Koumine ameliorates neuroinflammation by regulating microglia polarization via activation of Nrf2/HO-1 pathway.

BACKGROUND: Gelsemium elegans (Gardner & Chapm.) Benth (G. elegans) has been widely used as a traditional folk medicine in China and Southeast Asia. As the most abundant alkaloid in G. elegans, Koumine (KM) has been revealed the effect of inflammatory attenuation modulating by macrophage activation and polarization. PURPOSE: This study aimed to explore the effect of KM on modulation of microglia polarization that led to the suppression of neuroinflammation and further improved neurodegenerative behavior. METHODS: Inflammatory mediators, microglia M1 and M2 phenotype markers and Nrf2/HO-1 pathway related protein were assessed in LPS-induced BV2 cells and LPS-treated mice by RT-PCR, immunohistochemistry, immunofluorescence and Western blotting. Moreover, the learning and memory abilities of mice were evaluated by Morris water maze test, and the neuronal damage was evaluated by the Nissl staining. RESULTS: KM attenuated LPS-induced viability and morphological changes in BV2 microglial cells. Our findings showed that KM activated the Nrf2/HO-1 signaling pathway to promote phenotypic switch from M1 to M2 phenotypes. This switch suppresses the release of inflammatory mediators in LPS-induced BV2 cells. Meanwhile, KM attenuated neuroinflammation through modulating microglia polarization and subsequently reversed the behavioral alterations in LPS-induced mice model of neuroinflammation. CONCLUSIONS: KM may alleviate neuroinflammation by regulating microglia polarization with the involvement of Nrf2/HO-1 pathway, resulting of the neuroprotective effect.

Cognitive changes are associated with increased blood-brain barrier leakage in non-brain metastases lung cancer patients.

To explore the relationship between cognitive function and blood-brain barrier leakage in non-brain metastasis lung cancer and healthy controls. 75 lung cancers without brain metastasis and 29 healthy controls matched with age, sex, and education were evaluated by cognitive assessment, and the Patlak pharmacokinetic model was used to calculate the average leakage in each brain region according to the automated anatomical labeling atlas. After that, the relationships between cognitive and blood-brain barrier leakage were evaluated. Compared with healthy controls, the leakage of bilateral temporal gyrus and whole brain gyrus were higher in patients with lung cancers (P < 0.05), mainly in patients with advanced lung cancer (P < 0.05), but not in patients with early lung cancer (P > 0.05). The cognitive impairment of advanced lung cancers was mainly reflected in the damage of visuospatial/executive, and delayed recall. The left temporal gyrus with increased blood-brain barrier leakage showed negative correlations with delayed recall (r = -0.201, P = 0.042). An increase in blood-brain barrier leakage was found in non-brain metastases advanced lung cancers that corresponded to decreased delayed recall. With progression in lung cancer staging, blood-brain barrier shows higher leakage and may lead to brain metastases and lower cognitive development.

Blood-brain barrier and brain structural changes in lung cancer patients with non-brain metastases.

Purpose: To explore the relationship between blood-brain barrier (BBB) leakage and brain structure in non-brain metastasis lung cancer (LC) by magnetic resonance imaging (MRI) as well as to indicate the possibility of brain metastasis (BM) occurrence. Patients and methods: MRI were performed in 75 LC patients and 29 counterpart healthy peoples (HCs). We used the Patlak pharmacokinetic model to calculate the average leakage in each brain region according to the automated anatomical labeling (AAL) atlas. The thickness of the cortex and the volumes of subcortical structures were calculated using the FreeSurfer base on Destrieux atlas. We compared the thickness of the cerebral cortex, the volumes of subcortical structures, and the leakage rates of BBB, and evaluated the relationships between these parameters. Results: Compared with HCs, the leakage rates of seven brain regions were higher in patients with advanced LC (aLC). In contrast to patients with early LC (eLC), the cortical thickness of two regions was decreased in aLCs. The volumes of twelve regions were also reduced in aLCs. Brain regions with increased BBB penetration showed negative correlations with thinner cortices and reduced subcortical structure volumes (P<0.05, R=-0.2 to -0.50). BBB penetration was positively correlated with tumor size and with levels of the tumor marker CYFRA21-1 (P<0.05, R=0.2-0.70). Conclusion: We found an increase in BBB permeability in non-BM aLCs that corresponded to a thinner cortical thickness and smaller subcortical structure volumes. With progression in LC staging, BBB shows higher permeability and may be more likely to develop into BM.

