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Related Articles Bruceantin inhibits multiple myeloma cancer stem cell proliferation. Cancer Biol Ther. 2016 Jul 19;:0 Authors: Issa ME, Berndt S, Carpentier G, Pezzuto JM, Cuendet M Abstract Multiple myeloma (MM) continues to claim the lives of a majority of patients. MM cancer stem cells (CSCs) have been demonstrated to sustain tumor growth. Due to their ability to self-renew and to express detoxifying enzymes and efflux transporters, MM-CSCs are rendered highly resistant to conventional therapies. Therefore, managing MM-CSCs characteristics could have profound clinical implications. Bruceantin (BCT) is a natural product previously demonstrated to inhibit the growth of MM in RPMI 8226 cells-inoculated mouse xenograft models, and to cause regression in already established tumors. The objectives of the present study were to test the inhibitory effects of BCT on MM-CSCs growth derived from a human primary tumor, and to explore a mechanism of action underlying these effects. BCT exhibited potent antiproliferative activity in MM-CSCs starting at 25 nM. BCT induced cell cycle arrest, cell death and apoptosis in MM-CSCs as well as inhibited cell migration and angiogenesis in vitro. Using a qPCR screen, it was found that the gene expression of a number of Notch pathway members was altered. Pretreatment of MM-CSCs with the γ-secretase inhibitor RO4929097, a Notch pathway inhibitor, reversed BCT-induced effects on MM-CSCs proliferation. In this study, BCT was shown to be an effective agent in controlling the proliferation, viability and migration of MM-CSCs as well as angiogenesis in vitro. The effect on MM-CSCs proliferation may be mediated by the Notch pathway. These results warrant further investigation of BCT in a broader set of human-derived MM-CSCs and with in vivo models representative of MM. PMID: 27434731 [PubMed - as supplied by publisher] from Cancer via ola Kala on Inoreader via IFTTT

Related Articles Necroptosis: A New Way of Dying? Cancer Biol Ther. 2016 Jul 19;:0 Authors: Hanson B Abstract This review embarks upon a cell death journey from the discovery of apoptosis and necrosis through to the coalescence of these: necroptosis. The mechanisms of two emerging necrotic cell death pathways, pyroptosis and ferroptosis, will be explored before delving into apoptotic and necroptotic signalling cascades, highlighting the complex interplay between molecular players. The involvement of the ripoptosome, interferon signalling and DNA damage in necroptosis will be discussed briefly. The major focus is on necroptosis initiation by tumour necrosis factor-α (TNFα) and its cognate receptor TNFR1, caspase-independent RIP1/RIP3/MLKL necrosome activation and cell death propagation by damage-associated molecular pattern (DAMP) release. Finally, the implications of a complex cell death signalling network will be revealed in the context of cancer biology and therapy. The clinical contribution of the discovery of necroptosis as an unequivocally new way of dying is monumental and could drastically alter cancer therapy strategies in the future. PMID: 27434654 [PubMed - as supplied by publisher] from Cancer via ola Kala on Inoreader via IFTTT

Related Articles Bruceantin inhibits multiple myeloma cancer stem cell proliferation. Cancer Biol Ther. 2016 Jul 19;:0 Authors: Issa ME, Berndt S, Carpentier G, Pezzuto JM, Cuendet M Abstract Multiple myeloma (MM) continues to claim the lives of a majority of patients. MM cancer stem cells (CSCs) have been demonstrated to sustain tumor growth. Due to their ability to self-renew and to express detoxifying enzymes and efflux transporters, MM-CSCs are rendered highly resistant to conventional therapies. Therefore, managing MM-CSCs characteristics could have profound clinical implications. Bruceantin (BCT) is a natural product previously demonstrated to inhibit the growth of MM in RPMI 8226 cells-inoculated mouse xenograft models, and to cause regression in already established tumors. The objectives of the present study were to test the inhibitory effects of BCT on MM-CSCs growth derived from a human primary tumor, and to explore a mechanism of action underlying these effects. BCT exhibited potent antiproliferative activity in MM-CSCs starting at 25 nM. BCT induced cell cycle arrest, cell death and apoptosis in MM-CSCs as well as inhibited cell migration and angiogenesis in vitro. Using a qPCR screen, it was found that the gene expression of a number of Notch pathway members was altered. Pretreatment of MM-CSCs with the γ-secretase inhibitor RO4929097, a Notch pathway inhibitor, reversed BCT-induced effects on MM-CSCs proliferation. In this study, BCT was shown to be an effective agent in controlling the proliferation, viability and migration of MM-CSCs as well as angiogenesis in vitro. The effect on MM-CSCs proliferation may be mediated by the Notch pathway. These results warrant further investigation of BCT in a broader set of human-derived MM-CSCs and with in vivo models representative of MM. PMID: 27434731 [PubMed - as supplied by publisher] from Cancer via ola Kala on Inoreader via IFTTT

