tbuckley/cabot-search huggingface dataset:
NCBoost classifies pathogenic non-coding variants in Mendelian diseases through supervised learning on purifying selection signals in humans
Authors: Barthélémy Caron, Yufei Luo, Antonio Rausell
Journal: Genome biology (2019)

State-of-the-art methods assessing pathogenic non-coding variants have mostly been characterized on common disease-associated polymorphisms, yet with modest accuracy and strong positional biases. In this study, we curated 737 high-confidence pathogenic non-coding variants associated with monogenic Mendelian diseases. In addition to interspecies conservation, a comprehensive set of recent and ongoing purifying selection signals in humans is explored, accounting for lineage-specific regulatory elements. Supervised learning using gradient tree boosting on such features achieves a high predictive performance and overcomes positional bias. NCBoost performs consistently across diverse learning and independent testing data sets and outperforms other existing reference methods.
Esophageal Cancer Awareness Issue 2019
Authors: Peter Siersema
Journal: Endoscopy (2019)

April 2019 marks the 10th annual Esophageal Cancer Awareness Month. Esophageal cancer is one of the fastest-growing cancer diagnoses in the Western world and is the seventh most commonly occurring cancer in men and 13th most common in women [1]. Although squamous cell carcinoma (SCC) is the dominant subtype of esophageal cancer in central Asia and southern Africa, esophageal adenocarcinoma is the increasingly common subtype in Western Europe and the US.
Precision Medicine Test Is Similar but Faster Than Conventional Cytogenetics Predicting Response in AML Patients and Provides Alternative Treatments
Authors: Joan Ballesteros, David Martínez-Cuadron, Joaquin Martinez Lopez, Juan Miguel Miguel Bergua Burgues, Mar Tormo, Josefina Serrano, Ataulfo González, Jaime Perez De Oteyza, Susana Vives, Maria-Belen Vidriales, Pilar Herrera, Juan Antonio Vera, Aurelio Lopez Martinez, Adolfo de la Fuente, Lourdes Amador Barciela, Jose Angel Hernandez-Rivas, Maria Angeles Fernandez Fernandez, Carlos Cervero, Daniel Morillo, Pilar Hernandez, Daniel Primo, Julian Gorrochategui, Jose Luis Rojas, Iñaki Troconiz, Jesús Villoria, Miguel Sanz, Pau Montesinos
Journal: Blood (2018)
Abstract P031: Plasma Xanthine Oxidoreductase Activity is Associated With Edothelial Dysfucntion and Increased Arterial Stiffness in a General Japanese Population: the Iwate Tohoku Medical Megabank Project
Authors: Yuka Kotozaki, Kozo Tanno, Hideki Ohmomo, Fumitaka Tanaka, Ryo Otomo, Atsushi Shimizu, Kiyomi Sakata, Jiro Hitomi, Makoto Sasaki, Mamoru Satoh
Journal: Circulation (2019)

