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TCF4 Is a Key Mediator of Cell Identity and Oncogenesis in Neuroblastoma
Get PDFNeuroblastomas (NB) are embryonal childhood tumors that derive from the multipotent neural crest cells (NCCs) of the peripheral nervous system. NB accounts for more than 15% of all childhood cancer-related deaths. Despite the most intensive multimodal therapy, more than 50% of patients with high-risk NB relapse with often fatal, resistant disease. Novel therapies are desperately needed to improve cure rates. Previous studies proposed that the deregulation of normal neural crest developmental programs contributes to NB oncogenesis by retaining the highly migratory and proliferative traits of NCCs. Thus, activation or repression of neural crest developmental pathways have been implicated in NB pathogenesis. Recent data reported two identities in neuroblastoma cell lines: one establishing a more proliferative adrenergic (ADRN) cell state and a second establishing a more invasive, therapy-resistant mesenchymal (MES) cell state. Super-enhancer-associated transcription factor (TF) networks define cell identities in neuroblastoma (NB). Dysregulation of these TFs contributes to the initiation and maintenance of NB by enforcing early developmental identity states. We report the bHLH transcription factor TCF4 (E2-2) is a critical NB dependency gene that significantly contributes to these identity states through its heterodimerization with cell identity specific bHLH TFs. Mechanistically, we show that TCF4 promotes cell proliferation through direct transcriptional regulation of a MYC/MYCN oncogenic program. To identify potential therapeutic vulnerabilities, we characterized the TCF4 regulatory interactome and identified multiple epigenetic factors including HDACs and KDM1A. We determined that inhibitors to both HDACs and KDM1A, which often form complexes together, reduce TCF4 protein stability. Our work suggests that loss of TCF4 protein expression is an important biological readout for determining the efficacy of these epigenetic inhibitors in treating patients and could lead to improved patient outcomes
A Multi-Faceted Approach to the Alzheimer’s Disease Proteome: From Human to Mouse Models
Get PDFAmyloid pathology is the central hallmark of Alzheimer’s disease (AD) and related dementias (ADRD). We analyzed the dementia with Lewy bodies disease (DLBD) proteome, a disorder also associated with amyloid pathology, and compared to the AD proteome, identifying conserved alterations in amyloid pathology and shared components in amyloid plaques, including MDK and NTN1. We additionally evaluated major AD mouse models to determine their relevance to human disease and identify shared proteomic alterations. We observed alterations in several highly conserved matrisomal components consistently im- plicated in proteomic analyses of human amyloidosis disorders. We additionally identified several pathways influenced by amyloid-pathology that were consistently shared between human AD and the 5xFAD and APPNL-G-F mouse models, including amyloid regulation, nitric oxide regulation, superoxide regulation, cell, adhesion, and cellular component organization. Finally, we investigated global proteome turnover changes in 5xFAD mice to shed light on the discrepancy between transcriptome and proteome in AD. We achieved un- precedented quantitation of protein half-lives in mice and identified decreased turnover in key amyloidome components such as APOE. Our results indicate our proteomics workflow can serve as a powerful resource for studying fundamental protein turnover, interrogating biological questions, and developing therapeutics for neurodegenerative disorders
The NTF2L Domain Is a Date Hub That Interacts with SLiMs to Regulate Assembly of Stress Granules
Get PDFBiomolecular condensation has been recognized as an important strategy for spatial or- ganization within cells. Biomolecules condense through interactions. When the sum and duration of collective interactions reach the percolation threshold, a system-spanning inter- action network is achieved, resulting in phase separation to create a low-viscosity liquid, i.e., biomolecular condensate. Protein-protein interactions (PPIs) are essential for the formation of system-spanning interaction networks that drive biomolecular condensation. Short linear motifs (SLiMs) are the most abundant functional unit involved in protein-protein interactions (PPIs). The interactions between SLiMs and date hubs are crucial for various cellular processes. While SLiMs and date hubs are prevalent in biomolecular condensates and exhibit interaction attributes similar to those in the biomolecular condensate interaction network, the roles of the interactions between SLiMs and date hubs in contributing to biomolecular condensation remains unillustrated. Here, we take a prototypical biomolecu- lar condensate, stress granule (SG), as an example to illustrate how the interactions between SLiMs and date hubs contribute to the interaction networks that drive biomolecular con-densation.
