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Abstract Background Malignant extrarenal rhabdoid tumor (MERT) is a rare and highly metastatic tumor, which is more than 75% of patients dying within 6 months of initial diagnosis, and it often leads to misdiagnosis and delayed treatment. Case This paper reports a 16‐year‐old girl who presented with the chief complaint of acute abdominal pain. She underwent laparoscopic exploration and excisional biopsy, then pathological examination and immunohistochemistry revealed “extrarenal malignant rhabdomyoma.” One month after operation, she died of intra‐abdominal hemorrhage and multiple organ dysfunction. Conclusion MERT were often misdiagnosed and had a poor prognosis. The surgery and chemotherapy are usually beneficial to prolong the survival time of patients with MERT.

Skin hyperpigmentation is a worldwide condition associated with augmented melanogenesis. However, conventional therapies often entail various adverse effects. Here, we explore the safety range and depigmentary effects of polysaccharides extract of Tricholoma matsutake (PETM) in an in vitro model and further evaluated its efficacy at the clinical level. An induced-melanogenesis model was established by treating B16–F10 melanoma cells with 8-methoxypsoralen (8-MOP). Effects of PETM on cell viability and melanin content were examined and compared to a commonly used depigmentary agent, α-arbutin. Expressions of key melanogenic factors and upstream signaling pathway were analysed by quantitative PCR and western blot. Moreover, a placebo-controlled clinical study involving Chinese females with skin hyperpigmentation was conducted to measure the efficacy of PETM on improving facial pigmented spots, melanin index, and individual typology angle (ITA°). Results demonstrated that PETM (up to 0.5 mg/mL) had little effect on the viability and motility of B16–F10 cells. Notably, it significantly suppressed the melanin content and expressions of key melanogenic factors induced by 8-MOP in B16–F10 melanoma cells. Western blotting results revealed that PETM inhibited melanogenesis by inactivating c-Jun N-terminal kinase (JNK), and this inhibitory role could be rescued by JNK agonist treatment. Clinical findings showed that PETM treatment resulted in a significant reduction of facial hyperpigmented spot, decreased melanin index, and improved ITA° value compared to the placebo-control group. In conclusion, these in vitro and clinical evidence demonstrated the safety and depigmentary efficacy of PETM, a novel polysaccharide agent. The distinct mechanism of action of PETM on melanogenic signaling pathway positions it as a promising agent for developing alternative therapies.

Abstract Background Lenvatinib is appropriate for reducing the production of nitric oxide (NO) and facilitating as block angiogenesis. However, to our knowledge, there are no data that support the correlation between NO and clinical response in patients who received lenvatinib therapy for HCC. Therefore, we investigated the correlation between the change rate of NO levels and clinical responses including adverse events (AEs) after lenvatinib therapy for unresectable hepatocellular carcinoma (HCC). Methods This study was conducted using previously collected data from another study. We enrolled 70 patients who received lenvatinib for advanced or unresectable HCC. NO was measured by converting nitrate (NO3 −) to nitrite (NO2 −) with nitrate reductase, followed by quantitation of NO2 − based on Griess reagent. To determine whether lenvatinib influences NO in unresectable HCC, we evaluated the influence of the change rate of NO from baseline after administration of lenvatinib on maximal therapeutic response and SAE. Results After lenvatinib administration, a change rate in the NO from 0.27 to 4.16 was observed. There was no difference between the clinical response to lenvatinib and the change rate of NO (p = 0.632). However, the change rate of NO was significantly lower in patients with AEs than in those without AEs (p = 0.030). When a reduction in NO rate of

BackgroundThere are still differences in the prognostic factors of renal cell carcinoma with sarcomatoid dedifferentiation (sRCC). The aim of this study was to evaluate important predictors of survival in patients with sRCC.Patients and methodsA comprehensive search of PubMed, Embase, and Cochrane Library was conducted to identify eligible studies. The endpoints embraced overall survival (OS), cancer-specific survival (CSS), and progression-free survival (PFS). Hazard ratios (HRs) and related 95% confidence intervals (CIs) were extracted.ResultsA total of 13 studies were included for analyses. The pooled results showed that high European Cooperative Oncology Group performance score (HR 2.39, 95% CI 1.32–4.30; P = 0.004), high T stage (HR 2.18, 95% CI 1.66–2.86; P

