tbuckley/cabot-search huggingface dataset:
Abstract 3317: Genes encoding neuropeptide receptors are epigenetic markers in patients with head and neck cancer: A site-specific analysis
Authors: Daiki Mochizuki, Kiyoshi Misawa, Atsushi Imai, Takeharu Kanazawa, Hiroyuki Mineta
Journal: Cancer Research (2018)

Abstract Staging and pathological grading systems are useful but imperfect predictors of recurrence in head and neck squamous cell carcinoma (HNSCC). The aim of this study was to determine the methylation status of eight GPCR-encoding genes in HNSCCs and its relationship to recurrence, survival, and clinical characteristics (e.g., tumor location and lymph node metastasis). All eight genes (NPFFR1, NPFFR2, HCRTR1, HCRTR2, NPY1R, NPY2R, NPY4R, and NPY5R) encode neuropeptide receptors and are in the Class A β subgroup. This study is the first to implicate neuropeptide receptors in the genesis of HNSCC. To identify potential prognostic markers, we examined the methylation status of eight neuropeptide receptor gene promoters in 231 head and neck squamous cell carcinomas. The NPFFR1, NPFFR2, HCRTR1, HCRTR2, NPY1R, NPY2R, NPY4R, and NPY5R promoters were methylated in 80.5%, 79.2%, 67.1%, 73.2%, 35.1%, 36.4%, 38.5%, and 35.9% of the samples, respectively. In a multivariate Cox proportional hazards analysis, the odds ratio for recurrence was 2.044 (95% confidence interval [CI], 1.323-3.156; P = 0.001) when the NPY2R promoter was methylated. In patients without lymph node metastasis (n = 100), methylation of NPY2R (compared with methylation of the other seven genes) best correlated with poor disease-free survival (DFS) (odds ratio, 2.492; 95% CI, 1.190-5.215; P = 0.015). In patients with oral cancer (n = 69), methylated NPY1R and NPY2R were independent prognostic factors for poor DFS, both individually and, even more so, in combination (odds ratio, 3.90; 95% CI, 1.523-9.991; P = 0.005). Similar findings were observed for NPY2R and NPY4R in patients with oropharyngeal cancer (n = 162) (odds ratio, 5.663; 95% CI, 1.507- 21.28; P = 0.010). The present study suggests that the methylation status of the NPY1R, NPY2R, and NPY4R genes is an independent indicator of DFS in patients with oral and/or oropharyngeal cancers. Our findings support the use of methylation markers in patient selection for adjuvant therapy after initial surgical treatment and may aid oropharyngeal cancer screening and surveillance programs. However, they are preliminary and hence need to be validated in larger and more homogeneous HNSCC patient cohorts. Citation Format: Daiki Mochizuki, Kiyoshi Misawa, Atsushi Imai, Takeharu Kanazawa, Hiroyuki Mineta. Genes encoding neuropeptide receptors are epigenetic markers in patients with head and neck cancer: A site-specific analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3317.
Abstract 4510: SHH and GATA interplay: A potential therapeutic target for prostate cancer
Authors: Rami Z. Morsi, Wassim Abou Kheir, Layal El-Khatib, Hiba Msheik, Georges Daoud
Journal: Cancer Research (2018)

