tbuckley/cabot-search huggingface dataset:
Focusing on mitochondria in the brain: from biology to therapeutics
Authors: Nanshan Song, Shuyuan Mei, Xiangxu Wang, Gang Hu, Ming Lu
Journal: Translational Neurodegeneration (2024)

Abstract Mitochondria have multiple functions such as supplying energy, regulating the redox status, and producing proteins encoded by an independent genome. They are closely related to the physiology and pathology of many organs and tissues, among which the brain is particularly prominent. The brain demands 20% of the resting metabolic rate and holds highly active mitochondrial activities. Considerable research shows that mitochondria are closely related to brain function, while mitochondrial defects induce or exacerbate pathology in the brain. In this review, we provide comprehensive research advances of mitochondrial biology involved in brain functions, as well as the mitochondria-dependent cellular events in brain physiology and pathology. Furthermore, various perspectives are explored to better identify the mitochondrial roles in neurological diseases and the neurophenotypes of mitochondrial diseases. Finally, mitochondrial therapies are discussed. Mitochondrial-targeting therapeutics are showing great potentials in the treatment of brain diseases.
Immunotherapy-based regimens for patients with EGFR-mutated non-small cell lung cancer who progressed on EGFR-TKI therapy
Authors: Bao-Dong Qin, Xiao-Dong Jiao, Ling-Yan Yuan, Ying Wu, Yan Ling, Yuan-Sheng Zang
Journal: Journal for ImmunoTherapy of Cancer (2024)

The sustained benefit of immunotherapy-based regimens in epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) after EGFR-tyrosine kinase inhibitor (TKI) failure is debatable. Neither Checkmate-722 nor Keynote-789 reached the prespecified statistical level of clinical benefit, but the ORIENT-31 and ATTLAS trials showed that the addition of a VEGF inhibitor to immunotherapy plus chemotherapy could significantly prolong survival. However, head-to-head comparisons of the efficacy of immunotherapy plus bevacizumab with chemotherapy versus that of immunotherapy with chemotherapy in this patient population are lacking. In addition, the critical question of who would benefit from an immunotherapy-based regimen remains unclear. We conducted an indirect comparative meta-analysis using chemotherapy as a common comparator to classify the relative efficacy of the two immunotherapy-based regimens. The indirect comparison showed that immunotherapy and bevacizumab plus chemotherapy had a significantly better progression-free survival (PFS) (HR IO+Bev+Chemo/IO+Chemo =0.71, 95% CI 0.55 to 0.91) than immunotherapy plus chemotherapy. The EGFR mutation type and T790M mutation were found to be significantly associated with PFS of immunotherapy-based regimens. Compared with their counterparts, patients with L858R (HR 0.52, 95%CI 0.37 to 0.72), without T790M mutation (HR 0.50, 95% CI 0.35 to 0.71) tended to benefit significantly more from immunotherapy-based regimens. In conclusion, our findings support that the addition of VEGF inhibitor to immunotherapy and chemotherapy could be the preferred option for TKI-resistant, EGFR-mutated NSCLC, and that L858R mutation and T790M negativity could be identified as efficacy-associated factors for immunotherapy-based regimens.
Set7 Methyltransferase and Phenotypic Switch in Diabetic Glomerular Endothelial Cells
Authors: Scott Maxwell, Jun Okabe, Harikrishnan Kaipananickal, Hanah Rodriguez, Ishant Khurana, Keith Al-Hasani, Bryna S.M. Chow, Eleni Pitsillou, Tom C. Karagiannis, Karin Jandeleit-Dahm, Ronald C.W. Ma, Yu Huang, Juliana C.N. Chan, Mark E. Cooper, Assam El-Osta
Journal: Journal of the American Society of Nephrology (2024)

