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PURPOSE: Invasive lobular breast cancers (ILCs) respond poorly to neoadjuvant chemotherapy (NAC). The degree of benefit of NAC among non-classic ILC (NC-ILC) variants compared with classic ILCs (C-ILCs) is unknown. METHODS: Consecutive patients with Stage I-III ILC treated from 2003 to 2019 with NAC and surgery were identified, and grouped as C-ILC or NC-ILC as per the original surgical pathology report, with pathologist (A.G.) review performed if original categorization was unclear. A subset of similarly treated invasive ductal cancers (IDCs) was identified for comparison. Clinicopathologic characteristics and pathologic complete response (pCR) rates were evaluated. RESULTS: Of 145 patients with ILC, 101 (70%) were C-ILC and 44 (30%) were NC-ILC (IDC cohort: 1157 patients). ILC patients were older, more often cT3/T4 and cN2/N3, and less often high-grade compared to IDC patients. Those with NC-ILC were less often ER+/HER2- (55% versus 93%), and more often HER2 + (25% versus 7%) and TN (21% versus 0%, all p < 0.001). Breast pCR was more common among NC-ILC, but most frequent in IDC. Nodal pCR rates were also lowest among C-ILC patients, but similar among NC-ILC and IDC patients. On multivariable analysis, C-ILC (OR 0.09) and LVI (OR 0.51) were predictive of lack of breast pCR; non-ER+/HER2- subtypes and breast pCR were predictive of nodal pCR. When our analysis was repeated with patients stratified by receptor subtype, histology was not independently predictive of either breast or nodal pCR. CONCLUSION: NC-ILC patients were significantly more likely to achieve breast and nodal pCR compared with C-ILC patients, but when stratified by subtype, histology was not independently predictive of breast or nodal pCR.
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Neoplasias da Mama , Carcinoma Ductal de Mama , Carcinoma Lobular , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Carcinoma Lobular/patologia , Carcinoma Ductal de Mama/patologia , Terapia Neoadjuvante , Mama/patologiaRESUMO
Apparent mineralocorticoid excess is an autosomal recessive form of monogenic disease characterized by juvenile resistant low-renin hypertension, marked hypokalemic alkalosis, low aldosterone levels, and high ratios of cortisol to cortisone metabolites. It is caused by defects in the HSD11B2 gene, encoding the enzyme 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2), which is primarily involved in the peripheral conversion of cortisol to cortisone. To date, over 50 deleterious HSD11B2 mutations have been identified worldwide. Multiple molecular mechanisms function in the lowering of 11ß-HSD2 activity, including damaging protein stability, lowered affinity for the substrate and cofactor, and disrupting the dimer interface. Genetic polymorphism, environmental factors as well as epigenetic modifications may also offer an implicit explanation for the molecular pathogenesis of AME. A precise diagnosis depends on genetic testing, which allows for early and specific management to avoid the morbidity and mortality from target organ damage. In this review, we provide insights into the molecular genetics of classic and non-classic apparent mineralocorticoid excess and aim to offer a comprehensive overview of this monogenic disease.
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Cortisona , Hipertensão , Humanos , Cortisona/metabolismo , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/genética , Hidrocortisona/metabolismo , Biologia Molecular , Síndrome de Excesso Aparente de MinerolocorticoidesRESUMO
BACKGROUND: Breast cancer, the most diagnosed cancer, remains the second leading cause of cancer death in the United States, and excessive Progesterone (PRG) or Mifepristone (MIF) exposure may be at an increased risk for developing breast cancer. PRG exerts its cellular responses through signaling cascades involving classic, non-classic, or combined responses by binding to either classic nuclear PRG receptors (nPRs) or non-classic membrane PRG receptors (mPRs). Currently, the intricate balance and switch mechanisms between these two signaling cascades remain elusive. Three genes, CCM1-3, form the CCM signaling complex (CSC) which mediates multiple signaling cascades. METHODS: Utilizing molecular, cellular, Omics, and systems biology approaches, we analyzed the relationship among the CSC, PRG, and nPRs/mPRs during breast cancer tumorigenesis. RESULTS: We discovered that the CSC plays an essential role in coupling both classic and non-classic PRG signaling pathways by mediating crosstalk between them, forming the CmPn (CSC-mPRs-PRG-nPRs) signaling network. We found that mPR-specific PRG actions (PRG + MIF) play an essential role in this CmPn network during breast cancer tumorigenesis. Additionally, we have identified 4 categories of candidate biomarkers (9 intrinsic, 2 PRG-inducible, 1 PRG-repressive, 1 mPR-specific PRG-repressive, and 2 mPR-responsive) for Luminal-A breast cancers during tumorigenesis and have confirmed the prognostic application of RPL13 and RPL38 as intrinsic biomarkers using a dual validation method. CONCLUSIONS: We have discovered that the CSC plays an essential role in the CmPn signaling network for Luminal-A breast cancers with identification of two intrinsic biomarkers. Video Abstract.
