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1.
Mol Cell ; 63(6): 976-89, 2016 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-27594448

RESUMO

Prostate inflammation has been suggested as an etiology for benign prostatic hyperplasia (BPH). We show that decreased expression of the androgen receptor (AR) in luminal cells of human BPH specimens correlates with a higher degree of regional prostatic inflammation. However, the cause-and-effect relationship between the two events remains unclear. We investigated specifically whether attenuating AR activity in prostate luminal cells induces inflammation. Disrupting luminal cell AR signaling in mouse models promotes cytokine production cell-autonomously, impairs epithelial barrier function, and induces immune cell infiltration, which further augments local production of cytokines and chemokines including Il-1 and Ccl2. This inflammatory microenvironment promotes AR-independent prostatic epithelial proliferation, which can be abolished by ablating IL-1 signaling or depleting its major cellular source, the macrophages. This study demonstrates that disrupting luminal AR signaling promotes prostate inflammation, which may serve as a mechanism for resistance to androgen-targeted therapy for prostate-related diseases.


Assuntos
Células Epiteliais/metabolismo , Homeostase/genética , Macrófagos/metabolismo , Próstata/metabolismo , Hiperplasia Prostática/genética , Receptores Androgênicos/genética , Animais , Proliferação de Células , Quimiocina CCL2/genética , Quimiocina CCL2/imunologia , Quimiocina CXCL10/genética , Quimiocina CXCL10/imunologia , Células Epiteliais/imunologia , Células Epiteliais/patologia , Regulação da Expressão Gênica , Homeostase/imunologia , Humanos , Inflamação , Interleucina-1alfa/genética , Interleucina-1alfa/imunologia , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Antígenos Comuns de Leucócito/genética , Antígenos Comuns de Leucócito/imunologia , Macrófagos/imunologia , Macrófagos/patologia , Masculino , Camundongos , Infiltração de Neutrófilos , Próstata/imunologia , Próstata/patologia , Hiperplasia Prostática/imunologia , Hiperplasia Prostática/metabolismo , Hiperplasia Prostática/patologia , Receptores Androgênicos/imunologia , Transdução de Sinais , Células Estromais/imunologia , Células Estromais/metabolismo , Células Estromais/patologia
2.
Prostate ; 82(5): 517-530, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35014711

RESUMO

INTRODUCTION: The Wnt proteins play key roles in the development, homeostasis, and disease progression of many organs including the prostate. However, the spatiotemporal expression patterns of Wnt proteins in prostate cell lineages at different developmental stages and in prostate cancer remain inadequately characterized. METHODS: We isolated the epithelial and stromal cells in the developing and mature mouse prostate by flow cytometry and determined the expression levels of Wnt ligands. We used Visium spatial gene expression analysis to determine the spatial distribution of Wnt ligands in the mouse prostatic glands. Using laser-capture microscopy in combination with gene expression analysis, we also determined the expression patterns of Wnt signaling components in stromal and cancer cells in advanced human prostate cancer specimens. To investigate how the stroma-derived Wnt ligands affect prostate development and homeostasis, we used a Col1a2-CreERT2 mouse model to disrupt the Wnt transporter Wntless specifically in prostate stromal cells. RESULTS: We showed that the prostate stromal cells are a major source of several Wnt ligands. Visium spatial gene expression analysis revealed a distinct spatial distribution of Wnt ligands in the prostatic glands. We also showed that Wnt signaling components are highly expressed in the stromal compartment of primary and advanced human prostate cancer. Blocking stromal Wnt secretion attenuated prostate epithelial proliferation and regeneration but did not affect cell survival and lineage maintenance. DISCUSSION: Our study demonstrates a critical role of stroma-derived Wnt ligands in prostate development and homeostasis.


