Biological roles of RNA m7G modification and its implications in cancer.

M7G modification, known as one of the common post-transcriptional modifications of RNA, is present in many different types of RNAs. With the accurate identification of m7G modifications within RNAs, their functional roles in the regulation of gene expression and different physiological functions have been revealed. In addition, there is growing evidence that m7G modifications are crucial in the emergence of cancer. Here, we review the most recent findings regarding the detection techniques, distribution, biological functions and Regulators of m7G. We also summarize the connections between m7G modifications and cancer development, drug resistance, and tumor microenvironment as well as we discuss the research's future directions and trends.

HMGB1 Upregulates RAGE to Trigger the Expression of Inflammatory Factors in the Lung Tissue in a Hypoxic Pulmonary Hypertension Rat Model.

Hypoxic pulmonary hypertension (HPH), a form of pulmonary hypertension (PH) caused by hypoxia, could cause serious complications and has a high mortality rate, and no clinically effective treatments are currently available. In this study, we established an HPH preclinical model in rats by simulating clinicopathological indicators of the disease. Our results showed that high mobility group box-1 protein (HMGB1) aggravated the clinical symptoms of HPH. We aimed at establishing protocols and ideas for the clinical treatment of HPH by identifying downstream HMGB1 binding receptors. Our investigation showed that continuous hypoxia could cause significant lung injury in rats. ELISA and western blotting experiments revealed that HPH induces inflammation in the lung tissue and increases the expression of a hypoxia-inducible factor. Testing of lung tissue proteins in vivo and in human pulmonary artery endothelial cells in vitro revealed that the HMGB1-mediated increase in the receptor for advanced glycation end products (RAGE) expression promoted inflammation. In summary, we successfully established an HPH rat model providing a new model for preclinical HPH research and elucidated the role of HMGB1 in HPH. Furthermore, we describe that HMGB1 induced inflammation in the HPH model via RAGE, causing severe lung dysfunction. This study could potentially provide novel ideas and methods for the clinical treatment of HPH.

[Analysis of Coexisting Gene with NRAS in Acute Myeloid Leukemia].

OBJECTIVE: To investigate the coexisting mutations and clinical significance of Homo sapiens neuroblastoma RAS viral oncogene homolog (NRAS) gene in acute myeloid leukemia (AML) patients. METHODS: High-throughput DNA sequencing and Sanger sequencing were used to detect 51 gene mutations. The occurrence, clinical characteristics and treatment efficacy of coexisting genes with NRAS were investigated. RESULTS: A total of 57 NRAS mutations (17.5%) were detected in 326 patients with AML. Compared with the patients in NRAS non-mutation group, patients in the mutant group were younger (P=0.018) and showed lower platelet count (P=0.033), but there was no significant difference in peripheral leukocyte count, hemoglobin, and sex. For FAB classification, NRAS mutation and M2 subtype showed mutually exclusive (P=0.038). Among 57 patients carried with NRAS mutation, 51 (89.5%) patients carried with other gene mutations, 25 (43.9%) carried with double gene mutations, 10 (17.5%) carried with 3 gene mutations, and 16 (28.1%) corried with ≥ 4 gene mutations. The most common coexisting gene mutation was KRAS (24.6%, 14/57), followed by FLT3-ITD (14.0%, 8/57), RUNX1 (12.3%, 7/57), NPM1 (10.5%, 6/57), PTPN11 (10.5%, 6/57), DNMT3A (10.5%, 6/57) and so on. The age (P=0.013, P=0.005) and peripheral platelet count (P=0.007, P=0.021) of patients with NPM1 or DNMT3A mutations were higher than those of the patients with wild type, but there was no significant difference in peripheral leukocyte count and hemoglobin. Also, there was no significant difference in age, peripheral leukocyte count, hemoglobin, and peripheral platelet count between the patients in KRAS, FLT3-ITD, RUNX1 or PTPN11 mutant group and the wild group. Patients with FLT3-ITD mutations showed a lower complete remission (CR) rate (P=0.044). However, there was no significant difference in CR rate between the patients with KRAS, NPM1, RUNX1, PTPN11 or DNMT3A mutations and the wild group. The CR rate of the patents with single gene mutation, double gene mutations, 3 gene mutations, and≥ 4 gene mutations were decreased gradually, and there was no significant difference in CR rate between pairwise comparisons. CONCLUSION: The mutation rate of NRAS mutation is 17.5%, 89.5% of AML patients with NRAS mutation coexist with additional gene mutations. The type of coexisting mutations has a certain impact on clinical characteristics and CR rate of patients with AML.

