Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 363
Filtrar
2.
J Pathol Clin Res ; 10(4): e12389, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38970797

RESUMEN

Mesonephric-type (or -like) adenocarcinomas (MAs) of the ovary are an uncommon and aggressive histotype. They appear to arise through transdifferentiation from Müllerian lesions creating diagnostic challenges. Thus, we aimed to develop a histologic and immunohistochemical (IHC) approach to optimize the identification of MA over its histologic mimics, such as ovarian endometrioid carcinoma (EC). First, we screened 1,537 ovarian epithelial neoplasms with a four-marker IHC panel of GATA3, TTF1, ER, and PR followed by a morphological review of EC to identify MA in retrospective cohorts. Interobserver reproducibility for the distinction of MA versus EC was assessed in 66 cases initially without and subsequently with IHC information (four-marker panel). Expression of PAX2, CD10, and calretinin was evaluated separately, and survival analyses were performed. We identified 23 MAs from which 22 were among 385 cases initially reported as EC (5.7%) and 1 as clear cell carcinoma. The interobserver reproducibility increased from fair to substantial (κ = 0.376-0.727) with the integration of the four-marker IHC panel. PAX2 was the single most sensitive and specific marker to distinguish MA from EC and could be used as a first-line marker together with ER/PR and GATA3/TTF1. Patients with MA had significantly increased risk of earlier death from disease (hazard ratio = 3.08; 95% CI, 1.62-5.85; p < 0.0001) compared with patients with EC, when adjusted for age, stage, and p53 status. A diagnosis of MA has prognostic implications for stage I disease, and due to the subtlety of morphological features in some tumors, a low threshold for ancillary testing is recommended.


Asunto(s)
Biomarcadores de Tumor , Neoplasias Ováricas , Factor de Transcripción PAX2 , Humanos , Femenino , Neoplasias Ováricas/patología , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/mortalidad , Factor de Transcripción PAX2/análisis , Factor de Transcripción PAX2/metabolismo , Biomarcadores de Tumor/análisis , Persona de Mediana Edad , Reproducibilidad de los Resultados , Anciano , Adulto , Estudios Retrospectivos , Prevalencia , Inmunohistoquímica , Adenocarcinoma/patología , Adenocarcinoma/diagnóstico , Adenocarcinoma/mortalidad , Diagnóstico Diferencial , Variaciones Dependientes del Observador , Anciano de 80 o más Años , Carcinoma Endometrioide/patología , Carcinoma Endometrioide/diagnóstico , Carcinoma Endometrioide/mortalidad
3.
Child Adolesc Psychiatr Clin N Am ; 33(3): 437-445, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38823815

RESUMEN

The persistence of health inequity and the need for workforce diverse representation within child and adolescent psychiatry require systemic solutions. There are recommendations and strategies particularly for the training programs with "all of the above" approach to tackle these complex systemic issues. One of the ways is to think through existing and innovative training pipelines by making them less leaky, enhancing quality, expanding the type and size, and connecting them to reach children and adolescents in need.


Asunto(s)
Psiquiatría del Adolescente , Psiquiatría Infantil , Equidad en Salud , Adolescente , Niño , Humanos , Psiquiatría del Adolescente/educación , Psiquiatría Infantil/educación , Diversidad Cultural
4.
Cells ; 13(5)2024 Feb 29.
Artículo en Inglés | MEDLINE | ID: mdl-38474395

RESUMEN

Dystroglycan is a ubiquitously expressed heterodimeric cell-surface laminin receptor with roles in cell adhesion, signalling, and membrane stabilisation. More recently, the transmembrane ß-subunit of dystroglycan has been shown to localise to both the nuclear envelope and the nucleoplasm. This has led to the hypothesis that dystroglycan may have a structural role at the nuclear envelope analogous to its role at the plasma membrane. The biochemical fraction of myoblast cells clearly supports the presence of dystroglycan in the nucleus. Deletion of the dystroglycan protein by disruption of the DAG1 locus using CRISPR/Cas9 leads to changes in nuclear size but not overall morphology; moreover, the Young's modulus of dystroglycan-deleted nuclei, as determined by atomic force microscopy, is unaltered. Dystroglycan-disrupted myoblasts are also no more susceptible to nuclear stresses including chemical and mechanical, than normal myoblasts. Re-expression of dystroglycan in DAG1-disrupted myoblasts restores nuclear size without affecting other nuclear parameters.