Abstract Background: Prostate cancer is the second leading cause of cancer deaths in males worldwide. Typically, prostate cancer cells depend on androgens, and many therapeutic strategies target receptors involved in androgen regulation. However, certain castration-resistant tumors of the prostate are resistant to androgen deprivation therapies. Moreover, advanced-stage prostate tumors can proliferate uncontrollably either due to androgens or due to alteration in other signaling pathways. For instance, the activity of the sonic hedgehog (SHH) pathway, which usually decreases during post-natal development, is increased during prostate cancer progression. Of interest, a recent study reported a novel role for GATA transcription factors as potential repressors of SHH signaling. Based on the above-mentioned findings, we hypothesize that the balance between GATA and SHH pathways is perturbed in prostate cancer leading to overactivation of SHH pathways and its downstream effector proteins. Methods: We screened human prostate cancer cell lines, DU145, 22Rv1, and PC3, as well as a human immortalized normal prostate epithelial cell line, RWPE-1, for baseline levels of expression of SHH downstream effector proteins via real-time PCR using specific primers. Subsequently, we treated the cell lines with bone morphogenetic protein 4 (BMP4)-conditioned media in order to induce the expression of GATA transcription factors, and then we measured the levels of expression for each of the SHH pathway effector proteins by real-time PCR. Results: We demonstrated that GATA can interfere with the expression of SHH and its effector proteins in the human prostate cancer cell lines. Upon treatment with BMP4, we noted that there was a decrease in expression of Gli1, Gli2, and Gli3, downstream effectors of SHH, suggesting an anti-proliferative response. Additionally, Patched1 expression was also attenuated after treatment with BMP4. Similarly, Sox9 expression was also abrogated. Conclusion: Our results demonstrate that GATA transcription factors can act as potential repressors of the SHH pathway in the context of prostate cancer in vitro by interfering with the expression of SHH downstream effector proteins. Citation Format: Rami Z. Morsi, Wassim Abou Kheir, Layal El-Khatib, Hiba Msheik, Georges Daoud. SHH and GATA interplay: A potential therapeutic target for prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4510.
Angiotensin II Stimulates c-Jun NH2-Terminal Kinase in Cultured Cardiac Myocytes of Neonatal Rats
Authors: SumiyoKudoh, IsseiKomuro, TakehikoMizuno, TsutomuYamazaki, YounzengZou, IchiroShiojima, NoboruTakekoshi, YoshioYazaki
Journal: Circulation Research (1997)

Many lines of evidence have suggested that angiotensin II (Ang II) plays an important role in cardiac hypertrophy. Ang II not only increases protein synthesis but also induces the reprogramming of gene expression in cultured cardiac myocytes. In the present study, to elucidate the mechanism by which Ang II regulates gene expression in cardiac myocytes, we examined whether Ang II activates c-Jun NH2-terminal kinase (JNK), which is a member of the mitogen-activated protein kinase family and activates the transcription factor, activator protein-1 (AP-1). The activity of JNK increased 5 minutes after the addition of Ang II, peaked at 20 minutes, and gradually decreased thereafter. Examination of the Ang II dose-response relation revealed detectable JNK activation at 10−9 mol/L and maximal activation at 10−6 mol/L. Ang II activated JNK through the AT1 receptor, and the activation was attenuated by the downregulation of protein kinase C or the chelation of intracellular Ca2+. Although the addition of either Ca2...
Involvement of Phosphoinositide 3-Kinase γ in Angiogenesis and Healing of Experimental Myocardial Infarction in Mice
Authors: MauroSiragusa, RajeshKatare, MarcoMeloni, FedericoDamilano, EmilioHirsch, CostanzaEmanueli, PaoloMadeddu
Journal: Circulation Research (2010)

Rationale: Phosphoinositide 3-kinase (PI3K)γ is expressed in hematopoietic cells, endothelial cells (ECs), and cardiomyocytes and regulates different cellular functions relevant to inflammation, tissue remodeling and cicatrization. Recently, PI3Kγ inhibitors have been indicated for the treatment of chronic inflammatory/autoimmune diseases and atherosclerosis. Objective: We aimed to determine PI3Kγ contribution to the angiogenic capacity of ECs and the effect of PI3Kγ inhibition on healing of myocardial infarction (MI). Methods and Results: Human umbilical ECs were treated with a selective PI3Kγ inhibitor, AS605240, or a pan-phosphoinositide 3-kinases inhibitor, LY294002. Both inhibitory treatments and small interfering RNA–mediated PI3Kγ knockdown strongly impaired ECs angiogenic capacity, because of suppression of the PI3K/Akt and mitogen-activated protein kinase pathways. Constitutive activation of Akt rescued the angiogenic defect. Reparative angiogenesis was studied in vivo in a model of MI. AS605240 ...
First-Line Trastuzumab Plus an Aromatase Inhibitor, With or Without Pertuzumab, in Human Epidermal Growth Factor Receptor 2–Positive and Hormone Receptor–Positive Metastatic or Locally Advanced Breast Cancer (PERTAIN): A Randomized, Open-Label Phase II Trial
Authors: Mothaffar Rimawi, Jean-Marc Ferrero, Juan de la Haba-Rodriguez, Christopher Poole, Sabino De Placido, C. Kent Osborne, Roberto Hegg, Valerie Easton, Christine Wohlfarth, Grazia Arpino
Journal: Journal of Clinical Oncology (2018)

