bluuebunny/crossref_metadata_2025 huggingface dataset:
Enhanced specificity of high sensitivity somatic variant profiling in cell-free DNA via paired normal sequencing: design, validation, and clinical experience of the MSK-ACCESS liquid biopsy assay
Authors: Brannon Angela Rose , Jayakumaran Gowtham , Diosdado Monica , Patel Juber , Razumova Anna , Hu Yu , Meng Fanli , Haque Mohammad , Sadowska Justyna , Murphy Brian , Baldi Tessara , Johnson Ian , Ptashkin Ryan , Hasan Maysun , Sriniva Preethi , Rema Anoop Balakrishnan , Rijo Ivelise , Agarunov Aaron , Won Helen , Perera Dilmi , Brown David , Samoila Aliaksandra , Jing Xiaohong , Gedvilaite Erika , Yang Julie , Stephens Dennis , Dix Jenna-Marie , DeGroat Nicole , Nafa Khedoudja , Syed Aijazuddin , Li Alan , Lebow Emily , Bowman Anita , Ferguson Donna , Liu Ying , Mata Douglas , Sharma Rohit , Yang Soo-Ryum , Bale Tejus , Benhamida Jamal , Chang Jason , Dogan Snjezana , Hameed Meera , Hechtman Jaclyn , Moung Christine , Ross Dara , Vakiani Efsevia , Vanderbilt Chad , Yao JinJuan , Razavi Pedram , Smyth Lillian , Chandarlapaty Sarat , Iyer Gopa , Abida Wassim , Harding James , Krantz Benjamin , O'Reilly Eileen , Yu Helena , Li Bob , Rudin Charles , Diaz Luis , Solit David , Arcila Maria , Ladanyi Marc , Houck-Loomis Brian , Tsui Dana , Berger Michael , Zehir Ahmet , Benayed Ryma
Published: December 2020

Circulating cell-free DNA (cfDNA) from blood plasma of cancer patients can be used to interrogate somatic tumor alterations non-invasively or when adequate tissue is unavailable. We have developed and clinically implemented MSK-ACCESS (Analysis of Circulating cfDNA to Evaluate Somatic Status), an NGS assay for detection of very low frequency somatic alterations in select exons and introns of 129 genes. Analytical validation demonstrated 92% sensitivity in de-novo mutation calling down to 0.5% allele frequency and 99% for a priori mutation profiling. To evaluate the performance and utility of MSK-ACCESS, we report results from the first 681 prospective blood samples (617 patients) that underwent clinical analysis to guide patient management. Somatic mutations, copy number, and/or structural variants were detected in 73% of the samples, and 56% of these circulating-tumor DNA (ctDNA) positive samples had clinically actionable alterations. The utilization of matched white blood cell sequencing allowed retention of somatic alterations while filtering out over 10,000 germline and clonal hematopoiesis variants, thereby greatly enhancing the specificity of the assay. Taken together, our experience illustrates the importance of analyzing a matched normal sample when interpreting cfDNA results and highlights the potential of cfDNA profiling to guide treatment selection, monitor treatment response, and identify mechanisms of treatment resistance.
Effectiveness of Joint 3+1 Malaria Strategy Along China-Myanmar Cross Border Areas
Authors: Lin Zu-rui , Li Shi-gang , Sun Xiao-dong , Guo Xiang-rui , Zheng Zhi , Yang Jie , Pian Hong-ru , Tian Peng , Chen Qi-yan , Sun Xiao-ying , Ding Chun-li , Duan Kai-xia , Chen Hong-wei , Bee Dakhidam Yaw , Zhou Hong-ning
Published: December 2020

Background: Cross-border malaria in Laiza City of Myanmar seriously affected Yingjiang County of China and compromised the national malaria elimination goal. A pilot project on 3+1 strategy of joint cross-border malaria prevention and control was carried out in building border malaria buffer area in the both sides since 2017; Here, 3 was the three preventive lines in Yingjiang County to strengthen targeted measures of elimination malaria in China and +1 was a defined border area in Laiza City to adopt the integrated measures of malaria control in Myanmar.Methods: A retrospective analysis from 2015 to 2019 was conducted that included case detection, parasite prevalence and vector surveillance. Descriptive statistics was used and the incidence or rates were compared. The annual parasite incidence in +1 area of Myanmar, the annual importation rate in Yingjiang County of China and the density of An.Minimus were statistically significant indictors to assess the effect of the joint interventions.Results: In +1 area of Myanmar from 2015 to 2019, the average of annual parasite incidence was (59.11±40.73) / 1000 and plasmodium vivax accounted for 96.27 % of total confirmed cases. After the pilot project, the annual parasite incidence, microscopic parasite prevalence rate and density of An. Minimus reduced by 89%,100% and 93.93% respectively, but the submicroscopic parasite prevalence rate was no significant difference between the two surveys (p =0.084). In Yingjiang County of China, neither indigenous nor introduced case was reported and 100% cases were imported from Myanmar since 2017. The average of annual importation rate from 2015 to 2019 was (0.47±0.15)/1000. After the pilot project, it reduced by 53% of whole county, 67% of the first preventive line, 52% of the second preventive line and 36% of the third preventive line respectively. The density of An. Minimus in the first preventive line reduced by 94.51% and did not have significant difference between that of+1 area of Myanmar (Z value=-1.18，p value=0.24). Conclusion: The pilot project on 3+1 strategy has made remarkable effectiveness and a buffer area of border malaria was successfully established between Laiza City of Myanmar and Yingjiang County of China. The combined use and expanded coverage of indoor residual spraying and long-lasting insecticidal nets (LLINs) was more effective than only use of LLINs in reducing the transmission of plasmodium vivax caused by An. Minimus. It is necessary to adopt submicroscopic infection interventions to eliminate potential sources of infection in Laiza City of Myanmar.
The effectiveness of E-learning in continuing medical education for Tuberculosis health workers: a quasi-experiment from China
Authors: Wang Ziyue , Zhang Lijie , Liu Yuhong , Jiang Weixi , Tang Shenglan , Liu Xiaoyun
Published: December 2020

