Arming CTLs against immunosuppressors

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THE IMPACT OF THE NEW ITALIAN EARLY WARNING SYSTEM PROVIDED BY THE IC-CODE ON FAMILY SMES GOVERNANCE

The Early Warning System is intended as an instrument aimed at driving the companies in the identification of the very first signs of crisis. Monitoring the occurring of the crisis is no longer a responsibility of the sole entrepreneur or of the board of directors but other legitimized subjects are identified. The IC-Code sets up new corporate governance rules for a huge number of Italian Family SMEs pretending the introduction of independent control bodies, Board of Statutory Auditors, and/or External Auditor. Some of the suggestions coming from the family business framework seems then to be enforced by law in the Italian context

Corporate Governance in Downturn Times: Detection and Alert \u2013 The New Italian Insolvency and Crisis Code

In its life cycle, an enterprise may experience periods of crisis. If the crisis is monitored promptly and appropriate measures are taken, not only may the enterprise continue to operate but it may also be able to seize opportunities for growth. The Italian legislator is introducing a procedure aimed at supporting companies to detect the very irst warning signs of a crisis. The supervisory board of auditors, the audit irm, and certain qualiied creditors will have the right and duty to start the early warning procedure (\u201callerta\u201d). The board of statutory auditors (Collegio Sindacale) plays a fundamental role: its ex-ante supervisory and control activities over management allow it to efectively play an important role as main recipient of any crisis warning signs. The new regulatory framework lays down certain indicators and critical thresholds, which may trigger the alert process. Initially, the Delegated Legislation (Bill No.3671-bis) sets forth certain speciic inancial indicators. The new bill (Crisis and Insolvency Code) on the contrary refers to a more complex and sector-speciic system of indicators. The indings of an empirical research conducted by analysing a sample of more than 600 enterprises and testing the discriminating capacity of the indicators initially considered are presented herein

Corporate Governance in Downturn Times: Detection and Alert – The New Italian Insolvency and Crisis Code

In its life cycle, an enterprise may experience periods of crisis. If the crisis is monitored promptly and appropriate measures are taken, not only may the enterprise continue to operate but it may also be able to seize opportunities for growth. The Italian legislator is introducing a procedure aimed at supporting companies to detect the very first warning signs of a crisis. The supervisory board of auditors, the audit firm, and certain qualified creditors will have the right and duty to start the early warning procedure (“allerta”). The board of statutory auditors (Collegio Sindacale) plays a fundamental role: its ex-ante supervisory and control activities over management allow it to effectively play an important role as main recipient of any crisis warning signs. The new regulatory framework lays down certain indicators and critical thresholds, which may trigger the alert process. Initially, the Delegated Legislation (Bill No.3671-bis) sets forth certain specific financial indicators. The new bill (Crisis and Insolvency Code) on the contrary refers to a more complex and sector-specific system of indicators. The findings of an empirical research conducted by analysing a sample of more than 600 enterprises and testing the discriminating capacity of the indicators initially considered are presented herein

Immunotherapeutic Intervention against Sarcomas

<p>Advances in systemic therapy for sarcoma have produced, over the last two decades, relatively short-term benefits for the majority of patient. Among the novel biologic therapeutics that will likely increase our ability to cure human cancer in the years to come, immunotherapy is one of the most promising approaches. While past attempts to use immunotherapy have failed to dramatically shift the paradigm of care for the treatment of patients with sarcoma, major advances in basic and translational research have resulted, in more recent years, in clinical trial activity that is now beginning to generate promising results. However, to move from &#8220;proof of principle&#8221; to large scale clinical applicability, we need well-designed, multi-institutional clinical trials, along with continuous laboratory research to explore further the immunological characteristics of individual sarcoma subtypes and the consequent tailoring of therapy.</p

Immunotherapeutic Intervention against Sarcomas

Advances in systemic therapy for sarcoma have produced, over the last two decades, relatively short-term benefits for the majority of patient. Among the novel biologic therapeutics that will likely increase our ability to cure human cancer in the years to come, immunotherapy is one of the most promising approaches. While past attempts to use immunotherapy have failed to dramatically shift the paradigm of care for the treatment of patients with sarcoma, major advances in basic and translational research have resulted, in more recent years, in clinical trial activity that is now beginning to generate promising results. However, to move from “proof of principle” to large scale clinical applicability, we need well-designed, multi-institutional clinical trials, along with continuous laboratory research to explore further the immunological characteristics of individual sarcoma subtypes and the consequent tailoring of therapy

Minimal/Measurable Residual Disease Monitoring in NPM1-Mutated Acute Myeloid Leukemia: A Clinical Viewpoint and Perspectives

