tbuckley/cabot-search huggingface dataset:
A computational tool (H-MAGMA) for improved prediction of brain-disorder risk genes by incorporating brain chromatin interaction profiles
Authors: Nancy Y. A. Sey, Benxia Hu, Won Mah, Harper Fauni, Jessica Caitlin McAfee, Prashanth Rajarajan, Kristen J. Brennand, Schahram Akbarian, Hyejung Won
Journal: Nature Neuroscience (2020)
Abstract 4502: Aortic Valvular Calcification Predicts Restenosis after Implantation of Drug-Eluting Stents
Authors: Hideki Ishii, Toru Aoyama, Miho Tanaka, Hiroshi Takahashi, Takanobu Toriyama, Yoshihiro Kawamura, Yoshitaka Kumada, Motohiro Miyagi, Tetsuya Amano, Tadayuki Uetani, Tatsuaki Matsubara, Toyoaki Murohara
Journal: Circulation (2008)
Synthetic Conjugates of Ursodeoxycholic Acid Inhibit Cystogenesis in Experimental Models of Polycystic Liver Disease
Authors: Francisco J. Caballero‐Camino, Ivan Rivilla, Elisa Herraez, Oscar Briz, Alvaro Santos‐Laso, Laura Izquierdo‐Sanchez, Pui Y. Lee‐Law, Pedro M. Rodrigues, Patricia Munoz‐Garrido, Sujeong Jin, Estanislao Peixoto, Seth Richard, Sergio A. Gradilone, Maria J. Perugorria, Manel Esteller, Luis Bujanda, Jose J.G. Marin, Jesus M. Banales, Fernando P. Cossío
Journal: Hepatology (2020)

Background and Aims Polycystic liver diseases (PLDs) are genetic disorders characterized by progressive development of symptomatic biliary cysts. Current surgical and pharmacological approaches are ineffective, and liver transplantation represents the only curative option. Ursodeoxycholic acid (UDCA) and histone deacetylase 6 inhibitors (HDAC6is) have arisen as promising therapeutic strategies, but with partial benefits. Approach and Results Here, we tested an approach based on the design, synthesis, and validation of a family of UDCA synthetic conjugates with selective HDAC6i capacity (UDCA‐HDAC6i). Four UDCA‐HDAC6i conjugates presented selective HDAC6i activity, UDCA‐HDAC6i #1 being the most promising candidate. UDCA orientation within the UDCA‐HDAC6i structure was determinant for HDAC6i activity and selectivity. Treatment of polycystic rats with UDCA‐HDAC6i #1 reduced their hepatomegaly and cystogenesis, increased UDCA concentration, and inhibited HDAC6 activity in liver. In cystic cholangiocytes UDCA‐HDAC6i #1 restored primary cilium length and exhibited potent antiproliferative activity. UDCA‐HDAC6i #1 was actively transported into cells through BA and organic cation transporters. Conclusions These UDCA‐HDAC6i conjugates open a therapeutic avenue for PLDs.
Benefits and Risks of Primary Treatments for High-risk Localized and Locally Advanced Prostate Cancer: An International Multidisciplinary Systematic Review
Authors: Lisa Moris, Marcus G. Cumberbatch, Thomas Van den Broeck, Giorgio Gandaglia, Nicola Fossati, Brian Kelly, Raj Pal, Erik Briers, Philip Cornford, Maria De Santis, Stefano Fanti, Silke Gillessen, Jeremy P. Grummet, Ann M. Henry, Thomas B.L. Lam, Michael Lardas, Matthew Liew, Malcolm D. Mason, Muhammad Imran Omar, Olivier Rouvière, Ivo G. Schoots, Derya Tilki, Roderick C.N. van den Bergh, Theodorus H. van Der Kwast, Henk G. van Der Poel, Peter-Paul M. Willemse, Cathy Y. Yuan, Badrinath Konety, Tanya Dorff, Suneil Jain, Nicolas Mottet, Thomas Wiegel
Journal: European Urology (2020)
Hyperfractionated radiotherapy and biliary stenting for unresectable biliary tract cancers: Useful baseline data adding chemotherapy
Authors: M. Nakazawa, C. Shibayama, M. Nakamura, K. Akahane, K. Tamada
Journal: Journal of Clinical Oncology (2007)

