Irreversible electroporation (IRE) uses high-voltage electric fields to achieve cell death. Although the mechanism of IRE is mainly designated as nonthermal, development of secondary Joule heating is ...inevitable. The study purpose was to gain understanding of temperature development and distribution during IRE.
IRE was performed in a transparent polyacrylamide gel resembling soft tissue. Mechanical effects, changes in temperature gradient, and absolute temperature changes were measured with three different optical techniques (high-speed, color Schlieren, and infrared imaging) to investigate the effect on temperature of variations in voltage, pulse length, active tip length (ATL), interelectrode distance, electrode configuration (parallel, convergent, and divergent), and sequential pulsing (pulse delivery interrupted by breaks). The total delivered energy was calculated.
A temperature gradient, starting at the tips of both electrodes and expanding toward each other, developed immediately with pulse delivery. Temperatures increased with increasing voltage (by 2.5°C-40.4°C), pulse length (by 5.3°C-9.8°C), ATL (by 5.9°C-17.6°C), and interelectrode distance (by 7.6°C-21.5°C), in accordance with higher energy delivery. Nonparallel electrode placement resulted in heterogeneous temperature distribution with the peak temperature focused in the area with the shortest interelectrode distance. Sequential pulse delivery significantly reduced the temperature increase compared with continuous pulsing (4.3°C vs 11.7°C).
Voltage, pulse length, interelectrode distance, ATL, and electrode configuration each have a strong effect on temperature development and distribution during IRE. Sequential pulsing reduces the extent and volume of thermal distribution and may prove beneficial with respect to procedural safety.
Some American law enforcement agencies continue to experience disruptions in the level of trust and legitimacy ascribed to them by their communities. Citizen review boards (CRBs), may be an effective ...means for improving the police-community relationship. Utilizing a framework grounded in procedural justice and citizen participation, this study examines whether a link exists between CRBs and community satisfaction in the police and four procedural justice measures: 1) trust in the police, 2) belief the police are held accountable, 3) belief the police treat all people equally, and 4) belief the police are building positive community relationships. To estimate these correlations, this study uses a unique dataset from 48 U.S. cities and employs bivariate and multivariate methods to analyze the data. The findings indicate a mostly positive association between CRBs and procedural justice measures, which suggests that CRBs may be able to bolster legitimacy and enhance the police-community relationship in some communities.
The therapeutic potential of host-specific and tumour-specific immune responses is well recognized and, after many years, active immunotherapies directed at inducing or augmenting these responses are ...entering clinical practice. Antitumour immunization is a complex, multi-component task, and the optimal combinations of antigens, adjuvants, delivery vehicles and routes of administration are not yet identified. Active immunotherapy must also address the immunosuppressive and tolerogenic mechanisms deployed by tumours. This Review provides an overview of new results from clinical studies of therapeutic cancer vaccines directed against tumour-associated antigens and discusses their implications for the use of active immunotherapy.
After nerve injury, myelin and Remak Schwann cells reprogram to repair cells specialized for regeneration. Normally providing strong regenerative support, these cells fail in aging animals, and ...during chronic denervation that results from slow axon growth. This impairs axonal regeneration and causes significant clinical problems. In mice, we find that repair cells express reduced c-Jun protein as regenerative support provided by these cells declines during aging and chronic denervation. In both cases, genetically restoring Schwann cell c-Jun levels restores regeneration to control levels. We identify potential gene candidates mediating this effect and implicate Shh in the control of Schwann cell c-Jun levels. This establishes that a common mechanism, reduced c-Jun in Schwann cells, regulates success and failure of nerve repair both during aging and chronic denervation. This provides a molecular framework for addressing important clinical problems, suggesting molecular pathways that can be targeted to promote repair in the PNS.
Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma Motzer, Robert J; Escudier, Bernard; McDermott, David F ...
New England journal of medicine/The New England journal of medicine,
11/2015, Letnik:
373, Številka:
19
Journal Article
Recenzirano
Odprti dostop
Nivolumab, a programmed death 1 (PD-1) checkpoint inhibitor, was associated with encouraging overall survival in uncontrolled studies involving previously treated patients with advanced renal-cell ...carcinoma. This randomized, open-label, phase 3 study compared nivolumab with everolimus in patients with renal-cell carcinoma who had received previous treatment.
A total of 821 patients with advanced clear-cell renal-cell carcinoma for which they had received previous treatment with one or two regimens of antiangiogenic therapy were randomly assigned (in a 1:1 ratio) to receive 3 mg of nivolumab per kilogram of body weight intravenously every 2 weeks or a 10-mg everolimus tablet orally once daily. The primary end point was overall survival. The secondary end points included the objective response rate and safety.
