tbuckley/cabot-search huggingface dataset:
Prostaglandin driven pancreatitis and pancreatic tumorigenesis in the BK5.COX2 mouse
Authors: Jennifer K. Colby, Kaoru Kiguchi, Toru Kawamoto, Russell D. Klein, Susan M. Fischer
Journal: Cancer Research (2006)

1468  Prostaglandin (PG) signaling mediates a number of events associated with tumorigenesis driven by chronic inflammation, including increased proliferation, angiogenesis and invasiveness, decreased apoptosis, and altered immune function. In the BK5.COX2 mouse, chronic pancreatitis leads to pancreatic adenocarcinoma; subtle changes in pancreatic histology are seen as early as 6 weeks; in most mice, progression to carcinoma is seen by 4 to 6 months. Histological observations include loss of acinar cells, presence of highly proliferative ductal complexes (which can become cystic), intense desmoplasia, and influx of inflammatory cells. Inflammatory cells appearing early in the process include granulocytes and macrophages, which persist as lesions progress; infiltration of large numbers of B and T lymphocytes occur in more advanced lesions and tumors. All transgenics ultimately develop tumors. Levels of PGE2, a major pro-inflammatory metabolite of COX2, were measured by ELISA. In pre-tumor transgenic pancreata, levels were elevated ∼15 fold vs. normal wild-type FVB pancreata (means of 3623.25 and 229 pg/mg protein, for transgenic and wild-type, respectively); levels in transgenic tumors were elevated ∼120 fold compared to wild-type (mean of 27,466.2 pg/mg protein). Immunohistochemistry (IHC) for COX2 in young transgenic mice (6-8 wks) shows intense staining in acinar cells adjacent to keratin 5 positive transgene-expressing islets. This suggests that neighboring acinar cells are sensitive to PG signaling, leading to expression of endogenous COX2. This sets up a persistent, proinflammatory microenvironment in the tissue, which ultimately leads to acinar to ductal transdifferentiation, deposition of stroma, and chemoattraction of inflammatory cells. This type of reactive upregulation of COX2 at least partly explains the large increases in PGE2 observed in the tumors. In addition to COX2 increases, we have observed higher amounts of COX1 in the tumors, which may also contribute to high PGE2 levels. In this model, elevated levels of PGE2 are associated with a number of other molecular changes: increased growth factor signaling (e.g., upregulation of VEGF, pAkt), increased expression of matrix metalloproteases (MMPs 7 & 9), high levels of Ki-67 staining, and low levels of TUNEL staining. In a preliminary chemoprevention study, mice fed a diet of 1250 ppm celecoxib for > 9 months showed none of the histopathological changes typically observed, demonstrating that the process of tumor development in this model is largely initiated and driven by COX2 overexpression and its sequelae. Supported by CA100140 and 5 T32 ES07247 from NIH
Gender disparities in hepatocellular cancer survival
Authors: A. E. Hendifar, D. Yang, S. Iqbal, H. Lenz, A. El-Khoueiry
Journal: Journal of Clinical Oncology (2009)

