Blood–brain barrier impairment in patients living with hiv: Predictors and associated biomarkers

Despite the substantial changes resulting from the introduction of combination antiretroviral therapy (cART), the prevalence of HIV-associated neurocognitive disorders (HAND) remains substantial. Blood–brain barrier impairment (BBBi) is a frequent feature in people living with HIV (PLWH) and it may persist despite effective antiretroviral treatment. A cross-sectional study was performed in PLWH who underwent lumbar puncture for clinical reasons or research protocols and several cerebrospinal fluid biomarkers were studied. BBBi was defined as cerebrospinal fluid-to-serum albumin ratio (CSAR) >6.5 (<40 years) or >8 (>40 years). We included 464 participants: 147 cART-naïve and 317 on cART. Male sex was prevalent in both groups (72.1% and 72.2% respectively); median age was 44 (38–52) years in naïve and 49 (43–57) years in treated subjects. BBBi was observed in 35.4% naïve and in 22.7% treated participants; the use of integrase inhibitors was associated with a lower prevalence (18.3 vs. 30.9%, p = 0.050). At multivariate binary logistic regression (including age and sex) nadir CD4 cell count (p = 0.034), presence of central nervous system (CNS) opportunistic infections (p = 0.024) and cerebrospinal fluid (CSF) HIV RNA (p = 0.002) in naïve participants and male sex (p = 0.021), a history of CNS opportunistic infections (p = 0.001) and CSF HIV RNA (p = 0.034) in treated patients were independently associated with BBBi. CSF cells and neopterin were significantly higher in participants with BBBi. BBBi was prevalent in naïve and treated PLWH and it was associated with CSF HIV RNA and neopterin. Systemic control of viral replication seems to be essential for BBB integrity while sex and treatment influence need further studies

Niveles de contaminación de aire: relación con distintos factores

Se realizaron estudios de diferentes contaminantes gaseosos y material particulado en varias ciudades de la Provincia de Buenos Aires, Argentina. Estas ciudades tienen diferencias notables respecto del número de habitantes, la densidad vehicular, la actividad industrial, etc. Ellas son La Plata, Bahía Blanca, Mar del Plata, Pergamino, San Nicolás, entre otras. En cada ciudad, se instaló un equipo de monitoreo continuo con tecnología de sensores electroquímicos para determinar NOx, CO, HC, SO2 y O3. Las muestras del material particulado total para su análisis fisicoquímico fueron recogidas usando un equipo de alto volumen, y las concentraciones diarias de PM10 fueron determinadas por analizador de tecnología láser. Las partículas fueron caracterizadas por microscopías óptica y electrónica de barrido, y análisis por difracción electrónica de Rayos X. Los resultados obtenidos mostraron una relación directa entre el tipo y la cantidad de las partículas presentes y las características generales de las ciudades

Air quality in Buenos Aires Province, Argentina

Studies of different gaseous contaminants and particulate matter were made in several cities of the Buenos Aires Province in Argentina. These cities have noticeable differences in relation to the number of inhabitants, vehicular density, industrial activities, etc. They are La Plata, Bahía Blanca, Mar del Plata, Pergamino and San Nicolás, among other towns. In each city, continuous monitoring equipment with electrochemical sensor technology was installed, in order to determine the NOx, CO, HC, SO2 and O3 concentration. The particulate matter samples were picked up using high volume equipment and daily concentrations corresponding to total suspended solids (PM) were determined by a gravimetric method. The particles were characterized by optical microscopy, scanning electron microscopy (SEM) and electron diffraction analysis X-ray (EDAX). The results obtained showed a direct relationship between the type and quantity of the present particles and the general characteristics of the towns. The present study is part of the research project "Study of the Air Quality in Buenos Aires Province", financially supported by the National Agency of Scientific and Technological Promotion, Argentina.Facultad de Ciencias ExactasCentro de Investigación y Desarrollo en Ciencias Aplicada

Seroprevalence of five neglected parasitic diseases among immigrants accessing five infectious and tropical diseases units in Italy: a cross-sectional study.

: This multicentre cross-sectional study aims to estimate the prevalence of five neglected tropical diseases (Chagas disease, filariasis, schistosomiasis, strongyloidiasis, toxocariasis) among immigrants accessing health care facilities in five Italian cities (Bologna, Brescia, Florence, Rome, Verona). : Individuals underwent a different set of serological tests, according to country of origin and presence of eosinophilia. Seropositive patients were treated and further followed up. : A total of 930 adult immigrants were enrolled: 477 men (51.3%), 445 women (47.9%), 8 transgender (0.8%); median age was 37.81 years (range 18-80). Most of them were coming from the African continent (405/930, 43.5%), the rest from East Europe, South America and Asia. A portion of 9.6% (89/930) were diagnosed with at least one of the infections under study. Seroprevalence of each specific infection varied from 3.9% (7/180) for Chagas diseases to 9.7% (11/113) for toxocariasis. Seropositive people were more likely to be 35 to 40 years-old male and to come from South East Asia, Sub-Saharan Africa or South America. : The results of our study confirm that neglected tropical diseases represent a substantial health problem among immigrants and highlight the need for addressing this emerging public health issue.<br/

Activity and safety of NGR-hTNF, a selective vascular-targeting agent, in previously treated patients with advanced hepatocellular carcinoma

