Application and prospect of Bayesian spatio-temporal model in the study of hydatid disease / 中华地方病学杂志

With the development of computer technology and the abundance of spatio-temporal data, Bayesian spatio-temporal model (BSTM) has been developed rapidly, and wildly used by academics to investigate the spatial epidemiological feature of infectious diseases. Hydatid disease is a global natural focus disease that seriously endangers human health. Its epidemic process is complex and affected by many factors. BSTM provides a new method for study of hydatid disease. By modeling, we can not only analyze the influencing factors of hydatid disease, but also can predict the epidemic trend and make the disease distribution map, which is of great significance to public health decisionmaking. Based on a comprehensive review of the literatures, this paper expounds the principles, types and application status of BSTM in hydatid disease.

Spatial analysis of echinococcosis in pastoral area of Qinghai province, 2019 / 中华流行病学杂志

Objective: To understand the spatial characteristics of echinococcosis and associated factors in the pastoral area of Qinghai province, and provide evidence for the effective prevention and control of echinococcosis. Methods: The number of echinococcosis cases in the pastoral areas of Qinghai in 2019 was collected to perform spatial epidemiological analysis. The thematic map of the distribution of echinococcosis cases was generated with software ArcGIS 10.8 for visual analysis and spatial autocorrelation analysis. The spatial autocorrelation and spatial scanning analysis were performed to estimate the clustering of echinococcosis with software SaTScan 9.5. Software GeoDa 1.14 and ArcGIS 10.8 were used to establish spatial lag model and geographical weighted regression model to analyze the related factors of echinococcosis epidemic. Results: In 2019, the echinococcosis surveillance covered 64 741 people in the pastoral area of Qinghai, and 829 echinococcosis cases were found, with a prevalence rate of 1.28%. The distribution of the cases had spatial correlation (Moran's I=0.41, P<0.001). The most possible clustering areas indicated by spatial scanning analysis included Banma, Jiuzhi, Dari and Gande counties of Guoluo Tibetan Autonomous Prefecture (LLR=460.77, RR=9.20, P<0.001). The prevalence of echinococcosis in the pastoral areas was positively associated with the total annual precipitation (β=0.13, P=0.036), and negatively associated with population density (β=-1.36, P=0.019) and doctors/nurse ratio (β=-25.60, P=0.026). Conclusions: The distribution of echinococcosis cases in the pastoral areas of Qinghai in 2019 had spatial correlation, and the prevalence was affected by total annual precipitation, population density, and doctors/nurse ratio.

A subset of Memory B-derived antibody repertoire from 3-dose vaccinees is ultrapotent against diverse and highly transmissible SARS-CoV-2 variants, including Omicron

Omicron, the most heavily mutated SARS-CoV-2 variant so far, is highly resistant to neutralizing antibodies, raising unprecedented concerns about the effectiveness of antibody therapies and vaccines. We examined whether sera from individuals who received two or three doses of inactivated vaccine, could neutralize authentic Omicron. The seroconversion rates of neutralizing antibodies were 3.3% (2/60) and 95% (57/60) for 2- and 3-dose vaccinees, respectively. For three-dose recipients, the geometric mean neutralization antibody titer (GMT) of Omicron was 15, 16.5-fold lower than that of the ancestral virus (254). We isolated 323 human monoclonal antibodies derived from memory B cells in 3-dose vaccinees, half of which recognize the receptor binding domain (RBD) and show that a subset of them (24/163) neutralize all SARS-CoV-2 variants of concern (VOCs), including Omicron, potently. Therapeutic treatments with representative broadly neutralizing mAbs individually or antibody cocktails were highly protective against SARS-CoV-2 Beta infection in mice. Atomic structures of the Omicron S in complex with three types of all five VOC-reactive antibodies defined the binding and neutralizing determinants and revealed a key antibody escape site, G446S, that confers greater resistance to one major class of antibodies bound at the right shoulder of RBD through altering local conformation at the binding interface. Our results rationalize the use of 3-dose immunization regimens and suggest that the fundamental epitopes revealed by these broadly ultrapotent antibodies are a rational target for a universal sarbecovirus vaccine. One sentence summaryA sub-set of antibodies derived from memory B cells of volunteers vaccinated with 3 doses of an inactivated SARS-CoV-2 vaccine work individually as well as synergistically to keep variants, including Omicron, at bay.

