TFCP2L1, a potential differentiation regulator, predicts favorable prognosis and dampens thyroid cancer progression.

PURPOSE: Thyroid cancer has an overwhelming incidence in the population. Thus, there is an urgent need to understand the underlying mechanism of its occurrence and development, which may provide new insights into therapeutic strategies. The role and mechanism of TFCP2L1 in regulating the progression of thyroid cancer remains unclear. METHODS: Public databases and clinical samples were used to detect the expression of TFCP2L1 in cancer and non-cancer tissues. Kaplan-Meier and Cox regression analyses were used to compare the differences in survival probability of the TFCP2L1 highly expressing group and the TFCP2L1 lowly expressing group. Functional assays were used to evaluate the biological effect of TFCP2L1 on thyroid cancer cells. RNA sequencing and enrichment analyses were used to find out pathways that were activated or inactivated by TFCP2L1. RESULTS: We demonstrated that TFCP2L1 was significantly downregulated in thyroid cancer. Decreased expression of TFCP2L1 was associated with malignant clinicopathological characteristics. Kaplan-Meier and Cox regression analyses indicated that thyroid tumor patients with low TFCP2L1 expression presented shorter disease-free interval and progression-free interval. Additionally, TFCP2L1 expression was positively correlated with thyroid differentiation degree. Overexpression of TFCP2L1 in thyroid cancer cells inhibited cell growth and motility in vitro, and tumorigenicity and metastasis in vivo. Mechanistically, the NF-κB signaling pathway was found inactivated by overexpressing TFCP2L1. CONCLUSION: Our results suggest that TFCP2L1 is a tumor suppressor and potential differentiation regulator, and might be a potential therapeutic target in thyroid cancer.

ELABELA-APJ Axis Enhances Mesenchymal Stem Cell Proliferation and Migration via the METTL3/PI3K/AKT Pathway.

Mesenchymal stem cells (MSCs) possess a strong therapeutic potential in regenerative medicine. ELABELA (ELA) is a 32 amino acid peptide that binds to the apelin peptide jejunum receptor (APJ) to regulate cell proliferation and migration. The aim of this study was to investigate the function of ELA vis-a-vis the MSC proliferation and migration, and further explore the underlying mechanism. We demonstrated that the exogenous supplement of ELA boosts the proliferation and migration ability of MSCs, alongside improved in vitro cell viability. These capabilities were rendered moot upon APJ knockdown. In addition, ELA (5-20 µM) was shown to upregulate the expression of METTL3 in a concentrationdependent pattern, a capacity which was suppressed by APJ reduction, whereas the downregulation of METTL3 expression blocked the beneficial effects induced by ELA. ELA was also observed to upregulate the phosphorylation level of AKT. This ELA-induced activation of the PI3K/AKT pathway, however, is inhibited with knockdown of METTL3. Our data indicate that ELA could act as a promoter of MSC proliferation and migration in vitro through the APJ receptor, something which might be attributed to the activation of the METTL3/PI3K/AKT signaling pathway. Therefore, ELA is a candidate for optimizing MSC-based cell therapy, while METTL3 is a potential target for its promoting action on MSCs.

[Study of metal organic framework with siRNA for overcoming matrix barrierin breast cancer].

Objective: This study aimed to develop a new delivery strategy that utilized metal organic framework (MOF) loaded with small-interfering RNA (siRNA) targeting ITGAV to overcome tumor matrix barrier, and thus enhance drug penetration and immune accessibility in breast cancer. Methods: MOF@siITGAV particles were constructed and characterized. The uptake of MOF@siITGAV in breast cancer cell line 4T1 was observed by the cellular uptake assay. The toxicity of MOF@siITGAV was detected by cell counting kit 8 (CCK-8). The blank control group, naked siITGAV group and MOF@siITGAV group were set. Real-time fluorescent quantitative polymerase chain reaction (RT-qPCR) and Western blot were used to detect the expressions of ITGAV. The level of transforming growth factor ß1 (TGF-ß1) in the cell culture medium was detected by enzyme-linked immunosorbent assay (ELISA). The penetration of MOF@siITGAV in 4T1 cells was tested by constructing 3D spheroids. Mouse models of triple negative breast cancer were established. The effect of MOF@siITGAV on the growth of transplanted tumors and main organs was verified. Imminohistochemical (IHC) was used to test the expression of collagen and CD8. Results: MOF@siITGAV particles were constructed with sizes of (198.0±3.3) nm and zeta potential of -(20.2±0.4) mV. MOF@siITGAV could be engulfed by 4T1 cells and triggered to release siRNA. Compared to the blank control group, the expression of ITGAV in the MOF@siITGAV group [(46.5±11.3)%] and the naked siITGAV group [(109.9±19.0)%] was lower. TGF-ß1 in the cell culture medium of the blank control group, naked siITGAV group, and MOF@siITGAV group was (474.5±34.4) pg/ml, (437.2±16.5) pg/ml, and (388.4±14.4) pg/ml, respectively. MOF@siITGAV could better penetrate into 4T1 spheroids and exhibit no obvious toxicity. The cell viability was (99.7±3.5)%, (98.2±5.2)%, (97.3±6.6)%, (92.1±8.1)%, and (92.4±4.1)%, respectively, after MOF@siITGAV treatment with the concentration of 0, 10, 20, 40, 80, and 160 µg/ml, respectively, for 24 h. The tumor growth in the MOF@siITGAV group was suppressed significantly. After 15-day treatment, the tumor volume of the MOF@siITGAV group was (135.3±41.9) mm3, smaller than that of the blank control group [(691.1±193.0) mm3] (P=0.025). The expression of collagen and the number of CD8 positive cells of the MOF@siITGAV group were lower than those of the other two groups. No significant abnormalities were observed in the main organs of mice. Conclusions: Targeting the integrinαv on the surface of cancer cells could destroy extracellular matrix, improve drug delivery, and increase immune infiltration.

