TGFA expression is associated with poor prognosis and promotes the development of cervical cancer.

Cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) are the second most common cancers in women aged 20-39. While HPV screening can help with early detection of cervical cancer, many patients are already in the medium to late stages when they are identified. As a result, searching for novel biomarkers to predict CESC prognosis and propose molecular treatment targets is critical. TGFA is a polypeptide growth factor with a high affinity for the epidermal growth factor receptor. Several studies have shown that TGFA can improve cancer growth and progression, but data on its impact on the occurrence and advancement of CESC is limited. In this study, we used clinical data analysis and bioinformatics techniques to explore the relationship between TGFA and CESC. The results showed that TGFA was highly expressed in cervical cancer tissues and cells. TGFA knockdown can inhibit the proliferation, migration and invasion of cervical cancer cells. In addition, after TGFA knockout, the expression of IL family and MMP family proteins in CESC cell lines was significantly reduced. In conclusion, TGFA plays an important role in the occurrence and development of cervical cancer. Therefore, TGFA may become a new target for cervical cancer treatment.

Expression and immune infiltration studies of IL-33-ST2-NF-κB signaling pathway in prostate cancer.

BACKGROUND: To analyze the expression of interleukin-33 (IL-33), growth-stimulated expression gene 2 (ST2), nuclear factor-kappaB (NF-κB) and immune cell infiltration in prostate cancer, this study aims to provide an experimental basis for the clinical prevention and treatment of prostate cancer. METHODS: The expression of IL-33 in PCa tissues was analyzed using TCGA, TIMER and HPA databases. Using the UALCAN database, the systematic exploration of the relationship between IL-33 and various clinicopathological parameters was conducted. The correlation between IL-33 expression and immune cell infiltration was investigated using TIMER, CIBERSORT and GEPIA databases. To verify these analyses, 22 cases of normal prostate (NP), 76 cases of benign prostatic hyperplasia (BPH), and 100 cases of PCa were recruited. Immunohistochemical staining was performed to examine the expression of IL-33, ST2, NF-κB, and the infiltration of immune cells. Correlations between these factors were then determined. RESULTS: The expression of IL-33, ST2 and NF-κB was significantly lower in PCa tissues compared with NP (p < 0.05). IL-33 was not associated with age in PCa but showed associations with race, molecular characteristics, lymph node metastatic status, TP53 mutation and tumor grade. Furthermore, IL-33 was associated with immune cell infiltration. Positive correlations were observed between IL-33 and ST2 expressions, as well as between IL-33 and CD68+ macrophages in BPH and PCa. CONCLUSIONS: IL-33, ST2 and NF-κB are lowly expressed in PCa tissues, their expression decreases with the increasing malignancy of cancer. IL-33, ST2 and NF-κB are factors associated with PCa immune infiltration. IL-33 has an inhibitory effect on prostate cancer through the IL-33/ST2/NF-κB signalling pathway.

The Effects of Near-Infrared Phototherapy Preirradiation on Lower-Limb Muscle Strength and Injury After Exercise: A Systematic Review and Meta-analysis.

