Prediction of intervertebral disc mechanical response to axial load using isotropic and fiber reinforced FE models

International audienc

Anévrysme de l’aorte ascendante associé à une insuffisance aortique massive: complication rare et grave de la maladie de Behçet

L'atteinte artérielle au cours de la maladie de Behçet survient chez 2 à 12% des patients et se traduit par des lésions oblitérantes et/ou anévrysmales prédominant sur les gros troncs. Les complications cardiaques sont plus rares (1 à 6%) touchant les trois tuniques. En revanche, les anévrysmes de l'aorte ascendante associés à une insuffisance aortique restent une complication très rare de la maladie de Behçet. Nous rapportons l'observation d'un jeune patient de 35ans suivie pour une maladie de Behçet compliquée d'un anévrysme de l'aorte ascendante associé à une régurgitation aortique massive. Le diagnostic a été posé sur les données cliniques radiologiques de l'échocardiographie et de la tomodensitométrie puis confirmé à l'examen histologique de la pièce. Le traitement était chirurgical et a consisté en un remplacement total de la racine de l'aorte à coeur ouvert selon la technique de Bentall afin d'éviter le risque de rupture ou de dissection. L'évolution à 18 mois de l'intervention était favorable. Le traitement médical associant la corticothérapie et les immunosuppresseurs est la règle en postopératoire pour éviter les récidives

Limits to sustained energy intake. XXII. Reproductive performance of two selected mouse lines with different thermal conductance

Abstract Maximal sustained energy intake (SusEI) appears limited, but the factors imposing the limit are disputed. We studied reproductive performance in two lines of mice selected for high and low food intake (MH and ML, respectively), and known to have large differences in thermal conductance (29% higher in the MH line at 21°C). When these mice raised their natural litters, their metabolisable energy intake significantly increased over the first 13 days of lactation and then reached a plateau. At peak lactation, MH mice assimilated on average 45.3 % more energy than ML mice (222.9±7.1 and 153.4±12.5 kJ day-1, N=49 and 24, respectively). Moreover, MH mice exported on average 62.3 kJ day-1 more energy as milk than ML mice (118.9±5.3 and 56.6±5.4 kJ day-1, N= subset of 32 and 21, respectively). The elevated milk production of MH mice enabled them to wean litters (65.2±2.1 g) that were on average 50.2% heavier than litters produced by ML mothers (43.4±3.0 g), and pups that were on average 27.2% heavier (9.9±0.2 and 7.8±0.2 g, respectively). Lactating mice in both lines had significantly longer and heavier guts compared to non-reproductive mice. However, inconsistent with the central limit hypothesis, the ML mice had significantly longer and heavier intestines than MH mice. An experiment where the mice raised litters of the opposing line demonstrated that lactation performance was not limited by offspring growth capacity. Our findings are consistent with the idea that the SusEI at peak lactation is constrained by the capacity of the mothers to dissipate body heat.</jats:p

Selective Induction of Cell Death in Melanoma Cell Lines through Targeting of Mcl-1 and A1

Melanoma is an often fatal form of skin cancer which is remarkably resistant against radio- and chemotherapy. Even new strategies that target RAS/RAF signaling and display unprecedented efficacy are characterized by resistance mechanisms. The targeting of survival pathways would be an attractive alternative strategy, if tumor-specific cell death can be achieved. Bcl-2 proteins play a central role in regulating survival of tumor cells. In this study, we systematically investigated the relevance of antiapoptotic Bcl-2 proteins, i.e., Bcl-2, Bcl-xL, Bcl-w, Mcl-1, and A1, in melanoma cell lines and non-malignant cells using RNAi. We found that melanoma cells required the presence of specific antiapoptotic Bcl-2 proteins: Inhibition of Mcl-1 and A1 strongly induced cell death in some melanoma cell lines, whereas non-malignant cells, i.e., primary human fibroblasts or keratinocytes were not affected. This specific sensitivity of melanoma cells was further enhanced by the combined inhibition of Mcl-1 and A1 and resulted in 60% to 80% cell death in all melanoma cell lines tested. This treatment was successfully combined with chemotherapy, which killed a substantial proportion of cells that survived Mcl-1 and A1 inhibition. Together, these results identify antiapoptotic proteins on which specifically melanoma cells rely on and, thus, provide a basis for the development of new Bcl-2 protein-targeting therapies

Small interfering RNA targeting mcl-1 enhances proteasome inhibitor-induced apoptosis in various solid malignant tumors

