5. Vaccine development: basic considerations. Asexual blood stage vaccines: from merozoites to peptides

Asexual blood stage proliferation is responsible for the morbidity and mortality associated with malaria infection in man. These developmental stages are therefore obvious targets for the development of malaria vaccines. Several asexual blood stage components have been identified as potential candidates for the development of vaccines and some of them have been shown, following immunization, to induce at least partial protection in a variety of Plasmodium-host combinations. Studies on defined parasite components and on synthetic peptides derived from them have revealed new insights at the molecular level into parasite mechanisms involved in propagation and survival in the infected host, and into the interaction between parasite components and the host immune system. Practical application of these findings is likely to provide the basis for the design of more appropriate antigens for the development of vaccine

Multi-Temporal investigation of the Boulder Clay Glacier and Northern Foothills (Victoria Land, Antarctica) by integrated surveying techniques

The paper aims to detect the main changes that occurred in the area surrounding the Mario Zucchelli Station (MZS) through analysis of multi-temporal remote sensing integrated by geophysical measurements. Specific attention was directed at realizing an integrated geomorphological study of the Boulder Clay Glacier, a partially debris-covered glacier belonging to the Northern Foothills (Victoria Land, Antarctica). This area was recently chosen as the location for the construction of a new semi-permanent gravel runway for MZS logistical airfreight operations. Photogrammetric analysis was performed by comparing three historical aerial photogrammetric surveys (carried out in 1956, 1985, and 1993) and Very High Resolution (VHR) GeoEye-1 satellite stereo-image coverage acquired in 2012. The comparison of geo-referenced orthophoto-mosaics allowed the main changes occurring in some particular areas along the coast nearby MZS to be established. Concerning the study of the Boulder Clay Glacier, it has to be considered that glaciers and moraines are not steady-state systems by definition. Several remote sensing and geophysical investigations were carried out with the main aim of determining the general assessment of this glacier: Ground Penetrating Radar (GPR); Geodetic Global Positioning System (GPS) network; multi-temporal satellite Synthetic Aperture Radar (SAR) interferometry. The analysis of Boulder Clay Glacier moraine pointed out a deformation of less than 74 mm y-1 in a time span of 56 years, value that agrees with velocity and deformation data observed by GPS and InSAR methods. The presence of unexpected brine ponds at the ice/bedrock interface and the deformation pattern observed in the central part of the moraine has to be monitored and studied, especially under the long-term maintenance of the future runway

HER2-Enriched Subtype and ERBB2 Expression in HER2-Positive Breast Cancer Treated with Dual HER2 Blockade

Background: Identification of HER2-positive breast cancers with high anti-HER2 sensitivity could help de-escalate chemotherapy. Here, we tested a clinically applicable RNA-based assay that combines ERBB2 and the HER2-enriched (HER2-E) intrinsic subtype in HER2-positive disease treated with dual HER2-blockade without chemotherapy. Methods: A research-based PAM50 assay was applied in 422 HER2-positive tumors from five II-III clinical trials (SOLTI-PAMELA, TBCRC023, TBCRC006, PER-ELISA, EGF104090). In SOLTI-PAMELA, TBCRC023, TBCRC006, and PER-ELISA, all patients had early disease and were treated with neoadjuvant lapatinib or pertuzumab plus trastuzumab for 12-24 weeks. Primary outcome was pathological complete response (pCR). In EGF104900, 296 women with advanced disease were randomized to receive either lapatinib alone or lapatinib plus trastuzumab. Progression-free survival (PFS), overall response rate (ORR), and overall survival (OS) were evaluated. Results: A total of 305 patients with early and 117 patients with advanced HER2-positive disease were analyzed. In early disease, HER2-E represented 83.8% and 44.7% of ERBB2-high and ERBB2-low tumors, respectively. Following lapatinib and trastuzumab, the HER2-E and ERBB2 (HER2-E/ERBB2)-high group showed a higher pCR rate compared to the rest (44.5%, 95% confidence interval [CI] = 35.4% to 53.9% vs 11.6%, 95% CI = 6.9% to 18.0%; adjusted odds ratio [OR] = 6.05, 95% CI = 3.10 to 11.80, P <. 001). Similar findings were observed with neoadjuvant trastuzumab and pertuzumab (pCR rate of 66.7% in HER2-E/ERBB2-high, 95% CI = 22.3% to 95.7% vs 14.7% in others, 95% CI = 4.9% to 31.1%; adjusted OR = 11.60, 95% CI = 1.66 to 81.10, P =. 01). In the advanced setting, the HER2-E/ERBB2-high group was independently associated with longer PFS (hazard ratio [HR] = 0.52, 95% CI = 0.35 to 0.79, P <. 001); higher ORR (16.3%, 95% CI = 8.9% to 26.2% vs 3.7%, 95% CI = 0.8% to 10.3%, P =. 02); and longer OS (HR = 0.66, 95% CI = 0.44 to 0.97, P =. 01). Conclusions: Combining HER2-E subtype and ERBB2 mRNA into a single assay identifies tumors with high responsiveness to HER2-targeted therapy. This biomarker could help de-escalate chemotherapy in approximately 40% of patients with HER2-positive breast cancer

