tbuckley/cabot-search huggingface dataset:
Co-methylation analysis in lung tissue identifies pathways for fetal origins of COPD
Authors: Priyadarshini Kachroo, Jarrett D. Morrow, Alvin T. Kho, Carrie A. Vyhlidal, Edwin K. Silverman, Scott T. Weiss, Kelan G. Tantisira, Dawn L. DeMeo
Journal: European Respiratory Journal (2020)

COPD likely has developmental origins; however, the underlying molecular mechanisms are not fully identified. Investigation of lung tissue-specific epigenetic modifications such as DNA methylation using network approaches might facilitate insights linking in utero smoke (IUS) exposure and risk for COPD in adulthood. We performed genome-wide methylation profiling for adult lung DNA from 160 surgical samples and 78 fetal lung DNA samples isolated from discarded tissue at 8–18 weeks of gestation. Co-methylation networks were constructed to identify preserved modules that shared methylation patterns in fetal and adult lung tissues and associations with fetal IUS exposure, gestational age and COPD. Weighted correlation networks highlighted preserved and co-methylated modules for both fetal and adult lung data associated with fetal IUS exposure, COPD and lower adult lung function. These modules were significantly enriched for genes involved in embryonic organ development and specific inflammation-related pathways, including Hippo, phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT), Wnt, mitogen-activated protein kinase and transforming growth factor-β signalling. Gestational age-associated modules were remarkably preserved for COPD and lung function, and were also annotated to genes enriched for the Wnt and PI3K/AKT pathways. Epigenetic network perturbations in fetal lung tissue exposed to IUS and of early lung development recapitulated in adult lung tissue from ex-smokers with COPD. Overlapping fetal and adult lung tissue network modules highlighted putative disease pathways supportive of exposure-related and age-associated developmental origins of COPD.
Experience of short-term hydroxychloroquine and azithromycin in COVID-19 patients and effect on QTc trend
Authors: Chee Peng Hor, Narwani Hussin, Saravanaa Nalliah, Way Ti Ooi, Xing Yi Tang, Sara Zachariah, Gurpreet pal Singh Jugindar Singh, Rosilawati Abdul Rani, Kunaraj Perumal, Wee Kooi Cheah
Journal: Journal of Infection (2020)
Comprehensive molecular profiling of intrahepatic cholangiocarcinoms in Chinese population and therapeutic experience.
Authors: Longrong Wang, Lu Wang
Journal: Journal of Clinical Oncology (2020)

e16663 Background: The genomic alterations of intrahepatic cholangiocarcinoma in Chinese population have not been fully revealed. Molecular profiling may provide reference to clinical management especially targeted therapy. Methods: A prospective study was conducted in 122 intrahepatic cholangiocarcinoma patients accepted chemotherapy with or without targeted therapy. All patients had results of next generation sequencing assay that analyzes 489 cancer-associated genes. Results: The most commonly mutated genes were TP53 (34%), KRAS (25%), ARID1A (17%), CDKN2A (12%), FAT1 (12%), and NOTCH3 (12%). ERBB2 alterations were found in 13 (11%) patients, 10 of 13 were gene amplification. Application of Trastuzumab achieved a disease control rate of 7/8 and response rate of 6/8. Twenty-two patients with wild type KRAS/NRAS/BRAF accepted Cetuximab combined chemotherapy. Disease control rate and response rate were 78% and 47% respectively. Fifty-four patients accepted anti-VEGF treatment combined chemotherapy. Disease control rate and response rate were 85% and 60% respectively. Better therapeutic efficiency (P = 0.001) and longer progress free survival (P = 0.04) were observed in Bevacizumab treated group than chemotherapy alone. Two patients (1.6%) had signatures of microsatellite instability (MSI-H), and both benefited from immunotherapy. Conclusions: This study provides an over view on genetic alterations in Chinese intrahepatic cholangiocarcinoma patients, and indicates the potential clinical implications for targeted therapies.
Combination of multiple CT signs in diagnosis of nodular goiters
Authors: Miaoping Zhu, Yanyan Shu, Zhijiang Han
Journal: BMJ (2016)

Objective
To investigate the combination of multiple CT signs in diagnosis and differential diagnosis of nodular goiters (NGs).


