tbuckley/cabot-search huggingface dataset:
Initiating Pharmacologic Treatment in Tobacco-Dependent Adults
Authors: Atul Jain, Andrew M. Davis
Journal: JAMA (2021)

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KEYlargo: A phase II study of first-line pembrolizumab (P), capecitabine (C), and oxaliplatin (O) in HER2-negative gastroesophageal (GE) adenocarcinoma.
Authors: Hope Elizabeth Uronis, Christel Rushing, Gerard C. Blobe, Shiaowen David Hsu, Niharika B. Mettu, James Leroy Wells, Donna Niedzwiecki, Leighanne Hartman, Ashley Moyer, Herbert I. Hurwitz, John H. Strickler
Journal: Journal of Clinical Oncology (2021)

228 Background: Gastric and esophageal adenocarcinomas are a leading cause of cancer death worldwide. Many of these patients (pts) present with locally advanced unresectable or metastatic disease and are treated with combination cytotoxic chemotherapy. Single agent P is FDA approved for patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma (GEJ) whose tumors have a combined positive score (CPS) ≥ 1 after disease progression on or after two lines of therapy including fluoropyrimidine and platinum and her2/neu-targeted therapy (if indicated). More effective therapy is needed earlier in the disease trajectory. We conducted a single-arm phase II trial to establish the safety and efficacy of first-line C and O + P. Methods: Pts with previously untreated metastatic GE adenocarcinoma regardless of PDL-1 status received intravenous (IV) P 200mg with IV O 130mg/m 2 every three weeks and oral C 850mg/m 2 twice daily for 14 days on/7 days off. After the 6 patient safety cohort, pts first completed a biomarker cycle that included fresh tumor biopsy before P and one week after P before chemotherapy started. Archived FFPE tumor samples were also obtained from all pts with available tissue. The primary endpoint was progression free survival (PFS); secondary endpoints included response rate (RR) and overall survival (OS). Results: 36 pts were enrolled and 34 pts were evaluable for efficacy (1 pt withdrew for personal reasons before end of cycle 1 and 1 pt had immune-related toxicity during cycle 1 and was taken off study before any efficacy assessment). 9 pts (26%) had an esophageal primary, 18 pts (53%) had a GEJ primary and 7 pts (21%) had a gastric primary. Median PFS was 7.6 months [95% CI: 5.8 to 12.2], RR was 72.7% [95% CI: 57% to 88%], and median OS was 15.8 months [95% CI: 11.6 to NE]. 27 patients (81.8%) had decrease in disease burden (ranging from -19% to -100%). After &gt; 18 months of follow-up, 5 patients remained in durable complete response (CR). Immune-mediated treatment related adverse events (TRAEs) included thyroid disorders (n=5; 14%), colitis (n=4; 11%), adrenal insufficiency (n=2; 5%), and type 1 diabetes (n=1). Sixteen patients (44%) experienced grade 3 or 4 TRAEs. There were no grade 5 TRAEs. Conclusions: The combination of C and O + P had acceptable safety and significant clinical activity. These promising results indicate that C and O + P merits further study as a first line option for patients with unresectable locally advanced or metastatic GE adenocarcinoma. Updated survival and correlative data will be presented. Clinical trial information: NCT03342937.
FRI0025 CIRCADIAN RHYTHMS OF ENDOTHELIAL NITRIC OXIDE SYNTHASE PRODUCTION IN FEMALES WITH RHEUMATOID ARTHRITIS AND ARTERIAL HYPERTENSION DEPENDING ON NOS3 Т786С GENE POLYMORPHISM
Authors: K. Zaichko, M. Stanislavchuk, N. Zaichko, V. Khomenko
Journal: Annals of the Rheumatic Diseases (2020)

