tbuckley/cabot-search huggingface dataset:
Gene Tree Discordance Does Not Explain Away the Temporal Decline of Convergence in Mammalian Protein Sequence Evolution
Authors: Zhengting Zou, Jianzhi Zhang
Journal: Molecular Biology and Evolution (2017)

Several authors reported lower frequencies of protein sequence convergence between more distantly related evolutionary lineages and attributed this trend to epistasis, which renders the acceptable amino acids at a site more different and convergence less likely in more divergent lineages. A recent primate study, however, suggested that this trend is at least partially and potentially entirely an artifact of gene tree discordance (GTD). Here, we demonstrate in a genome-wide data set from 17 mammals that the temporal trend remains (1) upon the control of the GTD level, (2) in genes whose genealogies are concordant with the species tree, and (3) for convergent changes, which are extremely unlikely to be caused by GTD. Similar results are observed in a comparable data set of 12 fruit flies in some but not all of these tests. We conclude that, at least in some cases, the temporal decline of convergence is genuine, reflecting an impact of epistasis on protein evolution.
Pilot study of haploidentical natural killer cell transplantation in childhood acute myeloid leukemia
Authors: J. Rubnitz, H. Inaba, R. Ribeiro, S. Pounds, C. Pui, W. Leung
Journal: Journal of Clinical Oncology (2009)

10034 Background: In the setting of hematopoietic stem cell transplantation (HSCT), donor natural killer (NK) cells exhibit potent anti-leukemic effects without causing graft-versus-host disease. We hypothesized that the transplantation of purified haploidentical NK cells may be a safe and effective form of consolidation therapy that will reduce the risk of relapse among children with acute myeloid leukemia (AML) who are not treated with HSCT. In this pilot study, we assessed the safety, feasibility, and engraftment of NK cell infusions in 10 patients with AML in first remission.Methods: Patients received cyclophosphamide, 60 mg/kg on day -7; fludarabine, 25 mg/m 2 /day on days -6 through -2; and IL-2, 1 million units/m 2 , every other day for 6 doses starting on day -1. On day -1, the donor underwent apheresis and the product was purified for CD56 + cells by a two-step procedure. The entire purified product was infused on day 0.Results: The 10 patients had a median age of 2.5 years (range, 8 months to 21 years) and a median leukocyte count of 62 x 10 9 /L (range, 4 to 487) at diagnosis. Leukemic cell genetic abnormalities included CBFβ-MYH11in 4 cases, RBM15-MKL1in 2 cases, MLL-ENL and MLL-AF9 in 1 case each; 2 cases had no detectable abnormalities. Patients received a median of 29 × 10 6 /kg NK cells (range, 5 to 81 × 10 6 /kg). All patients had detectable donor NK cells at one or more time points: donor NK cell chimerism ranged from 0% to 30% during the first 4 weeks after the infusions and was greater than 1% in 9 cases at week 1, 4 cases at week 2, 5 cases at week 3, and 3 cases at week 4. One patient had prolonged NK engraftment (189 days), but no non-hematological toxicity. Grade 3–4 non-hematological toxicity was limited to one respiratory viral infection and one episode of febrile neutropenia. Median length of hospitalization was 2 days (range, 0–3) and median time to neutrophil recovery was 12 days (range, 9–56). With a median follow-up time of 637 days, all patients remain in remission. Conclusions: Haploidentical NK cells can be safely administered to AML patients who are in remission. All patients demonstrated temporary engraftment, which may have antileukemic effects. We have recently opened a new trial to evaluate the efficacy of NK cell therapy in children in first remission of AML. No significant financial relationships to disclose.