Asunto(s)
Distroglicanos , Laminina , Distroglicanos/metabolismo , Laminina/metabolismo , Núcleo Celular/metabolismo , Membrana Celular/metabolismo , Membrana Nuclear/metabolismo
5.
Mod Pathol ; 37(1): 100374, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37925057

RESUMEN

Dedifferentiated and undifferentiated ovarian carcinomas (DDOC/UDOC) are rare neoplasms defined by the presence of an undifferentiated carcinoma. In this study, we detailed the clinical, pathological, immunohistochemical, and molecular features of a series of DDOC/UDOC. We collected a multi-institutional cohort of 23 DDOC/UDOC and performed immunohistochemistry for core switch/sucrose nonfermentable (SWI/SNF) complex proteins (ARID1A, ARID1B, SMARCA4, and SMARCB1), mismatch repair (MMR) proteins, and p53. Array-based genome-wide DNA methylation and copy number variation analyses were performed on a subset of cases with comparison made to a previously reported cohort of undifferentiated endometrial carcinoma (UDEC), small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), and tubo-ovarian high-grade serous carcinoma (HGSC). The age of all 23 patients with DDOC/UDOC ranged between 22 and 71 years (with an average age of 50 years), and a majority of them presented with extraovarian disease (16/23). Clinical follow-up was available for 19 patients. Except for 2 patients, the remaining 17 patients died from disease, with rapid disease progression resulting in mortality within a year in stage II-IV settings (median disease-specific survival of 3 months). Eighteen of 22 cases with interpretable immunohistochemistry results showed loss of expression of core SWI/SNF protein(s) that are expected to result in SWI/SNF complex inactivation as 10 exhibited coloss of ARID1A and ARID1B, 7 loss of SMARCA4, and 1 loss of SMARCB1. Six of 23 cases were MMR-deficient. Two of 20 cases exhibited mutation-type p53 immunoreactivity. Methylation profiles showed coclustering of DDOC/UDOC with UDEC, which collectively were distinct from SCCOHT and HGSC. However, DDOC/UDOC showed an intermediate degree of copy number variation, which was slightly greater, compared with SCCOHT but much less compared with HGSC. Overall, DDOC/UDOC, like its endometrial counterpart, is highly aggressive and is characterized by frequent inactivation of core SWI/SNF complex proteins and MMR deficiency. Its molecular profile overlaps with UDEC while being distinct from SCCOHT and HGSC.


Asunto(s)
Neoplasias Encefálicas , Carcinoma de Células Pequeñas , Carcinoma , Neoplasias Colorrectales , Neoplasias Endometriales , Síndromes Neoplásicos Hereditarios , Neoplasias Ováricas , Femenino , Humanos , Persona de Mediana Edad , Adulto Joven , Adulto , Anciano , Proteína p53 Supresora de Tumor/genética , Variaciones en el Número de Copia de ADN , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Carcinoma/patología , Carcinoma Epitelial de Ovario , Neoplasias Endometriales/patología , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , ADN Helicasas/genética , ADN Helicasas/metabolismo , Proteínas Nucleares/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo
6.
J Pathol ; 262(1): 4-9, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-37850576

RESUMEN

Mesonephric-like adenocarcinoma (MLA) of the female genital tract is an uncommon histotype that can arise in both the endometrium and the ovary. The exact cell of origin and histogenesis currently remain unknown. Here, we investigated whole genome DNA methylation patterns and copy number variations (CNVs) in a series of MLAs in the context of a large cohort of various gynaecological carcinoma types. CNV analysis of 19 MLAs uncovered gains of chromosomes 1q (18/19, 95%), 10 (15/19, 79%), 12 (14/19, 74%), and 2 (10/19, 53%), as well as loss of chromosome 1p (7/19, 37%). Gains of chromosomes 1q, 10, and 12 were also identified in the majority of mesonephric adenocarcinomas of the uterine cervix (MAs) as well as subsets of endometrioid carcinomas (ECs) and low-grade serous carcinomas of the ovary (LGSCs) but only in a minority of serous carcinomas of the uterine corpus (USCs), clear cell carcinomas (CCCs), and tubo-ovarian high-grade serous carcinomas (HGSCs). While losses of chromosome 1p together with gains of chromosome 1q were also identified in both MA and LGSC, gains of chromosome 2 were almost exclusively identified in MLA and MA. Unsupervised hierarchical clustering and t-SNE analysis of DNA methylation data (Illumina EPIC array) identified a co-clustering for MLAs and MAs, which was distinct from clusters of ECs, USCs, CCCs, LGSCs, and HGSCs. Group-wise comparisons confirmed a close epigenetic relationship between MLA and MA. These findings, in conjunction with the established histological and immunophenotypical overlap, suggest bona fide mesonephric differentiation, and support a more precise terminology of mesonephric-type adenocarcinoma instead of MLA in these tumours. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.


