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The development of localized strains (shear banding) in soils near peak stress levels and the subsequent continued deformation within shear bands during observed softening render important issues such as critical state difficult to investigate. The determination and overall validity of critical state behavior in sand is of considerable importance, as it provides the basis both for failure criteria/postfailure behavior of many constitutive models and for stability analysis. A series of drained plane-strain experiments on sand specimens with detailed local analysis was carried out to investigate the evolution of stress state and void ratio, as well as the uniqueness of critical state. Persistent shear bands form at the peak effective stress ratio; subsequent strain softening behavior occurs in concert with localized deformation with the shear band. A unique critical stress state was found to exist for a given confining stress; however, the test results indicate that there is no unique relationship between void ratio and confining stress at the critical state.

Antibody-drug conjugates (ADCs) represent a novel and evolving class of antineoplastic agents, constituted by monoclonal antibody linked to biologically active drugs, delivering cytotoxic compounds at the tumor site, reducing the likelihood of systemic exposure and toxicity. They are generally well tolerated, nevertheless some predictable adverse reactions need careful monitoring and timely approach. These include neutropenia, nausea and vomiting, alopecia, diarrhea, left ventricular dysfunction, ILD/pneumonitis. The mechanisms leading to drug-associated toxicities are summarized, and prophylaxis protocols and appropriate management strategies are proposed, based on current literature. This review aims to collect the most updated evidence on toxicities potentially occurring during breast cancer treatment with approved or under clinical investigation (advanced stage) ADCs. A focus is dedicated to monitoring protocols and clinical management, aimed at preventing and/or promptly address relevant problems, in order to avoid premature discontinuation or improper dose reduction., Competing Interests: AV has received travel grants from Lilly, Novartis, Pierre Fabre, and Gilead. MP has received travel grants from Pfizer and Gilead. RC declares honoraria from Novartis, Lilly, Gilead, Seagen, Veracyte, Daichii Sankyo, Pierre-Fabre; she is advisory board member for Novartis, Lilly, Gilead, Seagen, Daichii Sankyo, Pierre-Fabre, Roche, Astra Zeneca, and MSD; she has received travel grants from Gilead, Lilly and Novartis. FP received honoraria for advisory boards, activities as a speaker, travel grants, research grants from AstraZeneca, Daichii Sankyo, Eisai, Lilly, Gilead, MSD, Novartis, Exact Sciences, Menarini, Pierre Fabre, Pfizer, Roche, and Seagen. He has received research funding from AstraZeneca, Eisai and Roche. MG is a consultant/advisory board member for AstraZeneca, Daichii Sankyo, Eisai, Gilead, Lilly, MSD, Novartis, Pfizer, and Seagen; he has received travel grants from AstraZeneca, Pfizer and research funding (to institution) from AstraZeneca. LDM is a consultant/advisory board member for Lilly, Novartis, Roche, Pfizer, Daiichi Sankyo, Exact science, Gilead, Pierre Fabre, Eisai, AstraZeneca, GSK, Seagen, and Agendia; she has received research support from Roche, Lilly, Seagen, Daiichi Sankyo and Novartis (to institution); she declares honoraria from Roche, Pfizer, Lilly, MSD, Seagen, Gilead, Pierre Fabre, Eisai, Ipsen, Exact science, AstraZeneca and Novartis; has received travel grants from Roche, Pfizer, Eisai, AstraZeneca, and Daiichi Sankyo. GA is a consultant/advisory board member for Roche, Lilly, AstraZeneca, Novartis, Seagen, Daiichi Sankyo, Eisai, and Gilead; she has received research support from AstraZeneca (to institution); declares honoraria from Roche, Pfizer, Lilly, Eisai, AstraZeneca, Gilead, Seagen, Viatris, Exact Sciences, Daiichi Sankyo, and Novartis; has received travel grants from Roche, Daiichi Sankyo, and Novartis. MDL is a consultant/advisory board member for Pfizer, AstraZeneca, Sanofi, Seagen, Novartis, Ipsen, Roche, Pierre Fabre, Daiichi Sankyo, and GSK; he declares honoraria from Lilly, Novartis, Seagen, Takeda, Roche, Daiichi Sankyo, Tomalab, Gilead, Genetic, Menarini, and Sophos; has received travel grants from Roche, AstraZeneca. FM is a consultant/advisory board member for Roche, Daiichi Sankyo, Seagen; he received honoraria from Roche, AstraZeneca, Daiichi Sankyo, Seagen Pierre Fabre, MSD, Novartis, and Pfizer; he has received travel grants from AstraZeneca. AD, FN, SP, and MV have no conflict of interest to declare., (© 2023 The Author(s).)

