tbuckley/cabot-search huggingface dataset:
Abstract 259: A Microrna Pathway That Promotes Cardiomyocyte Proliferation And Cardiac Regeneration By Inhibiting Hippo Signaling
Authors: Ying Tian, Li Chen, Tao Wang, Ning Zhou, Jun Kong, Ying Liu, Melinda Snitow, Michael Morley, Deqiang Li, Nataliya Petrenko, Minmin Lu, Kathleen Stewart, Edward Morrisey
Journal: Circulation Research (2014)

In contrast to lower vertebrates, the mammalian heart has limited capacity to regenerate after injury in part due to ineffective reactivation of cardiomyocyte proliferation. While evidence exists for a low level of cardiomyocyte proliferation in the adult heart, it remains unclear whether increasing the rate could be used to therapeutically promote cardiac regeneration. In this study, we show that the microRNA cluster miR302-367 is important for cardiomyocyte proliferation during development and is sufficient to induce cardiomyocyte proliferation in the adult and promote cardiac regeneration. Loss of miR302-367 leads to decreased cardiomyocyte proliferation during development. In contrast, increased miR302-367 expression leads to a profound increase in cardiomyocyte proliferation, in part through repression of the Hippo signal transduction pathway. Postnatal re-expression of miR302-367 leads to reactivation of the cell cycle in cardiomyocytes resulting in reduced scar formation after infarction. However, long-term expression of miR302-367 leads to cardiomyocyte de-differentiation and dysfunction, suggesting that persistent reactivation of the cell cycle in postnatal cardiomyocytes is not desirable. Importantly, this limitation can be overcome by transient systemic application of miR302-367 mimics, leading to increased cardiomyocyte proliferation and mass, decreased fibrosis, and improved function after injury. Our data demonstrate the ability of microRNA based therapeutic approaches to promote cardiac repair and regeneration through the transient activation of cardiomyocyte proliferation.
The management of dry eye
Authors: Drug and Therapeutics Bulletin
Journal: BMJ (2016)

Dry eye disease (also called keratoconjunctivitis sicca) is a common condition, with a prevalence ranging from 8 to 34%, depending on the criteria used.1 It becomes more common with increasing age and affects more women than men. Artificial tears and ocular lubricants are considered the mainstay of treatment, and there is a very wide range of these products available. In England in 2014, over 6.4 million prescription items for artificial tears, ocular lubricants, and astringents were dispensed in the community at a cost to the NHS of over £27 million.2 In this article we review the management of dry eye disease, focusing on artificial tears and ocular lubricants.

The tear film, which covers the cornea and exposed conjunctiva, is composed of three layers: a mucin layer that sits on the epithelial surface; a middle aqueous layer; and an outer lipid layer that plays a role in preventing tear evapouration.3 Dry eye has been defined as a multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface. It is accompanied by increased osmolarity of the tear film and inflammation of the ocular surface.4

There are two main types of dry eye: aqueous insufficiency (due to reduced aqueous secretion from lacrimal glands) and evapourative (due to a deficient lipid layer).

Aqueous insufficiency is divided into two main groups: Sjogren's syndrome-related dry eye and non-Sjogren's syndrome-related dry eye (which includes the use of systemic medication). Dry eye in Sjogren's syndrome (an autoimmune disease) is often severe and requires more aggressive treatment.5

Evapourative dry eye is most commonly a result of meibomian gland dysfunction.4 External causes include allergy, topical medication use (including preservative content), and contact lens wear.

Risk factors associated …
A new composite measure of colonoscopy: the Performance Indicator of Colonic Intubation (PICI)
Authors: Roland Valori, Sarah Damery, Daniel Gavin, John Anderson, Mark Donnelly, J. Williams, Edwin Swarbrick
Journal: Endoscopy (2017)

