bluuebunny/crossref_metadata_2025 huggingface dataset:
Suppressing Dazl modulates tumorigenicity and stemness in human glioblastoma cells
Authors: Zhang Fengyu , Liu Ruilai , Zhang Haishi , Liu Cheng , Liu Chunfang , Lu Yuan
Published: July 2020

Background

Glioblastoma is devastating cancer with a high frequency of occurrence and poor survival rate and it is urgent to discover novel glioblastoma-specific antigens for the therapy. Cancer-germline genes are known to be related to the formation and progression of several cancer types by promoting tumor transformation. Dazl is one such germline gene and is up-regulated in a few germ cell cancers. In this study, we analyzed the expression of Dazl in human glioblastoma tissues and cells, and investigated its significance in proliferation, migration, invasion and chemoresistance of the glioblastoma cell lines.

Methods

We evaluated the expression of Dazl in different pathologic grades of glioblastoma tissues by immunohistochemistry. We assessed the expression of Dazl in glioblastoma cells and normal human astrocytes (NHA) cells by western blotting and RT-qPCR. Then we generated Dazl knockout glioblastoma cell lines using the CRISPR/Cas9 gene-editing technology to explore the cellular function of Dazl. We detected the proliferation and germline traits via CCK-8 assays and alkaline phosphatase staining, respectively. Boyden chamber assays were performed to measure glioblastoma cell migration and invasion. Crystal violet staining was used to determine the number of viable cells after the treatment of Doxorubicin and Temozolomide. Finally, we used subcutaneous xenograft studies to measure the growth of tumors in vivo.

Results

We found that Dazl was upregulated in glioblastoma tissues and glioblastoma cell lines. Dazl knockdown glioblastoma cells showed decreased cellular proliferation, migration, invasion, and resistance in vitro, and inhibited the initiation of glioblastoma in vivo. The glioblastoma cell lines A172, U251, and LN229 were found to express stem cell markers CD133, Oct4, Nanog, and Sox2. The expression of these markers was downregulated in Dazl-deficient cells.

Conclusions

Our results indicated that Dazl contributes to the tumorigenicity of glioblastoma via reducing cell stemness. Therefore, cancer-germline genes might represent a new paradigm of glioblastoma-initiating cells in the treatment of malignant tumors.
Encephalitis due to herpes zoster without rash in an immunocompetent 12-year-old girl: case report and review of the literature
Authors: Ciancia Silvia , Crisafi Antonella , Fontana Ilaria , De Fanti Alessandro , Amarri Sergio , Iughetti Lorenzo
Published: July 2020

Background

Neurological complications due to reactivation of varicella-zoster virus (VZV) are very uncommon in immunocompetent patients. Generally a vesicular rash is present on one or more dermatomes, preceding or following the main manifestation. Few cases are reported in the international literature, but they concern mainly adult or elderly patients.

Case presentation

A 12-year-old girl was referred to our hospital for persisting headache, cough and rhinitis for six days. After first examination, diagnosis of anterior sinusitis was made by nasal endoscopy. The day after, the girl developed psychotic symptoms and altered mental status. Computed tomography (CT) scan was immediately performed but was unremarkable; lumbar puncture revealed leukocytosis with lymphocytic predominance and cerebrospinal fluid polymerase chain reaction (PCR) detected varicella-zoster virus DNA. The diagnosis of acute VZV encephalitis was made. The patient was promptly treated with acyclovir infused intravenously and her clinical conditions rapidly improved. Tests made did not show any condition of immunosuppression.

Conclusions

Although if rare, reactivation of VZV can occur in immunocompetent children and its complications can involve central nervous system. Among these complications, meningitis is more common, but cerebral parenchyma can also be involved leading to a severe medical condition that is defined meningoencephalitis. In rare cases vesicular rash may be absent; therefore high level of suspicion is required even in those patients in which suggestive clinical features are not present to guide the diagnosis. Intravenous acyclovir represents the treatment of choice to obtain a fast clinical response and to prevent the onset of late-term complications.
Feasibility and content validity of the PERF-FIT test battery to assess movement skills, agility and power among children in low-resource settings
Authors: Smits-Engelsman Bouwien C. M. , Bonney Emmanuel , Neto Jorge Lopes Cavalcante , Jelsma Dorothee L.
Published: July 2020

Background

Numerous movement skills and physical fitness tests have been developed for children in high-income countries. However, adaptation of these tests to low-resource settings has been slow and norms are still unavailable for children living in low-income communities. The aim of this paper was to describe the development and validation of the Performance and Fitness (PERF-FIT) test battery, a new test to assess motor skill-related physical fitness in children in low-resource settings.

Method

The PERF-FIT test was developed in a stepwise manner. This involved defining the relevant domains of the construct of interest and selecting and evaluating test items. The Content Validity Index (CVI) was used to estimate content validity. Following development of the PERF-FIT test, a preliminary study was performed to validate items and to examine the feasibility of implementing the test in a low-resource community. Structural validity was also determined based on data from eighty (n = 80) children (aged 7–12 years) using principal component analysis.

Results

The CVI for the throw and catch item was 0.86 and 1.00 for the other nine items, leading to a total CVI score of 0.99. The hierarchical sequence of the item series was demonstrated by highly significant (p < 0.001) linear trends, confirming the increase in difficulty of subsequent items. Principal component analysis revealed three factors; the first component is represented by locomotor skills that require static and dynamic balance, the second component by throwing and catching items and the third component by agility and power items. These findings suggest that it is feasible to implement the PERF-FIT in low-resource settings.

