Phase 1 dose expansion and biomarker study assessing first-in-class tumor microenvironment modulator VT1021 in patients with advanced solid tumors.

BACKGROUND: Preclinical studies have demonstrated that VT1021, a first-in-class therapeutic agent, inhibits tumor growth via stimulation of thrombospondin-1 (TSP-1) and reprograms the tumor microenvironment. We recently reported data from the dose escalation part of a phase I study of VT1021 in solid tumors. Here, we report findings from the dose expansion phase of the same study. METHODS: We analyzed the safety and tolerability, clinical response, and biomarker profile of VT1021 in the expansion portion of the phase I study (NCT03364400). Safety/tolerability is determined by adverse events related to the treatment. Clinical response is determined by RECIST v1.1 and iRECIST. Biomarkers are measured by multiplexed ion beam imaging and enzyme-linked immunoassay (ELISA). RESULTS: First, we report the safety and tolerability data as the primary outcome of this study. Adverse events (AE) suspected to be related to the study treatment (RTEAEs) are mostly grade 1-2. There are no grade 4 or 5 adverse events. VT1021 is safe and well tolerated in patients with solid tumors in this study. We report clinical responses as a secondary efficacy outcome. VT1021 demonstrates promising single-agent clinical activity in recurrent GBM (rGBM) in this study. Among 22 patients with rGBM, the overall disease control rate (DCR) is 45% (95% confidence interval, 0.24-0.67). Finally, we report the exploratory outcomes of this study. We show the clinical confirmation of TSP-1 induction and TME remodeling by VT1021. Our biomarker analysis identifies several plasmatic cytokines as potential biomarkers for future clinical studies. CONCLUSIONS: VT1021 is safe and well-tolerated in patients with solid tumors in a phase I expansion study. VT1021 has advanced to a phase II/III clinical study in glioblastoma (NCT03970447).

The network of cells that surround a tumor, the tumor microenvironment, can help cancers to grow. Therapies targeting the tumor microenvironment may help to stop tumor growth. One such therapy is VT1021. In animal models, VT1021 treatment stops tumor cells from growing by changing the tumor microenvironment. Here, we have tested VT1021 in a clinical trial and found that VT1021 treatment is safe and well tolerated in patients with cancer. We also see signs of efficacy in some patients and observe evidence that VT1021 modifies the tumor microenvironment, which may help to block tumor growth. Finally, we identified several markers from the blood that may help to predict which patients will best benefit from VT1021 treatment. With further testing in clinical trials, VT1021 may be a useful therapy for patients with cancer.

First-in-human phase I dose escalation trial of the first-in-class tumor microenvironment modulator VT1021 in advanced solid tumors.

BACKGROUND: VT1021 is a cyclic peptide that induces the expression of thrombospondin-1 (TSP-1) in myeloid-derived suppressor cells (MDSCs) recruited to the tumor microenvironment (TME). TSP-1 reprograms the TME via binding to CD36 and CD47 to induce tumor and endothelial cell apoptosis as well as immune modulation in the TME. METHODS: Study VT1021-01 (ClinicalTrials.gov ID NCT03364400) used a modified 3 + 3 design. The primary objective was to determine the recommended Phase 2 dose (RP2D) in patients with advanced solid tumors. Safety, tolerability, and pharmacokinetics (PK) were assessed. Patients were dosed twice weekly intravenously in 9 cohorts (0.5-15.6 mg/kg). Safety was evaluated using CTCAE version 5.0 and the anti-tumor activity was evaluated by RECIST version 1.1. RESULTS: The RP2D of VT1021 is established at 11.8 mg/kg. VT1021 is well tolerated with no dose-limiting toxicities reported (0/38). The most frequent drug-related adverse events are fatigue (15.8%), nausea (10.5%), and infusion-related reactions (10.5%). Exposure increases proportionally from 0.5 to 8.8 mg/kg. The disease control rate (DCR) is 42.9% with 12 of 28 patients deriving clinical benefit including a partial response (PR) in one thymoma patient (504 days). CONCLUSIONS: VT1021 is safe and well-tolerated across all doses tested. RP2D has been selected for future clinical studies. PR and SD with tumor shrinkage are observed in multiple patients underscoring the single-agent potential of VT1021. Expansion studies in GBM, pancreatic cancer and other solid tumors at the RP2D have been completed and results will be communicated in a separate report.

