The recommendation of re-classification of variants of uncertain significance (VUS) in adult genetic disorders patients.

Since variants of uncertain significance (VUS) reported in genetic testing cannot be acted upon clinically, this classification may delay or prohibit precise diagnosis and genetic counseling in adult genetic disorders patients. Large-scale analyses about qualitatively distinct lines of evidence used for VUS can make them re-classification more accurately. We analyzed 458 Chinese adult patients WES data, within 15 pathogenic evidence PS1, PS2, PM1, PM6 and PP4 were not used for VUS pathogenic classification, meanwhile the PP3, BP4, PP2 were used much more frequently. The PM2_Supporting was used most widely for all reported variants. There were also 31 null variants (nonsense, frameshift, canonical ±1 or 2 splice sites) which were probably the disease-causing variants of the patients were classified as VUS. By analyzed the evidence used for all VUS we recommend that appropriate genetic counseling, reliable releasing of in-house data, allele frequency comparison between case and control, expanded verification in patient family, co-segregation analysis and functional assays were urgent need to gather more evidence to reclassify VUS. We also found adult patients with nervous system disease were reported the most phenotype-associated VUS and the lower the phenotypic specificity, the more reported VUS. This result emphasized the importance of pretest genetic counseling which would make less reporting of VUS. Our result revealed the characteristics of the pathogenic classification evidence used for VUS in adult genetic disorders patients for the first time, recommend a rules-based process to evaluate the pathogenicity of VUS which could provide a strong basis for accurately evaluating the pathogenicity and clinical grade information of VUS. Meanwhile, we further expanded the genetic spectrum and improve the diagnostic rate of adult genetic disorders.

Comparison of AirSeal versus conventional insufflation system for retroperitoneal robot-assisted laparoscopic partial nephrectomy: a randomized controlled trial.

PURPOSE: AirSeal is a valve-less trocar insufflation system which is widely used in robotic urologic surgeries. More evidence is needed concerning the application and cost of AirSeal in retroperitoneal robot-assisted laparoscopic partial nephrectomy. METHODS: We conducted a randomized controlled trial enrolling 62 patients who underwent retroperitoneal robot-assisted laparoscopic partial nephrectomy from February 2022 to February 2023 in the Peking Union Medical College Hospital. Patients were randomly assigned into AirSeal insufflation (AIS) group and conventional insufflation (CIS) group. The primary outcome was the rate of subcutaneous emphysema (SCE). RESULTS: The SCE rate in the AIS group (12.9%) was significantly lower than that in the CIS group (35.5%) (P = 0.038). Lower maximum end-tidal carbon dioxide (CO2) (41 vs 45 mmHg, P = 0.011), PaCO2 at the end of the operation (40 vs 45 mmHg, P < 0.001), maximum tidal volume (512 vs 570 ml, P = 0.003), frequency of lens cleaning (3 vs 5, P < 0.001), pain score at 8 h (3 vs 4, P = 0.025), 12 h (2 vs 3, P = 0.029) postoperatively and at time of discharge (1 vs 2, P = 0.002) were observed in the AIS group, despite a higher hospitalization cost (68,197 vs 64658RMB, P < 0.001). Logistic regression analysis identified insufflation approach was the only influencing factor for the occurrence of SCE events. CONCLUSION: AirSeal insufflation system exhibited similar efficacy and improved safety for retroperitoneal robot-assisted laparoscopic partial nephrectomy than conventional insufflation system, despite an affordable increase of hospitalization costs.

Unexpected discovery of renal mass in a patient with granulomatosis with polyangiitis: accidental or inevitable?

Granulomatosis with polyangiitis (GPA) is an uncommon disorder that mainly involves the upper and lower respiratory tract and kidney, presenting as sinusitis, saddle nose, otitis media, pulmonary nodule and cavity, rapidly progressive glomerulonephritis. It also affects skin, eye, heart, joint and nervous system. Renal involvement in GPA is commonly manifested as necrotising glomerulonephritis, while renal mass is very rare. We herein present two hospitalised cases with fever, pulmonary cavity and renal mass. Clinical course and examinations of the cases, from symptoms to diagnosis, will be discussed in detail, along with a relevant literature review of this unusual renal manifestation.

