Based on its ability to express high levels of protein, baculovirus has been widely used for recombinant protein production in insect cells for more than thirty years with continued technical ...improvements. In addition, baculovirus has been successfully applied for foreign gene delivery into mammalian cells without any viral replication. However, several CpG motifs are present throughout baculoviral DNA and induce an antiviral response in mammalian cells, resulting in the production of pro-inflammatory cytokines and type I interferon through a Toll-like receptor (TLR)-dependent or -independent signaling pathway, and ultimately limiting the efficiency of transgene expression. On the other hand, by taking advantage of this strong adjuvant activity, recombinant baculoviruses encoding neutralization epitopes can elicit protective immunity in mice. Moreover, immunodeficient cells, such as hepatitis C virus (HCV)- or human immunodeficiency virus (HIV)-infected cells, are more susceptible to baculovirus infection than normal cells and are selectively eliminated by the apoptosis-inducible recombinant baculovirus. Here, we summarize the application of baculovirus as a gene expression vector and the mechanism of the host innate immune response induced by baculovirus in mammalian cells. We also discuss the future prospects of baculovirus vectors.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
An anti-programmed cell death protein 1 monoclonal antibody, nivolumab, is one of the most effective drugs for advanced melanoma. Tumor cell-derived or immune cell-derived markers and clinical ...predictors such as serum lactate dehydrogenase (LDH) and cutaneous adverse events, have already been described as prognostic factors for advanced melanoma treated with nivolumab. We sought to identify further clinical predictors that can be determined in routine clinical practice.
We retrospectively analyzed clinical findings of 98 consecutive patients with unresectable stage III or IV melanoma treated with nivolumab, at the National Cancer Center Hospital or at Keio University Hospital, in Tokyo, Japan, between July 2014 and July 2016. These patients had been administered nivolumab at a dose of 2mg/kg every 3 weeks.
As for pretreatment prognostic factors, ECOG performance status (PS) ≥1, maximum tumor diameters of ≥30mm, elevated LDH and elevated C-reactive protein were significantly associated with poor overall survival (OS) (hazard ratio HR 0.29 P<0.001, HR 0.40 p=0.003, HR 0.29 P<0.001, HR 0.42 P=0.004, respectively) on univariate analysis. Among these factors, PS and LDH were identified as independent variables by multivariate analysis. As for early markers examined during therapy, patients with absolute lymphocyte count (ALC) ≥ 1000/μl (Week3: HR 0.40 P=0.004, Week6: HR 0.33 P=0.001) and absolute neutrophil count (ANC) <4000/μl (Week3: HR 0.46 P=0.014, Week6: HR 0.51 P=0.046) had significantly better OS.
ALC≥1000/μl and ANC<4000/μl during treatment appear to be early markers associated with OS. Nivolumab might have minimal efficacy in patients with a massive tumor burden.
Chronic thromboembolic pulmonary hypertension leads to pulmonary hypertension and right-sided heart failure. The purpose of this study was to investigate the efficacy of percutaneous transluminal ...pulmonary angioplasty (PTPA) for the treatment of chronic thromboembolic pulmonary hypertension.
Twenty-nine patients with chronic thromboembolic pulmonary hypertension underwent PTPA. One patient had a wiring perforation as a complication of PTPA and died 2 days after the procedure. In the remaining 28 patients, PTPA did not produce immediate hemodynamic improvement at the time of the procedure. However, after follow-up (6.0 ± 6.9 months), New York Heart Association functional classifications and levels of plasma B-type natriuretic peptide significantly improved (both P<0.01). Hemodynamic parameters also significantly improved (mean pulmonary arterial pressure, 45.3 ± 9.8 versus 31.8 ± 10.0 mm Hg; cardiac output, 3.6 ± 1.2 versus 4.6 ± 1.7 L/min, baseline versus follow-up, respectively; both P<0.01). Twenty-seven of 51 procedures in total (53%), and 19 of 28 first procedures (68%), had reperfusion pulmonary edema as the chief complication. Patients with severe clinical signs and/or severe hemodynamics at baseline had a high risk of reperfusion pulmonary edema.
PTPA improved subjective symptoms and objective variables, including pulmonary hemodynamics. PTPA may be a promising therapeutic strategy for the treatment of chronic thromboembolic pulmonary hypertension.
URL: http://www.umin.ac.jp. Unique identifier: UMIN000001572.
