Tag: Academic research

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Salk to Lead $41.3M ARPA-H Effort to Advance Sonogenetics Therapies

The scientists responsible for developing sonogenetics, which refers to the application of low-intensity ultrasound to noninvasively achieve precise control of cellular proteins, have secured an influx of federal funding that will allow them and their collaborators transform the technology into a potential therapy for various conditions starting with peripheral neuropathies.

Late last week, Salk Institute for Biological Studies announced that Sreekanth Chalasani, PhD, an associate professor in Salk’s molecular neurobiology laboratory, and his partners in collaborating laboratories elsewhere, were awarded $41.3 million from the Advanced Research Projects Agency for Health (ARPA-H), an agency within the United States Department of Health and Human Services. Working on multiple fronts over the next five years, the partners will develop core biological tools and ultrasound delivery systems while generating the preclinical evidence needed to move sonogenetics into human clinical trials. 

“This award is a major step toward a long-held goal—a drug-free way to deliver therapy exactly where it’s needed and only when it’s needed,” said Chalasani, who serves as the principal investigator for the grant and is also the co-founder of SonoNeu, a startup launched to commercialize therapies based on the technology. Key to accomplishing that goal is “a platform that pairs engineered ultrasound-sensitive proteins with wearable ultrasound technology, which, unlike conventional pharmaceutical treatments, could let us treat conditions with cellular and temporal control.” 

Reaching cells through sound

In 2011, armed with support from Salk’s Innovation and Collaboration Grants program, Chalasani and his team pioneered sonogenetics, a technique for sensitizing specific cell types to ultrasound by equipping them with ultrasound-responsive proteins. In 2015, his group first identified a particular protein in the roundworm Caenorhabditis elegans (C. elegans) that makes cells sensitive to low-frequency ultrasound. When they added this protein to C. elegans neurons that did not usually have it, they were able to activate these cells using ultrasound waves. 

Since that initial discovery, Chalasani’s team and others have shown that they can use sonogenetics to manipulate mammalian cells. Some of their work was published in a 2022 Nature Communications paper which describes efforts to engineer a human channel protein in cultured mammalian cells and living animal models to confer cell-specific sensitivity to ultrasound stimulation.

Chalasani noted in an interview with GEN that the pace of their progress from an idea to potential clinical translation in the span of about 15 years is remarkable, compared to the typical multi-decade timeline for most new therapies. “In terms of how quickly this has gone from a [research] idea to what patients should we look at [and] how are we going to help them? The pace has been overwhelming,” he said. He attributed much of that progress to the work of the trainees, post-doctoral students, and collaborators through the years who were willing to take on “this crazy idea and work on this project, even though there was no guarantee it would get anywhere.” He also highlighted the early investment from Salk and other entities including the National Institutes of Health’s Brain Initiative as key to project’s success.  

Though Chalasani and his lab pioneered sonogenetics, the next phase of its development is not a solo effort. It involves a multiple institutions and teams all of whom are contributing essential and specialized expertise. The list of collaborators includes Scripps Research, where a team led by 2021 Nobel Laureate Ardem Patapoutian, PhD, will support the discovery and engineering of ultrasound-sensitive proteins. Then a team at St. Boniface Hospital Research and the University of Manitoba led by Paul Fernyhough, PhD, will help define how ultrasound-triggered signals move through cellular machinery and drive nerve repair pathways.

Another team, led by Aravind Asokan, PhD, at Duke University will work on targeted vectors for delivering ultrasound-sensitive proteins to specific cell types. Separately, a team led by Xuanhe Zhao, PhD, at Massachusetts Institute of Technology will work on targeted mechanisms for delivering ultrasound to animal and human targets. Then scientists at the University of California, San Diego, led by Nigel Calcutt, PhD, will validate the efficacy of sonogenetics across established paradigms and in mammalian systems. Finally, Ghassan Kassab, PhD, and his team at California Medical Innovations Institute, will support advanced translational validation and clinically relevant assessment in preclinical systems. 

For their part, Chalasani and his team at Salk will work on finding additional actuators or sensors for ultrasound that will be optimized for targeted delivery. “What we have are proteins that can respond to that small amount of mechanical deflection that ultrasound can cause,” Chalasani explained. “These proteins are channels [that] sit on the membrane of the cell and when the cell experiences ultrasound, the protein gets activated, it opens up, and allows calcium [for example] into the cell. Because these proteins can actuate an effect, they are called ultrasound actuators.” 

Currently, the group has identified proteins that can move things like calcium and chloride into cells in response to ultrasound but they are hunting for other proteins that can activate various signaling pathways. Besides new actuators, the Salk scientists will work on validation studies in mouse models, and lay the groundwork for experiments in larger animal models, specifically pigs, Chalasani told GEN. 

There is a plan in place to commercialize therapies developed using sonogenetics technology. Salk spinout SonoNeu will receive a portion of the ARPA-H funding to help  move potential therapies through the regulatory process and commercialization. Chalasani is listed as a co-founder as is Venkat Reddy, chief scientific officer of General Inception, a firm that partners with scientific founders to build their companies. The target, Chalasani said, is to have something ready for the U.S. Food and Drug Administration in the next five years. 

