tbuckley/cabot-search huggingface dataset:
Abstract 1164: Semaphorin 3C promotes de novo steroidogenesis in androgen-deprived prostate cancer cells
Authors: Parvin Yenki, Hans Adomat, Chi Wing Cheng, Christopher Ong
Journal: Cancer Research (2016)

Abstract Introduction: This project aims to study the biological role of Semaphorin 3C (SEMA3C) in castration resistant prostate cancer (CRPC) progression. We have found that SEMA3C is a key driver of prostate cancer (PCa) growth through activation of epidermal growth factor receptor (EGFR) and cMet receptor tyrosine kinase (RTK) pathways. RTK signalling activation has been shown to induce de novo steroidogenesis, therefore we hypothesize that SEMA3C-mediated RTK signalling may contribute to CRPC progression through promotion of androgen biosynthesis in androgen-deprived PCa cells. Methods: LNCaP and 22Rv1 cells stably overexpressing SEMA3C were compared to mock transfected cells with respect to their in vitro steroidogenesis, secreted hormone levels were measured by Liquid chromatography-mass spectrometry (LC-MS) technique. Also the expression of steroidogenic enzymes and regulatory proteins were tested by quantitative PCR and western blotting. De novo steroidogenesis was detected by pulsing cells with C14-labeled acetate as a steroid precursor; production of intermediates was measured by scintillation. Results: Steroid analysis showed that SEMA3C overexpression can significantly elevate testosterone and dihydrotestosterone secretion by prostate cancer cells. SEMA3C is also able to upregulate STAR, CYP17A1, HSD17β3, AKR1C3 and SRD5A1 expression. Steroid analysis of SEMA3C-overexpressing LNCaP cells incubated with C14-labeled acetate resulted in the increase of the radioisotope-labeled testosterone and pregnenolone. Conclusions: These findings indicate that SEMA3C can promote steroid biosynthesis in androgen deprived prostate cancer cells, thereby SEMA3C signaling pathway can contribute to maintain active AR signaling in CRPC cells. This research line will be followed to measure intratumoral androgen level by inducing subcutaneously xenografted tumors in athymic nude mice. Tumor homogenates’ steroids will then be extracted and run on LC-MS system. Citation Format: Parvin Yenki, Hans Adomat, Chi Wing Cheng, Christopher Ong. Semaphorin 3C promotes de novo steroidogenesis in androgen-deprived prostate cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1164.
A phase I dose-escalating and safety study of AZD8931 in combination with oxaliplatin and capecitabine chemotherapy in patients with oesophago-gastric adenocarcinoma.
Authors: Anne L. Thomas, Martin McKinlay Eatock, Nick Coupe, Naomi McGregor, Sharon Love, Cristian Ciria, Linda Collins, Cathy McDowell, Mark R. Middleton
Journal: Journal of Clinical Oncology (2015)

4037 Background: AZD8931 is a novel small-molecule inhibitor which has equipotent activity against signalling by three members of the erbB family; EGFR, erbB2(HER2), and erbB3. Our hypothesis is that combining AZD8931 with chemotherapy will be effective not just in oesophago-gastric cancer patients (pt) who overexpress high levels of HER2, but those with low HER2 expression as well. This study seeks to establish the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of AZD8931 with oxaliplatin and capecitabine (XELOX) in patients with oesophagogastric cancer (OGC). Methods: Chemonaive patients with metastatic OGC were recruited into this rolling 6 dose escalating study to determine MTD, safety (NCI-CTC version 4.0) and pharmacokinetics of the combination. Patients received oxaliplatin (130 mg/m2day(d) 1 every 21 days (q21) and capecitabine (X) (1250mg/m2/d) d1-21, for a maximum of 8 cycles. AZD8931 dosing was planned at 3 cohorts (20mg bd, 40 mg bd, 60 mg bd continuously). With emerging toxicity at 20mg bd, AZD8931 was also investigated at 2 intermittent schedules (14d on and 7d off, 4d on and 3d off, from d1, q21). Results: 24 pts (median age 60 years) were enrolled in 4 cohorts and 4 DLTs within cycle 1 were observed: diarrhoea, vomiting and skin rash (Table 1). 58% (14/24) patients showed SAE grade ≥ 3 (mostly GI disorders and infections). 95% (18/19) patients had at least stabilisation of disease as best tumour response from cycle 3 (8 stable disease, 9 partial and 1 complete response). PK data, full demographic data including HER2 status and justification of RP2D dose will be presented. Conclusions: In this pt group the RP2D of AZD8931 in combination with XELOX is 20mg bd 4d on and 3d off q21. We are now recruiting pts with operable disease into the randomised phase of the study with XELOX versus XELOX and AZD8931. Translational studies are ongoing. Clinical trial information: 2011-003169-13.Dosing cohorts and DLTs. Dose of AZD8931 bd No of Pts enrolled (evaluable for dose escalation) DLTs 20 mg continuous 6 (6) 1 G2 diarrhea* 20 mg 14d on and 7d off q21 7 (6) 1 G3 diarrhea* 20 mg 4d on and 3d off q21 7 (6) 0 40 mg 4d on and 3d off q21 4 (4) 1 G3 vomiting & 1 G3 skin rash *Requiring stoppage of X
A miR-155–Peli1–c-Rel pathway controls the generation and function of T follicular helper cells
Authors: Wen-Hsien Liu, Seung Goo Kang, Zhe Huang, Cheng-Jang Wu, Hyun Yong Jin, Christian J. Maine, Yi Liu, Jovan Shepherd, Mohsen Sabouri-Ghomi, Alicia Gonzalez-Martin, Shunbin Xu, Alexander Hoffmann, Ye Zheng, Li-Fan Lu, Nengming Xiao, Guo Fu, Changchun Xiao
Journal: The Journal of Experimental Medicine (2016)

