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Artigo em Inglês | MEDLINE | ID: mdl-31523983


We determined HIV-1 pol gene sequences from self-collected rectal swabs of HIV-positive young men who have sex with men and transgender women (YMSM/TW). HIV-1 pol was amplified from 39/96 (41%) rectal swabs, including 29/77 (38%) prevalent and 10/19 (53%) incident HIV-1 infections (p<0.001). Pol did not amplify from rectal swabs from participants with plasma viral load <1,000 copies/ml. Each rectal swab-derived amplicon consensus sequence was most closely related to the paired plasma virion RNA-derived sequence from the same participant. Results document a rectal mucosal source of HIV-1 in infected persons, and suggest usefulness for non-invasive study of biological mechanisms underlying the epidemiologic risk to an insertive partner of HIV-1 acquisition during condomless anal sex.

EBioMedicine ; 47: 33-43, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31466914


BACKGROUND: The dismal survival of glioblastoma (GBM) patients urgently calls for the development of new treatments. Chimeric antigen receptor T (CAR-T) cells are an attractive strategy, but preclinical and clinical studies in GBM have shown that heterogeneous expression of the antigens targeted so far causes tumor escape, highlighting the need for the identification of new targets. We explored if B7-H3 is a valuable target for CAR-T cells in GBM. METHODS: We compared mRNA expression of antigens in GBM using TCGA data, and validated B7-H3 expression by immunohistochemistry. We then tested the antitumor activity of B7-H3-redirected CAR-T cells against GBM cell lines and patient-derived GBM neurospheres in vitro and in xenograft murine models. FINDINGS: B7-H3 mRNA and protein are overexpressed in GBM relative to normal brain in all GBM subtypes. Of the 46 specimens analyzed by immunohistochemistry, 76% showed high B7-H3 expression, 22% had detectable, but low B7-H3 expression and 2% were negative, as was normal brain. All 20 patient-derived neurospheres showed ubiquitous B7-H3 expression. B7-H3-redirected CAR-T cells effectively targeted GBM cell lines and neurospheres in vitro and in vivo. No significant differences were found between CD28 and 4-1BB co-stimulation, although CD28-co-stimulated CAR-T cells released more inflammatory cytokines. INTERPRETATION: We demonstrated that B7-H3 is highly expressed in GBM specimens and neurospheres that contain putative cancer stem cells, and that B7-H3-redirected CAR-T cells can effectively control tumor growth. Therefore, B7-H3 represents a promising target in GBM. FUND: Alex's Lemonade Stand Foundation; Il Fondo di Gio Onlus; National Cancer Institute; Burroughs Wellcome Fund.

Artigo em Inglês | MEDLINE | ID: mdl-28208789


Exposure to nature provides a wide range of health benefits. A significant proportion of these are delivered close to home, because this offers an immediate and easily accessible opportunity for people to experience nature. However, there is limited information to guide recommendations on its management and appropriate use. We apply a nature dose-response framework to quantify the simultaneous association between exposure to nearby nature and multiple health benefits. We surveyed ca. 1000 respondents in Southern England, UK, to determine relationships between (a) nature dose type, that is the frequency and duration (time spent in private green space) and intensity (quantity of neighbourhood vegetation cover) of nature exposure and (b) health outcomes, including mental, physical and social health, physical behaviour and nature orientation. We then modelled dose-response relationships between dose type and self-reported depression. We demonstrate positive relationships between nature dose and mental and social health, increased physical activity and nature orientation. Dose-response analysis showed that lower levels of depression were associated with minimum thresholds of weekly nature dose. Nearby nature is associated with quantifiable health benefits, with potential for lowering the human and financial costs of ill health. Dose-response analysis has the potential to guide minimum and optimum recommendations on the management and use of nearby nature for preventative healthcare.

Meio Ambiente , Comportamentos Relacionados com a Saúde , Nível de Saúde , Atividades de Lazer/psicologia , Saúde Mental , Natureza , Saúde da População Urbana , Adulto , Idoso , Estudos Transversais , Depressão/prevenção & controle , Inglaterra , Exercício/psicologia , Feminino , Promoção da Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Características de Residência , Autorrelato , Ajustamento Social , Fatores de Tempo
Mol Syst Biol ; 11(5): 803, 2015 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-25953765


When cells are exposed to death ligands such as TRAIL, a fraction undergoes apoptosis and a fraction survives; if surviving cells are re-exposed to TRAIL, fractional killing is once again observed. Therapeutic antibodies directed against TRAIL receptors also cause fractional killing, even at saturating concentrations, limiting their effectiveness. Fractional killing arises from cell-to-cell fluctuations in protein levels (extrinsic noise), but how this results in a clean bifurcation between life and death remains unclear. In this paper, we identify a threshold in the rate and timing of initiator caspase activation that distinguishes cells that live from those that die; by mapping this threshold, we can predict fractional killing of cells exposed to natural and synthetic agonists alone or in combination with sensitizing drugs such as bortezomib. A phenomenological model of the threshold also quantifies the contributions of two resistance genes (c-FLIP and Bcl-2), providing new insight into the control of cell fate by opposing pro-death and pro-survival proteins and suggesting new criteria for evaluating the efficacy of therapeutic TRAIL receptor agonists.

Bortezomib/farmacologia , Caspase 8/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Apoptose , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células HEK293 , Células HeLa/efeitos dos fármacos , Humanos , Modelos Biológicos , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo