Immunological characterization of stroke-heart syndrome and identification of inflammatory therapeutic targets.

Acute cardiac dysfunction caused by stroke-heart syndrome (SHS) is the second leading cause of stroke-related death. The inflammatory response plays a significant role in the pathophysiological process of cardiac damage. However, the mechanisms underlying the brain-heart interaction are poorly understood. Therefore, we aimed to analysis the immunological characterization and identify inflammation therapeutic targets of SHS. We analyzed gene expression data of heart tissue 24 hours after induction of ischemia stoke by MCAO or sham surgery in a publicly available dataset (GSE102558) from Gene Expression Omnibus (GEO). Bioinformatics analysis revealed 138 differentially expressed genes (DEGs) in myocardium of MCAO-treated compared with sham-treated mice, among which, immune and inflammatory pathways were enriched. Analysis of the immune cells infiltration showed that the natural killer cell populations were significantly different between the two groups. We identified five DIREGs, Aplnr, Ccrl2, Cdkn1a, Irak2, and Serpine1 and found that their expression correlated with specific populations of infiltrating immune cells in the cardiac tissue. RT-qPCR and Western blot methods confirmed significant changes in the expression levels of Aplnr, Cdkn1a, Irak2, and Serpine1 after MCAO, which may serve as therapeutic targets to prevent cardiovascular complications after stroke.

Effects of the costoclavicular block versus interscalene block in patients undergoing arthroscopic shoulder surgery under monitored anesthesia care: a randomized, prospective, non-inferiority study.

BACKGROUND: Recent studies have reported that costoclavicular blocks (CCBs) can consistently block almost all branches of the brachial plexus while sparing the phrenic nerve and provide effective analgesia after shoulder surgery. We aimed to compare the efficacy of the CCB with that of the interscalene block (ISB) as the sole blocking technique for shoulder surgery. METHODS: A total of 212 patients undergoing elective arthroscopic shoulder surgery were randomized to receive an ISB or CCB based on a non-inferiority design. All patients received titration sedation with propofol under monitored anesthesia during surgery. The primary outcomes were the proportion of patients with complete motor blockade of the suprascapular nerve (SSN) and incidence of hemidiaphragmatic paralysis (HDP). The secondary outcomes included block-related variables, complications, and postoperative pain scores. RESULTS: The proportion of patients with complete motor blockade of the SSN at 20 min between the CCB and ISB groups (53% vs. 66%) exceeded the predefined non-inferiority margin of -5%, but was comparable at 30 min (87% vs. 91%). The CCB resulted in a significantly lower incidence of HDP (7.55% vs. 92.45%), Horner's syndrome (0% vs. 18.87%), and dyspnea (0% vs. 10.38%) than the ISB. None of the patients experienced failed blocks or required conversion to general anesthesia. Pain scores were comparable between the groups. CONCLUSIONS: Ultrasound-guided CCBs may be comparable to ISBs, with fewer unfavorable complications in patients with impaired lung function undergoing arthroscopic shoulder surgery.

Why breast cancer patients avoid communicating disease-related information to their dependent children: A qualitative study.

AIM AND OBJECTIVES: This qualitative study explores why breast cancer patients do not share disease-related information with their dependent children. BACKGROUND: 'Open' communication between breast cancer patients and their children is beneficial to both. However, some still try to avoid discussing their diagnosis and related information with their children. Some worries lie in communicating with dependent children, but the underlying cause remains unclear. DESIGN: Qualitative descriptive study. METHODS: Semi-structured interview was used in this study. Twenty breast cancer patients with children (aged 8-18 years) were recruited at two urban tertiary hospitals in mainland China. Qualitative content analysis was conducted to analyse and identify themes and subthemes. This study followed the COREQ checklist for qualitative studies. RESULTS: Three main themes were identified: (1) Uncertainty about the future: Their struggles with cancer remain a sensitive subject with their children. They described the uncertainty surrounding their disease prognosis and their children's response. They were also unsure whether, when and how to inform their children of their conditions; (2) Useless and risky for their children to know the truth: They considered it useless because their children can neither understand nor change the existing facts. They were concerned that it could affect their children's emotional state, character and academic performance; and (3) All for their children's sake: They were willing to take care of their affairs without troubling their dependent children as much as possible. CONCLUSION: Most mothers delayed communicating disease-related information to their dependent children. However, they often underestimated children's abilities and ignored their thoughts and wishes. Motherhood leads to avoidance and concealment in discussing health issues with their children. RELEVANCE TO CLINICAL PRACTICE: Mothers should try to understand their children's views towards cancer earlier. Healthcare professionals, especially nurses, should provide further consultation and intervention services to assist mothers and their children.

