tbuckley/cabot-search huggingface dataset:
Aberrations in androgen receptor ctDNA varies by race in metastatic castrate-resistant prostate cancer.
Authors: Bryce Raymon Christensen, Elisa Ledet, James Vu, Peter Steinwald, Lynne Chapman, Leta Ko, Lahiru Ranasinghe, Joshua Schiff, Marcus Marie Moses, Patrick Cotogno, Charlotte Manogue, Brian E. Lewis, Jodi Lyn Layton, A. Oliver Sartor
Journal: Journal of Clinical Oncology (2019)

247 Background: Characterization of circulating free DNA (ctDNA) may aid understanding of the pathophysiology of metastatic castrate resistant prostate cancer (mCRPC). The goal of this study was to evaluate and compare somatic alterations in ctDNA between African-American (AA) and Caucasian (C) mCRPC patients. Methods: 24 AA were retrospectively case-matched by prior treatment with 45 CA mCRPC; ctDNA was assessed with Guardant360 assay (Guardant Health, Redwood City, CA). Mutant allelic fraction, mutations, and gene amplification were compared. Results: Prior to testing, 6 AA pts and 12 CA pts had 0 lines of CRPC therapy, 7 AA pts and 10 CA pts had 1-2 lines, 5 AA and 17 CA had 3-4 lines, 5 AA and 2 CA had 5-6 lines, and 1 AA pt and 4 CA pts had &gt;6 lines. The median Gleason score was 8, regardless of race. The median ctDNA mutant allelic fraction was 0.40% for AA pts and 0.60% for the CA pts. Mutations and/or amplifications in individually assessed genes are shown in the Table. No statistically significant differences were detected except for the androgen receptor (AR) gene where alterations (mutations and/or amplifications) were more frequent in AA as compared to C (p=0.04). Conclusions: AR alterations were more commonly detected in ctDNA in AA men as compared to C suggesting that AR driven pathophysiology may predominate in this setting. Additional analyses with a larger cohorts are warranted. Data from prospective trials in mCRPC using abiraterone/prednisone (George et al. LBA 5009, ASCO 2018) similarly suggest that mCRPC may be comparatively more AR driven in this racial setting. Alterations in ctDNA compared between AA and C men with mCRPC. [Table: see text]
Oral administration of the cannabigerol derivative VCE-003.2 promotes subventricular zone neurogenesis and protects against mutant huntingtin-induced neurodegeneration
Authors: José Aguareles, Juan Paraíso-Luna, Belén Palomares, Raquel Bajo-Grañeras, Carmen Navarrete, Andrea Ruiz-Calvo, Daniel García-Rincón, Elena García-Taboada, Manuel Guzmán, Eduardo Muñoz, Ismael Galve-Roperh
Journal: Translational Neurodegeneration (2019)

The administration of certain cannabinoids provides neuroprotection in models of neurodegenerative diseases by acting through various cellular and molecular mechanisms. Many cannabinoid actions in the nervous system are mediated by CB1 receptors, which can elicit psychotropic effects, but other targets devoid of psychotropic activity, including CB2 and nuclear PPARγ receptors, can also be the target of specific cannabinoids. We investigated the pro-neurogenic potential of the synthetic cannabigerol derivative, VCE-003.2, in striatal neurodegeneration by using adeno-associated viral expression of mutant huntingtin in vivo and mouse embryonic stem cell differentiation in vitro. Oral administration of VCE-003.2 protected striatal medium spiny neurons from mutant huntingtin-induced damage, attenuated neuroinflammation and improved motor performance. VCE-003.2 bioavailability was characterized and the potential undesired side effects were evaluated by analyzing hepatotoxicity after chronic treatment. VCE-003.2 promoted subventricular zone progenitor mobilization, increased doublecortin-positive migrating neuroblasts towards the injured area, and enhanced effective neurogenesis. Moreover, we demonstrated the proneurogenic activity of VCE-003.2 in embryonic stem cells. VCE-003.2 was able to increase neuroblast formation and striatal-like CTIP2-mediated neurogenesis. The cannabigerol derivative VCE-003.2 improves subventricular zone-derived neurogenesis in response to mutant huntingtin-induced neurodegeneration, and is neuroprotective by oral administration.
Abstract MP41: A Diet High in Carbohydrate and Low in Fat Alters the HDL Proteome and Metabolism of 9 HDL Proteins in Humans
Authors: Allison B Andraski, Sasha A Singh, Lang Lee, Hideyuki Higashi, Nathaniel Smith, Masanori Aikawa, Frank M Sacks
Journal: Circulation (2019)

