Rational Design of Lipid Nanoparticles for Enhanced mRNA Vaccine Delivery via Machine Learning.

Since the coronavirus pandemic, mRNA vaccines have revolutionized the field of vaccinology. Lipid nanoparticles (LNPs) are proposed to enhance mRNA delivery efficiency; however, their design is suboptimal. Here, a rational method for designing LNPs is explored, focusing on the ionizable lipid composition and structural optimization using machine learning (ML) techniques. A total of 213 LNPs are analyzed using random forest regression models trained with 314 features to predict the mRNA expression efficiency. The models, which predict mRNA expression levels post-administration of intradermal injection in mice, identify phenol as the dominant substructure affecting mRNA encapsulation and expression. The specific phospholipids used as components of the LNPs, as well as the N/P ratio and mass ratio, are found to affect the efficacy of mRNA delivery. Structural analysis highlights the impact of the carbon chain length on the encapsulation efficiency and LNP stability. This integrated approach offers a framework for designing advanced LNPs and has the potential to unlock the full potential of mRNA therapeutics.

Examining plasma-generated ozone and nitric oxide's role in synthetic textile dye water remediation and ecotoxicological analysis.

Synthetic dyes produced by the textile dyeing industry and released into wastewater contribute significantly to water pollution. This study explores the efficacy and versatility of a novel multi-electrode dielectric barrier discharge (MEDBD) plasma system that mainly generates ozone (O3 generator) and nitric oxide (NO generator) selectively to degrade various synthetic textile dyes, namely Methylene Blue (MB), Congo Red (CR), Methyl Orange (MO), Crystal Violet (CV), and Evans Blue (EB). Plasma achieved selective enrichment of O3 and NO by utilizing optimized plasma generation duty cycles of 15% and 100%, respectively. The proposed O3 generator plasma involves plasma-generated aqua electron impact, excited species, and reactive oxygen species notably O3, which degrades synthetic textile dyes into simple forms such as CO2, H2O, and N2. This approach achieved over 95% degradation of the above synthetic textile dyes when employing the O3 enriched plasma with 2.44 ± 0.21 W of power. Ecotoxicological evaluation, including microbial, human cell, and phytotoxicity evaluations of the O3 generator plasma for MB and CR dye-contaminated water, underscored the potential of this plasma system for environmentally friendly dye degradation. Overall, this study promotes MEDBD plasma, particularly the O3 generator, as a sustainable and efficient solution for treating synthetic dye-contaminated water across industries.

Associations among screen time, sleep, mental health and cognitive functioning in school-aged children during the COVID-19 pandemic, November 2020 through to August 2022.

Objective: To examine children's screen time use and sleep patterns over 2 years of the pandemic and the downstream associations with children's executive functions and behavioural problems, as well as the moderating effects of parental factors. Method: This longitudinal cohort study examined school-aged children's lifestyle and behavioural changes over 2 years of the pandemic across 6 timepoints (November 2020 to August 2022). Latent growth modeling (LGM) was used to identify changes in screen time and sleep duration and multivariate LGM was used to determine how parental stress, positive parenting, changes in children's screen time and sleep over time were associated with children's executive functions and mental health outcomes at the final time point. Results: A total of 198 parents (children's mean age = 9.14 years) were recruited and followed up. Non-school screen time was elevated at the initial timepoint (3.6 ± 2.3 h). Positive parenting at the initial timepoint was associated with lower screen time use in children (ß = -.19, p < .001; ß = -.19, p < .001, in internalizing and externalizing models). Children whose screen time use was constant during the pandemic had shorter sleep durations (ß = -.45, p < .05 in internalizing model). Executive function was predicted by sleep duration at the first timepoint (ß = -.55, p < .001; ß = .73, p < .001, in internalizing and externalizing models) and changes in screen time during the pandemic was associated with both internalizing and externalizing symptoms (ß = .58, p < .05; ß = .54, p < .05, in internalizing and externalizing models). Conclusion: Children's screen time decreased slightly but remained significantly higher than Canadian and International guidelines during 2 years of the pandemic. Positive parenting styles can have a significant impact on children's screen time use. Reducing excessive screen time can help improve sleep patterns and, consequently, cognitive, and emotional well-being in children.