Multislice spiral CT images combined with CEA and lymphocyte-to-neutrophil ratio predict recurrence and post-operative metastasis of rectal cancer.

To explore the early predictors of post-operative recurrence and metastasis of rectal cancer, analyse the associated risk, and construct a model. Retrospective collection. Four hundred patients with rectal cancer underwent surgical resection and pathological diagnosis from September 2013 to September 2014. During the post-operative period, the patients were tested by imaging examination, serum tumour markers, and routine blood follow-up for at least 3 years. Preoperative CT examination of tumour size, lymphocyte-to-neutrophil ratio, and CEA were significant biomarkers for predicting recurrence and/or metastasis of post-operative rectal cancer. The stratified threshold of the lesion size cut-off point in CT images of patients with rectal cancer was 18.75 cm3, the cut-off point value of the lymphocyte-to-neutrophil ratio was 0.33, and the CEA cut-off point value was 16.97 ng/ml. We used the cut-off point to perform stratified survival analysis to obtain two K-M curves and conduct a log-rank test. The Cox multivariate risk regression results were as follows: preoperative CT images of lesion size, lymphocyte-to-neutrophil ratio, and CEA. The AUC of the normogram model for the prediction of post-operative recurrence and metastasis of rectal cancer is 0.939. Preoperative CT examination of tumour size can predict post-operative recurrence and metastasis of rectal cancer and can be used to analyse its risk. The lymphocyte-to-neutrophil ratio and CEA can also predict post-operative tumour recurrence and metastasis risk.

An Integrated Network, RNA Sequencing, and Experiment Pharmacology Approach Reveals the Active Component, Potential Target, and Mechanism of Gelsemium elegans in the Treatment of Colorectal Cancer.

In this study, a combination of network pharmacology, bioinformatics analysis, molecular docking and transcriptomics was used to investigate the active ingredient and potential target of Gelsemium elegans in the treatment of colorectal cancer. Koumine was screened as the active component by targeting PDK1 through network pharmacology and reverse docking. RNA-Seq, enrichment analysis and validation experiment were then further employed to reveal koumine might function in inhibiting Akt/mTOR/HK2 pathway to regulate cell glycolysis and detachment of HK2 from mitochondria and VDAC-1 to activate cell apoptosis both in vitro and in vivo. In the present study, we provide a systematical approach for the identification of effective ingredient and potential target of herbal medicine. Our results have important implication for the intensive study of koumine as novel anticancer agents for colorectal cancer and could be supportive in its further structural modification.

Nomogram For The Prediction Of Malignancy In Small (8-20 mm) Indeterminate Solid Solitary Pulmonary Nodules In Chinese Populations.

