Lutetium Texaphyrin-Celecoxib Conjugate as a Potential Immuno-Photodynamic Therapy Agent.

Immuno-photodynamic therapy (IPDT) has emerged as a new modality for cancer treatment. Novel photosensitizers can help achieve the promise inherent in IPDT, namely, the complete eradication of a tumor without recurrence. We report here a small molecule photosensitizer conjugate, LuCXB. This IPDT agent integrates a celecoxib (cyclooxygenase-2 inhibitor) moiety with a near-infrared absorbing lutetium texaphyrin photocatalytic core. In aqueous environments, the two components of LuCXB are self-associated through inferred donor-acceptor interactions. A consequence of this intramolecular association is that upon photoirradiation with 730 nm light, LuCXB produces superoxide radicals (O2-•) via a type I photodynamic pathway; this provides a first line of defense against the tumor while promoting IPDT. For in vivo therapeutic applications, we prepared a CD133-targeting, aptamer-functionalized exosome-based nanophotosensitizer (Ex-apt@LuCXB) designed to target cancer stem cells. Ex-apt@LuCXB was found to display good photosensitivity, acceptable biocompatibility, and robust tumor targetability. Under conditions of photoirradiation, Ex-apt@LuCXB acts to amplify IPDT while exerting a significant antitumor effect in both liver and breast cancer mouse models. The observed therapeutic effects are attributed to a synergistic mechanism that combines antiangiogenesis and photoinduced cancer immunotherapy.

Bifunctional black phosphorus quantum dots platform: Delivery and remarkable immunotherapy enhancement of STING agonist.

Cancer immunotherapy has been developed to improve therapeutic effects for patients by activating the innate immune stimulator of interferon gene (STING) pathway. However, most patients cannot benefit from this therapy, mainly due to the problems of excessively low immune responses and lack of tumor specificity. Herein, we report a solution to these two problems by developing a bifunctional platform of black phosphorus quantum dots (BPQDs) for STING agonists. Specifically, BPQDs could connect targeted functional groups and regulate surface zeta potential by coordinating metal ions to increase loading (over 5 times) while maintaining high universality (7 STING agonists). The controlled release of STING agonists enabled specific interactions with their proteins, activating the STING pathway and stimulating the secretion release of immunosuppressive factors by phosphorylating TBK1 and IFN-IRF3 and secreting high levels of immunostimulatory cytokines, including IL-6, IFN-α, and IFN-ß. Moreover, the immunotherapy was enhanced was enhanced mild photothermal therapy (PTT) of BPQDs platform, producing enough T cells to eliminate tumors and prevent tumor recurrence. This work facilitates further research on targeted delivery of small-molecule immune drugs to enhance the development of clinical immunotherapy.

Does COVID-19 vaccination increase the risk of interstitial lung disease at a population level?

This study showed a significantly lower incidence of ILD among COVID-19 vaccinated individuals compared to unvaccinated, suggesting that the risk of COVID-19 vaccine-related ILD is not as high as previously reported https://bit.ly/3TWzzxP.

An ATP-responsive metal-organic framework against periodontitis via synergistic ion-interference-mediated pyroptosis.

Periodontitis involves hyperactivated stromal cells that recruit immune cells, exacerbating inflammation. This study presents an ATP-responsive metal-organic framework (Mg/Zn-MOF) designed for periodontitis treatment, utilizing ion interference to modulate immune responses and prevent tissue destruction. Addressing the challenges of synergistic ion effects and targeted delivery faced by traditional immunomodulatory nanomaterials, the Mg/Zn-MOF system is activated by extracellular ATP-a pivotal molecule in periodontitis pathology-ensuring targeted ion release. Magnesium and zinc ions released from the framework synergistically inhibit membrane pore formation by attenuating Gasdermin D (GSDMD) expression and activation. This action curtails pyroptosis, lactate dehydrogenase and IL-1ß release, thwarting the onset of inflammatory cascades. Mechanistically, Mg/Zn-MOF intervenes in both the NLRP3/Caspase-1/GSDMD and Caspase-11/GSDMD pathways to mitigate pyroptosis. In vivo assessments confirm its effectiveness in diminishing inflammatory cell infiltration and preserving collagen integrity, thereby safeguarding against periodontal tissue damage and bone loss. This investigation highlights the promise of ion-interference strategies in periodontitis immunotherapy, representing a significant stride in developing targeted therapeutic approaches.

Association between obstructive sleep apnea and risk of Benign vocal fold lesions: A nationwide 9-year follow-up cohort study.

Since obstructive sleep apnea (OSA) affects various parts of the body, there has been little interest about the effect of OSA on voice. The objective of this study was to evaluate the risk of benign vocal fold lesions (BVFL) in OSA patients. This study used data from the National Health Insurance Service (NHIS) database. The study group was defined as the group diagnosed with OSA between 2008 and 2011. Non-OSA groups were selected based on propensity score (PS) matching. Incidence of BVFL among participants during the follow-up was analyzed. Cox proportional hazard regression analyses were performed to evaluate the association between OSA and incident BVFL. The HR value of the OSA group calculated by considering 8 variables indicates that the risk of developing BVFL is 79% higher than that of the control group. Further, among OSA patients, patients with a history of OP had a 35% lower risk of developing BVFL. The relationships between BVFL and 7 individual variables considered were as follows: For age, HR for the 40 to 59 years group was 1.20 (95%CI, 1.09-1.32). For sex, the HR in the female group was 1.22 (95%CI, 1.10-1.35). For residential areas, the HR values for "Seoul" 1.39 (95%CI, 1.23-1.59). In the high economic status group, the HR was 1.10 (95%CI, 1.01-1.21). This observational study indicated that OSA is associated with an increased incidence of BVFL. The incidence of BVFL increased with older age, female sex, and high SES.

An NIR Type I Photosensitizer Based on a Cyclometalated Ir(III)-Rhodamine Complex for a Photodynamic Antibacterial Effect toward Both Gram-Positive and Gram-Negative Bacteria.

Type I photosensitizers offer an advantage in photodynamic therapy (PDT) due to their diminished reliance on oxygen levels, thus circumventing the challenge of hypoxia commonly encountered in PDT. In this study, we present the synthesis and comprehensive characterization of a novel type I photosensitizer derived from a cyclometalated Ir(III)-rhodamine complex. Remarkably, the complex exhibits a shift in absorption and fluorescence, transitioning from "off" to "on" states in aprotic and protic solvents, respectively, contrary to initial expectations. Upon exposure to light, the complex demonstrates the effective generation of O2- and ·OH radicals via the type I mechanism. Additionally, it exhibits notable photodynamic antibacterial activity against both Gram-positive and Gram-negative bacteria, demonstrated through in vitro and in vivo experiments. This research offers valuable insights for the development of novel type I photosensitizers.

Risk of vitiligo in patients with SARS-CoV-2 vaccination or infection: a nationwide cohort study.

As recent sporadic case reports of newly developed vitiligo after SARS-CoV-2 infection or vaccination have been -published, a convincing large-scale study addressing this association is warranted. To investigate the association between SARS-CoV-2 infection or vaccination and vitiligo using the Korean National Health Insurance Service database. SARS-CoV-2-positive patients and those vaccinated against SARS-CoV-2 were recruited. In studies 1 and 2, control groups were selected based on 1:1 propensity score matching with vaccinated and SARS-CoV-2-positive patients, respectively. The occurrence of vitiligo was the main outcome. Each individual was monitored for six months. The hazard ratio (HR) for vitiligo was calculated using the Cox proportional hazards model. In study 1, the incidence of vitiligo in the vaccination group was 2.22-fold higher than that in the non-vaccination group (adjusted HR [aHR]: 2.22; 95% confidence interval [CI]: 1.54-3.19). Rheumatoid arthritis was a risk factor for vitiligo (aHR: 1.99; 95% CI: 1.12-3.54). Conversely, two factors associated with decreased incidence of vitiligo were male sex (aHR: 0.58; 95% CI: 0.40-0.82) and rural residency (aHR: 0.68; 95% CI: 0.49-0.96). In study 2, the incidence of newly-diagnosed vitiligo was not significantly different between SARS-CoV-2-positive patients and uninfected controls (aHR: 0.95; 95% CI: 0.51-1.78). SARS-CoV-2 vaccination may increase the risk of developing vitiligo in South Korea, although additional studies in other countries or with extended periods are needed. Clinicians should be aware of the impact of SARS-CoV-2 infection and vaccination on autoimmune skin diseases, including vitiligo.

