Search

The tumor microenvironment induces immunosuppression via recruiting and expanding suppressive immune cells such as regulatory T cells (Treg) to promote cancer progression. In this study, we documented that tumor-infiltrating CD73+ γδTregs were the predominant Tregs in human breast cancer and exerted more potent immunosuppressive activity than CD4+ or CD8+ Tregs. We further demonstrated that cancer-associated fibroblast (CAF)–derived IL6, rather than TGFβ1, induced CD73+ γδTreg differentiation from paired normal breast tissues via the IL6/STAT3 pathway to produce more adenosine and become potent immunosuppressive T cells. CD73+ γδTregs could in turn promote IL6 secretion by CAFs through adenosine/A2BR/p38MAPK signaling, thereby forming an IL6–adenosine positive feedback loop. CD73+ γδTreg infiltration also impaired the tumoricidal functions of CD8+ T cells and significantly correlated with worse prognosis of patients. The data indicate that the IL6–adenosine loop between CD73+ γδTregs and CAFs is important to promote immunosuppression and tumor progression in human breast cancer, which may be critical for tumor immunotherapy.

Supplemental Figures 1-12 and Supplementary Tables 1-3

In this paper, an approach to solve the normal contact forces of viscoelastic particles with the finite element method is presented. A viscoelastic constitutive model is deduced and established for the finite element solution, where the stress tensors of the Zener-type model expressed as partial differential equations are obtained by applying the generalized Hooke’s law, and the incremental equations are further deduced with the backward difference method. An iterative matrix of the viscoelastic constitutive model that depends on the current strain, current stress and strain increment is derived; a user material subroutine is programed based on the iterative matrix to implement the viscoelastic constitutive model in the displacement-based finite element modeling. The validity of the finite element solution to the normal contact forces of elastic particles is validated with the Hertz contact force model, and that of the solution to the normal contact forces of viscoelastic particles is verified by the experimental data. The results obtained by the proposed solution agree well with those predicted by the Prony series, and the computational efficiency of this solution is higher for different values of the shear viscosity.

The increased diversity of microstructure of nanoporous materials can be expected to greatly expand their functional application in more industries. By incorporating nanoporous metals into cold-welding technology, we report an approach to directly forming the nanoporous materials with various microstructure inside. Nanoporous gold (Au) with ideal bi-continuous nanoporous structures was modeled using spinodal decomposition. Understanding the mechanical properties is the primary step to improve the reliability on the operational performance of nanoporous structures. After the process of cold-welding manufacture, the well-interconnected nanoporous Au was successfully fabricated and the mechanical properties of cold-welded structures were studied. Molecular dynamic simulations on samples with ligament diameter ranging from 3.264 to 6.528 nm and relative density ranging from 0.30 to 0.45 were also carried out to study how these factors affect the assembly process. These results are believed to facilitate the bottom-up nanofabrication and nanoassembly of composite structures for better mechanical performance.

Integrating a polymer into the nanoporous metals (NPMs) could efficiently reduce the density change during plastic flow with better ductilization, which widens great potential applications of nanocomposites . In this work, a finite element model of stochastic bicontinuous nanoporous structure is generated for the first time. A nanocomposite material is generated by fitting a polymer into the pore space of NPMs, and the mechanical behaviors of the composite of nanoporous gold (npg) and epoxy under uniaxial compression are investigated via finite element analysis . Results show that the stress is mainly concentrated at the ligament necks rather than junctions of the npg constitute phase and the epoxy constitute phase during deformation. In analogy to npg, the Young’s modulus of npg-epoxy composite as a function of metal volume fraction displays a power-law relation and the yield stress has an approximately linear relation. It is worth noticing that the Young’s modulus and the yield stress of nanocomposite exceeds that of each of its constituent phases and are higher than the sum of two pure phases. The present study provides new insights into the mechanical behaviors of npg-epoxy composite, as well as a practical guide for designing a new class of strong and ductile nanocomposites.

BackgroundSystemic inflammatory response (SIR) plays important roles in initiation, promotion and progression of tumor. However, the prognostic role of baseline circulating platelet–to–lymphocyte ratio (PLR) (known as a marker of SIR) in human stage Ⅳ gastric cancer (GC) remains controversial. Hence, we performed this meta-analysis to assess the value of it in prognosis prediction for stage Ⅳ GC patients. MethodsWe searched PubMed, Embase and EBSCO to identify the studies and computed extracted data with STATA 12.0. ResultsA total of 2721 patients with stage Ⅳ GC from 12 published studies were incorporated into this meta-analysis. We found that elevated baseline circulating PLR was significantly associated with decreased overall survival (OS), but not with progression–free survival (PFS) in stage Ⅳ GC patients. However, in stratified analyses, high PLR was remarkably associated with worse 1-year OS, but not with 2-year, 3-year, 4-year or 5-year OS; In addition, it was considerably related with reduced 6-month PFS, but not with 1-year or 2-year PFS. Moreover, high PLR markedly correlated with peritoneal metastasis of patients. Conclusionelevated baseline circulating PLR decreased 1-year OS and 6-month PFS in stage Ⅳ GC patients, implicating that it is a valuable prognostic index for these patients and modifying the inflammatory responses may have a potential for effective treatment.

