Risk factors for severe and critically ill COVID-19 patients: A review.

The pandemic of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused an unprecedented global social and economic impact, and high numbers of deaths. Many risk factors have been identified in the progression of COVID-19 into a severe and critical stage, including old age, male gender, underlying comorbidities such as hypertension, diabetes, obesity, chronic lung diseases, heart, liver and kidney diseases, tumors, clinically apparent immunodeficiencies, local immunodeficiencies, such as early type I interferon secretion capacity, and pregnancy. Possible complications include acute kidney injury, coagulation disorders, thoromboembolism. The development of lymphopenia and eosinopenia are laboratory indicators of COVID-19. Laboratory parameters to monitor disease progression include lactate dehydrogenase, procalcitonin, high-sensitivity C-reactive protein, proinflammatory cytokines such as interleukin (IL)-6, IL-1ß, Krebs von den Lungen-6 (KL-6), and ferritin. The development of a cytokine storm and extensive chest computed tomography imaging patterns are indicators of a severe disease. In addition, socioeconomic status, diet, lifestyle, geographical differences, ethnicity, exposed viral load, day of initiation of treatment, and quality of health care have been reported to influence individual outcomes. In this review, we highlight the scientific evidence on the risk factors of severity of COVID-19.

Expression of tissue levels of matrix metalloproteinases and tissue inhibitors of metalloproteinases in gastric adenocarcinoma.

BACKGROUND AND OBJECTIVES: Matrix metalloproteinases (MMPs) are one of the major classes of proteolytic enzymes involved in tumor invasion and metastasis, being inhibited by naturally occurring tissue inhibitors of metalloproteinases (TIMPs). We examined mRNA expression for MMP-2, MMP-7, MMP-9, MT1-MMP, TIMP-1, and TIMP-2 in human gastric adenocarcinoma tissues, and the correlation between their expression and clinicopathological variables. METHODS: Gastric tissue samples from 72 patients with gastric adenocarcinoma were available for this study. To determine mRNA expression for MMP-2, MMP-7, MMP-9, MT1-MMP, TIMP-1, and TIMP-2, semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) was carried out on tumor and normal tissues, respectively. RESULTS: Mean MMP-2, MMP-7, MMP-9, MT1-MMP, TIMP-1, and TIMP-2 mRNA expression in the gastric adenocarcinomas was significantly higher than in the normal tissue. In terms of the invasion of the tumor, lymph node metastasis, and tumor stage of gastric adenocarcinoma, the differences in MMP-2, MMP-7, MMP-9, and MT1-MMP mRNA expression levels were significant. MMP-2, MMP-7, MMP-9, MT1-MMP, TIMP-1, and TIMP-2 mRNA expression did not differ significantly in relation to histological type of gastric adenocarcinoma. CONCLUSION: The correlation between the increased expression of MMP-2, MMP-7, MMP-9, and MTI-MMP and clinicopathological parameters reflects a role in predicting the aggressive behavior of gastric cancer.

Deacetylation as a receptor-regulated direct activation switch for pannexin channels.

Activation of Pannexin 1 (PANX1) ion channels causes release of intercellular signaling molecules in a variety of (patho)physiological contexts. PANX1 can be activated by G protein-coupled receptors (GPCRs), including α1-adrenergic receptors (α1-ARs), but how receptor engagement leads to channel opening remains unclear. Here, we show that GPCR-mediated PANX1 activation can occur via channel deacetylation. We find that α1-AR-mediated activation of PANX1 channels requires Gαq but is independent of phospholipase C or intracellular calcium. Instead, α1-AR-mediated PANX1 activation involves RhoA, mammalian diaphanous (mDia)-related formin, and a cytosolic lysine deacetylase activated by mDia - histone deacetylase 6. HDAC6 associates with PANX1 and activates PANX1 channels, even in excised membrane patches, suggesting direct deacetylation of PANX1. Substitution of basally-acetylated intracellular lysine residues identified on PANX1 by mass spectrometry either prevents HDAC6-mediated activation (K140/409Q) or renders the channels constitutively active (K140R). These data define a non-canonical RhoA-mDia-HDAC6 signaling pathway for GαqPCR activation of PANX1 channels and uncover lysine acetylation-deacetylation as an ion channel silencing-activation mechanism.

