tbuckley/cabot-search huggingface dataset:
Peptidomimetic Targeting of Ca <sub>v</sub> β2 Overcomes Dysregulation of the L-Type Calcium Channel Density and Recovers Cardiac Function
Authors: Francesca Rusconi, Paola Ceriotti, Michele Miragoli, Pierluigi Carullo, Nicolò Salvarani, Marcella Rocchetti, Elisa Di Pasquale, Stefano Rossi, Maddalena Tessari, Silvia Caprari, Magali Cazade, Paolo Kunderfranco, Jean Chemin, Marie-Louise Bang, Fabio Polticelli, Antonio Zaza, Giuseppe Faggian, Gianluigi Condorelli, Daniele Catalucci
Journal: Circulation (2016)

Background: L-type calcium channels (LTCCs) play important roles in regulating cardiomyocyte physiology, which is governed by appropriate LTCC trafficking to and density at the cell surface. Factors influencing the expression, half-life, subcellular trafficking, and gating of LTCCs are therefore critically involved in conditions of cardiac physiology and disease. Methods: Yeast 2-hybrid screenings, biochemical and molecular evaluations, protein interaction assays, fluorescence microscopy, structural molecular modeling, and functional studies were used to investigate the molecular mechanisms through which the LTCC Ca v β2 chaperone regulates channel density at the plasma membrane. Results: On the basis of our previous results, we found a direct linear correlation between the total amount of the LTCC pore-forming Ca v α1.2 and the Akt-dependent phosphorylation status of Ca v β2 both in a mouse model of diabetic cardiac disease and in 6 diabetic and 7 nondiabetic cardiomyopathy patients with aortic stenosis undergoing aortic valve replacement. Mechanistically, we demonstrate that a conformational change in Ca v β2 triggered by Akt phosphorylation increases LTCC density at the cardiac plasma membrane, and thus the inward calcium current, through a complex pathway involving reduction of Ca v α1.2 retrograde trafficking and protein degradation through the prevention of dynamin-mediated LTCC endocytosis; promotion of Ca v α1.2 anterograde trafficking by blocking Kir/Gem-dependent sequestration of Ca v β2, thus facilitating the chaperoning of Ca v α1.2; and promotion of Ca v α1.2 transcription by the prevention of Kir/Gem-mediated shuttling of Ca v β2 to the nucleus, where it limits the transcription of Ca v α1.2 through recruitment of the heterochromatin protein 1γ epigenetic repressor to the Cacna1c promoter. On the basis of this mechanism, we developed a novel mimetic peptide that, through targeting of Ca v β2, corrects LTCC life-cycle alterations, facilitating the proper function of cardiac cells. Delivery of mimetic peptide into a mouse model of diabetic cardiac disease associated with LTCC abnormalities restored impaired calcium balance and recovered cardiac function. Conclusions: We have uncovered novel mechanisms modulating LTCC trafficking and life cycle and provide proof of concept for the use of Ca v β2 mimetic peptide as a novel therapeutic tool for the improvement of cardiac conditions correlated with alterations in LTCC levels and function.
Abstract 3899: Preclinical development of tetra-branched NT4 peptide theranostics
Authors: Jlenia Brunetti, Lorenzo Depau, Chiara Falciani, Giulia Riolo, Elisabetta Mandarini, Alessandro Pini, Luisa Bracci
Journal: Cancer Research (2016)

