tbuckley/cabot-search huggingface dataset:
Abstract 2849: The combination of the PARP inhibitor talazoparib (BMN 673) with the ATR inhibitor VE-821 overcomes the drug resistance of Schlafen 11-deficient cells
Authors: Junko Murai, Yves Pommier
Journal: Cancer Research (2015)

Abstract Poly(ADP-ribose)polymerases (PARP) inhibitors work as catalytic inhibitors as well as PARP poisons by trapping PARP-DNA complexes (Murai et al., Cancer Res. 2012: 72:5588-99), and talazoparib is the most potent PARP inhibitor to date in terms of cytotoxicity and PARP trapping (Murai et al., Mol. Cancer Ther. 2014:13:433-43). Nevertheless, mining the NCI60 data shows that half of the 60 cell lines are tolerant to talazoparib. To elucidate the mechanisms of such tolerance, we searched for genes with expression levels correlated to talazoparib sensitivity using CellMiner (http://discover.nci.nih.gov/cellminer/). Schlafen 11 (SLFN11) turned out to be one of the most positively correlated genes whose expression is correlated with cellular sensitivity to talazoparib. Using genetically altered cells, we established that SLFN11 inactivation confers high resistance to talazoparib, revealing that SLFN11 inactivation, which is common in cancer cells (Zoppoli et al. PNAS 2014: 109:15030-5), is a novel mechanism of resistance for PARP inhibitors. Based on genetically engineered CRISPR/casp9 SLFN11-knockout cell lines and cell cycle analyses, we found that the parent SLFN11-proficient cells arrest in S phase without DNA replication, while SLFN11-knock out cells maintain their replication until entering G2 phase in the presence of talazoparib. Although ATR is the key regulator of intra-S phase check point, the addition of the ATR inhibitor (VE-821) (Josse et al., Cancer Res. 2014) does not rescue the replication arrest in SLFN11-proficient cells, suggesting the existence of a SLFN11-dependent replication arrest mechanism independently of ATR. On the other hand, the addition of the ATR inhibitor in SLFN11-knock out cells alters the arresting point from G2 to S phase, and eventually increases dead cells. This is probably because the prolonged replication block leads to the collapse of replication forks, resulting in DNA double-strand breaks. Consistent to these findings, the combination of the ATR inhibitor with talazoparib synergistically sensitizes SLFN11-knock out cells more efficiently than the parent SLFN11-proficient cells. Together, these results demonstrate that the combination of the ATR inhibitor with talazoparib can overcome the resistance of SLFN11-deficient cells to talazoparib. Citation Format: Junko Murai, Yves Pommier. The combination of the PARP inhibitor talazoparib (BMN 673) with the ATR inhibitor VE-821 overcomes the drug resistance of Schlafen 11-deficient cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2849. doi:10.1158/1538-7445.AM2015-2849
Adaptive Neoadjuvant Chemotherapy Guided by 18 F-FDG PET in Resectable Non–Small Cell Lung Cancers: The NEOSCAN Trial
Authors: Jamie E. Chaft, Mark Dunphy, Jarushka Naidoo, William D. Travis, Matthew Hellmann, Kaitlin Woo, Robert Downey, Valerie Rusch, Michelle S. Ginsberg, Christopher G. Azzoli, Mark G. Kris
Journal: Journal of Thoracic Oncology (2015)
Phase II randomized trial on protracted 5-fluorouracil infusion plus oxaliplatin (FOX) versus capecitabine plus oxaliplatin (XELOX) as first-line treatment in advanced colorectal cancer (ACRC): Preliminary results of the Italian FOCA Study
Authors: A. Martoni, C. Pinto, F. Di Fabio, G. Lelli, A. L. Gentile, F. L. Rojas Llimpe, V. Mutri, P. L. Ballardini, S. Giaquinta, E. Piana
Journal: Journal of Clinical Oncology (2005)