The median overall survival was 25.0 months (95% confidence interval CI, 21.8 to not estimable) with nivolumab and 19.6 months (95% CI, 17.6 to 23.1) with everolimus. The hazard ratio for death with nivolumab versus everolimus was 0.73 (98.5% CI, 0.57 to 0.93; P=0.002), which met the prespecified criterion for superiority (P≤0.0148). The objective response rate was greater with nivolumab than with everolimus (25% vs. 5%; odds ratio, 5.98 95% CI, 3.68 to 9.72; P<0.001). The median progression-free survival was 4.6 months (95% CI, 3.7 to 5.4) with nivolumab and 4.4 months (95% CI, 3.7 to 5.5) with everolimus (hazard ratio, 0.88; 95% CI, 0.75 to 1.03; P=0.11). Grade 3 or 4 treatment-related adverse events occurred in 19% of the patients receiving nivolumab and in 37% of the patients receiving everolimus; the most common event with nivolumab was fatigue (in 2% of the patients), and the most common event with everolimus was anemia (in 8%).
Among patients with previously treated advanced renal-cell carcinoma, overall survival was longer and fewer grade 3 or 4 adverse events occurred with nivolumab than with everolimus. (Funded by Bristol-Myers Squibb; CheckMate 025 ClinicalTrials.gov number, NCT01668784.).
The linear ubiquitin chain assembly complex (LUBAC) regulates immune signaling, and its function is regulated by the deubiquitinases OTULIN and CYLD, which associate with the catalytic subunit HOIP. ...However, the mechanism through which CYLD interacts with HOIP is unclear. We here show that CYLD interacts with HOIP via spermatogenesis-associated protein 2 (SPATA2). SPATA2 interacts with CYLD through its non-canonical PUB domain, which binds the catalytic CYLD USP domain in a CYLD B-box-dependent manner. Significantly, SPATA2 binding activates CYLD-mediated hydrolysis of ubiquitin chains. SPATA2 also harbors a conserved PUB-interacting motif that selectively docks into the HOIP PUB domain. In cells, SPATA2 is recruited to the TNF receptor 1 signaling complex and is required for CYLD recruitment. Loss of SPATA2 increases ubiquitination of LUBAC substrates and results in enhanced NOD2 signaling. Our data reveal SPATA2 as a high-affinity binding partner of CYLD and HOIP, and a regulatory component of LUBAC-mediated NF-κB signaling.
Display omitted
•CYLD recruitment to LUBAC and the TNF receptor 1 complex is mediated by SPATA2•SPATA2 forms a high-affinity complex with CYLD and stimulates CYLD’s activity•SPATA2, like OTULIN, uses a conserved PIM to dock to the HOIP PUB domain•SPATA2 limits ubiquitination of LUBAC substrates to regulate inflammatory signaling
Elliott et al. show that SPATA2 bridges CYLD with LUBAC to regulate substrate ubiquitination and inflammatory signaling. Structural and biochemical work defines SPATA2-CYLD and SPATA2-HOIP interfaces, reveals SPATA2-mediated CYLD activation, and provides first insights into stoichiometry of LUBAC complexes.
PURPOSE Pazopanib is an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit. This randomized, double-blind, ...placebo-controlled phase III study evaluated efficacy and safety of pazopanib monotherapy in treatment-naive and cytokine-pretreated patients with advanced renal cell carcinoma (RCC). PATIENTS AND METHODS Adult patients with measurable, locally advanced, and/or metastatic RCC were randomly assigned 2:1 to receive oral pazopanib or placebo. The primary end point was progression-free survival (PFS). Secondary end points included overall survival, tumor response rate (Response Evaluation Criteria in Solid Tumors), and safety. Radiographic assessments of tumors were independently reviewed. Results Of 435 patients enrolled, 233 were treatment naive (54%) and 202 were cytokine pretreated (46%). PFS was significantly prolonged with pazopanib compared with placebo in the overall study population (median, PFS 9.2 v 4.2 months; hazard ratio HR, 0.46; 95% CI, 0.34 to 0.62; P < .0001), the treatment-naive subpopulation (median PFS 11.1 v 2.8 months; HR, 0.40; 95% CI, 0.27 to 0.60; P < .0001), and the cytokine-pretreated subpopulation (median PFS, 7.4 v 4.2 months; HR, 0.54; 95% CI, 0.35 to 0.84; P < .001). The objective response rate was 30% with pazopanib compared with 3% with placebo (P < .001). The median duration of response was longer than 1 year. The most common adverse events were diarrhea, hypertension, hair color changes, nausea, anorexia, and vomiting. There was no evidence of clinically important differences in quality of life for pazopanib versus placebo. CONCLUSION Pazopanib demonstrated significant improvement in PFS and tumor response compared with placebo in treatment-naive and cytokine-pretreated patients with advanced and/or metastatic RCC.
