tbuckley/cabot-search huggingface dataset:
Circulating tumour cells from patients with colorectal cancer have cancer stem cell hallmarks in<i>ex vivo</i>culture
Authors: Fanny Grillet, Elsa Bayet, Olivia Villeronce, Luke Zappia, Ebba Louise Lagerqvist, Sebastian Lunke, Emmanuelle Charafe-Jauffret, Kym Pham, Christina Molck, Nathalie Rolland, Jean François Bourgaux, Michel Prudhomme, Claire Philippe, Sophie Bravo, Jean Christophe Boyer, Lucile Canterel-Thouennon, Graham Roy Taylor, Arthur Hsu, Jean Marc Pascussi, Frédéric Hollande, Julie Pannequin
Journal: Gut (2016)

Although counting of circulating tumour cells (CTC) has attracted a broad interest as potential markers of tumour progression and treatment response, the lack of functional characterisation of these cells had become a bottleneck in taking these observations to the clinic. Our objective was to culture these cells in order to understand them and exploit their therapeutic potential to the full.Here, hypothesising that some CTC potentially have cancer stem cell (CSC) phenotype, we generated several CTC lines from the blood of patients with advanced metastatic colorectal cancer (CRC) based on their self-renewal abilities. Multiple standard tests were then employed to characterise these cells.Our CTC lines self-renew, express CSC markers and have multilineage differentiation ability, both in vitro and in vivo. Patient-derived CTC lines are tumorigenic in subcutaneous xenografts and are also able to colonise the liver after intrasplenic injection. RNA sequencing analyses strikingly demonstrate that drug metabolising pathways represent the most upregulated feature among CTC lines in comparison with primary CRC cells grown under similar conditions. This result is corroborated by the high resistance of the CTC lines to conventional cytotoxic compounds.Taken together, our results directly demonstrate the existence of patient-derived colorectal CTCs that bear all the functional attributes of CSCs. The CTC culture model described here is simple and takes <1 month from blood collection to drug testing, therefore, routine clinical application could facilitate access to personalised medicine.ClinicalTrial.gov NCT01577511.
Warfarin with sulfonylureas and hypoglycemic events: consider dose, length of treatment, and all sulfonylureas
Authors: Pauline Bosco-Lévy, Francesco Salvo
Journal: BMJ (2016)

Romley and colleagues studied the association between the use of warfarin with common sulfonylureas and the development of serious hypoglycemic events.1 Data on potential interactions are essential because both drugs have a narrow therapeutic range and can also interact with many other drugs.2 3

The pharmacological effect of these drugs …
Bromodomain and Extraterminal Protein Inhibitor JQ1 Suppresses Thyroid Tumor Growth in a Mouse Model
Authors: Xuguang Zhu, Keisuke Enomoto, Li Zhao, Yuelin J. Zhu, Mark C. Willingham, Paul Meltzer, Jun Qi, Sheue-yann Cheng
Journal: Clinical Cancer Research (2016)