Introduction: When dietary carbohydrate replaces fat, HDL cholesterol (HDL-C) and the primary HDL protein apolipoprotein A1 (apoA1) decrease. The proportion in plasma of large HDL2 decreases while small HDL3 increases. These findings suggest that diet affects metabolically important attributes of HDL that produce the size changes. We studied in humans the effect of dietary carbohydrate and unsaturated fat on the HDL proteome and metabolism of 9 HDL proteins across 5 HDL sizes. Methods and Results: Twelve participants were placed on a healthy, controlled diet high in unsaturated fat (HF) or high in carbohydrate (HC) in a randomized crossover design. At the end of each 4-week diet period, subjects were infused with a stable isotope tracer (D3-Leu) in order to label all newly synthesized HDL proteins. Blood samples were collected and tracer was followed for 70 hrs post-infusion. ApoA1-HDL was isolated by immunoaffinity purification, separated into 5 HDL particle sizes, and prepared for analysis by mass spectrometry. We used label free quantification to characterize the HDL proteome. The proteome composition and distribution across the 5 HDL sizes were remarkably conserved in all subjects on both diets. Diet altered the abundance of several proteins on the major HDL sizes alpha2 and alpha3. The HC diet increased proteins involved in lipid metabolism (apoC3, apoA2) and decreased antioxidant (PON1, PON3) and protease inhibitor (SERPINA3, SERPING1) proteins. We also monitored the metabolism of 9 proteins that likely affect HDL metabolism - apoA1, apoA2, apoA4, apoC3, apoE, apoJ, apoL1, apoM and LCAT. We used parallel reaction monitoring and XPI software to measure the amount of D3-Leu tracer over time in these 9 proteins across the 5 HDL sizes. We found that the HC diet increased apoA2 and apoJ and decreased apoA1 pool sizes on large HDL. The HC diet also increased apoM turnover in large HDL, and apoA1, apoA2, and apoE turnover across the HDL size range. Conclusions: Dietary carbohydrate when it replaces unsaturated fat alters the HDL proteome and metabolism of several HDL proteins on specific HDL sizes. Carbohydrate increases the abundance of proteins involved in lipid metabolism, decreases antioxidant and protease inhibitor proteins, and accelerates turnover of apoA1, apoA2, apoE, and apoM. This study suggests that diet modulates HDL function by affecting HDL composition and the metabolism of major HDL proteins.
Uncontrolled chronic conditions prior to cancer diagnosis in older adults as a predictor of unplanned hospitalizations during cancer care: A Medicare claims analysis.
Authors: Noam Avraham VanderWalde, Tao Li, Cameron Kaplan, Erin Kaplan, Laura Stevens, Jennifer Webster, Barbara L. McAneny, Teresa Waters
Journal: Journal of Clinical Oncology (2015)

