12,391 research outputs found
The CTLA-4 and PD-1/PD-L1 inhibitory pathways independently regulate host resistance to Plasmodium-induced acute immune pathology.
No full textThe balance between pro-inflammatory and regulatory immune responses in determining optimal T cell activation is vital for the successful resolution of microbial infections. This balance is maintained in part by the negative regulators of T cell activation, CTLA-4 and PD-1/PD-L, which dampen effector responses during chronic infections. However, their role in acute infections, such as malaria, remains less clear. In this study, we determined the contribution of CTLA-4 and PD-1/PD-L to the regulation of T cell responses during Plasmodium berghei ANKA (PbA)-induced experimental cerebral malaria (ECM) in susceptible (C57BL/6) and resistant (BALB/c) mice. We found that the expression of CTLA-4 and PD-1 on T cells correlates with the extent of pro-inflammatory responses induced during PbA infection, being higher in C57BL/6 than in BALB/c mice. Thus, ECM develops despite high levels of expression of these inhibitory receptors. However, antibody-mediated blockade of either the CTLA-4 or PD-1/PD-L1, but not the PD-1/PD-L2, pathways during PbA-infection in ECM-resistant BALB/c mice resulted in higher levels of T cell activation, enhanced IFN-γ production, increased intravascular arrest of both parasitised erythrocytes and CD8(+) T cells to the brain, and augmented incidence of ECM. Thus, in ECM-resistant BALB/c mice, CTLA-4 and PD-1/PD-L1 represent essential, independent and non-redundant pathways for maintaining T cell homeostasis during a virulent malaria infection. Moreover, neutralisation of IFN-γ or depletion of CD8(+) T cells during PbA infection was shown to reverse the pathologic effects of regulatory pathway blockade, highlighting that the aetiology of ECM in the BALB/c mice is similar to that in C57BL/6 mice. In summary, our results underscore the differential and complex regulation that governs immune responses to malaria parasites
The challenges of implementing a PD-L1 proficiency testing program in Australia
No full textJulia Pagliuso, Suzanne Parry, Zenobia Haffajee, Tony Badrick, Keith Miller Background . One important initiative that commenced at the Royal College of Pathologists of Australasia Quality Assurance Program (RCPAQAP) in 2017 was the collaboration with United Kingdom National External Quality Assessment Scheme (UK NEQAS) Immunocytochemistry (ICC) and In-Situ Hybridization (ISH) for the challenging implementation of a PD-L1 immunohistochemistry (IHC) proficiency testing program for non-small cell lung carcinoma (NSCLC). A RCPAQAP participant survey in 2016 showed that only eight laboratories were performing PD-L1 testing. The aim of the collaboration was to increase the sample size of the pilot program to provide meaningful results that could be reported back to RCPAQAP participants with appropriate recommendations. Other challenges of assessment included standardising the clinical cut-offs for positivity for each commercial assay, interpretation of laboratory developed tests (LDTs), using appropriate tissue to cover the critical interpretation points for each assay, interchangeability of clones and interpretation proficiency testing. Methods . The use of a ‘Gold Standard’ for each commercial assay was used as a baseline to compare participant results and tumour proportion score bin categories were implemented to harmonise interpretation across clones. Conclusions . The findings of the pre-pilot test suggest that the use of a clinically validated PD-L1 IHC assay performs better during assessment than adopting a laboratory developed test (LDT). The assessment committee also concluded that tonsil showed a better dynamic range of positivity than placenta. It was acknowledged that participants are limited by the platforms they have available and so it was suggested that validating an optimal method against the clinical assay and continual verification of the test may produce the expected result. The next big challenge is to extend proficiency testing from technical to interpretation. This is being implemented globally via the International Quality Network for Pathology (IQNPath) with participation through local External Quality Assurance programs, including RCPAQAP.Full Tex
Increases in hip and spine bone mineral density are predictive for vertebral antifracture efficacy with ibandronate
No full textImplications of the Improvement of Teaching Quality for Professional Development (PD) of Academics at the Colleges of Applied Sciences (CASs) in the Sultanate of Oman
No full textThe Oman Accreditation Council (OAC), which is called later the Oman Academic Accreditation Authority (OAAA), designed a higher education institution (HEI) Quality Assurance (QA) framework for Omani public and private Higher Education Institutions (HEIs), starting with a quality audit process in 2008. The Colleges of Applied Sciences (CASs), as a public HEI, are required to ensure the quality of all services and activities to meet particular national standards (specified in the framework) in order to gain a HEI and programme certificate. In line with a quality audit scope, the quality of the fields of PD and related teaching quality should be ensured and enhanced by the promotion and contribution of the former field to the maintenance and improvement of the latter one.
