tbuckley/cabot-search huggingface dataset:
Minimal genome-wide human CRISPR-Cas9 library
Authors: Emanuel Gonçalves, Mark Thomas, Fiona M. Behan, Gabriele Picco, Clare Pacini, Felicity Allen, Alessandro Vinceti, Mamta Sharma, David A. Jackson, Stacey Price, Charlotte M. Beaver, Oliver Dovey, David Parry-Smith, Francesco Iorio, Leopold Parts, Kosuke Yusa, Mathew J. Garnett
Journal: Genome biology (2021)

Abstract CRISPR guide RNA libraries have been iteratively improved to provide increasingly efficient reagents, although their large size is a barrier for many applications. We design an optimised minimal genome-wide human CRISPR-Cas9 library (MinLibCas9) by mining existing large-scale gene loss-of-function datasets, resulting in a greater than 42% reduction in size compared to other CRISPR-Cas9 libraries while preserving assay sensitivity and specificity. MinLibCas9 provides backward compatibility with existing datasets, increases the dynamic range of CRISPR-Cas9 screens and extends their application to complex models and assays.
Small molecule inhibitors and biologics in treating nail psoriasis: A systematic review and network meta-analysis
Authors: I-Hsin Huang, Po-Chien Wu, Ting-Hua Yang, Hua Li, Yu-Ting Huang, Ying-Chih Cheng, Po-Hsiu Kuo, Ya-Han Lee, Yu-Chen Huang, Yu-Kang Tu
Journal: Journal of the American Academy of Dermatology (2021)
Initial experience of patients treated in a real-world clinical setting with bevacizumab-awwb: The first FDA-approved biosimilar to bevacizumab.
Authors: Ran Jin, Neil A Accortt, Darcie Sandschafer, Tatiana Lawrence, Arturo Loaiza-Bonilla
Journal: Journal of Clinical Oncology (2021)

81 Background: Bevacizumab-awwb is the first anti-cancer biosimilar and the first biosimilar to bevacizumab approved by the FDA. It was launched in the United States on July 19, 2019. Bevacizumab-awwb approval was based on a phase 3 study in a pre-determined sensitive population of non-squamous non-small cell lung cancer (NSCLC) patients. This study investigated initial use of bevacizumab-awwb, across its approved indications for advanced cancer management, in real-world US community and academic oncology practices. Methods: This retrospective observational study described demographic and clinical characteristics of patients who received bevacizumab-awwb using structured patient-level data from the nationwide de-identified Oncology Services Comprehensive Electronic Records (OSCER), a Flatiron Health EHR-derived database. The database is longitudinal, demographically and geographically diverse, and includes more than 2.2 million US cancer patients from &gt;280 cancer clinics. This analysis included adult patients who received ≥1 bevacizumab-awwb infusion between July 30, 2019 and April 30, 2020 and focused on describing initial biosimilar uptake in cancer patient populations beyond NSCLC. Results: First use of bevacizumab-awwb was in mCRC and occurred within 10 days of product launch. All bevacizumab-awwb approved cancer indications were represented among 2,422 patients treated with bevacizumab-awwb. Initial use of bevacizumab-awwb across indications: mCRC (68%), NSCLC (14%), brain cancer (11%), cervical cancer (5%), metastatic renal cell carcinoma (1%). Among 1657 mCRC patients treated with bevacizumab-awwb, 55% were male with a median age of 65 years (y). Most patients were white (60%), with ECOG scores of 0/1 (84%), and median body weight was 78 kg. Among mCRC patients, 59% had received the reference product before receiving the biosimilar. Among patients with other tumor types, 42-50% had prior bevacizumab exposure. Among mCRC patients with prior exposure to bevacizumab, 67% received bevacizumab-awwb within 28 days of last infusion of reference product (Table). Demographic and clinical characteristics were comparable between patients with and without prior bevacizumab use. Conclusions: Early evidence suggests physicians are comfortable initiating or transitioning patients to the first FDA-approved biosimilar to bevacizumab, with little evidence that demographic characteristics differ between patients with and without previous treatment with bevacizumab. Future analyses will determine whether these patterns persist across all indications. [Table: see text]
Abstract MP003: Development and Validation of a Prediction Model of Weight Loss Maintenance or Regain at 4 Years in the Look AHEAD Trial
Authors: Samantha E Berger, Gordon S Huggins, Jeanne M McCaffery, Alice H Lichtenstein
Journal: Circulation (2017)