Fibroblasts are a highly heterogeneous population in tumor microenvironment. PDGFR-β+ fibroblasts, a subpopulation of activated fibroblasts, have proven to correlate with cancer progression through multiple of mechanisms including inducing angiogenesis and immune evasion. However, the prognostic role of these cells in solid tumors is still not conclusive. Herein, we carried out a meta-analysis including 24 published studies with 6752 patients searched from PubMed, Embase and EBSCO to better comprehend the value of such subpopulation in prognosis prediction for solid tumors. We noted that elevated density of intratumoral PDGFR-β+ fibroblasts was remarkably associated with worse overall survival (OS) and disease-free survival (DFS) of patients. In subgroup analyses, the data showed that PDGFR-β+ fibroblast infiltration considerably decreased OS in non-small cell lung cancer (NSCLC), breast and pancreatic cancer, and reduced DFS in breast cancer. In addition, increased number of PDGFR-β+ fibroblasts appreciably correlated with advanced TNM stage of patients. In conclusion, PDGFR-β+ fibroblast infiltration deteriorates survival in human solid tumors especially in NSCLC, breast and pancreatic cancer. Hence, they may offer a practicable prognostic biomarker and a potential therapeutic strategy for these patients.

Background Activated eosinophils have been deemed to affect carcinogenesis and tumor progression via various mechanisms in tumor microenvironment. However, the prognostic role of tumor-associated tissue eosinophilia (TATE) in human cancers remains controversial. Therefore, we conducted this meta-analysis to better comprehend the association between TATE and clinical outcomes of patients. Methods We searched PubMed, Embase and EBSCO to determine the researches assessing the association between TATE and overall survival (OS) and/or disease-free survival (DFS) in patients with cancer, then combined relevant data into hazard ratios (HRs) or odds ratio (OR) for OS, DFS and clinicopathological features including lymph node metastasis etc. with STATA 12.0. Results Twenty six researches with 6384 patients were included in this meta-analysis. We found that the presence of TATE was significantly associated with improved OS, but not with DFS in all types of cancers. In stratified analyses based on cancer types, pooled results manifested that the infiltration of eosinophils was remarkably associated with better OS in esophageal carcinoma and colorectal cancer. In addition, TATE significantly inversely correlated with lymph node metastasis, tumor stage and lymphatic invasion of cancer. Conclusion TATE promotes survival in cancer patients, suggesting that it is a valuable prognostic biomarker and clinical application of biological response modifiers or agonists promoting TATE may be the novel therapeutic strategy for patients.

Additional file 1: Figure S1. Flow chart diagram of study selection. Figure S2. Plots describing the influence of individual studies on the overall HRs for OS (A) and DFS (B) in human cancers. Figure S3. Funnel plots displayed the potential publication bias between TATE and OS (A) or DFS (B) in patients. Table S1. Characteristics of the included studies for OR analysis of clinicopathological features.

Guoming Hu,1 Kefang Zhong,1 Wei Chen,1 Shimin Wang,2 Liming Huang1 1Department of General Surgery (Breast and Thyroid Surgery), 2Department of Nephrology, Shaoxing People’s Hospital (Shaoxing Hospital, Zhejiang University School of Medicine), Zhejiang, China Background: Cancer-associated fibroblasts (CAFs) are a heterogeneous population, and different subpopulations play differential roles in tumor microenvironment. However, the prognostic role of podoplanin-positive CAFs in human lung cancer still remains controversial. Methods: Herein, we performed a meta-analysis including 12 published studies with 1,802 patients identified from PubMed and EBSCO to assess the prognostic impact of podoplanin-positive CAFs in lung cancer patients. Results: We found that podoplanin+ fibroblast infiltration significantly decreased overall survival (OS), disease-free survival (DFS), and progression-free survival in patients. In stratified analyses, podoplanin+ fibroblast infiltration was significantly associated with worse OS and DFS in both squamous cell carcinoma and adenocarcinoma of lung. In addition, high density of podoplanin-positive CAFs significantly correlated with unfavorable clinicopathological features such as lymph node metastasis, and lymphatic, vascular, and pleural invasion of patients. Conclusion: Podoplanin+ fibroblast infiltration leads to worse clinical outcome in lung cancer patients, implicating that it is a valuable prognostic biomarker and targeting it may have a potential for effective treatment. Keywords: podoplanin-positive cancer-associated fibroblasts, worse outcome, lung cancer, meta-analysis

