Immunohistochemical Profile of Parathyroid Tumours: A Comprehensive Review.

Immunohistochemistry remains an indispensable tool in diagnostic surgical pathology. In parathyroid tumours, it has four main applications: to detect (1) loss of parafibromin; (2) other manifestations of an aberrant immunophenotype hinting towards carcinoma; (3) histogenesis of a neck mass and (4) pathogenetic events, including features of tumour microenvironment and immune landscape. Parafibromin stain is mandatory to identify the new entity of parafibromin-deficient parathyroid neoplasm, defined in the WHO classification (2022). Loss of parafibromin indicates a greater probability of malignant course and should trigger the search for inherited or somatic CDC73 mutations. Aberrant immunophenotype is characterised by a set of markers that are lost (parafibromin), down-regulated (e.g., APC protein, p27 protein, calcium-sensing receptor) or up-regulated (e.g., proliferation activity by Ki-67 exceeding 5%) in parathyroid carcinoma compared to benign parathyroid disease. Aberrant immunophenotype is not the final proof of malignancy but should prompt the search for the definitive criteria for carcinoma. Histogenetic studies can be necessary for differential diagnosis between thyroid vs. parathyroid origin of cervical or intrathyroidal mass; detection of parathyroid hormone (PTH), chromogranin A, TTF-1, calcitonin or CD56 can be helpful. Finally, immunohistochemistry is useful in pathogenetic studies due to its ability to highlight both the presence and the tissue location of certain proteins. The main markers and challenges (technological variations, heterogeneity) are discussed here in the light of the current WHO classification (2022) of parathyroid tumours.

Non-Aziridination Approaches to 3-Arylaziridine-2-carboxylic Acid Derivatives and 3-Aryl-(aziridin-2-yl)ketones.

Highly functionalized aziridines, including compounds with aromatic moieties, are attractive substrates both in synthetic and medical areas of chemistry. There is a broad and interesting set of synthetic methods for reaching these compounds. Aziridination represents the most explored tool, but there are several other more specific, less well-known, but highly promising approaches. Therefore, the current review focuses on recently described or updated ways to obtain 3-arylated aziridines via different non-aziridination-based synthetic methods, reported mainly since 2000. The presented methods belong to two main directions of synthesis, namely, cyclization of open-chain substrates and rearrangement of other heterocycles. Cyclization of open-chain substrates includes the classic Gabriel-Cromwell type cyclization of halogenated substrates with amines, base-promoted cyclization of activated aminoalcohols (or its analogues), and the oxidative cyclization of ß-dicarbonyls. Rearrangements of other heterocycles are presented as the Baldwin rearrangement of 4-isoxazolines, the cycloaddition of 1.3-dipoles or dienes to 2H-azirines, and the addition of C- and N-nucleophiles to the double bond of azirines.

An Easy Route to Aziridine Ketones and Carbinols.

N,N-Dimethylaziridine-2-carboxamides react with organolithium reagents yielding 2-aziridinylketones. The reaction with one equivalent of organolithium compound is selective to amide carbonyl at a low (-78 °C) temperature. These ketones, in reaction with organolithium reagents, give symmetrical and unsymmetrical aziridinyl carbinols. The usage of excess phenyllithium may serve as a special N-Boc-protecting group cleavage method for acid-sensitive substrates.

Molecular profile of parathyroid tissues and tumours: a heterogeneous landscape.

Advances in laboratory diagnostics and surgical treatment of primary hyperparathyroidism have ensured solid basis for research in parathyroid pathology in order to specify key molecules in pathogenesis and morphological diagnostics of difficult cases. The aim of this study was to assess the molecular landscape and its heterogeneity in primary parathyroid hyperplasia (PPH) and adenoma, compared to carcinoma and normal glands. In a retrospective analysis of 179 surgically removed parathyroid glands (102 adenomas; 27 PPH; 45 normal glands; 5 carcinomas), expression of Ki-67, p21, p27, p53, cyclin D1, Bcl-2 protein, vimentin, cytokeratin (CK) 19, E-cadherin, CD56, CD44 and parafibromin was detected by immunohistochemistry, followed by computer-assisted assessment of mean values and heterogeneity measures. Descriptive statistics and Kruskal-Wallis test were applied. Significant differences were disclosed regarding the mean and highest fraction of Ki-67 (both p < 0.001), p21 (both p < 0.001), cyclin D1 (p = 0.002) and p27-expressing cells (p = 0.010). Proliferative lesions (PPH, adenoma and carcinoma) showed statistically significantly up-regulated CK19 (p = 0.012), decreased E-cadherin levels and distinctive patterns of vimentin. CD44, CD56 and p53 were almost absent from parathyroid tissues. All carcinomas lacked parafibromin contrasting with invariable positivity in adenomas. Remarkable heterogeneity of cell cycle markers and intermediate filaments must be accounted for in scientific studies and elaboration of diagnostic cut-offs.

3-Arylaziridine-2-carboxylic Acid Derivatives and (3-Arylaziridin-2-yl)ketones: The Aziridination Approaches.

Aziridination reactions represent a powerful tool in aziridine synthesis. Significant progress has been achieved in this field in the last decades, whereas highly functionalized aziridines including 3-arylated aziridine-2-carbonyl compounds play an important role in both medical and synthetic chemistry. For the reasons listed, in the current review we have focused on the ways to obtain 3-arylated aziridines and on the recent advances (mainly since the year 2000) in the methodology of the synthesis of these compounds via aziridination.

A Novel Aziridine-based Bruton's Tyrosine Kinase Inhibitor Induces Apoptosis Through Down-regulation of p65/RelA Phosphorylation on Serine 536 and ERK1/2 in Mantle Cell Lymphoma.

BACKGROUND: Mantle cell lymphoma (MCL) is an aggressive non-Hodgkin's lymphoma characterized by hyperactive neoplastic B-cells and extended tumor cell survival. Bruton's tyrosine kinase (BTK), a crucial kinase in the B-cell antigen receptor signaling pathway, has emerged as a novel target of MCL therapy. A novel BTK-targeting inhibitor, JuSt-23F was prepared. MATERIALS AND METHODS: The WST-8 assay was used to determine cytotoxicity and half-maximal inhibitory concentration (IC50) values for JuSt-23F against the MCL cell lines Mino and Maver-1. JuSt-23F-mediated apoptosis was assessed using the annexin V assay. We detected phosphorylation of p65/RelA on serine 536 in whole Jurkat, Mino and Maver-1 cells treated with JuSt-23F and stimulated with tumor necrosis factor (TNFα). We assessed JuSt-23F-mediated phosphorylation of the extracellular signal-regulated kinases 1 and 2 (ERK1/2) in T-cell lymphoma and MCL cells stimulated by phorbol-12-myristate-13-acetate (PMA). RESULTS AND CONCLUSION: Our study suggests that JuSt-23F inhibits apoptosis selectively in B-cell lymphoma cells. JuSt-23F exerts its antiproliferative effects on MCL cells through targeting the downstream BTK signaling cascade via down-regulation of nuclear factor kappa-light-chain-enhancer of activated B-cells and ERK1/2 pathways. Thus, our findings propose the novel BTK inhibitor JuSt-23F as an attractive potential agent for investigation and treatment of MCL.