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As more patients with cancer have their tumors genomically profiled, and more therapies targeting genomic alterations enter clinical trials, the task of connecting patients to trials for which they are eligible can be especially challenging. A computer platform developed at Dana-Farber Cancer Institute makes the matching process both easier and faster, its designers report in a new study.
Called MatchMiner, the platform helps clinicians and clinical researchers find potential matches between patients and targeted therapy trials based on genetic alterations in patients’ tumors. During a five-year period at Dana-Farber, it helped bring about roughly one in every five consents to join precision medicine trials among patients with genomic data in MatchMiner. It also sped the process of enrolling patients in such trials by more than 20%, the authors of the study, published in npj Precision Oncology, found.
“Profiling patient tumors for genomic alterations has become a widespread part of cancer care, especially as new drugs targeting those alterations go into clinical trials or are approved as cancer therapies,” says Tali Mazor, PhD, the co-lead author of the paper with Dana-Farber colleague Harry Klein, PhD. “The combination of this growing body of genomic data and increasing number of precision medicine trials has created a kind of disconnect: finding the right trial for each patient can be a difficult task. MatchMiner helps bridge that gap.”
The platform, developed by the Knowledge Systems Group at Dana-Farber led by Ethan Cerami, PhD, and Michael Hassett, MD, MPH, draws on Dana-Farber’s extensive programs in genomic analysis and clinical research. Over the past decade, more than 40,000 patients at the Institute have had their tumor tissue analyzed for alterations in over 400 cancer-related genes. The Institute and its partners lead or participate in thousands of clinical trials, including about 450 involving targeted therapies since 2017. MatchMiner, which was launched in 2016, links these systems to help match patients to appropriate trials.
“MatchMiner can be used by an oncologist or other clinician to look up trial options for an individual patient,” Klein remarks. “Or it can be used by a trial team to identify potential trial participants by setting up a genomic filter that screens candidates for specific genomic criteria.”
Unlike most other matching platforms, which are designed for use at a single cancer center, MatchMiner is open-source and can be adapted by other institutions. As new trials open at Dana-Farber, a curator reviews them to see if they should be included in MatchMiner, ensuring the platform is up-to-date. As of March 2021, 354 precision medicine trials are integrated into MatchMiner.
In the new paper, investigators analyzed enrollment data for precision medicine trials at Dana-Farber to determine whether MatchMiner expedited the process of finding an appropriate trial for patients whose tumors had been genomically profiled. The researchers found 166 instances in which the platform identified a potential match between a patient and a trial, and the trial team or the patient’s oncologist viewed the match, leading to the patient’s consent to join the trial.
To further assess the impact of the platform, investigators compared the “time to consent” — the time between the genetic profiling of a tumor and the patient’s consent to participate in the trial — for the 166 consents obtained via MatchMiner and for 353 consents obtained without the platform. “We found the time to consent for the MatchMiner group was 55 days faster than for the non MatchMiner group, an improvement of 22%,” Klein says.
MatchMiner links patients to trials not only by the molecular features of the patient’s tumor but also by patient age and tumor type. Other trial criteria, such as tumor stage, previous treatment, and patient’s overall health are not considered for a patient-trial match. As a result, the matches proposed by MatchMiner are preliminary and need to be followed up to ensure that patients meet all the trial criteria, researchers say.
“MatchMiner provides a starting point for finding appropriate trials for patients whose tumors have defined genetic alterations,” Mazor says. The platform’s designers will be working to expand its capabilities to make a more comprehensive match, she adds. Through a collaboration with Kenneth Kehl, MD, MPH, MatchMiner is testing AI-based predictions to better identify patients who may soon need a new therapeutic option like a clinical trial.
MatchMiner is available for adoption at other institutions.

The mitochondria is a key energy-producing component of the human cell that plays an important role in cancer cell metabolism. In a research paper published in PLOS ONE, Dario C. Altieri, M.D., president and chief executive officer, director of the Ellen and Ronald Caplan Cancer Center, and the Robert and Penny Fox Distinguished Professor at The Wistar Institute, alongside national and international collaborators, distinguish a specific gene signature indicative of mitochondrial reprogramming in tumors that correlates with poor patient outcome.