ObjectiveTo evaluate the effectiveness of E-learning in continuing medical education (CME) programs for Tuberculosis (TB) health workers in terms of knowledge improvement and behaviour change, and provide policy recommendations based on the evidence from programs implemented in China.MethodsTB health professionals survey and in-depth interviews were conducted at provincial, prefectural, county, and primary care levels in the three project provinces. Difference-in-difference (DID) and multivariate linear regression models was employed to capture the effectiveness of knowledge improvement. Behaviour change was analysed using both qualitative and quantitative data.ResultsFor clinicians, pre-post data showed no significant difference in knowledge increases between pilot and non-pilot areas (pilot areas: +17 points vs. non-pilot areas: +18 points, p = 0.066). However, clinicians who attended the synchronous E-learning had an average score 7.3 points higher (p = 0.026) and an average knowledge score increase of 0.3 points (p = 0.028) for each event attended. Asynchronous E-learning did not have a significant impact among clinical doctors. For public health physicians, E-learning intervention had no significant effect on their knowledge score (DID model: pilot: +4 points vs. non-pilot: +9 points, p= 0.389, multivariate linear regression model: p = 0.161). For primary care workers, pre-post data showed a significantly higher score increase in the pilot areas (+10 points) than the non-pilot areas (+4 points, p = 0.005). Primary care workers who attended the E-learning activities had an average score 10.9 points higher (p<0.001) and an average increase of 1.8 points per training module attended (p = 0.002). More than half of participants (56.0% - 57.3%) agreed that they could apply what they learned to their practice, especially among well-educated health personnel from provincial level institutions. Traditional face-to-face training has no significant impact on all types of medical staff.ConclusionsE-learning interventions for TB clinical and primary care health workers were associated with higher TB knowledge level, and some participants have already started applying what they learned in their practice. However, public health physicians didn’t get much benefits from E-learning activities, probably due to the mismatch of training supply of & demand for training and environmental factors.
Urinary tract infections in culled sows from Greek herds: prevalence and associations between findings of histopathology, bacteriology and urinalysis
Authors: Cernat Mihaela , Skampardonis Vasilis , Papadopoulos Georgios A. , Kroustallas Fotios , Chalvatzi Sofia , Petridou Euanthia , Psychas Vassilios , Marouda Christina , Fortomaris Paschalis , Leontides Leonidas
Published: December 2020

Background
Urinary tract infections (UTI) of sows which include cystitis, which may progress to ureteritis and pyelonephritis affect their productivity, longevity and welfare. In this study we determined the prevalence of UTI by histopathology and bacteriology and investigated possible associations between histologically confirmed cystitis and the results of urinalysis and urine cultures in culled sows from three Greek farrow-to-finish herds.
Materials and methods
Routinely culled sows were included in the study. Their urinary bladders were collected from abattoirs and examined histopathologically. Furthermore, urinalysis and urine cultures were performed on urine samples aseptically collected from the bladders.
Results
Histologically confirmed cystitis was evident in 85/185 (45.94%) culled sows. Among those, 44 (51.76%) suffered from acute and 41 (48.24%) from chronic inflammation. The majority of the positive urine cultures were due to colonization of the urinary tract with E.coli, which was responsible for 55.81% of the total cases, followed by Staphylococcus spp. which caused 18.60% of the infections detected. Evidence of cystitis was associated with bacteriuria and sows with bacteriuria were 2.30 (p = 0.03, 95% CI: 1.10–4.83) times more likely to have histologically confirmed cystitis compared to sows with negative urine cultures. Bacteriuria was associated with proteinuria (p < 0.01), urine pH (p < 0.01) and presence of sediment (p < 0.01) in urine. Sows with proteinuria had 9.72 (2.63–35.88) times higher odds of bacteriuria than those without. Histologically defined cystitis was associated with proteinuria (p < 0.01) and increased urine pH (p < 0.01). Sows with proteinuria were 5.18 times (2.03–13.2) more likely to have histological lesions consistent with cystitis, than those without.
Conclusions
In the studied herds, UTI affected almost one out of two culled sows. Bacteriuria, which was more common among sows with UTI than those without, was mainly ascribed to members of the intestinal and environmental microbiota. Proteinuria and the existence of urine sediment which were associated with UTI may be proposed as likely on-farm predictors of UTI in live sows.
Evaluation of Methotrexate Toxicity and its Relationship with ABCB1 Genetic Polymorphism in Pediatric with Acute Lymphoblastic Leukemia
Authors: Moradveisi Borhan , Mohammadi Ebrahim , Ghaderi Ebrahim , Zamani Fatemeh , Zakaryaei Farima
Published: December 2020

