Neuroendocrine phenotype is commonly associated with therapy resistance and poor prognoses in small-cell neuroendocrine cancers (SCNCs), such as neuroendocrine prostate cancer (NEPC) and small-cell ...lung cancer (SCLC). Expression levels of current neuroendocrine markers exhibit high case-by-case variability, so multiple markers are used in combination to identify SCNCs. Here, we report that ACAA2 is elevated in SCNCs and is a potential molecular indicator for SCNCs.
ACAA2 expressions in tumour xenografts, tissue microarrays (TMAs), and patient tissues from prostate and lung cancers were analysed via immunohistochemistry. ACAA2 mRNA levels in lung and prostate cancer (PC) patients were assessed in published datasets.
ACAA2 protein and mRNA levels were elevated in SCNCs relative to non-SCNCs. Medium/high ACAA2 intensity was observed in 78% of NEPC PDXs samples (N = 27) relative to 33% of adeno-CRPC (N = 86), 2% of localised PC (N = 50), and 0% of benign prostate specimens (N = 101). ACAA2 was also elevated in lung cancer patient tissues with neuroendocrine phenotype. 83% of lung carcinoid tissues (N = 12) and 90% of SCLC tissues (N = 10) exhibited medium/high intensity relative to 40% of lung adenocarcinoma (N = 15).
ACAA2 expression is elevated in aggressive SCNCs such as NEPC and SCLC, suggesting it is a potential molecular indicator for SCNCs.
Glandular cancers are amongst the most prevalent types of cancer, which can develop in many different organs, presenting challenges in their detection as well as high treatment variability and ...failure rates. For that purpose, anticancer drugs are commonly tested in cancer cell lines grown in 2D tissue culture on plastic dishes
, or in animal models
. However, 2D culture models diverge significantly from the 3D characteristics of living tissues and animal models require extensive animal use and time. Glandular cancers, such as prostate cancer-the second leading cause of male cancer death-typically exist in co-centrical architectures where a cell layer surrounds an acellular lumen. Herein, this spatial cellular position and 3D architecture, containing dual compartments with different hydrogel materials, is engineered using a simple co-axial nozzle setup, in a single step utilizing prostate as a model of glandular cancer. The resulting hydrogel soft structures support viable prostate cancer cells of different cell lines and enable over-time maturation into cancer-mimicking aggregates surrounding the acellular core. The biofabricated cancer mimicking structures are then used as a model to predict the inhibitory efficacy of the poly ADP ribose polymerase inhibitor, Talazoparib, and the antiandrogen drug, Enzalutamide, in the growth of the cancer cell layer. Our results show that the obtained hydrogel constructs can be adapted to quickly obtain 3D cancer models which combine 3D physiological architectures with high-throughput screening to detect and optimize anti-cancer drugs in prostate and potentially other glandular cancer types.
Abstract
Metastasis is the main cause of cancer-associated morbidity which will account for ∼ 600,000 deaths in the USA in 2021. Defining new mechanisms that drive cancer metastasis is vital for ...developing new therapeutic strategies and improving clinical outcomes for cancer patients. Herein, we describe a recently established 3D Matrigel drop invasion assay to measure cancer cell invasion and migration capability in vitro. This assay is a versatile and simple tool to test the ability of cells to invade and migrate, test the functional role of genes of interest in cell invasion and migration, analyze the localization of the target proteins at the cell invasion edge in situ, and screen drug effects on cancer cell invasion and migration.
Matrix metalloproteases (MMP) are a large family of proteases, which synergistically degrade abundant extracellular matrix and play an essential role in tissue degradation and remodelling. Sensing of ...MMP levels, notably the pro- and activated matrix metalloproteinases (MMP-2 and MMP-9), would provide an early warning system of chronic inflammation in acute wounds. With this in mind, we developed a graphene-based electrochemical sensor for both of these relevant biomarkers using an innovative surface ligand, 1-pyrene pyridyl disulphide (PDS), engineered to not only capture the analyte with high affinity, but also to allow the regeneration of the whole ligand/analyte construct. The thiol–pyridyl disulphide exchange reaction was used in this work for sequential analysis of MMP-9 and MMP-2 via the engineered 1-pyrene pyridyl disulphide, the PDS surface ligand. The sensor was operational down to 0.1 pM (9.2 pg mL −1 ) for MMP-9 and allowed to sense MMP-2 on the same surface with a detection limit of 100 pM (950 pg mL −1 ) once treated with 1-pyrene pyridyl disulphide (PDS) (DTT) and 2-dipyridylsulfide (DPDS), followed by integration of the thiolated MMP-2 aptamer onto the PDS-modified renewable electrode interface. Using swab samples from diabetic patients with open wounds confirmed that the sensors characteristics are adapted for sensing of MMP levels in wound fluids and will open up the future for the development of intelligent bandage.
