In hepatocellular carcinoma (HepG2), aberrant histone modifications are closely linked to long non-coding RNA (lncRNA) expression. However, existing computational models lack physical interpretability at specific promoter coordinates. To address this, we developed a position-specific statistical scoring model based on adjacent and next-adjacent nucleotide frequencies. We trained two independent, position-specific matrices representing increased and decreased modification states across 600 bp promoter windows centered on the true signal summits. Finally, ten-fold cross-validation revealed that significant energy differences between sequences with increased and decreased histone signals enable excellent classification performance. These results indicted a strong correlation between the total energy of local DNA structures and histone modification signal.

Heparanase 1 (HPSE1) is the only mammalian endoglycosidase that cleaves heparan sulfate (HS), a glycosaminoglycan (GAG), and is frequently upregulated in cancers, thereby promoting tumor progression. Despite extensive efforts to develop inhibitors of its HS-degrading activity, its non-enzymatic functions limit therapeutic efficacy and pose a major challenge for therapeutic development. Thus, inhibiting HPSE1 expression is critical for controlling its enzymatic and non-enzymatic functions; however, no FDA-approved inhibitors are currently available. Here, we identify auranofin (AUF), an oral gold-containing drug used to treat rheumatoid arthritis, as a potent inhibitor of HPSE1 promoter activity. High-throughput screening revealed that an atypical protein kinase C (aPKC)-NF-κB signaling axis is a key regulator of HPSE1 expression. Notably, AUF treatment reduced HPSE1 expression and significantly suppressed the invasive capacity of MDA-MB-231 cells in a Transwell migration assay. We then investigated the role of HPSE1 in the invasive activity of MDA-MB-231 cells, which produce higher levels of hyaluronan (HA) and HS than non-invasive cells. Neither HS degradation, HA supplementation in Matrigel during Transwell migration, nor HPSE1 overexpression alone was sufficient to drive invasion, suggesting that invasive capacity depends on mesenchymal features and coordinated induction of HPSE1 and GAGs rather than HS degradation. Collectively, our findings demonstrate that AUF-mediated inhibition of aPKC suppresses HPSE1 expression, thereby inhibiting both its enzymatic and non-enzymatic functions and limiting cancer progression, metastasis, and angiogenesis. These results highlight the therapeutic potential of AUF for targeting HPSE1-driven tumor progression and support its repurposing for cancer treatment.

Comparative oncology can uncover novel mechanisms of cancer resistance and progression across animals. Non-traditional model organisms with naturally high or low cancer prevalence may provide further insights into metastasis or cancer resistance. In this context, the "lemon frost" morph of the leopard gecko (Eublepharis macularius) shows high prevalence of iridophoromas, exceeding 80%. These tumors can recur and metastasize, presenting a unique opportunity to study pigment cell cancer and tumor progression in a non-mammalian vertebrate.

We performed high-coverage whole-genome sequencing on matched tumor and non-tumor samples from three lemon frost individuals. A shared missense mutation in the TATA-box binding protein (TBP) suggests possible disruption to transcriptional regulation in tumor samples. Additionally, a recurrent gene fusion between IARS1 and RNF213 was identified across all tumor samples. Copy number neutral loss of heterozygosity events were observed in three mutated genes that have a role in cancer: MAP3K13, TENM4, and OR2AT4-like, while copy number gains were observed in four genomic regions. Pathway analysis revealed dysregulation in actin filament organization, a hallmark of metastatic potential. These findings suggest a multifaceted genomic basis for tumorigenesis in this model, including transcriptional misregulation, chromatin remodeling defects, and cytoskeletal disruption.

This study provides the first characterization of genomic changes associated with iridophoroma in a reptilian species and establishes the lemon frost gecko as a promising model for cancer research. Our findings identify candidate pathways of tumor progression and metastasis in a non-traditional system, highlighting both conserved and novel mechanisms relevant to human disease.