“To the best of our knowledge, this is the first time that a gene signature of mitochondrial dysfunction is linked to aggressive cancer subtypes, treatment resistance and, unfortunately low patient survival rates. Although our work has focused on the mitochondrial protein Mic60 in this response, we know that dysfunctional mitochondria are commonly generated during tumor growth, suggesting that this is a general trait in cancer,” says Altieri.
This paper stemmed from past research investigating the role of the protein Mic60 in tumor cell proliferation, motility, and metastases. Mic60, also called mitofilin or inner membrane mitochondrial protein (IMMT), is a key protein that is essential to the structure of mitochondria and thus has a downstream impact on mitochondrial functions and tumor metabolism.
Andrew Kossenkov, Ph.D., first author on the paper, assistant professor in Wistar’s Gene Expression and Regulation program and scientific director of the Institute’s Bioinformatics Facility, shares, “After original findings on the strong association of Mic60 in low levels in cancer tissues, we were curious if we could identify a small panel of Mic60 downstream genes of specific functions and if the Mic60-low gene panel signature has clinical relevance — i.e., if it is associated with clinical data like survival, cancer sub-types, response to treatment, etc. — and we did.”
Armed with this knowledge, the team — along with collaborators from Canada, Italy, and across the United States — analyzed tumor cells from three independent patient cohorts with pancreatic ductal adenocarcinoma (PDAC). They showed that an 11-gene Mic60-low signature is associated with aggressive disease, local inflammation, treatment failure, and shortened survival — ultimately demonstrating the clinical relevance of protein. Therefore, the Mic60-low gene signature may be used as a simple tool or biomarker to estimate cancer risk for PDAC and potentially other types of cancer, including glioblastoma.
“Gene signatures can be used to gain insight into specific tumor qualities,” Kossenkov explains. “If extensively developed, tested, and validated, this [Mic60-low gene signature] can be a potential simple point-of-service molecular tool for pancreatic cancer prognosis or stratification of patient risks and prediction of treatment response.”
“While the broad applicability of this new Mic60-low gene signature certainly awaits further confirmation in larger patient populations, we hope that this simple, easily implementable molecular tool will be of help in the clinic to stratify patients at higher risk of severe and progressive disease,” Altieri details.
Regarding future directions, Kossenkov suggests that studying broader datasets with extensive clinical information not limited to pancreatic cancer, but also other malignancies can help demonstrate the applicability of the 11gene Mic60-low signature in estimating cancer risks.
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Published12 hours agoSharecloseShare pageCopy linkAbout sharingImage source, Getty ImagesBlack people are more likely to develop dementia than white and South Asian people, a UK study suggests.It confirms previous study findings but the reasons are complex, University College London (UCL) researchers said.A mix of genes and underlying health conditions, such as high blood pressure and obesity, may play a role in dementia risk among black people.Larger studies with more dementia cases in ethnic groups are needed to tease out the precise causes.Experts are warning that by 2050, more than 153 million people worldwide could have dementia, up from 57 million in 2019.The predicted rise is largely down to ageing, and growing populations.Alzheimer’s-slowing drug labelled historicFresh clue to mystery of elderly super brainsI’ve got dementia – dementia hasn’t got meThe UCL research followed nearly 300,000 people who took part in the UK Biobank study for up to 14 years.During that time, about 6,000 people developed dementia – most were white, 91 were black and 79 were South Asian.Despite the small number affected in black and South Asian groups, the study found that the same factors increased the risk of dementia in all three ethnic groups, These risk factors were hypertension, or high blood pressure, obesity, smoking, social isolation, air pollution, depression, diabetes and hearing loss.Health checksThe study, published in PLoS One, found hypertension and obesity were more common in black people, compared to white or South Asian people.Black people in the study were also more likely to be carriers of a gene linked to dementia.But some risk factors were less common in black people, such as smoking, drinking more than 21 units of alcohol per week, and having high cholesterol.Dr Naaheed Mukadam, study author and senior research fellow in psychiatry at UCL, said what lies behind a higher risk of dementia in black people was a “complex picture”. “It could be driven by genetics or the way their risks are managed,” she said.”The difference means we need greater awareness in that population that dementia is a concern – and more proactive management of risk factors like hypertension, and more health checks.”Diverse communitiesA recent study by the same researchers, which looked at 20 years’ worth of GP and hospital health records, found black people had a 22% higher incidence of dementia being recorded than white people. They also found black and South Asian people were diagnosed at a younger average age than white people in the UK.Katherine Gray, research communications manager at Alzheimer’s Society, said 25,000 people living with dementia were from ethnically diverse communities, with the number predicted to double by 2026. “However, current research into dementia risk factors is mostly in people from white European ancestry,” she said, adding that there was a need to better understand and support diverse populations. She called for more research into the experiences of ethnically diverse communities and a doubling of dementia research funding. More on this storyAlzheimer’s-slowing drug labelled historic28 SeptemberFresh clue to mystery of elderly super brains30 SeptemberGlobal dementia cases expected to triple by 20507 JanuaryI’ve got dementia – dementia hasn’t got me13 October 2021

Oxygen is vital for life, and clinicians can provide supplemental oxygen to patients through face masks and nasal tubes, but there are no methods available for delivering oxygen directly into cells.