Key Points Set7 knockout improves diabetic glomerular structure and function and prevents diabetes-induced endothelial–mesenchymal transition (EDMT) by regulating Igfbp5. Set7 knockdown prevents, and (R)-PFI-2 hydrochloride reverses, diabetes-induced EDMT by regulating insulin growth factor binding protein 5. Set7 regulates the phenotypic EDMT switch, and inhibiting the methyltransferase attenuates glomerular injury in diabetic kidney disease. Background Hyperglycemia influences the development of glomerular endothelial cell damage, and nowhere is this more evident than in the progression of diabetic kidney disease (DKD). While the Set7 lysine methyltransferase is a known hyperglycemic sensor, its role in endothelial cell function in the context of DKD remains poorly understood. Methods Single-cell transcriptomics was used to investigate Set7 regulation in a mouse model of DKD, followed by validation of findings using pharmacological and short hairpin RNA inhibition inhibition of Set7. Results Set7 knockout (Set7KO) improved glomerular structure and albuminuria in a mouse model of diabetes. Analysis of single-cell RNA-sequencing data showed dynamic transcriptional changes in diabetic renal cells. Set7KO controls phenotype switching of glomerular endothelial cell populations by transcriptional regulation of the insulin growth factor binding protein 5 (IGFBP5). Chromatin immunoprecipitation assays confirmed that the expression of the IGFBP5 gene was associated with mono- and dimethylation of histone H3 lysine 4 (H3K4me1/2). This generalizability was investigated in human kidney and circulating hyperglycemic cells exposed to TGF β 1. We showed that the highly selective Set7 inhibitor (R)-PFI-2 hydrochloride attenuated indices associated with renal cell damage and mesenchymal transition, specifically ( 1 ) reactive oxygen species production, ( 2 ) IGFBP5 gene regulation, and ( 3 ) expression of mesenchymal markers. Furthermore, renal benefit observed in Set7KO diabetic mice closely corresponded in human glomerular endothelial cells with (R)-PFI-2 hydrochloride inhibition or Set7 short hairpin RNA silencing. Conclusions Set7 regulates the phenotypic endothelial–mesenchymal transition switch and suggests that targeting the lysine methyltransferase could protect glomerular cell injury in DKD. Podcast This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/JASN/2024_04_25_ASN0000000000000345.mp3
A Cohort Study of CNS Tumors in Multiple Endocrine Neoplasia Type 1
Authors: Thomas Graillon, Pauline Romanet, Clara Camilla, Camille Gélin, Romain Appay, Catherine Roche, Arnaud Lagarde, Grégory Mougel, Kaissar Farah, Maëlle Le Bras, Julien Engelhardt, Michel Kalamarides, Matthieu Peyre, Aymeric Amelot, Evelyne Emery, Elsa Magro, Hélène Cebula, Rabih Aboukais, Catherine Bauters, Emmanuel Jouanneau, Moncef Berhouma, Thomas Cuny, Henry Dufour, Hugues Loiseau, Dominique Figarella-Branger, Luc Bauchet, Christine Binquet, Anne Barlier, Pierre Goudet
Journal: Clinical Cancer Research (2024)

Multiple endocrine neoplasia type 1 (MEN1) is thought to increase the risk of meningioma and ependymoma. Thus, we aimed to describe the frequency, incidence, and specific clinical and histological features of central nervous system (CNS) tumors in the MEN1 population (except pituitary tumors).
Spatially Preserved Multi-Region Transcriptomic Subtyping and Biomarkers of Chemoimmunotherapy Outcome in Extensive-Stage Small Cell Lung Cancer
Authors: Melina Peressini, Rosario Garcia-Campelo, Bartomeu Massuti, Cristina Martí, Manuel Cobo, Vanesa Gutiérrez, Manuel Dómine, José Fuentes, Margarita Majem, Javier de Castro, Juan F. Córdoba, María P. Diz, Dolores Isla, Emilio Esteban, Enric Carcereny, Laia Vila, Alberto Moreno-Vega, Silverio Ros, Amaia Moreno, Francisco J. García, Gerardo Huidobro, Carlos Aguado, Victor Cebey-López, Javier Valdivia, Ramón Palmero, Pilar Lianes, Marta López-Brea, Oscar J. Vidal, Mariano Provencio, Edurne Arriola, Javier Baena, Mercedes Herrera, Helena Bote, Magdalena Molero, Vera Adradas, Santiago Ponce-Aix, Angel Nuñez-Buiza, Álvaro Ucero, Susana Hernandez, Fernando Lopez-Rios, Esther Conde, Luis Paz-Ares, Jon Zugazagoitia
Journal: Clinical Cancer Research (2024)