3617 Background: FOX regimen has shown to be safe and active in pretreated ACRC pts. Capecitabine (CAPE), an oral fluoropyrimidine, has been explored as an alternative to infusional 5-fluorouracil (5FU) in oxaliplatin (OXA) containing regimen (XELOX). The aim of this phase II randomized trial was to compare the efficacy and safety of FOX and XELOX as first line therapy in ACRC pts. Methods: From December 2001 to December 2004, 100 eligible untreated pts with ACRC have been randomized to arm A (FOX) (5-fluorouracil protracted infusion iv 250 mg/m2 d1–21 + oxaliplatin 130 mg/m2 iv d1, q3w) or arm B (XELOX) (capecitabine 1000 mg/m2 po bid d1–14, q3w + oxaliplatin 130 mg/m2 iv d1,q3w). Fourty-eight pts were randomized to arm A and 52 to arm B. Results: Baseline pt characteristics were well balanced between the two arms: M/F 52/48, median age 66.8 years (41–79); median KPS 90 (70–100); colon 71%, rectum 29%; primary tumor resection 80.9%; adjuvant chemotherapy 24%; metastatic sites: liver 77% (only liver 43%), lung 35%, lymph nodes 21%. Median number cycles was: 5 (1–10) in arm A and 6 (1–10) in arm B. Median dose intensity was: 5FU 100% (13–100) and OXA 100% (82–100) in arm A; CAPE 100% (16–100) and OXA 100% (60–100) in arm B. At the moment 75 pts were evaluable for response and 93 pts for toxicity. The objective responses were: arm A CR 3%, PR 48.5%, SD 27.3%, PD 21.2%; arm B CR 7.1%, PR 38.1%, SD 33.3%, PD 21.4%; RR 51.5% vs 45.2%. In arm A and B median TTP was 6 vs 9 months. Survival data are immature (58% of pts are still alive). Surgical resection of liver metastases after chemotherapy was performed in 4.1% pts in arm A vs 9.6% pts in arm B. Only 1 pt showed grade 4 toxicity (NCI-CTC2) (diarrhea) in arm A. Grade 3 treatment-related toxicity in arm A and B was: neutropenia 2.4% vs 0; thrombocytopenia 2.4% vs 2.4%; stomatitis 4.8% vs 0; diarrhea 14.3% vs 3.9%; hypertransaminasemia 0 vs 2%; hyperbilirubinemia 2.3% vs 2.1%; neurotoxicity 15.0% vs 20.4%. Conclusions: Our preliminary results suggest that FOX and XELOX, as administered in this trial, show high activity as first line treatment. Toxicity is low and similar in the two arms. No significant financial relationships to disclose.
The Role of DNA Methylation in Cardiovascular Risk and Disease
Authors: Jia Zhong, Golareh Agha, Andrea A. Baccarelli
Journal: Circulation Research (2016)

Epidemiological studies have demonstrated that genetic, environmental, behavioral, and clinical factors contribute to cardiovascular disease development. How these risk factors interact at the cellular level to cause cardiovascular disease is not well known. Epigenetic epidemiology enables researchers to explore critical links between genomic coding, modifiable exposures, and manifestation of disease phenotype. One epigenetic link, DNA methylation, is potentially an important mechanism underlying these associations. In the past decade, there has been a significant increase in the number of epidemiological studies investigating cardiovascular risk factors and outcomes in relation to DNA methylation, but many gaps remain in our understanding of the underlying cause and biological implications. In this review, we provide a brief overview of the biology and mechanisms of DNA methylation and its role in cardiovascular disease. In addition, we summarize the current evidence base in epigenetic epidemiology studies relevant to cardiovascular health and disease and discuss the limitations, challenges, and future directions of the field. Finally, we provide guidelines for well-designed epigenetic epidemiology studies, with particular focus on methodological aspects, study design, and analytical challenges.
Complications in thyroid surgery. Harmonic Scalpel , Harmonic Focus versus Conventional Hemostasis: A meta-analysis
Authors: Luca Revelli, Gianfranco Damiani, Caterina Bianca Neve Aurora Bianchi, Serafino Vanella, Walter Ricciardi, Marco Raffaelli, Celestino Pio Lombardi
Journal: International Journal of Surgery (2016)
Characterization of bacterial isolates from the microbiota of mothers' breast milk and their infants
Authors: Kimberly Kozak, Duane Charbonneau, Rosemary Sanozky-Dawes, Todd Klaenhammer
Journal: Gut Microbes (2015)

