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Eomesodermin (Eomes) is a T-box transcription factor that has been implicated in the etiology of colorectal cancer and other human malignancies. We screened a panel of human primary colon cancers and patient-matched controls (n = 30) and detected Eomes overexpression at the mRNA and protein level. Similar results were obtained in a panel of rat colon tumors and adjacent normal-looking colonic mucosa (n = 24). In human colon cancer cells, forced overexpression of Eomes enhanced cell viability and protected against staurosporine-induced apoptosis. On the other hand, knocking down Eomes resulted in reduced cell viability, G2/M cell cycle arrest, and apoptosis induction. The apoptotic mechanism centered on the reciprocal downregulation of anti-apoptotic BIRC5 (Survivin) and upregulation of proapoptotic Bcl-2 modifying factor (BMF). In patients with colorectal cancer, high EOMES expression (n = 95) was associated with poor overall survival compared with individuals exhibiting low EOMES levels (n = 80). We conclude from the current investigation, and prior literature, that Eomes has a divergent role in cancer development, with evidence for tumor suppressor and oncogenic functions, depending on stage and tissue context. Further studies are warranted on the apoptotic mechanisms linked to the reciprocal regulation of BMF and BIRC5 in human colorectal cancers characterized by Eomes overexpression. [ABSTRACT FROM AUTHOR]

Hydrogen Sulfide (H2S), an endogenously produced gasotransmitter, is involved in various important physiological and disease conditions, including vasodilation, stimulation of cellular bioenergetics, anti-inflammation, and pro-angiogenesis. In cancer, aberrant up-regulation of H2S-producing enzymes is frequently observed in different cancer types. The recognition that tumor-derived H2S plays various roles during cancer development reveals opportunities to target H2S-mediated signaling pathways in cancer therapy. In this review, we will focus on the mechanism of H2S-mediated protein persulfidation and the detailed information about the dysregulation of H2S-producing enzymes and metabolism in different cancer types. We will also provide an update on mechanisms of H2S-mediated cancer progression and summarize current options to modulate H2S production for cancer therapy. [ABSTRACT FROM AUTHOR]

• Modest efficacy, toxicity, and poor effectiveness against brain metastasis are common limitations of multi-targeted novel molecular inhibitors. • A promising prospect was shown recently in selective RET inhibitors. • The development of multitarget agents and specific inhibitors has been evaluated in clinical trials. • More studies need to be conducted on the targeted therapies against RET arrangement cancer. Genomic profiling has revolutionized treatment options for patients with oncogene-driven cancers, such as epidermal growth factor receptor (EGFR) mutant carcinoma. Rearranged during transfection (RET) rearrangement, as one of the main activated oncogenes, has been well studied and found to be involved in the malignant behavior of carcinogenesis, resulting in acquired resistance to EGFR tyrosine kinase inhibitors and inducing an intrinsic resistance to immunotherapy. Thus, targeted therapies have been investigated against RET arrangement cancers, including several multi-kinase inhibitors and selective RET inhibitors. However, modest efficacy, a relatively high rate of toxicity, and poor effectiveness against brain metastasis are common limitations of multi-targeted novel molecular inhibitors. A promising prospect was shown recently in selective RET inhibitors in several ongoing clinical trials. In this review, we reviewed the concurrent dilemmas of targeted therapies against RET arrangement cancer from preclinical and clinical studies and proposed several clinical considerations for clinical practice prospectively. [ABSTRACT FROM AUTHOR]

Except for cell-surface receptors, a range of transporters have been exploited as targets for the delivery of novel anti-tumour nanomaterials. Transporters, which are essential for delivering nutrients for the biosynthesis of mammalian cells, are significantly expressed in a range of tumour types; their expression is mostly tissue- and site-specific. The unique functional and expression characteristics of transporters make them ideal targets for mediating the selective delivery of nanomaterials to cancer cells, thus promoting cell accumulation, and enhancing the penetration of nanomaterials into biological barriers before they can specifically target cancer cells. In this review, we discuss the unique function of cancer-related transporters in the initiation and development of tumours, as well as the use of transporter-targeted nanocarriers in tumour-targeting therapy. First, the expression of various transporters in tumorigenesis and development is reviewed; this is followed by a discussion of the latest advances in targeted drug delivery strategies based on transporter nanocarriers. Finally, we review the molecular mechanisms and targeting efficiency of transporter-mediated nanocarriers. This review provides a state-of-the-art synthesis of this discipline and will facilitate the generation of new concepts for the design of highly efficacious and tumour-targeting nanocarriers. [ABSTRACT FROM AUTHOR]

