Increased Risk of Hereditary Prostate Cancer in Italian Families with Hereditary Breast and Ovarian Cancer Syndrome Harboring Mutations in BRCA and in Other Susceptibility Genes

Hereditary prostate cancer (HPCa) has the highest heritability of any cancer in men. Interestingly, it occurs in several hereditary syndromes, including breast and ovarian cancer (HBOC) and Lynch syndrome (LS). Several gene mutations related to these syndromes have been identified as biomarkers in HPCa. The goal of this study was to screen for germline mutations in susceptibility genes by using a multigene panel, and to subsequently correlate the results with clinical and laboratory parameters. This was undertaken in 180 HBOC families, which included 217 males with prostate cancer (PCa). Mutational analysis was further extended to 104 family members of mutated patients. Screening of HBOC families revealed that 30.5% harbored germline mutations in susceptibility genes, with 21.6% harboring pathogenic variants (PVs) and 8.9% having variants of uncertain significance (VUS). We found PVs at similar frequency in BRCA1 and BRCA2 genes (8.8% and 9.4%, respectively), while 0.56% of PVs were present in well-established susceptibility genes PALB2, TP53 and RAD51C. Moreover, 0.56% of monoallelic PVs were present in MUTYH, a gene whose function in tumorigenesis in the context of PCa is still unclear. Finally, we reported double heterozygosity (DH) in BRCA1/2 genes in a single family, and found double mutation (DM) present in BRCA2 in a separate family. There was no significant difference between the mean age of onset of PCa in HBOC families with or without germline mutations in susceptibility genes, while the mean survival was highest in mutated patients compared to wild type. Furthermore, PCa is the second most recurrent cancer in our cohort, resulting in 18% of cases in both mutated and non-mutated families. Our investigation shows that PVs were located mostly in the 3′ of BRCA1 and BRCA2 genes, and in BRCA2, most PVs fell in exon 11, suggesting a mutation cluster region relating to risk of HPCa. A total of 65 family members inherited the proband’s mutation; of these, 24 developed cancer, with 41 remaining unaffected

Antibody levels after BNT162b2 vaccine booster and SARS-CoV-2 Omicron infection

In the present study, immunogenicity data in 61 vaccinated healthcare workers (HCWs) either infection naïve (naïve HCWs) or with infection of Delta and/or Omicron COVID-19 (experienced HCWs) were evaluated up to 270 days after the second dose of BNT162b2 vaccine and up to 90 days after a booster dose. A decrease in antibody levels at 270 days following administration of the second dose (p = 0.0335) was observed, although values did not fall below the positivity threshold (33.8 BAU/ml). After booster vaccination, antibody levels increased after 30 days (p = 0.0486), with much higher values than after first and second vaccination. Antibody levels then decreased at 60 and 90 days after the booster dose. A comparison between mean antibody levels of naïve and experienced HCWs revealed higher values in experienced HCWs, resulting from both natural and vaccination-induced immunity. A total of 14.7% of HCWs contracted the Omicron virus variant after the vaccine booster, although none showed severe symptoms. These results support that a booster dose results in a marked increase in antibody response that subsequently decreases over time

A novel frameshift mutation in exon 12 of the adenomatous polyposis coli gene in an Italian family with familial adenomatous polyposis and desmoid tumour

[This corrects the article on p. 235 in vol. 4, PMID: 20589194.]

Platelet lysate-derived neuropeptide y influences migration and angiogenesis of human adipose tissue-derived stromal cells

Neuropeptide Y (NPY), a powerful neurotransmitter of the central nervous system, is a key regulator of angiogenesis and biology of adipose depots. Intriguingly, its peripheral vascular and angiogenic powerful activity is strictly associated to platelets, which are source of clinical hemoderivates, such as platelet lysate (PL), routinely employed in several clinical applications as wound healing, and to preserve ex vivo the progenitor properties of the adipose stromal cells pool. So far, the presence of NPY in PL and its biological effects on the adipose stromal cell fraction (ASCs) have never been investigated. Here, we aimed to identify endogenous sources of NPY such as PL-based preparations and to investigate which biological properties PL-derived NPY is able to exert on ASCs. The results show that PL contains a high amount of NPY, which is in part also excreted by ASCs when stimulated with PL. The protein levels of the three main NPY subtype receptors (Y1, Y2, Y5) are unaltered by stimulation of ASCs with PL, but their inhibition through selective pharmacological antagonists, considerably enhances migration, and a parallel reduction of angiogenic features of ASCs including decrease in VEGF mRNA and intracellular calcium levels, both downstream targets of NPY. The expression of VEGF and NPY is enhanced within the sites of neovascularisation of difficult wounds in patients after treatment with leuco-platelet concentrates. Our data highlight the presence of NPY in PL preparations and its peripheral effects on adipose progenitors

An explainable model of host genetic interactions linked to COVID-19 severity

We employed a multifaceted computational strategy to identify the genetic factors contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing (WES) dataset of a cohort of 2000 Italian patients. We coupled a stratified k-fold screening, to rank variants more associated with severity, with the training of multiple supervised classifiers, to predict severity based on screened features. Feature importance analysis from tree-based models allowed us to identify 16 variants with the highest support which, together with age and gender covariates, were found to be most predictive of COVID-19 severity. When tested on a follow-up cohort, our ensemble of models predicted severity with high accuracy (ACC = 81.88%; AUCROC = 96%; MCC = 61.55%). Our model recapitulated a vast literature of emerging molecular mechanisms and genetic factors linked to COVID-19 response and extends previous landmark Genome-Wide Association Studies (GWAS). It revealed a network of interplaying genetic signatures converging on established immune system and inflammatory processes linked to viral infection response. It also identified additional processes cross-talking with immune pathways, such as GPCR signaling, which might offer additional opportunities for therapeutic intervention and patient stratification. Publicly available PheWAS datasets revealed that several variants were significantly associated with phenotypic traits such as "Respiratory or thoracic disease", supporting their link with COVID-19 severity outcome.A multifaceted computational strategy identifies 16 genetic variants contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing dataset of a cohort of Italian patients

