TMEM11 regulates cardiomyocyte proliferation and cardiac repair via METTL1-mediated m7G methylation of ATF5 mRNA.

The mitochondrial transmembrane (TMEM) protein family has several essential physiological functions. However, its roles in cardiomyocyte proliferation and cardiac regeneration remain unclear. Here, we detected that TMEM11 inhibits cardiomyocyte proliferation and cardiac regeneration in vitro. TMEM11 deletion enhanced cardiomyocyte proliferation and restored heart function after myocardial injury. In contrast, TMEM11-overexpression inhibited neonatal cardiomyocyte proliferation and regeneration in mouse hearts. TMEM11 directly interacted with METTL1 and enhanced m7G methylation of Atf5 mRNA, thereby increasing ATF5 expression. A TMEM11-dependent increase in ATF5 promoted the transcription of Inca1, an inhibitor of cyclin-dependent kinase interacting with cyclin A1, which suppressed cardiomyocyte proliferation. Hence, our findings revealed that TMEM11-mediated m7G methylation is involved in the regulation of cardiomyocyte proliferation, and targeting the TMEM11-METTL1-ATF5-INCA1 axis may serve as a novel therapeutic strategy for promoting cardiac repair and regeneration.

Transarterial Chemoembolization Combined With Apatinib Plus PD-1 Inhibitors for Hepatocellular Carcinoma With Portal Vein Tumor Thrombus: A Multicenter Retrospective Study.

INTRODUCTION: The aim of this study was to compare transarterial chemoembolization (TACE) combined with apatinib and PD-1 inhibitors (TACE-AP) with TACE combined with apatinib alone (TACE-A) in the treatment of hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) and to explore the prognostic factors affecting the survival of patients. METHODS: This retrospective study analyzed data of patients with HCC with PVTT who were treated with TACE-AP or TACE-A between December 2018 and June 2021. The primary end points of the study were progression-free survival (PFS) and overall survival (OS), and the secondary end points were objective response rate (ORR) and adverse events (AEs). Propensity score matching (PSM) and stabilized inverse probability weighting (sIPTW) analyses were used to reduce patient selection bias, and Cox regression analysis was used to analyze prognostic factors affecting patient survival. RESULTS: Sixty-nine and 40 patients were included in the TACE-A and TACE-AP groups, respectively. After PSM and IPTW analyses, the median PFS and median OS in the TACE-AP group were significantly higher than those in the TACE-A group (PFS: after PSM, 6.9 vs 4.0 months, P < 0.001, after IPTW, 6.5 vs 5.1 months, P < 0.001; OS: after PSM, 14.6 vs 8.5 months P < 0.001, after IPTW, 16.1 vs 10.5 months, P < 0.001). After PSM and IPTW analyses, the tumor ORR in the TACE-AP group was significantly higher than that in the TACE-A group (PSM, 53.6% vs 17.9%, P = 0.005; IPTW, 52.5% vs 28.6%, P = 0.013). All treatment-related AEs were observed to be tolerated. Multivariate Cox regression analysis showed that the main prognostic factors affecting the survival of patients were tumor number, PVTT type, alpha-fetoprotein, and treatment mode. DISCUSSION: In the treatment of patients with HCC with PVTT, TACE-AP significantly improved PFS, OS, and ORR, and the AEs were safe and controllable.

Correlation of Serum Chemokine Ligand 14 with Barcelona Clinic Liver Cancer Stage, Lymphocyte Profile, and Response to Transarterial Chemoembolization in Patients with Hepatocellular Carcinoma.

