They also found a way to deliver immunotherapy’s cancer-killing impact without the unwelcome side effect.

The findings are published in Science.

“This is a good example of how understanding a mechanism helps you to develop an alternative therapy that’s more beneficial. Once we identified the mechanism causing the colitis, we could then develop ways to overcome this problem and prevent colitis while preserving the anti-tumor effect,” said senior study author Gabriel Nunez, M.D., Paul de Kruif Professor of Pathology at Michigan Medicine.

Immunotherapy has emerged as a promising treatment for several types of cancer. But immune checkpoint inhibitors can also cause severe side effects, including colitis, which is inflammation in the digestive tract.

Colitis can cause severe gastrointestinal discomfort, and some patients will discontinue their cancer treatment because of it.

The problem facing researchers was that while patients were developing colitis, the laboratory mice were not. So researchers couldn’t study what was causing this side effect.

To get past this, the Rogel team, led by first author Bernard C. Lo, Ph.D., created a new mouse model, injecting microbiota from wild-caught mice into the traditional mouse model.

In this model, the mice did develop colitis after administration of antibodies used for tumor immunotherapy. Now, researchers could trace back the mechanism to see what was causing this reaction.

In fact, colitis developed because of the composition of the gut microbiota, which caused immune T cells to be hyper-activated while regulatory T cells that put the brakes on T cell activation were deleted in the gut.

This was happening within a specific domain of the immune checkpoint antibodies.

Researchers then removed that domain, which they found still resulted in a strong anti-tumor response but without inducing colitis.

“Previously, there were some data that suggested the presence of certain bacteria correlated with response to therapy. But it was not proven that microbiota were critical to develop colitis. This work for the first time shows that microbiota are essential to develop colitis from immune checkpoint inhibition,” Nunez said.

To follow up what they saw in mice, researchers reanalyzed previously reported data from studies of human cells from patients treated with immune checkpoint antibodies, which reinforced the role of regulatory T cells in inducing colitis.

The antibody they used to stop the colitis was developed by Takeda Pharmaceuticals.

The Rogel team plans additional studies to further understand the mechanisms causing colitis and seeks clinical partners to move this knowledge to a clinical trial.

Additional authors are Ilona Kryczek, Jiali Yu, Linda Vatan, Roberta Caruso, Masanori Matsumoto, Yosuke Sato, Michael H. Shaw, Naohiro Inohara, Yuying Xie, Yu Leo Lei and Weiping Zou.

Funding for this work is from National Institutes of Health grants R01 DK121504, R01 DK095782, R01 DE026728, R01 DE030691, P30 CA046592; Takeda Millennium Pharmaceuticals, Canadian Institutes of Health, Crohn’s and Colitis Foundation, National Science Foundation grant IOS-2107215.

This work was supported by these Rogel Cancer Center Shared Resources: Single Cell Spatial Analysis, Tissue and Molecular Pathology

“Bird mortality has become an unintended consequence of renewable energy development,” said Hannah Vander Zanden, an assistant professor of biology at the University of Florida. “If we want to minimize or even offset these fatalities, especially for vulnerable populations, we need to identify the geographic origin of affected birds. In other words, are the dead birds local or are they coming from other parts of North America?”

Birds can be killed when they collide with wind turbines, fly into solar panels they mistake for bodies of water or become singed by the intense heat from concentrating solar power plants. While the death rate of birds due to these energy facilities is far less than deaths due to domestic cats and collisions with building, efforts to mitigate this problem is important, scientists say.

Vander Zanden and colleagues performed geospatial analyses of stable hydrogen isotope data obtained from feathers of 871 individual birds found dead at solar and wind energy facilities in California, representing 24 species.

Their analysis of natural-occurring markers in the feathers provided information about where the feathers were grown based on the water the birds consumed.

“With these markers, we could determine whether the bird was local or if it was migrating from somewhere else,” said Vander Zanden, who is the principal investigator of UF’s Animal Migration and Ecology Lab.

