Association of low-penetrance alleles with male breast cancer risk and clinicopathological characteristics: results from a multicenter study in Italy.

It is well-known that male breast cancer (MBC) susceptibility is mainly due to high-penetrance BRCA1/2 mutations. Here, we investigated whether common low-penetrance breast cancer (BC) susceptibility alleles may influence MBC risk in Italian population and whether variant alleles may be associated with specific clinicopathological features of MBCs. In the frame of the Italian Multicenter Study on MBC, we genotyped 413 MBCs and 745 age-matched male controls at 9 SNPs annotating known BC susceptibility loci. By multivariate logistic regression models, we found a significant increased MBC risk for 3 SNPs, in particular, with codominant models, for rs2046210/ESR1 (OR = 1.71; 95 % CI: 1.43-2.05; p = 0.0001), rs3803662/TOX3 (OR = 1.59; 95 % CI: 1.32-1.92; p = 0.0001), and rs2981582/FGFR2 (OR = 1.26; 95 % CI: 1.05-1.50; p = 0.013). Furthermore, we showed that the prevalence of the risk genotypes of ESR1 tended to be higher in ER- tumors (p = 0.062). In a case-case multivariate analysis, a statistically significant association between ESR1 and ER- tumors was found (OR = 1.88; 95 % CI: 1.03-3.49; p = 0.039). Overall, our data, based on a large and well-characterized MBC series, support the hypothesis that common low-penetrance BC susceptibility alleles play a role in MBC susceptibility and, interestingly, indicate that ESR1 is associated with a distinct tumor subtype defined by ER-negative status.

Corrigendum to "Circulating Cancer Stem Cell-Derived Extracellular Vesicles as a Novel Biomarker for Clinical Outcome Evaluation".

[This corrects the article DOI: 10.1155/2019/5879616.].

Application of a chemiluminescence immunoassay system and GC/MS for toxicological investigations on skeletonized human remains.

Hair, larvae and cardiac muscle, the only biological samples present on a skeletonized human body found in a rural area, were used for forensic toxicological analyses in order to determine possible causes of death. Since no information about the victim or the circumstances of death was available (except for the place where the corpse was found, known to be a gathering place for drug addicts), the first approach for the analysis of non-conventional matrices involved the screening of different classes of active principles, using a chemiluminescence-based screening assay designed for whole blood. The immunoassay test results showed positivity to amphetamines, cocaine and opiates on water/methanol extract from cardiac tissue, larvae and hair samples. Gas chromatography-mass spectrometry (GC/MS) analyses confirmed the immunoassay results, except for amphetamines. The minimal sample preparation (hydration and extraction in an ultrasonic bath), the reduced sample volume required for the analyses, together with the correctness of results as confirmed by GC/MS, showed the suitability of the screening test for forensic applications on non-conventional matrices. Quantitative analyses in GC/MS allowed the cause of death to be ascertained on the basis of the ratio between parent drugs and metabolites.

Circulating Cancer Stem Cell-Derived Extracellular Vesicles as a Novel Biomarker for Clinical Outcome Evaluation.

The recent introduction of the "precision medicine" concept in oncology pushed cancer research to focus on dynamic measurable biomarkers able to predict responses to novel anticancer therapies in order to improve clinical outcomes. Recently, the involvement of extracellular vesicles (EVs) in cancer pathophysiology has been described, and given their release from all cell types under specific stimuli, EVs have also been proposed as potential biomarkers in cancer. Among the techniques used to study EVs, flow cytometry has a high clinical potential. Here, we have applied a recently developed and simplified flow cytometry method for circulating EV enumeration, subtyping, and isolation from a large cohort of metastatic and locally advanced nonhaematological cancer patients (N = 106); samples from gender- and age-matched healthy volunteers were also analysed. A large spectrum of cancer-related markers was used to analyse differences in terms of peripheral blood circulating EV phenotypes between patients and healthy volunteers, as well as their correlation to clinical outcomes. Finally, EVs from patients and controls were isolated by fluorescence-activated cell sorting, and their protein cargoes were analysed by proteomics. Results demonstrated that EV counts were significantly higher in cancer patients than in healthy volunteers, as previously reported. More interestingly, results also demonstrated that cancer patients presented higher concentrations of circulating CD31+ endothelial-derived and tumour cancer stem cell-derived CD133 + CD326- EVs, when compared to healthy volunteers. Furthermore, higher levels of CD133 + CD326- EVs showed a significant correlation with a poor overall survival. Additionally, proteomics analysis of EV cargoes demonstrated disparities in terms of protein content and function between circulating EVs in cancer patients and healthy controls. Overall, our data strongly suggest that blood circulating cancer stem cell-derived EVs may have a role as a diagnostic and prognostic biomarker in cancer.

Physical Activity Among Organ Recipients: Data Collected From the Latin American Transplant Games.

