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Assessment of Functional Status of Human Leukocyte Antigen Class I Genes in Cancer Tissues in the Context of Personalized Neoantigen Peptide Vaccine Immunotherapy.
No full textPURPOSE: Accurate human leukocyte antigen (HLA) typing is an essential step for designing peptide vaccines used in the personalized neoantigen peptide vaccine immunotherapy (PNPVT) in patients with cancer. The reasons for variation in the patient response to PNPVT are yet unknown. One of the reasons could be the somatic changes in the HLA genes in the cancer cells. The objective of the present research was to analyze the somatic status of HLA class I genes in cancer tissue through integrative genomic analysis and to identify high-confidence subset of potentially functional cancer somatic HLA class I genotype relevant to PNPVT.
PATIENTS AND METHODS: Whole-exome (paired tumor-normal) and RNAseq (tumor) paired-end sequencing data from 24 patients with cancer were used for the analysis. The genotyping of HLA class I was performed using four HLA typing software tools. To assess the functional status of HLA class I genes in the cancer tissue, we analyzed somatic mutation, HLA gene loss of heterozygosity, and chromosome 6 copy loss status in cancer exome data.
RESULTS: Somatic mutations in HLA genes were detected in the tumor data of five patients, and somatic HLA gene loss of heterozygosity was identified in the tumor data of five patients. Complete or partial chromosome 6 copy loss was detected in eight patient samples.
CONCLUSION: The results indicate that HLA class I genes may get affected by somatic changes in cancer tissue, and assessment of the somatic status of the HLA genotype should be performed in the cancer tissues. The results provide robust rational for removal of mutated or lost HLAs from the personalized neoantigen peptide prediction pipeline to potentially increase the efficacy of the PNPVT. Further functional studies are needed to assess the impact of HLA gene mutations/loss on PNPVT outcomes
Nurse Leaders\u27 Well-being and Resilience: Influence of Professional and Demographic Factors.
No full textOBJECTIVE: To examine the impact of demographic and professional factors on the well-being and resilience of nurse leaders in US acute care settings.
BACKGROUND: Well-being and resilience are critical attributes for nurse leaders, directly impacting the quality of patient care and the overall performance of healthcare systems. However, research on factors influencing these traits in acute care is limited.
METHODS: Data were collected from 157 nurse leaders through an online survey assessing demographics, professional characteristics, well-being, and resilience. Data were analyzed using descriptive and inferential statistics.
RESULTS: Resilience scores varied significantly higher among Black/African American. Age positively correlated with well-being. Females reported higher well-being. Educational attainment and acuity setting were significantly associated with outcomes: associate\u27s/diplomas with higher well-being and high acuity settings with greater resilience.
CONCLUSIONS: Demographic and professional factors significantly affect nurse leaders\u27 well-being and resilience. Targeted interventions are needed to support nurse leaders in acute care settings
A multivariate cell-based liquid biopsy for lung nodule risk stratification: Analytical validation and early clinical evaluation.
No full textBACKGROUND: The Indicator Cell Assay Platform (iCAP) is a novel tool for blood-based diagnostics that uses living cells as biosensors to integrate and amplify weak, multivalent disease signals present in patient serum. In the platform, standardized cells are exposed to small volumes of patient serum, and the resulting transcriptomic response is analyzed using machine learning tools to develop disease classifiers.
METHODS: We developed a lung cancer-specific iCAP (LC-iCAP) as a rule-out test for the management of indeterminate pulmonary nodules detected by low-dose CT screening. This included assay parameterization, analytical reproducibility testing, and selection of a fixed 85-gene feature set for future clinical validation and regulatory development. Clinical performance was estimated using a prospective-specimen-collection, retrospective-blinded-evaluation (PRoBE) study design comprising 176 samples. Classifier variants were trained by nested cross validation using subsets of the 85 genes, and selected variants were evaluated by temporal blind validation using 39 control and 40 case samples (72 % Stage I, 22 % Stage II cancer).
