Effects of Lifestyle Interventions on Health and Life Quality of Colorectal Cancer Survivors: A Systematic Review and Meta-analysis.

BACKGROUND: The results of previous studies on the effects of lifestyle interventions on the quality of life (QoL) in colorectal cancer (CRC) survivors remain controversial, and there have been several new publications in this area in recent years. OBJECTIVES: To assess whether lifestyle interventions can lead to favorable health outcomes and improved QoL in CRC survivors, we performed a meta-analysis. METHODS: PubMed, EMBASE, Web of Science, and Cochrane Library were systematically searched to obtain relevant literature published from January 1, 1990, to November 1, 2021. The required data were extracted and summarized to compare the physical activity levels, QoL, mental health assessment, and anthropometric data between lifestyle interventions and routine nursing. RESULTS: Twelve studies were included. Compared with the control group, lifestyle interventions could significantly increase the physical activity time (weighted mean difference [WMD], 9.84; 95% confidence interval [CI], 1.20-18.48; P = .026), metabolic equivalent task levels (WMD, 10.40; 95% CI, 5.30-15.49; P < .001), and Functional Assessment of Cancer Therapy Scale-Colorectal scores (WMD, 3.12; 95% CI, 0.24-5.99; P = .034). However, lifestyle interventions were not noticeably able to improve the fatigue, depression levels, anxiety levels, waist circumference, or body mass index in CRC survivors. CONCLUSION: Lifestyle interventions could generate an increase in physical activity time, metabolic equivalent task levels, and QoL in CRC survivors. IMPLICATIONS FOR PRACTICE: Lifestyle interventions in the future that include physical activity, diet, or comprehensive programs are needed to increase physical activity levels and improve QoL in CRC survivors.

PRL2 Phosphatase Promotes Oncogenic KIT Signaling in Leukemia Cells through Modulating CBL Phosphorylation.

Receptor tyrosine kinase KIT is frequently activated in acute myeloid leukemia (AML). While high PRL2 (PTP4A2) expression is correlated with activation of SCF/KIT signaling in AML, the underlying mechanisms are not fully understood. We discovered that inhibition of PRL2 significantly reduces the burden of oncogenic KIT-driven leukemia and extends leukemic mice survival. PRL2 enhances oncogenic KIT signaling in leukemia cells, promoting their proliferation and survival. We found that PRL2 dephosphorylates CBL at tyrosine 371 and inhibits its activity toward KIT, leading to decreased KIT ubiquitination and enhanced AKT and ERK signaling in leukemia cells. IMPLICATIONS: Our studies uncover a novel mechanism that fine-tunes oncogenic KIT signaling in leukemia cells and will likely identify PRL2 as a novel therapeutic target in AML with KIT mutations.

Gut microbial dysbiosis is associated with metabolism and immune factors in liver fibrosis mice.

Gut microbial dysbiosis has always served as a potential factor in the occurrence and development of liver fibrosis. Liver and gut microflora can regulate each other through the gut-liver axis. In this study, the 16S rRNA and RNA-seq were chosen to sequence gut microbiota alteration and liver differentially expressed genes (DEGs) in carbon tetrachloride (CCl4) included-liver fibrosis mice, and analyze the correlations between gut microbiota constituents and DEGs. Results indicated that, CCl4 significantly increased the abundance of Desulfobactera in the phylum level, destroyed gut microbiota balance in the genus levels, especially Enterorhabdus and Desulfovibrio. Through analysis, 1416 genes were found differentially expressed in mice liver tissue in the CCl4 Group, compared with the Control Group; and the DEGs were mainly involved in the lipid metabolic process and immune system process. The correlation analysis revealed that the relative abundance of microbiota phylum (Desulfobactera) and genus (Enterorhabdus and Desulfovibrio) was negatively correlated with the metabolism related genes, while positively correlated with immune-related genes and the genes enriched in PI3K-Akt signaling pathway. To sum up, CCl4 can partially regulate gene expression in metabolism, immune response and the PI3K/Akt pathway, and further maintain the stability of the gut environment in liver fibrosis mice.

Nomogram for prognosis of elderly patients with cervical cancer who receive combined radiotherapy.

