bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparison of Longitudinal CA125 Algorithms as a First-Line Screen for Ovarian Cancer in the General Population
Authors: Blyuss Oleg , Burnell Matthew , Ryan Andy , Gentry-Maharaj Aleksandra , Mariño Inés P. , Kalsi Jatinderpal , Manchanda Ranjit , Timms John F. , Parmar Mahesh , Skates Steven J. , Jacobs Ian , Zaikin Alexey , Menon Usha 
Published: July 2018

Abstract
Purpose: In the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS), women in the multimodal (MMS) arm had a serum CA125 test (first-line), with those at increased risk, having repeat CA125/ultrasound (second-line test). CA125 was interpreted using the “Risk of Ovarian Cancer Algorithm” (ROCA). We report on performance of other serial algorithms and a single CA125 threshold as a first-line screen in the UKCTOCS dataset.
Experimental Design: 50,083 post-menopausal women who attended 346,806 MMS screens were randomly split into training and validation sets, following stratification into cases (ovarian/tubal/peritoneal cancers) and controls. The two longitudinal algorithms, a new serial algorithm, method of mean trends (MMT) and the parametric empirical Bayes (PEB) were trained in the training set and tested in the blinded validation set and the performance characteristics, including that of a single CA125 threshold, were compared.
Results: The area under receiver operator curve (AUC) was significantly higher (P = 0.01) for MMT (0.921) compared with CA125 single threshold (0.884). At a specificity of 89.5%, sensitivities for MMT [86.5%; 95% confidence interval (CI), 78.4–91.9] and PEB (88.5%; 95% CI, 80.6–93.4) were similar to that reported for ROCA (sensitivity 87.1%; specificity 87.6%; AUC 0.915) and significantly higher than the single CA125 threshold (73.1%; 95% CI, 63.6–80.8).
Conclusions: These findings from the largest available serial CA125 dataset in the general population provide definitive evidence that longitudinal algorithms are significantly superior to simple cutoff values for ovarian cancer screening. Use of these newer algorithms requires incorporation into a multimodal strategy. The results highlight the importance of incorporating serial change in biomarker levels in cancer screening/early detection strategies. Clin Cancer Res; 24(19); 4726–33. ©2018 AACR.
Final Report of a Phase I Trial of Olaparib with Cetuximab and Radiation for Heavy Smoker Patients with Locally Advanced Head and Neck Cancer
Authors: Karam Sana D. , Reddy Krishna , Blatchford Patrick J. , Waxweiler Tim , DeLouize Alicia M. , Oweida Ayman , Somerset Hilary , Marshall Carrie , Young Christian , Davies Kurtis D. , Kane Madeleine , Tan Aik Choo , Wang Xiao Jing , Jimeno Antonio , Aisner Dara L. , Bowles Daniel W. , Raben David 
Published: July 2018

AbstractPurpose: Our goal was to evaluate the safety and toxicity of combining a PARP inhibitor, olaparib, with cetuximab and fractionated intensity-modulated radiotherapy for patients with locally advanced head and neck cancer and heavy smoking histories.Patients and Methods: Patients with ≥10 packs/year history of smoking were treated with olaparib at doses ranging from 25–200 mg orally twice daily beginning approximately 10 days prior to initiation of and with concurrent radiation (69.3 Gy in 33 fractions) using a time-to-event continual reassessment method model. Cetuximab was administered starting approximately 5 days prior to radiation per standard of care.Results: A total of 16 patients were entered onto the study, with 15 evaluable for acute toxicity. The most common treatment-related grade 3–4 side effects were radiation dermatitis and mucositis (38% and 69%, respectively). The MTD was determined to be 50 mg orally twice daily, but the recommended phase II dose was deemed to be 25 mg orally twice daily. At a median follow-up of 26 months, the actuarial median overall survival was 37 months, but was not reached for other endpoints. Two-year overall survival, progression-free survival, local control, and distant control rates were 72%, 63%, 72%, and 79%, respectively. Patients who continued to smoke during therapy experienced higher recurrence rates. MYC and KMT2A were identified as potential correlatives of response on gene amplification and mutational analysis.Conclusions: Olaparib at 25 mg orally twice daily with concurrent cetuximab and radiation was well tolerated with reduced dermatitis within the radiation field. Response rates were promising for this high-risk population. Clin Cancer Res; 24(20); 4949–59. ©2018 AACR.
Mast Cell Activation and KSHV Infection in Kaposi Sarcoma
Authors: Ayers Leona W. , Barbachano-Guerrero Arturo , McAllister Shane C. , Ritchie Julie A. , Asiago-Reddy Elizabeth , Bartlett Linda C. , Cesarman Ethel , Wang Dongliang , Rochford Rosemary , Martin Jeffrey N. , King Christine A. 
Published: July 2018

