Theragnostics of TRK-targeting agents (trackins): a challenge that promises reward

Therminologically, theragnostics combines therapeutics and diagnostics. Life at cellular and molecular level is a binary event (e.g., phosphorylation-dephosphorylation of proteins, methylation-demethylations of DNA and acetylation-deacetylation of histones) aimed at the maintenance of a sanogenic phenotype of the homeostasis. Herein, we focus on the neurotrophins with metabotrophic or pathogenic potentials, particularly nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) and their receptors Trk (tyrosine/tropomyosin receptor kinase; pronounced “track”). Accordingly, the term trackins was introduced which stands for Trk-targeting agents influencing agonistically or antagonistically the activity of TrkANGF, TrkBBDNF, and TrkCNT-3 receptor. We argue that multiple diseases may be trackins curable, for instance: (i) agonistic trackins may have therapeutic potentials for cardiometabolic diseases (e.g., atherosclerosis, obesity, T2DM, and metabolic syndrome) and for neurometabolic diseases (e.g., Alzheimer’s disease/T3DM), whereas (ii) antagonistic trackins may be drugs for prostate, breast, gastric, pancreatic and colon cancers, also for pain, and eye, skin and male genitourinary track diseases. Moreover, TrkANGF, TrkBBDNF and TrkCNT-3 receptor may be promising biomarkers for diagnosis and prognosis of these diseases. Altogether, the presented data may be a challenge that promises reward requiring a further pursuit

Impaired Meningeal Lymphatic Vessel Development Worsens Stroke Outcome

The discovery of meningeal lymphatic vessels (LVs) has sparked interest in identifying their role in diseases of the central nervous system. Similar to peripheral LVs, meningeal LVs depend on vascular endothelial growth factor receptor-3 (VEGFR3) signaling for development. Here we characterize the effect of stroke on meningeal LVs, and the impact of meningeal lymphatic hypoplasia on post-stroke outcomes. We show that photothrombosis (PT), but not transient middle cerebral artery occlusion (tMCAo), induces meningeal lymphangiogenesis in young male C57Bl/J6 mice. We also show that Vegfr3wt/mut mice develop significantly fewer meningeal LVs than Vegfr3wt/wt mice. Again, meningeal lymphangiogenesis occurs in the alymphatic zone lateral to the sagittal sinus only after PT-induced stroke in Vegfr3wt/wt mice. Interestingly, Vegfr3wt/mut mice develop larger stroke volumes than Vegfr3wt/wt mice after tMCAo, but not after PT. Our results reveal differences between PT and tMCAo models of stroke and underscore the need to consider method of stroke induction when investigating the role of meningeal lymphatics. Taken together, our data indicate that ischemic injury can induce the growth of meningeal LVs and that the absence of these LVs can impact post-stroke outcomes

Space Charge at Nanoscale: Probing Injection and Dynamic Phenomena Under Dark/Light Configurations by Using KPFM and C-AFM

International audienc

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Mineralogy of the pliocene trachyte and its carbonatitic minette inclusions in Ostrvica, FYR of Macedonia

The trachyte at Ostrvica hill (age 3.21±0.10 Ма) in Vardar zone is the most evolved volcan- ics of the ultrapotassic Pliocene-Quaternary series in F.Y.R. of Macedonia. It is aphyric, with clinopy- roxene and phlogopite microphenocrysts within a sanidine-anorthoclase groundmass. It contains inclu- sions of carbonatitic minette ranging in size from several mm to 6–7 cm. They are light coloured por- phyric rocks, rich in vacuoles, composed of phlogopite and completely altered olivine(?) phenocrysts amongst acicular clinopyroxenes within a feldspar–calcite groundmass with abundant Fe-oxides and acicular apatite microlites. The inclusions are rimmed by a mm thick mixing zone composed of the same minerals but with intermediate composition between that of minette and trachyte. The clinopyroxenes are mainly diopside-augite with low Ti and Al content (with 6Al only in the minette). Positive correla- tions are observed between Na and Fe3+, Al and Ti, and negative one – between Al and Si. In the inclu- sions phlogopites the negative correlation between Mg# and 4Al is found. The feldspars in the trachyte and minette inclusions are Ca-sanidine to Ca-anorthoclase, in the mixing zone – sanidine only. In the in- clusions two plagioclase generations (An41 and An25) exist. The estimated crystallization temperature of the minette clinopyroxenes is 1280–1180С, of plagioclase (An41) – 1130С and in the hosting trachyte – 1080С, at the pressures 6.9 and 7.7 kbar, respectively. The temperature of the feldspars crystalliza- tion (K-Na-feldspars and Pl24) in the minette groundmass is 809–878C. By analogy with other ultrapo- tassic volcanics from F.Y.R Macedonia it is suggested, that the discussed volcanics originated from phlogopite-bearing metasomatised mantle

Prevalence of COPD in Patients with Lung Cancer

Introduction: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity, mortality, and healthcare costs worldwide. Lung cancer is the second most common cancer and is the leading cause of cancer mortality, accounting for almost 25% of all cancer deaths. This study aims to investigate the prevalence of COPD in patients with lung cancer (LC)