Targeting Energy Protection as a Novel Strategy to Disclose Di'ao Xinxuekang against the Cardiotoxicity Caused by Doxorubicin.

Doxorubicin (DOX) can induce myocardial energy metabolism disorder and further worsen heart failure. "Energy protection" is proposed as a new cardiac protection strategy. Previous studies have found that Di'ao Xinxuekang (DXXK) can improve doxorubicin-induced cardiotoxicity in mice by inhibiting ferroptosis. However, there are very few studies associating DXXK and energy protection. This study aims to explore the "energy protection" effect of DXXK on cardiotoxicity induced by DOX. A DOX-induced cardiotoxicity model established in rats and H9c2 cells are used to analyze the therapeutic effects of DXXK on serum indexes, cardiac function indexes and cardiac histopathology. The metabonomic methods were used to explore the potential mechanism of DXXK in treating DOX-induced cardiotoxicity. In addition, we also observed the mitochondrial- and autophagy-related indicators of myocardial cells and the mRNA expression level of the core target regulating energy-metabolism-related pathways. Our results indicated that DXXK can improve cardiac function, reduce myocardial enzymes and alleviate the histological damage of heart tissue caused by DOX. In addition, DXXK can improve mitochondrial damage induced by DOX and inhibit excessive autophagy. Metabonomics analysis showed that DOX can significantly affects the pathways related to energy metabolism of myocardial cells, which are involved in the therapeutic mechanism of DXXK. In conclusion, DXXK can treat DOX-induced cardiotoxicity through the AMPK-mediated energy protection pathway.

Renal and Extra Renal Manifestations in Adult Zebrafish Model of Cystinosis.

Cystinosis is a rare, incurable, autosomal recessive disease caused by mutations in the CTNS gene. This gene encodes the lysosomal cystine transporter cystinosin, leading to lysosomal cystine accumulation in all cells of the body, with kidneys being the first affected organs. The current treatment with cysteamine decreases cystine accumulation, but does not reverse the proximal tubular dysfunction, glomerular injury or loss of renal function. In our previous study, we have developed a zebrafish model of cystinosis through a nonsense mutation in the CTNS gene and have shown that zebrafish larvae recapitulate the kidney phenotype described in humans. In the current study, we characterized the adult cystinosis zebrafish model and evaluated the long-term effects of the disease on kidney and extra renal organs through biochemical, histological, fertility and locomotor activity studies. We found that the adult cystinosis zebrafish presents cystine accumulation in various organs, altered kidney morphology, impaired skin pigmentation, decreased fertility, altered locomotor activity and ocular anomalies. Overall, our data indicate that the adult cystinosis zebrafish model reproduces several human phenotypes of cystinosis and may be useful for studying pathophysiology and long-term effects of novel therapies.

Carnosinase-1 overexpression, but not aerobic exercise training, affects the development of diabetic nephropathy in BTBR ob/ob mice.

Manipulation of circulating histidine-containing dipeptides (HCD) has been shown to affect the development of diabetes and early-stage diabetic nephropathy (DN). The aim of the present study was to investigate whether such interventions, which potentially alter levels of circulating HCD, also affect the development of advanced-stage DN. Two interventions, aerobic exercise training and overexpression of the human carnosinase-1 (hCN1) enzyme, were tested. BTBR ob/ob mice were either subjected to aerobic exercise training (20 wk) or genetically manipulated to overexpress hCN1, and different diabetes- and DN-related markers were compared with control ob/ob and healthy (wild-type) mice. An acute exercise study was performed to elucidate the effect of obesity, acute running, and hCN1 overexpression on plasma HCD levels. Chronic aerobic exercise training did not affect the development of diabetes or DN, but hCN1 overexpression accelerated hyperlipidemia and aggravated the development of albuminuria, mesangial matrix expansion, and glomerular hypertrophy of ob/ob mice. In line, plasma, kidney, and muscle HCD were markedly lower in ob/ob versus wild-type mice, and plasma and kidney HCD in particular were lower in ob/ob hCN1 versus ob/ob mice but were unaffected by aerobic exercise. In conclusion, advanced glomerular damage is accelerated in mice overexpressing the hCN1 enzyme but not protected by chronic exercise training. Interestingly, we showed, for the first time, that the development of DN is closely linked to renal HCD availability. Further research will have to elucidate whether the stimulation of renal HCD levels can be a therapeutic strategy to reduce the risk for developing DN.

