Gratitude, optimism, and satisfaction with life and patient-reported outcomes in patients undergoing hematopoietic stem cell transplantation.

OBJECTIVE: Associations between positive psychological well-being (PPWB) and patient-reported outcomes (PROs, e.g., quality of life [QOL]) have yet to be studied extensively in patients with hematologic malignancies who are allogeneic hematopoietic stem cell transplant (HSCT) survivors, despite substantial evidence that PPWB impacts PROs of other medical populations. METHODS: We conducted a secondary analysis of cross-sectional data examining the association of PPWB and PROs at day 100 post-transplant among 158 allogeneic HSCT recipients. Optimism, gratitude, life satisfaction, and PROs (i.e., QOL, anxiety, depression, and PTSD symptoms) were assessed using the Life Orientation Test-Revised, Gratitude Questionnaire, Satisfaction with Life Scale, Functional Assessment of Cancer Therapy-Bone Marrow Transplant, Hospital Anxiety and Depression Scale, and Post-Traumatic Stress Disorder (PTSD) Checklist-Civilian Version, respectively. We used linear and multivariate regressions for all analyses and controlled for patient factors. RESULTS: Optimism was associated with better QOL (ß = 1.46; p < 0.001) and lower levels of anxiety (ß = -0.28; p < 0.001), depression (ß = -0.31; p < 0.001), and PTSD (ß = -0.58; p < 0.001). Gratitude was associated with better QOL (ß = 1.11; p < 0.001) and lower levels of anxiety (ß = -0.21; p = 0.001), depression (ß = -0.14; p = 0.021), and PTSD (ß = -0.32; p = 0.032). Finally, satisfaction with life was associated with better QOL (ß = 1.26; p < 0.001) and lower levels of anxiety (ß = -0.18; p < 0.001), depression (ß = -0.21; p < 0.001), and PTSD (ß = -0.49; p < 0.001). CONCLUSION: Optimism, gratitude, and satisfaction with life were all associated with better QOL and lower levels of psychological distress in allogeneic HSCT survivors. These data support studies to harness PPWB as a therapeutic intervention for this population throughout HSCT recovery.

Positive Psychological Well-Being in Hematopoietic Stem Cell Transplantation Survivors.

Positive thoughts and emotions contribute to overall psychological health in diverse medical populations, including patients undergoing HSCT. However, few studies have described positive psychological well-being (eg, optimism, gratitude, flourishing) in patients undergoing HSCT using well-established, validated patient-reported outcome measures. We conducted cross-sectional secondary analyses of baseline data in 156 patients at 100 days post-HSCT enrolled in a randomized controlled trial of a psychological intervention (ClinicalTrials.gov identifier NCT05147311) and a prospective study assessing medication adherence at a tertiary care academic cancer center from September 2021 to December 2022. We used descriptive statistics to outline participant reports of positive psychological well-being (PPWB) using validated measures for optimism, gratitude, positive affect, life satisfaction, and flourishing. The participants had a mean age of 57.4 ± 13.1 years, and 51% were male (n = 79). Many, but not all, participants reported high levels of PPWB (ie, optimism, gratitude, positive affect, life satisfaction, and flourishing), defined as agreement with items on a given PPWB measure. For example, for optimism, 29% of participants did not agree that "overall, I expect more good things to happen to me than bad." Aside from life satisfaction, mean PPWB scores were higher in the HSCT population than in other illness populations. Although many patients with hematologic malignancies undergoing HSCT report high levels of PPWB, a substantial minority of patients reported low PPWB (i.e., no agreement with items on a given PPWB measure). Because PPWB is associated with important clinical outcomes in medical populations, further research should determine whether an intervention to promote PPWB can improve quality of life in HSCT recipients.

Sexually Transmitted Infections & the Heart.

Sexually transmitted infections (STIs) have substantial morbidity and mortality worldwide, with over 1 million new infections occurring daily. Similarly, cardiovascular (CV) disease is the leading global cause of death and has tremendous impact on disability as well as quality of life. Several STIs have potential CV consequences and may precipitate reoccurrence of underlying CV comorbidity. Notably, untreated STIs and associated CV complications have an increased impact on marginalized individuals and those with limited access to health resources and care. Syphilis, human immunodeficiency virus, human papillomavirus, herpes simplex virus, hepatitis B, hepatitis C, cytomegalovirus, chlamydia, gonorrhea, and trichomoniasis have been identified as having CV implications. Yet, the data linking compromised CV health and STIs have not previously been summarized. The present review encapsulates the current knowledge surrounding the impacts of STIs on CV health as well as diagnostic and treatment strategies.