Comparison of metastasectomy and stereotactic body radiation therapy for pulmonary oligometastasis from hepatocellular carcinoma: a propensity score-weighted analysis.

PURPOSE: While there is a growing role for local therapy in patients with hepatocellular carcinoma (HCC) and pulmonary oligometastasis, it remains unclear whether metastatectomy or stereotactic body radiation therapy (SBRT) is the more effective treatment for these patients. We aimed to compare the oncologic outcomes of metastasectomy and SBRT for HCC with pulmonary oligometastasis. METHODS: We retrospectively analyzed 209 HCC patients with 322 metastatic lung lesions who underwent either metastasectomy (150 patients with 241 lesions) or SBRT (59 patients with 81 lesions) between January 2008 and December 2018. Propensity score-based inverse probability of treatment weighting (IPTW) was used to minimize potential bias between the two groups. RESULTS: The median follow-up duration was 39.8 months (range, 2.3-166.9). The 2-year rate of freedom from local progression (FFLP) was 98.2% in the metastasectomy group and 97.0% in the SBRT group (p = 0.197). The 2-year rates of overt systemic progression-free survival (ovPFS, 51.0% vs. 46.1%; p = 0.274), progression-free survival (PFS, 26.3% vs. 9.1%; p = 0.074), and overall survival (OS, 74.0% vs. 57.6%; p = 0.006) were higher in the metastasectomy group. After IPTW adjustment, the 2-year rates of ovPFS (50.8% vs. 52.7%; p = 0.396), PFS (23.0% vs. 24.7%; p = 0.478), and OS (72.6% vs. 83.0%, p = 0.428) were not significantly different between the two groups. In multivariate analysis, viable intrahepatic lesions and the number of prior liver-directed therapies were found to be significant prognostic factors for OS and PFS. The time interval between HCC diagnosis and the development of pulmonary metastases was also significantly associated with OS. CONCLUSIONS: Both metastasectomy and SBRT demonstrated excellent local control and comparable oncologic outcomes in patients with pulmonary oligometastasis from HCC. The treatment modality for these patients could be determined based on the individual patient's condition and intrahepatic disease status.

Tomonaga-Luttinger liquid and quantum criticality in spin- 1 2 antiferromagnetic Heisenberg chain C 14 H 18 CuN 4 O 10 via Wilson ratio.

The ground state of a one-dimensional spin- 1 2 uniform antiferromagnetic Heisenberg chain (AfHc) is a Tomonaga-Luttinger liquid which is quantum-critical with respect to applied magnetic fields up to a saturation field µ 0 H s beyond which it transforms to a fully polarized state. Wilson ratio has been predicted to be a good indicator for demarcating these phases [Phys. Rev. B 96, 220401 (2017)]. From detailed temperature and magnetic field-dependent magnetization, magnetic susceptibility and specific heat measurements in a metalorganic complex and comparisons with field theory and quantum transfer matrix method calculations, the complex was found to be a very good realization of a spin- 1 2 AfHc. Wilson ratio obtained from experimentally obtained magnetic susceptibility and magnetic contribution of specific heat values was used to map the magnetic phase diagram of the uniform spin- 1 2 AfHc over large regions of phase space demarcating Tomonaga-Luttinger liquid, saturation field quantum critical, and fully polarized states. Luttinger parameter and spinon velocity were found to match very well with the values predicted from conformal field theory.

Nursing care services to address unmet supportive care needs among cancer survivors: a systematic review.