An increase in xanthine oxidoreductase (XOR) activity is related to various diseases such as diabetes, hypertension and obesity has been reported. However, so far the association with XOR activity and pathogenesis of atherosclerosis in a general Japanese population are not known. The purpose of this study is to investigate the association between XOR activity and progression of atherosclerosis including pulse wave velocity (PWV) and flow mediated dilation (FMD) in a general Japanese population. The Iwate Tohoku Medical Megabank Organization pooled individual participant data from a general population-based cohort study in Iwate prefecture (n = 810, male / female = 271 / 539, age = 67.6 ± 7.2). Plasma levels of XOR activity in males were marginally higher than in females (89.6 ± 187.0 vs. 64.8 ± 145.8 pmol / h/ mL, p = 0.06). Arterial stiffness by PWV after log10 transformation was significantly higher in quartiles III and IV of XOR compared to quartiles I in females (F =4.768, p &lt; 0.01) (quartiles I vs. III, 3.187 ± 0.088 vs. 3.214 ± 0.081, p &lt; 0.01; quartiles I vs. IV, 3.187 ± 0.088 vs. 3.213 ± 0.080, p &lt; 0.05). Endothelial function as assessed by FMD was significantly lower in quartiles III and IV compared to quartiles I in females (F = 6.074, p &lt; 0.001) (quartiles I vs. III, 6.02 ± 3.19 vs. 4.90 ± 2.66 %, p &lt; 0.01; quartiles I vs. IV, 6.02 ± 3.19 vs. 5.04 ± 2.76 %, p &lt; 0.01). XOR activity was related to progression of atherosclerosis (FMD, OR = 0.930, p = 0.06) and the high risk for CVD in females (Suita Score ≥ 41, OR = 1.92, 95% confidence interval (CI) = 1.04 - 3.54, p &lt; 0.05). XOR activity was no significant association with progression of atherosclerosis and the high risk for CVD in males. The area under the curve (AUC) for XOR activity combined with Suita score was 0.66 (95% CI = 0.52 - 0.77, p &lt; 0.05). In conclusion, XOR activity is associated with endothelial dysfunction and increased arterial stiffness suggesting that elevated XOR activity may relate to progression of atherosclerosis and indicate the CV risk.
Therapy-Related Myeloid Neoplasms (tMN) Following Treatment of Acute Myeloid Leukemia (AML): Exome Sequencing Reveals the Presence of an Ancestral Clone Refractory to Chemotherapy
Authors: Luise Hartmann, Niroshan Nadarajah, Manja Meggendorfer, Alexander Höllein, Calogero Vetro, Anna Stengel, Wolfgang Kern, Torsten Haferlach, Claudia Haferlach
Journal: Blood (2018)
A phase Ib study of AUY922 and cetuximab in patients with KRAS wild-type (WT) metastatic colorectal cancer (mCRC).
Authors: Somasundaram Subramaniam, Gary E. Goodman, Barry Boatman, Andrew W. Smith, Desiree Iriarte, Philip Jordan Gold
Journal: Journal of Clinical Oncology (2015)

3540 Background: Heat shock protein-90 (HSP90) is a molecular chaperone which has an important role in EGFR stability. AUY922 inhibits ATPase activity of HSP90. Combined HSP90/EGFR inhibition is effective in pre-clinical models. In this phase IB study, we examined safety, tolerability and maximum tolerated dose of AUY922 in combination with cetuximab in patients with KRAS WT mCRC. Methods: This was a single-center open-label dose escalation study. Patients who had disease progression on ≥ 2 prior chemotherapy regimens were eligible. Treatment with prior cetuximab was allowed. Inclusion criteria: ECOG 0-1, ≥ 1 measurable lesion and adequate organ function. All patients received weekly treatment with cetuximab and AUY922, with dosing per table below. Results: Median age 54.5 (range 25 – 77), M/F: 5/11. Patients had a median of 3 prior regimens (range 2-6) and 15 patients (94%) had progressed on prior cetuximab. Median time to progression was 7.9 weeks (range 5.9 – 29.9) and median overall survival was 37.2 weeks (range 4.9 – 115.1). One patient (6%) had a partial response (PR) and 4 patients (25%) had stable disease (SD), for a disease control rate of 31.3%. For patients with disease control, median survival was 45.7 weeks (range 37.6 – 115.1). Treatment was well-tolerated without dose-limiting toxicities. Grade 3 toxicities were seen in 62.5% of patients treated including anemia(2 patients), nausea/vomiting(2), dehydration(2), fever(1), fatigue(1), anorexia(1), abdominal pain(1), headache (1), diarrhea(1) and prolonged QTc interval(1). There were no grade 4 toxicities. Pharmacokinetic studies showed AUY922 half-life of approximately 50 hours, and no interaction with co-administration of cetuximab. Conclusions: AUY922 can be safely administered with cetuximab in patients with mCRC. Median survival of 37.2 weeks is suggestive of clinical activity in this heavily pre-treated patient population. Further studies of this combination are warranted. Recommended Phase II dose is weekly cetuximab 250mg/m2 and AUY922 70mg/m2. Cohort AUY922 Dose (mg/m2) Cetuximab Dose (mg/m2) Number of patients Patients with Disease Control (PR/SD) 1 40 250 3 2 (1PR, 1SD) 2 55 250 5 1 (SD) 3 70 250 4 1 (SD) Expansion 70 250 4 1 (SD)
Addition of Polatuzumab Vedotin to Bendamustine and Rituximab (BR) Improves Outcomes in Transplant-Ineligible Patients with Relapsed/Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL) Versus BR Alone: Results from a Randomized Phase 2 Study
Authors: Laurie H. Sehn, Alex F. Herrera, Matthew J. Matasar, Manali Kamdar, Andrew K. McMillan, Tae Min Kim, Won Seog Kim, Mark Hertzberg, Muhit Ozcan, Elicia Penuel, Ji Cheng, Jamie M. Hirata, Grace Ku, Christopher Flowers
Journal: Blood (2017)
Preliminary Results of UCART19, an Allogeneic Anti-CD19 CAR T-Cell Product, in a First-in-Human Trial (CALM) in Adult Patients with CD19+ Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia
Authors: Charlotte Graham, Deborah Yallop, Agnieszka Jozwik, Piers Patten, Alan Dunlop, Rose Ellard, Orla Stewart, Victoria Potter, Victoria Metaxa, Shireen Kassam, Farzin Farzaneh, Stephen Devereux, Antonio Pagliuca, Amina Zinai, Florence Binlich, Sandra Dupouy, Anne Philippe, Svetlana Balandraud, Frédéric Dubois, Cyril Konto, Premal Patel, Ghulam Mufti, Reuben Benjamin
Journal: Blood (2017)
Characteristics and Outcomes of Ibrutinib-Associated Musculoskeletal Toxicities in CLL Patients
Authors: Joanna Rhodes, Anthony R. Mato, Nicole Winchell, Kaitlin Kennard, James Nathan Gerson, Daniel J. Landsburg, Sunita Dwivedy Nasta, Jakub Svoboda, Stephen J. Schuster
Journal: Blood (2018)
Final analysis of a phase II study of MRI based functional imaging of bone metastases in men with metastatic castrate-resistant prostate cancer (mCRPC) receiving cabozantinib.
Authors: Arpita Desai, Jamie Renee Brewer, Milica Medved, Aytekin Oto, Guimin Gao, Theodore Karrison, Daniel H. Shevrin, Greg S. Karczmar, Walter Michael Stadler, Russell Zelig Szmulewitz
Journal: Journal of Clinical Oncology (2019)

