bluuebunny/crossref_metadata_2025_split huggingface dataset:
EML4-ALK induces cellular senescence in mortal normal human cells and promotes anchorage-independent growth in hTERT-transduced normal human cells
Authors: Miyanaga Akihiko , Matsumoto Masaru , Beck Jessica A. , Horikawa Izumi , Oike Takahiro , Okayama Hirokazu , Tanaka Hiromi , Burkett Sandra S. , Robles Ana I. , Khan Mohammed , Lissa Delphine , Seike Masahiro , Gemma Akihiko , Mano Hiroyuki , Harris Curtis C. 
Published: December 2020

Abstract
Background: Chromosomal inversions involving anaplastic lymphoma kinase (ALK) and echinoderm microtubule associated protein like 4 (EML4) generate a fusion protein EML4-ALK in non-small cell lung cancer (NSCLC). The understanding of EML4-ALK function can be improved by a functional study using normal human cells.Methods: Here we for the first time conduct such study to examine the effects of EML4-ALK on cell proliferation, cellular senescence, DNA damage, gene expression profiles and transformed phenotypes.Results: The lentiviral expression of EML4-ALK in mortal, normal human fibroblasts caused, through its constitutive ALK kinase activity, an early induction of cellular senescence with accumulated DNA damage, upregulation of p16INK4A and p21WAF1, and senescence-associated b-galactosidase (SA-β-gal) activity. In contrast, when EML4-ALK was expressed in normal human fibroblasts transduced with telomerase reverse transcriptase (hTERT), which is activated in the vast majority of NSCLC, the cells showed accelerated proliferation and acquired anchorage-independent growth ability in soft-agar medium, without accumulated DNA damage, chromosome aberration, nor p53 mutation. EML4-ALK induced the phosphorylation of STAT3 in both mortal and hTERT-transduced cells, but RNA sequencing analysis suggested that the different signaling pathways contributed to the different phenotypic outcomes in these cells. While EML4-ALK also induced anchorage-independent growth in hTERT-immortalized human bronchial epithelial cells in vitro, the expression of EML4-ALK alone did not cause detectable in vivo tumorigenicity in immunodeficient mice.Conclusions: Our data indicate that the expression of hTERT is critical for EML4-ALK to manifest its in vitro transforming activity in human cells. This study provides the isogenic pairs of human cells with and without EML4-ALK expression.
A phase II study of first-line afatinib for patients aged ≥75 years with EGFR mutation-positive advanced non-small cell lung cancer: North East Japan Study Group Trial NEJ027
Authors: Minegishi Yuji , Yamaguchi Ou , Sugawara Shunichi , Kuyama Shoichi , Watanabe Satoshi , Usui Kazuhiro , Mori Masahide , Hataji Osamu , Nukiwa Toshihiro , Morita Satoshi , Kobayashi Kunihiko , Gemma Akihiko 
Published: December 2020

Abstract
Background: Lung cancer is most common among older individuals. However, polypharmacy and comorbidities, which are also more common in older individuals, can limit treatment options. Previous studies suggest that afatinib can be used safely and effectively in elderly patients. This study investigated the anti-tumour activity and safety profile of first-line afatinib in previously-untreated elderly Japanese patients with EGFR mutation-positive non-small cell lung cancer (NSCLC)Methods: This was a single-arm, open-label, phase II study, performed in multiple centres in Japan. Previously untreated patients, aged ≥75 years, with EGFR mutation-positive (Del19 or L858R) advanced NSCLC were treated with afatinib 40 mg until disease progression or unacceptable toxicity. Adverse events (AEs) were managed with protocol-defined dose adjustments. The primary endpoint was objective response rate (ORR) by central review. Results: In total, 38 patients received at least one dose of afatinib, and 37 were evaluable for response. Median age was 77.5 years (range 75–91), all patients had an Eastern Cooperative Oncology Group performance status of 0 or 1, and 60.5% had Del19-positive disease. Median follow-up was 838 days. ORR was 75.7% (2 complete responses and 26 partial responses). Median progression-free survival was 14.2 months (95% confidence interval [CI], 9.5–19.0). Median overall survival (OS) was 35.2 months (95% CI, 35.2–not reached); the 2-year OS rate was 78.3%. The most common grade III/IV treatment-related AEs (TRAEs) were diarrhoea (28.9%), paronychia (23.7%), and rash/acne (15.8%). Dose reductions due to TRAEs were reported in 78.9% of patients, and 8 (21.1%) patients discontinued afatinib due to TRAEs. No treatment-related deaths were reported.Conclusion: Although dose adjustments were relatively common in this small group of Japanese patients aged ≥75 years with EGFR mutation-positive NSCLC, discontinuation occurred much less frequently, and most patients were able to stay on treatment for well over a year. Further, afatinib was associated with high response rates and prolonged PFS and OS.Trial Registration: The trial is registered with Japan Registry of Clinical Trials (JRCT) as trial number 031180136 (date of initial registration: 19 February 2019), and the University Hospital Network (UMIN) as trial number 000017877 (date of initial registration: 11 June 2015).
A qualitative meta-synthesis of facilitators and barriers to tuberculosis diagnosis and treatment in Nigeria
Authors: Oga-Omenka Charity , Wakdet Lawrence , Menzies Dick , Zarowsky Christina 
Published: December 2020