[Estrogen, estrogen receptor and miR-21 in adenomyosis: their pathogenic roles and regulatory interactions].

OBJECTIVE: To explore the pathogenic roles of miR-21, estrogen (E2), and estrogen receptor (ER) in adenomyosis. METHODS: We examined the expression levels of miR-21 in specimens of adenomyotic tissue and benign cervical lesions using qRT-PCR. In primary cultures of cells isolated from the adenomyosis lesions, the effect of ICI82780 (an ER inhibitor) on miR-21 expression levels prior to E2 activation or after E2 deprivation were examined with qRT-PCR. We further assessed the effects of a miR-21 mimic or an inhibitor on proliferation, apoptosis, migration and autophagy of the cells. RESULTS: The expression level of miR-21 was significantly higher in adenomyosis tissues than in normal myometrium (P < 0.05). In the cells isolated from adenomyosis lesions, miR-21 expression level was significantly higher in E2 activation group than in ER inhibition + E2 activation group and the control group (P < 0.05); miR-21 expression level was significantly lower in cells in E2 deprivation+ER inhibition group than in E2 deprivation group and the control group (P < 0.05). The adenomyosis cells transfected with miR-21 inhibitor showed inhibited proliferation and migration, expansion of mitochondrial endoplasmic reticulum, increased lysosomes, presence of autophagosomes, and increased cell apoptosis, while transfection of the cells with the miR-21 mimic produced the opposite effects. CONCLUSION: MiR-21 plays an important role in promoting proliferation, migration, and antiapoptosis in adenomyosis cells by altering the cell ultrastructure, which may contribute to early pathogenesis of the disease. In addition to binding with E2, ER can also regulate miR-21 through other pathways to participate in the pathogenesis of adenomyosis, thus having a stronger regulatory effect on miR-21 than E2.

[Haploidentical donor peripheral blood stem cell transplantation using third-party cord blood compared with matched unrelated donor transplantation for patients with hematologic malignancies].

