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Pancreatic ductal adenocarcinoma (PDAC) is distinguished by its aggressive malignancy, limited treatment avenues and a tendency towards chemotherapy resistance, underscoring the critical need for advanced research to uncover new therapeutic approaches. Stress granules (SGs) that is implicated in cellular self-protection mechanism, along with its associated family molecules have shown pro-cancer effects and are closely related to tumor chemotherapy resistance. In this study we investigated the relationship between Ras GTPase-activating protein-binding proteins 2 (G3BP2), a core component of SGs, and the malignancy of PDAC as well as its resistance to the chemotherapy drug gemcitabine. Analyzing TCGA dataset revealed that the expression of G3BP1 and G3BP2 was significantly upregulated in PDAC compared with adjacent normal pancreatic tissues, and the high expression of G3BP2 rather than G3BP1 was significantly associated with poorer overall survival (OS) in PDAC patients. We demonstrated that knockdown of G3BP2 inhibited the proliferation and invasion of PANC-1 and CFPAC-1 cells in vitro and in vivo. By analyzing the differentially expressed genes in G3BP2 knockdown and overexpressed PANC-1 cells, we identified DKC1 that was associated with RNA stability and regulation as the target of G3BP2. We demonstrated that G3BP2 bound to PDIA3 mRNA and recruited them into SGs, increasing the stability of PDIA3 mRNA and attenuating its translation efficiency, thereby promoting DKC1 expression. Furthermore, DKC1 could bind to hENT mRNA and inhibited its expression, which enhanced gemcitabine resistance of PDAC. Therefore, we propose a novel mechanism wherein G3BP2 facilitates PDAC's resistance to chemotherapy by modulating PDIA3-DKC1-hENT in a SGs-dependent way, suggesting G3BP2 SGs a protentional therapeutic target for the treatment in PDAC., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

The triglyceride (TG)-to-high-density lipoprotein cholesterol (HDL-C) ratio (TG/HDL-C) is a simple approach to predicting unfavorable outcomes in cardiovascular disease. The influence of TG/HDL-C on acute ischemic stroke remains elusive. The purpose of this study was to investigate the precise effect of TG/HDL-C on 3-month mortality after acute ischemic stroke (AIS). Patients with AIS were enrolled in the present study from 2011 to 2017. A total of 1459 participants from a single city in China were divided into retrospective training and prospective test cohorts. Medical records were collected periodically to determine the incidence of fatal events. All participants were followed for 3 months. Optimal cutoff values were determined using X-tile software to separate the training cohort patients into higher and lower survival groups based on their lipid levels. A survival analysis was conducted using Kaplan-Meier curves and a Cox proportional hazards regression model. A total of 1459 patients with AIS (median age 68.5 years, 58.5% male) were analyzed. Univariate Cox regression analysis confirmed that TG/HDL-C was a significant prognostic factor for 3-month survival. X-tile identified 0.9 as an optimal cutoff for TG/HDL-C. In the univariate analysis, the prognosis of the TG/HDL-C >0.9 group was markedly superior to that of TG/HDL-C ≤0.9 group (P<0.001). A multivariate Cox regression analysis showed that TG/HDL-C was independently correlated with a reduced risk of mortality (hazard ratio [HR], 0.39; 95% confidence interval [CI], 0.24-0.62; P<0.001). These results were confirmed in the 453 patients in the test cohort. A nomogram was constructed to predict 3-month case-fatality, and the c-indexes of predictive accuracy were 0.684 and 0.670 in the training and test cohorts, respectively (P<0.01). The serum TG/HDL-C ratio may be useful for predicting short-term mortality after AIS., Competing Interests: Competing interests The authors declare that they have no competing interests.

Background: Stroke-induced immunodeficiency syndrome (SIDS) is regarded as a protective mechanism for secondary inflammatory injury as well as a contributor to infection complications. Although stroke-induced hyperactivation of the sympathetic system is proved to facilitate SIDS, the involved endogenous factors and pathways are largely elusive. In this study, we aim to investigate the function of beta-arrestin-2 (ARRB2) in the sympathetic-mediated SIDS., Methods: Splenic ARRB2 expression and the sympathetic system activity were detected after establishing transient models of middle cerebral artery occlusion (MCAO). In addition, a correlation between ARRB2 expression and the sympathetic system activity was analyzed using a linear correlation analysis. Any SIDS reflected in monocyte dysfunction was investigated by measuring inflammatory cytokine secretion and neurological deficit scores and infarct volume were tested to assess neurological outcome. Further, ARRB2 expression in the monocytes was knocked down in vitro by siRNAs. Following the stimulation of noradrenaline and lipopolysaccharide, cytokine secretion and the nuclear factor-κB (NF-κB) pathway were evaluated to gain insight into the mechanisms related to the contribution of ARRB2 to adrenergic-induced monocyte dysfunction., Results: Splenic ARRB2 expression was significantly increased after stroke and also showed a significant positive correlation with the sympathetic system activity. Stroke-induced monocyte dysfunction resulted in an increase of the interleukin-10 (IL-10) level as well as a decrease of the interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) levels. Also, blockade of adrenergic-activity significantly reversed these cytokine levels, and blockade of adrenergic-activity improved stroke-induced neurological results. However, the improved neurological results had no significant correlation with ARRB2 expression. Furthermore, the in vitro results showed that the deficiency of ARRB2 dramatically repealed adrenergic-induced monocyte dysfunction and the inhibition of NF-κB signaling phosphorylation activity., Conclusions: ARRB2 is implicated in the sympathetic-triggered SIDS, in particular, monocyte dysfunction after stroke. Accordingly, ARRB2 may be a promising therapeutic target for the immunological management of stroke in a clinic.

