Pre-operative management of Pleomorphic and florid lobular carcinoma in situ of the breast: Report of a large multi-institutional series and review of the literature

Background: Pleomorphic and Florid Lobular carcinoma in situ (P/F LCIS) are rare variants of LCIS, the exact nature of which is still debated. Aim: To collect a large series of P/F LCIS diagnosed on preoperative biopsies and evaluate their association with invasive carcinoma and high grade duct carcinoma in situ (DCIS). Data obtained were compared with those reported in the literature. Methods: A multi-institutional series of P/F LCIS was retrieved. All cases were diagnosed on pre-operative biopsies, which was followed by an open surgical excision. Data on post-operative histopathology were available. A literature review was performed. Results: A total of 117 cases were collected; invasive carcinoma and/or DCIS was present in 78/117 cases (66.7%). Seventy cases of P/F LCIS were pure on biopsy and 31 of these showed pathological upgrade in post-surgical specimens. Pre-operative biopsy accuracy was 47/78 (60.3%); pre-operative biopsy underestimation of cancer was 31/78 (39,7.%). In the literature review papers, invasive carcinoma or DCIS was associated with 274 of 418 (65.5%) cases of P/F LCIS. Pre-operative biopsy accuracy was 66% (181/274) whereas pre-operative biopsy underestimation of cancer was 33.9% (93/274). Conclusions: The data presented here indicate that P/F LCIS is frequently associated with invasive carcinoma or high grade DCIS and that pre-operative biopsy is associated with an underestimation of malignancy. Open surgery is indicated when P/F LCIS is diagnosed pre-operatively

Transcriptomic-based evaluation of trichloroethylene glutathione and cysteine conjugates demonstrate phenotype-dependent stress responses in a panel of human in vitro models

Environmental or occupational exposure of humans to trichloroethylene (TCE) has been associated with different extrahepatic toxic effects, including nephrotoxicity and neurotoxicity. Bioactivation of TCE via the glutathione (GSH) conjugation pathway has been proposed as underlying mechanism, although only few mechanistic studies have used cell models of human origin. In this study, six human derived cell models were evaluated as in vitro models representing potential target tissues of TCE-conjugates: RPTEC/TERT1 (kidney), HepaRG (liver), HUVEC/TERT2 (vascular endothelial), LUHMES (neuronal, dopaminergic), human induced pluripotent stem cells (hiPSC) derived peripheral neurons (UKN5) and hiPSC-derived differentiated brain cortical cultures containing all subtypes of neurons and astrocytes (BCC42). A high throughput transcriptomic screening, utilizing mRNA templated oligo-sequencing (TempO-Seq), was used to study transcriptomic effects after exposure to TCE-conjugates. Cells were exposed to a wide range of concentrations of S-(1,2-trans-dichlorovinyl)glutathione (1,2-DCVG), S-(1,2-trans-dichlorovinyl)-L-cysteine (1,2-DCVC), S-(2,2-dichlorovinyl)glutathione (2,2-DCVG), and S-(2,2-dichlorovinyl)-L-cysteine (2,2-DCVC). 1,2-DCVC caused stress responses belonging to the Nrf2 pathway and Unfolded protein response in all the tested models but to different extents. The renal model was the most sensitive model to both 1,2-DCVC and 1,2-DCVG, with an early Nrf2-response at 3 µM and hundreds of differentially expressed genes at higher concentrations. Exposure to 2,2-DCVG and 2,2-DCVC also resulted in the upregulation of Nrf2 pathway genes in RPTEC/TERT1 although at higher concentrations. Of the three neuronal models, both the LUHMES and BCC42 showed significant Nrf2-responses and at higher concentration UPR-responses, supporting recent hypotheses that 1,2-DCVC may be involved in neurotoxic effects of TCE. The cell models with the highest expression of γ-glutamyltransferase (GGT) enzymes, showed cellular responses to both 1,2-DCVG and 1,2-DCVC. Little to no effects were found in the neuronal models from 1,2-DCVG exposure due to their low GGT-expression. This study expands our knowledge on tissue specificity of TCE S-conjugates and emphasizes the value of human cell models together with transcriptomics for such mechanistic studies.Toxicolog

The human OR1G1 olfactory receptor is differentially activated by various sandalwood odorants. A joint approach combining in silico and in vitro experiments

International audienceSandalwood is a highly valuable component in perfumery. The action mode of sandalwood odorant molecules remains to be addressed. In fact, olfactory receptors involved in their perception have not yet been identified. The interaction of a human olfactory receptor, hOR1G1, with sandalwood odorants has been investigated. By means of cellular biology and functional tests experiments, we provide an additional insight to our atomic model of OR1G1 and our olfactophore approach performed on various odorants. The studied odorants cover a wide range of structures and sandalwood intensities. We experimentally show that beta-santalol is a strong agonist of hOR1G1, contrarily to alpha-santalol and other closely related compounds. An atomic-scale model is then inferred through the use of both a sandalwood pharmacophore and the prediction of the position of these compounds within the cavity of the receptor

Pocket histology at cardiac implantable electronic device replacement: What's new?

Background: Repeated procedures involving the cardiac implantable electronic device (CIED) pocket increase the infection risk, and the extent of pocket adhesions may prolong the procedure time. Few data on pocket histology at the time of CIED replacement are available. Objective: The purpose of this study was to describe CIED pocket histology in a cohort of patients undergoing CIED replacement or upgrade. Methods: All consecutive patients undergoing CIED replacement or upgrade at our center between November 2019 and May 2020 were enrolled. Subclinical pocket infection was ruled out by physical inspection and laboratory parameters before the procedure. Pocket tissue specimens from the anterior and posterior pockets were obtained intraoperatively. A systematic histological analysis of capsular thickness, fibrous connective tissue, neovascularization, inflammation, and calcifications was performed. Results: Thirty patients (6 women, 20%) were enrolled. The mean capsular thickness was 0.8 ± 0.3 mm in the anterior wall and 1.1 ± 0.4 mm in the posterior wall. Subcapsular fibrosis was mild and multifocal in the anterior wall and moderate and focal in the posterior wall. Neovascularization was focal in most cases, and vessel remodeling mainly involved the tunica media. Chronic inflammation was usually mild and nongranulomatous, and in a quarter of cases, subacute exudative fibrous inflammation was detected in the posterior pocket wall. Conclusion: The CIED pocket is a histopathologically dynamic environment, given the coexistence of both a subacute foreign body response and fibrous tissue growth, implying continuous remodeling due to an injury-repair mechanism. Strategies to interact with foreign body response might minimize inflammatory pocket activity, especially device encapsulation by tight fibrous tissue, and possibly complications related to repeated CIED procedures

Unraveling the activation mechanism of olfactory receptors. Towards the future of structure odor relationships

Unraveling the activation mechanism of olfactory receptors. Towards the future of structure odor relationships. 14. Weurman flavour research symposiu

Molecular dynamics simulations reveal the active and inactive states of olfactory receptors

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