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1.
Artigo em Inglês | MEDLINE | ID: mdl-32051088

RESUMO

S-Nitrosylation of protein cysteine thiol is a post-translational modification mediated by nitric oxide (NO). The overproduction of NO causes nitrosative stress, which is known to induce endoplasmic reticulum (ER) stress. We previously reported that S-nitrosylation of protein disulfide isomerase (PDI) and the ER stress sensor inositol-requiring enzyme 1 (IRE1) decreases their enzymatic activities. However, it remains unclear whether nitrosative stress affects ER-associated degradation (ERAD), a separate ER stress regulatory system responsible for the degradation of substrates via the ubiquitin-proteasomal pathway. In the present study, we found that the ubiquitination of a known ERAD substrate, serine/threonine-protein kinase 1 (SGK1), is attenuated by nitrosative stress. C-terminus of Hsc70-interacting protein (CHIP) together with ubiquitin-conjugating enzyme E2 D1 (UBE2D1) are involved in this modification. We detected that UBE2D1 is S-nitrosylated at its active site, Cys85 by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Furthermore, in vitro and cell-based experiments revealed that S-nitrosylated UBE2D1 has decreased ubiquitin-conjugating activity. Our results suggested that nitrosative stress interferes with ERAD, leading to prolongation of ER stress by co-disruption of various pathways, including the molecular chaperone and ER stress sensor pathways. Given that nitrosative stress and ER stress are upregulated in the brains of patient with Parkinson's disease (PD) and of those with Alzheimer's disease (AD), our findings may provide further insights into the pathogenesis of these neurodegenerative disorders.

2.
Int J Infect Dis ; 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31981766

RESUMO

OBJECTIVES: The usefulness of serial procalcitonin (PCT) measurements for predicting the prognosis and treatment efficacy for hospitalised community-acquired pneumonia (CAP) patients was investigated. METHODS: This prospective, multicentre, cohort study enrolled consecutive CAP patients who were hospitalised at 10 hospitals in western Japan from September 2013 to September 2016. PCT and C-reactive protein (CRP) were measured on admission (PCT D1 and CRP D1), within 48-72 h after admission (PCT D3 and CRP D3), and within 144-192 h after admission. CURB-65 and the Pneumonia Severity Index (PSI) were assessed on admission. The primary outcome was 30-day mortality; secondary outcomes were early and late treatment failure rates. RESULTS: A total of 710 patients were included. The 30-day mortality rate was 3.1%. On multivariate analysis, only PCT D3/D1 ratio >1 [odds ratio (95% confidence interval): 4.33 (1.46-12.82),P = 0.008] and PSI [odds ratio (95% confidence interval): 2.32 (1.07-5.03), P = 0.03] were significant prognostic factors. Regarding treatment efficacy, PCT D3/D1 >1 was a significant predictor of early treatment failure on multivariate analysis. PCT D3/D1 with the PSI significantly improved the prognostic accuracy over that of the PSI alone. CONCLUSIONS: PCT should be measured consecutively, not only on admission, to predict the prognosis and treatment efficacy in CAP.

3.
Clin Chem Lab Med ; 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31926074

RESUMO

Introduction Recently, an expert consensus on optimal use of procalcitonin (PCT)-guided antibiotic stewardship was published focusing mainly on Europe and the United States. However, for Asia-Pacific countries, recommendations may need adaptation due to differences in types of infections, available resources and standard of clinical care. Methods Practical experience with PCT-guided antibiotic stewardship was discussed among experts from different countries, reflecting on the applicability of the proposed Berlin consensus algorithms for Asia-Pacific. Using a Delphi process, the group reached consensus on two PCT algorithms for the critically ill and the non-critically ill patient populations. Results The group agreed that the existing evidence for PCT-guided antibiotic stewardship in patients with acute respiratory infections and sepsis is generally valid also for Asia-Pacific countries, in regard to proposed PCT cut-offs, emphasis on diagnosis, prognosis and antibiotic stewardship, overruling criteria and inevitable adaptations to clinical settings. However, the group noted an insufficient database on patients with tropical diseases currently limiting the clinical utility in these patients. Also, due to lower resource availabilities, biomarker levels may be measured less frequently and only when changes in treatment are highly likely. Conclusions Use of PCT to guide antibiotic stewardship in conjunction with continuous education and regular feedback to all stakeholders has high potential to improve the utilization of antibiotic treatment also in Asia-Pacific countries. However, there is need for adaptations of existing algorithms due to differences in types of infections and routine clinical care. Further research is needed to understand the optimal use of PCT in patients with tropical diseases.