Abstract The tetra-branched peptide NT4 is a potential cancer theranostic, which very selectively binds to human cancer tissues in different malignancies and can efficiently and selectively deliver drugs or liposomes for cancer cell imaging or therapy, in vitro and in vivo. By using NT4 conjugated to methotrexate or 5FdU we obtained significant reduction of tumor growth in xenografted nude mice. Very recently we reported that conjugation of paclitaxel to NT4 leads to increased therapeutic activity of the drug in an orthotopic model of breast cancer in mice and produces tumor regression which is not achieved with unconjugated paclitaxel in identical experimental conditions. We demonstrated that NT4 specifically binds to sulfated glycosaminoglycans and LRP receptors on cancer cells and tissues. Considering the role of sulfated glycosaminoglycans in cancer cell interaction with the extracellular matrix, we have analyzed the effect of NT4 in cancer cell adhesion and migration on different supports. NT4 inhibits adhesion and migration of different human cancer cell lines, strongly affecting directionality of cell movement. We have also constructed and validated a novel theranostics nanodevices, by conjugation of NT4 to quantum dots, for selective diagnosis and imaging of different human carcinomas. Thanks to their high cancer selectivity and versatile chemical conformation, NT4 peptides can be exploited for constructing cancer theranostics, which may also reduce tumor aggressiveness and metastatic potential by inhibiting cancer cell migration. References: Falciani, C. et al. Cancer selectivity of tetrabranched neurotensin peptides is generated by simultaneous binding to sulfated glycosaminoglycans and protein receptors. J Med Chem. 2013, 56, 5009-18. Brunetti, J. et al. Tumor-selective peptide-carrier delivery of Paclitaxel increases in vivo activity of the drug. Scientific Reports. DOI:10.1038/srep17736. Citation Format: Jlenia Brunetti, Lorenzo Depau, Chiara Falciani, Giulia Riolo, Elisabetta Mandarini, Alessandro Pini, Luisa Bracci. Preclinical development of tetra-branched NT4 peptide theranostics. [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 3899.
An update on the role of intestinal cytochrome P450 enzymes in drug disposition
Authors: Fang Xie, Xinxin Ding, Qing-Yu Zhang
Journal: Acta Pharmaceutica Sinica B (2016)

Oral administration is the most commonly used route for drug treatment. Intestinal cytochrome P450 (CYP)-mediated metabolism can eliminate a large proportion of some orally administered drugs before they reach systemic circulation, while leaving the passage of other drugs unimpeded. A better understanding of the ability of intestinal P450 enzymes to metabolize various clinical drugs in both humans and preclinical animal species, including the identification of the CYP enzymes expressed, their regulation, and the relative importance of intestinal metabolism compared to hepatic metabolism, is important for improving bioavailability of current drugs and new drugs in development. Here, we briefly review the expression of drug-metabolizing P450 enzymes in the small intestine of humans and several preclinical animal species, and provide an update of the various factors or events that regulate intestinal P450 expression, including a cross talk between the liver and the intestine. We further compare various clinical and preclinical approaches for assessing the impact of intestinal drug metabolism on bioavailability, and discuss the utility of the intestinal epithelium-specific NADPH-cytochrome P450 reductase-null (IECN) mouse as a useful model for studying in vivo roles of intestinal P450 in the disposition of orally administered drugs.
Crizotinib treatment for refractory pediatric acute myeloid leukemia with RAN-binding protein 2-anaplastic lymphoma kinase fusion gene
Authors: A Hayashi, R Tanoshima, S-I Tsujimoto, M Yanagimachi, M Takeuchi, K Sasaki, J Ikeda, R Kajiwara, S Ito, H Takahashi
Journal: Blood Cancer Journal (2016)

Crizotinib treatment for refractory pediatric acute myeloid leukemia with RAN-binding protein 2-anaplastic lymphoma kinase fusion gene
SUV in pelvic lymph node is a significant prognostic factor in previously untreated squamous carcinoma of the uterine cervix
Authors: C. Lai, T. Yen, S. Ma, C. Tsai, K. Ng, T. Chang
Journal: Journal of Clinical Oncology (2006)