It may be possible to treat cancers with therapies that modify the tumor microenvironment. This is the environment in the body in which tumors survive and grow and is composed of different types of cells. One such potential therapy is VT1021. Here, we conduct the first clinical trial to test this therapy in patients. We identify the optimal dose of the treatment to take into further studies, finding that VT1021 is safe and well tolerated by patients. We see some signs that the treatment is working in some patients and see evidence of modification of the tumor microenvironment. These findings help to inform further clinical trials of VT1021 to determine whether it is safe and effective in larger cohorts of patients.

PRSS2 remodels the tumor microenvironment via repression of Tsp1 to stimulate tumor growth and progression.

The progression of cancer from localized to metastatic disease is the primary cause of morbidity and mortality. The interplay between the tumor and its microenvironment is the key driver in this process of tumor progression. In order for tumors to progress and metastasize they must reprogram the cells that make up the microenvironment to promote tumor growth and suppress endogenous defense systems, such as the immune and inflammatory response. We have previously demonstrated that stimulation of Tsp-1 in the tumor microenvironment (TME) potently inhibits tumor growth and progression. Here, we identify a novel tumor-mediated mechanism that represses the expression of Tsp-1 in the TME via secretion of the serine protease PRSS2. We demonstrate that PRSS2 represses Tsp-1, not via its enzymatic activity, but by binding to low-density lipoprotein receptor-related protein 1 (LRP1). These findings describe a hitherto undescribed activity for PRSS2 through binding to LRP1 and represent a potential therapeutic strategy to treat cancer by blocking the PRSS2-mediated repression of Tsp-1. Based on the ability of PRSS2 to reprogram the tumor microenvironment, this discovery could lead to the development of therapeutic agents that are indication agnostic.

Long-term decrease in Asian monsoon rainfall and abrupt climate change events over the past 6,700 years.

Asian summer monsoon (ASM) variability and its long-term ecological and societal impacts extending back to Neolithic times are poorly understood due to a lack of high-resolution climate proxy data. Here, we present a precisely dated and well-calibrated tree-ring stable isotope chronology from the Tibetan Plateau with 1- to 5-y resolution that reflects high- to low-frequency ASM variability from 4680 BCE to 2011 CE. Superimposed on a persistent drying trend since the mid-Holocene, a rapid decrease in moisture availability between ∼2000 and ∼1500 BCE caused a dry hydroclimatic regime from ∼1675 to ∼1185 BCE, with mean precipitation estimated at 42 ± 4% and 5 ± 2% lower than during the mid-Holocene and the instrumental period, respectively. This second-millennium-BCE megadrought marks the mid-to late Holocene transition, during which regional forests declined and enhanced aeolian activity affected northern Chinese ecosystems. We argue that this abrupt aridification starting ∼2000 BCE contributed to the shift of Neolithic cultures in northern China and likely triggered human migration and societal transformation.

Small intestinal bacterial overgrowth and evaluation of intestinal barrier function in patients with ulcerative colitis.

OBJECTIVE: To investigate the small intestinal bacterial overgrowth (SIBO) and to evaluate the intestinal barrier function in ulcerative colitis (UC) patients treated with mesalazine and rifaximin. METHODS: 96 patients undergoing the methane-hydrogen breath test in our hospital from January 2018 to January 2020 were enrolled in the study group, and 40 healthy persons were enrolled in the control group during this period. The SIBO positive rate of the two groups were collected and compared. Then, the SIBO positive patients were divided into group A and group B. Group A and group B all received mesalazine, and group B received rifaximin plus. The clinical efficacy, erythrocyte sedimentation rate (ESR), C reactive protein (CRP), and intestinal barrier function indexes like diamine oxidase (DAO) and D-lactic acid (DLA) were recorded and compared. RESULTS: The study group presented higher SIBO positive rate compared with the control group (56% vs. 25%, P<0.05). After treatment, group B showed better clinical efficacy and lower levels of ESR and CRP than group A (all P<0.05). After treatment, the DAO and D-LA levels of the two groups were decreased, and presented lower levels in group B than group A (all P<0.05). CONCLUSION: UC patients present a higher positive rate in SIBO. Mesalazine and rifaximin are applied to patients with mild to moderate UC, and their clinical efficacy has been significantly enhanced after the eradication of SIBO.

