tbuckley/cabot-search huggingface dataset:
Sequential CD7 CAR T-Cell Therapy and Allogeneic HSCT without GVHD Prophylaxis
Authors: Yongxian Hu, Mingming Zhang, Tingting Yang, Zhuomao Mo, Guoqing Wei, Ruirui Jing, Houli Zhao, Rongrong Chen, Cheng Zu, Tianning Gu, Pingnan Xiao, Ruimin Hong, Jingjing Feng, Shan Fu, Delin Kong, Huijun Xu, Jiazhen Cui, Simao Huang, Bin Liang, Xiaolin Yuan, Qu Cui, Hongshan Guo, Yunxian Yu, Youqin Feng, Chunxiang Jin, Jiangtao Ren, Alex H Chang, Dongrui Wang, He Huang
Journal: New England Journal of Medicine (2024)

BackgroundPatients with relapsed or refractory hematologic cancers have a poor prognosis. Chimeric antigen receptor (CAR) T-cell therapy as a bridge to allogeneic hematopoietic stem-cell transplantation (HSCT) has the potential for long-term tumor elimination. However, pre-HSCT myeloablation and graft-versus-host disease (GVHD) prophylaxis agents have toxic effects and could eradicate residual CAR T cells and compromise antitumor effects. Whether the integration of CAR T-cell therapy and allogeneic HSCT can preserve CAR T-cell function and improve tumor control is unclear.MethodsWe tested a novel "all-in-one" strategy consisting of sequential CD7 CAR T-cell therapy and haploidentical HSCT in 10 patients with relapsed or refractory CD7-positive leukemia or lymphoma. After CAR T-cell therapy led to complete remission with incomplete hematologic recovery, patients received haploidentical HSCT without pharmacologic myeloablation or GVHD prophylaxis drugs. Toxic effects and efficacy were closely monitored.ResultsAfter CAR T-cell therapy, all 10 patients had complete remission with incomplete hematologic recovery and grade 4 pancytopenia. After haploidentical HSCT, 1 patient died on day 13 of septic shock and encephalitis, 8 patients had full donor chimerism, and 1 patient had autologous hematopoiesis. Three patients had grade 2 HSCT-associated acute GVHD. The median follow-up was 15.1 months (range, 3.1 to 24.0) after CAR T-cell therapy. Six patients remained in minimal residual disease–negative complete remission, 2 had a relapse of CD7-negative leukemia, and 1 died of septic shock at 3.7 months. The estimated 1-year overall survival was 68% (95% confidence interval [CI], 43 to 100), and the estimated 1-year disease-free survival was 54% (95% CI, 29 to 100).ConclusionsOur findings suggest that sequential CD7 CAR T-cell therapy and haploidentical HSCT is safe and effective, with remission and serious but reversible adverse events. This strategy offers a feasible approach for patients with CD7-positive tumors who are ineligible for conventional allogeneic HSCT. (Funded by the National Natural Science Foundation of China and the Key Project of Science and Technology Department of Zhejiang Province; ClinicalTrials.gov numbers, NCT04599556 and NCT04538599.)
Reply to Chi <i>et al.</i>: Ventilator Waveforms May Give Clues to Expiratory Muscle Activity
Authors: Glauco M. Plens, Eduardo L. V. Costa, Giacomo Bellani, Marcelo B. P. Amato
Journal: American Journal of Respiratory and Critical Care Medicine (2024)

"Reply to Chi et al.: Ventilator Waveforms May Give Clues to Expiratory Muscle Activity." American Journal of Respiratory and Critical Care Medicine, 0(ja), pp.
Corin and Left Atrial Cardiomyopathy, Hypertension, Arrhythmia, and Fibrosis
Authors: John Dominy, Christopher Koch, Lindsey Lamarche, Daniel Denning, Allan Gurtan, Maleeha Z Khan, Asif Rasheed, Muhammad R Mian, Muhammad Jahanzaib, Shareef Khalid, Danish Saleheen
Journal: New England Journal of Medicine (2024)
Case 13-2024: A 27-Year-Old Man with Leg Weakness
Authors: Andrew S Allegretti, Cynthia L Czawlytko, Nikolaos Stathatos, Peter M Sadow
Journal: New England Journal of Medicine (2024)

