A portable device for nucleic acid quantification powered by sunlight, a flame or electricity.

A decentralized approach to diagnostics can decrease the time to treatment of infectious diseases in resource-limited settings. Yet most modern diagnostic tools require stable electricity and are not portable. Here, we describe a portable device for isothermal nucleic-acid quantification that can operate with power from electricity, sunlight or a flame, and that can store heat from intermittent energy sources, for operation when electrical power is not available or reliable. We deployed the device in two Ugandan health clinics, where it successfully operated through multiple power outages, with equivalent performance when powered via sunlight or electricity. A direct comparison between the portable device and commercial qPCR (quantitative polymerase chain reaction) machines for samples from 71 Ugandan patients (29 of which were tested in Uganda) for the presence of Kaposi's sarcoma-associated herpesvirus DNA showed 94% agreement, with the four discordant samples having the lowest concentration of the herpesvirus DNA. The device's flexibility in power supply provides a needed solution for on-field diagnostics

Safety and preliminary efficacy of vorinostat with R-EPOCH in high-risk HIV-associated non-Hodgkin\u27s lymphoma (AMC-075)

We performed a phase I trial of vorinostat (VOR) given on days 1 to 5 with R-EPOCH (rituximab plus etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin hydrochloride) in patients with aggressive HIV-associated non-Hodgkin lymphoma. VOR was tolerable at 300 mg and seemingly efficacious with chemotherapy with complete response rate of 83% and 1-year event-free survival of 83%. VOR did not significantly alter chemotherapy steady-state concentrations, CD4+ cell counts, or HIV viral loads. Vorinostat (VOR), a histone deacetylase inhibitor, enhances the anti-tumor effects of rituximab (R) and cytotoxic chemotherapy, induces viral lytic expression and cell killing in Epstein-Barr virus-positive (EBV+) or human herpesvirus-8-positive (HHV-8+) tumors, and reactivates latent human immunodeficiency virus (HIV) for possible eradication by combination antiretroviral therapy (cART). We performed a phase I trial of VOR given with R-based infusional EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin hydrochloride) (n = 12) and cART in aggressive HIV-associated B-cell non-Hodgkin lymphoma (NHL) in order to identify safe dosing and schedule. VOR (300 or 400 mg) was given orally on days 1 to 5 with each cycle of R-EPOCH for 10 high-risk patients with diffuse large B-cell lymphoma (1 EBV+), 1 EBV+/HHV-8+ primary effusion lymphoma, and 1 unclassifiable NHL. VOR was escalated from 300 to 400 mg using a standard 3 + 3 design based on dose-limiting toxicity observed in cycle 1 of R-EPOCH. The recommended phase II dose of VOR was 300 mg, with dose-limiting toxicity in 2 of 6 patients at 400 mg (grade 4 thrombocytopenia, grade 4 neutropenia), and 1 of 6 treated at 300 mg (grade 4 sepsis from tooth abscess). Neither VOR, nor cART regimen, significantly altered chemotherapy steady-state concentrations. VOR chemotherapy did not negatively impact CD4+ cell counts or HIV viral loads, which decreased or remained undetectable in most patients during treatment. The response rate in high-risk patients with NHL treated with VOR(R)-EPOCH was 100% (complete 83% and partial 17%) with a 1-year event-free survival of 83% (95% confidence interval, 51.6%-97.9%). VOR combined with R-EPOCH was tolerable and seemingly efficacious in patients with aggressive HIV-NHL

Kaposi's sarcoma herpesvirus activates the hypoxia response to usurp HIF2α-dependent translation initiation for replication and oncogenesis

Kaposi's sarcoma herpesvirus (KSHV) is an angiogenesis-inducing oncovirus whose ability to usurp the oxygen-sensing machinery is central to its oncogenicity. By upregulating the hypoxia-inducible factors (HIFs), KSHV reprograms infected cells to a hypoxia-like state, triggering angiogenesis. Here we identify a link between KSHV replicative biology and oncogenicity by showing that KSHV's ability to regulate HIF2α levels and localization to the endoplasmic reticulum (ER) in normoxia enables translation of viral lytic mRNAs through the HIF2α-regulated eIF4E2 translation-initiation complex. This mechanism of translation in infected cells is critical for lytic protein synthesis and contributes to KSHV-induced PDGFRA activation and VEGF secretion. Thus, KSHV regulation of the oxygen-sensing machinery allows virally infected cells to initiate translation via the mTOR-dependent eIF4E1 or the HIF2α-dependent, mTOR-independent, eIF4E2. This “translation initiation plasticity” (TRIP) is an oncoviral strategy used to optimize viral protein expression that links molecular strategies of viral replication to angiogenicity and oncogenesis.Fil: Méndez Solís, Omayra. University of Miami; Estados UnidosFil: Bendjennat, Mourad. University of Miami; Estados UnidosFil: Naipauer, Julian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina. University of Miami; Estados UnidosFil: Theodoridis, Phaedra R.. University of Miami; Estados UnidosFil: Ho, J.J. David. University of Miami; Estados UnidosFil: Verdun, Ramiro E.. University of Miami; Estados UnidosFil: Hare, Joshua M.. University of Miami; Estados UnidosFil: Cesarman, Ethel. Weill Cornell Medicine; Estados UnidosFil: Lee, Stephen. University of Miami; Estados UnidosFil: Mesri, Enrique Alfredo. University of Miami; Estados Unido