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Neoplasias da Mama , Receptores de Progesterona , Carcinogênese , Feminino , Humanos , Proteínas de Neoplasias/metabolismo , Progesterona/metabolismo , Receptores de Progesterona/metabolismo , Proteínas Ribossômicas/metabolismo , Transdução de SinaisRESUMO
OBJECTIVE: To report clinical, hormonal and structural effects of CYP11B1 pathogenic variations in Indian patients with 11ß-hydroxylase deficiency (11ßOHD) and find hormonal criteria that accurately distinguish 11ßOHD from 21α-hydroxylase deficiency (21OHD). DESIGN: Retrospective record review of genetically diagnosed patients with 11ßOHD. PATIENTS AND MEASUREMENTS: Clinical features, hormonal parameters at diagnosis (by immunoassay) and recent follow-up of 13 genetically proven 11ßOHD patients managed at our centre were retrospectively reviewed. ACTH-stimulated serum adrenal steroids (measured by LC-MS/MS) of 11ßOHD were compared with those of simple virilizing and non-classic 21OHD. Structural analysis of the observed pathogenic variations was performed by computational modelling. RESULTS: Nine (four females) and four (all females) patients had classic and non-classic disease, respectively. All 11ßOHD patients had elevated ACTH-stimulated serum 11-deoxycortisol (26.5-342.7 nmol/L) whereas none had elevated serum 17-hydroxyprogesterone (4.2-21.2 nmol/L); both hormonal parameters distinguished 11ßOHD from 21OHD with 100% accuracy. ACTH-stimulated serum cortisol, but not 11-deoxycortisol, clearly distinguished classic (<70 nmol/L) from non-classic (>160 nmol/L) disease. Thirteen (eight novel, two recurrent) pathogenic variants were observed. Only missense mutations were observed among patients with non-classic disease. Computational modelling predicted the possible affection of enzyme structure and function for all the observed missense mutations. CONCLUSIONS: This first Indian study describes 13 11ßOHD patients, including four with the rarer non-classic variant. A total of eight novel pathogenic variants were identified in our study, highlighting regional genetic heterogeneity. Measurement of ACTH-stimulated adrenal steroids by LC-MS/MS will help avoid the misdiagnosis of 11ßOHD as 21OHD and has potential to distinguish classic from non-classic 11ßOHD.
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Hiperplasia Suprarrenal Congênita , Esteroide 11-beta-Hidroxilase , Esteroides , Hiperplasia Suprarrenal Congênita/diagnóstico , Hiperplasia Suprarrenal Congênita/genética , Cromatografia Líquida , Feminino , Humanos , Masculino , Mutação , Estudos Retrospectivos , Esteroide 11-beta-Hidroxilase/genética , Espectrometria de Massas em TandemRESUMO
OBJECTIVES: To evaluate the clinical and molecular spectrum, and factors affecting clinical outcome of patients in India diagnosed with infantile-onset Pompe disease (IOPD). STUDY DESIGN: In this multicenter, cross-sectional study, we evaluated the records of 77 patients with IOPD to analyze their clinical course, outcomes, and factors influencing the outcomes. RESULTS: Of the 77 patients with IOPD, phenotype data were available in 59; 46 (78%) had the classic phenotype. Overall, 58 of 77 (75%) and 19 of 77 (25%) patients were symptomatic before and after age 6 months, respectively. Alpha-glucosidase gene variant analysis available for 48 patients (96 alleles) showed missense variants in 49 alleles. Cross-reactive immunologic material (CRIM) status could be determined or predicted in 44 of 48 patients. In total, 32 of 44 patients (72%) were CRIM-positive, and 12 of 44 patients (27%) were CRIM-negative. Thirty-nine cases received enzyme-replacement therapy (ERT), alglucosidase alfa, and 38 patients never received ERT. Median age at initiation of ERT was 6.5 months. Response to ERT was better in babies who had CRIM-positive, non-classic IOPD. CONCLUSIONS: This study highlights the clinical spectrum of IOPD in India and provides an insight on various factors, such as undernutrition, feeding difficulties, and recurrent respiratory infection, as possible factors influencing clinical outcomes in these patients. The study also reiterates the importance of raising awareness among clinicians about the need for early diagnosis and timely treatment of IOPD.
