Memory/active T cell activation is associated with immunotherapeutic response in fumarate hydratase-deficient renal cell carcinoma.

PURPOSE: Fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) is a rare and lethal subtype of kidney cancer. However, the optimal treatments and molecular correlates of benefits for FH-deficient RCC are currently lacking. EXPERIMENTAL DESIGN: A total of 91 patients with FH-deficient RCC from 15 medical centers between 2009 and 2022 were enrolled in this study. Genomic and bulk RNA sequencing (RNA-seq) were performed on 88 and 45 untreated FH-deficient RCCs, respectively. Single-cell RNA-seq was performed to identify biomarkers for treatment response. Main outcomes included disease-free survival (DFS) for localized patients, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) for metastatic patients. RESULTS: In the localized setting, we found that a cell cycle progression signature enabled to predict disease progression. In the metastatic setting, first-line immune checkpoint inhibitor plus tyrosine kinase inhibitor (ICI+TKI) combination therapy showed satisfactory safety and was associated with a higher ORR (43.2% vs. 5.6%), apparently superior PFS (median PFS: 17.3 vs. 9.6 months, P=0.016) and OS (median OS: not reached vs. 25.7 months, P=0.005) over TKI monotherapy. Bulk and single-cell RNA-seq data revealed an enrichment of memory and effect T cells in responders to ICI plus TKI combination therapy. Furthermore, we identified a signature of memory and effect T cells that was associated with the effectiveness of ICI plus TKI combination therapy. CONCLUSIONS: ICI plus TKI combination therapy may represent a promising treatment option for metastatic FH-deficient RCC. A memory/active T cell-derived signature is associated with the efficacy of ICI+TKI but necessitates further validation.

Acceleration or retardation by a magnetic field of the anodic processes of iron in molybdate-bearing chloride solutions.

The modulation by a horizontal magnetic field of the anodic processes of iron in molybdate-bearing chloride solutions is determined. The magnetic field can accelerate or retard the anodic reaction depending on the rate-controlling steps at specified electrode potentials. The anodic current density arising from uniform dissolution from open or semi-open pits is increased by the magnetic field. The current density originating from occluded pits can be decreased by the magnetic field, where autocatalysis has a dominant effect on the pitting rate. The effect of the magnetic field on the pitting corrosion is a combination of the influence on electrochemical reactions at the interfaces of the pits and the disturbance of the autocatalysis process inside the pit enclave through the magnetohydrodynamic (MHD) effect. Micro-MHD effects for specific locations and macro-MHD effects for pitting systems are recommended to illustrate the magnetic effect on localized corrosion phenomena at various combinations of potentials and solution compositions.

Paeoniflorin alleviates AngII-induced cardiac hypertrophy in H9c2 cells by regulating oxidative stress and Nrf2 signaling pathway.

Cardiac hypertrophy is frequently associated with ventricular dysfunction and heart failure. Paeoniflorin, has been widely used to treat cardiovascular dysfunction-related diseases. However, the underlying mechanism has been unclear. Here, we investigated the potential inhibitory effects and mechanism of paeoniflorin on oxidative stress of cardiac hypertrophy induced by angiotensin II (AngII) in vitro. Using MTS assay, qRT-PCR, WGA staining assay, and western blot, different dosages (50-400 µM) of paeoniflorin were utilized to examine the antihypertrophy effects on H9c2 cells. Western blot examination revealed the presence of apoptosis-related proteins Bax, Bcl2, and Cytc, antioxidative stress-related proteins Nrf2, HO-1, SOD, and CAT, and mitophagy-related proteins PINK1 and Parkin. qRT-PCR was used to detect the mRNA expression of Bax, Bcl2, Nrf2, and HO-1. TUNEL, caspase3/9 enzyme viability, and MDA, T-AOC, and superoxide levels were all evaluated using commercial kits.The fluorescent probes DCFH-DA and JC-1 were employed to measure cellular ROS and MMP levels. Nrf2 siRNA was utilized to investigate Nrf2's role in paeoniflorin-treated cardiac hypertrophy. Paeoniflorin dramatically reduced cell section area (CSA) and hypertrophic marker (ANP, BNP) expression while inhibiting oxidative stress by modulating ROS and MDA, CAT, SOD, and T-AOC levels. Furthermore, in AngII-induced cardiomyocyte hypertrophy, paeoniflorin restores H9c2 apoptosis by restoring Bax, Bcl-2 Cyt-C, Caspase 3, and Caspase 9 levels. Paeoniflorin also restored Nrf2/HO-1 and PINK1/Parkin expression, and its anti-AngII activities were mediated by Nrf2, which was regulated by Nrf2 knockdown. In conclusion, Our data confirm that paeoniflorin alleviates cardiac hypertrophy through modulating oxidative stress and Nrf2 signaling pathway in vitro.