A Chinese Multi-Specialty Delphi Consensus to Optimize RAASi Usage and Hyperkalaemia Management in Patients with Chronic Kidney Disease and Heart Failure.

Objective: Variations are present in common clinical practices regarding best practice in managing hyperkalaemia (HK), there is therefore a need to establish a multi-specialty approach to optimal renin-angiotensin-aldosterone system inhibitors (RAASi) usage and HK management in patients with chronic kidney disease (CKD) & heart failure (HF).This study aimed to establish a multi-speciality approach to the optimal use of RAASi and how to manage HK in patients with CKD and HF.Methods: A steering expert group of cardiology and nephrology experts from across China convened to discuss challenges to HK management through a nominal group technique (NGT). The group then created a list of 41 statements for a consensus questionnaire, which was distributed for a further survey of in extended panel group of cardiologists and nephrologists across China. Consensus was assessed using a modified Delphi technique, with agreement defined as "strong" (≥75% and <90%) and "very strong" (≥90%). The steering group, data collection, and analysis were aided by an independent facilitator. Results: A total of 150 responses from 21 provinces across China were recruited in the survey. Respondents were comprised of an even split (n=75, 50%) between cardiologists and nephrologists. All 41 statements achieved the 75% consensus agreement threshold, of which 27 statements attained very strong consensus (≥90% agreement) and 14 attained strong consensus (agreement between 75% and 90%). Conclusions: Based on the agreement levels from respondents, the steering group agreed a set of recommendations intended to improve patient outcomes in the use of RAASi therapy and HK management in China.

Whole exome sequencing reveal 83 novel Mendelian disorders carrier P/LP variants in Chinese adult patients.

Carrier screening can identify people at risk of conceiving pregnancies affected with inherited genetic disorders or who have a genetic disorder with late or variable onset. Carrier screening based on whole exome sequencing (WES) data can offer more comprehensive assessment than on-target carrier screening tests. A total of 224 Chinese adult patients WES data was analyzed, except positive variants associated with the patients' major complaint, 378 pathogenic (P) and "likely pathogenic" (LP) variants from 175 adult patients were identified. Whole exome-wide frequency of carriers for Mendelian disorders in Chinese adult patients was about 78.13% in this study, which was lower than the previously reported carrier frequency in healthy population. Contrary to expectations, the number of P or LP variants did not increase with larger chromosome size or decrease with smaller chromosome size. Totally 83 novel P or LP variants were identified which could further expand the carrier variants spectrum of the Chinese population. GJB2: NM_004004.6:c.299_300delAT:p.His100fs*14 and C6:NM_000065.4:c.654T>A:p.Cys218* were found in two or more patients, which might be two underestimated carrier variants in Chinese population. We also found 9 late-onset or atypical symptoms autosomal/X-linked dominant Mendelian disorders causative genes, which were easily overlooked during pathogenicity analysis. These results can provide a strong basis for preventing and avoiding the prevalence rates of birth defects and reducing social and family burdens. By comparing with three different expanded carrier screening gene panels, we further confirmed carrier screening based on WES could offer more comprehensive assessment and WES was applicable for carrier screening.

Ablation for atrial fibrillation improves the outcomes in patients with heart failure with preserved ejection fraction.

