Integrated Analysis of Transcriptomic Data Reveals Key Anti-CKD Targets and Anti-ESRD Targets.

BACKGROUND: Chronic kidney disease (CKD) is a kidney disease in which there is gradual loss of kidney function over time and end-stage renal disease (ESRD) is the final stage of CKD. Both CKD and ESRD are worldwide health problems with a high economic cost to health systems. However, the molecular mechanisms of the development of CKD and ESRD remain poorly understood. This study aimed to systematically elucidate the molecular mechanisms of the development of CKD and ESRD. METHODS: Transcriptome data of CKD and ESRD were downloaded from the NCBI-GEO database. Differentially expressed genes between cases and controls (chronic kidney disease patients vs. controls, end-stage renal disease patients vs. controls) were calculated using the empirical Bayes algorithm. Gene set enrichment analysis (GSEA) was used for analyzing the KEGG pathway difference between cases and controls. Furthermore, CKD and ESRD target genes were obtained from the Thomson Reuters Integrity database. Tissue-specific gene interaction network analysis was performed using the GIANT web server. RESULTS: There were multiple damaged pathways in ESRD but only a few pathways were disturbed in CKD. Furthermore, we identified 9 dysregulated anti-ESRD genes but no dysregulated anti-CKD genes. Network analysis revealed that the NF-kB signaling pathway was essential for ESRD. CONCLUSIONS: This study revealed several crucial anti-ESRD genes that are involved in the regulation of the NF-kB signaling pathway. This information may be helpful for the treatment of ESRD.

Current Status of Research on the Role of Circular RNAs in Hepatocellular Carcinoma and Clinical Implications.

The latest statistics show that rates of morbidity and mortality for hepatocellular carcinoma are gradually increasing over time. Accumulating evidence indicates that circular RNAs (circRNAs) participate in the regulation of gene transcription and translation and exert a crucial role in endogenous RNA network. circRNAs are implicated in the pathogenesis of numerous tumors including hepatocellular carcinoma (HCC), gastric carcinoma and bladder cancer. Of note, the effect of circRNAs in HCC has drawn increasing public attention. Previous studies revealed that the function of circRNAs mainly consists of sponges of miRNA and RNA-binding proteins, alternative splicing of pre-mRNAs, transcriptional and translational regulators, and potential to encode proteins. In addition, recent research data indicate that the expression level of circRNAs is closely correlated with metastasis, invasion, and occurrence of HCC in patients. These findings imply that circRNAs may be useful as biomarkers for diagnosis and prediction of prognosis of HCC. In this review, we have systemically summarized current viewpoints regarding the role of circRNAs expression in HCC to provide an important reference illustrating the underlying mechanism of HCC.

Bioinformatics Analysis Identifies Protein Tyrosine Kinase 7 (PTK7) as a Potential Prognostic and Therapeutic Biomarker in Stages I to IV Hepatocellular Carcinoma.

BACKGROUND Worldwide, hepatocellular carcinoma (HCC) accounts for 80-90% of all cases of primary liver cancer, and is one of the ten most common malignancies. This study used bioinformatics analysis to identify genes associated with patient outcome in stages I-IV HCC and the gene pathways that distinguished between normal liver and liver cells and HCC and human HCC cell lines. MATERIAL AND METHODS Target genes were defined as those that had marketed drugs or drugs under development targeting a specific gene and acquired from the Clarivate Analytics Integrity Database. Differential expression gene analysis, co-expression network analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, survival analysis and receiver operating characteristic (ROC) curve analysis were used to explore the similarities and differences in gene expression profiles, functional associations, and survival in stage I-IV HCC. Normal liver cells (HL-7702) and HCC cell lines (HepaRG, HepG2, SK-Hep1, and Huh7) were studied using Western blot and quantitative reverse transcription PCR (RT-qPCR). RESULTS Hierarchical gene clustering identified target genes that distinguished between HCC and normal liver tissue. For stages I-IV HCC, there were seven commonly upregulated target genes EPHB1, LTK, NTRK2, PTK7, TBK1, TIE1, and TLR3, which were mainly involved in immune and signaling transduction pathways. PTK7 was highly expressed in stage I-IV HCC and was an independent prognostic marker for reduced overall survival (OS). CONCLUSIONS Bioinformatics analysis, combined with patient survival analysis, identified PTK7 gene expression as a potential therapeutic target and prognostic biomarker for all stages of HCC.

