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  • 1
    Online Resource
    Online Resource
    Transcriptional changes in multiple endocrine organs from lethal cases of COVID-19
    Springer Science and Business Media LLC ; 2023
    In:  Journal of Molecular Medicine Vol. 101, No. 8 ( 2023-08), p. 973-986
    Details
    In: Journal of Molecular Medicine, Springer Science and Business Media LLC, Vol. 101, No. 8 ( 2023-08), p. 973-986
    Abstract: Altered circulating hormone and metabolite levels have been reported during and post-COVID-19. Yet, studies of gene expression at the tissue level capable of identifying the causes of endocrine dysfunctions are lacking. Transcript levels of endocrine-specific genes were analyzed in five endocrine organs of lethal COVID-19 cases. Overall, 116 autoptic specimens from 77 individuals (50 COVID-19 cases and 27 uninfected controls) were included. Samples were tested for the SARS-CoV-2 genome. The adrenals, pancreas, ovary, thyroid, and white adipose tissue (WAT) were investigated. Transcript levels of 42 endocrine-specific and 3 interferon-stimulated genes (ISGs) were measured and compared between COVID-19 cases (virus-positive and virus-negative in each tissue) and uninfected controls. ISG transcript levels were enhanced in SARS-CoV-2-positive tissues. Endocrine-specific genes (e.g., HSD3B2 , INS , IAPP , TSHR , FOXE1 , LEP , and CRYGD ) were deregulated in COVID-19 cases in an organ-specific manner. Transcription of organ-specific genes was suppressed in virus-positive specimens of the ovary, pancreas, and thyroid but enhanced in the adrenals. In WAT of COVID-19 cases, transcription of ISGs and leptin was enhanced independently of virus detection in tissue. Though vaccination and prior infection have a protective role against acute and long-term effects of COVID-19, clinicians must be aware that endocrine manifestations can derive from virus-induced and/or stress-induced transcriptional changes of individual endocrine genes. Key messages • SARS-CoV-2 can infect adipose tissue, adrenals, ovary, pancreas and thyroid. • Infection of endocrine organs induces interferon response. • Interferon response is observed in adipose tissue independently of virus presence. • Endocrine-specific genes are deregulated in an organ-specific manner in COVID-19. • Transcription of crucial genes such as INS , TSHR and LEP is altered in COVID-19.
    Type of Medium: Online Resource
    ISSN: 0946-2716 , 1432-1440
    URL: Article
    DOI: 10.1007/s00109-023-02334-3
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 1462132-0
    SSG: 12
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  • 2
    Online Resource
    Online Resource
    Autopsy Study of Testicles in COVID-19: Upregulation of Immune-Related Genes and Downregulation of Testis-Specific Genes
    The Endocrine Society ; 2023
    In:  The Journal of Clinical Endocrinology & Metabolism Vol. 108, No. 4 ( 2023-03-10), p. 950-961
    Details
    In: The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, Vol. 108, No. 4 ( 2023-03-10), p. 950-961
    Abstract: Infection by SARS-CoV-2 may be associated with testicular dysfunction that could affect male fertility. Objective Testicles of fatal COVID-19 cases were investigated to detect virus in tissue and to evaluate histopathological and transcriptomic changes. Methods Three groups were compared: (a) uninfected controls (subjects dying of trauma or sudden cardiac death; n = 10); (b) subjects dying of COVID-19 (virus-negative in testes; n = 15); (c) subjects dying of COVID-19 (virus-positive in testes; n = 9). SARS-CoV-2 genome and nucleocapsid antigen were probed using RT-PCR, in situ hybridization, and immunohistochemistry (IHC). Infiltrating leukocytes were typed by IHC. mRNA transcripts of immune-related and testis-specific genes were quantified using the nCounter method. Results SARS-CoV-2 was detected in testis tissue of 9/24 (37%) COVID-19 cases accompanied by scattered T-cell and macrophage infiltrates. Size of testicles and counts of spermatogenic cells were not significantly different among groups. Analysis of mRNA transcripts showed that in virus-positive testes immune processes were activated (interferon-alpha and -gamma pathways). By contrast, transcription of 12 testis-specific genes was downregulated, independently of virus positivity in tissue. By IHC, expression of the luteinizing hormone/choriogonadotropin receptor was enhanced in virus-positive compared to virus-negative testicles, while expression of receptors for androgens and the follicle-stimulating hormone were not significantly different among groups. Conclusion In lethal COVID-19 cases, infection of testicular cells is not uncommon. Viral infection associates with activation of interferon pathways and downregulation of testis-specific genes involved in spermatogenesis. Due to the exceedingly high numbers of infected people in the pandemic, the impact of virus on fertility should be further investigated.