Assuntos
Próstata , Neoplasias da Próstata , Animais , Proliferação de Células , Humanos , Ligantes , Masculino , Camundongos , Próstata/metabolismo , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Células Estromais/metabolismo , Proteínas Wnt/genética , Via de Sinalização Wnt
3.
Stem Cells ; 38(11): 1479-1491, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32627901

RESUMO

The phenotypic and functional heterogeneity of the mouse prostate epithelial cell lineages remains incompletely characterized. We show that the Sca-1+ luminal cells at the mouse proximal prostate express Sox2. These cells are replicative quiescent, castration resistant, and do not possess secretory function. We use the Probasin-CreERT2 and Sox2-CreERT2 models in concert with a fluorescent reporter line to label the Sca-1- and Sca-1+ luminal cells, respectively. By a lineage tracing approach, we show that the two luminal cell populations are independently sustained. Sox2 is dispensable for the maintenance of the Sca-1+ luminal cells but is essential for their facultative bipotent differentiation capacity. The Sca-1+ luminal cells share molecular features with the human TACSTD2+ luminal cells. This study corroborates the heterogeneity of the mouse prostate luminal cell lineage and shows that the adult mouse prostate luminal cell lineage is maintained by distinct cellular entities rather than a single progenitor population.


Assuntos
Antígenos Ly/genética , Linhagem da Célula/genética , Proteínas de Membrana/genética , Neoplasias da Próstata/genética , Animais , Humanos , Masculino , Camundongos , Neoplasias da Próstata/patologia
4.
Dev Biol ; 409(1): 202-217, 2016 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-26526198

RESUMO

In the mammary gland, PTEN loss in luminal and basal epithelial cells results in differentiation defects and enhanced proliferation, leading to the formation of tumors with basal epithelial characteristics. In breast cancer, PTEN loss is associated with a hormone receptor-negative, basal-like subtype that is thought to originate in a luminal epithelial cell. Here, we show that luminal-specific PTEN loss results in distinct effects on epithelial homeostasis and mammary tumor formation. Luminal PTEN loss increased proliferation of hormone receptor-negative cells, thereby decreasing the percentage of hormone receptor-positive cells. Moreover, luminal PTEN loss led to misoriented cell divisions and mislocalization of cells to the intraluminal space of mammary ducts. Despite their elevated levels of activated AKT, Pten-null intraluminal cells showed increased levels of apoptosis. One year after Pten deletion, the ducts had cleared and no palpable mammary tumors were detected. These data establish PTEN as a critical regulator of luminal epithelial homeostasis and integrity in the adult mammary gland, and further show that luminal PTEN loss alone is not sufficient to promote the progression of mammary tumorigenesis.


Assuntos
Envelhecimento/metabolismo , Células Epiteliais/metabolismo , Homeostase , Glândulas Mamárias Animais/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Animais , Apoptose/efeitos dos fármacos , Adesão Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Polaridade Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Epitélio/metabolismo , Feminino , Homeostase/efeitos dos fármacos , Integrases/metabolismo , Queratina-8/genética , Glândulas Mamárias Animais/efeitos dos fármacos , Camundongos Knockout , Receptores de Progesterona/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fuso Acromático/efeitos dos fármacos , Fuso Acromático/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Tamoxifeno/farmacologia
5.
Stem Cells ; 34(1): 191-202, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26418304

RESUMO

Recent lineage tracing studies support the existence of prostate luminal progenitors that possess extensive regenerative capacity, but their identity remains unknown. We show that Sca-1 (stem cell antigen-1) identifies a small population of murine prostate luminal cells that reside in the proximal prostatic ducts adjacent to the urethra. Sca-1(+) luminal cells do not express Nkx3.1. They do not carry the secretory function, although they express the androgen receptor. These cells are enriched in the prostates of castrated mice. In the in vitro prostate organoid assay, a small fraction of the Sca-1(+) luminal cells are capable of generating budding organoids that are morphologically distinct from those derived from other cell lineages. Histologically, this type of organoid is composed of multiple inner layers of luminal cells surrounded by multiple outer layers of basal cells. When passaged, these organoids retain their morphological and histological features. Finally, the Sca-1(+) luminal cells are capable of forming small prostate glands containing both basal and luminal cells in an in vivo prostate regeneration assay. Collectively, our study establishes the androgen-independent and bipotent organoid-forming Sca-1(+) luminal cells as a functionally distinct cellular entity. These cells may represent a putative luminal progenitor population and serve as a cellular origin for castration resistant prostate cancer.