Objectives: To assess the efficacy of cord blood-assisted haploid peripheral blood stem cell transplantation (haplo-cord-PBSCT) versus unrelated donor peripheral blood stem cell transplantation (UD-PBSCT) in the treatment of malignant hematological diseases. Methods: A retrospective analysis was performed on one hundred and four patients with malignant hematological diseases who underwent haplo-cord-PBSCT and fifty-two patients who underwent UD-PBSCT at Xiangya Hospital of Central South University between January 2016 and December 2021. Results: ①The median implantation time for neutrophils in the haplo-cord-PBSCT and UD-PBSCT groups was 13 (9-22) days and 13 (10-24) days, respectively (P=0.834), whereas the median implantation time for platelets was 15 (7-103) days and 14 (8-38) days, respectively (P=0.816). The cumulative implantation rate of neutrophils at 30 days after transplantation in the haplo-cord-PBSCT group and the UD-PBSCT group was 100% (P=0.314), and the cumulative platelet implantation rate at 100 days after transplantation was 95.2% (95% CI 88.3% - 98.1% ) and 100% (P=0.927), respectively. 30 days after transplantation, both groups of patients achieved complete donor chimerism, and no umbilical cord blood stem cells were implanted. ②The cumulative incidence rates of grade Ⅱ-Ⅳ acute GVHD within 100 days after transplantation in the haplo-cord-PBSCT group and the UD-PBSCT group were 29.1% (95% CI 20.1% -38.1% ) and 28.8% (95% CI 17.2% -41.6% (P=0.965), respectively. The cumulative incidence rates of grade Ⅲ/Ⅳ acute GVHD were 7.8% (95% CI 3.6% -14.0% ) and 9.6% (95% CI 3.5% -19.5% ) (P=0.725). The cumulative incidence rates of 2-year chronic GVHD in the haplo-cord-PBSCT group and the UD-PBSCT group were 45.3% (95% CI 36.1% -56.1% ) and 35.1% (95% CI 21.6% -44.1% ), respectively (P=0.237). The cumulative incidence rates of severe chronic GVHD at 2 years after transplantation were 13.6% (95% CI 7.6% -21.3% ) and 12.9% (95% CI 5.1% -24.3% ), respectively (P=0.840). ③The 2-year CIR after transplantation in the haplo-cord-PBSCT group and UD-PBSCT group were 12.8% (95% CI 7.0% -20.5% ) and 10.0% (95% CI 3.6% -20.2% ), respectively (P=0.341), and the NRM were 14.7% (95% CI 8.4% -22.6% ) and 16.2% (95% CI 7.4% -28.0% ), respectively (P=0.681). ④The 2-year OS rates in the haplo-cord-PBSCT and UD-PBSCT groups after transplantation were 82.2% (95% CI 74.8% -90.3% ) and 75.5% (95% CI 64.2% -88.7% ), respectively (P=0.276). The 2-year DFS rates were 69.9% (95% CI 61.2% -79.8% ) and 73.8% (95% CI 62.4% -87.3% ), respectively (P=0.551). The 2-year rates of GVHD-free/recurrence-free survival (GRFS) were 55.3% (95% CI 44.8% -64.8% ) and 64.7% (95% CI 52.8% -79.3% ), respectively (P=0.284) . Conclusion: The findings of this study indicate that haplo-cord-PBSCT and UD-PBSCT have comparable efficacy and safety in the treatment of malignant hematological diseases and can be used as an alternative treatment options.

[Imaging risk factors for postoperative cerebral infarction in adults with ischemic Moyamoya disease].

Objective: To investigate the imaging factors associated with postoperative cerebral infarction in adult patients aged 18 and above with ischemic Moyamoya disease. Methods: The clinical data of adult patients who underwent surgeries for ischemic Moyamoya disease in the Department of Neurosurgery at Peking University International Hospital from October 2015 to October 2020 were retrospectively analyzed. Of the 239 patients, 120 were male and 119 were female, with ages ranging from 18 to 63 (41.7±10.3) years. A total of 239 patients(290 cases) underwent direct and indirect combined revascularization (CR).Gender, age, surgical side, preoperative transient ischemic attack (TIA), presence of old cerebral infarction, and imaging features were compared between the patients with (48 cases) and without (242 cases) cerebral infarction within 1 week after surgery. Multivariate logistic binary regression model was used to analyze the imaging risk factors of postoperative cerebral infarction. Results: Cerebral infarction occurred in 48 cases(16.5%) among the 290 CR group within 1 week after surgery. The proportion of patients with TIA, old cerebral infarction, ICA stenosis, A1 segment stenosis, M1 segment stenosis, abnormal posterior cerebral artery (PCA), and unstable compensation before CR in the cerebral infarction group was higher than that in the non-cerebral infarction group (P<0.05).Preoperative TIA (OR=4.514, 95%CI: 1.920-10.611), old cerebral infarction (OR=2.856,95%CI:1.176-6.936), A1 stenosis (OR=7.027,95%CI:1.877-26.308), M1 stenosis (OR=6.968,95%CI:2.162-22.459), abnormal PCA (OR=4.114,95%CI:1.330-12.728)and unstable compensation (OR=4.488,95%CI:1.194-16.865) were risk factors for cerebral infarction after CR surgery (all P<0.05). Conclusion: Among the imaging factors, TIA, old cerebral infarction, A1 stenosis, M1 stenosis, abnormal PCA and unstable compensation were risk factors for cerebral infarction in adult patients with ischemic Moyamoya disease treated by combined revascularization.

[Bibliometric and visual analysis of pneumoconiosis based on Cite Space].

