tbuckley/cabot-search huggingface dataset:
Abstract 3708: Targeting synthetic lethality with PARP inhibition in colorectal cancer
Authors: Titto Augustine, Radhashree Maitra, Jinghang Zhang, Jay Nayak, Sanjay Goel
Journal: Cancer Research (2016)

Abstract Background: Small molecule poly ADP-ribose (PAR) polymerase (PARP) inhibitors (PARPi) purportedly result in DNA damage and are promising agents in the treatment of cancer. In a quest to identify best “synthetic lethality” for treatment, we have screened various combination therapies in colorectal cancer (CRC) cell lines. In addition, we have interrogated if the presence of microsatellite instability (MSI) status favor susceptibility of cells to synthetic lethality and thus acts as a prognostic marker of combination therapy. Methods: Using the SRB assay, the 12 combinations of the PARPi, veliparib (V), rucaparib (R), olaparib (Ol) and PJ34, and the cytotoxic drugs, irinotecan (I), 5-fluorouracil (5-FU) and oxaliplatin (Ox) were screened in HCT116 and LIM2405 cell lines. We assessed the effect of the combination using the CalcuSyn software for combination index (CI). We next evaluated the effectiveness and sequence dependence of combination in an additional 2 cell lines that had MSI status (RKO and HCT15) and 2 that had microsatellite stable (MSS) status (HT29 and SW837) and in 7 HCT116 isogenic lines (mutants of Bax, p21, p53, PTEN, Kras and DNMT and wild type of PIK). The combination of I and R was confirmed by FACS analysis in HCT116 and LIM2405. Results: Ol and R showed synergy in combination with I, whereas, V and PJ34 showed antagonism with Ox, including in Ox-sensitive cells. Single agent cytotoxicity was observed at 200nM for R, whereas V required more than 30uM. Early PARP-1 protein upregulation was observed upon Ox administration; but the changes were not reversed with either R or V. Nevertheless, R at 200nM and V 1uM significantly reduced PAR formation in Ox-sensitive cell lines. FACS analysis showed S phase arrest in SW837 (MSS) (p = 0.03) whereas G2-M arrest was observed in LIM2405 (MSI) (non-significant) upon treatment with R 400nM and I 200nM. In addition, studies using isogenic cell lines revealed the importance of p21, p53 and PTEN in exerting synergistic effect while combining R and I. Administration of I prior to R (24h each) was more cytotoxic than vice versa and simultaneous treatment in MSI cell lines. Conclusion: Among the various combinations studied, R with I was the most synergistic. The effect appears to be more pronounced when I precedes R, particularly in MSI cell lines. Alteration in cell cycle is MSI status dependent. Further work to identify mechanism of synergy is ongoing. Citation Format: Titto Augustine, Radhashree Maitra, Jinghang Zhang, Jay Nayak, Sanjay Goel. Targeting synthetic lethality with PARP inhibition in colorectal cancer. [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 3708.
Abstract 844: High-resolution microbiome profiling and meta-analysis yields insight into microbial consortia associated with colorectal cancer
Authors: James R. White, Julia Drewes, Cynthia L. Sears
Journal: Cancer Research (2016)

Abstract Colorectal cancer (CRC) continues to be the second leading cause of cancer-related deaths globally. While multiple environmental factors are associated with incidence of CRC, multiple studies have reported that CRC is frequently linked with an altered colonic microbiota both in terms of taxonomic composition as well as structural organization. However, differences in study design and analysis methodologies among CRC microbiome profiling studies have generated inconsistent findings. To identify bacterial taxa consistently associated with CRC, we applied a uniform microbiome analysis methodology to sequence datasets followed by meta-analysis. Raw 16S rRNA amplicon sequence datasets from 12 studies including two new Malaysian cohorts were collected and analyzed using the Resphera Insight high-resolution taxonomic assignment protocol. Taxonomic abundances within each dataset were then assessed for significant enrichment or depletion in colorectal carcinoma samples versus controls. Alpha diversity and differences in predicted functional capacity were assessed utilizing QIIME and PICRUSt, respectively. Several bacterial species were consistently enriched in colorectal carcinoma samples relative to healthy controls including Fusobacterium nucleatum, Fusobacterium necrophorum, Leptotrichia trevisanii, Bacteroides fragilis, Parvimonas micra, Peptostreptococcus stomatis, and Gemella morbillorum. In contrast to other studies that have generally described Fusobacteria as enriched in CRC relative to controls, we identified multiple fusobacterial members that were often not strongly linked with CRC including Fusobacterium varium and Cetobacterium somerae. Evaluating functional predictions inferred from taxonomic composition, we observed consistent enrichment of specific KEGG categories in CRC including glycosyltransferases and carbohydrate digestion and absorption. Applying a uniform high-resolution analysis protocol for microbiome profiling enabled detection of specific species that were strongly associated with CRC across multiple studies. These findings demonstrate that higher level analyses (e.g. those at the genus or family level) may be insufficient for detection of indicator taxa in some populations. Citation Format: James R. White, Julia Drewes, Cynthia L. Sears. High-resolution microbiome profiling and meta-analysis yields insight into microbial consortia associated with colorectal cancer. [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 844.
EFFICACY OF LEFT VENTRICULAR ASSIST DEVICES OR INOTROPES FOR BRIDGING PATIENTS WITH PULMONARY HYPERTENSION TO HEART TRANSPLANTATION
Authors: Sadeer Al-Kindi, Sachin Kumar, Mobolaji Ige, Mahazarin Ginwalla, Chantal Elamm, Guilherme Oliveira
Journal: Journal of the American College of Cardiology (2015)
Met signaling in urothelial carcinoma of the bladder.
Authors: Donald P Bottaro, Young H. Lee, Piyush K. Agarwal, Andrea Borghese Apolo
Journal: Journal of Clinical Oncology (2014)