Assuntos
Androgênios/farmacologia , Ataxina-1/metabolismo , Linhagem da Célula/efeitos dos fármacos , Próstata/citologia , Animais , Antígenos CD/metabolismo , Diferenciação Celular/efeitos dos fármacos , Forma Celular/efeitos dos fármacos , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Organoides/citologia , Regeneração/efeitos dos fármacos
6.
Proc Natl Acad Sci U S A ; 111(5): E592-600, 2014 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-24367088

RESUMO

Chronic inflammation has been shown to promote the initiation and progression of diverse malignancies by inducing genetic and epigenetic alterations. In this study, we investigate an alternative mechanism through which inflammation promotes the initiation of prostate cancer. Adult murine prostate epithelia are composed predominantly of basal and luminal cells. Previous studies revealed that the two lineages are largely self-sustained when residing in their native microenvironment. To interrogate whether tissue inflammation alters the differentiation program of basal cells, we conducted lineage tracing of basal cells using a K14-CreER;mTmG model in concert with a murine model of prostatitis induced by infection from the uropathogenic bacteria CP9. We show that acute prostatitis causes tissue damage and creates a tissue microenvironment that induces the differentiation of basal cells into luminal cells, an alteration that rarely occurs under normal physiological conditions. Previously we showed that a mouse model with prostate basal cell-specific deletion of Phosphatase and tensin homolog (K14-CreER;Pten(fl/fl)) develops prostate cancer with a long latency, because disease initiation in this model requires and is limited by the differentiation of transformation-resistant basal cells into transformation-competent luminal cells. Here, we show that CP9-induced prostatitis significantly accelerates the initiation of prostatic intraepithelial neoplasia in this model. Our results demonstrate that inflammation results in a tissue microenvironment that alters the normal prostate epithelial cell differentiation program and that through this cellular process inflammation accelerates the initiation of prostate cancer with a basal cell origin.


Assuntos
Carcinogênese/patologia , Diferenciação Celular , Inflamação/patologia , Neoplasia de Células Basais/etiologia , Neoplasias da Próstata/etiologia , Prostatite/complicações , Prostatite/patologia , Animais , Infecções Bacterianas/complicações , Infecções Bacterianas/patologia , Proliferação de Células , Microambiente Celular , Modelos Animais de Doenças , Progressão da Doença , Humanos , Hiperplasia , Inflamação/complicações , Queratina-14/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neoplasia de Células Basais/patologia , PTEN Fosfo-Hidrolase/metabolismo , Próstata/microbiologia , Próstata/patologia , Neoplasias da Próstata/patologia , Prostatite/microbiologia , Células Estromais/patologia
7.
Surg Radiol Anat ; 38(6): 717-21, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26961800

RESUMO

PURPOSE: The aim of our study was to compare the difficulty in performing a posterior tympanotomy in chronic otitis media (COM) versus the same procedure in a normal mastoid. MATERIALS AND METHODS: The study included 122 patients who underwent tympanomastoidectomy for unilateral chronic otitis media with contralateral normal mastoid pneumatization. We evaluated the anatomical relationships between the mastoid segment and neighboring structures by analyzing axial temporal bone computed tomography scans. A vertical line (line A) was drawn tangential to the most lateral end of the posterior semicircular canal (point A). Three distances were measured: the distance (D1) between the point A and the most lateral end of the mastoid segment of the facial nerve (point B), the distance (D2) between the line A and the point B, and the distance (D3) between the point B and the posterior end of the bony annulus of the external auditory canal. RESULTS: The average measurements of D1 and D3 were 3.79 ± 0.55 and 2.63 ± 0.51 mm, respectively, in the normal mastoid ears and 3.47 ± 0.59 and 2.35 ± 0.44 mm, respectively, in the COM ears. The measurements of D1 and D3 were statistically shorter in the COM ears than in the normal ears. CONCLUSIONS: These findings suggest that the facial recess in COM may be narrower than in a normal mastoid and that performing a posterior tympanotomy may be riskier in COM than in a normal mastoid due to the potential for injury to the neighboring structures and the facial nerve.