    Type of Medium: Online Resource
    ISSN: 0021-972X , 1945-7197
    URL: Article
    DOI: 10.1210/clinem/dgac608
    RVK:
    XA 10000
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2023
    detail.hit.zdb_id: 2026217-6
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  • 3
    Online Resource
    Online Resource
    Predictive Biomarkers in Thyroid Cancer
    Frontiers Media SA ; 2022
    In:  Frontiers in Oncology Vol. 12 ( 2022-5-6)
    Details
    In: Frontiers in Oncology, Frontiers Media SA, Vol. 12 ( 2022-5-6)
    Abstract: In molecular pathology, predictive biomarkers identify which patients are likely to respond to targeted drugs. These therapeutic agents block specific molecules directly involved in cancer growth, dedifferentiation and progression. Until few years ago, the only targeted drugs available for advanced thyroid cancer included multi-tyrosine kinase inhibitors, mainly targeting the MAPK pathway and the angiogenic signaling. The administration of these drugs does not necessarily require a molecular characterization of tumors to assess the presence of predictive alterations. However, the availability of new selective targeted drugs for thyroid cancer patients is changing the diagnostic strategies for the molecular characterization of these tumors. The search for targetable alterations can be performed directly on tumor tissue by using a variety of methodologies, depending also on the number and type of alterations to test (i.e. single nucleotide variation or gene rearrangement). Herein, a comprehensive review of the currently available targeted treatments for thyroid cancer, related predictive markers and testing methodologies is provided.
    Type of Medium: Online Resource
    ISSN: 2234-943X
    URL: Article
    DOI: 10.3389/fonc.2022.901004
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 2649216-7
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  • 4
    Online Resource
    Online Resource
    Clinical-Pathological and Molecular Evaluation of 451 NIFTP Patients from a Single Referral Center
    MDPI AG ; 2022
    In:  Cancers Vol. 14, No. 2 ( 2022-01-14), p. 420-
    Details
    In: Cancers, MDPI AG, Vol. 14, No. 2 ( 2022-01-14), p. 420-
    Abstract: Background: Non-invasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTPs) were introduced in thyroid pathology in 2016. NIFTPs are a group of follicular neoplasm with an indolent behaviour. In this study, we gathered a large retrospective cohort of NIFTPs and compared those presenting as solitary lesions and NIFTPs found in multifocal setting. Methods: A retrospective search of NIFTPs was performed, and the clinico-pathological features were recorded. For a subgroup of patients, pre-surgical ultrasound (US) evaluation, cytological diagnosis, and molecular analysis were available. Results: We collected 451 NIFTPs; 254 (56.3%) were truly solitary tumours, while 197 coexisted with one or more NIFTP/cancer. Contrasting unifocal and multifocal settings, NIFTPs size was the only significantly different parameter. Preoperatively, NIFTP nodules mostly showed low-risk US characteristics, indeterminate cytology and a RAS-like molecular profile. Conclusion: NIFTPs often coexist with collateral thyroid tumours. However, no clinical-pathological differences can be observed between solitary and “multifocal” NIFTPs. Despite the well-established clinical indolence of NIFTP, a careful monitoring of the contralateral lobe should not be excluded.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers14020420
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2527080-1
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  • 5
    Online Resource
    Online Resource
    Molecular Genetics of Follicular-Derived Thyroid Cancer
    MDPI AG ; 2021
    In:  Cancers Vol. 13, No. 5 ( 2021-03-07), p. 1139-
    Details
    In: Cancers, MDPI AG, Vol. 13, No. 5 ( 2021-03-07), p. 1139-