Abstract
Background Despite progress in tuberculosis (TB) control globally, TB continues to be a leading cause of death from infectious diseases, claiming 1.2 million lives in 2018; 214,000 of these deaths were due to drug resistant strains. Of the estimated 10 million cases globally in 2018, 24% were in Africa, with Nigeria and South Africa making up most of these numbers.Nigeria ranks 6th in the world for TB burden, with an estimated 4.3% multi-drug resistance in new cases. However, the country had one of the lowest case detection rates, estimated at 24% of incident cases in 2018 - well below the WHO STOP TB target of 84%. This rate highlights the need to understand contextual issues influencing tuberculosis management in Nigeria. Our synthesis was aimed at synthesizing qualitative evidence on factors influencing TB care in Nigeria. Methods A three-stage thematic meta-synthesis of qualitative studies was used to identify barriers and facilitators to tuberculosis case finding and treatment in Nigeria. A search of eleven databases was conducted. The date of publication was limited to 2006 to June 2020. We analyzed articles using a three-stage process, resulting in coding, descriptive subthemes and analytical themes.Results Our final synthesis of 10 articles resulted in several categories including community and family involvement, education and knowledge, attitudes and stigma, alternative care options, health system factors (including coverage and human resource), gender, and direct and indirect cost of care. These were grouped into three major themes: individual factors; interpersonal influences; and health system factors.Conclusion Case finding and treatment for TB in Nigeria currently depends more on individual patients presenting voluntarily to the hospital for care, necessitating an understanding of patient behaviors towards TB diagnosis and treatment. Our synthesis has identified several related factors that shape patients’ behavior towards TB management at individual, community and health system levels that can inform future interventions.
‘Key stakeholder perspectives on the development and real-world implementation of a home-based physical activity program for mothers at risk of postnatal depression: A qualitative study’
Authors: Teychenne Megan , Apostolopoulos Maria , Ball Kylie , Olander Ellinor K , Opie Rachelle S , Rosenbaum Simon , Laws Rachel 
Published: December 2020