PINK1/Parkin mediated mitophagy ameliorates palmitic acid-induced apoptosis through reducing mitochondrial ROS production in podocytes.

Diabetic nephropathy (DN), the primary cause of end-stage renal disease (ESRD), is often accompanied by dyslipidemia, which is closely related to the occurrence and development of DN and even the progression to ESRD. Mitophagy, the selective degradation of damaged and dysfunctional mitochondria by autophagy, is a crucial mitochondrial quality control mechanism, and largely regulated by PINK1 (PTEN-induced putative kinase 1)/Parkin signaling pathway. In the present study, we demonstrated that PA induced mitochondrial damage and excessive mitoROS generation in podocytes. We also found PA treatment resulted in the activation of mitophagy by increasing co-localization of GFP-LC3 with mitochondria and enhancing the formation of mitophagosome, stabilization of PINK1 and mitochondrial translocation of Parkin, which indicated that PINK1/Parkin pathway was involved in PA-induced mitophagy in podocytes. Furthermore, inhibition of mitophagy by silencing Parkin dramatically aggravated PA-induced mitochondrial dysfunction, mitoROS production, and further enhanced PA-induced apoptosis of podocytes. Finally, we showed that PINK1/Parkin pathway were up-regulated in kidney of high fat diet (HFD)-induced obese rats. Taken together, our results suggest that PINK1/Parkin mediated mitophagy plays a protective role in PA-induced podocytes apoptosis through reducing mitochondrial ROS production and that enhancing mitophagy provides a potential therapeutic strategy for kidney diseases with hyperlipidemia, such as DN.

Role of marital status on the prognosis in esophagus adenocarcinoma: a real-world competing risk analysis.

Aim: The purpose of this study was to assess the role of marital status in esophageal adenocarcinoma (EAC). Methods: We identified 8341 EAC patients based on the Surveillance, Epidemiology and End Results database during 2007-2015, of whom 7275 were male and 1066 were female. Temporal trends, competing risk analysis and propensity score matching were performed. Results: There was an upward trend for the rate of unmarried patients in both male and female populations (p < 0.05). Unmarried status represented an independent risk factor for higher cancer-specific death (CSD) in males (hazard ratio: 1.11; 95% CI: 1.04-1.18; p = 0.001) but not in females (hazard ratio: 0.96; 95% CI: 0.81-1.13; p = 0.610). Married EAC patients experienced lower CSD compared with their unmarried counterparts in the male cohort.

Effects of Marital Status on Prognosis in Women with Infiltrating Ductal Carcinoma of the Breast: A Real-World 1: 1 Propensity-Matched Study.

BACKGROUND The effects of marital status on infiltrating ductal carcinoma of breast cancer (IDC) have not been studied in detail. This study investigated the impact of marital status on IDC patients. MATERIAL AND METHODS SEER databases were searched from 2010 to 2015 for subjects who were married, divorced, single, and widowed. The influence of marital status on breast cancer-specific survival (BCSS) and overall survival (OS) of IDC patients was investigated through multivariate Cox regression analysis and Kaplan-Meier analysis. To prevent bias, propensity score matching (PSM) analysis was performed. RESULTS The 5-year OS was 89.6%in married patients, 84.9% in divorced patients, 83.5% in single patients, and 71.3% in widowed patients (p<0.001). The 5-year BCSS were 92.9%, 90.2%, 87.6%, and 86.4%, respectively (p<0.001). Multivariate Cox regression analysis revealed that marriage was a protective factor for patients with IDC in terms of OS (divorced: HR, 1.27; 95% CI, 1.21-1.32; p<0.001; single: HR, 1.36; 95% CI, 1.31-1.42; p<0.001; widowed: HR, 1.42; 95% CI, 1.36-1.48; p<0.001) and BCSS (divorced: HR, 1.15; 95% CI, 1.09-1.21; p<0.001; single: HR, 1.27; 95% CI, 1.21-1.33; p<0.001; widowed: HR, 1.32; 95% CI, 1.25-1.40; p<0.001). Following subgroup and PSM analysis, married patients were shown to have better OS and BCSS as opposed to divorced, single, or widowed patients. CONCLUSIONS We identify marital status as a predictor of survival in those with IDC. Widowed patients showed the highest mortality risk.