Assuntos
Traumatismos do Nervo Facial/prevenção & controle , Nervo Facial/anatomia & histologia , Complicações Intraoperatórias/prevenção & controle , Processo Mastoide/cirurgia , Ventilação da Orelha Média/efeitos adversos , Otite Média/cirurgia , Adulto , Idoso , Doença Crônica , Meato Acústico Externo/anatomia & histologia , Meato Acústico Externo/diagnóstico por imagem , Nervo Facial/diagnóstico por imagem , Feminino , Humanos , Masculino , Processo Mastoide/anatomia & histologia , Processo Mastoide/diagnóstico por imagem , Pessoa de Meia-Idade , Otite Média/diagnóstico por imagem , Estudos Retrospectivos , Risco , Osso Temporal/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Adulto Jovem
8.
Angew Chem Int Ed Engl ; 55(14): 4582-6, 2016 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-26879376

RESUMO

The biodegradable inorganic nanovector based on a layered double hydroxide (LDH) holds great promise for gene and drug delivery systems. However, in vivo targeted delivery of genes through LDH still remains a key challenge in the development of RNA interference therapeutics. Here, we describe in vivo and in vitro delivery system for Survivin siRNA (siSurvivin) assembled with passive LDH with a particle size of 100 nm or active LDH conjugated with a cancer overexpressing receptor targeting ligand, folic acid (LDHFA), conferring them an ability to target the tumor by either EPR-based clathrin-mediated or folate receptor-mediated endocytosis. When not only transfected into KB cells but also injected into xenograft mice, LDHFA/siSurvivin induced potent gene silencing at mRNA and protein levels in vitro, and consequently achieved a 3.0-fold higher suppression of tumor volume than LDH/siSurvivin in vivo. This anti-tumor effect was attributed to a selectively 1.2-fold higher accumulation of siSurvivin in tumor tissue compared with other organs. Targeting to the tumor with inorganic nanovector can guide and accelerate an evolution of next-generation theranosis system.


Assuntos
Materiais Biocompatíveis , Vetores Genéticos , Nanoestruturas , Neoplasias/terapia , RNA Interferente Pequeno/metabolismo , Animais , L-Lactato Desidrogenase/metabolismo , Camundongos , Microscopia Eletrônica de Varredura
9.
Liver Int ; 34(4): 632-42, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24321089

RESUMO

BACKGROUND & AIMS: Hypoxia-inducible factor-1α (HIF-1α), a key transcription factor in the cellular response to hypoxia, and interleukin 8 (IL-8), a key mediator of angiogenesis, are important in cancerous tumour growth. In this study, we evaluated the effects of HIF-1α and IL-8 knockdown on angiogenesis and tumour growth in hepatocellular carcinoma (HCC). METHODS: Hepatocellular carcinoma cell lines were infected with adenoviruses expressing small-hairpin RNA (shRNA) specific for HIF-1α or IL-8, cultured under hypoxic conditions (1% O2), and examined for their levels of HIF-1α, IL-8, and angiogenesis factors using immunoblot. The effects of adenovirus-mediated shRNA-induced HIF-1α and IL-8 knockdown on tumour growth and angiogenesis were also investigated in a subcutaneous Hep3B-tumour mouse model. RESULTS: Hypoxia-inducible factor-1α knockdown directly repressed tumour growth, whereas IL-8 knockdown indirectly repressed tumour growth. Combined knockdown of HIF-1α and IL-8 increased survival rates of mice. HIF-1α and IL-8 knockdown also decreased microvessel density and tumour volume in vivo. Similarly, HIF-1α and IL-8 knockdown inhibited the angiogenic effects of HCC cell-conditioned media on tube formation and invasion by endothelial cells in vitro. CONCLUSION: These findings indicate that shRNA-induced HIF-1α and IL-8 knockdown inhibit angiogenesis and tumour growth in HCC. Further development of HIF-1α and IL-8 shRNA technologies could lead to effective therapies for HCC.


Assuntos
Carcinoma Hepatocelular/terapia , Terapia Genética/métodos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Interleucina-8/genética , Neoplasias Hepáticas/terapia , Neovascularização Patológica/fisiopatologia , Adenoviridae , Animais , Carcinoma Hepatocelular/genética , Técnicas de Silenciamento de Genes , Vetores Genéticos/genética , Células Endoteliais da Veia Umbilical Humana , Humanos , Immunoblotting , Neoplasias Hepáticas/genética , Camundongos , Invasividade Neoplásica/fisiopatologia , Neovascularização Patológica/genética , Reação em Cadeia da Polimerase em Tempo Real
10.
Oncogene ; 41(9): 1309-1323, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34999736