Related Articles Necroptosis: A New Way of Dying? Cancer Biol Ther. 2016 Jul 19;:0 Authors: Hanson B Abstract This review embarks upon a cell death journey from the discovery of apoptosis and necrosis through to the coalescence of these: necroptosis. The mechanisms of two emerging necrotic cell death pathways, pyroptosis and ferroptosis, will be explored before delving into apoptotic and necroptotic signalling cascades, highlighting the complex interplay between molecular players. The involvement of the ripoptosome, interferon signalling and DNA damage in necroptosis will be discussed briefly. The major focus is on necroptosis initiation by tumour necrosis factor-α (TNFα) and its cognate receptor TNFR1, caspase-independent RIP1/RIP3/MLKL necrosome activation and cell death propagation by damage-associated molecular pattern (DAMP) release. Finally, the implications of a complex cell death signalling network will be revealed in the context of cancer biology and therapy. The clinical contribution of the discovery of necroptosis as an unequivocally new way of dying is monumental and could drastically alter cancer therapy strategies in the future. PMID: 27434654 [PubMed - as supplied by publisher] from Cancer via ola Kala on Inoreader via IFTTT

Abstract Background This study was carried out to determine the prognostic significance of preoperative peripheral epithelial cell adhesion molecule- positive (EpCAM +) circulating tumor cell (CTC) and T regulatory (Treg) cell levels in hepatocellular carcinoma (HCC) patients for the prediction of postoperative recurrence following curative resection. Methods A total of 49 patients about to undergo curative resection for HCC were recruited into the study. PCR and FACS were used to detect the preoperative levels of EpCAM mRNA+ CTCs and CD4+CD25+Foxp3+ Treg cells. The prognostic value of EpCAM mRNA+ CTCs, CD4+CD25+Foxp3+ Treg cells, and other clinicopathological factors were analyzed by applying the Kaplan–Meier method and the multivariate Cox proportional hazards model. Results The number of EpCAM mRNA+ CTCs and Treg/CD4+ cells showed significant correlation as prognostic factors of postoperative HCC recurrence: EpCAM mRNA+ CTC ≥ 2.22 (P = 0.001) and Treg/CD4+ ≥ 5.07 (P = 0.045), with EpCAM mRNA+ CTC ≥ 2.22 (P = 0.003, HR = 6.668) being the most important indicator. Patients with high CTC/Treg levels showed a significantly higher risk of developing postoperative HCC recurrence than those with low CTC/Treg levels (66.7 % vs. 10.3 %, P < 0.001). The high CTC/low Treg group also presented higher 1-year recurrence rates compared with the low CTC/low Treg level group (50.0 % vs. 10.3 %, P = 0.004). Conclusions Elevated EpCAM mRNA+ CTC and Treg/CD4+ levels were associated with early recurrence of HCC, indicative of poor clinical outcome. The combined detection of EpCAM mRNA+ CTC and Treg/CD4+ may therefore provide a novel prognostic predictor for HCC patients. from Cancer via ola Kala on Inoreader via IFTTT

