bluuebunny/crossref_metadata_2025_split huggingface dataset:
Detection of Zoonotic Pathogens and Characterization of Novel Viruses Carried by Commensal Rattus norvegicus in New York City
Authors: Firth Cadhla , Bhat Meera , Firth Matthew A. , Williams Simon H. , Frye Matthew J. , Simmonds Peter , Conte Juliette M. , Ng James , Garcia Joel , Bhuva Nishit P. , Lee Bohyun , Che Xiaoyu , Quan Phenix-Lan , Lipkin W. Ian 
Published: October 2014

ABSTRACT

Norway rats (
Rattus norvegicus
) are globally distributed and concentrate in urban environments, where they live and feed in closer proximity to human populations than most other mammals. Despite the potential role of rats as reservoirs of zoonotic diseases, the microbial diversity present in urban rat populations remains unexplored. In this study, we used targeted molecular assays to detect known bacterial, viral, and protozoan human pathogens and unbiased high-throughput sequencing to identify novel viruses related to agents of human disease in commensal Norway rats in New York City. We found that these rats are infected with bacterial pathogens known to cause acute or mild gastroenteritis in people, including atypical enteropathogenic
Escherichia coli
,
Clostridium difficile
, and
Salmonella enterica
, as well as infectious agents that have been associated with undifferentiated febrile illnesses, including
Bartonella
spp.,
Streptobacillus moniliformis
,
Leptospira interrogans
, and Seoul hantavirus. We also identified a wide range of known and novel viruses from groups that contain important human pathogens, including sapoviruses, cardioviruses, kobuviruses, parechoviruses, rotaviruses, and hepaciviruses. The two novel hepaciviruses discovered in this study replicate in the liver of Norway rats and may have utility in establishing a small animal model of human hepatitis C virus infection. The results of this study demonstrate the diversity of microbes carried by commensal rodent species and highlight the need for improved pathogen surveillance and disease monitoring in urban environments.

IMPORTANCE
The observation that most emerging infectious diseases of humans originate in animal reservoirs has led to wide-scale microbial surveillance and discovery programs in wildlife, particularly in the developing world. Strikingly, less attention has been focused on commensal animals like rats, despite their abundance in urban centers and close proximity to human populations. To begin to explore the zoonotic disease risk posed by urban rat populations, we trapped and surveyed Norway rats collected in New York City over a 1-year period. This analysis revealed a striking diversity of known pathogens and novel viruses in our study population, including multiple agents associated with acute gastroenteritis or febrile illnesses in people. Our findings indicate that urban rats are reservoirs for a vast diversity of microbes that may affect human health and indicate a need for increased surveillance and awareness of the disease risks associated with urban rodent infestation.
The Communities First (ComFi) study: protocol for a prospective controlled quasi-experimental study to evaluate the impact of area-wide regeneration on mental health and social cohesion in deprived communities
Authors: White James , Greene Giles , Dunstan Frank , Rodgers Sarah , Lyons Ronan A , Humphreys Ioan , John Ann , Webster Chris , Palmer Stephen , Elliott Eva , Phillips Ceri J , Fone David 
Published: October 2014

IntroductionRecent systematic reviews have highlighted the dearth of evidence on the effectiveness of regeneration on health and health inequalities. ‘Communities First’ is an area-wide regeneration scheme to improve the lives of people living in the most deprived areas in Wales (UK). This study will evaluate the impact of Communities First on residents’ mental health and social cohesion.Methods and analysisA prospective controlled quasi-experimental study of the association between residence in Communities First regeneration areas in Caerphilly county borough and change in mental health and social cohesion. The study population is the 4226 residents aged 18–74 years who responded to the Caerphilly Health and Social Needs Study in 2001 (before delivery) and 2008 (after delivery of Communities First). Data on the location, type and cost of Communities First interventions will be extracted from records collected by Caerphilly county borough council. The primary outcome is the change in mental health between 2001 and 2008. Secondary outcomes are changes: in common mental disorder case status (using survey and general practice data), social cohesion and mental health inequalities. Multilevel models will examine change in mental health and social cohesion between Communities First and control areas, adjusting for individual and household level confounding factors. Further models will examine the effects of (1) different types of intervention, (2) contamination across areas, (3) length of residence in a Communities First area, and (4) population migration. We will carry out a cost-consequences analysis to summarise the outcomes generated for participants, as well as service utilisation and utility gains.Ethics and disseminationThis study has had approval from the Information Governance Review Panel at Swansea University (Ref: 0266 CF). Findings will be disseminated through peer-review publications, international conferences, policy and practice partners in local and national government, and updates on our study website (http://medicine.cardiff.ac.uk/clinical-study/communities-first-regeneration-programme/).
PAX-8 expression in renal tumours and distant sites: A useful marker of primary and metastatic renal cell carcinoma?
Authors: Barr Meaghan L , Jilaveanu Lucia B , Camp Robert L , Adeniran Adebowale J , Kluger Harriet M , Shuch Brian 
Published: October 2014