PURPOSE: To investigate the clinical relevance of serum chemokine ligand 14 (sCCL14) in patients with hepatocellular carcinoma (HCC) and the effect of transarterial chemoembolization (TACE) on the expression level of sCCL14 and the immune microenvironment. MATERIALS AND METHODS: In this prospective single-center observational study, 52 patients with HCC were recruited from January 2019 to December 2021, their clinical data and blood samples were collected, and the relationship between sCCL14 and progression-free survival (PFS) and TACE treatment response was analyzed. RESULTS: Among the 52 patients with HCC (Barcelona Clinic Liver Cancer [BCLC] Stage A, 25.0%; BCLC Stage B, 44.2%; and BCLC Stage C, 30.8%), patients with BCLC Stage C HCC had significantly lower sCCL14 levels than those of patients with BCLC Stages A and B HCC (P = .001). sCCL14 levels were significantly higher in the first week after treatment than before TACE treatment (P = .024). Baseline sCCL14 levels in patients who showed complete response after TACE treatment were significantly higher than those in other groups, and lower baseline sCCL14 values were associated with shorter PFS times. Multivariate Cox regression analysis showed that sCCL14 level (hazard ratio, 1.855; 95% CI, 1.039-3.311; P = .037) was an independent prognostic factor of PFS. sCCL14 levels negatively correlated with the proportion of B lymphocytes and regulatory T cells in circulating blood and positively correlated with the absolute T-lymphocyte count. CONCLUSIONS: sCCL14 may be a predictive biomarker of TACE effectiveness. Further studies are needed to validate and outline the role of combination immunotherapy.

Inhibition Ras/MEK/ERK pathway: An important mechanism of Baihu Jia Guizhi Decoction ameliorated rheumatoid arthritis.

ETHNOPHARMACOLOGICAL RELEVANCE: Alleviating rheumatism by inhibiting synovitis is a routine treatment for rheumatoid arthritis (RA). Baihu Jia Guizhi Decoction (BHJGZ) is a classic prescription and has a long history of application for treating RA with a good anti-inflammatory action. However, the underlying molecular mechanisms have not been fully elucidated. AIM OF THE STUDY: This work aimed to decipher the potential mechanism of BHJGZ against RA focusing on Ras/MEK/ERK pathway. MATERIALS AND METHODS: Based on the prediction of network pharmacology, the inhibition action of BHJGZ on Ras/MEK/ERK pathway was firstly validated in vivo and in vitro. Moreover, the affinity with the ingredients of BHJGZ in serum and the targets of Ras/MEK/ERK pathway were evaluated. Finally, the efficacy of BHJGZ for relieving RA was assessed in AA rats. RESULTS: The Ras/MEK/ERK pathway was predicted by network pharmacology as one of important mechanisms of BHJGZ to treat RA. The high expression of Ras protein in synovitis of AA rats was significantly reduced by the treatment with BHJGZ, and the activation of Ras/MEK/ERK pathway in vivo and in vitro was also markedly inhibited (p < 0.05 or p < 0.01). Moreover, the level of p-ERK/ERK, IL-6 and TNF-α in vitro were further suppressed after Ras or MEK was inhibited by mirdametinib or lonafarnib respectively (p < 0.01). Furthermore, the results of molecular docking showed a good affinity and stable binding with the ingredients of BHJGZ in serum and multiple key proteins of the Ras/MEK/ERK pathway. Finally, paw swelling, paw circumference and pathological changes of joint synovitis were significantly reduced by BHJGZ in AA rats (p < 0.05). CONCLUSION: The inhibition of Ras/MEK/ERK pathway is one of crucial mechanisms of BHJGZ for ameliorating synovitis of RA.

The role of miRNAs in T helper cell development, activation, fate decisions and tumor immunity.

T helper (Th) cells are central members of adaptive immunity and comprise the last line of defense against pathogen infection and malignant cell invasion by secreting specific cytokines. These cytokines then attract or induce the activation and differentiation of other immune cells, including antibody-producing B cells and cytotoxic CD8+ T cells. Therefore, the bidirectional communication between Th cells and tumor cells and their positioning within the tumor microenvironment (TME), especially the tumor immune microenvironment (TIME), sculpt the tumor immune landscape, which affects disease initiation and progression. The type, number, and condition of Th cells in the TME and TIME strongly affect tumor immunity, which is precisely regulated by key effectors, such as granzymes, perforins, cytokines, and chemokines. Moreover, microRNAs (miRNAs) have emerged as important regulators of Th cells. In this review, we discuss the role of miRNAs in regulating Th cell mediated adaptive immunity, focusing on the development, activation, fate decisions, and tumor immunity.

Proteoglycan-4 predicts good prognosis in patients with hepatocellular carcinoma receiving transcatheter arterial chemoembolization and inhibits cancer cell migration in vitro.

