Preoperative dexamethasone administration in reducing the incidence of nausea and vomiting after thyroidectomy: a systematic review and meta-analysis of drug dosage.

Background: Postoperative nausea and vomiting (PONV) are key contributors to the delay of recovery and cause patients' considerable discomfort. This study aimed to evaluate the influence of a specific dexamethasone dosage on PONV incidence, with a secondary objective of assessing its impact on postoperative pain in patients undergoing thyroid surgery. Methods: A meta-analysis was performed to examine the effects of preoperatively administering various doses of dexamethasone in combination with saline on PONV and pain relief in patients undergoing thyroidectomy. Relevant trials published before December 30, 2022, were searched in the PubMed, Embase, Cochrane Library, and Web of Science databases. The collected data were analyzed using RevMan 5.3 software (Cochrane), and a random-effects model or fixed-effects model was employed to conduct the meta-analysis. Results: Our meta-analysis included 11 randomized controlled trials (RCTs) with a total of 1,544 participants. The results suggested that administering dexamethasone at a dosage of 8-10 mg can reduce the incidence of PONV in patients after thyroid surgery [odds ratio (OR) 0.27; 95% CI: 0.15-0.50; I2=82%; P<0.0001]. Additionally, administering dexamethasone at a dosage of 8-10 mg was found to be significantly more effective in reducing the incidence of PONV than was a dosage of 4-5 mg (OR 0.39; 95% CI: 0.19-0.80; I2=29%; P=0.01). The study also revealed that administering dexamethasone at a dosage of 8-10 mg can significantly reduce pain in patients undergoing thyroidectomy [mean difference (MD): -1.19; 95% CI: -1.97 to -0.41; I2=96%; P=0.003]. However, administering dexamethasone at a dosage of 4-5 mg did not significantly reduce pain (MD: -0.27; 95% CI: -1.00 to 0.45; I2=0%; P=0.46) according to the subgroup analysis. Our study found that the intervention of administering dexamethasone did not have a significant impact on the consumption of analgesic drugs (MD: -0.19; 95% CI: -0.45 to 0.08; I2=62%; P=0.16). Conclusions: A preoperative single dose of 8-10 mg of dexamethasone can significantly reduce PONV and the requirement for additional antiemetic medications, as well as alleviate postoperative pain after thyroidectomy. However, more RCTs should be conducted to determine the effects of varied dexamethasone dosages, particularly 4-5 mg, on the incidence of PONV and pain.

A Prognostic Model for Cancer-Specific Survival Among Patients with Nodular Melanoma in Head and Neck.

OBJECTIVES: This study aims to evaluate the correlation between risk factors and treatment methods affecting nodular melanoma (NM) in the head and neck, as well as cancer-specific survival (CSS), and provide personalized predictive tools for clinical physicians. METHODS: The retrospective study data of 1848 patients were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. All variables were included in the correlation analysis using the Spearman method. Significant prognostic factors were extracted and integrated through Cox risk regression analysis to construct a nomogram. To assess the performance of the nomogram, Harrell's concordance index (C-index) and a receiver operating characteristic (ROC) curve analysis were employed. RESULTS: Spearman's correlation analysis revealed a positive correlation between radiotherapy and lymph node metastasis, whereas chemotherapy showed a stronger association with distant metastasis. However, Cox risk regression analysis demonstrated that Mohs surgery and wide excision with margins exceeding 1 cm yielded substantial therapeutic advantages. Five independent risk prognostic factors (Breslow thickness, ulceration, N classification, M classification, and surgery type) were employed to construct a nomogram. The C-index for this nomogram was 0.713 for the training set and 0.720 for the validation set. In the training set, the 3-, 5-, and 8-year areas under the curve (AUCs) for CSS were 0.752, 0.723, and 0.720, whereas the validation set's AUCs were 0.754, 0.763, and 0.760, respectively. Calibration curves indicated the nomogram's strong discriminative ability for predicting CSS. CONCLUSION: In this study, we identified independent prognostic factors for patients with NM in head and neck and developed a relatively accurate model to predict the survival probability of them, which could contribute to the tumor assessment and clinical decision-making. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:3611-3619, 2024.

A novel nomogram and recursive partitioning analysis for predicting cancer-specific survival of patients with subcutaneous leiomyosarcoma.