The polymorphism L412F in TLR3 inhibits autophagy and is a marker of severe COVID-19 in males

The polymorphism L412F in TLR3 has been associated with several infectious diseases. However, the mechanism underlying this association is still unexplored. Here, we show that the L412F polymorphism in TLR3 is a marker of severity in COVID-19. This association increases in the sub-cohort of males. Impaired macroautophagy/autophagy and reduced TNF/TNFα production was demonstrated in HEK293 cells transfected with TLR3L412F-encoding plasmid and stimulated with specific agonist poly(I:C). A statistically significant reduced survival at 28 days was shown in L412F COVID-19 patients treated with the autophagy-inhibitor hydroxychloroquine (p = 0.038). An increased frequency of autoimmune disorders such as co-morbidity was found in L412F COVID-19 males with specific class II HLA haplotypes prone to autoantigen presentation. Our analyses indicate that L412F polymorphism makes males at risk of severe COVID-19 and provides a rationale for reinterpreting clinical trials considering autophagy pathways. Abbreviations: AP: autophagosome; AUC: area under the curve; BafA1: bafilomycin A1; COVID-19: coronavirus disease-2019; HCQ: hydroxychloroquine; RAP: rapamycin; ROC: receiver operating characteristic; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; TLR: toll like receptor; TNF/TNF-α: tumor necrosis factor

IVS4-14 A/G and IVS4-73 C/T polymorphisms in OLR1 gene in patients with ischemic cerebrovascular diseases

INTRODUCTION: Oxidized low-density lipoprotein (ox-LDL) plays a key role in the processes of atherogenesis, the major cause of myocardial infarction. Increased levels of ox-LDL relate to plaque instability in human coronary atherosclerotic lesions. Moreover, ox-LDL levels show a direct correlation to the severity of coronary syndromes. Most of these effects are mediated by the interaction of ox-LDL with its major receptor, named LOX-1, that is encoded by OLR1 gene. AIMS AND METHODS: In the present study, we examined the prevalence of OLR1 gene polymorphisms, IVS4-14 A/G and IVS4-73 C/T, which regulate the expression of LOXIN, in patients with ischemic cerebrovascular diseases (ICVD). We studied 43 consecutive patients (males = 19; females = 24) aged 26 to 65 years. All the patients were from the same geographical area. They were affected by ICVD. The control group comprised 69 healthy blood donors, with age and sex comparable to those of the patients. RESULTS: The distribution of G/G genotype and A/G genotype was statistically significant between patients and controls (chi(2) = 5.87, p = 0.01 and chi(2) = 4.33, p = 0.04, respectively). CONCLUSION: These preliminary data would suggest that in ICVD patients the LOX-1 isoform that induces internalization of ox-LDL is more frequent and a cascade of events responsible for endothelial dysfunction and injury. LOX-1 might play a fundamental role in the initiation and progression of atherosclerosis and have a significant role in the pathogenesis of ICVD. Therefore, the patients with G homozygosity for IVS4-14 polymorphism and T homozygosity for IVS4-73 polymorphism have higher risk to develop ICVD. Future studies are warranted to assess whether the analysis of polymorphisms may be useful for the clinical approach to evaluate risk factors for atherosclerosis and related disorders.Introduction: Oxidized low-density lipoprotein (ox-LDL) plays a key role in the processes of atherogenesis, the major cause of myocardial infarction. Increased levels of ox-LDL relate to plaque instability in human coronary atherosclerotic lesions. Moreover, ox-LDL levels show a direct correlation to the severity of coronary syndromes. Most of these effects are mediated by the interaction of ox-LDL with its major receptor, named LOX-1, that is encoded by OLR1 gene. Aims and Methods: In the present study, we examined the prevalence of OLR1 gene polymorphisms, IVS4-14 A/G and IVS4-73 C/T, which regulate the expression of LOXIN, in patients with ischemic cerebrovascular diseases (ICVD). We studied 43 consecutive patients (males=19; females=24) aged 26 to 65 years. All the patients were from the same geographical area. They were affected by ICVD. The control group comprised 69 healthy blood donors, with age and sex comparable to those of the patients. Results: The distribution of G/G genotype and A/G genotype was statistically significant between patients and controls (χ2=5.87, p=0.01 and χ2=4.33, p=0.04, respectively). Conclusion: These preliminary data would suggest that in ICVD patients the LOX-1 isoform that induces internalization of ox-LDL is more frequent and a cascade of events responsible for endothelial dysfunction and injury. LOX-1 might play a fundamental role in the initiation and progression of atherosclerosis and have a significant role in the pathogenesis of ICVD. Therefore, the patients with G homozygosity for IVS4-14 polymorphism and T homozygosity for IVS4-73 polymorphism have higher risk to develop ICVD. Future studies are warranted to assess whether the analysis of polymorphisms may be useful for the clinical approach to evaluate risk factors for atherosclerosis and related disorders. © 2009, Mary Ann Liebert, Inc