Three-dimensional morphologic changes in the temporomandibular joint in asymptomatic patients who undergo orthodontic treatment: A systematic review.

OBJECTIVE: This systematic review aimed to summarize the morphologic changes in the temporomandibular joint (TMJ) in patients who underwent orthodontic treatment and were assessed by 3-dimensional (3D) imaging techniques (e.g., magnetic resonance imaging, cone beam computed tomography, and multidetector computed tomography). STUDY DESIGN: The authors searched PubMed, Web of Science, and Embase databases to identify original articles from 2014 to 2021 containing keywords for morphologic changes in the TMJ, orthodontic treatment, and three-dimensional imaging methods. Prospective and retrospective studies, including observational, cross-sectional, randomized, and nonrandomized clinical trials, cohort studies, and case-control studies, were reviewed. The review was conducted in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. The risk of bias was assessed in studies selected for the full-text review. RESULTS: The search strategy yielded 294 publications. After an initial screening and the application of exclusion criteria, 13 studies were selected for the final review. CONCLUSION: Differences were found in condylar positioning, typically in an anterior position; condylar morphology, primarily with increased diameter or head height; and articular disk position within the anterior-posterior plane post-treatment. Changes in the glenoid fossa were not consistent between the studies. The overall risk of bias among studies was moderate. The influence of orthodontic treatment on morphologic changes in the TMJ remains unclear.

TIRAP drives myelosuppression through an Ifnγ-Hmgb1 axis that disrupts the endothelial niche in mice.

Inflammation is associated with bone marrow failure syndromes, but how specific molecules impact the bone marrow microenvironment is not well elucidated. We report a novel role for the miR-145 target, Toll/interleukin-1 receptor domain containing adaptor protein (TIRAP), in driving bone marrow failure. We show that TIRAP is overexpressed in various types of myelodysplastic syndromes (MDS) and suppresses all three major hematopoietic lineages. TIRAP expression promotes up-regulation of Ifnγ, leading to myelosuppression through Ifnγ-Ifnγr-mediated release of the alarmin, Hmgb1, which disrupts the bone marrow endothelial niche. Deletion of Ifnγ blocks Hmgb1 release and is sufficient to reverse the endothelial defect and restore myelopoiesis. Contrary to current dogma, TIRAP-activated Ifnγ-driven bone marrow suppression is independent of T cell function or pyroptosis. In the absence of Ifnγ, TIRAP drives myeloproliferation, implicating Ifnγ in suppressing the transformation of MDS to acute leukemia. These findings reveal novel, noncanonical roles of TIRAP, Hmgb1, and Ifnγ in the bone marrow microenvironment and provide insight into the pathophysiology of preleukemic syndromes.

Recent developments in geriatric psychopharmacology.

INTRODUCTION: There is a tremendous growing need to address the burden of geriatric psychiatric disorders. Recent developments relevant to geriatric psychiatry have focused on Alzheimer's disease (AD), severe/refractory depression, and cancer/end of life care. AREAS COVERED: This is a non-systematic, narrative review (databases and websites for search: PubMed, Google Scholar, Medscape, ClinicalTrials.gov; focusing on the last 6 years), and covers developments in disease-modifying therapies for AD, diagnostic radiotracers for AD, medications for neuropsychiatric symptoms of dementia, ketamine/esketamine, psychedelics, and cannabinoids. EXPERT OPINION: The focus of on-going trials of anti-amyloid agents has been on individuals with very early stage AD; several agents are under phase 3 investigation, and aducanumab is under FDA review. Amyloid and tau PET scans have been approved by the FDA to assist in the diagnoses of AD. Promising pharmaceuticals for neuropsychiatric symptoms of dementia include pimavanserin, brexpiprazole, escitalopram, dextromethorphan/quinidine, and lithium. Esketamine, although approved for treatment-resistant depression in general adults, failed to demonstrate efficacy in elderly patients in a phase 3 trial. There is preliminary evidence for benefit of psychedelic-assisted psychotherapy in end-of-life and cancer-related depression/anxiety. Evidence for the use of cannabinoids is currently lacking.

Transcriptional response of vaginal epithelial cells to medroxyprogesterone acetate treatment results in decreased barrier integrity.