PURPOSE: This study aimed to develop and validate a nomogram for predicting the malignancy of small (8-20 mm) solid indeterminate solitary pulmonary nodules (SPNs) in a Chinese population by using routine clinical and computed tomography data. METHODS: The prediction model was developed using a retrospective cohort that comprised 493 consecutive patients with small indeterminate SPNs who were treated between December 2012 and December 2016. The model was independently validated using a second retrospective cohort comprising 216 consecutive patients treated between January 2017 and May 2018. The investigated variables included patient characteristics (e.g., age and smoking history), nodule parameters (e.g., marginal spiculation and significant enhancement), and tumor biomarker levels (e.g., carcinoembryonic antigen). A prediction model was developed by using multivariable logistic regression analysis, and the model's performance was presented as a nomogram. The model was evaluated based on its discriminative ability, calibration, and clinical usefulness. RESULTS: The developed nomogram was ultimately based on age, marginal spiculation, significant enhancement, and pleural indentation. The Harrell concordance index values were 0.869 in the training cohort (95% confidence interval: 0.837-0.901) and 0.847 in the validation cohort (95% confidence interval: 0.792-0.902). The Hosmer-Lemeshow test revealed good calibration in each of the training and validation cohorts. Decision curve analysis confirmed that the nomogram was clinically useful (risk threshold from 0.10 to 0.85). CONCLUSION: Patient age, marginal spiculation, significant enhancement, and pleural indentation are independent predictors of malignancy in small indeterminate solid SPNs. The developed nomogram is easy-to-use and may allow the accurate prediction of malignancy in small indeterminate solid SPNs among Chinese patients.

Cancer risk factors among people living with HIV/AIDS in China: a systematic review and meta-analysis.

Cancer is a leading cause of death among people living with HIV/AIDS (PLWHA). We conducted a systematic review and meta-analysis to evaluate prevalence of cancer risk factors among Chinese PLWHA based on 102 articles. Random effects meta-analysis was used to calculate the summary prevalence estimate (sPrev) and 95% confidence interval (CI) for each cancer risk factor by demographic group. Overall, the sPrev for each risk factor among Chinese PLWHA was: 41.1% (95% CI: 35.3-46.9%) for current smoking; 30.3% (95% CI: 23.3-37.4%) for current alcohol consumption; 24.4% (95% CI: 14.7-30.2%) for overweight and obesity; 12.5% (95% CI: 10.6-14.3%) for hepatitis B virus infection; 29.1% (95% CI: 23.6-34.5%) for hepatitis C virus infection; 33.9% (95% CI: 24.3-43.5%) for high-risk human papillomavirus infection from cervical samples and 78.6% (95% CI: 69.4-87.7%) from anal samples; 2.7% (95% CI: 0.7-4.7%) for Epstein-Barr virus (EBV) immunoglobulin M (IgM) positivity, 94.7% (95% CI: 90.7-98.8%) for EBV IgG positivity and 25.6% (95% CI: 12.4-38.8%) for EBV DNA positivity; 14.9% (95% CI: 12.4-17.4%) for human herpes virus 8 infection. The prevalence of major cancer risk factors was high among PLWHA in China, suggesting an urgent need for interventions to reduce cancer risk in this high-risk group.

Role of CT scan in differentiating the type of colorectal cancer.

OBJECTIVES: Most colorectal cancers are classical adenocarcinomas (AC), and less frequent subtypes include mucinous adenocarcinomas (MAC) and signet-ring cell carcinomas (SC). The purpose of this study was to evaluate the computed tomography (CT) findings that can help to differentiate MAC and SC from AC. METHODS: CT scans of 168 patients with pathologically proven MAC and 67 patients with pathologically proven SC were analyzed, and 220 patients with classical AC were also included as a control group. CT findings of the three groups were compared and contrasted in terms of the bowel involvement patterns, contrast enhancement patterns, and presence or absence of bowel obstruction, intratumoral calcification, pericolic fat infiltration, and local tumor extension to adjacent organs. Statistical analyses were made by using the one-way analysis of variance, least significant difference test, and Pearson's chi-square test. RESULTS: Compared with classical AC, the MAC showed more severe (6.29±2.69 cm vs 4.57±1.74 cm, P<0.001) and higher percentage of occurrence of eccentric bowel-wall thickening (37.2% vs 11.5%, P<0.001). Heterogeneous contrast enhancement was most common in MAC (P<0.01), and MAC showed more areas with hypoattenuation (P<0.001). The presence of intratumoral calcification was most frequent in MAC (17.9% vs 2% vs 6.8%) (P<0.001); the SC also were more severe (5.75±2.28 cm vs 4.57±1.74 cm. P=0.001) than AC, but SC tend to show more cases of concentric even bowel-wall thickening (67.2%); homogeneous contrast enhancement was most common in SC (P<0.01), and it showed a target appearance. The presence of peritoneal seeding was most frequent in SC (35.8% vs 8% vs 2.7%, P<0.001), while the presence of regional lymph node metastasis (P=0.190) and direct invasion of adjacent organs or metastasis (P=0.323) were not significantly different among them. CONCLUSION: Some radiological features by CT can be used to classify different colon tumor types.

