MLXIPL associated with tumor-infiltrating CD8+ T cells is involved in poor prostate cancer prognosis.

Introduction: Within tumor microenvironment, the presence of preexisting antitumor CD8+ T Q7 cells have been shown to be associated with a favorable prognosis in most solid cancers. However, in the case of prostate cancer (PCa), they have been linked to a negative impact on prognosis. Methods: To gain a deeper understanding of the contribution of infiltrating CD8+ T cells to poor prognosis in PCa, the infiltration levelsof CD8+ T cells were estimated using the TCGA PRAD (The Cancer Genome Atlas Prostate Adenocarcinoma dataset) and MSKCC (Memorial Sloan Kettering Cancer Center) cohorts. Results: Bioinformatic analyses revealed that CD8+ T cells likely influence PCa prognosis through increased expression of immune checkpoint molecules and enhanced recruitment of regulatory T cells. The MLXIPL was identified as the gene expressed in response to CD8+ T cell infiltration and was found to be associated with PCa prognosis. The prognostic role of MLXIPL was examined in two cohorts: TCGA PRAD (p = 2.3E-02) and the MSKCC cohort (p = 1.6E-02). Subsequently, MLXIPL was confirmed to be associated with an unfavorable prognosis in PCa, as evidenced by an independent cohort study (hazard ratio [HR] = 2.57, 95% CI: 1.42- 4.65, p = 1.76E-03). Discussion: In summary, the findings suggested that MLXIPL related to tumor-infiltrating CD8+ T cells facilitated a poor prognosis in PCa.

HCMMD: systematic evaluation of metabolites in body fluids as liquid biopsy biomarker for human cancers.

Metabolomics is a rapidly expanding field in systems biology used to measure alterations of metabolites and identify metabolic biomarkers in response to disease processes. The discovery of metabolic biomarkers can improve early diagnosis, prognostic prediction, and therapeutic intervention for cancers. However, there are currently no databases that provide a comprehensive evaluation of the relationship between metabolites and cancer processes. In this review, we summarize reported metabolites in body fluids across pan-cancers and characterize their clinical applications in liquid biopsy. We conducted a search for metabolic biomarkers using the keywords ("metabolomics" OR "metabolite") AND "cancer" in PubMed. Of the 22,254 articles retrieved, 792 were deemed potentially relevant for further review. Ultimately, we included data from 573,300 samples and 17,083 metabolic biomarkers. We collected information on cancer types, sample size, the human metabolome database (HMDB) ID, metabolic pathway, area under the curve (AUC), sensitivity and specificity of metabolites, sample source, detection method, and clinical features were collected. Finally, we developed a user-friendly online database, the Human Cancer Metabolic Markers Database (HCMMD), which allows users to query, browse, and download metabolite information. In conclusion, HCMMD provides an important resource to assist researchers in reviewing metabolic biomarkers for diagnosis and progression of cancers.

Upregulation of glycolytic enzyme PFKFB3 by deubiquitinase OTUD4 promotes cardiac fibrosis post myocardial infarction.

Metabolic dysregulations have emerged as a major mediator of cardiovascular disorders and fibrotic diseases. Metabolic reprogramming contributes a lot to cardiac fibroblast activation and cardiac fibrosis post-myocardial infarction (MI), yet the mechanism remains incompletely understood. Our work aimed to determine whether or not glycolytic reprogramming, regulated by phosphofructokinase-2/fructose-2,6-bisphosphatase 3 (PFKFB3), is a therapeutic target for alleviating post-MI cardiac fibrosis. Here, we showed that cardiac fibroblasts displayed cell energy phenotype toward augmented glycolysis in response to transforming growth factor-beta 1 (TGF-ß1), evidenced by significant extracellular acidification rate (ECAR) increase and lactate accumulation. The expression of glycolytic enzyme PFKFB3, a master activator of glycolysis, was up-regulated in TGF-ß1-treated cardiac fibroblasts and in cardiac fibroblasts of post-MI mice. Pharmacological inhibition of PFKFB3 by 3PO diminished TGF-ß1-mediated profibrotic phenotypes, attenuated cardiac fibrosis, and preserved cardiac functions in post-MI mice. Meanwhile, the genetic inhibition of PFKFB3 decreased the cardiac fibroblast activation and reversed the differentiated phenotypes in vitro and in vivo. Mechanistically, we identified deubiquitinase OTUD4 as a new binding protein of PFKFB3, and their interaction blocked PFKFB3 degradation via OTUD4-mediated deubiquitylation. Taken together, this work characterized a key role for PFKFB3 in cardiac fibroblast activation and suggested that inhibiting PFKFB3-involved glycolysis is an alternative way to alleviate post-MI cardiac fibrosis. KEY MESSAGES: PFKFB3, a master activator of glycolysis, was highly expressed in ischemic cardiac fibroblasts to enhance cardiac fibrosis The deubiquitinase OTUD4 was identified as a new binding protein of PFKFB3 TGF-ß1 blunted the ubiquitination-mediated degradation of PFKFB3 via OTUD4-mediated deubiquitylation Blockade of PFKFB3 contributed to ameliorating ischemia-induced cardiac fibrosis.

