tbuckley/cabot-search huggingface dataset:
Effects of Sodium-Glucose Cotransporter 2 Inhibitors for the Treatment of Patients With Heart Failure
Authors: Milton Packer, Stefan D. Anker, Javed Butler, Gerasimos Filippatos, Faiez Zannad
Journal: JAMA Cardiology (2017)

Only 1 class of glucose-lowering agents-sodium-glucose cotransporter 2 (SGLT2) inhibitors-has been reported to decrease the risk of cardiovascular events primarily by reducing the risk of the development or progression of heart failure. In a landmark trial called Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes [EMPA-REG Outcomes], long-term treatment with empagliflozin prevented fatal and nonfatal heart failure events but did not reduce the risk of myocardial infarction or stroke in diabetic patients.The beneficial effect of SGLT2 inhibitors on heart failure cannot be explained by their actions on glycemic control or as osmotic diuretics. Instead, in the kidneys, SGLT2 functionally interacts with the sodium-hydrogen exchanger, which is responsible for the majority of sodium tubular reuptake following filtration. The activity of sodium-hydrogen exchanger is markedly increased in patients with heart failure and may be responsible for both resistance to diuretics and to endogenous natriuretic peptides. In addition, in the heart, empagliflozin appears to inhibit sodium-hydrogen exchange, which may in turn lead to a reduction in cardiac injury, hypertrophy, fibrosis, remodeling, and systolic dysfunction. Furthermore, the major pathophysiological derangements of heart failure and a preserved ejection fraction may be mitigated by the actions of SGLT2 inhibitors to reduce blood pressure, body weight, and fluid retention as well as to improve renal function. The benefits of spironolactone in patients with heart failure with either a reduced or a preserved ejection fraction may also be attributable to the actions of the drug to inhibit the sodium-hydrogen exchange mechanism.The benefits of SGLT2 inhibitors in heart failure may be mediated by the inhibition of sodium-hydrogen exchange rather than the effect on glucose reabsorption. This hypothesis has important implications for the design and analysis of large-scale outcomes trials involving diabetic or nondiabetic patients with chronic heart failure.
Fibroblast Growth Factor 21—Metabolic Role in Mice and Men
Authors: Harald Staiger, Michaela Keuper, Lucia Berti, Martin Hrabě de Angelis, Hans-Ulrich Häring
Journal: Endocrine Reviews (2017)

Since its identification in 2000, the interest of scientists in the hepatokine fibroblast growth factor (FGF) 21 has tremendously grown, and still remains high, due to a wealth of very robust data documenting this factor's favorable effects on glucose and lipid metabolism in mice. For more than ten years now, intense in vivo and ex vivo experimentation addressed the physiological functions of FGF21 in humans as well as its pathophysiological role and pharmacological effects in human metabolic disease. This work produced a comprehensive collection of data revealing overlaps in FGF21 expression and function but also significant differences between mice and humans that have to be considered before translation from bench to bedside can be successful. This review summarizes what is known about FGF21 in mice and humans with a special focus on this factor's role in glucose and lipid metabolism and in metabolic diseases, such as obesity and type 2 diabetes mellitus. We highlight the discrepancies between mice and humans and try to decipher their underlying reasons.
Abstract 2318: Cyclopamine sensitizes endoplasmic reticulum stress-mediated increase of death receptor 5 and survivin degradation in trail-resistant gastric cancer cells
Authors: Yoo Jin Na, Dae-Hee Lee, Jung Lim Kim, Bo Ram Kim, Seong Hye Park, Min Jee Jo, Yoon A Jeong, Sang Cheul Oh
Journal: Cancer Research (2017)