Conclusion

The PERF-FIT test battery is easy to administer and may be suitable for measuring skill-related physical fitness in in low-resource settings. It has excellent content validity and good structural validity. After minor adaptions, further studies should be conducted to establish normative values, evaluate reliability, and document criterion and cross-cultural validity of this test.
Extensive tracheal resection in lung cancer and tuberculosis: a case report
Authors: Giller Dmitry , Giller Boris , Scherbakova Galina , Mikhaylenko Elizaveta V. , Mikhaleva Liudmila M. , Nikolenko Vladimir N. , Gavryushova Liliya V. , Somasundaram Siva G. , Kirkland Cecil E. , Aliev Gjumrakch
Published: July 2020

Background

Tracheal bifurcation resection remains the greatest challenge in airway reconstruction, especially with extensive lesions. Additionally, lung cancer and pulmonary tuberculosis comorbidity complicate the chemoradiotherapy treatment due to the TB reactivation. This case describes tracheal resection in a patient with both tuberculosis (TB) and lung cancer.

Case presentation

The patient was diagnosed with right lung tuberculosis and upper lobe cancer with trachea invasion complicated by hemoptysis. A right pneumonectomy with circular trachea bifurcation resection was performed. Radiotherapy and chemotherapy were not administered to avoid TB reactivation. At 5.5 years post-surgery, there was cancer recurrence that was treated with radiation therapy. At 10 years post-surgery, an invasive squamous-cell carcinoma of a three-segment bronchus on the left was revealed. Radiation therapy and a course of chemotherapy were carried out with almost complete tumor regression.

Conclusions

TB presence should not serve as a basis for the refusal of cancer treatment. Combined treatment may be recommended when the main infection focus in the pulmonary parenchyma is removed during surgery.
Diagnostic accuracy of perioperative electromyography in the positioning of pedicle screws in adolescent idiopathic scoliosis treatment: a cross-sectional diagnostic study
Authors: Barsotti Carlos Eduardo , Gavassi Bruno Moreira , Prado Francisco Eugenio , Batista Bernardo Nogueira , de Resende Pratali Raphael , Ribeiro Ana Paula , de Oliveira Carlos Eduardo Soares , Ferreira Ricardo Rodrigues
Published: July 2020

Background

To investigate in the conventional techniques of the pedicle screws using triggered screw electromyography (t-EMG), considering different threshold cutoffs: 10, 15, 20 25 mA, for predicting pedicle screw positioning during surgery of the adolescent with idiopathic scoliosis (AIS).

Methods

Sixteen patients (4 males, 12 females, average age 16.6 years) were included, with an average curve magnitude of 50 degrees and placement of 226 pedicle screws. Each screw was classified as “at risk for nerve injury” (ARNI) or “no risk for nerve injury” (NRNI) using CT and the diagnostic accuracy of EMG considering different threshold cutoffs (10,15, 20 and 25 mA) in the axial and Sagittal planes for predicting screw positions ARNI was investigated.

Results

The EMG exam accuracy, in the axial plane, 90.3% screws were considered NRNI. In the sagittal plane, 81% pedicle screws were considered NRNI. A 1-mA decrease in the EMG threshold was associated with a 12% increase in the odds of the screw position ARNI. In the axial and sagittal planes, the ORs were 1.09 and 1.12, respectively. At every threshold cutoff evaluated, the PPV of EMG for predicting screws ARNI was very low in the different threshold cutoff (10 and 15); the highest PPV was 18% with a threshold cutoff of 25 mA. The PPV was always slightly higher for predicting screws ARNI in the sagittal plane than in the axial plane. In contrast, there was a moderate to high NPV (78–93%) for every cutoff analyzed.

Conclusions

EMG had a moderate to high accuracy for positive predicting value screws ARNI with increase threshold cutoffs of 20 and 25 mA. In addition, showed to be effective for minimizing false-negative screws ARNI in the different threshold cutoffs of the EMG in adolescent with idiopathic scoliosis (AIS).
Physical fitness in older women with osteoporosis and vertebral fracture after a resistance and balance exercise programme: 3-month post-intervention follow-up of a randomised controlled trial
Authors: Stanghelle Brita , Bentzen Hege , Giangregorio Lora , Pripp Are Hugo , Skelton Dawn A. , Bergland Astrid
Published: July 2020

Background

Exercise is recommended for individuals with vertebral fractures, but few studies have investigated the effect of exercise on outcomes of importance for this population. Post-intervention effects of exercise are even less studied. The objective of this study was to evaluate habitual walking speed and other health-related outcomes after cessation of a 3-month exercise intervention.

Methods

This follow-up study was conducted 3 months post-intervention of a randomised controlled trial. A total of 149 community-dwelling Norwegian women aged 65 years or older, diagnosed with osteoporosis and vertebral fracture were randomised into either exercise or control group. Primary outcome was habitual walking speed at 3 months. Secondary outcomes were other measures of physical fitness – including the Four Square Step Test (FSST), functional reach, grip strength and Senior Fitness Test – measures of health-related quality of life and fear of falling. Herein we report secondary data analysis of all outcomes at 6 months (3 months post-intervention). Data were analysed according to the intention-to-treat principle, linear mixed regression models were employed.

Results

For the primary outcome, habitual walking speed, there was no statistically significant difference between groups (0.03 m/s, 95%CI − 0.02 to 0.08, p = 0.271) at the 3-month post-intervention follow-up. For secondary outcomes of physical fitness, statistically significant differences in favour of the intervention group were found for balance using the FSST (− 0.68 s, 95%CI − 1.24 to − 0.11, p = 0.019), arm curl (1.3, 95%CI 0.25 to 2.29, p = 0.015), leg strength using the 30-s sit to stand (1.56, 95%CI 0.68 to 2.44, p = 0.001) and mobility using the 2.45-m up and go (− 0.38 s, 95%CI − 0.74 to − 0.02, p = 0.039). There was a statistically significant difference between the groups regarding fear of falling in favour of the intervention group (− 1.7, 95%CI − 2.97 to − 0.38, p = 0.011). No differences between groups were observed for health-related quality of life.

