RGD peptide targeted lipid-coated nanoparticles for combinatorial delivery of sorafenib and quercetin against hepatocellular carcinoma.

CONTEXT: Combination therapies provide a potential solution to address the tumor heterogeneity and drug resistance issues by taking advantage of distinct mechanisms of action of the multiple therapeutics. OBJECTIVE: To design arginine-glycineaspartic acid (RGD) modified lipid-coated nanoparticles (NPs) for the co-delivery of the hydrophobic drugs against hepatocellular carcinoma (HCC). MATERIALS AND METHODS: RGD modified lipid-coated PLGA NPs were developed for the targeted delivery of both sorafenib (SRF) and quercetin (QT) (RGD-SRF-QT NPs). Chemical-physical characteristics and release profiles were evaluated. In vitro cell viability assays were carried out on HCC cells. In vivo antitumor efficacies were evaluated in HCC animal model. RESULTS AND DISCUSSION: The combination of SRF and QT formulations was more effective than the single drug formulations in both NPs and solution groups. RGD-SRF-QT NPs achieved the most significant tumor growth inhibition effect in vitro and in vivo. CONCLUSION: The resulting NPs could provide a promising platform for co-delivery of multiple anticancer drugs for achievement of combinational therapy and could offer potential for enhancing the therapeutic efficacy on HCC.

Clinical progress and risk factors for death in severe fever with thrombocytopenia syndrome patients.

BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease caused by the SFTS virus (SFTSV) with an average fatality rate of 12%. The clinical factors for death in SFTS patients remain unclear. METHODS: Clinical features and laboratory parameters were dynamically collected for 11 fatal and 48 non-fatal SFTS cases. Univariate logistic regression was used to evaluate the risk factors associated with death. RESULTS: Dynamic tracking of laboratory parameters revealed that during the initial fever stage, the viral load was comparable for the patients who survived as well as the ones that died. Then in the second stage when multi-organ dysfunction occurred, from 7-13 days after disease onset, the viral load decreased in survivors but it remained high in the patients that died. The key risk factors that contributed to patient death were elevated serum aspartate aminotransferase, lactate dehydrogenase, creatine kinase, and creatine kinase fraction, as well as the appearance of CNS (central nervous system) symptoms, hemorrhagic manifestation, disseminated intravascular coagulation, and multi-organ failure. All clinical markers reverted to normal in the convalescent stage for SFTS patients who survived. CONCLUSIONS: We identified a period of 7-13 days after the onset of illness as the critical stage in SFTS progression. A sustained serum viral load may indicate that disease conditions will worsen and lead to death.

Elevated serum YKL-40 level predicts poor prognosis in hepatocellular carcinoma after surgery.

BACKGROUND: YKL-40 is a member of the mammalian chitinase-like proteins. Elevated serum YKL-40 levels in patients with gastrointestinal cancer at time of diagnosis are associated with poor prognosis. The aim of this study is to evaluate the prognostic value of serum YKL-40 before surgery and during follow-up in hepatocellular carcinoma (HCC) patients receiving curative resection. METHODS: Serum YKL-40 levels were determined by enzyme-linked immunosorbent assay. Overall and recurrence-free survival (RFS) curves were constructed using the Kaplan-Meier method and compared by the log-rank test. A Cox proportional-hazards regression model was performed to identify independent prognostic factors. Median follow-up time was 35 months. RESULTS: Baseline serum YKL-40 was elevated in 56% of patients with HCC receiving curative resection. Patients with elevated serum YKL-40 had significantly shorter overall and RFS than patients with normal serum YKL-40 (P = 0.003 and P = 0.001, respectively). Multivariate Cox regression analyses indicated that baseline serum YKL-40 was an independent prognostic variable for overall and RFS [hazard ratio (HR) = 1.968, 95% confidence interval (CI): 1.093-3.543, P = 0.024; HR = 1.891, 95% CI: 1.106-3.232, P = 0.020; respectively]. After curative resection, high serum YKL-40 (log-transformed continuous variable) within 6 months predicted significantly poorer overall survival (HR = 3.003, 95% CI: 1.323-6.817, P = 0.009). CONCLUSIONS: This study indicated that serum YKL-40 was an independent prognostic factor for overall and RFS in HCC patients receiving curative resection. Serial monitoring of serum YKL-40 after curative resection may provide prognostic information.

