Understanding molecular mechanisms of resistance to immune checkpoint inhibitors in advanced non-small cell lung cancer (NSCLC)

Immune checkpoint inhibitors (ICI) that target PD-1/PD-L1 have recently emerged as an integral component of front-line treatment in metastatic NSCLC patients. The PD-1 inhibitor pembrolizumab is approved as monotherapy for advanced NSCLC with a PD-L1 tumor proportion score (TPS) of ≥1% and in combination with platinum doublet chemotherapy regardless of PD-L1 expression level. However, responses to either regimen occur in only a minority of cases, and PD-L1 TPS is limited as a biomarker in predicting whether a cancer will respond to PD-1 inhibition alone or would be more likely to benefit from PD-1 inhibition plus chemotherapy. Additional biomarkers of immunotherapy efficacy, such as tumor mutational burden (TMB), have not been incorporated into routine clinical practice for treatment selection. The identification of patients who have the greatest likelihood of responding to immunotherapies is critical for guiding treatment decisions. IN addition, early indicators of response could theoretically prevent patients from staying on an ineffective therapy where they might experience complications due to disease progression or develop toxicities from unnecessary exposure to an inactive agent. The aim of this research project is to investigate the clinicopathologic and molecular determinant of response/resistance to the currently available immune checkpoint inhibitors, in order to identify therapeutic vulnerabilities that can be exploited to improve the clinical outcomes of patients with advanced NSCLC.

Understanding Red Blood Cell Parameters In The Context Of The Frailty Phenotype: Interpretations Of The Fibra (frailty In Brazilian Seniors) Study.

Frailty and anemia in the elderly appear to share a common pathophysiology associated with chronic inflammatory processes. This study uses an analytical, cross-sectional, population-based methodology to investigate the probable relationships between frailty, red blood cell parameters and inflammatory markers in 255 community-dwelling elders aged 65 years or older. The frailty phenotype was assessed by non-intentional weight loss, fatigue, low grip strength, low energy expenditure and reduced gait speed. Blood sample analyses were performed to determine hemoglobin level, hematocrit and reticulocyte count, as well as the inflammatory variables IL-6, IL-1ra and hsCRP. In the first multivariate analysis (model I), considering only the erythroid parameters, Hb concentration was a significant variable for both general frailty status and weight loss: a 1.0g/dL drop in serum Hb concentration represented a 2.02-fold increase (CI 1.12-3.63) in an individual's chance of being frail. In the second analysis (model II), which also included inflammatory cytokine levels, hsCRP was independently selected as a significant variable. Each additional year of age represented a 1.21-fold increase in the chance of being frail, and each 1-unit increase in serum hsCRP represented a 3.64-fold increase in the chance of having the frailty phenotype. In model II reticulocyte counts were associated with weight loss and reduced metabolic expenditure criteria. Our findings suggest that reduced Hb concentration, reduced RetAbs count and elevated serum hsCRP levels should be considered components of frailty, which in turn is correlated with sarcopenia, as evidenced by weight loss.

Educação física e inclusão educacional : entender para atender = Physical education and educational inclusion : understanding to attend

Universidade Estadual de Campinas . Faculdade de Educação Física

Identification of protein-coding and non-coding RNA expression profiles in CD34(+) and in stromal cells in refractory anemia with ringed sideroblasts

