tbuckley/cabot-search huggingface dataset:
ctDNA-based molecular residual disease and survival in resectable colorectal cancer
Authors: Yoshiaki Nakamura, Jun Watanabe, Naoya Akazawa, Keiji Hirata, Kozo Kataoka, Mitsuru Yokota, Kentaro Kato, Masahito Kotaka, Yoshinori Kagawa, Kun-Huei Yeh, Saori Mishima, Hiroki Yukami, Koji Ando, Masaaki Miyo, Toshihiro Misumi, Kentaro Yamazaki, Hiromichi Ebi, Kenji Okita, Atsushi Hamabe, Hiroki Sokuoka, Satoshi Kobayashi, George Laliotis, Vasily N Aushev, Shruti Sharma, Adham Jurdi, Minetta C Liu, Alexey Aleshin, Matthew Rabinowitz, Hideaki Bando, Hiroya Taniguchi, Ichiro Takemasa, Takeshi Kato, Daisuke Kotani, Masaki Mori, Takayuki Yoshino, Eiji Oki
Journal: Nature Medicine (2024)

The interim analysis of the CIRCULATE-Japan GALAXY observational study demonstrated the association of circulating tumor DNA (ctDNA)-based molecular residual disease (MRD) detection with recurrence risk and benefit from adjuvant chemotherapy (ACT) in resectable colorectal cancer (CRC). This updated analysis with a 23-month median follow-up, including 2,240 patients with stage II-III colon cancer or stage IV CRC, reinforces the prognostic value of ctDNA positivity during the MRD window with significantly inferior disease-free survival (DFS; hazard ratio (HR): 11.99, P < 0.0001) and overall survival (OS; HR: 9.68, P < 0.0001). In patients who experienced recurrence, ctDNA positivity correlated with shorter OS (HR: 2.71, P < 0.0001). The significantly shorter DFS in MRD-positive patients was consistent across actionable biomarker subsets. Sustained ctDNA clearance in response to ACT was an indicator of favorable DFS and OS compared to transient clearance (24-month DFS: 89.0% versus 3.3%; 24-month OS: 100.0% versus 82.3%). True spontaneous clearance rate with no clinical recurrence was 1.9% (2/105). Overall, our findings provide evidence for the utility of ctDNA monitoring for post-resection recurrence and mortality risk stratification that could be used for guiding adjuvant therapy.
Targeted therapy guided by circulating tumor DNA analysis in advanced gastrointestinal tumors
Authors: Yoshiaki Nakamura, Hiroshi Ozaki, Makoto Ueno, Yoshito Komatsu, Satoshi Yuki, Taito Esaki, Hiroya Taniguchi, Yu Sunakawa, Kensei Yamaguchi, Ken Kato, Tadamichi Denda, Tomohiro Nishina, Naoki Takahashi, Taroh Satoh, Hisateru Yasui, Hironaga Satake, Eiji Oki, Takeshi Kato, Takashi Ohta, Nobuhisa Matsuhashi, Masahiro Goto, Naohiro Okano, Koushiro Ohtsubo, Kentaro Yamazaki, Riu Yamashita, Naoko Iida, Mihoko Yuasa, Hideaki Bando, Takayuki Yoshino
Journal: Nature Medicine (2024)

