bluuebunny/crossref_metadata_2025 huggingface dataset:
TRIM27 promotes the development of esophagus cancer via regulating PTEN/AKT signaling pathway
Authors: Ma Liang , Yao Ninghua , Chen Ping , Zhuang Zhixiang
Published: November 2019

Background

Tripartite motif‑containing 27 (TRIM27) belongs to the TRIM protein family, which is closely related to the progression of some certain human cancers. Nevertheless, the biological function of TRIM27 in esophageal squamous cell carcinoma (ESCC) is still not clear. The aim of present research is to examine the function of TRIM27 in ESCC cells.

Methods

In the present study, RNA interference (RNAi) and lentiviral vector were used to knockdown and overexpression of TRIM27 in ESCC cells respectively. qRT-PCR and western blot were used to examine the expression of TRIM27 in ESCC cells. Cell counting kit-8 (CCK-8) assay was performed to determine the proliferation of cells.

Results

Our analyses indicated that TRIM27 was a pro-proliferation factor in ESCC cells. Moreover, overexpression of TRIM27 deeply suppressed the apoptosis of ESCC cells and accelerated its glucose uptake. In addition, an AKT inhibitor LY294002 was used to determine the connection between TRIM27 and AKT in ESCC cells. Our results demonstrated that TRIM27 has involved in the PI3/AKT signaling pathway. Moreover, TRIM27 interacted with PTEN and mediated its poly-ubiquitination in ESCC cells. Importantly, the glycolysis inhibitor 3-BrPA also inhibited the effect of TRIM27 on ESCC cells. Hence, TRIM27 also participated in the regulation of energy metabolism in ESCC cells.

Conclusions

This research not only gained a deep insight into the biological function of TRIM27 but also elucidated its potential target and signaling pathway in human ESCC cells.
Health related quality of life and its correlates among people with depression attending outpatient department in Ethiopia: a cross sectional study
Authors: Shumye Seid , Belayneh Zelalem , Mengistu Nebiyu
Published: November 2019

Background

Depression is a common mental disorder negatively affects the cognitive, emotion, behavior, functionality and quality of life of people. Poor quality of life results in high rates of relapse, inability to perform occupational and social activities, impaired future outlook, and increases overall health care related costs. However, there is no available evidence regarding the health related quality of people with depression in Ethiopia. Therefore, evaluating the quality of life of people with depression is crucial.

Objective

The aim of this study was to assess the health related quality of life and its correlates among people with depression at Amanuel Mental Specialized Hospital, Addis Ababa, Ethiopia.

Methods

An institutional based cross-sectional study was conducted from May 1st to 30th, 2018. A randomly selected 394 clients with depression were participated in this study. Health related quality of life was measured using world health organization quality of life brief. The collected data were coded and entered to SPSS version 20 for analysis. Step wise multiple linear regression analysis was used to identify the correlates of quality of life and the strength of the correlation was measured by β coefficient with 95% confidence interval.

Results

The mean (±SD) scores of quality of life of people with depression were 41.3 ± 7.5, 42.8 ± 8.2, 38.9 ± 8.9 and 41.8 ± 6.5 for physical, psychological, social and environmental domains, respectively. The Multiple regression analysis showed that age of respondents, age of onset of depression, perceived stigma, living arrangement, social support level and duration of illness were statistically significant predictors of health related quality of life of people with depression in all or at least one domain of quality of life.

Conclusions

This study revealed that nearly half of study participants scored below the mean score in each domain of health related quality of life. This demonstrates a need for improving the quality of life of people with depression through the integration of a positive mental health approach and bio-psychosocial view together with the pharmacological treatments of depression. Moreover, strengthening social support, early identification and treatment of depression and prevention of stigma are also highly recommended to improve the quality of life of people with depression.
Patient’s quality of life after surgery and radiotherapy for extremity soft tissue sarcoma - a retrospective single-center study over ten years
Authors: Götzl Rebekka , Sterzinger Sebastian , Semrau Sabine , Vassos Nikolaos , Hohenberger Werner , Grützmann Robert , Agaimy Abbas , Arkudas Andreas , Horch Raymund E. , Beier Justus P.
Published: November 2019

Background and objectives

The purpose of this study is to analyze major complication rates and different aspects of health-related quality of life (HRQoL) in extremity soft tissue sarcoma (STS) patients treated with or without radio (chemo) therapy and surgery.

Methods

We performed a retrospective analysis of all patients who underwent Extremity STS excision from 2004 to 2014 (182 patients included). Patients’ data were collected from patients’ records. HRQoL was assessed by using EORTC QLQ-C30.

Results

A total of 182 patients underwent sarcoma resection. After neoadjuvant radiochemotherapy (RCT), the major-complication rate amounted to 28% (vs. 7%, no radiotherapy,p <  0.001). Major-complication rates after adjuvant radiotherapy (RT) occurred in 8% (vs. 7%, no radiotherapy,p = 0.265). Comparison QoL scores between treating with neoadjuvant RCT or without RT revealed significant worse scores with neoadjuvant RCT. Further stratification of disease control of these patients showed significant reduced scores in the group of disease-free patients with neoadjuvant RCT compared to irradiated disease-free patients.

Discussion

To date, there have only been a few investigations of QoL in STS. Retrospective study on quality of life have limitations, like a lack of baseline evaluation of QoL. Patient candidated to radiation therapy could have had worse QoL baseline due to more advanced disease. Disease status of the patients who answered the questionnaires could have been an influence of QoL and we could show reduced scores in the group of disease-free patients with neoadjuvant RCT, but not for the patients with recurrence or metastasis, so it is very hard to discriminate whether radiation therapy could really have an impact or not.