Purpose: To search for adaptive response molecules that affect the efficacy of transcatheter arterial chemoembolization (TACE), analyze their clinical correlation with and prognostic value for hepatocellular carcinoma (HCC), and explore their impact on cell biological behavior and their mechanisms of action. Methods: HCC tissue gene sequencing was used to identify differentially expressed genes. The expression of proteoglycan 4 (PRG4) in the serum of 117 patients with HCC who received TACE was detected by enzyme-linked immunosorbent assay. Serum-free medium mimicked TACE-induced nutrient deprivation. Cells with stable knockdown of PRG4 (shPRG4) were constructed to verify the effect and mechanism of PRG4 on the biological behavior of HCC cells in vitro. Results: The expression of PRG4 was significantly elevated under TACE-induced starvation conditions. Low PRG4 expression was associated with worse response to TACE treatment, shorter survival time, and stronger HCC migration ability. Furthermore, in vitro experiments showed that knockdown of PRG4 promoted HCC cell migration by enhancing epithelial-mesenchymal transition (EMT) while did not affect proliferation. When PRG4 expression was low, starvation treatment impaired the migratory ability of HCC cells and reduced the chemosensitivity of HCC cells to epirubicin. Conclusions: PRG4 expression predicts survival and TACE treatment response in patients with HCC. Furthermore, knockdown of PRG4 enhanced EMT, leading to HCC cell migration. PRG4 may serve as a biomarker for HCC patients receiving TACE.

Plasma arginase-1 as a predictive marker for early transarterial chemoembolization refractoriness in unresectable hepatocellular carcinoma.

Objective: To explore the relationship between plasma arginase-1 (ARG1) and early transarterial chemoembolization (TACE) refractoriness in patients with hepatocellular carcinoma (HCC) and develop nomograms for predicting early TACE refractoriness. Methods: A total of 200 patients with HCC, treated with TACE, were included in the study, including 120 in the training set and 80 in the validation set. Pre-treatment enzyme-linked immunosorbent assay was used to detected the plasma ARG1 levels of the patient, and independent predictors of early TACE refractoriness were determined using a multivariate logistic regression model, based on which a predictive model was developed using a nomogram. Results: Risk of early TACE refractoriness was negatively correlated with plasma ARG1 levels, and multivariate logistic analysis showed tumour size (OR = 1.138, 95% CI = 1.006-1.288, P = 0.041), multiple tumors (OR=4.374, 95% CI = 1.189-16.089, P = 0.026), platelet count (OR = 0.990, 95% CI = 0.980-0.999, P = 0.036), and plasma ARG1 levels (OR = 0.209, 95% CI = 0.079-0.551, P = 0.002) to be independent prognostic factors for early TACE refractoriness.The AUC value for the nomogram of the training cohort was 0.786 (95% CI = 0.702-0.870), and the validation set AUC value was 0.833 (95% CI = 0.791-0.875).The decision curve analysis suggested that the nomogram had good clinical utility. Conclusion: High plasma ARG1 expression was associated with a lower incidence of early TACE refractoriness. The nomogram constructed based on four independent prognostic factors could facilitate an individualised prediction of the incidence of early TACE refractoriness.

Transarterial chemoembolization combined with apatinib with or without PD-1 inhibitors in BCLC stage C hepatocellular carcinoma: A multicenter retrospective study.