e15517 Background: Recent reports suggest that estrogen mediated inhibition of IL-6 protects against the development of HCC and may explain the decreased risk of liver cancer in women. We investigated the relation-hip between gender, age, and survival for patients with localized HCC. Methods: We identified 11,097 patients with localized, histologically defined HCC, from 1988- 2003, using the Surveillance, Epidemiology, and End Results (SEER) registry. Age at diagnosis, sex, ethnicity, and overall survival were evaluated using Cox proportional hazards model. The models were adjusted for treatment modality, tumor differentiation, tumor size, lymph node involvement, and number of lesions; they were stratified by year of diagnosis and SEER registry site. Results: 8,111 (73%) patients were men and 2,986 (27%) were women. In univariate and multivariate analyses, female gender, young age (&lt; 55 yo), and Asian ethnicity were all associated with improved overall survival (p&lt;0.001). In patients less than 55 yo, women had a superior OS and cancer specific survival (CSS) when compared to men (OS: 18 months vs. 9, CSS: 31 months vs. 14, p&lt;0.001). Conversely, in patients older than 55, there were no gender differences (OS: 8 months vs. 8, CSS 13 months vs. 11, p = 0.08). Local therapies, including, ablation (HR = 0.47 [0.43–0.53]), hepatectomy (HR = 0.40 [0.36–0.44]), radiation (HR = 0.67 [0.57–0.78]) and transplantation (HR = 0.17 [0.15–0.20]) were also associated with improved survival. There were no interactions identified between gender and treatment use. Conclusions: To our knowledge, this is the first report to highlight the superior outcome of premenopausal women with HCC compared to men. We postulate a potential role for estrogen in influencing the biology of HCC and the response to treatment. These observations are consistent with ones made in other gastrointestinal cancers and with reported preclinical data suggesting a protective role for estrogen. Further studies that confirm these observations and elucidate the biology of estrogen's influence on HCC are needed. [Table: see text] No significant financial relationships to disclose.
Abstract A42: Potassium channel activity unveils ovarian cancer vulnerability: From signaling to precision medicine
Authors: Daniela Fukushiro Lopes, Alexandra Hegel, Vitaly Senyuk, Angela Russo, Margaret Liotta, Ronald Potkul, Craig Beeson, Joanna Brurgette, Saverio Gentile
Journal: Clinical Cancer Research (2020)

Abstract Decades of studies on ion channels have vastly demonstrated the critical functions of these proteins in many physiologic and pathologic conditions. Also, studies on ion channels have provided for an extraordinary pharmacopeia of useful compounds, often with selective actions and minimal side effects. Nevertheless, the function of ion channels in controlling cancer biology is still unknown and underexplored. Our research demonstrates that the Kir6.2/SUR2 potassium ion channel can be a prognostic factor in gynecologic cancers. Here we present data showing that the Kir6.2/SUR2 channel activity control biochemical pathways underlying proliferation and metabolism in gynecologic cancers, including endometrioid and high-grade serous ovarian cancer. Use of activators of the Kir6.2/SUR2 produced an arrest of the cell cycle, a significant mitochondrial dysfunction that is associated with alteration of the oxidative cellular state and DNA damage in cisplatin-resistant ovarian cancer. Also, our in vivo experiments show the antigrowth effects of pharmacologically targeting Kir6.2/SUR2 on ovarian cancer with FDA-approved molecules. This study offers the opportunity to consider the therapeutic benefits of repurposing drugs targeting the Kir6.2/SUR2 channel for a treatment of gynecologic cancers that is efficient and safe. Citation Format: Daniela Fukushiro Lopes, Alexandra Hegel, Vitaly Senyuk, Angela Russo, Margaret Liotta, Ronald Potkul, Craig Beeson, Joanna Brurgette, Saverio Gentile. Potassium channel activity unveils ovarian cancer vulnerability: From signaling to precision medicine [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A42.
Abstract 16203: The Roles of ABHD5 (Abhydrolase Domain Containing 5) in Plin2-Deficiency Mediated Autophagy Augmentation
Authors: Hsiao-Ju Lee, Benny Chang
Journal: Circulation (2017)

Ubiquitously expressed lipid droplet protein PLIN2 has been used as a protein marker for intracellular lipid droplets. The expression of Plin2 correlates positively with the amount of lipids in the...
Immunophenotyping of COVID-19 and influenza highlights the role of type I interferons in development of severe COVID-19
Authors: Jeong Seok Lee, Seongwan Park, Hye Won Jeong, Jin Young Ahn, Seong Jin Choi, Hoyoung Lee, Baekgyu Choi, Su Kyung Nam, Moa Sa, Ji-Soo Kwon, Su Jin Jeong, Heung Kyu Lee, Sung Ho Park, Su-Hyung Park, Jun Yong Choi, Sung-Han Kim, Inkyung Jung, Eui-Cheol Shin
Journal: Science Immunology (2020)

