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PURPOSE: To overview the recent literature regarding the relationship between COVID-19 vaccines and glycemic control. METHODS: Data were extracted from text and tables of all available articles published up to September 2023 in PubMed Database describing glucose homeostasis data in subjects exposed to COVID-19 vaccines, focusing on patients with diabetes mellitus (DM). RESULTS: It is debated if the immune system impairment observed in diabetic patients makes them susceptible to lower efficacy of vaccines, but evidence suggests a possible improvement in immune response in those with good glycemic control. Despite their proven protective role lowering infection rates and disease severity, COVID-19 vaccines can result in diabetic ketoacidosis, new-onset diabetes, or episodes of hyper- or hypoglycemia. CONCLUSIONS: Evidence with COVID-19 vaccines highlights the strong relationship existing between DM and immune system function. Clinicians should strive to achieve optimal glucose control before vaccination and promptly manage possible glucose homeostasis derangement following vaccine exposure.
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Glicemia , Vacinas contra COVID-19 , COVID-19 , Diabetes Mellitus , Humanos , Vacinas contra COVID-19/imunologia , Glicemia/metabolismo , COVID-19/prevenção & controle , COVID-19/imunologia , Diabetes Mellitus/imunologia , Controle Glicêmico/métodos , SARS-CoV-2/imunologia , Hipoglicemia/prevenção & controle , Hipoglicemia/imunologiaRESUMO
PURPOSE: The bone strain index (BSI) is a marker of bone deformation based on a finite element analysis inferred from dual X-ray absorptiometry (DXA) scans, that has been proposed as a predictor of fractures in osteoporosis (i.e., higher BSI indicates a lower bone's resistance to loads with consequent higher risk of fractures). We aimed to investigate the association between lumbar BSI and vertebral fractures (VFs) in acromegaly. METHODS: Twenty-three patients with acromegaly (13 males, mean age 58 years; three with active disease) were evaluated for morphometric VFs, trabecular bone score (TBS), bone mineral density (BMD) and BSI at lumbar spine, the latter being corrected for the kyphosis as measured by low-dose X-ray imaging system (EOS®-2D/3D). RESULTS: Lumbar BSI was significantly higher in patients with VFs as compared to those without fractures (2.90 ± 1.46 vs. 1.78 ± 0.33, p = 0.041). BSI was inversely associated with TBS (rho -0.44; p = 0.034), without significant associations with BMD (p = 0.151), age (p = 0.500), BMI (p = 0.957), serum IGF-I (p = 0.889), duration of active disease (p = 0.434) and sex (p = 0.563). CONCLUSIONS: Lumbar BSI corrected for kyphosis could be proposed as integrated parameter of spine arthropathy and osteopathy in acromegaly helping the clinicians in identifying patients with skeletal fragility possibly predisposed to VFs.
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Absorciometria de Fóton , Acromegalia , Densidade Óssea , Osso Esponjoso , Cifose , Vértebras Lombares , Fraturas da Coluna Vertebral , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Acromegalia/complicações , Acromegalia/fisiopatologia , Acromegalia/diagnóstico por imagem , Fraturas da Coluna Vertebral/diagnóstico por imagem , Fraturas da Coluna Vertebral/etiologia , Vértebras Lombares/diagnóstico por imagem , Osso Esponjoso/diagnóstico por imagem , Idoso , Cifose/diagnóstico por imagem , AdultoRESUMO
AIMS: To evaluate the determinants of cardiovascular (CV) protection in men and women treated with glucagon-like peptide-1 receptor agonists (GLP1-RA). METHODS: Retrospective cohort study of 550 patients (43% women), with and without established CV disease, followed at a single center after the first prescription of a GLP1-RA. We analyzed the determinants of major adverse cardiovascular events (MACE) in men and women. RESULTS: The rate of MACE was similar between sexes. In primary prevention, among men, older age (HR 1.13, 95 % C.I. 1.05-1.22; P = 0.001) and GLP-1 RA withdrawal by time (HR 2.77, 95 % C.I. 1.15-6.68; P = 0.023) increased the HR for MACE. Among women, significant predictors of MACE were diabetes duration (HR 1.05, C.I. 1.01-1.10; P = 0.020), GLP-1 withdrawal by time (HR 2.84, 95 % C.I. 1.13-7.10; P = 0.026) and BMI at GLP-1 RA withdrawal (HR 1.08, 95 % C.I. 1.01-1.15; P = 0.026). For individuals with prior CV disease, the HR for MACE was solely impacted by GLP-1 withdrawal over time in males (HR 2.18, 95 % C.I. 1.10-4.30; P = 0.025) and by older age at GLP-1 RA initiation (HR 1.17, 95 % C.I. 1.03-1.33; P = 0.015) in females. CONCLUSIONS: Although MACE rates were similar, the factors contributing to MACE differed by sex.
