tbuckley/cabot-search huggingface dataset:
Cancer-oocyte SAS1B protein is expressed at the cell surface of multiple solid tumors and targeted with antibody-drug conjugates
Authors: Arabinda Mandal, Jagathpala Shetty, Christine A Tran, Walter C Olson, Mriganka Mandal, Bhupal Ban, Eusebio S Pires, Sara J Adair, Todd W Bauer, Craig L Slingluff, John C Herr
Journal: Journal for ImmunoTherapy of Cancer (2024)

Sperm acrosomal SLLP1 binding (SAS1B) protein is found in oocytes, which is necessary for sperm-oocyte interaction, and also in uterine and pancreatic cancers. Anti-SAS1B antibody-drug conjugates (ADCs) arrested growth in these cancers. However, SAS1B expression in cancers and normal tissues has not been characterized. We hypothesized that SAS1B is expressed on the surface of other common solid cancer cells, but not on normal tissue cells, and might be selectively targeted therapeutically. SAS1B expression in human normal and cancer tissues was determined by immunohistochemistry, and complementary DNA (cDNA) libraries were employed to PCR amplify human SAS1B and its transcripts. Monoclonal antibodies (mAbs) to human SAS1B were generated using mouse hybridomas. SAS1B deletion constructs were developed to map SAS1B's epitope, enabling the creation of a blocking peptide. Indirect immunofluorescence (IIF) of human transfected normal and cancer cells was performed to assess SAS1B expression. SAS1B intracellular versus surface expression in normal and tumor tissues was evaluated by flow cytometry after staining with anti-SAS1B mAb, with specificity confirmed with the blocking peptide. Human cancer lines were treated with increasing mAb and ADC concentrations. ATP was quantitated as a measure of cell viability. SAS1B expression was identified in a subset of human cancers and the cytoplasm of pancreatic islet cells. Two new SAS1B splice variants were deduced. Monoclonal antibodies were generated to SAS1B splice variant A. The epitope for mAbs SB2 and SB5 is between SAS1B amino acids 32-39. IIF demonstrated intracellular SAS1B expression in transfected kidney cells and on the cell surface of squamous cell lung carcinoma. Flow cytometry demonstrated intracellular SAS1B expression in all tumors and some normal cells. However, surface expression of SAS1B was identified only on cancer cells. SB2 ADC mediated dose-dependent cytotoxic killing of multiple human cancer lines. SAS1B is a novel cancer-oocyte antigen with cell surface expression restricted to cancer cells. In vitro, it is an effective target for antibody-mediated cancer cell lysis. These findings support further exploration of SAS1B as a potential therapeutic cancer target in multiple human cancers, either with ADC or as a chimeric antigen receptor-T (CAR-T) cell target.
Modified FOLFOX6 plus bevacizumab with and without nivolumab for first-line treatment of metastatic colorectal cancer: phase 2 results from the CheckMate 9X8 randomized clinical trial
Authors: Heinz-Josef Lenz, Aparna Parikh, David R Spigel, Allen L Cohn, Takayuki Yoshino, Mark Kochenderfer, Elena Elez, Spencer H Shao, Dustin Deming, Regan Holdridge, Timothy Larson, Eric Chen, Amit Mahipal, Antonio Ucar, Dana Cullen, Edwina Baskin-Bey, Tong Kang, Amy B Hammell, Jin Yao, Josep Tabernero
Journal: Journal for ImmunoTherapy of Cancer (2024)

