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

Heavy element production in a compact object merger observed by JWST

The mergers of binary compact objects such as neutron stars and black holes are of central interest to several areas of astrophysics, including as the progenitors of gamma-ray bursts (GRBs) 1, sources of high-frequency gravitational waves (GWs) 2 and likely production sites for heavy-element nucleosynthesis by means of rapid neutron capture (the r-process) 3. Here we present observations of the exceptionally bright GRB 230307A. We show that GRB 230307A belongs to the class of long-duration GRBs associated with compact object mergers 4–6 and contains a kilonova similar to AT2017gfo, associated with the GW merger GW170817 (refs. 7–12). We obtained James Webb Space Telescope (JWST) mid-infrared imaging and spectroscopy 29 and 61 days after the burst. The spectroscopy shows an emission line at 2.15 microns, which we interpret as tellurium (atomic mass A = 130) and a very red source, emitting most of its light in the mid-infrared owing to the production of lanthanides. These observations demonstrate that nucleosynthesis in GRBs can create r-process elements across a broad atomic mass range and play a central role in heavy-element nucleosynthesis across the Universe

THE NEEDLE in the 100 deg² HAYSTACK: UNCOVERING AFTERGLOWS of FERMI GRB<inf>s</inf> with the PALOMAR TRANSIENT FACTORY

The Fermi Gamma-ray Space Telescope has greatly expanded the number and energy window of observations of gamma-ray bursts (GRBs). However, the coarse localizations of tens to a hundred square degrees provided by the Fermi GRB Monitor instrument have posed a formidable obstacle to locating the bursts' host galaxies, measuring their redshifts, and tracking their panchromatic afterglows. We have built a target-of-opportunity mode for the intermediate Palomar Transient Factory in order to perform targeted searches for Fermi afterglows. Here, we present the results of one year of this program: 8 afterglow discoveries out of 35 searches. Two of the bursts with detected afterglows (GRBs 130702A and 140606B) were at low redshift (z = 0.145 and 0.384, respectively) and had spectroscopically confirmed broad-line Type Ic supernovae. We present our broadband follow-up including spectroscopy as well as X-ray, UV, optical, millimeter, and radio observations. We study possible selection effects in the context of the total Fermi and Swift GRB samples. We identify one new outlier on the Amati relation. We find that two bursts are consistent with a mildly relativistic shock breaking out from the progenitor star rather than the ultra-relativistic internal shock mechanism that powers standard cosmological bursts. Finally, in the context of the Zwicky Transient Facility, we discuss how we will continue to expand this effort to find optical counterparts of binary neutron star mergers that may soon be detected by Advanced LIGO and Virgo. © 2015. The American Astronomical Society. All rights reserved

Effects of an Internet-based cognitive behaviour treatment for insomnia on self-report of emotional states: Preliminary results.

Recent studies have shown that insomnia is linked to increased negative emotions and decreased positive emotions. The aim of this study was to evaluate the efficacy of an internetbased cognitive-behaviour treatment for insomnia (CBT-I) in ameliorating self-reports of emotional states in the evening and in the morning. Until now, 10 patients with insomnia (8F, 2M), diagnosed according to DSM-IV criteria were assigned to either a CBT-I or a waiting-list (WL) group. Self-reports of positive and negative emotional states collected through emotion diaries filled in during the week preceding the treatment and the week following the end of the treatment were compared. Preliminary results showed that the CBT-I group at post-treatment reported reduced negative emotions in the morning both as compared to the WL group and to the pre-treatment. Preliminary results suggest that internet-delivered CBT-I is efficacious in ameliorating daytime symptoms of insomnia as altered emotional states

APC and MUTYH Analysis in FAP Patients: A Novel Mutation in APC Gene and Genotype-Phenotype Correlation

APC and MUTYH genes are mutated in 70&ndash;90% and 10&ndash;30% of familial adenomatous polyposis cases (FAP) respectively. An association between mutation localization and FAP clinical phenotype is reported. The aims of this study were to determine APC and MUTYH mutational status in a small cohort of FAP patients and to evaluate the genotype-phenotype correlation in mutated patients. Here, we report the identification of a novel APC germline mutation, c.510_511insA. Overall, mutational analysis showed pathogenic mutations in 6/10 patients: 5/10 in APC and 1/10 in MUTYH. Additionally, we found three variants of unknown significance in MUTYH gene that showed no evidence of possible splicing defects by in silico analysis. Molecular analysis was also extended to family members of mutated patients. A genotype-phenotype correlation was observed for colonic signs whereas a variation of disease onset age was revealed for the same mutation. Moreover, we found an intrafamilial variability of FAP onset age. Regarding extracolonic manifestations, the development of desmoid tumors was related to surgery and not to mutation position, while a genotype-phenotype correspondence was observed for the onset of thyroid or gastric cancer. These findings can be useful in association to clinical data for early surveillance and suitable treatment of FAP patients

