tbuckley/cabot-search huggingface dataset:
Covid-19: Some US states and hospitals recommend masks again
Authors: Janice Hopkins Tanne
Journal: BMJ (2024)

US hospitals and medical centres in some US states have reintroduced requirements to wear facemasks amid a rise in cases of covid-19, flu, and respiratory syncytial virus (RSV) in late December. 1 At least six states and several hospital systems decided to resume requirements for mask wearing among staff and patients.California, Illinois, Massachusetts, North Carolina, and Washington state have published guidelines requiring indoor masking. 2 New York City's 11 public hospitals have required staff to mask in areas where patients are being treated.The regulation also applies to all health clinics, nursing homes, and long term care facilities run by New York City's Health + Hospitals Corporation. 3 New York City health commissioner Ashwin Vasan said the reason for the change in policy was to protect staff and patients."We don't want staffing shortages.When we saw the omicron wave in 2022, the biggest problems were not only people getting sick, but that we had a lot of health workers out with covid," he said.Mass General Brigham and the Dana-Farber Cancer Institute in Boston, Massachusetts, said they would require masks for patients and staff.
When less is more: lower esophageal sphincter-preserving peroral endoscopic myotomy is effective for non-achalasia esophageal motility disorders
Authors: Varan Perananthan, Sunil Gupta, Anthony Whitfield, Ana Craciun, Oliver Cronin, Timothy O'Sullivan, Karen Byth, Mayenaaz Sidhu, Luke F. Hourigan, Spiro Raftopoulos, Nicholas G. Burgess, Michael J. Bourke
Journal: Endoscopy (2024)

Abstract Background Non-achalasia esophageal motility disorders (NAEMDs), encompassing distal esophageal spasm (DES) and hypercontractile esophagus (HCE), are rare conditions. Peroral endoscopic myotomy (POEM) is a promising treatment option. In NAEMDs, unlike with achalasia, the lower esophageal sphincter (LES) functions normally, suggesting the potential of LES preservation during POEM. Methods This retrospective two-center observational study focused on patients undergoing LES-preserving POEM (LES-POEM) for NAEMD. Eckardt scores were assessed pre-POEM and at 6, 12, and 24 months post-POEM, with follow-up endoscopy at 6 months to evaluate for reflux esophagitis. Clinical success, defined as an Eckardt score ≤3, served as the primary outcome. Results 227 patients were recruited over 84 months until May 2021. Of these, 16 underwent LES-POEM for an NAEMD (9 with HCE and 7 with DES). The median pre-POEM Eckardt score was 6.0 (interquartile range [IQR] 5.0–7.0), which decreased to 1.0 (IQR 0.0–1.8; P&lt;0.001) 6 months post-POEM. This was sustained at 24 months, with an Eckardt score of 1.0 (IQR 0.0–1.8; P&lt;0.001). Two patients (12.5%) developed Los Angeles grade A or B esophagitis. Conclusions LES-POEM for NAEMD demonstrates favorable clinical outcomes, with infrequent esophagitis and reintervention for LES dysfunction rarely required.
Nano-enhanced immunotherapy: Targeting the immunosuppressive tumor microenvironment
Authors: Yuzhi Jin, Yangyue Huang, Hui Ren, Huanhuan Huang, Chunyu Lai, Wenjun Wang, Zhou Tong, Hangyu Zhang, Wei Wu, Chuan Liu, Xuanwen Bao, Weijia Fang, Hongjun Li, Peng Zhao, Xiaomeng Dai
Journal: Biomaterials (2024)
Combining a prioritization strategy and functional studies nominates 5’UTR variants underlying inherited retinal disease
Authors: Alfredo Dueñas Rey, Marta del Pozo Valero, Manon Bouckaert, Katherine A Wood, Filip Van den Broeck, Malena Daich Varela, Huw B Thomas, Mattias Van Heetvelde, Marieke De Bruyne, Stijn Van de Sompele, Miriam Bauwens, Hanne Lenaerts, Quinten Mahieu, Dragana Josifova, Carlo Rivolta, Raymond T O’Keefe, Jamie Ellingford, Andrew R Webster, Gavin Arno, Carmen Ayuso, Julie De Zaeytijd, Bart P Leroy, Elfride De Baere, Frauke Coppieters
Journal: Genome Medicine (2024)

