tbuckley/cabot-search huggingface dataset:
Real-World Efficacy and Safety of Inclisiran
Authors: Paola Gargiulo, Federica Marzano, Mario Crisci, Rossella Marcucci, Dario Bruzzese, Alessandro Maloberti, Filippo Maria Sarullo, Gennaro Galasso, Ciro Indolfi, Giuseppe Musumeci, Antonella Corleto, Paolo Calabrò, Stefano Carugo, Gavino Casu, Amedeo Picciolo, Marco Matteo Ciccone, Claudio Bilato, Alberto Polimeni, Francesco Giallauria, Angelo Catalano, Leonardo De Luca, Giampaolo Niccoli, Elio Venturini, Marco Pepe, Roberta Montisci, Natale Daniele Brunetti, Giuseppe Patti, Italo Porto, Alberto Margonato, Marina Floresta, Saverio Muscoli, Matteo Cameli, Giuseppe Andò, Emilio Di Lorenzo, Martina Berteotti, Cristina Giannattasio, Silvia Sarullo, Ciro Formisano, Assunta Di Costanzo, Fabrizio Delnevo, Ferdinando Varbella, Arturo Cesaro, Monica Franzese, Costantino Mancusi, Sara Fontanarosa, Mariafrancesca Di Santo, Ciro Cotticelli, Fabrizio Perrone Filardi, Stefania Paolillo, Giovanni Esposito, Alberto Corsini, Pasquale Perrone Filardi
Journal: Journal of the American College of Cardiology (2024)
Rheumatic Valve Surgery in Sudan
Authors: Gina Portella, Liliane Chatenoud, Sofia Gatti, Alessandro C Salvati, Lino Asta, Salvatore Lentini, Juha Puntila, Franco Masini, Sofia Redaelli, Alessandro Mocini, Suha Abdelwahab Abdallah, Sohayda Hussein Abdalla Abdalla, Nicoletta Erba, Elena Giovanella, Dimiana Raafat Shafig Saber, Daniela Rocchi, Manahel Badr Saad, Lorenzo Valgoi, Paolo Malerba, Luca Rolla, Antonio Pesenti, Roberto Latini, Pietro Parrino, Rossella Miccio, Martin Langer
Journal: Journal of the American College of Cardiology (2024)
Sound amongst the din: primate strategies against noise
Authors: Julia Löschner, Steffen R. Hage
Journal: Trends in Cognitive Sciences (2024)

Ambient noise disrupts vocal communication amongst animals. Recent studies show that some species, such as marmosets, can rapidly adjust the patterns of ongoing calls according to noisy environments. This substantial vocal flexibility reveals that non-human primates have more advanced cognitive control over when and what to vocalize than previously thought.
Rapid Sex Chromosome Turnover in African Clawed Frogs (<i>Xenopus</i>) and the Origins of New Sex Chromosomes
Authors: Ben J Evans, Václav Gvoždík, Martin Knytl, Caroline M S Cauret, Anthony Herrel, Eli Greenbaum, Jay Patel, Tharindu Premachandra, Theodore J Papenfuss, James Parente, Marko E Horb, John Measey
Journal: Molecular Biology and Evolution (2024)

