bluuebunny/crossref_metadata_2025_split huggingface dataset:
Radiation increases BTB permeability in a preclinical model of breast cancer brain metastasis.
Authors: Sprowls Samuel Adam , Arsiwala Tasneem A , Kielkowski Brooke N , Pizzuti Vincenzo , Siochi R. Alfredo C. , Lockman Paul R 
Published: February 2020

Abstract
Background Brain metastasis is a devastating stage of cancer progression, occurring in ~30% of metastatic breast cancer patients. Two-year survival rates for these patients is low, and most typically survive less than one year. Treatments for these women are limited by the blood-brain barrier, but include cytotoxic chemotherapy, surgical resection, and radiation therapy (whole-brain radiotherapy or stereotactic radiosurgery). Radiotherapy is considered to be capable of inducing disruption of the blood-brain barrier and eliciting an abscopal response to extracranial tumors. Methods A combination of ionization chamber and Gafchromic film dosimetry was used to commission and determine dose outputs for our experimental design. Dose deposition in-vivo was verified by immunohistochemistry. To evaluate the effects of ionizing radiation at the normal blood-brain barrier and the blood-tumor barrier, athymic nude and FVB mice were used. Athymic nude mice were injected with MDA-MB-231Br cells. Lesions were allowed to develop for ~28 days. Mice were then irradiated at the prescribed dose. Prior to tissue collection, mice were injected with Texas red, followed by a vascular washout with physiological buffer. Fluorescence in normal and diseased brain was quantified by fluorescent microscopy. Results Using a 10mmx10mm collimator, determined to have adequate field homogeneity as determined by Gafchromic film analysis, we were able to successfully treat a single hemisphere in mice. The blood-brain-barrier remained undisrupted in athymic nude mice at doses up to 12Gy compared to untreated brain and radiation naïve controls. Immune competent FVB mice treated with radiation showed significant blood-brain barrier disruption at a dose of 12Gy only. The blood-tumor barrier showed significant disruption at 24hrs following radiation treatment (6 or 12Gy). Conclusion Our study demonstrated that radiation therapy disrupts the blood-tumor barrier, but fails to disrupt the normal blood-brain barrier in athymic nude mice. However, in FVB immune competent mice, the blood-brain barrier was disrupted at a dose of 12Gy, suggesting an abscopal-like response impacts extent of barrier leakage.
MDC1 depletion promotes Cisplatin induced cell death in Cervical cancer cells
Authors: Singh Neeru , Bhakuni Rashmi , Chhabria Dimple , Kirubakaran Sivapriya 
Published: February 2020

Abstract
Objective: Cisplatin, the most common chemotherapeutic drug for the treatment of advanced stage cervical cancers has limitations in terms of drugs resistance observed in patients partly due to functional DNA damage repair (DDR) processes in the cell. Mediator of DNA damage checkpoint1 (MDC1) is an important protein in the Ataxia telangiectasia mutated (ATM) mediated double stranded DNA break (DSB) repair pathway. In this regard, we investigated the effect of MDC1change in expression on the cisplatin sensitivity in cervical cancer cells.Results: Through modulation of MDC1 expression in the cervical cancer cell lines; Hela, SiHa and Caski, we found that all the three cell lines silenced for MDC1 exhibited higher sensitivity to cisplatin treatment with inefficiency in accumulation of p γH2AX, Ser 139 foci and increased accumulation of pChk2 Thr 68 at the damaged chromatin followed by enhanced apoptosis. Further, we observed the increased p53 Ser 15 phosphorylation in the MDC1 depleted cells. Our studies suggest that MDC1 expression could be a key determinant in cervical cancer prognosis and treatment and its depletion in combination with cisplatin has the potential to be explored for the sensitisation of chemo-resistant cervical cancer cells.
Contribution of rs2232365 Polymorphism of FOXP3 Gene in Cervical Cancer Development
Authors: Kldiashvili Ekaterina , Metreveli Tornike 
Published: February 2020