4551 Background: Mounting evidence of hepatocyte growth factor (HGF)/Met signaling in urothelial carcinoma (UC) suggests that pathway inhibition could have therapeutic benefit in some patients. The effects of two Met inhibitors, cabozantinib (which also targets VEGFR2), and crizotinib (which also targets ALK), on Met-driven UC cell growth, invasion and tumorigenicity were analyzed in biochemical, cell-based and animal models. Methods: The effects of cabozantinib or crizotinib on HGF signaling were assessed in 9 human UC-derived cell lines: RT4, TCC-SUP, T24M2, T24M3, J82, SW780, UMUC3, UMUC5, and 5637. Biochemical assays included total Met protein, phospho-Met (pMet), pAkt, total Akt, pErk and total Erk analysis. Cultured cell assays of invasion, proliferation and anchorage independent growth were performed in all 9 lines. The growth rates of SW780 xenografts in SCID and human HGF knock-in SCID (hHGF/SCID) mice treated daily with cabozantinib or vehicle alone, as well as tumor levels of Met and pMet, were determined. Results: Met content was low in RT4 and higher in T24M2, T24M3, TCC-SUP, J82, SW780 UMUC3, UMUC5, and 5637 cells. Basal pMet content in quiescent cells was universally low and significantly enhanced by added HGF, an effect that was reversed by treatment with cabozantinib or crizotinib. HGF-driven increases in pAkt/Akt and pErK/ErK in all 9 cell lines were also reversed by cabozantinib or crizotinib treatment, as were HGF-enhanced cell invasion, proliferation and anchorage independent growth. SW780 xenograft growth rate in hHGF/SCID mice was significantly higher than in SCID mice and significantly inhibited by cabozantinib treatment, as was tumor pMet content. Conclusions: Cultured UC cell Met content was higher in cell lines derived from higher stage disease. HGF stimulated the activation of Met and known effectors, and enhanced invasion, growth rate and anchorage-independent growth; treatment with cabozantinib or crizotinib effectively reversed these HGF-driven effects. Cabozantinib also significantly inhibited HGF-driven tumor xenograft growth and Met activation in SCID and, more dramatically, in hHGF/SCID mice. These preclinical studies support further investigation of Met inhibitors for the treatment of UC in human clinical trials.
Abstract 1475: Local immune activation resulting in tumor growth inhibition with MEDI9197 - an intratumorally administered TLR7/8 agonist
Authors: Stefanie Mullins, Iwen Grigsby, Lester I. Harrison, Song Ren, Serguei Soukharev, Lesley Young, James M. Elvecrog, Robert W. Wilkinson, Mark A. Tomai, Ronald Herbst, John P. Vasilakos, Andrew J. Leishman
Journal: Cancer Research (2016)

