tbuckley/cabot-search huggingface dataset:
The WASF3–NCKAP1–CYFIP1 Complex Is Essential for Breast Cancer Metastasis
Authors: Yong Teng, Haiyan Qin, Abdulaziz Bahassan, N. George Bendzunas, Eileen J. Kennedy, John K. Cowell
Journal: Cancer Research (2016)

Abstract Inactivation of the WASF3 gene suppresses invasion and metastasis of breast cancer cells. WASF3 function is regulated through a protein complex that includes the NCKAP1 and CYFIP1 proteins. Here, we report that silencing NCKAP1 destabilizes the WASF3 complex, resulting in a suppression of the invasive capacity of breast, prostate, and colon cancer cells. In an in vivo model of spontaneous metastasis in immunocompromized mice, loss of NCKAP1 also suppresses metastasis. Activation of the WASF protein complex occurs through interaction with RAC1, and inactivation of NCKAP1 prevents the association of RAC1 with the WASF3 complex. Thus, WASF3 depends on NCKAP1 to promote invasion and metastasis. Here, we show that stapled peptides targeting the interface between NCKAP1 and CYFIP1 destabilize the WASF3 complex and suppress RAC1 binding, thereby suppressing invasion. Using a complex-disrupting compound identified in this study termed WANT3, our results offer a mechanistic proof of concept to target this interaction as a novel approach to inhibit breast cancer metastasis. Cancer Res; 76(17); 5133–42. ©2016 AACR.
Somatic PHF6 mutations in 1760 cases with various myeloid neoplasms
Authors: T Mori, Y Nagata, H Makishima, M Sanada, Y Shiozawa, A Kon, T Yoshizato, A Sato-Otsubo, K Kataoka, Y Shiraishi, K Chiba, H Tanaka, K Ishiyama, S Miyawaki, H Mori, T Nakamaki, R Kihara, H Kiyoi, H P Koeffler, L-Y Shih, S Miyano, T Naoe, C Haferlach, W Kern, T Haferlach, S Ogawa, K Yoshida
Journal: Leukemia (2016)
Noninvasive assessment of the cardiac baroreflex
Authors: Naohiko Takahashi, Mikiko Nakagawa, Tetsunori Saikawa, Tatsuhiko Ooie, Tadafumi Akimitsu, Koji Kaneda, Masahide Hara, Tetsu Iwao, Hidetoshi Yonemochi, Morio Ito, Toshiie Sakata
Journal: Journal of the American College of Cardiology (1999)
Abstract 820: Molecular epidemiological studies of germinal center-associated nuclear protein (ganp) in the development of human sporadic breast cancers
Authors: Kazuhiko Kuwahara, Hidemi Ito, Kiyotaka Kuzushima, Hiroji Iwata, Hideo Tanaka, Keitaro Matsuo
Journal: Cancer Research (2016)

Abstract [Introduction] The altered expression of germinal center-associated nuclear protein (GANP), a member of mammalian TREX2 complex, has been observed in various tumors. Previously, we demonstrated that deficiency of GANP developed mammary gland tumors resembling human breast cancers in two mouse models. In addition, we showed that decreased expression of GANP was an independent prognostic factor of human breast cancer in a retrospective cohort study. These results suggested that GANP might be associated with breast cancer development. Although a little is know about functional significance of ganp polymorphisms, we explored possible association. [Methods] We conducted a case-control study to examine association between ganp polymorphisms and risk of breast cancer among Japanese population within the framework of the Hospital-based Epidemiologic Research Program at Aichi Cancer Center (HERPACC). Cases are 694 incident cases who had been diagnosed as breast cancer at Aichi Cancer Center Hospital (ACCH) during 2001-2005. A total of 1,376 non-cancer controls were patients who visited ACCH at same period as cases and were confirmed to have no evidence of cancer. Controls were individually matched for age and menopausal status with cases. ganp polymorphisms were assessed by iCOGS chip (Reference: Michailidou K et al. Nat. Genet. 2013;45:353-361). Multivariable conditional logistic regression models were applied to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for each locus. [Results] Ten out of 13 polymorphisms, in high linkage disequilibrium, showed statistically significant associations with breast cancer risk. For instance, in rs2839186, the OR for those with AA alleles compared with those with GG alleles is 0.41 (95% CI, 0.23-0.72, p = 0.002) in genotype model. As compared with those with G allele, the OR for those without was 0.40 (95% CI, 0.23-0.71, p = 0.002) in recessive model. On the other hand, in dominant model, the OR for those with A allele was 0.95 (95% CI, 0.78-1.16, p = 0.635) in comparison to those without that. [Conclusion] In this study, we clearly show that mutant SNPs in rs2839186 decrease breast cancer risk. We are currently analyzing if the ganp SNPs affect the prognosis of breast cancer patients. Citation Format: Kazuhiko Kuwahara, Hidemi Ito, Kiyotaka Kuzushima, Hiroji Iwata, Hideo Tanaka, Keitaro Matsuo. Molecular epidemiological studies of germinal center-associated nuclear protein (ganp) in the development of human sporadic breast cancers. [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 820.
Long-Term Outcome of a Prospective Study of Bortezomib, Dexamethasone and Rituximab (BDR) in Previously Untreated, Symptomatic Patients with Waldenstrom's Macroglobulinemia
Authors: Steven P Treon, Kirsten Meid, Joshua Gustine, Christopher J Patterson, Jeffrey V. Matous, Irene M. Ghobrial, Jorge J Castillo
Journal: Blood (2015)
Abstract 984: LncRNA LINC00668 predicts a poor prognosis of gastric cancer and promotes cell proliferation through epigenetically silencing of CKIs
Authors: Jinfei Chen
Journal: Cancer Research (2016)