Asunto(s)
Carcinoma Endometrioide , Cistadenocarcinoma Seroso , Neoplasias Ováricas , Femenino , Humanos , Cuello del Útero/patología , Variaciones en el Número de Copia de ADN , Metilación de ADN , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/patología , Cistadenocarcinoma Seroso/genética , Carcinoma Epitelial de Ovario/genética , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología
7.
Mod Pathol ; 36(11): 100318, 2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37634867

RESUMEN

Adult granulosa cell tumors (AGCTs) are a molecularly distinct group of malignant ovarian sex cord-stromal tumors (SCSTs) characterized by a nearly ubiquitous c.402C>G/p.C134W mutation in FOXL2 (hereafter referred to as "C134W"). In some cases, AGCT exhibits marked morphologic overlap with other SCSTs and has an identical immunophenotype, and molecular testing may be necessary to help confirm the diagnosis. However, molecular testing is time consuming, relatively expensive, and unavailable in many pathology laboratories. We describe the development and validation of an in situ hybridization (ISH) custom BaseScope assay for the detection of the FOXL2 C134W mutation. We evaluated 106 ovarian SCSTs, including 78 AGCTs, 9 juvenile granulosa cell tumors, 18 fibromas (cellular and conventional), and 1 SCST, not otherwise specified, as well as 53 epithelial ovarian tumors (42 endometrioid carcinomas and 11 carcinosarcomas) and 1 STK11 adnexal tumor for the presence or absence of FOXL2 wild-type and FOXL2 C134W RNA expression via BaseScope-ISH. Fifty-one tumors had previously undergone DNA sequencing of the FOXL2 gene. Across the entire cohort, the FOXL2 C134W probe staining was positive in 77 of 78 (98.7%) AGCTs. Two of 81 (2.5%) non-AGCTs also showed positive staining, both of which were epithelial ovarian tumors. The assay worked in tissue from blocks >20 years old. There was 100% concordance between the FOXL2 sequencing and BaseScope-ISH results. Overall, assessment of FOXL2 mutation status by custom BaseScope-ISH demonstrated 98.7% sensitivity and 97.5% specificity for the diagnosis of AGCT. BaseScope-ISH for FOXL2 C134W represents a reasonable alternative to sequencing, is quicker and less expensive, and is more easily incorporated than molecular testing into many pathology laboratories. It also has the advantage of requiring less tissue, and the neoplastic cells can be directly visualized on stained sections.


Asunto(s)
Tumor de Células de la Granulosa , Neoplasias Ováricas , Femenino , Adulto , Humanos , Adulto Joven , Tumor de Células de la Granulosa/diagnóstico , Tumor de Células de la Granulosa/genética , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Proteína Forkhead Box L2/genética , Mutación , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Hibridación in Situ
8.
PLoS Biol ; 21(5): e3001746, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-37134077

RESUMEN

Extramedullary hematopoiesis (EMH) expands hematopoietic capacity outside of the bone marrow in response to inflammatory conditions, including infections and cancer. Because of its inducible nature, EMH offers a unique opportunity to study the interaction between hematopoietic stem and progenitor cells (HSPCs) and their niche. In cancer patients, the spleen frequently serves as an EMH organ and provides myeloid cells that may worsen pathology. Here, we examined the relationship between HSPCs and their splenic niche in EMH in a mouse breast cancer model. We identify tumor produced IL-1α and leukemia inhibitory factor (LIF) acting on splenic HSPCs and splenic niche cells, respectively. IL-1α induced TNFα expression in splenic HSPCs, which then activated splenic niche activity, while LIF induced proliferation of splenic niche cells. IL-1α and LIF display cooperative effects in activating EMH and are both up-regulated in some human cancers. Together, these data expand avenues for developing niche-directed therapies and further exploring EMH accompanying inflammatory pathologies like cancer.