5051 Background: The aim of this prospective study was to identify prognostic factors (including 18 F-fluorodeoxyglucose positron emission tomography [FDG-PET] parameters) in previously untreated squamous carcinoma of the uterine cervix with MRI- or CT-defined pelvic or para-aortic lymph node (PLN or PALN) metastasis. Methods: This study included pooled patients selected from two prospective studies who had untreated squamous cell cervical cancer and PLN or PALN metastasis (diagnostic score 3 or 4) by CT-MRI and additional FDG-PET scans were performed for primary staging. Recurrence-free and overall survivals (RFS and OS) were evaluated using the Kaplan-Meier method. Prognostic variables were assessed by the log-rank test and Cox proportional hazards regression method. Optimal cut-offs of standardized uptake value (SUV) in primary tumor, PLN and PALN were determined by receiver operating characteristic and area under the curve analysis. Results: A total of 70 patients were eligible for analysis. The follow-up time ranged 16–59 months (mean ± SD: 38 ± 18). In univariate analyses, FIGO stage ≥ III, PET defined bilateral PLN-positive, PET defined PLN-positive, PET defined PALN-positive and SUV cut-off of 3.04 at PLN and 4.18 at PALN were significant for RFS. FIGO stage ≥ III, SUV cut-offs of 2.94–3.15 at PLN and SUV cut-offs of 2.61–4.91 at PALN were significant for OS. Multivariate analysis showed only SUVmax cut-off of 3.04 at PLN was a significant adverse factors for RFS (RR: 10.1 95% CI 2.2–46.0; P = 0.003) and OS (RR: 11.7 95% CI 1.5–92.6; P = 0.019), while SUVmax cut-off of 4.18 at PALN (P = 0.062) was marginally significant for OS. Conclusions: SUVmax cut-off of 3.04 at PLN was a significant adverse factor for RFS and OS in previously untreated squamous carcinoma of the uterine cervix with MRI- or CT-defined PLN or PALN metastasis. No significant financial relationships to disclose.
Electronic Health Records Quantify Previously Existing Phenomenon—Physicians Spend Hours Coordinating Care
Authors: Wen Dombrowski, Brian Clay, Jeana D. O'Brien
Journal: JAMA Internal Medicine (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 Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast 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 Internal Medicine journal
Abstract 3073: Targeting chronic lymphocytic leukemia by interfering glutathione synthesis using a novel therapeutic enzyme cyst(e)inase (AEB3103)
Authors: Jinyun Liu, Li Feng, Everett M. Stone, Joseph Tyler, Scott W. Rowlinson, Michael J. Keating, Peng Huang
Journal: Cancer Research (2016)

Abstract Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the Western countries. Despite recent advance in new therapeutic agents that have improved treatment outcomes, CLL remains incurable due in part to the inability to completely eradicate the leukemia cells in vivo. Previous studies showed that CLL cells have high intrinsic oxidative stress and are highly dependent on cellular antioxidant glutathione (GSH) to maintain redox balance and cell viability. One logical strategy to impact CLL cells would be to abrogate the glutathione protection of CLL cells in vivo. Recently we discovered that primary leukemia cells isolated from CLL patients were unable to effectively utilize cystine for GSH synthesis due to low expression of the cystine transporter Xc-, and that bone marrow stromal cells highly express Xc- and effectively take up cystine for conversion to cysteine (Zhang et al: Nature Cell Biology, 2012). These findings provide a biochemical basis to develop novel strategies to effectively target leukemia cells in the stromal microenvironment and improve in vivo therapeutic activity. In this study, we tested the depletion of extracellular cystine and cysteine using a novel therapeutic enzyme-cyst(e)inase (AEB3103), as a potential way to block GSH synthesis in CLL cells and abolish the stromal protection of the leukemia cells. Our study showed that AEB3103 was very effective in depleting GSH in CLL cells and caused massive CLL cell death even in the presence of stromal cells. Importantly, AEB3103 could also overcome drug resistance of CLL cells with p53 deficiency both in primary leukemia cells isolated from CLL patients with 17p deletion and mouse leukemic cells isolated from mouse model we recently reported (Liu et al: Leukemia, 2014). In addition, AEB3103 showed very low toxicity to normal cells. These promising in vitro data warrant further animal studies, which are currently on ongoing using the CLL mouse model with TCL1-Tg:p53-/- genotype. Our study suggests that AEB3103 and its combination with standard anti-CLL drugs may potentially be useful for clinical treatment of CLL, even for the more aggressive CLL subtypes with unfavorable cytogenetic alterations such as those with chromosome17p deletion and p53 mutations, and may improve in vivo therapeutic activity. Citation Format: Jinyun Liu, Li Feng, Everett M. Stone, Joseph Tyler, Scott W. Rowlinson, Michael J. Keating, Peng Huang. Targeting chronic lymphocytic leukemia by interfering glutathione synthesis using a novel therapeutic enzyme cyst(e)inase (AEB3103). [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 3073.
Abstract 4698: BET protein inhibitors prevent TKI-induced drug resistance in solid tumors
Authors: Yuan Zhao, Yiyuan Wu, Hexiang Wang, Bo Ren, Ye Liu, Min Wei, Changyou Zhou, Lusong Luo
Journal: Cancer Research (2016)

