bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cytidine Deaminase Deficiency Reveals New Therapeutic Opportunities against Cancer
Authors: Mameri Hamza , Bièche Ivan , Meseure Didier , Marangoni Elisabetta , Buhagiar-Labarchède Géraldine , Nicolas André , Vacher Sophie , Onclercq-Delic Rosine , Rajapakse Vinodh , Varma Sudhir , Reinhold William C. , Pommier Yves , Amor-Guéret Mounira 
Published: September 2016

Abstract
Purpose: One of the main challenges in cancer therapy is the identification of molecular mechanisms mediating resistance or sensitivity to treatment. Cytidine deaminase (CDA) was reported to be downregulated in cells derived from patients with Bloom syndrome, a genetic disease associated with a strong predisposition to a wide range of cancers. The purpose of this study was to determine whether CDA deficiency could be associated with tumors from the general population and could constitute a predictive marker of susceptibility to antitumor drugs.
Experimental Design: We analyzed CDA expression in silico, in large datasets for cancer cell lines and tumors and in various cancer cell lines and primary tumor tissues using IHC, PDXs, qRT-PCR, and Western blotting. We also studied the mechanism underlying CDA silencing and searched for molecules that might target specifically CDA-deficient tumor cells using in silico analysis coupled to classical cellular experimental approaches.
Results: We found that CDA expression is downregulated in about 60% of cancer cells and tissues. We demonstrate that DNA methylation is a prevalent mechanism of CDA silencing in tumors. Finally, we show that CDA-deficient tumor cells can be specifically targeted with epigenetic treatments and with the anticancer drug aminoflavone.
Conclusions: CDA expression status identifies new subgroups of cancers, and CDA deficiency appears to be a novel and relevant predictive marker of susceptibility to antitumor drugs, opening up new possibilities for treating cancer. Clin Cancer Res; 23(8); 2116–26. ©2016 AACR.
Phase I Study of the Anti-CD22 Antibody–Drug Conjugate Pinatuzumab Vedotin with/without Rituximab in Patients with Relapsed/Refractory B-cell Non-Hodgkin Lymphoma
Authors: Advani Ranjana H. , Lebovic Daniel , Chen Andy , Brunvand Mark , Goy Andre , Chang Julie E. , Hochberg Ephraim , Yalamanchili Sreeni , Kahn Robert , Lu Dan , Agarwal Priya , Dere Randall C. , Hsieh Hsin-Ju , Jones Surai , Chu Yu-Waye , Cheson Bruce D. 
Published: September 2016

Abstract
Purpose: Pinatuzumab vedotin is an antibody–drug conjugate with the potent antimicrotubule agent monomethyl auristatin E (MMAE) conjugated to an anti-CD22 antibody via a protease-cleavable linker. This phase I study determined its recommended phase II dose (RP2D) and evaluated its safety, tolerability, and antitumor activity alone and with rituximab in relapsed/refractory (r/r) non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL).
Experimental Design: Patients received escalating doses of pinatuzumab vedotin every 21 days. Clinical activity at the RP2D alone or with rituximab was evaluated in r/r diffuse large B-cell lymphoma (DLBCL) and r/r indolent NHL (iNHL) patients.
Results: Seventy-five patients received single-agent pinatuzumab vedotin. The RP2D was 2.4 mg/kg, based on dose-limiting toxicities (DLT) of grade 4 neutropenia &gt;7 days in 1 of 3 patients and grade 4 neutropenia &lt;7 days in 2 of 3 patients treated at 3.2 mg/kg (maximum assessed dose). No DLTs occurred at 2.4 mg/kg. At the RP2D, neutropenia was the most common grade ≥3 adverse event. Peripheral neuropathy–related grade ≥2 adverse events most frequently resulted in treatment discontinuation. Rituximab cotreatment did not impact safety, tolerability, or pharmacokinetics of pinatuzumab vedotin. Unconjugated MMAE exposure was much lower than antibody-conjugated MMAE exposure, without accumulation with repeat dosing. At the RP2D, objective responses were observed in DLBCL (9/25) and iNHL (7/14) patients; 2 of 8 patients treated with pinatuzumab vedotin (RP2D) and rituximab had complete responses. CLL patients showed no objective responses.
Conclusions: The RP2D of pinatuzumab vedotin alone and with rituximab was 2.4 mg/kg, which was well tolerated, with encouraging clinical activity in r/r NHL. Clin Cancer Res; 23(5); 1167–76. ©2016 AACR.
Detection of Therapeutically Targetable Driver and Resistance Mutations in Lung Cancer Patients by Next-Generation Sequencing of Cell-Free Circulating Tumor DNA
Authors: Thompson Jeffrey C. , Yee Stephanie S. , Troxel Andrea B. , Savitch Samantha L. , Fan Ryan , Balli David , Lieberman David B. , Morrissette Jennifer D. , Evans Tracey L. , Bauml Joshua , Aggarwal Charu , Kosteva John A. , Alley Evan , Ciunci Christine , Cohen Roger B. , Bagley Stephen , Stonehouse-Lee Susan , Sherry Victoria E. , Gilbert Elizabeth , Langer Corey , Vachani Anil , Carpenter Erica L. 
Published: September 2016

