tbuckley/cabot-search huggingface dataset:
Engineered oncolytic virus expressing B7H3-targeting BiTE enhances antitumor T-cell immune response
Authors: Haoran Zhu, Wanrong Zhang, Qingguo Guo, Ruoyue Fan, Guangzuo Luo, Ying Liu
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Bispecific T-cell engagers (BiTEs) are recombinant bispecific proteins designed to stimulate polyclonal T-cell immunity. In recent years, B7H3, a pan-cancer antigen, has been considered a promising target for future immunotherapy. However, the B7H3-targeting BiTE faces the challenge of systemic toxicity. Oncolytic viruses (OVs) represent a new class of cancer immunotherapeutics and serve as an appropriate platform for locoregional delivery of therapeutic genes. In this study, we designed an oncolytic adenovirus (OAd) encoding BiTE targeting human B7H3. We hypothesized that OVs encoding B7H3 BiTE deliver this molecule persistently to the tumor site while mediating polyclonal T-cell activation and redirecting it to tumor cells. Methods B7H3-targeting BiTE was constructed by linking a single-chain variable fragment (scFv) that recognizes human B7H3 to an scFv that recognizes human CD3. B7H3 BiTE was inserted into OAd to construct OAd-B7H3-BiTE. The function of the OV-delivered B7H3 BiTE was detected via co-culturing B7H3 + target cells and peripheral blood mononuclear cells. A humanized immune system mouse model was used to evaluate the therapeutic effects in vivo. Results B7H3 is highly expressed in a high proportion of human malignancies. OV-delivered BiTEs bind to T cells and target cells. We observed a series of phenomena reflecting T-cell activation induced by OAd-B7H3-BiTE, including cell clustering, cell size, activation markers, cytokine secretion, and proliferation. Furthermore, T-cell activation was mirrored by the corresponding cytotoxicity against B7H3 + tumor cells. In vivo, B7H3 BiTE was persistently expressed in tumors and enhanced the antitumor T-cell immune response. Conclusions Using an OV for the local expression of B7H3 BiTE maximizes the local concentration of BiTE while reducing systemic exposure. OV also provides a relatively “hot” T-cell immune environment for the function of BiTE. Because of its capacity to activate polyclonal T cells, BiTE has the potential to redirect virus-specific T cells to tumors. Our study provides new opportunities for the exploitation of B7H3-BiTE-armed OVs as therapeutic agents for the treatment of B7H3-positive malignancies.
Mutation-guided chemotherapy-free strategy in first-line immunotherapy for low PD-L1-expressing non-squamous NSCLC
Authors: Hui Li, Jingjing Liu, Liang Zhang, Yu Xu, Xinyue Wang, Shaowei Lan, Peng Cui, Guoqiang Wang, Shangli Cai, Ying Cheng
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background The necessity of platinum-doublet chemotherapy in first-line immunotherapy for non-squamous non-small cell lung cancer (nsqNSCLC) with programmed death-ligand 1 (PD-L1) expression on less than 50% of tumor cells remains poorly investigated. Biomarkers predicting this necessity can guide chemotherapy-free treatment to minimize unnecessary toxicity. Methods Treated with immune checkpoint inhibitor monotherapy (ICI-mono), chemotherapy, or combination (ICI-chemo), 790 low PD-L1-expressing nsqNSCLCs (in-house: n=83; public: n=707) were analyzed for development and validation of the interaction score for additional chemotherapy (ISAC). Transcriptomic (public, n=11) and multiplex immunofluorescence data (in-house, n=100) were analyzed to evaluate the immune microenvironment. Results ICI-chemo, compared with ICI-mono, tended to prolong progression-free survival (PFS; HR=0.72, p=0.004) and overall survival (OS; HR=0.77, p=0.071) as first-line therapy in low PD-L1-expressing nsqNSCLCs. The added value of chemotherapy was observed in the ISAC-low subgroup (PFS: HR=0.48, p&lt;0.001; OS: HR=0.53, p=0.001) rather than the ISAC-high subgroup (PFS: HR=1.08, p=0.65; OS: HR=1.14, p=0.56). This predictive utility was independent of tumor mutational burden and PD-L1 expression, indicated by subgroup and multivariable analyses. A high ISAC was associated with adaptive immune resistance reflected by more proinflammatory (eg, CD8 + T cells and M1 macrophages) rather than anti-inflammatory tumor-infiltrating immune cells (eg, M2 macrophages) and high expression of immune checkpoints except for PD-L1 (eg, programmed cell death protein-1). Conclusion A high ISAC was identified as a significant predictor for virtually no added value of platinum-doublet chemotherapy for first-line ICI treatment in low PD-L1-expressing nsqNSCLC. Our findings may help refine personalized therapeutic strategies for nsqNSCLC, thereby improving efficacy and reducing undue toxicity.
Phenotypic and Genotypic Correlates of the NaHCO3-Responsive Phenotype Among Methicillin-Resistant Staphylococcus aureus (MRSA) Isolates from Skin and Soft Tissue Infections (SSTIs)
Authors: Selvi C. Ersoy, Sabrina L. Madrigal, Liang Chen, Jose Mediavilla, Barry Kreiswirth, Evelyn A. Flores, Loren G. Miller, Yan Q. Xiong, Ewan M. Harrison, Beth Blane, Sharon J. Peacock, Robin Patel, Henry F. Chambers, Arnold S. Bayer, Richard A. Proctor
Journal: Clinical Microbiology and Infection (2024)
Clinical utility of the Fibrosis-4 index for predicting mortality in patients with heart failure with or without metabolic dysfunction-associated steatotic liver disease: a prospective cohort study
Authors: Joost Boeckmans, Jürgen H Prochaska, Alexander Gieswinkel, Michael Böhm, Philipp S Wild, Jörn M Schattenberg
Journal: The Lancet Regional Health - Europe (2024)
Novel Pharmacologic and Other Somatic Treatment Approaches for Posttraumatic Stress Disorder in Adults: State of the Evidence
Authors: Lauren M. Sippel, Jessica L. Hamblen, Benjamin Kelmendi, Jonathan E. Alpert, Linda L. Carpenter, Adrienne Grzenda, Nina Kraguljac, William M. McDonald, Carolyn I. Rodriguez, Alik S. Widge, Charles B. Nemeroff, Paula P. Schnurr, Paul E. Holtzheimer
Journal: American Journal of Psychiatry (2024)

