New insights into intranuclear inclusions in thyroid carcinoma: Association with autophagy and with BRAFV600E mutation

Schwertheim, Suzan; Theurer, Sarah; Jastrow, Holger; Herold, Thomas; Ting, Saskia; Westerwick, Daniela; Bertram, Stefanie; Schaefer, Christoph; Kälsch, Julia; Baba, Hideo A.; Schmid, Kurt Werner

doi:10.1371/journal.pone.0226199

Cited by 13 publications

(18 citation statements)

References 56 publications

(77 reference statements)

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“…Hence, the 1/2 criteria had higher specificity in distinguishing PTC from FA than the 1/3 criteria, and applying either criterion would be useful in distinguishing FA from follicular variant papillary carcinoma. Therefore, we agree with Schwertheim et al (7) that p62 is a useful marker for NuIns. However, since NuIns have different sizes, shapes, and numbers, distinct criteria for evaluating NuIns are mandatory.…”

Section: Discussionsupporting

confidence: 93%

“…We designed this study based on previous reports that p62 accumulation is pathogenic. As Schwertheim et al (7) concluded that p62 expression in NuIns indicates their contribution to autophagy, we hypothesized that p62In cells may be created due to accumulation of p62 not eliminated by autophagy, and that they drive pathological changes in the thyroid tissue in PTC. When stimulated by growth factors, normal cells generally increase their glutamine and glucose uptake as energy sources.…”

Section: Discussionmentioning

confidence: 99%

“…There have been several attempts to distinguish NuIns from NuVas using IHC to diagnose PTC (7,15,16). Schwertheimet al (7) examined the expression of several autophagy-associated proteins in NuIns, including LC3B, ubiquitin, cathepsin D, p62/sequestosome 1, and cathepsin B. They proved that NuIns are entirely closed on both two and three dimensions with no connection to the cytoplasm.…”

Section: Discussionmentioning

confidence: 99%

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Diagnostic Utility of p62 Expression in Intranuclear Inclusions in Thyroid Core Needle Biopsy Specimens

Kim

et al. 2021

In Vivo

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Background/Aim: Core needle biopsy (CNB) has been widely used as an alternative method to ultrasoundguided fine-needle aspiration cytology for histological diagnosis of thyroid specimens. However, nuclear artifactual vacuoles (NuVas) produced during tissue processing can be very difficult and sometimes impossible to distinguish from intranuclear inclusions (NuIns). P62 is an autophagy receptor that recognizes, targets, and eliminates toxic cellular materials during autophagy. Herein, we examined the utility of p62 immunohistochemical staining to detect NuIns in thyroid core needle biopsy specimens. Patients and Methods:Thirty-five thyroid CNB slides from 32 patients and corresponding resection specimens stained with hematoxylin and eosin were reviewed by two pathologists. The immunohistochemical staining pattern of p62 was used to differentiate NuIns from NuVas. The diameter of each nucleus (A) and NuIn (B) was measured, and the number of p62-expressing NuIn-positive (p62In) cells was counted using 1/2 (B/A) and 1/3 (B/A) criteria. The criterion of 1/3 includes NuIns larger than 1/3 and smaller than 1/2 of the nuclear diameter. The criteria of 1/2 includes NuIns larger than 1/2 of the nuclear diameter. Results: By applying the 1/2 criterion, there were no p62In cells in follicular adenoma (FA) samples. However, in papillary thyroid carcinoma (PTC) samples, 22 of 25 specimens exhibited p62In cells. The sensitivity and specificity to distinguish FA from PTC using the 1/2 criterion were 0.88 and 1.00, respectively. By applying the 1/3 criterion, there was one p62In cell hit in FA samples. However, 23 of 25 PTC specimens showed p62In cells. The sensitivity and specificity to distinguish FA from PTC using the 1/3 criterion were 1.00 and 0.90, respectively. Conclusion: P62 is a useful marker for distinguishing FA and PTC based on CNB specimens. We suggest the 1/2 criteria for identifying p62In cells.Ultrasound-guided fine-needle aspiration cytology (FNAC) is a common and useful method for diagnosing thyroid nodules (1). If FNAC fails or is inconclusive, patients should receive repeated FNAC or diagnostic surgery (2,3). Ultrasound-guided thyroid core needle biopsy (CNB) is widely used to diagnose lesions with inconclusive or atypia of undetermined significance FNAC results (3-6). CNB has the benefit of allowing for immunohistochemical staining (IHC) and observation of the features of stromal invasion. However, artifactual nuclear vacuoles (NuVas), intranuclear artifacts derived from the production of hematoxylin and eosin (HE)-stained slides, can be very difficult and sometimes impossible to distinguish from intranuclear inclusions (NuIns). NuIns are important pathological features for the diagnosis of papillary thyroid carcinoma (PTC). In PTC, NuIns have more sharply delineated rims than NuVas, whereas NuVas are more irregular in shape and only lightly stained withHE (2). Schwertheim et al. (7) used IHC of several autophagy-associated proteins, including p62, to detect NuIns in PTC. Theyproved that NuIns are entirely 1...

