Search

Nanomedicine enabled cancer combination immunotherapy not only sufficiently activates the host immune system, but also reprograms the immunosuppressive microenvironment, representing a new generation approach to treat cancer. Herein, we demonstrated a targeted photo- and immune-active nanoplatform termed NLG919@HA-Ce6 to simultaneously elicit efficient immunogenic cell death (ICD) using the photosensitizer Ce6 and modulate the tryptophan metabolic pathway using an indoleamine 2,3-dioxygenase (IDO) inhibitor NLG919 for the combined photodynamic therapy (PDT) and checkpoint blockade immunotherapy. Against the triple-negative and poorly immunogenic 4T1 breast cancer model, the stable spherical nanomicelle NLG919@HA-Ce6 selectively killed tumour cells via the toxic singlet oxygen upon laser excitation, thus in situ triggering a potent antitumor immune response, as seen via the obvious CRT exposure, ATP release, dendritic cell maturation, etc. Meanwhile, the IDO1-mediated immunosuppression was effectively reprogrammed to an immunostimulatory phenotype, which was accompanied by an enhanced cytotoxic T cell response as well as reduced Treg infiltration in tumour bed. Ultimately, the 4T1 tumour was synergistically suppressed by NLG919@HA-Ce6 due to the outcome of focused PDT, obvious ICD post PDT and IDO1 blockade. This study suggests the promise of NLG919@HA-Ce6 as an alternative simple, stimulative and targeted nanoagent to enable the whole-body photo-immune therapy against "immune cold" cancer.

In the past few years, we have witnessed great development and application potential of various up-conversion luminescent nanoparticles (UCNPs) in the nanomedicine field. Based on the unique luminescent mechanism of UCNPs and the distinguishable features of cancer biomarkers and the microenvironment, an increasing number of smart UCNPs nanoprobes have been designed and widely applied to molecular imaging, cancer diagnosis, and treatment. Considerable technological success has been achieved, but the main obstacles to oncology nanomedicine is becoming an incomplete understanding of nano-bio interactions, the challenges regarding chemistry manufacturing and controls required for clinical translation and so on. This review highlights the progress of the design principles, synthesis and surface functionalization preparation, underlying applications and challenges of UCNPs-based probes for cancer bioimaging, diagnosis and treatment that capitalize on our growing understanding of tumor biology and smart nano-devices for accelerating the commercialization of UCNPs.

The combination of magnetic hyperthermia and chemotherapy within a nanosystem is thought to be a promising approach for cancer therapies. However, the nonspecific accumulation and fast clearance of magnetic nanoparticles in the physiological environment limited their further biomedical applications. Herein, we report a highly selective theranostic nanocomplex, ZIPP-Apt:DOX/siHSPs, built with superparamagnetic zinc-doped iron oxide nano-octahedral core, cationic PAMAM dendrimer, and functional surface modifications such as PEG, AS1411 aptamer, and fluorescent tags (FITC or Cy5.5), together with the loading of hydrophobic anticancer drug doxorubicin (DOX) and HSP70/HSP90 siRNAs. Our results demonstrate that the cellular uptake and the tumor-specific accumulation of ZIPP-Apt:DOX/siHSPs were significantly increased due to the AS1411-nucleolin affinity and further confirmed that the simultaneous depletion of HSP70 and HSP90 sensitized magnetic hyperthermia and chemotherapy-induced cell death both in vitro and in vivo. Altogether, our study provides a theranostic nanoplatform for aptamer-targeted, NIR/MR dual-modality imaging guided, and HSP70/HSP90 silencing sensitized magnetochemotherapy, which has the potential to advance versatile magnetic nanosystems toward clinical applications.