RESULTS: The assay showed excellent reproducibility across various conditions and cell lineages, and case versus control transcriptomic signals were enriched for hypoxia-responsive genes, consistent with known lung cancer biology. Two models demonstrated discriminative ability in blind validation, one with AUC = 0.64 (95 % CI: 0.51-0.76). Post hoc integration with CT imaging features yielded a combined model with 90 % sensitivity, 64 % specificity, and 95 % negative predictive value at 25 % prevalence, suggesting clinical utility and surpassing performance of existing rule-out tests.
CONCLUSION: This study establishes the analytical reproducibility and biological relevance of the LC-iCAP. While clinical validation is preliminary, the results support the assay\u27s potential utility in lung nodule management. The study introduces a new paradigm of using scalable and cost-effective cell-based biosensor assays for liquid biopsies. With a multivariate readout, the platform is amenable to precision medicine applications such as multi-cancer early detection
Financial Resilience: A Guide to Rebuild Staffing Systems.
No full textMounting financial pressures continue to challenge health care institutions. Nurse executives with responsibility for efficient nursing resources must ensure the integrity of their staffing systems. Are your systems accurate? Are they connected with each other and the budget? Do all nurse managers have a strong grasp of the staffing systems? This article provides a guide for you to connect and improve staffing processes and tools. In this way, nurse executives ensure operational excellence and financial resilience
Outcomes of patients supported on Impella 5.5 for more than 14 days: A Cardiogenic Shock Working Group registry analysis.
No full textBACKGROUND: The Impella 5.5 (ABIOMED, Danvers, MA) is a micro-axial pump that is currently approved for up to 14 days of support in the United States. However, in clinical practice it is being used for longer durations of time, especially as a bridge to heart replacement therapies (HRT). We aimed to define patient characteristics and outcomes (mortality and serious adverse events/SAE) in patients supported on Impella 5.5 for \u3e14 days in a large, multi-center registry.
METHODS: The Cardiogenic Shock Working Group (CSWG) registry enrolling consecutive patients in heart failure (HF) or myocardial infarction related CS (MI-CS) from 34 international sites between 2022 and 2024 was analyzed. Patients supported with Impella 5.5 \u3e14 days were compared to those supported for ≤14 days for baseline characteristics. In-hospital outcomes were further classified as \u27\u27favorable\u27\u27 (heart recovery, successful bridge to HRT and discharged alive) or \u27\u27unfavorable\u27\u27 (death, need for escalation to veno-arterial extracorporeal membrane oxygenation [VA-ECMO]). Predictors of favorable outcomes were assessed using uni- and multi-variable analysis.
RESULTS: A total of 927 patients were supported on Impella 5.5 of whom 381 had the device for \u3e14 days. Median time of support in the 2 groups (\u3e or ≤14 days) was 23.9 [21.2] and 7.1 [IQR 5.7] days, respectively. Patients with Impella 5.5 \u3e14 days were younger (mean age 57 vs 61 years, p \u3c 0.001), more likely to have HF-CS vs MI-CS (78% vs 61%; p \u3c 0.001) and have a dilated left ventricle (left ventricular end diastolic dimension [LVEDD] 6.4 vs 5.9 cm, p = 0.002) and chronic kidney disease (38% vs 30%, p = 0.03) as compared to those supported ≤14 days. Baseline Society for Cardiovascular Angiography and Interventions (SCAI) stage, lactate, and vital signs were not significantly different. Unadjusted survival was higher (80% vs 68%, p \u3c 0.001) in those supported for \u3e14 days, with a significantly higher HRT for those supported for \u3e14 days, compared to the ≤14 days cohort (58% vs 38%, p \u3c 0.001). Less than a fourth (19.1%) had an SAE, with highest rates seen in MI-CS supported for ≤14 days. The majority (75%) of patients on support for \u3e14 days had favorable outcomes with no linear increments in rates of SAE with prolonged duration of support.
CONCLUSION: Patients supported with Impella 5.5 beyond the Food and Drug Administration (FDA) approved duration of 14 days had high rates of favorable outcomes, especially as bridge to HRT. Use of Impella 5.5 for longer durations needs to be further investigated in prospective studies
Addition of ADAMTS13 Testing to Cryptogenic Stroke Evaluation: Index Case and Single-Center Screening Initial Experience.
No full textEngineering noncovalent π-stacked organic framework for intrinsic near-infrared photoactivated drug delivery.
