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A 38-year-old pathologist developed multiple evanescent white dot syndrome (MEWDS). He documented his visual impairment in detail utilizing a light microscope for pathological diagnosis. Notably, the subjective defects illustrated by the patient were in good spatiotemporal agreement with diagnostic outcomes. The present report enhances the understanding of visual impairment associated with MEWDS through a comparative analysis of subjective experiences and objective clinical findings.
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INTRODUCTION: In contrast to the antihypertensive effect of esaxerenone, there is little evidence of its cardioprotective effect. We investigated the efficacy and safety of esaxerenone in patients with uncontrolled hypertension and left ventricular hypertrophy taking a renin-angiotensin system inhibitor (RASi) or calcium-channel blocker (CCB). METHODS: This was a multicenter, open-label, exploratory study with a 24-week treatment period. Esaxerenone was orally administered at an initial dose of 2.5 mg/day (maximum dose: 5 mg/day). The primary endpoints were the change in morning home systolic blood pressure (BP)/diastolic BP and change and percentage change in left ventricular mass index (LVMI) from baseline to end of treatment (EOT). Key secondary endpoints included change from baseline in bedtime home and office BP, achievement rate of target BP, and safety. RESULTS: In total, 60 patients were enrolled. Morning home systolic/diastolic BP was significantly decreased from baseline to EOT in the total population (- 11.5/ - 4.7 mmHg, p < 0.001) and in both the RASi and CCB subcohorts (all p < 0.01). Significant reductions in bedtime home and office BP were shown in the total population and both subcohorts. LVMI was also significantly decreased from baseline to EOT in the total population (- 9.9 g/m2, - 8.5%, both p < 0.001) and both subcohorts (all p < 0.05). The incidences of treatment-emergent adverse events (TEAEs) and drug-related TEAEs were 35.0% and 3.3%, respectively; most were mild or moderate. No new safety concerns were identified. CONCLUSION: Esaxerenone showed favorable antihypertensive and cardioprotective effects and safety in hypertensive patients with cardiac hypertrophy. TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCTs071190043).
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Hipertensión , Hipertrofia Ventricular Izquierda , Pirroles , Sulfonas , Humanos , Antihipertensivos/uso terapéutico , Presión Sanguínea , Bloqueadores de los Canales de Calcio/uso terapéutico , Hipertensión/complicaciones , Hipertensión/tratamiento farmacológico , Hipertrofia Ventricular Izquierda/complicaciones , Hipertrofia Ventricular Izquierda/tratamiento farmacológico , Estudios Prospectivos , Pirroles/efectos adversos , Sulfonas/efectos adversosRESUMEN
Excessive salt intake is one of the causes of hypertension, and reducing salt intake is important for managing the risk of hypertension and subsequent cardiovascular events. Esaxerenone, a mineralocorticoid receptor blocker, has the potential to exert an antihypertensive effect in hypertensive patients with excessive salt intake, but evidence is still lacking, especially in clinical settings. We aimed to determine if baseline sodium/potassium ratio and baseline estimated 24-h urinary sodium excretion can predict the antihypertensive effect of esaxerenone in patients with essential hypertension inadequately controlled with an angiotensin receptor blocker (ARB) or a calcium channel blocker (CCB). This was an exploratory, open-label, interventional study with a 4-week observation period and a 12-week treatment period. Esaxerenone was orally administered once daily in accordance with the Japanese package insert. In total, 126 patients met the eligibility criteria and were enrolled (ARB subcohort, 67; CCB subcohort, 59); all were included in the full analysis set (FAS) and safety analysis. In the FAS, morning home systolic blood pressure (SBP)/diastolic blood pressure (DBP) significantly decreased from baseline to end of treatment (primary efficacy endpoint) (-11.9 ± 10.9/ - 6.4 ± 6.8 mmHg, both p < 0.001); a similar trend was observed in both subcohorts. Significant reductions were also shown in bedtime home and office SBP/DBP (all p < 0.001). Each BP change was consistent regardless of the urinary sodium/potassium ratio or estimated 24-h urinary sodium excretion at baseline. The urinary albumin-creatinine ratio (UACR) and N-terminal pro-brain natriuretic peptide (NT-proBNP) significantly decreased from baseline to Week 12 in the total population and both subcohorts. No new safety concerns were raised. Esaxerenone significantly decreased morning home, bedtime home, and office BP; UACR; and NT-proBNP in this patient population, regardless of concomitant ARB or CCB use. The antihypertensive effect of esaxerenone was independent of the urinary sodium/potassium ratio and estimated 24-h urinary sodium excretion at baseline.