Supervised Exercise Interventions in Childhood Cancer Survivors: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Background: Childhood cancer survivors (CCSs) may suffer from a multitude of health impairments, resulting in a compromised quality of life (QoL). This review's objective was to examine CCSs' adherence to supervised exercise training interventions and the impact of these interventions on health outcomes. Methods: The following databases were searched in May 2022: PubMed, Embase, Cochrane Library, and Web of Science. The included studies were limited to randomized controlled trials (RCTs), published in English involving CCSs aged 18 years and below. Results: Nine RCTs (n = 642 participants) were included in the systematic review, and seven of them (n = 551 participants) were included in the meta-analysis. Both the mean retention rate and adherence to the supervised exercise interventions were 87%. Supervised exercise interventions significantly improved muscle strength (standardized mean difference (SMD) = 1.42, p = 0.03), level of daily physical activity (SMD = 1.05, p < 0.001), body mass index (BMI) (mean difference (MD) = 1.06, p = 0.03), and fatigue (SMD = −0.44, p < 0.001), while there was no statistical significance in the quality of life (QoL) (SMD = 0.21, p = 0.20). Conclusions: The adherence of CCSs to supervised exercise interventions is high, and supervised exercise interventions are safe and effective.

Effects of double vs triple injection on block dynamics for ultrasound-guided intertruncal approach to the supraclavicular brachial plexus block in patients undergoing upper limb arteriovenous access surgery: study protocol for a double-blinded, randomized controlled trial.

BACKGROUND: Ultrasound-guided intertruncal approach (IA) has been proposed to be an alternative and promising approach to the supraclavicular block (SCB), in which double injection (DI) of local anesthetics (LA) is sequentially administered between intertruncal planes. We would like to apply a refined injection technique, named triple injection (TI) technique, based on the 3 separate compartments visualized by ultrasound. The aim of this study is to compare the percentage of patients with complete sensory blockade at 20 min of DI vs TI technique, when they are applied in patients undergoing upper limb arteriovenous access surgery. METHODS: This study is a prospective parallel-group randomized controlled trial. A total of 86 end-stage renal disease patients will be randomly allocated to receive IA-SCB using either DI or TI technique with identical LA (0.5% ropivacaine 24 mL). The primary outcome is the percentage of patients with complete sensory blockade of all 4 terminal nerves (median, ulnar, radial, and musculocutaneous nerves) of the brachial plexus measured at 20 min after injection. The secondary outcomes will consist of the sensory or motor blockade of all individual nerves, onset times, performance time, diaphragmatic paralysis, surgical anesthesia, and adverse events. DISCUSSION: It is expected that ultrasound-guided IA-SCB with the TI technique results in better block dynamic in patients undergoing upper limb arteriovenous access surgery. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2100045075 .

Individual, Interpersonal, and Home Environmental Factors Influencing Health Behaviors Among Chinese Childhood Cancer Survivors: A Structural Equation Analysis.