Conclusion

This study might assist in further improving the understanding of QoL in STS patients and may animate for prospective studies examining the oncological therapies impact on HRQoL.
Extracellular vesicle cross-talk between pulmonary artery smooth muscle cells and endothelium during excessive TGF-β signalling: implications for PAH vascular remodelling
Authors: de la Cuesta Fernando , Passalacqua Ilaria , Rodor Julie , Bhushan Raghu , Denby Laura , Baker Andrew H.
Published: November 2019

Background

Excessive TGF-β signalling has been shown to underlie pulmonary hypertension (PAH). Human pulmonary artery smooth muscle cells (HPASMCs) can release extracellular vesicles (EVs) but their contents and significance have not yet been studied. Here, we aimed to analyse the contents and biological relevance of HPASMC-EVs and their transport to human pulmonary arterial endothelial cells (HPAECs), as well as the potential alteration of these under pathological conditions.

Methods

We used low-input RNA-Seq to analyse the RNA cargoes sorted into released HPASMC-EVs under basal conditions. We additionally analysed the effects of excessive TGF-β signalling, using TGF-β1 and BMP4, in the transcriptome of HPASMCs and their EVs. We then, for the first time, optimised Cre-loxP technology for its use with primary cells in vitro, directly visualising HPASMC-to-HPAEC communication and protein markers on cells taking up EVs. Furthermore we could analyse alteration of this transport with excessive TGF-β signalling, as well as by other cytokines involved in PAH: IL-1β, TNF-α and VEGFA.

Results

We were able to detect transcripts from 2417 genes in HPASMC-EVs. Surprisingly, among the 759 enriched in HPASMC-EVs compared to their donor cells, we found Zeb1 and 2 TGF-β superfamily ligands, GDF11 and TGF-β3. Moreover, we identified 90 genes differentially expressed in EVs from cells treated with TGF-β1 compared to EVs in basal conditions, including a subset involved in actin and ECM remodelling, among which were bHLHE40 and palladin. Finally, using Cre-loxP technology we showed cell-to-cell transfer and translation of HPASMC-EV Cre mRNA from HPASMC to HPAECs, effectively evidencing communication via EVs. Furthermore, we found increased number of smooth-muscle actin positive cells on HPAECs that took up HPASMC-EVs. The uptake and translation of mRNA was also higher in activated HPAECs, when stimulated with TGF-β1 or IL-1β.

Conclusions

HPASMC-EVs are enriched in RNA transcripts that encode genes that could contribute to vascular remodelling and EndoMT during development and PAH, and TGF-β1 up-regulates some that could enhance this effects. These EVs are functionally transported, increasingly taken up by activated HPAECs and contribute to EndoMT, suggesting a potential effect of HPASMC-EVs in TGF-β signalling and other related processes during PAH development.
Prognostic implications of Aquaporin 9 expression in clear cell renal cell carcinoma
Authors: Xu Wen-Hao , Shi Shen-Nan , Xu Yue , Wang Jun , Wang Hong-Kai , Cao Da-Long , Shi Guo-Hai , Qu Yuan-Yuan , Zhang Hai-Liang , Ye Ding-Wei
Published: November 2019

Background

Growing evidence has demonstrated immune reactivity as a confirmed important carcinogenesis and therapy efficacy for clear cell renal cell carcinoma (ccRCC). Aquaporin 9 (AQP9) is involved in many immune-related signals; however, its role in ccRCC remains to be elucidated. This study investigated AQP9 expression in tumor tissues and defined the prognostic value in ccRCC patients.

Methods

A total of 913 ccRCC patients with available RNA-sequence data from the Cancer Genome Atlas (TCGA) database and Fudan University Shanghai Cancer Center (FUSCC) were consecutively recruited in analyses. Differential transcriptional and proteome expression profiles were obtained and validated using multiple datasets. A partial likelihood test from Cox regression analysis was developed to address the influence of independent factors on progression-free survival (PFS) and overall survival (OS). The Kaplan–Meier method and log-rank test were performed to assess survival. Receiver operating characteristic (ROC) curves were used to describe binary classifier value of AQP9 using area under the curve (AUC) score. Functional enrichment analyses and immune infiltration analysis were used to describe significantly involved hallmark pathways of hub genes.

Results

Significantly elevated transcriptional and proteomic AQP9 expressions were found in ccRCC samples. Increased AQP9 mRNA expression was significantly associated with advanced clinicopathological parameters and correlated with shorter PFS and OS in TCGA and FUSCC cohorts (p < 0.001). ROC curves suggested the significant diagnostic and prognostic ability of AQP9 (PFS, AUC = 0.823; OS, AUC = 0.828). Functional annotations indicated that AQP9 is involved in the most significant hallmarks including complement, coagulation, IL6/JAK–STAT3, inflammatory response and TNF-alpha signaling pathways.

Conclusion

Our study revealed that elevated AQP9 expression was significantly correlated with aggressive progression, poor survival and immune infiltrations in ccRCC patients, and we validated its prognostic value in a real-world cohort. These data suggest that AQP9 may act as an oncogene and a promising prognostic marker in ccRCC.
Severe traumatic valgus instability of the elbow: pathoanatomy and outcomes of primary operation
Authors: Zhang Lei , Wang Laixu , Yu Shiyang , Lv Zhanhui , Zhang Peng , Fan Cunyi , Shen Yixin
Published: November 2019

Background

The objective of the study was to depict the pathoanatomy of traumatic valgus instability of the elbow and to report clinical outcomes of primary operation.

