tbuckley/cabot-search huggingface dataset:
Comparison of systemic therapy efficacy in advanced hepatocellular carcinoma: Systematic review and frequentist network meta-analysis of randomized controlled trials.
Authors: Robin Park, Laércio Lopes da Silva, Voravech Nissaisorakarn, Ivy Riano, Anwaar Saeed
Journal: Journal of Clinical Oncology (2021)

293 Background: Several systemic agents are approved for use in the first line and second line treatment settings for advanced hepatocellular carcinoma (aHCC). However, choosing among available options in both first and second line settings remain difficult due to the paucity of head-to-head comparative trials. Therefore, we have conducted a systematic review and network meta-analysis for the indirect comparison of the systemic agents in the first line and second line settings. Methods: Published clinical trials that have evaluated systemic agents in the first line and second line settings in advanced HCC from inception to April 2020 were identified by searching PubMed, EMBASE, and Cochrane Databases and abstracts presented in the main annual ASCO and ESMO conferences from 2017 to 2020. Studies published in English providing clinical outcomes data including overall survival (OS), progression free survival (PFS) and objective response rate (ORR) were included in the analysis. The primary outcomes of interest were pooled hazard ratios (HR) of OS and OR of ORR in first line studies and HR of PFS and OR of ORR for second line studies. OS for second line agents were synthesized in a qualitative analysis. Results: Overall, 8,335 patients (13 studies) and 4,612 patients (11 studies) were analyzed in phase II/III trials for first line and second line settings respectively. In the first line setting, atezolizumab plus bevacizumab and lenvatinib were ranked highest as the regimens associated with the greatest OS (A+B, HR 0.58, 95% CI, 0.42-0.80; P-score 0.993) and ORR (lenva, OR 3.34, 95% CI, 2.17-5.14; P-score 0.080) respectively. In the second line setting, cabozantinib showed the highest probability of greatest PFS benefit (HR 0.44, 95% CI, 0.29-0.66; P-score 0.854) as well as the highest probability of greatest ORR benefit (cabo, OR 9.40, 95% CI, 1.25-70.83, P-score, 0.266). Conclusions: In the first line setting, atezolizumab plus bevacizumab may be the superior regimen whereas lenvatinib may be considered as the initial option when robust tumor responses are preferred. In the second line setting, cabozantinib may be the preferred option including in cases when robust tumor responses are favored.
Bioinformatics workflows for clinical applications in precision oncology
Authors: Natalie Jäger
Journal: Seminars in Cancer Biology (2021)

High-throughput molecular profiling of tumors is a fundamental aspect of precision oncology, enabling the identification of genomic alterations that can be targeted therapeutically. In this context, a patient is matched to a specific drug or therapy based on the tumor's underlying genetic driver events rather than the histologic classification. This approach requires extensive bioinformatics methodology and workflows, including raw sequencing data processing and quality control, variant calling and annotation, integration of different molecular data types, visualization and finally reporting the data to physicians, cancer researchers and pharmacologists in a format that is readily interpretable for clinical decision making. This review comprises a broad overview of these bioinformatics aspects and discusses the multiple analytical, technical and interpretational challenges that remain to efficiently translate molecular findings into personalized treatment recommendations.
SARS-CoV-2 vaccination for patients with inflammatory bowel diseases: recommendations from an international consensus meeting
Authors: Corey A Siegel, Gil Y Melmed, Dermot PB McGovern, Victoria Rai, Florian Krammer, David T Rubin, Maria T Abreu, Marla C Dubinsky
Journal: Gut (2021)

The COVID-19 pandemic has claimed the lives of nearly 2 million people worldwide.1 Following rapid sequencing of SARS-CoV-2, pharmaceutical companies and academic institutions rapidly generated vaccine candidates on the back of a variety of both established and novel vaccine platforms.2–4 Vaccines accelerated at unprecedented pace to phase 3 development, and in December 2020, two mRNA vaccines and one inactivated vaccine were authorised for use in a number of countries. Additional vaccine platforms and candidates are in late stages of phase 3 testing.5 Prioritisation of vaccine access is generally determined by regional health authorities on the basis of risk of SARS-CoV-2 exposure and risk of developing complications from COVID-19 in order to equitably protect and promote global public well-being.6–8