Objective: Through the bibliometrics analysis and visual analysis of Chinese and English literature related to pneumoconiosis through CiteSpace, to understand the research situation, research trend and hotspots of pneumoconiosis, so as to provide reference for further research. Methods: In August 2022, CNKI (China National Knowledge Infrastructure) data baseand Web of Science core collection database were used as data sources for literature retrieval. Cite Space.5.8.R3c software was used to analyze the cooperation between authors and institutions, keyword co-occurrence analysis, keyword clustering analysis and keyword emergence analysis. Results: A total of 4726 Chinese literature and 2490 English literature related to pneumoconiosis were included; The annual publication volume of Chinese literature shows a fluctuating downward trend, while the annual publication volume of English literature shows a fluctuating upward trend. The Institute of Labor Health and Occupational Disease of the Chinese Academy of Preventive Medical Sciences and the Institute of Occupational Health and Poisoning Control of the Chinese Center for Disease Control and Prevention have the highest publication volume (55 articles) in the institutional cooperation network; The National Institute for Occupational Safety and Health (NIOSH) in the United States has the highest publication volume (153 articles) in the institutional collaboration network. The results of keyword co-occurrence, clustering, and prominence analysis show that Chinese literature focuses more on clinical research on pneumoconiosis, while English literature focuses more on experimental research related to the pathogenesis of pneumoconiosis. Conclusion: In the related field of pneumoconiosis research, the experimental research and clinical research on the pathogenesis are the main research hotspots.

[Zellweger syndrome caused by PEX6 gene variation in 2 cases and literature review].

Objective: To summarize the clinical features and genetic characteristics of Zellweger spectrum disorder caused by PEX6 gene variation. Methods: This was a case series research. Clinical date and genetic results of 2 neonatal cases of Zellweger syndrome caused by PEX6 gene variation in Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science & Technology and Affiliated Hospital of Guangdong Medical University from July 2021 to July 2022 were retrospectively collected and analyzed. Literature up to August 2023 was searched from electronic databases of China National Knowledge Infrastructure (CNKI), Wanfang Data and PubMed with the combined keywords of "Zellweger syndrome" "Zellweger spectrum disorder", and "PEX6 gene" both in Chinese and English. The main clinical features and genetic characteristics of Zellweger spectrum disorder caused by PEX6 gene variation were summarized. Results: The 2 male neonates both developed clinical manifestations as dyspnea, hypotonia, feeding difficulties, enlarged fontanelle, and high palatine arch after birth. Biochemical parameters indicated elevated bile acids, and the cranial ultrasound showed the enlarged bilateral ventricles and subependymal cyst in both 2 neonates. Zellweger syndrome was confirmed by whole exome sequencing, and the results revealed PEX6 gene variation in the 2 neonates, including compound heterozygous variants c.315G>A and c.2095-3T>G, and homozygous variant c.506_507del. Case 1 was hospitalized for 5 days, and case 2 for 32 days; they both died shortly after being discharged (the specific time is unknown). Literature review found 26 patients, including 2 neonates in this study, with Zellweger spectrum disorder caused by PEX6 gene defect reported in 1 Chinese article and 11 English articles. Clinical features included hearing loss (19 cases), developmental delay (19 cases), vision impairment (19 cases), elevated very long chain fatty acids (17 cases), brain malformations (15 cases), hypotonia (12 cases), hepatic insufficiency (12 cases), distinctive facies (10 cases), and dental impairment (9 cases). Compound heterozygous variations dominated the variation types (15 cases), and the frameshift variations (16 cases) were the main pathogenic variations. Conclusions: Zellweger spectrum disorder should be considered when neonates show hypotonia, feeding difficulty, distinctive facial appearance, brain malformations and failure of hearing screening, or when older children show retinitis pigmentosa, sensorineural hearing loss, amelogenesis imperfecta and developmental delays. Detection of genetic variation in the PEX gene is crucial for definitive diagnosis.

[Interaction of SENP6 with PINK1 Promotes Temozolomide Resistance in Neuroglioma Cells via Inducing the Mitophagy].

Temozolomide resistance is a major cause of recurrence and poor prognosis in neuroglioma. Recently, growing evidence has suggested that mitophagy is involved in drug resistance in various tumor types. However, the role and molecular mechanisms of mitophagy in temozolomide resistance in glioma remain unclear. In this study, mitophagy levels in temozolomide-resistant and -sensitive cell lines were evaluated. The mechanisms underlying the regulation of mitophagy were explored through RNA sequencing, and the roles of differentially expressed genes in mitophagy and temozolomide resistance were investigated. We found that mitophagy promotes temozolomide resistance in glioma. Specifically, small ubiquitin-like modifier specific protease 6 (SENP6) promoted temozolomide resistance in glioma by inducing mitophagy. Protein-protein interactions between SENP6 and the mitophagy executive protein PTEN-induced kinase 1 (PINK1) resulted in a reduction in small ubiquitin-like modifier 2 (SUMO2)ylation of PINK1, thereby enhancing mitophagy. Our study demonstrates that by inducing mitophagy, the interaction of SENP6 with PINK1 promotes temozolomide resistance in glioblastoma. Therefore, targeting SENP6 or directly regulating mitophagy could be a potential and novel therapeutic target for reversing temozolomide resistance in glioma.

Circulating Metabolites and Dental Traits: A Mendelian Randomization Study.

It is of great importance to uncover causal biomarkers to gain insight into the pathogenesis of oral diseases and identify novel treatment targets for prevention and treatment thereof. This study aimed to systematically evaluate the causal effects of hundreds of metabolites on 10 dental traits using a 2-sample Mendelian randomization (MR) approach. Genetic variants from genome-wide association studies of 309 known metabolites were used as instrumental variables. We selected 10 dental traits, including clinical measures of dental diseases, from the Gene-Lifestyle Interactions in Dental Endpoints Consortium and self-reported oral health data from the UK Biobank. The causal relationships between metabolites and dental traits were inferred using the inverse variance-weighted approach and further controlled for horizontal pleiotropy using 5 additional MR methods. After correcting for multiple tests, 5 metabolites were identified as causal biomarkers. Genetically predicted increased levels of mannose were associated with lower risk of bleeding gums (odds ratio [OR] = 0.72; 95% confidence interval [CI], 0.61-0.85; P = 9.9 × 10-5). MR also indicated 4 metabolites on the causal pathway to dentures, with fructose (OR = 0.50; 95% CI, 0.36-0.70; P = 5.2 × 10-5) and 1-palmitoleoyl-glycerophosphocholine (OR = 0.67; 95% CI, 0.56-0.81; P = 4.8 × 10-5) as potential protective factors and glycine (OR = 1.22; 95% CI, 1.11-1.35; P = 5.6×10-5) and 1,5-anhydroglucitol (OR = 1.32; 95% CI, 1.14-1.52; P = 1.5 × 10-4) as risk factors. The causal associations were robust in various sensitivity analyses. We further observed some shared metabolites among different dental traits, implying similar biological mechanisms underlying the pathogenic processes. Finally, the pathway analysis revealed several significant metabolic pathways that may be involved in the development of dental disorders. Our study provides novel insights into the combination of metabolomics and genomics to reveal the pathogenesis of and therapeutic strategies for dental disorders. It highlighted 5 metabolites and several pathways as causal candidates, warranting further investigation.

Adaptation and validation of a TB stigma scale for adolescents in Lima, Peru.

BACKGROUND: TB-related stigma contributes to poor clinical outcomes and reduced wellbeing for affected individuals. Adolescents may be particularly susceptible to TB-related stigma due to their heightened sensitivity to peer acceptance, yet few studies have evaluated TB-related stigma in this group. Without a validated scale, it remains challenging to measure TB-related stigma in adolescents.METHODS: We adapted and validated the Van Rie TB Stigma Scale (VTSS) for adolescents on treatment for rifampicin-susceptible TB in Lima, Peru. The modified stigma scale was administered within a larger survey, which measured other psychosocial factors, including depression, adverse childhood experiences (ACEs), and social support. Data analysis included factor analysis, internal consistency, and convergent validity.RESULTS: From October 2020 to September 2021, 249 adolescents (individuals aged 10-19 years) completed the survey. Preliminary confirmatory factor analysis led to removal of two items. The final 10-item scale demonstrated good internal consistency (Cronbach's α = 0.82) and adequate model fit (χ²/df = 2.0; root mean square error of approximation: 0.06; comparative fit index: 0.94; Tucker-Lewis Index: 0.92: standardized root mean square residual: 0.05). Stigma was positively correlated with ACEs (γ = 0.13), depression (γ = 0.39), and suicidal ideation (γ = 0.27), and negatively correlated with social support (γ = -0.19).CONCLUSION: This adolescent TB stigma scale may serve as a practical tool to measure TB-related stigma and evaluate the impact of stigma-reduction interventions in adolescents.

Radial source velocity estimation based on cross-spectrum equalization accumulation compensation in shallow water.

In the former work, the histogram was effectively used to improve the interference immunity of target velocity estimation based on the cross-spectrum. This paper proposes a new method to eliminate the bias introduced by the histogram and to further improve interference immunity. The equalization window is designed to preserve the cross-spectrum peaks while suppressing the interference peaks. All frequency points are compensated and accumulated to improve the interference immunity. Finally, the simulation and sea trial data verify the effectiveness of the proposed method in this paper.

Outcomes of WHO-conforming, longer, all-oral multidrug-resistant TB regimens and analysis implications.