The Green Synthesis of 2D Copper Nanosheets and Their Light Absorption.

In this study, a new green synthesis method for two-dimensional (2D) copper nanosheets is developed using methylsulfonylmethane (DMSO2). The chemical composition and light absorption of 2D copper nanosheets are also studied. A new green method is mainly to utilize DMSO2, which is environmentally friendly enough to be considered a food-grade chemical, unlike the conventional method using toxic chemicals, such as ammonia and hydrazine (N2H4). With a reducing agent, the aggregation of uncertain copper products was produced in the absence of DMSO2, while 2D copper nanosheets were formed in the presence of DMSO2. The optimum concentration of DMSO2 as a surfactant was determined to be 2 M, resulting in large surface areas with regular edges. FTIR spectrum confirmed C-H bonding from DMSO2 used to synthesize 2D copper nanosheets. The light absorption peak was revealed at 800 nm in the UV-vis spectrum. This proposed new green method not only has a simpler process than the conventional methods, such as hydrothermal method and chemical bath deposition, but also substitutes toxic chemicals with DMSO2. 2D copper nanosheets can be used for various applications, including conductive filler or ink in the flexible electronics and laser photonics fields.

Long Noncoding RNA Lnc-TLN2-4:1 Suppresses Gastric Cancer Metastasis and Is Associated with Patient Survival.

Gastric cancer (GC) is one of the most common malignancies worldwide, and the tumor metastasis leads to poor outcomes of GC patients. Long noncoding RNAs (lncRNAs) have emerged as new regulatory molecules that play a crucial role in tumor metastasis. However, the biological function and underlying mechanism of numerous lncRNAs in GC metastasis remain largely unclear. Here, we report a novel lncRNA, lnc-TLN2-4:1, whose expression is decreased in GC tissue versus matched normal tissue, and its low expression is involved in the lymph node and distant metastases of GC, as well as poor overall survival rates of GC patients. We further found that lnc-TLN2-4:1 inhibits the ability of GC cells to migrate and invade but does not influence GC cell proliferation and confirmed that lnc-TLN2-4:1 is mainly located in the cytoplasm of GC cells. We then found that lnc-TLN2-4:1 increases the mRNA and protein expression of TLN2 in GC cells and there is a positive correlation between the expression of lnc-TLN2-4:1 and TLN2 mRNA in GC tissue. Collectively, we identified a novel lncRNA, lnc-TLN2-4:1, in GC, where lnc-TLN2-4:1 represses cell migration and invasion. The low expression of lnc-TLN2-4:1 is associated with poor overall survival rates of GC patients. These suggest that lnc-TLN2-4:1 may be a tumor suppressor during GC metastasis.

Calcium Promotes Human Gastric Cancer via a Novel Coupling of Calcium-Sensing Receptor and TRPV4 Channel.

Although dietary calcium intake has long been recommended for disease prevention, the influence of calcium in development of cancer in the upper gastrointestinal tract has not been explored. Here, we assess the roles of calcium and calcium-sensing receptor (CaSR) in gastric cancer development. CaSR expression was enhanced in gastric cancer specimens, which positively correlated with serum calcium concentrations, tumor progression, poor survival, and male gender in gastric cancer patients. CaSR and transient receptor potential cation channel subfamily V member 4 (TRPV4) were colocalized in gastric cancer cells, and CaSR activation evoked TRPV4-mediated Ca2+ entry. Both CaSR and TRPV4 were involved in Ca2+-induced proliferation, migration, and invasion of gastric cancer cells through a Ca2+/AKT/ß-catenin relay, which occurred only in gastric cancer cells or normal cells overexpressing CaSR. Tumor growth and metastasis of gastric cancer depended on CaSR in nude mice. Overall, our findings indicate that calcium may enhance expression and function of CaSR to potentially promote gastric cancer, and that targeting the novel CaSR/TRPV4/Ca2+ pathway might serve as preventive or therapeutic strategies for gastric cancer. Cancer Res; 77(23); 6499-512. ©2017 AACR.

hTERT promotes gastric intestinal metaplasia by upregulating CDX2 via NF-κB signaling pathway.