Stevens-Johnson syndrome/toxic epidermal necrolysis successfully treated with Chinese herbal medicine Pi-Yan-Ning: A case report.

Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is a rare adverse cutaneous reaction with a low incidence and high mortality. Despite posing a serious threat to patients' health and lives, there is no high-quality evidence for a standard treatment regimen. Here we report the case of a 62-year-old man with stage IV pancreatic cancer who experienced immunotherapy-induced SJS/TEN. After consensus-based regular treatments at a local hospital, his symptoms became worse. Thus, he consented to receive Chinese herbal medicine (CHM) therapy. The affected parts of the patient were treated with the CHM Pi-Yan-Ning which was applied externally for 20 min twice a day. After 7 days of treatment, the dead skin began peeling away from the former lesions that had covered his hands, feet, and lips, indicating that skin had regenerated. After 12 days of treatment, the patient's skin was completely recovered. In this case, SJS/TEN was successfully treated with Pi-Yan-Ning, suggesting that there might be tremendous potential for the use of Pi-Yan-Ning in the treatment of severe skin reactions to drug treatments. Further basic investigations and clinical trials to explore the mechanism and efficacy are needed.

Prognostic Values of Platelet-Associated Indicators in Resectable Lung Cancers.

BACKGROUND: Lung cancer is the leading cause of cancer death. Platelet-related indictors, including platelet count, plateletcrit, mean platelet volume, and platelet distribution width, not only associate with morphology and functions of platelet but also correlate with tumor development and metastasis. In the present study, we investigated the values of platelet-related indictors in the prognosis evaluation of resectable lung cancers. METHODS: In total, 101 patients with resectable lung cancer were recruited in this study. Patients were divided into 2 groups according to the median pretreatment values. To evaluate the individual value changes after treatment, we introduced the concept of post-/pretreatment ratio (≤1 indicated value was not increased after treatment, while >1 suggested increased value). RESULTS: The high pretreatment platelet count level was correlated with larger tumor size. High pretreatment plateletcrit level was associated with more lymph nodes metastasis. Patients with high pretreatment plateletcrit level had worse overall survival, whereas pretreatment platelet count, mean platelet volume, and platelet distribution width levels were not correlated with outcomes. Surgery had no impact on the values of platelet count, plateletcrit, mean platelet volume, or platelet distribution width. Adjuvant chemotherapy significantly decreased the values of platelet count and plateletcrit, whereas it had no effect on the values of mean platelet volume or platelet distribution width. Whole course of treatment (surgery combined with adjuvant chemotherapy) significantly decreased the values of platelet count and platelet distribution width, whereas it had no effect on the values of plateletcrit or mean platelet volume. Post-/pretreatment platelet count, plateletcrit, mean platelet volume, and platelet distribution width ratios were not correlated with outcomes. Univariate analyses demonstrated that American Joint Committee on Cancer stage and pretreatment plateletcrit level were significant risk factors for prognosis. Cox regression analysis revealed that no factor independently associated with worse survival. CONCLUSION: Pretreatment plateletcrit level could be a potential prognostic factor in resectable lung cancers.

Values of applying white blood cell counts in the prognostic evaluation of resectable colorectal cancer.