Abstract Recently, long noncoding RNAs (lncRNAs) have been shown to have important regulatory roles in human cancer biology. By utilizing publicly available lncRNAs expression profiling data of gastric cancer and integrating analyses, we screened out LINC00668, whose expression is significantly increased and is correlated with outcomes in gastric cancer (GC). Further experiments revealed that LINC00668 knockdown significantly repressed the proliferation both in vitro and in vivo. Mechanistic investigations showed that LINC00668 was a direct transcriptional target of E2F transcription factor 1 (E2F1). Moreover, we also found that LINC00668 plays a key role in G0/G1 arrest, and further demonstrated that LINC00668 was associated with PRC2 and that this association was required for the epigenetic repression of cyclin-dependent protein kinase inhibitors (CKIs), including p15, p16, p21, p27 and p57, thus contributing to the regulation of gastric cancer cell cycle. To our knowledge, this is the first report showed that the role and molecular mechanism of LINC00668 in cancer. Together, our results suggest that E2F1-regulated LINC00668, as a cell cycle regulator, enriches a mechanistic link between lncRNA and E2F1-mediated cell cycle regulation pathway and may serve as a candidate prognostic biomarker and target for new therapies in human gastric cancer. Key words: E2F1; LINC00668; cell cycle; proliferation; gastric cancer Acknowledgements: The work was partly supported by the National 973 Basic Research Program of China (Grant No. 2013CB911300) grants from the National Natural Science Foundation of China (Grant No. 81272469, 81502071 and 81572928) and the clinical special project for Natural Science Foundation of Jiangsu Province (Grant No. BL2012016), and the grant from Nanjing 12th Five-Year key Scientific Project of medicine to Dr. Jinfei Chen. Citation Format: Jinfei Chen. LncRNA LINC00668 predicts a poor prognosis of gastric cancer and promotes cell proliferation through epigenetically silencing of CKIs. [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 984.
Culture Of Mobilized Rhesus Macaque CD34+ Cells In Hypoxic Conditions Does Not Improve Lentiviral Transduction Efficiency In Long-Term Repopulating Hematopoietic Stem Cells
Authors: Andre Larochelle, Ayla Cash, Zanetta Chang, Brian Ichwan, Jean-Yves Metais, Cynthia E. Dunbar
Journal: Blood (2013)
Synergistic Antileukemic Effect Of Sequential Administration Of Dichloroacetate (DCA) Combined With Arsenic Trioxide (ATO) In Primary Blasts From Patients With Acute Myeloid Leukemia (AML) and FLT3-ITD AML Cell Lines
Authors: Ashkan Emadi, Brandon Carter-Cooper, Mariola Sadowska, Omasiri Wonodi, Rena G. Lapidus, Mark Levis, Edward A. Sausville
Journal: Blood (2013)
Abstract 1766: An evaluation of the post-stroke cancer risk among post-menopausal women: The Women's Health Initiative
Authors: Shawnita Sealy-Jefferson, Michele L. Cote, Jennifer Beebe-Dimmer, Rowan Chlebowski, Kathryn Rexrode, Michael Simon
Journal: Cancer Research (2016)