BACKGROUND: hTERT has been reported involved in the proliferation and metastasis of gastric cancer, but the role of hTERT in gastric intestinal metaplasia, a premalignant lesion of the gastric mucosa was unknown. The aim of the present study was to investigate the role of hTERT in GIM and the effect of hTERT on CDX2 expression in gastric cells. RESULTS: Experiments showed that expression of hTERT was significantly higher in GIM than in normal gastric mucosa. Moreover, hTERT increased the KLF4 level via NF-κB during GIM. Furthermore, KLF4 is involved in the up-regulation of CDX2 induced by hTERT, and hTERT can interact with p50, thereby increasing the level of CDX2. MATERIALS AND METHODS: Immunohistochemistry was used to detect the expression of hTERT in gastric intestinal metaplasia tissue. Then, effect of hTERT on the expression of CDX2 was detected by qRT-PCR, WB and dual luciferase experiment. The role of p65 and p50 in the regulation of CDX2 were further detected by WB, CO-IP and ChIP. CONCLUSIONS: We may conclude that hTERT promotes GIM by up-regulating CDX2 via NF-κB signaling pathway.

Prolonged QT interval is linked to all-cause and cardiac mortality in chronic peritoneal dialysis patients.

AIM: Prolonged QT interval is related to changes of electrolytes in haemodialysis (HD) and is associated with all-cause mortality in HD patients. It is unknown if prolonged QT interval is associated with all-cause mortality in peritoneal dialysis (PD) patients as the electrolytes were relatively stable in PD. We therefore investigated the association of prolonged QT interval and all-cause mortality in chronic PD patients. METHODS: The QT intervals were measured in 2003 and all patients were followed to December 2012. A prolonged QT interval was defined as a QT interval > 450 ms. The association of prolonged QT interval with all-cause and cardiac-specific mortality was analyzed using Cox regression and Kaplan-Meier analysis. RESULTS: Of 306 patients, 196 (64%) patients had prolonged QT interval. The incidence density rate was 9.7 per 100 persons-years for all-cause mortality and 5.6 for cardiac specific mortality in patients with prolonged QT interval. Prolonged QT interval was associated with all-cause mortality with a hazard ratio (HR) of 1.59 (95% confidence interval (CI): 1.06-2.39, P = 0.03] and cardiac mortality (HR: 1.66, 95% CI: 1.00-2.78, P = 0.05) with adjustments for age, gender, diabetes, and vintage of dialysis. Longer QT interval (>500 ms, 450-500 ms, and < 450 ms) was significantly associated with a worse overall survival (P = 0.03, log-rank test) and cardiac mortality free survival (P = 0.05, log-rank test). CONCLUSIONS: Prolonged QT interval was associated with all-cause and cardiac mortality in patients on peritoneal dialysis. The association is independent of patient's age and diabetes.

Development of a prosaposin-derived therapeutic cyclic peptide that targets ovarian cancer via the tumor microenvironment.

The vast majority of ovarian cancer-related deaths are caused by metastatic dissemination of tumor cells, resulting in subsequent organ failure. However, despite our increased understanding of the physiological processes involved in tumor metastasis, there are no clinically approved drugs that have made a major impact in increasing the overall survival of patients with advanced, metastatic ovarian cancer. We identified prosaposin (psap) as a potent inhibitor of tumor metastasis, which acts via stimulation of p53 and the antitumorigenic protein thrombospondin-1 (TSP-1) in bone marrow-derived cells that are recruited to metastatic sites. We report that more than 97% of human serous ovarian tumors tested express CD36, the receptor that mediates the proapoptotic activity of TSP-1. Accordingly, we sought to determine whether a peptide derived from psap would be effective in treating this form of ovarian cancer. To that end, we developed a cyclic peptide with drug-like properties derived from the active sequence in psap. The cyclic psap peptide promoted tumor regression in a patient-derived tumor xenograft model of metastatic ovarian cancer. Thus, we hypothesize that a therapeutic agent based on this psap peptide would have efficacy in treating patients with metastatic ovarian cancer.