MicroRNA (miRNA) deficiency impairs the generation of T follicular helper (Tfh) cells, but the contribution of individual miRNAs to this phenotype remains poorly understood. In this study, we performed deep sequencing analysis of miRNAs expressed in Tfh cells and identified a five-miRNA signature. Analyses of mutant mice deficient of these miRNAs revealed that miR-22 and miR-183/96/182 are dispensable, but miR-155 is essential for the generation and function of Tfh cells. miR-155 deficiency led to decreased proliferation specifically at the late stage of Tfh cell differentiation and reduced CD40 ligand (CD40L) expression on antigen-specific CD4(+) T cells. Mechanistically, miR-155 repressed the expression of Peli1, a ubiquitin ligase that promotes the degradation of the NF-κB family transcription factor c-Rel, which controls cellular proliferation and CD40L expression. Therefore, our study identifies a novel miR-155-Peli1-c-Rel pathway that specifically regulates Tfh cell generation and function.
Abstract 4386: CETSA as a new strategy to understand efficacy, adverse effects and resistance development of anticancer drugs
Authors: Pär Nordlund, Sara Lööf, Henritte Laursen, Anette Öberg, Johan Lengqvist, Rozbeh Jafari, Lingyun Dai, Ka DIam Go, Nayana Prabhu, Radoslaw Sobota, Andreas Larsson, Anna Jansson, Chris Heng Tan Soon, Lekshmy Sreekumar, Yan Ting Lim, Daniel Martines Molina
Journal: Cancer Research (2016)

Abstract A key step of the action of most drugs is their binding (engagement) of the target protein(s). However, limitations in the available methods for directly accessing this critical step have added uncertainties in many stages of drug development. We have developed a generic method for evaluating drug binding to target proteins in cells and tissues (Martinez Molina et al. Science, 341:84). The technique is based on the physical phenomenon of ligand-induced thermal stabilization of target proteins; the method is therefore called the cellular thermal shift assay (CETSA). The technique allows for the first time to directly measure the biophysical interactions between a drug and protein target in non- engineered cells and tissues. We show that using CETSA a range of critical factors for drug development can be addressed at the target engagement level, including drug transport and activation, off-target effects, drug resistance as well as drug distribution in cells, patient and animal tissues. Using quantitative mass-spectrometry, proteome-wide CETSA has been established which allows for off-target effects as well as downstream biochemistry to be discovered (Savitsk et al. Science, 346, 6205:1255784). Together the data supports that CETSA is likely to become a valuable tool for developing and understanding the action of cancer drugs in the future. Citation Format: Pär Nordlund, Sara Lööf, Henritte Laursen, Anette Öberg, Johan Lengqvist, Rozbeh Jafari, Lingyun Dai, Ka DIam Go, Nayana Prabhu, Radoslaw Sobota, Andreas Larsson, Anna Jansson, Chris Heng Tan Soon, Lekshmy Sreekumar, Yan Ting Lim, Daniel Martines Molina. CETSA as a new strategy to understand efficacy, adverse effects and resistance development of anticancer drugs. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4386.
Improving Birth Outcomes Key to Improving Global Health
Authors: Catherine Y. Spong
Journal: JAMA (2016)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Voriconazole and Liposomal Amphotericin B (Ambisome) Effectively Prevent Mold Infections in Patients (pts) with Acute Myelogenous Leukemia (AML) Following Remission Induction Chemotherapy (RIC).
Authors: Gloria N. Mattiuzzi, Elihu H. Estey, Mike Hernandez, Maria E. Cabanillas, Francis Giles, Jorge E. Cortes, Susan O’Brien, Srdan Verstovsek, Hagop M. Kantarjian
Journal: Blood (2005)
Metabolic Effects of Monounsaturated Fatty Acid–Enriched Diets Compared With Carbohydrate or Polyunsaturated Fatty Acid–Enriched Diets in Patients With Type 2 Diabetes: A Systematic Review and Meta-analysis of Randomized Controlled Trials
Authors: Frank Qian, Andres Ardisson Korat, Vasanti Malik, Frank B. Hu
Journal: Diabetes Care (2016)