Sex chromosomes of some closely related species are not homologous, and sex chromosome turnover is often attributed to mechanisms that involve linkage to or recombination arrest around sex-determining loci. We examined sex chromosome turnover and recombination landscapes in African clawed frogs (genus Xenopus) with reduced representation genome sequences from 929 individuals from 19 species. We recovered extensive variation in sex chromosomes, including at least eight nonhomologous sex-associated regions-five newly reported here, with most maintaining female heterogamety, but two independent origins of Y chromosomes. Seven of these regions are found in allopolyploid species in the subgenus Xenopus, and all of these reside in one of their two subgenomes, which highlights functional asymmetry between subgenomes. In three species with chromosome-scale genome assemblies (Xenopus borealis, Xenopus laevis, and Xenopus tropicalis), sex-specific recombination landscapes have similar patterns of sex differences in rates and locations of recombination. Across these Xenopus species, sex-associated regions are significantly nearer chromosome ends than expected by chance, even though this is where the ancestral recombination rate is highest in both sexes before the regions became sex associated. As well, expansions of sex-associated recombination arrest occurred multiple times. New information on sex linkage along with among-species variation in female specificity of the sex-determining gene dm-w argues against a "jumping gene" model, where dm-w moves around the genome. The diversity of sex chromosomes in Xenopus raises questions about the roles of natural and sexual selection, polyploidy, the recombination landscape, and neutral processes in driving sex chromosome turnover in animal groups with mostly heterogametic females.
Real-world impact of the platinum chemotherapy shortage on US patients with advanced cancer
Authors: Jacob B Reibel, Lova L Sun, Ravi B Parikh, Nadim Mahmud, Lainie P Martin, Rebecca A Hubbard, Ronac Mamtani
Journal: JNCI Journal of the National Cancer Institute (2024)

Abstract The recent cisplatin and carboplatin (“platinum”) chemotherapy shortage, first announced on February 10, 2023, has impacted cancer patients nationwide. Here, we quantify the extent to which the shortage affected platinum chemotherapy prescribing and short-term mortality. This cohort study included 11 797 adults with advanced solid cancers who initiated first-line therapy during the 1-year period before (February 1, 2022–February 9, 2023) or during (February 10, 2023–January 31, 2024) the platinum shortage. During the shortage, there was a 2.7% absolute reduction in platinum use (95% CI = −4.4% to −0.9%) compared to the previous year. At the peak of the shortage, there was a 15.1% absolute reduction in platinum prescribing (June 2023: 57.8% [95% CI = 53.6% to 62.0%]) compared to 1 year prior (June 2022: 72.9% [95% CI = 70.7% to 75.2%]). There was no difference in mortality before vs during the shortage (adjusted hazard ratio 1.00; 95% CI = 0.94 to 1.07) with median follow-up time of 7.6 months. Further research is required to study shortage impacts on long-term mortality.
Machine Learning-based Prognostic Subgrouping of Glioblastoma: A Multi-center Study
Authors: Hamed Akbari, Spyridon Bakas, Chiharu Sako, Anahita Fathi Kazerooni, Javier Villanueva-Meyer, Jose A Garcia, Elizabeth Mamourian, Fang Liu, Quy Cao, Russell T Shinohara, Ujjwal Baid, Alexander Getka, Sarthak Pati, Ashish Singh, Evan Calabrese, Susan Chang, Jeffrey Rudie, Aristeidis Sotiras, Pamela LaMontagne, Daniel S Marcus, Mikhail Milchenko, Arash Nazeri, Carmen Balana, Jaume Capellades, Josep Puig, Chaitra Badve, Jill S Barnholtz-Sloan, Andrew E Sloan, Vachan Vadmal, Kristin Waite, Murat Ak, Rivka R Colen, Yae Won Park, Sung Soo Ahn, Jong Hee Chang, Yoon Seong Choi, Seung-Koo Lee, Gregory S Alexander, Ayesha S Ali, Adam P Dicker, Adam E Flanders, Spencer Liem, Joseph Lombardo, Wenyin Shi, Gaurav Shukla, Brent Griffith, Laila M Poisson, Lisa R Rogers, Aikaterini Kotrotsou, Thomas C Booth, Rajan Jain, Matthew Lee, Abhishek Mahajan, Arnab Chakravarti, Joshua D Palmer, Dominic DiCostanzo, Hassan Fathallah-Shaykh, Santiago Cepeda, Orazio Santo Santonocito, Anna Luisa Di Stefano, Benedikt Wiestler, Elias R Melhem, Graeme F Woodworth, Pallavi Tiwari, Pablo Valdes, Yuji Matsumoto, Yoshihiro Otani, Ryoji Imoto, Mariam Aboian, Shinichiro Koizumi, Kazuhiko Kurozumi, Toru Kawakatsu, Kimberley Alexander, Laveniya Satgunaseelan, Aaron M Rulseh, Stephen J Bagley, Michel Bilello, Zev A Binder, Steven Brem, Arati S Desai, Robert A Lustig, Eileen Maloney, Timothy Prior, Nduka Amankulor, Mac Lean P Nasrallah, Donald M O’Rourke, Suyash Mohan, Christos Davatzikos
Journal: Neuro-Oncology (2024)