Abstract Links between cancer history and incident stroke have been established, such that 15% of cancer patients experience a stroke at some point during their clinical course. However, we do not know whether stroke history is associated with cancer risk, especially for those cancers with overlapping risk factors with stroke. To address this, we used data from the observational and clinical trial of the Women's Health Initiative (n = 145,075), to test whether stroke history was associated with cancer risk and tumor type, and whether variation in cancer risk and tumor type exist by race/ethnicity. Time to incident cancer (in months) was estimated with bivariate and multivariate adjusted cox proportional hazards models, accounting for competing risks, comparing women with incident or prevalent stroke to women without stroke at baseline or at any point during follow-up, and models were stratified by race/ethnicity. Women with a stroke history, compared to those without, had significant differences in the following baseline characteristics: age, body mass index, smoking status, hormone replacement therapy usage, hypertension, hypercholesterolemia and diabetes, and differences were consistent among race/ethnic groups. In unadjusted and adjusted competing risk models of the overall sample, lower cancer risk was observed for women who had a prior stroke, compared to those with no stroke history (adjusted HR: 0.81; 95% CI: 0.75, 0.88). In race-stratified models, Non-Hispanic White (NHW) women experienced significantly lower risk of cancer following stroke, compared to those with no stroke history (adjusted HR: 0.81; 95% Confidence Interval: 0.74-0.89), and the magnitude of the association was similar, although not significant, for African American (AA) and ‘Other’ racial/ethnic groups. The associations with stroke were stronger for African American women with invasive breast (p = 0.02), lung (p = 0.04), and ‘other’ (p = 0.001) cancers, compared to NHW women. The results of the current study suggest that overall, women have lower cancer risk post-stroke, but that AA women, compared to their NHW counterparts, have higher risk of certain types of cancers after stroke. Future studies should investigate the mechanisms underlying the lower cancer risk among all stroke survivors, as well as examine why AA women develop certain tumors more often than NHW women. Citation Format: Shawnita Sealy-Jefferson, Michele L. Cote, Jennifer Beebe-Dimmer, Rowan Chlebowski, Kathryn Rexrode, Michael Simon. An evaluation of the post-stroke cancer risk among post-menopausal women: The Women's Health Initiative. [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 1766.
Von Willebrand Factor — A Rapid Sensor of Paravalvular Regurgitation during TAVR?
Authors: Firas E. Zahr, Steven R. Lentz
Journal: New England Journal of Medicine (2016)

Von Willebrand factor is unique among coagulation factors by virtue of its highly multimeric structure, which allows it to function as an endogenous sensor of hemodynamic forces.1 Under conditions of low shear stress (below the usual physiologic range), von Willebrand factor self-associates into compacted, high-molecular-weight (HMW) multimers that are unable to promote platelet adhesion. During physiologic shear stress (shear rate of 100 to 5000 sec−1), von Willebrand factor undergoes partial unfolding and elongation, exposing binding sites for platelets and collagen and allowing the metalloprotease ADAMTS13 to regulate the size distribution of the HMW multimers by cleaving von Willebrand factor . . .
Prenatal Residential Proximity to Agricultural Pesticide Use and IQ in 7-Year-Old Children
Authors: Robert B. Gunier, Asa Bradman, Kim G. Harley, Katherine Kogut, Brenda Eskenazi
Journal: Environmental Health Perspectives (2016)

Background: Residential proximity to agricultural pesticide use has been associated with neural tube defects and autism, but more subtle outcomes such as cognition have not been studied. Objectives: We evaluated the relationship between prenatal residential proximity to agricultural use of potentially neurotoxic pesticides and neurodevelopment in 7-year-old children. Methods: Participants included mothers and children (n=283) living in the agricultural Salinas Valley of California enrolled in the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) study. We estimated agricultural pesticide use within 1 km of maternal residences during pregnancy using a geographic information system, residential location, and California's comprehensive agricultural Pesticide Use Report data. We used regression models to evaluate prenatal residential proximity to agricultural use of five potentially neurotoxic pesticide groups (organophosphates, carbamates, pyrethroids, neonicotinoids, and manganese fungicides) and five individual organophosphates (acephate, chlorpyrifos, diazinon, malathion, and oxydemeton-methyl) and cognition in 7-year-old children. All models included prenatal urinary dialkyl phosphate metabolite concentrations. Results: We observed a decrease of 2.2 points [95% confidence interval (CI): −3.9, −0.5] in Full-Scale IQ and 2.9 points (95% CI: −4.4, −1.3) in Verbal Comprehension for each standard deviation increase in toxicity-weighted use of organophosphate pesticides. In separate models, we observed similar decrements in Full-Scale IQ with each standard deviation increase of use for two organophosphates (acephate and oxydemeton-methyl) and three neurotoxic pesticide groups (pyrethroids, neonicotinoids, and manganese fungicides). Conclusions: This study identified potential relationships between maternal residential proximity to agricultural use of neurotoxic pesticides and poorer neurodevelopment in children. https://doi.org/10.1289/EHP504
The landscape and clonal architecture in lower grade glioma.
Authors: Hiromichi Suzuki, Kosuke Aoki, Kenichi Chiba, Yusuke Sato, Yusuke Shiozawa, Yuichi Shiraishi, Teppei Shimamura, Atsushi Niida, Kazuya Motomura, Fumiharu Ohka, Hideo Nakamura, Masahiro Mizoguchi, Tatsuya Abe, Yoshihiro Muragaki, Reiko Watanabe, Ichiro Ito, Toshihiko Wakabayashi, Seishi Ogawa, Atsushi Natsume
Journal: Journal of Clinical Oncology (2015)