Standard first-line therapies for metastatic colorectal cancer (mCRC) include fluoropyrimidine-containing regimens with oxaliplatin and/or irinotecan and a biologic agent. Immunotherapy may enhance antitumor activity in combination with standard therapies in patients with mCRC. Here, we present phase 2 results of nivolumab plus standard-of-care therapy (SOC; 5-fluorouracil/leucovorin/oxaliplatin/bevacizumab) versus SOC in the first-line treatment of patients with mCRC (CheckMate 9X8).
Pembrolizumab versus placebo as adjuvant therapy in resected stage IIB or IIC melanoma: Outcomes in histopathologic subgroups from the randomized, double-blind, phase 3 KEYNOTE-716 trial
Authors: Dirk Schadendorf, Jason John Luke, Paolo A Ascierto, Georgina V Long, Piotr Rutkowski, Adnan Khattak, Michele Del Vecchio, Luis de la Cruz-Merino, Jacek Mackiewicz, Vanna Chiarion Sileni, John M Kirkwood, Caroline Robert, Jean-Jacques Grob, Reinhard Dummer, Matteo S Carlino, Yujie Zhao, Mizuho Kalabis, Clemens Krepler, Alexander Eggermont, Richard A Scolyer
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Adjuvant pembrolizumab significantly improved recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) versus placebo in the phase 3 KEYNOTE-716 study of resected stage IIB or IIC melanoma. At the prespecified third interim analysis (data cut-off, January 4, 2022), the HR for RFS in the overall population was 0.64 (95% CI, 0.50 to 0.84) and the HR for DMFS was 0.64 (95% CI, 0.47 to 0.88). We present a post hoc analysis of efficacy by subtypes defined by histopathologic characteristics. Methods Patients aged ≥12 years with newly diagnosed, resected stage IIB or IIC melanoma were randomly assigned (1:1) to pembrolizumab 200 mg every 3 weeks (2 mg/kg up to 200 mg for pediatric patients) or placebo. The primary end point was RFS per investigator review; DMFS per investigator review was secondary. Subgroups of interest were melanoma subtype (nodular vs non-nodular), tumor thickness (≤4 mm vs &gt;4 mm), presence of ulceration (yes vs no), mitotic rate (&lt;5 per mm 2 (median) vs ≥5 per mm 2 ), and presence of tumor-infiltrating lymphocytes (TILs; absent vs present). Results Between September 23, 2018, and November 4, 2020, 976 patients were assigned to pembrolizumab (n=487) or placebo (n=489). Median follow-up was 27.4 months (range, 14.0–39.4). The HR (95% CI) for RFS was 0.54 (0.37 to 0.79) for nodular and 0.77 (0.53 to 1.11) for non-nodular melanoma; 0.57 (0.37 to 0.89) for thickness ≤4 mm and 0.69 (0.50 to 0.96) for &gt;4 mm; 0.66 (0.50 to 0.89) for ulceration and 0.57 (0.32 to 1.03) for no ulceration; 0.57 (0.35 to 0.92) for mitotic rate &lt;5 per mm 2 and 0.57 (0.40 to 0.80) for ≥5 per mm 2 ; and 0.89 (0.52 to 1.54) for TILs absent and 0.51 (0.34 to 0.76) for TILs present. DMFS results were similar. In a Cox multivariate analysis, treatment arm, tumor thickness, and mitotic rate were significant independent factors for RFS, and treatment arm and mitotic rate were significant independent factors for DMFS. Conclusions In this post hoc analysis, the benefit of pembrolizumab was largely consistent with the overall study population regardless of histopathologic characteristics. These results support the use of adjuvant pembrolizumab in patients with resected stage IIB or IIC melanoma. Trial registration number ClinicalTrials.gov, NCT03553836 .
Phase II study of nivolumab in patients with genetic alterations in DNA damage repair and response who progressed after standard treatment for metastatic solid cancers (KM-06)
Authors: Ju Won Kim, Hyo Jin Lee, Ji Yoon Lee, Sook Ryun Park, Yu Jung Kim, In Gyu Hwang, Woo Kyun Bae, Jae Ho Byun, Jung Sun Kim, Eun Joo Kang, Jeeyun Lee, Sang Joon Shin, Won Jin Chang, Eun-Ok Kim, Jason K Sa, Kyong Hwa Park
Journal: Journal for ImmunoTherapy of Cancer (2024)