CCL5 derived from platelets increases megakaryocyte proplatelet formation.

In times of physiological stress, platelet count can transiently rise. What initiates this reactive thrombocytosis is poorly understood. Intriguingly, we found that treating megakaryocytes (MKs) with the releasate from activated platelets increased proplatelet production by 47%. Platelets store inflammatory cytokines, including the chemokine ligand 5 (CCL5, RANTES); after TRAP activation, platelets release over 25 ng/mL CCL5. We hypothesized that CCL5 could regulate platelet production by binding to its receptor, CCR5, on MKs. Maraviroc (CCR5 antagonist) or CCL5 immunodepletion diminished 95% and 70% of the effect of platelet releasate, respectively, suggesting CCL5 derived from platelets is sufficient to drive increased platelet production through MK CCR5. MKs cultured with recombinant CCL5 increased proplatelet production by 50% and had significantly higher ploidy. Pretreating the MK cultures with maraviroc prior to exposure to CCL5 reversed the augmented proplatelet formation and ploidy, suggesting that CCL5 increases MK ploidy and proplatelet formation in a CCR5-dependent manner. Interrogation of the Akt signaling pathway suggested that CCL5/CCR5 may influence proplatelet production by suppressing apoptosis. In an in vivo murine acute colitis model, platelet count significantly correlated with inflammation whereas maraviroc treatment abolished this correlation. We propose that CCL5 signaling through CCR5 may increase platelet counts during physiological stress.

Multidisciplinary care in patients with chronic kidney disease: A systematic review and meta-analysis.

BACKGROUND: Multidisciplinary care (MDC) was widely used in multiple chronic illnesses but the effectiveness of MDC in patients with chronic kidney disease (CKD) was inconclusive. The aim of this meta-analysis is to estimate the effectiveness of MDC for CKD. METHODS: We searched PubMed, Web of Science, Google Scholar, Cochrane Library, and China Journal Full-text Database for relevant articles published in English or Chinese. Studies investigating MDC and non-MDC in patients with CKD were included. Random effect model was used to compare all-cause mortality, dialysis, risk of temporal catheterization, and hospitalization in the two treatment entities. RESULTS: We analyzed 8853 patients of 18 studies in patients with CKD stages 3-5, aged 63±12 years. MDC was associated with lower risk of all-cause mortality with an odds ratio (OR) of 0.52 [95% confidence interval (CI): 0.44-0.88, p=0.01], mainly in cohort studies. MDC was associated with a lower risk of starting dialysis (p=0.02) and lower risk of temporal catheterization for dialysis (p<0.01). MDC was not associated with a higher chance of choosing peritoneal dialysis (p=0.18) or a lower chance of hospitalization for dialysis (p=0.13). CONCLUSIONS: Limited evidence from randomized controlled trials is currently available to support the benefit of MDC in patients with CKD. MDC is associated with lower all-cause mortality, lower risk of starting dialysis, and lower risk of temporal catheterization for dialysis in cohort studies. MDC is not associated with a higher chance of choosing peritoneal dialysis or a lower chance of hospitalization for dialysis. More studies are needed to determine the optimal professional that should be included in MDC.

Upper gastrointestinal bleeding in patients with CKD.

