tbuckley/cabot-search huggingface dataset:
Integration of clinical outcomes and molecular features in extramedullary disease in multiple myeloma
Authors: Rie Nakamoto-Matsubara, Valentina Nardi, Nora Horick, Tsuyoshi Fukushima, Ryan S. Han, Rajib Shome, Kiyosumi Ochi, Cristina Panaroni, Keertik Fulzele, Farah Rexha, Andrew R. Branagan, Diana Cirstea, Andrew J. Yee, David T. Scadden, Noopur S. Raje
Journal: Blood Cancer Journal (2024)

Multiple myeloma (MM) remains incurable despite novel therapeutics. A major contributor to the development of relapsed/refractory and resistant MM is extraosseous extramedullary disease (EMD), whose molecular biology is still not fully understood. We analyzed 528 MM patients who presented to our institution between 2014 and 2021 and who had undergone molecular testing. We defined EMD as organ plasmacytoma distinct from bones and evaluated patients for the development of EMD with the goal of defining their molecular characteristics. Here, we show that RAS/BRAF mutations are likely essential for the development of EMD. Our results also indicate that the underlying reason for the negative outcomes in patients with poor prognostic factors such as duplication 1q and deletion 17p is largely due to the development of EMD. However, the presence of TP53 mutation remains a poor prognostic factor regardless of EMD development. Furthermore, mutation sites of TP53 were different between EMD versus non-EMD patients, with gain-of-function mutations enriched in patients with EMD. Our data highlights distinct molecular abnormalities in patients with EMD and provides potential mechanistic insights for novel therapeutic targets for the future.
A tool for CRISPR-Cas9 sgRNA evaluation based on computational models of gene expression
Authors: Shai Cohen, Shaked Bergman, Nicolas Lynn, Tamir Tuller
Journal: Genome Medicine (2024)

CRISPR is widely used to silence genes by inducing mutations expected to nullify their expression. While numerous computational tools have been developed to design single-guide RNAs (sgRNAs) with high cutting efficiency and minimal off-target effects, only a few tools focus specifically on predicting gene knockouts following CRISPR. These tools consider factors like conservation, amino acid composition, and frameshift likelihood. However, they neglect the impact of CRISPR on gene expression, which can dramatically affect the success of CRISPR-induced gene silencing attempts. Furthermore, information regarding gene expression can be useful even when the objective is not to silence a gene. Therefore, a tool that considers gene expression when predicting CRISPR outcomes is lacking. We developed EXPosition, the first computational tool that combines models predicting gene knockouts after CRISPR with models that forecast gene expression, offering more accurate predictions of gene knockout outcomes. EXPosition leverages deep-learning models to predict key steps in gene expression: transcription, splicing, and translation initiation. We showed our tool performs better at predicting gene knockout than existing tools across 6 datasets, 4 cell types and ~207k sgRNAs. We also validated our gene expression models using the ClinVar dataset by showing enrichment of pathogenic mutations in high-scoring mutations according to our models. We believe EXPosition will enhance both the efficiency and accuracy of genome editing projects, by directly predicting CRISPR's effect on various aspects of gene expression. EXPosition is available at http://www.cs.tau.ac.il/~tamirtul/EXPosition . The source code is available at https://github.com/shaicoh3n/EXPosition .
Genetic analysis of myeloid neoplasms with der(1;7)(q10;p10)
Authors: Rurika Okuda, Yotaro Ochi, Ryunosuke Saiki, Toshiyuki Yamanaka, Chikashi Terao, Tetsuichi Yoshizato, Masahiro M. Nakagawa, Lanying Zhao, Kazuma Ohyashiki, Nobuhiro Hiramoto, Masashi Sanada, Hiroshi Handa, Senji Kasahara, Yasushi Miyazaki, Nobuo Sezaki, Lee-Yung Shih, Wolfgang Kern, Nobuhiro Kanemura, Toshiyuki Kitano, Shinsaku Imashuku, Mitsumasa Watanabe, Maria Creignou, Kazuhisa Chonabayashi, Kensuke Usuki, Takayuki Ishikawa, Akihiko Gotoh, Yoshiko Atsuta, Yuichi Shiraishi, Kinuko Mitani, Shigeru Chiba, Akifumi Takaori-Kondo, Satoru Miyano, Yoichiro Kamatani, Torsten Haferlach, Eva Hellström-Lindberg, Koichi Matsuda, Yoshinori Yoshida, Hideki Makishima, Yasuhito Nannya, Seishi Ogawa
Journal: Leukemia (2024)
HMGA2 overexpression with specific chromosomal abnormalities predominate in CALR and ASXL1 mutated myelofibrosis
Authors: Shivani Handa, Christoph Schaniel, Joseph Tripodi, Daiva Ahire, Md. Babu Mia, Sophie Klingborg, Douglas Tremblay, Bridget K. Marcellino, Ronald Hoffman, Vesna Najfeld
Journal: Leukemia (2024)