Abstract Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has been known as one of the most effective cancer treatment owing to its selective killing effect of cancer but not normal cells. However it has been reported that several gastric cancer cells showed resistance to TRAIL because of scarcity of death receptor 5 (DR5) expressed on the cell surface. In this study, we elucidated cyclopamine sensitizes to TRAIL-induced apoptosis by elevating the expression level of DR5 in gastric cancer cells. Interestingly, survivin hampers existence of DR5 protein under normal condition. Cyclopamine decreases expression level of survivin. It is a reason for cyclopamine to act as a TRAIL sensitizer. Mechanistically, cyclopamine induces endoplasmic reticulum (ER) stress by Reactive Oxygen species (ROS), and CHOP, which as a last protein of ER stress pathway regulates stability of survivin protein by proteasome degradation. Taken together, our results indicate that cyclopamine can be used for the purpose of combination therapy in TRAIL-resistant gastric cancer cells. Citation Format: Yoo Jin Na, Dae-Hee Lee, Jung Lim Kim, Bo Ram Kim, Seong Hye Park, Min Jee Jo, Yoon A Jeong, Sang Cheul Oh. Cyclopamine sensitizes endoplasmic reticulum stress-mediated increase of death receptor 5 and survivin degradation in trail-resistant gastric cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2318. doi:10.1158/1538-7445.AM2017-2318
Abstract 1699: Impact of whole blood interferon gamma production for patient selection in vaccination with autologous formalin-fixed tumor vaccine
Authors: Naoyuki Sakamoto, Takeshi Ishikawa, Tetsuya Okayama, Tomoyo Yasuda, Toshifumi Doi, Mari Tanigawa, Yuji Naito, Yoshito Itoh, Toshikazu Yoshikawa
Journal: Cancer Research (2017)

Abstract Introduction: Immune checkpoint blockade by anti-CTLA-4 antibody and anti-PD-1 antibody led to clinical breakthrough for the treatment of patients with solid tumors. Moreover, recent reports have shown that neoantigens are important functional targets mediating response to immune checkpoint inhibitors. Therefore, sequential combination of personalized cancer vaccines and immune checkpoint blockade has emerged as a potential therapeutic strategy. However, existing drawbacks is that it is difficult to identify robust biomarkers for patient selection in vaccination with cancer vaccine. In this study, we examined whether the development of delayed-type hypersensitivity (DTH) response, measured after vaccination with autologous formalin-fixed tumor vaccine (AFTV), correlates to parameters of immune function such as whole blood cytokine levels and peripheral regulatory T cells (Treg) in patients with solid tumors. Methods: Subjects comprised 52 patients with solid malignancy. AFTV treatment consisted of 3 courses of vaccination performed at intervals of 2 weeks. DTH test was performed before and after vaccination. A positive DTH response was defined as a ≥ 10mm diameter erythema/induration. We evaluated whole blood cytokine production after phytohemagglutinin (PHA) stimulation using the bioplex array system. We also assessed the number of peripheral Tregs as well as routine hematological and biochemical parameters. Results: DTH positive patients and DTH negative patients did not differ with respect to the number of peripheral Tregs, leukocytes, lymphocytes or granulocyte/lymphocyte ratio. Whole blood IFN-γ production levels after phytohemagglutinin (PHA) stimulation at baseline in DTH positive patients were significantly higher than those in DTH negative patients (p=0.0397). Conclusion: These data indicate that whole blood IFN-γ production at baseline is likely to be useful to assess immunologic competence in vaccinated patients with AFTV. Consequently, clinical utility of whole blood IFN-γ production, as immunomonitoring method for patient selection in vaccination with cancer vaccine, is required to investigate in larger clinical studies in the future. Citation Format: Naoyuki Sakamoto, Takeshi Ishikawa, Tetsuya Okayama, Tomoyo Yasuda, Toshifumi Doi, Mari Tanigawa, Yuji Naito, Yoshito Itoh, Toshikazu Yoshikawa. Impact of whole blood interferon gamma production for patient selection in vaccination with autologous formalin-fixed tumor vaccine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1699. doi:10.1158/1538-7445.AM2017-1699
Effets secondaires déclarés par les patients après une coloscopie en Norvège
Journal: Endoscopy (2017)

Bien que des recommandations européennes encouragent la déclaration d’effets secondaires et d’incidents éventuels directement par les patients au décours de la coloscopie, cela est rarement fait en pratique. Très peu de données sont publiées en dehors de rares résumés sur cette thématique.
Abstract 935: CD133+cancer stem cells promoted by VEGF accelerate the recurrence of hepatocellular carcinoma
Authors: Dexi Chen, Kai Liu, Meijun Hao, Yabo Ouyang, Jiasheng Zheng, Kishore Babu. Challagundla
Journal: Cancer Research (2017)