213 Background: Cabozantinib (C) is a small molecule inhibitor of receptor tyrosine kinases including VEGFR-2, c-MET. C trials have shown significant improvements in bone pain and bone scintigraphy in mCRPC patients (pts). We hypothesized that functional imaging using MRI could elucidate underlying biological processes by demonstrating an early decrease in vascular permeability (decrease in transfer consant - Ktrans) and subsequent decrease in cell density (increase in apparent diffusion coefficient - ADC) within bone metastases. Methods: mCRPC pts received C 60 mg daily. The primary endpoint was change in Ktrans at 2 weeks (wks) of treatment. Secondary endpoints included Ktrans and ADC longitudinal changes, and correlation with bone scan, PSA, RECIST, and changes in reported pain. All pts underwent MRI at baseline, day 0, day 15 and every 12 wks. Results: 17 pts were treated at two sites. Median age: 68 yrs (range:51-83), baseline PSA 94.78 ng/mL (7.4-2971), number of prior CRPC therapies 2 (1-8). Median progression free survival was 5.1 months; 5 pts discontinued therapy for adverse events, and 12 for progressive disease. The most common grades 3/4 toxicities were fatigue (24%) and palmarplantar erythrodysesthesia (12%). 14 pts were evaluable for the primary endpoint. At 2 wks, Ktrans decreased an average 35%, 0.074 to 0.048 min -1 (SD=0.016, p&lt;0.0001). There was no change in Ktrans between wk 2 and end of study. There was an increase in median ADC of 150 at wk 12. There were no RECIST or 50% PSA responses. Conclusions: Ktrans decreased significantly after 2 wks of treatment, consistent with antiangiogenic properties of C. Compared to wk 2, K trans at disease progression is unchanged, which could signify that adaptive vascular change is not the primary mechanism of tumor resistance to the drug. Contrary to our hypothesis, ADC increased during the trial, which perhaps correlates with the short median time to progression. Still, MRI of bone metastases could benefit drug development for other agents in mCRPC or interrogation of bone metastases, notoriously challenging for disease response analysis, in other cancers. Clinical trial information: NCT01599793.
Lessons from aviation: gradual, adaptive process improvement
Authors: Johan M van Schalkwyk
Journal: BMJ (2019)

I used to think that medicine was special and differed from aviation. An anaesthetist colleague of mine somewhat unkindly noted: “Anaesthesia is not like a plane flight. It must be exceptionally rare to fly an 80 year old plane with failing hydraulics while a lunatic tries his best to hack off one of the engines.”