Medroxyprogesterone acetate (MPA) is a frequently used hormonal contraceptive that has been shown to significantly increase HIV-1 susceptibility by approximately 40 %. However, the underlying mechanism by which this occurs remains unknown. Here, we examined the biological response to MPA by vaginal epithelial cells, the first cells to encounter HIV-1 during sexual transmission, in order to understand the potential mechanism(s) of MPA-mediated increase of HIV-1 infection. Using microarray analysis and in vitro assays, we characterized the response of vaginal epithelial cells, grown in biologically relevant air-liquid interface (ALI) cultures, to physiological levels of female sex hormones, estradiol (E2), progesterone (P4), or MPA. Transcriptional profiling of E2, P4 or MPA-treated vaginal epithelial cells indicated unique transcriptional profiles associated with each hormone. MPA treatment increased transcripts of genes related to cholesterol/sterol synthesis and decreased transcripts related to cell division and cell-cell adhesion, results not seen with E2 or P4 treatments. MPA treatment also resulted in unique gene expression indicative of decreased barrier integrity. Functional assays confirmed that MPA, but not E2 or P4 treatments, resulted in increased epithelial barrier permeability and inhibited cell cycle progression. The effects of MPA on vaginal epithelial cells seen in this study may help explain the increase of HIV-1 infection in women who use MPA as a hormonal contraceptive.

Functional profiling of circulating tumor cells with an integrated vortex capture and single-cell protease activity assay.

Tumor cells are hypothesized to use proteolytic enzymes to facilitate invasion. Whether circulating tumor cells (CTCs) secrete these enzymes to aid metastasis is unknown. A quantitative and high-throughput approach to assay CTC secretion is needed to address this question. We developed an integrated microfluidic system that concentrates rare cancer cells >100,000-fold from 1 mL of whole blood into ∼50,000 2-nL drops composed of assay reagents within 15 min. The system isolates CTCs by size, exchanges fluid around CTCs to remove contaminants, introduces a matrix metalloprotease (MMP) substrate, and encapsulates CTCs into microdroplets. We found CTCs from prostate cancer patients possessed above baseline levels of MMP activity (1.7- to 200-fold). Activity of CTCs was generally higher than leukocytes from the same patient (average CTC/leukocyte MMP activity ratio, 2.6 ± 1.5). Higher MMP activity of CTCs suggests active proteolytic processes that may facilitate invasion or immune evasion and be relevant phenotypic biomarkers enabling companion diagnostics for anti-MMP therapies.

miR-143/145 differentially regulate hematopoietic stem and progenitor activity through suppression of canonical TGFß signaling.

Expression of miR-143 and miR-145 is reduced in hematopoietic stem/progenitor cells (HSPCs) of myelodysplastic syndrome patients with a deletion in the long arm of chromosome 5. Here we show that mice lacking miR-143/145 have impaired HSPC activity with depletion of functional hematopoietic stem cells (HSCs), but activation of progenitor cells (HPCs). We identify components of the transforming growth factor ß (TGFß) pathway as key targets of miR-143/145. Enforced expression of the TGFß adaptor protein and miR-145 target, Disabled-2 (DAB2), recapitulates the HSC defect seen in miR-143/145-/- mice. Despite reduced HSC activity, older miR-143/145-/- and DAB2-expressing mice show elevated leukocyte counts associated with increased HPC activity. A subset of mice develop a serially transplantable myeloid malignancy, associated with expansion of HPC. Thus, miR-143/145 play a cell context-dependent role in HSPC function through regulation of TGFß/DAB2 activation, and loss of these miRNAs creates a preleukemic state.

Depression, Smoking, and Ego-Centric Social Network Characteristics in Ohio Appalachian Women.

Depression is a serious, costly, and debilitating disorder that is understudied in rural women. Studies show that depression is associated with low social integration and support, but few studies investigate the relationship between depression and social network characteristics. This study examined the associations among women from three Ohio Appalachian counties enrolled in a health study, which aimed to collect information for a future social network smoking cessation intervention. An address-based sampling method was used to randomly select and recruit 404 women. A cross-sectional survey and interview were used to collect information about demographic, psychosocial, behavioral factors, and ego-centric social network characteristics, which are variables derived from an individual (ego) and her first degree contacts (alters). The CES-D scale assessed depressive symptoms. A multivariable logistic regression analysis described the association between these factors and participants with depression (defined as CES-D≥16). Higher network density, or greater number of relationships among alters divided by the total amount of alters, reduced the risk for depression (OR = 0.84, 95% confidence interval [CI] 0.73-0.95). Additionally, women with a high percentage of smoking alters were at greater risk for depression (OR = 1.19, 95% CI 1.02-1.39). Other factors associated with risk for depression included perceived stress score (OR = 1.34, 95% CI 1.24-1.45), loneliness score (OR = 1.37, 95% CI 1.05-1.80), and days with poor physical health (OR = 1.06, 95% CI 1.02-1.11). Findings suggest that psychosocial factors and social networks should be considered when addressing depression in clinical practice.