OBJECTIVE: To assess near-infrared preirradiation effects on postexercise lower-limb muscle damage and function and determine optimal dosage. DATA SOURCES: PubMed, Embase, Cochrane Library, EBSCO, Web of Science, China National Knowledge Infrastructure, and Wanfang Data were systematically searched (2009-2023). STUDY SELECTION: Randomized controlled trials of near-infrared preirradiation on lower-limb muscles after fatigue exercise were incorporated into the meta-analysis. Out of 4550 articles screened, 21 met inclusion criteria. DATA EXTRACTION: The included studies' characteristics were independently extracted by 2 authors, with discrepancies resolved through discussion or by a third author. Quality assessment was performed using the Cochrane risk of bias tool and the Grading of Recommendations, Assessment, Development, and Evaluation System. DATA SYNTHESIS: In 21 studies, near-infrared preirradiation on lower-limb muscles inhibited the decline in peak torque (standardized mean difference [SMD], 1.33; 95% confidence interval [CI], 1.08-1.59; p<.001; increasing 27.97±4.87N·m), reduced blood lactate (SMD, -0.2; 95% CI, -0.37 to -0.03; p=.272; decreasing 0.54±0.42mmol/L), decreased creatine kinase (SMD, -2.11; 95% CI, -2.57 to -1.65; p<.001; decreasing 160.07±27.96U/L), and reduced delayed-onset muscle soreness (SMD, -0.53; 95% CI, -0.81 to 0.24; p<.001). Using a 24-hour cutoff revealed 2 trends: treatment effectiveness depended on power and energy density, with optimal effects at 24.16 J/cm2 and 275 J/cm2 for energy, and 36.81 mW/cm2 and 5495 mW/cm2 for power. Noting that out of 21 studies, 19 are from Brazil, 1 from the United States, and 1 from Australia, and the results exhibit high heterogeneity. CONCLUSIONS: Although we would have preferred a more geographic dispersion of laboratories, our findings indicate that near-infrared preirradiation mitigates peak torque decline in lower-limb muscles. Influenced by energy and power density with a 24-hour threshold, optimal energy and power densities are observed at 24.16 J/cm2, 275 J/cm2, 36.81 mW/cm2, and 5495 mW/cm2, respectively. Laser preirradiation also reduces blood lactate, creatine kinase, and delayed-onset muscle soreness.

PPP1R14B is a diagnostic prognostic marker in patients with uterine corpus endometrial carcinoma.

Uterine corpus endometrial carcinoma (UCEC) is one of the most common malignancies of the female genital tract. A recently discovered protein-coding gene, PPP1R14B, can inhibit protein phosphatase 1 (PP1) as well as different PP1 holoenzymes, which are important proteins regulating cell growth, the cell cycle, and apoptosis. However, the association between PPP1R14B expression and UCEC remains undefined. The expression profiles of PPP1R14B in multiple cancers were analysed based on TCGA and GTE databases. Then, PPP1R14B expression in UCEC was investigated by gene differential analysis and single gene correlation analysis. In addition, we performed gene ontology term analysis, Kyoto Encyclopedia of Genes and Genomes pathway analysis, gene set enrichment analysis, and Kaplan-Meier survival analysis to predict the potential function of PPP1R14B and its role in the prognosis of UCEC patients. Then, a tool for predicting the prognosis of UCEC, namely, a nomogram model, was constructed. PPP1R14B expression was higher in UCEC tumour tissues than in normal tissues. The results revealed that PPP1R14B expression was indeed closely associated with tumour development. The results of Kaplan-Meier plotter data indicated that patients with high PPP1R14b expression had poorer overall survival, disease-specific survival, and progression-free interval than those with low expression. A nomogram based on the results of multifactor Cox regression was generated. PPP1R14B is a key player in UCEC progression, is associated with a range of adverse outcomes, and can serve as a prognostic marker in the clinic.

MCM10: An effective treatment target and a prognostic biomarker in patients with uterine corpus endometrial carcinoma.

Molecular profiling has been applied for uterine corpus endometrial carcinoma (UCEC) management for many years. The aim of this study was to explore the role of MCM10 in UCEC and construct its overall survival (OS) prediction models. Data from TCGA, GEO, cbioPotal and COSMIC databases and the methods, such as GO, KEGG, GSEA, ssGSEA and PPI, were employed to bioinformatically detect the effects of MCM10 on UCEC. RT-PCR, Western blot and immunohistochemistry were used to validate the effects of MCM10 on UCEC. Based on Cox regression analysis using the data from TCGA and our clinical data, two OS prediction models for UCEC were established. Finally, the effects of MCM10 on UCEC were detected in vitro. Our study revealed that MCM10 was variated and overexpressed in UCEC tissue and involved in DNA replication, cell cycle, DNA repair and immune microenvironment in UCEC. Moreover, silencing MCM10 significantly inhibited the proliferation of UCEC cells in vitro. Importantly, based on MCM10 expression and clinical features, the OS prediction models were constructed with good accuracy. MCM10 could be an effective treatment target and a prognostic biomarker for UCEC patients. The OS prediction models might help establish the strategies of follow-up and treatment for UCEC patients.