Background: Acute lymphoblastic leukemia(ALL) is the most common type of hematologic malignancy in children. Based on COG protocol, one of the treatments for these children is methotrexate. Methotrexate has many complications in Pediatrics. Nowadays, the relationship between gene mutations and complications of each drug are discussed. This study aimed to evaluate the pharmacogenetics of methotrexate with emphasis on ABCB1 gene and its implications for the treatment of ALL children in Kurdistan province.Methods: Blood samples were obtained from children with ALL, and then DNA extraction and polymerase chain reaction (PCR) were performed with approximately 300μMol / μL of each direct primer in the final volume of 50µL. The PCR method was used to amplify the ABCB1 gene and the reaction products were identified by 0.5% agarose gel electrophoresis. The length of the PCR fragments was confirmed by observation by UV-Trans-illuminator. Moreover, blood and liver toxicity in all patients treated with methotrexate were measured by measuring leukocyte counts, platelets, neutrophil percentages, hemoglobin, alanine transaminase activity, and aspartate trans Aminase was evaluated.Results: 81 children with ALL, 45 males (55.5%) and 36 females with a mean age of 6.32 + 3.08 (y/o) were evaluated in this study. ABCB1 3435 C->T gene mutation frequency was 70.4% and the frequency of ABCB1 1199 G->A gene mutation was 4.9%.Frequency of gastrointestinal toxicity, leukopenia, anemia, thrombocytopenia, hepatotoxicity, neutropenia and renal toxicity were higher in patients with heterozygous and homozygous ABCB1 3435 C->T mutant polymorphisms than in patients with normal polymorphism, but the frequency of toxicity in patients with heterozygous and homozygous ABCB1 1199 G->A mutant polymorphisms were lower than patients with normal homozygous polymorphism, but these difference were not statistically significant.Conclusion: According to the results of our study, it can be concluded that methotrexate drug toxicity was higher in patients with ABCB1 3435 C->T gene mutation, but there was no significant correlation because of the low sample size. Furthermore it can be concluded that ABCB1 1199 G->A gene mutation may have a protective effect against the side effects of methotrexate, therefore it is recommended this hypothesis be tested in future studies.
Cancer-Associated Mutations Reveal a Novel Role for EpCAM as an Inhibitor of Cathepsin-L and Tumor Cell Invasion
Authors: Sankpal Narendra , Brown Taylor C. , Fleming Timothy P. , Herndon John M. , Amaravati Anusha A. , Loynd Allison N , Gillanders William E.
Published: December 2020

BackgroundEpithelial cell adhesion molecule (EpCAM) is a 40-kD type-I transmembrane protein that is frequently overexpressed in human epithelial cancers. Recent evidence implicates EpCAM in the regulation of oncogenic signaling pathways and epithelial-mesenchymal transition. Of note, multiple proteins with thyroglobulin-type-1 (TY-1) domains are known to inhibit cathepsin-L (CTSL), a cysteine protease that promotes tumor invasion and metastasis.MethodsHuman cancer sequencing studies reveal that somatic EpCAM mutations are present in up to 5.1% of tested tumors form public database search. To determine how EpCAM mutations affect cancer biology we studied C66Y, a damaging TY-1 domain mutation identified in liver cancer, as well as 13 other cancer-associated EpCAM mutations. Using in-vitro and in-vivo models, immunoprecipitations and localizations we demonstrate EpCAM inhibits CTSL activity based mutations and thereby its localization.ResultsWe demonstrate that wild type (WT) EpCAM, but not C66Y EpCAM, inhibits CTSL activity in vitro, and the TY-1 domain of EpCAM is responsible for this inhibition. WT EpCAM, but not C66Y EpCAM, inhibits tumor cell invasion in vitro and lung metastasis in vivo. In an extended panel of human cancer cell lines, EpCAM expression is inversely correlated with CTSL activity. Previous studies have demonstrated that EpCAM germline mutations can prevent EpCAM from being expressed at the cell surface. We demonstrate that C66Y and multiple other EpCAM cancer-associated mutations prevent surface expression of EpCAM. Cancer-associated mutations that prevent EpCAM cell surface expression abrogate the ability of EpCAM to inhibit CTSL activity and tumor cell invasion. ConclusionsThese studies reveal a novel role for EpCAM as a CTSL inhibitor, confirm the functional relevance of multiple cancer-associated EpCAM mutations, and suggest a therapeutic vulnerability in cancers harboring EpCAM mutations.
Opposite Effects of the Triple Target (DNA-PK/PI3K/mTOR) Inhibitor PI-103 on the Radiation Sensitivity of Glioblastoma Cell Lines MO59K and MO59J Differing in DNA-PK and ATM Status
Authors: Djuzenova Cholpon S. , Fischer Thomas , Katzer Astrid , Sisario Dmitri , Korsa Tessa , Steussloff Gudrun , Sukhorukov Vladimir L. , Flentje Michael
Published: December 2020

