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1.
Clin Nucl Med ; 49(5): 419-426, 2024 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-38546331

RESUMEN

INTRODUCTION: 123 I-MIBG has been well established as a functional imaging tool, and 131 I-MIBG therapy is being considered for catecholamine-secreting tumors. Tumors with the characteristics of a noradrenergic biochemical phenotype, small, malignant, metastatic, extra-adrenal, bilateral, and hereditary, especially SDHx -related tumors, are reported to correlate with reduced MIBG uptake. However, the potential molecular mechanisms influencing MIBG uptake have been poorly studied. PATIENTS AND METHODS: To identify critical genes that may enhance MIBG accumulation in pheochromocytomas (PCCs), we performed RNA-seq analyses for 16 operated patients with PCCs (6 MIBG-negative and 10 MIBG-positive) combined with RT-qPCR for 27 PCCs (5 MIBG-negative and 22 MIBG-positive) and examined primary cultures of the surgical tissues. RESULTS: In the present study, 6 adrenal nodules of 66 nodules surgically removed from 63 patients with PCCs (9%) were MIBG negative. MIBG, a guanethidine analog of norepinephrine, can enter chromaffin cells through active uptake via the cellular membrane, be deposited in chromaffin granules, and be released via Ca 2+ -triggered exocytosis from adrenal chromaffin cells. When we compared expression of several catecholamine biosynthesis and secretion-associated genes between MIBG-negative and MIBG-positive tumors using transcriptome analyses, we found that neuropeptide Y, which is contained in chromaffin granules, was significantly increased in MIBG-negative tumors. NPY stimulated norepinephrine secretion dose-dependently in primary cell culture derived from MIBG-positive PCC. In our study, MIBG-negative PCCs were all norepinephrine-hypersecreting tumors. CONCLUSIONS: These data indicate that NPY upregulation in PCCs may stimulate chromaffin granule catecholamine secretion, which is associated with false-negative 123 I-MIBG scintigraphy.


Asunto(s)
Neoplasias de las Glándulas Suprarrenales , Feocromocitoma , Humanos , Feocromocitoma/patología , 3-Yodobencilguanidina , Neuropéptido Y/metabolismo , Neoplasias de las Glándulas Suprarrenales/metabolismo , Catecolaminas/metabolismo , Cintigrafía , Norepinefrina/metabolismo
2.
BMC Endocr Disord ; 23(1): 276, 2023 Dec 18.
Artículo en Inglés | MEDLINE | ID: mdl-38110958

RESUMEN

BACKGROUND: Primary adrenal leiomyosarcoma is a rare and aggressive mesenchymal tumor derived from the smooth muscle wall of a central adrenal vein or its tributaries; therefore, tumors tend to invade the inferior vena cava and cause thrombosis. The great majority of tumors grow rapidly, which makes the disease difficult to diagnose in its early clinical stages and needs differentiation from adrenocortical carcinomas for the selection of chemotherapy including mitotane which causes adrenal insufficiency. CASE PRESENTATION: We presented two patients with adrenal leiomyosarcoma who were referred to our hospital with abdominal pain and harboring large adrenal tumors and inferior vena cava thrombosis. The endocrine findings, including serum catecholamine levels, were unremarkable. These two patients were considered clinically inoperable, and CT-guided core needle biopsy was performed to obtain the definitive histopathological diagnosis and determine the modes of therapy. The masses were subsequently diagnosed as primary adrenal leiomyosarcoma based on the histological features and positive immunoreactivity for SMA (smooth muscle actin), desmin, and vimentin. CONCLUSIONS: Adrenal leiomyosarcoma derived from the smooth muscle wall of a central adrenal vein or its tributaries is rare but should be considered a differential diagnosis in the case of nonfunctioning adrenal tumors extending directly to the inferior vena cava. CT-guided biopsy is considered useful for histopathological diagnosis and clinical management of patients with inoperable advanced adrenal tumors without any hormone excess.


Asunto(s)
Neoplasias de la Corteza Suprarrenal , Neoplasias de las Glándulas Suprarrenales , Leiomiosarcoma , Trombosis , Humanos , Leiomiosarcoma/diagnóstico , Leiomiosarcoma/patología , Trombosis/diagnóstico , Neoplasias de las Glándulas Suprarrenales/diagnóstico por imagen , Diagnóstico Diferencial , Neoplasias de la Corteza Suprarrenal/diagnóstico
3.
IJU Case Rep ; 6(6): 415-418, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37928280

RESUMEN

Introduction: Laparoscopic adrenalectomy is the standard treatment for adrenal tumors caused by Cushing's syndrome. However, few pregnant women have undergone adrenalectomy because of the risk of general anesthesia and surgery. Case presentation: A 28-year-old woman presented with gradually worsening Cushing's signs at around 12 weeks of pregnancy. Magnetic resonance imaging displayed a 38-mm left adrenal tumor, which was the cause of the adrenal Cushing's syndrome. Metyrapone was started, which increased androgen levels. Since the management of Cushing's syndrome by medication alone is challenging, unilateral laparoscopic adrenalectomy by a retroperitoneal approach was performed at 23 weeks of the pregnancy. No perioperative complications were noted. Conclusion: Adrenalectomy is considered safe in pregnant women with Cushing's syndrome. Laparoscopic adrenalectomy by retroperitoneal approach should be chosen and performed between 14 and 30 weeks of pregnancy to prevent mother and fetal complications.