Pancreatic Cancer with Mutation in BRCA1/2, MLH1, and APC Genes: Phenotype Correlation and Detection of a Novel Germline BRCA2 Mutation

Pancreatic ductal adenocarcinoma (PDAC) is the seventh leading cause of cancer death worldwide; most of cases are sporadic, however about 5% to 10% report a hereditary predisposition. Several hereditary syndromes have been associated with familial pancreatic cancer (FPC) onset, including hereditary breast and ovarian cancer syndrome (HBOC), Lynch syndrome (LS), Familial atypical multiple mole melanoma (FAMMM), Familial adenomatous polyposis (FAP), Li&ndash;Fraumeni syndrome (LFS), Peutz&ndash;Jeghers syndrome (PJS), and Hereditary pancreatitis (HP).The aim of this study was to determine the mutational status of a cohort of 56 HBOC families, 7 LS families, 3 FAP and FAMMM families, and 1 LFS family with at least one case of PDAC. Mutation analysis of BRCA1/2, ATM, CHEK2, PALB2, RAD51C, RAD51D, NBN, CDH1, TP53, MLH1, MSH2, MSH6, and PMS2 genes, showedmutation in BRCA1/2, MLH1, and APC genes. We founda high mutation rate in patients belong HBOC and LS families, with a percentage of 28.6% in both syndromes and prevalence in HBOC of BRCA2 mutations with one case of double mutation in BRCA2 gene. In FAP family, we found a pathogenic mutation in APC gene in 1/3 families. We observed an early onset of PDAC and a lower survival in PDAC patients belonging to mutated families, while no evidence of possible pancreatic cancer cluster regions was found. Moreover, we identified a novel BRCA2 germline mutation, c.5511delT (p.Phe1837LeufsX3), not reported in any database, that segregated with disease in HBOC patients. Mutational analysis was extended to family membersof mutated patients, both healthy and cancer affected, which revealed 23 unaffected family members that inherited the proband&rsquo;s mutation. Although correlative by its nature, the presence of a BRCA mutation in PDAC patients may have benefits in terms of optimized treatment and longer outcome

Hereditary Prostate Cancer: Genes Related, Target Therapy and Prevention

Prostate cancer (PCa) is globally the second most diagnosed cancer type and the most common cause of cancer-related deaths in men. Family history of PCa, hereditary breast and ovarian cancer (HBOC) and Lynch syndromes (LS), are among the most important risk factors compared to age, race, ethnicity and environmental factors for PCa development. Hereditary prostate cancer (HPCa) has the highest heritability of any major cancer in men. The proportion of PCa attributable to hereditary factors has been estimated in the range of 5–15%. To date, the genes more consistently associated to HPCa susceptibility include mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) and homologous recombination genes (BRCA1/2, ATM, PALB2, CHEK2). Additional genes are also recommended to be integrated into specific research, including HOXB13, BRP1 and NSB1. Importantly, BRCA1/BRCA2 and ATM mutated patients potentially benefit from Poly (ADP-ribose) polymerase PARP inhibitors, through a mechanism of synthetic lethality, causing selective tumor cell cytotoxicity in cell lines. Moreover, the detection of germline alterations in MMR genes has therapeutic implications, as it may help to predict immunotherapy benefits. Here, we discuss the current knowledge of the genetic basis for inherited predisposition to PCa, the potential target therapy, and the role of active surveillance as a management strategy for patients with low-risk PCa. Finally, the current PCa guideline recommendations are reviewed

Analysis of street cocaine samples in nasal fluid by Raman spectroscopy

The principal objective of this work was to demonstrate the capability of Raman spectroscopy to detectsmall amounts of cocaine in nasal fluid, and to identify the main drug and the most widely used cuttingagents. Initially, standard samples were analysed and sampling conditions were studied by comparingdifferent swabs used for the sample collection. Once the most appropriate swab was selected, whichpermitted a relatively simple detection of the standard cocaine hydrochloride, qualitative analyses of realsamples were carried out. Three street cocaine samples were analysed, and the presence of cuttingsubstances was highlighted by the appearance of different bands not corresponding to the ones of thestandard cocaine. To identify the substances present in each sample, the spectra of the street cocainesamples were collected and compared with a digital library created on purpose with the spectra of themost common cutting agents. In this case, correlation coefficients permitted to recognize the most importantsubstances presumably present in the samples, and gave an estimation of the purity of the cocaine.However, when nasal fluid was present, its strong signal could overlap or interfere with thesmaller signal of the cutting substances, hindering their identification