bluuebunny/crossref_metadata_2025_split huggingface dataset:
Locking compression plates versus locking plates for tibial plateau levelling osteotomy in dogs: progression of osteoarthritis, bone healing score and lameness degree
Authors: Macrì Francesco , Cicero Luca , Angileri Vito , Biondi Vito , Miele Piero , Scaletta Lorenzo , Costa Giovanna Lucrezia , Cassata Giovanni , Di Pietro Simona 
Published: May 2021

AbstractBackgroundThe partial or complete cranial cruciate ligament rupture is a common skeletal disease affecting the stifle joint in dogs. The tibial plateau levelling osteotomy, performed with several synthesis systems, changed the approach to its treatment in dogs. The aim of this study was to compare two types of fixation implants, locking compression system and locking system, evaluating radiographically the progression of osteoarthritis of the stifle joint in dogs with complete cranial cruciate ligament deficiency treated surgically with tibial plateau levelling osteotomy. Moreover, we evaluated bone healing and lameness scores to show biomechanical effects by the implant used. Twenty-eight dogs, who met the inclusion criteria, were divided into two groups. Group A: 14 dogs treated using locking compression plates; Group B: 14 dogs treated using locking plates. Radiographic osteoarthritis scores were evaluated up to 1 year following tibial plateau levelling osteotomy. At each visit, animals were clinically and radiographically assessed. Each dog was evaluated before (T0) and after two (T2) and twelve (T12) months after the surgery. At T2 the stage of bone healing was evaluated. The clinical follow up was performed before the surgery and at 10, 15 and 20 days after the surgery, grading the lameness at walk and trot.ResultsAn increase in osteoarthritis score at T12 versus T0 in both groups was detected. A decrease of the lameness score was observed in Group A versus Group B. The healing score system at T2 showed a lower score in Group A versus Group B.ConclusionsThe osteoarthritis score following tibial plateau levelling osteotomy did not differ when comparing the two different fixation systems. The locking compression system allowed a more rapid functional recovery of the limb and a quicker bone healing than the locking system. Locking compression system should be carefully considered for dogs subjected to tibial plateau levelling osteotomy surgery, because it may reduce the recovery time.
SGLT2 inhibitors and lower limb complications: the diuretic-induced hypovolemia hypothesis
Authors: Potier Louis , Mohammedi Kamel , Velho Gilberto , Roussel Ronan 
Published: May 2021

AbstractIn a recent meta-analysis of randomized controlled trials of sodium glucose co-transporter 2 inhibitors (SGLT2i) in patients with diabetes, Lin and colleagues showed a positive association between SGLT2i-induced blood pressure and weight reduction and the risk of lower limb events. These results support the potential mechanism of a volume depletion effect of SGLT2i to explain the increase risk of amputation observed with this pharmacological class. Since the first result of the CANVAS trial raised a concern regarding the risk of amputation with SGLT2i, this hypothesis emerged from studies showing a higher incidence of amputations in patients with diabetes using diuretics. Furthermore, recent data found that copeptin, a surrogate marker of hydration status was also associated with lower limb outcomes. In conclusion, this assumption of diuretic-induced hypovolemia explanation highlights the fact that medications that induce a contraction of plasma volume, both traditional and novel agents with a diuretic mode of action should be introduced cautiously in patients with diabetes at high risk of diabetic foot events.
Oncolytic virotherapy reverses the immunosuppressive tumor microenvironment and its potential in combination with immunotherapy
Authors: Zhang Yalei , Li Ye , Chen Kun , Qian Ling , Wang Peng 
Published: May 2021

AbstractIt has been intensively reported that the immunosuppressive tumor microenvironment (TME) results in tumor resistance to immunotherapy, especially immune checkpoint blockade and chimeric T cell antigen therapy. As an emerging therapeutic agent, oncolytic viruses (OVs) can specifically kill malignant cells and modify immune and non-immune TME components through their intrinsic properties or genetically incorporated with TME regulators. Strategies of manipulating OVs against the immunosuppressive TME include serving as a cancer vaccine, expressing proinflammatory factors and immune checkpoint inhibitors, and regulating nonimmune stromal constituents. In this review, we summarized the mechanisms and applications of OVs against the immunosuppressive TME, and strategies of OVs in combination with immunotherapy. We also introduced future directions to achieve efficient clinical translation including optimization of preclinical models that simulate the human TME and achieving systemic delivery of OVs.
CircMEMO1 modulates the promoter methylation and expression of TCF21 to regulate hepatocellular carcinoma progression and sorafenib treatment sensitivity
Authors: Dong Zhao-Ru , Ke Ai-Wu , Li Tao , Cai Jia-Bing , Yang Ya-fei , Zhou Wei , Shi Guo-Ming , Fan Jia 
Published: May 2021

Abstract
Background
Cirrhosis is a recognized risk factor for developing hepatocellular carcinoma (HCC). Few studies have reported the expression profile of circRNAs in HCC samples compared to paratumour dysplastic nodule (DN) samples.

