MiR-449b-5p inhibits human glioblastoma cell proliferation by inactivating WNT2B/Wnt/ß-catenin signaling pathway.

OBJECTIVE: As the most common primary brain cancer in adults, glioblastoma shows an extremely poor prognosis. Glioblastoma-associated deaths account for approximately 3%-4% of all malignancy-associated deaths. Numerous microRNAs (miRNAs) play important roles in the occurrence and progression of solid tumors. Herein, identifying functional miRNAs and the central molecular mechanisms would provide novel proofs for the development of targeted cancer therapies. In this study, we described the role of miR-449b-5p in restraining ontogenesis and progression of glioblastoma. PATIENTS AND METHODS: Human glioblastoma tissues were provided by our hospital. Human U251 glioblastoma cells were infected with lentivirus induced miR-449b-5p mimics or miR-449b-5p siRNA. Real-time qPCR was carried out to determine miRNA expression. Tumor spheres formation, MTT assay, and BrdU cell proliferation assay were used to evaluate the growth ability of U251 cells. Western blot assay was performed to measure protein expression. ChIP was used to detect the capacity of ß-catenin to recruit its downstream genes. Dual-Luciferase assay was conducted to detect the ability of miR-449b-5p to regulate the 3'UTR (untranslated regions) of WNT2B. TOP/FOP ratio was used to evaluate the activity of Wnt/ß-catenin signaling pathway. RESULTS: Down-regulation of miR-449b-5p expression was found in both human glioblastoma tissues and cell lines, which was negatively associated with the clinical stages. Up-regulation of miR-449b-5p inhibited tumor spheres formation, cell viability and proliferation ability of glioblastoma cells. The expression levels of WNT2B and nuclear ß-catenin were negatively associated with miR-449b-5p levels in glioblastoma cells. MiR-449b-5p inhibited Wnt/ß-catenin signaling by targeting WNT2B. CONCLUSIONS: MiR-449b-5p acts as a tumor suppressor and retards the oncogenesis of glioblastoma, which is achieved via inactivation of Wnt/ß-catenin signaling by directly targeting WNT2B.

Activation of HIF-1α/ACLY signaling axis promotes progression of clear cell renal cell carcinoma with VHL inactivation mutation / 中华病理学杂志

Objective: To explore the potential pathogenesis of clear cell renal cell carcinoma (ccRCC) based on the HIF-1α/ACLY signaling pathway, as well as to provide new ideas for the treatment of ccRCC. Methods: Seventy-eight ccRCC cases diagnosed at the First Affiliated Hospital of Soochow University, Suzhou, China were collected. The VHL mutation was examined using exon sequencing. The expression of HIF-1α/ACLY in VHL-mutated ccRCC was evaluated using immunohistochemical staining and further validated in VHL-mutated ccRCC cell lines (786-O, A498, UM-RC-2, SNU-333, and Caki-2) using Western blot. The mRNA and protein levels of ACLY were detected using real-time quantitative PCR and Western blot after overexpression or interference with HIF-1α in ccRCC cell lines. HeLa cells were treated with CoCl2 and hypoxia (1%O2) to activate HIF-1α and then subject to the detection of the ACLY mRNA and protein levels. The potential molecular mechanism of HIF-1α-induced ACLY activation was explored through JASPAR database combined with chromatin immunoprecipitation assay (ChIP) and luciferase reporter gene assay. The effect of HIF-1α/ACLY regulation axis on lipid accumulation was detected using BODIPY staining and other cell biological techniques. The expression of ACLY was compared between patients with ccRCC and those with benign lesions, and the feasibility of ACLY as a prognostic indicator for ccRCC was explored through survival analysis. Results: Exon sequencing revealed that 55 (70.5%) of the 78 ccRCC patients harbored a VHL inactivation mutation, and HIF-1α expression was associated with ACLY protein levels. The protein levels of ACLY and HIF-1α in ccRCC cell lines carrying VHL mutation were also correlated to various degrees. Overexpression of HIF-1α in A498 cells increased the mRNA and protein levels of ACLY, and knockdown of HIF-1α in Caki-2 cells inhibited the mRNA and protein levels of ACLY (P<0.001 for all). CoCl2 and hypoxia treatment significantly increased the mRNA and protein levels of ACLY by activating HIF-1α (P<0.001 for all). The quantification of transcriptional activity of luciferase reporter gene and ChIP-qPCR results suggested that HIF-1α could directly bind to ACLY promoter region to transcriptionally activate ACLY expression and increase ACLY protein level (P<0.001 for all). The results of BODIPY staining suggested that the content of free fatty acids in cell lines was associated with the levels of HIF-1α and ACLY. The depletion of HIF-1α could effectively reduce the accumulation of lipid in cells, while the overexpression of ACLY could reverse this process. At the same time, cell function experiments showed that the proliferation rate of ccRCC cells with HIF-1α knockdown was significantly decreased, and overexpression of ACLY could restore proliferation of these tumor cells (P<0.001). Survival analysis further showed that compared with the ccRCC patients with low ACLY expression, the ccRCC patients with high ACLY expression had a poorer prognosis and a shorter median survival (P<0.001). Conclusions: VHL mutation-mediated HIF-1α overexpression in ccRCC promotes lipid synthesis and tumor progression by activating ACLY. Targeting the HIF-1α/ACLY signaling axis may provide a theoretical basis for the clinical diagnosis and treatment of ccRCC.