Abstract Background Primary melanocytic neoplasms are rare in the pediatric age. Among them, the pattern of neoplastic meningitis represents a peculiar diagnostic challenge since neuroradiological features may be subtle and cerebrospinal fluid analysis may not be informative. Clinical misdiagnosis of neoplastic meningitis with tuberculous meningitis has been described in few pediatric cases, leading to a significant delay in appropriate management of patients. We describe the case of a child with primary leptomeningeal melanoma (LMM) that was initially misdiagnosed with tuberculous meningitis. We review the clinical and molecular aspects of LMM and discuss on clinical and diagnostic implications. Case presentation A 27-month-old girl with a 1-week history of vomiting with mild intermittent strabismus underwent Magnetic Resonance Imaging, showing diffuse brainstem and spinal leptomeningeal enhancement. Cerebrospinal fluid analysis was unremarkable. Antitubercular treatment was started without any improvement. A spinal intradural biopsy was suggestive for primary leptomeningeal melanomatosis. Chemotherapy was started, but general clinical conditions progressively worsened and patient died 11 months after diagnosis. Molecular investigations were performed post-mortem on tumor tissue and revealed absence of BRAFV600E, GNAQQ209 and GNA11Q209 mutations but the presence of a NRASQ61K mutation. Conclusions Our case adds some information to the limited experience of the literature, confirming the presence of the NRASQ61K mutation in children with melanomatosis. To our knowledge, this is the first case of leptomeningeal melanocytic neoplasms (LMN) without associated skin lesions to harbor this mutation. Isolated LMN presentation might be insidious, mimicking tuberculous meningitis, and should be suspected if no definite diagnosis is possible or if antitubercular treatment does not result in dramatic clinical improvement. Leptomeningeal biopsy should be considered, not only to confirm diagnosis of LMN but also to study molecular profile. Further molecular profiling and preclinical models will be pivotal in testing combination of target therapy to treat this challenging disease. from Cancer via ola Kala on Inoreader via IFTTT

Abstract Background High-risk Human Papillomavirus (HPV) testing is replacing cytology in cervical cancer screening as it is more sensitive for preinvasive cervical lesions. However, the bottleneck of HPV testing is the many false positive test results (positive tests without cervical lesions). Here, we evaluated to what extent these can be explained by cross-reactivity, i.e. positive test results without evidence of high-risk HPV genotypes. The patterns of cross-reactivity have been thoroughly studied for hybrid capture II (HC2) but not yet for newer HPV assays although the manufacturers claimed no or limited frequency of cross-reactivity. In this independent study we evaluated the frequency of cross-reactivity for HC2, cobas, and APTIMA assays. Methods Consecutive routine cervical screening samples from 5022 Danish women, including 2859 from women attending primary screening, were tested with the three evaluated DNA and mRNA HPV assays. Genotyping was undertaken using CLART HPV2 assay, individually detecting 35 genotypes. The presence or absence of cervical lesions was determined with histological examinations; women with abnormal cytology were managed as per routine recommendations; those with normal cytology and positive high-risk HPV test results were invited for repeated testing in 18 months. Results Cross-reactivity to low-risk genotypes was detected in 109 (2.2 %) out of 5022 samples on HC2, 62 (1.2 %) on cobas, and 35 (0.7 %) on APTIMA with only 10 of the samples cross-reacting on all 3 assays. None of the 35 genotypes was detected in 49 (1.0 %), 162 (3.2 %), and 56 (1.1 %) samples, respectively. In primary screening at age 30 to 65 years (n = 2859), samples of 72 (25 %) out of 289 with high-risk infections on HC2 and < CIN2 histology were due to cross-reactivity. On cobas, this was 106 (26 %) out of 415, and on APTIMA 48 (21 %) out of 224. Conclusions Despite manufacturer claims, all three assays showed cross-reactivity. In primary cervical screening at age ≥30 years, cross-reactivity accounted for about one quarter of false positive test results regardless of the assay. Cross-reactivity should be addressed in EU tenders, as this primarily technical shortcoming imposes additional costs on the screening programmes. from Cancer via ola Kala on Inoreader via IFTTT