BACKGROUND AND OBJECTIVES: Patients with CKD receiving maintenance dialysis are at risk for upper gastrointestinal bleeding. However, the risk of upper gastrointestinal bleeding in patients with early CKD who are not receiving dialysis is unknown. The hypothesis was that their risk of upper gastrointestinal bleeding is negatively linked to renal function. To test this hypothesis, the association between eGFR and risk of upper gastrointestinal bleeding in patients with stages 3-5 CKD who were not receiving dialysis was analyzed. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Patients with stages 3-5 CKD in the CKD program from 2003 to 2009 were enrolled and prospectively followed until December of 2012 to monitor the development of upper gastrointestinal bleeding. The risk of upper gastrointestinal bleeding was analyzed using competing-risks regression with time-varying covariates. RESULTS: In total, 2968 patients with stages 3-5 CKD who were not receiving dialysis were followed for a median of 1.9 years. The incidence of upper gastrointestinal bleeding per 100 patient-years was 3.7 (95% confidence interval, 3.5 to 3.9) in patients with stage 3 CKD, 5.0 (95% confidence interval, 4.8 to 5.3) in patients with stage 4 CKD, and 13.9 (95% confidence interval, 13.1 to 14.8) in patients with stage 5 CKD. Higher eGFR was associated with a lower risk of upper gastrointestinal bleeding (P=0.03), with a subdistribution hazard ratio of 0.93 (95% confidence interval, 0.87 to 0.99) for every 5 ml/min per 1.73 m(2) higher eGFR. A history of upper gastrointestinal bleeding (P<0.001) and lower serum albumin (P=0.004) were independently associated with higher upper gastrointestinal bleeding risk. CONCLUSIONS: In patients with CKD who are not receiving dialysis, lower renal function is associated with higher risk for upper gastrointestinal bleeding. The risk is higher in patients with previous upper gastrointestinal bleeding history and low serum albumin.

Association of walking with survival and RRT among patients with CKD stages 3-5.

BACKGROUND AND OBJECTIVES: Patients with CKD can benefit from an increase in physical activity. Walking is one of the most common exercises in patients with CKD; however, the association of walking with outcomes in patients with CKD is not clear. This study investigated the association of walking with overall mortality and RRT in patients with CKD stages 3-5. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: All patients with CKD stages 3-5 in the CKD program of China Medical University Hospital from June 2003 to May 2013 were enrolled. The risks of overall mortality and RRT were analyzed using competing-risks regressions. RESULTS: A total of 6363 patients (average age, 70 years) during a median of 1.3 (range=0.6-2.5) years of follow-up were analyzed. There were 1341 (21.1%) patients who reported walking as their most common form of exercise. The incidence density rate of overall mortality was 2.7 per 100 person-years for walking patients and 5.4 for nonwalking ones. The incidence density rate of RRT was 22 per 100 person-years for walking patients and 32.9 for nonwalking ones. Walking, independent of patients' age, renal function, and comorbidity, was linked to lower overall mortality and lower RRT risk in the multivariate competing-risks regression. The adjusted subdistribution hazard ratio (SHR) of walking was 0.67 (95% confidence interval [95% CI], 0.53 to 0.84; P<0.001) for overall mortality and 0.79 (95% CI, 0.73 to 0.85; P<0.001) for the risk of RRT. The SHRs of overall mortality were 0.83, 0.72, 0.42, and 0.41 for patients walking 1-2, 3-4, 5-6, and ≥7 times per week, and the SHRs of RRT were 0.81, 0.73, 0.57, and 0.56, respectively. CONCLUSIONS: Walking is the most popular form of exercise in patients with CKD and is associated with lower risks of overall mortality and RRT. The benefit of walking is independent of patients' age, renal function, and comorbidity.

GRK3 is essential for metastatic cells and promotes prostate tumor progression.

The biochemical mechanisms that regulate the process of cancer metastasis are still poorly understood. Because kinases, and the signaling pathways they comprise, play key roles in regulation of many cellular processes, we used an unbiased RNAi in vitro screen and a focused cDNA in vivo screen against human kinases to identify those with previously undocumented roles in metastasis. We discovered that G-protein-coupled receptor kinase 3 (GRK3; or ß-adrenergic receptor kinase 2) was not only necessary for survival and proliferation of metastatic cells, but also sufficient to promote primary prostate tumor growth and metastasis upon exogenous expression in poorly metastatic cells in mouse xenograft models. Mechanistically, we found that GRK3 stimulated angiogenesis, at least in part through down-regulation of thrombospondin-1 and plasminogen activator inhibitor type 2. Furthermore, GRK3 was found to be overexpressed in human prostate cancers, especially in metastatic tumors. Taken together, these data suggest that GRK3 plays an important role in prostate cancer progression and metastasis.

Bone marrow-derived Gr1+ cells can generate a metastasis-resistant microenvironment via induced secretion of thrombospondin-1.