Background:Hydrogen gas inhalation (HI) reduced infarct size and mitigated adverse left ventricular (LV) remodeling in a rat model of acute myocardial infarction (AMI). We designed a prospective, ...open-label, rater-blinded clinical pilot study in patients experiencing ST-elevated MI (STEMI).Methods and Results:The 20 patients with an initial diagnosis of STEMI were assigned to either an HI group (1.3% H2with 26% oxygen) or a control group (26% oxygen). There were no HI-related severe adverse events. In the full analysis set, the cardiac salvage index as evaluated using cardiac magnetic resonance imaging at 7 days after primary percutaneous coronary intervention (PCI), showed no significant between-group difference (HI: 50.0±24.3%; control: 60.1±20.1%; P=0.43). However, the improvement from day 7 in the HI group was numerically greater than that in the control group in some of the surrogate outcomes at 6-month follow-up, including the LV stroke volume index (HI: 9.2±7.1 mL/m2; control: −1.4±7.2 mL/m2; P=0.03) and the LV ejection fraction (HI: 11.0%±9.3%; control: 1.7%±8.3%; P=0.11).Conclusions:The first clinical study has shown that HI during PCI is feasible and safe and may also promote LV reverse remodeling at 6 months after STEMI. The study was not powered to test efficacy and a further large-scale trial is warranted. (Clinical trials registration: UMIN00006825)
Background
It is important to control chemotherapy‐induced nausea and vomiting (CINV) to maintain dose intensity and patients' quality of life. The National Comprehensive Cancer Network guidelines ...suggest combination therapy of antiemetic agents. The growing number of antiemetic regimens, and in particular the growing use of regimens containing antagonists to the Nk‐1 receptor (NK1RAs) and the antipsychotic drug olanzapine (OLZ), call for the re‐evaluation of the optimal regimen for CINV. This study assessed the efficacy and safety of antiemetic regimens for highly emetogenic chemotherapy, using Bayesian network meta‐analysis.
Methods
Randomized trials that compared different antiemetic regimens were included. We strictly followed Preferred Reporting Items for Systematic Reviews and Meta‐Analysis guidelines. The main outcomes were the odds ratio (OR) for overall complete response (absence of vomiting). We conducted network meta‐analysis within a Bayesian model to combine the direct and indirect evidence. Safety was assessed from the trial description. All statistical tests were two‐sided.
Results
We systematically reviewed 27 randomized control trials (13,356 participants), which compared 12 different antiemetic regimens: serotonin‐3 receptor antagonist (5HT3), 5HT3 + dexamethasone (Dex), palonosetron (PAL), PAL + Dex, PAL at 0.75 mg (PAL0.75), PAL0.75 + Dex, NK1RA + 5HT3 + Dex, NK1RA + PAL + Dex, an oral combination of netupitant and palonosetron (NEPA) + Dex, OLZ + 5HT3 + Dex, OLZ + PAL + Dex, and OLZ + NK1RA + 5HT3 + Dex. An NK1RA + 5HT3 + Dex regimen and an NK1RA + palonosetron + Dex regimen gave a higher complete response (CR) rate than the reference regimen, 5HT3 + Dex (OR, 1.75; 95% credibility interval 95% CrI, 1.56–1.97, and OR, 2.25; 95% CrI, 1.66–3.03, respectively). A regimen containing NEPA was more effective in producing CR than conventional regimens without NEPA or olanzapine. Further analysis, based on the surface under the cumulative ranking probability curve, indicated that olanzapine‐containing regimens were the most effective in producing CR.
Conclusion
Our meta‐analysis supports the conclusion that olanzapine‐containing regimens are the most effective for CINV of highly emetogenic chemotherapy. We confirmed that NK1RA + PAL + Dex is the most effective of conventional regimens. Substituting olanzapine for an Nk‐1 receptor antagonist may offer a less costly and more effective alternative for patients.
Implications for Practice
Nausea and vomiting during chemotherapy often pose difficulties for patients and doctors, making it hard to continue the proper therapy and to maintain the quality of life. This article gives insights into the optimal choice of medicine to treat nausea during chemotherapy. The findings reported here provide readers with a robust efficacy ranking of antinausea medicine, which can be used as a reference for the best possible treatment. Furthermore, the 70% less costly drug, olanzapine, is suggested to be equally effective to aprepitant in reducing nausea and vomiting. The possibility of offering a cost‐effective treatment to a wider range of the population is discussed.
The growing number of antiemetic regimens calls for a definition of the optimal regimen for chemotherapy‐induced nausea and vomiting (CINV). This meta‐analysis was conducted for direct and indirect comparisons of multiple randomized clinical trials to assess the efficacy and safety of antiemetic regimens for CINV of highly emetogenic chemotherapy.
Catalytic reforming provides a practical technique for on-board hydrogen production in fuel cell applications. The high energy density, easy transportation and non-toxicity of biomass-derived ...dimethyl ether (bio-DME) offer potential to replace methanol for on-board steam reforming (SR). Presently, the reaction mechanism over conventional Cu-based SR catalysts remains elusive, limiting the rational design of highly efficient reforming systems. Herein, we build a catalytic system for bio-DME SR with dual-sites of Cu species,
, Cu
and Cu
sites, and achieve a record-high H
production rate of 1145 mol kg
h
.
regulating the ratios of the dual-sites of Cu, we clearly describe molecular understandings on SR. And we discover that the substantially boosted activity is induced by a new Cu
-determined reaction path substituting the conventional Cu
-determined path. Intrinsically, Cu
O can act as a physical spacer and hydroxyl consumer to suppress the aggregation of metallic Cu species in SR. Due to the unique structure of metallic Cu surrounded by Cu
O, the catalyst exhibits robust catalytic performance even after severe thermal treatment. These findings open a new avenue for designing efficient catalytic reforming systems with commercial potential.