The CT and US features of Ewing's sarcoma/primary neuroectodermal tumor of the kidney: two case reports and review of literature.

Ewing's sarcoma/primary neuroectodermal tumor (EWS/PNET) is an extraordinarily rare primary tumor of the kidney with characteristic histology. To date, the imaging features of EWS/PNET have not been clearly described. Here, we report two cases of EWS/PNET confirmed by fine-needle aspiration biopsy and analyze the findings of computed tomography and ultrasound. The radiological features of EWS/PNET are presented along with a brief review of the pertinent literature to have a further understanding of EWS/PNET's imaging features.

Recurrent Thymoma in the Retroperitoneal Space: A Rare Case Report.

Thymoma is an epithelial neoplasm of the thymus, which commonly lies in the anterior mediastinum and recurrences of thymoma generally are locally, and retroperitoneal recurrence is considered to be rare. A 46-year old Asian woman with invasive thymoma had undergone thymectomy 10 years ago. Computed tomography demonstrated a well-circumscribed mass in the left retroperitoneal space. The patient had not any symptom including myasthenia gravis. Because on the anterior mediastinum area shows no sign of tumor recurrence and the mass adjacent to the vertebral body, neurogenic tumor was suspected. Surgical resection was performed using a retroperitoneal approach, which revealed the tumor adhering neighboring diaphragm. The tumor was histologically diagnosed to be type B1 thymoma according to the World Health Organization classification. The retroperitoneal mass was an unusual local recurrence after thymectomy. The patients whose had under invasive thymectomy should be evaluated carefully when finding retroperitoneal mass during follow-up.

In vitro molecular evolution yields an NEIBM with a potential novel IgG binding property.

Staphylococcus aureus protein A (SpA) and protein G of groups C and G streptococci (SpG) are two well-defined bacterial immunoglobulin (Ig)-binding proteins (IBPs) with high affinity for specific sites on IgG from mammalian hosts. Both SpA and SpG contain several highly-homologous IgG-binding domains, each of which possesses similar binding characteristic of the whole corresponding proteins. Whether specific combinations of these domains could generate a molecule with novel IgG-binding properties remained unknown. We constructed a combinatorial phage library displaying randomly-rearranged A, B, C, D and E domains of SpA as well as the B2 (G2) and B3 (G3) domains of SpG. In vitro molecular evolution directed by human, rabbit, bovine, or goat polyclonal IgGs and four subclasses of mouse monoclonal IgGs generated one common combination, D-C-G3. A series of assays demonstrated that D-C-G3 exhibited a potential novel IgG binding property that was obviously different from those of both parent proteins. This study provides an example of successful protein engineering through in vitro molecular evolution and useful approaches for structure and function studies of IBPs.

In vitro molecular evolution of AL NEIBMs improved immunoglobulin (Ig) binding and antibody detection.

