Dampening of ISGylation of RIG-I by ADAP regulates type I interferon response of macrophages to RNA virus infection.

While macrophage is one of the major type I interferon (IFN-I) producers in multiple tissues during viral infections, it also serves as an important target cell for many RNA viruses. However, the regulatory mechanism for the IFN-I response of macrophages to respond to a viral challenge is not fully understood. Here we report ADAP, an immune adaptor protein, is indispensable for the induction of the IFN-I response of macrophages to RNA virus infections via an inhibition of the conjugation of ubiquitin-like ISG15 (ISGylation) to RIG-I. Loss of ADAP increases RNA virus replication in macrophages, accompanied with a decrease in LPS-induced IFN-ß and ISG15 mRNA expression and an impairment in the RNA virus-induced phosphorylation of IRF3 and TBK1. Moreover, using Adap-/- mice, we show ADAP deficiency strongly increases the susceptibility of macrophages to RNA-virus infection in vivo. Mechanically, ADAP selectively interacts and functionally cooperates with RIG-I but not MDA5 in the activation of IFN-ß transcription. Loss of ADAP results in an enhancement of ISGylation of RIG-I, whereas overexpression of ADAP exhibits the opposite effect in vitro, indicating ADAP is detrimental to the RNA virus-induced ISGylation of RIG-I. Together, our data demonstrate a novel antagonistic activity of ADAP in the cell-intrinsic control of RIG-I ISGylation, which is indispensable for initiating and sustaining the IFN-I response of macrophages to RNA virus infections and replication.

Detection of TP53 gene mutation in blood of breast cancer patients based on circulating tumor DNA and its application in prognosis.

This experiment was carried out to explore the application value of high throughput gene sequencing technology in detecting TP53 gene mutations in the blood of patients with breast cancer by detecting ctDNA gene mutations, and exploring the relationship between TP53 mutations and clinicopathological characteristics and prognosis of patients. The gene mutation of peripheral blood ctDNA and tissue paraffin DNA (tDNA) of 50 patients was detected by high-throughput sequencing technology. The basic data of 50 cases of Medium to high-risk breast cancer diagnosed and were retrospectively collected, and the clinicopathological characteristics and survival results of TP53 mutant and wild-type patients were compared and analyzed according to the ctDNA detection results and relevant follow-up data. Analyze the impact of TP53 mutations on overall survival and progression-free survival using univariate and multivariate Cox regression models. Among 50 patients, there were 29 cases of 7 kinds of gene mutations detected by ctDNA, and 37 cases of 9 kinds of gene mutations detected by tDNA. Using the gene mutation results detected by tDNA as the gold standard, the sensitivity and specificity of peripheral blood ctDNA in diagnosing TP53 gene mutations are 75% to 100%, 92.31% to 100%, and the overall coincidence rate with tDNA results was 83.33% to 100%. Exon 5 was the most prone to mutation, with a frequency of 24.14% (7/29). The most common type of mutation was the missense mutation of 37.93% (11/29). There was no significant correlation between TP53 mutation and PFS (HR=0.67, 95% CI: 0.41-1.08, P=0.102), while TP53 mutation was a protective factor for OS (HR=0.49, 95% CI: 0.27-0.90, P=0.022). The detection of ctDNA in peripheral blood of breast cancer patients by high-throughput gene sequencing technology can replace tumor tissue sections to understand gene mutation. The TP53 mutation in breast cancer patients is related to tumor size, lymph node metastasis and vascular tumor thrombus, but the prognosis of TP53 mutant patients is similar to that of wild-type patients.

Change in urea to creatinine ratio is associated with postoperative complications and skeletal muscle wasting in pancreatic cancer patients following pancreatoduodenectomy.

BACKGROUND AND OBJECTIVES: Surgical patients with depleted skeletal muscle mass tend to have a worse outcome. Whether perioperative change of urea to creatinine ratio (CUCR) can reflect muscle wasting and predict postoperative complications have not been investigated. This study aimed to evaluate the relationship of perioperative CUCR with postoperative complications and skeletal muscle wasting in pancreatic cancer patients undergoing pancreatoduodenectomy (PD). METHODS AND STUDY DESIGN: Pancreatic cancer patients undergoing PD were included retrospectively. The association between postoperative complications and perioperative CUCR as well as other nutritional biomarkers was analyzed. In a subset of patients with serial CT scans, the correlation of the CUCR and the changes of CT-derived skeletal muscle area (SMA) were tested. Furthermore, the capacity of complication prediction of CUCR and CT-derived parameter were compared in these patients. RESULTS: A total of 321 surgical patients were included. Univariable and multivariable logistic regression demonstrated CUCR was a strong predictor for complications in these patients, independent of age, BMI and comorbidity. Patients with CUCR above the median have higher complication rate (p=0.007) and longer postoperative days to discharge (p=0.017). In a subset patients with both pre- and postoperative digital abdominal CT scans, spearman correlation analysis shown both L3 muscle area and L4-psoas area were significantly correlated with CUCR (R2=0.64, p<0.05; R2=0.62, p<0.05, respectively). CONCLUSIONS: Perioperative CUCR is an independent predictor for postoperative complications in pancreatic cancer patients undergoing PD. Elevated CUCR is a reflection of skeletal muscle wasting in postoperative surgical patients.