Accurately predicting prognosis subcutaneous leiomyosarcoma (LMS) is crucial for guiding treatment decisions in patients. The objective of this study was to develop prediction models for cancer-specific survival (CSS) in patients with subcutaneous LMS. The collected cases of diagnosed subcutaneous LMS were randomly divided into a training cohort and a validation cohort at a 6:4 ratio based on tumor location and histological code. The X-tile program was utilized to determine the optimal cutoff points for age index. Univariate and Cox multivariate regression analyses were conducted to identify independent risk factors for subcutaneous LMS patients. Nomograms were constructed to predict CSS, and their performance was assessed using C-index and calibration plots. Additionally, a decision tree model was established using recursive partitioning analysis to determine the total score for CSS prediction in subcutaneous LMS patients based on the nomogram model. A total of 1793 patients with subcutaneous LMS were found. X-tile software divides all patients into ≤ 61 years old, 61-82 years old, and ≥ 82 years old. The most important anatomical sites were the limbs (including the upper and lower limbs, 48.0%). Only 6.2% of patients received chemotherapy, while 44% had a history of radiotherapy and 92.9% underwent surgery. The independent risk factors for patients with subcutaneous LMS were age, summary stage, grade, and surgery. CSS was significantly decreased in patients with distant metastases, which showed the highest independent risk predictor (HR 4.325, 95% CI 3.010-6.214, p < 0.001). The nomogram prediction model of LMS was constructed based on four risk factors. The C-index for this model was 0.802 [95% CI 0.781-0.823] and 0.798 [95% CI 0.768-0.829]. The training cohort's 3-, 5-, and 10-year AUCs for CSS in patients with subcutaneous LMS were 0.833, 0.830, and 0.859, and the validation cohort's AUC for predicting CSS rate were 0.849, 0.830, and 0.803, respectively. Recursive segmentation analysis divided patients into 4 risk subgroups according to the total score in the nomogram, including low-risk group < 145, intermediate-low-risk group ≥ 145 < 176, intermediate-high-risk group ≥ 176 < 196, and high-risk group ≥ 196; The probability of the four risk subgroups is 9.1%, 34%, 49%, and 79% respectively. In this retrospective study, a novel nomogram or corresponding risk classification system for patients with subcutaneous LMS were developed, which may assist clinicians in identifying high-risk patients and in guiding the clinical decision.

Precise design of dual active-site catalysts for synergistic catalytic therapy of tumors.

A proven and promising method to improve the catalytic performance of single-atom catalysts through the interaction between bimetallic atoms to change the active surface sites or adjust the catalytic sites of reactants is reported. In this work, we used an iron-platinum bimetallic reagent as the metal source to precisely synthesise covalent organic framework-derived diatomic catalysts (FePt-DAC/NC). Benefiting from the coordination between the two metal atoms, the presence of Pt single atoms can successfully regulate Fe-N3 activity. FePt-DAC/NC exhibited a stronger ability to catalyze H2O2 to produce toxic hydroxyl radicals than Fe single-atom catalysts (Fe-SA/NC) to achieve chemodynamic therapy of tumors (the catalytic efficiency improved by 186.4%). At the same time, under the irradiation of an 808 nm laser, FePt-DAC/NC exhibited efficient photothermal conversion efficiency to achieve photothermal therapy of tumors. Both in vitro and in vivo results indicate that FePt-DAC/NC can efficiently suppress tumor cell growth by a synergistic therapeutic effect with photothermally augmented nanocatalytic therapy. This novel bimetallic dual active-site monodisperse catalyst provides an important example for the application of single-atom catalysts in the biomedical field, highlighting its promising clinical potential.

CoFeSe2 @DMSA@FA Nanocatalyst for Amplification of Oxidative Stress to Achieve Multimodal Tumor Therapy.