Abstract
Background Physical activity (PA) is a modifiable risk factor for postnatal depression (PND) and programs are needed to enhance PA amongst women at risk of PND. Key stakeholder involvement in informing development and implementation of such programs is vital. However, little research demonstrates key stakeholder insights to inform the design and delivery of PA programs for improving PND. The aim of this study was to explore key stakeholder perspectives on the design and delivery of a home-based PA program for mothers with PND symptoms to inform future real-world implementation and scale-up.Methods A descriptive qualitative study was undertaken whereby semi-structured interviews were conducted with representatives from various key stakeholder organisations involved in postnatal PA and/or mental health, public health and policy in Australia (n=11). Interviews were conducted between September to November 2019 and explored stakeholder perceptions on the design and delivery of a home-based PA program for mothers with PND symptoms. The interview schedule was informed by both the Consolidated Framework for Implementation Research (CFIR) and the PRACTical planning for Implementation and Scale-up (PRACTIS) guide. Data were analysed thematically using both deductive and inductive coding. Results The relative priority of PND and PA was high for most organisations involved, although none implemented PA programs supporting women at risk of PND. Most stakeholders perceived the program as appealing due to addressing barriers to postnatal PA, although identified some feasibility issues regarding funding and delivery mechanisms. Suggestions for program adaptations included an equity focus (e.g. providing socioeconomically disadvantaged women with a greater program dose; translating web-app based content into various languages). Planned components of the program were suggested to align (i.e. relative advantage) with existing initiatives (e.g. equipment hire for nurseries scheme) and screening systems for PND (timing of referral). Perceived barriers to scale-up included logistics/cost of equipment, organisational capacity demands and safety risks/liability. Perceived enablers to scale-up included linking the program with ‘adjunct’ programs and services. Conclusions While the program was appealing and most organisations could see a role in endorsing and/or referring to the program, funding and delivery mechanisms still need to be identified.
Early clearance of serum HE4 and CA125 in predicting platinum sensitivity and prognosis in epithelial ovarian cancer
Authors: Rong Yan , Li Li 
Published: December 2020

Abstract
Objectives: To assess the clinical value of early clearance of HE4 and CA125 for platinum sensitivity and prognosis in patients with ovarian cancer.Method: HE4 and CA125 value including clinical data of 89 patients with ovarian cancer were collected. The clearance of HE4 and CA125 were assessed base on the platinum sensitivity, two-year PFS, PFS and OS.Results: 16 patients were classified as platinum resistant and 73 as platinum sensitive according to the response to platinum-base chemotherapy. When HE4 clearance after 3rd cycle chemotherapy or CA125 clearance after 1st cycle chemotherapy, it gave the highest AUC of 0.788, with 100% of sensitivity and 57.5% of specificity respectively between platinum resistant and platinum sensitive group. In addition, 59 patients were classified as two-year PFS group and 30 as not achieved two-year PFS group according to obtaining two-year PFS or not. It gave the highest AUC of 0.730, with 83.3% of sensitivity and 62.7% of specificity respectively when HE4 clearance after 3rd cycle chemotherapy or CA125 clearance after 1st cycle. The prolonged PFS and OS were significantly associated by the clearance of HE4 after 3rd cycle chemotherapy (p<0.0001, p<0.0001) as well as CA125 after 1st cycle chemotherapy (p<0.0001, p<0.0001).Conclusions: Our data suggested that the early clearance of HE4 and CA125 could predict platinum response and prognosis in patients with ovarian cancer. Monitoring the HE4 and CA125 during first-line chemotherapy might be helpful in predicting platinum sensitivity and risk to progress and relapse.
The fluid management and hemodynamic characteristics of PiCCO employed on young children with severe Hand, Foot, and Mouth Disease—a retrospective study
Authors: Wang Fengyun , Qiang Xinhua , Jiang Suhua , Shao Jingsong , Fang Bin , Zhou Lixin 
Published: December 2020

Abstract
Background Hand, foot, and mouth disease (HFMD) is an acute infectious disease caused by human enterovirus 71 (EV71), coxsackievirus, or echovirus, which are particularly common in preschool children. Severe HFMD is prone to cause pulmonary edema, and successively progresses to respiratory and circulatory failure; thus hemodynamic monitoring and fluid management are important in the treatment process. Methods We reviewed young patients with severe HFMD, caused by EV71, and who had been successfully treated in our department. A total of 20 patients met the inclusion criteria. Eight cases were monitored by the pulse indicator continuous cardiac output (PiCCO) technique, and fluid management was administered according to its parameters. With regard to the treatment with PiCCO monitoring, patients were divided into two groups: the PiCCO group (8 patients) and the control group (12 patients). The groups were then compared comprehensively to evaluate whether PiCCO monitoring could improve the clinical outcomes. Results After analysis, the findings were that although PiCCO failed to shorten the length of ICU stay, reduce the days of vasoactive drug usage, or reduce the number of cases which needed mechanical ventilation, it did reduce the incidence of fluid overload (p=0.085) and shortened the days of mechanical ventilation (p=0.028). After effective treatment, PiCCO monitoring showed that the cardiac index (CI) increased gradually(p<0.0001), whereas the pulse (P, p<0.0001), the extra vascular lung water index (EVLWI, p<0.0001), the global end diastolic volume index (GEDVI, p=0.0043), and the systemic vascular resistance index (SVRI, p<0.0001) all decreased gradually. Conclusion Our study discovered that PiCCO hemodynamic monitoring in young children with severe HFMD has potential clinical benefits, such as reducing fluid overload and duration of mechanical ventilation. However, whether it can ameliorate the severity of the disease, reduce mortality, or prevent multiple organ dysfunction remain to be further investigated.
Protein signature of human skin fibroblasts allows the study of the molecular etiology of rare neurological diseases
Authors: Hentschel Andreas , Czech Artur , Münchberg Ute , Freier Erik , Schara-Schmidt Ulrike , Sickmann Albert , Reimann Jens , Roos Andreas 
Published: December 2020