T cell stimulatory and inhibitory molecules are critical for the regulation of immune responses. In this study, we identify a novel T cell co‐inhibitory molecule TAPBPL, whose amino acid sequence shares homology with known B7 family members. TAPBPL protein is expressed on resting and activated T cells, B cells, monocytes, and dendritic cells (DCs), as well as on some tumor tissues. The putative TAPBPL receptor is expressed on activated CD4 and CD8 T cells. A soluble recombinant human TAPBPL‐IgG Fc (hTAPBPL‐Ig) fusion protein inhibits the proliferation, activation, and cytokine production of both mouse and human T cells in vitro. In vivo administration of hTAPBPL‐Ig protein attenuates experimental autoimmune encephalomyelitis (EAE) in mice. Furthermore, an anti‐TAPBPL monoclonal antibody neutralizes the inhibitory activity of hTAPBPL‐Ig on T cells, enhances antitumor immunity, and inhibits tumor growth in animal models. Our results suggest that therapeutic intervention of the TAPBPL inhibitory pathway may represent a new strategy to modulate T cell‐mediated immunity for the treatment of cancer, infections, autoimmune diseases, and transplant rejection., T cells play a critical role in immune response. This study identifies a novel B7 family‐related T cell inhibitory molecule TAPBPL. Targeting the TAPBPL pathway may represent a new strategy to modulate T cell‐mediated immunity to treat autoimmune disease and cancer.

Transgenic adenocarcinoma of the mouse prostate (TRAMP) mice is a widely used transgenic animal model of prostate cancer (PCa). We performed a label-free quantitative proteomics analysis combined with a bioinformatics analysis on the entire prostate protein extraction from TRAMP mice and compared it with WT littermates. From 2379 total identified proteins, we presented a modest mice prostate reference proteome containing 919 proteins. 61 proteins presented a significant expression difference between two groups. The integrative bioinformatics analysis predicted the overexpression of platelet-derived growth factor B (PDGF-B) in tumor tissues and supports the hypothesis of the PDGF-B signaling network as a key upstream regulator in PCa progression. Furthermore, we demonstrated that Crenolanib, a novel PDGF receptor inhibitor, inhibited PCa cell proliferation in a dose-dependent manner. Finally, we revealed the importance of PDGF-B regulatory network in PCa progression, which will assist us in understanding the role and mechanisms of PDGF-B in promoting cancer growth and provide valuable knowledge for future research on anti-PDGF therapy.

The exploration of an intelligent multifunctional imaging-guided therapeutic platform is of great significance because of its ideal delivery efficiency and controlled release. In this work, a tumor microenvironment (TME)-responsive nanocarrier (denoted as MB@MSP) is designed for on-demand, sequentially release of a short D-peptide antagonist of programmed cell death-ligand 1 (named as PDPPA-1) and a photosensitizer methylene blue (MB). Fe3O4-Au located in the core of MB@MSP is used as a magnetic resonance imaging and micro-computed tomography imaging contrast agent for noninvasive diagnosis of solid tumors and simultaneous monitoring of drug delivery. The PDPPA-1 coated on MB@MSP can be shed due to the cleavage of the peptide substrate by matrix metalloproteinase-2 (MMP-2) that is highly expressed in the tumor stroma, and disulfide bonding is further broken when it encounters high levels of glutathione (GSH) in TME, which finally leads to significant size reduction and charge-reversal. These transitions facilitate penetration and uptake of nanocarriers against tumors. Noticeably, the released PDPPA-1 can block the immune checkpoint to create an environment that favors the activation of cytotoxic T lymphocytes and augment the antitumor immune response elicited by photodynamic therapy, thus significantly improving therapeutic outcomes. Studies of the underlying mechanisms suggest that the designed MMP-2 and GSH-sensitive delivery system not only induce apoptosis of tumor cells but also modulate the immunosuppressive tumor microenvironment to eventually augment the suppression tumor metastasis effect of CD8+ cytotoxic T cells. Overall, the visualization of the therapeutic processes with comprehensive information renders MB@MSP an intriguing platform to realize the combined treatment of metastatic tumors.

