The association between serum methylmalonic acid, cobalamin-related biomarkers, and long-term mortality risk in cancer survivors: a prospective cohort study.

BACKGROUND: Elevated serum methylmalonic acid (MMA), a marker of cobalamin (vitamin B12) deficiency, has been linked to cancer progression. However, the impact of MMA or cobalamin on mortality risk in cancer survivors remains unknown. OBJECTIVES: To explore the relationship between MMA, serum, dietary, and supplement of cobalamin, MMA metabolism-related genes, and poor prognosis in adult cancer survivors. METHODS: We analyzed data from 1988 cancer survivors aged ≥20 y. Patients were selected from the National Health and Nutrition Examination Survey and followed up until December 31, 2019. Weighted Cox proportional hazard regression was used to estimate hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs) for mortality risk assessment. Genomic analysis identified MMA metabolism-related genes linked to early death in a 33-cancer-type cohort from The Cancer Genome Atlas. RESULTS: Among 1988 participants, 872 deaths occurred over a 10-year follow-up. Higher serum MMA levels were significantly linked to increased long-term mortality risk (tertile 3 compared with tertile 1: adjusted HR: 1.37; 95% CI: 1.11, 1.70; P-trend < 0.001). No associations were found between serum, dietary, and supplement of cobalamin and cancer survivor mortality (each P-trend > 0.143). However, MMA-associated mortality was notable in patients without deficiency. When combining cobalamin and MMA categories, multivariate-adjusted HR (95% CI) for all-cause mortality was 2.06 (95% CI: 1.60, 2.65) in participants with >250 nmol/L and cobalamin >295.1 pmol/L compared with those with MMA ≤250 nmol/L and cobalamin >295.1 pmol/L. Moreover, reduced transcriptional levels of MMA metabolism-related genes, indicating decreased mitochondrial MMA metabolism capability, are linked to an unfavorable prognosis in certain cancer types. CONCLUSIONS: Serum MMA was associated with long-term mortality risk in adult cancer survivors, which was more significant among individuals with higher levels of serum cobalamin. These findings suggest that mortality related to MMA was attributed to the insufficient flux of MMA metabolism, not cobalamin deficiency.

Ultrasound-targeted microbubble technology facilitates SAHH gene delivery to treat diabetic cardiomyopathy by activating AMPK pathway.

Diabetic cardiomyopathy (DCM) is a cardiovascular complication with no known cure. In this study, we evaluated the combination of ultrasound-targeted microbubble destruction (UTMD) and cationic microbubbles (CMBs) for cardiac S-adenosyl homocysteine hydrolase (SAHH) gene transfection as potential DCM therapy. Models of high glucose/fat (HG/HF)-induced H9C2 cells and streptozotocin-induced DCM rats were established. Ultrasound-mediated SAHH delivery using CMBs was a safe and noninvasive approach for spatially localized drug administration both in vitro and in vivo. Notably, SAHH overexpression increased cell viability and antioxidative stress and inhibited apoptosis of HG/HF-induced H9C2 cells. Likewise, UTMD-mediated SAHH delivery attenuated apoptosis, oxidative stress, cardiac fibrosis, and myocardial dysfunction in DCM rats. Activation of the AMPK/FOXO3/SIRT3 signaling pathway may be a key mechanism mediating the role of SAHH in regulating myocardial injury. Thus, UTMD-mediated SAHH transfection may be an important advancement in cardiac gene therapy for restoring ventricular function after DCM.

Arsenic trioxide alleviates atherosclerosis by inhibiting CD36-induced endocytosis and TLR4/NF-κB-induced inflammation in macrophage and ApoE-/- mice.

BACKGROUND: Inflammation and lipid accumulation are key events in atherosclerosis progression. Despite arsenic trioxide's (ATO) toxicity, at appropriate doses, it is a useful treatment for various diseases treatment. ATO prevents vascular restenosis; however, its effects on atherosclerotic plaque development and instability remain unclear. METHODS: ApoE-/- mice were fed high-fat diet for 4 months, and starting at the third month, ATO was intravenously administered every other day. Atherosclerotic lesion size, histological characteristics, and related protein and lipid profiles were assessed using samples from the aorta, carotid artery, and serum. The anti-inflammatory and anti-pyroptosis effects of ATO were investigated by stimulating RAW264.7 and THP-1 cell lines with oxidized low-density lipoprotein (ox-LDL) or lipopolysaccharide (LPS). RESULTS: ATO reduced atherosclerotic lesion formation and plasma lipid levels in ApoE-/- mice. In the serum and aortic plaques, ATO reduced the levels of pro-inflammatory factors, including interleukin (IL) 6 and tumor necrosis factor α, but increased IL-10 levels. Mechanistically, ATO promoted the CD36-mediated internalization of ox-LDL in a peroxisome proliferator-activated receptor γ-dependent manner. Furthermore, ATO downregulated Toll-like receptor 4 (TLR4) expression in plaques and macrophages and inhibited p65 nuclear translocation and IκBα degradation. ATO reduced macrophage pyroptosis by downregulating NLR family pyrin domain-containing 3 (NLRP3) expression and caspase 1 activation. CONCLUSION: ATO has potential atheroprotective effects, especially in macrophages. The mechanisms were inhibition of CD36-mediated foam cell formation and suppression of inflammatory responses and pyroptosis mediated by TLR4/nuclear factor κB and NLRP3 activation. Our findings provide evidence supporting the potential atheroprotective value of ATO.