Abstract Acquired drug resistance is one of the major challenges for clinical application of tyrosine kinase inhibitor (TKI) in cancer treatment. TKI-induced drug resistance could develop as a result of adaptive cell reprogramming that leads to pathway feedback activation in the same signaling pathway or parallel pathways or gatekeeper mutations abolishing drug binding. The findings of reversible drug response and lack of genetic mutations in TKI-resistant tumor cells suggest epigenetic basis during resistance development process. Targeting epigenetic modifiers and readers, in particular, the bromodomain and extra-terminal (BET) protein family, has shown promising efficacies against both primary and drug-resistant hematological malignancies via modulating transcription profile and suppressing the MYC oncogene. BGB-3619 is a novel, potent inhibitor of BET family proteins (BRD2, BRD3, BRD4 and BRDT) with IC50 ranging from 20 to 49 nM. It demonstrates superior anti-proliferation activity than iBET762 in multiple leukemia and lymphoma cell lines. In this study, we investigated the effect of BGB-3619 and iBET762 on solid tumor cells during and after TKI-resistance development. From cell killing assays, BET inhibitors were found to be much more potent to TKI-resistant cells (vemurafenib-resistant A375, HT29, SK-MEL-5, cells and erlotinib-resistant HCC827 cells) than their parental cells. Notably, long-term colony formation assays showed that combination of low dose BET inhibitors and TKI effectively suppressed the expansion of TKI-tolerated cell populations. The enhanced sensitivity of TKI-resistant cells to BET inhibitor was due to strong G1 phase arrest rather than induction of apoptosis. Furthermore, BET inhibitors blocked cell proliferation independent of c-Myc inhibition, suggesting they might affect a broad transcription network and provide favorable epigenetic state to induce cell cycle arrest. Taken together, these findings suggested potential therapeutic activity of BET inhibitor in TKI-resistant solid tumors and a strategy of combining BET inhibitors with TKIs to overcome resistance to targeted cancer therapies. Citation Format: Yuan Zhao, Yiyuan Wu, Hexiang Wang, Bo Ren, Ye Liu, Min Wei, Changyou Zhou, Lusong Luo. BET protein inhibitors prevent TKI-induced drug resistance in solid tumors. [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 4698.
Abstract 2389: Microarray analysis of polysome-associated mRNAs from different regions of the same human glioblastoma reveals intratumoral heterogeneity
Authors: Glaucia N. Hajj, Fernanda S. Lupinacci, Martín Roffé, Hellen Kuasne, Tiago G. Santos, Victor P. Andrade, Paulo Sanematsu, Vilma R. Martins, Silvia R. Rogatto
Journal: Cancer Research (2016)