Results from the study, which were published Friday in the journal Conservation Biology, show that the birds killed at the facilities were from a broad area across the continent. Their geographical origins varied among species and included a mix of local and nonlocal birds.

Researchers found most birds killed at solar facilities were nonlocal and peaked during the migratory periods of April and September through October. The percentage of migratory birds found at wind facilities nearly matched that of local birds, at 51%, Vander Zanden said.

“This kind of data can help inform us about best strategies to use to minimize or mitigate the fatalities,” she said. “For example, facilities management could work with conservationists to improve the local habitat to help protect local birds or improve other parts of the species’ range where the migratory birds originate.”

The results also illustrate the power of stable isotope data to assess future population growth or decline patterns for birds due to a variety of reasons.

“Studying the remains of animals is a noninvasive approach to get information that is otherwise hard to track and apply to conservation,” Vander Zanden said. “It’s a great way to understand the mysteries about animals.”

Now, a study conducted in Japan has revealed the existence of around 11,000 vital genetic switches active in every cell type — housekeeping cis-regulatory elements (HK-CREs) — that play a role in maintaining the stability and function of our cells, far beyond the regulation of housekeeping genes. This study was performed by scientists from the Laboratory of Functional Analysis in silico (Nakai-lab) at The Institute of Medical Science, The University of Tokyo, Japan: Professor Kenta Nakai, head of the laboratory, and Dr. Martin Loza, Assistant Professor, in collaboration with Dr. Alexis Vandenbon, Associate Professor, from the Institute of Life and Medical Sciences, Kyoto University, Japan. Their work was published in Nucleic Acids Research on December 12, 2023.

Discussing his motivation behind this study, Dr. Loza states, “Given the significant association between cancer and mutations in epigenetic components, every small insight we gain could be key in the ongoing battle against this disease, which has tragically claimed innumerable lives. Through extensive bioinformatics analyses, we aimed to emphasize HK-CREs profound impact on fundamental cellular processes, including their potential as essential housekeeping tumor suppressors.” The research team found that HK-CREs were not solely confined to regulating the well-studied housekeeping genes (HKGs), which only constituted less than 20% of the genes associated with these elements. Instead, these elements predominantly resided within core promoter regions of many more genes (around 8,000), indicating a broader regulatory role beyond typical housekeeping gene functions. By employing bioinformatics analyses and levering diverse public datasets, the team validated the robustness of HK-CREs across 50 randomly selected healthy cell types, confirming the location of HK-CREs within the genome. These elements were highly conserved, residing in unmethylated CpG-rich regions, a trait strongly associated with their housekeeping regulatory function.

Sharing his concerns about the analysis, Dr. Lozastates, “By leveraging bioinformatics analyses of multiomics data, we offer an approach to harnessing publicly available datasets for exploring diverse biological mechanisms. We anticipate that employing similar workflows can significantly streamline analyses, cutting back both time and financial investments needed for comprehensive studies involving new data.”

The team remarked on the intricate cooperative interactions among housekeeping core promoters (HK-CPs), forming complex regulatory networks through promoter-promoter interactions. These observations hint at the significant influence of such interactions not only on HKGs but also on genes specific to various cell types. Turning their attention to cancer cells, researchers discovered a subset of HK-CREs displaying reduced activity in diverse cancer subtypes due to aberrant methylation, particularly those linked to zinc finger genes clustered in sub-telomere regions of chromosome 19. Identifying genes such as ZNF135, ZNF154, ZNF667, and ZNF667-AS1 under the influence of these foundational core promoters, the research suggests their potential as housekeeping tumor suppressor genes.

“Genes detected in our study have exhibited decreased activity in multiple cancer cell lines, and survival analysis across various cancer projects have revealed significant increases in survival probability in diverse cancer types like pancreas adenocarcinoma and uveal melanoma,” states Dr. Loza.