    Abstract: Thyroid cancer is the most common type of endocrine-related malignancy, whose incidence rates have increased dramatically in the last few decades. Neoplasms of follicular origin generally have excellent prognosis, with the exception of less differentiated tumors. Follicular-derived thyroid cancer can manifest as a variety of morphologically distinct entities, characterized by various degrees of differentiation and invasiveness. Histological evaluation is thus crucial for the definition of patients’ prognosis. However, within each histological subtype, tumor behavior can be highly variable, and, in this respect, molecular characterization can provide insightful information to refine the risk stratification of tumors. In addition to the importance of its prognostic role, molecular testing can be used to support the differential diagnosis of thyroid nodules in the absence of marked cyto-morphological aberrations. Finally, with the advent of targeted drugs, the presence of molecular alterations will guide the therapeutic strategies for patients with advanced tumors who do not respond to standard treatment. This review aims to describe the genetic landscape of follicular-derived thyroid tumors also highlighting differences across histological subtypes.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers13051139
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2527080-1
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  • 6
    Online Resource
    Online Resource
    Molecular Alterations in Relation to Histopathological Characteristics in a Large Series of Pediatric Papillary Thyroid Carcinoma from a Single Institution
    MDPI AG ; 2021
    In:  Cancers Vol. 13, No. 13 ( 2021-06-22), p. 3123-
    Details
    In: Cancers, MDPI AG, Vol. 13, No. 13 ( 2021-06-22), p. 3123-
    Abstract: Papillary thyroid carcinoma (PTC) presents distinct clinico-pathological and molecular differences in children compared with adult patients. Whether the presence of rearrangements or point mutations is associated with aggressive PTC clinical presentation is still controversial. In this study, PTCs diagnosed in patients aged less than 18 years were retrospectively searched from the institutional archive and tumor tissue was tested for point mutations in BRAF and RAS genes and for rearrangements in RET, NTRK1, NTRK3, ALK, PPARG, BRAF and THADA. A total of 163 PTCs were analyzed. Point mutations were found in 83 (51%) and gene fusions in 48 cases (30%). The most frequent alteration was the BRAFV600E mutation (36.8%), followed by NTRK3 fusion (11%), NRAS mutation (10.4%) and RET fusion (10.4%). Fusion-driven PTCs showed more frequently infiltrative growth, larger tumors, extrathyroidal extension and N1b disease. PTCs showing solid growth pattern were significantly enriched in gene fusions. This is one of the largest cohorts of pediatric PTCs. Fusion-driven tumors most frequently show aggressive pathological features; the search for rearrangements, especially in tumors with solid areas, could improve the characterization of pediatric PTCs and offer possible therapeutic options.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers13133123
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2527080-1
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  • 7
    Online Resource
    Online Resource
    Down-regulation of miR-7-5p and miR-548ar-5p predicts malignancy in indeterminate thyroid nodules negative for BRAF and RAS mutations
    Springer Science and Business Media LLC ; 2022
    In:  Endocrine Vol. 76, No. 3 ( 2022-06), p. 677-686
    Details
    In: Endocrine, Springer Science and Business Media LLC, Vol. 76, No. 3 ( 2022-06), p. 677-686