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Antihipertensivos , Hipertensión , Pirroles , Sulfonas , Humanos , Antihipertensivos/uso terapéutico , Antihipertensivos/farmacología , Cloruro de Sodio Dietético , Antagonistas de Receptores de Angiotensina/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Presión Sanguínea/fisiología , Bloqueadores de los Canales de Calcio/uso terapéutico , Sodio , PotasioRESUMEN
INTRODUCTION: The EAGLE-DH study assessed the efficacy and safety of esaxerenone in hypertensive patients with diabetes mellitus receiving sodium-glucose cotransporter 2 (SGLT2) inhibitors. METHODS: In this multicenter, open-label, prospective, interventional study, esaxerenone was started at 1.25 or 2.5 mg/day and could be gradually increased to 5 mg/day on the basis of blood pressure (BP) and serum potassium levels. Oral hypoglycemic or antihypertensive medications prior to obtaining consent was continued. Data were evaluated in the total population and creatinine-based estimated glomerular filtration rate (eGFR) subcohorts (eGFR ≥ 60 mL/min/1.73 m2 [G1-G2 subcohort] and 30 to < 60 mL/min/1.73 m2 [G3 subcohort]). RESULTS: In total, 93 patients were evaluated (G1-G2, n = 49; G3, n = 44). Morning home systolic/diastolic BP values (SBP/DBP) were significantly reduced from baseline to week 12 (- 11.8 ± 10.8/- 5.1 ± 6.3 mmHg, both P < 0.001) and week 24 (- 12.9 ± 10.5/- 5.7 ± 6.3 mmHg, both P < 0.001). Similar results were observed in both eGFR subcohorts. The urinary albumin-to-creatinine ratio significantly decreased from baseline to week 24 in the total population (geometric percentage change, - 49.1%, P < 0.001) and in both eGFR subcohorts. The incidences of treatment-emergent adverse events (TEAEs) and drug-related TEAEs were 45.2% and 12.9%, respectively; most were mild or moderate. Serum potassium levels increased over the first 2 weeks of esaxerenone treatment, gradually decreased by week 12, and remained constant to week 24. One patient in the G1-G2 subcohort had serum potassium levels ≥ 5.5 mEq/L. No patients had serum potassium ≥ 6.0 mEq/L. CONCLUSION: Esaxerenone effectively lowered BP, was safe, and showed renoprotective effects in hypertensive patients with diabetes mellitus receiving treatment with SGLT2 inhibitors. Esaxerenone and SGLT2 inhibitors did not interfere with either drug's efficacy and may reduce the frequency of serum potassium elevations, suggesting they are a compatible combination. CLINICAL TRIAL REGISTRATION: jRCTs031200273.
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Diabetes Mellitus Tipo 2 , Hipertensión , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Inhibidores del Cotransportador de Sodio-Glucosa 2/efectos adversos , Creatinina/farmacología , Creatinina/uso terapéutico , Estudios Prospectivos , Hipertensión/complicaciones , Hipertensión/tratamiento farmacológico , Presión Sanguínea , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Potasio/farmacología , Potasio/uso terapéutico , Glucosa/farmacología , Glucosa/uso terapéutico , Sodio/farmacología , Sodio/uso terapéuticoRESUMEN
The next-generation mineralocorticoid receptor blocker (MRB) esaxerenone has favorable antihypertensive effects in patients who do not respond to treatment with first-line antihypertensive agents and may be beneficial as a second-line treatment. However, MRBs are currently considered a fourth-line treatment as there is no clinical evidence comparing the efficacy of esaxerenone with other classes of antihypertensive agents. The multicenter, randomized, open-label, parallel-group EXCITE-HT study will evaluate the efficacy and safety of esaxerenone as a second-line agent in the treatment of Japanese patients with uncontrolled essential hypertension. After a 4-week run-in period, patients will receive either esaxerenone or trichlormethiazide for 12 weeks per the package insert and the Japanese Society of Hypertension Guidelines for the Management of Hypertension. At Weeks 4 and 8, the dose of esaxerenone or trichlormethiazide may be increased. Blood pressure (home [morning and bedtime] and office), serum biomarkers, and urinary biomarkers will be measured. The primary efficacy endpoint is the change from baseline in morning home systolic blood pressure/diastolic blood pressure to the end of treatment. The EXCITE-HT study is expected to validate the non-inferiority of esaxerenone to trichlormethiazide and provide the first evidence for the early use of esaxerenone as a second-line agent in the treatment of Japanese patients with uncontrolled essential hypertension instead of its current use as a fourth-line agent.