A 27-year-old man presented with weight loss, diarrhea, tremor, and proximal muscle weakness. The blood level of potassium was 1.8 mmol per liter. A diagnosis was made.
Exagamglogene Autotemcel for Transfusion-Dependent β-Thalassemia
Authors: Franco Locatelli, Peter Lang, Donna Wall, Roland Meisel, Selim Corbacioglu, Amanda M Li, Josu de la Fuente, Ami J Shah, Ben Carpenter, Janet L Kwiatkowski, Markus Mapara, Robert I Liem, Maria Domenica Cappellini, Mattia Algeri, Antonis Kattamis, Sujit Sheth, Stephan Grupp, Rupert Handgretinger, Puja Kohli, Daoyuan Shi, Leorah Ross, Yael Bobruff, Christopher Simard, Lanju Zhang, Phuong Khanh Morrow, William E Hobbs, Haydar Frangoul
Journal: New England Journal of Medicine (2024)

BackgroundExagamglogene autotemcel (exa-cel) is a nonviral cell therapy designed to reactivate fetal hemoglobin synthesis through ex vivo clustered regularly interspaced short palindromic repeats (CRISPR)–Cas9 gene editing of the erythroid-specific enhancer region of BCL11A in autologous CD34+ hematopoietic stem and progenitor cells (HSPCs).MethodsWe conducted an open-label, single-group, phase 3 study of exa-cel in patients 12 to 35 years of age with transfusion-dependent β-thalassemia and a β0/β0, β0/β0-like, or non–β0/β0-like genotype. CD34+ HSPCs were edited by means of CRISPR-Cas9 with a guide mRNA. Before the exa-cel infusion, patients underwent myeloablative conditioning with pharmacokinetically dose-adjusted busulfan. The primary end point was transfusion independence, defined as a weighted average hemoglobin level of 9 g per deciliter or higher without red-cell transfusion for at least 12 consecutive months. Total and fetal hemoglobin concentrations and safety were also assessed.ResultsA total of 52 patients with transfusion-dependent β-thalassemia received exa-cel and were included in this prespecified interim analysis; the median follow-up was 20.4 months (range, 2.1 to 48.1). Neutrophils and platelets engrafted in each patient. Among the 35 patients with sufficient follow-up data for evaluation, transfusion independence occurred in 32 (91%; 95% confidence interval, 77 to 98; P<0.001 against the null hypothesis of a 50% response). During transfusion independence, the mean total hemoglobin level was 13.1 g per deciliter and the mean fetal hemoglobin level was 11.9 g per deciliter, and fetal hemoglobin had a pancellular distribution (≥94% of red cells). The safety profile of exa-cel was generally consistent with that of myeloablative busulfan conditioning and autologous HSPC transplantation. No deaths or cancers occurred.ConclusionsTreatment with exa-cel, preceded by myeloablation, resulted in transfusion independence in 91% of patients with transfusion-dependent β-thalassemia. (Supported by Vertex Pharmaceuticals and CRISPR Therapeutics; CLIMB THAL-111 ClinicalTrials.gov number, NCT03655678.)
Correlation of immune fitness with response to teclistamab in relapsed/refractory multiple myeloma in the MajesTEC-1 study
Authors: Diana Cortes-Selva, Tatiana Perova, Sheri Skerget, Deeksha Vishwamitra, Sarah Stein, Rengasamy Boominathan, On Say Lau, Karl Nielsen, Cuc Davis, Jaymala H Patel, Arnob Banerjee, Tara Stephenson, Clarissa Uhlar, Rachel Kobos, Jenna D. Goldberg, Lixia Pei, Danielle Trancucci, Suzette Girgis, Shun Xin Wang Lin, Liviawati S. Wu, Philippe Moreau, Saad Z Usmani, Nizar J Bahlis, Niels W.C.J. van de Donk, Raluca Verona
Journal: Blood (2024)