Skeletal muscle depletion and nutrition support affected postoperative complications in patients who underwent pancreatoduodenectomy.

BACKGROUND: Body composition has been shown closely related to the outcome in surgical patients. The aim of the present study was to investigate whether preoperative skeletal muscle condition and postoperative nutrition would affect major complications in patients underwent pancreaticoduodenectomy (PD). METHODS: This retrospective study included 265 patients underwent PD. Body composition data was extracted from the L3 level of the preoperative CT scan. Univariable and multivariable regression analyses were performed to investigate correlations between body composition data and postoperative complications. Furthermore, a subgroup analysis was conducted to explore the relationship between postoperative nutrition strategy and the outcome. RESULTS: Of all the 265 patients, major complications occurred in 81 patients (30.6%). Cutoff values for skeletal muscle depletion were defined by ROC curve analysis from postoperative complications in skeletal muscle index (SMI) (male 47.32 cm2/m2 and female 40.65 cm2/m2). Univariable analysis and multivariable regression revealed age (OR 1.49, 95% CI 1.22-1.83, p = 0.026), SMI (OR 0.77, 95% CI 0.51-0.94, p = 0.015) and skeletal muscle density (SMD) (OR 0.85, 95% CI 0.64-1.03, p = 0.029) were independent predictors for major complications. Subgroup analysis showed the initial parenteral nutrition time (IPNT) (OR 1.89, 95% CI 1.43-2.49, p = 0.032) and average protein delivery (APD) (OR 0.76, 95% CI 0.53-0.89, p = 0.021) were significantly associated with major complications in patients with lower SMI. CONCLUSIONS: Preoperative skeletal muscle index and density were independently associated with major complications in patients underwent PD. In patients with lower SMI, early parenteral nutrition and higher protein delivery were related to better outcome.

Levetiracetam versus Phenytoin for the Pharmacotherapy of Benzodiazepine-Refractory Status Epilepticus: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Recent studies have shown conflicting results regarding the effectiveness of levetiracetam for treating benzodiazepine-refractory status epilepticus (SE) compared with phenytoin. Therefore, a meta-analysis was carried out to assess the value of levetiracetam versus phenytoin in the pharmacotherapy of benzodiazepine-refractory SE. OBJECTIVE: The aim of this systematic review and meta-analysis was to compare the efficacy and safety of levetiracetam and phenytoin in the treatment of benzodiazepine-refractory SE. METHODS: The MEDLINE, EMBASE, CENTRAL and ClinicalTrials.gov databases were searched for randomized controlled trials (RCTs) that had been conducted to evaluate levetiracetam versus phenytoin for benzodiazepine-refractory SE, to April 2020. The data were assessed using Review Manager 5.3 software. The risk ratio (RR) was analyzed using dichotomous outcomes, and calculated using a random-effect model. RESULTS: We pooled 1850 patients from 12 RCTs. Patients in the levetiracetam group had a significantly higher rate of clinical seizure cessation than in the phenytoin group (75.2% vs. 67.8%; RR 1.14, 95% confidence interval [CI] 1.05-1.25, p = 0.003). Moreover, less adverse events were observed in the levetiracetam group than in the phenytoin group (17.8% vs. 21.4%; RR 0.82, 95% CI 0.70-0.97, p = 0.02). In subgroup analysis, clinical seizure cessation was achieved more frequently with a higher dose of levetiracetam (> 30 mg/kg) [RR 1.15, 95% CI 1.00-1.32, p = 0.05]. Furthermore, in the subgroup of children, levetiracetam showed a higher rate of clinical seizure cessation than phenytoin (RR 1.13, 95% CI 1.02-1.25, p = 0.02). CONCLUSION: Pharmacotherapy for BZD-refractory SE by LEV is superior to PHT in efficacy and safety outcomes.

RING finger protein 38 induces gastric cancer cell growth by decreasing the stability of the protein tyrosine phosphatase SHP-1.

The function of the E3 ligase RNF38 is still unknown in gastric cancer. Here, we found that RNF38 is upregulated in gastric cancer, and it is associated with the overall survival of gastric cancer patients. Further studies showed that RNF38 interacts with the nonreceptor tyrosine phosphatase SH2-containing protein tyrosine phosphatase 1 (SHP-1) and induces the polyubiquitination of SHP-1, which leads to destabilization of SHP-1 and promotion of STAT3 signaling in gastric cancer cells. In addition, overexpression or knockdown of RNF38 induces or suppresses gastric cancer cell growth in vitro, respectively, and silencing RNF38 delays tumor growth in vivo. These findings demonstrate that RNF38 is functional in gastric cancer and promotes STAT3 signaling by destabilizing SHP-1; thus, RNF38 could be a novel target for gastric cancer therapy.

Cancer and non-cancer mortality among Inhabitants in the high background radiation area of Yangjiang, China (1979-1998).