Objective: To establish the relationship between the presence of type 1 diabetes mellitus (DM) and auditory dysfunction in clinical settings by a systematic review and meta-analysis of currently available published data., Data Sources and Review Methods: The electronic databases PubMed, Embase, and Wanfang Data were searched for eligible relevant studies up to May 2016, and the reference lists of the retrieved articles were used for additional manual search. All the articles included in this pooled analysis were determined according to the preset inclusion and exclusion criteria. Meta-analysis of pooled data was performed using Review Manager 5.3., Results: A total of 15 studies were included for further combined analysis. The results showed that patients with type 1 diabetes had a significantly higher prevalence of hearing loss than controls (odds ratio = 49.08, 95% confidence interval = 12.03-200.31, P < 0.00001); standardized mean of differences (SMD) of pure tone audiometry at 4,000 Hz between diabetes and controls was 0.87 (Z = 2.22, P = 0.03, I 2 = 95%); SMD of the latency time was 0.54 (Z = 2.69, P = 0.007, I 2 = 78%) for waves III and 0.61 (Z = 2.38, P = 0.02, I 2 = 86%) for wave V, respectively; and SMD of the interpeak latency time was 0.41 (Z = 2.84, P = 0.005, I 2 = 39%) for waves I to III and 0.61 (Z = 2.67, P = 0.008, I 2 = 81%) for waves I to V, respectively, between diabetics and controls., Conclusion: Our study reveals that there is relationship between the presence of type 1 DM and an increased risk for developing mild and subclinical hearing impairment., Level of Evidence: NA. Laryngoscope, 127:1689-1697, 2017., (© 2016 The Authors. The Laryngoscope published by Wiley Periodicals, Inc. on behalf of American Laryngological, Rhinological and Otological Society Inc, “The Triological Society” and American Laryngological Association (ALA).)

Background and Purpose: The effect of the triglyceride (TG) to high-density lipoprotein cholesterol (HDL-C) ratio (TG/HDL-C) on clinical outcomes of acute ischaemic stroke (AIS) patients is unclear. This study sought to determine whether the TG/HDL-C ratio in AIS patients is associated with worse outcomes at 3 months., Methods: Acute ischaemic stroke patients who were admitted from 2011 to 2014 were enrolled in this study. TG, total cholesterol (TC), HDL-C and low-density lipoprotein cholesterol (LDL-C) were collected on admission. Three end-points were defined according to the modified Rankin scale (mRS) score at 3 months after symptom onset (excellent outcome, mRS 0-1; good outcome, mRS 0-2; and death, mRS 6)., Results: In all, 1006 patients were included (median age 68.5 years; 58.2% male). Higher TG, non-HDL-C and TG/HDL-C were strongly associated with the three end-points after adjustments: excellent [odds ratio (OR) = 1.39, OR 1.89 and OR 2.34, respectively] and good (OR 1.48, OR 2.90 and OR 4.12) outcomes, and death (OR 0.59, OR 0.29 and OR 0.26). According to receiver operating characteristic (ROC) analysis, the best discriminating factor was a TG/HDL-C ≥ 0.87 for excellent outcomes [area under the ROC curve (AUC) 0.596; sensitivity 73.3%; specificity 42.7%] and non-death (AUC 0.674; sensitivity 67.8%; specificity 60.6%) as well as a TG/HDL-C ≥ 1.01 for a good outcome (AUC 0.652; sensitivity 61.6%; specificity 63.2%). Patients with a TG/HDL-C < 0.87 had a 2.94-fold increased risk of death (95% confidence interval 1.89-4.55) compared with patients with a TG/HDL-C ≥ 0.87., Conclusions: A lower TG/HDL-C was independently associated with death and worse outcome at 3 months in AIS., (© 2016 EAN.)