Although multiple genetic events are thought to play a role in promoting progression of the myeloproliferative neoplasms (MPN), the individual events that are associated with the development of more aggressive disease phenotypes remain poorly defined. Here, we report that novel genomic deletions at chromosome 12q14.3, as detected by a high-resolution array comparative genomic hybridization plus single nucleotide polymorphisms platform, occur in 11% of MPN patients with myelofibrosis (MF) and MPN-accelerated/blast phase (AP/BP) but was not detected in patients with polycythemia vera or essential thrombocythemia. These 12q14.3 deletions resulted in the loss of most of the non-coding region of exon 5 and MIRLET7 binding sites in the 3'UTR of the high mobility group AT hook 2 (HMGA2), which negatively regulate HMGA2 expression. These acquired 12q14.3 deletions were predominately detected in MF patients with CALR and ASXL1 co-mutations and led to a greater degree of HMGA2 transcript overexpression, independent of the presence of an ASXL1 mutation. Patients with 12q structural abnormalities involving HMGA2 exhibited a more aggressive clinical course, with a higher frequency of MPN-AP/BP evolution. These findings indicate that HMGA2 overexpression associated with genomic deletion of its 3'UTR region is a newly recognized genetic event that contributes to MPN progression.
Development of a Caco-2-based intestinal mucosal model to study intestinal barrier properties and bacteria–mucus interactions
Authors: Evelien Floor, Jinyi Su, Maitrayee Chatterjee, Elise S. Kuipers, Noortje IJssennagger, Faranak Heidari, Laura Giordano, Richard W. Wubbolts, Silvia M. Mihăilă, Daphne A. C. Stapels, Yvonne Vercoulen, Karin Strijbis
Journal: Gut Microbes (2024)

The intestinal mucosal barrier is a dynamic system that allows nutrient uptake, stimulates healthy microbe–host interactions, and prevents invasion by pathogens. The mucosa consists of epithelial cells connected by cellular junctions that regulate the passage of nutrients covered by a mucus layer that plays an important role in host–microbiome interactions. Mimicking the intestinal mucosa for in vitro assays, particularly the generation of a mucus layer, has proven to be challenging. The intestinal cell-line Caco-2 is widely used in academic and industrial laboratories due to its capacity to polarize, form an apical brush border, and reproducibly grow into confluent cell layers in different culture systems. However, under normal culture conditions, Caco-2 cultures lack a mucus layer. Here, we demonstrate for the first time that Caco-2 cultures can form a robust mucus layer when cultured under air–liquid interface (ALI) conditions on Transwell inserts with addition of vasointestinal peptide (VIP) in the basolateral compartment. We demonstrate that unique gene clusters are regulated in response to ALI and VIP single stimuli, but the ALI-VIP combination treatment resulted in a significant upregulation of multiple mucin genes and proteins, including secreted MUC2 and transmembrane mucins MUC13 and MUC17. Expression of tight junction proteins was significantly altered in the ALI-VIP condition, leading to increased permeability to small molecules. Commensal Lactiplantibacillus plantarum bacteria closely associated with the Caco-2 mucus layer and differentially colonized the surface of the ALI cultures. Pathogenic Salmonella enterica were capable of invading beyond the mucus layer and brush border. In conclusion, Caco-2 ALI-VIP cultures provide an accessible and straightforward way to culture an in vitro intestinal mucosal model with improved biomimetic features. This novel in vitro intestinal model can facilitate studies into mucus and epithelial barrier functions and in-depth molecular characterization of pathogenic and commensal microbe–mucus interactions.
Governing global health with a planetary mindset
Authors: Ilona Kickbusch, Rick A. Bright
Journal: BMJ (2024)