This retrospective study identified prognostic factors to help guide the clinical treatment of elderly patients (≥ 65 years) with cervical cancer who had undergone radiotherapy. A personalized model to predict 3- and 5-years survival was developed. A review was conducted of 367 elderly women with cervical cancer (staged II-III) who had undergone radiotherapy in our hospital between January 2012 and December 2016. The Cox proportional hazards regression model was used for survival analysis that considered age, hemoglobin, squamous cell carcinoma antigen, pathologic type, stage, pelvic lymph node metastasis status, and others. A nomogram was constructed to predict the survival rates. The median follow-up time was 71 months (4-118 months). The 3- (5-) years overall, progression-free, local recurrence-free, and distant metastasis-free survival rates were, respectively, 91.0% (84.4%), 92.3% (85.9%), 99.18% (99.01%), and 99.18% (97.82%). The following were significant independent prognostic factors for overall survival: tumor size, pre-treatment hemoglobin, chemotherapy, and pelvic lymph node metastasis. The C-index of the line chart was 0.699 (95% CI 0.652-0.746). The areas under the receiver operating characteristic curves for 3- and 5-years survival were 0.751 and 0.724. The nomogram was in good concordance with the actual survival rates. The independent prognostic factors for overall survival in elderly patients with cervical cancer after radiotherapy were: tumor size, pre-treatment hemoglobin, chemotherapy, and pelvic lymph node metastasis. The novel prognostic nomogram based on these factors showed good concordance with the actual survival rates and can be used to guide personalized clinical treatment.

Targeting PHB1 to inhibit castration-resistant prostate cancer progression in vitro and in vivo.

BACKGROUND: Castration-resistant prostate cancer (CRPC) is currently the main challenge for prostate cancer (PCa) treatment, and there is an urgent need to find novel therapeutic targets and drugs. Prohibitin (PHB1) is a multifunctional chaperone/scaffold protein that is upregulated in various cancers and plays a pro-cancer role. FL3 is a synthetic flavagline drug that inhibits cancer cell proliferation by targeting PHB1. However, the biological functions of PHB1 in CRPC and the effect of FL3 on CRPC cells remain to be explored. METHODS: Several public datasets were used to analyze the association between the expression level of PHB1 and PCa progression as well as outcome in PCa patients. The expression of PHB1 in human PCa specimens and PCa cell lines was examined by immunohistochemistry (IHC), qRT-PCR, and Western blot. The biological roles of PHB1 in castration resistance and underlying mechanisms were investigated by gain/loss-of-function analyses. Next, in vitro and in vivo experiments were conducted to investigate the anti-cancer effects of FL3 on CRPC cells as well as the underlying mechanisms. RESULTS: PHB1 expression was significantly upregulated in CRPC and was associated with poor prognosis. PHB1 promoted castration resistance of PCa cells under androgen deprivation condition. PHB1 is an androgen receptor (AR) suppressive gene, and androgen deprivation promoted the PHB1 expression and its nucleus-cytoplasmic translocation. FL3, alone or combined with the second-generation anti-androgen Enzalutamide (ENZ), suppressed CRPC cells especially ENZ-sensitive CRPC cells both in vitro and in vivo. Mechanically, we demonstrated that FL3 promoted trafficking of PHB1 from plasma membrane and mitochondria to nucleus, which in turn inhibited AR signaling as well as MAPK signaling, yet promoted apoptosis in CRPC cells. CONCLUSION: Our data indicated that PHB1 is aberrantly upregulated in CRPC and is involved in castration resistance, as well as providing a novel rational approach for treating ENZ-sensitive CRPC.

Protective effects of sinomenine hydrochloride on lead-induced oxidative stress, inflammation, and apoptosis in mouse liver.