5.
Sci Rep ; 13(1): 7291, 2023 05 05.
Artículo en Inglés | MEDLINE | ID: mdl-37147373

RESUMEN

Glutaminase 2 (GLS2), a master regulator of glutaminolysis that is induced by p53 and converts glutamine to glutamate, is abundant in the liver but also exists in pancreatic ß-cells. However, the roles of GLS2 in islets associated with glucose metabolism are unknown, presenting a critical issue. To investigate the roles of GLS2 in pancreatic ß-cells in vivo, we generated ß-cell-specific Gls2 conditional knockout mice (Gls2 CKO), examined their glucose homeostasis, and validated the findings using a human islet single-cell analysis database. GLS2 expression markedly increased along with p53 in ß-cells from control (RIP-Cre) mice fed a high-fat diet. Furthermore, Gls2 CKO exhibited significant diabetes mellitus with gluconeogenesis and insulin resistance when fed a high-fat diet. Despite marked hyperglycaemia, impaired insulin secretion and paradoxical glucagon elevation were observed in high-fat diet-fed Gls2 CKO mice. GLS2 silencing in the pancreatic ß-cell line MIN6 revealed downregulation of insulin secretion and intracellular ATP levels, which were closely related to glucose-stimulated insulin secretion. Additionally, analysis of single-cell RNA-sequencing data from human pancreatic islet cells also revealed that GLS2 expression was elevated in ß-cells from diabetic donors compared to nondiabetic donors. Consistent with the results of Gls2 CKO, downregulated GLS2 expression in human pancreatic ß-cells from diabetic donors was associated with significantly lower insulin gene expression as well as lower expression of members of the insulin secretion pathway, including ATPase and several molecules that signal to insulin secretory granules, in ß-cells but higher glucagon gene expression in α-cells. Although the exact mechanism by which ß-cell-specific GLS2 regulates insulin and glucagon requires further study, our data indicate that GLS2 in pancreatic ß-cells maintains glucose homeostasis under the condition of hyperglycaemia.


Asunto(s)
Hiperglucemia , Células Secretoras de Insulina , Islotes Pancreáticos , Ratones , Humanos , Animales , Hiperglucemia/metabolismo , Glucagón/metabolismo , Glutaminasa/genética , Glutaminasa/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Células Secretoras de Insulina/metabolismo , Islotes Pancreáticos/metabolismo , Insulina/metabolismo , Glucosa/metabolismo , Ratones Noqueados , Homeostasis
6.
Int J Hypertens ; 2023: 6453933, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36704237

RESUMEN

Design: Retrospective cohort study. Patients. The data was obtained from a total of 87 PA patients treated with esaxerenone. The treatment group comprised 33 patients who received esaxerenone as first-line therapy and 54 patients that switched from another MRA to esaxerenone. Measurements. Blood pressure (BP), plasma aldosterone concentration (PAC), plasma renin activity (PRA), serum potassium level, estimated glomerular filtration rate (eGFR), urinary albumin-creatinine ratio (UACR), and brain natriuretic peptide (BNP) were assessed before and after treatment with esaxerenone. Patients with overall reductions in their systolic or diastolic BP by 10 mmHg, or more, were considered responders. Unpaired t-tests of the biochemical and personal parameters between responders and nonresponders were run to find the most influencing characteristic for treatment success. Results: BP overall decreased after treatment with esaxerenone (systolic BP: P=0.025, diastolic BP: P=0.096). Serum potassium levels increased, while eGFR decreased (P=0.047 and 0.043, respectively). No patients needed a dose reduction or treatment discontinuation of esaxerenone based on the serum potassium and eGFR criteria. UACR and BNP decreased insignificantly. The responders were significantly older than the nonresponders of the esaxerenone treatment (P=0.0035). Conclusions: Esaxerenone was effective in older patients with primary aldosteronism.

