tbuckley/cabot-search huggingface dataset:
Ketogenic diet alters the epigenetic and immune landscape of prostate cancer to overcome resistance to immune checkpoint blockade therapy
Authors: Sean Murphy, Sharif Rahmy, Dailin Gan, Guoqiang Liu, Yini Zhu, Maxim Manyak, Loan Duong, Jianping He, James H. Schofield, Zachary T. Schafer, Jun Li, Xuemin Lu, Xin Lu
Journal: Cancer Research (2024)

Resistance to immune checkpoint blockade (ICB) therapy represents a formidable clinical challenge limiting the efficacy of immunotherapy. In particular, prostate cancer poses a challenge for ICB therapy due to its immunosuppressive features. A ketogenic diet (KD) has been reported to enhance response to ICB therapy in some other cancer models. However, adverse effects associated with continuous KD were also observed, demanding better mechanistic understanding and optimized regimens for using KD as an immunotherapy sensitizer. In this study, we established a series of ICB-resistant prostate cancer cell lines and developed a highly effective strategy of combining anti-PD1 and anti-CTLA4 antibodies with histone deacetylase inhibitor (HDACi) vorinostat, a cyclic KD (CKD), or dietary supplementation of the ketone body β-hydroxybutyrate (BHB), which is an endogenous HDACi. CKD and BHB supplementation each delayed prostate cancer tumor growth as monotherapy, and both BHB and adaptive immunity were required for the antitumor activity of CKD. Single-cell transcriptomic and proteomic profiling revealed that HDACi and ketogenesis enhanced ICB efficacy through both cancer cell-intrinsic mechanisms, including upregulation of MHC class I molecules, and -extrinsic mechanisms, such as CD8+ T-cell chemoattraction, M1/M2 macrophage rebalancing, monocyte differentiation toward antigen-presenting cells, and diminished neutrophil infiltration. Overall, these findings illuminate a potential clinical path of using HDACi and optimized KD regimens to enhance ICB therapy for prostate cancer.
How Artificial Intelligence Unravels the Complex Web of Cancer Drug Response
Authors: Olivier Elemento
Journal: Cancer Research (2024)

The intersection of precision medicine and artificial intelligence (AI) holds profound implications for cancer treatment, with the potential to significantly advance our understanding of drug responses based on the intricate architecture of tumor cells. A recent study by Park and colleagues titled "A Deep Learning Model of Tumor Cell Architecture Elucidates Response and Resistance to CDK4/6 Inhibitors" epitomizes this intersection by leveraging an interpretable deep learning model grounded in a comprehensive map of multiprotein assemblies in cancer, known as Nested Systems in Tumors. This study not only elucidates mechanisms underlying the response to CDK4/6 inhibitors in breast cancer therapy but also highlights the critical role of model interpretability leading to new mechanistic insights.
Synergistic large segmental bone repair by 3D printed bionic scaffolds and engineered ADSC nanovesicles: Towards an optimized regenerative microenvironment
Authors: Wenbin Jiang, Yichen Zhan, Yifan Zhang, Di Sun, Guo Zhang, Zhenxing Wang, Lifeng Chen, Jiaming Sun
Journal: Biomaterials (2024)

