Search

Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) is an autoimmune disorder associated with sudden onset of behavior changes. The prevalence of PANDAS is increasing in schools and interdisciplinary collaboration, knowledge, and the use of referrals to the school nurse are important for supporting students. This project sought to provide education on PANDAS to the interdisciplinary school team and implement a referral process for students exhibiting behavior changes. A self-directed online educational intervention was employed. A pretest-posttest design was utilized to assess knowledge before, immediately after, and six-weeks after the educational intervention. A referral log was implemented to track the number of referrals to the school nurse. The final sample size included 19 participants. Mean scores increased from pretest to posttest, and the implementation of a referral system produced 12 new school nurse referrals. Further strategies are needed to enhance interdisciplinary collaboration and support students experiencing health-related issues., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The TP53 tumor suppressor gene is mutated early in most of the patients with triple-negative breast cancer (TNBC). The most frequent TP53 alterations are missense mutations that contribute to tumor aggressiveness. Here, we used an autochthonous somatic TNBC mouse model, in which mutant p53 can be toggled on and off genetically while leaving the tumor microenvironment intact and wild-type for p53 to identify physiological dependencies on mutant p53. In TNBCs that develop in this model, deletion of two different hotspot p53R172H and p53R245W mutants triggers ferroptosis in vivo, a cell death mechanism involving iron-dependent lipid peroxidation. Mutant p53 protects cells from ferroptosis inducers, and ferroptosis inhibitors reverse the effects of mutant p53 loss in vivo. Single-cell transcriptomic data revealed that mutant p53 protects cells from undergoing ferroptosis through NRF2-dependent regulation of Mgst3 and Prdx6 , which encode two glutathione-dependent peroxidases that detoxify lipid peroxides. Thus, mutant p53 protects TNBCs from ferroptotic death.

The TP53 tumor suppressor gene is mutated early in the majority of patients with triple-negative breast cancer (TNBC). The most frequent TP53 alterations are missense mutations that contribute to tumor aggressiveness. We developed an autochthonous somatic K14-Cre driven TNBC mouse model with p53R172H and p53R245W mutations in which mutant p53 can be toggled on and off genetically while leaving the tumor microenvironment intact and wild-type for p53. These mice develop TNBCs with a median latency of 1 y. Deletion of mutant p53R172H or p53R245W in vivo in these tumors blunts their tumor growth and significantly extends survival of mice. Downstream analyses revealed that deletion of mutant Trp53 activated the cyclic GMP-AMP Synthase-Stimulator of Interferon Genes pathway but did not cause apoptosis implicating other mechanisms of tumor regression. Furthermore, we determined that only tumors with stable mutant p53 are dependent on mutant p53 for growth.

Cell state plasticity is carefully regulated in adult epithelia to prevent cancer. The aberrant expansion of the normally restricted capability for cell state plasticity in neoplasia is poorly defined. Using genetically engineered and carcinogen-induced mouse models of intestinal neoplasia, we observed that impaired differentiation is a conserved event preceding cancer development. Single-cell RNA sequencing (scRNA-seq) of premalignant lesions from mouse models and a patient with hereditary polyposis revealed that cancer initiates by adopting an aberrant transcriptional state characterized by regenerative activity, marked by Ly6a (Sca-1), and reactivation of fetal intestinal genes, including Tacstd2 (Trop2). Genetic inactivation of Sox9 prevented adenoma formation, obstructed the emergence of regenerative and fetal programs, and restored multilineage differentiation by scRNA-seq. Expanded chromatin accessibility at regeneration and fetal genes upon Apc inactivation was reduced by concomitant Sox9 suppression. These studies indicate that aberrant cell state plasticity mediated by unabated regenerative activity and developmental reprogramming precedes cancer development.