The initial treatment target condition is peripheral neuropathies and in that context, “there are a lot of interesting places for us to evaluate,” he said. “But I think the real question is going to be what pathway are we targeting? We can do calcium and chloride [but] is that enough to get a therapeutic benefit in a patient or should we have to activate something else other than that? Do we have to activate an enzyme [or] a kinase? And how would we do that? Can we link these proteins to those signals? So there are some unknowns here.”  

If all goes well, other patient populations could benefit from sonogenetics-based therapies besides peripheral neuropathies including people with diabetes, heart conditions or it could help with bladder control, Chalasani said. There are even possible applications in the context of brain-computer interfaces. 

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AACR 2026: Professional Awards Acknowledge Community’s Contributions to Cancer Research

The American Association for Cancer Research (AACR) has released the names of the recipients of several annual professional awards. These awards recognize outstanding accomplishments and achievements in cancer research, therapy development, education, mentorship, and more. The honorees, listed below, will give lectures during this year’s meeting, which is being held in San Diego, CA. This year’s meeting runs from April 17-22.

 

AACR Lifetime Achievement in Cancer Research Award 

James P. Allison, PhD, FAACR

This award honors individuals who have made fundamental contributions to cancer research through a single scientific discovery or a body of work. Allison is being recognized for his contributions to cancer research and patient care. Most notably, he is being celebrated for his identification of CTLA-4 as a negative regulator of T-cell activation, an insight that has since been translated into a first-in-class therapy that revitalized the field of cancer immunology and led to a revolution in cancer immunotherapies. Allison is a fellow of the AACR Academy, a professor and chair of the department of immunology, vice president for immunobiology, and the founding director of the James P. Allison Institute at the University of Texas MD Anderson Cancer Center.

 

AACR Outstanding Achievement in Basic Cancer Research Award 

Housheng Hansen He, PhD

This award recognizes early-career investigators for meritorious achievements in basic cancer research. He is a professor in the department of medical biophysics at the University of Toronto and a senior scientist in the Princess Margaret Cancer Center. He is recognized for contributions to cancer epigenetics and RNA medicine, particularly in revealing how chromatin accessibility and epigenomic landscapes govern oncogenic transcription. His studies of FOXA1-androgen receptor networks, noncoding RNAs, and RNA modifications have improved scientists’ understanding of tumor progression, plasticity, and therapeutic resistance.  

 

AACR Outstanding Achievement in Blood Cancer Research Award 

John F. DiPersio, MD, PhD

This award recognizes individuals with meritorious achievements and contributions to blood cancer research. DiPersio is this year’s recipient for his work in leukemia and stem cell biology, including essential contributions to the development of the hematopoietic stem cell mobilizing agents plerixafor and motixafortide. DiPersio identified AK1/2 signaling in graft-versus-host disease, which led to the identification and approval of JAK inhibitors, including ruxolitinib (Jakafi). DiPersio is the Virginia E. and Sam J. Golman professor of medicine and a professor of medicine, immunology, and pathology at Washington University School of Medicine in St. Louis. He is also director of the Center for Gene and Cellular Immunotherapy at Siteman Cancer Center at Barnes-Jewish Hospital and WashU Medicine.

 

AACR Outstanding Achievement in Chemistry in Cancer Research Award 

Cheryl H. Arrowsmith, PhD

This award honors individuals who have done novel and significant chemistry research that has led to important contributions in basic and translational cancer research, cancer diagnosis, prevention, and treatment. Arrowsmith is being recognized for foundational studies defining the structure and function of chromatin-associated proteins that regulate gene expression in cancer. Her work enabled the development of chemical probes that target epigenetic regulators. She is a senior scientist at the Princess Margaret Cancer Centre, University Health Network and chief scientist of the Structural Genomics Consortium. She is also a professor in the department of medical biophysics at the University of Toronto.

 

AACR Daniel D. Von Hoff Award for Outstanding Contributions to Education and Training in Cancer Research

Charles W.M. Roberts, MD, PhD, FAACR

This award recognizes significant contributions to education and training for cancer scientists and physicians at any career level. Roberts is a fellow of the AACR Academy and the executive vice president and director of the St. Jude Comprehensive Cancer Center. He is also a member in the department of oncology and the Lillian R. Cannon Comprehensive Cancer Center Director Endowed Chair at the St. Jude Children’s Research Hospital. This award recognizes his leadership and dedication to the education and training of cancer researchers across the spectrum of childhood cancer research, including basic, translational, clinical, and population science. 

 

AACR James S. Ewing-Thelma B. Dunn Award for Outstanding Achievement in Pathology in Cancer Research 

David L. Rimm, MD, PhD

The award celebrates pathologists who have contributed to advancing cancer research, diagnosis, treatment, and prevention. Rimm is recognized this year for innovations in quantitative biomarker science that transformed cancer diagnostics and treatment. His invention of the fluorescence-based Automated Quantitative Analysis platform improved immunohistochemistry by enabling precise, reproducible protein quantification in tissue specimens. Rimm is the Anthony N. Brady professor of pathology, a professor of medicine in oncology, director of quantitative diagnostics in the anatomic pathology lab, director of Yale Pathology Tissues Services, and director of the physician scientist training program in pathology at Yale University School of Medicine. He is also a member of Yale Cancer Center and director of the Yale Cancer Center Tissue Microarray Facility.