BACKGROUND: Childhood cancer survivors (CCSs) are at increased risk of chronic health conditions, which could be controlled with health behaviors. However, the health behaviors and related factors of Chinese CCSs remain unclear. OBJECTIVE: The aims of this study were to examine multiple health behaviors among Chinese CCSs and explore the individual, interpersonal, and home environmental factors affecting health behaviors. METHODS: This cross-sectional study recruited 204 participants from 3 grade-A tertiary hospitals in Guangzhou, China. Participants provided data on health behaviors (smoking, drinking, drug use, screen time, internet addiction, dietary behaviors, physical activity, and sleep behaviors) and their determining factors. Structural equation modeling was used to analyze the data. RESULTS: Chinese CCSs reported low rates of smoking, drinking, and drug use (0%-6.4%), but only 51% of survivors met screen time recommendations, and 24.5% of them had Internet addiction. Few survivors reported frequent soft-drink, sugar, and fast-food intake (2.0 to 7.4%), but many were finicky eaters (55.4%) or seldom drank milk (41.7%). In addition, 67.6% and 47.5% of survivors did not meet physical activity and sleep time recommendations. Childhood cancer survivors' health behaviors were influenced by the individual (age, education level, and time since diagnosis), interpersonal (peer and family support), and home environmental (residential location, parents' educations level, and household income) factors. CONCLUSIONS: There were suboptimal health behaviors among Chinese CCSs. Targeted interventions should consider their individual, interpersonal, and home environmental factors. IMPLICATIONS FOR PRACTICE: Knowledge of health behaviors and related factors of Chinese CCSs would help healthcare professionals develop further interventions to improve their care of this population.

Identification of MDM2, YTHDF2 and DDX21 as potential biomarkers and targets for treatment of type 2 diabetes.

Type 2 diabetes (T2D) is a multifactorial and polygenetic disease, although its exact etiology remains poorly understood. The objective of this study was to identify key biomarkers and potential molecular mechanisms in the development of T2D. Human RNA-Seq datasets across different tissues (GSE18732, GSE41762, and GSE78721) were collected from the Gene Expression Omnibus (GEO) database and differentially expressed genes (DEGs) between T2D and controls were identified using differential analysis. A total of 90 overlapping DEGs were identified, among which YTHDF2, DDX21, and MDM2 were considered as key genes due to their central positions in the PPI network and the same regulatory pattern in T2D. Logistic regression analysis showed that low expression of the key genes increased the risk of T2D. Enrichment analysis revealed that the key genes are involved in various important biological functions and signaling pathways including Notch, Fork head box O (FOXO), and phosphoinositide 3-kinase (PI3K)-Akt. RT-qPCR and Western blot analysis showed that all three key genes were down-regulated in pancreatic islets of both prediabetic and diabetic mouse models. Finally, the insulin-sensitizer, pioglitazone was used to treat db/db mice and immunofluorescence analysis showed that the expression of all three key genes was significantly down-regulated in db/db islets, an effect that was overcome by pioglitazone treatment. Together, these results suggest that the identified key genes could be involved in the development of T2D and serve as potential biomarkers and therapeutic targets for this disease.

Clinical research: low-level laser therapy in accelerating orthodontic tooth movement.

BACKGROUND: The present study aimed to investigate the effects of low-level laser therapy (LLLT) on orthodontic tooth movement and its correlation with the levels of interleukin-1ß (IL-1ß), receptor activator of nuclear factor kappa B ligand (RANKL) and osteoprotegerin (OPG) in gingival crevicular fluid (GCF). METHODS: This split-mouth design study included 12 patients scheduled for the extraction of both upper first premolars. Patients were randomly selected for experimental group that received left- or right-side radiation with a diode laser (810 nm wavelength, 100 mW power output, 6.29 J/cm2 energy density). Laser treatment was applied on days 0, 7, 14, and 21, after loading the canine retraction forces. GCF concentrations of IL-1ß, RANKL, and OPG were analyzed. The upper arch of each patient was scanned with an intraoral scanner to assess tooth movement. RESULTS: The cumulative tooth movement over 28 days was significantly higher in the laser group than in the control group. We observed significant reductions in OPG levels and increases in IL-1ß and RANKL levels in GCF samples on the experimental sides. CONCLUSION: With the parameter settings used in this study, LLLT could, to some extent, lead to changes in bone metabolism, which could accelerate orthodontic tooth movement. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR2000039594. Registered 2 November 2020-Retrospectively registered, www.chictr.org.cn/edit.aspx?pid=62465&htm=4 .

