tbuckley/cabot-search huggingface dataset:
Abstract 4834: Preclinical analysis of the Notch gamma secretase inhibitor BMS-906024 in combination with chemotherapy in the treatment of lung adenocarcinoma
Authors: Katherine M. Morgan, Francis Lee, Erin Michaud, Bruce S. Fischer, Sharon R. Pine
Journal: Cancer Research (2016)

Abstract Notch signaling is aberrantly activated in approximately one third of non-small cell lung cancer (NSCLC) cases, primarily through loss of the endogenous Notch inhibitor, Numb, or via gain-of-function mutations in the Notch1 receptor. Notch activity is associated with poor overall survival among NSCLC patients whose tumors are wildtype for TP53. Here, we characterized the interaction between BMS-906024, a clinically relevant gamma secretase inhibitor (GSI) that inhibits Notch activation, and front-line chemotherapy in preclinical models of NSCLC. MTS drug synergy assays consisting of treatment with BMS-906024, cisplatin or paclitaxel, or the combination of GSI and chemotherapy were performed on a panel of human NSCLC cell lines, most of which were derived from adenocarcinomas. Analysis of the drug effects with CalcuSyn yielded significantly lower CI values for the GSI BMS-906024 combined with paclitaxel than with cisplatin (average CI = 0.54 vs 0.85, respectively; P = 0.001). The synergy between BMS-906024 and paclitaxel was significantly greater in Kras-wildtype than Kras-mutant cells (average CI = 0.39 vs 0.68, respectively; P = 0.009), while there was no correlation with EGFR or TP53 status. Treatment of lung adenocarcinoma xenografts in NOD scid gamma mice confirmed enhanced antitumor activity for the combination treatment of BMS-906024 and paclitaxel by mechanisms currently under investigation. These results are a step toward identification of the optimal combination of the GSI BMS-906024 with standard chemotherapies, as well as potential biomarkers that could be used to predict patient response to Notch-targeted therapy. Citation Format: Katherine M. Morgan, Francis Lee, Erin Michaud, Bruce S. Fischer, Sharon R. Pine. Preclinical analysis of the Notch gamma secretase inhibitor BMS-906024 in combination with chemotherapy in the treatment of lung adenocarcinoma. [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 4834.
Abstract 228: Tumor suppressor functions of BNIP3 and mitophagy in pancreatic ductal adenocarcinoma
Authors: Aparajita H. Chourasia, Maya Z. Springer, Kay F. Macleod
Journal: Cancer Research (2016)

Abstract The role of mitochondrial dysfunction in cancer is an emerging research field fuelled by the growing realization that mitochondrial dynamics are subject to oncogenic control, with mitochondrial biogenesis and mitophagy in particular modulated directly or indirectly by key oncogenes (c-Myc, B-Raf, K-ras) and tumor suppressors (p53, pRB). Work from our lab has focused on understanding how defects in mitophagy influence tumorigenesis with a particular focus on how BNIP3 loss during tumor progression influences disease outcome. BNIP3 functions as a dimer at the outer mitochondrial membrane to target mitochondria for degradation at the autophagolysosome through its interaction with processed LC3 at nascent phagophores. BNIP3 is a transcriptional target of HIF-1, E2F and FoxO3A transcription factors and is induced by activated Ras and suppressed by the RB and p53 tumor suppressors. Various studies have shown BNIP3 expression to be induced at early stages of human cancers and then lost as cancers progress to malignancy. In particular, epigenetic silencing of BNIP3 in human pancreas cancer has been correlated with reduced median survival. However, the mechanisms by which loss of BNIP3 may be contributing to cancer progression are not well delineated and a better understanding of how BNIP3-dependent mitophagy modulates pancreatic cancer in particular could provide new insight to the development of this deadly disease. We set out to examine how loss of BNIP3 affects the progression of pancreatic ductal adenocarcinoma using human cell lines and genetically engineered mouse models. We show that loss of BNip3 markedly accelerates tumor initiation and progression to invasive PDAC in the Pdx1-Cre;LSL-KRasG12D mouse model with metastases to the liver and lungs evident in BNip3 null mice but not in age-matched wild-type mice. Supporting a role for BNIP3 in suppressing pancreatic tumorigenesis, we also showed that re-expression of exogenous BNIP3 in Miapaca-2 cells (in which endogenous BNIP3 is silenced) resulted in reduced growth while knockdown of BNIP3 in CFPAC1 cells (that express BNIP3) promotes cell growth. Work described here examines the underlying mechanisms explaining these tumor suppressor functions of BNIP3 in pancreatic ductal adenocarcinoma. Citation Format: Aparajita H. Chourasia, Maya Z. Springer, Kay F. Macleod. Tumor suppressor functions of BNIP3 and mitophagy in pancreatic ductal adenocarcinoma. [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 228.
PWE-338 Digital rectal examination: a discriminatory test in the diagnosis of colo rectal cancer: Abstract PWE-338 Table 1
Authors: J Grainger, P Skaife
Journal: Gut (2015)