Abstract
Objective Cervical cancer is the second common malignancy in women. This is an immunogenic malignancy, and high-risk human papilloma virus (HPV) subtypes may cause its development. Persistent infection of high-risk HPV subtypes may significantly facilitate the development of cervical intraepithelial neoplasia, which has been confirmed as a major risk factor of cervical cancer. Regulatory T cells (Treg cells) are a group of mature T cells generated in the thymus following the induction of peripheral naïve T cells. They are essential for the inhibition of immune overreaction induced damage, but over-production of Treg cells may block the protective immune response to infection and tumors. FOXP3 (Forkhead box protein P3) is a key transcription factor in regulatory T cells (Tregs), and has important roles in the immunosuppressive functions in Tregs. The role of FOXP3 gene polymorphisms in cancer patients is not determined till now. Results We have investigated the association of rs2232365 (A to G) of FOXP3 gene with cervical cancer. rs2232365A/G polymorphism has been detected in cervical cancer (25 cases, 73.53% of cancer cases, p=0.03) and CIN (36 cases, 64.29% of CIN cases, p=0.02). We assume that rs2232365 polymorphism of the Foxp3 gene may contribute to the cervical cancer development.
Prognostic Value of Sarcopenia in Patients Treated by Radiochemotherapy for Locally Advanced Oesophageal Cancer
Authors: Mallet Romain , Modzelewski Romain , Lequesne Justine , Decazes Pierre , Auvray Hugues , Benyoucef Ahmed , Fiore Frederic Di , Vera Pierre , Dubray Bernard , THUREAU SEBASTIEN 
Published: February 2020

Abstract
Background Sarcopenia is defined by a loss of skeletal muscle mass with or without loss of fat mass. Sarcopenia has been associated to reduced tolerance to treatment and worse prognosis in cancer patients, including patients undergoing surgery for limited oesophageal cancer. Concomitant chemo-radiotherapy is the standard treatment for locally-advanced tumour, not accessible to surgical resection. Using automated delineation of the skeletal muscle, we have investigated the prognostic value of sarcopenia in locally advanced oesophageal cancer patients treated by curative-intent chemo-radiotherapy. Methods The clinical, nutritional, anthropometric, and functional-imaging ( 18 FDG-PET/CT) data were collected in 97 patients treated between 2006 and 2012 in our institution (RTEP3). The skeletal muscle area was automatically delineated on cross-sectional CT images acquired at the 3 rd . lumbar vertebra level and divided by the patient’s squared height (SML3/h 2 ) to obtain the Skeletal Muscle Index (SMI). The primary endpoint was overall survival probability. Results Seventy-six deaths were reported. The median survival time was 27 [95% Confidence Interval 23 – 40] months for the whole population. Univariate analyses (Cox Proportional Hazard Model) showed decreased survival probabilities in patients with reduced SMI, WHO >0, Body Mass Index ≤21, and Nutritional Risk Index ≤97.5. Multivariate analyses showed that reduced SMI (Hazard Ratio 0.948 [0.919 - 0.978] and male sex (2.977 [1.427 - 6.213] were significantly associated to decreased survival. Using Receiver Operating Characteristics curves, the Area Under the Curve (AUC) was 0.73 in males (p=0.0002], the optimal threshold being 51.5 cm 2 /m 2 . In women, the AUC was 0.65 (p=0.19). Conclusion Sarcopenia is a powerful independent prognostic factor, associated with a rise of the overall mortality in patients treated exclusively by radiochemotherapy for a locally advanced oesophageal cancer. L3 CT images are easily gathered from 18 FDG-PET/CT acquisitions
The involvement of MCTP1 in the drug-resistance of esophageal cancer cells
Authors: Kong Lingsuo , Wei Ran , Yang Wan , Chen Lanren , Qian Liting 
Published: February 2020

Abstract
Background: Accumulating studies demonstrated that drug-resistance remains a great obstacle for the effective treatment of cancers. Esophageal cancer (EC) is still one of the most common cancers worldwide, which also suffers from drug-resistance during clinical treatment. Methods: We performed the drug-resistance profiling assays and identified several drug-resistant and drug-sensitive EC cell lines. The following methylation sequencing showed that the MCTP1 gene is hypermethylated in the drug-resistant EC cells. Results: As a result, the expression of MCTP1 is down-regulated in the drug-resistant EC cells. Down-regulation of MCTP1 also affects the cell proliferation and apoptosis of EC cells, as revealed by the cell proliferation and apoptosis assays. Further investigations proposed two signaling pathways that might involve in the MCTP1-mediated drug-resistance of EC cell. Conclusions: All these results suggested that MCTP1 is associated with the drug-resistance of EC cells, which has implications for further design of new biomarker of EC treatment.
Antibiotic resistance associated with air quality and transferred by airborne particulate matter
Authors: Zhou Zhen-Chao , Liu Yang , Lin Ze-Jun , Shuai Xin-Yi , Zhu Lin , Xu Lan , Meng Ling-Xuan , Sun Yu-Jie , Chen Hong 
Published: February 2020