Single-cell RNA sequencing of blood immune cells reveals type I interferon–associated hyper-inflammation in severe COVID-19.
Wavelength‐Selective Light‐Controlled Stepwise Photolysis from Single Gold Nanoparticles
Authors: Yekui Zhou, Yuanwei Zhang, Wenhai Lin, Samuel J. Kesseli, Ling Huang, Yang Zhao, Xikuang Yao, Kai Huang, Gang Han
Journal: Advanced Healthcare Materials (2020)

Abstract Light‐controlled sequential photolysis from a single nanoparticle is a challenge for controlled release. A wavelength‐selective sequential photolysis from single gold nanoparticles is reported for the first time. In particular, it is also demonstrated that such nanoparticle can be used to sequentially release two payloads in living cells. In principle, this system can be extended to sequential release of multiple different types of payloads by rational design of diverse photocleavable linkers. It is expected that this work can provide a new tool for better orderly controlling cellular events that request high spatiotemporal manners.
HBA-DEALS: accurate and simultaneous identification of differential expression and splicing using hierarchical Bayesian analysis
Authors: Guy Karlebach, Peter Hansen, Diogo FT Veiga, Robin Steinhaus, Daniel Danis, Sheng Li, Olga Anczukow, Peter N Robinson
Journal: Genome biology (2020)

Abstract We present Hierarchical Bayesian Analysis of Differential Expression and ALternative Splicing (HBA-DEALS), which simultaneously characterizes differential expression and splicing in cohorts. HBA-DEALS attains state of the art or better performance for both expression and splicing and allows genes to be characterized as having differential gene expression, differential alternative splicing, both, or neither. HBA-DEALS analysis of GTEx data demonstrated sets of genes that show predominant DGE or DAST across multiple tissue types. These sets have pervasive differences with respect to gene structure, function, membership in protein complexes, and promoter architecture.
P-41 Understanding the clinical profiles that influence the concordance of RAS mutations between blood and tissue to guide therapy in metastatic colorectal cancer
Authors: E. Brozos Vázquez, R. Lago-Lestón, M. Covela-Rúa, J. De la Cámara-Gómez, A. Fernández-Montes, S. Candamio Folgar, Y. Vidal Ínsua, F. Vázquez-Rivera, R. López-Rodríguez, C. Blanco-Freire, I. Ferreirós-Vidal, L. Muinelo-Romay, R. López-López
Journal: Annals of Oncology (2020)
Universal Masking to Prevent SARS-CoV-2 Transmission—The Time Is Now
Authors: John T. Brooks, Jay C. Butler, Robert R. Redfield
Journal: JAMA (2020)

Xiaowen Wang, MD; Enrico G. Ferro, MD; Guohai Zhou, PhD; Dean Hashimoto, MD, JD; Deepak L. Bhatt, MD, MPH
Impact of Acarbose on Incident Diabetes and Regression to Normoglycemia in People With Coronary Heart Disease and Impaired Glucose Tolerance: Insights From the ACE Trial
Authors: Hertzel C. Gerstein, Ruth L. Coleman, Charles A.B. Scott, Shishi Xu, Jaakko Tuomilehto, Lars Rydén, Rury R. Holman
Journal: Diabetes Care (2020)