Purpose: Activated tumor-infiltrating fibroblasts were significantly associated with survival of cancer patients. However, they are heterogeneous population, and the prognostic role of these cells in human breast cancer still remains controversial. Herein, we performed the meta-analysis to better understand the role of these cells in prognosis prediction for breast cancer patients. Methods: We searched PubMed and EBSCO to identify the studies evaluating the association of intratumoral activated fibroblast density detected by immunohistochemical (IHC) method and overall survival (OS) and/or disease-free survival (DFS) in breast cancer patients, then computed extracted data into hazard ratios (HRs) for OS, DFS and clinicopathological features such as lymph node metastasis, TNM stage with STATA 12.0. Results: A total of 3680 patients with breast cancer from 15 published studies were incorporated into this meta-analysis. We found that the infiltration of activated fibroblasts significantly decreased overall survival (OS) and disease-free survival (DFS) in patients. In stratified analyses, high density of FSP-1+ or podoplanin+ fibroblasts was significantly associated with worse OS; while α-SMA+ or podoplanin+ fibroblast infiltration was associated with worse DFS in breast cancer. In addition, elevated number of activated tumor-infiltrating fibroblasts significantly correlated with lymph node metastasis and poor tumor differentiation of patients. Conclusion: The infiltration of activated fibroblasts, especially the FSP-1+ or podoplanin+ fibroblasts leads to worse clinical outcome in breast cancer patients, implicating that it is a valuable prognostic biomarker and targeting it may have a potential for effective treatment.

The prognostic role of tumor-infiltrating tryptase+ mast cells in human solid tumors remains controversial. Herein, we conducted a meta-analysis including 28 published studies with 4224 patients identified from PubMed and EBSCO to assess the prognostic impact of tumor-infiltrating tryptase+ mast cells in human solid tumors. We found that tryptase+ mast cell infiltration significantly decreased overall survival (OS) and disease-free survival (DFS) in all types of solid tumors. In stratified analyses, tryptase+ mast cell infiltration was significantly associated with worse OS in non-small cell lung cancer, hepatocellular carcinoma and 5-year survival in colorectal cancer. And these cells were inversely associated with DFS in hepatocellular and colorectal cancer. In addition, high density of intratumoral tryptase+ mast cells significantly correlated with lymph node metastasis of solid tumor. In conclusion, Tryptase+ mast cell infiltration leads to an unfavorable clinical outcome in solid tumors, implicating that it is a valuable biomarker for prognostic prediction for human solid malignances and targeting it may have a potential for effective treatment.

Lobular carcinoma in situ (LCIS) represents 5.3% of in situ specimens, and is thought to carry a low risk for developing to the invasive lobular breast cancer (ILC). There is still no standard care approach for patients with LCIS. We aimed to define the impacts of surgical and radiation intervention on survival outcomes of LCIS. LCIS cases from 2004 to 2013 of the recent Surveillance, Epidemiology, and End Results (SEER) database were analyzed. Clinicopathologic features were analyzed in 16002 patients between 2004 and 2013. Treatment modalities included no surgery (NS), lumpectomy alone (LA), lumpectomy with radiation treatment (LRT), mastectomy alone (MA) and mastectomy with radiation treatment (MRT). The overall survival (OS) was calculated by the Kaplan-Meier method. Univariate and multivariate analyses were performed using the variables of treatment, race, hormone receptor status, grade and age. Among 16002 patients, median follow-up was 54 months. Patients treated with LA had superior OS for NS (P = 0.001), MA (P < 0.001) and MRT P = 0.018). LRT only had superior OS for MRT (P = 0.009). There was no statistically significance between LA and LRT (P = 0.317). Improved OS was also correlated with younger age (P < 0.001), progesterone receptor positive (P = 0.001). Black patients had the worst OS (P < 0.001). There was no obvious survival difference among grade groups (P = 0.536). The LCIS patients treated with LA or LRT had better survival comparing with other groups. Considering the medical expense and the risk of radiotherapy, LA may be the most appropriate therapy for patients with LCIS.

The prognostic role of tumor-infiltrating CD45RO+ memory T lymphocytes (CD45RO+ T cells) in human solid tumors remains controversial. Herein, we conducted a meta-analysis including 25 published studies with 4720 patients identified from PubMed and EBSCO to assess the prognostic impact of tumor-infiltrating CD45RO+ T cells in human solid tumors. We found that CD45RO+ T cell infiltration was significantly associated with improved overall survival (OS) and disease-free survival (DFS) in all types of solid tumors. In stratified analyses, CD45RO+ T cell infiltration significantly improved 1-year, 3-year and 5-year OS in colorectal, gastric and esophageal cancer, but only 5-year OS in hepatocellular carcinoma. And these cells were positively associated with 1-year, 3-year and 5-year DFS in hepatocellular, colorectal and esophageal cancer. In addition, high density of intratumoral CD45RO+ T cells inversely correlated with TNM stage of solid tumor. In conclusion, CD45RO+ memory T lymphocyte infiltration leads to a favorable clinical outcome in solid tumors, implicating that it is a valuable biomarker for prognostic prediction for human solid malignances.