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Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Receptor do Peptídeo Semelhante ao Glucagon 1 , Hipoglicemiantes , Humanos , Masculino , Feminino , Diabetes Mellitus Tipo 2/tratamento farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Estudos Retrospectivos , Pessoa de Meia-Idade , Idoso , Hipoglicemiantes/uso terapêutico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/prevenção & controle , Fatores Sexuais , Agonistas do Receptor do Peptídeo 1 Semelhante ao GlucagonRESUMO
Somatostatin receptor ligands (SRLs) with high affinity for somatostatin receptors 2 and 5 (SSTR2 and SSTR5) are poorly efficacious in NF-PitNETs, expressing high levels of SSTR3. ITF2984 is a pan-SSTR ligand with high affinity for SSTR3, able to induce SSTR3 activation and to exert antitumoral activity in the MENX rat model. The aim of this study was to test ITF2984's antiproliferative and proapoptotic effects in NF-PitNET primary cultured cells derived from surgically removed human tumors and to characterize their SSTR expression profile. We treated cells derived from 23 NF-PitNETs with ITF2984, and a subset of them with octreotide, pasireotide (SRLs with high affinity for SSTR2 or 5, respectively), or cabergoline (DRD2 agonist) and we measured cell proliferation and apoptosis. SSTR3, SSTR2, and SSTR5 expression in tumor tissues was analyzed by qRT-PCR and Western blot. We demonstrated that ITF2984 reduced cell proliferation (-40.8 (17.08)%, p < 0.001 vs. basal, n = 19 NF-PitNETs) and increased cell apoptosis (+41.4 (22.1)%, p < 0.001 vs. basal, n = 17 NF-PitNETs) in all tumors tested, whereas the other drugs were only effective in some tumors. In our model, SSTR3 expression levels did not correlate with ITF2984 antiproliferative nor proapoptotic effects. In conclusion, our data support a possible use of ITF2984 in the pharmacological treatment of NF-PitNET.
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Antimitóticos , Tumores Neuroendócrinos , Neoplasias Hipofisárias , Humanos , Tumores Neuroendócrinos/tratamento farmacológico , Octreotida/farmacologia , Octreotida/uso terapêutico , Neoplasias Hipofisárias/tratamento farmacológico , Neoplasias Hipofisárias/genética , Receptores de Somatostatina/genéticaRESUMO
PURPOSE: Identifying patients requiring glucocorticoid replacement therapy after pituitary surgery is challenging as the tests commonly used for the diagnosis of secondary adrenal insufficiency (SAI) are not recommended in the immediate postoperative period. There are controversial data on the role of postoperative days' morning cortisol, with no specific data for each cortisol assay. The aim of this study is to investigate the reliability of 8.00 a.m. cortisol of the first and second postoperative days in predicting SAI. METHODS: Data of patients underwent pituitary surgery in Humanitas Research Hospital in Italy, from March 2017 to August 2022, were retrospectively analyzed. Definitive diagnosis of SAI was made through ACTH test 1 µg six weeks after surgery. Cortisol was measured through Beckman Access Cortisol and the diagnosis of SAI was made if cortisol peak was below 14.8 µg/dL (408 nmol/L) at 30 or 60 min after stimulus. RESULTS: Of the sixty-four patients enrolled, seven developed SAI. The ROC curves demonstrated that both first- and second-day postoperative 8.00 a.m. cortisol predict SAI (AUC 0.94 and 0.95, respectively). The optimal thresholds were 15.6 µg/dL (430.3 nmol/L; accuracy 89%) for the first day and 11.5 µg/dL (317.2 nmol/L, accuracy 81%) for the second day. Patients who developed SAI had larger tumors (p = 0.004) and lower fT4 (p = 0.038) before surgery. CONCLUSIONS: Clinicians might rely on the first- and second- postoperative days 8.00 a.m. cortisol to identify patients to discharge with glucocorticoid replacement therapy waiting for the confirmation of SAI through the ACTH test.