Glioblastoma is the most aggressive adult primary brain cancer, characterized by significant heterogeneity, posing challenges for patient management, treatment planning, and clinical trial stratification.
Dual role of vascular endothelial growth factor-C in post-stroke recovery
Authors: Yun Hwa Choi, Martin Hsu, Collin Laaker, Jenna Port, Kristóf G. Kovács, Melinda Herbath, Heeyoon Yang, Peter Cismaru, Alexis M. Johnson, Bailey Spellman, Kelsey Wigand, Matyas Sandor, Zsuzsanna Fabry
Journal: The Journal of Experimental Medicine (2024)

Cerebrospinal fluid (CSF), antigens, and antigen-presenting cells drain from the central nervous system (CNS) into lymphatic vessels near the cribriform plate and dura, yet the role of these vessels during stroke is unclear. Using a mouse model of ischemic stroke, transient middle cerebral artery occlusion (tMCAO), we demonstrate stroke-induced lymphangiogenesis near the cribriform plate, peaking at day 7 and regressing by day 14. Lymphangiogenesis is restricted to the cribriform plate and deep cervical lymph nodes and is regulated by VEGF-C/VEGFR-3 signaling. The use of a VEGFR-3 inhibitor prevented lymphangiogenesis and led to improved stroke outcomes at earlier time points, with no effects at later time points. VEGF-C delivery after tMCAO did not further increase post-stroke lymphangiogenesis, but instead induced larger brain infarcts. Our data support the damaging role of VEGF-C acutely and a pro-angiogenic role chronically. This nuanced understanding of VEGFR-3 and VEGF-C in stroke pathology advises caution regarding therapeutic VEGF-C use in stroke.
Baseline colitogenicity and acute perturbations of gut microbiota in immunotherapy-related colitis
Authors: Joan Shang, Diane Marie Del Valle, Graham J. Britton, K.R. Mead, Urvija Rajpal, Alice Chen-Liaw, Ilaria Mogno, Zhihua Li, Rajita Menon, Edgar Gonzalez-Kozlova, Arielle Elkrief, Jonathan U. Peled, Tina Ruth Gonsalves, Neil J. Shah, Michael Postow, Jean-Frederic Colombel, Sacha Gnjatic, David M. Faleck, Jeremiah J. Faith
Journal: The Journal of Experimental Medicine (2024)

Immunotherapy-related colitis (irC) frequently emerges as an immune-related adverse event during immune checkpoint inhibitor therapy and is presumably influenced by the gut microbiota. We longitudinally studied microbiomes from 38 ICI-treated cancer patients. We compared 13 ICI-treated subjects who developed irC against 25 ICI-treated subjects who remained irC-free, along with a validation cohort. Leveraging a preclinical mouse model, predisease stools from irC subjects induced greater colitigenicity upon transfer to mice. The microbiota during the first 10 days of irC closely resembled inflammatory bowel disease microbiomes, with reduced diversity, increased Proteobacteria and Veillonella, and decreased Faecalibacterium, which normalized before irC remission. These findings highlight the irC gut microbiota as functionally distinct but phylogenetically similar to non-irC and healthy microbiomes, with the exception of an acute, transient disruption early in irC. We underscore the significance of longitudinal microbiome profiling in developing clinical avenues to detect, monitor, and mitigate irC in ICI therapy cancer patients.
Optimizing public private partnerships to support clinical cancer research
Authors: Roy S Herbst, Gideon Blumenthal, Samir N Khleif, Scott M Lippman, Neal J Meropol, Kristen Rosati, Lawrence N Shulman, Heind Smith, Meina Wang, Robert A Winn, Richard L Schilsky
Journal: JNCI Journal of the National Cancer Institute (2024)

