Knowing Is Half the Battle: Underestimating SUDEP.
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ABSTRACT:
SUBMITTER: Carlson C
PROVIDER: S-EPMC5967585 | biostudies-literature | 2018 Jan-Feb
REPOSITORIES: biostudies-literature
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Project description:Anaplastic lymphoma kinase (ALK) translocations are responsible of neoplastic transformation in a limited subset of non-small cell lung cancer (NSCLC) patients. In recent years outcomes of these patients improved due to the development and clinical availability of specific and extremely active targeted therapies [i.e., next-generation Tyrosine Kinase Inhibitors (TKI)]: ALK+ patients are now reaching impressive results when treated with more potent inhibitors upfront with an average median progression-free survival (mPFS) around 35 months. However, under drug pressure, cancer cells develop resistance and patients eventually progress. Multiple mechanisms of intrinsic or acquired resistance have been extensively characterized. Less potent ALK inhibitors (ALKi)-like crizotinib-usually tend to induce a large spectrum of secondary intra-kinase mutations; however, these alterations may be observed also after sequential administration of multiple ALKi. Noteworthy, neoplastic cells may evade ALK targeting through a myriad of different mechanisms involving cell-stroma interaction, activation of parallel signaling pathways, intracellular downstream adaptation and histological reshaping, as relevant molecular events. Often these phenomena are restricted to a limited number of cases or even can be patient-specific, thus hindering the development of therapeutic strategies largely applicable. Consequently, the recognition of specific resistance mechanisms seldom translates in clinical opportunities. Management of ALK+ patients is drastically changed and deciphering the molecular biology underlying this disease during treatment is of paramount relevance. The bedrock of resistance to TKI is that, after the diagnosis, we face with a different disease that needs to be re-characterized through tissue or/and liquid biopsies. Understanding molecular pathways driving the resistant phenotype will give us the chance to know what we are dealing with and, rather than choose an empirical approach, will help us to properly define the best targeted treatment for these patients.
| S-EPMC7815358 | biostudies-literature
Project description:Student-centered pedagogies increase learning and retention. Quantifying change in both student learning gains and student perception of their experience allows faculty to evaluate curricular transformation more fully. Student buy-in, particularly how much students value and enjoy the active learning process, has been positively associated with engagement in active learning and increased learning gains. We hypothesize that as the frequency of students who have successfully completed the course increases in the student population, current students may be more likely to buy-in to the curriculum because this common experience could create a sense of community. We measured learning gains and attitudes during the transformation of an introductory biology course at a small, liberal arts college using our novel curriculum, Integrating Biology and Inquiry Skills (IBIS). Students perceived substantial learning gains in response to this curriculum, and concept assessments confirmed these gains. Over time, buy-in increased with each successive cohort, as demonstrated by the results of multiple assessment instruments, and students increasingly attributed specific components of the curriculum to their learning. These findings support our hypothesis and should encourage the adoption of curricular transformation using IBIS or other student-centered approaches.
| S-EPMC6329493 | biostudies-literature
Project description:Pluralistic ignorance-a shared misperception of how others think or behave-poses a challenge to collective action on problems like climate change. Using a representative sample of Americans (N = 6119), we examine whether Americans accurately perceive national concern about climate change and support for mitigating policies. We find a form of pluralistic ignorance that we describe as a false social reality: a near universal perception of public opinion that is the opposite of true public sentiment. Specifically, 80-90% of Americans underestimate the prevalence of support for major climate change mitigation policies and climate concern. While 66-80% Americans support these policies, Americans estimate the prevalence to only be between 37-43% on average. Thus, supporters of climate policies outnumber opponents two to one, while Americans falsely perceive nearly the opposite to be true. Further, Americans in every state and every assessed demographic underestimate support across all polices tested. Preliminary evidence suggests three sources of these misperceptions: (i) consistent with a false consensus effect, respondents who support these policies less (conservatives) underestimate support by a greater degree; controlling for one's own personal politics, (ii) exposure to more conservative local norms and (iii) consuming conservative news correspond to greater misperceptions.