Systematic identification of signaling pathways required for the fitness of cancer cells will facilitate the development of new cancer therapies. We used gene essentiality measurements in 1,086 cancer cell lines to identify selective coessentiality modules and found that a ubiquitin ligase complex composed of UBA6, BIRC6, KCMF1, and UBR4 is required for the survival of a subset of epithelial tumors that exhibit a high degree of aneuploidy. Suppressing BIRC6 in cell lines that are dependent on this complex led to a substantial reduction in cell fitness in vitro and potent tumor regression in vivo. Mechanistically, BIRC6 suppression resulted in selective activation of the integrated stress response (ISR) by stabilization of the heme-regulated inhibitor, a direct ubiquitination target of the UBA6/BIRC6/KCMF1/UBR4 complex. These observations uncover a novel ubiquitination cascade that regulates ISR and highlight the potential of ISR activation as a new therapeutic strategy., Significance: We describe the identification of a heretofore unrecognized ubiquitin ligase complex that prevents the aberrant activation of the ISR in a subset of cancer cells. This provides a novel insight on the regulation of ISR and exposes a therapeutic opportunity to selectively eliminate these cancer cells. See related commentary Leli and Koumenis, p. 535. This article is highlighted in the In This Issue feature, p. 517., (©2022 The Authors; Published by the American Association for Cancer Research.)

Inflammation has long been recognized to contribute to cancer development, particularly across the gastrointestinal tract. Patients with inflammatory bowel disease have an increased risk for bowel cancers, and it has been posited that a field of genetic changes may underlie this risk. Here, we define the clinical features, genomic landscape, and germline alterations in 174 patients with colitis-associated cancers and sequenced 29 synchronous or isolated dysplasia. TP53 alterations, an early and highly recurrent event in colitis-associated cancers, occur in half of dysplasia, largely as convergent evolution of independent events. Wnt pathway alterations are infrequent, and our data suggest transcriptional rewiring away from Wnt. Sequencing of multiple dysplasia/cancer lesions from mouse models and patients demonstrates rare shared alterations between lesions. These findings suggest neoplastic bowel lesions developing in a background of inflammation experience lineage plasticity away from Wnt activation early during tumorigenesis and largely occur as genetically independent events., (© 2023. The Author(s).)

Collateral lethality occurs when loss of a gene/protein renders cancer cells dependent on its remaining paralog. Combining genome-scale CRISPR/Cas9 loss-of-function screens with RNA sequencing in over 900 cancer cell lines, we found that cancers of nervous system lineage, including adult and pediatric gliomas and neuroblastomas, required the nuclear kinase vaccinia-related kinase 1 (VRK1) for their survival in vivo. VRK1 dependency was inversely correlated with expression of its paralog VRK2. VRK2 knockout sensitized cells to VRK1 loss, and conversely, VRK2 overexpression increased cell fitness in the setting of VRK1 loss. DNA methylation of the VRK2 promoter was associated with low VRK2 expression in human neuroblastomas and adult and pediatric gliomas. Mechanistically, depletion of VRK1 reduced barrier-to-autointegration factor phosphorylation during mitosis, resulting in DNA damage and apoptosis. Together, these studies identify VRK1 as a synthetic lethal target in VRK2 promoter-methylated adult and pediatric gliomas and neuroblastomas.

Aim: This scoping review examined the work-life balance (WLB) of nursing faculty., Background: The nursing faculty shortage has resulted in increasing workloads that make it challenging for faculty to achieve WLB. Understanding WLB may be important for strengthening the nursing faculty workforce., Method: This study used Arksey and O'Malley's scoping review methodology to examine articles published between January 2000 and December 2020 that reported on the WLB of nursing faculty. All articles were eligible for inclusion, including those that used quantitative, qualitative, or mixed-method research approaches, as well as editorials and other summary articles., Results: Thirty-three articles were included in the review. Three major categories emerged: perceptions of WLB, characteristics associated with WLB, and strategies to achieve WLB among nursing faculty., Conclusion: Research on the WLB of nursing faculty is limited. Further research on strategies that improve WLB may play an integral role in the recruitment and retention of nursing faculty., Competing Interests: The author has declared no conflict of interest., (Copyright © 2022 National League for Nursing.)

