miR-126 regulates the proliferation, migration, invasion, and apoptosis of non-small lung cancer cells via AKT2/HK2 axis.

This study tended to clarify the role of miR-126 in non-small cell lung cancer (NSCLC) cell biological behaviors in vitro, containing cell proliferation, migration, invasion, and apoptosis. miRNA expression microarray related to NSCLC was accessed from gene expression omnibus (GEO) database and subjected to differential analysis using the "limma" package. Real-time quantitative PCR was conducted to assess the expression of miR-126 in NSCLC cell lines. wIn vitro experiments including 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT), wound healing assay, Transwell, and flow cytometry assay were used for evaluating the effect of miR-126 on cell proliferation, migration, invasion, and apoptosis. Additionally, target mRNA for miR-126 was predicted and further validated by bioinformatics analysis and dual-luciferase reporter assay, respectively. It suggested that miR-126 was significantly down-regulated in NSCLS based on the expression microarray, and similar expression trend was exhibited in cancer cell lines. In the meantime, overexpression of miR-126 was found to result in inhibition of cell proliferation, migration, and invasion while promotion of cell apoptosis, with reductions in protein expression of AKT2 and phosphorylated HK2 (p-HK2) as well. AKT2, identified to be a direct target of miR-126 in NSCLC as judged by dual-luciferase reporter assay. Additionally, overexpression of AKT2 was observed to have the ability of elevating p-HK2 protein expression and reversing the effect of miR-126 on NSCLC cell proliferation, migration, and invasion. Given the above findings, we can see that miR-126 exerts its role in NSCLC cell proliferation, migration, invasion, and apoptosis with the aid of AKT2/HK2 axis.

Endothelial Cells Regulate Physiological Cardiomyocyte Growth via VEGFR2-Mediated Paracrine Signaling.

BACKGROUND: Heart failure, which is a major global health problem, is often preceded by pathological cardiac hypertrophy. The expansion of the cardiac vasculature, to maintain adequate supply of oxygen and nutrients, is a key determinant of whether the heart grows in a physiological compensated manner or a pathological decompensated manner. Bidirectional endothelial cell (EC)-cardiomyocyte (CMC) cross talk via cardiokine and angiocrine signaling plays an essential role in the regulation of cardiac growth and homeostasis. Currently, the mechanisms involved in the EC-CMC interaction are not fully understood, and very little is known about the EC-derived signals involved. Understanding how an excess of angiogenesis induces cardiac hypertrophy and how ECs regulate CMC homeostasis could provide novel therapeutic targets for heart failure. METHODS: Genetic mouse models were used to delete vascular endothelial growth factor (VEGF) receptors, adeno-associated viral vectors to transduce the myocardium, and pharmacological inhibitors to block VEGF and ErbB signaling in vivo. Cell culture experiments were used for mechanistic studies, and quantitative polymerase chain reaction, microarrays, ELISA, and immunohistochemistry were used to analyze the cardiac phenotypes. RESULTS: Both EC deletion of VEGF receptor (VEGFR)-1 and adeno-associated viral vector-mediated delivery of the VEGFR1-specific ligands VEGF-B or placental growth factor into the myocardium increased the coronary vasculature and induced CMC hypertrophy in adult mice. The resulting cardiac hypertrophy was physiological, as indicated by preserved cardiac function and exercise capacity and lack of pathological gene activation. These changes were mediated by increased VEGF signaling via endothelial VEGFR2, because the effects of VEGF-B and placental growth factor on both angiogenesis and CMC growth were fully inhibited by treatment with antibodies blocking VEGFR2 or by endothelial deletion of VEGFR2. To identify activated pathways downstream of VEGFR2, whole-genome transcriptomics and secretome analyses were performed, and the Notch and ErbB pathways were shown to be involved in transducing signals for EC-CMC cross talk in response to angiogenesis. Pharmacological or genetic blocking of ErbB signaling also inhibited part of the VEGF-B-induced effects in the heart. CONCLUSIONS: This study reveals that cross talk between the EC VEGFR2 and CMC ErbB signaling pathways coordinates CMC hypertrophy with angiogenesis, contributing to physiological cardiac growth.

Three-port single-intercostal versus multiple-intercostal thoracoscopic lobectomy for the treatment of lung cancer: a propensity-matched analysis.

