COVID-19 severity by vaccination status in the NCI COVID-19 and Cancer Patients Study (NCCAPS).

We investigated the association of SARS CoV-2 vaccination with COVID-19 severity in a longitudinal study of adult cancer patients with COVID-19. A total of 1610 patients who were within 14 days of an initial positive SARS CoV-2 test and had received recent anticancer treatment or had a history of stem cell transplant or CAR-T cell therapy were enrolled between May 21, 2020, and February 1, 2022. Patients were considered fully vaccinated if they were 2 weeks past their second dose of mRNA vaccine (BNT162b2 or mRNA-1273) or a single dose of adenovirus vector vaccine (Ad26.COV2.S) at the time of positive SARS CoV-2 test. We defined severe COVID-19 disease as hospitalization for COVID-19 or death within 30 days. Vaccinated patients were significantly less likely to develop severe disease compared with those who were unvaccinated (odds ratio = 0.44, 95% confidence interval = 0.28 to 0.72, P < .001). These results support COVID-19 vaccination among cancer patients receiving active immunosuppressive treatment.

Network for Biomarker Immunoprofiling for Cancer Immunotherapy: Cancer Immune Monitoring and Analysis Centers and Cancer Immunologic Data Commons (CIMAC-CIDC).

PURPOSE: Immunoprofiling to identify biomarkers and integration with clinical trial outcomes are critical to improving immunotherapy approaches for patients with cancer. However, the translational potential of individual studies is often limited by small sample size of trials and the complexity of immuno-oncology biomarkers. Variability in assay performance further limits comparison and interpretation of data across studies and laboratories. EXPERIMENTAL DESIGN: To enable a systematic approach to biomarker identification and correlation with clinical outcome across trials, the Cancer Immune Monitoring and Analysis Centers and Cancer Immunologic Data Commons (CIMAC-CIDC) Network was established through support of the Cancer MoonshotSM Initiative of the National Cancer Institute (NCI) and the Partnership for Accelerating Cancer Therapies (PACT) with industry partners via the Foundation for the NIH. RESULTS: The CIMAC-CIDC Network is composed of four academic centers with multidisciplinary expertise in cancer immunotherapy that perform validated and harmonized assays for immunoprofiling and conduct correlative analyses. A data coordinating center (CIDC) provides the computational expertise and informatics platforms for the storage, integration, and analysis of biomarker and clinical data. CONCLUSIONS: This overview highlights strategies for assay harmonization to enable cross-trial and cross-site data analysis and describes key elements for establishing a network to enhance immuno-oncology biomarker development. These include an operational infrastructure, validation and harmonization of core immunoprofiling assays, platforms for data ingestion and integration, and access to specimens from clinical trials. Published in the same volume are reports of harmonization for core analyses: whole-exome sequencing, RNA sequencing, cytometry by time of flight, and IHC/immunofluorescence.

Type 2 Myocardial Infarction: CURRENT CONCEPTS AND OUR EXPERIENCE WITH CARDIAC REHABILITATION.

BACKGROUND: Type 2 myocardial infarction (T2MI) is commonly encountered in clinical practice, yet little is known about this challenging condition. Outpatient cardiac rehabilitation (CR) is an integral component in the care of patients with MI. However, specific recommendations for CR, information on the feasibility of participation, and outcome measures for patients with T2MI are lacking. CLINICAL CONSIDERATIONS: The frequency of T2MI is markedly variable and depends on the studied population, disease definition, adjudication process, cardiac troponin assays, and cutoff values used to make the diagnosis of T2MI. Clinically, it is difficult to distinguish T2MI from type 1 MI or myocardial injury. Type 2 myocardial infarction occurs due to myocardial oxygen supply-demand mismatch without acute atherothrombotic plaque disruption and is associated with adverse short- and long-term prognoses. Currently, there are substantial gaps in knowledge regarding T2MI and there are no clear guidelines for the optimal management of these patients. SUMMARY: In this article, we present important current concepts surrounding T2MI including the definition, pathophysiology, epidemiology, diagnosis, prognosis, and management. We also discuss referral patterns to CR and participation rates and provide our experience with a case series of 17 patients. Very few patients with T2MI are referred to and participate in CR. Our small case series indicated that patients with T2MI respond favorably to CR and that exercise training following standard guidelines appears safe and is well tolerated.

EXERCISES THAT FACILITATE OPTIMAL HAMSTRING AND QUADRICEPS CO-ACTIVATION TO HELP DECREASE ACL INJURY RISK IN HEALTHY FEMALES: A SYSTEMATIC REVIEW OF THE LITERATURE.