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Insuficiência Adrenal , Doenças da Hipófise , Humanos , Hidrocortisona , Estudos Retrospectivos , Glucocorticoides/uso terapêutico , Reprodutibilidade dos Testes , Sistema Hipotálamo-Hipofisário , Sistema Hipófise-Suprarrenal , Insuficiência Adrenal/diagnóstico , Hormônio AdrenocorticotrópicoRESUMO
PURPOSE: Neuroendocrine neoplasms (NENs) are tumors that arise from cells of the endocrine system and are most common in the gastrointestinal tract, the pancreas, and the lungs. Their incidence is rapidly increasing and the therapeutic options available are limited. METHODS: Since the immune system can interfere with tumor growth and response to therapy, using flow cytometry we investigated the immunophenotype in samples of peripheral blood leukocytes from patients with pancreatic (Pan-NENs) and pulmonary NENs (Lung-NENs). Moreover, we performed a multiplex analysis of 13 key cytokines and growth factors essential for the immune response in the plasma of NEN patients and controls. RESULTS: Patients presented with a higher percentage of granulocytes, a lower percentage of lymphocytes, and an increase in the granulocytes to lymphocytes ratio compared to healthy donors. These alterations were more marked in patients with metastasis. Somatostatin analogs (SSAs) restored the immunophenotype of patients to that seen in healthy donors. Finally, Pan-NEN patients showed a higher plasma concentration of IP-10, MCP-1, and IL-8 compared to healthy donors, suggesting a potential role for these cytokines as diagnostic biomarkers. CONCLUSION: This study highlighted differences in the immunophenotype of patients with Pan- and Lung-NENs compared to healthy individuals; these alterations were partially restored by therapy.
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Carcinoma Neuroendócrino , Neoplasias Gastrointestinais , Neoplasias Pulmonares , Tumores Neuroendócrinos , Neoplasias Pancreáticas , Humanos , Tumores Neuroendócrinos/patologia , Somatostatina , Neoplasias Pancreáticas/patologia , Neoplasias Gastrointestinais/patologiaRESUMO
BACKGROUND & AIMS: Intrahepatic cholangiocarcinoma (iCCA) is a primary liver tumour, characterized by poor prognosis and lack of effective therapy. The cytoskeleton protein Filamin A (FLNA) is involved in cancer progression and metastasis, including primary liver cancer. FLNA is cleaved by calpain, producing a 90 kDa fragment (FLNACT ) that can translocate to the nucleus and inhibit gene transcription. We herein aim to define the role of FLNA and its cleavage in iCCA carcinogenesis. METHODS & RESULTS: We evaluated the expression and localization of FLNA and FLNACT in liver samples from iCCA patients (n = 82) revealing that FLNA expression was independently correlated with disease-free survival. Primary tumour cells isolated from resected iCCA patients expressed both FLNA and FLNACT , and bulk RNA sequencing revealed a significant enrichment of cell proliferation and cell motility pathways in iCCAs with high FLNA expression. Further, we defined the impact of FLNA and FLNACT on the proliferation and migration of primary iCCA cells (n = 3) and HuCCT1 cell line using silencing and Calpeptin, a calpain inhibitor. We observed that FLNA silencing decreased cell proliferation and migration and Calpeptin was able to reduce FLNACT expression in both the HuCCT1 and iCCA cells (p < .05 vs. control). Moreover, Calpeptin 100 µM decreased HuCCT1 and primary iCCA cell proliferation (p <.00001 vs. control) and migration (p < .05 vs. control). CONCLUSIONS: These findings demonstrate that FLNA is involved in human iCCA progression and calpeptin strongly decreased FLNACT expression, reducing cell proliferation and migration.