AbstractPurpose: Kaposi sarcoma (KS) is a vascular tumor initiated by infection of endothelial cells (ECs) with KS–associated herpesvirus (KSHV). KS is dependent on sustained proinflammatory signals provided by intralesional leukocytes and continued infection of new ECs. However, the sources of these cytokines and infectious virus within lesions are not fully understood. Here, mast cells (MCs) are identified as proinflammatory cells within KS lesions that are permissive for, and activated by, infection with KSHV.Experimental Design: Three validated MC lines were used to assess permissivity of MCs to infection with KSHV and to evaluate MCs activation following infection. Biopsies from 31 AIDS-KS cases and 11 AIDS controls were evaluated by IHC for the presence of MCs in KS lesions and assessment of MC activation state and infection with KSHV. Plasma samples from 26 AIDS-KS, 13 classic KS, and 13 healthy adults were evaluated for levels of MC granule contents tryptase and histamine.Results: In culture, MCs supported latent and lytic KSHV infection, and infection-induced MC degranulation. Within KS lesions, MCs were closely associated with spindle cells. Furthermore, MC activation was extensive within patients with KS, reflected by elevated circulating levels of tryptase and a histamine metabolite. One patient with clinical signs of extensive MC activation was treated with antagonists of MC proinflammatory mediators, which resulted in a rapid and durable regression of AIDS-KS lesions.Conclusions: Using complimentary in vitro and in vivo studies we identify MCs as a potential long-lived reservoir for KSHV and a source of proinflammatory mediators within the KS lesional microenvironment. In addition, we identify MC antagonists as a promising novel therapeutic approach for KS. Clin Cancer Res; 24(20); 5085–97. ©2018 AACR.
Efficacy of the MDM2 Inhibitor SAR405838 in Glioblastoma Is Limited by Poor Distribution Across the Blood–Brain Barrier
Authors: Kim Minjee , Ma Daniel J. , Calligaris David , Zhang Shuangling , Feathers Ryan W. , Vaubel Rachael A. , Meaux Isabelle , Mladek Ann C. , Parrish Karen E. , Jin Fang , Barriere Cedric , Debussche Laurent , Watters James , Tian Shulan , Decker Paul A , Eckel-Passow Jeanette E. , Kitange Gaspar J. , Johnson Aaron J. , Parney Ian F. , Anastasiadis Panos Z. , Agar Nathalie Y.R. , Elmquist William F. , Sarkaria Jann N. 
Published: July 2018

Abstract
Controversy exists surrounding whether heterogeneous disruption of the blood–brain barrier (BBB), as seen in glioblastoma (GBM), leads to adequate drug delivery sufficient for efficacy in GBM. This question is especially important when using potent, targeted agents that have a poor penetration across an intact BBB. Efficacy of the murine double minute-2 (MDM2) inhibitor SAR405838 was tested in patient-derived xenograft (PDX) models of GBM. In vitro efficacy of SAR405838 was evaluated in PDX models with varying MDM2 expression and those with high (GBM108) and low (GBM102) expression were evaluated for flank and orthotopic efficacy. BBB permeability, evaluated using TexasRed-3 kDa dextran, was significantly increased in GBM108 through VEGFA overexpression. Drug delivery, MRI, and orthotopic survival were compared between BBB-intact (GBM108-vector) and BBB-disrupted (GBM108-VEGFA) models. MDM2-amplified PDX lines with high MDM2 expression were sensitive to SAR405838 in comparison with MDM2 control lines in both in vitro and heterotopic models. In contrast with profound efficacy observed in flank xenografts, SAR405838 was ineffective in orthotopic tumors. Although both GBM108-vector and GBM108-VEGFA readily imaged on MRI following gadolinium contrast administration, GBM108-VEGFA tumors had a significantly enhanced drug and gadolinium accumulation, as determined by MALDI-MSI. Enhanced drug delivery in GBM108-VEGFA translated into a marked improvement in orthotopic efficacy. This study clearly shows that limited drug distribution across a partially intact BBB may limit the efficacy of targeted agents in GBM. Brain penetration of targeted agents is a critical consideration in any precision medicine strategy for GBM. Mol Cancer Ther; 17(9); 1893–901. ©2018 AACR.
Drug-Sensitivity Screening and Genomic Characterization of 45 HPV-Negative Head and Neck Carcinoma Cell Lines for Novel Biomarkers of Drug Efficacy
Authors: Lepikhova Tatiana , Karhemo Piia-Riitta , Louhimo Riku , Yadav Bhagwan , Murumägi Astrid , Kulesskiy Evgeny , Kivento Mikko , Sihto Harri , Grénman Reidar , Syrjänen Stina M. , Kallioniemi Olli , Aittokallio Tero , Wennerberg Krister , Joensuu Heikki , Monni Outi 
Published: July 2018