Abstract Purpose: New therapeutic approaches are needed for patients with thyroid cancer refractory to radioiodine treatment. An inhibitor of bromodomain and extraterminal domain (BET) proteins, JQ1, shows potent antitumor effects in hematological cancers and solid tumors. To evaluate whether JQ1 is effective against thyroid cancer, we examined antitumor efficacy of JQ1 using the ThrbPV/PVKrasG12D mouse, a model of anaplastic thyroid cancer. Experimental Design: We treated ThrbPV/PVKrasG12D mice with vehicle or JQ1 at a dose of 50 mg/kg body weight/day starting at the age of 8 weeks for a 10-week period and monitored thyroid tumor progression. Results: JQ1 markedly inhibited thyroid tumor growth and prolonged survival of these mice. Global differential gene expression analysis showed that JQ1 suppressed the cMyc (hereafter referred to as Myc) transcription program by inhibiting mRNA expression of Myc, ccnd1, and other related genes. JQ1-suppressed Myc expression was accompanied by chromatin remodeling as evidenced by increased expression of histones and hexamethylene bis-acetamide inducible 1, a suppressor of RNA polymerase II transcription elongation. Analyses showed that JQ1 decreased MYC abundance in thyroid tumors and attenuated the cyclin D1–CDK4–Rb–E2F3 signaling to decrease tumor growth. Further analysis indicated that JQ1 inhibited the recruitment of BDR4 to the promoter complex of the Myc and Ccnd1 genes in rat thyroid follicular PCCL3 cells, resulting in decreased MYC expression at the mRNA and protein levels to inhibit tumor cell proliferation. Conclusions: These preclinical findings suggest that BET inhibitors may be an effective agent to reduce thyroid tumor burden for the treatment of refractory thyroid cancer. Clin Cancer Res; 23(2); 430–40. ©2016 AACR.
Timely follow-up of a GATA2 deficiency patient allows successful treatment
Authors: Sara Ciullini Mannurita, Marina Vignoli, Gloria Colarusso, Fabio Tucci, Marinella Veltroni, Stefano Frenos, Veronica Tintori, Maurizio Aricò, Venetia Bigley, Matthew Collin, Claudio Favre, Eleonora Gambineri
Journal: Journal of Allergy and Clinical Immunology (2016)
Abstract 3097: Structural and biophysical characterization of anti-apoptotic protein Bcl-2 and GTPase Rac1 interaction
Authors: Shani Ajumal, Jia Kang, Thomas Joseph, Shazib Pervaiz, Kunchithapadam Swaminathan
Journal: Cancer Research (2016)

Abstract We have recently reported a novel mechanism linking the pro-oxidant activity of the anti-apoptotic protein Bcl-2 to its interaction with the small GTPase Rac1. In this current study, we investigate the nature of this interaction using activated (GTP loaded) Rac1 and Bcl-2 peptides (spanning the BH3 domain and its adjacent loop region) using coimmunoprecipitation, isothermal titration calorimetry (ITC), X-ray crystallography, docking/modeling, fluorescence spectroscopy, molecular dynamics and mutational studies. Our results will develop to translational relevance in the treatment of human cancers that are refractory to chemotherapy due to overexpression of Bcl-2. Citation Format: Shani Ajumal, Jia Kang, Thomas Joseph, Shazib Pervaiz, Kunchithapadam Swaminathan. Structural and biophysical characterization of anti-apoptotic protein Bcl-2 and GTPase Rac1 interaction. [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 3097.
In adults, quitting smoking abruptly improved abstinence more than quitting gradually
Authors: Hannah Wilson, Scott Sherman MD
Journal: Annals of Internal Medicine (2016)

ACP Journal Club19 July 2016In adults, quitting smoking abruptly improved abstinence more than quitting graduallyHannah Wilson, BA, Scott Sherman MD, MPHHannah Wilson, BANYU School of Medicine, New York, New York, USA (H.W., S.S.M.)Search for more papers by this author, Scott Sherman MD, MPHNYU School of Medicine, New York, New York, USA (H.W., S.S.M.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/ACPJC-2016-165-2-003 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Source CitationLindson-Hawley N, Banting M, West R, et al. Gradual versus abrupt smoking cessation: a randomized, controlled noninferiority trial. Ann Intern Med. 2016;164:585-92. https://pubmed.ncbi.nlm.nih.gov/26975007Clinical Impact RatingsGIM/FP/GP: References1 Society for Research on Nicotine and Tobacco. National treatment guidelines. Madison, Wisconsin: Society for Research on Nicotine and Tobacco; 2012. Google Scholar2 Fiore MC, Jaen CR, Baker TB, et al. Treating tobacco use and dependence: 2008 update. Clinical practice guideline. Rockville, MD: US Department of Health and Human Services Public Health Service; May 2008. www.ncbi.nlm.nih.gov/books/NBK63952/. Accessed 19 May 2016. Google Scholar Author, Article, and Disclosure InformationAffiliations: NYU School of Medicine, New York, New York, USA (H.W., S.S.M.)This article was published at Annals.org on 5 July 2016. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited bySmoking reduction interventions for smoking cessationStudy protocol for a non-inferiority trial of a blended smoking cessation treatment versus face-to-face treatment (LiveSmokefree-Study) 19 July 2016Volume 165, Issue 2Page: JC3KeywordsAttentionCarbon monoxideIntent to treat analysisMotivationNicotineNicotine replacement therapyNumber needed to treatNursesSmoking cessationSubstance abuse ePublished: 19 July 2016 Issue Published: 19 July 2016 Copyright & PermissionsCopyright © 2016 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Discordance Between Central (Brain) and Pancreatic Action of Exenatide in Lean and Obese Subjects
Authors: Roy Eldor, Giuseppe Daniele, Claudia Huerta, Mariam Al-Atrash, John Adams, Ralph DeFronzo, Timothy Duong, John Lancaster, Mahmoud Zirie, Amin Jayyousi, Muhammad Abdul-Ghani
Journal: Diabetes Care (2016)

