Germline PTCH1: c.361_362insAlu alteration identified by comprehensive exome and RNA sequencing in a patient with Gorlin syndrome.

Gorlin syndrome can be caused by pathogenic/likely pathogenic (P/LP) variants in the tumor suppressor gene PTCH1 (9q22.1-q31), which encodes the receptor for the sonic hedgehog (SHH) ligand. We present a 12-month-old boy clinically diagnosed with Gorlin syndrome who was found to have significantly delayed development, palmar pitting, palmar and plantar keratosis, short hands, frontal bossing, coarse face, hypertelorism, a bifid rib, misaligned and missing teeth, and SHH-activated medulloblastoma. Genetic testing, including a pediatric cancer panel and genome sequencing with peripheral blood, failed to identify any P/LP variants in PTCH1. Paired tumor/normal exome sequencing was performed, which identified a germline NM_000264.5 (PTCH1): c.361_362ins? alteration through manual review of sequencing reads. Clinical RNA sequencing further demonstrated an Alu insertion at this region (PTCH1: c.361_362insAlu), providing molecular confirmation of Gorlin syndrome. This finding exemplifies a unique mechanism for PTCH1 disruption in the germline and highlights the importance of comprehensive analysis, including manual review of DNA sequencing reads and the utility of RNA analysis to detect variant types which may not be identified by routine genetic screening techniques.

Pragmatic nationwide master observational trial based on genomic alterations in advanced solid tumors: KOrean Precision Medicine Networking Group Study of MOlecular profiling guided therapy based on genomic alterations in advanced Solid tumors (KOSMOS)-II study protocol KCSG AL-22-09.

BACKGROUND: Next-generation sequencing (NGS) has been introduced to many Korean institutions to support molecular diagnostics in cancer since 2017, when it became eligible for reimbursement by the National Health Insurance Service. However, the uptake of molecularly guided treatment (MGT) based on NGS results has been limited because of stringent regulations regarding prescriptions outside of approved indications, a lack of clinical trial opportunities, and limited access to molecular tumor boards (MTB) at most institutions. The KOSMOS-II study was designed to demonstrate the feasibility and effectiveness of MGT, informed by MTBs, using a nationwide precision medicine platform. METHODS: The KOSMOS-II trial is a large-scale nationwide master observational study. It involves a framework for screening patients with metastatic solid tumors for actionable genetic alterations based on local NGS testing. It recommends MGT through a remote and centralized MTB meeting held biweekly. MGT can include one of the following options: Tier 1, the therapeutic use of investigational drugs targeting genetic alterations such as ALK, EGFR, ERBB2, BRAF, FH, ROS1, and RET, or those with high tumor mutational burden; Tier 2, comprising drugs with approved indications or those permitted for treatment outside of the indications approved by the Health Insurance Review and Assessment Service of Korea; Tier 3, involving clinical trials matching the genetic alterations recommended by the MTB. Given the anticipated proportion of patients receiving MGT in the range of 50% ± 3.25%, this study aims to enroll 1,000 patients. Patients must have progressed to one or more lines of therapy and undergone NGS before enrollment. DISCUSSION: This pragmatic master protocol provides a mass-screening platform for rare genetic alterations and high-quality real-world data. Collateral clinical trials, translational studies, and clinico-genomic databases will contribute to generating evidence for drug repositioning and the development of new biomarkers. TRIAL REGISTRATION: NCT05525858.

Effects of ambient air pollution on brain cortical thickness and subcortical volume: A longitudinal neuroimaging study.