Nanomedicine has significantly advanced precise tumor therapy, providing essential technical blessing for active drug accumulation, targeted consignment, and mitigation of noxious side effects. To enhance anti-tumor efficacy, the integration of multiple therapeutic modalities has garnered significant attention. Here, we designed an innovative CoFeSe2 @DMSA@FA nanocatalyst with Se vacancies (abbreviated as CFSDF), which exhibits synergistic chemodynamic therapy (CDT) and photothermal therapy (PTT), leading to amplified tumor oxidative stress and enhanced photothermal effects. The multifunctional CFSDF nanocatalyst exhibits the remarkable ability to catalyze the Fenton reaction within the acidic tumor microenvironment, efficiently converting hydrogen peroxide (H2 O2 ) into highly harmful hydroxyl radicals (⋅OH). Moreover, the nanocatalyst effectively diminishes GSH levels and ameliorates intracellular oxidative stress. The incorporation of FA modification enables CFSDF to evade immune detection and selectively target tumor tissues. Numerous in vitro and in vivo investigations have consistently demonstrated that CFSDF optimizes its individual advantages and significantly enhances therapeutic efficiency through synergistic effects of multiple therapeutic modalities, offering a valuable and effective approach to cancer treatment.

Survival and analysis of prognostic factors for severe burn patients with inhalation injury: based on the respiratory SOFA score.

BACKGROUND: It is important to determine the severity of inhalation injury in severely burned patients. The oxygenation index PaO2/FiO2(PF) ratio is a key clinical indicator of inhalation injury. Sequential organ failure assessment (SOFA) is developed to assess the acute incidence of critical illness in the population. We hope to provide an assessment of survival or prognostic factor for severely burned patients with inhalation injury based on the respiratory SOFA score. METHODS: This is a retrospective cohort study of all admissions to Department of Burn and Plastic Surgery at West China Hospital of Sichuan University from July 2010 to March 2021. Data was analyzed using Cox regression models to determine significant predictors of mortality. Survival analysis with time to death event was performed using the Kaplan-Meier survival curve with the log-rank test. All potential risk factors were considered independent variables, while survival was considered the risk dependent variable. RESULTS: One hundred eighteen severe burn patients with inhalation injury who met the inclusion and exclusion criteria were admitted, including men accounted for 76.3%. The mean age and length of stay were 45.9 (14.8) years and 44.3 (38.4) days. Flame burns are the main etiology of burn (74.6%). Patients with the respiratory SOFA score greater than 2 have undergone mechanical ventilation. Univariate Kaplan-Meier analysis identified age, total body surface area burned (TBSA), ICU admission and the respiratory SOFA score as significant factors on survival. Cox regression analysis showed that TBSA and the respiratory SOFA score were associated with patient survival (p < 0.001). In some patients with severe burns and inhalation damage, the survival probability drops to less than 10% (TBSA greater than 80%: 8.9% and respiratory SOFA score greater than 2: 5.6%). This study statistically found that the TBSA with the respiratory SOFA score model (AUROC: 0.955) and the rBaux score (AUROC: 0.927) had similar predictive value (p = 0.175). CONCLUSION: The study indicates that a high respiratory system SOFA score was identified as a strong and independent predictor of severely burned patients with inhalation injury during hospitalization. When combined with TBSA, the respiratory SOFA scores can dynamically assess the severity of the patient's lung injury and improve the predictive level.

TRAIL inhibition by soluble death receptor 5 protects against acute myocardial infarction in rats.

Acute myocardial infarction (AMI) is associated with high morbidity and mortality. An effective therapeutic strategy is to rescue cardiomyocytes from death. Apoptosis is a key reason of cardiomyocyte death that can be prevented. In this study, we investigated the role of TNF-related apoptosis-inducing ligand (TRAIL) in initiating apoptosis by binding to death receptor 5 (DR5), and this procession is inhibited by soluble DR5 (sDR5) in rats after AMI. First, we found that the level of TRAIL in serum was down-regulated in AMI patients. Then, TRAIL and DR5 expression was analysed in the myocardium of rats after AMI, and their expression was up-regulated. sDR5 treatment reduced the myocardial infarct size and the levels of CK-MB and cTn-I in serum. The expression of caspase 3 and PARP is decreased, but the anti-apoptotic factor Bcl-2 was increased in sDR5 treatment rats after AMI. DR5 expression was also analysed after sDR5 treatment and it was down-regulated, and a low level of DR5 expression seemed to be beneficial for the myocardium. Overall, our findings indicated that sDR5 decreases myocardial damage by inhibiting apoptosis in rat after AMI. We expect to observe the potential therapeutic effects of sDR5 on AMI in the future.

Survival analysis in head and neck melanoma after negative sentinel lymph node biopsy: A seer-based population study.