Background: There are inconsistent and limited data regarding the risk of myeloid neoplasms (MN) among breast cancer survivors who received radiotherapy (RT) in the absence of chemotherapy. Concern about subsequent MN might influence the decision to use adjuvant RT for women with localized disease. As patients with therapy-related MN have generally poor outcomes, the presumption of subsequent MN being therapy-related could affect treatment recommendations. Methods: We used the Surveillance, Epidemiology, and End Results (SEER)–Medicare linked database to study older women with in-situ or stage 1–3 breast cancer diagnosed 2001–2009 who received surgery. Chemotherapy and RT were ascertained using Medicare claims, and new MN diagnoses were captured using both SEER registry and Medicare claims. We excluded women who received chemotherapy for initial treatment, and censored at receipt of subsequent chemotherapy. Competing-risk survival analysis was used to assess the association between RT and risk of subsequent MN adjusting for relevant characteristics. Results: Median follow-up for 60,426 eligible patients was 68 months (interquartile range, 46 to 92 months), with 47.6% receiving RT. In total, 316 patients (0.52%) were diagnosed with MN; the cumulative incidence per 10,000 person-years was 10.6 vs 9.0 among RT-treated vs non-RT-treated women, respectively (p = .004); the increased risk of subsequent MN persisted in the adjusted analysis (hazard ratio = 1.36, 95% confidence interval: 1.03–1.80). The results were consistent in multiple sensitivity analyses. Conclusions: Our data suggest that RT is associated with a significant risk of subsequent MN among older breast cancer survivors, though the absolute risk increase is very small. These findings suggest the benefits of RT outweigh the risks of development of subsequent MN. [ABSTRACT FROM AUTHOR]

Cell membrane- covered drug-delivery nanoplatforms have been garnering attention because of their enhanced bio-interfacing capabilities that originate from source cells. In this top-down technique, nanoparticles (NPs) are covered by various membrane coatings, including membranes from specialized cells or hybrid membranes that combine the capacities of different types of cell membranes. Here, hybrid membrane-coated doxorubicin (Dox)-loaded poly(lactic-co-glycolic acid) (PLGA) NPs (DPLGA@[RAW-4T1] NPs) were fabricated by fusing membrane components derived from RAW264.7(RAW) and 4T1 cells (4T1). These NPs were used to treat lung metastases originating from breast cancer. This study indicates that the coupling of NPs with a hybrid membrane derived from macrophage and cancer cells has several advantages, such as the tendency to accumulate at sites of inflammation, ability to target specific metastasis, homogenous tumor targeting abilities in vitro, and markedly enhanced multi-target capability in a lung metastasis model in vivo. The DPLGA@[RAW-4T1] NPs exhibited excellent chemotherapeutic potential with approximately 88.9% anti-metastasis efficacy following treatment of breast cancer-derived lung metastases. These NPs were robust and displayed the multi-targeting abilities of hybrid membranes. This study provides a promising biomimetic nanoplatform for effective treatment of breast cancer metastasis. [ABSTRACT FROM AUTHOR]

Molecular-targeted drugs are generally effective against tumors containing driver oncogenes, such as EGFR, ALK, and NTRK1. However, patients harboring these oncogenes frequently experience a progression of brain metastases during treatment. Here, we present an in vivo imaging model for brain tumors using human cancer cell lines, including the EGFR-L858R/T790M-positive H1975 lung adenocarcinoma cells, the NUGC4 hepatocyte growth factor ( HGF)-dependent gastric cancer cells, and the KM12 SM colorectal cancer cells containing the TPM3- NTRK1 gene fusion. We investigated the efficacy of targeted drugs by comparison with their effect in extracranial models. In vitro, H1975 cells were sensitive to the third-generation epidermal growth factor receptor inhibitor osimertinib. Moreover, HGF stimulated the proliferation of NUGC4 cells, that was inhibited by crizotinib, which has anti- MET activity. KM12 SM cells were sensitive to the tropomyosin-related kinase-A inhibitors crizotinib and entrectinib. In in vivo H1975 cell models, osimertinib inhibited the progression of both brain and subcutaneous tumors. Furthermore, in in vivo NUGC4 cell models, crizotinib remarkably delayed the progression of brain tumors, and that of peritoneal carcinomatosis. Interestingly, in in vivo KM12 SM cell models, treatment with crizotinib delayed the progression of liver metastases, but not that of brain tumors. Conversely, treatment with entrectinib discernibly delayed the progression of both tumor types. Thus, the effect of targeted drugs against brain tumors can differ from the one reported in extracranial tumors. Moreover, the same multikinase inhibitory drug can display different efficacies in brain tumor models containing different drivers. Therefore, our in vivo imaging model for brain tumors may prove useful for preclinical drug screening against brain metastases. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to analyze the clinicopathological features and prognosis of esophageal signet ring cell (SRC) carcinoma in China. Methods: Patients with poorly differentiated adenocarcinoma were identified in two hospitals from January 2006 to June 2016. The patients were divided into three groups according to component of SRCs: SRC≥50% group, SRC < 50% group and non-SRC poorly differentiated adenocarcinoma group. Results: Fifty-seven patients had carcinoma (SRC≥50%), and 79 patients had tumors containing <50% SRCs, and 535 patients was in non-SRC poorly differentiated adenocarcinoma group. There were no significant differences among the three groups in clinicopathological characteristics. Patients in SRC≥50% group had a lower overall survival rate (at 3-year 37.6%versus71.1%; at 5-year 0% versus 43.3%; p<0.001) compared with the control group. Even survival outcome of patients in SRC < 50%was inferior to that of in control group (at 3-year 53.0%versus71.1%; at 5-year 25.9% versus 43.3%; p<0.001). Female sex, large tumor size and increasing TNM stage were independent prognostic factors for SRC ≥50% esophageal carcinoma patients. Conclusions: The incidence of esophageal SRC carcinoma is relatively rare and the worst outcome is observed in the SRC≥ 50% group. It is necessary to explore new therapeutic modalities to achieve further improvements in the clinical outcome of these patients. [ABSTRACT FROM AUTHOR]