Role of Small Interfering RNA Silencing Protein Kinase C-α Gene on the Occurrence of Ultrafiltration Failure in Peritoneal Dialysis Rats.

This study aims to explore the effect of PKC-α gene silencing on the occurrence of ultrafiltration failure (UFF) in peritoneal dialysis (PD) rats. Forty-eight male SD rats were collected to establish 5/6 renal resection uremic and uremic PD rats models. Rats were assigned into control, sham operation, uremia, PD-2 W (peritoneal dialysis for 2 weeks), PD-4 W (peritoneal dialysis for 4 weeks), negative control (NC) (peritoneal dialysis for 4 weeks, and injected 0.1 mg/kg blank plasmid into abdominal cavity) and PKC-α siRNA (peritoneal dialysis for 4 weeks, and injected 0.1 mg/kg PKC-α siRNA into abdominal cavity) groups. CD34 staining was performed to determine microvessel density (MVD) for peritoneal tissues. The mRNA and protein expression of PKC-α in peritoneal tissue were detected by qRT-PCR and Western blot. Compared with the control group, MVD, the mRNA and protein expression of PKC-α were significantly increased in rats of the uremia, PD-2 W, PD-4 W, NC, and PKC-α siRNA groups. Compared with the uremia group, MVD, the mRNA and protein expression of PKC-α were increased, the changes observed in the PD-4 W and NC groups were better obvious than in the PD-2 W group. In comparison with the PD-4 W and NC groups, MVD, the mRNA and protein expression of PKC-α in rats were decreased in the PKC-α siRNA group. PKC-α gene has a high expression in uremic PD rats, and PKC-α gene silencing is able to increase UF while decrease MVD and glucose transport in peritoneal tissues thus reversing UFF in PD rats. J. Cell. Biochem. 118: 4607-4616, 2017. © 2017 Wiley Periodicals, Inc.

[Clinical Significance of Serum ADA Combined with GLB, CREA, ß2-MG and HGB in Newly Diagnosed Multiple Myeloma].

OBJECTIVE: To investigate the role of serum adenosine deaminase (ADA) combined with globulin (GLB), creatinine (CREA), ß2-microglobulin (ß2-MG) and hemoglobin (HGB) in the initial screening of multiple myeloma (MM), in order to reduce missed diagnosis and misdiagnosis of MM. METHODS: A retrospective analysis was performed on 62 newly diagnosed multiple myeloma (NDMM) patients who were admitted to the Department of Hematology of the First Affiliated Hospital of Chengdu Medical College from April 2018 to December 2021, and 33 patients with benign hematologic diseases and 30 healthy subjects were selected as the control group. The expression of ADA in pan-cancer was analyzed using TCGA and GTEx databases. The general data and laboratory indicators of the subjects were collected, and the differences of ADA activity and other laboratory indicators in each group were compared. The relationship between serum ADA activity and clinical data of NDMM patients was analyzed. The changes of ADA activity before and after chemotherapy in NDMM patients and the differences of ADA activity in NDMM patients with different DS and ISS stages were compared. Multivariate logistic regression was used to analyze the risk factors of NDMM. The receiver operating characteristic(ROC) curve was used to evaluate the diagnostic efficacy of ADA and other laboratory indicators in MM. Bioinformatics method was used to analyze the co-expression networks and enrichment pathways of ADA. RESULTS: ADA level was significantly upregulated in tissues of 14 types of cancer in TCGA database, and ADA was highly expressed in 11 types of cancer in TCGA combined with GTEx databases. The serum levels of ADA, GLB, uric acid (UA), cystatin C (CysC) and ß2-MG in the NDMM group were significantly higher than those in benign hematologic disease group and healthy control group ( P < 0.05), while the levels of ALB and the value of albumin to globulin ratio (A∶G) in the NDMM group were significantly lower than those in the other two groups ( P < 0.001). There were significant differences in DS stage (P =0.036), ISS stage (P =0.019) and the levels of CREA (P =0.036), UA (P =0.034), ß2-MG (P =0.019) in NDMM patients with different ADA activity levels. After primary chemotherapy, ADA activity and ß2-MG concentration were decreased in NDMM patients ( P < 0.01). The comparison results of patients in different stages showed that ADA activity of patients in DS stage I+II was significantly lower than that of patients in DS stage III (P <0.05), and ADA activity of patiens in ISS stage I+II was significantly lower than that of patients in ISS stage III ( P < 0.01). Multivariate logistic regression analysis showed that increased GLB, increased ADA activity, increased CREA, increased ß2-MG and decreased HGB were independent risk factors for NDMM. The area under the curve (AUC) of ADA in the diagnosis of MM was 0.847, and the AUC of ADA combined with GLB, CREA, ß2-MG and HGB in the diagnosis of MM was 0.940. The results of co-expression network and enrichment pathway analysis showed that ADA bounded to 20 proteins and it was significantly associated with the metabolic pathways of purine, pyrimidine, nicotinate and nicotinamide. CONCLUSION: The detection of ADA activity in serum is of positive significance for the auxiliary diagnosis, therapeutic evaluation and monitoring the progress of NDMM patients. ADA combined with GLB, CREA, ß2-MG and HGB can improve the detection rate of MM, and reduce missed diagnosis and misdiagnosis to a certain extent.