BACKGROUND: Cutaneous malignant melanoma (CMM) is one of the most aggressive skin tumors. Sentinel lymph node biopsy (SLNB) is an important test before thorough treatment of melanoma. The aim of this study was to investigate cancer-specific survival (CSS) in patients with head and neck CMM after negative SLNB and to analyze predictors of decreased survival. METHODS: Based on the Surveillance, Epidemiology and End Results (SEER) database, a study was conducted using data from patients with head and neck CMM after negative SLNB. The demographic, clinical, and pathological characteristics of the case population were analyzed. Cox univariate, Kaplan-Meier analysis, and multivariate Cox regression models were used to explore predictors of decreased survival; propensity score matching (PSM) analysis was used to reduce confounding bias, and outcomes were compared between the wide margin excision and narrow margin excision groups. RESULTS: A total of 1597 confirmed head and neck CMM patients with SLNB-negative were found. A Breslow>4.0 mm was the highest independent risk predictor for patients (HR 3.82, 95% CI 2.04-7.16, P < .001), and significant risk independent predictors also included a high mitotic rate >4 (HR 1.54, 95% CI 1.06-2.25, P = .023). Age< 60 years old was a significant survival predictor (HR 0.56, 95% CI .37-.85, P = .007), and not scalp and neck CMM were also important factors for longer survival (auricle skin: HR .51, 95% CI .29-.90, P = .02; unspecified parts of face: HR .59, 95% CI .40-.87, P = .007). After harmonizing baseline data by PSM, it was found that the extent of surgical resection did not affect patient survival. CONCLUSION: This study analyzed the risk factors affecting CSS in patients with CMM of the head and neck region with SLNB-negative and observed a statistically significant difference in the prognosis of patients with CMM in different aesthetic subunits of the head and neck region. Close clinical follow-up for this population is necessary, and periodic medical examinations should be carried out.

Prognostic model for predicting overall and cancer-specific survival among patients with superficial spreading melanoma: A SEER based study.

Skin malignant melanoma is one of the most aggressive skin tumors. Superficial spreading melanoma (SSM) is the most common histological type, which can originate from different body skin sites, and some patients can still accumulate regional lymph nodes and even have distant metastasis in some cases. This study used the relevant data from the monitoring, epidemiology and results database of the National Cancer Institute database to study the overall survival (OS) and cancer-specific survival (CSS) of SSM patients and established an SSM nomogram to evaluate the prognosis of patients. A total of 13,922 patients were collected from the monitoring, epidemiology and results database of the National Cancer Institute and randomly divided into a training cohort (8353 cases) and a validation cohort (5569 cases). Univariate and multivariate Cox regression analysis were used to determine prognostic factors, and these factors were used to construct OS and CSS nomograms for patients with SSM. Finally, the discrimination and consistency of the nomogram model were evaluated by the consistency index (C-index), area under the curve (AUC) and calibration curve. Multivariate Cox regression analysis suggested that age, sex, tumor site, the American joint committee on cancer T stage and the first primary melanoma were independent predictors of OS and CSS in patients with SSM and that the American joint committee on cancer N stage was also an independent predictor of CSS in patients with SSM. Based on the above prognostic factors, this study constructed a predictive model. The C-index of the model OS and CSS for this training cohort was 0.805 [95% CI: 0.793-0.817] and 0.896 [95% CI: 0.878-0.913], respectively. The AUC values for 1-, 3-, and 5-year OS were 0.822, 0.820, and 0.821, respectively, and the AUC values for CSS were 0.914, 0.922, and 0.893, respectively. The data indicated that both nomograms showed better predictive accuracy. The calibration curves of the training cohort and the validation cohort were in good agreement. The nomogram has superior predictive performance in predicting 1-, 3-, and 5-year OS and CSS prognosis in patients with SSM and can provide a reference for individualized treatment and clinical counseling of SSM.

Inhibition of hepatocyte nuclear factor 1ß contributes to cisplatin nephrotoxicity via regulation of nf-κb pathway.

