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1.
Anticancer Res ; 40(8): 4413-4418, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32727771

RESUMO

BACKGROUND/AIM: To compare the predictive efficacy of National Comprehensive Cancer Network (NCCN) and European Association of Urology (EAU) risk stratification systems in radiotherapy of prostate cancer. PATIENTS AND METHODS: One-thousand-nine-hundred-nine patients treated with definitive (1,074), adjuvant (381), and salvage radiotherapy (454) were analysed. RESULTS: Both systems significantly predicted biochemical-relapse-free-survival, metastasis-free-survival, and disease-free-survival, while only the NCCN system correlated with local-control in the definitive radiotherapy group. In the adjuvant setting, both systems failed to predict all outcomes. In the salvage setting, only the NCCN system significantly predicted biochemical-relapse-free-survival, metastasis-free-survival and disease-free-survival. CONCLUSION: This analysis confirms the efficacy of both systems in definitive radiotherapy and suggests the utility of the NCCN also in salvage radiotherapy.


Assuntos
Neoplasias da Próstata/radioterapia , Radioterapia Adjuvante/estatística & dados numéricos , Terapia de Salvação/estatística & dados numéricos , Idoso , Humanos , Calicreínas/metabolismo , Masculino , Estudos Multicêntricos como Assunto , Estudos Observacionais como Assunto , Antígeno Prostático Específico/metabolismo , Neoplasias da Próstata/metabolismo , Dosagem Radioterapêutica , Estudos Retrospectivos , Medição de Risco , Análise de Sobrevida , Resultado do Tratamento
2.
Prostate ; 80(13): 1097-1107, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32628300

RESUMO

BACKGROUND: Kallikrein-related peptidase 2 (KLK2)-like KLK3 (prostate-specific antigen [PSA])-belongs to the highly conserved serine proteases of the glandular kallikrein protein family (KLK family). Studies suggested that measurement of KLK2 serum levels advanced the predictive accuracy of PSA testing in prostate cancer. METHODS: To clarify the potential utility of KLK2 as a prognostic tissue biomarker, KLK2 expression was analyzed by immunohistochemistry in more than 12 000 prostate cancers. RESULTS: Normal epithelium cells usually showed weak to moderate KLK2 immunostaining, whereas KLK2 was negative in 23%, weak in 38%, moderate in 35%, and strong in 4% of 9576 analyzable cancers. Lost or reduced KLK2 immunostaining was associated with advanced tumor stage, high Gleason score, lymph node metastasis, increased cell proliferation, positive resection margin, and early PSA recurrence (P < .0001). Comparison with previously analyzed molecular alterations revealed a strong association of KLK2 loss and presence of TMPRSS2:ERG fusion (P < .0001), most of all analyzed common deletions (9 of 11; P ≤ .03), and decreased PSA immunostaining (P < .0001 each). Cancers with combined negative or weak immunostaining of KLK2 and PSA showed worse prognosis than cancers with at least moderate staining of one or both proteins (P < .0001). Multivariate analyses including established preoperative and postoperative prognostic parameters showed a strong independent prognostic impact of KLK2 loss alone or in combination of PSA, especially in erythroblast transformation-specific-negative cancers (P ≤ .006). CONCLUSIONS: Loss of KLK2 expression is a potentially useful prognostic marker in prostate cancer. Analysis of KLK2 alone or in combination with PSA may be useful for estimating cancer aggressiveness at the time of biopsy.


Assuntos
Calicreínas/biossíntese , Neoplasias da Próstata/enzimologia , Idoso , Humanos , Imuno-Histoquímica , Calicreínas/genética , Calicreínas/metabolismo , Masculino , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Fenótipo , Prognóstico , Antígeno Prostático Específico/biossíntese , Antígeno Prostático Específico/genética , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Receptores Androgênicos/biossíntese , Receptores Androgênicos/genética , Regulador Transcricional ERG/biossíntese , Regulador Transcricional ERG/genética , Regulador Transcricional ERG/metabolismo
3.
Anticancer Res ; 40(5): 2487-2495, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32366393

RESUMO

BACKGROUND/AIM: This study analyzed the gene expression of the "classic" KLK1 and "new" kallikreins KLK4-KLK15, in relation to the molecular characteristics and in vitro invasiveness of 21 breast cancer (BC) and three normal breast-derived cell lines (CLs). MATERIALS AND METHODS: Gene expression of KLKs was determined by using real-time polymerase chain reaction (PCR). The invasiveness of the CLs was examined using a fibroblast-collagen-based in vitro cell culture assay. RESULTS: KLK5 and KLK7-KLK11 were down-regulated in several BCCLs. In contrast, KLK4, KLK8, KLK12 and KLK15 demonstrated strikingly high expression in two BCCLs, UACC 812 and MDA-MB 330. The KLK expression differed frequently according to the presence of androgen receptor (KLK1 and KLK5-KLK9), and occasionally according to estrogen receptor (KLK9) and EGFR (KLK7). Two KLK clusters were detected (first: KLK1, 4, 12, 15; second: all other KLKs), with two subclasses within the second cluster (KLK5-9 and KLK10, 11, 13, and 14). The CLs that expressed at least six KLKs belonged predominantly to basal or HER2 intrinsic subtypes. No KLK predicted the in vitro invasiveness of CLs. CONCLUSION: Gene expression of KLKs was altered in BCCLs. This change was mostly down-regulation and often related to the presence of androgen receptor. The observed clusters point to a possible functional interplay of selected KLKs in BCCLs.