The count and classification of white blood cells (WBCs) may be used as prognostic markers in certain types of cancer. The present study investigated the prognostic potential of the counts of WBCs, including lymphocytes (LYs), monocytes (MOs), neutrophils (NEs), eosinophils (EOs) and basophils (BAs), in the prognosis of resectable colorectal cancer. The present study recruited 153 resectable colorectal cancer cases retrospectively, which were pathologically confirmed. All patients were divided into two groups, according to the median value of LY (low LY, ≤1.632x109/l or high LY, >1.632x109/l), MO (low MO, ≤0.330x109/l or high MO, >0.330x109/l), NE (low NE, ≤3.600x109/l or high NE, >3.600x109/l), EO (low EO, ≤0.085x109/l or high EO, >0.085x109/l), BA (low BA, ≤0.010x109/l or high BA, >0.010x109/l), or WBC (low WBC, ≤5.780x109/l or high WBC, >5.780x109/l). To evaluate the alterations in WBC counts following surgery and adjuvant chemotherapy; all samples received oxiplatin and capecitabine (XELOX) for 6­8 cycles or 5­fluorouracil, leucovorin and oxaliplatin (mFOLFOX6) for 10­12 cycles. XELOX included oxaliplatin administered intravenously at a dose of 130 mg/m2 on day 1 and 850­1,250 mg/m2 capecitabine twice daily for days 1­14, repeated every 3 weeks. mFOLFOX6 included oxaliplatin administered intravenously at a dose of 85 mg/m2, 400 mg/m2 leucovorin and 400 mg/m2 5­FU on day 1 followed by 1,200 mg/m2/days continuous infusion for 2 days (in total, 2,400 mg/m2 over 46­48 h), repeated every 2 weeks. The present study investigated the post/pre­treatment of LY, MO, NE, EO, BA and WBC ratios (≤1 indicated that LY, MO, NE, EO, BA and WBC counts were not increased following therapy; whereas, >1 suggested increased counts). Kaplan­Meier curves were constructed to demonstrate overall survival (OS). A multivariate and univariate logistic regression analyses model was employed to identify the independent risk factors. Low pre­treatment BA counts were associated with larger tumor size (>5 cm); pre­treatment BA levels were positively associated with OS. Surgery significantly decreased the count of BAs and increased the count of EOs; whereas, no effect was observed on LYs, MOs, NEs or WBCs. Adjuvant chemotherapy markedly decreased the counts of LY, NE and WBC; whereas, no notable effects on MOs, EOs or BAs were observed. Whole course treatment (surgery combined with adjuvant chemotherapy) significantly decreased the values of LY, NE and WBC; however, increased the value of EO; no effects on the MO or BA counts were observed. An increased post­/pre­treatment NE ratio suggested poorer prognosis. Multivariate Cox regression analysis revealed that sex, tumor size, pre­treatment BA count and the post­/pre­treatment NE ratio were independent prognostic factors affecting OS. The results of the present study suggested that the pre­treatment BA count and post­/pre­treatment NE ratio may be potential prognostic factors for resectable colorectal cancer.

The combination of cantharidin and antiangiogenic therapeutics presents additive antitumor effects against pancreatic cancer.

Cantharidin, one of the active components of mylabris, is believed to have antitumor activity. Cantharidin selectively inhibits protein phosphatase 2A (PP2A), which can repress multiple oncogenic kinases (ERK, JNK, PKC, and NF-κB). Researches in vitro have shown that cantharidin suppresses cell viability and metastasis in pancreatic cancer cells. This study aims to investigate the effects of cantharidin on pancreatic cancer xenografts in vivo. Xenograft models were established using cells stably expressing luciferase. Xenograft growth was evaluated by living imaging. Gene expression was determined using a microarray, real-time PCR, a RayBiotech antibody array, and the Milliplex assay. Surprisingly, cantharidin significantly accelerated xenograft growth. Living imaging showed a rapid distribution of D-luciferin in cantharidin-treated xenografts, suggesting a rich blood supply. Immunohistochemistry confirmed increased angiogenesis. Microarray and antibody array identified upregulated proangiogenic and downregulated antiangiogenic factors. The Milliplex assay suggested elevated secretion of IL-6, IL-8, TNF-α, and VEGF. Inhibitors of ERK, JNK, PKC, and NF-κB pathway attenuated the cantharidin-induced changes to proangiogenic gene expression. PKC pathway-inhibiting tamoxifen or antiangiogenic therapeutics, including Ginsenoside Rg3, bevacizumab, Apatinib, and Endostar, antagonized the proangiogenic effect of cantharidin or its derivatives. These regimens presented remarkable additive antitumor effects in vivo. Although cantharidin presents antitumor effects in vitro and has been applied in clinical practice, we revealed an unfavorable proangiogenic side effect. We recommend that the clinical application of cantharidin should be performed on the premise of antivascularization therapy.