MLL3 suppresses tumorigenesis through regulating TNS3 enhancer activity.

MLL3 is a histone H3K4 methyltransferase that is frequently mutated in cancer, but the underlying molecular mechanisms remain elusive. Here, we found that MLL3 depletion by CRISPR/sgRNA significantly enhanced cell migration, but did not elevate the proliferation rate of cancer cells. Through RNA-Seq and ChIP-Seq approaches, we identified TNS3 as the potential target gene for MLL3. MLL3 depletion caused downregulation of H3K4me1 and H3K27ac on an enhancer ~ 7 kb ahead of TNS3. 3C assay indicated the identified enhancer interacts with TNS3 promoter and repression of enhancer activity by dCas9-KRAB system impaired TNS3 expression. Exogenous expression of TNS3 in MLL3 deficient cells completely blocked the enhanced cell migration phenotype. Taken together, our study revealed a novel mechanism for MLL3 in suppressing cancer, which may provide novel targets for diagnosis or drug development.

Dietary behaviours, physical activity and quality of life among childhood cancer survivors in Mainland China: A cross-sectional study.

OBJECTIVE: To examine the dietary behaviours, physical activity (PA) and quality of life (QoL) of childhood cancer survivors (CCS) in Mainland China and explore the relationships between these behaviours and QoL. METHODS: This cross-sectional study recruited 181 CCS from three Grade-A tertiary hospitals in Guangzhou. Survivors completed questionnaires assessing their dietary behaviours, PA and QoL. RESULTS: Only 2.2%, 7.7% and 2.2% of CCS reported frequent soft drinks, sugar and fast food intake, which were lower compared to CCS in Western studies. Most survivors (72.9%) failed to drink milk daily, and many (54.7%) were picky eating. Sixty percent of CCS reported less moderate-to-vigorous physical activity (MVPA) time than 60 min/day recommended by WHO. Picky eating was significantly associated with lower overall (p < 0.001), physical (p < 0.001) and psychosocial (p < 0.001) QoL. MVPA was significantly positively associated with overall (p < 0.05) and psychosocial (p < 0.01) QoL. CONCLUSIONS: Chinese CCS engaged better dietary behaviours of less soft drinks, sugar and fast food consumption, but many were picky eaters and did not meet milk intake and PA recommendations. Early behavioural interventions aimed at increasing the dietary diversity and MVPA level of this population should be taken to improve their QoL.

Association of maximum standardized uptake value with occult mediastinal lymph node metastases in cN0 non-small cell lung cancer.

OBJECTIVES: The management of non-small cell lung cancer (NSCLC) relies on the tumour-node-metastasis (TNM) stage, and the treatment regimen differs based on the N status. Positron emission tomography-computed tomography (PET-CT) has emerged as a powerful imaging tool for the detection of various cancers with a relatively low false-negative rate. We explored predictors to identify false-negative N2 disease in PET-CT. METHODS: A total of 284 consecutive cN0 patients with peripheral NSCLC who underwent PET-CT scans followed by curative intent resections were enrolled as a training set to identify predictors of occult N2 metastases by multivariable analysis. The accuracy and cut-off values for the predictors were calculated using a receiver operating characteristic curve. Clinical and pathological data were analysed retrospectively. An additional 151 patients were collected as a test set to validate the results, including the occult N2 rate and accuracy. RESULTS: In total, 8.5% (24/284) PET-CT-diagnosed N0 NSCLC cases had pathologically diagnosed N2 metastases. The SUVmax of the primary tumour was a unique independent risk factor for occult N2 NSCLC [P = 0.003, 95% confidence interval = 0.81-0.96, odds ratio (OR) = 0.88]. Occult N2 metastases occurred more frequently in the subcarinal (16/24) and right lower paratracheal lymph nodes (12/24). Accordingly, we divided the patients into two groups by SUVmax: the occult N2 rates in the SUVmax of <2.6 and SUVmax of ≥2.6 groups were 1.0% (1/100) and 12.5% (23/184), respectively (P = 0.001). In the test set, the occult N2 incidence rate was 9.3% (14/151), with the highest rates occurring in the subcarinal (9/14) and right lower paratracheal lymph nodes (6/14). In the two groups defined by SUVmax, the occult N2 rates were 4% (2/50) and 11.9% (12/101), respectively. CONCLUSIONS: The SUVmax of the primary tumour was an independent risk factor for occult N2 metastases in NSCLC patients diagnosed as clinical N0 by PET-CT. SUVmax of ≥2.6 of the primary tumour may indicate the risk of N2 metastases, and invasive mediastinal staging techniques or comprehensive therapy should not be ignored in these patients.