IBD, including Crohn’s disease and ulcerative colitis, are characterised by chronic intestinal inflammation due to immune dysregulation. IBD is often treated with immune-modifying therapies including corticosteroids, immunomodulators, biologic agents including monoclonal antibody inhibitors of tumour necrosis factor (TNF) alpha, interleukin 12/23, integrins and small molecules such as Janus kinase (JAK) inhibitors. Prior studies have evaluated the safety and effectiveness of various vaccines in patients with IBD, with specific focus on the impact of immune-modifying therapies on serologic responses. In general, non-live vaccines are considered safe in patients with IBD regardless of IBD therapy, although those on specific types of immune-modifying treatments at the time of vaccination may have reduced vaccine immune responses.9–12 In spite of decreased efficacy associated with immune-modifying medication, most vaccines are broadly recommended for those with IBD.13–15 Patients with immune conditions (including IBD) were excluded from the SARS-CoV-2 vaccine clinical development programmes,16 and novel vaccine platforms not previously studied in IBD populations are now authorised in many countries. Therefore, many questions regarding the safety and effectiveness of SARS-CoV-2 vaccination in patients with …
Systematic evaluation of IgG responses to SARS-CoV-2 spike protein-derived peptides for monitoring COVID-19 patients
Authors: Yang Li, Dan-yun Lai, Qing Lei, Zhao-wei Xu, Feng Wang, Hongyan Hou, Lingyun Chen, Jiaoxiang Wu, Yan Ren, Ming-liang Ma, Bo Zhang, Hong Chen, Caizheng Yu, Jun-biao Xue, Yun-xiao Zheng, Xue-ning Wang, He-wei Jiang, Hai-nan Zhang, Huan Qi, Shu-juan Guo, Yandi Zhang, Xiaosong Lin, Zongjie Yao, Pengfei Pang, Dawei Shi, Wei Wang, Xiao Yang, Jie Zhou, Huiming Sheng, Ziyong Sun, Hong Shan, Xionglin Fan, Sheng-ce Tao
Journal: Cellular and Molecular Immunology (2021)

Abstract Serological tests play an essential role in monitoring and combating the COVID-19 pandemic. Recombinant spike protein (S protein), especially the S1 protein, is one of the major reagents used for serological tests. However, the high cost of S protein production and possible cross-reactivity with other human coronaviruses pose unavoidable challenges. By taking advantage of a peptide microarray with full spike protein coverage, we analyzed 2,434 sera from 858 COVID-19 patients, 63 asymptomatic patients and 610 controls collected from multiple clinical centers. Based on the results, we identified several S protein-derived 12-mer peptides that have high diagnostic performance. In particular, for monitoring the IgG response, one peptide (aa 1148–1159 or S2–78) exhibited a sensitivity (95.5%, 95% CI 93.7–96.9%) and specificity (96.7%, 95% CI 94.8–98.0%) comparable to those of the S1 protein for the detection of both symptomatic and asymptomatic COVID-19 cases. Furthermore, the diagnostic performance of the S2–78 (aa 1148–1159) IgG was successfully validated by ELISA in an independent sample cohort. A panel of four peptides, S1–93 (aa 553–564), S1–97 (aa 577–588), S1–101 (aa 601–612) and S1–105 (aa 625–636), that likely will avoid potential cross-reactivity with sera from patients infected by other coronaviruses was constructed. The peptides identified in this study may be applied independently or in combination with the S1 protein for accurate, affordable, and accessible COVID-19 diagnosis.
Prediction of Relapse Based on Remission ADAMTS13 Activity in Patients with Immune-Mediated Thrombotic Thrombocytopenic Purpura
Authors: Camila Masias Castanon, Clare Stevens, Lauren Jay, Haiwa Wu, Michael McGookey, Jian Chen, James N. George, Shangbin Yang, Spero R Cataland
Journal: Blood (2017)
Whole-exome sequencing reveals germline-mutated small cell lung cancer subtype with favorable response to DNA repair–targeted therapies
Authors: Camille Tlemsani, Nobuyuki Takahashi, Lorinc Pongor, Vinodh N. Rajapakse, Manoj Tyagi, Xinyu Wen, Grace-Ann Fasaye, Keith T. Schmidt, Parth Desai, Chul Kim, Arun Rajan, Shannon Swift, Linda Sciuto, Rasa Vilimas, Santhana Webb, Samantha Nichols, William Douglas Figg, Yves Pommier, Kathleen Calzone, Seth M. Steinberg, Jun S. Wei, Udayan Guha, Clesson E. Turner, Javed Khan, Anish Thomas
Journal: Science Translational Medicine (2021)