| S-EPMC9399177 | biostudies-literature
Project description:The neural mechanism underlying preparation for tasks that vary in difficulty has not been explored. This functional magnetic resonance imaging study manipulated task difficulty by varying the working memory (WM) load of the n-back task. Each n-back task block was preceded by a preparation period involving a screen that indicated the level of difficulty of the upcoming task. Consistent with previous work, activation in some brain regions depended on WM load in the task. These regions were used as regions of interest for the univariate and multivariate (classification) analyses of preparation periods. The findings were that the patterns of brain activation during task preparation contain information about the upcoming task difficulty. (1) A support vector machine classifier was able to decode the n-back task difficulty from the patterns of brain activation during task preparation. Those individuals whose activation patterns for anticipated 1- versus 2- versus 3-back conditions were classified with higher accuracy showed better behavioral performance on the task, suggesting that task performance depends on task preparation. (2) Left inferior frontal gyrus, intraparietal sulcus, and anterior cingulate cortex parametrically decreased activation as anticipated task difficulty increased. Taken together, these results suggest dynamic involvement of the WM network not only during WM task performance, but also during task preparation.
| S-EPMC4318533 | biostudies-literature
Project description:ObjectiveTo obtain medical records, family interviews, and death-related reports of sudden unexpected death in epilepsy (SUDEP) cases to better understand SUDEP.MethodsAll cases referred to the North American SUDEP Registry (NASR) between October 2011 and June 2018 were reviewed; cause of death was determined by consensus review. Available medical records, death scene investigation reports, autopsy reports, and next-of-kin interviews were reviewed for all cases of SUDEP. Seizure type, EEG, MRI, and SUDEP classification were adjudicated by 2 epileptologists.ResultsThere were 237 definite and probable cases of SUDEP among 530 NASR participants. SUDEP decedents had a median age of 26 (range 1-70) years at death, and 38% were female. In 143 with sufficient information, 40% had generalized and 60% had focal epilepsy. SUDEP affected the full spectrum of epilepsies, from benign epilepsy with centrotemporal spikes (n = 3, 1%) to intractable epileptic encephalopathies (n = 27, 11%). Most (93%) SUDEPs were unwitnessed; 70% occurred during apparent sleep; and 69% of patients were prone. Only 37% of cases of SUDEP took their last dose of antiseizure medications (ASMs). Reported lifetime generalized tonic-clonic seizures (GTCS) were <10 in 33% and 0 in 4%.ConclusionsNASR participants commonly have clinical features that have been previously been associated with SUDEP risk such as young adult age, ASM nonadherence, and frequent GTCS. However, a sizeable minority of SUDEP occurred in patients thought to be treatment responsive or to have benign epilepsies. These results emphasize the importance of SUDEP education across the spectrum of epilepsy severities. We aim to make NASR data and biospecimens available for researchers to advance SUDEP understanding and prevention.
| S-EPMC6656646 | biostudies-literature
Project description:Adoptive therapy with chimeric antigen receptor (CAR)-redirected T cells showed spectacular efficacy in the treatment of leukemia in recent early phase trials. Patient's T cells were ex vivo genetically engineered with a CAR, amplified and re-administered to the patient. While T cells mediating the primary response were predominantly of young effector and central memory phenotype, repetitive antigen engagement irreversible triggers T cell maturation leaving late memory cells with the KLRG1(+) CD57(+) CD7(-) CCR7(-) phenotype in the long-term. These cells preferentially accumulate in the periphery, are hypo-responsive upon TCR engagement and prone to activation-induced cell death. A recent report indicates that those T cells can be rescued by CAR provided CD28 and OX40 (CD134) stimulation. We discuss the strategy with respect to prolong the anti-tumor response and to improve the over-all efficacy of adoptive cell therapy.
