Cachexia as evidence of the mechanisms of resistance and tolerance during the evolution of cancer disease

During its evolution, cancer induces changes in patients’ energy metabolism that strongly affect the overall clinical state and are responsible for cancer‐related cachexia syndrome. To better understand the mechanisms underlying cachexia and its metabolic derangements, research efforts should focus on the events that are driven by the immune system activation during the evolution of neoplastic disease and on the phenomena of “resistance” and “tolerance” typically involved in the human body response against stress, pathogens, or cancer. Indeed, in the case where resistance is not able to eliminate the cancer, tolerance mechanisms can utilize the symptoms of cachexia (anemia, anorexia, and fatigue) to counteract unregulated cancer growth. These notions are also sustained by the evidence that cancer cachexia may be reversible if the resistance and tolerance phases are supported by appropriate antineoplastic treatments. Accordingly, there is no doubt that anticachectic therapies have an irreplaceable role in cases of reversible cancer cachexia where, if harmoniously associated with effective antineoplastic therapies, they can contribute to preserve the quality of life and improve prognosis. Such anticachectic treatments should be based on targeting the complex immunological, inflammatory, and metabolic pathways involved in the complex pathogenesis of cachexia. Meanwhile, the role of the anticachectic therapies is very different in the stage of irreversible cachexia when the available antineoplastic treatments are not able to control the disease and the resistance mechanisms fail with the prevalence of the tolerance phenomena. At this stage, they can be useful only to improve the quality of life, allowing the patient and their family to get a better awareness of the final phases of life, thereby opening to the best spiritual remodulation of the final event, death

A naphthalene diimide dyad for fluorescence switch-on detection of G-quadruplexes

A non-fluorescent dimeric naphthalene diimide dye becomes red emitting upon G-quadruplex binding

The effects of cerebrospinal fluid tap-test on idiopathic normal pressure hydrocephalus: an inertial sensors based assessment

BACKGROUND: Gait disturbances are typical of persons with idiopathic normal pressure hydrocephalus (iNPH) without signs distinctive from other neurodegenerative and vascular conditions. Cerebrospinal fluid tap-test (CSF-TT) is expected to improve the motor performance of iNPH patients and is a prognostic indicator in their surgical management. This observational prospective study aims to determine which spatio-temporal gait parameter(s), measured during instrumented motor tests, and clinical scale(s) may provide a relevant contribution in the evaluation of motor performance pre vs. post CSF-TT on iNPH patients with and without important vascular encephalopathy. METHODS: Seventy-six patients (20 with an associated vascular encephalopathy) were assessed before, and 24 and 72\u2009h after the CSF-TT by a timed up and go test (TUG) and an 18\u2009m walking test (18\u2009mW) instrumented using inertial sensors. Tinetti Gait, Tinetti Balance, Gait Status Scale, and Grading Scale were fulfilled before and 72\u2009h after the CSF-TT. Stride length, cadence and total time were selected as the outcome measures. Statistical models with mixed effects were implemented to determine the relevant contribution to response variables of each quantitative gait parameter and clinical scales. RESULTS AND CONCLUSION: From baseline to 72\u2009h post CSF-TT patients improved significantly by increasing cadence in 18\u2009mW and TUG (on average of 1.7 and 2.4 strides/min respectively) and stride length in 18\u2009mW (on average of 3.1\u2009cm). A significant reduction of gait apraxia was reflected by modifications in double support duration and in coordination index. Tinetti Gait, Tinetti Balance and Gait Status Scale were able to explain part of the variability of response variables not covered by instrumental data, especially in TUG. Grading Scale revealed the highest affinity with TUG total time and cadence when considering clinical scales alone. Patients with iNPH and an associated vascular encephalopathy showed worst performances compared to pure iNPH but without statistical significance. Gait improvement following CSF-TT was comparable in the two groups. Overall these results suggest that, in order to augment CSF-TT accuracy, is key to assess the gait pattern by analyzing the main spatio-temporal parameters and set post evaluation at 72\u2009h. TRIAL REGISTRATION: Approved by ethics committee: CE 14131 23/02/2015

Unrelated bone marrow transplantation in Thalassemia. The experience of the Italian Bone Marrow transplant Group (GITMO)