Acute myeloid leukemia (AML) with NPM1 gene mutations is currently recognized as a distinct entity, due to its unique biological and clinical features. We summarize here the results of published studies investigating the clinical application of minimal/measurable residual disease (MRD) in patients with NPM1-mutated AML, receiving either intensive chemotherapy or hematopoietic stem cell transplantation. Several clinical trials have so far demonstrated a significant independent prognostic impact of molecular MRD monitoring in NPM1-mutated AML and, accordingly, the Consensus Document from the European Leukemia Net MRD Working Party has recently recommended that NPM1-mutated AML patients have MRD assessment at informative clinical timepoints during treatment and follow-up. However, several controversies remain, mainly with regard to the most clinically significant timepoints and the MRD thresholds to be considered, but also with respect to the optimal source to be analyzed, namely bone marrow or peripheral blood samples, and the correlation of MRD with other known prognostic indicators. Moreover, we discuss potential advantages, as well as drawbacks, of newer molecular technologies such as digital droplet PCR and next-generation sequencing in comparison to conventional RQ-PCR to quantify NPM1-mutated MRD. In conclusion, further prospective clinical trials are warranted to standardize MRD monitoring strategies and to optimize MRD-guided therapeutic interventions in NPM1-mutated AML patients

Segregated anatomical input to sub-regions of the rodent superior colliculus associated with approach and defense

The superior colliculus (SC) is responsible for sensorimotor transformations required to direct gaze toward or away from unexpected, biologically salient events. Significant changes in the external world are signaled to SC through primary multisensory afferents, spatially organized according to a retinotopic topography. For animals, where an unexpected event could indicate the presence of either predator or prey, early decisions to approach or avoid are particularly important. Rodents’ ecology dictates predators are most often detected initially as movements in upper visual field (mapped in medial SC), while appetitive stimuli are normally found in lower visual field (mapped in lateral SC). Our purpose was to exploit this functional segregation to reveal neural sites that can bias or modulate initial approach or avoidance responses. Small injections of Fluoro-Gold were made into medial or lateral sub-regions of intermediate and deep layers of SC (SCm/SCl). A remarkable segregation of input to these two functionally defined areas was found. (i) There were structures that projected only to SCm (e.g., specific cortical areas, lateral geniculate and suprageniculate thalamic nuclei, ventromedial and premammillary hypothalamic nuclei, and several brainstem areas) or SCl (e.g., primary somatosensory cortex representing upper body parts and vibrissae and parvicellular reticular nucleus in the brainstem). (ii) Other structures projected to both SCm and SCl but from topographically segregated populations of neurons (e.g., zona incerta and substantia nigra pars reticulata). (iii) There were a few brainstem areas in which retrogradely labeled neurons were spatially overlapping (e.g., pedunculopontine nucleus and locus coeruleus). These results indicate significantly more structures across the rat neuraxis are in a position to modulate defense responses evoked from SCm, and that neural mechanisms modulating SC-mediated defense or appetitive behavior are almost entirely segregated

T cell therapy with EBV-specific cytotoxic T-lymphocytes for patients with nasopharyngeal carcinoma

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Alloantigen-induced human lymphocytes rendered nonresponsive by a combination of anti-CD80 monoclonal antibodies and Cyclosporin-A suppress mixed lymphocyte reaction in vitro

Induction of a state of long-term, alloantigen-specific T cell nonresponsiveness has significant implications for human transplantation. It has been previously described that alloantigen-specific anergy may be induced by addition of cyclosporin-A together with anti-CD80(B7-1) mAb to a MLR. In this study we endeavored to verify whether alloantigen-induced PBL rendered anergic by the addition of a combination of anti-B7 mAb and cyclosporin-A during a MLR had a suppressive effect when added to autologous lymphocytes activated in MLR. We found that: 1) the addition of cells rendered anergic by this procedure to a MLR suppress both proliferative and cytotoxic response of autologous responsive PBL to either the same or third-party stimulator cells; 2) the suppressive effect is limited to alloantigen-induced T cell activation, as addition of anergic cells does not influence mitogen- or antigen-induced proliferation of autologous responsive T cells; 3) nonresponsiveness of suppressed cells cannot be reversed by either subsequent restimulation with allogeneic cells or addition of exogenous IL-2 to the cultures; 4) the suppressive effect is apparently not due to secretion of anergic cell-derived soluble factors, but it seems to be dependent on cell-cell contact between anergic, responsive, and stimulator cells. These data suggest that: 1) the delivery of a direct signal mediated by anergic lymphocytes through a cell-cell contact is likely to be the mechanism responsible for the suppressive effect here described; 2) anergic cells may propagate alloantigen-specific tolerance to potentially responsive autologous lymphocytes. Preliminary experiments indicate that anti-CD86(B7-2) mAb may play a similar role in the generation of alloantigen-induced nonresponsiveness