UNLABELLED: Metastatic tumors have been shown to establish permissive microenvironments for metastases via recruitment of bone marrow-derived cells. Here, we show that metastasis-incompetent tumors are also capable of generating such microenvironments. However, in these situations, the otherwise prometastatic Gr1(+) myeloid cells create a metastasis-refractory microenvironment via the induction of thrombospondin-1 (Tsp-1) by tumor-secreted prosaposin. Bone marrow-specific genetic deletion of Tsp-1 abolished the inhibition of metastasis, which was restored by bone marrow transplant from Tsp-1(+) donors. We also developed a 5-amino acid peptide from prosaposin as a pharmacologic inducer of Tsp-1 in Gr1(+) bone marrow cells, which dramatically suppressed metastasis. These results provide mechanistic insights into why certain tumors are deficient in metastatic potential and implicate recruited Gr1(+) myeloid cells as the main source of Tsp-1. The results underscore the plasticity of Gr1(+) cells, which, depending on the context, promote or inhibit metastasis, and suggest that the peptide could be a potential therapeutic agent against metastatic cancer. SIGNIFICANCE: The mechanisms of metastasis suppression are poorly understood. Here, we have identified a novel mechanism whereby metastasis-incompetent tumors generate metastasis-suppressive microenvironments in distant organs by inducing Tsp-1 expression in the bone marrow­derived Gr1+myeloid cells. A 5-amino acid peptide with Tsp-1­inducing activity was identified as a therapeutic agent against metastatic cancer.

Comparison of hepatitis B surface antibody decay rates after vaccination between hemodialysis and peritoneal dialysis patients.

BACKGROUND AND OBJECTIVES: The available information about maintaining effective immunity after hepatitis B virus (HBV) vaccination in dialysis patients is limited. The aim of this study was to determine whether a difference exists in the persistence of immunity between hemodialysis (HD) and peritoneal dialysis (PD) patients. We compared the decay rate of hepatitis B surface antibody (anti-HBs) titers after HBV vaccination between HD and PD patients. DESIGN, SETTING, PARTICIPANTS, AND MEASURES: A total of 103 HD and 53 PD patients who were completely vaccinated were enrolled. We examined their anti-HBs titers at the 1st month after vaccination then annually thereafter. Changes in the anti-HBs titers were assessed by comparing annual geometric mean titers (GMTs). RESULTS: The slopes of the anti-HBs titer decay rates plotted on a logarithmic scale for the HD and PD groups were -23.41 and -31.48, respectively. The decay rate of the PD group was significantly faster than that of the HD group (P=0.0053). CONCLUSION: The decay rate of anti-HBs titers in the PD group was faster than that in the HD group. Hepatitis B vaccination could not offer long-term protection in HD or PD patients. Post-vaccination testing every 6-12 months is necessary and revaccination may be protective in dialysis patients, especially in hyper-endemic areas of hepatitis B infection.

Analysis and evaluation of the source of heavy metals in water of the River Changjiang.

In order to analyze and evaluate different trace metals on surface water of the Changjiang River, concentrations of dissolved trace metals (Cu, Ni, Fe, Co, Sc, Al, Zn, Pb, Cd, Se, As, Cr, and Hg), major elements (Ca and Mg), and nutrient (NO3- were measured. Samples were taken at 76 positions along Changjiang River in flood and dry seasons during 2007-2008. Spatial distributions identified two main large zones mainly influenced by mineral erosion (sites 1-22) and anthropogenic action (sites 23-76), respectively. Principal component analysis (PCA) and hierarchical cluster analysis were used to identify the variance distinguishing the origin of water. Four significant components were extracted by PCA, explaining 74.91% of total variable. Cu, Ni, Fe, Co, Sc, Al, Ca, and Mg were mainly associated with the weathering and erosion of various rocks and minerals, while an anthropogenic source was identified for Cd and As. Although erosion was one source of Pb and Zn, they were also input by atmospheric deposition and industrial pollutions. NO3- and Se were mainly associated with agriculture activities. However, Hg and Cr showed different sources. CA confirmed and completed the results obtained by PCA, classifying the data into two large groups representing different areas. Group 1 referred to the upper reaches which represented samples mainly corresponding to natural background areas. Group 2 referred to the middle and lower reaches including samples under anthropogenic influence. Meanwhile, group 2 was subdivided into three new groups, representing agricultural, industrial, and various artificial pollution sources, respectively.