To assess pertuzumab plus trastuzumab and an aromatase inhibitor (AI) in patients with human epidermal growth factor receptor 2 (HER2)-positive and hormone receptor-positive metastatic/locally advanced breast cancer (MBC/LABC).The PERTAIN trial (NCT01491737) is an ongoing randomized, open-label, multicenter-80 sites and eight countries-phase II trial. Patients have HER2-positive, hormone receptor-positive MBC/LABC and no prior systemic therapy with the exception of endocrine. Random assignment was 1:1 to intravenous pertuzumab (840 mg loading dose followed by 420 mg every 3 weeks) plus trastuzumab (8 mg/kg followed by 6 mg/kg every 3 weeks), and oral anastrozole (1 mg every day) or letrozole (2.5 mg every day), or trastuzumab and an AI. Induction intravenous docetaxel every 3 weeks or paclitaxel every week could be administered for 18 to 24 weeks at the investigator's discretion (decided before but given after random assignment). Primary end point was progression-free survival (PFS). Patients were stratified by whether they received induction chemotherapy and their time since adjuvant hormone therapy.One hundred twenty-nine patients were randomly assigned per arm (February 2012 to October 2014; intent-to-treat populations); 75 in one arm and 71 in the other were chosen to receive induction chemotherapy. Stratified median PFS was 18.89 months (95% CI, 14.09 to 27.66 months) in the pertuzumab plus trastuzumab arm and 15.80 months (95% CI, 11.04 to 18.56 months) in the trastuzumab arm (stratified hazard ratio, 0.65; 95% CI, 0.48 to 0.89; P = .0070). Serious adverse events (AEs) were reported for 42 (33.1%) of 127 and 24 (19.4%) of 124 patients in the safety populations of the pertuzumab plus trastuzumab and trastuzumab arms, respectively. Rates of grade ≥ 3 AEs were 64 (50.4%) of 127 and 48 (38.7%) of 124, respectively. There were no deaths as a result of AEs.PERTAIN met its primary PFS end point. Pertuzumab plus trastuzumab and an AI is effective for the treatment of HER2-positive MBC/LABC. The safety profile was consistent with previous trials of pertuzumab plus trastuzumab.
Abstract 5901: The role of POU3F2 in the aggressive behavior of neuroendocrine prostate cancer
Authors: Naoko Kobayashi, Dai Hong, Chun Wang, Joyce Yamashiro, Johnny Guan, Robert E. Reiter
Journal: Cancer Research (2018)