Because tobacco is a potent carcinogen, secondary causes of lung cancer are often diminished in perceived importance. To assess the extent of inherited susceptibility to small cell lung cancer (SCLC), the most lethal type of lung cancer, we sequenced germline exomes of 87 patients (77 SCLC and 10 extrapulmonary small cell) and considered 607 genes, discovering 42 deleterious variants in 35 cancer-predisposition genes among 43.7% of patients. These findings were validated in an independent cohort of 79 patients with SCLC. Loss of heterozygosity was observed in 3 of 14 (21.4%) tumors. Identification of variants influenced medical management and family member testing in nine (10.3%) patients. Unselected patients with SCLC were more likely to carry germline RAD51 paralog D (RAD51D), checkpoint kinase 1 (CHEK1), breast cancer 2 (BRCA2), and mutY DNA glycosylase (MUTYH) pathogenic variants than healthy controls. Germline genotype was significantly associated with the likelihood of a first-degree relative with cancer or lung cancer (odds ratio: 1.82, P = 0.008; and 2.60, P = 0.028), and longer recurrence-free survival after platinum-based chemotherapy (P = 0.002), independent of known prognostic factors. Treatment of a patient with relapsed SCLC and germline pathogenic mutation of BRCA1 interacting protein C-terminal helicase 1 (BRIP1), a homologous recombination-related gene, using agents synthetically lethal with homologous recombination deficiency, resulted in a notable disease response. This work demonstrates that SCLC, currently thought to result almost exclusively from tobacco exposure, may have an inherited predisposition and lays the groundwork for targeted therapies based on the genes involved.
The complexities of the diet-microbiome relationship: advances and perspectives
Authors: Emily R. Leeming, Panayiotis Louca, Rachel Gibson, Cristina Menni, Tim D. Spector, Caroline I. Le Roy
Journal: Genome Medicine (2021)

Personalised dietary modulation of the gut microbiota may be key to disease management. Current investigations provide a broad understanding of the impact of diet on the composition and activity of the gut microbiota, yet detailed knowledge in applying diet as an actionable tool remains limited. Further to the relative novelty of the field, approaches are yet to be standardised and extremely heterogeneous research outcomes have ensued. This may be related to confounders associated with complexities in capturing an accurate representation of both diet and the gut microbiota. This review discusses the intricacies and current methodologies of diet-microbial relations, the implications and limitations of these investigative approaches, and future considerations that may assist in accelerating applications. New investigations should consider improved collection of dietary data, further characterisation of mechanistic interactions, and an increased focus on -omic technologies such as metabolomics to describe the bacterial and metabolic activity of food degradation, together with its crosstalk with the host. Furthermore, clinical evidence with health outcomes is required before therapeutic dietary strategies for microbial amelioration can be made. The potential to reach detailed understanding of diet-microbiota relations may depend on re-evaluation, progression, and unification of research methodologies, which consider the complexities of these interactions.
Duration of Culturable SARS-CoV-2 in Hospitalized Patients with Covid-19
Authors: Min-Chul Kim, Chunguang Cui, Kyeong-Ryeol Shin, Joon-Yong Bae, Oh-Joo Kweon, Mi-Kyung Lee, Seong-Ho Choi, Sun-Young Jung, Man-Seong Park, Jin-Won Chung
Journal: New England Journal of Medicine (2021)

Duration of Positive SARS-CoV-2 on RT-PCR and Culture In 21 consecutive patients with confirmed Covid-19, the median times from symptom onset to negative viral culture and negative real-time RT-PCR...
Hypertrophic Cardiomyopathy, Fibrosis, and Aortic Stiffness: An Unidentified Association Unraveled by Magnetic Resonance Imaging⁎⁎Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
Authors: Harald P. Kühl
Journal: Journal of the American College of Cardiology (2009)
Examining patterns of and reasons for delays to treatment in colon cancer.
Authors: Ali Kalam, Vanessa Arientyl, Jacob B Schriner, Adam Kopp, Patricia Friedmann, Jiyue Qin, Haejin In
Journal: Journal of Clinical Oncology (2021)

