tbuckley/cabot-search huggingface dataset:
Abstract 16457: Markers of Diabetes and Renal Function Extend Sudden Death Risk Assessment Beyond the Ejection Fraction
Authors: Kumar Narayanan, Audrey Uy-Evanado, Carmen Teodorescu, Kyndaron Reinier, Karen Gunson, Jonathan Jui, Sumeet S Chugh
Journal: Circulation (2015)

Introduction: Although diabetes and renal dysfunction are known to be associated with SCD risk, the cumulative risk of objective laboratory markers in combination with left ventricular ejection fraction (LVEF) has not been previously evaluated. Hypothesis: Addition of glycosylated hemoglobin (HbA1C) and serum creatinine levels to LVEF can improve the SCD risk stratification model. Methods: As part of a large, prospective, ongoing study of SCD in a Northwestern US metropolitan region (catchment population about 1 million), SCD cases were compared with controls with coronary artery disease (CAD) and no SCD from the same geographic location. HbA1C, serum creatinine levels and LVEF (all prior and unrelated to the SCD event for cases) were obtained for all subjects. Odds ratios for SCD associated with abnormal HbA1C (≥ 7%) and creatinine (≥ 1.5 mg/dL) levels was calculated. Cumulative odds and improvement in model performance on addition of elevated lab markers to low LVEF (≤ 35%) was assessed. Results: 243 SCD cases (68.7 ± 13.2 yrs; 62.1% male) and 159 CAD controls (66.2 ± 9.9 yrs; 65.6% male) with appropriate lab values and LVEF information were evaluated. The mean HbA1C (7.3 ± 2.3 vs. 6.6 ± 1.5%) and creatinine (1.8 ± 1.7 vs. 1.2 ± 0.7 mg/dL) levels were significantly higher in cases. Cases were significantly more likely to have HbA1C ≥ 7% (49.4 vs. 27.7%; p&lt;0.0001) or creatinine ≥ 1.5 mg/dL (39.1% vs. 13.8%) (all p&lt;0.0001). After adjustment for age, sex and low LVEF, high HbA1C (OR 2.3, 95% CI 1.4-3.6; p=0.001) and high creatinine (OR 3.3, 95% CI 1.9-5.7; p&lt;0.0001) were independently associated with SCD; LVEF ≤ 35% was associated as well (OR 1.8, 95% CI 1.1-3.2; p=0.05). As compared to neither lab marker being high, elevation of one marker (OR 2.4, 95% CI 1.5-3.9) or both markers (OR 7.9, 95% CI 3.5-17.6) was associated with progressive increase in SCD odds. Addition of lab markers to a risk stratification model with only LVEF improved model discrimination significantly (AUC 0.613 vs. 0.709; p=0.01). Conclusions: HbA1C and serum creatinine improved the SCD risk stratification model when added to LVEF. Further investigation is warranted before clinical use, including consideration of competing risks that influence overall mortality.
Adopting physical activity to help combat end-stage renal disease
Authors: Wilson Du
Journal: British Journal of Sports Medicine (2019)

Wilson D u 

Alameda, California, USA 

Wilson Du is on Instagram at @RenalWarrior2016.

I was diagnosed in June 2016 with end-stage renal disease (ESRD). At the time of diagnosis, I was 34 years old, morbidly obese, had serious hypertension, and I felt broken spiritually and physically. I spent the first few months following my diagnosis in a wheelchair, unable to walk, and bedridden for the most part.

Since then, I have conquered many fears, both physically and mentally, and have used my mindset to become a ‘ Renal Warrior’ . I have trained my body and mind to be more athletic, and thanks to this mindset I have lost over 130 lbs (59 kg) since I was diagnosed. Currently I am undertaking haemodialysis treatment in preparation for a living kidney donor.

At the time of my diagnosis, I presumed that a simple surgical procedure or taking prescribed medications would fix my health and situation. I was terrified. Initially, this news made me think deeply about my life, if I was happy, and how I would leave this world if I passed. I wanted to do better, but I also wanted to ensure I pass on some goodness in the world, both for my immediate family and for the wider renal community.