2008 Background: Lower grade gliomas (LGGs, WHO grade II/III gliomas) account for approximately one third of all gliomas. Although LGGs are typically slowly progressive, their clinical course is invariably indolent and most patients ultimately succumb to death. In contrast to glioblastoma, our knowledge about the genetic lesions and clonal evolution in LGG is still incomplete. Methods: To obtain a complete registry of gene mutations involved in LGG pathogenesis and their role in clonal evolution, we analyzed whole exome sequencing and/or targeted sequencing of 757 LGG cases from Japan and the Cancer Genome Atlas consortium. Clonal evolution in LGG was investigated using multi-time point/regional sampling in 14 cases with LGGs. Results: Massive parallel sequencing revealed LGGs were clearly grouped into three subgroups with or without IDH1/2 mutation and 1p/19q loss of heterozygous (LOH). Type I tumor with IDH1/2 mutation and 1p/19q LOH had a most favorable survival and harbored mutations in TERT promoter, CIC, FUBP1 and NOTCH1. Type II tumor with IDH1/2 mutant/1p19q intact subtype represented TP53 bialleleic inactivation and/or ATRX mutations. Type III tumor with IDH1/2 intact showed GBM-like mutation profile and poor prognosis. Multi regional/time-points sampling analysis supported mutational order and revealed a close correlation of regional heterogeneity with the history of clonal evolution, illustrating the way by which a tumor expands from its origin to surrounding regions, while increasing intratumor heterogeneity and spatially intermingling different evolutional branches in periphery. Conclusions: Our findings delineated the landscape of gene mutations in LGG. LGG had mutually exclusive mutational patterns with hierarchical order in discrete subtypes. LGG contiguously developed and generated heterogeneity through acquiring new mutations in a complex but ordered fashion.
Tumour-suppressive TANs identified in humans
Authors: Peter Sidaway
Journal: Nature Reviews Clinical Oncology (2016)

FAK regulates sensitivity to immunotherapyNewly published research in mouse models of pancreatic ductal adenocarcinoma (PDAC), in which immunotherapy alone is largely ineffective, has revealed that inhibition of focal adhesion kinase (FAK) promotes sensitivity to adoptive T-cell transfer and inhibition of both cytotoxic T-lymphocyte protein-4 (CTLA-4) and programmed cell death-1 (PD-1).Based upon the finding of increased FAK expression in human PDAC biopsy samples, researchers inhibited FAK in a mouse model of PDAC.FAK inhibition delayed tumour progression and markedly reduced the extent of tumour fibrosis.When FAK inhibition was combined with other therapies, such as gemcitabine, it significanty increased overall survival, and the addition of adoptive T-cell transfer resulted in further inhibition of tumour growth.The combination of anti-PD1/anti-CTLA-4 with FAK inhibition resulted in significantly improved overall survival: ~20% of mice treated with this regimen survived for 180 days from the start of treatment, thus indicating a need for further investigation of FAK inhibition in patients with PDAC.
Abstract 89: Whole-exome sequencing and immune profiling of early-stage lung adenocarcinoma
Authors: Humam Kadara, Murim Choi, Jiexin Zhang, Edwin Parra Cuentas, Jaime Rodriguez Canales, Stephen Gaffney, Zi-Ming Zhao, Carmen Behrens, Junya Fujimoto, Chi-Wan Chow, Neda Kalhor, Cesar Moran, David Rimm, Stephen G. Swisher, Don L. Gibbons, John V. Heymach, Edward Kaftan, Jeffrey Townsend, Thomas J. Lynch, Joseph Schlessinger, J. Jack Lee, Richard Lifton, Ignacio I. Wistuba, Roy S. Herbst
Journal: Cancer Research (2016)