Methods

Thirty-one patients presented with traumatic valgus instability of the elbow without dislocation. Thirty-one patients underwent surgical intervention of radial head fractures (28 open reduction and internal fixation and 3 radial head resection) and anatomical repair of the anterior bundle of medial collateral ligament (AMCL) with suture anchors. Twenty patients with disruption of the flexor-pronator tendon (FPT) and 14 patients with tears of the anterior capsule had primary repair of the FPT and anterior capsule simultaneously. Clinical outcomes were evaluated with the Mayo Elbow Performance Score (MEPS), modified hospital for special surgery assessment scale (HSS), and Disabilities of the Arm, Shoulder, and Hand (DASH) score.

Results

The median follow-up was 37.3 months (range, 15–53 months). Radial head fractures and complete avulsion of the medial collateral ligament (MCL) from its humeral footprint were confirmed in all patients intraoperatively. Intraoperative findings indicated disruption of the FPT in 20 patients and tears of the anterior capsule in 14 patients. Twenty-nine of 31 patients returned to previous activity and work levels within 6 months after surgery. The MEPS, modified HSS, and DASH score were 94 ± 4, 91 ± 5, and 8 ± 2 at the latest follow-up.

Conclusions

Radial head fractures with avulsion of the MCL can lead to severe valgus instability of the elbow. Primary operation to repair these disrupted structures, especially repair of the AMCL, can effectively restore valgus stability.
The effects of tourniquet use on blood loss in primary total knee arthroplasty for patients with osteoarthritis: a meta-analysis
Authors: Cai D. F. , Fan Q. H. , Zhong H. H. , Peng S. , Song H.
Published: November 2019

Background

The tourniquet is a common medical instrument used in total knee arthroplasty (TKA). However, there has always been a debate about the use of a tourniquet and there is no published meta-analysis to study the effects of a tourniquet on blood loss in primary TKA for patients with osteoarthritis.

Methods

We performed a literature review on high-quality clinical studies to determine the effects of using a tourniquet or not on blood loss in cemented TKA. PubMed, Web of Science, MEDLINE, Embase, and the Cochrane Library were searched up to November 2018 for relevant randomized controlled trials (RCTs). We conducted a meta-analysis following the guidelines of the Cochrane Reviewer’s Handbook. We used the Cochrane Collaboration’s tool for assessing the risk of bias of each trial. The statistical analysis was performed with Review Manager statistical software (version 5.3).

Results

Eleven RCTs involving 541 patients (541 knees) were included in this meta-analysis. There were 271 patients (271 knees) in the tourniquet group and 270 patients (270 knees) in the no tourniquet group. The results showed that using a tourniquet significantly decreased intraoperative blood loss (P < 0.002), calculated blood loss (P < 0.002), and the time of operation (P < 0.002), but tourniquet use did not significantly decrease postoperative blood loss (P > 0.05), total blood loss (P > 0.05), the rate of transfusion (P > 0.05), and of deep vein thrombosis (DVT) (P > 0.05) in TKA.

Conclusions

Using a tourniquet can significantly decrease intraoperative blood loss, calculated blood loss, and operation time but does not significantly decrease the rate of transfusion or the rate of DVT in TKA. More research is needed to determine if there are fewer complications in TKA without the use of tourniquets.
Active clearance of chest tubes is associated with reduced postoperative complications and costs after cardiac surgery: a propensity matched analysis
Authors: Baribeau Yvon , Westbrook Benjamin , Baribeau Yanick , Maltais Simon , Boyle Edward M. , Perrault Louis P.
Published: November 2019

Background

Chest tubes are routinely used to evacuate shed mediastinal blood in the critical care setting in the early hours after heart surgery. Inadequate evacuation of shed mediastinal blood due to chest tube clogging may result in retained blood around the heart and lungs after cardiac surgery. The objective of this study was to compare if active chest tube clearance reduces the incidence of retained blood complications and associated hospital resource utilization after cardiac surgery.

Methods

Propensity matched analysis of 697 consecutive patients who underwent cardiac surgery at a single center. 302 patients served as a baseline control (Phase 0), 58 patients in a training and compliance verification period (Phase 1) and 337 were treated prospectively using active tube clearance (Phase 2). The need to drain retained blood, pleural effusions, postoperative atrial fibrillation, ICU resource utilization and hospital costs were assessed.

Results

Propensity matched patients in Phase 2 had a reduced need for drainage procedures for pleural effusions (22% vs. 8.1%, p < 0.001) and reduced postoperative atrial fibrillation (37 to 25%, P = 0.011). This corresponded with fewer hours in the ICU (43.5 [24–79] vs 30 [24–49], p = < 0.001), reduced median postoperative length of stay (6 [4–8] vs 5 [4–6.25], p < 0.001) median costs reduced by $1831.45 (− 3580.52;82.38, p = 0.04) and the mean costs reduced by an average of $2696 (− 6027.59;880.93, 0.116).

Conclusions

This evidence supports the concept that efforts to actively maintain chest tube patency in early recovery is useful in improving outcomes and reducing resource utilization and costs after cardiac surgery.

