ANKRd44 gene silencing: a putative role in trastuzumab resistance in HER2-like breast cancer

Trastuzumab is an effective therapeutic treatment for Her2-like breast cancer; despite this most of these tumors develop resistance to therapy due to specific gene mutations or alterations in gene expression. Understanding the mechanisms of resistance to Trastuzumab could be a useful tool in order to identify combinations of drugs that elude resistance and allow a better response for the treated patients. Twelve primary biopsies of Her2+/hormone receptor negative (ER-/PgR-) breast cancer patients were selected based on the specific response to neoadjuvant therapy with Trastuzumab and their whole exome was sequenced leading to the identification of 18 informative gene mutations that discriminate patients selectively based on response to treatment. Among these genes, we focused on the study of the ANKRD44 gene to understand its role in the mechanism of resistance to Trastuzumab. The ANKRD44 gene was silenced in Her2-like breast cancer cell line (BT474), obtaining a partially Trastuzumab-resistant breast cancer cell line that constitutively activates the NF-kb protein via the TAK1/AKT pathway. Following this activation an increase in the level of glycolysis in resistant cells is promoted, also confirmed by the up-regulation of the LDHB protein and by an increased TROP2 protein expression, found generally associated with aggressive tumors. These results allow us to consider the ANKRD44 gene as a potential gene involved in Trastuzumab resistance

The impact of immediate breast reconstruction on the time to delivery of adjuvant therapy: the iBRA-2 study

Background: Immediate breast reconstruction (IBR) is routinely offered to improve quality-of-life for women requiring mastectomy, but there are concerns that more complex surgery may delay adjuvant oncological treatments and compromise long-term outcomes. High-quality evidence is lacking. The iBRA-2 study aimed to investigate the impact of IBR on time to adjuvant therapy. Methods: Consecutive women undergoing mastectomy ± IBR for breast cancer July–December, 2016 were included. Patient demographics, operative, oncological and complication data were collected. Time from last definitive cancer surgery to first adjuvant treatment for patients undergoing mastectomy ± IBR were compared and risk factors associated with delays explored. Results: A total of 2540 patients were recruited from 76 centres; 1008 (39.7%) underwent IBR (implant-only [n = 675, 26.6%]; pedicled flaps [n = 105,4.1%] and free-flaps [n = 228, 8.9%]). Complications requiring re-admission or re-operation were significantly more common in patients undergoing IBR than those receiving mastectomy. Adjuvant chemotherapy or radiotherapy was required by 1235 (48.6%) patients. No clinically significant differences were seen in time to adjuvant therapy between patient groups but major complications irrespective of surgery received were significantly associated with treatment delays. Conclusions: IBR does not result in clinically significant delays to adjuvant therapy, but post-operative complications are associated with treatment delays. Strategies to minimise complications, including careful patient selection, are required to improve outcomes for patients

Effect of fillers and their fractional voids on fundamental fracture properties of asphalt mixtures and mastics

A laboratory investigation was performed to evaluate the influence of filler type and Rigden fractional voids on fundamental fracture limits of asphalt mixtures and mastics. Fracture properties of 14 different asphalt mixtures and mastics composed by the combination of 7 different fillers and 2 asphalt binders were evaluated using: a visco-elastic fracture mechanics-based crack growth law for mixtures; the Bending Beam rheometer for mastics at low temperatures and a Modified Direct Tension Test for mastics at intermediate temperatures. A Digital Image Correlation System was employed to detect strain distribution and damage evolution in mastics. Experimental results indicate that the filler type and Rigden fractional voids affect the fracture limits and the definition of strain distribution and damage evolution of both mixtures and mastics, while other properties result more dependent on the physio-chemical interaction between filler and asphalt binder

Mechanical influence of mineral fillers on asphalt mixture cracking behaviourAsphalt Pavements

The role of asphalt modifiers and/or modified fillers on the cracking behaviour of asphalt mixtures is extremely complex and has not been fully explained. To characterize the mechanical influence of fillers on asphalt mixture cracking behaviour it is essential to assess the viscoelastic properties of the mastic. Accurate description of strain evolution and distribution in mastics is essential for revealing significant information on mixtures macroscopic behaviour. In this study, 16 different mastics composed by the combination of four different fillers and four asphalt binders, were evaluated on the basis of test results and their mechanical analyses. The Dynamic Shear Rheometer (DSR) and the Bending Beam Rheometer (BBR) were used to characterize the rheological properties of the different mastics. Their cracking behaviour was investigated using a Modified Direct Tension Test (MDTT). Strain localization and damage distribution were observed using a completely redesigned in-house developed Digital Image Correlation System (DIC) capable of accurately capturing localized or non-uniform stress distributions in asphalt materials. The role of fillers in cracking resistance was quantified, and induced mechanisms due to filler addition were investigated. The effect of hydrated lime was further discussed by comparing test results from hydrated lime filler and test results from limestone and clay fillers

Should attention be paid to the cone depth in the fully visible transformation zone? Retrospective analysis of 517 patients with cervical intraepithelial neoplasia grade 3

Objective: The predictors of positive endocervical margin (EM) and a cone-depth cutoff value are not established in the fully visible transformation zone (TZ). The present study aimed to assess the independent variables associated with positive EM in women with high-grade cervical intraepithelial neoplasia (CIN) and fully visible TZ. Methods: The current investigation was a retrospective study including women with fully visible TZ and CIN 3 cone histology between 2014 and 2019. The sample was divided into women with positive versus those with negative EM. Univariate and multivariate analyses were performed. Finally, receiver operating characteristic curve analysis was also used. Results: A total of 123 of 517 women (23.8%) showed positive EM at conization. Multivariate analysis found a positive association with type 2 TZ (odds ratio [OR], 2.17 [95% confidence interval (CI), 1.19-3.94]) and lesion extension ≥2 cervical quadrants (OR, 35.57 [95% CI, 17.96-70.45]). Cone depth was inversely related to positive EM (OR, 0.71 [95% CI, 0.63-0.80]). In women with type 2 TZ and lesion extension ≥2 cervical quadrants, the cutoff value was achieved at 8-mm cone depth (area under the curve, 0.79 [95% CI, 0.67-0.90]). Conclusion: In women with high-grade CIN and fully visible TZ undergoing conization, the lesion extension and the TZ subtype (1 or 2) should be considered. A no less than 9-mm cone depth provided a fair predictive value in achieving free EM