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The shear strength characterization of bonded joints involving adherends with a remarkably different stiffness has a peculiar interest in industrial applications. This work proposes and investigates three innovative specimens (an axisymmetric annular, a tensile and a torsional one) purposely developed to manage dissimilar adherends bonded with adhesive in thin film. A Thick Adherend Shear Test specimen between rigid adherends is used for the assessment of the adhesive by itself. The work focuses on metal-elastomeric polyurethane bonded joints with a solventbased adhesive. All the tests are performed through an axial dynamometer, using a purposely developed fixture to convert the tensile load in a torque for the torsional specimen. The tensile and the torsional specimens provide the most reliable shear strength characterization.

The sodium-dependent multivitamin transporter (hSMVT) encoded by the SLC5A6 gene is required for the intestinal absorption of biotin, pantothenic acid and lipoate, three micronutrients essential for normal growth and development. Systemic deficiency of these elements, either occurring from nutritional causes or genetic defects, is associated with neurological disorders, growth delay, skin and hair changes, metabolic and immunological abnormalities. A few patients with biallelic variants of SLC5A6 have been reported, exhibiting a spectrum of neurological and systemic clinical features with variable severity. We describe three patients from a single family carrying a homozygous p.(Leu566Valfs*33) variant of SLC5A6 disrupting the frame of the C-terminal portion of the hSMVT. In these patients, we documented a severe disorder featuring developmental delay, sensory polyneuropathy, optic atrophy, recurrent infections, and repeated episodes of intestinal pseudo-obstruction. Two patients who did not receive multivitamin supplementation therapy died in early infancy. In a third patient, early supplementation of biotin and pantothenic acid stabilized the clinical picture changing the course of the disease. These findings extend genotype-phenotype correlations and show how a timely and lifelong multivitamin treatment may be crucial to reduce the risk of life-threatening events in patients with pathogenic variants of the SLC5A6 gene., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: circulating tumor DNA (ctDNA) is a source of tumor genetic material for EGFR testing in NSCLC. Real-word data about liquid biopsy (LB) clinical practice are lacking. The aim of the study was to describe the LB practice for EGFR detection in North Eastern Italy., Methods: we conducted a multi-regional survey on ctDNA testing practices in lung cancer patients., Results: Median time from blood collection to plasma separation was 50 min (20-120 min), median time from plasma extraction to ctDNA analysis was 24 h (30 min-5 days) and median turnaround time was 24 h (6 h-5 days). Four hundred and seventy five patients and 654 samples were tested. One hundred and ninety-two patients were tested at diagnosis, with 16% EGFR mutation rate. Among the 283 patients tested at disease progression, 35% were T790M+. Main differences in LB results between 2017 and 2018 were the number of LBs performed for each patient at disease progression (2.88 vs. 1.2, respectively) and the percentage of T790M+ patients (61% vs. 26%).

The evaluation of the isocitrate dehydrogenase (IDH) mutation status in the glioma decision-making process has diagnostic, prognostic and therapeutic implications. The aim of this study was to evaluate whether conventional magnetic resonance imaging (MRI) and apparent diffusion coefficient (ADC) can noninvasively predict the most common IDH mutational status (R132H) in GIII-astrocytomas and the overall survival (OS). Hence, twenty-two patients (9-F, 13-M) with a histological diagnosis of GIII-astrocytoma and evaluation of IDH-mutation status (12-wild type, 10-mutant) were retrospectively evaluated. Imaging studies were reviewed for the morphological feature and mean ADC values (ADCm). Statistics included a Fisher's exact test, Student's t -test, Spearman's Test and receiver operating characteristic analysis. A p ≤ 0.05 value was considered statistically significant for all the tests. A younger age and a frontal location were more likely related to mutational status. IDH-wild type (Wt) exhibited a slight enhancement ( p = 0.039). The ADCm values in IDH-mutant (Mut) patients were higher than those of IDH-Wt patients ( p < 0.0004). The value of ADC ≥ 0.99 × 10 -3 mm 2 /s emerged as a "cut-off" to differentiate the mutation state. In the overall group, a positive relationship between the ADCm values and OS was detected ( p = 0.003; r = 0.62). Adding quantitative measures of ADC values to conventional MR imaging could be used routinely as a noninvasive marker of specific molecular patterns.

Purpose: The EGFR (Epidermal Growth Factor Receptor) mutations may predict sensitivity and resistance to EGFR-TKIs (Tyrosine Kinases Inhibitors) in metastatic lung adenocarcinoma. The detection of these mutations is usually performed on tumor tissue samples. However, when a biopsy is not feasible or the amount of tissue is limited, circulating tumor DNA (ctDNA) may represent an alternative source for genotyping the tumor., Methods: In the first phase of the study, the liquid biopsy was performed in newly diagnosed metastatic lung adenocarcinoma patients with and without EGFR mutations to evaluate the concordance between EGFR mutational analysis on ctDNA by real time PCR and on tissue. In the second phase it was performed in EGFR positive patients progressing after first or second generation TKIs in order to detect the T790M mutation., Results: In the first phase, a 100% concordance between EGFR on ctDNA and tissue was revealed, leading to validation of the test. In the second phase, 44.8% of patients showed T790M positive result at liquid biopsy. Considering the re-biopsies performed in 31% of the cases, the overall positivity rate of T790M was 58.6%. Sensitivity and specificity were 76% and 75%, respectively. The median time to development of T790M mutation from the start of first line EGFR TKI was 244 days., Conclusions: Our experience confirms that liquid biopsy is a valid method to detect sensitizing and resistant EGFR mutations in patients with metastatic lung adenocarcinoma. Nevertheless, in the presence of negative ctDNA analysis, a rebiopsy should be performed whenever possible to confirm this result.