Effect of nasal irrigation in adults infected with Omicron variant of COVID-19: A quasi-experimental study.

Objective: To investigate the effect of nasal irrigation on the duration of symptoms and nucleic acid conversion in adults infected with the Omicron variant of COVID-19. Methods: This quasi-experimental study enrolled patients diagnosed with asymptomatic, mild, or moderate Omicron infection at the Shandong Public Health Clinical Center between April 1, 2022 and May 1, 2022. Patients were divided into two groups to receive Lianhua Qingwen granules and traditional Chinese medicine (TCM) prescriptions (conventional group) and 3% hypertonic saline nasal irrigation based on conventional treatment (nasal irrigation groups), respectively. Primary outcomes were symptom disappearance time and nucleic acid negative conversion time. Secondary outcomes were peripheral blood white blood cell (WBC), lymphocyte (LYM) count, neutrophil (NEU) count, C-reactive protein (CRP) level, and chest CT examination findings. Results: Eighty patients were included (40 patients/group). Multiple linear regression analysis showed that, after adjustment for comorbidities, smoking history, LYM count, and Ct values of N gene, the patients in the nasal irrigation group were more likely to get lower nucleic acid negative conversion time (ß = -11.052, 95% CI: -8.277-13.827, P < 0.001) compared with the conventional group. The symptom disappearance time showed no significant improvement (P > 0.05). Subgroup analysis for treatment-naïve patients in the nasal irrigation group showed similar nucleic acid negative conversion time improvement (P = 0.038). Conclusion: Early nasal irrigation shortens the nucleic acid negative conversion time in adults infected with the Omicron variant but without improvements in symptom disappearance time.

Serum sHLA-G levels: a useful indicator in distinguishing colorectal cancer from benign colorectal diseases.

Soluble human leukocyte antigen-G (sHLA-G) has been reported in malignancies and is implicated in mediating immune surveillance of tumor. The aim of our study is to detect serum sHLA-G levels in colorectal cancer and to determine whether sHLA-G may be helpful in distinguishing colorectal cancer from benign colorectal diseases. Serum sHLA-G levels were determined using enzyme-linked immunosorbent assay. Receiver operating characteristic (ROC) curve was used to evaluate the feasibility of sHLA-G in differentiating colorectal cancer from benign colorectal diseases. Median sHLA-G concentrations were significantly higher in colorectal cancer compared to normal colorectum, hyperplastic polyp, inflammatory bowel disease and adenoma (all at p < 0.001, respectively). ROC curve for sHLA-G revealed an area under the curve of 84.2%, and when 88.6 U/mL was used as cutoff, a sensitivity of 72.2% and a specificity of 87.8% were achieved. Comparison of sHLA-G and carcinoembryogenic antigen ROC curves indicated that sHLA-G was superior to CEA in differentiating colorectal cancer from benign colorectal diseases (p < 0.001). ROC curves analysis of the combined sHLA-G and CEA showed a higher detection capacity (area under the ROC curve, 87.4%) than that of markers considered singly. These findings reveal that serum levels of sHLA-G are significantly increased in colorectal cancer which may serve as a potent mediator of immune escape in colorectal cancer, and sHLA-G may be a useful indicator in differentiating colorectal cancer from benign colorectal diseases.

Correlation between the sulfamethoxazole-trimethoprim resistance of Shigella flexneri and the sul genes.

