Novel Cytotoxic Chemotherapies in Small Cell Lung Carcinoma.

Small cell lung cancer (SCLC) is one of the deadliest thoracic neoplasms, in part due to its fast doubling time and early metastatic spread. Historically, cytotoxic chemotherapy consisting of platinum-etoposide or anthracycline-based regimens has demonstrated a high response rate, but early chemoresistance leads to a poor prognosis in advanced SCLC. Only a fraction of patients with limited-disease can be cured by chemo-radiotherapy. Given the disappointing survival rates in advanced SCLC, new cytotoxic agents are eagerly awaited. Unfortunately, few novel chemotherapy drugs have been developed in the latest decades. This review describes the results and potential application in the clinical practice of novel chemotherapy agents for SCLC.

Inflammatory activation during coronary artery surgery and its dose-dependent modulation by statin/ACE-inhibitor combination.

BACKGROUND: On-pump coronary artery bypass graft (CABG) surgery triggers an inflammatory response (IR) which may impair revascularization. The study aimed at (1) characterizing the temporal profile of the IR by assaying appropriate markers in both systemic and coronary blood, and (2) determining whether (and which doses of) cardiovascular drugs known to have antiinflammatory properties, namely statins and ACE-inhibitors (ACEI), inhibit the response. METHODS AND RESULTS: Patients scheduled for CABG (n=22) were randomized to statin/ACEI combination treatment at standard doses (STD, ramipril 2.5/simvastatin 20 mg, or atorvastatin 10 mg), or at high doses (HiDo, ramipril 10 mg, or enalapril 20 mg/simvastatin 80 mg, or atorvastatin 40 mg). Plasma levels of interleukin 6, tumor necrosis factor alpha, E-selectin, von Willebrand factor (vWF), and sVCAM-1 were serially assayed (ELISA) before, during, and after CABG. Blood was drawn from an artery, a systemic vein, and the coronary sinus. Myocardial perfusion scans were obtained before and 2 months after surgery in 19 out of 22 subjects. In the STD group both IL-6 and TNF displayed striking increases which were similar at all sites and peaked 10 to 60 minutes after aortic declamping. Such increases were drastically attenuated in the HiDo group. Instead, only modest increases in venous E-selectin, vWF, and sVCAM-1 were observed. Scintigraphic ischemia scores were entirely normalized after versus before CABG in the HiDo but not in the STD treatment group. CONCLUSIONS: On-pump CABG surgery is associated with an intense systemic inflammatory response, which can be almost completely prevented by early treatment with high (but not standard) doses of ACE-inhibitors and statins.

[Next generation biobanking: the challenge of data]. / Le next-generation biobanking - Un défi des données numériques.

Human biological samples are key resources in unravelling physiopathological factors underlying diseases and influencing their outcome. By making use of these resources, genomics, proteomics and molecular imaging techniques have achieved unprecedented progress in the past decade. The development of genomics platforms, molecular imaging as well as bioinformatics allowed a significant development of the biomarkers field thus realizing significant advances towards personalized medicine. The exponential increase of data, their complexity, the necessity of their integration for analysis require the development of appropriate infrastructures. These latter should integrate experts from different fields as well as an optimal organisation of biobanks including novel access and exchange rules for biological material and data.

Liquid dynamic medicine and N-of-1 clinical trials: a change of perspective in oncology research.

The increasing use of genomics to define the pattern of actionable mutations and to test and validate new therapies for individual cancer patients, and the growing application of liquid biopsy to dynamically track tumor evolution and to adapt molecularly targeted therapy according to the emergence of tumor clonal variants is shaping modern medical oncology., In order to better describe this new therapeutic paradigm we propose the term "Liquid dynamic medicine" in the place of "Personalized or Precision medicine". Clinical validation of the "Liquid dynamic medicine" approach is best captured by N-of-1 trials where each patient acts as tester and control of truly personalized therapies.

Regulation of cell size and contractile function by AKT in cardiomyocytes.

AKT is a serine-threonine kinase involved in several different cellular functions, including the control of cell size and the regulation of survival and metabolism. Many studies have demonstrated that AKT also plays a critical role in the homeostasis of the cardiomyocyte. In these cells, AKT is activated by upstream molecules such as beta-adrenergic receptor, insulin-like growth factor-1 or insulin receptor, through PI3K alpha; whereas its activation is inhibited by the PTEN molecule. Downstream targets of AKT in the cardiomyocyte include glycogen-synthase kinase-3 beta and S6 kinase. Major effects of AKT activation in the cardiomyocyte are increase in cell size, prevention of apoptosis, and regulation of glucose metabolism. Interestingly, the AKT-dependent hypertrophic pathway is distinct from that activated by MAPKs. In fact, overexpression of AKT does not lead to MAPK activation. Our group has shown, moreover, that AKT exerts a positive effect on both inotropism and relaxation. In fact, mice overexpressing the E40K mutant of AKT in the heart showed improved cardiac function. Thus, AKT increases both cell size through the S6 kinase pathway and inotropism through the functional regulation of critical Ca(2+)-handling proteins. Therefore, AKT is a critical mediator of physiological hypertrophy.