15079 Background: The morbidity and survival advantage treated with the combination of hyperfractionated radiotherapy (HF) and biliary stenting has not yet established for patients with unresectable biliary tract cancers. A prospective study was carried out using HF and metallic stent in consecutive patients over 10 years in a single institution. Methods: From 1993 to 2003, consecutive 162 pts (radical 74, postoperative 83, postoperative relapse 5) were treated with HF. Out of 74 radical cases, 71 pts (36 male/35 female; median age 70yrs, range 35–88) were analyzed except 3 cases (manifestation of liver metastasis 1, ascites 1, rejection of treatment 1). Primary sites were; extrahepatic bile duct 56, gall bladder 15. Bile cytology showed adenocarcinoma in every case. HF was administered twice daily by 10MV photon, using 2 portals (ant-post), 3 portals (ant-post-right lateral) or wedged pairs (ant-lateral) with relatively small radiation fields (PTV was CTV +1∼1.5cm). Fractional dose was 1.4Gy with the interfractional interval of 4.5 hrs to a total median dose of 59.8Gy. Endpoints were overall survival and acute and late complications. Results: 1) Obstructive jaundice was relieved before HF through endoscopic biliary drainage in 92.9% (66/71). Metallic stent was applied in 66.2%(47/71), before HF in 35.2% (25/71) and after HF in 31.0% (22/71). 2) Median survival was 8 months (1–90) and 5-year survival was 28%. Multivariate analysis showed total HF dose as a sole significant prognostic factor (p=0.0347). 3) Acute complication was observed mainly in digestive tract, i.e., Grade 1–2 symptoms (anorexia, nausea) in 50.7% (36/71). Late complications were Grade 1–2 gastritis in 9.9% (7/71), Grade 3 gastric ulcer in 2.8% (2/71) and cholangitis in 1.4% (1/71). Conclusions: HF combined with meticulous biliary drainage and stenting by G-I specialists for advanced biliary tract cancers demonstrated excellent pt’s quality of life with less serious morbidities. This modality would offer useful baseline data further with appropriate systemic chemotherapy. No significant financial relationships to disclose.
Advancing biology-based therapeutic approaches for atypical teratoid rhabdoid tumors
Authors: Lindsey M Hoffman, Elizabeth Anne Richardson, Ben Ho, Ashley Margol, Alyssa Reddy, Lucie Lafay-Cousin, Susan Chi, Irene Slavc, Alexander Judkins, Martin Hasselblatt, Franck Bourdeaut, Michael C Frühwald, Rajeev Vibhakar, Eric Bouffet, Annie Huang
Journal: Neuro-Oncology (2020)

Atypical teratoid rhabdoid tumor (ATRT) is a rare, highly malignant central nervous system cancer arising in infants and younger children, historically considered to be homogeneous, monogenic, and incurable. Recent use of intensified therapies has modestly improved survival for ATRT; however, a majority of patients will still succumb to their disease. While ATRTs almost universally exhibit loss of SMARCB1 (BAF47/INI1/SNF5), recent whole genome, transcriptome, and epigenomic analyses of large cohorts reveal previously underappreciated molecular heterogeneity. These discoveries provide novel insights into how SMARCB1 loss drives oncogenesis and confer specific therapeutic vulnerabilities, raising exciting prospects for molecularly stratified treatment for patients with ATRT.
Comparison of weight loss with a National Cancer Institute diet and a plant-based olive oil diet in overweight women with invasive breast cancer
Authors: M. M. Flynn
Journal: Journal of Clinical Oncology (2007)