7.
Cancer Res ; 82(18): 3209-3222, 2022 Sep 16.
Artículo en Inglés | MEDLINE | ID: mdl-35895807

RESUMEN

Glutamine synthase 2 (GLS2) is a key regulator of glutaminolysis and has been previously implicated in activities consistent with tumor suppression. Here we generated Gls2 knockout (KO) mice that develop late-occurring B-cell lymphomas and hepatocellular carcinomas (HCC). Further, Gls2 KO mice subjected to the hepatocarcinogenic Stelic Animal Model (STAM) protocol produce larger HCC tumors than seen in wild-type (WT) mice. GLS2 has been shown to promote ferroptosis, a form of cell death characterized by iron-dependent accumulation of lipid peroxides. In line with this, GLS2 deficiency, either in cells derived from Gls2 KO mice or in human cancer cells depleted of GLS2, conferred significant resistance to ferroptosis. Mechanistically, GLS2, but not GLS1, increased lipid reactive oxygen species (ROS) production by facilitating the conversion of glutamate to α-ketoglutarate (αKG), thereby promoting ferroptosis. Ectopic expression of WT GLS2 in a human hepatic adenocarcinoma xenograft model significantly reduced tumor size; this effect was nullified by either expressing a catalytically inactive form of GLS2 or by blocking ferroptosis. Furthermore, analysis of cancer patient datasets supported a role for GLS2-mediated regulation of ferroptosis in human tumor suppression. These data suggest that GLS2 is a bona fide tumor suppressor and that its ability to favor ferroptosis by regulating glutaminolysis contributes to its tumor suppressive function. SIGNIFICANCE: This study demonstrates that the key regulator of glutaminolysis, GLS2, can limit HCC in vivo by promoting ferroptosis through αKG-dependent lipid ROS, which in turn might lay the foundation for a novel therapeutic approach.


Asunto(s)
Carcinoma Hepatocelular , Ferroptosis , Glutaminasa/metabolismo , Neoplasias Hepáticas , Animales , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Ferroptosis/genética , Glutamatos , Glutaminasa/genética , Glutamina/metabolismo , Humanos , Hierro , Ácidos Cetoglutáricos , Peróxidos Lipídicos , Neoplasias Hepáticas/patología , Ratones , Especies Reactivas de Oxígeno
8.
J Endocr Soc ; 6(8): bvac088, 2022 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-35795807

RESUMEN

Context: Growth hormone deficiency (GHD) develops early in patients with hypothalamic-pituitary disorder and is frequently accompanied by other anterior pituitary hormone deficiencies, including secondary adrenal insufficiency (AI). A growth hormone-releasing peptide-2 (GHRP2) test, which is widely used for the diagnosis of patients with GHD, is thought to induce release of not only growth hormone (GH) but also ACTH. However, its clinical usefulness in hypothalamic-pituitary disorder is unclear. Objective: We aimed to determine the clinical utility of the GHRP2 test in patients with hypothalamic-pituitary disorders, particularly for AI concomitant with GHD. Methods: The GHRP2 test, a cosyntropin stimulation test, corticotropin-releasing hormone (CRH) tests, and/or insulin tolerance tests (ITTs) were performed on 36 patients with hypothalamic-pituitary disorder. Results: Twenty-two (61%) had severe GHD, and 3 (8%) had moderate GHD by GHRP2. There was no difference in baseline ACTH and cortisol between non-GHD, moderate GHD, and severe GHD participants. However, a cosyntropin stimulation test and subsequent CRH tests and/or ITTs revealed that 17 (47%) had secondary AI and 16/17 (94%) cases of secondary AI were concomitant with severe GHD. ROC curve analysis demonstrated that the ACTH response in the GHRP2 test was useful for screening pituitary-AI, with a cutoff value of 1.55-fold (83% sensitivity and 88% specificity). Notably, the combination of ACTH response and the peak cortisol level in the GHRP2 test using each cutoff value (1.55-fold and 10 µg/dL, respectively) showed high specificity (100%) with high accuracy (0.94) for diagnosis of pituitary-AI. Conclusion: We recommend measuring ACTH as well as GH during the GHRP2 test to avoid overlooking or delaying diagnosis of secondary AI that frequently accompanies GHD.

9.
Intern Med ; 61(22): 3391-3399, 2022 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-35491128

RESUMEN

Cushing's disease causes numerous metabolic disorders, cognitive decline, and sarcopenia, leading to deterioration of the general health in older individuals. Cushing's disease can be treated with transsphenoidal surgery, but thus far, surgery has often been avoided in older patients. We herein report an older woman with Cushing's disease whose cognitive impairment and sarcopenia improved after transsphenoidal surgery. Although cognitive impairment and sarcopenia in most older patients show resistance to treatment, our case indicates that normalization of the cortisol level by transsphenoidal surgery can be effective in improving the cognitive impairment and muscle mass loss caused by Cushing's disease.