The Role of Gynostemma pentaphyllum in Regulating Hyperlipidemia.

Developing effective and safe lipid-lowering drugs is highly urgent. This study aims to investigate the effectiveness and underlying mechanisms of Gynostemma pentaphyllum (GP) in the treatment of hyperlipidemia. First, a meta-analysis was performed to determine the lipid-lowering effects of GP. Thereafter, hyperlipidemia was induced in mice using a high-fat diet (HFD) and was subsequently treated with Gynostemma pentaphyllum extract (GPE) by daily gavage for 12 weeks. The body weight, tissue weight, blood lipid level, and liver lipid level were determined. Additionally, mouse serum samples were subjected to metabolomic profiling and feces were collected at different time points for metagenomic analysis via 16S rDNA sequencing. A total of 15 out of 1520 studies were retrieved from six databases. The pooled results of the meta-analysis showed that GP effectively reduced triglyceride levels and increased high-density lipoprotein cholesterol (both [Formula: see text]). Animal experiments revealed that GPE administration significantly reduced body weight, ameliorated high blood lipid levels, limited lipid deposition, and improved insulin resistance. Furthermore, GPE treatment markedly changed the intestinal microbiota structure and constitution of tryptophan metabolites. In conclusion, our results confirm the lipid-lowering effect of GP, which may be partly attributable to regulation of the intestinal microbiota and tryptophan metabolism.

Diagnostic role of plasma ORM2 in differentiating prostate cancer from benign prostatic hyperplasia.

PURPOSE: Markers are needed to increase the diagnostic accuracy of prostate-specific antigen (PSA) in prostate cancer (PCa) screening. Mounting evidence has shown that plasma proteins can be hopeful biomarkers for cancer diagnosis. METHODS: Tandem mass tag (TMT)-based proteomics and parallel reaction monitoring (PRM) analysis were used to screen the differential proteins and further validated in other independent studies (n = 539). Receiver-operating characteristic (ROC), decision curves and nomograms were applied to assess the diagnostic accuracy of biomarkers. RESULTS: Three candidate proteins (DBP, LCAT and ORM2) were preliminarily screened. Subsequent validation studies revealed significant upregulation of ORM2 in PCa patients across other independent cohorts. ORM2 yielded excellent discriminative power for PCa from benign prostatic hyperplasia (BPH) patients (AUC = 0.861 and 0.814 in validation phases 2a and 2b, respectively). Importantly, the combination of ORM2 and PSA gave better predictive accuracy than PSA alone. We incorporated age, PSA and ORM2 into a nomogram, which yielded C-index of 0.883 in validation phase 2a. A similar C-index of 0.879 was obtained in external validation phase 2b. CONCLUSIONS: In summary, our study suggests that ORM2 could be treated as a complementary biomarker for PSA in distinguishing PCa from BPH.

Variability of body mass index and risks of prostate, lung, colon, and ovarian cancers.

Objective: We investigated the association between cancer incidence and body mass index (BMI) variability calculated from the recall of weight at decades of age by participants in the USA Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. Methods: A total of 89,822 individuals' BMI were recorded as recalled the participant's aged 30, 40, 50, 60, 70 years, and baseline. BMI variability was assessed using four indices: SD, coefficient of variation (CV), variability independent of the mean (VIM), and average real variability (ARV). The multivariate Cox regression analysis was performed to calculate hazard ratios (HRs) of these measures for incident cancers and corresponding 95% CIs. Results: During the median follow-up of 11.8 years, there were newly diagnosed 5,012 cases of prostate cancer, 792 cases of lung cancer, 994 cases of colon cancer, and 132 cases of ovarian cancer. Compared with the lowest quartile (Q1) group, the highest quartile (Q4) group of BMI variability indices was associated with increased lung cancer risk, including BMI_SD (HR, 1.58; 95% CI, 1.17-2.12), BMI_CV (HR, 1.46; 95% CI, 1.10-1.94), BMI_VIM (HR, 1.73; 95% CI, 1.33-2.25), and BMI_ARV (HR, 2.17; 95% CI, 1.62-2.91). Associations between BMI variability and prostate, colon, and ovarian cancer incidences were of limited significance. Conclusion: The findings imply that maintaining a stable weight across adulthood is associated with a decreased incidence of lung cancer.