This study aimed to identify the prevalence of leisure-time physical activity (LTPA) and fruit and vegetable intake (FVI) behaviors and to examine relationships between biological, sociocultural, and psychological personal factors and these behaviors among young adult Millennials aged 20 years to 32 years. Descriptive and inferential statistics were performed on data from the 2013-2014 National Health and Nutrition Examination Survey. Of the 1,137 respondents, 47% met the recommendations for LTPA, and only 13% and 17% met the recommendations for intake of fruits and vegetables, respectively. Engagement in LTPA was associated with being male, race/ethnicity, and increased education and income. Obesity, measured by body mass index, and poor perceived health status were associated with not meeting the recommendations for LTPA. Increased education was associated with meeting the recommendations for vegetable intake. No other regression models were significant. These findings suggest contemporary young adults would benefit from health promotion efforts.

Cell stress and DNA damage activate the tumor suppressor p53, triggering transcriptional activation of a myriad of target genes. The molecular, morphological, and physiological consequences of this activation remain poorly understood in vivo. We activated a p53 transcriptional program in mice by deletion of Mdm2 , a gene that encodes the major p53 inhibitor. By overlaying tissue-specific RNA-sequencing data from pancreas, small intestine, ovary, kidney, and heart with existing p53 chromatin immunoprecipitation (ChIP) sequencing, we identified a large repertoire of tissue-specific p53 genes and a common p53 transcriptional signature of seven genes, which included Mdm2 but not p21 Global p53 activation caused a metaplastic phenotype in the pancreas that was missing in mice with acinar-specific p53 activation, suggesting non-cell-autonomous effects. The p53 cellular response at single-cell resolution in the intestine altered transcriptional cell state, leading to a proximal enterocyte population enriched for genes within oxidative phosphorylation pathways. In addition, a population of active CD8+ T cells was recruited. Combined, this study provides a comprehensive profile of the p53 transcriptional response in vivo, revealing both tissue-specific transcriptomes and a unique signature, which were integrated to induce both cell-autonomous and non-cell-autonomous responses and transcriptional plasticity., Competing Interests: The authors declare no competing interest.

Tumor sequencing studies have emphasized the role of epigenetics and altered chromatin homeostasis in cancer. Mutations in DAXX , which encodes a chaperone for the histone 3.3 variant, occur in 25% of pancreatic neuroendocrine tumors (PanNETs). To advance our understanding of physiological functions of Daxx, we developed a conditional Daxx allele in mice. We demonstrate that Daxx loss is well tolerated in the pancreas but creates a permissive transcriptional state that cooperates with environmental stress (inflammation) and other genetic lesions ( Men1 loss) to alter gene expression and cell state, impairing pancreas recovery from inflammatory stress in vivo. The transcriptional changes are associated with dysregulation of endogenous retroviral elements (ERVs), and dysregulation of endogenous genes near ERVs is also observed in human PanNETs with DAXX mutations. Our results reveal a physiologic function of DAXX, provide a mechanism associated with impaired tissue regeneration and tumorigenesis, and expand our understanding of ERV regulation in somatic cells., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

TP53 mutations occur in ∼50% of all human tumors, with increased frequency in aggressive cancers that are notoriously difficult to treat. Additionally, p53 missense mutations are remarkably predictive of refractoriness to chemo/radiotherapy in various malignancies. These observations have led to the development of mutant p53-targeting agents that restore p53 function. An important unknown is which p53-mutant tumors will respond to p53 reactivation-based therapies. Here, we found a heterogeneous impact on therapeutic response to p53 restoration, suggesting that it will unlikely be effective as a monotherapy. Through gene expression profiling of p53 R172H -mutant lymphomas, we identified retinoic acid receptor gamma (RARγ) as an actionable target and demonstrated that pharmacological activation of RARγ with a synthetic retinoid sensitizes resistant p53-mutant lymphomas to p53 restoration, while additively improving outcome and survival in inherently sensitive tumors., Competing Interests: The authors declare no conflict of interest.

