CXCL16/CXCR6 axis drives microglia/macrophages phenotype in physiological conditions and plays a crucial role in glioma

Microglia are patrolling cells that sense changes in the brain microenvironment and respond acquiring distinct phenotypes that can be either beneficial or detrimental for brain homeostasis. Anti-inflammatory microglia release soluble factors that might promote brain repair; however, in glioma, anti-inflammatory microglia dampen immune response and promote a brain microenvironment that foster tumor growth and invasion. The chemokine CXCL16 is expressed in the brain, where it is neuroprotective against brain ischemia, and it has been found to be over-expressed in glioblastoma (GBM). Considering that CXCL16 specific receptor CXCR6 is diffusely expressed in the brain including in microglia cells, we wanted to investigate the role of CXCL16 in the modulation of microglia cell activity and phenotype, and in the progression of glioma. Here we report that CXCL16 drives microglia polarization toward an anti-inflammatory phenotype, also restraining microglia polarization toward an inflammatory phenotype upon LPS and IFN? stimulation. In the context of glioma, we demonstrate that CXCL16 released by tumor cells is determinant in promoting glioma associated microglia/macrophages (GAMs) modulation toward an anti-inflammatory/pro-tumor phenotype, and that cxcr6ko mice, orthotopically implanted into the brain with GL261 glioma cells,survive longer compared to wild-type mice. We also describe that CXCL16/CXCR6 signaling acts directly on mouse glioma cells, as well as human primary GBM cells, promoting tumor cell growth, migration and invasion. All together these data suggest that CXCL16 signaling could represent a good target to modulate microglia phenotype in order to restrain inflammation or to limit glioma progression

KCa3.1 channel inhibition sensitizes malignant gliomas to temozolomide treatment

Malignant gliomas are among the most frequent and aggressive cerebral tumors, characterized by high proliferative and invasive indexes. Standard therapy for patients, after surgery and radiotherapy, consists of temozolomide (TMZ), a methylating agent that blocks tumor cell proliferation. Currently, there are no therapies aimed at reducing tumor cell invasion. Ion channels are candidate molecular targets involved in glioma cell migration and infiltration into the brain parenchyma. In this paper we demonstrate that: i) blockade of the calcium-activated potassium channel KCa3.1 with TRAM-34 has co-adjuvant effects with TMZ, reducing GL261 glioma cell migration, invasion and colony forming activity, increasing apoptosis, and forcing cells to pass the G2/M cell cycle phase, likely through cdc2 de-phosphorylation; ii) KCa3.1 silencing potentiates the inhibitory effect of TMZ on glioma cell viability; iii) the combination of TMZ/TRAM-34 attenuates the toxic effects of glioma conditioned medium on neuronal cultures, through a microglia dependent mechanism since the effect is abolished by clodronate-induced microglia killing; iv) TMZ/TRAM-34 co-treatment increases the number of apoptotic tumor cells, and the mean survival time in a syngeneic mouse glioma model (C57BL6 mice implanted with GL261 cells); v) TMZ/TRAM-34 co-treatment reduces cell viability of GBM cells and cancer stem cells (CSC) freshly isolated from patients.Taken together, these data suggest a new therapeutic approach for malignant glioma, targeting both glioma cell proliferating and migration, and demonstrate that TMZ/TRAM-34 co-treatment affects both glioma cells and infiltrating microglia, resulting in an overall reduction of tumor cell progression

Clinical features and metabolic complications for non-alcoholic fatty liver disease (NAFLD) in youth with obesity

Pediatric obesity has become in the last forty years the most common metabolic disease in children and adolescents affecting about 25% of the pediatric population in the western world. As obesity worsens, a whole-body insulin resistance (IR) occurs. This phenomenon is more pronounced during adolescence, when youth experience a high degree of insulin resistance due the production of growth hormone. As IR progresses, the blunted control of insulin on adipose tissue lipolysis causes an increased flux of fatty acids with FFA deposition in ectopic tissues and organs such as the liver, leading to the development of NAFLD. In this brief review, we will discuss the clinical implications of IR and NAFLD in the context of pediatric obesity. We will review the pathogenesis and the link between these two entities, the major pathophysiologic underpinnings, including the role of genetics and metagenomics, how these two entities lead to the development of type 2 diabetes, and which are the therapeutic options for NAFLD in youth

The role of the innate immune response in HPV-related oral and oropharyngeal cancer