Calcium dobesilate-induced hyperpyrexia: A case report.

RATIONALE: Calcium dobesilate, a vasoprotective and antioxidant agent, is gradually being used for the treatment of chronic kidney disease. Calcium dobesilate-induced hyperpyrexia is a rare clinical event, and few studies have reported it. PATIENT CONCERNS: The patient took calcium dobesilate, which caused high fever. After stopping calcium dobesilate, his body temperature returned to normal. DIAGNOSES: Based on the medical history, symptoms and signs, the patient was diagnosed with drug fever caused by calcium dobesilate. INTERVENTIONS: Calcium dobesilate was stopped, and supportive treatment was given at the same time. OUTCOMES: The present case was initially misdiagnosed as a fever caused by a bacterial infection, but treatment with the antibiotic moxifloxacin was ineffective. Based on the patient's medical history, laboratory and examination results, body temperature changes, and Naranjo Advanced Drug Response Scale, calcium dobesilate-induced hyperpyrexia was diagnosed. After discontinuation of calcium dobesilate, the patient's body temperature normalized, and no additional episode of fever was observed at follow-up. LESSON: Moreover, misdiagnosis and mistreatment of this condition can deteriorate the patient's condition. Herein, we report a case of calcium dobesilate-induced hyperpyrexia that occurred during the treatment of chronic renal insufficiency. Subsequently, a systematic analysis of the patient's diagnosis and treatment was reviewed. If unexplained high fever develops during the use of calcium dobesilate, calcium dobesilate-induced hyperpyrexia should be considered. Accordingly, calcium dobesilate should be discontinued.

Profiling of gene fusion involving targetable genes in Chinese gastric cancer.

BACKGROUND: Approximately half of all new cases of gastric cancer (GC) and related deaths occur in China. More than 80% of patients with GC are diagnosed at an advanced stage, which results in poor prognosis. Although HER2-directed therapy and immune checkpoint inhibitors have been somewhat successful, new drugs are still needed for the treatment of GC. Notably, several gene fusion-targeted drugs have been approved by the United States Food and Drug Administration for solid tumors, including GC, such as larotrectinib for NTRK fusion-positive cancers and zenocutuzumab for NRG1 fusion-positive cancers. However, gene fusions involving targetable genes have not been well characterized in Chinese patients with GC. AIM: To identify the profile of fusions involving targetable genes in Chinese patients with GC using clinical specimens and determine the distribution of patients with gene fusion variants among the molecular subtypes of GC. METHODS: We retrospectively analyzed gene fusion events in tumor tissue samples from 954 Chinese patients with GC. Clinicopathological characteristics were obtained from their medical records. Genetic alterations, such as single nucleotide variants, indels, amplifications, and gene fusions, were identified using a targeted sequencing panel containing 825 genes. Fusions were validated by fluorescence in situ hybridization (FISH) using break-apart probes. The microsatellite instability (MSI) status was evaluated using MSIsensor from the targeted sequencing panel data. Tumor mutational burden (TMB) was calculated using the total number of nonsynonymous mutations divided by the total genomic targeted region. Chi-square analysis was used to determine the enrichment of gene fusions associated with the molecular subtypes of GC. RESULTS: We found that 1.68% (16/954) of patients harbored 20 fusion events involving targetable genes. RARA fusions (n = 5) were the most common, followed by FGFR2, BRAF, MET, FGFR3, RET, ALK, EGFR, NTRK2, and NRG1 fusions. Two of the RARA fusions, EML4-ALK (E6:E20) and EGFR-SEPTIN14 (E7:E10), have been identified in other tumors but not in GC. Surprisingly, 18 gene fusion events were previously not reported in any cancer types. Twelve of the eighteen novel gene fusions included complete exons encoding functional domains of targetable genes, such as the tyrosine kinase domain of receptor tyrosine kinases and the DNA- and ligand-binding domains of RARA. Consistent with the results of detection using the targeted sequencing fusion panel, the results of FISH (fluorescence in situ hybridization) confirmed the rearrangement of FGFR2 and BRAF in tumors from patients 04 and 09, respectively. Genetic analysis indicated that the fusion genes were significantly enriched in patients with ERBB2 amplification (P = 0.02); however, there were no significant differences between fusion-positive and fusion-negative patients in age, sex, MSI status, and TMB. CONCLUSION: We characterized the landscape of fusions involving targetable genes in a Chinese GC cohort and found that 1.68% of patients with GC harbor potential targetable gene fusions, which were enriched in patients with ERBB2 amplification. Gene fusion detection may provide a potential treatment strategy for patients with GC with disease progression following standard therapy.