Posttraumatic stress disorder (PTSD) is a highly prevalent psychiatric disorder that can become chronic and debilitating when left untreated. The most commonly recommended first-line treatments for PTSD among adults are individual trauma-focused psychotherapies. Other evidence-based treatments include specific antidepressant medications and non-trauma-focused psychotherapies. Despite the effectiveness of these available treatments, many patients' symptoms do not remit. This has led to the search for novel treatments for PTSD. In this review, the authors critically evaluate the data supporting several emerging pharmacological and other somatic interventions in the categories of medication-assisted psychotherapy, novel medication monotherapy strategies, and neuromodulation, selected because of the salience of their mechanisms of action to the pathophysiology of PTSD (e.g., MDMA-assisted psychotherapy, ketamine, cannabidiol, transcranial magnetic stimulation). The authors also evaluate the evidence for treatments that are the focus of increasing scientific or public interest (i.e., hyperbaric oxygen therapy, stellate ganglion block, neurofeedback). To date, the evidence supporting most novel pharmacological and somatic treatments for PTSD is preliminary and highly variable; however, the data for several specific treatments, such as transcranial magnetic stimulation, are encouraging.
An Honest Reckoning With the Amygdala and Mental Illness
Authors: Andrew S. Fox, Alexander J. Shackman
Journal: American Journal of Psychiatry (2024)