<h3>Introduction</h3> Rapid access clinics exist for patients who are symptomatic from symptoms suggestive of colorectal cancer. Eighty-five to 90% of such symptomatic patients have non- malignant pathology. This results in unnecessary and hurried use of expense resources. Working on the principle that colonic tumours bleed, an immunological faecal occult blood test (FOBTi) – which uses antibodies specific for human haemoglobin – can identify patients who may have colorectal cancer. <h3>Aim</h3> To determine the sensitivity and specificity of FOBTi in detecting patients with colorectal cancer (in the absence of covert per rectal bleeding) referred to rapid access colorectal clinics. <h3>Method</h3> A prospective cohort study was performed on patients referred to Rapid Access Colorectal clinic. A digital rectal exam (DRE) was performed on each patient and faecal sample obtained for FOBTi testing. Colonic investigations were arranged for each patient and results correlated to the FOBTi result. <h3>Results</h3> To date 107 FOBTi samples with complete colonic investigations are available. Twenty-seven patients tested FOBT positive, 81 FOBT negative. In the positive group, 44% had cancer (58% rectal cancer; 25% left sided cancer, 8% right sided cancer, 8% transverse colon cancer). Other diagnoses are shown below: In the FOBTi negative group no cancers were detected on further investigations. Using these results, FOBTi has a sensitivity of 100% and 84% specificity. The positive predictive value is 44% and negative predictive value 100%. <h3>Conclusion</h3> Immunological FOBTi is an instant and objective test which utilises immuno-chromatography to detect blood loss in the stool. When used with DRE in patients with clinical symptoms it has 100% sensitivity and 84% specificity. A negative result means patients are unlikely to have a cancer diagnosis, which may lead a reduction in unnecessary investigations. <h3>Disclosure of interest</h3> None Declared.
Quantitative assessment of <i>BRAF</i> V600 mutant cell-free tumor DNA from plasma as a diagnostic and therapeutic biomarker in pts with <i>BRAF</i> V600 mutant melanoma.
Authors: Max Schreuer, Geert Meersseman, Yanina Jansen, Teofila Seremet, Ines Chevolet, Ambre Bott, Sofie Wilgenhof, Geert Maertens, Bart Neyns
Journal: Journal of Clinical Oncology (2015)

9015 Background: Analysis of BRAF V600 mutant cell-free tumor DNA (ctDNA) from plasma is under consideration as a biomarker in pts with advanced melanoma. Methods: Plasma samples were obtained from pts with advanced melanoma who participated in 3 prospective clinical trials. Quantitative allele-specific PCR analysis for BRAF V600 E/E2/D/K/R/M mutations was performed on cell-free DNA extracted from 1ml plasma (Idylla, Biocartis). Results: From 2/2014 to 12/2014, 232 plasma samples from 41 pts were analyzed. Detection of BRAF V600 mutant ctDNA at the time of diagnosis of metastatic disease was concordant with tumor tissue analysis in 100% of pts (BRAF mutant 3/10, BRAF wt 7/10). In the 3 BRAF mutant pts, ctDNA results preceded tissue results with a median of 40 days (14-93). Therapeutic monitoring of BRAF mutant ctDNA was performed in 33 pts (median of 7 analyses per pt [range 2-13]; median follow up of 4.8 months [0.5-9]). Treatment consisted of BRAF/MEK targeted therapy (n = 26 pts), ipilimumab (n = 5) or pembrolizumab (n = 9). In the 6 pts who had a detectable BRAF mutant ctDNA fraction (range 7-53%) at initiation of BRAF/MEK targeted therapy, the BRAF mutant ctDNA fraction became undetectable (n = 5) or < 1% (n = 1) after a median of 14 days (5-40) notwithstanding the absence of radiological CR. During BRAF/MEK targeted therapy, an increase in the BRAF mutant ctDNA fraction was detected prior to PD on imaging in 7/12 pts (58%; median interval of 1.1 month [0.8-1.7]) and concomitantly with PD on imaging in 2/12 pts (17%). An increase in BRAF mutant ctDNA fraction predicted PD during the following month in 67% of cases (n = 14/21, p < 0.001) and in 100% of cases within the following 2 months (n = 21/21, p < 0.001). Undetectable BRAF mutant ctDNA predicted absence of PD in the following month in 91% of analyses (n = 94/103; p < 0.001) and in the following 2 months in 83% of analyses (n = 77/93; p < 0.001). Conclusions: Analysis of BRAF mutant ctDNA from plasma allows for a rapid diagnosis of the BRAF status in pts with advanced melanoma. BRAF mutant ctDNA likely reflects the BRAF mutant proliferative tumor burden and holds promise as a therapeutic monitoring tool for pts with advanced BRAF V600 mutant melanoma.
The influence of pretreatment body mass index on long-term prognosis of patients with esophageal carcinoma after surgery.
Authors: Y. Hayashi, A. M. Correa, W. L. Hofstetter, A. A. Vaporciyan, D. C. Rice, G. L. Walsh, R. J. Mehran, S. Swisher, J. A. Ajani
Journal: Journal of Clinical Oncology (2010)