Abstract
Purpose: The expanding number of targeted therapeutics for non–small cell lung cancer (NSCLC) necessitates real-time tumor genotyping, yet tissue biopsies are difficult to perform serially and often yield inadequate DNA for next-generation sequencing (NGS). We evaluated the feasibility of using cell-free circulating tumor DNA (ctDNA) NGS as a complement or alternative to tissue NGS.
Experimental Design: A total of 112 plasma samples obtained from a consecutive study of 102 prospectively enrolled patients with advanced NSCLC were subjected to ultra-deep sequencing of up to 70 genes and matched with tissue samples, when possible.
Results: We detected 275 alterations in 45 genes, and at least one alteration in the ctDNA for 86 of 102 patients (84%), with EGFR variants being most common. ctDNA NGS detected 50 driver and 12 resistance mutations, and mutations in 22 additional genes for which experimental therapies, including clinical trials, are available. Although ctDNA NGS was completed for 102 consecutive patients, tissue sequencing was only successful for 50 patients (49%). Actionable EGFR mutations were detected in 24 tissue and 19 ctDNA samples, yielding concordance of 79%, with a shorter time interval between tissue and blood collection associated with increased concordance (P = 0.038). ctDNA sequencing identified eight patients harboring a resistance mutation who developed progressive disease while on targeted therapy, and for whom tissue sequencing was not possible.
Conclusions: Therapeutically targetable driver and resistance mutations can be detected by ctDNA NGS, even when tissue is unavailable, thus allowing more accurate diagnosis, improved patient management, and serial sampling to monitor disease progression and clonal evolution. Clin Cancer Res; 22(23); 5772–82. ©2016 AACR.
High-Risk Premenopausal Luminal A Breast Cancer Patients Derive no Benefit from Adjuvant Cyclophosphamide-based Chemotherapy: Results from the DBCG77B Clinical Trial
Authors: Nielsen Torsten O. , Jensen Maj-Brit , Burugu Samantha , Gao Dongxia , Jørgensen Charlotte L. Tykjaer , Balslev Eva , Ejlertsen Bent 
Published: September 2016

AbstractPurpose: Luminal A breast cancers have better prognosis than other molecular subtypes. Luminal A cancers may also be insensitive to adjuvant chemotherapy, although there is little high-level evidence to confirm this concept. The primary hypothesis in this formal prospective–retrospective analysis was to assess interaction between subtype (Luminal A vs. other) and treatment (chemotherapy vs. not) for the primary endpoint (10-year invasive disease-free survival) of a breast cancer trial randomizing women to adjuvant chemotherapy, analyzed in multivariate Cox proportional hazards models using the Wald interaction test.Experimental Design: The Danish Breast Cancer Cooperative Group 77B clinical trial randomized 1,072 premenopausal women to no systematic treatment (control), levamisole, cyclophosphamide, or cyclophosphamide–methotrexate–fluorouracil arms. All arms included radiotherapy but no endocrine therapy. Researchers with no access to clinical data performed intrinsic subtype analysis on tissue microarrays using published immunohistochemical methods based on estrogen receptor, progesterone receptor, HER2, Ki67, and basal markers.Results: Patients (n = 709) had tissue available; chemotherapy benefit in these patients was similar to the original trial (HR, 0.56). Immunohistochemistry classified 165 as Luminal A, 319 Luminal B, 58 HER2-enriched, and 82 core basal (among 91 triple-negative). Patients with Luminal A breast tumors did not benefit from chemotherapy [HR, 1.06; 95% confidence interval (CI), 0.53–2.14; P = 0.86], whereas patients with non–luminal A subtypes did (HR, 0.50; 95% CI, 0.38-0.66; P &lt; 0.001; Pinteraction = 0.048).Conclusions: In a prospective–retrospective analysis of a randomized trial, patients with Luminal A breast cancers did not benefit from adjuvant cyclophosphamide-based chemotherapy. Clin Cancer Res; 23(4); 946–53. ©2016 AACR.
Who's Eligible Anyway? Risk Modeling for Clinical Trial Accrual
Authors: Mileham Kathryn F. , Kim Edward S. 
Published: September 2016