Introduction: Metastatic castration-resistant prostate cancer (mCRPC) is a deadly disease. Enzalutamide is an oral second-generation anti-androgen that is active in mCRPC. Circulating tumor cells (CTC) count correlates with overall survival (OS) in mCRPC, whereas detection of the androgen-receptor splice variant 7 (AR-V7) in CTC predicts poor response to oral second-generation anti-androgens. Also, loss of PTEN (phosphatase and tensin homolog) in CTC is a biomarker of poor prognosis in mCRPC., Patients and Methods: In this translational study, we employed flow cytometry to assess total, PTEN - , and AR-V7 + CTC count per 7.5 mL of whole blood in a prospective cohort of patients with mCRPC receiving enzalutamide., Results: CTCs were assessed in a total of 45 men with mCRPC at baseline and at 12 weeks. Overall, CTC, PTEN - CTC, and AR-V7 + CTC detection rate was high, at baseline, with 84.4%, 71.1%, and 51.1% of samples showing at least 1 cell/7.5-mL blood, respectively, and after 3 months, with 93.3%, 64.4%, and 77.7% of samples showing at least 1 cell/7.5-mL blood, respectively. Median radiographic progression-free survival (rPFS) and OS were 6 (95% confidence interval [CI], 5.6-9) and 14.3 (95% CI, 12.8-20.3) months, respectively. Median (interquartile range) total CTC count at baseline was 5 (3; 8), whereas median (interquartile range) PTEN - CTC count was 2 (0; 4) and median (interquartile range) AR-V7 + CTC count was 1 (0; 3). At baseline, ≥ 5 versus < 5 total CTC count was associated with worse rPFS (hazard ratio [HR], 2.35; 95% CI, 1.14-4.84; P= .021) and OS (HR, 3.08; 95% CI, 1.45-6.54; P = .003), whereas ≥ 2 versus < 2 PTEN - CTC count was associated with worse rPFS (HR, 3.96; 95% CI, 1.8-8.72; P= .001) and OS (HR, 2.36; 95% CI, 1.12-5; P= .025). Finally, ≥ 1 versus < 1 AR-V7 + CTC count was also associated with worse rPFS (HR, 5.05; 95% CI, 2.4-10.64; P< .001) and OS (HR, 2.25; 95% CI, 1.1-4.58; P= .026)., Conclusions: Despite multiple limitations, including the small sample size, our preliminary study suggests that assessment of CTC via flow cytometry may provide potentially useful prognostic and predictive information in advanced prostate cancer. Further studies are warranted. Micro-Abstract: In this study, men with metastatic castration-resistant prostate cancer, scheduled to start enzalutamide, were assessed for circulating tumor cell count and molecular characterization (total, PTEN - , and AR-V7 + circulating tumor cell count) by the use of flow cytometry. We found that flow cytometry could be used to enumerate circulating tumor cells, but also to assess molecular biomarkers on their surface., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Legionella spp. are widespread bacteria in aquatic environments with a growing impact on human health. Between the 61 species, Legionella pneumophila is the most prevalent in human diseases; on the contrary, Legionella non- pneumophila species are less detected in clinical diagnosis or during environmental surveillance due to their slow growth in culture and the absence of specific and rapid diagnostic/analytical tools. Reliable and rapid isolate identification is essential to estimate the source of infection, to undertake containment measures, and to determine clinical treatment. Matrix-assisted laser desorption ionization-time-of-flight mass spectrometry (MALDI-TOF MS), since its introduction into the routine diagnostics of laboratories, represents a widely accepted method for the identification of different bacteria species, described in a few studies on the Legionella clinical and environmental surveillance. The focus of this study was the improvement of MALDI-TOF MS on Legionella non- pneumophila species collected during Legionella nosocomial and community surveillance. Comparative analysis with cultural and mip -gene sequencing results was performed. Moreover, a phylogenetic analysis was carried out to estimate the correlations amongst isolates. MALDI-TOF MS achieved correct species-level identification for 45.0% of the isolates belonging to the Legionella anisa , Legionella rubrilucens , Legionella feeleii , and Legionella jordanis species, displaying a high concordance with the mip- gene sequencing results. In contrast, less reliable identification was found for the remaining 55.0% of the isolates, corresponding to the samples belonging to species not yet included in the database. The phylogenetic analysis showed relevant differences inside the species, regruped in three main clades; among the Legionella anisa clade, a subclade with a divergence of 3.3% from the main clade was observed. Moreover, one isolate, identified as Legionella quinlivanii , displayed a divergence of 3.8% from the corresponding reference strain. However, these findings require supplementary investigation. The results encourage the implementation of MALDI-TOF MS in routine diagnostics and environmental Legionella surveillance, as it displays a reliable and faster identification at the species level, as well as the potential to identify species that are not yet included in the database. Moreover, phylogenetic analysis is a relevant approach to correlate the isolates and to track their spread, especially in unconventional reservoirs, where Legionella prevention is still underestimated., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Pascale, Mazzotta, Salaris, Girolamini, Grottola, Simone, Cordovana, Bisognin, Dal Monte, Bucci Sabattini, Viggiani and Cristino.)