The values of applying classification and counts of white blood cells to the prognostic evaluation of resectable gastric cancers.

BACKGROUND: The classifications and counts of white blood cells (WBCs) have been proved to be able to be used as prognostic markers in cancer cases. The present study investigated the potential values of the classifications and counts of WBC, including lymphocyte (LY), monocyte (MO), neutrophil (NE), eosinophil (EO), and basophil (BA) in the prognosis of resectable gastric cancers (GCs). METHODS: This retrospective study recruited 104 resectable GC cases which were pathologically confirmed. The patients were divided into two groups according to the median pre-treatment values. To evaluate the changes in WBC counts and classification after treatment, we introduced the concept of post/pre-treatment ratios (≤ 1 indicated count was not increased after therapy, while > 1 suggested increased count). RESULTS: Pre-treatment NE and total WBC counts were negatively correlated with overall survival (OS). Surgery significantly decreased the level of NE count, but increased the level of EO, whereas had no effect on the levels of LY, MO, BAor total WBC. Adjuvant chemotherapy significantly decreased the level of BA. Whole course of treatment (surgery combined with adjuvant chemotherapy) had no significant effect on the counts of LY, MO, NE, EO, BA or total WBC. Post/pre-treatment ratios of LY, MO NE, EO, BA and total WBC levels had no effects on OS. Univariate analysis indicated that AJCC stage (III) and higher level of pre-treatment total WBC count were prognostic factors affecting OS. Multivariate Cox regression analysis revealed that AJCC stage (III) and higher level of pre-treatment total WBC count were independent prognostic factors. CONCLUSIONS: Pre-treatment NE count and pre-treatment total WBC count may be potential prognostic factors for the prognostic evaluation of GCs.

Genomic characteristics of pancreatic squamous cell carcinoma, an investigation by using high throughput sequencing after in-solution hybrid capture.

Squamous cell carcinoma (SCC) of pancreas is a rare histotype of pancreatic ductal carcinoma which is distinct from pancreatic adenocarcinoma (AC). Although there are standard treatments for pancreatic AC, no precise therapies exist for pancreatic SCC. Here, we screened 1033 cases of pancreatic cancer and identified 2 cases of pure SCC, which were pathologically diagnosed on the basis of finding definite intercellular bridges and/or focal keratin peal formation in the tumor cells. Immunohistochemistry assay confirmed the positive expression of CK5/6 and p63 in pancreatic SCC. To verify the genomic characteristics of pancreatic SCC, we employed in-solution hybrid capture targeting 137 cancer-related genes accompanied by high throughput sequencing (HTS) to compare the different genetic variants in SCC and AC of pancreas. We compared the genetic alterations of known biomarkers of pancreatic adenocarcinoma in different pancreatic cancer tissues, and identified nine mutated genes in SCC of pancreas: C7orf70, DNHD1, KPRP, MDM4, MUC6, OR51Q1, PTPRD, TCF4, TET2, and nine genes (ABCB1, CSF1R, CYP2C18, FBXW7, ITPA, KIAA0748, SOD2, SULT1A2, ZNF142) that are mutated in pancreatic AC. This study may have taken one step forward on the discovery of potential biomarkers for the targeted treatment of SCC of the pancreas.

TNF-α sensitizes chemotherapy and radiotherapy against breast cancer cells.