BACKGROUND: The increasing population of cancer survivors poses a significant challenge for healthcare systems globally, necessitating comprehensive post-treatment care to address diverse physical, psychological, and social needs. OBJECTIVE: This systematic review aims to synthesize and critically evaluate the current evidence concerning the unmet needs for nursing services among cancer survivors, spanning various dimensions of survivorship care. METHODS: A systematic search was conducted across major databases, including PubMed, CINAHL, and PsycINFO, to identify relevant studies investigating the unmet needs and health-related quality-of-life (HRQOL) of nursing services led by nurses among cancer survivors. The final search update was conducted in June 2024. Unmet needs dimensions were categorized by the biopsychosocial-spiritual framework. RESULTS: Of the 9503 records searched, 18 studies were included. This review revealed mixed findings in the domains of unmet needs and interventions aimed at addressing them. While nurse-led interventions showed promise in addressing physical and daily living needs, outcomes related to psychological and emotional needs varied across studies. Additionally, nurse-led interventions were effective in addressing patient-clinician communication and health system/information needs, although statistical significance was not consistently observed. HRQOL assessments using general and cancer-specific measures yielded mixed findings. CONCLUSIONS: Despite limitations of the risk of bias of included studies and weak study designs for evaluating nurse-led intervention effects for cancer survivors, the findings highlight the potential of nursing practice to significantly contribute to improving unmet needs of physical, psychological, and social perspectives and ultimately improving their HRQOL. However, the impact on the spiritual needs of nursing care services is limited by the low number of studies. IMPLICATIONS FOR CANCER SURVIVORS: By providing comprehensive support and management, nursing practice can enhance post-treatment outcomes and HRQOL for cancer survivors, contributing to more patient-centered and effective care delivery. More rigorous research considering a biopsychosocial-spiritual perspective to help cancer survivors improve HRQOL is needed.

Clinical data on treatment regimen and use of medication among patients with hemophilia B in Korea.

BACKGROUND: To investigate the clinical treatment status, such as treatment regimen, bleeding events, and drug dose, in patients with hemophilia B in South Korea. METHODS: In this retrospective chart review, data of patients with hemophilia B from eight university hospitals were collected. Demographic and clinical data, treatment data, such as regimen and number of injections, dose of factor IX concentrate, and bleeding data were reviewed. Descriptive analyses were performed with annual data for 2019, 2020, and 2021, as well as the three years consecutively. RESULTS: The medical records of 150 patients with hemophilia B between January 1, 2019, and December 31, 2021, were collected. Among these, 72 (48.0%) were severe, 47 (31.3%) were moderate, and 28 (18.7%) were mild. The results showed approximately two times more patients receiving prophylaxis as those receiving on-demand therapy, with 66.1% of patients receiving prophylaxis in 2019, 64.9% in 2020, and 72.1% in 2021. Annualized bleeding rates were 2.2% (± 3.1) in 2019, 1.8% (± 3.0) in 2020, and 1.8% (± 2.9) in 2021 among patients receiving prophylaxis. For the doses of factor IX concentrate, patients receiving prophylaxis received an average of 41.6 (± 11.9) IU/Kg/Injection in 2019, 45.7 (± 12.9) IU/Kg/Injection in 2020, and 60.1 (± 24.0) IU/Kg/Injection in 2021. CONCLUSIONS: Clinically, prophylaxis is more prevalent than reported. Based on insights gained from current clinical evidence, it is expected that the unmet medical needs of patients can be identified, and physicians can evaluate the status of patients and actively manage hemophilia B using more effective treatment strategies.

Fabrication of granular three-dimensional graphene oxide/UiO-66 adsorbent for high uranium adsorption: Density functional theory and fixed bed column studies.

This study presents a thorough investigation of the novel application of graphene oxide (GO) modified with melamine formaldehyde to fabricate granular three-dimensional GO (3D-GO), followed by the introduction of UiO-66 doping (3D-GO/U) for high uranium (U) adsorption. The U(VI) adsorption isotherms revealed that 3D-GO/U-10 with 10 % UiO-66 incorporation exhibited an impressive adsorption capacity of 375.5 mg g-1 and remained high U(VI) sorption performance in wide pH range. The introduction of UiO-66 to 3D-GO (3D-GO/U-10) led to the deagglomeration of the UiO-66 particles. The in situ surface-enhanced-Raman-spectroscopy-analysis and density-functional-theory simulations showed the symmetric metal center site Zr-O2 on UiO-66 was discovered to exhibit the highest adsorption energy (-3.21 eV) for U(VI) species due to the electrons transfer from the oxygen atom to U(VI) drives the covalent bonding between the symmetric metal center sites Zr-O2 and U(VI) on 3D-GO/U-10. The 3D-GO/U-10 was regenerated using a 0.1 M Na2CO3/0.01 M H2O2 solution and achieved up to 89.7 % U(VI) removal in the 5th cycle. The continuous flow column experiments results revealed 3D-GO/U-10 can regenerate and maintain a U(VI) removal capacity of ∼76 % for up to 4 cycles column experiments. Therefore, 3D-GO/U-10 exhibits great potential for removing U(VI) from water bodies.