Background: Myelodysplastic syndromes (MDS) are a group of clonal hematological disorders characterized by ineffective hematopoiesis with morphological evidence of marrow cell dysplasia resulting in peripheral blood cytopenia. Microarray technology has permitted a refined high-throughput mapping of the transcriptional activity in the human genome. Non-coding RNAs (ncRNAs) transcribed from intronic regions of genes are involved in a number of processes related to post-transcriptional control of gene expression, and in the regulation of exon-skipping and intron retention. Characterization of ncRNAs in progenitor cells and stromal cells of MDS patients could be strategic for understanding gene expression regulation in this disease. Methods: In this study, gene expression profiles of CD34(+) cells of 4 patients with MDS of refractory anemia with ringed sideroblasts (RARS) subgroup and stromal cells of 3 patients with MDS-RARS were compared with healthy individuals using 44 k combined intron-exon oligoarrays, which included probes for exons of protein-coding genes, and for non-coding RNAs transcribed from intronic regions in either the sense or antisense strands. Real-time RT-PCR was performed to confirm the expression levels of selected transcripts. Results: In CD34(+) cells of MDS-RARS patients, 216 genes were significantly differentially expressed (q-value <= 0.01) in comparison to healthy individuals, of which 65 (30%) were non-coding transcripts. In stromal cells of MDS-RARS, 12 genes were significantly differentially expressed (q-value <= 0.05) in comparison to healthy individuals, of which 3 (25%) were non-coding transcripts. Conclusions: These results demonstrated, for the first time, the differential ncRNA expression profile between MDS-RARS and healthy individuals, in CD34(+) cells and stromal cells, suggesting that ncRNAs may play an important role during the development of myelodysplastic syndromes.

Understanding the Influences of Spatial Patterns on N Availability Within the Brazilian Amazon Forest

Nitrogen variations at different spatial scales and integrated across functional groups were addressed for lowland tropical forests in the Brazilian Amazon as follows: (1) how does N availability vary across the region over different spatial scales (regional x landscape scale); ( 2) how are these variations in N availability integrated across plant functional groups ( legume 9 non-legume trees). Leaf N, P, and Ca concentrations as well the leaf N isotope ratios (delta(15)N) from a large set of legume and non-legume tree species were measured. Legumes had higher foliar N/Ca ratios than non-legumes, consistent with the high energetic costs in plant growth associated with higher foliar P/Ca ratios found in legumes than in non-legumes. At the regional level, foliar delta(15)N decreased with increasing rainfall. At the landscape level, N availability was higher in the forests on clayey soils on the plateau than in forests on sandier soils. The isotope as well as the non-isotope data relationships here documented, explain to a large extent the variation in delta(15)N signatures across gradients of rainfall and soil. Although at the regional level, the precipitation regime is a major determinant of differences in N availability, at the landscape level, under the same precipitation regime, soil type seems to be a major factor influencing the availability of N in the Brazilian Amazon forest.

Culturable endophytic filamentous fungi from leaves of transgenic imidazolinone-tolerant sugarcane and its non-transgenic isolines

The diversity of endophytic filamentous fungi from leaves of transgenic imidazolinone-tolerant sugarcane plants and its isoline was evaluated by cultivation followed by amplified rDNA restriction analysis (ARDRA) of randomly selected strains. Transgenic and non-transgenic cultivars and their crop management (herbicide application or manual weed control) were used to assess the possible non-target effects of genetically modified sugarcane on the fungal endophytic community. A total of 14 ARDRA haplotypes were identified in the endophytic community of sugarcane. Internal transcribed spacer (ITS) sequencing revealed a rich community represented by 12 different families from the Ascomycota phylum. Some isolates had a high sequence similarity with genera that are common endophytes in tropical climates, such as Cladosporium, Epicoccum, Fusarium, Guignardia, Pestalotiopsis and Xylaria. Analysis of molecular variance indicated that fluctuations in fungal population were related to both transgenic plants and herbicide application. While herbicide applications quickly induced transient changes in the fungal community, transgenic plants induced slower changes that were maintained over time. These results represent the first draft on composition of endophytic filamentous fungi associated with sugarcane plants. They are an important step in understanding the possible effects of transgenic plants and their crop management on the fungal endophytic community.

A new graphic format to facilitate the understanding of technological innovation models: the seesaw of competitiveness

Many models exist in the literature to explain the success of technological innovation. However, no studies have been made regarding graphic formats representing the technological innovation models and their impact, or on the understanding of these models by non-specialists in technology management. Thus, the main objective of this paper is to propose a new graphic configuration to represent the technological innovation management. Based on the literature, the innovation model is presented in the traditional format. Next, the same model is designed in the graphic format - named `the see-saw of competitiveness` - showing the interfaces among the identified factors. The two graphic formats were compared by a group of graduate students in terms of the ease in understanding the conceptual model of innovation. The statistical analysis shows that the seesaw of competitiveness is preferred.