Background: Radiotherapy is routinely used to combat glioblastoma multiforme (GBM). However, the treatment efficacy is often limited by the radioresistance of GBM cells.Methods: Two isogenic GBM lines MO59K and MO59J, differing in intrinsic radiosensitivity and mutational status of DNA-PK and ATM, were analyzed regarding their response to DNA-PK/PI3K/mTOR inhibition by PI-103 in combination with radiation. To this end we assessed colony-forming ability, induction and repair of DNA damage by γH2AX, expression of marker proteins, including those belonging to NHEJ and HR repair pathways, degree of apoptosis, autophagy, and cell cycle alterations.Results: We found that PI-103 radiosensitized MO59K cells but, surprisingly, it induced radiation resistance in MO59J cells. In MO59K cells, combined PI-103 and radiation treatment induced much higher γH2AX expression measured by Western blot as compared to MO59J. Another cell line-specific difference includes diminished expression of p53 in MO59J cells, which was further reduced by PI-103. Additionally, PI-103-treated MO59K cells exhibited an increased expression of the apoptosis marker cleaved PARP. In contrast, PI-103-treated MO59J cells showed an increased level of LC3BII, indicative of cytoprotective autophagy. Moreover, irradiation induced a strong G2 arrest in MO59J cells (~80% vs. ~50% in MO59K), which was, however, partially abolished by PI-103 thus allowing cell-cycle progression of a fraction of cells. In contrast, treatment with PI-103 increased the G2 fraction in irradiated MO59K cells.Conclusions: The triple-target inhibitor PI-103 exerted radiosensitization on MO59K cells, but, unexpectedly, caused radioresistance in the MO59J line, lacking DNA-PK. The difference is most likely due to low expression of the DNA-PK substrate p53 in MO59J cells, which was further reduced by PI-103. This led to less apoptosis as compared to drug-free MO59J cells and enhanced survival via partially abolished cell-cycle arrest. The findings suggest that the lack of DNA-PK-dependent NHEJ in MO59J line might be compensated by DNA-PK independent DSB repair via a yet unknown mechanism. Future research on an extended cell panel should focus on finding ways to enhance the radiosensitivity of cell lines with deficiencies in DNA-PK and ATM, the key proteins involved in the DNA damage response.
Reduction of Initial Dose of Enzalutamide does not Decrease the Incidence and Severity of Adverse Events in Castration-Resistant Prostate Cancer
Authors: Tsuzuki Shunsuke , Nakanishi Shotaro , Tamaki Mitsuyoshi , Oshiro Takuma , Miki Jun , Yamada Hiroki , Shimomura Tatsuya , Kimura Takahiro , Furuta Nozomu , Saito Seiichi , Egawa Shin
Published: December 2020

Background: There was no clear evidence whether the initial dose of enzalutamide affects the incidence of adverse events (AEs), and oncological outcome in patients with castration-resistant prostate cancer (CRPC). Methods: The clinical chart of 233 CRPC patients treated with enzalutamide was reviewed retrospectively. After 1:3 propensity score matching (PSM), 124 patients were classified to whom introduced with full dose of enzalutamide or whom with reduced dose and the oncological outcomes were compared. To investigate the independent predictive factors with progression-free survival (PFS) and overall survival (OS), univariate and multivariate Cox regression analyses were performed.Results: Of total, 190 CRPC patients initiated with full dose enzalutamide were younger and better performance status compared with 43 patients beginning with reduced dose. After PSM, the baseline characteristics were not different between full and reduced dose group. The incidence rate of patients with prostate specific antigen (PSA) decline of >90% in reduced dose group was significantly lower than that in full dose group (34.8% vs46.2%) (p-value 0.03). The incidence rates of AEs were not statistically different between reduced dose group (22.6%) and full dose group (34.4%) (p-value 0.24). On multivariate analyses, initial enzalutamide dose was not a predictive factor of PFS and OS. Conclusion: Initiating with reduced dose of enzalutamide did not significantly decrease the incidence rate of AEs, and it showed less PSA response rate. There is no clear rationale of treating with initial reduction of enzalutamide resulted in overcome incidence of AEs.
Patient-Reported Recovery in Upper Abdominal Cancer Surgery Care: A Prospective Study
Authors: Johansson Anna , Karlsson Jessica , Fomichov Victoria , Björnsson Bergthor , Larsson Anna Lindhoff , Sandström Per , Drott Jenny
Published: December 2020

Background To describe and analyse patient-reported recovery in patients after upper abdominal cancer surgery.Methods This study had a quantitative and prospective design. Patients eligible for upper abdominal cancer surgery were consecutively included in a university hospital in southern Sweden. Twenty-four patients answered the Postoperative Recovery Profile (PRP) questionnaire at 3 measurement points. The PRP includes 5 dimensions of recovery: physical symptoms, physical function, psychological function, social function, and activity.Results The results were based on 72 answered questionnaires. All 5 dimensions were affected. Symptoms were rated preoperatively, and >60% of patients were not fully recovered upon discharge according to the PRP. In the physical symptoms dimension, the majority of patients reported a lack of energy upon discharge. High levels of anxiety were reported. Over 50% of patients reported some degree of depressed mood at all three measurement points. In the social dimension, the majority of patients reported some degree of inconvenience with respect to being dependent on help from others and restrictions in everyday life at four weeks after discharge.Conclusion Patients undergoing surgery for upper abdominal cancer are affected by psychological, physiological, social, and habitual factors, and according to the PRP, most estimates of these symptoms increase significantly after the surgery. Few patients are fully recovered at four weeks after discharge, and the majority of patients experience symptoms preoperatively. Individual patient-reported recovery estimates based on preoperative status and follow-up data may be valuable in identifying and planning interventions tailored to each patient's needs throughout the care process.
Efficacy and Acquired Resistance of EGFR-TKI Combined with Chemotherapy as First-Line Treatment for Chinese Patients with Advanced Non-Small Cell Lung Cancer in a Real-world Setting
Authors: Wang Qianqian , Gao Wen , Gao Fangyan , Jin Shidai , Qu Tianyu , Lin Fan , Zhang Chen , Zhang Jingya , Zhang Zhihong , Chen Liang , Guo Renhua
Published: December 2020