AIMS: Patients with heart failure with preserved ejection fraction (HFpEF) and atrial fibrillation (AF) have worse clinical outcomes than those with sinus rhythm (SR). We aim to investigate whether maintaining SR in patients with HFpEF through a strategy such as AF ablation would improve outcomes. METHODS AND RESULTS: This is a cohort study that analysed 1034 patients (median age 69 [63-76] years, 46.2% [478/1034] female) with HFpEF and AF. Of these, 392 patients who underwent first-time AF ablation were assigned to the ablation group, and the remaining 642 patients, who received only medical therapy, were assigned to the no ablation group. The primary endpoint was a composite of all-cause death or rehospitalization for worsening heart failure. After a median follow-up of 39 months, the cumulative incidence of the primary endpoint was significantly lower in the ablation group compared to the no ablation group (adjusted hazard ratio [HR], 0.55 [95% CI, 0.37-0.82], P = 0.003) in the propensity score-matched model. Secondary endpoint analysis showed that the benefit of AF ablation was mainly driven by a reduction in rehospitalization for worsening heart failure (adjusted HR, 0.52 [95% CI, 0.34-0.80], P = 0.003). Patients in the ablation group showed a 33% relative decrease in atrial tachycardia/AF recurrence compared to the no ablation group (adjusted HR, 0.67 [95% CI, 0.54-0.84], P < 0.001). CONCLUSION: Among patients with HFpEF and AF, the strategy of AF ablation to maintain SR was associated with a lower risk of the composite outcome of all-cause death or rehospitalization for worsening heart failure.

Targeting MAGI2-AS3-modulated Akt-dependent ATP-binding cassette transporters as a possible strategy to reverse temozolomide resistance in temozolomide-resistant glioblastoma cells.

Drug resistance is a major impediment to the successful treatment of glioma. This study aimed to elucidate the effects and mechanisms of the long noncoding RNA membrane-associated guanylate kinase inverted-2 antisense RNA 3 (MAGI2-AS3) on temozolomide (TMZ) resistance in glioma cells. MAGI2-AS3 expression in TMZ-resistant glioblastoma (GBM) cells was analyzed using the Gene Expression Omnibus data set GSE113510 and quantitative real-time PCR (qRT-PCR). Cell viability and TMZ half-maximal inhibitory concentration values were determined using the MTT assay. Apoptosis and cell cycle distribution were evaluated using flow cytometry. The expression of multidrug resistance 1 (MDR1), ATP-binding cassette superfamily G member 2 (ABCG2), protein kinase B (Akt), and phosphorylated Akt was detected using qRT-PCR and/or western blot analysis. MAGI2-AS3 was expressed at low levels in TMZ-resistant GBM cells relative to that in their parental cells. MAGI2-AS3 re-expression alleviated TMZ resistance in TMZ-resistant GBM cells. MAGI2-AS3 overexpression also accelerated TMZ-induced apoptosis and G2/M phase arrest. Mechanistically, MAGI2-AS3 overexpression reduced MDR1 and ABCG2 expression and inhibited the Akt pathway, whereas Akt overexpression abrogated the reduction in MDR1 and ABCG2 expression induced by MAGI2-AS3. Moreover, activation of the Akt pathway inhibited the effects of MAGI2-AS3 on TMZ resistance. MAGI2-AS3 inhibited tumor growth and enhanced the suppressive effect of TMZ on glioma tumorigenesis in vivo. In conclusion, MAGI2-AS3 reverses TMZ resistance in glioma cells by inactivating the Akt pathway.

Angiotensin-Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction.