Objective: We evaluated the efficacy and safety of transarterial chemoembolization (TACE) combined with apatinib plus PD-1 inhibitors (TACE-AP) compared with TACE combined with apatinib (TACE-A) in patients with advanced hepatocellular carcinoma (HCC) and to explore the prognostic factors affecting patient survival. Methods: Data from patients with unresectable HCC who received TACE-AP or TACE-A from December 2018 to June 2021 were collected retrospectively. The main outcome of the study was overall survival (OS) and prognostic factors affecting survival, while the secondary outcomes were progression-free survival (PFS), the objective response rate (ORR), and treatment-related adverse events (TRAEs). Propensity score matching (PSM) analysis was used to reduce patient selection bias, and the random survival forest (RF) model was employed to explore prognostic factors affecting patient survival. Results: We enrolled 216 patients, including 148 and 68 patients in the TACE-A and TACE-AP groups, respectively. A total of 59 pairs of patients were matched using PSM analysis. Before and after PSM, the OS, PFS, and ORR in the TACE-AP group were significantly higher than in the TACE-A group (before, OS: 22.5 months vs. 12.8 months, P < 0.001; PFS: 6.7 months vs. 4.3 months, P < 0.001; ORR: 63.2% vs. 34.5%, P < 0.001; after, OS: 22.5 months vs. 12.0 months, P < 0.001; PFS: 6.7 months vs. 4.3 months, P < 0.001; ORR: 62.7% vs. 30.5%, P = 0.003). Multivariate Cox regression and RF models before and after PSM analysis revealed that the main prognostic factors affecting survival were tumor number, portal vein tumor thrombus (PVTT) invasion, alpha-fetoprotein (AFP) levels, total bilirubin (TBIL) level, and treatment. There was no significant difference in TRAEs between the two groups (P > 0.05). Conclusion: Compared with TACE-A, TACE-AP significantly improved OS, PFS, and ORR in patients with advanced HCC. The number of tumors, PVTT invasion, AFP levels, TBIL level, and treatment were significant prognostic factors associated with patient survival. All observed TRAEs were mild and controllable.

Genome-wide identification of microRNA targets reveals positive regulation of the Hippo pathway by miR-122 during liver development.

Liver development is a highly complex process that is regulated by the orchestrated interplay of epigenetic regulators, transcription factors, and microRNAs (miRNAs). Owing to the lack of global in vivo targets of all miRNAs during liver development, the mechanisms underlying the dynamic control of hepatocyte differentiation by miRNAs remain elusive. Here, using Argonaute (Ago) high-throughput sequencing of RNA isolated by crosslinking immunoprecipitation (HITS-CLIP) in the mouse liver at different developmental stages, we characterized massive Ago-binding RNAs and obtained a genome-wide map of liver miRNA-mRNA interactions. The dynamic changes of five clusters of miRNAs and their potential targets were identified to be differentially involved at specific stages, a dozen of high abundant miRNAs and their epigenetic regulation by super-enhancer were found during liver development. Remarkably, miR-122, a liver-specific and most abundant miRNA in newborn and adult livers, was found by its targetome and pathway reporter analyses to regulate the Hippo pathway, which is crucial for liver size control and homeostasis. Mechanistically, we further demonstrated that miR-122 negatively regulates the outcomes of the Hippo pathway transcription factor TEAD by directly targeting a number of hippo pathway regulators, including the coactivator TAZ and a key factor of the phosphatase complex PPP1CC, which contributes to the dephosphorylation of YAP, another coactivator downstream of the Hippo pathway. This study identifies for the first time the genome-wide miRNA targetomes during mouse liver development and demonstrates a novel mechanism of terminal differentiation of hepatocytes regulated by the miR-122/Hippo pathway in a coordinated manner. As the Hippo pathway plays important roles in cell proliferation and liver pathological processes like inflammation, fibrosis, and hepatocellular carcinoma (HCC), our study could also provide a new insight into the function of miR-122 in liver pathology.

Localized Photothermal Ablation Therapy of Obstructive Rectal Cancer Using a Nanofunctionalized Stent in a Mouse Model.

The self-expanding metal stent (SEMS) is a versatile, palliative treatment method for unresectable, malignant, non-vascular strictures. Colorectal cancer (CRC) is one of the candidates for the application of the SEMS, in combination with the photothermal ablation (PTA) technique that enhances its therapeutic efficacy. The objective of this study was to investigate the efficacy of stent-mediated PTA therapy in an endoscopy-guided, orthotopic rectal cancer model. A total of 30 of 40 mice with the tumor size of grade 4 were included and were divided into three groups of 10 mice each. Group A underwent a gold nanoparticle (AuNP)-coated SEMS but no near-infrared (NIR) irradiation, group B received an uncoated control SEMS with NIR irradiation, and group C received a AuNP-coated SEMS and NIR irradiation together. Colonoscopy and in vivo imaging, immunohistochemical analysis, and quantitative reverse-transcription polymerase chain reaction of major tumor markers were performed. Stent placement and PTA were technically successful using colonoscopy. The tumor grade reduction after PTA is significant in group C, compared with groups A or B (p < 0.001). Molecular analysis validated this observation with a significantly reduced Mapk1 proliferation marker or increased Jnk expression. Histological analysis confirmed the localized PTA therapy using AuNP-coated SEMS profoundly ablated tumor outgrowth through the stent. Our results indicate that this novel strategy of localized PTA therapy could be a promising option for palliative treatment of CRC and to support prolonged stent patency with a decreased tumor volume.