Background To compare the benefits and explore the cause of acquired resistance of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) and its combination with chemotherapy in advanced non-small-cell lung cancer (NSCLC) patients harboring EGFR mutation in a real-life setting.Methods This retrospective analysis included 117 advanced NSCLC patients with EGFR mutation who underwent next-generation sequencing (NGS) prior to treatment. The combination group included 50 patients who received the regimen of EGFR-TKI combined with chemotherapy, while the EGFR-TKI monotherapy group included 67 patients treated with TKI only. The primary endpoint of this study was progression-free survival (PFS); the secondary endpoints were overall survival (OS), response rate, and toxicity.Results The median PFS was significantly longer in the combination group than in the EGFR-TKI monotherapy group (19.00 months [95% CI, 14.674-23.326] vs. 11.70 months [95% CI, 10.807-12.593], p = 0.000). Subgroup analysis showed a similar trend of results. The median OS was not reached in the combination group and was 38.50 (95% CI, 35.300-41.700) months in the EGFR-TKI monotherapy group (p = 0.586). Patients in the combination group were more likely to experience adverse events, most of which showed the severity of grade 1 or 2. T790M mutation remains the main reason for acquired resistance, and the frequency of T790M mutation was similar between the two groups (p = 0.898). Conclusions Compared with EGFR-TKI monotherapy, EGFR-TKI combined with chemotherapy significantly improved PFS in advanced NSCLC patients with EGFR mutation, with acceptable toxicity.
Salvage Surgery for Patients With Residual Diseases After Improper or Insufficient Treatment of Oral Squamous Cell Carcinoma: Can We Rectify These Mistakes?
Authors: He Yue , Liu Zhonglong , Sheng Surui , Gao Weijin , Tang Xiao , Li Xiaoguang , Chunyue Ma
Published: December 2020

Background:Patterns of failure after treatment of oral and squamous cell carcinomas (OSCC) are diversified, with recurrences being one of the common causes. A special group of patients are sometimes encountered in the outpatient clinic for improper or insufficient initial treatment with reports of positive margins, implying residual diseases. The question of whether these patients can be surgically salvaged remain unanswered.Methods:A retrospective study was performed between January 2013 and December 2017 for patients with residual or rapid recurrent (within 3 months) OSCCs, who received salvage surgeries in our institution. The patients with residual OSCCs were those with microscopic or macroscopic positive surgical margins, while those with rapid recurrent OSCCs were those with close or negative margins, but unabated painful symptoms right after treatment. Both clinicopathological and prognostic variables were analyzed. The focus was also directed towards lessons for possible initial mistakes, resulting in these residual diseases. Results:Of 103 patients, 68 (66%) were men, with mean age of 56.3 years. The overall survival reached 60.2%. Regarding the primary OSCC status, most of our patients (n=75, 72.8%) were diagnosed with T2-3 stages. Besides, most patients were found with macroscopic residual diseases (52.4%) before our salvage surgery. The sizes of the residual OSCCs were generally under 4 cm (87.3%) with minimally residual in 21 (20.4%). Among all the variables, primary T stage (p=0.003), and residual lesion size (p<0.001) were significantly associated with the prognosis in multivariate analysis. Though the causes for the initial surgical failure were multifactorial, most were stemmed from poor planning and unstandardized execution. Conclusions:Cases with residual OSCCs were mostly due to mistakes which could have been avoided under well-round treatment plans and careful surgical practice. Salvage surgery for cases with smaller residual OSCCs is still feasible with acceptable outcomes.
MCM6 indicates adverse tumor features and poor outcomes and promotes G1/S cell cycle progression in neuroblastoma
Authors: Gu Yaoyao , Hu Xiaoxiao , Liu Xiaowei , Cheng Cheng , Chen Kai , Wu Yeming , Wu Zhixiang
Published: December 2020

Background
Minichromosome maintenance complex component 6(MCM6),as an important replication permission factor, is involved in the pathogenesis of various tumors. Here we studied the expression of MCM6 in neuroblastoma and its influence on tumor characteristics and prognosis.
Methods
Publicly available datasets were used to explore the influence of the differential expression of MCM6 on neuroblastoma tumor stage, risk and prognosis. In cell experiments, human neuroblastoma cell lines SK-N-SH and SK-N-BE(2) were utilized to verify the ability of MCM6 to promote cell proliferation, migration and invasion. We further explored the possible molecular mechanism of MCM6 affecting the phenotype of neuroblastoma cells by mutual verification of RNA-seq and western blotting, and flow cytometry to inquire about its potential specific roles in the cell cycle.
Results
Through multiple datasets mining, we found that high expression of MCM6 was positively correlated with elevated tumor stage, high risk and poor prognosis in neuroblastoma. At the cellular level, neuroblastoma cell proliferation, migration and invasion were significantly inhibited after MCM6 was interfered by siRNA. Mutual verification of RNA-seq and western blotting suggested that the downstream cell cycle-related genes were differentially expressed after MCM6 interference. Flow cytometry analysis revealed that neuroblastoma cells were blocked in G1/S phase after MCM6 interference.
Conclusion
MCM6 is considered to be the driving force of G1/S cell cycle progression, and it is also a potential diagnostic and prognostic marker in neuroblastoma.
Human nasal septal chondrocytes (NSCs) preconditioned on NSC-derived matrix improve their chondrogenic potential
Authors: Noh Yong Kwan , Kim Sung Won , Kim Ik Hwan , Park Kwideok
Published: December 2020