This study examined the effect of exenatide on brain activity measured by functional (f)MRI and on insulin secretion in lean and obese normal-glucose-tolerant individuals.The brain fMRI signal in response to high-calorie-content food pictures was measured with and without intravenous exenatide infusion in 10 lean and 10 obese healthy volunteers. Insulin secretion was measured with a two-step (+100 and +200 mg/dL) hyperglycemic clamp with exenatide and with saline infusion.The brain fMRI signal in response to food pictures in amygdala, insula, hippocampus, and frontal cortex was significantly greater in obese versus lean individuals. Intravenous exenatide significantly inhibited the fMRI signal in response to food pictures in obese individuals but did not affect the brain fMRI signal in lean subjects. Conversely, exenatide infusion caused an 18.5-fold increase in insulin secretion in lean individuals compared with an 8.8-fold increase in obese subjects. No significant correlation was observed between inhibition of the brain fMRI signal and increase in insulin secretion during exenatide infusion.Exenatide causes greater augmentation in insulin secretion in lean compared with obese individuals but inhibits the brain response to food pictures only in obese individuals.
First-in-man combination phase I study of TAS-114 and S-1 in patients (pts) with advanced solid tumors.
Authors: Toshihiko Doi, Kiyotaka Yoh, Kohei Shitara, Hideaki Takahashi, Makoto Ueno, Satoshi Kobayashi, Manabu Morimoto, Shinichi Ohkawa, Takuji Okusaka, Hideki Ueno, Chigusa Morizane, Satoshi Shiba, Naohiro Okano, Daisuke Naruge, Fumio Nagashima, Junji Furuse, Kazuo Koba, Kazuharu Noguchi
Journal: Journal of Clinical Oncology (2015)