1532 Background: The risk of breast cancer increases with increasing body weight, higher blood levels of fasting insulin and triglycerides, and lower HDL-c. Weightloss and diet can affect these variables. While diets lower in fat are routinely recommended for weightloss and cancer prevention, there is no firm evidence that they have an advantage compared to diets higher in dietary fat. Further, lower-fat diets can adversely affect fasting blood levels of insulin, triglycerides and HDL-c. Methods: Overweight women diagnosed with invasive breast cancer after the age of 50 consumed a National Cancer Institute diet (NCI; total fat: ≥15% to &lt;30%) and a plant-based, olive oil diet (PBOO; total fat: ≥35%, primarily from extra virgin olive oil) for 8 weeks each in a crossover trial with random assignment to order. Fasting blood samples at the end of each diet were analyzed for insulin, triglycerides and HDL-c. Results: Results for 14 subjects. Percent weightloss (NCI: 4.2 ± 2.3; PBOO: 6.2 ± 2.1) in this preliminary group exhibited a significant diet-order effect. Ten of the 14 had lower levels of fasting insulin while on the PBOO diet. Conclusions: These initial results suggest that weightloss can be achieved with a plant-based, higher-fat diet emphasizing extra virgin olive oil, and such a diet may have a metabolic advantage compared to the standard, lower-fat diet. [Table: see text] No significant financial relationships to disclose.
Epigenome-wide meta-analysis of blood DNA methylation in newborns and children identifies numerous loci related to gestational age
Authors: Simon Kebede Merid, Alexei Novoloaca, Gemma C. Sharp, Leanne K. Küpers, Alvin T. Kho, Ritu Roy, Lu Gao, Isabella Annesi-Maesano, Pooja Jain, Michelle Plusquin, Manolis Kogevinas, Catherine Allard, Florianne O. Vehmeijer, Nabila Kazmi, Lucas A. Salas, Faisal I. Rezwan, Hongmei Zhang, Sylvain Sebert, Darina Czamara, Sheryl L. Rifas-Shiman, Phillip E. Melton, Debbie A. Lawlor, Göran Pershagen, Carrie V. Breton, Karen Huen, Nour Baiz, Luigi Gagliardi, Tim S. Nawrot, Eva Corpeleijn, Patrice Perron, Liesbeth Duijts, Ellen Aagaard Nohr, Mariona Bustamante, Susan L. Ewart, Wilfried Karmaus, Shanshan Zhao, Christian M. Page, Zdenko Herceg, Marjo-Riitta Jarvelin, Jari Lahti, Andrea A. Baccarelli, Denise Anderson, Priyadarshini Kachroo, Caroline L. Relton, Anna Bergström, Brenda Eskenazi, Munawar Hussain Soomro, Paolo Vineis, Harold Snieder, Luigi Bouchard, Vincent W. Jaddoe, Thorkild I. A. Sørensen, Martine Vrijheid, S. Hasan Arshad, John W. Holloway, Siri E. Håberg, Per Magnus, Terence Dwyer, Elisabeth B. Binder, Dawn L. DeMeo, Judith M. Vonk, John Newnham, Kelan G. Tantisira, Inger Kull, Joseph L. Wiemels, Barbara Heude, Jordi Sunyer, Wenche Nystad, Monica C. Munthe-Kaas, Katri Räikkönen, Emily Oken, Rae-Chi Huang, Scott T. Weiss, Josep Maria Antó, Jean Bousquet, Ashish Kumar, Cilla Söderhäll, Catarina Almqvist, Andres Cardenas, Olena Gruzieva, Cheng-Jian Xu, Sarah E. Reese, Juha Kere, Petter Brodin, Olivia Solomon, Matthias Wielscher, Nina Holland, Akram Ghantous, Marie-France Hivert, Janine F. Felix, Gerard H. Koppelman, Stephanie J. London, Erik Melén
Journal: Genome Medicine (2020)

Preterm birth and shorter duration of pregnancy are associated with increased morbidity in neonatal and later life. As the epigenome is known to have an important role during fetal development, we investigated associations between gestational age and blood DNA methylation in children.
Abstract P314: Physical Activity-Mediated Associations of Perceived Neighborhood Violence and Problems on Depressive Symptoms Among Jackson Heart Study Participants
Authors: Kosuke Tamura, Steven D Langerman, Stephanie L Orstad, Sam J Neally, Marcus R Andrews, Joniqua N Ceasar, Mario Sims, Jae E Lee, Tiffany M Powell-Wiley
Journal: Circulation (2020)