Background
Extracellular matrix (ECM) has a profound effect on cell behaviors. In this study, we prepare a decellularized human nasal septal chondrocyte (NSC)-derived ECM (CHDM), as a natural (N-CHDM) or soluble form (S-CHDM), and investigate their impact on NSCs differentiation.
Methods
N-CHDM, S-CHDM were obtained from NSC. To evaluate function of NSC cultured on each substrate, gene expression using chondrogenic marker, and chondrogenic protein expression were tested. Preconditioned NSCs-loaded scaffolds were transplanted in nude mice for 3 weeks and analyzed.
Results
When cultivated on each substrate, NSCs exhibited similar cell spread area but showed distinct morphology on N-CHDM with significantly lower cell circularity. They were highly proliferative on N-CHDM than S-CHDM and tissue culture plastic (TCP), and showed more improved cell differentiation, as assessed via chondrogenic marker (Col2, Sox9, and Aggrecan) expression and immunofluorescence of COL II. We also investigated the effect of NSCs preconditioning on three different 2D substrates while NSCs were isolated from those substrates, subsequently transferred to 3D mesh scaffold, then cultivated them in vitro or transplanted in vivo. The number of cells in the scaffolds was similar to each other at 5 days but cell differentiation was notably better with NSCs preconditioned on N-CHDM, as assessed via real-time q-PCR, Western blot, and immunofluorescence. Moreover, when those NSCs-loaded polymer scaffolds were transplanted subcutaneously in nude mice for 3 weeks and analyzed, the NSCs preconditioned on the N-CHDM showed significantly advanced cell retention in the scaffold, more cells with a chondrocyte lacunae structure, and larger production of cartilage ECM (COL II, glycosaminoglycan).
Conclusion
Taken together, a natural form of decellularized ECM, N-CHDM would present an advanced chondrogenic potential over a reformulated ECM (S-CHDM) or TCP substrate, suggesting that N-CHDM may hold more diverse signaling cues, not just limited to ECM component.
High Salt Diet Down Regulates TREM2 Expression and Blunts Efferocytosis of Macrophage After Acute Ischemic Stroke
Authors: Hu Mengyan , Lin Yinyao , Men Xuejiao , Zhu Qiang , Lu Danli , Liu Sanxin , Zhang Bingjun , Cai Wei , Lu Zhengqi
Published: December 2020

Background: High salt diet (HSD) is one of the major risk factors for acute ischemic stroke (AIS). As a potential mechanism, surplus salt intake primes macrophage towards a proinflammatory phenotype. The study investigated whether HSD could blunt efferocytosis of macrophage after ischemic stroke, which was a vital process that alleviated post stroke neuroinflammation. Besides, the underlying mechanism was explored.Methods: Wild type male C57/Bl6 mice were fed with fodder containing 8% sodium chloride for 4 weeks and subjected to transient middle cerebral occlusion (tMCAO). Disease severity, macrophage polarization as well as their efferocytic activities were evaluated. In in vitro study, bone marrow derived macrophages were cultured and the impact of high salinity environment on their efferocytic capacity, as well as their expression of phagocytic molecules were analyzed. The relationship of sodium concentration, macrophage phenotype, and disease severity in AIS patients with ischemic stroke was explored. Results: HSD-fed-mice displayed increased infarct volume and aggravated neurological deficiency. Mice fed with HSD suffered exacerbated neural inflammation as higher level of inflammatory mediators and immune cells infiltration were documented. Polarization shift towards pro-inflammatory phenotype impaired efferocytosis of infiltrated macrophages within stroke lesion in HSD-fed-mice were detected. As was uncovered by PCR array, macrophage expression of triggering receptor expressed on myeloid cells 2 (TREM2), a receptor relevant with phagocytosis, was down regulated in high salt environment. Enhancing TREM2 signaling restored the efferocytosis capacity and cellular inflammatory resolution of macrophages in high salinity environment. In AIS patients, high concentration of urine sodium was correlated with lower expression of TREM2 and detrimental stroke outcomes.Conclusions: HSD blunted efferocytic capacity of macrophages through down regulating the expression of TREM2, thus impeded inflammatory resolution after ischemic stroke. Enhancing TREM2 signaling in monocyte/macrophage could be a promising therapeutic strategy to enhance efferocytosis and promote post-stroke inflammatory resolution.
Access to Systemic Anti-cancer Therapies for Women With Secondary Breast Cancer - Protocol for a Mixed Methods Systematic Review
Authors: Pearson Sally Anne , Taylor Sally , Marsden Antonia , Yorke Janelle
Published: December 2020