The present study aimed to evaluate the effects of high background radiation (HBR) on mortality. A cohort of 31,604 men and women aged 30-74 y living in the study area in Guangdong Province, China, was followed during the period 1979-1998. The information on deaths and migrations of cohort members was collected by visiting study areas every 3-4 y. Cumulative external radiation dose, lagged by 2 y for leukemia and 10 y for cancer excluding leukemia, was estimated for each individual based on hamlet-specific indoor and outdoor doses, and gender- and age-specific house occupancy factors. The follow-up study accumulated 736,942 person-years at risk and ascertained 6,005 deaths, including 956 cancer deaths and 4,525 non-cancer disease deaths. Mean cumulative radiation doses from natural radiation in the HBR and control area residents were 84.8 mGy and 21.6 mGy, respectively. Mortality due to leukemia (15 deaths) or cancer excluding leukemia (941 deaths) was not related to cumulative radiation dose. The excess relative risk (ERR) Gy of cancer excluding leukemia was estimated to be -1.01 (95% CI: -2.53, 0.95). In site-specific analysis, liver-cancer mortality was inversely related to the cumulative dose (p=0.002). Note, however, that liver cancer is well known for its difficulty in accurate diagnosis. The ERR Gy of cancer excluding leukemia and liver cancer was 0.19 (95% CI: -1.87, 3.04). Non-cancer disease mortality was not related to cumulative radiation dose either. The cumulative HBR dose was not related to the mortality due to cancer or all non-cancer diseases among residents in Yangjiang HBR areas.

Dose limits below which the effect of radiation on health becomes undetectable due to background variation.

To clarify the low-dose limit at which the effect of radiation on health becomes undetectable is important in the regulation of radiation. As one of a series of cytogenetical studies on the effect of radiation on health, we present low-dose limits determined by analyzing the background frequencies of translocations in the lymphocytes of people living in normal circumstances. The frequencies of translocations in the lymphocytes were analyzed in 20 non-smokers (61.2-year-old on the average) in a large city, and 16 non-smokers (64.4-year-old on the average) and 8 children (12.3-year-old on the average) in a remote village. The radiation dose was calculated based on the background frequencies of translocations assuming that all the translocations had been induced by radiation. The calculated doses were 384+/-200, 336+/-124 and 128+/-80 mSv in the case of chronic exposure, and 248+/-153, 225+/-104 and 107+/-72 mSv in acute exposure. Standard deviation of the calculated doses is considered to be the dose level below which the effect of radiation becomes undetectable due to the background variation in the effects of all kind of mutagenic factors, i.e., the dose level below which an epidemiological study will not be able to show any significant increase in malignant diseases. The results obtained from epidemiological studies are in fairly good agreement with our results.

Effect of smoking on chromosomes compared with that of radiation in the residents of a high-background radiation area in China.

Cytogenetic investigation of stable-type aberrations (translocations) was carried out with our improved methods on 28 elderly individuals in a high-background radiation area (HBRA) in China, and on 24 elderly individuals in a control area (CA). The level of radiation in HBRA is 3 to 5 times higher than in CA. The mean frequencies of translocations per 1,000 cells in HBRA and CA were 12.4 +/- 5.3 and 10.0 +/- 3.8, respectively. No significant difference was found in the frequencies between HBRA and CA (P>0.05, Mann-Whitney U test). When elderly individuals in HBRA and CA were classified into four subgroups of HBRA nonsmokers, HBRA smokers, CA nonsmokers, and CA smokers, a significant difference was found in the frequencies between CA smokers and CA nonsmokers (P<0.05, Mann-Whitney U test). Furthermore a tendency of difference (a near T-value of 0.05 level) was found in a comparison of HBRA smokers vs. CA nonsmokers. The present results indicate that the elevated level of natural radiation in HBRA plays a less significant part than smoking in bringing about the induction rate of stable-type aberrations (translocations) in those areas.

Imperceptible effect of radiation based on stable type chromosome aberrations accumulated in the lymphocytes of residents in the high background radiation area in China.

Cytogenetic investigation of stable type aberrations (translocations) was performed with our improved methods in 6 children and 15 elderly persons in a high background radiation area (HBRA) in China, and in 8 children and 11 elderly persons in a control area. The total numbers of cells analyzed in elderly persons were 68,297 in HBRA and 35,378 in controls and in children were 45,535 in HBRA and 56,198 in controls. On average 5138 cells per subject were analyzed. The variation in the frequencies of translocations per 1000 cells was small in children while it was large in elderly persons. No significant difference was found in the frequencies between HBRA and control (P > 0.05, Mann-Whitney U test). On the other hand, correlation between age and translocation frequencies was significant at the 1% level (rs = 0.658 with 37DF, Spearman rank correlation test). The contribution of an elevated level of natural radiation in HBRA in China to the induction of stable type chromosome aberrations does not have a significant effect compared with the contribution of chemical mutagens and/or metabolic factors. The present study suggests that the probability of the risk of causing malignant and/or congenital diseases by the increased amount of radiation is imperceptible in HBRA where the level of natural radiation is 3 to 5 times higher than that in the control area.