BACKGROUND: Evidence of the effectiveness of the WHO-recommended design of longer individualized regimens for multidrug- or rifampicin-resistant TB (MDR/RR-TB) is limited.OBJECTIVES: To report end-of-treatment outcomes for MDR/RR-TB patients from a 2015-2018 multi-country cohort that received a regimen consistent with current 2022 WHO updated recommendations and describe the complexities of comparing regimens.METHODS: We analyzed a subset of participants from the endTB Observational Study who initiated a longer MDR/RR-TB regimen that was consistent with subsequent 2022 WHO guidance on regimen design for longer treatments. We excluded individuals who received an injectable agent or who received fewer than four likely effective drugs.RESULTS: Of the 759 participants analyzed, 607 (80.0%, 95% CI 77.0-82.7) experienced successful end-of-treatment outcomes. The frequency of success was high across groups, whether stratified on number of Group A drugs or fluoroquinolone resistance, and ranged from 72.1% to 90.0%. Regimens were highly variable regarding composition and the duration of individual drugs.CONCLUSIONS: Longer, all-oral, individualized regimens that were consistent with 2022 WHO guidance on regimen design had high frequencies of treatment success. Heterogeneous regimen compositions and drug durations precluded meaningful comparisons. Future research should examine which combinations of drugs maximize safety/tolerability and effectiveness.

Concordance of three approaches for operationalizing outcome definitions for multidrug-resistant TB.

BACKGROUND: The WHO provides standardized outcome definitions for rifampicin-resistant (RR) and multidrug-resistant (MDR) TB. However, operationalizing these definitions can be challenging in some clinical settings, and incorrect classification may generate bias in reporting and research. Outcomes calculated by algorithms can increase standardization and be adapted to suit the research question. We evaluated concordance between clinician-assigned treatment outcomes and outcomes calculated based on one of two standardized algorithms, one which identified failure at its earliest possible recurrence (i.e., failure-dominant algorithm), and one which calculated the outcome based on culture results at the end of treatment, regardless of early occurrence of failure (i.e., success-dominant algorithm).METHODS: Among 2,525 patients enrolled in the multi-country endTB observational study, we calculated the frequencies of concordance using cross-tabulations of clinician-assigned and algorithm-assigned outcomes. We summarized the common discrepancies.RESULTS: Treatment success calculated by algorithms had high concordance with treatment success assigned by clinicians (95.8 and 97.7% for failure-dominant and success-dominant algorithms, respectively). The frequency and pattern of the most common discrepancies varied by country.CONCLUSION: High concordance was found between clinician-assigned and algorithm-assigned outcomes. Heterogeneity in discrepancies across settings suggests that using algorithms to calculate outcomes may minimize bias.

[Role of myelin and lymphocyte protein in regulating pulmonary artery smooth muscle cell proliferation and apoptosis in pulmonary hypertension].

OBJECTIVE: To investigate the role of myelin and lymphocyte protein (MAL) in pulmonary hypertension (PAH). METHODS: Blood samples were collected from 50 patients with PAH (PAH group) and 50 healthy individuals for detection of plasma MAL expression using ELISA.According to the echocardiographic findings, the patients were divided into moderate/severe group (n=18) and mild group (n=32), and the correlation between MAL protein level and the severity of PAH was analyzed.In a pulmonary artery smooth muscle cell model of PAH with hypoxia-induced abnormal proliferation, the effects of mal gene knockdown and overexpression on cell growth, proliferation and starvation-induced apoptosis were observed; the changes in NK-κB signaling pathway in the transfected cells were detected to explore the molecular mechanism by which MAL regulates PAMSC proliferation and apoptosis. RESULTS: The plasma level of MAL was significantly higher in patients with PAH than in healthy individuals (P < 0.05), and the patients with moderate/severe PAH had significantly higher MAL level than those with mild PAH (P < 0.001).In PAMSCs, exposure to hypoxia significantly increased the mRNA and protein expression levels of MAL (P < 0.05), and MAL knockdown obviously inhibited hypoxia-induced proliferation and promoted starvation-induced apoptosis of the PAMSCs (P < 0.05).Knocking down mal significantly inhibited the activation of NK-κB signaling pathway that participated in regulation of PAMSC proliferation (P < 0.05). CONCLUSION: The plasma level of MAL is elevated in PAH patients in positive correlation with the disease severity.MAL knockdown inhibits abnormal proliferation and promotes apoptosis of PAMSCs by targeted inhibition of the NF-κB signaling pathway to improve vascular remodeling in PAH.

The impact of local colleges' interference in middle school students' family psychological intervention on the psychological health status of students learning at home - a case study of northern Guangdong.