BACKGROUND: Anterior cruciate ligament (ACL) injury is common among females due to many anatomic, hormonal, and neuromuscular risk factors. One modifiable risk factor that places females at increased risk of ACL injury is a poor hamstrings: quadriceps (H:Q) co-activation ratio, which should be 0.6 or greater in order to decrease the stress placed on the ACL. Exercises that produce more quadriceps dominant muscle activation can add to the tension placed upon the ACL, potentially increasing the risk of ACL injury. HYPOTHESIS/PURPOSE: The purpose of this systematic review was to compare quadriceps and hamstring muscle activation during common closed kinetic chain therapeutic exercises in healthy female knees to determine what exercises are able to produce adequate H:Q co-activation ratios. STUDY DESIGN: Systematic Review. METHODS: Multiple online databases were systematically searched and screened for inclusion. Eight articles were identified for inclusion. Data on mean electromyography (EMG) activation of both quadriceps and hamstring muscles, % maximal voluntary isometric contraction (MVIC), and H:Q co-activation ratios were extracted from the studies. Quality assessment was performed on all included studies. RESULTS: Exercises analyzed in the studies included variations of the double leg squat, variations of the single leg squat, lateral step-up, Fitter, Stairmaster® (Core Health and Fitness, Vancouver, WA), and slide board. All exercises, except the squat machine with posterior support at the level of the scapula and feet placed 50 cm in front of the hips, produced higher quadriceps muscle activation compared to hamstring muscle activation. CONCLUSION: Overall, two leg squats demonstrate poor H:Q co-activation ratios. Single leg exercises, when performed between 30 and 90 degrees of knee flexion, produce adequate H:Q ratios, thereby potentially reducing the risk of tensile stress on the ACL and ACL injury. LEVEL OF EVIDENCE: 2a- Systematic Review of Cohort Studies.

Supraphysiologic levels of the AML1-ETO isoform AE9a are essential for transformation.

Chromosomal translocation 8;21 is found in 40% of the FAB M2 subtype of acute myeloid leukemia (AML). The resultant in-frame fusion protein AML1-ETO (AE) acts as an initiating oncogene for leukemia development. AE immortalizes human CD34(+) cord blood cells in long-term culture. We assessed the transforming properties of the alternatively spliced AE isoform AE9a (or alternative splicing at exon 9), which is fully transforming in a murine retroviral model, in human cord blood cells. Full activity was realized only upon increased fusion protein expression. This effect was recapitulated in the AE9a murine AML model. Cotransduction of AE and AE9a resulted in a strong selective pressure for AE-expressing cells. In the context of AE, AE9a did not show selection for increased expression, affirming observations of human t(8;21) patient samples where full-length AE is the dominant protein detected. Mechanistically, AE9a showed defective transcriptional regulation of AE target genes that was partially corrected at high expression. Together, these results bring an additional perspective to our understanding of AE function and highlight the contribution of oncogene expression level in t(8;21) experimental models.

Usefulness of Cardiac Rehabilitation After Spontaneous Coronary Artery Dissection.

Spontaneous coronary artery dissection (SCAD) is an increasingly recognized cause of myocardial infarction; however, the role of cardiac rehabilitation (CR) for patients with SCAD has not been well defined. To further understand CR in patients with SCAD, we studied a large cohort of patients with confirmed SCAD enrolled in the Mayo Clinic SCAD Registry from January 2010 to December 2014 (n = 354). Demographics, clinical characteristics, mental health status, and details about CR participation and experience were collected through medical record review and questionnaires. Participants at time of SCAD were 46 ± 10 years old; 96% were women. Most (76%) attended ≥1 CR sessions, averaging 18 ± 12 sessions. Most reported CR-related physical and emotional benefits (82% and 75%, respectively). Of the CR nonparticipants, 57 of 85 reported not participating because CR was not recommended by their health care provider. Other reasons included inadequate transportation (10 of 85), no insurance coverage (7 of 85), cost (2 of 85), no energy (2 of 85), being too ill (2 of 85), and miscellaneous comments (5 of 85). In conclusion, 3 of 4 of patients with SCAD participated in CR, most of whom reported benefit. Lack of recommendation for CR by a health care provider was the primary reason patients did not participate.

Multiple Family Groups to reduce child disruptive behavior difficulties: moderating effects of child welfare status on child outcomes.