My main concern initially was to find a way to lose …
Abstract 770: MiR628-5p targets Jagged 1 and inhibits growth, stemness and invasiveness of advanced prostate cancer cells
Authors: Leslimar Rios-Colon, Juliet Chijioke, Anvesha Srivastava, Malathi Ramalinga, Habib Kedir, Elena Arthur, Patrice Cagle, Gagan Deep, Deepak Kumar
Journal: Cancer Research (2019)

Abstract Prostate cancer (PCa) is the most common non-cutaneous cancer in men, and according to the American Cancer Society reports, 164,690 new cases and 29,430 deaths from PCa are estimated in the United States in 2018. To reduce PCa mortality, we need a better understanding of molecular regulators of prostate carcinogenesis. MicroRNAs (MiRs) are small, non-coding RNA molecules that have been implicated in various cancers, and offer a novel opportunity to diagnose and treat cancer. We have previously identified MiR628-5p as a potential biomarker in PCa patients. This miRNA was found to be downregulated in the serum of both African American and Caucasian men with PCa compared to healthy individuals. In the present study, we further characterized the anti-cancer role of MiR628-5p in various PCa cell culture models. Results showed that MiR628-5p mimic treatment (100 nM) for 5 days significantly decreased the cell proliferation (~43% inhibition, p&amp;lt;0.001) in human prostate carcinoma PC3 cells compared to random mimic control. Similarly, MiR628-5p mimic treatment decreased the number of clones (clone size ≥50 cells) formed by PC3 cells by 40% (p&amp;lt;0.001) compared to random mimic control. Interestingly, miRNA 628-5p mimic treatment also reduced the stemness of PC3 cells as reflected in significant decrease in prostasphere size and CD44 expression. In mechanistic studies, we identified Jagged-1 as a molecular target regulated by MiR628-5p. MiR628-5p mimic treatment strongly decreased the Jagged-1 expression in several PCa cell lines (PC3, DU145, LNCaP and C4-2) as well as reduced the Jagged-1 luciferase activity. Jagged 1 inhibition by MiR628-5p was associated with reduced Notch signaling as well as decreased expression of transcription factors (snail and slug) regulating EMT. Moreover, MiR628-5p mimic treatment increased the expression of epithelial biomarkers (E-cadherin and ZO1), reduced the expression of mesenchymal marker (vimentin) and strongly inhibited the invasiveness of PC3 cells. In conclusion, we present evidence that MiR628-5p is a key regulator of prostate carcinogenesis, and offers a novel therapeutic opportunity to inhibit the growth of advanced PCa. Citation Format: Leslimar Rios-Colon, Juliet Chijioke, Anvesha Srivastava, Malathi Ramalinga, Habib Kedir, Elena Arthur, Patrice Cagle, Gagan Deep, Deepak Kumar. MiR628-5p targets Jagged 1 and inhibits growth, stemness and invasiveness of advanced prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 770.
Abstract 1907: Tenascin-C promotes the activation of mammary fibroblasts to calponin-expressing myofibroblasts
Authors: Daisuke Katoh, Aya Noro, Kyoko Imanaka-Yoshida, Tomoko Ogawa, Toshimichi Yoshida
Journal: Cancer Research (2019)

