Cisplatin and carboplatin — which have been approved for more than 30 years — are widely used to treat a variety of cancers, including lung, head and neck, breast, bladder, ovarian, uterine, and testicular cancers. When the FDA announced a shortage of cisplatin in February 2023, followed by a shortage of carboplatin in April 2023, it drew attention to the ongoing challenge of generic drug shortages, and prompted major national oncology societies to recommend best practices for priority use and alternative medicines.

“At the time, national surveys showed that most cancer centers in the US were reporting shortages of these platinum chemotherapies, but it wasn’t clear how the shortages were actually affecting patients,” said lead author Jacob B. Reibel, MD, a third-year fellow in Hematology-Oncology. “When we looked at the data on prescribing practices over the shortage period, compared to the previous year, we found that although reporting of the shortages was widespread, it didn’t affect as many patients as we had feared.”

Reibel, senior author Ronac Mamtani, MD, section chief of Genitourinary Cancers, and colleagues, analyzed data from 11,797 adults across the U.S. with advanced solid cancers for which platinum chemotherapy is recommended as the first line of therapy and who began treatment during the one-year period before or during the platinum chemotherapy shortage. Because cisplatin and carboplatin were prioritized for patients with curable cancers during the shortage, the researchers expected that patients with advanced cancers would be most affected by drug availability.

From February 2023 through January 2024, there was a 2.7 percent decrease in platinum chemotherapy use compared to the previous year. This translates into 137 fewer patients in this advanced cancer cohort receiving platinum chemotherapy than expected, and the researchers estimate about 1,000 patients affected overall in the US, based on the rates observed in the study. At the peak of the shortage in June 2023, the decrease was 15.1 percent compared to the previous year. With a median follow-up time of 7.6 months after beginning treatment, there was no difference in mortality compared to the previous year.

Alternative therapies help mitigate the crisis, but are not first choice

The researchers hypothesized that the limited impact on mortality was likely due to the use of effective alternative medications recommended by medical societies, such as immune checkpoint inhibitors, targeted therapy or other forms of chemotherapy. The study did not assess the potential drawbacks of alternative medications, including the financial burden of more expensive non-generic alternatives and side effects of different drugs.

“We always want to prioritize the best treatments that we have for patients, and platinum chemotherapies just happen to also be very cost-effective because they’re generic and have been around for decades,” Mamtani said. “While the alternative options may be effective, we want to be able to provide the ‘standard-of-care’ medications to any patient in need. Even one hundred patients who can’t get the preferred chemotherapy for their cancer type due to supply chain issues is far too many.”

The FDA listed the cisplatin shortage as resolved at the end of June 2024 and carboplatin remains on the shortage list, though the research team found prescribing levels have returned to normal.

The study was funded by the National Institutes of Health (T32CA009679).

The findings, published in the Journal of Clinical Oncology, show that a diet low in omega-6 and high in omega-3 fatty acids, combined with fish oil supplements, significantly reduced the growth rate of prostate cancer cells in men with early-stage disease.

“This is an important step toward understanding how diet can potentially influence prostate cancer outcomes,” said Dr. William Aronson, Professor of Urology at the David Geffen School of Medicine at UCLA and first author of the study. “Many men are interested in lifestyle changes, including diet, to help manage their cancer and prevent the progression of their disease. Our findings suggest that something as simple as adjusting your diet could potentially slow cancer growth and extend the time before more aggressive interventions are needed.”

Many men with low-risk prostate cancer choose active surveillance over immediate treatment, however, within five years, about 50% of these men eventually need to undergo therapy with either surgery or radiation. Because of this, patients are eager to find ways to delay the need for treatment, including through dietary changes or supplements. However, specific dietary guidelines in this area have yet to be established. While other clinical trials have looked at increasing vegetable intake and healthy diet patterns, none have found a significant impact on slowing cancer progression.