BACKGROUND: The angiotensin receptor-neprilysin inhibitor sacubitril-valsartan led to a reduced risk of hospitalization for heart failure or death from cardiovascular causes among patients with heart failure and reduced ejection fraction. The effect of angiotensin receptor-neprilysin inhibition in patients with heart failure with preserved ejection fraction is unclear. METHODS: We randomly assigned 4822 patients with New York Heart Association (NYHA) class II to IV heart failure, ejection fraction of 45% or higher, elevated level of natriuretic peptides, and structural heart disease to receive sacubitril-valsartan (target dose, 97 mg of sacubitril with 103 mg of valsartan twice daily) or valsartan (target dose, 160 mg twice daily). The primary outcome was a composite of total hospitalizations for heart failure and death from cardiovascular causes. Primary outcome components, secondary outcomes (including NYHA class change, worsening renal function, and change in Kansas City Cardiomyopathy Questionnaire [KCCQ] clinical summary score [scale, 0 to 100, with higher scores indicating fewer symptoms and physical limitations]), and safety were also assessed. RESULTS: There were 894 primary events in 526 patients in the sacubitril-valsartan group and 1009 primary events in 557 patients in the valsartan group (rate ratio, 0.87; 95% confidence interval [CI], 0.75 to 1.01; P = 0.06). The incidence of death from cardiovascular causes was 8.5% in the sacubitril-valsartan group and 8.9% in the valsartan group (hazard ratio, 0.95; 95% CI, 0.79 to 1.16); there were 690 and 797 total hospitalizations for heart failure, respectively (rate ratio, 0.85; 95% CI, 0.72 to 1.00). NYHA class improved in 15.0% of the patients in the sacubitril-valsartan group and in 12.6% of those in the valsartan group (odds ratio, 1.45; 95% CI, 1.13 to 1.86); renal function worsened in 1.4% and 2.7%, respectively (hazard ratio, 0.50; 95% CI, 0.33 to 0.77). The mean change in the KCCQ clinical summary score at 8 months was 1.0 point (95% CI, 0.0 to 2.1) higher in the sacubitril-valsartan group. Patients in the sacubitril-valsartan group had a higher incidence of hypotension and angioedema and a lower incidence of hyperkalemia. Among 12 prespecified subgroups, there was suggestion of heterogeneity with possible benefit with sacubitril-valsartan in patients with lower ejection fraction and in women. CONCLUSIONS: Sacubitril-valsartan did not result in a significantly lower rate of total hospitalizations for heart failure and death from cardiovascular causes among patients with heart failure and an ejection fraction of 45% or higher. (Funded by Novartis; PARAGON-HF ClinicalTrials.gov number, NCT01920711.).

GeO2-doped ring-core photonic crystal fiber for supporting robust orbital angular momentum modes.

Orbital angular momentum (OAM)-mode-supported photonic crystal fibers (PCFs) have inspired intensive research in modern fiber optics due to the robust propagation and theoretically unlimited signal-carried channels. In this paper, a dual-cladding GeO2-doped ring-core PCF is designed, and a strategy for optimizing OAM mode properties is analyzed by structure parameters and GeO2-doping concentration. Numeric results show that high structural degrees of freedom are available to improve the effective refractive index separation (within the vector modes), chromatic dispersion, effective mode field area, nonlinear coefficient, and OAM mode purity in terms of inner cladding, outer cladding, and ring-core. In particular, the effective refractive index separation and chromatic dispersion can exhibit a high order magnitude of 10-3 and a low value in the broad band from 1.3 µm to 1.7 µm, respectively. In addition to structural optimization, doping high index material into the ring-core is another way to regulate the fiber performance by controlling the doping concentration. A systematic investigation shows that as the doping concentration increases, the effective refractive index separation and mode purity increase obviously, while the dispersion and mode field area gradually decrease. This flexible manipulation offers a method for customizing the optical properties of OAM-supported PCFs in communication and sensor systems.

Fully Condensed Poly (Triazine Imide) Crystals: Extended π-Conjugation and Structural Defects for Overall Water Splitting.

Conventional polymerization for the synthesis of carbon nitride usually generates amorphous heptazine-based melon with an abundance of undesired structural defects, which function as charge carrier recombination centers to decrease the photocatalytic efficiency. Herein, a fully condensed poly (triazine imide) crystal with extended π-conjugation and deficient structure defects was obtained by conducting the polycondensation in a mild molten salt of LiCl/NaCl. The melting point of the binary LiCl/NaCl system is around 550 °C, which substantially restrain the depolymerization of triazine units and extend the π-conjugation. The optimized polymeric carbon nitride crystal exhibits a high apparent quantum efficiency of 12 % (λ=365 nm) for hydrogen production by one-step excitation overall water splitting, owing to the efficient exciton dissociation and the subsequent fast transfer of charge carriers.

