Therapy-induced antitumor vaccination in neuroblastomas by the combined targeting of IL-2 and TNF alpha

L19-IL2 and L19TNF are fusion proteins composed of L19(scFv), specific for the angiogenesis-associated ED-B containing fibronectin isoform and IL-2 or TNF. Because of the tumor targeting properties of L19, IL-2 and TNF concentrate at therapeutic doses at the tumor vascular level. To evaluate the therapeutic effects of L19-IL2 and L19mTNF in neuroblastoma (NB)-bearing mice, A/J mice bearing Neuro2A or NIE115 NB were systemically treated with L19-IL2 and L19mTNF, alone or in combination protocols. Seventy percent of Neuro2A- and 30% of NIE115-bearing mice were cured by the combined treatment with L19-IL2 and L19mTNF, and further rejected a homologous tumor challenge, indicating specific antitumor immune memory. The immunological bases of tumor cure and rejection were studied. A highly efficient priming of CD4+ T helper cells and CD8+ CTL effectors was generated, paralleled by massive infiltration in the tumor tissue of CD4+ and CD8+ T cells at day 16 after tumor cell implantation, when, after therapy, tumor volume was drastically reduced and tumor necrosis reached about 80%. The curative treatment resulted in a long-lasting antitumor immune memory, accompanied by a mixed Th1/Th2 type of response. Concluding, L19-IL2 and L19mTNF efficiently cooperate in determining a high percentage of NB cure that, in our experimental models, is strongly associated to the generation of adaptive immunity involving CD4+ and CD8+ T cells

Bacteriological Quality of Milk in Raw Bovine Bulk Milk in the Selected Milk Collection Centers : Smallholder Dairy Processing Ethiopia

Cross-sectional study was conducted to examine and identify quality of raw bovine milk from in Arsi Zone and East Shewa Zone, in Oromia, Ethiopia. The purpose of the study was to assess hygienic practices during milking, milk collection and bacteriological quality of cow\u2019s milk in Arsi and East Shewa Zones milk collection centers. Total of 246 bacterial isolates were obtained from milk samples taken from Tiyo, Digeluna Tijo, and Lemuna Bilbilo Districts in Arsi Zone and Ada district in East Shewa Zone. Identification of Escherichia coli done using API 20 E biochemical test kit, Gram stain was used to identify staphylococcus aureus, Listeria was identified using Rapid Listeria monocytogenes (RLM), and Brucella identified using Milk ring test (MRT). These included Escherichia coli 19.8%, Listeria monocytogenes 1.2%, Staphylococcus aureus 3.2% and Brucella 3.3%

The “Personal Health Budget” intervention model in early psychosis: Preliminary findings from the Parma experience

Objectives Personal Health Budget (PHB) has recently been provided to people with severe mental illness, reflecting a policy shift towards a personalized mental health care based on individual unmet needs. However, evidence on effectiveness of PHB initiatives is still limited. Aim of this research was to provide preliminary data about the beneficial effects of adding PHB to a multicomponent EIP intervention in patients with First-Episode Psychosis (FEP) along a 2-year follow-up period. Methods Participants (n = 49) were FEP patients, aged 18-50 years, entered the “Parma Early Psychosis” program and completing the Health of Nation Outcome Scale (HoNOS), the Brief Psychiatric Rating Scale (BPRS) and the Global Assessment of Functioning (GAF). Friedman test for repeated measure (with Wilcoxon test as post-hoc procedure) was performed to evaluate the longitudinal stability of functioning and clinical parameters. A linear regression analysis was also carried out. Results A significant effect of time on all HoNOS, BPRS and GAF scores along the 2 years of follow-up was found. Regression analysis results specifically showed a relevant association between a PHB multiaxial intervention and the longitudinal decrease in BPRS “Negative Symptoms” subscores, as well as in HoNOS “Behavioral Problems” and “Social Problems” scores. Conclusions Our results support the general applicability of a PHB approach within an “Early Intervention in Psychosis” program for help-seeking adults with FEP

Making the most of data:An information selection and assessment framework to improve water systems operations

Advances in Environmental monitoring systems are making a wide range of data available at increasingly higher temporal and spatial resolution. This creates an opportunity to enhance real-time understanding of water systems conditions and to improve prediction of their future evolution, ultimately increasing our ability to make better decisions. Yet, many water systems are still operated using very simple information systems, typically based on simple statistical analysis and the operator’s experience. In this work, we propose a framework to automatically select the most valuable information to inform water systems operations supported by quantitative metrics to operationally and economically assess the value of this information. The Hoa Binh reservoir in Vietnam is used to demonstrate the proposed framework in a multiobjective context, accounting for hydropower production and flood control. First, we quantify the expected value of perfect information, meaning the potential space for improvement under the assumption of exact knowledge of the future system conditions. Second, we automatically select the most valuable information that could be actually used to improve the Hoa Binh operations. Finally, we assess the economic value of sample information on the basis of the resulting policy performance. Results show that our framework successfully select information to enhance the performance of the operating policies with respect to both the competing objectives, attaining a 40% improvement close to the target trade-off selected as potentially good compromise between hydropower production and flood control

Hybrid fibroin/polyurethane small-diameter vascular grafts: from fabrication to in vivo preliminary assessment