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Diagnostic Utility of p62 Expression in Intranuclear Inclusions in Thyroid Core Needle Biopsy Specimens

Kim

et al. 2021

In Vivo

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“…The lysosome proteases cathepsin B and D together with the presence of heterolysosomes in TEM are suggestive for an active proteolytic activity in type1 NI. This proteolytic activity could also explain the nearby degenerated cell organelles, which we and others have observed in NI 20,21,33,34 . This hypothesis is supported by the identification of autophagy related proteins such as LC3B, p62, ubiquitin and cathepsins in NI.…”

Section: Discussionsupporting

confidence: 64%

“…In NAFLD, nuclear vacuolation is linked to aging process or senescence but no differentiation is made between NI with or without a limiting membrane 19 . Our recent study of membrane-bounded NI in HCC 20 and in thyroid carcinomas 21 has shown the presence of autophagy-associated proteins and proteases within the inclusions; in HCC the occurrence of inclusions was associated with patients' survival benefit 20 . Jaskolski et al described that autophagy is involved in the pathogenesis of intranuclear vacuolation in meningeomas 22 ; their electron microscopic studies revealed lysosomal bodies and autophagic vacuoles within these NI, suggesting an active macroautophagy process 22 .…”

mentioning

confidence: 99%

Characterization of two types of intranuclear hepatocellular inclusions in NAFLD

Schwertheim

Kälsch

Jastrow

et al. 2020

Sci Rep

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Nuclear inclusions (NI) are a common finding in hepatocytes from patients with liver disease especially in diabetes mellitus and non-alcoholic fatty liver disease (NAFLD) but studies examining the shape and content of these inclusions in detail are lacking. In this study we define two distinct types of NI in NAFLD: inclusions bounded by the nuclear membrane, containing degenerative cell organelles and heterolysosomes (type1) and inclusions with deposits of glycogen but without any kind of organelles and delimiting membrane (type2). NI in 77 paraffin-embedded patients of NAFLD including NAFL and non-alcoholic steatohepatitis (NASH) were analyzed. In 4–12% of type1 NI immunopositivity for the autophagy-associated proteins LC3B, ubiquitin, p62/sequestosome1, cathepsin D and cathepsin B were detected with co-localizations of ubiquitin and p62; type2 NI showed no immunoreactivity. Three-dimensional reconstructions of isolated nuclei revealed that NI type1 are completely enclosed within the nucleus, suggesting that NI, although probably derived from cytoplasmic invaginations, are not just simple invaginations. Our study demonstrates two morphologically different types of inclusions in NAFLD, whereby both gained significantly in number in advanced stages. We suggest that the presence of autophagy-associated proteins and degenerated organelles within type1 NI plays a role in disease progression.

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Tau‐induced deficits in nonsense‐mediated mRNA decay contribute to neurodegeneration

Zuniga

Levy

Ramirez

et al. 2022

Alzheimer's & Dementia

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Introduction While brains of patients with Alzheimer's disease and related tauopathies have evidence of altered RNA processing, we lack a mechanistic understanding of how altered RNA processing arises in these disorders and if such changes are causally linked to neurodegeneration. Methods Using Drosophila melanogaster models of tauopathy, we find that overall activity of nonsense‐mediated mRNA decay (NMD), a key RNA quality‐control mechanism, is reduced. Genetic manipulation of NMD machinery significantly modifies tau‐induced neurotoxicity, suggesting that deficits in NMD are causally linked to neurodegeneration. Mechanistically, we find that deficits in NMD are a consequence of aberrant RNA export and RNA accumulation within nuclear envelope invaginations in tauopathy. We identify a pharmacological activator of NMD that suppresses neurodegeneration in tau transgenic Drosophila, indicating that tau‐induced deficits in RNA quality control are druggable. Discussion Our studies suggest that NMD activators should be explored for their potential therapeutic value to patients with tauopathies.

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New insights into intranuclear inclusions in thyroid carcinoma: Association with autophagy and with BRAFV600E mutation

Cited by 13 publications

References 56 publications

Diagnostic Utility of p62 Expression in Intranuclear Inclusions in Thyroid Core Needle Biopsy Specimens

Diagnostic Utility of p62 Expression in Intranuclear Inclusions in Thyroid Core Needle Biopsy Specimens

Characterization of two types of intranuclear hepatocellular inclusions in NAFLD

Tau‐induced deficits in nonsense‐mediated mRNA decay contribute to neurodegeneration

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