This capability would be useful initially as a research tool but could eventually have important medical applications — for example, to enhance therapies that lose effectiveness when oxygen levels are low.
As reported in PNAS, investigators at Massachusetts General Hospital (MGH) recently developed a technology that allows them to engineer cells to make oxygen on demand in response to an added chemical.
The work was led by Vamsi K. Mootha, MD, a Professor of Systems Biology and Medicine in the Department of Molecular Biology at MGH, whose laboratory focuses on mitochondria. These specialized compartments within cells produce energy, and they require oxygen to do so. “We are interested in how mitochondria, cells, and organisms adapt to changes in ambient oxygen,” says Mootha.
Currently, if the scientists want to manipulate cells’ oxygen levels in the lab, they place a petri dish containing cells in an environmentally controlled chamber. While this is useful, they can’t change oxygen levels in select cells at a specific time.
“From this need came the idea for a genetically encoded system that could be deployed in human cells to produce their own oxygen on demand,” says Mootha.
The technology involves simultaneously expressing a transporter and a bacterial enzyme within a cell — together, these proteins promote the uptake of chlorite into the cell and enzymatically convert it into oxygen and chloride.
The researchers call their new genetic technology SNORCL, for SupplemeNtal Oxygen Released from ChLorite. The first generation SNORCL is capable of producing short and modest pulses of oxygen inside of cells in response to added chlorite.
“In the near-term SNORCL is really for the research arena, for evaluating the role of oxygen in signaling, metabolism, and physiology in great detail. But then in the future, technologies based on SNORCL could have a variety of clinical uses,” says Mootha.
For example, tumors often have low oxygen levels that limit the effectiveness of some anti-cancer therapies. SNORCL might be used to improve these therapies’ effectiveness in such environments.
Additional co-authors include Andrew L. Markhard, Jason G. McCoy, and Tsz-Leung To.
This work was supported by the Howard Hughes Medical Institute.
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Scientists at St. Jude Children’s Research Hospital have shown how a protein responsible for adapting to low oxygen conditions (hypoxia), causes increased expression of fetal hemoglobin (HbF) in adults. The finding has implications for treating sickle cell disease and beta-thalassemia, serious blood disorders that affect millions of individuals. The research was published today in Nature.
Hemoglobin is like a protein sponge that soaks up oxygen and allows red blood cells to ferry it throughout the body. Adult hemoglobin contains four protein subunits — two beta-globin and two alpha-globin. Mutations in beta-globin cause sickle cell disease and beta-thalassemia. But humans have another hemoglobin subunit gene (gamma-globin), which is expressed instead of beta-globin during fetal development. Gamma-globin combines with alpha-globin to form HbF. Normally around birth, gamma-globin expression is turned off and beta-globin is turned on, resulting in a switch from HbF to adult hemoglobin.
“We have known for many years that persistent HbF expression after birth can alleviate the symptoms of sickle cell disease and beta-thalassemia,” said corresponding author Mitchell J. Weiss, M.D., Ph.D., St. Jude Hematology Department chair. “And very high HbF levels can cure these diseases, despite the defective beta-globin genes being present. Therefore, many laboratories are focused on understanding the perinatal switch from gamma- to beta-globin gene expression and figuring out new ways to reverse it with drugs or genetic therapies.”