Abstract MEDI9197 (formerly 3M-052) is a sustained-release imidazoquinoline toll like receptor (TLR) TLR7/8 agonist designed with a lipid tail that, when injected, is retained within the tumor. This has been shown in pharmacokinetic studies in mice and rats injected with MEDI9197 via the subcutaneous (SC) or intratumoral (IT, mouse only) routes. Stimulation of TLR7 and TLR8 in primary human dendritic cells induces the release of interferon-alpha (IFN-a) from plasmacytoid dendritic cells (pDCs) and interleukin 12 (IL-12) from myeloid dendritic cells (mDCs). Intratumoral administration of MEDI9197 induces a local immune response characterized by upregulation of genes involved in activation of innate and adaptive immunity both from the injected tumor and tumor draining lymph node. Furthermore, flow cytometric analysis of tumor infiltrating lymphocytes (TILs) show increased expression of activation markers, such as CD69, on natural killer (NK) cells and CD8 cytotoxic T cells. This local stimulation of immune cells with MEDI9197 results in tumor growth inhibition as shown in the B16F10 luc syngeneic mouse tumor model using in vivo imaging system (IVIS) equipment. Additionally, combination of MEDI9197 with immune checkpoint inhibitors enhances the efficacy observed in syngeneic mouse tumor models. The data presented shows intratumoral administration of MEDI9197 induces local immune activation leading to tumor growth inhibition in preclinical models of cancer. MEDI9197 is currently being evaluated as a monotherapy for safety and efficacy in human clinical trials. Citation Format: Stefanie Mullins, Iwen Grigsby, Lester I. Harrison, Song Ren, Serguei Soukharev, Lesley Young, James M. Elvecrog, Robert W. Wilkinson, Mark A. Tomai, Ronald Herbst, John P. Vasilakos, Andrew J. Leishman. Local immune activation resulting in tumor growth inhibition with MEDI9197 - an intratumorally administered TLR7/8 agonist. [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 1475.
Phase II study of the early start of chemotherapy after excision of primary colorectal cancer with distant metastases (Pearl Star 02).
Authors: Syu Tanimura, Yoichiro Yoshida, Naoya Aisu, Akira Komono, Daibo Kojima, Toshiyuki Mera, Yuichi Yamashita
Journal: Journal of Clinical Oncology (2016)

746 Background: The start of chemotherapy usually requires a delay of about 4 weeks after surgical resection of colorectal cancer. However, there is no evidence for the required length of this delay interval. In addition, there is a chance that a patient may die because postoperative chemotherapy was not started soon enough and a metastatic tumor was able to develop rapidly. We have previously reported the first pilot study to determine the safety and feasibility of an early start of chemotherapy after resection of primary colorectal cancer with distant metastases. We therefore conducted a next study to determine the safety and efficacy of the early start of chemotherapy after the resection of colorectal cancer with distant metastases. Methods: The Pearl Star 02 study was a prospective and single-arm trial. They received XELOX therapy (130 mg/m2 of oxaliplatin on day 1 plus 1,000 mg/m2 of capecitabine twice daily on days 1–14) on the 7th postoperative day and XELOX+bevacizumab (7.5 mg/kg of bevacizumab on day 1) after the 2nd cycle of chemotherapy. Results: A total of 20 patients were enrolled from September 2011 to June 2015. Baseline characteristics included a median age of 64 years (range: 43-72) for 15 men and 5 women. The procedures included right hemicolectomy in 6 patients, sigmoidectomy in 3 patients, high anterior resection in 3 patients, low anterior resection in 2 patients, and Hartmann procedure in 6 patients. All patients started chemotherapy on postoperative day 7. Grade 3 or higher hemotoxicity and grade 3 or higher non-hematological toxicity was noted in 5.0 % and 25.0 % of patients, respectively. Postoperative complications were observed in 2 patients (superficial incisional surgical site infection and Ileus). Median progression-free survival was 14.9 months. Overall response rate was 75%. Conclusions: An early start of chemotherapy after surgery is safe and effective. These findings suggest possible changes in the start time of chemotherapy after surgery in the future. However, further studies are certainly needed to confirm these findings. Clinical trial information: UMIN000006310.
Abstract 4562: Inhibition of STAT3 signaling in human liver cancer cells using Evista
Authors: Yina Wang, Chongqiang Zhao, Haiyan Ma, Huameng Li, Jiagao Lu, Chenglong Li, Jiayuh Lin, Li Lin
Journal: Cancer Research (2016)