    Abstract: The value of molecular markers in refining preoperative risk assessment of indeterminate thyroid nodules is being widely investigated. MicroRNAs (miRNA) are emerging as promising biomarkers for diagnostic and prognostic purposes. The aim of this study is to identify miRNAs specifically deregulated in mutation-negative indeterminate thyroid nodules. Methods Ninety-eight nodules preoperatively diagnosed as TIR 3A or TIR 3B with available histological diagnosis of follicular adenoma (FA), noninvasive follicular neoplasm with papillary-like nuclear features (NIFTP), and follicular variant papillary thyroid carcinoma (FV-PTC) have been retrospectively selected. Mutations in BRAF and RAS genes have been tested in all samples by real-time PCR; miRNAs were purified from cytology slides of 60 samples; expression analysis of 798 miRNAs was measured by the nCounter system. Results Point mutations in BRAF and RAS genes were detected in 32 out of 98 nodules (32.7%), the majority of which in FV-PTCs. Differential expression of miRNA in wild-type nodules highlighted that two miRNAs, namely miR-7-5p and miR-548ar-5p , were downregulated in FV-PTCs compared to FAs. The combined expression of these miRNAs, tested by ROC analysis, showed an area under the curve of 0.79. Sensitivity and negative predictive value were high both in wild-type (93% and 92%, respectively) and in mutated nodules (94% and 85%, respectively). Conclusion The analysis of miR-7-5p and miR-548ar-5p expression in indeterminate thyroid nodules demonstrated a promising value in ruling out malignancy.
    Type of Medium: Online Resource
    ISSN: 1559-0100
    URL: Article
    DOI: 10.1007/s12020-022-03034-7
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 2074043-8
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  • 8
    Online Resource
    Online Resource
    Suppression of Pituitary Hormone Genes in Subjects Who Died From COVID-19 Independently of Virus Detection in the Gland
    The Endocrine Society ; 2022
    In:  The Journal of Clinical Endocrinology & Metabolism Vol. 107, No. 8 ( 2022-07-14), p. 2243-2253
    Details
    In: The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, Vol. 107, No. 8 ( 2022-07-14), p. 2243-2253
    Abstract: Involvement of the pituitary gland in SARS-CoV-2 infection has been clinically suggested by pituitary hormone deficiency in severe COVID-19 cases, by altered serum adrenocorticotropic hormone (ACTH) levels in hospitalized patients, and by cases of pituitary apoplexy. However, the direct viral infection of the gland has not been investigated. Objective To evaluate whether the SARS-CoV-2 genome and antigens could be present in pituitary glands of lethal cases of COVID-19, and to assess possible changes in the expression of immune-related and pituitary-specific genes. Methods SARS-CoV-2 genome and antigens were searched in the pituitary gland of 23 patients who died from COVID-19 and, as controls, in 12 subjects who died from trauma or sudden cardiac death. Real-time reverse transcription polymerase chain reaction (PCR), in situ hybridization, immunohistochemistry, and transmission electron microscopy were utilized. Levels of mRNA transcripts of immune-related and pituitary-specific genes were measured by the nCounter assay. Results The SARS-CoV-2 genome and antigens were detected in 14/23 (61%) pituitary glands of the COVID-19 group, not in controls. In SARS-CoV-2–positive pituitaries, the viral genome was consistently detected by PCR in the adeno- and the neurohypophysis. Immunohistochemistry, in situ hybridization, and transmission electron microscopy confirmed the presence of SARS-CoV-2 in the pituitary. Activation of type I interferon signaling and enhanced levels of neutrophil and cytotoxic cell scores were found in virus-positive glands. mRNA transcripts of pituitary hormones and pituitary developmental/regulatory genes were suppressed in all COVID-19 cases irrespective of virus positivity. Conclusion Our study supports the tropism of SARS-CoV-2 for human pituitary and encourages exploration of pituitary dysfunction after COVID-19.