FoxP3+ regulatory T cells (FoxP3+ Tregs) are considered to be a key mediator in immune escape and tumor progression. However, the role of FoxP3+ Tregs in human colorectal cancer (CRC) remains controversial. Herein, we conducted a meta-analysis including 17 published studies with 3811 patients identified from PubMed and EBSCO to assess the prognostic impact of tumor-infiltrating FoxP3+ Tregs in human CRC. We found FoxP3+ Tregs infiltrating into both intraepithelium and stroma within tumor were significantly positively correlated with 1, 3, 5 and 10-year overall survival (OS), but not with 1, 3, 5-year disease-free survival (DFS) of patients. Interestingly, in stratified analyses by compartments within tumor FoxP3+ Tregs infiltrating into, FoxP3+ Tregs invading stromal compartment significantly improved 3 and 5-year OS, yet OS wasn't improved when FoxP3+ Tregs infiltrated into intraepithelium only. Furthermore, FoxP3+ Tregs invading both intraepithelium and stroma significantly inversely correlated with TNM stage of CRC. In conclusion, High density of FoxP3+ Tregs within tumor especially at stromal compartment leads to a favorable outcome in CRC, implicating FoxP3+ Tregs are one of valuable indexes for prognostic prediction in human CRC.

Background: Activated eosinophils have been deemed to affect carcinogenesis and tumor progression via various mechanisms in tumor microenvironment. However, the prognostic role of tumor-associated tissue eosinophilia (TATE) in human cancers still remains controversial. Therefore, we performed the meta-analysis to better understand the role of TATE in prognosis prediction for cancer patients. Methods: We searched PubMed and EBSCO to identify the studies evaluating the association of TATE and overall survival (OS) and/or disease-free survival (DFS) in cancer patients, then computed extracted data into hazard ratios (HRs) for OS, DFS and clinicopathological features such as lymph node metastasis etc with STATA 12.0. Results: A total of 6125 patients from 25 published studies were incorporated into this meta-analysis. We found that the presence of TATE significantly improved OS and 5-year DFS in all types of cancers. In stratified analyses based on cancer types, pooled results indicated that eosinophils infiltrating into tumor tissue was significantly associated with better OS in oral cancer, esophageal carcinoma and colorectal cancer. In addition, TATE was significantly inversely correlated with lymph node metastasis, tumor stage and lymphatic invasion of cancer. Conclusion: TATE leads to a favorable clinical outcome in cancer patients, implicating that it is a valuable biomarker for prognostic prediction for human cancers and clinical application of biological response modifiers or agonists promoting TATE may be the novel therapeutic strategy for patients.

Using the finite element analysis, we investigate the shock response, deformation behavior and energy–absorbing characteristics of stochastic bicontinuous nanoporous gold computationally, considering the effects of impact speed and relative density of materials. Three deformation modes during shocking, quasi–static compression, transition state and dynamic compression, are observed with the increasing impact speeds and the corresponding internal deformation mechanisms are demonstrated. The shock response under low–speed loading is similar to the R–LHP–L materials model, and it is more inclined to the R–S–H model as the impact speed rises. The peak stress, plateau stress, densification strain, energy, specific energy absorption (per unit volume) are assessed quantitatively. The peak stress shows a monotonous increase with impact speed, due to the enhanced inertial effect. The plateau stress and energy–absorbing efficiency are insensitive to low impact velocity, but significantly enhanced under high–speed loading. Remarkably, the results show that the energy absorption efficiency of nanoporous gold is better than conventional foam materials and nanofluidic energy absorption and dissipation system. The research not only further clarifies the shock responses and associated mechanisms of NPG, but also promotes its industrial application as an energy–absorbing material.