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Antihipertensivos , Hipertensión , Humanos , Antihipertensivos/efectos adversos , Triclormetiazida/farmacología , Triclormetiazida/uso terapéutico , Hipertensión Esencial/tratamiento farmacológico , Presión SanguíneaRESUMEN
Cell adhesion molecules, including integrins, cadherins, and claudins (CLDNs), are known to activate Src-family kinases (SFKs) that organize a variety of physiological and pathological processes; however, the underlying molecular basis remains unclear. Here, we identify the SFK members that are coupled with the CLDN6-adhesion signaling. Among SFK subtypes, BLK, FGR, HCK, and SRC were highly expressed in F9 cells and concentrated with CLDN6 along cell borders during epithelial differentiation. Immunoprecipitation assay showed that BLK and SRC, but not FGR or HCK, form a complex with CLDN6 via the C-terminal cytoplasmic domain. We also demonstrated, by pull-down assay, that recombinant BLK and SRC proteins directly bind to the C-terminal cytoplasmic domain of CLDN6 (CLDN6C). Unexpectedly, both recombinant SFK proteins recognized the CLDN6C peptide in a phosphotyrosine-independent manner. Furthermore, by comparing phenotypes of F9:Cldn6:Blk-/- and F9:Cldn6:Src-/- cells with those of wild-type F9 and F9:Cldn6 cells, we revealed that BLK and SRC are essential for CLDN6-triggered cellular events, namely epithelial differentiation and the expression of retinoid acid receptor target genes. These results indicate that selective SFK members appear to participate in the CLDN-adhesion signaling.
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Transducción de Señal , Familia-src Quinasas , Familia-src Quinasas/metabolismo , Moléculas de Adhesión Celular , Integrinas , Receptores de Ácido Retinoico , Claudinas/genética , Claudinas/metabolismoRESUMEN
We previously identified the AKT-phosphorylation sites in nuclear receptors and showed that phosphorylation of S379 in mouse retinoic acid γ and S518 in human estrogen receptor α regulate their activity independently of the ligands. Since this site is conserved at S510 in human liver receptor homolog 1 (hLRH1), we developed a monoclonal antibody (mAb) that recognized the phosphorylation form of hLRH1S510 (hLRH1pS510) and verified its clinicopathological significance in hepatocellular carcinoma (HCC). We generated the anti-hLRH1pS510 mAb and assessed its selectivity. We then evaluated the hLRH1pS510 signals in 157 cases of HCC tissues by immunohistochemistry because LRH1 contributes to the pathogenesis of diverse cancers. The developed mAb specifically recognized hLRH1pS510 and worked for immunohistochemistry of formalin-fixed paraffin-embedded tissues. hLRH1pS510 was exclusively localized in the nucleus of HCC cells, but the signal intensity and positive rates varied among the subjects. According to the semi-quantification, 45 cases (34.9%) showed hLRH1pS510-high, and the remaining 112 cases (65.1%) exhibited hLRH1pS510-low. There were significant differences in the recurrence-free survival (RFS) between the two groups, and the 5-year RFS rates in the hLRH1pS510-high and hLRH1pS510-low groups were 26.5% and 46.1%, respectively. In addition, high hLRH1pS510 was significantly correlated with portal vein invasion, hepatic vein invasion, and high levels of serum alpha-fetoprotein (AFP). Furthermore, multivariable analysis revealed that hLRH1pS510-high was an independent biomarker for HCC recurrence. We conclude that aberrant phosphorylation of hLRH1S510 is a predictor of poor prognosis for HCC. The anti-hLRH1pS510 mAb could provide a powerful tool to validate the relevance of hLRH1pS510 in pathological processes such as tumor development and progression.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , alfa-Fetoproteínas/metabolismo , Biomarcadores de Tumor/análisis , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Fosforilación , Pronóstico , Serina , HumanosRESUMEN
BACKGROUND: Ovarian cancer has the worst outcome among gynecological malignancies; therefore, biomarkers that could contribute to the early diagnosis and/or prognosis prediction are urgently required. In the present study, we focused on the secreted protein spondin-1 (SPON1) and clarified the prognostic relevance in ovarian cancer. METHODS: We developed a monoclonal antibody (mAb) that selectively recognizes SPON1. Using this specific mAb, we determined the expression of SPON1 protein in the normal ovary, serous tubal intraepithelial carcinoma (STIC), and ovarian cancer tissues, as well as in various normal adult tissues by immunohistochemistry, and verified its clinicopathological significance in ovarian cancer. RESULTS: The normal ovarian tissue was barely positive for SPON1, and no immunoreactive signals were detected in other healthy tissues examined, which was in good agreement with data obtained from gene expression databases. By contrast, upon semi-quantification, 22 of 242 ovarian cancer cases (9.1%) exhibited high SPON1 expression, whereas 64 (26.4%), 87 (36.0%), and 69 (28.5%) cases, which were designated as SPON1-low, possessed the moderate, weak, and negative SPON1 expression, respectively. The STIC tissues also possessed SPON1-positive signals. The 5-year recurrence-free survival (RFS) rate in the SPON1-high group (13.6%) was significantly lower than that in the SPON1-low group (51.2%). In addition, high SPON1 expression was significantly associated with several clinicopathological variables. Multivariable analysis revealed that high SPON1 was an independent prognostic factor for RFS of ovarian cancer. CONCLUSIONS: SPON1 represents a prognostic biomarker for ovarian cancer, and the anti-SPON1 mAb could be valuable as an outcome predictor.