2544 Background: TAS-114 is a first-in-class oral deoxyuridine triphosphatase inhibitor, which acts as a modulator of the pyrimidine nucleotide metabolic pathway. We are conducting a first combination phase 1 dose escalation and expansion study of TAS-114 and S-1 to investigate the safety, maximum-tolerated dose (MTD), pharmacokinetics (PK), pharmacogenomics and preliminary antitumor efficacy in pts with advanced solid tumors refractory to standard therapy. Methods: TAS-114 was administrated orally BID for 14 days followed by 7 days rest at the starting dosage of 5 mg/m² with the fixed dosage of S-1 (30 mg/m²). Dose-limiting toxicity (DLT) was evaluated during the 1st cycle in dose escalation cohort (DEC), using a 3 + 3 design. Expansion cohort (EC) is conducted in parallel with DEC at the dosage which was confirmed tolerable in DEC. Results: As of 25 September 2014, 56 pts were enrolled with 36 pts in the DEC and 20 pts in the EC. In DEC, dosage of TAS-114 was escalated up to 240 mg/m² with a MTD not yet reached. In EC, TAS-114 was administrated at the dosage of 120 and 160 mg/m² with the fixed dosage of S-1 (30 mg/m²). Currently, we are planning the dose escalation of TAS-114 with Japanese approved fixed dose of S-1 (36 mg/m²). A recommended phase 2 dose is expected to be reached soon. Two pts at the dosage of 10 and 240 mg/m² developed DLTs, including grade 2 platelet count decreased and grade 3 aspartate aminotransferase increased. The most common treatment related adverse events were white blood cell decreased, anemia and rash. TAS-114 exposures tend to increase dose-dependently with large inter-individual variability. Preliminary antitumor efficacy was observed with acceptable safety in pts with NSCLC, gastric cancer and pancreatic neuroendocrine tumor. Especially, partial responses were confirmed in 2 of efficacy evaluable 6 pts with NSCLC. Further safety, PK and efficacy data will be presented. Conclusions: The combination therapy of TAS-114 and S-1 was well tolerated in pts with severe treated advanced solid tumors, resulting in the promising antitumor efficacy. Further safety and efficacy of this combination therapy will be investigated in this phase 1 and subsequent phase 2 study. Clinical trial information: NCT01610479 Clinical trial information: NCT01610479.
Human CLL Intraclonal Fractions Differ in Their Abilities to Respond to, Elicit, and Suppress Pro-Engraftment and Growth Signals From Autologous T Cells in a Murine Adoptive Transfer Model
Authors: Shih-Shih Chen, Piers E.M. Patten, Rita Simone, Sonia Marsilio, Jacqueline C. Barrientos, Jonathan E. Kolitz, Steven L. Allen, Kanti R. Rai, Nicholas Chiorazzi
Journal: Blood (2012)
Abstract 3687: p53 downregulates CRKL oncogene through miR-200
Authors: Takashi Tokino, Miyuki Tamura, Masashi Idogawa, Yasushi Sasaki
Journal: Cancer Research (2016)

Abstract Tumor suppressive miRNAs targeting oncogenes are frequently downregulated in cancers, which leads to the activation of the oncogene pathways. Thus, tumor suppressive miRNAs as well as their target oncogenes are proposed to be useful for cancer treatment. The downregulation of the miR-200 family has been involved in the progression and metastasis in cancers. The miR-200 family consists of two gene clusters: miR-200b/200a/429 and miR-200c/141 are located on human chromosome 1 and 12, respectively. Here, we identified that p53 response elements are located around both clusters of miR-200s and confirmed miR-200s as transcriptional targets of p53. in silico analysis of miRNA target predicted an oncogene CRKL as a potential target for miR-200b/200c/429. Moreover, miR-200b/200c/429 inhibit the expression of CRKL mRNA and protein by directly targeting its 3’-UTR region. Importantly, endogenous CRKL expression was decreased in cancer cells with introduction of wild-type p53. Moreover, downregulation of CRKL by siRNA in cancer cells inhibits cell growth. Oncomine database shows that CRKL levels are overexpressed in a subset of cancer types. Furthermore, CRKL is significantly overexpressed in primary breast cancer tissues harboring mutant TP53. Our results demonstrate that p53-target miRNAs, miR-200b/200c/429 are negative regulators of the CRKL oncogene. Citation Format: Takashi Tokino, Miyuki Tamura, Masashi Idogawa, Yasushi Sasaki. p53 downregulates CRKL oncogene through miR-200. [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 3687.
Phase I Study of Ontuxizumab, a Humanized Monoclonal Antibody Recognizing Endosialin/Tumor Endothelial Marker1 (Tem1), in Japanese Patients with Solid Tumor
Authors: T. Doi, K. Shitara, Y. Naito, K. Yoh, N. Matsubara, M. Tahara, K. Nakai, A. Ohtsu
Journal: Annals of Oncology (2014)
Osteoanabolic Implants: Osteoanabolic Implant Materials for Orthopedic Treatment (Adv. Healthcare Mater. 14/2016)
Authors: Yun‐Fei Ding, Rachel W. Li, Masaaki Nakai, Trina Majumdar, Dong‐Hai Zhang, Mitsuo Niinomi, Nick Birbilis, Paul N. Smith, Xiao‐Bo Chen
Journal: Advanced Healthcare Materials (2016)