The formins inhibitor SMIFH2 inhibits the cytoskeleton dynamics and mitochondrial function during goat oocyte maturation.

The cytoskeleton plays a crucial role in facilitating the successful completion of the meiotic maturation of oocytes. Its influence extends to the process of oocyte nuclear maturation and the proper functioning of various organelles during cytoplasmic maturation. The formin family of proteins plays a crucial role in the molecular regulation of cytoskeletal assembly and organization; however, its role in goat oocytes are not fully understood. Our study examined the inhibition of formins activity, which revealed its crucial role in the maturation of goat oocytes. We observed that the inhibition of formins resulted in meiotic defects in goat oocytes, as evidenced by the hindered extrusion of polar bodies and the expansion of cumulus cells. Additionally, the oocytes exhibited altered actin dynamics and compromised spindle/chromosome structure upon formins inhibition. The results of the transcriptomic analysis highlighted a noteworthy alteration in the mRNA levels of genes implicated in mitochondrial functions and oxidative phosphorylation in formins inhibited oocytes. Validation experiments provided evidence that the meiotic defects observed in these oocytes were due to the excessive early apoptosis induced by reactive oxygen species (ROS). Our findings demonstrate that the involvement of formins in sustaining the cytoskeletal dynamics and mitochondrial function is crucial for the successful meiotic maturation of goat oocytes.

Experimental study on the suppressive effect of B3GNT3 on the apoptosis of lung adenocarcinoma cells and its application in early screening for lung adenocarcinoma.

Background: Lung adenocarcinoma, as a common histological type in lung cancer, the overall survival is very low, and the prognosis is poor because it is difficult to find and easily recurs. Therefore, this study aimed to explore the role of the secreted protein beta-1,3-N-acetylglucosaminyltransferase 3 (B3GNT3) in the development of lung adenocarcinoma and to evaluate its potential significance for early clinical biomarker screening. Methods: The mRNA expression profiles of patients with lung adenocarcinoma and normal controls were analyzed via The Cancer Genome Atlas (TCGA) database. Serum samples of clinical lung cancer patients and healthy people were obtained, and the differences in B3GNT3 expression in different stages of lung adenocarcinoma and in healthy tissues were compared. Kaplan-Meier (K-M) curves were drawn to clarify the influence of high and low expression of B3GNT3 on the prognosis of patients. Peripheral blood samples from patients with lung adenocarcinoma and healthy people were obtained clinically, and receiver operating characteristic (ROC) curves were drawn to clarify the sensitivity and specificity of B3GNT3 expression for the diagnosis of lung adenocarcinoma. Lung adenocarcinoma cells were cultured in vitro, the expression of B3GNT3 was knocked down by lentivirus infection. The expression of the apoptosis-associated genes was detected by reverse transcription-polymerase chain reaction (RT-PCR). Results: The secreted protein B3GNT3 is significantly differentially expressed in the serum of patients with lung adenocarcinoma versus normal controls. Subgroup analysis according to lung adenocarcinoma clinical stage showed that the higher the clinical stage of lung adenocarcinoma was, the higher the B3GNT3 expression. Enzyme-linked immunosorbent assay (ELISA) revealed that B3GNT3 expression was significantly increased in the serum of patients with lung adenocarcinoma and significantly decreased after surgery. By inhibiting programmed cell death-ligand 1 (PD-L1), the level of apoptosis was significantly increased and the proliferative capacity was significantly inhibited. In contrast, the level of apoptosis was significantly increased and the proliferation ability was significantly inhibited after simultaneous overexpression of B3GNT3 and inhibition of PD-L1. Conclusions: High expression of the secreted protein B3GNT3 in lung adenocarcinoma is closely related to prognosis and can serve as a potential biological marker for the early screening of lung adenocarcinoma.