Abstract Background 5’ untranslated regions (5’UTRs) are essential modulators of protein translation. Predicting the impact of 5’UTR variants is challenging and rarely performed in routine diagnostics. Here, we present a combined approach of a comprehensive prioritization strategy and functional assays to evaluate 5’UTR variation in two large cohorts of patients with inherited retinal diseases (IRDs). Methods We performed an isoform-level re-analysis of retinal RNA-seq data to identify the protein-coding transcripts of 378 IRD genes with highest expression in retina. We evaluated the coverage of their 5’UTRs by different whole exome sequencing (WES) kits. The selected 5’UTRs were analyzed in whole genome sequencing (WGS) and WES data from IRD sub-cohorts from the 100,000 Genomes Project ( n = 2397 WGS) and an in-house database ( n = 1682 WES), respectively. Identified variants were annotated for 5’UTR-relevant features and classified into seven categories based on their predicted functional consequence. We developed a variant prioritization strategy by integrating population frequency, specific criteria for each category, and family and phenotypic data. A selection of candidate variants underwent functional validation using diverse approaches. Results Isoform-level re-quantification of retinal gene expression revealed 76 IRD genes with a non-canonical retina-enriched isoform, of which 20 display a fully distinct 5’UTR compared to that of their canonical isoform. Depending on the probe design, 3–20% of IRD genes have 5’UTRs fully captured by WES. After analyzing these regions in both cohorts, we prioritized 11 (likely) pathogenic variants in 10 genes ( ARL3 , MERTK , NDP , NMNAT1 , NPHP4 , PAX6 , PRPF31 , PRPF4 , RDH12 , RD3 ), of which 7 were novel. Functional analyses further supported the pathogenicity of three variants. Mis-splicing was demonstrated for the PRPF31 :c.-9+1G&gt;T variant. The MERTK :c.-125G&gt;A variant, overlapping a transcriptional start site, was shown to significantly reduce both luciferase mRNA levels and activity. The RDH12 :c.-123C&gt;T variant was found in cis with the hypomorphic RDH12 :c.701G&gt;A (p.Arg234His) variant in 11 patients. This 5’UTR variant, predicted to introduce an upstream open reading frame, was shown to result in reduced RDH12 protein but unaltered mRNA levels. Conclusions This study demonstrates the importance of 5’UTR variants implicated in IRDs and provides a systematic approach for 5’UTR annotation and validation that is applicable to other inherited diseases.
Duchenne muscular dystrophy treatment with lentiviral vector containing mini‐dystrophin gene in vivo
Authors: Xiaoyu Wang, Yanghui Zhu, Taiqing Liu, Lingyan Zhou, Yunhai Fu, Jinhua Zhao, Yinqi Li, Yeteng Zheng, Xiaodong Yang, Xiangjie Di, Yang Yang, Zhiyao He
Journal: MedComm (2024)

Duchenne muscular dystrophy (DMD) is an incurable X-linked recessive genetic disease caused by mutations in the dystrophin gene. Many researchers aim to restore truncated dystrophin via viral vectors. However, the low packaging capacity and immunogenicity of vectors have hampered their clinical application. Herein, we constructed four lentiviral vectors with truncated and sequence-optimized dystrophin genes driven by muscle-specific promoters. The four lentiviral vectors stably expressed mini-dystrophin in C2C12 muscle cells in vitro. To estimate the treatment effect in vivo, we transferred the lentiviral vectors into neonatal C57BL/10ScSn-
<i>Mycobacterium tuberculosis</i>: immune response, biomarkers, and therapeutic intervention
Authors: Li Zhuang, Ling Yang, Linsheng Li, Zhaoyang Ye, Wenping Gong
Journal: MedComm (2024)