Increasing ductility beyond post-uniform deformation through Zn lamellae deformation in Al at room temperature.

The Zn element precipitates during aging in the Al-Zn binary alloy. Increased Zn content and prolonged aging leads to discontinuous Zn precipitation. The addition of 2 wt% Cu to the Al-43 wt%Zn alloy accelerates this discontinuous precipitation, resulting in decreased thickness of Zn layers and inter-distance between them. This acceleration is attributed to the influence of Cu solutes on the Zn phase, thereby reducing the interface energy between Zn precipitates and the Al matrix. The Al-Zn-Cu alloy demonstrates exceptional behavior during tensile tests, displaying a simultaneous increase in tensile strength and ductility alongside an 75 % reduction in area at room temperature drawing. Notably, despite the drawn beyond uniform deformation limit, there is an observed increase in total elongation. Our demonstration highlights this phenomenon, attributing it to the sustained coherent interface between the Zn layer and the Al matrix, as well as the uninterrupted continuity of Zn layers during drawing.

Intracellular pyruvate as one of the major bioactive substances of lactic acid bacteria isolated from kimchi.

The present study aimed to identify the metabolites associated with the physiological activity of kimchi-derived lactic acid bacteria (LAB). A clear difference was observed between the 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS) radical scavenging rates when the pyruvate content was high (273.5 ng/µL; radical removal speed 6.50% per min) and the rates when the pyruvate content had decreased (131.9 ng/µL; radical removal speed 3.63% per min). Additionally, the characteristics of LAB antioxidant activity (increase in ABTS radical scavenging activity with reaction time, low level of 2,2-diphenyl-1-picrylhydrazyl radical scavenging activity) were similar to those of pyruvate-derived activity. Hydrogen peroxide content (WiKim0124, 2.08 → 0.26; WiKim0121, 0.99 → 0.47; WiKim39, 1.93 → 0.24) and lactate dehydrogenase activity (WiKim0124, 1.53 → 0.00; WiKim0121, 0.73 → 0.01; WiKim39, 1.72 → 0.02) decreased more in heat-killed LAB than in non-heat-killed LAB. Accordingly, this resulted in increased pyruvate content and the inhibitory activity of lipid peroxide production increased by 2-3 times. Our findings indicate that pyruvate is one of the major metabolites regulating LAB physiological activity. PRACTICAL APPLICATION: The safety of utilizing live probiotics remains a topic of debate. To mitigate associated risks, there is a growing interest in non-viable microorganisms or microbial cell extracts for use as probiotics. Various methods can be employed for probiotic inactivation. Heat treatment typically emerges as the preferred choice for inactivating probiotic strains in many instances. The present study shows the distinctions between inactivating lactic acid bacteria (LAB) through heat treatment and non-heat treatment. It may serve as a valuable reference for selecting an appropriate inactivation method for LAB in industrial processes.

An Accurate and Rapidly Calibrating Speech Neuroprosthesis.

BACKGROUND: Brain-computer interfaces can enable communication for people with paralysis by transforming cortical activity associated with attempted speech into text on a computer screen. Communication with brain-computer interfaces has been restricted by extensive training requirements and limited accuracy. METHODS: A 45-year-old man with amyotrophic lateral sclerosis (ALS) with tetraparesis and severe dysarthria underwent surgical implantation of four microelectrode arrays into his left ventral precentral gyrus 5 years after the onset of the illness; these arrays recorded neural activity from 256 intracortical electrodes. We report the results of decoding his cortical neural activity as he attempted to speak in both prompted and unstructured conversational contexts. Decoded words were displayed on a screen and then vocalized with the use of text-to-speech software designed to sound like his pre-ALS voice. RESULTS: On the first day of use (25 days after surgery), the neuroprosthesis achieved 99.6% accuracy with a 50-word vocabulary. Calibration of the neuroprosthesis required 30 minutes of cortical recordings while the participant attempted to speak, followed by subsequent processing. On the second day, after 1.4 additional hours of system training, the neuroprosthesis achieved 90.2% accuracy using a 125,000-word vocabulary. With further training data, the neuroprosthesis sustained 97.5% accuracy over a period of 8.4 months after surgical implantation, and the participant used it to communicate in self-paced conversations at a rate of approximately 32 words per minute for more than 248 cumulative hours. CONCLUSIONS: In a person with ALS and severe dysarthria, an intracortical speech neuroprosthesis reached a level of performance suitable to restore conversational communication after brief training. (Funded by the Office of the Assistant Secretary of Defense for Health Affairs and others; BrainGate2 ClinicalTrials.gov number, NCT00912041.).