To determine whether diet or supplements can play a role in managing prostate cancer, the UCLA-led team conducted a prospective clinical trial, called CAPFISH-3, that included 100 men with low risk or favorable intermediate risk prostate cancer who chose active surveillance. Participants were randomly assigned to either continue their normal diet or follow a low omega-6, high omega-3 diet, supplemented with fish oil, for one year.

Participants in the intervention arm received dietary personalized counseling by a registered dietician nutritionist, either in-person, through telehealth or by phone. Patients were guided on healthier, lower fat alternatives for high fat/high calorie foods (such as using olive oil or lemon and vinegar for salad dressing), and on reducing consumption of foods with higher omega-6 content (such as, chips, cookies, mayonnaise and other fried or processed foods). The goal was to create a favorable balance of their intake of omega-6 and omega-3 fats and make participants feel empowered to control how they change their behavior. They were also given fish oil capsules for extra omega-3s. The control group did not get any dietary counseling or take fish oil capsules.

The researchers tracked changes in a biomarker called the Ki-67 index, which indicates how fast cancer cells are multiplying — a key predictor of cancer progression, metastasis and survival.

Same site biopsies were obtained at the start of the study and again after the one-year mark, using an image fusion device that helps track and locate the cancer sites.

Results showed that the low omega-6, omega-3 rich diet and fish oil group had a 15% decrease in the Ki-67 index, while the control group saw a 24% increase.

“This significant difference suggests that the dietary changes may help slow cancer growth, potentially delaying or even preventing the need for more aggressive treatments,” said Aronson, who is also the Chief of urologic oncology at the West Los Angeles Veterans Affairs Medical Center and member of the UCLA Health Jonsson Comprehensive Cancer Center.

While the results are promising, researchers did not find any differences in other cancer growth markers, such as Gleason grade, which are commonly used to track prostate cancer progression.

The investigators caution that further research is necessary to confirm the long-term benefits of omega-3 fatty acids and lowering omega-6 in managing prostate cancer. The findings support further, larger trials to explore the long-term impact of dietary changes on cancer progression, treatment outcomes and survival rates in men on active surveillance.

The study’s senior author is Dr. Susanne Henning, adjunct professor emerita and former director of the nutritional biomarker laboratory at the Center for Human Nutrition at UCLA. Other UCLA co-authors are Tristan Grogan, Dr. Pei Liang, Patricia Jardack, Amana Liddell, Claudia Perez, Dr. David Elashoff, Dr. Jonathan Said and Dr. Leonard Marks.

The study was funded in part by the National Cancer Institute, the UCLA Health Jonsson Comprehensive Cancer Center, Howard B. Klein and the Seafood Industry Research Fund.

In a study published in Nature Communications, Lewis Zhichang Shi, M.D., Ph.D., and University of Alabama at Birmingham colleagues show, for the first time, how HIF1α in T cells is key for induction of interferon gamma, or IFN-γ, in that hypoxic environment. The cytokine IFN-γ is known to be essential to induce the tumor-killing capacity of T cells. Additionally, an alternative metabolism called glycolysis, which is able to produce energy in human cells when no oxygen is present, is similarly known to be required for IFN-γ induction in T cells.

“Intriguingly, under normal oxygen levels in the body, called normoxia, IFN-g induction and glycolysis in T cells are not mediated by HIF1α, a primary regulator of glycolysis, but by its widely regarded downstream target LDHa, as reported in an early study by another group,” said Shi, a professor in the UAB Department of Radiation Oncology. “However, it has been unknown, under hypoxia, whether and how HIF1α regulates IFN-γ induction and glycolysis in T cells.”

The UAB researchers found that HIF1α-glycolysis is indispensable for IFN-γ induction in hypoxic T cells. HIF1α is a subunit of HIF, or hypoxia-inducible factor, that is known to play a crucial role in orchestrating cellular responses to hypoxia.

Shi and colleagues showed this key role for HIF1α in hypoxia by combining genetic mouse models, metabolic flux analysis using ¹³C-labeled glucose tracing assays and a Seahorse analyzer, as well as pharmacological approaches.