Cecal intubation rate (CIR) is an established performance indicator of colonoscopy. In some patients, cecal intubation with acceptable tolerance is only achieved with additional sedation. This study proposes a composite Performance Indicator of Colonic Intubation (PICI), which combines CIR, comfort, and sedation. METHODS : Data from 20 085 colonoscopies reported in the 2011 UK national audit were analyzed. PICI was defined as the percentage of procedures achieving cecal intubation with median dose (2 mg) of midazolam or less, and nurse-assessed comfort score of 1 - 3/5. Multivariate logistic regression analysis evaluated possible associations between PICI and patient, unit, colonoscopist, and diagnostic factors. RESULTS : PICI was achieved in 54.1 % of procedures. PICI identified factors affecting performance more frequently than single measures such as CIR and polyp detection, or CIR + comfort alone. Older age, male sex, adequate bowel preparation, and a positive fecal occult blood test as indication were associated with a higher PICI. Unit accreditation, the presence of magnetic imagers in the unit, greater annual volume, fewer years' experience, and higher training/trainer status were associated with higher PICI rates. Procedures in which PICI was achieved were associated with significantly higher polyp detection rates than when PICI was not achieved. CONCLUSIONS : PICI provides a simpler picture of performance of colonoscopic intubation than separate measures of CIR, comfort, and sedation. It is associated with more factors that are amenable to change that might improve performance and with higher likelihood of polyp detection. It is proposed that PICI becomes the key performance indicator for intubation of the colon in colonoscopy quality improvement initiatives.
Abstract 2897: Oncogenic Kras activation in gastric adenocarcinoma promotes cancer stem cell phenotypes including metastasis & chemotherapy resistance
Authors: Changhwan Yoon, Kevin K. Chang, Jacob Till, Sandra W. Ryeom, Sam S. Yoon
Journal: Cancer Research (2017)

Abstract INTRODUCTION: The Cancer Genome Atlas found that the receptor tyrosine kinase (RTK)-Ras signaling pathway is altered in half of gastric adenocarcinomas (GAs). We added oncogenic Kras to the Atp4b-Cre;Cdh1fl/fl;Trp53fl/fl mouse model of GA and found accelerated tumorigenesis and metastasis. We also found Kras activity to be higher in gastric cancer stem-like cells (CSCs). Thus we hypothesized that Kras activty is critical for maintenance of gastric CSCs and promotes CSC phenotypes. METHODS: Human and murine GA cell lines were examined. The effect of Kras pathway inhibition was examined in GA spheroid cells and monolayer cells in various in vitro assays. Kras activity and Kras pathway inhibition was examined in CSCs, primary tumors and metastases in our GA mouse model. The combination of chemotherapy and Kras pathway inhibition was tested in human GA xenografts. RESULTS: Kras inhibition with shRNA or MEK inhibitor PD0325901 decreased the ability of GA cells to form spheroids and deceased expression of the stem cell transcription factor, Sox2. CD44(+) gastric CSCs had 65.8-75.4% higher migration, 64.2-79.5% higher invasion, and 63.1-70.2% more anchorage-independent growth compared to unselected cells. These properties could all blocked by 71.1-82.7% with Kras shRNA or PD0325901. In our GA mouse model, PD0325901 starting at 6 weeks of life increased median survival from 76 days to 95 days. Primary tumors and metastases from these mice with and without treatment with MEK inhibition are being analyzed for level of CD44 CSCs, Kras activity, and extent of metastases. Gastric CSCs were resistant to 5-fluorouracil and cisplatin chemotherapy, and this chemotherapy resistance could be reversed in human GA xenografts transducing cells with Kras shRNA. CONCLUSION: Kras is more active in gastric CSCs than non-CSCs and promotes malignant phenotypes including metastasis and chemotherapy resistance. Kras pathway inhibition can block these CSC phenotypes, and thus may prove useful in various combination therapies. Note: This abstract was not presented at the meeting. Citation Format: Changhwan Yoon, Kevin K. Chang, Jacob Till, Sandra W. Ryeom, Sam S. Yoon. Oncogenic Kras activation in gastric adenocarcinoma promotes cancer stem cell phenotypes including metastasis &amp; chemotherapy resistance [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 2897. doi:10.1158/1538-7445.AM2017-2897
Annexin A11 is targeted by IgG4 and IgG1 autoantibodies in IgG4-related disease
Authors: Lowiek M Hubers, Harmjan Vos, Alex R Schuurman, Robin Erken, Ronald P Oude Elferink, Boudewijn Burgering, Stan F J van de Graaf, Ulrich Beuers
Journal: Gut (2017)