AimsImmunohistochemical stains have greatly improved the diagnostic accuracy of renal cell carcinoma (RCC) for primary and distant tumours. We evaluate a marker that has recently been incorporated in clinical practice, PAX-8, in primary and metastatic RCCs.MethodsTwo distinct tissue microarrays were used, one consisting of over 334 renal tumours, 294 with adjacent normal kidney and the other with 40 matched nephrectomy and metastatic sites of RCC. PAX-8 expression was assessed by a method of quantitative immunofluorescence.ResultsPAX-8 was positive in 96% (146/152) of normal renal tissue and 83% (227/272) of renal tumours. PAX-8 staining was positive in clear cell, papillary and chromophobe tumours in 80% (165/207), 95% (39/41) and 100% (6/6) of samples, respectively. Overall, intensity of PAX-8 expression was significantly higher in RCC metastatic sites than in the primary site (p=0.0047), however, in matched sites there was no statistically significant difference in the proportion of positive versus negative specimens (p=0.274).ConclusionsAs the role of molecular markers expands in the diagnostic algorithm, this study confirms that PAX-8 expression is a useful diagnostic marker for RCC. PAX-8 expression was found in the primary tumour and distant sites. Compared with normal tissue and other histological types, clear cell RCC has lower PAX-8 expression and is less frequently positive, therefore, the lack of expression does not exclude a tumour of renal origin.
MicroRNA Classifier and Nomogram for Metastasis Prediction in Colon Cancer
Authors: Goossens-Beumer Inès J. , Derr Remco S. , Buermans Henk P.J. , Goeman Jelle J. , Böhringer Stefan , Morreau Hans , Nitsche Ulrich , Janssen Klaus-Peter , van de Velde Cornelis J.H. , Kuppen Peter J.K. 
Published: October 2014

Abstract
Background: Colon cancer prognosis and treatment are currently based on a classification system still showing large heterogeneity in clinical outcome, especially in TNM stages II and III. Prognostic biomarkers for metastasis risk are warranted as development of distant recurrent disease mainly accounts for the high lethality rates of colon cancer. miRNAs have been proposed as potential biomarkers for cancer. Furthermore, a verified standard for normalization of the amount of input material in PCR-based relative quantification of miRNA expression is lacking.
Methods: A selection of frozen tumor specimens from two independent patient cohorts with TNM stage II–III microsatellite stable primary adenocarcinomas was used for laser capture microdissection. Next-generation sequencing was performed on small RNAs isolated from colorectal tumors from the Dutch cohort (N = 50). Differential expression analysis, comparing in metastasized and nonmetastasized tumors, identified prognostic miRNAs. Validation was performed on colon tumors from the German cohort (N = 43) using quantitative PCR (qPCR).
Results: miR25-3p and miR339-5p were identified and validated as independent prognostic markers and used to construct a multivariate nomogram for metastasis risk prediction. The nomogram showed good probability prediction in validation. In addition, we recommend combination of miR16-5p and miR26a-5p as standard for normalization in qPCR of colon cancer tissue–derived miRNA expression.
Conclusions: In this international study, we identified and validated a miRNA classifier in primary cancers, and propose a nomogram capable of predicting metastasis risk in microsatellite stable TNM stage II–III colon cancer.
Impact: In conjunction with TNM staging, by means of a nomogram, this miRNA classifier may allow for personalized treatment decisions based on individual tumor characteristics. Cancer Epidemiol Biomarkers Prev; 24(1); 187–97. ©2014 AACR.
Dual mTORC1/2 Blockade Inhibits Glioblastoma Brain Tumor Initiating Cells In Vitro and In Vivo and Synergizes with Temozolomide to Increase Orthotopic Xenograft Survival
Authors: Luchman H. Artee , Stechishin Owen D.M. , Nguyen Stephanie A. , Lun Xueqing Q. , Cairncross J. Gregory , Weiss Samuel 
Published: October 2014