Assuntos
Expressão Gênica , Calicreínas/genética , Biomarcadores Tumorais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Perfilação da Expressão Gênica , Humanos , Calicreínas/metabolismo
4.
J Biol Regul Homeost Agents ; 34(1): 93-100, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32400148

RESUMO

Endometriosis is a gynecological health problem for women of reproductive stage. Kallikrein 4 is a proliferative factor and has important roles in cancer development and progression. To explore the role of Kallikrein 4 in endometriosis, we detected the expression of Kallikrein 4 in ectopic and normal control endometriosis tissues. Moreover, the underlying influence of Kallikrein 4 on migration and invasion of endometrial stromal cells was investigated. Furthermore, the correlations between this gene and E-cadherin and N-cadherin were also evaluated. The results demonstrated that the expression level of Kallikrein 4 in endometrial tissues was significantly increased compared to normal endometrial tissues, and over-expression of Kallikrein 4 up-regulated expression of N-cadherin but down-regulated E-cadherin in endometrial stromal cells. The ability of migration and invasion of endometrial stromal cells in vitro was increased by up-regulating Kallikrein 4 expression, suggesting that Kallikrein 4 might be involved in the development of ovarian endometriosis.


Assuntos
Movimento Celular , Endometriose/fisiopatologia , Transição Epitelial-Mesenquimal , Calicreínas/metabolismo , Células Estromais/citologia , Caderinas/metabolismo , Proliferação de Células , Endométrio/citologia , Endométrio/patologia , Feminino , Humanos
5.
Nat Commun ; 11(1): 2132, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32358539

RESUMO

Brown adipose tissue (BAT) is known to secrete regulatory factors in response to thermogenic stimuli. Components of the BAT secretome may exert local effects that contribute to BAT recruitment and activation. Here, we found that a thermogenic stimulus leads to enhanced secretion of kininogen (Kng) by BAT, owing to induction of kininogen 2 (Kng2) gene expression. Noradrenergic, cAMP-mediated signals induce KNG2 expression and release in brown adipocytes. Conversely, the expression of kinin receptors, that are activated by the Kng products bradykinin and [Des-Arg9]-bradykinin, are repressed by thermogenic activation of BAT in vivo and of brown adipocytes in vitro. Loss-of-function models for Kng (the circulating-Kng-deficient BN/Ka rat) and bradykinin (pharmacological inhibition of kinin receptors, kinin receptor-null mice) signaling were coincident in showing abnormal overactivation of BAT. Studies in vitro indicated that Kng and bradykinin exert repressive effects on brown adipocyte thermogenic activity by interfering the PKA/p38 MAPK pathway of control of Ucp1 gene transcription, whereas impaired kinin receptor expression enhances it. Our findings identify the kallikrein-kinin system as a relevant component of BAT thermogenic regulation that provides auto-regulatory inhibitory signaling to BAT.


Assuntos
Tecido Adiposo Marrom/metabolismo , Calicreínas/metabolismo , Cininas/metabolismo , Animais , Bradicinina/genética , Bradicinina/metabolismo , Sistema Endócrino/metabolismo , Imunofluorescência , Calicreínas/genética , Cininogênios/genética , Cininogênios/metabolismo , Cininas/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais/genética , Transdução de Sinais/fisiologia
6.
Elife ; 92020 04 27.
Artigo em Inglês | MEDLINE | ID: covidwho-125320

RESUMO

COVID-19 patients can present with pulmonary edema early in disease. We propose that this is due to a local vascular problem because of activation of bradykinin 1 receptor (B1R) and B2R on endothelial cells in the lungs. SARS-CoV-2 enters the cell via ACE2 that next to its role in RAAS is needed to inactivate des-Arg9 bradykinin, the potent ligand of the B1R. Without ACE2 acting as a guardian to inactivate the ligands of B1R, the lung environment is prone for local vascular leakage leading to angioedema. Here, we hypothesize that a kinin-dependent local lung angioedema via B1R and eventually B2R is an important feature of COVID-19. We propose that blocking the B2R and inhibiting plasma kallikrein activity might have an ameliorating effect on early disease caused by COVID-19 and might prevent acute respiratory distress syndrome (ARDS). In addition, this pathway might indirectly be responsive to anti-inflammatory agents.


