bluuebunny/crossref_metadata_2025_split huggingface dataset:
Does drinking water influence hospital-admitted sialolithiasis on an epidemiological level in Denmark?
Authors: Schrøder Stine , Homøe Preben , Wagner Niels , Vataire Anne-Lise , Lundager Madsen Hans Erik , Bardow Allan 
Published: May 2015

ObjectivesSialolithiasis, or salivary stones, is not a rare disease of the major salivary glands. However, the aetiology and incidence remain largely unknown. Since sialoliths are comprised mainly of calcium phosphate salts, we hypothesise that drinking water calcium levels and other elements in drinking water could play a role in sialolithiasis. Owing to substantial intermunicipality differences in drinking water composition, Denmark constitutes a unique environment for testing such relations.DesignAn epidemiological study based on patient data extracted from the National Patient Registry and drinking water data from the Geological Survey of Denmark and Greenland retrieved as weighted data on all major drinking water constituents for each of the 3364 waterworks in Denmark.All patient cases with International Statistical Classification of Diseases 10th Revision (ICD-10) codes for sialolithiasis registered between the years 2000 and 2010 were included in the study (n=3014) and related to the drinking water composition on a municipality level (n=98).Primary and secondary outcome measuresMultiple regression analysis using iterative search and testing among all demographic and drinking water variables with sialolithiasis incidence as the outcome in search of possible relations among the variables tested.ResultsThe nationwide incidence of hospital-admitted sialolithiasis was 5.5 cases per 100 000 citizens per year in Denmark. Strong relations were found between the incidence of sialolithiasis and the drinking water concentration of calcium, magnesium and hydrogen carbonate, however, in separate models (p<0.001). Analyses also confirmed correlations between drinking water calcium and magnesium and their concentration in saliva whereas this was not the case for hydrogen carbonate.ConclusionsDifferences in drinking water calcium and magnesium may play a role in the incidence of sialolithiasis. These findings are of interest because many countries have started large-scale desalination programmes of drinking water.
A retrospective cohort study to investigate fatigue, psychological or cognitive impairment after TIA: protocol paper
Authors: Moran Grace M , Calvert Melanie , Feltham Max G , Ryan Ronan , Marshall Tom 
Published: May 2015

IntroductionTransient ischaemic attack (TIA) is defined by short-lasting, stroke-like symptoms, and is recognised as a medical emergency. Symptoms are assumed to completely resolve, and treatment is focused on secondary stroke/TIA prevention. However, evidence suggests that patients with TIA may experience ongoing residual impairments, which they do not receive therapy for as standard practice. TIA-induced sequelae could impact on patients’ quality of life and ability to return to work or social activities. We aim to investigate whether TIA is associated with subsequent consultation for fatigue, psychological or cognitive impairment in primary care.Methods and analysisA retrospective open cohort study of patients with first-ever TIA and matched controls. Relevant data will be extracted from The Health Improvement Network (THIN) database, an anonymised primary care database which includes data for over 12 million patients and covers approximately 6% of the UK population. Outcomes will be the first consultation for fatigue, anxiety, depression, post-traumatic stress disorder or cognitive impairment. Principal analysis will use Kaplan-Meier survivor functions to estimate time to first consultation, with log-rank tests to compare TIA and control patients. Cox proportional hazard models will predict the effect of demographic and patient characteristics on time to first consultation.Ethics and disseminationApproval was granted by a THIN Scientific Review Committee (ref: 14-008). The study's findings will be published in a peer-reviewed journal and disseminated at national and international conferences and through social media.
Molecular Pathways: Targeting the Cyclin D–CDK4/6 Axis for Cancer Treatment
Authors: VanArsdale Todd , Boshoff Chris , Arndt Kim T. , Abraham Robert T. 
Published: May 2015