Cisplatin nephrotoxicity has been considered as serious side effect caused by cisplatin-based chemotherapy. Recent evidence indicates that renal tubular cell apoptosis and inflammation contribute to the progression of cisplatin-induced acute kidney injury (AKI). Hepatocyte nuclear factor 1ß (HNF1ß) has been reported to regulate the development of kidney cystogenesis, diabetic nephrotoxicity, etc However, the regulatory mechanism of HNF1ß in cisplatin nephrotoxicity is largely unknown. In the present study, we examined the effects of HNF1ß deficiency on the development of cisplatin-induced AKI in vitro and in vivo. HNF1ß down-regulation exacerbated cisplatin-induced RPTC apoptosis by indirectly inducing NF-κB p65 phosphorylation and nuclear translocation. HNF1ß knockdown C57BL/6 mice were constructed by injecting intravenously with HNF1ß-interfering shRNA and PEI. The HNF1ß scramble and knockdown mice were treated with 30 mg/kg cisplatin for 3 days to induce acute kidney injury. Cisplatin treatment caused increased caspase 3 cleavage and p65 phosphorylation, elevated serum urea nitrogen and creatinine, and obvious histological damage of kidney such as fractured tubules in control mice, which were enhanced in HNF1ß knockdown mice. These results suggest that HNF1ß may ameliorate cisplatin nephrotoxicity in vitro and in vivo, probably through regulating NF-κB signalling pathway.

Blocking the death checkpoint protein TRAIL improves cardiac function after myocardial infarction in monkeys, pigs, and rats.

Myocardial infarction (MI) is a leading cause of death worldwide for which there is no cure. Although cardiac cell death is a well-recognized pathological mechanism of MI, therapeutic blockade of cell death to treat MI is not straightforward. Death receptor 5 (DR5) and its ligand TRAIL [tumor necrosis factor (TNF)-related apoptosis-inducing ligand] are up-regulated in MI, but their roles in pathological remodeling are unknown. Here, we report that blocking TRAIL with a soluble DR5 immunoglobulin fusion protein diminished MI by preventing cardiac cell death and inflammation in rats, pigs, and monkeys. Mechanistically, TRAIL induced the death of cardiomyocytes and recruited and activated leukocytes, directly and indirectly causing cardiac injury. Transcriptome profiling revealed increased expression of inflammatory cytokines in infarcted heart tissue, which was markedly reduced by TRAIL blockade. Together, our findings indicate that TRAIL mediates MI directly by targeting cardiomyocytes and indirectly by affecting myeloid cells, supporting TRAIL blockade as a potential therapeutic strategy for treating MI.

Suppressed Expression of CXCL14 in Hepatocellular Carcinoma Tissues and Its Reduction in the Advanced Stage of Chronic HBV Infection.

INTRODUCTION: CXCL14 was a significantly under-expressed mRNA in hepatocellular carcinoma tissues according to our microarray analysis, as well as head and neck squamous cell carcinoma and cervical squamous cell carcinoma. CXCL14 was considered a tumor suppressor in some studies; however, its role in HBV infection has not been identified. METHODS: CXCL14 mRNA expression was quantified from 20 male HCC patients, and the fold change in cancer tissues was calculated by comparisons with normal adjacent tissues. Overall, 212 patients with chronic HBV infection and 180 HBV-free controls were recruited to investigate the association between CXCL14 polymorphisms and HBV progression as well as liver function parameters. Serum CXCL14 levels were determined by enzyme-linked immunosorbent assay (ELISA), and comparisons were made between different HBV status and different CXCL14 genotypes. RESULTS: The mRNA expression of CXCL14 was 0.33-fold in HCC tissues when compared with adjacent tissues. The frequencies of rs2237062 and rs2547, but not rs2237061, were significantly different between patients with mild hepatitis and moderate-to-severe hepatitis. Moreover, rs2237062 and rs2547 polymorphisms correlated with impaired liver function parameters. ELISA results suggested that HBV-free controls had the highest level of CXCL14, while mild hepatitis patients had low levels, and patients with moderate-to-severe hepatitis had the lowest level. GA+AA genotypes of rs2547 were associated with reduced levels of serum CXCL14 because it introduced a stop codon at residue 109. CONCLUSION: CXCL14 was significantly suppressed in HBV-related HCC tissues, and its polymorphisms were linked with advanced stage chronic HBV infection and impaired liver function.

RACK1 deficiency synergizes with all-trans retinoic acid to induce apoptosis in human acute promyelocytic leukemia cells.

