Chloroquine (CQ) has been evaluated as an autophagy blocker for cancer treatment, but it is unknown if it acts solely by inhibiting cancer cell autophagy. We report that CQ reduced tumor growth but improved the tumor milieu. By normalizing tumor vessel structure and function and increasing perfusion, CQ reduced hypoxia, cancer cell invasion, and metastasis, while improving chemotherapy delivery and response. Inhibiting autophagy in cancer cells or endothelial cells (ECs) failed to induce such effects. CQ's vessel normalization activity relied mainly on alterations of endosomal Notch1 trafficking and signaling in ECs and was abrogated by Notch1 deletion in ECs in vivo. Thus, autophagy-independent vessel normalization by CQ restrains tumor invasion and metastasis while improving chemotherapy, supporting the use of CQ for anticancer treatment.

Amyloid β (Aβ) peptides, the primary constituents of senile plaques and a hallmark in Alzheimer's disease pathology, are generated through the sequential cleavage of amyloid precursor protein (APP) by β-site APP cleaving enzyme 1 (BACE1) and γ-secretase. The early endosome is thought to represent a major compartment for APP processing; however, the mechanisms of how BACE1 encounters APP are largely unknown. In contrast to APP internalization, which is clathrin-dependent, we demonstrate that BACE1 is sorted to early endosomes via a route controlled by the small GTPase ADP ribosylation factor 6 (ARF6). Altering ARF6 levels or its activity affects endosomal sorting of BACE1, and consequently results in altered APP processing and Aβ production. Furthermore, sorting of newly internalized BACE1 from ARF6-positive towards RAB GTPase 5 (RAB5)-positive early endosomes depends on its carboxyterminal short acidic cluster-dileucine motif. This ARF6-mediated sorting of BACE1 is confined to the somatodendritic compartment of polarized neurons in agreement with Aβ peptides being primarily secreted from here. These results demonstrate a spatial separation between APP and BACE1 during surface-toendosome transport, suggesting subcellular trafficking as a regulatory mechanism for this proteolytic processing step. It thereby provides a novel avenue to interfere with Aβ production through a selective modulation of the distinct endosomal transport routes used by BACE1 or APP.

Alzheimer’s disease (AD) is the most common form of dementia in the elderly. This brain neuropathology is characterized by a progressive synaptic dysfunction and neuronal loss, which lead to decline in memory and other cognitive functions. Histopathologically, AD manifests via synaptic abnormalities, neuronal degeneration as well as the deposition of extracellular amyloid plaques and intraneuronal neurofibrillary tangles. While the exact pathogenic contribution of these two AD hallmarks and their abundant constituents [aggregation-prone amyloid β (Aβ) peptide species and hyperphosphorylated tau protein, respectively] remain debated, a growing body of evidence suggests that their development may be paralleled or even preceded by the alterations/dysfunctions in the endolysosomal and the autophagic system. In AD-affected neurons, abnormalities in these cellular pathways are readily observed already at early stages of disease development, and even though many studies agree that defective lysosomal degradation may relate to or even underlie some of these deficits, specific upstream molecular defects are still deliberated. In this review we summarize various pathogenic events that may lead to these cellular abnormalities, in light of our current understanding of molecular mechanisms that govern AD progression. In addition, we also highlight the increasing evidence supporting mutual functional dependence of the endolysosomal trafficking and autophagy, in particular focusing on those molecules and processes which may be of significance to AD.

ARF6-mediated endosomal transport of Telencephalin affects dendritic filopodia-to-spine maturationThe GTPase Arf6 and its exchange factor EFA6A promote internalization of the Ig-like molecule Telencephalin in hippocampal neurons leading to the maturation of filopodia into dendritic spines, important for synapse formation.

CC16 and ECP measured in nasal secretions could be reliable markers for assessment of the recovery function of sinonasal mucosa during corticosteroid treatment.

Angiofibromas are rare vascular tumors which originate predominantly in the nasopharynx and occur typically in male adolescents. Extranasopharyngeal sites such as nasal cavity and paranasal sinuses are less frequent. This review article was undertaken to evaluate the incidence, clinical features and management of extranasopharyngeal angiofibromas originating exclusivelly from nasal cavity structures. Our focus of interest was to evaluate the significance of immunohistochemical analysis in diagnosis of such extremely rare neoplasms. In the PubMed and Google Search, we found only 39 cases of nasal angifibroma, 27 males and 12 females from 1980 to 2012. The most prevalent site of origin was nasal septum, followed by inferior and middle turbinate. The commonest symptoms were nasal obstruction and epistaxis. Nasal angiofibromas are clinically distinct from nasopharyneal angiofibromas and can therefore be misdiagnosed. The differential diagnosis includes other vascular lesions, such as lobular capillary hemangioma and sinonasal-type hemangiopericytoma. Although immunohistochemistry is not necessary for differentiation between angiofibroma and capillary hemangioma, that diagnostic procedure may be helpful in distinction from sinonasal hemangiopericytoma. As an ilustration for immunohistochemical analysis, we presented a case of an elderly woman with tumor arising from the middle turbinate, diagnosed as angiofibroma. The staining was positive for CD34, CD31, factor VIII, vimentin and smooth muscle alpha-actin, and negative for desmin.