INTRODUCTION: Long-term exposure to air pollutants is associated with an increased risk of Alzheimer's disease and mild cognitive impairment. Therefore, we investigated the association between long-term air pollution exposure and changes in neuroimaging markers. METHODS: In this longitudinal study, we studied a prospective cohort of 361 adults residing in four cities in the Republic of Korea. Long-term concentrations of particulate matter with aerodynamic diameters of ≤10 µm (PM10) and ≤2.5 µm (PM2.5) and nitrogen dioxide (NO2) at residential addresses were estimated. Neuroimaging markers (cortical thickness and subcortical volume) were obtained from brain magnetic resonance images at baseline (August 2014 to March 2017) and at the 3-year follow-up (until September 2020). Linear mixed-effects models were used, adjusting for covariates. RESULTS: A 10-µg/m3 increase in PM10 was associated with reduced whole-brain mean (ß= -0.45, standard error (SE)= 0.10, P< 0.001), frontal (ß= -0.53, SE= 0.11; P< 0.001) and temporal thicknesses (ß= -0.37, SE= 0.12; P= 0.002). A 10-ppb increase in NO2 was associated with a decline in the whole brain mean cortical thickness (ß= -0.23, SE= 0.05; P< 0.001), frontal (ß= -0.25, SE= 0.05; P< 0.001), parietal (ß= -0.12, SE= 0.05; P= 0.025), and temporal thicknesses (ß= -0.19, SE= 0.06; P= 0.001). Subcortical structures associated with air pollutants include the thalamus volume. CONCLUSIONS: Long-term exposure to PM10 and NO2 may lead to cortical thinning in adults.

Amikacin in 30% poloxamer 407 is a versatile local therapy with method of application and outcome documented in 29 dogs.

OBJECTIVE: To report the clinical use, adverse events, and outcomes after using amikacin in 30% poloxamer 407 (amikacin-P407) during open wound management or in a closed wound application in dogs. ANIMALS: 29 client-owned dogs. METHODS: Medical records from January 2017 to August 2023 from a single hospital were reviewed for dogs that received amikacin-P407 in an open or closed wound application. Information reviewed included signalment, nature of wound and/or surgical site infection (SSI), bacterial cultures, amikacin dose, gel volume, route of administration, estimated wound surface area, biochemistry parameters, urine casts, wound progression, and general clinical outcome. RESULTS: Amikacin-P407 was applied during open wound care (10 dogs), via injection (5 dogs), and at time of wound closure (13 dogs) and was used both in open and closed wound management (1 dog). Wounds were associated with SSIs in 18 of 30 sites. Multidrug resistance was noted in 21 of 30 preapplication cultures. Median amikacin dose was 14.5 mg/kg (range, 3 to 59.5 mg/kg), median total volume was 5.0 mL (range, 1 to 12 mL), and median tissue surface area was 6.6 cm2 (range, 1.6 to 36 cm2), for a local wound dose of 62.5 mg/cm2 (range, 6.9 to 214.3 mg/cm2). No short-term adverse local or systemic effects were noted in any wounds or dogs. No dehiscence was seen in 17 of 19 closed sites. CLINICAL RELEVANCE: The results of this case series suggested that Amikacin-P407 can be applied in a variety of ways with no adverse effects. Amikacin-P407 may be considered in open wound management or in a closed setting for infected wounds and SSIs.

Report from the World Health Organization's immunization and vaccines-related implementation research advisory committee (IVIR-AC) meeting, virtual gathering, 26 February-1 March 2024.

The Immunization and Vaccine-related Implementation Research Advisory Committee (IVIR-AC) is the World Health Organization's key standing advisory body to conduct an independent review of research, particularly of transmission and economic modeling analyses that estimate the impact and value of vaccines. From 26th February-1st March 2024, at its first of two semi-annual meetings, IVIR-AC provided feedback and recommendations across four sessions; this report summarizes the proceedings and recommendations from that meeting. Session topics included modeling of the impact and cost-effectiveness of the R21/Matrix-M malaria vaccine, meta-analysis of economic evaluations of vaccines, a global analysis estimating the impact of vaccination over the last 50 years, and modeling the impact of different RTS,S malaria vaccine dose schedules in seasonal settings.

Atlantoaxial joint stabilization using patient-specific 3-D-printed drill guides and 3-D-printed titanium plates or polymethyl methacrylate is effective in toy-breed dogs.