Methods
The Arraystar Human circRNA Array combined with laser capture microdissection (LCM) was used to analyse the expression profile of circRNAs in HCC samples compared to paratumour DN samples. Then, both in vitro and in vivo HCC models were used to determine the role and mechanism of key circRNA in HCC progression and treatment sensitivity.

Results
We found that circMEMO1 was significantly downregulated in HCC samples and that the level of circMEMO1 was closely related to the OS and disease-free survival (DFS) of HCC patients. Mechanistic analysis revealed that circMEMO1 can modulate the promoter methylation and gene expression of TCF21 to regulate HCC progression by acting as a sponge for miR-106b-5p, which targets the TET family of genes and increases the 5hmC level. More importantly, circMEMO1 can increase the sensitivity of HCC cells to sorafenib treatment.

Conclusion
Our study determined that circMEMO1 can promote the demethylation and expression of TCF21 and can be considered a crucial epigenetic modifier in HCC progression.
Nanoscopic quantification of sub-mitochondrial morphology, mitophagy and mitochondrial dynamics in living cells derived from patients with mitochondrial diseases
Authors: Zou Weiwei , Chen Qixin , Slone Jesse , Yang Li , Lou Xiaoting , Diao Jiajie , Huang Taosheng 
Published: May 2021

AbstractSLC25A46 mutations have been found to lead to mitochondrial hyper-fusion and reduced mitochondrial respiratory function, which results in optic atrophy, cerebellar atrophy, and other clinical symptoms of mitochondrial disease. However, it is generally believed that mitochondrial fusion is attributable to increased mitochondrial oxidative phosphorylation (OXPHOS), which is inconsistent with the decreased OXPHOS of highly-fused mitochondria observed in previous studies. In this paper, we have used the live-cell nanoscope to observe and quantify the structure of mitochondrial cristae, and the behavior of mitochondria and lysosomes in patient-derived SLC25A46 mutant fibroblasts. The results show that the cristae have been markedly damaged in the mutant fibroblasts, but there is no corresponding increase in mitophagy. This study suggests that severely damaged mitochondrial cristae might be the predominant cause of reduced OXPHOS in SLC25A46 mutant fibroblasts. This study demonstrates the utility of nanoscope-based imaging for realizing the sub-mitochondrial morphology, mitophagy and mitochondrial dynamics in living cells, which may be particularly valuable for the quick evaluation of pathogenesis of mitochondrial morphological abnormalities.
Contextual differences considered in the Tunisian ADOLOPMENT of the European guidelines on breast cancer screening
Authors: Kahale Lara A. , Ouertatani Hella , Brahem Asma Ben , Grati Hela , Hamouda Mohammed Ben , Saz-Parkinson Zuleika , Akl Elie A. 
Published: May 2021

Abstract
Background
Breast cancer is a common disease in Tunisia and is associated with high mortality rates. The “Instance Nationale de l’Evaluation et de l’Accréditation en Santé” (INEAS) and the Tunisian Society of Oncology decided to develop practice guidelines on the subject. While the development of de novo guidelines on breast cancer screening is a demanding process, guideline adaptation appears more appropriate and context sensitive. The objective of this paper is to describe the adaptation process of the European Guidelines on Breast Cancer Screening and Diagnosis to the Tunisian setting in terms of the methodological process, contextual differences between the source and adoloped guideline, and changes in the recommendations.

Methods
We used the ‘Grading of Recommendations Assessment, Development and Evaluation’ (GRADE)-ADOLOPMENT methodology to prioritize the topic, select the source guideline, and prioritize the questions and the outcomes. Once the source guideline was selected—the European Breast Cancer Guidelines—the European Commission´s Joint Research Centre shared with the project team in Tunisia all relevant documents and files. In parallel, the project team searched for local studies on the disease prevalence, associated outcomes’ baseline risks, patients’ values and preferences, cost, cost-effectiveness, acceptability, and feasibility. Then, the adoloping panel reviewed the GRADE evidence tables and the Evidence to Decision tables and discussed whether their own judgments were consistent with those from the source guideline or not. They based their judgments on the evidence on health effects, the contextual evidence, and their own experiences.

