Functional and clinical roles of stromal PDGF receptors in tumor biology.

PDGF receptors play pivotal roles in both developmental and physiological processes through the regulation of mesenchymal cells involved in paracrine instructive interactions with epithelial or endothelial cells. Tumor biology studies, alongside analyses of patient tissue samples, provide strong indications that the PDGF signaling pathways are also critical in various types of human cancer. This review summarizes experimental findings and correlative studies, which have explored the biological mechanisms and clinical relevance of PDGFRs in mesenchymal cells of the tumor microenvironment. Collectively, these studies support the overall concept that the PDGF system is a critical regulator of tumor growth, metastasis, and drug efficacy, suggesting yet unexploited targeting opportunities. The inter-patient variability in stromal PDGFR expression, as being linked to prognosis and treatment responses, not only indicates the need for stratified approaches in upcoming therapeutic investigations but also implies the potential for the development of PDGFRs as biomarkers of clinical utility, interestingly also in settings outside PDGFR-directed treatments.

Multiomics characterization of mouse hepatoblastoma identifies yes-associated protein 1 target genes.

BACKGROUND AND AIMS: Hepatoblastoma (HB) is the most common primary liver malignancy in childhood and lacks targeted therapeutic options. We previously engineered, to our knowledge, the first yes-associated protein 1 (YAP1) S127A -inducible mouse model of HB, demonstrating tumor regression and redifferentiation after YAP1 withdrawal through genome-wide enhancer modulation. Probing accessibility, transcription, and YAP1 binding at regulatory elements in HB tumors may provide more insight into YAP1-driven tumorigenesis and expose exploitable vulnerabilities in HB. APPROACH AND RESULTS: Using a multiomics approach, we integrated high-throughput transcriptome and chromatin profiling of our murine HB model to identify dynamic activity at candidate cis -regulatory elements (cCREs). We observed that 1301 of 305,596 cCREs exhibit "tumor-modified" (TM) accessibility in HB. We mapped 241 TM enhancers to corresponding genes using accessibility and histone H3K27Ac profiles. Anti-YAP1 cleavage under targets and tagmentation in tumors revealed 66 YAP1-bound TM cCRE/gene pairs, 31 of which decrease expression after YAP1 withdrawal. We validated the YAP1-dependent expression of a putative YAP1 target, Jun dimerization protein 2 (JDP2), in human HB cell lines using YAP1 and LATS1/2 small interfering RNA knockdown. We also confirmed YAP1-induced activity of the Jdp2 TM enhancer in vitro and discovered an analogous human enhancer in silico. Finally, we used transcription factor (TF) footprinting to identify putative YAP1 cofactors and characterize HB-specific TF activity genome wide. CONCLUSIONS: Our chromatin-profiling techniques define the regulatory frameworks underlying HB and identify YAP1-regulated gene/enhancer pairs. JDP2 is an extensively validated target with YAP1-dependent expression in human HB cell lines and hepatic malignancies.

Intratracheally administered LNA gapmer antisense oligonucleotides induce robust gene silencing in mouse lung fibroblasts.

The lung is a complex organ with various cell types having distinct roles. Antisense oligonucleotides (ASOs) have been studied in the lung, but it has been challenging to determine their effectiveness in each cell type due to the lack of appropriate analytical methods. We employed three distinct approaches to study silencing efficacy within different cell types. First, we used lineage markers to identify cell types in flow cytometry, and simultaneously measured ASO-induced silencing of cell-surface proteins CD47 or CD98. Second, we applied single-cell RNA sequencing (scRNA-seq) to measure silencing efficacy in distinct cell types; to the best of our knowledge, this is the first time scRNA-seq has been applied to measure the efficacy of oligonucleotide therapeutics. In both approaches, fibroblasts were the most susceptible to locally delivered ASOs, with significant silencing also in endothelial cells. Third, we confirmed that the robust silencing in fibroblasts is broadly applicable by silencing two targets expressed mainly in fibroblasts, Mfap4 and Adam33. Across independent approaches, we demonstrate that intratracheally administered LNA gapmer ASOs robustly induce gene silencing in lung fibroblasts. ASO-induced gene silencing in fibroblasts was durable, lasting 4-8 weeks after a single dose. Thus, lung fibroblasts are well aligned with ASOs as therapeutics.

Can a global score be derived from the Integration of Stressful Life Experiences Scale-Short Form (ISLES-SF)? Empirical support for a bi-factor model.