Clinicopathologic characteristics and prognosis of mucinous gastric carcinoma.

BACKGROUND AND OBJECTIVES: Reports of clinicopathological features and prognosis in patients with mucinous gastric carcinoma (MGC) are conflicting. The aim was to describe the clinicopathological features and prognosis of patients with MGC in comparison with nonmucinous gastric carcinoma (NMGC). METHODS: We reviewed the records of 1,278 consecutive patients diagnosed with gastric carcinoma who were resected surgically from 1993 to 2003. Among them, 48 patients (3.8%) with MGC were compared to 1,230 patients with NMGC. RESULTS: There were significant differences in tumor location, stage of disease, lymphatic invasion, and vascular invasion between the patients with MGC and NMGC. The overall 5-year survival of patients with MGC was 27.2% as compared with 42.8% for patients with NMGC (P = 0.031). For the patients with the same stage, there was no significant difference between MGC and NMGC. With respect to patients with MGC, multivariate analysis showed that lymph node metastasis and curative resection were significant factors affecting survival. CONCLUSIONS: MGC is rare and detected mostly in an advanced stage. Mucinous histology type itself is not an independent prognostic factor.

[Effects of EGCG on Proliferation, Cell Cycle and DAPK1 Gene Methylation of Acute Promyelocytic Leukemia NB4 Cell Line].

OBJECTIVE: To investigate the effects of epigallocatechin-3-gallate (EGCG) on proliferation and cell cycle of acute promyelocytic leukemia NB4 cell line and to clarify the molecular mechanism. METHODS: NB4 cells were treated with 0,50,75,100 and 125µmol/L of EGCG for 24, 48, 72 and 96 h, respectively. The proliferation level of NB4 cells was measured by CCK-8 assay. The cell cycle progression of NB4 cells was assayed by flow cytometry. The mRNA expression levels of DNMT1, DNMT3a and DAPK1 were detected by RT-PCR. The methylation status of gene was tested by methylation specific PCR, and the expression level of DAPK1 protein was detected by Western blot. RESULTS: The proliferation and cell cycle progression of NB4 cells treated with EGCG were inhibited and showed the characteristic of time-dependent and dose-dependent manner. The expression level of DAPK1 and DNMT3a decreased in NB4 cells treated with EGCG. The expression level of DAPK increased in NB4 cells treated with EGCG, while the methylation of DAPK1 gene decreased. CONCLUSION: EGCG inhibits the proliferation and cell cycle progression of NB4 cells by inhibiting the expression of DNMT1 and DNMT3a and down-regulating the methylation status of DAPK1 gene.

[Effect of kurarinone on renal tubular epithelial cell-mesenchyma trans-differentiation in rats with renal interstitial fibrosis].

OBJECTIVE: To study the effect of Kurarinone on renal tubular epithelial cell-mesenchyma (ECM) trans-differentiation in rats with renal interstitial fibrosis and to explore its possible mechanisms. METHODS: The rat model of renal interstitial fibrosis was established by unilateral ureteral obstruction (UUO). Sprague-Dawley male rats were randomly divided into 3 groups, the sham-operated group, the UUO group and the Kurarinone treated group (KTG). Rats in the KTG were intraperitoneally injected with Kurarinone 100 mg/kg daily after modeling. Five rats of each group were killed respectively at day 7, 14 and 21 after UUO. The serum levels of blood urea nitrogen (BUN), serum creatinine (SCr), total protein (TP) and albumin (ALB), 24-h urinary protein excretion in rats were measured. Pathological changes of renal tissue were observed by PAS and Masson stain. The expression of transforming growth factor beta1 (TGF-beta1), Smad3, alpha-smooth muscle actin (alpha-SMA) and collagen I (Col I) in kidney were determined with immunohistochemistry. And the expressions of TGF-beta1 and alpha-SMA mRNA in renal tissue were determined using reverse transcription polymerase chain reaction (RT-PCR). RESULTS: The expression of TGF-beta1, Smad3, alpha-SMA and Col I in the KTG was significantly decreased as compared with that in the UUO group respectively, and the degree of tubular damage and renal interstitial fibrosis was also ameliorated more obviously in the KTG. The TGF-beta1 and alpha-SMA mRNA expressions in KTG were significantly lower than those in the UUO group determined at the corresponding time points (P < 0.05). CONCLUSION: Kurarinone could down-regulate the expression of TGF-beta1 and Col I, inhibit EC-M trans-differentiation, suppress the activation and proliferation of myofibroblast. The probable pathway may be by way of down-regulating Smad3 expression to interfere its induction on intercellular signal transduction and consequently ameliorate renal interstitial fibrosis.