In essence, the results of this research have uncovered a previously unknown class of HK-CREs critical for cellular stability, extending their influence beyond housekeeping gene regulation. “Our discovery on housekeeping tumor suppressor genes unveils a novel avenue in cancer therapy, harnessing the intrinsic elements within the DNA of every cell. Future approaches to cancer treatment, focusing on these housekeeping tumor suppressor genes, offer a unique solution that could potentially target a broad range of cancers, sidestepping the challenges associated with personalized medicine,” remarks Dr. Loza. He further adds, “Our findings on housekeeping cis-regulatory elements fill a big gap in the current knowledge regarding gene regulatory processes. We anticipate that our findings will enhance the understanding of these processes and serve as a valuable resource for researchers striving to uncover elements inherent in the genome for combating various diseases.”

Technological advancements have enabled scientists to comprehensively explore genetic control elements, unraveling the complexities of gene activation mechanisms in our genetic code. New evidence challenges the simplistic view that cis-regulatory elements (CREs) are mere on/off switches for genes, emphasizing their ability to exhibit complex behaviors, such as the simultaneous enhancement of gene activity and initiation of gene transcription, e.g., simultaneous enhancer and promoter activities. These switches aren’t only important for the enhancement of specific genes but are crucial for the basic functions that keep our cells healthy. Now, a study conducted in Japan has revealed the existence of around 11,000 vital genetic switches active in every cell type — housekeeping cis-regulatory elements (HK-CREs) — that play a role in maintaining the stability and function of our cells, far beyond the regulation of housekeeping genes. This study was performed by scientists from the Laboratory of Functional Analysis in silico (Nakai-lab) at The Institute of Medical Science, The University of Tokyo, Japan: Professor Kenta Nakai, head of the laboratory, and Dr. Martin Loza, Assistant Professor, in collaboration with Dr. Alexis Vandenbon, Associate Professor, from the Institute of Life and Medical Sciences, Kyoto University, Japan. Their work was published in Nucleic Acids Research on December 12, 2023.

Discussing his motivation behind this study, Dr. Loza states, “Given the significant association between cancer and mutations in epigenetic components, every small insight we gain could be key in the ongoing battle against this disease, which has tragically claimed innumerable lives. Through extensive bioinformatics analyses, we aimed to emphasize HK-CREs profound impact on fundamental cellular processes, including their potential as essential housekeeping tumor suppressors.” The research team found that HK-CREs were not solely confined to regulating the well-studied housekeeping genes (HKGs), which only constituted less than 20% of the genes associated with these elements. Instead, these elements predominantly resided within core promoter regions of many more genes (around 8,000), indicating a broader regulatory role beyond typical housekeeping gene functions. By employing bioinformatics analyses and levering diverse public datasets, the team validated the robustness of HK-CREs across 50 randomly selected healthy cell types, confirming the location of HK-CREs within the genome. These elements were highly conserved, residing in unmethylated CpG-rich regions, a trait strongly associated with their housekeeping regulatory function.

Sharing his concerns about the analysis, Dr. Lozastates, “By leveraging bioinformatics analyses of multiomics data, we offer an approach to harnessing publicly available datasets for exploring diverse biological mechanisms. We anticipate that employing similar workflows can significantly streamline analyses, cutting back both time and financial investments needed for comprehensive studies involving new data.”

The team remarked on the intricate cooperative interactions among housekeeping core promoters (HK-CPs), forming complex regulatory networks through promoter-promoter interactions. These observations hint at the significant influence of such interactions not only on HKGs but also on genes specific to various cell types. Turning their attention to cancer cells, researchers discovered a subset of HK-CREs displaying reduced activity in diverse cancer subtypes due to aberrant methylation, particularly those linked to zinc finger genes clustered in sub-telomere regions of chromosome 19. Identifying genes such as ZNF135, ZNF154, ZNF667, and ZNF667-AS1 under the influence of these foundational core promoters, the research suggests their potential as housekeeping tumor suppressor genes.

“Genes detected in our study have exhibited decreased activity in multiple cancer cell lines, and survival analysis across various cancer projects have revealed significant increases in survival probability in diverse cancer types like pancreas adenocarcinoma and uveal melanoma,” states Dr. Loza.