Background:It is well recognised that access and receipt of appropriate guideline recommended treatment with systemic anti-cancer therapies for secondary breast cancer is a key determinant in overall survival. Where there is disparity in access this may result in unwarranted variation and disparity in outcomes. Individual, clinical and wider contextual factors have been associated with these disparities, however this remains poorly understood for women with secondary breast cancer. The purpose of the review is to address this gap by bringing together the available quantitative and qualitative evidence to examine factors associated with access to systemic anti-cancer therapies for women with secondary breast cancer and explore barriers and facilitators in relation to women and clinicians experience of access.Methods: A mixed methods approach with a segregated design will be used to examine and explore factors which influence access to systemic anti-cancer therapies for women with secondary breast cancer. Quantitative and qualitative appraisal, analysis and syntheses will be conducted discretely prior to final integration of findings. The review will use a comprehensive search strategy to search published and gray literature. Titles and abstracts will be screened against the eligibility criteria and full text articles will be retrieved for all records that meet the inclusion criteria. A data extraction tool will be developed, piloted and refined prior to full data extraction. Methodological quality and risk of bias will be assessed using the Mixed Methods Appraisal Tool. Discussion:Understanding individual, clinical and wider contextual factors associated with access and receipt of systemic anti-cancer therapies for secondary breast cancer is a complex phenomenon. These will be examined to determine any association with access. Review findings will be used to guide future research in this area and the development of an evidence-based service level intervention designed to address unwarranted variation in access based upon the Medical Research Council (MRC) approach to the development, implementation and evaluation of complex interventions.Systematic review registration:The review protocol has been registered in PROSPERO CRD42020196490
Protocol for a Systematic Review of the in vivo Studies on Radiofrequency (100 kHz – 300 GHz) Electromagnetic Field Exposure and Cancer
Authors: Pinto Rosanna , Ardoino Lucia , Giardullo Paola , Villani Paola , Marino Carmela
Published: December 2020

Background. An Italian project aims to review the scientific literature on the possible carcinogenicity of radiofrequency (100 kHz – 300 GHz) electromagnetic field (RF-EMF) exposure. The ENEA team has to carry out a systematic review of the in vivo studies on this topic. Objectives: Development of a protocol for a systematic review (meta-analysis included) to investigate the potential carcinogenic risk following RF-EMF in vivo exposure to doses above or within legal limits. The aim of this review is - to provide a descriptive and, if possible, a quantitative summaries of the results of the examined RF-EMF in vivo studies, together with an assessment of the consistency of observations and of the causes of heterogeneity. - to assess the weight of evidence to support or refute the hypothesis of carcinogenic effects caused by RF-EMF exposure and to draw conclusions about the potential for carcinogenicity of RF-EMF exposure.Methods: We will search for relevant studies in electronic academic databases and in the reference list of selected papers and reviews on the topic, including the descriptive reviews on RF-EMF carcinogenic effect carried out by international panels of experts since 2011. PECO’s statements were defined: experimental studies on rodents of both sexes, all ages and species, all genetic background (Population) exposed to RF-EMF alone, or in combination with other physical or chemical agents (Exposure); only studies reporting outcome data in exposed and sham control groups (Comparison);all types of cancer with all tumor-related outcome measures (Outcome) will be included.Only peer-reviewed articles written in English will be considered without limit in publication date.Eligibility criteria were defined for screening of papers, moreover the risk of bias assessment will be performed using a specific risk of bias tool for animal studies. Only studies with "definitely low and/or probably low risk of bias" will be included in the analysis. A meta-analysis will be performed, if feasible, for all outcome measures: for subgroup analysis a minimum of 3 studies per subgroup will be required. If meta-analysis will not be possible, data will be reported through the descriptive summary.Systematic review registration: PROSPERO CRD42020191105.
Validating the CUIDARE Scale in Measuring the Impact on Patients and the Adaptation Process of their Family Caregivers.
Authors: Gálvez Ana María Porcel , García Elena Fernández , García Eugenia Gil , Parra Juan Manuel Laguna , Trigo Sergio Barrientos
Published: December 2020

Background: The family caregiving process requires adaptation and be evaluated to ensure a correct approach in supporting patients and their caregivers. The objective of the present study is to design and validate an instrument to determine the family caregivers’ adaptation to the caregiving process in relation to the care dependency of hospitalized patients. This paper presents CUIDARE, a validated scale based on the Nursing Outcomes Classification indicators and the Roy Adaptation Model, that evaluates the adaptation process of caregivers in hospital settings and its impact on hospitalized patients. Methods: A cross-sectional and psychometric validation study was carried out in ten public hospitals in the Andalusian Healthcare System. Data collection was undertaken between May 2016 and February 2017 in medical and surgical units, included 432 family caregivers. Results: The CUIDARE scale was shown to be internally consistent (Cronbach’s alpha = 0.818). The Exploratory Factor Analysis grouped 4 items into a single component with a variance-explanatory power of 65.6%. The Confirmatory Factor Analysis tested the unidimensionality of the scale with good fit model (CMIN/DF = 2.152; AGFI = 0.975; NFI = 0.993; CFI = 0.996; RFI = 0.979; RMSEA = 0.052). Conclusions: There is an association between the patients’ care dependency level and the family caregiver’s adaptation to caregiving (p-value <.001). Nursing professionals are encouraged to apply this instrument for the purpose of screening to facilitate the adaptation process of family caregivers and to improve the quality of care.
Identification of Selection Signatures in Commercial Asian Rice Subspecies Deciphered Selection Footprints for Four Overrepresented Biological Processes
Authors: Ardestani Siavash Salek , Roudbar Mahmoud Amiri , Banabazi Mohammad Hossein , Mousavi Seyedeh Fatemeh , Bhatta Madhav , Momen Mehdi
Published: December 2020

