bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel ABCG2 Antagonists Reverse Topotecan-Mediated Chemotherapeutic Resistance in Ovarian Carcinoma Xenografts
Authors: Ricci Jerec W. , Lovato Debbie M. , Severns Virginia , Sklar Larry A. , Larson Richard S. 
Published: September 2016

Abstract
Chemotherapeutic resistance remains a challenge in the treatment of ovarian carcinoma, especially in recurrent disease. Despite the fact that most patients with newly diagnosed tumors attain complete remission following cytoreductive surgery and chemotherapy, ovarian carcinoma has a recurrence rate that exceeds 75%. The ATP-binding cassette family G member 2 (ABCG2) efflux protein has been described as one mechanism that confers multiple-drug resistance to solid tumors and contributes to topotecan resistance in ovarian carcinoma. In fact, one clinical trial demonstrated ABCG2 expression in all patients with primary or recurrent ovarian carcinoma. On the basis of our previous work, we hypothesized that three compounds (CID44640177, CID1434724, and CID46245505), which represent a new piperazine-substituted pyrazolo[1,5]pyrimidine substructure class of ABCG2-specific antagonists, would restore chemosensitivity to drug-resistant ovarian cancer in vitro and in vivo. To address the treatment difficulties associated with chemotherapeutic resistance in ovarian cancer, we combined each compound (CID44640177, CID1434724, and CID46245505) with topotecan and administered the mixture to chemoresistant Igrov1/T8 ovarian cancer cells in vitro and Igrov1/T8 xenografts in CB-17 SCID mice. We found that only nanomolar concentrations of each ABCG2 inhibitor in combination with topotecan were required to restore chemosensitivity to Igrov1/T8 cells in vitro. In vivo, substantial tumor reduction was achieved with each compound in 4 days, with CID1434724 causing the largest reduction in excess of 60%. No signs of secondary toxic effects were observed with the ABCG2 antagonists. These novel compounds should be viewed as promising drug candidates to reverse ABCG2-mediated chemoresistance. Mol Cancer Ther; 15(12); 2853–62. ©2016 AACR.
Integrated Genetic, Epigenetic, and Transcriptional Profiling Identifies Molecular Pathways in the Development of Laterally Spreading Tumors
Authors: Hesson Luke B. , Ng Benedict , Zarzour Peter , Srivastava Sameer , Kwok Chau-To , Packham Deborah , Nunez Andrea C. , Beck Dominik , Ryan Regina , Dower Ashraf , Ford Caroline E. , Pimanda John E. , Sloane Mathew A. , Hawkins Nicholas J. , Bourke Michael J. , Wong Jason W.H. , Ward Robyn L. 
Published: September 2016

Abstract
Laterally spreading tumors (LST) are colorectal adenomas that develop into extremely large lesions with predominantly slow progression to cancer, depending on lesion subtype. Comparing and contrasting the molecular profiles of LSTs and colorectal cancers offers an opportunity to delineate key molecular alterations that drive malignant transformation in the colorectum. In a discovery cohort of 11 LSTs and paired normal mucosa, we performed a comprehensive and unbiased screen of the genome, epigenome, and transcriptome followed by bioinformatics integration of these data and validation in an additional 84 large, benign colorectal lesions. Mutation rates in LSTs were comparable with microsatellite-stable colorectal cancers (2.4 vs. 2.6 mutations per megabase); however, copy number alterations were infrequent (averaging only 1.5 per LST). Frequent genetic, epigenetic, and transcriptional alterations were identified in genes not previously implicated in colorectal neoplasia (ANO5, MED12L, EPB41L4A, RGMB, SLITRK1, SLITRK5, NRXN1, ANK2). Alterations to pathways commonly mutated in colorectal cancers, namely, the p53, PI3K, and TGFβ pathways, were rare. Instead, LST-altered genes converged on axonal guidance, Wnt, and actin cytoskeleton signaling. These integrated omics data identify molecular features associated with noncancerous LSTs and highlight that mutation load, which is relatively high in LSTs, is a poor predictor of invasive potential.
Implications: The novel genetic, epigenetic, and transcriptional changes associated with LST development reveal important insights into why some adenomas do not progress to cancer. The finding that LSTs exhibit a mutational load similar to colorectal carcinomas has implications for the validity of molecular biomarkers for assessing cancer risk. Mol Cancer Res; 14(12); 1217–28. ©2016 AACR.
ECM Composition and Rheology Regulate Growth, Motility, and Response to Photodynamic Therapy in 3D Models of Pancreatic Ductal Adenocarcinoma
Authors: Cramer Gwendolyn M. , Jones Dustin P. , El-Hamidi Hamid , Celli Jonathan P. 
Published: September 2016

