Elucidating the clinical spectrum and molecular basis of HYAL2 deficiency.

PURPOSE: We previously defined biallelic HYAL2 variants causing a novel disorder in 2 families, involving orofacial clefting, facial dysmorphism, congenital heart disease, and ocular abnormalities, with Hyal2 knockout mice displaying similar phenotypes. In this study, we better define the phenotype and pathologic disease mechanism. METHODS: Clinical and genomic investigations were undertaken alongside molecular studies, including immunoblotting and immunofluorescence analyses of variant/wild-type human HYAL2 expressed in mouse fibroblasts, and in silico modeling of putative pathogenic variants. RESULTS: Ten newly identified individuals with this condition were investigated, and they were associated with 9 novel pathogenic variants. Clinical studies defined genotype-phenotype correlations and confirmed a recognizable craniofacial phenotype in addition to myopia, cleft lip/palate, and congenital cardiac anomalies as the most consistent manifestations of the condition. In silico modeling of missense variants identified likely deleterious effects on protein folding. Consistent with this, functional studies indicated that these variants cause protein instability and a concomitant cell surface absence of HYAL2 protein. CONCLUSION: These studies confirm an association between HYAL2 alterations and syndromic cleft lip/palate, provide experimental evidence for the pathogenicity of missense alleles, enable further insights into the pathomolecular basis of the disease, and delineate the core and variable clinical outcomes of the condition.

Women supporting women: Supportive/educative groups for ethnically diverse, urban, impoverished women dealing with depression and anxiety.

Depression and anxiety are mental health issues that disproportionately affect urban, ethnically diverse, impoverished women. Using community based participatory research and in the context of long-term partnerships between a nursing department and underserved neighborhoods that are predominately Black, Hispanic, and White respectively, supportive/educative groups were offered. The study employed a quasi-experimental, nonequivalent comparison group pretest-posttest design. Seventy-two women aged 17-88 years participated. Repeated measures ANOVA indicated a significant increase in knowledge for self-care for depression and anxiety and a significant decrease in anxiety and depression symptomatology from before to after the group sessions.

An Analysis of Global Surgery Opportunities in American Otolaryngology Residency Programs.

OBJECTIVES: To depict the current state of global surgery opportunities in United States ACGME-approved Otolaryngology residency programs and compare the characteristics of programs with and without these opportunities. METHODS: In this cross-sectional analysis, websites of ACGME-accredited Otolaryngology residency programs were analyzed for information on program size, rank, age, and geographic region as obtained through the Doximity platform in 2023. Additional parameters were obtained for programs listing global surgery opportunities such as funding, faculty oversight, location/region, focus, and relationship to the community served. Data were tabulated and analyzed in Microsoft Excel and Stata. RESULTS: Of the 131 ACGME-accredited Otolaryngology residency programs, 26 (20%) of programs advertised a global surgery opportunity. Nine (35%) of these promoted funding, 15 (58%) offered a clinical focus, one (4%) offered a research focus, and 10 (38%) offered a combined approach. The Midwest region had the most programs with global surgery opportunities (n = 8, 31%). Less than half (42%) of programs had an established partnership with local partners within low and middle-income countries (LMICs). When comparing programs, the average Doximity rank, average program age, and average program size of programs that offered global surgery opportunities was significantly higher than those that did not (37.2 vs. 71.5, 54 vs. 41, 19.5 vs. 13.7; all p < 0.05). CONCLUSIONS: Approximately one-fifth of Otolaryngology training programs have a global surgery opportunity. Programs that offer these opportunities had a higher Doximity ranking, older program age, and a larger trainee cohort. These results highlight potential areas for expanding global surgery opportunities in academic institutions. LEVEL OF EVIDENCE: NA Laryngoscope, 134:4501-4505, 2024.

Feasible diet and circadian interventions reduce in vivo progression of FLT3-ITD-positive acute myeloid leukemia.

BACKGROUND: Acute myeloid leukemia (AML) with an internal tandem duplication in the fms-like tyrosine kinase receptor 3 gene (FLT3-ITD) is associated with poor survival, and few studies have examined the impact of modifiable behaviors, such as nutrient quality and timing, in this subset of acute leukemia. METHODS: The influence of diet composition (low-sucrose and/or low-fat diets) and timing of diet were tested in tandem with anthracycline treatment in orthotopic xenograft mouse models. A pilot clinical study to test receptivity of pediatric leukemia patients to macronutrient matched foods was conducted. A role for the circadian protein, BMAL1 (brain and muscle ARNT-like 1), in effects of diet timing was studied by overexpression in FLT3-ITD-bearing AML cells. RESULTS: Reduced tumor burden in FLT3-ITD AML-bearing mice was observed with interventions utilizing low-sucrose and/or low-fat diets, or time-restricted feeding (TRF) compared to mice fed normal chow ad libitum. In a tasting study, macronutrient matched low-sucrose and low-fat meals were offered to pediatric acute leukemia patients who largely reported liking the meals. Expression of the circadian protein, BMAL1, was heightened with TRF and the low-sucrose diet. BMAL1 overexpression and treatment with a pharmacological inducer of BMAL1 was cytotoxic to FLT3-ITD AML cells. CONCLUSIONS: Mouse models for FLT3-ITD AML show that diet composition and timing slows progression of FLT3-ITD AML growth in vivo, potentially mediated by BMAL1. These interventions to enhance therapy efficacy show preliminary feasibility, as pediatric leukemia patients responded favorable to preparation of macronutrient matched meals.