Infusion of Escherichia coli lipopolysaccharide toxin in rats produces an early and severe impairment of baroreflex function in absence of blood pressure changes.

The assessment of baroreflex function since the first appearance of endotoxemia is important because the arterial baroreflex should exert a protective role during sepsis. Nevertheless, contrasting results were previously reported. This could be due to the hemodynamic instability characterizing this condition that may per se interfere with reflex cardiovascular adjustments. The aim of our study was therefore to study the baroreflex function (a) since the very beginning of infusion of Escherichia coli lipopolysaccharide (LPS) toxin and (b) in absence of the unloading effect produced by a decrease in blood pressure. Lipopolysaccharide was infused in 10 rats for 20 min at the infusion rate of 0.05 mg · kg · min. Blood pressure was continuously measured before, during, and after infusion, and the baroreflex function was evaluated analyzing spontaneous fluctuations of systolic blood pressure and pulse interval by the sequence and transfer-function techniques. Plasma concentrations of inflammatory (interleukin 6, tumor necrosis factor α) and anti-inflammatory (interleukin 10) cytokines were measured in other eight rats, similarly instrumented, four of which receiving the same LPS infusion. We found that blood pressure levels did not change with the infusion of LPS, whereas inflammatory cytokines increased significantly. The baroreflex sensitivity was significantly reduced 10 min after the beginning of LPS infusion, reached values about half those at baseline within 15 min after the start of infusion, and remained significantly low after the end of infusion. In conclusion, we documented that septic shock inducing LPS infusion is responsible for a very rapid impairment of the baroreflex function, independent from the level of blood pressure.

Targeting reactive astrogliosis by novel biotechnological strategies.

Neuroglial cells are fundamental for control of brain homeostasis and synaptic plasticity. Decades of pathological and physiological studies have focused on neurons in neurodegenerative disorders, but it is becoming increasingly evident that glial cells play an irreplaceable part in brain homeostasis and synaptic plasticity. Animal models of brain injury and neurodegenerative diseases have largely contributed to current understanding of astrocyte-specific mechanisms participating in brain function and neurodegeneration. Specifically, gliotransmission (presence of glial neurotransmitters, and their receptors and active transporters), trophic support (release, maturation and degradation of neurotrophins) and metabolism (production of lactate and GSH components) are relevant aspects of astrocyte function in neuronal metabolism, synaptic plasticity and neuroprotection. Morpho-functional changes of astrocytes and microglial cells after traumatic or toxic insults to the central nervous system (namely, reactive gliosis) disrupt the complex neuro-glial networks underlying homeostasis and connectivity within brain circuits. Thus, neurodegenerative diseases might be primarily regarded as gliodegenerative processes, in which profound alterations of glial activation have a clear impact on progression and outcomes of neuropathological processes. This review provides an overview of current knowledge of astrocyte functions in the brain and how targeting glial-specific pathways might ultimately impact the development of therapies for clinical management of neurodegenerative disorders.

Clinical and genetic familial study of a large cohort of Italian children with idiopathic epilepsy.

Epilepsies are characterized by genetic heterogeneity and by the possible coexistence of different phenotypes in one family. Moreover, in different epilepsies, mutations in the same gene have been reported. We aimed to collect data in a large Italian cohort of 81 families with children affected by partial or generalized epilepsies and to evaluate the prevalence of several ion channel mutations. In particular, a clinical and genetic survey was performed and DNA regions known to be associated with several epilepsies were analysed by sequencing. We observed genetic complexity in all phenotype groups: any epileptic type may be transmitted as either autosomal dominant or recessive. No significant phenotype identity among generations and no differences among genders could be observed. Two missense mutations in SCN1A were identified in two GEFS+ probands confirming the importance of this channel for this epilepsy. Moreover, a previously unreported CLCN2 mutation was detected in a proband showing CAE. In conclusion, even in this highly heterogeneous cohort, the complexity of the epileptic condition was highlighted and mutations in the analysed candidate region of ion channel genes appear to explain only a minority of cases.

An international opinion poll of well-educated people regarding awareness and feelings about organ donation for transplantation.

Despite repeated campaigns promoting transplantation, the high donation refusal rate remains unchanged. We targeted a well-educated population to assess the impact of our current transplantation promoting programs and personal feelings toward new approaches to organ donation. A questionnaire was proposed in five universities to students and university staffs that would have been likely to benefit from previous information campaigns in two South American and three European countries. All of the 2321 people interviewed replied to at least one question. Organ shortage was considered as a serious public health issue. However, there was a widespread ignorance of religious precepts concerning transplantation that contributed to the low acceptance rate of organ sharing after death. Financial rewards for donors or their families remain controversial. There was a general agreement for early educational programs in schools. Most people still consider organ donation as a gift, but many would now agree to readily share body parts after death. This biased population of well-educated people has still little knowledge of organ donation. The negative impact of ignorance surrounding religious precepts and the high acceptance rate of educational programs in schools, justify supporting an intensive international effort in education that should also include Church leaders.