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Industries, among them the aeronautics industry, have to justify the reliability of the structures they design. Static and modal analyzes are the classical methods to validate designs. Nowadays, these are not sufficient anymore, and the damage tolerance approaches, characterizing the severity of a flaw occurring in the designed assembly, are thenceforth commonly used. Various methods such as boundary element models or finite elements models (classical or extended formulation) can be applied. These methods may introduce conservatism into the model that may be an issue with respect to some of the design constraints (light-weighting, final cost...). Moreover, they are often computationally expensive. This paper proposes a methodology for the computation of sudden failure probability applied to industrial assemblies at a reasonable computational cost while keeping a similar level of accuracy considering the computed probabilities. To that purpose, two strategies are coupled. First, a sub-modeling strategy is set up. It allows to reduce the restitution time by considering separately all the critical zones. The critical areas are identified through a dedicated methodology based on the assessment of maximal principal stresses. For each of them, a surrogate model is built based on a limited number of numerical simulations. Even though this solution allows non negligible gain on the restitution time, a co- Kriging multi-fidelity approach is also applied. The surrogate model is built thanks to the combination of two sampling databases that are computed using XFEM simulations with different levels of refinement. Thanks to this methodology, a response with an equivalent level of accuracy is built-up. The failure probability is finally determined by running a large Monte-Carlo analysis based on the previously built surrogate models. The gains, limitations and perspectives to improve the current methodology are discussed. [ABSTRACT FROM AUTHOR]

The genetic abnormalities underlying hereditary non-polyposis colorectal cancer (HNPCC) are germline mutations in one of five DNA mismatch repair genes or in the TGFbetaRII gene. The aim of our study was to evaluate the significance of simple tests performed on tumours to select appropriate candidates for germline mutational analysis. We studied three groups of patients, HNPCC kindreds fulfilling the International Collaborative Group (ICG) criteria (n = 10), families in which at least one of the criteria was not satisfied (n = 7) and sporadic colorectal cancer (CRC) diagnosed before the age of 50 (n = 17). We searched for microsatellite instability (MSI), presence of hMSH2 and hMLH1 germline mutations, expression of hMSH2, hMLH1 and p53 proteins in tumoural tissue samples by immunostaining. Fifteen out of 17 (88%) of HNPCC and incomplete HNPCC cases were MSI and eight pathogenic germline mutations in hMSH2 or hMLH1 were detected in these two groups (53%). All the 17 early-onset sporadic cases were MSS and no germline mutations were detected among the seven investigated cases. Thirteen out of 15 (81%) familial cases were MSI and p53 protein-negative, whereas 13/14 (93%) sporadic cases were MSS and strongly p53 protein-positive. This extensive molecular investigation shows that simple tests such as MS study combined with hMSH2 and hMLH1 protein immunostaining performed on tumoural tissues may provide valuable information to distinguish between familial, and probably hereditary, and sporadic CRC cases. [ABSTRACT FROM AUTHOR]

Purpose: Alopecia is a common side-effect of chemotherapy and can be extremely distressing to patients. Scalp cooling can be used to reduce hair loss, but the optimal duration of cooling remains unclear. Our aim was to determine whether increasing the duration of scalp cooling improves hair preservation., Methods: Patients with HER2-negative, non-metastatic, breast cancer received scalp cooling during adjuvant chemotherapy: three cycles of epirubicin/cyclophosphamide (EC) followed by three cycles of paclitaxel. The patients were randomly assigned to two groups. Group A (n=18) wore a Paxman cooling cap during each infusion and for 30 min post-infusion while Group B (n=19) wore the cap from 30 min before to 2 h after each infusion. All patients were asked to complete a questionnaire recording hair loss/regrowth, adverse events, and quality of life. Success of treatment was defined as <50% hair loss., Results: The success rates after each of the three cycles did not differ significantly between the two groups (EC: Group A: 40%, Group B: 44%; paclitaxel: Group A: 50%, Group B: 36%; p>0.05). Hair regrowth was significantly higher in Group B at the 8-week follow-up, but not at the 6-month follow-up. Head discomfort affected more patients in Group B than in Group A during the first session (94% vs. 62%, respectively; p=0.039)., Conclusion: Long duration scalp cooling during chemotherapy might increase patients' discomfort and does not appear to improve hair preservation., (© 2024. The Author(s).)

Heterozygous missense mutations in coatomer protein subunit α, COPA, cause a syndrome overlapping clinically with type I IFN-mediated disease due to gain-of-function in STING, a key adaptor of IFN signaling. Recently, increased levels of IFN-stimulated genes (ISGs) were described in COPA syndrome. However, the link between COPA mutations and IFN signaling is unknown. We observed elevated levels of ISGs and IFN-α in blood of symptomatic COPA patients. In vitro, both overexpression of mutant COPA and silencing of COPA induced STING-dependent IFN signaling. We detected an interaction between COPA and STING, and mutant COPA was associated with an accumulation of ER-resident STING at the Golgi. Given the known role of the coatomer protein complex I, we speculate that loss of COPA function leads to enhanced type I IFN signaling due to a failure of Golgi-to-ER STING retrieval. These data highlight the importance of the ER-Golgi axis in the control of autoinflammation and inform therapeutic strategies in COPA syndrome., Competing Interests: Disclosures: M. Wislez reported personal fees from Boeringher Ingelheim, Roche, MSD, BMS, Astra Zeneca, and Amgen outside the submitted work. Y.J. Crow reported "other" from Biogen outside the submitted work. No other disclosures were reported., (© 2020 Lepelley et al.)