Assuntos
Antivirais/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/patologia , Desenvolvimento de Medicamentos , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/patologia , Angioedema/tratamento farmacológico , Angioedema/metabolismo , Angioedema/patologia , Anti-Inflamatórios/uso terapêutico , Betacoronavirus/fisiologia , Antagonistas dos Receptores da Bradicinina/uso terapêutico , Infecções por Coronavirus/metabolismo , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Humanos , Inflamação/imunologia , Inflamação/patologia , Calicreínas/metabolismo , Cininas/metabolismo , Pulmão/metabolismo , Pulmão/patologia , Pandemias , Pneumonia Viral/metabolismo , Receptor B1 da Bradicinina/metabolismo , Receptor B2 da Bradicinina/metabolismo , Síndrome do Desconforto Respiratório do Adulto/tratamento farmacológico , Síndrome do Desconforto Respiratório do Adulto/patologia , Síndrome do Desconforto Respiratório do Adulto/prevenção & controle , Transdução de Sinais
7.
Elife ; 92020 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-32338605

RESUMO

COVID-19 patients can present with pulmonary edema early in disease. We propose that this is due to a local vascular problem because of activation of bradykinin 1 receptor (B1R) and B2R on endothelial cells in the lungs. SARS-CoV-2 enters the cell via ACE2 that next to its role in RAAS is needed to inactivate des-Arg9 bradykinin, the potent ligand of the B1R. Without ACE2 acting as a guardian to inactivate the ligands of B1R, the lung environment is prone for local vascular leakage leading to angioedema. Here, we hypothesize that a kinin-dependent local lung angioedema via B1R and eventually B2R is an important feature of COVID-19. We propose that blocking the B2R and inhibiting plasma kallikrein activity might have an ameliorating effect on early disease caused by COVID-19 and might prevent acute respiratory distress syndrome (ARDS). In addition, this pathway might indirectly be responsive to anti-inflammatory agents.


Assuntos
Antivirais/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/patologia , Desenvolvimento de Medicamentos , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/patologia , Angioedema/tratamento farmacológico , Angioedema/metabolismo , Angioedema/patologia , Anti-Inflamatórios/uso terapêutico , Betacoronavirus/fisiologia , Antagonistas dos Receptores da Bradicinina/uso terapêutico , Infecções por Coronavirus/metabolismo , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Humanos , Inflamação/imunologia , Inflamação/patologia , Calicreínas/metabolismo , Cininas/metabolismo , Pulmão/metabolismo , Pulmão/patologia , Pandemias , Pneumonia Viral/metabolismo , Receptor B1 da Bradicinina/metabolismo , Receptor B2 da Bradicinina/metabolismo , Síndrome do Desconforto Respiratório do Adulto/tratamento farmacológico , Síndrome do Desconforto Respiratório do Adulto/patologia , Síndrome do Desconforto Respiratório do Adulto/prevenção & controle , Transdução de Sinais
8.
Gene ; 749: 144708, 2020 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-32334022

RESUMO

The kallikrein-related peptidase 15 (KLK15) gene is a member of the largest cluster of serine proteases in the human genome. Exhibiting trypsin-like activity, KLK15 is most likely involved in the activation of prostate-specific antigen (PSA; also known as KLK3), an established biomarker for the diagnosis and screening of prostate cancer. High mRNA expression levels of KLK15 have already been reported in ovarian and prostate cancer, in contrast with breast cancer, where KLK15 has been proposed as a biomarker of favorable prognosis. In this study, we exploited the next-generation sequencing (NGS) technology along with 3' rapid amplification of cDNA ends (3' RACE) to discover alternative KLK15 splice variants. Extensive computational analysis of the obtained NGS data revealed the existence of novel splice junctions, thus supporting the existence of novel KLK15 transcripts. Six novel KLK15 splice variants were identified and verified by Sanger sequencing. Two of them (KLK15 v.11 and v.12) contain an open reading frame and are hence predicted to encode two novel KLK15 protein isoforms. Expression analysis of each KLK15 splice variant in sixteen cDNA pools from malignant cell lines and in normal cell lines (HEK293, HaCaT, and BJ cells) revealed very different expression profiles of particular KLK15 transcripts. Moreover, the new KLK15 splice variants were shown to be expressed in breast, ovarian, prostate, urinary bladder, colon, and renal tissue specimens. Due to the prominent clinical value of KLK15 mRNA expression, the novel KLK15 transcripts appear as candidate cancer biomarkers for diagnostic and/or prognostic purposes and, therefore, merit further investigation.