Increased ratio of sST2/LVMI predicted cardiovascular mortality and heart failure rehospitalization in heart failure with reduced ejection fraction patients: a prospective cohort study.

BACKGROUND: Inflammation is one of the principal triggering mechanisms for left ventricular fibrosis and remodeling in heart failure, leading to adverse clinical outcomes. Soluble suppression of tumorigenicity 2 (sST2), a member of the interleukin-1 receptor family, is assumed to play a significant role in the fibrotic response to inflammation. Left ventricular mass index (LVMI) is a parameter of the prefibrotic inflammatory phase of heart failure preceding remodeling. The present study aimed to investigate the prognostic value of the sST2/LVMI ratio in heart failure with reduced ejection fraction. METHODS: This was a prospective cohort study. A total of 45 consecutive patients with heart failure with reduced ejection fraction, treated between September 2015 and December 2016, were enrolled. The sST2/LVMI ratio was measured at baseline. The primary endpoint was a composite of cardiovascular mortality and readmission for heart failure. The prognostic impact of the sST2/LVMI ratio was evaluated using a multivariable Cox proportional hazards regression model. RESULTS: Forty-five patients were enrolled in this study. Their average age was 48 ± 14 years, and approximately 20% of them were men. Patients were followed for 9 months, during which the primary outcome occurred in 15 patients. Kaplan-Meier analysis showed that patients with a high sST2/LVMI ratio (≥ 0.39) had shorter event-free survival than those with intermediate (between 0.39 and 0.24) and low ratios (< 0.24) (log-rank, P = 0.022). The fully adjusted multivariable Cox regression analysis showed that the sST2/LVMI ratio was positively associated with the composite outcome in patients with heart failure with reduced ejection fraction after adjusting for confounders (hazard ratio 1.64, 95% confidence interval 1.06 to 2.54). By subgroup analysis, a stronger association was found with age between 40 and 55 years, systolic blood pressure < 115 or ≥ 129 mmHg, diastolic blood pressure < 74 mmHg, hematocrit < 44.5%, and interventricular septum thickness ≥ 8.5 mm. CONCLUSION: In patients with heart failure with reduced ejection fraction, the relationship between the sST2/LVMI ratio and the composite outcome was linear. A higher baseline ratio of sST2/LVMI was associated with an increased risk of cardiovascular mortality and heart failure rehospitalization in the short-term follow-up.

Qiliqiangxin attenuates hypoxia-induced injury in primary rat cardiac microvascular endothelial cells via promoting HIF-1α-dependent glycolysis.

Protection of cardiac microvascular endothelial cells (CMECs) against hypoxia injury is an important therapeutic strategy for treating ischaemic cardiovascular disease. In this study, we investigated the effects of qiliqiangxin (QL) on primary rat CMECs exposed to hypoxia and the underlying mechanisms. Rat CMECs were successfully isolated and passaged to the second generation. CMECs that were pre-treated with QL (0.5 mg/mL) and/or HIF-1α siRNA were cultured in a three-gas hypoxic incubator chamber (5% CO2 , 1% O2 , 94% N2 ) for 12 hours. Firstly, we demonstrated that compared with hypoxia group, QL effectively promoted the proliferation while attenuated the apoptosis, improved mitochondrial function and reduced ROS generation in hypoxic CMECs in a HIF-1α-dependent manner. Meanwhile, QL also promoted angiogenesis of CMECs via HIF-1α/VEGF signalling pathway. Moreover, QL improved glucose utilization and metabolism and increased ATP production by up-regulating HIF-1α and a series of glycolysis-relevant enzymes, including glucose transport 1 (GLUT1), hexokinase 2 (HK2), 6-phosphofructokinase 1 (PFK1), pyruvate kinase M2 (PKM2) and lactate dehydrogenase A (LDHA). Our findings indicate that QL can protect CMECs against hypoxia injury via promoting glycolysis in a HIF-1α-dependent manner. Lastly, the results suggested that QL-dependent enhancement of HIF-1α protein expression in hypoxic CMECs was associated with the regulation of AMPK/mTOR/HIF-1α pathway, and we speculated that QL also improved HIF-1α stabilization through down-regulating prolyl hydroxylases 3 (PHD3) expression.