Children who remain at home with their permanent caregivers following a child welfare (CW) involvement (e.g., investigation, out-of-home placement) manifest high rates of behavioral difficulties, which is a risk factor for further maltreatment and out-of-home placement if not treated effectively. A recently tested Multiple Family Group (MFG) service delivery model to treat youth Disruptive Behavior Disorders (DBDs) has demonstrated effectiveness in improving child behavior difficulties among hard-to-engage, socioeconomically disadvantaged families by addressing parenting skills, parent-child relationships, family communication and organization, social support, and stress. This exploratory study examines whether child behavioral outcomes for MFG differ for families with self-reported lifetime involvement in CW services compared to other families, as families with CW involvement struggle with additional stressors that can diminish treatment success. Youth (aged 7-11) and their families were assigned to MFG or services as usual (SAU) using a block comparison design. Caregivers reported on child behavior, social skills, and functional impairment. Mixed effects regression modeled multilevel outcomes across 4 assessment points (i.e., baseline, mid-test, post-test, 6-month follow-up). Among CW-involved families, MFG participants reported significantly reduced child oppositional defiant disorder symptoms at 6-month follow-up compared with SAU participants. No other differences were found in the effect of MFG treatment between CW and non-CW involved families. Findings suggest that MFG may be as effective in reducing child behavior difficulties for both CW and non-CW involved families. As a short-term, engaging, and efficient intervention, MFG may be a particularly salient service offering for families involved in the CW system.

Antigenic Stimulation of Kv1.3-Deficient Th Cells Gives Rise to a Population of Foxp3-Independent T Cells with Suppressive Properties.

Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the CNS that has been linked with defects in regulatory T cell function. Therefore, strategies to selectively target pathogenic cells via enhanced regulatory T cell activity may provide therapeutic benefit. Kv1.3 is a voltage-gated potassium channel expressed on myelin-reactive T cells from MS patients. Kv1.3-knockout (KO) mice are protected from experimental autoimmune encephalomyelitis, an animal model of MS, and Kv1.3-KO Th cells display suppressive capacity associated with increased IL-10. In this article, we demonstrate that myelin oligodendrocyte glycoprotein-specific Kv1.3-KO Th cells exhibit a unique regulatory phenotype characterized by high CD25, CTLA4, pSTAT5, FoxO1, and GATA1 expression without a corresponding increase in Foxp3. These phenotypic changes result from increased signaling through IL-2R. Moreover, myelin oligodendrocyte glycoprotein-specific Kv1.3-KO Th cells can ameliorate experimental autoimmune encephalomyelitis following transfer to wild-type recipients in a manner that is partially dependent on IL-2R and STAT5 signaling. The present study identifies a population of Foxp3(-) T cells with suppressive properties that arises in the absence of Kv1.3 and enhances the understanding of the molecular mechanism by which these cells are generated. This increased understanding could contribute to the development of novel therapies for MS patients that promote heightened immune regulation.

Observed parent-child relationship quality predicts antibody response to vaccination in children.

BACKGROUND: Quality of the parent-child relationship is a robust predictor of behavioral and emotional health for children and adolescents; the application to physical health is less clear. METHODS: We investigated the links between observed parent-child relationship quality in an interaction task and antibody response to meningococcal conjugate vaccine in a longitudinal study of 164 ambulatory 10-11 year-old children; additional analyses examine associations with cortisol reactivity, BMI, and somatic illness. RESULTS: Observed Negative/Conflict behavior in the interaction task predicted a less robust antibody response to meningococcal serotype C vaccine in the child over a 6 month-period, after controlling for socio-economic and other covariates. Observer rated interaction conflict also predicted increased cortisol reactivity following the interaction task and higher BMI, but these factors did not account for the link between relationship quality and antibody response. CONCLUSIONS: The results begin to document the degree to which a major source of child stress exposure, parent-child relationship conflict, is associated with altered immune system development in children, and may constitute an important public health consideration.

Aryl Hydrocarbon Receptor Interacting Protein Targets IRF7 to Suppress Antiviral Signaling and the Induction of Type I Interferon.

The transcription factor IRF7 (interferon regulatory factor 7) is a key regulator of type I interferon and plays essential roles in restricting virus infection and spread. IRF7 activation is tightly regulated to prevent excessive inflammation and autoimmunity; however, how IRF7 is suppressed by negative regulators remains poorly understood. Here, we have identified AIP (aryl hydrocarbon receptor interacting protein) as a new binding partner of IRF7. The interaction between AIP and IRF7 is enhanced upon virus infection, and AIP potently inhibits IRF7-induced type I IFN (IFNα/ß) production. Overexpression of AIP blocks virus-induced activation of IFN, whereas knockdown of AIP by siRNA potentiates virally activated IFN production. Consistently, AIP-deficient murine embryonic fibroblasts are highly resistant to virus infection because of increased production of IFNα/ß. AIP inhibits IRF7 function by antagonizing the nuclear localization of IRF7. Together, our study identifies AIP as a novel inhibitor of IRF7 and a negative regulator of innate antiviral signaling.