Belatedly, I’ve realised we …
Are conflict of interest (COI) slides displayed long enough to comprehend?
Authors: James Austin Talcott, Ashley D'Silva, Jonah Shulman, David Lucido
Journal: Journal of Clinical Oncology (2015)

6576 Background: Conflicts of Interest (COI) are displayed to alert the scientific audiences to potential financial biases. At scientific meetings, COI of oral presenters are visually displayed. COI slides increase in complexity with disclosed COI categories (CC) and relationships (R), requiring more time for audience members to process the information. We reviewed the COI slides displayed at the 2014 ASCO Annual Meeting in video presentations archived for the Virtual Meeting to assess the relationship between display time (DT) and the information they contained. Methods: Two reviewers (AD and JS) reported the following information for each oral scientific presentation: session, role (presenter, discussant), disclosed CG and R, and COI slide display time. To estimate the required time (RT) to process the information, we measured the required time to process the content of a sample of COI slides and created a predictive model, assuming that 1 second is required to focus on COI, and CC items require more process time than R items. Results: Of 485 presenters, over half reported 0 (43.1%), 1 (12.8%) or 2 (10.7%) R, but up to 29 R were reported. COI slides were visible for 1-65 seconds. However, we observed no relationship between R and COI slide display time (slope: = -.055, p = 0.39). RT (in seconds) = 1 + (1 x CC) + (0.85 x R) fit the observed RT data. We found DT ³ calculated RT for three-fourths of presenters when reported R was 1 or 2, but < 50% if reported R³3 (P < 0.001). Conclusions: At a major cancer scientific meeting, measured DT of presenter COI slides did not increase with disclosed R. Based on estimated RT to process the COI information, DT was inadequate for comprehension for most presentations if reported R exceeded 2. R (number) 0 1 2 3-4 5-7 8-10 > 10 Total Presentations (%) 209 (43) 62 (13) 52 (11) 42 (9) 45 (9) 31 (6) 44 (9) 455 (100) DT adequate, % 100 77 73 33 24 10 2 67
Autologous oxidized whole-tumor antigen vaccine in combination with angiogenesis blockade to elicit antitumor immune response in ovarian cancer.
Authors: Janos L. Tanyi, Lana Kandalaft, Eran Ophir, Sarah Bobisse, Raphael Genolet, Emese Zsiros, Drew A. Torigian, Rosemarie Mick, Alexander Harari, George Coukos
Journal: Journal of Clinical Oncology (2015)