Abstract Teclistamab, an off-the-shelf B-cell maturation antigen (BCMA) × CD3 bispecific antibody that mediates T-cell activation and subsequent lysis of BCMA-expressing myeloma cells, is approved for the treatment of patients with relapsed/refractory multiple myeloma (R/RMM). As a T-cell redirection therapy, clinical outcomes with teclistamab may be influenced by patient immune fitness and tumor antigen expression. We correlated tumor characteristics and baseline immune profiles with clinical response and disease burden in patients with R/RMM from the pivotal phase 1/2 MajesTEC-1 study, focusing on patients treated with 1.5 mg/kg of teclistamab (N = 165). Peripheral blood samples were collected at screening, and bone marrow samples were collected at screening and cycle 3. Better clinical outcomes to teclistamab correlated with higher baseline total T-cell counts in the periphery. In addition, responders (partial response or better) had a lower proportion of immunosuppressive regulatory T cells (Tregs), T cells expressing coinhibitory receptors (CD38, PD-1, and PD-1/TIM-3), and soluble BCMA and a T-cell profile suggestive of a more cytolytic potential, compared with nonresponders. Neither frequency of baseline bone marrow BCMA expression nor BCMA-receptor density was associated with clinical response to teclistamab. Improved progression-free survival was observed in patients with a lower frequency of T cells expressing exhaustion markers and immunosuppressive Tregs. Overall, response to teclistamab was associated with baseline immune fitness; nonresponders had immune profiles suggestive of immune suppression and T-cell dysfunction. These findings illustrate the importance of the contribution of the immune landscape to T-cell redirection therapy response. This trial was registered at www.ClinicalTrials.gov as #NCT03145181/NCT04557098.
Gasdermin D drives focal crystalline thrombotic microangiopathy by accelerating immunothrombosis and necroinflammation
Authors: Kanako Watanabe-Kusunoki, Chenyu Li, Tâmisa Seeko Bandeira Honda, Danyang Zhao, Yoshihiro Kusunoki, John Ku, Hao Long, Martin Klaus, Chao Han, Attila Braun, Elmina Mammadova-Bach, Andreas Linkermann, Kristof Van Avondt, Mathis Richter, Oliver Soehnlein, Monika I. Linder, Christoph Klein, Stefanie Steiger, Hans-Joachim Anders
Journal: Blood (2024)

Abstract Thrombotic microangiopathy (TMA) is characterized by immunothrombosis and life-threatening organ failure but the precise underlying mechanism driving its pathogenesis remains elusive. In this study, we hypothesized that gasdermin D (GSDMD), a pore-forming protein that serves as the final downstream effector of the pyroptosis/interleukin-1β (IL-1β) pathway, contributes to TMA and its consequences by amplifying neutrophil maturation and subsequent necrosis. Using a murine model of focal crystalline TMA, we found that Gsdmd deficiency ameliorated immunothrombosis, acute tissue injury, and failure. Gsdmd−/− mice exhibited a decrease in mature IL-1β, as well as in neutrophil maturation, β2-integrin activation, and recruitment to TMA lesions, in which they formed reduced neutrophil extracellular traps in both arteries and interstitial tissue. The GSDMD inhibitor disulfiram dose-dependently suppressed human neutrophil pyroptosis in response to cholesterol crystals. Experiments with GSDMD–deficient, human–induced, pluripotent stem cell–derived neutrophils confirmed the involvement of GSDMD in neutrophil β2-integrin activation, maturation, and pyroptosis. Both prophylactic and therapeutic administration of disulfiram protected the mice from focal TMA, acute tissue injury, and failure. Our data identified GSDMD as a key mediator of focal crystalline TMA and its consequences, including ischemic tissue infarction and organ failure. GSDMD could potentially serve as a therapeutic target for the systemic forms of TMA.
The ATF4-RPS19BP1 axis modulates ribosome biogenesis to promote erythropoiesis
Authors: Zhaofeng Zheng, Shangda Yang, Fanglin Gou, Chao Tang, Zhaoru Zhang, Quan Gu, Guohuan Sun, Penglei Jiang, Nini Wang, Xiangnan Zhao, Junnan Kang, Yifei Wang, Yicheng He, Meng Yang, Ting Lu, Shihong Lu, Pengxu Qian, Ping Zhu, Hui Cheng, Tao Cheng
Journal: Blood (2024)