Abstract
Background: The elucidation of pathomechanisms leading to the manifestation of rare (genetically caused) neurological diseases including neuromuscular diseases (NMD) represents an important step toward the understanding of the genesis of the respective disease and might help to define starting points for (new) therapeutic intervention concepts. However, these “discovery studies” are often limited by the availability of human biomaterial. Moreover, given that results of next-generation-sequencing approaches frequently result in the identification of ambiguous variants, testing of their pathogenicity is crucial but also depending on patient-derived material. Methods: Human skin fibroblasts were used to generate a spectral library using pH8-fractionation of followed by nano LC-MS/MS. Afterwards, Allgrove-patient derived fibroblasts were subjected to a data independent acquisition approach (DIA). In addition, proteomic signature of an enriched nuclear protein fraction was studied. Proteomic findings were confirmed by immunofluorescence in a muscle biopsy derived from the same patient and cellular lipid homeostasis in the cause of Allgrove syndrome was analysed by fluorescence (BODIPY-staining) and coherent anti-Stokes Raman scattering (CARS) microscopy. Results: To systematically address the question if human skin fibroblasts might serve as valuable biomaterial for (molecular) studies of NMD, we generated a protein library cataloguing 8280 proteins including a variety of such linked to genetic forms of motoneuron diseases, congenital myasthenic syndromes, neuropathies and muscle disorders. In silico-based pathway analyses revealed expression of a diversity of proteins involved in muscle contraction and such decisive for neuronal function and maintenance suggesting the suitability of human skin fibroblasts to study the etiology of NMD. Based on these findings, next we aimed to further demonstrate the suitability of this in vitro model to study NMD by a use case: the proteomic signature of fibroblasts derived from an Allgrove-patient was studied. Dysregulation of paradigmatic proteins could be confirmed in muscle biopsy of the patient and protein-functions could be linked to neurological symptoms known for this disease. Moreover, proteomic investigation of nuclear protein composition allowed the identification of protein-dysregulations according with structural perturbations observed in the muscle biopsy. BODIPY-staining on fibroblasts and CARS microscopy on muscle biopsy suggest altered lipid storage as part of the underlying disease etiology. Conclusions: our combined data reveal that human fibroblasts may serve as an in vitro system to study the molecular etiology of rare neurological diseases exemplified on Allgrove syndrome in an unbiased fashion.
Long-term target tracking combined with re-detection
Authors: Wang Juanjuan , Yang HaoRan , Xu Ning , Wu Chengqin , Zhao ZengShun , Zhang Jixiang , Wu Dapeng Oliver 
Published: December 2020

Abstract
The long-term visual tracking undergoes more challenges and is closer to realistic applications than short-term tracking. However, the performances of most existing methods have been limited in the long-term tracking tasks. In this work, we present a reliable yet simple long-term tracking method, which extends the state-of-the-art Learning Adaptive Discriminative Correlation Filters (LADCF) tracking algorithm with a re-detection component based on the SVM model. The LADCF tracking algorithm localizes the target in each frame and the re-detector is able to efficiently re-detect the target in the whole image when the tracking fails. We further introduce a robust confidence degree evaluation criterion that combines the maximum response criterion and the average peak-to correlation energy (APCE) to judge the confidence level of the predicted target. When the confidence degree is generally high, the SVM is updated accordingly. If the confidence drops sharply, the SVM re-detects the target. We perform extensive experiments on the OTB-2015 and UAV123 datasets. The experimental results demonstrate the effectiveness of our algorithm in long-term tracking.
Using exosomal miRNAs extracted from porcine follicular fluid to investigate their role in oocyte development
Authors: Hu Junhe , Dong Jinyi , Zeng Zhi , Wu Juan , Tan Xiansheng , Tang Tao , Yan Jiao , Jin Chenzhong 
Published: December 2020