Conclusion

The results show the improved effects of a multicomponent exercise programme on outcomes like muscle strength, balance and mobility as well as fear of falling in a group of older women with osteoporosis and vertebral fracture 3 months post-intervention.

Trial registration

ClinicalTrials.gov Identifier: NCT02781974. Registered 25.05.16. Retrospectively registered.
Non-active implantable device treating acid reflux with a new dynamic treatment approach: 1-year results
Authors: Bjelović Miloš , Harsányi László , Altorjay Áron , Kincses Zsolt , Forsell Peter ,   Investigators of the RefluxStop™ Clinical Investigation Study Group, Gunjić Dragan , Veselinović Milan , Babič Tamara , Lukovich Péter , Kakucs Timea , Kathy Sándor
Published: July 2020

Background

RefluxStop™ is an implantable, non-active, single use device used in the laparoscopic treatment of GERD. RefluxStop™ aims to block the movement of the LES up into the thorax and keep the angle of His in its original, anatomically correct position. This new device restores normal anatomy, leaving the food passageway unaffected.

Methods

In a prospective, single arm, multicentric clinical investigation analyzing safety and effectiveness of the RefluxStop™ device to treat GERD, 50 subjects with chronic GERD were operated using a standardized surgical technique between December 2016 and September 2017. They were followed up for 1 year (CE-mark investigation 6-months). Primary safety outcome was prevalence of serious adverse events related to the device, and primary effectiveness outcome reduction of GERD symptoms based on GERD-HRQL score. Secondary outcomes were prevalence of adverse events other than serious adverse events, reduction of total acid exposure time in 24-h pH monitoring, and reduction in average daily PPI usage and subject satisfaction.

Results

There were no serious adverse events related to the device. Average GERD-HRQL total score at 1 year improved 86% from baseline (p < 0.001). 24-h pH monitoring compared to baseline showed a mean reduction percentage of overall time with pH < 4 from 16.35 to 0.80% at the 6-month visit (p < 0.001), with 98% of subjects showing normal 24-h pH. At 1 year: No new cases of dysphagia were recorded, present in 2 subjects, which existed already at baseline. Regular daily PPI usage occurred in all 50 subjects at baseline. At 1-year follow-up, only 1 subject took regular daily PPIs due to a too low placement of the device thereby prohibiting its function. None or minimal occasional episodes of regurgitation occurred in 97.8% of evaluable subjects. Gas bloating disappeared in 30 subjects and improved in 7 subjects.

Conclusion

The new principle of RefluxStop™ is safe and effective to treat GERD according to investigation results. At 1-year follow-up, both the GERD-HRQL score and 24-h pH monitoring results indicate success for the new treatment principle. In addition, with the dynamic treatment for acid reflux, which avoids compressing the food passageway, prevalence of dysphagia and gas bloating are significantly reduced.

Trial registration

ClinicalTrials.gov, NCT02759094. Registered 3 May, 2016,
Squamous cell carcinoma of the renal parenchyma presenting as hydronephrosis: a case report and review of the recent literature
Authors: Zhang Xirong , Zhang Yuanfeng , Ge Chengguo , Zhang Junyong , Liang Peihe
Published: July 2020

Background

Primary squamous cell carcinoma of the renal parenchyma is extremely rare, only 5 cases were reported.

Case presentation

We probably report the fifth case of primary Squamous cell carcinoma (SCC) of the renal parenchyma in a 61-year-old female presenting with intermittent distending pain for 2 months. Contrast-enhanced computed tomography (CECT) revealed hydronephrosis of the right kidney, but a tumor cannot be excluded completely. Finally, nephrectomy was performed, and histological analysis determined that the diagnosis was kidney parenchyma squamous cell carcinoma involving perinephric adipose tissue.

Conclusions

The present case emphasizes that it is difficult to make an accurate preoperative diagnosis with the presentation of hidden malignancy, such as hydronephrosis.
What’s in a name? A comparison of attitudes towards artificial intelligence (AI) versus augmented human intelligence (AHI)
Authors: Romero-Brufau Santiago , Wyatt Kirk D. , Boyum Patricia , Mickelson Mindy , Moore Matthew , Cognetta-Rieke Cheristi
Published: July 2020

Background

“Artificial intelligence” (AI) is often referred to as “augmented human intelligence” (AHI). The latter term implies that computers support—rather than replace—human decision-making. It is unclear whether the terminology used affects attitudes and perceptions in practice.

Methods

In the context of a quality improvement project implementing AI/AHI-based decision support in a regional health system, we surveyed staff’s attitudes about AI/AHI, randomizing question prompts to refer to either AI or AHI.

Results

Ninety-three staff completed surveys. With a power of 0.95 to detect a difference larger than 0.8 points on a 5-point scale, we did not detect a significant difference in responses to six questions regarding attitudes when respondents were alternatively asked about AI versus AHI (mean difference range: 0.04–0.22 points; p > 0.05).

