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.].

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.

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.

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.

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.

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.

Alkaptonuria and renal failure: a case report and review of the literature.

In alkaptonuric ochronosis, the absence of homogentisic acid oxidase results in the accumulation of homogentisic acid in the body. Associated renal failure is rare and usually occurs in the later stages of the disease. We report a 19-yr-old girl who presented initially with severe renal failure, without family or past history of illness. There was no significant proteinuria or hematuria. No clinical evidence of pigmentation such as skin and subcutaneous cartilages was noted. However, pigment deposits were identified in the renal biopsy specimens obtained within a week after admission and another after a month. Two months later the peritoneal dialysis fluid and skin progressively darkened, suggesting ochronosis. This was confirmed by the detection of homogentisic acid in the serum and urine. The patient expired in renal failure. Renal biopsy tissues showed diffuse chronic tubulo-interstitial disease characterized by widespread tubular atrophy, interstitial fibrosis, and a moderate degree of inflammation. Many tubular cells contained brown, coarsely granular ochronotic pigment (OP) and a few pigment casts were in the lumina. Similar deposits were also in the interstitium and within histiocytes. Ultrastructural studies of the glomeruli revealed small sparse OP deposits in the visceral and parietal epithelial cells, mesangial cells, and rare extracellular and basement membrane deposits. The tubulointerstitial changes were varied: atrophy and dilatation of tubules, varying degrees of lysosomal OP and degeneration of tubular cells, casts containing OP with crystalline material, histiocytes distended with OP, and free interstitial pigment deposition.(ABSTRACT TRUNCATED AT 250 WORDS)