We firstly confirmed that the NTF2L domain of G3BP1 protein, the central node of the SG interaction network, is a date hub that interacts with SLiMs. We found that the NTF2L domain has one binding surface, comprising four closely neighboring, degenerated binding areas. We then defined the SLiM patterns for NTF2L recognition and applied these SLiM patterns to predict novel NTF2L binding motifs in human proteome. We successfully verified that NUFIP2 is a novel NTF2L direct interactor. Leveraging the structural insights into the interactions between NTF2L and its binding SLiMs, we generated in silico NTF2L mutants designed to manipulate these interactions. We confirmed that two mutants, F33W and H31A, indeed altered the NTF2L interactome as predicted. Furthermore, we found that the interactions between NTF2L and SLiMs not only introduce NTF2L direct interactors into the SG interaction network, but these SLiM-containing proteins also serve as bridges, connecting many other SG components into the SG interaction network. Caprin1 bridges NTF2L and small ribosomal proteins, NUFIP2 bridges NTF2L and both ATXN2L and DDX6. The mutations in NTF2L impact recruitment of both NTF2L direct interactors and the indirect interactors dependent on the corresponding direct interactors. NTF2L F33W lost interactions with multiple direct interactors, including caprin1, USP10, and NUFIP2, and we showed that G3BP1 F33W impairs the assembly of SGs. Using SG as an example, we demonstrated that the interactions between SLiMs and date hubs play important roles in the interaction networks that drive biomolecular condensation. Manipulating the interactions between SLiMs and date hubs regulates biomolecular condensation
Impact of Mobile Text Reminders on Medication Compliance
Get PDFPurpose/Background
Patient noncompliance with medication leads to longer and more frequent infections and health issues. Using mobile reminders, patients can be prompted to take their medication, schedule their followup appointments, or fill their prescription to encourage compliance and better overall health.
Methods
A search of PubMed, LibKey, and EBSCO was conducted. Articles reviewed included meta-analysis, randomized controlled trials, and systematic reviews in the use of mobile reminders on patient compliance, specifically in medication adherence. Then, we reviewed the article methods and outcomes across various health issues addressed. The articles were then reviewed for criteria such as population size, length of study, and health issues addressed before being recorded to a spreadsheet for further analysis.
Results
The articles included 4 randomized controlled trials, 2 clinical trials, and 1 systematic review. Per the articles, the most effective methods to increase the rate of compliance are behavior change techniques, improving general T2DM care, providing evidence-based informational leaflets about direct reminders to patients, incorporating direct reminder systems into primary care appointments, and adding a point-of-care reminder to the electronic medical record. Interventions that did not improve adherence were financial incentives and printed reminders to the PCPs.
Implications for Nursing Practice
Further studies are needed, especially with longer length of study, the results tend to be beneficial. Selected studies showed that there was at least some degree of improvement in patient compliance though not all were able to say there was a positive effect on long term health. These results are promising and promote continued research on implementing technology to improve health outcomes
The Effectiveness of a Ventilator Care Bundle Protocol in Decreasing Incidence of Ventilator-Acquired Pneumonia: A Scoping Review
Get PDFPurpose/Background
Ventilator-acquired pneumonia (VAP) is a preventable hospital-acquired infection with a high mortality rate. Ventilator care bundles (VCB) are implemented to decrease the risk of infection while patients are mechanically ventilated. The aim of this scoping review was to assess how adult patients in the intensive care unit (ICU) requiring mechanical ventilation and the incidence of VAP are affected by staff’s compliance to a VCB.
Methods
From August of 2022 to November 2022, literature research was done among databases such as PubMed, MEDLINE, and CINAHL. The systematic search in PubMed yielded 55 results with the headings of “(ventilator) AND (care bundle) AND (pneumonia)”. 43 articles were excluded due the inclusion of non-adult patients. From the 12 articles remaining, only 3 from PubMed were relevant. 7 articles from similar searches were also included. The final 10 articles went through rapid critical appraisal and the primary outcomes were synthesized in a data table.
Results
2 systematic reviews, 1 controlled trial without randomization, 6 case-control studies, and 1 quality improvement project were included. Each article provided evidence supporting staff compliance with a VCB improved patient outcomes. These outcomes include decreased incidence of VAP, hospital and ICU length of stay, and patient mortality.
Implications for Nursing Practice
A VCB is a feasible protocol to improve patient outcomes. Prioritization of these interventions decreases incidence rates of VAP. All staff caring for ventilated patients should be educated on the success of VCBs to ensure appropriate compliance and improve patient outcomes
Evaluating the Efficacy of Medication-Assisted Treatment for First Episode Psychosis: A Scoping Review
Get PDFPurpose/Background
The Substance Abuse and Mental Health Services Administration (SAMHSA) recommends that individuals with substance use disorder (SUD) receive medicated-assisted treatment (MAT), as a complete approach to substance use treatment (SAMHSA, 2019). However, treatment measures using combination treatment for SUD in individuals experiencing first episode psychosis (FEP) are seldom used. This scoping review assesses the efficacy of MAT in conjunction with antipsychotics compared to the use of antipsychotic monotherapy for FEP individuals on hospital readmission rates.