4.
Artigo em Inglês | MEDLINE | ID: mdl-31810867

RESUMO

INTRODUCTION: We aimed to evaluate the treatment sequence for patients with metastatic castration-resistant prostate cancer (mCRPC) in real-world practice and compare overall survival in each sequential therapy. PATIENTS AND METHODS: We retrospectively evaluated 146 patients with mCRPC who were initially treated with androgen deprivation therapy as metastatic hormone-naive prostate cancer in 14 hospitals between January 2010 and March 2019. The agents for the sequential therapy included new androgen receptor-targeted agents (ART: abiraterone acetate or enzalutamide), docetaxel, and/or cabazitaxel. We evaluated the treatment sequence for mCRPC and the effect of sequence patterns on overall survival. RESULTS: The median age was 71 years. A total of 35 patients received ART-ART, 33 received ART-docetaxel, 68 received docetaxel-ART, and 10 received docetaxel-cabazitaxel sequences. The most prescribed treatment sequence was docetaxel-ART (47%), followed by ART-ART (24%). Overall survival calculated from the initial diagnosis reached 83, 57, 79, and 37 months in the ART-ART, ART-docetaxel, docetaxel-ART, and docetaxel-cabazitaxel, respectively. Multivariate Cox regression analyses showed no significant difference in overall survival between the first-line ART (n = 68) and first-line docetaxel (n = 78) therapies (hazard ratio [HR], 0.84; P = .530), between the ART-ART (n = 35) and docetaxel-mixed (n = 111) sequences (HR, 0.82; P = .650), and between the first-line abiraterone (n = 32) and first-line enzalutamide (n = 36) sequences (HR, 1.58; P = .384). CONCLUSION: The most prescribed treatment sequence was docetaxel followed by ART. No significant difference was observed in overall survival among the treatment sequences in real-world practice.

5.
J Infect Chemother ; 2019 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-31787528

RESUMO

The usefulness of existing pneumonia severity indices for predicting mortality in nursing and healthcare-associated pneumonia (NHCAP) is unclear. This study compared the usefulness of existing pneumonia severity indices for predicting mortality in NHCAP and community-acquired pneumonia (CAP). Consecutive hospitalized pneumonia patients including NHCAP and CAP patients were prospectively enrolled between October 2010 and November 2017. Admission pneumonia severity was assessed using CURB-65, Pneumonia Severity Index (PSI), A-DROP, Infectious Diseases Society of America (IDSA)/American Thoracic Society (ATS) severe pneumonia criteria, and I-ROAD. The primary outcome was 30-day mortality. The discriminatory ability of each severity index was evaluated by receiver operating characteristic curve analysis. Overall, 828 patients had NHCAP, and 1330 patients had CAP. Thirty-day mortality was 12.8% and 5.6% in NHCAP and CAP patients, respectively. The area under the curve of PSI (0.717, 95% confidence interval 0.673-0.761) was the highest among all pneumonia severity indices, with significant differences compared with CURB-65 (0.651, 95% confidence interval 0.598-0.705, P = 0.02) and IDSA/ATS severe pneumonia criteria (0.659, 95% confidence interval 0.612-0.707, P = 0.03). The predictive abilities for 30-day mortality of the pneumonia severity indices, excluding PSI and I-ROAD, were significantly inferior for NHCAP than for CAP. PSI may be the most useful pneumonia severity score for predicting mortality in NHCAP. However, the predictive ability for mortality of each pneumonia severity score was worse for NHCAP than for CAP; therefore, the prognostic factors in NHCAP need to be identified for better management of NHCAP patients.