Development and external validation of a machine learning-based prediction model for the cancer-related fatigue diagnostic screening in adult cancer patients: a cross-sectional study in China.

PURPOSE: Cancer-related fatigue (CRF) is the most common symptom in cancer patients and may interfere with patients' daily activities and decrease survival rate. However, the etiology of CRF has not been identified. Diagnosing CRF is challenging. Thus, our study aimed to develop a CRF prediction model in cancer patients, using data that healthcare professionals routinely obtained from electronic health records (EHRs) based on the 3P model and externally validate this model in an independent dataset collected from another hospital. METHODS: Between April 2022 and September 2022, a cross-sectional study was conducted on adult cancer patients at two first-class tertiary hospitals in China. Data that healthcare professionals routinely obtained from electronic health records (EHRs) based on the 3P model were collected. The outcome measure was according to ICD-10 diagnostic criteria for CRF. Data from one hospital (n = 305) were used for model development and internal validation. An independent data set from another hospital (n = 260) was utilized for external validation. logistic regression, random forest (RF), Naive Bayes (NB), and extreme gradient boosting (XGBoost) were constructed and compared. The model performance was evaluated in terms of both discrimination and calibration. RESULTS: The prevalence of CRF in the two centers was 57.9% and 56.1%, respectively. The Random Forest model achieved the highest AUC of 0.86 among the four types of classifiers in the internal validation. The AUC of RF and NB were above 0.7 in the external validation, suggesting that the models also have an acceptable generalization ability. CONCLUSIONS: The incidence of CRF remains high and deserves more attention. The fatigue prediction model based on the 3P theory can accurately predict the risk of CRF. Nonlinear algorithms such as Random Forest and Naive Bayes are more suitable for diagnosing and evaluating symptoms.

Effects of reminiscence therapy combined with memory specificity training (RT-MeST) on depressive symptoms in older adults: a randomized controlled trial protocol.

BACKGROUND: Geriatric depression has become a serious public health problem, and reduced autobiographical memory and increased overgeneral memory, as the main cognitive markers of depression, are not only associated with current depressive symptoms but also associated with the onset and course of depression, which can lead to a range of harms. Economic and effective psychological interventions are urgently needed. The aim of this study is to confirm the effectiveness of reminiscence therapy combined with memory specificity training in improving autobiographical memory and depressive symptoms in older adults. METHODS: In this multicentre, single-blind, three-arm parallel randomized controlled study, we aim to enrol 78 older adults aged 65 years or older with a score of ≥ 11 on the Geriatric Depression Scale, and participants will be randomly assigned to either a reminiscence therapy group, a reminiscence therapy with memory specificity training group or a usual care group. Assessments will be conducted at baseline (T0) as well as immediately post-intervention (T1) and 1 (T2), 3 (T3) and 6 (T4) months post-intervention. The primary outcome measure is self-reported depressive symptoms, measured using the GDS. Secondary outcome measures include measures of autobiographical memory, rumination, and social engagement. DISCUSSION: We believe that the intervention will play a positive role in improving autobiographical memory and depressive symptoms in older adults. Poor autobiographical memory is a predictor of depression and a major cognitive marker, and improving autobiographical memory is of great significance in alleviating depressive symptoms in older people. If our program is effective, it will provide a convenient and feasible strategy for further promoting healthy ageing. TRIAL REGISTRATION: ChiCTR2200065446.

The Effect of Web-Based Telerehabilitation Programs on Children and Adolescents With Brain Injury: Systematic Review and Meta-Analysis.

