tbuckley/cabot-search huggingface dataset:
Abstract 4684: MYC inhibition in human malignancy by BET-Bromodomain inhibitor JQ1, using a 3-D human tumor primary culture micro-spheroid platform to explore clinically relevant observations
Authors: Robert Alan Nagourney, Steven S. Evans, Alexander J. Nagourney, Paula J. Bernard, Federico R. Francisco, Milan Sheth, Nilesh Vora, Eknath Deo
Journal: Cancer Research (2017)

Abstract The transcription factor MYC is associated with the regulation of over 15% of human gene expression. Deregulation of MYC is found in up to 70% of human cancers. As MYC is responsible for the reprogramming of cell metabolism, growth and survival, it is an attractive therapeutic target, yet effective drug development has been slow. As the Bromodomain/BET proteins epigenetically regulate MYC, BET inhibitors like JQ1 have been developed as MYC therapeutics. We used the Ex Vivo Analysis of Programmed Cell Death (EVA/PCD) previously shown to correlate with response, time to progression and survival, to examine JQ1 activity in 46 human tumor specimens isolated from surgical biopsies. Methods: Surgical biopsies were mechanically and enzymatically disaggregated, with micro spheroids of desired size isolated by density centrifugation. Five-Point dose response curves were interpolated to provide LC50 values for comparison by Z-score. Synergy was conducted by median-effect. Results: JQ1 revealed activity in hematologic, breast, glial &amp; gastrointestinal (GI) tumors. By rank order, JQ1 activity favored hematologic (AML &amp; NHL) &amp; breast tumors over Lung, Ovary and GI with inter-patient differences observed within tumor types. MYC association with histone acetylation and aurora kinase (AURK) activity, led to an exploration of JQ1 synergy with SAHA (HDACi), MLN 8054 &amp; Tozasertib (both AURKi). JQ1 synergy analysis revealed SAHA &amp;gt; Tozasertib &amp;gt; MLN 8054. Conclusions: Based upon JQ1 activity, several tumor types appear to be candidates for agents that target MYC-mediated cell survival, offering potential treatment options for patients with advanced malignancies. JQ1 synergy with HDACi &amp; AURKi suggests novel drug combinations for future development. As MYC signaling influences thousands of gene targets, phenotypic analyses like the EVA/PCD platform can offer insights into cellular cell death events that serve as surrogate markers for clinical response to MYC inhibition. Supported in part by the Vanguard Cancer Foundation, the Nagourney Institute and the Malcolm C. Todd Cancer Institute. Citation Format: Robert Alan Nagourney, Steven S. Evans, Alexander J. Nagourney, Paula J. Bernard, Federico R. Francisco, Milan Sheth, Nilesh Vora, Eknath Deo. MYC inhibition in human malignancy by BET-Bromodomain inhibitor JQ1, using a 3-D human tumor primary culture micro-spheroid platform to explore clinically relevant observations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4684. doi:10.1158/1538-7445.AM2017-4684
Are pertussis cases reported too late for public health interventions? Retrospective analysis of cases in London and South East England, 2010 to 2015
Authors: Helen Crabbe, María Saavedra-Campos, Neville Q Verlander, Anusha Leonard, Jill Morris, Amanda Wright, Sooria Balasegaram
Journal: Eurosurveillance (2017)

In the United Kingdom, pertussis guidance recommends prophylaxis for household contacts within 21 days of case symptom onset if the household includes a vulnerable contact. The aim of our study was to identify characteristics associated with cases reported late for public health action. We reviewed the epidemiology of cases reported in London and South East England for the period 2010 to 2015. We characterised risk factors associated with late reporting of cases and described public health actions taken on timely reported cases. From 2010 to 2015, 9,163 cases of pertussis were reported to health protection teams. Only 11% of cases were reported within 21 days of onset, limiting opportunities for secondary prevention. Timely reporting was associated with younger age groups, pregnancy, being a healthcare worker and being reported by schools or hospital clinicians. Late reporting was associated with older age groups and general practitioner or laboratory reporting. Delays, such as those due to insidious onset and late presentation to healthcare, may be unavoidable; however, delay in reporting once a patient presents can be reduced since cases can be reported before laboratory confirmation. Thus we recommend working with clinicians and laboratories to determine causes and improve early reporting to public health.
The effect of multiple adverse childhood experiences on health: a systematic review and meta-analysis
Authors: Karen Hughes, Mark A Bellis, Katherine A Hardcastle, Dinesh Sethi, Alexander Butchart, Christopher Mikton, Lisa Jones, Michael P Dunne
Journal: The Lancet Public Health (2017)