In 2023, a disturbing milestone was reached: six out of nine planetary boundaries were crossed, signalling an unprecedented threat to Earth's stability. 1imultaneously, the world grappled with a relentless series of disease outbreaks-Ebola, dengue, Zika, covid-19, Mpox, and Nipah.This convergence of crises is not coincidental.As Tulio de Oliveira, a leading genomics expert, warns, "Over half of known pathogen outbreaks will increase due to climate change." 2 The message is clear: our planet's health and human health are inextricably linked, demanding an urgent, integrated response.Recent years have seen tentative steps towards recognising this interconnection.The COP28 climate talks featured an official health day 3 and the World Health Assembly adopted a climate and health resolution. 3The CEPI Global Pandemic Preparedness Summit in Brazil highlighted the cascading effects of climate change on infectious diseases, even impacting marine mammals like sea lions. 4However, these initiatives fall short of the substantial shift that is required.Three critical gaps hinder meaningful progress
Adaptive spatiotemporal encoding network for cognitive assessment using resting state EEG
Authors: Jingnan Sun, Anruo Shen, Yike Sun, Xiaogang Chen, Yunxia Li, Xiaorong Gao, Bai Lu
Journal: npj Digital Medicine (2024)

Cognitive impairment, marked by neurodegenerative damage, leads to diminished cognitive function decline. Accurate cognitive assessment is crucial for early detection and progress evaluation, yet current methods in clinical practice lack objectivity, precision, and convenience. This study included 743 participants, including healthy individuals, mild cognitive impairment (MCI), and dementia patients, with collected resting-state EEG data and cognitive scale scores. An adaptive spatiotemporal encoding framework was developed based on resting-state EEG, achieving an MAE of 3.12% (95% CI: 2.9034, 3.3975) in testing (sensitivity: 0.97, 95% CI: 0.779,1; specificity: 0.97, 95% CI: 0.779,1). The model's effectiveness was also validated on the neurofeedback (sensitivity: 0.867, 95% CI: 0.621, 0.963; specificity: 1, 95% CI: 0.439, 1.0) and TMS datasets (sensitivity: 0.833, 95% CI: 0.608, 0.942), which effectively reflect the participants' cognitive changes. The model effectively extracted repetitive spatiotemporal patterns from resting-state EEG, aiding in cognitive disease diagnosis and assessment in various scenarios.
When I use a word . . . Academic integrity—principles and definitions
Authors: Jeffrey K Aronson
Journal: BMJ (2024)

In this article I summarise the main results of 10 previous articles in which I have discussed the nature of academic practice, highlighting academic norms and violations thereof, offering definitions of important terms. The following are the relevant definitions: ● academic: A person interested in or excelling at pursuits involving reading, thinking, study, teaching, and research. ● academic integrity: Uncorrupted moral virtue in relation to truth, uprightness, honesty, and sincerity in the pursuit of research, education, and scholarship. ● academic norm: A standard or pattern of behaviour that is accepted or expected in all academic activities, including research, education, and scholarship. ● academic violation: An infringement, breach, or contravention of an academic norm. ● academic felony: Fabrication, falsification, or plagiarism in proposing, performing, or reviewing research, or in reporting research results, or in other academic activities. ● academic fabrication: Making up research data or results or other forms of academic outputs and recording or reporting them. ● academic falsification: Manipulating research materials, equipment, or processes, or changing or omitting research data or results, or other forms of academic outputs, such as to misrepresent the original outputs. ● academic plagiarism: Appropriation and use by an academic of another person9s ideas, processes, results, or words, without giving appropriate credit. ● academic misdemeanour: Any minor violation or infringement of an academic norm or norms, short of the major violations of fabrication, falsification, and plagiarism. I also include lists that extensionally define academic integrity, academic norms, academic plagiarism, and academic misdemeanours.
Improving access to cardiovascular care for 1.4 billion people in China using telehealth
Authors: Xiaohang Liu, Wei Chen, Yu Qiu, Xiang Li, Fei Liu, Zhili Jiang, Fuwei Jia, Chenggang Wang, Rongrong Ji, Tawquir R Nawaz, Dingding Zhang, Yong Zeng, Hai Gao, Jeffrey Hsu
Journal: npj Digital Medicine (2024)