The clinical significance of neutrophil-lymphocyte ratio in patients treated with hemodialysis complicated with lung infection.

ABSTRACT: The goal of this work was to investigate the potential significance of neutrophil-lymphocyte ratio (NLR) in patients treated with maintenance hemodialysis (MHD).Herein, we retrospectively reviewed the electronic medical records of 100 patients with end-stage renal failure who were treated with MHD. All patients enrolled in this study met the inclusion criteria and were followed. The differences in each indicator between the two groups were compared using the Wilcoxon rank-sum test. On the other hand, Spearman correlation and logistic regression analysis were used to explore the correlation and risk factors for pulmonary infection between NLR and other indicators. Finally, we determined the optimal cut-off values for NLR, hypersensitive c-reactive protein (hs-CRP), and procalcitonin (PCT) diagnosis of pulmonary infection using the receiver operating characteristic curve.We found that NLR was positively correlated with age, PCT, hs-CRP, and hospital stay, but negatively correlated with hemoglobin, red blood cell, and Albumin. The expression levels of PCT, hs-CRP, and NLR in the infected group decreased significantly than those before treatment. Multiple regression analysis revealed that NLR is an important independent risk factor for MHD patients with pulmonary infection. Additionally, receiver operating characteristic curve analysis showed that the sensitivity, specificity, and area under the curve were 87.76%, 100%, and 0.920 when using NLR combined with hs-CRP to predict pulmonary infection in MHD patients, whereas that of NLR combined with PCT were 87.76%, 96.08%, and 0.944, respectively.Findings from this study suggested that NLR is an independent risk factor for MHD patients with pulmonary infection, which can effectively predict pulmonary infection. Moreover, sensitivity and specificity were greatly enhanced when using NLR combined with PCT/hs-CRP to predict pulmonary infection in MHD patients.

Recycling lower continental crust in the North China craton.

Foundering of mafic lower continental crust into underlying convecting mantle has been proposed as one means to explain the unusually evolved chemical composition of Earth's continental crust, yet direct evidence of this process has been scarce. Here we report that Late Jurassic high-magnesium andesites, dacites and adakites (siliceous lavas with high strontium and low heavy-rare-earth element and yttrium contents) from the North China craton have chemical and petrographic features consistent with their origin as partial melts of eclogite that subsequently interacted with mantle peridotite. Similar features observed in adakites and some Archaean sodium-rich granitoids of the tonalite-trondhjemite-granodiorite series have been interpreted to result from interaction of slab melts with the mantle wedge. Unlike their arc-related counterparts, however, the Chinese magmas carry inherited Archaean zircons and have neodymium and strontium isotopic compositions overlapping those of eclogite xenoliths derived from the lower crust of the North China craton. Such features cannot be produced by crustal assimilation of slab melts, given the high Mg#, nickel and chromium contents of the lavas. We infer that the Chinese lavas derive from ancient mafic lower crust that foundered into the convecting mantle and subsequently melted and interacted with peridotite. We suggest that lower crustal foundering occurred within the North China craton during the Late Jurassic, and thus provides constraints on the timing of lithosphere removal beneath the North China craton.