An electrochemical method for measuring magnetic flux density.

A magneto-electrochemical method is designed and validated for measuring magnetic flux density. This method is based on the correlation of the change of open circuit potential to the flux density of an applied magnetic field. Electrochemical systems with iron in ferric solutions are selected for demonstrating the validity of the proposed methods. Magnetic flux density can be measured with this method by voltmeter without using a Tesla meter.

Impact of cardiovascular disease on health-related quality of life among older adults in eastern China: evidence from a national cross-sectional survey.

Objective: This study explores the health-related quality of life (HRQoL) scores of Chinese older adults with Cardiovascular Disease(CVD) using the EQ-5D-3L, the aim of this study is to investigate the association between health and HRQoL in older adults with CVD. Methods: The data for this study were obtained from a cross-sectional study involving older adults residing in Chinese communities The EQ-5D-3L is used to measure the HRQoL scores in the older adults with CVD. One-way analyses were conducted using the Wilcoxon rank sum test and the Kruskal-Wallis H test to assess differences between groups. A binary logistic regression model was employed to analyze the influence each variable has on the presence of "any problem" on each dimension of EQ-5D-3L in older adults with CVD. An ordinal least squares (OLS) model is used to assess the relationship between older adults with CVD and HRQoL. Results: The mean EQ-5D-3L score for older adults with CVD is 0.774. 40.0% of older adults with CVD reported problems with pain/discomfort, followed by Mobility (35.9%), Self-care (31.5%), and Anxiety/depression (17.0%). Binary logistic regression models show that financial resources were the main factor influencing the five dimensions of EQ-5D-3L. The OLS model further indicates that younger age, financial resources, and a lower number of chronic conditions among older adults with CVD are associated with higher HRQoL scores. Conclusion: Chinese older adults with CVD have low HRQoL scores. Variousfactors influence both overall HRQoL scores and scores on each EQ-5D-3L dimension. This study is helpful in enhancing society's attention to the HRQoL of older adults with CVD and taking targeted measures to improve them.

Curvilinear relationship between burnout and work engagement among staff in community services for the elderly: A correlation study.

Objective: To investigate whether there is a curvilinear relationship between burnout and work engagement among staff in Chinese community services for the elderly. Methods: A stratified whole-group random sampling method was used to survey 244 staff members from eight communities in two cities. Data were collected using the Maslach Burnout Inventory scale (MBI) and the Utrecht Work Engagement Scale- 9 (UWES- 9). The curve estimation method explored the functional model of burnout and work engagement scales. Results: Two hundred forty-four staff members completed the survey. Burnout, depersonalization (DP), and personal accomplishment (PA) were found to be related to work engagement in a cubic function (R2 = 0.166, P < 0.05), (R2 = 0.061, P < 0.05), and (R2 = 0.2230, P < 0.05), respectively. There was no statistically significant relationship between emotional exhaustion (EE) and work engagement (P > 0.05). "Personal Accomplishment" is related to work engagement in a U-shaped curve. Conclusions: There was a cubic function relationship between burnout and work engagement, where "personal accomplishment" was related to work engagement in a U-shaped curve. Therefore, the government and related service organizations should understand the impact of different levels of burnout on work engagement and take targeted measures to alleviate burnout and improve work engagement by targeting emotions and stroke.

Validation of a three-dimensional printed dry lab pancreaticojejunostomy model in surgical assessment: a cross-sectional study.

OBJECTIVES: Until now, there have been few tools to evaluate whether a surgeon was technically ready to perform a safe pancreaticojejunostomy (PJ). In the current study, we aimed to evaluate whether a three-dimensional model could mimic a real surgical situation and distinguish between surgeons of different levels of experiences. DESIGN: A three-dimensional PJ dry laboratory model was printed. Eight experienced pancreatic surgeons were tasked to evaluate the appearance and tactile sensation of the model. Proficiency was scored based on 15 surgeons with various levels of pancreatic experience performing a PJ on the three-dimensional model. Additionally, the time of manipulation and NASA Task Load Index (NASA-TLX) scores were recorded for each operation. SETTING: Our study was conducted in multimedical centre in China. RESULTS: Compared with real surgical situations, this model had similar appearance (3.96±0.55 out of five points) and tactile sensation (3.85±0.46 out of five points) according to the expert evaluation. Additionally, the chief surgeon group scored the best in proficiency (based on NASA-TLX scores and operative time), and there were statistical differences for performances among surgeons of various levels (p<0.05). CONCLUSION: The three-dimensional PJ model could mimic a real surgical situation and can distinguish between surgeons of different levels of experiences.

