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Androgen deprivation therapy (ADT) is a systemic therapy for advanced prostate cancer (PCa); although most patients initially respond to ADT, almost all cancers eventually develop castration-resistant PCa (CRPC). Currently, most research focuses on castration-resistant tumors, and the role of tumors in remission is almost completely ignored. Here, we report that odorant-binding protein (OBP2A) released from tumors in remission during ADT catches survival factors, such as CXCL15/IL8, to promote PCa cell androgen-independent growth and enhance the infiltration of myeloid-derived suppressor cells (MDSCs) into tumor microenvironment, leading to the emergence of castration resistance. OBP2A knockdown significantly inhibits CRPC and metastatic CRPC development and improves therapeutic efficacy of CTLA-4/PD-1 antibodies. Treatment with OBP2A-binding ligand α-pinene interrupts the function of OBP2A and suppresses CRPC development. Furthermore, α-pinene–conjugated doxorubicin/docetaxel can be specifically delivered to tumors, resulting in improved anticancer efficacy. Thus, our studies establish a novel concept for the emergence of PCa castration resistance and provide new therapeutic strategies for advanced PCa.

Background Castration-resistant prostate cancer (CRPC) is associated with a very poor prognosis, and the treatment of which remains a serious clinical challenge. Methods RNA-seq, qPCR, western blot and immunohistochemistry were employed to identify and confirm the high expression of indolethylamine N-methyltransferase (INMT) in CRPC and the clinical relevance. Chip assay was used to identify Histone-Lysine N-Methyltransferase (SMYD3) as a major epigenetic regulator of INMT. LC-MS/MS were used to identify new substrates of INMT methylation in CRPC tissues. Gene knockdown/overexpression, MTT and mouse cancer models were used to examine the role of INMT as well as the anticancer efficacy of INMT inhibitor N,N-dimethyltryptamine (DMT), the SMYD3 inhibitor BCl-12, the selenium compounds methaneseleninic acid (MSA) and Se-(Methyl)selenocysteine hydrochloride (MSC), and the newly identified endogenous INMT substrate Bis(7)-tacrine. Results We found that the expression of INMT was highly increased in CRPC and was correlated with poor prognosis of clinical prostate cancer (PCa). INMT promoted PCa castration resistance via detoxification of anticancer metabolites. Knockdown of INMT or treatment with INMT inhibitor N,N-dimethyltryptamine (DMT) significantly suppressed CRPC development. Histone-Lysine N-Methyltransferase SMYD3 was a major epigenetic regulator of INMT expression, treatment with SMYD3 inhibitor BCl-121 suppressed INMT expression and inhibits CRPC development. Importantly, INMT knockdown significantly increased the anticancer effect of the exogenous selenium compounds methaneseleninic acid (MSA) and Se-(Methyl)selenocysteine hydrochloride (MSC) as well as the endogenous metabolite Bis(7)-tacrine. Conclusions Our study suggests that INMT drives PCa castration resistance through detoxification of anticancer metabolites, targeting INMT or its regulator SMYD3 or/and its methylation metabolites represents an effective therapeutic avenue for CRPC treatment.

Acute myeloid leukemia (AML) is prone to drug-resistant relapse with a low 5-year survival rate. New therapeutic modalities are sorely needed to provide hope for AML relapse patients. Herein, we demonstrated a specific inhibitor of type 4 phosphodiesterase (PDE4), Zl-n-91, could significantly reduce the proliferation of AML cells, block DNA replication process, and increase AML cell death. Zl-n-91 also impeded the growth of subcutaneous xenograft and prolonged the survival of the MLL-AF9-driven AML model. Bioinformatic analysis revealed that elevated mitochondrial gene signatures inversely correlate with the survival of AML patients; and importantly, Zl-n-91 strongly suppressed the function of mitochondria. In addition, this PDE4 inhibitor induced alterations in multiple signaling pathways, including the reduction of β-catenin activity. Stimulation of the Wnt/β-catenin pathway could attenuate the inhibitory effect of Zl-n-91 on AML cell proliferation as well as mitochondrial function. Taken together, we revealed for the first time that targeting PDE4 activity could attenuate mitochondrial function through a Wnt/β-catenin pathway, which in turn would block the growth of AML cells. Specific PDE4 inhibitors can potentially serve as a new treatment modality for AML patients.