Restoring HbF production in adults
The St. Jude group discovered that hypoxia inducible factor 1 (HIF1) directly promotes transcription of the gamma-globin gene to enhance HbF production. HIF1 is an important component of cells’ ability to sense and adapt to hypoxic conditions. In low oxygen conditions, HIF1 accumulates in many tissues and activates hundreds of genes, including HbF in red blood cells.
First author Ruopeng Feng, Ph.D., a scientist in the Weiss lab, showed that a drug that activates part of the cellular hypoxia response inhibits sickling of red blood cells derived from adults with sickle cell disease. The drug, a proline hydroxylase inhibitor, caused HIF1 to accumulate, bind a DNA regulatory region near the gamma globin gene, activating its transcription to produce HbF and inhibit cell ‘sickling.’ Proline hydroxylase inhibitors are currently in late stage clinical development for the treatment of anemia associated with chronic kidney disease. These drugs work by stabilizing HIF proteins to stimulate the production of erythropoietin, a hormone that drives red blood cell production.

Students learn about the nucleus in ninth grade biology — it’s the inner sanctum of biological cells, where the genome resides with the blueprints for cells to make proteins that are the building-blocks of life.
Apertures called nuclear pore complexes (NPC) perforate the otherwise iron-clad membrane and act like crossing guards for macromolecular traffic in and out of the nucleus. If the crossing-guard misfires, it can cause human diseases such as cancer, viral infections, and neurodegenerative conditions.
Nuclear Pore Complex Mechanism Discovered
A new mechanism has been determined for the first time for the passive transport of biomolecules through the nuclear pore complex. The work was published in the journal Nature Communications in August 2022.
The research team developed their NPC model through supercomputer simulations on the Frontera and Stampede2 systems of the Texas Advanced Computing Center (TACC) — and hope their work will help guide the development of future therapeutics.
“Our main finding is that a mesh-like interior of the nuclear pore exhibits a switch-over behavior based on protein size changing from a soft barrier for small proteins to a hard barrier beyond a certain threshold, essentially making it very difficult for proteins to get through,” said study co-author David Winogradoff.

New research in Zambia finds that children infected with HIV are significantly more likely to do worse in neurological assessments despite having well-controlled HIV disease, suggesting that they may struggle with cognitive and mental health issues. However, the research also indicates that early intervention — in the form of better nutrition and antiretroviral therapies — may help close the gap.
“HIV remains a major global health burden and children who are exposed to the virus during childbirth are known to be at greater risk for neurocognitive and psychiatric problems, like depression, as they age,” said David Bearden, M.D., assistant professor of Neurology and Pediatrics at the University of Rochester Medical Center (URMC) and senior author of the study, which appears in the Journal of Acquired Immune Deficiency Syndromes. “This research is an attempt to understand if these problems persist and become more pronounced over time, and whether we can predict who will do well cognitively and who will not.”
The study is the most recent example of a decades-long collaboration involving an international team of researchers. Since 1994, URMC neurologist Gretchen Birbeck, M.D., has partnered with the Government of Zambia and clinicians and researchers with the University Teaching Hospital (UTH) in Lusaka, Zambia to study neurological problems associated with infectious diseases like HIV and malaria, which remain major public health problems in sub-Saharan Africa.
The Neurology Research Office established by Birbeck on the main hospital campus now serves as a hub for several National Institutes of Health-funded research and training programs that have helped grow the number of UTH neurologists and clinical research staff and increase opportunities to collaborate with URMC neurologists, medical students, and trainees. The new findings come from the HIV-Associated Neurocognitive Disorders in Zambia (HANDZ) study, an ongoing longitudinal study that is following a cohort of 600 HIV positive and negative Zambian children ages 8 to 18 for 5 years.
With approximately 70 percent of global cases, Sub-Saharan Africa is disproportionately impacted by HIV. While combination antiretroviral therapy (cART) is widely accessible, many infected children still go on to experience associated neurocognitive and psychiatric deficits, such as delayed academic development and depression.