Abstract Neuroendocrine and Small Cell Prostate Cancer (NEPC) is a lethal disease emerging from Castrate Resistant Prostate Cancer (CRPC) after treatment with next-generation anti-androgen therapies such as abiraterone and enzalutamide. The mechanisms by which treatment resistant prostate epithelial cancer cells trans-differentiate to poorly differentiated small cell cancer are not well understood. We and others found that Nervous System-Specific Octamer-Binding Transcription Factor (POU3F2) expression is induced in NEPC. POU3F2 is a reprogramming transcription factor that controls cellular differentiation and can induce stem-like cells from differentiated glioblastoma. POU3F2 also plays a critical role in melanoma progression and in small cell carcinoma of the lung. NEPC shares similarities with small cell carcinoma from other organs. We hypothesized that POU3F2 may be a key transcription factor that is required for transdifferentiation and the survival of NEPC cells. We further hypothesize that the underlying mechanism of therapy resistance in NEPC is that NEPC consists of stem-like cells that were reprogrammed from differentiated prostate cancer cells under the selective pressure of androgen receptor (AR) pathway-targeted therapy. We elucidated the functional role of POU3F2 in the aggressive cancer behavior of NEPC —including stem-cell properties, tumorigenesis, invasion, and chemo-resistance. We also characterized the mechanisms that regulate POU3F2 expression in therapy-resistant NEPC. The study provides a rational for targeted therapy for treatment of NEPC. It could also be used to design a strategy to halt the emergence of NEPC from CRPC. Citation Format: Naoko Kobayashi, Dai Hong, Chun Wang, Joyce Yamashiro, Johnny Guan, Robert E. Reiter. The role of POU3F2 in the aggressive behavior of neuroendocrine prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5901.
Abstract 4354: Molecular signature of multiple myeloma progression through single-cell RNA-seq
Authors: Jin Sung Jang
Journal: Cancer Research (2018)

Abstract Multiple myeloma (MM) is a malignant plasma cell disorder with well-defined primary genetic/cytogenetic abnormalities. Investigating genetic heterogeneity in the MM cells, may have an impact on therapeutic approaches and assessment of response to treatment. Single cell genomic profiling technology provides an opportunity for us to identify genetic heterogeneity during the pathogenesis of MM progression and select the most appropriate clinical interventions. We performed single cell whole transcriptome analysis in 597 CD138 positive cells derived from 15 patients at different stages of MM progression. Using Coefficient of Variation (CV) approach, we identified 790 genes and defined four main groups reflective of increasing levels of aggressiveness at the single cell level. Differential gene expression and gene set enrichment analyses showed that protein homeostasis pathways, unfolded protein response and mTORC1 related gene sets were significantly enriched at the most aggressive level consistent with the MM cell progression and predicts the overall survival. Our results provide novel insights into the cellular heterogeneity within each MM patient and a foundation for therapeutic opportunities including proteasome inhibitors. Citation Format: Jin Sung Jang. Molecular signature of multiple myeloma progression through single-cell RNA-seq [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4354.
Heterozygous carriage of the alpha1-antitrypsin Pi*Z variant increases the risk to develop liver cirrhosis
Authors: Pavel Strnad, Stephan Buch, Karim Hamesch, Janett Fischer, Jonas Rosendahl, Renate Schmelz, Stefan Brueckner, Mario Brosch, Carolin V Heimes, Vivien Woditsch, David Scholten, Hans Dieter Nischalke, Sabina Janciauskiene, Mattias Mandorfer, Michael Trauner, Michael J Way, Andrew McQuillin, Matthias C Reichert, Marcin Krawczyk, Markus Casper, Frank Lammert, Felix Braun, Witigo von Schönfels, Sebastian Hinz, Greta Burmeister, Claus Hellerbrand, Andreas Teufel, Alexandra Feldman, Joern M Schattenberg, Heike Bantel, Anita Pathil, Muenevver Demir, Johannes Kluwe, Tobias Boettler, Monika Ridinger, Norbert Wodarz, Michael Soyka, Marcella Rietschel, Falk Kiefer, Thomas Weber, Silke Marhenke, Arndt Vogel, Holger Hinrichsen, Ali Canbay, Martin Schlattjan, Katharina Sosnowsky, Christoph Sarrazin, Johann von Felden, Andreas Geier, Pierre Deltenre, Bence Sipos, Clemens Schafmayer, Michael Nothnagel, Elmar Aigner, Christian Datz, Felix Stickel, Marsha Yvonne Morgan, Jochen Hampe, Thomas Berg, Christian Trautwein
Journal: Gut (2018)