The chief purpose of this study was to identify the uptake and implications of the growing requirement to improve teaching quality and the PD of academics at the CASs in the Sultanate of Oman especially in the context of the application of the QA framework. The study focused on examining the academics’ participation in professional development programmes (PDPs) and current perceptions of PD with respect to the improvement of teaching quality improvement at these colleges. The current study also dealt with a reorganization and prioritization of academics’ PD needs, barriers to effective PD, and factors to enhance PD of academics regarding teaching quality improvement in the colleges.
Based on the purpose and research objectives, the current study adopted both positivist (quantitative) and interpretive (qualitative) research paradigms. Because the study perused quantitative and qualitative data regarding certain variables, it chose a mixed-research design. The researcher designed survey questionnaire to collect quantitative data and a semi-structured interview and a focus group discussion to probe and interpret quantitative findings. After fulfillment of the validity and reliability measurements, a self-completion questionnaire was distributed to a stratified random sample of academics (170) over the six CASs. A total of 150 questionnaires (out of 170) were completed and returned and the response-rate reached 88.2%. The quantitative data was analyzed by appropriate analysis using the Statistical Package for Social sciences (SPSS), while the qualitative data was analyzed by appropriate qualitative analysis.
The findings of the study showed that the level of academics’ participation in PDPs to improve teaching quality in the last two years in the CASs seems to be unsatisfactorily low. The current perceptions of the PD situations in the colleges, relating to teaching quality improvement, signified a shortage in the number of available PDPs and/or a discouragement of academics’ participation in these programmes in the last two years. The study also revealed all the 22 PD needs of academics regarding the improvement of teaching quality are significantly demanded by participants; the higher rated needs focused on a development of ‘student centred’ skills, such as critical thinking and problem-solving skills.
Furthermore, the study illustrated that the highest significant perceived barriers to effective PD in the CASs, as related to teaching quality improvement, focus on a lack of a clear institutional PD policy and a lack of appropriately systematic PD plans. The study also revealed all 10 perceived factors to enhance PD regarding teaching quality improvement are very important. The most significant factors represented and stressed particular problematic issues (the high rated barriers) and a reduction of a heavy workload to enhance academics’ participation in PD regarding the improvement of teaching quality.
Conclusions drawn from the discussion of the findings of study include a lack of a clear PD policy at national and institutional levels and absence of a particular authority/unit concerning PD issues in Omani HEIs. The two problematic issues resulted in a lack of systematic and realistic PD plans in the CASs, involving a lack of academics’ involvement in PD plans, a misconnection of academics’ PD needs to PD, inappropriate facilities and resources allocation, and inappropriate evaluation processes of PD. In addition, the conclusions also include that PD of academics regarding the improvement of teaching quality in the colleges requires more attention and focus to manage particular significant issues perceived by participants as both barriers and potential facilitators relating to PD of academics.