6587 Background: Unplanned hospitalizations (UH) during cancer care have been identified as a poor outcome that may significantly increase costs of care. We hypothesized that poor quality of care prior to cancer diagnosis, as defined by preventable hospitalizations for Ambulatory Care Sensitive Conditions (ACSCs), predicts for UH during cancer care. Methods: A retrospective claims study was conducted among Medicare fee-for-service enrollees with a first time diagnosis of one of seven cancers (breast, lung, colorectal, lymphoma, melanoma, pancreatic, or thyroid) from 6 different states (TX, OH, ME, NM, GA, and FL) between 2011 and 2012. Date of diagnosis was defined as the first cancer diagnosis claim from inpatient or outpatient claims. At least nine months of pre-diagnosis claims was required to identify pre-cancer Charlson comorbidity (CCI) and ACSC hospitalizations as measured by ER and hospitalization diagnosis codes. UHs were defined as hospitalization, with admission type of urgent or emergent within 1 year from diagnosis, excluding those for cancer treatment. Multivariate logistic regression analysis was used to model UH using known patient and county level socio-demographic variables. Results: A total of 21,735 cancer patients were identified. The majority of patients had breast (n = 7,548), lung (n = 5,841) or colorectal cancer (n = 3,904). Median age at diagnosis was 74. Thirty four percent of patients were male. UHs were experienced by 33% of all patients during their cancer care, while 8% had pre-diagnosis ACSC hospitalizations. ACSC hospitalizations were strongly associated with UH during cancer care (OR: 1.49, 95% CI: 1.34 – 1.66, p-value: < .001). Other variables associated with higher likelihood of UH include CCI (OR: 1.22, p-value < .001) AA race (OR: 1.30 p-value < .001), and cancer type compared to breast (lung cancer OR 3.30, p-value < .001). Conclusions: There is a strong association between pre-diagnosis ACSC preventable hospitalizations and UHs during cancer care, even after controlling for comorbidity. Interventions that identify vulnerable older adults at diagnosis may help improve outcomes and costs of cancer related care.
Risk of recurrence in patients with positive surgical margin at apex only versus other locations after radical prostatectomy.
Authors: Masashi Kato, Akiyuki Yamamoto, Ryo Ishida, Tohru Kimura, Tomoyasu Sano, Takayuki Owaki, Naoto Sassa, Momokazu Gotoh, Toyonori Tsuzuki
Journal: Journal of Clinical Oncology (2019)

124 Background: Some reported that positive surgical margin at radical prostatectomy (RP) was a prognostic factor of clinical recurrence and prostate cancer death, and others showed that was not necessarily true. The prostatic apex is most popular location of positive surgical margin at RP and the frequency of apex is reported to be about 20-40% of all positive cases. Prostatic apex is also reported to lack a well-defined capsule and to be hardly retracted during operation. In this study, we evaluated the effect of positive surgical margin at apex-only on prognosis after RP in a large cohort. Methods: We retrospectively evaluated 1019 patients with prostate cancer who underwent radical prostatectomy without neoadjuvant or adjuvant therapy at the hospitals that the authors were affiliated with between 2005 and 2013. The operative approach (open, laparoscopic, or robotic) was decided by each institution. All prostatectomy specimen slides were reviewed by a single genitourinary pathologist according to ISUP 2014 criteria. Recurrence following RP was defined according to AUA guidelines. Results: The median patient age was 67 (range, 45–80) years. The median initial PSA was 6.8 ng/ml (range, 0.4–82 ng/ml). The median follow-up period was 69 (range, 0.7–135) months. Pathological T stage was in 72.5% of pT2 (n = 739), 23.4% of pT3a (n = 238), and 4.1% of pT3b (n = 42). There were 163 Grade Group (GG) 1 cases, 502 GG 2, 217 GG 3, 39 GG 4, and 98 GG 5 cases. 372 cases had positive surgical margin. Details were 201 (54%) apex only, 57 (15%) anterior, 43 (12%) posterior, 76 (20%) lateral, 40 (11%) bladder. Some patients showed multiple positive surgical margin. The patients with positive surgical margin at apex-only showed significantly better prognosis than other locations (P = 0.0001). This result was confirmed in each operative approach (open; P = 0.008, laparoscopic; P = 0.001, robotic; P = 0.01). Conclusions: Among surgical margin positive patients after RP, those at prostatic apex-only showed lower biochemical recurrence than other locations regardless of operative approach. Physician should follow such a patient carefully without adjuvant therapy.
Reexamining Recommendations for Treatment of Hypercholesterolemia in Older Adults
Authors: Neil Skolnik
Journal: JAMA (2019)

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Response and neurologic toxicity to taxano regarding to CYP2C8*3 and CYP2C8*2 polymorphisms in Peruvian breast cancer cases.
Authors: Cindy Alcarraz, Carlos Castaneda Altamirano, Henry Gomez, Amparo Zavaleta, Carol Flores, Miluska Castillo Garcia, Ketty Dolores Cerna, Julio E. Abugattas Saba, Tatiana Vidaurre
Journal: Journal of Clinical Oncology (2015)