RESUMO

Macrophages are increased in human benign prostatic hyperplasia and prostate cancer. We generate a Pb-Csf1 mouse model with prostate-specific overexpression of macrophage colony-stimulating factor (M-Csf/Csf1). Csf1 overexpression promotes immune cell infiltration into the prostate, modulates the macrophage polarity in a lobe-specific manner, and induces senescence and low-grade prostatic intraepithelial neoplasia (PIN). The Pb-Csf1 prostate luminal cells exhibit increased stem cell features and undergo an epithelial-to-mesenchymal transition. Human prostate cancer patients with high CSF-1 expression display similar transcriptional alterations with the Pb-Csf1 model. P53 knockout alleviates senescence but fails to progress PIN lesions. Ablating epithelial Gp130 but not Il1r1 substantially blocks PIN lesion formation. The androgen receptor (AR) is downregulated in Pb-Csf1 mice. ChIP-Seq analysis reveals altered AR binding in 2482 genes although there is no significant widespread change in global AR transcriptional activity. Collectively, our study demonstrates that increased macrophage infiltration causes PIN formation but fails to transform prostate cells.


Assuntos
Neoplasia Prostática Intraepitelial
11.
Nat Commun ; 13(1): 6828, 2022 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-36369237

RESUMO

Cancer-associated fibroblasts (CAFs) mediate an immunosuppressive effect, but the underlying mechanism remains incompletely defined. Here we show that increasing prostatic stromal Foxf2 suppresses the growth and progression of both syngeneic and autochthonous mouse prostate cancer models in an immunocompetent context. Mechanistically, Foxf2 moderately attenuates the CAF phenotype and transcriptionally downregulates Cxcl5, which diminish the immunosuppressive myeloid cells and enhance T cell cytotoxicity. Increasing prostatic stromal Foxf2 sensitizes prostate cancer to the immune checkpoint blockade therapies. Augmenting lung stromal Foxf2 also mediates an immunosuppressive milieu and inhibits lung colonization of prostate cancer. FOXF2 is expressed higher in the stroma of human transition zone (TZ) than peripheral zone (PZ) prostate. The stromal FOXF2 expression level in primary prostate cancers inversely correlates with the Gleason grade. Our study establishes Foxf2 as a stromal transcription factor modulating the tumor immune microenvironment and potentially explains why cancers are relatively rare and indolent in the TZ prostate.


Assuntos
Fatores de Transcrição Forkhead , Próstata , Neoplasias da Próstata , Animais , Humanos , Masculino , Camundongos , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Regulação da Expressão Gênica , Próstata/patologia , Neoplasias da Próstata/patologia , Microambiente Tumoral/genética
12.
Oncogene ; 40(1): 203-214, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33110232

RESUMO

Prostate adenocarcinoma undergoes neuroendocrine differentiation to acquire resistance toward antihormonal therapies. The underlying mechanisms have been investigated extensively, among which Sox2 has been shown to play a critical role. However, genetic evidence in mouse models for prostate cancer to support the crucial role of Sox2 is missing. The adult mouse prostate luminal cells contain both castration-resistant Sox2-expressing Sca-1+ cells and castration-responsive Sca-1- cells. We show that both types of the luminal cell are susceptible to oncogenic transformation induced by loss of function of the tumor suppressor Pten. The tumors derived from the Sca-1+ cells are castration resistant and are more inclined to develop castration-induced neuroendocrine differentiation. Genetic ablation of Sox2 suppresses neuroendocrine differentiation but does not impact the castration-resistant property. This study provides direct genetic evidence that Sox2 is necessary for androgen ablation-induced neuroendocrine differentiation of Pten null prostate adenocarcinoma, corroborates that the lineage status of the prostate cancer cells is a determinant for its propensity to exhibit lineage plasticity, and supports that the intrinsic features of cell-of-origin for prostate cancers can dictate their clinical behaviors.