Background: Evidence has led to the consideration of immunodepression after stroke as an important contributor to stroke associated infection (SAI). However, so far no specific immunological indicator has been identified for SAI, and the underlying mechanism remains poorly understood., Results: SAI patients had significantly higher IL-6 and IL-10 levels and lower HLA-DR levels than no-infection patients within 48h after stroke onset. NA significantly increased IL-10 levels, reduced HLA-DR expression, and decreased IL-6 expression by increasing β-arrestin2 expression which reduced the activation of the NF-κB pathway. Propranolol reversed this effect of NA by reducing β-arrestin2 expression., Materials and Methods: A systematic search for eligible clinical studies was applied to pool the differences in peripheral cytokine levels between infection and no-infection stroke patients. The underlying mechanism behind these differences was investigated in vitro by applying norepinephrine (NA) and lipopolysaccharide (LPS) to simulate sympathetic pathway activation and sepsis respectively in THP-1 cells. Propranolol was applied to determine the effect of reversing the activation of the sympathetic pathway. Immunological indicators were also detected to assess the immune activation of THP-1 cells and measurements of the expression of β-arrestin2, NF-κB, IκBα and phosphor-IκBα were performed to assess the activation of the sympathetic pathway., Conclusion: IL-6, IL-10 and HLA-DR are good candidate biomarkers for SAI. The activation of the sympathetic pathway could partly account for the specific immunological alterations found in SAI patients including HLA-DR decrease and IL-10 increase, which both could be reversed by propranolol. However, the mechanism underlying IL-6 increase still needs further exploration., Competing Interests: The authors declare that there is no conflict of interest. The authors confirm that neither the submitted manuscript nor any similar manuscript, in whole or in part, is under consideration, in press, published, or reported elsewhere.

Stoke results in activation of the sympathetic nervous system (SNS), inducing systemic immunosuppression. However, the potential mechanisms underlying stroke-induced immunosuppression remain unclear. Here, we determined the SNS effects on functional outcome and explored the interactions among SNS, β-arrestin2 and nuclear factor-κB (NF-κB) after experimental stroke in rats. In the current study, stroke was induced by a transient middle cerebral artery occlusion (MCAO) in rats, and SNS activity was inhibited by intraperitoneal injection of 6-hydroxydopamine HBr (6-OHDA). 7.0 T Micro-MRI and Longa score were employed to assess the functional outcome after stroke. Flow cytometry and ELISA assay were used to measure the expression of MHC class II, tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ). Western blot was conducted to analyze β-arrestin2 and NF-κB protein expression levels after experimental stroke. We found significantly increased infarct volumes and functional impairment after MCAO at different post-surgery time points, which were not aggravated by 6-OHDA treatment. SNS blockade partially reversed the expression of MHC class II after stroke over time, as well as TNF-α and IFN-γ levels in lipopolysaccharide-stimulated macrophages in vitro. Treatment of MCAO rats with SNS-inhibitor significantly diminished NF-κB activation and enhanced β-arrestin2 expression after stroke. This study suggests that pharmacological SNS inhibition dose not aggravate functional outcome after stroke. Stroke-induced immunosuppression may be involved in the SNS-β-arrestin2-NF-κB pathway.

A review is presented of the occurrence of 24 abnormal hemoglobins (13 alpha-chain variants and 11 beta-chain variants) in populations in the Silk Road area of Northwestern China. Most frequently occurring were Hb D-Punjab [beta 121(GH4)Glu----Gln] in Uygurs, Kazaks, and Khalkhas, Hb G-Taipei [beta 22(B4)Glu----Gly] in persons of the Han nationality, and Hb G-Coushatta [beta 22 (B4)Glu----Ala] in the Uygurs, Kazaks, Hans, and related nationalities. The data suggest that these variants likely originated in Central Asia, in the Han nationality of China, and in the minorities of northern China, respectively. Other variants occurred at considerably lower frequencies and were imported from other countries or arose as independent mutations. Two variants [Hb Tashikuergan or alpha 19(AB1)Ala----Glu; Hb Tianshui or beta 39(C5) Gln----Arg] were observed for the first time. The data from this study of the many variants support the movements of various populations in this area, as reported in numerous historical documents.

This paper summarizes data obtained during a screening program involving 11,563 persons from the Silk Road region in China. The mean incidence of thalassemia is 1.62% with an increase from east to west. The incidence in the Hui population (3.01%) is higher than in Kazaks (2.92%), and in Uygur (2.22%). The Han population also has a higher incidence (0.98%) than seen for other regions in Northern China. The thalassemias observed are classified into seven groups; beta-thalassemia accounts for 89.48% of the total, and alpha-thalassemia for 10.52%.