Risk factors for acute kidney injury following coronary artery bypass graft surgery in a Chinese population and development of a prediction model.

BACKGROUND: Acute kidney injury (AKI) after coronary artery bypass graft (CABG) surgery is associated with significant morbidity and mortality. This retrospective study aimed to establish a risk score for postoperative AKI in a Chinese population. METHODS: A total of 1138 patients undergoing CABG were collected from September 2018 to May 2020 and divided into a derivation and validation cohort. AKI was defined according to the Kidney Disease Improving Global Outcomes (KDIGO) criteria. Multivariable logistic regression analysis was used to determine the independent predictors of AKI, and the predictive ability of the model was determined using a receiver operating characteristic (ROC) curve. RESULTS: The incidence of cardiac surgery-associated acute kidney injury (CSA-AKI) was 24.17%, and 0.53% of AKI patients required dialysis (AKI-D). Among the derivation cohort, multivariable logistic regression showed that age ≥ 70 years, body mass index (BMI) ≥ 25 kg/m2, estimated glomerular filtration rate (eGFR) ≤ 60 mL/min per 1.73 m2, ejection fraction (EF) ≤ 45%, use of statins, red blood cell transfusion, use of adrenaline, intra-aortic balloon pump (IABP) implantation, postoperative low cardiac output syndrome (LCOS) and reoperation for bleeding were independent predictors. The predictive model was scored from 0 to 32 points with three risk categories. The AKI frequencies were as follows: 0-8 points (15.9%), 9-17points (36.5%) and ≥ 18 points (90.4%). The area under of the ROC curve was 0.730 (95% CI: 0.691-0.768) in the derivation cohort. The predictive index had good discrimination in the validation cohort, with an area under the curve of 0.735 (95% CI: 0.655-0.815). The model was well calibrated according to the Hosmer-Lemeshow test (P = 0.372). CONCLUSION: The performance of the prediction model was valid and accurate in predicting KDIGO-AKI after CABG surgery in Chinese patients, and could improve the early prognosis and clinical interventions.

[Online moisture detection technology and its application prospect in drying of traditional Chinese medicine].

Drying is one of the most common unit operations in the production of traditional Chinese medicine. The drying process of traditional Chinese medicine materials is accompanied by the dynamic reduction of water content. As a key index to determine the end of the drying process, the moisture content of materials plays an important role in improving drying efficiency and saving energy. Recently, the drying process of traditional Chinese medicine is mostly monitored by offline detection, and there are few reports of online moisture detection applications. In this paper, the principle and current application of online inspection technology for the material drying process in different fields were introduced. The significance of online detection technology in drying of traditional Chinese medicine was also analyzed. Meanwhile, the application prospect of online detection technology in the field of drying of traditional Chinese medicine was predicted. In response to urgent transformation and upgrading of the traditional Chinese medicine manufacturing industry, the application of online moisture detection technology is expected to be a key breakthrough in the intelligent upgrading of traditional Chinese medicine drying technology and equipment.

Chlorogenic acid enhances autophagy by upregulating lysosomal function to protect against SH-SY5Y cell injury induced by H2O2.