e12520 Background: An option in the BC neoadyuvant treatment is paclitaxel, being the goal achieving pathological complete response (pRC). The single nucleotide polymorphisms (SNPs) in genes encoding proteins responsible for drug metabolism can affect their effectiveness. Methods: DNA was isolated from blood samples and by polymerase chain reaction we identified CYP2C8 * 2/CYP2C8 * 3 alleles in Peruvian patients before starting the neoadyuvant treatment with paclitaxel. Endpoints were to determine the presence of single nucleotide polymorphism CYP2C8 * 2/CYP2C8 *3 and evaluate its association with pR and neurological toxicity. Results: Thirty-nine patients were included. Median age was 40 years, Stage II was present in 10.2% and stage III in 89.9%. Infiltrating ductal carcinoma (94.8%) were most frequent followed by Infiltrating lobular carcinoma (5.2%); 87.1% completed 12 courses of paclitaxel. 29 (74.3%) had surgery, 26 (66.6%) mastectomy and 3 (7.6%) conservative surgery. 10 (25.5%) had failed surgery due to disease progression; 13.7% achieved pRC in the tumor and the axilla. 22 (56.5%) had neurological toxicity (2 had grade 2/3).Three (7.6%) patients had SNPs CYP2C8 *3, 2 GG homozygous and 1 AG heterozygous, all in patients EC IIIB, the homozygous variant was ER +, PR +, CerbB2 ±/- while the heterozygote was triple negative. Only 2 patients completed 12 courses of paclitaxel, then had partial mastectomy and achieved pRC, presented only grade 1 neurological toxicity; 1 patient with SNPs progress locally. No association between the presence of SNPs and clinical response or with neurological toxicity was found. Conclusions: In this pilot study, 3 Peruvian patients had CYP2C8 * 3 SNPs and none SNPs CYP2C8 *2 so it should extend the study of SNPs with more patients and evaluate other genes involved in the metabolism of paclitaxel.
Next generation N-terminal domain androgen receptor inhibitors with improved potency and metabolic stability in castration-resistant prostate cancer models.
Authors: Ronan Le Moigne, Han-Jie Zhou, Nasrin R Mawji, C. Adriana Banuelos, Jun Wang, Kunzhong Jian, Peter Virsik, Raymond J Andersen, Marianne Sadar
Journal: Journal of Clinical Oncology (2019)

220 Background: EPI-506, pro-drug of EPI-002, was a first-in-class oral small molecule from the Aniten family of compounds, which inhibit androgen receptor (AR) activity by binding to the N-terminal domain of the AR. EPI-506 was tested in a Phase 1 study in men with metastatic castration-resistant prostate cancer (mCRPC) resistant to current therapies and demonstrated a favorable tolerability profile with signs of moderate efficacy. Metabolic vulnerabilities in the chemical scaffold of EPI-506 were identified and new Aniten molecules, EPI-7170 and EPI-7245 , with improved potency, metabolic stability and pharmaceutical properties have been generated. Methods: Chemical structure activity relationships were developed in order to increase molecule potency in cellular and in vivo assays, while metabolic stability improvements were assessed in in vitro ADME assays and in animal pharmacokinetic studies. In addition, the on-target activity and selectivity was also optimized using a variety of cellular experiments. Results: Next generation Anitens demonstrated a 10-20 fold improvement on AR-driven cellular potency, with IC50’s of 0.5-1 uM when compared to 10-12 uM for EPI-002. In vitro proliferation assays demonstrated on target activity, with an IC50 ~ 2 uM in LNCaP and &gt; 10 uM in the AR-independent cell model PC-3. EPI-7170 was also active in AR-V7-driven LNCaP95 cells. The antiproliferative effect was in alignment with the inhibitory effect on a subset of AR driven genes. In vivo activity in castrated mice bearing LNCaP tumors showed tumor growth inhibition of approximately 70%. While EPI-7170 represents a major advance, subsequent chemistry efforts led to the generation of EPI-7245 and other next generation Anitens which exhibit IC50’s &lt; 500 nM and favorable ADME and PK profiles. Conclusions: Promising next-generation Aniten compounds have been identified. Major chemistry efforts led to the identification of several Anitens with &gt; 10-20 fold improvements in cellular potency compared to EPI-506 which are also metabolically stable. IND-selection preclinical studies are underway on the most promising Aniten’s with an IND submission planned shortly.
Abstract P144: Cardiovascular Risk Assessment in Western Honduras; An Epidemiological Perspective
Authors: Carlos A Godoy Rivas, Eleazar E Montalván, Samuel A Urrutia, Aida A Rodríguez, Eva E Ordoñez, Axel A Murillo, Ricardo J Rivera, Karla G Duarte, Artemisa J Viana, José L Aguilera, Laura Young, Karla P Torres, Haitham Ahmed
Journal: Circulation (2018)