In essence, the results of this research have uncovered a previously unknown class of HK-CREs critical for cellular stability, extending their influence beyond housekeeping gene regulation. “Our discovery on housekeeping tumor suppressor genes unveils a novel avenue in cancer therapy, harnessing the intrinsic elements within the DNA of every cell. Future approaches to cancer treatment, focusing on these housekeeping tumor suppressor genes, offer a unique solution that could potentially target a broad range of cancers, sidestepping the challenges associated with personalized medicine,” remarks Dr. Loza. He further adds, “Our findings on housekeeping cis-regulatory elements fill a big gap in the current knowledge regarding gene regulatory processes. We anticipate that our findings will enhance the understanding of these processes and serve as a valuable resource for researchers striving to uncover elements inherent in the genome for combating various diseases.”

The evidence suggests that the long-term solution to elephant survival requires not only that areas are protected but that they are also connected to allow populations to stabilize naturally, an international research team says.

Their study, published on January 5th in the peer-reviewed journal Science Advances, collected survey estimates and calculated growth rates for more than 100 elephant populations in southern Africa between 1995 and 2020, accounting for an estimated 70% of the global savanna elephant population.

“This is the most comprehensive analysis of growth rates for any large mammal population in the world,” said co-author Rob Guldemond, director of the Conservation Ecological Research Unit (CERU) at the University of Pretoria, in South Africa.

Overall, the survey’s results are positive: There are the same number of elephants now as there were 25 years ago, a rare conservation win at a time when the planet is rapidly losing biodiversity. However, the pattern is not consistent across regions. Some areas, such as south Tanzania, eastern Zambia, and northern Zimbabwe, experienced severe declines due to illegal ivory poaching. In contrast, populations in other regions like north Botswana are booming.

“Unchecked growth isn’t necessarily a good thing, however,” says study co-author Stuart Pimm, the Doris Duke Professor of Conservation at Duke University in North Carolina. “Rapidly increasing populations can outgrow and damage their local environment and prove hard to manage — introducing a threat to their long-term stability,” Pimm says.

In addition to documenting local growth rates, the team also looked at the features of the local populations to identify what makes them stable, that is neither growing nor declining.

Elephant populations in well-protected but isolated parks, sometimes called “fortress conservation,” grow rapidly in the absence of threats but are unsustainable in the long term. These elephants will likely need future conservation interventions, such as translocation or birth control, which are both costly and intensive endeavors.

The team found that the most stable populations occur in large, core areas that are surrounded by buffer zones. The core areas are defined by their strong levels of environmental protection and minimal human impact, whereas the buffers allow some activities such as sustainable farming, forestry, or trophy hunting. Unlike the insular fortresses, core areas are connected to other parks, allowing herds to move naturally.

“What’s crucial is that you need a mix of areas with more stable core populations linked to more variable buffer areas,” said lead author Ryan Huang, a Duke Ph.D. now doing postdoctoral research at CERU.

“These buffers absorb immigrants when core populations get too high, but also provide escape routes when elephants face poor environmental conditions or other threats such as poaching,” Huang said.

Connecting protected areas means elephants can freely move in and out. This allows a natural equilibrium to occur without human intervention, sparing conservationists from using their limited resources to maintain balance.

“Calling for connecting parks isn’t something new. Many have done so,” Huang said. “But surprisingly, there has not been a lot of published evidence of its effectiveness so far. This study helps quantify why this works.”

“Connecting protected areas is essential for the survival of African savanna elephants and many other animal and plant species,” said Celesté Maré, co-author and doctoral student at Aarhus University in Denmark. “Populations with more options for moving around are healthier and more stable, which is important given an uncertain future from climate change.”

The new diagnostic is based on nanosensors that can be delivered by an inhaler or a nebulizer. If the sensors encounter cancer-linked proteins in the lungs, they produce a signal that accumulates in the urine, where it can be detected with a simple paper test strip.

