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The quality of care provided to nursing home residents has been the subject of broad criticism for years. Mounting evidence suggests that the quality of nursing home care can be improved by strengthening the roles of nurses in these facilities. This article reviews the literature on programs designed to enhance nursing leadership in long-term care, examines outcomes associated with leadership in long-term care, and outlines recommendations for programs to enhance nursing leadership in nursing home settings. The findings suggest that nursing leadership training programs for nurses working in nursing homes are urgently needed to improve quality in the nation's nursing homes and stabilize the workforce. To maximize their effectiveness, these leadership training programs should be part of a continuum of leadership development that begins in nursing education programs and persists throughout a nurse's career trajectory. [ABSTRACT FROM AUTHOR]

Clinical faculty often struggle to design competency demonstrations that promote quality learning experiences. A nursing program in Oregon combined mental health and community health nursing practica and required well-planned, integrated competency demonstrations. This requirement became the impetus for students to promote the health of clients and learn clinical concepts that are difficult to experience in a typical term. Faculty coached students to make a significant contribution that would last beyond their clinical practica. A case study in competency demonstration design is described, and implications for curriculum development are presented. [ABSTRACT FROM AUTHOR]

Hematopoietic stem cell gene therapy (GT) using a γ-retroviral vector (γ-RV) is an effective treatment for Severe Combined Immunodeficiency due to Adenosine Deaminase deficiency. Here, we describe a case of GT-related T-cell acute lymphoblastic leukemia (T-ALL) that developed 4.7 years after treatment. The patient underwent chemotherapy and haploidentical transplantation and is currently in remission. Blast cells contain a single vector insertion activating the LIM-only protein 2 (LMO2) proto-oncogene, confirmed by physical interaction, and low Adenosine Deaminase (ADA) activity resulting from methylation of viral promoter. The insertion is detected years before T-ALL in multiple lineages, suggesting that further hits occurred in a thymic progenitor. Blast cells contain known and novel somatic mutations as well as germline mutations which may have contributed to transformation. Before T-ALL onset, the insertion profile is similar to those of other ADA-deficient patients. The limited incidence of vector-related adverse events in ADA-deficiency compared to other γ-RV GT trials could be explained by differences in transgenes, background disease and patient's specific factors., (© 2024. The Author(s).)

Within the chromatin, distal elements interact with promoters to regulate specific transcriptional programs. Histone acetylation, interfering with the net charges of the nucleosomes, is a key player in this regulation. Here, we report that the oncoprotein SET is a critical determinant for the levels of histone acetylation within enhancers. We disclose that a condition in which SET is accumulated, the severe Schinzel-Giedion Syndrome (SGS), is characterized by a failure in the usage of the distal regulatory regions typically employed during fate commitment. This is accompanied by the usage of alternative enhancers leading to a massive rewiring of the distal control of the gene transcription. This represents a (mal)adaptive mechanism that, on one side, allows to achieve a certain degree of differentiation, while on the other affects the fine and corrected maturation of the cells. Thus, we propose the differential in cis-regulation as a contributing factor to the pathological basis of SGS and possibly other the SET-related disorders in humans., (© 2023. The Author(s).)

Acute myeloid leukemia may be characterized by a fraction of leukemia stem cells (LSCs) that sustain disease propagation eventually leading to relapse. Yet, the contribution of LSCs to early therapy resistance and AML regeneration remains controversial. We prospectively identify LSCs in AML patients and xenografts by single-cell RNA sequencing coupled with functional validation by a microRNA-126 reporter enriching for LSCs. Through nucleophosmin 1 (NPM1) mutation calling or chromosomal monosomy detection in single-cell transcriptomes, we discriminate LSCs from regenerating hematopoiesis, and assess their longitudinal response to chemotherapy. Chemotherapy induced a generalized inflammatory and senescence-associated response. Moreover, we observe heterogeneity within progenitor AML cells, some of which proliferate and differentiate with expression of oxidative-phosphorylation (OxPhos) signatures, while others are OxPhos (low) miR-126 (high) and display enforced stemness and quiescence features. miR-126 (high) LSCs are enriched at diagnosis in chemotherapy-refractory AML and at relapse, and their transcriptional signature robustly stratifies patients for survival in large AML cohorts., (© 2023. The Author(s).)