10.
AACE Clin Case Rep ; 7(4): 249-255, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34307847

RESUMEN

OBJECTIVE: Intravascular large B-cell lymphoma (IVLBCL) is a rare and aggressive type of B-cell lymphoma with large cells growing within the lumen of blood vessels. Although previous reports revealed highly variable symptoms resulting from small-vessel occlusion by neoplastic cells in a variety of organs, there are few reports of IVLBCL with pituitary involvement. METHOD: We present a case of IVLBCL with pituitary infiltration from our institution together with a literature review of similar cases to better understand this rare case of IVLBCL involving the pituitary gland. RESULTS: Our case and the pertinent literature demonstrated that IVLBCL with pituitary involvement predominantly occurred in women at a mean age of 64 years, and most of them showed panhypopituitarism that was reversible after standard therapy of rituximab-containing chemotherapy with intrathecal methotrexate. Notably, the pituitary biopsy in our case revealed that atypical large B-cells found within blood vessels and the pituitary gland were negative for intercellular adhesion molecule 1. Intercellular adhesion molecule 1-negative lymphoid cells may have contributed to panhypopituitarism by extravasation into the pituitary tissues, which do not have a blood-brain barrier and receive abundant blood flow. CONCLUSION: IVLBCL of the pituitary gland is a rare lymphoma with nonspecific manifestations and a dismal prognosis. Recognition of the clinicopathological features is necessary for early clinical diagnosis and appropriate treatment.

11.
Eur J Endocrinol ; 185(1): 155-165, 2021 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-33960957

RESUMEN

INTRODUCTION: Although 18F-FDG PET was originally developed to evaluate benign and malignant tumors, the frequency of detection of benign adrenocortical adenomas showing FDG-PET accumulation has increased. However, the details of FDG-PET-accumulated benign adrenocortical adenomas have not been elucidated. METHODS: To elucidate the pathophysiology of FDG-PET-positive cortisol-producing adrenal tumors, we performed clinicopathological and genetic analyses of adrenocortical adenomas examing FDG-PET in 30 operated patients with unilateral cortisol-producing adrenal tumors (26 adrenal adenomas and 4 adrenal cancers). RESULTS: All adrenocortical carcinomas and 17/26 (65%) benign adrenocortical adenomas showed high FDG accumulation (SUVmax ≥ 3). In adrenocortical adenomas with high FDG accumulation (SUVmax ≥ 3), SUVmax showed a positive correlation with the CT Hounsfield units. A higher SUVmax showed a clear black adenoma appearance with predominantly compact cells, which exhibited high T1 and T2 signals, a lack of signal drop on out-of-phase imaging on MRI, and less accumulation on 131-I adsterol scintigraphy. Furthermore, RNA-sequencing analysis revealed significant increases in the lysosomal and autophagy pathways and metabolic pathways, including glycolysis through glucose transporter (GLUT) 1 and 3, in black adenomas with high-level FDG accumulation. DISCUSSION: A black adenoma is blackish due to lipofuscin, which accumulates as a result of damaged mitochondria or proteins that escape lysosomal degradation or autophagy. Since FDG in PET is taken up via GLUTs, alteration of the intracellular metabolic dynamics associated with mitochondrial damage in black adenomas may increase PET accumulation. CONCLUSION: Black adrenal adenomas should be considered with adrenal tumors showing PET accumulation and low lipid contents.


Asunto(s)
Neoplasias de la Corteza Suprarrenal , Adenoma Corticosuprarrenal , Fluorodesoxiglucosa F18/farmacocinética , Tomografía de Emisión de Positrones/métodos , Adolescente , Neoplasias de la Corteza Suprarrenal/diagnóstico por imagen , Neoplasias de la Corteza Suprarrenal/genética , Neoplasias de la Corteza Suprarrenal/metabolismo , Neoplasias de la Corteza Suprarrenal/patología , Adenoma Corticosuprarrenal/diagnóstico por imagen , Adenoma Corticosuprarrenal/genética , Adenoma Corticosuprarrenal/metabolismo , Adenoma Corticosuprarrenal/patología , Adulto , Anciano , Estudios de Cohortes , Femenino , Fluorodesoxiglucosa F18/análisis , Humanos , Hidrocortisona/sangre , Hidrocortisona/orina , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , RNA-Seq , Tomografía Computarizada por Rayos X , Transcriptoma , Carga Tumoral , Adulto Joven
12.
Clin Endocrinol (Oxf) ; 94(4): 544-550, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33296503