AbstractThere is an unmet need for effective targeted therapies for patients with advanced head and neck squamous cell carcinoma (HNSCC). We correlated gene expression, gene copy numbers, and point mutations in 45 human papillomavirus–negative HNSCC cell lines with the sensitivity to 220 anticancer drugs to discover predictive associations to genetic alterations. The drug response profiles revealed diverse efficacy of the tested drugs across the cell lines. Several genomic abnormalities and gene expression differences were associated with response to mTOR, MEK, and EGFR inhibitors. NOTCH1 and FAT1 were the most commonly mutated genes after TP53 and also showed some association with response to MEK and/or EGFR inhibitors. MYC amplification and FAM83H overexpression associated with sensitivity to EGFR inhibitors, and PTPRD deletion with poor sensitivity to MEK inhibitors. The connection between high FAM83H expression and responsiveness to the EGFR inhibitor erlotinib was validated by gene silencing and from the data set at the Cancer Cell Line Encyclopedia. The data provide several novel genomic alterations that associated to the efficacy of targeted drugs in HNSCC. These findings require further validation in experimental models and clinical series. Mol Cancer Ther; 17(9); 2060–71. ©2018 AACR.
Inhibition of Parp1 by BMN673 Effectively Sensitizes Cells to Radiotherapy by Upsetting the Balance of Repair Pathways Processing DNA Double-Strand Breaks
Authors: Soni Aashish , Li Fanghua , Wang You , Grabos Martha , Krieger Lisa Marie , Chaudhary Shipra , Hasan Mohammad Sharif Mortoga , Ahmed Mansoor , Coleman C. Norman , Teicher Beverly A. , Piekarz Richard L. , Wang Dian , Iliakis George E. 
Published: July 2018

Abstract
Parp inhibitors (Parpi) are commonly used as single agents for the management of tumors with homologous recombination repair (HRR) deficiencies, but combination with radiotherapy (RT) is not widely considered due to the modest radiosensitization typically observed. BMN673 is one of the most recently developed Parpi and has been shown to mediate strong cell sensitization to methylating agents. Here, we explore the mechanisms of BMN673 radiosensitization to killing, aiming to combine it with RT. We demonstrate markedly stronger radiosensitization by BMN673 at concentrations substantially lower (50 nmol/L) than olaparib (3 μmol/L) or AG14361 (0.4 μmol/L) and dramatically lower as compared with second-generation inhibitors such as PJ34 (5 μmol/L). Notably, BMN673 radiosensitization peaks after surprisingly short contact times (∼1 hour) and at pharmacologically achievable concentrations in vivo. BMN673 exerts a complex set of effects on DNA double-strand break (DSB) processing, including inhibition of classic nonhomologous end-joining (cNHEJ) and alternative end-joining (altEJ) pathway at high doses of ionizing radiation (IR). BMN673 enhances resection at DSB and favors HRR and altEJ at low clinically relevant IR doses. The combined outcome of these effects is an abrogation in the inherent balance of DSB processing culminating in the formation of chromosomal translocations that underpin radiosensitization. Our observations pave the way to clinical trials exploring inherent benefits in combining BMN673 with RT for the treatment of various forms of cancer. Mol Cancer Ther; 17(10); 2206–16. ©2018 AACR.
Impact of Insufficient Response with an Increase in Tumor Number in Predicting Transcatheter Arterial Chemoembolization Refractoriness for Hepatocellular Carcinoma
Authors: Furuta Mitsuhiro , Moriguchi Michihisa , Okuda Keiichiro , Kataoka Seita , Mizuno Naoki , Takemura Masashi , Taketani Hiroyoshi , Hara Tasuku , Seko Yuya , Umemura Atsushi , Nishikawa Taichiro , Yamaguchi Kanji , Yasui Koichiroh , Minami Masahito , Itoh Yoshito 
Published: July 2018