Antihypertensive Drug Use and the Risk of Depression: A Systematic Review and Network Meta-analysis.

Background: Although numerous cohort studies have reported an association between antihypertensives use and depression, the exact effect of antihypertensives on depression remains unclear. Objective: To clarify the association between antihypertensives use and risk of depression. Methods: We retrieved relevant literature using PubMed database until August 30, 2021. Four main classes of antihypertensives, thus, angiotensin antagonists, beta blockers, calcium channel blockers and diuretics were studied. The incidence of depression was pooled based on a single drug category. Network meta-analyses were conducted to comprehensively assess the effects of the four classes of antihypertensives on the risk of depression. Results: A total of nine out of 9,557 studies involving 414,873 subjects were retrieved. The pooled results showed a positive association between the use of calcium channel blockers and symptoms of depression [odds ratio (OR): 1.09, 95% confidence interval (CI):1.06-1.13], while use of the angiotensin antagonists, beta blockers and diuretics was not associated with risk of depression. Subgroup analysis suggested a significant relationship between beta blockers usage and risk of depression in cohort studies (OR:1.21, 95% CI: 1.16-1.26). The results of network meta-analysis indicated that all other three classes of drugs increased the risk of depression: angiotensin antagonists (OR: 1.30, 95% CI: 1.04-1.63), beta blockers (OR: 1.53, 95% CI: 1.22-1.91), and calcium channel blockers (OR: 1.40, 95% CI: 1.12-1.75), compared with diuretics. Conclusion: In conclusion, our results indicate that the use of angiotensin antagonists, beta blockers and calcium channel blockers are potential risk factors of depression.

Prognostic comparison between radical prostatectomy and radiotherapy in prostate cancer patients at different stages and ages.

Radical prostatectomy (RP) and radiotherapy (RT) are both evidence-based nonconservative treatments for prostate cancer (PCa). However, which treatment is better remains controversial. This study aimed to compare the prognostic difference between radical prostatectomy (RP) and radiotherapy (RT) in PCa patients at different stages and ages. Two independent PCa cohorts (the Surveillance, Epidemiology, and End Results, SEER; and the Prostate, Lung, Colorectal, and Ovarian, PLCO) were employed. Cox regression was used to calculate the hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs). In both cohorts, patients who received RT exhibited a worse prognostic outcome than those who underwent RP. When stratified analysis was performed by tumor node metastasis (TNM) stage and age at diagnosis in the SEER cohort, the HR of RT versus RP for overall survival increased with TNM stage but decreased with age. Specifically, PCa patients in stage I in the age range of 55-84 years, stage IIA at 70-85+ years, and stage IIB at 75-85+ years had better survival with RT than RP patients (p < 0.05). In contrast, patients in stages IIA, IIB, III and IV with respective age ranges of 55-64 years; 50-74 years; 55-59, 65-74 years; and 45-74 years showed worse survival with RT compared with RP (p < 0.05). These findings were partially validated in the PLCO dataset. Our results indicated that the choice between RT and RP should be guided by TNM stage and age. These findings may facilitate counseling regarding the prognostic effect of RT and RP for PCa patients.

Metabolomics identifying biomarkers of PM2.5 exposure for vulnerable population: based on a prospective cohort study.