Hematopoietic differentiation is controlled by intrinsic regulators and the extrinsic hematopoietic niche. Activating transcription factor 4 (ATF4) plays a crucial role in the function of fetal and adult hematopoietic stem cell maintenance. However, the precise function of ATF4 in the bone marrow (BM) niche and the mechanism by which ATF4 regulates adult hematopoiesis remain largely unknown. Here, we used 4 cell-type-specific mouse Cre lines to achieve conditional knockout of Atf4 in Cdh5+ endothelial cells, Prx1+ BM stromal cells, Osx+ osteoprogenitor cells, and Mx1+ hematopoietic cells and uncovered the role of Atf4 in niche cells and hematopoiesis. Intriguingly, depletion of Atf4 in niche cells did not affect hematopoiesis; however, Atf4-deficient hematopoietic cells exhibited erythroid differentiation defects, leading to hypoplastic anemia. Mechanistically, ATF4 mediated direct regulation of Rps19bp1 transcription, which is, in turn, involved in 40 S ribosomal subunit assembly to coordinate ribosome biogenesis and promote erythropoiesis. Finally, we demonstrate that under conditions of 5-fluorouracil-induced stress, Atf4 depletion impedes the recovery of hematopoietic lineages, which requires efficient ribosome biogenesis. Taken together, our findings highlight the indispensable role of the ATF4-RPS19BP1 axis in the regulation of erythropoiesis.
Myocardial Hypoperfusion in Severe Aortic Stenosis Is Reversed Early After Aortic Valve Replacement
Authors: George D. Thornton, Jonathan B. Bennett, Christian Nitsche, Francisco Gama, Nikoo Aziminia, Kristopher Knott, Rhodri H. Davies, James C. Moon, Peter Kellman, Thomas A. Treibel
Journal: JACC. Cardiovascular imaging (2024)
Association of Water Arsenic With Incident Diabetes in U.S. Adults: The Multi-Ethnic Study of Atherosclerosis and the Strong Heart Study
Authors: Maya Spaur, Marta Galvez-Fernandez, Qixuan Chen, Melissa A. Lombard, Benjamin C. Bostick, Pam Factor-Litvak, Amanda M. Fretts, Steven J. Shea, Ana Navas-Acien, Anne E. Nigra
Journal: Diabetes Care (2024)

We examined the association of arsenic in federally regulated community water systems (CWS) and unregulated private wells with type 2 diabetes (T2D) incidence in the Strong Heart Family Study (SHFS), a prospective study of American Indian communities, and the Multi-Ethnic Study of Atherosclerosis (MESA), a prospective study of racially and ethnically diverse urban U.S. communities.
Warburg Effect Reshapes Tumor Immunogenicity
Authors: José A. Enríquez, María Mittelbrunn
Journal: Cancer Research (2024)

Tumor cells rewire their metabolism to fulfill the demands of highly proliferative cells. This changes cellular metabolism to adapt to fuel and oxygen availability for energy production and to increase the synthesis capacity of building blocks for cell division and growth. In addition, the metabolic shift modulates the immunogenicity of the tumor cells. Recently, Mahmood and colleagues reported a connection between mitochondrial DNA mutations in cancer cells and their response to immunotherapy in a mouse model of melanoma.
Extracellular Vesicles Containing circMYBL1 Induce CD44 in Adenoid Cystic Carcinoma Cells and Pulmonary Endothelial Cells to Promote Lung Metastasis
Authors: Min Fu, Qian Gao, Mian Xiao, Rui-Feng Li, Xin-Yi Sun, Sheng-Lin Li, Xin Peng, Xi-Yuan Ge
Journal: Cancer Research (2024)