Autophagy serves an important role in amyloid-ß (Aß) metabolism and τ processing and clearance in Alzheimer's disease. The progression of Aß plaque accumulation and hyperphosphorylation of τ proteins are enhanced by oxidative stress. A hydrogen peroxide (H2O2) injury cell model was established using SH-SY5Y cells. Cells were randomly divided into normal, H2O2 and chlorogenic acid (5-caffeoylquinic acid; CGA) groups. The influence of CGA on cell viability was evaluated using a Cell Counting Kit-8 assay and cell death was assessed using Hoechst 33342 nuclear staining. Autophagy induction and fusion of autophagic vacuoles assays were performed using monodansylcadaverine staining. Additionally, SH-SY5Y cells expressing Ad-mCherry-green fluorescent protein-LC3B were established to detect autophagic flow. LysoTracker Red staining was used to evaluate lysosome function and LysoSensor™ Green staining assays were used to assess lysosomal acidification. The results demonstrated that CGA decreased the apoptosis rate, increased cell viability and improved cell morphology in H2O2-treated SH-SY5Y cells. Furthermore, CGA alleviated the accumulation of autophagic vacuoles, reduced the LC3BII/I ratio and decreased P62 levels, resulting in increased autophagic flux. Additionally, CGA upregulated lysosome acidity and increased the expression levels of cathepsin D. Importantly, these effects of CGA on H2O2-treated SH-SY5Y cells were mediated via the mTOR-transcription factor EB signaling pathway. These results indicated that CGA protected cells against H2O2-induced oxidative damage via the upregulation of autophagosomes, which promoted autophagocytic degradation and increased autophagic flux.

Clinical characteristics and risk factors for fatal outcome of patients receiving Sun's procedure after previous cardiac surgery.

BACKGROUND: Cardiac reoperation has always been a difficult problem in clinical practice. Because of the difficulty of operation, the incidence of complications and mortality rate is high. Secondary aortic surgery, especially the reoperation involving arch, has higher risk and is more difficult for patients with renal failure. Sun's operation (total arch replacement + stent elephant nose) has achieved good results in the treatment of diseases involving aortic arch, and occupies an important position in the treatment of patients with secondary arch lesions after cardiac surgery. METHODS: A total of 395 patients with a history of cardiac surgery were recorded in our center from January 1, 2009 to December 31, 2017, among whom 118 (30.1%) patients underwent aortic reoperation via the original incision using Sun's aortic procedure owing to postoperative great vessel disease. We analyzed the clinical data and survival time, and used Cox regression to analyze the risk factors for 30-day mortality as well as long term mortality. RESULTS: The interval between the last operation and the present operation was 0.08-19 years. Sixteen patients died within 30 days after operation and the average mortality rate was 13.6%. During the follow-up period, 28 patients died, with the mortality rate of 23.7%. As of December 31, 2017, the longest survival time was 9.36 years, and the survival time of 70 patients was more than 3.05 years. The main risk factor associated with the 30-day survival was cardiopulmonary bypass (CPB) time. The longer the CPB time was, the greater the risk of death was. The main risk factors associated with the long-term survival were CPB time and 24-h bleeding volume. The longer the CPB time was, the more the 24-h bleeding volume was, the higher long-term mortality rate was. CONCLUSION: The second Sun's operation, as a surgical treatment after cardiac surgery, showed a high survival rate, with long survival time and good curative effect. CPB is the main risk factor for the 30-day survival state after operation, and CPB time and 24-h bleeding volume are the main risk factors for the long-term survival state after operation.

Ligustilide alleviates neurotoxicity in SH-SY5Y cells induced by Aß25-35 via regulating endoplasmic reticulum stress and autophagy.

Ligustilide is a phenolic compound isolated from Asian plants of Umbelliferae family. This study was aimed at exploring the neuroprotective effects of Ligustilide from the perspective of endoplasmic reticulum stress (ERS) and autophagy. The Alzheimer's disease (AD) cell models were constructed by SH-SY5Y cell line, which was exposed to 20 µM Aß25-35 . CCK-8 was used to evaluate the cell viability of Ligustilide on AD cell model. Hoechst staining and LysoTracker Red were used to test the cell apoptosis and Lysosome function, respectively. ERS in living cells were detected by Thioflavin T. The expression of autophagy-related proteins (LC3B-II/I, P62/SQSTM1, Beclin1, and Atg5), ERS marker proteins (PERK, GRP78, and CHOH), and apoptosis proteins (Bax, Bcl-2, and Caspase-12) were analyzed by Western blot analyses. Aß25-35 could induce ERS and autophagy in a time-dependent manner in SH-SY5Y cells. We demonstrated that Ligustilide significantly decreased the rate of apoptosis, and improved the viability of cells. Simultaneously, Ligustilide effectively modulated ERS via inhibiting the over-activation of GRP78/PERK/CHOP signaling pathway. In addition, Ligustilide alleviated the accumulation of autophagy vacuoles, reduced the ratio of LC3B-II/I and the level of P62/SQSTM1. Ligustilide significantly up-regulated lysosomal acidity and the expression of Cathepsin D (CTSD). Ligustilide could rescue lysosomal function to promote autophagy flux and inhibit the over-activation of ERS. This finding may contribute to the development of new therapeutic strategies for AD.