Methods
The CT images of 242 pathologically confirmed lesions (>10 mm in diameter) from 188 patients with nodular goiters were retrospectively reviewed. The CT signs, including regular shape, cystic degeneration, clearer enhancement margin, strong enhancement of nodular goiters were compared with those of 236 pathologically confirmed lesions (>10 mm in diameter) from 225 patients with papillary thyroid carcinomas (PTCs). The sensitivity, specificity and accuracy of different CT signs or their combination in diagnosis and differential diagnosis of NGs were analyzed.


Results
Regular shape was present in 208 of 242 NGs (86.0%) and in 35 of 236 PTCs (14.8%) (χ2=241.804, P=0.000). Cystic degeneration was present in 143 of 242 NGs (59.1%) and 7 of 236 PTCs (3.0%) (χ2=174.783, P=0.000). Clearer enhancement margin was present in 192 of 242 NGs (79.3%) and in 51 of 236 PTCs (21.6%) (χ2=159.318, P=0.000). Strong enhancement was present in 41 of 242 NGs (16.9%) and in 3 of 236 PTCs (1.3%) (χ2=35.108, P=0.000). Regular shape showed the highest sensitivity and accuracy for diagnosis of NGs (86.0% and 85.6%), while strong enhancement showed the highest specificity (98.7%). The combination of regular shape and clearer enhancement margin showed the highest sensitivity and accuracy of 67.4% and 80.5%, respectively. The combination of strong enhancement with any of other signs showed the highest specificity of 100.0%. The combination of regular shape, cystic degeneration and clearer enhancement margin showed the highest sensitivity, specificity and accuracy of 45.5%, 99.6% and 72.2% respectively. The combing of 4 signs showed a sensitivity, specificity, and accuracy of 2.9%, 100.0% and 50.8%.


Conclusion
CT scan is effective for diagnosis of NGs, and the combination of different CT signs can significantly improve the specificity and reduce the incidence of misdiagnosis to avoid unnecessary surgery.


Key words: 
Thyroid carcinoma; Goiters, nodular; Computed tomography, Spiral computer
High incidence of brain metastasis in young patients with lung adenocarcinoma.
Authors: Ilene Ramirez, Maximiliano Brandon, Mariana Abal, Gaston Martin Reinas, Alba Marin Ordoñez, Monica Montiel, Liliana D Gonzalez, Ernesto Gil Deza, Eduardo L. Morgenfeld, Edgardo G. J. Rivarola, Felipe G. Gercovich
Journal: Journal of Clinical Oncology (2020)

e21677 Background: Young patients with lung cancer are unusual. This paper focuses on our experience with Young Patients (&lt;45 yo) with Lung Adenocarcinoma (YPLA), treated at Instituto Oncológico Henry Moore (IOHM). Methods: Out of all lung cancer patients, we selected YPLA admitted between September 2012 and September 2019. We analyzed their medical history forms, electronic clinical records, treatments and outcomes. Results: We included 31 out of 1,119 Pt (3%) patients. Median Age: 39 (24-44). Sex F/M: 15/16. The table shows the clinical characteristics of population and outcomes. Conclusions: 1) Young patients with lung adenocarcinoma presented aggressive tumors, as evidenced by: advanced stages, poor performance status and CNS compromise. 2) In our series, smoking is a predominant etiological factor. 3) Further research will analyze genomic profiles of these tumors. 4) Screening for CNS metastasis should be mandatory in this population. [Table: see text]
Association of T- and B-cell receptor repertoires with molecular subtypes and outcome in HER2+ breast cancer: An analysis of the NeoALTTO clinical trial.
Authors: Mattia Rediti, David Venet, Francoise Rothe, Tao Qing, Marion Maetens, Ian Bradbury, Miguel A. Izquierdo, Serena Di Cosimo, Florentine Hilbers, Mohammed Bajji, Nadia Harbeck, Michael Untch, Minetta C. Liu, Cristina Saura, Jens Bodo Huober, Paolo Nuciforo, Roberto Salgado, Sherene Loi, Lajos Pusztai, Christos Sotiriou
Journal: Journal of Clinical Oncology (2020)

511 Background: Clinicopathological and molecular features, including estrogen receptor (ER) status and PAM50 subtypes, have shown an association with immunogenicity and tumor-infiltrating lymphocyte (TIL) levels in breast cancer (BC). To investigate the complexity of the immune response in HER2+ BC, we explored the association of T- and B-cell receptor (TCR and BCR) repertoires with clinicopathological characteristics, PAM50 subtypes and outcome in the NeoALTTO phase III trial. Methods: RNA sequencing (RNAseq) data from baseline tumor biopsies were available for 254 out of the 455 patients enrolled. TCR and BCR repertoires were extracted from RNAseq data using the MiXCR software. Repertoire and diversity measures (read counts, number of clones, evenness, Gini index, Shannon entropy, length of the complementarity-determining region 3 [CDR3], top and second top clone proportions) were estimated. PAM50 subtypes were computed from RNAseq data. Univariate and multivariate (adjusted for clinicopathological characteristics, TIL levels dichotomized using the median value of 12.5% and treatment arm) Cox proportional hazard models were used for survival analysis, while logistic regressions were used for pathological complete response (pCR), defined as ypT0/is. All results reported had a false discovery rate (FDR) &lt;0.05. Results: Higher BCR read counts, number of clones and Gini index were significantly associated with ER-negative as well as grade 3 tumors. Among the PAM50 subtypes, HER2-enriched (HER2-E) showed significantly higher BCR read counts, number of clones and Gini index along with lower evenness compared to luminal A and B, as well as higher length of CDR3 than luminal A. Of note, basal-like showed similar BCR diversity measures to HER2-E. No significant differences were noted for TCR diversity measures. In multivariate analyses, neither TCR nor BCR features were associated with pCR, while BCR evenness (HR 1.5; 95%CI 1.1-2.1) and Gini index (HR 0.66; 95%CI 0.5-0.88) were associated with event-free survival. Conclusions: BCR repertoire measures suggest a clonal expansion in HER2-E and basal-like PAM50 subtypes. Furthermore, the implementation of BCR-derived biomarkers can help to identify patients with an improved clinical outcome after neoadjuvant anti-HER2 treatment. Our findings highlight the heterogeneity of the immune response within HER2+ BC and provide support for biomarker-driven treatment strategies including immunotherapy in this BC subtype. Further validation is required. Clinical trial information: NCT00553358 .
The role of radiation dose-dependent enhancement of fatty acid oxidation in radiation surviving/resistant lung cancer cells.
Authors: Shangbiao Li, Xiaoxia Zhu, Lijuan Wang, Zhihao Zheng
Journal: Journal of Clinical Oncology (2020)