Non-cancer mortality among people diagnosed with cancer (Australia)

Objective To investigate whether people diagnosed with cancer have an increased risk of death from non-cancer causes compared to the general population. Methods The non-cancer mortality of people diagnosed with cancer in Queensland (Australia) between 1982 and 2002 who had not died before 1 January 1993 was compared to the mortality of the total Queensland population, matching by age group and sex, and reporting by standardised mortality ratios. Results Compared to the non-cancer mortality in the general population, cancer patients (all cancers combined) were nearly 50% more likely to die of non-cancer causes (SMR = 149.9, 95% CI = [147-153]). This varied by cancer site. Overall melanoma patients had significantly lower non-cancer mortality, female breast cancer patients had similar non-cancer mortality to the general population, while increased non-cancer mortality risks were observed for people diagnosed with cervical cancer, colorectal cancer, prostate cancer, non-Hodgkin lymphoma and lung cancer. Conclusions Although cancer-specific death rates underestimate the mortality directly associated with a diagnosis of cancer, quantifying the degree of underestimation is difficult due to various competing explanations. There remains an important role for future research in understanding the causes of morbidity among cancer survivors, particularly those looking at both co-morbid illnesses and reductions in quality of life.

Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies

Introduction Associations between systemic lupus erythematosus (SLE) and primary immunodeficiencies (PIDs) were analyzed to gain insight into the physiopathology of SLE. Some PIDs have been consistently associated with SLE or lupus-like manifestations: (a) homozygous deficiencies of the early components of the classical complement pathway in the following decreasing order: in C1q, 93% of affected patients developed SLE; in C4, 75%; in C1r/s, 57%; and in C2, up to 25%; (b) female carriers of X-linked chronic granulomatous disease allele; and (c) IgA deficiency, present in around 5% of juvenile SLE. Discussion In the first two groups, disturbances of cellular waste-disposal have been proposed as the main mechanisms of pathogenesis. On the other hand and very interestingly, there are PIDs systematically associated with several autoimmune manifestations in which SLE has not been described, such as autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), immunedys-regulation polyendocrinopathy enteropathy X-linked (IPEX), and autoinumme lymphoproliferative syndrome (ALPS), suggesting that mechanisms considered as critical players for induction and maintenance of tolerance to autoantigens, such as (1) AME-mediated thymic negative selection of lymphocytes, (2) Foxp3+ regulatory T cell-mediated peripheral tolerance, and (3) deletion of auto-reactive lymphocytes by Fas-mediated apoptosis, could not be relevant in SLE physiopathology. The non-description of SLE and neither the most characteristic SLE clinical features among patients with agammaglobulinemia are also interesting observations, which reinforce the essential role of B lymphocytes and antibodies for SLE pathogenesis. Conclusion Therefore, monogenic PIDs represent unique and not fully explored human models for unraveling components of the conundrum represented by the physiopathology of SLE, a prototypical polygenic disease.

Platyhelminth phylogenetics - a key to understanding parasitism?

The comparative method, the inference of biological processes from phylogenetic patterns, is founded on the reliability of the phylogenetic tree. In attempting to apply the comparative method to the understanding of the evolution of parasitism in the phylum Platyhelminthes, we have highlighted several points we consider to be of value along with many problems. We discuss four of these topics. Firstly, we view the group at a phylum level, in particular discussing the importance of establishing the sister taxon to the obligate parasite group, the Neodermata, for addressing such questions as the monophyly, parasitism or the endo or ectoparasitic nature of the early parasites. The variety of non-congruent phylogenetic trees presented so far, utilising either or both morphological and molecular data, gives rise to the suggestion that any evolutionary scenarios presented at this stage be treated as interesting hypotheses rather than well-supported theories. Our second point of discussion is the conflict between morphological and molecular estimates of monogenean evolution. The Monogenea presents several well-established morphological autapomorphies, such that morphology consistently estimates the group as monophyletic, whereas molecular sequence analyses indicate paraphyly, with different genes giving different topologies. We discuss the problem of reconciling gene and species trees. Thirdly, we use recent phylogenetic results on the tapeworms to interpret the evolution of strobilation, proglottization, segmentation and scolex structure. In relation to the latter, the results presented indicate that the higher cestodes are diphyletic, with one branch difossate and the other tetrafossate. Finally, we use a SSU rDNA phylogenetic tree of the Trematoda as a basis for the discussion of an aspect of the digenean life-cycle, namely the nature of the first intermediate host. Frequent episodes of host-switching, between gastropod and bivalve hosts or even into annelids, are indicated.