Abstract
Purpose: The EGFR and PI3K/mTORC1/2 pathways are frequently altered in glioblastoma (GBM), but pharmacologic targeting of EGFR and PI3K signaling has failed to demonstrate efficacy in clinical trials. Lack of relevant models has rendered it difficult to assess whether targeting these pathways might be effective in molecularly defined subgroups of GBMs. Here, human brain tumor–initiating cell (BTIC) lines with different combinations of endogenous EGFR wild-type, EGFRvIII, and PTEN mutations were used to investigate response to the EGFR inhibitor gefitinib, mTORC1 inhibitor rapamycin, and dual mTORC1/2 inhibitor AZD8055 alone and in combination with temozolomide (TMZ)
Experimental Design: In vitro growth inhibition and cell death induced by gefitinib, rapamycin, AZD8055, and TMZ or combinations in human BTICs were assessed by alamarBlue, neurosphere, and Western blotting assays. The in vivo efficacy of AZD8055 was assessed in subcutaneous and intracranial BTIC xenografts. Kaplan–Meier survival studies were performed with AZD8055 and in combination with TMZ.
Results: We confirm that gefitinib and rapamycin have modest effects in most BTIC lines, but AZD8055 was highly effective at inhibiting Akt/mTORC2 activity and dramatically reduced the viability of BTICs regardless of their EGFR and PTEN mutational status. Systemic administration of AZD8055 effectively inhibited tumor growth in subcutaneous BTIC xenografts and mTORC1/2 signaling in orthotopic BTIC xenografts. AZD8055 was synergistic with the alkylating agent TMZ and significantly prolonged animal survival.
Conclusion: These data suggest that dual inhibition of mTORC1/2 may be of benefit in GBM, including the subset of TMZ-resistant GBMs. Clin Cancer Res; 20(22); 5756–67. ©2014 AACR.
Plasma Levels of Heat Shock Protein 90 Alpha Associated with Lung Cancer Development and Treatment Responses
Authors: Shi Yuankai , Liu Xiaoqing , Lou Jiatao , Han Xiaohong , Zhang Lijian , Wang Qingtao , Li Baolan , Dong Mei , Zhang Yinghong 
Published: October 2014

Abstract
Purpose: Altered expression of heat shock protein 90 alpha (Hsp90α) was associated with tumor development, progression, and metastasis. This study explored plasma levels of Hsp90α protein in patients with lung cancer and other controls to assess its diagnostic value and monitor treatment responses for patients with lung cancer.
Experimental Design: A total of 2,247 individuals were recruited and assigned into two cohorts as static and dynamic groups. ELISA analysis and confirmation of plasma Hsp90α protein levels for association with tumor stages and treatment responses, respectively, were performed.
Results: The average plasma levels of Hsp90α protein in patients with lung cancer were significantly higher than in healthy controls (P &lt; 0.0001). Plasma levels of Hsp90α protein in patients with advanced lung cancer (stage III–IV) were higher than in patients with early-stage lung cancer (stage I–II; P &lt; 0.001). Using a cutoff value of 56.33 ng/mL to separate lung cancer from other controls, the sensitivity and specificity reached 72.18% (95% CI, 0.695–0.749) and 78.70% (95% CI, 0.761–0.813), respectively. To confirm the different levels in the second cohort, plasma levels of Hsp90α protein showed a statistically significant difference between preoperative and postoperative patients in surgical patient groups (P &lt; 0.007). There was also a statistically significant difference between the disease progressive group and stable disease group, with regard to partial response after chemotherapy (P &lt; 0.0001).
Conclusions: This study demonstrated that plasma Hsp90α protein levels are useful as a diagnostic biomarker in lung cancer and predict the responses of patients with lung cancer to chemotherapy. Clin Cancer Res; 20(23); 6016–22. ©2014 AACR.
Whole-Exome Sequencing of Muscle-Invasive Bladder Cancer Identifies Recurrent Mutations of UNC5C and Prognostic Importance of DNA Repair Gene Mutations on Survival
Authors: Yap Kai Lee , Kiyotani Kazuma , Tamura Kenji , Antic Tatjana , Jang Miran , Montoya Magdeline , Campanile Alexa , Yew Poh Yin , Ganshert Cory , Fujioka Tomoaki , Steinberg Gary D. , O'Donnell Peter H. , Nakamura Yusuke 
Published: October 2014