Objective Homozygous alpha1-antitrypsin (AAT) deficiency increases the risk for developing cirrhosis, whereas the relevance of heterozygous carriage remains unclear. Hence, we evaluated the impact of the two most relevant AAT variants (‘Pi*Z’ and ‘Pi*S’), present in up to 10% of Caucasians, on subjects with non-alcoholic fatty liver disease (NAFLD) or alcohol misuse. Design We analysed multicentric case–control cohorts consisting of 1184 people with biopsy-proven NAFLD and of 2462 people with chronic alcohol misuse, both cohorts comprising cases with cirrhosis and controls without cirrhosis. Genotyping for the Pi*Z and Pi*S variants was performed. Results The Pi*Z variant presented in 13.8% of patients with cirrhotic NAFLD but only in 2.4% of counterparts without liver fibrosis (p&lt;0.0001). Accordingly, the Pi*Z variant increased the risk of NAFLD subjects to develop cirrhosis (adjusted OR=7.3 (95% CI 2.2 to 24.8)). Likewise, the Pi*Z variant presented in 6.2% of alcohol misusers with cirrhosis but only in 2.2% of alcohol misusers without significant liver injury (p&lt;0.0001). Correspondingly, alcohol misusers carrying the Pi*Z variant were prone to develop cirrhosis (adjusted OR=5.8 (95% CI 2.9 to 11.7)). In contrast, the Pi*S variant was not associated with NAFLD-related cirrhosis and only borderline with alcohol-related cirrhosis (adjusted OR=1.47 (95% CI 0.99 to 2.19)). Conclusion The Pi*Z variant is the hitherto strongest single nucleotide polymorphism-based risk factor for cirrhosis in NAFLD and alcohol misuse, whereas the Pi*S variant confers only a weak risk in alcohol misusers. As 2%–4% of Caucasians are Pi*Z carriers, this finding should be considered in genetic counselling of affected individuals.
Abstract 3198: Comprehensive transcriptome analysis identifies integrated mRNA-lncRNA signature of triple-negative breast cancer treated with radiotherapy
Authors: Xingxing CHEN, Zhaozhi YANG, Yizhou JIANG, Jinli MA, Xiaoli YU, Zhimin SHAO, Xiaomao GUO
Journal: Cancer Research (2018)

Abstract Triple-negative breast cancer (TNBC), with a lack expression of ER, PR, and HER-2 as potential treatment targets, is insensitive to the hormonal and trastuzumab therapies. Thus, local and regional treatment, such as radiotherapy is placed with more emphasis when treating TNBC patients. In the current study, expression profiles of mRNAs and long noncoding RNAs (lncRNAs) in TNBC patients, who received radiotherapy in our institute, was investigated to develop radiation-related gene signatures to facilitate individualized TNBC treatment. Specifically, 44 TNBC samples including 14 recurrences and 30 non-recurrences after radiotherapy were analyzed by using transcriptome microarrays. A total of 626 mRNAs were identified as differentially expressed (DEGs) between recurrent patients and non-recurrent patients (|fold change| &amp;gt; 1.5, p &amp;lt; 0.05). GeneOntology analysis showed that these DEGs were enriched in immune response, mitotic cell cycle, inflammatory response, cell adhesion as well as extracellular matrix organization, which indicated that these biological processes may exert significant impacts on the therapeutic effects of radiation. In addition, a total of 150 lncRNAs were identified as differentially expressed between recurrent patients and non-recurrent patients (|fold change| &amp;gt; 1.5, p &amp;lt; 0.05). The differentially expressed mRNAs and lncRNAs were confirmed by quantitative real-time PCR. Cox regression model was further applied to explore potential lncRNAs involved in certain signaling pathways such as JAK/STAT, EGRF/ATK/PI3K are highly co-expressed with mRNAs in these signaling pathways. Overall, our results revealed a panel of mRNAs and lncRNAs with significant impacts on evaluating the TNBC radio-therapeutic effects as well predicting the possibility of recurrence. Citation Format: Xingxing CHEN, Zhaozhi YANG, Yizhou JIANG, Jinli MA, Xiaoli YU, Zhimin SHAO, Xiaomao GUO. Comprehensive transcriptome analysis identifies integrated mRNA-lncRNA signature of triple-negative breast cancer treated with radiotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3198.
Effectiveness of a Nonselective ETA/B and a Selective ETA Antagonist in Rats With Monocrotaline-Induced Pulmonary Hypertension
Authors: Jean-FrançoisJasmin, MartinLucas, PeterCernacek, JocelynDupuis
Journal: Circulation (2001)