Simple, selective yet sensitive methods to quantify low-abundance bacterial biomarkers derived from complex samples are required in clinical, biological, and environmental applications. In this report, a new strategy to integrate sample pretreatment with chemical analysis is investigated using on-line preconcentration with chemical derivatization by CE and UV detection. Single-step enantioselective analysis of muramic acid (MA) and diaminopimelic acid (DAP) was achieved by CE via sample enrichment by dynamic pH junction with ortho-phthalaldehyde/N-acetyl-L-cysteine labeling directly in-capillary. The optimized method resulted in up to a 100-fold enhancement in concentration sensitivity compared to conventional off-line derivatization procedures. The method was also applied toward the detection of micromolar levels of MA and DAP excreted in the extracellular medium of Escherichia coli bacterial cell cultures. On-line preconcentration with chemical derivatization by CE represents a unique approach for conducting rapid, sensitive, and high-throughput analyses of other classes of amino acid and amino sugar metabolites with reduced sample handling, where the capillary functions simultaneously as a concentrator, microreactor, and chiral selector.

P73, a p53-homologue gene, has been studied for its possible role in head and neck squamous epithelium (HNSE) differentiation and carcinogenesis. P73 RNA and protein were analysed in 50 biopsies, including well- and moderately-differentiated carcinomas, and 21 matched normal adjacent tissues. P73 immunohistochemical analyses revealed intense p73 nuclear staining in basal and parabasal cells of normal squamous epithelium, in contrast with complete absence of staining in the more superficial cell layers. Moderately-differentiated carcinomas demonstrated homogeneous and diffuse staining in all tumour cells, while only basal cells were stained in well-differentiated carcinomas as in normal tissue. No correlation was observed between p73 and p53 protein expression. Immunostaining for p63, another p53-related protein previously described as being involved in HNSE morphogenesis and overexpressed in head and neck squamous cell carcinomas (HNSCC), was found to be similar to p73 labelling in carcinomas, but spread to the more differentiated layers in normal epithelium. Biallelic expression of p73 was found in tumours as well as in matched normal tissues. Comparison of p73 transcript levels between tumours and normal tissues showed decreased mRNA expression in 5/17 (30%) tumours independently of the differentiation status. Mutation and loss of heterozygosity analyses of the p73 gene revealed wild type status and no deletion. Our results strongly suggest that: (i) p73 is associated with homeostasis and control of differentiation of head and neck squamous epithelium probably in concert with p53 and p63; (ii) down-regulation of p73 expression could participate in HNSE carcinogenesis.

Our aim was to compare the prognostic value of c-erbB-2 gene amplification analyzed by Southern blot with that of protein (p185) over-expression measured by immunohistochemistry in 172 patients with operable breast cancer (BC). Amplification and p185 over-expression were found in 31 (18%) and 51 (30%) BCs, respectively. All but 1 of the tumors showed both amplification and over-expression, while 21 (12%) tumors displayed over-expression without amplification. The risk of death associated with c-erbB-2 gene amplification and p185 over-expression was evaluated by multivariate analysis, taking into account tumor size, histoprognostic grade, hormone receptors and axillary node status. During a mean follow-up of 9.5 (+/-2) years, node involvement (p < 0.001), c-erbB-2 gene amplification (p = 0.02) and negative hormone receptors (p = 0.02) were found to be independent prognostic indicators of the risk of death. Over-expression of p185 with no amplification was not correlated with this risk. When the risk of death associated with c-erbB-2 amplification was studied according to chemo- and hormone therapy, no significant difference was observed between subgroups of subjects. Amplification was also associated (p = 0.02) with the risk of multifocal distant metastases (i.e., metastases detected concomitantly in at least 2 sites) and, thus, with BC aggressiveness. These data show the importance of c-erbB-2 gene amplification in predicting the long-term outcome of patients and in selecting eligible patients for c-erbB-2-targeted therapies., (Copyright 2001 Wiley-Liss, Inc.)

