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1.
J Nurs Educ ; 63(6): 394-398, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38900266

ABSTRACT

BACKGROUND: The mental health of students and faculty has become a growing issue in academia. Faculty need to provide role-modeling early in nursing programs to enhance psychological well-being for future nurses that will have lasting effects throughout their careers. METHOD: A total of 29 faculty members participated in a descriptive study investigating types of self-care goals and how they could be achieved by College of Nursing faculty during their annual performance appraisal. RESULTS: Seventy-three percent of respondents reported they anticipated that achieving these self-care goals would enhance their faculty role. Further, the respondents associated achievement of self-care goals as a way to improve their faculty performance. CONCLUSION: Since every individual has a unique perspective of the world, a self-care approach that works for one person might not work for another. Self-care goals should therefore be tailored to the unique needs and perspectives of each person. [J Nurs Educ. 2024;63(6):394-398.].


Subject(s)
Faculty, Nursing , Self Care , Humans , Faculty, Nursing/psychology , Female , Male , Adult , Middle Aged , Education, Nursing , Nursing Education Research , Students, Nursing/psychology , Students, Nursing/statistics & numerical data , Education, Nursing, Baccalaureate
2.
Nephrol Nurs J ; 51(2): 165-172, 2024.
Article in English | MEDLINE | ID: mdl-38727592

ABSTRACT

Chronic kidney disease (CKD) and depression often coexist, resulting in a complex interaction that can be detrimental to patient outcomes. This article examines the reciprocal association between CKD and depression, with a focus on the increased incidence of depression and the harmful effects of depressive symptoms among patients with CKD. Next, it investigates the role CKD plays as a risk factor for the onset and worsening of depression because symptoms of depression may interfere with the progression of CKD. In addition, it highlights the difficulties in making a suitable diagnosis between CKD progression and depression regarding overlapping symptoms. Finally, it emphasizes the impact of depression on CKD outcomes, and proposes routine screening and non-pharmacological and pharmaceutical therapies to ease this dual burden. It is critical to identify and treat depression in the context of CKD to maximize patient outcomes and promote a comprehensive treatment approach.


Subject(s)
Depression , Humans , Renal Insufficiency, Chronic/complications , Risk Factors , Kidney Failure, Chronic/complications
3.
Nephrol Nurs J ; 50(1): 49-53, 2023.
Article in English | MEDLINE | ID: mdl-36961074

ABSTRACT

Nurses are a critical part of the health care system. Yet the nursing profession continually faces shortages in all specialties. Several causes and issues of concern related to the nursing shortage in nephrology are discussed, including the prevalence of kidney disease and its increasing number of associated comorbidities, which has also heightened the urgent need for nephrology nurses. Data have shown that the lack of nephrology nurses caring for patients with kidney disease impacts patient outcomes and nephrology nurse burnout. Strategies must be implemented to manage these growing needs that affect both patient outcomes and nurse staffing. This article aims to identify methods to combat the nursing shortage, promote recruitment and retention strategies for nephrology nurses, and discuss leadership issues related to the topic.


Subject(s)
Burnout, Professional , Nephrology , Nurses , Humans , Workforce , Leadership
4.
Cell Death Dis ; 13(10): 885, 2022 10 21.
Article in English | MEDLINE | ID: mdl-36270982

ABSTRACT

Tumor necrosis factor receptor 1 (TNFR1), encoded by TNFRSF1A, is a critical transducer of inflammatory pathways, but its physiological role in human cancer is not completely understood. Here, we observed high expression of TNFR1 in many human lung squamous cell carcinoma (SCCs) samples and in spontaneous lung SCCs derived from kinase-dead Ikkα knock-in (KA/KA) mice. Knocking out Tnfrf1a in KA/KA mice blocked lung SCC formation. When injected via tail vein, KALLU+ lung SCC cells that highly expressed TNFR1/TNF, Sox2, c-Myc, Twist1, Bcl2, and UBCH10, generated dedifferentiated spindle cell carcinomas with epithelial-mesenchymal transition markers in mouse lungs. In contrast, KALLU+ cells with silenced TNFR1 and KALLU- cells that expressed low levels of TNFR1 generated well-differentiated lung SCCs and were less tumorigenic and metastatic. We identified a downstream effector of TNFR1: oncogenic UBCH10, an E2 ubiquitin-conjugating enzyme with targets including Twist1, c-Myc, and Sox2, which enhanced SCC cell dedifferentiation. Furthermore, Tg-K5.TNFR1;KA/KA mice, which expressed transgenic TNFR1 in keratin 5-positve epithelial cells, developed more poorly differentiated and metastatic lung SCCs than those found in KA/KA mice. These findings demonstrate that an overexpressed TNFR1-UBCH10 axis advances lung carcinogenesis and metastasis through a dedifferentiation mechanism. Constituents in this pathway may contribute to the development of differentiation-related therapies for lung SCC.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Carcinoma, Squamous Cell , Lung Neoplasms , Humans , Mice , Animals , I-kappa B Kinase/metabolism , Ubiquitin-Conjugating Enzymes/metabolism , Keratin-5 , Receptors, Tumor Necrosis Factor, Type I , Carcinoma, Squamous Cell/metabolism , Carcinogenesis , Lung Neoplasms/pathology , Proto-Oncogene Proteins c-bcl-2 , Lung/metabolism
5.
Nephrol Nurs J ; 49(4): 345-349, 2022.
Article in English | MEDLINE | ID: mdl-36054807