Abstract Background Synovial sarcoma (SS) is a soft tissue sarcoma of unknown histogenesis. Most metastatic or unresectable cases are incurable. Novel antitumor agents and precise prognostication are needed for SS patients. The protein forkhead box M1 (FOXM1), which belongs to the FOX family of transcription factors, is considered to be an independent predictor of poor survival in many cancers and sarcomas, but the prognostic implications and oncogenic roles of FOXM1 in SS are poorly understood. Here we examined the correlation between FOXM1 expression and clinicopathologic and prognostic factors, and we investigated the efficacy of FOXM1 target therapy in SS cases. Methods Immunohistochemical study of 106 tumor specimens was conducted to evaluate their immunohistochemical expression of FOXM1. An in vitro study examined the antitumor effect of the FOXM1 inhibitor thiostrepton and small interference RNA (siRNA) on two SS cell lines. We also assessed the efficacy of the combined use of doxorubicin (DOX) and thiostrepton. Results Univariate and multivariate analyses revealed that FOXM1 expression was associated with poor prognosis in SS. The cDNA microarray analysis using clinical samples revealed that the expression of cell cycle-associated genes was correlated with FOXM1 expression. FOXM1 inhibition by thiostrepton showed significant antitumor activity on the SS cell lines in vitro. FOXM1 interruption by siRNA increased the chemosensitivity for DOX in both SS cell lines. Conclusion FOXM1 expression is a novel biomarker, and its inhibition is a potential treatment option for SS. from Cancer via ola Kala on Inoreader via IFTTT

Abstract Background Occult invasive cervical cancer (OICC) is sometimes incidentally found in surgical specimens after a simple hysterectomy (SH). This study was aimed at identifying a subset of patients with OICC who have a favorable prognosis. This patient group may not require adjuvant radiotherapy and other procedures. Methods The medical records of women in whom OICC was detected after an inadvertent SH were retrospectively reviewed. The relevant data, including clinicopathological characteristics, treatment and clinical outcome were evaluated. The primary and secondary endpoints were overall survival (OS) and relapse-free survival (RFS), respectively. Results Eighty-nine patients who met the inclusion criteria were included for analysis, and the risk of OICC was found to be 1.9 %. Finding an invasive cancer in a hysterectomy specimen after a conization procedure that shows positive margins was the most common reason (41.6 %) for the performance of inadvertent SH. In the univariate analysis, a tumor width > 20 mm, deep stromal invasion, and lymph node metastasis (LNM) were adversely associated with relapse (P < 0.001, < 0.001, and = 0.001, respectively) and survival (P = 0.003, 0.004, and 0.027, respectively), although these parameters were not independently associated with patient prognoses in the multivariate analysis. In patients with a tumor width ≤ 20 mm and superficial stromal invasion in the observation subgroup, the 5-year RFS and 5-year OS were both 100 %, whereas they were 57.1 % and 66.7 %, respectively, in patients with a tumor size > 20 mm and deep stromal invasion in the radiotherapy or chemotherapy subgroup (P < 0.001, and = 0.008, respectively). Conclusions Simple observation after a lymphadenectomy procedure may be feasible in OICC patients with a tumor width ≤ 20 mm, superficial stromal invasion, a negative section margin in hysterectomy specimens, and no LNM. from Cancer via ola Kala on Inoreader via IFTTT