BACKGROUND: Cardiovascular complications after transplantation are an important cause of non-transplant-related deaths. Depression and anxiety are not unusual among organ recipients. Physical activity reduces cardiovascular risk and promotes a sensation of well-being. The aims of the study were to examine how exercise affects psychological well-being sensation in organ recipients and to describe the physician's role in promoting and controlling safe sport training in transplanted patients. METHODS: A descriptive study was conducted. A questionnaire was answered by participants of the "2012 Latin American Transplant Games." RESULTS: One hundred sixty-six organ recipients completed the questionnaire. Eleven percent heard about the transplant games from a physician. Seventy percent had not received a proper medical pre-competitive evaluation. Only 39% trained in a supervised manner and 53% had experienced some kind of sport-related injury. Self-perception of global health was reported as excellent by 19.75%, very good by 43.95%, good by 30.67%, and regular or poor by 5.73%. An excellent or very good health perception was reported by 47.8% of those who practiced only one kind of sport versus 71.5% of those who practiced more than one sport and by 89.6% of those who performed isometric activity versus 59.3% of those who did not perform isometric activity. CONCLUSIONS: Diversity of practiced sports and isometric activity are associated with a better self-reported health condition. Most participants had not received a proper medical pre-competitive evaluation; they trained in an unsupervised manner, and injuries were common.

Interaction of HMG14 with chromatin.

Neutron scattering has been used to study the interaction of HMG14 with chromatin. Chromatin depleted of H1/H5 was reconstituted separately with histones H1 and H5, and complexed with HMG14. We have also studied the conformation of complexes formed by the binding of HMG14 to nucleosome dimers without linker DNA. Our data on the binding of HMG14 to linkerless nucleosome dimers argue against a significant change in the exit and entry angles of nucleosomal core DNA. Data on the condensation of chromatin into a higher-order structure suggest that there is no dramatic difference between the roles of H1 and H5 in their influence on HMG14 complex formation. However, there is a decrease of about 25% in the mass per unit length of chromatin fibers on HMG14 binding, which is not accompanied by a change in the fiber repeat distance. This is evidence that there are fewer nucleosomes per repeat in HMG14 containing chromatin fibers than in normal chromatin. Alteration of chromatin structure in this manner may be part of the role of HMG14 in actively transcribed chromatin.

Reconstitution of chromatin higher-order structure from histone H5 and depleted chromatin.

Reconstitution of the 30 nm filament of chromatin from pure histone H5 and chromatin depleted of H1 and H5 has been studied using small-angle neutron-scattering. We find that depleted, or stripped, chromatin is saturated by H5 at the same stoichiometry as that of linker histone in native chromatin. The structure and condensation behavior of fully reconstituted chromatin is indistinguishable from that of native chromatin. Both native and reconstituted chromatin condense continuously as a function of salt concentration, to reach a limiting structure that has a mass per unit length of 6.4 nucleosomes per 11 nm. Stripped chromatin at all ionic strengths appears to be a 10 nm filament, or a random coil of nucleosomes. In contrast, both native and reconstituted chromatin have a quite different structure, showing that H5 imposes a spatial correlation between neighboring nucleosomes even at low ionic strength. Our data also suggest that five to seven contiguous nucleosomes must have H5 bound in order to be able to form a higher-order structure.

Crystallization of the globular domain of histone H5.

The globular domain of histone H1/H5 binds to the nucleosome and is crucial for the formation of chromatin higher order structure. We have expressed in Escherichia coli a gene that codes for the globular domain of H5. The protein produced in E. coli is functional in nucleosome binding assays. We have obtained crystals of the protein that diffract to beyond 2.5 A (1 A = 0.1 nm) resolution. The crystals are orthorhombic with unit cell dimensions of a = 80.1 A, b = 67.5 A and c = 38.0 A.

Leukocyte immunotherapy improves live delivery rates following embryo transfer in women with at least two previous failures: a retrospective review.

PURPOSE: To determine whether leukocyte immunotherapy (LIT) could improve live delivery rate following embryo transfer (ET) in women who were not successful in prior attempts. METHODS: Paternal leukocytes were intradermally injected in some women who had failed to have a successful pregnancy following at least two prior ETs approximately two weeks prior to fresh or frozen ET and repeated at the time of the 3rd rising serum beta human chorionic gonadotropin level and at eight weeks if a pregnancy occurred. Clinical pregnancy and live pregnancy rates (PRs) were compared to those women having ETs during the same time period not receiving LIT. RESULTS: Thirty-six of 94 (38.3%) patients receiving LIT (group 1) conceived following fresh or frozen ET vs 98 of 341 (28.7%) for women not receiving LIT (group 2) (p = NS). The live delivery rate per ET cycle was 30.8% (39/94) vs 19.7% for group 2 (p = .02). For the subset of women failing despite five previous ETs 17 of 37 (45.9%) group 1 women had a clinical pregnancy vs 18 of 64 (28.1%) group 2 women (p = .07%) and live delivery rates were 35.1% (13/37) vs 15.6% (10/64) (p = .024). CONCLUSIONS: These retrospective data encourage a prospective study of LIT combined with progesterone vs controls receiving progesterone only for recalcitrant patients having ETs.