Introduction. During the last 20 years, the incidence of HPV-associated oropharyngeal cancer is increased. Principal actors of the innate immune response against HPV are represented by the TLRs (Toll like receptors). On the other hand different studies have reported that HPV can directly inhibit the functions of the TLRs pathway through interferons (IFNs). There are very few preliminary studies on the role of TLRs mediated HPV clearance in human oncology. Our study aim has been to evaluate whether TLR4 identifies HR-HPV integration state in OSCC. Methods. Protein levels of TLR4 in OSCC were assessed using Immunohistochemistry (IHC). In situ hybridization (ISH) for HPV-DNA detection in morphological context and Pyro-sequencing method have been performed in order to detect viral integration or episomic status. The relationship between TLR expression with or without HPV infection has been elucidated. Results. ISH HPV positive samples have reported lower TLR4 intensity than negative samples and it has confirmed by statistically significant difference (p = .002). There is no statistical correlation between TLR4 intensity and PCR HPV results (p > 0.05). Point-biserial correlation coefficient revealed statistically significant association between TLR4 expression and HR-HPV integration status (p = .0001) and between TLR4 expression index and HR-HPV infection (p = .001). Conclusions. We retain that TLR4 down-regulation is not associated to the histological tumoral grade but rather to HPV-16 infection and to its integration state into the host DNA

Cardiovascular Issues in Tyrosine Kinase Inhibitors Treatments for Chronic Myeloid Leukemia: A Review

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm driven by a fusion gene, encoding for the chimeric protein BCR-ABL, with constitutive tyrosine kinase activity. The use of tyrosine kinase inhibitors (TKIs) has drastically improved survival, but there are significant concerns about cardiovascular toxicity. Cardiovascular risk can be lowered with appropriate baseline evaluation, accurate choice of TKI therapy, improvement of modifiable cardiovascular risk factors through lifestyle modifications, and prescription of drugs for primary or secondary prevention. Which examinations are necessary, and when do they have to be scheduled? How often should a TKI-treated patient undergo which cardiology test or exam? Is there an accurate way to estimate the risk that each TKI may determine a cardiovascular adverse event in a CML patient? In a few words, how can we optimize the cardiovascular risk management in CML patients before and during TKI treatment? The aim of this review is to describe cardiac and vascular toxicity of TKIs used for CML treatment according to the most recent literature and to identify unmet clinical needs in cardiovascular risk management and complications in these patients. Regarding the TKI-induced cardiovascular toxicity, the full mechanism is still unclear, but it is accepted that different factors may play different roles: endothelial damage and atherosclerosis, metabolic impairment, hypertensive effect, glomerular impairment, and mast-cell disruption. Preventive strategies are aimed at minimizing cardiovascular risk when CML is diagnosed. Cardio-oncology units in specialized hematology centers may afford a personalized and multidisciplinary approach to the patient, optimizing the balance between treatment of the neoplasm and management of cardiovascular risk

The new HFA/ICOS risk assessment tool to identify patients with chronic myeloid leukaemia at high risk of cardiotoxicity

AimsTyrosine kinase inhibitors (TKIs) used to treat chronic myeloid leukaemia (CML) can cause cardiovascular adverseevents. So far, the Systematic Coronary Risk Evaluation (SCORE) charts of the European Society of Cardiology (ESC) have beenused to identify cancer patients at increased cardiovascular risk. The primary aim of our study was to evaluate the usefulnessof the new cardiovascular risk assessment model proposed by the Cardio-Oncology Study Group of the Heart Failure Associ-ation (HFA) of the ESC in collaboration with the International Cardio-Oncology Society (ICOS) to stratify the cardiovascular riskin CML patients, compared with SCORE risk charts. The secondary aim was to establish the incidence of adverse arterial events(AEs) in patients with CML treated with TKIs and the influence of preventive treatment with aspirin.Methods and resultsA retrospective single-centre observational study was carried out on 58 patients (32 men and 26women; mean age ± SD: 59 ± 15 years) with CML treated with TKIs for a median period of 43 ± 31 months. Cardiological eval-uation was performed and cardiovascular risk was estimated with SCORE risk charts and with the new risk assessment toolproposed by HFA/ICOS. AEs were recorded. According to SCORE charts and the new HFA/ICOS risk stratification tool, respec-tively, 46% (Group A1) and 60% (Group A2) of patients were at high–very high risk, and 54% (Group B1) and 40% (Group B2) atlow–moderate risk. AEs were significantly more frequent in Group A1 than Group B1 (Pvalue<0.01) when considered overall;they were significantly more frequent in Group A2 than Group B2 either overall or considered individually. HFA/ICOS risk strat-ification tool was significantly more sensitive than SCORE (P<0.01) in identifying patients at higher risk of cardiovascular tox-icity. In addition, we did notfind AEs in patients pretreated with aspirin.ConclusionsThe new HFA/ICOS risk stratification model allows a more tailored cardiovascular risk stratification in patientswith CML and it is more sensitive than SCORE chart