Transcriptomic subtyping holds promise for personalized therapy in extensive-stage small cell lung cancer (ES-SCLC). In this study, we aimed to assess intratumoral transcriptomic subtype diversity and to identify biomarkers of long-term chemoimmunotherapy benefit in human ES-SCLC.
Mast cells: a novel therapeutic avenue for cardiovascular diseases?
Authors: Remo Poto, Gianni Marone, Stephen J Galli, Gilda Varricchi
Journal: Cardiovascular Research (2024)

Abstract Mast cells are tissue-resident immune cells strategically located in different compartments of the normal human heart (the myocardium, pericardium, aortic valve, and close to nerves) as well as in atherosclerotic plaques. Cardiac mast cells produce a broad spectrum of vasoactive and proinflammatory mediators, which have potential roles in inflammation, angiogenesis, lymphangiogenesis, tissue remodelling, and fibrosis. Mast cells release preformed mediators (e.g. histamine, tryptase, and chymase) and de novo synthesized mediators (e.g. cysteinyl leukotriene C4 and prostaglandin D2), as well as cytokines and chemokines, which can activate different resident immune cells (e.g. macrophages) and structural cells (e.g. fibroblasts and endothelial cells) in the human heart and aorta. The transcriptional profiles of various mast cell populations highlight their potential heterogeneity and distinct gene and proteome expression. Mast cell plasticity and heterogeneity enable these cells the potential for performing different, even opposite, functions in response to changing tissue contexts. Human cardiac mast cells display significant differences compared with mast cells isolated from other organs. These characteristics make cardiac mast cells intriguing, given their dichotomous potential roles of inducing or protecting against cardiovascular diseases. Identification of cardiac mast cell subpopulations represents a prerequisite for understanding their potential multifaceted roles in health and disease. Several new drugs specifically targeting human mast cell activation are under development or in clinical trials. Mast cells and/or their subpopulations can potentially represent novel therapeutic targets for cardiovascular disorders.
Phase II, Single-Arm Trial of Induction and Concurrent Vismodegib With Curative-Intent Radiation Therapy for Locally Advanced, Unresectable Basal Cell Carcinoma
Authors: Christopher A. Barker, Suzanne Dufault, Sarah T. Arron, Alan L. Ho, Alain P. Algazi, Lara A. Dunn, Audrey A. Humphries, Carter Hultman, Ming Lian, P. Daniel Knott, Sue S. Yom
Journal: Journal of Clinical Oncology (2024)

Locally advanced, unresectable basal cell carcinoma (LA BCC) can be treated with radiation therapy (RT), but locoregional control (LRC) rates are unsatisfactory. Vismodegib is a hedgehog pathway inhibitor (HPI) active in BCC that may radiosensitize BCC. We evaluated the combination of vismodegib and RT for patients with LA BCC.
Glial Activity Load on PET Reveals Persistent “Smoldering” Inflammation in MS Despite Disease-Modifying Treatment
Authors: Tarun Singhal, Steven Cicero, Eero Rissanen, John Ficke, Preksha Kukreja, Steven Vaquerano, Bonnie Glanz, Shipra Dubey, William Sticka, Kyle Seaver, Marie Kijewski, Alexis M. Callen, Renxin Chu, Kelsey Carter, David Silbersweig, Tanuja Chitnis, Rohit Bakshi, Howard L. Weiner
Journal: Clinical Nuclear Medicine (2024)

