Spectrum of germline pathogenic variants in brca1/2 genes in the apulian southern italy population: Geographic distribution and evidence for targeted genetic testing

BRCA1/2-associated hereditary breast and ovarian cancer is the most common form of hereditary breast and ovarian cancer and occurs in all ethnicities and racial populations. Different BRCA1/BRCA2 pathogenic variants (PVs) have been reported with a wide variety among populations. In this study, we retrospectively analyzed prevalence and geographic distribution of pathogenic germline BRCA1/2 variants in families from Apulia in southern Italy and evaluated the genotype–phenotype correlations. Data were collected from Oncogenetic Services present in Apulian hospitals and a shared database was built containing Apulian native probands (n = 2026) that had undergone genetic testing from 2004 to 2019. PVs were detected in 499 of 2026 (24.6%) probands and 68.5% of them (342 of 499) were in the BRCA1 gene. We found 65 different PVs in BRCA1 and 46 in BRCA2. There were 10 most recurrent PVs and their geographical distribution appears to be significantly specific for each province. We have assumed that these PVs are related to the historical and geopolitical changes that occurred in Apulia over time and/or to a “founder effect”. Broader knowledge of BRCA1/2 prevalence and recurring PVs in specific geographic areas could help establish more flexible genetic testing strategies that may enhance our ability to detect high-risk subjects

Collaborating for Innovation: the socialised management of knowledge

Although the importance of diverse knowledge is widely recognised for open innovation, there may be a gap in our understanding of the social processes that shape how collaborators engage in knowledge exchange. This social gap may be significant because of the powerful, but largely unexplained, role attributed to trust as a social artefact. Moreover, we see trust as a process and that different types of trust are involved in the collaborative process. Thus, this paper uses a qualitative methodology to capture the experiences of innovation collaborators. As explanation of the dynamic interplays of knowledge and trust, we offer a description of phases in the process. Our analysis finds that the relationship moves from transactional to social. The early phases are characterised by technical knowledge, but the later and mature phases are identified with knowledge of the person and by personal trust. The success of innovation is a result of relationships with augmented trust. We found that a fabric of trust is woven from the weft of professional knowledge and the warp of personal knowledge to support innovation. We propose that this developing of relationships might be conceived as becoming more open in the sense of sharing with one another. If so, we seem to have described and offered a social dimension of open innovation

Activation of the RAS/RAF/ERK signaling pathway contributes to resistance to sunitinib in thyroid carcinoma cell lines

CONTEXT: Sunitinib is currently being evaluated in advanced human thyroid carcinomas, based on the rationale that the vascular endothelial growth factor and platelet-derived growth factor receptors and the RET/PTC rearrangement are valuable targets for the treatment of this malignancy. However, criteria for selecting thyroid tumors that may benefit from sunitinib are lacking. DESIGN: The effect of activating somatic mutations in the KRAS and BRAF genes on the responsiveness to sunitinib was evaluated in a panel of thyroid cancer cell lines harboring wild-type KRAS and BRAF genes, the RET/PTC1 rearrangement, the G12R KRAS, or the V600E BRAF mutation. RESULTS: Sunitinib was found to selectively inhibit cell proliferation, induce cell accumulation in the G0-G1 phase, and inhibit the phosphorylation of ERK1/2 in both KRAS/BRAF wild-type thyroid cancer cells and in tumor cells harboring the RET/PTC rearrangement, whereas it was completely ineffective in KRAS- or BRAF-mutated thyroid carcinoma cells. This differential antitumor activity of sunitinib did not correlate with the expression profile of the vascular endothelial growth factor receptors 1, 2, and 3, platelet-derived growth factor receptor-α and cKIT genes. Of note, the constitutive activation of RAS/RAF/ERK signaling in KRAS/BRAF wild-type cells by transfection of the R12 HRAS or V600E BRAF mutants or stimulation with epithelial growth factor resulted in the loss of responsiveness to sunitinib, whereas pharmacological inhibition of MAPK kinase activity resulted in the resensitization of KRAS- or BRAF-mutated cells to the multikinase inhibitor. CONCLUSIONS: The constitutive activation of the RAS/RAF/ERK pathway may favor resistance to sunitinib in thyroid carcinoma cells