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Cistadenocarcinoma Seroso , Neoplasias de las Trompas Uterinas , Neoplasias Ováricas , Adulto , Femenino , Humanos , Neoplasias Ováricas/genética , Pronóstico , Cistadenocarcinoma Seroso/patología , Neoplasias de las Trompas Uterinas/patología , Biomarcadores , Biomarcadores de Tumor/metabolismoRESUMEN
There is limited evidence on the blood pressure (BP)-lowering effect of esaxerenone on home BP, including nighttime BP. Using two newly developed nocturnal home BP monitoring devices (brachial and wrist), this multicenter, open-label, prospective study investigated the nighttime home BP-lowering effect of esaxerenone in patients with uncontrolled nocturnal hypertension being treated with an angiotensin receptor blocker (ARB) or calcium-channel blocker (CCB). In total, 101 patients were enrolled. During the 12-week study period, change in nighttime home systolic/diastolic BP from baseline to end of treatment measured by the brachial device was -12.9/-5.4 mmHg in the total population and -16.2/-6.6 and -10.0/-4.4 mmHg in the ARB and CCB subcohorts, respectively (all p < 0.001). For the wrist device, the change was -11.7/-5.4 mmHg in the total population and -14.6/-6.2 and -8.3/-4.5 mmHg in each subcohort, respectively (all p < 0.001). Similar significant reductions were shown for morning and bedtime home BP and office BP. Urinary albumin-to-creatinine ratio, N-terminal pro-brain natriuretic peptide, and cardio-ankle vascular index improved in the total population and each subcohort. Incidences of treatment-emergent adverse events (TEAEs) and drug-related TEAEs were 38.6% and 16.8%, respectively; most were mild or moderate. The most frequent drug-related TEAEs were associated with serum potassium elevation (hyperkalemia, 9.9%; blood potassium increased, 3.0%); however, no new safety concerns were raised. Esaxerenone was effective in lowering nighttime home BP as well as morning and bedtime home BP and office BP, safe, and showed organ-protective effects in patients with uncontrolled nocturnal hypertension. Caution is warranted regarding elevated serum potassium levels. This study investigated the effect of esaxerenone on nighttime home BP and organ damage (UACR and NT-proBNP) in patients with uncontrolled nocturnal hypertension despite treatment with an ARB or CCB. Our results show that safe 24-h BP control and organ protection are possible with esaxerenone.
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Antihipertensivos , Hipertensión , Humanos , Presión Sanguínea/fisiología , Antihipertensivos/efectos adversos , Antagonistas de Receptores de Angiotensina/uso terapéutico , Estudios Prospectivos , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Bloqueadores de los Canales de Calcio/uso terapéutico , Potasio , Monitoreo Ambulatorio de la Presión ArterialRESUMEN
BACKGROUND: Cell adhesion is indispensable for appropriate tissue architecture and function in multicellular organisms. Besides maintaining tissue integrity, cell adhesion molecules, including tight-junction proteins claudins (CLDNs), exhibit the signaling abilities to control a variety of physiological and pathological processes. However, it is still fragmentary how cell adhesion signaling accesses the nucleus and regulates gene expression. METHODS: By generating a number of knockout and rescued human breast cell lines and comparing their phenotypes, we determined whether and how CLDN4 affected breast cancer progression in vitro and in vivo. We also identified by RNA sequencing downstream genes whose expression was altered by CLDN4-adhesion signaling. Additionally, we analyzed by RT-qPCR the CLDN4-regulating genes by using a series of knockout and add-back cell lines. Moreover, by immunohistochemistry and semi-quantification, we verified the clinicopathological significance of CLDN4 and the nuclear receptor LXRß (liver X receptor ß) expression in breast cancer tissues from 187 patients. RESULTS: We uncovered that the CLDN4-adhesion signaling accelerated breast cancer metabolism and progression via LXRß. The second extracellular domain and the carboxy-terminal Y197 of CLDN4 were required to activate Src-family kinases (SFKs) and the downstream AKT in breast cancer cells to promote their proliferation. Knockout and rescue experiments revealed that the CLDN4 signaling targets the AKT phosphorylation site S432 in LXRß, leading to enhanced cell proliferation, migration, and tumor growth, as well as cholesterol homeostasis and fatty acid metabolism, in breast cancer cells. In addition, RT-qPCR analysis showed the CLDN4-regulated genes are classified into at least six groups according to distinct LXRß- and LXRßS432-dependence. Furthermore, among triple-negative breast cancer subjects, the "CLDN4-high/LXRß-high" and "CLDN4-low and/or LXRß-low" groups appeared to exhibit poor outcomes and relatively favorable prognoses, respectively. CONCLUSIONS: The identification of this machinery highlights a link between cell adhesion and transcription factor signalings to promote metabolic and progressive processes of malignant tumors and possibly to coordinate diverse physiological and pathological events.