Purpose of the Report 18 F-PBR06-PET targeting 18-kDa translocator protein can detect abnormal microglial activation (MA) in multiple sclerosis (MS). The objectives of this study are to develop individualized mapping of MA using 18 F-PBR06, to determine the effect of disease-modifying treatment (DMT) efficacy on reducing MA, and to determine its clinical, radiological, and serological correlates in MS patients. Patients and Methods Thirty 18 F-PBR06-PET scans were performed in 22 MS patients (mean age, 46 ± 13 years; 16 females) and 8 healthy controls (HCs). Logarithmically transformed “glial activity load on PET” scores (calculated as the sum of voxel-by-voxel z -scores ≥4), “lnGALP,” were compared between MS and HC and between MS subjects on high-efficacy DMTs (H-DMT, n = 13) and those on no or lower-efficacy treatment, and correlated with clinical measures, serum biomarkers, and cortical thickness. Results Cortical gray matter (CoGM) and white matter (WM) lnGALP scores were higher in MS versus HC (+33% and +48%, P &lt; 0.001). In H-DMT group, CoGM and WM lnGALP scores were significantly lower than lower-efficacy treatment ( P &lt; 0.01) but remained abnormally higher than in HC group ( P = 0.006). Within H-DMT patients, CoGM lnGALP scores correlated positively with physical disability, fatigue and serum glial fibrillary acid protein levels ( r = 0.65–0.79, all P 's &lt; 0.05), and inversely with cortical thickness ( r = −0.66, P &lt; 0.05). Conclusions High-efficacy DMTs decrease, but do not normalize, CoGM and WM MA in MS patients. Such “residual” MA in CoGM is associated with clinical disability, serum biomarkers, and cortical degeneration. Individualized mapping of translocator protein PET using 18 F-PBR06 is clinically feasible and can potentially serve as an imaging biomarker for evaluating “smoldering” inflammation in MS patients.
Endobronchial Ultrasound-guided Cryobiopsy of Pulmonary Artery Intimal Sarcoma
Authors: Simone Petrarulo, Claudia Ravaglia, Arianna Johanna De Grauw, Stefano Oldani, Suman Paul, Alessandra Dubini, Sara Piciucchi, Venerino Poletti
Journal: American Journal of Respiratory and Critical Care Medicine (2024)

"Endobronchial Ultrasound-guided Cryobiopsy of Pulmonary Artery Intimal Sarcoma." American Journal of Respiratory and Critical Care Medicine, 0(ja), pp.
Solitary Pulmonary Perivascular Epithelial Cell Tumor Mimicking Pulmonary Metastasis on 68Ga-DOTATATE PET/CT in a Patient With Pancreatic Neuroendocrine Tumor
Authors: Shuang Liang, Xiaoliang Chen
Journal: Clinical Nuclear Medicine (2024)

Abstract We report the findings of 68 Ga-DOTATATE PET/CT in a 56-year-old woman with solitary pulmonary perivascular epithelioid cell tumor. 68 Ga-DOTATATE PET/CT showed a lesion with intense uptake in the region of pancreatic head and a solitary nodule with moderate uptake in the left lung. Pancreatic neuroendocrine tumor with pulmonary metastasis was considered. The postoperative pathological results showed a benign perivascular epithelioid cell tumor of the lung. This case emphasizes the need to increase awareness of benign perivascular epithelioid cell tumors in the differential diagnosis of solitary pulmonary nodule with moderate DOTATATE activity.
Systemic Air Embolism after Image Guided Percutaneous Biopsy of the Lung
Authors: Angeline Jie-Yin Tey, Jonathan Jia Jun Wong, Norman Fangxuan Lim, Sharlene Ho
Journal: American Journal of Respiratory and Critical Care Medicine (2024)

"Systemic Air Embolism after Image Guided Percutaneous Biopsy of the Lung." American Journal of Respiratory and Critical Care Medicine, 0(ja), pp.
Chemokine Receptor 4–Targeted PET/CT With 68Ga-Pentixather Detects More Lesions Than 68Ga-Pentixafor PET/CT in Multiple Myeloma
Authors: Qiao Yang, Fujing Zhang, Zhixin Hao, Junling Zhuang, Li Huo
Journal: Clinical Nuclear Medicine (2024)

Abstract An 83-year-old woman with newly diagnosed multiple myeloma (MM) was enrolled in our 68 Ga-pentixather and 68 Ga-pentixafor PET/CT trial for evaluation of tumor burden. 68 Ga-pentixather PET/CT detected more focal bone lesions, and the uptake levels of focal bone lesions on 68 Ga-pentixather PET/CT were higher than those on 68 Ga-pentixafor PET/CT. This suggests that 68 Ga-pentixather PET/CT may be an alternative imaging modality and more sensitive in detecting MM lesions than 68 Ga-pentixafor PET/CT.
Overall Survival with Adjuvant Pembrolizumab in Renal-Cell Carcinoma
Authors: Toni K Choueiri, Piotr Tomczak, Se Hoon Park, Balaji Venugopal, Tom Ferguson, Stefan N Symeonides, Jaroslav Hajek, Yen-Hwa Chang, Jae-Lyun Lee, Naveed Sarwar, Naomi B Haas, Howard Gurney, Piotr Sawrycki, Mauricio Mahave, Marine Gross-Goupil, Tian Zhang, John M Burke, Gurjyot Doshi, Bohuslav Melichar, Evgeniy Kopyltsov, Ajjai Alva, Stephane Oudard, Delphine Topart, Hans Hammers, Hiroshi Kitamura, David F McDermott, Adriano Silva, Eric Winquist, Jerry Cornell, Aymen Elfiky, Joseph E Burgents, Rodolfo F Perini, Thomas Powles
Journal: New England Journal of Medicine (2024)