A growing body of research identifies the harmful effects that adverse childhood experiences (ACEs; occurring during childhood or adolescence; eg, child maltreatment or exposure to domestic violence) have on health throughout life. Studies have quantified such effects for individual ACEs. However, ACEs frequently co-occur and no synthesis of findings from studies measuring the effect of multiple ACE types has been done.In this systematic review and meta-analysis, we searched five electronic databases for cross-sectional, case-control, or cohort studies published up to May 6, 2016, reporting risks of health outcomes, consisting of substance use, sexual health, mental health, weight and physical exercise, violence, and physical health status and conditions, associated with multiple ACEs. We selected articles that presented risk estimates for individuals with at least four ACEs compared with those with none for outcomes with sufficient data for meta-analysis (at least four populations). Included studies also focused on adults aged at least 18 years with a sample size of at least 100. We excluded studies based on high-risk or clinical populations. We extracted data from published reports. We calculated pooled odds ratios (ORs) using a random-effects model.Of 11 621 references identified by the search, 37 included studies provided risk estimates for 23 outcomes, with a total of 253 719 participants. Individuals with at least four ACEs were at increased risk of all health outcomes compared with individuals with no ACEs. Associations were weak or modest for physical inactivity, overweight or obesity, and diabetes (ORs of less than two); moderate for smoking, heavy alcohol use, poor self-rated health, cancer, heart disease, and respiratory disease (ORs of two to three), strong for sexual risk taking, mental ill health, and problematic alcohol use (ORs of more than three to six), and strongest for problematic drug use and interpersonal and self-directed violence (ORs of more than seven). We identified considerable heterogeneity (I2 of >75%) between estimates for almost half of the outcomes.To have multiple ACEs is a major risk factor for many health conditions. The outcomes most strongly associated with multiple ACEs represent ACE risks for the next generation (eg, violence, mental illness, and substance use). To sustain improvements in public health requires a shift in focus to include prevention of ACEs, resilience building, and ACE-informed service provision. The Sustainable Development Goals provide a global platform to reduce ACEs and their life-course effect on health.Public Health Wales.
Abstract 4176: Targeting TAM family members with antibody or small molecule inhibitors enhances therapeutic modalities of HNSCC
Authors: Nellie K. Black, Mari Iida, Tamara S. Rodems, Toni M. Brand, Randall J. Kimple, Deric L. Wheeler
Journal: Cancer Research (2017)