Pre-mRNA processing factor 19 (PRPF19) is a multifaceted protein and participates in DNA damage response and pre-mRNA processing. The role of PRPF19 in cancer is unclear. Here, we report that the expression of PRPF19 in human tongue cancer is associated with unfavorable prognosis. Overexpression of PRPF19 promotes while knockdown of PRPF19 inhibits tongue cancer cell migration, proliferation, and tumor growth. Overexpression of PRPF19 increases the resistance of tongue cancer cells to radiation and cisplatin treatment. Furthermore, PRPF19 regulates the expression of solute carrier family 40 member 1 (SLC40A1) and mono-ADP ribosylhydrolase 2 (MACROD2), knockdown of SLC40A1 or MACROD2 decreases the sensitivity of tongue cancer cells to radiation and cisplatin treatment. Thus, our results establish a key role of PRPF19 in tongue cancer growth and chemoradiotherapy resistance, targeting PRPF19 would be an effective therapeutic strategy for tongue cancer, especially for those resistant to chemoradiotherapy.

Recent findings have identified microbiota as crucial participants in many disease conditions, including cancers. Competing endogenous RNA (ceRNA) is regarded as a candidate mechanism involving relevant biological processes. We therefore constructed a ceRNA network using the TCGA and GEO database, to determine the potential mechanisms of microbiota-mediated colorectal carcinogenesis and progression. We found a total of 75 lncRNAs, 8 miRNAs, and 9 mRNAs in the probiotics-mediated ceRNA network and a total of 49 lncRNAs, 4 miRNAs, and 3 mRNA in the pathobiont-mediated ceRNA network, which could induce the microbiota-mediated carcinogenesis and progression. The GO and KEGG analysis indicated that the ceRNA network is mainly enriched in the metabolic process, and two unique pathways (the p53 signaling pathway and microRNA in cancer), respectively. A four-gene signature (FRMD6-AS2, DIRC3, LIFR-AS1, and MRPL23-AS1) was suggested as an independent prognostic factor. Four lncRNAs (LINC00355, KCNQ1OT1, LINC00491, and HOTAIR) were associated with poor survival. Three small molecule candidate anticancer drugs (Pentoxyverine, Rimexolone, and Doxylamine) were identified. A four-gene signature (FAM129A, BCL2, PMAIP1, and RPS6) is significantly correlated with immune infiltration level. This study provides a promising biomarker reservoir to explore the mechanism by which microbiota regulate the ceRNA network involving the immune response, and further participate in colorectal carcinogenesis and progression., Graphical Abstractt

Multifunctional pro-inflammatory cytokine CXCL8 is a small peptide of 8–10 kDa in size and it functions as a monomer or dimer. CXCL8 harbors 2 disulfide bonds for its stability. Although production...

Yes-associated protein (YAP) is a transcriptional coactivator that promotes cell proliferation, migration, and tissue homeostasis in colorectal cancer (CRC). Here, we established 5-Fu resistant CRC cell line (SW620R) and examined the role of YAP in chemotherapy resistance. We showed that YAP promoted cell proliferation, migration, and chemotherapy resistance in CRC. To increase efficacy of CRC treatment, we employed another therapeutic target EGFR which interacts with the upstream signaling molecules of YAP in Hippo pathway. Verteporfin, a YAP specific inhibitor, inhibits YAP activity by blocking the YAP-TEAD complex in the cell nucleus, and AG1478, an inhibitor of EGFR/ErbB1, induces the phosphorylation and degradation of YAP. We found that combinational inhibition of YAP by VP and AG1478 synergistically suppressed the CRC development and reversed chemotherapy resistance in vitro and in vivo. Therefore, our results demonstrated a novel therapeutic strategy, the combination of inhibitors targeting EGFR and YAP, to suppress and reverse chemotherapy resistance in colorectal cancer.