Based on identified conclusions, particular implications for policy and practice to enhance PD to improve teaching quality were set at three levels: governmental, institutional, and individual. Moreover, achievements of the current study according to the research questions were identified and contributions of the study to the fields of PD, teaching quality, and the context of QA and quality audit in HE were addressed. Based on the findings and conclusions, particular directions and recommended issues were suggested to be studied by further research to benefit the enhancement of PD and related teaching quality improvement
Obtenção, caracterização e avaliação da atividade de um nanocatalisador de Pd(0) sintetizado in situ sob a superfície de Fe3O4@dextrana para redução do 4-nitrofenol
No full textTese (doutorado) - Universidade Federal de Santa Catarina, Centro de Ciências Físicas e Matemáticas, Programa de Pós-Graduação em Química, Florianópolis, 2015.O objetivo principal deste trabalho é a preparação, caracterização e avaliação da atividade catalítica das nanopartículas (NPs) de Pd impregnadas no suporte magnético magnetita e estabilizada por dextrana. As NPs-Pd foram preparadas por crescimento in situ sob a superfície de nanopartículas superparamagnéticas (NPSMs) (Fe3O4@dextrana/Pd(0)). O controle do crescimento das NPs-Pd foi feito com o auxílio de NaBH4, como agente redutor. O catalisador de Fe3O4@dextrana/Pd foi totalmente caracterizado por diversas técnicas tais como espectroscopia de infravermelho, espalhamento de luz dinâmico, espalhamento de raios-X a baixos ângulos, microscopia eletrônica de transmissão e varredura, e difração de raios-X de pó. A caracterização mostrou que o catalisador é constituído de um suporte feito de Fe3O4@dextrana composto por unidades de nanocristais com tamanho de 9,7 nm, formando nanoclusters de 105,6 nm, contendo as NPs-Pd de 7,8 nm impregnadas em sua superfície. Os estudos cinéticos foram realizados por UV-vis, sendo que a atividade catalítica foi avaliada pela reação modelo de redução do p-nitrofenol (Nip), utilizando NaBH4. Aplicando um modelo de reação de superfície pseudo-molecular, a reação foi investigada pelo modelo teórico de isoterma de adsorção, revelando ser uma reação bimolecular que segue o mecanismo de Langmuir-Hinshelwood. A atividade catalítica do nanocatalisador Fe3O4@ dextrana/Pd com área superficial de 3,33 m2L-1x10-3 (0, 0053 mg L-1 de Pd) pode ser efetivamente analisada, e foi possível obter os parâmetros cinéticos kL, KBH4- e KNip. Os resultados mostraram que as moléculas de Nip possuem afinidade de adsorção muito maior do que BH4- pela superfície das NPs-Pd, resultado da influência do caráter hidrofóbico do Nip sob a constante de adsorção do substrato. Um novo parâmetro de atividade catalítica ??? foi proposto e utilizado com sucesso na comparação com outros catalisadores reportados na literatura. As NPSMs de Fe3O4@dextrana/Pd apresentaram um valor de ? = 3,65 L mg-1 s-1, superior ao citado na literatura. O estudo do reuso de Fe3O4@dextrana/Pd demonstrou que é possível reutilizar as mesmas por até 5 vezes com cerca de 99% de conversão do Nip e valor alto de TOF, 692 h-1.Abstract : The aim of this work was the preparation, characterization and evaluation of catalytic activity of Pd nanoparticles (NPs) impregnated in magnetite and stabilized by dextran. The Pd NPs were prepared by the in situ growth under the surface of superparamagnetic nanoparticles. The growth control of Pd NPs was made with the aid of NaBH4, as reducing agent. The catalyst Fe3O4@dextran/Pd was fully characterized by several techniques such as: infrared spectroscopy, dynamic light scattering, X-ray scattering at small angle, transmission and scanning electron microscopy , and diffraction X-ray powder. The characterization revealed that the catalyst consisted of a