Asunto(s)
Enfermedades Hematológicas , Hematopoyesis Extramedular , Neoplasias , Humanos , Animales , Ratones , Hematopoyesis Extramedular/fisiología , Factor Inhibidor de Leucemia/farmacología , Interleucina-1alfa/farmacología , Hematopoyesis
9.
Nat Commun ; 14(1): 1677, 2023 03 25.
Artículo en Inglés | MEDLINE | ID: mdl-36966138

RESUMEN

DICER1 syndrome is a tumor predisposition syndrome that is associated with up to 30 different neoplastic lesions, usually affecting children and adolescents. Here we identify a group of mesenchymal tumors which is highly associated with DICER1 syndrome, and molecularly distinct from other DICER1-associated tumors. This group of DICER1-associated mesenchymal tumors encompasses multiple well-established clinicopathological tumor entities and can be further divided into three clinically meaningful classes designated "low-grade mesenchymal tumor with DICER1 alteration" (LGMT DICER1), "sarcoma with DICER1 alteration" (SARC DICER1), and primary intracranial sarcoma with DICER1 alteration (PIS DICER1). Our study not only provides a combined approach to classify DICER1-associated neoplasms for improved clinical management but also suggests a role for global hypomethylation and other recurrent molecular events in sarcomatous differentiation in mesenchymal tumors with DICER1 alteration. Our results will facilitate future investigations into prognostication and therapeutic approaches for affected patients.


Asunto(s)
Síndromes Neoplásicos Hereditarios , Sarcoma , Niño , Adolescente , Humanos , Mutación de Línea Germinal , Sarcoma/genética , Síndromes Neoplásicos Hereditarios/genética , Genómica , Ribonucleasa III/genética , Predisposición Genética a la Enfermedad , Enfermedades Raras , Mutación , ARN Helicasas DEAD-box/genética
10.
Mod Pathol ; 36(3): 100044, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36788095

RESUMEN

High-grade endometrial stromal sarcomas (HGESSs) are aggressive uterine tumors harboring oncogenic fusion proteins. We performed a molecular study of 36 HGESSs with YWHAE::NUTM2 gene fusion, assessing co-occurring genetic events, and showed that these tumors frequently harbor recurrent events involving the CDKN2A locus on chromosome 9p. Using array-based copy number profiling and CDKN2A fluorescence in situ hybridization, we identified homozygous and hemizygous deletions of CDKN2A in 18% and 14% of tumors (n = 22 analyzed), respectively. While all YWHAE-rearranged HGESSs with retained disomy for CDKN2A were immunohistochemically positive for p16INK4 (p16), all tumors with homozygous deletion of CDKN2A showed complete absence of p16 staining. Of the 2 tumors with a hemizygous deletion of CDKN2A, 1 showed diffuse and strong p16 positivity, whereas the other showed complete absence of staining. In the p16-negative case, we did not find intragenic mutations or DNA promoter methylation to explain the p16 protein loss, implicating other mechanisms in the regulation of protein expression. In our cohort, subclonal or complete absence of p16 staining was associated with worse overall survival compared with positive p16 staining (1-year overall survival: 28.6% vs 90.7%, respectively; n = 32; P < .001), with all 7 patients in the p16-negative group having succumbed to their disease within 2 years of diagnosis. Our results suggested CDKN2A alterations as a cooperative driver of tumorigenesis in a subset of HGESSs with the YWHAE::NUTM2 gene fusion and showed p16 to be a potential prognostic marker.