Erythropoietin-producing hepatoma receptor A2 (EphA2), receptor tyrosine kinase, the most widespread member of the largest receptor tyrosine kinase family, plays a critical role in physiological and pathological conditions. In recent years, the role of EphA2 in the occurrence and development of cancer has become a research hotspot and is considered a promising potential target. Our previous studies have shown that EphA2 has an indisputable cancer-promoting role in cervical cancer, but its related mechanism requires further research. In this study, high-throughput sequencing was performed on EphA2 knockdown cervical cancer cells and the control group. An analysis of differentially expressed genes revealed that EphA2 may exert its cancer-promoting effect through C-X-C motif chemokine ligand 11 (CXCL11). In addition, we found that EphA2 could further regulate programmed cell death ligand 1 (PD-L1) through CXCL11. This has also been further demonstrated in in vivo experiments. Our study demonstrated that EphA2 plays a tumor-promoting role in cervical carcinoma through the CXCL11/PD-L1 pathway, providing new guidance for the targeted therapy and combination therapy of cervical carcinoma.

Yes-associated protein (YAP) is a transcriptional coactivator that promotes cell proliferation, stem cell maintenance and tissue homeostasis. The YAP activity is primarily regulated through an inhibitory phosphorylation by the serine/threonine kinases of Hippo pathway. Here, we show that receptor tyrosine kinase (RTK) erythropoietin-producing hepatocellular receptor A2 (EphA2) interacts with and phosphorylates YAP protein, leading to stabilization, nuclear translocation and activation of YAP in gastric cancer (GC) cells. EphA2 induces chemotherapy-resistance by increasing YAP stability and nuclear YAP protein. Knockdown of YAP blocks EphA2-induced tumor growth in GC xenograft mouse models. Importantly, the coactivation of EphA2 and YAP is manifested in clinical human GC, and is related to GC recurrence. Thus, our results establish a novel EphA2-to-YAP pathway that drives GC growth, progression and therapy-resistance, targeting this pathway would be an efficient way for the treatment of GC, particularly chemotherapy-resistant GC.

The conventional k-modes algorithm and its variants have been extensively used for categorical data clustering. However, these algorithms have some drawbacks, e.g., they can be trapped into local optima and sensitive to initial clusters/modes. Our numerical experiments even showed that the k-modes algorithm could not identify the optimal clustering results for some special datasets regardless the selection of the initial centers. In this paper, we developed an integer linear programming (ILP) approach for the k-modes clustering, which is independent to the initial solution and can obtain directly the optimal results for small-sized datasets. We also developed a heuristic algorithm that implements iterative partial optimization in the ILP approach based on a framework of variable neighborhood search, known as IPO-ILP-VNS, to search for near-optimal results of medium and large sized datasets with controlled computing time. Experiments on 38 datasets, including 27 synthesized small datasets and 11 known benchmark datasets from the UCI site were carried out to test the proposed ILP approach and the IPO-ILP-VNS algorithm. The experimental results outperformed the conventional and other existing enhanced k-modes algorithms in literature, updated 9 of the UCI benchmark datasets with new and improved results.

Increasing evidence suggests that long non-coding RNAs (lncRNAs) are crucial in cancer biological processes. To investigate if lncRNA contributes to gastric cancer (GC), we conducted a bioinformatics analysis in human microarray datasets, and the results showed that lncRNA prostate cancer-associated transcript 19 (PCAT19) was upregulated in GC. Quantitative reverse-transcriptase PCR and in situ hybridization assays also revealed that PCAT19 was upregulated in GC tissues. The PCAT19 expression in GC was significantly related to tumor size, lymph node metastasis, and pathological stage. Moreover, patients with higher PCAT19 expression levels were more likely to have a poor prognosis for overall survival. The knockdown of PCAT19 by siRNA significantly suppressed the proliferation and invasion of GC cells. The cell distribution of PCAT19 in GC cells was examined by fluorescence in situ hybridization assay, and the results showed that it was mainly located in the cytoplasm. Mechanistically, PCAT19 sponges miR-429 and promotes DHX9 expression. In addition, the transcription factor SP1 is involved in PCAT19 activation. Our results demonstrate that lncRNA PCAT19 is induced by SP1 and acts as an oncogene in GC that competitively binds to miR429 and upregulates DHX9.