Abstract Background Colorectal cancer (CRC) is closely linked to Wnt signalling, with 94 % of cases exhibiting a Wnt related mutation. ROR2 is a receptor tyrosine kinase that is thought to repress β-catenin dependent Wnt signalling. Our study aims to determine if ROR2 is epigenetically silenced in CRC and determine if in vitro silencing of ROR2 potentiates Wnt signalling, and alters the proliferative, migratory or invasive potential of cells. Methods ROR2 expression was examined in CRC cell lines and patient adenomas using qRT-PCR, while COBRA and bisulphite sequencing was used to analyse ROR2 promoter methylation. 258 patient primary tumour samples from publicly available databases were also examined for ROR2 expression and methylation. In addition, the functional effects of ROR2 modulation were investigated in HCT116 cells following ROR2 siRNA knockdown and in RKO and SW620 cells following ectopic ROR2 expression. Results Reduced ROR2 expression was found to correlate with ROR2 promoter hypermethylation in colorectal cancer cell lines, carcinomas and adenomas. ROR2 expression was downregulated in 76.7 % (23/30) of CRC cell lines with increasing ROR2 promoter hypermethylation correlating with progressively lower expression. Analysis of 239 primary tumour samples from a publicly available cohort also found a significant correlation between reduced ROR2 expression and increased promoter methylation. Methylation analysis of 88 adenomas and 47 normal mucosa samples found greater percentage of adenoma samples to be methylated. Additional analysis also revealed that adenoma samples with reduced ROR2 expression also possessed ROR2 promoter hypermethylation. ROR2 knockdown in the CRC cell line HCT116 significantly decreased expression of the β-catenin independent Wnt targets genes JNK and NFATC1, increased cellular proliferation and migration but decreased invasion. When ROR2 was ectopically expressed in RKO and SW620 cells, there was no significant change to either cellular proliferation or migration. Conclusion ROR2 is frequently epigenetically inactivated by promoter hypermethylation in the early stages of colorectal neoplasia and this may contribute to colorectal cancer progression by increasing cellular proliferation and migration. from Cancer via ola Kala on Inoreader via IFTTT

Abstract Background In treatment-refractory liver dominant metastatic colorectal cancer, the role of liver directed therapies still is unclear. We sought to determine a prognostic score for Y90 radioembolization in these patients. Methods We analyzed 106 patients with refractory liver dominant mCRC who had undergone a total of 178 Y90 radioembolizations with resin microspheres was collected. Potential factors influencing survival were analyzed using a Cox regression. The Log rank test served to establish prognostic factors and to form a clinical score for outcome prediction after Y90 radioembolization. Results Median survival of all patients was 6.7 months. Neither age nor prior surgical or systemic therapy nor metastatic spread had an effect on survival. In contrast, hepatic tumor load, Karnofsky index as well as CEA and CA19-9 serums level had a significant influence (p < 0.001, p = 0.037, p = 0.023 and p < 0.001, respectively). These three factors formed a score with 1 point each for tumor load >20 %, CEA >130 ng/ml or CA19-9 > 200U/ml and Karnofsky index <80 %. Patients with a score of 0 and 1 displayed a median OS of 10.4 months. Patients with a score of 2 and 3 demonstrated a median OS of 5.1 months only (p < 0.001). Conclusion Overaggressive patient selection for Y90 radioembolization of liver dominant chemorefractory mCRC is of questionable benefit. A scoring system comprising hepatic tumor load, CEA and CA19-9 serum levels and Karnofsky index (TuCK-score) may support an improved patient selection. In our cohort of liver only versus liver dominant disease, extrahepatic lung or lymphatic metastases did not significantly alter the prognosis. from Cancer via ola Kala on Inoreader via IFTTT

Related Articles Bruceantin inhibits multiple myeloma cancer stem cell proliferation. Cancer Biol Ther. 2016 Jul 19;:0 Authors: Issa ME, Berndt S, Carpentier G, Pezzuto JM, Cuendet M Abstract Multiple myeloma (MM) continues to claim the lives of a majority of patients. MM cancer stem cells (CSCs) have been demonstrated to sustain tumor growth. Due to their ability to self-renew and to express detoxifying enzymes and efflux transporters, MM-CSCs are rendered highly resistant to conventional therapies. Therefore, managing MM-CSCs characteristics could have profound clinical implications. Bruceantin (BCT) is a natural product previously demonstrated to inhibit the growth of MM in RPMI 8226 cells-inoculated mouse xenograft models, and to cause regression in already established tumors. The objectives of the present study were to test the inhibitory effects of BCT on MM-CSCs growth derived from a human primary tumor, and to explore a mechanism of action underlying these effects. BCT exhibited potent antiproliferative activity in MM-CSCs starting at 25 nM. BCT induced cell cycle arrest, cell death and apoptosis in MM-CSCs as well as inhibited cell migration and angiogenesis in vitro. Using a qPCR screen, it was found that the gene expression of a number of Notch pathway members was altered. Pretreatment of MM-CSCs with the γ-secretase inhibitor RO4929097, a Notch pathway inhibitor, reversed BCT-induced effects on MM-CSCs proliferation. In this study, BCT was shown to be an effective agent in controlling the proliferation, viability and migration of MM-CSCs as well as angiogenesis in vitro. The effect on MM-CSCs proliferation may be mediated by the Notch pathway. These results warrant further investigation of BCT in a broader set of human-derived MM-CSCs and with in vivo models representative of MM. PMID: 27434731 [PubMed - as supplied by publisher] from Cancer via ola Kala on Inoreader via IFTTT

