Origin and distribution of the BRCA2-8765delAG mutation in breast cancer

Background: The BRCA2-8765delAG mutation was firstly described in breast cancer families from French-Canadian and Jewish-Yemenite populations; it was then reported as a founder mutation in Sardinian families. We evaluated both the prevalence of the BRCA2-8765delAG variant in Sardinia and the putative existence of a common ancestral origin through a haplotype analysis of breast cancer family members carrying such a mutation. Methods: Eight polymorphic microsatellite markers (D13S1250, centromeric, to D13S267, telomeric) spanning the BRCA2 gene locus were used for the haplotype analysis. Screening for the 8765delAG mutation was performed by PCR-based amplification of BRCA2-exon 20, followed by automated sequencing. Results: Among families with high recurrence of breast cancer (≥ 3 cases in first-degree relatives), those from North Sardinia shared the same haplotype whereas the families from French Canadian and Jewish-Yemenite populations presented distinct genetic assets at the BRCA2 locus. Screening for the BRCA2-8765delAG variant among unselected and consecutively-collected breast cancer patients originating from the entire Sardinia revealed that such a mutation is present in the northern part of the island only [9/648 (1.4%) among cases from North Sardinia versus 0/493 among cases from South Sardinia]. Conclusion: The BRCA2-8765delAG has an independent origin in geographically and ethnically distinct populations, acting as a founder mutation in North but not in South Sardinia. Since BRCA2- 8765delAG occurs within a triplet repeat sequence of AGAGAG, our study further confirmed the existence of a mutational hot-spot at this genomic position (additional genetic factors within each single population might be involved in generating such a mutation)

The yellow gorgonian Eunicella cavolini: demography and disturbance levels across the Mediterranean Sea

The yellow octocoral Eunicella cavolini is one of the most common gorgonians thriving in Mediterranean hard-bottom communities. However, information regarding its distribution and ecology in several parts of the Mediterranean is lacking, while population trends and conservation status remain largely unknown. We investigated 19 populations of E. cavolini over three representative geographic regions: the NW Mediterranean, CE Adriatic, and N Aegean. Focusing on the upper bathymetric range of the species (30 cm). The CE Adriatic displayed intermediate densities, with well-structured populations, and continuous recruitment. In the N Aegean, most populations presented low densities, high proportion of large colonies, but low number of small colonies, signifying limited recruitment. Disturbance levels, as a function of extent and type of injury, are discussed in relation to past or present human-induced threats. This work represents geographically the most wide ranging demographic study of a Mediterranean octocoral to date. The quantitative information obtained provides a basis for future monitoring at a Mediterranean scale

Main roads to melanoma

The characterization of the molecular mechanisms involved in development and progression of melanoma could be helpful to identify the molecular profiles underlying aggressiveness, clinical behavior, and response to therapy as well as to better classify the subsets of melanoma patients with different prognosis and/or clinical outcome. Actually, some aspects regarding the main molecular changes responsible for the onset as well as the progression of melanoma toward a more aggressive phenotype have been described. Genes and molecules which control either cell proliferation, apoptosis, or cell senescence have been implicated. Here we provided an overview of the main molecular changes underlying the pathogenesis of melanoma. All evidence clearly indicates the existence of a complex molecular machinery that provides checks and balances in normal melanocytes. Progression from normal melanocytes to malignant metastatic cells in melanoma patients is the result of a combination of down- or up-regulation of various effectors acting on different molecular pathways

Integrated Somatic and Germline Whole-Exome Sequencing Analysis in Women with Lung Cancer after a Previous Breast Cancer

open20Women treated for breast cancer (BC) are at risk of developing secondary tumors, such as lung cancer (LC). Since rare germline variants have been linked to multiple cancer development, we hypothesized that BC survivors might be prone to develop LC as a result of harboring rare variants. Sixty patients with LC with previous BC (the study population; SP) and 53 women with either BC or LC and no secondary cancer (control population; CP) were enrolled. Whole exome sequencing was performed in both tumors and unaffected tissues from 28/60 SP patients, and in germline DNA from 32/53 CP. Candidate genes were validated in the remaining individuals from both populations. We found two main mutational signature profiles: S1 (C>T) in all BCs and 16/28 LCs, and S2 (C>A) which is strongly associated with smoking, in 12/28 LCs. The burden test over rare germline variants in S1-LC vs CP identified 248 genes. Validation confirmed GSN as significantly associated with LC in never-smokers. In conclusion, our data suggest two signatures involved in LC onset in women with previous BC. One of these signatures is linked to smoking. Conversely, regardless of smoking habit, in a subgroup of BC survivors genetic susceptibility may contribute to LC risk.openCoco, Simona; Bonfiglio, Silvia; Cittaro, Davide; Vanni, Irene; Mora, Marco; Genova, Carlo; Dal Bello, Maria Giovanna; Boccardo, Simona; Alama, Angela; Rijavec, Erika; Sini, Claudio; Rossella, Valeria; Barletta, Giulia; Biello, Federica; Truini, Anna; Bruzzo, Cristina; Gallo, Maurizio; Lazarevic, Dejan; Ballestrero, Alberto; Grossi, FrancescoCoco, Simona; Bonfiglio, Silvia; Cittaro, Davide; Vanni, Irene; Mora, Marco; Genova, Carlo; Dal Bello, Maria Giovanna; Boccardo, Simona; Alama, Angela; Rijavec, Erika; Sini, Claudio; Rossella, Valeria; Barletta, Giulia; Biello, Federica; Truini, Anna; Bruzzo, Cristina; Gallo, Maurizio; Lazarevic, Dejan; Ballestrero, Alberto; Grossi, Francesc