Abstract
Cancer cells bypass normal controls over mitotic cell-cycle progression to achieve a deregulated state of proliferation. The retinoblastoma tumor suppressor protein (pRb) governs a key cell-cycle checkpoint that normally prevents G1-phase cells from entering S-phase in the absence of appropriate mitogenic signals. Cancer cells frequently overcome pRb-dependent growth suppression via constitutive phosphorylation and inactivation of pRb function by cyclin-dependent kinase (CDK) 4 or CDK6 partnered with D-type cyclins. Three selective CDK4/6 inhibitors, palbociclib (Ibrance; Pfizer), ribociclib (Novartis), and abemaciclib (Lilly), are in various stages of development in a variety of pRb-positive tumor types, including breast cancer, melanoma, liposarcoma, and non–small cell lung cancer. The emerging, positive clinical data obtained to date finally validate the two decades-old hypothesis that the cyclin D–CDK4/6 pathway is a rational target for cancer therapy. Clin Cancer Res; 21(13); 2905–10. ©2015 AACR.
Abstract 3522: A novel BAP1 mutation is associated with melanocytic neoplasms and thyroid and pancreatic cancers
Authors: Gallanis Gregory T. , Heller Kathleen A. , Melas Eleni-Marina , Gruber Stephen B. 
Published: May 2015

Abstract
BRCA1 associated protein-1 (BAP1) functions as a tumor suppressor gene by modulating fundamental cellular mechanisms such as cell cycle progression and cell growth. Inactivating germline mutations of BAP1 predispose to multiple cancers including uveal and cutaneous melanoma as well as malignant mesothelioma. In the present study we document a family with a novel germline mutation of BAP1 (g.1777C&gt;T) that results in expression of a truncated BAP1 protein. Family members with this mutation demonstrated a primary clinical phenotype of autosomal dominant, early-onset melanocytic neoplasms with immunohistochemistry (IHC) of these tumors demonstrating lack of BAP1 protein expression. In addition, family members harboring the BAP1 germline mutation developed other neoplastic disease such as thyroid cancer and pancreatic cancer. IHC analysis of these cancers also demonstrated loss of BAP1 protein expression. Our investigation identifies a new BAP1 mutation, further underscores the relevance of BAP1 as a clinically important tumor suppressor gene and broadens the range of cancers associated with BAP1 inactivation. Further study will be required to understand the full scope of BAP1-associated neoplastic disease.
Citation Format: Gregory T. Gallanis, Kathleen A. Heller, Eleni-Marina Melas, Stephen B. Gruber. A novel BAP1 mutation is associated with melanocytic neoplasms and thyroid and pancreatic cancers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3522. doi:10.1158/1538-7445.AM2014-3522
Abstract 3529: KIM-1 is a novel therapeutic target in renal cell carcinoma
Authors: Sabbisetti Venkata S. 
Published: May 2015

Abstract
Background. Renal cell carcinoma (RCC) is characterized by lack of early warning signs, diverse clinical manifestations, absence of a reliable diagnostic and predictive biomarker, and resistance to targeted therapy. Given the high incidence and worse prognosis, novel approaches for diagnosis, management and treatment of RCC are urgently needed. Kidney Injury Molecule-1 (KIM-1) is not expressed in normal kidney tissues but markedly up-regulated in dedifferentiated proximal tubular epithelial cells following renal injury. We demonstrated KIM-1 is expressed ubiquitoulsy by both primary and metastatic lesions of clear cell and papillary renal cell carcinoma, while barely detectable in other subtypes of RCC. The ectodomain of KIM-1 molecule cleaves by matrix metaloproteinases and sheds into surround milieu. In the present study, we investigated the role of KIM-1 in the pathogenesis of RCC. Methods. KIM-1 is stably transfected in immortalized tubular epithelial cells (LLC-PK1, gain-of-function) and KIM-1 was knockdown in RCC cell lines (loss-of-function) using lentiviral apporach and interoggated KIM-1 function in carcinogenesis. Results. Heterologous expression of KIM-1 increased cell proliferation, induced anchorage indepdent growth, increased migration and invasion potential, and increased the secreation of tumor promoting fractors, including TGF beta and IL-6 in immortalized tubular epithelial cells (PK1-KIM-1); while depletion of KIM-1 in RCC cells leads to cell cycle arrest at G1 phase and senescence. Recently, we and others have demonstrated that KIM-1 is a phosphatildyl serine receptor and the expression of KIM-1 converts a normal epithelial cell into a “semi professional phagocyte” and facilitates the removal of apoptotic and necrotic cells by recognizing phosphotidyl serine (PS) on their cell surface. Our data suggests that during this process, tumor epithelial cells undergo reprogramming and secrete and activate cytokines involved in cell survival and angiogenesis programs. Conclusions. The present study demonstrates that KIM-1-expression promotes tumorigenesis primarily by two distinct mechanisms: i) by directly conferring oncogenic properties to renal epithelial cells; ii) by resulting in production of a variety of chemokines and cytokines that support tumor progression and angiogenesis. We believe that our findings can significantly contribute to the development of novel therapeutic apporaches and in the advancement of management strategies in renal cell carcinoma and help reduce associated mortality and morbidity.
Citation Format: Venkata S. Sabbisetti. KIM-1 is a novel therapeutic target in renal cell carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3529. doi:10.1158/1538-7445.AM2014-3529
Abstract 3564: A new method for preparation of low-input, PCR-free next generation sequencing libraries
Authors: Kurihara Laurie , Banks L. , Chupreta S. , Couture C. , Kelchner V. , Laliberte J. , Sandhu S. , Spurbeck R. , Makarov V. 
Published: May 2015