Background—Both nonselective ETA/B receptor and selective ETA receptor antagonists can reduce pulmonary hypertension (PH) and right ventricular hypertrophy (RVH) in various animal models. Depending on their net effects after blockade of endothelial and smooth muscle ETB receptors, nonselective ETA/B antagonists could be more or less effective than selective ETA antagonists. Methods and Results—Two weeks after injection of saline or 60 mg/kg monocrotaline (MCT), rats received 50 mg · kg−1 · d−1 of a selective (LU135252) or nonselective (BSF420627) antagonist for 3 weeks. This resulted in 4 groups: control (n=15), MCT (n=60), MCT+ETA (n=39), and MCT+ETA/B (n=40). Five-week survival was 35% in the MCT group; this was increased to 56% in the MCT+ETA group (P=0.10) and to 67% in the MCT+ETA/B group (P=0.0015). Drug administration was stopped 48 hours before hemodynamic measurements to evaluate the chronic effects of therapy: PH in the MCT group (RV systolic pressure 87±1 mm Hg) was improved similarly in both M...
Abstract 15737: Passive Range of Motion Exercise to Enhance Growth in Infants Following the Norwood Procedure: A Pilot Study
Authors: Linda M Lambert, Nicholas Dagincourt, Victoria Pemberton, Felicia L Trachtenberg, Shelley Andreas, Robin R Schlosser, Teresa Barnard, Janine Wood, Kaitlyn Daniels, Ann T Harrington, Thomas A Miller
Journal: Circulation (2015)

Background: Growth impairment is common in infants with single ventricle (SV) physiology, especially after the Norwood operation. Passive range of motion (ROM) exercise increases somatic growth in preterm infants without adverse effects but has not been studied in infants with SV. Objective: To evaluate the safety and feasibility of a passive ROM exercise program in infants with SV physiology. Methods: Passive ROM exercise was administered to all extremities daily according to a standardized protocol, by a trained physical therapist, during post-Norwood hospitalization for up to 21 days or until discharge. Vital signs were measured pre-, intra- and post-procedure and height and weight were measured at baseline, 14 and 21 days, and 3 months of age or at the time of their pre-Glenn visit. Feasibility was determined by percent of days that medium (50-75%) or high (&gt;75%) completion of the ROM exercise was performed. Adverse events (AE) were collected up to 3 months of age or pre-Glenn visit; all were adjudicated by the medical monitor. Results: Of 20 infants enrolled at 3 institutions, 70% were male. Parents voluntarily withdrew 1 subject on day 3. Median age at enrollment was 8 days (5-23), with the first ROM exercise started on a median post op day 4 (2-12). Median hospital length of stay following surgery was 15 days (9-131), allowing for an average of 13.4 in-hospital days/patient (3-21) for attempted ROM exercise. High completion of the exercise protocol across all subjects was achieved on 88% of eligible days and medium completion was achieved on an additional 2% of the days. Of 11 AE’s reported in 6 subjects; all were expected and one was determined to be possibly related to the study intervention (midsternal wound dehiscence). There were no clinically significant changes in vital signs. At 3 months, weight for age z-score (-0.84 ±1.2) and length for age z-score (-0.83 ±1.31) were higher than previous reports in SV populations. Conclusion: A passive ROM exercise program is safe and feasible in infants with SV physiology and may improve growth following Norwood operation. Larger studies are required to explore the optimal duration of passive ROM exercise and its effect on growth.