Long-term exposure to particular matter (PM), especially fine PM (< 2.5 µm in the aerodynamic diameter, PM2.5), is associated with increased risk of cardiovascular disorders. This study aimed to evaluate the association between long-term exposure to PM2.5/PM10 and the metabolic change in the plasma. Specifically, using metabolomics, we sought to identify the biomarkers for the vulnerable subgroup to PM2.5 exposure. A total of 78 college student volunteers were recruited into this prospective cohort study. All participants received 8 rounds of physical examinations at twice quarterly. Air purifiers were placed in 40 of 78 participants' dormitories for 14 days. Before and after intervention, physical examinations were performed and the peripheral blood was collected. Plasma metabolomics was determined by ultra-performance liquid chromatography-mass spectrometry. During the follow-up, the average concentrations of PM2.5 and PM10 were 53 µg/m3 and 93 µg/m3, respectively. Totally, 42 and 120 differential metabolic features were detected for PM10 and PM2.5 exposure, respectively. In total, 25 differential metabolites were identified for PM2.5 exposure, most of which were phospholipids. No distinctive metabolites were found for PM10 exposure. A total of 6 differential metabolites (lysoPC (P-20:0), lysoPC (P-18:1(9z)), lysoPC (20:1), lysoPC (O-16:0), choline, and found 1,3-diphenylprop-2-en-1-one) were characterized and confirmed for sensitive individuals. Importantly, we found LysoPC (P-20:0) and LysoPC (P-18:1(9z)) changed significantly before and after air purifier intervention. Our results indicated that the phospholipid catabolism was involved in long-term PM2.5 exposure. LysoPC (P-20:0) and LysoPC (P-18:1(9z)) may be the biomarkers of PM2.5 exposure.

The Association Between Obesity and Risk of Acute Kidney Injury After Cardiac Surgery.

Objective: To determine the relationship between obesity and the risk of AKI after cardiac surgery (CS-AKI) in a cohort study. Methods: A total of 1,601 patients undergoing cardiac surgery were collected and their incidence of CS-AKI was recorded. They were divided into underweight, normal weight, overweight, and obese groups. Logistic regression was used to estimate the association between BMI (body mass index) and CS-AKI risk. Then, a meta-analysis of published cohort studies was conducted to confirm this result using PubMed and Embase databases. Results: A significant association was observed in this independent cohort after adjusting age, gender, hypertension and New York Heart Association classification (NYHA) class. Compared with normal BMI group (18.5 ≤ BMI < 24.0), the individuals with aberrant BMI level had an increased AKI risk (OR: 1.68, 95% CI: 1.01-2.78) for BMI < 18.5 group and (OR: 1.43, 95% CI: 0.96-2.15) for BMI ≥ 28.0. Interestingly, the U-shape curve showed the CS-AKI risk reduced with the increasing of BMI when BMI ≤ 24.0. As BMI increases with BMI > 24.0, the risk of developing CS-AKI increased significantly. In the confirmed meta-analysis, compared with normal weight, overweight group with cardiac surgery had higher AKI risk (OR: 1.28, 95% CI: 1.16-1.41, Pheterogeneity = 0.49). The similar association was found in obesity subgroup (OR: 1.79, 95% CI: 1.57-2.03, Pheterogeneity = 0.42). Conclusion: In conclusion, the results suggested that abnormal BMI was a risk factor for CS-AKI independently.

Integrative omic and transgenic analyses reveal the positive effect of ultraviolet-B irradiation on salvianolic acid biosynthesis through upregulation of SmNAC1.

Salvianolic acids (SalAs), a group of secondary metabolites in Salvia miltiorrhiza, are widely used for treating cerebrovascular diseases. Their biosynthesis is modulated by a variety of abiotic factors, including ultraviolet-B (UV-B) irradiation; however, the underlying mechanisms remain largely unknown. Here, an integrated metabolomic, proteomic, and transcriptomic approach coupled with transgenic analyses was employed to dissect the mechanisms underlying UV-B irradiation-induced SalA biosynthesis. Results of metabolomics showed that 28 metabolites, including 12 SalAs, were elevated in leaves of UV-B-treated S. miltiorrhiza. Meanwhile, the contents of several phytohormones, including jasmonic acid and salicylic acid, which positively modulate the biosynthesis of SalAs, also increased in UV-B-treated S. miltiorrhiza. Consistently, 20 core biosynthetic enzymes and numerous transcription factors that are involved in SalA biosynthesis were elevated in treated samples as indicated by a comprehensive proteomic analysis. Correlation and gene expression analyses demonstrated that the NAC1 gene, encoding a NAC transcriptional factor, was positively involved in UV-B-induced SalA biosynthesis. Accordingly, overexpression and RNA interference of NAC1 increased and decreased SalA contents, respectively, through regulation of key biosynthetic enzymes. Furthermore, ChIP-qPCR and Dual-LUC assays showed that NAC1 could directly bind to the CATGTG and CATGTC motifs present in the promoters of the SalA biosynthesis-related genes PAL3 and TAT3, respectively, and activate their expression. Our results collectively demonstrate that NAC1 plays a crucial role in UV-B irradiation-induced SalA biosynthesis. Taken together, our findings provide mechanistic insights into the UV-B-induced SalA biosynthesis in S. miltiorrhiza, and shed light on a great potential for the development of SalA-abundant varieties through genetic engineering.