Abstract
Background: Environmental spread of antibiotic resistance has become a public health problem, but the relationship between air quality and antibiotic resistance has not been fully investigated, the effect and mechanism of air pollutants on horizontal genes transfer of antibiotic resistance are rarely mentioned. Results: In the present study, significant correlation ( P < 0.05) between resistance rates of 10 clinical antibiotic-resistant pathogens and number of days when air quality index was below 100 were observed in an extensive survey from 2014 to 2017 in China. In addition, characterization of antibiotic resistance genes (ARGs), mobile genetic elements (MGEs), and bacterial communities in airborne particulate matter (PM), dust, and human airway sputum samples were profiled in a hospital. PM 2.5 and PM 10 were shown to contain ARGs and MGEs high relative abundance and diversity index. Importantly, transferable multi-resistant plasmids were identified from air, e.g., pTAir-3 with 26 MGEs and 10 ARGs, using conjugative mating assays and nanopore sequencing . Furthermore, PM 2.5 and PM 10 significantly enhanced the conjugative transfer frequencies between bacteria, via inducing increased levels of reactive oxygen species and cell membrane permeability; upregulated gene expression levels were confirmed by genome-wide RNA sequencing. Conclusions: These findings provide a new perspective on antibiotic resistance research and have profound implications for antibiotic resistance control in clinics and environments.
G-protein subunit Gai in mitochondria, MrGPA1, affects conidiation, stress resistance, and virulence of entomopathogenic fungus Metarhizium robertsii﻿
Authors: Tong Youmin , Wu Hao , Liu Zhenbang , Wang Zhangxun , huang bo 
Published: February 2020

Abstract
G proteins are critical modulators or transducers in various transmembrane signaling systems. They play key roles in numerous biological processes in fungi, including vegetative growth, development of infection-related structures, asexual sporulation, and virulence. However, their function in entomopathogenic fungi remains unclear. Here, we characterized the roles of MrGPA1, a G-protein subunit Gα i , in conidiation, stress resistance, and virulence in Metarhizium robertsii . MrGPA1 was localized in the mitochondria. MrGpa1 deletion resulted in a significant reduction (47%) in the conidiation capacity, and reduced expression of several key conidiation-related genes, including fluG , flbD , brlA , wetA , phiA , and stuA . Further, MrGpa1 disruption resulted in decreased fungal sensitivity to UV irradiation and thermal stress, as determined based on conidial germination of ∆MrGpa1 and wild-type strains. Chemical stress analysis indicated that MrGpa1 contributes to fungal antioxidant capacity and cell wall integrity, but is not involved in antifungal ability and osmotic stress. Importantly, insect bioassays involving (topical inoculation and injection) of Galleria mellonella larvae revealed decreased virulence of ∆MrGpa1 strain after cuticle infection. This was accompanied by decreased rates of appressorium formation and reduced expression of several cuticle penetration-related genes. These observations suggest that MrGpa1 contributes to the regulation of conidiation, UV irradiation, thermal stress response, antioxidant capacity and cell wall integrity in M. robertsii . This gene is also involved in insect cuticle penetration during infection. These findings raise the possibility of designing powerful strategies for genetic improvement of M. robertsii conidiation capacity and virulence for killing pests.
Prognostic Accuracy of the Eighth Edition of TNM Classification Compared with the Seventh and Sixth Edition for Perihilar Cholangiocarcinoma
Authors: Hau Hans Michael , Meyer Felix , Rademacher Sebastian , Sucher Robert , Seehofer Daniel 
Published: February 2020

Abstract
Background This study was conducted to evaluate and compare the prognostic value and performance of the 6th, 7th, and 8th editions of the American Joint Committee on Cancer (AJCC) staging system when applied to patients undergoing surgery for perihilar cholangiocarcinoma (PHC). Methods Patients undergoing liver resection with curative intention for PHC between 2002 and 2019 were identified from a prospective database. Histopathological parameters and stage of the PHC were assessed according to the 6th, 7th, and 8th editions of the tumor node metastasis (TNM) classification. The prognostic accuracy between staging systems was compared using the area under the receiver operating characteristic curve (AUC) model. Results Data for a total of 95 patients undergoing liver resection for PHC were analyzed. The median overall survival time was 21 months (95% CI 8.1–33.9), and the 3- and 5-year survival rates were 46.1% and 36.2%, respectively. Staging according to the 8th edition versus the 7th edition resulted in reclassification of 25 patients (26.3%). The log-rank p-values for the 7th and 8th edition were highly statistically significant (p ≤ 0.01) compared to the 6th edition (p = 0.035). The AJCC 8th edition staging system had a slightly better discrimination ability, with an AUC of 0.69 (95% CI: 0.52–0.84) compared to 0.61 (95% CI: 0.51–0.73) for the 7th edition. Multivariate survival analysis revealed male gender, age > 65 years, positive resection margins, presence of distant metastases, poorly tumor differentiation, lymph node involvement such as no caudate lobe resection as independent predictors of poor survival (p < 0.05). Conclusion The newly released 8th edition of the AJCC staging system demonstrated a poor to moderate ability to predict prognosis of patients undergoing liver resection for perihilar cholangiocarcinoma; the result was only slightly better than the previous 7th edition. Further refinements are needed to improve the prognostic ability of the AJCC staging system for perihilar cholangiocarcinoma and to identify other prognostic factors that can potentially improve individual patient prognostication.
The role of resistin gene polymorphisms in bladder cancer
Authors: Deng Shi , He Yin sheng , zhao pan , Zhang Peng 
Published: February 2020