BACKGROUND: Acquired brain injury (ABI) in children and adolescents can lead to motor and executive impairments that often require long-term treatment. The implementation of web-based telerehabilitation therapy at home is a method to improve the functional status of patients. Therefore, we performed a systematic review of the effects of web-based telerehabilitation programs on functional outcomes in children and adolescents with brain injury and supplemented the findings with a meta-analysis. OBJECTIVE: This study evaluated the therapeutic effect of web-based telerehabilitation training on children and adolescents with brain injury to determine whether web-based telerehabilitation therapy improved motor function, executive function, physical activity level, lower limb strength, hand and upper limb function, visual processing skills, and occupational functional performance in children and adolescents with brain injury. METHODS: PubMed, Embase, Scopus, Web of Science, and the Cochrane Library were searched for randomized controlled trials on web-based telerehabilitation programs in children and adolescents with brain injury until December 2022, and the risk of bias was evaluated using the Cochrane Collaboration Tool. Relevant data were extracted, and a meta-analysis was performed using RevMan5.3 software. RESULTS: Overall, 17 studies involving 848 patients were included. Web-based telerehabilitation therapy improved the motor function (standardized mean difference [SMD] 0.29, 95% CI 0.01-0.57; P=.04), physical activity level (SMD 0.42, 95% CI 0.11-0.73; P=.007), lower limb strength (SMD 0.52, 95% CI 0.13-0.90; P=.009), and visual processing skills (SMD 0.26, 95% CI 0.02-0.50; P=.04) of children and adolescents with brain injury. It also improved executive function in letter-number sequencing (SMD 1.26, 95% CI 0.26-2.26; P=.01), attention (SMD 0.38, 95% CI 0.09-0.66; P=.009), and symbol search (SMD 1.18, 95% CI 0.43-1.93, P=.002). CONCLUSIONS: Web-based telerehabilitation therapy improved motor function, physical activity level, lower limb strength, letter-number sequencing, attention, and symbol search, which improved the quality of life in children and adolescents with brain injury. Web-based telerehabilitation programs provide great convenience for children and adolescents with ABI who need long-term treatment and allow them to exercise at home for rehabilitation training. The widespread implementation of remote interventions also provides children and adolescents in remote areas with better access to rehabilitation services. This review provides evidence for the effectiveness of web-based telerehabilitation therapy, but there was heterogeneity in some of the results because of different disease types and intervention programs. Future studies can expand the sample size according to disease type and increase follow-up time according to different exercise prescriptions to further refine the long-term effects of this intervention on various functions of children and adolescents with ABI. TRIAL REGISTRATION: PROSPERO CRD42023421917; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=421917.

Atrazine promotes breast cancer development by suppressing immune function and upregulating MMP expression.

There is evidence that the triazine herbicide atrazine, which is used extensively, is present in both surface water and groundwater, and its interfering effect on immune systems, endocrine systems, and tumours has been reported by laboratory and epidemiological studies. This study explored how atrazine affected 4T1 breast cancer cell development in vitro and in vivo. The obtained results showed that after exposure to atrazine, the cell proliferation and tumour volume were significantly increased and the expression of MMP2, MMP7, and MMP9 was upregulated. The thymus and spleen indices, the CD4 + and CD3 + lymphocyte percentages which from the spleen and inguinal lymph nodes, and the CD4 + /CD8 + ratio were noticeably lower than they were in the control group. Importantly, tumour-infiltrating lymphocytes such as CD4 + , CD8 + , and NK cells were decreased while Treg cells were increased. Moreover, IL-4 was increased and IFN-γ and TNF-α were decreased in the serum and tumour microenvironment. These results suggested that atrazine can suppress systemic as well as local tumour immune function and upregulate MMPs to promote breast tumour development.

Prolonged exposure to the herbicide atrazine promotes kidney fibrosis by activating Wnt/ß-catenin signaling in rats.

Exposure to atrazine (ATR), a widely-used herbicide, is a potential harmful to human health due to its long-term environmental persistence and bioaccumulation. The effects of chronic exposure to ATR on renal function in rats were evaluated in this research. Female Sprague-Dawley rats at 4 weeks of age were treated with different concentrations of ATR for 6 months. No significant differences  in terms of renal functions were observed after ATR treatment. In histopathological examination of the kidney, Hematoxylin-Eosin staining indicated the development of degenerative changes in a dose-dependent manner. The results revealed that ATR exposure leads to renal fibrosis and that activation of the Wnt/ß-catenin pathway plays a potential role in ATR-related renal fibrosis. Levels of transforming growth factor (TGF)-ß and TGF-ß1 levels and the reactive oxygen species were significantly upregulated after ATR treatment. In conclusion, long-term exposure to ATR could cause kidney fibrosis, which is the result of epithelial-mesenchymal transition caused by inflammation and oxidative stress.