Abstract
Accrual continues to be a challenge for oncology clinical trials. Interventions to enhance accrual after study activation exist, including corrective action plans for NCI-sponsored trials. Clinical trials would benefit from a proactive approach rather than a reactive approach. Accrual strategy planning early in trial development is suggested. Clin Cancer Res; 22(22); 5397–9. ©2016 AACR.
See related article by Massett et al., p. 5408
Selumetinib Attenuates Skeletal Muscle Wasting in Murine Cachexia Model through ERK Inhibition and AKT Activation
Authors: Quan-Jun Yang , Yan Huo , Yong-Long Han , Li-Li Wan , Jie Li , Jin-Lu Huang , Jin Lu , Peng-Guo Chen , Run Gan , Cheng Guo 
Published: September 2016

Abstract
Cancer cachexia is a multifactorial syndrome affecting the skeletal muscle. Previous clinical trials showed that treatment with MEK inhibitor selumetinib resulted in skeletal muscle anabolism. However, it is conflicting that MAPK/ERK pathway controls the mass of the skeletal muscle. The current study investigated the therapeutic effect and mechanisms of selumetinib in amelioration of cancer cachexia. The classical cancer cachexia model was established via transplantation of CT26 colon adenocarcinoma cells into BALB/c mice. The effect of selumetinib on body weight, tumor growth, skeletal muscle, food intake, serum proinflammatory cytokines, E3 ligases, and MEK/ERK–related pathways was analyzed. Two independent experiments showed that 30 mg/kg/d selumetinib prevented the loss of body weight in murine cachexia mice. Muscle wasting was attenuated and the expression of E3 ligases, MuRF1 and Fbx32, was inhibited following selumetinib treatment of the gastrocnemius muscle. Furthermore, selumetinib efficiently reduced tumor burden without influencing the cancer cell proliferation, cumulative food intake, and serum cytokines. These results indicated that the role of selumetinib in attenuating muscle wasting was independent of cancer burden. Detailed analysis of the mechanism revealed AKT and mTOR were activated, while ERK, FoxO3a, and GSK3β were inhibited in the selumetinib -treated cachexia group. These indicated that selumetinib effectively prevented skeletal muscle wasting in cancer cachexia model through ERK inhibition and AKT activation in gastrocnemius muscle via cross-inhibition. The study not only elucidated the mechanism of MEK/ERK inhibition in skeletal muscle anabolism, but also validated selumetinib therapy as an effective intervention against cancer cachexia. Mol Cancer Ther; 16(2); 334–43. ©2016 AACR.
Sexual size dimorphism in the viviparous caecilian amphibian Geotrypetes seraphini seraphini (Gymnophiona: Dermophiidae) including an updated overview of sexual dimorphism in caecilian amphibians
Authors: Maerker Markus , Reinhard Sandy , Pogoda Peter , Kupfer Alexander 
Published: September 2016

Sexual size dimorphism (SSD) describing intersexual size differences of a given taxon is a widespread phenomenon in the animal kingdom. SSD plays a significant role in understanding life history and mating system evolution. The snakelike morphology of limbless caecilian amphibians lacking obvious secondary sexual characters (in contrast to frogs and salamanders) impedes an accurate comparison between sexes.Here, the phylogenetically derived teresomatan and viviparous caecilianGeotrypetes seraphini seraphiniwas analysed for patterns of sexual dimorphism. In terms of body size females were the larger sex, but when body length was adjusted male-biased intersexual differences in cloacal shape appeared. The larger female size is likely explained by fecundity selection as clutch size was positively correlated to female body length. Unexpectedly a cryptic, ontogeny related variation of the nuchal collars was found. An overview of SSD in caecilians including data for 27 species of nine out of ten existing families revealed a quite high number of taxa showing sexually dimorphic head size dimensions exclusively present among phylogenetically derived teresomatan caecilians. Still further research including insights into the behavioural ecology and molecular ecology of mating systems is warranted to better understand the evolution of sexual size dimorphism of caecilian amphibians.
Global Precipitation Measurement Mission Products and Services at the NASA GES DISC
Authors: Liu Z. , Ostrenga D. , Vollmer B. , Deshong B. , Macritchie K. , Greene M. , Kempler S. 
Published: September 2016

