The ambitious role of anti angiogenesis molecules: Turning a cold tumor into a hot one

In renal cancer emerging treatment options are becoming available and there is a strong need to combine therapies to reformulate and adjourn clinical practice. We here highlight and discuss the need to take advantage of the common immune targets to design combined strategies to increase clinical responses

CD137+ T-cells: protagonists of the immunotherapy revolution

The CD137 receptor is expressed by activated antigen-specific T-cells. CD137+ T-cells were identified inside TILs and PBMCs of different tumor types and have proven to be the naturally occurring antitumor effector cells, capable of expressing a wide variability in terms of TCR specificity against both shared and neoantigenic tumor-derived peptides. The aim of this review is thus summarizing and highlighting their role as drivers of patients’ immune responses in anticancer therapies as well as their potential role in future and current strategies of immunotherapy. The CD137 receptor (4-1BB, TNF RSF9) is an activation induced molecule expressed by antigen-specific T-cells. The engagement with its ligand, CD137L, is capable of increasing Tcell survival, proliferation, and cytokine production. This allowed to identify the CD137+ T-cells as the real tumor-specific activated T-cell population. In fact, these cells express various TCRs that are specific for a wide range of tumor-derived peptides, both shared and neoantigenic ones. Moreover, their prevalence in sites close to the tumor and their unicity in killing cancer cells both in vitro and in vivo, raised particular interest in studying their potential role in different strategies of immunotherapy. They indeed showed to be a reliable marker able to predict patient’s outcome to immune-based therapies as well as monitor their response. In addition, the possibility of isolating and expanding this population, turned promising in order to generate effector antitumor T-cells in the context of adoptive T-cell therapies. CD137-targeting monoclonal antibodies have already shown their antitumor efficacy in cancer patients and a number of clinical trials are thus ongoing to test their possible introduction in different combination approaches of immunotherapy. Finally, the intracellular domain of the CD137 receptor was introduced in the anti-CD19 CAR-T cells that were approved by FDA for the treatment of pediatric B-cell leukemia and refractory B-cell lymphoma

a simplified procedure for base sliding evaluation of concrete gravity dams under seismic action

Possible base sliding induced by an earthquake on concrete gravity dams is obtained by a simplified procedure. The model is a nonlinear single-degree-of-freedom system which takes into account dam-water-foundation interaction based on the model developed by Fenves and Chopra (1987). The nonlinearity is in the foundation rock, since a threshold value for the sliding foundation resistance, modeled with the Mohr-Coulomb yielding criterion including a frictional and a cohesive component, is imposed. Nonlinear step by dams is obtained by a simplified procedure. The model is a nonlinear single-degree-of-freedom system which takes into account dam-water-foundation interaction based on the model developed by Fenves and Chopra (1987). The nonlinearity is in the foundation rock, since a threshold value for the sliding foundation resistance, modeled with the Mohr-Coulomb yielding criterion including a frictional and a cohesive component, is imposed. Nonlinear step by step dynamic analyses are carried out on four case studies representing typical examples of Italian concrete gravity dams by utilizing several natural earthquakes. On the basis of the obtained results, a simplified methodology to estimate residual displacement without performing nonlinear dynamic analysis is presented. An example of application using as seismic input the elastic response spectra furnished by the Italian Code is also presented

Relationships between technical efficiency and the quality and costs of health care in Italy†

Objectives This paper reports the measurement of technical efficiency of Tuscan Local Health Authorities and its relationship with quality and appropriateness of care. Design First, a bias-corrected measure of technical efficiency was developed using the bootstrap technique applied to data envelopment analysis. Then, correlation analysis was used to investigate the relationships among technical efficiency, quality and appropriateness of care. Setting and Participants These analyses have been applied to the Local Health Authorities of Tuscany Region (Italy), which provide not only hospital inpatient services, but also prevention and primary care. All top managers of Tuscan Local Health Authorities were involved in selection of the inputs and outputs for calculating technical efficiency. Main Outcome Measures The main measures used in this study are volume, quality and appropriateness indicators monitored by the multidimensional performance evaluation system developed in the Tuscany Region. Results On average, Tuscan Local Health Authorities experienced 14(%) of bias-corrected inefficiency in 2007. Correlation analyses showed a significant negative correlation between per capita costs and overall performance. No correlation was found in 2007 between technical efficiency and overall performance or between technical efficiency and per capita costs. Conclusions Technical efficiency cannot be considered as an extensive measure of healthcare performance, but evidence shows that Tuscan Local Health Authorities have room for improvement in productivity levels. Indeed, correlation findings suggest that, to pursue financial sustainability, Local Health Authorities mainly have to improve their performance in terms of quality and appropriateness

Healthcare resources and expenditure in financial crisis: scenarios and managerial strategies

What are the implications of financial crisis on healthcare expenditure? This paper explores different approaches applied across European countries focusing on the role that managerial tools may have in coping with this challenge. Method: The paper reports the results of recent studies on responses to financial crisis from European countries and which are the techniques they had applied to reallocate resources. Results: Although resources scarcity, some governments did not reduce the healthcare expenditure because they believe in its focal role on the economic development and on maintaining social cohesion and protection of vulnerable people. Other countries decided a strong reduction of costs which often has affected services delivered. In both cases authors suggest to avoid across-the-board cuts in favor of approach involving priority setting. Conclusion: The public sector has assumed new responsibilities following the global crisis and the rising demand for social services. Some countries shifted the healthcare costs from the public purse to private households undermining the survival of the health system and the universal coverage. A way to avoid this risk is based on the ability to share discussion about where to cut and where to reallocate resources

Natriuretic peptides and NGAL in heart failure: does a link exist?

In recent years there has been growing interest in the development of new diagnostic tools and particularly in laboratory tests for the identification of heart failure (HF) patients. Because of the rise in HF occurrence, it is necessary to use simple and reliable method to recognize those patients at risk before the onset of the clinical symptoms. To date HF diagnosis remains difficult: its symptoms and signs are often non specific as well as being poor sensitive indicators for HF severity. Throughout the last 10 years published literature has highlighted a boom in the use of biomarkers for HF. Both B-type and N-terminal pro-B-type natriuretic peptides have demonstrated specific role in heart failure diagnosis, as well as risk assessment. A single determination of BNP at any time during the development of chronic heart failure (CHF) provides a clinically useful tool to establish the outcome. Renal dysfunction is often associated with heart failure and predicts adverse clinical outcomes. Many studies have recently suggested the clinical use of serum neutrophil gelatinase-associated lipocalin (NGAL) levels in patients admitted to the hospital for acute HF can be used to estimate the risk of early worsening renal function. This could be potentially applied in clinical practice for early identification of renal dysfunction development in patients with HF. NGAL levels appear also to predict renal dysfunction in patients with chronic HF and preserved renal function. For all these reasons, BNP and NGAL are two emerging tools useful for diagnosis and prognosis in HF. The combination of two laboratory biomarkers could potentially identify patients with more elevated risks of both cardiac hemodynamic impairment and kidney dysfunction