// Tingting Men 1, * , Cuicui Yu 2, * , Dan Wang 3 , Fang Liu 3 , Jingjing Li 3 , Xiaoying Qi 3 , Chunhua Yang 3 , Wenguo Jiang 3 , Xiaodan Wei 3 , Xuri Li 3 , Bin Wang 4 , Jia Mi 3 and Geng Tian 3 1 School of Nursing, Binzhou Medical University, Yantai, Shandong, China 2 Department of Anesthesiology, Yantai Yu Huang Ding Hospital, Yantai, Shandong, China 3 Medicine and Pharmacy Research Center, Binzhou Medical University, Yantai, Shandong, China 4 Institute of Molecular Imaging, Binzhou Medical University, Yantai, Shandong, China * These authors have contributed equally to this work Correspondence to: Geng Tian, email: tiangengshandong@yeah.net Jia Mi, email: Jia.mi@kemi.uu.se Bin Wang, email: binwang001@aliyun.com Keywords: prostate cancer, interleukin-10, polymorphism, peripheral blood interleukin-10, meta-analysis Received: December 16, 2016 Accepted: April 11, 2017 Published: April 29, 2017 ABSTRACT This study purported to investigate the impact of interleukin-10 (IL-10) gene 4 polymorphisms (-1082G>A, -819T>C, -592A>C and 210T>C) on peripheral blood IL-10 variation and prostate cancer (PCa) risk, with a special consideration given to various origins of between-study heterogeneity. 2 researchers independently fulfilled literature retrieval, quality assessment and information collection. Sub-grouped analyses per ethnicity, continent, design type, control source, genotyping procedure, genotype validation, age-matched status, study sample size, quality score and controls’ mean age were conducted, respectively. Total 17 unduplicated studies (patients/controls: 7561/8101) were assessable for PCa risk, and 4 unduplicated studies (1189 subjects) for peripheral blood IL-10 variation. Pooling all assessable studies identified a marginally significant association between the -1082A allele and increased PCa risk (odds ratio (OR)=1.10, 95% confidence interval [CI]: 1.00 to 1.21) (Heterogeneity I 2 =64.3%), and no significance was detected in sub-grouped analyses of this polymorphism. Contrastingly, the -592C allele was significantly associated with reduced PCa risk in both prospective (OR=0.85, 95% CI: 0.77 to 0.95) and population-based (OR=0.92, 95% CI: 0.84 to 1.00) studies (Heterogeneity I 2 =0.0% and 18.1%). Moreover, carriers of combined -592CA/CC genotypes had a significant higher level of peripheral blood IL-10 than the -592AA genotype carriers (weighted mean difference=0.45 and 0.54 mg/dL, 95% CI: 0.23 to 0.67 and 0.30 to 0.39). The above comparisons possessed a low probability of publication bias. In sum, our findings suggested that IL-10 gene -592A>C polymorphism may represent a promising candidate locus for the occurrence of PCa, and further signified a contributing role of this polymorphism in prostate carcinogenesis.

// Fang Liu 1, 2, * , Yuan Zhang 1, * , Tingting Men 1 , Xingyue Jiang 2 , Chunhua Yang 1 , He Li 4 , Xiaodan Wei 1 , Dong Yan 1 , Gangming Feng 5 , Jianke Yang 1 , Jonas Bergquist 3 , Bin Wang 2 , Wenguo Jiang 1 , Jia Mi 1, 3 , Geng Tian 1 1 Medicine and Pharmacy Research Center, Binzhou Medical University, Yantai, Shandong Province, 264003 China 2 Department of Radiology, Affiliated Hospital of Binzhou Medical University, Binzhou, Shandong Province, 256603 China 3 Department of Chemistry – BMC, Uppsala University, Uppsala, 75124, Sweden 4 Department of Gastric and Intestine, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, Shandong Province, 264003 China 5 Yantai Institute, China Agriculture University, Yantai, Shandong Province, 264670 China * Shared first author Correspondence to: Geng Tian, email: Tiangeng@live.se Wenguo Jiang, email: jiangwg@foxmail.com Jia Mi, email: jia.mi@kemi.uu.se Keywords: proteomic, PDGF-B, gastric cancer, PRDX5, pathway Received: December 02, 2016 Accepted: February 07, 2017 Published: March 06, 2017 ABSTRACT Gastric cancer is one of the most common cancers in Asian countries. Searching for reliable biomarkers involving the development of gastric cancer is important for clinical practice. Quantitative proteomics has become an important method contributed to the discovery of novel diagnostic or therapeutic targets for the management of cancer. Here, we identified differently expressed proteins in gastric cancer and normal gastric tissues by using the high resolution mass spectrometer. Among the total of 2280 identified proteins, 87 were differentially expressed between gastric cancer and normal gastric tissues. Notably, several significant proteins are in the PDGF-B signaling pathway, including peroxiredoxin5 (PRDX5), S100A6, calreticulin (CALR) and cathepsin D (CTSD), which were validated by western blot. Furthermore, upstream regulators including PDGF-B, PDGFR-β, Akt, eIF4E and p70s6K were found significantly increased in the gastric cancer tissues. In addition, silencing of PRDX5 and PDGF-B suppressed the proliferation of gastric cancer cells in vitro . The administration of exogenous PDGF-BB recovered the reduced expression of PDGF-B signaling pathway in PDGF-B knockdown cells. Taken together, our findings suggested that PDGF-B signaling pathway plays an important role in the regulation of gastric cancer proliferation and the inhibition of this pathway may be a potential approach for treatment of gastric cancer.