Lead, one of the most common heavy metal toxins, seriously affects the health of humans and animals. Sinomenine hydrochloride (SH) shows antioxidative, anti-inflammatory, antiviral, and anticancer properties. Hence, this study investigated the protective effects of SH against Pb-induced liver injury and explored the underlying mechanisms. First, a mouse model of lead acetate (0.5 g/L lead acetate in water, 8 weeks) was established, and SH (100 mg/kg bw in water, 8 weeks) intervention was administered by gavage. Then, the protective effect of SH against lead-induced liver injury was evaluated through serum biochemical analysis, histopathological analysis, and determination of malondialdehyde (MDA) and total antioxidant capacity (T-AOC) levels. The messenger RNA (mRNA) expression levels of the cytokines IL-1ß and TNF-α and the apoptosis factors Bax, Bcl-2, and Caspase3 in the liver were detected by quantitative real-time PCR. Then, the expression levels of IL-1ß and TNF-α in the liver were detected by ELISA. Immunohistochemical determination of the expression of the apoptosis factors Bax, Bcl-2, and Caspase3 was performed. SH treatment reduced the levels of liver alanine aminotransferase, aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and MDA in Pb-treated mice, indicating that SH protected the liver from injury and oxidative stress in Pb-treated mice. SH also increased the liver T-AOC of Pb-treated mice. Quantitative real-time PCR, ELISA, and immunohistochemical analysis showed that SH inhibited apoptosis, as indicated by the regulation of the mRNA expression of Bax and Bcl-2 and the reduced expression of Caspase3 and pro-inflammatory factors (IL-1ß and TNF-α) in the livers of Pb-treated mice. These results suggest that SH protects the mouse liver from Pb-induced injury. The underlying mechanism involves antioxidative, anti-inflammatory, and anti-apoptotic processes.

PRL2 phosphatase enhances oncogenic FLT3 signaling via dephosphorylation of the E3 ubiquitin ligase CBL at tyrosine 371.

Acute myeloid leukemia (AML) is an aggressive blood cancer with poor prognosis. FMS-like tyrosine kinase receptor-3 (FLT3) is one of the major oncogenic receptor tyrosine kinases aberrantly activated in AML. Although protein tyrosine phosphatase PRL2 is highly expressed in some subtypes of AML compared with normal human hematopoietic stem and progenitor cells, the mechanisms by which PRL2 promotes leukemogenesis are largely unknown. We discovered that genetic and pharmacological inhibition of PRL2 significantly reduce the burden of FLT3-internal tandem duplications-driven leukemia and extend the survival of leukemic mice. Furthermore, we found that PRL2 enhances oncogenic FLT3 signaling in leukemia cells, promoting their proliferation and survival. Mechanistically, PRL2 dephosphorylates the E3 ubiquitin ligase CBL at tyrosine 371 and attenuates CBL-mediated ubiquitination and degradation of FLT3, leading to enhanced FLT3 signaling in leukemia cells. Thus, our study reveals that PRL2 enhances oncogenic FLT3 signaling in leukemia cells through dephosphorylation of CBL and will likely establish PRL2 as a novel druggable target for AML.

Single-Cell Transcriptomics of Endothelial Cells in Upper and Lower Human Esophageal Squamous Cell Carcinoma.

Esophageal squamous cell carcinoma (ESCC) is a type of progressive and distant metastatic tumor. Targeting anti-angiogenic genes could effectively hinder ESCC development and metastasis, whereas ESCC locating on the upper or the lower esophagus showed different response to the same clinical treatment, suggesting ESCC location should be taken into account when exploring new therapeutic targets. In the current study, to find novel anti-angiogenic therapeutic targets, we identified endothelial cell subsets in upper and lower human ESCC using single-cell RNA sequencing (scRNA-seq), screened differentially expressed genes (DEGs), and performed gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. The results showed that common DEGs shared in the upper and the lower endothelial cells mainly are involved in vessel development, angiogenesis, and cell motility of endothelial cells by regulating PI3K-AKT, Rap1, Ras, TGF-beta, and Apelin signaling pathways. The critical regulatory genes were identified as ITGB1, Col4A1, Col4A2, ITGA6, LAMA4, LAMB1, LAMC1, VWF, ITGA5, THBS1, PDGFB, PGF, RHOC, and CTNNB1. Cell metabolism-relevant genes, e.g., MGST3, PNP, UPP1, and HYAL2 might be the prospective therapeutic targets. Furthermore, we found that DEGs only in the upper endothelial cells, such as MAPK3, STAT3, RHOA, MAPK11, HIF1A, FGFR1, GNG5, GNB1, and ARHGEF12, mainly regulated cell adhesion, structure morphogenesis, and motility through Phospholipase D, Apelin, and VEGF signaling pathways. Moreover, DEGs only in the lower endothelial cells, for instance PLCG2, EFNA1, CALM1, and RALA, mainly regulated cell apoptosis and survival by targeting calcium ion transport through Rap1, Ras, cAMP, Phospholipase D, and Phosphatidylinositol signaling pathways. In addition, the upper endothelial cells showed significant functional diversity such as cytokine-responsive, migratory, and proliferative capacity, presenting a better angiogenic capacity and making it more sensitive to anti-angiogenic therapy compared with the lower endothelial cells. Our study has identified the potential targeted genes for anti-angiogenic therapy for both upper and lower ESCC, and further indicated that anti-angiogenic therapy might be more effective for upper ESCC, which still need to be further examined in the future.

