In recent years, with increased the prevalence of viral infections and having no specific for their treatment and also the continuous appearance of resistant viral strains, the finding of novel ...antiviral agents is necessary. In this study, monoterpenes of thymol, carvacrol, p-cymene and essential oils from Sinapis arvensis L., Lallemantia royleana Benth. and Pulicaria vulgaris Gaertn. were screened for their inhibitory effect against herpes simplex virus type 1 (HSV-1) in vitro on Vero cell line CCL-81-ATCC using a plaque reduction assay. The antiviral activity of three monoterpenes (thymol, carvacrol and p-cymene) and three essential oils were evaluated by cytotoxicity assay, direct plaque test. In addition, the modes of antiviral action of these compounds were investigated during the viral infection cycle. Results showed that the inhibitory concentrations (IC50) were determined at 0.002%, 0.037%, >0.1%, 0.035%, 0.018% and 0.001% for thymol, carvacrol, p-cymene, S. arvensis oil, L. royleana oil and P. vulgaris oil, respectively. A manifestly dose-dependent virucidal activity against HSV-1 could be exhibited for compounds tested. In order to determine the mode of the inhibitory effect, compounds were added at different stages during the viral infection cycle. At maximum noncytotoxic concentrations of the compounds, plaque formation was significantly reduced by more than 80% when HSV-1 was preincubated with p-cymene. However, no inhibitory effect could be observed when the compounds were added to the cells prior to infection with HSV-1 or after the adsorption period.
These results indicate that compounds affected HSV-1 mostly before adsorption and might interact with the viral envelope. Thymol exhibited a high selectivity index and seems to be a promising candidate for topical therapeutic application as antiviral agent for treatment of herpetic infections.
BACKGROUND Respiratory syncytial virus (RSV) infection is a cause of substantial morbidity and mortality. There is no known effective therapy. METHODS We conducted a randomized, double-blind, ...clinical trial in healthy adults inoculated with RSV. Participants received the oral nucleoside analogue ALS-008176 or placebo 12 hours after confirmation of RSV infection or 6 days after inoculation. Treatment was administered every 12 hours for 5 days. Viral load, disease severity, resistance, and safety were measured throughout the 28-day study period, with measurement beginning before inoculation. The primary end point was the area under the curve (AUC) for viral load, which was assessed immediately before administration of the first dose through the 12th day after inoculation in participants infected with RSV. RESULTS A total of 62 participants received placebo or one of three ALS-008176 dosing regimens: 1 loading dose of 750 mg followed by 9 maintenance doses of 500 mg (group 1), 1 loading dose of 750 mg followed by 9 maintenance doses of 150 mg (group 2), or 10 doses of 375 mg (group 3). In the 35 infected participants (23 of whom were treated with ALS-008176), the AUCs for viral load for groups 1, 2, and 3 and the placebo group were 59.9, 73.7, 133.4, and 500.9 log10 plaque-forming-unit equivalents × hours per milliliter, respectively (P≤0.001). The time to nondetectability on polymerase-chain-reaction assay (P<0.001), the peak viral load (P≤0.001), the AUC for symptom score (P<0.05), and the AUC for mucus weight were lower in all groups receiving ALS-008176 than in the placebo group. Antiviral activity was greatest in the two groups that received a loading dose--viral clearance was accelerated (P≤0.05), and the AUC for viral load decreased by 85 to 88% as compared with the placebo group. Within this small trial, no viral rebound or resistance was identified. There were no serious adverse events, and there was no need for premature discontinuation of the study drug. CONCLUSIONS In this RSV challenge study, more rapid RSV clearance and a greater reduction of viral load, with accompanying improvements in the severity of clinical disease, were observed in the groups treated with ALS-008176 than in the placebo group. (Funded by Alios BioPharma; ClinicalTrials.gov number, NCT02094365.).