AL (SpA A domain-PpL B3 domain), LD5 (PpL B3 domain-SpA D domain-PpL B3 domain-SpA D domain-PpL B3 domain, L-D-L-D-L) and LD3 (PpL B3 domain-SpA D domain-PpL B3 domain, L-D-L) are novel evolved Ig binding molecules (NEIBMs) derived from the in vitro molecular evolution of combinatorial phage libraries displaying randomly rearranged Ig-binding domains of protein A and protein L. These molecules all showed novel Ig-binding properties of double-site binding to the VH3 and Vκ regions of human Ig Fab and high affinity for human IgM, which enhanced IgM detection in the anti-HCV ELISA assay. In this double-site binding, the A domain binds to the VH3 chain with low affinity. Whether the appropriate mutations in the A domain could improve this binding remains unknown. In this study, four combinatorial phage libraries displaying AL mutants with random mutations at different amino acid positions in the A domain were constructed. Seven AL mutant phages with significantly improved Ig binding activity were obtained from the phage library displaying AL mutants randomly mutated at positions 27 and 34 through human IgM-directed in vitro evolution. Two of the seven prokaryotically expressed AL mutants, AL (VV) and AL (KA), exhibited IgM and IgG binding activities equivalent to those of wild-type AL, whereas other mutants showed attenuated binding. However, after labeling with HRP, AL (VV) and AL (KA) showed improved IgM and IgG binding activity, which significantly improved the detection in the anti-HCV assay. Thus, the present study demonstrates that the binding properties of AL were successfully improved through phage-based molecular evolution, which could substantially contribute to the use of AL in antibody detection, and provides an example of successful protein engineering through in vitro molecular evolution.

Discovery of a potent benzoxaborole-based anti-pneumococcal agent targeting leucyl-tRNA synthetase.

Streptococcus pneumoniae causes bacterial pneumonia with high mortality and morbidity. The emergency of multidrug-resistant bacteria threatens the treatment of the disease. Leucyl-tRNA synthetase (LeuRS) plays an essential role in cellular translation and is an attractive drug target for antimicrobial development. Here we report the compound ZCL039, a benzoxaborole-based derivative of AN2690, as a potent anti-pneumococcal agent that inhibits S. pneumoniae LeuRS (SpLeuRS) activity. We show using kinetic, biochemical analyses combined with the crystal structure of ZCL039-AMP in complex with the separated SpLeuRS editing domain, that ZCL039 binds to the LeuRS editing active site which requires the presence of tRNA(Leu), and employs an uncompetitive inhibition mechanism. Further docking models establish that ZCL039 clashes with the eukaryal/archaeal specific insertion I4ae helix within editing domains. These findings demonstrate the potential of benzoxaboroles as effective LeuRS inhibitors for pneumococcus infection therapy, and provide future structure-guided drug design and optimization.

Facing HIV as a family: predicting depressive symptoms with correlated responses.

This study makes an effort to go beyond traditional analytical models to explore the complex and interactive nature of family processes. A total of 79 families affected by HIV in China participated in the study (79 persons living with HIV [PLH] and 79 seronegative family members), with in-person interviews conducted in 2009. A higher level of depressive symptoms was reported by PLH participants than their family members. Negative associations between depressive symptoms and social support and family relations were observed for both PLH and their family members. Results from actor-partner interdependence models indicate that the depressive symptoms of PLH and their family members were positively correlated when either the family relations measure or the social support measure was included in the model. Results highlight the link between family experience and individual well-being, with implications for designing and implementing interventions for families impacted by HIV.

Normative beliefs and sexual risk in China.

We examined normative beliefs about multiple sexual partners and social status in China and their association with risky sexual behaviors and sexually transmitted infections (STIs). Self-reported and biological markers of sexual risk were examined among 3,716 market vendors from a city in eastern China. Men who were older or with less education believed having multiple sexual partners was linked to higher social status. Adjusting for demographic characteristics, normative beliefs were significantly associated with having multiple sexual partners, while having multiple sexual partners was significantly associated with STIs. Normative beliefs regarding sexual behaviors may play an important role in individual risk behaviors. Future HIV/STI interventions must address community beliefs about the positive meaning of sexual risks, particularly among men with traditional beliefs about gender roles.