As a classic differentiation agent, all-trans retinoic acid (ATRA) has been widely used in the treatment of acute promyelocytic leukemia (APL). However, the clinical application of ATRA has strict limitations, for its severe side effects due to the accumulation of peripheral blood leukocytes. The scaffold protein RACK1 (Receptor for activated C kinase 1), which regulates multiple signaling pathways, has been proposed to contribute to the survival of leukemic progenitors. But it remains unclear whether it is also involved in the oncogenic growth of APL. In the present study, we demonstrate that silencing of endogenous RACK1 expression synergized with ATRA to promote the death of NB4 and HL-60 APL cells without effect on cell differentiation induced by ATRA. Interestingly, RACK1 knockdown combined with ATRA treatment mainly induces apoptosis. It is distinct to the necrotic cell death induced by idarubicin in combination with ATRA, a regimen extensively used in the clinic to prevent neutrophil accumulation. Further exploration revealed that the lysosome-autophagy pathway is likely to be responsible for the anti-apoptotic role of RACK1. Taken together, our findings indicate that RACK1 is essential in maintaining the malignant features of APL, and targeting RACK1 may have promising therapeutic implications in the treatment of APL.

Treponema pallidum promotes macrophage polarization and activates the NLRP3 inflammasome pathway to induce interleukin-1ß production.

BACKGROUND: The involvement of inflammasome activation and macrophage polarization during the process of syphilis infection remains unknown. In this study, A series of experiments were performed using human macrophages to research the role of NLRP3 inflammasome regulation in interleukin (IL)-1ß production and its influence on macrophage polarization triggered by T. pallidum. RESULTS: The results showed that in M0 macrophages treated with T. pallidum, the M1-associated markers inducible nitric oxide synthase (iNOS), IL-1ß and TNF-α were upregulated, and the M2-associated markers CD206 and IL-10 were downregulated. In addition, we observed NLRP3 inflammasome activation and IL-1ß secretion in T. pallidum-treated macrophages, and the observed production of IL-1ß occurred in a dose- and time-dependent manner. Moreover, the secretion of IL-1ß by macrophages after T. pallidum treatment was notably reduced by anti-NLRP3 siRNA and caspase-1 inhibitor treatment. NAC, KCl, and CA074-ME treatment also suppressed IL-1ß release from T. pallidum-treated macrophages. CONCLUSIONS: These findings showed that T. pallidum induces M0 macrophages to undergo M1 macrophage polarization and elevate IL-1ß secretion through NLRP3. Moreover, the process of NLRP3 inflammasome activation and IL-1ß production in macrophages in response to T. pallidum infection involves K+ efflux, mitochondrial ROS production and cathepsin release. This study provides a new insight into the innate immune response to T. pallidum infection.

Development of tissue inflammation accompanied by NLRP3 inflammasome activation in rabbits infected with Treponema pallidum strain Nichols.

BACKGROUND: The inflammasome responses in Treponema pallidum infection have been poorly understood to date. This study aimed to investigate the expression of the nucleotide-binding leucine-rich receptor protein 3 (NLRP3) inflammasome in the development of tissue inflammation in rabbits infected with T. pallidum. METHODS: Forty-five rabbits were randomly assigned to a blank group or an infection group, and the latter was divided into no benzathine penicillin G (BPG) and BPG treatment subgroups. Rabbits in the infection group were injected intradermally with 0.1 mL of a 107/mL T. pallidum suspension at 10 marked sites along the back, and the blank group was treated with normal saline. The BPG treatment subgroup received 200,000 U of BPG administered intramuscularly twice, at 14 d and 21 d post-infection. The development of lesions was observed, and biopsies of the injection site and various organs, including the kidney, liver, spleen, lung, and testis, were obtained for NLRP3, caspase-1, and interleukin-1ß (IL-1ß) mRNA analysis during infection. Blood was also collected for the determination of IL-1ß concentration. RESULTS: Rabbits infected with T. pallidum (both the BPG treatment and no BPG treatment subgroups), exhibited NLRP3 inflammasome activation and IL-1ß secretion in cutaneous lesions, showing a trend in elevation to decline; NLRP3 mRNA expression reached a peak at 18 d in the BPG treatment subgroup and 21 d in the no BPG treatment subgroup and returned to "normal" levels [vs. the blank group (P > 0.05)] at 42 d post-infection. The trend was similar to the change in cutaneous lesions in the infected rabbits, which reached a peak at 16 d in the BPG treatment subgroup and 18 d in the no BPG treatment subgroup. NLRP3, caspase-1, and IL-1ß mRNA expression levels were slightly different in different organs. NLRP3 inflammasome activation was also observed in the kidney, liver, lung, spleen and testis. IL-1ß expression was observed in the kidney, liver, lung and spleen; however, there was no detectable level of IL-1ß in the testes of the infected rabbits. CONCLUSIONS: This study established a clear link between NLRP3 inflammasome activation and the development of tissue inflammation in rabbits infected with T. pallidum. BPG therapy imperceptibly adjusted syphilitic inflammation.