Achieving sufficient bone regeneration in large segmental defects is challenging, with the structure of bone repair scaffolds and their loaded bioactive substances crucial for modulating the local osteogenic microenvironment. This study utilized digital laser processing (DLP)-based 3D printing technology to successfully fabricate high-precision methacryloylated polycaprolactone (PCLMA) bionic bone scaffold structures. Adipose-derived stem cell-engineered nanovesicles (ADSC-ENs) were uniformly and stably modified onto the bionic scaffold surface using a perfusion device, constructing a conducive microenvironment for tissue regeneration and long bone defect repair through the scaffold's structural design and the vesicles' biological functions. Scanning electron microscopy (SEM) examination of the scaffold surface confirmed the efficient loading of ADSC-ENs. The material group loaded with vesicles (PCLMA-BAS-ENs) demonstrated good cell compatibility and osteogenic potential when analyzed for the adhesion and osteogenesis of primary rabbit bone marrow mesenchymal stem cells (BMSCs) on the material surface. Tested in a 15 mm critical rabbit radial defect model, the PCLMA-BAS-ENs scaffold facilitated near-complete bone defect repair after 12 weeks. Immunofluorescence and proteomic results indicated that the PCLMA-BAS-ENs scaffold significantly improved the osteogenic microenvironment at the defect site in vivo, promoted angiogenesis, and enhanced the polarization of macrophages towards M2 phenotype, and facilitated the recruitment of BMSCs. Thus, the PCLMA-BAS-ENs scaffold was proven to significantly promote the repair of large segmental bone defects. Overall, this strategy of combining engineered vesicles with highly biomimetic scaffolds to promote large-segment bone tissue regeneration holds great potential in orthopedic and other regenerative medicine applications.
Integrin αvβ3 Upregulation in Response to Nutrient Stress Promotes Lung Cancer Cell Metabolic Plasticity
Authors: Arin Nam, Shashi Jain, Chengsheng Wu, Alejandro Campos, Ryan M. Shepard, Ziqi Yu, Joshua P. Reddy, Tami Von Schalscha, Sara M. Weis, Mark Onaitis, Hiromi I. Wettersten, David A. Cheresh
Journal: Cancer Research (2024)

Abstract Cancer stem/tumor-initiating cells display stress tolerance and metabolic flexibility to survive in a harsh environment with limited nutrient and oxygen availability. The molecular mechanisms underlying this phenomenon could provide targets to prevent metabolic adaptation and halt cancer progression. Here, we showed in cultured cells and live human surgical biopsies of non–small cell lung cancer that nutrient stress drives the expression of the epithelial cancer stem cell marker integrin αvβ3 via upregulation of the β3 subunit, resulting in a metabolic reprogramming cascade that allows tumor cells to thrive despite a nutrient-limiting environment. Although nutrient deprivation is known to promote acute, yet transient, activation of the stress sensor AMP-activated protein kinase (AMPK), stress-induced αvβ3 expression via Src activation unexpectedly led to secondary and sustained AMPK activation. This resulted in the nuclear localization of peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC1α) and upregulation of glutamine metabolism, the tricarboxylic acid cycle, and oxidative phosphorylation. Pharmacological or genetic targeting of this axis prevented lung cancer cells from evading the effects of nutrient stress, thereby blocking tumor initiation in mice following orthotopic implantation of lung cancer cells. These findings reveal a molecular pathway driven by nutrient stress that results in cancer stem cell reprogramming to promote metabolic flexibility and tumor initiation. Significance: Upregulation of integrin αvβ3, a cancer stem cell marker, in response to nutrient stress activates sustained AMPK/PGC1α signaling that induces metabolic reprogramming in lung cancer cells to support their survival. See related commentary by Rainero, p. 1543
PD-1 downregulation enhances CAR-T cell antitumor efficiency by preserving a cell memory phenotype and reducing exhaustion
Authors: Wanyan Ouyang, Shi-Wei Jin, Nan Xu, Wei-Yang Liu, Han Zhao, Liuqingqing Zhang, Liqing Kang, Yi Tao, Yuanfang Liu, Yan Wang, Jin Wang, Feng Liu, Lei Yu, Zhiqiang Liu, Jian-Qing Mi
Journal: Journal for ImmunoTherapy of Cancer (2024)