The Integration of Stressful Life Experiences Scale-Short Form (ISLES-SF) is a popular, two-factor measure of meaning-making. Although researchers have used this instrument to calculate a global index of meaning-making, there has been little evidence to support this practice. Therefore, the objective of this study was to examine the validity of this approach by analyzing data from 2,380 American adults during the beginning of the COVID-19 pandemic. A series of confirmatory factor analyses, reliability analyses, and concurrent validity analyses support a bi-factor model of meaning-making. These results affirm the practice of not only using the ISLES-SF to measure meaning-making at a global level, but also to interpret its two specific dimensions (Comprehensibility and Footing in the World) as well.

New Psychometric Evidence of the Grief Impairment Scale (GIS) in People Who Have Experienced the Death of a Loved One From a Network Psychometric Approach in Two Latin American Countries.

This study aimed to evaluate the psychometric properties of the Grief Impairment Scale (GIS) using a network psychometric model. A total of 1048 individuals from Peru and El Salvador participated. A network psychometric model was used to determine internal structure, reliability, and cross-country invariance. The results indicate that the GIS items were grouped into a single network structure through Exploratory Graph Analysis. Reliability was estimated by structural consistency, and it was found that when replicating the network structure within an empirical dimension, a single network structure was consistently obtained, and all items remained stable. Furthermore, the network structure was invariant, thus functioning similarly across the different country groups. In conclusion, the GIS presented solid psychometric evidence of validity based on its internal structure, reliability, and cross-country invariance. Therefore, the GIS is a psychometrically sound measure of functional impairment symptoms due to grief for Peruvian and Salvadoran individuals.

Treatment of COVID-19 pneumonia with low-dose radiotherapy plus standard of care versus standard of care alone in frail patients : The SEOR-GICOR IPACOVID comparative cohort trial.

PURPOSE: To assess the efficacy of lung low-dose radiotherapy (LD-RT) in the treatment of patients with COVID-19 pneumonia. MATERIALS AND METHODS: Ambispective study with two cohorts to compare treatment with standard of care (SoC) plus a single dose of 0.5 Gy to the whole thorax (experimental prospective cohort) with SoC alone (control retrospective cohort) for patients with COVID-19 pneumonia not candidates for admission to the intensive care unit (ICU) for mechanical ventilation. RESULTS: Fifty patients treated with LD-RT were compared with 50 matched controls. Mean age was 85 years in both groups. An increase in arterial oxygen partial pressure (PaO2)/fraction of inspired oxygen (PAFI) in the experimental LD-RT-treated group compared to the control group could not be found at 48 h after LD-RT, which was the primary endpoint of the study. However, PAFI values significantly improved after 1 month (473 vs. 302 mm Hg; p < 0.0001). Pulse oxymetric saturation/fraction of inspired oxygen (SAFI) values were also significantly higher in LD-RT-treated patients than in control patients at 1 week (405 vs. 334 mm Hg; p = 0.0157) and 1 month after LD-RT (462 vs. 326 mm Hg; p < 0.0001). All other timepoint measurements of the respiratory parameters were similar across groups. Patients in the experimental group were discharged from the hospital significantly earlier (23 vs. 31 days; p = 0.047). Fifteen and 26 patients died due to COVID-19 pneumonia in the experimental and control cohorts, respectively (30% vs. 48%; p = 0.1). LD-RT was associated with a decreased odds ratio (OR) for 1­month COVID-19 mortality (OR = 0.302 [0.106-0.859]; p = 0.025) when adjusted for potentially confounding factors. Overall survival was significantly prolonged in the LD-RT group compared to the control group (log-rank p = 0.027). No adverse events related to radiation treatment were observed. CONCLUSION: Treatment of frail patients with COVID-19 pneumonia with SoC plus single-dose LD-RT of 0.5 Gy improved respiratory parameters, reduced the period of hospitalization, decreased the rate of 1­month mortality, and prolonged actuarial overall survival compared to SoC alone.

Relationship Satisfaction in Young Couples: Evidence for Validity of Short Scale Combining CFA and IRT.

This study aimed to validate a short relationship satisfaction scale (RAS) in a sample of young people and adults in the Lima metropolitan area. There were a total of 806 participants aged between 18 and 30 years: 622 females (77.20%) and 184 males (22.80%). Every participant was currently in a love relationship of a minimum of three months. The methodologies of Confirmatory Factor Analysis (CFA) and Item Response Theory (IRT) were combined to determine the structure and assess the reliability of the instrument. The Omega coefficient (ω) was used from CFA, while the test information function and empirical reliability (rxx) were used from IRT. The results showed that the RAS could be interpreted as a one-dimensional scale when eliminating the items 4-7 and joining the items 1-2. This model shows high goodness of fit from a CFA-perspective. A similar situation occurs in IRT, except that error covariance is not considered. Nevertheless, assuming the elimination of items 4-7 is still a good option. The reliability in both CFA (ω = .838) and IRT (rxx = .862) was satisfactory. The evidence of relationship with other variable showed inverse and big relationship with violent spells of tension and difficulty.