Abstract
Sequence analysis of PCR-free Next Generation Sequencing (NGS) libraries demonstrates improved evenness of coverage relative to NGS libraries that have undergone PCR amplification. However, existing PCR-free methods require 1ug or more of input DNA quantity in order to obtain sufficient library yield which restricts such analysis when DNA sample quantity is insufficient. To expand the applicability of PCR-free sequencing, Swift Biosciences has developed a novel adapter attachment chemistry that is more efficient than existing methods. This new technology, Accel-NGS™, results in libraries that capture a higher complexity of each sample which enables a lower input DNA requirement. For Illumina systems, PCR-free Accel-NGS libraries can be prepared from 100ng of input DNA for direct sequencing. PCR-free Accel-NGS libraries demonstrate even coverage across a broad GC content as well as when analyzing whole genome sequence coverage. To enable library preparation from even less DNA, Accel-NGS libraries can also be prepared with a low number of PCR cycles for direct sequencing. The Accel-NGS method with PCR results in more even coverage and less PCR duplicates when compared to existing methods that use PCR. For exome hybridization capture, comparable coverage was achieved for Accel-NGS libraries from 100ng DNA input when compared to an existing method that requires 1ug of DNA input. The Accel-NGS method is fast and automatable; additional advantages when applied to clinical samples are under investigation. PCR-free Accel-NGS libraries can also be prepared for Ion Torrent systems from 5ng of input DNA with comparable sequence quality to existing methods.
Citation Format: Laurie Kurihara, L. Banks, S. Chupreta, C. Couture, V. Kelchner, J.Laliberte, S. Sandhu, R. Spurbeck, V. Makarov. A new method for preparation of low-input, PCR-free next generation sequencing libraries. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3564. doi:10.1158/1538-7445.AM2014-3564
Abstract 3662: Tumor-derived interleukin-1 promotes lymphangiogenesis and lymph node metastasis through activation of M2-type macrophages by lung cancer cells
Authors: Watari Kosuke , Shibata Tomohiro , Kawahara Akihiko , Murakami Yuichi , Nabeshima Hiroshi , Shinoda Ai , Azuma Koichi , Izumi Hiroto , Kage Masayoshi , Kuwano Michihiko , Ono Mayumi 
Published: May 2015

