The PML1-WDR5 axis regulates H3K4me3 marks and promotes stemness of estrogen receptor-positive breast cancer.

The alternative splicing of PML precursor mRNA gives rise to various PML isoforms, yet their expression profile in breast cancer cells remains uncharted. We discovered that PML1 is the most abundant isoform in all breast cancer subtypes, and its expression is associated with unfavorable prognosis in estrogen receptor-positive (ER+) breast cancers. PML depletion reduces cell proliferation, invasion, and stemness, while heterologous PML1 expression augments these processes and fuels tumor growth and resistance to fulvestrant, an FDA-approved drug for ER+ breast cancer, in a mouse model. Moreover, PML1, rather than the well-known tumor suppressor isoform PML4, rescues the proliferation of PML knockdown cells. ChIP-seq analysis reveals significant overlap between PML-, ER-, and Myc-bound promoters, suggesting their coordinated regulation of target gene expression, including genes involved in breast cancer stem cells (BCSCs), such as JAG1, KLF4, YAP1, SNAI1, and MYC. Loss of PML reduces BCSC-related gene expression, and exogenous PML1 expression elevates their expression. Consistently, PML1 restores the association of PML with these promoters in PML-depleted cells. We identified a novel association between PML1 and WDR5, a key component of H3K4 methyltransferase (HMTs) complexes that catalyze H3K4me1 and H3K4me3. ChIP-seq analyses showed that the loss of PML1 reduces H3K4me3 in numerous loci, including BCSC-associated gene promoters. Additionally, PML1, not PML4, re-establishes the H3K4me3 mark on these promoters in PML-depleted cells. Significantly, PML1 is essential for recruiting WDR5, MLL1, and MLL2 to these gene promoters. Inactivating WDR5 by knockdown or inhibitors phenocopies the effects of PML1 loss, reducing BCSC-related gene expression and tumorsphere formation and enhancing fulvestrant's anticancer activity. Our findings challenge the conventional understanding of PML as a tumor suppressor, redefine its role as a promoter of tumor growth in breast cancer, and offer new insights into the unique roles of PML isoforms in breast cancer.

Barriers to dental utilization among Medicaid-enrolled young children from primary care practices in Northeast Ohio.

OBJECTIVES: To evaluate the individual and community factors that contribute to dental utilization among young children on Medicaid utilizing the Anderson Model and the Socio-Ecological Framework. METHODS: This observational cross-sectional study was conducted using baseline data (socio-demographics, clinical dental need) from a cluster-randomized hybrid effectiveness-implementation trial among 1021 child-parent dyads recruited from primary care practices across northeast Ohio. The baseline data were then linked to dental Medicaid claims data (categorized as any dental visit, volume, and type in the past 12 months) and ICD-10 codes from the child's EHR data (individual-level) together with Dental Health Provider Shortage Area (HPSA) status and Area Deprivation Index (ADI) which were obtained at the neighbourhood-level using home address of each dyad (community-level). Multivariable analyses using generalized estimating equations (GEE) accounted for clustering by practice, and models included individual-level alone, and individual + community-level factors to evaluate their effects on dental utilization. RESULTS: Medicaid claims data indicated that among the 1021 children (mean age: 4.3 ± 1.1 years; 54.4% males; 43.8% Black, Non-Hispanic), a majority of children were seeing the dentist at least once a year by the age of 4 (56.1%). The mean ADI of their neighbourhoods was 109.22 (20.2) and 27.5% lived in a HPSA area. The GEE analyses revealed that individual factors such as older children, parents being married, and continuous Medicaid enrollment were associated with significantly higher dental utilization. Among community factors, being in a HPSA had an OR = 1.53 (CI: 1.03, 2.27) associated with higher dental utilization. CONCLUSIONS: Being in a HPSA was associated with higher dental utilization possibly due to dentists or safety net dental clinics in these areas accepting Medicaid-eligible children.

Adoption of New Oral Health Interventions in Primary Care: Qualitative Findings.

Introduction: This is the first study to use the Common-Sense Model of Self-Regulation theory for oral health interventions in pediatric practices. The objective of this qualitative study was to assess adoption and implementation of theory-based multilevel oral health interventions, by clinicians (pediatricians and nurse practitioners) participating in a cluster randomized clinical trial, to create an oral health toolkit for widespread dissemination into pediatric practices. Methods: Semistructured interviews were conducted at the conclusion of the cluster randomized clinical trial with 21 clinicians from 9 practices participating in the intervention arm. Clinicians in this arm received Common-Sense Model of Self-Regulation theory-based education and resources to deliver oral health interventions to parents/caregivers and document in electronic medical record. Semistructured interview questions were based on the Diffusion of Innovations Theory, assessing adoption and implementation. The interviews were coded using NVivo (QRS International) software. Main themes were identified using a thematic analysis approach. Results: Five themes identified from the interviews included strengths of theory-based oral health training for clinicians, oral health resources to improve quality of care, considerations for efficient future implementation, financial considerations, and parent benefits and challenges. Clinicians found that the theory-based training and resources increased knowledge and confidence when addressing oral health with parents and required only ≤2 minutes in their workflow with no financial consequences. Clinicians reported an increase in oral health awareness among parents but suggested an overall need for more pediatric dentists. Conclusions: The Common-Sense Model of Self-Regulation theory-based education and resources were well received by clinicians and perceived to be beneficial without adverse impact on workflow or practice finances. An online toolkit is planned because these oral health interventions can be successfully implemented and delivered in medical settings.