We examined the impact of acarbose, an α-glucosidase inhibitor, on incident diabetes and regression to normoglycemia in 6,522 Acarbose Cardiovascular Evaluation (ACE) trial participants in China who had impaired glucose tolerance (IGT) and coronary heart disease (CHD).Participants were randomly assigned to acarbose or placebo and followed with four monthly fasting plasma glucose (FPG) tests and annual oral glucose tolerance tests. Incident diabetes was defined as two successive diagnostic FPG levels ≥7 mmol/L or 2-h plasma glucose (PG) levels ≥11.1 mmol/L while taking study medication or a masked adjudicated confirmation of this diagnosis. Regression to normoglycemia was defined as FPG <6.1 mmol/L and 2-h PG <7.8 mmol/L. Intention-to-treat and on-treatment analyses were conducted using Poisson regression models, overall and for subgroups (age, sex, CHD type, HbA1c, FPG, 2-h PG, BMI, estimated glomerular filtration rate, for IGT alone, for IGT + impaired fasting glucose, and for use of thiazides, ACE inhibitors [ACEis]/angiotensin receptor blockers [ARBs], β-blockers, calcium channel blockers, or statins).Incident diabetes was less frequent with acarbose compared with placebo (3.2 and 3.8 per 100 person-years, respectively; rate ratio 0.82 [95% CI 0.71, 0.94], P = 0.005), with no evidence of differential effects within the predefined subgroups after accounting for multiple testing. Regression to normoglycemia occurred more frequently in those randomized to acarbose compared with placebo (16.3 and 14.1 per 100 person-years, respectively; 1.16 [1.08, 1.25], P < 0.0001). This effect was greater in participants not taking an ACEi or ARB (1.36 [1.21, 1.53], Pinteraction = 0.0006). The likelihood of remaining in normoglycemic regression did not differ between the acarbose and placebo groups (P = 0.41).Acarbose reduced the incidence of diabetes and promoted regression to normoglycemia in Chinese people with IGT and CHD.
XPD gene Lys751Gln polymorphism is associated with an early onset of basal cell carcinoma
Authors: Jaime L. Matta, Abigail Ruiz, Edu Suarez, Jaime R. Villa, Jocelyn Matias, Rafael Ortiz, Juan M. Ramos
Journal: Cancer Research (2006)

820  Introduction: Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the most common human cancers collectively termed as non-melanoma skin cancer (NMSC). NMSC risk factors include UV exposure, age, DNA repair capacity (DRC), and certain genetic traits. The prevalence of NMSC is higher among people of 55 years or older. Polymorphisms of DNA repair genes involved in the nucleotide excision pathway (NER) are particularly important in the development of cancer. Recent studies by Brewster et al. 2004 suggest that individuals with NMSC who have the variant Gln allele are at increased risk of developing a secondary primary cancer. Although two previous studies examined genotypic features of persons younger than 35 years with NMSC (Zhang et al, 2001; Dahl, et al 1992), no studies have been undertaken to determine whether polymorphisms in the XPD gene are associated with the early onset of NMSC. As part of a large-scale population study aimed at testing the hypothesis that reduced DNA repair capacity may explain differences in NMSC risk, we identified a group of seven (7) individuals that developed NMSC at an early age (≤35 years). This subpopulation was selected to examine the association between XPD Lys751Gln genotype and risk for the development of early onset NMSC. Methods: This pilot study was undertaken as part of an ongoing large scale (700 participants) case-control study aimed at identifying interindividual differences in DRC as a risk factor for NMSC. Inclusion and exclusion factors were previously described (Matta et al. 2003). Informed consent was obtained from each participant before enrollment and all the protocols were approved by the IRB at Ponce School of Medicine. The participants were residents of Puerto Rico and 21 years or older. The BCC participant9s diagnosis was confirmed histopathologically. Seven age-matched controls who were negative for skin cancer as confirmed by a dermatologist were selected for the study. Genomic DNA was extracted from peripheral lymphocytes. The XPD Lys751Gln genotype (A/A, A/C, C/C) was assessed by using Restriction fragment length polymorphisms (RFLP) and agarose gel electrophoresis. Results: The C allele presented a 0.50 allele frequency in BCC participants in comparison with a 0.14 in the controls. The presence of the C allele (A/C or C) in this younger subpopulation resulted in a 15 fold increase risk (OR=15) for developing NMSC at an early age (≤35 years).These results were statistically significant (p=0.03, Student9s t-test) Conclusions: The presence of the mutant C allele for the XPD Lys751Gln polymorphism is associated with the early onset of basal cell carcinoma. This is the first study that demonstrates that the XPD Lys751 polymorphism is associated with a higher risk of BCC in younger persons (≤35 years). Supported by 2G12 RR03050-17 RCMI Program, NCRR, NIH to Ponce School of Medicine.
Association of progression-free or event-free survival with overall survival in diffuse large B-cell lymphoma after immunochemotherapy: a systematic review
Authors: Jie Zhu, Yong Yang, Jin Tao, Shu-Lian Wang, Bo Chen, Jian-Rong Dai, Chen Hu, Shu-Nan Qi, Ye-Xiong Li
Journal: Leukemia (2020)

