tbuckley/cabot-search huggingface dataset:
Abstract 1114: Combining anti-androgen therapy and PARP inhibition results in synergistic cytotoxicity of metastatic castration-resistant prostate cancer (mCRPC) cells
Authors: Sahithi Pamarthy, Vinay Sagar, Rajita J. Vatapalli, Zachary Reinstein, Muhammad Zayd Ansari, Benedito A. Carneiro Filho, Francis J. Giles, Sarki A. Abdulkadir
Journal: Cancer Research (2017)

Abstract Androgen deprivation therapy is an efficient first line therapy for advanced prostate cancer. However, in most cases resistance inevitably develops resulting in metastatic castration-resistant prostate cancer (mCRPC). Abiraterone and enzalutamide are approved to treat mCRPC and act by inhibiting androgen biosynthesis and androgen receptor (AR) signaling, respectively. Poly (ADP-ribose) polymerase 1 (PARP1) is a key enzyme in the DNA damage repair pathway and has also been implicated in AR signaling cascade. Recent reports suggest significant efficacy combining anti-androgens and inhibitors of Poly (ADP-ribose) polymerase (PARP) particularly against cells harboring mutations in the DNA repair pathway. Here, we provide evidence of synergistic cytotoxicity combining PARP inhibition and androgen signaling ablation in the AR positive human CRPC cell line 22RV1 harboring mutation in the DNA repair gene BRCA2. The PARP inhibitor talazoparib (IC50 - 0.05 μM) was upto 20 times more potent than olaparib (IC50 – 1.0 μM) in inducing cell death in 22RV1 as seen by cell viability and clonogenic assays. When combined with AR antagonist enzalutamide (IC50 – 0.25 μM) or androgen synthesis inhibitor abiraterone (IC50 – 1.25 μM) both PARP inhibitors showed significant synergy, although talazoparib was more prominent owing to its superior potency. Higher concentrations of enzalutamide and abiraterone (&amp;gt;10μM) induced PARP cleavage and increased expression of γ-H2AX, a marker for DNA damage. Our results suggest that AR signaling inhibition involves PARP mediated apoptosis and highlight the crosstalk between PARP and AR pathways. In summary, combining anti-androgen therapy and PARP inhibitors carry significant therapeutic potential for CRPC patients harboring mutations in DNA repair pathway. Citation Format: Sahithi Pamarthy, Vinay Sagar, Rajita J. Vatapalli, Zachary Reinstein, Muhammad Zayd Ansari, Benedito A. Carneiro Filho, Francis J. Giles, Sarki A. Abdulkadir. Combining anti-androgen therapy and PARP inhibition results in synergistic cytotoxicity of metastatic castration-resistant prostate cancer (mCRPC) cells [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 1114. doi:10.1158/1538-7445.AM2017-1114
Abstract P160: N-Type Ca <sup>2+</sup> Channel Blockade Prevents Sudden Death in Mice with Heart Failure
Authors: Yuko Yamada, Koichiro Kuwahara, Hideyuki Kinoshita, Yoshihiro Kuwabara, Yasuaki Nakagawa, Junko Shibata, Takeya Minami, Shinji Yasuno, Satoshi Usami, Toshio Nishikimi, Kenji Ueshima, Yasuo Mori, Kazuwa Nakao
Journal: Circulation Research (2011)

Background - Increased sympathetic nerve activity is involved in the increased arrhythmogenicity seen in patients with chronic heart failure. N-type Ca 2+ channel (NCC) modulates sympathetic nerve activity by regulating calcium entry at sympathetic nerve terminal, which triggers the release of the neurotransmitter noradrenalin. The ability of NCC blockade to prevent lethal arrhythmias associated with heart failure has never been tested, however. Methods and Results - We compared effects of cilnidipine (Cil), dual N-and L-type Ca 2+ channel blocker, with those of nitrendipine (Nit), a selective L-type Ca 2+ channel blocker, in a cardiac-specific, dominant-negative form of neuron-restrictive silencer factor transgenic mice (dnNRSF-Tg), a mouse model of dilated cardiomyopathy leading to sudden arrhythmic death. Hemodynamic and echocardiographic analyses showed no significant difference among the control, Cil, and Nit groups. In contrast, Cil dramatically improved the survival rate (p&lt;0.001) and reduced ventricular arrhythmia (p&lt;0.05) among dnNRSF-Tg mice, compared with control vehicle or Nit (n=22 for WT, n=20 for Tg without drugs, n=22 for Tg with Cil, n=23 for Tg with Nit). Cil improved the imbalance in autonomic nerve activity assessed by heart rate valiability, and also reduced the increased urinary excretion of noradrenalin seen in dnNRSF-Tg, whereas Nit did not. Conclusions - NCC blockade ameliorated disturbed autonomic nerve function and improved survival in a mouse model of dilated cardiomyopathy and sudden death. Our findings suggest NCC blockade is a potentially useful approach to preventing sudden cardiac death in patients with heart failure.