Abstract [Introduction] Tenascin-C (TN-C), an extracellular matrix molecules, is highly expressed in cancer stroma. Recent studies have demonstrated that cancer associated fibroblasts (CAFs) expressed TN-C in many tumors, including breast cancer. Here, we clarified the effects of TN-C on phenotype changes of the fibroblasts. [Methods] We examined the cell morphology, expression of CAFs markers, and contractile ability in the fibroblasts after TNC treatment in vitro, using human mammary gland fibroblasts (HMFs) and dermal ones (HDFs). We also investigated the correlation between the expression of the CAF markers and TNC deposition in human breast cancer tissues, using immunohistochemical staining. [Results] TN-C (10μg/mL) induced morphological changes of HMFs from spindle-shaped cells to stellate-shaped cells on plastic as well as on glass coverslips. After the treatment of TN-C, the protein expressions of α-SMA and calponin were significantly increased. Immunofluorescence analysis revealed TN-C increased the actin-stress fiber formation and the expression of α-SMA and calponin. Furthermore, TN-C promoted contraction of collagen gel by HMFs. These results indicated TN-C induces transformation of HMFs into high-contractile myofibroblasts. In human breast cancer tissues, α-SMA and calponin-positive fibroblasts were localized in TN-C-positive cancer stroma. Interestingly, calponin-expressing fibroblasts were not observed in the skin metastatic lesions of breast cancer. In addition, the increased expression of α-SMA and calponin after TN-C treatment in HDFs were significantly lower compared to HMFs in vitro. These results suggested the responses of TN-C on fibroblasts differs according to the residential tissues. Next, we examined the receptor to TNC and signaling pathway for TNC-induced change of HMFs. TN-C increased the colocalization of integrin αv and β1 in focal adhesion. Furthermore, phosphorylation of SMAD2 and SMAD3 were significantly increased and SMAD3 translocated from cytoplasm to nucleus after TN-C addition. Inhibition of TGF-β type I receptor (SB-505124) or SMAD3 (SIS3) suppressed the expression of α-SMA and calponin after TN-C treatment. [Conclusion] TNC could contribute cancer stroma formation characteristics of breast cancer tissues, following induction of phenotypical change to myofibroblasts and enhanced stromal contraction via integrin αvβ1/TGF-β/SMAD signaling. Phenotypic differences between HMFs and HDFs after TN-C administration may be present. Citation Format: Daisuke Katoh, Aya Noro, Kyoko Imanaka-Yoshida, Tomoko Ogawa, Toshimichi Yoshida. Tenascin-C promotes the activation of mammary fibroblasts to calponin-expressing myofibroblasts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1907.
Abstract 1602: Genomic profiling of lung cancer associated with idiopathic pulmonary fibrosis
Authors: Rintaro Noro, Akihiko Miyanaga, Aya Fukuizumi, Shinobu Kunugi, Teppei Sugano, Miwako Omori, Yuji Minegish, Jitsuo Usuda, Masahiro Seike, Kaoru Kubota, Mamiko Hirao, Kuniko Matsuda, Akihiko Gemma
Journal: Cancer Research (2019)

Abstract Idiopathic pulmonary fibrosis (IPF) is reportedly associated with an increased risk of lung cancer. However, optimal diagnosis and treatment for lung cancer associated with IPF remains unclear. In this study, we aimed to clarify the mechanism of carcinogenesis and progression in lung cancer with IPF. We used tumor tissues and adjacent non-tumor lung tissues from 29 lung cancer patients who had undergone complete surgical resection at Nippon Medical School Hospital between 2013 and 2017. Whole-Exon Sequencing was performed on 29 paired samples, consisted of 19 lung cancers with IPF (IPF group) and 10 lung cancers with normal lung (non-IPF group). The candidate gene alterations discriminating between the IPF and non-IPF group, were identified using the random-forest method, RelifF method along with the data from Catalogue Of Somatic Mutations In Cancer (COSMIC). Twenty-five gene alterations were specifically found in IPF tissues and/or tumor tissues with IPF. Whenever 5 of 25 genes including MUC2 and TTF1, were altered in both IPF tissues and tumor tissues, 20 of 25 genes including CADM1, were altered in only tumor tissues. We are undergoing the validation study using other tissues in independent cohorts. Among the candidate genes, Cell adhesion molecule genes (CADM1) gene alterations were frequently found in 15 out of 19 in only tumor tissues with IPF. The CADM1 protein expression was decreased in tumors than in non-tumor fibrotic tissues by western blotting. The CADM1 induced the epithelial-mesenchymal transition (EMT) on the multifunctional cell process involved in the pathogenesis of fibrosis in vitro study. Whenever the down-regulation of CADM1 was frequently detected in various human cancers through its allelic loss as well as hypermethylation within promoter region in addition to inactivate gene mutation, the up-regulation of CADM1 was frequently detected in paired IPF tissues. The CADM1 may be a target candidate in lung cancer associated with IPF. Citation Format: Rintaro Noro, Akihiko Miyanaga, Aya Fukuizumi, Shinobu Kunugi, Teppei Sugano, Miwako Omori, Yuji Minegish, Jitsuo Usuda, Masahiro Seike, Kaoru Kubota, Mamiko Hirao, Kuniko Matsuda, Akihiko Gemma. Genomic profiling of lung cancer associated with idiopathic pulmonary fibrosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1602.
Abstract 280: Cardiac Fibroblast Specific Deletion of Gsk3α Alleviate From Cardiac Dysfunction and Fibrotic Remodeling in Ischemic Heart
Authors: Vipin K Verma, Firdos Ahmad, Qinkun Zhang, Thomas L Force, Hind Lal
Journal: Circulation Research (2016)

