78 research outputs found
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Loss of testosterone impairs anti-tumor neutrophil function.
In men, the incidence of melanoma rises rapidly after age 50, and nearly two thirds of melanoma deaths are male. The immune system is known to play a key role in controlling the growth and spread of malignancies, but whether age- and sex-dependent changes in immune cell function account for this effect remains unknown. Here, we show that in castrated male mice, neutrophil maturation and function are impaired, leading to elevated metastatic burden in two models of melanoma. Replacement of testosterone effectively normalized the tumor burden in castrated male mice. Further, the aberrant neutrophil phenotype was also observed in prostate cancer patients receiving androgen deprivation therapy, highlighting the evolutionary conservation and clinical relevance of the phenotype. Taken together, these results provide a better understanding of the role of androgen signaling in neutrophil function and the impact of this biology on immune control of malignancies
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Cancer epithelia-derived mitochondrial DNA is a targetable initiator of a paracrine signaling loop that confers taxane resistance.
Stromal-epithelial interactions dictate cancer progression and therapeutic response. Prostate cancer (PCa) cells were identified to secrete greater concentration of mitochondrial DNA (mtDNA) compared to noncancer epithelia. Based on the recognized coevolution of cancer-associated fibroblasts (CAF) with tumor progression, we tested the role of cancer-derived mtDNA in a mechanism of paracrine signaling. We found that prostatic CAF expressed DEC205, which was not expressed by normal tissue-associated fibroblasts. DEC205 is a transmembrane protein that bound mtDNA and contributed to pattern recognition by Toll-like receptor 9 (TLR9). Complement C3 was the dominant gene targeted by TLR9-induced NF-κB signaling in CAF. The subsequent maturation complement C3 maturation to anaphylatoxin C3a was dependent on PCa epithelial inhibition of catalase in CAF. In a syngeneic tissue recombination model of PCa and associated fibroblast, the antagonism of the C3a receptor and the fibroblastic knockout of TLR9 similarly resulted in immune suppression with a significant reduction in tumor progression, compared to saline-treated tumors associated with wild-type prostatic fibroblasts. Interestingly, docetaxel, a common therapy for advanced PCa, further promoted mtDNA secretion in cultured epithelia, mice, and PCa patients. The antiapoptotic signaling downstream of anaphylatoxin C3a signaling in tumor cells contributed to docetaxel resistance. The inhibition of C3a receptor sensitized PCa epithelia to docetaxel in a synergistic manner. Tumor models of human PCa epithelia with CAF expanded similarly in mice in the presence or absence of docetaxel. The combination therapy of docetaxel and C3 receptor antagonist disrupted the mtDNA/C3a paracrine loop and restored docetaxel sensitivity
FYN is overexpressed in human prostate cancer
To test the hypothesis that FYN , a member of the SRC family of kinases (SFKs), is up-regulated in prostate cancer, as FYN is functionally distinct from other SFKs, and interacts with FAK and paxillin (PXN), regulators of cell morphology and motility. MATERIALS AND METHODS Through data-mining in Oncomine ( http://www.oncomine.org ), cell-line profiling with immunoblotting, quantitative reverse transcription and polymerase chain reaction (RT-PCR) and immunohistochemical analysis, we described FYN expression in prostate cancer. The analysis included 32 cases of prostate cancer, nine of prostatic intraepithelial neoplasia (PIN) and 19 normal prostates. Samples were scored for the percentage of stained glands and intensity of staining (from 0 to 3). Each sample was assigned a composite score generated by multiplying percentage and intensity. RESULTS Data-mining showed an eight times greater FYN expression in prostate cancer than in normal tissue; this was specific to FYN and not present for other SFKs. Expression of FYN in prostate cancer cell lines (LNCaP, 22Rv1, PC3, DuPro) was detected using quantitative RT-PCR and immunoblotting. Expression of FYN and its signalling partners FAK and PXN was detected in human tissue. Comparing normal with cancer samples, there was a 2.1-fold increase in median composite score for FYN ( P < 0.001) 1.7-fold increase in FAK ( P < 0.001), and a doubling in PXN ( P < 0.05). There was a 1.7-fold increase in FYN ( P < 0.05) and a 1.6-fold increase in FAK ( P < 0.01) in cancer compared with PIN. CONCLUSIONS These studies support the hypothesis that FYN and its related signalling partners are up-regulated in prostate cancer, and support further investigation into the role of the FYN as a therapeutic target.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/71987/1/j.1464-410X.2008.08009.x.pd
Determinación de escenarios de inundaciones en la subcuenca del río Cunas, Junín, Perú
Se presenta una metodología basada en el procesamiento del modelo digital del terreno en SAGA-GIS para determinar los escenarios de inundaciones en caso de lluvias intensas o prolongadas en la subcuenca del río Cunas, Junín, Perú. Las variables calculadas a partir del DTM ALOS PALSAR fueron: Depresiones cerradas (CD), Distancia vertical a la red de drenaje (VD), Área de captación modificada (MCA), Escorrentía superficial - Escorrentía terrestre flujo D8, y el índice de humedad topográfico (TW1). La susceptibilidad a las inundaciones se obtiene como CD + MCA + D8 + TW1- VD. El mapa resultante validado en el campo, muestra diferentes grados de susceptibilidad a inundaciones, destacando tres sectores donde un grupo significativo de núcleos de población se encuentran expuestos a potenciales inundaciones de grado medio a alto
Determinación de escenarios de inundaciones en la subcuenca del río Cunas, Junín, Perú