[Survival analysis on 3103 HIV/AIDS patients receiving antiretroviral treatment in Dehong prefecture, Yunnan province].

OBJECTIVE: To determine the survival rate of HIV/AIDS patients after receiving free antiretroviral treatment in Dehong prefecture, Yunnan province. METHODS: A retrospective cohort analysis was conducted on all the HIV/AIDS patients aged over 16 years who had started antiretroviral treatment during January 2007 throughout December 2009 in Dehong prefecture. RESULTS: A total of 3103 HIV/AIDS patients had received antiretroviral treatment during the study period. Among them, the mean age was (36.0 ± 9.9) years and 62.4% were males. 66.2% of them were infected with HIV through heterosexual transmission, and the mean treatment follow-up time was 21.7 months. Most patients well complied with the treatment, i.e., the average times of not taking the medicine were less than 5 per month. The cumulative survival rate of antiretroviral treatment after 1, 2, 3, 4, and 5 years were 0.95, 0.94, 0.93, 0.92, and 0.92, respectively. Data from the Cox proportional hazard regression model analysis indicated that, after adjustment for age, gender, and marital status, the baseline CD4(+)T cell counts and transmission route could significantly predicate the rates of survival. Those who were with baseline CD4(+)T cell counts as 200 - 350/mm(3)were less likely to die of AIDS than those with CD4(+) T cell counts < 200/mm(3) (Hazard Ratio or HR = 0.16, 95%CI: 0.09 - 0.28), and HIV-infected through mother-to-child transmission or routes other than heterosexual transmission were less likely to die of AIDS than through injecting drug use (HR = 0.35, 95%CI: 0.13 - 1.00). CONCLUSION: Free antiretroviral treatment had significantly improved the survival of HIV/AIDS patients. Earlier initiation of antiretroviral treatment was likely to have achieved better survival effects.

[Survival and immune response of rural HIV/AIDS patients after free antiretroviral therapy].

OBJECTIVE: To assess the adherence, immunologic and survival responses in HIV-infected patients receiving free antiretroviral therapy (ART). METHODS: All adult HIV-infected patients in Wenxi county who started antiretroviral treatment (ART) between 01 July 2001 and 31 December 2006 and aged above 18 years were included in this study. Epidemiological survey and laboratory tests were performed before, 0.5 months after, 1 months after, 2 months after and every 3 months after initiation of ART to recognize the adherence, efficacy (CD(4)(+) T cell counts) and survival to the regimens. RESULTS: The median follow-up time period was 16.5 months (Interquartile: 15.5 - 20.8 months). At baseline, the median of CD(4)(+) T cell counts were 154 cells/microl (Interquartile: 81 - 212 cells/microl). Treatment was effective in most of the patients, the CD(4)(+) T cell count of patients increased after the initiation of ART. The maximum increase was recorded at month 3, from the median of 154 cells/microl to 220 cells/microl (P < 0.001), and thereafter the count remained stable. When comparing with patients with baseline CD(4)(+) T cell count > or = 100 cells/microl, those with baseline CD(4)(+) T cell count < 100 cells/microl showed a higher mean increase in the first three months of treatment. The cumulative probability rates of remaining alive were 0.94, 0.88 and 0.87 at 3, 12, 24 months, respectively. In multivariate Cox's proportional hazard models, after adjustment for the type ofinitial regimens (NVP vs. EFV/IDV), CD(+)(4) T cell count of less than 50 cells/microl (vs. 50 cells/microl or more) was strongly associated with death hazard ratio 0.21 (95%CI: 0.06 - 0.68). CONCLUSION: Our data showed that ART was effective for improving immunologic response of adult patients with HIV/AIDS. CD(4)(+) T cell count at initiation was associated with survival time in patients starting ART, suggesting that monitoring of CD(4)(+) T count should be strengthened to early initiate antiretroviral therapy for HIV-infected patients.