Abstract Radiation, cisplatin, and cetuximab are clinical therapeutics used in the treatment of head and neck squamous cell carcinoma (HNSCC). Despite clinical success with these modalities, development of both intrinsic and acquired resistance is an emerging problem in the management of HNSCC. Thus, identifying and targeting molecules driving this drug resistance is essential for improving efficacy of treatment approaches. Recent studies have identified a role for the TAM family of receptor tyrosine kinases (Tyro, Axl, and Mer) in tumor biology, especially the Axl receptor in promoting tumor growth and metastasis. Previously, we identified Axl as a logical molecular target in HNSCC and indicated that it may play a pivotal role in resistance to radiation, cisplatin, and cetuximab. In the current study, we advanced these early findings into pre-clinical models using patient-derived xenografts (PDXs). We have shown that small molecules targeting Axl can enhance therapy in PDXs that express high levels of Axl and have been identified as resistant to radiation, cisplatin, and cetuximab. Current studies are focusing on antibody-based targeting of Axl using PDXs and genetically-modified models of resistance. Furthermore, studies focused on co-targeting of Axl and Mer in vitro and in vivo have shown striking results and denote the importance of establishing logical approaches to target TAMs in the management of HNSCC. Finally, investigations into the molecular mechanisms of how Axl signaling can lead to resistance have underscored the importance of tyrosine 821 (Y821) of Axl. Overexpression of Axl rendered cetuximab sensitive lines resistant, but cell lines overexpressing Axl-Y821F retained their sensitivity to cetuximab. Advancing this line of study in vivo indicated that tumors expressing Axl were resistant to cetuximab whereas tumors harboring the Y821 mutation were sensitive demonstrating that signals emanating from Y821 may be critical for cetuximab resistant pathways. Collectively, the studies presented herein identify the TAM family of receptors as key players in radiation, cisplatin, and cetuximab resistance. These results provide rationale for the clinical targeting of TAM receptors to enhance the therapeutic modalities used in treating HNSCC. Citation Format: Nellie K. Black, Mari Iida, Tamara S. Rodems, Toni M. Brand, Randall J. Kimple, Deric L. Wheeler. Targeting TAM family members with antibody or small molecule inhibitors enhances therapeutic modalities of HNSCC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4176. doi:10.1158/1538-7445.AM2017-4176
Abstract P148: C-Reactive Protein (CRP) and the Prediction of Cardiovascular Death Among Mexican-Americans
Authors: Lenny Lopez, Carmen A Peralta, Anne Lee, Allison Aiello, Mary N Haan
Journal: Circulation (2012)

Background: Addition of C-reactive protein (CRP) improves risk stratification provided by traditional Framingham risk factors (FRFs) in some populations, but findings vary by gender and by race/ethnicity. Whether CRP levels can improve risk prediction of cardiovascular mortality (CVD) among elderly Hispanics is unknown. Hypothesis: CRP will add incremental CVD risk prediction in addition to FRFs. Methods: We evaluated whether addition of baseline CRP to the Framingham risk score can improve CVD risk stratification for CVD death among 1,422 participants (536 males, 886 females) from the Sacramento Area Latino Study on Aging (SALSA). SALSA is a well-characterized, NIH funded cohort study of Mexican Americans aged &gt; 60 followed since 1998–1999. Death was ascertained by participant contacts, obituary reviews and cause of death from death certificates. We evaluated the association of CRP levels with CVD death using Cox proportional hazards models adjusting for FRFs stratified by gender. We calculated gender stratified net reclassification improvement (NRI) in models with and without CRP to predict 10-year CVD risks using the established FRFs categories (&lt;5%, 5–10%, 10–20%, &gt; 20%). Results: Mean baseline age was 70.7 and mean CRP level was 5.86 ng/ml. There were 167 CVD male deaths (mortality rate 39.2 per 1,000 person years) and174 among women (mortality rate 27.8 per 1,000 person years). Higher CRP levels were significantly associated with higher CVD mortality risk in men, HR of 1.29 (95% CI 1.11 – 1.50) but not women, HR 0.94 (95% CI 0.81 – 1.08) after adjustment for covariates. Addition of CRP was useful in reclassifying CVD death risk among men defined by FRF alone, and this was due to correct reclassification of those who did not experience CVD death from the highest risk group to a lower risk category. The majority of male participants (619/745=83%) were classified as having &gt;20%risk in the model without CRP. Mortality rate for men initially classified as having &gt; 20% risk was 37.9 per 1,000 person years. After addition of CRP, 6% were reclassified into an intermediate risk category (NRI 7.4%, p&lt; 0.001) and their mortality rate was 10.3 per 1,000 person years. Overall, NRI for men was 4.2% (p=0.05). In contrast, addition of CRP among women was associated with increased misclassification to a higher risk category (NRI= − 13.4%, p=0.0001). Conclusion: A risk prediction model that includes CRP improves cardiovascular risk classification among elderly Mexican-American men but not women as defined by traditional FRFs.
Abstract 242: Mitophagy is Required for Mitochondrial Biogenesis and Myogenic Differentiation of Myoblasts
Authors: Jon Sin, Allen Andres, David J Taylor, Aleksandr Stotland, Chengqun Huang, Roberta A Gottlieb
Journal: Circulation Research (2015)