Although comprehensive genomic profiling has become standard in oncology for advanced solid tumors, the full potential of circulating tumor DNA (ctDNA)-based profiling in capturing tumor heterogeneity and guiding therapy selection remains underexploited, marked by a scarcity of evidence on its clinical impact and the assessment of intratumoral heterogeneity. The GOZILA study, a nationwide, prospective observational ctDNA profiling study, previously demonstrated higher clinical trial enrollment rates using liquid biopsy compared with tissue screening. This updated analysis of 4,037 patients further delineates the clinical utility of ctDNA profiling in advanced solid tumors, showcasing a significant enhancement in patient outcomes with a 24% match rate for targeted therapy. Patients treated with matched targeted therapy based on ctDNA profiling demonstrated significantly improved overall survival compared with those receiving unmatched therapy (hazard ratio, 0.54). Notably, biomarker clonality and adjusted plasma copy number were identified as predictors of therapeutic efficacy, reinforcing the value of ctDNA in reflecting tumor heterogeneity for precise treatment decisions. These new insights into the relationship between ctDNA characteristics and treatment outcomes advance our understanding beyond the initial enrollment benefits. Our findings advocate for the broader adoption of ctDNA-guided treatment, signifying an advancement in precision oncology and improving survival outcomes in advanced solid tumors.
Proteasome inhibition enhances the anti-leukemic efficacy of chimeric antigen receptor (CAR) expressing NK cells against acute myeloid leukemia
Authors: David Sedloev, Qian Chen, Julia M Unglaub, Nicola Schanda, Yao Hao, Eleni Besiridou, Brigitte Neuber, Anita Schmitt, Simon Raffel, Yi Liu, Maike Janssen, Carsten Müller-Tidow, Michael Schmitt, Tim Sauer
Journal: Journal of Hematology & Oncology (2024)

Relapsed and refractory acute myeloid leukemia (AML) carries a dismal prognosis. CAR T cells have shown limited efficacy in AML, partially due to dysfunctional autologous T cells and the extended time for generation of patient specific CAR T cells. Allogeneic NK cell therapy is a promising alternative, but strategies to enhance efficacy and persistence may be necessary. Proteasome inhibitors (PI) induce changes in the surface proteome which may render malignant cells more vulnerable to NK mediated cytotoxicity. Here, we investigated the potential benefit of combining PIs with CAR-expressing allogeneic NK cells against AML.
Multiple Myeloma Risk and Outcomes are Associated with Pathogenic Germline Variants in DNA Repair Genes
Authors: Santiago Thibaud, Ryan L. Subaran, Scott Newman, Alessandro Lagana, David T. Melnekoff, Saoirse Bodnar, Meghana Ram, Zachry Soens, William Genthe, Tehilla Brander, Tarek H. Mouhieddine, Oliver Van Oekelen, Jane Houldsworth, Hearn Jay. Cho, Shambavi Richard, Joshua Richter, Cesar Rodriguez, Adriana Rossi, Larysa Sanchez, Ajai Chari, Erin Moshier, Sundar Jagannath, Samir Parekh, Kenan Onel
Journal: Blood Cancer Discovery (2024)

First-degree relatives of patients with multiple myeloma are at increased risk for the disease, but the contribution of pathogenic germline variants (PGV) in hereditary cancer genes to multiple myeloma risk and outcomes is not well characterized. To address this, we analyzed germline exomes in two independent cohorts of 895 and 786 patients with multiple myeloma. PGVs were identified in 8.6% of the Discovery cohort and 11.5% of the Replication cohort, with a notable presence of high- or moderate-penetrance PGVs (associated with autosomal dominant cancer predisposition) in DNA repair genes (3.6% and 4.1%, respectively). PGVs in BRCA1 (OR = 3.9, FDR < 0.01) and BRCA2 (OR = 7.0, FDR < 0.001) were significantly enriched in patients with multiple myeloma when compared with 134,187 healthy controls. Five of the eight BRCA2 PGV carriers exhibited tumor-specific copy number loss in BRCA2, suggesting somatic loss of heterozygosity. PGVs associated with autosomal dominant cancer predisposition were associated with younger age at diagnosis, personal or familial cancer history, and longer progression-free survival after upfront high-dose melphalan and autologous stem-cell transplantation (P < 0.01). Significance: Our findings suggest up to 10% of patients with multiple myeloma may have an unsuspected cancer predisposition syndrome. Given familial implications and favorable outcomes with high-dose melphalan and autologous stem-cell transplantation in high-penetrance PGV carriers, genetic testing should be considered for young or newly diagnosed patients with a personal or family cancer history. See related commentary by Walker, p. 375.
Author Correction: Serum proteomics reveal APOE-ε4-dependent and APOE-ε4-independent protein signatures in Alzheimer’s disease
Authors: Elisabet A Frick, Valur Emilsson, Thorarinn Jonmundsson, Anna E Steindorsdottir, Erik C B Johnson, Raquel Puerta, Eric B Dammer, Anantharaman Shantaraman, Amanda Cano, Mercè Boada, Sergi Valero, Pablo García-González, Elias F Gudmundsson, Alexander Gudjonsson, Rebecca Pitts, Xiazi Qiu, Nancy Finkel, Joseph J Loureiro, Anthony P Orth, Nicholas T Seyfried, Allan I Levey, Agustin Ruiz, Thor Aspelund, Lori L Jennings, Lenore J Launer, Valborg Gudmundsdottir, Vilmundur Gudnason
Journal: Nature Aging (2024)
Omalizumab reduces anaphylactic reactions and allows food introduction in food‐allergic in children with severe asthma: An observational study
Authors: Stefania Arasi, Arianna Cafarotti, Francesca Galletta, Valentina Panetta, Carla Riccardi, Veronica Calandrelli, Vincenzo Fierro, Lamia Dahdah, Maria Cristina Artesani, Rocco Luigi Valluzzi, Valentina Pecora, Valeria Tallarico, Giulio Dinardo, Lucia Lo Scalzo, Alessandro Fiocchi
Journal: Allergy (2024)