LncRNA TP73-AS1 Promotes Cell Proliferation and Inhibits Cell Apoptosis in Clear Cell Renal Cell Carcinoma Through Repressing KISS1 Expression and Inactivation of PI3K/Akt/mTOR Signaling Pathway.

BACKGROUND/AIMS: Emerging evidence suggests that long non-coding RNAs (lncRNAs) play a vital regulatory role in the pathogenesis and progression of renal cell carcinoma (RCC). We aim to determine lncRNA profiles in clear cell RCC (ccRCC) and investigate key lncRNAs involved in ccRCC tumorigenesis and progression. METHODS: RNA sequencing technique and qPCR were used to determine the candidate lncRNAs in ccRCC tissues. The correlations between lncRNA P73 antisense RNA 1T (TP73-AS1) levels and survival outcomes were analyzed to elucidate its clinical significance. The underlying mechanisms of TP73-AS1 in ccRCC were analyzed through in vitro functional assays. RESULTS: We found TP73-AS1 was upregulated in 40 ccRCC tissues compared with adjacent normal renal tissues and increased TP73-AS1 was correlated to aggressive clinicopathologic features and unfavorable prognosis. Knockdown of TP73-AS1 suppressed cell proliferation, invasion and induced cell apoptosis. We also identified KISS-1 metastasis-suppressor (KISS1) was significantly upregulated in TP73-AS1 knockdown cells. Further, we revealed that TP73-AS1 suppressed KISS1 expression through the interaction with Enhancer of zeste homolog 2 (EZH2) and the specific binding to KISS1 gene promoter region. Knockdown of KISS1 partly reversed TP73-AS1 knockdown-induced inhibition of cell proliferation and promotion of apoptosis. We further determined that TP73-AS1 knockdown activated PI3K/Akt/mTOR signaling pathway, while overexpression of TP73-AS1 induced inhibition of PI3K/Akt/mTOR pathway and these effects could be partly abolished by overexpression of KISS1. CONCLUSION: In conclusion, we identified that TP73-AS1 as an oncogenic lncRNA in the development of ccRCC and a potential target for human renal carcinoma treatment.

Mechanical stresses induce paracrine ß-2 microglobulin from cardiomyocytes to activate cardiac fibroblasts through epidermal growth factor receptor.

By employing a proteomic analysis on supernatant of mechanically stretched cardiomyocytes, we found that stretch induced a significantly high level of ß-2 microglobulin (ß2M), a non-glycosylated protein, which is related to inflammatory diseases but rarely known in cardiovascular diseases. The present data showed that serum ß2M level was increased in patients with hypertension and further increased in patients with chronic heart failure (HF) as compared with control group, and the high level of serum ß2M level correlated to cardiac dysfunction in these patients. In pressure overload mice model by transverse aortic constriction (TAC), ß2M levels in serum and heart tissue increased progressively in a time-dependent manner. Exogenous ß2M showed pro-fibrotic effects in cultured cardiac fibroblasts but few effects in cardiomyocytes. Adeno-associated virus 9 (AAV9)-mediated knockdown of ß2M significantly reduced cardiac ß2M level and inhibited myocardial fibrosis and cardiac dysfunction but not cardiac hypertrophy at 4 weeks after TAC. In vitro, mechanical stretch induced the rapid secretion of ß2M mainly from cardiomyocytes by activation of extracellular-regulated protein kinase (ERK). Conditional medium (CM) from mechanically stretched cardiomyocytes activated cultured cardiac fibroblasts, and the effect was partly abolished by CM from ß2M-knockdown cardiomyocytes. In vivo, knockdown of ß2M inhibited the increase in phosphorylation of epidermal growth factor receptor (EGFR) induced by TAC. In cultured cardiac fibroblasts, inhibition of EGFR significantly attenuated the ß2M-induced the activation of EGFR and pro-fibrotic responses. The present study suggests that ß2M is a paracrine pro-fibrotic mediator and associated with cardiac dysfunction in response to pressure overload.