In both human and mouse T cells that were activated under hypoxia, they found that the deletion of HIF1α from the T cells prevented the metabolic reprogramming shift from catabolic metabolism to anabolic metabolism, of which anaerobic glycolysis is a major component; the deletion also suppressed the induction of IFN-γ. Additionally, pharmacologic inhibition of T cell glycolysis under hypoxia prevented induction of IFN-γ. Conversely, stabilization of HIF1α by knocking out a negative regulator of HIF1α increased IFN-γ under hypoxic conditions.

With regard to defense against cancer, the researchers found that hypoxic T cells deleted for HIF1α were less able to kill tumor cells in vitro. In vivo, tumor-bearing mice that had the HIF1α-deleted in T cells did not respond to ICB therapy.

The researchers then showed a way to overcome that resistance to ICB therapy. Elucidation of the mechanistic function of the HIF1α deletion showed that loss of HIF1α greatly diminished glycolytic activity in hypoxic T cells, resulting in depleted intracellular acetyl-CoA and attenuated activation-induced cell death, or AICD. Restoration of intracellular acetyl-CoA by supplementing growth media with acetate reengaged AICD and rescued IFN-γ production for hypoxic Hif1α-deletion T cells.

Shi and colleagues then demonstrated, in living mice, that acetate supplementation was an effective strategy to bypass ICB resistance in tumor-bearing mice with specific deletion of HIF1α in T cells. When Hif1α-deletion tumor-bearing mice were given acetate supplementation followed by combination ICB therapy, the mice had significant improvement in ICB therapy, as seen by potent suppression of tumor growth and greatly reduced tumor weights.

“TILs and tumor cells utilize the same metabolic pathways for their growth and function, and co-live in the metabolically harsh tumor-microenvironments characterized by hypoxia and poor nutrition, placing them in a fierce metabolic tug-of-war,” Shi said. “How to tilt this metabolic battle to favor TILs would be key, and we showed that acetate supplementation restored IFN-γ production in Hif1α-deletion-TILs and overcame ICB resistance derived from HIF1α loss in T cells.”

“Our study, together with an early report by others, compellingly shows that the impaired HIF1α function in T cells is a major T cell-intrinsic mechanism of therapeutic resistance to ICBs, like anti-CTLA-4 and anti-PD-1/L1,” Shi said.

Co-authors with Shi in the study, “HIF1α-regulated glycolysis promotes activation-induced cell death and IFN-γ induction in hypoxic T cells,” are Hongxing Shen, Oluwagbemiga A. Ojo, Haitao Ding, Chuan Xing, Abdelrahman Yassin, Vivian Y. Shi, Zach Lewis, Ewa Podgorska and James A. Bonner, UAB Department of Radiation Oncology; Logan J. Mullen, University of Alaska Fairbanks, Fairbanks, Alaska; M. Iqbal Hossain and Shaida A. Andrabi, UAB Department of Pharmacology and Toxicology; and Maciek R. Antoniewicz, University of Michigan, Ann Arbor, Michigan.

Support came from UAB; the O’Neal Comprehensive Cancer Center at UAB; National Institutes of Health grants CA230475-01A1, CA25972101A1 and CA279849-01A1; V Foundation Scholar Award V2018-023; Department of Defense-Congressionally Directed Medical Research Programs grant ME210108; and Cancer Research Institute CLIP Grant CRI4342.

At UAB Radiation Oncology and Pharmacology and Toxicology are departments in the Marnix E. Heersink School of Medicine. Shi is a scientist in the O’Neal Comprehensive Cancer Center and holds the Koikos-Petelos-Jones-Bragg ROAR Endowed Professorship for Cancer Research.

The study, which was published Dec. 13 in the print edition of the journal Patterns and featured on the journal’s cover, describes a computer program named PlacentaVision that can analyze a simple photograph of the placenta to detect abnormalities associated with infection and neonatal sepsis, a life-threatening condition that affects millions of newborns globally.