Abstract The function of cancer stem cells (CSCs) on inducing HCC recurrence after radiofrequency ablation (RFA) is still unclear. Here, 19 RFA-treated primary HCC patients were enrolled. We identified a dramatic increase of plasma VEGF in some patients (termed type II, n=9) after RFA, who suffered early HCC recurrence; the other patients (termed type I, n=10) had no increased plasma VEGF but had longer interval for HCC recurrence. Moreover, the expression of CSCs marker, CD133, was dramatically increased in recurrent HCC tissue of Type II in comparison with type I, suggesting induction of CD133+ CSCs may contribute to early HCC recurrence. In vitro studies demonstrated that VEGF stimulus enhanced the level of CD133+ CSCs and their self-renewal ability by inducing Nanog dependently on activation of VEGFR2. In vivo studies further demonstrated that CD133+ CSCs with VEGF stimulus formed larger tumor size in comparison with non-stimulus; and VEGF stimulus increased the tumorigenic cell frequency of primary HCC cells dependently on the presence of Nanog and VEGFR2. In recurrent HCC tissue of type II, but not type I, almost all CD133+ cells were Nanog and p-VEGFR2 positive cells, suggesting that activation VEGFR2 is critical for RFA-induced tumor stemness in HCC. Taken together, RFA-induced VEGF promotes tumor stemness and accelerates tumorigenesis in HCC dependently on Nanog and VEGFR2, which is valuable for the prediction of HCC recurrence after RFA and development of novel therapeutics. Citation Format: Dexi Chen, Kai Liu, Meijun Hao, Yabo Ouyang, Jiasheng Zheng, Kishore Babu. Challagundla. CD133+ cancer stem cells promoted by VEGF accelerate the recurrence of hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 935. doi:10.1158/1538-7445.AM2017-935
Abstract 5314: Long-term folate intake and prostate cancer risk in the health professionals follow-up study
Authors: Nadine M. Hamieh, Julie L. Batista, Sarah C. Markt, Mary K. Downer, Lorelei A. Mucci, Meir J. Stampfer, Edward L. Giovannucci, Kathryn M. Wilson
Journal: Cancer Research (2017)

Abstract Background: Randomized trials of supplemental folate and observational studies of circulating folate support a positive association with prostate cancer risk. However, epidemiological studies of dietary and synthetic folate intake are conflicting. Given mandatory folic acid fortification of grains in the US beginning in 1998, evaluation of long-term folate intake from natural and synthetic sources in relation to prostate cancer risk is warranted. Methods: We examined the association between folate intake and prostate cancer risk among 47,884 men in the Health Professionals Follow-up Study who were free from diagnosed cancer at baseline in 1986. Total, natural (from food sources), and synthetic (from supplements/fortification) folate intake was assessed every 4 years using a validated food frequency questionnaire, and categorized as the cumulative average and lagged (0-4, 4-8, 8-12, and 12-16 years in the past) intakes. Cox proportional hazards regression was used to calculate multivariable hazard ratios (HRs) and 95% confidence intervals (CI). Results: We identified 6,186 incident prostate cancer cases from 1986-2012, including 1,078 with lethal disease (distant metastasis or death). Mean total folate intake was 481 µg/day in 1986 and increased to 671 µg/day by 2010. The proportion of men meeting the recommended intake of 400 µg/day increased from 47% in 1986 to 74% after fortification began in 1998. Folate intake was positively correlated with physical activity, multivitamin use, and PSA testing, and inversely correlated with smoking. Total folate intake averaged over time was not significantly associated with total prostate cancer risk: HR≥800 vs. 400-599=1.03 (95% CI: 0.95-1.13, p-trend=0.76). Neither natural nor synthetic folate intake was associated with risk of total prostate cancer. No associations were observed between total, natural, or synthetic folate intake and risk of lethal, advanced stage, or high-grade disease. Conclusions: Our findings do not support strong associations between intakes of total, natural, or synthetic folate and prostate cancer risk. We found no indication that folate intake of ≥800 µg/day (twice the recommended level) increases prostate cancer risk. Citation Format: Nadine M. Hamieh, Julie L. Batista, Sarah C. Markt, Mary K. Downer, Lorelei A. Mucci, Meir J. Stampfer, Edward L. Giovannucci, Kathryn M. Wilson. Long-term folate intake and prostate cancer risk in the health professionals follow-up study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5314. doi:10.1158/1538-7445.AM2017-5314
Abstract 1212: Co-targeting epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase overcomes EGFR inhibitor resistance in head and neck squamous cell carcinoma patient-derived models
Authors: Xiaoming Ouyang, Ashley Barling, Aletha Lesch, Jeffrey Tyner, Sophia Jeng, Christina Zheng, Sara A. Courtneidge, Shannon McWeeney, Molly Kulesz-Martin
Journal: Cancer Research (2017)