Assuntos
Processamento Alternativo , Calicreínas/genética , Linhagem Celular , Linhagem Celular Tumoral , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Isoenzimas/genética , Isoenzimas/metabolismo , Calicreínas/metabolismo
9.
Cancer Causes Control ; 31(5): 431-449, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32162172

RESUMO

PURPOSE: The relationship between body mass index (BMI) and prostate cancer remains unclear. However, there is an inverse association between BMI and prostate-specific antigen (PSA), used for prostate cancer screening. We conducted this review to estimate the associations between BMI and (1) prostate cancer, (2) advanced prostate cancer, and (3) PSA. METHODS: We searched PubMed and Embase for studies until 02 October 2017 and obtained individual participant data from four studies. In total, 78 studies were identified for the association between BMI and prostate cancer, 21 for BMI and advanced prostate cancer, and 35 for BMI and PSA. We performed random-effects meta-analysis of linear associations of log-PSA and prostate cancer with BMI and, to examine potential non-linearity, of associations between categories of BMI and each outcome. RESULTS: In the meta-analyses with continuous BMI, a 5 kg/m2 increase in BMI was associated with a percentage change in PSA of - 5.88% (95% CI - 6.87 to - 4.87). Using BMI categories, compared to normal weight men the PSA levels of overweight men were 3.43% lower (95% CI - 5.57 to - 1.23), and obese men were 12.9% lower (95% CI - 15.2 to - 10.7). Prostate cancer and advanced prostate cancer analyses showed little or no evidence associations. CONCLUSION: There is little or no evidence of an association between BMI and risk of prostate cancer or advanced prostate cancer, and strong evidence of an inverse and non-linear association between BMI and PSA. The association between BMI and prostate cancer is likely biased if missed diagnoses are not considered.


Assuntos
Calicreínas/metabolismo , Antígeno Prostático Específico/metabolismo , Neoplasias da Próstata/diagnóstico , Índice de Massa Corporal , Detecção Precoce de Câncer/métodos , Humanos , Masculino , Obesidade/epidemiologia , Sobrepeso/epidemiologia
10.
Ecotoxicol Environ Saf ; 195: 110491, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32213367

RESUMO

Epidemiological studies have reported short-term fine particulate matter (PM2.5) exposure to increase incidence of asthma, related to the increase of airway hyperresponsiveness (AHR); however, the underlying mechanism remains unclear. Aim of this study was to elucidate the role of kallikrein in PM2.5-induced airway hyperresponsiveness and understand the underlying mechanism. Nose-only PM2.5 exposure system was used to generate a mouse model of airway hyperresponsiveness. Compared with the control group, PM2.5 exposure could significantly increase airway resistance, lung inflammation, kallikrein expression of bronchi-lung tissue and bradykinin (BK) secretion. However, these changes could be alleviated by kallikrein inhibitor. In addition,PM2.5 could increase the viability of human airway smooth muscle cells (hASMCs), accompanied by increased expression of kallikrein 14 (Klk14), bradykinin 2 receptor (B2R), bradykinin secretion and cytosol calcium level, while kallikrein 14 gene knockdown could significantly amelioratethe above response induced by PM2.5. Taken together, the data suggested kallikrein to play a key role in PM2.5-induced airway hyperresponsiveness, and that it could be a potential therapeutic target in asthma.


Assuntos
Poluentes Atmosféricos/toxicidade , Bradicinina/metabolismo , Calicreínas/metabolismo , Material Particulado/toxicidade , Hipersensibilidade Respiratória/induzido quimicamente , Animais , Líquido da Lavagem Broncoalveolar/imunologia , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Citocinas/imunologia , Modelos Animais de Doenças , Humanos , Exposição por Inalação/efeitos adversos , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/imunologia , Miócitos de Músculo Liso/patologia , Tamanho da Partícula , Pneumonia/induzido quimicamente , Pneumonia/metabolismo , Hipersensibilidade Respiratória/imunologia , Hipersensibilidade Respiratória/metabolismo , Transdução de Sinais
11.
Clin Biochem ; 77: 41-47, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31904348

RESUMO

OBJECTIVES: Kallikrein-related peptidases (KLKs) are a subgroup of 15 secreted chymotrypsin- and trypsin-like serine proteases that have been reported to possess novel functions in innate immunity and inflammation. Since the potential role of KLKs in immunity has not been studied in detail at the protein level, we examined the expression pattern of 12 members of the KLK family in immune-related tissues. DESIGN & METHODS: Protein expression in tissue extracts was evaluated using immunoassays (ELISA). Immunohistochemistry (IHC) was performed on representative sections of tonsil and lymph nodes to determine the cellular localization of the KLK family members. RESULTS: ELISA profiling of KLK3-KLK15 (except KLK12) revealed higher protein levels in the tonsil, compared to the lymph nodes and spleen. Relatively high protein levels in the tonsil were observed for KLK7, KLK9, KLK10 and KLK13. Expression of these KLKs was significantly lower in lymph nodes and spleen. IHC analysis in tonsil unveiled that KLK9 and KLK10 were differentially expressed in lymphoid cells. KLK9 was strongly expressed in the germinal center of lymphoid follicles where activated B-cells reside, whereas KLK10 was expressed in the follicular dendritic cells (FDCs) that are vital for maintaining the cycle of B cell maturation. CONCLUSION: Overall, our study revealed the possible implications of KLK expression and regulation in the immune cells of lymphoid tissues.