Using community-based participatory research to explore social determinants of women's mental health and barriers to help-seeking in three urban, ethnically diverse, impoverished, and underserved communities.

Depression and anxiety are significant mental health issues that affect urban, ethnically diverse, impoverished women disproportionately. This study sought to identify social determinants of mental health and barriers to help-seeking for this population. Using community based participatory research and focus groups, sixty-one Black, Hispanic, and White women identified economic, family, cultural, and neighborhood issues as perceived determinants of their depression/anxiety. They identified practical, psychosocial, and cultural barriers to their help-seeking behavior. These results can promote women's health by fostering an understanding of social factors as perceived determinants of depression/anxiety and shaping practice and policy initiatives that foster positive aggregate outcomes.

A Spectrum of Disease: Breast Implant-Associated Anaplastic Large Cell Lymphoma, Atypicals, and Other Implant Associations.

Breast implant associated anaplastic large cell lymphoma (BIA-ALCL) is an uncommon and emerging malignancy caused by textured breast implants. The most common patient presentation is delayed seromas, other presentations include breast asymmetry, overlying skin rashes, palpable masses, lymphadenopathy, and capsular contracture. Confirmed diagnoses should receive lymphoma oncology consultation, multidisciplinary evaluation, and PET-CT or CT scan evaluation prior to surgical treatment. Disease confined to the capsule is curable in the majority of patients with complete surgical resection. BIA-ALCL is now recognized as one disease among a spectrum of inflammatory mediated malignancies which include implant-associated squamous cell carcinoma and B cell lymphoma.

Two-Stage SN38 Release from a Core-Shell Nanoparticle Enhances Tumor Deposition and Antitumor Efficacy for Synergistic Combination with Immune Checkpoint Blockade.

Long-circulating nanomedicines efficiently deliver chemotherapies to tumors to reduce general toxicity. However, extended blood circulation of nanomedicines can increase drug exposure to leukocytes and lead to hematological toxicity. Here, we report a two-stage release strategy to enhance the drug deposition and antitumor efficacy of OxPt/SN38 core-shell nanoparticles with a hydrophilic oxaliplatin (OxPt) prodrug coordination polymer core and a lipid shell containing a hydrophobic cholesterol-conjugated SN38 prodrug (Chol-SN38). By conjugating cholesterol to the phenol group of SN38 via an acetal linkage and protecting the 20-hydroxy position with a trimethylsilyl (TMS) group, Chol-SN38 releases SN38 in two stages via esterase-catalyzed cleavage of the acetal linkage in the liver followed by acid-mediated hydrolysis of the TMS group to preferentially release SN38 in tumors. Compared to irinotecan, OxPt/SN38 reduces SN38 blood exposure by 9.0 times and increases SN38 tumor exposure by 4.7 times. As a result, OxPt/SN38 inhibits tumor growth on subcutaneous, spontaneous, and metastatic tumor models by causing apoptotic and immunogenic cell death. OxPt/SN38 exhibits strong synergy with the immune checkpoint blockade to regress subcutaneous colorectal and pancreatic tumors with 33-50% cure rates and greatly inhibits tumor growth and invasion in a spontaneous prostate cancer model and a liver metastasis model of colorectal cancer without causing side effects. Mechanistic studies revealed important roles of enhanced immunogenic cell death and upregulated PD-L1 expression by OxPt/SN38 in activating the tumor immune microenvironment to elicit potent antitumor immunity. This work highlights the potential of combining innovative prodrug design and nanomedicine formulation to address unmet needs in cancer therapy.

Tumor-Activatable Nanoparticles Target Low-Density Lipoprotein Receptor to Enhance Drug Delivery and Antitumor Efficacy.

The binding of plasma proteins to nanomedicines is widely considered detrimental to their delivery to tumors. Here, the design of OxPt/SN38 nanoparticle containing a hydrophilic oxaliplatin (OxPt) prodrug in a coordination polymer core and a hydrophobic cholesterol-conjugated SN38 prodrug on the lipid shell for active tumor targeting is reported. OxPt/SN38 hitchhikes on low-density lipoprotein (LDL) particles, concentrates in tumors via LDL receptor-mediated endocytosis, and selectively releases SN38 and OxPt in acidic, esterase-rich, and reducing tumor microenvironments, leading to 6.0- and 4.9-times higher accumulations in tumors over free drugs. By simultaneously crosslinking DNA and inhibiting topoisomerase I, OxPt/SN38 achieved 92-98% tumor growth inhibition in five colorectal cancer tumor models and prolonged mouse survival by 58-80 days compared to free drug controls in three human colorectal cancer tumor models without causing serious side effects. The study has uncovered a novel nanomedicine strategy to co-deliver combination chemotherapies to tumors via active targeting of the LDL receptor.