Immune-modulating antibodies targeting programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) have demonstrated promising antitumor efficacy in various types of cancers, especially highly mutated ones. Genetic alterations in DNA damage response and repair (DDR) genes can lead to genetic instability, often accompanied by a high tumor mutation burden (TMB). However, few studies have validated the aberration of DDR genes as a predictive biomarker for response to immune-modulating antibodies. The KM-06 open-label, multicenter, single-arm, phase II trial evaluated the safety and efficacy of nivolumab in refractory solid cancers with DDR gene mutations assessed by clinically targeted sequencing. Nivolumab (3 mg/kg) was administered every 2 weeks until disease progression, unacceptable toxicity, or for 24 months. The primary endpoint was the objective response rate (ORR) as per RECIST V.1.1 criteria. A total of 48 patients were enrolled in the study (median age 61, 58.3% male). The most common cancer type was colorectal cancer (41.7%), followed by prostate and biliary tract cancer (8.3% each). Eight patients achieved a partial response as their best overall response, resulting in an ORR of 17.8%. The disease control rate was 60.0%. The median progression-free survival was 2.9 months. Treatment-related adverse events of any grade and grade ≥3 occurred in 44 (91.7%) and 4 (8.3%) patients, respectively. Clinically targeted sequencing data inferred both TMB and microsatellite instability (MSI). Using a TMB cut-off of 12 mut/Mb, there were significant differences in overall survival (p=0.00035), progression-free survival (p=0.0061), and the best overall response (p=0.05). In the RNA sequencing analysis, nivolumab responders showed activation of the interleukin signaling pathway. Patients who experienced early progression presented high epithelial-mesenchymal transition signaling pathway activation. The responders exhibited a marked increase in PD-1-/Ki67+CD8 T cells at the early stage of treatment (C3D1) compared with non-responders (p=0.03). In this phase II trial, nivolumab demonstrated moderate efficacy and manageable toxicity in patients with solid cancer harboring DDR gene mutations. A high TMB (>12 mut/Mb) and MSI score (>2.5) determined through clinically target sequencing presented significant discriminatory power for the nivolumab response. NCT04761744.
Differentiating generalized pustular psoriasis from acute generalized exanthematous pustulosis
Authors: Mika Yamanaka-Takaichi, Miki Watanabe, Nneka I. Comfere, Olayemi Sokumbi, Christeebella O. Akpala, Austin Todd, Emily L. Branch, Aaron R. Mangold, Sho Hiroyasu, Daisuke Tsuruta, Afsaneh Alavi
Journal: Journal of the American Academy of Dermatology (2024)
Prostate Cancers in the Prostate-specific Antigen Interval of 1.8–3 ng/ml: Results from the Göteborg-2 Prostate Cancer Screening Trial
Authors: Fredrik Möller, Marianne Månsson, Jonas Wallström, Mikael Hellström, Jonas Hugosson, Rebecka Arnsrud Godtman
Journal: European Urology (2024)

Magnetic resonance imaging(MRI) and targeted biopsies reduce overdiagnosis of prostate cancer(PC). It is uncertain how this strategy performs for low PSA levels. The objective was to investigate the PI-RADS distribution, frequency and characteristics of screen-detected PC with PSA of 1.8-<3ng/ml and 3-<10ng/ml.
Systemic and Tumor-directed Therapy for Oligometastatic Prostate Cancer: The SOLAR Phase 2 Trial in De Novo Oligometastatic Prostate Cancer
Authors: Nicholas G. Nickols, Sonny Tsai, Nathanael Kane, Samantha Tran, Leila Ghayouri, Silvia Diaz-Perez, May Thein, Nancy Anderson-Berman, Jeanie Eason, Amar U. Kishan, Michael L. Steinberg, Robert E. Reiter, Steve P. Lee, Greg E. Gin, Robert Kwon, Michael G. Chang, Hann-Hsiang Chao, Abhiskek A. Solanki, Rachael Sexton, Michael Lewis, William Lorentz, Michael K. Cheung, Diana L. Gage, Sai Duriseti, Luca Valle, Gholam Berenji, William J. Aronson, Isla P. Garraway, Matthew B. Rettig
Journal: European Urology (2024)
Long-term Outcomes and Patterns of Relapse Following High-dose Elective Salvage Radiotherapy and Hormone Therapy in Oligorecurrent Pelvic Nodes in Prostate Cancer: OLIGOPELVIS (GETUG-P07)
Authors: Loig Vaugier, Cyrille Morvan, David Pasquier, Xavier Buthaud, Nicolas Magné, Veronique Beckendorf, Paul Sargos, Gilles Crehange, Pascal Pommier, Genevieve Loos, Ali Hasbini, Igor Latorzeff, Marlon Silva, Julie Paul, Audrey Blanc-Lapierre, Stéphane Supiot
Journal: European Urology (2024)
Whole-body Magnetic Resonance Imaging as a Treatment Response Biomarker in Castration-resistant Prostate Cancer with Bone Metastases: The iPROMET Clinical Trial
Authors: Alonso Garcia-Ruiz, Carlos Macarro, Francesca Zacchi, Rafael Morales-Barrera, Francesco Grussu, Irene Casanova-Salas, Francesco Sanguedolce, Macarena Gonzalez, Pablo Cresta-Morgado, Matias de Albert, Josep Garcia-Bennett, David Marmolejo, Jacques Planas, Sarai Roche, Richard Mast, Christina Zatse, Josep M Piulats, Bernardo Herrera-Imbroda, Lucas Regis, Laura Agundez, David Olmos, Nahum Calvo, Manuel Escobar, Joan Carles, Joaquin Mateo, Raquel Perez-Lopez
Journal: European Urology (2024)
Reply to: Insights on the ERS/ESTS statement on the management of pleural infection in adults
Authors: Eihab O. Bedawi, Najib M. Rahman
Journal: European Respiratory Journal (2024)