Vadastuximab talirine (SGN-CD33A, 33A) is an antibody-drug conjugate consisting of pyrrolobenzodiazepine dimers linked to a monoclonal antibody targeting CD33, which is expressed in the majority of ...acute myeloid leukemia (AML) patients. This phase 1 study evaluated the safety, pharmacokinetics, and preliminary activity of vadastuximab talirine and determined the recommended monotherapy dose in patients with relapsed or refractory AML. Additional expansion cohorts tested vadastuximab talirine in specific subpopulations of relapsed AML, and in a cohort of older, treatment-naive patients. Patients received vadastuximab talirine IV on day 1 (5-60 µg/kg) or on days 1 and 4 (20 µg/kg) of 21-day cycles. A total of 131 patients (median age, 73 years range, 26-89 years) had intermediate I-II (48%) or adverse (34%) risk by European LeukemiaNet classification; 50% of patients had underlying myelodysplasia. Two dose-limiting toxicities (grade 2 pulmonary embolism and grade 4 hypocellular marrow) occurred during dose finding. Most adverse events (AEs) were consistent with myelosuppression; nonhematologic AEs included fatigue, nausea, and diarrhea. The 30-day mortality was 8%. At the recommended monotherapy dose of 40 µg/kg, the complete remission + CRi rate was 28% (5 of 18 patients); 50% of patients who responded achieved minimal residual disease negativity. In patients across dose levels who achieved CR or CRi, the median time to full count recovery was 6.4 weeks for neutrophils (≥1000/µL) and 10.6 weeks for platelets (≥100 × 109/L). Vadastuximab talirine demonstrates activity and a tolerable safety profile as a single agent in patients with AML. The recommended monotherapy dose of vadastuximab talirine is 40 µg/kg. This trial was registered at www.clinicaltrials.gov as # NCT01902329.
•Vadastuximab talirine, a novel antibody-drug conjugate, consists of an anti-CD33 monoclonal antibody conjugated to pyrrolobenzodiazepine dimers.•In a phase 1 trial, vadastuximab talirine demonstrated single-agent activity and minimal nonhematologic toxicity in patients with AML.
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•Electrospun PHBV scaffolds containing HABR nanoparticles were modified with PLL.•The PLL modification was done using EDC/NHS surface attachment and blending methods.•PLL surface ...modified PHBV-HABR showed increased wettability and surface roughness.•Enhanced hFob proliferation, mineralization and differentiation were confirmed.•PLL surface treatment was more effective than blending for in vitro bone formation.
Regulation of cell-scaffold interactions is an important factor for modulating the cellular activity in bone tissue engineering applications. Tailoring the physical and chemical properties of the scaffolds to better mimic the extracellular matrix (ECM) of native bone is a more effective strategy for enhancing the cell-scaffold interactions. In this work, we aim at investigating the novel poly L lysine (PLL)-modified poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV)-hydroxyapatite/bredigite (HABR) nanofibrous scaffolds towards bone tissue engineering. The PHBV-HABR scaffolds were modified with PLL through two different routes: (i) covalent attachment of PLL to the surface of PHBV-HABR nanofibrous scaffolds using EDC/NHS, and (ii) blending of PLL with PHBV-HABR nanofibers. Characterization of the resultant nanofibrous scaffolds was done using scanning electron microscopy (SEM), Fourier transform infrared (FTIR) spectroscopy, contact angle, atomic force microscopy (AFM) and tensile strength. According to the results obtained from contact angle measurements and AFM analysis, PLL surface modified PHBV-HABR scaffolds exhibited higher wettability and surface roughness than PLL blended PHBV-HABR and unmodified PHBV-HABR scaffolds. Cell–scaffold interactions were investigated by culturing human fetal osteoblast (hFob) cells, whereby the cell proliferation, mineralization, alkaline phosphatase activity, and bone protein expression was evaluated. Results demonstrated that the cells seeded on PLL surface modified PHBV-HABR displayed enhanced cell adhesion and proliferation compared to cells seeded on other scaffolds, as proved by SEM and MTS assay. Additionally, the enhanced osteogenic differentiation of hFob incubated on PLL surface modified PHBV-HABR was confirmed by ALP activity, alizarin red-s staining and immunofluorescence staining of osteocalcin, suggesting the potential application of PLL surface modified PHBV-HABR nanofibrous scaffolds for bone regeneration.
Our study compare the short and long-term efficacy of the intra articular injections (IAIs) of hyaluronic acid (HA), platelet-rich plasma (PRP), plasma rich in growth factors (PRGF), and ozone in ...patients with knee osteoarthritis (OA).
In this randomized clinical trial, 238 patients with mild to moderate knee OA were randomized into 4 groups of IAIs: HA (3 doses weekly), PRP (2 doses with 3 weeks interval), PRGF (2 doses with 3 weeks interval), and Ozone (3 doses weekly). Our outcome measures were the mean changes from baseline (immediately from the first injections) until 2,6, and 12 months post intervention in scores of visual analog scale (VAS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and Lequesne index.