Significantly elevated number of human infections with H7N9 virus in Jiangsu in eastern China, October 2016 to January 2017
Authors: Xiang Huo, Liling Chen, Xian Qi, Haodi Huang, Qigang Dai, Huiyan Yu, Yu Xia, Wendong Liu, Ke Xu, Wang Ma, Jun Zhang, Changjun Bao
Journal: Eurosurveillance (2017)

Since first identified in 2013, the H7N9 virus has caused several waves of human infections in China, with a current wave including a number of patients with very severe disease. Jiangsu is one of the most impacted provinces, whereby as of 31 January 2017, the number of human infections (n = 109) in the ongoing fifth H7N9 wave has exceeded the sum of those in the four preceding ones. Ten of 13 cities in Jiangsu have been affected, and clustered infections as well as one co-infection with seasonal influenza have been observed. With a median age of 58 years and 74.3% (81/109) of patients being male, the characteristics of cases are similar to those in previous waves, however patients with H7N9 seem to have an accelerated disease progression. Preliminary case fatality remains above 30%. No significant viral mutations have been found in key functional loci. Environmental H7N9 detection rate and number of days with high risk ambient temperatures were both significantly elevated during the month of December 2016 when most human infections were reported. A number of municipal governments in Jiangsu have implemented live poultry market closures to impede viral transmission to humans. A detectable decline in human infections has been observed in these municipalities and the entire province since January 2017.
Safety of imatinib in patients with liver cirrhosis and hepatocellular carcinoma
Authors: G. Ramadori, E. Schleyer, T. Armbrust
Journal: Journal of Clinical Oncology (2004)

4244 Background: Hepatocellular carcinoma (HCC) almost exclusively arising in cirrhotic livers may derive from hepatic stem cells, the oval cells, that express c-kit, target of the tyrosine kinase inhibitor imatinib. After having successfully treated a HCC-patient with imatinib (Anti-Cancer Drugs, in press) we treated ten consecutive patients with HCC and Child A-cirrhosis. Methods: Ten patients with liver cirrhosis (Child-Pugh A) and c-kit-positive HCC were informed about the experimental treatment with imatinib. After obtaining consent treatment was started at dosages from 200mg/d to 400mg/d. Routine chemical values and alpha-fetoprotein (AFP) were determined after 1, 2 and 4 weeks, and imatinib serum concentrations were analyzed by HPLC in parallel. Tumor size was monitored by abdominal ultrasound. Results: During the first 8 weeks 9 patients continued treatment without side effects. Laboratory findings remained unchanged and imatinib serum concentrations were within the expected range. However, imatinib metabolites were below the expected range. One patient stopped imatinib after ten days due to diarrhea. The patient developed ascites and gastrointestinal bleeding from esophageal varices. While treatment was well tolerated by the remaining 9 patients within the first 6–8 weeks 7 patients developed side effects (nausea, diarrhea, skin rush, fuzzy vision, spasms, edema) during the next 3 months. Treatment was temporarily discontinued. After disappearing of side effects treatment was continued at a reduced dosage of 200mg/d that was well tolerated. Monitoring of the tumor size revealed constant tumor size in 2 of 9 patients with a drop of AFP serum level to normal and histological signs of tumor necrosis in 1 patient. However, an increase in tumor size was observed in the other patients. Conclusions: Imatinib at 200mg/d seems to be safe in patients with liver cirrhosis stage Child-Pugh A, while higher dosages induce side effect rates higher than those observed in other tumor entities like gastrointestinal stroma tumors. Efficacy of imatinib treatment in patients with liver cirrhosis and HCC should be tested in a randomized trial with dosages not higher than 200mg/d. No significant financial relationships to disclose.