Trial registration

Clinicaltrial.gov, NCT02145858, Registered: May 23, 2014.
Endophytes from Ginkgo biloba and their secondary metabolites
Authors: Yuan Zhihui , Tian Yun , He Fulin , Zhou Haiyan
Published: November 2019

Ginkgo biloba is a medicinal plant which contains abundant endophytes and various secondary metabolites. According to the literary about the information of endophytics from Ginkgo biloba, Chaetomium, Aspergillus, Alternaria, Penicillium and Charobacter were isolated from the root, stem, leaf, seed and bark of G. biloba. The endophytics could produce lots of phytochemicals like flavonoids, terpenoids, and other compounds. These compounds have antibacteria, antioxidation, anticardiovascular, anticancer, antimicrobial and some novel functions. This paper set forth the development of active extracts isolated from endophytes of Ginkgo biloba and will help to improve the resources of Ginkgo biloba to be used in a broader field.
Higher matrix stiffness as an independent initiator triggers epithelial-mesenchymal transition and facilitates HCC metastasis
Authors: Dong Yinying , Zheng Qiongdan , Wang Zhiming , Lin Xiahui , You Yang , Wu Sifan , Wang Yaohui , Hu Chao , Xie Xiaoying , Chen Jie , Gao Dongmei , Zhao Yan , Wu Weizhong , Liu Yinkun , Ren Zhenggang , Chen Rongxin , Cui Jiefeng
Published: November 2019

Background

Increased liver stiffness exerts a detrimental role in driving hepatocellular carcinoma (HCC) malignancy and progression, and indicates a high risk of unfavorable outcomes. However, it remains largely unknown how liver matrix stiffness as an independent cue triggers epithelial-mesenchymal transition (EMT) and facilitates HCC metastasis.

Methods

Buffalo rat HCC models with different liver stiffness backgrounds and an in vitro Col I-coated cell culture system with tunable stiffness were used in the study to explore the effects of matrix stiffness on EMT occurrence and its underlying molecular mechanism. Clinical significance of liver stiffness and key molecules required for stiffness-induced EMT were validated in HCC cohorts with different liver stiffness.

Results

HCC xenografts grown in higher stiffness liver exhibited worse malignant phenotypes and higher lung metastasis rate, suggesting that higher liver stiffness promotes HCC invasion and metastasis. Cell tests in vitro showed that higher matrix stiffness was able to strikingly strengthen malignant phenotypes and independently induce EMT occurrence in HCC cells, and three signaling pathways converging on Snail expression participated in stiffness-mediated effect on EMT including integrin-mediated S100A11 membrane translocation, eIF4E phosphorylation, and TGF β1 autocrine. Additionally, the key molecules required for stiffness-induced EMT were highly expressed in tumor tissues of HCC patients with higher liver stiffness and correlated with poor tumor differentiation and higher recurrence.

Conclusions

Higher matrix stiffness as an initiator triggers epithelial-mesenchymal transition (EMT) in HCC cells independently, and three signaling pathways converging on Snail expression contribute to this pathological process. This work highlights a significant role of biomechanical signal in triggering EMT and facilitating HCC invasion and metastasis.
Organoids of epithelial ovarian cancer as an emerging preclinical in vitro tool: a review
Authors: Dumont Sander , Jan Ziga , Heremans Ruben , Van Gorp Toon , Vergote Ignace , Timmerman Dirk
Published: November 2019

Epithelial ovarian cancer (EOC) remains the most lethal gynecological cancer in developed countries, indicating the need for further research. Although current cancer models prove useful, they have major limitations. Organoids, a novel in vitro 3D cell culture technique, derived from stem cells, could provide a bridge between the current preclinical platforms. However, this technique is still in its early stages. After conducting a systematic literature search, only sixteen manuscripts concerning ovarian related organoids could be retrieved.

In this review, we discuss current tumor models, including organoids and provide a comprehensive review about organoids of ovarian tissue. Potential future applications are addressed, proving organoids to be an interesting platform for modeling tumorigenesis, drug testing and screening and other applications. Recent advancements could usher in a new era of highly personalized medicine in EOC.
Prognostic values and prospective pathway signaling of MicroRNA-182 in ovarian cancer: a study based on gene expression omnibus (GEO) and bioinformatics analysis
Authors: Li Yaowei , Li Li
Published: November 2019

Background

Ovarian carcinoma (OC) is a common cause of death among women with gynecological cancer. MicroRNAs (miRNAs) are believed to have vital roles in tumorigenesis of OC. Although miRNAs are broadly recognized in OC, the role of has-miR-182-5p (miR-182) in OC is still not fully elucidated.

Methods

We evaluated the significance of miR-182 expression in OC by using analysis of a public dataset from the Gene Expression Omnibus (GEO) database and a literature review. Furthermore, we downloaded three mRNA datasets of OC and normal ovarian tissues (NOTs), GSE14407, GSE18520 and GSE36668, from GEO to identify differentially expressed genes (DEGs). Then the targeted genes of hsa-miR-182-5p (TG_miRNA-182-5p) were predicted using miRWALK3.0. Subsequently, we analyzed the gene overlaps integrated between DEGs in OC and predicted target genes of miR-182 by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. STRING and Cytoscape were used to construct a protein-protein interaction (PPI) network and the prognostic effects of the hub genes were analyzed.

Results

A common pattern of up-regulation for miR-182 in OC was found in our review of the literature. A total of 268 DEGs, both OC-related and miR-182-related, were identified, of which 133 genes were discovered from the PPI network. A number of DEGs were enriched in extracellular matrix organization, pathways in cancer, focal adhesion, and ECM-receptor interaction. Two hub genes, MCM3 and GINS2, were significantly associated with worse overall survival of patients with OC. Furthermore, we identified covert miR-182-related genes that might participate in OC by network analysis, such as DCN, AKT3, and TIMP2. The expressions of these genes were all down-regulated and negatively correlated with miR-182 in OC.