OBJECTIVE: To report the clinical outcomes in toy-breed dogs with atlantoaxial instability (AAI) stabilized with patient-specific 3-D-printed titanium plates or polymethyl methacrylate (PMMA), both with the assistance of 3-D-printed drill guides. ANIMALS: 15 client-owned dogs undergoing surgical treatment for AAI between January 1, 2020, and October 31, 2022. METHODS: The clinical characteristics, diagnostic images, and neurological outcomes of 15 dogs treated for AAI using 3-D-printing technology were reviewed. Postoperative CT images were examined to evaluate the screw placement accuracy in the atlas and axis. Clinical outcomes, including postoperative neurological improvement and screw loosening, were evaluated in dogs treated with a patient-specific titanium plate and those treated with PMMA. RESULTS: Patient-specific titanium plates (7 dogs) and PMMA (8 dogs) were used for AAI stabilization. The mean follow-up period was 15.2 months (range 7 to 22 months). A reduction of the axis without vertebral canal violation was confirmed on postoperative CT in 14 dogs. The mean deviation from the preoperative planning ranged from 0.30 to 1.27 mm at the insertion and exit points of 84 screws using this method. The neurological grade had improved in each dog postoperatively and at the final follow-up. Screw loosening was noted in 4 dogs in the titanium plates groups without neurological deterioration. CLINICAL RELEVANCE: Patient-specific 3-D-printed drill guides and titanium plates or PMMA are effective for AAI stabilization in toy-breed dogs, providing accurate guidance.

Update on Cancer Predisposition Syndromes and Surveillance Guidelines for Childhood Brain Tumors.

Tumors of the central nervous system (CNS) comprise the second most common group of neoplasms in childhood. The incidence of germline predisposition among children with brain tumors continues to grow as our knowledge on disease etiology increases. Some children with brain tumors may present with nonmalignant phenotypic features of specific syndromes (e.g., nevoid basal cell carcinoma syndrome, neurofibromatosis type 1 and type 2, DICER1 syndrome, and constitutional mismatch-repair deficiency), while others may present with a strong family history of cancer (e.g., Li-Fraumeni syndrome) or with a rare tumor commonly found in the context of germline predisposition (e.g., rhabdoid tumor predisposition syndrome). Approximately 50% of patients with a brain tumor may be the first in a family identified to have a predisposition. The past decade has witnessed a rapid expansion in our molecular understanding of CNS tumors. A significant proportion of CNS tumors are now well characterized and known to harbor specific genetic changes that can be found in the germline. Additional novel predisposition syndromes are also being described. Identification of these germline syndromes in individual patients has not only enabled cascade testing of family members and early tumor surveillance but also increasingly affected cancer management in those patients. Therefore, the AACR Cancer Predisposition Working Group chose to highlight these advances in CNS tumor predisposition and summarize and/or generate surveillance recommendations for established and more recently emerging pediatric brain tumor predisposition syndromes.

Hepatomegaly and Splenomegaly: An Approach to the Diagnosis of Lysosomal Storage Diseases.

Clinical findings of hepatomegaly and splenomegaly, the abnormal enlargement of the liver and spleen, respectively, should prompt a broad differential diagnosis that includes metabolic, congestive, neoplastic, infectious, toxic, and inflammatory conditions. Among the metabolic diseases, lysosomal storage diseases (LSDs) are a group of rare and ultrarare conditions with a collective incidence of 1 in 5000 live births. LSDs are caused by genetic variants affecting the lysosomal enzymes, transporters, or integral membrane proteins. As a result, abnormal metabolites accumulate in the organelle, leading to dysfunction. Therapeutic advances, including early diagnosis and disease-targeted management, have improved the life expectancy and quality of life of people affected by certain LSDs. To access these new interventions, LSDs must be considered in patients presenting with hepatomegaly and splenomegaly throughout the lifespan. This review article navigates the diagnostic approach for individuals with hepatosplenomegaly particularly focusing on LSDs. We provide hints in the history, physical exam, laboratories, and imaging that may identify LSDs. Additionally, we discuss molecular testing, arguably the preferred confirmatory test (over biopsy), accompanied by enzymatic testing when feasible.

Physical Activity-Induced Modification of the Association of Long-Term Air Pollution Exposure with the Risk of Depression in Older Adults.