On page 1740, Xiao-Bo Chen and co-workers report an orthopedic implant material specifically designed for osteoporotic bone fractures. A newl strontium phosphate coating applied to a bone-mimicking low elastic titanium alloy with a comparative Young's modulus to that of natural bone results in upregulating the growth of osteoblasts and downregulating that of osteoclasts. Such a promising osteoanabolic effect reveals a suitability in particular for patients who suffer from low quality bone organism and slow fracture recovery.
Abstract 3158: Prostate cancer derived biomarkers within platelets have the ability to predict therapeutic response in castration resistant patients
Authors: Lee-Ann Tjon-Kon-Fat, Marie Lundholm, Thomas Wurdinger, Camilla Thellenberg-Karlsson, Anders Widmark, Pernilla Wikström, Jonas Nilsson
Journal: Cancer Research (2016)

Abstract Background: Novel therapies for castration resistant prostate cancer (CRPC) have been introduced in the clinic with possibilities for individualized treatment plans. Best practice of those expensive drugs requires predictive biomarker monitoring. In this article a novel platform for circulating biomarker analysis has been used to follow cancer-derived transcripts implicated in therapy resistance. Method: The platelet population of blood samples and QRT-PCR were used to identify selected biomarkers in CRPC patient's prior chemo- or androgen synthesis (AS)-directed therapies. The association between biomarker statuses (positive vs. negative) and therapy response, progression-free survival (PFS) and overall survival (OS) was examined. Results: 40 patients received either docetaxel (n = 17) or AS-directed (n = 23) therapy, with a therapy response rate of 29% respectively 48%. The cancer-associated biomarkers were present within the platelet fraction. Analyzing these biomarkers in the chemotherapy group were associated with a short OS (p = 0.025). In the AS-directed group, the biomarkers were associated with shorter PFS (p = 0.015), and with an increased risk of therapy failure (HR: 5,5; p = 0,023), as well as short OS (p = 0.012). Conclusions: Analyzing circulating biomarkers in the platelet population enables us to predict who will benefit from AS-directed therapy with high accuracy, and platelet based analysis of cancer derived biomarkers may be used in treatment stratification of patients scheduled for AS-directed therapies. Citation Format: Lee-Ann Tjon-Kon-Fat, Marie Lundholm, Thomas Wurdinger, Camilla Thellenberg-Karlsson, Anders Widmark, Pernilla Wikström, Jonas Nilsson. Prostate cancer derived biomarkers within platelets have the ability to predict therapeutic response in castration resistant 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 3158.
Abstract 2926: The regulatory mechanism of human LY6K related to carcinogenesis and metastasis in breast cancer
Authors: Hyun Kyung Kong, Da Som Son, Jong Hoon Park
Journal: Cancer Research (2016)