Conclusions

Our study suggests that miR-182 is essential for the biological progression of OC.
Phase I clinical trial of the combination of eribulin and everolimus in patients with metastatic triple-negative breast cancer
Authors: Lee Jin Sun , Yost Susan E. , Blanchard Suzette , Schmolze Daniel , Yin Hongwei Holly , Pillai Raju , Robinson Kim , Tang Aileen , Martinez Norma , Portnow Jana , Wen Wei , Yim John H. , Brauer Heather Ann , Ren Yuqi , Luu Thehang , Mortimer Joanne , Yuan Yuan
Published: November 2019

Background

Alteration of the PI3K/AKT/mTOR pathway is a common genomic abnormality detected in triple-negative breast cancer (TNBC). Everolimus acts synergistically with eribulin in TNBC cell lines and xenograft models. This phase I trial was designed to test the safety and tolerability of combining eribulin and everolimus in patients with metastatic TNBC.

Methods

The primary objective of this study was to evaluate the safety and toxicities of the combination. Patients with metastatic TNBC who had up to four lines of prior chemotherapies were enrolled. The combination of eribulin and everolimus was tested using three dosing levels: A1 (everolimus 5 mg daily; eribulin 1.4 mg/m2 days 1 and 8 every 3 weeks), A2 (everolimus 7.5 mg daily; eribulin 1.4 mg/m2, days 1 and 8 every 3 weeks), and B1 (everolimus 5 mg daily; eribulin 1.1 mg/m2 days 1 and 8 every 3 weeks).

Results

Twenty-seven patients with median age 55 years were enrolled. Among 8 evaluable patients who received dose level A1, 4 had dose-limiting toxicities (DLTs). Among 3 evaluable patients treated with dose level A2, 2 had DLTs. Among 12 evaluable patients who received dose level B1, 4 had DLTs. The DLTs were neutropenia, stomatitis, and hyperglycemia. Over the study period, 59% had a ≥ grade 3 toxicity, 44% had ≥ grade 3 hematologic toxicities, and 22% had grade 4 hematologic toxicities. The most common hematological toxicities were neutropenia, leukopenia, and lymphopenia. Thirty-three percent had grade 3 non-hematologic toxicities. The most common non-hematological toxicities were stomatitis, hyperglycemia, and fatigue. The median number of cycles completed was 4 (range 0–8). Among 25 eligible patients, 9 patients (36%) achieved the best response as partial response, 9 (36%) had stable disease, and 7 (28%) had progression. The median time to progression was 2.6 months (95% CI [2.1, 4.0]), and median overall survival (OS) was 8.3 months (95% CI [5.5, undefined]).

Conclusion

Eribulin 1.1 mg/m2 days 1 and 8 every 3 weeks with everolimus 5 mg daily was defined as the highest dose with acceptable toxicity (RP2D). The combination is safe, and efficacy is modest. A post hoc analysis showed that participants that used dexamethasone mouthwash stayed on treatment for one additional cycle.

Trial registration

ClinicalTrials.gov, NCT02120469. Registered 18 April 2014
Comparative risk of malignancies and infections in patients with rheumatoid arthritis initiating abatacept versus other biologics: a multi-database real-world study
Authors: Simon Teresa A. , Boers Maarten , Hochberg Marc , Baker Nicole , Skovron Mary L. , Ray Nitesh , Singhal Sanket , Suissa Samy , Gomez-Caminero Andres
Published: November 2019

Background

Patients with rheumatoid arthritis (RA) are at an increased risk of developing certain cancers and infections compared with the general population. Biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) are effective treatment options for RA, but limited evidence is available on the comparative risks among b/tsDMARDs. We assessed the risk of malignancies and infections in patients with RA who initiated abatacept versus other b/tsDMARDs in a real-world setting.

Methods

This retrospective, observational study used administrative data from three large US healthcare databases (MarketScan, PharMetrics, and Optum) to identify patients treated with abatacept or other b/tsDMARDs. In both groups, age-stratified incidence rates (IRs) with 95% confidence intervals (CIs) were calculated for total malignancy and hospitalized infections; propensity score matching and Cox proportional hazards regression models were used to estimate hazard ratios (HRs) with 95% CIs for total malignancy, lung cancer, lymphoma, breast cancer, non-melanoma skin cancer (NMSC), hospitalized infections, opportunistic infections, and tuberculosis (TB), both within individual databases and in meta-analyses across the three databases.

Results

A rounded total of 19.2, 13.6, and 4.2 thousand patients initiating abatacept and 55.3, 40.8, and 13.8 thousand initiating other b/tsDMARDs were identified in the MarketScan, PharMetrics, and Optum databases, respectively. The IRs for total malignancy and hospitalized infections were similar between the two groups in each age stratum. In meta-analyses, total malignancy risk (HR [95% CI] 1.09 [1.02–1.16]) of abatacept versus other b/tsDMARDs was slightly but statistically significantly increased; small, but not statistically significant, increases were seen for lung cancer (1.10 [0.62–1.96]), lymphoma (1.27 [0.94–1.72]), breast cancer (1.15 [0.92–1.45]), and NMSC (1.10 [0.93–1.30]). No significant increase in hospitalized infections (0.96 [0.84–1.09]) or opportunistic infections (1.06 [0.96–1.17]) was seen. For TB, low event counts precluded meta-analysis.