 

AACR Margaret Foti Award for Leadership and Extraordinary Achievements in Cancer Research

Antoni Ribas, MD, PhD, FAACR

This award recognizes individuals whose leadership and achievements contributed to the acceleration of progress against cancer, raising national or international awareness of the importance of cancer research, among other achievements. Ribas is being recognized for contributions to melanoma biology and cancer immunotherapy that were instrumental to the clinical development of pembrolizumab (Keytruda) and other transformative therapies. His research helped define mechanisms of immunotherapy response and resistance, which guided the design of innovative combination therapy approaches. Ribas is a fellow of the AACR Academy and AACR Past President. He is also a professor of medicine, surgery, and molecular and medical pharmacology at the University of California Los Angeles (UCLA), as well as director of the tumor immunology program at the UCLA Jonsson Comprehensive Cancer Center. He also serves as the director of the Parker Institute for Cancer Immunotherapy Center at UCLA. 

 

AACR Team Science Award

The Cancer Dependency Map (DepMap) team

This award recognizes interdisciplinary research teams for science that advances or is likely to advance our fundamental knowledge of cancer, or a team that has applied existing knowledge to advance the detection, diagnosis, prevention, or treatment of cancer. The Broad Institute Cancer Dependency Map (DepMap) team is recognized this year for systematically mapping genetic dependencies across cancer cells and creating a comprehensive resource that reveals genes and pathways essential for tumor survival. By combining large-scale CRISPR functional genomic screens, drug response data, and multiomic profiling, the team uncovered lineage- and genotype-specific cancer vulnerabilities, including synthetic lethal dependencies such as WRN in microsatellite instability cancers and PRMT5 dependencies in cancers with MTAP deletions. 

 

AACR American Cancer Society Award for Research Excellence in Cancer Epidemiology and Prevention

Elizabeth A. Platz, ScD, MPH 

This award recognizes research accomplishments in cancer epidemiology, biomarkers, and prevention. Platz is the Martin D. Abeloff, MD Scholar in Cancer Prevention in the epidemiology department at the Johns Hopkins Bloomberg School of Public Health. She is also the associate director of population sciences at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins. This award recognizes her contributions to scientists’ understanding of prostate cancer development, progression, and prevention. Her research linked intraprostatic inflammation to prostate cancer risk, identified telomere length patterns as prognostic biomarkers, and demonstrated protective associations between statin use, cholesterol, and disease lethality. 

 

AACR Cancer Research Institute Lloyd J. Old Award in Cancer Immunology 

Kenneth M. Murphy, MD, PhD 

This award recognizes scientists whose research has had a major impact on the cancer field and has the potential to stimulate new directions in cancer immunology.  Murphy is the Eugene Opie First Centennial Professor in pathology and immunology at the Washington University School of Medicine in St. Louis. This award recognizes his work on discoveries related to the development and functional specialization of dendritic cell subsets that regulate adaptive immune responses. His work elucidated the transcriptional programs that control dendritic cell lineage commitment, including the role of transcription factors such as BATF3 in the development of cross-presenting dendritic cells required to prime cytotoxic T-cell responses. 

 

AACR G.H.A. Clowes Award for Outstanding Basic Cancer Research 

Andrew P. Feinberg, MD, MPH

This award, which has the distinction of being AACR’s oldest award, recognizes individuals who have made outstanding recent accomplishments in basic cancer research. Feinberg is recognized this year for discoveries about the fundamental role of epigenetic alterations in cancer, including the identification of early, widespread DNA methylation abnormalities and the role of genomic imprinting in tumor development. His research demonstrated that large-scale epigenomic alterations contribute to tumor initiation, progression, and cellular heterogeneity, leading to the concept of epigenetic plasticity as a driver of cancer evolution. Feinberg is the Bloomberg Distinguished Professor at the Johns Hopkins University Schools of Medicine, Engineering, and Public Health. He also serves as director of the Center for Epigenetics of the Institute for Basic Biomedical Sciences.

 

AACR Irving Weinstein Foundation Distinguished Lectureship Award

Dennis Lo, DM, DPhil

The recipient for this award is selected by the AACR president, and acknowledges individuals whose personal innovation in science and whose position as a thought leader in fields relevant to cancer research have the potential to inspire creative thinking and new directions in cancer research. Lo is the vice-chancellor and president of the Chinese University of Hong Kong, where he also serves as the Li Ka Shing Professor of Medicine and professor of chemical pathology. He is being recognized for his discovery of fetal DNA in maternal plasma. Lo was the first to identify cell-free fetal DNA and fetal epigenetic markers in maternal plasma, enabling safer and earlier prenatal diagnostics. He also demonstrated that DNA released by tumors may be used for cancer screening, an insight that led to the development of circulating DNA-based tools for early cancer detection and screening. 