Introduction: The development of type 2 diabetes is strongly associated with excess weight gain and can often be partially ameliorated or reversed by weight loss. While many lifestyle interventions have resulted in successful weight loss, strategies to maintain the weight loss have been considerably less successful. Prior studies have identified multiple predictors of weight regain, but none have synthesized them into one analytic stream. Methods: We developed a prediction model of 4-year weight regain after a one-year lifestyle-induced weight loss intervention followed by a 3 year maintenance intervention in 1791 overweight or obese adults with type 2 diabetes from the Action for Health in Diabetes (Look AHEAD) trial who lost ≥3% of initial weight by the end of year 1. Weight regain was defined as regaining &lt;50% of the weight lost during the intervention by year 4. Using machine learning we integrated factors from several domains, including demographics, psychosocial metrics, health status and behaviors (e.g. physical activity, self-monitoring, medication use and intervention adherence). We used classification trees and stochastic gradient boosting with 10-fold cross validation to develop and internally validate the prediction model. Results: At the end of four years, 928 individuals maintained ≥50% of their initial weight lost (maintainers), whereas 863 did not met that criterion (regainers). We identified an interaction between age and several variables in the model, as well as percent initial weight loss. Several factors were significant predictors of weight regain based on variable importance plots, regardless of age or initial weight loss, such as insurance status, physical function score, baseline BMI, meal replacement use and minutes of exercise recorded during year 1. We also identified several factors that were significant predictors depending on age group (45-55y/ 56-65y/66-76y) and initial weight loss (lost 3-9% vs. ≥10% of initial weight). When the variables identified from machine learning were added to a logistic regression model stratified by age and initial weight loss groups, the models showed good prediction (3-9% initial weight loss, ages 45-55y (n=293): ROC AUC=0.78; ≥10% initial weight loss, ages 45-55y (n=242): ROC AUC=0.78; (3-9% initial weight loss, ages 56-65y (n=484): ROC AUC=0.70; ≥10% initial weight loss, ages 56-65y (n=455): ROC AUC = 0.74; 3-9% initial weight loss, ages 66-76y (n=150): ROC AUC=0.84; ≥10% initial weight loss, ages 66-76y (n=167): ROC AUC=0.86). Conclusion: The combination of machine learning methodology and logistic regression generates a prediction model that can consider numerous factors simultaneously, can be used to predict weight regain in other populations and can assist in the development of better strategies to prevent post-loss regain.
Delta-Like Ligand–Notch1 Signaling Is Selectively Modulated by HPV16 E6 to Promote Squamous Cell Proliferation and Correlates with Cervical Cancer Prognosis
Authors: Maryam Khelil, Heather Griffin, Maaike C.G. Bleeker, Renske D.M. Steenbergen, Ke Zheng, Taylor Saunders-Wood, Sanne Samuels, Jossie Rotman, Wim Vos, Brendy E. van den Akker, Renée X. de Menezes, Gemma G. Kenter, John Doorbar, Ekaterina S. Jordanova
Journal: Cancer Research (2021)

Abstract Human papillomavirus (HPV) drives high-grade intraepithelial neoplasia and cancer; for unknown reasons, this occurs most often in the cervical transformation zone. Either mutation or HPV E6–driven inhibition of Notch1 can drive neoplastic development in stratified squamous epithelia. However, the contribution of Notch1 and its Delta-like ligands (DLL) to site susceptibility remains poorly understood. Here, we map DLL1/DLL4 expression in cell populations present in normal cervical biopsies by immunofluorescence. In vitro keratinocyte 2D monolayer models, growth assays, and organotypic raft cultures were used to assess the functional role of DLL–Notch signaling in uninfected cells and its modulation by HPV16 in neoplasia. An RNA sequencing–based gene signature was used to suggest the cell of origin of 279 HPV-positive cervical carcinomas from The Cancer Genome Atlas and to relate this to disease prognosis. Finally, the prognostic impact of DLL4 expression was investigated in three independent cervical cancer patient cohorts. Three molecular cervical carcinoma subtypes were identified, with reserve cell tumors the most common and linked to relatively good prognosis. Reserve cells were characterized as DLL1−/DLL4+, a proliferative phenotype that is temporarily observed during squamous metaplasia and wound healing but appears to be sustained by HPV16 E6 in raft models of low-grade and, more prominently, high-grade neoplasia. High expression of DLL4 was associated with an increased likelihood of cervical cancer–associated death and recurrence. Taken together, DLL4–Notch1 signaling reflects a proliferative cellular state transiently present during physiologic processes but inherent to cervical reserve cells, making them strongly resemble neoplastic tissue even before HPV infection has occurred. Significance: This study investigates cervical cancer cell-of-origin populations and describes a DLL–Notch1 phenotype that is associated with disease prognosis and that might help identify cells that are susceptible to HPV-induced carcinogenesis.
Association of Neural Reward Circuitry Function With Response to Psychotherapy in Youths With Anxiety Disorders
Authors: Stefanie L. Sequeira, Jennifer S. Silk, Cecile D. Ladouceur, Jamie L. Hanson, Neal D. Ryan, Judith K. Morgan, Dana L. McMakin, Philip C. Kendall, Ronald E. Dahl, Erika E. Forbes
Journal: American Journal of Psychiatry (2021)