Assuntos
Antígenos Ly/genética , Proteínas de Membrana/genética , PTEN Fosfo-Hidrolase/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Fatores de Transcrição SOXB1/genética , Tamoxifeno/efeitos adversos , Animais , Diferenciação Celular , Linhagem da Célula , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Masculino , Camundongos , Neoplasias Experimentais , Neoplasias de Próstata Resistentes à Castração/induzido quimicamente , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/metabolismo , Células Tumorais Cultivadas
13.
Oncogene ; 39(48): 7142-7151, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33009488

RESUMO

Neuroendocrine prostate cancer (NEPC) is an aggressive variant of prostate cancer that either develops de novo or arises from prostate adenocarcinoma as a result of treatment resistance. Although the prostate basal cells have been shown to directly generate tumor cells with neuroendocrine features when transduced with oncogenic signaling, the identity of the cell-of-origin for de novo NEPC remains unclear. We show that the TACSTD2high human prostate luminal epithelia cells highly express SOX2 and are relatively enriched in the transition zone prostate. Both TACSTD2high and TACSTD2low luminal cells transduced by constitutively activated AKT1 (caAKT1), and c-Myc can form organoids containing versatile clinically relevant tumor cell lineages with regard to the expression of AR and the neuroendocrine cell markers Synaptophysin and Chromogranin A. Tumor organoid cells derived from the TACSTD2high luminal cells are more predisposed to neuroendocrine differentiation along passaging and are relatively more castration-resistant. Knocking down TACSTD2 and SOX2 both attenuate neuroendocrine differentiation of tumor organoid cells. This study demonstrates de novo neuroendocrine differentiation of the human prostate luminal epithelial cells induced by caAKT1 and c-Myc and reveals an impact of cellular status on initiation of lineage plasticity.


Assuntos
Linhagem da Célula , Células Epiteliais/citologia , Próstata/citologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Antígenos de Neoplasias/metabolismo , Moléculas de Adesão Celular/metabolismo , Linhagem Celular Tumoral , Ativação Enzimática , Humanos , Masculino , Organoides/citologia , Fatores de Transcrição SOXB1/metabolismo
14.
Phys Rev E ; 100(3-1): 033203, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31640049

RESUMO

In the present study, three different electronic state-to-state methods are proposed to analyze nonequilibrium air plasma flows behind a strong shock wave. In the first approach representing the conventional method, a two-temperature model combined with the electronic quasi-steady-state assumption is adopted. In the second and the third methods, atomic and molecular electronic master equations are coupled with a conservation equation to describe the electronic state-to-state kinetics. State-of-the-art electronic transition rates for atmospheric gas species are compiled with comparisons of existing data. A prediction of the measured nonequilibrium radiation is made for the flow conditions of recent electric-arc shock tube experiments. In a comparison with the measured spectrum, the present electronic master equation coupling methods are more accurate than the conventional approach when used to estimate the initial rising rate and peak value of the diatomic intensity and small amounts of atomic radiation when the diatomic nonequilibrium condition is dominant. Moreover, the spatial distributions of the intensity and electron number density are more accurately predicted by the present methods when the flow fields are dominated by atomic nonequilibrium.

15.
iScience ; 13: 328-338, 2019 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-30878879

RESUMO

We perform a single-cell RNA sequencing analysis to investigate the phenotypic and functional heterogeneity of the adult mouse prostate stromal cells. Our analysis identifies three major cell populations representing the smooth muscle cells and two types of fibroblast cells enriched by Sca-1 and CD90. The Sca-1+CD90+ fibroblast cells are in direct contact with the epithelial cells and express growth factors and genes associated with cell motility, developmental process, and androgen biosynthesis. This suggests that they may regulate epithelial cell survival and growth. The Sca-1+CD90-/low myofibroblast-like cells highly express genes associated with the extracellular matrix and cytokine-mediated signaling pathways, indicating a role in tissue repair and immune responses. The Sca-1+CD90-/low cells significantly suppress the capacity of the basal cells for bipotent differentiation in the prostate organoid assay. Collectively, we identify the surface markers enabling physical separation of stromal subpopulations and generate the gene expression profiles implying their cellular functions.