Anxiety disorders are a leading source of human misery, morbidity, and premature mortality. Existing treatments are far from curative for many, underscoring the need to clarify the underlying neural mechanisms. Although many brain regions contribute, the amygdala has received the most intense scientific attention. Over the past several decades, this scrutiny has yielded a detailed understanding of amygdala function, but it has failed to produce new clinical assays, biomarkers, or cures. Rising to this urgent public health challenge demands an honest reckoning with the functional-neuroanatomical complexity of the amygdala and a shift from theories anchored on "the amygdala" to models centered on specific amygdala nuclei and cell types. This review begins by examining evidence from studies of rodents, monkeys, and humans for the "canonical model," the idea that the amygdala plays a central role in fear- and anxiety-related states, traits, and disorders. Next, the authors selectively highlight work indicating that the canonical model, while true, is overly simplistic and fails to adequately capture the actual state of the evidentiary record, the breadth of amygdala-associated functions and illnesses, or the complexity of the amygdala's functional architecture. The authors describe the implications of these facts for basic and clinical neuroimaging research. The review concludes with some general recommendations for grappling with the complexity of the amygdala and accelerating efforts to understand and more effectively treat amygdala-related psychopathology.
Pathways to Homelessness: Childhood Maltreatment and Psychiatric Symptoms Increase Risk of Homelessness
Authors: Cathy Spatz Widom, Kellie Courtney, Hang (Heather) Do
Journal: American Journal of Psychiatry (2024)

Homelessness is a serious and increasing public health concern. Childhood maltreatment and psychiatric problems have been associated with homelessness as risk factors; however, reliance on cross-sectional studies introduces ambiguity into interpreting previous findings. This study seeks to understand whether psychiatric symptoms in part explain the relationship between childhood maltreatment and homelessness.
Dual-Modality Visual Feature Flow for Medical Report Generation
Authors: Quan Tang, Liming Xu, Yongheng Wang, Bochuan Zheng, Jiancheng Lv, Xianhua Zeng, Weisheng Li
Journal: Medical Image Analysis (2024)

Medical report generation, a cross-modal task of generating medical text information, aiming to provide professional descriptions of medical images in clinical language. Despite some methods have made progress, there are still some limitations, including insufficient focus on lesion areas, omission of internal edge features, and difficulty in aligning cross-modal data. To address these issues, we propose Dual-Modality Visual Feature Flow (DMVF) for medical report generation. Firstly, we introduce region-level features based on grid-level features to enhance the method's ability to identify lesions and key areas. Then, we enhance two types of feature flows based on their attributes to prevent the loss of key information, respectively. Finally, we align visual mappings from different visual feature with report textual embeddings through a feature fusion module to perform cross-modal learning. Extensive experiments conducted on four benchmark datasets demonstrate that our approach outperforms the state-of-the-art methods in both natural language generation and clinical efficacy metrics.
A blood glucose fluctuation-responsive delivery system promotes bone regeneration and the repair function of Smpd3-reprogrammed BMSC-derived exosomes
Authors: Lingxiao Wang, Haoqing Yang, Chen Zhang, Yue Zhang, Yilin He, Yang Liu, Pan Ma, Jun Li, Zhipeng Fan
Journal: International Journal of Oral Science (2024)