“Placenta is one of the most common specimens that we see in the lab,” said study co-author Dr. Jeffery Goldstein, director of perinatal pathology and an associate professor of pathology at Northwestern University Feinberg School of Medicine. “When the neonatal intensive care unit is treating a sick kid, even a few minutes can make a difference in medical decision making. With a diagnosis from these photographs, we can have an answer days earlier than we would in our normal process.”

Northwestern provided the largest set of images for the study, and Goldstein led the development and troubleshooting of the algorithms.

Alison D. Gernand, contact principal investigator on the project, conceived the original idea for this tool through her global health work, particularly with pregnancies where women deliver in their homes due to lack of health care resources.

“Discarding the placenta without examination is a common but often overlooked problem,” said Gernand, associate professor in the Penn State College of Health and Human Development (HHD) Department of Nutritional Sciences. “It is a missed opportunity to identify concerns and provide early intervention that can reduce complications and improve outcomes for both the mother and the baby.”

Why early examination of the placenta matters

The placenta plays a vital role in the health of both the pregnant individual and baby during pregnancy, yet it is often not thoroughly examined at birth, especially in areas with limited medical resources.

“This research could save lives and improve health outcomes,” said Yimu Pan, a doctoral candidate in the informatics program from the College of Information Sciences and Technology (IST) and lead author on the study. “It could make placental examination more accessible, benefitting research and care for future pregnancies, especially for mothers and babies at higher risk of complications.”

Early identification of placental infection through tools like PlacentaVision might enable clinicians to take prompt actions, such as administering antibiotics to the mother or baby and closely monitoring the newborn for signs of infection, the scientists said.

PlacentaVision is intended for use across a range of medical demographics, according to the researchers.

“In low-resource areas — places where hospitals don’t have pathology labs or specialists — this tool could help doctors quickly spot issues like infections from a placenta,” Pan said. “In well-equipped hospitals, the tool may eventually help doctors determine which placentas need further, detailed examination, making the process more efficient and ensuring the most important cases are prioritized.”

“Before such a tool can be deployed globally, core technical obstacles we faced were to make the model flexible enough to handle various diagnoses related to the placenta and to ensure that the tool can be robust enough to handle various delivery conditions, including variation in lighting conditions, imaging quality and clinical settings” said James Z. Wang, distinguished professor in the College of IST at Penn State and one of the principal investigators on the study. “Our AI tool needs to maintain accuracy even when many training images come from a well-equipped urban hospital. Ensuring that PlacentaVision can handle a wide range of real-world conditions was essential.”

How the tool learned how to analyze pictures of placentas

The researchers used cross-modal contrastive learning, an AI method for aligning and understanding relationship between different types of data — in this case, visual (images) and textual (pathological reports) — to teach a computer program how to analyze pictures of placentas. They gathered a large, diverse dataset of placental images and pathological reports spanning a 12-year period, studied how these images relate to health outcomes and built a model that could make predictions based on new images. The team also developed various image alteration strategies to simulate different photo-taking conditions so the model’s resilience can be evaluated properly.

The result was PlacentaCLIP+, a robust machine-learning model that can analyze photos of placentas to detect health risks with high accuracy. It was validated cross-nationally to confirm consistent performance across populations.

According to the researchers, PlacentaVision is designed to be easy to use, potentially working through a smartphone app or integrated into medical record software so doctors can get quick answers after delivery.

Next step: A user-friendly app for medical staff

“Our next steps include developing a user-friendly mobile app that can be used by medical professionals — with minimal training — in clinics or hospitals with low resources,” Pan said. “The user-friendly app would allow doctors and nurses to photograph placentas and get immediate feedback and improve care.”

The researchers plan to make the tool even smarter by including more types of placental features and adding clinical data to improve predictions while also contributing to research on long-term health. They’ll also test the tool in different hospitals to ensure it works in a variety of settings.

“This tool has the potential to transform how placentas are examined after birth, especially in parts of the world where these exams are rarely done,” Gernand said. “This innovation promises greater accessibility in both low- and high-resource settings. With further refinement, it has the potential to transform neonatal and maternal care by enabling early, personalized interventions that prevent severe health outcomes and improve the lives of mothers and infants worldwide.”

