We describe direct measurements of ozone concentration achievable in small enclosed containers (plastic storage boxes) for use as improvised decontamination systems for small articles such as disposable PPE (N95 masks, nitrile gloves, etc.), clothing, mail and small packages, food, and other miscellaneous articles. The emphasis is on the reliable and sustained generation of ozone gas concentrations of sufficient concentration and duration to create an effective virucidal environment to achieve more than 95% to 99% viral inactivation, based upon the data already published in the peer-review literature on this topic. The suggestion that ozone be used to inactivate virus is certainly not a new idea. Our objective in this report is to make clear that the necessary levels of ozone can be improvised using simple, easy-to-use, inexpensive, and widely available supplies, and that there is every theoretical and experimental reason to believe that this approach is as highly effective in viral inactivation by ozone as are the far more expensive, complex, cumbersome, and less available equivalent ozone (and other) disinfectant systems that have themselves become unavailable during times of pandemic crisis. Using multiple types of readily available commercial ozone generators, concentration in the tested improvised enclosure is tracked over time to assess ozone charging and decay rates, and the ozone quenching effects of items placed in the box. Generator performance is compared against published ozone dosage values for virucidal and antimicrobial activity. Bubbler and box-fan-type ozone generators were found to be effective at achieving and maintaining target concentrations of 10ppm ozone or higher, whereas automotive cigarette lighter and universal serial bus type plug in “air freshener” ozone generators could not achieve the target concentrations in these experiments. Calculations and practical guidelines for assembly and effective use of an ozone box for improvised decontamination are offered. The majority of this report is directed toward the scientific justification and rationale for this approach. The end of the document summarizes the findings and offers simplified designs for the construction and use of ozone boxes as an improvised method of disinfection.
During the transition from an initiation complex to an elongation complex (EC), T7 RNA polymerase undergoes major conformational changes that involve reorientation of a "core" subdomain as a rigid body and extensive refolding of other elements in the 266 residue N-terminal domain. The pathway and timing of these events is poorly understood. To examine this, we introduced proline residues into regions of the N-terminal domain that become ␣-helical during the reorganization and changed the charge of a key residue that interacts with the RNA:DNA hybrid 5 bp upstream of the active site in the EC but not in the initiation complex. These alterations resulted in a diminished ability to make products >5-7 nt and/or a slow transition through this point. The results indicate that the transition to an EC is a multistep process and that the movement of the core subdomain and reorganization of certain elements in the N-terminal domain commence prior to promoter release (at 8 -9 nt).
Background: Patients (pts) with relapsed/refractory classical Hodgkin lymphoma (r/r cHL) who fail or cannot tolerate both brentuximab vedotin (BV) and PD-1 inhibitors (PD-1i) have limited treatment options. Hodgkin Reed-Sternberg cells and the pro-inflammatory tumor microenvironment are rich in therapeutic targets including those in the PI3K/AKT/mTOR and JAK/STAT pathways. Tumors resistant to PD-1i may be particularly enriched for JAK/STAT mutations (Zaretsky et al, NEJM 2016). Everolimus, an oral mTOR inhibitor, is active in r/r cHL pts with overall response rate (ORR) about 46% (Johnston et al, Exp Hematol Oncol 2018). Ruxolitinib, an oral JAK inhibitor, showed best ORR of only 19% in r/r cHL (Van Den Neste et al, Haematologica 2018). Pre-clinical studies have shown that co-treatment with mTOR and JAK inhibitors has synergistic activity against proliferation of JAK-mutated cell lines (Zhang et al, Oncotarget 2018). Methods: We designed an open label, investigator initiated, phase I/II trial using the combination of everolimus with itacitinib, an oral JAK inhibitor, for adult pts with r/r cHL. Eligible pts had to undergo at least 2 prior lines of therapy and autologous stem cell transplant (SCT) or be ineligible for SCT. Pts also had to either progress after treatment with, be intolerant of, or not a candidate for BV and PD-1i. Pts with a history pneumonitis requiring corticosteroids were excluded. Pts were treated with everolimus 5 mg daily for all dose levels and a starting dose of itacitinib at 300 