Adjuvant pembrolizumab therapy after surgery for renal-cell carcinoma was approved on the basis of a significant improvement in disease-free survival in the KEYNOTE-564 trial. Whether the results regarding overall survival from the third prespecified interim analysis of the trial would also favor pembrolizumab was uncertain. In this phase 3, double-blind, placebo-controlled trial, we randomly assigned (in a 1:1 ratio) participants with clear-cell renal-cell carcinoma who had an increased risk of recurrence after surgery to receive pembrolizumab (at a dose of 200 mg) or placebo every 3 weeks for up to 17 cycles (approximately 1 year) or until recurrence, the occurrence of unacceptable toxic effects, or withdrawal of consent. A significant improvement in disease-free survival according to investigator assessment (the primary end point) was shown previously. Overall survival was the key secondary end point. Safety was a secondary end point. A total of 496 participants were assigned to receive pembrolizumab and 498 to receive placebo. As of September 15, 2023, the median follow-up was 57.2 months. The disease-free survival benefit was consistent with that in previous analyses (hazard ratio for recurrence or death, 0.72; 95% confidence interval [CI], 0.59 to 0.87). A significant improvement in overall survival was observed with pembrolizumab as compared with placebo (hazard ratio for death, 0.62; 95% CI, 0.44 to 0.87; P = 0.005). The estimated overall survival at 48 months was 91.2% in the pembrolizumab group, as compared with 86.0% in the placebo group; the benefit was consistent across key subgroups. Pembrolizumab was associated with a higher incidence of serious adverse events of any cause (20.7%, vs. 11.5% with placebo) and of grade 3 or 4 adverse events related to pembrolizumab or placebo (18.6% vs. 1.2%). No deaths were attributed to pembrolizumab therapy. Adjuvant pembrolizumab was associated with a significant and clinically meaningful improvement in overall survival, as compared with placebo, among participants with clear-cell renal-cell carcinoma at increased risk for recurrence after surgery. (Funded by Merck Sharp and Dohme, a subsidiary of Merck; KEYNOTE-564 ClinicalTrials.gov number, NCT03142334.).
Auto-Fluorescence Imaging of Bronchoscopy in Mounier–Kuhn Syndrome: Negative Auto-Fluorescence Sign
Authors: Takayuki Takimoto, Hiromitsu Sumikawa, Yoshikazu Inoue, Toru Arai
Journal: American Journal of Respiratory and Critical Care Medicine (2024)

"Auto-Fluorescence Imaging of Bronchoscopy in Mounier–Kuhn Syndrome: Negative Auto-Fluorescence Sign." American Journal of Respiratory and Critical Care Medicine, 0(ja), pp.
Fair Allocation of GLP-1 and Dual GLP-1–GIP Receptor Agonists
Authors: Ezekiel J Emanuel, Johan L Dellgren, Matthew S McCoy, Govind Persad
Journal: New England Journal of Medicine (2024)

A shortage of GLP-1 receptor agonists and other drugs raises questions about how limited supplies should be allocated. A proposed framework could guide governments, professional societies, and physicians.
Radionuclide Therapy With 177Lu-PSMA in a Patient With Hepatocellular Carcinoma
Authors: Valentin Pretet, Anne Laure Giraudet, Laure Vergnaud, Emilie Paquet, David Kryza
Journal: Clinical Nuclear Medicine (2024)