A comparison of luteal phase support in graduated estradiol/progesterone replacement cycles using intramuscular progesterone alone versus combination with vaginal suppositories on outcome following frozen embryo transfer.

PURPOSE: To compare pregnancy outcome following frozen embryo transfer according to type of progesterone (P) support given in the luteal phase. METHODS: Retrospective cohort analysis of frozen embryo transfer (ET) cycles in which ovulation was suppressed by graduated estradiol in the follicular phase. Two P regimens in the luteal phase were compared: P vaginal suppositories and intramuscular P vs intramuscular alone. RESULTS: The clinical and viable pregnancy rates were significantly higher for the women receiving only intramuscular P (57.6% and 43.7%) vs those receiving combined therapy (45.9% and 35.6%, respectively). The implantation rates were not significantly different (22.6% vs 19.5%). CONCLUSION: The increased pregnancy rates with intramuscular P may have been related to a higher number of embryos transferred (3.69 vs 3.26). Nevertheless, intramuscular P alone is at least as effective, if not more effective, than combined therapy for frozen embryo transfers.

Effect of cellulose structure and morphology on the properties of poly(butylene succinate-co-butylene adipate) biocomposites.

Composites based on poly(butylene succinate-co-butylene adipate) (PBSA) containing amorphized and crystalline cellulose reinforcements have been prepared and characterized. In order to improve the polymer/filler interfacial adhesion, an efficient compatibilizing agent has been synthesized by chemical modification of PBSA and characterized by FT-IR, FT-NIR and (1)H NMR spectroscopy. Uncompatibilized and compatibilized composites have been tested through morphological, mechanical, calorimetric and thermogravimetric analysis. Moreover, water vapor permeability and biodegradation kinetics of composites have been investigated. The addition to PBSA of cellulose fillers differing from each other by crystallinity degree and morphology, and the use of a compatibilizing agent have allowed modulating tensile and thermal properties, water vapor transmission rate and biodegradation kinetic of the composites.

Neither sildenafil nor vaginal estradiol improves endometrial thickness in women with thin endometria after taking oral estradiol in graduating dosages.

PURPOSE: To determine if sildenafil improves endometrial thickness better than vaginal estradiol (E2) in women with a history of thin endometria. METHODS: Women failing to attain an 8 mm endometrial thickness on either the oocyte retrieval cycle or their first frozen embryo transfer (ET) despite an oral graduated E2 regimen were treated again with graduated oral E2 and were also randomly assigned to vaginal sildenafil or vaginal E2 therapy. Endometrial thickness was compared between the groups. RESULTS: Neither vaginal E2 nor sildenafil significantly improved endometrial thickness or blood flow in the subsequent frozen ET-cycle. CONCLUSIONS: These data fail to corroborate previous claims that 25 mg sildenafil four times daily intravaginally can improve endometrial thickness.

[Computerized axial tomography in dentistry. Preliminary note]. / La tomografia assiale computerizzata (T.A.C.) in odontostomatologia. Nota preliminare.

Early results in the use of computerized axial tomography (C.A.T.) in odontostomatology are reported. The results obtained with this new technique open new horizons in the clinico-radiological diagnosis of maxillofacial conditions.

BAG3: a multifaceted protein that regulates major cell pathways.

Bcl2-associated athanogene 3 (BAG3) protein is a member of BAG family of co-chaperones that interacts with the ATPase domain of the heat shock protein (Hsp) 70 through BAG domain (110-124 amino acids). BAG3 is the only member of the family to be induced by stressful stimuli, mainly through the activity of heat shock factor 1 on bag3 gene promoter. In addition to the BAG domain, BAG3 contains also a WW domain and a proline-rich (PXXP) repeat, that mediate binding to partners different from Hsp70. These multifaceted interactions underlie BAG3 ability to modulate major biological processes, that is, apoptosis, development, cytoskeleton organization and autophagy, thereby mediating cell adaptive responses to stressful stimuli. In normal cells, BAG3 is constitutively present in a very few cell types, including cardiomyocytes and skeletal muscle cells, in which the protein appears to contribute to cell resistance to mechanical stress. A growing body of evidence indicate that BAG3 is instead expressed in several tumor types. In different tumor contexts, BAG3 protein was reported to sustain cell survival, resistance to therapy, and/or motility and metastatization. In some tumor types, down-modulation of BAG3 levels was shown, as a proof-of-principle, to inhibit neoplastic cell growth in animal models. This review attempts to outline the emerging mechanisms that can underlie some of the biological activities of the protein, focusing on implications in tumor progression.