ABSTRACT

Non-medical factors can have a positive or negative effect on health outcomes and equity. These social determinants of health can play a role in patients' risk of developing kidney failure, as well as their access to kidney transplantation and long-term allograft survival. Nephrology nurses have the opportunity to identify and address negative social determinants of health factors in their patients because they are often patients' first contact in the nephrology setting. The purpose of this article is to promote nephrology nurses' and other nephrology health care providers' understanding of social determinants of health factors, and the fundamental practices for addressing them among kidney transplant candidates and kidney transplant recipients.


Subject(s)
Kidney Transplantation , Nephrology , Health Personnel , Humans , Kidney Transplantation/adverse effects , Social Determinants of Health , Transplant Recipients
7.
Proc Natl Acad Sci U S A ; 119(6)2022 02 08.
Article in English | MEDLINE | ID: mdl-35121655

ABSTRACT

The tumor microenvironment (TME) provides potential targets for cancer therapy. However, how signals originating in cancer cells affect tumor-directed immunity is largely unknown. Deletions in the CHUK locus, coding for IκB kinase α (IKKα), correlate with reduced lung adenocarcinoma (ADC) patient survival and promote KrasG12D-initiated ADC development in mice, but it is unknown how reduced IKKα expression affects the TME. Here, we report that low IKKα expression in human and mouse lung ADC cells correlates with increased monocyte-derived macrophage and regulatory T cell (Treg) scores and elevated transcription of genes coding for macrophage-recruiting and Treg-inducing cytokines (CSF1, CCL22, TNF, and IL-23A). By stimulating recruitment of monocyte-derived macrophages from the bone marrow and enforcing a TNF/TNFR2/c-Rel signaling cascade that stimulates Treg generation, these cytokines promote lung ADC progression. Depletion of TNFR2, c-Rel, or TNF in CD4+ T cells or monocyte-derived macrophages dampens Treg generation and lung tumorigenesis. Treg depletion also attenuates carcinogenesis. In conclusion, reduced cancer cell IKKα activity enhances formation of a protumorigenic TME through a pathway whose constituents may serve as therapeutic targets for KRAS-initiated lung ADC.


Subject(s)
Adenocarcinoma of Lung/immunology , Cytokines/immunology , I-kappa B Kinase/immunology , Lung Neoplasms/immunology , T-Lymphocytes, Regulatory/immunology , Tumor Microenvironment/immunology , Animals , CD4-Positive T-Lymphocytes/immunology , Cell Line, Tumor , Cell Transformation, Neoplastic/immunology , Humans , Immunosuppression Therapy/methods , Macrophages/immunology , Mice , Mice, Inbred C57BL , Monocytes/immunology , Receptors, Tumor Necrosis Factor, Type II/immunology , Signal Transduction/immunology
8.
Nephrol Nurs J ; 48(5): 489-492, 2021.
Article in English | MEDLINE | ID: mdl-34756003

ABSTRACT

Chronic kidney disease (CKD) is a national public health problem. In the United States, diabetes, hypertension, and glomerular disease are the leading causes of end stage kidney disease (ESKD). However, Blacks/African Ameri cans are four times more likely than Whites/Caucasians to develop CKD. The progression of CKD and ESKD are examples of health disparities among the races. Address ing the social determinants of health is essential in improving the overall health of Blacks/African Americans and reducing longstanding inequities in health.