Mdm2 and Mdm4 are negative regulators of the tumor suppressor p53; hence, this relationship is the focus of many cancer related studies. A multitude of experiments across various developmental stages have been conducted to explore the tissue-specific roles of these proteins in the mouse. When Mdm2 or Mdm4 are deleted in the germline or specific tissues, they display different phenotypic defects, some of which lead to embryonic lethality. Mdm2 loss is often more deleterious than loss of its homolog Mdm4 All tissues experience activation of p53 target genes upon loss of Mdm2 or Mdm4; however, the degree to which the p53 pathway is perturbed is highly tissue-specific and does not correlate to the severity of the morphological phenotypes. Therefore, a need for further understanding of how these proteins regulate p53 activity is warranted, as therapeutic targeting of the p53 pathway is rapidly evolving and gaining attention in the field of cancer research. In this review, we discuss the tissue-specificity of Mdm proteins in regulating p53 and expose the need for investigation at the cell-specific level., (© The Author (2017). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS. All rights reserved.)

Background: Multiple sulfatase deficiency is an autosomal recessive lysosomal storage disorder characterized by the absence of several sulfatases and resulting from mutations in the gene encoding the human C (alpha)-formylglycine-generating enzyme. There have been a variety of biochemical and clinical presentations reported in this disorder., Patient Description: We present a 4-year-old girl with clinical findings of microcephaly, spondylolisthesis and neurological regression without ichthyosis, coarse facies, and organomegaly., Results: The child's magnetic resonance imaging demonstrated confluent white matter abnormalities involving the periventricular and deep cerebral white matter with the U-fibers relatively spared. Biochemical testing showing low arylsulfatase A levels were initially thought to be consistent with a diagnosis of metachromatic leukodystrophy. The diagnosis of multiple sulfatase deficiency was pursued when genetic testing for metachromatic leukodystrophy was negative., Conclusion: This child illustrates the clinical heterogeneity of multiple sulfatase deficiency and that this disorder can occur without the classic clinical features., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Few studies examine whether and how parental attitudes towards genetic testing change over time. In this study we interviewed parents of 14 children with newly identified hearing loss at two time points: after referral to genetics and 1 year later. Qualitative analyses of parental narratives indicate that parental attitudes did not change significantly over this time. Parents who perceived genetic testing to be useful continued to value it after testing, while parents who did not perceive it as being useful for their child's future held the same view a year later. The only parents who changed their views regarding the usefulness of genetic testing for hearing loss were those who reported that their children underwent significant changes in their hearing loss or were faced with other life threatening conditions. Parents were also often unaware of the role of the genetic counselor and how genetic counseling could help address many of their lingering questions and concerns. These emergent themes indicate the need for geneticists and genetic counselors to be aware of and sensitized to the questions and attitudes that bring parents to a genetic evaluation, as well as the reasons why parents may not follow up with genetic testing for hearing loss when recommended.

The assessment and management of a child's pain in the postoperative period remain a challenge to the PACU nurse. Assessment of pain in children is often difficult; ongoing clinical research in this area continues to expand knowledge of how to improve children's communication of their pain to caregivers. Many pain management strategies are available, both pharmacologic and nonpharmacologic, to ease pain and distress postoperatively. Through understanding and knowledge of pain, its assessment and its management, the PACU nurse contributes positively to the child's surgical experience.

Evoked cortical potentials (VEPs) to grid patterns flashed to one eye were suppressed in amplitude when grid patterns were continuously presented to the other eye. The degree of interocular suppression of VEPs was influenced by the stereoacuity of the subjects. VEPs were obtained to each of two grid sizes flashed to one eye (individual squares subtending 15 and 60 min of arc) and changes in amplitude of these VEPs were considered as a function of four stimuli continuously presented to the other eye (diffuse light, 15, 30, and 60 min of arc squares in grids). Interocular suppression of VEPs was greater (a) when the continuously presented grid was of high (38.00 mL) as compared to low (00.38 mL) intensity, (b) when the continuous and flashed grids were of the same as compared to different sizes, and (c) in six subjects who had good as compared to six subjects who had poor binocularity. Eleven of the twleve subjects could be classified correctly as having good or poor binocularity on the basis of statistically significant interocular suppression of VEPs. The results were interpreted in terms of centrally located binocular neurons responsive to specific grid sizes or spatial frequencies and the decreased functioning of such neurons in subjects with poor binocularity.