6.
Sci Rep ; 9(1): 18406, 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31804572

RESUMO

Whether macrolide combination therapy reduces the mortality of patients with severe community-acquired pneumonia (CAP) hospitalized in the non-intensive care unit (ICU) remains unclear. Therefore, we investigated the efficacy of adding azithromycin to ß-lactam antibiotics for such patients. This prospective cohort study enrolled consecutive patients with CAP hospitalized in the non-ICU between October 2010 and November 2016. The 30-day mortality between ß-lactam and azithromycin combination therapy and ß-lactam monotherapy was compared in patients classified as mild to moderate and severe according to the CURB-65, Pneumonia Severity Index (PSI), and Infectious Diseases Society of America (IDSA)/American Thoracic Society (ATS) criteria. Inverse probability of treatment weighting (IPTW) analysis was used to reduce biases. Based on the CURB-65 and PSI, combination therapy did not significantly reduce the 30-day mortality in either group (179 patients in the combination group, 952 in the monotherapy group). However, based on the IDSA/ATS criteria, combination therapy significantly reduced the 30-day mortality in patients with severe (odds ratio [OR] 0.12, 95% confidence interval [CI] 0.007-0.57), but not non-severe pneumonia (OR 1.85, 95% CI 0.51-5.40); these results were similar after IPTW analysis. Azithromycin combination therapy significantly reduced the mortality of patients with severe CAP who met the IDSA/ATS criteria.

7.
Neurotherapeutics ; 2019 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-31758411

RESUMO

The repair and regeneration of transected peripheral nerves is an important area of clinical research, and the adhesion of anastomosis sites to surrounding tissues is a vital factor affecting the quality of nerve recovery after nerve anastomosis. This study involves the generation of a novel nerve repair membrane derived from decellularized porcine nerves using a unique, innovative technique. The decellularized nerve matrix was verified to be effective in eliminating cellular components, and it still retained some neural extracellular matrix components and bioactive molecules (collagens, glycosaminoglycans, laminin, fibronectin, TGF-ß, etc.), which were mainly determined by proteomic analysis, histochemistry, immunohistochemistry, and enzyme-linked immunosorbent assay. Cytotoxicity, intracutaneous reactivity, hemolysis, and cell affinity analyses were conducted to confirm the biosecurity of the nerve repair membrane. The in vivo functionality was assessed in a rat sciatic nerve transection model, and indices of functional nerve recovery, including the measurement of the claw-spread reflex, nerve anastomosis site adhesion, electrophysiological properties, and the number of regenerated nerve fibers, were evaluated. The results indicated that the nerve repair membrane could effectively prevent adhesion between the nerve anastomosis sites and the surrounding tissues and enhance nerve regeneration, which could be attributed to its various bioactive components. In conclusion, the novel nerve repair membrane derived from xenogeneic decellularized nerves described in this study shows great potential auxiliary clinical treatment for peripheral nerve injuries.

8.
Chemistry ; 25(68): 15455-15462, 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31647599

RESUMO

Radical cations of bis(dianisylamino)-terminated oligo(p-phenylene)s (OPPs) with up to five phenyl moieties were characterized by means of UV/Vis-NIR and variable-temperature ESR spectroscopy to investigate the bridge-length-dependence on intramolecular charge/spin self-exchange between two nitrogen redox-active centers. Additionally, a comparative study between bis(dianisylamine)-based mixed-valence (MV) radical cations connected by p-terphenylene and hexa-peri-hexabenzocoronene (HBC) π-bridging units also provided information on the influence of extended π-conjugation over the OPP-bridge due to the planarization between adjacent phenylene units on the strength of electronic coupling. The present study on a homologous series of organic MV systems clarifies the attenuation factor through the OPP-bridge and the linear relationship between the electrochemical potential splitting and the electronic coupling in the region of intermediate-to-weak electronic coupling regime.

9.
Anticancer Res ; 39(9): 4711-4720, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519570

RESUMO

BACKGROUND/AIM: Dynamics of circulating tumor cells (CTCs) after molecular targeting therapy remain unclear. MATERIALS AND METHODS: We examined changes in CTC numbers and morphology early after targeting therapy in EGFR-mutated PC-9 human lung cancer and HER2-gene amplified GLM-1 gastric cancer mouse CTC models using a cytology-based semi-automated CTC detection platform. RESULTS: Erlotinib and T-DM1 inhibited cell growth mainly by induction of apoptosis in vitro. The number of CTCs detected 5-10 days after targeting therapy in mice was significantly increased compared to CTC numbers before therapy. The increased CTCs after therapy consisted of apoptotic CTCs and viable CTCs. This heterogeneous population of CTCs reflects well the cell population of the primary tumor disrupted by therapy. CONCLUSION: CTCs can be mobilized from the primary tumor due to tissue disruption in acute response to targeting therapy, suggesting potential usefulness of CTC monitoring as a predictor of therapeutic response in the clinical settings.