PURPOSE: Evidence suggests that long-term air pollution exposures may induce depression; however, the influence of physical activity on this effect is unclear. We investigated modification of the associations between air pollution exposures and depression by the intensity of physical activity. MATERIALS AND METHODS: This cross-sectional study included 1454 Korean adults. Depression was defined as a Geriatric Depression Scale score ≥8. Concentrations of particulate matter (PM10 and PM2.5: diameter ≤10 µm and ≤2.5 µm, respectively) and nitrogen dioxide (NO2) level at each participant's residential address were estimated. Based on metabolic equivalents, physical activity intensity was categorized as inactive, minimally active, or health-enhancing physical activity (HEPA). RESULTS: Each 1-part per billion (ppb) NO2 concentration increase was significantly associated with a 6% [95% confidence interval (CI), 4%-8%] increase in depression risk. In older adults (≥65 years), a 1-ppb NO2 increase was associated (95% CI) with a 4% (1%-7%), 9% (5%-13%), and 21% (9%-33%) increase in depression risk in the inactive, minimally active, and HEPA groups, respectively. Compared with the inactive group, the minimally active (p=0.039) and HEPA groups (p=0.004) had higher NO2 exposure-associated depression risk. Associations of PM10 and PM2.5 with depression did not significantly differ by the intensity of physical activity. CONCLUSION: We suggest that older adults who vigorously exercise outdoors may be susceptible to air pollution-related depression.

Association between high levels of nitrogen dioxide and increased cumulative incidence of lung cancer in patients with idiopathic pulmonary fibrosis.

BACKGROUND: Lung cancer is a fatal complication of idiopathic pulmonary fibrosis (IPF) with a poor prognosis. However, the association between individual exposure to air pollutants and lung cancer development in patients with IPF is unknown. This study aimed to assess the effect of individual exposure to nitrogen dioxide (NO2) on lung cancer development in patients with IPF. METHODS: We enrolled 1085 patients from an IPF cohort in the Republic of Korea (mean age 65.6 years, males 80.6%). We estimated individual-level long-term exposures to NO2 at the patients' residential addresses using a national-scale exposure prediction model based on data from air quality regulatory monitoring stations. To evaluate the association between NO2 levels and lung cancer development in IPF, we used an individual- and area-level covariates adjusted model as our primary model. RESULTS: The estimated average annual NO2 concentration was 23.1 ppb. During a median follow-up of 4.3 years, 86 patients (7.9%) developed lung cancer. NO2 concentration was associated with lung cancer development in an unadjusted model (HR 1.219; p=0.042), while a marginal association was found in the primary model (HR 1.280; p=0.084). When NO2 concentration was stratified by the median value (21.0 ppb), exposure to high NO2 levels (≥21.0 ppb) was associated with a 2.0-fold increase in the risk of lung cancer development (HR 2.023; p=0.047) in the primary model. CONCLUSION: Individual exposure to high NO2 levels may increase the risk of lung cancer development in patients with IPF.

14q22.3 duplication including OTX2 in a girl with medulloblastoma: A case report with literature review.

Orthodenticle homeobox 2 (OTX2) is a known oncogenic driver of medulloblastoma. Germline duplication of 14q22.3 including OTX2 is a rare condition reported in patients with combined pituitary hormone deficiency, oculo-auriculo-vertebral spectrum, and hemifacial microsomia. There has been one previously published case of a patient carrying a 14q22.3 duplication that included OTX2 with hemifacial microsomia who also developed medulloblastoma. Here, we present a case of a 6-year-old girl with a history of delayed development who was diagnosed with medulloblastoma. Genetic evaluations revealed that she inherited a germline duplication of 14q22.3, which included OTX2. This genetic alteration was passed down from her mother, who also had a history of delayed development. Results from other genetic testing, including exome sequencing, fragile X syndrome, and mtDNA testing, were negative/normal. This is the second report of a 14q22.3 duplication that included OTX2 in a patient with medulloblastoma. Further studies are necessary to establish a clear association.

Regulation of hypothalamic reactive oxygen species and feeding behavior by phosphorylation of the beta 2 thyroid hormone receptor isoform.

Unlike other thyroid hormone receptors (THRs), the beta 2 isoform (THRB2) has a restricted expression pattern and is uniquely and abundantly phosphorylated at a conserved serine residue S101 (S102 in humans). Using tagged and or phosphorylation-defective (S101A) THRB2 mutant mice, we show that THRB2 is present in a large subset of POMC neurons and mitigates ROS accumulation during ROS-triggering events, such as fasting/refeeding or high fat diet (HFD). Excessive ROS accumulation in mutant POMC neurons was accompanied by a skewed production of orexigenic/anorexigenic hormones, resulting in elevated food intake. The prolonged exposure to pathogenic hypothalamic ROS levels during HFD feeding lead to a significant loss of POMC neurons in mutant versus wild-type (WT) mice. In cultured cells, the presence of WT THRB2 isoform, but not other THRs, or THRB2S101A, reduced ROS accumulation upon exogenous induction of oxidative stress by tert-butyl hydroperoxide. The protective function of phospho-THRB2 (pTHRB2) did not require thyroid hormone (TH), suggesting a TH-independent role of the THRB2 isoform, and phospho-S101 in particular, in regulating oxidative stress. We propose that pTHRB2 has a fundamental role in neuronal protection against ROS cellular damage, and mitigates hypothalamic pathological changes found in diet-induced obesity.