Gold core@CeO2 halfshell Janus nanocomposites catalyze targeted sulfate radical for periodontitis therapy.

The sulfate radical (SO4•-), known for its high reactivity and long lifespan, has emerged as a potent antimicrobial agent. Its exceptional energy allows for the disruption of vital structures and metabolic pathways in bacteria that are usually inaccessible to common radicals. Despite its promising potential, the efficient generation of this radical, particularly through methods involving enzymes and photocatalysis, remains a substantial challenge. Here, we capitalized on the peroxidase (POD)-mimicking activity and photocatalytic properties of cerium oxide (CeO2) nanozymes, integrating these properties with the enhanced concept of plasma gold nanorod (GNR) to develop a half-encapsulated core@shell GNRs@CeO2 Janus heterostructure impregnated with persulfate. Under near-infrared irradiation, the GNRs generate hot electrons, thereby boosting the CeO2's enzyme-like activity and initiating a potent reactive oxygen species (ROS) storm. This distinct nanoarchitecture facilitates functional specialization, wherein the heterostructure and efficient light absorption ensured continuous hot electron flow, not only enhancing the POD-like activity of CeO2 for the production of SO4•- effectively, but also contributing a significant photothermal effect, disrupting periodontal plaque biofilm and effectively eradicating pathogens. Furthermore, the local temperature elevation synergistically enhances the POD-like activity of CeO2. Transcriptomics analysis, as well as animal experiments of the periodontitis model, have revealed that pathogens undergo genetic information destruction, metabolic disorders, and pathogenicity changes in the powerful ROS system, and profound therapeutic outcomes in vivo, including anti-inflammation and bone preservation. This study demonstrated that energy transfer to augment nanozyme activity, specifically targeting ROS generation, constitutes a significant advancement in antibacterial treatment.

Herpesviral Keratitis Following COVID-19 Vaccination: Analysis of NHIS Database in Korea.

PURPOSE: The purpose of this study was to determine the risk of herpesviral keratitis associated with 4 coronavirus disease 2019 (COVID-19) vaccines approved in South Korea, using large-scale data from the National Health Insurance Service. METHODS: The study included 8,528,254 individuals, with cohorts categorized based on COVID-19 vaccination status. Two investigations were conducted: The first aimed to assess the risk of new-onset herpesviral keratitis while the second study focused on the risk of relapse in individuals with a preexisting diagnosis. Propensity score matching was used for cohort balancing, and various covariates, including vaccine types and comorbidities, were considered. Statistical analyses, including Cox proportional hazard regression, were used to calculate adjusted hazard ratio (aHR) and assess the risk of herpesviral keratitis. RESULTS: Individuals receiving COVID-19 vaccination exhibited a higher risk of new-onset herpesviral keratitis compared with the unvaccinated control group (aHR 1.43, 95% confidence interval, 1.19-1.73). Both mRNA and non-mRNA vaccines demonstrated an increased risk. Individuals with preexisting herpetic keratitis who received COVID-19 vaccination showed a higher risk of relapse herpesviral keratitis compared with the unvaccinated control group (aHR 1.98, 95% CI, 1.29-3.03). Sensitivity analyses supported the robustness of the results. CONCLUSIONS: This analysis of a large national health insurance database suggests an increased risk of both new-onset and relapse of herpesviral keratitis associated with COVID-19 vaccination in South Korea. While COVID-19 vaccination is crucial for pandemic control, health care providers should be aware of potential herpesvirus reactivation and consider appropriate prophylaxis and treatment for at-risk individuals.

Luciferase-Decorated Gold Nanorods as Dual-Modal Contrast Agents for Tumor-Targeted High-Performance Bioluminescence/Photoacoustic Imaging.