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Doença de Depósito de Glicogênio Tipo II/genética , Doença de Depósito de Glicogênio Tipo II/fisiopatologia , Idade de Início , Estudos Transversais , Feminino , Doença de Depósito de Glicogênio Tipo II/mortalidade , Doença de Depósito de Glicogênio Tipo II/terapia , Humanos , Índia/epidemiologia , Lactente , Recém-Nascido , Masculino , Fenótipo , Estudos Retrospectivos , Resultado do TratamentoRESUMO
OBJECTIVE: We aimed at defining the most effective routine immunoassay- or liquid chromatography-tandem mass spectrometry (LC-MS/MS)-determined steroid biomarkers for identifying non-classic adrenal hyperplasia due to 21-hydroxylase deficiency (21-NCAH) in a PCOS-like population before genotyping. METHODS: Seventy PCOS-like patients in reproductive age with immunoassay-determined follicular 17OH-progesterone (17OHP) ≥ 2.00 ng/mL underwent CYP21A2 gene analysis and 1-24ACTH test. Serum steroids were measured by immunoassays at baseline and 60 min after ACTH stimulation; basal steroid profile was measured by LC-MS/MS. RESULTS: Genotyping revealed 23 21-NCAH, 15 single allele heterozygous CYP21A2 mutations (21-HTZ) and 32 PCOS patients displaying similar clinical and metabolic features. Immunoassays revealed higher baseline 17OHP and testosterone, and after ACTH stimulation, higher 17OHP (17OHP60) and lower cortisol, whereas LC-MS/MS revealed higher 17OHP (17OHPLC-MS/MS), progesterone and 21-deoxycortisol and lower corticosterone in 21-NCAH compared with both 21-HTZ and PCOS patients. Steroid thresholds best discriminating 21-NCAH from 21-HTZ and PCOS were estimated, and their diagnostic accuracy in identifying 21-NCAH from PCOS was established by ROC analysis. The highest accuracy was observed for 21-deoxycortisol ≥ 0.087 ng/mL, showing 100% sensitivity, while the combination of 17OHPLC-MS/MS ≥ 1.79 ng/mL and corticosterone ≤ 8.76 ng/mL, as well as the combination of ACTH-stimulated 17OHP ≥ 6.77 ng/mL and cortisol ≤ 240 ng/mL by immunoassay, showed 100% specificity. CONCLUSIONS: LC-MS/MS measurement of basal follicular 21-deoxycortisol, 17OHP and corticosterone seems the most convenient method for diagnosing 21-NCAH in a population of PCOS with a positive first level screening, providing high accuracy and reducing the need for ACTH stimulation test.