Cardiovascular diseases (CVDs) pose a significant health burden in China, where the large population and vast geography limit access to care. Telehealth (tHealth) services provide a virtual model of care that can enhance CVD management. This study aims to describe the trajectory of tHealth services for cardiovascular care between 2016 and 2020 in China, assess their utilization, and discuss their implications for improving access to care in resource-scarce regions. Data were collected on patient-facing, operational tHealth apps in Mainland China. In 2016, 45.8% of tertiary hospitals were accessible via tHealth apps, with a 10.7% annual growth rate. Wealthier regions had better tHealth coverage, irrespective of CVD burden. In 2016 and 2020, 34% and 67% of patients, respectively, consulted doctors located outside of their provinces, primarily in wealthier areas. The most common CVDs managed were hypertension, coronary artery disease, and arrhythmia. These findings suggest that tHealth services improve care access, especially in underdeveloped regions, but widespread technology adoption remains crucial.
Outcomes of <scp>CD19 CAR</scp> T in Transformed Indolent Lymphoma Compared to De Novo Aggressive Large B‐Cell Lymphoma
Authors: Swetha Kambhampati Thiruvengadam, Reid Merryman, Yan Wang, Charles Gaulin, Evandro Bezerra, Timothy Voorhees, Madhav R. Seshadri, Ayo Falade, Alma Habib, Amy A. Ayers, Megumi Bailey, Annette Brown, Neil Bailey, Krish Patel, Charalambos B. Andreadis, Adam S. Kittai, Caron Jacobson, Joycelynne Palmer, Stephen J. Forman, Loretta Nastoupil, Lihua E. Budde
Journal: American Journal of Hematology (2024)

ABSTRACT Chimeric antigen receptor (CAR) T‐cell therapy has revolutionized treatment of aggressive large B‐cell lymphoma (aLBCL). Patients with transformed indolent non‐Hodgkin lymphoma (tiNHL) were included in key CAR trials, but outcomes of CAR for this distinct, historically high‐risk group are poorly understood. We conducted a multicenter retrospective study of 1182 patients with aLBCL receiving standard‐of‐care CAR T between 2017 and 2022, including 338 (29%) with tiNHL. Rates of grade ≥ 3 cytokine release syndrome (CRS) were similar between tiNHL and de novo cohorts (7% vs. 8%, p = 0.6), while grade ≥ 3 immune effector cell‐associated neurotoxicity syndrome was lower in tiNHL (21% vs. 27%, p = 0.02). Overall response rate was similar in both cohorts (83% vs. 81%, p = 0.3), while complete response rate was higher in tiNHL (67% vs. 59%, p = 0.017). With a median follow‐up of 22.3 months, the progression/relapse‐free (PFS) and overall survival (OS) were similar between the tiNHL and de novo cohorts (24‐month PFS 41% [95% CI: 35%–46%] vs. 38% [95% CI: 35%–42%]; 24‐month OS 58% [95% CI: 52%–63%] vs. 52% [95% CI: 48%–56%], respectively). After adjusting for key risk factors, there was a trend toward a lower hazard of disease progression, relapse or death post‐CAR for tiNHL patients compared to de novo aLBCL patients (HR: 0.84 [95% CI: 0.69–1.0], p = 0.07). Elevated LDH, advanced stage, prior bendamustine within 12 months of CAR, receipt of bridging therapy, CNS involvement, and ≥ 3 prior lines of therapy were each associated with inferior PFS. In conclusion, CAR T therapy is highly effective with an acceptable toxicity profile in patients with tiNHL.
The acute effect of E-cigarette use on pulmonary function: a nonrandomized controlled trial
Authors: Simanta Roy, Sreshtha Chowdhury, Tarana Ferdous, Rime Jebai, Wasim Maziak
Journal: European Respiratory Journal (2024)