mg daily with escalation to 400 mg daily or de-escalation to 200 mg daily using a traditional 3+3 design. Duration of therapy was planned for up to 24 cycles (each cycle lasting 28 days). All pts received PJP prophylaxis and after an amendment anti-viral prophylaxis. The primary objective of phase I was to evaluate dose-limiting toxicities (DLTs) of the novel combination and to establish a recommended phase II dose (RP2D). DLT was defined as the occurrence of any ≥ grade 3 non-hematological toxicity or selected grade 4 hematological toxicities occurring during Cycle 1. All DLTs were assessed using CTCAE v5 criteria. The primary objective of phase II was to evaluate the efficacy of the drug combination by investigator-based assessment using Lugano 2014 criteria (Cheson et al, JCO 2014). Enrollment began in 2/2019 with data cut off on 7/10/2020. Results: We enrolled 15 pts with r/r cHL with 14 pts evaluable for safety and response. Median age was 36 years (range 22-68), 71% were male, and median number of prior therapies was 5 (range 3-9). All pts had received prior BV and PD-1i, 64% had a prior auto-SCT, 14% had a prior allo-SCT, and 14% had prior anti-CD30 CAR T cells. There were no Cycle 1 DLTs in the phase I cohort, and the RP2D was determined as everolimus 5 mg and itacitinib 400 mg daily. Hematological adverse events (AEs) of any grade included thrombocytopenia (79%), neutropenia (43%), and anemia (36%). Most common non-hematological AEs were hyperlipidemia (29%), acneiform rash (21%) and stomatitis (14%). Notable grade 3 and 4 toxicities at least possibly related to the study treatment included thrombocytopenia (43%), neutropenia (21%), infection (7%), and hypertension (7%). There were no deaths related to study treatment and no patient discontinued therapy due to AEs. Six pts required dose modification for hematologic toxicities after the DLT period. The ORR in the combined phase I/II cohorts was 79% (95% CI: 49-95%) with a complete response rate 14% (95% CI: 2-43%). With median follow-up of 6.8 months (range 3.6-15.7), the overall survival was 92% (95% CI: 54-99%) with one patient dying of progressive disease at 2 months after discontinuing the study treatment due to progression. The median progression-free survival was estimated to be 3.8 months (95% CI: 1.8-not reached). Responses over 6 months are ongoing in several pts (Figure 1). Conclusion: The combination of everolimus and itacitinib is feasible and its efficacy compares favorably to historical reports for everolimus or JAK inhibitor monotherapy in r/r cHL. Our results suggest that the rational design for targeting multiple pathways can improve therapeutic outcomes in r/r cHL and warrants further investigation, particularly in pts with disease refractory to BV and PD-1i. Attempts to determine predictive biological markers of efficacy in long-term responders are ongoing. Figure 1 Disclosures Svoboda: Genmab: Consultancy; Adaptive: Consultancy; Astra-Zeneca: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Imbrium: Consultancy; Incyte: Research Funding; Merck: Research Funding; Atara: Consultancy; Pharmacyclics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; TG: Research Funding. Barta:Pfizer: Honoraria; Janssen: Honoraria; Seattle Genetics: Honoraria, Research Funding; Atara: Honoraria; Monsanto: Consultancy. Landsburg:Seattle Genetics: Speakers Bureau; Takeda: Research Funding; Triphase: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Curis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Dwivedy Nasta:Debiopharm: Research Funding; Roche: Research Funding; Incyte: Research Funding; Forty Seven: Research Funding; Atara: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Rafael Pharmaceuticals: Research Funding. Hwang:Novartis: Research Funding; Tmunity Therapeutics: Research Funding. Gerson:Pharmacyclics: Consultancy; Genentech: Consultancy; Loxo: Research Funding; Abbvie: Consultancy. Chong:Novartis: Membership on an entity's Board of Directors or advisory committees; Tessa: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; KITE Pharma: Membership on an entity's Board of Directors or advisory committees. Hughes:Acerta Pharma and HOPA: Research Funding; AstraZeneca: Consultancy; Genzyme: Consultancy; Janssen: Consultancy; AbbVie: Consultancy. Ruella:Abclon: Consultancy, Research Funding; Abclon, BMS, NanoString: Consultancy; UPenn/Novartis: Patents & Royalties. Schuster:AlloGene, AstraZeneca, BeiGene, Genentech, Inc./ F. Hoffmann-La Roche, Juno/Celgene, Loxo Oncology, Nordic Nanovector, Novartis, Tessa Therapeutics: Consultancy, Honoraria; Novartis, Genentech, Inc./ F. Hoffmann-La Roche: Research Funding. OffLabel Disclosure: everolimus for relapsed and refractory Hodgkin lymphoma
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