Abstract
Pancreatic ductal adenocarcinoma is characterized by prominent stromal involvement, which plays complex roles in regulating tumor growth and therapeutic response. The extracellular matrix (ECM)-rich stroma associated with this disease has been implicated as a barrier to drug penetration, although stromal depletion strategies have had mixed clinical success. It remains less clear how interactions with ECM, acting as a biophysical regulator of phenotype, not only a barrier to drug perfusion, regulate susceptibilities and resistance to specific therapies. In this context, an integrative approach is used to evaluate invasive behavior and motility in rheologically characterized ECM as determinants of chemotherapy and photodynamic therapy (PDT) responses. We show that in 3D cultures with ECM conditions that promote invasive progression, response to PDT is markedly enhanced in the most motile ECM-infiltrating populations, whereas the same cells exhibit chemoresistance. Conversely, drug-resistant sublines with enhanced invasive potential were generated to compare differential treatment response in identical ECM conditions, monitored by particle tracking microrheology measurements of matrix remodeling. In both scenarios, ECM-infiltrating cell populations exhibit increased sensitivity to PDT, whether invasion is consequent to selection of chemoresistance, or whether chemoresistance is correlated with acquisition of invasive behavior. However, while ECM-invading, chemoresistant cells exhibit mesenchymal phenotype, induction of EMT in monolayers without ECM was not sufficient to enhance PDT sensitivity, yet does impart chemoresistance as expected. In addition to containing platform development with broader applicability to inform microenvironment-dependent therapeutics, these results reveal the efficacy of PDT for targeting the most aggressive, chemoresistant, invasive pancreatic ductal adenocarcinoma associated with dismal outcomes for this disease.
Implications: ECM-infiltrating and chemoresistant pancreatic tumor populations exhibit increased sensitivity to PDT. Mol Cancer Res; 15(1); 15–25. ©2016 AACR.
Molecular Triage of Premalignant Lesions in Liquid-Based Cervical Cytology and Circulating Cell-Free DNA from Urine, Using a Panel of Methylated Human Papilloma Virus and Host Genes
Authors: Guerrero-Preston Rafael , Valle Blanca L. , Jedlicka Anne , Turaga Nitesh , Folawiyo Oluwasina , Pirini Francesca , Lawson Fahcina , Vergura Angelo , Noordhuis Maartje , Dziedzic Amanda , Pérez Gabriela , Renehan Marisa , Guerrero-Diaz Carolina , De Jesus Rodríguez Edgar , Diaz-Montes Teresa , Rodríguez Orengo José , Méndez Keimari , Romaguera Josefina , Trock Bruce J. , Florea Liliana , Sidransky David 
Published: September 2016

Abstract
Clinically useful molecular tools to triage women for a biopsy upon referral to colposcopy are not available. We aimed to develop a molecular panel to detect cervical intraepithelial neoplasia (CIN) grade 2 or higher lesions (CIN2+) in women with abnormal cervical cytology and high-risk HPV (HPV+). We tested a biomarker panel in cervical epithelium DNA obtained from 211 women evaluated in a cervical cancer clinic in Chile from 2006 to 2008. Results were verified in a prospective cohort of 107 women evaluated in a high-risk clinic in Puerto Rico from 2013 to 2015. Promoter methylation of ZNF516, FKBP6, and INTS1 discriminated cervical brush samples with CIN2+ lesions from samples with no intraepithelial lesions or malignancy (NILM) with 90% sensitivity, 88.9% specificity, 0.94 area under the curve (AUC), 93.1% positive predictive value (PPV), and 84.2% negative predictive value (NPV). The panel results were verified in liquid-based cervical cytology samples from an independent cohort with 90.9% sensitivity, 60.9% specificity, 0.90 AUC, 52.6% PPV, and 93.3% NPV, after adding HPV16-L1 methylation to the panel. Next-generation sequencing results in HPV+ cultured cells, and urine circulating cell-free DNA (ccfDNA) were used to design assays that show clinical feasibility in a subset (n = 40) of paired plasma (AUC = 0.81) and urine (AUC = 0.86) ccfDNA samples obtained from the prospective cohort. Viral and host DNA methylation panels can be tested in liquid cytology and urine ccfDNA from women referred to colposcopy, to triage CIN2+ lesions for biopsy and inform personalized screening algorithms. Cancer Prev Res; 9(12); 915–24. ©2016 AACR.
Targeted Next Generation Sequencing Identifies Markers of Response to PD-1 Blockade
Authors: Johnson Douglas B. , Frampton Garrett M. , Rioth Matthew J. , Yusko Erik , Xu Yaomin , Guo Xingyi , Ennis Riley C. , Fabrizio David , Chalmers Zachary R. , Greenbowe Joel , Ali Siraj M. , Balasubramanian Sohail , Sun James X. , He Yuting , Frederick Dennie T. , Puzanov Igor , Balko Justin M. , Cates Justin M. , Ross Jeffrey S. , Sanders Catherine , Robins Harlan , Shyr Yu , Miller Vincent A. , Stephens Philip J. , Sullivan Ryan J. , Sosman Jeffrey A. , Lovly Christine M. 
Published: September 2016