BACKGROUND AND OBJECTIVES: Allogeneic bone marrow transplantation (BMT) is a widely accepted therapeutic approach in homozygous beta-thalassemia. However, the majority of patients do not have a genotypically identical donor within the family. This prompted us to conduct a pilot study to investigate the feasibility of matched unrelated bone marrow transplantation in thalassemia. The major drawback was the high risk of immunologic and transplant-related complications, mainly graft-versus-host disease (GvHD) and graft failure. DESIGN AND METHODS: Our aim was to reduce this risk through careful selection of donor/recipient pairs. HLA haplotypes that show a high linkage disequilibrium among their class I, class II and class III alleles are considered extended or ancestral haplotypes. RESULTS: These haplotypes are conserved and can be shared by apparently unrelated individuals. Our study shows that matching for these haplotypes significantly improves the outcome of unrelated bone marrow transplantation in thalassemia. In fact, results were comparable to those obtained in transplants using HLA-identifical family donors. INTERPRETATION AND CONCLUSIONS: Better results were obtained in patients with lesser iron overload and when the donor shared an identity for the DPB1 alleles

Allosteric Interactions between the Myristate- and ATP-Site of the Abl Kinase

Abl kinase inhibitors targeting the ATP binding pocket are currently employed as potent anti-leukemogenic agents but drug resistance has become a significant clinical limitation. Recently, a compound that binds to the myristate pocket of Abl (GNF-5) was shown to act cooperatively with nilotinib, an ATP-competitive inhibitor to target the recalcitrant “T315I” gatekeeper mutant of Bcr-Abl. To uncover an explanation for how drug binding at a distance from the kinase active site could lead to inhibition and how inhibitors could combine their effects, hydrogen exchange mass spectrometry (HX MS) was employed to monitor conformational effects in the presence of both dasatinib, a clinically approved ATP-site inhibitor, and GNF-5. While dasatinib binding to wild type Abl clearly influenced Abl conformation, no binding was detected between dasatinib and T315I. GNF-5, however, elicited the same conformational changes in both wild type and T315I, including changes to dynamics within the ATP site located approximately 25 Å from the site of GNF-5 interaction. Simultaneous binding of dasatinib and GNF-5 to T315I caused conformational and/or dynamics changes in Abl such that effects of dasatinib on T315I were the same as when it bound to wild type Abl. These results provide strong biophysical evidence that allosteric interactions play a role in Abl kinase downregulation and that targeting sites outside the ATP binding site can provide an important pharmacological tool to overcome mutations that cause resistance to ATP-competitive inhibitors

Experimental drugs for chemotherapy-and cancer-related anemia

Anemia in cancer patients is a relevant condition complicating the course of the neoplastic disease. Overall, we distinguish the anemia which arises under chemotherapy as pure adverse event of the toxic effects of the drugs used, and the anemia induced by the tumour-associated inflammation, oxidative stress, and systemic metabolic changes, which can be worsened by the concomitant anticancer treatments. This more properly cancer-related anemia depends on several overlapping mechanism, including impaired erythropoi-esis and functional iron deficiency, which make its treatment more difficult. Standard therapies approved and recommended for cancer anemia, as erythropoiesis-stimulating agents and intravenous iron administration, are limited to the treatment of chemotherapy-induced anemia, preferably in patients with advanced disease, in view of the still unclear effect of erythropoiesis-stimulating agents on tumour progression and survival. Outside the use of chemotherapy, there are no recommendations for the treatment of cancer-related anemia. For a more complete approach, it is fundamentally a careful evaluation of the type of anemia and iron homeostasis, markers of inflammation and changes in energy metabolism. In this way, anemia management in cancer patient would permit a tailored approach that could give major benefits. Experimental drugs targeting hepcidin and activin II receptor pathways are raising great expectations, and future clinical trials will confirm their role as remedies for cancer-related anemia. Recent evidence on the effect of integrated manage-ments, including nutritional support, antioxidants and anti-inflammatory substances, for the treatment of cancer anemia are emerging. In this review article, we show standard, innova-tive, and experimental treatment used as remedy for anemia in cancer patients