support made of Fe3O4@dextran nanocrystals composed of units with 9.7 nm in size, forming nanoclusters of 105.6 nm containing NPs of Pd with 7.8 nm diameter, impregnated in the surface. The kinetic studies were performed by UV-vis spectrocopy, and the catalytic activity was evaluated by the model reaction of the p-nitrophenol (Nip) reduction, using NaBH4 as a reducing agent. Applying a pseudo-molecular surface reaction approach, the reduction reaction could be investigated by means of a theoretical adsorption model, revealing that the reaction is bimolecular and followed the Langmuir-Hinshelwood mechanism.The catalytic activity of nano-catalyst of Fe3O4@dextran/Pd, with a surface area of 3.33m2L-1x103 (0.0053 mg L-1Pd), could be effectively determined, obtaining the kinetic parameters kL, KBH4- and KNip. These kinetics results showed that the Nip molecules have higheraffinity for the catalyst surface than the molecules of BH4-, as a result of the influence of the Nip hydrophobic character. A new catalytic activity parameter "?" was proposed and effectively used for comparison with other recent reported catalysts. The reuse studies showed that could be reused up to 5 times with about 99% conversion of Nip and a high TOF value, 692 h-1
Fullerene-like WS<sub>2</sub> supported Pd catalyst for hydrogen evolution reaction
No full textHydrogen is the most desirable green energy carrier and electrocatalytic hydrogen evolution reaction (HER) from water is a promising route for hydrogen production. The search for efficient, low-cost HER catalysts is a challenging and attracting topic. In this work, we report that inorganic fullerene-like WS2 supported Pd nanoparticles (Pd/WS2), with Pd loading of 0.76 wt%, are active for electrocatalytic HER conducted in 0.5 M H2SO4 solution, with overpotential at 10 mA cm−2 current density of ~130 mV and Tafel slope of 82.4 mV dec−1, which is comparable to that of Pt/WS2 (0.88 wt% Pt loading) with higher costs. Characteristic results indicate that WO3 impurities were in-situ produced on the WS2 surface and the Pd NPs are primarily located inside the WS2 nanocages. Contrasting experiments suggest that the WO3 impurities play a crucial role in generating Hads intermediate and the Pd NPs are active sites of H2 production, and a reaction mechanism is proposed. The Pd/WS2 catalyst also shows good long-term stability owing to the location of Pd NPs inside the WS2 cages. The high HER activity, low costs and good stability make the Pd catalyst a potential alternative to Pt catalyst for HER.Green Open Access added to TU Delft Institutional Repository 'You share, we take care!' - Taverne project https://www.openaccess.nl/en/you-share-we-take-care Otherwise as indicated in the copyright section: the publisher is the copyright holder of this work and the author uses the Dutch legislation to make this work public.Micro and Nano Engineerin
FIGURE 2 from Validation of Immunotherapy Response Score as Predictive of Pan-solid Tumor Anti-PD-1/PD-L1 Benefit
No full textConfirmation of the added utility of the IRS versus clinical PD-L1 IHC and TMB alone. A, Normalized PD-L1 (CD274) expression (and the other IRS expression components) by the qTP platform used to generate IRS were validated versus qRT-PCR in a validation cohort of 96 FFPE tumor tissue samples tested by clinical CGP and in parallel qTP. The Pearson correlation and linear range of each component is shown (Supplementary Fig. S1). B and C, The Pearson correlation of normalized PD-L1 expression by qTP [log2 normalized reads per million (nRPM) units] versus clinical PD-L1 IHC score (in submitted pathology reports) was determined in two cohorts of clinical FFPE tumor tissues [regardless of TMB availability and anti-PD-(L)1 treatment]. B, PD-L1 expression by qTP (log2 normalized units) versus PD-L1 IHC by TPS [using the 22C3 antibody