Trends in Electronic Cigarette Use Among US Adults With a History of Cardiovascular Disease.

This cross-sectional study analyzes the prevalence of electronic cigarette (e-cigarette) use among adults with cardiovascular disease in the US between 2014 and 2020.

Cost-related medication nonadherence in US adults with asthma: The National Health Interview Survey, 2013-2020.

BACKGROUND: Asthma is a chronic disease that needs long-term control for secondary prevention. Health-related expenditures resulting from asthma are rising in the United States, and medication nonadherence is associated with adverse health outcomes in patients with asthma. OBJECTIVE: To estimate the prevalence and risk factors of cost-related medication nonadherence (CRN) in individuals with asthma in the United States. METHODS: We identified patients aged above or equal to 18 years with a history of asthma in nationally representative cross-sectional data, the National Health Interview Survey 2013 to 2020. Participants were considered to have experienced CRN if at any time in the 12 months they reported skipping doses, taking less medication, or delaying filling a prescription to save money. The weighted prevalence of CRN was estimated overall and by subgroups. Logistic regression was used to identify CRN-related characteristics. RESULTS: Of the 26,539 National Health Interview Survey participants with a history of asthma, 4360 (15.77%; representing 3.92 million of the US population) reported CRN, with 10.12% (weighted 2.51 million) of patients skipping doses to save money, 10.82% (weighted 2.69 million) taking less medication to save money, and 13.35% (weighted 3.31 million) delaying filling a prescription to save money. The subgroups young, women, low income, no health insurance, currently smoking, and with comorbidities had a higher prevalence of CRN. The results of this sensitivity analysis did not differ from the overall results. CONCLUSION: In the United States, 1 in 6 adults with a history of asthma is nonadherence with medications due to costs. Removing financial barriers to accessing medication can improve medication adherence in patients with asthma.

Cardiac-targeted delivery of nuclear receptor RORα via ultrasound targeted microbubble destruction optimizes the benefits of regular dose of melatonin on sepsis-induced cardiomyopathy.

BACKGROUND: Large-dose melatonin treatment in animal experiments was hardly translated into humans, which may explain the dilemma that the protective effects against myocardial injury in animal have been challenged by clinical trials. Ultrasound-targeted microbubble destruction (UTMD) has been considered a promising drug and gene delivery system to the target tissue. We aim to investigate whether cardiac gene delivery of melatonin receptor mediated by UTMD technology optimizes the efficacy of clinically equivalent dose of melatonin in sepsis-induced cardiomyopathy. METHODS: Melatonin and cardiac melatonin receptors in patients and rat models with lipopolysaccharide (LPS)- or cecal ligation and puncture (CLP)-induced sepsis were assessed. Rats received UTMD-mediated cardiac delivery of RORα/cationic microbubbles (CMBs) at 1, 3 and 5 days before CLP surgery. Echocardiography, histopathology and oxylipin metabolomics were assessed at 16-20 h after inducing fatal sepsis. RESULTS: We observed that patients with sepsis have lower serum melatonin than healthy controls, which was observed in the blood and hearts of Sprague-Dawley rat models with LPS- or CLP-induced sepsis. Notably, a mild dose (2.5 mg/kg) of intravenous melatonin did not substantially improve septic cardiomyopathy. We found decreased nuclear receptors RORα, not melatonin receptors MT1/2, under lethal sepsis that may weaken the potential benefits of a mild dose of melatonin treatment. In vivo, repeated UTMD-mediated cardiac delivery of RORα/CMBs exhibited favorable biosafety, efficiency and specificity, significantly strengthening the effects of a safe dose of melatonin on heart dysfunction and myocardial injury in septic rats. The cardiac delivery of RORα by UTMD technology and melatonin treatment improved mitochondrial dysfunction and oxylipin profiles, although there was no significant influence on systemic inflammation. CONCLUSIONS: These findings provide new insights to explain the suboptimal effect of melatonin use in clinic and potential solutions to overcome the challenges. UTMD technology may be a promisingly interdisciplinary pattern against sepsis-induced cardiomyopathy.