BACKGROUND: In this retrospective study, we aimed to demonstrated that three-port single-intercostal (SIC) thoracoscopic lobectomy is an effective choice for lung cancer by comparing the perioperative outcomes of patients with non-small-cell lung cancer treated with three-port SIC and conventional multiple-intercostal (MIC) thoracoscopic lobectomy. METHODS: From January 2013 to January 2018, 642 non-small-cell lung cancer patients underwent thoracoscopic lobectomy via a three-port SIC or MIC technique. Propensity-matched analysis incorporating preoperative clinical variables was used to compare the perioperative outcomes between the two groups. RESULTS: The first 20 patients were excluded to account for the learning curve effect in the SIC group. Propensity matching yielded 186 patients in each group. A small percentage of patients had major morbidity, including 4.8% in the SIC group and 6.5% in the MIC group; there was no significant difference between the two groups. Although the total number of lymph nodes harvested (25.3 vs. 23.8, p = 0.160) and stations removed (6.5 vs. 6.7, p = 0.368) were similar between the two groups, more subcarinal lymph nodes were removed (6.9 vs. 5.2, p < 0.001) in the SIC group than in the MIC group. Furthermore, other perioperative outcomes in the SIC group were not fewer than those in the MIC group. CONCLUSIONS: Both techniques are acceptable for the treatment of non-small-cell lung cancer. Three-port SIC VATS lobectomy can provide an alternative procedure in thoracoscopic surgery.

Distribution and sources of phthalate esters in the topsoils of Beijing, China.

Phthalate esters in the topsoil samples collected from Beijing were determined by derivatization and gas chromatography-mass spectrometry techniques. The results showed that diethyl phthalate (DEP), diisobutyl phthalate ester (DIBP), dibutyl phthalate ester (DBP), dibutyl (2-ethyl hexyl) phthalate (DEHP), and dimethyl phthalate (DMP) were found in the topsoils. The total concentrations of the five phthalate esters varied from 2.30 to 24.71 µg g(-1). According to phthalate esters (PAEs) control standards in soil of the USA, the standard exceeding rates of DMP, DBP, and DEHP were 100 %, 100 %, and 4.84 % in soils of Beijing, respectively. The rate of DBP exceeding soil remediation standard was 12.9 %. Overall, concentrations of PAEs in Beijing were at a high level in China. The concentrations of DBP, DEHP, and DIBP were high, and the total concentrations of all the phthalate esters were higher in the areas with intensive human activities than in the other areas, which may be related to the use of phthalate compounds (such as the use of plastic products). The total and individual concentrations of phthalate compounds were relatively low in the areas that used plastic films compared with other samples due to the diffusion of atmospheric motion, categories, and amounts of plastic products and other factors. The greatest contributor may be the usage amount of plastic products in people's daily lives.

MiR-129-2-3p Inhibits Esophageal Carcinoma Cell Proliferation, Migration, and Invasion via Targeting DNMT3B.

PURPOSE: The study aims to explore the regulatory mechanism of miR-129-2-3p underlying esophageal carcinoma (EC) cell progression and generate new ideas for targeted treatment of EC. METHODS: Mature miRNA expression data and total RNA sequencing data of EC in the TCGAESCA dataset were utilized to explore differentially expressed miRNAs (DEmiRNAs). StarBase database was then utilized to predict targets of miRNA. MiR-129-2-3p and DNMT3B expression in EC cell lines was assayed through qRT-PCR and Western blot. CCK-8, scratch healing, and transwell assays were conducted to assess the impact of miR-129-2-3p on EC cell phenotypes. In addition, a dual-luciferase assay was completed to identify the binding relationship between DNMT3B and miR-129-2-3p. RESULTS: MiR-129-2-3p was noticeably less expressed in EC cell lines, while DNMT3B was highly expressed. MiR-129-2-3p could bind to DNMT3B. Furthermore, in vitro functional experiments uncovered that overexpressed miR-129-2-3p repressed EC cell progression while further overexpressing DNMT3B would restore the above inhibitory effect. CONCLUSION: MiR-129-2-3p is a cancer repressor in EC cells, and it could target DNMT3B, thus hampering the progression of EC cells.

