“Therapies that use the patient’s immune system to fight their disease have a lot of potential to change how patients are treated. However, one of the biggest problems in the field right now is that these immunotherapies work well only in a small fraction of patients,” Elise Alspach, Ph.D., assistant professor of molecular microbiology and immunology at SLU, senior author on the paper.

Alspach and her team aimed to understand what determines good T-cell responses in patients, why some patients seem to have better T-cell responses than others, and why some patients respond well to immunotherapies. Research findings recently published in Cancer Immunology Research show that a protein called CXCL13 that has recently been linked to immunotherapy response in patients is more highly expressed in females than males. Additionally, Alspach and her team found that CXCL13 expression is a better marker of immunotherapy response in females than in males.

Alspach and her team used single-cell RNA sequencing in human datasets to understand more about differences in how male and female immune systems respond to tumors. Single-cell RNA sequencing allows scientists to learn what’s happening inside individual cells. Using this technology, Alspach and her team determined that T-cells that infiltrate female tumors are highly activated and ready to identify tumor cells and kill them. They also noted immune suppressive T-cells present more frequently in male tumors than in female tumors.

Alspach and her team discovered that there is growing evidence that the male sex is associated with a better response to immunotherapy, which she said appears to contrast with their work and recently published papers showing that females mount stronger immune responses against their tumors.

“We currently don’t understand why males would respond better than females to immune targeting therapies, but this interesting juxtaposition highlights the need for more research into the variable of sex in the immune response against cancer,” Alspach said.

Alspach said the potential of immunotherapy is revolutionary as it mediates tumor rejection in patients and induces long-term remission.

“When we get infected with a virus, the immune system generates a population of cells that can remember that virus and do a better job of eliminating it from your body, so the immune system does the same thing against tumors,” she said. “The memory response against that tumor partly generates long-term remissions that we see in patients treated with immunotherapies.”

Before the advent of immunotherapies, Alspach said cancer treatments were hard on the body and not tumor-specific or, in the case of small molecule drugs that targeted specific proteins inside tumor cells, frequently become resistant to therapies. Current immunotherapies are typically much better tolerated in more patients, and patients can maintain a higher quality of life because the immune system can be educated to specifically target the tumor rather than all the tissues in the body.

Because immune responses against tumors are different between the sexes, Alspach and her colleagues concluded that it makes sense to potentially design different treatments for male versus female patients. In the future, she hopes more appropriate therapeutic strategies will be devised to target the pathways that mediate better tumor control in ways that benefit individual patients.

This research was possible thanks to a recent investment in single-cell RNA sequencing technology at Saint Louis University, allowing researchers to bring us closer to new cures.

Additional authors include Richard J. DiPaolo, Ph.D.; Ryan M. Teague, Ph.D.; Michelle Brennan, Ph.D.; David DeBruin; Chinye Nwokolo; Katey S. Hunt; Alexander Piening; Maureen J. Donlin; and Stephen T. Ferris, Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine.

The approach, detailed in the journal Cell Stem Cell, uses patients’ own tumor cells that replicate the unique characteristics of a patient’s tumor allowing scientists to quickly screen a large number of drugs in order to identify personalized treatments that can target this rare and diverse group of cancers.

“Sarcoma is a rare and complex disease, which makes conducting clinical trials to identify effective treatments particularly challenging. Some of the rarer subtypes lack standard treatment altogether. Even when multiple therapy options are available, there is often no reliable, data-driven method to determine the best course of action for an individual patient. Choosing the most effective treatment is akin to searching for a needle in a haystack,” said Dr. Alice Soragni, the senior author of the study and assistant professor in the department of Orthopaedic Surgery at the David Geffen School of Medicine at UCLA. “Testing drugs with patient-derived tumor organoids has potential to help predict how a patient may respond to treatment, with the goal of improving patient outcomes for diseases where treatment options are often limited.”

While sarcomas, which can develop in the bones or soft tissues like muscles and adipose tissue, only account for less than 1% of all cancers, they carry a high mortality rate, particularly among young people. The rarity and diversity of sarcoma types — more than 100 distinct subtypes — makes them particularly difficult to study. Responses to conventional therapies can vary widely between patients, making it challenging to determine the most effective course of action for each individual.