Despite the encouraging outcome of chimeric antigen receptor T cell (CAR-T) targeting B cell maturation antigen (BCMA) in managing relapsed or refractory multiple myeloma (RRMM) patients, the therapeutic side effects and dysfunctions of CAR-T cells have limited the efficacy and clinical application of this promising approach. In this study, we incorporated a short hairpin RNA cassette targeting PD-1 into a BCMA-CAR with an OX-40 costimulatory domain. The transduced PD-1KD BCMA CAR-T cells were evaluated for surface CAR expression, T-cell proliferation, cytotoxicity, cytokine production, and subsets when they were exposed to a single or repetitive antigen stimulation. Safety and efficacy were initially observed in a phase I clinical trial for RRMM patients. Compared with parental BCMA CAR-T cells, PD-1KD BCMA CAR-T cell therapy showed reduced T-cell exhaustion and increased percentage of memory T cells in vitro. Better antitumor activity in vivo was also observed in PD-1KD BCMA CAR-T group. In the phase I clinical trial of the CAR-T cell therapy for seven RRMM patients, safety and efficacy were initially observed in all seven patients, including four patients (4/7, 57.1%) with at least one extramedullary site and four patients (4/7, 57.1%) with high-risk cytogenetics. The overall response rate was 85.7% (6/7). Four patients had a stringent complete response (sCR), one patient had a CR, one patient had a partial response, and one patient had stable disease. Safety profile was also observed in these patients, with an incidence of manageable mild to moderate cytokine release syndrome and without the occurrence of neurological toxicity. Our study demonstrates a design concept of CAR-T cells independent of antigen specificity and provides an alternative approach for improving the efficacy of CAR-T cell therapy.
Single-Cell Multimodal Profiling of Atherosclerosis Identifies CD200 as a Cell Surface Lineage Marker of Vascular Smooth Muscle Cells and Their Derived Cells
Authors: Alexander C. Bashore, Allen Chung, Chinyere Ibikunle, Hanying Yan, Chenyi Xue, Mingyao Li, Robert C. Bauer, Muredach P. Reilly
Journal: Circulation (2024)
The Pan-RAF–MEK Nondegrading Molecular Glue NST-628 Is a Potent and Brain-Penetrant Inhibitor of the RAS–MAPK Pathway with Activity across Diverse RAS- and RAF-Driven Cancers
Authors: Meagan B. Ryan, Bradley Quade, Natasha Schenk, Zhong Fang, Marshall Zingg, Steven E. Cohen, Brooke M. Swalm, Chun Li, Ayşegül Özen, Chaoyang Ye, Maria Stella Ritorto, Xin Huang, Arvin C. Dar, Yongxin Han, Klaus P. Hoeflich, Michael Hale, Margit Hagel
Journal: Cancer Discovery (2024)

Alterations in the RAS-MAPK signaling cascade are common across multiple solid tumor types and are a driver for many cancers. NST-628 is a potent pan-RAF-MEK molecular glue that prevents the phosphorylation and activation of MEK by RAF, overcoming the limitations of traditional RAS-MAPK inhibitors and leading to deep durable inhibition of the pathway. Cellular, biochemical, and structural analyses of RAF-MEK complexes show that NST-628 engages all isoforms of RAF and prevents the formation of BRAF-CRAF heterodimers, a differentiated mechanism from all current RAF inhibitors. With a potent and durable inhibition of the RAF-MEK signaling complex as well as high intrinsic permeability into the brain, NST-628 demonstrates broad efficacy in cellular and patient-derived tumor models harboring diverse MAPK pathway alterations, including orthotopic intracranial models. Given its functional and pharmacokinetic mechanisms that are differentiated from previous therapies, NST-628 is positioned to make an impact clinically in areas of unmet patient need. Significance: This study introduces NST-628, a molecular glue having differentiated mechanism and drug-like properties. NST-628 treatment leads to broad efficacy with high tolerability and central nervous system activity across multiple RAS- and RAF-driven tumor models. NST-628 has the potential to provide transformative clinical benefits as both monotherapy and vertical combination anchor.
Infectious diseases and the role of needle biopsy post-mortem
Authors: Lucia Molinengo, Theodore Estrin-Serlui, Brian Hanley, Michael Osborn, Robert Goldin
Journal: The Lancet Microbe (2024)