Correlation between polymorphisms in toll-like receptor genes and the activity of hepatitis B virus among treatment-naïve patients: a case-control study in a Han Chinese population.

BACKGROUND: Because of the high prevalence and absence of cure for infection, chronic hepatitis B virus (HBV) infection has been acknowledged as a pressing public health issue. Toll-like receptors (TLRs) activate the human innate immune system and the polymorphisms in TLRs may alter their function. The present study aimed to investigate the association between TLR polymorphisms and disease progression of chronic HBV infection. METHODS: During the study period, 211 treatment-naïve patients with chronic HBV infection were recruited, and blood samples were collected from each individual. Matrix-assisted laser desorption/ionization time of flight mass spectrometry was employed to genotype the selected TLR polymorphisms after human genome extraction. In addition, HbsAg, TNF-α, and IL-6 levels were quantified using enzyme linked immunosorbent assay (ELISA). Statistical analyses were conducted to investigate the association between TLR polymorphisms and hepatitis activity, liver function parameters, HbsAg level, and cytokine level. RESULTS: We did not observe any mutations in rs4986790, rs4986791, and rs5743708 among all study subjects. A logistic regression revealed that mutations in rs3804099 and rs4696480 were associated with milder hepatitis activity. Consistent with the logistic regression, improved liver function parameters and reduced level of both HbsAg and cytokines were also correlated with the mutant carriers of rs3804099 and rs4696480. CONCLUSIONS: TLR mutations were significantly associated with milder hepatitis activity among patients with chronic HBV infection. Therefore, we conclude that the activation of TLR pathways may further intensify the inflammation of hepatocytes, and leads to progression of disease.

Heat shock factor 4 regulates lens epithelial cell homeostasis by working with lysosome and anti-apoptosis pathways.

Activation of Heat shock factor 4-mediated heat shock response is closely associated with postnatal lens development. HSF4 controls the expression of small heat shock proteins (e.g. HSP25 and CRYAB) in lens epithelial cells. However, their roles in modulating lens epithelium homeostasis remain unclear. In this paper, we find that HSF4 is developmentally expressed in mouse lens epithelium and fiber tissue. HSF4 and alpha B-crystallin can selectively protect lens epithelial cells from cisplatin and H2O2 induced apoptosis by stabilizing mitochondrial membrane potential (ΔYm) and reducing ROS production. In addition, to our surprise, HSF4 is involved in upregulating lysosome activity. We found mLEC/HA-Hsf4 cells to have increased DLAD expression, lysosome acidity, cathepsin B activity, and degradation of plasmid DNA and GFP-LC3 protein when compared to mLEC/Hsf4-/- cells. Knocking down Cryab from mLEC/HA-Hsf4 cells inhibits HSF4-mediated lysosome acidification, while overexpression of CRYAB can upregulate cathepsin B activity in mLEC/Hsf4-/- cells. CRAYAB can interact with ATP6V1/A the A subunit of the H+ pump vacuolar ATPase, and is colocalized to lamp1 and lamp2 in the lysosome. Collectively, these results suggest that in addition to modulating anti-apoptosis, HSF4 is able to regulate lysosome activity by at least controlling alpha B-crystallin expression, shedding light on a novel molecular mechanism of HSF4 in regulating lens epithelial cell homeostasis.

Defective heat shock factor 1 inhibits the growth of fibrosarcoma derived from simian virus 40/T antigen­transformed MEF cells.