Assuntos
Amplificação de Genes , Mutação , Células Neoplásicas Circulantes/metabolismo , Receptor ErbB-2/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Animais , Antineoplásicos/farmacologia , Biomarcadores , Biomarcadores Tumorais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Receptores ErbB/genética , Cloridrato de Erlotinib/farmacologia , Xenoenxertos , Humanos , Imuno-Histoquímica , Camundongos , Células Neoplásicas Circulantes/patologia , Neoplasias Gástricas/tratamento farmacológico
10.
Molecules ; 24(18)2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31510043

RESUMO

S-trityl-l-cysteine (STLC) is a well-recognized lead compound known for its anticancer activity owing to its potent inhibitory effect on human mitotic kinesin Eg5. STLC contains two free terminal amino and carboxyl groups that play pivotal roles in binding to the Eg5 pocket. On the other hand, such a zwitterion structure complicates the clinical development of STLC because of the solubility issues. Masking either of these radicals reduces or abolishes STLC activity against Eg5. We recently identified and characterized a new class of nicotinamide adenine dinucleotide-dependent deacetylase isoform 2 of sirtuin protein (SIRT2) inhibitors that can be utilized as cytotoxic agents based on an S-trityl-l-histidine scaffold. Herein, we propose new STLC-derived compounds that possess pronounced SIRT2 inhibition effects. These derivatives contain modified amino and carboxyl groups, which conferred STLC with SIRT2 bioactivity, representing an explicit repurposing approach. Compounds STC4 and STC11 exhibited half maximal inhibitory concentration values of 10.8 ± 1.9 and 9.5 ± 1.2 µM, respectively, against SIRT2. Additionally, introduction of the derivatizations in this study addressed the solubility limitations of free STLC, presumably due to interruption of the zwitterion structure. Therefore, we could obtain drug-like STLC derivatives that work by a new mechanism of action. The new derivatives were designed, synthesized, and their structure was confirmed using different spectroscopic approaches. In vitro and cellular bioassays with various cancer cell lines and in silico molecular docking and solubility calculations of the synthesized compounds demonstrated that they warrant attention for further refinement of their bioactivity.

11.
Respir Investig ; 57(6): 574-581, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31427269

RESUMO

BACKGROUND: Empyema is an important and serious disease with high morbidity and mortality worldwide. However, the bacteriology and prognostic factors of empyema remain poorly understood, and data on the relationships among these parameters are scant. METHODS: We retrospectively analyzed a prospectively collected database of patients with empyema admitted to Kurashiki Central Hospital, Japan, between May 2007 and September 2015. Only patients who had positive results on pleural fluid bacterial culture were included. We collected patient characteristics, bacteriology findings, treatments, and outcomes, and we assessed the prognostic factors for in-hospital mortality. RESULTS: We included 71 patients in this study. The most commonly isolated bacteria were members of the Streptococcus anginosus group (37%), followed by anaerobes (30%). In-hospital mortality was 11%. On multivariate analysis, polymicrobial empyema (odds ratio [OR], 8.25; 95% confidence interval [CI], 1.08-62.90) and RAPID (renal, age, purulence, infection source, and dietary factors) score (OR, 6.89; 95% CI, 1.73-27.40) were significant risk factors for in-hospital mortality. The most common etiology of polymicrobial empyema was a combination of the members of the S. anginosus group and anaerobes, but no relationship was observed between the combination of microorganisms and outcomes. Although no significant difference was observed in treatment between the survivor and non-survivor groups, all patients who underwent surgery survived. CONCLUSIONS: Members of the S. anginosus group and anaerobes were frequent pathogens in empyema, and polymicrobial etiology was independently associated with mortality in addition to the RAPID score. Surgery may be one option for preventing mortality.

12.
Sci Rep ; 9(1): 9952, 2019 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-31289306

RESUMO

KDM5 family members (A, B, C and D) that demethylate H3K4me3 have been shown to be involved in human cancers. Here we performed screening for KDM5A inhibitors from chemical libraries using the AlphaScreen method and identified a battery of screening hits that inhibited recombinant KDM5A. These compounds were further subjected to cell-based screening using a reporter gene that responded to KDM5A inhibition and 6 compounds were obtained as candidate inhibitors. When further confirmation of their inhibition activity on cellular KDM5A was made by immunostaining H3K4me3 in KDM5A-overexpressing cells, ryuvidine clearly repressed H3K4me3 demethylation. Ryuvidine prevented generation of gefitinib-tolerant human small-cell lung cancer PC9 cells and also inhibited the growth of the drug-tolerant cells at concentrations that did not affect the growth of parental PC9 cells. Ryuvidine inhibited not only KDM5A but also recombinant KDM5B and C; KDM5B was the most sensitive to the inhibitor. These results warrant that ryuvidine may serve as a lead compound for KDM5 targeted therapeutics.