Abstract Blood glucose fluctuation leads to poor bone defect repair in patients with type 2 diabetes (T2DM). Strategies to safely and efficiently improve the bone regeneration disorder caused by blood glucose fluctuation are still a challenge. Neutral sphingophospholipase 2 (Smpd3) is downregulated in jawbone-derived bone marrow mesenchymal stem cells (BMSCs) from T2DM patients. Here, we investigated the effect of Smpd3 on the osteogenic differentiation of BMSCs and utilized exosomes from stem cells overexpressing Smpd3 as the main treatment based on the glucose responsiveness of phenylboronic acid-based polyvinyl alcohol crosslinkers and the protease degradability of gelatin nanoparticles. The combined loading of Smpd3-overexpressing stem cell-derived exosomes (Exos-Smpd3) and nanosilver ions (Ns) to construct a hydrogel delivery system (Exos-Smpd3@Ns) promoted osteogenesis and differentiation of BMSCs in a glucose-fluctuating environment, ectopic osteogenesis of BMSCs in a glucose-fluctuating environment and jawbone regeneration of diabetic dogs in vitro. Mechanistically, Smpd3 promoted the osteogenesis and differentiation of jawbone-derived BMSCs by activating autophagy in the jawbone and inhibiting macrophage polarization and oxidative stress caused by blood glucose fluctuations. These results reveal the role and mechanism of Smpd3 and the Smpd3 overexpression exosome delivery system in promoting BMSC function and bone regeneration under blood glucose fluctuations, providing a theoretical basis and candidate methods for the treatment of bone defects in T2DM patients.
Is Lenacapavir Needed for Individuals Adherent to Daily Oral PrEP?
Authors: Xin Niu, Paul K. Drain
Journal: JAMA (2024)

This Viewpoint discusses the potential advantages of injectable preexposure prophylaxis (PrEP) drugs such as lenacapavir for persons unable to adhere to daily oral HIV PrEP and highlights ways in which lenacapavir and expanded PrEP options could offer tailored and effective ways to better meet the diverse needs of at-risk individuals.
Overcoming Hepatitis B Vaccine Nonresponsiveness
Authors: Ivan Hung, Anna S. Lok
Journal: JAMA (2024)

Kristen M. Marks, MD; Minhee Kang, PhD; Triin Umbleja, MSc; Andrea Cox, MD, PhD; Karen J. Vigil, MD; Ngan T. Ta, MD, PhD; Ayotunde Omoz-Oarhe, MD; Hugo Perazzo, MD, PhD; Josphat Kosgei, MBChB; Timothy Hatlen, MD; Jennifer Price, MD, PhD; Leolin Katsidzira, DPhil; Khuanchai Supparatpinyo, MD; Kevin Knowles, PhD; Beverly L. Alston-Smith, MD; Parita Rathod, BS; Kenneth E. Sherman, MD, PhD; ACTG 5379 (BEe-HIVe) Study Team; Oladapo Alli; Ceora Beijer; Stephanie Caruso; Shawn Chiambah; Lillian Collins; Kim Epperson; Francoise Giguel; Jan Kosmyna; Michael Leonard; Terence Mohammed; Leonard Sowah; Christina Vernon; Sara Zabih; Katrina Shea; Matthew Planchon; Paul Sax; Cheryl Keenan; Joyce Jones; Alex Hessel; Aleen Khodabakhshian; Lisa Mark; Eric S. Daar; Ruben Lopez; Rosemarie Ramirez; Dawn Rosenblum; Dennis Dentoni-Lasofsky; Cecilia Rivas Alfaro; Madhu Choudhary; Jen Sullivano; Rachel Bender Ignacio; Eli Burnham; Teresa Spitz; Raghd Alyatim; Susan Koletar; Robyn Cicarella; Carl J. Fichtenbaum; Michelle Saemann; Leila Hojat; Brenda Brown; Vivek Paul; Claudia Hawkins; Jaclyn Leone; Jonathan Oakes; Cornelius Van Dam; Kelly Phillips; Tracey Watkins; Ericka R. Patrick; Clifford Gunthel; Joslyn Axinn; Nicola Haakonsen; William Short; Pablo Tebas; Keisha Ballentine-Cargill; Nadi Islam; Daniel Finn; Catherine Jerry; Sharlaa Badal-Faesen; Iveshni Govender; Penelope Madlala; Rosie Mngqibisa; Nathalia Soliva; Tania Brum; Breno Riegel Santos; Rita de Cassia Alves Lira; Lerato Mohapi; Nadia Marengo; Sandra Rwambuya; Francis Ntengereze Ssali; Josphat Kosgei; Geoffrey Koskei; Ditlamelo Mareme; Boitshepho Seme; Mulinda Nyirenda; Maxwell Yohane; Michael Yin; Anyelina Cantos ; Karen J. Vigil; Mariano J. Lodigiani; Patcharaphan Sugandhavesa; Daralak Tavornprasit; Shobha Swaminathan; Christie Lyn Costanza; Sonal S. Munsiff; Susan E. Hulse; Sonya L. Heath; E. Turner Overton; Megan Dieterich; Carrington Koebele; Anchalee Avihingsanon; Hay Mar Su Lwin; Maria Tarcela Gler; Melchor Frias III; Ngan Ta Thi Dieu; Dat Quoc Vu
Advances in Treatment and Prevention of HIV
Authors: Timothy J. Hatlen, Rachel Bender Ignacio, Eric S. Daar
Journal: JAMA (2024)