Among men, prostate cancer is the second leading cause of cancer-associated mortality, with advanced disease remaining a major clinical challenge. We describe a small molecule, SU086, as a ...therapeutic strategy for advanced prostate cancer. We demonstrate that SU086 inhibits the growth of prostate cancer cells in vitro, cell-line and patient-derived xenografts in vivo, and ex vivo prostate cancer patient specimens. Furthermore, SU086 in combination with standard of care second-generation anti-androgen therapies displays increased impairment of prostate cancer cell and tumor growth in vitro and in vivo. Cellular thermal shift assay reveals that SU086 binds to heat shock protein 90 (HSP90) and leads to a decrease in HSP90 levels. Proteomic profiling demonstrates that SU086 binds to and decreases HSP90. Metabolomic profiling reveals that SU086 leads to perturbation of glycolysis. Our study identifies SU086 as a treatment for advanced prostate cancer as a single agent or when combined with second-generation anti-androgens.
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•SU086 inhibits prostate cancer growth in preclinical models of prostate cancer•SU086 targets heat shock protein 90•SU086 alters prostate cancer glycolysis and decreases intratumoral metabolism•SU086 in combination with anti-androgens halts prostate cancer growth
Rice et al. identify SU086 as a therapeutic strategy for treatment of prostate cancer, as it impairs prostate cancer growth, inhibits HSP90, and impairs glycolysis and intratumoral metabolism. SU086 alone and in combination therapy strategies has strong therapeutic potential in pre-clinical models of prostate cancer.
Ebeveynler açısından engelli bir çocuğa sahip olmak, çok fazla görev ve sorumluluk gerektiren, sürekli fedakarlık isteyen ve duygusal yönden de anne babaları tüketen bir durumdur. Bunun bir sonucu ...olarak tükenmişlik sendromunun ortaya çıkma olasılığı yüksektir. Bu araştırmada temel amaç; zihinsel engelli çocuğa sahip ebeveynlerin yaşam kalitesi, aile işlevlerinin değerlendirilmesi ile tükenmişlik düzeyleri arasındaki ilişkiyi ölçmek ve incelemektir. Araştırmanın örneklemini zihinsel engelli çocuğa sahip 107 ebeveyn oluşturmaktadır. Bu çalışmada, Demografik Bilgi Formu, Aile Değerlendirme Ölçeği, Maslach Tükenmişlik Ölçeği ve Yaşam Kalitesi Ölçeği (WHOQOL-BREF TR) kullanılmıştır. Araştırma sonuçlarına göre, zihinsel engelli çocuğa sahip ebeveynlerin tükenmişlik düzeyleri engel düzeyine bağlı olarak değişmekte ve engel derecesinin artması tükenmeyi arttırmaktadır. Bir diğer sonuca göre ise, ilköğretim düzeyinde eğitim alan ebeveynlerin duygusal tükenmişlik düzeyleri ortaokul ve üzeri eğitim alan ebeveynlere göre daha yüksek olduğu bulgusuna ulaşılmıştır.
Postmodern romanların önemli özellikleri arasında üstkurmaca, metinlerarasılık, oyunsuluk, ironi ve çoğulculuk sayılabilir. Bunun yanı sıra postmodern roman kurgusu kişiler ve zaman bağlamında da ...alışılmış roman özelliklerinden farklıdır. Roman kurgusu iç içe geçmiş olaylardan ve bir dizi belirsizlik ve parçalanmışlıktan oluşur. Tarihi, bir arka plan olarak kullanan postmodern romanlar, roman kişilerini tarihî gerçek kişilikler arasından da seçebilir. Postmodern roman diğer romanlar gibi belli bir kronolojiyle ilerlemez yer yer geriye gitmeler ve ileriye sıçramalar içerebilir. Okuru eğitme amacı gütmeyen postmodern roman daha çok eğlenme amacıyla hareket eder. Bunu oyunsuluk ve ironi özelliğiyle yapar. Metin içerisinde kurguladığı oyuna okuyucuyu dâhil etmeye çalışır roman boyunca oyuna dâhil olan okur metnin bir parçası konumuna gelir.Emre Kongar’ın ilk ve tek romanı olan Hocaefendi’nin Sandukası postmodern roman özellikleri gösterir. Yazar, yazmaları nasıl bulduğunu kaleme aldığı ilk bölüm olan Romanın Öyküsü bölümünde üstkurmacadan yararlanır ve roman boyunca okura kendini yer yer hatırlatarak bilgi verir. Metinlerarasılık bağlamında Gülün Adı ve Beyaz Kale romanlarından yararlanılmıştır. Yazar, Hocaefendi’nin sandukasının şifresini bulmaya çalışırken kurguladığı oyuna okuyucuyu dâhil etmek için olay örgüsü boyunca yapılan sandukanın şifresini çözme hesaplarını resimlerle okuyucuya iletir böylelikle yapılan hesaplamalara okuyucuyu da dâhil etmeye çalışır. Tarihi de bir arka plan olarak kullanan yazar gerçek kişilere yer vererek okurun gerçek ve kurmaca sınırını zorlar.
