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Diffuse large B-cell lymphoma (DLBCL) is the most common invasive type of non-Hodgkin lymphoma. Cell-of-origin (COO) classification is related to patients’ prognoses. Primary drug resistance in treatment for DLBCL has been observed. The specific serum biomarkers in these patients who suffer from relapsed and refractory (R/R)-DLBCL remains unclear. In the current study, using single-cell RNA sequencing (scRNA-seq) and mass cytometry (CyTOF), we determined and verified immune cell biomarkers at the mRNA and protein levels in single-cell resolution from 18 diagnostic PBMC specimens collected from patients with R/R DLBCL. As controls, 5 PBMC specimens from healthy volunteers were obtained. We identified a panel of 35 surface marker genes for the features of R/R DLBCL unique cell cluster by scRNA-seq of 8 R/R DLBCL patient samples and validated its efficiency in an external cohort consisting of 10 R/R DLBCL patients by CyTOF. The cell clustering and dimension reduction were compared among R/R DLBCL samples in CyTOF Space with COO as well as the C-MYC expression designation. Immune cells from each patient occupied unique regions in the 32-dimensional phenotypic space with no apparent clustering of samples into discrete subtypes. Significant heterogeneity observed in subgroups was mainly attributed to individual differences among samples and not to expression differences in a single, homogeneous immune cell subpopulation. The marker panel showed reliability in labeling R/R DLBCL without any influence from COO stratification and C-MYC expression designation. Furthermore, we compared all the markers between R/R DLBCL and normal samples. A total of 12 biomarkers were significantly overexpressed in R/R DLBCL relative to the normal samples. Therefore, we further optimized the diagnostic biomarker panel of R/R DLBCL comprising CD82, CD55, CD36, CD63, CD59, IKZF1, CD69, CD163, CD14, CD226, CD84, and CD31. In summary, we developed a novel set of biomarkers for the diagnoses of patients with R/R DLBCL. Detections procedures at single-cell resolution provide precise biomarkers, which may substantially overcome intertumoral and intratumoral heterogeneity among primary samples. The findings confirmed that each case was unique and may comprise multiple, genetically distinct subclones.

Peritoneal membrane dysfunction and the resulting ultrafiltration failure are the major disadvantages of long‐term peritoneal dialysis (PD). It becomes increasingly clear that mesothelial cells play a vital role in the pathophysiological changes of the peritoneal membrane. Matrix metalloproteinases (MMPs) function in the extracellular environment of cells and mediate extracellular matrix turnover during peritoneal membrane homeostasis. We showed here that dialysate MMP‐7 levels markedly increased in the patients with PD, and the elevated MMP‐7 level was negatively associated with peritoneal ultrafiltration volume. Interestingly, MMP‐7 could regulate the cell osmotic pressure and volume of human peritoneal mesothelial cells. Moreover, we provided the evidence that MMP‐7 activated mitogen‐activated protein kinases (MAPKs)‐extracellular signal‐regulated kinase 1/2 (ERK) pathway and subsequently promoted the expression of aquaporin‐1 (AQP‐1) resulting in the change of cell osmotic pressure. Using a specific inhibitor of ERK pathway abrogated the MMP‐7‐mediating AQP‐1 up‐regulation and cellular homeostasis. In summary, all the findings indicate that MMP‐7 could modulate the activity of peritoneal cavity during PD, and dialysate MMP‐7 might be a non‐invasive biomarker and an alternative therapeutic target for PD patients with ultrafiltration failure.

Background The aim of the present study was to analyze the association of programmed cell death-ligand 1 (PD-L1) and vascular endothelial growth factor receptor 2 (VEGFR2) expression levels with clinicopathological characteristics and survival to provide a treatment strategy for rectal cancer. Methods Immunohistochemical staining of VEGFR2 and PD-L1 was carried out, and the association of PD-L1 and VEGFR2 expression levels with clinicopathological characteristics and survival were investigated in 77 pair-matched rectal cancer patients. Results PD-L1 and VEGFR2 expression levels in surgical tumor tissues were higher than those in paired adjacent normal tissues, respectively (both P