Cardiac rehabilitation after spontaneous coronary artery dissection.

PURPOSE: Although cardiac rehabilitation (CR) improves outcomes in patients after atherosclerotic myocardial infarctions, little is known of the CR benefit among patients with spontaneous coronary artery dissection (SCAD), who are primarily young, otherwise healthy women. The purpose of this study was to describe SCAD patient outcomes in phase 2 outpatient CR. METHODS: Patients with SCAD who enrolled in CR were retrospectively identified. Patients participated in standard CR, which included supervised and independent flexibility, stretching, aerobic, and strength training exercises. Patients received counseling regarding nutrition, weight and stress management. Assessments at baseline and program completion included cardiopulmonary exercise testing or 6-Minute Walk Test, body composition using plethysmography, depression (Patient Health Questionnaire-9), and stress (a scale of 1-10) scores. RESULTS: Nine patients, all women, enrolled in CR an average of 12.3 days (range, 7-21 days) after their SCAD event, with one enrolling again after a recurrence. Cardiac rehabilitation was well received, with participants completing an average of 28 CR sessions (range, 5-39 sessions). Patients did not report cardiac symptoms and there were no adverse events during exercise testing or training. Peak oxygen uptake increased by an average of 18% (n = 4) and 6-minute walk distance increased 22% (n = 4). Average body mass decreased 1.1 kg, fat mass decreased 1.6 kg, and lean mass increased 0.4 kg. Depression and stress scores improved by an average of 2.3 and 1.3 points, respectively. CONCLUSIONS: Standard CR beginning 1 to 2 weeks after SCAD seems to be feasible and safe and results in improved aerobic capacity, body composition, and measures of depression and stress. Because of these benefits, we recommend that patients with SCAD participate in CR.

Depressive symptoms and immune response to meningococcal conjugate vaccine in early adolescence.

Research findings in psychoneuroimmunology document reliable, bidirectional linkages among psychological processes, the nervous system, and the immune system. However, available data are based almost entirely on animal and adult human studies; the application to children and adolescents is uncertain. We capitalized on the experimental leverage provided by a routine vaccination to examine the link between mood symptoms and the immune response to a vaccine challenge in early adolescence. One hundred twenty-six 11-year-olds for whom vaccine response data were available were assessed at prevaccination and 4 weeks, 3 months, and 6 months following vaccination; self-report ratings of depression and anxiety as well as measures of psychosocial and somatic risk were assessed prior to vaccine response. Analyses indicated that children's internalizing mood symptoms were associated with elevated and persistently higher antibody responses, with evidence extending to two of the four serogroups. The associations remained after controlling for multiple possible confounders (social class, body mass index, sleep, psychosocial risk, and pubertal status). The observed enhanced vaccine response associated with depressive and anxious symptoms in early adolescence may reflect an important developmental difference in immune system-brain interplay between adults and children, and it underscores the need for further developmental studies of psychoneuroimmunology.

Genetic engineering of Nicotiana tabacum for reduced nornicotine content.

UNLABELLED: Nornicotine is an undesirable secondary alkaloid in cultivated tobacco, because it serves as a precursor to N'-nitrosonornicotine (NNN), a tobacco-specific nitrosamine with suspected carcinogenic properties. Nornicotine is produced through the oxidative N-demethylation of nicotine by a nicotine N-demethylase enzyme during the senescence and curing of tobacco leaves. While the nornicotine content of most commercial burley tobacco is low, a process termed "conversion" can bestow considerably increased nornicotine levels in a portion of the plants within the population. Previously, we isolated a nicotine N-demethylase gene, designated CYP82E4, and demonstrated that RNAi-induced silencing of CYP82E4 and its close homologues is an effective means for suppressing nicotine to nornicotine conversion. In this study, we used real-time polymerase chain reaction to confirm the central role of CYP82E4 in nicotine N-demethylation by demonstrating that the transcript accumulation of CYP82E4 is enhanced as much as 80-fold in converter vs nonconverter tobacco. We also show the design of an optimized RNAi construct (82E4Ri298) that suppressed nicotine to nornicotine conversion from 98% to as low as 0.8% in a strong converter tobacco line, a rate of nornicotine production that is about 3.6-fold lower than typically detected in commercial varieties. Southern blot analysis showed that a single copy of the RNAi transgene was as effective in suppressing nornicotine accumulation as multiple copies. Greenhouse-grown transgenic plants transformed with the RNAi construct were morphologically indistinguishable from the empty vector or wild-type controls. These results demonstrate that the genetic transformation of tobacco with the 82E4Ri298 construct is an effective strategy for reducing nornicotine and ultimately NNN levels in tobacco. KEYWORDS: Alkaloid; cytochrome P450; gene silencing; nicotine N-demethylase; N'-nitrosonornicotine; plant genetic engineering; metabolic engineering; Nicotiana tabacum L.; real-time PCR; RNA interference; tobacco-specific nitrosamines.