Abstract Public-private partnerships (PPPs) in cancer research have emerged as a pivotal model in the development of strategies to rapidly advance therapeutic innovations. The collaboration between public entities, such as government agencies and research institutions, and private entities, including pharmaceutical and biotechnology companies, as well as nonprofit organizations, brings together diverse expertise, resources, and perspectives to address the challenges of efficient drug development and equitable care delivery. This synergy has the potential to accelerate the translation of basic research findings into tangible clinical applications. However, the implementation of PPPs is challenging and fraught with pitfalls that must be overcome if the PPP is to be successful in achieving its goals. To address these issues, in October 2023, the National Cancer Policy Forum and the Forum on Drug Discovery, Development, and Translation held the “Optimizing Public-Private Partnerships for Clinical Cancer Research” workshop in Washington, DC. The goal of the workshop was to examine opportunities to promote collaboration among these various entities through PPPs to facilitate more timely and effective clinical cancer research. Key guiding principles and strategies were highlighted, and the challenges and barriers to implementing a PPP and recommendations to overcome those obstacles are summarized herein.
Genomic and the tumor microenvironment heterogeneity in multifocal hepatocellular carcinoma
Authors: Yongheng Yang, Qingqiang Ni, Hongguang Li, Jiuzheng Sun, Xia Zhou, Lingxin Qu, Liyuan Wang, Chuanzong Zhao, Xiaolu Zhang
Journal: Hepatology (2024)

Background and Aims: Ambiguous understanding of tumors and tumor microenvironments (TMEs) hinders accurate diagnosis and available treatment for multifocal hepatocellular carcinoma (﻿HCC) covering intrahepatic metastasis (IM) and multicentric occurrence (MO). Here, we characterized the diverse TMEs of IM and MO identified by whole-exome sequencing at single-cell resolution. Approach and Results: We performed parallel whole-exome sequencing and scRNA-seq on 23 samples from 7 patients to profile their TMEs when major results were validated by immunohistochemistry in the additional cohort. Integrative analysis of whole-exome sequencing and single-cell RNA sequencing found that malignant cells in IM showed higher intratumor heterogeneity, stemness, and more activated metabolism than those in MO. Tumors from IM shared similar TMEs while distinct TMEs were noticed in those from MO. Furthermore, CD20+ B cells, plasma cells, and conventional type II dendritic cells (cDC2s) were decreased in IM relative to MO while T cells in IM exhibited a more terminally exhausted capacity with a higher proportion of proliferative/exhausted T cells than that in MO. Both CD20 and CD1C correlated with better prognosis in multifocal HCC. Additionally, MMP9+ tumor-associated macrophages were enriched across IM and MO, which formed cellular niches with regulatory T cells and proliferative/exhausted T cells. Conclusions: Our findings deeply decipher the heterogeneous TMEs between IM and MO, which provide a comprehensive landscape of multifocal HCC.
Dynamics of Immune Reconstitution and Impact on Outcomes Across CAR-T Cell Products in Large B-Cell Lymphoma
Authors: Danny Luan, Susan DeWolf, Teng Fei, Sandeep Raj, Gunjan L. Shah, Caleb A. Lareau, Mohammad Alhomoud, Gilles Salles, Alfredo Rivas-Delgado, Kai Rejeski, Jae H. Park, Efrat Luttwak, Alejandro Luna de Abia, Magdalena Corona, Evangelos Ntrivalas, Giulio Cassanello, Marina Gomez-Llobell, Allison Parascondola, Michael Scordo, Katharine C. Hsu, M. Lia. Palomba, Miguel-Angel Perales, Roni Shouval
Journal: Blood Cancer Discovery (2024)