To determine whether organoids could enhance the understanding of how a patient’s tumor might respond to specific drugs or combinations, the team assembled a biobank of 294 samples from 126 UCLA patients diagnosed with 25 different subtypes of bone and soft tissue sarcoma. While tumor organoids have been widely used to study carcinomas, this study is the first of its scale to extend organoid development to sarcoma.

The team successfully created tumor organoids from over 110 samples and conducted detailed histopathological and molecular analyses to confirm that the organoids retained the key characteristics of the original tumors. These organoids were then subjected to high-throughput drug screening using the mini-ring pipeline developed by Soragni and her team, enabling the testing of hundreds of drugs in a 3D format within a short timeframe.

Using this process, the team was able to identify at least one potentially effective U.S. Food and Drug Administration (FDA)-approved treatment for 59% of the samples tested. Additionally, they found the drug responses observed in the lab matched how the patients themselves responded to treatment for a small number of cases, suggesting that these organoids could be a powerful tool for guiding clinical decisions.

“We’ve shown that it’s possible to generate sarcoma organoids quickly — within a week after surgery or biopsy — and use them to screen a large number of drugs, including FDA-approved therapies and other treatments currently in clinical trials,” said Soragni.

“This gives us the ability to identify which drugs are most likely to work for a particular patient, which is crucial for a disease as complex as sarcoma, where genomic precision medicine has often fallen short,” added study author Dr. Noah Federman, the Glaser Family Endowed Chair and director of the UCLA Health Jonsson Comprehensive Cancer Center’s Pediatric Bone and Soft Tissue Sarcoma Program.

In addition, the study demonstrated that a large-scale, functional precision medicine program could be implemented within a single institution, offering a streamlined and scalable model for organoid-based testing.

“Organoids provide a tangible way to match patients with the most promising therapies and this could be a game-changer for sarcoma patients,” said Dr. Nicholas Bernthal, chair and executive medical director of the Department of Orthopaedic Surgery at UCLA. “We’re optimistic that this approach will lead to better, more personalized care for those who need it most.”

Following the results of this study, the UCLA team will validate the findings in a larger clinical trial that is aimed at confirming the effectiveness of the organoid-based approach in predicting treatment responses in patients with osteosarcoma, the most common type of bone cancer that mainly affects children and young adults.

Soragni, Federman and Bernthal are all members of the UCLA Health Jonsson Comprehensive Cancer Center. The study’s first authors are Ahmad Shihabi, a project scientist in the Soragni laboratory; Peyton Tebon, a visiting project scientist; and Huyen Thi Lam Nguyen, a graduate student. Other UCLA authors are Sara Sartini, Ardalan Davarifar, Alexandra Jensen, Miranda Diaz-Infante, Hannah Cox, Alfredo Enrique Gonzalez, Summer Swearingen, Helena Winata, Sorel Fitz-Gibbon, Takafumi Yamaguchi, Jae Jeong, Sarah Dry, Arun Singh, Bartosz Chmielowski, Joseph Crompton, Fritz Eilber, Scott Nelson, Paul Boutros and Jane Yanagawa.

The study was supported by grants from the National Cancer Institute, the Alan B. Slifka Foundation, David Geffen School of Medicine at UCLA and the UCLA Health Jonsson Comprehensive Cancer Center.

In findings published today (Sept. 19) in the Journal of Clinical Microbiology, the researchers report that the bacteria Salmonella enterica was detected in samples from two wastewater treatment plants in central Pennsylvania during June 2022.

“Non-typhoidal Salmonella is a common cause of gastroenteritis worldwide, but current surveillance for the disease is suboptimal, so in this research we evaluated the utility of wastewater monitoring to enhance surveillance for this foodborne pathogen,” said Nkuchia M’ikanatha, lead epidemiologist, Pennsylvania Department of Health and an affiliated researcher in Penn State’s Department of Food Science, in the College of Agricultural Sciences. “In this study, we explored wastewater monitoring as a tool to enhance surveillance for this foodborne pathogen. Wastewater testing can detect traces of infectious diseases circulating in a community, even in asymptomatic individuals, offering an early warning system for potential outbreaks.”