MiR-218-XOR-ROS Pathway Regulates the Progression of Nonalcoholic Steatohepatitis.

BACKGROUND: To investigate the role of the miR-218-xanthine oxidoreductase (XOR) pathway in the pathogenesis of nonalcoholic steatohepatitis (NASH) and to explore the potential downstream mechanisms involving oxidative stress and energy metabolism. METHODS: The NASH animal model was established by feeding BALB/c mice with an MCD diet, while BRL-3A cells were cultured with a mixture of oleate and palmitate for 72 hours to mimic the steatosis and inflammation of NASH in vitro. The steatosis and inflammation levels were assessed by H-E/oil-red staining and serum/supernatant TG, ALT, and AST levels. The apoptosis degree was tested by the TUNEL/flow cytometry method both in animals and cultured cells. The XOR and miR-218 levels were detected by western blotting and qRT-PCR. RESULTS: Decreased miR-218 and increased XOR levels were identified in the NASH animal and cell models, while the regulation of miR-218 on XOR was also confirmed. NASH alleviation was achieved after miR-218 over-expression in vivo and in vitro, according to the declination of steatosis and inflammation-related markers. Although H2O2 and ATP levels were increased and decreased in NASH models, respectively, antagonizing miR-218 could significantly alleviate those changes. CONCLUSIONS: The miR-218-XOR pathway may provide a novel mechanism and treatment option for NASH.

Dynamic Electrocardiography is Useful in the Diagnosis of Persistent Atrial Fibrillation Accompanied with Second-Degree Atrioventricular Block.

BACKGROUND: Periodic electrocardiography (ECG) at every clinical visit is generally performed for heart rhythm surveillance, and 24-h Holter ECG is usually used as the gold standard. We aimed to investigate the electrocardiographic features of persistent atrial fibrillation (AF) accompanied with second-degree atrioventricular block (AVB). METHODS: From October 2012 to November 2015, 204 patients with an RR interval > 2.0 s before radiofrequency ablation were included. Dynamic ECG (DCG) was performed before and after the radiofrequency ablation. The patients were divided into two groups based on changes in DCG after radiofrequency ablation: group A (non-second-degree AVB group) and group B (second-degree AVB group). An RR interval > 2.0 s, the distribution of escape rhythm, mean heart rate and the long RR interval in the two groups were analyzed. RESULTS: After radiofrequency ablation, all 204 patients who had persistent AF converted to sinus rhythm successfully. In group A (n = 193), the distribution of an RR interval > 2.0 s and escape rhythm were significantly correlated with sleep or rest, while no correlation was observed in group B (n = 11). The average RR interval prolongation and escape rhythm were significantly higher in group B than in group A (p < 0.05). The average number of long RR intervals > 3.0 s and average number of escape rhythm episodes (< 35 bpm) were significant predictive factors of second-degree AVB after radiofrequency ablation. CONCLUSIONS: DCG is a useful tool for the diagnosis of persistent AF accompanied with second-degree AVB.

Association between Serum Sialic Acid Levels and Nonalcoholic Fatty Liver Disease: A Cross-Sectional Study.

BACKGROUND: To assess the association between serum sialic acid (SA) levels and nonalcoholic fatty liver disease (NAFLD) in a Chinese population. METHODS: A cross-sectional study was performed among 3,898 Chinese who took their annual health examination. Serum SA levels and other clinical and laboratory parameters were measured. RESULTS: A total of 18.11% fulfilled the diagnostic criteria of NAFLD. NAFLD subjects with/without metabolic syndrome (MS) had significantly higher serum SA levels than those without NAFLD. Serum SA levels were significantly and positively correlated with components of MS (body mass index, systolic blood pressure, diastolic blood pressure, triglyceride and fasting plasma glucose) in the NAFLD group. Stepwise logistic regression analysis showed that SA levels were significantly associated with the risk factor for NAFLD. Serum SA levels were negatively correlated with the FIB-4 score, and lower serum SA levels were independent factors predicting advanced fibrosis in subjects with NAFLD. CONCLUSIONS: Our results showed a significant association between serum SA levels and NAFLD.