<title>Extract</title> Studying the acute effect of e-cigarettes on pulmonary function is important, given that the lungs are the primary target organ for e-cigarette exposure and that the majority of e-cigarette users are young people[1]. Prior studies of pulmonary function tests (PFTs) in e-cigarette users, have shown mixed results, mostly due to small sample sizes, participants' selection, and study design limitations (e.g., no objectively validated abstinence) [2–7]. For example, none of the prior studies included exclusive e-cigarette users, which can introduce bias due to the contribution of other tobacco use [2–7]. In this study, we apply a within-subject design to study the acute effects of single-session e-cigarette use on PFTs and diffusion capacity among primarily e-cigarette users.
Preclinical model for evaluating human TCRs against chimeric syngeneic tumors
Authors: Aikaterini Semilietof, Evangelos Stefanidis, Elise Gray-Gaillard, Julien Pujol, Alessia D'Esposito, Patrick Reichenbach, Philippe Guillaume, Vincent Zoete, Melita Irving, Olivier Michielin
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background The adoptive cell transfer (ACT) of T cell receptor (TCR)-engineered T cells targeting the HLA-A2-restricted epitope NY-ESO-1 157-165 (A2/NY) has yielded important clinical responses against several cancers. A variety of approaches are being taken to augment tumor control by ACT including TCR affinity-optimization and T-cell coengineering strategies to address the suppressive tumor microenvironment (TME). Most TCRs of clinical interest are evaluated in immunocompromised mice to enable human T-cell engraftment and do not recapitulate the dynamic interplay that occurs with endogenous immunity in a treated patient. A variety of humanized mouse models have been described but they have limitations in immune reconstitution and are technically challenging to implement. Here, we have developed a chimeric syngeneic tumor model in which A2Kb transgenic C57BL/6 mice are engrafted with B16 expressing A2Kb:NY as a single chain trimer (SCT) and treated by ACT with murine T cells expressing A2/NY TCRs comprising human variable fused to mouse constant regions. Methods We compared the function of a supraphysiological affinity A2/NY TCR (wtc51m), a computationally designed TCR in an optimal affinity range (DMβ), and a near non-binding TCR (V49I), engineered in both primary human and murine T cells by lentiviral and retroviral transduction, respectively. We evaluated a variety of strategies to stably express A2Kb:NY on the surface of mouse tumor cell lines including B16 melanoma, ultimately achieving success with an SCT comprising human β2m fused by GS linkers to both the NY-peptide and to α1 of the HLA complex. ACT studies were performed in B16-A2Kb:NY tumor-bearing, non-preconditioned immune-competent HLA-A*0201/H-2Kb (A2Kb) transgenic C57BL/6 mice and tumors characterized post-transfer. Results We observed significantly improved function of DMβ-T cells as well as superior infiltration and tumor control upon ACT as compared to the control TCR-T cells. Moreover, with our chimeric syngeneic tumor model, we were able to track dynamic and favorable changes in the TME upon DMβ-T cell transfer. Conclusions We have developed a robust, simple, and inexpensive preclinical strategy for evaluating human TCRs in the context of a fully competent murine immune system that can aid in the development of coengineered TCR-T cells and combination treatments translated to the clinic.
Engineered GM-CSF polarizes protumorigenic tumor-associated macrophages to an antitumorigenic phenotype and potently synergizes with IL-12 immunotherapy
Authors: Seounghun Kang, Aslan Mansurov, Trevin Kurtanich, Hye Rin Chun, Anna J Slezak, Lisa R Volpatti, Kevin Chang, Thomas Wang, Aaron T Alpar, Kirsten C Refvik, O Isabella Hansen, Gustavo J Borjas, Brendan T K Berg, Ha-Na Shim, Kevin T Hultgren, Suzana Gomes, Yue Wang, Ani Solanki, Jun Ishihara, Melody A Swartz, Jeffrey A Hubbell
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background The use of immune checkpoint inhibitors (CPIs) has become a dominant regimen in modern cancer therapy, however immune resistance induced by tumor-associated macrophages (TAMs) with immune suppressive and evasion properties limits responses. Therefore, the rational design of immune modulators that can control the immune suppressive properties of TAMs and polarize them, as well as dendritic cells (DCs), toward a more proinflammatory phenotype is a principal objective in cancer immunotherapy. Methods Here, using a protein engineering approach to enhance cytokine residence in the tumor microenvironment, we examined combined stimulation of the myeloid compartment via tumor stroma-binding granulocyte–macrophage colony-stimulating factor (GM-CSF) to enhance responses in both DCs and T cells via stroma-binding interleukin-12 (IL-12). We evaluated tumor responses at the levels of outcome, cellular responses, and cytokine responses in both the tumors and the tumor-draining lymph nodes. We further investigated the potentiation of DC response to IL-12 by GM-CSF stimulation ex vivo. Results Engineered GM-CSF restored an antitumorigenic tumor myeloid microenvironment otherwise suppressed by TAMs, while engineered IL-12 provided effector signals to T cells, thereby boosting both tumor-resident antitumor macrophage and CD8 + T cell populations. Furthermore, engineered GM-CSF potentiated DC response to IL-12, upregulating DC expression of IL-12 receptor and enhancing their expression of proinflammatory cytokines and chemokines on IL-12 exposure. This resulted in remarkable synergistic efficacy in multiple solid tumor models treated with the dual cytokine combination. The combination therapy also improved the efficacy of CPI in a CPI-resistant genetically-engineered melanoma model and exhibited synergistic antitumor efficacy in a pulmonary metastasis model. Conclusion Our strategy provides a rational design for combination immunotherapy targeting both myeloid and lymphoid compartments through complementary mechanisms.
Rock ‘n’ roll doctor Hank Wangford’s love song to the NHS
Authors: Richard Hurley
Journal: BMJ (2024)