Abstract Background In Europe, Omalizumab (anti‐IgE) is indicated for the treatment of moderate to severe asthma, but not for IgE‐mediated food allergy (FA). Objective We assessed the impact of Omalizumab on efficacy, safety, and quality of life (FA‐QoL) in patients with moderate to severe asthma and who have a history of anaphylaxis to peanut, tree nuts, fish, egg, milk, and/or wheat. Methods Food‐allergic children (6–18 years) with moderate to severe asthma underwent oral food challenges (OFCs) to establish the threshold of reaction to the culprit food(s) at baseline (T0) and at 4‐month intervals (T1, T2, and T3) during their first year of treatment with Omalizumab. We recorded the number and severity of food‐allergic reactions, Asthma Control Test (ACT) scores, FA‐QoL, and total IgE levels. Results In 65 patients allergic to 107 foods, the No Observed Adverse Events Level (NOAEL) at T1 increased: 243‐ and 488‐fold for fresh and baked milk, respectively; 172‐ and 134‐fold for raw and baked egg; 245‐fold for hazelnut; 55‐fold for peanut; 31‐fold for wheat; and 10‐fold for fish. Full tolerance was achieved in 66.4% of OFCs at T1, 58.3% at T2, and 75% at T3. Ninety‐five foods were liberalized in the diet of 55 patients; the remaining 12 were introduced by 10 patients at least in traces. Throughout the study, 40 out of 65 were able to get a free diet. ACT increased from 17 (Q1‐Q3: 15–17) to 23.6 (Q1‐Q3: 23–25). The FA‐QoL score in children ≤12 years decreased from 4.63 ± 0.74 to 2.02 ± 1.13, and in adolescents from 4.68 ± 0.92 to 1.90 ± 1.50. Conclusions During Omalizumab therapy, a safe reintroduction of allergenic foods is feasible. Trial Registration Number ClinicalTrials.gov , NCT06316414.
Gastrointestinal-inert prebiotic micro-composites improve the growth and community diversity of mucosal-associated bacteria.
Authors: Linh P Ta, Sarah Corrigan, Chris Tselepis, Tariq H Iqbal, Christian Ludwig, Richard D Horniblow
Journal: Journal of Controlled Release (2024)