<h3>Shareable abstract</h3> <b>The use of tunnelled indwelling pleural catheters in pleural infection is limited to chronic empyema cavities with incomplete lung expansion in those unfit for decortication</b>https://bit.ly/3SSAxdC
Systematic pulmonary embolism follow-up: why we should all do it!
Authors: Luke S. Howard, Laura C. Price
Journal: European Respiratory Journal (2024)

<h3>Shareable abstract</h3> <b>Cumulative prevalence of CTEPH following confirmed PE was 2.1% in this Sheffield cohort undergoing consecutive follow-up. A fifth of those with CTEPH had CT signs of chronicity at index presentation, highlighting these patients for close follow-up.</b>https://bit.ly/49qby6P
Insights on the ERS/ESTS statement on the management of pleural infection in adults
Authors: Yalun Li, Hao Zeng, Panwen Tian, Weimin Li
Journal: European Respiratory Journal (2024)

<h3>Shareable abstract</h3> <b>Pleural fluid pH and LDH are reliable to inform indwelling pleural catheters (IPC) in patients whose fluid is not frankly purulent. Ongoing pleural drainage <i>via</i> IPC is required for patients with a confirmed pleural infection, including CPPE and empyema.</b> https://bit.ly/3He48HO
2024 ACC/AHA Clinical Performance and Quality Measures for Adults With Valvular and Structural Heart Disease
Authors: Hani Jneid, Joanna Chikwe, Suzanne V. Arnold, Robert O. Bonow, Steven M. Bradley, Edward P. Chen, Rebecca L. Diekemper, Setri Fugar, Douglas R. Johnston, Dharam J. Kumbhani, Roxana Mehran, Arunima Misra, Manesh R. Patel, Ranya N. Sweis, Molly Szerlip
Journal: Journal of the American College of Cardiology (2024)
Myocardin reverses insulin resistance and ameliorates cardiomyopathy by increasing IRS-1 expression in a murine model of lipodystrophy caused by adipose deficiency of vacuolar H<sup>+</sup>-ATPase V0d1 subunit
Authors: Wenlin Yuan, Hui Lin, Yuan Sun, Lihuan Liu, Meijuan Yan, Yujuan Song, Xiaofan Zhang, Xiangling Lu, Yipei Xu, Qiyue He, Kunfu Ouyang, Chenglin Zhang, Yong Pan, Yu Huang, Ying Li, Xifeng Lu, Jie Liu
Journal: Theranostics (2024)

