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Masato Yasui, Yoriko Hasegawa, Takashi Kawahara, Yohei Kumano, Yasuhide Miyoshi, Nobuaki Matsubara, Hiroji Uemura
Abiraterone acetate (AA), a CYP17 inhibitor, now has a crucial role in the treatment of castration-resistant prostate cancer (CRPC), and previous studies have reported several prognostic clinical factors for AA treatment. The neutrophil-to-lymphocyte ratio (NLR) has also been investigated for a CRPC treatments in a few reports, however it has not been identified to be a prognostic factor for AA treatment in Japanese patients. The present study aimed to assess the association of the baseline NLR with the overall survival (OS) in CPRC patients treated by AA...
April 2018: Molecular and Clinical Oncology
Michael V Fiandalo, John J Stocking, Elena A Pop, John H Wilton, Krystin M Mantione, Yun Li, Kristopher M Attwood, Gissou Azabdaftari, Yue Wu, David S Watt, Elizabeth M Wilson, James L Mohler
Androgen deprivation therapy (ADT) is palliative and prostate cancer (CaP) recurs as lethal castration-recurrent/resistant CaP (CRPC). One mechanism that provides CaP resistance to ADT is primary backdoor androgen metabolism, which uses up to four 3α-oxidoreductases to convert 5α-androstane-3α,17β-diol (DIOL) to dihydrotestosterone (DHT). The goal was to determine whether inhibition of 3α-oxidoreductase activity decreased conversion of DIOL to DHT. Protein sequence analysis showed that the four 3α-oxidoreductases have identical catalytic amino acid residues...
February 16, 2018: Oncotarget
Tong Sun, Shin-Yi Du, Joshua Armenia, Fangfang Qu, Jingyu Fan, Xiaodong Wang, Teng Fei, Kazumasa Komura, Shirley X Liu, Gwo-Shu Mary Lee, Philip W Kantoff
Mechanisms by which non-coding RNAs contribute to the progression of hormone-sensitive prostate cancer (PCa) (HSPC) to castration-resistant PCa (CRPC) remain largely unknown. We previously showed that microRNA-221/222 is up-regulated in CRPC and plays a critical role in modulating androgen receptor function during CRPC development. With further investigation, we characterized a putative promoter region located 23.3 kb upstream of the miR-221/222 gene, and this promoter is differentially activated in CRPC LNCaP-Abl cells, leading to the up-regulation of miR-221/222...
March 13, 2018: Oncogenesis
Rachana Patel, Janis Fleming, Ernest Mui, Carolyn Loveridge, Peter Repiscak, Arnaud Blomme, Victoria Harle, Mark Salji, Imran Ahmad, Katy Teo, Freddie C Hamdy, Ann Hedley, Niels van den Broek, Gillian Mackay, Joanne Edwards, Owen J Sansom, Hing Y Leung
Metastatic castration-resistant prostate cancer (mCRPC) is a lethal form of treatment-resistant prostate cancer and poses significant therapeutic challenges. Deregulated receptor tyrosine kinase (RTK) signalling mediated by loss of tumour suppressor Sprouty2 (SPRY2) is associated with treatment resistance. Using pre-clinical human and murine mCRPC models, we show that SPRY2 deficiency leads to an androgen self-sufficient form of CRPC Mechanistically, HER2-IL6 signalling axis enhances the expression of androgen biosynthetic enzyme HSD3B1 and increases SRB1-mediated cholesterol uptake in SPRY2-deficient tumours...
March 14, 2018: EMBO Molecular Medicine
Ryuji Yamamoto, Tsuyoshi Osawa, Yusuke Sasaki, Shogo Yamamoto, Motonobu Anai, Kouji Izumi, Yoshihiro Matsumura, Juro Sakai, Hiroyuki Aburatani, Atsushi Mizokami, Tatsuhiko Kodama, Toshiya Tanaka
The non-POU domain-containing octamer binding protein p54nrb /NONO is a multifunctional nuclear protein involved in RNA splicing, processing, and transcriptional regulation of nuclear hormone receptors. Through chromosome copy number analysis via whole-exome sequencing, we revealed amplification of the chromosome Xq11.22-q21.33 locus containing the androgen receptor ( AR ) and NONO genes in androgen-independent, castration-resistant prostate cancer (CRPC)-like LNCaP-SF cells. Moreover, NONO was frequently amplified and overexpressed in patients with CRPC...
February 13, 2018: Oncotarget
Christian D Fankhauser, Peter J Schüffler, Silke Gillessen, Aurelius Omlin, Niels J Rupp, Jan H Rueschoff, Thomas Hermanns, Cedric Poyet, Tullio Sulser, Holger Moch, Peter J Wild
Background: We aimed to analyze the frequency and distribution of PD-L1 expression in specimens from prostate cancer (PC) patients using two different anti-PD-L1 antibodies (E1L3N, SP263). Materials and Methods: PD-L1 immunohistochemistry was performed in a tissue microarray consisting of 82 castration-resistant prostate cancer (CRPC) specimens, 70 benign prostate hyperplasia (BPH) specimens, 96 localized PC cases, and 3 PC cell lines, using two different antibodies (clones E1L3N, and SP263)...