Abstract
Therapeutic antibodies blocking programmed death-1 and its ligand (PD-1/PD-L1) induce durable responses in a substantial fraction of melanoma patients. We sought to determine whether the number and/or type of mutations identified using a next-generation sequencing (NGS) panel available in the clinic was correlated with response to anti–PD-1 in melanoma. Using archival melanoma samples from anti–PD-1/PD-L1-treated patients, we performed hybrid capture–based NGS on 236–315 genes and T-cell receptor (TCR) sequencing on initial and validation cohorts from two centers. Patients who responded to anti–PD-1/PD-L1 had higher mutational loads in an initial cohort (median, 45.6 vs. 3.9 mutations/MB; P = 0.003) and a validation cohort (37.1 vs. 12.8 mutations/MB; P = 0.002) compared with nonresponders. Response rate, progression-free survival, and overall survival were superior in the high, compared with intermediate and low, mutation load groups. Melanomas with NF1 mutations harbored high mutational loads (median, 62.7 mutations/MB) and high response rates (74%), whereas BRAF/NRAS/NF1 wild-type melanomas had a lower mutational load. In these archival samples, TCR clonality did not predict response. Mutation numbers in the 315 genes in the NGS platform strongly correlated with those detected by whole-exome sequencing in The Cancer Genome Atlas samples, but was not associated with survival. In conclusion, mutational load, as determined by an NGS platform available in the clinic, effectively stratified patients by likelihood of response. This approach may provide a clinically feasible predictor of response to anti–PD-1/PD-L1. Cancer Immunol Res; 4(11); 959–67. ©2016 AACR.
Distribution records and extended range of the Sri Lanka Frogmouth Batrachostomus moniliger (Aves: Caprimulgiformes: Podargidae) in the Western Ghats: a review from 1862 to 2015
Authors: Mahabal Anil , Thakur Sanjay , Patil Rajgopal 
Published: September 2016

The Sri Lanka Frogmouth (or Ceylon Frogmouth) Batrachostomus moniliger is an endemic resident bird confined to the evergreen and secondary forests of Sri Lanka and the Western Ghats of India. The earlier distribution range of the Frogmouth was from the Uttara Kannada District of Karnataka to the southern tip of India and most of Sri Lanka. Recently, the range has been extended further north to Goa and up to Mumbai in Maharashtra. A number of observations summarized into 202 distributional records (published reports and records uploaded to eBird basic data set, Oriental Bird Images, and GBIF.org from the years 1862 to 2015) of the Frogmouth have been tabulated with its maps, and reviewed for their state-wise distribution records. The need of undertaking surveys to fill up the gaps in their distribution range as well as any further northward extension till the culmination of the Western Ghats has been discussed. It is urged that taxonomical and molecular phylogenetic studies are required to be carried out in different populations of Frogmouths across the entire range.
Role of Early Repolarization Pattern in Increasing Risk of Death
Authors: Cheng Yun‐Jiu , Lin Xiao‐Xiong , Ji Cheng‐Cheng , Chen Xu‐Miao , Liu Li‐Juan , Tang Kai , Wu Su‐Hua 
Published: September 2016

Background

An early repolarization pattern (
ERP
) has been hypothesized to be arrhythmogenic in experimental studies, but the prognostic significance of the
ERP
in the general population is controversial. We performed a meta‐analysis to examine the link between
ERP
and the risk of sudden cardiac arrest (
SCA
), cardiac death, and death from any cause.

