HER2-Displaying M13 Bacteriophages induce Therapeutic Immunity against Breast Cancer

The advent of trastuzumab has significantly improved the prognosis of HER2-positive (HER2+) breast cancer patients; nevertheless, drug resistance limits its clinical benefit. Anti-HER2 active immunotherapy represents an attractive alternative strategy, but effective immunization needs to overcome the patient's immune tolerance against the self-HER2. Phage display technology, taking advantage of phage intrinsic immunogenicity, permits one to generate effective cancer vaccines able to break immune tolerance to self-antigens. In this study, we demonstrate that both preventive and therapeutic vaccination with M13 bacteriophages, displaying the extracellular (EC) and transmembrane (TM) domains of human HER2 or its Δ16HER2 splice variant on their surface (ECTM and Δ16ECTM phages), delayed mammary tumor onset and reduced tumor growth rate and multiplicity in ∆16HER2 transgenic mice, which are tolerant to human ∆16HER2. This antitumor protection correlated with anti-HER2 antibody production. The molecular mechanisms underlying the anticancer effect of vaccine-elicited anti-HER2 antibodies were analyzed in vitro against BT-474 human breast cancer cells, sensitive or resistant to trastuzumab. Immunoglobulins (IgG) purified from immune sera reduced cell viability mainly by impairing ERK phosphorylation and reactivating retinoblastoma protein function in both trastuzumab-sensitive and -resistant BT-474 cells. In conclusion, we demonstrated that phage-based HER2 vaccines impair mammary cancer onset and progression, opening new perspectives for HER2+ breast cancer treatment

Twelve Variants Polygenic Score for Low-Density Lipoprotein Cholesterol Distribution in a Large Cohort of Patients With Clinically Diagnosed Familial Hypercholesterolemia With or Without Causative Mutations

: Background A significant proportion of individuals clinically diagnosed with familial hypercholesterolemia (FH), but without any disease-causing mutation, are likely to have polygenic hypercholesterolemia. We evaluated the distribution of a polygenic risk score, consisting of 12 low-density lipoprotein cholesterol (LDL-C)-raising variants (polygenic LDL-C risk score), in subjects with a clinical diagnosis of FH. Methods and Results Within the Lipid Transport Disorders Italian Genetic Network (LIPIGEN) study, 875 patients who were FH-mutation positive (women, 54.75%; mean age, 42.47±15.00 years) and 644 patients who were FH-mutation negative (women, 54.21%; mean age, 49.73±13.54 years) were evaluated. Patients who were FH-mutation negative had lower mean levels of pretreatment LDL-C than patients who were FH-mutation positive (217.14±55.49 versus 270.52±68.59 mg/dL, P<0.0001). The mean value (±SD) of the polygenic LDL-C risk score was 1.00 (±0.18) in patients who were FH-mutation negative and 0.94 (±0.20) in patients who were FH-mutation positive (P<0.0001). In the receiver operating characteristic analysis, the area under the curve for recognizing subjects characterized by polygenic hypercholesterolemia was 0.59 (95% CI, 0.56-0.62), with sensitivity and specificity being 78% and 36%, respectively, at 0.905 as a cutoff value. Higher mean polygenic LDL-C risk score levels were observed among patients who were FH-mutation negative having pretreatment LDL-C levels in the range of 150 to 350 mg/dL (150-249 mg/dL: 1.01 versus 0.91, P<0.0001; 250-349 mg/dL: 1.02 versus 0.95, P=0.0001). A positive correlation between polygenic LDL-C risk score and pretreatment LDL-C levels was observed among patients with FH independently of the presence of causative mutations. Conclusions This analysis confirms the role of polymorphisms in modulating LDL-C levels, even in patients with genetically confirmed FH. More data are needed to support the use of the polygenic score in routine clinical practice

Evolution and Relocation in Fashion-led Italian Districts: Evidence from two Case-Studies

The aim of this paper is to contribute to the debate about how, in advanced countries, industrial districts specialised in traditional manufacturing industries evolve as a consequence of new challenges linked to the globalisation process. Using a multiple case study design, the study examines the evolution of two fashion-led Italian districts: the Montebelluna sportswear system and the Vibrata-Tordino-Vomano clothing district. Our findings reveal that cluster firms’ ability to shift from manufacturing to other activities providing higher returns along the global value chain is key to understanding the effect of globalisation and relocation processes on the cluster’s long-term competitiveness. As illustrated in this study, weak learning districts are the most threatened while innovative districts are able to enact a selective process of relocation, substituting outplaced activities with more valuable ones and attracting inward investments.

Influence of the surface morphology on the channel mobility of lateral implanted 4H-SiC(0001) metal-oxide-semiconductor field-effect transistors

The influence of the surface morphology on the channel mobility of 4H-SiC metal-oxidesemiconductor field effect transistors annealed under two different conditions is discussed. The devices were fabricated using post-implantation annealing at 1650 C. In particular, while the use of a protective capping layer during post-implantation annealing preserved a smooth 4H-SiC surface resulting in a channel mobility of 24 cm2 V1 s1, a rougher morphology of the channel region (with the presence of surface macrosteps) was observed in the devices annealed without protection, which in turn exhibited a higher mobility (40 cm2 V1 s1). An electrical analysis of SiO2/SiC capacitors demonstrated a reduction of the interface state density from 7.21011 to 3.61011 cm2 eV1, which is consistent with the observed increase of the mobility. However, high resolution transmission electron microscopy showed an almost atomically perfect SiO2/4HSiC interface. The electrical results were discussed considering the peculiar surface morphology of the annealed 4H-SiC surfaces, i.e., attributing the overall reduction of the interface state density to the appearance of macrosteps exposing non-basal planes

Learning At The Boundaries In An “Open Regional Innovation System”: A Focus On Firms’ Innovation Strategies In The Emilia Romagna Life Science Industry

The paper investigates the existence of an Open Regional Innovation System (ORIS model). This model is characterised by the firms’ adoption of an open innovation strategy, which overcomes not only the boundaries of the firms but also the boundaries of the region. Using data collected in a sample of life science firms, our research provides the evidence that the Emilia Romagna RIS has evolved towards an ORIS model, where firms’ innovation search strategy, despite being still embedded in local nets (involving several regional public research organisations - PROs), is open to external-to-the-region research networks and knowledge sources. It also shows that innovation openness influences significantly the firms’ innovative performance.life science sector, learning at the boundaries, Regional Innovation Systems, networks, open innovation model