<h3>Objective</h3> Immunoglobulin G4-related disease (IgG4-RD) is a multiorgan immune-mediated disease that predominantly affects the biliary tract (IgG4-associated cholangitis, IAC) and pancreas (autoimmune pancreatitis, AIP). We recently identified highly expanded IgG4+ B-cell receptor clones in blood and affected tissues of patients with IAC/AIP suggestive of specific (auto)antigenic stimuli involved in initiating and/or maintaining the inflammatory response. This study aimed to identify (auto)antigen(s) that are responsible for the clonal expansion of IgG4+ B cells in IgG4-RD. <h3>Design</h3> We screened sera of patients with IAC/AIP (n=50), in comparison to control sera of patients with primary sclerosing cholangitis (PSC) and pancreatobiliary malignancies (n=47), for reactivity against human H69 cholangiocyte lysates on immunoblot. Subsequently, target antigens were immunoprecipitated and analysed by mass spectrometry. <h3>Results</h3> Prominent reactivity against a 56 kDa protein was detected in human H69 cholangiocyte lysates exposed to sera of nine patients with IAC/AIP. Affinity purification and mass spectrometry analysis identified annexin A11, a calcium-dependent phospholipid-binding protein. Annexin A11-specific IgG4 and IgG1 antibodies were only detected in serum of patients with IgG4-RD of the biliary tract/pancreas/salivary glands and not in disease mimickers with PSC and pancreatobiliary malignancies. Epitope analysis showed that two annexin A11 epitopes targeted by IgG1 and IgG4 autoantibodies were shared between patients with IAC/AIP and IgG4 antibodies blocked binding of IgG1 antibodies to the shared annexin A11 epitopes. <h3>Conclusion</h3> Our data suggest that IgG1-mediated pro-inflammatory autoreactivity against annexin A11 in patients with IgG4-RD may be attenuated by formation of annexin A11-specific IgG4 antibodies supporting an anti-inflammatory role of IgG4 in IgG4-RD.
Abstract LB-230: Oncogenic PKC epsilon and Pten loss converge on activating CXCL13 via atypical NF-κB transcriptional signaling in prostate cancer progression
Authors: Rachana Garg, Jorge Blando, Carlos Perez, Martin Abba, Fernando Benavides, Marcelo Kazanietz
Journal: Cancer Research (2017)

Abstract Protein Kinase C epsilon (PKCϵ), a pro-oncogenic member of the PKC family of phorbol ester/diacylglycerol receptors, has been shown to be up-regulated in most epithelial cancers, including prostate cancer. PKCϵ transgenic overexpression in the mouse prostate causes preneoplastic lesions, however when intercrossed with mice haploinsufficient for Pten, the resulting compound mice (PB-PKCϵ;Pten+/-) develops invasive adenocarcinoma. We found that Pten-deficient prostate cell lines engineered to overexpress PKCϵ (CaP8-PKCϵ) cells become highly invasive and tumorigenic. Microarray gene expression profiling in this cell line revealed marked changes in the expression of genes implicated in proliferation, migration, adhesion, EMT, angiogenesis and metabolism. In particular, the chemokine CXCL13 was identified as the top-most up-regulated gene in CaP8-PKCϵ cells. Measurements of either CXCL13 mRNA, protein release to the culture medium (CM), or Cxcl13 promoter activity showed clear enhancements in cells overexpressing PKCϵ or Pten depleted, and these effects were enriched synergistically in CaP8-PKCϵ cells. CaP8-PKCϵ subjected to CXCL13 RNAi depletion showed reduced motility and tumorigenic growth. Similar results were observed upon silencing of CXCR5, the CXCL13 receptor. CXCL13 expression and promoter activity in CaP8-PKCϵ cells were significantly reduced by GF109203X (PKC inhibitor), IKK16, wedelolactone (NF-κB inhibitors), and BKM120 (PI3K inhibitor), but were insensitive to BX795 (PDK1 inhibitor). RNAi-mediated depletion of NIK or IKKα significantly blunted Cxcl13 luciferase promoter activity in CaP8-PKCϵ cells, but the effect was partially inhibited by IKKβ RNAi, suggesting the role of the atypical NF-κB pathway. Mutation of a responsive element for atypical NF-κB in the CXCL13 promoter abolished CXCL13 reporter activity in CaP8-PKCϵ cells. Taken together, our study identifies a novel paradigm depicting atypical NF-κB as the transcriptional signaling pathway by which PKCϵ overexpression/Pten loss regulates overproduction of the chemokine CXCL13 in prostate cancer cells. Citation Format: Rachana Garg, Jorge Blando, Carlos Perez, Martin Abba, Fernando Benavides, Marcelo Kazanietz. Oncogenic PKC epsilon and Pten loss converge on activating CXCL13 via atypical NF-κB transcriptional signaling in prostate cancer progression [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 LB-230. doi:10.1158/1538-7445.AM2017-LB-230
Abstract 3128: TRPM7 regulates glioma cell proliferation and migration through different function domains
Authors: Mingli Liu
Journal: Cancer Research (2017)