Qiliqiangxin protects against anoxic injury in cardiac microvascular endothelial cells via NRG-1/ErbB-PI3K/Akt/mTOR pathway.

Cardiac microvascular endothelial cells (CMECs) are important angiogenic components and are injured rapidly after cardiac ischaemia and anoxia. Cardioprotective effects of Qiliqiangxin (QL), a traditional Chinese medicine, have been displayed recently. This study aims to investigate whether QL could protect CMECs against anoxic injury and to explore related signalling mechanisms. CMECs were successfully cultured from Sprague-Dawley rats and exposed to anoxia for 12 hrs in the absence and presence of QL. Cell migration assay and capillary-like tube formation assay on Matrigel were performed, and cell apoptosis was determined by TUNEL assay and caspase-3 activity. Neuregulin-1 (NRG-1) siRNA and LY294002 were administrated to block NRG-1/ErbB and PI3K/Akt signalling, respectively. As a result, anoxia inhibited cell migration, capillary-like tube formation and angiogenesis, and increased cell apoptosis. QL significantly reversed these anoxia-induced injuries and up-regulated expressions of NRG-1, phospho-ErbB2, phospho-ErbB4, phospho-Akt, phospho-mammalian target of rapamycin (mTOR), hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) in CMECs, while NRG-1 knockdown abolished the protective effects of QL with suppressed NRG-1, phospho-ErbB2, phospho-ErbB4, phospho-Akt, phospho-mTOR, HIF-1α and VEGF expressions. Similarly, LY294002 interrupted the beneficial effects of QL with down-regulated phospho-Akt, phospho-mTOR, HIF-1α and VEGF expressions. However, it had no impact on NRG-1/ErbB signalling. Our data indicated that QL could attenuate anoxia-induced injuries in CMECs via NRG-1/ErbB signalling which was most probably dependent on PI3K/Akt/mTOR pathway.

Complex inhibition of autophagy by mitochondrial aldehyde dehydrogenase shortens lifespan and exacerbates cardiac aging.

Autophagy, a conservative degradation process for long-lived and damaged proteins, participates in a cascade of biological processes including aging. A number of autophagy regulators have been identified. Here we demonstrated that mitochondrial aldehyde dehydrogenase (ALDH2), an enzyme with the most common single point mutation in humans, governs cardiac aging through regulation of autophagy. Myocardial mechanical and autophagy properties were examined in young (4months) and old (26-28months) wild-type (WT) and global ALDH2 transgenic mice. ALDH2 overexpression shortened lifespan by 7.7% without affecting aging-associated changes in plasma metabolic profiles. Myocardial function was compromised with aging associated with cardiac hypertrophy, the effects were accentuated by ALDH2. Aging overtly suppressed autophagy and compromised autophagy flux, the effects were exacerbated by ALDH2. Aging dampened phosphorylation of JNK, Bcl-2, IKKß, AMPK and TSC2 while promoting phosphorylation of mTOR, the effects of which were exaggerated by ALDH2. Co-immunoprecipitation revealed increased dissociation between Bcl-2 and Beclin-1 (result of decreased Bcl-2 phosphorylation) in aging, the effect of which was exacerbated with ALDH2. Chronic treatment of the autophagy inducer rapamycin alleviated aging-induced cardiac dysfunction in both WT and ALDH2 mice. Moreover, activation of JNK and inhibition of either Bcl-2 or IKKß overtly attenuated ALDH2 activation-induced accentuation of cardiomyocyte aging. Examination of the otherwise elderly individuals revealed a positive correlation between cardiac function/geometry and ALDH2 gene mutation. Taken together, our data revealed that ALDH2 enzyme may suppress myocardial autophagy possibly through a complex JNK-Bcl-2 and IKKß-AMPK-dependent mechanism en route to accentuation of myocardial remodeling and contractile dysfunction in aging. This article is part of a Special Issue entitled: Genetic and epigenetic control of heart failure - edited by Jun Ren & Megan Yingmei Zhang.