Role of p53 in regulation of hematopoiesis in health and disease.

PURPOSE OF REVIEW: Human aging is associated with an exponential increase in the occurrence of clonal hematopoiesis of indeterminate potential (CHIP). CHIP is associated with increased risks of de novo and therapy-related hematologic neoplasms and serves as a reservoir for leukemic relapse. Somatic mutations in the TP53 gene, which encodes the tumor suppressor protein p53, rank in the top five among genes that were mutated in CHIP. TP53 mutations in CHIP are associated with an increased incidence of myeloid neoplasms such as myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). This review focuses on mechanisms by which mutant p53 promotes CHIP progression and drives the pathogenesis of MDS and AML. We will also discuss potential therapeutic approaches that can target mutant p53 and improve treatment outcomes of MDS and AML. RECENT FINDINGS: TP53 was frequently mutated in individuals with CHIP as well as in patients with MDS and AML. While clinical studies suggest that p53 mutant hematopoietic stem and progenitor cell expansion may predispose the elderly to hematologic neoplasms, the underlying mechanisms are not fully understood. Recent findings suggest that mutant p53 may utilize both cell autonomous and noncell autonomous mechanisms to promote CHIP development. Furthermore, we and others have demonstrated that several gain-of-function mutant p53 proteins have enhanced oncogenic potential beyond dominant-negative and loss-of-function effects. Notably, TP53 allelic state has important implications for genome stability, clinical presentation, and outcomes in MDS. Some small molecules reactivating wild-type p53 tumor suppressor activity show promising effects on some human MDS and AML cells with TP53 mutations in preclinical and early phases of clinical studies. SUMMARY: TP53 mutations in MDS and AML are correlated with advanced disease, poor prognosis, reduced overall survival, and dismal outcomes. Deep understanding of the functions of mutant p53 proteins is essential to devise effective therapies for patients with myeloid neoplasms and other human cancers with TP53 mutations. Targeting mutant p53 directly or pathways regulated by mutant p53 holds great potential in preventing CHIP progression and treating MDS and AML patients with TP53 mutations.

Characterization of plasma exosomal microRNAs in responding to radiotherapy of human esophageal squamous cell carcinoma.

Radiotherapy is one of the main treatment methods for esophageal squamous cell carcinoma (ESCC). Previous research has shown that plasma exosomal microRNAs (miRNAs) can predict therapeutic outcome. In the present study, to identify potential exosomal miRNAs that respond to radiotherapy, plasma exosomal miRNAs from ESCC patients undergoing radiotherapy were isolated and sequenced. Upregulated and downregulated miRNAs were detected from patients pre­ and post­radiotherapy, and it was found that they play distinct roles in DNA damage process and endosomal mediated transport. Based on wound healing and Cell Counting Kit­8 assays in TE­1 human esophageal cancer cells, it was identified that representative miRNA miR­652 and miR­30a alter migration but not proliferation. The present findings identified differentially expressed miRNAs in responding to radiotherapy, and added a reference to explore non­invasive plasma biomarkers to evaluate therapeutic effects in ESCC.

Systematic review and meta-analysis of the risk factors of surgical site infection in patients with colorectal cancer.

Background: Surgical site infection (SSI) influenced the result of surgical treatment, which was known as the second most prevalent hospital-based infection. But, the factors of SSI are not uniform. The purpose of this study was to identify the risk factors of SSI in patients with colorectal cancer. We conducted a meta-analysis of epidemiological research to provide a scientific basis for the prevention of SSI. Methods: The PubMed, Medline, Embase, China National Knowledge Infrastructure (CNKI), and Wanfang databases were independently searched by 2 researchers to identify all relevant studies. Studies were selected if they met the selection criteria, which was defined according to the PICOS principles. The quality of the evidence was assessed using Egger's P value, study heterogeneity, and sample size. Studies were categorized into 3 groups as follows: low quality (Class 4), moderate quality (Class 2/3), and high quality (Class 1). The meta-analysis was performed using RevMan 5.3 software. Results: A total of 17 studies involving 61,611 patients were included in the meta-analysis. The results identified 7 patient-related risk factors of SSI, including male gender, obesity, diabetes mellitus, American Society of Anesthesiologists (ASA) score, cigarette smoking, tumor location, and serum albumin level, and 5 treatment-related risk factors, including laparoscopic surgery, operation time, blood loss, blood transfusion, and abdominal surgical history. Age was not directly related to SSI in colorectal cancer. Conclusions: It is possible that patients can be treated effectively by identifying these factors of SSI.