Prognostic value of gut microbiota-derived metabolites in patients with ST-segment elevation myocardial infarction.

BACKGROUND: Studies about the prognostic role of gut microbiota-derived metabolites including phenylacetyl glutamine (PAGln), indoxyl sulfate (IS), lithocholic acid (LCA), deoxycholic acid (DCA), trimethylamine (TMA), trimethylamine N-oxide (TMAO), and its precursor trimethyllysine (TML) are limited in patients with ST-segment elevation myocardial infarction (STEMI). OBJECTIVES: To examine the relationship between plasma metabolite levels and major adverse cardiovascular events (MACEs), including nonfatal MI, nonfatal stroke, all-cause mortality, and heart failure in patients with STEMI. METHODS: We enrolled 1004 patients with STEMI undergoing percutaneous coronary intervention (PCI). Plasma levels of these metabolites were determined by targeted liquid chromatography/mass spectrometry. The associations of metabolite levels with MACEs were assessed with the Cox regression model and quantile g-computation. RESULTS: During a median follow-up of 360 d, 102 patients experienced MACEs. Higher plasma PAGln (hazard ratio [HR], 3.17 [95% CI: 2.05, 4.89]; P < 0.001), IS (2.67 [1.68, 4.24], P < 0.001), DCA (2.36 [1.40, 4.00], P = 0.001), TML (2.66 [1.77,3.99], P < 0.001), and TMAO (2.61 [1.70, 4.00], P < 0.001) levels were significantly associated with MACEs independent of traditional risk factors. According to quantile g-computation, the joint effect of all these metabolites was 1.86 (95% CI: 1.46, 2.27). PAGln, IS and TML had the greatest proportional positive contributions to the mixture effect. Additionally, plasma PAGln and TML combined with coronary angiography scores including the Synergy between PCI with Taxus and cardiac surgery (SYNTAX) score (area under the curve [AUC]: 0.792 vs. 0.673), Gensini score (0.794 vs. 0.647) and Balloon pump-assisted Coronary Intervention Study (BCIS-1) jeopardy score (0.774 vs. 0.573) showed better prediction performance for MACEs. CONCLUSIONS: Higher plasma PAGln, IS, DCA, TML, and TMAO levels are independently associated with MACEs suggesting that these metabolites may be useful markers for prognosis in patients with STEMI.

The Regulation and Characterization of Mitochondrial-Derived Methylmalonic Acid in Mitochondrial Dysfunction and Oxidative Stress: From Basic Research to Clinical Practice.

Methylmalonic acid (MMA) can act as a diagnosis of hereditary methylmalonic acidemia and assess the status of vitamin B12. Moreover, as a new potential biomarker, it has been widely reported to be associated with the progression and prognosis of chronic diseases such as cardiovascular events, renal insufficiency, cognitive impairment, and cancer. MMA accumulation may cause oxidative stress and impair mitochondrial function, disrupt cellular energy metabolism, and trigger cell death. This review primarily focuses on the mechanisms and epidemiology or progression in the clinical study on MMA.

A Concomitant Cancer Diagnosis Is Associated With Poor Cardiovascular Outcomes Among Acute Myocardial Infarction Patients.

BACKGROUND AND AIMS: With the increasing coexistence of cardiovascular disease and cancer in contemporary clinical practice, studies on the outcomes in acute myocardial infarction (AMI) patients with cancer has not been systematically investigated. This study sought to investigated the effect of coexisting cancer on the treatment and clinical outcomes among AMI patients. METHODS: We retrospectively integrated and analyzed cardiovascular data of 6,607 AMI patients between June 2016 and December 2019. Patients with cancer were compared with pair-matched cancer-naive patients. Cox proportional hazards models were constructed to compare the differences in outcomes. RESULTS: Of 6,607 patients, 2.3% (n = 150) had been diagnosed with cancer. Patients with cancer were older (70.3 ± 10.0 vs. 63.9 ± 11.5 years, P < 0.001) and had a higher burden of comorbidities. Moreover, patients with cancer tended to receive clopidogrel (52.0 vs. 40.0%, P = 0.004) rather than ticagrelor (45.6 vs. 58.2%, P = 0.003) than those without cancer. After pairwise matching, patients with cancer were less likely to undergo in-hospital percutaneous coronary intervention (61.3 vs. 70.0%, P = 0.055). And after 3-year follow-up, the cumulative incidence of cardiovascular death (14.0 vs. 8.3%; adjusted HR, 1.93; 95% CI, 1.11-3.39; P = 0.021) among patients with cancer was significantly higher than that among the matched controls, a similar pattern was observed for the composite outcome of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke (16.0 vs. 10.3%; adjusted HR, 1.98; 95% CI, 1.21-3.26; P = 0.007). Moreover, patients with a historical cancer diagnosis within 5 years had a higher risk of cardiovascular ischemic events. CONCLUSIONS: AMI patients with a concomitant diagnosis of cancer tended to be treated with conservative therapies and were at substantially higher risk for adverse cardiovascular outcomes.