Results
The most relevant contextual differences between the source and adoloped guidelines were related to the perspective, scope, prioritized questions, rating of outcome importance, baseline risks, and indirectness of the evidence. The ADOLOPMENT process resulted in keeping 5 out of 6 recommendations unmodified. One recommendation addressing “screening versus no screening with ultrasound in women with high breast density on mammography screening” was modified from ‘conditional against’ to ‘conditional for either’ due to more favorable ratings by the adoloping panel in terms of equity and feasibility.

Conclusion
This process illustrates both the feasibility of GRADE-ADOLOPMENT approach and the importance of consideration of contextual evidence. It also highlights the value of collaboration with the organization that developed the source guideline.
METTL13 inhibits progression of clear cell renal cell carcinoma with repression on PI3K/AKT/mTOR/HIF-1α pathway and c-Myc expression
Authors: Liu Zhuonan , Sun Tianshui , Piao Chiyuan , Zhang Zhe , Kong Chuize 
Published: May 2021

Abstract
Background
Clear cell renal cell carcinoma (ccRCC) is the most common and aggressive type of renal malignancy. Methyltransferase like 13 (METTL13) functions as an oncogene in most of human cancers, but its function and mechanism in ccRCC remains unreported.

Methods
qRT-PCR, western blotting and immunohistochemistry were used to detect METTL13’s expression in tissues. The effects of METTL13 on ccRCC cells’ growth and metastasis were determined by both functional experiments and animal experiments. Weighted gene co-expression network analysis (WGCNA) was performed to annotate METTL13’s functions and co-immunoprecipitation (co-IP) was used to determine the interaction between METTL13 and c-Myc.

Results
METTL13 was underexpressed in ccRCC tissues compared to normal kidney tissues and its low expression predicted poor prognosis for ccRCC patients. The in vitro studies showed that knockdown and overexpression of METTL13 respectively led to increase and decrease in ccRCC cells’ proliferation, viability, migratory ability and invasiveness as well as epithelial-mesenchymal transition (EMT). The in vivo experiment demonstrated the inhibitory effect that METTL13 had on ccRCC cells’ growth and metastasis. Bioinformatic analyses showed various biological functions and pathways METTL13 was involved in. In ccRCC cells, we observed that METTL13 could negatively regulate PI3K/AKT/mTOR/HIF-1α pathway and that it combined to c-Myc and inhibited c-Myc protein expression.

Conclusions
In general, our finding suggests that high expression of METTL13 is associated with favorable prognosis of ccRCC patients. Meanwhile, METTL13 can inhibit growth and metastasis of ccRCC cells with participation in multiple potential molecular mechanisms. Therefore, we suggest METTL13 can be a new diagnostic and therapeutic target for ccRCC in the future.
Acute inflammatory profiles differ with sex and age after spinal cord injury
Authors: Stewart Andrew N. , Lowe John L. , Glaser Ethan P. , Mott Caitlin A. , Shahidehpour Ryan K. , McFarlane Katelyn E. , Bailey William M. , Zhang Bei , Gensel John C. 
Published: May 2021

