tbuckley/cabot-search huggingface dataset:
Metabolic shifts during coffee consumption refresh the immune response: insight from comprehensive multiomics analysis
Authors: Pinglang Ruan, Ming Yang, Xinyi Lv, Kai Shen, Yiran Chen, Hongli Li, Di Zhao, Jianhua Huang, Yang Xiao, Weijun Peng, Haijing Wu, Qianjin Lu
Journal: MedComm (2024)

Abstract Coffee, a widely consumed beverage, has shown benefits for human health but lacks sufficient basic and clinical evidence to fully understand its impacts and mechanisms. Here, we conducted a cross‐sectional observational study of coffee consumption and a 1‐month clinical trial in humans. We found that coffee consumption significantly reshaped the immune system and metabolism, including reduced levels of inflammatory factors and a reduced frequency of senescent T cells. The frequency of senescent T cells and the levels of the senescence‐associated secretory phenotype were lower in both long‐term coffee consumers and new coffee consumers than in coffee nondrinking subjects, suggesting that coffee has anti‐immunosenescence effects. Moreover, coffee consumption downregulated the activities of the The Janus kinase/signal transduction and activator of transcription (JAK/STAT) and mitogen‐activated protein kinases (MAPK) signaling pathways and reduced systemic proinflammatory cytokine levels. Mechanistically, coffee‐associated metabolites, such as 1‐methylxanthine, 3‐methylxanthine, paraxanthine, and ceramide, reduced the frequency of senescent CD4 + CD57 + T cells in vitro. Finally, in vivo, coffee intake alleviated inflammation and immunosenescence in imiquimod‐induced psoriasis‐like mice. Our results provide novel evidence of the anti‐inflammatory and anti‐immunosenescence effects of coffee, suggesting that coffee consumption could be considered a healthy habit.
Beyond benchmarking and towards predictive models of dataset-specific single-cell RNA-seq pipeline performance
Authors: Cindy Fang, Alina Selega, Kieran R. Campbell
Journal: Genome biology (2024)

Abstract Background The advent of single-cell RNA-sequencing (scRNA-seq) has driven significant computational methods development for all steps in the scRNA-seq data analysis pipeline, including filtering, normalization, and clustering. The large number of methods and their resulting parameter combinations has created a combinatorial set of possible pipelines to analyze scRNA-seq data, which leads to the obvious question: which is best? Several benchmarking studies compare methods but frequently find variable performance depending on dataset and pipeline characteristics. Alternatively, the large number of scRNA-seq datasets along with advances in supervised machine learning raise a tantalizing possibility: could the optimal pipeline be predicted for a given dataset? Results Here, we begin to answer this question by applying 288 scRNA-seq analysis pipelines to 86 datasets and quantifying pipeline success via a range of measures evaluating cluster purity and biological plausibility. We build supervised machine learning models to predict pipeline success given a range of dataset and pipeline characteristics. We find that prediction performance is significantly better than random and that in many cases pipelines predicted to perform well provide clustering outputs similar to expert-annotated cell type labels. We identify characteristics of datasets that correlate with strong prediction performance that could guide when such prediction models may be useful. Conclusions Supervised machine learning models have utility for recommending analysis pipelines and therefore the potential to alleviate the burden of choosing from the near-infinite number of possibilities. Different aspects of datasets influence the predictive performance of such models which will further guide users.
Exploring different objectives in non-inferiority trials
Authors: Conor D Tweed, Matteo Quartagno, Michelle N Clements, Rebecca M Turner, Andrew J Nunn, David T Dunn, Ian R White, Andrew J Copas
Journal: BMJ (2024)

Non-inferiority trials compare the efficacy of a new treatment with an existing one where the new treatment is expected to have broadly similar efficacy to the existing treatment, but where other benefits might make the new treatment desirable. These trials might aim to demonstrate that a new treatment is either an alternative to, or a replacement for, the current treatment. In this article, how treatment comparisons can be based only on efficacy, or on both efficacy and other benefits, is explained, and guidance on how to choose the correct objective for a trial is given. This choice should influence the design of the trial (eg, choosing the non-inferiority margin and secondary outcomes), analysis, and reporting of the trial. Most non-inferiority trials aim to show only that a new treatment is an alternative to the standard of care. Being more transparent about the trial objective, however, could mean that more trials are conducted with an emphasis on the risk-benefit trade-off for a new treatment and generate more clinically meaningful trial results with a greater effect on practice.
SpRY-mediated screens facilitate functional dissection of non-coding sequences at single-base resolution
Authors: Yao Yao, Zhiwei Zhou, Xiaoling Wang, Zhirui Liu, Yixin Zhai, Xiaolin Chi, Jingyi Du, Liheng Luo, Zhigang Zhao, Xiaoyue Wang, Chaoyou Xue, Shuquan Rao
Journal: Cell Genomics (2024)