Background: Melanoma is highly curable in early stages but holds devastating consequences in advanced phases with a median survival of 6-10 months. Lungs are a common metastasis target, but despite this, limited data are available on the molecular status of pulmonary lesions., Materials and Methods: 25 patients with surgically resected melanoma lung metastases were screened for BRAF, NRAS, CKIT and EGFR alterations. The results were correlated with time to lung metastasis (TLM), relapse-free survival after metastasectomy (RFS) and overall survival (OS)., Results: BRAF or NRAS were mutated in 52% and 20% of cases while CKIT was unaffected. Chromosome 7 polysomy was detected in 47% of cases with 17.5% showing EGFR amplification and concomitant BRAF mutation. NRAS mutated patients developed LM within 5 yrs from primary melanoma with larger lesions compared with BRAF (mean diameter 3.3 ± 2.2cm vs 1.9 ± 1.1cm, p = 0.2). NRAS was also associated with a shorter median RFS and OS after metastasectomy. Moreover, Cox regression analysis revealed that NRAS mutation was the only predictive factor of shorter survival from primary melanoma (p = 0.039, OR = 5.5 (1.1-27.6))., Conclusions: Molecular characterization identifies advanced melanoma subgroups with distinct prognosis and therapeutic options. The presence of NRAS mutation was associated to a worse disease evolution.

The Hybrid Capture 2 (HC2) test targets 13 human papillomavirus (HPV) types. Here, cross-reactivity with non-HC2-targeted HPV types is described. We aimed to define the proportion of HC2-positive women who had negative results with HC2-targeted HPV types and estimate its determinants and impact on women's health management. The New Technologies for Cervical Cancer (NTCC) trial was followed in two predetermined phases. Women in the experimental arm were tested for the presence of HPV DNA by HC2 following a sample collection in PreservCyt (first phase) or Digene specimen transport medium (STM) (second phase). HPV genotyping was performed on DNA samples from HC2-positive women by PCR with GP5(+)/GP6(+) primers and reverse line blot (RLB) hybridization. Untyped samples were submitted to direct sequencing or restriction fragment length polymorphism. Multivariate logistic regression analysis estimated the adjusted odds ratios (ORs) between the presence of HC2-targeted types and age, viral load, and type of transport medium. Out of 2,920 HC2-positive samples, 2,310 (79.1%) were positive on RLB for HC2-targeted types, 396 were positive (13.6%) for only non-HC2-targeted types (mostly represented by HPV-53, HPV-66, and HPV-70), and in 214 (7.33%) samples, no HPV types were detected. The probability of detecting HC2-targeted types increased with increasing viral load expressed as the relative light unit/positive-control specimen ratio (RLU/PC) (OR for unitary increase of log RLU/PC, 1.35; 95% confidence interval [CI], 1.30 to 1.42) and with STM versus PreservCyt (OR, 1.56; 95% CI, 1.25 to 1.84). If only the samples containing HC2-targeted types tested positive, the positive predictive value (PPV) would have increased from 7.0% (95% CI, 6.1% to 8.0%) to 8.4% (95% CI, 7.3 to 9.6), although 4.9% (95% CI, 2.4% to 8.8%) of cervical intraepithelial neoplasia grade 2(+) (CIN2(+)) cases would have been missed. In conclusion, STM use and an increased cutoff would reduce the HC2 analytical false-positive rate and increase the positive predictive value for high-grade CIN. The gain in clinical sensitivity by detecting non-HC2-targeted HPV types is limited.

Purpose: KRAS mutations represent the main cause of resistance to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (MoAbs) in metastatic colorectal cancer (mCRC). We evaluated whether highly sensitive methods for KRAS investigation improve the accuracy of predictions of anti-EGFR MoAbs efficacy., Experimental Design: We retrospectively evaluated objective tumor responses in mCRC patients treated with cetuximab or panitumumab. KRAS codons 12 and 13 were examined by direct sequencing, MALDI-TOF MS, mutant-enriched PCR, and engineered mutant-enriched PCR, which have a sensitivity of 20%, 10%, 0.1%, and 0.1%, respectively. In addition, we analyzed KRAS codon 61, BRAF, and PIK3CA by direct sequencing and PTEN expression by immunohistochemistry., Results: In total, 111 patients were considered. Direct sequencing revealed mutations in codons 12 and 13 of KRAS in 43/111 patients (39%) and BRAF mutations in 9/111 (8%), with almost all of these occurring in nonresponder patients. Using highly sensitive methods, we identified up to 13 additional KRAS mutations compared with direct sequencing, all occurring in nonresponders. By analyzing PIK3CA and PTEN, we found that of these 13 patients, 7 did not show any additional alteration in the PI3K pathway., Conclusions: The application of highly sensitive methods for the detection of KRAS mutations significantly improves the identification of mCRC patients resistant to anti-EGFR MoAbs.