Subject(s)
Kidney Failure, Chronic , Renal Insufficiency, Chronic , Black or African American , Humans , Social Determinants of Health , United States/epidemiology , White People
9.
PLoS One ; 16(6): e0252995, 2021.
Article in English | MEDLINE | ID: mdl-34170918

ABSTRACT

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (HCT) is an often curative intent treatment, however it is associated with significant gastrointestinal (GI) toxicity and treatment related mortality. Graft-versus-host disease is a significant contributor to transplant-related mortality. We performed a phase 2 trial of the somatostatin analog pasireotide to prevent gastrointestinal toxicity and GVHD after myeloablative allogeneic HCT. METHODS: Patients received 0.9mg pasireotide every 12 hours from the day prior to conditioning through day +4 after HCT (or a maximum of 14 days). The primary outcomes were grade 3-4 gastrointestinal toxicity through day 30 and acute GVHD. Secondary outcomes were chronic GVHD, overall survival and relapse free survival at one year. Stool and blood samples were collected from before and after HCT for analyses of stool microbiome, local inflammatory markers, and systemic inflammatory and metabolic markers. Results were compared with matched controls. RESULTS: Twenty-six patients received pasireotide and were compared to 52 matched contemporaneous controls using a 1-2 match. Grade 3-4 GI toxicity occurred in 21 (81%) patients who received pasireotide and 35 (67%) controls (p = 0.33). Acute GVHD occurred in 15 (58%) patients in the pasireotide group and 28 (54%) controls (p = 0.94). Chronic GVHD occurred in 16 patients in the pasireotide group (64%) versus 22 patients in the control group (42%) (p = 0.12). Overall survival at 1 year in the pasireotide group was 63% (95% CI: 47%,86%) versus 82% (95% CI: 72%, 93%) in controls (log-rank p = 0.006). Relapse-free survival rate at one year was 40% (95% CI: 25%, 65%) in the pasireotide group versus 78% (95% CI: 68%, 91%) in controls (log-rank p = 0.002). After controlling for the effect of relevant covariates, patients in the pasireotide group had attenuated post-HCT loss of microbial diversity. Analysis of systemic inflammatory markers and metabolomics demonstrated feasibility of such analyses in patients undergoing allogeneic HCT. Baseline level and pre-to-post transplant changes in several inflammatory markers (including MIP1a, MIP1b, TNFa, IL8Pro, and IL6) correlated with likelihood of survival. CONCLUSIONS: Pasireotide did not prevent gastrointestinal toxicity or acute GVHD compared to contemporaneous controls. Pasireotide was associated with numerically higher chronic GVHD and significantly decreased OS and RFS compared to contemporaneous controls. Pasireotide may provide a locally protective effect in the stool microbiome and in local inflammation as measured by stool calprotectin, stool beta-defensin, and stool diversity index.


Subject(s)
Gastrointestinal Diseases/prevention & control , Graft vs Host Disease/prevention & control , Hematologic Neoplasms/therapy , Hematopoietic Stem Cell Transplantation/methods , Somatostatin/analogs & derivatives , Adult , Combined Modality Therapy , Female , Gastrointestinal Diseases/etiology , Gastrointestinal Diseases/pathology , Graft vs Host Disease/etiology , Graft vs Host Disease/pathology , Hematologic Neoplasms/pathology , Hematopoietic Stem Cell Transplantation/adverse effects , Hormones/therapeutic use , Humans , Male , Middle Aged , Somatostatin/therapeutic use , Transplantation Conditioning , Transplantation, Homologous
10.
Nephrol Nurs J ; 48(2): 131-145, 2021.
Article in English | MEDLINE | ID: mdl-33886243

ABSTRACT

Social determinants of health (SDOH) are non-medical factors, such as socioeconomic status, education, neighborhood/physical environment, social network, employment, and access to health care, which can shape individuals' health and affect a wide range of health risks and outcomes. These social determinants of health and their associated health disparities and inequities are powerful predictors of mortality and morbidity. Chronic kidney disease disproportionally affects populations with relatively poor social determinants of health. Knowledge of social determinants, applying what one knows, and addressing the social, economic, and physical barriers to health can help improve individual and population health, reduce health disparities, and advance health equity.