IRGM/Irgm1 facilitates macrophage apoptosis through ROS generation and MAPK signal transduction: Irgm1+/- mice display increases atherosclerotic plaque stability.

Rationale: Atherosclerosis plaque rupture (PR) is the pathological basis and chief culprit of most acute cardiovascular events and death. Given the complex and important role of macrophage apoptosis and autophagy in affecting plaque stability, an important unanswered question include is whether, and how, immunity-related GTPase family M protein (IRGM) and its mouse orthologue IRGM1 affect macrophage survival and atherosclerotic plaque stability. Methods: To investigate whether serum IRGM of ST-segment elevation myocardial infarction (STEMI) patients is related to plaque morphology, we divided 85 STEMI patients into those with and without plaque rupture (PR and non-PR, respectively) based on OCT image analysis, and quantified the patients' serum IRGM levels. Next, we engineered Irgm1 deficient mice (Irgm1+/-) and chimera mice with Irgm1 deficiency in the bone marrow on an ApoE-/- background, which were then fed a high-fat diet for 16 weeks. Pathological staining was used to detect necrotic plaque cores, ratios of neutral lipids and cholesterol crystal, as well as collagen fiber contents in these mice to characterize plaque stability. In addition, immunofluorescence, immunohistochemical staining and western blot were used to detect the apoptosis of macrophages in the plaques. In vitro, THP-1 and RAW264.7 cells were stimulated with ox-LDL to mimic the in vivo environment, and IRGM/IRGM1 expression were modified by specific siRNA (knockdown) or IRGM plasmid (knocked-in). The effect of IRGM/Irgm1 on autophagy and apoptosis of macrophages induced by ox-LDL was then evaluated. In addition, we introduced inhibitors of the JNK/p38/ERK signaling pathway to verify the specific mechanism by which Irgm1 regulates RAW264.7 cell apoptosis. Results: The serum IRGM levels of PR patients is significantly higher than that of non-PR patients and healthy volunteers, which may be an effective predictor of PR. On a high-fat diet, Irgm1-deficient mice exhibit reduced necrotic plaque cores, as well as neutral lipid and cholesterol crystal ratios, with increased collagen fiber content. Additionally, macrophage apoptosis is inhibited in the plaques of Irgm1-deficient mice. In vitro, IRGM/Irgm1 deficiency rapidly inhibits ox-LDL-induced macrophage autophagy while inhibiting ox-LDL-induced macrophage apoptosis in late stages. Additionally, IRGM/Irgm1 deficiency suppresses reactive oxygen species (ROS) production in macrophages, while removal of ROS effectively inhibits macrophage apoptosis induced by IRGM overexpression. We further show that Irgm1 can affect macrophage apoptosis by regulating JNK/p38/ERK phosphorylation in the MAPK signaling pathway. Conclusions: Serum IRGM may be related to the process of PR in STEMI patients, and IRGM/Irgm1 deficiency increases plaque stability. In addition, IRGM/Irgm1 deficiency suppresses macrophage apoptosis by inhibiting ROS generation and MAPK signaling transduction. Cumulatively, these results suggest that targeting IRGM may represent a new treatment strategy for the prevention and treatment of acute cardiovascular deaths caused by PR.

Decreased risk of all-cause and heart-specific mortality is associated with low-fat or skimmed milk consumption compared with whole milk intake: A cohort study.

BACKGROUND&AIMS: It is controversial to preferentially choose low-fat milk or full-fat items. This study aimed to investigate the association of total and cause-specific mortality with 2 g/100 g or ≤ 1 g/100 g low-fat milk consumption compared with whole milk in general population. METHODS: Overall, 29,283 adults aged ≥20 years from US National Health and Nutrition Examination Survey 1999-2014 were recruited with a median follow-up of 8.3 years. The types of milk consumption at baseline (e.g., whole-fat, 2 g/100 g low-fat, and ≤1 g/100 g low-fat) were reported during in-house interviews. Hazard ratios for the associations between milk types and mortality were assessed with the weighted Cox proportional regression. RESULTS: During 241,572 person-years of follow-up, 4170 deaths occurred including 730 heart disease-related deaths and 846 cancer deaths. Consumption of milk contained lower fat exhibited an inverse association with total and cardiovascular mortality after multivariable adjustment. Compared with participants consuming whole-fat milk, those consuming 2 g/100 g or ≤1 g/100 g low-fat milk had a 14%-22% decrease in total mortality (p trend ≤0.001). Individuals consuming 2 g/100 g and ≤1 g/100 g low-fat milk had hazard ratios (95%CI) of 0.73 (0.55-0.97) and 0.67 (0.49-0.91) for heart-related mortality (p trend = 0.009). No significant difference was noted between whole-fat and lower-fat milk for mortality due to cancer, Alzheimer's disease, or diabetes mellitus. A similar trend was noted in the stratification and sensitivity analyses. CONCLUSION: Compared with whole milk, low-fat or skim milk intake was associated with reduced total and heart-related mortality. Low-fat milk may be more conducive than whole milk for promoting cardiovascular health in general adults.