This research was supported by the National Institutes of Health National Institute of Biomedical Imaging and Bioengineering (grant R01EB030130). The team used supercomputing resources from the National Science Foundation-funded Advanced Cyberinfrastructure Coordination Ecosystem: Services & Support (ACCESS) program.

The jet coming out of the center of M87 is seven orders of magnitude — tens of millions of times — larger than the event horizon, or surface of the black hole itself. The bright burst of high-energy emission was well above the energies typically detected by radio telescopes from the black hole region. The flare lasted about three days and probably emerged from a region less than three light-days in size, or a little under 15 billion miles.

A gamma ray is a packet of electromagnetic energy, also known as a photon. Gamma rays have the most energy of any wavelength in the electromagnetic spectrum and are produced by the hottest and most energetic environments in the universe, such as regions around black holes. The photons in M87’s gamma ray flare have energy levels up to a few teraelectronvolts. Teraelectronvolts are used to measure the energy in subatomic particles and are equivalent to the energy of a mosquito in motion. This is a huge amount of energy for particles that are many trillion times smaller than a mosquito. Photons with several teraelectronvolts of energy are vastly more energetic than the photons that make up visible light.

As matter falls toward a black hole, it forms an accretion disk where particles are accelerated due to the loss of gravitational potential energy. Some are even redirected away from the black hole’s poles as a powerful outflow, called “jets,” driven by intense magnetic fields. This process is irregular, which often causes a rapid energy outburst called a “flare.” However, gamma rays cannot penetrate Earth’s atmosphere. Nearly 70 years ago, physicists discovered that gamma rays can be detected from the ground by observing the secondary radiation generated when they strike the atmosphere.

“We still don’t fully understand how particles are accelerated near the black hole or within the jet,” said Weidong Jin, a postdoctoral researcher at UCLA and a corresponding author of a paper describing the findings published by an international team of authors in Astronomy & Astrophysics. “These particles are so energetic, they’re traveling near the speed of light, and we want to understand where and how they gain such energy. Our study presents the most comprehensive spectral data ever collected for this galaxy, along with modeling to shed light on these processes.”

Jin contributed to analysis of the highest energy part of the dataset, called the very-high-energy gamma rays, which was collected by VERITAS — a ground-based gamma-ray instrument operating at the Fred Lawrence Whipple Observatory in southern Arizona. UCLA played a major role in the construction of VERITAS — short for Very Energetic Radiation Imaging Telescope Array System — participating in the development of the electronics to read out the telescope sensors and in the development of computer software to analyze the telescope data and to simulate the telescope performance. This analysis helped detect the flare, as indicated by large luminosity changes that are a significant departure from the baseline variability.

More than two dozen high-profile ground- and space-based observational facilities, including NASA’s Fermi-LAT, Hubble Space Telescope, NuSTAR, Chandra and Swift telescopes, together with the world’s three largest imaging atmospheric Cherenkov telescope arrays (VERITAS, H.E.S.S. and MAGIC) joined this second EHT and multi-wavelength campaign in 2018. These observatories are sensitive to X-ray photons as well as high-energy and very-high-energy gamma-rays, respectively.

One of the key datasets used in this study is called spectral energy distribution.

“The spectrum describes how energy from astronomical sources, like M87, is distributed across different wavelengths of light,” Jin said. “It’s like breaking the light into a rainbow and measuring how much energy is present in each color. This analysis helps us uncover the different processes that drive the acceleration of high-energy particles in the jet of the supermassive black hole.”

Further analysis by the paper’s authors found a significant variation in the position and angle of the ring, also called the event horizon, and the jet position. This suggests a physical relationship between the particles and the event horizon, at different size scales, influences the jet’s position.

“One of the most striking features of M87’s black hole is a bipolar jet extending thousands of light years from the core,” Jin said. “This study provided a unique opportunity to investigate the origin of the very-high-energy gamma-ray emission during the flare, and to identify the location where the particles causing the flare are being accelerated. Our findings could help resolve a long-standing debate about the origins of cosmic rays detected on Earth.”