Drinking water temperature affects cognitive function and progression of Alzheimer's disease in a mouse model.

Lifestyle factors may affect mental health and play a critical role in the development of neurodegenerative diseases including Alzheimer's disease (AD). However, whether the temperatures of daily beverages have any impact on cognitive function and AD development has never been studied. In this study, we investigated the effects of daily drinking water temperatures on cognitive function and AD development and progression in mice and the underlying mechanisms. Cognitive function of mice was assessed using passive avoidance test, open field test, and Morris water maze. Wild-type Kunming mice receiving intragastric water (IW, 10 mL/kg, 2 times/day) at 0 °C for consecutive 15 days displayed significant cognitive defects accompanied by significant decrease in gain of body weight, gastric emptying rate, pepsin activity, and an increase in the energy charge in the cortex when compared with mice receiving the same amount of IW at 25 °C (a temperature mimicking most common drinking habits in human), suggesting the altered neuroenergetics may cause cognitive decline. Similarly, in the transgenic APPwse/PS1De9 familial AD mice and their age- and gender-matched wild-type C57BL/6 mice, receiving IW at 0 °C, but not at 25 °C, for 35 days caused a significant time-dependent decrease in body weight and cognitive function, accompanied by a decreased expression of PI3K, Akt, the glutamate/GABA ratio, as well as neuropathy with significant amyloid lesion in the cortex and hippocampus. All of these changes were significantly aggravated in the APPwse/PS1De9 mice than in the control C57BL/6 mice. These data demonstrate that daily beverage at 0 °C may alter brain insulin-mediated neuroenergetics, glutamate/GABA ratio, cause cognitive decline and neuropathy, and promote AD progression.

The Establishment of a Fast and Safe Orthotopic Colon Cancer Model Using a Tissue Adhesive Technique.

PURPOSE: We aimed to develop a novel method for orthotopic colon cancer model, using tissue adhesive in place of conventional surgical method. MATERIALS AND METHODS: RFP HCT 116 cell line were used to establish the colon cancer model. Fresh tumor tissue harvested from a subcutaneous injection was grafted into twenty nude mice, divided into group A (suture method) and group B (tissue adhesive method). For the group A, we fixed the tissue on the serosa layer of proximal colon by 8-0 surgical suture. For the group B, tissue adhesive (10 µL) was used to fix the tumor. The mortality, tumor implantation success, tumor metastasis, primary tumor size, and operation time were compared between the two groups. Dissected tumor tissue was analyzed for the histology and immunohistochemistry. Also, we performed tumor marker analysis. RESULTS: We observed 30% increase in graft success and 20% decrease in mortality, by using tissue adhesive method, respectively. The median colon tumor size was significantly increased by 4 mm and operation time was shortened by 6.5 minutes. The H&E showed similar tumor structure between the two groups. The immunohistochemistry staining for cancer antigen 19-9, carcinoembryonic antigen, cytokeratin 20, and Ki-67 showed comparable intensities in both groups. Real-time quantitative reverse transcription analysis showed eight out of nine tumor markers are unchanged in the tissue adhesive group. Western blot indicated the tissue adhesive group expressed less p-JNK (apototic marker) and more p-MEK/p-p38 (proliferation marker) levels. CONCLUSION: We concluded the tissue adhesive method is a quick and safe way to generate orthotopic, colon cancer model.

Prophylactic intra-aortic balloon pump in patients with left main disease undergoing off-pump coronary artery bypass grafting.