Abstract Liver cancer is one of the major causes of morbidity and mortality in China and also around the World. Constitutive activation of Signal Transducers and Activators of Transcription 3 (STAT3) signaling is frequently detected in human cancer including liver cancer and has emerged as a viable molecular target for liver cancer treatment. Novel therapeutic approaches of more effective treatments are much needed. To date, few STAT3 inhibitors are available for the therapy of liver cancer yet. Evista (Raloxifene HCI) is used for the prevention and treatment of osteoporosis and was approved for reducing the risk of invasive breast cancer in postmenopausal women with osteoporosis and in postmenopausal women at high risk for invasive breast cancer. We reported the discovery of Raloxifene as novel inhibitors of IL-6/GP130 protein­protein interactions (PPIs) using multiple ligand simultaneous docking (MLSD) and drug repositioning. The possible effect of Evista in STAT3 signaling or liver cancer cells is still unclear. The ability of Evista to inhibit STAT3 was tested. Evista inhibited the P-STAT3 stimulated by IL-6 but not the induction of STAT1, STAT2, and STAT4 phosphorylation by IFN-α and IL-4. Evista inhibited STAT3 phosphorylation and resulted in the induction apoptosis on human liver cancer cell lines HEPG2, 7721, and HUH-7 as evidenced by caspase-3 cleavage. Evista also inhibited the cell viability, cell migration and colony formation in liver cancer cells. Furthermore, administration daily of Evista suppressed the HEPG2 tumor growth in mice in vivo. In summary, our study is the first report indicating that Evista also exhibits biology activity against persistent STAT3 signaling in human liver cancer cells. These results suggest that Evista may also be a chemoprevention agent for liver cancer by targeting persistent STAT3 signaling. Citation Format: Yina Wang, Chongqiang Zhao, Haiyan Ma, Huameng Li, Jiagao Lu, Chenglong Li, Jiayuh Lin, Li Lin. Inhibition of STAT3 signaling in human liver cancer cells using Evista. [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 4562.
Abstract 3993: Th1 cytokines regulate apoptotic cell death and HER family RTK expression in murine and human breast cancer lines
Authors: Prachi M. Namjoshi, Lori Showalter, Brian Czerniecki, Gary K. Koski
Journal: Cancer Research (2016)

Abstract A recent neoadjuvant vaccine trial to treat early breast cancer demonstrated powerful induction of Th1 immunity against the HER-2, complete pathologic responses in over 18% of subjects, and for many subjects, evidence of down-regulated HER-2 expression on residual disease. To explain these observations, we investigated the action of archetypical Th1 cytokines (TNF-α + IFN-γ) on both murine and human breast cancer cell lines that varied in the surface expression of HER-family receptor tyrosine kinases. We found that most tumor cell lines were sensitive to dual Th1 cytokines as evidenced by lower metabolic activity (alamar blue assay), lower proliferation, and enhanced apoptosis (AnnexinV/PI staining and TUNEL assay) as well as a reversible inhibition of surface expression of HER proteins. Apoptotic cell death was accompanied by demonstrated increases in activated caspase-3. Furthermore, the pharmacologic caspase-3 activator, procaspase-activating compound (PAC-1), mimicked both the killing effects and HER-2 suppressive activities of Th1 cytokines, while the caspase 3/7 inhibitor ((5-[(S)-(+)-2-(Methoxymethyl)pyrrolidino]sulfonylisatin), prevented cytokine-induced HER-2 downregulation. These studies therefore demonstrated that many of the in vivo effects of vaccination (apparent tumor cell death and loss of HER-2 expression) could be replicated in vitro using only the principle Th1 cytokines. These findings are consistent with the notion that IFN-γ and TNF-α work in concert to mediate some of the biological effects of therapeutic Th1-polarizing vaccination through the induction of a caspase 3-dependent cellular death mechanism. Citation Format: Prachi M. Namjoshi, Lori Showalter, Brian Czerniecki, Gary K. Koski. Th1 cytokines regulate apoptotic cell death and HER family RTK expression in murine and human breast cancer lines. [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 3993.
Abstract 4316: Pharmacological targeting of the TGF-beta-induced epithelial-mesenchymal transition by anthocyanidins in glioblastoma
Authors: Amira Ouanouki, Evelyne Muhire, Sylvie Lamy, Borhane Annabi
Journal: Cancer Research (2016)