Heat shock factor 1 (Hsf1) serves an important role in regulating the proliferation of human tumor cell lines in vitro and tissue specific tumorigenesis in certain mouse models. However, its role in viral­oncogenesis remains to be fully elucidated. In the current study, the role of Hsf1 in fibroblastoma derived from simian virus 40/T antigen (SV40/TAG)­transformed mouse embryonic fibroblast (MEF) cell lines was investigated. Knockout of Hsf1 inhibited MEF cell proliferation in vitro and fibroblastoma growth and metastasis to the lungs in vivo in nude mice. Knockout of Hsf1 increased the protein expression levels of p53 and phosphorylated retinoblastoma protein (pRb), however reduced the expression of heat shock protein 25 (Hsp25) in addition to the expression of the angiogenesis markers vascular endothelial growth factor, cluster of differentiation 34 and factor VIII related antigen. Furthermore, immunoprecipitation indicated that knockout of Hsf1 inhibited the association between SV40/TAG and p53 or pRb. These data suggest that Hsf1 is involved in the regulation of SV40/TAG­derived fibroblastoma growth and metastasis by modulating the association between SV40/TAG and tumor suppressor p53 and pRb. The current study provides further evidence that Hsf1 may be a novel therapeutic target in the treatment of cancer.

Glucose regulates heat shock factor 1 transcription activity via mTOR pathway in HCC cell lines.

HSF1-mediated heat shock response is activated in most tumors and plays important roles in regulating tumor homeostasis. However, the signals underlying HSF1 activation is still not completely understood. In this paper, we find that glucose, the dominant tumor energy supplement, participates in regulating HSF1's activation in HCC cell lines. The immunoblotting results indicate that the phosphorylation of HSF1/S326, a hallmark of HSF1 activation, varies between the HCC cell lines (e.g., SMMC7721, HapG2, plc/prf5, and Chang-liver). Glucose, but not 2D-glucose, can induce the phosphorylation of HSF1 at S326 and upregulate the expression of HSF1's downstream alpha B-crystallin and Hsp70 as well as the none-heat shock proteins CSK2 and RBM23 in two tested hepatocellular carcinoma cell lines (prl/prf5 and SMMC7721). Rapamycin, an inhibitor of mTOR, can suppress the glucose-induced phosphorylation of HSF1/S326 and the expression of alpha B-crystallin. Knockdown of HSF1 with shRNA enhances the glucose-depletion-mediated inhibition of plc/prf5 cell proliferation. Our data reveal that HSF1 can be activated by glucose-mTOR pathway, providing an alternative pathway for targeting HSF1 in tumor therapy.

The tetravalent anti-DR5 antibody without cross-linking direct induces apoptosis of cancer cells.

Tumor necrosis factor-related apoptosis-inducing ligand can induce apoptosis in many tumor cell lines. This apoptotic effect is mediated by interaction of TRAIL and its receptors, which include Death Receptor 4 (DR4) and Death Receptor 5 (DR5). Some antibodies to DR4 or DR5 do not have anti-tumor ability without cross-linking but exhibit anti-tumor ability in the presence of a cross-linking reagent. Here, we suggest that the tetravalent anti-DR5 antibody can induce apoptosis of cancer cells independent of cross-linking reagent. The single-chain variable fragment of the anti-DR5 antibody, HSA (human serum albumin) - p53 gene, comprising residues 490-513 of HSA and the tetramerization domain of human p53 were assembled into the tetravalent antibody by an overlapping PCR. Results of size exclusion HPLC indicated that the purified protein exhibited a major peak (tetramer) and a minor peak (dimer). MTT assay demonstrated the tetravalent antibody without cross-linking could inhibit survival of Jurkat and EC9706 cells in a dose-dependent manner while the monovalent antibody could not inhibit survival of Jurkat and EC9706 cells. IC50 of Jurkat cell was 3.2 mg/L and IC50 of EC9706 cell was 3.9 mg/L. Furthermore, the Annexin V/PI assay and the Hoechst 33258 staining showed that the tetravalent antibody could efficiently induce apoptosis of Jurkat and EC9706 cells. Therefore, the tetravalent anti-DR5 antibody can act as a direct agonistic antibody, and initiate efficient apoptotic independent of cross-linking reagent. Thus, the tetravalent anti-DR5 antibody will be a new kind of candidate for potential cancer therapeutics.