Gene expression data from microarrays are being applied to predict preclinical and clinical endpoints, but the reliability of these predictions has not been established. In the MAQC-II project, 36 independent teams analyzed six microarray data sets to generate predictive models for classifying a sample with respect to one of 13 endpoints indicative of lung or liver toxicity in rodents, or of breast cancer, multiple myeloma or neuroblastoma in humans. In total, >30,000 models were built using many combinations of analytical methods. The teams generated predictive models without knowing the biological meaning of some of the endpoints and, to mimic clinical reality, tested the models on data that had not been used for training. We found that model performance depended largely on the endpoint and team proficiency and that different approaches generated models of similar performance. The conclusions and recommendations from MAQC-II should be useful for regulatory agencies, study committees and independent investigators that evaluate methods for global gene expression analysis.
Diabetic nephropathy (DN) is a serious complication of diabetes with a poorly defined etiology and limited treatment options. Early intervention is key to preventing the progression of DN. Mitofusin 2 (Mfn2) regulates mitochondrial morphology and signaling, and is involved in the pathogenesis of numerous diseases. Furthermore, Mfn2 is also closely associated with the development of diabetes, but its functional roles in the diabetic kidney remain unknown. This study investigated the effect of Mfn2 at an early stage of DN. Mfn2 was overexpressed by adenovirus-mediated gene transfer in streptozotocin-induced diabetic rats. Clinical parameters (proteinuria, albumin/creatinine ratio), pathological changes, ultra-microstructural changes in nephrons, expression of collagen IV and phosph-p38, ROS production, mitochondrial function, and apoptosis were evaluated and compared with diabetic rats expressing control levels of Mfn2. Endogenous Mfn2 expression decreased with time in DN. Compared to the blank transfection control group, overexpression of Mfn2 decreased kidney weight relative to body weight, reduced proteinuria and ACR, and improved pathological changes typical of the diabetic kidney, like enlargement of glomeruli, accumulation of ECM, and thickening of the basement membrane. In addition, Mfn2 overexpression inhibited activation of p38, and the accumulation of ROS; prevented mitochondrial dysfunction; and reduced the synthesis of collagen IV, but did not affect apoptosis of kidney cells. This study demonstrates that Mfn2 overexpression can attenuate pathological changes in the kidneys of diabetic rats. Further studies are needed to clarify the underlying mechanism of this protective function. Mfn2 might be a potential therapeutic target for the treatment of early stage DN.
Many patients with chronic hepatitis B (CHB) seek help from traditional Chinese medicine (TCM). TCM treatment is based on syndrome differentiation. This study aimed to investigate the syndrome distribution in populations of CHB patients. The pre-specific search strategy was set, and 93 studies (20,106 participants) were identified by electronic and hand searches. The methodological quality of included studies was assessed. Data on syndrome distribution and correlations between syndromes and severity of CHB, were extracted and analyzed. Forty-seven syndromes were identified under 24 different syndrome diagnosis systems for CHB. The majority of included studies reported Liver Depression and Spleen Deficiency (LDSD) (52.54% of studies) or Liver-Gallbladder Dampness Heat (LGDH)/Dampness-Heat Obstructing Middle Energizer (DHME) (32.20%) as the major syndromes in CHB patients without cirrhosis. Pooled analysis revealed that LDSD and LGDH/DHME accounted for 61.19% of participants without cirrhosis. In addition, Liver-Kidney Yin Deficiency (LKYinD) (40.99%) and Spleen-Kidney Yang Deficiency (SKYangD) (40.43%) syndromes were common in patients with severe CHB. The percentage of patients with Blood Stasis syndrome increased as the disease progressed to cirrhosis (32.09%). To conclude, LDSD and LGDH/DHME syndromes are found in a significant majority of CHB patients, particularly in the early stages. LKYinD, SKYangD and Blood Stasis dominate in patients at more advanced stages. More epidemiological studies of high methodological quality on syndrome distribution in CHB and standardization of syndrome differentiation for CHB are required to confirm the trends indicated by the studies reviewed here; confirming these trends can increase the efficacy of treatment and give guidance to doctors.
ER negative cell clusters showed a significantly higher expressing frequency of multiple tumor progression related genes than their adjacent ER positive counterparts, suggesting that they are likely to be biologically more aggressive and have a greater potential for invasion.