Objective The microRNA expression profile of plasma exosomes in prostate cancer (PCa) is of critical importance in the disease exploration. This study aimed to explore the clinical application of exosomal miRNAs as biomarkers for PCa. Methods Exosome-like vesicles of PCa patients and healthy controls were purified by differential centrifugation. The purified vesicles within the ranges of 50 and 100 nm were classified as exosomes according to the results of transmission electron microscopy and Western blot. Both, in vitro and in vivo, validations were performed by small RNA sequencing, CCK8, RT-qPCR, flow cytometry, Western blot, transwell and immunofluorescent staining assays. Results High-throughput sequencing identified that 94 miRNAs were differentially expressed in PCa patients in comparison with healthy controls (P Conclusion This study identified the dysregulated expression of exosomal miRNAs in PCa patients, including miR-217 and miR-23b-3p, by validating their function on proliferation and invasion in PCa cells. This regulation may have been affected by the epithelial-mesenchymal transition process, suggesting that they can be used as potential targets in the diagnosis and treatment of PCa.

Atopic dermatitis (AD) is a severe inflammatory skin disease caused by a combination of genetic, immune, and environmental factors. Intestinal microbiome disorders and changes in the immune microenvironment are associated with AD. We observed that gut bacterial metabolite enterolactone (ENL) was significantly reduced in AD model mice. Notably, patients with early childhood-onset AD exhibited decreased sera ENL level compared to the healthy controls, and the ENL level was negatively correlated with the SCORAD index. Secoisolariciresinol-diglycoside (SDG) is a natural dietary lignan of flaxseeds that can be converted by intestinal bacteria to ENL. Repeated applications of 2,4-dinitrochlorobenzene (DNCB) were performed on the ear and dorsal skin of mice to induce AD-like symptoms and skin lesions. Oral administration of SDG significantly decreased serum IgE levels and limited skin inflammation in the DNCB-induced AD mice. In addition, SDG treatment strongly limited the Th2 responses in AD mice. Moreover, we demonstrated that the IL-4 production was significantly suppressed by ENL under Th2 polarization conditions via the JAK-STAT6 signaling pathway in a concentration-dependent manner. We concluded that SDG and its derived metabolite ENL ameliorated AD development by reducing the Th2 immune response. These results suggested that SDG and ENL might be exploited as potential therapeutic candidates for AD treatment.

Acute myeloid leukemia (AML) is a highly aggressive disease that causes high mortality. Long noncoding RNA (lncRNA) have studied in recent years that could be a potential biomarker and therapeutic target. Therefore, it is urgently necessary to explore the novel lncRNAs in AML. Microarray analysis was performed to determine the differentially expressed lncRNAs between mononuclear cells of AML and normal samples. The biological function of lncRNA on cell proliferation and migration was measured in vitro. The predicted downstream target of lncRNA was validated by dual-luciferase reporter assay, RNA immunoprecipitation, RNA pull-down, and rescue experiments. The tumor formation and metastasis study were conducted in vivo. The expression of lncRNA in clinical samples was determined by a quantitative reverse transcription-polymerase chain reaction. LINC00449 was one of the most differentially expressed lncRNA which is mainly located in the cytoplasm. We found that overexpression of LINC00449 could inhibit the cell proliferation and invasion of AML cells in vitro and in vivo. Besides, miR-150 was identified as the downstream target gene that was negatively regulated by LINC00449 and FOXD3 was targeted by miR-150. The results were confirmed by dual-luciferase reporter assay, RNA immunoprecipitation, RNA pull-down, rescue experiments, and in vivo assays. Patients with AML with high expression of LINC0049 may characterize a favorable survival. All the above-mentioned findings indicated that the LINC00449/miR-150/FOXD3 signaling pathway might represent a novel prognostic biomarker or therapeutic target for the treatment of AML.

The lncRNA biomarkers in melanoma remain to be further explored. The lncRNAs with different expression levels in melanoma tissue were identified by microarray analysis. To investigate the biological functions of target lncRNA, several in-vivo and in-vitro studies were performed. Potential mechanisms of competitive endogenous RNAs (ceRNAs) were predicted by using bioinformatics analysis and explored by western blot assay, fluorescence in situ hybridization assay, real-time quantitative PCR (RT-qPCR) array, RNA pull-down analysis, AGO2-RIP assay, and dual-luciferase reporter assay. The results demonstrated decreased LINC00459 in melanoma cell lines and tissues. According to the in-vitro and in-vivo experiments, up-regulated LINC00459 had inhibitory effect on cell proliferation and invasion. Bioinformatics analyses suggested that miR-218 could be a direct target of LINC00459. In addition, miR-218 was proved to be able to directly target the dickkopf-related protein 3 (DKK3) gene. In conclusion, our analysis suggested that the LINC00459 could sponge miR-218 and increase the expression of DKK3 gene, thus inhibiting the invasion and proliferation of melanoma cells, which indicated that the LINC00459 could be an effective biomarker for melanoma and its potential as the therapeutic target.