Viral colonization in exhaled breath condensate of lung cancer patients: Possible role of EBV and CMV

Introduction: Today, an increasing interest is being addressed to the viral etiology of lung tumors. As a consequence, research efforts are currently being directed to the identification of the new viruses involved in lung carcinogenesis toward which the screening programs could be directed. Objectives: The aim of this study was to investigate the airways colonization by the Epstein-Barr virus (EBV) and Citomegalovirus (CMV) in patients affected by lung cancer using, as a respiratory non-invasive sample, the exhaled breath condensate (EBC). Methods: About 70 lung-cancer patients and 40 controls were enrolled. All subjects underwent bronchial brushing and EBC collection. EBV-DNA and CMV-DNA were evaluated in both samples by real-time PCR assay. Results: They were able to detect EBV and CMV in the EBC. An increase of the EBV positivity in non-small cell lung cancer (NSCLC) patients compared with controls and of the CMV in advanced stages of lung cancer were observed. The association of the positivity of the cytology and the CMV test (in EBC or brushing) slightly increased the sensitivity of malignant diagnosis. Conclusion: EBV and CMV resulted detectable in the EBC. In consideration of the potential involvement of these viruses in lung cancer, which was confirmed in this study, future studies in this direction were supported

Comparative gene expression profiling of tobacco-associated HPV-positive versus negative oral squamous carcinoma cell lines

Background: HPV-positive oral squamous cell carcinomas (OSCCs) are specific biological and clinical entities, characterized by a more favorable prognosis compared to HPV-negative OSCCs and occurring generally in non-smoking and non-drinking younger individuals. However, poor information is available on the molecular and the clinical behavior of HPV-positive oral cancers occurring in smoking/drinking subjects. Thus, this study was designed to compare, at molecular level, two OSCC cell lines, both derived from drinking and smoking individuals and differing for presence/absence of HPV infection. Methods: HPV-negative UPCI-SCC-131 and HPV16-positive UPCI-SCC-154 cell lines were compared by whole genome gene expression profiling and subsequently studied for activation of Wnt/βCatenin signaling pathway by the expression of several Wnt-target genes, βCatenin intracellular localization, stem cell features and miRNA let-7e. Gene expression data were validated in head and neck squamous cell carcinoma (HNSCC) public datasets. Results: Gene expression analysis identified Wnt/βCatenin pathway as the unique signaling pathway more active in HPV-negative compared to HPV-positive OSCC cells and this observation was confirmed upon evaluation of several Wnt-target genes (i.e., Cyclin D1, Cdh1, Cdkn2a, Cd44, Axin2, c-Myc and Tcf1). Interestingly, HPV-negative OSCC cells showed higher levels of total βCatenin and its active form, increase of its nuclear accumulation and more prominent stem cell traits. Furthermore, miRNA let-7e was identified as potential upstream regulator responsible for the downregulation of Wnt/βCatenin signaling cascade since its silencing in UPCI-SCC-154 cell resulted in upregulation of Wnt-target genes. Finally, the analysis of two independent gene expression public datasets of human HNSCC cell lines and tumors confirmed that Wnt/βCatenin pathway is more active in HPV-negative compared to HPV-positive tumors derived from individuals with smoking habit. Conclusions: These data suggest that lack of HPV infection is associated with more prominent activation of Wnt/βCatenin signaling pathway and gain of stem-like traits in tobacco-related OSCCs

Adipose Tissue Secretion Pattern Influences β-Cell Wellness in the Transition from Obesity to Type 2 Diabetes

The dysregulation of the β-cell functional mass, which is a reduction in the number of β-cells and their ability to secure adequate insulin secretion, represents a key mechanistic factor leading to the onset of type 2 diabetes (T2D). Obesity is recognised as a leading cause of β-cell loss and dysfunction and a risk factor for T2D. The natural history of β-cell failure in obesity-induced T2D can be divided into three steps: (1) β-cell compensatory hyperplasia and insulin hypersecretion, (2) insulin secretory dysfunction, and (3) loss of β-cell mass. Adipose tissue (AT) secretes many hormones/cytokines (adipokines) and fatty acids that can directly influence β-cell function and viability. As this secretory pattern is altered in obese and diabetic patients, it is expected that the cross-talk between AT and pancreatic β-cells could drive the maintenance of the β-cell integrity under physiological conditions and contribute to the reduction in the β-cell functional mass in a dysmetabolic state. In the current review, we summarise the evidence of the ability of the AT secretome to influence each step of β-cell failure, and attempt to draw a timeline of the alterations in the adipokine secretion pattern in the transition from obesity to T2D that reflects the progressive deterioration of the β-cell functional mass