<p>Abstract</p> <p>Background</p> <p>Targeting the ubiquitin-proteasome pathway is a promising approach for anticancer strategies. Recently, we found Bik accumulation in cancer cell lines after they were treated with bortezomib. However, recent evidence indicates that proteasome inhibitors may also induce the accumulation of anti-apoptotic Bcl-2 family members. The current study was designed to analyze the levels of several anti-apoptotic members of Bcl-2 family in different human cancer cell lines after they were treated with proteasome inhibitors.</p> <p>Methods</p> <p>Different human cancer cell lines were treated with proteasome inhibitors. Western blot were used to investigate the expression of Mcl-1 and activation of mitochondrial apoptotic signaling. Cell viability was investigated using SRB assay, and induction of apoptosis was measured using flow cytometry.</p> <p>Results</p> <p>We found elevated Mcl-1 level in human colon cancer cell lines DLD1, LOVO, SW620, and HCT116; human ovarian cancer cell line SKOV3; and human lung cancer cell line H1299, but not in human breast cancer cell line MCF7 after they were treated with bortezomib. This dramatic Mcl-1 accumulation was also observed when cells were treated with other two proteasome inhibitors, MG132 and calpain inhibitor I (ALLN). Moreover, our results showed Mcl-1 accumulation was caused by stabilization of the protein against degradation. Reducing Mcl-1 accumulation by Mcl-1 siRNA reduced Mcl-1 accumulation and enhanced proteasome inhibitor-induced cell death and apoptosis, as evidenced by the increased cleavage of caspase-9, caspase-3, and poly (ADP-ribose) polymerase.</p> <p>Conclusions</p> <p>Our results showed that it was not only Bik but also Mcl-1 accumulation during the treatment of proteasome inhibitors, and combining proteasome inhibitors with Mcl-1 siRNA would enhance the ultimate anticancer effect suggesting this combination might be a more effective strategy for cancer therapy.</p

Uncoupling of the LKB1-AMPKα Energy Sensor Pathway by Growth Factors and Oncogenic BRAFV600E

BACKGROUND: Understanding the biochemical mechanisms contributing to melanoma development and progression is critical for therapeutical intervention. LKB1 is a multi-task Ser/Thr kinase that phosphorylates AMPK controlling cell growth and apoptosis under metabolic stress conditions. Additionally, LKB1(Ser428) becomes phosphorylated in a RAS-Erk1/2-p90(RSK) pathway dependent manner. However, the connection between the RAS pathway and LKB1 is mostly unknown. METHODOLOGY/PRINCIPAL FINDINGS: Using the UV induced HGF transgenic mouse melanoma model to investigate the interplay among HGF signaling, RAS pathway and PI3K pathway in melanoma, we identified LKB1 as a protein directly modified by HGF induced signaling. A variety of molecular techniques and tissue culture revealed that LKB1(Ser428) (Ser431 in the mouse) is constitutively phosphorylated in BRAF(V600E) mutant melanoma cell lines and spontaneous mouse tumors with high RAS pathway activity. Interestingly, BRAF(V600E) mutant melanoma cells showed a very limited response to metabolic stress mediated by the LKB1-AMPK-mTOR pathway. Here we show for the first time that RAS pathway activation including BRAF(V600E) mutation promotes the uncoupling of AMPK from LKB1 by a mechanism that appears to be independent of LKB1(Ser428) phosphorylation. Notably, the inhibition of the RAS pathway in BRAF(V600E) mutant melanoma cells recovered the complex formation and rescued the LKB1-AMPKalpha metabolic stress-induced response, increasing apoptosis in cooperation with the pro-apoptotic proteins Bad and Bim, and the down-regulation of Mcl-1. CONCLUSIONS/SIGNIFICANCE: These data demonstrate that growth factor treatment and in particular oncogenic BRAF(V600E) induces the uncoupling of LKB1-AMPKalpha complexes providing at the same time a possible mechanism in cell proliferation that engages cell growth and cell division in response to mitogenic stimuli and resistance to low energy conditions in tumor cells. Importantly, this mechanism reveals a new level for therapeutical intervention particularly relevant in tumors harboring a deregulated RAS-Erk1/2 pathway

Explainable Vision Transformers and Radiomics for COVID-19 Detection in Chest X-rays

The rapid spread of COVID-19 across the globe since its emergence has pushed many countries&rsquo; healthcare systems to the verge of collapse. To restrict the spread of the disease and lessen the ongoing cost on the healthcare system, it is critical to appropriately identify COVID-19-positive individuals and isolate them as soon as possible. The primary COVID-19 screening test, RT-PCR, although accurate and reliable, has a long turn-around time. More recently, various researchers have demonstrated the use of deep learning approaches on chest X-ray (CXR) for COVID-19 detection. However, existing Deep Convolutional Neural Network (CNN) methods fail to capture the global context due to their inherent image-specific inductive bias. In this article, we investigated the use of vision transformers (ViT) for detecting COVID-19 in Chest X-ray (CXR) images. Several ViT models were fine-tuned for the multiclass classification problem (COVID-19, Pneumonia and Normal cases). A dataset consisting of 7598 COVID-19 CXR images, 8552 CXR for healthy patients and 5674 for Pneumonia CXR were used. The obtained results achieved high performance with an Area Under Curve (AUC) of 0.99 for multi-class classification (COVID-19 vs. Other Pneumonia vs. normal). The sensitivity of the COVID-19 class achieved 0.99. We demonstrated that the obtained results outperformed comparable state-of-the-art models for detecting COVID-19 on CXR images using CNN architectures. The attention map for the proposed model showed that our model is able to efficiently identify the signs of COVID-19