Abstract Although tuberculosis (TB) is an infectious disease, the progression of the disease following Mycobacterium tuberculosis (MTB) infection is closely associated with the host's immune response. In this review, a comprehensive analysis of TB prevention, diagnosis, and treatment was conducted from an immunological perspective. First, we delved into the host's immune response mechanisms against MTB infection as well as the immune evasion mechanisms of the bacteria. Addressing the challenges currently faced in TB diagnosis and treatment, we also emphasized the importance of protein, genetic, and immunological biomarkers, aiming to provide new insights for early and personalized diagnosis and treatment of TB. Building upon this foundation, we further discussed intervention strategies involving chemical and immunological treatments for the increasingly critical issue of drug‐resistant TB and other forms of TB. Finally, we summarized TB prevention, diagnosis, and treatment challenges and put forward future perspectives. Overall, these findings provide valuable insights into the immunological aspects of TB and offer new directions toward achieving the WHO's goal of eradicating TB by 2035.
Cellular dynamics following CAR T cell therapy are associated with response and toxicity in relapsed/refractory myeloma
Authors: Luise Fischer, Nora Grieb, Patrick Born, Ronald Weiss, Sabine Seiffert, Andreas Boldt, Stephan Fricke, Paul Franz, Simone Heyn, Anne Sophie Kubasch, Ronny Baber, Heike Weidner, Song Yau Wang, Enrica Bach, Sandra Hoffmann, Jule Ussmann, Janine Kirchberg, Saskia Hell, Sebastian Schwind, Klaus H. Metzeler, Marco Herling, Madlen Jentzsch, Georg-Nikolaus Franke, Ulrich Sack, Kristin Reiche, Ulrike Köhl, Uwe Platzbecker, Vladan Vucinic, Maximilian Merz
Journal: Leukemia (2024)

B-cell maturation antigen (BCMA)-targeting chimeric antigen receptor (CAR) T cells revolutionized the treatment of relapsed/refractory multiple myeloma (RRMM). However, data on cellular (CAR) T cell dynamics and the association with response, resistance or the occurrence of cytokine release syndrome (CRS) are limited. Therefore, we performed a comprehensive flow cytometry analysis of 27 RRMM patients treated with Idecabtagene vicleucel (Ide-cel) to assess the expansion capacity, persistence and effects on bystander cells of BCMA-targeting CAR T cells. Additionally, we addressed side effects, like cytokine release syndrome (CRS) and cytopenia. Our results show that in vivo expansion of CD8
N6-methyladenosine-modified circPLPP4 sustains cisplatin resistance in ovarian cancer cells via PIK3R1 upregulation
Authors: Han Li, Run Lin, Yanna Zhang, Yanni Zhu, Shuting Huang, Jing Lan, Nian Lu, Chuanmiao Xie, Shanyang He, Weijing Zhang
Journal: Molecular Cancer (2024)

Abstract Background Cisplatin (CDDP) is the first-line chemotherapeutic strategy to treat patients with ovarian cancer (OC). The development of CDDP resistance remains an unsurmountable obstacle in OC treatment and frequently induces tumor recurrence. Circular RNAs (circRNAs) are noncoding RNAs with important functions in cancer progression. Whether circRNAs function in CDDP resistance of OC is unclear. Methods Platinum-resistant circRNAs were screened via circRNA deep sequencing and examined using in situ hybridization (ISH) in OC. The role of circPLPP4 in CDDP resistance was assessed by clone formation and Annexin V assays in vitro, and by OC patient-derived xenografts and intraperitoneal tumor models in vivo . The mechanism underlying circPLPP4-mediated activation of miR-136/PIK3R1 signaling was examined by luciferase reporter assay, RNA pull-down, RIP, MeRIP and ISH. Results circPLPP4 was remarkably upregulated in platinum resistant OC. circPLPP4 overexpression significantly enhanced, whereas circPLPP4 silencing reduced, OC cell chemoresistance. Mechanistically, circPLPP4 acts as a microRNA sponge to sequester miR-136, thus competitively upregulating PIK3R1 expression and conferring CDDP resistance. The increased circPLPP4 level in CDDP-resistant cells was caused by increased RNA stability, mediated by increased N6-methyladenosine (m 6 A) modification of circPLPP4 . In vivo delivery of an antisense oligonucleotide targeting circPLPP4 significantly enhanced CDDP efficacy in a tumor model. Conclusions Our study reveals a plausible mechanism by which the m 6 A -induced circPLPP4/ miR-136/ PIK3R1 axis mediated CDDP resistance in OC, suggesting that circPLPP4 may serve as a promising therapeutic target against CDDP resistant OC. A circPLPP4-targeted drug in combination with CDDP might represent a rational regimen in OC.
Bionanoengineered 2D monoelemental selenene for piezothrombolysis
Authors: Hui Hu, Lili Xia, Junfeng Wang, Xuefei Huang, Qianqian Zhao, Xinyu Song, Lei Hu, Shuai Ren, Chao Lu, Yongzhen Ren, Xiaoqin Qian, Wei Feng, Zhongqiu Wang, Yu Chen
Journal: Biomaterials (2024)
Reply
Authors: Todd P. Margolis, Anat Galor
Journal: Ophthalmology (2024)