Primary immune thrombocytopenia (ITP) is an autoimmune bleeding disorder which characterizes with platelet production impairment and platelet destruction increment. CD4+CD25+ Foxp3+ Treg cells (Tregs) are involved in the immune pathogenesis of ITP. MicroRNAs (miRNAs) are also involved in ITP and their loss of function is shown to facilitate immune disorders. Thus, the miRNA expression profile in Tregs from ITP was analyzed in this study. We assessed the genome-wide miRNA expression profile of three newly diagnosed adult patients with ITP and three healthy controls using microarray analysis of CD4+CD25+CD127dim/− Tregs that were sorted using an immune magnetic bead kit. The miRNA microarray chip was based on miRBase 18.0 and Volcano Plot filtering software used to analyze the miRNA profile in Tregs. Distinct miRNA expression was further validated by fluorescence-based real-time quantitative PCR (qPCR). We found that 502 human miRNAs were differentially expressed (244 upregulated and 258 downregulated) in patients with ITP compared with healthy donors. We identified 37 miRNAs expressed significantly, including 26 upregulated and 11 downregulated. Among the deregulated miRNAs, three downregulated miRNAs including miR-155–5p, miR-146b-5p, and miR-142–3p were selected for qPCR verification. We confirmed that miR-155–5p, miR-146b–5p, and miR-142–3p were significantly decreased in Tregs from patients with ITP compared with healthy controls. Compared with the healthy controls, miRNAs expressed differentially in the Tregs of patients with ITP. The levels of expression of miR-155–5p, miR-146b-5p, and miR-142–3p were significantly decreased. Therefore, the deregulation of miRNAs may affect the function of Tregs in the course of ITP.

Background Colorectal cancer is a heterogeneous disease with complex genetic and epigenetic changes. LncRNA has recently been regarded as the biomarker in cancers. Novel biomarkers in colon cancer need to be identified. Purpose The objective of this study was to identify the differentially expressed lncRNAs between colon cancer tissue and adjacent tissue, as well as to explore its biological functions. Patients and methods There were 130 colon cancer patients included in this study. Of them, 6 colon cancer samples and 3 normal samples were selected for microarray profiling. Another 121 colon cancer samples with complete clinical information were used for immunohistochemical assay and survival analysis. Microarray analysis was performed to determine the differentially expressed lncRNAs between colon cancer tissue and adjacent tissue. Gain-of-function experiments was conducted in vitro and in vivo. In situ hybridization and survival analysis were applied to determine the prognostic impact on survival. Results LncRNA XIRP2-AS1 was significantly less expressed in colon cancer tissue. XIRP2-AS1 was remarkably downregulated in colon cancer tissues and cell lines. Functionally, XIRP2-AS1 could inhibit the proliferation and invasion ability of colon cancer cells in vitro and in vivo. Clinical sample analysis showed that XIRP2-AS1 had a favorable impact on the overall survival and progression free survival of patients with colon cancer. miR-182 was validated as the target of XIRP2-AS1 according to luciferase reporter assays, RNA immunoprecipitation and RNA pull down. Conclusions Our results suggested that XIRP2-AS1 may act as a favorable biomarker for patients with colon cancer.

The aberrant release of endoplasmic reticulum (ER) calcium leads to the disruption of intracellular calcium homeostasis, which is associated with the occurrence of ER stress and closely related to the pathogenesis of liver damage. Mannan-binding lectin (MBL) is a soluble calcium-dependent protein synthesized primarily in hepatocytes and is a pattern recognition molecule in the innate immune system. MBL deficiency is highly prevalent in the population and has been reported to be associated with susceptibility to several liver diseases. We here showed that genetic MBL ablation strongly sensitized mice to ER stress-induced liver injury. Mechanistic studies established that MBL directly interacted with ER-resident chaperone immunoglobulin heavy chain binding protein (BiP), and MBL deficiency accelerated the separation of PKR-like ER kinase (PERK) from BiP during hepatic ER stress. Moreover, MBL deficiency led to enhanced activation of the PERK-C/EBP-homologous protein (CHOP) pathway and initiates an inositol 1,4,5-trisphosphate receptor (IP3R)-mediated calcium release from the ER, thereby aggravating the hepatic ER stress response. Our results demonstrate an unexpected function of MBL in ER calcium homeostasis and ER stress response, thus providing new insight into the liver injury related to ER stress in patients with MBL deficiency.