Abstract Background Response patterns to nivolumab differ from those seen with other approved targeted therapies. Objective To investigate the efficacy of nivolumab in previously treated patients ...with advanced renal cell carcinoma who were treated beyond (Response Evaluation Criteria In Solid Tumors) RECIST progression. Design, setting, and participants This was a subgroup analysis of patients treated with nivolumab in the phase 3 CheckMate 025 study. Patients continuing to tolerate therapy and exhibiting investigator-assessed clinical benefit were eligible to be treated beyond RECIST progression (TBP) and received therapy for ≥4 wk after first progression; patients not treated beyond RECIST progression (NTBP) received 0 wk to <4 wk of therapy after progression. Interventions Nivolumab 3 mg/kg intravenously every 2 wk. Results and limitations Of 406 nivolumab-treated patients, 316 (78%) progressed by RECIST criteria. Of those who progressed, 48% were TBP, 52% were NTBP. Before being TBP, objective response rate (95% confidence interval) was 20% (14–28) and 14% (9–21) in patients TBP and NTBP, respectively. Differences in clinical characteristics assessed at first progression between patients TBP versus NTBP included better Karnofsky performance status, less deterioration in Karnofsky performance status, shorter time to response, lower incidence of new bone lesions, and improved quality of life. Postprogression, 13% of all patients TBP (20/153) had ≥30% tumor burden reduction including patients with preprogression and postprogression tumor measurements ( n = 142) and complete/partial response (28%, 8/29), stable disease (6%, 3/47), and progressive disease (14%, 9/66) as their best response before being TBP. Incidence of treatment-related adverse events in patients TBP was lower after (59%) versus before (71%) progression. Limitations included potential bias from the nonrandomized nature of the analysis. Conclusions A subset of patients with advanced renal cell carcinoma and RECIST progression experienced tumor reduction postprogression with nivolumab, and had an acceptable safety profile. Clinical judgment remains essential when switching therapy. ClinicalTrials.gov Identifier: NCT01668784. Patient summary A subset of patients with advanced renal cell carcinoma and disease progression may continue to benefit from nivolumab treatment beyond progression as evidenced by tumor reduction postprogression and an acceptable safety profile.
Globally, the oldest old population is expected to triple by 2050. Hospitalization and malnutrition can result in progressive functional decline in older adults. Minimizing the impact of ...hospitalization on functional status in older adults has the potential to maintain independence, reduce health and social care costs, and maximize years in a healthy state. This study aimed to systematically review the literature to identify nutritional interventions that target physical function, body composition, and cognition in the older population (≥ 75 years).
A systematic review was conducted to evaluate the efficacy of nutritional interventions on physical function, body composition, and cognition in adults aged ≥ 75 years or mean age ≥80 years. Searches of PubMed (National Institutes of Health, National Library of Medicine), Scopus (Elsevier), EMBASE (Elsevier), Cumulative Index to Nursing and Allied Health Literature (CINAHL) with Full Text (EBSCOhost), and PsycInfo (EBSCOhost) were conducted. Screening, data extraction, and quality assessment were performed in duplicate and independently (CRD42022355984; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=355984).
Of 8311 citations identified, 2939 duplicates were excluded. From 5372 citations, 189 articles underwent full-text review leaving a total of 12 studies for inclusion. Interventions were food-based, protein-based, carbohydrate-based, personalized, or used parenteral nutrition. Ten studies monitored anthropometric or body composition changes with three showing maintenance or improvements in lean mass, body mass index, triceps skinfold, and mid-upper arm circumference compared with the control group. Six studies monitored physical function but only the largest study found a beneficial effect on activities of daily living. Two of three studies showed the beneficial effects of nutritional intervention on cognition.
There are few, high-quality, nutrition-based interventions in older adults ≥75 years. Despite heterogeneity, our findings suggest that large, longer-term (>2 weeks) nutritional interventions have the potential to maintain body composition, physical function, and cognition in adults aged 75 years and older during hospitalization.
Valid methods are needed to identify anesthesia resident performance gaps early in training. However, many assessment tools in medicine have not been properly validated. The authors designed and ...tested use of a behaviorally anchored scale, as part of a multiscenario simulation-based assessment system, to identify high- and low-performing residents with regard to domains of greatest concern to expert anesthesiology faculty.
An expert faculty panel derived five key behavioral domains of interest by using a Delphi process (1) Synthesizes information to formulate a clear anesthetic plan; (2) Implements a plan based on changing conditions; (3) Demonstrates effective interpersonal and communication skills with patients and staff; (4) Identifies ways to improve performance; and (5) Recognizes own limits. Seven simulation scenarios spanning pre-to-postoperative encounters were used to assess performances of 22 first-year residents and 8 fellows from two institutions. Two of 10 trained faculty raters blinded to trainee program and training level scored each performance independently by using a behaviorally anchored rating scale. Residents, fellows, facilitators, and raters completed surveys.
Evidence supporting the reliability and validity of the assessment scores was procured, including a high generalizability coefficient (ρ = 0.81) and expected performance differences between first-year resident and fellow participants. A majority of trainees, facilitators, and raters judged the assessment to be useful, realistic, and representative of critical skills required for safe practice.
The study provides initial evidence to support the validity of a simulation-based performance assessment system for identifying critical gaps in safe anesthesia resident performance early in training.
PDF