We thank Dr Chaluvadi for her interest in our editorial. We appreciate hearing about her hypothesis about the pathogenesis of superior limbic keratoconjunctivitis (SLK), and her letter offers us an opportunity to reinforce critical points in our editorial about myths and hypotheses in contrast to data-driven mechanisms of disease. We also have a hypothesis about the pathogenesis of SLK, but with only circumstantial data to support it. We hypothesize that SLK is an autoimmune disease for the following reasons. First, SLK occurs in the context of two other autoimmune diseases of the conjunctiva and episclera: graft-versus-host disease and thyroid eye disease; second, SLK is well-controlled with local immunosuppression; and third, SLK is well-controlled after excision of the conjunctiva and the episclera, the tissues that we hypothesize are under autoimmune attack. Our hypothesis does not require a tight lid, poor lubrication, or an uneven surface of the palpebral conjunctiva for the disease to occur. However, we recognize that our hypothesis is simply a hypothesis, and should not be taught as the cause of SLK to impressionable residents and fellows, lest it quickly achieve myth status. The data to support either the tight lid hypothesis or the autoimmune hypothesis simply do not exist at this time. Better that we teach our trainees that, although several hypotheses exist, the pathogenesis of SLK remains unknown. Teaching our trainees the difference between myth, hypothesis, and data-driven mechanisms of disease is one of the key points of our editorial. To do this, we need to engage our trainees in critical thinking. In the absence of this, we are concerned that our specialty will become the realm of supertechs, capable of efficiently carrying out amazing surgical procedures and quoting chapter and verse of established texts, but with little capacity to acknowledge or differentiate hypothesis from data-driven science. Re: Margolis et al.: Six myths of the anterior segment: misunderstandings and critical thinking in ophthalmology (Ophthalmology. 2023;130:783-785)OphthalmologyVol. 131Issue 5PreviewThe editorial1 in the August 2023 issue was much appreciated. Having seen my fair share of superior limbic keratoconjunctivitis (SLK) cases, I have one comment, a detail perhaps worth studying further, in the rare unilateral cases. From my clinical observation, a confluence of factors seems critical in each SLK patient, although any single factor alone will likely not. Recognizing various factors and their roles in any given patient helps the management plan to be more effective. In my experience, three or more factors contribute to focal inflammation from repetitive mechanical microtrauma (friction) at the superior limbal conjunctiva. Full-Text PDF
CircPPAP2B controls metastasis of clear cell renal cell carcinoma via HNRNPC-dependent alternative splicing and targeting the miR-182-5p/CYP1B1 axis
Authors: Zaosong Zheng, Xiangbo Zeng, Yuanchao Zhu, Mengxin Leng, Zhiyong Zhang, Qiong Wang, Xiaocen Liu, Siying Zeng, Yongyuan Xiao, Chenxi Hu, Shiyu Pang, Tong Wang, Bihong Xu, Peidan Peng, Fei Li, Wanlong Tan
Journal: Molecular Cancer (2024)