Current binary defocus technology mainly focuses on fringe generation suitable for specific frequencies without considering fringe adaptability for defocus-degree variation, which decreases the measuring accuracy for this scenario. To achieve a high-quality measurement, we propose a robust binary fringe generation method to minimize the phase error caused by changes in defocus and the random error in measurement. In the method, we establish a complete phase error model and construct a novel objective function, to the best of our knowledge, to optimize the binarization threshold of each pixel. Through derivation of the threshold gradient calculation formula, we quickly obtain optimal binary fringes that can adapt to different fringe pitches and various degrees of defocus. The experimental results verify that the proposed method can generate robust binary fringes adaptive to different fringe pitches and defocus degree variation, and thus achieve high-quality 3D measurements.

Objective The microRNA expression profile of plasma exosomes in prostate cancer (PCa) is of critical importance in the disease exploration. This study aimed to explore the clinical application of exosomal miRNAs as biomarkers for PCa. Methods Exosome-like vesicles of PCa patients and healthy controls were purified by differential centrifugation. The purified vesicles within the ranges of 50 and 100 nm were classified as exosomes according to the results of transmission electron microscopy and Western blot. Both, in vitro and in vivo, validations were performed by small RNA sequencing, CCK8, RT-qPCR, flow cytometry, Western blot, transwell and immunofluorescent staining assays. Results High-throughput sequencing identified that 94 miRNAs were differentially expressed in PCa patients in comparison with healthy controls (P

// Tao Ding 1, * , Zhuojun Zheng 2, * , Renfang Xu 1 and Cuixing Zhou 1 1 Department of Urology, Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China 2 Department of Hematology, Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China * Tao Ding and Zhuojun Zheng are the co-first authors of this work Correspondence to: Cuixing Zhou, email: zhoucuixingcz@163.com Keywords: primary transitional cell carcinoma of the ureter, upper tract urothelial carcinomas, SEER, surgery, radiation Received: March 13, 2017 Accepted: June 30, 2017 Published: July 27, 2017 ABSTRACT Objective: This study investigated the prognostic factors and outcomes of a large observational cohort of patients with primary transitional cell carcinoma of the ureter, which was obtained from the Surveillance, Epidemiology, and End Results database. Methods: We used the Surveillance, Epidemiology, and End Results program to identify 1910 patients who had available clinical and follow-up information and were diagnosed for primary transitional cell carcinoma of the ureter between 2004 and 2013. Descriptive statistics were used to explore the epidemiology, treatment practices, and tumor characteristics of the patients. Univariate and multivariable Cox regression models were used to analyze the patient data. Results: The median overall survival (OS) was 46 months, and the 5-year OS rate was 41.8%. The median CSS was 78 months, and the 5-year CSS rate was 54.3%. Multivariate analysis identified tumor grade, tumor size, AJCC stage, M stage, cancer-directed surgical procedure and radiation as independent factors of primary transitional cell carcinoma of the ureter. For early stage patients, the surgical procedure was associated with fairly longer survival and additional radiation may cause more harm than benefit. Meanwhile, for advanced stage patients, the impact of surgery on OS and CSS greatly decreased. Radiation exerted a very limited impact on clinical outcomes. Patients with bad tumor differentiation or a large tumor size were more likely to have advanced stage disease. Conclusion: Durable cancer control can be expected in patients treated with surgery for early stage UTUC. The presence of advanced stage disease exerts a profound detrimental effect on the survival of patients.