Potential Phytotherapy of DSS-Induced Colitis: Ameliorating Reactive Oxygen Species-Mediated Necroptosis and Gut Dysbiosis with a New Crataegus pinnatifida Bunge Variety-Daehong.

Developing new plant varieties plays a crucial role in competitiveness in the agricultural and food industries and enhancing food security. Daehong (DH) is a new variety of Crataegus pinnatifida Bunge (CP); however, its physiological functions and potential as a nutraceutical ingredient remain unknown. Here, the efficacy of DH on inflammatory bowel disease (IBD) was investigated using dextran sulfate sodium (DSS)-induced colitis mice, and its relative pharmacological effects were analyzed against CP. DH improved colitis-induced weight loss, colon shortening, and inflammatory responses and reduced intestinal permeability. The reactive oxygen species (ROS)-mediated necroptotic signal that triggers enterocyte cell death in DSS-induced colitis was effectively controlled by DH, attributed to epicatechin. DSS-induced gut dysbiosis was recovered into a healthy gut microbiome environment by DH, increasing beneficial bacteria, like Akkermansia muciniphila, and changing harmful bacteria, including Bacteroides vulgatus and Peptostreptococcaceae. DH shows potential as a dietary or pharmaceutical ingredient to promote gut health and to prevent and treat IBD.

Report from the World Health Organization's immunization and vaccines related implementation research advisory committee (IVIR-AC) meeting, Geneva, 11-13 September 2023.

Evaluating vaccine-related research is critical to maximize the potential of vaccination programmes. The WHO Immunization and Vaccine-related Implementation Research Advisory Committee (IVIR-AC) provides an independent review of research that estimates the performance, impact and value of vaccines, with a particular focus on transmission and economic modelling. On 11-13 September 2023, IVIR-AC was convened for a bi-annual meeting where the committee reviewed research and presentations across eight different sessions. This report summarizes the background information, proceedings and recommendations from that meeting. Sessions ranged in topic from timing of measles supplementary immunization activities, analyses of conditions necessary to meet measles elimination in the South-East Asia region, translating modelled evidence into policy, a risk-benefit analysis of dengue vaccine, COVID-19 scenario modelling in the African region, therapeutic vaccination against human papilloma virus, the Vaccine Impact Modelling Consortium, and the Immunization Agenda 2030 vaccine impact estimates.

Cervical enamel projections from a periodontal perspective: A scoping review.

Cervical enamel projections (CEPs) represent a unique developmental and anatomical anomaly wherein the enamel structure extends apically beyond the cemento-enamel junction of the tooth. In this scoping review, the existing literature on CEPs was evaluated to delineate their characteristics, prevalence, predilection for specific teeth and surfaces, clinical significance, and management approaches. Searches were conducted on MEDLINE (PubMed), Cochrane Library, and Embase databases using the keywords "enamel projection(s)" or "ectopic enamel." In total, 24 studies meeting inclusion criteria were included in the review. The prevalence of CEPs varied widely (8.3%-85.1%), predominantly manifesting as grade I or grade III. Mandibular first and second molars exhibited a higher incidence of CEPs, with a notable predilection for buccal surfaces. The consensus in most studies was that CEPs are associated with localized periodontal diseases. Recommendations inclined toward the removal of ectopic enamel during periodontal surgery to enhance periodontal attachment formation. However, decision-making should involve careful consideration of the benefits and drawbacks based on individual circumstances.

PM10 increases mortality risk in rheumatoid arthritis-associated interstitial lung disease.