Background: The long non-coding RNA SNHG7 is upregulated in many types of cancer and plays a role as an oncogene. However, its overall predictive ability in human cancer prognosis has not been assessed using existing databases. Therefore, further study of its prognostic value and clinical significance in human malignancies is warranted.Methods: We systematically collected relevant literature from multiple electronic document databases about the relationship between SNHG7 expression level and prognosis in patients with solid cancers. We further screened them for eligibility. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were used to assess the prognostic value. Odds ratios (ORs) and their 95% CIs were collected to evaluate the relationship between the expression of SNHG7 and clinicopathological features, including lymph node metastasis (LNM), tumour size, tumour node metastasis (TNM) stage and histological grade.Results: Fourteen original studies involving 971 patients were enrolled strictly following the inclusion and exclusion criteria. The meta-analysis showed that SNHG7 expression was significantly correlated with poor overall survival (HR = 1.93, 95% CI: 1.64–2.26, p SNHG7 was associated with earlier LNM (OR = 1.83, 95% CI: 1.44–2.32; P P Conclusions: High SNHG7 expression may predict poor oncological outcomes in patients with multiple human cancers, which could be a novel prognostic biomarker of unfulfilled clinicopathological features. However, further high-quality studies are needed to verify and strengthen the clinical value of SNHG7 in different types of cancer.

Nuclear insulin-like growth factor 1 receptor (nIGF1R) has been associated with poor overall survival and chemotherapy resistance in various types of cancer; however, the underlying mechanism remains unclear. In the present study, immunoprecipitation-coupled mass spectrometry was performed in an IGF1R-overexpressing SW480-OE colorectal cancer cell line to identify the nIGF1R interactome. Network analysis revealed 197 proteins of interest which were involved in several biological pathways, including RNA processing, DNA double-strand break (DSB) repair and SUMOylation pathways. Nuclear mitotic apparatus protein (NuMA) was identified as one of nIGF1R's colocalizing partners. Proximity ligation assay (PLA) revealed different levels of p53-binding protein 1 (53BP1)-NuMA colocalization between IGF1R-positive (R+) and IGF1R-negative (R−) mouse embryonic fibroblasts following exposure to ionizing radiation (IR). 53BP1 was retained by NuMA in the R− cells during IR-induced DNA damage. By contrast, the level of NuMA-53BP1 was markedly lower in R+ cells compared with R− cells. The present data suggested a regulatory role of nIGF1R in 53BP1-dependent DSB repair through its interaction with NuMA. Bright-field PLA analysis on a paraffin-embedded tissue microarray from patients with colorectal cancer revealed a significant association between increased nuclear colocalizing signals of NuMA-53BP1 and a shorter overall survival. These results indicate that nIGF1R plays a role in facilitating 53BP1-dependent DDR by regulating the NuMA-53BP1 interaction, which in turn might affect the clinical outcome of patients with colorectal cancer.

ObjectiveAnorectal melanoma (AM) is a rare but aggressive tumour with limited information in the existing literature. This study aimed to assess the effect of surgical treatment for AM and predict the prognosis of affected patients.DesignA retrospective cohort study.SettingData of patients diagnosed with AM between 1975 and 2016 in the USA were collected from the Surveillance, Epidemiology, and End Results (SEER) database.ParticipantsThis study enrolled a total of 795 patients with AM from the SEER database and the validation cohort comprised 40 patients with AM enrolled from Chinese institutes.Primary and secondary outcome measuresOverall survival (OS) and AM-specific survival (AM-SS).ResultsA total of 795 patients with AM diagnosed between 1975 and 2016 were enrolled in this study. Data over the past four decades showed a trend of increase in incidence rate. A nomogram based on a multivariate Cox regression model was generated to predict AM-SS. The C-index of the nomogram was 0.74 (95% CI 0.71 to 0.77) on internal verification. In the validation cohort, the C-index of the nomogram was 0.72 (95% CI 0.68 to 0.76). The results of propensity score matching (PSM) analysis showed that patients who underwent surgical treatment achieved significant survival (OS: log-rank=17.41, p0.05).ConclusionsThe nomogram based on the analysis of SEER data showed good performance in predicting OS and AM-SS. Patients with AM can benefit from surgery; however, extensive surgery and appendectomy may not improve AM-SS or OS.