// Zhuojun Zheng 1,2,3,4,* , Yuandong Zhu 1 , Xiaodong Li 2,3,4,5,* , Wenwei Hu 2,3,4,5 and Jingting Jiang 2,3,4 1 Department of Hematology, The Third Affiliated Hospital of Soochow University, Changzhou, China 2 Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, China 3 Cancer Immunotherapy Engineering Research Center of Jiangsu Province, Changzhou, China 4 Institute of Cell Therapy Soochow University, Changzhou, China 5 Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, China * Co-first authors of this work Correspondence to: Jingting Jiang, email: // Wenwei Hu, email: // Keywords : acute myeloid leukemia, marital status, SEER, survival analysis, subgroup analysis Received : November 24, 2016 Accepted : February 28, 2017 Published : April 09, 2017 Abstract Objective: This study investigated the impact of marital status on cancer-caused specific mortality among acute myeloid leukemia (AML) patients in the United States. Methods: We used the Surveillance, Epidemiology and End Results program to identify 50,825 patients who had their clinical and follow-up information available and were diagnosed for AML between the years 1988 and 2015. The univariate and multivariable Cox regression models were used to analyze the patient data, and to minimize the group differences due to covariates between groups, a 1:1 propensity score matching was used in subsequent subgroup analysis. Results: Our study demonstrated that married patients were less likely to die due to AML after adjusting for demographic and clinicopathological variables, than patients with variable unmarried status. Further analysis indicated that widowed, divorced and never married status correlated with poor cancer-cause specific survival than being married in almost all subgroups after being adjusted for the aforementioned variables ( P

The microRNA expression profile of plasma exosomes in osteosarcoma needs to be further explored. The present study intends to investigate the practicality of plasma exosomal miRNAs as novel biomarkers of osteosarcoma. In the study, exosome-like vesicles were purified from the plasma of patients with osteosarcoma and healthy control. Differential centrifugation was used. The purified vesicles which ranged from 50 to 100 nm in size were identified as exosomes by transmission electron microscopy and western blot. Validating assays in vitro and in vivo were performed via CCK8, reverse transcription-quantitative PCR, flow cytometry, transwell and wound healing assays and xenograft model. High-throughput sequencing identified that 57 miRNAs, 20 of which were upregulated and 37 downregulated, were differentially expressed in patients with osteosarcoma and healthy control (p

The measurement accuracy of high-speed binary defocusing fringe projection profilometry depends on the fringe pitch and defocus degree. During the measurement process, the degree of defocus changes with the measurement depth of the scenes. This makes it difficult to obtain a suitable defocus degree and achieve high-precision measurement owing to dynamic changes in the measurement object or environment. To address this problem, we propose a highly dynamic defocus response method to adaptively adjust fringe pitches for binary defocusing fringe projection profilometry. As the defocus degree changes significantly, the proposed method can respond quickly and adjust the fringe pitches adaptively to the scenes. Therefore, a high-precision dynamic measurement can be achieved for the current measuring scene. In this study, considering the effect of random error and nonlinear error, we established a complete phase-error model and used it as an optimization function. Based on this function, we obtained the optimal fringe pitch expression with the defocus degree and harmonic response parameters as variables. With the proposed method, we can obtain the defocus degree and harmonic response parameters during the measurement process and calculate the optimal fringe pitches for the current scenes. Thus, the proposed method can dynamically adapt to the measuring depth change and achieve an accurate measurement without modifying any hardware parameters.

// Wenwei Hu 1, 2, 3, * , Chen Wu 1, 2, 3, * , Xiaodong Li 1, 2, 3, * , Zhuojun Zheng 2 , Quanqin Xie 2 , Xu Deng 2 , Jingting Jiang 2, 3 and Changping Wu 1 1 Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, China 2 Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, China 3 Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, Jiangsu Province, China * These authors should be considered as co-first authors Correspondence to: Changping Wu, email: wcpjjt@163.com Jingting Jiang, email: jiangjingting@suda.edu.cn Keywords: IL-33, gastric cancer, chemotherapy, decline extent, progression-free survival Received: February 03, 2017 Accepted: March 02, 2017 Published: March 28, 2017 ABSTRACT This study aimed to evaluate the association between of serum IL-33 (sIL-33) level in gastric cancer (GC) patients and progression-free survival (PFS). A total of 62 patients with advanced GC and 32 healthy subjects were enrolled. sIL-33 level was detected in pre-chemotherapy patients, post-chemotherapy patients and healthy subjects, respectively. sIL-33 levels were 131.9 (95% CI 105.9-184.9) pg/mL, 95.1 (95% CI 70.8-140.2) pg/mL and 95.7 (95% CI 73.3-114.3) pg/mL in pre-chemotherapy patients, post-chemotherapy patients and controls, respectively. The sIL-33 level in pre-chemotherapy patients was significantly higher than that in both post-chemotherapy patients and controls ( P 0.05). PFS in patients with the decline extent > 30.1% (median PFS not reached) was statistically significant longer than that (median PFS 7 months, 95% CI 1.569 - 12.431) in patients with the decline extent ≤ 30.1% ( P = 0.003). The decline extent of sIL-33 level (> 30.1%) was associated with longer PFS ( P = 0.006). Distant metastasis was associated with the decline extent of sIL-33 level ( P = 0.034). The decline extent of sIL-33 after chemoresistance could be regarded as a predictor of the PFS of GC patients.