Background: One of the most common comorbidity in patients with rheumatoid arthritis (RA) is arterial hypertension (AH), with incidence ranging from 20 to 60%. Mechanisms of this comorbidity arises a lot of interest. In our previous study was established the association of T786C NOS3 (rs2070744) gene polymorphism with AH in females with RA in the Ukrainian population [1]. Objectives: So next, we were aiming to investigate daily fluctuation of endothelial nitric oxide synthase (NOS3) in RA patients with AH depending on NOS3 T786C gene polymorphism. Methods: In the study were enrolled 173 females with RA aged 43.7 ± 7.35 years (Mean ± SD) and 34 age-matched healthy women without joint diseases and autoimmune diseases (control). Serum NOS3 level was determined at 08:00 and 20:00 using Cloud-Clone Corp kits (USA). NOS3 T-786С polymorphism was determined by Real-Time PCR (Bio-Rad iCycler IQ5) using SNP-express kit. Study was carried out in compliance with bioethical standards and provisions of the WHO, Helsinki Declaration of the General Assembly of the World Medical Association (1989). Results: Among enrolled patients prevailed individuals with more than 5 years disease history, ІІ-ІІІ radiographic stage (80.9 %), and were seropositive for anti-cyclic citrullinated peptide (80.6%). There were 114 (66%) normotensive patients and 59 (34%) patients with AH (13% - I stage, 20.8% - II stage). The daily fluctuation of NOS3 serum level was established in the control group. The evening NOS3 level was higher in 1.3 times, than the morning level (р&lt;0.001). In RA patients the similar fluctuations of NOS3 level was registered, but the daily NOS3 production was lower, than in control. Diurnal variation of NOS3 level depended on comorbid AH and NOS3 T-786С genotype. In CC genotype NOS3 levels at 08:00 and at 20:00 were lower in 1.2-1.3 times (p&lt;0.05) than in TT and TC genotypes. In patients with RA and AH the lowest diurnal variation of NOS3 level was in CC genotype. The decrease of evening NOS3 production was strong associated with comorbid AH (OR 3.78; 95% CI 1.96-7.28). Conclusion: Circadian rhythms of NOS3 production in females with RA and AH depend on NOS3 Т786С gene polymorphism. The depression of NOS3 production in the evening can be predictor of comorbid AH in females with RA. References: [1]Zaichko, K., &amp; Stanislavchuk, M. (2017, April). T-786C gene promoter polymorphism of endothelial nitric oxide synthase: its association to the disease activity and arterial hypertension in patients with rheumatoid arthritis in the ukraine population. In rheumatology (vol. 56, pp. 129-129). GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND: OXFORD UNIV PRESS. Acknowledgments: NA Disclosure of Interests: None declared
Abstract 15018: Endothelium- Restricted Overexpression of Cystathionine γ-Lyase Protects Against Pressure-Overload Induced Heart Failure
Authors: Zhen Li, John W Elrod, David J Lefer
Journal: Circulation (2018)

Background: Endogenous hydrogen sulfide (H2S) is critical for cardiovascular homeostasis. H2S protects against myocardial ischemia/reperfusion injury and heart failure by ameliorating oxidative str...
Genetics of 35 blood and urine biomarkers in the UK Biobank
Authors: Nasa Sinnott-Armstrong, Yosuke Tanigawa, David Amar, Nina Mars, Christian Benner, Matthew Aguirre, Guhan Ram Venkataraman, Michael Wainberg, Hanna M. Ollila, Tuomo Kiiskinen, Aki S. Havulinna, James P. Pirruccello, Junyang Qian, Anna Shcherbina, Fatima Rodriguez, Themistocles L. Assimes, Vineeta Agarwala, Robert Tibshirani, Trevor Hastie, Samuli Ripatti, Jonathan K. Pritchard, Mark J. Daly, Manuel A. Rivas
Journal: Nature Genetics (2021)
Prognostic value of tumor deposits in stage III colon cancer patients, a post-hoc analysis of CALGB/SWOG 80702 phase III study.
Authors: Romain Cohen, Qian Shi, Jeffrey P. Meyers, Zhaohui Jin, Magali Svrcek, Charles S. Fuchs, Felix Couture, J. Phillip Kuebler, Johanna C. Bendell, Ana De Jesus-Acosta, Pankaj Kumar, DeQuincy Andrew Lewis, Benjamin R. Tan, Monica M. Bertagnolli, Howard S. Hochster, Charles David Blanke, Eileen Mary O'Reilly, Anthony Frank Shields, Jeffrey A. Meyerhardt
Journal: Journal of Clinical Oncology (2021)