Zhen Wang,1 Pin Wu,1,2 Dang Wu,1 Zhigang Zhang,3 Guoming Hu,1 Shuai Zhao,1 Yucheng Lai,1 Jian Huang1,41Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, Key Laboratory of Molecular Biology in Medical Sciences, China National Ministry of Education, 2Department of Thoracic Surgery, 3Department of Gynecology, 4Department of Surgical Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, People’s Republic of ChinaPurpose: Interleukin-6 (IL-6) plays an important role in human colorectal cancer (CRC) development. However, the exact clinical and prognostic significance of IL-6 in CRC is still unclear. Here, we conducted this meta-analysis to explore this issue in detail.Methods: A meta-analysis was performed to clarify the association between serum IL-6 expression and clinical outcomes in articles published up to June 2015. Weighted mean difference (WMD) and its corresponding 95% confidence interval (CI) were used to assess the association between serum IL-6 expression and the clinicopathological characteristics of CRC. Hazard ratio (HR) with 95% CI was used to quantify the predictive value of IL-6 on CRC prognosis.Results: Fourteen studies comprising 1,245 patients were included. Analysis of these data showed that serum IL-6 expression was highly correlated with poor 5-year overall survival (OS) rate (HR =0.43, 95% CI: 0.31–0.59, P=0.755). Simultaneously, we also found that serum IL-6 expression was associated with certain clinical parameters of CRC, such as tumor invasion (T category: T0–T2, T3–T4) (WMD =3.15, 95% CI: 1.92–4.39, P=0.816), distant metastasis (M category: M0, M1) (WMD =4.69, 95% CI: 3.33–6.06, P=0.377), and tumor stage (I–II, III–IV) (WMD =2.65, 95% CI: 1.09–4.21, P=0.066).Conclusion: A high serum IL-6 expression is associated with adverse OS in CRC. The IL-6 expression can be an important supplement in establishing prognostic score for clinical decision.Keywords: interleukin-6, colorectal cancer, prognosis, meta-analysis

Background/Aims: Tumor-infiltrating fibroblasts are a heterogeneous population, and different subpopulations play differential roles in tumor microenvironment. However, the prognostic role of podoplanin+ fibroblasts in human solid tumors still remains controversial. Therefore, we performed the meta-analysis to better understand the role of this subpopulation in prognosis prediction for patients with solid tumor. Methods: We searched PubMed and EBSCO to identify the studies evaluating the association of intratumoral podoplanin+ fibroblast density detected by immunohistochemical method and overall survival (OS) and/or disease-free survival (DFS) in patients with solid tumor, then computed extracted data into hazard ratios for OS, DFS and clinicopathological features with STATA 12.0. Results: A total of 4883 patients from 29 published studies were incorporated into this meta-analysis. We found that podoplanin+ fibroblast infiltration significantly decreased OS and DFS in all types of solid tumors. In stratified analyses, podoplanin+ fibroblast infiltration was significantly associated with worse OS in cholangiocarcinoma, breast, lung and pancreatic cancer. And these cells were inversely associated with DFS in breast, lung and pancreatic cancer. In addition, high density of these cells significantly correlated with unfavorable clinicopathological features such as lymph node metastasis, TNM stage, lymphatic and vascular invasion of solid tumor. Conclusion: Podoplanin+ fibroblast infiltration leads to worse clinical outcome in solid tumors, implicating that it is a valuable prognostic biomarker and targeting it may have a potential for effective treatment.

The prognostic role of tumor-infiltrating CD57-positive lymphocytes (CD57+ lymphocytes) in human solid tumors remains controversial. Herein, we conducted a meta-analysis including 26 published studies with 7656 patients identified from PubMed and EBSCO to assess the prognostic impact of tumor-infiltrating CD57+ lymphocytes in human solid tumors. We found that CD57+ lymphocyte infiltration significantly improved overall survival (OS) including 1 - year, 3 - year and 5 - year survival, and disease - free survival (DFS) in all types of solid tumors. In stratified analyses, CD57+ lymphocyte infiltration was significantly associated with better OS in hepatocellular, esophageal, head and neck carcinoma, non-small cell lung cancer, 5 - year survival in colorectal cancer, and 3 - year and 5 - year survival in gastric cancer, but not with 1 - year survival in gastric cancer, or 1 - year or 3 - year survival in colorectal cancer. In addition, high density of intratumoral CD57+ lymphocytes was significantly inversely correlated with lymph node metastasis and TNM stage of solid tumor. In conclusion, CD57+ lymphocyte infiltration leads to a favorable clinical outcome in solid tumors, implicating that it is a useful biomarker for prognosis and adoptive immunotherapy based on these cells may be a promising choice for treatment.

Breast cancer is a heterogeneous group of diseases with diverse clinicopathological and molecular features. At present, chemo-resistance still poses a major obstacle to successful treatment of HER-2 negative breast cancer. Reliable biomarkers are urgently needed to accurately predict the therapeutic sensitivity and prognosis of such patients. In this study, we identified 3145 distant relapse-free survival (DRFS) associated genes in 310 patients with HER-2 negative breast cancer receiving taxane and anthracycline-based chemotherapy in the GSE25055 dataset using univariate survival analysis. Four genes (SRPK1, PCCA, PRLR and FBP1) were further selected by a robust likelihood-based survival model. A risk score model was then constructed with the regression coefficients of the four signature genes. Patients in the training set were successfully divided into high- and low-risk groups with significant differences in DRFS between the two groups. The predictive value was further validated in GSE25065 dataset and similar results were observed. Moreover, the 4-gene signature was proved to have superior prognostic power compared with several clinical signatures such as tumor size, lymph node invasion, TNM stage and PAM50 signature. Our findings indicated that the 4-gene signature was a robust prognostic marker with a good prospect of clinical application for HER-2 negative breast cancer patients receiving taxane-anthracycline combination therapy.