ErbB4 localization to cardiac myocyte nuclei, and its role in myocyte DNA damage response.

The intracellular domain of ErbB4 receptor tyrosine kinase is known to translocate to the nucleus of cells where it can regulate p53 transcriptional activity. The purpose of this study was to examine whether ErbB4 can localize to the nucleus of adult rat ventricular myocytes (ARVM), and regulate p53 in these cells. We demonstrate that ErbB4 does locate to the nucleus of cardiac myocytes as a full-length protein, although nuclear location occurs as a full-length protein that does not require Protein Kinase C or γ-secretase activity. Consistent with this we found that only the non-cleavable JM-b isoform of ErbB4 is expressed in ARVM. Doxorubicin was used to examine ErbB4 role in regulation of a DNA damage response in ARVM. Doxorubicin induced p53 and p21 was suppressed by treatment with AG1478, an EGFR and ErbB4 kinase inhibitor, or suppression of ErbB4 expression with small interfering RNA. Thus ErbB4 localizes to the nucleus as a full-length protein, and plays a role in the DNA damage response induced by doxorubicin in cardiac myocytes.

Emerging anticancer therapeutic targets and the cardiovascular system: is there cause for concern?

The race for a cure to cancer continues, fueled by unprecedented discoveries of fundamental biology underlying carcinogenesis and tumorigenesis. The expansion of the target list and tools to approach them is moving the oncology community extraordinarily rapidly to clinical trials, bringing new hope for cancer patients. This effort is also propelling biological discoveries in cardiovascular research, because many of the targets being explored in cancer play fundamental roles in the heart and vasculature. The combined efforts of cardiovascular and cancer biologists, along with clinical investigators in these fields, will be needed to understand how to safely exploit these efforts. Here, we discuss a few of the many research foci in oncology where we believe such collaboration will be particularly important.

Factors influencing the development of bone starvation syndrome after total parathyroidectomy in patients with renal hyperparathyroidism.

Purpose: To investigate the factors affecting the development of bone starvation syndrome (HBS) after total parathyroidectomy in patients with renal hyperparathyroidism (SHPT). Patients and methods: The clinical data and perioperative indices of 141 patients who underwent PTX for SHPT were retrospectively analyzed. The patients were divided into HBS and non-HBS groups based on postoperative minimum blood calcium <1.87 mmol/L. The differences in general clinical data and perioperative related indices between the two groups were compared; logistic regression analysis was performed to analyze the risk factors influencing HBS occurrence after surgery. Multiple linear regression method was used to analyze the factors influencing the maintenance time of intravenous calcium supplementation and total amount of calcium supplementation during intravenous calcium supplementation. The threshold value for the diagnosis of HBS was analyzed using the ROC subjects' working curve. Results: HBS occurred in 46 (32.6%) patients. Univariate analysis showed statistically significant differences in dialysis age, preoperative calcitonin, preoperative parathyroid hormone, preoperative blood phosphorus, and preoperative alkaline phosphatase between both groups (P < 0.05). Logistic regression analysis using stepwise entry method concluded that preoperative alkaline phosphatase was an independent factor for the development of HBS after surgery. Preoperative parathyroid hormone was an independent factor for the duration of intravenous calcium supplementation and total calcium supplementation during intravenous calcium supplementation in the HBS group. Based on the ROC curve, for postoperative HBS, the cut-off ALP value was 199.5 U/L, with a sensitivity of 80.85% and specificity of 82.61%. Conclusion: Preoperative serum ALP may be an independent factor for HBS occurrence after surgery. When preoperative ALP > 199.5 U/L, patients with SHPT are prone to HBS after surgery, and the higher the preoperative ALP, the higher the incidence of HBS, and vice versa. In addition, preoperative PTH may be the factor in the timing of postoperative intravenous calcium supplementation and the total amount of calcium supplementation during intravenous calcium supplementation in patients with HBS.

Identification of a dysregulated ceRNA network modulated by copy number variation-driven lncRNAs in lung squamous cell carcinoma.