ARID1A deficient undifferentiated spindle cell and rhabdoid sarcoma of the prostate: report of a unique case with emphasis on diagnostic implications.

BACKGROUND: SWItch Sucrose Non-Fermentable (SWI/SNF) chromatin-remodeling complex functions collectively as a tumor suppressor and the inactivation of any of its constituent components is frequently associated with tumor initiation and/or progression. Most SWI/SNF deficient tumors share common rhabdoid morphology. ARID1A is the most frequently dysregulated SWI/SNF subunit in human cancer and inactivation of ARID1A is frequent across carcinomatous types while very rarely drives the tumorigenesis of sarcomas. Herein, we report a rare case of primary prostatic undifferentiated spindle cell sarcoma with focal rhabdoid morphology, harboring biallelic inactivation of ARID1A detected by next-generation sequencing with complete loss of ARID1A expression by immunohistochemistry. CASE PRESENTATION: The patient is a 58-year-old man who presented with dysuria and obstructive voiding symptoms for 3 month and was found to have a large, ill-defined, prostatic mass lesion with circumferential extension into the rectal wall on imaging studies. A needle biopsy showed a spindle cell undifferentiated sarcoma of the prostate and the patient was treated by chemotherapy of combined etoposide and cisplatin for 2 months. A subsequent imaging study showed that the tumor was significantly enlarged, and the patient underwent laparoscopically radical prostatectomy. Gross examination showed a disrupted, 10 × 7 × 5 cm, solid and cystic mass involving almost the entire prostate and sparing the seminal vesicle glands. Histologic examination showed that tumor was composed mainly of mildly atypical, oval to spindle-shaped cells, arranged in sheets and fascicles or herringbone-like patterns within a small amount of edematous to myxoid, vascularized stroma. Notably, groups of discohesive rhabdoid tumor cells with eccentric nuclei, prominent nucleoli, and abundant globular cytoplasm were observed. There were prominent mitotic figures, multifocal geographic necroses, and foci of lymphovascular invasion. Immunohistochemistry showed that the tumor cells were diffusely positive for TLE-1 and vimentin and focally positive for epithelial membrane antigen, AE1/3, Cam5.2, SATB2, and CD34 (all in less than 10% tumor cells). Next-generation sequencing showed biallelic inactivation mutation of ARID1A; the predicted inactivating effect of ARID1A deletion was confirmed by immunohistochemical staining. After the surgery, the patient received an alternative combined chemotherapy of doxorubicin and ifosfamide for 5 months. The patient died 9 months after initial presentation due to extensive abdominal metastases. CONCLUSIONS: We report an ARID1A deficient undifferentiated spindle cell and rhabdoid sarcoma of the prostate, adding to the growing spectrum of SWI/SNF driven undifferentiated sarcoma. Rhabdoid cells can be a helpful morphological clue for promoting molecular and immunohistochemical analyses for deficiency of SWI/SNF subunits, in the diagnostic workup of undifferentiated neoplasms featuring epithelioid or rhabdoid morphology.

Utilisation willingness for institutional care by the disabled elderly and its influencing factors based on Andersen's model: a cross-sectional survey of Henan, China.