The prognostic role of tumor-infiltrating CD45RO+ memory T lymphocytes (CD45RO+ T cells) in human solid tumors remains controversial. Herein, we conducted a meta-analysis including 25 published studies with 4720 patients identified from PubMed and EBSCO to assess the prognostic impact of tumor-infiltrating CD45RO+ T cells in human solid tumors. We found that CD45RO+ T cell infiltration was significantly associated with improved overall survival (OS) and disease-free survival (DFS) in all types of solid tumors. In stratified analyses, CD45RO+ T cell infiltration significantly improved 1-year, 3-year and 5-year OS in colorectal, gastric and esophageal cancer, but only 5-year OS in hepatocellular carcinoma. And these cells were positively associated with 1-year, 3-year and 5-year DFS in hepatocellular, colorectal and esophageal cancer. In addition, high density of intratumoral CD45RO+ T cells inversely correlated with TNM stage of solid tumor. In conclusion, CD45RO+ memory T lymphocyte infiltration leads to a favorable clinical outcome in solid tumors, implicating that it is a valuable biomarker for prognostic prediction for human solid malignances.

// Shimin Wang 1 , Zhi’an Li 2 and Guoming Hu 3 1 Department of Nephrology, Shaoxing People’s Hospital, Shaoxing Hospital of Zhejiang University, 312000, Zhejiang, China 2 Department of Surgical Oncology, Shaoxing Second Hospital, 312000, Zhejiang, China 3 Department of General Surgery, Breast and Thyroid Surgery, Shaoxing People’s Hospital, Shaoxing Hospital of Zhejiang University, 312000, Zhejiang, China Correspondence to: Guoming Hu, email: hgmplj@126.com Keywords: intratumoral IL-17A overexpression, immunohistochemistry, worse outcome, solid tumor, meta-analysis Received: February 06, 2017 Accepted: May 20, 2017 Published: June 29, 2017 ABSTRACT IL-17A is an important proinflammatory cytokine which is frequently elevated in tumor microenvironment. However, the role of intratumoral IL-17A in solid tumors remains controversial. Herein, we conducted a meta-analysis to assess the prognostic impact of intratumoral IL-17A in patients with solid tumor. PubMed and EBSCO were searched to identify the studies evaluating the associations between intratumoral IL-17A measured by immunohistochemistry (IHC) and overall survival (OS) and disease-free survival (DFS) in solid tumors. A total of 2972 patients with solid tumor from 21 published studies were incorporated into this meta-analysis. We found that high level of intratumoral IL-17A was significantly associated with worse 3-year, 5-year OS and 1-year, 3-year DFS, but not with 1-year OS or 5-year DFS in solid tumors. In addition, in stratified analyses by cancer types, IL-17A overexpression was significantly associated with worse OS in hepatic carcinoma, but with improved OS in esophageal squamous cell carcinoma (ESCC). Furthermore, high IL-17A expression positively correlated with advanced TNM stage. In conclusion, High expression of intratumoral IL-17A leads to an unfavorable clinical outcome in majority of solid tumors, implicating IL-17A is a valuable biomarker for prognostic prediction of human solid malignances and targeting it may have a potential for effective treatment.

SummaryDevelopment of cancer has been linked to chronic inflammation, particularly via interleukin-23 (IL-23) and IL-17 signaling pathways. However, the cellular source of IL-17 and underlying mechanisms by which IL-17-producing cells promote human colorectal cancer (CRC) remain poorly defined. Here, we demonstrate that innate γδT (γδT17) cells are the major cellular source of IL-17 in human CRC. Microbial products elicited by tumorous epithelial barrier disruption correlated with inflammatory dendritic cell (inf-DC) accumulation and γδT17 polarization in human tumors. Activated inf-DCs induced γδT17 cells to secrete IL-8, tumor necrosis factor alpha, and GM-CSF with a concomitant accumulation of immunosuppressive PMN-MDSCs in the tumor. Importantly, γδT17 cell infiltration positively correlated with tumor stages and other clinicopathological features. Our study uncovers an inf-DC-γδT17-PMN-MDSC regulatory axis in human CRC that correlates MDSC-meditated immunosuppression with tumor-elicited inflammation. These findings suggest that γδT17 cells might be key players in human CRC progression and have the potential for treatment or prognosis prediction.