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Hiperplasia Suprarrenal Congênita/diagnóstico , Biomarcadores/sangue , Síndrome do Ovário Policístico/diagnóstico , Esteroides/sangue , 17-alfa-Hidroxiprogesterona/sangue , Adolescente , Hiperplasia Suprarrenal Congênita/sangue , Hiperplasia Suprarrenal Congênita/complicações , Hiperplasia Suprarrenal Congênita/genética , Adulto , Biomarcadores/análise , Análise Química do Sangue/métodos , Cromatografia Líquida , Estudos de Coortes , Análise Mutacional de DNA , Técnicas de Diagnóstico Endócrino , Feminino , Técnicas de Genotipagem , Humanos , Síndrome do Ovário Policístico/sangue , Síndrome do Ovário Policístico/complicações , Síndrome do Ovário Policístico/genética , Reprodutibilidade dos Testes , Esteroide 21-Hidroxilase/análise , Esteroide 21-Hidroxilase/genética , Esteroides/análise , Espectrometria de Massas em Tandem , Testosterona/sangue , Adulto JovemRESUMO
Congenital adrenal hyperplasia (CAH) is the most common cause of primary adrenal insufficiency in children and adolescents. It comprises several clinical entities associated with mutations in genes, encoding enzymes involved in cortisol biosynthesis. The mutations lead to considerable (non-classic form) to almost complete (classic form) inhibition of enzymatic activity, reflected by different phenotypes and relevant biochemical alterations. Up to 95% cases of CAH are due to mutations in CYP21A2 gene and subsequent 21α-hydroxylase deficiency, characterized by impaired cortisol synthesis and adrenal androgen excess. In the past two decades an alternative ("backdoor") pathway of androgens' synthesis in which 5α-androstanediol, a precursor of the 5α-dihydrotestosterone, is produced from 17α-hydroxyprogesterone, with intermediate products 3α,5α-17OHP and androsterone, in the sequence and with roundabout of testosterone as an intermediate, was reported in some studies. This pathway is not always considered in the clinical assessment of patients with hyperandrogenism. The article describes the case of a 17-year-old female patient with menstrual disorders and androgenization (persistent acne, advanced hirsutism). Her serum dehydroepiandrosterone sulfate and testosterone were only slightly elevated, along with particularly high values for 5α-dihydrotestosterone. In 24 h urine collection, an increased excretion of 16α-OHDHEA-a dehydroepiandrosterone metabolite-and pregnanetriolone-a 17α-hydroxyprogesterone metabolite-were observed. The investigations that we undertook provided evidence that the girl suffered from non-classic 21α-hydroxylase deficiency with consequent enhancement of the androgen "backdoor" pathway in adrenals, peripheral tissues or both, using adrenal origin precursors. The paper presents diagnostic dilemmas and strategies to differentiate between various reasons for female hyperandrogenism, especially in childhood and adolescence.
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Hiperplasia Suprarrenal Congênita/metabolismo , Hiperplasia Suprarrenal Congênita/fisiopatologia , Esteroide 21-Hidroxilase/metabolismo , Adolescente , Glândulas Suprarrenais/metabolismo , Hiperplasia Suprarrenal Congênita/genética , Androgênios/metabolismo , Di-Hidrotestosterona/metabolismo , Feminino , Humanos , Esteroide 17-alfa-Hidroxilase/metabolismo , Esteroide 21-Hidroxilase/genética , Esteroides/metabolismo , Testosterona/metabolismoRESUMO
Objectives: To analyze occurrence and plasticity of two recently described distinct subtypes of Th1 cells named classic (CD161-/CCR6-) and non-classic (CD161+/CCR6+) Th1 cells in early rheumatoid arthritis (RA) patients and healthy controls (HCs).Methods: Frequencies of in vivo-generated Th1 cell populations were assessed after cytokine secretion assay for IFNγ/IL-17 and surface staining for CD161/CCR6. Viable Th1 cells (IFNγ+IL-17-) were sorted into classic Th1 (CD161-CCR6-) and non-classic Th1 (CD161+CCR6+) cells, trans-differentiated under different Th cell-inducing conditions, and assessed for plastic changes by analyzing the Th cell-associated cytokine and transcription factor profiles.Results: Ex vivo frequencies of classic (CD161-CCR6-) and non-classic (CD161+CCR6+) Th1 cells as well as related Th1 cell subpopulations CD161+CCR6- and CD161-/CCR6+ did not differ significantly between RA and HCs. However, trans-differentiation of ex vivo non-classic (CD161+CCR6+) and CD161-/CCR6+ Th1 cells resulted in a substantial shift toward Th17 and Th1/Th17 phenotypes, particularly under Th17-inducing conditions. In contrast, classic (CD161-/CCR6-) and CD161+CCR6- Th1 cells showed higher plasticity towards IL-4-producing cells, most of them shifting to a Th1/Th2 phenotype.Conclusion: Whereas non-classic (CD161+/CCR6+) and CD161-CCR6+ Th1 cells demonstrated an increased plasticity towards IL-17- phenotypes, classic Th1 and CD161+CCR6- Th1 cells showed more plasticity towards IL-4-producing phenotypes.