This investigation assessed the potential of isolating novel probiotics from mothers and their infants. A subset of 21 isolates among 126 unique bacteria from breast milk and infant stools from 15 mother-infant pairs were examined for simulated GI transit survival, adherence to Caco-2 cells, bacteriocin production, and lack of antibiotic resistance. Of the 21 selected isolates a Lactobacillus crispatus isolate and 3 Lactobacillus gasseri isolates demonstrated good profiles of in vitro GI transit tolerance and Caco-2 cell adherence. Bacteriocin production was observed only by L. gasseri and Enterococcus faecalis isolates. Antibiotic resistance was widespread, although not universal, among isolates from infants. Highly similar isolates (≥ 97% similarity by barcode match) of Bifidobacterium longum subsp. infantis (1 match), Lactobacillus fermentum (2 matches), Lactobacillus gasseri (6 matches), and Enterococcus faecalis (1 match) were isolated from 5 infant–mother pairs. Antibiotic resistance profiles between these isolate matches were similar, except in one case where the L. gasseri isolate from the infant exhibited resistance to erythromycin and tetracycline, not observed in matching mother isolate. In a second case, L. gasseri isolates differed in resistance to ampicillin, chloramphenicol and vancomycin between the mother and infant. In this study, gram positive bacteria isolated from mothers' breast milk as well as their infants exhibited diversity in GI transit survival and acid inhibition of pathogens, but demonstrated limited ability to produce bacteriocins. Mothers and their infants offer the potential for identification of probiotics; however, even in the early stages of development, healthy infants contain isolates with antibiotic resistance.
Abstract 13775: Clinical Significance of Flow Energy Loss inside the Left Ventricle via Cardiovascular Magnetic Resonance in Non-ischemic Dilated Cardiomyopathy
Authors: Takeru Nabeta, Keiichi Itatani, Yuichiro Iida, Yuki Ikeda, Syunsuke Ishii, Takashi Naruke, Hisahito Shinagawa, Takayuki Inomata, Kagami Miyazi, Junya Ako
Journal: Circulation (2014)

Background:  Blood flow patterns are closely linked to the morphology and function of the cardiovascular system and its efficiency can be estimated with flow energy loss (FEL). We have made it passible to measure FEL by using 2D cine phase-contrast (PC) cardiac magnetic resonance (CMR) technique. The object of the present study is to reveal the relationship of the clinical parameter and FEL in patients with non-ischemic dilated cardiomyopathy (DCM).   Methods:  A cross-sectional study was carried out on patients with DCM. All patients underwent CMR technique including late gadolinium enhancement (LGE). Intramural geometry was extracted with Steady-state free precession series, and PC-CMR was superposed. Blood flow was visualized and FEL with viscous dissipation was calculated in-house code.   Results:  A total of nineteen such patients were included in this study. FEL inside the left ventricle (LV) was 331 ± 117 mW/m2 (range 188-626). FEL was significantly correlated with age (r = -0.53, P = 0.02) and LV end-diastolic volume (LVEDV) (r = 0.50, P = 0.03), but not with LV ejection fraction (r = -0.08, P = 0.75) or plasma blood natriuretic peptide level (r = 0.05, P = 0.85). Especially, FEL tended to be correlated with LVEDV (r = 0.69, P = 0.06) in LGE positive patients, but did not in LGE negative. Well organized vortex flow dissipated small FEL, whereas disturbed flow inside highly-dilated LV dissipated large FEL (figure A, B).   Conclusions:  FEL was significantly correlated with age and LVEDV in DCM patients. Large LV caused disturbed flow resulting in high FEL. FEL was considered to be more sensitive parameter in damaged LV tissue than in non-damaged.
Phase I trial of 5-azacitidine (5AC) and SNDX-275 in advanced lung cancer (NSCLC)
Authors: R. A. Juergens, F. Vendetti, B. Coleman, R. S. Sebree, M. A. Rudek, S. A. Belinsky, M. V. Brock, J. G. Herman, S. B. Baylin, C. M. Rudin
Journal: Journal of Clinical Oncology (2008)