FoxP3+ regulatory T cells (FoxP3+ Tregs) are considered to be a key mediator in immune escape and tumor progression. However, the role of FoxP3+ Tregs in human colorectal cancer (CRC) remains controversial. Herein, we conducted a meta-analysis including 17 published studies with 3811 patients identified from PubMed and EBSCO to assess the prognostic impact of tumor-infiltrating FoxP3+ Tregs in human CRC. We found FoxP3+ Tregs infiltrating into both intraepithelium and stroma within tumor were significantly positively correlated with 1, 3, 5 and 10-year overall survival (OS), but not with 1, 3, 5-year disease-free survival (DFS) of patients. Interestingly, in stratified analyses by compartments within tumor FoxP3+ Tregs infiltrating into, FoxP3+ Tregs invading stromal compartment significantly improved 3 and 5-year OS, yet OS wasn’t improved when FoxP3+ Tregs infiltrated into intraepithelium only. Furthermore, FoxP3+ Tregs invading both intraepithelium and stroma significantly inversely correlated with TNM stage of CRC. In conclusion, High density of FoxP3+ Tregs within tumor especially at stromal compartment leads to a favorable outcome in CRC, implicating FoxP3+ Tregs are one of valuable indexes for prognostic prediction in human CRC.

Tumor microenvironment (TME) promotes immune suppression through recruiting and expanding suppressive immune cells such as regulatory T cells (Tregs) to facilitate cancer progression. In this study, we identify a novel CD39+ γδTreg in human colorectal cancer (CRC). CD39+ γδTregs are the predominant regulatory T cells and have more potent immunosuppressive activity than CD4+ or CD8+ Tregs via the adenosine-mediated pathway but independent of TGF-β or IL-10. They also secrete cytokines including IL-17A and GM-CSF, which may chemoattract myeloid-derived suppressive cells (MDSCs), thus establishing an immunosuppressive network. We further demonstrate that tumor-derived TGF-β1 induces CD39+ γδT cells from paired normal colon tissues to produce more adenosine and become potent immunosuppressive T cells. Moreover, CD39+ γδTreg infiltration is positively correlated with TNM stage and other unfavorable clinicopathological features, implicating that CD39+ γδTregs are one of the key players in establishment of immunosuppressive TME in human CRC that may be critical for tumor immunotherapy.

Background Diagnosing breast cancer during the early stage may be helpful for decreasing cancer-related mortality. In Western developed countries, mammographies have been the gold standard for breast cancer detection. However, Chinese women usually have denser and smaller-sized breasts compared to Caucasian women, which decreases the diagnostic accuracy of mammography. However, breast specific gamma imaging, a type of molecular functional breast imaging, has been used for the accurate diagnosis of breast cancer and is not influenced by breast density. Our objective was to analyze the breast specific gamma imaging (BSGI) diagnostic value for Chinese women. Methods During a 2-year period, 357 women were diagnosed and treated at our oncology department and received BSGI in addition to mammography (MMG), ultrasound (US) and magnetic resonance imaging (MRI) for diagnostic assessment. We investigated the sensitivity and specificity of each method of detection and compared the biological profiles of the four imaging methods. Results A total of 357 women received a final surgical pathology diagnosis, with 168 malignant diseases (58.5 %) and 119 benign diseases (41.5 %). Of these, 166 underwent the four imaging tests preoperatively. The sensitivity of BSGI was 80.35 and 82.14 % by US, 75.6 % by MMG, and 94.06 % by MRI. Furthermore, the breast cancer diagnosis specificity of BSGI was high (83.19 % vs. 77.31 % vs. 66.39 % vs. 67.69 %, respectively). The BSGI diagnostic sensitivity for mammographic breast density in women was superior to mammography and more sensitive for non-luminal A subtypes (luminal A vs. non-luminal A, 68.63 % vs. 88.30 %). Conclusions BSGI may help improve the ability to diagnose early stage breast cancer for Chinese women, particularly for ductal carcinoma in situ (DCIS), mammographic breast density and non-luminal A breast cancer.

A bearing is an important component in contemporary machinery and equipment, whose main function is to support the mechanical rotator, reduce the friction coefficient during its movement, and guarantee the turning accuracy. However, assembly of a nanoscale bearing and sleeve is a challenging process for micro-nano mechanical manufacturers. Hence, we show the cold-welding mechanism of a copper nanobearing-nanosleeve via molecular dynamic simulations. We demonstrate that it is feasible to assemble a bearing and sleeve at the nanoscale to form a stable mechanism. The effect of temperature in the range of 150 to 750 K is investigated. As the temperature rises, the mechanical strength and the weld stress of the welded structures markedly decrease, accompanied by the observation of increasing disorder magnitude. This comparison study is believed to facilitate future mechanical processing and structural nano-assembly of metallic elements for better mechanical performance.