Apoptosis is an important physiological process controlled by multiple genes, including c-myc, p53 and bcl-2, and its inhibition may lead to the development of human cancers. In this study, we analyzed expression of the c-myc gene using Northern blot and of the p53 and bcl-2 proteins by immuno-histochemistry in 175 breast tumor specimens obtained from patients with operable breast cancer. We evaluated the relation between expression of these 3 genes and (i) the main usual prognostic factors (tumor size, histo-prognostic grade, hormone receptors and number of positive nodes); (ii) the risk of death and relapse, taking into account these 4 factors, after a mean period of follow-up of 9.5 years (SD 2 years). Over-expression of c-myc, p53 and bcl-2 was observed in 35%, 23% and 63% of tumors, respectively. Over-expression of c-myc was strongly linked to the number of positive nodes (p = 0.0005). p53 protein expression was associated with both high-grade (p = 0.0001) and hormone receptor-negative (p = 0.0001) tumors. In contrast, bcl-2 protein over-expression was associated with the main favorable prognostic factors and, more particularly, with hormone receptor-positive tumors (p = 0.0001). Multivariate analysis, using the Cox model, showed that only 2 factors were independently linked to the risk of death: number of positive nodes, which increased the risk (p = 0.0001), and bcl-2 protein over-expression, which decreased the risk (p = 0.008). When bcl-2 over-expression was studied in relation to nodal status, hormone receptor status and chemo- and hormone therapy, no significant difference was observed between different subgroups of patients. bcl-2 expression was also associated with a significantly lower risk of distant metastasis (p = 0.04). In conclusion, bcl-2 expression characterizes a particular phenotype of breast cancer with a favorable prognosis, and it may therefore be used as a marker of long-term survival. Int. J. Cancer (Pred. Oncol.) 84:562-567, 1999., (Copyright 1999 Wiley-Liss, Inc.)

Mutation of the p53 tumor suppressor gene is the most commonly observed gene alteration in human cancers. In order to identify new prognostic factors and tumor aggressiveness in squamous cell head and neck carcinomas, we analyzed 50 node metastases and 28 primary tumors including 13 matched specimens for p53 alterations. Mutations were found in 54 (69%) tumors, 76% of which were missense, 9% were nonsense and 15% were microdeletions or microinsertions. Twenty-five mutations were transitions mostly G-->A (40%) and 20 were transversions mostly G-->T (25%) thus confirming the role of tobacco carcinogens in the induction of these mutations. For eight patients mutations were observed in matched primary tumors and metastases, indicating clonal dissemination of tumor cells in most of these carcinomas. Furthermore the incidence of mutations was not different in primary tumors and node metastases indicating that this gene alteration was not related to the metastatic dissemination. No correlation was found between mutation and clinical parameters, the 8-year survival rates were not different (log rank test: P = 0.49) in patients with and without mutation. There was a good correlation between p53 mutation and protein overexpression (Fisher's exact test: P < 10(-4). Interestingly, immunostaining was also observed in basal cells from normal mucosa and in early lesions adjacent to the primary tumor in 11/15 specimens irrespective of the presence of mutation in the corresponding tumors. p53 protein overexpression may therefore constitute a biomarker for early stages of carcinogenesis of the head and neck epithelium.

We have analysed 78 head and neck carcinomas (50 node metastases and 28 primary tumors including 13 matched specimens) in 65 patients for p53 alterations. Mutations were found in 54 (69%) tumors. Of the 53 mutations within exons, 40 (76%) were missense, five (9%) nonsense and eight (15%) microdeletions or microinsertions. Twenty-five (47%) mutations were transitions mostly G-->A (40%) and 20 (38%) were transversions, mostly G-->T (25%), thus confirming the role of tobacco carcinogens in the induction of these mutations. The incidence of mutations was not different in primary tumors (68%) and node metastases (70%) indicating that this gene alteration was not related to the metastatic dissemination. For eight patients, mutations were observed in matched primary tumors and metastases, indicating clonal dissemination of tumor cells in most of these carcinomas. There was a good correlation between mutations and protein overexpression (Fisher's exact test P < 10(-4). Immunostaining was also observed in basal cells from normal epithelium and in early lesions adjacent to the primary tumor in 11/15 (73%) specimens irrespective of the presence of mutation in the corresponding tumors. These data confirm that p53 overexpression is an early event in the multistep process of epithelial cell carcinogenesis. Loss of heterozygosity for the TP53 locus was detected in 54% of tumors but no association was found with mutation (Fisher's exact test P = 0.14). No mdm-2 amplification was detected in any tumors. No correlation was found between mutation and clinical parameters, the 5-year survival rates were not different (log rank test P = 0.39) in patients with and without mutation. In conclusion, we have shown that p53 gene mutations and deletions and protein overexpression are frequent in the most aggressive head and neck carcinomas but are not associated with disease progression. The presence of protein in normal mucosa and in non-invasive lesions may constitute a biomarker for early stages of carcinogenesis.

OEsophageal manometry, acid perfusion test and recording of oesophageal pH after gastric filling with 300 ml HCI were carried out in 55 patients with at least one symptom of gastro-oesophageal reflux (GER). None of the patients complained of dysphagia or had a history of haemorrage, but 19 had oesophagitis on endoscopy. pH probe recordings showed evidence of GER in 72% of the patients, and acid perfusion was painful in 44%. The resting lower oesophageal sphincter pressure was below normal in 20%. Thirty-eight p. cent had peristaltic disorders associated with significantly decreased sphincter pressure. In this category of patients, oesophageal pH recordings constitute the best method for diagnosing GER. Apositive acid perfusion test indicates that the clinical symptoms are due to abnormal sensitivity of the mucosa to hydrogen ions. Manometry is useful for a study of motor disorders resulting from GER, but insufficient to determine whether or not GER is present.