MicroRNA-9 inhibits the gastric cancer cell proliferation by targeting TNFAIP8.

BACKGROUND AND OBJECTIVES: MicroRNA-9 is frequently dysregulated in many human carcinoma types, including gastric cancer (GC). Previous studies demonstrated that the expression of TNFAIP8 in GC is correlated with tumour occurrence, development, invasion, metastasis and prognosis. However, till now, the relationship between MicroRNA-9 and TNFAIP8 in GC has not been reported. MATERIALS AND METHODS: Levels of miR-9 and TNFAIP8 expression in GC tissues and in human GC cell lines were studied using qualitative real-time PCR (qRT-PCR) and Western blotting. Cell viability was detected using the CCK-8 and clone formation assays. A dual-luciferase reporter system was used to confirm the target gene of miR-9. RESULTS: We found that the expression level of MicroRNA-9 in GC tissues and cell lines was significantly lower than that in adjacent non-cancerous tissues and human immortalized gastric epithelial cell (GES) line, respectively. In addition, overexpression of MicroRNA-9 markedly inhibited GC cell proliferation in vitro and tumour growth in vivo. Further experiments revealed that TNFAIP8 was a direct and functional target of MicroRNA-9 in GC and overexpression of MicroRNA-9 obviously down-regulated the expression of TNFAIP8, which was involved in the gastric carcinogenesis and cancer progression. CONCLUSION: Our results suggested that MicroRNA-9-TNFAIP8 might represent a promising diagnostic biomarker for GC patients and could be a potential therapeutic target in the prevention and treatment of GC.

Microarray expression profiles of long non-coding RNAs in germinal center-like diffuse large B-cell lymphoma.

Long non-coding RNAs (lncRNAs) are continuously transcribed and are involved in various cellular activities. However, their contributions to the occurrence and development of germinal center B-cell (GCB)-like diffuse large B-cell lymphoma (DLBCL) remain largely unknown. We applied microarray technology to profile the expression of lncRNAs in two different GCB-DLBCL cell lines (OCI-ly1 and OCI-ly19) and normal B lymphocytes. We demonstrated that 21,539 lncRNAs were expressed in all of the samples analyzed. This included 1,648 lncRNAs that showed a ≥2-fold upregulation and 2,671 lncRNAs that displayed a ≥2-fold downregulation in tumor cell lines (P<0.05). The expression levels of 8 lncRNAs were validated by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Bioinformatic analyses (Gene Ontology, pathway and network analysis) were performed to predict how the differentially expressed lncRNAs may function in GCB-DLBCL. Results from the pathway analysis suggested that totals of 64 and 62 biological pathways corresponded to upregulated and downregulated transcripts, respectively (P<0.05). Additionally, we constructed a lncRNA­mRNA network for the purpose of identifying specific coding genes which were co-expressed with 5 selected lncRNAs. Conclusively, our results may contribute to a better understanding of GCB-DLBCL pathogenesis.

Downregulation of Notch1 inhibits the invasion and metastasis of human gastric cancer cells SGC7901 and MKN74 in vitro through PTEN activation and dephosphorylation of Akt and FAK.