Centromere Destiny in Dicentric Chromosomes: New Insights from the Evolution of Human Chromosome 2 Ancestral Centromeric Region
Authors: Giorgia Chiatante, Giuliana Giannuzzi, Francesco Maria Calabrese, Evan E. Eichler, Mario Ventura
Journal: Molecular Biology and Evolution (2017)

Dicentric chromosomes are products of genomic rearrangements that place two centromeres on the same chromosome. Due to the presence of two primary constrictions, they are inherently unstable and overcome their instability by epigenetically inactivating and/or deleting one of the two centromeres, thus resulting in functionally monocentric chromosomes that segregate normally during cell division. Our understanding to date of dicentric chromosome formation, behavior and fate has been largely inferred from observational studies in plants and humans as well as artificially produced de novo dicentrics in yeast and in human cells. We investigate the most recent product of a chromosome fusion event fixed in the human lineage, human chromosome 2, whose stability was acquired by the suppression of one centromere, resulting in a unique difference in chromosome number between humans (46 chromosomes) and our most closely related ape relatives (48 chromosomes). Using molecular cytogenetics, sequencing, and comparative sequence data, we deeply characterize the relicts of the chromosome 2q ancestral centromere and its flanking regions, gaining insight into the ancestral organization that can be easily broadened to all acrocentric chromosome centromeres. Moreover, our analyses offered the opportunity to trace the evolutionary history of rDNA and satellite III sequences among great apes, thus suggesting a new hypothesis for the preferential inactivation of some human centromeres, including IIq. Our results suggest two possible centromere inactivation models to explain the evolutionarily stabilization of human chromosome 2 over the last 5–6 million years. Our results strongly favor centromere excision through a one-step process.
Outcome of hematopoietic cell transplantation for DNA double-strand break repair disorders
Authors: James Slack, Michael H. Albert, Dmitry Balashov, Bernd H. Belohradsky, Alice Bertaina, Jack Bleesing, Claire Booth, Jochen Buechner, Rebecca H. Buckley, Marie Ouachée-Chardin, Elena Deripapa, Katarzyna Drabko, Mary Eapen, Tobias Feuchtinger, Andrea Finocchi, H. Bobby Gaspar, Sujal Ghosh, Alfred Gillio, Luis I. Gonzalez-Granado, Eyal Grunebaum, Tayfun Güngör, Carsten Heilmann, Merja Helminen, Kohei Higuchi, Kohsuke Imai, Krzysztof Kalwak, Nubuo Kanazawa, Gülsün Karasu, Zeynep Y. Kucuk, Alexandra Laberko, Andrzej Lange, Nizar Mahlaoui, Roland Meisel, D. Moshous, Hideki Muramatsu, Suhag Parikh, Srdjan Pasic, Irene Schmid, Catharina Schuetz, Ansgar Schulz, Kirk R. Schultz, Peter J. Shaw, Mary A. Slatter, Karl-Walter Sykora, Shinobu Tamura, Mervi Taskinen, Angela Wawer, Beata Wolska-Kuśnierz, Morton J. Cowan, Alain Fischer, Andrew R. Gennery
Journal: Journal of Allergy and Clinical Immunology (2017)
Malignancy grade and immunohistochemical myogenic/rhabdomyoblastic differentiation as an outcome determinant in retroperitoneal liposarcoma.
