The balance of Th17/Treg plays an important role in hepatic ischemia–reperfusion (I/R) injury. Glycolysis and glutaminolysis for energy metabolism governs the differentiate of CD 4+ T-cells to ...Th17/Treg. Metformin can regulate glucose metabolism in the liver, but its protective effect on I/R liver injury and its effect on Th17/Treg balancestill unknown. In this study, the I/R liver injury rat model and the primary hepatocyte hypoxia/reoxygenation injury model were established. The biochemical indexes, inflammatory factor indexes, Th17/Treg balance and energy metabolism were evaluated. RNA-seq and gene knockout cells were used to investigated the target protein of metformin. The results showed that metformin could effectively improve liver injury caused by I/R, significantly inhibit the glycolysis, improve the Th17/Treg balance, and inhibit the expression of inflammatory factors. RNA-seq results showed that TIGAR was a possible regulatory site of metformin. However, the protective effect and the regulating effect of Th17/Treg balance by metformin in TIGAR knock-out cells were disappeared. In conclusion, metformin could regulate TIGAR inhibit glycolysis then regulate Th17/Treg balance, inhibit the release of liver inflammatory factors, and finally play a role in inhibiting the occurrence of liver injury caused by ischemia-reperfusion.
Immunosuppression plays a significant role in tumor recurrence and metastasis, ultimately causing poor survival outcomes. Overcoming immunosuppression and stimulating durable antitumor immunity are ...essential for tumor treatment. In our previous study, a novel cryo-thermal therapy involving liquid nitrogen freezing and radiofrequency heating could reduce the proportion of Myeloid-derived suppressor cells (MDSCs), but the remaining MDSCs produced IL-6 by the NF-κB pathway, resulting in an impaired therapeutic effect. Therefore, here we combined cryo-thermal therapy with anti-IL-6 treatment to target the MDSC-dominant immunosuppressive environment, thereby optimizing the efficacy of cryo-thermal therapy. We found that combinational treatment significantly increased the long-term survival rate of breast cancer-bearing mice. Mechanistic investigation revealed that combination therapy was capable of reducing the proportion of MDSCs in the spleen and blood while promoting their maturation, which resulted in increased Th1-dominant CD4
T-cell differentiation and enhancement of CD8
T-mediated tumor killing. In addition, CD4
Th1 cells promoted mature MDSCs to produce IL-7 through IFN-γ, indirectly contributing to the maintenance of Th1-dominant antitumor immunity in a positive feedback loop. Our work suggests an attractive immunotherapeutic strategy targeting the MDSC-dominant immunosuppressive environment, which would offer exciting opportunities for highly immunosuppressive and unresectable tumors in the clinic.
Targeting myeloid-derived suppressive cells (MDSCs) has been considered a potential strategy in tumor therapy. However, a single drug targeting MDSCs remains a challenge in the clinic. An increasing ...number of studies have shown that combination agents targeting MDSCs and immunotherapy may provide exciting new insights and avenues to explore in tumor therapy. In our previous study, a novel cryo-thermal therapy was developed for metastatic tumors that systematically activate innate and adaptive immunity. Moreover, cryo-thermal therapy was shown to dramatically decrease the levels of MDSCs and induce their differentiation toward potent antigen-presenting cells. However, the therapeutic effects of cryo-thermal therapy on the 4T1 mouse breast cancer model were still not satisfactory because of the high level of MDSCs before and after treatment. Therefore, in this study, we combined cryo-thermal therapy with all-trans retinoid acid (ATRA), a small molecule drug that can induce the inflammatory differentiation of MDSCs. We found that combination therapy notably upregulated the long-term survival rate of mice. Mechanically, combination therapy promoted the phenotype and functional maturation of MDSCs, efficiently decreasing suppressive molecule expression and inhibiting glutamine and fatty acid metabolism. Moreover, MDSCs at an early stage after combination therapy significantly decreased the proportions of Th2 and Treg subsets, which eventually resulted in Th1-dominant CD4
+
T-cell differentiation, as well as enhanced cytotoxicity of CD8
+
T cells and natural killer cells at the late stage. This study suggests a potential therapeutic strategy for combination ATRA treatment targeting MDSCs with cryo-thermal therapy to overcome the resistance of MDSC-induced immunosuppression in the clinic.
We explored the predictors and predictive models of loss to follow-up (LTFU) during the first year of anti-retroviral therapy (ART). LTFU was defined as the failure to visit the clinic for ...antiretroviral drugs for ≥ 90 days after the last missed scheduled visit. Based on the electronic medical records of 5953 patients who were HIV positive and began ART between 2016 and 2019 in China, the LTFU rate was 7.24 (95% confidence interval 6.49–7.97) per 100 person-years during the first year of ART. ART baseline factors were associated with LTFU, but were non-optimal predictors. A model including ART process-related factors such as follow-up behaviors and physical health status had an area under the receiver operating characteristic curve of 73.4% for predicting LTFU. Therefore, the medical records of follow-up visits can be used to identify patients with a high risk of LTFU and allow interventions to be implemented proactively.