This approach could potentially replace or supplement the current gold standard for diagnosing lung cancer, low-dose computed tomography (CT). It could have an especially significant impact in low- and middle-income countries that don’t have widespread availability of CT scanners, the researchers say.

“Around the world, cancer is going to become more and more prevalent in low- and middle-income countries. The epidemiology of lung cancer globally is that it’s driven by pollution and smoking, so we know that those are settings where accessibility to this kind of technology could have a big impact,” says Sangeeta Bhatia, the John and Dorothy Wilson Professor of Health Sciences and Technology and of Electrical Engineering and Computer Science at MIT, and a member of MIT’s Koch Institute for Integrative Cancer Research and the Institute for Medical Engineering and Science.

Bhatia is the senior author of the paper, which appears today in Science Advances. Qian Zhong, an MIT research scientist, and Edward Tan, a former MIT postdoc, are the lead authors of the study.

Inhalable particles

To help diagnose lung cancer as early as possible, the U.S. Preventive Services Task Force recommends that heavy smokers over the age of 50 undergo annual CT scans. However, not everyone in this target group receives these scans, and the high false-positive rate of the scans can lead to unnecessary, invasive tests.

Bhatia has spent the last decade developing nanosensors for use in diagnosing cancer and other diseases, and in this study, she and her colleagues explored the possibility of using them as a more accessible alternative to CT screening for lung cancer.

These sensors consist of polymer nanoparticles coated with a reporter, such as a DNA barcode, that is cleaved from the particle when the sensor encounters enzymes called proteases, which are often overactive in tumors. Those reporters eventually accumulate in the urine and are excreted from the body.

Previous versions of the sensors, which targeted other cancer sites such as the liver and ovaries, were designed to be given intravenously. For lung cancer diagnosis, the researchers wanted to create a version that could be inhaled, which could make it easier to deploy in lower resource settings.

“When we developed this technology, our goal was to provide a method that can detect cancer with high specificity and sensitivity, and also lower the threshold for accessibility, so that hopefully we can improve the resource disparity and inequity in early detection of lung cancer,” Zhong says.

To achieve that, the researchers created two formulations of their particles: a solution that can be aerosolized and delivered with a nebulizer, and a dry powder that can be delivered using an inhaler.

Once the particles reach the lungs, they are absorbed into the tissue, where they encounter any proteases that may be present. Human cells can express hundreds of different proteases, and some of them are overactive in tumors, where they help cancer cells to escape their original locations by cutting through proteins of the extracellular matrix. These cancerous proteases cleave DNA barcodes from the sensors, allowing the barcodes to circulate in the bloodstream until they are excreted in the urine.

In the earlier versions of this technology, the researchers used mass spectrometry to analyze the urine sample and detect DNA barcodes. However, mass spectrometry requires equipment that might not be available in low-resource areas, so for this version, the researchers created a lateral flow assay, which allows the barcodes to be detected using a paper test strip.

The researchers designed the strip to detect up to four different DNA barcodes, each of which indicates the presence of a different protease. No pre-treatment or processing of the urine sample is required, and the results can be read about 20 minutes after the sample is obtained.

“We were really pushing this assay to be point-of-care available in a low-resource setting, so the idea was to not do any sample processing, not do any amplification, just to be able to put the sample right on the paper and read it out in 20 minutes,” Bhatia says.

Accurate diagnosis

The researchers tested their diagnostic system in mice that are genetically engineered to develop lung tumors similar to those seen in humans. The sensors were administered 7.5 weeks after the tumors started to form, a time point that would likely correlate with stage 1 or 2 cancer in humans.

In their first set of experiments in the mice, the researchers measured the levels of 20 different sensors designed to detect different proteases. Using a machine learning algorithm to analyze those results, the researchers identified a combination of just four sensors that was predicted to give accurate diagnostic results. They then tested that combination in the mouse model and found that it could accurately detect early-stage lung tumors.

For use in humans, it’s possible that more sensors might be needed to make an accurate diagnosis, but that could be achieved by using multiple paper strips, each of which detects four different DNA barcodes, the researchers say.