Post-mortem examinations continue to play a crucial role in understanding the epidemiology and pathogenesis of infectious diseases. However, the perceived infection risk can preclude traditional, invasive, complete diagnostic autopsy. Post-mortem examination is especially important in emerging infectious diseases with potentially unknown infection risks, but rapid acquisition of good quality tissue samples is needed as part of the scientific and public health response. Needle biopsy post-mortem is a minimally invasive, rapid, closed-body autopsy technique that was originally developed to minimise the infection risk to practitioners. Since its inception, needle biopsy post-mortem has also been used as a technique to support complete diagnostic autopsy provision in poorly resourced regions and to facilitate post-mortem examinations in communities that might have religious or cultural objections to an invasive autopsy. This Review analyses the evolution and applicability of needle biopsy post-mortem in investigating endemic and emerging infectious diseases.
FFR-Guided Complete or Culprit-Only PCI in Patients with Myocardial Infarction
Authors: Felix Böhm, Brynjölfur Mogensen, Thomas Engstrøm, Goran Stankovic, Ilija Srdanovic, Jacob Lønborg, Sammy Zwackman, Mehmet Hamid, Thomas Kellerth, Jörg Lauermann, Olli A. Kajander, Jonas Andersson, Rikard Linder, Oskar Angerås, Henrik Renlund, Andrejs Ērglis, Madhav Menon, Carl Schultz, Mika Laine, Claes Held, Andreas Rück, Ollie Östlund, Stefan James
Journal: New England Journal of Medicine (2024)

The benefit of fractional flow reserve (FFR)-guided complete revascularization in patients with ST-segment elevation myocardial infarction (STEMI) and multivessel coronary artery disease remains unclear.
Comprehensive Transcriptomic Analysis of EWSR1::WT1 Targets Identifies CDK4/6 Inhibitors as an Effective Therapy for Desmoplastic Small Round Cell Tumors
Authors: Justin W. Magrath, Shruthi Sanjitha Sampath, Dane A. Flinchum, Alifiani B. Hartono, Ilon N. Goldberg, Julia R. Boehling, Suzana D. Savkovic, Sean B. Lee
Journal: Cancer Research (2024)

Abstract Desmoplastic small round cell tumors (DSRCT) are a type of aggressive, pediatric sarcoma characterized by the EWSR1::WT1 fusion oncogene. Targeted therapies for DSRCT have not been developed, and standard multimodal therapy is insufficient, leading to a 5-year survival rate of only 15% to 25%. Here, we depleted EWSR1::WT1 in DSRCT and established its essentiality in vivo. Transcriptomic analysis revealed that EWSR1::WT1 induces unique transcriptional alterations compared with WT1 and other fusion oncoproteins and that EWSR1::WT1 binding directly mediates gene upregulation. The E-KTS isoform of EWSR1::WT1 played a dominant role in transcription, and it bound to the CCND1 promoter and stimulated DSRCT growth through the cyclin D–CDK4/6–RB axis. Treatment with the CDK4/6 inhibitor palbociclib successfully reduced growth in two DSRCT xenograft models. As palbociclib has been approved by the FDA for the treatment of breast cancer, these findings demonstrate the sensitivity of DSRCT to palbociclib and support immediate clinical investigation of palbociclib for treating this aggressive pediatric cancer. Significance: EWSR1::WT1 is essential for desmoplastic small round cell tumors and upregulates the cyclin D–CDK4/6–RB axis that can be targeted with palbociclib, providing a targeted therapeutic strategy for treating this deadly tumor type.
Randomized Placebo-Controlled, Biomarker-Stratified Phase Ib Microbiome Modulation in Melanoma: Impact of Antibiotic Preconditioning on Microbiome and Immunity
Authors: Isabella C. Glitza, Yongwoo David Seo, Christine N. Spencer, Jennifer R. Wortman, Elizabeth M. Burton, Farah A. Alayli, Christopher P. Loo, Shikha Gautam, Ashish Damania, Julie Densmore, Justin Fairchild, Christopher R. Cabanski, Matthew C. Wong, Christine B. Peterson, Brian Weiner, Nathan Hicks, John Aunins, Christopher McChalicher, Emily Walsh, Michael T. Tetzlaff, Omid Hamid, Patrick A. Ott, Genevieve M. Boland, Ryan J. Sullivan, Kenneth F. Grossmann, Nadim J. Ajami, Theresa LaVallee, Matthew R. Henn, Hussein A. Tawbi, Jennifer A. Wargo
Journal: Cancer Discovery (2024)