RESUMEN

CONTEXT: Mild autonomous cortisol secretion (ACS) is associated with an increased risk of vertebral fractures (VFx). However, the influence of this condition on bone turnover or its association with mild ACS is still controversial. OBJECTIVE: This study aimed to evaluate the impact of mild ACS on bone quality among patients living with the disease. DESIGN AND SETTING: A retrospective study was conducted using data from 55 mild ACS and 12 nonfunctioning adrenal tumour (NFT) patients who visited Chiba University Hospital, Japan, from 2006 to 2018. PATIENTS AND MAIN OUTCOME MEASURES: We analysed clinical features and bone-related factors, including bone mineral density (BMD) and VFx, performed blood tests to assess bone metabolism markers in patients with mild ACS and NFT, and assessed the associations between bone-related markers and endocrinological parameters in patients with mild ACS. RESULTS: No significant differences between mild ACS and NFT patients were observed with respect to the presence or absence of VFx and BMD. Urinary free cortisol (UFC) was higher in mild ACS patients with VFx than those without (p = .037). The T-score and young adult mean (YAM) of the BMD of the femoral neck in mild ACS patients with a body mass index <25 were positively correlated with dehydroepiandrosterone sulphate levels (ρ: 0.42, p = .017; ρ: 0.40, p = .024, respectively). Pearson's correlation analysis showed that bone-specific alkaline phosphatase was negatively correlated with UFC in the patients with mild ACS (ρ: -0.37, p = .026). CONCLUSIONS: These results suggest that urinary free cortisol may be useful for predicting bone formation in mild ACS patients.


Asunto(s)
Hidrocortisona , Osteogénesis , Fracturas de la Columna Vertebral , Densidad Ósea , Humanos , Hidrocortisona/orina , Estudios Retrospectivos , Fracturas de la Columna Vertebral/orina , Adulto Joven
13.
BMC Endocr Disord ; 20(1): 173, 2020 Nov 23.
Artículo en Inglés | MEDLINE | ID: mdl-33228607

RESUMEN

BACKGROUND: Approximately 60% of adrenocortical carcinomas (ACC) are functional, and Cushing's syndrome is the most frequent diagnosis that has been revealed to have a particularly poor prognosis. Since 30% of ACC present steroid hormone-producing disorganization, measurement of steroid metabolites in suspected ACC is recommended. Previous reports demonstrated that steroid hormone precursors or their urine metabolites, which can be assessed using liquid chromatography tandem mass spectrometry (LC-MS/MS) or gas chromatography mass spectrometry (GC-MS) respectively, are useful for distinguishing ACC from cortisol-producing adenomas (CPA); however, despite high precision, LC-MS/MS and GC-MS require a highly trained team, are expensive and have limited capacity. METHODS: Here, we examined 12 serum steroid metabolites using an immunoassay, which is a more rapid and less costly method than LC-MS/MS, in cortisol-producing ACC and CPA. Further, the correlation of each steroid metabolite to the classification stage and pathological status in ACC was analyzed. RESULTS: Reflecting disorganized steroidogenesis, the immunoassay revealed that all basal levels of steroid precursors were significantly increased in cortisol-producing ACC compared to CPA; in particular, 17-hydroxypregnenolone (glucocorticoid and androgen precursor) and 11-deoxycorticosterone (mineralocorticoid precursor) showed a large area under the ROC curve with high sensitivity and specificity when setting the cut-off at 1.78 ng/ml and 0.4 mg/ml, respectively. Additionally, a combination of androstenedione and DHEAS also showed high specificity with high accuracy. In cortisol-producing ACC, 11-deoxycortisol (glucocorticoid precursor) showed significant positive correlations with predictive prognostic factors used in ENSAT classification, while testosterone showed significant positive correlations to the Ki67-index in both men and women. CONCLUSION: Less expensive and more widely available RIA and ECLIA may also biochemically distinguish ACC from CPA and may predict the clinicopathological features of ACC.


Asunto(s)
Neoplasias de la Corteza Suprarrenal/patología , Carcinoma Corticosuprarrenal/patología , Biomarcadores/metabolismo , Hidrocortisona/metabolismo , Esteroides/metabolismo , Neoplasias de la Corteza Suprarrenal/metabolismo , Carcinoma Corticosuprarrenal/metabolismo , Anciano , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos
14.
Am J Med Sci ; 360(5): 552-559, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32376002