The researchers now plan to analyze human biopsy samples to see if the sensor panels they are using would also work to detect human cancers. In the longer term, they hope to perform clinical trials in human patients. A company called Sunbird Bio has already run phase 1 trials on a similar sensor developed by Bhatia’s lab, for use in diagnosing liver cancer and a form of hepatitis known as nonalcoholic steatohepatitis (NASH).

In parts of the world where there is limited access to CT scanning, this technology could offer a dramatic improvement in lung cancer screening, especially since the results can be obtained during a single visit.

“The idea would be you come in and then you get an answer about whether you need a follow-up test or not, and we could get patients who have early lesions into the system so that they could get curative surgery or lifesaving medicines,” Bhatia says.

The research was funded by the Johnson & Johnson Lung Cancer Initiative, the Howard Hughes Medical Institute, the Koch Institute Support (core) Grant from the National Cancer Institute, and the National Institute of Environmental Health Sciences.

A collaborative research team led by Professor Sung-Min Park from the Departments of Convergence IT Engineering, Mechanical Engineering, and Electrical Engineering, and the School of Interdisciplinary Bioscience and Bioengineering at POSTECH, alongside Jiho Lee, enrolled in the MS/Ph.D. program, and Professor Sang-Woo Kim from Yonsei University’s Department of Materials Science and Engineering, together with Dr. Young-Jun Kim and MS/Ph.D. student Joon-Ha Hwang from Sungkyunkwan University, has achieved a groundbreaking development. They’ve created electrostatic materials that function even with extremely weak ultrasound, heralding the era of permanent implantable electronic devices in biomedicine. This research has been published in the international academic journal Advanced Materials.

Patients with implanted devices need to undergo periodic surgeries for battery replacement. This process carries a significant risk of complications and imposes both economic and physical burdens on patients. Recent research explores implantable medical devices that operate wirelessly, yet finding a safe energy source and protective materials remains challenging. Presently, titanium (Ti) is used due to its biocompatibility and durability. However, radio waves cannot pass through this metal, necessitating a separate antenna for wireless power transmission. Consequently, this enlarges the device size, creating more discomfort for patients.

The research team addresses this issue by opting for ultrasound, a safety-validated method in various medical fields for diagnoses and treatments, instead of radio waves. They developed an electrostatic material capable of responding to weak ultrasound by utilizing a composite of high dielectric polymers (P(VDF-TrFE)) and a high dielectric constant ceramic material known as calcium copper titanate (CCTO, CaCu₃Ti₄O₁₂). This material generates static electricity through friction between its material layers, producing effective electrical energy, and possesses an extremely low output impedence, facilitating efficient transmission of the generated electricity.

Using this technology, the research team created an implantable neurological stimulator powered by ultrasound-based energy transmission, eliminating the need for batteries. This was confirmed through experimental validation. In animal model trials, the device was activated even at standard imaging ultrasound levels (500 mW/cm²), imposing minimal strain on the human body. Furthermore, it effectively mitigated symptoms related to abnormal urination caused by overactive bladder disorders through nerve stimulation.

Professor Sung-Min Park stated: “We have addressed the challenges in the field of implantable medical devices using ultrasound-based energy transmission technology that is harmless to the human body. This research serves as a case of introducing advanced material technology into medical devices, and we anticipate that it will promote the emergence of a next-generation medical industry, including the treatment of intractable diseases using implantable devices.”

Professor Sang-Woo Kim remarked: “Devices manufactured based on highly biocompatible materials exhibit excellent mechanical and chemical stability, making them suitable for treating various diseases requiring long-term therapy. Non-battery, miniaturized components with established long-term stability are expected to bring forth new innovations in the market of human-insertable medical devices.”

The research was conducted with support from the Research Leader Program, Pioneer Program of Future Technology, and Bio & Medical Technology Development Program by the National Research Foundation of Korea and the Ministry of Science and ICT, along with Yonsei Fellowship.