Identifying neural correlates of response to psychological treatment may inform targets for interventions designed to treat psychiatric disorders. This study examined the extent to which baseline functioning in reward circuitry is associated with response to psychotherapy in youths with anxiety disorders.A randomized clinical trial of cognitive-behavioral therapy compared with supportive therapy was conducted in youths with anxiety disorders. Before treatment, 72 youths (9-14 years old) with anxiety disorders and 37 group-matched healthy comparison youths completed a monetary reward functional MRI task. Treatment response was defined categorically as at least a 35% reduction in diagnostician-rated anxiety severity from pre- to posttreatment assessment. Pretreatment neural activation in the striatum and medial prefrontal cortex (mPFC) during monetary wins relative to losses was examined in relation to treatment response.Responders, nonresponders, and healthy youths differed significantly in mPFC activation to rewards versus losses at baseline. Youths with anxiety exhibited higher mPFC activity relative to healthy youths, although this may have been driven by differences in depressive symptoms. Planned comparisons between treatment responders (N=48) and nonresponders (N=24) also revealed greater pretreatment neural activation in a cluster encompassing the subgenual anterior cingulate cortex and nucleus accumbens among responders.Striatal activation to reward receipt may not differentiate youths with anxiety from healthy youths. However, higher striatal responsivity to rewards may allow youths with anxiety to improve during treatment, potentially through greater engagement in therapy. Function in reward circuitry may guide development of treatments for youths with anxiety.
Single-cell proteomic and transcriptomic analysis of macrophage heterogeneity using SCoPE2
Authors: Harrison Specht, Edward Emmott, Aleksandra A. Petelski, R. Gray Huffman, David H. Perlman, Marco Serra, Peter Kharchenko, Antonius Koller, Nikolai Slavov
Journal: Genome biology (2021)

Abstract Background Macrophages are innate immune cells with diverse functional and molecular phenotypes. This diversity is largely unexplored at the level of single-cell proteomes because of the limitations of quantitative single-cell protein analysis. Results To overcome this limitation, we develop SCoPE2, which substantially increases quantitative accuracy and throughput while lowering cost and hands-on time by introducing automated and miniaturized sample preparation. These advances enable us to analyze the emergence of cellular heterogeneity as homogeneous monocytes differentiate into macrophage-like cells in the absence of polarizing cytokines. SCoPE2 quantifies over 3042 proteins in 1490 single monocytes and macrophages in 10 days of instrument time, and the quantified proteins allow us to discern single cells by cell type. Furthermore, the data uncover a continuous gradient of proteome states for the macrophages, suggesting that macrophage heterogeneity may emerge in the absence of polarizing cytokines. Parallel measurements of transcripts by 10× Genomics suggest that our measurements sample 20-fold more protein copies than RNA copies per gene, and thus, SCoPE2 supports quantification with improved count statistics. This allowed exploring regulatory interactions, such as interactions between the tumor suppressor p53, its transcript, and the transcripts of genes regulated by p53. Conclusions Even in a homogeneous environment, macrophage proteomes are heterogeneous. This heterogeneity correlates to the inflammatory axis of classically and alternatively activated macrophages. Our methodology lays the foundation for automated and quantitative single-cell analysis of proteins by mass spectrometry and demonstrates the potential for inferring transcriptional and post-transcriptional regulation from variability across single cells.
Prognostic impact of chemoradiation-related lymphopenia in patients with gastric and gastroesophageal cancer.
Authors: Daniel W Kim, Grace Lee, Theodore S. Hong, Guichao Li, Eric Roeland, Florence Keane, Christine Elissa Eyler, Lorraine C. Drapek, David P. Ryan, Jill N. Allen, David L. Berger, Aparna Raj Parikh, John Mullen, Samuel J Klempner, Jeffrey William Clark, Jennifer Y Wo
Journal: Journal of Clinical Oncology (2021)