Synthesis and Structure-Activity Relationship Studies of N-monosubstituted Aroylthioureas as Urease Inhibitors.

BACKGROUND: Thiourea is a classical urease inhibitor which is usually used as a positive control, and many N,N'-disubstituted thioureas have been determined as urease inhibitors. However, due to steric hindrance, N,N'-disubstituted thiourea motif could not bind urease as thiourea. On the contrary, N-monosubstituted thiourea with a tiny thiourea motif could theoretically bind into the active pocket as thiourea. OBJECTIVE: A series of N-monosubstituted aroylthioureas were designed and synthesized for evaluation as urease inhibitors. METHODS: Urease inhibition was determined by the indophenol method and IC50 values were calculated using computerized linear regression analysis of quantal log dose-probit functions. The kinetic parameters were estimated via surface plasmon resonance (SPR) and by nonlinear regression analysis based on the mixed type inhibition model derived from Michaelis-Menten kinetics. RESULTS: Compounds b2, b11, and b19 reversibly inhibited urease with a mixed mechanism, and showed excellent potency against both cell-free urease and urease in the intact cell, with IC50 values being 90- to 450-fold and 5- to 50-fold lower than the positive control acetohydroxamic acid, respectively. The most potent compound b11 showed an IC50 value of 0.060 ± 0.004µM against cell-free urease, which bound to urea binding site with a very low KD value (0.420±0.003nM) and a very long residence time (6.7 min). Compound b11 was also demonstrated to have very low cytotoxicity to mammalian cells. CONCLUSION: The results revealed that N-monosubstituted aroylthioureas bound to the active site of urease as expected, and represent a new class of urease inhibitors for the development of potential therapeutics against infections caused by urease-containing pathogens.

[Curative Efficacy and Survival Analysis of Low-Intensity Traditional Chemotherapy Regimen in the Elderly Patients with Acute Myeloid Leukemia (non-M3)].

OBJECTIVE: To investigate the short-term and long-term curative efficacy of low-intensity traditional chemotherapy regimen for elderly patients with acute myeloid leukemia (AML, non-M3) and related adverse reactions, in order to explore whether low-intensity traditional chemotherapy regimen still has application value in the treatment of elderly AML patients today. METHODS: The clinical characteristics, treatment response and prognosis of 67 elderly patients with AML (non-M3) admitted to our hospital from June 2008 to December 2018 were retrospectively analyzed. All patients received low-intensity conventional chemotherapy (i.e. lower standard dose, and without new drugs listed in China since the 21st century), including DA, HA, CAG, etc. The CR rate, median survival time and 5-year cumulative survival rate of patients were evaluated, and the related indexes were compared with the data reported in domestic and foreign literatures at the same time. RESULTS: The CR rate was 55.2% (37/67), the median survival time was 13.7 months, and the 5-year cumulative survival rate was (24.4±6.3)% in patients received low-intensity tradional chemotherapeutic regimens. The CR rates of high-risk group and non-high-risk group were 38.7% (12/31) and 69.4% (25/36), respectively; the median survival time of high-risk group and non-high-risk group was 8.9 months and 25.2 months respectively; the 5-year cumulative survival rate of high-risk group was (10.2±6.6)% and that of non-high-risk group was (36.0± 9.4)%. Compared with the data reported in the literature at the same time, the data obtained from the low-intensity traditional chemotherapy regimen for the elderly AML did not have an obvious disadvantage, morever had relatively short bone marrow suppression time, low induction early mortality rate and low incidence of severe infection. CONCLUSION: At present, the low-intensity traditional chemotherapy regimen still has good curative effect and survival advantages for elderly AML patients, especially for non-high-risk patients. The adverse reactions are controllable, and the physical and economic conditions of the vast majority of patients can bear the treatment regimen.

A systematic review of lopinavir therapy for SARS coronavirus and MERS coronavirus-A possible reference for coronavirus disease-19 treatment option.