Subject(s)
Renal Insufficiency, Chronic , Social Determinants of Health , Delivery of Health Care , Health Status Disparities , Humans , Renal Insufficiency, Chronic/epidemiology
11.
J Invest Dermatol ; 141(6): 1404-1415, 2021 06.
Article in English | MEDLINE | ID: mdl-33188780

ABSTRACT

Patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy show diverse endocrine and nonendocrine manifestations initiated by self-reactive T cells because of AIRE mutation-induced defective central tolerance. A large number of American patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy suffer from early-onset cutaneous inflammatory lesions accompanied by an infiltration of T cells and myeloid cells. The role of myeloid cells in this setting remains to be fully investigated. In this study, we characterize the autoinflammatory phenotypes in the skin of both autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy-like kinase-dead Ikkα knockin mice and patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. We found a marked infiltration of autoreactive CD4 T cells, macrophages, and neutrophils; elevated uric acid; and increased NLRP3, a major inflammasome component. Depleting autoreactive CD4 T cells or ablating Ccl2/Cxcr2 genes significantly attenuated the inflammasome activity, inflammation, and skin phenotypes in kinase-dead Ikkα knockin mice. Importantly, treatment with an NLRP3 inhibitor reduced skin phenotypes and decreased infiltration of CD4 T cells, macrophages, and neutrophils. These results suggest that increased myeloid cell infiltration contributes to autoreactive CD4 T cell-mediated skin autoinflammation. Thus, our findings reveal that the combined infiltration of macrophages and neutrophils is required for autoreactive CD4 T cell-mediated skin disease pathogenesis and that the NLRP3-dependent inflammasome is a potential therapeutic target for the cutaneous manifestations of autoimmune diseases.


Subject(s)
CD4-Positive T-Lymphocytes/drug effects , Furans/pharmacology , Indenes/pharmacology , NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitors , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Polyendocrinopathies, Autoimmune/drug therapy , Sulfonamides/pharmacology , Animals , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Disease Models, Animal , Furans/therapeutic use , Gene Knockout Techniques , Humans , I-kappa B Kinase/genetics , Indenes/therapeutic use , Inflammasomes/drug effects , Inflammasomes/immunology , Inflammasomes/metabolism , Mice , Mice, Transgenic , Mutation , NLR Family, Pyrin Domain-Containing 3 Protein/analysis , Polyendocrinopathies, Autoimmune/genetics , Polyendocrinopathies, Autoimmune/immunology , Polyendocrinopathies, Autoimmune/pathology , Skin/drug effects , Skin/immunology , Skin/pathology , Sulfonamides/therapeutic use , Transcription Factors/genetics , Up-Regulation/immunology , AIRE Protein
12.
Biomed Pharmacother ; 132: 110856, 2020 Dec.
Article in English | MEDLINE | ID: mdl-33125970

ABSTRACT

PURPOSE: The incidence of retinopathy of prematurity (ROP) has increased continuously in recent years. However, the therapeutic effects of current treatments still remain undesired. This study aims to investigate the role of C-CBL in retinal angiogenesis in ROP and its potential as a therapeutic target. METHODS: Mouse retina microvascular endothelial cells (mRMECs) and induced experimental ROP/ oxygen-induced retinopathy (OIR) mice were employed to investigate the role of C-CBL in angiogenesis with combined molecular and cellular approaches, and histopathology methods. OIR mouse pups at postnatal day 12 (P12) were either injected intravitreally with adenovirus overexpressing c-Cbl or c-Cbl siRNA. Retinal neovascularization and avascular status were evaluated by retinal immunofluorescence (IF) staining, whole-mounts and hematoxylin and eosin (H&E) staining. RESULTS: C-CBL inhibits neovascularization by negatively regulating JAK2/STAT3/VEGF signaling axis in a ubiquitination-dependent manner. Knockdown of c-Cbl by siRNA reduced ubiquitin-mediated JAK2 degradation and increased levels of p-JAK2, p-STAT3, VEGF, and neovascularization in mRMECs, which can be reversed by JAK2 inhibitor treatment. While knockdown of c-Cbl significantly increased neovascular (NV) zone in the retinas, c-Cbl overexpression inhibited neovascularization in the retinal tissues in OIR mice. CONCLUSION: We found that C-CBL is required for anti-neovascularization process in ROP development by inhibiting JAK2/STAT3-dependent angiogenesis. Thus, our finding strongly suggest that C-CBL may be a potential novel therapeutic target for treating ROP.