Investigating the synergy of rapidly synthesized iron oxide predecessor and plasma-gaseous species for dye-removal to reuse water in irrigation.

This study explores a novel and sustainable approach to reusing textile wastewater for irrigation. This is investigated by degrading Evans blue dye, a model azo dye, in wastewater by combining iron oxide predecessor (IOP) catalyst with gaseous species generated by multi-electrode cylindrical plasma device (MCPD). Analysis of IOP-plasma gaseous species revealed the generation of different types of reactive oxygen species in solution which were responsible for degradation of model dye. Key factors influencing the degradation process were studied by performing optimization experiments that resulted in rates of up to 0.008 L mg-1 min-1, more than twice as fast as using plasma gas treatment alone. These studies included mechanistic response of MCPD generated gaseous species with the IOP. In particular, reusability testing of IOP affirmed the robustness and performance efficiency up to three cycles. Finally, toxicity analysis revealed not only reduced negative effects on plant growth by the treated wastewater, but also it can used as minerals to plants. These findings highlight the feasibility of the IOP-MCPD system as a sustainable and eco-friendly solution to reduce scarcity of water in irrigation by treating textile effluent.

Human papillomavirus and Merkel cell polyomavirus in Korean patients with nonsmall cell lung cancer: Evaluation and genetic variability of the noncoding control region.

Human papillomavirus (HPV) is an important causative factor of cervical cancer and is associated with nonsmall cell lung cancer (NSCLC). Merkel cell polyomavirus (MCPyV) is a rare and highly fatal cutaneous virus that can cause Merkel cell carcinoma (MCC). Although coinfection with oncogenic HPV and MCPyV may increase cancer risk, a definitive etiological link has not been established. Recently, genomic variation and genetic diversity in the MCPyV noncoding control region (NCCR) among ethnic groups has been reported. The current study aimed to provide accurate prevalence information on HPV and MCPyV infection/coinfection in NSCLC patients and to evaluate and confirm Korean MCPyV NCCR variant genotypes and sequences. DNA from 150 NSCLC tissues and 150 adjacent control tissues was assessed via polymerase chain reaction (PCR) targeting regions of the large T antigen (LT-ag), viral capsid protein 1 (VP1), and NCCR. MCPyV was detected in 22.7% (34 of 150) of NSCLC tissues and 8.0% (12 of 150) of adjacent tissues from Korean patients. The incidence rates of HPV with and without MCPyV were 26.5% (nine of 34) and 12.9% (15 of 116). The MCPyV NCCR genotype prevalence in Korean patients was 21.3% (32 of 150) for subtype I and 6% (nine of 150) for subtype IIc. Subtype I, a predominant East Asian strain containing 25 bp tandem repeats, was most common in the MCPyV NCCR data set. Our results confirm that coinfection with other tumor-associated viruses is not associated with NSCLC. Although the role of NCCR rearrangements in MCPyV infection remains unknown, future studies are warranted to determine the associations of MCPyV NCCR sequence rearrangements with specific diseases.

The Long-Term Outcomes and Risk Factors of Complications After Fontan Surgery: From the Korean Fontan Registry (KFR).