Effects of miR-145-5p on cardiomyocyte proliferation and apoptosis, GIGYF1 expression and oxidative stress response in rats with myocardial ischemia-reperfusion.

This study aimed to investigate the effects of miR-145-5p on cardiomyocyte proliferation and apoptosis, GIGYF1 expression, inflammation, and oxidative stress in rats with myocardial ischemia-reperfusion injury (IRI). For this purpose, SPF male SD rats were used for IRI modeling. Experimental animals were subjected to specimen sampling and myocardial HE staining. The relative expression of miR-145-5p was detected by qRT-PCR; the protein expressions of GIGYF1, p-AKT, p53, Bax, p38MAPK, and ERK1/2 were detected by Western blot. Mouse embryonic cardiomyocytes H9C2 were used for H/R modeling, which was then subjected to cell transfection according to different grouping protocols. The target of miR-145-5p was confirmed to be GIGYF1 by dual-luciferase reporter assay. Further experiments were performed to detect the survival rate of transfected cells, the apoptosis of transfected cells, SOD activity determination, as well as IL-1ß and IL-6 concentrations. The results showed that the expression level of miR-145-5p was downregulated in H2C2 cells (P < 0.05). After 24h of transfection, there was a significant increase in the expression of miR-145-5p in the H/R+miR-145-5p mimic group (P < 0.05), but an evident decrease in the H/R+miR-145-5p inhibitor group (P > 0.05). Compared with the H/R+NC inhibitor group, the H/R+miR-145-5p mimic group had significantly increased cell proliferation, improved release of SOD, and upregulated expressions of ERK1/2 and p-AKT; but downregulated concentrations of IL-1ß and IL-6, and decreased expressions of P38MAPK, p53, and Bax (all P < 0.05). Also, the IRI+miR-145-5p agomir group had significantly upregulated expression of miR-145-5p and improved injury degree of heart tissue improved; a significant increase in the protein expressions ERK1/2 and p-AKT, but downregulated protein expressions of P38MAPK, p53, and Bax (all P < 0.05). Dual-luciferase reporter assay identified that GIGYF1 was the target gene of miR-145-5p. Furthermore, through the stimulated overexpression of miR-145-5p, there were significantly increased cell proliferation, improved release of SOD, and upregulated expressions of ERK1/2 and p-AKT; but downregulated concentrations of IL-1ß and IL-6, and decreased expressions of P38MAPK, p53, and Bax (all P < 0.05), while the above trends were reversed following the simultaneous upregulation of miR-145-5p and GIGYF1 (all P < 0.05). In general, our study confirmed a decreased expression of miR-145-5p and increased expression of GIGYF1 in the IRI or H/R model in vivo and in vitro. Overexpression of miR-145-5p can downregulate the expression of GIGYF1, further promote cell proliferation, inhibit cell apoptosis, alleviate inflammation and oxidative stress, and hence exert a protective role in myocardial infarction IRI.

First Report of Trichoderma crassum Causing Leaf Spot on Tomato (Solanum lycopersicum cv. M82) in Ohio.