Lung cancer is primarily responsive for cancer death, and its progression is aggressively affected by copy number variation (CNV). Through bioinformatics approach, a ceRNA network of CNV-driven lncRNAs in lung squamous cell carcinoma (LUSC) patients was constructed. Data on normal and LUSC tumor tissue from The Cancer Genome Atlas (TCGA)-LUSC dataset were subjected to differential analysis, and differentially expressed lncRNAs (DElncRNAs), DEmiRNAs, and DEmRNAs were obtained. Based on TCGA-LUSC, CNVs of normal and tumor tissue samples were then compared using a Chi-square test, and lncRNAs were intersected based on their CNVs and expression alternation. In combination with the Kruskal-Wallis test, CNV-driven lncRNAs were acquired. Afterwards, miRNAs and mRNAs that interacted with CNV-driven lncRNAs were obtained based on databases (LncBase, starBase, miRDB, mirDIP and TargetScan), DElncRNAs, DEmiRNAs and DEmRNAs, and correlation analysis. The acquired lncRNAs, miRNAs and mRNAs were subjected to Cytoscape software to construct a CNV-driven ceRNA network, which involved 5 lncRNAs (MIR143HG, LINC00702, MIR22HG, RP11-180 N14.1, RP11-473 M20.9), 6 miRNAs (miR-3200-3p, miR-1301-3p, miR-93-3p, miR-96-5p, miR-96-5p, miR-130b-5p, miR-205-5p) and 80 mRNAs. Kyoto Encyclopedia of Genes and Genomes and Gene Ontology enrichment analyses indicated that downstream mRNAs were mainly correlated with blood vessel development and T cell-mediated immunity. In summary, we devoted to analyzing CNV-related lncRNAs, mRNAs, and miRNAs in LUSC, thus clarifying 5 lncRNAs that may influence the malignant progression of LUSC. The ceRNA network regulated by these lncRNAs may be the novel pathogenesis of LUSC.

EZH2 affects malignant progression and DNA damage repair of lung adenocarcinoma cells by regulating RAI2 expression.

BACKGROUND: Lung adenocarcinoma (LUAD) is featured in high morbidity and mortality. Aberrant activation of the histone methyltransferase EZH2 has close association with cancer progression. This research aimed to deeply dive into the role and possible molecular mechanisms of EZH2 and its downstream genes in malignant progression and DNA damage repair of LUAD cells. METHODS: Expression of EZH2 in LUAD cells was analyzed by qRT-PCR, and the effects of EZH2 on proliferation, and apoptosis of LUAD cells were examined by CCK-8, colony formation and flow cytometry assays. The downstream targets of EZH2 were predicted by bioinformatics analysis. Then, the targeting relationship between EZH2 and RAI2 was examined by CHIP and luciferase reporter assays. Rescue assay were used to further validate the effect of EZH2/RAI2 on the malignant progression of LUAD cells. The expression levels of EZH2, RAI2 and p53 were examined by Western blot. RESULTS: Upregulation of EZH2 was identified in LUAD tissues and cells. RAI2 was a downstream target gene of EZH2, and the two were negatively correlated. Silencing EZH2 suppressed proliferation of LUAD cells, promoted expression of p53, cell cycle arrest and apoptosis. While silencing RAI2 could reverse the above-mentioned effects caused by EZH2 silencing. CONCLUSION: These results demonstrated that EZH2 promoted malignant progression and DNA damage repair of LUAD cells by targeting and negatively regulating RAI2.

Neuregulin-1ß regulation of embryonic endothelial progenitor cell survival.

Endothelial progenitor cells (EPCs) are mobilized into the vascular space and home to damaged tissues, where they promote repair in part through a process of angiogenesis. Neuregulins (NRGs) are ligands in the epidermal growth factor family that signal through type I receptor tyrosine kinases in the erbB family (erbB2, erbB3, and erbB4) and regulate endothelial cell biology, promoting angiogenesis. Stimuli such as ischemia and exercise that promote EPC mobilization also induce cleavage and release of transmembrane NRG from cardiac microvascular endothelial cells (CMECs). We hypothesized that NRG/erbB signaling may regulate EPC biology. Using an embryonic (e)EPC cell line that homes to and repairs injured myocardium, we were able to detect erbB2 and erbB3 transcripts. Identical receptor expression was found in EPCs isolated from rat bone marrow and human whole blood. NRG treatment of eEPCs induces phosphorylation of kinases including Akt, GSK-3ß, and Erk1/2 and the nuclear accumulation and transcriptional activation of ß-catenin. NRG does not induce eEPC proliferation or migration but does protect eEPCs against serum deprivation-induced apoptosis. These results suggest a role for tissue-derived NRG in the regulation of EPC survival.