CT-Guided Survival Prediction of Esophageal Cancer.

Survival prediction of esophageal cancer is an essential task for doctors to make personalized cancer treatment plans. However, handcrafted features from medical images need prior medical knowledge, which is usually limited and not complete, yielding unsatisfying survival predictions. To address these challenges, we propose a novel and efficient deep learning-based survival prediction framework for evaluating clinical outcomes before concurrent chemoradiotherapy. The proposed model consists of two key components: a 3D Coordinate Attention Convolutional Autoencoder (CACA) and an uncertainty-based jointly Optimizing Cox Model (UOCM). The CACA is built upon an autoencoder structure with 3D coordinate attention layers, capturing latent representations and encoding 3D spatial characteristics with precise positional information. Additionally, we designed an Uncertainty-based jointly Optimizing Cox Model, which jointly optimizes the CACA and survival prediction task. The survival prediction task models the interactions between a patient's feature signatures and clinical outcome to predict a reliable hazard ratio of patients. To verify the effectiveness of our model, we conducted extensive experiments on a dataset including computed tomography of 285 patients with esophageal cancer. Experimental results demonstrated that the proposed method achieved a C-index of 0.72, outperforming the state-of-the-art method.

Preliminary Efficacy and Safety of Camrelizumab in Combination With XELOX Plus Bevacizumab or Regorafenib in Patients With Metastatic Colorectal Cancer: A Retrospective Study.

BACKGROUND: For a majority of patients with metastatic colorectal cancer (mCRC) with MS stable (MSS) or mismatch repair proficient (pMMR), the role of immunotherapy is undetermined. This study investigated the efficacy and safety of camrelizumab when added to XELOX chemotherapy plus bevacizumab or regorafenib as first-line therapy for mCRC. MATERIALS AND METHODS: Medical records of mCRC patients who received camrelizumab and XELOX plus bevacizumab or regorafenib at the First Hospital of Quanzhou Affiliated to Fujian Medical University between June 1, 2019, and April 30, 2021, were retrospectively collected. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and side effects of the drug were recorded and reviewed. RESULTS: Twenty-five eligible patients received combination therapy, including bevacizumab in 19 patients and regorafenib in 6. Twenty-one patients had pMMR/MSS and one MSI-H. Of the 25 patients who could be evaluated for efficacy, 18 (72%) achieved PR, 6 (24%) achieved SD, and 1 (4%) achieved PD. The ORR and DCR were 72% (18/25) and 96% (24/25), respectively. The median progression-free survival (PFS) was 11.2 months (95% CI 8.9-13.9), and OS had not yet been reached. The combination regimen of regorafenib in six (24%) patients was unassociated with treatment outcomes. Most AEs were either grade 1 or 2, and treatment-related grade 3 toxicities were observed in 8/25 (32%) patients. CONCLUSION: Camrelizumab combined with XELOX plus bevacizumab or regorafenib was feasible, producing high rates of responses as first-line therapy in unselected Chinese patients with MSS mCRC. The toxicities were generally tolerable and manageable. Prospective randomized trials with large sample sizes are needed to evaluate these findings.

Identification of an Exopolysaccharide Biosynthesis Gene in Bradyrhizobium diazoefficiens USDA110.

Exopolysaccharides (EPS) play critical roles in rhizobium-plant interactions. However, the EPS biosynthesis pathway in Bradyrhizobium diazoefficiens USDA110 remains elusive. Here we used transposon (Tn) mutagenesis with the aim to identify genetic elements required for EPS biosynthesis in B. diazoefficiens USDA110. Phenotypic screening of Tn5 insertion mutants grown on agar plates led to the identification of a mutant with a transposon insertion site in the blr2358 gene. This gene is predicted to encode a phosphor-glycosyltransferase that transfers a phosphosugar onto a polyprenol phosphate substrate. The disruption of the blr2358 gene resulted in defective EPS synthesis. Accordingly, the blr2358 mutant showed a reduced capacity to induce nodules and stimulate the growth of soybean plants. Glycosyltransferase genes related to blr2358 were found to be well conserved and widely distributed among strains of the Bradyrhizobium genus. In conclusion, our study resulted in identification of a gene involved in EPS biosynthesis and highlights the importance of EPS in the symbiotic interaction between USDA110 and soybeans.