Palbociclib is a potent cyclin-dependent kinase (CDK)4/6 inhibitor that disrupts cell cycle progression and has been recently approved in combination with an aromatase inhibitor or fulvestrant as first- and second-line treatment in hormone receptor (HR) + , human epidermal growth factor receptor (HER)2 - metastatic breast cancer. There is evidence that palbociclib may reverse endocrine therapy resistance and that it may also be added to ongoing endocrine therapy beyond progression to obtain clinical benefit. The aim of the present study was to explore this possibility in 5 patients who received palbociclib + fulvestrant following disease progression while under treatment with fulvestrant alone. The median progression-free survival was not reached during a median follow-up of 25 months, and the most frequent best response was stable disease. Three patients remained under treatment on the last re-evaluation. All patients had highly endocrine-sensitive disease and had previously received fulvestrant for ≥12 months. The hypothesis that a selected subpopulation of patients with HR + /HER2 - metastatic breast cancer may benefit from the addition of palbociclib to ongoing endocrine therapy beyond disease progression merits further investigation., (Copyright: © Schettini et al.)

Purpose: Rates of progression of endometrial hyperplasia (EH) to endometrial cancer (EC) are highly variable. Among several prognostic markers, PTEN has been recommended by ESMO-ESGO-ESTRO to identify premalignant EH. However, its prognostic accuracy is unclear. Thus, we aimed to assess: (1) the association between PTEN loss in EH and risk of cancer, and (2) the prognostic accuracy of PTEN immunohistochemistry in EH., Methods: Electronic databases were searched from their inception to June 2018. All studies assessing PTEN immunohistochemistry in EH and the presence of EC on subsequent hysterectomy were included. Odds ratio (OR), sensitivity, specificity, positive and negative predictive value (PPV and NPV), positive and negative likelihood ratio (LR + and LR-) and area under the curve (AUC) on SROC curves were calculated with subgroup analysis (short/long-term; atypical/non-atypical EH)., Results: Nine retrospective studies assessing 933 EH were included. PTEN loss in EH was significantly associated with increased risk of EC (OR = 3.32, p = 0.001). The association was significant only on the short term ( < 1 year) (OR = 3.45, p = 0.002) and in atypical EH (OR = 1.89, p = 0.01). For overall analysis and short-term/atypical EH subgroup the prognostic accuracy was low, with sensitivity = 0.58 and 0.68, specificity = 0.60 and 0.48, VPp = 0.41 and 0.54, VPN = 0.75 and 0.63, LR +  = 1.80 and 1.37, LR - =  0.62 and 0.56, AUC = 0.687 and 0.721, respectively., Conclusion: PTEN loss in EH is a risk factor for EC, but is not reliable in predicting the risk of EC. In atypical EH, PTEN loss is associated with a risk of concurrent EC of over 50%. This information might integrate the patients' informed consent for the choice of treatment (conservative/hysterectomy), especially in borderline cases. In conservative approach, PTEN loss might suggest closer follow-up.

Legionella quantification in environmental samples is overestimated by qPCR. Combination with a viable dye, such as Propidium monoazide (PMA), could make qPCR (named then vPCR) very reliable. In this multicentre study 717 artificial water samples, spiked with fixed concentrations of Legionella and interfering bacterial flora, were analysed by qPCR, vPCR and culture and data were compared by statistical analysis. A heat-treatment at 55 °C for 10 minutes was also performed to obtain viable and not-viable bacteria. When data of vPCR were compared with those of culture and qPCR, statistical analysis showed significant differences (P < 0.001). However, although the heat-treatment caused an abatement of CFU/mL ≤1 to 1 log10 unit, the comparison between untreated and heat-treated samples analysed by vPCR highlighted non-significant differences (P > 0.05). Overall this study provided a good experimental reproducibility of vPCR but also highlighted limits of PMA in the discriminating capability of dead and live bacteria, making vPCR not completely reliable., (Copyright © 2016 Elsevier Inc. All rights reserved.)