10 Background: In colon cancer, tumor deposits (TD) have been associated with worse prognosis, but they are included in the TNM staging system only in the absence of lymph node metastasis (i.e., stage III pN1c tumors). Here we aimed at evaluating the prognostic value of TD and the impact of the addition of TD in the count of lymph node metastases in patients with stage III colon cancer from the CALGB/SWOG 80702 phase III trial (NCT01150045). Methods: Pathological reports of all patients were reviewed for the presence and the count of TD, primary tumor sidedness, lymphovascular invasion and perineural invasion. Cases without available pathological report or without specific information of TD were excluded. Prognostic associations were evaluated by multi-variable Cox models adjusting for treatment arm, T-stage, N-stage, lymphovascular invasion, perineural invasion and lymph node ratio. Results: Overall, 2028 patients were included, with 524 (26%) TD-positive and 1504 (74%) TD-negative stage III tumors. Of the TD-positive patients, 80 (15.4%) were node negative (i.e., pN1c), 239 (46.1%) were pN1a/b and 200 (38.55%) were pN2. 17.2% and 37.0% of all pN1a/b and pN2 tumors had TD. Overall median follow-up was 69.3 months. The presence of TD was associated with poorer DFS (adjusted hazard ratio (aHR) = 1.59, 95%CI 1.28-1.91) and OS (aHR = 1.52, 95%CI 1.18-1.95) in the overall population. The negative effect of TD on DFS and OS was observed for both pN1a/b and pN2 groups and confirmed in multivariate Cox model. Among TD-positive patients, the number of TD had a linear negative effect on DFS and OS. Adding TD to the count of lymph node metastases, 104 of 1570 (6.6%) patients initially considered as pN1 were re-staged as pN2. Re-staged pN2 patients experienced worse DFS (3-year DFS rate: 65.5% versus 80.3%, P = .0003) and OS (5-year OS rate: 69.1 versus 87.8%, P = .0005) than patients confirmed as pN1. Re-staged pN2 patients had similar DFS than patients initially staged as pN2 (3-year DFS rate: 65.5% versus 63.1%, P = .1992). OS curves of these 2 groups crossed, with better outcomes during the first 3 years of follow-up but poorer 5-year estimates for re-staged pN2 patients (5-year OS rate: 69.1% versus 74.8%, P = .0436). Conclusions: TD are found in more than one fourth of stage III colon cancer specimens. The number of TD has a linear deleterious effect on patients’ prognosis. Adding the number of TD to the count of lymph node metastases improves the prognostication accuracy of the TNM staging. Support: U10CA180821, U10CA180882; https://acknowledgments.alliancefound.org . Clinical trial information: NCT01150045.
Parotid Oncocytoma on 99mTc-Sestamibi Scintigraphy and SPECT/CT
Authors: John W. Kirkland, Jason M. Zhao, Nathan E. McWhorter, Kevin P. Banks
Journal: Clinical Nuclear Medicine (2021)

Abstract Oncocytomas in the parotid gland are a rare benign neoplasm composed of mitochondrial-rich oncocytes. Here we present the case of an 85-year-old man with a history of biopsy-proven right parotid gland oncocytoma who underwent 99m Tc-sestamibi scintigraphy and SPECT/CT in the context of primary hyperparathyroidism. Focal intense uptake of radiotracer is detected within the right parotid gland on sestamibi scintigraphy. SPECT/CT confirms the localization of sestamibi uptake to the hyperattenuating parotid gland oncocytoma.
Trade-Offs Between Harms and Benefits of Different Breast Cancer Screening Intervals Among Low-Risk Women
Authors: Nicolien T van Ravesteyn, Clyde B Schechter, John M Hampton, Oguzhan Alagoz, Jeroen J van den Broek, Karla Kerlikowske, Jeanne S Mandelblatt, Diana L Miglioretti, Brian L Sprague, Natasha K Stout, Harry J de Koning, Amy Trentham-Dietz, Anna N A Tosteson
Journal: JNCI Journal of the National Cancer Institute (2021)

A paucity of research addresses breast cancer screening strategies for women at lower-than-average breast cancer risk. The aim of this study was to examine screening harms and benefits among women aged 50-74 years at lower-than-average breast cancer risk by breast density.Three well-established, validated Cancer Intervention and Surveillance Network models were used to estimate the lifetime benefits and harms of different screening scenarios, varying by screening interval (biennial, triennial). Breast cancer deaths averted, life-years and quality-adjusted life-years gained, false-positives, benign biopsies, and overdiagnosis were assessed by relative risk (RR) level (0.6, 0.7, 0.85, 1 [average risk]) and breast density category, for US women born in 1970.Screening benefits decreased proportionally with decreasing risk and with lower breast density. False-positives, unnecessary biopsies, and the percentage overdiagnosis also varied substantially by breast density category; false-positives and unnecessary biopsies were highest in the heterogeneously dense category. For women with fatty or scattered fibroglandular breast density and a relative risk of no more than 0.85, the additional deaths averted and life-years gained were small with biennial vs triennial screening. For these groups, undergoing 4 additional screens (screening biennially [13 screens] vs triennially [9 screens]) averted no more than 1 additional breast cancer death and gained no more than 16 life-years and no more than 10 quality-adjusted life-years per 1000 women but resulted in up to 232 more false-positives per 1000 women.Triennial screening from age 50 to 74 years may be a reasonable screening strategy for women with lower-than-average breast cancer risk and fatty or scattered fibroglandular breast density.
Abstract 845: Do Statins Increase Incidence of Diabetes Mellitus? A Meta-analysis of Randomized Clinical Trials
Authors: Marcelo C Shibata, Hernando Leon, Marlene Dorgan, Trish Chatterley
Journal: Circulation (2009)