AbstractBackgroundSex and age are emerging as influential variables that affect spinal cord injury (SCI) recovery. Despite a changing demographic towards older age at the time of SCI, the effects of sex or age on inflammation remain to be elucidated. This study determined the sex- and age-dependency of the innate immune response acutely after SCI.MethodsMale and female mice of ages 4- and 14-month-old received T9 contusion SCI and the proportion of microglia, monocyte-derived macrophages (MDM), and neutrophils surrounding the lesion were determined at 3- and 7-day post-injury (DPI) using flow cytometry. Cell counts of microglia and MDMs were obtained using immunohistochemistry to verify flow cytometry results at 3-DPI. Microglia and MDMs were separately isolated using fluorescence-activated cell sorting (FACS) at 3-day post-injury (DPI) to assess RNA expression of 27 genes associated with activation, redox, and debris metabolism/clearance.ResultsFlow cytometry revealed that being female and older at the time of injury significantly increased MDMs relative to other phagocytes, specifically increasing the ratio of MDMs to microglia at 3-DPI. Cell counts using immunohistochemistry revealed that male mice have more total microglia within SCI lesions that can account for a lower MDM/microglia ratio. With NanoString analyses of 27 genes, only 1 was differentially expressed between sexes in MDMs; specifically, complement protein C1qa was increased in males. No genes were affected by age in MDMs. Only 2 genes were differentially regulated in microglia between sexes after controlling for false discovery rate, specifically CYBB (NOX2) as a reactive oxygen species (ROS)-associated marker as well as MRC1 (CD206), a gene associated with reparative phenotypes. Both genes were increased in female microglia. No microglial genes were differentially regulated between ages. Differences between microglia and MDMs were found in 26 of 27 genes analyzed, all expressed higher in MDMs with three exceptions. Specifically, C1qa, cPLA2, and CD86 were expressed higher in microglia.ConclusionsThese findings indicate that inflammatory responses to SCI are sex-dependent at both the level of cellular recruitment and gene expression.
Rupture of contralateral mainstem bronchus during uniportal video-assisted thoracoscopy surgery lobectomy and 3 successful cases of repair
Authors: Luo Zhilin , Wang Tianhu , Zhang Hong 
Published: May 2021

Abstract
Background
Our goal was to discuss the treatment for rupture of contralateral mainstem bronchus during uniportal video-assisted thoracoscopy surgery (uniportal VATS) lobectomy.

Case presentation
We analyzed clinical data of 3 cases of rupture of contralateral mainstem bronchus during uniportal VATS. Surgical repair was performed immediately under an uniportal VATS during operation, as a result, 3 cases of bronchial rupture all were repaired successfully, and we continued to complete lobectomy and systemic lymph node dissection. Reexamination was performed after 1 week, and no fistula was found in trachea and bronchi through a fiberoptic bronchoscopy. The time range for indwelling the chest tube is 6–9 days, and the hospital stay is 8–10 days. No abnormality was observed on chest radiography when the 3 patients returned to the hospital 1 month after the operation for the second reexamination.

Conclusions
Instant surgical repair is recommended to the treatment of bronchial rupture in thoracic surgery. It is safe and feasible to repair bronchial tear with uniportal VATS.
Calcium channelopathies and intellectual disability: a systematic review
Authors: Kessi Miriam , Chen Baiyu , Peng Jing , Yan Fangling , Yang Lifen , Yin Fei 
Published: May 2021

Abstract
Background
Calcium ions are involved in several human cellular processes including corticogenesis, transcription, and synaptogenesis. Nevertheless, the relationship between calcium channelopathies (CCs) and intellectual disability (ID)/global developmental delay (GDD) has been poorly investigated. We hypothesised that CCs play a major role in the development of ID/GDD and that both gain- and loss-of-function variants of calcium channel genes can induce ID/GDD. As a result, we performed a systematic review to investigate the contribution of CCs, potential mechanisms underlying their involvement in ID/GDD, advancements in cell and animal models, treatments, brain anomalies in patients with CCs, and the existing gaps in the knowledge. We performed a systematic search in PubMed, Embase, ClinVar, OMIM, ClinGen, Gene Reviews, DECIPHER and LOVD databases to search for articles/records published before March 2021. The following search strategies were employed: ID and calcium channel, mental retardation and calcium channel, GDD and calcium channel, developmental delay and calcium channel.

Main body
A total of 59 reports describing 159 cases were found in PubMed, Embase, ClinVar, and LOVD databases. Variations in ten calcium channel genes including CACNA1A, CACNA1C, CACNA1I, CACNA1H, CACNA1D, CACNA2D1, CACNA2D2, CACNA1E, CACNA1F, and CACNA1G were found to be associated with ID/GDD. Most variants exhibited gain-of-function effect. Severe to profound ID/GDD was observed more for the cases with gain-of-function variants as compared to those with loss-of-function. CACNA1E, CACNA1G, CACNA1F, CACNA2D2 and CACNA1A associated with more severe phenotype. Furthermore, 157 copy number variations (CNVs) spanning calcium genes were identified in DECIPHER database. The leading genes included CACNA1C, CACNA1A, and CACNA1E. Overall, the underlying mechanisms included gain- and/ or loss-of-function, alteration in kinetics (activation, inactivation) and dominant-negative effects of truncated forms of alpha1 subunits. Forty of the identified cases featured cerebellar atrophy. We identified only a few cell and animal studies that focused on the mechanisms of ID/GDD in relation to CCs. There is a scarcity of studies on treatment options for ID/GDD both in vivo and in vitro.