Assuntos
Calicreínas/metabolismo , Tecido Linfoide/metabolismo , Peptídeo Hidrolases/metabolismo , Ensaio de Imunoadsorção Enzimática , Humanos , Calicreínas/genética , RNA Mensageiro/genética
12.
Mol Immunol ; 119: 27-34, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31955064

RESUMO

Mutations in Factor XII, plasminogen gene, angiopoietin-1 gene and kininogen 1 gene have been found in some patients with hereditary angioedema with normal C1 inhibitor (HAE-nl-C1inh), but the underlying disease mechanisms remain unclear. Additionally, there are no accepted biomarkers for this disease. Because the contact system has been implicated in hereditary angioedema with C1 inhibitor deficiency (HAE-C1inh), we studied the fragmentation patterns of serum glycoprotein 120 (sgp120), a protein that is highly susceptible to cleavage by kallikrein, in 31 HAE-C1inh and 13 HAE-nl-C1inh patient plasma samples. Compared to normal controls, the majority of plasma samples from patients with HAE-C1inh contained fragmented sgp120. These samples also showed increased kallikrein amidolytic activity indicating spontaneous contact system activation. In contrast, most samples from HAE-nl-C1inh patients exhibited intact sgp120. However, if these samples were incubated at 4 °C in plastic, significant sgp120 fragmentation and spontaneous contact system activation were observed. Concurrently, there was C1 inhibitor fragmentation that generated the nonfunctional 94 kD fragment and a reduction in C1 inhibitor function. Normal samples did not show sgp120 or C1 inhibitor fragmentation after incubation. We sequenced sgp120 and found it to be identical to inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4). These results suggest that sgp120 or ITIH4 is cleaved when the contact system is activated and that this cleavage could be used as a biomarker in patients with HAE-nl-C1inh.


Assuntos
Angioedemas Hereditários/sangue , Angioedemas Hereditários/diagnóstico , Proteína Inibidora do Complemento C1/metabolismo , Proteínas Secretadas Inibidoras de Proteinases/sangue , Angioedemas Hereditários/genética , Biomarcadores/sangue , Fatores de Coagulação Sanguínea/metabolismo , Cromatografia/métodos , Ativação do Complemento , Fator XII/genética , Humanos , Calicreínas/metabolismo , Caulim/metabolismo , Fragmentos de Peptídeos/sangue , Plasminogênio/genética , Plásticos , Proteólise
13.
PLoS One ; 14(11): e0218645, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31743339

RESUMO

Prostate biopsies are frequently performed to screen for prostate cancer (PCa) with complications such as infections and bleeding. To reduce unnecessary biopsies, here we designed an improved predictive model of MRI-based prostate volume and associated zone-adjusted prostate-specific antigen (PSA) concentrations for diagnosing PCa and risk stratification. Multiparametric MRI administered to 422 consecutive patients before initial transrectal ultrasonography-guided 13-core prostate biopsies from January 2012 to March 2018 at Fujian Medical University Union Hospital. Univariate and multivariate logistic regression analyses and determination of the area under the curve (AUC) of the receiver operating characteristic (ROC) curve was performed to evaluate and integrate the predictors of PCa and high-risk prostate cancer (HR-PCa). The detection rates of PCa was 43.84% (185/422). And the detection rates of HR-PCa was 71.35% (132/185) in PCa patients. Multivariate analysis revealed that prostate volume(PV), PSA density(PSAD), transitional zone volume(TZV), PSA density of the transitional zone(PSADTZ), and MR were independent predictors of PCa and HR-PCa. PSA, peripheral zone volume(PZV) and PSA density of the peripheral zone(PSADPZ) were independent predictors of PCa but not HR-PCa. The AUC of our best predictive model including PSA + PV + PSAD + MR + TZV or PSA + PV + PSAD + MR + PZV was 0.906 for PCa. The AUC of the best predictive model of PV + PSAD + MR + TZV was 0.893 for HR-PCa. In conclusion, our results will likely improve the detection rate of prostate cancer, avoiding unnecessary prostate biopsies, and for evaluating risk stratification.