Association of pulse pressure with death, myocardial infarction, and stroke among cardiovascular outcome trial participants.

Background: Prior evidence demonstrates that pulse pressure (PP), a surrogate marker of arterial stiffness, is an independent risk factor for mortality and major adverse cardiovascular (CV) events. Objectives: The study aimed to identify the association of PP with death, myocardial infarction, and stroke among participants enrolled in large CV outcome clinical trials and determine if this association was impacted by pre-existing CV disease, or specific CV risk factors. Methods: A total of 65,382 individuals, ages 19 to 98 years, that were enrolled in one of five CV outcome trials were analyzed. Baseline demographics, history, blood pressures, and medications were collected. Univariate and multivariable analyses were conducted to explore temporal patterns, risks, and adjusted survival rates. Results: Mean baseline PP was 52 ± 12 mmHg. For every 10 mmHg increase in PP, there was an increased risk of death, stroke, or myocardial infarction (hazard ratio (HR) 1.11, 95 % CI 1.08 to 1.14, p < 0.001). Similarly, a PP ≥ 60 mmHg demonstrated an HR of 1.27 (95 % CI 1.19 to 1.36, p < 0.001) compared with PP < 60 mmHg. A similar association existed for all subgroups analyzed except for participants with a history of stroke where increasing PP did not increase risk (HR 1.02, 95 % CI 0.95 to 1.10, p = 0.53). PP was a better predictor of adverse outcomes when compared to both systolic and diastolic blood pressures using the AIC and C-index. Conclusions: Among participants enrolled in CV outcome trials, baseline PP is associated with increased risk of death, myocardial infarction, and stroke for those with pre-existing CV disease and risk factors with the exception of a prior history of stroke.

The PML1-WDR5 axis regulates H3K4me3 marks and promotes stemness of estrogen receptor-positive breast cancer.

The alternative splicing of PML precursor mRNA gives rise to various PML isoforms, yet their expression profile in breast cancer cells remains uncharted. We discovered that PML1 is the most abundant isoform in all breast cancer subtypes, and its expression is associated with unfavorable prognosis in estrogen receptor-positive (ER+) breast cancers. PML depletion reduces cell proliferation, invasion, and stemness, while heterologous PML1 expression augments these processes and fuels tumor growth and resistance to fulvestrant, an FDA-approved drug for ER + breast cancer, in a mouse model. Moreover, PML1, rather than the well-known tumor suppressor isoform PML4, rescues the proliferation of PML knockdown cells. ChIP-seq analysis reveals significant overlap between PML-, ER-, and Myc-bound promoters, suggesting their coordinated regulation of target gene expression, including genes involved in breast cancer stem cells (BCSCs), such as JAG1, KLF4, YAP1, SNAI1, and MYC. Loss of PML reduces BCSC-related gene expression, and exogenous PML1 expression elevates their expression. Consistently, PML1 restores the association of PML with these promoters in PML-depleted cells. We identified a novel association between PML1 and WDR5, a key component of H3K4 methyltransferase (HMTs) complexes that catalyze H3K4me1 and H3K4me3. ChIP-seq analyses showed that the loss of PML1 reduces H3K4me3 in numerous loci, including BCSC-associated gene promoters. Additionally, PML1, not PML4, re-establishes the H3K4me3 mark on these promoters in PML-depleted cells. Significantly, PML1 is essential for recruiting WDR5, MLL1, and MLL2 to these gene promoters. Inactivating WDR5 by knockdown or inhibitors phenocopies the effects of PML1 loss, reducing BCSC-related gene expression and tumorsphere formation and enhancing fulvestrant's anticancer activity. Our findings challenge the conventional understanding of PML as a tumor suppressor, redefine its role as a promoter of tumor growth in breast cancer and offer new insights into the unique roles of PML isoforms in breast cancer.

A Scoping Review of Trauma-Informed Pediatric Interventions in Response to Natural and Biologic Disasters.