    Type of Medium: Online Resource
    ISSN: 0021-972X , 1945-7197
    URL: Article
    DOI: 10.1210/clinem/dgac312
    RVK:
    XA 10000
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2022
    detail.hit.zdb_id: 2026217-6
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  • 9
    Online Resource
    Online Resource
    Outcomes of the Tall-Cell Variant of Papillary Thyroid Carcinoma in Patients with Different Ages: A 17-Year Mono-Institutional Experience
    MDPI AG ; 2023
    In:  Cancers Vol. 15, No. 7 ( 2023-04-05), p. 2152-
    Details
    In: Cancers, MDPI AG, Vol. 15, No. 7 ( 2023-04-05), p. 2152-
    Abstract: The tall-cell variant of papillary thyroid carcinoma (TCPTC) is the most common aggressive variant of papillary thyroid carcinoma (PTC) and typically occurs in older patients. In this study, we analyzed retrospectively the largest mono-institutional series of PTCs with tall-cell features (989 patients) over a 17-year period, re-evaluating tumors based on age at presentation and outcomes in different age groups. We divided patients into three age groups following different criteria (the criterion from the American Joint Committee on Cancer Tumor Node Metastasis (AJCC TNM) guidelines, criterion for the statistical division into tertiles and adolescent/post-adolescent criterion) to analyze the clinicopathological characteristics in different age groups, especially in terms of recurrence-free survival (RFS) and distant recurrence-free survival (DRFS). We obtained three main results: 1. the population is distributed among the different age groups, and therefore, this type of cancer is not exclusively found among those of an older age; 2. in the RFS analysis, we can see a higher probability of local recurrence in the younger and older groups and, unexpectedly, a lower probability of local recurrence in the “median age” group; and 3. in the DRFS analysis, we can observe a higher probability of distant recurrence in older patients. From a molecular perspective, no significant differences in the mutational status of BRAF were detected according to different age groups, while mutations in the TERT promoter were exclusively present in older patients of all age groups, highlighting the potential prognostic implications of TERT promoter mutations in PTCs. In conclusion, the results of this series confirm that TC morphology alone in PTCs does not have the same negative prognostic significance in the younger population as in the older population. The reason for these different outcomes remains unclear and needs further studies.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers15072152
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2527080-1
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  • 10
    Online Resource
    Online Resource
    SARS-CoV-2 spread to endocrine organs is associated with obesity: an autopsy study of COVID-19 cases
    Springer Science and Business Media LLC ; 2023
    In:  Endocrine
    Details
    In: Endocrine, Springer Science and Business Media LLC
    Abstract: SARS-CoV-2 infection may be limited to the respiratory tract or may spread to multiple organs. Besides disease severity, factors associated with virus spread within the host are elusive. Here, we tried to identify features associated with SARS-CoV-2 spread to endocrine organs. Methods In a retrospective autoptic cohort of 51 subjects who died because of COVID-19, we analyzed the severity and type of lung pathology, patients’ features and the detection of virus in thyroid, testis, adrenal gland, pancreas, anterior pituitary, and the white adipose tissue (WAT). Results The SARS-CoV-2 genome was detected in endocrine organs of 30/51 cases. The anterior pituitary and WAT were most frequently positive for virus. While pathological features of lung were not associated with the presence of virus in endocrine organs, obesity (BMI  〉  30) was significantly associated to virus detection in pancreas ( p  = 0.01) and thyroid ( p  = 0.04). WAT infection was detected more frequently in males ( p  = 0.03). Conclusion In subject with obesity dying of COVID-19, the virus frequently spreads to endocrine organs. The findings emphasize the need for optimal treatment of patients with obesity at the very onset of COVID-19. Since post-COVID conditions remain a major issue worldwide, a rigorous follow-up of endocrine function—especially of thyroid and pancreas—is advocated in subjects with obesity.
    Type of Medium: Online Resource
    ISSN: 1559-0100
    URL: Article
    DOI: 10.1007/s12020-023-03518-0
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 2074043-8
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