Refining soil nutrient assessment: Incorporating land use boundaries for precision agriculture.

Soil nutrient levels play a crucial role in determining crop yield. A comprehensive understanding of the spatial distribution patterns and evaluation grades of soil nutrients is of significant practical importance for informed fertilization practices, enhancing crop production, and optimizing agricultural land utilization. This study focuses on the urban area of Kashi Prefecture in Xinjiang as a case study. Utilizing soil sample data, GIS spatial interpolation analysis was conducted, incorporating plot boundary information to propose a comprehensive evaluation method for assessing soil nutrient levels at the plot level. Experimental findings revealed the following: (1) The average values of soil organic matter (SOM), total nitrogen (AN), total potassium (AK), and total phosphorus (AP) in the study area were determined to be 13.3 g/kg, 0.74 g/kg, 0.33 g/kg, and 0.03 g/kg, respectively. Among these, AN and SOM were classified as the fourth grade, indicating relatively deficient levels, while AK and AP were classified as the first and second grade, indicating relatively abundant levels. (2) The comprehensive evaluation of soil nutrient grades in the study area primarily fell within the third, fourth, and second grades, representing areas of 29.08 km2, 25 km2, and 4.05 km2, accounting for 50.03%, 43%, and 6.97% of the total area, respectively. (3) The evaluation results of soil nutrient levels at the plot level emphasized the boundary characteristics and provided a more refined assessment grade. This evaluation method is better suited to meet the practical production requirements of farmers and is considered feasible. The outcomes of this study can serve as a reference for precision agriculture management.

Reducing heat exposure from personal cooling strategies to green city construction in China's tropical city.

With rapid industrialization and urbanization, the risk of summer heat exposure for urban dwellers has increased. The use of air conditioners (ACs) has become the most common personal cooling strategy, but further increasing fossil fuel consumption. As sustainable and affordable cooling strategies, urban parks can reduce heat exposure and substitute a part of air conditioners use. This study evaluates the heat exposure reduction from personal cooling to urban parks based on satellite images, questionnaire surveys, and network analysis in Liuzhou, one tropical city in China. We found that residents with lower income had a higher risk of heat exposure. Among the respondents, 85 % of residents chose to use ACs to alleviate high temperatures in summer, and 81.8 % among them were willing to access park cooling area (PCA) to cool off instead of using ACs. About one third parks could serve as potential alternatives (with temperatures <28 °C) to air conditioning, reducing carbon emissions by 175.93 tons per day during the hot summer and offsetting 2.5 % of urban fossil fuel carbon emissions. The design of parks should give more consideration to elder people and provide a good cooling platform for various social income groups. Future planning should also focus on accessibility to enable residents to fully utilize the parks. Building parks within 34.10 ha would provide a more efficient use of land. This research guides sustainable, high-quality growth in industrial cities and might contribute to promotion of low-carbon cities and social equity.

Deep learning-based classification of early-stage mycosis fungoides and benign inflammatory dermatoses on hematoxylin and eosin-stained whole-slide images: a retrospective, proof-of-concept study.

The diagnosis of early-stage mycosis fungoides (MF) is challenging due to shared clinical and histopathological features with benign inflammatory dermatoses (BIDs). Recent evidence has shown that deep learning (DL) can assist pathologists in cancer classification, but this field is largely unexplored for cutaneous lymphomas. This study evaluates DL in distinguishing early-stage MF from BIDs using a unique dataset of 924 hematoxylin and eosin-stained whole-slide images from skin biopsies, including 233 early-stage MF and 353 BID patients. All MF patients were diagnosed after clinicopathological correlation. The classification accuracy of weakly-supervised DL models was benchmarked against three expert pathologists. The highest performance on a temporal test set was at 200x magnification (0.25 µm per pixel resolution), with a mean area-under-the-curve of 0.827 ± 0.044 and a mean balanced accuracy of 76.2 ± 3.9%. This nearly matched the 77.7% mean balanced accuracy of the three expert-pathologists. Most (63.5%) attention heatmaps corresponded well with the pathologists' region-of-interest. Considering the difficulty of the MF versus BID classification task, the results of this study show promise for future applications of weakly-supervised DL in diagnosing early-stage MF. Achieving clinical-grade performance will require larger multi-institutional datasets and improved methodologies, such as multimodal DL with incorporation of clinical data.