Discrimination, stigma and mental health: what's next?

Stigma and discrimination are a major ongoing problem in the field of mental health as these impact on patient outcomes, access to and acceptability of therapeutic interventions, their quality of life, general wellbeing, social inclusion and opportunities. Social stereotypes, culture and prejudices all contribute to continuing discrimination in mental health. Different settings where people function may also be sources of discrimination such as work and educational environments. The lack of knowledge and understanding of mental health/illness by individuals, their families, carers and policymakers as well as the social media reporting also impact on social attitudes to discrimination. It has been also described a relevant impact of stigma among specific social minorities reporting poor mental health such as elderly people, youths, sexual variants, persons with disability. Educational programs, raising awareness trainings and proper public policies may be developed in order to reduce stigma at social level with favourable outcomes for people with mental illness.

A Psychometric Analysis of the Spanish Version of the Grief Impairment Scale: A Screening Tool of Biopsychosocial Grief-Related Functional Impairment in a Salvadoran Sample.

The objective of this study was to translate and psychometrically evaluate a Spanish version of the Grief Impairment Scale (GIS) using a sample of bereaved adults from El Salvador (N = 579). The results confirm the unidimensional structure of the GIS, and solid reliability, item characteristics, and criterion-related validity, where the GIS scale significantly and positively predicts depression. However, this instrument only showed evidence of configural and metric invariance between different sex groups. Overall, these results support the Spanish version of the GIS as a psychometrically sound screening tool for health professionals and researchers to use in their clinical work.

COVID-19 Bereavement in Ten Latin American Countries: Measurement Invariance of the Pandemic Grief Scale and Its Relation to Suicidal Ideation.

The present study aimed to evaluate the cross-cultural measurement invariance of the Pandemic Grief Scale (PGS) in ten Latin American countries. A total of 2,321 people who had lost a family member or other loved one due to COVID-19 participated, with a mean age of 34.22 years old (SD = 11.99). In addition to the PGS, a single item of suicidal ideation was applied. The unidimensional model of the PGS had adequate fit in most countries and good reliability estimates. There was evidence of measurement invariance by country and gender. Also, a one-point increase in the PGS was associated with an almost twofold increase in the odds of suicidal ideation. Scores greater than or equal to 4 on the PGS are proposed as a cut off to identify individuals with suicidal ideation. Strong evidence of the cross-cultural validity of the PGS is provided.

Assessment of Obsessive Thoughts About COVID-19 in 7 Latin American Countries: Structure and Measurement Invariance of the Obsession With COVID-19 Scale.

The present study aimed to evaluate the measurement invariance of the Obsession with COVID-19 Scale (OCS) among seven Latin American countries: Bolivia, Brazil, Cuba, El Salvador, Guatemala, Paraguay, and Uruguay. Although the OCS has been used in several countries and languages, there is a need for approaches that better integrate the cross-cultural equivalence of the scale. A total of 3185 people participated in the study. The results indicated the presence of a unidimensional structure and good reliability indices for the OCS in each country. The alignment method indicated that the OCS is an invariant measure of COVID-19 obsession among the populations of seven Latin American countries. The findings based on IRT analysis indicated that all OCS items had adequate discrimination and difficulty parameters. The findings contribute to the understanding of the internal structure of the scale in different countries at the same time, something that has been pending evaluation.

YAP1 Withdrawal in Hepatoblastoma Drives Therapeutic Differentiation of Tumor Cells to Functional Hepatocyte-Like Cells.