Adenoid cystic carcinoma (ACC) is a rare malignant epithelial neoplasm that arises in secretory glands and commonly metastasizes to the lungs. MYBL1 is frequently overexpressed in ACC and has been suggested to be a driver of the disease. In this study, we identified a circular RNA (circRNA) derived from MYBL1 pre-mRNA that was accompanied by the overexpression of MYBL1 in ACC. Overexpression of circMYBL1 was correlated with increased lung metastasis and poor overall survival in patients with ACC. Ectopic circMYBL1 overexpression promoted malignant phenotypes and lung metastasis of ACC cells. Mechanistically, circMYBL1 formed a circRNA-protein complex with CCAAT enhancer-binding protein β (CEBPB), which inhibited ubiquitin-mediated degradation and promoted nuclear translocation of CEBPB. In the nucleus, circMYBL1 increased the binding of CEBPB to the CD44 promoter region and enhanced its transcription. In addition, circMYBL1 was enriched in small extracellular vesicles (sEV) isolated from the plasma of patients with ACC. Treatment with sEVs containing circMYBL1 in sEVs enhanced prometastatic phenotypes of ACC cells, elevated the expression of CD44 in human pulmonary microvascular endothelial cells (HPMEC), and enhanced the adhesion between HPMECs and ACC cells. Moreover, circMYBL1 encapsulated in sEVs increased the arrest of circulating ACC cells in the lung and enhanced lung metastatic burden. These data suggest that circMYBL1 is a tumor-promoting circRNA that could serve as a potential biomarker and therapeutic target for ACC. Significance: circMYBL1 stabilizes CEBPB and upregulates CD44 to promote adhesion between cancer cells and endothelial cells and enables lung metastasis of adenoid cystic carcinoma, suggesting that inhibition of this axis could improve patient outcomes.
Effective fall prevention exercise in residential aged care: an intervention component analysis from an updated systematic review
Authors: Rik Dawson, Jenni Suen, Catherine Sherrington, Wing Kwok, Marina B Pinheiro, Abby Haynes, Charlotte McLennan, Katy Sutcliffe, Dylan Kneale, Suzanne Dyer
Journal: British Journal of Sports Medicine (2024)

Objective The effect of fall prevention exercise programmes in residential aged care (RAC) is uncertain. This paper reports on an intervention component analysis (ICA) of randomised controlled trials (RCTs), from an update of a Cochrane review, to develop a theory of features of successful fall prevention exercise in RAC. Methods Trial characteristics were extracted from RCTs testing exercise interventions in RAC identified from an update of a Cochrane review to December 2022 (n=32). Eligible trials included RCTs or cluster RCTs in RAC, focusing on participants aged 65 or older, assessing fall outcomes with stand-alone exercise interventions. ICA was conducted on trials with &gt;30 participants per treatment arm compared with control (n=17). Two authors coded trialists’ perceptions on intervention features that may have contributed to the observed effect on falls. Inductive thematic analysis was used to identify the key differences between the trials which might account for positive and negative outcomes. Results 32 RCTs involving 3960 residents including people with cognitive (57%) and mobility (41%) impairments were included. ICA on the 17 eligible RCTs informed the development of a theory that (1) effective fall prevention exercise delivers the right exercise by specifically targeting balance and strength, tailored to the individual and delivered simply at a moderate intensity and (2) successful implementation needs to be sufficiently resourced to deliver structured and supervised exercise at an adequate dose. Conclusions This analysis suggests that delivering the right exercise, sufficiently resourced, is important for preventing falls in RAC. This clinical guidance requires confirmation in larger trials.
Immunomodulatory Peptides for Tumor Treatment
Authors: Yang Song, Longtianyang Lei, Xingyu Cai, Hua Wei, Cui‐Yun Yu
Journal: Advanced Healthcare Materials (2024)