[Diagnostic value of automated breast volume scanner in high-risk and small breast lesions].

OBJECTIVE: To assess the accuracy of detection by automated breast volume scanner (ABVS) in diagnosis of high-risk and small breast lesions. METHODS: One hundred and twelve patients with solid high-risk and small breast lesions were identified by ABVS. The patients were divided into benign lesion group and cancer group after pathological examination. The clinicopathological findings and ultrasonographic features of the lesions were compared. RESULTS: Among the 112 lesions there were 49 benign and 63 malignant lesions. The mean size on ABVS and pathology were (1.59 ± 0.52) cm and (1.52 ± 0.58) cm. There was no significant difference in tumor sizes determined by ABVS and pathology (P = 0.194). The mean age of patients with benign lesions was (38.5 ± 7.4) years and that of malignant lesions was (52.4 ± 13.6) years, showing a significant difference between the two groups (P < 0.001) . The mass shape, orientation, margin, lesion boundary, echo pattern, calcification, BI-RADS category and retraction phenomenon were significantly different of the malignant and benign masses (P < 0.05). But there was no significant difference in the location of lesions and posterior acoustic features (P > 0.05) . Retraction phenomenon was significantly associated with pathological type and histologic grade of the breast cancer (P < 0.01). The specificity, sensitivity and accuracy of retraction phenomenon were 100% (46/46), 73.0% (46/63), and 84.8% (95/112), respectively. CONCLUSIONS: ABVS provides advantages of better size prediction of high-risk and small breast lesions. Furthermore, the retraction phenomenon in coronal plane shows high specificity and sensitivity in detecting breast cancer.

[The significance of urine N-acetyl-beta-D-glucosaminidase in kidney injury with patients acute paraquat poisoning].

OBJECTIVES: To test the hypothesis that urine N-acetyl-beta-D-glucosaminidase (NAG) is a nearly biomarker for acute kidney injury in patients with acute paraquat poisoning. METHODS: Forty-four patients with paraquat intoxication and 40 age and gender-matched healthy control participants were recruited. The urine N-acetyl-beta-D-glucosaminidase was determined by spectrophotometric methods. RESULTS: The urine N-acetyl-beta-D-glucosaminidase activities in the patients with paraquat poisoning were higher than the corresponding values in the control participants (P<0.01); The prevalence rate of mortality was significantly higher in subjects with N-acetyl-beta-D-glucosaminidase activities ≥25 U/g Cr than in those N-acetyl-beta-D-glucosaminidase activities <25 Ulg Cr (34.4% vs 16.7%, P<0.01). CONCLUSIONS: The urine N-acetyl-beta-D-glucosaminidase could be used as an early biomarker for acute kidney injury and predictor of mortality inpatients with acute paraquat intoxication.

Probing microstructural changes in muscles of leptin-deficient zebrafish by non-invasive ex-vivo magnetic resonance microimaging.

Leptin is a hormone that plays a key role in controlling food intake and energy homeostasis. Skeletal muscle is an important target for leptin and recent studies have shown that leptin deficiency may lead to muscular atrophy. However, leptin deficiency-induced structural changes in muscles are poorly understood. The zebrafish has emerged as an excellent model organism for studies of vertebrate diseases and hormone response mechanisms. In this study, we explored ex-vivo magnetic resonance microimaging (µMRI) methods to non-invasively assess muscle wasting in leptin-deficient (lepb-/-) zebrafish model. The fat mapping performed by using chemical shift selective imaging shows significant fat infiltration in muscles of lepb-/- zebrafish compared to control zebrafish. T2 relaxation measurements show considerably longer T2 values in the muscle of lepb-/- zebrafish. Multiexponential T2 analysis detected a significantly higher value and magnitude of long T2 component in the muscles of lepb-/- as compared to control zebrafish. For further zooming into the microstructural changes, we applied diffusion-weighted MRI. The results show a significant decrease in the apparent diffusion coefficient indicating increased constraints of molecular movements within the muscle regions of lepb-/- zebrafish. The use of the phasor transformation for the separation of diffusion-weighted decay signals showed a bi-component diffusion system which allows us to estimate each fraction on a voxel-wise basis. A substantial difference was found between the ratio of two components in lepb-/- and control zebrafish muscles, indicating alterations in diffusion behavior associated with the tissue microstructural changes in muscles of lepb-/- zebrafish as compared to control zebrafish. Taken together, our results demonstrate that the muscles of lepb-/- zebrafish undergo significant fat infiltration and microstructural changes leading to muscle wasting. This study also demonstrates that µMRI provides excellent means to non-invasively study the microstructural changes in the muscles of the zebrafish model.