Abstract To investigate progression-free survival (PFS) and event-free survival (EFS) as early efficacy endpoints in diffuse large B-cell lymphoma (DLBCL), this systematic review included phase III randomized controlled trials (RCTs), phase II trials, and retrospective studies in newly diagnosed DLBCL receiving rituximab-containing chemotherapy through databases search up to 2019. Quality control was performed, where studies with high risk of bias were excluded. Prediction models were first established using the RCTs, and then externally validated in the phase II and retrospective populations. Trial-level surrogacy analysis was conducted by correlating the logarithmic (log) hazard ratio (HR) for PFS or EFS and log HR for OS. Correlation analysis at treatment arm-level was performed between 1-, 2-, 3-, and 5-year PFS or EFS rates and 5-year OS. The correlation was evaluated using the Pearson correlation coefficient r in weighted linear regression, with weight equal to patient size. Sensitivity analyses were performed to assess the consistency of predictive model by leaving one subgroup of trials out at a time. Twenty-six phase III RCTs, 4 phase II trials and 47 retrospective studies were included. In trial-level surrogacy, PFS ( r , 0.772; 95% confidence interval [CI], 0.471–0.913) or EFS ( r , 0.838; 95% CI, 0.625–0.938) were associated with OS. For rituximab immunochemotherapy treatment arms in RCTs, there was a linear correlation between 1 and 5-year PFS ( r , 0.813–0.873) or EFS ( r , 0.853–0.931) and 5-year OS. Sensitivity analysis demonstrated reasonable overall consistency. The correlation between PFS and OS was externally validated using independent phase II, and retrospective data ( r , 0.795–0.897). We recommend PFS and EFS as earlier efficacy endpoints in patients with DLBCL primarily treated with rituximab-containing immunochemotherapy.
Screening for hearing loss in adults with CF: does it make sense?
Authors: Andrew Jones
Journal: Thorax (2020)

Cystic fibrosis (CF) is a condition characterised by chronic pulmonary infection and progressive lung damage with those affected requiring frequent course of antibiotics. Pseudomonas aeruginosa is by far the most common chronic pathogen in CF. While measures comprising regular screening for initial onset of P. aeruginosa infection, aggressive therapy for eradication of early carriage and stringent infection control precautions have extended the age of onset, the majority of patients still eventually develop chronic infection. An aminoglycoside combined with a β-lactam antibiotic is the first-line treatment option for patients with P. aeruginosa requiring intravenous antibiotics and therefore most patients with CF will be exposed to intravenous aminoglycosides during their lifetime, often on multiple occasions.

Several studies, including that by Vijayasingam and colleagues in this current issue of Thorax, provide compelling evidence that patients with CF have an increased risk for hearing impairment.1 The findings of Vijayasingam and colleagues concur with most other studies in CF that hearing impairment is closely associated with cumulative exposure to aminoglycosides and increasing age.1–4 A degree of hearing loss was common, being found in 57 (45%) of 126 individuals. Ten (8%) of the subjects had hearing impairment in frequencies 0.5–4 kHz critical for speech recognition; half of these were under 50 years of age and all but one had a documented history of intravenous aminoglycoside exposure. As the study excluded any subjects who were already using hearing aids these figures may be an underestimation of significant hearing loss affecting speech recognition in the population at their CF centre. Hearing impairment is …
P-124 Tumor budding and CDX2 as additional prognostic factors in stage II colon cancer
Authors: M. Roberto, D. Ierinò, M. Panebianco, A. Romiti, A. Di Cerbo, R. Falcone, M. Ferri, G. Balducci, G. Ramacciato, E. Pilozzi, P. Marchetti, F. Mazzuca
Journal: Annals of Oncology (2020)
Covid-19: The inside story of the RECOVERY trial
Authors: Jacqui Wise, Rebecca Coombes
Journal: BMJ (2020)