Introduction: Little is known about whether links between perceived neighborhood social environment (PNSE) and depressive symptoms are mediated by physical activity (PA) levels. Hypothesis: We tested the hypotheses that total PA mediates relations between PNSE and depressive symptoms. Methods: We used Jackson Heart Study (JHS) baseline data. JHS is a prospective, community-based study of African Americans in the Jackson, MS (valid samples=2082; M age 52.4 years; 64% female). PNSE variables included neighborhood violence, problems (higher value=more violence or problems), and social cohesion (higher value=more cohesion). Depressive symptoms were measured by the Center for Epidemiological Studies Depression (CES-D) scale. Validated total PA, based on active living, sport, and work indices, was tested as the mediator. Linear regressions with bootstrap-generated 95% bias-corrected confidence intervals (BC CIs) were estimated using SAS 9.4 to test for significant unstandardized indirect effects, controlling for all covariates. Results: Participants had a mean depressive symptoms score of 10.8 ( SD =8.1). Neighborhood violence and problems were indirectly related to depressive symptoms via total PA ( β for indirect effects=.21, 95% BC CI =.02, .48 and .13, 95% BC CI =.01, .32, respectively). That is, higher violence and problems were related to lower total PA. In turn, higher total PA was associated with lower depressive symptoms ( Figure 1 ). Neighborhood violence and problems also were directly related to depressive symptoms ( p &lt;.05). Yet, social cohesion was not indirectly or directly related to depressive symptoms. Conclusions: Higher perceived neighborhood violence and problems were positively related to depressive symptoms. These associations may be explained in part via lower total PA levels. Future interventions to reduce depressive symptoms attributed to neighborhood issues should consider PA promotion in conjunction with community efforts to reduce neighborhood violence and problems.
Cost-effectiveness Evaluation of Targeted Surgical and Endoscopic Therapies for Early Colorectal Adenocarcinoma Based on Biomarker Profiles
Authors: Se Ryeong Jang, Han Truong, Aaron Oh, Jin Choi, Angela C. Tramontano, Monika Laszkowska, Chin Hur
Journal: JAMA Network Open (2020)

Colorectal cancer (CRC) is the second leading cause of cancer-related mortality in the United States. The prognosis for patients with CRC varies widely, but new prognostic biomarkers provide the opportunity to implement a more individualized approach to treatment selection.To assess the cost-effectiveness of 3 therapeutic strategies, namely, endoscopic therapy (ET), laparoscopic colectomy (LC), and open colectomy (OC), for patients with T1 CRC with biomarker profiles that prognosticate varying levels of tumor progression in the US payer perspective.In this economic evaluation study, a Markov model was developed for the cost-effectiveness analysis. Risks of all-cause mortality and recurrent cancer after ET, LC, or OC were estimated with a 35-year time horizon. Quality of life was based on EuroQoL 5 Dimensions scores reported in the published literature. Hospital and treatment costs reflected Medicare reimbursement rates. Deterministic and probabilistic sensitivity analyses were performed. Data from patients with T1 CRC and 6 biomarker profiles that included adenomatous polyposis coli (APC), TP53 and/or KRAS, or BRAFV600E were used as inputs for the model. Data analyses were conducted from February 27, 2019, to May 13, 2019.Endoscopic therapy, LC, and OC.The primary outcomes were unadjusted life-years, quality-adjusted life-years (QALYs), and the incremental cost-effectiveness ratio (ICER) between competing treatment strategies.Endoscopic therapy had the highest QALYs and the lowest cost and was the dominant treatment strategy for T1 CRC with the following biomarker profiles: BRAFV600E, APC(1)/KRAS/TP53, APC(2) or APC(2)/KRAS or APC(2)/TP53, or APC(1) or APC(1)/KRAS or APC(1)/TP53. The QALYs gained ranged from 16.97 to 17.22, with costs between $68 902.75 and $77 784.53 in these subgroups. For the 2 more aggressive biomarker profiles with worse prognoses (APC(2)/KRAS/TP53 and APCwt [wild type]), LC was the most effective strategy (with 16.45 and 16.61 QALYs gained, respectively) but was not cost-effective. Laparoscopic colectomy cost $65 234.87 for APC(2)/KRAS/TP53 and $71 250.56 for APCwt, resulting in ICERs of $113 290 per QALY and $178 765 per QALY, respectively.This modeling analysis found that ET was the most effective strategy for patients with T1 CRC with less aggressive biomarker profiles. For patients with more aggressive profiles, LC was more effective but was costly, rendering ET the cost-effective option. This study highlights the potential utility of prognostic biomarkers in T1 CRC treatment selection.
Abstract P378: Higher Non-exercise Estimated Cardiorespiratory Fitness in Midlife is Associated With Lower Risk of Cardiovascular Disease and Mortality in Later Life: The Framingham Heart Study
Authors: Joowon Lee, Ramachandran S Vasan, Vanessa Xanthakis
Journal: Circulation (2020)