Authors: Alessandro Gronchi, Paola Collini, Barbara Valeri, Marco Fiore, Roberta Sanfilippo, Marta Barisella, Chiara Colombo, Carlo Morosi, Silvia Stacchiotti, Paolo Giovanni Casali, Angelo Paolo Dei Tos, Silvana Pilotti
Journal: Journal of Clinical Oncology (2014)

10588 Background: To explore the impact of malignancy grade and myogenic/rhabdomyoblastic differentiation on the natural course of retroperitoneal liposarcoma, uniformly treated at a single institution. Methods: All consecutive patients affected by primary WD/DD retroperitoneal liposarcoma surgically treated at our institution between January 2002 and December 2011 were retrospectively evaluated. Tumors were stained for mdm2 and 5 myogenic markers (smooth muscle alpha-actin [1A4], h-caldesmon, calponin, desmin, myogenin). French National Federation of the Centers for the Fight Against Cancer criteria (FNCLCC grade: 1,2,3) were applied. A diagnosis of myogenic differentiation was rendered when at least one myogenic marker was expressed. A diagnosis of rhabdomyoblastic component was rendered only if myogenin was positive. Overall survival (OS), local recurrence free survival (LRFS) and distant metastases free survival (DMFS) were calculated according to grading and absence/presence/type of myogenic differentiation. Results: 146 patients were identified. Median follow-up was 35 months (IQ, 22-66). 54 patients were affected by WD and 92 by DD liposarcoma. Among the latter, 60 were G2 and 32 G3. Myogenic differentiation was present in 52 cases (29/59 G2, 23/32 G3). 8 cases had a rhabdomyoblastic component (3/59 G2 and 5/32 G3). 5-yr OS were 92%, 51%, 24%; LRFS were 77%, 43%, 45% and DMFS were 100%, 82%, 32% for WD liposarcoma, G2 and G3 DD liposarcoma, respectively (p< 0.001). The outcome on the short run was strongly associated to the absence/presence of myogenic differentiation or rhabdomyoblastic component (3-yr OS 70%, 56% and 38%, respectively < 0.001). In particular all patients affected by G3 DD liposarcoma with a rhabdomyoblastic component died within 1 yr, recurring shortly after surgery with widespread disease. Conclusions: Beside FNLCC grade, absence / presence of myogenic differentiation with or without rhabdomyoblastic component significantly predicted the outcome of retroperitoneal liposarcoma. They should be factored in the treatment decision making and possibly used to stratify patients in clinical trials.
The effect of tivantinib on QTc interval in subjects with advanced solid tumors and healthy subjects.
Authors: Masaya Tachibana, Kyriakos P. Papadopoulos, Lon S. Smith, Danielle Mutz, Alain C. Mita, Monica M. Mita, Ronald B. Natale, Joel Morganroth, Ronald Savage, Roohi Gajee, Shuquan Chen, Hamim Zahir
Journal: Journal of Clinical Oncology (2014)

e13528 Background: Tivantinib is an orally administered MET inhibitor currently under development as a cancer therapy. The effect of tivantinib on ECG parameters was evaluated in clinical settings. Methods: A prospective-retrospective analysis was conducted to evaluate the relationship between the plasma concentrations and change from baseline in QTc intervals. Combined PK and ECG paired data from three healthy and three cancer subject trials were analyzed using linear mixed effect modeling approach. Additionally, a phase 1, single-blind, single-sequence, placebo-controlled study (NCT01699061) was conducted in subjects with advanced solid tumors to evaluate tivantinib’s effect on QTc intervals. In this study, serial three repeated 12-lead ECG and time-matched plasma concentration data were collected over 12 hours following single and multiple doses of tivantinib at 360 mg BID. All ECG results were analyzed by a core ECG laboratory. The predefined FDA approved hypothesis was that no clinically relevant QTc effect compared to placebo would be concluded if the upper bounds of the 1-sided 95% CIs for mean time-matched placebo-adjusted change from baseline in QTcF (ΔΔQTcF) did not exceed 20 ms. Results: There was a concentration dependent reduction in heart rate in the range of 5–15 bpm observed only in the cancer subject trials. The integrated QTc-exposure analysis of 685 assessments revealed no signal of QTc interval prolongation. The model estimated QTcB at Cmax was −3.9 ms and one-sided upper bound of 95% CI bound was −1.7 ms. In the QTc study with a total of 37 evaluable subjects, there was no evidence of clinically significant QTcF/QTcB interval prolongation demonstrated at all timepoints following administration of tivantinib. No subject had a placebo-adjusted QTcF interval > 480 ms orΔΔQTcF > 60 ms at any postdose timepoint. Conclusions: Based on the predefined hypothesistivantinib does not appear to cause any clinically relevant changes in QTc intervals. Clinical trial information: NCT01699061.
