Arrested development: the dysfunctional life history of medulloblastoma.

Medulloblastoma is a heterogeneous embryonal tumor of the cerebellum comprised of four distinct molecular subgroups that differ in their developmental origins, genomic landscapes, clinical presentation, and survival. Recent characterization of the human fetal cerebellum at single-cell resolution has propelled unprecedented insights into the cellular origins of medulloblastoma subgroups, including those underlying previously elusive groups 3 and 4. In this review, the molecular pathogenesis of medulloblastoma is examined through the lens of cerebellar development. In addition, we discuss how enhanced understanding of medulloblastoma origins has the potential to refine disease modeling for the advancement of treatment and outcomes.

Meniscus Allograft Transplantation in Conjunction With Arthroscopic Biologic Knee Restoration Delays Arthroplasty in Patients Older Than 50 Years.

PURPOSE: To evaluate the utility of meniscus allografts in combination with other procedures to delay knee arthroplasty in patients older than 50 years previously advised joint arthroplasty. METHODS: A total of 108 meniscus allograft transplants using the arthroscopic 3-tunnel technique between 1997 and 2019 in patients older than 50 years were retrospectively reviewed with a 2-year minimum follow-up period. Inclusion criteria were patients recommended for knee arthroplasty with pain and preservation of some joint space by standing flexion radiographs. Exclusion criteria were lack of joint space, failure to comply with rehabilitation protocol, and failure to complete research questionnaires. International Knee Documentation Committee composite and isolated pain scale were evaluated longitudinally. Time from meniscus allograft transplant to arthroplasty was measured, with failure defined as allograft excision or revision, progression to arthroplasty, or same or increased pain. RESULTS: Eighty-six of 108 (79.6%) patients met eligibility criteria. Over the follow-up mean 8.55 (range 0.68 to 25.2) years, 42 of 87 (48.2%) grafts progressed to arthroplasty with mean time of 8.64 (median 8.05) years. Concomitant procedures did not have significant impact on survival; however, survival medians were higher among paste graft and chondroplasty and lower among osteotomy groups. At the time of reporting, 41 of 84 (48.8%) patients had intact meniscus transplants, demonstrating significant improvements (P < .001) in pain and function as assessed by International Knee Documentation Committee Score. These improvements were sustained 10 years postoperatively, correlated to a mean of 65.8 years of age. At least 50% of patients achieved Minimal Clinically Important Difference through 10 years postoperatively. CONCLUSIONS: Meniscus allografts in combination with other arthroscopic interventions delay knee arthroplasty and improve knee symptoms of pain and function in a population of knee arthroplasty candidates older than 50 years. Influences of concomitant procedures cannot be defined. LEVEL OF EVIDENCE: Level IV, therapeutic case series, retrospective.

Coronary artery calcium and cardiovascular outcomes in patients with lymphoma undergoing autologous hematopoietic cell transplantation.

BACKGROUND: Patients undergoing autologous hematopoietic cell transplantation (HCT) have a >2-fold risk of developing cardiovascular disease (CVD; heart failure, myocardial infarction, and stroke), compared to the general population. Coronary artery calcium (CAC) is predictive of CVD in nononcology patients but is not as well studied in patients who underwent HCT and survivors of HCT.The objective of this study was to examine the association between CAC and CVD risk and outcomes after HCT in patients with lymphoma. METHODS: This was a retrospective cohort study of 243 consecutive patients who underwent a first autologous HCT for lymphoma between 2009 and 2014. CAC (Agatston score) was determined from chest computed tomography obtained <60 days from HCT. Multivariable Cox regression analysis was used to calculate hazard ratio (HR) estimates and 95% confidence intervals (CIs), adjusted for covariates (age, conventional risk factors [e.g., hypertension and dyslipidemia], and cancer treatment). RESULTS: The median age at HCT was 55.7 years (range, 18.5-75.1 years), 59% were male, and 60% were non-Hispanic White. The prevalence of CAC was 37%. The 5-year CVD incidence for the cohort was 12%, and there was an incremental increase in the incidence according to CAC score: 0 (6%), 1-100 (20%), and >100 (32%) (p = .001). CAC was significantly associated with CVD risk (HR, 3.0; 95% CI, 1.2-7.5) and worse 5-year survival (77% vs. 50%; p < .001; HR, 2.0; 95% CI, 1.1-3.4), compared to those without CAC. CONCLUSIONS: CAC is independently associated with CVD and survival after HCT. This highlights the importance of integrating readily available imaging information in risk stratification and decision-making in patients undergoing HCT, which sets the stage for strategies to optimize outcomes after HCT.