Living-floors and Structures from the Lower Palaeolithic to the Bronze Age in Italy

Summary report of the research carried out on the Living floors of the Palaeolithic to Neolithic periods in many prehistoric sites of northern Ital

Indagini Geofisiche

Nell'ambito del progetto per la Microzonazione sismica dell'area aquilana, coordinata dal DPC, il Gruppo di Lavoro ha condotto le indagini di MS nella Conca di Roio.Published336-3854T. Sismologia, geofisica e geologia per l'ingegneria sismic

RAD51 foci as a functional biomarker of homologous recombination repair and PARP inhibitor resistance in germline BRCA-mutated breast cancer.

BACKGROUND: BRCA1 and BRCA2 (BRCA1/2)-deficient tumors display impaired homologous recombination repair (HRR) and enhanced sensitivity to DNA damaging agents or to poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi). Their efficacy in germline BRCA1/2 (gBRCA1/2)-mutated metastatic breast cancers has been recently confirmed in clinical trials. Numerous mechanisms of PARPi resistance have been described, whose clinical relevance in gBRCA-mutated breast cancer is unknown. This highlights the need to identify functional biomarkers to better predict PARPi sensitivity. PATIENTS AND METHODS: We investigated the in vivo mechanisms of PARPi resistance in gBRCA1 patient-derived tumor xenografts (PDXs) exhibiting differential response to PARPi. Analysis included exome sequencing and immunostaining of DNA damage response proteins to functionally evaluate HRR. Findings were validated in a retrospective sample set from gBRCA1/2-cancer patients treated with PARPi. RESULTS: RAD51 nuclear foci, a surrogate marker of HRR functionality, were the only common feature in PDX and patient samples with primary or acquired PARPi resistance. Consistently, low RAD51 was associated with objective response to PARPi. Evaluation of the RAD51 biomarker in untreated tumors was feasible due to endogenous DNA damage. In PARPi-resistant gBRCA1 PDXs, genetic analysis found no in-frame secondary mutations, but BRCA1 hypomorphic proteins in 60% of the models, TP53BP1-loss in 20% and RAD51-amplification in one sample, none mutually exclusive. Conversely, one of three PARPi-resistant gBRCA2 tumors displayed BRCA2 restoration by exome sequencing. In PDXs, PARPi resistance could be reverted upon combination of a PARPi with an ataxia-telangiectasia mutated (ATM) inhibitor. CONCLUSION: Detection of RAD51 foci in gBRCA tumors correlates with PARPi resistance regardless of the underlying mechanism restoring HRR function. This is a promising biomarker to be used in the clinic to better select patients for PARPi therapy. Our study also supports the clinical development of PARPi combinations such as those with ATM inhibitors

Stazione della media età del Bronzo sul Colle di Sant'Anna a Brescia

Newspaper published in Holland, Michigan, from 1872-1977, to serve the English-speaking people in Holland, Michigan. Purchased by local Dutch language newspaper, De Grondwet, owner in 1888.https://digitalcommons.hope.edu/hcn_1929/1015/thumbnail.jp