Purpose
We aimed to investigate the prevalence and risk factors of filamentous fungi (FF) carriage in human immunodeficiency virus (HIV)-infected patients in Guangdong province, along with its ...subsequent incidence of invasive fungal disease (IFD).
Methods
Seven hundred and sixteen HIV-infected individuals from the outpatient clinic and 293 sex-matched healthy controls were recruited prospectively from May 1 to August 31, 2017. Fungi were isolated from oropharyngeal and nasopharyngeal swabs, then identified by morphological and molecular biological techniques. Logistic regression analysis was used to identify risk factors of pathogenic FF carriage. Pathogenic FF carriers were followed up through the end of 2019.
Results
Of the 716 included HIV-infected patients, 602 (84.1%) were male, the median age was 34 (27–42) years, and the median CD4+ count was 385 (254–542) cells/μl. Pathogenic FF were isolated in 119 (16.6%) cases with HIV infection and 40 (13.7%) healthy controls. Mucorales were found in 3 HIV-infected individuals and
Talaromyces marneffei
in 2 HIV-infected individuals, but not in healthy controls. History of cured opportunistic infections (OIs; OR, 1.97; 95% CI, 1.23–3.13,
p
= 0.004), and smoking (OR, 1.55; 95%CI, 1.03–2.32,
p
= 0.035) were independent risk factors of pathogenic FF carriage in HIV-infected individuals. A total of 119 pathogenic FF carriers with HIV infection were followed. During follow-up, 119 (100%) cases received antiretroviral therapy (ART) for at least 28 months, 107 (90%) cases had CD4+ counts>200 cells/μl, and none developed IFD.
Discussion
Pathogenic FF carriage is common in HIV-infected individuals but may not develop IFD in those who achieved immune reconstitution. Smoking and cured OIs history increase the risk of pathogenic FF carriage. Smoking abstinence and ART adherence are especially important for these patients.
BackgroundMyeloid‐derived suppressor cells (MDSCs) can potently inhibit T-cell activity, promote growth and metastasis of tumor and contribute to resistance to immunotherapy. Targeting MDSCs to ...alleviate their protumor functions and immunosuppressive activities is intimately associated with cancer immunotherapy. Natural killer (NK) cells can engage in crosstalk with multiple myeloid cells to alter adaptive immune responses, triggering T-cell immunity. However, whether the NK-cell-MDSC interaction can modulate the T-cell immune response requires further study. Cryo-thermal therapy could induce the maturation of MDSCs by creating an acute inflammatory environment to elicit a CD4+ Th1-dominant immune response, but the mechanism regulating this process remains unclear.MethodsNK cells were depleted and NKG2D was blocked with monoclonal antibodies in vivo. MDSCs, NK cells and T cells were assessed by flow cytometry and isolated by magnetic-activated cell sorting (MACS). MDSCs and NK cells were cocultured with T cells to determine their immunological function. The transcriptional profiles of MDSCs were measured by qRT-PCR and RNA-sequencing. Isolated NK cells and MDSCs by MACS were cocultured to study the viability and maturation of MDSCs regulated by NK cells. TIMER was used to comprehensively examine the immunological, clinical, and genomic features of tumors.ResultsNK-cell activation after cryo-thermal therapy decreased MDSC accumulation and reprogrammed immunosuppressive MDSCs toward a mature phenotype to promote T cell antitumor immunity. Furthermore, we discovered that NK cells could kill MDSCs via the NKG2D-NKG2DL axis and promote MDSC maturation by interferon gamma (IFN-γ) in response to NKG2D. In addition, CD4+ Th1-dominant antitumor immune response was dependent on NKG2D, which promoted the major histocompatibility complex Ⅱ pathway of MDSCs. High activated NK-cell infiltration and NKG2D level in tumors were positively correlated with better clinical outcomes.ConclusionsCryo-thermal therapy induces effective CD4+ Th1-dominant antitumor immunity by activating NK cells to reprogram MDSCs, providing a promising therapeutic strategy for cancer immunotherapy.
The neuronal synchronous discharging may cause an epileptic seizure. Currently, most of the studies conducted to investigate the mechanism of epilepsy are based on EEGs or functional magnetic ...resonance imaging (fMRI) recorded during the ictal discharging or the resting-state, and few studies have probed into the dynamic patterns during the inter-ictal discharging that are much easier to record in clinical applications. Here, we propose a time-varying network analysis based on adaptive directed transfer function to uncover the dynamic brain network patterns during the inter-ictal discharging. In addition, an algorithm based on the time-varying outflow of information derived from the network analysis is developed to detect the epileptogenic zone. The analysis performed revealed the time-varying network patterns during different stages of inter-ictal discharging; the epileptogenic zone was activated prior to the discharge onset then worked as the source to propagate the activity to other brain regions. Consistence between the epileptogenic zones detected by our proposed approach and the actual epileptogenic zones proved that time-varying network analysis could not only reveal the underlying neural mechanism of epilepsy, but also function as a useful tool in detecting the epileptogenic zone based on the EEGs in the inter-ictal discharging.