A scoping review was performed of trauma-informed psychological interventions to treat anxiety, depression, and posttraumatic stress symptoms in youth in response to natural/biologic disasters. The specific aims were to identify psychosocial interventions used in response to natural/biologic disasters, report the interventions' effectiveness, describe limitations, and provide treatment recommendations and future directions. Of the 45 studies extracted, 28 were on natural disasters and 17 on biologic disasters with the majority related to the COVID-19 pandemic. The most commonly implemented interventions were Cognitive Behavioral Therapy (CBT), Trauma-Focused Cognitive Behavioral Therapy (TF-CBT), and eye movement desensitization and reprocessing (EMDR). The UCLA Posttraumatic Stress Disorder Reaction Index (UCLA PTSD-RI) and the Strengths and Difficulties Questionnaire (SDQ) were the most frequently used measures. Methodological rigor was varied, with 60% randomized, controlled trials. Overall, there was a significant decrease in posttraumatic stress symptoms, distress, anxiety, and depression regardless of whether the participant received CBT, TF-CBT, or EMDR. Generally, there was not a significant decrease in anxiety and depression with yoga, cognitive fear-reduction, emotion-based drawing, and community health education. Recommendations for future directions include larger-scale studies with group and on-line interventions that include younger children with moderation analyses by gender and race/ethnicity.

An Evaluation of Core Decompression and Cancellous Bone Grafting for Early-Stage Avascular Necrosis of the Femoral Head.

Background Avascular necrosis (AVN) is characterized by bone death due to impaired blood supply leading to its collapse causing pain and suboptimal joint function. The blood supply of the femoral head is so tenuous that even a slight vascular injury can predispose to AVN. Hence, AVN is commonly seen in the femoral head. Core decompression can arrest or even reverse the process of AVN and can avoid femoral head collapse and its sequelae. A lateral trochanteric approach is used for core decompression. The necrotic bone is removed from the femoral head. The use of a non-vascularized bone graft is more attractive than a vascularized graft because it is significantly less technically challenging. The regenerative properties due to the presence of osteoblasts in the trabecular bone and the ability to procure a large amount of graft make the iliac crest the gold standard site of cancellous bone graft harvesting. Core decompression can be considered an effective treatment modality in early-stage AVN (up to stage 2B) of the femoral head. Methodology A prospective, interventional study was conducted in a tertiary care teaching hospital in southern Rajasthan, India. 20 Patients with AVN of the femoral head (up to grade 2B of Ficat and Arlet classification) who met the inclusion and exclusion criteria and presented to the orthopedic outpatient department of our institute were included in this study. Patients were treated with core decompression and cancellous bone grafting with a graft taken from the iliac crest. The Harris Hip Score (HHS) and Visual Analog Scale (VAS) score were used to assess the outcomes. Results In our study, the majority (50%) of the patients were in the 20-30-year age group, making it the most common age group with a male predominance (85%). In this study, the final result was calculated according to the HHS and VAS scores. The mean HHS was 69.45 preoperatively and 83.55 at six months postoperatively. Similarly, the mean VAS score was 6.3 preoperatively and 3.8 at six months postoperatively. Conclusions Core decompression with cancellous bone grafting is a promising procedure in stages 1 and 2 as it reduces the symptoms in the majority of cases and improves functional outcomes.

A Study of the Functional Outcome of Supplementation of Hamstring Graft With Anterior Half of the Peroneus Longus Tendon in Arthroscopic Anterior Cruciate Ligament Reconstruction.

INTRODUCTION: The present study was done to analyze the functional outcome, donor site morbidities, and associated parameters when using the anterior half of the peroneus longus for augmentation of an inadequate hamstring graft when performing arthroscopic anterior cruciate ligament (ACL) reconstruction. METHODS: Thirty patients with complete ACL tears were operated on. In all these patients, the thickness or length of the hamstring graft taken was found to be inadequate (less than 8 mm and 7.5 cm, respectively). So, additionally, the anterior half of the peroneus longus tendon (AHPLT) graft was harvested to reach an optimum size of the final graft. Functional outcome was assessed using the International Knee Documentation Committee (IKDC) score at six weeks, three months, and six months. The Foot and Ankle Disability Index (FADI) score at six months was used to assess ankle stability. RESULTS: The mean age in our study was 28.8 years with male predominance (73.33%). The mean operative time was 86.4 minutes. The mean hamstring graft thickness in our study was 6.5 mm, which improved to 9.12 mm after augmentation. The mean graft length after AHPLT augmentation was 9.38 cm. The mean IKDC score at six months was 87.35. At the end of six months, FADI scores were found within normal limits (range: 135-136) in all the patients. No complications were noted in any of the patients. CONCLUSION: The AHPLT graft was always found to be sufficient enough for augmenting the hamstring graft to reach an acceptable thickness and length. There was no graft site morbidity and the ankle functional levels remained the same as preoperative levels, making it an excellent choice for augmentation of inadequate hamstring grafts.