Background: Cardiovascular Disease (CVD) epidemiology varies significantly among Low and Middle-Income Countries. Honduras is the Central American country with the highest ischemic heart disease and CVD mortality rates. The objective of this study is to provide an epidemiologic perspective of CVD in Western Honduras by analyzing cardiovascular (CV) risk in a population of Hispanics/mestizos and calculating their predicted CVD mortality using Cardiovascular Risk Assessment Scores (CVRAS) such as AHA/ACC Pooled-Cohort Equations (PCEs), Framingham Risk Score (FRS) and Multi-Ethnic Study on Atherosclerosis (MESA) Risk Score. Methods: Data was derived from Torres et al study, which was a cross-sectional, primary-prevention study, including 382 subjects between 45-75 years, in Copán, Honduras, between November 2016 and January 2017. Results: Out of 379 subjects meeting inclusion criteria, 38% (143 of 379) were male and 62% (237 of 379) were female. Age was 57 ± 8.2 for men and 58 ± 7.7 for women. Prevalence of hypertension was 49.7% (71 of 143) in men and 47.7% (113 of 237) in women; 91.3% (168 of 184) were being treated. DM was present in 19% (27 of 143) of men and 22.1% (52 of 237) of women; 96.2% (75 of 79) were being treated. Obesity was 24.5% (35 of 143) in men and 24.1% (57 of 237) in women. Total cholesterol was ≥ 200 mg/dl in 63.1% (239 of 379) of subjects, 21.8% (52 of 239) were taking lipid-lowering medications. For men and women respectively; AHA/ACC-PCEs was ≥7.5% (high-risk) in 62.2% (89 of 143) and 29.8% (71 of 237), FRS was ≥20% in 46.2% (66 of 143) and 15.2% (36 of 237), and MESA Risk Score was ≥7.5% in 70.6% (101 of 143) and 17.7% (42 of 237). Conclusions: After collecting anthropometric and laboratory data, calculation of CVRAS showed significantly elevated rates of high-CV risk patients according to all 3 scores. This is the first study of its type in Honduras. Efforts should be made to aggressively reduce CVD risk factors, and follow this cohort of subjects to better understand CVD morbidity and mortality in Western Honduras.
Ventilatory and Heart Rate Responses to Exercise
Authors: Mark Robbins, Gary Francis, Fredric J. Pashkow, Claire E. Snader, Kathy Hoercher, James B. Young, Michael S. Lauer
Journal: Circulation (1999)

Background —An abnormally low chronotropic response and an abnormally high ventilatory response (V̇ e /V̇ co 2 ) to exercise are common in patients with severe heart failure, but their relative prognostic impacts have not been well explored. Methods and Results —Consecutive patients with heart failure referred for metabolic stress testing who were not taking β-blockers or intravenous inotropes (n=470) were followed for 1.5 years. The chronotropic index was calculated while peak V̇ o 2 and V̇ e /V̇ co 2 were directly measured. Chronotropic index and peak V̇ o 2 were considered abnormal if in the lowest 25th percentiles of the patient cohort, whereas V̇ e /V̇ co 2 was considered abnormal if in the highest 25th percentile. For comparative purposes, a group of 17 healthy controls underwent metabolic testing as well. Compared with controls, heart failure patients had markedly abnormal ventilatory and chronotropic responses to exercise. In the heart failure cohort, there were 71 deaths. In univariate analyses, predictors of death included high V̇ e /V̇ co 2 , low chronotropic index, low V̇ o 2 , low resting systolic blood pressure, and older age. Nonparametric Kaplan-Meier plots demonstrated that by dividing the population according to peak V̇ e /V̇ co 2 and peak V̇ o 2 , it is possible to identify low, intermediate, and very high risk groups. In multivariate analyses, the only independent predictors of death were high V̇ e /V̇ co 2 (adjusted relative risk [RR] 3.20, 95% CI 1.95 to 5.26, P &lt;0.0001) and low chronotropic index (adjusted RR 1.94, 95% CI 1.18 to 3.19, P =0.0009). Conclusions —The ventilatory and chronotropic responses to exercise are powerful and independent predictors of heart failure mortality.