BackgroundDiabetic kidney disease (DKD) is the primary cause of end-stage renal disease, raising a considerable burden worldwide. Recognizing novel biomarkers by metabolomics can shed light on new biochemical insight to benefit DKD diagnostics and therapeutics. We hypothesized that serum metabolites can serve as biomarkers in the progression of DKD.MethodsA cross-sectional study of 1,043 plasma metabolites by untargeted LC/MS among 89 participants identified associations between proteinuria severity and metabolites difference. Pathway analysis from differently expressed metabolites was used to determine perturbed metabolism pathways. The results were replicated in an independent, cross-sectional cohort of 83 individuals. Correlation and prediction values were used to examine the association between plasma metabolites level and proteinuria amount.ResultsDiabetes, and diabetic kidney disease with different ranges of proteinuria have shown different metabolites patterns. Cysteine and methionine metabolism pathway, and Taurine and hypotaurine metabolism pathway were distinguishable in the existence of DKD in DC (diabetes controls without kidney disease), and DKD with different ranges of proteinuria. Two interesting tetrapeptides (Asn-Met-Cys-Ser and Asn-Cys-Pro-Pro) circulating levels were elevated with the DKD proteinuria progression.ConclusionsThese findings underscore that serum metabolomics provide us biochemical perspectives to identify some clinically relevant physiopathologic biomarkers of DKD progression.

Abstract Background Interleukin (IL)-35 regulates imbalance between regulatory T cells (Tregs) and T helper (Th) 17 cells, leading to an important modulator in autoimmune disorder, cancer, and infectious diseases. Our previous study revealed an immunosuppressive activity of IL-35 in chronic hepatitis B virus (HBV) infection. Thus, the aim of the current study was to investigate the role of regulatory function of IL-35 to viral specific Tregs/Th17 cells balance in chronic HBV infection. Methods A total of 44 HLA-A2 restricted chronic HBV infected patients, including 21 of chronic hepatitis B (CHB) and 23 of asymptomatic HBV carriers (ASC) were enrolled. Purified CD4+ T cells or CD4+CD25+CD127dim/− Tregs were stimulated with recombinant IL-35. HBV core antigen specific Tregs and Th17 cells were determined by flow cytometry. FoxP3 and RORγt mRNA was measured by real-time PCR. Cytokines production (IL-10 and IL-17) was investigated by ELISA. Results Peripheral viral specific Tregs was comparable between CHB and ASC. However, increased percentage of viral specific Th17 cells was found in CHB, leading to the reduction of Tregs/Th17 ratio in CHB patients. IL-35 stimulation elevated viral specific Tregs, but not Th17 cells frequency, in both CHB and ASC, resulting in the elevation of Tregs/Th17 ratio in both groups. This process was accompanied by increased expression of FoxP3 mRNA and IL-10 production, and decreased IL-17 secretion and STAT3 phosphorylation in purified CD4+ T cells. Moreover, IL-35 stimulation inhibited viral specific Th17-like phenotype differentiation from Tregs in CHB patients. Effective anti-HBV therapy did not affect viral specific Tregs/Th17 cells frequency or IL-35 expression in CHB patients, however, reduced responsiveness of CD4+ T cells or Tregs to IL-35 stimulation in vitro. Conclusion Our findings indicated that IL-35 regulation to viral specific Tregs/Th17 balance may contribute to viral persistence in chronic HBV infection.