Methods
The authors conducted a literature review utilizing PubMed, EBSCO, Elsevier, Google Scholar, PsychINFO, and Medline from August 2020 to November 2022. Key phrases in the database search included: first-episode psychosis, comorbid substance use, alcohol use disorder, cannabis use disorder, medication-assisted treatment, buprenorphine, methadone, and antipsychotics. Eligibility criteria included individuals experiencing psychosis defined by hallucination, delusion, or paranoia symptoms with co-occurring substance use. Inclusion criteria include publication within the past five years, English or available English translation, full text, institutional review board-approved, and peer-reviewed. Ultimately, we selected ten articles for this scoping review.
Results
The ten articles demonstrated improvement of psychotic symptoms but showed mixed results in hospital readmission rates after combination therapy. The most notable restriction for this review was the paucity of published literature on MAT for FEP and comorbid substance use. Of the literature reviewed, patients experiencing comorbid FEP and SUDs were vulnerable to poor outcomes due to the illnesses, limited treatment options targeting both symptoms, and poor retention rates in MAT programs.
Implications for Nursing Practice
This scoping review highlights the treatment of comorbid SUD and FEP with the use of MAT to potentially reduce hospital readmission rates. There was insufficient evidence to outline targeted treatment regimens for our patient population; therefore, more research is needed in this area
CRNA Decision-Making Within the Anesthesia Care Team
Get PDFThis research focused on Certified Registered Nurse Anesthesiologists’ (CRNAs’) perspectives on the value placed on their decision-making skills within the Anesthesia Care Team (ACT). The emphasis of the study was to examine CRNA’s perspectives on the strengths, challenges, conflict resolutions, and any other information they were willing to divulge when working with physician anesthesiologists in the ACT model. An electronic survey questionnaire was sent to practicing CRNAs, primarily in the southeast region of the United States, with 171 informants completing the questionnaire. Data analysis included demographic information of the convenience sample that included age, gender, initial educational preparation as a CRNA, and practice settings and arrangements. Four free-test questions were asked regarding their perspectives on decision-making strengths, challenges, conflict resolutions, and any additional information about their practice. The researcher and research advisor jointly analyzed the qualitative data and developed themes and subthemes of the informant’s responses. Data analysis revealed CRNAs enjoyed and supported collaboration within the ACT and found the team approach led to efficient patient care while having extra hands to help and minds to problem-solve complicated patient scenarios. They did not believe supervision by physicians over their practice was necessary. They found that supervision generated a lack of respect and a restricted scope of practice for CRNAs. They also reported physician microaggressions that lead to tense workenvironments and role confusion for hospital staff and patients. CRNAs often relied on collaboration, accommodation, or compromise to resolve decision-making conflicts within the ACT. However, many avoid or leave the ACT care model for independent practice when these approaches do not. Many CRNAs who left ACTs stated they were much happier with their profession and would never return to the ACT model. The recommendations from this study include a political call to action, a change in payment structure for anesthesia services, and reformed hospital credentialing. These recommendations would allow CRNAs to have a full scope of practice and work independently to deliver the high-quality anesthesia care for which they trained
Impact of Medicaid Expansion on Adherence to Antidiabetic Medications Among Low-Income Adults
Get PDFPurpose. Low-income adults are disproportionately afflicted with diabetes and are more likely to suffer from advanced forms of diabetes related sequelae. Uninterrupted therapy on antidiabetic medications can postpone or prevent the damaging and costly complications associated with the progression of diabetes; however, many low-income individuals face significant barriers adhering to drug regimens. Medicaid, the primary source of health insurance among low-income people, mitigates access and cost barriers by providing access to health services and prescription drugs at a reduced cost. In 2014, Medicaid expansion, a provision of the Patient Protection and Affordable Care Act (PPACA), would have had the potential to significantly increase the number of Americans with Medicaid coverage. Yet only 27 states and Washington D.C. had expanded that year, following the Supreme Court’s decision that yielded Medicaid expansion noncompulsory for states. This schism amongst states conceived a unique opportunity in which researchers could compare Medicaid expansion effects on health outcomes. Since the implementation of Medicaid expansion, several studies have determined those states that adopted the expansion have had largely positive impacts on coverage, access to care and utilization, economic outcomes, as well as diminished disparities. There is a paucity of literature concerning the impact of PPACA on adherence to antidiabetic medication. Methods. This cross-sectional study analyzed pharmacy claims data collected