BackgroundAccurate assessment of asthma symptom control is central to effective management. Spirometry is the gold standard for evaluating lung function and monitoring physiological impairment, and the Global Lung Function Initiative (GLI) has developed widely used spirometric reference equations applicable across populations. However, population-specific equations may better reflect regional characteristics. This study examined the impact of using different spirometric reference equations on asthma assessment.MethodsIn this cross-sectional study, pre-bronchodilator forced expiratory volume in one second (FEV₁), forced vital capacity (FVC), and FEV₁/FVC were assessed in 384 adults with asthma, and symptom control status was assessed using the Asthma Control Test (ACT). Reference values, z-scores, and lower limits of normal (LLN) were derived using the GLI Global (GLI-2022 race-neutral) equation (GLIgl), GLI-2012 Caucasian equation (GLI2012_cauc), GLI-2012 Other/mixed equation (GLI2012_other), and Al-Qerem local equation (LOCAL). Agreement between equations was evaluated using Cohen's kappa, and their sensitivity and specificity for identifying ACT-defined uncontrolled symptoms were assessed.ResultsSpirometric values differed significantly across equations. Associations between spirometric impairment and ACT-defined uncontrolled symptoms were modest, with low-to-moderate discrimination. Higher FEV₁ and FVC z-scores were consistently associated with higher ACT scores across all equations, although explained variance was limited and model-fit differences were minimal. Pairwise agreement between equation sets was substantial to near-perfect for FEV1 < LLN (kappa = 0.692-0.907) and FEV1/FVC < LLN (kappa = 0.757-0.945), while LLN-defined impairment rates differed across equations.ConclusionsThe choice of spirometric reference equation substantially influences impairment classification and its concordance with ACT-defined symptom control, but overall predictive performance remains modest. Spirometry should be interpreted as a complementary, rather than standalone, tool in asthma assessment, with careful consideration of population-appropriate reference standards.

New York City has the largest homeless population of any city in the United States, with thousands of people experiencing unsheltered homelessness on its streets. These individuals have poor health outcomes and limited connection to care. To better meet their health and social needs, New York City Health+Hospitals, the largest public hospital system in the United States, has implemented the Street Health Outreach and Wellness (SHOW) initiative to bring unsheltered New Yorkers health care, material goods, and connections to transitional housing. This article documents the evolution of the program - from its first iteration as an external contractor-staffed initiative during the coronavirus disease 2019 pandemic to its integration into the health care system in January 2023 - while also highlighting how it is currently operationalized. Since its integration, teams have completed more than 46,000 street engagements, including more than 10,000 clinical visits, 1700 connections to substance use services, and more than 500 connections to homeless shelters. The authors provide key lessons about trust-building, navigating complex organizational hierarchies and partnerships, and the importance of community-based interventions to provide homeless health care.

To define cut-off values for acoustic measures extracted from the sustained vowel [a] task to discriminate between the presence and absence of vocal disorders in Brazilian Portuguese speakers.

The sample consisted of 376 participants, 288 female and 88 male, with a mean age of 41.20 ± 14.04 years. All individuals underwent a laryngological evaluation and a voice recording session, during which a sustained vowel [a] sample was collected. Subsequently both auditory-perceptual and acoustic analyses of the voice were performed. Among the participants 277 were classified as having a vocal disorder and 99 as having no vocal disorder. A total of 44 acoustic measures were extracted and analyzed using ROC curves to determine the cut-off value for each measure, along with their performance metrics (sensitivity, specificity and AUC).

Cut-off values were established for 23 of the 44 extracted acoustic measures. Six measures showed robust and clinically relevant performance in discriminating between voices with and without vocal disorders in Brazilian Portuguese speakers. The measures with AUC values greater than 0.70 and balanced sensitivity and specificity above 70% were: Amplitude Variability Index (AVI) (≤0,91), Glottal-to-noise excitation (GNE)2000Hz (>0,92), Spectral Noise Level (SNL)100-2600Hz (≤7,71), SNL100-3000Hz (≤3,38), SNL100-8000Hz (≤10,95) and SNL5100-8000Hz (≤-1,84).

Six acoustic measures demonstrated satisfactory performance in identifying the presence of vocal disorders in Brazilian Portuguese speakers. Ten measures showed good performance for voice screening purposes and seven for diagnostic confirmation of vocal disorders.

The aim of this study was to compare the nutritional status of individuals with cystic fibrosis (CF) diagnosed either through newborn screening (NBS) or based on clinical findings (early vs. late), at the time of diagnosis and 1 year later.

This was an observational study including CF patients followed at a Referral Center from 2005 to 2023. Participants were classified into three subgroups according to the method and age at diagnosis: 1 (NBS); 2 (early signs and symptoms if the CF diagnosis was before 2 years of age); and 3 (late signs and symptoms if the CF diagnosis was after 2 years of age). Nutritional parameters were compared at diagnosis and 1 year after treatment.

A total of 63 individuals were included, 57.1% male, 81.0% non-white, and median (interquartile range) age at diagnosis of 6 (2-42) months. There were 21, 23, and 19 in subgroups 1, 2, and 3, respectively. At diagnosis, 26 (41.3%) individuals had short stature (SST) or very SST, corresponding to 57.1, 43.5, and 21.1% of children in subgroups 1, 2, and 3, respectively. After 1 year, these proportions decreased to 28.5 and 30.4% in subgroups 1 and 2, while remaining unchanged in subgroup 3. Pancreatic insufficiency was present in 85.7, 69.6, and 68.4% of participants in subgroups 1, 2, and 3, respectively.

