An analogue of the antibiotic teicoplanin prevents flavivirus entry in vitro.

There is an urgent need for potent inhibitors of dengue virus (DENV) replication for the treatment and/or prophylaxis of infections with this virus. We here report on an aglycon analogue of the antibiotic teicoplanin (code name LCTA-949) that inhibits DENV-induced cytopathic effect (CPE) in a dose-dependent manner. Virus infection was completely inhibited at concentrations that had no adverse effect on the host cells. These findings were corroborated by quantification of viral RNA levels in culture supernatant. Antiviral activity was also observed against other flaviviruses such as the yellow fever virus and the tick-borne encephalitis virus (TBEV). In particular, potent antiviral activity was observed against TBEV. Time-of-drug-addition experiments indicated that LCTA-949 inhibits an early stage in the DENV replication cycle; however, a virucidal effect was excluded. This observation was corroborated by the fact that LCTA-949 lacks activity on DENV subgenomic replicon (that does not encode structural proteins) replication. Using a microsopy-based binding and fusion assay employing DiD-labeled viruses, it was shown that LCTA-949 targets the early stage (binding/entry) of the infection. Moreover, LCTA-949 efficiently inhibits infectivity of DENV particles pre-opsonized with antibodies, thus potentially also inhibiting antibody-dependent enhancement (ADE). In conclusion, LCTA-949 exerts in vitro activity against several flaviviruses and does so (as shown for DENV) by interfering with an early step in the viral replication cycle.Fil: De Burghgraeve, Tine. Katholikie Universiteit Leuven; BélgicaFil: Kaptein, Suzanne J. F.. Katholikie Universiteit Leuven; BélgicaFil: Ayala Nunez, Nilda V.. University of Groningen; Países BajosFil: Mondotte, Juan Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Pastorino, Boris. Université de la Méditerranée; FranciaFil: Printsevskaya, Svetlana S.. Russian Academy of Medical Sciences; RusiaFil: de Lamballerie, Xavier. Université de la Méditerranée; FranciaFil: Jacobs, Michael. Royal Free & University College Medical School; Reino UnidoFil: Preobrazhenskaya, Maria. Russian Academy of Medical Sciences; RusiaFil: Gamarnik, Andrea Vanesa. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Smit, Jolanda M.. University of Groningen; Países BajosFil: Neyts, Johan. Katholikie Universiteit Leuven; Bélgic

Occurrence of malnutrition and associated factors in community-dwelling older adults: Those with a recent diagnosis of cancer are at higher risk

OBJECTIVES: In older adults, nutritional health is essential for good quality of life and living independently at home. Especially in cancer patients, malnutrition is common and known to complicate treatment. This study aims to evaluate the nutritional status and its associated factors in community-dwelling older adults with and without cancer. DESIGN: This is an observational study. SETTING: This study focuses on older community-dwelling people. PARTICIPANTS: This study included older people with and without cancer (≥70 years). Cancer patients included patients with a new diagnosis of breast, lung, prostate, or colorectal cancer. MEASUREMENTS: Data collection included measures of nutritional status, quality of life, depression, fatigue, distress and functional status. We used multivariate logistic regression analysis to assess the association between personal characteristics and malnutrition. RESULTS: Data were available for 657 people; 383 people without cancer and 274 with a cancer diagnosis. Overall, malnutrition was detected in 245 (37.5%) people; in cancer patients this was 66.1%. Multivariate analysis showed that having cancer (OR 14.4, 95% CI: 8.01 - 23.3), being male (OR 2.38, 95% CI: 1.49 - 3.70), having depression (OR 13.5, 95% CI: 6.02-30.0), distress (OR 2.60, 95% CI: 1.55 - 4.37) and impaired instrumental activities of daily living (IADL) (OR 2.63, 95% CI: 1.63 - 4.24) were associated with a higher risk of malnutrition. CONCLUSION: The prevalence of malnutrition in community-dwelling older people is high, particularly in patients with cancer. Benchmarking and routine screening of older patients may be helpful strategies to increase awareness of (risk of) malnutrition among professionals.status: publishe

Occurrence of malnutrition and associated factors in community-dwelling older adults: Those with a recent diagnosis of cancer are at higher risk

Objectives: In older adults, nutritional health is essential for good quality of life and living independently at home. Especially in cancer patients, malnutrition is common and known to complicate treatment. This study aims to evaluate the nutritional status and its associated factors in community-dwelling older adults with and without cancer. Design: This is an observational study. Setting: This study focuses on older community-dwelling people. Participants: This study included older people with and without cancer (≥70 years). Cancer patients included patients with a new diagnosis of breast, lung, prostate, or colorectal cancer. Measurements: Data collection included measures of nutritional status, quality of life, depression, fatigue, distress and functional status. We used multivariate logistic regression analysis to assess the association between personal characteristics and malnutrition. Results: Data were available for 657 people; 383 people without cancer and 274 with a cancer diagnosis. Overall, malnutrition was detected in 245 (37.5%) people; in cancer patients this was 66.1%. Multivariate analysis showed that having cancer (OR 14.4, 95% CI: 8.01 - 23.3), being male (OR 2.38, 95% CI: 1.49–3.70), having depression (OR 13.5, 95% CI: 6.02-30.0), distress (OR 2.60, 95% CI: 1.55–4.37) and impaired instrumental activities of daily living (IADL) (OR 2.63, 95% CI: 1.63–4.24) were associated with a higher risk of malnutrition. Conclusion: The prevalence of malnutrition in community-dwelling older people is high, particularly in patients with cancer. Benchmarking and routine screening of older patients may be helpful strategies to increase awareness of (risk of) malnutrition among professionals