Abstract Introduction: Glioblastoma multiforme (GBM) is the most common primary brain tumor, known for its invasiveness and high resistance to standard treatments. Therefore, better understanding of the mechanisms that promote mesenchymal changes in GBM are of great clinical importance. Epithelial to mesenchymal transition (EMT) is a reversible biological process in which epithelial cells adopt mesenchymal properties. During EMT, migration, adhesion and cellular morphology are altered allowing benign tumor cells to infiltrate surrounding tissues and to metastasize to distant sites. Several growth factors have been shown to trigger EMT in tumor development; the Transforming Growth Factor-beta (TGF-b) is the most prominent inducer of EMT. Epidemiological studies have shown that diets rich in fruits and vegetables play an important role in preventing cancer due to their polyphenol content. Among polyphenols, the anthocyanidins, found in berries, red grapes, and other pigmented foods, plants and vegetables, have anti-inflammatory, cardioprotective, anti-angiogenic and anti-carcinogenic properties. Despite the well-known role of TGB-b in tumor progression, the impact of anthocyanidins on TGF-b-induced EMT remains misunderstood. Objectives: 1) Characterize the pharmacological effects of anthocyanidins (cyanidin, delphinidin, malvidin, pelargonidin and petunidin) on EMT, 2) identify the molecular targets leading to the inhibition of EMT modulated by anthocyanidins, and 3) characterize their effect on cellular activities involved in this tumor process. Methodology: The human U-87 glioblastoma (U-87 MG) cells were treated with anthocyanidins in pre-, co- and post-treatment with TGF-b. Results: Depending on the treatment, anthocyanidins affect differently the EMT induction by inhibiting U-87 MG cell migration. This inhibition resulted in a down-regulation of mesenchymal markers (fibronectin, snail), phosphorylation of Smad2 proteins and the mitogen-activated protein kinases (ERK, JNK) in a dose-dependent manner. Overall, delphinidin was the most potent inhibitor for all treatments. Conclusion: This study highlights a new antimetastatic action of anthocyanidins that supports the beneficial health and chemopreventive effects of dietary-based strategies against cancer. Citation Format: Amira Ouanouki, Evelyne Muhire, Sylvie Lamy, Borhane Annabi. Pharmacological targeting of the TGF-beta-induced epithelial-mesenchymal transition by anthocyanidins in glioblastoma. [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 4316.
RSPO3 expands intestinal stem cell and niche compartments and drives tumorigenesis
Authors: John Hilkens, Nikki C Timmer, Mandy Boer, Gerjon J Ikink, Matthias Schewe, Andrea Sacchetti, Martijn A J Koppens, Ji-Ying Song, Elvira R M Bakker
Journal: Gut (2016)

The gross majority of colorectal cancer cases results from aberrant Wnt/β-catenin signalling through adenomatous polyposis coli (APC) or CTNNB1 mutations. However, a subset of human colon tumours harbour, mutually exclusive with APC and CTNNB1 mutations, gene fusions in RSPO2 or RSPO3, leading to enhanced expression of these R-spondin genes. This suggested that RSPO activation can substitute for the most common mutations as an alternative driver for intestinal cancer. Involvement of RSPO3 in tumour growth was recently shown in RSPO3-fusion-positive xenograft models. The current study determines the extent into which solely a gain in RSPO3 actually functions as a driver of intestinal cancer in a direct, causal fashion, and addresses the in vivo activities of RSPO3 in parallel.We generated a conditional Rspo3 transgenic mouse model in which the Rspo3 transgene is expressed upon Cre activity. Cre is provided by cross-breeding with Lgr5-GFP-CreERT2 mice.Upon in vivo Rspo3 expression, mice rapidly developed extensive hyperplastic, adenomatous and adenocarcinomatous lesions throughout the intestine. RSPO3 induced the expansion of Lgr5+ stem cells, Paneth cells, non-Paneth cell label-retaining cells and Lgr4+ cells, thus promoting both intestinal stem cell and niche compartments. Wnt/β-catenin signalling was modestly increased upon Rspo3 expression and mutant Kras synergised with Rspo3 in hyperplastic growth.We provide in vivo evidence that RSPO3 stimulates the crypt stem cell and niche compartments and drives rapid intestinal tumorigenesis. This establishes RSPO3 as a potent driver of intestinal cancer and proposes RSPO3 as a candidate target for therapy in patients with colorectal cancer harbouring RSPO3 fusions.
La consommation de fruits de mer et la conscience du risque d'acquisition de l'hépatite A parmi des familles napolitaines - Italie, 1997
Authors: G Salamina, P D'Argenio
Journal: Eurosurveillance (1998)

En 1996, environ 15% des 8651 cas d'hepatite A declares en Italie etaient originaires de Campanie, l'incidence la plus elevee (34,9/100 000) etant rapportee a Naples. Les 15 a 24 ans representaient presque la moitie de tous les cas. La consommation de coquillages, surtout crus ou insuffisamment cuits, est responsable de 70% des cas d'hepatite A rapportes en Italie dans les dernieres annees (1,2) et plusieurs epidemies recentes d'hepatite A sont liees a cette consommation (3-5).