Epithelial wound healing in Clytia hemisphaerica provides insights into extracellular ATP signaling mechanisms and P2XR evolution.

Epithelial wound healing involves the collective responses of many cells, including those at the wound margin (marginal cells) and those that lack direct contact with the wound (submarginal cells). How these responses are induced and coordinated to produce rapid, efficient wound healing remains poorly understood. Extracellular ATP (eATP) is implicated as a signal in epithelial wound healing in vertebrates. However, the role of eATP in wound healing in vivo and the cellular responses to eATP are unclear. Almost nothing is known about eATP signaling in non-bilaterian metazoans (Cnidaria, Ctenophora, Placozoa, and Porifera). Here, we show that eATP promotes closure of epithelial wounds in vivo in the cnidarian Clytia hemisphaerica (Clytia) indicating that eATP signaling is an evolutionarily ancient strategy in wound healing. Furthermore, eATP increases F-actin accumulation at the edges of submarginal cells. In Clytia, this indicates eATP is involved in coordinating cellular responses during wound healing, acting in part by promoting actin remodeling in cells at a distance from the wound. We also present evidence that eATP activates a cation channel in Clytia epithelial cells. This implies that the eATP signal is transduced through a P2X receptor (P2XR). Phylogenetic analyses identified four Clytia P2XR homologs and revealed two deeply divergent major branches in P2XR evolution, necessitating revision of current models. Interestingly, simple organisms such as cellular slime mold appear exclusively on one branch, bilaterians are found exclusively on the other, and many non-bilaterian metazoans, including Clytia, have P2XR sequences from both branches. Together, these results re-draw the P2XR evolutionary tree, provide new insights into the origin of eATP signaling in wound healing, and demonstrate that the cytoskeleton of submarginal cells is a target of eATP signaling.

Exploring the link between home garden use and severe obesity: Insights from a nationwide survey in Tuvalu.

Background: Obesity is prevalent and increasing but understudied across Pacific Islanders. Tuvalu is a South Pacific country with a high obesity rate and faces multiple threats of food insecurity. Home garden serves as a sustainable food source and can be a possible intervention for the obesity pandemic in Tuvalu. This study investigated Tuvaluans' home garden use and obesity, and explored factors associated with increased use of home gardens. Methods: We conducted a nationwide, cross-sectional study in Tuvalu during 2022. Structured questionnaires were administered during the in-person interviews, and trained interviewers measured the height and weight of each participant. The association between home garden use, obesity and severe obesity were tested with univariate and multivariable logistic regression. We also applied overlapping weights to balance the distribution of baseline demographic factors. Results: The average body mass index was 34.87 kilogrammes (kg) / square metre (m2) among the study population of 1024 adults (630 from Funafuti and 394 from other islands in Tuvalu). Overall, people having home gardens was associated lower odds for severe obesity compared to those without a home garden in overlap weighting models (odds ratio (OR) = 0.946, 95% CI = 0.897-0.997, P = 0.039) and the association was stronger in Funafuti (OR = 0.927, 95% CI = 0.866-0.991, P = 0.027) than in the outlying islands (OR = 0.967, 95% CI = 0.889-1.052, P = 0.435). Furthermore, increased age was positively associated with having a home garden in Funafuti, and smoking showed an inverse association. Conclusions: Having a home garden is associated with lower odds of severe obesity in Tuvalu, and the association is stronger in Funafuti. Smokers are less likely to have home gardens, and increased age is positively associated with having home gardens. These findings promote more home garden utilisation and provide evidence for targeted interventions in Tuvalu.

Effects of six pyrimidine analogs on the growth of Tetrahymena thermophila and their implications in pyrimidine metabolism.