52 Background: Delays in colon cancer (CC) treatment can impact patient outcomes. Detailed examination into the patterns and reasons for delay in the diagnostic and pre-treatment work up are understudied, hindering the development of strategies to improve timeliness of care. Methods: CC patients diagnosed at an urban academic institution in 2018 were investigated. Chart review yielded presentation location, diagnostic-work up, treatment and patient characteristics. Time between presentation to the healthcare provider to treatment initiation of ≥ 60 days was considered a delay (Total_Delay). Total time further examined as 3 phases: presentation to diagnosis (PtoD), diagnosis to staging completion (DtoS), and staging completion to treatment (StoT). Delays for each phase was defined as ≥ 30 days. Total_Lt60d vs non-Total_Ge60d were compared. A logistic regression model was used to calculate odds ratio (OR) and 95% confidence intervals (CI) to identify associations with Total_Ge60d. Results: Among 121 CC patients, the median time and interquartile range (IQR) between presentation and treatment initiation was 29 (IQR 8, 53) days. Total_Delay occurred in 21% of patients. The median time between presentation and treatment and interquartile range (IQR) for Total_Delay was 106 (IQR 82, 162) and 16 (IQR 6, 39) for non-Total_Delay. Age, sex, race, and comorbidities were similar between Total_Delay and non-Total_Delay. Total_Delay patients were generally more functionally independent (92% vs 74%, p &lt; .06), presented to locations other than the emergency department (64% vs 42%, p &lt; .075) and were less likely to have hospital admission work-up (20% vs 60%, p &lt; .001) compared to non-Total_Delay. The logistic model showed that Total_Delay is associated with non-hospital work-up (OR 8.3, 95% CI 1.9-45.3), adjusting for comorbidities, symptoms, functional status, cancer severity, and insurance. Delays similarly occurred in all three phases for Total_Delay patients; 48% had delay during PtoD, 60% during DtoS, and 48% during StoT. The most common reason for delay by phase was the following; in the PtoD phase, 5 of 11 (46%) was due to obtaining endoscopy, in DtoS and StoT, 6 of 15 (40%) and 5 of 11 (46%), respectively, was in getting outpatient specialty appointments. Delays due to patient factors (PtoD 18%, DtoS 27%, StoT 28%) were less frequent. Conclusions: Delays to treatment for CC are largely driven by health systems delays. Bundling of diagnostic evaluation and pre-treatment that mimics work-up during a hospital admission may overcome delays in cancer care.
Association of Graduate Medical Education With Hospital Performance and Patient Outcomes
Authors: Radoslav Zinoviev, Harlan M. Krumholz, Kevin Pirruccio, Howard Forman
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Graduate medical education (GME) funding consists of more than $10 billion annual subsidies awarded to academic hospitals to offset the cost of resident training. Critics have questioned the utility of these subsidies and accountability of recipient hospitals. <h3>Objective</h3> To determine the association of GME funding with hospital performance by examining 3 domains of hospital operations: financial standing, clinical outcomes, and resident academic performance. <h3>Design, Setting, and Participants</h3> This study is an economic evaluation of all academic centers that received GME funding in 2017. GME funding data were acquired from the Hospital Compare Database. Statistical analysis was performed from May 2016 to April 2020. <h3>Exposures</h3> GME funding. <h3>Main Outcomes and Measures</h3> This study assessed the association between GME funding and each aspect of hospital operations. Publicly available hospital financial data were used to calculate a financial performance score from 0 to 100 for each hospital. Clinical outcomes were defined as 30-day mortality, readmission, and complication rates for a set of predefined conditions. Resident academic performance was determined by Board Certification Examination (BCE) pass rates at 0, 2, and 5 years after GME funding was awarded. Confounder-adjusted linear regression models were used to test association between GME funding data and a hospital's financial standing, clinical outcomes, and resident academic performance. <h3>Results</h3> The sample consisted of 1298 GME-funded hospitals, with a median (IQR) of 265 (168-415) beds and 32 (10-101) residents per training site. GME funding was negatively correlated with hospitals' financial scores (β = –7.9; 95% CI, –10.9 to –4.8,<i>P</i> = .001). Each additional $1 million in GME funding was associated with lower 30-day mortality from myocardial infarction (–2.34%; 95% CI, –3.59% to –1.08%,<i>P</i> &lt; .001), heart failure (–2.59%; 95% CI, –3.93% to –1.24%,<i>P</i> &lt; .001), pneumonia (–2.20%; 95% CI, –3.99% to –0.40%,<i>P</i> = .02), chronic obstructive pulmonary disease ( –1.20%; 95% CI, –2.35% to –0.05%,<i>P</i> = .04), and stroke (–3.40%; 95% CI, –5.46% to –1.33%,<i>P</i> = .001). There was no association between GME funding and readmission rates. There was an association between higher GME funding and higher internal medicine BCE pass rates (0.066% [95% CI, 0.033% to 0.099%] per $1 million in GME funding;<i>P</i> &lt; .001). <h3>Conclusions and Relevance</h3> This study found a negative linear correlation between GME funding and patient mortality and a positive correlation between GME funding and resident BCE pass rates in adjusted regression models. The findings also suggest that hospitals that receive more GME funding are not more financially stable.
Targeted inhibition of GRK2 kinase domain by CP-25 to reverse fibroblast-like synoviocytes dysfunction and improve collagen-induced arthritis in rats
Authors: Chenchen Han, Yifan Li, Yuwen Zhang, Yang Wang, Dongqian Cui, Tingting Luo, Yu Zhang, Qian Liu, Hao Li, Chun Wang, Dexiang Xu, Yang Ma, Wei Wei
Journal: Acta Pharmaceutica Sinica B (2021)