clone (log2 TPS) in 276 clinically tested FFPE NSCLC tumors with available TPS is plotted]. The linear fit, Pearson correlation (r), and P value are shown. C, PD-L1 expression by qTP versus PD-L1 IHC by CPS using the 22C3 antibody clone (log2 CPS) in 221 clinically tested FFPE tumors (23 tumor types; most frequently EGC) with available TPS is plotted. The linear fit, Pearson correlation (r), and P value are shown. D, Using B and C, we identified a cohort of all 189 eligible NCT03061305 patients with IRS and PD-(L)1 IHC in accompanying pathology reports who were treated with anti-PD-(L)1 therapy (± chemotherapy). The association of biomarkers with anti-PD-(L)1 rwPFS was determined by Cox proportional hazards modeling [adjusting for age, sex assigned at birth, line of therapy, tumor type, therapy type (monotherapy vs. chemotherapy combination), and inclusion in IRS discovery status]. PD-L1 IHC score (continuous; log2) was included in the baseline model (Model 1), with the aHR, 95% CI, number (n) of patients and events, and P value shown for the biomarker term by forest plot. TMB status (-H vs. -L; pink) and IRS status (-H vs. -L; light blue) were separately added to this model (Models 2 and 3, respectively). The significance of each biomarker term is shown and the P value of the LRT comparing the full (Model 2 or 3) versus reduced (Model 1) model is shown. Model 4 includes PD-L1 IHC, TMB, and IRS. Significant biomarker terms are shown by filled in aHR estimates. E, Anti-PD-(L)1 rwPFS stratified by IRS group is shown by unadjusted Kaplan–Meier analysis, with the aHR from Model 4 in D shown. See Supplementary Table S7 for full subgroup analysis.</p
FIGURE 1 from Validation of Immunotherapy Response Score as Predictive of Pan-solid Tumor Anti-PD-1/PD-L1 Benefit
No full textValidation of IRS to stratify anti-PD-(L)1 monotherapy benefit in patients with advanced solid tumors. A, Clinical characteristics of the anti-PD-(L)1 monotherapy validation cohort are shown in an alluvial diagram. All patients with available clinical molecular profiling data necessary for IRS (TMB and normalized expression of PD-1, PD-L1, ADAM12, and TOP2A from in-parallel qTP) from FFPE tumor tissue enrolled in the Strata Trial (NCT03061305) and treated with systemic anti-PD-(L)1 monotherapy were considered. Patients in previous IRS discovery or validation were excluded. The locked IRS model and thresholds were used to assign IRS-L (light blue) or IRS-H (increased benefit; dark blue) status. For the 352 eligible patients, IRS status, MSI/TMB status (MSI-H or TMB-H as MSI/TMB-H), type of anti-PD-(L)1 therapy [pembrolizumab (pembro) vs. other anti-PD-(L)1], systemic line of anti-PD-(L)1 therapy, and tumor type [all tumor types with >15 samples considered individually: NSCLC, cancer of unknown primary (CUP), bladder cancer (Blad.), melanoma (Mel.), head and neck cancer (H&N), and EGC; remaining 25 other tumor types considered together] are shown. Stratum are colored by IRS status. IRS stratifies anti-PD-(L)1 monotherapy clinical benefit by rwPFS (by time to next therapy; B) and OS (C). B, Anti-PD-(L)1 monotherapy rwPFS stratified by IRS group is shown by unadjusted Kaplan–Meier analysis, with the aHR [adjusted for age, sex assigned at birth, line of therapy, tumor type and anti-PD-(L)1 therapy type], 95% CI and P value for IRS status (IRS-H vs. IRS-L) shown. The number (n) of patients, events, and median rwPFS (with 95% CI) for each group are shown. Forest plot analyses of rwPFS by IRS status in key subgroups are shown below (Remaining 4 = Blad., Mel., H&N, and EGC). Significant associations are shown by filled in aHR estimates. C, As in B, except assessing OS.</p
FIGURE 4 from Validation of Immunotherapy Response Score as Predictive of Pan-solid Tumor Anti-PD-1/PD-L1 Benefit