Conclusions

In this real-world multi-database study, the risks for specific cancers and infections did not differ significantly between patients in the abatacept and other b/tsDMARDs groups. The slight increase in total malignancy risk associated with abatacept needs further investigation. These results are consistent with the established safety profile of abatacept.
Acute kidney injury associated with febuxostat and allopurinol: a post-marketing study
Authors: Rey Amayelle , Batteux Benjamin , Laville Solène M. , Marienne Justine , Masmoudi Kamel , Gras-Champel Valérie , Liabeuf Sophie
Published: November 2019

Background

For patients with recurrent flares of gout, tophi, urate crystal arthropathy, and renal stones, urate-lowering therapies (ULTs, including allopurinol and febuxostat) are the first-line treatment. Due to the widespread use of these ULTs (especially in patients with impaired renal function), assessment of the associated renal risk is essential. Accordingly, we performed a disproportionality analysis of reported cases of acute renal failure (ARF) associated with allopurinol and febuxostat.

Methods

We carried out a case/non-case study of the World Health Organization’s VigiBase® pharmacovigilance database between January 1, 2008, and December 31, 2018. The frequency of reports of ARF as a standardized Medical Dictionary for Regulatory Activities query for allopurinol and febuxostat was compared with that of all other reports for the two drugs and quoted as the reporting odds ratio (ROR) [95% confidence interval (CI)]. The results’ stability was assessed in a series of sensitivity analyses (notably after the exclusion of putative competing drugs).

Results

Among 3509 “suspected drug” notifications for febuxostat and 18,730 for allopurinol, we identified respectively 317 and 1008 cases of ARF. Acute renal failure was reported significantly more frequently for febuxostat and allopurinol than for other drugs (ROR [95%CI] 5.67 [5.05–6.36] and 3.25 [3.05–3.47], respectively). For both drugs, the ROR was higher in women than in men, respectively 11.60 [9.74–13.82] vs. 3.14 [2.69–3.67] for febuxostat and 4.45 [4.04–4.91] vs. 2.29 [2.11–2.50] for allopurinol. The sensitivity analyses confirmed the disproportionality for these two ULTs.

Conclusions

Acute renal failure was reported respectively 5.7 and 3.3 times more frequently for febuxostat and for allopurinol than for other drugs. Due to the potential consequences of ARF, physicians should take account of this disproportionality signal when prescribing the ULTs febuxostat and allopurinol.
Lower serum 25-hydroxyvitamin D3 concentration is associated with higher pain and disability in subjects with low back pain: a case–control study
Authors: Pishgahi Alireza , Dolatkhah Neda , Shakouri Seyed Kazem , Hashemian Maryam , Amiri Atefeh , Delkhosh Reihany Morteza , Jahanjou Fatemeh
Published: November 2019

Objectives

Low back pain (LBP) is a common medical problem worldwide. The aim of this study is to evaluate the association between serum concentration of 25-hydroxivitamin D3 and functional disability in patients suffering from LBP in a sample of Azeri middle-aged subjects, North West of Iran.

Results

In this case–control study, 63 eligible patients with LBP and 55 healthy subjects enrolled in the study. Peripheral venous blood was taken for evaluating the serum concentration of 25-hydroxivitamin D3. We recognized factors related with LBP by multiple regression analyses. The average serum 25-hydroxivitamin D3 concentration in case group was significantly lower than that of the matched controlled group (26.25 ± 15.95 vs. 34.20 ± 14.92, p-value < 0.01 respectively). Subjects with vitamin D deficiency or insufficiency were more likely to exhibit LBP than subjects with normal serum 25-hydroxivitamin D3 concentration [(OR = 2.388, 95% CI (1.114 to 5.119)]. According to the partial correlation analysis, there was a reverse correlation between serum 25-hydroxivitamin D3 concentration with functional disability measured by Modified Oswestry Questionnaire (r = − 0.307, p = 0.017) and also with pain intensity according to Visual Analogue Scale (VAS) score (r = − 0.268, p = 0.040) whilst adjusting for age, sex and body mass index (BMI).
Adherence to adrenaline autoinjector prescriptions in patients with anaphylaxis
Authors: Parke Louise , Senders Annemarie Schaeffer , Bindslev-Jensen Carsten , Lassen Annmarie Touborg , Oropeza Athamaica Ruiz , Halken Susanne , Broesby-Olsen Sigurd , Kjær Henrik Fomsgaard , Mortz Charlotte G.
Published: November 2019

This study evaluates adherence to adrenaline autoinjector prescriptions in a cohort of well-characterized anaphylaxis patients. The overall retrieval rate was 76% with the highest rate in patients with severe anaphylaxis. Special attention is needed in patients with unknown elicitors and in young adults, comprising the largest proportion of non-adherent patients.