Circulating insulin-like growth factor-1 and its binding protein-3: metabolic and genetic correlates in the community.

OBJECTIVE: The metabolic and genetic correlates of circulating insulin-like growth factor-1 (IGF-1) and its main circulating carrier, IGF-1-binding-protein-3 (IGFBP-3), are unclear. METHODS AND RESULTS: We measured serum IGF-1 and IGFBP-3 concentrations in a sample of the Framingham Heart Study (N=3977, aged 40+/-9 years, 46% male) and evaluated their relations to cardiovascular risk factors using multivariable regression. Serum IGF-1 was inversely correlated with age, body mass index, total cholesterol, the presence of diabetes, alcohol consumption, and glomerular filtration rate (all P<0.01), whereas the ratio of IGF-1:IGFBP-3 was lower in women and inversely related to age, triglycerides, high-density lipoprotein cholesterol, systolic blood pressure, and alcohol consumption (all P<0.0001). Circulating IGF-1 correlated negatively with insulin resistance (homeostatic model assessment) (r=-0.1; P<0.0001) and was lower in participants with more components of the metabolic syndrome (Adult Treatment Panel III criteria) (P<0.0001). Additive genetic factors (heritability) accounted for 43% and 39% of the variation of IGF-1 and IGFBP-3, respectively (both P<10(-27)). CONCLUSIONS: Our cross-sectional observations in a large community-based sample link lower circulating IGF-1 to greater metabolic risk burden and underscore substantial genetic influences on IGF-1 concentrations. Prospective studies are warranted to elucidate whether lower IGF-1 concentrations predict greater metabolic risk longitudinally.

Evaluation of the diagnostic performance of contrast-enhanced ultrasound combined with BRAF V600E gene detection in nodules of unclear significance by thyroid fine-needle aspiration.

BACKGROUND: Our study aims to test the diagnostic performance of contrast-enhanced ultrasound (CEUS) combined with the detection of serine/threonine-protein kinase V600E (BRAF V600E) in nodules of unclear significance by thyroid fine-needle aspiration (FNA). METHODS: From January 2015 to December 2019, 244 patients were subjected to ultrasonic strain imaging and elastography, CEUS, and BRAF V600E gene detection at Lishui Hospital of Zhejiang University. Thyroid FNA does not confirm the benignancy and malignancy of the thyroid nodules. With postoperative pathology as the gold standard, the diagnostic value of CEUS, BRAF V600E detection, and the combination in differentiating benign and malignant thyroid nodules were evaluated. The negative predictive value (NPV) and accuracy of CEUS, BRAF V600E detection, and the combination were calculated along with sensitivity, specificity, and positive predictive value (PPV). RESULTS: In this study, the sensitivity, specificity, PPV, NPV, accuracy, and AUC of CEUS alone in predicting benign and malignant thyroid nodules were 69.8%, 94.9%, 98.6%, 37.4%, 73.8% and 0.884, respectively. The sensitivity, specificity, PPV, NPV, accuracy and AUC of BRAF V600E detection alone were 65.4%, 100%, 100%, 35.5%, 70.9% and 0.827, respectively. The sensitivity, specificity, PPV, NPV, accuracy and AUC of the combination were 73.2%, 94.9%, 98.7%, 40.2%, 76.6% and 0.923, respectively. CONCLUSIONS: Therefore, compared with CEUS or BRAF V600E gene detection alone, the combination of CEUS and BRAF V600E gene detection has a higher sensitivity, NPV, and accuracy in the diagnosis of thyroid nodules.

MiR-196b Promotes the Invasion and Migration of Lung Adenocarcinoma Cells by Targeting AQP4.