 

AACR Joseph H. Burchenal Award for Outstanding Achievement in Clinical Cancer Research 

Luis A. Diaz Jr., MD, FAACR

This award recognizes outstanding achievements in clinical cancer research. Diaz, a fellow of the AACR Academy, heads the division of solid tumor oncology and is the Grayer Family Chair at the Memorial Sloan Kettering Cancer Center. This award recognizes his pioneering discoveries such as biomarker-driven immunotherapies and for demonstrating that tumors with mismatch repair deficiencies and microsatellite instability are highly responsive to immune checkpoint blockade. Diaz has also advanced the use of circulating tumor DNA to detect minimal residual disease and led clinical trials of PD-1 blockade in mismatch repair-deficient cancers. 

 

AACR Minorities in Cancer Research Jane Cooke Wright Lectureship

Ahmedin M. Jemal, DVM, PhD

This lectureship recognizes scientists with meritorious contributions to the field of cancer research and who have furthered the advancement of minority investigators in cancer research. This year’s awardee is recognized for research that quantified temporal and geographic trends in cancer burden using large-scale analysis of cancer registries, mortality rates, and risk factor data, and identified population-level determinants of cancer incidence, survival, and stage at diagnosis across demographic groups. Jemal’s work linked changes in risk factor exposure, screening uptake, and treatment advances to declines in cancer mortality and informed strategies for cancer prevention, early detection, and population-level cancer control. He is the senior vice president of the Surveillance, Prevention, & Health Services Research department at the American Cancer Society. He is also an adjunct professor in the department of epidemiology at the Rollins School of Public Health at Emory University. 

 

AACR Princess Takamatsu Memorial Lectureship 

David C. Lyden, MD, PhD

This award recognizes individual scientists whose work has had or may have a far-reaching impact on the detection, diagnosis, treatment, or prevention of cancer. Lyden is the Stavros S. Niarchos Professor in pediatric cardiology and professor of pediatrics at Weill Cornell Medicine. He is also director of the physician-scientist training program in pediatrics, a founding member of the Drukier Institute for Children’s Health  and a member of the Sandra and Edward Meyer Cancer Center. He is being recognized for describing how primary tumors systemically promote metastasis by forming pre-metastatic niches in distant organs. Lyden’s research demonstrated that tumor-derived extracellular vesicles and exomeres, together with bone marrow-derived progenitor cells, remodel distant microenvironments and determine organ-specific metastatic tropism.

 

AACR St. Baldrick’s Foundation Award for Outstanding Achievement in Pediatric Cancer Research

Kimberly Stegmaier, MD, FAACR

This award recognizes individuals who have contributed to pediatric cancer research, resulting in the fundamental improvement of the understanding and/or treatment of pediatric cancer. Stegmaier serves as chair in the department of pediatric oncology at Dana-Farber Cancer Institute and the David G. Nathan professor of pediatrics at Harvard Medical School. She is also the associate chief of the division of hematology/oncology at Boston Children’s Hospital and an institute member at the Broad Institute. This award recognizes her genomic discoveries that defined the molecular landscape of childhood cancers and led to the identification of key drivers of fusion oncoprotein positive malignancies. Her research used systematic functional genomic screening and chemical biology strategies to identify critical dependencies in high-risk acute leukemias and pediatric solid tumors. 

 

AACR Waun Ki Hong Award for Outstanding Achievement in Translational and Clinical Cancer Research

Eliezer M. Van Allen, MD

This award recognizes cancer researchers under the age of 51 who have conducted meritorious translational and clinical cancer research anywhere in the world. Van Allen is the Chandra Nohria Family Chair for AI in Cancer Research and chief of the division of population sciences at Dana-Farber Cancer Institute. He is also a professor of medicine at Harvard Medical School and an institute member at the Broad Institute. Through large-scale tumor sequencing and integrative genomic analyses, Van Allen’s research defined genomic mechanisms underlying resistance to targeted therapies, including BRAF inhibition in melanoma, and identified genomic features associated with response to immune checkpoint blockade. His work has advanced biomarker discovery and the use of genomic data to guide personalized cancer treatments, as well as bridged advances in artificial intelligence with translational cancer research.

 

AACR Women in Cancer Research Charlotte Friend Lectureship 

Maryellen L. Giger, PhD

This award recognizes scientists’ contributions to the cancer research field and those who have furthered the advancement of women in science through leadership or by example. Giger is the A.N. Pritzker Distinguished Service Professor of Radiology at the University of Chicago. Giger’s research has established quantitative imaging and radiomics approaches that extract high-dimensional features from radiologic images to characterize tumor phenotype and predict cancer risk, diagnosis, and treatment response. She has also guided more than 120 trainees and consistently championed the careers of women scientists and clinicians.