In the past few decades, coronaviruses have risen as a global threat to public health. Currently, the outbreak of coronavirus disease-19 (COVID-19) from Wuhan caused a worldwide panic. There are no specific antiviral therapies for COVID-19. However, there are agents that were used during the severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) epidemics. We could learn from SARS and MERS. Lopinavir (LPV) is an effective agent that inhibits the protease activity of coronavirus. In this review, we discuss the literature on the efficacy of LPV in vitro and in vivo, especially in patients with SARS and MERS, so that we might clarify the potential for the use of LPV in patients with COVID-19.

Correlations of MIF polymorphism and serum levels of MIF with glucocorticoid sensitivity of sudden sensorineural hearing loss.

OBJECTIVE: This study explored the relationship between macrophage migration inhibitory factor (MIF) gene polymorphism (-173G/C) and glucocorticoid sensitivity in sudden sensorineural hearing loss (SSNHL). METHODS: A total of 120 patients with SSNHL were divided into a glucocorticoid-sensitive group and a glucocorticoid-resistant group. A group of 93 healthy individuals served as the control group. Serum MIF levels of the participants were measured and MIF genotyping was performed. RESULTS: The frequency of the MIF -173C allele was significantly higher in glucocorticoid-sensitive patients than in glucocorticoid-resistant patients. Serum MIF levels were significantly higher in SSNHL patients than in healthy controls, and higher in the glucocorticoid-sensitive group than in the glucocorticoid-resistant group of SSNHL patients, which was unexpected. Compared with patients with the GG genotype, patients with the -173C allele (GC and CC genotypes) had significantly higher levels of serum MIF and superoxide dismutase activity and lower levels of tumor necrosis factor-α and malondialdehyde. CONCLUSION: The MIF -173G/C polymorphism is associated with glucocorticoid sensitivity in SSNHL patients. The C allele can result in higher MIF production, reduced oxidative stress, and greater glucocorticoid sensitivity.

CUL4A expression is associated with tumor stage and prognosis in nasopharyngeal carcinoma.

Cullin 4A (CUL4A) is a protein of E3 ubiquitin ligase with many cellular processes. CUL4A could regulate cell cycle, development, apoptosis, and genome instability. This study aimed to analyze the expression of CUL4A in nasopharyngeal carcinoma (NPC) tissues and the associations of CUL4A expression with prognostic significance. A total of 115 NPC patients were collected to assess the protein expression of CUL4A by immunohistochemistry, so as to analyze the relationships between CUL4A expression and clinicopathological and prognostic parameters. All patients were followed-up until death or 5 years. The results showed that high expression of CUL4A was significantly associated with larger primary tumor size (P = .026), higher nodal status (P = .013), more distant metastasis (P = .020), and higher TNM stage (P = .005). Kaplan-Meier curves showed that patients with higher CUL4A expression had significantly shorter overall survival (OS) and progression-free survival (PFS) (both P < .001). In multivariate Cox analysis, CUL4A is an independent prognostic factor for OS (P = .016; hazard ratio [HR] = 2.770, 95% CI: 1.208-6.351) and PFS (P = .022; HR = 2.311, 95% CI: 1.126-4.743). In conclusion, high expression of CUL4A was associated with advanced disease status of NPC, and might serve as an independent prognostic factor.

Inflammation marker ESR is effective in predicting outcome of diffuse large B-cell lymphoma.

BACKGROUND: Systemic inflammation has been implicated in cancer development and progression. This study examined the best cutoff value of erythrocyte sedimentation rate (ESR) in diffuse large B-cell lymphoma (DLBCL) patients. METHODS: The relationship between ESR and clinical characteristics was analyzed in 182 DLBCL patients from 2006 to 2017. The log-rank test, univariate analysis, and Cox regression analysis were applied to evaluate the relationship between ESR and survival. An ESR of more than 37.5 mm/hour was found to be the optimal threshold value for predicting prognosis. RESULTS: ESR was associated with more frequent advanced Ann Arbor stage, poorer performance status, elevated lactate dehydrogenase level, the presence of B symptoms, high-risk International Prognostic Index (IPI 3-5), more extranodal involvement (ENI ≥2), non-germinal-center B-cell (non-GCB) subtypes, and more frequent Myc protein positivity. Shorter overall survival (OS) and progression-free survival (PFS) were found for patients with higher ESRs. Multivariate analysis demonstrated that ESR level is an independent prognostic factor of both OS and PFS. In addition, dynamic changes in ESR are valuable in assessing curative effect and predicting disease recurrence. CONCLUSION: High ESR in DLBCL patients indicated unfavorable prognosis that may require alternative treatment regimens.