Mouse models of myelodysplastic syndromes.

Myelodysplastic syndromes (MDS) are hematopoietic malignancies characterized by peripheral cytopenias in the face of normo- or hypercellular, dysplastic bone marrow that arise from mutations in the hematopoietic stem/progenitor cell (HSPC). The disease is characterized by multiple cytogenetic and molecular defects, which result in an extremely heterogeneous phenotype. Recently, significant efforts have been made to develop appropriate mouse models to study this complex disease. Because of the heterogeneity of MDS, no single model is able to capture the MDS phenotype in its entirety. In this review, we describe several MDS mouse models and discuss the advances made in our understanding of the different disease mechanisms within the malignant clone and the marrow microenvironment. In addition, we describe progress in xenotransplantation models of MDS and discuss questions that remain to be answered.

Irinophore C, a novel nanoformulation of irinotecan, alters tumor vascular function and enhances the distribution of 5-fluorouracil and doxorubicin.

PURPOSE: To examine the antitumor effects of Irinophore C, a nanopharmaceutical formulation of irinotecan, on the tissue morphology and function of tumor vasculature in HT-29 human colorectal tumors. EXPERIMENTAL DESIGN: Fluorescence microscopy was used to map and quantify changes in tissue density, tumor vasculature, hypoxia, and the distribution of Hoechst 33342, a perfusion marker, and the anticancer drug, doxorubicin. Noninvasive magnetic resonance imaging was used to quantify Ktrans, the volume transfer constant of a solute between the blood vessels and extracellular tissue compartment of the tumor, as a measure of vascular function. Following treatment with Irinophore C, 19F magnetic resonance spectroscopy was used to monitor the delivery of 5-fluorouracil (5-FU) to the tumor tissue, whereas scintigraphy was used to quantify the presence of bound [14C]5-FU. RESULTS: Irinophore C decreased cell density (P = 8.42 x 10(-5)), the overall number of endothelial cells in the entire section (P = 0.014), tumor hypoxia (P = 5.32 x 10(-9)), and K(trans) (P = 0.050). However, treatment increased the ratio of endothelial cells to cell density (P = 0.00024) and the accumulation of Hoechst 33342 (P = 0.022), doxorubicin (P = 0.243 x 10(-5)), and 5-FU (P = 0.0002) in the tumor. Vascular endothelial growth factor and interleukin-8, two proangiogenic factors, were down-regulated, whereas the antiangiogenic factor TIMP-1 was up-regulated in Irinophore C-treated tumors. CONCLUSIONS: Irinophore C treatment improves the vascular function of the tumor, thereby reducing tumor hypoxia and increasing the delivery and accumulation of a second drug. Reducing hypoxia would enhance radiotherapy, whereas improving delivery of a second drug to the tumor should result in higher cell kill.

DNA aptamer folding on gold nanoparticles: from colloid chemistry to biosensors.

We have investigated the effect of the folding of DNA aptamers on the colloidal stability of gold nanoparticles (AuNPs) to which an aptamer is tethered. On the basis of the studies of two different aptamers (adenosine aptamer and K+ aptamer), we discovered a unique colloidal stabilization effect associated with aptamer folding: AuNPs to which folded aptamer structures are attached are more stable toward salt-induced aggregation than those tethered to unfolded aptamers. This colloidal stabilization effect is more significant when a DNA spacer was incorporated between AuNP and the aptamer or when lower aptamer surface graft densities were used. The conformation that aptamers adopt on the surface appears to be a key factor that determines the relative stability of different AuNPs. Dynamic light scattering experiments revealed that the sizes of AuNPs modified with folded aptamers were larger than those of AuNPs modified with unfolded (but largely collapsed) aptamers in salt solution. From both the electrostatic and steric stabilization points of view, the folded aptamers that are more extended from the surface have a higher stabilization effect on AuNP than the unfolded aptamers. On the basis of this unique phenomenon, colorimetric biosensors have been developed for the detection of adenosine, K+, adenosine deaminase, and its inhibitors. Moreover, distinct AuNP aggregation and redispersion stages can be readily operated by controlling aptamer folding and unfolding states with the addition of adenosine and adenosine deaminase.

Simple and rapid colorimetric enzyme sensing assays using non-crosslinking gold nanoparticle aggregation.

Non-crosslinking gold nanoparticle (AuNP) aggregation induced by the loss (or screen) of surface charges is applied for enzymatic activity sensing and potentially inhibitor screening.