Subject(s)
Proto-Oncogene Proteins c-cbl/genetics , Retinal Neovascularization/pathology , Retinopathy of Prematurity/pathology , Animals , Cells, Cultured , Disease Models, Animal , Endothelial Cells/pathology , Gene Knockdown Techniques , Janus Kinase 2/metabolism , Mice , Mice, Inbred C57BL , Oxygen , Retinal Neovascularization/genetics , Retinal Vessels/cytology , Retinal Vessels/pathology , Retinopathy of Prematurity/genetics , STAT3 Transcription Factor/metabolism , Signal Transduction , Vascular Endothelial Growth Factor A/metabolism
14.
Bone Marrow Transplant ; 55(4): 804-810, 2020 04.
Article in English | MEDLINE | ID: mdl-31616065

ABSTRACT

In this multicenter Phase 2 single arm study, we substituted low dose total body irradiation (TBI) for antithymocyte globulin (ATG) in a reduced intensity conditioning regimen with the intent to lower the risk for viral infections after double umbilical cord blood (UCB) transplantation. The conditioning regimen consisted of fludarabine (30 mg/m2/day, Day -7 to -2), melphalan (100 mg/m2/day, Day -1), and TBI (200cGy, Day 0). Graft-versus-host disease prophylaxis was sirolimus and tacrolimus. Thirty-one patients were treated on the protocol. The median time of follow-up for survivors was 24 months (range, 3.3-55.1). Nineteen patients experienced a total of 24 clinically significant viral reactivations or infections, with 1-year cumulative incidence rate of first significant viral event as 64% (95% CI, 43-79%), compared with our historical control of 53%. Within the context of these 24 clinically significant viral reactivations, there were a total of 10 infections with organ involvement. Nonrelapse mortality was 28% (95% CI 13-45%) at 2 years. The 2-year overall and progression-free survivals were 53% (95% CI 33-69%) and 47% (95% CI 28-64%), respectively. In conclusion, the substitution of low dose TBI for ATG did not decrease the incidence of significant viral events after UCB transplantation.


Subject(s)
Cord Blood Stem Cell Transplantation , Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Graft vs Host Disease/prevention & control , Humans , Melphalan , Transplantation Conditioning , Vidarabine/analogs & derivatives , Whole-Body Irradiation
15.
Genes Immun ; 20(3): 224-233, 2019 03.
Article in English | MEDLINE | ID: mdl-29740197

ABSTRACT

Only few genes have been confidently identified to be involved in the Follicular (FO) and Marginal Zone (MZ) B cell differentiation, migration, and retention in the periphery. Our group previously observed that IKKα kinase inactive mutant mice IKKαK44A/K44A have significantly lower number of MZ B cells whereas FO B cell numbers appeared relatively normal. Because kinase dead IKKα can retain some of its biological functions that may interfere in revealing its actual role in the MZ and FO B cell differentiation. Therefore, in the current study, we genetically deleted IKKα from the pro-B cell lineage that revealed novel functions of IKKα in the MZ and FO B lymphocyte development. The loss of IKKα produces a significant decline in the percentage of immature B lymphocytes, mature marginal zone B cells, and follicular B cells along with a severe disruption of splenic architecture of marginal and follicular zones. IKKα deficiency affect the recirculation of mature B cells through bone marrow. A transplant of IKKα knockout fetal liver cells into Rag-/- mice shows a significant reduction compared to control in the B cells recirculating through bone marrow. To reveal the genes important in the B cell migration, a high throughput gene expression analysis was performed on the IKKα deficient recirculating mature B cells (B220+IgMhi). That revealed significant changes in the expression of genes involved in the B lymphocyte survival, homing and migration. And several among those genes identified belong to G protein family. Taken together, this study demonstrates that IKKα forms a vial axis controlling the genes involved in MZ and FO B cell differentiation and migration.