Conclusion

Although findings may be setting-specific, we observed that use of the terms “AI” and “AHI” in a survey on attitudes of clinical staff elicited similar responses.
Feasibility study to identify women of childbearing age at risk of pregnancy not using any contraception in The Health Improvement Network (THIN) database
Authors: Cea Soriano Lucía , Asiimwe Alex , Van Hemelrijck Mieke , Bosco Cecilia , García Rodríguez Luis A.
Published: July 2020

Background

Worldwide the rate of unplanned pregnancies is more than 40%. Identifying women at risk of pregnancy can help prevent negative outcomes and also reduce healthcare costs of potential complications. It can also allow the investigation of the natural history of pregnancy outcomes, such as ectopic pregnancies or miscarriages. The use of medical records databases has been a crucial development in the field of pharmacoepidemiology – e.g. The Health Improvement Network (THIN) database is a validated database representative of the UK population. This project aimed to test the feasibility of identifying a population of women of childbearing age who are at risk of pregnancy not using any contraception in THIN database.

Methods

First a cohort of women of childbearing age (15-45yo) was identified. By applying a computer-based algorithm, containing codes for contraception methods or other suggestion of contraception, the risk of pregnancy was then ascertained. Next, two validation steps were implemented: 1) Revision of medical records/free text and 2) Questionnaires were sent to primary care practitioners (PCP) of women whose medical records had been reviewed. Positive predicted values (PPV) were calculated.

Results

A total of 266,433 women were identified in THIN. For the first validation step, 123 records were reviewed, with a PPV of 99.2% (95%CI: 95.5–99.9). For the questionnaires step, the PPV was of 82.3% (95%CI: 70–91.1). Information on sexual behaviour and attitudes towards conception was not captured by THIN.

Conclusion

This study shows that by applying a comprehensive computer-based algorithm, THIN can be used to identify women at risk of pregnancy.
Identification of potential crucial genes in atrial fibrillation: a bioinformatic analysis
Authors: Zhang Junguo , Huang Xin , Wang Xiaojie , Gao Yanhui , Liu Li , Li Ziyi , Chen Xuejiao , Zeng Jie , Ye Zebing , Li Guowei
Published: July 2020

Background

Atrial fibrillation (AF) is at least partially heritable, affecting 2–3% of the population in Europe and the USA. However, a substantial proportion of heritability is still lacking. In the present study, we aim to identify potential crucial genes associated with AF through bioinformatic analyses of public datasets.

Methods

Microarray data sets of GSE115574, GSE31821, GSE79768, GSE41177 and GSE14975 from the Gene Expression Omnibus (GEO) database were retrieved. After merging all microarray data and adjusting batch effect, differentially expressed genes (DEGs) were identified. Functional enrichment analyses based on Gene Ontology (GO) resource, Kyoto Encyclopedia of Genes and Genomes (KEGG) resource, Gene Set Enrichment Analysis (GSEA), Reactome Pathway Database and Disease Ontology (DO) were carried out. Protein-protein interaction (PPI) network was constructed using the STRING database. Combined with aforementioned significant bioinformatics information, potential crucial genes were subsequently selected. The comparative toxicogenomics database (CTD) was used to explore the interaction between potential crucial genes and AF.

Result

We identified 27 of DEGs with gene expression fold change (FC) ≥ 1.5 or ≤ 2/3 (|log2 FC| ≥ 0.58) and 5 with FC ≥ 2 or ≤ 0.5 (|log2 FC| ≥ 1) of AF patients compared with sinus rhythm controls. The most significantly enriched pathway was regulation of insulin-like growth factor transport and uptake by insulin-like growth factor binding proteins. IGFBP2, C1orf105, FHL2, CHGB, ATP1B4, IGFBP3, SLC26A9, CXCR4 and HTR2B were considered the potential crucial genes. CTD showed CXCR4, IGFBP2, IGFBP3 and FHL2 had higher scores with AF.

Conclusions

The 9 potential crucial genes, especially CXCR4, IGFBP2, IGFBP3 and FHL2, may be associated with risk of AF. Our study provided new insights of AF into genetics, molecular pathogenesis and new therapeutic targets.
Investigation of occurrence patterns of respiratory syncytial virus A and B in infected-patients from Cheonan, Korea
Authors: Kim Ga-Yeon , Rheem Insoo , Joung You Hyun , Kim Jae Kyung
Published: July 2020

Background

Respiratory infections caused by viruses affect the lower respiratory tract; these infections are severe in patients with underlying diseases and can even lead to death. Respiratory syncytial virus (RSV), one of the causative agents of respiratory viral infections, is the most common cause of pneumonia and bronchiolitis in children and adults.

Methods

Respiratory specimens (nasopharyngeal aspirate, nasal swab, throat swab, etc.), which were sent to the Department of laboratory medicine from January 2012 to December 2018 for detection of respiratory viruses via real time reverse transcription PCR (Real time RT-PCR) were used in this study. RSV detected by real-time RT-PCR were analyzed on the basis of co-infection, sex and age of the patients, and year and month of sample collection.

Results

During the study period, we observed that the RSV detection rate was 12.8% (n = 1150/9010); the detection rate of RSV-A (7.1%) was higher than that of RSV-B (5.8%). The detection rate of RSV was the highest at 36.5% in December, and RSV-A and RSV-B were in vogue every year. Co-infection rate of RSVs was the highest in the patients over 80 years of age; RSVs showed the highest Co-infection with Rhinoviruses.