Impact of Sustained Virologic Response with Direct‐Acting Antiviral Treatment on Mortality in Patients with Advanced Liver Disease
Authors: Lisa I. Backus, Pamela S. Belperio, Troy A. Shahoumian, Larry A. Mole
Journal: Hepatology (2017)

The impact of sustained virologic response (SVR) on mortality after direct‐acting antiviral treatment is not well documented. This study evaluated the impact of direct‐acting antiviral–induced SVR on all‐cause mortality and on incident hepatocellular carcinoma (HCC) in 15,059 hepatitis C virus–infected patients with advanced liver disease defined by a FIB‐4 &gt;3.25. Overall, 1,067 patients did not achieve SVR (no SVR) and 13,992 patients achieved SVR. In a mean follow‐up period of approximately 1.6 years, 195 no SVR patients and 598 SVR patients died. Mortality rates were 12.3 deaths/100 patient years of follow‐up for no SVR patients and 2.6 deaths/100 patient years for SVR patients, a 78.9% reduction ( P &lt; 0.001). Among patients without a prior diagnosis of HCC, 140 no SVR patients and 397 SVR patients were diagnosed with incident HCC. HCC rates were 11.5 HCCs/100 patient years for no SVR patients and 1.9 HCCs/100 patient years for SVR patients, an 83.5% reduction ( P &lt; 0.001). In multivariable Cox proportional hazard models controlling for baseline demographics, clinical characteristics, and comorbidities, SVR was independently associated with reduced risk of death compared to no SVR (hazard ratio, 0.26; 95% confidence interval, 0.22‐0.31; P &lt; 0.001). A history of decompensated liver disease (hazard ratio, 1.57; 95% confidence interval, 1.34‐1.83; P &lt; 0.001) and decreased albumin (hazard ratio, 2.70 per 1 g/dL decrease; 95% confidence interval, 2.38‐3.12; P &lt; 0.001) were independently associated with increased risk of death. Conclusion: Those achieving SVR after direct‐acting antiviral treatment had significantly lower all‐cause mortality and lower incident HCC rates than those who did not achieve SVR.
Abstract 804: Zebrafish as a model organism to study human pancreatic CSC's
Authors: Laura E. Sanchez, Pablo Cabezas Sainz, Bruno Sainz, Laura Muinelo, Rafael Lopez
Journal: Cancer Research (2017)

Abstract Zebrafish is establishing itself as a powerful animal model for understanding human disease, including cancer. Xenotransplantation of human cancer cells into zebrafish is becoming an attractive research tools for studying cancer behaviour, both for established lines and primary tumours, however, its utility as a model for cancer stem cells (CSCs) is still in its infancy. In addition, only when the differences between primary tumours and established cancer cell lines are minimized will we be truly one step closer to developing biologically relevant personalized medicine platforms for cancer. To address these two limitations, we set out to achieve a deeper behavioral understanding of pancreatic CSCs inside the zebrafish embryo. The main methodology of this study was focused on the xenotransplantation of human primary pancreatic ductal adenocarcinoma (PDAC) cells (185 scd line) into zebrafish embryos using two different conditions: adherent cells (non-CSCs) vs sphere-derived cells (CSCs). Marked with a lipophilic dye, cells were injected into zebrafish embryos and incubated at 36ºC during 48h/72h to assess the proliferation of the injected cells. Self-developed Matlab software was used to analyze the intensity and area of the injected cells in order to give a ‘proliferation ratio’. Results obtained indicated that the sphere-derived cells proliferated and migrated at a higher rate than adherent cells. This is likely due to the different CSC content present between the two conditions tested: adherent pancreatic 185 cells contain 1% CSCs versus the 15% enrichment of CSCs in sphere-derived 185 cells. Apart from the differential CSC content, we also hypothesize that the 3D environment afforded