Background and Objectives: Crizotinib (250 mg twice daily) is the first anaplastic lymphoma kinase (ALK) inhibitor approved for treatment of ALK-positive non-small-cell lung cancer (NSCLC). The objectives of the current study were to evaluate the effects of mild, moderate, and severe renal impairment on crizotinib pharmacokinetics and to make crizotinib dosing recommendations for ALK-positive NSCLC patients with renal impairment on the basis of the findings. Methods: The effects of varying degrees of renal impairment on crizotinib pharmacokinetics were evaluated by: (1) analysis of mild and moderate renal impairment on multiple-dose pharmacokinetics of crizotinib in ALK-positive NSCLC patients from the PROFILE 1001 and PROFILE 1005 trials; (2) analysis of severe renal impairment on single-dose pharmacokinetics of crizotinib in volunteers (Study 1020); and (3) prediction of the effect of severe renal impairment on multiple-dose crizotinib pharmacokinetics using a physiologically-based pharmacokinetic model of crizotinib. Results: No clinically relevant changes in plasma crizotinib exposure were observed in NSCLC patients with mild or moderate renal impairment. After a single 250-mg dose, the area under the plasma concentration-time curve (AUC) for crizotinib was 1.8-fold greater in subjects with severe renal impairment than in those with normal renal function. Physiologically-based pharmacokinetic modeling indicated a similar increase in steady-state AUC after multiple dosing. Conclusions: These results suggest no dose adjustment for patients with mild or moderate renal impairment. The recommended crizotinib dose for patients with severe renal impairment not requiring dialysis is 250 mg once daily. [ABSTRACT FROM AUTHOR]

Objectives: To utilize phosphorescence to monitor hypoxic microenvironment in solid-tumors and investigate cancer chemotherapeutic effects in vivo. Methods: A hypoxia-sensitive probe named BTP was used to monitor hypoxic microenvironment in solid-tumors. The low-dose metronomic treatment with cisplatin was used in anti-angiogenetic chemotherapeutic programs. The phosphorescence properties of BTP were detected by a spectrofluorometer. BTP cytotoxicity utilized cell necrosis and apoptosis, which were evaluated by trypan blue dye exclusion and Hoechst33342 plus propidium iodide assays. Tumor-bearing mouse models of colon adenocarcinoma were used for tumor imaging in vivo. Monitoring of the hypoxic microenvironment in tumors was performed with a Maestro 2 fluorescence imaging system. Tumor tissues in each group were harvested regularly and treated with pathological hematoxylin and eosin and immunohistochemical staining to confirm imaging results. Results: BTP did not feature obvious cytotoxicity for cells, and tumor growth in low-dose metronomic cisplatin treated mice was significantly inhibited by chemotherapy. Hypoxic levels significantly increased due to cisplatin, as proven by the expression level of related proteins. Phosphorescence intensity in the tumors of mice in the cisplatin group was stronger and showed higher contrast than that in tumors of saline treated mice. Conclusions: We develop a useful phosphorescence method to evaluate the chemotherapeutic effects of cisplatin. The proposed method shows potential as a phosphorescence imaging approach for evaluating chemotherapeutic effects in vivo, especially anti-angiogenesis. [ABSTRACT FROM AUTHOR]

Resistance to TKI treatment is a major obstacle in effective treatment of NSCLC. Besides EGFR mutation status, the mechanisms involved are largely unknown. Some evidence supports a role for microRNA 21 in modulating drug sensitivity of chemotherapy but its role in NSCLC TKI resistance still remains unexplored. This study aimed to investigate whether NSCLC miR-21 mediated resistance to TKIs also results from Pten targeting. Here, we show miR-21 promotes cancer by negatively regulating Pten expression in human NSCLC tissues: high miR-21 expression levels were associated with shorter DFS in 47 NSCLC patients; high miR-21/low Pten expression levels indicated a poor TKI clinical response and shorter overall survival in another 46 NSCLC patients undergoing TKI treatment. In vitro assays showed that miR-21 was up-regulated concomitantly to down-regulation of Pten in pc-9/GR cells in comparison with pc-9 cells. Moreover, over-expression of miR-21 significantly decreased gefitinib sensitivity by down-regulating Pten expression and activating Akt and ERK pathways in pc-9 cells, while miR-21 knockdown dramatically restored gefitinib sensitivity of pc-9/GR cells by up-regulation of Pten expression and inactivation of AKT and ERK pathways, in vivo and in vitro. We propose alteration of miR-21/Pten expression as a novel mechanism for TKI resistance in NSCLC cancer. Our findings provide a new basis for using miR 21/Pten-based therapeutic strategies to reverse gefitinib resistance in NSCLC. [ABSTRACT FROM AUTHOR]