Abstract
Purpose: Because of suboptimal outcomes in muscle-invasive bladder cancer even with multimodality therapy, determination of potential genetic drivers offers the possibility of improving therapeutic approaches and discovering novel prognostic indicators.
Experimental Design: Using pTN staging, we case-matched 81 patients with resected ≥pT2 bladder cancers for whom perioperative chemotherapy use and disease recurrence status were known. Whole-exome sequencing was conducted in 43 cases to identify recurrent somatic mutations and targeted sequencing of 10 genes selected from the initial screening in an additional 38 cases was completed. Mutational profiles along with clinicopathologic information were correlated with recurrence-free survival (RFS) in the patients.
Results: We identified recurrent novel somatic mutations in the gene UNC5C (9.9%), in addition to TP53 (40.7%), KDM6A (21.0%), and TSC1 (12.3%). Patients who were carriers of somatic mutations in DNA repair genes (one or more of ATM, ERCC2, FANCD2, PALB2, BRCA1, or BRCA2) had a higher overall number of somatic mutations (P = 0.011). Importantly, after a median follow-up of 40.4 months, carriers of somatic mutations (n = 25) in any of these six DNA repair genes had significantly enhanced RFS compared with noncarriers [median, 32.4 vs. 14.8 months; hazard ratio of 0.46, 95% confidence interval (CI), 0.22–0.98; P = 0.0435], after adjustment for pathologic pTN staging and independent of adjuvant chemotherapy usage.
Conclusion: Better prognostic outcomes of individuals carrying somatic mutations in DNA repair genes suggest these mutations as favorable prognostic events in muscle-invasive bladder cancer. Additional mechanistic investigation into the previously undiscovered role of UNC5C in bladder cancer is warranted. Clin Cancer Res; 20(24); 6605–17. ©2014 AACR.
Minimal Residual Disease after Conventional Treatment Significantly Impacts on Progression-Free Survival of Patients with Follicular Lymphoma: The FIL FOLL05 Trial
Authors: Galimberti Sara , Luminari Stefano , Ciabatti Elena , Grassi Susanna , Guerrini Francesca , Dondi Alessandra , Marcheselli Luigi , Ladetto Marco , Piccaluga Pier Paolo , Gazzola Anna , Mannu Claudia , Monitillo Luigia , Mantoan Barbara , Del Giudice Ilaria , Della Starza Irene , Cavalli Marzia , Arcaini Luca , Tucci Alessandra , Palumbo Giuseppe Alberto , Rigacci Luigi , Pulsoni Alessandro , Vitolo Umberto , Boccomini Carola , Vallisa Daniele , Bertoldero Giovanni , Gaidano Gianluca , Musto Pellegrino , Petrini Mario , Federico Massimo 
Published: October 2014

Abstract
Purpose: The role of the minimal residual disease (MRD) in follicular lymphoma is still debated. In this study, we assessed whether the BCL2/IGH rearrangement could have a prognostic role in patients receiving R-CHOP, R-FM, or R-CVP.
Experimental Design: DNAs from 415 patients among the 504 cases enrolled in the FOLL05 trial (NCT00774826) were centralized and assessed for the BCL2/IGH at diagnosis, at the end of treatment, and after 12 and 24 months.
Results: At diagnosis, the molecular marker was detected in 53% of cases. Patients without molecular marker or with a low molecular tumor burden (&lt;1 × 10−4 copies) showed higher complete remission (CR) rate and longer progression-free survival (PFS; 3-year PFS 80% vs. 59%; P = 0.015). PFS was significantly conditioned by the PCR status at 12 and 24 months, with 3-year PFS of 66% for MRD− cases versus 41% for those MRD+ at 12 months (P = 0.015), and 84% versus 50% at 24 months (P = 0.014). The MRD negativity at 12 and 24 months resulted in an improved PFS both in CR and in partial remission (PR) patients (3-year PFS = 72% for cases CR/PCR− vs. 32% for those CR/PCR+ vs. 62% for those PR/PCR− and 25% for patients in PR/PCR+; P = 0.001). The prognostic value of MRD at 12 and 24 months of follow-up was confirmed also in multivariate analysis.
Conclusions: In this study, standardized molecular techniques have been adopted and applied on bone marrow samples from a large cohort. Data reported show that the MRD detection is a powerful independent predictor of PFS in patients with follicular lymphoma receiving conventional chemoimmunotherapy. Clin Cancer Res; 20(24); 6398–405. ©2014 AACR.
The Human Agonistic CD40 Antibody ADC-1013 Eradicates Bladder Tumors and Generates T-cell–Dependent Tumor Immunity
Authors: Mangsbo Sara M. , Broos Sissela , Fletcher Erika , Veitonmäki Niina , Furebring Christina , Dahlén Eva , Norlén Per , Lindstedt Malin , Tötterman Thomas H. , Ellmark Peter 
Published: October 2014