Gold nanorods (AuNRs) have been considered highly compelling materials for early cancer diagnosis and have aroused a burgeoning fascination among the biomedical sectors. By leveraging the versatile tunable optical properties of AuNRs, herein, we have developed a novel tumor-targeted dual-modal nanoprobe (FFA) that exhibits excellent bioluminescence and photoacoustic imaging performance for early tumor diagnosis. FFA has been synthesized by anchoring the recombinant bioluminescent firefly luciferase protein (Fluc) on the folate-conjugated AuNRs via the PEG linker. TEM images and UV-vis studies confirm the nanorod morphology and successful conjugation of the biomolecules to AuNRs. The nanoprobe FFA relies on the ability of the folate module to target the folate receptor-positive tumor cells actively, and simultaneously, the Fluc module facilitates excellent bioluminescent properties in physiological conditions. The success of chemical engineering in the present study enables stronger bioluminescent signals in the folate receptor-positive cells (Skov3, Hela, and MCF-7) than in folate receptor-negative cells (A549, 293T, MCF-10A, and HepG2). Additionally, the AuNRs induced strong photoacoustic conversion performance, enhancing the resolution of tumor imaging. No apparent toxicity was detected at the cellular and mouse tissue levels, manifesting the biocompatibility nature of the nanoprobe. Prompted by the positive merits of FFA, the in vivo animal studies were performed, and a notable enhancement was observed in the bioluminescent/photoacoustic intensity of the nanoprobe in the tumor region compared to that in the folate-blocking region. Therefore, this synergistic dual-modal bioluminescent and photoacoustic imaging platform holds great potential as a tumor-targeted contrast agent for early tumor diagnosis with high-performance imaging information.

Injectable hydrogel harnessing foreskin mesenchymal stem cell-derived extracellular vesicles for treatment of chronic diabetic skin wounds.

Chronic skin wounds are a serious complication of diabetes with a high incidence rate, which can lead to disability or even death. Previous studies have shown that mesenchymal stem cells derived extracellular vesicles (EVs) have beneficial effects on wound healing. However, the human foreskin mesenchymal stem cell (FSMSCs)-derived extracellular vesicle (FM-EV) has not yet been isolated and characterized. Furthermore, the limited supply and short lifespan of EVs also hinder their practical use. In this study, we developed an injectable dual-physical cross-linking hydrogel (PSiW) with self-healing, adhesive, and antibacterial properties, using polyvinylpyrrolidone and silicotungstic acid to load FM-EV. The EVs were evenly distributed in the hydrogel and continuously released. In vivo and vitro tests demonstrated that the synergistic effect of EVs and hydrogel could significantly promote the repair of diabetic wounds by regulating macrophage polarization, promoting angiogenesis, and improving the microenvironment. Overall, the obtained EVs-loaded hydrogels developed in this work exhibited promising applicability for the repair of chronic skin wounds in diabetes patients.

An AIE-based fluorescent probe to detect peroxynitrite levels in human serum and its cellular imaging.

An AIE-based fluorescent probe was designed to evaluate peroxynitrite levels in complex biological samples. The newly synthesized hydrazone-conjugated probe fluoresces strongly in the presence of peroxynitrite. Clinically, the peroxynitrite levels can be measured in human serum and cellular mitochondria with an LOD of 6.5 nM by fluorescence imaging in vitro.

Long-Term Impacts of COVID-19 on Severe Exacerbation and Mortality in Adult Asthma: A Nationwide Population-Based Cohort Study.

BACKGROUND: In adults with asthma, the long-term impact of previous coronavirus disease 2019 (COVID-19) on severe exacerbations and mortality is unclear. OBJECTIVE: We evaluated the long-term risk of severe exacerbation and mortality in adults with asthma who recovered from COVID-19. METHODS: Using the Korean National Health Insurance claim-based database, we compared the risk of severe exacerbations (emergency room visits or hospitalization) and mortality in adults with asthma aged greater than 20 years who had recovered from COVID-19 between October 8, 2020, and December 16, 2021 (COVID-19 cohort, n = 10,739) with 1:1 propensity score-matched controls (n = 10,739). RESULTS: During a median follow-up of 87 days (range, 15-448 days), the incidence rate of severe exacerbations in the COVID-19 cohort and the matched cohort was 187.3 and 119.3 per 10,000 person-years, respectively. The COVID-19 cohort had a higher risk of severe exacerbation compared with the matched cohort (hazard ratio = 1.57; 95% CI, 1.06-2.32). During a median follow-up of 360 days (range, 15-721 days), the incidence rate of death in the COVID-19 and matched cohorts was 128.3 and 73.5 per 10,000 person-years, respectively. The COVID-19 cohort had a higher risk of death (hazard ratio = 1.76; 95% CI, 1.33-2.30) compared with the matched cohort. When further analyzed by COVID-19 severity, severe COVID-19 was associated with a 5.12-fold (95% CI, 3.27-8.01) and 7.31-fold (95% CI, 5.41-9.88) increased risk of severe exacerbation and death, respectively, but non-severe COVID-19 was not. CONCLUSIONS: Our study shows that severe COVID-19 is associated with an increased long-term risk of severe exacerbation and mortality among individuals with asthma.