<b><i>Aim:</i></b> In Japan, transcatheter arterial chemoembolization (TACE) refractoriness for hepatocellular carcinoma has been defined as an insufficient therapeutic effect after ≥2 procedures. Insufficient TACE for intrahepatic lesions is defined as the presence of &#x3e; 50% viable lesions (ineffective) or an increase in their number (progressive). This study aimed to examine the possibility of earlier evaluation of TACE refractoriness. <b><i>Methods:</i></b> Patients who underwent TACE for hepatocellular carcinomas &#x3e; 3 cm in size or with &#x3e; 3 nodules at our hospital between 2010 and 2014 were analyzed. The cases assessed as TACE insufficient for the first time were divided into 2 groups: the “either” group, evaluated as either “ineffective” or “progressive,” and the “both” group, that is, both “ineffective” and “progressive.” <b><i>Results:</i></b> The study participants included 40 of 212 consecutive patients who underwent TACE, divided into the either (<i>n</i> = 23) and both (<i>n</i> = 17) groups. Seventeen of 23 (73.9%) patients in the either group and all 17 (100%) in the both group had TACE refractoriness (<i>p</i> = 0.0295). <b><i>Conclusions:</i></b> Patients with both “ineffective” and “progressive” lesions are extremely likely to be TACE ­refractory at a significantly higher frequency than are those with either condition. Thus, when both of these factors are observed, switching to other therapies should be considered.
Impact of Ventricular Morphology on Fiber Stress and Strain in Fontan Patients
Authors: Ghelani Sunil J. , Colan Steven D. , Azcue Nina , Keenan Ellen M. , Harrild David M. , Powell Andrew J. , Geva Tal , Rathod Rahul H. 
Published: July 2018

Background:
Right ventricular (RV) morphology has been associated with adverse clinical outcomes in Fontan patients. The impact of RV versus left ventricular morphology on ventricular stress and strain in single ventricles is not well known.

Methods and Results:

Cardiac magnetic resonance examinations in 193 patients with the Fontan circulation were retrospectively analyzed. Ventricular mass, volume, global circumferential and longitudinal strain, and global average end-systolic fiber stress were calculated using previously published methods. Compared with left ventricular morphology, RV morphology (48%) was associated with higher ventricular end-diastolic volume (110 mL/BSA
1.3
versus 84 mL/BSA
1.3
,
P
<0.001), lower mass-to-volume ratio (0.46 versus 0.57,
P
<0.001), higher global average end-systolic fiber stress (23 kPa versus 20 kPa,
P
=0.002), worse global circumferential strain (−21% versus −24%,
P
<0.001), and higher prevalence of greater than or equal to moderate atrioventricular valve regurgitation (25% versus 6%,
P
<0.001). Ejection fraction and global longitudinal strain were similar between the groups. Death or listing for heart transplantation occurred in 24 (12%) with a median follow-up of 6.2 years. On univariate analysis, RV morphology, ventricular dilatation, and worse global circumferential strain were associated with this composite outcome.

Conclusions:
In comparison to Fontan patients with a dominant left ventricle, those with a dominant RV have higher fiber stress, a higher rate of ventricular dilatation, lower circumferential fiber shortening, and similar longitudinal shortening. RV morphology, ventricular dilation, and worse circumferential strain are associated with death or heart transplantation. The difference in myofiber architecture may contribute to suboptimal adaptation of the RV as a systemic ventricle.
Museum specimens indicate genetic erosion in an endangered lizard
Authors: Cornetti Luca , Girardi Matteo , Ghielmi Samuele , Vernesi Cristiano 
Published: July 2018

Abstract
Genetic variability, one of the main factors that guarantees species persistence, and species’ conservation status are generally evaluated with indices calculated at the present time. Natural history collections might help compare historical and current genetic diversity so to identify major trends. Here we analysed museum specimens of the lizard Zootoca vivipara carniolica, with a specific and stringent protocol for degraded DNA, in order to contrast its past and current genetic variability, using fragments of one mitochondrial DNA gene. Part of the distributional range of Z. v. carniolica (Po Plain, Italy), heavily impacted by human activities, was investigated. We found two previously unknown haplotypes in populations that are extinct today, suggesting the loss of these haplotypes and thus an overall shrinking of genetic variability. We argue that these results, together with the increasing threats posed by climate and land use changes, suggest that specific conservation measures for the persistence of Z. v. carniolica in Northern Italian lowlands have to be considered.
Isolating the Effects of Moisture Entrainment on Convectively Coupled Equatorial Waves in an Aquaplanet GCM
Authors: Peatman Simon C. , Methven John , Woolnough Steven J. 
Published: July 2018