A mass spectrometry database for identification of saponins in plants.

Saponins constitute an important class of secondary metabolites of the plant kingdom. Here, we present a mass spectrometry-based database for rapid and easy identification of saponins henceforth referred to as saponin mass spectrometry database (SMSD). With a total of 4196 saponins, 214 of which were obtained from commercial sources. Through liquid chromatography-tandem high-resolution/mass spectrometry (HR/MS) analysis under negative ion mode, the fragmentation behavior for all parent fragment ions almost conformed to successive losses of sugar moieties, α-dissociation and McLafferty rearrangement of aglycones in high-energy collision induced dissociation. The saccharide moieties produced sugar fragment ions from m/z (monosaccharide) to m/z (polysaccharides). The parent and sugar fragment ions of other saponins were predicted using the above mentioned fragmentation pattern. The SMSD is freely accessible at http://47.92.73.208:8082/ or http://cpu-smsd.com (preferrably using google). It provides three search modes ("CLASSIFY", "SEARCH" and "METABOLITE"). Under the "CLASSIFY" function, saponins are classified with high predictive accuracies from all metabolites by establishment of logistic regression model through their mass data from HR/MS input as a csv file, where the first column is ID and the second column is mass. For the "SEARCH" function, saponins are searched against parent ions with certain mass tolerance in "MS Ion Search". Then, daughter ions with certain mass tolerance are input into "MS/MS Ion Search". The optimal candidates were screened out according to the match count and match rate values in comparison with fragment data in database. Additionally, another logistic regression model completely differentiated between parent and sugar fragment ions. This function designed in front web is conducive to search and recheck. With the "METABOLITE" function, saponins are searched using their common names, where both full and partial name searches are supported. With these modes, saponins of diverse chemical composition can be explored, grouped and identified with a high degree of predictive accuracy. This specialized database would aid in the identification of saponins in complex matrices particular in the study of traditional Chinese medicines or plant metabolomics.

Advanced paternal age and risk of cancer in offspring.

Many risk factors of cancer have been established, but the contribution of paternal age in this regard remains largely unexplored. To further understand the etiology of cancer, we investigated the relationship between paternal age and cancer incidence using PLCO cohort. Cox proportional hazards models were performed to assess the association between paternal age and the risk of cancers. During follow-up time (median 11.5 years), 18,753 primary cancers occurred. Paternal age was associated with reduced risk of cancers of the female genitalia (HR, 0.79; 95%CI, 0.66-0.94; P = 0.008) as well as cancers of the respiratory and intrathoracic organs (HR, 0.78; 95%CI, 0.63-0.97; P = 0.026). The association was stronger for lung cancer (HR, 0.67; 95%CI, 0.52-0.86; P = 0.002). The subgroup analysis suggested that age, gender, smoking and BMI were related to the decreased cancer incidence of the respiratory and intrathoracic organs, lung and the female genitalia. Positive linear associations were observed between paternal age and cancer incidence of the female genitalia, respiratory and intrathoracic organs and the lungs. These findings indicate that advanced paternal age is an independent protective factor against various cancers in offspring.

Cerebrospinal fluid-based metabolomics to characterize different types of brain tumors.