Abstract
Background: Published studies have demonstrated that resistin, a recently discovered adipokine, is connected to insulin resistance, type 2 diabetes mellitus, obesity, inflammation, and atherosclerotic vascular disease. A comprehensive study of the adipocytokine family and tumor pathogenesis indicates an intimate relationship between resistin and the incidence, progression, and metastasis of gastric cancer, esophageal cancer, choriocarcinoma, colorectal cancer, pancreatic cancer, and biliary tract cancer. To date, the connection between resistin and bladder cancer has not been thoroughly investigated and remains unclear. Methods: Overall, 322 patients with bladder cancer and 366 normal controls were included in the study. Two SNPs of the resistin gene, rs1862513 (also known as −420 C/G) and rs10401670 (3’UTR C/T) were genotyped across the entire cohort. Next, the association between the two SNPs and the incidence, risk factors, and prognosis of bladder cancer, were analyzed. Results: The frequency of T allele and CT/TT genotype of rs10401670 was significantly lower in bladder cancer patients (P=0.03, OR=0.79 and P = 0.018, OR = 0.68, respectively) compared to normal controls. No differences were found with regards to the rs1862513 genotype frequency and the distribution of allele frequency between the two groups. Stratified analyses showed that the CT heterozygous genotype of rs10401670 was associated with bladder cancer at an earlier age (OR=1.97, 95% CI=1.14–3.40) and the CG heterozygous genotype of rs1862513 was correlated with high incidence of bladder cancer in smokers (OR=1.73, 95 % CI=1.05–2.87). Multiple Cox regression analysis showed that for bladder cancer patients, the presence of a CG heterozygous genotype of rs1862513 was associated with a decrease in the risk of recurrence in MIBC patients (P = 0.04，OR= 0.49). Additionally, the rs1040167 CT/TT genotype (P = 0.03，OR= 2.45), especially the TT homozygous genotype (P = 0.02，OR= 3.00) was associated with high risk of death. These results indicate that the rs1040167 CT/TT and TT homozygous genotype may be a risk factor for overall survival of bladder cancer patients. Conclusions: Our results suggest that resistin genotype serves as a risk factors for the occurrence and prognosis of bladder cancer, and could be be a potential biomarker for this devastating disease.
A multicenter, descriptive epidemiologic survey of the clinical features of spinal metastatic disease in China
Authors: Zhang Hao-ran , Qiao Rui-qi , Yang Xiong-gang , Xu Ming-you , Hu Yong-cheng 
Published: February 2020

Abstract
Background: Spinal metastases have unique epidemiological features and treatment methods. Unfortunately, the relative scarcity of spinal metastases has limited the widespread development of descriptive epidemiological studies, especially in Asian countries. The purpose of this study was to describe the epidemiological characteristics of patients with metastatic spinal tumors in China between 2007 and 2019.Methods: From January 2007 and July 2019, data on patients with spinal metastases were collected from five cancer centers in China, and demographic characteristics, primary tumor types, segments and numbers of vertebral lesions, disease-related scores, and treatment methods were reviewed.Results: A total of 2228 patients with spinal metastases were reviewed in this study, including 1279 male patients and 949 female patients, and the male to female ratio was 1.35: 1. More than half of patients developed metastatic diseases between the ages of 50 years and 69 years (64%). Overall, lung cancer (824 cases, 37%) was the most common primary tumor type and the most common level of spinal involvement was multi-level of metastases (860 cases, 39%). 705 patients (32%) had undergone surgical treatments, 1028 patients (46%) had undergone radiotherapy for metastatic vertebrae, and 855 patients (38%) had received systemic treatments. The age, primary tumor type, number of involved vertebrae, Frankel grade, and spinal instability neoplastic score would affect the surgical decision-making.Conclusions: This study provides insight into the epidemiological characteristics of spinal metastasis and health care service utilization in spinal metastasis patients in China.
Frequency of CDK2 , CCNE1&nbsp;Copy Number Variation in Acral Melanoma and Implications for CDK Inhibitor&nbsp;in&nbsp;Targeted Therapy
Authors: Wu Xiaowen , Yan Junya , Yu Jiayi , Yu Jinyu , Cheng Zhiyuan , Yin Ting , Guo Qian , Xie Yihong , Kong Yan , Guo Jun 
Published: February 2020