Understanding the Epidemiology of Heart Failure to Improve Management Practices: An Asia-Pacific Perspective.

Heart failure (HF) is a major global healthcare problem with an estimated prevalence of approximately 26 million. In Asia-Pacific regions, HF is associated with a significant socioeconomic burden and high rates of hospital admission. Epidemiological data that could help to improve management approaches to address this burden in Asia-Pacific regions are limited, but suggest patients with HF in the Asia-Pacific are younger and have more severe signs and symptoms of HF than those of Western countries. However, local guidelines are based largely on the European Society of Cardiology and American College of Cardiology Foundation/American Heart Association guidelines, which draw their evidence from studies where Western patients form the major demographic and patients from the Asia-Pacific region are underrepresented. Furthermore, regional differences in treatment practices likely affect patient outcomes. In the following review, we examine epidemiological data from existing regional registries, which indicate that these patients represent a distinct subpopulation of patients with HF. In addition, we highlight that patients with HF are under-treated in the region despite the existence of local guidelines. Finally, we provide suggestions on how data can be enriched throughout the region, which may positively affect local guidelines and improve management practices.

Clinical Diagnosis and Treatment of Male Breast Cancer:Analysis of 24 Cases.

Objective To summarize our experiences in the clinical diagnosis and treatment of male breast cancer(MBC).Methods The clinical date of 24 MBC patients treated in our hospital from January 2006 to December 2012 were retrospective analyzed.Results The average age of these 24 patients was(55.7±2.1) years.All the patients received surgical treatment,and the surgical procedures were simple excision of breast lesion in 6 patients,breast resection alone in 5 patients,and modified radical mastectomy in 13 patients(bilateral in 1 case).The pathological diagnoses included invasive ductal carcinoma in 18 cases,papillary carcinoma in 4 cases,mucinous adenocarcinoma in 1 case,and malignant solitary fibrous tumor in 1 case.Twenty patients received chemotherapy,7 received radiotherapy,and 15 received endocrine therapy after operation.The 5-year survival rate was 54.2%.Conclusions The incidence of MBC is low.This malignancy is mainly seen in elderly individuals,with relatively long disease course,poor prognosis,and high risk of metastasis.MBC is mainly treated by surgery,and adjuvant chemotherapy,radiotherapy,and endocrine therapy may be applied,if appropriate,after the operation.

Optimizing the Management of Heart Failure With Preserved Ejection Fraction in the Elderly by Targeting Comorbidities (OPTIMIZE-HFPEF).

AIMS: The pathophysiology of heart failure with preserved ejection fraction (HFPEF) is not fully understood. A recently proposed mechanism for HFPEF is that it is a systemic pro-inflammatory state induced by comorbidities, leading to microvascular endothelial dysfunction and subsequent cardiac remodeling and dysfunction. We hypothesize that targeting comorbidities will improve outcomes in elderly patients with HFPEF. Thus, the aim of this study is to determine whether the combination of systematic screening and optimal management of prespecified comorbidities associated with HFPEF improves outcomes. METHODS: This multicenter, prospective, randomized intervention trial uses an open procedure with blinded endpoint assessment. Patients with HFPEF aged >60 years (n = 360) will be randomized 1:1 to the usual care or intervention arm of the trial. When randomized to the intervention arm, all patients will be systematically screened and optimally treated for the most frequent cardiovascular, metabolic, respiratory, and renal comorbidities. The primary endpoint is a composite clinical score that classifies each randomized patient as improved or deteriorated based on objective and subjective data at a 24-month follow-up performed by a blinded endpoint committee. CONCLUSION: Rather than targeting cardiac dysfunction, our study aims to present evidence for a possible paradigm shift in the management of HFPEF. Our novel concept focuses on the management of comorbidities as predisposing factors in HFPEF.