Abstract Background Effective therapy for hepatocellular carcinoma (HCC) is currently an imperative issue, and sorafenib is a first-line drug for the treatment of HCC. However, the clinical benefit of sorafenib is often impaired by drug resistance. Accordingly, the present study was conducted to investigate the molecular mechanisms involving sorafenib resistance, with a focus on large tumor suppressor 2 (LATS2) and mitophagy. Methods HepG2 liver cancer cells were treated with sorafenib and infected with adenovirus-loaded LATS2 (Ad-LATS2). Cell death, proliferation and migration were measured via western blotting analysis, immunofluorescence and qPCR. Mitochondrial function and mitophagy were determined via western blotting and immunofluorescence. Results Our data indicated that LATS2 expression was repressed by sorafenib treatment, and overexpression of LATS2 could further enhance sorafenib-mediated apoptosis in HepG2 liver cancer cells. At the molecular level, mitochondrial stress was triggered by sorafenib treatment, as evidenced by decreased mitochondrial membrane potential, increased mitochondrial ROS production, more cyc-c release into the nucleus, and elevated mitochondrial pro-apoptotic proteins. However, in response to mitochondrial damage, mitophagy was activated by sorafenib treatment, whereas LATS2 overexpression effectively inhibited mitophagy activity and thus augmented sorafenib-mediated mitochondrial stress. Subsequently, we also demonstrated that the AMPK–MFN2 signaling pathway was involved in mitophagy regulation after exposure to sorafenib treatment and/or LATS2 overexpression. Inhibition of the AMPK pathway interrupted mitophagy and thus enhanced the antitumor property of sorafenib, similar to the results obtained via overexpression of LATS2. Conclusions Altogether, our findings revealed the importance of the LATS2/AMPK/MFN2/mitophagy axis in understanding sorafenib resistance mechanisms, with a potential application to increase the sensitivity response of sorafenib in the treatment of liver cancer.

BackgroundTo compare perioperative, functional and oncological outcomes between transperitoneal robotic partial nephrectomy (TRPN) and retroperitoneal robotic partial nephrectomy (RRPN).MethodsA literature searching of Pubmed, Embase, Cochrane Library and Web of Science was performed in August, 2020. Pooled odds ratios (ORs) or weighted mean differences (WMDs) with 95% confidence intervals (CIs) were estimated using fixed-effect or random-effect model. Publication bias was evaluated with funnel plots. Only comparative studies with matched design or similar baseline characteristics were included.ResultsEleven studies embracing 2,984 patients were included. There was no significant difference between the two groups regarding conversion to open (P = 0.44) or radical (P = 0.31) surgery, all complications (P = 0.06), major complications (P = 0.07), warm ischemia time (P = 0.73), positive surgical margin (P = 0.87), decline in eGFR (P = 0.42), CKD upstaging (P = 0.72), and total recurrence (P = 0.66). Patients undergoing TRPN had a significant higher minor complications (P = 0.04; OR: 1.39; 95% CI, 1.01–1.91), longer operative time (P < 0.001; WMD: 21.68; 95% CI, 11.61 to 31.76), more estimated blood loss (EBL, P = 0.002; WMD: 40.94; 95% CI, 14.87 to 67.01), longer length of hospital stay (LOS, P < 0.001; WMD: 0.86; 95% CI, 0.35 to 1.37). No obvious publication bias was identified.ConclusionRRPN is more favorable than TRPN in terms of less minor complications, shorter operative time, less EBL, and shorter LOS. Methodological limitations of the included studies should be considered while interpreting these results.