Background: B3GNT6 encodes the core 3 synthase in O-glycan biosynthesis. It is commonly expressed in the GI tract, while its clinical significance in colorectal cancer remains largely unknown.Methods: We gathered mRNA transcriptomic sequencing data from 3 Gene Expression Omnibus (GEO) datasets (GSE37182, GSE39582, GSE103512) and The Cancer Genome Atlas (TCGA) to compare the B3GNT6 mRNA level between colorectal cancer tissues and normal tissues and to evaluate its value as a prognostic marker. We further validated this in protein level using online database Human Protein Atlas and with immunohistochemical staining of B3GNT6 with our own cohort. Results: B3GNT6 expression was downregulated in colorectal cancer tissue compared with that in normal tissue in both mRNA and in protein level. Downregulation of B3GNT6 was associated with poor overall survival of colorectal cancer in GSE39582 and in TCGA database. Low B3GNT6 mRNA level was significantly associated with chromosome stable (CIN negative) and KRAS mutated group colorectal cancer patient. GSEA revealed that low B3GNT6 level in colorectal cancer is associated with upregulated proteasome activity.Conclusions: Downregulated B3GNT6 was correlated with poor overall survival of colorectal cancer patients. B3GNT6 could be used as a good prognostic marker in colorectal cancer.

Erythropoietin‐producing hepatocellular receptor A2 (EphA2) receptor tyrosine kinase plays an important role in tissue organization and homeostasis in normal organs. EphA2 is overexpressed in a variety of types of solid tumours with oncogenic functions. However, the role of EphA2 in cervical cancer (CC) is still needed to be further explored. Here, we examined the role of EphA2 by establishing a stable EphA2 knock‐down CC cell lines or a stable EphA2‐overexpressed CC cells lines. Overexpression of EphA2 increased cell proliferation and migration of CC while EphA2 knock‐down decreased the CC tumorigenicity. In addition, EphA2 knock‐down suppressed CC tumour development in the xenograft mouse model. Inhibition of EphA2 by AWL‐II‐41‐27, EphA2‐specific tyrosine kinase inhibitor, or knock‐down of EphA2 decreased mRNA and protein expression of cyclin‐dependent kinase (CDK) 6 in CC cells, which increased cellular susceptibility to epirubicin (EPI), an anti‐cancer chemotherapy drug. A clinicopathological study of EphA2 was conducted on a cohort of 158 human CC patients. EphA2 protein expression was positively correlated with CDK6 protein expression, invasion depth, lymph node metastasis and clinicopathological stage (P

Erythropoietin-producing hepatocellular receptor A2 (EphA2) is a key member of the receptor tyrosine kinase (RTK) family, while YES Proto-Oncogene 1 (YES1) is a non-receptor tyrosine kinase (nRTK) and annexin A2 (ANXA2) belongs to the calcium-dependent phospholipid-binding protein family annexins. Here, we show that EphA2, YES1, and ANXA2 form a signal axis, in which YES1 activated by EphA2 phosphorylates ANXA2 at Tyr24 site, leading to ANXA2 activation and increased ANXA2 nuclear distribution in gastric cancer (GC) cells. Overexpression (OE) of YES1 increases, while knockdown (KD) of YES1 or ANXA2 decreases GC cell invasion and migration in vitro and tumor growth in mouse models. Reexpression of wildtype (WT) rather than mutant ANXA2 (Tyr24F) in ANXA2 knockdown (ANXA2-KD) GC cells restores YES1-induced cell invasion and migration, while neither WT nor mutant ANXA2 (Tyr24F) can restore cell invasion and migration in YES1-KD GC cells. In addition, the activation of EphA2–YES1–ANXA2 pathway is correlated with poor prognosis. Thus, our results establish EphA2–YES1–ANXA2 axis as a novel pathway that drives GC invasion and metastasis, targeting this pathway would be an efficient way for the treatment of GC.