by the yolk sac of the zebrafish embryo additionally favors the expansion of CSCs. Importantly, similar results were obtained with CSCs isolated via FACsorting, using autofluorescence as a marker for CSCs. This work not only contributes to the behavioral understanding of pancreatic CSCs using the zebrafish model organism but more importantly concludes that 1) PDAC CSC proliferation and migration can be studied in zebrafish, 2) the zebrafish model represents a potentially powerful surrogate model for the study of PDAC CSC biology in vivo, and 3) this model can potentially be adapted for to test chemotherapeutics that specifically target PADC CSCs, the cell type considered to be the most chemoresistant and tumorigenic in pancreatic cancer. Citation Format: Laura E. Sanchez, Pablo Cabezas Sainz, Bruno Sainz, Laura Muinelo, Rafael Lopez. Zebrafish as a model organism to study human pancreatic CSC's [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 804. doi:10.1158/1538-7445.AM2017-804
Abstract 3549: C-MYC sensitizes GBM with primitive features to glutamine metabolism disruption
Authors: Brad Andrew Poore, Isabella Taylor, Jeffrey Rubens, Allison Hanaford, Micah Maxwell, Charles Eberhart, Eric Raabe
Journal: Cancer Research (2017)

Abstract Glioblastoma (GBM) is among the most lethal of known human cancers, with a median survival of less than 15 months. The highly infiltrative nature and genetic heterogeneity of GBM renders treatment difficult. Therefore, better and more targeted therapies are needed for patients with GBM. There is a new WHO subset of GBM that contains primitive neuronal components (GBM-PNC). These tumors can arise from a histologically classic GBM, and often the GBM-PNC portions of the tumor contain C-MYC or N-MYC amplifications. High MYC expression is known to alter cellular metabolism, increasing reliance on glutamine, which may create opportunities for therapeutic intervention. We hypothesized that depriving GBM-PNC cells of glutamine using metabolic inhibitors would suppress growth and tumorigenicity. To create genetically appropriate GBM-PNC models, we derived cortex (CTX) human neural stem cells and transformed them through lentiviral expression of mutant p53, constitutively-active AKT and hTERT. Transformed neurospheres were then lentivirally transduced with either C-MYC or BMI1. These models formed aggressive tumors in mice and recapitulated the histological features of GBM with expression of NESTIN, GFAP, and MAP2. When treated with the glutamine metabolic inhibitors DON or Acivicin, transformed neurospheres that expressed C-MYC had decreased cellular proliferation (BrdU incorporation, P&amp;lt;0.05) and increased apoptosis (cleaved caspase-3 expression, P&amp;lt;0.05) while neurospheres expressing BMI1 had no statistically significant changes. Additionally, cells overexpressing C-MYC had an increased expression of glutaminase, an essential enzyme for glutamine incorporation into the TCA cycle. We hypothesize that C-MYC expression sensitizes GBM-PNET cancer cell lines to DON or Acivicin inhibition through greater reliance upon glutamine for its TCA cycle intermediates. In addition C-MYC upregulates multiple glutamine transporters, which may also be used to transport DON and/or Acivicin inside the cell, conferring increased sensitivity. After further validating glutamine metabolic inhibitors in orthotopic xenografts and investigating the mechanism of action by metabolomics, we anticipate that metabolic inhibitors may have a therapeutic role in GBM-PNC. Citation Format: Brad Andrew Poore, Isabella Taylor, Jeffrey Rubens, Allison Hanaford, Micah Maxwell, Charles Eberhart, Eric Raabe. C-MYC sensitizes GBM with primitive features to glutamine metabolism disruption [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 3549. doi:10.1158/1538-7445.AM2017-3549
Costly comorbidities of COPD: the ignored side of the coin?