13.
Biol Pharm Bull ; 42(6): 1044-1047, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31155581

RESUMO

Nitric oxide (NO) is a key signaling molecule that has various effects via S-nitrosylation, a reversible post-translational modification that affects the enzymatic activity, localization, and metabolism of target proteins. As chronic nitrosative stress correlates with neurodegeneration, the targets have received focused attention. Macrophage migration inhibitory factor (MIF) plays a pivotal role in the induction of gene expression to control inflammatory responses. MIF acts as a ligand for CD74 receptor and activates the Src-p38 mitogen-activated protein kinase (MAPK) cascade. MIF also elevates the expression of brain-derived neurotrophic factor (BDNF), which contributes to the viability of neurons. Here, we show that MIF is S-nitrosylated by a physiological NO donor. Interestingly, the induction of S-nitrosylation resulted in a loss of MIF activity following stimulation of the Src and p38 MAPK signaling pathways and the induction of BDNF expression. Our results shed light on the pathogenic mechanisms of neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease.


Assuntos
Cisteína/análogos & derivados , Fatores Inibidores da Migração de Macrófagos/metabolismo , Doadores de Óxido Nítrico/farmacologia , S-Nitrosotióis/farmacologia , Animais , Linhagem Celular Tumoral , Cisteína/farmacologia , Células HEK293 , Humanos , Camundongos , Transdução de Sinais , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Quinases da Família src/metabolismo
14.
Glycoconj J ; 36(5): 409-418, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31243630

RESUMO

Stage-specific embryonic antigen-4 (SSEA-4), a specific marker for pluripotent stem cells, plays an important role in the malignant behavior of several cancers. Here, SSEA-4 expression was evaluated by immunohistochemistry using monoclonal antibody RM1 specific to SSEA-4 in 181 and 117 prostate cancer (PC) specimens obtained by biopsy and radical prostatectomy (RP), respectively. The relationships between SSEA-4 expression in cancer cells or the presence of SSEA-4-positive tumor-infiltrating immune cells (TICs) and clinicopathological parameters were analyzed. SSEA-4 expression in cancer cells was significantly associated with Gleason score, local progression, and lymph node and distant metastasis. In RP specimens, high SSEA-4 expression in cancer cells and the presence of SSEA-4-positive TICs were significant predictors of pT3, i.e., invasion and worse biochemical recurrence (BCR) after RP, respectively, in univariate analysis. In contrast, combination of high SSEA-4 expression in cancer cells and the presence of SSEA-4-positive TICs was an independent predictor for pT3 and BCR in multivariate analysis. Biologically this combination was also independently associated with suppression of apoptosis. Thus, the co-expression of SSEA-4 in cancer cells and TICs may have crucial roles in the malignant aggressiveness and prognosis of PC. Invasive potential and suppression of apoptosis may be linked to SSEA-4 expression.

15.
Clin Chem Lab Med ; 57(10): 1632-1637, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31120857

RESUMO

Background This study aimed to investigate the usefulness of inflammatory biomarkers such as white blood cell (WBC) count, C-reactive protein (CRP) and procalcitonin (PCT) for differentiating cryptogenic organising pneumonia (COP) from community-acquired pneumonia (CAP). Methods COP patients hospitalised in Kurashiki Central Hospital between January 2010 and December 2017 whose WBC counts and CRP and PCT levels were measured were investigated retrospectively, and their results were compared with those of hospitalised CAP patients who were prospectively enrolled between October 2010 and November 2017. Definite COP was defined by specific histopathological findings, and possible COP was defined as a consolidation shadow on chest computed tomography and lymphocyte dominance in bronchoalveolar lavage fluid in the absence of specific histopathological findings or lung specimens. The discriminatory abilities of WBC counts, CRP and PCT were evaluated by receiver operating characteristic (ROC) curve analysis. Results There were 56 patients in the entire COP group, 35 (61.4%) with definite COP, and 914 CAP patients. All three biomarkers were significantly lower in COP than in CAP. The AUC value of PCT in all COP patients was 0.79, significantly higher than of both CRP (AUC 0.59, p < 0.001) and WBC (AUC 0.69, p = 0.048). In definite COP patients, the AUC value of PCT was 0.79, which was also significantly higher than of both WBC (AUC 0.64, p = 0.006) and CRP (AUC 0.64, p = 0.001). Conclusions PCT is a more useful biomarker for differentiating COP from CAP than WBC count or CRP. However, PCT should be used as an adjunct to clinical presentation and radiological findings.