Hyperglycemia Promotes Liver Metastasis of Colorectal Cancer via Upregulation of Integrin αvß6.

BACKGROUND Diabetes is related to higher risk of multiple cancers. This study aimed to explore the effect and mechanism of diabetes on liver metastasis of CRC. MATERIAL AND METHODS Overall and liver metastasis-free survival in diabetic and non-diabetic CRC patients were compared by Kaplan-Meier analysis. Expression of alphavß6 was detected by immunohistochemistry in clinical specimens. Effects of hyperglycemia on alphavß6 expression in colon cancer cells were assessed by western blot, real-time PCR, and flowcytometry. Effects of hyperglycemia on migration and invasion were demonstrated by Transwell assay. Expression and activity of MMP-9 and MMP-2 were determined by real-time PCR and gelatin zymography. Liver metastatic nodules were counted and b6 expression was detected by western blot in a liver metastasis mouse model. RESULTS CRC patients with diabetes had poorer overall and liver metastasis-free survival, and diabetes was associated with higher alphavß6 expression in CRC specimens. Hyperglycemia promoted the invasion and migration of colon cancer cells, and upregulated the expression and activity of MMP-9, which were attenuated by inhibition of alphavß6. Hyperglycemia upregulated the expression of ß6 and cell surface expression of avb6, which was reduced by ERK inhibitor. The in vitro results were confirmed in vivo in the mouse model. CONCLUSIONS Our study demonstrated the enhancing effect of hyperglycemia on liver metastasis of CRC, and showed that alphavß6 was involved in this process, suggesting that control of glucose levels and inhibition of alphavß6 can reduce the risk of liver metastasis in diabetic CRC patients.

Temporal trend of circulating trans-fatty acids and risk of long-term mortality in general population.

BACKGROUND & AIMS: There has been controversial evidence regarding the relationship between isomers of circulating trans-fatty acids (TFAs) and mortality. This study aimed to ascertain the relationships between plasma TFAs and overall or cause-specific mortality of the general population in two independent subsets from the US National Health and Nutrition Examination Survey (1999-2000 and 2009-2010 cycles). METHODS AND RESULTS: Plasma TFA isomers (C16:1n-7t, C18:1n-7t, C18:1n-9t and C18:2n-6,9t) in 3439 adults free of cancer or severe cardiovascular disease were analyzed by gas chromatography/mass spectrometry. Overall, 259 died among 1376 individuals over a median follow-up of 15.6 years in the 1999-2000 cycle, and 105 died in the latter subset of 2063 subjects during a median of 5.9 years. Cox proportional hazards regression was conducted to estimate the hazard ratios of mortality. The main isomer of industrially derived TFAs, elaidic acid (C18:1n-9t) was considerably associated with long-term total mortality in the 1999-2000 cycle after adjusting for confounders, with a 54% increase in the top tertile compared with the bottom one. However, the association disappeared with halving C18:1n-9t by 2009-2010. In contrast, neither of the ruminant-derived TFAs (C16:1n-7t and C18:1n-7t) suggested any inverse correlations with all-cause death, mortality due to heart disease, cancer or other causes. CONCLUSION: The major isomer of industrial TFAs, the higher circulating C18:1n-9t might be associated with increased long-term mortality. The associations with death risk turned slight with the reduction of TFAs consumption by half. However, dietary guidelines should rigorously identify the healthy effect of animal TFAs consumption.

Proteomics Profiling Reveals Insulin-Like Growth Factor 1, Collagen Type VI α-2 Chain, and Fermitin Family Homolog 3 as Potential Biomarkers of Plaque Erosion in ST-Segment Elevated Myocardial Infarction.