Pathologic response and survival after neoadjuvant chemotherapy with or without pertuzumab in patients with HER2-positive breast cancer: the Neopearl nationwide collaborative study

PurposeClinical trials have shown a significant increase in pathologic complete response (pCR) with the addition of pertuzumab to neoadjuvant chemotherapy for patients with early-stage HER-2 positive breast cancer. To date, limited studies have examined comparative outcomes of neoadjuvant pertuzumab in real-world setting. The Neopearl study aimed to assess comparative real-life efficacy and safety of neoadjuvant pertuzumab for these patients.MethodsWe conducted a nationwide retrospective analysis involving 17 oncology facilities with a certified multidisciplinary breast cancer treatment committee. We identified patients with HER-2 positive stage II-III breast cancer treated with neoadjuvant chemotherapy based on trastuzumab and taxanes with or without pertuzumab. All patients underwent breast surgery and received a comprehensive cardiologic evaluation at baseline and after neoadjuvant treatment. Patients who received the combination of pertuzumab, trastuzumab, and chemotherapy constituted case cohort (PTCT), whereas those treated with trastuzumab and chemotherapy accounted for control cohort (TCT). The pCR rate and 5-year event free survival (EFS) were the primary outcomes. Secondary end-points were rates of conversion from planned modified radical mastectomy (MRM) to breast conservation surgery (BCS) and cardiotoxicities.ResultsFrom March 2014 to April 2021, we included 271 patients, 134 (49%) and 137 (51%) in TCT and PTCT cohort, respectively. Positive axillary lymph nodes and stage III were more frequent in PTCT cohort. The pCR rate was significantly increased in patients who received pertuzumab (49% vs 62%; OR 1.74, 95%CI 1.04-2.89) and with HER-2 enriched subtypes (16% vs 85%; OR 2.94, 95%CI 1.60-5.41). After a median follow-up of 5 years, the 5-year EFS was significantly prolonged only in patients treated with pertuzumab (81% vs 93%; HR 2.22, 95%CI 1.03-4.79). The same analysis performed on propensity score matched population showed concordant results. On univariate analysis, only patients with positive lymph nodes were found to benefit from pertuzumab for both pCR and 5-year EFS. The rates of conversion from MRM to BCS and cardiologic toxicities did not differ between the cohorts.ConclusionOur findings support previous data on improved outcomes with the addition of pertuzumab to trastuzumab-based neoadjuvant chemotherapy. This benefit seems to be more significant in patients with clinically positive lymph nodes

Unpublished Mediterranean records of marine alien and cryptogenic species

Good datasets of geo-referenced records of alien species are a prerequisite for assessing the spatio-temporal dynamics of biological invasions, their invasive potential, and the magnitude of their impacts. However, with the exception of first records on a country level or wider regions, observations of species presence tend to remain unpublished, buried in scattered repositories or in the personal databases of experts. Through an initiative to collect, harmonize and make such unpublished data for marine alien and cryptogenic species in the Mediterranean Sea available, a large dataset comprising 5376 records was created. It includes records of 239 alien or cryptogenic taxa (192 Animalia, 24 Plantae, 23 Chromista) from 19 countries surrounding the Mediterranean Sea. In terms of records, the most reported Phyla in descending order were Chordata, Mollusca, Chlorophyta, Arthropoda, and Rhodophyta. The most recorded species was Caulerpa cylindracea, followed by Siganus luridus, Magallana sp. (cf. gigas or angulata) and Pterois miles. The dataset includes records from 1972 to 2020, with the highest number of records observed in 2018. Among the records of the dataset, Dictyota acutiloba is a first record for the Mediterranean Sea. Nine first country records are also included: the alga Caulerpa taxifolia var. distichophylla, the cube boxfish Ostracion cubicus, and the cleaner shrimp Urocaridella pulchella from Israel; the sponge Paraleucilla magna from Libya and Slovenia; the lumpfish Cyclopterus lumpus from Cyprus; the bryozoan Celleporaria vermiformis and the polychaetes Prionospio depauperata and Notomastus aberans from Malta