RESUMEN

BACKGROUND: Diabetes carries a known risk of bone fracture despite high bone mineral density (BMD). The fracture risk assessment tool (FRAX) predicts the 10-year major osteoporotic fracture risk and hip fracture risk. We investigated the effects of clinical parameters on the FRAX score and evaluated the validity of FRAX for evaluating current bone fragility in diabetes subjects. MATERIALS AND METHODS: Forty-seven thousand, three hundred eighty-nine Japanese women participated in the Chiba bone survey, a population-based, multicenter, cross-sectional study of postmenopausal osteoporosis; we estimated FRAX scores without BMD and compared scores between subjects with and without type 2 diabetes. RESULTS: Mean FRAX major osteoporotic fracture risk was significantly higher in the diabetes group. A multiple regression model demonstrated some clinical parameters that affected the FRAX score and, after adjusting for such parameters, the FRAX score was not significantly different between the diabetes and nondiabetes groups, although the type 2 diabetes rate was significantly higher in subjects with a fracture in the past 5 years, which reflected current bone fragility. After adjusting for clinical parameters, the diabetes rate remained significantly higher in subjects with a fracture in the past 5 years, confirming that type 2 diabetes influences current bone fragility. Our study demonstrated that type 2 diabetes truly carries a risk of bone fracture, but adjusted FRAX major osteoporotic fracture risk is not significantly different between subjects with and without type 2 diabetes. CONCLUSIONS: The FRAX major osteoporotic fracture risk without BMD does not correctly indicate current bone fragility in Japanese middle-aged women with type 2 diabetes.


Asunto(s)
Densidad Ósea/fisiología , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiología , Encuestas Epidemiológicas/normas , Fracturas Osteoporóticas/diagnóstico , Fracturas Osteoporóticas/epidemiología , Adulto , Anciano , Estudios Transversales , Femenino , Encuestas Epidemiológicas/métodos , Humanos , Japón/epidemiología , Persona de Mediana Edad , Osteoporosis/diagnóstico , Osteoporosis/epidemiología , Medición de Riesgo/métodos , Factores de Riesgo
15.
J Clin Endocrinol Metab ; 105(3)2020 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-31628466

RESUMEN

OBJECTIVE: Accurate assessment and localization of aldosterone-producing adenomas (APAs) are essential for the treatment of primary aldosteronism (PA). Although adrenal venous sampling (AVS) is the standard method of reference for subtype diagnosis in PA, controversy exists concerning the criteria for its interpretation. This study aims to determine better indicators that can reliably predict subtypes of PA. METHOD: Retrospective, single-cohort analysis including 209 patients with PA who were subjected to AVS. Eighty-two patients whose plasma aldosterone concentrations (PAC) were normalized after surgery were histopathologically or genetically diagnosed with APA. The accuracy of image findings was compared to AVS results. Receiver operating characteristic (ROC) curve analysis between the operated and the no-apparent laterality groups was performed using AVS parameters and loading test for diagnosis of PA. RESULT: Agreement between image findings and AVS results was 56.3%. ROC curve analysis revealed that the lateralization index (LI) after adrenocorticotropin stimulation cutoff was 2.40, with 98.8% sensitivity and 97.1% specificity. The contralateral suppression index (CSI) cutoff value was 1.19, with 98.0% sensitivity and 93.9% specificity. All patients over the LI and CSI cutoff values exhibited unilateral subtypes. Among the loading test, the best classification accuracy was achieved using the PAC reduction rate after a saline infusion test (SIT) >33.8%, which yielded 87.2% sensitivity or a PAC after a SIT <87.9 pg/mL with 86.2% specificity for predicting bilateral PA. CONCLUSION: The combined criteria of the PAC reduction rate and PAC after the SIT can determine which subset of patients with APA who should be performed AVS for validation.


Asunto(s)
Aldosterona/sangre , Biomarcadores/sangre , Recolección de Muestras de Sangre , Hiperaldosteronismo/diagnóstico , Solución Salina/administración & dosificación , Adulto , Anciano , Femenino , Estudios de Seguimiento , Humanos , Hiperaldosteronismo/sangre , Hiperaldosteronismo/cirugía , Masculino , Persona de Mediana Edad , Pronóstico , Curva ROC , Estudios Retrospectivos
16.
Sci Rep ; 9(1): 10009, 2019 07 10.
Artículo en Inglés | MEDLINE | ID: mdl-31292513

RESUMEN

Statins have been reported to increase the plasma concentration of arachidonic acid (AA), an omega-6 long chain polyunsaturated fatty acid (LCPUFA) in several clinical studies indicating that statins affect the endogenous synthesis of LCUFAs. In the present study, we investigated the roles of the intrinsic mevalonate cascade and Rho-dependent pathway in LCPUFA synthesis, especially focusing on fatty acid desaturases (Fads) 2, using the human hepatocellular carcinoma cell line HepG2. Cell number and the activity of caspase-3 and 7 (caspase-3/7) was measured using a commercial kit. Gene expression was analyzed by quantitative real-time PCR. Protein expression was detected by Western blot analysis. Atorvastatin decreased cell viability and increased caspase-3/7 activity in a dose-dependent manner. At lower concentrations, atorvastatin stimulated both mRNA and protein expression of Fads2, and increased mRNA expression of FADS1 and ELVOL5. Both mevalonate and geranylgeranyl-pyrophosphate (GGPP), but not cholesterol, fully reversed atorvastatin-induced upregulation of Fads2, and mevalonate-effected reversal was inhibited by treatment with the Rho-associated protein kinase inhibitor Y-27632. These data clearly demonstrated that in human HepG2 cells, statins affect the endogenous synthesis of LCPUFAs by regulation of not only Fads2, but also Fads1 and Elovl5, through the GGPP-dependent Rho kinase pathway.