The Role of Non-Market Valuation in Forest Management and Recreation Policy

Forests, and particularly those where native and mixed species are gown, provide a variety of non-wood values, important among which are recreation and environmental services. Substantial progress has been made in recent years in estimating economic values on these services. A considerable amount of research on forest values has been carried out recently in tropical and sub-tropical eastern Australia, some of which is reported in the following papers. The need for estimates of non-wood forest benefits is apparent, and it is clear that further development of techniques and a greater understanding of the way these values can be integrated into public-sector decision making is required.

A role for the dominant thalamus in language? A linguistic comparison of two cases subsequent to unilateral thalamotomy procedures in the dominant and non-dominant hemispheres

Background: Thalamotomy has been reported to be successful in ameliorating the motor symptoms of tremor and/or rigidity in people with Parkinson's disease (PD), emphasising the bona fide contribution of this subcortical nucleus to the neural circuitry subserving motor function. Despite evidence of parallel yet segregated associative and motor cortico-subcortical-cortical circuits, comparatively few studies have investigated the effects of this procedure on cognitive functions. In particular, research pertaining to the impact of thalamotomy on linguistic processes is fundamentally lacking. Aims: The purpose of this research was to investigate the effects of thalamotomy in the language dominant and non-dominant hemispheres on linguistic functioning, relative to operative theoretical models of subcortical participation in language. This paper compares the linguistic profiles of two males with PD, aged 75 years (10 years of formal education) and 62 years (22 years of formal education), subsequent to unilateral thalamotomy procedures within the language dominant and non-dominant hemispheres, respectively. Methods & Procedures: Comprehensive linguistic profiles comprising general and high-level linguistic abilities in addition to on-line semantic processing skills were compiled up to 1 month prior to surgery and 3 months post-operatively, within perceived on'' periods (i.e., when optimally medicated). Pre- and post-operative language performances were compared within-subjects to a group of 16 non-surgical Parkinson's controls (NSPD) and a group of 16 non-neurologically impaired adults (NC). Outcomes & Results: The findings of this research suggest a laterality effect with regard to the contribution of the thalamus to high-level linguistic abilities and, potentially, the temporal processing of semantic information. This outcome supports the application of high-level linguistic assessments and measures of semantic processing proficiency to the clinical management of individuals with dominant thalamic lesions. Conclusions: The results reported lend support to contemporary theories of dominant thalamic participation in language, serving to further elucidate our current understanding of the role of subcortical structures in mediating linguistic processes, relevant to cortical hemispheric dominance.

An investigation into commitment in non-Western industrial marketing relationships

This paper reports an investigation into the antecedents of commitment in non-Western industrial marketing relationships. The authors draw the antecedents from extant literature and posit that commitment is related to trust (integrity and reliability), communication quality, conflict, and similarity (social, ethnic, and economic). It is further argued that trust mediates the effects of communication, conflict, and similarity on commitment. As an extension, the authors examine the moderating effects of normative contracts (an implicit understanding of roles and responsibilities) on the construct interrelationships. The hypotheses are tested using data collected from approximately 150 industrial marketing relationships sampled from overseas Chinese firms. The results generally support the authors' framework; however, the mediating hypotheses are not supported. There is evidence of systematic differences in the effects of the studied antecedents on commitment and trust. Furthermore, a multigroup analysis provides evidence of significant moderating effects due to contracting mode. The study provides new insights into the theory and practice of industrial marketing. (C) 2003 Elsevier Science Inc. All rights reserved.