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Artrite Reumatoide/imunologia , Plasticidade Celular , Fenótipo , Células Th1/citologia , Células Th17/citologia , Adulto , Diferenciação Celular , Feminino , Humanos , Interleucina-17/genética , Interleucina-17/metabolismo , Masculino , Pessoa de Meia-Idade , Subfamília B de Receptores Semelhantes a Lectina de Células NK/genética , Subfamília B de Receptores Semelhantes a Lectina de Células NK/metabolismo , Células Th1/imunologia , Células Th17/imunologiaRESUMO
PURPOSE OF REVIEW: The aim of this review is to summarize recently published literature addressing atypical ductal hyperplasia (ADH), lobular neoplasia (atypical lobular hyperplasia [ALH] and classic lobular carcinoma in situ [C-LCIS]), non-classic lobular carcinoma in situ (NC-LCIS), papillary lesions, and flat epithelial atypia (FEA). RECENT FINDINGS: While ADH, ALN, and C-LCIS are well-established markers of an increased risk of future breast cancers, the risk implications are less clear for papillary lesions and FEA. NC-LCIS is the least well-characterized lesion, with scant published literature on its natural history and surgical management when encountered on needle biopsy. Recent data suggest that lobular neoplasia on core biopsy of a BI-RADS ≤ 4 concordant lesion does not require an excision, while ADH, atypical papillomas, and NC-LCIS should be excised. Evidence on FEA and papillomas without atypia suggests a low risk of upgrade on excision, and prospective studies on the upgrade of these lesions are ongoing.
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Doenças Mamárias/diagnóstico , Doenças Mamárias/terapia , Carcinoma in Situ/patologia , Carcinoma Intraductal não Infiltrante/patologia , Carcinoma Lobular/patologia , Guias de Prática Clínica como Assunto/normas , Doenças Mamárias/classificação , Feminino , HumanosRESUMO
11-oxygenated C19 steroids (11oxC19s) are newly specified human androgens. Although median serum levels of 11oxC19 were reported to be higher in patients with polycystic ovary syndrome (PCOS) than in unaffected women, inter-individual variations in androgen levels among PCOS patients have poorly been investigated. Here, we quantified four 11oxC19s, i.e., 11-ketotestosterone (11KT), 11ß-hydroxytestosterone (11OHT), 11ß-hydroxyandrostenedione (11OHΔ4A), and 11-ketoandrostenedione (11KΔ4A), in blood samples of 28 PCOS patients and 31 eumenorrheic women using liquid chromatography-tandem mass spectrometry. We referred to our previous data of classic androgens in these individuals. We found that 11OHT levels were higher in the PCOS group than in the eumenorrheic group. Moreover, although the median values of 11KT, 11KΔ4A, and 11OHΔ4A were comparable between the two groups, these steroids were markedly increased in some patients. Of the 28 patients, 8 had high levels of both 11oxC19s and classic androgens, whereas 4 had an increase only in 11oxC19 levels, and 12 had an increase only in classic androgen levels. Intragroup variations in androgen levels were relatively large in the PCOS group. Levels of 11OHT and 11KT were significantly higher in overweight/obese patients than in normal weight patients and correlated with body mass indexes. These results highlight the clinical significance of 11oxC19s as circulating androgens in PCOS patients and indicate that the accumulation of 11oxC19s and/or classic androgens is an essential feature of PCOS. The profiles of circulating androgens appear to vary among patients. In particular, overweight/obesity likely enhances the 11oxC19s accumulation in PCOS, although this notion awaits further validation.
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Androgênios/sangue , Síndrome do Ovário Policístico/sangue , Adulto , Índice de Massa Corporal , Cromatografia Líquida , Feminino , Humanos , Obesidade/sangue , Espectrometria de Massas em Tandem , Adulto JovemRESUMO
In the present study, we evaluated tumor-infiltrating lymphocytes (TILs) and blood regulatory T lymphocyte (Tregs, CD4+/CD25+/FoxP3+) expression in bladder cancer patients. The number of CD4+, CD8+, CD25+, FoxP3+ and CD20+ TILs was analyzed in association with clinico-pathomorphological features. In more advanced metastasizing tumors, showing non-classic differentiation (ND) and a more aggressive tissue invasion type (TIT), the number of TILs decreased. A low number of CD4+ TILs was associated with poor prognosis. Similarly, Treg frequency before surgery and after surgical treatment was significantly lower in more advanced tumors. The changes in TILs, as well as of local and systemic Tregs, were accompanied by changes in the histological phenotype of urothelial carcinoma regarding pT stage, NDs, TIT, and clinical outcomes. The number of TILs and the frequency of blood Tregs (indicators of antitumor response) may be essential for choosing an immunotherapy that is adjusted to the immune status according to the phase of tumor growth. Moreover, a significant reduction in the number of CD4+ and CD8+ TILs with the development of NDs in more advanced tumors may be associated with lower tumor immunogenicity, resulting in immune tolerance towards tumor tissue. These observations and the tendency of urothelial bladder carcinoma to undergo NDs in a heterogeneous manner during tumor progression suggest complex interactions between bladder cancer immunogenicity and stages of tumor progression.