Conclusions

During the study period, prevalence was different among the two subtypes of RSV, and the average age of RSV-B-positive patients was higher than that of RSV-A. Co-infection rate tended to increase every year. RSVs cause mild as well as severe infections. There are reports of serious clinical progress as RSVs cause overlapping infections with other viruses and increase the risk of secondary bacterial infections. Thus, further research on RSV should be done.
Quantitative assessment of coronary plaque volume change related to triglyceride glucose index: The Progression of AtheRosclerotic PlAque DetermIned by Computed TomoGraphic Angiography IMaging (PARADIGM) registry
Authors: Won Ki-Bum , Lee Byoung Kwon , Park Hyung-Bok , Heo Ran , Lee Sang-Eun , Rizvi Asim , Lin Fay Y. , Kumar Amit , Hadamitzky Martin , Kim Yong-Jin , Sung Ji Min , Conte Edoardo , Andreini Daniele , Pontone Gianluca , Budoff Matthew J. , Gottlieb Ilan , Chun Eun Ju , Cademartiri Filippo , Maffei Erica , Marques Hugo , de Araújo Gonçalves Pedro , Leipsic Jonathon A. , Shin Sanghoon , Choi Jung Hyun , Virmani Renu , Samady Habib , Chinnaiyan Kavitha , Raff Gilbert L. , Stone Peter H. , Berman Daniel S. , Narula Jagat , Shaw Leslee J. , Bax Jeroen J. , Min James K. , Chang Hyuk-Jae
Published: July 2020

Background

The association between triglyceride glucose (TyG) index and coronary atherosclerotic change remains unclear. We aimed to evaluate the association between TyG index and coronary plaque progression (PP) using serial coronary computed tomography angiography (CCTA).

Methods

A total of 1143 subjects (aged 60.7 ± 9.3 years, 54.6% male) who underwent serial CCTA with available data on TyG index and diabetic status were analyzed from The Progression of AtheRosclerotic PlAque DetermIned by Computed TomoGraphic Angiography IMaging (PARADIGM) registry. PP was defined as plaque volume (PV) (mm3) at follow-up minus PV at index > 0. Annual change of PV (mm3/year) was defined as PV change divided by inter-scan period. Rapid PP was defined as the progression of percent atheroma volume (PV divided by vessel volume multiplied by 100) ≥ 1.0%/year.

Results

The median inter-scan period was 3.2 (range 2.6–4.4) years. All participants were stratified into three groups based on TyG index tertiles. The overall incidence of PP was 77.3%. Baseline total PV (group I [lowest]: 30.8 (0.0–117.7), group II: 47.2 (6.2–160.4), and group III [highest]: 57.5 (8.4–154.3); P < 0.001) and the annual change of total PV (group I: 5.7 (0.0–20.2), group II: 7.6 (0.5–23.5), and group III: 9.4 (1.4–27.7); P = 0.010) were different among all groups. The risk of PP (odds ratio [OR] 1.648; 95% confidence interval [CI] 1.167–2.327; P = 0.005) and rapid PP (OR 1.777; 95% CI 1.288–2.451; P < 0.001) was increased in group III compared to that in group I. TyG index had a positive and significant association with an increased risk of PP and rapid PP after adjusting for confounding factors.

Conclusion

TyG index is an independent predictive marker for the progression of coronary atherosclerosis.

Clinical registration ClinicalTrials.gov NCT02803411
Engineering transcription factor-based biosensors for repressive regulation through transcriptional deactivation design in Saccharomyces cerevisiae
Authors: Qiu Chenxi , Chen Xiaoxu , Rexida Reheman , Shen Yu , Qi Qingsheng , Bao Xiaoming , Hou Jin
Published: July 2020

Background

With the development of engineering the microbial cell factories, biosensors have been used widely for regulation of cellular metabolism and high-throughput screening. However, most of the biosensors constructed in Saccharomyces cerevisiae are designed for transcriptional activation. Very few studies have dedicated to the development of genetic circuit for repressive regulation, which is also indispensable for the dynamic control of metabolism.

Results

In this study, through transcriptional deactivation design, we developed transcription-factor-based biosensors to allow repressive regulation in response to ligand. Using a malonyl-CoA sensing system as an example, the biosensor was constructed and systematically engineered to optimize the dynamic range by comparing transcriptional activity of the activators, evaluating the positions and numbers of the operators in the promoter and comparing the effects of different promoters. A biosensor with 82% repression ratio was obtained. Based on this design principle, another two biosensors, which sense acyl-CoA or xylose and downregulate gene expression, were also successfully constructed.

Conclusions

Our work systematically optimized the biosensors for repressive regulation in yeast for the first time. It provided useful framework to construct similar biosensors. Combining the widely reported biosensors for transcriptional activation with the biosensors developed here, it is now possible to construct biosensors with opposing transcriptional activities in yeast.
SUV39H1-DNMT3A-mediated epigenetic regulation of Tim-3 and galectin-9 in the cervical cancer
Authors: Zhang Li , Tian Sijuan , Zhao Minyi , Yang Ting , Quan Shimin , Yang Qing , Song Lihua , Yang Xiaofeng
Published: July 2020

Background

Methylation of histone 3 at lysine 9 (H3K9) and DNA methylation are epigenetic marks correlated with genes silencing. The tumor microenvironment significantly influences therapeutic responses and clinical outcomes. The epigenetic-regulation mechanism of the costimulatory factors Tim-3 and galectin-9 in cervical cancer remains unknown.

Methods

The methylation status of HAVCR2 and LGALS9 were detected by MS-PCR in cervical cancer tissues and cell lines. The underlying molecular mechanism of SUV39H1-DNMT3A-Tim-3/galectin-9 regulation was elucidated using cervical cancer cell lines containing siRNA or/and over-expression system. Confirmation of the regulation of DNMT3A by SUV39H1 used ChIP-qPCR.

Results

SUV39H1 up-regulates H3K9me3 expression at the DNMT3A promoter region, which in turn induced expression of DNMT3A in cervical cancer. In addition, the mechanistic studies indicate that DNMT3A mediates the epigenetic modulation of the HAVCR2 and LGALS9 genes by directly binding to their promoter regions in vitro. Moreover, in an in vivo assay, the expression profile of SUV39H1 up-regulates the level of H3K9me3 at the DNMT3A promoter region was found to correlate with Tim-3 and galectin-9 cellular expression level.