OBJECTIVE: To explore the factors that influence institutional care for the disabled elderly in China and the key factors that influence individuals based on the Andersen model. DESIGN: Cross-sectional survey. SETTING: The research was conducted in 18 cities in Henan Province, China. MAIN OUTCOME MEASURES: A multistage, stratified sampling design was employed. The χ2 test was used to compare the differences in basic information of the disabled elderly. A binary Logit model was used to examine the factors influencing the willingness to institutionalise elderly people with disabilities. The determinants of willingness to care in an institution were also explored in a stratified study by gender, age and region to identify the key differences affecting institutionalisation. The Andersen model was used as the theoretical framework to infer the impact strength of each model. RESULTS: Of the 2810 disabled elderly people in Henan, China, 7.4% of the elderly had a willingness for institutional care. In the binary logistic regression analysis, whether living alone (OR (95% CI)=0.596 (0.388 to 0.916)), medical payment method (basic medical insurance for urban employees: OR (95% CI)=2.185 (1.091 to 4.377)), having mental illness (OR (95% CI)=2.078 (1.044 to 4.137)) had a statistically significant difference (p<0.05) on the impact on the willingness of the disabled elderly to receive institutional care. Validation of the fitted coefficients of the model revealed that the needs factor had the most significant effect on the enabling variable, while the predisposing factor had more minerally effect. CONCLUSIONS: Several factors influence the willingness of the disabled elderly to institutionalise. Therefore, it is recommended that relevant authorities take targeted measures to focus on the disabled elderly to identify more precise elderly care services to deal with the ageing crisis.

Previous School Bullying-Associated Depression in Chinese College Students: The Mediation of Personality.

Previous school bullying was associated with increased risk of depression in students. However, little was known about the role of the Big Five personality traits in this association. The purpose of this study was to investigate the possible mediation by the Big Five personality traits in this association in a large group of Chinese college students, and to provide help for educators to prevent students from serious psychological and mental diseases caused by school bullying. Random stratified cluster sampling was used to survey 2152 college students ranging from freshmen to seniors at three universities in Qiqihar city, Heilongjiang Province, China. The risk factors for previous school bullying included gender, living expenses per month, caregivers, parents often quarreling, and divorced parents. Males were more likely to be bullied at school than females. The influencing factors of depression include gender, caregivers, living expenses per month, frequent parents quarreling, and parental divorce. Females were more prone to depression than males. Depression was significantly correlated with all dimensions of school bullying and the Big Five personality traits (p < 0.05). The Big Five personality traits were found to play a significant mediating role between depression and school bullying in up to 45% of cases involving depression. Our major findings highlighted the promising role of personality-based intervention measures in reducing the risk of depression associated with school bullying in Chinese students.

Perceived participation and autonomy structural relationships among related factors in patients with stroke and hypertension in China: A ISM model approach.

Aims: To explore the structural relationship between perceived participation and autonomy among older adults with stroke and hypertension in home and community-based services (HCBSs) in the eastern coastal region of China. Design: An explorative cross-sectional study. Methods: From July to September 2021, a total of 714 respondents were reported to have stroke and hypertension, and their information was used in the analysis of this study. A multiple linear regression analysis was used to explore the factors influencing factors older adults' perceived participation and autonomy. Using the ISM model, we analyzed the factors affecting social participation in patients with stroke and hypertension and explained the logical relationships and hierarchy among the factors. Results: The mean score of perceived participation was 58.34 ± 27.57. Age, marital status, health insurance, living status, number of children, chronic diseases, sleep time, frequency of outings, and health utility value were significant factors affecting perceived participation and autonomy with stroke and hypertension patients. Among them, health insurance is the direct factor on the surface, age, number of children, chronic diseases, sleep time, frequency of outings, and health utility value are the intermediate indirect factors, and marital status and living status are the deep-rooted factors. Conclusion: By the study that the hierarchical structure provides a visualization of interrelationships and interdependences among the influencing factors of perceived participation and autonomy. It also may be a significant complement to traditional variable-entered approaches and construct an optimized multidimensional perspective of participation and autonomy. Future research should focus on optimizing the living environment of older adults with stroke and hypertension to explore the model of rehabilitative intervention and help patients successfully reintegrate into their families/societies.

Use of Circulating Tumor DNA for the Clinical Management of Metastatic Castration-Resistant Prostate Cancer: A Multicenter, Real-World Study.