Authors: Job F.M. van Boven
Journal: European Respiratory Journal (2017)

Correct, the alliteration in this editorial's title is not a co-incidence! Ironically, COPD and comorbidity both start with two identical letters and previously in this journal it has even been suggested twice that COPD could also stand for "COmorbidity with Pulmonary Disease" [1, 2]. However, after having been the only notorious couple for a long time, from now on they will have to face some fierce competition from a new rising kid on the "co"-block: costs. Comorbidities more costly than COPD itself: multimorbidity requires change in healthcare practice and financing! <http://ow.ly/2fSU30cAGTI>
Abstract 1184: Characterization of novel STAT5 inhibitors to interfere with the oncogenic activities of STAT5 in hematopoietic diseases
Authors: Bettina Wingelhofer, Barbara Maurer, Elizabeth C. Heyes, Patricia Freund, Abbarna A. Cumaraswamy, Jisung Park, Stefan Kubicek, Peter Valent, Patrick T. Gunning, Richard Moriggl
Journal: Cancer Research (2017)

Abstract Activation of the transcription factor STAT5 is essential for the pathogenesis of acute myeloid leukemia (AML) containing the FLT3 internal tandem duplication (ITD). FLT3 ITD is a constitutively active tyrosine kinase (TK) that drives the activation of STAT5 leading to the growth and survival of AML cells. Although there has been some success in identifying TK inhibitors that block the function of FLT3 ITD, treatment options are still limited. This is mainly due to drug resistance development by mutations that allow for the continued activation of STATs. Since STAT5 represents a critical mediator of malignant cellular behavior and sits at the convergence point of many kinase pathways, the direct targeting of STAT5 may be an effective means of overcoming this resistance to TK inhibitors. First, we screened a library of potential STAT5 inhibitors for specific SH2 domain binders using a fluorescent polarization assay. Thereby, we identified small inhibitory molecules, called AC-3-019 and AC-4-130, that bind to the SH2 domain of STAT5, subsequently resulting in the disruption of the reciprocal STAT5-phosphopeptide interactions. They efficiently blocked kinase-mediated phosphorylation, dimer formation, nuclear translocation, DNA binding and STAT5 mediated target gene expression. Further, we observed a time- and dose-dependent impairment of proliferation, blocked cell cycle progression and increased apoptosis. Studies with human AML patient-derived samples similarly showed an induction of apoptotic cell death and decreased colony forming capabilities. A combinatorial drug screen revealed synergistic effects with TK inhibitors, as well as with drugs standardly used in the treatment of AML patients, e.g. Cytarabine. Finally, AC-3-019 and AC-4-130 significantly suppressed tumor growth in vivo without general toxicity in healthy organs. Overall, our findings indicate that AC-3-019 and AC-4-130 are potent and selective inhibitors of STAT5. These compounds provide lead structures for further chemical modifications and clinical development for the identification of compounds to improve existing therapies. Citation Format: Bettina Wingelhofer, Barbara Maurer, Elizabeth C. Heyes, Patricia Freund, Abbarna A. Cumaraswamy, Jisung Park, Stefan Kubicek, Peter Valent, Patrick T. Gunning, Richard Moriggl. Characterization of novel STAT5 inhibitors to interfere with the oncogenic activities of STAT5 in hematopoietic diseases [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 1184. doi:10.1158/1538-7445.AM2017-1184
Abstract 2894: Epinephrine-induced gamma-secretase/Notch signaling in pancreatic cancer stem cells
Authors: Xuemin Xu, Chen Hu, Hildegard M. Schuller
Journal: Cancer Research (2017)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer deaths with 5-year survivals below 10%. Cancer stem cells represent a small population of cells in PDAC and are thought to drive the development, progression, metastasis and drug resistance of this cancer. The Notch pathway regulates the self-renewal of pancreatic cancer stem cells as well as angiogenesis and drug resistance. Gamma-secretase cleaves the Notch-1 receptor, resulting in release of the Notch intracellular domain (NICD) that then translocates to the nucleus and activates the transcription of target genes. Aberrant Notch signaling activated by γ-secretase activity is associated with progression, angiogenesis and drug resistance of PDAC and is being explored as a target for PDAC therapy. Smoking and psychological stress are risk factors for PDAC. However, the potential modulation of γ-secretase/Notch by