Abstract Patients treated with chimeric antigen receptor T-cell (CAR-T) therapy are subject to profound immune suppression. Dynamics of immune reconstitution (IR) and impacts of IR on outcomes following infusion across CAR-T products are not well understood. Here, we profiled IR in 263 patients with relapsed/refractory large B-cell lymphoma receiving CAR-T therapy (axicabtagene ciloleucel 44.9%, lisocabtagene maraleucel 30.4%, tisagenlecleucel 24.7%). Following infusion, patients remain persistently immunosuppressed, with 48.1% having CD4+ T cell counts &amp;lt;200/µL and median CD3-19+ B cell counts remaining zero through 1 year after CAR-T. IR differences exist by product, with fastest CD4+ T cell recovery seen for tisagenlecleucel, driven primarily by more rapid recovery of the CD4+CCR7-45RA- effector memory subset. Natural killer cell, but not CD4+ T cell, recovery is significantly associated with favorable progression-free (HR: 0.647; 95% CI: 0.476-0.880) and overall survival (HR: 0.637; 95% CI: 0.441-0.920) and inversely correlated with inflammatory markers measured at time of infusion.
Cracking HCC: Targeting diacylglycerol kinase eta to tackle therapy resistance and cancer stemness
Authors: Guisheng Song
Journal: Hepatology (2024)

1Departments of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota 55455 2Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, Minnesota 55455 Correspondence Guisheng Song, 516 Delaware Street SE, Minneapolis MN 55455. E-mail: [email protected]
Human papillomavirus genotype and cycle threshold value from self-samples and risk of high-grade cervical lesions: A post hoc analysis of a modified stepped-wedge implementation feasibility trial
Authors: Jiayao Lei, Kate Cuschieri, Hasit Patel, Alexandra Lawrence, Katie Deats, Peter Sasieni, Anita W. W. Lim
Journal: PLoS Medicine (2024)

Background Human papillomavirus (HPV) testing of self-collected vaginal samples has potential to improve coverage of cervical screening programmes, but current guidelines mostly require those HPV positive on a self-sample to attend for routine screening. Methods and findings A pragmatic modified stepped-wedge implementation feasibility trial was conducted at primary care practices in England. Individuals aged 25 to 64 years who were at least 6 months overdue for cervical screening could provide a self-collected sample. The primary outcomes included the monthly proportion of non-attenders screened, changes in coverage, and uptake within 90 days. Self-samples from 7,739 individuals were analysed using Roche Cobas 4800. Individuals with a positive self-sample were encouraged to attend clinical screening. In this post hoc study of the trial, we related the HPV type (HPV16, HPV18, or other high-risk type) and cycle threshold (Ct) value on the self-sample to the results of clinician-collected sample and cervical intraepithelial neoplasia grade 2 or worse (CIN2+). We wished to triage HPV–positive individuals to immediate colposcopy, clinician sampling, or 12-month recall depending on risk. A total of 1,001 women tested positive through self-samples, and 855 women who had both an HPV–positive self-sample and a subsequent clinician-sample were included in this study. Of these, 71 (8.3%) had CIN2+. Self-sample Ct values were highly predictive of HPV in the clinician sample. Combining HPV type and Ct value allowed stratification into 3 risk groups; 44/855 (5%) were high-risk of whom 43% (19/44, 95% confidence interval [29.7%, 57.8%]) had CIN2+. The majority (52.9%, 452/855) were low-risk, of whom 4% (18/452, 95% CI [2.5%, 6.2%]) had CIN2+. The main limitation of our study was the colposcopy assessment was restricted to individuals who had abnormal cytology after positive results of both self-sample and clinician-collected sample. Conclusions HPV type and Ct value on HPV–positive self-samples may be used for triage. The difference in the risk of CIN2+ in these groups appears sufficient to justify differential clinical management. A prospective study employing such triage to evaluate laboratory workflow, acceptability, and follow-up procedure and to optimise clinical performance seems warranted. Trial Registration ISRCTN12759467 .
MYO1F regulates T-cell activation and glycolytic metabolism by promoting the acetylation of GAPDH
Authors: Zhihui Cui, Heping Wang, Xiong Feng, Chuyu Wu, Ming Yi, Ruirui He, Ting Pan, Ru Gao, Lingyun Feng, Bo Zeng, Guoling Huang, Yuan Wang, Yanyun Du, Cun-Jin Zhang, Xue Xiao, Chenhui Wang
Journal: Cellular and Molecular Immunology (2024)
Olaparib as Treatment Versus Nonplatinum Chemotherapy in Patients With Platinum-Sensitive Relapsed Ovarian Cancer: Phase III SOLO3 Study Final Overall Survival Results
Authors: Giovanni Scambia, Ricardo Villalobos Valencia, Nicoletta Colombo, David Cibula, Charles A. Leath, Mariusz Bidziński, Jae-Weon Kim, Joo Hyun Nam, Radoslaw Madry, Carlos Hernández, Paulo A.R. Mora, Sang Young Ryu, Mei-Lin Ah-See, Elizabeth S. Lowe, Natalia Lukashchuk, Dave Carter, Richard T. Penson
Journal: Journal of Clinical Oncology (2024)