// Min Li 1,* , Peiyuan Wang 2,* , Chunhua Yang 1 , Wenguo Jiang 1 , Xiaodan Wei 1 , Xinbo Mu 3 , Xuri Li 1 , Jia Mi 1 and Geng Tian 1 1 Medicine and Pharmacy Research Center, Binzhou Medical University, Yantai, Shandong, China 2 Institute of Imaging, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, Shandong, China 3 Personnel Department, Binzhou Medical University, Yantai, Shandong, China * These authors have contributed equally to this work Correspondence to: Geng Tian, email: // Jia Mi, email: // Xuri Li, email: // Keywords : hepatitis C virus; chronic kidney disease; meta-analysis; effect estimate Received : August 19, 2016 Accepted : October 14, 2016 Published : October 25, 2016 Abstract We aimed to meta-analytically assess the predisposition of hepatitis C virus (HCV) infection to the occurrence and severity of chronic kidney disease (CKD). Two authors independently searched articles and abstracted information. Odds ratio (OR) or hazard ratio (HR) along with 95% confidence interval (CI) was converged separately in 12 longitudinal (1,972,044 subjects) and 15 cross-sectional (937,607 subjects) studies. Overall effect estimate was remarkably significant in longitudinal studies (HR, 95% CI, P : 1.45, 1.23-1.71, 95%). HCV infection was also associated with an 1.54-fold (95% CI, P : 1.27-1.87, < 0.001) increased risk of having prevalent proteinuria. In longitudinal studies with estimated glomerular filtration rate (eGFR) < 60, < 30 and < 15 ml/min/1.73m 2 , the corresponding HR was 1.39 (95% CI, P : 1.14-1.69, 0.001), 1.79 (0.91-3.51, 0.091) and 2.30 (1.26-4.19, 0.007). Further grouping the longitudinal studies by median follow-up time at 5 years revealed that the effect estimate was reinforced in long-term studies (HR, 95% CI, P : 1.86, 1.19-2.89, 0.006; I 2 =98.1%) relative to that in short-term studies (1.21, 1.03-1.43, 0.024; 92.0%). In conclusion, our findings demonstrate the significant risk of experiencing incident CKD after HCV infection, with the lower eGFR and longer HCV exposure time entailing a greater risk.

Randomization is a common technique used in clinical trials to eliminate potential bias and confounders in a patient population. Equal allocation to treatment groups is the standard due to its optimal efficiency in many cases. However, in certain scenarios, unequal allocation can improve efficiency. In superiority trials with more than two groups, the optimal randomization is not always a balanced randomization. In non-inferiority trials, additive margin with equal variance is the only instance with balanced randomization. Optimal randomization for non-inferiority trials can be far from 1:1 and can greatly improve efficiency, a fact which is commonly overlooked. A tool for sample size calculation for non-inferiority trials with additive or multiplicative margin with normal, binomial or Poisson distribution is available at http://www.statlab.wisc.edu/shiny/SSNI/.

Background Apurinic/apyrimidinic endonuclease-1 (APE1) is a rate-limiting enzyme in DNA base excision repair and has been implicated in carcinogenesis. In this study, we summarize available data to examine the susceptibility of APE1 gene Asp148Glu variant to digestive cancer via a meta-analysis. Material/Methods Study selection and data abstraction were conducted independently by 2 authors. Random-effects model was utilized to pool effect estimates. Heterogeneity and publication bias were addressed. Results Sixteen articles involving 4916 digestive cancer patients and 7748 controls were qualified for this meta-analysis. Overall association showed an indicative association between Asp148Glu variant and digestive cancer under allelic (odds ratio or OR=1.11; 95% confidence interval or CI: 0.99–1.25; P=0.074) and dominant (OR=1.18; 95% CI: 1.00–1.40; P=0.056) models, with strong evidence of heterogeneity. Deviation from Hardy-Weinberg equilibrium was an obvious source of heterogeneity. In subgroup analyses by cancer sites, this variant was significantly associated with the increased risk for hepatocellular cancer under allelic (OR=1.50; 95% CI: 1.25–1.80; P