A brief review concerning Chimeric Antigen Receptors T cell therapy.

The understanding concerning the function of immune system in cancer has achieved considerable advance with time passes by. Manipulating genetically engineered immune cells were investigated as a novel strategy for treating cancer. Chimeric antigen receptors (CARs) are recombinant protein molecules by merging the exquisite targeting the potent cytotoxicity of T cells and specificity of monoclonal antibodies and, which could trigger serial cascades of signal transduction and thereby activate T cells to directly destroy the tumor cells. Manufacturing CAR-modified T lymphocytes were successfully implemented in treating cancer derived from they could specifically retarget tumor-associated antigens, causing effective elimination of tumor cells, which spurred the optimization and development of new CAR-T cell technology. The advancement of synthetic biology methodologies of cell therapy in CAR-T would ultimately provide us with a much safer, reliable and efficient modality to against cancer. This review primarily described the emergence, development and application of cell therapy in CAR-T, then discuss the side effects and the potential factors of tumor reccurrence caused by CAR-T cell therapy, in addition to the corresponding countermeasure concerning complications.

PLCε knockdown prevents serine/glycine metabolism and proliferation of prostate cancer by suppressing YAP.

The metabolic reprogramming is an important basis for the development of many tumors, including prostate cancer (PCa). Metabolic changes in many amino acids consist of serine and glycine affect the biological behavior of them. Phospholipase C epsilon (PLCε) plays an important role as an oncogene. However, its role in regulating amino acid metabolism remains unclear. In this study, results found significantly positive correlation between PLCε and Yes-associated protein (YAP) in PCa tissues. LC-MS/MS and GC-MS results further displayed abnormally elevated levels of serine, glycine and its some downstream metabolites in the blood of PCa patients. Secondly, PLCε knockdown can inhibit serine/glycine producing and proliferation of PCa both in vivo and in vitro. Mechanistically, PLCε may affect the serine/glycine metabolism by regulating dephosphorylation and nuclear translocation of YAP. More interestingly, verteporfin (VP, a specific inhibitor of YAP) could effectively enhance the PLCε-depletion induced inhibition of serine/glycine secretion and growth. Overall, this research revealed the possibility of anomalous serine/glycine levels in the blood for the diagnosis of PCa, identified the important role of the PLCε/YAP axis in regulating serine/glycine metabolism, cell proliferation and tumor growth, and suggested the combination of VP with PLCε-depletion may provide a new idea for the treatment of PCa.

Cloning and expression of a novel human galectin cDNA, predominantly expressed in placenta(1).

A novel human galectin cDNA (PPL13) was isolated by screening a human 18-week fetal brain library. The mRNA was predominantly expressed in placenta, while the expression of it was not or barely detectable in heart, brain, lung, liver, skeletal muscle, kidney, and pancreas by Northern blot. COS-7 cells transfected with cDNA encoding human PPL13 sequestered the protein in nuclei although it lacked any known nuclear localization signal. STS of Unigene Hs. 24236 placed the cDNA to human chromosome 19q13.2.

Cloning and expression pattern of a spermatogenesis-related gene, BEX1, mapped to chromosome Xq22.

Through screening a human fetal brain cDNA library, a cDNA similar to the mouse Bex1 was isolated. This new gene was named brain expressed X-linked protein 1 (BEX1). Northern blot analysis revealed a 1.0 kb transcript highly expressed in brain, pancreas, testis, and ovary, with lower levels present in heart, placenta, liver, kidney, spleen, thymus, prostate, small intestine, colon (no mucus), thyroid, spinal cord, and adrenal gland. No hybridization signal was seen in lung, skeletal muscle, peripheral blood leukocyte, stomach, lymph node, trachea, and bone marrow. The BEX1 gene was localized to chromosome band Xq22 between markers between DXS990 and DXS1059 by screening Stanford radiation hybrid G3 panels. In situ hybridization of mouse testis using BEX1 as a probe detected the signal in the pachytene spermatocytes and spermatids but not in spermatogonia. Furthermore, it was not detected at 6, 9, and 12 days postpartum, was present in low amount on Days 15 and 18 and its expression increased sharply after the initiation of puberty (about 21 days) in mouse testis.