PURPOSE: Despite new developments in cancer therapy, chemotherapy and radiotherapy remain the cornerstone of breast cancer treatment. Therefore, finding ways to reduce the toxicity and increase sensitivity is particularly important. Tumor necrosis factor alpha (TNF-α) exerts multiple functions in cell proliferation, differentiation and apoptosis. In the present study, we investigated whether TNF-α could enhance the effect of chemotherapy and radiotherapy against breast cancer cells. METHODS: Cell growth was determined by MTT assay in vitro, and by using nude mouse tumor xenograft model in vivo. Cell cycle and apoptosis/necrosis were evaluated by flow cytometry. DNA damage was visualized by phospho-Histone H2A.X staining. mRNA expression was assessed by using real-time PCR. Protein expression was tested by Western blot assay. RESULTS: TNF-α strengthened the cytotoxicity of docetaxel, 5-FU and cisplatin against breast cancer cells both in vitro and in vivo. TNF-α activated NF-κB pathway and dependently up-regulated expressions of CyclinD1, CyclinD2, CyclinE, CDK2, CDK4 and CDK6, the key regulators participating in G1→S phase transition. As a result, TNF-α drove cells out of quiescent G0/G1 phase, entering vulnerable proliferating phases. Treatment of TNF-α brought more DNA damage after Cs137-irradiation and strengthened G2/M and S phase cell cycle arrest induced by docetaxel and cisplatin respectively. Moreover, the up-regulation of RIP3 (a necroptosis marker) by 5-FU, and the activation of RIP3 by TNF-α, synergistically triggered necroptosis (programmed necrosis). Knockdown of RIP3 attenuated the synergetic effect of TNF-α and 5-FU. CONCLUSION: TNF-α presented radiotherapy- and chemotherapy-sensitizing effects against breast cancer cells.

Inflammatory stimuli promote growth and invasion of pancreatic cancer cells through NF-κB pathway dependent repression of PP2Ac.

Previous studies have indicated that inflammatory stimulation represses protein phosphatase 2A (PP2A), a well-known tumor suppressor. However, whether PP2A repression participates in pancreatic cancer progression has not been verified. We used lipopolysaccharide (LPS) and macrophage-conditioned medium (MCM) to establish in vitro inflammation models, and investigated whether inflammatory stimuli affect pancreatic cancer cell growth and invasion PP2A catalytic subunit (PP2Ac)-dependently. Via nude mouse models of orthotopic tumor xenografts and dibutyltin dichloride (DBTC)-induced chronic pancreatitis, we evaluated the effect of an inflammatory microenvironment on PP2Ac expression in vivo. We cloned the PP2Acα and PP2Acß isoform promoters to investigate the PP2Ac transcriptional regulation mechanisms. MCM accelerated pancreatic cancer cell growth; MCM and LPS promoted cell invasion. DBTC promoted xenograft growth and metastasis, induced tumor-associated macrophage infiltration, promoted angiogenesis, activated the nuclear factor-κB (NF-κB) pathway, and repressed PP2Ac expression. In vitro, LPS and MCM downregulated PP2Ac mRNA and protein. PP2Acα overexpression attenuated JNK, ERK, PKC, and IKK phosphorylation, and impaired LPS/MCM-stimulated cell invasion and MCM-promoted cell growth. LPS and MCM activated the NF-κB pathway in vitro. LPS and MCM induced IKK and IκB phosphorylation, leading to p65/RelA nuclear translocation and transcriptional activation. Overexpression of the dominant negative forms of IKKα attenuated LPS and MCM downregulation of PP2Ac, suggesting inflammatory stimuli repress PP2Ac expression NF-κB pathway-dependently. Luciferase reporter gene assay verified that LPS and MCM downregulated PP2Ac transcription through an NF-κB-dependent pathway. Our study presents a new mechanism in inflammation-driven cancer progression through NF-κB pathway-dependent PP2Ac repression.

The association between expressions of Ras and CD68 in the angiogenesis of breast cancers.