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Proteínas Proto-Oncogénicas c-akt , Neoplasias de la Mama Triple Negativas , Humanos , Claudina-4/genética , Claudina-4/metabolismo , Receptores X del Hígado/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Claudinas/genética , Claudinas/metabolismo , Neoplasias de la Mama Triple Negativas/patología , Línea Celular TumoralRESUMEN
INTRODUCTION: This study investigated factors associated with the antihypertensive effects of esaxerenone and the incidence of serum potassium elevation in patients with hypertension. METHODS: Using pooled data from seven phase III studies, the study analyzed factors associated with changes in office systolic (SBP) and diastolic (DBP) blood pressure from baseline to 12 weeks, and factors associated with incidence of serum potassium levels ≥ 5.5 mEq/L in esaxerenone-treated patients. RESULTS: Overall, 1466 and 1472 patients were included in the full analysis and safety analysis sets, respectively. Male sex (4.02/2.40 mmHg), weight ≥ 78.4 kg (4.62/2.09 mmHg), hypertension duration ≥ 10 years (2.66/1.71 mmHg), prior antihypertensive treatment (2.38/1.40 mmHg), plasma aldosterone concentration ≥ 120 pg/mL (1.66/1.17 mmHg), urinary albumin-to-creatinine ratio (UACR) ≥ 300 mg/gCr (8.94/4.85 mmHg) or 30-299 mg/gCr (5.17/4.15 mmHg), and smoking (2.62/1.27 mmHg) were associated with mean changes in SBP and DBP. Fasting blood glucose ≥ 126 mg/dL (- 2.73 mmHg) was associated with the mean change in SBP only, and older age (65-74 years, - 2.12 mmHg; and ≥ 75 years, - 3.06 mmHg) with mean change in DBP only. Factors significantly associated with incidence of serum potassium levels ≥ 5.5 mEq/L were higher baseline serum potassium (≥ 4.5 mEq/L, odds ratio [OR] 6.702); lower estimated glomerular filtration rate (≥ 90 mL/min/1.73 m2, OR 0.148; 60-89 mL/min/1.73 m2, OR 0.331 vs 30-59 mL/min/1.73 m2, respectively); higher UACR (30-299 mg/gCr, OR 7.317); higher DBP (≥ 100 mmHg, OR 3.248); and grade I hypertension (OR 2.168). CONCLUSION: Esaxerenone is effective in patients with a broad range of backgrounds, though some factors may predict increased benefit. Regarding elevated serum potassium, careful therapeutic management is recommended for patients with higher baseline serum potassium and reduced renal function. CLINICAL TRIAL REGISTRATION: UMIN000047026.
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Antihipertensivos , Hipertensión , Humanos , Masculino , Antihipertensivos/uso terapéutico , Hipertensión/tratamiento farmacológico , Pirroles/uso terapéutico , Presión Sanguínea , Potasio/uso terapéutico , Potasio/farmacologíaRESUMEN
The role of T cells in appendage regeneration remains unclear. In this study, we revealed an important role for regulatory T cells (Tregs), a subset of T cells that regulate tolerance and tissue repair, in the epimorphic regeneration of zebrafish caudal fin tissue. Upon amputation, fin tissue-resident Tregs infiltrate into the blastema, a population of progenitor cells that produce new fin tissues. Conditional genetic ablation of Tregs attenuates blastemal cell proliferation during fin regeneration. Blastema-infiltrating Tregs upregulate the expression of igf2a and igf2b, and pharmacological activation of IGF signaling restores blastemal proliferation in Treg-ablated zebrafish. These findings further extend our understandings of Treg function in tissue regeneration and repair.