Aim: Adipose tissue (AT) dysfunction that occurs in both obesity and lipodystrophy is associated with the development of cardiomyopathy.However, it is unclear how dysfunctional AT induces cardiomyopathy due to limited animal models available.We have identified vacuolar H + -ATPase subunit Vod1, encoded by Atp6v0d1, as a master regulator of adipogenesis, and adipose-specific deletion of Atp6v0d1 (Atp6v0d1 AKO ) in mice caused generalized lipodystrophy and spontaneous cardiomyopathy.Using this unique animal model, we explore the mechanism(s) underlying lipodystrophy-related cardiomyopathy.Methods and Results: Atp6v0d1 AKO mice developed cardiac hypertrophy at 12 weeks, and progressed to heart failure at 28 weeks.The Atp6v0d1 AKO mouse hearts exhibited excessive lipid accumulation and altered lipid and glucose metabolism, which are typical for obesity-and diabetes-related cardiomyopathy.The Atp6v0d1 AKO mice developed cardiac insulin resistance evidenced by decreased IRS-1/2 expression in hearts.Meanwhile, the expression of forkhead box O1 (FoxO1), a transcription factor which plays critical roles in regulating cardiac lipid and glucose metabolism, was increased.RNA-seq data and molecular biological assays demonstrated reduced expression of myocardin, a transcription coactivator, in Atp6v0d1 AKO mouse hearts.RNA interference (RNAi), luciferase reporter and ChIP-qPCR assays revealed the critical role of myocardin in regulating IRS-1 transcription through the CArG-like element in IRS-1 promoter.Reducing IRS-1 expression with RNAi increased FoxO1 expression, while increasing IRS-1 expression reversed myocardin downregulation-induced FoxO1 upregulation in cardiomyocytes.In vivo, restoring myocardin expression specifically in Atp6v0d1 AKO cardiomyocytes increased IRS-1, but decreased FoxO1 expression.As a result, the abnormal expressions of metabolic genes in Atp6v0d1 AKO hearts were reversed, and cardiac dysfunctions were ameliorated.Myocardin expression was also reduced in high fat diet-induced diabetic cardiomyopathy and palmitic acid-treated cardiomyocytes.Moreover, increasing systemic insulin resistance with rosiglitazone restored cardiac myocardin expression and improved cardiac functions in Atp6v0d1 AKO mice.Conclusion: Atp6v0d1 AKO mice are a novel animal model for studying lipodystrophy-or metabolic dysfunction-related cardiomyopathy.Moreover, myocardin serves as a key regulator of cardiac insulin sensitivity and metabolic homeostasis, highlighting myocardin as a potential therapeutic target for treating lipodystrophy-and diabetes-related cardiomyopathy.
Disassembly of the TRIM56-ATR complex promotes cytoDNA/cGAS/STING axis–dependent intervertebral disc inflammatory degeneration
Authors: Weifeng Zhang, Gaocai Li, Xingyu Zhou, Huaizhen Liang, Bide Tong, Di Wu, Kevin Yang, Yu Song, Bingjin Wang, Zhiwei Liao, Liang Ma, Wencan Ke, Xiaoguang Zhang, Jie Lei, Chunchi Lei, Xiaobo Feng, Kun Wang, Kangcheng Zhao, Cao Yang
Journal: Journal of Clinical Investigation (2024)

As the leading cause of disability worldwide, low back pain (LBP) is recognized as a pivotal socioeconomic challenge to the aging population and is largely attributed to intervertebral disc degeneration (IVDD). Elastic nucleus pulposus (NP) tissue is essential for the maintenance of IVD structural and functional integrity. The accumulation of senescent NP cells with an inflammatory hypersecretory phenotype due to aging and other damaging factors is a distinctive hallmark of IVDD initiation and progression. In this study, we reveal a mechanism of IVDD progression in which aberrant genomic DNA damage promoted NP cell inflammatory senescence via activation of the cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) axis but not of absent in melanoma 2 (AIM2) inflammasome assembly. Ataxia-telangiectasia–mutated and Rad3-related protein (ATR) deficiency destroyed genomic integrity and led to cytosolic mislocalization of genomic DNA, which acted as a powerful driver of cGAS/STING axis–dependent inflammatory phenotype acquisition during NP cell senescence. Mechanistically, disassembly of the ATR–tripartite motif–containing 56 (ATR-TRIM56) complex with the enzymatic liberation of ubiquitin-specific peptidase 5 (USP5) and TRIM25 drove changes in ATR ubiquitination, with ATR switching from K63- to K48-linked modification, c thereby promoting ubiquitin-proteasome–dependent dynamic instability of ATR protein during NP cell senescence progression. Importantly, an engineered extracellular vesicle–based strategy for delivering ATR-overexpressing plasmid cargo efficiently diminished DNA damage–associated NP cell senescence and substantially mitigated IVDD progression, indicating promising targets and effective approaches to ameliorate the chronic pain and disabling effects of IVDD.
Recent advances in carbon monoxide-releasing nanomaterials
Authors: Xiaomei Ning, Xinyuan Zhu, Youfu Wang, Jinghui Yang
Journal: Bioactive Materials (2024)