Asunto(s)
Neoplasias Endometriales , Sarcoma Estromático Endometrial , Sarcoma , Femenino , Humanos , Neoplasias Endometriales/patología , Pronóstico , Hibridación Fluorescente in Situ , Sarcoma Estromático Endometrial/genética , Sarcoma Estromático Endometrial/patología , Homocigoto , Eliminación de Secuencia , Sarcoma/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Fusión Génica , Proteínas 14-3-3/genética , Proteínas 14-3-3/metabolismo
11.
Sci Rep ; 13(1): 278, 2023 01 06.
Artículo en Inglés | MEDLINE | ID: mdl-36609632

RESUMEN

Plasma circulating tumour DNA (ctDNA) has been suggested to be a viable biomarker of response to treatment in patients with high grade serous ovarian carcinoma (HGSOC). TP53 mutations are present in more than 90% of HGSOCs but somatic variants are distributed across all exonic regions of the gene, requiring next generation sequencing (NGS) technologies for mutational analysis. In this study, we compared the suitability of the Accel (Swift) and Oncomine (ThermoFisher) panels for identification of TP53 mutations in ctDNA of HGSOC patients (N = 10). Only 6 patients (60%) were found to have TP53 mutations using the ACCEL panel but the addition of molecular tags in the Oncomine panel improved ctDNA detection with at least one mutation detected in all cases (100%). Orthogonal validation of the 14 somatic variants found by Oncomine, using droplet digital PCR, confirmed 79% (11/14) of the identified mutations. Overall, the Oncomine panel with unique molecular identifiers (UMI) appears more useful for ctDNA analysis in HGSOC.


Asunto(s)
ADN Tumoral Circulante , Neoplasias Ováricas , Humanos , Femenino , ADN Tumoral Circulante/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Mutación , Neoplasias Ováricas/patología , Biomarcadores de Tumor/genética , Proteína p53 Supresora de Tumor/genética
12.
Am J Surg Pathol ; 47(4): 490-496, 2023 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-36583307

RESUMEN

Sertoli-Leydig cell tumors (SLCTs) are uncommon ovarian sex cord-stromal neoplasms which are currently classified into well, moderately, and poorly differentiated and retiform types. Well-differentiated SLCT is the least common and typically occurs in pure form, whereas moderately and poorly differentiated and retiform types often comprise a morphologic spectrum with an admixture of all 3. DICER1 pathogenic variants are very common in SLCTs but, as far as we are aware, have not been reported in well-differentiated neoplasms, although the number of cases studied is small due to the rarity of this neoplasm. We undertook DICER1 molecular testing in a cohort of 18 well-differentiated SLCTs and show all these to be DICER1 wild-type. None of the cases harbored the p. FOXL2 C134W hotspot mutation. Based upon the DICER1 molecular results, together with morphologic observations, we propose that well-differentiated SLCT is an unrelated neoplasm to the more common moderately/poorly differentiated and retiform SLCTs and is a fundamentally distinct and unrelated tumor type within the ovarian sex cord-stromal tumor family. The implications for tumor nomenclature and recommendations for future tumor classification are discussed within the context of tumors collectively known as SLCTs.


Asunto(s)
Neoplasias Ováricas , Tumor de Células de Sertoli-Leydig , Tumores de los Cordones Sexuales y Estroma de las Gónadas , Masculino , Femenino , Humanos , Tumor de Células de Sertoli-Leydig/genética , Tumor de Células de Sertoli-Leydig/patología , Tumores de los Cordones Sexuales y Estroma de las Gónadas/genética , Tumores de los Cordones Sexuales y Estroma de las Gónadas/patología , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Mutación , Técnicas de Diagnóstico Molecular , Ribonucleasa III/genética , ARN Helicasas DEAD-box/genética
13.
Hum Mol Genet ; 32(2): 177-191, 2023 01 06.
Artículo en Inglés | MEDLINE | ID: mdl-35925868