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Neoplasias dos Ductos Biliares , Colangiocarcinoma , Neoplasias Hepáticas , Humanos , Filaminas/genética , Colangiocarcinoma/patologia , Neoplasias Hepáticas/genética , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/patologia , Ductos Biliares Intra-Hepáticos/patologiaRESUMO
Introduction: Germline loss-of-function variants in PAM, encoding peptidylglycine α-amidating monooxygenase (PAM), were recently discovered to be enriched in conditions of pathological pituitary hypersecretion, specifically: somatotrophinoma, corticotrophinoma, and prolactinoma. PAM is the sole enzyme responsible for C-terminal amidation of peptides, and plays a role in the biosynthesis and regulation of multiple hormones, including proopiomelanocortin (POMC). Methods: We performed exome sequencing of germline and tumour DNA from 29 individuals with functioning pituitary adenomas (12 prolactinomas, 10 thyrotrophinomas, 7 cyclical Cushing's disease). An unfiltered analysis was undertaken of all PAM variants with population prevalence <5%. Results: We identified five coding, non-synonymous PAM variants of interest amongst seven individuals (six germline, one somatic). The five variants comprised four missense variants and one truncating variant, all heterozygous. Each variant had some evidence of pathogenicity based on population prevalence, conservation scores, in silico predictions and/or prior functional studies. The yield of predicted deleterious PAM variants was thus 7/29 (24%). The variants predominated in individuals with thyrotrophinomas (4/10, 40%) and cyclical Cushing's disease (2/7, 29%), compared to prolactinomas (1/12, 8%). Conclusion: This is the second study to demonstrate a high yield of suspected loss-of-function, predominantly germline, PAM variants in individuals with pathological pituitary hypersecretion. We have extended the association with corticotrophinoma to include the specific clinical entity of cyclical Cushing's disease and demonstrated a novel association between PAM variants and thyrotrophinoma. PAM variants might act as risk alleles for pituitary adenoma formation, with a possible genotype-phenotype relationship between truncating variants and altered temporal secretion of cortisol.
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Adenoma Hipofisário Secretor de ACT , Adenoma , Hipersecreção Hipofisária de ACTH , Neoplasias Hipofisárias , Prolactinoma , Humanos , Adenoma Hipofisário Secretor de ACT/genética , Adenoma Hipofisário Secretor de ACT/complicações , Adenoma/patologia , Hipersecreção Hipofisária de ACTH/genética , Hipersecreção Hipofisária de ACTH/complicações , Neoplasias Hipofisárias/patologia , Prolactinoma/genética , Prolactinoma/complicaçõesRESUMO
Introduction: Pituitary adenomas (PAs) are common, usually benign tumors of the anterior pituitary gland which, for the most part, have no known genetic cause. PAs are associated with major clinical effects due to hormonal dysregulation and tumoral impingement on vital brain structures. PAM encodes a multifunctional protein responsible for the essential C-terminal amidation of secreted peptides. Methods: Following the identification of a loss-of-function variant (p.Arg703Gln) in the peptidylglycine a-amidating monooxygenase (PAM) gene in a family with pituitary gigantism, we investigated 299 individuals with sporadic PAs and 17 familial isolated PA kindreds for PAM variants. Genetic screening was performed by germline and tumor sequencing and germline copy number variation (CNV) analysis. Results: In germline DNA, we detected seven heterozygous, likely pathogenic missense, truncating, and regulatory SNVs. These SNVs were found in sporadic subjects with growth hormone excess (p.Gly552Arg and p.Phe759Ser), pediatric Cushing disease (c.-133T>C and p.His778fs), or different types of PAs (c.-361G>A, p.Ser539Trp, and p.Asp563Gly). The SNVs were functionally tested in vitro for protein expression and trafficking by Western blotting, splicing by minigene assays, and amidation activity in cell lysates and serum samples. These analyses confirmed a deleterious effect on protein expression and/or function. By interrogating 200,000 exomes from the UK Biobank, we confirmed a significant association of the PAM gene and rare PAM SNVs with diagnoses linked to pituitary gland hyperfunction. Conclusion: The identification of PAM as a candidate gene associated with pituitary hypersecretion opens the possibility of developing novel therapeutics based on altering PAM function.