Conclusion
Our results suggest that CCs play a major role in ID/GDD. While both gain- and loss-of-function variants are associated with ID/GDD, the mechanisms underlying their involvement need further scrutiny.
Long-term renal outcome in methylmalonic acidemia in adolescents and adults
Authors: Dao Myriam , Arnoux Jean-Baptiste , Bienaimé Frank , Brassier Anaïs , Brazier François , Benoist Jean-François , Pontoizeau Clément , Ottolenghi Chris , Krug Pauline , Boyer Olivia , de Lonlay Pascale , Servais Aude 
Published: May 2021

Abstract
Background
Chronic kidney disease (CKD) is one of the main long-term prognosis factors in methylmalonic acidemia (MMA), a rare disease of propionate catabolism. Our objective was to precisely address the clinical and biological characteristics of long-term CKD in MMA adolescent and adult patients.

Patients and methods
In this retrospective study, we included MMA patients older than 13 years who had not received kidney and/or liver transplantation. We explored tubular functions, with special attention to proximal tubular function. We measured glomerular filtration rate (mGFR) by iohexol clearance and compared it to estimated glomerular filtration rate (eGFR) by Schwartz formula and CKD-EPI.

Results
Thirteen patients were included (M/F = 5/8). Median age was 24 years (13 to 32). Median mGFR was 57 mL/min/1.73 m2 (23.3 to 105 mL/min/1.73 m2). Ten out of 13 patients had mGFR below 90 mL/min/1.73 m2. No patient had significant glomerular proteinuria. No patient had complete Fanconi syndrome. Only one patient had biological signs suggestive of incomplete proximal tubulopathy. Four out of 13 patients had isolated potassium loss, related to a non-reabsorbable anion effect of urinary methylmalonate. Both Schwartz formula and CKD-EPI significantly overestimated GFR. Bias were respectively 16 ± 15 mL/min/1.73 m2 and 37 ± 22 mL/min/1.73 m2.

Conclusion
CKD is a common complication of the MMA. Usual equations overestimate GFR. Therefore, mGFR should be performed to inform therapeutic decisions such as dialysis and/or transplantation. Mild evidence of proximal tubular dysfunction was found in only one patient, suggesting that other mechanisms are involved.
AKT-mediated phosphorylation of Sox9 induces Sox10 transcription in a murine model of HER2-positive breast cancer
Authors: Al-Zahrani Khalid N. , Abou-Hamad John , Pascoal Julia , Labrèche Cédrik , Garland Brennan , Sabourin Luc A. 
Published: May 2021

Abstract
Background
Approximately 5–10% of HER2-positive breast cancers can be defined by low expression of the Ste20-like kinase, SLK, and high expression of SOX10. Our lab has observed that genetic deletion of SLK results in the induction of Sox10 and significantly accelerates tumor initiation in a HER2-induced mammary tumor model. However, the mechanism responsible for the induction of SOX10 gene expression in this context remains unknown.

Methods
Using tumor-derived cell lines from MMTV-Neu mice lacking SLK and biochemical approaches, we have characterized the signaling mechanisms and relevant DNA elements driving Sox10 expression.

Results
Biochemical and genetic analyses of the SOX10 regulatory region in SLK-deficient mammary tumor cells show that Sox10 expression is dependent on a novel −7kb enhancer that harbors three SoxE binding sites. ChIP analyses demonstrate that Sox9 is bound to those elements in vivo. Our data show that AKT can directly phosphorylate Sox9 in vitro at serine 181 and that AKT inhibition blocks Sox9 phosphorylation and Sox10 expression in SLK(-/-) tumor cells. AKT-mediated Sox9 phosphorylation increases its transcriptional activity on the Sox10 −7kb enhancer without altering its DNA-binding activity. Interestingly, analysis of murine and human mammary tumors reveals a direct correlation between the levels of active phospho-Sox9 S181 and Sox10 expression.

Conclusions
Our results have identified a novel Sox10 enhancer and validated Sox9 as a direct target for AKT. As Sox10 is a biomarker for triple-negative breast cancers (TNBC), these findings might have major implications in the targeting and treatment of those cancers.