Sequential Treatment of Bioresponsive Nanoparticles Elicits Antiangiogenesis and Apoptosis and Synergizes with a CD40 Agonist for Antitumor Immunity.

The combination of antiangiogenesis and chemotherapy regimens with cancer immunotherapy has the potential to synergistically boost antitumor immunity. Herein, we report the construction of two bioresponsive nanoparticles, namely, Podo-NP and CbP-NP, comprising prodrugs of podophyllotoxin (Podo) and carboplatin, respectively. Sequential treatment with esterase-responsive Podo-NP, redox-sensitive CbP-NP, and a CD40 agonist promotes antitumor T cell response. Podo-NP suppresses angiogenesis by preventing proliferation and migration of endothelial cells, sprouting of neovessels, formation of tubules, and stabilization of newly formed vessels. Vascular endothelial growth factor blockade and endostatin stimulation normalize tortuous tumor vasculatures to allow efficient infiltration of effector immune cells. Subsequent treatment with CbP-NP arrests the cell-division cycle and elicits the apoptosis of tumor cells. CD40 agonist activates antigen-presenting cells to process the released tumor-associated antigens from dying tumor cells, thus reversing immunosuppressive tumor microenvironments. Sequential delivery of antiangiogenic and chemotherapeutic agents with bioresponsive NPs activates tumor microenvironments and synergizes with CD40 agonist to regress transplanted tumors and inhibit disseminated tumors in a lung cancer mouse model.

Point-source burst of coordination polymer nanoparticles for tri-modality cancer therapy.

Cancer immunotherapy, particularly the inhibition of immune checkpoints with neutralizing antibodies, has revolutionized the treatment of some cancer patients. However, immune checkpoint blockade has not provided survival benefits to most patients with colorectal and ovarian cancers. This work reports the design of acid-sensitive core-shell nanoscale coordination polymer particles (NCP) comprising a carboplatin prodrug and an siRNA against PD-L1 (siPD-L1) in the core and digitoxin on the shell for tri-modality cancer therapy. Upon cellular uptake, NCP particles rapidly burst in acidic organelles to release carboplatin for apoptosis, digitoxin for inducing immunogenicity, and siPD-L1 for PD-L1 knockdown. With long blood circulation and high tumor accumulation, NCP particles efficiently suppress the growth and metastasis of syngeneic cancers through reactivating innate and adaptive immune responses. NCP particles thus provide a promising platform to synergistically combine chemotherapy and immunotherapy for the treatment of advanced and aggressive cancers.

The complete mitochondrial genome of the brown pansy butterfly, Junonia stygia (Aurivillius, 1894), (Insecta: Lepidoptera: Nymphalidae).

The brown pansy, Junonia stygia (Aurivillius, 1894) (Lepidoptera: Nymphalidae), is a widespread West African forest butterfly. Genome skimming by Illumina sequencing allowed assembly of a complete 15,233 bp circular mitogenome from J. stygia consisting of 79.5% AT nucleotides. Mitochondrial gene order and composition is identical to other butterfly mitogenomes. Junonia stygia COX1 features an atypical CGA start codon, while ATP6, COX1, COX2, ND4, and ND4L exhibit incomplete stop codons. Phylogenetic reconstruction supports a monophyletic Subfamily Nymphalinae, Tribe Junoniini, and genus Junonia. The phylogenetic tree places Junonia iphita and J. stygia as basal mitogenome lineages sister to the remaining Junonia sequences.

Meta-analysis of academic interventions derived from neuropsychological data.

Several scholars have recommended using data from neuropsychological tests to develop interventions for reading and mathematics. The current study examined the effects of using neuropsychological data within the intervention process with meta-analytic procedures. A total of 1,126 articles were found from an electronic search and compared to inclusion criteria, which resulted in 37 articles that were included in the current study. Each article was coded based on how the data were used (screening-86% or designing interventions-14%), size of the group for which interventions were delivered (small group-45%, individual students-45%, or entire classroom-10%), and type of data collected (cognitive functions-24%, reading fluency-33%, phonemic/phonological awareness-35%, or mixed-8%). A corrected Hedges' g was computed for every study and reported for variables of interest. A Fail-safe N was also computed to determine how many studies with a zero effect would have to be found to change the conclusions. The data resulted in a small effect (g = 0.17) for measures of cognitive functioning, but moderate effects of g = 0.43 and g = 0.48 for measures of reading fluency and phonemic/phonological awareness. There were few studies that examined measures of cognitive functioning within the intervention process. Taken together with previous research, the data do not support the use of cognitive measures to develop interventions but instead favor more direct measures of academic skills (e.g., reading fluency) in a skill-by-treatment interaction. Implications for practice and future research are discussed.