Global histone modification profiling reveals the epigenomic dynamics during malignant transformation in a four-stage breast cancer model.

BACKGROUND: Epigenetic regulation has emerged to be the critical steps for tumorigenesis and metastasis. Multiple histone methyltransferase and demethylase have been implicated as tumor suppressors or oncogenes recently. But the key epigenomic events in cancer cell transformation still remain poorly understood. METHODS: A breast cancer transformation model was established via stably expressing three oncogenes in primary breast epithelial cells. Chromatin immunoprecipitation followed by the next-generation sequencing of histone methylations was performed to determine epigenetic events during transformation. Western blot, quantitative RT-PCR, and immunostaining were used to determine gene expression in cells and tissues. RESULTS: Histones H3K9me2 and me3, two repressive marks of transcription, decrease in in vitro breast cancer cell model and in vivo clinical tissues. A survey of enzymes related with H3K9 methylation indicated that KDM3A/JMJD1A, a demethylase for H3K9me1 and me2, gradually increases during cancer transformation and is elevated in patient tissues. KDM3A/JMJD1A deficiency impairs the growth of tumors in nude mice and transformed cell lines. Genome-wide ChIP-seq analysis reveals that the boundaries of decreased H3K9me2 large organized chromatin K9 modifications (LOCKs) are enriched with cancer-related genes, such as MYC and PAX3. Further studies show that KDM3A/JMJD1A directly binds to these oncogenes and regulates their transcription by removing H3K9me2 mark. CONCLUSIONS: Our study demonstrates reduction of histones H3K9 me2 and me3, and elevation of KDM3A/JMJD1A as important events for breast cancer, and illustrates the dynamic epigenomic mechanisms during breast cancer transformation.

The selective activation of p53 target genes regulated by SMYD2 in BIX-01294 induced autophagy-related cell death.

Transcription regulation emerged to be one of the key mechanisms in regulating autophagy. Inhibitors of H3K9 methylation activates the expression of LC3B, as well as other autophagy-related genes, and promotes autophagy process. However, the detailed mechanisms of autophagy regulated by nuclear factors remain elusive. In this study, we performed a drug screen of SMYD2-/- cells and discovered that SMYD2 deficiency enhanced the cell death induced by BIX01294, an inhibitor of histone H3K9 methylation. BIX-01294 induces accumulation of LC3 II and autophagy-related cell death, but not caspase-dependent apoptosis. We profiled the global gene expression pattern after treatment with BIX-01294, in comparison with rapamycin. BIX-01294 selectively activates the downstream genes of p53 signaling, such as p21 and DOR, but not PUMA, a typical p53 target gene inducing apoptosis. BIX-01294 also induces other autophagy-related genes, such as ATG4A and ATG9A. SMYD2 is a methyltransferase for p53 and regulates its transcription activity. Its deficiency enhances the BIX-01294-induced autophagy-related cell death through transcriptionally promoting the expression of p53 target genes. Taken together, our data suggest BIX-01294 induces autophagy-related cell death and selectively activates p53 target genes, which is repressed by SMYD2 methyltransferase.