No full textValidation of IRS to stratify anti-PD-(L)1, chemotherapy and anti-PD-(L)1 + chemotherapy benefit in relevant tumor types. A, Clinical characteristics of the anti-PD-(L)1 and/or chemotherapy (chemo) validation cohort are shown in an alluvial diagram. Across all eligible NCT03061305 patients treated with anti-PD-(L)1 monotherapy, chemotherapy, or anti-PD-(L)1 + chemotherapy, we identified a validation cohort of 1,229 total eligible therapy lines (from 1,103 patients) in five relevant tumor types with anti-PD-(L)1 and/or chemotherapy treatment decisions: NSCLC, TNBC, EGC, H&N, and SCLC. Anti-PD-(L)1 ± chemotherapy lines used in IRS training were excluded. The IRS model and three-group classification thresholds were used to assign IRS-UL (gray), IRS-IL (light blue), and IRS-H (dark blue) status. For all 1,229 eligible therapy lines, IRS status, treatment group [PD-(L)1: purple; chemo: orange; PD-(L)1+chemo green], the systemic line of treatment, and tumor types are shown. Stratum are colored by IRS status. B, rwPFS by treatment group is shown separately for each IRS group by unadjusted Kaplan–Meier analysis. The number (n) of patients, events, and median rwPFS (with 95% CI) are shown. Treatment group outcomes were compared in each IRS group by Cox proportional hazards modeling (adjusting for age, gender, treatment group, line of therapy, tumor type, and PD-L1 RNA expression). Forest plots were used to visualize the aHR for each treatment group comparison, with the 95% CI, number of patients and events, and P value for each comparison shown. aHR estimates are colored by the treatment group comparison and significant associations are shown by outlined aHR estimates. In addition to the entire cohort (All), key subgroups are shown. See Supplementary Fig. S6 for covariate adjusted plots, Supplementary Fig. S7 for overlap weighting propensity score analysis, and Supplementary Table S12 for full subgroup analysis.</p
Enhanced T-Cell Immunity to Osteosarcoma Through Antibody Blockade of PD-1/PD-L1 Interactions
No full textabstract: Osteosarcoma is the most common bone cancer in children and adolescents. Although 70% of patients with localized disease are cured with chemotherapy and surgical resection, patients with metastatic osteosarcoma are typically refractory to treatment. Numerous lines of evidence suggest that cytotoxic T lymphocytes (CTLs) limit the development of metastatic osteosarcoma. We have investigated the role of PD-1, an inhibitory TNFR family protein expressed on CTLs, in limiting the efficacy of immune-mediated control of metastatic osteosarcoma. We show that human metastatic, but not primary, osteosarcoma tumors express a ligand for PD-1 (PD-L1) and that tumor-infiltrating CTLs express PD-1, suggesting this pathway may limit CTLs control of metastatic osteosarcoma in patients. PD-L1 is also expressed on the K7M2 osteosarcoma tumor cell line that establishes metastases in mice, and PD-1 is expressed on tumor-infiltrating CTLs during disease progression. Blockade of PD-1/PD-L1 interactions dramatically improves the function of osteosarcoma-reactive CTLs in vitro and in vivo, and results in decreased tumor burden and increased survival in the K7M2 mouse model of metastatic osteosarcoma. Our results suggest that blockade of PD-1/PD-L1 interactions in patients with metastatic osteosarcoma should be pursued as a therapeutic strategy.This is a non-final version of an article published in final form as Lussier, Danielle M., O'Neill, Lauren, Nieves, Lizbeth M., McAfee, Megan S., Holechek, Susan A., Collins, Andrea W., Dickman, Paul, Jacobsen, Jeffrey, Hingorani, Pooja, & Blattman, Joseph N. (2015). Enhanced T-Cell Immunity to Osteosarcoma Through Antibody Blockade of PD-1/PD-L1 Interactions. JOURNAL OF IMMUNOTHERAPY, 38(3), 96-106. http://dx.doi.org/10.1097/CJI.000000000000006
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