Incidence and risk factors of breast cancer-related lymphedema in Korea: a nationwide retrospective cohort study.

BACKGROUND: Breast cancer-related lymphedema (BCRL) is a secondary lymphedema that occurs after breast cancer related treatments. BCRL develops from damage or dysfunction of the normally functioning lymphatic system due to surgery, radiation therapy, and rarely due to cancer recurrence. This nationwide, retrospective study was aimed at investigating the incidence and risk factors of BCRL using the database of the Korean National Health Insurance Service (NHIS). METHODS: Patients with newly diagnosed breast cancer who underwent breast surgery from 1 January 2017 to 31 December 2020, were recruited. The incidence was compared by four groups according to the operation type of breast cancer [breast conserving surgery (BCS) with sentinel lymph node biopsy (S), BCS with axillary lymph node dissection (A), total mastectomy (TM) with S, modified radical mastectomy (MRM)]. The incidence rates of lymphedema were calculated by the number of incident events by the total follow-up period. Cox proportional hazard regression was used to calculate the risk of incidence of lymphedema based on a patients' characteristics, breast cancer treatment, and comorbidities. RESULTS: The final cohort of operation subjects that satisfied the inclusion criteria was 34 676. BCRL occurred in 4242 patients (12.2%), and the median follow-up period was 695.4 days. The BCRL was diagnosed in the BCS with S (8.0%), BCS with A (23.5%), TM with S (10.7%), and MRM (28.5%) with an incidence of 40.8, 132.2, 55.8, and 171.8 per 1000 person-years, respectively. Young age, obesity, chemotherapy, radiotherapy, residence in metropolitan areas, and hyperlipidemia were identified as risk factors. CONCLUSION: In Korea, the incidence of BCRL was found to be 12.2%, with the highest risk observed among patients who underwent MRM. Therefore, surgical oncologists should meticulously assess the appropriate surgical approach and consider providing education to patients with risk factors for BCRL, aiming to ensure effective prevention strategies.

Augmenting Cancer Therapy with a Supramolecular Immunogenic Cell Death Inducer: A Lysosome-Targeted NIR-Light-Activated Ruthenium(II) Metallacycle.

Though immunogenic cell death (ICD) has garnered significant attention in the realm of anticancer therapies, effectively stimulating strong immune responses with minimal side effects in deep-seated tumors remains challenging. Herein, we introduce a novel self-assembled near-infrared-light-activated ruthenium(II) metallacycle, Ru1105 (λem = 1105 nm), as a first example of a Ru(II) supramolecular ICD inducer. Ru1105 synergistically potentiates immunomodulatory responses and reduces adverse effects in deep-seated tumors through multiple regulated approaches, including NIR-light excitation, increased reactive oxygen species (ROS) generation, selective targeting of tumor cells, precision organelle localization, and improved tumor penetration/retention capabilities. Specifically, Ru1105 demonstrates excellent depth-activated ROS production (∼1 cm), strong resistance to diffusion, and anti-ROS quenching. Moreover, Ru1105 exhibits promising results in cellular uptake and ROS generation in cancer cells and multicellular tumor spheroids. Importantly, Ru1105 induces more efficient ICD in an ultralow dose (10 µM) compared to the conventional anticancer agent, oxaliplatin (300 µM). In vivo experiments further confirm Ru1105's potency as an ICD inducer, eliciting CD8+ T cell responses and depleting Foxp3+ T cells with minimal adverse effects. Our research lays the foundation for the design of secure and exceptionally potent metal-based ICD agents in immunotherapy.

Deep learning algorithm for the automated detection and classification of nasal cavity mass in nasal endoscopic images.