| S-EPMC3672777 | biostudies-literature
Project description:ObjectiveTo identify the molecular signaling pathways underlying sudden unexpected death in epilepsy (SUDEP) and high-risk SUDEP compared to control patients with epilepsy.MethodsFor proteomics analyses, we evaluated the hippocampus and frontal cortex from microdissected postmortem brain tissue of 12 patients with SUDEP and 14 with non-SUDEP epilepsy. For transcriptomics analyses, we evaluated hippocampus and temporal cortex surgical brain tissue from patients with mesial temporal lobe epilepsy: 6 low-risk and 8 high-risk SUDEP as determined by a short (<50 seconds) or prolonged (≥50 seconds) postictal generalized EEG suppression (PGES) that may indicate severely depressed brain activity impairing respiration, arousal, and protective reflexes.ResultsIn autopsy hippocampus and cortex, we observed no proteomic differences between patients with SUDEP and those with non-SUDEP epilepsy, contrasting with our previously reported robust differences between epilepsy and controls without epilepsy. Transcriptomics in hippocampus and cortex from patients with surgical epilepsy segregated by PGES identified 55 differentially expressed genes (37 protein-coding, 15 long noncoding RNAs, 3 pending) in hippocampus.ConclusionThe SUDEP proteome and high-risk SUDEP transcriptome were similar to those in other patients with epilepsy in hippocampus and cortex, consistent with diverse epilepsy syndromes and comorbid conditions associated with SUDEP. Studies with larger cohorts and different epilepsy syndromes, as well as additional anatomic regions, may identify molecular mechanisms of SUDEP.
| S-EPMC8205452 | biostudies-literature
Project description:Several potential pathophysiologic phenomena, including "cerebral shutdown," are postulated to be responsible for SUDEP. Since the evidence for a seizure-related mechanism is strong, a poor understanding of the physiology of human seizure termination is a major handicap. However, rather than a failure of a single homeostatic mechanism, such as postictal arousal, it may be a "perfect storm" created by the lining up of a several factors that lead to death.
| S-EPMC3854734 | biostudies-other
Project description:Populations often contain discrete classes or morphs (e.g., sexual dimorphisms, wing dimorphisms, trophic dimorphisms) characterized by distinct patterns of trait expression. In quantitative genetic analyses, the different morphs can be considered as different environments within which traits are expressed. Genetic variances and covariances can then be estimated independently for each morph or in a combined analysis. In the latter case, morphs can be considered as separate environments in a bivariate analysis or entered as fixed effects in a univariate analysis. Although a common approach, we demonstrate that the latter produces downwardly biased estimates of additive genetic variance and heritability unless the quantitative genetic architecture of the traits concerned is perfectly correlated between the morphs. This result is derived for four widely used quantitative genetic variance partitioning methods. Given that theory predicts the evolution of genotype-by-environment (morph) interactions as a consequence of selection favoring different trait combinations in each morph, we argue that perfect correlations between the genetic architectures of the different morphs are unlikely. A sampling of the recent literature indicates that the majority of researchers studying traits expressed in different morphs recognize this and do estimate morph-specific quantitative genetic architecture. However, ca. 16% of the studies in our sample utilized only univariate, fixed-effects models. We caution against this approach and recommend that it be used only if supported by evidence that the genetic architectures of the different morphs do not differ.
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Project description:We consider the privacy-preserving computation of node influence in distributed social networks, as measured by egocentric betweenness centrality (EBC). Motivated by modern communication networks spanning multiple providers, we show for the first time how multiple mutually-distrusting parties can successfully compute node EBC while revealing only differentially-private information about their internal network connections. A theoretical utility analysis upper bounds a primary source of private EBC error—private release of ego networks—with high probability. Empirical results demonstrate practical applicability with a low 1.07 relative error achievable at strong privacy budget Electronic supplementary material The online version of this chapter (10.1007/978-3-030-47436-2_12) contains supplementary material, which is available to authorized users.
| S-EPMC7206295 | biostudies-literature