Assuntos
Calicreínas/metabolismo , Antígeno Prostático Específico/metabolismo , Próstata/diagnóstico por imagem , Neoplasias da Próstata/diagnóstico por imagem , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/imunologia , Adenocarcinoma/patologia , Idoso , Área Sob a Curva , Biópsia , Estudos de Coortes , Humanos , Imagem por Ressonância Magnética/métodos , Imagem por Ressonância Magnética/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Valor Preditivo dos Testes , Próstata/imunologia , Próstata/patologia , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/patologia , Estudos Retrospectivos , Fatores de Risco , Conduta Expectante
14.
Am J Case Rep ; 20: 1521-1525, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31615974

RESUMO

BACKGROUND Prostate cancer is a common cancer in men. Radical prostatectomy, i.e., the surgical removal of the entire prostate, is a frequently used option. Biochemical recurrence (BCR), i.e., detectable prostate specific antigen (PSA), is common in some men following such treatment. The timing of BCR to metastatic spread of disease in bones is usually a few years. If the biochemical failure occurs after a longer duration from the time of curative intent, it is generally believed to lead to local recurrence. CASE REPORT We report on two cases. A 78-year-old male was diagnosed with Gleason 7, prostate cancer in 2001. He subsequently underwent an open radical prostatectomy. Serial post-operative PSA's were undetectable (<0.01 ng/mL) up to 2016. He was diagnosed with a detectable PSA for the first time with a value of 0.3 ng/mL, that year. The PSA continued to rise to a level of 1.1 ng/mL. This rise in the PSA was within a 12-month interval. Subsequent bone scan and bone biopsy detected prostate cancer metastasis in multiple bones. Our second case was a 65-year-old male who underwent a laparoscopic radical prostatectomy in the year 2006 for a biopsy proven prostate cancer with Gleason 3+4=7. Serial post-operative PSA's were undetectable up to 2017. Within a span of 8 months, the PSA rose from 0.3 ng/mL to 1.52 ng/mL. A positron emission tomography scan demonstrated pubic bone lesion indicative of prostate cancer metastasis. CONCLUSIONS BCR can occur a decade after curative intent treatment of prostate cancer. The duration from BCR to detectable metastasis can be shorter. We demonstrated here that the site of recurrence, in such scenarios, can be distant metastasis and not local recurrence alone. Better imaging modalities are needed to identify the spread of prostate cancer at low levels of PSA.


Assuntos
Neoplasias Ósseas/secundário , Calicreínas/metabolismo , Antígeno Prostático Específico/metabolismo , Próstata/patologia , Prostatectomia , Neoplasias da Próstata/cirurgia , Idoso , Fenômenos Bioquímicos , Biópsia , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Neoplasias da Próstata/patologia , Fatores de Tempo
15.
Forensic Sci Int ; 303: 109940, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31550598

RESUMO

The determination of cell type in biological casework samples would be helpful to identify the type of body fluids and interpret the DNA source in forensic laboratories. Exfoliated epidermal cells are considered to be a reasonable source of touch DNA; therefore, we developed and assessed an immunohistochemistry (IHC) procedure for identifying exfoliated epidermal cells as a screening test of touch DNA samples. Among five candidate protein markers investigated in this study, keratin 10 and kallikrein-related peptidase 5 were strongly expressed in the stratum corneum layer of the skin; however, their specificity was insufficient to identify epidermal cells. In contrast, IHC for corneodesmosin (CDSN), desmocollin 1 (DSC1), and filaggrin (FLG) was considered to be applicable because of their detectability and specificity on skin swab samples. Actually, CDSN and DSC1 could be good markers for exfoliated epidermal cells on touched contact traces that were contaminated with many unidentified impurities. Besides, positivity for FLG on mock casework samples appeared to be lower than for the other markers, which might be caused by its instability. Finally, the relationship between positivity for IHC and DNA yield was analyzed using skin swab samples. Although it was difficult to determine these correlations quantitatively because of the heterogeneous distribution of cells and the presence of cell-free DNA, the DNA-quantifiable samples analyzed in this study contained at least some of IHC-positive epidermal cells. In conclusion, IHC detection of skin-enriched proteins, especially CDSN and DSC1, could be useful for screening samples that have been handled or touched by someone before DNA analysis.


Assuntos
Desmocolinas/metabolismo , Células Epidérmicas/citologia , Imuno-Histoquímica , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Pele/metabolismo , Tato , Biomarcadores/metabolismo , Análise Química do Sangue , Muco do Colo Uterino/química , DNA/análise , Ciências Forenses , Humanos , Proteínas de Filamentos Intermediários/metabolismo , Calicreínas/metabolismo , Queratina-10/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Saliva/química , Sêmen/química , Coloração e Rotulagem
16.
Prostate ; 79(15): 1767-1776, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31475741