HPV in exhaled breath condensate of lung cancer patients

Background: A recent intriguing carcinogenetic hypothesis for lung cancer foresees its viral aetiology. The human papilloma virus (HPV) is the main virus actually recognised in the pathogenesis of lung cancer. The aim of this study was to investigate, for the first time to our knowledge, the presence of HPV in the exhaled breath condensate (EBC) of lung cancer patients.Materials and method:We enrolled 89 patients affected by lung cancer and 68 controls. HPV infections were investigated in their EBC, paired bronchial brushing and neoplastic lung tissue through genotyping. Results: We were able to detect HPV in the EBC, bronchial brushing and neoplastic lung tissue. We described the presence of an HPV infection in 16.4% of the subjects affected by non-small cell lung cancer, but in none of the controls. HPV 16 and 31 turned out to be the most widespread genotypes. The HPV positivity in airways as well as in the smoking habit was seen to independently increase the individual's susceptibility to developing lung cancer. Conclusion: When summing up, we demonstrated the possibility to identify an HPV infection in the EBC of lung cancer patients; further, we supported the notion that the EBC is a suitable tool to study airway colonisation. That being said, although further studies are needed to confirm our results, we retain the study of HPV in EBC to be very interesting in terms of future programmes involving lung-cancer screening. © 2011 Cancer Research UK All rights reserved

Negative influence of Melanocortin-1 receptor (MC1R) polymorphisms on clinical outcomes of metastatic melanoma (MM) patients (pts) harboring BRAF mutation and treated with BRAF inhibitors (BRAFi)

Background: In the pigmentation of hair and skin a key role is played by MC1R gene whose inherited variations encoding for a non-functional receptor are linked with melanoma risk. MC1R also mediates cell signals regulating DNA repair, survival and migration of melanoma. MC1R status does not seem to affect melanoma histology while its association with BRAF V600 mutation and pts survival are still debated. Our aim was to evaluate the effect of MC1R variants on outcomes of BRAF V600 pts treated with BRAFi considering that no data are available. Patients and methods: Fifty-three pts treated with BRAFi (vemurafenib 46, dabrafenib 7) were studied. We divided pts in 2 groups according to MC1R status (wild type, 21 pts vs minor/major functional variants, 32 pts). BRAF and MC1R status was evaluated by sequencing methods on tumor tissue and peripheral blood samples, respectively. Baseline characteristics of pts and disease (age, sex, M stage, number and site of metastases, site of progression), overall survival (OS), overall response rate (ORR) and progression free survival (PFS) under BRAFi were compared between the 2 groups. MAPK pathway activation was also studied by measuring p/ERK and p/p38 levels in 2 representative BRAF V600 mutated melanoma cell lines (MBA72, Hmel-1) with different MC1R status (wt and presence of variants) in order to reproduce in vitro the features of the two pts groups. Results: Baseline evaluation revealed a significant association between the presence of bone metastases and MC1R polymorphisms (p 0.0172). Moreover, the presence of MC1R variants was significantly associated with a worst outcomes under BRAFi in term of both ORR and median PFS (respectively 59% vs 95% [p 0.018 Ods Ratio 9.980] and 5 months vs 8 months [p 0.017Hazard Ratio 2.107] in MC1R variant vs wt). No significant difference was found in OS probably owing the influence of prior or subsequent treatments on this outcome. Data in vitro demonstrated high levels of p-Erk1/2 in both cell lines but significant higher levels in activation of p38 MAPK was found in MC1R variants. Conclusions: These data demonstrated for the first time that MC1R variants have detrimental effects on clinical outcomes of pts treated with BRAFi by increasing the state of the hyperactivation of MAPK pathway. These evidences could shed further light on BRAFi resistance and suggest new therapeutic targets for MM