Abstract Background Renal cell carcinoma (RCC) is one of the most common malignant tumor worldwide. Metastasis is a leading case of cancer-related deaths of RCC. Circular RNAs (circRNAs), a class of noncoding RNAs, have emerged as important regulators in cancer metastasis. However, the functional effects and regulatory mechanisms of circRNAs on RCC metastasis remain largely unknown. Methods High-throughput RNA sequencing techniques were performed to analyze the expression profiles of circRNAs and mRNAs in highly and poorly invasive clear cell renal cell carcinoma (ccRCC) cell lines. Functional experiments were performed to unveil the regulatory role of circPPAP2B in the proliferation and metastatic capabilities of ccRCC cells. RNA pulldown, Mass spectrometry analysis, RNA methylation immunoprecipitation (MeRIP), RNA immunoprecipitation (RIP), co-immunoprecipitation (CoIP), next-generation RNA-sequencing and double luciferase experiments were employed to clarify the molecular mechanisms by which circPPAP2B promotes ccRCC metastasis. Results In this study, we describe a newly identified circular RNA called circPPAP2B, which is overexpressed in highly invasive ccRCC cells, as determined through advanced high-throughput RNA sequencing techniques. Furthermore, we observed elevated circPPAP2B in ccRCC tissues, particularly in metastatic ccRCC tissues, and found it to be associated with poor prognosis. Functional experiments unveiled that circPPAP2B actively stimulates the proliferation and metastatic capabilities of ccRCC cells. Mechanistically, circPPAP2B interacts with HNRNPC in a m6A-dependent manner to facilitate HNRNPC nuclear translocation. Subcellular relocalization was dependent upon nondegradable ubiquitination of HNRNPC and stabilization of an HNRNPC/Vimentin/Importin α7 ternary complex. Moreover, we found that circPPAP2B modulates the interaction between HNRNPC and splicing factors, PTBP1 and HNPNPK, and regulates pre-mRNA alternative splicing. Finally, our studies demonstrate that circPPAP2B functions as a miRNA sponge to directly bind to miR-182-5p and increase CYP1B1 expression in ccRCC. Conclusions Collectively, our study provides comprehensive evidence that circPPAP2B promotes proliferation and metastasis of ccRCC via HNRNPC-dependent alternative splicing and miR-182-5p/CYP1B1 axis and highlights circPPAP2B as a potential therapeutic target for ccRCC intervention.
Exploring the relationship between hyperlactatemia and anemia
Authors: Shuping Zhang, Wei Liu, Tomas Ganz, Sijin Liu
Journal: Trends in Endocrinology and Metabolism (2024)

Hyperlactatemia and anemia commonly coexist and their crosstalk is a longstanding mystery with elusive mechanisms involved in physical activities, infections, cancers, and genetic disorders. For instance, hyperlactatemia leads to iron restriction by upregulating hepatic hepcidin expression. Increasing evidence also points to lactate as a crucial signaling molecule rather than merely a metabolic byproduct. Here, we discuss the mutual influence between anemia and hyperlactatemia. This opinion calls for a reconsideration of the multifaceted roles of lactate and lactylation in anemia and emphasizes the need to fill knowledge gaps, including the dose dependence of lactate's effects, its sources, and its subcellular localization.
Adoptive cell transfer therapy with ex vivo primed peripheral lymphocytes in combination with anti-PDL1 therapy effectively inhibits triple-negative breast cancer growth and metastasis
Authors: Odd L. Gammelgaard, Mikkel G. Terp, Alexei F. Kirkin, Simone Johansen, Sofie Traynor, Henriette Vever, Per Guldberg, Annette R. Kodahl, Morten F. Gjerstorff, Henrik J. Ditzel
Journal: Molecular Cancer (2024)

Abstract Background Adoptive cell transfer cancer immunotherapy holds promise for treating disseminated disease, yet generating sufficient numbers of lymphocytes with anti-cancer activity against diverse specificities remains a major challenge. We recently developed a novel procedure (ALECSAT) for selecting, expanding and maturating polyclonal lymphocytes from peripheral blood with the capacity to target malignant cells. Methods Immunodeficient mice were challenged with triple-negative breast cancer cell lines or patient-derived xenografts (PDX) and treated with allogeneic or autologous ALECSAT cells with and without anti-PDL1 therapy to assess the capacity of ALECSAT cells to inhibit primary tumor growth and metastasis. Results ALECSAT mono therapy inhibited metastasis, but did not inhibit primary tumor growth or prolong survival of tumor-bearing mice. In contrast, combined ALECSAT and anti-PDL1 therapy significantly inhibited primary tumor growth, nearly completely blocked metastasis, and prolonged survival of tumor-bearing mice. Conclusions Combined ALECSAT and anti-PDL1 therapy results in favorable anti-cancer responses in both cell line-derived xenograft and autologous PDX models of advanced triple-negative breast cancer.
Inhibition of PCSK9 prevents and alleviates cholesterol gallstones through PPARα-mediated CYP7A1 activation
Authors: Zhenmei Chen, Weiqing Shao, Yitong Li, Xiandi Zhang, Yan Geng, Xiaochen Ma, Baorui Tao, Yue Ma, Chenhe Yi, Bo Zhang, Rui Zhang, Jing Lin, Jinhong Chen
Journal: Metabolism (2024)
Perylene‐Mediated Cytoskeletal Dysfunction Remodels Cancer‐Associated Fibroblasts to Augment Antitumor Immunotherapy
Authors: Bing Shi, Xue Lou, Feiyan Ma, Yanling Nie, Haoxing Chen, Yongwei Huang, Wei Zhang, Tie Wang
Journal: Advanced Healthcare Materials (2024)