The process of microencapsulation and the development of microparticle-based drug formulations have gained increased pharmaceutical interest, particularly for drug delivery and bacterial-encapsulation purposes for probiotic delivery. Existing studies have examined microcomposite (MC) responses to gastrointestinal (GI) conditions with the aim of controlling disintegration, and thus release, across the small and large bowel. However, the delivery of MCs which remain intact, without degrading, could act as bacterial growth scaffolds or materials providing a prebiotic support, conferring potentially beneficial GI health properties. This present study employs prilling as a method to produce a portfolio of MCs using a variety of biopolymers (alginate, chitosan, pectin and gellan gum) with a range of MC diameters and density compositions. Fluorescent probes are co-encapsulated within each MC to enable flow-cytometry directed release profile assessments following exposure to chemical simulated gastric and intestinal digestion conditions. We observe that MC size, gel-strength, density, and biopolymer material all influence response to gastric and intestinal conditions. Gellan gum (GG) MCs demonstrated complete resistance to disintegration throughout GI-simulation in the stomach and small intestine. Considering these MCs could reach the colon intact, we then examined how such MCs, doped with prebiotic growth supporting carboxymethyl cellulose (CMC) polymers, could impact microbial communities using a bioreactor model of the colonic microbiome. Following supplementation with GGCMC MCs, mucosal bacterial diversity (using 16 s rRNA sequencing and Shannon entropy and observed feature diversity metrics) and taxonomic composition changes were observed. Concentrations of short chain fatty acid (SCFA) metabolites were also found to be altered. This is the first study to comprehensivelyexamine how MC physicochemistry can be manipulated to tailor MCs to have the desired GI release performance and subsequently, how GI-resistant MCs could have influential microbial altering properties and be adopted in novel prebiotic strategies.
Methotrexate versus Ciclosporin in the Treatment of Severe Atopic Eczema in Children: An economic evaluation
Authors: Tracey H Sach, Kaitlyn R Chan, Ashley P Jones, Anna Rosala-Hallas, Catherine Spowart, Farhiya Ashoor, Alan Irvine, Paula Beattie, Susannah Baron, Fiona Browne, Mandy Wan, Amina Ahmed, Carsten Flohr
Journal: British Journal of Dermatology (2024)

Ciclosporin (CsA) and methotrexate (MTX) are both frequently prescribed drugs for the treatment of atopic dermatitis (AD) in children and young people. Historically, CsA has been the most commonly used conventional systemic treatment for severe paediatric AD, but MTX is being increasingly used as an alternative first-line conventional systemic treatment, especially in middle- and low-income settings. We found that MTX provides an effective and low-cost first-line systemic treatment for severe AD and is a suitable alternative to CsA.
RNA lipid nanoparticles as efficient in vivo CRISPR-Cas9 gene editing tool for therapeutic target validation in glioblastoma cancer stem cells
Authors: Nadia Rouatbi, Adam A Walters, Pedro M Costa, Yue Qin, Revadee Liam-Or, Vivien Grant, Steven M Pollard, Julie Tzu-Wen Wang, Khuloud T Al-Jamal
Journal: Journal of Controlled Release (2024)

In vitro and ex-vivo target identification strategies often fail to predict in vivo efficacy, particularly for glioblastoma (GBM), a highly heterogenous tumor rich in resistant cancer stem cells (GSCs). An in vivo screening tool can improve prediction of therapeutic efficacy by considering the complex tumor microenvironment and the dynamic plasticity of GSCs driving therapy resistance and recurrence. This study proposes lipid nanoparticles (LNPs) as an efficient in vivo CRISPR-Cas9 gene editing tool for target validation in mesenchymal GSCs. LNPs co-delivering mRNA (mCas9) and single-guide RNA (sgRNA) were successfully formulated and optimized facilitating both in vitro and in vivo gene editing. In vitro, LNPs achieved up to 67 % reduction in green fluorescent protein (GFP) expression, used as a model target, outperforming a commercial transfection reagent. Intratumoral administration of LNPs in GSCs resulted in ∼80 % GFP gene knock-out and a 2-fold reduction in GFP signal by day 14. This study showcases the applicability of CRISPR-Cas9 LNPs as a potential in vivo screening tool in GSCs, currently lacking effective treatment. By replacing GFP with a pool of potential targets, the proposed platform presents an exciting prospect for therapeutic target validation in orthotopic GSCs, bridging the gap between preclinical and clinical research.
Systematic prioritization of functional variants and effector genes underlying colorectal cancer risk
Authors: Philip J Law, James Studd, James Smith, Jayaram Vijayakrishnan, Bradley T Harris, Maria Mandelia, Charlie Mills, Malcolm G Dunlop, Richard S Houlston
Journal: Nature Genetics (2024)