February 13, 2018: Oncotarget
Matthew J Schiewer, Karen E Knudsen
Prostatic adenocarcinoma (PCa) remains a significant health concern. Although localized PCa can be effectively treated, disseminated disease remains uniformly fatal. PCa is reliant on androgen receptor (AR); as such, first-line therapy for metastatic PCa entails suppression of AR signaling. Although initially effective, recurrent tumors reactivate AR function, leading to a lethal stage of disease termed castration-resistant PCa (CRPC). Recent findings implicate AR signaling in control of DNA repair and show that alterations in DNA damage repair pathways are strongly associated with disease progression and poor outcome...
March 12, 2018: Cold Spring Harbor Perspectives in Medicine
Adriana C Vidal, Lauren E Howard, Amanda de Hoedt, Christopher J Kane, Martha K Terris, William J Aronson, Matthew R Cooperberg, Christopher L Amling, Stephen J Freedland
OBJECTIVE: At the population level, obesity is associated with prostate cancer (PC) mortality; however, some studies found higher body mass index (BMI) is associated with better long-term PC outcomes among men with metastatic castration-resistant PC (mCRPC). PATIENTS AND METHODS: We tested whether obesity was associated with progression to metastasis, PC-specific mortality (PCSM), and all-cause mortality (ACM) among 1192 non-metastatic CRPC patients from the SEARCH Database...
March 9, 2018: BJU International
Takatsugu Okegawa, Naoki Ninomiya, Kazuki Masuda, Yu Nakamura, Mitsuhiro Tambo, Kikuo Nutahara
OBJECTIVE: We examined whether androgen receptor splice variant 7 (AR-V7) in circulating tumor cell(CTC)clusters can be used to predict survival in patients with bone metastatic castration resistant-prostate cancer (mCRPC) treated with abiraterone or enzalutamide. METHODS: We retrospectively enrolled 98 patients with CRPC on abiraterone or enzalutamide, and investigated the prognostic value of CTC cluster detection (+ v -) and AR-V7 detection (+ v -) using a CTC cluster detection - based AR-V7 mRNA assay...
March 5, 2018: Prostate
Yusuke Ito, Marianne D Sadar
Enzalutamide is a nonsteroidal antiandrogen for the treatment of metastatic castration-resistant prostate cancer (mCRPC) both before and after chemotherapy. Enzalutamide is more effective than its predecessor bicalutamide, which was analyzed in head-to-head studies of patients with CRPC. This family of nonsteroidal antiandrogens is now comprised of four drugs approved by the US Food and Drug Administration with two investigational drugs in clinical trials. Antiandrogens have been employed clinically for more than five decades to provide a rich resource of information...
2018: Research and Reports in Urology
Anna Maria Mangano, Massimiliano Pacilio, Pasquale Ialongo, Alessandro Semprebene, Guido Ventroni, Lucio Mango
Here, we present the case of a 64-year-old male patient diagnosed with castration-resistant prostate cancer (CRPC) with bone metastasis, treated with abiraterone prednisone/prednisolone in combination with223 Ra-dichloride therapy, who had remission and a subsequent relapse of bone metastasis on repeated bone scans after therapy. We also discuss the possibility of continuing the223 Ra-dichloride therapy over the six planned administrations by administering other cycles at the same dose or at higher doses, if shown to be devoid of a significant increase in side effects, based on dosimetry considerations...
February 27, 2018: Diagnostics
Anders R Holmberg, Marcela Marquez, Lena Lennartsson, Lennart Meurling, Sten Nilsson
BACKGROUND/AIM: Prostate-specific membrane antigen (PSMA) is emerging as a target for treatment of castration-resistant prostate cancer (CRPC) while its up-regulated in the majority of CRPC tumors. The most common approach is targeted radionuclide therapy. MATERIALS AND METHODS: The PSMA binding pharmacophore Glu-Urea-Lysine (GUL) and lysine were conjugated to oxidized dextran with reductive amination and subsequently labelled with fluorosceinisothiocyanate (FITC)...
March 2018: Anticancer Research
Aishwarya Pawar, Paradesi Naidu Gollavilli, Shaomeng Wang, Irfan A Asangani
BRD4 plays a major role in the transcription networks orchestrated by androgen receptor (AR) in castration-resistant prostate cancer (CRPC). Several BET inhibitors (BETi) that displace BRD4 from chromatin are being evaluated in clinical trials for CRPC. Here, we describe mechanisms of acquired resistance to BETi that are amenable to targeted therapies in CRPC. BETi-resistant CRPC cells displayed cross-resistance to a variety of BETi in the absence of gatekeeper mutations, exhibited reduced chromatin-bound BRD4, and were less sensitive to BRD4 degraders/knockdown, suggesting a BRD4-independent transcription program...