An analogue of the antibiotic teicoplanin prevents flavivirus entry in vitro

There is an urgent need for potent inhibitors of dengue virus (DENV) replication for the treatment and/or prophylaxis of infections with this virus. We here report on an aglycon analogue of the antibiotic teicoplanin (code name LCTA-949) that inhibits DENV-induced cytopathic effect (CPE) in a dose-dependent manner. Virus infection was completely inhibited at concentrations that had no adverse effect on the host cells. These findings were corroborated by quantification of viral RNA levels in culture supernatant. Antiviral activity was also observed against other flaviviruses such as the yellow fever virus and the tick-borne encephalitis virus (TBEV). In particular, potent antiviral activity was observed against TBEV. Time-of-drug-addition experiments indicated that LCTA-949 inhibits an early stage in the DENV replication cycle; however, a virucidal effect was excluded. This observation was corroborated by the fact that LCTA-949 lacks activity on DENV subgenomic replicon (that does not encode structural proteins) replication. Using a microsopy-based binding and fusion assay employing DiD-labeled viruses, it was shown that LCTA-949 targets the early stage (binding/entry) of the infection. Moreover, LCTA-949 efficiently inhibits infectivity of DENV particles pre-opsonized with antibodies, thus potentially also inhibiting antibody-dependent enhancement (ADE). In conclusion, LCTA-949 exerts in vitro activity against several flaviviruses and does so (as shown for DENV) by interfering with an early step in the viral replication cycle.status: publishe

A Derivate of the Antibiotic Doxorubicin Is a Selective Inhibitor of Dengue and Yellow Fever Virus Replication In Vitro ▿ †

A doxorubicin derivate, SA-17, that carries a squaric acid amide ester moiety at the carbohydrate (α-l-daunosaminyl) group was identified as a selective inhibitor of in vitro dengue virus (DENV) serotype 2 replication (50% effective concentration [EC50] = 0.34 ± 0.20 μg/ml [0.52 ± 0.31 μM]). SA-17 is markedly less cytostatic than the parent compound, resulting in a selectivity index value of ∼100. SA-17 also inhibits yellow fever virus 17D (YFV-17D) replication (EC50 = 3.1 ± 1.0 μg/ml [4.8 ± 1.5 μM]), although less efficiently than DENV replication, but proved inactive against a variety of enveloped and nonenveloped viruses. SA-17 inhibits in vitro flavivirus replication in a dose-dependent manner, as was assessed by virus yield reduction assays and quantification of viral RNA by means of real-time quantitative reverse transcriptase PCR (RT-qPCR) (∼2 to 3 log reduction). The anti-DENV activity was confirmed using a Renilla luciferase-expressing dengue reporter virus. Time-of-drug-addition studies revealed that SA-17 acts at the very early stages of the viral replication cycle (i.e., virus attachment and/or virus entry). This observation was corroborated by the observation that SA-17, unlike the nucleoside analogue ribavirin, does not inhibit the replication of DENV subgenomic replicons. Preincubation of high-titer stocks of DENV or YFV-17D with ≥5 μg/ml SA-17 resulted in 100% inhibition of viral infectivity (≥3 log reduction). SA-17, however, did not prove virucidal

<i>In vitro</i> antiviral effect of LCTA-949 against selected flaviviruses.

*<p>Data are mean values ± standard deviations (SD) for three independent experiments.</p><p>EC₅₀: 50% effective concentration, CC₅₀: 50% cytostatic concentration.</p

Dose-dependent inhibition of flavivirus replication by LCTA-949 and ribavirin.

<p>Vero-B cell cultures infected with DENV-2 (panels A and B) or YFV-17D (panels C and D) were treated with different concentrations of LCTA-949 (panels A and C) or ribavirin (panels B and D). Viral RNA levels were quantified on day 4 p.i. by means of RNA RT-qPCR (bars). Mock-infected cells were treated with the same dilution series of LCTA-949 or ribavirin. Cell viability was determined by the MTS/PMS method (lines). Data represent mean values ± standard deviations (SD) for three independent experiments.</p

LCTA-949 prevents antibody-dependent enhancement of DENV infection.

<p>P388D1 cells were infected with DENV pre-opsonized with anti-E mAb DV2-104 at an MOI of 10 in presence of increasing concentrations of LCTA-949. Anti-E DV2-104 was used at a concentration of 400 ng/ml. The percentage of inhibition of infection after LCTA-949 treatment was calculated with respect to the positive control of untreated opsonized virus. Data are expressed as the means ± SD from two separate experiments, each of which was carried out in duplicate.</p

Dose-dependent inhibition of virus-induced CPE formation by LCTA-949 and effect of LCTA-949 on flavivirus protein expression.

<p>A: Vero-B cell cultures infected with DENV-2 were treated with different concentrations of LCTA-949. CPE formation was monitored at day 8 p.i. B: Vero-B cell cultures (panels A and D) were treated with 12.5 µM LCTA-949 (panels C and F) and infected with DENV-2 (panels B and C) or YFV-17D (panels E and F). DENV-2 E protein and YFV-17D NS1 protein expression was visualized on day 3 p.i.</p