BACKGROUND: This study aimed to describe the aberrations of DNA damage repair genes and other important driving genes in Chinese patients with metastatic castration-resistant prostate cancer (mCRPC) using circulating tumor (ctDNA) sequencing and to evaluate the associations between the clinical outcomes of multiple therapies and key genomic alterations in mCRPC, especially DNA damage repair genes. PATIENTS AND METHODS: A total of 292 Chinese patients with mCRPC enrolled from 8 centers. Multigene targeted sequencing was performed on 306 ctDNA samples and 23 matched tumor biopsies. The frequency of genomic alterations were compared with the Stand Up to Cancer-Prostate Cancer Foundation (SU2C-PCF) cohort. The Kaplan-Meier method was used to evaluate progression-free survival (PFS) following standard systemic treatments for mCRPC. Cox regression analyses were performed to determine prognostic factors associated with PFS resulting from treatments for mCRPC. RESULTS: In total, 33 of 36 (91.7%) mutations were found consistently between ctDNA and paired biopsy samples. The most common recurrent genomic alterations were found in AR (34.6%), TP53 (19.5%), CDK12 (15.4%), BRCA2 (13%), and RB1 (5.8%). The frequency of CDK12 alterations (15.4%) in our cohort was significantly higher than that in Western populations (5%-7%). AR amplification and TP53 and/or RB1 alterations were associated with resistance to abiraterone or docetaxel. Patients with a CDK12 defect showed rapid disease progression after abiraterone treatment. However, the clinical outcome after docetaxel treatment was similar between patients with and without CDK12 defects. In multivariate Cox regression analysis, a CDK12 defect was significantly associated with inferior PFS after abiraterone treatment. Patients with a BRCA2 defect showed marked response to both PARP inhibitors and platinum-based chemotherapy. CONCLUSIONS: Our study explored the genomic landscape of Chinese patients with mCRPC at different treatment stages using minimally invasive methods and evaluated the clinical implications of the driver genomic alterations on patients' response to the most widely used therapies for mCRPC. We observed a significantly higher alteration frequency of CDK12 in our cohort compared with the SU2C-PCF cohort.

Dose escalation and expansion (phase Ia/Ib) study of GLS-010, a recombinant fully human antiprogrammed death-1 monoclonal antibody for advanced solid tumors or lymphoma.

BACKGROUND: GLS-010, a novel engineered fully human immunoglobin G4 monoclonal antibody, can specially block the PD-1/PD-L1/2 axis and reactivate the antitumor immunity. AIM: This phase Ia/Ib study was carried out to evaluate the safety, recommended phase II dose (R2PD), and primary antitumor effects of GLS-010 in patients with advanced, refractory lymphoma and solid tumors. METHODS: In phase Ia study, patients with refractory solid tumors and lymphoma enrolled and received GLS-010 at a dose of 1, 4, or 10 mg/kg Q2W; 240 mg Q3W or Q2W. The primary objective was to assess the dose-limiting toxicity (DLT). In phase Ib study, doses were expanded in 9 specific tumors to ensure the R2PD and explore the efficacy. Tumor mutation burden level and PD-L1 expression were also assessed with whole-exome sequencing and immunohistochemistry (SP263), respectively. RESULTS: Up to April 18, 2020, a total of 289 patients (n = 24, phase Ia; n = 265, phase Ib) were enrolled. DLT was not observed in phase Ia part. The T1/2, CLss, and Vd were similar among all dose groups and different tumors. The most common treatment-emergent adverse events (TEAEs) were anemia, leukopenia, elevated alanine aminotransaminase/asparate aminotransferase (ALT/AST), and elevated bilirubin. And hypothyroidism was the most common immune-related adverse event (irAE). The incidence of grade ≥3 TEAE was 39.8%, while grade ≥3 irAE was only 4.5%. Based on safety studies, pharmacokinetics/pharmacodynamics, and preclinical data, 240-mg Q2W was recommended as the expansion dose. The overall objective response rate was 23.6%, with 10 patients achieving complete response. Patients with a high PD-L1 expression level (31.3% Versus. 13.7%, p = 0.012) or t-issue tumor mutation burden level (31.3% Versus. 5.6%, p = 0.009) showed a significantly better response. CONCLUSION: GLS-010 showed acceptable safety profile and favorable clinical response. The dose of 240 mg Q2W was an optimal recommended dose as monotherapy.

Paeoniflorin and Plycyrrhetinic Acid Synergistically Alleviate MPP+/MPTP-Induced Oxidative Stress through Nrf2-Dependent Glutathione Biosynthesis Mechanisms.