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Doenças da Hipófise , Neoplasias Hipofisárias , Criança , Humanos , Variações do Número de Cópias de DNA , Hipófise , Neoplasias Hipofisárias/genética , Oxigenases de Função MistaRESUMO
The molecular events underlying the variable effectiveness of dopamine receptor type 2 (DRD2) agonists in pituitary neuroendocrine tumors (PitNETs) are not known. Besides the canonical pathway induced by DRD2 coupling with Gi proteins, the ß-arrestin 2 pathway contributes to DRD2's antimitotic effects in PRL- and NF-PitNETs. A promising pharmacological strategy is the use of DRD2-biased agonists that selectively activate only one of these two pathways. The aim of the present study was to compare the effects of two biased DRD2 ligands, selectively activating the G protein (MLS1547) or ß-arrestin 2 (UNC9994) pathway, with unbiased DRD2 agonist cabergoline in PRL- and NF-PitNET cells. In rat tumoral pituitary PRL-secreting MMQ cells, UNC9994 reduced cell proliferation with a greater efficacy compared to cabergoline (-40.2 ± 20.4% vs. -21 ± 10.9%, p < 0.05), whereas the G-protein-biased agonist induced only a slight reduction. ß-arrestin 2 silencing, but not pertussis toxin treatment, reverted UNC9994 and cabergoline's antiproliferative effects. In a cabergoline-resistant PRL-PitNET primary culture, UNC9994 inhibited cell proliferation and PRL release. In contrast, in NF-PitNET primary cultures (n = 23), biased agonists did not show better antiproliferative effects than cabergoline. In conclusion, the preferential activation of the ß-arrestin 2 pathway by UNC9994 improves DRD2-mediated antiproliferative effects in PRL-PitNETs, suggesting a new pharmacological approach for resistant or poorly responsive tumors.
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Secondary Adrenal Insufficiency (SAI) is a condition characterized by inappropriately low ACTH secretion due to a disease or injury to the hypothalamus or the pituitary. The evaluation when suspected is often challenging for the non-specific symptoms, the rarity of the disease, and the pitfalls associated with laboratory tests. A prompt and correct diagnosis of SAI is essential because although an adequate hormonal replacement therapy could be lifesaving, inappropriate life-long therapy with steroids can be harmful. The gold standard test for assessing the hypothalamus-pituitary-adrenal axis (HPA) is the insulin tolerance test (ITT), but due to safety issues is not widely used. Conversely, the ACTH stimulation test is a safer and well-tolerated tool for SAI diagnosis. However, data about its diagnostic accuracy show great variability due to both technical and interpretative aspects, such as dose, route of administration, the timing of the test, and assay used for cortisol measurements. Consequently, the clinical background of the patient and the pretest probability of HPA axis impairment become of paramount importance. We aimed to summarize the recent literature evidence in the conduction and interpretation of the ACTH stimulation test for the diagnosis of SAI to provide updated insights on its correct use in clinical practice.
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OBJECTIVE: Prediction of fragility fractures in Cushing syndrome (CS) is a challenge since dual energy X-ray absorptiometry (DXA) measurement of bone mineral density (BMD) does not capture all the alterations in bone microstructure induced by glucocorticoid excess. In this study we investigated the relationship between trabecular bone score (TBS), bone marrow fat (BMF) and vertebral fractures (VFs) in endogenous CS. DESIGN: Cross-sectional. METHODS: Thirty subjects (7 M and 23 F, mean age 44.8 ± 13.4 yrs, range: 25-71) with active hypercortisolism were evaluated for VFs by quantitative morphometry, BMD and TBS by lumbar spine DXA and BMF by single-voxel magnetic resonance spectroscopy of vertebral body of L3. RESULTS: Subjects with VFs (17 cases; 56.7%) had higher BMF (P = 0.014) and lower BMD T-score (P = 0.012) and TBS (P = 0.004) as compared to those without VFs. Prevalence of VFs resulted to be significantly higher in individuals with impaired TBS as compared to those with normal TBS (77.8% vs. 25.0%; P = 0.008). Among patients with VFs, only 6 (35.3%) had either osteoporosis or "low BMD for age". In logistic regression analysis, impaired TBS maintained the significant association with VFs [odds ratio (OR) 6.60, 95% C.I. 1.07-40.61; P = 0.042] independently of BMF (OR 1.03, 95% C.I. 0.99-1.08; P = 0.152). CONCLUSIONS: TBS might be more accurate than BMF in identifying subjects with active CS and skeletal fragility at risk of VFs. SIGNIFICANCE STATEMENT: Excess in glucocorticoids is associated with alterations in bone remodeling and metabolism, leading to fragility fractures regardless of bone mineral density, making more challenging for the clinician the identification of high-risk population and the definition of preventing strategies. In this context, instrumental parameters suggestive of bone quality alterations and predictive of increased fracture risk are needed. In this study, we found CS patients to have bone quality alterations as indicated by the decreased trabecular bone score and increased bone marrow fat, as measured by DEXA and MRI respectively. Both parameters were associated with high risk of VFs, and were inversely correlated, although TBS seems to be more accurate than BMF in fractures prediction in this clinical setting.