Heart failure is the leading cause of mortality, morbidity and healthcare expenditures worldwide. Numerous studies from our lab and others have implicated GSK-3 as a promising therapeutic target for cardiovascular diseases. Recently, we reported that cardiomyocyte-specific deletion of GSK3α limits adverse remodeling and preserves cardiac function, post-MI. However, the role of cardiac fibroblast GSK3α (CF-GSK-3α) in myocardial biology is unknown. To determine the role of CF-GSK-3α in MI-induced fibrotic remodeling, we created CF-GSK-3α KO mice in which Cre recombinase is driven by Postn (periostin) promoter. WT and CF-GSK-3α-KO mice were subjected to MI or sham surgery at 2 months age and cardiac function were monitored by serial echocardiography. Interestingly, at four weeks post-MI, CF-GSK-3α-KO mice showed preserved chamber dimensions and LV functions as reflected by preserved ejection fraction and fractional shortening as compared to littermate controls. The preserved LV dimensions and cardiac function were remained significantly better up to the end of the study i.e., 8 weeks post-MI. At 8 weeks post MI, hearts were excised, and Masson trichrome staining was performed. LV scar circumference was measured and expressed as a percentage of total area of LV myocardium. Scar tissue percent circumference was significantly reduced in CF-GSK-3α-KO hearts. Furthermore, GSK3α KO heart scars were thicker with much higher numbers of viable cardiomyocytes as compared to WT. To gain the mechanistic insights of observed GSK-3α mediated fibrotic remodeling, we examined profibrotic TGFβ signaling and myofibroblast transformation. WT and GSK-3α KO mouse embryonic fibroblasts (MEFs) were treated with TGF-β1 (10 ng/mL) for 1 hour, and phosphorylation of SMAD-3 (Ser423/25) was determined. Indeed, TGF-β1 induced activation of SMAD3 was significantly reduced in GSK3α KO cells. Consistently, deletion of GSK-3α leads to reduced myofibroblast transformation as reflected by significantly reduced expression of α-SMA in GSK-3α KO cells. These findings suggest that CF-specific deletion of GSK3α is protective in ischemic heart and GSK3α could be a novel therapeutic target for management of adverse fibrotic remodeling in the diseased heart.
Clinical characteristics and genetic analyses of 187 patients with undefined autoinflammatory diseases
Authors: Nienke M Ter Haar, Charlotte Eijkelboom, Luca Cantarini, Riccardo Papa, Paul A Brogan, Isabelle Kone-Paut, Consuelo Modesto, Michael Hofer, Nicolae Iagaru, Sárka Fingerhutová, Antonella Insalaco, Francesco Licciardi, Yosef Uziel, Marija Jelusic, Irina Nikishina, Susan Nielsen, Efimia Papadopoulou-Alataki, Alma Nunzia Olivieri, Rolando Cimaz, Gordana Susic, Valda Stanevica, Marielle van Gijn, Antonio Vitale, Nicolino Ruperto, Joost Frenkel, Marco Gattorno
Journal: Annals of the Rheumatic Diseases (2019)

To describe the clinical characteristics, treatment response and genetic findings in a large cohort of patients with undefined systemic autoinflammatory diseases (SAIDs).Clinical and genetic data from patients with undefined SAIDs were extracted from the Eurofever registry, an international web-based registry that retrospectively collects clinical information on patients with autoinflammatory diseases.This study included 187 patients. Seven patients had a chronic disease course, 180 patients had a recurrent disease course. The median age at disease onset was 4.3 years. Patients had a median of 12 episodes per year, with a median duration of 4 days. Most commonly reported symptoms were arthralgia (n=113), myalgia (n=86), abdominal pain (n=89), fatigue (n=111), malaise (n=104) and mucocutaneous manifestations (n=128). In 24 patients, relatives were affected as well. In 15 patients, genetic variants were found in autoinflammatory genes. Patients with genetic variants more often had affected relatives compared with patients without genetic variants (p=0.005). Most patients responded well to non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, colchicine and anakinra. Complete remission was rarely achieved with NSAIDs alone. Notable patterns were found in patients with distinctive symptoms. Patients with pericarditis (n=11) were older at disease onset (33.8 years) and had fewer episodes per year (3.0/year) compared with other patients. Patients with an intellectual impairment (n=8) were younger at disease onset (2.2 years) and often had relatives affected (28.6%).This study describes the clinical characteristics of a large cohort of patients with undefined SAIDs. Among these, patients with pericarditis and intellectual impairment appear to comprise distinct subsets.
Abstract 2365: Selective Stat3 inhibition in the tumor microenvironment restricts gastrointestinal tumor growth
Authors: Mariah Grace Alorro, Frederick Masson, Moritz Eissmann, Matthias Ernst
Journal: Cancer Research (2019)

