Neoadjuvant eribulin mesylate following anthracycline and taxane in triple negative breast cancer: Results from the HOPE study

Background Eribulin mesylate (E) is indicated for metastatic breast cancer patients previously treated with anthracycline and taxane. We argued that E could also benefit patients eligible for neoadjuvant chemotherapy. Methods Patients with primary triple negative breast cancer 2 cm received doxorubicin 60 mg/m2 and paclitaxel 200 mg/m2 x 4 cycles (AT) followed by E 1.4 mg/m2 x 4 cycles. Primary endpoint was pathological complete response (pCR) rate; secondary and explorative endpoints included clinical/metabolic response rates and safety, and biomarker analysis, respectively. Using a two-stage Simon design, 43 patients were to be included provided that 4 of 13 patients had achieved pCR in the first stage of the study. Results In stage I of the study 13 women were enrolled, median age 43 years, tumor size 2–5 cm in 9/13 (69%), positive nodal status in 8/13 (61%). Main grade 3 adverse event was neutropenia (related to AT and E in 4 and 2 cases, respectively). AT followed by E induced clinical complete + partial responses in 11/13 patients (85%), pCR in 3/13 (23%). Median measurements of maximum standardized uptake value (SUVmax) resulted 13, 3, and 1.9 at baseline, after AT and E, respectively. Complete metabolic response (CMR) occurred after AT and after E in 2 and 3 cases, respectively. Notably, 2 of the 5 (40%) patients with CMR achieved pCR at surgery. Immunostaining of paired pre-/post-treatment tumor specimens showed a reduction of β-catenin, CyclinD1, Zeb-1, and c-myc expression, in the absence of N-cadherin modulation. The study was interrupted at stage I due to the lack of the required patients with pCR. Conclusions Despite the early study closure, preoperative E following AT showed clinical and biological activity in triple negative breast cancer patients. Furthermore, the modulation of β-catenin pathway core proteins, supposedly outside the domain of epithelial–mesenchymal transition, claims for further investigation. Trial registration EU Clinical Trial Register, EudraCT number 2012-004956-12

Genetic and epigenetic characterization of a discordant kmt2a/aff1-rearranged infant monozygotic twin pair

The KMT2A/AFF1 rearrangement is associated with an unfavorable prognosis in infant acute lymphocytic leukemia (ALL). Discordant ALL in monozygotic twins is uncommon and represents an attractive resource to evaluate intrauterine environment–genetic interplay in ALL. Mutational and epigenetic profiles were characterized for a discordant KMT2A/AFF1-rearranged infant monozygotic twin pair and their parents, and they were compared to three independent KMT2A/AFF1-positive ALL infants, in which the DNA methylation and gene expression profiles were investigated. A de novo Q61H NRAS mutation was detected in the affected twin at diagnosis and backtracked in both twins at birth. The KMT2A/AFF1 rearrangement was absent at birth in both twins. Genetic analyses conducted at birth gave more insights into the timing of the mutation hit. We identified correlations between DNA methylation and gene expression changes for 32 genes in the three independent affected versus remitted patients. The strongest correlations were observed for the RAB32, PDK4, CXCL3, RANBP17, and MACROD2 genes. This epigenetic signature could be a putative target for the development of novel epigenetic-based therapies and could help in explaining the molecular mechanisms characterizing ALL infants with KMT2A/AFF1 fusions

SHBG levels in primary infertile men : A critical interpretation in clinical practice

Objective: We aimed to test the association between age, BMI and sex-hormone\u2013binding globulin (SHBG) in a homogenous cohort of white-European men presenting for primary couple\u2019s infertility. Design: Retrospective study. Methods: Data from 1547 infertile men were analysed. Health-significant comorbidities were scored with the Charlson comorbidity index (CCI). Fasting serum hormones were measured in every patient. Age was considered according to quartile groups (<33, 33-41, >41 years) and BMI as normal weight (18.5\u201324.9 kg/m2), overweight (25.0\u201329.9 kg/m2) and obesity (>30 kg/m2). Descriptive statistics and linear regression analysis tested the associations between age, BMI and SHBG. Results: Median SHBG levels increased across quartiles of age and decreased along with BMI increases (all P < 0.001). For each year increase in age, SHBG increased 0.32 nmol/L; conversely, for each unit increase in BMI, SHBG decreased by 1.1 nmol/L (all P < 0.001). SHBG levels decline with increasing BMI was greater than SHBG progressive increase with age. Overall, BMI explained 3.0 times more of the variability in SHBG than did ageing. At multivariate linear model, age and BMI were the most significant factors influencing SHBG concentration (all P < 0.001), after accounting for CCI, albumin levels and smoking status. Conclusions: We found a wide distribution of SHBG concentrations across age and BMI values in primary infertile men. The association between BMI and lowered SHBG levels seems to be greater than the association of ageing with increased SHBG

Pmca-generated prions from the olfactory mucosa of patients with fatal familial insomnia cause prion disease in mice

Background: Fatal Familial Insomnia (FFI) is a genetic prion disease caused by the D178N mutation in the prion protein gene (PRNP) in coupling phase with methionine at PRNP 129. In 2017, we have shown that the olfactory mucosa (OM) collected from FFI patients contained traces of PrPSc detectable by Protein Misfolding Cyclic Amplification (PMCA). Methods: In this work, we have challenged PMCA-generated products obtained from OM and brain homogenate of FFI patients in BvPrP-Tg407 transgenic mice expressing the bank vole prion protein to test their ability to induce prion pathology. Results: All inoculated mice developed mild spongiform changes, astroglial activation, and PrPSc deposition mainly affecting the thalamus. However, their neuropathological alterations were different from those found in the brain of BvPrP-Tg407 mice injected with raw FFI brain homogenate. Conclusions: Although with some experimental constraints, we show that PrPSc present in OM of FFI patients is potentially infectious. Funding: This work was supported in part by the Italian Ministry of Health (GR-2013-02355724 and Ricerca Corrente), MJFF, ALZ, Alzheimer’s Research UK and the Weston Brain Institute (BAND2015), and Euronanomed III (SPEEDY) to FM; by the Spanish Ministerio de Economía y Competitividad (grant AGL2016-78054-R [AEI/FEDER, UE]) to JMT and JCE; AM-M was supported by a fellowship from the INIA (FPI-SGIT-2015-02)