Targeted reprogramming of cancer-associated fibroblasts (CAFs) is one of the most essential cancer therapies. However, how to reprogram active CAFs toward deactivated state still remains immense challenge. To tackle this challenge, herein, one perylene N, N'-bis(2-((dimethylammonium)ethylene)-2-(methoxylethyl))-1, 6, 7, 12-tetrachloroperylene-3, 4, 9, 10-tetracarboxylic diimide (PDIC-OC) is prepared, which can trigger endogenous reactive oxygen species (ROS) burst to result in cytoskeletal dysfunction and cell apoptosis so that suppress transforming growth factor β (TGF-β) production. As a result, PDIC-OC can reprogram the activated CAFs and relieve immunosuppressive tumor microenvironment by efficient polarization of M2-typed macrophages into M1-typed ones, downregulation of alpha-smooth muscle actin (α-SMA), alleviation of hypoxic state to promote infiltration of cytotoxic T lymphocytes, and ultimately realizes outstanding antitumor performance on B16F10 tumor-xenografted and lung-metastatic mouse model even at low concentration of 1 mg kg
Non-IG::MYC in diffuse large B-cell lymphoma confers variable genomic configurations and MYC transactivation potential
Authors: Chunye Zhang, Ellen Stelloo, Sharon Barrans, Francesco Cucco, Dan Jiang, Maria-Myrsini Tzioni, Zi Chen, Yan Li, Joost F. Swennenhuis, Jasmine Makker, Lívia Rásó-Barnett, Hongxiang Liu, Hesham El-Daly, Elizabeth Soilleux, Nimish Shah, Sateesh Kumar Nagumantry, Maw Kyaw, Mahesh Panatt Prahladan, Reuben Tooze, David R. Westhead, Harma Feitsma, Andrew J. Davies, Catherine Burton, Peter W. M. Johnson, Ming-Qing Du
Journal: Leukemia (2024)

Abstract MYC translocation occurs in 8–14% of diffuse large B-cell lymphoma (DLBCL), and may concur with BCL2 and/or BCL6 translocation, known as double-hit (DH) or triple-hit (TH). DLBCL- MYC / BCL2 -DH/TH are largely germinal centre B-cell like subtype, but show variable clinical outcome, with IG :: MYC fusion significantly associated with inferior survival. While DLBCL- MYC / BCL6 -DH are variable in their cell-of-origin subtypes and clinical outcome. Intriguingly, only 40-50% of DLBCL with MYC translocation show high MYC protein expression (&gt;70%). We studied 186 DLBCLs with MYC translocation including 32 MYC/BCL2/BCL6 -TH , 75 MYC/BCL2 -DH and 26 MYC/BCL6 -DH. FISH revealed a MYC / BCL6 fusion in 59% of DLBCL- MYC/BCL2/BCL6 -TH and 27% of DLBCL- MYC / BCL6 -DH. Targeted NGS showed a similar mutation profile and LymphGen genetic subtype between DLBCL- MYC/BCL2/BCL6 -TH and DLBCL- MYC/BCL2 -DH, but variable LymphGen subtypes among DLBCL- MYC / BCL6 -DH. MYC protein expression is uniformly high in DLBCL with IG::MYC , but variable in those with non- IG::MYC including MYC / BCL6 -fusion. Translocation breakpoint analyses of 8 cases by TLC-based NGS showed no obvious genomic configuration that enables MYC transactivation in 3 of the 4 cases with non- IG: : MYC , while a typical promoter substitution or IGH super enhancer juxtaposition in the remaining cases. The findings potentially explain variable MYC expression in DLBCL with MYC translocation, and also bear practical implications in its routine assessment.