OBJECTIVE: Angiogenesis is a critical step of breast cancer metastasis. Oncogenic Ras promotes the remodeling of cancer microenviroment. Tumor-associated macrophages (TAMs) are a prominent inflammatory cell population emerging in the microenviroment and facilitating the angiogenesis and metastasis. In the present study, we tried to investigate the relationship between the expression of Ras and infiltration of TAM, both of which could further promote angiogenesis. METHODS: Expressions of Ras, CD68 and CD34 were assessed by immunohistochemistry. The infiltration of macrophages was evaluated by counting the number of CD68(+) cells. Vessel endothelial cells were defined as CD34(+) cells. Angiogenesis vascularity was defined by microvessel density (MVD) assay through counting the number of vessels per field counted in the area of highest vascular density. The Kaplan-Meier survival analysis was used to estimate the overall survival (OS). Macrophages were derived from monocytes in the presence of macrophage colony-stimulating-factor (MCSF). Breast cancer cells were treated with macrophage-conditioned medium (MCM) and tested the expressions of K-, H- and N-Ras by using realtime-PCR. RESULTS: Ras positive status was correlated with ER, PR and Her-2 positivity, larger tumour size and lymph node metastasis, as well as higher TNM stages. A higher number of CD68(+) cells was correlated with larger tumour size, higher TNM stages and Her-2 positivity. Both Ras positivity and infiltration of CD68(+) macrophages correlated with poor OS. The number of CD68(+) cells was positively correlated with the expression of Ras. Treatment with MCM did not up-regulate but repressed the expression of Ras. Both up-regulation of Ras and infiltration of TAMs correlated with increased MVD. CONCLUSION: Expression of Ras and infiltration of TAM were positively correlated, and both participated in angiogenesis. Elevated Ras could be responsible for the infiltration of TAM.

Tamoxifen enhances the anticancer effect of cantharidin and norcantharidin in pancreatic cancer cell lines through inhibition of the protein kinase C signaling pathway.

Cantharidin is an active constituent of mylabris, a traditional Chinese therapeutic agent. Cantharidin is a potent and selective inhibitor of protein phosphatase 2A (PP2A). Cantharidin has been previously reported to efficiently repress the growth of pancreatic cancer cells. However, excessively activated protein kinase C (PKC) has been shown to improve cell survival following the adminstration of cantharidin. Tamoxifen is widely used in the treatment of estrogen receptor-positive breast cancer. In addition, an increasing number of studies have found that tamoxifen selectively inhibits PKC and represses growth in estrogen receptor-negative cancer cells. Administration of a combination of PKC inhibitor and PP2A inhibitors has been demonstrated to exert a synergistic anticancer effect. The proliferation of pancreatic cancer cells was analyzed by 3-(4,5-dimethyltiazol-2-yl]2, 5-diphenyltetrazo-lium bromide assay. The expression levels of ERα and ERß in various pancreatic cancer cell lines were determined by reverse transcription polymerase chain reaction. In addition, the protein levels of PKCα and phosphorylated PKCα in pancreatic cell lines were analyzed by western blot analysis. In the present study, tamoxifen was found to exert a cytotoxic effect against pancreatic cancer cells independent of the hormone receptor status. Tamoxifen repressed the phosphorylation of PKC, and amplified the anticancer effect induced by cantharidin and norcantharidin. The findings reveal a novel potential strategy against pancreatic cancer using co-treatment with tamoxifen plus cantharidin or cantharidin derivatives.

Study on VNTR diversity of clinical Mycobacterium tuberculosis isolates from Qinghai / 中华流行病学杂志

<p><b>OBJECTIVE</b>To investigate the variable number tandem repeats (VNTR) genetic polymorphisms, genotyping and distribution pattern of clinical Mycobacterium (M.) tuberculosis isolates from Qinghai province.</p><p><b>METHODS</b>The clinical M. tuberculosis strains isolated from the patients with tuberculosis and related background data were collected from Qinghai Provincial Center for Disease Control and Prevention from 2009 to 2012. Genotyping was conducted by using multiple locus VNTR analysis (MLVA). Genomic DNA was extracted and 15 VNTR loci were amplified with PCR and the PCR products were detected with gel electrophoresis. The VNTR diversity and clusters of genotyping were analyzed with BioNumerics (Version 5.0).</p><p><b>RESULTS</b>A total of 251 clinical M. tuberculosis isolates were analyzed with 15 VNTR loci showing that there were great genetic diversity in these isolates. Six of the 15 VNTR loci, showed that the Hunter-Gaston index (HGI) were higher than 0.6, in which the highest resolution was MIRU26. The clusters of genotyping showed that these isolates could be categorized into four gene clusters and 238 genotypes. The four gene clusters accounted for 4.9%, 91.9%, 1.6% and 1.6% of the clinical isolates, respectively.</p><p><b>CONCLUSION</b>The results showed that there is great variety of VNTR genetic polymorphisms in clinical M. tuberculosis isolates in Qinghai province.</p>

PP2A inhibitors suppress migration and growth of PANC-1 pancreatic cancer cells through inhibition on the Wnt/ß-catenin pathway by phosphorylation and degradation of ß-catenin.