Abstract A 69-year-old man diagnosed with progressive bone metastatic castration-resistant prostate adenocarcinoma and concurrent alcoholic cirrhosis with multiple hepatocellular carcinoma (HCC) nodules was referred to our nuclear medicine service for 177 Lu-PSMA-617 therapy. The patient’s pretreatment screening using 68 Ga-PSMA-11 PET/CT revealed high prostate-specific membrane antigen expression in both prostatic and HCC lesions. The patient underwent 2 doses of 177 Lu-PSMA-617. Subsequent imaging assessments with 68 Ga-PSMA-11 PET/CT and hepatic MRI indicated progressive HCC nodules, while showing a partial response in prostatic bone metastases. Positive clinical and biological responses were observed only in prostatic disease, but not in HCC nodules.
A Rare Manifestation of Airway Invasion from Pulmonary Artery Liposarcoma
Authors: Jinrui Miao, Run Tong, Yongming Zhang, Mingming Deng, Yiding Bian, Ruixia Li, Gang Hou
Journal: American Journal of Respiratory and Critical Care Medicine (2024)

"A Rare Manifestation of Airway Invasion from Pulmonary Artery Liposarcoma." American Journal of Respiratory and Critical Care Medicine, 0(ja), pp.
Efficacy of LCMV-based cancer immunotherapies is unleashed by intratumoral injections of polyI:C
Authors: Celia Gomar, Claudia Augusta Di Trani, Angela Bella, Leire Arrizabalaga, Jose Gonzalez-Gomariz, Myriam Fernandez-Sendin, Maite Alvarez, Joan Salvador Russo-Cabrera, Nuria Ardaiz, Fernando Aranda, Timo Schippers, Marisol Quintero, Ignacio Melero, Klaus K Orlinger, Henning Lauterbach, Pedro Berraondo
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Lymphocytic choriomeningitis virus (LCMV) belongs to the Arenavirus family known for inducing strong cytotoxic T-cell responses in both mice and humans. LCMV has been engineered for the development of cancer immunotherapies, currently undergoing evaluation in phase I/II clinical trials. Initial findings have demonstrated safety and an exceptional ability to activate and expand tumor-specific T lymphocytes. Combination strategies to maximize the antitumor effectiveness of LCMV-based immunotherapies are being explored. Methods We assessed the antitumor therapeutic effects of intratumoral administration of polyinosinic:polycytidylic acid (poly(I:C)) and systemic vaccination using an LCMV-vector expressing non-oncogenic versions of the E6 and E7 antigens of human papillomavirus 16 (artLCMV-E7E6) in a bilateral model engrafting TC-1/A9 cells. This cell line, derived from the parental TC-1, exhibits low MHC class I expression and is highly immune-resistant. The mechanisms underlying the combination’s efficacy were investigated through bulk RNA-seq, flow cytometry analyses of the tumor microenvironment, selective depletions using antibodies and clodronate liposomes, Batf3 deficient mice, and in vivo bioluminescence experiments. Finally, we assessed the antitumor effectiveness of the combination of artLCMV-E7E6 with BO-112, a GMP-grade poly(I:C) formulated in polyethyleneimine, currently under evaluation in clinical trials. Results Intratumoral injection of poly(I:C) enhanced the antitumor efficacy of artLCMV-E7E6 in both injected and non-injected tumor lesions. The combined treatment resulted in a significant delay in tumor growth and often complete eradication of several tumor lesions, leading to significantly improved survival compared with monotherapies. While intratumoral administration of poly(I:C) did not impact LCMV vector biodistribution or transgene expression, it significantly modified leucocyte infiltrates within the tumor microenvironment and amplified systemic efficacy through proinflammatory cytokines/chemokines such as CCL3, CCL5, CXCL10, TNF, IFNα, and IL12p70. Upregulation of MHC on tumor cells and a reconfiguration of the gene expression programs related to tumor vasculature, leucocyte migration, and the activation profile of tumor-infiltrating CD8 + T lymphocytes were observed. Indeed, the antitumor effect relied on the functions of CD8 + T lymphocytes and macrophages. The synergistic efficacy of the combination was further confirmed when BO-112 was included. Conclusion Intratumoral injection of poly(I:C) sensitizes MHC low tumors to the antitumor effects of artLCMV-E7E6, resulting in a potent therapeutic synergy.