Methods and Results

We performed a literature search using
MEDLINE
(January 1, 1966 to July 31, 2015) and
EMBASE
(January 1, 1980 to July 31, 2015) with no restrictions. Studies that reported relative risk (
RR
) estimates with 95% confidence intervals (
CI
s) for the associations of interest were included. Sixteen studies involving 334 524 subjects were identified. Compared with those without
ERP
, subjects with
ERP
experienced significantly increased risk for developing
SCA
(
RR
2.18; 95%
CI
1.29–3.68), cardiac death (
RR
1.48; 95%
CI
1.06–2.07), and death from any cause (
RR
1.21; 95%
CI
1.02–1.42), respectively. The increased risk was present predominantly in Asians and whites but not in African Americans.
ERP
with J‐point elevation in inferior leads, notching configuration, and horizontal or descending
ST
segment connote higher risk.
ERP
was associated with an absolute risk increase of 139.6 (95%
CI
130.3–149.3) additional
SCA
s per 100 000 person‐years and responsible for 7.3% (95%
CI
1.9–15.2) of
SCA
in the general population.

Conclusions

ERP
is associated with significant increased risk for
SCA
, cardiac death, and death from any cause. Future studies should focus on understanding the exact mechanisms for the arrhythmia risk and developing reliable tools for risk stratification.
Effect of Late Gadolinium Enhancement on the Recovery of Left Ventricular Systolic Function After Pulmonary Vein Isolation
Authors: Addison Daniel , Farhad Hoshang , Shah Ravi V. , Mayrhofer Thomas , Abbasi Siddique A. , John Roy M. , Michaud Gregory F. , Jerosch‐Herold Michael , Hoffmann Udo , Stevenson William G. , Kwong Raymond Y. , Neilan Tomas G. 
Published: September 2016

Background

The factors that predict recovery of left ventricular (
LV
) systolic dysfunction among patients with atrial fibrillation (
AF
) are not completely understood. Late gadolinium enhancement (
LGE
) of the
LV
has been reported among patients with
AF
, and we aimed to test whether the presence
LGE
was associated with subsequent recovery of
LV
systolic function among patients with
AF
and
LV
dysfunction.

Methods and Results

From a registry of 720 consecutive patients undergoing a cardiac magnetic resonance study prior to pulmonary vein isolation (
PVI
), patients with
LV
systolic dysfunction (ejection fraction [
EF
] <50%) were identified. The primary outcome was recovery of
LVEF
defined as an
EF
>50%; a secondary outcome was a combined outcome of subsequent heart failure (
HF
), admission, and death. Of 720 patients, 172 (24%) had an
LVEF
of <50% prior to
PVI
. The mean
LVEF
pre‐
PVI
was 41±6% (median 43%, range 20% to 49%). Forty‐three patients (25%) had
LGE
(25 [58%] ischemic), and the extent of
LGE
was 7.5±4% (2% to 19%). During follow‐up (mean 42 months), 91 patients (53%) had recovery of
LVEF
, 68 (40%) had early recurrence of
AF
, 65 (38%) had late
AF
, 18 (5%) were admitted for
HF
, and 23 died (13%). Factors associated with nonrecovery of
LVEF
were older age, history of myocardial infarction, early
AF
recurrence, late
AF
recurrence, and
LGE
. In a multivariable model, the presence of
LGE
and any recurrence of
AF
had the strongest association with persistence of
LV
dysfunction. Additionally, all patients without recurrence of
AF
and
LGE
had normalization of
LVEF
, and recovery of
LVEF
was associated with reduced
HF
admissions and death.

Conclusions

In patients with
AF
and
LV
dysfunction undergoing
PVI
, the absence of
LGE
and
AF
recurrence are predictors of
LVEF
recovery and
LVEF
recovery in
AF
with associated reduction in subsequent death and heart failure.
Transient Receptor Potential Vanilloid 1 Regulates Mitochondrial Membrane Potential and Myocardial Reperfusion Injury
Authors: Hurt Carl M. , Lu Yao , M. Stary Creed , Piplani Honit , Small Bryce A. , Urban Travis J. , Qvit Nir , Gross Garrett J. , Mochly‐Rosen Daria , Gross Eric R. 
Published: September 2016

Background

The transient receptor potential vanilloid 1 (
TRPV
1) mediates cellular responses to pain, heat, or noxious stimuli by calcium influx; however, the cellular localization and function of
TRPV
1 in the cardiomyocyte is largely unknown. We studied whether myocardial injury is regulated by
TRPV
1 and whether we could mitigate reperfusion injury by limiting the calcineurin interaction with
TRPV
1.