KIF15 Promotes Progression of Castration Resistant Prostate Cancer by Activating EGFR Signaling Pathway.

Castration-resistant prostate cancer (CRPC) continues to be a major clinical problem and its underlying mechanisms are still not fully understood. The epidermal growth factor receptor (EGFR) activation is an important event that regulates mitogenic signaling. EGFR signaling plays an important role in the transition from androgen dependence to castration-resistant state in prostate cancer (PCa). Kinesin family member 15 (KIF15) has been suggested to be overexpressed in multiple malignancies. Here, we demonstrate that KIF15 expression is elevated in CRPC. We show that KIF15 contributes to CRPC progression by enhancing the EGFR signaling pathway, which includes complex network intermediates such as mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/AKT pathways. In CRPC tumors, increased expression of KIF15 is positively correlated with EGFR protein level. KIF15 binds to EGFR, and prevents EGFR proteins from degradation in a Cdc42-dependent manner. These findings highlight the key role of KIF15 in the development of CRPC and rationalize KIF15 as a potential therapeutic target.

Bmi1 Regulates Wnt Signaling in Hematopoietic Stem and Progenitor Cells.

Polycomb group protein Bmi1 is essential for hematopoietic stem cell (HSC) self-renewal and terminal differentiation. However, its target genes in hematopoietic stem and progenitor cells are largely unknown. We performed gene expression profiling assays and found that genes of the Wnt signaling pathway are significantly elevated in Bmi1 null hematopoietic stem and progenitor cells (HSPCs). Bmi1 is associated with several genes of the Wnt signaling pathway in hematopoietic cells. Further, we found that Bmi1 represses Wnt gene expression in HSPCs. Importantly, loss of ß-catenin, which reduces Wnt activation, partially rescues the HSC self-renewal and differentiation defects seen in the Bmi1 null mice. Thus, we have identified Bmi1 as a novel regulator of Wnt signaling pathway in HSPCs. Given that Wnt signaling pathway plays an important role in hematopoiesis, our studies suggest that modulating Wnt signaling may hold potential for enhancing HSC self-renewal, thereby improving the outcomes of HSC transplantation.

Ginsenoside Rg3 enhances the anticancer effect of 5­FU in colon cancer cells via the PI3K/AKT pathway.

Chemotherapy is one of the most commonly used treatments for patients with advanced colon cancer, yet the toxicity of chemotherapy agents, such as 5­fluorouracil (5­FU), limits the effectiveness of chemotherapy. Ginsenoside Rg3 (Rg3) is an active ingredient isolated from ginseng. Rg3 has been shown to display anticancer effects on a variety of malignancies. Yet, whether Rg3 synergizes the effect of 5­FU to inhibit the growth of human colon cancer remains unknown. The present study was designed to ascertain whether Rg3 is able to enhance the anti­colon cancer effect of 5­FU. The results revealed that combined treatment of Rg3 and 5­FU significantly enhanced the inhibition of the proliferation, colony formation, invasion and migration of human colon cancer cells (SW620 and LOVO) in vitro. We also found that combined treatment of Rg3 and 5­FU significantly enhanced the apoptosis of colon cancer cells by activating the Apaf1/caspase 9/caspase 3 pathway and arrested the cell cycle of the colon cancer cells in G0/G1 by promoting the expression of Cyclin D1, CDK2 and CDK4. In addition, the PI3K/AKT signaling pathway in colon cancer cells was suppressed by Rg3 and 5­FU. In vivo, Rg3 synergized the effect of 5­FU to inhibit the growth of human colon cancer xenografts in nude mice. Similarly, combined treatment of Rg3 and 5­FU altered the expression of colon cancer protein in vivo and in vitro. Collectively, the present study demonstrated that ginsenoside Rg3 enhances the anticancer effect of 5­FU in colon cancer cells via the PI3K/AKT pathway.

Associations of White Matter Hyperintensities with Cognitive Decline: A Longitudinal Study.