Italy’s national and international cooperations on R&D: an overview

Purpose: The paper aims at discussing the Italian ability to cooperate with national and international partners. More in depth, given the scarce attitude to collaborate with foreign partners in generate patents, the paper is meant at analyzing the Italian ability to involve in R&D cooperation, in order to detect if the inactivity is due to a lack of financial resources available for research. Design of the study/methodology: The methodology followed involved the elaboration of three composite indicators starting from Business Enterprises R&D Expenditures (BERD), Higher Education R&D Expenditures (HERD), and Government R&D Expenditures (GOVERD) whose data was available in the OECD statistical database. Considering money transfers from industry, government, universities and foreign organizations these indicators have been decomposed and properly reassembled through the use of aggregative composition functions with the aim to compare the Italian performance with that of the countries of Europe 28. Then, the qualitative analysis of data on co-patenting and co-ownerships conclude the discussion. Findings: Despite the higher potential in patenting, data showed a scarce collaboration attitude of Italy at the international level. Moreover, it seems that for firms, collaborations with government and foreign partners are relevant to sustain R&D investment. On the contrary, 2 money transfers among higher education institutions and industry are weak, probably due to national innovation policy which doesn’t stimulate knowledge transfer through partnerships. Government also is well supported testifying the relevance of public –private partnerships to push the national innovation system. Practical implications: The study is an attempt to capture Italian capacity to collaborate with public and private entities at the national and international level. However, the work requires deep investigation in order to detect the causes of a negative performance of international cooperation. Originality: The paper’s originality is an attempt to discuss the potential and limits of Italy with regard to cooperation for innovation generation. Limitations: Limits of the study are connected to the lack of data on national collaboration outputs. Moreover, the sample of countries considered is small due to the low availability of data

Antecedents of innovative work behaviour in healthcare: does efficacy play a role?

Purpose: Exploring how to enhance innovative work behaviour has been the main concern of top managers and researchers, particularly in knowledge-intensive and public organizations. Yet, studies investigating factors that shape innovative behaviour at work are scarce. Focusing on the healthcare setting, this study hypothesizes a direct relationship between individuals’ perceived creative selfefficacy, creative collective efficacy and innovative work behaviour. Design: The research used survey data from 446 clinical managers working in public healthcare organizations in six different Italian regions and a set of previously validated questionnaires to measure the study variables. Findings: Findings suggest that clinical managers’ perceptions of their creative self-efficacy and their perceived creative collective efficacy significantly influence their self-reported innovative work behaviour. Research implications: Findings highlight the importance of constructing and developing clinical managers’ efficacy in creativity at both an individual and team level in order to incentivize the emergence of innovation behaviour. Further research is needed to assess the existence of mediating and/or moderating mechanisms underlying the relationships emerging from this study in order to support decision makers in diffusing innovation and creativity in healthcare organizations. Originality: The research adds to the debate on improving innovative work behaviour by introducing perceived individual and team creative efficacy as determinants of innovative work behaviour in healthcare organizations. The research is among the first attempts to contribute to healthcare organizations’ management through exploring clinical managers’ characteristics that influence their innovative work behaviour.Purpose: Exploring how to enhance innovative work behaviour (IWB) has been the main concern of top managers and researchers, particularly in knowledge-intensive and public organizations. Yet, studies investigating factors that shape innovative behaviour at work are scarce. Focussing on the healthcare setting, the purpose of this paper is to hypothesize a direct relationship between individuals’ perceived creative self-efficacy (CSE), creative collective efficacy (CCE) and IWB. Design/methodology/approach: The research used survey data from 446 clinical managers working in public healthcare organizations in six different Italian regions and a set of previously validated questionnaires to measure the study variables. Findings: Findings suggest that clinical managers’ perceptions of their CSE and their perceived CCE significantly influence their self-reported IWB. Research limitations/implications: Findings highlight the importance of constructing and developing clinical managers’ efficacy in creativity at both an individual and team level in order to incentivize the emergence of innovation behaviour. Further research is needed to assess the existence of mediating and/or moderating mechanisms underlying the relationships emerging from this study in order to support decision makers in diffusing innovation and creativity in healthcare organizations. Originality/value: The research adds to the debate on improving IWB by introducing perceived individual and team creative efficacy as determinants of IWB in healthcare organizations. The research is among the first attempts to contribute to healthcare organizations’ management through exploring clinical managers’ characteristics that influence their IWB

The sustainability of Thalassemia’s treatments: Developed countries vs Developing countries’ perspective

-