BackgroundSelective breeding pressures have led to gradual genomic changes in Asian commercial rice, which have shaped selection footprints on its genome level. Tracing genomic selection footprints might be illuminative for better understanding of recent selection breeding objectives, and how breeding strategies have formed the Asian commercial rice genome. ResultsIn this study, the genotypic information (HDRA 700K) of four Asian commercial rice subspecies including Indica (n=498), Aus (n=187), Temperate japonica (n=241), and Tropical japonica (n=361) were downloaded from Rice Diversity Project database (http://www.ricediversity.org) to detect selection signatures by employing the Z-transformed of fixation index and Tajima’s D test, based on a sliding window approach. Although we could not identify overrepresented genomic regions underlying selection pressure among all aforementioned Asian commercial rice subspecies, interestingly, our findings revealed four overrepresented biological processes underlying selection pressure including proteolysis (GO:0006508), phosphorylation (GO:0016310), protein catabolic process (GO:0030163), and transmembrane transport (GO:0055085) that might be associated with immunity, senescing leaves, transporting, and absorption of ions. ConclusionsThese results can provide knowledge on how breeding efforts shaped the Asian commercial rice subspecies genome, and which genomic regions of these subspecies have been targeted in recent decades.
Spatial variations in seismicity characteristics in and around the source region of the 2019 Yamagata-Oki Earthquake, Japan
Authors: Ueda Taku , Kato Aitaro , Ogata Yoshihiko , Yamaya Lina
Published: December 2020

The 2019 Mj 6.7 Yamagata-Oki earthquake occurred adjacent to the northeastern edge of the source region of the 1964 Mj 7.5 Niigata earthquake, offshore of Yamagata Prefecture, Japan. Few aftershocks occurred in the source region of the Yamagata-Oki earthquake immediately following the Niigata earthquake, and the recent seismicity rate in this region is low compared with the source region of the Niigata earthquake. This spatial variation in seismicity may allow us to elucidate plausible physical processes that shape the spatiotemporal evolution of these shallow-crustal environments. Here, we investigate the spatial variations in seismicity characteristics by applying the HIerarchical Space–Time Epidemic Type Aftershock Sequence (HIST-ETAS) model to an earthquake catalog compiled by the Japan Meteorological Agency for events in and around the Yamagata-Oki earthquake rupture region. We compare spatial variations in the background seismicity rate and aftershock productivity estimated from the HIST-ETAS model with the geophysical features in the study region. The background seismicity rate is high along the eastern margin of the Sea of Japan and correlates well with a previously identified zone that possesses a high geodetic E-W strain rate. The two major earthquakes occurred in and around a high E-W strain rate zone, suggesting that the background seismicity rate may serve as a key parameter for evaluating seismic hazard across the Japanese Archipelago. Furthermore, the source region of the Yamagata-Oki earthquake has a higher aftershock productivity and lower seismic-wave velocity than that of the Niigata earthquake. We interpret this low-velocity zone to be a well-developed damaged rock that resulted in an increase in aftershock productivity based on previous laboratory experiments and numerical results; this damage makes the rock more ductile at the macroscopic scale. The higher ductility in the source region of the Yamagata-Oki earthquake may have worked as a barrier against the propagation of dynamic rupture that occurred during the Niigata earthquake.
Female University Students’ Preferences for Different Types of Sexual Relationships. Implications for Gender-Based Violence Prevention Programs and Policies.
Authors: Ruiz-Eugenio Laura , Racionero-Plaza Sandra , Duque-Sanchez Elena , Puigvert-Mallart Lidia
Published: December 2020

Background: Gender-based violence among young women is a growing problem worldwide. The consequences of this victimization have been well reported in the scientific literature, among which negative health outcomes stand out. The factors influencing this problem are many; one highlighted by research is socialization into a dominant coercive discourse that associates sexual-affective attraction to males with violent attitudes and behaviors, while in turn such discourse empties males with egalitarian behaviors from sexual attractiveness. This coercive discourse may be shaping the sexual preferences of female youth. The current paper explores young women’s preferences for different types of sexual relationships and, more particularly, for what type of sexual affective relationships they coercively preferred men with violent attitudes and behavior. Methods: A quantitative, mixed-design vignette study was conducted with 191 college females in Spain. We focused the analysis only on responses about vignettes including narratives of men with violent attitudes and behaviors. In addition, we examined whether participants would report higher coerced preferences for violent men when asked about the coerced preferences of their female friends than when asked about their own preferences. Results: Only 28.95% of participants responded that their female friends would prefer a young man with violent behavior for a stable relationship, meanwhile 58.42% would do it for hooking up. When reporting about themselves, the difference was greater: 28.42% would prefer a young man with violent behavior for hooking up and just 5.78% for a stable relationship. Conclusions: The dominant coercive discourse that links attractiveness to people with violent attitudes and behaviors may be explaining the results obtained in this study. The findings can help eliminate the stereotype largely adopted by some intervention and prevention programs which assume that gender-based violence occurs mainly in stable relationships, considering that falling in love is the reason that lead women to suffer from violence. Our results can also support health professionals and others serving young women to enhance their identification of gender violence victimization, as well as our findings point to the need to include the evidence of gender violence in sporadic relationships in prevention programs and campaigns addressed to young women.