Tetrahymena are ciliated protists that have been used to study the effects of toxic chemicals, including anticancer drugs. In this study, we tested the inhibitory effects of six pyrimidine analogs (5-fluorouracil, floxuridine, 5'-deoxy-5-fluorouridine, 5-fluorouridine, gemcitabine, and cytarabine) on wild-type CU428 and conditional mutant NP1 Tetrahymena thermophila at room temperature and the restrictive temperature (37°C) where NP1 does not form the oral apparatus. We found that phagocytosis was not required for pyrimidine analog entry and that all tested pyrimidine analogs inhibited growth except for cytarabine. IC50 values did not significantly differ between CU428 and NP1 for the same analog at either room temperature or 37°C. To investigate the mechanism of inhibition, we used two pyrimidine bases (uracil and thymine) and three nucleosides (uridine, thymidine, and 5-methyluridine) to determine whether the inhibitory effects from the pyrimidine analogs were reversible. We found that the inhibitory effects from 5-fluorouracil could be reversed by uracil and thymine, from floxuridine could be reversed by thymidine, and from 5'-deoxy-5-fluorouridine could be reversed by uracil. None of the tested nucleobases or nucleosides could reverse the inhibitory effects of gemcitabine or 5-fluorouridine. Our results suggest that the five pyrimidine analogs act on different sites to inhibit T. thermophila growth and that nucleobases and nucleosides are metabolized differently in Tetrahymena.

Progression to Hindfoot Charcot Neuroarthropathy After Midfoot Charcot Correction in Patients With and Without Subtalar Joint Arthrodesis.

Charcot neuroarthropathy (CNA) is a disabling and progressive disease that affects the bones and joints of the foot. Successful Charcot reconstruction focuses on restoring anatomic alignment, obtaining multiple joint arthrodesis, selecting stable fixation, preserving foot length, and creating a foot suitable for community ambulation in supportive shoegear. Intramedullary fixation arthrodesis of the medial and lateral columns has been previously reported to produce improvement in midfoot Charcot reconstruction. More recently, a growing trend of stabilization of the subtalar joint (STJ) has been incorporated alongside the medial and lateral column fusion. Our objectives were to retrospectively review patients who underwent midfoot Charcot reconstructive surgery, whether with or without accompanying STJ arthrodesis, and establish which patients progressed to ankle CNA. Of the 72 patients who underwent midfoot Charcot reconstruction, 28 (38.9%) underwent STJ arthrodesis, and 22 converted to ankle CNA (30.6%). Fourteen (63.6%) of 22 ankle CNA cases had not undergone STJ arthrodesis; 8 patients (36.4%) had it. A Fisher exact test was performed to identify the relationship between those without STJ arthrodesis and those progressing to ankle CNA; it revealed statistical significance (p = .001). Performing an STJ arthrodesis with midfoot Charcot reconstructive surgery may be beneficial to aiding in hindfoot stability, establishing a plantigrade foot, and providing further insight into the management of midfoot Charcot.

UHRF1 overexpression promotes osteosarcoma metastasis through altered exosome production and AMPK/SEMA3E suppression.

Loss-of-function mutations at the retinoblastoma (RB1) gene are associated with increased mortality, metastasis, and poor therapeutic outcome in several cancers, including osteosarcoma. However, the mechanism(s) through which RB1 loss worsens clinical outcome remains understudied. Ubiquitin-like with PHD and Ring Finger domains 1 (UHRF1) has been identified as a critical downstream effector of the RB/E2F signaling pathway that is overexpressed in various cancers. Here, we determined the role and regulatory mechanisms of UHRF1 in rendering osteosarcoma cells more aggressive. Higher UHRF1 expression correlated with malignancy in osteosarcoma cell lines, clinical samples, and genetically engineered mouse models. Gain- and loss-of-function assays revealed that UHRF1 has cell-intrinsic and extrinsic functions promoting cell proliferation, migration, invasion, angiogenesis, and metastasis. UHRF1 overexpression induced angiogenesis by suppressing AMPK activation and Semaphorin 3E (SEMA3E) expression. Further, UHRF1-mediated migration and metastasis resulted, at least in part, through altered expression of extracellular vesicles and their cargo, including urokinase-type plasminogen activator (uPA). Novel osteosarcoma genetically engineered mouse models confirmed that knocking out Uhrf1 considerably decreased metastasis and reversed the poorer survival associated with Rb1 loss. This presents a new mechanistic insight into RB1 loss-associated poor prognosis and novel oncogenic roles of UHRF1 in the regulation of angiogenesis and exosome secretion, both critical for osteosarcoma metastasis. This provides substantial support for targeting UHRF1 or its downstream effectors as novel therapeutic options to improve current treatment for osteosarcoma.