Abstract
This article describes NASA/JAXA Global Precipitation Measurement (GPM) mission products and services at the NASA Goddard Earth Sciences (GES) Data and Information Services Center (DISC). Built on the success of the Tropical Rainfall Measuring Mission (TRMM), the next-generation GPM mission consists of new precipitation measurement instruments and a constellation of international research and operational satellites to provide improved measurements of precipitation globally. To facilitate data access, research, applications, and scientific discovery, the GES DISC has developed a variety of data services for GPM. This article is intended to guide users in choosing GPM datasets and services at the GES DISC.
Sampling Issues in Estimating Radar Variables from Disdrometer Data
Authors: Smith Paul L. 
Published: September 2016

AbstractSimulation of sampling from gamma-distributed raindrop populations demonstrates that significant biases and substantial errors can occur in estimates of polarimetric radar variables based on samples of raindrop populations obtained with disdrometers. Biases and RMS errors of 0.5 dB or more in estimates of differential reflectivity Zdr can occur with samples of even a few hundred drops; significant biases and errors also occur in estimates of reflectivity ZH or specific differential phase Kdp. The results indicate that very large samples would be required to obtain adequate representation of the population characteristics for many radar applications. They also suggest that greater attention is needed to the sample sizes in the disdrometer data used in developing polarimetric rainfall-rate estimators or hydrometeor classification algorithms.
Primary Caregiver Perception of Pain Control following Pediatric Adenotonsillectomy
Authors: Sowder Justin C. , Gale Craig M. , Henrichsen Jacob L. , Veale Kristy , Liljestrand Katie B. , Ostlund Barbara C. , Sherwood Aaron , Smith Austin , Olsen Griffin H. , Ott Mark , Meier Jeremy D. 
Published: September 2016

ObjectivesTo (1) review pain medications prescribed following pediatric adenotonsillectomy (T&A), (2) identify pain medications reported to be helpful, and (3) compare parent‐reported outcomes among various combinations of pain medications.Study DesignCase series with planned data collection.SettingMultihospital network.Subjects and MethodsThe primary caregivers of children aged 1 to 18 years who underwent isolated T&A from June to December 2014 were contacted 14 to 21 days after surgery. Data collected included pain medications prescribed, medications most helpful in controlling pain, and duration that pain medication was required. Parents rated their children’s pain on postoperative days 2, 3, 7, and 14 and reported the time to resumption of normal diet/activity, as well as any hospital return visits.ResultsThe study cohort included 672 subjects of 1444 potential participants (46% response rate). The mean age of the patients was 7.9 ± 3.6 years. Narcotics were prescribed in 71.9%, and 70.4% were told to use ibuprofen. Children who took ibuprofen alone were significantly younger (P <. 001). Pain was significantly less on postoperative days 2 and 3 in the ibuprofen‐only group as compared with the groups taking narcotics only (P <. 001) and ibuprofen with narcotics (P =. 002). Those taking ibuprofen alone returned to normal activity (P <. 001) and diet (P =. 026) sooner than those taking ibuprofen with narcotics. No difference was seen in pain control on subgroup analysis comparing oxycodone and hydrocodone.ConclusionsFor pediatric T&A, significant variation exists in the management of postoperative pain. Parents of children given ibuprofen reported less pain than those given narcotics with and without ibuprofen. Further studies are needed to identify the optimal pain regimen for children after T&A.
Perioperative Deep Vein Thrombosis Risk Stratification: A Comparative Analysis of Free and Pedicled Flap Patients
Authors: Sinha Sumi , Puram Sidharth V. , Sethi Rosh K. V. , Goyal Neerav , Emerick Kevin S. , Lin Derrick , Durand Marlene L. , Deschler Daniel G. 
Published: September 2016