Migration and invasion are both vital causes of mortality in patients with gastric cancer. Therefore, the inhibition of these tumour cell processes is of great importance in gastric cancer therapy. Activation of Notch has been reported in many cancers. The critical role of Notch and its regulation in tumourigenesis has been noted. Although the studies on Notch in the field of cancer have been performed extensively, the role of Notch1 signalling in gastric cancer requires further study. Inactivation of PTEN has been observed in the development of many malignant tumors, and loss of PTEN function has been implicated in tumorigenic processes. Notch acts as an upstream signalling pathway that regulates PTEN activities. However, the effect of Notch on invasion and metastasis in gastric cancer and the regulation of PTEN during this process remain poorly understood. In the present study, small interfering RNA (siRNA) was used to knock down Notch1 expression in gastric cancer cell lines SGC7901 and MKN74. The mRNA and protein expression of Notch1, PTEN, Akt and FAK were measured upon depletion of Notch1. phospho­PTEN, phospho­Akt and phospho­FAK expression were measured using western blot analysis. Migration and invasion assays were also used after Notch1 depletion. Our results showed that the knockdown of Notch1 leads to the inhibition of cell invasion and metastasis of human gastric cancer cells SCG7901 and MKN74 in vitro. Compared to control and mock groups, PTEN activities were significantly promoted following depletion of Notch1, and the expression of Phospho­Akt and Phospho­FAK were downregulated. Taken together, our findings suggest that Notch1 could be used as a therapeutic target to inhibit cell invasion and migration in gastric cancer.

Effective treatment of manganese-induced occupational Parkinsonism with p-aminosalicylic acid: a case of 17-year follow-up study.

OBJECTIVE: Chronic manganese (Mn) intoxication induces syndromes resembling Parkinson disease. The clinical intervention has largely been unsuccessful. We report a 17-year follow-up study of effective treatment of occupational Mn parkinsonism with sodium para-aminosalicylic acid (PAS). METHODS: The patient, female and aged 50 at the time of treatment, was exposed to airborne Mn for 21 years (1963-1984). The patient had palpitations, hand tremor, lower limb myalgia, hypermyotonia, and a distinct festinating gait. She received 6 g PAS per day through an intravenous drip infusion for 4 days and rested for 3 days as one therapeutic course. Fifteen such courses were carried out between March and June 1987. RESULTS: At the end of PAS treatment, her symptoms were significantly alleviated, and handwriting recovered to normal. Recent follow-up examination at age 67 years (in 2004) showed a general normal presentation in clinical, neurologic, brain magnetic resonance imaging, and handwriting examinations with a minor yet passable gait. CONCLUSIONS: This case study suggests that PAS appears to be an effective drug for treatment of severe chronic Mn poisoning with a promising prognosis.

Microinjection of histone deacetylase inhibitor into the ventrolateral orbital cortex potentiates morphine induced behavioral sensitization.

Accumulating evidence indicates that epigenetic regulation, such as changes in histone modification in reward-related brain regions, contributes to the memory formation of addiction to opiates and psychostimulants. Our recent results suggested that the ventrolateral orbital cortex (VLO) is involved in the memories of stress and drug addiction. Since addiction and stress memories share some common pathways, the present study was designed to investigate the role of histone deacetylase (HDAC) activity in the VLO during morphine induced-behavioral sensitization. Rats received a single exposure to morphine for establishing the behavioral sensitization model. The effect of HDAC activity in the VLO in morphine induced-behavioral sensitization was examined by microinjection of HDAC inhibitor Trichostatin A (TSA). Furthermore, the protein expression levels of extracellular signal-regulated kinase (ERK) and phosphorylated ERK (p-ERK), histone H3 lysine 9 acetylation (aceH3K9) and brain-derived neurotrophic factor (BDNF) in the VLO in morphine-induced behavioral sensitization were examined. The results showed that the bilateral VLO lesions suppressed the expression phase, but not the developmental phase of morphine-induced behavioral sensitization. Microinjection of TSA into the VLO significantly increased both the development and expression phases. Moreover, the protein levels of p-ERK, aceH3K9 and BDNF except ERK in the VLO were significantly upregulated in morphine-treated rats in the expression phase. These effects were further strengthened by intra-VLO injection of TSA. Our findings suggest that HDAC activity in the VLO could potentiate morphine-induced behavioral sensitization. The upregulated expression of p-ERK, aceH3K9 and BDNF in the VLO might be the underlying mechanism of histone acetylation enhancing the morphine-induced behavioral sensitization.