Recently, combination therapy has proven to be an effective strategy for treating polygenic/multifactorial/complex disorder such as Parkinson's disease (PD). Here, we hypothesized that dual up-regulation of glutamate cysteine ligase (GCL) catalytic subunit (GCLc) and GCL modifier subunit (GCLm) via nuclear factor E2-related factor (Nrf2) contribute to the antioxidant effect of paeoniflorin (PF) synergistically with glycyrrhetinic acid (GA) (henceforth called PF/GA) in the context of MPP+/MPTP neurotoxicity. Expectedly, CompuSyn synergism/antagonism analysis showed that PF/GA exerts synergistic neuroprotection. Moreover, the antioxidant effect of PF was significantly enhanced by the combined administration of GA, although GA alone did not confer the effect. Mechanistically, PF triggered extracellular signal-regulated kinase (ERK1/2) phosphorylation, resulting in Nrf2 nuclear translocation from cytoplasmic pool via de novo synthesis in MPP+-challenged SH-SY5Y cells. Concomitantly, GA activates Akt which in turn induces nuclear accumulation of Nrf2. Especially, PF/GA up-regulated glutamate-cysteine ligase catalytic subunit (Gclc) and glutamate-cysteine ligase modifier subunit (Gclm) are formed via two separate pathways. Furthermore, these results were confirmed through pathway blockade assays using PD98059 (ERK1/2 inhibitor), LY294002 (phosphatidylinositol-3-kinase inhibitor), and shRNA-induced Nrf2 knockdown. Additionally, using a mouse MPTP-induced model of PD, we demonstrated that PF/GA synergistically ameliorates both motor deficits and oxidative stress in the ventral midbrain. In parallel, PF/GA also up-regulated both GCLc and GCLm expression at levels of transcription and translation. Conversely, antiparkinsonism and antioxidant effects of PF/GA were not observed in Nrf2-knockout MPTP-mice. Collectively, these results show that ERK1/2 and Akt activation contribute to the synergistic antioxidant effect of PF/GA. Hence, PF/GA regimen warrants further preclinical and possible clinical study for PD.

Effect of glycosylated hemoglobin protein molecule in treating diabetes.

The object of this study was to observe and analyze the effect of glycosylated hemoglobin in treating diabetes and provide valuable guidance for clinical treatment. For this purpose, 160 patients treated in our hospital who were definitely diagnosed with diabetes after relevant examinations were classified into the study group. 160 cases with healthy physical examinations for the same period were enrolled as a reference group. Fasting blood glucose and glycosylated hemoglobin levels were measured in both groups, and inter-group comparisons were made. The detection results showed that the study group had significantly higher fasting blood glucose and glycosylated hemoglobin levels than the healthy reference group. The difference was statistically significant (p<0.05). Diabetic patients in the study group were also observed. The results showed that patients with complications had significantly higher fasting blood glucose and glycosylated hemoglobin levels than those without complications. Statistical significance existed, p<0.05. For diabetic patients, glycosylated hemoglobin detection is of great significance in profoundly affecting diabetes diagnosis and treatment and providing positive guidance, which means great value for evaluating disease control effects.

Linc00514 promotes breast cancer metastasis and M2 polarization of tumor-associated macrophages via Jagged1-mediated notch signaling pathway.

BACKGROUND: Tumor-associated macrophages (TAMs) and tumor cells are important components of the tumor microenvironment. M2 polarization of TAMs, which is a major actor in breast cancer malignancy and metastasis, can be induced by breast cancer cells. However, the potential mechanisms of the interaction between breast cancer cells and TAMs remain unclear. METHODS: The candidate breast cancer-associated long non-coding RNAs (lncRNAs) were analyzed using the GEO database. Functional assays, including MTT assay, Transwell assay, and EdU labeling detection, were performed to investigate the oncogenic role of linc00514 in breast cancer progression. The co-culture and ELISA assays were used to assess the role of linc00514 in macrophage recruitment and M2 polarization. RNA immunoprecipitation, RNA pull-down, and luciferase reporter assays were applied to determine the mechanism of linc00514 in breast cancer metastasis. Mouse xenograft models, mouse pulmonary metastatic models, and mouse primary tumor models were used to assess the role of linc00514 in M2 macrophage polarization and breast cancer tumorigenicity. RESULTS: Linc00514 was highly expressed in clinical breast cancer tissues and breast cancer cell lines. Overexpression of linc00514 promoted the proliferation and invasion of breast cancer cells and increased xenograft tumor volumes and pulmonary metastatic nodules. Overexpression of linc00514 also increased the percentage of macrophages expressing M2 markers CD206 and CD163. Mechanistically, linc00514 promoted Jagged1 expression in a transcriptional manner by increasing the phosphorylation of a transcription factor STAT3. Subsequently, Jagged1-mediated Notch signaling pathway promoted IL-4 and IL-6 secretions in breast cancer cells and ultimately inducing M2 polarization of macrophages. CONCLUSION: Linc00514 plays an important role in regulating breast cancer tumorigenicity and M2 macrophage polarization via Jagged1-mediated Notch signaling pathway.