16.
Tohoku J Exp Med ; 248(1): 31-36, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31092738

RESUMO

Aldosterone affects various systems and organs, including the cardiovascular system, through mineralocorticoid receptors. We here report a primary aldosteronism patient with severe cardiac dysfunction who showed dramatic improvement after laparoscopic adrenalectomy. The 57-year-old man presented with acute heart failure exacerbation. Performance status was 4, and New York Heart Association classification was 4. Echocardiography showed diffuse hypokinetic wall motion with an ejection fraction of 20%. The patient was found to have a high plasma level of brain natriuretic peptide (4,935 pg/mL), hypokalemia (2.7 mEq/L), an extremely elevated plasma aldosterone concentration (1,804 pg/mL), and high aldosterone-to-renin ratio [plasma aldosterone concentration (pg/mL)/plasma renin activity (ng/mL/hr)] (9,002). Computed tomography revealed a tumor 42 mm in diameter in the right adrenal gland. Primary aldosteronism was diagnosed with adrenal venous sampling. Medical treatment for heart failure was continued for several months, but the cardiac function was not sufficiently improved, suggesting the indication of heart transplantation. However, the patient could not be considered a candidate because of the adrenal tumor. Laparoscopic adrenalectomy was therefore performed. Immediately after surgery, echocardiography showed improved wall motion with an ejection fraction of 36%. Performance status and New York Heart Association classification were improved to 0 and 2, respectively. The present case has shown the efficacy of laparoscopic adrenalectomy for primary aldosteronism patients with severe heart failure.


Assuntos
Adrenalectomia , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/cirurgia , Testes de Função Cardíaca , Hiperaldosteronismo/fisiopatologia , Hiperaldosteronismo/cirurgia , Laparoscopia , Biópsia , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/diagnóstico por imagem , Hormônios/metabolismo , Humanos , Hiperaldosteronismo/complicações , Hiperaldosteronismo/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Miocárdio/patologia , Radiografia Torácica , Fatores de Tempo
18.
Cancer Sci ; 110(8): 2573-2589, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31145522

RESUMO

To reduce unnecessary prostate biopsies (Pbx), better discrimination is needed. To identify clinically significant prostate cancer (CSPC) we determined the performance of LacdiNAc-glycosylated prostate-specific antigen (LDN-PSA) and LDN-PSA normalized by prostate volume (LDN-PSAD). We retrospectively measured LDN-PSA, total PSA (tPSA), and free PSA/tPSA (F/T PSA) values in 718 men who underwent a Pbx in 3 academic urology clinics in Japan and Canada (Pbx cohort) and in 174 PC patients who subsequently underwent radical prostatectomy in Australia (preop-PSA cohort). The assays were evaluated using the area under the receiver operating characteristics curve (AUC) and decision curve analyses to discriminate CSPC. In the Pbx cohort, LDN-PSAD (AUC 0.860) provided significantly better clinical performance for discriminating CSPC compared with LDN-PSA (AUC 0.827, P = 0.0024), PSAD (AUC 0.809, P < 0.0001), tPSA (AUC 0.712, P < 0.0001), and F/T PSA (AUC 0.661, P < 0.0001). The decision curve analysis showed that using a risk threshold of 20% and adding LDN-PSA and LDN-PSAD to the base model (age, digital rectal examination status, tPSA, and F/T PSA) permitted avoidance of even more biopsies without missing CSPC (9.89% and 18.11%, respectively vs 2.23% [base model]). In the preop-PSA cohort, LDN-PSA values positively correlated with tumor volume and tPSA and were significantly higher in pT3, pathological Gleason score ≥ 7. Limitations include limited sample size, retrospective nature, and no family history information prior to biopsy. LacdiNAc-glycosylated PSA is significantly better than the conventional PSA test in identifying patients with CSPC. This study was approved by the ethics committee of each institution ("The Study about Carbohydrate Structure Change in Urological Disease"; approval no. 2014-195).