The α1 adrenoceptors in ventrolateral orbital cortex contribute to the expression of morphine-induced behavioral sensitization in rats.

The aim of the present study was to investigate the effect of microinjection of benoxathian, selective α1 adrenoceptor antagonist, into the ventrolateral orbital cortex (VLO) on morphine-induced behavioral sensitization and its underlying molecular mechanism in rats. A single morphine treatment protocol was used in establishing the behavioral sensitization model. The effect of bilateral intra-VLO benoxathian injection on locomotor activity was examined and the protein expression levels of α1 adrenoceptors and activation of extracellular signal-regulated kinase (ERK) in the VLO were detected after locomotor test. The results showed that a single injection of morphine could induce behavioral sensitization by a low challenge dosage of morphine after a 7-days drug free period. Benoxathian significantly suppressed the expression but not the development of morphine-induced behavioral sensitization. Morphine treatment significantly elicited ERK phosphorylation and downregulated the expression level of α1 adrenoceptors in the VLO. In addition, intra-VLO benoxathian injection enhanced the expression levels of α1 adrenoceptors and phosphorylated ERK. These results suggest that α1 adrenoceptors in the VLO are involved in regulating the expression of morphine-induced behavioral sensitization. The effect of decreased locomotor activity by blocking α1 adrenoceptors might be associated with activation of ERK in the VLO.

Diagnostic Value of Endorectal Ultrasound in Preoperative Assessment of Lymph Node Involvement in Colorectal Cancer: a Meta-analysis.

BACKGROUND: Nodal invasion by colorectal cancer is a critical determinant in estimating patient survival and in choosing appropriate preoperative treatment. The present meta-analysis was designed to evaluate the diagnostic value of endorectal ultrasound (EUS) in preoperative assessment of lymph node involvement in colorectal cancer. MATERIALS AND METHODS: We systematically searched PubMed, Web of Science, Embase, and China National Knowledge Infrastructure (CNKI) databases for relevant studies published on or before December 10th, 2014. The sensitivity, specificity, likelihood ratios, diagnostic odds ratio (DOR) and area under the summary receiver operating characteristics curve (AUC) were assessed to estimate the diagnostic value of EUS. Subgroup analysis and meta-regression were performed to explore heterogeneity across studies. RESULTS: Thirty-three studies covering 3,016 subjects were included. The pooled sensitivity and specificity were 0.69 (95%CI: 0.63-0.75) and 0.77 (95%CI: 0.73-0.82), respectively. The positive and negative likelihood ratios were 3.09 (95%CI: 2.52-3.78) and 0.39 (95%CI: 0.32-0.48), respectively. The DOR was 7.84 (95%CI: 5.56-11.08), and AUC was 0.80 (95%CI: 0.77-0.84). CONCLUSIONS: This meta-analysis indicated that EUS has moderate diagnostic value in preoperative assessment of lymph node involvement in colorectal cancer. Further refinements in technology and diagnostic criteria are necessary to improve the diagnostic accuracy of EUS.

Electromagnetic field exposure and male breast cancer risk: a meta-analysis of 18 studies.

BACKGROUND: The possibility that electromagnetic fields (EMF) exposure may increase male breast cancer risk has been discussed for a long time. However, arguments have been presented that studies limited by poor quality could have led to statistically significant results by chance or bias. Moreover, data fo the last 10 years have not been systematically summarized. METHODS AND RESULTS: To confirm any possible association, a meta-analysis was performed by a systematic search strategy. Totals of 7 case-control and 11 cohort studies was identified and pooled ORs with 95% CIs were used as the principal outcome measures. Data from these studies were extracted with a standard meta-analysis procedure and grouped in relation to study design, cut-off point, exposure assessment method, adjustment and exposure model. A statistical significant increased risk of male breast cancer with EMF exposure was defined (pooled ORs = 1.32, 95% CI = 1.14 -1.52, P < 0.001), and subgroup analyses also showed similar results. CONCLUSIONS: This meta-analysis suggests that EMF exposure may be associated with the increase risk of male breast cancer despite the arguments raised.