Neuroendocrine carcinomas, such as neuroendocrine prostate cancer and small-cell lung cancer, commonly have a poor prognosis and limited therapeutic options. We report that ubiquitin carboxy-terminal ...hydrolase L1 (UCHL1), a deubiquitinating enzyme, is elevated in tissues and plasma from patients with neuroendocrine carcinomas. Loss of UCHL1 decreases tumor growth and inhibits metastasis of these malignancies. UCHL1 maintains neuroendocrine differentiation and promotes cancer progression by regulating nucleoporin, POM121, and p53. UCHL1 binds, deubiquitinates, and stabilizes POM121 to regulate POM121-associated nuclear transport of E2F1 and c-MYC. Treatment with the UCHL1 inhibitor LDN-57444 slows tumor growth and metastasis across neuroendocrine carcinomas. The combination of UCHL1 inhibitors with cisplatin, the standard of care used for neuroendocrine carcinomas, significantly delays tumor growth in pre-clinical settings. Our study reveals mechanisms of UCHL1 function in regulating the progression of neuroendocrine carcinomas and identifies UCHL1 as a therapeutic target and potential molecular indicator for diagnosing and monitoring treatment responses in these malignancies.
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•UCHL1 is a potential molecular indicator for neuroendocrine carcinomas•UCHL1 regulates neuroendocrine carcinoma tumor growth and metastasis•UCHL1 stabilizes POM121 and regulates POM121-driven E2F1 nuclear localization•UCHL1 is a therapeutic target for neuroendocrine carcinomas and neuroblastoma
Liu et al. identify UCHL1 as a blood and tissue marker that is elevated across cancers with neuroendocrine features. These cancers are characterized by poor patient outcomes and lack effective treatments. UCHL1 inhibition exhibits anticancer effects in malignancies with neuroendocrine features, presenting a potent therapeutic strategy for these patients.
Upon the observation of an increase in teicoplanin resistance rates in coagulase negative staphylococci (CoNS) isolates determined by the automated system, we aimed to compare the automated system ...and gradient test methods with the gold standard broth microdilution method. In addition, the effect of standard antimicrobial susceptibility guidelines on teicoplanin susceptibility test results in CoNS was investigated. A total of 81 CoNS isolates, 52 resistant and 29 susceptible to teicoplanin determined by automated system (Phoenix, Becton Dickinson, USA), were tested. The minimum inhibitory concentration (MIC) values were determined by gradient test (M.I.C. Evaluators, OXOID, UK) and broth microdilution methods. Susceptibility categories were determined according to EUCAST and CLSI criteria and the results were compared. Among 29 isolates found to be susceptible by automated system, one isolate was found resistant by gradient and broth microdilution tests. Of the 52 resistant isolates determined by automated system, 12 (23%) were found to be resistant by gradient test and 22 (42.3%) were resistant by broth microdilution. According to CLSI criteria, no resistant isolates were detected by broth microdilution and six isolates were intermediately susceptible while, two isolates were detected to be resistant and five isolates were found to be intermediately susceptible by the gradient test. In conclusion, compared to microdilution, teicoplanin resistance was detected at a higher rate in CoNS isolates by the automated system used. On the other hand, the gradient test method which is frequently used for confirmation was not reliable in MIC values close to the EUCAST breakpoint values (4 μg/mL). In addition, lower resistance rates were observed when the CLSI breakpoints were used in gradient test and broth microdilution methods.
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