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IJS, KILJ, NUK, UL, UM, UPUK
Background: The aim of this study was to review our experience of mitral valve (MV) repair for acute and active infective endocarditis (AAIE) and to identify the feasibility of a new approach ...together with the mid-term results. Methods and Results: A retrospective analysis was performed on 35 consecutive AAIE patients surgically treated in the isolated mitral position. Mean follow-up after the surgery was 4.3±3.7 years. 30 of the 35 patients were successfully treated by MV plasty (MVP); however, MV replacement (MVR) was necessary in the remaining 5 patients. Our novel approach included resection of the infective lesion, approximation with direct suture and/or patch repair with bovine or autopericardium after 2-min treatment of it and the defective leaflet edge(s) with 0.625% glutaraldehyde solution, reconstruction with artificial chordae and ring annuloplasty. The success rate of MVP was 85.7%. The longest postoperative follow-up echocardiography showed no mitral regurgitation (MR) in 4, trivial MR in 4, mild MR in 16 and moderate MR in 5 patients in the MVP group. The 5-year survival rate in the MVP group was 89±6%. MVR was required in 1 patient 2 months after MVP because of increasing MR. Recurrence of endocarditis has not been observed in any case. Conclusions: Glutaraldehyde was safely used in a surgical intervention for AAIE in the mitral position with acceptable early and mid-term results.
We aimed to determine the characteristics of quantitative pupillary response parameters other than amplitude of pupillary light reflex (PLR) early after return of spontaneous circulation (ROSC) and ...their implications for predicting neurological outcomes early after cardiac arrest (CA). Fifty adults resuscitated after non-traumatic out-of-hospital CA from four emergency hospitals were enrolled. Pupil diameters, PLR, constriction velocity (CV), maximum CV (MCV), dilation velocity (DV), latency of constriction, and Neurological Pupil index (NPi) were quantitatively measured at 0, 6, 12, 24, 48, and 72 h post-ROSC using an automated pupillometer. Change over time of each parameter was compared between favorable (Cerebral Performance Category CPC 1 or 2) and unfavorable neurological outcome (CPC 3-5) groups. Prognostic values of 90-day favorable outcome by these parameters and when combined with clinical predictors (witness status, bystander cardiopulmonary resuscitation, initial shockable rhythm, implementation of target temperature management) were tested. Thirteen patients achieved favorable outcome. CV, MCV, DV (P < 0.001), and NPi (P = 0.005) were consistently greater in the favorable group than in the unfavorable outcome group. Change over time was not statistically different between the groups in all parameters. CV, MCV, DV (ρ = 0.96 to 0.97, P < 0.001, respectively), and NPi (ρ = 0.65, P < 0.001) positively correlated with PLR. The prognostic value of 0-hour CV (area under the curve, AUC 95% confidence interval: 0.92 0.80-1.00), DV (0.84 0.68-0.99), and NPi (0.88 0.74-1.00) was equivalent to that of PLR (0.84 0.69-0.98). Prognostic values improved to AUC of 0.95-0.96 when 0-hour PLR, CV, DV, or NPi was combined with clinical predictors. The 0-hour CV, MCV, and NPi showed equivalent prognostic values to PLR alone/in combination with clinical predictors. Using PLR among several quantitative pupillary response parameters for early neurological prognostication of post-CA patients is a simple and effective strategy.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract The current study aimed to identify the indications for manual reduction in incarcerated obturator hernias (OH). Further, whether time to symptom onset and manual reduction outcomes can be ...predictors of bowel viability and the need for bowel resection in incarcerated OH were examined. This retrospective study included 26 patients with incarcerated OH who underwent surgery. All patients underwent manual reduction, and computed tomography scan after manual reduction confirmed hernia release. Multivariate analyses were performed to determine the predictors of bowel resection. The bowel resection group had a significantly longer average time to symptom onset than the nonbowel resection group (88 vs 36 h). Further, the bowel resection group was more likely to have failed manual reduction than the nonbowel resection group. A time to symptom onset of ≥ 72 h and failed manual reduction were significant predictors of bowel viability. Age, sex, hernia localization, American Society of Anesthesiologists physical status score, and laboratory findings did not differ significantly between the bowel resection and nonbowel resection groups. Time to symptom onset and manual reduction outcomes are significant predictors of bowel viability in incarcerated OH. Patients with a time to symptom onset of ≥ 72 h and failed manual reduction require surgical evaluation due to a high risk of bowel nonviability. Therefore, a cautious approach is required in the management of OH, and further research on optimized treatment protocols should be conducted.
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