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Síndrome de Cushing , Fraturas por Osteoporose , Fraturas da Coluna Vertebral , Humanos , Adulto , Pessoa de Meia-Idade , Síndrome de Cushing/complicações , Síndrome de Cushing/diagnóstico por imagem , Síndrome de Cushing/patologia , Osso Esponjoso/diagnóstico por imagem , Osso Esponjoso/patologia , Medula Óssea/diagnóstico por imagem , Estudos Transversais , Densidade Óssea , Fraturas da Coluna Vertebral/diagnóstico por imagem , Fraturas da Coluna Vertebral/epidemiologia , Fraturas da Coluna Vertebral/complicações , Vértebras Lombares/diagnóstico por imagem , Glucocorticoides , Fraturas por Osteoporose/diagnóstico por imagem , Fraturas por Osteoporose/epidemiologia , Fraturas por Osteoporose/etiologia , Absorciometria de Fóton/métodosRESUMO
Pituitary adenomas (PAs) are common, usually benign tumors of the anterior pituitary gland which, for the most part, have no known genetic cause. PAs are associated with major clinical effects due to hormonal dysregulation and tumoral impingement on vital brain structures. Following the identification of a loss-of-function variant (p.Arg703Gln) in the PAM gene in a family with pituitary gigantism, we investigated 299 individuals with sporadic PAs and 17 familial isolated pituitary adenomas kindreds for PAM variants. PAM encodes a multifunctional protein responsible for the essential C-terminal amidation of secreted peptides. Genetic screening was performed by germline and tumor sequencing and germline copy number variation (CNV) analysis. No germline CNVs or somatic single nucleotide variants (SNVs) were identified. We detected seven likely pathogenic heterozygous missense, truncating, and regulatory SNVs. These SNVs were found in sporadic subjects with GH excess (p.Gly552Arg and p.Phe759Ser), pediatric Cushing disease (c.-133T>C and p.His778fs), or with different types of PAs (c.-361G>A, p.Ser539Trp, and p.Asp563Gly). The SNVs were functionally tested in vitro for protein expression and trafficking by Western blotting, for splicing by minigene assays, and for amidation activity in cell lysates and serum samples. These analyses confirmed a deleterious effect on protein expression and/or function. By interrogating 200,000 exomes from the UK Biobank, we confirmed a significant association of the PAM gene and rare PAM SNVs to diagnoses linked to pituitary gland hyperfunction. Identification of PAM as a candidate gene associated with pituitary hypersecretion opens the possibility of developing novel therapeutics based on altering PAM function.
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Skeletal fragility with high risk of vertebral fractures (VFs) is an emerging complication of growth hormone (GH) hypersecretion. VFs often coexist with spine arthropathy and both clinical conditions negatively impact on quality of life of acromegalic subjects. Management of spine osteopathy and arthropathy in acromegaly could be challenging since both complications can persist or even progress after biochemical control of disease. This article analyzes the latest evidence about possible pathophysiological links between VFs and spine arthropathy in active and controlled acromegaly, as well as the diagnostic and therapeutic aspects concerning the holistic management of acromegalic osteo-arthropathy.