Background: Statins reduce mortality and morbidity in patients at risk or with documented coronary artery disease and thus are widely prescribed. Report from randomized trials (RCT) suggested that ...
Inducible skin‐associated lymphoid tissue (iSALT) in a patient with Schnitzler syndrome who manifested wheals on recurrent localized erythema
Authors: H. Kamido, D. Shimomiya, T. Kogame, R. Takimoto‐Ito, T.R. Kataoka, M. Hirata, C. Ueshima, A. Otsuka, F.M. Ghazawi, T. Nomura, N. Kambe, K. Kabashima
Journal: British Journal of Dermatology (2021)
Asthma diagnosis: into the fourth dimension
Authors: Ran Wang, Clare S Murray, Stephen J Fowler, Angela Simpson, Hannah Jane Durrington
Journal: Thorax (2021)

Asthma is the most common chronic respiratory disease in the UK; however, the misdiagnosis rate is substantial. The lack of consistency in national guidelines and the paucity of data on the performance of diagnostic algorithms compound the challenges in asthma diagnosis. Asthma is a highly rhythmic disease, characterised by diurnal variability in clinical symptoms and pathogenesis. Asthma also varies day to day, seasonally and from year to year. As much as it is a hallmark for asthma, this variability also poses significant challenges to asthma diagnosis. Almost all established asthma diagnostic tools demonstrate diurnal variation, yet few are performed with standardised timing of measurements. The dichotomous interpretation of diagnostic outcomes using fixed cut-off values may further limit the accuracy of the tests, particularly when diurnal variability straddles cut-off values within a day, and careful interpretation beyond the ‘positive’ and ‘negative’ outcome is needed. The day-to-day and more long-term variations are less predictable and it is unclear whether performing asthma diagnostic tests during asymptomatic periods may influence diagnostic sensitivities. With the evolution of asthma diagnostic tools, home monitoring and digital apps, novel strategies are needed to bridge these gaps in knowledge, and circadian variability should be considered during the standardisation process. This review summarises the biological mechanisms of circadian rhythms in asthma and highlights novel data on the significance of time (the fourth dimension) in asthma diagnosis.
MethylationToActivity: a deep-learning framework that reveals promoter activity landscapes from DNA methylomes in individual tumors
Authors: Justin Williams, Beisi Xu, Daniel Putnam, Andrew Thrasher, Chunliang Li, Jun Yang, Xiang Chen
Journal: Genome biology (2021)

Abstract Although genome-wide DNA methylomes have demonstrated their clinical value as reliable biomarkers for tumor detection, subtyping, and classification, their direct biological impacts at the individual gene level remain elusive. Here we present MethylationToActivity (M2A), a machine learning framework that uses convolutional neural networks to infer promoter activities based on H3K4me3 and H3K27ac enrichment, from DNA methylation patterns for individual genes. Using publicly available datasets in real-world test scenarios, we demonstrate that M2A is highly accurate and robust in revealing promoter activity landscapes in various pediatric and adult cancers, including both solid and hematologic malignant neoplasms.
The Plasticity of Nanofibrous Matrix Regulates Fibroblast Activation in Fibrosis
Authors: Yuanbo Jia, Yanzhong Wang, Lele Niu, Hang Zhang, Jin Tian, Dengfeng Gao, Xiaohui Zhang, Tian Jian Lu, Jin Qian, Guoyou Huang, Feng Xu
Journal: Advanced Healthcare Materials (2021)