OBJECTIVES: The effect of air pollution on the prognosis of rheumatoid arthritis-associated interstitial lung disease (RA-ILD) remains poorly understood. We aimed to evaluate the effect of long-term exposure to particulate matter with an aerodynamic diameter of ≤10 µm (PM10) and nitrogen dioxide (NO2) on mortality in patients with RA-ILD. METHODS: We included 309 patients (mean age, 61.7 years; male, 44.3%) with RA-ILD. Individual-level long-term exposures to PM10 and NO2 at their residential addresses were estimated using a national-scale exposure prediction model. The effect of the two air pollutants on mortality was estimated using a Cox-proportional hazards model adjusted for individual-level and area-level characteristics. RESULTS: The median follow-up period was 4.8 years, and 40.8% of patients died or underwent lung transplantation. The annual average concentrations of PM10 and NO2 were 56.3 µg/m3 and 22.4 ppb, respectively. When air pollutant levels were stratified by quartiles, no association was observed between air pollutant concentration and mortality in patients with RA-ILD. However, when stratified by two groups (high exposure (top 25th percentile) vs low exposure (bottom 75th percentile)), we observed a significant association between high PM10 exposure and mortality (HR 1.68; 95% CI 1.11 to 2.52; p=0.013) but no association between NO2 exposure and mortality. In the subgroup analyses, the effect of high PM10 exposure on mortality was significant in patients aged <65 years (HR 1.98; 95% CI 1.02 to 3.85; p=0.045). CONCLUSIONS: Our results indicated that high PM10 exposure may be associated with mortality in patients with RA-ILD.

Outcomes of 11 dogs with short radius syndrome treated with acute arthroscopically assisted ulnar shortening.

OBJECTIVE: To describe the short-term outcome of acute arthroscopically assisted ulnar shortening (AUS), to treat short radius syndrome in dogs. STUDY DESIGN: Case series. ANIMALS: Eleven client owned dogs. METHODS: Records of dogs that had undergone AUS for treatment of short radius syndrome were reviewed for inclusion. Reporting data included among others pre- and postoperative radioulnar, humeroradial and humeroulnar distances, lameness scores, surgical times, complications and clinical outcome. RESULTS: Following AUS, radiohumeral articulation was improved in all dogs. Median presurgery radioulnar, humeroradial and humeroulnar values were 4.5, 3.2, and 2.2 mm and were improved with surgery by a median of 3.2, 1.8, and 1.2 mm, respectively. Median surgery time was 140 min. Median time to bone healing was 8 weeks (range: 4-14). Median time to last follow-up was 9 weeks (4-468). Median lameness score (scale 0-4) improved from 2 to 1. No major complications were reported. Short-term clinical outcome was graded by the surgeons as full function in four cases and acceptable function in seven. CONCLUSION AND CLINICAL RELEVANCE: Radiographic and arthroscopic radiohumeral articulation were improved and short-term clinical improvement was documented following AUS in all 11 dogs.

The CUL3A-LFH1-UBC15 ubiquitin ligase complex mediates SHORT VEGETATIVE PHASE degradation to accelerate flowering at high ambient temperature.

Ambient temperature affects flowering time in plants, and the MADS-box transcription factor SHORT VEGETATIVE PHASE (SVP) plays a crucial role in the response to changes in ambient temperature. SVP protein stability is regulated by the 26S proteasome pathway and decreases at high ambient temperature, but the details of SVP degradation are unclear. Here, we show that SVP degradation at high ambient temperature is mediated by the CULLIN3-RING E3 ubiquitin ligase (CRL3) complex in Arabidopsis thaliana. We identified a previously uncharacterized protein that interacts with SVP at high ambient temperature and contains a BTB/POZ domain. We named this protein LATE FLOWERING AT HIGH TEMPERATURE 1 (LFH1). Single mutants of LFH1 or CULLIN3A (CUL3A) showed late flowering specifically at 27°C. LFH1 protein levels increased at high ambient temperature. We found that LFH1 interacts with CUL3A in the cytoplasm and is important for SVP-CUL3A complex formation. Mutations in CUL3A and/or LFH1 led to increased SVP protein stability at high ambient temperature, suggesting that the CUL3-LFH1 complex functions in SVP degradation. Screening E2 ubiquitin-conjugating enzymes (UBCs) using RING-BOX PROTEIN 1 (RBX1), a component of the CRL3 complex, as bait identified UBC15. ubc15 mutants also showed late flowering at high ambient temperature. In vitro and in vivo ubiquitination assays using recombinant CUL3A, LFH1, RBX1, and UBC15 showed that SVP is highly ubiquitinated in an ATP-dependent manner. Collectively, these results indicate that the degradation of SVP at high ambient temperature is mediated by a CRL3 complex comprising CUL3A, LFH1, and UBC15.