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Acromegalia , Hormônio do Crescimento Humano , Fraturas da Coluna Vertebral , Humanos , Acromegalia/terapia , Acromegalia/tratamento farmacológico , Qualidade de Vida , Densidade Óssea/fisiologia , Fraturas da Coluna Vertebral/complicações , Fraturas da Coluna Vertebral/diagnóstico por imagem , Hormônio do Crescimento Humano/uso terapêuticoRESUMO
BACKGROUND: Since low-intensity shockwave treatment (LISWT) has putative effects on penile hemodynamics remodeling, the aim of this study was to evaluate any improvement of penile vascular flows after LISWT treatment in patients with erectile dysfunction (ED) and poor response to PDE5i. METHODS: Twenty-one eugonadal patients with different ED severity underwent 6 weekly LISWT sessions (1500-4000 pulses) after 2 weeks withdrawal from PDE5i assumption. Once daily Tadalafil (2.5 mg daily) was reintroduced 4 weeks apart from LISWT termination and patients were evaluated at 1, 2 and 6 months follow-up (T1, T2, T6) by the International Index of Erectile Function-15 items questionnaire (IIEF-15) erectile function (EF) domain, Erection Hardness Score (EHS) and Global Assessment Questionnaires (GAQ). Basal Penile Color-Doppler Ultrasound parameters in the flaccid state (B-PCDU) were evaluated before, during and after interventional protocol. RESULTS: Mean EHS score improved in 35% of patients at T1, and in up to 50% of patients at T2 and T6 follow-up visits (P<0.05). We found 25% improvement of EF scores at T1 session, 43.75% at T2 and 62.5% at T6, respectively (P<0.05). No statistically significant differences in flow parameters, EF-domain and testosterone levels were found when baseline and last observation carried forward (LOCF) parameters were compared. The GAQ questionnaire scored higher satisfaction rates either at the end of the treatment (100%), or at LOCF (92.5%). CONCLUSIONS: Despite the study limitations with respect to B-PCDU in this setting, our results confirm a trend toward improvement of erectile questionnaire scores after LISWT with higher overall satisfaction rates among patients with ED. We conclude that LISWT may be an effective option in some difficult-to-treat patients with ED by improving the erectile response to PDE5i.
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Disfunção Erétil , Masculino , Humanos , Disfunção Erétil/terapia , Projetos Piloto , Resultado do Tratamento , Pênis/diagnóstico por imagem , Pênis/irrigação sanguínea , Ereção Peniana/fisiologiaRESUMO
Bone-active drugs are recommended to protect the skeleton from detrimental actions of aromatase inhibitors (AIs). However, most of literature data are focused on bone mineral density (BMD), whereas data on fractures are scant. The aim of this prospective study was to investigate the real-life effectiveness of denosumab, oral bisphosphonates (BPs) and intravenous zoledronate on risk of vertebral fractures (VFs) induced by AIs. 567 consecutive women (median age 62 years, range 28-83) with early breast cancer undergoing treatment with AIs were evaluated for morphometric VFs and BMD at baseline and after 18-24 months of follow-up. After enrollment, 268 women (47.3%) started denosumab 60 mg subcutaneously every 6 months, 115 (20.3%) BPs (59 with oral BPs and, 56 with intravenous zoledronate 5 mg/12 months), whereas 184 women (32.5%) were not treated with bone-active drugs for several reasons. During follow-up, 54 women (9.5%) developed incident VFs in association with age of subjects (P < 0.001), baseline FRAX scores for major fractures (P < 0.001) and hip fractures (P = 0.003), pre-existing VFs (P < 0.001), change in BMD at lumbar spine (P = 0.015), femoral neck (P = 0.003) and total hip (P < 0.001). Risk of VFs was higher in subjects who were untreated as compared to those treated with bone-active drugs (32/184 vs. 22/383; P < 0.001). Specifically, fracture risk was significantly decreased by denosumab [odds ratio (OR) 0.22; P < 0.001] and zoledronate (OR 0.27; P = 0.035), but not by oral BPs (P = 0.317). These data suggest that in real-world clinical practice, denosumab and zoledronate can reduce AI-related risk of VFs after only 24 months of treatment.