On histopathological examination, nasal polyps and nasal mucosa in allergic rhinitis show different forms of pseudostratifi ed respiratory epithelium, whereas the dominant characteristic of lamina propria is an eosinophilic infi ltration. The aim of this study was to compare interleukin (IL)-5 and eosinophilic cationic protein (ECP) levels in the nasal fl uid of 42 patients: 12 with allergic rhinitis and nasal septal deviation, 17 non-atopic patients with nasal polyposis, and 13 atopic nasal polyp patients were enrolled in this crosssectional study. Nasal secretion samples were collected a few days before surgery. The levels of IL-5 were measured using fl ow cytometry and the ECP using a commercial ELISA kit. In addition, we counted eosinophils in hematoxylin-and-eosin-stained sections of all nasal polyp and all nasal mucosa samples taken from the inferior nasal turbinates during septoplasty. A signifi cantly higher concentration of IL-5 was found in the nasal fl uid of atopic patients with nasal polyposis than in non-atopic nasal polyp patients (p=0.025) and patients with allergic rhinitis (p=0.05). ECP was higher in atopic nasal polyp patients than in patients with allergic rhinitis (p<0.0001) and than in non-atopic nasal polyp patients (p<0.0001). Polyp eosinophils were higher in atopic' than in non-atopic patients (p<0.0001) and higher than in the mucosa of patients with allergic rhinitis (p<0.0001). These however had signifi cantly more mucosal eosinophils than was found in the polyps of non-atopic patients' (p=0.025). ECP levels in nasal fl uid and eosinophil counts in tissue specimens correlated well in all three groups of patients. Our study has shown that atopic nasal polyp patients have a higher level of eosinophilic infl ammation than non-atopic patients with nasal polyps and patients with allergic rhinitis. Arh Hig Rada Tokiskol 2011;62:341-348 Allergic rhinitis is the most common atopic disease in the human population as it affects one in four people worldwide (1, 2). Its prevalence in the European countries ranges between 15 % and 25 %, with a tendency to rise by about 3.5 % with every decade (3). It is a type I allergic reaction mediated by mast cellbound immunoglobulin E (IgE) with a typical helper T-cell type 2 (Th2) profi le (3). KEY WORDS: eosinophilic cationic protein, eosinophils, epithelium, interleukin-5, nasal fl uid Perić A, et al. INFLAMMATORY MEDIATORS IN ALLERGIC RHINITIS AND NASAL POLYPOSISNasal polyposis is characterised by the proliferation of pseudostratifi ed respiratory epithelium, thickening of the basement membrane, oedema, proliferation of fi broblasts, focal fi brosis, and infl ammatory infi ltration of the lamina propria (4). The stromal layer of the polyp tissue includes mixed infl ammatory cells. The predominant histological form of nasal polyposis is the eosinophilic type, with an incidence of about 90 % (5). The non-eosinophilic form of nasal polyps is much less common and the dominant cells in the stroma are lymphocytes and plasmocytes (5). Polyps usually originate ...

Background: Health literacy is an important determinant of health. This concept is under-researched in the Republic of Srpska, Bosnia and Herzegovina. Objectives: To assess health literacy and its association with sociodemographic variables, self-perception of health and the presence of chronic conditions in primary healthcare setting. Methods: In May 2016, a cross-sectional study was executed in two primary healthcare centres. Out of approximately 1500 patients who visited both health centres during four consecutive days, about 800 were eligible. Of these, 110 patients agreed to complete the translated Short Test of Functional Health Literacy in Adults (S-TOFHLA). The influence of demographic, social, economic, and health characteristics (independent variables) on the S-TOFHLA score (dependent variable) was assessed by multiple logistic regression analysis. Results: One questionnaire was incomplete and therefore 109 questionnaires were analysed. Inadequate, marginal, and adequate health literacy were present in 19 (17.4%), 16 (14.7%) and 74 (67.9%) respondents. Adequate health literacy was found predominantly among respondents younger than 55 years and those with a high level of education. Regression analyses showed that low level of education (OR: 5.3), age 55 years and over (OR: 3.9), living in a rural area (OR: 3.7) and having three or more chronic diseases (OR: 2) were independently associated with inadequate or marginal health literacy. Conclusion: In this study performed in two primary healthcare centres in the Republic of Srpska, Bosnia and Herzegovina, low health literacy was associated with low level of education, older age, living in a rural area, and having more chronic diseases.