Abstract PURPOSE: Lung adenocarcinomas (LUADs) lead to the preponderance of deaths attributable to lung cancer. We performed whole-exome sequencing (WES), comprehensive immune profiling and clinicopathological analysis of LUADs to better understand the molecular pathogenesis of this disease and identify clinically relevant molecular markers. METHODS: We performed WES of 108 paired surgically resected stage I-III LUADs and normal lung tissues using the Illumina HiSeq 2000 platform. Additionally, ten immune related markers (PD-L1, PD-1, CD3, CD4, CD8, CD45ro, CD57, CD68, FOXP3 and Granzyme B) were profiled by imaging-based immunohistochemistry in a subset of LUADs (n = 92). Associations among mutations, immune markers and clinicopathological variables were analyzed using ANOVA and Fishers Exact tests. Cox proportional hazards regression models were employed for multivariate analysis of clinical outcome. RESULTS: LUADs in this cohort exhibited an average of 243 coding mutations per tumor. We identified 28 genes with significant enrichment for mutation. SETD2-mutant LUADS exhibited relatively poor recurrence-free survival (RFS) and mutations in STK11 and ATM were associated with poor RFS in KRAS-mutant tumors. EGFR, KEAP1 and PIK3CA mutations were predictive of poor response to adjuvant therapy. Immune marker analysis demonstrated that PD-L1 expression was increased in smoker compared to non-smoker LUADs and, along with other immune markers, was positively correlated with somatic mutation burden. Moreover, immune marker levels including PD-L1 were elevated in TP53-mutant LUADs. In contrast, STK11 and U2AF1 mutant tumors exhibited a suppressed immune response and LUADs with PIK3CA mutations exhibited markedly decreased tumoral PD-L1 expression. CONCLUSION: Our study highlights mutations that may impact clinical outcome and personalized strategies for immune-based therapy of early-stage LUAD patients. Citation Format: Humam Kadara, Murim Choi, Jiexin Zhang, Edwin Parra Cuentas, Jaime Rodriguez Canales, Stephen Gaffney, Zi-Ming Zhao, Carmen Behrens, Junya Fujimoto, Chi-Wan Chow, Neda Kalhor, Cesar Moran, David Rimm, Stephen G. Swisher, Don L. Gibbons, John V. Heymach, Edward Kaftan, Jeffrey Townsend, Thomas J. Lynch, Joseph Schlessinger, J. Jack Lee, Richard Lifton, Ignacio I. Wistuba, Roy S. Herbst. Whole-exome sequencing and immune profiling of early-stage 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 89.
Ambulatory redesign: Strategies for quality improvement in patient care.
Authors: Naralys Estevez Sinanis, Catherine A. Lyons, Nancy Smith, Maureen McGlennon, Terri L. Parker, Carolyn Truini, Maureen Major-Campos, Jill Lacy, Karen Michaels, Vanna Dest, Richard Lisitano, Kerin B. Adelson, Rogerio Lilenbaum
Journal: Journal of Clinical Oncology (2016)

85 Background: Growing outpatient volume poses patient flow challenges, making it difficult to accommodate the complexities of academic medical practice. Volume increases create operational inefficiencies like delays in lab turnaround time (TAT) and limited rooming capacity resulting in delays in patient access and reduced provider productivity. These bottlenecks negatively impact patient satisfaction. Methods: Four multidisciplinary teams assessed barriers to patient flow in the lab, rooming and scheduling process. We sought to maximize the Advanced Practice Provider (APP) role within clinical programs. Each team was led jointly by an MD and RN and included subject matter experts, advisors and facilitators. The groups met regularly for 2 months to evaluate operational data, national benchmarks and surveyed staff. Monthly progress was presented during the Ambulatory Clinic Committee (ACC) meetings. Number of labs not completed on time, wait-time and APP visit volume were tracked. Results: Recommendations included provider education on lab order process, purchasing a second instrument for chemistries, APP independent visits standards, and realistic scheduling times. Preliminary findings indicate that the lab reduced their average TAT defect rate by 52.3% (CBC) and 76.1% (CMP) compared to January 2014 (baseline) and January 2015 (post implementation). This difference was statistically significant at a 95% CI, with p &lt; .001 for both CBCs and CMPs. In addition, APP total visit volume increased by 81% from FY 2014 to FY 2015. Finally, the overall Press-Ganey mean in patient satisfaction with physician wait time increased from 81.7 to 82.7 (2014 vs. 2015). Conclusions: Multidisciplinary teams recommended valuable process improvement changes to reduce the TAT in the lab and to promote that APPs work within the full scope of their license. Implementation requires extensive project management support and continuous tracking to evaluate outcomes. Opportunities exist to maximize space and room utilization and optimize the scheduling process as the outpatient volume continues to increase.