OBJECTIVE: We aimed to investigate the mechanism of the regulatory axis of miR-196b/AQP4 underlying the invasion and migration of lung adenocarcinoma (LUAD) cells. METHODS: LUAD miRNA and mRNA expression profiles were downloaded from TCGA database and then differential analysis was used to identify the target miRNA. Target gene for the miRNA was obtained via prediction using 3 bioinformatics databases and intersection with the differentially expressed mRNAs searched from TCGA-LUAD. Then, qRT-PCR and western blot were used to validate the expression of miR-196b and AQP4. Dual-luciferase reporter assay was performed to confirm the targeting relationship between miR-196b and AQP4. Transwell assay was used to investigate the migration and invasion of LUAD cells. RESULTS: MiR-196b was screened out by differential and survival analyses, and the downstream target gene AQP4 was identified. In LUAD, miR-196b was highly expressed while AQP4 was poorly expressed. Besides, overexpression of miR-196b promoted cell invasion and migration, while overexpression of AQP4 had negative effects. Moreover, the results of the dual-luciferase reporter assay suggested that AQP4 was a direct target of miR-196b. In addition, we also found that overexpressing AQP4 could suppress the promotive effect of miR-196b on cancer cell invasion and migration. CONCLUSION: MiR-196b promotes the invasion and migration of LUAD cells by down-regulating AQP4, which helps us find new molecular targeted therapies for LUAD.

Laparoscopic needle catheter jejunostomy by using a double semipurse string suture method in minimally invasive Ivor Lewis esophagectomy.

BACKGROUND: To investigate the safety and effectiveness of a double semipurse string suture method for jejunum fixation in laparoscopic needle catheter jejunostomy in minimally invasive Ivor Lewis esophagectomy (MIILE). METHODS: Two hundred and six esophageal cancer patients continuously receiving MIILE from March 2014 to February 2018 were enrolled. In all patients, the double semipurse string suture method was applied for jejunum fixation in laparoscopic needle catheter jejunostomy. The methods and details of this technique are introduced herein. General information, clinical data, postoperative complications and follow-up results were retrospectively analyzed, and the complication causes and treatment methods are discussed. RESULTS: Laparoscopic needle catheter jejunostomy-using the double semipurse string suture method was successfully performed in 206 patients. The operative time of laparoscopic needle catheter jejunostomy was 10.56±2.04 min. No conversion to laparotomy or postoperative death or serious infection associated with the jejunostomy tube occurred. The incidence of complications associated with the jejunostomy tube was 16.50% (34/206), and most of the complications were mild. Severe complications occurred in 2 cases (0.97%), which were cured after reoperation, without serious consequence. CONCLUSIONS: The double semipurse string suture method is safe, simple and feasible for the jejunum fixation in laparoscopic needle catheter jejunostomy in MIILE. It is worth popularization and clinical application.

Correlation between thyroid autoantibodies and the risk of thyroid papillary carcinoma.

BACKGROUND: To investigate the correlation of thyroglobulin antibody (TgAb) and thyroid peroxidase antibody (TPOAb) with the risk of papillary thyroid carcinoma (PTC). METHODS: The clinical data of 322 patients with pathologically confirmed thyroid nodules who underwent surgical treatment in Lishui Hospital of Zhejiang University from January 2018 to December 2019 were enrolled in this study. The enrolled patients were divided into a benign nodule group and a PTC group according their pathological results. Comparison was drawn based around the difference of thyroid autoantibody distribution between groups and its correlation with the risk of PTC. RESULTS: The positive rate of TgAb in the PTC group was significantly higher than that in the benign nodule group (P<0.05). The incidence of PTC was significantly higher in TgAb positive patients in the presence of negative TPOAb (P<0.05). Further regression analysis revealed positive TgAb to be a risk factor of PTC (OR =3.097, P<0.05), while age ≥55 years old (OR =0.188, P<0.05) and nodule diameter ≥10 mm (OR =0.064, P<0.05) reduced the risk of PTC. Simultaneously, positive TgAb was also a risk factor for PTC in females (OR =3.532, P<0.05), but not in males (P>0.05). The risk of PTC in females was not associated with further increase in the titer of TgAb. CONCLUSIONS: TgAb may be associated with an increased risk of PTC in females, but there is no clear correlation between the risk of PTC and higher antibody titer in these patients.

Erratum to laparoscopic needle catheter jejunostomy by using a double semipurse string suture method in minimally invasive Ivor Lewis esophagectomy.

[This corrects the article DOI: 10.21037/jtd.2020.01.53.].

Palmitate alters neuregulin signaling and biology in cardiac myocytes.