Rheumatoid arthritis (RA) is an autoimmune disease and is mainly characterized by abnormal proliferation of fibroblast-like synoviocytes (FLS). The up-regulated cellular membrane expression of G protein coupled receptor kinase 2 (GRK2) of FLS plays a critical role in RA progression, the increase of GRK2 translocation activity promotes dysfunctional prostaglandin E4 receptor (EP4) signaling and FLS abnormal proliferation. Recently, although our group found that paeoniflorin-6ʹ-O-benzene sulfonate (CP-25), a novel compound, could reverse FLS dysfunction via GRK2, little is known as to how GRK2 translocation activity is suppressed. Our findings revealed that GRK2 expression up-regulated and EP4 expression down-regulated in synovial tissues of RA patients and collagen-induced arthritis (CIA) rats, and prostaglandin E2 (PGE2) level increased in arthritis. CP-25 could down-regulate GRK2 expression, up-regulate EP4 expression, and improve synovitis of CIA rats. CP-25 and GRK2 inhibitors (paroxetine or GSK180736A) inhibited the abnormal proliferation of FLS in RA patients and CIA rats by down-regulating GRK2 translocation to EP4 receptor. The results of microscale thermophoresis (MST), cellular thermal shift assay, and inhibition of kinase activity assay indicated that CP-25 could directly target GRK2, increase the protein stability of GRK2 in cells, and inhibit GRK2 kinase activity. The docking of CP-25 and GRK2 suggested that the kinase domain of GRK2 might be an important active pocket for CP-25. G201, K220, K230, A321, and D335 in kinase domain of GRK2 might form hydrogen bonds with CP-25. Site-directed mutagenesis and co-immunoprecipitation assay further revealed that CP-25 down-regulated the interaction of GRK2 and EP4 via controlling the key amino acid residue of Ala321 of GRK2. Our data demonstrate that FLS proliferation is regulated by GRK2 translocation to EP4. Targeted inhibition of GRK2 kinase domain by CP-25 improves FLS function and represents an innovative drug for the treatment of RA by targeting GRK2.
Longitudinal evaluation of quality of life (QoL) in patients (Pts) with FGFR2-driven cholangiocarcinoma (CCA) treated with pemigatinib.
Authors: Juan W. Valle, Kristen Bibeau, Yohan Cho, Haobo Ren, Luis Féliz, Christine Francis Lihou, Ghassan K. Abou-Alfa
Journal: Journal of Clinical Oncology (2021)

276 Background: CCA is associated with poor prognosis and reduced QoL. In the phase 2 FIGHT-202 study (NCT02924376) of the selective oral FGFR1–3 inhibitor pemigatinib, 35.5% and 46.7% of pts with previously treated advanced CCA and FGFR2 fusions/rearrangements (RE) had a complete or partial response (CR/PR) and stable disease (SD), respectively; 14.9% had progressive disease (PD) [Abou-Alfa et al., Lancet Oncology 2020;21:671-684]. QoL was an exploratory endpoint. Methods: Pts received pemigatinib 13.5 mg once daily (21-day cycle; 2 weeks on, 1 week off). QoL was assessed longitudinally by best overall response (BOR) per RECIST with the EORTC-QLQ-C30 and the biliary tract cancer-specific EORTC-QLQ-BIL21 questionnaires. QoL scores and longitudinal changes from baseline (BL) were analyzed using descriptive statistics. Treatment-related changes in QoL were a priori expected to be evident by cycle 6 day 1 (week 16). Results: Of 107 pts with FGFR2 RE, 100 (93%) were evaluable for QoL, including36, 48, and 15 with CR/PR, SD, and PD, respectively. From BL to week 16, QLQ-C30 overall health status was maintained in pts with CR/PR and SD and worsened in pts with PD (Table). Emotional functioning remained stable and similar in pts with CR/PR and SD but worsened in pts with PD. All subgroups showed decline in role and social functioning. Pts with CR/PR and SD experienced decreases in QLQ-BIL21 pain and anxiety; all subgroups showed increases in QLQ-BIL21 treatment side effects. Conclusions: In these pts with advanced CCA, those with an SD as BOR had a similar pattern of changes in QoL as those with CR/PR to pemigatinib. Changes in QoL were directionally more favorable in pts with CR/PR or SD than pts with PD. Clinical trial information: NCT02924376. [Table: see text]