Background:Hepatocellular carcinoma (HCC) is a highly vascularised and poor-prognosis tumour. NGR-hTNF is a vascular-targeting agent consisting of human tumour necrosis factor-alpha fused to the tumour-homing peptide NGR, which is able to selectively bind an aminopeptidase N overexpressed on tumour blood vessels.Methods:Twenty-seven patients with advanced-stage disease resistant to either locoregional (59%; range, 1-3), systemic treatments (52%; range, 1-3) or both (33%) received NGR-hTNF 0.8 gm-2 once every 3 weeks. The primary aim of the study was progression-free survival (PFS).Results:No grade 3-4 treatment-related toxicities were noted. Common toxicity included mild-to-moderate, short-lived chills (63%). Median PFS was 2.3 months (95% CI: 1.7-2.9). A complete response ongoing after 20 months was observed in a sorafenib-refractory patient and a partial response in a Child-Pugh class-B patient, yielding a response rate of 7%. Six patients (22%) experienced stable disease. The disease control rate (DCR) was 30% and was maintained for a median PFS time of 4.3 months. Median survival was 8.9 months (95% CI: 7.5-10.2). In a subset of 12 sorafenib-resistant patients, the response rate was 8% and the median survival was 9.5 months.Conclusion:NGR-hTNF was well tolerated and showed single-agent activity in HCC. Further investigation in HCC is of interest

Phenotype and immune function of lymph node and peripheral blood CLL cells are linked to transendothelial migration

everal lines of evidence suggest that homing of tumor cells to lymphoid tissue contributes to disease progression in chronic lymphocytic leukemia (CLL). Here, we demonstrate that lymph node (LN)-derived CLL cells possess a distinct phenotype, and exhibit enhanced capacity for T-cell activation and superior immune synapse formation when compared with paired peripheral blood (PB) samples. LN-derived CLL cells manifest a proliferative, CXCR4(dim)CD5(bright) phenotype compared with those in the PB and higher expression of T-cell activation molecules including CD80, CD86, and HLA-D-related (DR). In addition, LN-CLL cells have higher expression of α4β1 (CD49d) which, as well as being a co-stimulatory molecule, is required for CLL cells to undergo transendothelial migration (TEM) and enter the proliferation centers of the LNs. Using an in vitro system that models circulation and TEM, we showed that the small population of CLL cells that migrate are CXCR4(dim)CD5(bright) with higher CD49d, CD80, CD86, and HLA-DR compared with those that remain circulating; a phenotype strikingly similar to LN-derived CLL cells. Furthermore, sorted CD49d(hi) CLL cells showed an enhanced capacity to activate T cells compared with CD49d(lo) subpopulations from the same patient. Thus, although PB-CLL cells have a reduced capacity to form immune synapses and activate CD4(+) T cells, this was not the case for LN-CLL cells or those with the propensity to undergo TEM. Taken together, our study suggests that CLL cell immunologic function is not only modulated by microenvironmental interactions but is also a feature of a subpopulation of PB-CLL cells that are primed for lymphoid tissue homing and interaction with T cells

Phase Ib study of NGR–hTNF, a selective vascular targeting agent, administered at low doses in combination with doxorubicin to patients with advanced solid tumours

Contains fulltext : 81937timmer-bonte.pdf (publisher's version ) (Closed access)BACKGROUND: Asparagine-glycine-arginine-human tumour necrosis factor (NGR-hTNF) is a vascular targeting agent exploiting a tumour-homing peptide (NGR) that selectively binds to aminopeptidase N/CD13, overexpressed on tumour blood vessels. Significant preclinical synergy was shown between low doses of NGR-TNF and doxorubicin. METHODS: The primary aim of this phase I trial was to verify the safety of low-dose NGR-hTNF combined with doxorubicin in treating refractory/resistant solid tumours. Secondary objectives included pharmacokinetics (PKs), pharmacodynamics, and clinical activity. In all 15 patients received NGR-hTNF (0.2-0.4-0.8-1.6 microg m(-2)) and doxorubicin (60-75 mg m(-2)), both given intravenously every 3 weeks. RESULTS: No dose-limiting toxicity occurred and the combination was well tolerated. Around two cases of neutropenic fevers, lasting 2 days, and two cases of cardiac ejection-fraction drops, one asymptomatic and the other symptomatic, were registered. Only 11% of the adverse events were related to NGR-hTNF and were short-lasting and mild-to-moderate in severity. There was no apparent PK interaction and the shedding of soluble TNF-receptors did not increase to 0.8 microg m(-2). One partial response (7%), at dose level 0.8 microg m(-2), and 10 stable diseases (66%), lasting for a median duration of 5.6 months, were observed. CONCLUSIONS: NGR-hTNF plus doxorubicin was administered safely and showed promising activity in patients pre-treated with anthracyclines. The dose level of 0.8 microg m(-2) NGR-hTNF plus doxorubicin 75 mg m(-2) was selected for phase II development

Broad targeting of resistance to apoptosis in cancer

Apoptosis or programmed cell death is natural way of removing aged cells from the body. Most of the anti-cancer therapies trigger apoptosis induction and related cell death networks to eliminate malignant cells. However, in cancer, de-regulated apoptotic signaling, particularly the activation of an anti-apoptotic systems, allows cancer cells to escape this program leading to uncontrolled proliferation resulting in tumor survival, therapeutic resistance and recurrence of cancer. This resistance is a complicated phenomenon that emanates from the interactions of various molecules and signaling pathways. In this comprehensive review we discuss the various factors contributing to apoptosis resistance in cancers. The key resistance targets that are discussed include (1) Bcl-2 and Mcl-1 proteins; (2) autophagy processes; (3) necrosis and necroptosis; (4) heat shock protein signaling; (5) the proteasome pathway; (6) epigenetic mechanisms; and (7) aberrant nuclear export signaling. The shortcomings of current therapeutic modalities are highlighted and a broad spectrum strategy using approaches including (a) gossypol; (b) epigallocatechin-3-gallate; (c) UMI-77 (d) triptolide and (e) selinexor that can be used to overcome cell death resistance is presented. This review provides a roadmap for the design of successful anti-cancer strategies that overcome resistance to apoptosis for better therapeutic outcome in patients with cancer