Abstract Background: HNSCC is the sixth most common cancer worldwide. EGFR is overexpressed in up to 90% of HNSCC and associated with poor outcome. An EGFR monoclonal antibody is the only approved molecular targeted therapy for HNSCC, however, resistance eventually occurs in all patients. Methods: Functional screens including a small-molecule kinase inhibitor panel and an RNAi screen panel were used to identify agents that synergized with EGFR inhibitors in reducing cell viability in HNSCC patient-derived tumor cells. Effective combination therapies were validated in scale-up experiments in 2D and 3D, and their true targets were evaluated using siRNAs to rule out off-target effects of the drugs. Cell viability, cell number and cell colony formation ability were tested upon siRNA treatment. qRT-PCR and immunofluorescent staining was used to test ALK expression in tumor cells before and after anti-EGFR treatment. Results: Two ALK inhibitors on the drug screen panel showed synergistic effects with EGFR inhibitors in 6/8 HNSCC patients’ tumor cells, despite ineffectiveness of single drug. Scale-up dose-response experiments confirmed patient cell sensitivity to 4 different ALK inhibitors in combination with the EGFR inhibitor Gefitinib. siRNA targeting ALK synergized with Gefitinib in reducing cell viability in the patient cells that responded to EGFR/ALK inhibitor combinations, indicating specificity to ALK. Scale-up RNAi experiments confirmed synergy between siRNAs targeting ALK and EGFR in reducing cell viability, cell number, and colony formation ability. Inhibition of EGFR by siRNA or Gefitinib each increased ALK expression at the mRNA level and protein level, suggesting induction of ALK as a novel mechanism of EGFR inhibitor resistance in HNSCC. Conclusion: We identified EGFR/ALK inhibitor combinations as a potential strategy for treating EGFR inhibitor resistant HNSCC. Citation Format: Xiaoming Ouyang, Ashley Barling, Aletha Lesch, Jeffrey Tyner, Sophia Jeng, Christina Zheng, Sara A. Courtneidge, Shannon McWeeney, Molly Kulesz-Martin. Co-targeting epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase overcomes EGFR inhibitor resistance in head and neck squamous cell carcinoma patient-derived models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1212. doi:10.1158/1538-7445.AM2017-1212
Abstract 5172: E7386, an orally active CBP/beta-catenin modulator, induces T cells infiltration into tumor and enhances antitumor activity of anti-PD-1 mAb in Wnt1 tumor syngeneic mice model
Authors: Yusaku Hori, Kazuhiko Yamada, Yu Kato, Yoichi Ozawa, Takenao Odagami, Junji Matsui, Tomohiro Matsushima, Kenichi Nomoto, Hiroyuki Kouji, Takashi Owa
Journal: Cancer Research (2017)