White matter hyperintensities (WMHs), mainly caused by cerebrovascular injury, may lead to cognitive impairment. In order to identify whether the volume of WMHs is associated with cognitive decline over years, this longitudinal study involved 818 individuals from the ADNI-2 dataset from August 2010 to May 2017. Cross-sectional and longitudinal associations of WMHs with 8 cognitive domains were explored, using Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Clinical Dementia Rating Sum of Boxes (CDRSB), Alzheimer Disease Assessment Scale-Cognitive (ADAS-Cog13), Rey Auditory Verbal Learning Test (RAVLT), Functional Assessment Questionnaire (FAQ), executive function (ADNI-EF), and memory function (ADNI-Mem). The association analyses were performed using multiple linear regression models, linear mixed models, Spearman rank correlation, and Kaplan-Meier survival curves. The volumes of WMHs were greater in patients with Alzheimer's disease (AD) dementia compared with controls (p < 0.001) and mild cognitive impairment (p = 0.006) patients at baseline. The bigger volumes of WMHs correlated with worse performances on ADAS-Cog13 and ADNI-EF (p = 0.029; p = 0.003) at baseline and MMSE, MoCA, CDRSB, ADAS-Cog13, FAQ, and ADNI-Mem (overall p < 0.05) longitudinally, after adjusting for age, sex, educational level, apolipoprotein E ɛ4 genotype, hypertension, hyperlipidemia, diabetes, smoking, infarction, and diagnosis. Additionally, the correlations between the change rate of WMHs and change rates of MMSE, MoCA, CDRSB, FAQ, ADNI-EF, and ADNI-Mem were statistically significant. Furthermore, patients with high WMH volumes showed an increased likelihood of dementia. The results of the study suggest that WMH volume is associated with cognitive decline, and it contributes to the conversion to AD.

Mutant p53 drives clonal hematopoiesis through modulating epigenetic pathway.

Clonal hematopoiesis of indeterminate potential (CHIP) increases with age and is associated with increased risks of hematological malignancies. While TP53 mutations have been identified in CHIP, the molecular mechanisms by which mutant p53 promotes hematopoietic stem and progenitor cell (HSPC) expansion are largely unknown. Here we discover that mutant p53 confers a competitive advantage to HSPCs following transplantation and promotes HSPC expansion after radiation-induced stress. Mechanistically, mutant p53 interacts with EZH2 and enhances its association with the chromatin, thereby increasing the levels of H3K27me3 in genes regulating HSPC self-renewal and differentiation. Furthermore, genetic and pharmacological inhibition of EZH2 decreases the repopulating potential of p53 mutant HSPCs. Thus, we uncover an epigenetic mechanism by which mutant p53 drives clonal hematopoiesis. Our work will likely establish epigenetic regulator EZH2 as a novel therapeutic target for preventing CHIP progression and treating hematological malignancies with TP53 mutations.

The SOX4/miR-17-92/RB1 Axis Promotes Prostate Cancer Progression.

Although androgen-deprivation treatment (ADT) is the main treatment for advanced prostate cancer (PCa), it eventually fails. This failure invariably leads to castration-resistant prostate cancer (CRPC) and the development of the neuroendocrine (NE) phenotype. The molecular basis for PCa progression remains unclear. Previously, we and others have demonstrated that the sex-determining region Y-box 4 (SOX4) gene, a critical developmental transcription factor, is overexpressed and associated with poor prognosis in PCa patients. In this study, we show that SOX4 expression is associated with PCa progression and the development of the NE phenotype in androgen deprivation conditions. High-throughput microRNA profiling and bioinformatics analyses suggest that SOX4 may target the miR-17-92 cluster. SOX4 transcriptionally upregulates miR-17-92 cluster expression in PCa cells. SOX4-induced PCa cell proliferation, migration, and invasion are also mediated by miR-17-92 cluster members. Furthermore, RB1 is a target gene of miR-17-92 cluster. We found that SOX4 downregulates RB1 protein expression by upregulating the miR-17-92 expression. In addition, SOX4-knockdown restrains NE phenotype and PCa cell proliferation. Clinically, the overexpression of miR-17-92 members is shown to be positively correlated with SOX4 expression in PCa patients, whereas RB1 expression is negatively correlated with SOX4 expression in patients with the aggressive PCa phenotype. Collectively, we propose a novel model of a SOX4/miR-17-92/RB1 axis that may exist to promote PCa progression.