of stars or cell phone towers, the researchers are homing in on intestinal bugs. Based on the method of elimination, the technique involves the gradual narrowing down of bacterial species to identify specific microbes that modulate the risk for specific diseases. In the current study, researchers adapted the principles to identify beneficial, protective bacteria.
“Our approach can help scientists find the proverbial needles in a ‘haystack’ of thousands of microbes that are currently thought to modulate health,” said investigator Dennis Kasper, professor of microbiology and immunobiology at Harvard Medical School. “If the field is to move past associations—the Achilles’ heel in microbiome research—we need a system that reliably teases out causative relationships between gut bacteria and disease. We believe our method achieves that,” added Kasper, who is also the Harvard Medical School William Ellery Channing Professor of Medicine at Brigham and Women’s Hospital.
Over the last decade, study after study has identified thousands of commensal microbes—those residing innocently in our bodies—and catalogued observations of possible links between groups of microbes and the presence or absence of a panoply of diseases, including diabetes, multiple sclerosis and inflammatory bowel disease. Yet, scientists don’t know whether and how the presence of specific microbes—or fluctuations in their numbers—affects health. It remains unclear whether certain microbes are innocent bystanders, mere markers of disease, or whether they are active agents, causing harm or providing protection against certain ailments.
The holy grail of this work would be not to merely define whether a microbe fuels or minimizes the risk for a given disease but to discover microbes and microbial molecules that can be used therapeutically.
“The ultimate goal is to clarify the mechanisms of disease and then identify bacterial molecules that can be used to treat, reverse or prevent it,” said study lead author Neeraj Surana, Harvard Medical School instructor in pediatrics and an infectious disease specialist at Boston Children’s Hospital.
For their study, Kasper and Surana compared the gut microbiomes of several groups of mice that harboured different populations of intestinal bacteria.
The researchers started out with two groups of mice. One group had been bred with human gut microbiomes—housing intestinal bacteria normally found in human intestines. The other group had been bred to harbour normal mouse microbiomes. When researchers gave the animals a chemical compound that triggered intestinal inflammation, or colitis, mice that harboured human intestinal microbes were protected from the effects of the disease. Mice whose guts harboured typical mouse bacteria, however, developed severe symptoms.
Next, the researchers housed all mice in the same living space. Sharing living space for as briefly as one day led to noticeable changes in how the animals responded to disease. Mice that had been originally protected from colitis started showing more serious signs of it, while colitis-prone mice grew increasingly resistant to the effects of the condition and developed milder symptoms—a proof-of-principle finding which shows that exchange of intestinal bacteria through shared living space can lead to changes in the animals’ ability to cope with the disease.
The disease-modulating microbe would be lurking amid the hundreds of bacterial species present in all mice. But given that each mouse group harboured between 700 and 1,100 bacterial species in their guts, how could scientists identify the one that truly mattered in colitis? The team began by analysing the intestinal makeup of each one of the mouse groups, comparing their microbial profiles before and after they shared a living space. To “triangulate” the suspect’s identity, scientists looked for microbes that were either scarce or abundant, tracking with colitis severity. In other words, the numbers of the causative microbe would either go up or down with disease severity, the scientists reasoned. Only one such microbial group fit the profile—a bacterial family known as Lachnospiraceae, commonly found in human intestines as well as the guts of other mammals.
To pinpoint the one organism within the Lachnospiraceae family that regulates response to colitis, the researchers isolated one bacterial species and gave it to colitis-prone mice. To compare its effects against other microbes, they also gave the animals organisms from different bacterial families. The only bacterium that protected colitis-prone animals from the ravages of the disease was a never-before-described microbe that the researchers had isolated from the guts of mice seeded with human feces, the animals that had harboured human microbiomes. The microbe was notably absent from mice with mouse microbiomes. Because of its immune-protective properties, Kasper and Surana christened the newly identified organism Clostridium immunis.
The isolation of the disease-modifying microbe makes a powerful case for testing it as therapy in people with inflammatory bowel disease, the researchers said.
Harvard Medical Schoolhttps://tinyurl.com/yawe5qvh

Siemens Healthineers is developing “The Enterprise Project” with the Hermes Pardini Group of Minas Gerais, Brazil. The Enterprise Project is the largest and most complex clinical analysis laboratory known to date and is expected to be capable of handling 110 million sample tubes per year upon completion. Siemens Healthineers, in collaboration with Inpeco, has designed and will deliver this fully automated multidisciplinary solution on an unprecedented scale, which will include at least 100 analysers—including more than 50 Atellica Solution clinical chemistry and immunoassay analysers from Siemens Healthineers, the largest IVD supplier in this project. The highly sophisticated solution will provide automation of clinical and operational workflow, from sample reception through testing to disposal. Sited in Vespasiano, Grande Belo Horizonte in Minas Gerais, the lab will occupy 3,500 square meters of floor space, will conduct operations 24 hours a day, and is expected to be fully operational during 2019.
“The automation track will be more than 330 meters long upon completion and will be used to automatically transport and distribute sample tubes to specific analysers that can run the specific type of test requested by clinicians,” said Guilherme Collares, Chef Operations Officer of the Hermes Pardini Group. “Unlike conventional laboratory set-ups, where sample tubes have to be moved manually between different analysers, our enterprise lab is designed to employ a ‘one-touch, one workflow’ concept to eliminate the need for manual interventions, ensure sample traceability, and reduce the turnaround time to results. The Enterprise Project also will rely on Atellica Process Manager, an IT solution that delivers a 3D view of the laboratory configuration, to enable operators to manage alerts, control instruments and reagent monitoring remotely, and see test progression in real time. Siemens Healthineers will implement the first Laboratory Control Room, which will centralize management and provide holistic visibility of operations in the central Vespasiano laboratory, and other Hermes Pardini satellite lab units in São Paulo, Rio de Janeiro, Goiania, and Belo Horizonte.
https://tinyurl.com/y9h4mtgm