Abstract Background The nucleus accumbens in the midbrain dopamine limbic system plays a key role in cocaine addiction. Toll-like receptors (TLRs) are important pattern-recognition receptors (PPRs) in the innate immune system that are also involved in drug dependence; however, the detailed mechanism is largely unknown. Methods The present study was designed to investigate the potential role of TLR3 in cocaine addiction. Cocaine-induced conditioned place preference (CPP), locomotor activity, and self-administration were used to determine the effects of TLR3 in the rewarding properties of cocaine. Lentivirus-mediated re-expression of Tlr3 (LV-TLR3) was applied to determine if restoration of TLR3 expression in the NAc is sufficient to restore the cocaine effect in TLR3−/− mice. The protein levels of phospho-NF-κB p65, IKKβ, and p-IκBα both in the cytoplasm and nucleus of cocaine-induced CPP mice were detected by Western blot. Results We showed that both TLR3 deficiency and intra-NAc injection of TLR3 inhibitors significantly attenuated cocaine-induced CPP, locomotor activity, and self-administration in mice. Importantly, the TLR3−/− mice that received intra-NAc injection of LV-TLR3 displayed significant increases in cocaine-induced CPP and locomotor activity. Finally, we found that TLR3 inhibitor reverted cocaine-induced upregulation of phospho-NF-κB p65, IKKβ, and p-IκBα. Conclusions Taken together, our results describe that TLR3 modulates cocaine-induced behaviors and provide further evidence supporting a role for central pro-inflammatory immune signaling in drug reward. We propose that TLR3 blockade could be a novel approach to treat cocaine addiction.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Interleukin (IL)-35 is a newly identified IL-12 cytokine family member, which has been demonstrated to induce immunotolerance by suppression of CD8+ T cells function in chronic viral hepatitis. However, the role of IL-35 in modulating CD8+ T cells activity in non-viral hepatitis-related hepatocellular carcinoma (HCC) was not fully elucidated. Forty-four patients with non-viral hepatitis-related HCC and 20 healthy individuals were enrolled. Serum IL-35 concentration was measured by ELISA. CD8+ T cells were purified from peripheral bloods and liver tissues. mRNA expression of cytotoxic/inhibitory molecules in CD8+ T cells with IL-35 stimulation was semi-quantified by real-time PCR. Direct and indirect contact co-culture systems of CD8+ T cells and HCC cell lines were set up. The modulatory function of IL-35 on peripheral and liver-resident CD8+ T cells was assessed by measurement of lactate dehydrogenase release and cytokine production in the co-culture supernatants. Serum IL-35 was notably elevated in HCC patients, while effective anti-tumor therapies down-regulated IL-35 concentration. Recombinant IL-35 stimulation suppressed cytotoxicity and proinflammatory cytokine secretion of peripheral and liver-resident CD8+ T cells in direct and indirect contact co-culture systems. This process was accompanied by reduction of perforin expression and interferon-γ production, as well as programmed death-1 and cytotoxic T-lymphocyte-associated protein 4 elevation in CD8+ T cells. The current data suggested that IL-35 inhibited both cytolytic and non-cytolytic function of CD8+ T cells to non-viral hepatitis-related HCC probably via repression of perforin expression. IL-35 might be considered to be one of the therapeutic targets for patients with HCC.

Studies have showed that prenatal cocaine exposure (PCOC) can impair cognitive function and social behavior of the offspring; however, the mechanism underlying such effect is poorly understood. Insulin-like growth factor II (Igf-II), an imprinted gene, has a critical role in memory consolidation and enhancement. We hypothesized that epigenetic regulation of hippocampal Igf-II may attribute to the cognitive deficits of PCOC offspring. We used Morris water maze and open-field task to test the cognitive function in PCOC offspring. The epigenetic alteration involved in hippocampal Igf-II expression deficit in PCOC offspring was studied by determining Igf-II methylation status, DNA methyltransferases (DNMT) expressions and l-methionine level. Moreover, IGF-II rescue experiments were performed and the downstream signalings were investigated in PCOC offspring. In behavioral tests, we observed impaired spatial learning and memory and increased anxiety in PCOC offspring; moreover, hippocampal IGF-II mRNA and protein expressions were significantly decreased. Hippocampal methylation of cytosine-phospho-guanine (CpG) dinucleotides in differentially methylated region (DMR) 2 of Igf-II was elevated in PCOC offspring, which may be driven by the upregulation of l-methionine and DNA methyltransferase (DNMT) 1. Importantly, intra-hippocampal injection of recombinant IGF-II reactivated the repressed calcium calmodulin kinase II α (CaMKIIα) and reversed cognitive deficits in PCOC offspring. Collectively, our findings suggest that cocaine exposure during pregnancy impairs cognitive function of offspring through epigenetic modification of Igf-II gene. Enhancing IGF-II signaling may represent a novel therapeutical strategy for cocaine-induced cognitive impairment.