 

Pezcoller Foundation-AACR International Award for Extraordinary Achievement in Cancer Research

Douglas R. Lowy, MD, FAACR and John T. Schiller, PhD, FAACR

This award is presented to international scientists who have made a scientific discovery in basic cancer research or who have made significant contributions to translational cancer research. Lowy is principal deputy director of the National Cancer Institute (NCI) and chief of the Laboratory of Cellular Oncology at NCI. Schiller is deputy chief of the Laboratory of Cellular Oncology at NCI and chief of the lab’s neoplastic disease section. Both awardees are also fellows of the AACR Academy and NIH Distinguished Investigators. They are being recognized for pioneering the molecular and immunologic foundations of human papillomavirus vaccines, engineering virus-like particles for safe and effective immunization, and driving their translation into global cancer prevention strategies that have dramatically reduced cervical and other HPV-related cancer incidence.  

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Why Leukemia Cells Escape Immune Attack—and How to Stop Them

Immunotherapy strategies that harness the body’s innate immune system have long focused on a central concept: cancer cells evade destruction by displaying “don’t eat me” signals that inhibit macrophages. Blocking these signals, most notably CD47, has been a major therapeutic goal. Yet in acute myeloid leukemia (AML), clinical responses to CD47-targeting therapies have been inconsistent, raising questions about whether additional immune evasion mechanisms are at play.

A new study published in Science by researchers at Mass General Brigham, Dana-Farber Cancer Institute, and the Broad Institute suggests that the field may have been overlooking a more dominant signal. The team identifies CD43, a heavily glycosylated surface protein, as a key regulator of macrophage evasion in AML.

Revisiting macrophage immune evasion

Macrophages are critical components of the innate immune system, capable of recognizing and engulfing tumor cells through phagocytosis. This process is regulated by a balance between pro-phagocytic “eat me” signals and inhibitory “don’t eat me” signals expressed on the surface of cancer cells.

Therapeutic efforts have largely focused on CD47, a well-characterized inhibitory signal that binds to SIRPα on macrophages to suppress phagocytosis. However, the limited success of CD47 inhibitors in AML has suggested that this pathway may not fully account for immune evasion in these cancers.

To systematically explore alternative mechanisms, the researchers performed a genome-scale loss-of-function screen in AML cell lines, turning off genes one by one and assessing their impact on macrophage recognition.

CD43 emerges as a dominant signal

The results were unexpected. While CD47 had only a modest effect, CD43 stood out as a major determinant of whether leukemia cells were engulfed by macrophages.

The study reveals that CD43 functions not simply as a surface marker, but as part of a broader protective structure. Specifically, its sialylated form creates a dense, glycosylation-based barrier that interferes with immune recognition.

As described by the authors, “Sialylated CD43 forms a glyco-immune barrier that restrains anti-leukemic immunity.”

This finding introduces a new conceptual framework for immune evasion in AML—one that emphasizes the role of glycosylation and surface architecture, rather than individual receptor–ligand interactions alone.

Explaining limits of current therapies

The identification of CD43 helps clarify why targeting CD47 alone has not produced the expected therapeutic outcomes in AML. If CD43-mediated shielding plays a dominant role, then blocking CD47 may be insufficient to restore effective macrophage activity.

The study suggests that immune evasion in AML is more complex than previously appreciated, involving multiple overlapping mechanisms that together suppress phagocytosis.

By uncovering this additional layer, the work highlights the need for combination strategies or alternative targets in macrophage-based immunotherapy.

A new therapeutic opportunity

From a translational perspective, CD43 represents a promising new target. Interventions that disrupt its glycosylation or block its function could weaken the protective barrier surrounding leukemia cells, making them more susceptible to immune clearance.

Because CD43 operates through a distinct mechanism, targeting it could complement existing therapies rather than replace them. Combining CD43 inhibition with CD47 blockade or other immunotherapies may enhance overall efficacy.

The findings also point to the broader relevance of glyco-immune interactions in cancer. Similar glycosylation-dependent barriers may exist in other tumor types, suggesting that the implications of this work could extend beyond AML.

A shift toward glyco-immunology

The study reflects a growing recognition of the role of glycobiology in cancer and immunology. While protein-based signaling pathways have dominated the field, complex carbohydrate structures on the cell surface are increasingly understood to play critical roles in immune recognition.

By identifying CD43 as a key mediator of immune evasion, the research highlights how these glycosylated molecules can shape interactions between cancer cells and the immune system.

Looking ahead

Although the findings are based on preclinical models, the researchers believe that they provide a strong rationale for further investigation in patient samples and clinical settings. Future studies will be needed to determine how CD43 expression varies across AML subtypes and whether it correlates with treatment response.

If validated, targeting CD43 could represent a new direction for immunotherapy in AML—one that addresses a fundamental mechanism of immune escape.

More broadly, the work highlights the importance of revisiting established paradigms in cancer biology. By moving beyond well-studied targets like CD47 and systematically exploring the full landscape of immune interactions, researchers are uncovering new vulnerabilities that could be exploited therapeutically.

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Combined Small-Cell Lung Cancer Evolution Insights May Improve Diagnosis, Treatment

A spatial multi-omics study of the rare lung cancer subtype known as combined small-cell lung cancer (cSCLC) has shown that these mixed tumors, which contain features of both small-cell and non-small-cell lung cancer (NSCLC), arise from a single ancestral cell that evolves and transitions between the two cancer types over time.