Conclusion

These results indicate that SUV39H1-DNMT3A is a crucial Tim-3 and galectin-9 regulatory axis in cervical cancer.
Linc00473 potentiates cholangiocarcinoma progression by modulation of DDX5 expression via miR-506 regulation
Authors: Huang Lining , Jiang Xingming , Li Zhenglong , Li Jinglin , Lin Xuan , Hu Zengtao , Cui Yunfu
Published: July 2020

Background

Cholangiocarcinoma (CCA) is a mortal cancer with high mortality, whereas the function and mechanism of occurrence and progression of CCA are still mysterious. Long non-coding RNAs (lncRNAs) could function as important regulators in carcinogenesis and cancer progression. Growing evidences have indicated that the novel lncRNA linc00473 plays an important role in cancer progression and metastasis. However, its function and molecular mechanism in CCA remain unknown.

Methods

The linc00473 expression in CCA tissues and cell lines was analyzed using qRT-PCR. Gain- and loss-of-function experiments were conducted to investigate the biological functions of linc00473 both in vitro and in vivo. Insights into the underlying mechanisms of competitive endogenous RNAs (ceRNAs) were determined by bioinformatics analysis, dual-luciferase reporter assays, qRT-PCR arrays, RNA immunoprecipitation (RIP) and rescue experiments.

Results

Linc00473 was highly expressed in CCA tissues and cell lines. Linc00473 knockdown inhibited CCA growth and metastasis. Furthermore, linc00473 acted as miR-506 sponge and regulated its target gene DDX5 expression. Rescue assays verified that linc00473 modulated the tumorigenesis of CCA by regulating miR-506.

Conclusions

The data indicated that linc00473 played an oncogenic role in CCA growth and metastasis, and could serve as a novel molecular target for treating CCA.
Multifunctional TPP-PEG-biotin self-assembled nanoparticle drug delivery-based combination therapeutic approach for co-targeting of GRP78 and lysosome
Authors: Purushothaman Baskaran , Lee Jeongmin , Hong Sera , Song Joon Myong
Published: July 2020

Background

In this study, a multifunctional tetraphenylporphyrin (TPP) conjugated polyethylene glycol with biotin (TPP-PEG-biotin) as a photo-dynamic therapy (PDT) material encapsulating a ruthenium complex 1 (Ru-1) was fabricated as self-assembled nanoparticle (Ru-1@TPP-PEG-biotin SAN) to co-target glucose-regulated protein 78 (GRP78) and the lysosome as a new anti-cancer therapeutic strategy.

Results

The MTT assay results reveals the enhanced anticancer activity of the Ru-1@TPP-PEG-biotin SANs due to the co-targeting of the GRP78 and lysosome. The Ru-1@TPP-PEG-biotin reduced level of GRP78 and lysosomal ceramide that contributed to the stability of the lysosomal membrane. The endoplasmic reticulum (ER) stress concomitant with the inhibition of GRP78 was clearly monitored by the phosphorylation of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), and inositol-requiring enzyme 1 α (IRE1α) kinases to indicate the activation of the unfolded protein response (UPR) signaling using immunofluorescence assay. On the other hand, the degradation of the lysosome was observed through PDT action by the Ru-1@TPP-PEG-biotin SAN treatment. This was confirmed by the co-localization assay showing the disappearance of cathepsin D and lysosomal-associated membrane protein 1 (LAMP1) in the lysosome.

Conclusions

Considering lysosome-mediated autophagy is an effective cancer cell survival mechanism, the degradation of the lysosome along with GRP78 inhibition by the Ru-1@TPP-PEG-biotin SAN combination therapy is suggested as a new co-targeting cancer treatment.
The effect and safety of preoperative biliary drainage in patients with hilar cholangiocarcinoma: an updated meta-analysis
Authors: Teng Fei , Tang You-yin , Dai Jun-long , Li Yongkun , Chen Zhe-yu
Published: July 2020

Background

The effect and safety of preoperative biliary drainage (PBD) in patients with perihilar cholangiocarcinoma are still controversial; the aim of our study is to evaluate all aspects of PBD.

Methods

All included studies featured PBD versus non-PBD (NPBD) groups were from 1996 to 2019 and were extracted from Cochrane Library, Embase, PubMed, and Science Citation Index Expanded.

Results

Sixteen studies met the inclusion criteria and were included in this analysis. PBD may lead to a significantly higher incidence of overall morbidities (OR 0.67, 95% CI 0.53, 0.85; P = 0.0009) and intraoperative transfusions (OR 0.72, 95% CI 0.55, 0.94; P = 0.02); moreover, bile leakage (OR 0.58, 95% CI 0.24, 1.41; P = 0.04), infection (OR 0.31, 95% CI 0.20, 0.47; P < 0.00001), and cholangitis (OR 0.18, 95% CI 0.007, 0.48; P = 0.0007) are also related to PBD. However, NPBD was associated with more frequent hepatic insufficiency (OR 3.09, 95% CI 1.15, 8.31; P = 0.03). In the subgroup meta-analysis, the differences in the outcomes of bile leakage and overall morbidity lost significance between the PBD and NPBD groups when the mean total serum bilirubin (TSB) concentration was above 15 mg/dl.