Background: This study aimed to investigate the Bmi-1 expression and the clinical significance in colon cancer (CC). Patients and Methods: Bmi-1 expression in tumor tissue and the corresponding normal tissue was detected using immunohistological staining. The correlations between Bmi-1 expression and clinicopathological characteristics and the overall survival (OS) time were analyzed. Results: The median H-scores of Bmi-1 in CC tissues and the corresponding tissues were 80.0 (0-270) and 5.0 (0-90), with no statistically significant difference (Z=-13.7, P

Phase-shifting profilometry (PSP) is an efficient three-dimensional (3D) measurement technique. The accuracy of the PSP based 3D measurement system is generally affected by the nonlinear intensity response of the projector. In general, nonlinear errors can be reduced by projecting more fringe patterns, but this approach significantly increases the measuring time. To improve the measurement accuracy and speed, a new composite sine-trapezoidal phase-shifting profilometry technique that suppresses nonlinear error is proposed in this study. The main idea of the proposed method is projecting a set of sinusoidal fringe patterns and two sets of composite sine-trapezoidal fringe patterns with different intensity ranges in sequence. Among these patterns, the sinusoidal fringe is used to encode the pixel position, and the order of the wrapping phase is determined by the region code of the composite fringe. The flat intensity parts of the composite fringe are used to encode the nonlinear intensity response of the measurement system. Through system identification, the response parameters of the pixels can be obtained, and the gray value of the pixels can be corrected to gain a better phase distribution. Compared to the straight edges of the trapezoidal fringe, the sinusoidal edges of the composite fringe are more robust to the projector defocus, which improves the accuracy of the identification of the system intensity response model. Simulation results show that the proposed method can achieve a higher phase retrieval accuracy than the trapezoidal PSP and the sine PSP. The experiment results indicate that the proposed method has a better measurement accuracy than those of the standard 3-step and 4-step sine PSP methods.

This study intended to present a practicable prognostic nomogram for patients with mantle cell lymphoma (MCL). The clinical data of 281 patients were reviewed. A nomogram that could predict overall survival (OS) was constructed based on the Cox proportional hazard model. To compare the capacity of the nomogram with the International Prognostic Index (IPI) and MCL International Prognostic Index (MIPI) scoring systems, we used the concordance index (C-index) to validate the veracity and the calibration curve. Age, Eastern Cooperation Oncology Group, lactate dehydrogenase, white cell count and Ki-67 were independent prognostic factors in the multivariate analysis and were subsequently included in the nomogram construction. The C-index was 0.81 and 0.79 in the primary and validation cohorts, respectively, which were superior to the predictive capacity of the IPI and MIPI systems in both cohorts. The nomogram makes it possible for physicians to predict patient OS individually and correctly, but certain limitations are noted.

Erbin has been shown to have significant effects on the development of solid tumors. However, little is known about its function and regulatory mechanism in hematological malignancies. The biological function of Erbin on cell proliferation was measured in vitro and in vivo. The predicted target of Erbin was validated by dual-luciferase reporter assay and rescue experiment. We found that overexpression of Erbin could inhibit the cell proliferation and promote the cell differentiation of acute myeloid leukemia (AML) cells, whereas depletion of Erbin could enhance the cell proliferation and block the cell differentiation in AML cells in vitro and in vivo. Besides, miR-183-5p was identified as the upstream regulator that negatively regulated the Erbin expression. The results were confirmed by dual-luciferase reporter and RNA pull-down assay. Furthermore, we found that miR-183-5p negatively regulated Erbin, resulting in enhanced cell proliferation of AML cells via activation of RAS/RAF/MEK/ERK and PI3K/AKT/FoxO3a pathways. The activation of RAS/RAF/MEK/ERK and PI3K/AKT/FoxO3a pathways was mediated by Erbin interacting with Grb2. These results were also validated by rescue experiments in vitro and in vivo. All above-mentioned findings indicated that the miR-183-5p/Erbin signaling pathway might represent a novel prognostic biomarker or therapeutic target for treatment of AML., Regulation mechanism of Erbin in hematological malignancy especially in leukemia remains unexplored. In this issue of Molecular Therapy, Zheng et al. report that the miR-183-5p/Erbin pathway modulates proliferation and differentiation of acute myeloid leukemia cells and may be served as a novel therapeutic target.