Despite the unequivocal success of hematopoietic stem and progenitor cell gene therapy, limitations still exist including genotoxicity and variegation/silencing of transgene expression. A class of DNA regulatory elements known as chromatin insulators (CIs) can mitigate both vector transcriptional silencing (barrier CIs) and vector-induced genotoxicity (enhancer-blocking CIs) and have been proposed as genetic modulators to minimize unwanted vector/genome interactions. Recently, a number of human, small-sized, and compact CIs bearing strong enhancer-blocking activity were identified. To ultimately uncover an ideal CI with a dual, enhancer-blocking and barrier activity, we interrogated these elements in vitro and in vivo . After initial screening of a series of these enhancer-blocking insulators for potential barrier activity, we identified three distinct categories with no, partial, or full protection against transgene silencing. Subsequently, the two CIs with full barrier activity (B4 and C1) were tested for their ability to protect against position effects in primary cells, after incorporation into lentiviral vectors (LVs) and transduction of human CD34 + cells. B4 and C1 did not adversely affect vector titers due to their small size, while they performed as strong barrier insulators in CD34 + cells, both in vitro and in vivo , shielding transgene's long-term expression, more robustly when placed in the forward orientation. Overall, the incorporation of these dual-functioning elements into therapeutic viral vectors will potentially provide a new generation of safer and more efficient LVs for all hematopoietic stem cell gene therapy applications.

We investigated the efficacy of liver-directed gene therapy using lentiviral vectors in a large animal model of hemophilia B and evaluated the risk of insertional mutagenesis in tumor-prone mouse models. We showed that gene therapy using lentiviral vectors targeting the expression of a canine factor IX transgene in hepatocytes was well tolerated and provided a stable long-term production of coagulation factor IX in dogs with hemophilia B. By exploiting three different mouse models designed to amplify the consequences of insertional mutagenesis, we showed that no genotoxicity was detected with these lentiviral vectors. Our findings suggest that lentiviral vectors may be an attractive candidate for gene therapy targeted to the liver and may be potentially useful for the treatment of hemophilia., (Copyright © 2015, American Association for the Advancement of Science.)

Self-inactivating (SIN) lentiviral vectors (LV) have an excellent therapeutic potential as demonstrated in preclinical studies and clinical trials. However, weaker mechanisms of insertional mutagenesis could still pose a significant risk in clinical applications. Taking advantage of novel in vivo genotoxicity assays, we tested a battery of LV constructs, including some with clinically relevant designs, and found that oncogene activation by promoter insertion is the most powerful mechanism of early vector-induced oncogenesis. SIN LVs disabled in their capacity to activate oncogenes by promoter insertion were less genotoxic and induced tumors by enhancer-mediated activation of oncogenes with efficiency that was proportional to the strength of the promoter used. On the other hand, when enhancer activity was reduced by using moderate promoters, oncogenesis by inactivation of tumor suppressor gene was revealed. This mechanism becomes predominant when the enhancer activity of the internal promoter is shielded by the presence of a synthetic chromatin insulator cassette. Our data provide both mechanistic insights and quantitative readouts of vector-mediated genotoxicity, allowing a relative ranking of different vectors according to these features, and inform current and future choices of vector design with increasing biosafety.

Clinical faculty often struggle to design competency demonstrations that promote quality learning experiences. A nursing program in Oregon combined mental health and community health nursing practica and required well-planned, integrated competency demonstrations. This requirement became the impetus for students to promote the health of clients and learn clinical concepts that are difficult to experience in a typical term. Faculty coached students to make a significant contribution that would last beyond their clinical practica. A case study in competency demonstration design is described, and implications for curriculum development are presented.

A new type of agents are proposed for combined cancer therapy. They are organocobalt (III) chelates containing a sigma-bounded organyl group and a mixed tridentate ligand derived from a Schiff base. These complexes generate free radicals due to the action of protons in physiological ranges of pH and temperature, and hence are conceivably capable of selectively attacking a malignant neoplasm that is slightly acidic and can be made even more so by introducing some means intensifying glycolysis. An in vivo examination was performed using transplanted rat tumours (Guerin and Walker 256 carcinomas, Sarcoma 45). The modifying effect of one of these complexes on the tumour response to cis-DDP, radiation and/or local hyperthermia was tested by means of tumour growth delay assay and local tumour control. The potentiating effect of the complex was maximal when it was administered 60-90 minutes prior to other agents (cisDDP, X-irradiation heat). The enhancement ratio was found to be ca. 2.0-4.0 for cisDDP and 2.0 for radiation. In conclusion, in our tumour models, an increase of the antitumour effect was obtained for conventional antitumour agents when they were supplemented with organocobalt complex. It can be hypothesised that DNA in tumour cells may be considered to be the main target for organocobalt complexes.