// Dan Wang 1,* , Xiaoying Qi 1 , Fang Liu 1,* , Chuanhua Yang 1 , Wenguo Jiang 1 , Xiaodan Wei 1 , Xuri Li 1 , Jia Mi 1 and Geng Tian 1 1 Medicine and Pharmacy Research Center, Binzhou Medical University, Yantai, Shandong, China * The first two authors have contributed equally to this work Correspondence to: Geng Tian, email: // Jia Mi, email: // Xuri Li, email: // Keywords : hepatocellular carcinoma; HMGB1/RAGE axis; polymorphism; genetic susceptibility; haplotype Received : December 22, 2016 Accepted : January 25, 2017 Published : February 08, 2017 Abstract Based on 540 hepatocellular carcinoma patients and 540 age- and gender-matched controls, we tested the hypothesis that high mobility group protein box1 ( HMGB1 ) and the receptor for advanced glycation end products ( RAGE ) genes are two potential candidate susceptibility genes for hepatocellular carcinoma in a multicenter hospital-based case-control analysis. The genotypes of seven widely-studied polymorphisms were determined, and their distributions respected the Hardy-Weinberg equilibrium. The mutant alleles of two polymorphisms, rs1045411 in HMGB1 gene and rs2070600 in RAGE gene, had significantly higher frequencies in patients than in controls ( P < 0.001), with the power to detect this significance of being over 99.9%. Moreover, the above two polymorphisms increased the risk of developing hepatocellular carcinoma significantly, particularly for rs2070600 under the additive (odds ratio [OR] = 1.77; 95% confidence interval [CI]: 1.34-2.32; P < 0.001) and dominant (OR = 1.75; 95% CI: 1.23-2.50; P = 0.002) models after adjusting for body mass index, smoking and drinking. Haplotype analysis showed that the T-C-T haplotype (rs1045411-rs2249825-rs1415125) in HMGB1 gene was associated with a 2.47-fold (95% CI: 1.41-4.34; P = 0.002) increased risk of hepatocellular carcinoma compared with the commonest C-C-T haplotype after adjustment. In RAGE gene, the T-T-A-G (rs1800625-rs1800624-rs2070600-rs184003) (adjusted OR; 95% CI; P: 1.75; 1.02-3.03; 0.045) and T-T-A-T (adjusted OR; 95% CI; P: 1.95; 1.01-3.76; 0.048) haplotypes were associated with a marginally increased risk of hepatocellular carcinoma compared with the commonest T-T-G-G haplotype. In summary, we identified two risk-associated polymorphisms (rs1045411 and rs2070600), and more importantly a joint impact of seven polymorphisms from the HMGB1/RAGE axis in susceptibility to hepatocellular carcinoma.

Interleukin-6 (IL-6) plays a contributory role in the progression and severity of many forms of cancer; it however remains unclear whether the relevance between circulating IL-6 and cancer is causal. We therefore meta-analyzed published articles in this regard using IL-6 gene -174G/C variant as an instrument. Seventy-eight and six articles were eligible for the association of -174G/C variant with cancer and circulating IL-6, respectively. Overall analyses failed to identify any significance between -174G/C and cancer risk. In Asians, carriers of the -174CC genotype had an 1.95-fold increased cancer risk compared with the -174GG genotype carriers (P = 0.009). By cancer type, significance was only attained for liver cancer with the -174C allele conferring a reduced risk under allelic (odds ratio or OR = 0.74; P = 0.001), homozygous genotypic (OR = 0.59; P = 0.029) and dominant (OR = 0.67; P = 0.004) models. Carriers of the -174CC genotype (weighted mean difference or WMD = −4.23 pg/mL; P