The prognostic value of percent positive biopsies in intermediate to high risk prostate cancer treated with brachytherapy and supplemental beam radiotherapy
Authors: R. D. Nurani, K. E. Wallner, G. S. Merrick, P. Orio, J. Virgin, L. True
Journal: Journal of Clinical Oncology (2006)

4645 Background: Percent biopsy core positivity (%BCP) has been correlated with tumor volume, extraprostatic disease and biochemical progression free survival (bPFS) in surgical series. In an external beam series, it can predict time to progression in a subset of patients. Methods: The percentage of biopsy cores involved with cancer was determined from original pathology reports of 566 patients with clinical stage T1c-T2a, Gleason grade 7–10 and/or PSA 10–20 CaP. These patients had previously been treated on a prospective study that randomized between 20 or 44 Gy of supplemental beam radiation therapy followed by Pd-103 brachytherapy. bPFS was defined as having a serum PSA ≤0.5 ng/ml at last follow-up. Patients were censored at last follow-up if their serum PSA was still decreasing. Results: 5 year bPFS was 79% for the entire group of 566 patients and 84% for the sub-group of 333 patients with %BCP quantified. On Cox regression analysis, biological variables analyzed included PSA, PSA &lt; or ≥ 10, Gleason score, Gleason score &lt; or ≥8, %BCP divided into two different grouping schemes (&lt;34, 34 through 50 and ≥50) and &lt; or ≥50. Treatment related variables analyzed included V100, V100 &lt; or ≥90%, D 90, D 90 &lt; or ≥80%, supplemental beam dose of 20 or 40 Gy. On univariate analysis, significant factors were limited to: %BCP &lt; vs. ≥50 (p = 0.004), %BCP &lt;34 Vs. ≥50% (p = 0.006), PSA, PSA &lt; or ≥10, Gleason score, V100 &lt; or ≥90%, D 90. On multivariate analysis, %BCP was the only significant determinant (p = 0.006) irregardless of which stratification scheme was utilized. For %BCP ≥50%, the hazard ratio for biochemical failure was 3.6 (95% confidence interval 1.4 to 8.8). On Kaplan-Meier analysis, 5 year bPFS was 90% and 79% for patients with &lt;50% and ≥50% cores involved respectively (p = 0.002). Conclusions: With implementation of implant techniques that uniformly meet optimal dosimetric criteria in patients felt to be at intermediate to high risk of failure based on Gleason and PSA, the percent of biopsy cores positive with malignancy emerges as the single most important factor in predicting biochemical failure. There is a statistically significant reduction in bPFS in patients with ≥50% of their core needle biopsies involved with malignancy. No significant financial relationships to disclose.
Abstract P069: Heat, Heat Waves and Hospital Admissions in Indianapolis, Indiana
Authors: Yi Wang
Journal: Circulation (2017)

Background: The association between heat and hospital admissions is well studied, but in Indiana where the regulatory agencies cites lack of evidence for global climate change, local evidence of such an association is critical for Indiana to mitigate the impact of increasing heat. Methods: Using a distributed-lag non-linear model, we studied the effects of moderate (31.7 °C or 90 th percentile of daily mean apparent temperature (AT)), severe (33.5 °C or 95 th percentile of daily mean apparent temperature (AT)) and extreme (36.4 °C or 99 th percentile of AT) heat on hospital admissions (June-August 2007-2012) for cardiovascular (myocardial infarction, myocardial infarction, heart failure) and heat-related diseases in Indianapolis, Indiana located in Marion County. We also examined the added effects of moderate heat waves (AT above the 90 th percentile lasting 2-6 days), severe heat waves (AT above the 95 th percentile lasting 2-6 days) and extreme heat waves (AT above the 99 th percentile lasting 2-6 days). In sensitivity analysis, we tested robustness of our results to 1) different temperature and lag structures and 2) temperature metrics (daily min, max and diurnal temperature range). Results: The relative risks of moderate heat, relative to 29.2°C (75 th percentile of AT), on admissions for cardiovascular disease (CVD), myocardial infarction (MI), heart failure (HF), and heat-related diseases (HD) were 0.98 (0.67, 1.44), 6.28 (1.48, 26.6), 1.38 (0.81, 2.36) and 1.73 (0.58, 5.11). The relative risk of severe heat on admissions for CVD, MI, HF, and HD were 0.93 (0.60, 1.43), 4.46 (0.85, 23.4), 1.30 (0.72, 2.34) and 2.14 (0.43, 10.7). The relative risk of extreme heat were 0.79 (0.26, 2.39), 0.11 (0.087, 1.32), 0.68 (0.18, 2.61), and 0.32 (0.005, 19.5). We also observed statistically significant added effects of moderate heat waves lasting 4 or 6 days on hospital admission for MI and HD and extreme heat waves lasting 4 days on hospital admissions for HD. Results were strengthened for people older than 65. Conclusions: Moderate heat wave lasting 4-6 days were associated with increased hospital admissions for MI and HD diseases and extreme heat wave lasting 4 days were associated with increased admissions for HD.