Methods and Results

In primary cardiomyocytes, confocal and electron microscopy demonstrates that
TRPV
1 is localized to the mitochondria. Capsaicin, the specific
TRPV
1 agonist, dose‐dependently reduced mitochondrial membrane potential and was blocked by the
TRPV
1 antagonist capsazepine or the calcineurin inhibitor cyclosporine. Using in silico analysis, we discovered an interaction site for
TRPV
1 with calcineurin. We synthesized a peptide, V1‐cal, to inhibit the interaction between
TRPV
1 and calcineurin. In an in vivo rat myocardial infarction model, V1‐cal given just prior to reperfusion substantially mitigated myocardial infarct size compared with vehicle, capsaicin, or cyclosporine (24±3% versus 61±2%, 45±1%, and 49±2%, respectively; n=6 per group;
P
<0.01 versus all groups). Infarct size reduction by V1‐cal was also not seen in
TRPV
1 knockout rats.

Conclusions

TRPV
1 is localized at the mitochondria in cardiomyocytes and regulates mitochondrial membrane potential through an interaction with calcineurin. We developed a novel therapeutic, V1‐cal, that substantially reduces reperfusion injury by inhibiting the interaction of calcineurin with
TRPV
1. These data suggest that
TRPV
1 is an end‐effector of cardioprotection and that modulating the
TRPV
1 protein interaction with calcineurin limits reperfusion injury.
Reconsideration of the genera Merogomphus Martin, 1904, and Anisogomphus Selys, 1857, including erection of a new genus, with a new species and discussion of additional specimens from Cambodia
Authors: KOSTERIN OLEG E. 
Published: September 2016

In the current sense, Merogomphus Martin, 1904, is an artificial genus. It includes two unrelated groups of species: those with lyrate cerci with or without an outer spine and those with simple cerci, plus two species with large and broad epiproct branches placed in Merogomphus obviously in error. At the same time a number of species similar and obviously related to the former group were described from China in the genus Anisogomphus Selys, 1857. To resolve this taxonomic tangle, the genus Merogomphus is restricted to include only species with lyrate cerci: M pavici (Martin, 1904) (the type species), M. longistigmus (Fraser, 1922), M. vandykei (Needham, 1930), M. femoralis (Laidlaw, 1931), M. vespertinus (Chao, 1999) and M. torpens (Needham, 1930). A new genus Euthygomphus (type species: Leptogomphus martini Fraser, 1922) is erected to contain species with simple cerci and moderately divergent epiproct branches, formerly attributed to either Merogomphus or Anisogomphus: Euthygomphus parvus (Krüger, 1899) comb. nov., E. martini (Fraser, 1922) comb. nov., E. koxingai Chao, 1954 comb. nov., E. chaoi Liu 1991 comb. nov., E. jinggangshanus Liu, 1991 comb. nov., E. yunnanensis Zhou et Wu, 1992 comb. nov. Euthygomphus schorri Kosterin, 2016, sp. nov. is described (type locality: Cambodia, Mondulkiri Province, 3.5–3.8 km ESE of Sen Monorom, holotype in RMNH), A new synonymy Merogomphus chaoi Yang & Davies, 1993 = Anisogomphus pinratani Hämäläinen, 1991, and a new combination Anisogomphus tamdaoensis (Karube, 2001) comb. nov. are proposed. The published records of ‘Merogomphus parvus’ from Laos, Thailand, Vietnam, Cambodia and Vietnam are reidentified as E. yunnanensis, and new records and illustrations of this species from Cambodia are provided.
Impact of Removing Covariance Localization in an Ensemble Kalman Filter: Experiments with 10 240 Members Using an Intermediate AGCM
Authors: Kondo Keiichi , Miyoshi Takemasa 
Published: September 2016

AbstractThe ensemble Kalman filter (EnKF) with high-dimensional geophysical systems usually employs up to 100 ensemble members and requires covariance localization to reduce the sampling error in the forecast error covariance between distant locations. The authors’ previous work pioneered implementation of an EnKF with a large ensemble of up to 10 240 members, but this method required application of a relatively broad covariance localization to avoid memory overflow. This study modified the EnKF code to save memory and enabled for the first time the removal of completely covariance localization with an intermediate AGCM. Using the large sample size, this study aims to investigate the analysis and forecast accuracy, as well as the impact of covariance localization when the sampling error is small. A series of 60-day data assimilation cycle experiments with different localization scales are performed under the perfect model scenario to investigate the pure impact of covariance localization. The results show that the analysis and 7-day forecasts are much improved by removing covariance localization and that the long-range covariance between distant locations plays a key role. The eigenvectors of the background error covariance matrix based on the 10 240 ensemble members are explicitly computed and reveal long-range structures.