Abstract
Background: Follicular development is crucial to normal oocyte maturation, with follicular size closely related to oocyte maturation. To better understand the molecular mechanisms behind porcine oocyte maturation, we obtained exosomal miRNA from porcine follicular fluid (PFF). These miRNA samples were then sequenced and analyzed regarding their different follicular sizes, as described in the methods section. Results：First, these results showed that this process successfully isolated PFF exosomes. Nearly all valid reads from the PFF exosomal sequencing data were successfully mapped to the porcine genome database. Second, we used hierarchical clustering methods to determine that significantly expressed miRNAs were clustered into A, B, C, and D groups in our heatmap according to different follicle sizes. These results allowed for the targeting of potential mRNAs genes related to porcine oocyte development. Third, we chose ten, significantly expressed miRNAs and predicted their target genes for further GO analysis. These results showed that the expression levels of neurotransmitter secretion genes were greatly changed, as were many target genes involved in the regulation of FSH secretion. Notably, these are genes that are very closely related to oocyte maturation in growing follicles. We then used pathway analysis for these targeted genes based on the originally selected ten miRNAs. Results indicated that the pathways were mainly related to the biosynthesis of TGF-beta and its signaling pathway, which are very closely related to reproductive system functions.Conclusions：Finally, these exosomal miRNAs obtained from PFF may provide a valuable addition to our understanding of the mechanism of porcine oocyte maturation. It is also likely that these exosomal miRNAs could function as molecular biomarkers to choose high-quality oocytes and allow for in vitro porcine embryo production.
Effect of a 980-nm diode laser on post-operative pain after endodontic treatment in teeth with apical periodontitis: A randomized clinical trial
Authors: Kaplan Tuna , Sezgin Güzide Pelin , Kaplan Sema Sönmez 
Published: December 2020

Abstract
Background: This study aimed to assess the effect of a 980-nm diode laser following chemomechanical root canal preparation on the severity of post-operative pain (PP) after root canal treatment (RCT).Methods: This study included asymptomatic, single-rooted teeth with a periapical index (PAI) score of 3 or 4. All the patients received RCT, including dressing with calcium hydroxide (Ca(OH)2), during two visits. The patients were randomly divided into two groups (n:30): a control group, in which the final irrigation was performed using 5 ml of 2.5% sodium hypochlorite (NaOCI), followed by 5 ml of 17% and ethylenediaminetetraacetic acid (EDTA) and 5 ml of distilled water, and a laser group, in which the root canals were irradiated using a 980-nm diode laser after the final irrigation at both visits. The pain levels after both visits were evaluated using a visual analogue scale (VAS) after 8 h, 24 h, 48 h and 7 d. In addition, the time intervals to medication intake were recorded. The collected data were statistically analysed using the chi-square and Mann–Whitney U test (p<0.05).Results: The average pain level in the control group 24 h after the first visit was significantly higher than that in the laser group (p<0.05). The average pain level 24 h and 48 h after the second visit was significantly higher in the control group (p<0.05). The levels of PP 24 h after the first visit were higher than those after the second visit only in the control group (p<0.05). After the first visit, analgesic use in the control group was significantly higher after 8 h (40%) and 24 h (23%) as compared with that in the laser group (p<0.05).Conclusions: Root canal irradiation with a diode laser may reduce PP after RCT in single-rooted teeth with a PAI score of 3 or 4.Trial registration: Effect of the Diode Laser on Post-operative Pain After Endodontic Treatment in Teeth with Apical Periodontitis: NCT04486196. Registered 24 July 2020 - Retrospectively registered, http://clinicaltrials.gov/ct2/show/NCT04486196