Trial registration No intervention performed. Retrospective data used with permission from the Danish Data Protection Agency and Regional Committees on Health Research Ethics
Extracellular RNA in systemic lupus erythematosus
Authors: Liu Shanshan , Wang Dandan , Liu Yuan
Published: November 2019

Since the discovery of extracellular RNA (exRNA), it has been shown that exRNAs play a significant role as a transducer in intercellular communication and biomarkers in various diseases. Systemic lupus erythematosus (SLE) is a kind of autoimmune disease that has protean manifestations. The survival and long-term prognosis of patients with SLE has improved in these 5–10 years, while disease pathogenesis is still not clear. Many researchers found the changes in exRNA profile, and exRNAs are likely participating in the process of SLE. In this review, we summarize the current profile and function of exRNA in SLE. Circulating miRNAs, in particular, have been identified as biomarkers for SLE diagnosis. We also explore the function of lncRNA in SLE and the potential correlation with disease progression and activity. These studies show that exRNAs may take parts in the process of SLE and some of them can be used as diagnostic tool for SLE.
Patients With Primary Aldosteronism Respond to Unilateral Adrenalectomy With Long-Term Reduction in Salt Intake
Authors: Adolf Christian , Heinrich Daniel A , Holler Finn , Lechner Benjamin , Nirschl Nina , Sturm Lisa , Görge Veronika , Riester Anna , Williams Tracy A , Treitl Marcus , Ladurner Roland , Beuschlein Felix , Reincke Martin
Published: November 2019

Context

High dietary salt intake is known to aggravate arterial hypertension. This effect could be of particular relevance in the setting of primary aldosteronism (PA), which is associated with cardiovascular damage independent of blood pressure levels. The aim of this study was to determine the impact of therapy on salt intake in PA patients.

Patients and Methods

A total of 148 consecutive PA patients (66 with unilateral and 82 with bilateral PA) from the database of the German Conn’s Registry were included. Salt intake was quantified by 24-hour urinary sodium excretion before and after initiation of PA treatment.

Study design

Observational longitudinal cohort study.

Setting

Tertiary care hospital.

Results

At baseline, unilateral PA patients had a significantly higher urinary sodium excretion than patients with bilateral disease (205 vs 178 mmol/d, P = 0.047). Higher urinary sodium excretion correlated with an increased cardiovascular risk profile including proteinuria, impaired lipid, and glucose metabolism and was associated with higher daily doses of antihypertensive drugs to achieve blood pressure control. In unilateral disease, urinary sodium excretion dropped spontaneously to 176 mmol/d (P = 0.012) 1 year after unilateral adrenalectomy and remained low at 3 years of follow-up (174 mmol/d). In contrast, treatment with mineralocorticoid receptor antagonists (MRA) in bilateral PA patients was not associated with a significant change in urinary sodium excretion at follow-up (179 mmol/d vs 183 mmol/d).

Conclusion

PA patients consuming a high-salt diet, estimated based on urinary sodium excretion, respond to adrenalectomy with a significant reduction of salt intake, in contrast to MRA treatment.
The Molecular Basis of Congenital Hypopituitarism and Related Disorders
Authors: Gregory Louise Cheryl , Dattani Mehul Tulsidas
Published: November 2019

Context

Congenital hypopituitarism (CH) is characterized by the presence of deficiencies in one or more of the 6 anterior pituitary (AP) hormones secreted from the 5 different specialized cell types of the AP. During human embryogenesis, hypothalamo–pituitary (HP) development is controlled by a complex spatio-temporal genetic cascade of transcription factors and signaling molecules within the hypothalamus and Rathke’s pouch, the primordium of the AP.

Evidence Acquisition

This mini-review discusses the genes and pathways involved in HP development and how mutations of these give rise to CH. This may present in the neonatal period or later on in childhood and may be associated with craniofacial midline structural abnormalities such as cleft lip/palate, visual impairment due to eye abnormalities such as optic nerve hypoplasia (ONH) and microphthalmia or anophthalmia, or midline forebrain neuroradiological defects including agenesis of the septum pellucidum or corpus callosum or the more severe holoprosencephaly.

Evidence Synthesis

Mutations give rise to an array of highly variable disorders ranging in severity. There are many known causative genes in HP developmental pathways that are routinely screened in CH patients; however, over the last 5 years this list has rapidly increased due to the identification of variants in new genes and pathways of interest by next-generation sequencing.

Conclusion

The majority of patients with these disorders do not have an identified molecular basis, often making management challenging. This mini-review aims to guide clinicians in making a genetic diagnosis based on patient phenotype, which in turn may impact on clinical management.
Dissecting the Role of Thyrotropin in the DNA Damage Response in Human Thyrocytes after 131I, γ Radiation and H2O2
Authors: Kyrilli Aglaia , Gacquer David , Detours Vincent , Lefort Anne , Libert Frédéric , Twyffels Laure , Van Den Eeckhaute Laura , Strickaert Aurélie , Maenhaut Carine , De Deken Xavier , Dumont Jacques Emile , Miot Françoise , Corvilain Bernard
Published: November 2019

Background

The early molecular events in human thyrocytes after 131I exposure have not yet been unravelled. Therefore, we investigated the role of TSH in the 131I-induced DNA damage response and gene expression in primary cultured human thyrocytes.

Methods

Following exposure of thyrocytes, in the presence or absence of TSH, to 131I (β radiation), γ radiation (3 Gy), and hydrogen peroxide (H2O2), we assessed DNA damage, proliferation, and cell-cycle status. We conducted RNA sequencing to profile gene expression after each type of exposure and evaluated the influence of TSH on each transcriptomic response.

Results

Overall, the thyrocyte responses following exposure to β or γ radiation and to H2O2 were similar. However, TSH increased 131I-induced DNA damage, an effect partially diminished after iodide uptake inhibition. Specifically, TSH increased the number of DNA double-strand breaks in nonexposed thyrocytes and thus predisposed them to greater damage following 131I exposure. This effect most likely occurred via Gα q cascade and a rise in intracellular reactive oxygen species (ROS) levels. β and γ radiation prolonged thyroid cell-cycle arrest to a similar extent without sign of apoptosis. The gene expression profiles of thyrocytes exposed to β/γ radiation or H2O2 were overlapping. Modulations in genes involved in inflammatory response, apoptosis, and proliferation were observed. TSH increased the number and intensity of modulation of differentially expressed genes after 131I exposure.