Related Articles Necroptosis: A New Way of Dying? Cancer Biol Ther. 2016 Jul 19;:0 Authors: Hanson B Abstract This review embarks upon a cell death journey from the discovery of apoptosis and necrosis through to the coalescence of these: necroptosis. The mechanisms of two emerging necrotic cell death pathways, pyroptosis and ferroptosis, will be explored before delving into apoptotic and necroptotic signalling cascades, highlighting the complex interplay between molecular players. The involvement of the ripoptosome, interferon signalling and DNA damage in necroptosis will be discussed briefly. The major focus is on necroptosis initiation by tumour necrosis factor-α (TNFα) and its cognate receptor TNFR1, caspase-independent RIP1/RIP3/MLKL necrosome activation and cell death propagation by damage-associated molecular pattern (DAMP) release. Finally, the implications of a complex cell death signalling network will be revealed in the context of cancer biology and therapy. The clinical contribution of the discovery of necroptosis as an unequivocally new way of dying is monumental and could drastically alter cancer therapy strategies in the future. PMID: 27434654 [PubMed - as supplied by publisher] from Cancer via ola Kala on Inoreader via IFTTT

Abstract Background Malignant mesothelioma is a rare and aggressive tumor with a poor prognosis. Distant metastases are very rare, and the oral cavity metastases are exceedingly rare. Only a few cases with metastasis to oral gingiva are reported. To our knowledge, this is the first case report of pleural mesothelioma metastasized to the retromolar trigone. Case presentation A 59-year-old male was referred with a painless growth at retromolar trigone area. It had been present for 2 months and had increased in size during this period of time. Past medical history revealed a malignant mesothelioma. Intraoral examination showed a soft, haemorrhagic, ulcerated lesion at the right retromolar trigone area. There was no destruction of the bony architecture. An incisional biopsy was performed under local anaesthesia. Based on the histopathological and immunohistochemical findings, a final diagnosis of metastatic mesothelioma was made. The patient was informed about the possibility of multiple metastases within the body, but he succumbed after 45 days following deterioration of his medical condition. Conclusions Biopsy, history of the patient and clinical picture were provided to the clinicians to make an efficient differential diagnosis. Differential diagnosis must be performed with other oral cancers, because the management is totally different. from Cancer via ola Kala on Inoreader via IFTTT

Purpose: Tumorigenesis of gastrointestinal stromal tumors (GIST) is driven by gain of function mutations in the KIT gene, which result in over-expression of activated mutant KIT proteins (MT-KIT). However, the mechanism of MT-KIT over-expression is poorly understood. Experimental Design: By protein expression analysis and immunofluorescent microscopic analysis, we determine the stability and localization of MT-KIT in four GIST cell lines with different mutations and HeLa cells transfected with mutant KIT model vectors. We also used 154 human GIST tissues to analyze the relationship between the expression of PKC- and MT-KITs, and correlations between PKC- over-expression and clinicopathological parameters. Results: We report that four different MT-KIT proteins are intrinsically less stable than wild type KIT due to proteasome-mediated degradation and abnormally localized to the endoplasmic reticulum (ER) or the Golgi complex. By screening a MT-KIT-stabilizing factor, we find that PKC- is strongly and exclusively expressed in GISTs and interacts with intracellular MT-KIT to promote its stabilization by increased retention in the Golgi complex. In addition, western blotting analysis using 50 GIST samples shows strong correlation between PKC- and MT-KIT expression (correlation coefficient = 0.682, P < 0.000001). Immunohistochemical analysis using 154 GISTs further demonstrates that PKC- over-expression significantly correlates with several clinicopathological parameters such as high tumor grade, frequent recurrence/metastasis, and poor patient survival. Conclusions: Our findings suggest that sustained MT-KIT over-expression through PKC--mediated stabilization in the Golgi contributes to GIST progression, and provides a rationale for anti-PKC- therapy in GISTs. from Cancer via ola Kala on Inoreader via IFTTT