BACKGROUND AND AIMS: Despite surgical and chemotherapeutic advances, the 5-year survival rate for stage IV hepatoblastoma (HB), the predominant pediatric liver tumor, remains at 27%. Yes-associated protein 1 (YAP1) and ß-catenin co-activation occurs in 80% of children's HB; however, a lack of conditional genetic models precludes tumor maintenance exploration. Thus, the need for a targeted therapy remains unmet. Given the predominance of YAP1 and ß-catenin activation in HB, we sought to evaluate YAP1 as a therapeutic target in HB. APPROACH AND RESULTS: We engineered the conditional HB murine model using hydrodynamic injection to deliver transposon plasmids encoding inducible YAP1S127A , constitutive ß-cateninDelN90 , and a luciferase reporter to murine liver. Tumor regression was evaluated using bioluminescent imaging, tumor landscape characterized using RNA and ATAC sequencing, and DNA footprinting. Here we show that YAP1S127A withdrawal mediates more than 90% tumor regression with survival for 230+ days in mice. YAP1S127A withdrawal promotes apoptosis in a subset of tumor cells, and in remaining cells induces a cell fate switch that drives therapeutic differentiation of HB tumors into Ki-67-negative hepatocyte-like HB cells ("HbHeps") with hepatocyte-like morphology and mature hepatocyte gene expression. YAP1S127A withdrawal drives the formation of hbHeps by modulating liver differentiation transcription factor occupancy. Indeed, tumor-derived hbHeps, consistent with their reprogrammed transcriptional landscape, regain partial hepatocyte function and rescue liver damage in mice. CONCLUSIONS: YAP1S127A withdrawal, without silencing oncogenic ß-catenin, significantly regresses hepatoblastoma, providing in vivo data to support YAP1 as a therapeutic target for HB. YAP1S127A withdrawal alone sufficiently drives long-term regression in HB, as it promotes cell death in a subset of tumor cells and modulates transcription factor occupancy to reverse the fate of residual tumor cells to mimic functional hepatocytes.

Identification of Novel Microcystins Using High-Resolution MS and MSn with Python Code.

Cyanotoxins called microcystins (MCs) are highly toxic and can be present in drinking water sources. Determining the structure of MCs is paramount because of its effect on toxicity. Though over 300 MC congeners have been discovered, many remain unidentified. Herein, a method is described for the putative identification of MCs using liquid chromatography (LC) coupled with high-resolution (HR) Orbitrap mass spectrometry (MS) and a new bottom-up sequencing strategy. Maumee River water samples were collected during a harmful algal bloom and analyzed by LC-MS with simultaneous HRMS and MS/MS. Unidentified ions with characteristic MC fragments (135 and 213 m/z) were recognized as possible novel MC congeners. An innovative workflow was developed for the putative identification of these ions. Python code was written to generate the potential structures of unidentified MCs and to assign ions after the fragmentation for structural confirmation. The workflow enabled the putative identification of eight previously reported MCs for which standards are not available and two newly discovered congeners, MC-HarR and MC-E(OMe)R.

Long-term complications of cosmetic iris implants.

BACKGROUND: Additive cosmetic implants (NewColorIris, Kahn Medical Devices, Panama City, Panama) are placed in the anterior chamber, in order to externally change iris color. There is a lack of robust clinical long-term prospective studies regarding the safety of these devices, as they have been related to the early-onset presentation of corneal decompensation, elevated intraocular pressure (IOP), uveitis and hyphema. However, in this case report some mild complications started to manifest unexpectedly late: 15 years after an uneventful procedure. CASE PRESENTATION: A 41-year-old Caucasian woman presented with blurred vision in both eyes over the last 6 months. Fifteen years earlier, she had undergone bilateral implantation of additive iris implants for aesthetic purposes, without any complication or ocular trauma during the follow-up. Ocular examination showed bilateral mild corneal edema, iris atrophy, and presence of pigment in the endothelium. Increased IOP (28 mmHg) was identified in the right eye. Anterior segment optical coherence tomography (AS-OCT) confirmed the decentration of the iris implant from the pupillary axis in that eye. Gonioscopy demonstrated pigment dispersion in both eyes, as well as a tendency to bilateral angle closure, that was also illustrated by AS-OCT analysis. Endothelial cell count was 1268 cells/mm2 in the right eye and 1122 cells/mm2 in the left eye. The presence of both implants was affecting corneal endothelium and anterior chamber angle in both eyes, and additionally, the decentration of the device in the case of the right eye led to secondary ocular hypertension in that eye. CONCLUSIONS: Cosmetic implants in contact to the iris can remain quiescent for years, leading to possible complications that can present even in the long-term. The degree of implant decentration, the stage of angle closure disease and the magnitude of pigment dispersion may be some important factors related to the onset time of complications in these cases.

Dorsal Column Stimulation and Cannabinoids in the Treatment of Chronic Nociceptive and Neuropathic Pain: a Review of the Clinical and Pre-clinical Data.

PURPOSE OF REVIEW: The main objective of this review is to appraise the literature on the role of spinal cord stimulation (SCS), cannabinoid therapy, as well as SCS and cannabinoid combination therapy for the management of chronic neuropathic and nociceptive pain. Current research suggests that SCS reduces pain and increases functional status in carefully selected patients with minimal side effects. RECENT FINDINGS: As cannabinoid-based medications become a topic of increasing interest in pain management, data remains limited regarding the clinical efficacy of cannabinoids for pain relief. Furthermore, from a mechanistic perspective, although various pain treatment modalities utilize overlapping pain-signaling pathways, clarifying whether cannabinoids work synergistically with SCS via shared mechanisms remains to be determined. In considering secondary outcomes, the current literature suggests cannabinoids improve quality of life, specifically sleep quality, and that SCS decreases opioid consumption, increases functional capacity, and decreases long-term healthcare costs. These findings, along with the high safety profiles of SCS and cannabinoids overall, incentivize further exploration of cannabinoids as an adjunctive therapy to SCS in the treatment of neuropathic and nociceptive pain.