The results “provide a foundation for understanding cSCLC evolution and advancing innovative diagnostics and therapeutics,” write the authors in Cell Reports Medicine.

cSCLC represents approximately 2–5% of all SCLC cases, with diagnosis primarily based on pathologic evaluation of surgically resected tumor specimens. This can lead to underdiagnosis because small biopsies may not capture the full histological diversity of the tumor. Although cSCLC is more diverse and has a worse prognosis than typical SCLC, it is usually treated the same way because its underlying biology and tumor environment are not well understood.

Traditionally, the mixed histologies within cSCLC were thought to arise from independent tumor populations, but recent studies have revealed that the different histological components share common genetic mutations.

To investigate further, Zhuo Wang, from Fudan University in Shanghai, China, and colleagues applied spatially resolved genomic and transcriptomic sequencing, alongside single-cell RNA sequencing, to 19 treatment-naive cSCLC tumors.

“We found that these tumors are not simply mixtures of different cancer types,” said Wei Wei, PhD, associate professor at the Institute for Systems Biology in Seattle and co-corresponding author of the study. “They are dynamic systems, with cancer cells actively changing their identity. That flexibility may help explain why they are so difficult to treat.”

The team reports that the different tumor components originate from a single clone but later diverge as they acquire different mutations and copy-number changes.

The study also revealed that tumor cells can exist in intermediate or hybrid states, carrying features of multiple cancer types at once. About one-third of the SCLC-like tumor cells analyzed showed these mixed identities, suggesting that cancer progression is not a simple on-off switch, but a continuum.

In addition, the researchers found that different regions within the same tumor create distinct microenvironments. Some areas were rich in immune cells, while others were largely immune-excluded. Dense bands of fibroblasts often separated these regions. Those fibroblast-rich boundaries may help wall off parts of the tumor from immune attack.

“By combining spatial genomics, single-cell analysis, and multi-region sequencing, we were able to trace how these tumors evolve across both space and time,” said Fudan University’s Qihui Shi, PhD, co-corresponding author of the study. “This approach allowed us to capture transitional cell states that are not visible using conventional methods.”

Finally, the researchers developed “cSCLC Detector,” a four-gene diagnostic tool that may help identify these mixed tumors more accurately. The tool was built on a key insight from the study: although the small-cell and non-small-cell parts of cSCLC can look very different under the microscope, they come from the same ancestral tumor and share early trunk mutations.

In independent biopsy and blood samples, the assay, which detects mutations in the NSCLC-specific driver genes EGFR, KRAS, BRAF, and PIK3CA, identified cSCLC-like cases in 14% of samples, compared with a prevalence of 2%–5% estimated from surgically resected specimens.

The findings highlight the importance of understanding not just the genetic mutations in cancer, but also how cancer cells change state and interact with their environment.

“Cancer is not static,” Wei said. “To treat it effectively, we need to understand how it evolves—not just what it is at a single point in time.”

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Why opinion on AI is so divided

This story originally appeared in The Algorithm, our weekly newsletter on AI. To get stories like this in your inbox first, sign up here.

In an industry that doesn’t stand still, Stanford’s AI Index, an annual roundup of key results and trends, is a chance to take a breath. (It’s a marathon, not a sprint, after all.)

This year’s report, which dropped today, is full of striking stats. A lot of the value comes from having numbers to back up gut feelings you might already have, such as the sense that the US is gunning harder for AI than everyone else: It hosts 5,427 data centers (and counting). That’s more than 10 times as many as any other country.  

There’s also a reminder that the hardware supply chain the AI industry relies on has some major choke points. Here’s perhaps the most remarkable fact: “A single company, TSMC, fabricates almost every leading AI chip, making the global AI hardware supply chain dependent on one foundry in Taiwan.” One foundry! That’s just wild.

But the main takeaway I have from the 2026 AI Index is that the state of AI right now is shot through with inconsistencies. As my colleague Michelle Kim put it today in her piece about the report: “If you’re following AI news, you’re probably getting whiplash. AI is a gold rush. AI is a bubble. AI is taking your job. AI can’t even read a clock.” (The Stanford report notes that Google DeepMind’s top reasoning model, Gemini Deep Think, scored a gold medal in the International Math Olympiad but is unable to read analog clocks half the time.)

Michelle does a great job covering the report’s highlights. But I wanted to dwell on a question that I can’t shake. Why is it so hard to know exactly what’s going on in AI right now?  

The widest gap seems to be between experts and non-experts. “AI experts and the general public view the technology’s trajectory very differently,” the authors of the AI Index write. “Assessing AI’s impact on jobs, 73% of U.S. experts are positive, compared with only 23% of the public, a 50 percentage point gap. Similar divides emerge with respect to the economy and medical care.”

That’s a huge gap. What’s going on? What do experts know that the public doesn’t? (“Experts” here means US-based researchers who took part in AI conferences in 2023 and 2024.)