5519 Background: Personalized tumor lysate vaccines can encompass all putative antigens in tumors. Methods: A pilot clinical trial was conducted using an autologous oxidized whole tumor cell lysate dendritic cell (DC) based vaccine (vx) injected intranodally, alone or in combination with bevacizumab (Bev) with or without low-dose IV cyclophosphamide (Cy) and/or oral aspirin (ASA), in recurrent ovarian cancer patients (pts). Pts were treated every 3 weeks. Most of the pts were platinum-resistant and heavily pretreated. Adverse events (AEs) were graded by CTCAE v4.0 and clinical responses by RECIST v1.1. Results: To date, 35 pts (cohort 1 (vx only; n = 5), 2 (vx+bev; n = 10), 3 (vx+bev+Cy; n = 10) and 4 (vx+Bev+Cy+ASA; n = 10) have received over 392 vx doses. The treatment was well tolerated without serious AEs. Immune response to autologous antigen was seen mainly in cohorts 3 and 4, which received low-dose Cy. An increase in the frequency of T cells recognizing known tumor associated antigens (Her2, WT1, mesothelin, NY-ESO-1) was observed post-vx. Moreover, it is demonstrated for the first time that vaccination with whole tumor lysate-loaded DCs elicited a CD8 T cell response against mutated peptides derived from private non-synonymous somatic tumor mutations. Six pts achieved a partial response or were disease-free at end of treatment. The median progression-free survival (PFS) of cohort 1, 2, 3 and 4 were 4, 3.8, 11.1 and 10.1 mos, respectively. The median overall survival (OS) of cohorts 1 and 2 were 35.3 and 11.4 mos, while for cohorts 3 and 4 it has not been reached, with median potential follow up of 19 mos. A historic population (HP) of 16 pts from the same institution who received Bev+Cy (without vx) had PFS and OS of 4.1 and 26.4 mos respectively. Estimated PFS at 6 mos was 70% for cohorts 3 and 4 and 31% in the HP. The OS at 20 mos was 100% and 90% for cohorts 3 and 4, respectively and 61% for the historic cohort. Conclusions: Clinical benefit was demonstrated only in pts who exhibited an immune response against whole tumor lysate or autologous tumor. The use of oxidized whole tumor lysate DC vaccine is safe, effective in eliciting a broad antitumor immunity including private neoantigens. Clinical trial information: NCT01132014.
Abstract P045: Sun Exposure is Not Associated With Lower Cardiovascular Risk in Mexican Women
Authors: Mercedes Aguilar, Mario Flores, Carlos Cantú-Brito, Martín Lajous, Ruy López-Ridaura
Journal: Circulation (2019)

Background: Sun exposure has been associated with reduced risk of stroke and all-cause mortality possibly due to a decreased vascular tone related to vitamin D production. However, previous studies have measured sun exposure based on geographical estimations of radiation, and have been mostly conducted in latitudes far from the Equator where UV radiation is lower than in tropical and subtropical latitudes and where there is little variation in skin tone. Hypothesis: Sun exposure is inversely associated with subclinical cardiovascular disease in Mexican women. Methods: We conducted a cross-sectional analysis in 2,257 disease-free women from the Mexican Teachers‘ Cohort who were invited to clinical examinations in 4 different Mexican states. Participants responded to questions on sun exposure habits at 4 age periods (12-24, 25-35, 36-59, &gt;60). Sun exposure was defined as the weighted average of weekly hours spent under the solar noon from age 12 to the age at clinical examination. Carotid intima-media thickness (c-IMT) was measured on both carotid arteries through ultrasound by standardized neurologists and log transformed. We defined carotid atherosclerosis as mean right or left c-IMT ≥0.8 mm or the presence of plaque. We used linear and logistic regression to evaluate the association between quartiles of sun exposure, c-IMT and carotid atherosclerosis, with quartile 1 as reference. Results: Mean age of participants was 49.6 (5.5) years and the prevalence of carotid atherosclerosis was 12.3% in quartile 1 vs 10.6% in quartile 4. The median weekly hours of exposure for each quartile were: 1 (Q1), 1.79 (Q2), 3 (Q3), 4 (Q4). The age-adjusted % mean difference in c-IMT comparing women in the first quartile to women in the fourth quartile was -1.5% (95% CI -2.9, -0.1). After further adjustment for site, socioeconomic status, smoking status, ethnicity and physical activity the % mean difference was no longer significant (-0.7%, 95% CI -2.0, 0.7). The age-adjusted OR for carotid atherosclerosis for women in the fourth quartile compared to women in the first quartile was 0.81 (95% CI 0.57, 0.95). However, in the multivariable model, the OR was non-significant (0.94, 95% CI 0.69, 1.2). Stratified analysis for ethnicity and obesity showed no difference between groups. Conclusion: Sun exposure was associated with neither cIMT nor carotid atherosclerosis in Mexican women. Atherosclerosis might not play a role in the biological mechanism explaining the inverse association between sun exposure and cardiovascular risk.
Impact of elevated bilirubin on eligibility of metastatic pancreatic cancer (MPC) patients (pts) for nab-paclitaxel plus gemcitabine (N+G).
Authors: Sally C Lau, Renata Peixoto, Winson Y. Cheung
Journal: Journal of Clinical Oncology (2015)