OBJECTIVE Dietary interventions in patients with type 2 diabetes (T2D) are important for preventing long-term complications. Although a healthy diet is crucial, there is still uncertainty about the optimal macronutrient composition. We performed a meta-analysis comparing diets high in cis-monounsaturated fatty acids (MUFA) to diets high in carbohydrates (CHO) or in polyunsaturated fatty acids (PUFA) on metabolic risk factors in patients with T2D. RESEARCH DESIGN AND METHODS We systematically reviewed PubMed, MEDLINE, and Cochrane databases and prior systematic reviews and meta-analyses to identify interventions assessing HbA1c, fasting plasma glucose and insulin, LDL and HDL cholesterol, triglycerides, body weight, or systolic/diastolic blood pressure. Meta-analyses were conducted using both fixed- and random-effects models to calculate the weighted mean difference (WMD) and 95% CI. RESULTS We identified 24 studies totaling 1,460 participants comparing high-MUFA to high-CHO diets and 4 studies totaling 44 participants comparing high-MUFA to high-PUFA diets. When comparing high-MUFA to high-CHO diets, there were significant reductions in fasting plasma glucose (WMD −0.57 mmol/L [95% CI −0.76, −0.39]), triglycerides (−0.31 mmol/L [−0.44, −0.18]), body weight (−1.56 kg [−2.89, −0.23]), and systolic blood pressure (−2.31 mmHg [−4.13, −0.49]) along with significant increases in HDL cholesterol (0.06 mmol/L [0.02, 0.10]). When high-MUFA diets were compared with high-PUFA diets, there was a significant reduction in fasting plasma glucose (−0.87 mmol/L [−1.67, −0.07]). All of the outcomes had low to medium levels of heterogeneity, ranging from 0.0 to 69.5% for diastolic blood pressure (Phet = 0.011). CONCLUSIONS Our meta-analysis provides evidence that consuming diets high in MUFA can improve metabolic risk factors among patients with T2D.
Dual blockade of hepatitis C virus entry at a gatekeeper of hepatocytes: Not only a preventive, but also therapeutic target of claudin 1
Authors: Masaya Sugiyama, Tatsuya Kanto
Journal: Hepatology (2016)

1Genome Medical Science Project, The Research Center for Hepatitis and ImmunologyNational Center for Global Health and MedicineIchikawaJapan 2Department of Liver Diseases, The Research Center for Hepatitis and ImmunologyNational Center for Global Health and MedicineIchikawaJapan
Factors influencing the quality of sunscreen application in a pilot comparative study
Authors: D. Antonov, G. Marx, P. Elsner
Journal: British Journal of Dermatology (2016)

Occupational UV exposure represents a considerable part of the cumulative lifelong UV exposure in many outdoor professions 1, and squamous cell carcinoma of the skin has recently been recognized as an occupational disease in Germany 2. Prevention is thus required by law. Sunscreens are popular methods of sun protection. This explorative pilot study aimed to compare the quality of sunscreen application in an occupational and a leisure setting and the factors which may influence it.