As an endogenous signaling molecule, carbon monoxide (CO) has emerged as an increasingly promising option regarding as gas therapy due to its positive pharmacological effects in various diseases. Owing to the gaseous nature and potential toxicity, it is particularly important to modulate the CO release dosages and targeted locations to elucidate the biological mechanisms of CO and facilitate its clinical applications. Based on these, diverse CO-releasing molecules (CORMs) have been developed for controlled release of CO in biological systems. However, practical applications of these CORMs are limited by several disadvantages including low stability, poor solubility, weak releasing controllability, random diffusion, and potential toxicity. In light of rapid developments and diverse advantages of nanomedicine, abundant nanomaterials releasing CO in controlled ways have been developed for therapeutic purposes across various diseases. Due to their nanoscale sizes, diversified compositions and modified surfaces, vast CO-releasing nanomaterials (CORNMs) have been constructed and exhibited controlled CO release in specific locations under various stimuli with better pharmacokinetics and pharmacodynamics. In this review, we present the recent progress in CORNMs according to their compositions. Following a concise introduction to CO therapy, CORMs and CORNMs, the representative research progress of CORNMs constructed from organic nanostructures, hybrid nanomaterials, inorganic nanomaterials, and nanocomposites is elaborated. The basic properties of these CORNMs, such as active components, CO releasing mechanisms, detection methods, and therapeutic applications, are discussed in detail and listed in a table. Finally, we explore and discuss the prospects and challenges associated with utilizing nanomaterials for biological CO release.
Circadian and Diurnal Regulation of Cerebral Blood Flow
Authors: Alastair J.S. Webb, Elizabeth B. Klerman, Emiri T. Mandeville
Journal: Circulation Research (2024)

Circadian and diurnal variation in cerebral blood flow directly contributes to the diurnal variation in the risk of stroke, either through factors that trigger stroke or due to impaired compensatory mechanisms. Cerebral blood flow results from the integration of systemic hemodynamics, including heart rate, cardiac output, and blood pressure, with cerebrovascular regulatory mechanisms, including cerebrovascular reactivity, autoregulation, and neurovascular coupling. We review the evidence for the circadian and diurnal variation in each of these mechanisms and their integration, from the detailed evidence for mechanisms underlying the nocturnal nadir and morning surge in blood pressure to identifying limited available evidence for circadian and diurnal variation in cerebrovascular compensatory mechanisms. We, thus, identify key systemic hemodynamic factors related to the diurnal variation in the risk of stroke but particularly identify the need for further research focused on cerebrovascular regulatory mechanisms.
Phase 2, Double-Blind, Placebo-controlled Trial of a c-Jun N-Terminal Kinase Inhibitor in Idiopathic Pulmonary Fibrosis
Authors: Waldo L. L. D. Mattos, Nasreen Khalil, Lisa G. Spencer, Francesco Bonella, Rodney J. Folz, J. Douglass Rolf, Nesrin Mogulkoc, Lisa H. Lancaster, R. Gisli Jenkins, David A. Lynch, Paul W. Noble, Toby M. Maher, Vincent Cottin, Stefanie Senger, Gerald S. Horan, Steven Greenberg, Zoran Popmihajlov
Journal: American Journal of Respiratory and Critical Care Medicine (2024)

Idiopathic pulmonary fibrosis is a fatal and progressive disease with limited treatment options.