The UK's flagship covid-19 clinical trial has been hailed worldwide—but some say it is far from perfect. <b>Jacqui Wise</b> and <b>Rebecca Coombes</b> unpick the criticisms that still surround a vital cog in the pandemic response
Face masks can be devastating for people with hearing loss
Authors: Joshua Chodosh, Barbara E Weinstein, Jan Blustein
Journal: BMJ (2020)

The covid-19 pandemic has literally changed the face of medical care: clinicians, nurses, other staff, and patients are all wearing masks.We are trying to communicate while keeping the required distance apart.With masks covering the faces around us, we are unable to access the facial expressions and lip movements that are so vital to daily communication.Masking is challenging for everyone, but it is especially difficult for people with hearing loss.Here we focus on how masks undermine speech communication for patients with hearing loss in medical care settings.Masks also create enormous challenges for members of the Deaf community who use sign language, clinicians with hearing loss, and other populations.
Multicentre, randomised, open-label, parallel-group study evaluating the efficacy and safety of ixekizumab versus adalimumab in patients with psoriatic arthritis naïve to biological disease-modifying antirheumatic drug: final results by week 52
Authors: Josef S Smolen, Philip Mease, Hasan Tahir, Hendrik Schulze-Koops, Inmaculada de la Torre, Lingnan Li, Maja Hojnik, Christophe Sapin, Masato Okada, Roberto Caporali, Jordi Gratacós, Philippe Goupille, Soyi Liu Leage, Sreekumar Pillai, Peter Nash
Journal: Annals of the Rheumatic Diseases (2020)

SPIRIT head-to-head (H2H) is a 52-week (Wk) trial comparing ixekizumab (IXE) with adalimumab (ADA) for simultaneous American College of Rheumatology (ACR)50 and Psoriasis Area and Severity Index (PASI)100 responses in 566 patients (distributed evenly across both groups) with psoriatic arthritis (PsA). IXE was superior to ADA for this primary end point at Wk24. We aimed to determine the final efficacy and safety results through Wk52 including a prespecified subgroup analysis of concomitant conventional synthetic disease-modifying anti-rheumatic drugs (csDMARD) use.SPIRIT-H2H is a Wk52 multicentre, open-label, blinded-assessor study comparing IXE and ADA in bionaïve patients with PsA. Patients were randomised 1:1 to IXE or ADA with stratification by concomitant csDMARD use and presence of moderate-to-severe plaque psoriasis. Prespecified end points at Wk24 and Wk52 included musculoskeletal, psoriasis, quality-of life outcomes, subgroup analyses and safety.A significantly higher proportion of patients treated with IXE versus ADA simultaneously achieved ACR50 and PASI100 (39% vs 26%, p<0.001), PASI100 (64% vs 41%, p<0.001) at Wk52. Efficacy of IXE and ADA was similar at Wk52 for ACR50 (49.8% vs 49.8%, p=0.924), treat-to-target outcomes, enthesitis and dactylitis resolution. Responses to IXE were consistent irrespective of concomitant csDMARD use. Significantly more patients on IXE monotherapy versus ADA monotherapy had simultaneous ACR50 and PASI100 (38% vs 19%, p=0.007), and PASI100 responses (66% vs 35%, p<0.001) at Wk52. There were no new safety findings for IXE or ADA.IXE provided significantly greater simultaneous joint and skin improvement than ADA through Wk52 in bionaïve patients with PsA. IXE showed better efficacy on psoriasis and performed at least as well as ADA on musculoskeletal manifestations. IXE efficacy was consistent irrespective of concomitant csDMARD use.NCT03151551.