Conclusions

TSH specifically increased 131I-induced DNA damage probably via a rise in ROS levels and produced a more prominent transcriptomic response after exposure to 131I.
The cyclin B2/CDK1 complex inhibits separase activity in mouse oocyte meiosis I
Authors: Li Jian , Ouyang Ying-Chun , Zhang Chun-Hui , Qian Wei-Ping , Sun Qing-Yuan
Published: November 2019

Chromosome segregation is driven by separase, activity of which is inhibited by binding to securin and cyclin B1/CDK1. In meiosis, premature separase activity will induce aneuploidy or abolish chromosome segregation owing to the untimely destruction of cohesin. Recently, we have proved that cyclin B2 can compensate for cyclin B1 in CDK1 activation for the oocyte meiosis G2/M transition. In the present study, we identify an interaction between cyclin B2/CDK1 and separase in mouse oocytes. We find that cyclin B2 degradation is required for separase activation during the metaphase I-anaphase I transition because the presence of stable cyclin B2 leads to failure of homologous chromosome separation and to metaphase I arrest, especially in the simultaneous absence of securin and cyclin B1. Moreover, non-phosphorylatable separase rescues the separation of homologous chromosomes in stable cyclin B2-arrested cyclin B1-null oocytes. Our results indicate that cyclin B2/CDK1 is also responsible for separase inhibition via inhibitory phosphorylation to regulate chromosome separation in oocyte meiosis, which may not occur in other cell types.
In vivo cerebellar circuit function is disrupted in an mdx mouse model of Duchenne muscular dystrophy
Authors: Stay Trace L. , Miterko Lauren N. , Arancillo Marife , Lin Tao , Sillitoe Roy V.
Published: November 2019

Duchenne muscular dystrophy (DMD) is a debilitating and ultimately lethal disease involving progressive muscle degeneration and neurological dysfunction. DMD is caused by mutations in the dystrophin gene, which result in extremely low or total loss of dystrophin protein expression. In the brain, dystrophin is heavily localized to cerebellar Purkinje cells, which control motor and non-motor functions. In vitro experiments in mouse Purkinje cells revealed that loss of dystrophin leads to low firing rates and high spiking variability. However, it is still unclear how the loss of dystrophin affects cerebellar function in the intact brain. Here, we used in vivo electrophysiology to record Purkinje cells and cerebellar nuclear neurons in awake and anesthetized female mdx (also known as Dmd) mice. Purkinje cell simple spike firing rate is significantly lower in mdx mice compared to controls. Although simple spike firing regularity is not affected, complex spike regularity is increased in mdx mutants. Mean firing rate in cerebellar nuclear neurons is not altered in mdx mice, but their local firing pattern is irregular. Based on the relatively well-preserved cytoarchitecture in the mdx cerebellum, our data suggest that faulty signals across the circuit between Purkinje cells and cerebellar nuclei drive the abnormal firing activity. The in vivo requirements of dystrophin during cerebellar circuit communication could help explain the motor and cognitive anomalies seen in individuals with DMD.

This article has an associated First Person interview with the first author of the paper.
Quantitative whole-brain 3D imaging of tyrosine hydroxylase-labeled neuron architecture in the mouse MPTP model of Parkinson's disease
Authors: Roostalu Urmas , Salinas Casper B. G. , Thorbek Ditte D. , Skytte Jacob L. , Fabricius Katrine , Barkholt Pernille , John Linu M. , Jurtz Vanessa Isabell , Knudsen Lotte Bjerre , Jelsing Jacob , Vrang Niels , Hansen Henrik H. , Hecksher-Sørensen Jacob
Published: November 2019

Parkinson's disease (PD) is a basal ganglia movement disorder characterized by progressive degeneration of the nigrostriatal dopaminergic system. Immunohistochemical methods have been widely used for characterization of dopaminergic neuronal injury in animal models of PD, including the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) mouse model. However, conventional immunohistochemical techniques applied to tissue sections have inherent limitations with respect to loss of 3D resolution, yielding insufficient information on the architecture of the dopaminergic system. To provide a more comprehensive and non-biased map of MPTP-induced changes in central dopaminergic pathways, we used iDISCO immunolabeling, light-sheet fluorescence microscopy (LSFM) and deep-learning computational methods for whole-brain three-dimensional visualization and automated quantitation of tyrosine hydroxylase (TH)-positive neurons in the adult mouse brain. Mice terminated 7 days after acute MPTP administration demonstrated widespread alterations in TH expression. Compared to vehicle controls, MPTP-dosed mice showed a significant loss of TH-positive neurons in the substantia nigra pars compacta and ventral tegmental area. Also, MPTP dosing reduced overall TH signal intensity in basal ganglia nuclei, i.e. the substantia nigra, caudate-putamen, globus pallidus and subthalamic nucleus. In contrast, increased TH signal intensity was predominantly observed in limbic regions, including several subdivisions of the amygdala and hypothalamus. In conclusion, mouse whole-brain 3D imaging is ideal for unbiased automated counting and densitometric analysis of TH-positive cells. The LSFM–deep learning pipeline tracked brain-wide changes in catecholaminergic pathways in the MPTP mouse model of PD, and may be applied for preclinical characterization of compounds targeting dopaminergic neurotransmission.