Determinants of unhealthy living by gender, age group, and chronic health conditions across districts in Korea using the 2010-2017 Community Health Surveys.

OBJECTIVES: We investigated the prevalence and determinants of unhealthy living by gender, age, and comorbidities across Korean districts. METHODS: For 806,246 men and 923,260 women from 245 districts who participated in the 2010-2017 Korean Community Health Surveys, risk scores were calculated based on obesity, physical inactivity, smoking, and high-risk alcohol consumption, each scored from 0 (lowest risk) to 2 (highest risk). A risk score ≥4 was defined as indicating unhealthy living, and weighted proportions were calculated for each district. Using multivariate regression, an ecological model including community socioeconomic, interpersonal, and neighborhood factors was examined by gender, age, and comorbidities. RESULTS: The mean age-standardized rate of unhealthy living was 24.05% for men and 4.91% for women (coefficients of variation, 13.94% and 29.51%, respectively). Individuals with chronic diseases more frequently exhibited unhealthy lifestyles. Unhealthy lifestyles were associated with educational attainment (ß-coefficients: men, -0.21; women, -0.15), high household income (ß=0.08 and 0.03, respectively), pub density (ß=0.52 and 0.22, respectively), and fast-food outlet density (ß=2.81 and 1.63, respectively). Negative associations were observed with manual labor, social activity participation, and hospital bed density. Unhealthy living was positively associated with living alone among women and with being unemployed among middle-aged men. Access to parks was negatively associated with unhealthy living among young men and women. The ecological model explained 32% of regional variation in men and 41% in women. CONCLUSIONS: Improving the neighborhood built and socioeconomic environment may reduce regional disparities in lifestyle behaviors; however, the impacts may vary according to socio-demographic traits and comorbidities.

ANXA2 (annexin A2) is crucial to ATG7-mediated autophagy, leading to tumor aggressiveness in triple-negative breast cancer cells.

Triple-negative breast cancer (TNBC) is associated with a poor prognosis and metastatic growth. TNBC cells frequently undergo macroautophagy/autophagy, contributing to tumor progression and chemotherapeutic resistance. ANXA2 (annexin A2), a potential therapeutic target for TNBC, has been reported to stimulate autophagy. In this study, we investigated the role of ANXA2 in autophagic processes in TNBC cells. TNBC patients exhibited high levels of ANXA2, which correlated with poor outcomes. ANXA2 increased LC3B-II levels following bafilomycin A1 treatment and enhanced autophagic flux in TNBC cells. Notably, ANXA2 upregulated the phosphorylation of HSF1 (heat shock transcription factor 1), resulting in the transcriptional activation of ATG7 (autophagy related 7). The mechanistic target of rapamycin kinase complex 2 (MTORC2) played an important role in ANXA2-mediated ATG7 transcription by HSF1. MTORC2 did not affect the mRNA level of ANXA2, but it was involved in the protein stability of ANXA2. HSPA (heat shock protein family A (Hsp70)) was a potential interacting protein with ANXA2, which may protect ANXA2 from lysosomal proteolysis. ANXA2 knockdown significantly increased sensitivity to doxorubicin, the first-line chemotherapeutic regimen for TNBC treatment, suggesting that the inhibition of autophagy by ANXA2 knockdown may overcome doxorubicin resistance. In a TNBC xenograft mouse model, we demonstrated that ANXA2 knockdown combined with doxorubicin administration significantly inhibited tumor growth compared to doxorubicin treatment alone, offering a promising avenue to enhance the effectiveness of chemotherapy. In summary, our study elucidated the molecular mechanism by which ANXA2 modulates autophagy, suggesting a potential therapeutic approach for TNBC treatment.Abbreviation: ATG: autophagy related; ChIP: chromatin-immunoprecipitation; HBSS: Hanks' balanced salt solution; HSF1: heat shock transcription factor 1; MTOR: mechanistic target of rapamycin kinase; TNBC: triple-negative breast cancer; TFEB: transcription factor EB; TFE3: transcription factor binding to IGHM enhancer 3.