BACKGROUND: Brain tumors cause significant morbidity and mortality due to rapid progression and high recurrence risks. Reliable biomarkers to improve diagnosis thereof are desirable. OBJECTIVE: This work aimed to identify panels of biomarkers for diagnostic purposes using cerebrospinal fluid (CSF)-based metabolomics. METHODS: A cohort of 163 histologically-proven patients with brain disorders was involved. Comprehensive CSF-based metabolomics was achieved by liquid chromatography-quadrupole time-of-flight spectrometric (LC-Q/TOF-MS) and multivariate statistical analyses. The diagnostic performance of the metabolic markers was evaluated using receiver operating characteristic curves. RESULTS: A total of 508 ion features were detected by the LC-Q/TOF-MS analysis, of which 27 metabolites were selected as diagnostic markers to discriminate different brain tumor types. The area under the curve (AUC) was 0.91 for lung adenocarcinoma patients with brain metastases (MBT) vs. lung adenocarcinoma patients without brain metastases (NMBT), 0.83 for primary central nervous system lymphoma (PCNSL) vs. secondary central nervous system involvement of systemic lymphoma (SCNSL), 0.77 for PCNSL vs. MBT, 0.87 for SCNSL vs. MBT, 0.86 for MBT vs. nontumorous brain diseases (NT), and 0.80 for PCNSL vs. NT. Perturbed metabolic pathways between the comparisons related mainly to amino acids and citrate metabolism. CONCLUSIONS: CSF-based metabolomics to a large extent reliably identifies significant metabolic differences between different brain tumors and shows great potential for diagnosis of brain tumors.

Intestinal Surgery Contributes to Acute Cerebellar Ataxia Through Gut Brain Axis.

Introduction: Acute cerebellar ataxia (ACA) is the most common form of pediatric ataxia. Changes in gut flora can modulate the nervous system, influencing brain function via the gut-brain axis (GBA). This study aimed to illustrate the relationship between intestinal microbiota and ACA. Method: A total of 30 and 12 children were randomly sampled from history of intestinal surgery (HOIS) and no intestinal surgery groups (NHOIS), respectively. In addition, 10 healthy children who sought physical examination in Children's Hospital of Nanjing Medical University were recruited as a control group. The stool samples were 16S rRNA detected. Results: We observed that many ACA children had intestinal surgery history prior to the onset of ACA. The 16S rRNA sequencing indicated that HOIS and control groups were well-distinguished by principal component analysis. The discrepancy between HOIS and NHOIS groups were also displayed by principal component analysis score plot. However, no differences were found between NHOIS and control groups. The results of student's t-test were consistent with principal component analysis. A total of nine different genera were identified between HOIS and control groups. Five genera and a phylum showed significant differences between HOIS and NHOIS groups. Conclusion: Altered genera and phyla associated with ACA were identified. Our findings provide new insight into treating and preventing ACA.

Plasma metabolites mediate the effect of HbA1c on incident cardiovascular disease.

BACKGROUND: We aim to discover whether HbA1c affects incident cardiovascular disease (CVD) through regulating endogenous metabolites. METHODS AND RESULTS: Totally, 2019 plasma samples were analyzed by liquid chromatography-quadrupole time-of-flight mass spectrometry. Logistic regression and linear regression were used to screen metabolites which were associated with both CVD and HbA1c. The VanderWeele's mediation approach was performed to assess the direct effect and indirect effect (IE) in the counterfactual model. Forty-eight metabolites showed an association with both HbA1c and CVD risk. Forty-four of the 48 metabolites worked as mediators mediated in HbA1c's effect on CVD (odds ratio [OR]IE from 0.997 to 6.098, false discovery rate q < 0.05, mediated proportion from 0.4% to 85.4%). Pathway enrichment analysis indicated that different metabolic pathway showed significant IE (butanoate metabolism ORIE = 1.058, mediated proportion = 16.0%; alanine, aspartate and glutamate metabolism ORIE = 1.082, mediated proportion = 21.8%; TCA (citric acid) cycle metabolism ORIE = 1.048, mediated proportion = 13.8%; phenylalanine metabolism ORIE = 1.067, mediated proportion = 18.4%; glycerophospholipid metabolism ORIE = 3.007, mediated proportion = 82.2%; all the P < .01). CONCLUSIONS: Our findings suggest that metabolites mediate the effect of HbA1c on incident CVD and provide a new study sight into pathogenesis of CVD.

Efficacy and safety of drug-eluting stenting compared with bypass grafting in diabetic patients with multivessel and/or left main coronary artery disease.

Although percutaneous coronary intervention (PCI) with drug-eluting stents (DESs) and bypass grafting are generally believed to be superior revascularization strategies in patients with coronary artery disease (CAD), the optimal strategy for diabetic patients is still controversial. This meta-analysis was performed to compare two methods of revascularization for patients with diabetes mellitus with left main coronary artery lesions or disease in multiple coronary arteries. Compared with the coronary artery bypass grafting (CABG) group, those receiving PCI-DES showed a greater risk of major adverse cardiovascular events (MACEs) (hazard ratio [HR]: 1.12, 95% confidence interval [CI]: 1.01-1.25, P = 0.03), major adverse cardiac and cerebrovascular events (MACCEs) (HR: 1.85, 95% CI: 1.58-2.16; P < 0.001), stroke (HR: 1.15, 95% CI: 1.02-1.29, P = 0.02), myocardial infarction (MI) (HR: 1.48, 95% CI: 1.04-2.09, P = 0.03), and repeat revascularization (HR: 3.23, 95% CI: 1.37-7.59, P = 0.007). CABG for diabetic patients with multivessel and/or left main CAD was superior to PCI-DES with regard to MACEs, MACCEs, MI, repeat revascularization and stroke, but there was no clear difference in all-cause mortality.