Nasal endoscopy is routinely performed to distinguish the pathological types of masses. There is a lack of studies on deep learning algorithms for discriminating a wide range of endoscopic nasal cavity mass lesions. Therefore, we aimed to develop an endoscopic-examination-based deep learning model to detect and classify nasal cavity mass lesions, including nasal polyps (NPs), benign tumors, and malignant tumors. The clinical feasibility of the model was evaluated by comparing the results to those of manual assessment. Biopsy-confirmed nasal endoscopic images were obtained from 17 hospitals in South Korea. Here, 400 images were used for the test set. The training and validation datasets consisted of 149,043 normal nasal cavity, 311,043 NP, 9,271 benign tumor, and 5,323 malignant tumor lesion images. The proposed Xception architecture achieved an overall accuracy of 0.792 with the following class accuracies on the test set: normal = 0.978 ± 0.016, NP = 0.790 ± 0.016, benign = 0.708 ± 0.100, and malignant = 0.698 ± 0.116. With an average area under the receiver operating characteristic curve (AUC) of 0.947, the AUC values and F1 score were highest in the order of normal, NP, malignant tumor, and benign tumor classes. The classification performances of the proposed model were comparable with those of manual assessment in the normal and NP classes. The proposed model outperformed manual assessment in the benign and malignant tumor classes (sensitivities of 0.708 ± 0.100 vs. 0.549 ± 0.172, 0.698 ± 0.116 vs. 0.518 ± 0.153, respectively). In urgent (malignant) versus nonurgent binary predictions, the deep learning model achieved superior diagnostic accuracy. The developed model based on endoscopic images achieved satisfactory performance in classifying four classes of nasal cavity mass lesions, namely normal, NP, benign tumor, and malignant tumor. The developed model can therefore be used to screen nasal cavity lesions accurately and rapidly.

Theranostic Fluorescent Probes.

The ability to gain spatiotemporal information, and in some cases achieve spatiotemporal control, in the context of drug delivery makes theranostic fluorescent probes an attractive and intensely investigated research topic. This interest is reflected in the steep rise in publications on the topic that have appeared over the past decade. Theranostic fluorescent probes, in their various incarnations, generally comprise a fluorophore linked to a masked drug, in which the drug is released as the result of certain stimuli, with both intrinsic and extrinsic stimuli being reported. This release is then signaled by the emergence of a fluorescent signal. Importantly, the use of appropriate fluorophores has enabled not only this emerging fluorescence as a spatiotemporal marker for drug delivery but also has provided modalities useful in photodynamic, photothermal, and sonodynamic therapeutic applications. In this review we highlight recent work on theranostic fluorescent probes with a particular focus on probes that are activated in tumor microenvironments. We also summarize efforts to develop probes for other applications, such as neurodegenerative diseases and antibacterials. This review celebrates the diversity of designs reported to date, from discrete small-molecule systems to nanomaterials. Our aim is to provide insights into the potential clinical impact of this still-emerging research direction.

Increasing incidence of Parkinson's disease in patients with epilepsy: A Nationwide cohort study.

BACKGROUND: Although epilepsy is an uncommon comorbidity of Parkinson's disease (PD), the exact incidence of PD among the patients with epilepsy is not clarified yet. OBJECTIVES: We aimed to estimate the incidence of PD in patients with epilepsy and explore the association between epilepsy and PD. METHODS: Epilepsy patients enrolled in the National Health Insurance Service Health Screening Cohort (NHIS-HealS) (2002-2013) between 2003 and 2007 were set up as the experimental group. The major outcome was the occurrence of PD. Non-epilepsy patients were obtained through Propensity Score Matching of 'greedy nearest neighbor' algorithm in 1:1 ratio. The Cox Proportional Hazards model was used to calculate PD incidence and hazard ratio (HR). RESULTS: A total of 10,510 patients were finally included in the study, which contained 5255 patients in epilepsy and non-epilepsy groups, respectively. During the follow-up period, 85 patients with Parkinson's disease among 5255 patients with epilepsy and 57 patients with Parkinson's disease among 5255 patients without epilepsy occurred. The 10,000 Person-Year (PY), representing the number of PD patients per 10,000 per year, was 21.38 in the epilepsy group and 11.18 in the non-epilepsy group. When all variables were adjusted, it was found that the epilepsy group had a 2.19 times significantly higher risk of developing Parkinson's disease than the control group (The adjusted HR: 2.19 (95% CI, 1.55-3.12)). CONCLUSION: This study indicates an increased risk of PD in patients with epilepsy. However, further research is needed to prove an exact causal relationship between these two brain disorders.