Cancer immunotherapy has revolutionised treatment for patients, whereby the body’s own immune system is harnessed to destroy cancer cells.

Typically, several molecules restrain the ability of T cells to target cancer cells and developing approaches to limit this restraining effect can lead to improved effectiveness of cancer immunotherapy.

Research published in Science Immunology has determined the structure of how an inhibitory molecule, LAG3, interacts with its main ligand and provides a new targeted approach to improving the effectiveness of immunotherapy for certain forms of cancer.

The publication is the first to show the crystal structure of a human LAG-3/HLA-II complex and provides a better foundation for development of blocking LAG-3 therapeutics.

Led by Professor Jamie Rossjohn at Monash University’s Biomedicine Discovery Institute (BDI), in Melbourne, Australia, in collaboration with Immutep, this research resolves how the human LAG-3 receptor binds to HLA II molecules.

First author Dr Jan Petersen said: “The way the PD-1 and CTLA-4 immune checkpoint molecules bind to their respective ligands has been resolved for many years.

“However, the resolution of the interface between another important checkpoint molecule, LAG-3, and its main ligands, HLA-II molecules, has remained elusive.

“Solved using data collected at the Australian Synchrotron, a structure of a LAG-3/HLA-II complex provides a structural foundation to harness rationally for future development of antibodies and small molecule therapeutics designed to block LAG-3 activity.”

Dr Frédéric Triebel, Immutep’s CSO, added: “These findings add to the strong foundation of our work with Professor Rossjohn and his team to develop a deeper understanding of the structure and function of the LAG-3 immune control mechanism, particularly as it relates to our anti-LAG-3 small molecule program.”

The struggle of our cells

Imagine trying to fit two meters of rope into a space much smaller than the tip of a needle — that’s the challenge every cell in your body faces when packing its DNA into its tiny nucleus. To achieve this, nature employs ingenious strategies, like twisting the DNA into coils of coils, so-called ‘supercoils’ (see pictures for a visualisation) and wrapping it around special proteins for compact storage.

Small DNA loops regulate chromosome functions

However, compaction isn’t enough. Cells also need to regulate the chromosome structure to enable its function. For example, when genetic information needs to be accessed, the DNA is locally read off. In particular when it’s time for a cell to divide, the DNA must first unpack, duplicate, and then properly separate into two new cells. Specialised protein machines called SMC complexes (Structural Maintenance of Chromosomes) play a critical role in these processes. Just a few years ago, scientists at Delft and other places discovered that these SMC proteins are molecular motors that make long loops in our DNA, and that these loops are the key regulators of chromosome function.

A new twist

In the lab of Cees Dekker at TU Delft, postdocs Richard Janissen and Roman Bath now provide clues that help to crack this puzzle. They deloped a new way to use ‘magnetic tweezers’ by which they could watch individual SMC proteins make looping steps in DNA. Importantly, they were also able to resolve if the SMC protein would change the twist in the DNA. And strikingly, the team found that it did: the human SMC protein cohesin does indeed not only pull DNA into a loop, but also twists the DNA in a left-handed way by 0.6 turns in each step of creating the loop.

A glimpse into the evolution of SMC proteins

What’s more, the team found that this twisting action isn’t unique to humans. Similar SMC proteins in yeast behave the same way. Strikingly, all the various types of SMC proteins from human and yeast add the same amount of twist — they turn DNA 0.6 times at every at every DNA loop extrusion step. This shows that the DNA extrusion and twisting mechanisms stayed the same for very long times during evolution. No matter whether DNA is looped in humans, yeast, or any other cell — nature employs the same strategy.

Essential clues

These new findings will provide essential clues for resolving the molecular mechanism of this new type of motor. Additionally, they make clear that DNA looping also affects the supercoiling state of our chromosomes, which directly affects processes like gene expression. Finally, these SMC proteins are related to various diseases such as Cornelia de Lange Syndrome, and a better understanding of these processes is vital for tracking down the molecular origins of these serious illnesses.