[Silencing hypoxia inducible factor-2α gene by small interference RNA inhibits the growth of mammosphere cells in nude mice under hypoxic microenvironment].

OBJECTIVE: To explore the effects of silencing hypoxia inducible factor-2α (HIF-2α) by small interference RNA on the growth of mammosphere cells in nude mice under hypoxic microenvironment. METHODS: The empty and interference vectors were transfected into MCF-7 cell. Then G418 was added to screen the positive cells to obtain stable cell line. The empty and interference vectors were inoculated subcutaneously into left and right back near hind limb of nude mice. The volume and weight of tumors were calculated respectively. The expressions of HIF-2α, CD44, OCT-4 and KLF-4 protein in xenograft tumor tissues were detected by Western blot. RESULTS: The expression vector of HIF-2α-siRNA was successfully established. The formation of mammosphere was lowered by silencing HIF-2α gene expression. In contract to empty vector group cell, there were obvious decreases in the volumes and weights of tumors in interference group (P < 0.05). The expression of HIF-2α protein of interference group (0.42 ± 0.01) was much lower than that of the empty vector group (0.89 ± 0.03, P < 0.05), the expression of CD44 protein of interference group (0.21 ± 0.01) was much lower than the empty vector group (0.78 ± 0.03, P < 0.05), the expression of OCT-4 protein of interference group (0.42 ± 0.01)was much lower than the empty vector group (0.68 ± 0.03, P < 0.05) and the expression of KLF-4 protein of interference group (0.34 ± 0.01) was much lower than the empty vector group (0.72 ± 0.03, P < 0.05). CONCLUSION: Silencing HIF-2α gene can effectively inhibit the growth of breast cancer stem cells in nude mice under hypoxic microenvironment. Its mechanism may be through inhibited capacity for self-renewal and proliferation of breast cancer stem cells in vivo through the down-regulated expressions of markers associated with stem cells. HIF-2α is expected to become a new target for gene therapy of breast cancer.

[Expression of breast cancer resistance protein and p-glycoprotein in residual breast cancer tissue after chemotherapy and its correlation with cancer stem cells].

OBJECTIVE: To compare the expression differences of breast cancer resistance protein(BCRP/ABCG2) and P-glycoprotein(P-gp) in breast cancer tissue before chemotherapy and in residual breast cancer tissue, and to explore its correlation with breast cancer stem cells. METHODS: Immunohistochemistry was used to detect the expression of ABCG2, P-gp, and breast cancer stem cells(BCSCs) markers(CD44 and CD24) in breast cancer tissue before chemotherapy and residual breast cancer tissue after chemotherapy. Immunofluorescence was applied for determination of the CD44 and CD24 protein expressions of BCSCs microspheres cells. The monoclone-forming ability of BCSCs microspheres cells was detected by limited dilution assay. The expressions of ABCG2, P-gp, CD44, and CD24 proteins were detected by Western blot. RESULTS: Compared with those in breast cancer tissue before chemotherapy, the expression levels of ABCG2 and P-gp were positively correlated with the expression level of CD44 protein(Χ(2)=41.34, r=0.83;Χ(2)=22.81, r=0.61) in residual breast cancer tissue after chemotherapy;meanwhile, they were negatively correlated with the expression of CD24 protein(Χ(2)=-21.25, r=0.72;Χ(2)=-17.26, r=0.65) (all P<0.05) .The diameter of BCSCs microspheres were increased significantly after chemotherapy.The content of BCSCs increased by about 2.5 times after chemotherapy.The expressions of ABCG2, P-gp and CD44 proteins significantly increased and that of CD24 protein significantly declined(P<0.05) . CONCLUSION: Chemotherapy endows residual breast cancer tissue with cancer stem cells-like features, leading to multidrug resistance of breast cancer.