CRISPR mutagenesis screens conducted with SpCas9 and other nucleases have identified certain cis-regulatory elements and genetic variants but at a limited resolution due to the absence of protospacer adjacent motif (PAM) sequences. Here, leveraging the broad targeting scope of the near-PAMless SpRY variant, we have demonstrated that saturated SpRY mutagenesis and base editing screens can faithfully identify functional regulatory elements and essential genetic variants for target gene expression at single-base resolution. We further extended this methodology to investigate a genome-wide association study (GWAS) locus at 10q22.1 associated with a red blood cell trait, where we identified potential enhancers regulating HK1 gene expression, despite not all of these enhancers exhibiting typical chromatin signatures. More importantly, our saturated base editing screens pinpoint multiple causal variants within this locus that would otherwise be missed by Bayesian statistical fine-mapping. Our approach is generally applicable to functional interrogation of all non-coding genomic elements while complementing other high-coverage CRISPR screens.
H19 influenza A virus exhibits species-specific MHC class II receptor usage
Authors: Umut Karakus, Ignacio Mena, Jithesh Kottur, Sara S. El Zahed, Rocío Seoane, Soner Yildiz, Leanne Chen, Magdalena Plancarte, LeAnn Lindsay, Rebecca Halpin, Timothy B. Stockwell, David E. Wentworth, Geert-Jan Boons, Florian Krammer, Silke Stertz, Walter Boyce, Robert P. de Vries, Aneel K. Aggarwal, Adolfo García-Sastre
Journal: Cell Host & Microbe (2024)
High recallability of memory B cells requires ZFP318-dependent transcriptional regulation of mitochondrial function
Authors: Yifeng Wang, Wen Shao, Xin Liu, Qingtai Liang, Jiaqi Lei, Wenjuan Shi, Miao Mei, Ying Li, Xu Tan, Guocan Yu, Li Yu, Linqi Zhang, Hai Qi
Journal: Immunity (2024)
Short-term cold exposure induces persistent epigenomic memory in brown fat
Authors: Shin-ichi Inoue, Matthew J. Emmett, Hee-Woong Lim, Mohit Midha, Hannah J. Richter, Isaac J. Celwyn, Rashid Mehmood, Maria Chondronikola, Samuel Klein, Amy K. Hauck, Mitchell A. Lazar
Journal: Cell Metabolism (2024)
Neoadjuvant S-1 plus cisplatin-based chemoradiotherapy compared with surgery alone for locally advanced gastric cancer: Randomized, phase II trial.
Authors: Moonki Hong, Kum-Hee Yun, Minkyu Jung, Sun Young Rha, Hyoung-Il Kim, Jun Chul Park, Sang Kil Lee, Seo Hee Choi, Inkyung Jung, Joon Seok Lim, Woo Jin Hyung, Woong Sub Koom, Hyo Song Kim
Journal: Journal of Clinical Oncology (2024)

4076 Background: Patients with locally advanced gastric cancer (LAGC), are known to have a high risk of recurrence even after surgery. This study was designed to delineate whether neoadjuvant concurrent chemoradiotherapy (CCRT) using the S-1/Cisplatin (SP) regimen can effectively downstage the T stage in patients with clinically T4 stage compared with surgery alone (OP). Methods: This is a randomized phase II open label trial and gastric cancer patients with initial clinical T4 were enrolled. Patients were randomized into neoadjuvant CCRT or OP. For the CCRT group, S-1 (20 mg/m2 twice daily, 2 weeks on and 1 week off) and cisplatin (30 mg/m 2 /day, first day of week 1, 2, 4, and 5) were administered concurrent with radiotherapy (day 1-5 for 5 weeks, total 45 Gy/25 fractions,). Surgery was performed within 3 to 6 weeks after the completion of CCRT. For the OP group, curative surgery was performed within 3 weeks after randomization. Post-operative adjuvant chemotherapy was chosen as S-1 monotherapy or combination of Capecitabine, and Oxaliplatin according to the physician’s choice. The primary objective of this study was to compare the downstaging rates between the groups (65% and 40% for the CCRT and OP group). Using a type I error rate of 0.10 and a power of 0.80, the planned sample size was 51 patients per group but the study was closed prematurely. Results: Between November 2016 and August 2021, 49 patients with T4 were enrolled. Of those, 26 (CCRT) and 23 (OP) patients were randomized but diagnostic laparoscopy for preoperative screening revealed peritoneal seeding in some patients. Finally, 23 (CCRT) and 17 (OP) patients were evaluable and clinicopathologic characteristics were well balanced between the two groups in per protocol analysis. For CCRT, 19 out of 23 (82.61%) patients satisfied downstage, while among 8 out of 17 (47.06%) patients in OP group satisfied downstage ( P=0.038). The median disease-free survival (DFS) was 27.91 months in CCRT group, and 45.96 months in OP group ( P=0.985). The median overall survival (OS) was not reached in CCRT group, and 51.2 months in OR group ( P=0.335). There were no statistically significant differences between neoadjuvant CCRT and surgery group in the aspect of both hematologic and non-hematologic adverse events. Conclusions: In this study, neoadjuvant SP based CCRT significantly increased downstaging in T stage compared than OP alone. The prespecified genomic analysis with transcriptomic sequencing will be available at the meeting. Clinical trial information: NCT03814759 .
Safety and feasibility of esophagectomy following neoadjuvant immunotherapy combined with chemotherapy or chemoradiotherapy for locally advanced esophageal squamous cell carcinoma: Analysis of two phase 2 clinical trials.
Authors: dijian shen, Runzhe Chen, Yongling Ji, Qixun Chen, Ming Chen
Journal: Journal of Clinical Oncology (2024)