e14525 Background: Obesity, a serious health problem in the United States, is a risk factor for gastroesophageal adenocarcinoma. However, the influence of obesity on patient's survival has not been established. We examined the impact of obesity on the long-term mortality after surgery. Methods: We, retrospectively, reviewed 243 consecutive esophageal cancer patients who had surgery. Two groups by baseline body mass index (BMI) were examined: normal/low (< 25 kg/m2) and overweight (≥ 25 kg/m2). Results: 67 patients (28%) had normal/low BMI and 176 patients (72%) had BMI ≥ 25. In the high BMI group, there were more men (p < 0.001), more adenocarcinoma (p < 0.001), and lower pathologic stage (p = 0.003). Postoperative morbidity was similar in both groups. The 5-year overall survival rates were 41% in the normal/low BMI group, and 67% in the high BMI group (p = 0.002). The 5-year disease free survival rates were 37% in the normal/low BMI group, and 65% in the high BMI group (p = 0.001). In multivariate analysis, age, pathologic stage and tumor location were independent prognostic factors. Lower esophageal tumor (p = 0.015; HR, 0.386; 95% CI, 0.179-0.833) was associated with improved survival, and older age (p = 0.014; HR, 1.032; 95% CI, 1.006-1.057) and stage III disease (p = 0.015; HR, 6.162; 95% CI, 1.744-21.766) were associated with poor survival. Conclusions: High BMI is common in patients with adenocarcinoma of the esophagus. Patients with high BMI presented with lower stage of cancer and thus had better survival compared to those with normal/low BMI. No significant financial relationships to disclose.
Comparison of PIK3CA gene status between primary tumors and paired metastases in metastatic or recurrent colorectal cancer.
Authors: Jieer Ying, Qiong He, Qi Xu, Bixia Liu, Wei Wu
Journal: Journal of Clinical Oncology (2015)

e14599 Comparison of PIK3CA gene status between primary tumors and paired metastases in metastatic or recurrent Colorectal Cancer Jieer Ying*, Qiong He, Qi Xu, Bixia Liu, Wei Wu Department of Chemotherapy, Zhejiang Cancer Hospital, 38 Guangji Road, Hangzhou, 310022, China * The presenting author Abstract Background: In metastatic or recurrent colorectal cancer (MRCRC), the concordance of PIK3CA mutation status between the primary tumors and metastases is still controversial. The purpose of this study was to evaluate the association between PIK3CA mutational status and various clinicopathologic features, and compare its genotype of primary tumors with that of the paired metastatic tumors. Methods: We compared the mutation status of PIK3CA between the primary tumors and the paired metastases of 59 MRCRC patients with available tissues (resection or biopsy). The presence of PIK3CA mutation was determined on both primary tumors and paired metastatic samples by direct sequencing analysis. Results: 46 patients (80.0%) had the PI3KCA mutation in any place of the primary or metastatic tumors. PIK3CA mutation was found in 26 primary tumors and 32 related metastatic tumors (44.1% vs. 54.2%). PIK3CA status was concordant between primary and metastatic sites in 25 patients (42.4%, kappa = -0.141). PIK3CA status discordance rate was significantly higher in 40 patients undergoing metachronous resection of primary tumor or metastasis [67.5% (27/40)], compared to that in 19 patients with synchronous resection of primary tumor or metastasis [36.8% (7/19); p= 0.026]. Conclusions: Our results demonstrate that high disconcordance of PIK3CA mutational status exist between the primary tumors and paired metastasis, and these findings remind us to have second thoughts about the need to evaluate metastatic tumors separately rather than only based on the primary tumor data when targeted therapy is considered in future.
Best practice guidelines in the psychosocial management of HPV-related head and neck cancer: recommendations from the European Head and Neck Cancer Society's Make Sense Campaign
Authors: M. Reich, L. Licitra, J.B. Vermorken, J. Bernier, S. Parmar, W. Golusinski, X. Castellsagué, C.R. Leemans
Journal: Annals of Oncology (2016)
Abstract 2715: Cell cycle regulated mitophagy: a key step at the G1/S metabolic checkpoint
Authors: Daniela Annibali
Journal: Cancer Research (2016)