Mitral annular disjunction: A case series and review of the literature.

Mitral annular disjunction (MAD) is an abnormal displacement of the mitral valve leaflet onto the left atrial wall and is commonly found in patients with mitral valve prolapse (MVP). The diagnosis is usually made by transthoracic echocardiography (TTE) although findings can be subtle and further cardiac imaging may be necessary. MAD has been associated with a risk of malignant ventricular arrhythmias and sudden cardiac death, therefore recognition of this diagnosis and risk stratification are highly important. In this review, we will discuss the diagnosis, clinical implications, risk stratification and management of MAD based upon currently available literature, as well as provide a series of cases showing the heterogeneity in presentation and our experience with management of this rare but potentially fatal entity.

Inhibition of CCL28/CCR10-Mediated eNOS Downregulation Improves Skin Wound Healing in the Obesity-Induced Mouse Model of Type 2 Diabetes.

Chronic, nonhealing skin wounds, such as diabetic foot ulcers (DFUs), are common in patients with type 2 diabetes. Here, we investigated the role of chemokine (C-C motif) ligand 28 (CCL28) and its receptor C-C chemokine receptor type 10 (CCR10) in downregulation of endothelial nitric (NO) oxide synthase (eNOS) in association with delayed skin wound healing in the db/db mouse model of type 2 diabetes. We observed reduced eNOS expression and elevated CCL28/CCR10 levels in dorsal skin of db/db mice and subdermal leg biopsy specimens from human subjects with type 2 diabetes. Further interrogation revealed that overexpression of CCR10 reduced eNOS expression, NO bioavailability, and tube formation of human dermal microvascular endothelial cells (HDMVECs) in vitro, which was recapitulated in mouse dorsal skin. In addition, incubation of HDMVECs with CCL28 led to internalization of the CCR10/eNOS complex and colocalization with lysosome-associated membrane protein 1. Finally, topical application of myristoylated CCR10 binding domain 7 amino acid (Myr-CBD7) peptide prevented CCR10-eNOS interaction and subsequent eNOS downregulation, enhanced eNOS/NO levels, eNOS/VEGF-R2+ microvessel density, and blood perfusion, reduced inflammatory cytokine levels, and importantly, decreased wound healing time in db/db mice. Thus, endothelial cell CCR10 activation in genetically obese mice with type 2 diabetes promotes eNOS depletion and endothelial dysfunction, and targeted disruption of CCR10/eNOS interaction improves wound healing.

Modeling the relative risk of incidence and mortality of select vaccine-preventable diseases by wealth group and geographic region in Ethiopia.

Immunization is one of the most effective public health interventions, saving millions of lives every year. Ethiopia has seen gradual improvements in immunization coverage and access to child health care services; however, inequalities in child mortality across wealth quintiles and regions remain persistent. We model the relative distributional incidence and mortality of four vaccine-preventable diseases (VPDs) (rotavirus diarrhea, human papillomavirus, measles, and pneumonia) by wealth quintile and geographic region in Ethiopia. Our approach significantly extends an earlier methodology, which utilizes the population attributable fraction and differences in the prevalence of risk and prognostic factors by population subgroup to estimate the relative distribution of VPD incidence and mortality. We use a linear system of equations to estimate the joint distribution of risk and prognostic factors in population subgroups, treating each possible combination of risk or prognostic factors as computationally distinct, thereby allowing us to account for individuals with multiple risk factors. Across all modeling scenarios, our analysis found that the poor and those living in rural and primarily pastoralist or agrarian regions have a greater risk than the rich and those living in urban regions of becoming infected with or dying from a VPD. While in absolute terms all population subgroups benefit from health interventions (e.g., vaccination and treatment), current unequal levels and pro-rich gradients of vaccination and treatment-seeking patterns should be redressed so to significantly improve health equity across wealth quintiles and geographic regions in Ethiopia.