Multiple PDE5Is use as a marker of decreased overall men's health: A real-life study

Erectile dysfunction (ED) is considered a sentinel marker for poor general men's health status. Severe ED has been associated with poor response to phosphodiesterase type 5 inhibitors (PDE5Is) therapy. We sought to assess the association of multiple PDE5Is prescription with the overall patients' health status. Socio-demographic and clinical variables from 939 consecutive white-European, heterosexual, sexually-active men seeking medical help for ED at same tertiary-referral academic outpatient clinic were analyzed. Health-significant comorbidities were scored with the Charlson Comorbidity Index (CCI). Patients have been stratified into na\uefve and non-na\uefve according to their history of previous prescriptions of any PDE5I. Every patient completed the International Index of Erectile Function (IIEF) questionnaire. Logistic regression models tested the association between patients' baseline characteristics (thus including previous PDE5Is prescriptions) and the overall health status. Overall, 328 (35%) patients were non-na\uefve for PDE5Is. Of them, 172 (52%), 99 (30%), and 57 (17%) had been prescribed with 1, 2 or 3 different PDE5Is, respectively. Na\uefve and nonna\uefve patients did not differ in terms of age, BMI, baseline ED severity; conversely, nonna\uefve patients had a higher CCI score. At logistic MVA, the number of PDE5Is prescriptions emerged as an independent predictor of a higher burden of comorbidities regardless of ED severity; the higher the number of PDE5Is prescriptions, the higher the CCI score (OR 1.69, 2.49, and 2.90 for 1, 2 or 3 previous PDE5Is, respectively), after accounting for age, BMI, baseline ED severity and cigarette smoking. More than a third of patients seeking medical help for ED at a single tertiary-referral center were non-na\uefve for PDE5Is. The increasing number of previous prescriptions of PDE5Is emerged as a worrisome marker of a poorer overall men's health status regardless of ED severity

Perovskite solar cell resilience to fast neutrons

The high power-per-weight ratio displayed by metal-halide perovskite solar cells is a key advantage of these promising devices for applications that require low payload, such as in space and avionics. However, little is known about the effect of the outer space radiation environment on these devices. Here, we report the first in operando study on fast neutron irradiation of perovskite solar cells. We show the remarkable resilience of these devices against one of the most hazardous forms of radiation that can be found at flight altitude and in space. In particular, our results highlight a comparable in operando degradation pattern between light soaked and light + neutron irradiated devices. However, whereas light-induced degradation is fully reversible, fast neutrons lead to permanent effects likely originating from atomic displacement in the active material. We also propose that such irreversible worsening is alleviated by the formation of neutron-induced shallow traps, which act as dopants and contribute to the increase of open circuit voltage and the decrease of leakage current in light + neutron irradiated devices. The high radiation dose that perovskite-based solar cells can potentially withstand renders these devices highly appealing for space and avionic applications

Report drawn up on behalf of the Committee on Energy, Research and Technology on the development of advanced reactors, Part A: Motion for a resolution. Working Documents 1984-85, Document 1-224/84/A, 8 May 1984

Background Population/based studies about contact allergy are scarce. Objectives To obtain reliable estimates of the prevalence of contact allergy in the general population in Europe. Methods A cross-sectional study of a random sample from the general population, aged 18-74 years, in five different European countries (Sweden, the Netherlands, Germany, Italy and Portugal). In total, 12 377 subjects were interviewed and a random sample (n = 3119) patch tested to TRUE Test panels 1-3 and Fragrance Mix (FM) II, hydroxyisohexyl 3-cyclohexene carboxaldehyde (HICC) and sesquiterpene lactone mix. A positive patch test reaction is considered as contact allergy. Results In total, 27.0% [95% confidence interval (CI) 25.5-28.5] had at least one positive reaction to an allergen of the European baseline series, with a significantly higher prevalence in women than in men. The highest age-standardized prevalences (>= 1%) were found for nickel (14.5%, 95% CI 13.2-15.8), thiomersal (5.0%, 95% CI 4.2-5.8), cobalt (2.2%, 95% CI 1.7-2.7), FM II (1.9%, 95% CI 1.5-2.5), FM I (1.8%, 95% CI 1.4-2.3), HICC (1.4%, 95% CI 1.0-1.9), p-tert-butylphenol formaldehyde resin (1.3%, 95% CI 0.9-1.7) and para-phenylenediamine (1.0%, 95% CI 0.6-1.3). Only nickel and thiomersal showed a statistically significantly different prevalence for contact allergy among the different European populations. Subjects reporting contact dermatitis in their lifetime (age-standardized prevalence 15.1%, 95% CI 13.8-16.3) had an increased risk for contact allergy (odds ratio 1.9, 95% CI 1.5-2.5). The risk of having a contact allergy was not increased in those with atopic dermatitis (prevalence 7.6%, 95% CI 6.7-8.6; odds ratio 1.0, 95% CI 0.7-1.4). Conclusions Contact allergy to at least one allergen of the European baseline series was diagnosed in more than one-quarter of the general European population. Therefore measures to improve the primary prevention of contact allergy have to be enforced