Trichoderma is a genus of wood-decaying fungi generally found in soil (Druzhinina and Kubicek 2005). Trichoderma crassum was confirmed to be a sister species to T. virens according to the molecular sequencing results (Chaverri et al. 2003). A foliar disease with ~70% incidence on Solanum lycopersicum was observed in a greenhouse at The Ohio State University (40°0'8'' north latitude, 83°1'36'' west longitude), Columbus, United States, in December 2021. On average up to 60% of the leaves per two-month-old tomato plant were infected. Initially, the dark-grey color and irregular spots appeared at the leaf tips. As the disease progressed, the yellow necrotic lesions were observed surrounding the preformed disease spots. Finally, the infected leaves appeared curled and wilted as a whole. The leaf fragments from three tomato plants 40 inches apart were cut from the diseased lesions and surface sterilized with 75% ethanol (30 seconds) and 1% NaOCl (60 seconds), subsequently rinsed with sterilized deionized water three times. Nine pieces of the sterilized leaf tissues were then placed on the PDA plates at 28℃ in the dark and incubated in one incubator for 4 days. The pure cultures of five isolates were acquired and examined with a light microscope. The fungus from all the isolates changed from white to dark green with the radial pattern and profuse sporulation on the PDA. The produced round conidia were observed under a light microscope (Fig S1). The DNA was extracted from two representative isolates which showed the same morphology. The internal transcribed spacer (ITS) region and a conserved fungal rRNA region were amplified using the primers ITS1/ITS4 (5'-TCCGTAGGTGAACCTGCGG-3' and 5'-TCCTCCGCTTATTGATATGC-3') (White et al. 1990) and SR6f/SR7r (5'-TGTTACGACTTTTACTT-3' and 5'-AGTTAAAAAGCTCGTAGTTG-3') (Hirose et al. 2012), respectively. The PCR products were further sequenced by Sanger sequencing (Table S1). Based on the BLAST results through NCBI website, the ITS sequences of the two isolates were 99% (566/572) and 98% (558/572) identical to Trichoderma crassum DAOM 164916 (EU280067). Their SR sequences both showed 99% (290/293; 289/293) identity to the same strain. The phylogenetic tree was also created with the sequences of ITS region by MEGA software (version 11) (Fig S2). Therefore, the fungus was identified as Trichoderma crassum based on its morphological characteristics (green conidia), Sanger sequencing results, and phylogenetic tree. To complete Koch's postulates, the 5-mm-diameter fungal agar discs of 7-day-old pure cultures were used for the inoculation on 18 healthy leaves of six tomato cv. M82 plants with two-month-old. The sterile pure PDA discs of the equal size were used for the mock inoculation as a comparison. Fungal plug method was chosen in this study because it had been widely applied to characterization of the fungal pathogens causing leaf spot disease (Pornsuriya et al. 2020; Yang et al. 2021). Five days later, the same symptom as those that occurred on the previously naturally infected tomato plants were observed on all the inoculated leaves (Fig S3A). However, there were no symptoms on the leaves with the mock inoculation. The fungus re-isolated from the symptomatic leaves showed the consistent morphology (dark-green color with radial sporulation) with the original isolates (Fig S3B). Thus, Trichoderma crassum was verified as the causal agent of the foliar disease on Solanum lycopersicum cv. M82 in our greenhouse. To our knowledge, it is the first report of Trichoderma crassum leading to the leaf spot and wilt on tomato in Ohio. The identification of the causal agent lays the groundwork for the development of necessary disease management techniques. We acknowledge the funding support from CFAES Internal Grants Program 2021009.

Mesoporous silica nanoparticles combined with AKR1C3 siRNA inhibited the growth of castration-resistant prostate cancer by suppressing androgen synthesis in vitro and in vivo.

Intracrine androgen synthesis plays a critical role in the development of castration-resistant prostate cancer (CRPC). Aldo-keto reductase family 1 member C3 (AKR1C3) is a vital enzyme in the intracrine androgen synthesis pathway. In this study, mesoporous silica nanoparticles (MSNs) were employed to deliver small interfering RNA targeting AKR1C3 (siAKR1C3) to downregulate AKR1C3 expression in CPRC cells. The optimal weight ratio of MSNs/siAKR1C3 was determined by a gel retardation assay. Prostate cancer cells such as VCaP cells, which intracrinally express AKR1C3, and LNCaP-AKR1C3 cells stably transfected with AKR1C3 were used to investigate the antitumour effect of MSNs-siAKR1C3. Fluorescence detection and Western blot analyses were applied to confirm the entrance of MSNs-siAKR1C3 into the cells. A SRB (Sulforhodamine B) assay was employed to assess the cell viability, and a radioimmunoassay was used to measure the androgen concentration. Moreover, real-time PCR (RT-PCR), Western blot analysis and ELISA were used to determine the transcription and expression of prostate-specific antigen (PSA), AKR1C3 and androgen receptor (AR). Meanwhile, a reporter gene assay was performed to determine the AR activity. Additionally, a castrated nude mouse xenograft tumour model was produced to verify the inhibitory effect of MSNs-siAKR1C3 in vivo. The results showed that the optimal weight ratio of MSNs/siAKR1C3 was 140:1, and the complex could effectively enter cells, downregulate AKR1C3 expression, reduce the androgen concentration, inhibit AR activation, and inhibit CRPC development both in vitro and in vivo. These results indicate that decreasing intracrine androgen synthesis and inactivating AR signals by MSNs-siAKR1C3 may be a potential effective method for CRPC treatment.