Introduction: This pooled analysis study aimed to reveal the prognostic relevance of microRNAs (miRNAs) in patients with diffuse large B-cell lymphoma (DLBCL). Materials and Methods: We examined the impact of miRNAs on clinical outcome. Eligible studies were identified and quality assessed using multiple search strategies. Data were extracted from included studies which correlated survival with expression of miRNAs (serum or tissue). Results: We pooled proper studies, and combined the hazard ratios with 95% confidence intervals to estimate strength of the correlations. There were 18 studies including 1950 patients with DLBCL eligible for pooled analysis. We found significant combined HRs for poor overall survival for high expression of miR-21 and low expression of miR-224 in tumor tissue, but for favorable relapse free survival for high expression of miR-21 in serum. Progression free survival was shortened in patients with low expression of miR-199a/b, miR-146b-5p, miR-224 and high expression of miR-222. Conclusion: MiRNAs may act as independent prognostic factors in patients with DLBCL, and useful in risk stratification.

// Zhuojun Zheng 1, 2, 3, 4, * , Xiaodong Li 2, 3, 4, 5, * , Yuandong Zhu 1 , Weiying Gu 1 , Xiaobao Xie 1 , Jingting Jiang 2, 3, 4 1 Department of Hematology, The Third Affiliated Hospital of Soochow University, China 2 Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, China 3 Cancer Immunotherapy Engineering Research Center of Jiangsu Province, China 4 Institute of Cell Therapy, Soochow University, China 5 Department of Oncology, The Third Affiliated Hospital of Soochow University, China * Co-first authors Correspondence to: Jingting Jiang, email: jiangjingting@suda.edu.cn Keywords: acute myeloid leukemia, nomogram, prognosis, prediction, TCGA Received: March 29, 2016 Accepted: September 19, 2016 Published: September 26, 2016 ABSTRACT This study was designed to perform an acceptable prognostic nomogram for acute myeloid leukemia. The clinical data from 311 patients from our institution and 165 patients generated with Cancer Genome Atlas Research Network were reviewed. A prognostic nomogram was designed according to the Cox’s proportional hazard model to predict overall survival (OS). To compare the capacity of the nomogram with that of the current prognostic system, the concordance index (C-index) was used to validate the accuracy as well as the calibration curve. The nomogram included 6 valuable variables: age, risk stratifications based on cytogenetic abnormalities, status of FLT3 -ITD mutation, status of NPM1 mutation, expression of CD34, and expression of HLA-DR. The C-indexes were 0.71 and 0.68 in the primary and validation cohort respectively, which were superior to the predictive capacity of the current prognostic systems in both cohorts. The nomogram allowed both patients with acute myeloid leukemia and physicians to make prediction of OS individually prior to treatment.

Immunotherapy with immune checkpoint inhibitors has emerged as promising treatment modality for cancer based on the success of anti-CTLA-4 and -PD-1/PD-L1 antibodies. LAG-3 and TIM-3 are two new immune checkpoints. The aim of this work is to review the role and application of LAG-3 and TIM-3 for cancer immunotherapy.Literatures were searched and collected in Medline/PubMed.LAG-3 is presented as a CD4 homolog type I transmembrane protein which binds MHC class II molecules. LAG-3 negatively regulates T cell proliferation, homeostasis and function. IMP321 is formed of an extracellular portion of human LAG-3 fused to the Fc fraction of human IgG1 and has shown increased T cell responses and tolerability in phase I studies on advanced renal cell cancer. When combined with paclitaxel, IMP321 has exerted immune enhancement and tumor inhibition with no significant IMP321-related adverse events. TIM-3 belongs to the TIM family and mainly negatively regulates Th1 immunity. The TIM-3/galectin-9 pathway contributes to the suppressive tumor microenvironment. TIM-3 overexpression is associated with poor prognosis in a variety of cancers. Both LAG-3 and TIM-3 are coexpressed with other immune checkpoints. The application of LAG-3 or TIM-3 does play an important role in anti-tumor responses, and maybe better when combing with anti-CTLA-4 and anti-PD-1/L1 antibodies.These two immune checkpoints play crucial roles in cancer development and may be used in future clinical practice of cancer therapy.