249 Background: Limited data exists on how chemoradiation (CRT)-induced lymphopenia affects survival outcomes in patients with gastric and gastroesophageal junction (GEJ) cancer. We evaluated the association between severe lymphopenia and its association with survival in gastric and GEJ cancer patients treated with CRT. We hypothesized that severe lymphopenia would be a poor prognostic factor. Methods: We performed a retrospective analysis of 154 patients with stage 1-3 gastric or GEJ cancer who underwent CRT at our institution. Patients underwent photon-based radiation therapy (RT) with a median dose of 50.4 Gy (IQR 45.0-50.4 Gy) over 28 fractions and concurrent chemotherapy (CTX) with carboplatin/paclitaxel, 5-fluorouracil based regimen, or capecitabine. 49% received CTX prior to RT. 84% underwent surgical resection, 57% pre-CRT and 26% post-CRT. Absolute lymphocyte count (ALC) at baseline and at 2 months since initiating RT were analyzed. Severe lymphopenia, defined as Grade 3 or worse lymphopenia (ALC &lt; 0.5 k/μl), was analyzed for any association with overall survival (OS). Results: Median time of follow up was 48 months. Median age was 65. 77% were male and 86% were Caucasian. ECOG PS was 0 or 1 in 90% and 2 in 10%. Tumor location was stomach in 38% and GEJ in 62%. Timing of CRT was preoperative among 68% and postoperative among 32%. The median ALC at baseline for the entire cohort was 1.6 k/ul (range 0.3-7.0 k/ul). At 2 months post-CRT, 49 (32%) patients had severe lymphopenia. Patients with severe lymphopenia post-CRT had a slightly lower baseline TLC compared to patients without severe lymphopenia (median TLC 1.4 k/ul vs. 1.6 k/ul; p = 0.005). There were no differences in disease and treatment characteristics between the two groups. On the multivariable Cox model, severe lymphopenia post-CRT was significantly associated with increased risk of death (HR = 3.99 [95% CI 1.55-10.28], p = 0.004). ECOG PS 2 (HR = 34.97 [95% CI 2.08-587.73], p = 0.014) and postoperative CRT (HR = 5.55 [95% CI 1.29-23.86], p = 0.021) also predicted worse OS. The 4-year OS among patients with severe lymphopenia was 41% vs. 61% among patients with vs. without severe lymphopenia (log-rank test p = 0.041). Conclusions: Severe lymphopenia significantly correlated with poorer OS in patients with gastric or GEJ cancer treated with CRT. CRT-induced lymphopenia may be an important prognostic factor for survival in this patient population. Closer observation in high-risk patients and treatment modifications may be potential approaches to mitigating CRT-induced lymphopenia.
Preliminary results of the phase II ALTER-H003 trial: Anlotinib plus toripalimab as a first-line treatment for patients with unresectable hepatocellular carcinoma.
Authors: Haifeng Lin, Jie Ma, Manyun Zhuo, Chengsheng Zhang, Jingru Luo, Xiaohong Zhuang, Zhiming Zeng, Lihua Yang
Journal: Journal of Clinical Oncology (2021)

314 Background: Hepatocellular carcinoma (HCC) is particularly prevalent in China because of the high prevalence of chronic hepatitis B infection. In the last decade, sorafenib was the first molecular target drug approved for the treatment of advanced liver cancer. Until recently, the combination of angiogenic inhibitor with anti-PD-1 /L1 monoclonal antibody has represented significant efficacy over sorafenib monotherapy in the first-line regimen of unresectable HCC. Nevertheless, there are still unmet needs in clinical practice due to limited choice of drugs. Anlotinib is a novel oral multi-targeted tyrosine kinase inhibitor that targets VEGF receptors 1/2/3, FGF receptors 1-4, PDGF receptors α and β, and c-kit, and has been approved for standard treatment of non-small cell lung cancer, small cell lung cancer and soft tissue sarcoma in China. Toripalimab, a humanized IgG4 mAb against PD-1, is the first Chinese-produced PD-1 inhibitor marketed, which has been approved as a second-line treatment for metastasis melanoma. This study aims to evaluate the efficacy and safety of anlotinib plus toripalimab as the first-line treatment for unresectable HCC. Methods: This was a single-arm, multicenter, phase II trial. 30 patients with unresectable HCC, Child-Pugh ≤7 and ECOG PS &lt;2 will be enrolled if they had not been treated with prior treatment. Pts received anlotinib (12 mg, p.o., qd, d1-14, q3w) and toripalimab (240 mg, iv, d1, q3w) until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) assessed by investigator according to mRECIST and irRECIST. Secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), duration of response (DoR) and safety. Results: By the cutoff date of September 21, 2020, 11 pts were enrolled and of those 8 pts were evaluable. 9 pts (81.8%) experienced treatment related adverse events (TRAEs) and grade 3 TRAEs occurred in 5 pts (45.5%). No grade 4 or above TRAEs occurred. The most common TRAEs were decreased appetite (n =6, 54.5%) and fatigue (n =5, 45.5%).Among 8 evaluable pts, unconfirmed ORR was 25% (95% CI 0.032-0.651) with 1 unconfirmed CR and 1 unconfirmed PR, and DCR was 87.5% (95% CI 0.473-0.997) according to mRECIST. Conclusions: Anlotinib in combination with toripalimab showed tolerant toxicity and preliminary anti-tumor efficacy in first-line regimen for uHCC patients. Furthermore, it is needed to be proved in update results and large scale studies. Clinical trial information: ChiCTR1900028295.
Correlation between comprehensive genomic profiling (CGP) utilizing tissue-based testing (T-CGP) and cell-free DNA (cfDNA) in patients (pts) with pancreatic ductal adenocarcinoma (PDAC).
Authors: Ben George, James Haberberger, Naomi L Ferguson, Ole Gjoerup, Kimberly McGregor, Andrew Eugene Hendifar, Daniel A. Laheru, Colin D. Weekes, Jeffrey S. Ross, Amanda Hemmerich
Journal: Journal of Clinical Oncology (2021)