Genome-wide association studies of colorectal cancer (CRC) have identified 170 autosomal risk loci. However, for most of these, the functional variants and their target genes are unknown. Here, we perform statistical fine-mapping incorporating tissue-specific epigenetic annotations and massively parallel reporter assays to systematically prioritize functional variants for each CRC risk locus. We identify plausible causal variants for the 170 risk loci, with a single variant for 40. We link these variants to 208 target genes by analyzing colon-specific quantitative trait loci and implementing the activity-by-contact model, which integrates epigenomic features and Micro-C data, to predict enhancer-gene connections. By deciphering CRC risk loci, we identify direct links between risk variants and target genes, providing further insight into the molecular basis of CRC susceptibility and highlighting potential pharmaceutical targets for prevention and treatment.
HIV, malnutrition, and noncommunicable disease epidemics among tuberculosis-affected households in east and southern Africa: A cross-sectional analysis of the ERASE-TB cohort
Authors: Claire Jacqueline Calderwood, Edson Tawanda Marambire, Leyla Larsson, Denise Banze, Alfred Mfinanga, Celina Nhamuave, Tejawsi Appalarowthu, Mishelle Mugava, Jorge Ribeiro, Peter Edwin Towo, Karlos Madziva, Justin Dixon, Kathrin Held, Lilian Tina Minja, Junior Mutsvangwa, Celso Khosa, Norbert Heinrich, Katherine Fielding, Katharina Kranzer
Journal: PLoS Medicine (2024)

Background As a result of shared social and structural risk factors, people in households affected by tuberculosis may have an increased risk of chronic conditions; at the same time, tuberculosis screening may be an opportunity for interventions. We sought to describe the prevalence of HIV, nutritional disorders, and noncommunicable diseases (NCDs) among members of tuberculosis-affected households in 3 African countries. Methods and findings A part of a multicountry cohort study, we screened for tuberculosis, HIV, nutritional disorders (underweight, anaemia, overweight/obesity), and NCDs (diabetes, hypertension, and chronic lung disease) among members of tuberculosis-affected households aged ≥10 years in Mozambique, Tanzania, and Zimbabwe. We describe the prevalence of these conditions, their co-occurence within individuals (multimorbidity) and household-level clustering. Of 2,109 household contacts recruited, 93% ( n = 1,958, from 786 households) had complete data and were included in the analysis. Sixty-two percent were female, median age was 27 years, and 0.7% ( n = 14) were diagnosed with co-prevalent tuberculosis. Six percent of household members ( n = 120) had previous tuberculosis, 15% ( n = 294) were living with HIV, 10% ( n = 194) had chronic lung disease, and 18% ( n = 347) were anaemic. Nine percent of adults ( n = 127) had diabetes by HbA1c criteria, 32% ( n = 439) had hypertension. By body mass index criteria, 18% household members ( n = 341) were underweight while 29% ( n = 549) were overweight or obese. Almost half the household members ( n = 658) had at least 1 modifiable tuberculosis risk factor. Sixty-one percent of adults ( n = 822) had at least 1 chronic condition, 1 in 4 had multimorbidity. While most people with HIV knew their status and were on treatment, people with NCDs were usually undiagnosed and untreated. Limitations of this study include use of point-of-care HbA1c for definition of diabetes and definition of hypertension based on single-day measurements. Conclusions Households affected by tuberculosis also face multiple other health challenges. Integrated approaches to tuberculosis screening may represent an opportunity for identification and treatment, including prioritisation of individuals at highest risk for tuberculosis to receive preventive therapy.
Class I Recalls of Cardiovascular Devices Between 2013 and 2022
Authors: Claudia See, Maryam Mooghali, Sanket S. Dhruva, Joseph S. Ross, Harlan M. Krumholz, Kushal T. Kadakia
Journal: Annals of Internal Medicine (2024)

Cardiovascular devices account for one third of all Class I recalls, the U.S. Food and Drug Administration's (FDA) most severe designation, indicating a reasonable probability of "serious adverse health consequences or death." Understanding recalls and their causes is important for patient safety.
Clinical Outcomes of Continuation and Maintenance Electroconvulsive Therapy
Authors: Anders Jørgensen, Frederikke Hoerdam Gronemann, Maarten P. Rozing, Martin B. Jørgensen, Merete Osler
Journal: JAMA Psychiatry (2024)