4070 Background: Despite the survival benefit of preoperative chemotherapy (CT) or chemoradiotherapy (CRT) in patients with locally advanced esophageal squamous cell carcinoma (ESCC), the prognosis remains dismal. With the potential benefit of combining immune checkpoint inhibitors (ICIs) neoadjuvantly, we initiated two phase II single-armed clinical trials to explore the efficacy, feasibility, and safety of esophagectomy following the combination of preoperative PD-1 inhibitor with CT or CRT in ESCC. Methods: A total of 55 patients with histologically confirmed ESCC (clinical stage II-IVA according to the American Joint Committee on Cancer 8th staging system) from two phase 2, single-arm trials underwent neoadjuvant ICIs combined with chemotherapy (nICT) (n=38) (NCT04506138) or chemoradiotherapy (nICRT) (n=17) (NCT03940001) between May 2019 and June 2022 were enrolled. Patients received 2 doses of intravenous PD-1 inhibitor every 3 weeks, combined with 2 cycles of CT or CRT. Data on the pathological complete response (pCR) rates, operative time, blood loss volume, 30-day complications, hospital stay, and 30-day mortality were collected and assessed between these two groups using a multivariable log-binomial regression model to obtain adjusted relative risk ratios. The primary endpoints of the studies were the safety and feasibility of esophagectomy after the combination of preoperative CT or CRT and PD-1 inhibitor. We also evaluated pCR, primary tumor pCR, operation time, postoperative stay, and 30-day mortality. Results: All the included patients successfully completed neoadjuvant therapy. Age, sex, performance status, clinical stage, histologic subtype, procedure type, operative time, and blood loss volume were similar between the two groups. The primary tumor pCR rates were 52.9% in the nICRT group and 21.6% in the nICT group, respectively (p=0.03), while the postoperative pCR rates were 41.2% in the nICRT group and 21.6% in the nICT group, respectively (p=0.19). Minimally invasive surgery was performed in 89.2% (33/37) of the nICT group and 94.1% (16/17) of the nICRT group. The risk of developing pulmonary, anastomotic, or other complications was similar in the two groups. Conclusions: Esophagectomy was safe after the addition of PD-1 inhibitor to preoperative CT or CRT in ESCC neoadjuvant therapies. Follow-up and exploratory endpoints, including biomarker analyses are ongoing. Clinical trial information: NCT03940001 ; NCT04506138 .
The clinical utility of plasma cell-free DNA (cfDNA) in NET-02: Randomised, phase II trial of liposomal irinotecan (nal-IRI)/5-fluorouracil (5-FU)/folinic acid or docetaxel as second-line (2L) therapy in patients (pts) with progressive poorly differentiated extra-pulmonary neuroendocrine carcinoma (PD-EP-NEC).
Authors: Mairead Geraldine McNamara, Simon Pearce, Jayne Swain, Mollie Anne Halford, Rohini Sharma, Olusola Olusesan Faluyi, Jonathan Wadsley, Carys Morgan, Lucy R. Wall, Ian Chau, Nick Reed, Debashis Sarker, Jane Margetts, Alan Anthoney, Jamie B. Oughton, Angela Lamarca, Richard Hubner, Dominic G. Rothwell, Juan W. Valle, Alexandra Clipson
Journal: Journal of Clinical Oncology (2024)