BACKGROUND: Plaque erosion (PE) has been considered a secondary pathogenesis of ST-segment elevated myocardial infarction (STEMI) following plaque rupture (PR). Previous studies demonstrated that they had different demographic and histology characteristics and need different treatment strategy. But there are few non-invasive plasma biomarkers for distinguishing them. The present study aimed to identify non-invasive predictive biomarkers for PE and PR in patients with STEMI.Methods and Results:A total 108 patients were recruited and grouped into a PE group (n=36), a PR group (n=36), and an unstable angina pectoris (UAP) (n=36) group for analysis. A 9-plex tandem mass tag (TMT)-based proteomics was used to compare plasma protein profiles of PE, PR, and UAP. In total, 36 significant differential proteins (DPs) were identified among groups, 10 of which were screened out using bio-information analysis and validated with enzyme-linked immunosorbent assay (ELISA). The relationship of angiography and optical coherence tomography (OCT) imaging data and the 10 target DPs was analyzed statistically. Logistic regression showed elevated collagen type VI α-2 chain (COL6A2) and insulin-like growth factor 1 (IGF1), and decreased fermitin family homolog 3 (FERMT3), were positively associated with PE. Multivariate analysis indicated IGF1, FERMT3, and COL6A2 had independent predictive ability for PE. IGF1 was inversely correlated with lumen stenosis and the lipid arc of the plaque. CONCLUSIONS: IGF1, COL6A2, and FERMT3 are potential predictive biomarkers of PE in STEMI patients. And IGF1 was negatively correlated with the developing of culprit plaque.

Removal of pediatric stage IV neuroblastoma by robot-assisted laparoscopy: A case report and literature review.

BACKGROUND: Neuroblastoma (NB) is the most common extracranial solid tumor in children, with an incidence of approximately 1/10000. Surgical resection is an effective treatment for children with NB. Robot-assisted laparoscopic surgery is a new method and is superior to conventional laparoscopic surgery, since it has been preliminarily applied in clinical practice with a significant curative effect. This paper discusses significance and feasibility of complete resection of stage IV NB using robot-assisted laparoscopic surgery, while comparing its safety and effectiveness with conventional laparoscopic surgery. CASE SUMMARY: In June 2018, a girl with stage IV retroperitoneal NB, aged 3 years and 5 mo, was admitted. Her weight was 15 kg, and her height was 100 cm. Robot-assisted, five-port laparoscopic resection of NB was performed. Starting from the middle point between the navel and the anterior superior iliac spine to the left lower abdomen, the pneumoperitoneum and observation hole (10 mm) were established using the Hasson technique. Operation arm #1 was located between the left anterior axillary line, the navel, and the costal margin (8 mm); operation arm #2 was located at the intersection of the right anterior axillary line and Pfannenstiel line (8 mm); one auxiliary hole was located between arm #2 (on the Pfannenstiel line) and the observation hole (12 mm); and another auxiliary hole (5 mm) was located slightly below the left side of the xiphoid. Along the right line of Toldt and the hepatic flexure of the transverse colon, the colon was turned to the left and below with a hook electrode. Through Kocher's incision, the duodenum and the pancreatic head were turned to the left to expose the inferior vena cava and the abdominal aorta. The vein was separated along the right external iliac, and the inferior vena cava was then lifted to expose the right renal vein from the bottom to the top. The tumor was transected horizontally below the renal vein, and it was first cut into pieces and then resected. The right renal artery and the left renal vein were also exposed, and the retrohepatic inferior vena cava was isolated. The tumor was resected along the surface of the psoas muscle, the back of the inferior vena cava, and the right side of the abdominal aorta. Finally, the lymph node metas-tases in front of the abdominal aorta and left renal vein were completely removed. The specimens were loaded into a disposable specimen retrieval bag and removed from the enlarged auxiliary hole. T-tube drainage was placed and brought out through a hole in the right lower quadrant of the abdomen. The operative time was 389 min, the time of pneumoperitoneum was 360 min, the intraoperative blood loss was approximately 200 mL, and the postoperative recovery was smooth. There were no complications, such as lymphatic fistula, diarrhea, bleeding, and paralytic ileus. Two months after discharge, there were no other complications. The literature on the application of robot-assisted laparoscopic surgery in the treatment of NB in children was reviewed. CONCLUSION: The robot has the advantages of a three-dimensional view and flexible operation, and it can operate finely along blood vessels. The successful experience of this case confirmed that robot-assisted laparoscopic surgery can skeletonize the abdominal blood vessels in the tumor and cut the tumor into pieces, indicating that robot-assisted laparoscopic surgery is feasible.

Retroperitoneoscopic approach for partial nephrectomy in children with duplex kidney: A case report.