19036 Background: Epigenetic gene silencing is a key contributor to lung carcinogenesis. Pre-clinical studies suggest that combining inhibitors of DNA methyltransferase (DNMT) with inhibitors of histone deacetylase (HDAC) synergistically induce re-expression of epigenetically-silenced tumor suppressor genes. Combination of the DNMT inhibitor, 5AC, with the HDAC inhibitor, SNDX-275, in hematologic malignancies has shown remarkable activity. This study proposed to find a safe and tolerable dose of 5AC and SNDX-275 in NSCLC. Methods: Eligible patients were adults with advanced NSCLC and progressive disease after at least one previous chemotherapy regimen. 5AC was given SQ days 1–6 and 8–10 with SNDX-275 at a fixed dose of 7 mg/day on days 3 and 10 of a 28 day cycle. 5AC dose was varied between cohorts using a standard 3+3 phase I dose assessment schema. Diagnostic tumor blocks and serial sputum and serum samples were obtained for pharmacodynamic (PD) analysis of promoter methylation status of candidate genes of interest at baseline and with therapy. Serial blood draws were performed for pharmacokinetic (PK) analysis of both 5AC and SNDX-275. Results: Ten subjects were enrolled in this phase I study. Demographics include: mean age (range) - 63 (51–80); M:F - 5:5; 100% former smokers; Adenocarcinoma:squamous - 8:2; mean number of previous therapies - 3. No dose limiting toxicities (DLT) were seen in the 30 mg/m2 dose cohort. At 40 mg/m2, one subject was replaced due to rapidly progressive disease during week 1. One subject experienced a hematologic DLT (grade 3 neutropenia and thrombocytopenia). No long term adverse outcomes from the DLT were seen. Common low grade toxicities included injection site reactions, nausea/vomiting, constipation, fatigue, and cytopenias. A major and durable partial response has been observed in one patient, which is ongoing at >8 months. Two patients had disease stabilization through ≥2 cycles of therapy; the remaining patients had progressive disease. PK and PD correlative analyses are in progress. Conclusions: 5AC and SNDX-275 are safe and tolerable, and associated with clinical activity in advanced NSCLC patients. We have determined a recommended phase II dose and have initiated phase II enrollment of the same patient population. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Oncomethylome Sciences, Pharmion Oncomethylome Sciences, Pharmion Oncomethylome Sciences, Pharmion
Bioabsorbable bone plates enabled with local, sustained delivery of alendronate for bone regeneration
Authors: Woojune Hur, Min Park, Jae Yeon Lee, Myung Hun Kim, Seung Ho Lee, Chun Gwon Park, Se-Na Kim, Hye Sook Min, Hye Jeong Min, Jin Ho Chai, Sang Jeong Lee, Sukwha Kim, Tae Hyun Choi, Young Bin Choy
Journal: Journal of Controlled Release (2015)
The Prognostic Relevance of Histological Subtype in Patients with Peritoneal Carcinomatosis of Colorectal Cancer: a Nationwide Population-Based Study
Authors: L. Razenberg, Y. van Gestel, V. Lemmens, J. De Wilt, G. Creemers, I.H.J.T. De Hingh
Journal: Annals of Oncology (2014)
A spiral scaffold underlies cytoadherent knobs in Plasmodium falciparum–infected erythrocytes
Authors: Jean M. Watermeyer, Victoria L. Hale, Fiona Hackett, Daniel K. Clare, Erin E. Cutts, Ioannis Vakonakis, Roland A. Fleck, Michael J. Blackman, Helen R. Saibil
Journal: Blood (2015)
Clinical characteristics of clear cell adenocarcinoma of the ovary -<i>Japan Clear Cell Carcinoma Study Group</i>-
Authors: M. Takano, T. Kita, Y. Kikuchi, N. Yaegashi, K. Kuzuya, H. Tsuda, M. Suzuki, J. Kigawa, S. Takeuchi, T. Sugiyama
Journal: Journal of Clinical Oncology (2005)

5123 Background: The purpose of this study was to evaluate the clinical characteristics of clear cell adenocarcinoma of the ovary with retrospective review of multi-institutional patients. Methods: Between 1992 and 2002, 334 patients with clear cell adenocarcinoma of the ovary were identified by scanning the medical records of the collaborating institutions and central pathologic review. Clinical characteristics of the patients and chemotherapeutic effects were investigated. Results: Patients characteristics: Mean age was 53.2 years (range 23–90 years). Tumors were 14% (46/334) stage Ia, 42% (142/334) stage Ic, 17% (47/334) stage II, 24% (80/334) stage III, and 6% (19/334) stage IV. Response and Survival: Response was evaluable in 84 cases (26%) in 317 patients who received first-line chemotherapy. Response rates were 14% with platinum-based chemotherapy, 31% with paclitaxel+platinum, and 24% with irinotecan-based regimen. Response of second-line chemotherapy was assessable in 75 cases, but there were no regimens with response rate beyond 17%. 5-year survival was 95% in stage Ia, 84% in stage Ic, 62% in stage II, 31% in stage III and 0% in stage IV. Patients with stage Ic(b) had significantly worse 5-year survival rate than those with stage Ia (p=0.001). Moreover, progression-free survival of patients with stage Ic(2) was significantly worse than that of stage Ic(b). Although progression-free and over-all survival rate seemed better with irinotecan-based adjuvant chemotherapy than other regimens, only no residual tumor was independent progression-free prognostic factor in stage III and IV patients (p=0.02). Conclusions: In early stage cases, positive peritoneal washing was a prognostic factor, but complete surgery including paraaortic lymphadenectomy might improve the survival. Response rates of adjuvant chemotherapy including paclitaxel-based regimens were only approximately 30%. Survival rates of advanced cases were significantly improved in cases of achieving no macroscopic residual tumors. No significant financial relationships to disclose.
Depression and anxiety among family caregivers of patients with advanced cancer.
Authors: Ryan David Nipp, Joel Fishbein, Areej El-Jawahri, William F. Pirl, Samantha M.C. Moran, Caitlin McCarty, Justin Eusebio, Emily R. Gallagher, Elyse R. Park, Vicki A. Jackson, Joseph A. Greer, Jennifer S. Temel
Journal: Journal of Clinical Oncology (2015)