Photogenerated Electrical Fields for Biomedical Applications

The application of electrical engineering principles to biology represents the main issue of bioelectronics, focusing on interfacing of electronics with biological systems. In particular, it includes many applications that take advantage of the peculiar optoelectronic and mechanical properties of organic or inorganic semiconductors, from sensing of biomolecules to functional substrates for cellular growth. Among these, technologies for interacting with bioelectrical signals in living systems exploiting the electrical field of biomedical devices have attracted considerable attention. In this review, we present an overview of principal applications of phototransduction for the stimulation of electrogenic and non-electrogenic cells focusing on photovoltaic-based platforms

Connective tissue lung: different composition between male and female

Abnormal elasticity of lung tissue has a major impact on the clinical progression and outcome of many lung diseases including respiratory distress syndrome, asthma, emphysema and pneumothorax post thoracic injury. The major components of lung connective tissue are elastin, collagen and together provide the lung with its elasticity and tensile strength. Elastin is composed of flexible cross-linked polypeptides and has a linear stress-strain relation up to 200% strain; collagen has a more organized structure with both crystalline and amorphous phases and exhibits a highly unlinear stress-strain curve. The thoracic injury is responsible for about 25% of death for injury and in particular it represent 12% of all death in man in comparison to 7% of dealt in female. This different in death rate is due to the different hormone levels between man and female. On the other hand female sex hormones, estrogens (e.g. 17b-estradiol) exert important biological actions, both protective and undesirable. In particular in addition to their primary function as reproductive hormones, estrogens (e.g. 17b-estradiol) influence a wide range of other physiological processes in humans and other mammals, including cardiovascular, respiratory, and neuronal function, and bone density.. With special respect to the cardiorespiratory system, estrogens promote lung development and differentiation and exhibit pulmonary and cardiovascular protective properties. However, very little is known about the different composition of the two major constituents of the connective tissue of the female and men lung. We have studied by CLSM the elastin an collagen in man and female lung. All proteins tested are present in lung tissue of male and female and they are localized in the peribronchiolar and in the interalveolar septum. The reaction to elastin shows very differences staining in the basal laminae of small and medium bronchioles in two sexes, in particular these structures stained very strongly in female but not in male. Opposite behavior we have showed to collagen type IV reactions. In male the collagen type IV is localized as a continuous network throughout the lung parenchymal tissue and in the basal laminae it shows strongly staining

Smoking influence in Takotsubo syndrome: insights from an international cohort

Takotsubo syndrome; Mortality; Smoking habitSíndrome de Takotsubo; Mortalidad; Hábito de fumarSíndrome de Takotsubo; Mortalitat; Hàbit de fumarAims: To assess the influence of tobacco on acute and long-term outcomes in Takotsubo syndrome (TTS). Methods: Patients with TTS from the international multicenter German Italian Spanish Takotsubo registry (GEIST) were analyzed. Comparisons between groups were performed within the overall cohort, and an adjusted analysis with 1:1 propensity score matching was conducted. Results: Out of 3,152 patients with TTS, 534 (17%) were current smokers. Smoker TTS patients were younger (63 ± 11 vs. 72 ± 11 years, p < 0.001), less frequently women (78% vs. 90%, p < 0.001), and had a lower prevalence of hypertension (59% vs. 69%, p < 0.01) and diabetes mellitus (16% vs. 20%, p = 0.04), but had a higher prevalence of pulmonary (21% vs. 15%, p < 0.01) and/or psychiatric diseases (17% vs. 12%, p < 0.01). On multivariable analysis, age less than 65 years [OR 3.85, 95% CI (2.86–5)], male gender [OR 2.52, 95% CI (1.75–3.64)], history of pulmonary disease [OR 2.56, 95% CI (1.81–3.61)], coronary artery disease [OR 2.35, 95% CI (1.60–3.46)], and non-apical ballooning form [OR 1.47, 95% CI (1.02–2.13)] were associated with smoking status. Propensity score matching (PSM) 1:1 yielded 329 patients from each group. Smokers had a similar rate of in-hospital complications but longer in-hospital stays (10 vs. 9 days, p = 0.01). During long-term follow-up, there were no differences in mortality rates between smokers and non-smokers (5.6% vs. 6.9% yearly in the overall, p = 0.02, and 6.6%, vs. 7.2% yearly in the matched cohort, p = 0.97). Conclusions: Our findings suggest that smoking may influence the clinical presentation and course of TTS with longer in-hospital stays, but does not independently impact mortality.FIC (Fundación Interhospitalaria para la Investigación en Cardiología) supported RETAKO