RESUMEN

Mutations in LMNA, the gene encoding A-type lamins, cause laminopathies-diseases of striated muscle and other tissues. The aetiology of laminopathies has been attributed to perturbation of chromatin organization or structural weakening of the nuclear envelope (NE) such that the nucleus becomes more prone to mechanical damage. The latter model requires a conduit for force transmission to the nucleus. NE-associated Linker of Nucleoskeleton and Cytoskeleton (LINC) complexes are one such pathway. Using clustered regularly interspaced short palindromic repeats to disrupt the Nesprin-1 KASH (Klarsicht, ANC-1, Syne Homology) domain, we identified this LINC complex protein as the predominant NE anchor for microtubule cytoskeleton components, including nucleation activities and motor complexes, in mouse cardiomyocytes. Loss of Nesprin-1 LINC complexes resulted in loss of microtubule cytoskeleton proteins at the nucleus and changes in nuclear morphology and positioning in striated muscle cells, but with no overt physiological defects. Disrupting the KASH domain of Nesprin-1 suppresses Lmna-linked cardiac pathology, likely by reducing microtubule cytoskeleton activities at the nucleus. Nesprin-1 LINC complexes thus represent a potential therapeutic target for striated muscle laminopathies.


Asunto(s)
Laminopatías , Músculo Estriado , Animales , Ratones , Proteínas de Microtúbulos/metabolismo , Proteínas Nucleares/metabolismo , Proteínas de la Membrana/genética , Citoesqueleto/genética , Citoesqueleto/metabolismo , Matriz Nuclear/genética , Microtúbulos/metabolismo , Membrana Nuclear/genética , Membrana Nuclear/metabolismo , Proteínas de Filamentos Intermediarios/metabolismo , Músculo Estriado/metabolismo , Laminopatías/metabolismo
15.
Cancer Res ; 82(19): 3499-3515, 2022 Oct 04.
Artículo en Inglés | MEDLINE | ID: mdl-35913887

RESUMEN

CDC20 is a coactivator of the anaphase promoting complex/cyclosome (APC/C) and is essential for mitotic progression. APC/CCDC20 is inhibited by the spindle assembly checkpoint (SAC), which prevents premature separation of sister chromatids and aneuploidy in daughter cells. Although overexpression of CDC20 is common in many cancers, oncogenic mutations have never been identified in humans. Using whole-exome sequencing, we identified heterozygous missense CDC20 variants (L151R and N331K) that segregate with ovarian germ cell tumors in two families. Functional characterization showed these mutants retain APC/C activation activity but have impaired binding to BUBR1, a component of the SAC. Expression of L151R and N331K variants promoted mitotic slippage in HeLa cells and primary skin fibroblasts derived from carriers. Generation of mice carrying the N331K variant using CRISPR-Cas9 showed that, although homozygous N331K mice were nonviable, heterozygotes displayed accelerated oncogenicity of Myc-driven cancers. These findings highlight an unappreciated role for CDC20 variants as tumor-promoting genes. SIGNIFICANCE: Two germline CDC20 missense variants that segregate with cancer in two families compromise the spindle assembly checkpoint and lead to aberrant mitotic progression, which could predispose cells to transformation. See related commentary by Villarroya-Beltri and Malumbres, p. 3432.


Asunto(s)
Neoplasias , Huso Acromático , Ciclosoma-Complejo Promotor de la Anafase/genética , Animales , Proteínas Cdc20/genética , Proteínas Cdc20/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Células Germinativas/metabolismo , Células HeLa , Humanos , Ratones , Mitosis/genética , Neoplasias/metabolismo , Unión Proteica , Huso Acromático/metabolismo
16.
Stem Cell Reports ; 17(8): 1810-1823, 2022 08 09.
Artículo en Inglés | MEDLINE | ID: mdl-35839773

RESUMEN

Accurate modeling of the heart electrophysiology to predict arrhythmia susceptibility remains a challenge. Current electrophysiological analyses are hypothesis-driven models drawing conclusions from changes in a small subset of electrophysiological parameters because of the difficulty of handling and understanding large datasets. Thus, we develop a framework to train machine learning classifiers to distinguish between healthy and arrhythmic cardiomyocytes using their calcium cycling properties. By training machine learning classifiers on a generated dataset containing a total of 3,003 healthy derived cardiomyocytes and their various arrhythmic states, the multi-class models achieved >90% accuracy in predicting arrhythmia presence and type. We also demonstrate that a binary classifier trained to distinguish cardiotoxic arrhythmia from healthy electrophysiology could determine the key biological changes associated with that specific arrhythmia. Therefore, machine learning algorithms can be used to characterize underlying arrhythmic patterns in samples to improve in vitro preclinical models and complement current in vivo systems.