BACKGROUND: Renal duplication is a common deformity of the urinary system, with an incidence of approximately 1/125 in children. Symptomatic patients with hydronephrosis, vesicoureteral reflux, or incontinence may require surgical interventions. Laparoscopy and retroperitoneoscopy are the two main accesses for partial nephrectomy. CASE SUMMARY: A 9-year-old child was admitted to the hospital for hydronephrosis of the left kidney. Ultrasonography showed that the left kidney was larger, approximately 12.6 cm × 6.3 cm × 5.5 cm in size, with visible separation of the pelvis and an obviously separated lower portion. The upper segment of the left ureter was dilated (approximately 2.6 cm in width), and no significant dilation was observed in the middle and upper segments. The right kidney and ureter were normal. Primary diagnosis was left renal duplication malformation and hydronephrosis. Retroperitoneal laparoscopic nephrectomy and ureterectomy were performed. Intraoperative exploration revealed a dilated pelvis and thin renal parenchyma at the lower pole of the left kidney. The upper left kidney was smaller than normal, and the pelvis and ureter were larger than normal. The renal artery was blocked for 40 min. A hemolock was used to clamp down the kidney ureter, and a drainage tube was retained in the retroperitoneal cavity. The operation was uneventful, and the estimated amount of blood loss was 100 mL. Total abdominal drainage amount was 116 mL. The drainage tube was removed on postoperative day (POD) 3 and the patient was discharged on POD6. The pathological diagnosis confirmed the atrophy of the renal parenchyma, the dilation of the renal pelvis, hydronephrosis, and ureteral cystic dilation. CONCLUSION: The retroperitoneoscopic approach for partial nephrectomy is feasible and effective in selective pediatric patients with a duplex kidney.

Robot-assisted gallbladder-preserving hepatectomy for treating S5 hepatoblastoma in a child: A case report and review of the literature.

BACKGROUND: Hepatoblastoma (HB) is the most common hepatic malignant tumour in children, accounting for approximately 50%-60% of primary hepatic malignant tumours in children, mostly in children under 3 years old. In Western countries, the incidence of hepatoblastoma is approximately 1-2/100000. Da Vinci surgical system is fast becoming a key instrument in microinvasive surgery. The past decade has seen the rapid development of robot-assisted laparoscopy, which expends many fields including the liver surgery. This paper discusses the significance and feasibility of robot-assisted gallbladder-preserving hepatectomy for treating S5 hepatoblastoma in children. The aim of this essay is to compare the safety and effectiveness of robotic surgery with conventional laparoscopic surgery, and explore the meaning of preservation of the gallbladder by sharing this case. CASE SUMMARY: A 3-year-old child with a liver mass in the 5th segment was treated using the Da Vinci surgical system, and the gallbladder was retained. The child was admitted to the hospital for 20 d for the discovery of the right hepatic lobe mass. Ultrasonography revealed a low echo mass, 46 mm × 26 mm × 58 mm in size, indicating hepatoblastoma in the right lobe, and enhanced computed tomography showed continuous enhancement of iso-low-density lesions with different sizes and nodules and unclear boundaries, without the dilation of the intrahepatic bile duct, no enlargement of the gallbladder, and uniform thickness of the wall. The diagnosis was "liver mass, hepatoblastoma". It was decided to perform S5 liver tumour resection. During surgery, the tumour and gallbladder were isolated first, and the gallbladder could be completely separated from the tumour surface without obvious infiltration; therefore, the gallbladder was preserved. The cutting line was marked with an electric hook. The hepatic duodenal ligament was blocked with a urethral catheter using the Pringle method, and the tumour and part of the normal liver tissue were completely resected with an ultrasound knife along the incision. The hepatic portal interdiction time was approximately 25 min. An abdominal drainage tube was inserted. The auxiliary hole was connected to the lens, and the specimen was removed. The patient's status was uneventful, and the operation time was 166 min. The robotic time was 115 min, and the bleeding amount was approximately 200 mL. In total, 300 mL of red blood cell suspension and 200 mL of plasma were injected. No serious complications occurred. Pathological findings confirmed fetal hepatoblastoma and R0 resection. A gallbladder contraction test was performed two weeks after surgery. CONCLUSION: Robot-assisted S5 hepatectomy with gallbladder preservation is safe and feasible for specific patients.

Cardiac-specific Mst1 deficiency inhibits ROS-mediated JNK signalling to alleviate Ang II-induced cardiomyocyte apoptosis.