BACKGROUND AND OBJECTIVES: This study aimed to analyze the outcomes of Fontan surgery in the Republic of Korea, as there were only a few studies from Asian countries. METHODS: The medical records of 1,732 patients who underwent Fontan surgery in 10 cardiac centers were reviewed. RESULTS: Among them, 1,040 (58.8%) were men. The mean age at Fontan surgery was 4.3±4.2 years, and 395 (22.8%) patients presented with heterotaxy syndrome. According to the types of Fontan surgery, 157 patients underwent atriopulmonary (AP) type; 303, lateral tunnel (LT) type; and 1,266, extracardiac conduit (ECC) type. The overall survival rates were 91.7%, 87.1%, and 74.4% at 10, 20, and 30 years, respectively. The risk factors of early mortality were male, heterotaxy syndrome, AP-type Fontan surgery, high mean pulmonary artery pressure (mPAP) in pre-Fontan cardiac catheterization, and early Fontan surgery year. The risk factors of late mortality were heterotaxy syndrome, genetic disorder, significant atrioventricular valve regurgitation (AVVR) before Fontan surgery, high mPAP in pre-Fontan cardiac catheterization, and no fenestration. CONCLUSIONS: In Asian population with a high incidence of heterotaxy syndrome, the heterotaxy syndrome was identified as the poor prognostic factors for Fontan surgery. The preoperative low mPAP and less AVVR are associated with better early and long-term outcomes of Fontan surgery.

Evaluation of FVIII pharmacokinetic profiles in Korean hemophilia A patients assessed with myPKFiT: a retrospective chart review.

PURPOSE: This study aimed to investigate the pharmacokinetics (PK) of factor VIII (FVIII) in Korean patients, as limited information is available on the PK of FVIII in this population. METHODS: We collected the FVIII PK results from patients with moderate-to-severe hemophilia A using myPKFiT. PK variations were assessed according to age, blood type, inhibitor history, von Willebrand factor antigen (vWF:Ag) level, and body mass index. Additionally, the correlation between the PK profile and prophylaxis regimen was specifically analyzed for each product in severe cases. RESULTS: The PK data of 48 and 81 patients treated with octocog alfa and rurioctocog alfa pegol, respectively, were obtained. The median half-lives of octocog alfa and rurioctocog alfa pegol were 9.9 (range: 6.3-15.2) h and 15.3 (range: 10.4-23.9) h, respectively. The PK profiles for each product did not differ according to age group; however, blood type-O patients had shorter half-lives and time to 1% compared to non-blood type-O patients. In regression analysis, the PK of octocog alfa showed a statistically significant difference according to age, whereas the PK of rurioctocog alfa pegol correlated with vWF:Ag. Only the frequency of rurioctocog alfa pegol use showed a statistically significant difference in relation to time to 1%, although the coefficient of determination was small. CONCLUSION: This study confirmed significant interpatient variation in the PK of FVIII among Korean patients with hemophilia A. To achieve optimized prophylaxis, personalizing the regimen based on the PK profile of each individual patient is essential.

Discovery of novel arylpyridine derivatives for motile ciliogenesis.

Motile cilia are crucial for maintaining healthy bodily functions by facilitating fluid transport and removing foreign substances or debris from the body. The dysfunction of motile cilia leads to ciliopathy. In particular, damage to the motile cilia of the airways can cause or worsen respiratory disease, making it an attractive target for therapeutic interventions. However, there are no treatments to induce motile ciliogenesis. Forkhead box transcription factor J1 (FOXJ1), the master regulator, has been implicated in motile cilia formation. Mice lacking the Foxj1 gene show loss of axoneme, a key component of cilia, that further highlights the importance of FOXJ1 in motile cilia formation. This prompted us to identify new small molecules that could induce motile ciliogenesis. A phenotype-based high-throughput screening (HTS) in a Tg(foxj1a:eGFP) zebrafish model was performed and a novel hit compound was identified. Among the synthesized compounds, compound 16c effectively enhanced motile ciliogenesis in a transgenic zebrafish model. To further test the efficacy of compound 16c on a mammalian airway system consisting of multiciliated cells (MCCs), ex vivo mice tracheal epithelial cell culture was adopted under an air-liquid interface system (ALI). Compound 16c significantly increased the number of MCCs by enhancing motile ciliogenesis. In addition, compound 16c exhibited good liver microsomal stability, in vivo PK profiles with AUC, and oral bioavailability. There was no significant inhibition of CYP and hERG, and no cell cytotoxicity was shown. In an elastase-induced COPD (chronic obstructive pulmonary disease) mouse model, compound 16c effectively prevented the development and onset of COPD. Taken together, compound 16c has great promise as a therapeutic agent for treating and alleviating motile ciliopathies.

Detection of Hepatocellular Carcinoma in an Orthotopic Patient-Derived Xenograft with an Epithelial Cell Adhesion Molecule-Specific Peptide.