e21724 Background: Radiotherapy plays a critical role in the integrated management of lung cancer. However, radioresistance limits the long-term control. Exploring the dynamic changes of metabolic reprogramming in radiation surviving/resistant (S/R) lung cancer cells is helpful to clarify the metabolic mechanism of radiation resistance and to develop new targets for intervention and early detection. Methods: Cell lines were irradiated with different doses (2Gy × 20F, 2Gy × 30F, 2Gy × 40F) in conventional dose fractionation. The cellular radiosensitivity was verified by colony formation assay and neutral comet assay. Cell proliferation ability was determined by EdU assay. Metabonomic analysis was used to identify the differentially expressed metabolites between high-dose radiation-resistant cells and their parent cells. Lipid droplet content was detected by Oil Red O (ORO) staining. Cell oxygen consumption rate (OCR) was measured by Seahorse XF24e analyzer. Western blot was used to detect the expression of metabolic enzymes. The growth of xenograft tumors from these cell lines in BALB/c nude mice were measured after the treatment of radiation (2Gy×5F), Etomoxir, or radiation combined with Etomoxir. Results: Compared with parent cells, the radioresitance of S/R lung cancer cells after different doses of radiationwas significantly increased with the increase of radiation exposure. ORO staining showed that fatty deposition of radiation S/R cells was obviously higher than their parent cells, and more fatty deposition in cells received higher dose of radiation. The ketone body metabolism-related substances, including acetoacetic acid, a metabolite of FAO, were significantly enriched in high-dose radiation-resistant cells. The expression of carnitine palmitoyltransferase1 (CPT1) and the OCR in radiation S/R cells were also radiation-dose dependently increased. Etomoxir, an inhibitor of fatty acid oxidation, significantly enhanced the radiosensitivity and decreased the OCR and DNA repair ability of various S/R cells exposed to radiation. We further confirmed that Etomoxir could significantly inhibit proliferation of radiation S/R cells in vivo, which also presented with radiation-dose dependent model. Conclusions: The enhancement of radiation dose-dependent FAO promotes radiation surviving/resistance of lung cancer cells. CPT1A, a key metabolic enzyme mediating FAO, may be a potential target for treatment of radiation resistant lung cancer. Funding: 81972853, 81572279, 2016J004, LC2019ZD009, 2018CR033.
Patiromer versus placebo to enable spironolactone use in patients with resistant hypertension and chronic kidney disease (<scp><b>AMBER</b></scp>): results in the pre‐specified subgroup with heart failure
Authors: Patrick Rossignol, Bryan Williams, Martha R Mayo, Suzette Warren, Susan Arthur, Gail Ackourey, William B White, Rajiv Agarwal
Journal: European Journal of Heart Failure (2020)

Aims The AMBER trial demonstrated that concomitant use of patiromer enabled the more persistent use of spironolactone by reducing the risk of hyperkalaemia in patients with resistant hypertension and advanced chronic kidney disease. We report herein the pre‐specified subgroup analysis in patients with heart failure (HF). Methods and results Participants were randomly assigned (1:1) to receive either placebo or patiromer (8.4 g once daily), in addition to open‐label spironolactone (starting at 25 mg once daily) and their baseline blood pressure medications. Dose titrations were permitted after 1 week for patiromer/placebo and after 3 weeks for spironolactone. The primary endpoint was the between‐group difference at week 12 in the proportion of patients on spironolactone. Efficacy endpoints and safety were assessed in all randomized patients (intention to treat). A total of 295 patients were enrolled, of whom 132 (45%) had HF. In the HF subgroup, 68.1% of patients receiving placebo remained on spironolactone at week 12, compared with 84.1% of patients receiving patiromer ( P = 0.0504). The reason for discontinuation from spironolactone use was hyperkalaemia in the majority of both groups. There was no significant interaction between the subgroups with HF and without HF ( P = 0.8085) for the primary endpoint. Conclusions Consistent with the overall AMBER trial results, this pre‐specified subgroup analysis in patients with HF, resistant hypertension and advanced chronic kidney disease demonstrated that patiromer enabled more persistent use of spironolactone by reducing the risk of hyperkalaemia.
Endocrine biomarkers in low-grade serous ovarian cancers (LGSC) and serous ovarian tumors of low malignant potential (LMP).
Authors: Sarah E. Taylor, Alyssa Wield, Yusi Fang, Rohit Bhargava, Susan Lang, George Tseng, Lan Gardner Coffman, Steffi Oesterreich
Journal: Journal of Clinical Oncology (2020)