While health care providers are required to report salmonellosis cases, many go undetected. Salmonella bacteria, inhabiting the intestines of animals and humans, are shed in feces. The CDC estimates Salmonella causes roughly 1.35 million infections, 26,500 hospitalizations and 420 deaths annually in the U.S., primarily through contaminated food.

In June 2022, the researchers tested raw sewage samples collected twice a week from two treatment plants in central Pennsylvania for non-typhoidal Salmonella and characterized isolates using whole genome sequencing. They recovered 43 Salmonella isolates from wastewater samples, differentiated by genomic analysis into seven serovars, which are groupings of microorganisms based on similarities. Eight of the isolates, or nearly 20%, were from a rare type of Salmonella called Baildon.

The researchers assessed genetic relatedness and epidemiologic links between non-typhoidal Salmonella isolates from wastewater and similar bacteria from patients with salmonellosis. The Salmonella Baildon serovars isolated from wastewater were genetically indistinguishable from a similar bacteria found in a patient associated with a salmonellosis outbreak in the same period in the area. Salmonella Baildon from wastewater and 42 outbreak-related isolates in the national outbreak detection database had the same genetic makeup. One of the 42 outbreak-related isolates was obtained from a patient residing in the wastewater study sample collection catchment area, which serves approximately 17,000 people.

Salmonella Baildon is a rare serovar — reported in less than 1% of cases nationally over five years, noted M’ikanatha, the study’s first author. He pointed out that this research demonstrates the value of monitoring sewage from a defined population to supplement traditional surveillance methods for evidence of Salmonella infections and to determine the extent of outbreaks.

“Using whole genome sequencing, we showed that isolates of variant Salmonella Baildon clustered with those from an outbreak that occurred in a similar time frame,” he said. “Case reports were primarily from Pennsylvania, and one individual lived within the treatment plant catchment area. This study provides support for using domestic sewage surveillance in assisting public health agencies to identify communities impacted by infectious diseases.”

Ed Dudley, a professor of food science and the senior author on the study, said these findings highlight the potential of wastewater monitoring as an early warning system for foodborne disease outbreaks, potentially even before physicians and laboratories report cases. This proactive approach could enable health officials to swiftly trace the source of contaminated food, ultimately reducing the number of people affected, suggested Dudley, who also directs Penn State’s E. coli Reference Center.

“While it may not happen overnight, I foresee a future where many, if not most, domestic wastewater treatment plants contribute untreated sewage samples for monitoring evidence of various illnesses,” he said. “This would likely involve collaboration among public health agencies, academia and federal entities, much like our pilot study. I see this as yet another crucial lesson from the pandemic.”

Contributing to the research at Penn State were Jasna Kovac, associate professor of food science and Lester Earl and Veronica Casida Career Development Professor of Food Safety; Erin Nawrocki and Yezhi Fu, postdoctoral scholars in the Dudley Lab; Zoe Goldblum, undergraduate researcher in the Department of Food Science; and Nicholas Cesari, Division of Infectious Disease Epidemiology, Pennsylvania Department of Health.

The CDC, the U.S. Food and Drug Administration and the U.S. Department of Agriculture’s National Institute of Food and Agriculture provided funding for this research.

Researchers from Ann & Robert H. Lurie Children’s Hospital of Chicago and colleagues analyzed data using Emergency Medical Services (EMS) encounters from January 2018 to December 2022. They found that opioid overdoses in youth increased at pandemic onset and remained elevated compared to pre-pandemic levels. The majority (86 percent) occurred in young adults in the 18-24 age group. Adolescents aged 12-17, however, also emerged as high-risk, with significantly increasing trends both before and during the pandemic. Most of the opioid overdoses in youth (58 percent) happened at home.

“Since so many overdoses occur at home, a critical message for parents of youth, especially adolescents, is to keep naloxone, an over-the-counter medication that can reverse opioid overdoses, at home,” said lead author Jamie Lim, MD, a third-year fellow in Pediatric Emergency Medicine at Lurie Children’s. “Providers also need to screen youth for substance use and risk of opioid overdose, since it is clearly a growing concern among young people. Parents and patients need to be advised that fentanyl is now in a lot of street drugs too and can lead to accidental overdoses.”