RESUMO

BACKGROUND: The development of phenotypic biomarkers to aid the selection of treatment for patients with castrate-resistant prostate cancer (CRPC) is an important priority. Plasma exosomes have excellent potential as real-time biomarkers to characterize the tumor because they are easily accessible in the blood and contain DNA, RNA, and protein from the parent cell. This study aims to investigate the characteristics of putative prostate-specific plasma extracellular vesicle (EV) markers and their relationship with clinical outcomes. METHODS AND PATIENTS: We investigated plasma EVs in a total of 89 patients with prostate cancer (PCa) at different stages of disease progression. EVs were isolated using both precipitation and ultracentrifugation methods; physical characterization was performed using dynamic light scattering, acetylcholinesterase (AChE) activity, and velocity gradients. An immunocapture method was developed for the evaluation of prostate-specific membrane antigen (PSMA)-positive exosomes. Exosomal messenger RNA (mRNA) was quantified using droplet digital polymerase chain reaction for the expression of KLK3 and androgen receptor splice variant 7 (AR-V7) genes, which code prostate-specific antigen (PSA) and AR-V7, respectively. Serum sex steroids were measured using liquid chromatography-tandem mass spectroscopy. RESULTS: Isolated exosomes from patients with CRPC had a smaller hydrodynamic size than those isolated from localized patients with PCa, while AChE activity showed no difference. Moreover, no differences were observed after initiation of androgen deprivation therapy in serial patient samples. Velocity gradients identified that PSMA-positive exosomes occupied a specific fraction of isolated EVs. A total of 35 patients with CRPC had mRNA analyzed from isolated plasma exosomes. Detectable exosomal KLK3 corresponded with higher concomitant serum PSA measurements, as expected (mean, 112.6 vs 26.61 ng/mL; P = .065). Furthermore, detectable levels of AR-V7 mRNA were associated with a shorter time to progression (median, 16.0 vs 28.0 months; P = .0499). Furthermore, detectable exosomal AR-V7 was significantly associated with testosterone levels below the lower limit of quantification (<0.1 nM). CONCLUSIONS: Our results suggest that exosomal AR-V7 is correlated with lower sex steroid levels in CRPC patients with a poorer prognosis. PSMA immunocapture does not appear sufficient to isolate PCa-specific exosomes.


Assuntos
Vesículas Extracelulares/metabolismo , Neoplasias de Próstata Resistentes à Castração/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Progressão da Doença , Humanos , Calicreínas/metabolismo , Masculino , Pessoa de Meia-Idade , Fenótipo , Intervalo Livre de Progressão , Antígeno Prostático Específico/sangue , Antígeno Prostático Específico/metabolismo , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/mortalidade , Neoplasias de Próstata Resistentes à Castração/patologia , Taxa de Sobrevida
17.
Med Sci Monit ; 25: 6230-6235, 2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31424055

RESUMO

BACKGROUND Although magnetic resonance imaging (MRI)-targeted biopsy and saturation biopsy can improve the accuracy of prostate biopsy, transrectal ultrasound (TRUS)-guided prostate biopsy is still the cornerstone for diagnosis of prostate cancer. However, it is not clear whether it is necessary to perform the same TRUS-guided biopsy scheme for patients with different prostate specific antigen (PSA) or prostate specific antigen density (PSAD) levels. The purpose of this study was to evaluate the optimal core number for specific suspected prostate cancer patients. MATERIAL AND METHODS There were 398 patients who underwent 12-core biopsy scheme, who were included in this retrospective analysis. The 12-core scheme incorporated a classic sextant scheme and 4-core biopsies from the base and middle regions bilaterally. The cancer detection rates of patients with different PSA or PSAD levels between the 12-core, sextant, 4-core, and 2-core biopsy were compared. RESULTS The differences in cancer detection rates between the 12-core biopsy scheme and the sextant biopsy scheme were significant in patients with PSA <20 ng/mL or PSAD <0.3. There were no differences in the cancer detection rates between the 12-core biopsy scheme and the 4-core biopsy scheme in patients with PSA ≤50 ng/mL or PSAD ≤1.0. There were significant differences between 12-core and 2-core scheme when PSA ≤70 ng/mL or PSAD ≤1.5. CONCLUSIONS We recommend that the 12-core biopsy should be used for patients with PSA <20 ng/mL or PSAD <0.3. The biopsy scheme in patients with PSA 20-50 ng/mL or PSAD 0.3-1.0 should be considered in combination with DRE and MRI. For patients with PSA >50 ng/mL or PSAD >1.0, we recommend 6-core or 4-core biopsy by comprehensively considering multiple factors. The 2-core biopsy is recommended for patients with PSA >70 ng/mL or PSAD >1.5.


Assuntos
Biópsia/métodos , Calicreínas/análise , Antígeno Prostático Específico/análise , Próstata/patologia , Idoso , Idoso de 80 Anos ou mais , Biópsia com Agulha de Grande Calibre/métodos , China , Humanos , Calicreínas/metabolismo , Masculino , Microscopia Acústica/métodos , Pessoa de Meia-Idade , Próstata/diagnóstico por imagem , Antígeno Prostático Específico/metabolismo , Neoplasias da Próstata/patologia , Estudos Retrospectivos , Ultrassonografia/métodos
18.
Integr Cancer Ther ; 18: 1534735419864434, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31370719