Abstract How tumor cells coordinate their high demand for biosynthetic processes with nutrient availability, proliferation rate and oxidative stress tolerance is still not completely understood. We recently showed that highly proliferating cells, whether normal or tumorigenic, display different metabolic requirements throughout the cell cycle, in term of glucose and glutamine utilization. The role of autophagy in cancer cells is still debated, but recent evidence pointed to its involvement in the regulation of cellular bioenergetics and nutrients utilization. To investigate autophagy regulation during cancer cells proliferation and to characterize in detail the metabolic behaviour associated with tumor cell proliferation in the different phases of the cell cycle, we used synchronized HeLaS3, a human epithelial carcinoma cell line. Treatment of the cells with a double thymidine block (DTB) results in an arrest at the G1/S boundary and the possibility to study their progression through a complete division cycle. Here we show that in the highly proliferating HeLaS3 cancer cells basal autophagy is a cell cycle regulated phenomenon, responsible for mitochondria quality control and that it plays an essential role at the G1/S checkpoint. Both general autophagy genetic inhibition and mitophagy pharmacological inhibition with Mdivi-1 during cell cycle progression lead the cells to enter faster in S phase. However, probably due to the high levels of oxidative stress dictated by their proliferation rate, autophagy-incompetent cells start to accumulate insulted and less functional mitochondria. Autophagy is likely to be involved in the induction of resistance mechanisms to treatments in different types cancers. Because of this, there is an increased interest in the possibility to use inhibitors of the autophagic pathways as adjuvants for current anti-tumor therapies. Further investigations of the mechanisms here described will be of importance to elucidate whether drugs which inhibit autophagy may be a viable and effective approach in combination with chemotherapy for the treatment of highly proliferating cancers. Citation Format: Daniela Annibali. Cell cycle regulated mitophagy: a key step at the G1/S metabolic checkpoint. [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 2715.
<i>Cave Dwellings</i>
Authors: Carrie A. Butt
Journal: JAMA (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 HomeNew OnlineCurrent IssueFor Authors 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) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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 journal
Abstract 2501: Combination therapy with mebendazole, trametinib and metformin eliminates recalcitrant NRASQ61K melanoma cells
Authors: Maryam AbdusSamad, Anirudh Gaur, Cynthia M. Simbulan-Rosenthal, Edward C. McCarron, Dean S. Rosenthal
Journal: Cancer Research (2016)