Multifunctional pro-inflammatory cytokine CXCL8 is a small peptide of 8-10 kDa in size and it functions as a monomer or dimer. CXCL8 harbors 2 disulfide bonds for its stability. Although production of the CXCL8 protein in a large quantity in both mammalian and bacterial systems has been reported, the processes are complicated and lengthy. Here, we develop a new bacterial expression system for recombinant CXCL8 and simplify the purification system to yield a high amount of protein quickly. The purified CXCL8 protein from our new system develops a crystal structure that is identical to that produced through the mammalian expression system. Thus, we have established a simple and efficient recombinant CXCL8-producing system, which can be easily operated and is suitable to those requiring a large quantity of CXCL8.

We conducted this meta-analysis to explore the association between passive smoking and the risk of colorectal cancer. A literature search of online databases, including MEDLINE, EMBASE, the Cochrane Library, and Web of Science was performed up to June 30, 2015. A fixed-effects meta-analysis using Stata 12.0 was carried out to estimate the relative risks (RRs) and 95% confidence intervals (CIs) for the associations. Eleven articles, including 6 case-control studies and 6 cohort studies, were included in our analysis according to inclusion and exclusion criteria. The pooled RR of all studies showed a statistically significant association between passive smoking and colorectal cancer (RR = 1.14; 95% CI = 1.05-1.24). Results of subgroup analysis showed a positive association between passive smoking and rectal cancer ((RR = 1.33; 95% CI = 1.15-1.53) and that male passive smokers were at greater risks of colorectal cancer (RR = 1.73; 95% CI = 1.37-2.19) than females. Results suggested that passive smoking is associated with an increased risk of colorectal cancer.

LXRα is a subtype of the liver X receptors (LXRs). There is accumulating evidence to support the involvement of LXRα in a variety of malignancies. However, the function and specific mechanism of LXRα in gastric cancer (GC) remain unclear. In this study, the expression of LXRα was significantly lower in poorly differentiated and undifferentiated GC tissues compared with well- and moderately differentiated GC tissues by immunohistochemistry analysis. The activation of LXRα leads to the decreased expression of β-catenin, CD44, and Cyclin D1, whereas the inhibition of LXRα has opposite effect. The same results were obtained in animal experiments. Furthermore, results showed that CD44 and Cyclin D1 expression significantly decreased when Wnt/β-catenin signaling was blocked in LXRα silent GC cells, whereas it was significantly increased when Wnt/β-catenin signaling was activated in LXRα over-expressed GC cells. CD44 and Cyclin D1, downstream targets of Wnt/β-catenin signaling, are specific markers for cell differentiation. Therefore, we conclude that LXRα may promote the differentiation of human GC cells through inactivation of Wnt/β-catenin signaling.

Vehicle Routing Problem(VRP) is one of the most important and classical issues in the logistics distribution field. However, the excessive consumption of oil resources makes a dramatic increase in emissions of carbon dioxide in the atmosphere which causes a deterioration of the environment around us for the past few years. The electric vehicle(EV) is a better alternative which operates with batteries instead of using gasoline. In this paper, we present the Electric Vehicle Problem(EVRP) and describe it with a mathematical programming model. Then, we verity the model via the mathematic program software called AMPL/CPLEX and the mathematic instances are extracted from the Solomon's instances. We propose a programming algorithm as an exact solution approach for the EVRP. Problem examples and numerical calculation have been provided to evaluate the solution approach and the optimality.