We investigated whether molecular defects in the CYP21 gene were detectable in two common sex chromosome aberrations, the Turner and the Klinefelter syndromes. We found abnormal 17-hydroxyprogesterone levels after adrenal stimulation in 26/60 (43.3%) patients affected by these chromosome aberrations, as compared with only 11/68 (16.2%) normal controls (P=0.0014, odds ratio 4.0). Screening of the CYP21 gene identified a single Val281Leu missense mutation in exon 7 in 9/63 (14.3%) of the patients, all nine of whom were heterozygote carriers; the mutation frequency was significantly higher than in the general population (P=0.007, odds ratio=3.5). The hormonal and molecular data indicate that these common sex chromosome aberrations are associated with a remarkably high frequency of steroidogenic defects. It may be hypothesised that reduced levels of steroid 21-hydroxylase could confer a survival advantage, leading to a successful pregnancy.

Background: Homocysteine metabolism is often impaired in heart transplant recipients, and increased total homocysteine plasma levels may constitute a risk factor for the development of heart allograft vascular disease. Although 677C-->T transition in methylenetetrahydrofolate reductase (MTHFR) is associated with increased homocysteine levels in the general population, it is unclear whether MTHFR polymorphism influences homocysteine metabolism after heart transplant., Methods: Homocysteine, serum folate, renal function, concentrations of cyclosporine and its metabolites, and MTHFR genotype were determined in 57 heart transplant recipients (age, 55 +/- 11 yr; 21% women; time from transplant, 48 +/- 42 months)., Results: Forty nine percent of the study population presented with hyperhomocysteinemia. Homocysteine was 17.1 +/- 5.9 micromol/liter, 19.4 +/- 4.9 micromol/liter, and 26.3 +/- 14.2 micromol/liter for genotypes CC, CT, and TT, respectively (p = 0.028, Kruskal-Wallis test). At multivariate analysis, MTHFR genotype was independently associated with homocysteine (p = 0.005). When the study population was divided into 2 groups accordingly to serum folate levels (above/below the median value of 6.1 ng/ml), MTHFR genotype remained a significant predictor of homocysteine only in patients with low serum folate (p = 0.048)., Conclusions: This study demonstrates that hyperhomocysteinemia is frequent in heart transplant recipients and that the 677C-->T transition in the MTHFR gene independently and unfavorably influences homocysteine metabolism in this group of patients. Adequate folate intake may overcome genetic predisposition to hyperhomocysteinemia.

Objective: To evaluate by molecular typing the possible associations of HLA-DRB1, DQA1, and DQB1 alleles with biopsy proven giant cell arteritis (GCA) in a Mediterranean country, and to examine possible relationships between these alleles and GCA clinical subsets., Methods: Thirty-nine patients from the Reggio Emilia area diagnosed over a 12 year period with biopsy proven GCA were studied. The clinical findings at diagnosis and during the followup were evaluated through interviews and by reviewing the medical records. HLA-DRB1, DQA1, and DQB1 alleles were determined in the 39 patients and in 250 healthy controls from the same geographic area by polymerase chain reaction amplification using sequence-specific primers., Results: No associations were found between GCA and the shared epitope, the DRYF epitope, or the DRB1*04 or DQA1 alleles. The only significant association was with DQB1*0302 allele (p = 0.03, RR = 2.2). However, the association was weak and the significance was lost when corrected for the number of antigens tested. The frequencies of DQB1*0301 and 0302 in DR4 patients were not significantly different from those observed in DR4 positive controls. Significant associations were found between DRB1*04 allele and the presence of systemic signs and/or symptoms (p = 0.04, RR = 1.5) and between DRB1*07 allele and the male patients (p = 0.04, RR = 2.6)., Conclusion: Our data showed no associations of biopsy proven GCA with HLA-DRB1*04 and HLA-DRB1*01 alleles, rheumatoid epitope, or DRYF epitope. Discrepancies with other studies may be related to the different ethnic backgrounds of the populations studied and to differences in the referral patterns of patients with GCA.