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Linfocitos T Reguladores , Pez Cebra , Animales , Proliferación Celular , Transducción de Señal/genética , Linfocitos T Reguladores/metabolismo , Pez Cebra/genética , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismoRESUMEN
The tightjunction protein claudin9 (CLDN9) is barely distributed in normal adult tissues but is ectopically expressed in various cancer types. Although multiple databases indicated upregulation of CLDN9 in endometrial cancers at the mRNA level, its protein expression and biological roles remain obscure. In the present study, the prognostic significance of CLDN9 expression in endometrial cancer was evaluated by immunohistochemical staining and semiquantification using formalinfixed paraffinembedded specimens obtained from 248 endometrial carcinoma cases. A total of 43 cases (17.3%) had high CLDN9 expression, whereas 205 cases (82.7%) exhibited low CLDN9 expression. The 5year diseasespecific survival rates in the high and low CLDN9 expression groups were 62.8 and 87.8% (P<0.001), respectively. In addition, multivariate analysis revealed that high CLDN9 expression was an independent prognostic factor (hazard ratio, 4.99; 95% CI, 1.9612.70; P<0.001). Furthermore, CLDN9 expression was significantly correlated with the expression of CLDN6 (P<0.001), which is the closest CLDN member to CLDN9 and a poor prognostic factor for endometrial carcinoma. The 5year diseasespecific survival rate of cases with CLDN6high/CLDN9high, CLDN6high/CLDN9low and CLDN6low/CLDN9high status was 30.0, 37.5 and 72.7%, respectively, whereas that of CLDN6low/CLDN9low was 89.8% (P=0.004). In conclusion, aberrant CLDN9 expression is a predictor of poor prognosis for endometrial cancer and may be utilized in combination with CLDN6 to achieve higher sensitivity.
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Claudinas , Neoplasias Endometriales , Biomarcadores , Claudinas/genética , Claudinas/metabolismo , Neoplasias Endometriales/genética , Neoplasias Endometriales/patología , Femenino , Formaldehído , Humanos , Pronóstico , ARN Mensajero/metabolismoRESUMEN
INTRODUCTION: Clinical data of esaxerenone in hypertensive patients with diabetic kidney disease (DKD) are lacking. We evaluated the efficacy and safety of esaxerenone in patients with DKD and an inadequate response to blood pressure (BP)-lowering treatment. METHODS: In this multicenter, open-label, prospective study, patients were divided into urinary albumin-to-creatinine ratio subcohorts (UACR < 30, 30 to < 300, and 300 to < 1000 mg/gCr). Esaxerenone was initiated at 1.25 mg/day and followed by incremental dose escalation based on BP and serum potassium level monitoring. The treatment period was 12 weeks. The primary endpoint was change in morning home systolic BP/diastolic BP (SBP/DBP) from baseline to end of treatment (EOT). Secondary endpoints included achievement rate of target BP, change in UACR from baseline, and safety. RESULTS: In total, 113 patients were enrolled. Morning home SBP/DBP significantly decreased from baseline to EOT in the total population (- 11.6/- 5.2 mmHg, both p < 0.001) and in all UACR subcohorts (all p < 0.001). The target BP achievement rate was 38.5%. Significant reductions in bedtime home and office BPs were also shown in the total population and all UACR subcohorts. UACR significantly improved from baseline to EOT in the total (- 50.9%, p < 0.001) and all UACR subcohorts (all p < 0.001). Incidence of serum potassium elevation as drug-related treatment emergent adverse events was 2.7%. The change from baseline in estimated glomerular filtration rate (eGFR) was - 4.8 mL/min/1.73 m2. CONCLUSION: Esaxerenone demonstrated a BP-lowering effect and improved albuminuria. The effects were consistent regardless of the severity of albuminuria without clinically relevant serum potassium elevation and eGFR reduction. CLINICAL TRIAL REGISTRATION: jRCTs06119002.
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Diabetes Mellitus , Nefropatías Diabéticas , Hipertensión , Albúminas/uso terapéutico , Albuminuria/tratamiento farmacológico , Albuminuria/etiología , Presión Sanguínea , Creatinina/farmacología , Creatinina/uso terapéutico , Nefropatías Diabéticas/complicaciones , Nefropatías Diabéticas/tratamiento farmacológico , Tasa de Filtración Glomerular , Humanos , Hipertensión/complicaciones , Hipertensión/tratamiento farmacológico , Potasio/farmacología , Potasio/uso terapéutico , Estudios Prospectivos , Pirroles , SulfonasRESUMEN
Anti-N-methyl-D-aspartate receptor (NMDAR) antibody encephalitis is caused by a reversible inhibition of ion channel actions by autoantibodies and is associated with a relatively good prognosis. Pathological findings of NMDAR encephalitis usually do not show neurophagorous nodules, but rare or mild inflammatory infiltration. We report a patient of small cell lung cancer (SCLC)-related paraneoplastic encephalitis with NMDAR antibodies, a cytotoxic T-cell-mediated pathology of the brain, and a rapid clinical course. This case highlights that the neuropathological diversity of NMDAR encephalitis may be even broader than previously thought and that NMDAR antibodies may also be found in various pathological conditions with a vigorous immune response.