Asunto(s)
Células Madre Pluripotentes Inducidas , Miocitos Cardíacos , Arritmias Cardíacas , Calcio , Humanos , Aprendizaje Automático
17.
Hum Mol Genet ; 31(18): 3161-3180, 2022 09 10.
Artículo en Inglés | MEDLINE | ID: mdl-35567414

RESUMEN

RTL1/PEG11, which has been associated with anxiety disorders, is a retrotransposon-derived imprinted gene in the placenta. However, imprinting patterns and functions of RTL1 in the brain have not been well-investigated. We found Rtl1 was paternally, but not maternally, expressed in brain stem, thalamus, and hypothalamus of mice, and imprinting status of RTL1 was maintained in human brain. Paternal Rtl1 knockout (Rtl1m+/p-) mice had higher neonatal death rates due to impaired suckling, and low body weights beginning on embryonic day 16.5. High paternal expression of Rtl1 was detected in the locus coeruleus (LC) and Rtl1m+/p- mice showed an increased delay in time of onset for action potentials and inward currents with decreased neuronal excitability of LC neurons. Importantly, Rtl1m+/p- mice exhibited behaviors associated with anxiety, depression, fear-related learning and memory, social dominance, and low locomotor activity. Taken together, our findings demonstrate RTL1 is imprinted in brain, mediates emotional and social behaviors, and regulates excitability in LC neurons.


Asunto(s)
Proteínas Gestacionales , Retroelementos , Animales , Ansiedad/genética , Trastornos de Ansiedad/genética , Femenino , Impresión Genómica , Humanos , Locus Coeruleus/metabolismo , Ratones , Neuronas/metabolismo , Embarazo , Proteínas Gestacionales/genética , Proteínas Gestacionales/metabolismo , Conducta Social
18.
Histopathology ; 81(1): 44-54, 2022 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-35394077

RESUMEN

AIMS: Dedifferentiated endometrial carcinomas (DDECs)/undifferentiated endometrial carcinomas (UDECs) frequently harbour genomic activation of switch/sucrose non-fermentable (SWI/SNF)-complex proteins, and can show histological overlap with neuroendocrine carcinoma (NEC). The aim of this study was to compare the extent of the expression of neuroendocrine markers, SWI/SNF proteins and mismatch repair (MMR) proteins in DDEC/UDEC and NEC. METHODS AND RESULTS: The extent of expression of synaptophysin, chromogranin, CD56, ARID1A, ARID1B, SMARCA4, SMARCB1 and MMR proteins was evaluated by immunohistochemistry on 44 SWI/SNF-deficient DDECs/UDECs and 15 NECs. Thirty-three of 44 (75%) DDECs/UDECs showed expression of at least one neuroendocrine marker, with 18 of 44 (41%) expressing two or more neuroendocrine markers, whereas all 15 NECs showed expression of at least one neuroendocrine marker, with 14 of 15 (93%) expressing two or more neuroendocrine markers. Neuroendocrine marker expression in DDECs/UDECs was typically focal when present, with average extents of 17%, 4% and 8% for synaptophysin, chromogranin and CD56 in the positive cases, respectively, in contrast to 73%, 40% and 62% in the positive NEC cases, respectively. All 15 NECs showed intact expression of SWI/SNF-complex proteins, except for one that showed isolated loss of ARID1A. Thirty-eight of 44 DDECs/UDECs were MMR-abnormal (34 with loss of MLH1 and PMS2, and four with loss of PMS2 alone), whereas all NECs retained MMR protein expression. CONCLUSIONS: Our study demonstrates frequent but typically focal neuroendocrine marker expression in SWI/SNF-deficient DDECs/UDECs, whereas NECs typically express two or more neuroendocrine markers, with diffuse expression of at least one marker. ARID1B, SMARCA4 and SMARCB1 immunohistochemistry can be used to aid in the differentiation between DDEC/UDEC and NEC.