Abstract
Widespread metastases including lymph node have often led to the failure of cancer patient treatments. Lymph node metastasis is closely associated with lymphangiogenesis and poor prognosis in lung cancer. Identifying the molecules involved in these processes could help to advance therapeutic strategies for lung cancer patients. We have asked how cancer cells acquire malignant characteristics including lymph node metastasis and lymphangiogenesis, and also how such highly malignant tumor could be therapeutically overcome. Human malignancies are often initiated and promoted by inflammation, in close association with angiogenesis and lymphangiogenesis, while the recruitment of macrophages and neutrophils to the tumor microenvironment activates cells to support cancer progression. Interleukin (IL-1), a representative inflammatory cytokine, is often expressed in human malignancies including lung cancers with poor prognosis. In this study we examined how IL-1 promotes lymph node metastasis and lymphangiogenesis by lung cancer cell lines expressing higher IL-lα. In our present study, we observed following experimental results.
[1] Tumor growth, lymph node metastasis, lymphangiogenesis and enhanced infiltration of neutrophils and macrophage were all markedly augmented by the highly metastatic cancer cells.
[2] In the highly metastatic tumors, we observed higher expression of IL-1α, IL-1β and CXC chemokines by cancer cells, and also that of VEGF-A and VEGF-C by tumor-associated macrophages, respectively. These tumor-associated macrophages were found to be mainly of the M2 type.
[3] Treatment with an IL-1R antagonist (IL-1Ra) significantly blocked expression of CXC chemokines by cancer cells, and also expression of VEGFs by macrophages when co-cultured with cancer cells in vitro.
[4] Administration of IL-1Ra significantly suppressed tumor growth, lymph node metastasis and lymphangiogenesis, accompanying by significantly decreased infiltration of M2-type macrophage in the highly metastatic tumors.
Together, targeting IL-1/IL-1R signaling pathway and/or M2-type macrophages could be expected to provide useful therapeutic strategy against lymph node metastasis by inflammatory malignant cancer cells.
Citation Format: Kosuke Watari, Tomohiro Shibata, Akihiko Kawahara, Yuichi Murakami, Hiroshi Nabeshima, Ai Shinoda, Koichi Azuma, Hiroto Izumi, Masayoshi Kage, Michihiko Kuwano, Mayumi Ono. Tumor-derived interleukin-1 promotes lymphangiogenesis and lymph node metastasis through activation of M2-type macrophages by lung cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3662. doi:10.1158/1538-7445.AM2014-3662
Abstract 3821: A prognostic model of head and neck cancer ties TP53 mutation to 3p loss
Authors: Gross Andrew M. , Orosco Ryan K. , Shen John P. , Egloff Ann Marie , Carter Hannah , Hoffree Matan , Choueiri Michel , Coffey Charles S. , Lippman Scott M. , Hayes David Neil , Cohen Ezra E. , Grandis Jennifer R. , Nguyen Quyen T. , Ideker Trey 
Published: May 2015

Abstract
Head and neck squamous cell carcinoma (HNSCC) is frequently characterized by aggressive clinical behavior with a propensity for metastasis and recurrence. Current understanding of HNSCC pathogenesis remains limited, and there are few biomarkers that reliably predict patient outcomes such as survival or response to therapy. Here we report a comprehensive analysis of the molecular and clinical features of HNSCC that define patient survival. Building on data and infrastructure established by The Cancer Genome Atlas (TCGA), we develop an approach that integrates molecular events across multiple tiers of ‘omics data to progressively factor patients into subgroups with the greatest survival differences. We show that in HPV negative patients, the detrimental impact of TP53 mutation occurs only in combination with loss of chromosome 3p, leading to a marked decrease in median survival from &gt;5 years for TP53 mutation only to 1.7 years for both events. Conditioned on TP53/3p, patients are stratified by a hierarchy of events incorporating MUC5B mutation, mir-548k expression, and mutation and expression of Abnormal Spindle Protein (ASPM), while in the absence of the TP53/3p event RAS signaling is an important driver. We also show in HPV positive patients that HPV-mediated inactivation of TP53 acts in synergy with 3p deletion. The major findings are replicated in an independent HNSCC cohort as well as a pan-cancer TCGA cohort of over 3000 patients. Together, the identified markers enable a new multi-tiered molecular classification of HNSCC.
Citation Format: Andrew M. Gross, Ryan K. Orosco, John P. Shen, Ann Marie Egloff, Hannah Carter, Matan Hoffree, Michel Choueiri, Charles S. Coffey, Scott M. Lippman, David Neil Hayes, Ezra E. Cohen, Jennifer R. Grandis, Quyen T. Nguyen, Trey Ideker. A prognostic model of head and neck cancer ties TP53 mutation to 3p loss. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3821. doi:10.1158/1538-7445.AM2014-3821
Abstract 3840: Cetuximab-induced testicular toxicity
Authors: Levi Mattan , Popovtzer Aaron , Tzabari Moran , Stemmer Salomon M. , Shalgi Ruth , Ben-Aharon Irit 
Published: May 2015