Assuntos
Lactose/análogos & derivados , Próstata/metabolismo , Próstata/patologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Idoso , Glicosilação , Humanos , Lactose/metabolismo , Masculino , Pessoa de Meia-Idade , Gradação de Tumores/métodos , Antígeno Prostático Específico , Curva ROC , Estudos Retrospectivos , Carga Tumoral/fisiologia
19.
Blood Adv ; 3(7): 1047-1060, 2019 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-30944097

RESUMO

Chronic myelomonocytic leukemia (CMML) constitutes a hematopoietic stem cell (HSC) disorder characterized by prominent monocytosis and myelodysplasia. Although genome sequencing has revealed the CMML mutation profile, the mechanism of disease development remains unclear. Here we show that aberrant histone acetylation by nucleoporin-98 (NUP98)-HBO1, a newly identified fusion in a patient with CMML, is sufficient to generate clinically relevant CMML pathogenesis. Overexpression of NUP98-HBO1 in murine HSC/progenitors (HSC/Ps) induced diverse CMML phenotypes, such as severe leukocytosis, increased CD115+ Ly6Chigh monocytes (an equivalent subpopulation to human classical CD14+ CD16- monocytes), macrocytic anemia, thrombocytopenia, megakaryocyte-lineage dysplasia, splenomegaly, and cachexia. A NUP98-HBO1-mediated transcriptional signature in human CD34+ cells was specifically activated in HSC/Ps from a CMML patient cohort. Besides critical determinants of monocytic cell fate choice in HSC/Ps, an oncogenic HOXA9 signature was significantly activated by NUP98-HBO1 fusion through aberrant histone acetylation. Increased HOXA9 gene expression level with disease progression was confirmed in our CMML cohort. Genetic disruption of NUP98-HBO1 histone acetyltransferase activity abrogated its leukemogenic potential and disease development in human cells and a mouse model. Furthermore, treatment of azacytidine was effective in our CMML mice. The recapitulation of CMML clinical phenotypes and gene expression profile by the HBO1 fusion suggests our new model as a useful platform for elucidating the central downstream mediators underlying diverse CMML-related mutations and testing multiple compounds, providing novel therapeutic potential.

20.
Hypertension ; 73(6): 1283-1290, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31006333

RESUMO

Peripheral 18-oxocortisol (18oxoF) level could contribute to the detection of aldosterone-producing adenoma (APA) in patients with primary aldosteronism. However, peripheral 18oxoF varies among such patients, which is a big drawback concerning its clinical application. We studied 48 cases of APA, 35 harboring KCNJ5 mutation, to clarify the significance of clinical and pathological parameters about peripheral 18oxoF. Peripheral 18oxoF concentration ranged widely from 0.50 to 183.13 ng/dL and correlated positively with intratumoral areas stained positively for steroidogenic enzymes ( P<0.0001). The peripheral 18oxoF level also correlated significantly with that of circulating aldosterone ( P<0.0001) but not with that of cortisol, a precursor of 18oxoF. However, a significant correlation was detected between peripheral 18oxoF and intratumoral glucocorticoids ( P<0.05). In addition, peripheral 18oxoF correlated positively with the number of hybrid cells double positive for 11ß-hydroxylase and aldosterone synthase ( P<0.0001). Comparing between the cases with and those without KCNJ5 mutation, the KCNJ5-mutated group demonstrated a significantly higher concentration of peripheral 18oxoF (28.4±5.6 versus 3.0±0.9 ng/dL, P<0.0001) and a larger intratumoral environment including the hybrid cells ( P<0.001), possibly representing a deviation from normal aldosterone biosynthesis. After multivariate analysis, KCNJ5 mutation status turned out to be the most associated factor involved in 18oxoF synthesis in APA ( P<0.0001). Results of our present study first revealed that enhanced 18oxoF synthesis in APA could come from a functional deviation of aldosterone biosynthesis from the normal zona glomerulosa and the utility of peripheral 18oxoF measurement could be influenced by the prevalence of KCNJ5 mutation in an APA.


Assuntos
Neoplasias do Córtex Suprarrenal/genética , Adenoma Adrenocortical/genética , Aldosterona/metabolismo , DNA de Neoplasias/genética , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/genética , Hidrocortisona/análogos & derivados , Mutação/genética , Neoplasias do Córtex Suprarrenal/metabolismo , Adenoma Adrenocortical/metabolismo , Análise Mutacional de DNA , Feminino , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/metabolismo , Humanos , Hidrocortisona/biossíntese , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
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