these risk factors has not been investigated to date. Nicotine and psychological stress both cause hyperactivity of the sympathetic nervous system and adrenal glands, resulting in increased blood and organ levels of the stress neurotransmitters norepinephrine (NOR) and epinephrine (EPI), which are the physiological agonists of beta-adrenergic receptors (β-ARs). In turn, β-ARs are coupled to the stimulatory G-protein Gαs that stimulates the formation of intracellular cAMP, which activates multiple signaling pathways in a cell type-specific manner. Using spheroid formation assays and Western blotting, our data show, -for the first time,- that the stress neurotransmitter Epi significantly increases the self-renewal of pancreatic cancer stem cells by increasing the expression of the activated forms (c-terminal) of the γ-secretase component presenilin1 and of Notch1 (NICD). These responses were inhibited by the β-AR antagonist (beta-blocker) propranolol and by the inhibitory neurotransmitter γ-aminobutyric acid (GABA) that inhibits cAMP formation via activation of Gαi-coupled GABAB receptors. These findings suggest that the γ-sexretasesecretase/Notch pathway in pancreatic cancer stem cells is under regulatory control by neurotransmitters, with Epi as stimulator and GABA as inhibitor. These data could open up new avenues for the prevention and therapy of PDAC. Additional experiments are currently underway to further investigate mechanistic aspects of this novel concept. Supported by RO1CA042829 with NIH. Note: This abstract was not presented at the meeting. Citation Format: Xuemin Xu, Chen Hu, Hildegard M. Schuller. Epinephrine-induced gamma-secretase/Notch signaling in pancreatic cancer stem cells [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 2894. doi:10.1158/1538-7445.AM2017-2894
Efficacy and Safety of MIN-101: A 12-Week Randomized, Double-Blind, Placebo-Controlled Trial of a New Drug in Development for the Treatment of Negative Symptoms in Schizophrenia
Authors: Michael Davidson, Jay Saoud, Corinne Staner, Nadine Noel, Elisabeth Luthringer, Sandra Werner, Joseph Reilly, Jean-Yves Schaffhauser, Jonathan Rabinowitz, Mark Weiser, Remy Luthringer
Journal: American Journal of Psychiatry (2017)

Objective: The authors assessed the efficacy, safety, and tolerability of MIN-101, a compound with affinities for sigma-2 and 5-HT2A receptors and no direct dopamine affinities, in comparison with placebo in treating negative symptoms in stabilized patients with schizophrenia. Method: The trial enrolled 244 patients who had been symptomatically stable for at least 3 months and had scores of at least 20 on the negative subscale of the Positive and Negative Syndrome Scale (PANSS). After at least 5 days’ withdrawal from all antipsychotic medication, patients were randomly assigned to receive placebo or 32 mg/day or 64 mg/day of MIN-101 for 12 weeks. The primary outcome measure was the PANSS negative factor score (pentagonal structure model). Secondary outcome measures were PANSS total score and scores on the Clinical Global Impressions Scale (CGI), the Brief Negative Symptom Scale, the Brief Assessment of Cognition in Schizophrenia, and the Calgary Depression Scale for Schizophrenia. Results: A statistically significant difference in PANSS negative factor score was observed, with lower scores for the MIN-101 32 mg/day and 64 mg/day groups compared with the placebo group (effect sizes, d=0.45 and d=0.57, respectively). Supporting these findings were similar effects on several of the secondary outcome measures, such as the PANSS negative symptom, total, and activation factor scores, the CGI severity item, and the Brief Negative Symptom Scale. There were no statistically significant differences in PANSS positive scale score between the MIN-101 and placebo groups. No clinically significant changes were observed in vital signs, routine laboratory values, weight, metabolic indices, and Abnormal Involuntary Movement Scale score. Conclusions: MIN-101 demonstrated statistically significant efficacy in reducing negative symptoms and good tolerability in stable schizophrenia patients.
Low Incidence of Chronic Gvhd after Haploidentical T-Cell Replete Peripheral Blood Stem Cell Transplantation with Post Transplantation Cyclophosphamide (PT-Cy)
Authors: Angela Granata, Sabine Furst, Jean marie Boher, Luca Castagna, Patrice Chevallier, Alice Garnier, Thierry Guillaume, Remy Dulery, Mohamad Mohty, Faezeh Legrand, Samia Harbi, Raynier Devillier, Catherine Faucher, Stefania Bramanti, Claude Lemarie, Boris Calmels, Pierre Jean Weiller, Christian Chabannon, Didier Blaise
Journal: Blood (2016)