ß-asarone relieves chronic unpredictable mild stress induced depression by regulating the extracellular signal-regulated kinase signaling pathway.

The present study aimed to investigate the effect of ß-asarone treatment in a rat model of depression induced by chronic unpredictable mild stress (CUMS) and to further explore the underlying molecular mechanisms. A rat model of depression was established by subjecting rat to CUMS and treated with various concentrations of ß-asarone (12.5, 25 and 50 mg/kg/day) and fluoxetine (20 mg/kg/day). Next, behavioral tests, including an open field, sucrose preference and forced swimming tests, were performed. In addition, the apoptosis of hippocampal neuronal cells was determined by flow cytometry, gene expression levels were detected by reverse transcription-quantitative polymerase chain reaction and protein levels were determined by western blot assay. The results revealed that ß-asarone significantly mitigated CUMS-induced depression-like behavior, evidenced by the increased sucrose intake, crossing and rearing numbers, and decreased immobility time in the forced swimming test. Furthermore, ß-asarone significantly decreased the apoptosis rate of hippocampal neuronal cells in rats subjected to CUMS. ß-asarone was also found to enhance CREB, BDNF, Trk-B and Bcl-2 levels, and reduce Bad level in the hippocampus of CUMS-treated rats. In addition, the activation of extracellular signal-regulated kinase pathway inhibited by CUMS was promoted by ß-asarone treatment. In conclusion, the present study findings indicated the antidepressant-like effects of ß-asarone on CUMS-induced depression in rats.

Reduced iteration image reconstruction of incomplete projection CT using regularization strategy through Lp norm dictionary learning.

BACKGROUND: For sparse and limited angle projection Computed Tomography (CT), the reconstructed image usually suffers from considerable artifacts due to undersampled data. OBJECTIVE: To improve image reconstruction quality of sparse and limited angle projection CT, this study tested a novel reconstruction algorithm based on Dictionary Learning (DL) from sparse and limited projections. METHODS: The study used signal sparse representation and feature extraction to render the DL technology, which is constrained by L2 and Lp norms, respectively. A Lp Norm Dictionary Learning term is suitable for regular term of objective function for CT image reconstruction. This is helpful for solving the objective function by combining algorithm of ART. Based on these features, the new algorithm of ART-DL-Lp is proposed for CT image reconstruction. The alternate solving strategy of the algorithm of "ART first, then adaptive DL" is provided in sequence. The impact on reconstruction results of ART-DL-Lp at different p values (0 < p < 1) is also considered. RESULTS: For non-ideal projections with noise, the digital experiments show that ART-DL-Lp data were superior to those of ART, SART, and ART-DL-L2. Accordingly, the objective evaluation metrics for non-ideal situation of RMSE, MAE, PSNR, Residuals and SSIM are all better than those of contrasted three algorithms. The metrics curves of ART-DL-Lp algorithm are recorded as the best. In both incomplete projection situations, smaller p-value of ART-DL-Lp algorithm induces more close reconstructed images to the original form and better five objective evaluation metrics. CONCLUSIONS: Overall, the reconstruction efficiency of the proposed ART-DL-Lp for CT imaging using the noisy incomplete projections outperforms ART, SART and ART-DL-L2 algorithms. For ART-DL-Lp algorithm, lower p-values result in better reconstruction performance.