Patients with head and neck cancer who undergo reconstructive surgery are at risk for deep venous thrombosis (DVT), but the risk profile for patients undergoing major flap reconstruction is highly variable. Herein, we report our findings from a retrospective analysis of head and neck cancer patients (n = 517) who underwent free (n = 384) or pedicled (n = 133) flap reconstructive operations at a major tertiary care center from 2011 to 2014. DVTs developed perioperatively in 9 (1.7%) patients. Compared with pedicled flap patients, free flap patients had a longer mean operative time (421.4 ± 4.4 vs 332.7 ± 10.7 min, P <. 0001), but the DVT incidence did not differ significantly between free and pedicled flap patients (1.6% vs 2.2%, respectively, P =. 28). These data suggest that perioperative DVT risk in head and neck oncology patients may be largely similar regardless of the reconstructive strategy pursued.
A new method to measure oxygenator oxygen transfer performance during cardiopulmonary bypass: clinical testing using the Medtronic Fusion oxygenator
Authors: Hamilton Carole , Marin Denise , Weinbrenner Frank , Engelhardt Branka , Rosenzweig Dow , Beck Ulrich , Borisov Pavel , Hohe Stephen 
Published: September 2016

Background: There is no acceptable method of testing oxygen transfer performance in membrane oxygenators quickly and easily during cardiopulmonary bypass. Pre-clinical testing of oxygenators is performed under controlled situations in the laboratory, correlating oxygen transfer to blood flow using 100% oxygen. This laboratory method cannot be used clinically as oxygen transfer values vary significantly at each blood flow and the FiO2 is not kept at 1. Therefore, a formula was developed which corrects the existing FiO2 to attain a PaO2 of 150 mmHg: the corrected FiO2 at 150 mmHg. In graph form, this corrected FiO2 (x-axis) is correlated to the patient’s oxygen consumption levels (y-axis), which determines the membrane oxygenator oxygen transfer performance. Methods: Blood gas and hemodynamic parameters taken during cardiopulmonary bypass using the Medtronic Fusion were used to calculate the oxygen consumption (inlet conditions to the oxygenator) and the corrected FiO2 for a PaO2 of 150 mmHg. Validation of the formula “FiO2-PaO2/(Pb−pH2O)+0.21” was carried out by plotting the calculated values on a graph using PaO2 values between 145 to 155 mmHg and then, using the corrected FiO2 for PaO2s outside of this range. Results: All trend-lines correlated significantly to confirm that the Medtronic Fusion had an extrapolated oxygen transfer of 419 milliliters O2/min at an FiO2 of 1 to achieve a PaO2 of 150 mmHg. Conclusions: Use of the corrected FiO2 correlated to the oxygen transfer conditions of the membrane oxygenator can easily be used on a routine basis, providing valuable information clinically. When used by the manufacturer under laboratory conditions, further clinically relevant data is provided in terms of FiO2 and resultant PaO2s instead of the present limitations using blood flow. In this way, a clinically justifiable method has been developed to finally establish a standard in testing membrane oxygenator performance.
Navigating Return to Work and Breastfeeding in a Hospital with a Comprehensive Employee Lactation Program
Authors: Froh Elizabeth B. , Spatz Diane L. 
Published: September 2016

Background: The Surgeon General’s Call to Action to Support Breastfeeding details the need for comprehensive employer lactation support programs. Our institution has an extensive employee lactation program, and our breastfeeding initiation and continuation rates are statistically significantly higher than state and national data, with more than 20% of our employees breastfeeding for more than 1 year. Objective: The objective of this research was complete secondary data analysis of qualitative data collected as part of a larger study on breastfeeding outcomes. In the larger study, 545 women who returned to work full or part time completed an online survey with the ability to provide free text qualitative data and feedback regarding their experiences with breastfeeding after return to work. Methods: Qualitative data were pulled from the online survey platform. The responses to these questions were analyzed using conventional content analysis by the research team (2 PhD-prepared nurse researchers trained and experienced in qualitative methodologies and 1 research assistant) in order to complete a thematic analysis of the survey data. Results: Analysis of the data yielded 5 major themes: (1) positive reflections, (2) nonsupportive environment/work culture, (3) supportive environment/work culture, (4) accessibility of resources, and (5) internal barriers. The themes that emerged from this research clearly indicate that even in a hospital with an extensive employee lactation program, women have varied experiences—some more positive than others. Conclusion: Returning to work while breastfeeding requires time and commitment of the mother, and a supportive employee lactation program may ease that transition of return to work.