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Carcinoma/imunologia , Neoplasias da Bexiga Urinária/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Carcinoma/patologia , Feminino , Humanos , Linfócitos do Interstício Tumoral/imunologia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Linfócitos T Reguladores/imunologia , Neoplasias da Bexiga Urinária/patologiaRESUMO
Congenital adrenal hyperplasia is generally associated with oligo-amenorrhea, and its presentation with polymenorrhagia is rare. Here we present a case of an Asian female who presented with polymenorrhagia since menarche, increased body hair growth and enlargement of clitoris for 7-8 years. Examination revealed a normal Body Mass Index, moderate hirsutism, Tanner 5 breasts and significant clitoromegaly. Serum testosterone and 17-hydroxyprogesterone levels were elevated. Ultrasonography revealed normal adrenal glands and polycystic ovaries. adrenocorticotropic hormone stimulation test uncovered borderline cortisol deficiency. Oral dexamethasone was commenced and six months later, she showed improvement though there was no change in hirsutism or clitoromegaly. The case is unique because it presented with polymenorrhagia. Also, such phenomenally high 17-hydroxyprogesterone levels are not expected in non-classic congenital adrenal hyperplasia.
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17-alfa-Hidroxiprogesterona/sangue , Hiperplasia Suprarrenal Congênita/diagnóstico , Hirsutismo/etiologia , Distúrbios Menstruais/etiologia , Síndrome do Ovário Policístico/diagnóstico , Hiperplasia Suprarrenal Congênita/sangue , Hiperplasia Suprarrenal Congênita/complicações , Erros de Diagnóstico , Feminino , Humanos , Adulto JovemRESUMO
AIMS: Pathogenic variants in the CYP21A2 gene are related to the classic and non-classic forms of congenital adrenal hyperplasia (CAH). However, the role of CAH carrier status in the clinical presentation of polycystic ovarian syndrome (PCOS) is still unclear. Moreover, the possible associations of different CYP21A2 gene polymorphisms with metabolic and reproductive abnormalities in PCOS have not been investigated. Therefore, the present study aims to examine the prevalence of the most common CYP21A2 pathogenic variant IVS2-13A/C>G (c.293-13A/C>G) in Eastern European women with PCOS and to evaluate the associations between common intron 2 genetic polymorphisms and the clinical symptoms of the patients. METHODS: Sixty consecutively recruited women with PCOS were genotyped for the CYP21A2 intron 2 IVS2-13A/C>G genetic variant. Additionally, CYP21A2 intron 2 polymorphic variants rs6453 (c.293-44G>T), rs6451 (c.293-67C>A/G), rs369651496 (c.293-104del), and rs6474 (c.308G>A/p.R103L) were tested and described. The clinical and hormonal characteristics were compared in women with PCOS and with polymorphic and wild-type genotypes. RESULTS: The heterozygous CYP21A2 pathogenic variant IVS2-13A/C>G was found in one of the investigated PCOS patients (1.67%) with a non-hyperandrogenic type of PCOS. The presence of the rs6453 (c.293-44G>T) T-allele was associated with increased levels of DHEAS (15.18 vs. 9.14 µmol/L, p = 0.003) compared to the wild-type genotype in the investigated group. The rs6451 (c.293-67C>A/G) minor alleles were associated with an earlier age of menarche in the patients (12.0 vs. 13.0 years, p = 0.007). The polymorphic rs369651496 minor 6G allele was related to a better lipid profile in the women with PCOS, while the rs6474 variant modulated the blood pressure of the patients. CONCLUSIONS: The presence of CYP21A2 genetic minor alleles of rs6467 (IVS2-13A/C, c.293-13A/C), rs6453 (c.293-44G>T), rs6451 (c.293-67C>A/G), rs369651496 (c.293-104del), and rs6474 (c.308G>A/p.R103L) might modulate the adrenal androgens, age of menarche, and metabolic features in women with PCOS. Further studies on 21-hydroxylase genetic variants (pathogenic and polymorphisms) in different ethnic groups might help reveal the influence of adrenal steroidogenesis on PCOS development, clinical manifestations, and lifelong cardiovascular risks.