Abstract Background: Transient Receptor Potential Melastatin-related 7 (TRPM7) is a non-selective cation channel fused with a functional kinase domain. TRPM7 channel expression is aberrant in numerous cancers. We have previously reported that suppression of TRPM7 inhibits the proliferation, migration, and invasion of malignant human glioma cells using A172 glioma cell line and brain tissue of human glioma [CNS Neuroscience &amp; Therapeutics 2015,21(3):252-61]. We further found that TRPM7 channels regulate glioma stem cell growth/proliferation through STAT3 and Notch signaling pathways [Cellular Signaling, 2014; 26: 2773-2781]. Since TRPM7 is a bifunctional protein with channel and α-kinase domain, we next investigated whether the changes in glioma cancer cell proliferation and migration might be caused through channel domain-mediated and/or kinase domain mediated TRPM7 activation. Methods: 1) A172 cells expressing wild-type human TRPM7 (wtTRPM7) or constructs in which the α-kinase domain was deleted (Δkinase) or rendered inactive with a point mutation in the ATP binding site of the α-kinase domain (K1648R) were studied. 2) The effects of TRPM7 on glioma cell proliferation and invasion were determined using MTT assay and transwell invasion assay by TRPM7 expression using wtTRPM7, Δkinase, and K1648R, respectively. Results: 1) Treatment of A172 cells with Δkinase and K1648R significantly increased TRPM7 expression demonstrated by Western blot assay. 2) The cell invasion was significantly reduced when treated with Δkinase and K1648R which indicate that TRPM7 kinase activity is required for changes in cell migration and invasion. 3) The cell proliferation was not significantly changed when treated with Δkinase and K1648R which indicate that TRPM7 channel rather than kinase activity is required in cell growth of A172 cells. Conclusion: TRPM7 regulates glioma cell proliferation and migration/invasion through different function domains. The channel activity of TRPM7 is required for the cell growth while the kinase domain is required for the cell migration/invasion. The finding is important for designing and developing drugs targeting TRPM7 in human malignancies. Note: This abstract was not presented at the meeting. Citation Format: Mingli Liu. TRPM7 regulates glioma cell proliferation and migration through different function domains [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 3128. doi:10.1158/1538-7445.AM2017-3128
Abstract 35: The dual inhibition of Met and EGFR by ME22S, a novel Met/EGFR bispecific monoclonal antibody, suppresses the proliferation and invasion of laryngeal cancer
Authors: Bok-Soon Lee, Dae Ho Kim, Yeon Soo Kim, Jae Won Chang, Bon Seok Koo, Ho Ryun Won, Haeng-Jun Kim, Hyun-Young Cha, Ji Min Lee, Kyung-Ah Kim, Chul-Ho Kim
Journal: Cancer Research (2017)