The editor has retracted this article [1] because Fig. 2f has been duplicated from Fig. 6j in a previously published article [2]. In addition, the article contains sections that substantially overlap with a previously published article [3]. The data reported in this article are therefore unreliable.

The mechanisms of hepatitis B virus (HBV) persistent infection are not completely understood. Interleukin (IL)-35, which is a newly identified cytokine belongs to IL-12 family, has been demonstrated to induce immunotolerance. Thus, the aim of current study was to investigate the role of IL-35 during chronic HBV infection. A total of 61 patients with chronic HBV infection [37 chronic hepatitis B (CHB) and 24 asymptomatic HBV carriers (ASC)] and 20 healthy individuals were enrolled. IL-35 concentration as well as the modulatory function of IL-35 on CD4+CD25+CD127dim/− regulatory T cells (Tregs) and on HBV antigen-specific CD8+ T cells was investigated. IL-35 expression was significantly increased in both CHB and ASC, and was positively correlated with the levels of HBV DNA. Inhibition of viral replication induced the reduction in serum levels of IL-35. IL-35 stimulation led to inhibition of proinflammatory cytokine productions and elevation of apoptosis in peripheral blood mononuclear cells (PBMCs), but not in HepG2.2.15 cells. Moreover, IL-35 stimulation not only robustly inhibited cellular proliferation, but also up-regulated the production of IL-10 and IL-35 in a HBV antigen-specific and non-specific manner in Tregs/CD4+CD25− T cells coculture system, which indicated enhancement of suppressive function of Tregs. Furthermore, IL-35 also reduced both cytolytic activity (direct lysis of HepG2.2.15 cells) and noncytolytic function (IFN-γ and TNF-α production) of HBV antigen-specific CD8+ T cells. The current data suggested that IL-35 contributed to maintain viral persistence by suppressing antiviral immune responses and reducing inflammatory responses in chronic HBV infection.

Nicotine, one of the most commonly used drugs, has become a major concern because tobacco serves as a gateway drug and is linked to illicit drug abuse, such as cocaine and marijuana. However, previous studies mainly focused on certain genes or neurotransmitters which have already been known to participate in drug addiction, lacking endogenous metabolic profiling in a global view. To further explore the mechanism by which nicotine modifies the response to cocaine, we developed two conditioned place preference (CPP) models in mice. In threshold dose model, mice were pretreated with nicotine, followed by cocaine treatment at the dose of 2 mg/kg, a threshold dose of cocaine to induce CPP in mice. In high-dose model, mice were only treated with 20 mg/kg cocaine, which induced a significant CPP. (1)H nuclear magnetic resonance based on metabonomics was used to investigate metabolic profiles of the nucleus accumbens (NAc) and striatum. We found that nicotine pretreatment dramatically increased CPP induced by 2 mg/kg cocaine, which was similar to 20 mg/kg cocaine-induced CPP. Interestingly, metabolic profiles showed considerable overlap between these two models. These overlapped metabolites mainly included neurotransmitters as well as the molecules participating in energy homeostasis and cellular metabolism. Our results show that the reinforcing effect of nicotine on behavioral response to cocaine may attribute to the modification of some specific metabolites in NAc and striatum, thus creating a favorable metabolic environment for enhancing conditioned rewarding effect of cocaine. Our findings provide an insight into the effect of cigarette smoking on cocaine dependence and the underlying mechanism.

Large-particle porous propellant has good surface-enhancing combustion performance and may improve the muzzle velocity of combustion propulsion system effectively. The proposed particle element method is further refined to investigate particle motion characteristics and flow field distribution in a large-particle charge combustion system with moving boundary. The particle element parameter aggregation is established to describe particle parameter distribution in the system, and the motion is controlled by particle motion equations during combustion and propulsion, so that the particle element is stretched and coupled with the gas phase. The particle element method accurately describes the distribution of the particle movement process and the evolution of the flow field in the chamber, and the numerical simulation results are in good agreement with the AGARD code. In particular, the overall efficiency of the entire calculating procedure is improved by 21.7%. The research results will effectively solve the flow field problem in the large-particle charge combustion system. [ABSTRACT FROM AUTHOR]