The HDAC and PI3K dual inhibitor CUDC-907 synergistically enhances the antileukemic activity of venetoclax in preclinical models of acute myeloid leukemia.

Venetoclax is a promising agent in the treatment of acute myeloid leukemia, though its antileukemic activity is limited to combination therapies. Mcl-1 downregulation, Bim upregulation, and DNA damage have been identified as potential ways to enhance venetoclax activity. In this study, we combine venetoclax with the dual PI3K and histone deacetylase inhibitor CUDC-907, which can downregulate Mcl-1, upregulate Bim, and induce DNA damage, as well as downregulate c-Myc. We establish that CUDC-907 and venetoclax synergistically induce apoptosis in acute myeloid leukemia cell lines and primary acute myeloid leukemia patient samples ex vivo. CUDC-907 downregulates CHK1, Wee1, RRM1, and c-Myc, which were found to play a role in venetoclax-induced apoptosis. Interestingly, we found that venetoclax treatment enhances CUDC-907-induced DNA damage potentially through inhibition of DNA repair. In vivo results show that CUDC-907 enhances venetoclax efficacy in an acute myeloid leukemia cell line derived xenograft mouse model, supporting the development of CUDC-907 in combination with venetoclax for the treatment of acute myeloid leukemia.

Associations of the cerebrospinal fluid hepatocyte growth factor with Alzheimer's disease pathology and cognitive function.

BACKGROUND: Hepatocyte growth factor (HGF) plays a role in neuronal survival and development, and has been implicated in neurodegenerative diseases. We sought to examine the associations of the CSF HGF with Alzheimer's disease (AD) pathology and cognitive function. METHODS: A total of 238 participants (including 90 cognitively normal (CN) and 148 mild cognitive impairment (MCI)) who had measurements of CSF HGF were included from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Multiple linear regression models were utilized to explore the cross-sectional associations of CSF HGF with AD biomarkers (including Aß42, pTau, and tTau proteins) in non-demented participants. Moreover, linear mixed-effects regression models were utilized to explore the longitudinal associations of HGF subgroups with cognitive function. Mediation analyses were utilized to explore the mediation effects of AD markers. RESULTS: MCI individuals had significantly increased CSF HGF compared with the CN individuals. Results of multiple linear regressions showed significant correlations of CSF HGF with CSF Aß42, pTau, and tTau in non-demented participants. Higher level of baseline CSF HGF was associated with faster cognitive decline. Influences of the baseline CSF HGF on cognition were partially mediated by Aß42, pTau, and tTau pathologies. CONCLUSIONS: High concentrations of HGF in CSF may be related to faster cognitive decline. The cognitive consequences of higher CSF HGF partly stem from AD pathology, which suggests that the CSF HGF may be an attractive biomarker candidate to track AD progression.

Prolonged exposure to the herbicide atrazine suppresses immune cell functions by inducing spleen cell apoptosis in rats.