BACKGROUND: Preventive intra-aortic balloon pump (IABP) for high-risk patients with stable hemodynamics is controversial, and its definition of high-risk is still unclear. This study aimed to investigate the effect of prophylactic IABP on the early outcome of left main disease (LMD) patients receiving off-pump coronary artery bypass grafting (OPCABG) with stable hemodynamics. METHODS: From January 2013 to April 2020, 257 consecutive patients who underwent OPCABG through sternotomy were enrolled in this study. All LMD patients (greater than 70%) had stable hemodynamics (BP>100 mmHg without vasoconstrictor substance infusion). Early outcomes of 125 patients with prophylactic IABP (IABP group) and 132 patients without IABP (Control group) were compared in this study. RESULTS: IABP did not show favorable effect on the conversion to CPB (RR 0.63, 95%CI 0.05-7.89, P = 0.7211), perioperative MI (RR 0.69, 95%CI 0.22-2.12, P = 0.5163), mortality (RR 0.65, 95%CI 0.04-10.25, P = 0.7608) or the composite end of the conversion, MI and mortality (RR 0.63, 95%CI 0.23-1.74, P = 0.3747). There was greater incidence of prolonged ventilation in IABP after adjustment (RR2.16, 95%CI 1.12-4.18, P = 0.0221). There was no IABP-related mortality or limb ischemia. CONCLUSION: No significant difference in early outcomes was observed in hemodynamically stable patients with LMD between prophylactic IABP group and control group. Prophylactic IABP may be unnecessary in patients with LMD undergoing OPCABG.

Does preoperative serum creatinine affect the early surgical outcomes of acute Stanford type A aortic dissection?

BACKGROUND: Acute Stanford type A aortic dissection is a lethal disease requiring surgery. Evidence regarding the effects of preoperative creatinine in mortality is limited, and few studies have evaluated the effect of postoperative dialysis treatment on it. METHODS: In this cohort study, we continuously recruited 632 surgical patients who were treated for acute type A aortic dissection in our hospital between January 2015 and May 2017. The preoperative level of serum creatinine was measured. All patients were followed up after surgery for 30 days to determine early mortality. RESULTS: The 30-day mortality after surgery increased with elevated levels of preoperative serum creatinine. Median (interquartile range) serum creatinine levels in survivors were 9.61 µmol/dL (7.28-12.62 µmol/dL) versus 13.41 µmol/dL (10.28-20.63 µmol/dL) in death (p < 0.01). Adjusted odds ratios for increasing per µmol/dL serum creatinine were 1.09 (95% confidence interval, 1.03-1.15). We also found that the effect of preoperative creatinine on 30-day mortality was diminished by dialysis treatment after surgery. CONCLUSION: Preoperative serum creatinine predicts outcome in patients undergoing surgery for Stanford type A aortic dissection, and postoperative dialysis treatment can reduce its hazard.

Morphine-induced RACK1-dependent autophagy in immortalized neuronal cell lines.

BACKGROUND AND PURPOSE: Autophagy is a critical cellular catabolic process in cell homoeostasis and brain function. Recent studies indicate that receptor for activated C kinase 1 (RACK1) is involved in autophagosome formation in Drosophila and mice, and that it plays an essential role in morphine-associated memory. However, the exact mechanism of the role of RACK1 in morphine-induced autophagy is not fully understood. EXPERIMENTAL APPROACH: SH-SY5Y cells were cultured and morphine, rapamycin, 3-methyladenine and RACK1 siRNA were used to evaluate the regulation of RACK1 protein in autophagy. Western blotting and immunofluorescence were used to assess protein expression. KEY RESULTS: Activation of autophagy (i.e. autophagosome accumulation and an increase in the LC3-II/LC3-I ratio) induced by morphine contributes to the maintenance of conditioned place preference (CPP) memory in mice. Moreover, morphine treatment significantly increased Beclin-1 expression and decreased the p-mTOR/mTOR and SQSTM1/p62 levels, whereas knockdown of RACK1 prevented morphine-induced autophagy in vitro. Furthermore, we found that in the mouse hippocampus, knockdown of RACK1 also markedly suppressed morphine-induced autophagy (decreased LC3-II/LC3-I ratio and increased p-mTOR/mTOR ratio). Importantly, morphine-induced autophagy in a RACK1-dependent manner. Conversely, morphine-induced RACK1 upregulation in vitro is partially inhibited by autophagy feedback. CONCLUSIONS AND IMPLICATIONS: Our findings revealed a critical role for RACK1-dependent autophagy in morphine-promoted maintenance of CPP memory in mice and supported the notion that control of RACK1-dependent autophagic pathways may become an important target for novel therapeutics for morphine-associated memory.