Myogenesis is a crucial process governing muscle development and homeostasis. Differentiation of primitive myoblasts into mature myotubes requires a metabolic switch to support the increased energetic demand of contractile muscle. Skeletal myoblasts specifically shift from a highly glycolytic state to relying predominantly on oxidative phosphorylation (OXPHOS) upon differentiation. We have found that this phenomenon requires dramatic remodeling of the mitochondrial network involving both mitochondrial clearance and biogenesis. During early myogenic differentiation, autophagy is robustly upregulated and this coincides with DNML1/DRP1-mediated fragmentation and subsequent removal of mitochondria via p62/SQSTM-mediated mitophagy. Mitochondria are then repopulated via PPARGC1A/PGC-1α-mediated biogenesis. Mitochondrial fusion protein OPA1 is then briskly upregulated, resulting in the reformation of mitochondrial networks. The final product is a myotube replete with new mitochondria. Respirometry reveals that the constituents of these newly established mitochondrial networks are better primed for OXPHOS and are more tightly coupled than those in myoblasts. Additionally, we have found that blocking autophagy with various inhibitors during differentiation results in a blockade in myogenic differentiation. Together these data highlight the integral role of autophagy and mitophagy in myogenic differentiation.
Abstract 197: Anti-cancer activity of extract from the Jamaican round-leaf yellow yam (RLY2) (Dioscorea cayenensis)
Authors: Sasha-Gay A. Wright, Wesley G. Gray, Helen Asemota
Journal: Cancer Research (2017)

Abstract The Jamaican Round-Leaf yellow yams (RLY2), Dioscorea cayenensis, are edible tubers, bulbils or rhizomes that are of considerable economic value and possess several health benefits. These RLY2 are a rich source of anti-oxidants, vitamins and phytochemicals. In addition to its nutritional value, the Jamaican populace regards RLY2 as an herbal medicine useful in treatment of diabetes mellitus, hypertension and certain kind of cancers. Chemical analysis of RLY2 revealed the presence of a myriad of bioactive ingredients that are likely to be lost due to the method of preparation for consumption. Thus, we hypothesized that mild extraction of RLY2 will preserved the bioactive analytes that give RLY2 its anti-cancer property. To test this hypothesis, different ethanolic extracts of RLY2 were prepared, and their bioactivity demonstrated in two models of prostate cancer. The present study demonstrates dosage and time-dependence inhibition in both the androgen sensitive LNCaP and androgen insensitive DU-145 prostate cancer cell lines. We observed that DU-145 was three-times more sensitive to RLY2 ethanol extract than LNCaP. Growth of LNCaP for 3-days with varying concentration of RLY2 ethanol extract resulted in an IC50 of 750 ppm (95% C.I. 726-791ppm), whereas DU-145 resulted in an IC 50 of 250 ppm (95% C.I. 236-281ppm). The maximum growth inhibition by RLY2 extract occurs within twenty-four hours for both LNCaP and DU-145 with no significant changes after 5-days. To determine the mechanism of toxicity by RLY2, we induced both LNCaP and DU-145 with RLY2 for 0-24h and prepared cells for flow cytometer analysis. The effect of RLY2 on cell cycle and degree of apoptosis will be discussed. Our data indicated that the ethanol extract of RLY2 was more sensitive toward androgen-insensitive prostate cancer. Thus, this study suggests that RLY2 contain bioactive chemical that may be used in grade II prostate adenocarcinoma represented by the DU-145 phenotype. Citation Format: Sasha-Gay A. Wright, Wesley G. Gray, Helen Asemota. Anti-cancer activity of extract from the Jamaican round-leaf yellow yam (RLY2) (Dioscorea cayenensis) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 197. doi:10.1158/1538-7445.AM2017-197
Abstract 1839: TGFBR1*6A mouse model mimics human breast cancer development and progression
Authors: Michael James Pennison, Minghui Wang, Hugo Jimenez, Boris Pasche
Journal: Cancer Research (2017)