by the Medical Expenditure Panel Survey (MEPS), a family of large-scale surveys that provides nationally representative estimates of health care use, expenditures, sources of payment, and health insurance coverage for the U.S. civilian noninstitutionalized population. MEPS respondents in years 2012/2013 (before expansion), and 2015/2016 (after expansion) were included in the study sample if they were between the ages of 19 and 64, reported income below 138% of the federal poverty level, and filled at least one antidiabetic medication during the study period. We utilized the difference-in-differences (D-I-D) statistical technique to estimate the causal effect of Medicaid expansion policy on adherence to antidiabetic medications among low-income adults who have been diagnosed with diabetes, characterizing treatment effect variation within specific marginalized subgroups. Adherence is determined in two ways: A multiple linear regression model estimated the effect of Medicaid expansion on mean adherence determined by the Medication Possession Ratio (MPR), and a multiple logistic regression model estimated the effect of Medicaid expansion on clinical adherence determined by MPR above 80%. Results. The sample included 1017 (weighted- 5,885,519) participants. The D-I-D estimate, which represents the change as a result of Medicaid expansion policy between treatment and control groups over time, was not significant in the multiple linear regression model (p=0.614). Likewise, the difference-in-differences estimate was not significant in the multiple logistic regression model (p=0.344). Among the studied subgroups, there was no significant association between Medicaid expansion and any measures of adherence studied; mean adherence or MPR greater than 80% (p\u3e0.05). Conclusion. The findings suggest that Medicaid expansion policy alone could not overcome the barriers associated with medication adherence in this population. Policies are needed that intentionally address barriers associated with medication adherence among low-income adults with diabetes
Cortical Tracking of Syntax in Post-Stroke Aphasia: An EEG Investigation of Disrupted Sentence Comprehension
Get PDFPurpose. People with aphasia following stroke commonly exhibit marked difficulties in sentence comprehension, referred to as receptive agrammatism. However, theories of receptive agrammatism differ in their assumptions regarding the underlying mechanisms of impairment. Representation-based theories ascribe receptive agrammatism to a loss of grammatical knowledge. Processing-based theories suggest that individuals with receptive agrammatism have intact grammatical knowledge but may possess insufficient neurocognitive resources to apply this knowledge within cognitively demanding contexts. In this study, we used electroencephalography (EEG) to investigate whether these perspectives may be disambiguated by the neural activity profiles of people with aphasia during comprehension. For this purpose, we examined aphasia-related changes in cortical “tracking” of phrases—which has been suggested as a neural correlate of successfully encoded grammatical content. By considering cortical tracking alongside subject-specific performance on a set of clinical assessments, we aimed to identify which cognitive-linguistic mechanisms best explain the patterns of impaired sentence comprehension presented by individuals with receptive agrammatism.
Methods. Nine individuals with post-stroke aphasia and nine age- and education-matched neurologically healthy controls participated in this study. All were native English speakers. Language abilities were assessed using the Quick Aphasia Battery, and working memory was assessed using a modified listening span task. Following assessment, we recorded EEG as participants listened to sentences that varied in their syntactic and semantic complexity. After each sentence, participants were asked to identify pictures that matched the sentence they had just heard. Cortical tracking was quantified via Mutual Information (MI) between EEG responses and the syntactic features of the sentences. We evaluated how cortical tracking differed between groups and across levels of linguistic complexity, as well as whether these differences predicted participant performance.
Results. Both groups tracked syntactic structure similarly and showed delayed cortical responses for trials where they responded incorrectly. Both groups also showed increased tracking for semantically reversible sentences. However, people with aphasia performed worse on these items than controls, and there was no clear relationship between cortical tracking and task performance. Further investigation revealed that scores on offline clinical assessments of sentence processing were significant predictors of cortical tracking, whereas performance on the sentence-picture matching task was best explained by age, overall severity, and decreases in theta band (4-7Hz) power.
Conclusion. Our findings suggested that people with aphasia may be subtly impaired in their syntactic abilities. Our EEG findings also suggested that patients presented with delayed syntactic processing speeds and increased reliance on phonological working memory when sentences were semantically reversible. Moreover, individuals with aphasia may have possessed insufficient neural resources for post-interpretive task completion, when task-demands were high and sentence content was complex. We interpret these findings as being consistent with processing-based accounts of receptive agrammatism