ABSTRACT: The aim of this study was to discuss the correlation between the sulfamethoxazole-trimethoprim resistance of Shigella flexneri (S. flexneri) and the antibiotic resistance genes sul1, sul2, and sul3 and SXT element.From May 2013 to October 2018, 102 isolates of S. flexneri were collected from the clinical samples in Jinan. The Kirby-Bauer (K-B) test was employed to determine the antibiotic susceptibility of the S. flexneri isolates. The antibiotic resistance rate was analyzed with the WHONET5.4 software. The isolates were subject to the PCR amplification of the sul genes (sul1, sul2, and sul3) and the SXT element. On the basis of the sequencing results, the correlation between the sulfamethoxazole-trimethoprim resistance of the S. flexneri isolates and the sul genes was analyzed.The antibiotic resistance rates of the 102 S. flexneri isolates to ampicillin, streptomycin, chloramphenicol, tetracycline, and sulfamethoxazole-trimethoprim were 90.2%, 90.2%, 88.2%, 88.2%, and 62.7%, respectively. The antibiotic resistance rates of these isolates to cefotaxime, ceftazidime, and ciprofloxacin varied between 20% and 35%. However, these isolates were 100% susceptible to cefoxitin. Positive fragments were amplified from 59.8% (61/102) of the 102 S. flexneri isolates, the sizes of the sul1 and sul2 genes being 338 bp and 286 bp, respectively. The sequence alignment revealed the presence of the sul1 and sul2 genes encoding for dihydrofolate synthase. The carrying rate of the sul1 gene was 13.7% (14/102), and that of the sul2 gene was 48.0% (49/102). No target gene fragments were amplified from the 3 isolates resistant to sulfamethoxazole-trimethoprim. The sul3 gene and SXT element were not amplified from any of the isolates. The testing and statistical analysis showed that the resistance of the S. flexneri isolates to sulfamethoxazole-trimethoprim correlated to the sul1 and sul2 genes.The acquired antibiotic resistance genes sul1 and sul2 were closely associated with the resistance of the 102 S. flexneri isolates to sulfamethoxazole-trimethoprim.

Overexpression of Bmi-1 in uterine cervical cancer: correlation with clinicopathology and prognosis.

INTRODUCTION: B-cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1) is a member of polycomb group, which participates in axial patterning, hematopoiesis, cell cycle regulation, and senescence. Recently, overexpression of Bmi-1 has been reported in various human cancers and proved to be associated with poor survival. The aim of this study was to investigate the expression of Bmi-1 protein in human uterine cervical cancer (UCC) and explore its associations with clinicopathological factors and prognosis. METHODS: Western blot was used to detect the expression of Bmi-1 in 4 human cervical cancer cell lines (Hela, SiHa, CasKi, and C33A) and a normal cervical epithelial cell line. In addition, 152 UCC and 30 adjacent normal cervical paraffin-embedded samples were collected to detect Bmi-1 expression by immunohistochemistry. RESULTS: Western blot analysis showed Bmi-1 was overexpressed in 4 human UCC cell lines but not in the normal cervical epithelial cell line. Moreover, immunohistochemical staining revealed Bmi-1 was overexpressed in 63.2% UCC tissues (Bmi-1 ++ or +++), and the overexpression of Bmi-1 protein was significantly correlated with tumor size (P = 0.046), clinical stage (P = 0.021), and regional lymph nodes metastasis (P = 0.010). Survival analysis showed a significant difference between Bmi-1 protein overexpression and poor survival (P = 0.021). Cox proportional hazards risk analysis indicated that Bmi-1 protein overexpression was an independent prognostic factor for overall survival. CONCLUSIONS: B-cell-specific Moloney murine leukemia virus integration site 1 is overexpressed in UCC and correlated with adverse clinical characteristics and poor prognosis, which suggests that the Bmi-1 might participate in the development and progression of UCC and have clinical potential not only as a useful predictor of aggressive phenotype but also a promising prognostic predictor.

DJ-1: a promising marker in metastatic uveal melanoma.