Introduction: Studies have demonstrated that higher cardiorespiratory fitness (CRF) is associated with a lower risk of cardiovascular disease (CVD) and mortality. However, exercise CRF test is not routinely performed in clinical settings because it requires specialized equipment and trained personnel. Therefore, non-exercise estimated CRF (eCRF) using easily accessible health indicators in clinical practice may be a time- and cost-effective alternative for evaluating fitness. Hypothesis: We hypothesized that higher eCRF in midlife will be associated with a lower risk of CVD and all-cause mortality in later life. Methods: We evaluated 2,501 Framingham Offspring cohort participants (mean age 65 yrs., 52% women). We used a longitudinal non-exercise algorithm that includes age, sex, body mass index, waist circumference, resting heart rate, physical activity, and smoking status. We then used SAS PROC TRAJ to identify sex-specific latent patterns of eCRF (low, moderate, and high eCRF categories) between exam 2 and 8 (1979-2008). Multivariable Cox proportional hazards regression models were used to relate the long-term trajectories of eCRF to incident CVD and all-cause mortality on follow-up. Results: We identified three distinct trajectories of eCRF (Low [n=268, 10.7%] vs. moderate [n=1,273, 50.9%] vs. high [n=960, 38.4%]). Overall, 265 participants developed CVD and 429 died during 10 years of median follow-up. Participants in the “high eCRF” group were at lower risk of CVD and all-cause mortality compared to those in the “low eCRF” group, after adjustment for potential confounders ( Table ). Conclusions: Our findings suggest that lower eCRF during midlife may be a marker of risk of CVD and mortality in older adulthood.
Abstract 10124: Genetic Admixture and Survival in Diverse Populations With Pulmonary Arterial Hypertension (PAH)
Authors: Jason H Karnes, Howard Wiener, Tae-Hwi Schwantes-An, Balaji Natarajan, Abhishek Chaturvedi, Amit H Arora, Ken Batai, Vineet Nair, Heidi Steiner, Jason Giles, Jeffrey Yu, Maryam Hosseini, Michael Pauciulo, Katie Lutz, Anna Coleman, Jeremy Feldman, Rebecca Vanderpool, Haiyang Tang, Joe Garcia, Jason Yuan, Franz Rischard, Rick Kittles, Hemant K Tiwari, Bill Nichols, Raymond Benza, Ankit Desai
Journal: Circulation (2019)

Introduction: Limited information is available on racial/ethnic differences in PAH. We report effects of race/ethnicity on mortality and disease outcomes with PAH. Methods: Group 1 PAH patients wer...
Measurement of innate immune response biomarkers in peritoneal dialysis effluent using a rapid diagnostic point-of-care device as a diagnostic indicator of peritonitis
Authors: Catriona Goodlad, Sophiamma George, Shella Sandoval, Stephen Mepham, Gita Parekh, Matthias Eberl, Nicholas Topley, Andrew Davenport
Journal: Kidney International (2020)
サイトカイン依存性ヒト白血病細胞株F-36の樹立および赤血球分化:顆粒球マクロファージコロニー刺激因子またはインターロイキン3を必要とする親系統およびエリスロポエチンを必要とする亜系統
Authors: Chiba S, Takaku F, Tange T, Shibuya K, Misawa C, Sasaki K, Miyagawa K, Yazaki Y, Hirai H
Journal: Blood (1991)
Systemic capecitabine and oxaliplatin administered with hepatic arterial infusion (HAI) of floxuridine (FUDR) following complete resection of colorectal metastases (M-CRC) confined to the liver
Authors: S. Alberts, M. R. Mahoney, J. H. Donohue, M. S. Roh, E. M. Green, D. J. Sargent, L. D. Wagman, J. S. Bolton
Journal: Journal of Clinical Oncology (2007)