Abstract The transcription factor Stat3 plays essential roles in biological processes involving development, immunity and inflammation. Stat3 is known to regulate the expression of a large repertoire of genes which when deregulated, as in the context of tumorigenesis, can lead to the development of some of the well-known hallmarks of cancer, such as resistance to cell death and sustained proliferation. Indeed the aberrant activation of Stat3 has been characterized across a number of different cancers including gastrointestinal cancers, presenting Stat3 and its signalling pathway a promising therapeutic target. Although intrinsic Stat3 signalling in tumor cells is well characterized, the effect(s) of Stat3 signalling among the infiltrating cells of the tumor microenvironment is still poorly understood. With this project we aim to elucidate the role of Stat3 in the non-tumoral compartment, and explore the therapeutic value of Stat3 inhibition for gastric and colon cancer. We generated the CAGsrtTA3;STAT3.1348 (shStat3) mouse that utilizes short-hairpin RNAi technology allowing for conditional and reversible Stat3 reduction. To study the effects of systemic Stat3 inhibition, the shStat3 was crossed with the gp130F/F mutant mouse that spontaneously develops gastric cancer. To assess the effects of Stat3 suppression in the non-tumoral compartment alone, the shStat3 mice were sub-cutaneously injected with MC38 murine colon cancer cells. Tumors and other tissues of these mice were excised and analysed. We found that shStat3-mediated systemic Stat3 suppression resulted in significant tumor reduction in the gp130F/F gastric cancer mice. Similarly, isolated Stat3 reduction in the non-tumoral compartment of the shStat3 mice, restricted the growth of Stat3-proficient MC38 tumor allografts. Immunophenotyping of excised tumors highlighted an increase of a monocytic Ly6C+Ly6G- myeloid population. Our data provides evidence for the therapeutic value of specific Stat3 targeting in gastrointestinal cancers. Interestingly, we have shown that Stat3 suppression in the non-tumoral compartment alone was enough to result in significant tumor reduction, indicating a prominent role of Stat3 in creating a pro-tumorigenic microenvironment. We have also identified a monocytic population as candidate cell type that drives this Stat3 suppression mediated anti-tumor effect. Citation Format: Mariah Grace Alorro, Frederick Masson, Moritz Eissmann, Matthias Ernst. Selective Stat3 inhibition in the tumor microenvironment restricts gastrointestinal tumor growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2365.
Abstract 3016: Dicer overexpression contributes to chemoresistance in colorectal cancer via up-regulating a set of miRNAs
Authors: Li Jyuan Lin, Liang-Yi Hung
Journal: Cancer Research (2019)

Abstract Chemotherapy has a good success rate in the treatment of colorectal cancer; however, recurrence of colorectal cancer is still frequent due to acquired resistance. Aurora-A, a cell cycle-regulated kinase, plays an important role in colorectal cancer development and drug resistance. Dicer, one of the key enzymes of the microRNA (miRNA) biogenesis pathway, may be involved in chemoresistance through regulating the expression of miRNAs. According to the TCGA database, the expression levels of Dicer and Aurora-A were increased in colorectal cancer, which may contribute to chemoresistance. Our results showed that the protein levels of Dicer and Aurora-A are increased in oxaliplatin resistant cell lines. Knocked-down expression of Dicer or Aurora-A can enhance drug sensitivity in oxaliplatin-resistant cells; in contrast, overexpression of Dicer or Aurora-A increased drug resistance in parental drug sensitive cells. By next-generation sequencing, we found that the expression of a set of miRNAs is increased in oxaliplatin resistant cells. Dicer overexpression enhances the expression of those miRNAs in drug sensitive parental cells. Clinical evaluation further confirmed the increased expression of those miRNA in the plasma of CRC patients with a poor response to oxaliplatin. Our results suggest that those miRNAs may act as biomarkers to predict oxaliplatin response in colorectal cancer by detecting their plasma miRNAs. The molecular mechanism of those miRNAs in regulating the drug response is currently under our investigation. Citation Format: Li Jyuan Lin, Liang-Yi Hung. Dicer overexpression contributes to chemoresistance in colorectal cancer via up-regulating a set of miRNAs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3016.