No full textPhotoactivated drug delivery is a promising therapeutic strategy that enables spatial and temporal control of payload release. A critical component of this approach is the photoresponsive material that has sufficient drug-loading capacity and can be actuated by near-infrared (NIR) light with considerable penetration depths. Here, we establish a photoactivated drug delivery platform based on the π-stacked organic framework (πOF), which demonstrates an intrinsic NIR absorption and superior photothermal effect. πOF not only has considerable loading capacity for a variety of drugs but also prompts the inducible burst release of loaded cargoes under NIR irradiation with notable increase of the release rate. Based on these features, πOF is used to effectively modulate the delivery of resiquimod (R848) and simultaneously induce photothermal effect by NIR irradiation. In 4T1-bearing mouse models, the photoactivated release of R848 can significantly potentiate treatment efficacy
Aligning Competency Committee and Observing Faculty Needs in Pursuit of Useful Written Evaluations of Residents.
No full textOBJECTIVES: End-of-rotation narrative evaluations by faculty of Internal Medicine residents provide feedback to residents directly and to the program leadership to assess resident competency; however, observing faculty often lack an understanding of what information is useful to the program leadership. Faculty also face barriers in completing evaluations and formulating high-quality evaluations. We sought to qualitatively evaluate the interplay of the needs of the program leadership and barriers faculty face in providing high-quality evaluations.
METHODS: We conducted a descriptive qualitative study through semistructured interviews with six faculty with program leadership positions and six observing clinical faculty at a single large Internal Medicine residency program.
RESULTS: Interview themes elucidated a multifaceted process that observing faculty must navigate in writing narrative evaluations and the important features of a useful narrative evaluation itself. Faculty must navigate assessment committee needs and their own competing priorities and be skilled in observing residents and navigating emotional barriers with residents. Successfully navigating these factors allows them to produce useful narrative evaluations that ultimately inform assessment committee decisions.
CONCLUSIONS: Understanding the complex dynamics of observing faculty factors and assessment committee needs can help guide future interventions to improve the quality and utility of written evaluations in assessing residents
Mitochondrial complex I deficiency induces Alzheimer\u27s disease-like signatures that are reversible by targeted therapy.
No full textIntroduction: Mitochondrial dysfunction is implicated in Alzheimer\u27s disease (AD), but whether it drives AD-associated changes is unclear. We assessed transcriptomic alterations in the brains of Ndufs4-/- mice, a model of mitochondrial complex I (mtCI) deficiency, and evaluated the therapeutic effects of the neuroprotective mtCI inhibitor CP2.
Methods: Cortico-hippocampal tissue from Ndufs4-/- and wild-type mice was subjected to transcriptomic analysis, followed by cross-species comparisons to human late-onset AD and familial AD mouse datasets.
Results: Knockout of Ndufs4-mediated mtCI deficiency disrupted mitochondrial homeostasis, energy metabolism, and synaptic gene expression, recapitulating transcriptomic signatures of AD. CP2 treatment partially reversed these changes, with female Ndufs4-/- mice showing greater compensatory adaptations and treatment responses.
Discussion: Loss of mtCI activity alone is sufficient to induce AD-like molecular changes in the brain, independent of amyloid beta or phosphorylated tau. CP2-mediated rescue highlights the potential of targeting mitochondria as a therapeutic strategy for AD. Sex-specific responses suggest important considerations for personalized therapeutics.
Highlights: Activity of mitochondrial complex I (mtCI) affects broad mitochondrial and neuronal transcriptional networks. A reduction of mtCI activity is sufficient to induce transcriptomic changes reminiscent of those observed in late-onset Alsheimer\u27s disease (AD) patients and familial mouse models of AD. Pharmacological targeting of mtCI mediates neuroprotective signaling. Male and female mice have differential responses to the loss of mtCI activity and to the mitochondria-targeted therapeutics. Mitochondria play a key role in AD development and treatment.
Keywords: Alzheimer\u27s disease; Ndufs4 knockout mice; biological domains; mitochondrial complex I; mitochondria‐targeted therapeutics; mitophagy; sex‐specific differences; sex‐specific response; transcriptomic analysis; ubiquitin; weak complex I inhibitors