Abstract
Background: Acral melanoma have a high frequency of cell cycle-related gene copy number variation. However, the status and clinical significance of CNVs of CDK 2 and CCNE1 have not been fully elucidated. Methods: A total of 490 acral melanoma samples were examined for CNVs of CDK 2 and CCNE1 using QuantiGenePlex DNA Assay. Correlations of CDK2 and CCNE1 CNVs to clinicopathologic features and prognosis of acral melanoma were evaluated.The sensitivity of cell lines and cell-derived xenograft (CDX) containing CCNE1 CNVs to CDK inhibitor AT7519,Dinaciclib and proteasome inhibitor Bortezomib were also analyzed. Results: Among the 490 samples,140 cases, 139 cases and 39 cases respectively showed CDK2 gain (28.5%), CCNE1 gain (28.3%) and CDK2 gain plus CCNE1 gain (8.0%).The median progression-free survival (PFS) time for acral patients with CCNE1 gain was significantly shorter than that for patients without CCNE1 gain (17.0 versus 27.0 months; P =0.002). Furthermore, CCNE1 gain was an independent prognostic factor for patients receiving chemotherapy. The pan-CDK inhibitor AT7519 could inhibit the cell proliferation, induce apoptosis and cause cell cycle arrest in G2 phase of acral melanoma cells and inhibit the tumor growth of CDX with CCNE1 gain. Dinaciclib and Bortezomib showed CCNE1 copy number independent inhibitory effects on the proliferation of melanoma cells. Conclusions: CDK2 and CCNE1 copy number variations were frequent in acral melanoma and CCNE1 gain may be a useful biomarker to predict the outcome of receiving chemotherapy in patients with acral melanoma. In addition, our study provides a basis for the use of CDK inhibitor in the treatment of acral melanoma. Keywords: acral melanoma, targeted therapy, CDK2 , CCNE1 , copy number variation
Identification of potential biomarkers for CAD using integration with expression and methylation data and validation by case-control study
Authors: Zhang Xiaokang , Xiang Yang , He Dingdong , Liang Bin , Wang Chen , Luo Jing , Zheng Fang 
Published: February 2020

Abstract
Background: DNA methylation plays an essential role in the pathogenesis of coronary artery disease (CAD) through regulating mRNA expressions. This study aimed to identify hub genes as biomarkers functioning in CAD and regulated by DNA methylation. Methods: Gene expression and methylation datasets of peripheral blood leukocytes (PBLs) of CAD were downloaded from Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) and differentially methylated genes (DMGs) were identified based on differentially methylated CpG sites (DMCs) in intragenic regions. The overlapped genes in DEGs and DMGs were filtered and defined as differentially expressed-methylated genes (DEMGs). Multiple computational approaches were performed to analyze the regulatory networks of DEMGs and recognize hub genes, subsequently. Finally, top hub genes were verified in a case-control study based on their differential expression levels between CAD cases and controls. Results: Totally 535 DEMGs were identified and partitioned into 4 subgroups. TSS200 and 5’UTR were confirmed as high enrichment areas of DMCs. DEMGs mainly enriched in processes of histone H3-K27 methylation, regulation of posttranscription and DNA-directed RNA polymerase activity. Pathway enrichment showed DEMGs participated in VEGF signaling pathway, adipocytokine signaling pathway and PI3K-Akt signaling pathway. Besides, hub genes FN1 (fibronectin 1), PTEN (phosphatase and tensin homolog), POLR3A (RNA polymerase III subunit A) were experimentally proved discordantly expressed in CAD patients when compared with controls. Conclusions: In conclusion, our study demonstrated the probable functional genes of PBLs in CAD, in which FN1, PTEN and POLR3A were confirmed. The underlying mechanism that differential expression-methylation of FN1, PTEN and POLR3A in CAD need further study.