16.
Cell Stem Cell ; 24(5): 753-768.e6, 2019 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-30982770

RESUMO

Cell-autonomous Wnt signaling has well-characterized functions in controlling stem cell activity, including in the prostate. While niche cells secrete Wnt ligands, the effects of Wnt signaling in niche cells per se are less understood. Here, we show that stromal cells in the proximal prostatic duct near the urethra, a mouse prostate stem cell niche, not only produce multiple Wnt ligands but also exhibit strong Wnt/ß-catenin activity. The non-canonical Wnt ligand Wnt5a, secreted by proximal stromal cells, directly inhibits proliefration of prostate epithelial stem or progenitor cells whereas stromal cell-autonomous canonical Wnt/ß-catenin signaling indirectly suppresses prostate stem or progenitor activity via the transforming growth factor ß (TGFß) pathway. Collectively, these pathways restrain the proliferative potential of epithelial cells in the proximal prostatic ducts. Human prostate likewise exhibits spatially restricted distribution of stromal Wnt/ß-catenin activity, suggesting a conserved mechanism for tissue patterning. Thus, this study shows how distinct stromal signaling mechanisms within the prostate cooperate to regulate tissue homeostasis.


Assuntos
Células Epiteliais/fisiologia , Próstata/citologia , Células-Tronco/fisiologia , Células Estromais/fisiologia , Proteína Wnt-5a/metabolismo , Animais , Proliferação de Células , Células Cultivadas , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos SCID , Receptor Cross-Talk , Nicho de Células-Tronco , Fator de Crescimento Transformador beta/metabolismo , Via de Sinalização Wnt , beta Catenina/metabolismo
17.
Sci Rep ; 8(1): 1420, 2018 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-29362367

RESUMO

Glioblastoma is a highly aggressive and malignant type of cancer that is apoptosis resistant and difficult to cure by conventional cancer therapies. In this regard, an oncolytic adenovirus that selectively targets the tumour tissue and induces tumour cell lysis is a promising treatment option. We designed and constructed a hypoxia-responsive and cancer-specific modified human telomerase reverse transcriptase (H5CmTERT) promoter to drive replication of an oncolytic adenovirus (H5CmTERT-Ad). To enhance the anti-tumour efficacy of H5CmTERT-Ad against malignant glioblastoma, we also generated an H5CmTERT-Ad expressing secretable trimeric tumour necrosis factor-related apoptosis-inducing ligand (H5CmTERT-Ad/TRAIL). H5CmTERT promoter-regulated oncolytic adenoviruses showed cancer-specific and superior cell-killing effect in contrast to a cognate control oncolytic adenovirus replicating under the control of the endogenous adenovirus promoter. The cancer cell-killing effects of H5CmTERT-Ad and H5CmTERT-Ad/TRAIL were markedly higher during hypoxia than normoxia owing to hypoxia responsiveness of the promoter. H5CmTERT-Ad/TRAIL showed more potent anti-tumour efficacy than H5CmTERT-Ad did in a xenograft model of TRAIL-resistant subcutaneous and orthotopic glioblastoma through superior induction of apoptosis and more extensive virus distribution in the tumour tissue. Altogether, our findings show that H5CmTERT-Ad/TRAIL can promote dispersion of an oncolytic adenovirus through robust induction of apoptosis in a highly TRAIL-resistant glioblastoma.


Assuntos
Adenoviridae/fisiologia , Neoplasias Encefálicas/terapia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Glioblastoma/terapia , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Telomerase/genética , Adenoviridae/genética , Animais , Apoptose , Neoplasias Encefálicas/genética , Hipóxia Celular , Linhagem Celular Tumoral , Vetores Genéticos/administração & dosagem , Glioblastoma/genética , Humanos , Camundongos , Terapia Viral Oncolítica , Vírus Oncolíticos/genética , Regiões Promotoras Genéticas , Ligante Indutor de Apoptose Relacionado a TNF/genética , Replicação Viral , Ensaios Antitumorais Modelo de Xenoenxerto
18.
J Audiol Otol ; 21(3): 140-145, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28942628