Peptides exhibit various biological activities, including biorecognition, cell targeting, and tumor penetration, and can stimulate immune cells to elicit immune responses for tumor immunotherapy. Peptide self-assemblies and peptide-functionalized nanocarriers can reduce the effect of various biological barriers and the degradation by peptidases, enhancing the efficiency of peptide delivery and improving antitumor immune responses. To date, the design and development of peptides with various functionalities have been extensively reviewed for enhanced chemotherapy; however, peptide-mediated tumor immunotherapy using peptides acting on different immune cells, to the knowledge, has not yet been summarized. Thus, this work provides a review of this emerging subject of research, focusing on immunomodulatory anticancer peptides. This review introduces the role of peptides in the immunomodulation of innate and adaptive immune cells, followed by a link between peptides in the innate and adaptive immune systems. The peptides are discussed in detail, following a classification according to their effects on different innate and adaptive immune cells, as well as immune checkpoints. Subsequently, two delivery strategies for peptides as drugs are presented: peptide self-assemblies and peptide-functionalized nanocarriers. The concluding remarks regarding the challenges and potential solutions of peptides for tumor immunotherapy are presented.
Exploring Novel Therapeutic Avenues for Chemotherapy-Related Cognitive Impairment
Authors: Jorg Dietrich, Michael W. Parsons, Emiliano Santarnecchi
Journal: Cancer Research (2024)

Many patients with cancer are at risk of developing cognitive symptoms that often become evident during or after cancer-directed therapy and may have difficulties with attention, concentration, multitasking, executive function, and memory. Despite recent advances in identifying potential molecular and cellular mechanisms underlying cancer and chemotherapy-related cognitive impairment, there is generally a lack of effective treatment strategies, and the development of novel therapeutic interventions represents a major unmet medical need in clinical practice. A recent study by Kim and colleagues suggests that multisensory 40-Hz gamma entrainment using sensory stimuli with combined visual and auditory stimuli is associated with powerful neuroprotective effects in mouse models of cisplatin- or methotrexate-induced "chemobrain." Although the study has some limitations and successful interventions in animal models have often failed to translate into clinical practice, this noninvasive treatment modality has shown promise in preserving brain structure and function and could be tested in patients with cancer who are at risk of cognitive decline.
Nanofiber-induced hierarchically-porous magnesium phosphate bone cements accelerate bone regeneration by inhibiting Notch signaling
Authors: Jingteng Chen, Ling Yu, Tian Gao, Xiangyang Dong, Shiyu Li, Yinchu Liu, Jian Yang, Kezhou Xia, Yaru Yu, Yingshuo Li, Sen Wang, ZhengFu Fan, Hongbing Deng, Weichun Guo
Journal: Bioactive Materials (2024)
Cellular senescence in cancer: molecular mechanisms and therapeutic targets
Authors: Ping Jin, Xirui Duan, Lei Li, Ping Zhou, Cheng‐Gang Zou, Ke Xie
Journal: MedComm (2024)

Abstract Aging exhibits several hallmarks in common with cancer, such as cellular senescence, dysbiosis, inflammation, genomic instability, and epigenetic changes. In recent decades, research into the role of cellular senescence on tumor progression has received widespread attention. While how senescence limits the course of cancer is well established, senescence has also been found to promote certain malignant phenotypes. The tumor‐promoting effect of senescence is mainly elicited by a senescence‐associated secretory phenotype, which facilitates the interaction of senescent tumor cells with their surroundings. Targeting senescent cells therefore offers a promising technique for cancer therapy. Drugs that pharmacologically restore the normal function of senescent cells or eliminate them would assist in reestablishing homeostasis of cell signaling. Here, we describe cell senescence, its occurrence, phenotype, and impact on tumor biology. A “one‐two‐punch” therapeutic strategy in which cancer cell senescence is first induced, followed by the use of senotherapeutics for eliminating the senescent cells is introduced. The advances in the application of senotherapeutics for targeting senescent cells to assist cancer treatment are outlined, with an emphasis on drug categories, and the strategies for their screening, design, and efficient targeting. This work will foster a thorough comprehension and encourage additional research within this field.