224 Background: Despite the important role family caregivers (CGs) play in the care of patients with cancer, little is known about their psychological distress. We sought to describe rates and correlates of depression and anxiety in CGs of patients with advanced cancer to determine those at greatest risk for psychological distress. Methods: As part of an ongoing trial of early palliative care, we are assessing baseline depression and anxiety in patients within 8 weeks of advanced lung or gastrointestinal cancer diagnosis and their CGs. We are administering the Hospital Anxiety and Depression Scale (HADS), with subscale scores &gt;7 denoting clinically significant depression or anxiety. We are assessing patient coping styles with the Brief COPE. We used multiple logistic regression with purposeful selection of covariates to identify correlates of CG depression and anxiety. Results: Of 240 CGs (mean age=57 years), 156 (65%) were spouses/partners, 167 (70%) were female, and 131 (55%) were working. 37 (15%) and 102 (43%) CGs reported significant depression and anxiety, respectively. CG age, gender and employment status, as well as patients’ anxiety and lack of acceptance coping were associated with higher rates of CG depression. CG age, gender, marital status and education level, as well as patients’ anxiety and presence of brain metastases were associated with higher rates of CG anxiety. Conclusions: Younger, female CGs were at greatest risk of both depression and anxiety. Thus, this CG population should be monitored closely and referred for cancer center support services for distress management. We also found that patients’ anxiety was associated with higher rates of both CG depression and anxiety, underscoring the importance of interventions that address both patient and CG psychological distress. Clinical trial information: NCT01401907. [Table: see text]
Role of second-line gemcitabine after FOLFIRINOX failure in advanced pancreatic adenocarcinoma: A retrospective analysis.
Authors: Aline Da Rocha Lino, Rodnei Merlrina Martins Junior, Carina Mina Abrahao, Raphael Brandao Moreira, Tarcia Tarciane Soares de Sousa, Jessica Ribeiro Gomes, Matheus Bongers Alessandretti, Marcus Paulo Fernandes Amarante, Andrea Malta Ferrian, Fabio Augusto Barros Schutz, Carolina Kawamura, Rafael Schmerling, Marcelo Rocha Cruz, Renata D'Alpino Peixoto, Marcel Cerqueira Cesar Machado, Antonio C. Buzaid, Fernando C. Maluf
Journal: Journal of Clinical Oncology (2015)

473 Background: Cancer of the exocrine pancreas is a highly lethal malignancy. Based on a phase III study, FOLFIRINOX regimen became the standard first-line treatment for patients with good performance status. However, the optimal management strategy for patients who fail initial FOLFIRINOX remains undefined. We aim at reporting our experience with single-agent gemcitabine as a second-line treatment for advanced pancreatic cancer patients who progressed on FOLFIRINOX. Methods: Patients with advanced exocrine pancreatic adenocarcinoma who received gemcitabine (1.000 mg/m² on days 1, 8 and 15 every 4 weeks) until disease progression, as second-line therapy after FOLFIRINOX failure at our institution were retrospectively evaluated. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Results: A total of 20 patients were reviewed. Most of them (60%) had metastatic disease while 40% had locally advanced tumors. Median age was 60 years (range 43–74) and 80% were male. Eastern Cooperative Oncology Group (ECOG) performance status was 0 or 1 in 65% and 2 or 3 in 35% of the patients. Median time on prior FOLFIRINOX therapy was 5 months. Median PFS and OS with gemcitabine were 2,0 (95% CI 1,2-2,8) and 5,7 months (95% CI 3,9-7,4), respectively. There were no deaths due to the treatment. Conclusions: In this study, gemcitabine was a reasonable second-line treatment option for patients with advanced pancreatic adenocarcinoma. Phase III trials are urgently needed exploring the role of gemcitabine in the second-line setting.