RESUMO

Objective: To identify prognostic biomarkers and drugs that target them in colon adenocarcinoma (COAD) based on the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus databases. Methods: The TCGA dataset was used to identify the top 50 upregulated differentially expressed genes (DEGs), and Gene Expression Omnibus profiles were used for validation. Survival analyses were conducted with the TCGA dataset using the RTCGAToolbox package in the R software environment. Drugs targeting the candidate prognostic biomarkers were searched in the DrugBank and herbal databases. Results: Among the top 50 upregulated DEGs in patients with COAD in the TCGA dataset, the Wnt signaling pathway and cytokine-cytokine receptor interactions and pathways in cancer Kyoto Encyclopedia of Genes and Genomes pathway analysis were enriched in DEGs. Tissue development and regulation of cell proliferation were the main Gene Ontology biological processes associated with upregulated DEGs. MYC and KLK6 were overexpressed in tumors validated in the TCGA, GSE41328, and GSE113513 databases (all P < .001) and were significantly associated with overall survival in patients with COAD (P = .021 and P = .047). Nadroparin and benzamidine were identified as inhibitors of MYC and KLK6 in DrugBank, and 8 herbs targeting MYC, including Da Huang (Radix Rhei Et Rhizome), Hu Zhang (Polygoni Cuspidati Rhizoma Et Radix), Huang Lian (Coptidis Rhizoma), Ban Xia (Arum Ternatum Thunb), Tu Fu Ling (Smilacis Glabrae Rhixoma), Lei Gong Teng (Tripterygii Radix), Er Cha (Catechu), and Guang Zao (Choerospondiatis Fructus), were identified. Conclusion: MYC and KLK6 may serve as candidate prognostic predictors and therapeutic targets in patients with COAD.


Assuntos
Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Biomarcadores Tumorais/metabolismo , Colo/metabolismo , Colo/patologia , Neoplasias do Colo/patologia , Neoplasias do Colo/metabolismo , Biologia Computacional/métodos , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , Calicreínas/metabolismo , Prognóstico , Análise de Sobrevida , Transcriptoma/fisiologia , Regulação para Cima/fisiologia , Via de Sinalização Wnt/fisiologia
19.
Acta Crystallogr F Struct Biol Commun ; 75(Pt 8): 543-546, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31397325

RESUMO

Kallikrein 4 (KLK4) is a serine protease that is predominantly expressed in the prostate and is overexpressed in prostate cancer. As such, it has gained attention as an attractive target for prostate cancer therapeutics. Currently, only liganded structures of KLK4 exist in the Protein Data Bank. Until now, inferences about the subtle structural changes in KLK4 upon ligand binding have been made by comparison to other liganded forms, rather than to an apo form. In this study, an inhibitor-free form of KLK4 was crystallized. The crystals obtained belonged to space group P1, contained four molecules in the asymmetric unit and diffracted to 1.64 Šresolution. Interestingly, a nonstandard rotamer of the specificity-determining residue Asp189 was observed in all chains. This model will provide a useful unliganded structure for the future structure-guided design of KLK4 inhibitors.


Assuntos
Cristalografia por Raios X/métodos , Calicreínas/química , Calicreínas/metabolismo , Humanos , Modelos Moleculares , Conformação Proteica , Especificidade por Substrato
20.
Eur J Dermatol ; 29(3): 268-273, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31389785

RESUMO

BACKGROUND: Mycosis fungoides (MF) is the most common variant of cutaneous T-cell lymphomas (CTCL). Itching can be a major symptom for patients with CTCL, however, itching associated with MF is not relieved by conventional therapy using anti-histamines, suggesting that histamine is not the main pruritogen. Therefore, the underlying mechanisms of itching in MF patients remain unclear. OBJECTIVES: To investigate the clinical and histopathological features associated with MF-related itching. MATERIALS AND METHODS: Skin sections from MF patients and healthy subjects were used for pathophysiological analysis and evaluation of protease activity. These results were compared with the degree of itching. RESULTS: Of the MF patients, 40% did not report itching and 60% reported itching (moderate itching: 40%; strong itching: 20%). The number of eosinophils, but not mast cells, that infiltrated into skin was increased in the group with strong itching. In the skin of patients, both serine protease activity and immunoreactivity to kallikrein 5 (KLK5), a known itch mediator, increased relative to the grade of itching. CONCLUSION: These results suggest that KLK5 and eosinophil infiltration may be involved in itching in patients with MF.


Assuntos
Eosinofilia/patologia , Calicreínas/metabolismo , Linfoma Cutâneo de Células T/patologia , Micose Fungoide/patologia , Prurido/fisiopatologia , Adulto , Biomarcadores/sangue , Biópsia por Agulha , Estudos de Casos e Controles , Progressão da Doença , Eosinofilia/fisiopatologia , Feminino , Humanos , Imuno-Histoquímica , Linfoma Cutâneo de Células T/fisiopatologia , Masculino , Pessoa de Meia-Idade , Micose Fungoide/fisiopatologia , Prognóstico , Valores de Referência , Índice de Gravidade de Doença , Calicreínas Teciduais/metabolismo
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