Abstract The human lymphocyte antigen 6 complex locus K (LY6K) belongs to the lympocyte antigen 6/urokinase-type plasminogen activator receptor (Ly-6/uPAR) superfamily which are associated with development of the immune system and carcinogenesis. LY6K is a cancer biomarker and a therapeutic target that induces invasion and metastasis by activating the Raf-1/MEK/ERK signaling pathway and that stimulates cytotoxic T lymphocytes. However, the molecular mechanisms including genetic and epigenetic that determine human LY6K transcription are complete unknown. To elucidate the genetic mechanisms involved in human LY6K gene regulation and expression, multiple cis elements were predicted using TRANSFAC software, and the LY6K regulatory region was identified using the lucifearse assay in the human LY6K gene promoter. We performed chromatin immunoprecipitation, electrophoretic mobility shift analysis, and supershift assays to investigate the transcription factor activity on the LY6K promoter, and the effect of a single nucleotide polymorphism (SNP) and CpG site methylation on AP-1 transcription factor binding affinity. AP-1 and the CREB transcription factor bound to LY6K promoter within -550/-1, which was essential for LY6K expression but only the AP-1 heterodimer, JunD and Fra-1, modulates LY6K gene transcriptional level. A decrease in LY6K was associated with the SNP242 C allele, a polymorphic G/C-SNP at the 242 nucleotide in the LY6K promoter region (rs2585175), or methylation of the CpG site, which was closely located with the AP-1 site by interfering with binding of the AP-1 transcription factor to the LY6K promoter. In summary, AP-1 activation is important role in promoting LY6K gene expression that regulates cell mobility of breast cancer cells, whereas the SNP242 C allele or methylation of the CpG site may reduce the risk of invasion or metastasis by interfering AP-1 activation. And DNA methylation and histone modification in the 5’-flanking region of the LY6K gene plays an important role in LY6K expression in both breast cancer cells and breast cancer. An understanding of genetic and epigenetic changes in LY6K may contribute to the diagnosis of carcinogenic risk and to an enhanced prediction of outcome in patients with breast cancer. Citation Format: Hyun Kyung Kong, Da Som Son, Jong Hoon Park. The regulatory mechanism of human LY6K related to carcinogenesis and metastasis in breast 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 2926.
197. Balancing Anti-Tumor Efficacy with Local Inflammatory Toxicity for the Treatment of Diffuse Intrinsic Pontine Glioma and Other Brain Tumors
Authors: Matthew Schuelke, Laura Evgin, Tim Kottke, Jill Thompson, Christopher Driscoll, Elizabeth Ilett, Julia Cockle, Amulya NageswaraRao, Richard Bram, Alan Melcher, Richard Vile
Journal: Molecular Therapy (2016)

We have shown previously that multiple rounds of a systemic treatment of GM-CSF, followed by intravenous reovirus, leads to effective treatment of subcutaneous melanomas (Ilett et al., Mol. Ther. 2015). We show here that a similar regimen is also effective at treating both melanoma (B16) and glioma (GL261) tumors growing intra-cranially. As a result of these pre-clinical studies, we initiated a Phase I clinical trial in paediatric patients with gliomas of GM-CSF and reovirus therapy. To date, three patients have been treated. In two of three of these patients there were possible indications of pseudoprogression and intra-cranial inflammation, both of which were clinically resolved upon treatment with dexamethasone. Whilst this trial continues to recruit, we have investigated additional treatments for paediatric brain tumors, especially those in which direct virus injection may allow greater local access to tumor. In this respect, there is a constant tension between the pro-inflammatory, anti-tumor nature of oncolytic viroimmunotherapy and the need to reduce potentially toxic local inflammatory reactions within the brain. Our overall hypothesis is that it will be possible to balance the anti tumor effects of viral oncolysis, in part caused by inflammatory reactions to the virus, with the associated toxicity. Nowhere is this more relevant than for the treatment of Diffuse Pontine Gliomas (DIPG), which grow in the brain stem. Our experiments show that it is indeed possible to treat tumors growing in the pons/and or medulla, with inflammatory, immune based therapies (both T cell mediated and locally cytotoxic) without increasing toxicity over that caused by tumor growth alone. Therefore, we have screened multiple oncolytic virus types for their ability to kill DIPG cell lines both in vitro and in vivo. In particular, we have compared viruses with different speeds of oncolysis and different inflammatory properties to investigate how the efficacy can be balanced with local toxicity, using standard of care anti inflammatory treatments (with dexamethasone) as well as with novel agents and viruses designed to suppress local inflammatory reactions.