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Encefalitis Antirreceptor N-Metil-D-Aspartato , Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Encefalitis Antirreceptor N-Metil-D-Aspartato/complicaciones , Encefalitis Antirreceptor N-Metil-D-Aspartato/etiología , Autoanticuerpos , Humanos , Neoplasias Pulmonares/complicaciones , Receptores de N-Metil-D-Aspartato , Carcinoma Pulmonar de Células Pequeñas/complicaciones , Linfocitos T CitotóxicosRESUMEN
INTRODUCTION: The blood pressure (BP) control mechanism for mineralocorticoid receptor blockers is unclear, and analysis of their use as a single agent in the clinical setting is required to resolve this uncertainty. There is a paucity of data on esaxerenone monotherapy assessing its long-term antihypertensive effect and urinary biomarkers. METHODS: This post hoc exploratory substudy of a long-term phase 3 study evaluated the effect of esaxerenone monotherapy (2.5 or 5 mg/day) in treatment-naïve patients who continued the therapy during the 52-week study period (n = 25). In addition to blood biomarkers, urinary biomarkers were also assessed in 24-h urine collection samples. RESULTS: Esaxerenone monotherapy was associated with consistent reductions in systolic/diastolic BP in the substudy population (- 23.5/- 13.1 mmHg at week 52, p < 0.001 vs baseline). Plasma aldosterone concentrations and plasma renin activity significantly increased during esaxerenone monotherapy at all time points. On the basis of the observations that both urine volume and urinary sodium excretion also decreased up to the end of the study, and were significantly lower at 12 weeks, patients were further categorized into higher/lower urinary sodium excretion subgroups according to whether their baseline values were above or below the median. In the group with higher baseline urinary sodium excretion, esaxerenone exhibited a significantly greater decrease in systolic/diastolic BP compared to the lower baseline group. CONCLUSION: Esaxerenone exhibited sustained and stable antihypertensive activity even when administered as a single agent for 52 weeks in patients with essential hypertension. The additional urinary biomarker analysis suggests that the BP-lowering effects of esaxerenone may be partly exerted via mechanisms related to salt and water retention, and that the effect is particularly pronounced in patients with hypertension and higher baseline urinary sodium excretion, which may reflect a state of excessive salt intake. TRIAL REGISTRATION: NCT02722265.
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Antihipertensivos , Hipertensión , Antihipertensivos/uso terapéutico , Biomarcadores , Presión Sanguínea , Hipertensión Esencial/tratamiento farmacológico , Humanos , Hipertensión/tratamiento farmacológico , Pirroles , Sodio/farmacología , Sodio/uso terapéutico , Sodio/orina , SulfonasRESUMEN
AIMS/INTRODUCTION: We evaluated the effect of co-administration of esaxerenone and a sodium-glucose cotransporter 2 (SGLT2) inhibitor on the magnitude of serum potassium elevation in Japanese patients with diabetic kidney disease. MATERIALS AND METHODS: We carried out a prespecified subanalysis of data from two phase III studies: a multicenter, randomized, double-blind, placebo-controlled trial in patients with type 2 diabetes and microalbuminuria (J308); and a multicenter, single-arm, open-label trial in patients with type 2 diabetes and macroalbuminuria (J309). Changes in serum potassium levels during the studies and other measures were evaluated according to SGLT2 inhibitor use. RESULTS: In both studies, time-course changes in serum potassium levels, and incidence rates of serum potassium elevation were lower in patients with co-administration of SGLT2 inhibitor in both the placebo and esaxerenone groups than those without the inhibitor. In contrast, time-course changes and mean percentage changes from baseline in urinary albumin-to-creatinine ratio, the proportion of patients with albuminuria remission and time-course changes in blood pressure did not change with or without SGLT2 inhibitor, whereas the albumin-to-creatinine ratio and blood pressure were reduced with esaxerenone. The blood glucose-lowering effect of SGLT2 inhibitor was not affected by esaxerenone. CONCLUSIONS: In Japanese patients with type 2 diabetes and albuminuria treated with esaxerenone, concomitant use of SGLT2 inhibitor reduced the magnitude of serum potassium elevation without any change of its antihypertensive and albuminuria-suppressing effects. Co-administration of esaxerenone and SGLT2 inhibitor might be a beneficial treatment option for patients with diabetic kidney disease.