Abstract Melanoma is an aggressive and lethal form of cancer with increasing incidence worldwide. In recent years, the FDA approved several promising treatments for malignant melanoma. However, treatment often fails due to the survival and regrowth of drug-resistant cells. Studies by our lab and others suggest that Melanoma Initiating Cells (MIC), a CD133+ population that forms xenograft tumors, may represent an intermediate stage in the acquisition of stable drug resistance. This study aims to determine the effect of CD133-expression and drug resistance in metastatic melanoma cells harboring difficult-to-treat mutation signatures by focusing on the two main downstream cascades of MAPK and PI3K/AKT/mTOR. Our results show that triple combination therapy using mebendazole (repurposed anthelmintic BRAF inhibitor), trametinib (MEK inhibitor) and metformin (repurposed anti-diabetic mTOR inhibitor) synergistically reduces cell viability of NRASQ61K melanoma cells when compared with mebendazole, trametinib or metformin alone. Further, the surviving fraction from each monotherapy is highly enriched for CD133+ cells. Thus, the multi-kinase inhibitor trametinib, along with repurposed anthelmintic and anti-diabetic drugs may inhibit MAPK and PI3K/AKT/mTOR pathways, which could potentially be an effective therapy for the resistant subpopulation of melanoma initiating cells. Citation Format: Maryam AbdusSamad, Anirudh Gaur, Cynthia M. Simbulan-Rosenthal, Edward C. McCarron, Dean S. Rosenthal. Combination therapy with mebendazole, trametinib and metformin eliminates recalcitrant NRASQ61K melanoma cells. [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 2501.
The value of hormone serum concentration to predict the gonadotoxic effect of chemotherapy and the efficacy of LHRH analogs as a strategy to reduce treatment-related premature ovarian failure in breast cancer
Authors: G. Rossi, R. Iadarola, M. Lambertini, F. Poggio, A. Levaggi, C. Bighin, S. Giraudi, A. D'Alonzo, S. Pastorino, E. Blondeaux, A. Abate, G. Iacono, P. Pronzato, L. Del Mastro
Journal: Annals of Oncology (2015)
Physical Interaction Between Mutant Calreticulin and the Thrombopoietin Receptor Is Required for Hematopoietic Transformation
Authors: Shannon Elf, Nouran Abdelfattah, Edwin Chen, Javier Perales-Patón, Emily Rosen, Amy Ko, Fabian Peisker, Natalie Florescu, Silvia Giannini, Ofir Wolach, Elizabeth A. Morgan, Julie-Aurore Losman, Rebekka K. Schneider, Fatima Al-Shahrour, Ann Mullally
Journal: Blood (2015)
Perinatal Exposure to Traffic-Related Air Pollution and Autism Spectrum Disorders
Authors: Tong Gong, Christina Dalman, Susanne Wicks, Henrik Dal, Cecilia Magnusson, Cecilia Lundholm, Catarina Almqvist, Göran Pershagen
Journal: Environmental Health Perspectives (2016)

Studies from the United States indicate that exposure to air pollution in early life is associated with autism spectrum disorders (ASD) in children, but the evidence is not consistent with European data.We aimed to investigate the association between exposure to air pollution from road traffic and the risk of ASD in children, with careful adjustment for socioeconomic and other confounders.Children born and residing in Stockholm, Sweden, during 1993-2007 with an ASD diagnosis were identified through multiple health registers and classified as cases (n = 5,136). A randomly selected sample of 18,237 children from the same study base constituted controls. Levels of nitrogen oxides (NOx) and particulate matter with diameter ≤ 10 μm (PM10) from road traffic were estimated at residential addresses during mother's pregnancy and the child's first year of life by dispersion models. Odds ratios (OR) and 95% confidence intervals (CI) for ASD with or without intellectual disability (ID) were estimated using logistic regression models after conditioning on municipality and calendar year of birth as well as adjustment for potential confounders.Air pollution exposure during the prenatal period was not associated with ASD overall (OR = 1.00; 95% CI: 0.86, 1.15 per 10-μg/m3 increase in PM10 and OR = 1.02; 95% CI: 0.94, 1.10 per 20-μg/m3 increase in NOx during mother's pregnancy). Similar results were seen for exposure during the first year of life, and for ASD in combination with ID. An inverse association between air pollution exposure and ASD risk was observed among children of mothers who moved to a new residence during pregnancy.Early-life exposure to low levels of NOx and PM10 from road traffic does not appear to increase the risk of ASD. Citation: Gong T, Dalman C, Wicks S, Dal H, Magnusson C, Lundholm C, Almqvist C, Pershagen G. 2017. Perinatal exposure to traffic-related air pollution and autism spectrum disorders. Environ Health Perspect 125:119-126; http://dx.doi.org/10.1289/EHP118.
Similar 5-Year Survival after Peripheral Blood Autotransplants (AutoPB) Versus HLA Matched Sibling Myeloablative Transplants (AlloBMT) for Acute Myeloid Leukemia (AML) in First Complete Remission (CR1).
Authors: Armand Keating, Manisha Kukreja, Gisela Tunes da Silva, Vikas Gupta, Corey Cutler, Martin S. Tallman, Jorge Sierra, John F. DiPersio, Mary M. Horowitz, Daniel J. Weisdorf
Journal: Blood (2008)