We summarized published data on the associations of apolipoprotein E (APOE) gene ε2/ε3/ε4 polymorphism with both cancer risk and circulating lipid profiles, aiming to examine the causal relevance between lipids and cancer risk. Article identification and data abstraction were conducted in duplicate and independently by two authors. Data were analyzed by STATA software. Twenty-five articles that examined the associations of APOE gene ε2/ε3/ε4 polymorphism with either cancer risk (n = 22) or circulating lipid changes (n = 4) were eligible. The presence of ε2 and ε4 alleles showed no overall associations with overall cancer risk when compared with ε3 allele. The ε4 allele was significantly associated with 1.40-fold (odds ratio or OR = 1.40; 95% confidence interval or CI: 1.00–1.94; P = 0.047) increased risk of developing cancer in Asian populations and the presence of heterogeneity was low (I2 = 37.6%). Carriers of ε3/ε4 genotype had a significant reduction in circulating HDL-C (WMD = −2.62; 95% CI: −4.19 to −1.04; P = 0.001) without heterogeneity (I2 = 16.6%). The predicted odds of having cancer for 1 mg/dL reduction in circulating HDL-C was 1.14 (95% CI: 1.00 to 1.89). The findings of this Mendelian randomization meta-analysis demonstrate that reduced circulating HDL-C might be a potentially causal risk factor for the development of overall cancer in Asians.

Background The severity of ischemic stroke symptoms varies among patients and is a critical determinant of patient outcome. To date, the association between the number of stenotic intracranial arteries and stroke severity remains unclear. Aims We aimed to investigate the association between the number of stenotic major intracranial arteries (NSMIA) and ischemic stroke severity, as well as the degree of stenosis and common stroke risk factors. Methods We performed a retrospective analysis of patients with digital subtraction angiography (DSA)-confirmed ischemic stroke. Clinical stroke severity was measured using the National Institutes of Health Stroke Scale (NIHSS). The number of stenotic vessels was counted from the internal carotid arteries and vertebral arteries, bilaterally. Results Eighty three patients were recruited from a single center and included in the study. NSMIA was significantly correlated with stroke severity (Pearson Correlation Coefficient = 0.485, P < 0.001), but not with the degree of stenosis (Pearson Correlation Coefficient = 0.01, P = 0.90). Multivariate regression analysis revealed that NSMIA was significantly associated with the NIHSS score after adjusting for stroke risk factors. The adjusted odds ratio (per lateral) was 2.092 (95% CI, 0.865 to 3.308, P = 0.001). The degree of stenosis was also significantly associated with the NIHSS score after adjusting for common risk factors. The odds ratio (per 10%) was 0.712 (95% CI, 0.202 to 1.223, P = 0.007). Conclusions The number of stenotic intracranial major arteries is associated with the severity of ischemic stroke independent of the degree of stenosis and other stroke risk factors. To the best of our knowledge, this has not been previosuly studied in great detail using DSA. Our data highlight the importance of examining all major arteries in stroke patients.

Densitometry centers commonly request patients abstain from ingesting calcium supplements prior to dual-energy X-ray absorptiometry (DXA) examination to avoid interference with bone mineral density (BMD) measurement. However, it is not clear that this practice is necessary. This study assessed the impact of recent calcium supplement intake on lumbar spine BMD measurement. The phase 1 experiment demonstrated BMD differences when placing a supplement over various areas of two encapsulated phantoms. To determine whether these results were clinically relevant, the phase 2 study enrolled 36 subjects who received spine scans before and after random assignment to ingest one Citracal, OsCal or People's Choice tablet providing 315, 500, and 600 mg of elemental calcium, respectively. The phase 3 study evaluated 15 subjects that had three spine scans with repositioning between to establish BMD precision, and then ingested a calcium carbonate tablet. Post-dosing scans were performed 15 and 30 minutes after tablet ingestion. The difference in L1-L4 BMD on subsequent scans was compared with the study derived least significant change (LSC) of 0.028 g/cm(2). In phase 2, L1-L4 BMD changes outside the LSC occurred in 36% of subjects with 47% having visualized tablets. Similarly, 33% of the phase 3 subjects demonstrated changes outside the LSC after calcium ingestion and 53% of the subjects in phase 3 had tablets visualized. Visualization of calcium tablets was not associated with BMD changes. In conclusion, calcium tablet intake may affect measured L1-L4 BMD within 30 minutes of ingestion. As such, it is appropriate to request patients abstain from calcium tablet ingestion prior to a spine DXA examination.