MIF protects against oxygen-glucose deprivation-induced ototoxicity in HEI-OC1 cochlear cells by enhancement of Akt-Nrf2-HO-1 pathway.

Ischemia and oxidative stress play crucial roles in the pathophysiology of sudden sensorineural hearing loss (SSNHL). Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine and serves an important role in hearing function. The present study was designed to evaluate the effect of MIF on oxygen-glucose deprivation (OGD)-induced ototoxicity and to elucidate its molecular mechanism. In HEI-OC1 auditory cells, OGD reduced cell viability and increased supernatant lactate dehydrogenase (LDH) and MIF in a time-dependent manner. However, the reduced cell viability exerted by OGD was attenuated by antioxidant and MIF. Luciferase reporter assay demonstrated that MIF could activate NF-E2-related factor 2 (Nrf2), and real-time PCR showed increased mRNA expressions of Nrf2 and two Nrf2-responsive genes, including heme oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO1). MIF also suppressed oxidative stress induced by OGD, as demonstrated by decreased MDA and increased GSH in cellular supernatant. Inhibition of Nrf2 using siRNA suppressed HO-1 protein expression, the protective effect on OGD-induced injury and decrease in oxidative stress by MIF. Moreover, MIF prevented OGD-induced reduction of Akt1 phosphorylation at Ser473. LY294002, an inhibitor of PI3K/Akt signaling, attenuated the enhancement of Nrf2 protein and protective effect of MIF in OGD-treated cochlear cells. We demonstrate that MIF protects cochlear cells against OGD-induced injury through activation of Akt-Nrf2-HO-1 pathway.

[Expression of the costimulatory molecule BTLA in synovial tissues from rheumatoid arthritis patients].

AIM: To detect the expression of B and T lymphocyte attenuator (BTLA) antigen in synovial tissues from rheumatoid arthritis (RA) patients. METHODS: The expression and distribution of BTLA antigen was analyzed by immunohistochemistry. Moreover, fluorescence double-staining was used to further identify the cell types expressing BTLA. RESULTS: Immunohistochemical analysis revealed that a great deal of BTLA positive cells were found in RA synovium, and fluorescence double-staining further demonstrated that BTLA positive cells were CD3(+); T cells, CD68(+); macrophages, and occasionally CD31(+); endothelial cells. In contrast to other members of B7 superfamily, the expression of BTLA was also found on B7-H1(+);, B7-H4(+); and HVEM(+); cells, while it was absence on B7-DC(+); cells as well as B7-H3(+); cells. CONCLUSION: The expression of BTLA has been observed on the surface of several kinds of cells within synovial tissues of RA patients, which indicates this signal might be involved in the regulation of local T cell activation and the pathogenesis of RA.

Long-term recurrence-free survival in a patient with pancreatic carcinosarcoma: a case report with a literature review.

Here, we presented a case of carcinosarcoma of the pancreas in a 53-year-old woman. The carcinosarcoma was in the head of pancreas. She underwent a pancreaticoduodenectomy. The tumor was grossly yellowish-whitish. Histologic evaluation of the tumor revealed 2 elements separated from each other. One component was conventional pancreatic ductal adenocarcinoma, and the other component showed sarcomatous growth pattern composed of pleomorphic spindle cells. Immunohistochemically, the adenocarcinoma component was reactive for antibodies to cytokeratin 18 and epithelial membrane antigen. The sarcomatous component was reactive for smooth muscle antibody. These findings led to a diagnosis of pancreatic carcinosarcoma. The patient was treated with gemcitabine, adriamycin, and cisplatin after the operation. Although previously reported patients with pancreatic carcinosarcoma showed a very poor outcome, this patient has remained free of recurrence for 20 months, which is the longest recurrence-free survival time recorded for this type of cancer. This treatment plan may be a feasible option.