Senior author and attending physician from Boston Children’s Hospital’s Division of Emergency Medicine, Michael Toce, MD, expands on the broader impact of the findings: “Evaluating prehospital data for opioid overdose among U.S. youth may provide crucial insights into the opioid epidemic outside of emergency department surveillance data. Although overdose rates have stabilized post-pandemic, it’s important to understand at-risk youth populations to develop better-targeted prevention strategies and inform future public health measures.”

Co-authors from Lurie Children’s include Sriram Ramgopal, MD, and Jennifer Hoffmann, MD, MS.

Several approaches have been studied to reduce the amount of Sm reagents to catalytic amounts. However, most of the currently available methods require harsh conditions and highly reactive reducing agents and still require significant amounts of Sm, typically 10-20% of the raw materials. Considering the high cost of Sm, there is a significant demand for an efficient catalyst system that uses minimal Sm under mild conditions.

In a recent breakthrough, a research team from Chiba University in Japan, led by Assistant Professor Takahito Kuribara from the Institute for Advanced Academic Research and the Graduate School of Pharmaceutical Sciences, developed an innovative method that significantly reduces the amount of Sm. The team developed a 9,10-diphenyl anthracene (DPA)-substituted bidentate phosphine oxide ligand for coordination to trivalent samarium, enabling the use of visible light to facilitate Sm-catalyzed reductive transformations. They call this ligand a visible-light antenna. Assistant Professor Kuribara explains, “Antenna ligands are known to help in the excitation of lanthanoid metals like Sm. Previously, we reported a DPA-substituted secondary phosphine oxide ligand capable of reduction-oxidation reactions under visible light. Inspired by this, we designed a new DPA-substituted bidentate phosphine oxide ligand that uses visible light to reduce the amount of Sm to a catalytic level.”

The team included Ayahito Kaneki, Yu Matsuda, and Tetsuhiro Nemoto from the Graduate School of Pharmaceutical Sciences at Chiba University. Their study was made available online on July 20, 2024, and published in Volume 146, Issue 30 of the Journal of the American Chemical Society on July 31, 2024.

Through a series of experiments, the research team showed that using the Sm catalyst in combination with DPA-1 under blue-light irradiation produced high yields of up to 98% for pinacol coupling reactions of aldehydes and ketones, which are commonly used in pharmaceuticals. Remarkably, these reactions could proceed with only 1-2 mol% of the Sm catalyst, a significant reduction compared to the stoichiometric amounts typically required. Furthermore, the reactions could proceed even with mild organic reducing agents like amines, in contrast to the highly reducing agents previously used.

The results showed that the addition of a small amount of water improved yields, while excess water inhibited the reaction. In comparison, DPA-2 and DPA, which have similar structures to DPA-1, yielded poor results.

To understand why DPA-1 was so effective, the researchers studied the emission characteristics of the Sm catalyst and DPA-1 combination. They found that DPA-1, with its visible-light antenna, functions as a multifunctional ligand that coordinates with Sm, selectively absorbs blue light, and efficiently transfers electrons from the antenna to Sm.

The researchers successfully applied the Sm catalyst and DPA-1 combination to various molecular transformation reactions, including carbon-carbon bond formation and carbon-oxygen and carbon-carbon bond cleavage, which are crucial for drug development. Moreover, by utilizing visible light as an energy source, they also achieved molecular transformations that combined Sm-based reduction with photo-oxidation.

“Our new visible-light antenna ligand reduced the amount of Sm to 1-2 mol%, a significant decrease compared to the stoichiometric amounts typically required, by utilizing low-energy visible light,” remarks Assistant Professor Kuribara. Adding further, he says, “Importantly, we were able to use trivalent Sm as the starting material, which is more stable and easier to handle as compared to divalent Sm.”

Overall, this study provides valuable insights for further development and design of Sm-based catalysts, marking a significant step forward in organic chemistry by enabling efficient Sm-catalyzed reductive transformations under mild conditions with minimal Sm loading.