Cantharidin is an active constituent of mylabris, a traditional Chinese medicine, and presents strong anticancer activity in various cell lines. Cantharidin is a potent and selective inhibitor of serine/threonine protein phosphatase 2A (PP2A). Our previous studies revealed the prospect of application of cantharidin, as well as other PP2A inhibitors, in the treatment of pancreatic cancer. However, the mechanisms involved in the anticancer effect of PP2A inhibitors have not been fully explored. The Wnt/ß­catenin pathway is involved in cell migration and proliferation and participates in the progression of pancreatic cancer. If ß­catenin is phosphorylated and degraded, the Wnt/ß­catenin pathway is blocked. PP2A dephosphorylates ß­catenin and keeps the Wnt/ß­catenin pathway active. In the present study, we found that PP2A inhibitor treatment induced phosphorylation and degradation of ß­catenin. The suppression on the migration and growth of PANC­1 pancreatic cancer cells could be attenuated by pretreatment with FH535, a ß­catenin pathway inhibitor. Microarray showed that PP2A inhibitor treatment induced expression changes in 13 of 138 genes downstream of the ß­catenin pathway. Real­time PCR further confirmed that FH535 attenuated the expression changes induced by PP2A inhibitors in 6 of these 13 candidate genes. These 6 genes, VEGFB, Dkk3, KRT8, NRP1, Cacnalg and WISP2, have been confirmed to participate in the migration and/or growth regulation in previous studies. Thus, the phosphorylation- and degradation-mediated suppression on ß­catenin participates in the cytotoxicity of PP2A inhibitors. Our findings may provide insight into the treatment of pancreatic cancer using a targeting PP2A strategy.

Artesunate induces G2/M cell cycle arrest through autophagy induction in breast cancer cells.

We found that artesunate (ART) inhibited the growth of MCF-7 and MDA-MB-231 breast cancer cells. ART arrested the cell cycle in the G2/M phase, which was accompanied by an upregulation of p21. ART upregulated the expression of Beclin1, an initiator of autophagy (type II programmed cell death). In addition, ART stimulated the aggregation of LC3, which is considered to be a marker of autophagosome formation. We further verified the transformation of LC3 from type I into type II. 3-MA, a classical autophagy inhibitor, attenuated ART-induced autophagosome formation, cell growth repression, G2/M arrest, and p21 upregulation. Autophagy induction and p21 upregulation were also repressed by knockdown of Beclin1. Furthermore, ART sensitized breast cancer cells to the chemotherapeutic agent epirubicin through an autophagy-dependent cascade. Our study showed that ART induced autophagy in breast cancer cells and indicated that the anticancer effects of ART were exerted through an autophagy pathway. Moreover, ART sensitized breast cancer cells to epirubicin chemotherapy. Our results provide a basis for further development of ART as a novel therapeutic agent for the treatment of breast cancer.

The outcomes of 1120 severe multiple trauma patients with hemorrhagic shock in an emergency department: a retrospective study.

OBJECTIVE: Uncontrolled hemorrhagic shock is a significant factor in death of severe multiple trauma patients. The acute management of injured bleeding in emergency department (ED) may improve patient outcomes. The medical records of severe multiple trauma patients with hemorrhagic shock in our ED were reviewed to summarize an evidence-based approach to the management of critically injured bleeding trauma patients. METHODS: A retrospective study was carried out from January 2002 to December 2011 in a Chinese tertiary hospital. Clinical data from major trauma patients with hemorrhagic shock admitted to ED were evaluated. The patients were stratified based on the characteristics of traumatic condition and resuscitation strategies. The medical treatments and the outcomes of these severe multiple trauma patients were described. RESULTS: A total of 1120 major trauma patients, consisting of 832 males and 288 females, were enrolled. 906 of the patients (80.9%) were injured in traffic accidents, 104 (9.3%) from falling, and 100 from other reasons. The number of injured sites varied from 2 to 6, 616(55.0%) more than 3. 902 (80.5%) trauma patients have recovered and been discharged from hospital. CONCLUSIONS: Uncontrolled hemorrhagic shock is a main reason of trauma patients' death. The resuscitation strategy should center upon permissive hypotension and early hemostatic resuscitation combined identified and corrects coagulopathy. The current approach to the management of critically injured bleeding trauma patients is able to improve patient outcomes.