Abstract Gut-microbiota modulation shows promise in improving immune-checkpoint blockade (ICB) response; however, precision biomarker-driven, placebo-controlled trials are lacking. We performed a multicenter, randomized placebo-controlled, biomarker-stratified phase I trial in patients with ICB-naïve metastatic melanoma using SER-401, an orally delivered Firmicutesenriched spore formulation. Fecal microbiota signatures were characterized at baseline; patients were stratified by high versus low Ruminococcaceae abundance prior to randomization to the SER-401 arm (oral vancomycin-preconditioning/SER-401 alone/nivolumab + SER-401), versus the placebo arm [placebo antibiotic/placebo microbiome modulation (PMM)/nivolumab + PMM (NCT03817125)]. Analysis of 14 accrued patients demonstrated that treatment with SER-401 + nivolumab was safe, with an overall response rate of 25% in the SER-401 arm and 67% in the placebo arm (though the study was underpowered related to poor accrual during the COVID-19 pandemic). Translational analyses demonstrated that vancomycin preconditioning was associated with the disruption of the gut microbiota and impaired immunity, with incomplete recovery at ICB administration (particularly in patients with high baseline Ruminococcaceae). These results have important implications for future microbiome modulation trials. Significance: This first-of-its-kind, placebo-controlled, randomized biomarker-driven microbiome modulation trial demonstrated that vancomycin + SER-401 and anti–PD-1 are safe in melanoma patients. Although limited by poor accrual during the pandemic, important insights were gained via translational analyses, suggesting that antibiotic preconditioning and interventional drug dosing regimens should be carefully considered when designing such trials. See author Yongwoo David Seo discuss this research brief, published simultaneously at the AACR Annual Meeting 2024: https://vimeo.com/932607668/63addff7fc
Single-cell systems pharmacology identifies development-driven drug response and combination therapy in B cell acute lymphoblastic leukemia
Authors: Xin Huang, Yizhen Li, Jingliao Zhang, Lei Yan, Huanbin Zhao, Liang Ding, Sheetal Bhatara, Xu Yang, Satoshi Yoshimura, Wenjian Yang, Seth E. Karol, Hiroto Inaba, Charles Mullighan, Mark Litzow, Xiaofan Zhu, Yingchi Zhang, Wendy Stock, Nitin Jain, Elias Jabbour, Steven M. Kornblau, Marina Konopleva, Ching-Hon Pui, Elisabeth Paietta, William Evans, Jiyang Yu, Jun J. Yang
Journal: Cancer Cell (2024)

Leukemia can arise at various stages of the hematopoietic differentiation hierarchy, but the impact of developmental arrest on drug sensitivity is unclear. Applying network-based analyses to single-cell transcriptomes of human B cells, we define genome-wide signaling circuitry for each B cell differentiation stage. Using this reference, we comprehensively map the developmental states of B cell acute lymphoblastic leukemia (B-ALL), revealing its strong correlation with sensitivity to asparaginase, a commonly used chemotherapeutic agent. Single-cell multi-omics analyses of primary B-ALL blasts reveal marked intra-leukemia heterogeneity in asparaginase response: resistance is linked to pre-pro-B-like cells, with sensitivity associated with the pro-B-like population. By targeting BCL2, a driver within the pre-pro-B-like cell signaling network, we find that venetoclax significantly potentiates asparaginase efficacy in vitro and in vivo. These findings demonstrate a single-cell systems pharmacology framework to predict effective combination therapies based on intra-leukemia heterogeneity in developmental state, with potentially broad applications beyond B-ALL.
Genetic interactions reveal distinct biological and therapeutic implications in breast cancer
Authors: Cai-Jin Lin, Xi Jin, Ding Ma, Chao Chen, Yang Ou-Yang, Yu-Chen Pei, Chao-Zheng Zhou, Fei-Lin Qu, Yun-Jin Wang, Cheng-Lin Liu, Lei Fan, Xin Hu, Zhi-Ming Shao, Yi-Zhou Jiang
Journal: Cancer Cell (2024)
Transgender and nonbinary young people’s bathroom avoidance and mental health
Authors: Jonah P. DeChants, Myeshia N. Price, Ronita Nath, Steven Hobaica, Amy E. Green
Journal: International Journal of Transgender Health (2024)