Abstract
Background:
Cetuximab, an anti-EGFR monoclonal antibody, is the only targeted therapy approved for the treatment of head and neck squamous cell carcinoma (HNSCC) in patients with locally advanced tumors, in association with radiotherapy, and in patients with recurrent or metastatic disease, in association with cisplatin-based chemotherapy. We aimed to study the effect of cetuximab on testicular function and reserve.
Methods:
Male mice were injected intraperitoneally with cetuximab (1mg), or cisplatin (8mg/kg) or the combination of both and sacrificed either 1 week or 6 weeks later. Saline-injected mice served as controls. Testes were excised, weighed and further processed. Glutathione and apoptosis assays were performed on 6 weeks samples for determination of oxidative stress. Immunohistochemistry and confocal microscopy were used to study the effect of cetuximab, cisplatin and their combination on the testis histology as well as on the spermatogonial reserve.
Results:
Cetuximab induced mild apoptosis in the testis. Cisplatin induced enhanced apoptosis and depleted spermatogonial reserve, reflected by reduced DAZL staining (early spermatocyte marker). The combined treatment resulted in further decline in testicular weight compared with cisplatin-only treated mice at 1-month post treatment (p&lt;0.05). Cetuximab enhanced cisplatin-induced oxidative stress, and further depletion of spermatogonial reserve (p&lt;0.05).
Conclusions:
Cetuximab has a mild effect on testicular reserve. Nevertheless, the addition of cetuximab to cisplatin exacerbates cisplatin-induced testicular toxicity.
Citation Format: Mattan Levi, Aaron Popovtzer, Moran Tzabari, Salomon M. Stemmer, Ruth Shalgi, Irit Ben-Aharon. Cetuximab-induced testicular toxicity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3840. doi:10.1158/1538-7445.AM2014-3840
Abstract 3868: Six1 overexpression promotes malignant progression in models of cervical and colon cancer
Authors: Xu Hanwen , Zhang Yu , Pirisi Lucia , Pena Maria Marjorette , Creek Kim E. 
Published: May 2015

Abstract
The overexpression of Six1, a member of the Six family of homeodomain transcription factors, has been found in various human cancers, and is associated with increased tumor progression and metastasis. Previous studies in our laboratory discovered that the expression of Six1 mRNA increased during in vitro progression of human papillomavirus type 16 (HPV16) immortalized human keratinocytes (HKc/HPV16) toward a differentiation-resistant (HKc/DR) phenotype. The overexpression of Six1 induced Epithelial-Mesenchymal Transition (EMT) by the activation of p38 MAPK in HKc/DR. Although immortalized and resistant to serum and calcium-induced differentiation, HKc/DR are not tumorigenic. To further explore the role of Six1 in HPV16 immortalized cells we determined whether overexpression of Six1 in HKc/DR resulted in malignant conversion. We found that HKc/DR overexpressing Six1 (DR-Six1), but not HKc/DR controls (DR-Ctrl), formed squamous cell carcinomas in nude mice. Cancer stem cells are proposed to drive tumor initiation and progression; for this reason we analyzed cancer stem cell markers in DR-Ctrl and DR-Six1. We found that DR-Six1 had an increased CD24-/CD44+ population and increased aldehyde dehydrogenase 1 (ALDH1) expression as compared to DR-Ctrl, indicating a cancer stem cell-like phenotype in Six1 overexpressing cells. We then used the human cervical cancer cell line HeLa to further explore the enhanced tumorigenic and malignant properties associated with Six1 overexpression. We determined that overexpressing Six1 in HeLa increased their ability to form spheroids in vitro and increased tumor size in vivo. As an extension of this work, we investigated the role of Six1 on tumorigenesis and metastasis in colon cancer in vivo and in vitro by using the murine colon cancer cell line MC38. We found that Six1 promoted colon cancer tumorigenesis, progression and metastasis, and increased the population of cancer stem cell-like cells. Taken together, our studies demonstrate that Six1 overexpression increases the cancer stem cell-like cell population, and promotes malignant progression in models of cervical and colon cancer.
Supported by grant P20MD001770 from the National Institute on Minority Health and Health Disparities.
Citation Format: Hanwen Xu, Yu Zhang, Lucia Pirisi, Maria Marjorette Pena, Kim E. Creek. Six1 overexpression promotes malignant progression in models of cervical and colon cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3868. doi:10.1158/1538-7445.AM2014-3868