The saturated fatty acid palmitate alters normal cell function via disruption of cell signaling, and this effect has been implicated in the end-organ damage associated with dyslipidemia. Neuregulin-1beta (NRG-1beta) is a growth and survival factor in cardiac myocytes. We tested the hypothesis that palmitate alters NRG-1beta signaling and biology in isolated neonatal rat cardiac myocytes. Palmitate treatment inhibited NRG-1beta activation of the PI3-kinase/Akt pathway in myocytes. We found that the pro-apoptotic activity of palmitate was increased by NRG-1beta treatment. The effects of palmitate on NRG-1beta signaling and survival were reversed by the mono-unsaturated fatty acid oleate. Under control conditions NRG-1beta decreases p53 expression in myocytes. In the presence of palmitate, NRG-1beta caused an increase in p53 expression, bax multimer formation, concurrent with degradation of mdm2, a negative regulator of p53. Thus in the presence of palmitate NRG-1beta activates pro-apoptotic, rather than pro-survival signaling in cardiac myocytes.

Thoracoscopic surgery for management of pleuroperitoneal communication complicating continuous ambulatory peritoneal dialysis: A case report.

RATIONALE: Pleuroperitoneal communication (PPC) has been reported to complicate continuous ambulatory peritoneal dialysis (CAPD). However, cases of patients in whom the results of the methylene blue dye test and peritoneopleural scintigraphy were negative and treatment was thoracoscopic surgery have been rarely reported. PATIENT CONCERNS: A 58-year-old man with end-stage chronic renal failure who underwent CAPD presented with massive right-sided hydrothorax. The pleural fluid glucose level was high. Results of both the methylene blue dye test and peritoneopleural scintigraphy were negative. DIAGNOSIS: The presence of end-stage chronic renal failure and diaphragm defects amenable to repair, which were identified during thoracoscopic surgery, indicated a definite diagnosis of PPC complicating CAPD. INTERVENTIONS AND OUTCOMES: CAPD was performed twice after the defects were repaired during thoracoscopic surgery. There was no evidence that the repaired sites were leaking again, and the patient did not complain of any discomfort during the second CAPD. LESSON: Although special methods such as the methylene blue dye test and peritoneopleural scintigraphy may not be useful in some cases, thoracoscopic surgery is still effective and reliable in diagnosing and repairing diaphragmatic defects.

Molecular and cellular mechanisms of anthracycline cardiotoxicity.

The molecular and cellular mechanisms that cause cumulative dose-dependent anthracycline-cardiotoxicity remain controversial and incompletely understood. Studies examining the effects of anthracyclines in cardiac myocytes inA vitro have demonstrated several forms of cellular injury. Cell death in response to anthracyclines can be observed by one of several mechanisms including apoptosis and necrosis. Cell death by apoptosis can be inhibited by dexrazoxane, the iron chelator that is known to prevent clinical development of heart failure at high cumulative anthracycline exposure. Together with clinical evidence for myocyte death after anthracycline exposure, in the form of elevations in serum troponin, make myocyte cell death a probable mechanism for anthracycline-induced cardiac injury. Other mechanisms of myocyte injury include the development of cellular \'sarcopenia\' characterized by disruption of normal sarcomere structure. Anthracyclines suppress expression of several cardiac transcription factors, and this may play a role in the development of myocyte death as well as sarcopenia. Degradation of the giant myofilament protein titin may represent an important proximal step that leads to accelerated myofilament degradation. Titin is an entropic spring element in the sarcomere that regulates length-dependent calcium sensitivity. Thus titin degradation may lead to impaired diastolic as well as systolic dysfunction, as well as potentiate the effect of suppression of transcription of sarcomere proteins. An interesting interaction has been noted clinically between anthracyclines and newer cancer therapies that target the erbB2 receptor tyrosine kinase. Studies of erbB2 function in viro suggest that signaling through erbB2 by the growth factor neuregulin may regulate cardiac myocyte sarcomere turnover, as well as myocyte-myocyte/myocyte-matrix force coupling. A combination of further in vitro studies, with more careful monitoring of cardiac function after exposure to these cancer therapies, may help to understand to what extent these mechanisms are at work during clinical exposure of the heart to these important pharmaceuticals.