RUNDC1 inhibits autolysosome formation and survival of zebrafish via clasping ATG14-STX17-SNAP29 complex.

Autophagy serves as a pro-survival mechanism for a cell or a whole organism to cope with nutrient stress. Our understanding of the molecular regulation of this fusion event remains incomplete. Here, we identified RUNDC1 as a novel ATG14-interacting protein, which is highly conserved across vertebrates, including zebrafish and humans. By gain and loss of function studies, we demonstrate that RUNDC1 negatively modulates autophagy by blocking fusion between autophagosomes and lysosomes via inhibiting the assembly of the STX17-SNAP29-VAMP8 complex both in human cells and the zebrafish model. Moreover, RUNDC1 clasps the ATG14-STX17-SNAP29 complex via stimulating ATG14 homo-oligomerization to inhibit ATG14 dissociation. This also prevents VAMP8 from binding to STX17-SNAP29. We further identified that phosphorylation of RUNDC1 Ser379 is crucial to inhibit the assembly of the STX17-SNAP29-VAMP8 complex via promoting ATG14 homo-oligomerization. In line with our findings, RunDC1 is crucial for zebrafish in their response to nutrient-deficient conditions. Taken together, our findings demonstrate that RUNDC1 is a negative regulator of autophagy that restricts autophagosome fusion with lysosomes by clasping the ATG14-STX17-SNAP29 complex to hinder VAMP8 binding.

The role of chemotherapy in patients with T1bN0M0 triple-negative breast cancer: a real-world competing risk analysis.

The objective of the present study was to implement Kaplan-Meier analysis, competing risk analysis, and propensity score matching to evaluate whether the patients with T1bN0M0 triple-negative breast (TNBC) could benefit from adjuvant chemotherapy. A total of 1849 patients were identified in the Surveillance, Epidemiology, and End Results (SEER) database from 2010 to 2015. All eligible patients were divided into two cohorts, the chemotherapy (1155 patients) and the no-chemotherapy (694 patients) cohorts. Similar 5-year breast cancer-specific survival (BCSS) was observed in the chemotherapy and no-chemotherapy cohorts (96.1% vs. 96.0%, p=0.820). The results of the competing risk analysis showed a comparable 5-year breast cancer-specific death (BCSD) in both groups (chemotherapy 3.6% vs. no-chemotherapy 3.4%, p=0.778). Also, a higher 5-year other causes death (OCD) was observed in the no-chemotherapy cohort (0.7% vs. 5.4%, p<0.001). Multivariable competing risks regression models showed no association between chemotherapy and BCSS (HR, 1.21; 95%CI, 0.64-2.31; p=0.560). After 1:1 PSM, no significant difference was also observed for BCSD and OCD between two cohorts. The value of adjuvant chemotherapy in patients with T1bN0M0 TNBC is less than the present guidelines recommend, suggesting that de-escalated treatment could be a potentially beneficial strategy in appropriately selected patients.

Berberine alleviates palmitic acid­induced podocyte apoptosis by reducing reactive oxygen species­mediated endoplasmic reticulum stress.