Abstract Transforming Growth Factor-ß (TGF-β) is one of the most commonly altered cellular signaling pathways in human cancer. Our group was the first to discover TGFBR1*6A (*6A), a common hypomorphic variant of the type I TGF-ß receptor (TGFBR1), which has been associated with increased risk for breast cancer in multiple epidemiological studies. Functional analysis also suggests that *6A is associated with decreased tumor suppressive TGF-β signaling in early tumor development and is involved with promoting tumorigenesis in advanced carcinomas. To better understand the functional impact of *6A and constitutively reduced TGF-ß signaling on breast cancer development and progression, we have recently developed a series of transgenic knock-in mouse model variants by replacing exon 1 of the mouse Tgfbr1 sequence with human exon 1 sequences harboring both *6A and wild-type (*9A) TGFBR1 variants and crossed them with MMTVneu mice. We generated a total of 5 FVB double and/or triple transgenic mouse strains: MMTVneu;9A/9A, MMTVneu;6A/6A, MMTVneu;9A/6A, MMTVneu;*9A/-, and MMTVneu;6A/-. Following tumor development, measurements were performed three times per week to determine tumor volume. All mice were allowed to live up to 18 months (548 days) or until they died of natural causes. Specimens were collected for later analysis of blood, tumors, normal mammary tissue, and were evaluated for lung metastases. Statistical comparisons performed using Student’s t-test. Only 34.4% of MMTVneu;9A/9A mice (11/32) developed mammary tumors, while 80% of MMTVneu;6A/6A mice (24/30; p=0.0002) and 62.5% of MMTVneu;6A/- mice (19/32, p=0.046) developed tumors. The percentage of MMTVneu;9A/6A and MMTVneu;*9A/- mice that developed tumors was higher than MMTVneu;9A/9A mice (48.3% and 50%, respectively) but was not statistically significant. Additionally, 66.7% of MMTVneu;6A/6A mice (20/30) developed 2 or more tumors, while only 25% of MMTVneu;9A/9A mice (8/32) developed multiple tumors (p=0.0007). Our data suggests that we have developed transgenic mouse strains that accurately mimic human breast cancer susceptibility associated with *6A and constitutively decreased TGFBR1 expression in humans, as evidenced by other studies. These mouse models may be a tool to provide invaluable insight to better understand the role of TGFBR1 variants in the development and progression of breast cancer. Citation Format: Michael James Pennison, Minghui Wang, Hugo Jimenez, Boris Pasche. TGFBR1*6A mouse model mimics human breast cancer development and progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1839. doi:10.1158/1538-7445.AM2017-1839
The three-dimensional genome organization of Drosophila melanogaster through data integration
Authors: Qingjiao Li, Harianto Tjong, Xiao Li, Ke Gong, Xianghong Jasmine Zhou, Irene Chiolo, Frank Alber
Journal: Genome biology (2017)

Abstract Background Genome structures are dynamic and non-randomly organized in the nucleus of higher eukaryotes. To maximize the accuracy and coverage of three-dimensional genome structural models, it is important to integrate all available sources of experimental information about a genome’s organization. It remains a major challenge to integrate such data from various complementary experimental methods. Here, we present an approach for data integration to determine a population of complete three-dimensional genome structures that are statistically consistent with data from both genome-wide chromosome conformation capture (Hi-C) and lamina-DamID experiments. Results Our structures resolve the genome at the resolution of topological domains, and reproduce simultaneously both sets of experimental data. Importantly, this data deconvolution framework allows for structural heterogeneity between cells, and hence accounts for the expected plasticity of genome structures. As a case study we choose Drosophila melanogaster embryonic cells, for which both data types are available. Our three-dimensional genome structures have strong predictive power for structural features not directly visible in the initial data sets, and reproduce experimental hallmarks of the D. melanogaster genome organization from independent and our own imaging experiments. Also they reveal a number of new insights about genome organization and its functional relevance, including the preferred locations of heterochromatic satellites of different chromosomes, and observations about homologous pairing that cannot be directly observed in the original Hi-C or lamina-DamID data. Conclusions Our approach allows systematic integration of Hi-C and lamina-DamID data for complete three-dimensional genome structure calculation, while also explicitly considering genome structural variability.