e18045 Background: LGSC and serous ovarian LMP tumors are rare entities along a disease continuum. Because they are relatively chemotherapy resistant, there is interest in targeted treatment, including endocrine therapy. In studies of endocrine agents for treatment of recurrent ovarian cancer, tumor estrogen receptor (ER) status alone does not effectively predict outcomes. The objective of this study is to utilize protein and gene expression from ER and downstream targets to identify signaling components that will act as prognostic and predictive biomarkers. Methods: A single institution tumor registry was queried for patients with LGSC or serous LMP tumors between 1993-2016. Formalin-fixed, paraffin embedded (FFPE) tissue was obtained. Clinicopathologic data was collected. Immunohistochemistry (IHC) was performed and scored as dichotomous (+/-) and continuous (H-score). NanoString nCounter platform was used for gene expression of a predesigned endocrine biomarker panel. Wilcoxon Rank Sum was used to compare mRNA and protein expression. Survival analyses were performed using Cox proportional hazard (PH) method with elastic net to fit the prediction model for the gene panel. Results: Tissue was analyzed from 23 LGSC, 71 serous LMP tumors, and 2 recurrences. At diagnosis, 86% of patients with LMP tumors had stage I disease vs 78% of patients with LGSC had stage III/IV disease. There were 7 (10%) LMP and 13 (56.5%) LGSC recurrences. Median initial PFS was 76 and 37 months and median OS was 88 and 82 months for LMP and LGSC, respectively. Fourteen received endocrine therapy; nine for treatment of recurrent LGSC. Median therapy was 21 months, with 3 complete responses, 2 partial responses and 1 stable disease. All tumors were ER+ (median H-score 210) and 89% were PR+ (median H-score 130). ER H-scores and ESR1 expression levels were not significantly different between LGSC and LMP tumors (p = 0.1942, p = 0.0893). PR H-scores were higher in LMP tumors (p &lt; 0.00001) but PGR expression was not significantly different (p = 0.6581). In the Cox PH analysis, ER H-score was a significant predictor of both PFS and OS (p &lt; 0.001, p = 0.004). The Cox model identified independent sets of gene expression associated with PFS and OS in both the LGSC and LMP cohorts (c-indices 0.679, 0.570, 0.626, 0.689). Conclusions: Endocrine therapy is an active area of interest in the treatment of ovarian neoplasms. ER H-score and gene expression of downstream ER targets could improve upon the use of hormone receptors to determine risk of recurrence and guide use of adjuvant endocrine therapy.
Improve recognition, diagnosis and treatment for chronic obstructive pulmonary disease
Authors: 赵鸣武
Journal: BMJ (2004)

慢性阻塞性肺疾病(COPD)是近10年来世界各国日益关心与重视的一种疾病. 说到COPD,就不得不从慢性支气管炎和肺气肿说起,我们知道,慢性支气管炎是指支气管及其周围组织的慢性非特异性炎症,主要表现为咳嗽、咳痰、部分有喘息等症状.现在规定,咳嗽、咳痰每年持续3个月、连续2年以上,在排除其他相同症状的疾病(如肺结核、支气管扩张、支气管哮喘等)后,即可做出诊断.肺气肿的定义为,终未细支气管远端气腔持续性异常扩大,肺泡壁破坏、且无明显纤维化者.慢性支气管炎与肺气肿为两种不同的病理改变,但两者关系密切,往往合并存在,难以区分.
Modeling differentially expressed genes in patient tumors to guide expression-based biomarker development.
Authors: Derek Liu, Meng Xiao He, Kevin Bi, Eliezer Mendel Van Allen, David Liu
Journal: Journal of Clinical Oncology (2020)