Olaparib treatment significantly improved objective response rate (primary end point) and progression-free survival versus nonplatinum chemotherapy in patients with BRCA-mutated platinum-sensitive relapsed ovarian cancer in the open-label phase III SOLO3 trial (ClinicalTrials.gov identifier: NCT02282020 ). We report final overall survival (OS; prespecified secondary end point), post hoc OS analysis by number of previous chemotherapy lines, and exploratory BRCA reversion mutation analysis. Two hundred sixty-six patients were randomly assigned 2:1 to olaparib tablets (300 mg twice daily; n = 178) or physician's choice of single-agent nonplatinum chemotherapy (pegylated liposomal doxorubicin, paclitaxel, gemcitabine, or topotecan; n = 88). OS was similar with olaparib versus chemotherapy (hazard ratio [HR], 1.07 [95% CI, 0.76 to 1.49]; P = .71, median 34.9 and 32.9 months, respectively, full analysis set). OS with olaparib was favorable in patients with two previous chemotherapy lines (HR, 0.83 [olaparib v chemotherapy] [95% CI, 0.51 to 1.38]; median 37.9 v 28.8 months); however, a potential detrimental effect was seen in patients with at least three previous chemotherapy lines (HR, 1.33 [95% CI, 0.84 to 2.18]; median 29.9 v 39.4 months). BRCA reversion mutations might have contributed to this finding. No patient randomly assigned to olaparib with a BRCA reversion mutation detected at baseline (6 of 170 [3.5%]) achieved an objective tumor response.
Tailoring capsid directed evolution technology for improved AAV-mediated CAR-T generation
Authors: Adrian Westhaus, Elena Barba-Sarasua, Yuyan Chen, Kenneth Hsu, Suzanne Scott, Maddison Knight, Florencia Haase, Santiago Mesa Mora, Benjamin C Houghton, Ramon Roca-Pinilla, Predrag Kalajdzic, Geraldine O'Neill, Adrian J Thrasher, Giorgia Santilli, Leszek Lisowski
Journal: Molecular Therapy (2024)

Chimeric antigen receptor (CAR) T-cell (CAR-T) therapies present options for patients diagnosed with certain leukemias. Recent advances of the technology included a method to integrate the CAR into the T-cell receptor alpha constant (TRAC) locus to take advantage of the endogenous promoter and regulatory elements for CAR expression. This method used adeno-associated viral (AAV) vectors based on AAV6 to deliver the donor template encoding the CAR construct. Since the original publication, improvements have been made to this targeted CAR integration technique, however, none of those techniques focused on improving the AAV vector used to deliver the therapeutic cargo. The herein presented study developed a novel AAV capsid directed evolution platform that allows to specifically select for novel AAV capsid variants that enable more efficient targeted gene editing-mediated CAR construct integration into the TRAC locus in primary T-cells. Using this new platform, we selected several novel AAVs that enable more efficient editing in T-cells than AAV6. Two novel capsids, AAV-T1 and AAV-T2, were able to mediate five-fold improvement for on-target knock-in, which resulted in five-fold reduction of the vector dose to produce highly cytolytic T-cells against a brain tumor cell line.