4130 Background: In NET-02, nal-IRI/5-FU, but not docetaxel, met the primary endpoint of 6-month (mo) progression-free survival (PFS) rate in pts with progressive PD-EP-NEC (1). The prognostic potential of cfDNA in progressive PD-EP-NEC has not been explored in a prospective randomised trial. Methods: NET-02 was a multi-centre, randomised (1:1), phase II trial of IV nal-IRI/5-FU/folinic acid, Q14 days (ARM A), or IV docetaxel, Q21 days (ARM B), as 2L therapy in pts with progressive PD-EP-NEC. Plasma samples were taken at baseline (T0), following 6 weeks of treatment (T1) and at progression (T2). Samples were analysed using a multi-omic next-generation sequencing (NGS) approach (T7-MBD-seq) (measures genome-wide methylation and low pass whole genome copy number alterations (CNA)). The tumour fraction (TF) of cfDNA was determined using ichorCNA and correlated with clinical outcomes using Cox proportional hazards model and Logistic regression. Results: Of 56 pts evaluable for efficacy, there were 54 (96%) T0 samples (48 passed quality control), 31 (55%) at T1 and 20 (36%) at T2. At T0, 36/48 (75%) samples had detectable TF by copy number (using 3% TF cut-off). For the entire cohort, T0 TF was negatively prognostic for overall survival (OS) (Hazard Ratio (HR) 1.17, 95% Confidence interval (CI) 1.00-1.37, P=.044), but not for 6 mo PFS rate (Odds ratio (OR) 1.25, 95% CI 0.91-1.73, P=.17), response rate (RR) (OR 1.11, 95% CI 0.67-1.76, P=.65) or PFS (HR 1.04, 95%CI 0.91-1.20, P=.53). In the entire cohort, median OS split by TF (N=16 each) was 10.2 mo (95% CI 4.1-not available (NA)) for low (TF≤8.6%), 6.9 mo (95% CI 3.4-14.8) for medium (8.6&lt;TF≤24.3%) and 3.7 mo (95% CI 2.8-NA) for high (TF&gt;24.3%). T0 TF was also negatively prognostic for 6 mo PFS rate and OS in ARM A (P=.02, P=.03), but not ARM B (P=.61, P=.48), but was not prognostic for RR or PFS (Table). TF correlated with the presence of liver metastases (Wilcoxon Rank Sum P=.009), but not with ECOG PS (P=.14), sex (P=.10), Ki-67 (P=.39) or age (Spearman rank correlation P=.45). Longitudinal copy number and methylation cfDNA analysis is on-going. Conclusions: These results suggest that it may be possible to stratify prognosis based on amount of baseline TF in patients with progressive PD-EP-NEC, and may also identify patients who would benefit most from the nal-IRI combination. 1. McNamara 2023, EClin Med. Clinical trial information: 03837977. [Table: see text]
OPTIMIZE-1 primary analysis: Safety, efficacy and biomarker results of a phase 1b/2 study combining CD40 agonist mitazalimab with mFOLFIRINOX in previously untreated metastatic pancreatic ductal adenocarcinoma (mPDAC).
Authors: Jean-Luc Van Laethem, Ivan Borbath, Karen Paula Geboes, Philippe Alexandre Cassier, Aurélien Lambert, Emmanuel Mitry, Hans Prenen, Lorenzo Pilla, Jean-Frédéric Blanc, Inmaculada Gallego Jiménez, Roberto A. Pazo Cid, Mercedes Rodríguez Garrote, Jaime Feliú, Karin Nordbladh, Karin Enell Smith, David Gomez Jimenez, Peter Ellmark, Yago Pico de Coaña, Sumeet Vijay Ambarkhane, Teresa Macarulla
Journal: Journal of Clinical Oncology (2024)