Atrazine (ATR) is a herbicide used widely worldwide. Because of its prolonged persistence in the environment and accumulation in the body, ATR exposure is a potential threat to human health. Our previous study showed that subacute exposure to ATR suppresses cellular immune function in mice. In this study, the effects of long-term exposure to ATR on rat immunological system function were measured. Four-week-old female Sprague-Dawley (SD) rats were treated with 0.4 µmol/L, 2 µmol/L and 10 µmol/L ATR for 24 weeks. The results showed that the spleen index increased, white blood cells decreased, and monocytes and eosinophils increased. No obvious changes were detected in the numbers of neutrophils and lymphocytes. Th1, Th2, and Th17 cells decreased significantly, while Treg cells increased after long-term ATR exposure. Moreover, serum levels of cytokines, including TNF-α, INF-γ, IL-6, and IL-12, decreased, while IL-1, IL-4, and IL-5 increased. Degenerative changes and cell apoptosis were found in the spleen; Caspase-3 and Caspase-9 were upregulated, and Bcl-2 was downregulated. These results suggested that long-term ATR exposure may inhibit immune system function.

Raddeanin A down-regulates androgen receptor and its splice variants in prostate cancer.

Castration-resistant progression of prostate cancer is a major cause of prostate cancer mortality, and increased expression and activity of the full-length and the splice variants of androgen receptor (AR) have been indicated to drive castration resistance. Consequently, there is an urgent need to develop agents that can target both the full-length and the splice variants of AR for more effective treatment of prostate cancer. In the present study, we showed that raddeanin A (RA), an oleanane-type triterpenoid saponin, suppresses the transcriptional activities of both the full-length and the splice variants of AR. This is attributable to their decreased expression as a result of RA induction of proteasome-mediated degradation and inhibition of the transcription of the AR gene. We further showed the potential of using RA to enhance the growth inhibitory efficacy of docetaxel, the first-line chemotherapy for prostate cancer. This study identifies RA as a new agent to target both the full-length and the splice variants of AR and provides a rationale for further developing RA for prostate cancer treatment.

Effects of Mind-Body Exercise on Cognitive Function in Older Adults With Cognitive Impairment: A Systematic Review and Meta-analysis.

To quantify the effects of mind-body exercise on cognitive function in older adults with cognitive impairment, we systematically searched five databases. Findings were analyzed according to the mean change of global cognition, memory, and executive function. Subgroup analyses were conducted based on the level of cognitive impairment and types of exercise. Thirteen studies were included. Analyses revealed that mind-body exercise was effective in promoting global cognition in individuals with cognitive impairment (standardized mean difference [SMD] = 0.61; 95% confidence interval, 0.21-1.00; p = 0.003), as well as in individuals with mild cognitive impairment (SMD = 0.46; 95% confidence interval, 0.06-0.85; p = 0.02) or dementia; dance was effective in promoting global cognition (SMD = 0.84; 95% confidence interval, 0.23-1.46; p = 0.007) and memory (SMD = 0.27; 95% confidence interval, 0.02-0.52; p = 0.04) in individuals with cognitive impairment, but tai chi was not. Nevertheless, additional well-designed randomized clinical trials are further needed.

Taurine Protects Primary Neonatal Cardiomyocytes Against Apoptosis Induced by Hydrogen Peroxide.

The aim of this study was to investigate the effects of taurine (Tau) on primary cultured neonatal myocardial cells treated with hydrogen peroxide (H2O2) and the underlying mechanism. Primary cardiac myocytes from neonatal Wistar rats were pre-incubated with Tau, and its effects on cell viability and expression of CaM, CaMKII, p53, Bcl-2, and Bax were examined. Tau enhanced the viability of myocardial cells, decreased apoptosis, and alleviated the intracellular calcium overload, especially at dosages of 40 or 80 mM (P < 0.01 or P < 0.001, respectively). Moreover, Tau could inhibit the H2O2-induced decrease in CamKII and CaM expression at both the mRNA and protein levels. The pattern of CaMKII expression was consistent with that of the anti-apoptotic protein Bcl-2, but contrasted the pattern of the pro-apoptotic proteins p53 and Bax. Thus, our results show that Tau protects myocardial cells against damage caused by H2O2 exposure, suggesting that it might play a role in the mitochondrial apoptotic pathway by upregulating the expression of CaMKII to rescue myocardial cells. However, the underlying mechanism still needs to be investigated. In addition, we tested the protective effect of taurine on cardiac myocytes, and the effect of taurine on another model, specifically an animal model.