OBJECTIVE: Using college psychological resources, this paper attempts to intervene in the family psychology of middle school students learning at home during the epidemic in northern Guangdong. Focusing on the impact of family system on the psychological health status of middle school students learning at home, it provides reference for targeted family psychological intervention and treatment of students. SUBJECTS AND METHODS: The "Psychological Health Survey Questions for Middle School Students Learning at Home during the Epidemic" was compiled to conduct a class-based random sampling survey of primary and secondary schools in northern Guangdong. Family psychological intervention is provided for key groups. RESULTS: (1) The middle school students' psychological health level was above average on the whole, but with great individual differences. (2) Families have a significant impact on students' psychological health, among which parents' occupation, family integrity, family economy, family atmosphere, and the number of children in the family all exert a significant impact on middle school students' psychological health. (3) Stepwise regression analysis reveals that the six factors of gender, grade, ethnicity and place of residence, family economy and atmosphere in the family environment system are included in the regression equation, explaining 11.6% of middle school students' psychological health. (4) Family psychological intervention significantly improves middle school students' psychological health. CONCLUSIONS: Local colleges' interference in middle school students' family psychological intervention can effectively improve psychological health of middle school students learning at home. Society, families and schools should value family psychological construction, and effectively unite social forces to jointly promote students' psychological health.

The Safety and Efficacy of Flow Diversion versus Conventional Endovascular Treatment for Intracranial Aneurysms: A Meta-analysis of Real-world Cohort Studies from the Past 10 Years.

BACKGROUND: Although the flow diverter has advantages in the treatment of intracranial aneurysms, pooled studies that directly compare it with conventional endovascular treatments are rare. PURPOSE: Our aim was to compare the safety and efficacy of flow-diverter and conventional endovascular treatments in intracranial aneurysms. DATA SOURCES: We performed a comprehensive search of the literature using PubMed, EMBASE, and the Cochrane Database. STUDY SELECTION: We included only studies that directly compared the angiographic and clinical outcomes of flow-diverter and conventional endovascular treatments. DATA ANALYSIS: Random effects or fixed effects meta-analysis was used to pool the cumulative rate of short- and long-term angiographic and clinical outcomes. DATA SYNTHESIS: Eighteen studies with 1001 patients with flow diverters and 1133 patients with conventional endovascular treatments were included; 1015 and 1201 aneurysm procedures were performed, respectively. The flow-diverter group had aneurysms of a larger size (standard mean difference, 0.22; 95% CI, 0.03-0.41; P = .026). There was a higher risk of complications in the flow-diverter group compared with the conventional endovascular group (OR, 1.4; 95% CI, 1.01-1.96; P = .045) during procedures. The follow-up angiographic results of flow-diverter treatment indicated a higher rate of complete occlusion (OR, 2.55; 95% CI, 1.70-3.83; P < .001) and lower rates of recurrence (OR, 0.24; 95% CI, 0.12-0.46; P < .001) and retreatment (OR, 0.31; 95% CI, 0.21-0.47; P < .001). LIMITATIONS: Limitations include a retrospective, observational design in some studies, high heterogeneity, and selection bias. CONCLUSIONS: Compared with the conventional endovascular treatments, the placement of a flow diverter may lead to more procedure-related complications, but there is no difference in safety, and it is more effective in the long term.

[Effects of typical PKC subtypes on the proliferation of mouse pulmonary artery smooth muscle cells and the expression of ERK1/2 and Akt induced by hypoxia].