Importance Large-scale evidence for the efficacy of continuation and maintenance electroconvulsive therapy (c/mECT) is lacking. Objective To provide an exhaustive and naturalistic insight into the real-world outcomes and the cost-effectiveness of c/mECT in a large dataset. Design, Setting, and Participants This cohort study included all patients in the Danish National Patient Registry who initiated treatment with ECT from 2003 through 2022. The data were analyzed from October 2023 to February 2024. Exposures ECT. An algorithm to identify c/mECTs in the dataset was developed: (&amp;amp;gt;3 treatments with ≥7 and &amp;amp;lt;90 days between adjacent treatments, occurring within a time frame of 180 days [cECT] or more [mECT] after an acute [aECT] series). Main Outcomes and Measures The association of c/mECT with subsequent 6- to 12-month risk of hospitalization or suicidal behavior using Cox proportional hazard regression with multiple adjustments and aECT only as a reference, propensity score matching, and self-controlled case series analysis using a Poisson regression model. A cost-effectiveness analysis based on hospitalization and ECT expenses was made. Results A total of 19 944 individuals were treated with ECT (12 157 women [61%], 7787 men [39%]; median [IQR] age, 55 [41-70] years). Of these, 1533 individuals (7.7%) received c/mECT at any time point (1017 [5.1%] cECT only and 516 [2.6%] mECT). Compared with patients receiving aECT only, c/mECT patients more frequently experienced schizophrenia (odds ratio [OR], 2.14; 95% CI, 1.86-2.46) and schizoaffective disorder (OR, 2.42; 95% CI, 1.90-3.09) and less frequently unipolar depression (OR, 0.56; 95% CI, 0.51-0.62). In all models, c/mECT was associated with a lower rate of hospitalization after finishing aECT (eg, 6-month adjusted hazard ratio, 0.68; 95% CI, 0.60-0.78 [Cox regression]; 6-month incidence rate ratio, 0.51; 95% CI, 0.41-0.62 [Poisson regression]). There was no significant difference in the risk of suicidal behavior. Compared with the periods before the end of aECT, c/mECT was associated with a substantial reduction in total treatment costs. Conclusions and Relevance In a nationwide and naturalistic setting, c/mECT after aECT was infrequently used but associated with a lower risk of readmission than aECT alone. The totality of the evidence indicates that c/mECT should be considered more often to prevent relapse after successful aECT in patients whose condition does not respond sufficiently to other interventions.
A Paradigm Shift in Tumor Immunology: Th17 Cells and TGF-β in Intestinal Cancer Initiation
Authors: Megan M. Wyatt, Chrystal M. Paulos
Journal: Cancer Research (2024)

Cancer remains one of the most complex challenges in modern medicine, with intricate relationships between immune responses and tumor development. This article examines a groundbreaking study by Fesneau, Thevin and colleagues, published in Nature Immunology. This elegant body of work explores the link between chronic inflammation and cancer, particularly focusing on Th17 cells involved in intestinal cancer initiation. Th17 cells, known for their dual roles in immunity, can promote or inhibit tumor growth depending on their environment. This study reveals that a specific subset of Th17 cells, derived from IL-17-producing cells, can transition to a tumorigenic state when TGF-β signaling is impaired. Surprisingly, TGF-β acts as a crucial regulatory factor, maintaining the balance between immune tolerance and tumorigenesis by preventing Th17 cells from becoming tumorigenic. This research highlights the potential for therapeutic interventions targeting TGF-β signaling to prevent cancer initiation in chronic inflammatory conditions. The findings have clinical implications for improving cancer immunotherapies, including immune checkpoint inhibitors and adoptive T cell therapies, by enhancing the efficacy of treatments and mitigating the risk of tumorigenic transformations. Overall, this study provides insights into the mechanisms linking inflammation and cancer, paving the way for innovative strategies to harness the immunity in cancer treatment.