Assuntos
Conservadores da Densidade Óssea , Neoplasias da Mama , Fraturas Ósseas , Fraturas da Coluna Vertebral , Inibidores da Aromatase/efeitos adversos , Densidade Óssea , Conservadores da Densidade Óssea/farmacologia , Neoplasias da Mama/tratamento farmacológico , Criança , Pré-Escolar , Denosumab , Difosfonatos/uso terapêutico , Feminino , Fraturas Ósseas/tratamento farmacológico , Humanos , Estudos Prospectivos , Fraturas da Coluna Vertebral/tratamento farmacológico , Fraturas da Coluna Vertebral/prevenção & controle , Ácido Zoledrônico/uso terapêuticoRESUMO
The mammalian target of rapamycin (mTOR) inhibitor everolimus has been shown to display antiproliferative effects on a wide spectrum of tumors. In vitro studies demonstrated that everolimus inhibited pituitary neuroendocrine tumor (PitNET) cell growth in a subset of patients. Sensitivity to everolimus is reduced by an escape mechanism that increases AKT phosphorylation (p-AKT), leading to pro-survival pathway activation. Dopamine receptor type 2 (DRD2) mediates a reduction of p-AKT in a subgroup of non-functioning PitNETs (NF-PitNETs) and in prolactin-secreting tumor cells (MMQ cells) through a ß-arrestin 2-dependent mechanism. The aim of this study was to investigate the efficacy of everolimus combined with DRD2 agonist cabergoline in reducing NF-PitNET primary cells and MMQ cell proliferation and to evaluate AKT phosphorylation and a possible role of ß-arrestin 2. We found that 9 out of 14 NF-PitNETs were resistant to everolimus, but the combined treatment with cabergoline inhibited cell proliferation in 7 out of 9 tumors (-31.4 ± 9.9%, p < 0.001 vs. basal) and reduced cyclin D3 expression. In the everolimus-unresponsive NF-PitNET group, everolimus determined a significant increase of p-AKT/total-AKT ratio (2.1-fold, p < 0.01, vs. basal) that was reverted by cabergoline cotreatment. To investigate the molecular mechanism involved, we used MMQ cells as a model of everolimus escape mechanism. Indeed everolimus did not affect MMQ cell proliferation and increased the p-AKT/total-AKT ratio (+1.53 ± 0.24-fold, p < 0.001 vs. basal), whereas cabergoline significantly reduced cell proliferation (-22.8 ± 6.8%, p < 0.001 vs. basal) and p-AKT. The combined treatment of everolimus and cabergoline induced a reduction of both cell proliferation (-34.8 ± 18%, p < 0.001 vs. basal and p < 0.05 vs. cabergoline alone) and p-AKT/total-AKT ratio (-34.5 ± 14%, p < 0.001 vs. basal and p < 0.05 vs. cabergoline alone). To test ß-arrestin 2 involvement, silencing experiments were performed in MMQ cells. Our data showed that the lack of ß-arrestin 2 prevented the everolimus and cabergoline cotreatment inhibitory effects on both p-AKT and cell proliferation. In conclusion, this study revealed that cabergoline might overcome the everolimus escape mechanism in NF-PitNETs and tumoral lactotrophs by inhibiting upstream AKT activation. The co-administration of cabergoline might improve mTOR inhibitor antitumoral activity, paving the way for a potential combined therapy in ß-arrestin 2-expressing NF-PitNETs or other PitNETs resistant to conventional treatments.
Assuntos
Cabergolina , Everolimo , Tumores Neuroendócrinos , Neoplasias Hipofisárias , Receptores de Dopamina D2 , Serina-Treonina Quinases TOR , Cabergolina/farmacologia , Interações Medicamentosas , Everolimo/farmacologia , Humanos , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/metabolismo , Tumores Neuroendócrinos/patologia , Neoplasias Hipofisárias/tratamento farmacológico , Neoplasias Hipofisárias/metabolismo , Neoplasias Hipofisárias/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , beta-Arrestina 2/metabolismoRESUMO
Primary biliary cholangitis and primary sclerosing cholangitis (PSC) are the most common cholestatic liver diseases (CLD) in adults and are both characterized by an immune pathogenesis. While primary biliary cholangitis is a model autoimmune disease, with over 90% of patients presenting very specific autoantibodies against mitochondrial antigens, PSC is considered an immune mediated disease. Osteoporosis is the most common bone disease in CLD, resulting in frequent fractures and leading to significant morbidity. Further, sarcopenia is emerging as a frequent complication of chronic liver diseases with a significant prognostic impact and severe implications on the quality of life of patients. The mechanisms underlying osteoporosis and sarcopenia in CLD are still largely unknown and the association between these clinical conditions remains to be dissected. Although timely diagnosis, prevention, and management of osteosarcopenia are crucial to limit the consequences, there are no specific guidelines for management of osteoporosis and sarcopenia in patients with CLD. International guidelines recommend screening for bone disease at the time of diagnosis of CLD. However, the optimal monitoring strategies and treatments have not been defined yet and vary among centers. We herein aim to comprehensively outline the pathogenic mechanisms and clinical implications of osteosarcopenia in CLD, and to summarize expert recommendations for appropriate diagnostic and therapeutic approaches.