4057 Background: The prognosis for patients with hepatic metastases from M-CRC can be poor. However, surgery followed by HAI FUDR plus systemic (SYS) 5-FU improves 5-yr survival. Dual therapy OXAL+CAPE has demonstrated activity in advanced CRC. We report final results of an analysis of SYS OXAL+CAPE, alternating with HAI FUDR. The primary endpoint is 2-yr survival (2YS), with 36 of 45 patients surviving 2 yrs as evidence of promising efficacy. Methods: Patients with M-CRC liver lesions amenable to resection ± ablation were eligible. Prior adjuvant chemotherapy for completely resected primary was allowed. HAI+SYS therapy was initiated 21–56 days post-metastasectomy. Four alternating courses of HAI consisted of 0.2 mg/m 2 /d FUDR and dexamethasone, d1–14 wks 1&amp;2. SYS included 130 mg/m 2 OXAL d1, with CAPE at 1,000 mg/m 2 po BID, d1–14, wks 4&amp;5. Two additional 3-wk courses of SYS were given. CAPE was reduced to 850 mg/m 2 /BID after interim review of toxicity. Results: 54 of 73 eligible patients initiated HAI FUDR + SYS. 52% had a solitary met and 24% presented with bilobar mets. Patients completed median of 6 cycles (range 1–6). Reasons for discontinuation included: refusal/toxicity (10), completed per protocol (32), recurrence (4), and medical/other (3). No HAI+SYS related deaths occurred. Median follow-up on the 42 survivors is 28 months (range 7–51). 6 deaths occurred within 2 yrs. 48% (26/54) have recurred; 42% (11/26) with liver involvement. Median time-to-progression is 30 months. The estimated 2YS rate is 88% (95% CI 80–98%) and median overall survival is 46 months (95% CI 41.3-NA). Conclusions: The combination of HAI FUDR and SYS therapy appears to improve outcome following resection of hepatic CRC-M. A 2YS of 88% exceeds our preplanned level of success, supporting the use of this combination in the ongoing NSABP trial C-09. Supported by NIH Grant CA25224–18, Sanofi-Synthelabo, and Roche Laboratories, Inc. No significant financial relationships to disclose.
Is it time to nationalise the pharmaceutical industry?
Authors: Mariana Mazzucato, Henry Lishi Li, Ara Darzi
Journal: BMJ (2020)

Drug companies fail to take account of the public interest and relentlessly focus on short term returns, say <b>Mariana Mazzucato</b> and <b>Henry Lishi Li</b>. But <b>Ara Darzi</b> argues that the profits drug companies make are vital for developing new medicines
Origin and Evolution of Polycyclic Triterpene Synthesis
Authors: Carlos Santana-Molina, Elena Rivas-Marin, Ana M Rojas, Damien P Devos
Journal: Molecular Biology and Evolution (2020)

Polycyclic triterpenes are members of the terpene family produced by the cyclization of squalene. The most representative polycyclic triterpenes are hopanoids and sterols, the former are mostly found in bacteria, whereas the latter are largely limited to eukaryotes, albeit with a growing number of bacterial exceptions. Given their important role and omnipresence in most eukaryotes, contrasting with their scant representation in bacteria, sterol biosynthesis was long thought to be a eukaryotic innovation. Thus, their presence in some bacteria was deemed to be the result of lateral gene transfer from eukaryotes. Elucidating the origin and evolution of the polycyclic triterpene synthetic pathways is important to understand the role of these compounds in eukaryogenesis and their geobiological value as biomarkers in fossil records. Here, we have revisited the phylogenies of the main enzymes involved in triterpene synthesis, performing gene neighborhood analysis and phylogenetic profiling. Squalene can be biosynthesized by two different pathways containing the HpnCDE or Sqs proteins. Our results suggest that the HpnCDE enzymes are derived from carotenoid biosynthesis ones and that they assembled in an ancestral squalene pathway in bacteria, while remaining metabolically versatile. Conversely, the Sqs enzyme is prone to be involved in lateral gene transfer, and its emergence is possibly related to the specialization of squalene biosynthesis. The biosynthesis of hopanoids seems to be ancestral in the Bacteria domain. Moreover, no triterpene cyclases are found in Archaea, invoking a potential scenario in which eukaryotic genes for sterol biosynthesis assembled from ancestral bacterial contributions in early eukaryotic lineages.