Short stature was frequent at diagnosis, even among children identified by NBS. After 1 year of follow-up, height improved in subgroups 1 and 2 but remained unchanged in subgroup 3. Early diagnosis and timely nutritional interventions are essential to prevent and correct growth deficits in individuals with CF.

While the individual effects of biologics in asthma are well demonstrated, the potential impact of the use of biologics on overall asthma-related hospitalization at a population-based level has not been reported.

A territory-wide study conducted in Hong Kong, involving all adult patients with asthma managed in Hospital Authority. The primary outcome was the change in asthma-related hospitalization from 2014 to 2023, correlating with the number of biologic use among patients with asthma and adjusted for Air Quality Health Index and influenza case number.

The weekly asthma-related hospitalization was 96 episodes at the start of the study period and 78 episodes at the end of the study period. There was a significant reduction of asthma-related hospitalization associated with biologic usage, giving the estimated risk ratio of 0.994 (95% CI = 0.991-0.996, p value < 0.05). The estimated break-point for the change in asthma-related hospitalization was at Week 169 (95% CI = 130.3-207.7), which was the week of 19/3/2017 to 25/3/2017. The slopes before and after the break-point were 0.022 and -0.191 with the difference in the two slope estimates being significant (p < 0.001) according to the Davies test. The significant difference in the slope before and after the break-point suggested that beyond Week 169, there was a trend of significant reduction in asthma-related hospitalization.

We observed a reduction in asthma-related hospitalizations throughout the study period with a potential temporal association with the increase in biologic prescription. While biologics provided benefits in individual level, the possible benefits in a population-based level could be related to a more comprehensive care in severe asthma patients from the introduction of biologics for severe asthma.

To investigate the incidence of idiopathic epistaxis in Changshu, China, and its correlations with meteorological factors.

We retrospectively enrolled 24,193 patients with idiopathic epistaxis from March 2011 to November 2022. Matched clinical, population, and meteorological data were analyzed. Spearman's correlation and variance inflation factor analyses were performed to assess multicollinearity. We conducted quartile stratification and sequential robust negative binomial regression with three progressively adjusted models, as well as 1-4 day lag effect analyses.

The highest incidence was in patients <18 years (40.3%) and the lowest in those ≥60 years (14.3%), while males accounted for approximately 60% of all cases. Incidence was higher in spring (32%) and summer (27%). Regression analysis showed that higher relative humidity reduced disease risk by 17% (IRR = 0.83, 95% CI: -21 - -12%, p < 0.001). Extremely low atmospheric pressure increased risk by 85% with a threshold effect and no significant linear trend. Higher temperature raised risk by 12% (IRR = 1.12, 95% CI: 0-24%, p < 0.05). Wind speed and daily temperature difference showed no significant associations. During lag days 1-4, effects of humidity and daily temperature difference peaked at lag 1 day. Temperature exerted divergent effects at lag 1 and 2 days. No lag effects were observed for wind speed or atmospheric pressure.

Low humidity and high temperature are independent risk factors for idiopathic epistaxis. Atmospheric pressure presents a threshold effect, and meteorological factors exert diverse short-term lag effects on disease onset.

Mycobacterium tuberculosis (Mtb) remains the leading cause of death from a single infectious agent, despite the availability of the Bacillus Calmette-Guérin (BCG) vaccine and antibiotic therapies. New tuberculosis (TB) vaccines are urgently needed to effectively protect adults against pulmonary Mtb infections, whether used alone, as a BCG booster, or as a therapeutic strategy. We developed TBpV1, a multivalent TB vaccine, using recombinant Pichinde virus (rPICV) vector rP18tri. TBpV1 comprises three rP18tri-vectored components that collectively deliver 13 known and novel antigens targeting both the latent and active stages of the Mtb infection cycle. In mice, the pooled TBpV1 vaccine elicited robust antigen-specific CD4⁺ and CD8⁺ T cell responses, including polyfunctional Th1 and IL-17-producing cells, at levels equivalent to individual rP18tri-vectored vaccines. As a standalone vaccine, TBpV1 significantly reduced bacterial burden following an Mtb Erdman aerosol challenge, achieving protection comparable to BCG. TBpV1 also enhanced protection when administered as a BCG booster, reducing lung inflammation and bacterial loads. Lastly, TBpV1 reduced splenic bacterial burden in a post-exposure setting. These results demonstrate that pooling multi-stage antigens via the rP18tri vector maintains immunogenicity while improving protective efficacy. TBpV1 is a promising candidate for both TB prevention and therapeutic intervention, supporting further evaluation in preclinical models.