Abstract Background and purpose: It has been reported that the abnormal activation of receptor tyrosine kinases is associated with the development of many human carcinomas and the high activation of EGFR and Met mediates the tumorigenicity of laryngeal carcinoma. In this study, we have done the therapeutic efficacy of ME22S, a novel EGFR/Met bispecific antibody, in laryngeal carcinoma in vitro and in vivo was thoroughly evaluated. Methods: The effects of ME22S on cell viability was assessed through MTT assays, then Western blotting and immunocytochemistry were used to determine the expression of EGFR and Met. Also, wound healing and invasion assays were performed to observe the inhibitory effects of ME22S. Results: We found the ability of ME22S reducing the expression of both EGFR and Met and significantly inhibiting the cell migration, invasion, and proliferation of SNU899 and HN3 in vitro. Also the notably reduced levels of p-Met, p-ERK, and p-AKT were found when the cells were treated with only ME22S alone or with HGF together. Meanwhile, ME22S, interestingly enough, caused caspase-3-dependent apoptotic cell death when HN3 cells were treated with ME22S for 72h, decreased the HGF-induced Slug expression, and also inhibited the tumor growth of HN3 cells in a xenograft model in vivo. Conclusion: Taken together, our findings suggest that the dual inhibition of EGFR and Met through ME22S largely suppresses the invasion and growth of laryngeal carcinoma both in vitro and in vivo, hence, can be a practical approach as a novel therapeutic strategy for the treatment of laryngeal carcinoma. Citation Format: Bok-Soon Lee, Dae Ho Kim, Yeon Soo Kim, Jae Won Chang, Bon Seok Koo, Ho Ryun Won, Haeng-Jun Kim, Hyun-Young Cha, Ji Min Lee, Kyung-Ah Kim, Chul-Ho Kim. The dual inhibition of Met and EGFR by ME22S, a novel Met/EGFR bispecific monoclonal antibody, suppresses the proliferation and invasion of laryngeal cancer [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 35. doi:10.1158/1538-7445.AM2017-35
Abstract 544: Hypoxia response signaling is linked to TACE resistance in hepatocellular carcinoma (HCC) patients
Authors: Valerie Fako, Joyce Lee, Tan-To Cheung, Irene O. Ng, Xin W. Wang
Journal: Cancer Research (2017)

Abstract Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and outcome is dismal, due to tumor heterogeneity and lack of effective treatment options for patients with later stage disease. Transcatheter arterial chemoembolization (TACE) is the gold standard of therapy for patients with intermediate to locally advanced tumors. TACE delivers a high dose of chemotherapy directly to the tumor via the hepatic artery, followed by an embolizing agent to restrict tumor blood supply. However, tumor hypoxia is linked to alterations in metabolism, such as increased glycolysis (the Warburg effect), and can lead to enhanced cell survival. Several randomized control trials (RCTs) showed a survival benefit with TACE, but only with strict patient selection criteria. In Asia, TACE is also commonly used as adjuvant therapy after surgical resection, yet RCTs evaluating adjuvant TACE have shown conflicting results, likely due to patient selection and stratification. We hypothesize that tumor gene expression is predictive of response following TACE, and that differential cellular metabolism resembling a hypoxic phenotype prior to treatment is responsible for TACE resistance. We retrospectively analyzed gene expression data in treatment-naive tumor tissue from a cohort of Chinese patients who received TACE. Using hierarchical clustering, followed by class comparison and survival risk prediction, we identified a 14-gene signature that is predictive of response vs. non-response to TACE, as measured by overall survival, independent of other clinical variables. We found that hypoxia- and glycolysis-related genes are enriched among differentially expressed genes in TACE Responders vs. Non-Responders, and that hypoxia master regulator HIF-1α and hypoxia target gene VEGF are significantly up-regulated in Non-Responders. We determined that a key glycolysis gene is up-regulated in Non-Responders, and conversely, two rate-limiting genes involved in gluconeogenesis, the pathway opposing glycolysis, are up-regulated in Responders. We also examined metabolomic data from the TACE cohort, and found an enrichment of glycolysis-related metabolites in Non-Responders, and gluconeogenesis-related metabolites in Responders. Further investigation will be required to connect altered glucose metabolism to TACE resistance and to determine driver genes linking hypoxia and metabolism, which, together with our 14-gene signature, may serve as a stratification tool to guide personalized treatment modalities for HCC patients. Citation Format: Valerie Fako, Joyce Lee, Tan-To Cheung, Irene O. Ng, Xin W. Wang. Hypoxia response signaling is linked to TACE resistance in hepatocellular carcinoma (HCC) patients [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 544. doi:10.1158/1538-7445.AM2017-544