Immune biomarkers and response to checkpoint inhibition of BRAFV600 and BRAF non-V600 altered lung cancers.

BACKGROUND: While 2-4% of lung cancers possess alterations in BRAF, little is known about the immune responsiveness of these tumours. METHODS: Clinical and genomic data were collected from 5945 patients with lung cancers whose tumours underwent next-generation sequencing between 2015 and 2018. Patients were followed through 2020. RESULTS: In total, 127 patients with metastatic BRAF-altered lung cancers were identified: 29 tumours had Class I mutations, 59 had Class II/III alterations, and 39 had variants of unknown significance (VUS). Tumour mutation burden was higher in Class II/III than Class I-altered tumours (8.8 mutations/Mb versus 4.9, P < 0.001), but this difference was diminished when stratified by smoking status. The overall response rate to immune checkpoint inhibitors (ICI) was 9% in Class I-altered tumours and 26% in Class II/III (P = 0.25), with median time on treatment of 1.9 months in both groups. Among patients with Class I-III-altered tumours, 36-month HR for death in those who ever versus never received ICI was 1.82 (1.17-6.11). Nine patients were on ICI for >2 years (two with Class I mutations, two with Class II/III alterations, and five with VUS). CONCLUSIONS: A subset of patients with BRAF-altered lung cancers achieved durable disease control on ICI. However, collectively no significant clinical benefit was seen.

Improving spatial data in health geographics: a practical approach for testing data to measure children's physical activity and food environments using Google Street View.

BACKGROUND: Geographic information systems (GIS) are often used to examine the association between both physical activity and nutrition environments, and children's health. It is often assumed that geospatial datasets are accurate and complete. Furthermore, GIS datasets regularly lack metadata on the temporal specificity. Data is usually provided 'as is', and therefore may be unsuitable for retrospective or longitudinal studies of health outcomes. In this paper we outline a practical approach to both fill gaps in geospatial datasets, and to test their temporal validity. This approach is applied to both district council and open-source datasets in the Taranaki region of Aotearoa New Zealand. METHODS: We used the 'streetview' python script to download historic Google Street View (GSV) images taken between 2012 and 2016 across specific locations in the Taranaki region. Images were reviewed and relevant features were incorporated into GIS datasets. RESULTS: A total of 5166 coordinates with environmental features missing from council datasets were identified. The temporal validity of 402 (49%) environmental features was able to be confirmed from council dataset considered to be 'complete'. A total of 664 (55%) food outlets were identified and temporally validated. CONCLUSIONS: Our research indicates that geospatial datasets are not always complete or temporally valid. We have outlined an approach to test the sensitivity and specificity of GIS datasets using GSV images. A substantial number of features were identified, highlighting the limitations of many GIS datasets.

Additive Effects of Arsenic and Aristolochic Acid in Chemical Carcinogenesis of Upper Urinary Tract Urothelium.

BACKGROUND: Aristolochic acids (AA) and arsenic are chemical carcinogens associated with urothelial carcinogenesis. Here we investigate the combined effects of AA and arsenic toward the risk of developing upper tract urothelial carcinoma (UTUC). METHODS: Hospital-based (n = 89) and population-based (2,921 cases and 11,684 controls) Taiwanese UTUC cohorts were used to investigate the association between exposure to AA and/or arsenic and the risk of developing UTUC. In the hospital cohort, AA exposure was evaluated by measuring aristolactam-DNA adducts in the renal cortex and by identifying A>T TP53 mutations in tumors. In the population cohort, AA exposure was determined from prescription health insurance records. Arsenic levels were graded from 0 to 3 based on concentrations in well water and the presence of arseniasis-related diseases. RESULTS: In the hospital cohort, 43, 26, and 20 patients resided in grade 0, 1+2, and 3 arseniasis-endemic areas, respectively. Aristolactam-DNA adducts were present in >90% of these patients, indicating widespread AA exposure. A>T mutations in TP53 were detected in 28%, 44%, and 22% of patients residing in grade 0, 1+2, and 3 arseniasis-endemic areas, respectively. Population studies revealed that individuals who consumed more AA-containing herbs had a higher risk of developing UTUC in both arseniasis-endemic and nonendemic areas. Logistic regression showed an additive effect of AA and arsenic exposure on the risk of developing UTUC. CONCLUSIONS: Exposure to both AA and arsenic acts additively to increase the UTUC risk in Taiwan. IMPACT: This is the first study to investigate the combined effect of AA and arsenic exposure on UTUC.