4133 Background: With a 5 year overall survival (OS) rate &lt;5%, PDAC is a leading cause of cancer related mortality. Currently available systemic therapies are not curative and new therapeutic options are needed. Mitazalimab is a human CD40 agonistic IgG1antibody that reduces immune suppression, sensitizes the tumor to chemotherapy, and induces long lasting anti-tumor T cell responses. OPTIMIZE-1 (NCT04888312) is a Phase 1b/2, open label, multicenter study assessing mitazalimab's safety and efficacy combined with mFOLFIRINOX (mFFX) in chemotherapy naïve mPDAC patients (pts). Methods: In the first 21 day cycle, mitazalimab was administered on day 1 and 10 and mFFX infusion started on day 8. In subsequent cycles, treatment followed a 14 day cycle with mitazalimab given 2 days after mFFX. The primary endpoint is objective response rate (ORR) compared to 30% ORR for FFX (Conroy, 2011) (80% power; α (1-sided) =0.10). Secondary and exploratory endpoints include Duration of Response (DoR), progression free survival (PFS), OS, safety, PK and PD biomarker assessments. Results: Seventy pts with mPDAC were treated with mFFX + mitazalimab (safety set: 5 at 450 µg/kg and 65 at 900 µg/kg). 57 patients at 900 µg/kg received ≥2 treatment cycles and were efficacy evaluable. The most common grade ≥3 AEs were neutropenia (25.7%), anemia (11.4%), hypokalemia (15.7%) and thrombocytopenia (11.4%), consistent with FFX safety profile. Two pts discontinued treatment due to AEs. Confirmed ORs were observed in 23 pts (40.4%), including 1 complete responder (CR). Median OS, PFS and duration of Response (DoR) were 14.3 months (mo), 7.4 mo and 12.5 mo respectively, with a median follow up of 12.7 mo. 29 pts (51%) remain in the study (32% on treatment, 19% in survival follow up). Efficacy results including correlation with detected KRAS G12 mutations are summarized (Table). Conclusions: Mitazalimab in combination with mFFX is a feasible regimen with a manageable safety profile. The primary endpoint was met; KRAS G12 V and R mutations were associated with better efficacy. Given the promising DoR linked with survival benefit in previously untreated mPDAC, these results merit continued development of mitazalimab in a confirmatory phase 3 study. Clinical trial information: NCT04888312 . [Table: see text]
Neoadjuvant toripalimab plus chemotherapy followed by concurrent chemoradiotherapy in locally advanced esophageal squamous cell carcinoma (GASTO 1071).
Authors: Bo Qiu, FangJie Liu, DaQuan Wang, QiaoTing Luo, YingJia Wu, JinYu Guo, YingYi Zou, YuMing Rong, GuangYu Luo, Hui Liu
Journal: Journal of Clinical Oncology (2024)

4077 Background: The combination of immune checkpoint inhibitor and concurrent chemoradiotherapy (CCRT) has been under investigation in patients with unresectable, locally advanced esophageal squamous cell carcinoma (ESCC). We explored the efficacy and safety of neoadjuvant toripalimab plus chemotherapy followed by CCRT in patients with locally advanced ESCC. Methods: This phase II, non-randomized, 2-cohort study enrolled patients with unresectable, stage T1-4N0-3M0-1 ESCC (M1 only includes patients with lymph node metastasis in the supraclavicular region). All patients were aged 18–80 years with an Eastern Cooperative Oncology Group performance status of 0–1. Patients in both cohorts received neoadjuvant therapy comprised of paclitaxel-albumin, nedaplatin and toripalimab 240 mg every 3 weeks, for 2 cycles, followed by CCRT (total dose 60Gy in cohort A, 50 Gy in cohort B, combined with oral capecitabine). The primary endpoint was progression-free survival (PFS) from enrollment. The trial is registered with ClinicalTrials.gov, NCT04844385. Results: Between February 26, 2021, and June 20, 2023, a total of 63 patients were enrolled in cohort A (54 men [85.7%]; median [interquartile range] age, 63 [58-65] years; 57 [90.5%] patients had stage III to IVB disease), and 61 patients were enrolled in cohort B (43 men [70.5%]; median [interquartile range] age, 65 [57-69] years; 52 [85.2%] patients had stage III to IVB disease). The objective response rate assessed 2 months after CCRT was 93.7% in cohort A and 93.4% in cohort B. At data cutoff (January 31, 2024), the median (range) follow-up duration was 31.3 (2.5-47.1) months in cohort A, and 17.0 (5.7-38.7) months in cohort B. The 12-month and 18-month PFS rates were 78.3%, 64.4% in cohort A, and 75.7%, 63.6% in cohort B. Median PFS was not reached in either cohort. Locoregional recurrence was observed in 19.0% (12/63) of patients in cohort A, and 24.6% (15/61) of patients in cohort B. Distant metastasis was observed in 12.7% (8/63) of patients in cohort A, and 3.3% (2/61) of patients in cohort B. Grade 3 and 5 pneumonitis occurred in 3.2% (2/63) and 1.6% (1/63) in cohort A, respectively, while no grade 3+ pneumonitis occurred in cohort B. Treatment-related esophageal fistula occurred in 1.6% (1/63) in cohort A and 1.6% (1/61) in cohort B. Conclusions: Neoadjuvant toripalimab plus chemotherapy followed by definitive CCRT demonstrated promising efficacy and acceptable toxicity in patients with locally advanced ESCC. Further study is warranted to confirm this conclusion. Clinical trial information: NCT04844385 .