422 Background: Early systemic dissemination is a salient feature of PDAC and the ability to reliably detect as well as monitor cfDNA based alterations may have predictive and/or prognostic value. However, a clear correlation between the clonality of the primary tumor and micro-metastatic disease has not been established in PDAC. We examined the correlation between T-CGP and cfDNA based CGP in pts with PDAC. Methods: We performed a retrospective analysis of PDAC pts who had both T-CGP (October 2010 – March 2020) and cfDNA based CGP (May 2016 – March 2020), with an average of 645 days between tests (Range: 21 – 2101 days) For T-CGP, exonic regions and select intronic regions of cancer related genes were sequenced to a high uniform depth (&gt;500X median coverage) using FoundationOne Heme (Exons: 315 genes; Select Introns: 28 genes) and FoundationOne CDx (Exons: 310 genes; Select Introns: 34 genes). cfDNA based CGP, was performed using either FoundationOne Liquid (Exons: 70 genes; Select Introns: 7 genes) or Foundation-ACT (Exons: 59 genes; Select Introns: 6 genes) platform. Results: Eighty-one pts were identified with both T-CGP and cfDNA based CGP - median age was 61 years, 59.3% (48/81) were male and 66.2% (49/74) had reported metastatic disease. The median tumor DNA content available for T-CGP analysis was 112.3 ng. The median cfDNA concentration was 1.7 ng/µL, and the number of reported ct-DNA based somatic alterations correlated significantly with the concentration of ct-DNA (Spearman’s R = 0.19, p &lt; 10 -8 ). 75/81 (92.6%) and 41/81 (50.6%) of pts had at least one pathogenic somatic alteration detected by T-CGP and cfDNA based CGP, respectively. KRAS, TP53 and CDKN2A were the most frequently altered genes in both T-CGP and cfDNA based CGP (Table1). Homologous Recombination DNA Damage Repair (HR-DDR) gene alterations [ BRCA2, ATM, and CHEK2 alterations] were detected in 7.4% (6/81) of T-CGP and 7.4% (6/81) cfDNA based CGP, respectively. Two BRAF fusions were detected from samples tested with T-CGP, however these were not detected with the cfDNA assay. Conversely, an ALK-EML4 fusion was detected using both platforms. Conclusions: The concordance between T-CGP and cfDNA based CGP in HR-DDR gene alterations may be indicative of the germline status of some of these alterations; nevertheless, it suggests the predictive utility of cfDNA based CGP in PDAC. The differential prevalence of other gene alterations between the two modalities is likely reflective of the cfDNA yield available for CGP and to a lesser extent, clonal evolution. cfDNA based CGP holds promise as a complimentary predictive tool to T-CGP. [Table: see text]
대한간학회 특별기고 : 우리나라 만성 간질환 환자들이 당면한 문제점과 대한간학회의 역할 -사회적 편견, 건강보험 요양급여의 미비, 복지지원제도로부터의 소외를 중심으로-
Authors: 김동준 ( Dong Joon Kim ), 김홍수 ( Hong Soo Kim ), 임형준 ( Hyung Joon Yim ), 서정일 ( Jeong Ill Suh ), 정재연 ( Jae Youn Cheong ), 김인희 ( In Hee Kim ), 탁원영 ( Won Young Tark ), 이영석 ( Yong Sok Lee ), 이창희 ( Ser Gio Lee ), 이지연 ( Ji Youn Lee )
Journal: Clinical and Molecular Hepatology (2008)