RESUMO

BACKGROUND AND OBJECTIVES: The aim of our study was to evaluate postoperative mastoid aeration according to the preoperative middle ear disease and investigate the factors affecting it. SUBJECTS AND METHODS: We retrospectively reviewed the high-resolution computed tomography (CT) scans of temporal bones that were taken 1 year after surgery. The postoperative mastoid aeration was evaluated according to the preoperative diagnosis, and classified into three groups: grade 1 (complete mastoid aeration), an air-filled epitympanum and mastoid cavity; grade 2 (partial mastoid aeration), an air-filled epitympanum and partially aerated mastoid cavity; and grade 3 (absence of mastoid aeration), no air space in the mastoid cavity. RESULTS: The overall mastoid aeration rate was 55.8%, with adhesive otitis media accounting for 21.2%, attic cholesteatoma 53.8%, and chronic otitis media 75.4%. The rates of postoperative mastoid aeration were significantly higher in the chronic otitis media cases and attic cholesteatoma cases than in the adhesive otitis media cases. There were 14 cases requiring revision operations due to the development of a retraction pocket in the tympanic membrane. All of the revised cases had grade 3 postoperative mastoid aeration, and underwent canal wall down mastoidectomies. CONCLUSIONS: The degree of postoperative mastoid aeration is associated with the preoperative middle ear disease. When planning a canal wall up mastoidectomy, the surgeon should contemplate the middle ear disease, because a canal wall down mastoidectomy or mastoid obliteration is recommended if the patient has adhesive otitis media.

19.
Stem Cell Res ; 16(3): 682-91, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-27107344

RESUMO

Recent lineage tracing studies showed that the prostate basal and luminal cells in adult mice are two independent lineages under the physiological condition, but basal cells are capable of generating luminal progenies during bacterial infection-induced prostatitis. Because acute bacterial infection in human prostate tissues is relatively rare, the disease relevance of the bacterial infection-induced basal-to-luminal differentiation is uncertain. Herein we employ a high fat diet-induced sterile prostate inflammation model to determine whether basal-to-luminal differentiation can be induced by inflammation irrespective of the underlying etiologies. A K14-CreER model and a fluorescent report line are utilized to specifically label basal cells with the green fluorescent protein. We show that high fat diet promotes immune cell infiltration into the prostate tissues and basal-to-luminal differentiation. Increased cell proliferation accompanies basal-to-luminal differentiation, suggesting a concurrent regulation of basal cell proliferation and differentiation. This study demonstrates that basal-to-luminal differentiation can be induced by different types of prostate inflammation evolved with distinct etiologies. Finally, high fat diet also accelerates initiation and progression of prostatic intraepithelial neoplasia that are originated from basal cells with loss-of-function of the tumor suppressor Pten. Because prostate cancer originated from basal cells tends to be invasive, our study also provides an alternative explanation for the association between obesity and aggressive prostate cancer.


Assuntos
Dieta Hiperlipídica , Células Epiteliais/citologia , Próstata/citologia , Hiperplasia Prostática/patologia , Animais , Diferenciação Celular , Linhagem da Célula , Células Cultivadas , Queratina-14/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia de Fluorescência , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Hiperplasia Prostática/metabolismo , Células-Tronco/citologia
20.
J Audiol Otol ; 20(1): 36-40, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27144232

RESUMO

BACKGROUND AND OBJECTIVES: The epidermoid cyst is a common benign disease of the skin caused by inflammation of hair cortex follicles and proliferation of epidermal cells within the dermis or superficial subcutaneous tissue. The purpose of this study was to investigate the characteristics of epidermoid cysts of the external auditory canal (EAC) by analyzing the clinical and radiologic features. SUBJECTS AND METHODS: The clinical records were retrospectively reviewed for patients diagnosed with epidermoid cyst of the EAC from March 2004 to December 2013. The epidermoid cysts were diagnosed clinically by endoscopy and microscopy examinations and by temporal bone CT images, and were confirmed by histopathologic examination. Characteristics of epidermoid cysts in bony EAC and cartilaginous EAC were compared. RESULTS: Eight patients had an epidermoid cyst in the bony EAC and nine patients had one in the cartilaginous EAC. Swelling and otalgia were common symptoms, but 47% of cysts were found incidentally. The mean age of patients was 49.6 years (age range, 26-67 years) in the bony EAC cases and 26.1 years (age range, 6-57 years) in the cartilaginous EAC cases. The mean size of the epidermoid cyst was 3.50 mm (size range, 2-7 mm) in the bony EAC cases and 9.55 mm (size range, 2-20 mm) in the cartilaginous EAC cases. CONCLUSIONS: Comparison of epidermoid cysts of the bony EAC and the cartilaginous EAC revealed that epidermoid cysts of the bony EAC is usually found incidentally, arose in older patients and had smaller size.

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