Lipid accumulation in podocytes can lead to the destruction of cellular morphology, in addition to cell dysfunction and apoptosis, which is a key factor in the progression of chronic kidney disease (CKD). Berberine (BBR) is an isoquinoline alkaloid extracted from medicinal plants such as Coptis chinensis, which has been reported to have a lipid­lowering effect and prevent CKD progression. Therefore, the present study aimed to investigate the effect of BBR on palmitic acid (PA)­induced podocyte apoptosis and its specific mechanism using an in vitro model. Cell death was measured using the Cell Counting Kit­8 colorimetric assay. Cell apoptotic rate was assessed by flow cytometry. The expression of endoplasmic reticulum (ER) stress­ and apoptosis­related proteins was detected by western blotting or immunofluorescence. Reactive oxygen species (ROS) were evaluated by 2',7'­dichlorofluorescein diacetate fluorescence staining. The results of the present study revealed that BBR treatment decreased PA­induced podocyte apoptosis. In addition, 4­phenylbutyric acid significantly reduced PA­induced cell apoptosis and the expression of ER stress­related proteins, which indicated that ER stress was involved in PA­induced podocyte apoptosis. In addition, N­acetylcysteine inhibited PA­induced excessive ROS production, ER stress and cell apoptosis of podocytes. BBR also significantly reduced PA­induced ROS production and ER stress in podocytes. These results suggested that PA mediated podocyte apoptosis through enhancing ER stress and the production of ROS. In conclusion, BBR may protect against PA­induced podocyte apoptosis, and suppression of ROS­dependent ER stress may be the key mechanism underlying the protective effects of BBR.

The Role of Adjuvant Chemotherapy in Metaplastic Breast Carcinoma: A Competing Risk Analysis of the SEER Database.

Purpose: Chemotherapy is the clinically recommended treatment for patients with operable metaplastic breast carcinoma (MBC); however, its impact remains controversial. This study investigated the possible role of chemotherapy in the treatment of MBC. Methods: The Surveillance, Epidemiology, and End Results (SEER) database was used to identify the operable MBC patients. The competing risk analysis along with the propensity score matching (PSM) method was performed to evaluate the effect of chemotherapy. Moreover, a competing risk nomogram was built to identify prognosis in patients with MBC. Results: Of the 1137 patients with MBC, 775 received chemotherapy and 362 did not receive chemotherapy. The 5-year cumulative incidence of breast cancer-specific death (BCSD) showed similar outcomes in both the Chemo and No-Chemo groups (21.1 vs. 24.3%, p = 0.57). Chemotherapy showed no apparent association with BCSD (HR, 1.07; 95% CI, 0.72-1.60; p = 0.72), even after subgroup analysis or PSM. Race, tumor size, lymph node status, and radiation were identified as the significant factors for MBC after a penalized variable selection process. In addition, a competing risk nomogram showed relatively good accuracy of prediction with a C-index of 0.766 (95% CI, 0.700-0.824). Conclusion: Our findings demonstrated that chemotherapy did not improve BCSD for operable MBC patients. Thus, it may indicate the need to reduce exposure to the current chemotherapy strategies for patients with resectable MBC. Additionally, some novel treatment strategies are required urgently to identify and target the potential biomarkers.

Leptin deficiency affects glucose homeostasis and results in adiposity in zebrafish.

Leptin is a hormone which functions in the regulation of energy homeostasis via suppression of appetite. In zebrafish, there are two paralogous genes encoding leptin, called lepa and lepb. In a gene expression study, we found that the lepb gene, not the lepa gene, was significantly downregulated under the state of insulin-resistance in zebrafish larvae, suggesting that the lepb plays a role in glucose homeostasis. In the current study, we characterised lepb-deficient (lepb-/-) adult zebrafish generated via a CRISPR-CAS9 gene editing approach by investigating whether the disruption of the lepb gene would result in the development of type 2 diabetes mellitus (T2DM) and diabetic complications. We observed that lepb-/- adult zebrafish had an increase in body weight, length and visceral fat accumulation, compared to age-matched control zebrafish. In addition, lepb-/- zebrafish had significantly higher blood glucose levels compared to control zebrafish. These data collectively indicate that lepb-/- adult zebrafish display the features of T2DM. Furthermore, we showed that lepb-/- adult zebrafish had glomerular hypertrophy and thickening of the glomerular basement membrane, compared to control zebrafish, suggesting that lepb-/- adult zebrafish develop early signs of diabetic nephropathy. In conclusion, our results demonstrate that lepb regulates glucose homeostasis and adiposity in zebrafish, and suggest that lepb-/- mutant zebrafish are a promising model to investigate the role of leptin in the development of T2DM and are an attractive model to perform mechanistic and therapeutic research in T2DM and its complications.