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Non-classic congenital adrenal hyperplasia (CAH) usually presents later in life with signs of androgen excess but may also be diagnosed after the detection of an incidental adrenal myelolipoma. This is a patient with previously undiagnosed CAH who presented to the emergency department with chest discomfort and palpitations. A computed tomography (CT) scan of the chest done to rule out pulmonary embolism showed bilateral large adrenal myelolipomas. She also had evidence of marked hirsutism on examination, which prompted further workup, and her laboratory data was in keeping with CAH. Further management was unable to be pursued due to the patient's poor compliance, and she was subsequently lost to follow-up. Chronic exposure of the adrenal glands to high adrenocorticotropic hormone (ACTH) levels increases the risk of developing myelolipomas. CAH needs to be considered as a diagnosis in the evaluation of incidental adrenal myelolipomas.
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Congenital adrenal hyperplasia (CAH) is a common genetic disorder in endocrinology, especially its milder clinical presentation, often caused by a partial or total deficiency of the 21-hydroxylase enzyme located in the adrenal cortex. CAH is characterized by the overproduction of androgen, along with variable degrees of cortisol and aldosterone deficiency. The age at diagnosis can provide some information about underlying mutations, with those diagnosed at birth/early infancy more likely to have severe enzymatic defects, which may include adrenal insufficiency, sexual development disorders, short stature in adulthood, hirsutism, and a higher risk for metabolic syndrome and infertility. Non-classic CAH, a milder form of CAH, is usually manifested later in life and is a common differential diagnosis of Polycystic Ovary Syndrome and should be actively evaluated during initial studies of clinical or biochemical hyperandrogenism. The main goals of CAH treatment are hormone supplementation for severe cases, controlling adrenal androgen overproduction to minimize long-term side effects, managing fertility and genetic counseling, and optimizing patients' quality of life.
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Epithelial ovarian cancer (EOC) is the most lethal gynecologic cancer. The disease is often diagnosed after wide-spread dissemination, and the standard treatment combines aggressive surgery with platinum-based chemotherapy; however, most patients experience relapse in the form of peritoneal carcinomatosis, resulting in a 5-year mortality below 45%. There is clearly a need for the development of novel treatments and cancer immunotherapies offering a different approach. Immunotherapies have demonstrated their efficacy in many types of cancers; however, only <15% of EOC patients show any evidence of response. One of the main barriers behind the poor therapeutic outcome is the reduced expression of Major Histocompatibility Complexes class I (MHC I) which occurs in approximately 60% of EOC cases. This review aims to gather and enhance our current understanding of EOC, focusing on its distinct cancer characteristics related to MHC I expression, immunogenicity, antigen presentation, epithelial-to-mesenchymal transition, and various ongoing immunotherapeutic strategies designed to stimulate antitumor immunity.
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Premature pubarche (PP) could represent the first manifestation of non-classic congenital adrenal hyperplasia caused by 21 hydroxylase deficiency (NC21OHD) (10-30% of cases). In the last 20 years, the necessity of performing an ACTH test to diagnose NC21OHD in all cases with PP has been questioned, with conflicting results. This study aims to retrospectively evaluate the predictive value of the basal androgens, 17-OHP levels, and auxological features in suggesting the presence of NC21OHD and, thus, the need for a standard ACTH test to confirm the diagnosis. In all, 111 consecutive patients (87 females) with PP and advanced bone age underwent an ACTH test. Of these, 6/111 cases (1 male) were diagnosed with NC21OHD. The mean baseline 17 hydroxyprogesterone (17-OHP), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), delta 4 androstenedione (Δ4A), and testosterone serum levels were higher in NC21OHD patients than in the others (p < 0.05). We found three predictive features for NC21OHD: basal 17 OHP of >200 ng/mL, bone age advance of >2 years, and DHEA-S levels of >228 ng/mL with sensitivity and specificity of 83.3% and 97.1%, 83.3% and 65.7%, and 83.3% and 96.2%, respectively. Our data confirm that the prevalence of NC21OHD is low among patients with PP. Serum 17-OHP of >200 ng/mL could be helpful to decide, in most cases, which patients should undergo the ACTH test. Bone age advance represented an inadequately specific predictive marker of NC21OHD.