Integrase strand transfer inhibitors (INSTIs) in anti-retroviral therapy (ART) have been recommended by the World Health Organization for their higher efficacy, favorable safety and tolerability. ...However, the clinical evidence supporting switching to INSTI-containing regimens in low-and-middle-income countries (LMICs) is limited, as few patients have access to these regimens. We aimed to assess the effectiveness of INSTI-containing regimens in real-world settings in China compared to government-provided free ART. We compared the short-term (first 4 mo following ART initiation) and long-term (1 year after ART initiation) effectiveness between INSTI-containing regimens and free ART drugs provided by the Chinese government in 4 dimensions: viral suppression status, immune response, liver and kidney function, and AIDS-related diseases. We obtained data from electronic medical records in the National Infectious Disease Surveillance System. To control baseline confounders, we used propensity score matching (PSM), calculated using logistic regression including socio-demographic and baseline factors. Among 12,836 patients from 2012 to 2019, 673 (5.2%) used INSTI-containing regimens. Patients with INSTI-containing regimens were matched to those with free drugs (644 vs 644). For short-term effectiveness, patients initiating INSTI-containing regimens were more likely to achieve viral suppression (81.4% vs 52.0%; P < .001). The differences in immune response, liver and kidney function and AIDS-related diseases were not significant between the 2 groups. For long-term effectiveness, viral suppression rates were similar (87.96% vs 84.59%; P = .135), with no significant differences in immune response, liver and kidney function, or AIDS-related diseases. Our study suggests that patients initiating ART with INSTI-containing regimens have worse physical status at baseline than patients starting with free ART drugs. Furthermore, we found better virological performances of INSTI-containing regimens in the short-term but not in the long-term due to a high rate of drug changes. Our findings have clinical implications and provide new evidence regarding the effectiveness of INSTI-containing regimens in LMICs.
•The rate of alcohol use in patients with epilepsy (PWE) was 24.2%.•Been males, had a history of alcohol use were associated with alcohol use in PWE.•Heavy, frequent alcohol use were associated with ...worsening of seizure control in PWE.
Alcohol consumption has multiple negative consequences for people with epilepsy, including precipitation of seizure or status epilepticus, worsening of seizure control, increased adverse effects of anti-seizure medications, increased sudden unexpected death in epilepsy, and premature mortality. The aim of this study was to investigate alcohol use and explore the sociodemographic and clinical factors associated with alcohol use among patients with epilepsy in western China.
A face-to-face questionnaire on alcohol use was conducted at Sichuan Provincial People’s Hospital from December 2020 to June 2021. All adult patients who came to our epilepsy center (inpatient and outpatient) were invited to participate in this study. Logistic regression was used to evaluate the possible risk factors associated with alcohol use within the last 12 months.
A total of 425 patients completed this study, 24.2% of patients with epilepsy had used alcohol within the last 12 months, being male and having a history of alcohol use were independently associated factors. Among patients who had used alcohol within the last 12 months, 52.4% complained of worsening of seizure control, heavy alcohol use, and frequent alcohol use were independently associated with worsening of seizure control after alcohol use in patients with epilepsy.
This study revealed that the rate of alcohol use among patients with epilepsy was high. Male patients with a history of alcohol use were more prone to alcohol use after a diagnosis of epilepsy. Heavy alcohol use and frequent alcohol use were independently associated with worsening of seizure control after alcohol use in patients with epilepsy. Patient education on the destructive effects of alcohol use is needed for patients with epilepsy.
Drug refractory epilepsy (RE) is believed to be associated with structural lesions, but some RE patients show no significant structural abnormalities (RE-no-SA) on conventional magnetic resonance ...imaging scans. Since most of the medically controlled epilepsy (MCE) patients also do not exhibit structural abnormalities, a reliable assessment needs to be developed to differentiate RE-no-SA patients and MCE patients to avoid misdiagnosis and inappropriate treatment. Using resting-state scalp electroencephalogram (EEG) datasets, we extracted the spatial pattern of network (SPN) features from the functional and effective EEG networks of both RE-no-SA patients and MCE patients. Compared to the performance of traditional resting-state EEG network properties, the SPN features exhibited remarkable superiority in classifying these two groups of epilepsy patients, and accuracy values of 90.00% and 80.00% were obtained for the SPN features of the functional and effective EEG networks, respectively. By further fusing the SPN features of functional and effective networks, we demonstrated that the highest accuracy value of 96.67% could be reached, with a sensitivity of 100% and specificity of 92.86%. Overall, these findings not only indicate that the fused functional and effective SPN features are promising as reliable measurements for distinguishing RE-no-SA patients and MCE patients but also may provide a new perspective to explore the complex neurophysiology of refractory epilepsy.
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