Abstract
Purpose: Local administration of immune-activating antibodies may increase the efficacy and reduce the immune-related adverse events associated with systemic immunotherapy of cancer. Here, we report the development and affinity maturation of a fully human agonistic CD40 antibody (IgG1), ADC-1013.
Experimental Design: We have used molecular engineering to generate an agonistic antibody with high affinity for CD40. The functional activity of ADC-1013 was investigated in human and murine in vitro models. The in vivo effect was investigated in two separate bladder cancer models, both using human xenograft tumors in immune deficient NSG mice and using a syngeneic bladder cancer model in a novel human CD40 transgenic mouse.
Results: Activation of dendritic cells (DC) by ADC-1013 results in upregulation of the costimulatory molecules CD80 and CD86, and secretion of IL12. ADC-1013 also activates DCs from human CD40 transgenic mice, and peptide-pulsed and ADC-1013–stimulated DCs induce antigen-specific T-cell proliferation in vitro. In vivo, treatment with ADC-1013 in a syngeneic bladder cancer model, negative for hCD40, induces significant antitumor effects and long-term tumor-specific immunity. Furthermore, ADC-1013 demonstrates significant antitumor effects in a human bladder cancer transplanted into immunodeficient NSG mice.
Conclusions: Our data demonstrate that ADC-1013 induces long-lasting antitumor responses and immunologic memory mediated by CD40 stimulation. To the best of our knowledge, ADC-1013 represents the first immunomodulatory antibody developed for local immunotherapy of cancer. Clin Cancer Res; 21(5); 1115–26. ©2014 AACR.
See related commentary by Dronca and Dong, p. 944
The Novel Organic Arsenical Darinaparsin Induces MAPK-Mediated and SHP1-Dependent Cell Death in T-cell Lymphoma and Hodgkin Lymphoma Cells and Human Xenograft Models
Authors: Ravi Dashnamoorthy , Bhalla Savita , Gartenhaus Ronald B. , Crombie Jennifer , Kandela Irawati , Sharma Jaya , Mazar Andrew , Evens Andrew M. 
Published: October 2014

Abstract
Purpose: Darinaparsin (Zio-101) is a novel organic arsenical compound with encouraging clinical activity in relapsed/refractory T-cell lymphoma (TCL) and Hodgkin lymphoma (HL); however, little is known about its mechanism of action.
Experimental Design: TCL cell lines (Jurkat, Hut78, and HH) and HL cell lines (L428, L540, and L1236) were examined for in vitro cell death by MTT assay and Annexin V–based flow cytometry. Jurkat and L540-derived xenografts in SCID mice were examined for in vivo tumor inhibition and survival. Biologic effects of darinaparsin on the MAPK pathway were investigated using pharmacologic inhibitors, RNAi and transient transfection for overexpression for SHP1 and MEK.
Results: Darinaparsin treatment resulted in time- and dose-dependent cytotoxicity and apoptosis in all TCL and HL cell lines. In addition, darinaparsin had more rapid, higher, and sustained intracellular arsenic levels compared with arsenic trioxide via mass spectrometry. In vivo experiments with Jurkat (TCL) and L540 (HL)-derived lymphoma xenografts showed significant inhibition of tumor growth and improved survival in darinaparsin-treated SCID mice. Biologically, darinaparsin caused phosphorylation of ERK (and relevant downstream substrates) primarily by decreasing the inhibitory SHP1 phosphatase and coimmunoprecipitation showed significant ERK/SHP1 interaction. Furthermore, ERK shRNA knockdown or constitutive overexpression of SHP1 resulted in increased apoptosis, whereas cotreatment with pharmacologic MEK inhibitors resulted in synergistic cell death. Conversely, SHP1 blockade (via pharmacologic inhibition or RNAi) and MEK constitutive activation decreased darinaparsin-related cell death.
Conclusions: Altogether, these data show that darinaparsin is highly active in HL and TCL and its activity is dependent primarily on MAPK mechanisms. Clin Cancer Res; 20(23); 6023–33. ©2014 AACR.