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Cerebral cavernous malformations (CCMs) arise when capillaries within the brain enlarge abnormally, causing the blood-brain barrier (BBB) to break down. The BBB serves as a sophisticated interface that controls molecular interactions between the bloodstream and the central nervous system. The neurovascular unit (NVU) is a complex structure made up of neurons, astrocytes, endothelial cells (ECs), pericytes, microglia, and basement membranes, which work together to maintain blood-brain barrier (BBB) permeability. Within the NVU, tight junctions (TJs) and adherens junctions (AJs) between endothelial cells play a critical role in regulating the permeability of the BBB. Disruptions to these junctions can compromise the BBB, potentially leading to a hemorrhagic stroke. Understanding the molecular signaling cascades that regulate BBB permeability through EC junctions is, therefore, essential. New research has demonstrated that steroids, including estrogens (ESTs), glucocorticoids (GCs), and metabolites/derivatives of progesterone (PRGs), have multifaceted effects on blood-brain barrier (BBB) permeability by regulating the expression of tight junctions (TJs) and adherens junctions (AJs). They also have anti-inflammatory effects on blood vessels. PRGs, in particular, have been found to play a significant role in maintaining BBB integrity. PRGs act through a combination of its classic and non-classic PRG receptors (nPR/mPR), which are part of a signaling network known as the CCM signaling complex (CSC). This network couples both nPR and mPR in the CmPn/CmP pathway in endothelial cells (ECs).
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Progesterone (PRG) is a key cyclical reproductive hormone that has a significant impact on female organs in vertebrates. It is mainly produced by the corpus luteum of the ovaries, but can also be generated from other sources such as the adrenal cortex, Leydig cells of the testes and neuronal and glial cells. PRG has wide-ranging physiological effects, including impacts on metabolic systems, central nervous systems and reproductive systems in both genders. It was first purified as an ovarian steroid with hormonal function for pregnancy, and is known to play a role in pro-gestational proliferation during pregnancy. The main function of PRG is exerted through its binding to progesterone receptors (nPRs, mPRs/PAQRs) to evoke cellular responses through genomic or non-genomic signaling cascades. Most of the existing research on PRG focuses on classic PRG-nPR-paired actions such as nuclear transcriptional factors, but new evidence suggests that PRG also exerts a wide range of PRG actions through non-classic membrane PRG receptors, which can be divided into two sub-classes: mPRs/PAQRs and PGRMCs. The review will concentrate on recently found non-classical membrane progesterone receptors (mainly mPRs/PAQRs) and speculate their connections, utilizing the present comprehension of progesterone receptors.
RESUMO
Liver cancer, comprising hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), is a leading cause of cancer-related deaths worldwide. The liver is a primary metabolic organ for progesterone (PRG) and PRG exerts its effects through classic nuclear PRG receptors (nPRs) and non-classic membrane PRG receptors (mPRs) or a combination of both. Previous studies have shown that the CCM signaling complex (CSC) couples both nPRs and mPRs to form the CmPn (CSC-mPR-PRG-nPR) signaling network, which is involved in multiple cellular signaling pathways, including tumorigenesis of various cancers. Despite advances in treatment, 5-year survival rates for liver cancer patients remain low, largely due to the chemoresistant nature of HCCs. The lack of sensitive and specific biomarkers for liver cancer diagnosis and prognosis emphasizes the need for identifying new potential biomarkers. We propose the potential use of CmPn members' expression data as prognostic biomarkers or biomarker signatures for the major types of hepatic cancer, including HCCs and CCAs, as well as rare subtypes such as undifferentiated pleomorphic sarcoma (UPS) and hepatic angiosarcoma (HAS). In this study, we investigated the CmPn network through RNAseq data and immunofluorescence techniques to measure alterations to key cancer pathways during liver tumorigenesis. Our findings reveal significant differential expression of multiple CmPn members, including CCM1, PAQR7, PGRMC1, and nPRs, in both HCCs and CCAs, highlighting the crucial roles of mPRs, nPRs, and CSC signaling during liver tumorigenesis. These key members of the CmPn network may serve as potential biomarkers for the diagnosis and prognosis of liver cancer subtypes, including rare subtypes.