Conclusion

Meta-analysis demonstrated that compared to NPBD, PBD is associated with a greater risk of several kinds of infection and morbidities, but its ability to reduce postoperative hepatic insufficiency cannot be ignored. In patients with a high TSB concentration, PBD tends to be a better choice. However, these results need to be confirmed in a future prospective randomized trial with large samples to clarify the effects and find a specific TSB concentration for PBD.
Time evolution of frontal plane dynamic balance during locomotor transitions of altered anticipation and complexity
Authors: Li Wentao , Pickle Nathaniel T. , Fey Nicholas P.
Published: July 2020

Background

Locomotor transitions between different ambulatory tasks are essential activities of daily life. During these transitions, biomechanics are affected by various factors such as anticipation, movement direction, and task complexity. These factors are thought to influence the neuromotor regulation of dynamic balance, which can be quantified using whole-body angular momentum (H). However, the specific effects of these factors on balance during transitions are not well understood. The ability to regulate dynamic balance in the presence of these contextual factors is especially important in the frontal plane, as it is usually challenging to maintain walking balance in the frontal plane for individuals with neuromuscular impairments. The purpose of this study was to apportion their effects on the time evolution of frontal plane dynamic balance during locomotor transitions of healthy, unimpaired individuals.

Methods

Five healthy young subjects performed 10 separate types of transitions with discrete combinations of factors including complexity (straight walking, cuts, combined cut/stair ascent), cut style (crossover, sidestep), and anticipation (anticipated and unanticipated). A three-way analysis of variance (ANOVA) was used to compare the maxima, minima, and average rates of change of frontal-plane H among all transitions.

Results

Before transition, within anticipated state peak value of H increased 307% in crossover style relative to sidestep style (p < 0.0001). During Transition Phase, within unanticipated state the magnitudes of average rate of change and peak value increased 70 and 46% in sidestep style compared to crossover style (p < 0.0001 and p = 0.0003). Within sidestep style, they increased in unanticipated state relative to anticipated state. Later in Correction Phase, within both anticipation states peak value of H increased 41 and 75% in cut/stairs transitions relative to cuts (p = 0.010 and p < 0.0001). For cut/stairs transitions, peak value of H increased 45% in unanticipated state compared to anticipated state (p = 0.0001).

Conclusions

These results underlined the detrimental effects of unanticipated state and task complexity on dynamic balance during walking transitions. These findings imply increased demand of neuromuscular system and functional deficits of individuals with neuromuscular disorders during these tasks. In addition, cutting style influenced frontal plane dynamic balance before transition and in response to unanticipated direction change. Collectively, these results may help identify impaired balance control of fall-prone individuals and inform interventions targeting specific destabilizing scenarios.
Deep learning vs. atlas-based models for fast auto-segmentation of the masticatory muscles on head and neck CT images
Authors: Chen Wen , Li Yimin , Dyer Brandon A. , Feng Xue , Rao Shyam , Benedict Stanley H. , Chen Quan , Rong Yi
Published: July 2020

Background

Impaired function of masticatory muscles will lead to trismus. Routine delineation of these muscles during planning may improve dose tracking and facilitate dose reduction resulting in decreased radiation-related trismus. This study aimed to compare a deep learning model with a commercial atlas-based model for fast auto-segmentation of the masticatory muscles on head and neck computed tomography (CT) images.

Material and methods

Paired masseter (M), temporalis (T), medial and lateral pterygoid (MP, LP) muscles were manually segmented on 56 CT images. CT images were randomly divided into training (n = 27) and validation (n = 29) cohorts. Two methods were used for automatic delineation of masticatory muscles (MMs): Deep learning auto-segmentation (DLAS) and atlas-based auto-segmentation (ABAS). The automatic algorithms were evaluated using Dice similarity coefficient (DSC), recall, precision, Hausdorff distance (HD), HD95, and mean surface distance (MSD). A consolidated score was calculated by normalizing the metrics against interobserver variability and averaging over all patients. Differences in dose (∆Dose) to MMs for DLAS and ABAS segmentations were assessed. A paired t-test was used to compare the geometric and dosimetric difference between DLAS and ABAS methods.

Results

DLAS outperformed ABAS in delineating all MMs (p < 0.05). The DLAS mean DSC for M, T, MP, and LP ranged from 0.83 ± 0.03 to 0.89 ± 0.02, the ABAS mean DSC ranged from 0.79 ± 0.05 to 0.85 ± 0.04. The mean value for recall, HD, HD95, MSD also improved with DLAS for auto-segmentation. Interobserver variation revealed the highest variability in DSC and MSD for both T and MP, and the highest scores were achieved for T by both automatic algorithms. With few exceptions, the mean ∆D98%, ∆D95%, ∆D50%, and ∆D2% for all structures were below 10% for DLAS and ABAS and had no detectable statistical difference (P > 0.05). DLAS based contours had dose endpoints more closely matched with that of the manually segmented when compared with ABAS.

Conclusions

DLAS auto-segmentation of masticatory muscles for the head and neck radiotherapy had improved segmentation accuracy compared with ABAS with no qualitative difference in dosimetric endpoints compared to manually segmented contours.
Accuracy and safety of C2 pedicle or pars screw placement: a systematic review and meta-analysis
Authors: Azimi Parisa , Yazdanian Taravat , Benzel Edward C. , Aghaei Hossein Nayeb , Azhari Shirzad , Sadeghi Sohrab , Montazeri Ali
Published: July 2020

Study design

Systematic review and meta-analysis.

Aim

The purpose of this study was to compare the safety and accuracy of the C2 pedicle versus C2 pars screws placement and free-hand technique versus navigation for upper cervical fusion patients.