Abstract
The rate of humidity entrainment in the convective parameterization scheme in a general circulation model affects the simulation of convectively coupled waves. However, it is unclear whether this is caused directly by the effects of entrainment on waves or indirectly through associated impacts such as on the basic state. Therefore, using an aquaplanet model, we employ a novel framework in which we entrain a weighted average of the resolved humidity field and a prescribed zonally symmetric field, with the weighting controlled by a decoupling parameter. Hence, we can vary the entrainment rate of basic-state humidity independently of the entrainment of humidity perturbations, simultaneously minimizing changes in the basic state. Thus, we isolate the effect of moisture entrainment on the waves. Enhancing the entrainment rate increases spectral power over all zonal wavenumbers and frequencies, with an increase in the ratio of eastward-to-westward power. The Kelvin wave speed decreases as entrainment increases, which can be partially accounted for by an associated change in basic-state humidity. Increasing the decoupling parameter reduces spectral power in Kelvin waves relative to the background, with only long waves still prominent when entrainment is almost fully decoupled from the resolved moisture field, suggesting the wave structure in humidity is required for convection to organize into short-wave structures. For long waves, the increase in the ratio of eastward-to-westward power as entrainment rate increases cannot be explained by the changes in the coupling with the wave structure in humidity but is consistent with the changes in the basic state.
Impacts of Saharan Dust on Atlantic Regional Climate and Implications for Tropical Cyclones
Authors: Pan Bowen , Wang Yuan , Hu Jiaxi , Lin Yun , Hsieh Jen-Shan , Logan Timothy , Feng Xidan , Jiang Jonathan H. , Yung Yuk L. , Zhang Renyi 
Published: July 2018

AbstractThe radiative and microphysical properties of Saharan dust are believed to impact the Atlantic regional climate and tropical cyclones (TCs), but the detailed mechanism remains uncertain. In this study, atmosphere-only simulations are performed from 2002 to 2006 using the Community Atmospheric Model, version 5.1, with and without dust emission from the Sahara Desert. The Saharan dust exhibits noticeable impacts on the regional longwave and shortwave radiation, cloud formation, and the convective systems over West Africa and the tropical Atlantic. The African easterly jet and West African monsoon are modulated by dust, leading to northward shifts of the intertropical convergence zone and the TC genesis region. The dust events induce positive midlevel moisture and entropy deficit anomalies, enhancing the TC genesis. On the other hand, the increased vertical wind shear and decreased low-level vorticity and potential intensity by dust inhibit TC formation in the genesis region. The ventilation index shows a decrease in the intensification region and an increase in the genesis region by dust, corresponding to favorable and unfavorable TC activities, respectively. The comparison of nondust scenarios in 2005 and 2006 shows more favorable TC conditions in 2005 characterized by higher specific humidity and potential intensity, but lower ventilation index, wind shear, and entropy deficit. Those are attributable to the observed warmer sea surface temperature (SST) in 2005, in which dust effects can be embedded. Our results imply significant dust perturbations on the radiative budget, hydrological cycle, and large-scale environments relevant to TC activity over the Atlantic.
Systematic Climate Model Rainfall Biases over Southern Africa: Links to Moisture Circulation and Topography
Authors: Munday C. , Washington R. 
Published: July 2018

AbstractAn important challenge for climate science is to understand the regional circulation and rainfall response to global warming. Unfortunately, the climate models used to project future changes struggle to represent present-day rainfall and circulation, especially at a regional scale. This is the case in southern Africa, where models from phase 5 of the Coupled Model Intercomparison Project (CMIP5) overestimate summer rainfall by as much as 300% compared to observations and tend to underestimate rainfall in Madagascar and the southwest Indian Ocean. In this paper, we explore the climate processes associated with the rainfall bias, with the aim of assessing the reliability of the CMIP5 ensemble and highlighting important areas for model development. We find that the high precipitation rates in models that are wet over southern Africa are associated with an anomalous northeasterly moisture transport (~10–30 g kg−1 s−1) that penetrates across the high topography of Tanzania and Malawi and into subtropical southern Africa. This transport occurs in preference to a southeasterly recurvature toward Madagascar that is seen in drier models and reanalysis data. We demonstrate that topographically related model biases in low-level flow are important for explaining the intermodel spread in rainfall; wetter models have a reduced tendency to block the oncoming northeasterly flow compared to dry models. The differences in low-level flow among models are related to upstream wind speed and model representation of topography, both of which should be foci for model development.