Asunto(s)
Atorvastatina/farmacología , Ácido Graso Desaturasas/genética , Ácido Graso Desaturasas/metabolismo , Fosfatos de Poliisoprenilo/farmacología , Transducción de Señal/efectos de los fármacos , Amidas/farmacología , Supervivencia Celular/efectos de los fármacos , delta-5 Desaturasa de Ácido Graso , Relación Dosis-Respuesta a Droga , Ácidos Eicosanoicos/metabolismo , Elongasas de Ácidos Grasos/genética , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Células Hep G2 , Humanos , Ácido Mevalónico/farmacología , Piridinas/farmacología , Regulación hacia Arriba , Quinasas Asociadas a rho/metabolismo
17.
Proc Natl Acad Sci U S A ; 115(33): 8370-8375, 2018 08 14.
Artículo en Inglés | MEDLINE | ID: mdl-30061407

RESUMEN

The tumor suppressor p53 regulates multiple cellular functions, including energy metabolism. Metabolic deregulation is implicated in the pathogenesis of some cancers and in metabolic disorders and may result from the inactivation of p53 functions. Using RNA sequencing and ChIP sequencing of cancer cells and preadipocytes, we demonstrate that p53 modulates several metabolic processes via the transactivation of energy metabolism genes including dihydropyrimidinase-like 4 (DPYSL4). DPYSL4 is a member of the collapsin response mediator protein family, which is involved in cancer invasion and progression. Intriguingly, DPYSL4 overexpression in cancer cells and preadipocytes up-regulated ATP production and oxygen consumption, while DPYSL4 knockdown using siRNA or CRISPR/Cas9 down-regulated energy production. Furthermore, DPYSL4 was associated with mitochondrial supercomplexes, and deletion of its dihydropyrimidinase-like domain abolished its association and its ability to stimulate ATP production and suppress the cancer cell invasion. Mouse-xenograft and lung-metastasis models indicated that DPYSL4 expression compromised tumor growth and metastasis in vivo. Consistently, database analyses demonstrated that low DPYSL4 expression was significantly associated with poor survival of breast and ovarian cancers in accordance with its reduced expression in certain types of cancer tissues. Moreover, immunohistochemical analysis using the adipose tissue of obese patients revealed that DPYSL4 expression was positively correlated with INFg and body mass index in accordance with p53 activation. Together, these results suggest that DPYSL4 plays a key role in the tumor-suppressor function of p53 by regulating oxidative phosphorylation and the cellular energy supply via its association with mitochondrial supercomplexes, possibly linking to the pathophysiology of both cancer and obesity.


Asunto(s)
Adipocitos/metabolismo , Metabolismo Energético , Mitocondrias/metabolismo , Neoplasias/metabolismo , Proteínas del Tejido Nervioso/fisiología , Proteína p53 Supresora de Tumor/fisiología , Adenosina Trifosfato/biosíntesis , Animales , Línea Celular Tumoral , Humanos , Masculino , Ratones , Ratones SCID , Obesidad/metabolismo , Consumo de Oxígeno , Proteínas Supresoras de Tumor/fisiología
18.
J Clin Endocrinol Metab ; 103(7): 2417-2423, 2018 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-29688432