I suspect part of what’s going on is that experts and non-experts base their views on very different experiences. “The degree to which you are awed by AI is perfectly correlated with how much you use AI to code,” a software developer posted on X the other day. Maybe that’s tongue-in-cheek, but there’s definitely something to it.

The latest models from the top labs are now better than ever at producing code. Because technical tasks like coding have right or wrong results, it is easier to train models to do them, compared with tasks that are more open-ended. What’s more, models that can code are proving to be profitable, so model makers are throwing resources at improving them.

This means that people who use those tools for coding or other technical work are experiencing this technology at its best. Outside of those use cases, you get more of a mixed bag. LLMs still make dumb mistakes. This phenomenon has become known as the “jagged frontier”: Models are very good at doing some things and less good at others.

The influential AI researcher Andrej Karpathy also had some thoughts. “Judging by my [timeline] there is a growing gap in understanding of AI capability,” he wrote in reply to that X post. He noted that power users (read: people who use LLMs for coding, math, or research) not only keep up to date with the latest models but will often pay $200 a month for the best versions. “The recent improvements in these domains as of this year have been nothing short of staggering,” he continued.

Because LLMs are still improving fast, someone who pays to use Claude Code will in effect be using a different technology from someone who tried using the free version of Claude to plan a wedding six months ago. Those two groups are speaking past each other.

Where does that leave us? I think there are two realities. Yes, AI is far better than a lot of people realize. And yes, it is still pretty bad at a lot of stuff that a lot of people care about (and it may stay that way). Anyone making bets about the future on either side should bear that in mind.

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Neural Mechanism Underlying Sensory Behavior Revealed in C. elegans

Animal behavior reflects a complex interplay between an animal’s brain and its sensory surroundings. In a new study published in Nature Neuroscience titled, “Neural sequences underlying directed turning in Caenorhabditis elegans,” researchers from Massachusetts Institute of Technology (MIT) have shown how neuron circuits within C. elegans nematode worms respond to odors and generate movement as they pursue favorable versus unfavorable smells. The results inform understanding of the basic principles of the sensory nervous system for therapeutic applications. 

“Across the animal kingdom, there are just so many remarkable behaviors,” said Steven Flavell, PhD, associate professor at the Picower Institute at MIT, Howard Hughes Medical Institute (HHMI) investigator, and corresponding author of the study. “With modern neuroscience tools, we are finally gaining the ability to map their mechanistic underpinnings.” 

Whether moving toward a food source or away from a predator, animals must integrate sensory stimuli to navigate to favorable locations. The neural circuits for navigation are tasked with generating directed movement while simultaneously integrating sensory input to update behavior. Understanding how neural circuits select, execute and adapt sensory-guided navigation behaviors uncovers basic principles of how nervous systems are organized to integrate sensory information and control behavior. 

In C. elegans, the authors identified error-correcting turns during navigation and used whole-brain calcium imaging and cell-specific perturbations to determine their neural underpinnings. Defined neurons activated in a stereotyped order during each turn. Distinct neurons in this sequence respond to the spatial distribution of attractive and aversive olfactory cues, anticipate upcoming turn directions and drive movement, linking key features of this sensorimotor behavior across time. 

“One thing that really excited us about this study is that we were able to see what a sensorimotor arc looks like at the scale of a whole nervous system: all the bits and pieces, from responses to the sensory cue until the behavioral response is implemented,” Flavell said.  

The electrical activity of more than 100 neurons was tracked during sensory movement. Notably, C. elegans only have 302 neurons total. Instead of random movements, the worms executed turns with advantageous timing and at well-chosen angles.  

The activity of SAA neurons was crucial for integrating odor detection with planned movement and predicted the direction of upcoming turns. Several neurons showed different activity patterns depending on the location of odors were and whether the worm was moving forward or in reverse. 

Additionally, the neuromodulator, tyramine, was essential for turning and shifting gears. When the worms moved in reverse, tyramine from the neuron RIM enabled other neurons in the sequence to change their activity appropriately to execute the turns. In several experiments, the scientists knocked out RIM tyramine, which disrupted the navigation behaviors and the sequence of neural activity. 

The post Neural Mechanism Underlying Sensory Behavior Revealed in <i>C. elegans</i> appeared first on GEN – Genetic Engineering and Biotechnology News.

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A novel behavioral paradigm using mice to study predictive postural control

Postural control circuitry performs the essential function of maintaining balance and body position in response to perturbations that are either self-generated (e.g., reaching to pick up an object) or externally delivered (e.g., being pushed by another person). Human studies have shown that anticipation of predictable postural disturbances can modulate such responses. This indicates that postural control could involve higher-level neural structures associated with predictive functions, rather than being purely reactive. However, the underlying neural circuitry remains largely unknown. To enable studies of predictive postural control circuits, we developed a novel experimental paradigm for mice. In this paradigm, modeled after studies in humans and rats, a dynamic platform generated reproducible translational perturbations. While mice stood on their hind legs atop a perch to receive water rewards, they experienced backward translations that were either unpredictable or preceded by an auditory cue. To validate the paradigm, we investigated the effect of the auditory cue on postural responses to perturbations across multiple days in three mice. These preliminary results serve to validate a new postural control experimental paradigm, opening the door to the types of neural recordings and circuit manipulations that are currently possible in mice.
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In silico exploration of electric field distribution in tDCS: integrating white matter anisotropy and subject-specific structural connectivity

Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulation technique with promising application in the treatment of neurological and psychiatric disorders. However, its effectiveness is often limited by the high inter-subject variability of the induced effects, mainly attributable to individual anatomical differences, which are not considered in the design of the stimulation protocols. Among these, structural connectivity plays a crucial role but remains often overlooked in tDCS research. Objective—This study aims to evaluate how variations in structural connectivity influence the distribution of the electric field (EF) during tDCS session. In particular, we analyse how the inclusion of white matter anisotropy affects the EF distribution and spread compared to classical isotropic models, and how the strength of connection across cortical parcels affects the EF spread. Approach—The study proposes an advancement in the computational modelling of tDCS through the integration of white matter anisotropy into finite element method (FEM) simulations. By combining advanced computational approaches, we explore the relationship between EF strength and cortical connectivity. Main results—Neglecting white matter anisotropy in electromagnetic simulations lead to a relative error in EF magnitude greater than 10% and to an orientation error of the EF vector of almost 20 degrees. The DTI-informed simulations lead to a more focalized EF distribution, moreover it was found a positive and significant (p < 0.05) correlation between EF focality and the strength of connectivity between cortical areas below P2 and P1 electrodes. Significance—These findings highlight the importance of including white matter anisotropy into tDCS simulation to prevent distortions in EF distribution and suggest the need to integrate structural connectivity information into the definition of subject-specific dose in tDCS protocols.
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The associations of systemic inflammation and insulin resistance-related indicators with psychopathology and BDNF in patients with chronic schizophrenia

BackgroundThe triglyceride-glucose (TyG) index and C-reactive protein-triglyceride-glucose index (CTI) are innovative indicators for assessing insulin resistance (IR) and inflammation, yet research on them in patients with schizophrenia remains limited. This study aimed to explore TyG index and CTI levels and their associations with psychopathology and brain-derived neurotrophic factor (BDNF) in patients with chronic schizophrenia (CS).MethodsThis cross-sectional study was conducted across one general hospital and two psychiatric hospitals in Anhui Province, China. Socio-demographic information and hematological parameters were collected from participants, and their psychiatric and depressive symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS) and the Calgary Depression Scale for Schizophrenia (CDSS), respectively.ResultsA total of 324 patients with CS and 150 healthy controls (HCs) were enrolled in the study. Compared with HCs, patients had higher TyG index and CTI levels (all P < 0.001). Binary logistic regression analyses revealed that among patients, a high TyG index level was significantly associated with higher BDNF levels and lower negative factor scores of the PANSS, while a high CTI level was significantly associated with higher depression-hopelessness factor scores of the CDSS and lower negative factor scores of the PANSS (all P < 0.05).ConclusionPatients with CS had higher levels of TyG index and CTI, which were significantly associated with the severity of negative and depressive symptoms, as well as BDNF levels. It is suggested that the integration of the TyG index and CTI into clinical monitoring for patients with CS is necessary.
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Patient safety incidents in mental health residential services: a multicenter, crosssectional, survey-based study

IntroductionWhile patient safety in general hospitals is well-researched, residential mental health services have received less attention. Psychiatric patients and staff working in such facilities face unique and complex risks. This study aims to explore and describe the frequency and characteristics of patient safety incidents (PSIs) experienced by professionals working in a cohort of Italian mental health residential services.MethodsA multicenter, cross-sectional, questionnaire-based observational study was conducted involving workers from 68 psychiatric mental health services from seven different Italian provinces. A total of 159 respondents, including both healthcare and non-healthcare professionals, took part in the study. Participants reported incidents personally experienced (FHE) or reported by colleagues (CRE) over the previous 12 months, using a taxonomy adapted from the World Health Organization’s Conceptual Framework for the International Classification for Patient Safety. Data was analyzed using descriptive statistics and zero-inflated models to identify associations between respondent characteristics and reporting behaviors.ResultsA total of 4,432 FHE and 4,807 CRE were reported. The behavior-related events were the most frequently reported, followed by incidents related to organizational or infrastructure issues, and medication errors. Secondary analyses suggested that facilities with more than ten employees had significantly higher rates of both FHE and CRE. Furthermore, residential facilities showed a higher incidence rate of CRE compared to non-residential ones, and non-healthcare workers reported witnessing fewer incidents to colleagues (28%) compared to healthcare workers. Significant variability was also observed across different provinces.ConclusionResidential mental health services experience a high incidence of PSIs, suggesting a risk profile distinct from general hospital settings. The predominance of behavior-related incidents corroborates the hypothesis that primary risks are mainly driven by relational dynamics. The findings highlight that both healthcare and non-healthcare staff are exposed to significant risks, suggesting the need of inclusive and comprehensive safety interventions. Consequently, specific training programs focused on relational risk management, de-escalation, and empathic communication are essential for all workers employed in these settings.