Subject(s)
B-Lymphocytes/metabolism , Cell Differentiation , I-kappa B Kinase/genetics , Animals , B-Lymphocytes/cytology , Bone Marrow Cells/cytology , Bone Marrow Cells/metabolism , Cell Lineage , Cell Movement , Cells, Cultured , Hepatocytes/cytology , Hepatocytes/metabolism , I-kappa B Kinase/deficiency , I-kappa B Kinase/metabolism , Mice , Spleen/cytology , Spleen/metabolism
16.
Cell Death Discov ; 4: 46, 2018.
Article in English | MEDLINE | ID: mdl-29844930

ABSTRACT

Human lung squamous cell carcinoma (SCC) is highly associated with increased pulmonary macrophage infiltration. Previously, we showed that marked pulmonary infiltrating macrophages were required for spontaneous lung SCC development in a mouse model (L-IkkαKA/KA , KA/KA) that resembles human lung SCC. Interestingly the lung SCC-associated macrophages specifically express elevated inducible nitric oxide synthase (NOS2). However, the role of macrophage NOS2 in lung carcinogenesis has not been explored. Here, we show that NOS2 ablation inhibits macrophage infiltration, fibrosis, and SCC development in the lungs of KA/KA mice. Macrophage NOS2 was found to circulate inflammation and enhance macrophage migration and survival. NOS2 promotes foamy macrophage formation characterized with impaired lipid metabolism. NOS2 null bone marrow transplantation reduces foamy macrophage numbers and carcinogenesis in KA/KA chimaeras. This finding sheds light on a new mechanism by which macrophage NOS2 increases pulmonary inflammatory responses and macrophage survival and impairs macrophage lipid metabolism, thereby promoting lung SCC formation.

17.
Biol Blood Marrow Transplant ; 24(9): 1836-1840, 2018 09.
Article in English | MEDLINE | ID: mdl-29758393

ABSTRACT

We conducted a phase I study of brentuximab vedotin (BV), an antibody-drug conjugate targeting CD30, for the treatment of steroid-refractory chronic graft-versus-host disease (cGVHD). A modified 3 + 3 study design was used with the primary endpoint to determine the maximum tolerated dose of BV in this population. Escalating doses of BV were planned, starting with .6 mg/kg every 3 weeks (dose level 0) and increasing by .3 mg/kg per dose level. BV was administered in 21-day cycles for up to 16 cycles of therapy. Nineteen patients were enrolled on the study, with 2 withdrawing consent before dosing. The median number of cycles of therapy was 4 (range, 1 to 16). Reasons for stopping therapy prematurely included toxicities (n = 9), patient decision (n = 3), lack of response (n = 2), and death (n = 1). There were 2 dose-limiting toxicities observed: posterior reversible encephalopathy syndrome (cohort 4, grade 3) and sepsis (cohort 4, grade 4). The maximum tolerated dose was not reached because the trial was prematurely closed due to toxicity. Seven patients (41%) developed grade 3 or 4 adverse events that were attributed to therapy, including 4 patients who developed moderate or severe peripheral neuropathy that led to cessation of treatment in each case. According to National Institutes of Health cGVHD response criteria, 8 patients (47%) experienced a partial response, whereas 9 patients (53%) had a lack of response. There were no complete responses observed. Eleven patients (65%) were able to decrease their systemic corticosteroid dose by ≥50% by 6 months after initiation of BV, including 3 patients who were able to stop corticosteroids completely. The median soluble CD30 level before therapy was 61.5 ng/mL (range, 7.8 to 474.9); however, we did not observe any association between soluble CD30 level and cGVHD severity at enrollment or clinical responses to BV. In conclusion, BV may have activity in treatment of steroid-refractory cGVHD, yet its use is limited by treatment-emergent toxicities, including peripheral neuropathy. Continued efforts to investigate targeted approaches to cGVHD that do not cause broad immunosuppression are needed.


Subject(s)
Graft vs Host Disease/drug therapy , Hematopoietic Stem Cell Transplantation/methods , Immunoconjugates/therapeutic use , Transplantation Conditioning/methods , Transplantation, Homologous/methods , Adult , Aged , Brentuximab Vedotin , Female , Graft vs Host Disease/pathology , Humans , Immunoconjugates/pharmacology , Male , Middle Aged , Young Adult
18.
Blood Adv ; 2(7): 745-753, 2018 04 10.
Article in English | MEDLINE | ID: mdl-29592876