Abstract Natural extracellular matrix (ECM) mostly has a fibrous structure that supports and mechanically interacts with local residing cells to guide their behaviors. The effect of ECM elasticity on cell behaviors has been extensively investigated, while less attention has been paid to the effect of matrix fiber‐network plasticity at microscale, although plastic remodeling of fibrous matrix is a common phenomenon in fibrosis. Here, a significant decrease is found in plasticity of native fibrotic tissues, which is associated with an increase in matrix crosslinking. To explore the role of plasticity in fibrosis development, a set of 3D collagen nanofibrous matrix with constant modulus but tunable plasticity is constructed by adjusting the crosslinking degree. Using plasticity‐controlled 3D culture models, it is demonstrated that the decrease of matrix plasticity promotes fibroblast activation and spreading. Further, a coarse‐grained molecular dynamic model is developed to simulate the cell–matrix interaction at microscale. Combining with molecular experiments, it is revealed that the enhanced fibroblast activation is mediated through cytoskeletal tension and nuclear translocation of Yes‐associated protein. Taken together, the results clarify the effects of crosslinking‐induced plasticity changes of nanofibrous matrix on the development of fibrotic diseases and highlight plasticity as an important mechanical cue in understanding cell–matrix interactions.
Targeted multiplex proteomics (TMP) and genomics of early-onset colorectal cancer (EO-CRC).
Authors: Audrey E. Kam, Ateeq M. Khaliq, Nida Alam, Dana Hayden, Anuradha R. Bhama, Henry Govekar, Sam Pappas, Ethan M. Ritz, Ajaypal Singh, Sheeno P. Thyparambil, Wei-Li Liao, Anuja Bhalkikar, Xuefeng B. Ling, Mia Alyce Levy, Timothy Kuzel, Ashiq Masood
Journal: Journal of Clinical Oncology (2021)

97 Background: The incidence and mortality of early-onset colorectal cancer (EO-CRC) is on the rise. Consequently, there is an urgent unmet need to better understand their unique tumor biology to expand therapeutic options and improve clinical outcomes. Methods: Exploratory Targeted multiplex proteomics (TMP) and targeted 648 gene panel was performed on specimens from 35 patients with resected colon cancer diagnosed at age &lt; = 40 years. TMP panel consisted of 72 proteins involved in differentiation, tumorigenesis, and response to chemotherapy, targeted therapy, and immunotherapy. Clinicopathologic and genomic data were also collected. Results: The median age of diagnosis was 33 years. The cohort included 15 male and 20 female patients. 20 (57%) had left-sided tumors and 6 (17%) had stage IV disease. Notable genomic alterations included mutations in: BRAF V600E (2/35); RAS (15/35); PIK3CA exon 9 or 20 (5/35); and ERBB2 (2/35). One patient exhibited ERBB2 amplification. 9/35 tumors were MSI-H. TMP analysis revealed overexpression of chemotherapy resistance proteins in several patients: ALDH1A1:16/35; ERCC1:1/35; GART:26/35; MDR1:9/35; MGMT:5/35; RRM1:6/35; TUBB3:1/35; TYMS:2/35; XRCC1:11/35. In contrast, some tumors exhibited elevated biomarkers of chemosensitivity: hENT1:8/35; DHFR:12/35; TYMP:15/35; OPRT:8/35; SLFN11:1/35; TLE:11/35; TOPO1:12/35; TOPO2A:1/35. Protein targets of cell signaling pathways were overexpressed in a number of tumors: CAT:16/35; CAV-1: 6/35; CBL:2/35; E-Cadherin: 19/35; HSP90A:16/35; HSP90B:18/35; MET:5/35; NQO1:18/35; paxillin:4/35; SRC:21/35; STAT3:11/35. Regarding EGFR and KRAS, none of the tumors exhibited elevated protein expression level. Furthermore, RAS mutational status did not correlate with the level of EGFR or KRAS protein expression. Antibody drug conjugate biomarkers were observed. HER2 overexpression was noted in one patient who had a confirmed ERBB2 amplification. Regarding immunotherapy targets, PDL-1 protein was not overexpressed in any tumor, whereas MSLN and TROP2 were elevated in 1/35 and 2/35 patients, respectively. Conclusions: TMP analysis of EO-CRC patients revealed marked heterogeneity in the expression of proteins involved in differentiation, tumorigenesis, and response to chemotherapy, targeted therapy, and immunotherapy. Differential protein expression may provide insight into therapeutic vulnerabilities for EO-CRC. Furthermore, the discordance between detected genomic alterations and protein expression levels highlights the complementary nature of genomic sequencing and TMP analysis.