Sex differences in cerebral venous sinus thrombosis after adenoviral vaccination against COVID-19

Introduction: Cerebral venous sinus thrombosis associated with vaccine-induced immune thrombotic thrombocytopenia (CVST-VITT) is a severe disease with high mortality. There are few data on sex differences in CVST-VITT. The aim of our study was to investigate the differences in presentation, treatment, clinical course, complications, and outcome of CVST-VITT between women and men. Patients and methods: We used data from an ongoing international registry on CVST-VITT. VITT was diagnosed according to the Pavord criteria. We compared the characteristics of CVST-VITT in women and men. Results: Of 133 patients with possible, probable, or definite CVST-VITT, 102 (77%) were women. Women were slightly younger [median age 42 (IQR 28–54) vs 45 (28–56)], presented more often with coma (26% vs 10%) and had a lower platelet count at presentation [median (IQR) 50x109/L (28–79) vs 68 (30–125)] than men. The nadir platelet count was lower in women [median (IQR) 34 (19–62) vs 53 (20–92)]. More women received endovascular treatment than men (15% vs 6%). Rates of treatment with intravenous immunoglobulins were similar (63% vs 66%), as were new venous thromboembolic events (14% vs 14%) and major bleeding complications (30% vs 20%). Rates of good functional outcome (modified Rankin Scale 0-2, 42% vs 45%) and in-hospital death (39% vs 41%) did not differ. Discussion and conclusions: Three quarters of CVST-VITT patients in this study were women. Women were more severely affected at presentation, but clinical course and outcome did not differ between women and men. VITT-specific treatments were overall similar, but more women received endovascular treatment.</p

Collaborative Database to Track Mass Mortality Events in the Mediterranean Sea

Anthropogenic climate change, and global warming in particular, has strong and increasing impacts on marine ecosystems (Poloczanska et al., 2013; Halpern et al., 2015; Smale et al., 2019). The Mediterranean Sea is considered a marine biodiversity hot-spot contributing to more than 7% of world's marine biodiversity including a high percentage of endemic species (Coll et al., 2010). The Mediterranean region is a climate change hotspot, where the respective impacts of warming are very pronounced and relatively well documented (Cramer et al., 2018). One of the major impacts of sea surface temperature rise in the marine coastal ecosystems is the occurrence of mass mortality events (MMEs). The first evidences of this phenomenon dated from the first half of'80 years affecting the Western Mediterranean and the Aegean Sea (Harmelin, 1984; Bavestrello and Boero, 1986; Gaino and Pronzato, 1989; Voultsiadou et al., 2011). The most impressive phenomenon happened in 1999 when an unprecedented large scale MME impacted populations of more than 30 species from different phyla along the French and Italian coasts (Cerrano et al., 2000; Perez et al., 2000). Following this event, several other large scale MMEs have been reported, along with numerous other minor ones, which are usually more restricted in geographic extend and/or number of affected species (Garrabou et al., 2009; Rivetti et al., 2014; Marbà et al., 2015; Rubio-Portillo et al., 2016, authors' personal observations). These events have generally been associated with strong and recurrent marine heat waves (Crisci et al., 2011; Kersting et al., 2013; Turicchia et al., 2018; Bensoussan et al., 2019) which are becoming more frequent globally (Smale et al., 2019). Both field observations and future projections using Regional Coupled Models (Adloff et al., 2015; Darmaraki et al., 2019) show the increase in Mediterranean sea surface temperature, with more frequent occurrence of extreme ocean warming events. As a result, new MMEs are expected during the coming years. To date, despite the efforts, neither updated nor comprehensive information can support scientific analysis of mortality events at a Mediterranean regional scale. Such information is vital to guide management and conservation strategies that can then inform adaptive management schemes that aim to face the impacts of climate change.MV-L was supported by a postdoctoral contract Juan de la Cierva-Incorporación (IJCI-2016-29329) of Ministerio de Ciencia, Innovación y Universidades. AI was supported by a Technical staff contract (PTA2015-10829-I) Ayudas Personal Técnico de Apoyo of Ministerio de Economía y Competitividad (2015). Interreg Med Programme (grant number Project MPA-Adapt 1MED15_3.2_M2_337) 85% cofunded by the European Regional Development Fund, the MIMOSA project funded by the Foundation Prince Albert II Monaco and the European Union's Horizon 2020 research and innovation programme under grant agreement no 689518 (MERCES). DG-G was supported by an FPU grant (FPU15/05457) from the Spanish Ministry of Education. J-BL was partially supported by the Strategic Funding UID/Multi/04423/2013 through national funds provided by FCT - Foundation for Science and Technology and European Regional Development Fund (ERDF), in the framework of the programme PT2020