Se presenta una metodología basada en el procesamiento del modelo digital del terreno en SAGA-GIS para determinar los escenarios de inundaciones en caso de lluvias intensas o prolongadas en la subcuenca del río Cunas, Junín, Perú. Las variables calculadas a partir del DTM ALOS PALSAR fueron: Depresiones cerradas (CD), Distancia vertical a la red de drenaje (VD), Área de captación modificada (MCA), Escorrentía superficial - Escorrentía terrestre flujo D8, y el índice de humedad topográfico (TW1). La susceptibilidad a las inundaciones se obtiene como CD + MCA + D8 + TW1- VD. El mapa resultante validado en el campo, muestra diferentes grados de susceptibilidad a inundaciones, destacando tres sectores donde un grupo significativo de núcleos de población se encuentran expuestos a potenciales inundaciones de grado medio a alto
Cultured circulating tumor cells and their derived xenografts for personalized oncology
AbstractRecent cancer research has demonstrated the existence of circulating tumor cells (CTCs) in cancer patient's blood. Once identified, CTC biomarkers will be invaluable tools for clinical diagnosis, prognosis and treatment. In this review, we propose ex vivo culture as a rational strategy for large scale amplification of the limited numbers of CTCs from a patient sample, to derive enough CTCs for accurate and reproducible characterization of the biophysical, biochemical, gene expressional and behavioral properties of the harvested cells. Because of tumor cell heterogeneity, it is important to amplify all the CTCs in a blood sample for a comprehensive understanding of their role in cancer metastasis. By analyzing critical steps and technical issues in ex vivo CTC culture, we developed a cost-effective and reproducible protocol directly culturing whole peripheral blood mononuclear cells, relying on an assumed survival advantage in CTCs and CTC-like cells over the normal cells to amplify this specified cluster of cancer cells
Systematic review of Ethiopian medicinal plants used for their anti-inflammatory and wound healing activities
Ethnopharmacological relevance: Plant materials are used worldwide as complementary and alternative therapeutics for the treatment of various illnesses. In Ethiopia, folk medicines are utilized across a wide range of cultures and settings. Ethiopia has numerous plant species of which around 12% are endemic, making it a rich source of medicinal plants that are potentially important for human wellbeing.
Aim of the study: The aim of this study was to assess Ethiopian medicinal plants with anti-inflammatory or wound healing activities, in an attempt to compile the information required for further investigation of their potential role in the management of lymphoedema.
Methods: A systematic review protocol was developed according to the preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) statement. The protocol for this review was registered on PROSPERO with registration number CRD42019127471. This review considers all controlled in vivo and in vitro anti-inflammatory and wound healing studies evaluating the efficacy and safety of Ethiopian medicinal plants. The search strategy included all articles containing descriptors such as Ethiopia, medicinal plants, herbal products, care, management, lymphoedema, lymphedema, swelling, podoconiosis, elephantiasis, wound, wound healing, inflammation, and anti-inflammatory that were published up to June 28, 2019. Outcomes were measured as the percentage of inflammatory and pro-inflammatory cell inhibition, as the percentage of carrageenan-induced oedema (anti-inflammation) inhibition, and the percentage of cell migration and proliferation (wound healing). For quality assessment of individual animal studies, the Risk of Bias tool for animal intervention studies (SYRCLE’s RoB tool) criteria was used. For quality assessment of individual in vitro studies, the OECD guidelines and the WHO Good Laboratory Practice (GLP) handbook were used.
Results: A total of 46 articles on anti-inflammatory and 17 articles on wound healing properties were reviewed. For the in vivo studies, Swiss albino mice and Wistar rats were used, and the concentration of plant extracts or fractions administered to the lab animals varied considerably. Acetone extract of Vernonia amygdalina showed the fastest anti-inflammatory activity at lower concentrations in carrageenan-induced paw oedema.
Conclusion: Lawsonia inermis, Azadirachta indica, Achyranthes aspera, and Cuminum cyminum are the most studied plant species in terms of anti-inflammatory activity, while Lawsonia inermis and Azadirachta indica are the most studied for wound healing. The most common in vivo techniques used for the anti-inflammatory and the wound healing assays were carrageenan-induced paw oedema, and excision and incision wound models, respectively
The 5-Hydroxymethylcytosine Landscape of Prostate Cancer
Analysis of DNA methylation is a valuable tool to understand disease progression and is increasingly being used to create diagnostic and prognostic clinical biomarkers. While conversion of cytosine to 5-methylcytosine (5mC) commonly results in transcriptional repression, further conversion to 5-hydroxymethylcytosine (5hmC) is associated with transcriptional activation. Here we perform the first study integrating whole-genome 5hmC with DNA, 5mC, and transcriptome sequencing in clinical samples of benign, localized, and advanced prostate cancer. 5hmC is shown to mark activation of cancer drivers and downstream targets. Furthermore, 5hmC sequencing revealed profoundly altered cell states throughout the disease course, characterized by increased proliferation, oncogenic signaling, dedifferentiation, and lineage plasticity to neuroendocrine and gastrointestinal lineages. Finally, 5hmC sequencing of cell-free DNA from patients with metastatic disease proved useful as a prognostic biomarker able to identify an aggressive subtype of prostate cancer using the genes TOP2A and EZH2, previously only detectable by transcriptomic analysis of solid tumor biopsies. Overall, these findings reveal that 5hmC marks epigenomic activation in prostate cancer and identify hallmarks of prostate cancer progression with potential as biomarkers of aggressive disease. SIGNIFICANCE: In prostate cancer, 5-hydroxymethylcytosine delineates oncogene activation and stage-specific cell states and can be analyzed in liquid biopsies to detect cancer phenotypes. See related article by Wu and Attard, p. 3880.publishedVersionPeer reviewe
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