The purpose of this paper is to investigate inter-tablet coating thickness variability based on different tablet shapes and filling levels. To achieve this goal, the Discrete Element Method (DEM) is applied, and efforts are made as following: For the first step, four different tablet shapes, referred to as Sphere, SRC (Standard Round Concave), Oval and Triangular, are built by importing three (except Sphere) CAD templates to create one or more spherical surfaces. Furthermore, a spray zone in the coating pan is presented to monitor the change of the “coating mass”, by virtue of which we calculate the inter-tablet coating variability. And to complete this work, custom contact models and properties are created to describe coating. Then, three different filling levels are added to the simulation. Eventually, the compared results are analyzed between three diverse filling degrees among tablet particles with four discrepant shapes.

Tumor microenvironment (TME) promotes immune suppression through recruiting and expanding suppressive immune cells such as regulatory T cells (Tregs) to facilitate cancer progression. In this study, we identify a novel CD39+ γδTreg in human colorectal cancer (CRC). CD39+ γδTregs are the predominant regulatory T cells and have more potent immunosuppressive activity than CD4+ or CD8+ Tregs via the adenosine-mediated pathway but independent of TGF-β or IL-10. They also secrete cytokines including IL-17A and GM-CSF, which may chemoattract myeloid-derived suppressive cells (MDSCs), thus establishing an immunosuppressive network. We further demonstrate that tumor-derived TGF-β1 induces CD39+ γδT cells from paired normal colon tissues to produce more adenosine and become potent immunosuppressive T cells. Moreover, CD39+ γδTreg infiltration is positively correlated with TNM stage and other unfavorable clinicopathological features, implicating that CD39+ γδTregs are one of the key players in establishment of immunosuppressive TME in human CRC that may be critical for tumor immunotherapy.

Based on motion and impact analysis, a theoretical model is presented for optimization of grinding performance of a tumbling ball mill. The motion of ball media in the tumbling ball mill is analyzed. The impact parameters of the ball media caused by the falling motion are deduced. The impact and attrition grindabilities are studied. The grinding performance is expressed as the proportion of grindability of all collisions to that of the collisions of ball media in the arc of the shell at a theoretically suitable speed, and is calculated from the point of view of the separation layer. The mathematical model is established and program coding is implemented to optimize grinding performance for the tumbling ball mill. An example of design calculations is given which shows that the grinding performance under the optimized operation parameters is improved significantly.

The transportation of bulk materials is of importance in many industrial applications, ranging from minerals, agriculture, pharmaceuticals, chemicals, pigments, plastics, cement, sand, salt and food processing. Screw conveyors are widely used for transportation of particulates at controlled and steady rates. In this paper, we use the Discrete Element Method (DEM) to analyze the performance of a screw conveyor including visualization of the motion of particles, angular and axial velocity of particles, overall torque and total force, kinetic energy and total energy dissipation. The DEM model was established by applying periodic boundary conditions to a single pitch of the screw and the particles are modeled as spheres. DEM simulation shows that the nature of the particle flow in a horizontal screw conveyor is surprisingly complex and is reasonably sensitive to the operating conditions. The dependence of the performance of a screw conveyor on the operating conditions is analyzed..

Gamma delta T (γδT) cells are innate-like lymphocytes with strong, MHC-unrestricted cytotoxicity against cancer cells and show a promising prospect in adoptive cellular immunotherapy for various malignancies. However, the clinical outcome of commonly used Vγ9Vδ2 γδT (Vδ2 T) cells in adoptive immunotherapy for most solid tumors is limited. Here, we demonstrate that freshly isolated Vδ1 γδT (Vδ1 T) cells from human peripheral blood (PB) exhibit more potent cytotoxicity against adherent and sphere-forming human colon cancer cells than Vδ2 T cells in vitro. We also develop an optimized protocol to preferentially expand Vδ1 T cells isolated from PB of both healthy donors and colon cancer patients by in vitro short-term culture with phytohemagglutinin (PHA) and interleukin-7 (IL-7). Expanded Vδ1 T cells highly expressed cytotoxicity-related molecules, chemokine receptors and cytokines with enhanced cytolytic effect against adherent and sphere-forming colon cancer cells in a cell-to-cell contact dependent manner. In addition, PHA and IL-7 expanded Vδ1 T cells showed proliferation and survival advantage partly through an IL-2 signaling pathway. Furthermore, ex vivo expanded Vδ1 T cells also restrained the tumor growth and prolonged the tumor-burdened survival of human colon carcinoma xenografted mice. Our findings suggest that human PB Vδ1 T cells expanded by PHA and IL-7 are a promising candidate for anticancer adoptive immunotherapy for human solid tumors such as colon cancer.