A total of 200 patients enrolled in the final analysis. The mean age of patients was 56.9 ± 6.3 years, and 69.5% were women. In 2 months follow up, significant improvement of pain, stiffness, and function were seen in all groups compared to the baseline, but the ozone group had the best results (P < 0.05). In 6 month follow up HA, PRP, and PRGF groups demonstrated better therapeutic effects in all scores in comparison with ozone (P < 0.05). At the end of the 12th month, only PRGF and PRP groups had better results versus HA and ozone groups in all scores (P < 0.05). Despite the fact that ozone showed better early results, its effects begin to wear off earlier than other products and ultimately disappear in 12 months.
Ozone injection had rapid effects and better short-term results after 2 months, but its therapeutic effects did not persist after 6 months and at the 6-month follow up, PRP,PRGF and HA were superior to ozone. Only patients in PRP and PRGF groups improved symptoms persisted for 12 months. Therefore, these products could be the preferable choices for long-term management.
Registered in the Iranian Center of Clinical Trials ( www.irct.ir ) in 11/11/2017 with the following code: IRCT2017082013442N17.
The degradation of surfaces and its possible dependence on shape, size, and elemental composition of plastic particles were subjected. The surfaces of 146 microplastics were classified from smooth to ...fully eroded (%) by SEM/EDS. Structural elements and various additives were found on microplastics depending on their shapes. The surface of plastic items > 100 µm in length showed a relatively more eroded area than smaller ones, regardless of their shapes. Depending on shape, the percentage of surface erosion of irregularly shaped fragments < 100 µm was significantly enhanced compared to microbeads of the same size. These results may provide insights into assessing potential risks posed by microplastics and improve our understanding of the role of these parameters concerning possible adverse health effects on the environment.
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•Relationship of MPs' degraded surface with predictors of surface erosion is studied.•Surfaces of 146 MPs were classified from smooth to fully eroded (%) by SEM/EDS.•Structural elements and many additives were found on MPs depending on their shapes.•MPs > 100 µm possessed more eroded area than smaller ones, regardless of their shape.•Surface erosion (%) of fragments was enhanced compared to microbeads, both < 100 µm.
Current tobacco treatment guidelines have established the efficacy of available interventions, but they do not provide detailed guidance for common implementation questions frequently faced in the ...clinic. An evidence-based guideline was created that addresses several pharmacotherapy-initiation questions that routinely confront treatment teams.
Individuals with diverse expertise related to smoking cessation were empaneled to prioritize questions and outcomes important to clinicians. An evidence-synthesis team conducted systematic reviews, which informed recommendations to answer the questions. The GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach was used to rate the certainty in the estimated effects and the strength of recommendations.
The guideline panel formulated five strong recommendations and two conditional recommendations regarding pharmacotherapy choices. Strong recommendations include using varenicline rather than a nicotine patch, using varenicline rather than bupropion, using varenicline rather than a nicotine patch in adults with a comorbid psychiatric condition, initiating varenicline in adults even if they are unready to quit, and using controller therapy for an extended treatment duration greater than 12 weeks. Conditional recommendations include combining a nicotine patch with varenicline rather than using varenicline alone and using varenicline rather than electronic cigarettes.
Seven recommendations are provided, which represent simple practice changes that are likely to increase the effectiveness of tobacco-dependence pharmacotherapy.
Machine learning (ML) integrated with medical imaging has introduced new perspectives in precision diagnostics of high-grade gliomas, through radiomics and radiogenomics. This has raised hopes for ...characterizing noninvasive and in vivo biomarkers for prediction of patient survival, tumor recurrence, and genomics and therefore encouraging treatments tailored to individualized needs. Characterization of tumor infiltration based on pre-operative multi-parametric magnetic resonance imaging (MP-MRI) scans may allow prediction of the loci of future tumor recurrence and thereby aid in planning the course of treatment for the patients, such as optimizing the extent of resection and the dose and target area of radiation. Imaging signatures of tumor genomics can help in identifying the patients who benefit from certain targeted therapies. Specifying molecular properties of gliomas and prediction of their changes over time and with treatment would allow optimization of treatment. In this article, we provide neuro-oncology, neuropathology, and computational perspectives on the promise of radiomics and radiogenomics for allowing personalized treatments of patients with gliomas and discuss the challenges and limitations of these methods in multi-institutional clinical trials and suggestions to mitigate the issues and the future directions.