Cantharidin and norcantharidin inhibit the ability of MCF-7 cells to adhere to platelets via protein kinase C pathway-dependent downregulation of α2 integrin.

Cancer metastasis is a highly coordinated and dynamic multistep process in which cancer cells interact with a variety of host cells. Morphological studies have documented the association of circulating tumor cells with host platelets, where a surface coating of platelets protects tumor cells from mechanical trauma and the immune system. Cantharidin is an active constituent of mylabris, a traditional Chinese medicine. Cantharidin and norcantharidin are potent protein phosphatase 2A (PP2A) inhibitors that exhibit in vitro and in vivo antitumor activity against several types of cancer, including breast cancer. We investigated whether cantharidin and norcantharidin could repress the ability of MCF-7 breast cancer cells to adhere to platelets. Using MTT, clone formation, apoptosis, adhesion and wound-healing assays, we found that cantharidin and norcantharidin induced apoptosis and repressed MCF-7 cell growth, adhesion and migration. Moreover, we developed a flow cytometry-based analysis of tumor cell adhesion to platelets. We proved that cantharidin and norcantharidin repressed MCF-7 cell adhesion to platelets through downregulation of α2 integrin, an adhesion molecule present on the surface of cancer cells. The repression of α2 integrin expression was found to be executed through the protein kinase C pathway, the activation of which could have been due to PP2A inhibition.

Practice of PBL method in the teaching of epidemiology and its reflection / 中华医学教育探索杂志

In order to improve the teaching quality of epidemiology and better serve the situation of disease prevention and control,problem-based learning (PBL) teaching method was applied in the teaching of epidemiology. This paper introduced the implementation of PBL and its advantages and disad-vantages. PBL teaching method can improve students' self-learning ability,communication skills,team cooperation,practical ability and capability of integrating knowledge of many subjects.

The changing trends of HIV/AIDS in an ethnic minority region of China: modeling the epidemic in Liangshan prefecture, Sichuan Province / 生物医学与环境科学（英文）

<p><b>OBJECTIVE</b>This study was to investigate the HIV current situation in Liangshan prefecture, in order to predict prevalence and transmission trends.</p><p><b>METHODS</b>Region-specific population, behavior, serosurveillence, and policy/program data (from 1995 to 2010) were gathered from various local and national organizations and applied to the Asian Epidemic Model (AEM) and used to derive estimates of future HIV prevalence, epidemic trends, and outcomes of intervention strategies.</p><p><b>RESULTS</b>The AEM projections for 2020 included increased number of people living with HIV (PLHIV; to 136 617), increased HIV prevalence (2.51%), and 8037 deaths from acquired immunodeficiency syndrome (AIDS) in this region. However, the overall HIV incidence rate (per 10 000) was projected to decline from 27 in 2015 to 22 in 2020, largely due to a predicted decrease in HIV infection rate (per 10 000) from 658 in 2013 to 621 in 2020 among intravenous drug users. In contrast, the cases of HIV infection per 10 000 was projected to increase from 420 in 2010 to 503 in 2020 among men who have sex with men, and from 8 in 2010 to 15 in 2020 among the general population. The predominant risk factor for HIV transmission over the next decade in Liangshan was casual sex. Community-based outreach strategies to reduce injected drug use and casual sex, and to promote condom use, were predicted as effective interventions to decrease HIV transmission.</p><p><b>CONCLUSION</b>Implementation of a comprehensive public health program, with targeting to the region-specific at-risk populations, will help to mitigate HIV/AIDS spread in Liangshan.</p>