Asunto(s)
Carcinoma Endometrioide , Carcinoma Neuroendocrino , Neoplasias Endometriales , Biomarcadores de Tumor/genética , Carcinoma Endometrioide/patología , Carcinoma Neuroendocrino/diagnóstico , Cromograninas , ADN Helicasas , Neoplasias Endometriales/patología , Femenino , Humanos , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto , Proteínas Nucleares , Sinaptofisina , Factores de Transcripción
19.
J Clin Oncol ; 40(18): 2036-2047, 2022 06 20.
Artículo en Inglés | MEDLINE | ID: mdl-35263119

RESUMEN

PURPOSE: Tubo-ovarian cancer (TOC) is a sentinel cancer for BRCA1 and BRCA2 pathogenic variants (PVs). Identification of a PV in the first member of a family at increased genetic risk (the proband) provides opportunities for cancer prevention in other at-risk family members. Although Australian testing rates are now high, PVs in patients with TOC whose diagnosis predated revised testing guidelines might have been missed. We assessed the feasibility of detecting PVs in this population to enable genetic risk reduction in relatives. PATIENTS AND METHODS: In this pilot study, deceased probands were ascertained from research cohort studies, identification by a relative, and gynecologic oncology clinics. DNA was extracted from archival tissue or stored blood for panel sequencing of 10 risk-associated genes. Testing of deceased probands ascertained through clinic records was performed with a consent waiver. RESULTS: We identified 85 PVs in 84 of 787 (11%) probands. Familial contacts of 39 of 60 (65%) deceased probands with an identified recipient (60 of 84; 71%) have received a written notification of results, with follow-up verbal contact made in 85% (33 of 39). A minority of families (n = 4) were already aware of the PV. For many (29 of 33; 88%), the genetic result provided new information and referral to a genetic service was accepted in most cases (66%; 19 of 29). Those who declined referral (4 of 29) were all male next of kin whose family member had died more than 10 years before. CONCLUSION: We overcame ethical and logistic challenges to demonstrate that retrospective genetic testing to identify PVs in previously untested deceased probands with TOC is feasible. Understanding reasons for a family member's decision to accept or decline a referral will be important for guiding future TRACEBACK projects.


Asunto(s)
Neoplasias de la Mama , Neoplasias Ováricas , Australia , Neoplasias de la Mama/genética , Carcinoma Epitelial de Ovario/genética , Familia , Femenino , Predisposición Genética a la Enfermedad , Pruebas Genéticas/métodos , Humanos , Masculino , Neoplasias Ováricas/genética , Neoplasias Ováricas/prevención & control , Proyectos Piloto , Estudios Retrospectivos
20.
Hum Pathol ; 123: 46-58, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35245609

RESUMEN

Many sarcomas with DICER1 pathogenic variants (PVs) exhibit a characteristic morphology, including a subepithelial layer of malignant mesenchymal cells, areas of rhabdomyoblastic differentiation and cartilaginous and/or osseous elements. We report 5 DICER1-associated neoplasms (1 moderately to poorly differentiated Sertoli Leydig cell tumour and 4 sarcomas) containing variable amounts of neuroectodermal elements. The neoplasms predominantly involved or were in close proximity to the female genital tract (ovary, uterine corpus, abdominal and pelvic cavity) and occurred in females aged 14 months to 54 years. The neuroectodermal elements were characterised by solid and tubular/rosette-like patterns and variable immunoreactivity with SALL4 and neuroendocrine markers. In some cases, the neuroectodermal component was focal while in others it was exclusive. In one case, the focal neuroectodermal component within an ovarian Sertoli Leydig cell tumour resulted in extraovarian metastasis. In reporting these cases, we suggest that neuroectodermal elements, including pure neuroectodermal tumours, are part of the morphological spectrum of DICER1-associated neoplasms. It is important that pathologists recognize that a neuroectodermal component (often admixed with other elements) may be a feature of such neoplasms. This will facilitate appropriate tumour and/or germline testing which could lead to the identification of germline DICER1 PVs (DICER1 syndrome). Three of the patients we report were subsequently shown to have a germline DICER1 PV.


Asunto(s)
Sarcoma , Tumor de Células de Sertoli-Leydig , Tumores de los Cordones Sexuales y Estroma de las Gónadas , ARN Helicasas DEAD-box/genética , Femenino , Humanos , Masculino , Mutación , Ribonucleasa III/genética , Tumor de Células de Sertoli-Leydig/genética , Tumor de Células de Sertoli-Leydig/patología , Tumores de los Cordones Sexuales y Estroma de las Gónadas/patología
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA
...