Apoptosis is associated with various myocardial diseases. Angiotensin II (Ang II) plays a central role in the pathogenesis of RAAS-triggered cardiac apoptosis. Our previous studies showed that mammalian Ste20-like kinase 1 (Mst1) aggravates cardiac dysfunction in cardiomyocyte under pathological conditions, but its role in Ang II-mediated cardiomyocyte apoptosis is not known. We addressed this in the present study by investigating whether cardiac-specific Mst1 knockout can alleviate Ang II-induced cardiomyocyte apoptosis along with the underlying mechanisms. In vitro and in vivo experiments showed that Ang II increased intracellular reactive oxygen species (ROS) production and cardiomyocyte apoptosis; these were reversed by administration of the ROS scavenger N-acetylcysteine and by Mst1 deficiency, which suppressed c-Jun N-terminal kinase (JNK) phosphorylation and downstream signaling. Interestingly, Mst1 knockout failed to alleviate Ang II-induced phosphorylation of extracellular signal-regulated kinase 1/2, and inactivated apoptosis signal-regulating kinase1 (ASK1) by promoting its association with thioredoxin (Trx), which reversed the Ang II-induced activation of the ASK1-JNK pathway and suppressed Ang II-induced cardiomyocyte apoptosis. Thus, cardiac-specific Mst1 knockout inhibits ROS-mediated JNK signalling to block Ang II-induced cardiomyocyte apoptosis, suggesting Mst1 as a potential therapeutic target for treatment of RAAS-activated heart failure.

Mst1 knockout enhances cardiomyocyte autophagic flux to alleviate angiotensin II-induced cardiac injury independent of angiotensin II receptors.

AIMS: Angiotension II (Ang II) plays a central role in the pathogenesis of renin-angiotensin-aldosterone system (RAAS)-induced heart failure. Mst1 exerts its function in cardiomyocytes subjected to pathological stimuli via inhibiting autophagy and aggravating apoptosis, but its role in RAAS-mediated cardiac injury is still unknown. Here, we aimed to determine whether cardiomyocyte-specific Mst1 knockout can alleviate Ang II-induced cardiac injury by improving cardiomyocyte autophagy and whether these functions depend on Ang II receptors. RESULTS: Mst1 knockout alleviated Ang II-induced heart failure, without affecting blood pressure and compensatory concentric hypertrophy. Mst1 specific knockout improved the effects of Ang II on cardiomyocyte autophagy, as evidenced by further increased LC3-II expression and decreased P62 expression. More typical autophagosomes accompanied by less damaged mitochondria were also observed by electron microscopy in Ang II-treated Mst1Δ/Δ mice. In vitro, Mst1 knockdown promoted cardiomyocyte autophagic flux, as demonstrated by more GFP-mRFP-LC3 puncta per cell. Increased LC3-II and decreased P62 expression both in the presence and absence of chloroquine were observed in Mst1 knockdown cardiomyocytes administered with Ang II. Treatment with 3-MA, an inhibitor of autophagy, abolished the beneficial effects of Mst1 knockout against Ang II-induced cardiac dysfunction. The compensatory effects of Ang II on upregulated autophagy were associated with Mst1 inhibition. Interestingly, the knockdown or antagonization of AT1R inhibited cardiomyocyte autophagy, which may represent a threat to cardiac function. Importantly, Mst1 knockout consistently enhanced cardiomyocyte autophagy following the knockdown or blocking of AT1R and AT2R. CONCLUSION: Cardiomyocyte-specific Mst1 knockout alleviates Ang II-induced cardiac injury by enhancing cardiomyocyte autophagy. Mst1 inhibition may counteract the undesirable effects of Ang II receptors blockage on cardiomyocyte autophagy and represent a promising complementary treatment strategy against Ang II-induced cardiac injury.

Melatonin activates Parkin translocation and rescues the impaired mitophagy activity of diabetic cardiomyopathy through Mst1 inhibition.

Mitophagy eliminates dysfunctional mitochondria and thus plays a cardinal role in diabetic cardiomyopathy (DCM). We observed the favourable effects of melatonin on cardiomyocyte mitophagy in mice with DCM and elucidated their underlying mechanisms. Electron microscopy and flow cytometric analysis revealed that melatonin reduced the number of impaired mitochondria in the diabetic heart. Other than decreasing mitochondrial biogenesis, melatonin increased the clearance of dysfunctional mitochondria in mice with DCM. Melatonin increased LC3 II expression as well as the colocalization of mitochondria and lysosomes in HG-treated cardiomyocytes and the number of typical autophagosomes engulfing mitochondria in the DCM heart. These results indicated that melatonin promoted mitophagy. When probing the mechanism, increased Parkin translocation to the mitochondria may be responsible for the up-regulated mitophagy exerted by melatonin. Parkin knockout counteracted the beneficial effects of melatonin on the cardiac mitochondrial morphology and bioenergetic disorders, thus abolishing the substantial effects of melatonin on cardiac remodelling with DCM. Furthermore, melatonin inhibited Mammalian sterile 20-like kinase 1 (Mst1) phosphorylation, thus enhancing Parkin-mediated mitophagy, which contributed to mitochondrial quality control. In summary, this study confirms that melatonin rescues the impaired mitophagy activity of DCM. The underlying mechanism may be attributed to activation of Parkin translocation via inhibition of Mst1.