PURPOSE: Overexpression of DJ-1 was associated with metastatic uveal melanoma (UM). The purpose of this study was to evaluate the potential of serum DJ-1 as a biomarker for metastasis of uveal melanoma. METHODS: Serum DJ-1 levels were determined by ELISA assays in 27 patients with metastatic UM metastatic uveal melanoma and in 76 patients who were disease free for at least 10 years and 30 age- and sex-matched controls. Receiver operating characteristic (ROC) curve was used to evaluate the feasibility of DJ-1 in detection of metastatic uveal melanoma. RESULTS: Serum DJ-1 levels were significantly higher in patients with metastatic UM compared with patients who were disease free for at least 10 years (P < 0.001) or with controls (P < 0.001). ROC curve for DJ-1 revealed an area under the curve of 86.3%, and when 3.350 ng/mL was used as the cutoff value, a sensitivity of 74.1% and a specificity of 94.3% were achieved. Comparison of DJ-1 and liver function tests (LFTs) ROC curves indicated that DJ-1 was superior to LFTs in detection of metastatic UM. CONCLUSIONS: Our data suggest that DJ-1 might be a promising serum marker for monitoring metastatic uveal melanoma.

Serum YKL-40 independently predicts outcome after transcatheter arterial chemoembolization of hepatocellular carcinoma.

BACKGROUND: Transcatheter arterial chemoembolization (TACE) is the most widely used treatment option for unresectable hepatocellular carcinoma (HCC). Elevated serum YKL-40 level has been shown to predict poor prognosis in HCC patients undergoing resection. This study was designed to validate the prognostic significance of serum YKL-40 in patients with HCC undergoing TACE treatment. METHODS: Serum YKL-40 level was determined by enzyme-linked immunosorbent assay. Overall survival (OS) was evaluated with the Kaplan-Meier method and compared by the log-rank test. Multivariate study with Cox proportional hazard model was used to evaluate independent prognostic variables of OS. RESULTS: The median pretreatment serum YKL-40 in HCC patients with was significantly higher than that in healthy controls (P<0.001). The YKL-40 could predict survival precisely either in a dichotomized or continuous fashion (P<0.001 and P = 0.001, respectively). Multivariate Cox regression analysis indicated that serum YKL-40 was an independent prognostic factor for OS in HCC patients (P = 0.001). In further stratified analyses, YKL-40 could discriminate the outcomes of patients with low and high alpha-fetoprotein (AFP) level (P = 0.006 and 0.016, respectively). Furthermore, the combination of serum YKL-40 and AFP had more capacity to predict patients' outcomes. CONCLUSIONS: Serum YKL-40 was demonstrated to be an independent prognostic biomarker in HCC patients treated with TACE. Our results need confirmation in an independent study.

Detection of circulating antigen with a MAb-based sandwich-ELISA and its comparison with specific IgM detection in sera of patients with hemorrhagic fever with renal syndrome.

A monoclonal antibody (1H2) against nucleocapsid protein of Hantavirus was developed. A sandwich enzyme-linked immunosorbent assay (ELISA) with the monoclonal antibody (MAb) was established and evaluated for detecting circulating antigen (CAg) in serum of patients with hemorrhagic fever with renal syndrome (HFRS). Results were compared to that of an immunoglobulin M (IgM)-detecting ELISA. Of 143 patients with HFRS, 106 were positive for CAg of Hantavirus and 128 positive for specific IgM. Among the 15 HFRS patients in whom specific IgM was not detected, 10 were positive for CAg. Of 100 controls including 40 hepatitis B cases, 40 measles cases, and 20 healthy persons all were negative for both CAg and specific IgM. Detection of Hantavirus CAg with a MAb-based sandwich ELISA (MBS-ELISA) established in the present study adds a new diagnostic tool for HFRS, and it increases the diagnostic rate to conventional specific IgM detection, especially for patient in the early stage of HFRS.