Abstract Recently, immunotherapeutic approaches have come to forefront in melanoma, non-small cell lung cancer, bladder cancer, and so on. However, sufficient benefits from these treatments have been limited. T cell infiltrating into tumor tissues is reported as one of the response biomarker candidates for the immune checkpoint inhibitors. Recent studies have shown that the activation of the Wnt/beta-catenin signaling pathway results in T cell exclusion and resistance to immune checkpoint inhibitor in melanoma patients. We established the Wnt1 tumor syngeneic mice model (Wnt1 model) by implantation of mammary adenocarcinomas isolated from MMTV-Wnt1 transgenic mice. Here we demonstrate whether E7386, a first-in-class orally active CBP/beta-catenin modulator, affects the recruitment of T cells into tumor tissues, leading to the enhancement of anti-PD-1 mAb in Wnt/beta-catenin signaling pathway activating tumor model. The mice were treated with E7386 (50 mg/kg, orally, BID) and/or anti-mouse PD-1 mAb (10 mg/kg, intraperitoneal, twice a week) for three weeks. Tumor diameters are measured with digital calipers, and the tumor volume in mm3 is calculated. Immunohistochemical (IHC) analysis was evaluated for tumor-infiltrating T cells. E7386 showed significant antitumor activity in Wnt1 model, but anti-PD-1 mAb did not. In contrast, E7386 with anti-PD-1 mAb indicated prominent antitumor activity compared to each single treatment. Enhancement of body weight loss in combination group was not observed. In IHC analysis, infiltration of T cells was limited in vehicle control group, in contrast T cell infiltration into tumors was clearly observed in both E7386 treatment group and combination group. As a result, antitumor activity of immune checkpoint inhibitor was limited in Wnt-driven tumor model and E7386 as a novel CBP/beta-catenin modulator enhanced the antitumor activity of anti-PD-1 mAb via induction of tumor-infiltrating T cells. Citation Format: Yusaku Hori, Kazuhiko Yamada, Yu Kato, Yoichi Ozawa, Takenao Odagami, Junji Matsui, Tomohiro Matsushima, Kenichi Nomoto, Hiroyuki Kouji, Takashi Owa. E7386, an orally active CBP/beta-catenin modulator, induces T cells infiltration into tumor and enhances antitumor activity of anti-PD-1 mAb in Wnt1 tumor syngeneic mice model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5172. doi:10.1158/1538-7445.AM2017-5172
Abstract 2435: Smoothened a new perspective for uterine leiomyoma treatment
Authors: Natalia Garcia, Laura Gonzalez Anjos, Giovana De Nardo Maffazioli, Nilo Bozzini, Edmund Chada Baracat, Katia Candido Carvalho
Journal: Cancer Research (2017)

Abstract Background: Uterine leiomyomas (LM) are the most common gynecologic tumors occurring in women of reproductive age. Patients may present clinical complications such as bleeding, pain and infertility. Additionally, some researchers believe that a leiomyosarcoma can arise from a degenerated LM. Efficient treatments for LM are still limited. Identification of gene markers can help to elucidate these tumors pathogenesis and to reveal molecules that can be used as therapeutic targets. Objective: To assess gene and miRNAs expression, and DNA methylation profiles of genes related to the Sonic Hedgehog (SHH) signaling pathway in uterine leiomyoma samples in order to look for potential therapeutic targets. Methods: 80 samples of LM and 20 myometrium (MM) were obtained in the Department of Obstetrics and Gynecology at HCFMUSP/Sao Paulo - Brazil. Expression profile of 106 genes and 84 miRNAs sequences related to SHH regulation, and the percentage of methylation in the promoter region of the SHH, PTCH1, SMO, SUFU, GLI and GLI3 genes were performed by quantitative Real Time PCR. Results: Among 106 genes evaluated, 16 showed hyper- and 11 showed hypoexpression in LM samples, compared to MM. Only SMOOTHENED (SMO) was found hyperegulated in LM. miRNAs analysis showed 16 sequences with different regulation profiles between LM and MM. None of them is involved in the regulation of SMO expression. DNA methylation profile showed a higher percentage of methylation in LM samples, but this difference did not exceed 2% of methylation for the PTCH1, SMO, GLI1 and GLI3 genes. Conclusion: Our results suggest an activation of SHH pathway in LMs by hyperexpression of SMO. These results are very interesting because there are SMO specific drugs approved by FDA for other tumors types. Citation Format: Natalia Garcia, Laura Gonzalez Anjos, Giovana De Nardo Maffazioli, Nilo Bozzini, Edmund Chada Baracat, Katia Candido Carvalho. Smoothened a new perspective for uterine leiomyoma treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2435. doi:10.1158/1538-7445.AM2017-2435