Participants in the HANDZ study were asked to complete a series of neurocognitive assessments, using an instruments called the NIH Toolbox Cognition Battery, which measure several cognitive processes, including processing speed, reaction time, memory, and executive function. They found that HIV positive children on cART did significantly worse on the cognitive measures at baseline and did not improve over the two-year study period, compared to their HIV negative peers.
The data suggests interventions that could improve neurological function. Children who were malnourished or who suffered more severe cases of HIV infection did worse on the assessments.
“These findings suggest that one of the most important thing that we can do is find kids with HIV early and get them on antiretroviral therapy, because if kids don’t get real sick from HIV, then they do much better cognitively,” said Bearden. “The other key factor here is the nutritional piece and we’re doing more research to try to figure out exactly what kind of support could help improve cognition or prevent cognitive impairment in this population.”
Additional co-authors of the study include Gauri Patil, Hannah Smith, Alexandra Buta, Heather Adams, Michael Potchen, Brent Johnson, Giovanni Schifitto, and Handy Gelbard with URMC, and Esau Mbewe and Pelekelo Kabundula with the University of Zambia, and Milimo Mweemba with the University Teaching Hospital, Lusaka. The research was supported by funding from the National Institute of Neurological Disorders and Stroke, the University of Rochester Center for AIDS Research, and the University of Rochester School of Medicine.
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Materials provided by University of Rochester Medical Center. Original written by Mark Michaud. Note: Content may be edited for style and length.

Researchers from the University of Maryland Center for Environmental Science have released a first-of-its-kind study quantifying cropland phosphorus budgets around the world, which will help in identifying nutrient management gaps in different regions in food production and consumption systems. This new database will help countries and regions to evaluate their performances in addressing phosphorus pollution and scarcity challenges, and guide actions towards a more sustainable future.
“To address these management challenges, it is critical to use phosphorus more efficiently in agriculture,” said lead study author Tan Zou. “Knowing these gaps and potential drivers can help to guide the development and implementation of best management practices, such as soil testing and specialized fertilizers that are better absorbed by crops.”
Phosphorus is an essential nutrient for crops and living organisms, but excess phosphorus running off of agricultural fields and into bodies of water has led to harmful algal blooms and low oxygen zones that are detrimental to aquatic ecosystems. Poor nutrient management can lead to nutrient waste, loss, or shortage, resulting in social and environmental problems such as environmental pollution and crop yield reduction.
“The dominant global challenge is to enhance crop yield while bringing human disturbance of phosphorus cycles back to the planetary boundary,” said Zou. “This could be achieved by developing and implementing more efficient nutrient management practices and allocating production and input resources to regions with higher phosphorus use efficiency levels.”
While many efforts have been devoted to improving nutrient management practices on farms, few studies have examined the historical trends of phosphorus use efficiency (PUE) and their socioeconomic and agronomic drivers on a national scale. This is the first study to present a unique database of agricultural phosphorus budgets and phosphorus use efficiency by country, year, and crop type, examining the significant contribution of several socioeconomic drivers and discussing phosphorus management challenges and opportunities in croplands by country.
Phosphorus management challenges and opportunities in croplands vary widely among countries and are related to multiple socioeconomic and agronomic factors, such as economic development stage, nitrogen use efficiency, and farm size. Recent levels of phosphorus loss from cropland have exceeded a proposed planetary boundary, highlighting the need for more efficient use of phosphorus fertilizer in order to reduce the environmental damage of phosphorus while securing future food supplies. To meet the predicted food demand in 2050,while bringing the phosphorus surplus level below the planetary boundary, global phosphorus use efficiency needs to be improved to about 70-80%.
“While nutrient management practices are typically carried out on farms, decisions by stakeholders along the food supply chain largely determine which crops are being produced and how much is lost from the farm to the fork,” said co-author and UMCES Professor Eric Davidson.
The challenge of phosphorus scarcity is more concerning for countries that have very limited reserves, such as India and Mexico. All countries that rely upon imported fertilizers need to consider their vulnerability to geopolitical events, such as those in Ukraine today, that could affect fertilizer and food trade and identify alternative sources.