Offloading for the Diabetic Foot: Considerations and Implications.

Offloading the diabetic foot remains the major consideration for ulceration prevention and healing. This narrative literature review presents a brief overview of current guidelines for offloading the diabetic foot and discusses the implications that come with offloading treatment modalities and their effects on the kinetic chain of the lower extremity. We also present the latest innovative studies from the Dr. William M. Scholl College of Podiatric Medicine at Rosalind Franklin University of Medicine and Science that advance the knowledge in this field and provide avenues for future research opportunities.

Chromatin remodeling protein HELLS is critical for retinoblastoma tumor initiation and progression.

Retinoblastoma is an aggressive childhood cancer of the developing retina that initiates by biallelic RB1 gene inactivation. Tumor progression in retinoblastoma is driven by epigenetics, as retinoblastoma genomes are stable, but the mechanism(s) that drive these epigenetic changes remain unknown. Lymphoid-specific helicase (HELLS) protein is an epigenetic modifier directly regulated by the RB/E2F pathway. In this study, we used novel genetically engineered mouse models to investigate the role of HELLS during retinal development and tumorigenesis. Our results indicate that Hells-null retinal progenitor cells divide, undergo cell-fate specification, and give rise to fully laminated retinae with minor bipolar cells defects, but normal retinal function. Despite the apparent nonessential role of HELLS in retinal development, failure to transcriptionally repress Hells during retinal terminal differentiation due to retinoblastoma (RB) family loss significantly contributes to retinal tumorigenesis. Loss of HELLS drastically reduced ectopic division of differentiating cells in Rb1/p107-null retinae, significantly decreased the incidence of retinoblastoma, delayed tumor progression, and increased overall survival. Despite its role in heterochromatin formation, we found no evidence that Hells loss directly affected chromatin accessibility in the retina but functioned as transcriptional co-activator of E2F3, decreasing expression of cell cycle genes. We propose that HELLS is a critical downstream mediator of E2F-dependent ectopic proliferation in RB-null retinae. Together with the nontoxic effect of HELLS loss in the developing retina, our results suggest that HELLS and its downstream pathways could serve as potential therapeutic targets for retinoblastoma.

An open-label trial of cryopreserved human umbilical cord in the treatment of complex diabetic foot ulcers complicated by osteomyelitis.

Clinical trials of potential new therapies for diabetic foot ulcers rarely enroll patients whose wounds extend to muscle, fascia, or bone with clinical and radiographic evidence of underlying osteomyelitis. An open-label, multicenter trial of cryopreserved human umbilical cord (TTAX01) was undertaken in 32 subjects presenting with such complex wounds with a mean duration of 6.1 ± 9.0 (range: 0.2-47.1) months and wound area at screening of 3.8 ± 2.9 (range: 1.0-9.6) cm2 . Aggressive surgical debridement at baseline resulted in 17 minor amputations and an increase in mean wound area to 7.4 ± 5.8 (range: 1.1-28.6) cm2 . All subjects were placed on systemic antibiotics for at least 6 weeks in conjunction with baseline application of TTAX01. Repeat applications were made at no less than 4-week intervals over the 16-week trial. Initial closure occurred in 18 of 32 (56%) wounds, with 16 (50%) of these having confirmed closure in 16 weeks with a median of one-product application. Cases with biopsy confirmed osteomyelitis (n = 20) showed initial closure in 12 (60%) wounds and confirmed closure in 10 (50%) wounds. Four of the five ulcers presenting as recurrences experienced confirmed closure. Mean overall time to healing was 12.8 ± 4.3 weeks. Mean wound area reduction from baseline was 91% for all wounds. Of the 16 wounds without confirmed closure during the 16-week treatment period, five (31.3%) achieved 99-100% wound area reduction by their final visit. The product was well tolerated. Two minor amputations occurred during the study period due to recurrent or persistent osteomyelitis; however, there were no major amputations.