Interstitial cystitis (IC) is a severely debilitating and chronic disorder with unclear etiology and pathophysiology, which makes the diagnosis difficult and treatment challenging. To investigate the role of immunity in IC bladders, we sequenced 135,091 CD45+ immune cells from 15 female patients with IC and 9 controls with stress urinary incontinence using single-cell RNA sequencing (scRNA-seq). 22 immune subpopulations were identified in the constructed landscape. Among them, M2-like macrophages, inflammatory CD14+ macrophages, and conventional dendritic cells had the most communications with other immune cells. Then, a significant increase of central memory CD4+ T cells, regulatory T cells, GZMK+CD8+ T cells, activated B cells, un-switched memory B cells, and neutrophils, and a significant decrease of CD8+ effector T cells, Th17 cells, follicular helper T cells, switched memory B cells, transitional B cells, and macrophages were noted in IC bladders. The enrichment analysis identified a virus-related response during the dynamic change of cell proportion, furthermore, the human polyomavirus-2 was detected with a positive rate of 95% in urine of patients with IC. By integrating the results of scRNA-seq with spatial transcriptomics, we found nearly all immune subpopulations were enriched in the urothelial region or located close to fibroblasts in IC bladders, but they were discovered around urothelium and smooth muscle cells in control bladders. These findings depict the immune landscape for IC and might provide valuable insights into the pathophysiology of IC.
Background: To determine the efficacy of magnetic stimulation (MS) in female patients with stress urinary incontinence (SUI) by performing a meta-analysis on peer-reviewed randomized controlled trails (RCTs). Methods: PubMed, Embase, and Cochrane library were retrieved for any peer-reviewed original articles in English. Databases were searched up to July 2018. Included studies investigated effects of MS on SUI. The data were analyzed by review manager 5.3 software (Cochrane Collaboration, Oxford, UK). Results: A total of 4 studies involving 232 patients were identified and included in present meta-analysis. Compared with the sham stimulation, the MS group had statistically significantly fewer leaks/3 days (MD = −1.42; 95%CI: −2.42 to −0.59; P = .007), less urine loss on pad test (g.)/24 h (MD = −4.99; 95%CI: −8.46 to −1.53; P = .005), higher QoL scores (MD = 0.42; 95%CI: 0.02–0.82; P = .009), and lower ICIQ scores (MD = −4.60; 95%CI: −5.02 to −4.19; P < .001). MS presented higher cure or improvement rate, with a statistically significant improvement in UDI and IIQ-SF scores compared to sham stimulation. No MS-related adverse effects were reported in study. Conclusion: MS leads to an improvement in SUI without any reported safety concerns and an improvement in patient quality of life. The long-term outcome of this technique remains unclear and is the subject of ongoing research.
Aims The cellular functions of bladder urothelial cells in interstitial cystitis/bladder pain syndrome (IC/BPS) have not been well revealed and understood. Thus, the study aims to identify key genes and significant pathways in urothelium corresponding to IC/BPS in a lipopolysaccharide (LPS)‐induced cystitis model and provide novel clues related to diagnosis and treatment of IC/BPS. Methods Human urothelial cells (HUCs) were incubated with LPS (50 μg/ml for 24 h). Microarray was applied to analyze the differentially expressed genes (DEGs) between HUCs under LPS treatment and the control group. DEGs in the two groups were identified and then used for enrichment analysis. Subsequently, protein–protein interaction (PPI) network based on DEGs was constructed. Lastly, the top five key genes were identified through the Cytoscape (version 3.7.2) using the “Clustering Coefficient” algorithm. Results One hundred and seventy‐one DEGs (96 upregulated genes and 75 downregulated genes) were identified between the LPS treatment and control group. The established PPI network was composed of 169 nodes and 678 edges. Moreover, C19orf33, TRIM31, MUC21, ELF3, and IFI27 were identified as hub genes in the PPI network. Subsequently, a statistically increased expression level of TRIM31 and ELF3 was validated by real‐time quantitative‐polymerase chain reaction and immunohistochemistry in bladder tissues from 20 patients with IC/BPS. Conclusions TRIM31 and ELF3 may be the two hub genes in urothelium corresponding to IC/BPS. More studies are warranted to further validate the findings. The identified marker genes may be useful targets for further studies to develop diagnostic tools and more effective therapies for a broader group of women with IC/PBS.
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