Phase III trial of bisphosphonates as adjuvant therapy in primary breast cancer: SWOG/Alliance/ECOG-ACRIN/NCIC Clinical Trials Group/NRG Oncology study S0307.
Authors: Julie Gralow, William E. Barlow, Alexander H. G. Paterson, Danika Lew, Alison Stopeck, Daniel F. Hayes, Dawn L. Hershman, Mark Schubert, Mark J. Clemons, Catherine H. Van Poznak, Elizabeth Claire Dees, James N. Ingle, Carla Isadora Falkson, Anthony D. Elias, Michael J. Messino, Jeffrey H. Margolis, Shaker R. Dakhil, Helen K. Chew, Robert B. Livingston, Gabriel N. Hortobagyi
Journal: Journal of Clinical Oncology (2015)

503 Background: Randomized trials and a recent meta-analysis suggest that adjuvant bisphosphonates can decrease recurrence and death, primarily in a postmenopausal population. SWOG S0307 compares efficacy of 3 bisphosphonates in early stage breast cancer. Methods: Patients with stage I-III breast cancer receiving adjuvant systemic therapy were randomized to receive 3 years of clodronate (CLOD) (1600 mg po qd), ibandronate (IBAN) (50 mg po qd) or zoledronic acid (ZA) (4 mg IV q month x 6, then q3 months x 2.5 years). The primary endpoint was disease-free survival (DFS). The target accrual of 5,400 gave ≥ 86% power to detect a statistically significant difference (2-sided α = 0.05) among the arms in an ITT analysis. Results: Late rapid accrual led to over-accrual, 6,097 patients were enrolled between 1/06-02/10. Median age was 53 with 58% post-menopausal or age 50+. 77% of tumors were ER positive, 17% HER2 positive, 16% triple negative, and 49% lymph node positive. There were more patients with grade 3/4 events with IBAN (10.5%) than CLOD (8.3%) or ZA (8.8%). Rates of ONJ were highest for ZA (1.2%), then IBAN (0.6%), followed by CLOD (0.3%). Fractures were equal across arms. 73% of patients indicated a preference for oral versus intravenous formulation if all agents showed equal efficacy. At the fourth formal interim analysis, with 56% of 1,314 expected events, the DSMC concluded that there was no realistic chance of a statistically significant difference and recommended early reporting of the trial outcomes. The primary outcome DFS did not differ across arms in a log-rank test (p = 0.71). 5-year DFS was 88% in the CLOD and ZA arms, and 87% in the IBAN arm. Overall survival was 93% in all 3 arms. Additional analyses based on age and menopausal status show no evidence of treatment differences. Conclusions: We found no evidence of differences in efficacy by type of bisphosphonate either in the intent to treat analysis or based on age and menopausal status. Despite differences in the type of toxicity, overall grade differed little across arms. Given that the oral study drugs are preferred by patients and approved elsewhere, efforts to make them available in the U.S. should be considered. Clinical trial information: NCT00127205.