February 27, 2018: Cell Reports
Sebastian Frees, Shusuke Akamatsu, Samir Bidnur, Daniel Khalaf, Claudia Chavez-Munoz, Werner Struss, Bernhard J Eigl, Martin Gleave, Kim N Chi, Alan So
PURPOSE: Time to metastasis is often used as a surrogate parameter of treatment success in clinical trials for prostate cancer. However, it has not been shown that there is a clear correlation between time to metastasis and overall survival. Our objective was to evaluate the impact of time to metastasis on OS in patients with prostate cancer. METHODS: Between 2008 and 2015, 269 patients with mPCa were included in this retrospective study with a median follow-up of 7...
February 27, 2018: World Journal of Urology
Joël R Federer-Gsponer, Cristina Quintavalle, David C Müller, Tanja Dietsche, Valeria Perrina, Thomas Lorber, Darius Juskevicius, Elisabeth Lenkiewicz, Tobias Zellweger, Thomas Gasser, Michael T Barrett, Cyrill A Rentsch, Lukas Bubendorf, Christian Ruiz
Understanding the evolutionary mechanisms and genomic events leading to castration resistant (CR) prostate cancer (PC) is key to improve the outcome of this otherwise deadly disease. Here, we delineated the tumour history of seven patients progressing to castration resistance by analysing matched prostate cancer tissues before and after castration. We performed genomic profiling of DNA-content based flow-sorted populations in order to define the different evolutionary patterns. In one patient, we discovered that a catastrophic genomic event, known as chromothripsis, resulted in multiple CRPC tumour populations with distinct, potentially advantageous copy number aberrations, including an amplification of FK506 Binding Protein 4 (FKBP4, also known as FKBP52), a protein enhancing the transcriptional activity of androgen receptor signalling...
February 27, 2018: Journal of Pathology
Bhakti R Pathak, Ananya A Breed, Priyanka Deshmukh, Smita D Mahale
Cysteine-rich secretory protein 3 (CRISP3) is one of the most upregulated genes in prostate cancer. Androgen receptor (AR) plays an important role not only in initial stages of prostate cancer development but also in the advanced stage of castration-resistant prostate cancer (CRPC). Role of AR in regulation of CRISP3 expression is not yet known. In order to understand the regulation of CRISP3 expression, various overlapping fragments of CRISP3 promoter were cloned in pGL3 luciferase reporter vector. All constructs were transiently and stably transfected in PC3 (CRISP3 negative) and LNCaP (CRISP3 positive) cell lines and promoter activity was measured by luciferase assay...
February 22, 2018: Journal of Steroid Biochemistry and Molecular Biology
Yuan-Chin Tsai, Wei-Yu Chen, Wassim Abou-Kheir, Tao Zeng, Juan Juan Yin, Hisham Bahmad, Yi-Chao Lee, Yen-Nien Liu
The chemokine CC motif ligand 2 (CCL2) is important in recruiting tumor-associated macrophages and is involved in the development of castration-resistance prostate cancer (CRPC) after androgen-deprivation therapy (ADT); however, the underlying mechanism remains unclear. We found that inactivation of the androgen receptor (AR) reduces a transcriptional repressor (SAM pointed domain-containing ETS transcription factor, SPDEF) of CCL2, which mediates epithelial-to-mesenchymal transition (EMT) of prostate tumor cells...
February 22, 2018: Biochimica et Biophysica Acta
Pedro Barata, Matthew Cooney, Allison Tyler, John Wright, Robert Dreicer, Jorge A Garcia
Background The inhibition of insulin-like growth factor receptor-1 (IGF-1R) induces cell cycle arrest and enhancing the effect of castration by delay of progression of human prostate cancer models. Linsitinib is a small molecule and potent dual inhibitor of IGF-1R and insulin receptor tyrosine kinase activity. We report results of a single-arm, phase II study evaluating the safety and efficacy of linsitinib in men with chemotherapy-naïve asymptomatic or mildly symptomatic metastatic castration resistant prostate cancer (mCRPC)...
February 23, 2018: Investigational New Drugs
Kagenori Ito, Takahiro Kimura, Hajime Onuma, Ryuji Tabata, Tatsuya Shimomura, Kenta Miki, Masayuki Tomita, Shin Egawa
BACKGROUND: Guidelines define docetaxel as a first-line therapeutic option for metastatic castration-resistant prostate cancer (mCRPC). However, the role of docetaxel in non-metastatic castration-resistant prostate cancer (nmCRPC) has not been fully investigated. The aim of this retrospective study was to evaluate the potential role of docetaxel in nmCRPC. Clinical outcomes including overall survival were compared between CRPC patients who had docetaxel introduced while in nonmetastatic versus metastatic diseases...
February 23, 2018: Prostate
Karyn A Sullivan, Ngaire Kingi, Phillip Good, Petra Vayne-Bossert, Janet R Hardy
BACKGROUND: Palliative care patients are inherently difficult to recruit to and retain on studies. Even when patients are recruited, it is hard to complete studies with sufficient data. There is a dearth of literature specific to men with castrate resistant prostate cancer (CRPC) and the clinical trials coordinator/research nurse's perspective in improving trial outcomes in palliative care. Objectives To describe the lessons learnt (by the nursing research team) from a prospective cohort study of men with CRPC and the practical implications for future research in this area...
February 2, 2018: International Journal of Palliative Nursing
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