This article is protected by copyright. All rights reserved.
In insulin-treated type 1 diabetes, canagliflozin increased diabetic ketoacidosis
Authors: Jad G. Sfeir, Victor M. Montori
Journal: Annals of Internal Medicine (2016)

Source Citation Peters AL, Henry RR, Thakkar P, Tong C, Alba M. Diabetic ketoacidosis with canagliflozin, a sodium-glucose cotransporter 2 inhibitor, in patients with type 1 diabetes. Diabetes Care. 2016;39:532-8. 26989182
Abstract 3233: Macrophages orchestrate early dissemination of HER2+ cancer cells
Authors: Nina Linde, Arthur Mortha, Nicole Saenger, Maria Soledad Sosa, Kathryn Harper, Ethan Tardio, Tanja Fehm, Thomas Karn, Miriam Merad, Julio A. Aguirre-Ghiso
Journal: Cancer Research (2016)

Abstract Metastatic dissemination was proposed to occur only in invasive cancer. However, detection of cancer cells in the bone marrow of patients with pre-invasive breast ductal carcinoma in situ (DCIS) showed that dissemination could, through unknown mechanisms, take place earlier. Late evolved invasive breast cancer cells disseminated by recruiting circulating monocyte-derived tumor associated macrophages (TAMs). We therefore investigated whether macrophages might actively participate in early dissemination. We show that pre-malignant cancer cells in MMTV-HER2 mice produced CCL2 in an NFkB dependent manner and thereby recruited resident mammary tissue macrophages into the duct, months before monocyte-derived TAMs arrived. Intra-epithelial mammary tissue macrophages induced an epithelial-to-mesenchymal transition in early HER2+ cells in a Wnt-dependent manner and thereby drove early dissemination. Consequently, depletion of macrophages from pre-malignant MMTV-HER2 mice significantly reduced early dissemination of pre-malignant cancer cells as measured by reduction in levels of circulating cancer cells and disseminated cancer cells in lungs. Interestingly, macrophage depletion during pre-malignant stages alone was sufficient to reduce the onset of late metastasis in MMTV-HER2 mice, indicating that early disseminating cancer cells contributed to late metastasis formation. In humans DCIS samples we frequently found intra-epithelial macrophages inside of ducts and their presence correlated with reduced E-Cadherin levels. Finally, a first pilot study indicated that those patients whose DCIS lesions contained macrophage +/E-Cadherin low microenvironments frequently had DCCs in the bone marrow. Taken together, we reveal that resident mammary tissue macrophages can promote early dissemination, and unravel a mechanism how early cancer spread might proceed in breast cancer patients and in other cancers where metastasis are diagnosed and the primary tumor is never detected (cancer of unknown primary). We also propose that early DCCs play a long-term causal role in metastasis development when patients are diagnosed in late stages, implying that the heterogeneity of metastases is higher than we might anticipate. Citation Format: Nina Linde, Arthur Mortha, Nicole Saenger, Maria Soledad Sosa, Kathryn Harper, Ethan Tardio, Tanja Fehm, Thomas Karn, Miriam Merad, Julio A. Aguirre-Ghiso. Macrophages orchestrate early dissemination of HER2+ cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3233.
Abstract 73: Exploring arrayed synthetic CRISPR for functional genomic screening
Authors: Jenille M. Tan, Scott E. Martin
Journal: Cancer Research (2016)

Abstract Over the past decade, RNAi has been the workhorse for loss-of-function genomic screening. Although powerful, RNAi is hampered by a high rate of false positives driven by off-target effects. New screening technologies based on the CRISPR/Cas9 system are being rapidly adopted, and appear to be significantly less prone to off-target effects. CRISPR/Cas9 screens are conducted in pooled formats for positive and negative selection. However, this format is not amenable to many assay types (e.g., protein translocation assays). In an effort to expand and achieve a more comprehensive approach to functional genomics, we explored the use of arrayed CRISPR/Cas9 screening with synthetic CRISPR RNAs. Testing was performed by reverse transfecting synthetic CRISPR reagents into HCT 116 cells stably expressing Cas9, thereby making the workflow analogous to high-throughput siRNA screening. We first explored and optimized the system with reagents targeting genes associated with DNA replication, including geminin (GMNN). Loss of GMNN is known to result in enlarged nuclei due to aberrant DNA replication, which is easily observed and quantitated by automated microscopy. Analysis of individual cells by microscopy also enables the identification of effects that are only observed in a fraction of the population. After optimizing transfection and assay conditions, we observed CRISPR-induced phenotypes similar to siRNA knockdown. Surprisingly, these effects were observed within 72 hours and affected the vast majority of cells. These effects were even more pronounced in some clonal populations of HCT 116 Cas9. Loss of GMNN was confirmed by immunofluorescence, western blot, and enzyme mismatch cleavage assay. We then expanded this approach to other genes with similar success. By testing and validating the utility of synthetic CRISPR on cells already harboring Cas9, we show that arrayed synthetic CRISPR screening can be a valuable new tool for hit validation and screening. Citation Format: Jenille M. Tan, Scott E. Martin. Exploring arrayed synthetic CRISPR for functional genomic screening. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 73.
Should exercise therapy for chronic musculoskeletal conditions focus on the anti-inflammatory effects of exercise?
Authors: J Runhaar, S M A Bierma-Zeinstra
Journal: British Journal of Sports Medicine (2016)