Tumor-derived p53 mutants induce NF-kappaB2 gene expression.

Overexpression of mutant p53 is a common theme in tumors, suggesting a selective pressure for p53 mutation in cancer development and progression. To determine how mutant p53 expression may lead to survival advantage in human cancer cells, we generated stable cell lines expressing p53 mutants p53-R175H, -R273H, and -D281G by use of p53-null human H1299 (lung carcinoma) cells. Compared to vector-transfected cells, H1299 cells expressing mutant p53 showed a survival advantage when treated with etoposide, a common chemotherapeutic agent; however, cells expressing the transactivation-deficient triple mutant p53-D281G (L22Q/W23S) had significantly lower resistance to etoposide. Gene expression profiling of cells expressing transcriptionally active mutant p53 proteins revealed the striking pattern that all three p53 mutants induced expression of approximately 100 genes involved in cell growth, survival, and adhesion. The gene NF-kappaB2 is a prominent member of this group, whose overexpression in H1299 cells also leads to chemoresistance. Treatment of H1299 cells expressing p53-R175H with small interfering RNA specific for NF-kappaB2 made these cells more sensitive to etoposide. We have also observed activation of the NF-kappaB2 pathway in mutant p53-expressing cells. Thus, one possible pathway through which mutants of p53 may induce loss of drug sensitivity is via the NF-kappaB2 pathway.

Epistatic and environmental control of genome-wide gene expression.

All etiological studies of complex human traits focus on analyzing the causes of variation. Given this complexity, there is a premium on studying those processes that mediate between gene products and cellular or organismal phenotypes. Studies of levels of gene expression could offer insight into these processes and are likely to be especially useful to the extent that the major sources of their variation are known in normal tissues. The classical study of monozygotic (MZ) and dizygotic (DZ) twins was employed to partition the genetic and environmental influences in gene expression for over 6500 human genes measured using microarrays from lymphoblastoid cell lines. Our results indicate that mean expression levels are correlated about .3 in monozygotic (MZ) and .0 in dizygotic (DZ) twins suggesting an overall epistatic regulation of gene expression. Furthermore, the functions of several of the genes whose expression was most affected by environmental effects, after correction for measurement error, were consistent with their known role in mediating sensitivity to environmental influences.

Modulation of gene expression by tumor-derived p53 mutants.

p53 mutants with a single amino acid substitution are overexpressed in a majority of human cancers containing a p53 mutation. Overexpression of the mutant protein suggests that there is a selection pressure on the cell indicative of an active functional role for mutant p53. Indeed, H1299 cells expressing mutant p53-R175H, p53-R273H or p53-D281G grow at a faster rate compared with a control cell line. Using p53-specific small interfering RNA, we show that the growth rate of mutant p53-expressing cells decreases as mutant p53 level decreases, demonstrating that the increased cellular growth is dependent on p53 expression. Increased growth rate is not observed for H1299 cell clones expressing mutant p53-D281G (L22Q/W23S), which has been shown to be defective in transactivation in transient transcriptional assays. This shows that the increased growth rate imparted by mutant p53 in H1299 cells requires the transactivation function of mutant p53. By performing microarray hybridization analyses, we show that constitutive expression of three common p53 mutants (p53-R175H, p53-R273H, and p53-D281G) in H1299 human lung carcinoma cells evokes regulation of a common set of genes, a significant number of which are involved in cell growth regulation. Predictably, H1299 cells expressing p53-D281G (L22Q/W23S) are defective in up-regulating a number of these genes. The differences in expression profiles induced by individual p53 mutants in the cells may be representative of the p53 mutants and how they can affect gene expression resulting in the observed "gain of function" phenotypes (i.e., increased growth rate, decreased sensitivity to chemotherapeutic agents, and so forth).