Predictors of mental health during the COVID-19 pandemic in older adults: the role of socio-demographic variables and COVID-19 anxiety.

The objective of this study was to evaluate factors related to the mental health of Peruvian older adults during the COVID-19 pandemic. The study had a cross-sectional and observational design. A total of 274 older adults in Lima, Peru (Mage = 67.86) filled out a sociodemographic survey, the Coronavirus Anxiety Scale, Mental Health Inventory-5, Patient Health Questionnaire-2 item, and Generalized Anxiety Disorder Scale. A Structural Equation Model (SEM) was estimated to test an a priori model that relates the sociodemographic variables, COVID-19 Anxiety, psychological well-being, anxiety and depression. The model fit indices indicated a good fit to the data. The socio-demographic variables explained 23.8% of the variance of the COVID-19 Anxiety (R2 = .238). Socio-demographic variables explained 50.5% of psychological well-being variance, 52% of anxiety and 46.9% of depression. Also, sex, work; being diagnosed with COVID-19; family member with COVID-19 diagnosis; and time of exposure to COVID-19 information had statistically significant effects psychological well-being, anxiety and depression. In conclusion, some sociodemographic characteristics and COVID-19 anxiety affect the psychological well-being, anxiety and depression. The findings may allow for a better understanding of the mental health of older adults during the COVID-19 pandemic and guide government responses to detect, anticipate and minimize its impact on the mental health of this population.

Fear of COVID-19 scale: Validity, reliability and factorial invariance in Argentina's general population.

This study evaluated the psychometric properties of the Scale of Fear of COVID-19 (FCV-19S) in a sample of 1,291 Argentines. The two-related factor structure of the FCV-19S had satisfactory goodness-of-fit indices using structural equation modeling and item response theory. Further results showed that the reliability was adequate, the factor structure was strictly invariable across age groups, and the model that evaluated the relationships between fear of COVID-19, anxiety, and depression had adequate goodness of fit indices as well. The results indicated that FCV-19S has strong psychometric properties to measure fear of COVID-19 in the general population of Argentina.

Is it possible to find a bifactor structure in the Fear of COVID-19 Scale (FCV-19S)? Psychometric evidence in an Ecuadorian sample.

The aim of the study was to evaluate the construct validity based on the internal structure, the relationship with other variables, and the internal consistency among items of the Fear of COVID-19 Scale (FCV-19S) in a sample of 743 Ecuadorians. The findings confirm the presence of a bifactor structure, which includes a general factor and two specific factors: one emotional and the other physiological. The general factor, and the specific factors presented adequate levels of internal consistency. Finally, the FCV-19S showed a highly significant relationship with GAD-7 at the latent level. The scale has adequate psychometric properties for its application.

Obsession with Covid-19 in Peruvian police and armed forces: Validation of the obsession with Covid-19 Scale in Spanish using SEM and IRT models.

The study evaluated the psychometric properties of the Spanish version of the Obsession with COVID-19 Scale (OCS) in 214 police and members of the armed forces (Mage = 29.33 years, SD = 11.28). The one-dimensionality and satisfactory reliability of OCS were confirmed with confirmatory factor analysis, Item Response Theory analysis, Cronbach's alpha, and McDonald's omega. The scale is useful for identifying individuals with low levels of persistent and disturbing thoughts about COVID-19. COVID-19 obsession was associated with COVID-19 fear, anxiety, and depression. The OCS is suitable for investigating the psychological impact of COVID-19 on members of the police and armed forces.

Coronavirus Anxiety Scale: New psychometric evidence for the Spanish version based on CFA and IRT models in a Peruvian sample.

The aim of the study was to analyze the psychometric properties of the Spanish version of the Coronavirus Anxiety Scale (CAS), using Item Response Theory (IRT) and Confirmatory Factor Analysis (CFA). The participants were 790 Peruvians, selected through a convenience sampling, where the majority were women. The CFA models indicated that the one-dimensional structure better represents the data, is reliable and invariant between men and women. Likewise, IRT findings indicate that CAS is more informative for high levels of COVID-19 anxiety. The CAS in Spanish has adequate psychometric properties to be used as a short measure of COVID-19 anxiety.