Perivascular epithelioid cell tumor of the lung: a clinicopathological analysis of eight cases / 中华病理学杂志

Objective: To investigate the clinicopathological features of perivascular epithelioid cell tumor (PEComa) of the lung. Methods: Eight PEComa cases of the lung diagnosed at the First Affiliated Hospital of Soochow University, Suzhou, China from July 2008 to December 2021 were collected and subject to immunohistochemical staining, fluorescence in situ hybridization and next generation sequencing. The relevant literature was reviewed and the clinicopathological features were analyzed. Results: There were 5 males and 3 females, aged from 18 to 70 years (mean 39 years). There were 3 cases of the right upper lung, 3 cases of the left lower lung, 1 case of the left upper lung and 1 case of the right middle lung. Seven cases were solitary and 1 case was multifocal (4 lesions). Seven cases were benign while one was malignant. The tumors were all located in the peripheral part of the lung, with a maximum diameter of 0.2-4.0 cm. Grossly, they were oval and well circumscribed. Microscopically, the tumor cells were oval, short spindle-shaped, arranged in solid nests, acinar or hemangiopericytoma-like patterns, with clear or eosinophilic cytoplasm. The stroma was rich in blood vessels with hyalinization. Coagulated necrosis and high-grade nuclei were seen in the malignant case, and calcification was seen in 2 cases. Immunohistochemically, the tumor cells were positive for Melan A (8/8), HMB45 (7/8), CD34 (6/8), TFE3 (4/7), and SMA (3/8). All cases were negative for CKpan and S-100. TFE3 (Xp11.2) gene fusion was examined using the TFE3 break-apart fluorescence in situ hybridization in 5 cases, in which only the malignant case was positive. The next generation sequencing revealed the SFPQ-TFE3 [t(X;1)(p11.2;p34)] fusion. Follow-up of the patients ranged from 12 to 173 months while one patient was lost to the follow-up. The malignant case had tumor metastasis to the brain 4 years after the operation and then received radiotherapy. Other 6 cases had no recurrence and metastasis, and all the 7 patients survived. Conclusions: Most of the PEComas of the lung are benign. When there are malignant morphological features such as necrosis, high-grade nuclei or SFPQ-TFE3 gene fusion, close follow-up seems necessary.

Impact of COVID-19 on Endoscopy Training: Perspectives from a Global Survey of Program Directors and Endoscopy Trainers

Background/Aims@#The coronavirus disease of 2019 (COVID-19) pandemic has impacted the training of medical trainees internationally. The aim of this study was to assess the global impact of COVID-19 on endoscopy training from the perspective of endoscopy trainers and to identify strategies implemented to mitigate the impact on trainee education. @*Methods@#Teaching faculty of gastroenterology (GI) training programs globally were invited to complete a 36-question web-based survey to report the characteristics of their training programs and the impact of COVID-19 on various aspects of endoscopy training, including what factors decisions were based on. @*Results@#The survey response rate was 52.6% (305 out of 580 individuals); 92.8% reported a negative impact on endoscopy training, with suspension of elective procedures (77.1%) being the most detrimental factor. Geographic variations were noted, with European programs reporting the lowest percentage of trainee participation in procedures. A higher proportion of trainees in the Americas were allowed to continue performing procedures, and trainers from the Americas reported receiving the greatest support for endoscopy teaching. @*Conclusions@#This study demonstrated that the COVID-19 pandemic has had a significant negative impact on GI endoscopy training internationally, as reported by endoscopy trainers. Focus-optimizing endoscopy training and assessment of competencies are necessary to ensure adequate endoscopy training.