Rajesh T. Gandhi, MD; Raphael J. Landovitz, MD; Paul E. Sax, MD; Davey M. Smith, MD; Sandra A. Springer, MD; Huldrych F. Günthard, MD; Melanie A. Thompson, MD; Roger J. Bedimo, MD; Constance A. Benson, MD; Susan P. Buchbinder, MD; Brenda E. Crabtree-Ramirez, MD; Carlos del Rio, MD; Ellen F. Eaton, MD; Joseph J. Eron Jr, MD; Jennifer F. Hoy, MBBS; Clara Lehmann, MD; Jean-Michel Molina, MD; Donna M. Jacobsen, BS; Michael S. Saag, MD
Antiretroviral Drugs for Treatment and Prevention of HIV in Adults: 2024 Recommendations of the International Antiviral Society–USA Panel
Authors: Rajesh T. Gandhi, Raphael J. Landovitz, Paul E. Sax, Davey M. Smith, Sandra A. Springer, Huldrych F. Günthard, Melanie A. Thompson, Roger J. Bedimo, Constance A. Benson, Susan P. Buchbinder, Brenda E. Crabtree-Ramirez, Carlos del Rio, Ellen F. Eaton, Joseph J. Eron, Jennifer F. Hoy, Clara Lehmann, Jean-Michel Molina, Donna M. Jacobsen, Michael S. Saag
Journal: JAMA (2024)

Importance New data and new antiretroviral drugs and formulations continue to become available for the prevention and management of HIV infection. Objective To provide updated recommendations for HIV treatment and clinical management and HIV prevention. Methods A panel of volunteer expert physician scientists were appointed to provide updated consensus recommendations for 2024. Relevant evidence in the literature since the last report was identified from PubMed and Embase searches (which initially yielded 3998 unique citations, of which 249 were considered relevant); from ongoing monitoring of the literature by the panel members; from data submitted by product manufacturers; and from studies presented at peer-reviewed scientific conferences between June 2022 and October 2024. Findings Antiretroviral therapy continues to be recommended for all individuals with HIV. For most people with HIV, initial regimens composed of an integrase strand transfer inhibitor (InSTI), specifically bictegravir or dolutegravir, with 2 (and in some cases 1) nucleoside or nucleotide reverse transcriptase inhibitors are recommended. Recommendations are made for those with particular clinical circumstances, such as pregnancy and active opportunistic diseases, as well as for those unable to take InSTIs. Regimens may need to be changed for virologic failure, adverse effects, convenience, or cost, among other reasons. Long-acting injectable therapy is available for those who prefer not to take daily oral medications and for people struggling with adherence to daily therapy. Recommendations are provided for laboratory monitoring, management of substance use disorders and weight changes, as well as use of statins for cardiovascular disease prevention. For HIV prevention, oral (daily or intermittent) and injectable long-acting medications are effective options for people at increased likelihood of HIV exposure. Further, new tools for maintaining health and well-being among people with HIV, such as doxycycline postexposure prophylaxis to avert sexually transmitted infection, and strategies to treat substance use disorders, are recommended. Disparities in HIV acquisition and care access are discussed and solutions proposed. Conclusions New approaches for treating and preventing HIV offer additional tools to help end the HIV epidemic, but achieving this goal depends on addressing disparities and inequities in access to care.
Taking the STING out of radiotherapy: STING checkpoints mediate radiation resistance
Authors: Michael C. Brown, Justin T. Low, Michelle L. Bowie, David M. Ashley
Journal: Journal of Clinical Investigation (2024)

The cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) pathway is a critical driver of type I interferon (IFN-I) and antitumor CD8+ T cell responses after radiotherapy (RT). In this issue of the JCI, two reports describe mechanisms that restrained STING signaling and abrogated antitumor immunity after RT. Wen, Wang, and colleagues discovered that IFN-I mediated the induction of YTHDF1, an RNA N6-methyladenosine-binding protein, in DCs after RT promoted cathepsin-mediated STING degradation. Zhang, Deng, Wu, and colleagues discovered that hemeoxygenase 1 (HO-1) was induced and proteolytically cleaved after RT to suppress cGAS cytoplasmic export as well as STING oligomerization at the ER. Blocking the STING-suppressive functions of YTHDF1 and HO-1, respectively, improved antitumor T cell immunity and tumor control after RT. Together, these studies support the development of clinical avenues to sustain STING signaling during RT, a standard treatment for approximately 50% of malignancies.
Reduced thymic IL-4 impairs negative T cell selection in nonobese diabetic mice
Authors: Alexis N Cattin-Roy, Kimberly G Laffey, Luan B Le, Adam G Schrum, Habib Zaghouani
Journal: Journal of Clinical Investigation (2024)

Type 1 diabetes (T1D) develops spontaneously despite functional antigen presentation machinery in the thymus and a perceptible central tolerance process. We found that intrathymic enrichment with IL-4 fine tunes signaling through the IL-4/IL-13 heteroreceptor (HR) in early thymic progenitors (ETPs), augments negative selection of self-reactive T cells, sustains a diverse T cell repertoire devoid of clones expressing disease-associated T cell receptor (TCR) genes, and protects the nonobese diabetic (NOD) mouse from T1D. Indeed, optimal IL-4 activates STAT transcription factors to program ETP fate decision toward CD11c+CD8α+ dendritic cells (DCs) agile in negative T cell selection and clonal deletion of diabetogenic T cells. However, due to diminished invariant natural killer T (iNKT) 2 cell frequency in the NOD thymus, IL-4 is as suboptimal level, metering STAT activation to program ETP fate decision toward the T cell lineage leading to diminished negative selection, a clonally restricted TCR repertoire, and manifestation of spontaneous T1D. These insights uncover yet another interplay by which IL-4 affects T1D.
Palmitoylation acts as a checkpoint for MAVS aggregation to promote antiviral innate immune responses
Authors: Liqiu Wang, Mengqiu Li, Guangyu Lian, Shuai Yang, Jing Cai, Zhe Cai, Yaoxing Wu, Jun Cui
Journal: Journal of Clinical Investigation (2024)

Upon RNA virus infection, the signaling adaptor MAVS forms functional prion-like aggregates on the mitochondrial outer membrane, which serve as a central hub that links virus recognition to downstream antiviral innate immune responses. Multiple mechanisms regulating MAVS activation have been revealed; however, the checkpoint governing MAVS aggregation remains elusive. Here, we demonstrated that the palmitoylation of MAVS at cysteine 79 (C79), which is catalyzed mainly by the palmitoyl S-acyltransferase ZDHHC12, was essential for MAVS aggregation and antiviral innate immunity upon viral infection in macrophages. Notably, the systemic lupus erythematosus-associated mutation MAVS C79F was associated with defective palmitoylation, resulting in low type I interferon (IFN) production. Accordingly, Zdhhc12 deficiency apparently impaired RNA virus-induced type I IFN responses, and Zdhhc12-deficient mice were highly susceptible to lethal viral infection. These findings reveal a previously unknown mechanism by which the palmitoylation of MAVS is a checkpoint for its aggregation during viral infection to ensure timely activation of antiviral defense.