Isobutene is an important intermediate in the pyrolysis and oxidation of higher-order branched alkanes, and it is also a component of commercial gasolines. To better understand its combustion ...characteristics, a series of ignition delay time (IDT) and laminar flame speed (LFS) measurements have been performed. In addition, flow reactor speciation data recorded for the pyrolysis and oxidation of isobutene is also reported. Predictions of an updated kinetic model described herein are compared with each of these data sets, as well as with existing jet-stirred reactor (JSR) species measurements.
IDTs of isobutene oxidation were measured in four different shock tubes and in two rapid compression machines (RCMs) under conditions of relevance to practical combustors. The combination of shock tube and RCM data greatly expands the range of available validation data for isobutene oxidation models to pressures of 50atm and temperatures in the range 666–1715K. Isobutene flame speeds were measured experimentally at 1atm and at unburned gas temperatures of 298–398K over a wide range of equivalence ratios. For the flame speed results, there was good agreement between different facilities and the current model in the fuel-rich region. Ab initio chemical kinetics calculations were carried out to calculate rate constants for important reactions such as H-atom abstraction by hydroxyl and hydroperoxyl radicals and the decomposition of 2-methylallyl radicals.
A comprehensive chemical kinetic mechanism has been developed to describe the combustion of isobutene and is validated by comparison to the presently considered experimental measurements. Important reactions, highlighted via flux and sensitivity analyses, include: (a) hydrogen atom abstraction from isobutene by hydroxyl and hydroperoxyl radicals, and molecular oxygen; (b) radical–radical recombination reactions, including 2-methylallyl radical self-recombination, the recombination of 2-methylallyl radicals with hydroperoxyl radicals; and the recombination of 2-methylallyl radicals with methyl radicals; (c) addition reactions, including hydrogen atom and hydroxyl radical addition to isobutene; and (d) 2-methylallyl radical decomposition reactions. The current mechanism accurately predicts the IDT and LFS measurements presented in this study, as well as the JSR and flow reactor speciation data already available in the literature.
The differences in low-temperature chemistry between alkanes and alkenes are also highlighted in this work. In normal alkanes, the fuel radical Ṙ adds to molecular oxygen forming alkylperoxyl (RȮ2) radicals followed by isomerization and chain branching reactions which promote low-temperature fuel reactivity. However, in alkenes, because of the relatively shallow well (∼20kcalmol–1) for RȮ2 formation compared to ∼35kcalmol–1 in alkanes, the Ṙ+O2 ⇌ RȮ2 equilibrium lies more to the left favoring Ṙ+O2 rather than RȮ2 radical stabilization. Based on this work, and related studies of allylic systems, it is apparent that reactivity for alkene components at very low temperatures (<800K) emanates from hydroxyl radical addition followed by addition of molecular oxygen to radical. At intermediate temperatures (800–1300K), alkene reactivity is controlled by hydrogen abstraction by molecular oxygen and the reactions between resonantly stabilized radicals and hydroperoxyl radicals which results in chain branching. At higher temperatures (>1300K), the reactivity is mainly governed by the competition between hydrogen abstractions by molecular oxygen and ȮH radicals.
ABSTRACT Compiling data from literature and the Atacama Large Millimeter/submillimeter Array archive, we show enhanced HCN(4-3)/HCO+(4-3) and/or HCN(4-3)/CS(7-6) integrated intensity ratios in ...circumnuclear molecular gas around active galactic nuclei (AGNs) compared to those in starburst (SB) galaxies (submillimeter HCN enhancement). The number of sample galaxies is significantly increased from our previous work. We expect that this feature could potentially be an extinction-free energy diagnostic tool of nuclear regions of galaxies. Non-LTE radiative transfer modelings of the above molecular emission lines involving both collisional and radiative excitation, as well as a photon trapping effect, were conducted to investigate the cause of the high line ratios in AGNs. As a result, we found that enhanced abundance ratios of HCN to HCO+ and HCN to CS in AGNs as compared to SB galaxies by a factor of a few to even 10 are a plausible explanation for the submillimeter HCN enhancement. However, a counterargument of a systematically higher gas density in AGNs than in SB galaxies can also be a plausible scenario. Although we cannot fully distinguish these two scenarios at this moment owing to an insufficient amount of multi-transition, multi-species data, the former scenario is indicative of abnormal chemical composition in AGNs. Regarding the actual mechanism to realize the composition, we suggest that it is difficult with conventional gas-phase X-ray-dominated region ionization models to reproduce the observed high line ratios. We might have to take into account other mechanisms such as neutral-neutral reactions that are efficiently activated in high-temperature environments and/or mechanically heated regions to further understand the high line ratios in AGNs.
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