Over the past decades, the role of low-grade systemic inflammation has been acknowledged in several chronic musculoskeletal conditions.1 For many of these musculoskeletal conditions, exercise therapy is one of the most effective non-surgical and non-pharmacological treatments and the recommended treatment of first choice.1 ,2 Most guidelines do not provide specific guidance on the content of the exercise therapy, since different modalities of exercise therapy show comparable effectiveness. This highlights the lack of knowledge on the possible mechanisms of action of exercise therapy for musculoskeletal conditions and this black box phenomenon makes optimising the positive effects of physical exercise interventions difficult. We therefore possibly do not provide these patients an optimal treatment for their symptoms when prescribing a physical exercise intervention.

The comparable effectiveness for different modalities of exercise therapy also suggests that systemic effects might be more important than local effects. One such systemic effect might be systemic inflammation. Individuals who are more physically active show lower …
Abstract 1157: Single nucleotide polymorphisms in ARHGAP17 are associated with pancreatic intraepithelial neoplasia in 2401 autopsied elderly patients
Authors: Yoko Matsuda, Masashi Tanaka, Atsuko Seki, Keisuke Nonaka, Makoto Nishimura, Toshiyuki Ishiwata, Hisashi Yoshimura, Kaiyo Takubo, Tomio Arai
Journal: Cancer Research (2016)

Abstract Background: Aging, obesity, smoking, alcohol consumption, diabetes, and pancreatitis have been reported to be the risk factors for pancreatic cancer. There is much evidence showing that single nucleotide polymorphisms (SNPs), especially those in BCAR1, PDX1, ZNRF3, or TERT, influence one's predisposition to pancreatic cancers and survival. However, the association between SNP and pancreatic precancerous lesions is not yet clarified. In the present study, we clarified the clinicopathological features of precancerous lesions of the pancreas by examining autopsied elderly cases. Methods: We analyzed serial autopsy cases (men, 1326; women, 1075; mean age, 80.6) of pancreatic intraepithelial neoplasia (PanIN) and performed a comparative analysis based on the sex, age, and body mass index (BMI) of the patients. The SNPs were analyzed using HumanExome BeadChip. Results: The occurrence of PanIN increased with advanced age. Approximately, 60% of the elderly patients showed low-grade PanIN. The autopsy cases showed that the occurrence of low-grade PanIN was positively correlated with the female sex, advanced age, and increase in BMI. The SNPs of the ARHGAP17 gene, p.G782D (rs28365822) and rs1106576, were risk factors for PanIN (Table, P&amp;lt;0.0001, *adjusted with age and gender). Discussion: A high incidence of low-grade PanIN in the elderly might be related to the increased risk of pancreatic cancer in the elderly. Further studies are needed to clarify the role of SNPs of ARHGAP17 in the carcinogenesis of pancreatic cancer. Association between SNPs in ARHGAP17 and pancreatic intraepithelial neoplasiasGenotypePanIN (-)PanIN (+)P valueunadjustedadjusted*rs28365822(%)Chi squareDominant-FisherLogistic regressionOdds ratio(95% confidence interval)CC1028(99.1)1192(96.7)&amp;lt;0.00010.000040.00023.934.05TC9(0.9)41(3.3)(1.90-8.12)(1.94-8.47)TT0(0)0(0)GenotypePanIN (-)PanIN (+)P valueunadjustedadjusted*rs1106576(%)Chi squareDominant-FisherLogistic regressionOdds ratio(95% confidence interval)TT1027(99.1)1192(96.7)&amp;lt;0.00010.000040.00023.934.05TC9(0.9)41(3.3)(1.90-8.12)(1.94-8.47)CC0(0)0(0) Citation Format: Yoko Matsuda, Masashi Tanaka, Atsuko Seki, Keisuke Nonaka, Makoto Nishimura, Toshiyuki Ishiwata, Hisashi Yoshimura, Kaiyo Takubo, Tomio Arai. Single nucleotide polymorphisms in ARHGAP17 are associated with pancreatic intraepithelial neoplasia in 2401 autopsied elderly patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1157.