3627 Background: Differential gene expression (DGE) methods, initially developed for analyzing bulk RNA changes in pure tumor cell lines under experimental settings, are commonly used to identify biomarkers in and infer biological differences between patient tumor samples, which are admixtures of tumor and non-tumor components. Methods to sensitively and accurately detect cell type-specific expression differences in admixed patient samples are not well characterized but may greatly affect emerging targeted and immunotherapy biomarker strategies. To address this issue, we developed a simulation framework to benchmark our ability to detect changes in tumor-intrinsic gene expression. Methods: Pseudobulk RNAseq melanoma cohorts were simulated by sampling from melanoma single cell RNAseq data. Simulation parameters were optimized to maximize concordance of gene expression means and variances (Spearman r = 0.81, 0.68, respectively) between the TCGA SKCM cohort (n = 462) and matched simulated cohort, and then validated in two independent melanoma cohorts (n = 42, 129; means Spearman r = 0.80, 0.78; variances Spearman r = 0.68, 0.63). Using this simulation framework, we benchmarked the effect of sample size, magnitude of differential expression, and differences in cell type proportions on the sensitivity and positive predictive value (PPV) of detecting true differentially expressed genes in the tumor-intrinsic compartment. Results: Reference cohorts of 50 total tumors (n = 10) were simulated to contain a 2 standard deviation tumor-intrinsic expression change in 50 randomly selected genes and a 11% difference in mean purity between two equally sized 25-tumor subgroups. DGE analysis using DESeq2 with an FDR q-value threshold of 0.1 yielded a sensitivity of 0.37 and PPV of 0.29. DGE analysis of the same simulated cohorts using a non-parametric Mann-Whitney U test with an FDR q-value threshold of 0.1 yielded a sensitivity of 0.13 and PPV of 0.76. Conclusions: Commonly used DGE methods for existing expression-based biomarker strategies have poor sensitivity and PPV in admixed tumor samples, limiting our ability to find meaningful transcriptional biomarkers in clinical cohorts. We are currently developing methods to more accurately detect true differentially expressed genes in admixed bulk RNAseq samples and applying these approaches for biomarker discovery in immunotherapy-treated patient cohorts and other clinical tumor cohorts.
Updated overall survival (OS) and genomic analysis from a single-arm phase II study of dabrafenib (D) + trametinib (T) in patients (pts) with <i>BRAF</i> V600E mutant (Mut) metastatic non-small cell lung cancer (NSCLC).
Authors: David Planchard, Benjamin Besse, Harry Groen, Sayed MS Hashemi, Julien Mazieres, Tae Min Kim, Elisabeth A. Quoix, Pierre Jean Souquet, Fabrice Barlesi, Christina S Baik, Liza C Villaruz, Ronan Joseph Kelly, Shirong Zhang, Monique Tan, Eduard Gasal, Libero Santarpia, Bruce E. Johnson
Journal: Journal of Clinical Oncology (2020)

9593 Background: The phase II multicenter, open label study, which evaluated efficacy and safety of D+T in pretreated (cohort B) and treatment (tx)-naive (cohort C) pts with BRAF V600E mut metastatic NSCLC. The results of the primary analysis have been reported. Here, we present an updated survival and genomic analysis data for cohorts B and C. Methods: Tx-naïve (n=36) and pretreated (n=57) pts received D 150 mg twice daily + T 2 mg daily. Primary objective: ORR, secondary objectives: PFS, DOR, OS, safety, tolerability and PK of D+T. Tumor samples were centrally tested using a NGS cancer targeted panel (Oncomine Dx Target test, ThermoFisher Scientific). KM curves and Cox regression models were used to evaluate potential associations between baseline genomic landscape and pt efficacy endpoints. Results: As of June 22, 2019, median (m) follow-up was 16.3 mo in tx-naïve pts and 16.6 mo in pretreated pts. mOS was 17.3 mo (95% CI: 12.3, 40.2; 3 yr OS: 40%) and 18.2 mo (95% CI: 14.3, 28.6; 3 yr OS: 33%) with 14/36 and 11/57 pts alive in tx naïve and pretreated pts respectively. Detailed efficacy results are presented in table. 57/62 tumor samples retrieved from 93 pts were centrally confirmed to have BRAF V600E mut; 5 non-confirmed BRAF tumors (3 pts had PR) were positive for c-MET T1010I, KRAS G12V, ALK fusion and 2 JAK3 S493C with mPFS of 13.8 mo while OS was NE due to limited data points. Eleven pts (18%) had concomitant somatic mutations and/or genetic alterations in addition to BRAF V600E mut: 4 had alterations within PI3K pathway4 had concomitant mutations at IDH1 R132X, and 3 pts had additional mutations at BRAF G466V, KRAS G13C and a cMET exon 14 skipping, respectively. Pts whose tumors had concomitant genetic alterations, particularly in PI3K pathway, showed a trend towards decreased PFS and OS. Safety profile was similar to previous reported results. Conclusions: This update of BRF113928 study reported improved and durable OS rates with combination D+T in BRAF V600E mut NSCLC pts. Co-occurring genetic alterations might influence clinical outcomes of such pts. Further validation is ongoing to corroborate current genomic findings. Clinical trial information: NCT01336634 . [Table: see text]