RESUMEN

Context: Necrolytic migratory erythema (NME) occurs in approximately 70% of patients with glucagonoma syndrome. Excessive stimulation of metabolic pathways by hyperglucagonemia, which leads to hypoaminoacidemia, contributes to NME pathogenesis. However, the molecular pathogenesis of glucagonoma and relationships between metabolic abnormalities and clinical symptoms remain unclear. Patient: A 53-year-old woman was referred to our hospital with a generalized rash and weight loss. NME was diagnosed by histopathological examination of skin biopsy tissue. Laboratory tests revealed diabetes, hyperglucagonemia, marked insulin resistance, severe hypoaminoacidemia, ketosis, and anemia. Enhanced computed tomography scans detected a 29-mm pancreatic hypervascular tumor, which was eventually diagnosed as glucagonoma. Preoperative treatment with octreotide long-acting release reduced the glucagon level, improved the amino acid profile, and produced NME remission. Surgical tumor excision normalized the metabolic status and led to remission of symptoms, including NME. Interventions: Whole-exome sequencing (WES) and subsequent targeted capture sequencing, followed by Sanger sequencing and pyrosequencing, identified biallelic alteration of death-domain associated protein (DAXX) with a combination of loss of heterozygosity and frameshift mutations (c.553_554del:p.R185fs and c.1884dupC:p.C629fs) in the glucagonoma. Consistently, immunohistochemistry confirmed near-absence of DAXX staining in the tumor cells. Tumor expression of glucagon and somatostatin receptor subtype 2 and 3 messenger RNA was markedly upregulated. Conclusions: This is a report of glucagonoma with biallelic inactivation of DAXX determined by WES. The tumor manifested as glucagonoma syndrome with generalized NME. This case showed the relationship between hypoaminoacidemia and NME status. Further investigations are required to elucidate the underlying mechanisms of NME onset and glucagonoma tumorigenesis.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Silenciador del Gen , Glucagonoma/genética , Metaboloma/genética , Eritema Necrolítico Migratorio/genética , Proteínas Nucleares/genética , Neoplasias Pancreáticas/genética , Alelos , Proteínas Co-Represoras , Femenino , Humanos , Persona de Mediana Edad , Chaperonas Moleculares
19.
Intern Med ; 57(3): 367-375, 2018 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-29093382

RESUMEN

We herein report the case of a 25-year-old woman who presented with severe headache and visual field defects after childbirth. Magnetic resonance imaging revealed marked swelling of the pituitary gland, and an endocrinological examination revealed panhypopituitarism and diabetes insipidus. An immunohistological analysis of a transsphenoidal biopsy sample of the pituitary gland showed the significant accumulation of an immunogloblin G4 (IgG4)-positive population, leading to the diagnosis of IgG4-related hypophysitis. The patient was treated with prednisolone, which markedly reduced the swelling of the pituitary gland, in association with recovery of the pituitary function. This is a rare case of biopsy-proven IgG4-related hypophysitis with a postpartum onset.


Asunto(s)
Hipofisitis Autoinmune/diagnóstico , Hipofisitis Autoinmune/tratamiento farmacológico , Inmunoglobulina G/análisis , Enfermedades de la Hipófisis/diagnóstico , Enfermedades de la Hipófisis/tratamiento farmacológico , Hipófisis/diagnóstico por imagen , Prednisolona/uso terapéutico , Adulto , Femenino , Humanos , Imagen por Resonancia Magnética , Enfermedades de la Hipófisis/patología , Hipófisis/patología , Periodo Posparto , Resultado del Tratamiento
20.
Endocr J ; 65(2): 193-202, 2018 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-29151451

RESUMEN

Osteoporosis not only increases bone fracture risk but also affects survival in postmenopausal women. Although osteoporosis is diagnosed based on low bone mineral density (BMD) determined by dual energy X-ray absorptiometry (DXA), BMD measurement is sometimes difficult because DXA is not widely available in the community. The Fracture Risk Assessment tool (FRAX) can predict 10-year major osteoporotic fracture risk and hip fracture risk with or without femoral neck BMD. The FRAX has not been investigated adequately in community-dwelling Japanese women. We administered the FRAX tool in 13,421 Japanese women who underwent DXA-based forearm BMD measurement in Chiba Bone Survey, a population-based, multicenter, cross-sectional study of postmenopausal osteoporosis conducted in Chiba, Japan. Mean age was 57.77 ± 9.24 years. Mean forearm BMD was 87.94 ± 17.00% of young adult mean (YAM). Mean FRAX major osteoporotic fracture risk without femoral neck BMD was 7.06 ± 5.22%. BMD decreased and percentage of osteoporosis increased from age 55 onward. Age distribution of percentage of subjects with FRAX major osteoporotic fracture risk >15% was similar to that of percentage of osteoporosis subjects. We identified the cutoff value of FRAX major osteoporotic fracture risk for diagnosis of osteoporosis as 7.2%. With this cutoff, the positive likelihood ratio was over 1.0 at age 55 and above but accuracy was low. In conclusion, FRAX without femoral neck BMD reflects bone status, and may be useful to diagnose osteoporosis in Japanese women aged 55 and above, although the sensitivity was low for osteoporosis screening, especially in middle-aged women.


Asunto(s)
Osteoporosis Posmenopáusica/diagnóstico , Fracturas Osteoporóticas/diagnóstico , Absorciometría de Fotón , Anciano , Anciano de 80 o más Años , Densidad Ósea , Estudios Transversales , Femenino , Cuello Femoral , Fracturas de Cadera/diagnóstico , Fracturas de Cadera/etiología , Humanos , Japón , Persona de Mediana Edad , Osteoporosis Posmenopáusica/complicaciones , Fracturas Osteoporóticas/etiología , Factores de Riesgo , Encuestas y Cuestionarios
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