“The price of phosphorus and nitrogen fertilizer is at an all-time high, potentially exacerbating the ‘too much, too little’ dilemma. While part of the world is applying ‘too much’ nutrient fertilizers causing pollution, the other part of the world is struggling with the lack of accessible and affordable fertilizer to support the production of basic nutrition needs by the population. Addressing such dilemma is essential for achieving Sustainable Development Goals and requires collaboration across countries,” said co-author and UMCES Associate Professor Xin Zhang.
By examining historical trajectories of phosphorus budgets for crop production by country and crop type in the past five decades, this work demonstrates a common trajectory of phosphorus use efficiency as countries develop their economies and intensify crop production. This study fills those research gaps in phosphorus use efficiency studies to inform policymaking for tackling the challenges that come with phosphorus pollution and scarcity.
“Global Trends of Cropland Phosphorus Use and Sustainability Challenges” was published in Nature by Tan Zou, Xin Zhang, and Eric Davidson of the University of Maryland Center for Environmental Science.

The study, published today (12 October) in Nature, is the largest ever genome-wide association study, using the DNA of over 5 million people from 281 contributing studies. It plugs a sizeable gap in our understanding of how our genetic differences account for differences in height. Over 1 million of the study’s participants are of non-European — African, East Asian, Hispanic or South Asian — ancestry.
The 12,111 variants, which cluster around parts of the genome associated with skeletal growth, provide a powerful genetic predictor for height. The variants identified explain 40% of the variation in height for people of European ancestry, and around 10-20% for those of non-European ancestry.
Adult height is mostly determined by the information encoded in our DNA — children from tall parents tend to be taller and those from short parents are shorter, but these estimates aren’t perfect. Growth from a small baby into an adult, and the role genetics play in this, have traditionally been a complex and poorly understood area of human biology. Previously, the largest genome-wide association study looking at height used a sample size of up to 700,000 individuals, the current sample is about seven times more than previous studies.
The unprecedented scale of the research provides new levels of detail and biological insight as to why people are tall or short, with heritability being linked to various specific genomic regions. The findings show that genetic variants associated with height are concentrated in regions covering just over 20% of the genome.
The study’s findings could help doctors to identify people who are not able to reach their genetically predicted height, which may then aid in the diagnosis of hidden diseases or conditions that may be stunting their growth or impacting their health. The research also provides a valuable blueprint on how it could be possible to use genome-wide studies to identify a disease’s biology and subsequently its hereditary components.
Greater genomic diversity needed
While this study has a large number of participants from non-European ancestries compared to previous studies, the researchers emphasise the need for more diversity in genomic research.

Regulators authorized the shots for older age groups in late August, but much of the general population appears either unaware or uninterested in them.WASHINGTON — Federal regulators on Wednesday broadened access to updated coronavirus booster shots to include children as young as 5, hoping to bolster protection against the now-dominant version of the virus.The revised shot developed by Pfizer-BioNTech previously had been cleared for those 12 and older, while Moderna’s updated booster was available only to those 18 and older. The Food and Drug Administration’s action will expand access to Pfizer’s shot to children as young as 5, and to Moderna’s shot to children 6 and older.“Since children have gone back to school in person and people are resuming prepandemic behaviors and activities, there is the potential for increased risk of exposure to the virus,” said Dr. Peter Marks, the agency’s top vaccine regulator. While Covid-19 is typically less severe in children than adults, he said, “more children have gotten sick with the disease and have been hospitalized” as the pandemic has progressed.The new boosters are authorized for administration at least two months after a child has completed the initial two-shot series or received a booster dose. Regulators authorized the shots for older age groups in late August, but much of the general population appears either unaware or uninterested in them.Dr. Ashish K. Jha, the White House Covid-19 coordinator, estimated on Tuesday that 13 million to 15 million Americans had received the updated shots through last weekend. Nearly 226 million people have received the initial two-dose series, and more than 110 million have received at least one booster shot.Dr. Rochelle P. Walensky, the director of the Centers for Disease Control and Prevention, is expected to quickly approve distribution of the shots. Moderna’s updated shots would then speedily become available for children at tens of thousands of sites, while Pfizer’s shots will be available next week, federal officials said.