Asunto(s)
Diabetes Mellitus Tipo 2 , Nefropatías Diabéticas , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Albúminas , Albuminuria/complicaciones , Albuminuria/tratamiento farmacológico , Glucemia , Creatinina/orina , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Nefropatías Diabéticas/complicaciones , Nefropatías Diabéticas/tratamiento farmacológico , Humanos , Potasio/uso terapéutico , Pirroles , Sodio , Transportador 2 de Sodio-Glucosa , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , SulfonasRESUMEN
Background: The complication of left ventricular (LV) hypertrophy (LVH) is associated with increased incidence of major cardiovascular events. Hypertension is an independent risk factor among several factors contributing to the development of LVH, and thus appropriate treatment of both hypertension and LVH reduces the risk of developing heart failure. Mineralocorticoid-receptor blockers (MRBs) have been reported to improve the prognosis of LVH, but use of currently available MRBs is limited by adverse events. Esaxerenone is a novel selective nonsteroidal MRB recently approved for treatment of hypertension. Although the renoprotective effect of esaxerenone has been demonstrated in both preclinical and clinical studies, little data is available in terms of its cardioprotective effects. MethodsâandâResults: This multicenter, open-label, exploratory interventional study was designed to evaluate the safety and efficacy of esaxerenone in combination with renin-angiotensin system (RAS) inhibitors or calcium-channel blockers (CCBs). Eligible criteria are hypertensive patients with LVH, and target blood pressure (BP) not reached with an RAS inhibitor or a CCB. The primary endpoints are change from baseline in seated home BP (early morning systolic/diastolic BPs), and change and %change from baseline in the LV mass index at the end of treatment. Conclusions: This study will provide the first clinical evidence of the antihypertensive effect and safety of esaxerenone in hypertensive patients with LVH.
RESUMEN
Recent studies have revealed that aberrant expression of tight junction (TJ) proteins is a hallmark of various solid tumors and it is recognized as a useful therapeutic target. Claudin-6 (CLDN6), a member of the family of TJ transmembrane proteins, is an ideal therapeutic target because it is not expressed in human adult normal tissues. In this study, we found that CLDN6 is highly expressed in uterine cervical adenocarcinoma (ADC) and that high CLDN6 expression was correlated with lymph node metastasis and lymphovascular infiltration and was an independent prognostic factor. Shotgun proteome analysis revealed that cell-cell adhesion-related proteins and drug metabolism-associated proteins (aldo-keto reductase [AKR] family proteins) were significantly increased in CLDN6-overexpressing cells. Furthermore, overexpression of CLDN6 enhanced cell-cell adhesion properties and attenuated sensitivity to anticancer drugs including doxorubicin, daunorubicin, and cisplatin. Taken together, the results indicate that aberrant expression of CLDN6 enhances malignant potentials and drug resistance of cervical ADC, possibly due to increased cell-cell adhesion properties and drug metabolism. Our findings provide an insight into a new therapeutic strategy, a CLDN6-targeting therapy, against cervical ADC.
Asunto(s)
Adenocarcinoma , Neoplasias del Cuello Uterino , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/genética , Adulto , Claudinas/genética , Resistencia a Medicamentos , Femenino , Humanos , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/genéticaRESUMEN
BACKGROUND: Cancer vaccines that induce endogenous antitumor immunity represent an ideal strategy to overcome intractable cancers. However, doing this against a pre-established cancer using autologous immune cells has proven to be challenging. "Allogeneic effects" refers to the induction of an endogenous immune response upon adoptive transfer of allogeneic lymphocytes without utilizing hematopoietic stem cell transplantation. While allogeneic lymphocytes have a potent ability to activate host immunity as a cell adjuvant, novel strategies that can activate endogenous antitumor activity in cancer patients remain an unmet need. In this study, we established a new method to destroy pre-developed tumors and confer potent antitumor immunity in mice using alloantigen-activated CD4+ (named AAA-CD4+) T cells. METHODS: AAA-CD4+ T cells were generated from CD4+ T cells isolated from BALB/c mice in cultures with dendritic cells (DCs) induced from C57BL/6 (B6) mice. In this culture, allogeneic CD4+ T cells that recognize and react to B6 mouse-derived alloantigens are preferentially activated. These AAA-CD4+ T cells were directly injected into the pre-established melanoma in B6 mice to assess their ability to elicit antitumor immunity in vivo. RESULTS: Upon intratumoral injection, these AAA-CD4+ T cells underwent a dramatic expansion in the tumor and secreted high levels of IFN-γ and IL-2. This was accompanied by markedly increased infiltration of host-derived CD8+ T cells, CD4+ T cells, natural killer (NK) cells, DCs, and type-1 like macrophages. Selective depletion of host CD8+ T cells, rather than NK cells, abrogated this therapeutic effect. Thus, intratumoral administration of AAA-CD4+ T cells results in a robust endogenous CD8+ T cell response that destroys pre-established melanoma. This locally induced antitumor immunity elicited systemic protection to eliminate tumors at distal sites, persisted over 6 months in vivo, and protected the animals from tumor re-challenge. Notably, the injected AAA-CD4+ T cells disappeared within 7 days and caused no adverse reactions. CONCLUSIONS: Our findings indicate that AAA-CD4+ T cells reinvigorate endogenous cytotoxic T cells to eradicate pre-established melanoma and induce long-term protective antitumor immunity. This approach can be immediately applied to patients with advanced melanoma and may have broad implications in the treatment of other types of solid tumors.