Purpose: New therapeutic approaches are needed for patients with thyroid cancer refractory to radioiodine treatment. An inhibitor of bromodomain and extraterminal domain (BET) proteins, JQ1, shows potent anti-tumor effects in hematological cancers and solid tumors. To evaluate whether JQ1 is effective against thyroid cancer, we examined anti-tumor efficacy of JQ1 using the ThrbPV/PVKrasG12D mouse, a model of anaplastic thyroid cancer. Experimental Design: We treated ThrbPV/PVKrasG12D mice with vehicle or JQ1 at a dose of 50 mg/kg body weight/day starting at the age of 8 weeks for a 10-week period and monitored thyroid tumor progression. Results: JQ1 markedly inhibited thyroid tumor growth and prolonged survival of these mice. Global differential gene expression analysis showed that JQ1 suppressed the cMyc (hereafter referred to as Myc) transcription program by inhibiting mRNA expression of Myc, ccnd1, and other related genes. JQ1-suppressed Myc expression was accompanied by chromatin remodeling as evidenced by increased expression of histones and hexamethylene bis-acetamide inducible 1, a suppressor of RNA polymerase II transcription elongation. Analyses showed that JQ1 decreased MYC abundance in thyroid tumors and attenuated the cyclin-CDK4-Rb-E2F3 signaling to decrease tumor growth. Further analysis indicated that JQ1 inhibited the recruitment of BDR4 to the promoter complex of the Myc and Ccnd1 genes in rat thyroid follicular PCCL3 cells, resulting in decreased MYC expression at the mRNA and protein levels to inhibit tumor cell proliferation. Conclusions: These preclinical findings suggest that BET inhibitors may be an effective agent to reduce thyroid tumor burden for the treatment of refractory thyroid cancer. from Cancer via ola Kala on Inoreader via IFTTT

Purpose: The androgen receptor (AR) mRNA splice variant AR-V7 has emerged as a predictive biomarker for response to AR targeted therapies. There are currently no commercially available assays to detect AR splice variants. The branched chain RNA in situ hybridization (ISH) platform enables the highly sensitive detection of RNA transcripts in formalin-fixed, paraffin-embedded (FFPE) tissues. Experimental Design: We designed a branched chain RNA ISH probe to target the unique cryptic exon CE3 of AR-V7 using multiple tiling probes. This automated ISH assay was applied to tumor tissue from two distinct clinical cohorts that we hypothesized would differ in AR-V7 status. Results: We detected AR-V7 in all tumor samples from men with metastatic castration-resistant prostate cancer with tissue obtained after disease progression despite at least one subsequent line of hormonal therapy (abiraterone, enzalutamide, or bicalutamide; n=12). We detected AR-V7 in just one tumor from men who had undergone prostatectomy for localized adenocarcinoma (n=30; Gleason 4+5=9 in the AR-V7 positive sample). Given the apparent distinction between the above groups by AR-V7 signal, we analyzed pre-treatment AR-V7 status as a predictive and prognostic biomarker in men with treatment-naive metastatic disease. Patients with metastases but without detectable AR-V7 RNA at baseline had significantly longer overall survival (logrank P = 0.044) and a trend toward superior progression-free survival (logrank P = 0.055). Conclusions: Within an institutional cohort, the RNA ISH assay identified AR-V7 within FFPE tissue and may have prognostic value in metastatic castration-sensitive prostate cancer. These preliminary findings warrant further study in larger cohorts. from Cancer via ola Kala on Inoreader via IFTTT

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Medicine by Alexandros G.Sfakianakis