e15235 Background: The MPACT study demonstrated a significant survival benefit with N+G as compared to G alone, but the eligibility criteria in the trial excluded pts with an abnormal bilirubin. Given the prevalence of pancreatic head tumors, this exclusion may limit a significant number of otherwise fit pts from receiving an effective treatment. We aimed to characterize the presentation and management of hyperbilirubinemia in a population-based cohort of MPC pts and determine how this may inform eligibility of patients for N+G. Methods: Pts who presented with MPC and initiated chemotherapy with G from 2000 to 2011 in British Columbia were reviewed for their eligibility for NG, as per criteria in the MPACT study. Hyperbilirubinemia was categorized into mild (1.2-1.5mg/dL), moderate (1.5-3.5mg/dL) and severe ( > 3.5mg/dL) and classified as reversible or irreversible. Results: We identified 469 MPC pts: median age 66 years, 45% women, 3%/41% ECOG 0/1, and 48% pancreatic head tumors. A total of 189 (40%) pts presented with jaundice of whom 28 (7%), 33 (8%) and 78(20%) were considered to have mild, moderate, and severe hyperbilirubinemia, respectively. All of these cases would be deemed ineligible for N+G. Common causes of hyperbilirubinemia included biliary obstruction (74%) and liver metastases (22%). Among them, 149 (79%) pts successfully underwent either biliary stenting or surgical bypass whereas the remainder (21%) did not proceed to any interventions because of heavy disease burden, poor technical feasibility, or declining function. In the cohort of reversible cases (n = 149), 34 (23%) experienced > 50% decrease in bilirubin and 82 (55%) would be considered suitable for N+G following stenting or bypass. Overall, only 337 (72%) in the entire cohort were eligible for NG with a bilirubin cutoff of upper limit of normal (ULN), but an additional 18 (4%) and 35 (8%) would be eligible for treatment if the cutoff was 1.25 x ULN and 1.5 x ULN, respectively. Conclusions: Most cases of hyperbilirubinemia were reversible. Prompt referrals for stenting or bypass may increase the number of MPC pts eligible for N+G. A small modification to the bilirubin cutoff can significantly improve generalizability.
Abstract P385: Cigarette Smoking and Incident Stroke in African Americans of the Jackson Heart Study
Authors: Adebamike A Oshunbade, Wondwosen K Yimer, Karen A Valle, Donald Clark, Wendy B White, Andrew P Defilippis, Michael J Blaha, Emelia J Benjamin, Emily O’Brien, Javed Butler, Adolfo Correa, Michael E Hall
Journal: Circulation (2019)

Background: African-Americans (AAs) are disproportionately affected more by stroke compared to whites, however less is known about the relationship between stroke and cigarette smoking, a modifiable risk factor, in AAs. Therefore, we evaluated the relationship between cigarette smoking and incident stroke in the Jackson Heart Study (JHS). Methods and Results: JHS participants without a history of stroke (n= 4894) were classified by self-reported baseline smoking status into current, past (smoked at least 400 cigarettes/life) or never smokers at baseline (2000-2004). Current smokers were further classified by smoking intensity [number of cigarettes smoked per day (1-10,10-19 and ≥20)] and followed for incident stroke (through 2014). Stroke events were adjudicated in the JHS. Hazard ratios for incident stroke for each smoking group compared to never smokers were estimated using the Cox proportional hazard regression models after adjusting for covariates. At baseline there were 633 (13.1%) current, 892 (18.4%) past and 3327 (68.6%) never smokers. During follow-up (11.8 median follow-up years), 201 participants developed incident stroke. After adjusting for age, sex, body mass index, hypertension, diabetes mellitus status, total cholesterol, triglycerides, prevalent cardiovascular disease, physical activity, aspirin, statin, and alcohol consumption in the past 12 months and level of education, the risk for stroke in current smokers was significantly higher compared to never smokers (HR 2.33, 95% CI 1.16-4.68) but there was no significant difference between past smokers and never smokers (HR 0.96, 95% CI 0.53-1.75).There was a dose-dependent increased risk of stroke with smoking intensity which was not statistically significant. Conclusions: In a large prospective cohort of AAs, current cigarette smoking was associated with incident stroke in adjusted models. These findings suggest that smoking cessation may have potential benefits in reducing the incidence of stroke in this population.