ABSTRACT

We hypothesized that third-party fecal microbiota transplantation (FMT) may restore intestinal microbiome diversity after allogeneic hematopoietic cell transplantation (allo-HCT). In this open-label single-group pilot study, 18 subjects were enrolled before allo-HCT and planned to receive third-party FMT capsules. FMT capsules were administered no later than 4 weeks after neutrophil engraftment, and antibiotics were not allowed within 48 hours before FMT. Five patients did not receive FMT because of the development of early acute gastrointestinal (GI) graft-versus-host disease (GVHD) before FMT (n = 3), persistent HCT-associated GI toxicity (n = 1), or patient decision (n = 1). Thirteen patients received FMT at a median of 27 days (range, 19-45 days) after HCT. Participants were able to swallow and tolerate all FMT capsules, meeting the primary study endpoint of feasibility. FMT was tolerated well, with 1 treatment-related significant adverse event (abdominal pain). Two patients subsequently developed acute GI GVHD, with 1 patient also having concurrent bacteremia. No additional cases of bacteremia occurred. Median follow-up for survivors is 15 months (range, 13-20 months). The Kaplan-Meier estimates for 12-month overall survival and progression-free survival after FMT were 85% (95% confidence interval, 51%-96%) and 85% (95% confidence interval, 51%-96%), respectively. There was 1 nonrelapse death resulting from acute GI GVHD (12-month nonrelapse mortality, 8%; 95% confidence interval, 0%-30%). Analysis of stool composition and urine 3-indoxyl sulfate concentration indicated improvement in intestinal microbiome diversity after FMT that was associated with expansion of stool-donor taxa. These results indicate that empiric third-party FMT after allo-HCT appears to be feasible, safe, and associated with expansion of recipient microbiome diversity. This trial was registered at www.clinicaltrials.gov as #NCT02733744.


Subject(s)
Fecal Microbiota Transplantation/methods , Hematopoietic Stem Cell Transplantation/methods , Adult , Aged , Allografts , Bacteremia/etiology , Fecal Microbiota Transplantation/mortality , Female , Gastrointestinal Tract/pathology , Graft vs Host Disease/etiology , Graft vs Host Disease/pathology , Humans , Male , Microbiota/genetics , Middle Aged , Pilot Projects , Survival Analysis
19.
Proc Natl Acad Sci U S A ; 115(4): E812-E821, 2018 01 23.
Article in English | MEDLINE | ID: mdl-29311298

ABSTRACT

Lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC) are two distinct and predominant types of human lung cancer. IκB kinase α (IKKα) has been shown to suppress lung SCC development, but its role in ADC is unknown. We found inactivating mutations and homologous or hemizygous deletions in the CHUK locus, which encodes IKKα, in human lung ADCs. The CHUK deletions significantly reduced the survival time of patients with lung ADCs harboring KRAS mutations. In mice, lung-specific Ikkα ablation (IkkαΔLu ) induces spontaneous ADCs and promotes KrasG12D-initiated ADC development, accompanied by increased cell proliferation, decreased cell senescence, and reactive oxygen species (ROS) accumulation. IKKα deletion up-regulates NOX2 and down-regulates NRF2, leading to ROS accumulation and blockade of cell senescence induction, which together accelerate ADC development. Pharmacologic inhibition of NADPH oxidase or ROS impairs KrasG12D-mediated ADC development in IkkαΔLu mice. Therefore, IKKα modulates lung ADC development by controlling redox regulatory pathways. This study demonstrates that IKKα functions as a suppressor of lung ADC in human and mice through a unique mechanism that regulates tumor cell-associated ROS metabolism.


Subject(s)
Adenocarcinoma/genetics , I-kappa B Kinase/physiology , Lung Neoplasms/genetics , Acetophenones , Acetylcysteine , Adenocarcinoma/metabolism , Animals , Cell Proliferation , Cellular Senescence , Cyclin-Dependent Kinase Inhibitor p21/metabolism , Epigenesis, Genetic , Humans , Lung Neoplasms/metabolism , Mice , NADPH Oxidase 2/metabolism , NF-E2-Related Factor 2/metabolism , Proto-Oncogene Proteins p21(ras)/metabolism , Reactive Oxygen Species/metabolism , Tumor Suppressor Protein p53/metabolism
20.
Nephrol Nurs J ; 44(5): 391-398, 2017.
Article in English | MEDLINE | ID: mdl-29160974

ABSTRACT

Dealing with a growing older adult patient population, keeping pace with current guidelines, and adhering to new recommendations is a perpetual endeavor for healthcare professionals. Because determining the best access for individual patients is not always obvious, vascular access is a challenging aspect of patient care. This article presents information on the ever-evolving and improving world of vascular access, specifically synthetic grafts.


Subject(s)
Arteriovenous Shunt, Surgical/nursing , Nephrology Nursing , Humans , Polytetrafluoroethylene , Renal Dialysis , Time Factors
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