Impact of COVID-19 on Endoscopy Training: Perspectives from a Global Survey of Program Directors and Endoscopy Trainers

Background/Aims@#The coronavirus disease of 2019 (COVID-19) pandemic has impacted the training of medical trainees internationally. The aim of this study was to assess the global impact of COVID-19 on endoscopy training from the perspective of endoscopy trainers and to identify strategies implemented to mitigate the impact on trainee education. @*Methods@#Teaching faculty of gastroenterology (GI) training programs globally were invited to complete a 36-question web-based survey to report the characteristics of their training programs and the impact of COVID-19 on various aspects of endoscopy training, including what factors decisions were based on. @*Results@#The survey response rate was 52.6% (305 out of 580 individuals); 92.8% reported a negative impact on endoscopy training, with suspension of elective procedures (77.1%) being the most detrimental factor. Geographic variations were noted, with European programs reporting the lowest percentage of trainee participation in procedures. A higher proportion of trainees in the Americas were allowed to continue performing procedures, and trainers from the Americas reported receiving the greatest support for endoscopy teaching. @*Conclusions@#This study demonstrated that the COVID-19 pandemic has had a significant negative impact on GI endoscopy training internationally, as reported by endoscopy trainers. Focus-optimizing endoscopy training and assessment of competencies are necessary to ensure adequate endoscopy training.

Chinese burn referral criteria (2018 version) / 中华烧伤杂志

There is no national referral criteria for burns in China till now, which brings inconvenience and confusion. Based on the oversea experiences and the actual situation in China, many famous experts on burns discussed and developed this Chinese burn referral criteria (2018 version). We hope these referral criteria will be helpful in clinical practice in burn field and can be improved continuously during application.

A proposal: a comprehensive platform to characterize tumors in Chinese and improve success in cancer drug discovery and development / 癌症

Cancer is a collection of complex diseases in which cell proliferation and apoptosis are dysregulated due to the acquisition of genetic changes in cancer cells. These genetic changes, combined with the interrelated physiologic adaptations of neo-angiogenesis, recruitment of stromal support tissues, and suppression of immune recognition, are measurable characteristics in tumor gene expression profiles and biochemical pathways. These measures can lead to identification of disease drivers and, ultimately, can be used to assign therapy. With advances in RNA sequencing technologies, the ability to simultaneously measure all genetic and gene expression changes with a single technology is now possible. The ability to create a comprehensive catalog of genotypic and phenotypic changes in a collection of histologically similar but otherwise distinct tumors should allow for a more precise positioning of existing targeted therapies and identification of new targets for intervention.

Lack of awareness amongst community patients with diabetes and diabetic retinopathy: the Singapore Malay eye study

<p><b>INTRODUCTION</b>We assessed awareness of diabetes and diabetic retinopathy in a Singaporean Malay population. We hypothesised that poor awareness is associated with poorer control of diabetic retinopathy risk factors (glycaemic and blood pressure levels) and suboptimal treatment with laser therapy.</p><p><b>MATERIALS AND METHODS</b>A population-based survey of 3280 (78.7% response rate) persons among Singaporean Malays aged between 40 and 80 years old. Diabetes was defined in persons with random glucose >or=11.1mmoL/L, use of diabetic medication, or a previous physician diagnosis. Diabetic retinopathy was graded from retinal photographs following the modified Airlie House classification. Patient awareness was assessed via structured interviews. Glycosylated haemoglobin was measured from venous blood.</p><p><b>RESULTS</b>Of the 3280 study participants, 768 had diabetes, of whom 13.2% (n = 101) were unaware of their diabetes status. Participants unaware of their diabetes status had significantly higher mean glycosylated haemoglobin (9.7% vs 8.2%, P <0.001), systolic blood pressure (160.0 mmHg vs 153.7 mmHg, P = 0.01) and diastolic blood pressure (83.5 mmHg vs 78.5 mmHg, P <0.001), compared to participants who were aware. Of the 272 (35.4%) participants detected to have diabetic retinopathy, 83.4% (n = 227) were unaware of having retinopathy. Of the 77 with vision-threatening retinopathy, laser treatment had been performed in only 55.6% of those unaware of having retinopathy.</p><p><b>CONCLUSION</b>In a sample of Malays with diabetes, high proportions were unaware of their disease. Unawareness was associated with poorer control of diabetic retinopathy risk factors. Only half of persons who were unaware that they had vision-threatening diabetic retinopathy had received laser treatment. These data highlight room for improvement in diabetic retinopathy prevention through better patient education and screening.</p>

Understanding Convergence Between Non-Hispanic Black and White COVID-19 Mortality: A County-Level Approach