Hepatocellular carcinoma (HCC) has emerged as a major contributor to the worldwide cancer burden. Improved methods are needed for early cancer detection and image-guided surgery. Peptides have small dimensions that can overcome delivery challenges to achieve high tumor concentrations and deep penetration. We used phage display methods to biopan against the extra-cellular domain of the purified EpCAM protein, and used IRDye800 as a near-infrared (NIR) fluorophore. The 12-mer sequence HPDMFTRTHSHN was identified, and specific binding to EpCAM was validated with HCC cells in vitro. A binding affinity of kd = 67 nM and onset of k = 0.136 min-1 (7.35 min) were determined. Serum stability was measured with a half-life of T1/2 = 2.6 h. NIR fluorescence images showed peak uptake in vivo by human HCC patient-derived xenograft (PDX) tumors at 1.5 h post-injection. Also, the peptide was able to bind to foci of local and distant metastases in liver and lung. Peptide biodistribution showed high uptake in tumor versus other organs. No signs of acute toxicity were detected during animal necropsy. Immunofluorescence staining of human liver showed specific binding to HCC compared with cirrhosis, adenoma, and normal specimens.

Reprogramming of breast tumor-associated macrophages with modulation of arginine metabolism.

HER2+ breast tumors have abundant immune-suppressive cells, including M2-type tumor-associated macrophages (TAMs). Although TAMs consist of the immune-stimulatory M1 type and immune-suppressive M2 type, the M1/M2-TAM ratio is reduced in immune-suppressive tumors, contributing to their immunotherapy refractoriness. M1- versus M2-TAM formation depends on differential arginine metabolism, where M1-TAMs convert arginine to nitric oxide (NO) and M2-TAMs convert arginine to polyamines (PAs). We hypothesize that such distinct arginine metabolism in M1- versus M2-TAMs is attributed to different availability of BH4 (NO synthase cofactor) and that its replenishment would reprogram M2-TAMs to M1-TAMs. Recently, we reported that sepiapterin (SEP), the endogenous BH4 precursor, elevates the expression of M1-TAM markers within HER2+ tumors. Here, we show that SEP restores BH4 levels in M2-like macrophages, which then redirects arginine metabolism to NO synthesis and converts M2 type to M1 type. The reprogrammed macrophages exhibit full-fledged capabilities of antigen presentation and induction of effector T cells to trigger immunogenic cell death of HER2+ cancer cells. This study substantiates the utility of SEP in the metabolic shift of the HER2+ breast tumor microenvironment as a novel immunotherapeutic strategy.

Decoding LncRNA in COPD: Unveiling Prognostic and Diagnostic Power and Their Driving Role in Lung Cancer Progression.

Chronic obstructive pulmonary disease (COPD) and lung cancer represent formidable challenges in global health, characterized by intricate pathophysiological mechanisms and multifaceted disease progression. This comprehensive review integrates insights from diverse perspectives to elucidate the intricate roles of long non-coding RNAs (lncRNAs) in the pathogenesis of COPD and lung cancer, focusing on their diagnostic, prognostic, and therapeutic implications. In the context of COPD, dysregulated lncRNAs, such as NEAT1, TUG1, MALAT1, HOTAIR, and GAS5, emerge as pivotal regulators of genes involved in the disease pathogenesis and progression. Their identification, profiling, and correlation with the disease severity present promising avenues for prognostic and diagnostic applications, thereby shaping personalized disease interventions. These lncRNAs are also implicated in lung cancer, underscoring their multifaceted roles and therapeutic potential across both diseases. In the domain of lung cancer, lncRNAs play intricate modulatory roles in disease progression, offering avenues for innovative therapeutic approaches and prognostic indicators. LncRNA-mediated immune responses have been shown to drive lung cancer progression by modulating the tumor microenvironment, influencing immune cell infiltration, and altering cytokine production. Their dysregulation significantly contributes to tumor growth, metastasis, and chemo-resistance, thereby emphasizing their significance as therapeutic targets and prognostic markers. This review summarizes the transformative potential of lncRNA-based diagnostics and therapeutics for COPD and lung cancer, offering valuable insights into future research directions for clinical translation and therapeutic development.