Background Transgender and nonbinary young people report disparities in both physical and mental health due to negative experiences associated with their identity. Despite bathrooms being an everyday necessity, transgender and nonbinary young people may avoid using them due to previous negative experiences or anxieties surrounding them, which may be related to poor health. This study examines the association of avoiding public bathrooms and mental health indicators among transgender and nonbinary young people.
The concept of resilience to Alzheimer’s Disease: current definitions and cellular and molecular mechanisms
Authors: Luuk E. de Vries, Inge Huitinga, Helmut W. Kessels, Dick F. Swaab, Joost Verhaagen
Journal: Molecular Neurodegeneration (2024)

Abstract Some individuals are able to maintain their cognitive abilities despite the presence of significant Alzheimer’s Disease (AD) neuropathological changes. This discrepancy between cognition and pathology has been labeled as resilience and has evolved into a widely debated concept. External factors such as cognitive stimulation are associated with resilience to AD, but the exact cellular and molecular underpinnings are not completely understood. In this review, we discuss the current definitions used in the field, highlight the translational approaches used to investigate resilience to AD and summarize the underlying cellular and molecular substrates of resilience that have been derived from human and animal studies, which have received more and more attention in the last few years. From these studies the picture emerges that resilient individuals are different from AD patients in terms of specific pathological species and their cellular reaction to AD pathology, which possibly helps to maintain cognition up to a certain tipping point. Studying these rare resilient individuals can be of great importance as it could pave the way to novel therapeutic avenues for AD.
Endocrine health in survivors of adult-onset cancer
Authors: Cornelia S Link-Rachner, Andy Göbel, Nikolai P Jaschke, Tilman D Rachner
Journal: The Lancet Diabetes & Endocrinology (2024)

Long-term survivors of cancer (ie, the patient who is considered cured or for whom the disease is under long-term control and unlikely to recur) are at an increased risk of developing endocrine complications such as hypothalamic-pituitary dysfunctions, hypogonadisms, osteoporosis, or metabolic disorders, particularly when intensive tumour-directed therapies are applied. Symptom severity associated with these conditions ranges from mild and subclinical to highly detrimental, affecting individual health and quality of life. Although they are usually manageable, many of these endocrine pathologies remain underdiagnosed and untreated for years. To address this challenge, a higher degree of awareness, standardised screening tools, comprehensible treatment algorithms, and a close collaborative effort between endocrinologists and oncologists are essential to early identify patients who are at risk, and to implement appropriate treatment protocols. This Review highlights common symptoms and conditions related to endocrine disorders among survivors of adult-onset cancer, provides a summary of the currently available practice guidelines, and proposes a practical approach to diagnose affected patients among this group.
Plasma-based antigen persistence in the post-acute phase of COVID-19
Authors: Michael J Peluso, Zoe N Swank, Sarah A Goldberg, Scott Lu, Thomas Dalhuisen, Ella Borberg, Yasmeen Senussi, Michael A Luna, Celina Chang Song, Alexus Clark, Andhy Zamora, Megan Lew, Badri Viswanathan, Beatrice Huang, Khamal Anglin, Rebecca Hoh, Priscila Y Hsue, Matthew S Durstenfeld, Matthew A Spinelli, David V Glidden, Timothy J Henrich, J Daniel Kelly, Steven G Deeks, David R Walt, Jeffrey N Martin
Journal: The Lancet Infectious Diseases (2024)