BackgroundNon-Hispanic Black populations have suffered greater per capita COVID-19 mortality at more than 1.5 times that of White populations. Previous work has established that, over time, rates of Black and White mortality have converged; however, some studies suggest that regional shifts in COVID-19 prevalence may play a role in the relative change between racial groups. This studys objective was to investigate changes in Black and White COVID-19 mortality over time and uncover potential mechanisms driving these changes. Methods and FindingsUsing county-level COVID-19 mortality data stratified by race, we investigate the trajectory of non-Hispanic Black mortality, White mortality, and the Black/White per capita mortality ratio from June 2020-January 2021. Over this period, in the counties studied, cumulative mortality rose by 56.7% and 82.8% for Black and White populations respectively, resulting in a decrease in mortality ratio of 0.369 (23.8%). These trends persisted even when a county-level fixed-effects model was used to estimate changes over time within counties (controlling for all time-invariant county level characteristics and removing the effects of changes in regional distribution of COVID-19). Next, we leverage county-level variation over time in COVID-19 prevalence to show that the decline in the Black/White mortality ratio can be explained by changes in COVID-19 prevalence. Finally, we study heterogeneity in the time trend, finding that convergence occurs most significantly in younger populations, areas with less dense populations, and outside of the Northeast. Limitations include suppressed data in counties with fewer than 10 deaths in a racial category, and the use of provisional COVID-19 death data that may be incomplete. ConclusionsThe results of this study suggest that convergence in Black/White mortality is not driven by county-level characteristics or changes in the regional dispersion of COVID-19, but instead by changes within counties. Further, declines in the Black/White mortality ratio appear strongly linked to changes in COVID-19 prevalence, rather than a time-specific effect. Further studies on changes in exposure by race over time, or on the vulnerability of individuals who died at different points in the pandemic, may provide crucial insight on mechanisms and strategies to further reduce COVID-19 mortality disparities.

Social distancing across vulnerability, race, politics, and employment: How different Americans changed behaviors before and after major COVID-19 policy announcements

BackgroundAs states reopen in May 2020, the United States is still trying to curb the spread of the COVID-19 pandemic. To appropriately design policies and anticipate behavioral change, it is important to understand how different Americans social distancing behavior shifts in relation to policy announcements according to individual characteristics, and community vulnerability. MethodsThis cross-sectional study used Unacasts social distancing data from February 24th - May 10th, 2020 to study how social distancing changed before and after: 1) The World Health Organizations declaration of a global pandemic, 2) White House announcement of "Opening Up America Again" (OUAA) guidelines, and 3) the week of April 27 when several states reopened. To measure intention to social distance, we assessed the difference between weekday and weekend behavior as more individuals have more control over weekend leisure time. To investigate social distancings sensitivity to different population characteristics, we compared social distancing time-series data across county vulnerability as measured by the COVID-19 Community Vulnerability Index (CCVI) which defines vulnerability across socioeconomic, household composition, minority status, epidemiological, and healthcare-system related factors. We also compared social distancing across population groupings by race, 2016 presidential election voting choice, and employment sectors. ResultsMovement reduced significantly throughout March reaching peak reduction on April 12th (-56.1%) prior the enactment of any reopening policies. Shifts in social distancing began after major announcements but prior to specific applied policies: Following the WHO declaration, national social distancing significantly increased on weekdays and weekends (-18.6% and -41.3% decline in mobility, respectively). Social distancing significantly declined on weekdays and weekends after OUAA guidelines (i.e. before state reopening) (+1.1% and +5.3% increase in mobility, respectively) with additional significant decline after state reopening (+10.0% and +20.9% increase in mobility, respectively). Social distancing was significantly greater on weekends than weekdays throughout March, however, the trend reversed by early May with significantly less social distancing on weekends, suggesting a shift in intent to social distance during leisure time. In general, vulnerable counties social distanced less than non-vulnerable counties, and had a greater difference between weekday and weekend behavior until state reopening. This may be driven by structural barriers that vulnerable communities face, such as higher rates of employment in particular sectors. At all time periods studied, the average black individual in the US social distanced significantly more than the average white individual, and the average 2016 Clinton voter social distanced significantly more than the average 2016 Trump voter. Social distancing behavior differed across industries with three clusters of employment sectors. ConclusionBoth signaling of a policy change and implementation of a policy are important factors that seem to influence social distancing. Behaviors shifted with national announcements prior to mandates, though social distancing further declined nationwide as the first states reopened. The variation in behavioral drivers including vulnerability, race, political affiliation, and employment industry demonstrates the need for targeted policy messaging and interventions tailored to address specific barriers for improved social distancing and mitigation.