A longtime pioneer of British country music, Hank Wangford, aka retired GP Sam Hutt, has released a new song."NHS Our Precious Thing (Lub Dup)" declares the health service "the heart and soul of our country." 1 It's under threat, and Wangford tells The BMJ that the public and the NHS's staff (its "queens and kings") have to fight for it."NHS Our Precious Thing (Lub Dup)" and Wangford's albums Holey Holey and Promises Promises are available on all good streaming services, such as Spotify and Apple Music.
Reply to: Accurate Determinants of Outcome in ALL
Authors: Ti-Cheng Chang, Wenan Chen, Chunxu Qu, Zhongshan Cheng, Abdelrahman Elsayed, Stanley B. Pounds, Mary Shago, Karen R. Rabin, Elizabeth A. Raetz, Meenakshi Devidas, Cheng Cheng, Anne Angiolillo, Pradyuamma Baviskar, Michael Borowitz, Michael J. Burke, Andrew Carroll, William L. Carroll, I-Ming Chen, Richard Harvey, Nyla Heerema, Ilaria Iacobucci, Jeremy R. Wang, Sima Jeha, Eric Larsen, Leonard Mattano, Kelly Maloney, Ching-Hon Pui, Nilsa C. Ramirez, Wanda Salzer, Cheryl Willman, Naomi Winick, Brent Wood, Stephen P. Hunger, Gang Wu, Charles G. Mullighan, Mignon L. Loh
Journal: Journal of Clinical Oncology (2024)