Objective: To study the effects of specific isoforms of classic protein kinase C (cPKCs) on hypoxia-induced proliferation and the expression of ERK1/2 and Akt using drug intervention or virus transfection in vitro. Methods: Dynal MPC-1 magnetic particle concentrator was used to separate iron-containing pulmonary arterioles fragments, and the pulmonary artery smooth muscle cells (PASMCs) were primary cultured and identified. The cells were intervened by PKC agonist (PMA), PKCα inhibitor (safingol), PKCßⅠ inhibitor (Go6976) and PKCßⅡ inhibitor (LY333531) respectively, and the changes in protein expressions of cPKCs, and the phosphorylation levels of ERK1/2 and Akt were observed by immunoblotting under the condition of normal oxygen or hypoxia. The lentiviral vectors of PKCα and PKCß were used to specifically knock-down the activity of target genes by virus transfection techniques, and Western blotting was used to observe the protein expressions of cPKCs, and the phosphorylation levels of ERK1/2 and Akt in hypoxia-induced PASMCs in mice. Results: With Brdu method, the proliferation of PASMCs induced by hypoxia was significantly inhibited by safingol, Go6976 and LY333531 by inhibiting cPKCα, ßⅠ and ßⅡ respectively. Compared with the hypoxic control group, the rates of Brdu positive cells were (7.35±0.26)% vs (11.28±0.43)%, (3.76±0.25)% vs (7.98±0.28)% and (4.12±0.46)% vs (7.78±0.53)%. We also observed that PMA could significantly promote the proliferation of PASMCs under normoxic condition. Compared with the normoxia control group, the Brdu-positive cell rates were (9.65±0.47)% vs (6.34±0.52)%, (9.34±0.38)% vs (5.42±0.21)% and (7.78±0.53)% vs (4.12±0.46)%. In addition, after transfection with PKCα or PKCß lentiviral vector, the proliferation of PASMCs was significantly lower in hypoxia transfection group than in the control group. The rates of Brdu positive cells were (3.58±0.54)% vs (5.97±0.63)%, respectively. Using Western blotting, we also observed that after being inhibited by safingol, Go6976 and LY333531 respectively, the phosphorylation levels of ERK1/2 and Akt in PASMCs induced by hypoxia was significantly lower than the control group. After using safingol, the phosphorylation levels of ERK1/2 and Akt were (0.56±0.07) vs (1.08±0.13) and (0.49±0.04) vs (0.97±0.08). After using Go6976, the phosphorylation levels of ERK1/2 and Akt were (0.41±0.09) vs (0.79±0.10) and (0.48±0.09) vs (0.82±0.16), after using LY333531, the phosphorylation levels of ERK1/2 and Akt were (0.42±0.03) vs (0.87±0.06) and (0.34±0.07) vs (0.78±0.05). While PMA could promote the phosphorylation levels of ERK1/2 and Akt under normoxic condition, 1.25±0.12 vs 0.41±0.07 and 0.98±0.06 vs 0.37±0.08, respectively. Using transfection technique to specifically knock down the expression of cPKCα and ß, we found that under hypoxic conditions, transfection of PASMCs could significantly lower the phosphorylation levels of ERK1/2, its phosphorylation level was 0.29±0.06 vs 0.76±0.05, with no evident change in the phosphorylation levels of Akt. Conclusions: Hypoxia may lead to phosphorylation of ERK1/2 by promoting the protein expression of cPKCα, cPKCßⅠ and cPKCßⅡ respectively, which eventually induces abnormal proliferation of PASMCs from the distal pulmonary arteries, participating in the development of hypoxic pulmonary hypertension (HPH) of the mice. Regulation of the expression of cPKCα, cPKCßⅠ and cPKCßⅡ may help to attenuate the formation of pulmonary vascular remodeling. Target therapy based on cPKCs is expected to be a new direction for HPH therapy in the future.

[Establishment of a prediction model for colorectal cancer immune cell infiltration based on the cancer genome atlas (TCGA) database].

OBJECTIVE: To study the correlation between immune cell infiltration in colorectal cancer tissue and clinical prognosis and to explore the levels of some immune cell genes for predicting the prognosis of patients with glioma colorectal cancer. METHODS: In this study, we extracted colorectal cancer data from the cancer genome atlas (TCGA). Based on a deconvolution algorithm (called CIBERSORT) and clinically annotated expression profiles, the analysis assessed the infiltration patterns of 22 immune cells in colorectal cancer tissue to determine the association between each cell type and survival. Differences in five-year survival rate effectively illustrate the clinical prognostic value of each immune cell proportion in colorectal cancer, using a bar graph, correlation-based heatmap to represent the proportion of immune cells in each colorectal cancer sample. RESULTS: A total of 473 colorectal cancer tissues and 41 normal control tissues were extracted from the TCGA database, and the comparative analysis showed that there were differences in the proportion of various TIICs in colorectal cancer tissues, which could characterize individual differences and have prognostic value. Among the cell subsets studied, the proportions of memory B cells, plasma cells, CD4+ T cells, natural killer (NK) cells, M0 macrophages, M2 macrophages, and activated mast cells were significantly different between normal and cancer tissues. Resting NK cells, CD8+ T cells, and plasma cells were associated with T phase, activated dendritic cells were associated with N phase, and eosinophils, M1 macrophages, and activated mast cells were associated with M phase. Survival analysis showed that activated dendritic cells were positively associated with five-year survival rate in colorectal cancer patients. Naive CD4+ T cells were inversely associated with five-year survival rate. CONCLUSION: There are different degrees of immune cell infiltration in colorectal cancer tissues, and these differences may be important determinants of prognosis and treatment response. We conducted a new gene expression-based study of immune cell subtype levels and prognosis in colorectal cancer, which has potential clinical prognostic value in colorectal cancer patients.