To address the need of alternatives to autologous vessels for small-calibre vascular applications (e.g. cardiac surgery), a bio-hybrid semi-degradable material composed of silk fibroin (SF) and polyurethane (Silkothane (R)) was herein used to fabricate very small-calibre grafts (o(in) = 1.5 mm) via electrospinning. Bio-hybrid grafts were in vitro characterized in terms of morphology and mechanical behaviour, and compared to similar grafts of pure SF. Similarly, two native vessels from a rodent model (abdominal aorta and vena cava) were harvested and characterized. Preliminary implants were performed on Lewis rats to confirm the suitability of Silkothane (R) grafts for small-calibre applications, specifically as aortic insertion and femoral shunt. The manufacturing process generated pliable grafts consisting of a randomized fibrous mesh and exhibiting similar geometrical features to rat aortas. Both Silkothane (R) and pure SF grafts showed radial compliances in the range from 1.37 +/- 0.86 to 1.88 +/- 1.01% 10(-2) mmHg(-1), lower than that of native vessels. The Silkothane (R) small-calibre devices were also implanted in rats demonstrating to be adequate for vascular applications; all the treated rats survived the surgery for three months after implantation, and 16 rats out of 17 (94%) still showed blood flow inside the graft at sacrifice. The obtained results lay the basis for a deeper investigation of the interaction between the Silkothane (R) graft and the implant site, which may deal with further analysis on the potentialities in terms of degradability and tissue formation, on longer time-points

Treatment with the CC chemokine-binding protein Evasin-4 improves post-infarction myocardial injury and survival in mice

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factors influencing acute and late toxicity in the era of adjuvant hypofractionated breast radiotherapy

Abstract Purpose To evaluate toxicity in breast cancer patients treated with anthracycline and taxane based chemotherapy and whole breast hypofractionated radiotherapy, and to identify the risk factors for toxicity. Methods and materials 537 early breast cancer patients receiving hypofractionated radiotherapy after conservative surgery were enrolled from April 2009 to December 2014, in an Italian cancer institute. The dose was 42.4 Gy in 16 daily fractions, 2.65 Gy per fraction. The boost to the tumor bed was administered only in grade III breast cancer patients and in patients with close or positive margins. Acute and late toxicity were prospectively assessed during and after radiotherapy according to RTOG scale. The impact of patients clinical characteristics, performed treatments and dose inhomogeneities on the occurrence of an higher level of acute skin toxicity and late fibrosis has been evaluated by univariate and multivariate analysis. Results The mean age was 74 (range 46–91 yrs). 27% of patients received boost. 22% of cases (n = 119) received also chemotherapy. The median follow-up was 32 months. G1 and G2/G3 acute skin toxicity were 61.3% and 20.5% and G1 and G2/G3 late fibrosis 12.6% and 4.3% respectively. Chemotherapy (p = 0.04), diabetes (p = 0.04) and boost administration (p Conclusions The results of our study, according to the large randomized trials, confirmed that hypofractionated whole breast irradiation is safe, and only the boost administration seems to be an important predictor for toxicity. Chemotherapy does not impact on acute and late skin toxicity

Patient-specific Instrumentation Affects Rotational Alignment of the Femoral Component in Total Knee Arthroplasty : A Prospective Randomized Controlled Trial

Objective: To evaluate whether patient-specific instrumentation (PSI) improve the accuracy of femoral component rotational alignment with respect to conventionally-implanted total knee arthroplasty (TKA). Methods: Twenty-four patients were randomized to receive a TKA implanted with PSI or conventional instrumentation. Implant orientation was compared on Computed Tomography (CT). Surgical time, recuts, and component size variations from planning were recorded. Preoperative and postoperative Oxford knee score and visual analogue scale were compared to assess clinical outcomes. Results: Femoral components implanted with patient-specific instrumentation were aligned with greater external rotation than those implanted with conventional instrumentation (P = 0.022). No significant differences were found in surgical times, number of recuts, and clinical outcomes. Surgeon modifications from the planned size were necessary in 58% of PSI cases. Conclusion: Femoral components implanted with PSI had greater external rotation than with conventional instrumentation. Surgeons must carefully evaluate component sizes when using PSI, both in planning and during surgery

Influence of pharmacogenetic variability on the pharmacokinetics and toxicity of the aurora kinase inhibitor danusertib

Objectives Danusertib is a serine/threonine kinase inhibitor of multiple kinases, including aurora-A, B, and C. This explorative study aims to identify possible relationships between single nucleotide polymorphisms in genes coding for drug metabolizing enzymes and transporter proteins and clearance of danusertib, to clarify the interpatient variability in exposure. In addition, this study explores the relationship between target receptor polymorphisms and toxicity of danusertib. Methods For associations with clearance, 48 cancer patients treated in a phase I study were analyzed for ABCB1, ABCG2 and FMO3 polymorphisms. Association analyses between neutropenia and drug target receptors, including KDR, RET, FLT3, FLT4, AURKB and AURKA, were performed in 30 patients treated at recommended phase II dose-levels in three danusertib phase I or phase II trials. Results No relationships between danusertib clearance and drug metabolizing enzymes and transporter protein polymorphisms were found. Only, for the one patient with FMO3 18281AA polymorphism, a significantly higher clearance was noticed, compared to patients carrying at least 1 wild type allele. No effect of target receptor genotypes or haplotypes on neutropenia was observed. Conclusions As we did not find any major correlations between pharmacogenetic variability in the studied enzymes and transporters and pharmacokinetics nor toxicity, it is unlikely that danusertib is highly susceptible for pharmacogenetic variation. Therefore, no dosing alterations of danusertib are expected in the future, based on the polymorphisms studied. However, the relationship between FMO3 polymorphisms and clearance of danusertib warrants further research, as we could study only a small group of patients