Methods

Databases searched included PubMed, Scopus, Web of Science, and Cochrane Library to identify all papers published up to April 2020 that have evaluated C2 pedicle/pars screws placement accuracy. Two authors individually screened the literature according to the inclusion and exclusion criteria. The accuracy rates associated with C2 pedicle/pars were extracted. The pooled accuracy rate estimated was performed by the CMA software. A funnel plot based on accuracy rate estimate was used to evaluate publication bias.

Results

From 1123 potentially relevant studies, 142 full-text publications were screened. We analyzed data from 79 studies involving 4431 patients with 6026 C2 pedicle or pars screw placement. We used the Newcastle-Ottawa Scale (NOS) to evaluate the quality of studies included in this review. Overall, funnel plot and Begg’s test did not indicate obvious publication bias. The pooled analysis reveals that the accuracy rates were 93.8% for C2 pedicle screw free-hand, 93.7% for pars screw free-hand, 92.2% for navigated C2 pedicle screw, and 86.2% for navigated C2 pars screw (all, P value < 0.001). No statistically significant differences were observed between the accuracy of placement C2 pedicle versus C2 pars screws with the free-hand technique and the free-hand C2 pedicle group versus the navigated C2 pedicle group (all, P value > 0.05).

Conclusion

Overall, there was no difference in the safety and accuracy between the free-hand and navigated techniques. Further well-conducted studies with detailed stratification are needed to complement our findings.
Systematic review of factors associated with quality of life of asylum seekers and refugees in high-income countries
Authors: van der Boor Catharina F. , Amos Rebekah , Nevitt Sarah , Dowrick Christopher , White Ross G.
Published: July 2020

The stressful experiences that many asylum seekers and refugees (AS&R) are exposed to during forced migration, and during resettlement in host countries, can have a profound impact on their mental health. Comparatively less research attention has been allocated to exploring other indices of quality of life (QoL) in AS&R populations. This review aimed to (i) synthesize the predictors and correlates of QoL of AS&R populations in high-income countries, and (ii) to identify the methodological strengths and weaknesses of this body of research.

Fourteen databases were systematically searched (Medline, PsychINFO, CINAHL, Cochrane Library, Health Technology Assessment, National Health Service Economic Evaluation, Educational Resource Index and Abstracts, BiblioMap, Scopus, Social Sciences Citation Index, Evidence Aid, DARE, Web of Science and PubMed). Eligibility criteria included: adults seeking asylum or refuge in a high-income country, primary quantitative data, the use of a measure based on the WHO’s definition of QoL, published in a peer-reviewed journal. A narrative synthesis approach was used, and the quality was assessed using the AXIS tool for cross-sectional studies and the CASP tool for longitudinal studies.

Of the 13.656 papers identified, 23 met the eligibility criteria. A wide range of factors were found to have significant associations with QoL. Both positive and negative correlates of QoL were largely dominated by social (e.g. social networks) and mental health factors (e.g. depression). Although all of the cross-sectional studies met over half of the quality criteria, only 12 met 75% or more of these criteria. For the longitudinal studies, for all but one study lacked statistical precision and the results cannot be applied to the local population.

Key findings across the various forms of QoL (overall, physical, psychological, social and environmental) were that having established social networks and social integration were associated with higher QoL, whereas having mental disorders (i.e. PTSD or depression) was strongly associated with reduced QoL. More research is needed into physical and environmental predictors and correlates of QoL. The findings of the review can be used to inform policies and interventions aimed at supporting AS&R and promoting the integration and wellbeing of these populations.
CDK7 inhibitor THZ1 enhances antiPD-1 therapy efficacy via the p38α/MYC/PD-L1 signaling in non-small cell lung cancer
Authors: Wang Jian , Zhang Ruiguang , Lin Zhenyu , Zhang Sheng , Chen Yaobing , Tang Jing , Hong Jiaxin , Zhou Xiaoshu , Zong Yan , Xu Yingzhuo , Meng Rui , Xu Shuangbing , Liu Li , Zhang Tao , Yang Kunyu , Dong Xiaorong , Wu Gang
Published: July 2020

Background

The cyclin-dependent kinase 7 (CDK7) subunit of TFIIH regulates RNA polymerase-II-based transcription and promotes tumor progression. However, the mechanisms involved in CDK7-mediated immune evasion are unclear in non-small cell lung cancer (NSCLC).

Methods

RNA silencing and pharmacologic inhibitors were used to evaluate the functions of CDK7/p38α/MYC/PD-L1 axis in cancer cell proliferation and antiPD-1 therapy resistance. Flow cytometry was performed to detect the status of the immune microenvironment after CDK7 inhibition and antiPD-1 therapy in vivo. CD8 depletion antibodies were used to assess the role of CD8+ T cells in combined CDK7 and PD-1 blockade. The associations among CDK7, p38α, MYC, PD-L1, infiltrating T cells, and survival outcomes were validated in two tissue microarrays and public transcriptomic data of NSCLC.

Results

High CDK7 mRNA and protein levels were identified to be associated with poor prognosis in NSCLC. CDK7 silencing and CDK7 inhibitor THZ1 elicited apoptosis and suppressed tumor growth. Moreover, CDK7 ablation specifically suppressed p38α/MYC-associated genes, and THZ1 inhibited MYC transcriptional activity through downregulating p38α. CDK7 inhibition sensitized NSCLC to p38α inhibitor. Further, THZ1 suppressed PD-L1 expression by inhibiting MYC activity. THZ1 boosted antitumor immunity by recruiting infiltrating CD8+ T cells and synergized with antiPD-1 therapy. The CDK7/MYC/PD-L1 signature and infiltrating T cell status collectively stratified NSCLC patients into different risk groups.

Conclusion

These data suggest that the combined CDK7 inhibitor THZ1 and antiPD-1 therapy can be an effective treatment in NSCLC.