Abstract Glioblastoma is among the most aggressive tumor type and less responsive to chemotherapeutic agents, thus a better understanding of the behavior of these tumors may help to develop new treatments for this disease. Currently, many genome-wide projects attempt to define general patterns of gene expression based on deep sequencing or microarray data from total mRNA populations. However, this approach provides little information about the molecular mediators of tumor biology, because the expression levels of mRNAs do not necessarily reflect the levels of proteins. The identification of mRNAs target of translational alterations in tumors can show gene expression profiles that better reflect the population of proteins. In this work we were able to identify mRNAs differentially translated in a human glioblastoma that presented histologically different parts. The sample was divided in 8 pieces that were classified as high or low grade based on histological characteristics. Actively translating ribosomes and their associated mRNAs were isolated biochemically through a polysomal profile. Total and polysomal mRNA was then extracted and submitted to a microarray analysis. By comparing high vs low grade tumor pieces, we were able to identify more differentially translated genes (138 genes) than differentially expressed genes (43 genes). Among the differentially translated mRNAs, there are many related to proliferation, development and cancer. By Integrated Pathway Analysis, we identified the TGF-β pathway among the the most relevant for grade progression. Thus, the technique of isolating mRNAs engaged in translation can be used to identify biomarkers of tumor progression, leading to new therapeutic approaches. Citation Format: Glaucia N. Hajj, Fernanda S. Lupinacci, Martín Roffé, Hellen Kuasne, Tiago G. Santos, Victor P. Andrade, Paulo Sanematsu, Vilma R. Martins, Silvia R. Rogatto. Microarray analysis of polysome-associated mRNAs from different regions of the same human glioblastoma reveals intratumoral heterogeneity. [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 2389.
Abstract 398: Real-life example of biobanking: results of the PATH Biobank
Authors: Tobias Anzeneder, Ulla Ohlms, Heinz Bodenmüller
Journal: Cancer Research (2016)

Abstract Introduction: Since 2002, PATH Foundation has kept a biobank collecting high-quality fresh frozen breast cancer specimens adhering to uniform SOPs at seven certified breast cancer centres in Germany. Research groups from academia and industry can obtain samples after application and review. PATH Biobank is a not-for-profit organisation and asks for a cost recovery fee in exchange for sample allocation to sustainably finance the expenses it incurs. Material and methods: The PATH Biobank consists of a centralized database and a decentralized bio repository. The samples are collected and stored at seven institutes for pathology at certified German breast cancer centres. Tumour tissue, along with normal (benign) adjacent tissue and blood serum aliquots are processed, labelled and stored according to uniform SOPs. Informed consent to biobanking and the use of the samples and data for research is obtained from the donors individually during pre-operation discussions. Results: Since 2004, more than 8,600 breast cancer patients have given their informed consent to the storage and analysis of their tissue and blood serum for research purposes. Breast cancer tissue samples from 59% of donors could be stored due to size of the surgically removed tissue specimen. In addition, normal adjacent tissue is available from 62% of donors and blood serum aliquots can be derived from 92% of patients. Using the annotating data, 96% of donors can be classified into the intrinsic molecular breast cancer subtypes in accordance with the St. Gallen Criteria. In 2008, PATH Biobank started to support research groups by providing breast cancer samples and data as well as informing the public about the projects on-line. In 2015 three co operations resulted in scientific publications. One landmark collaborations started in 2012 and has been studying the frequency and background of defined mutations in breast cancer. A number of 701 tissue samples have been used for this study. All samples were subject to quality testing, only 11% failed due to less than 5% tumour content. Tumour content depended on clinical conditions and staging (ranging from 34% failure in samples derived from neo adjuvantly treated patients to 2% in cases with staging UICC IV). Additional results concerning the quality of samples from PATH Biobank will be presented. Conclusions: For breast cancer research and biomarker studies, PATH Biobank can be a valuable resource. Citation Format: Tobias Anzeneder, Ulla Ohlms, Heinz Bodenmüller. Real-life example of biobanking: results of the PATH Biobank. [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 398.