Profiling Humoral Immunity After Mixing and Matching COVID-19 Vaccines Using SARS-CoV-2 Variant Protein Microarrays.

In November 2022, 68% of the population received at least one dose of COVID-19 vaccines. Owing to the ongoing mutations, especially for the variants of concern (VOCs), it is important to monitor the humoral immune responses after different vaccination strategies. In this study, we developed a SARS-CoV-2 variant protein microarray that contained the spike proteins from the VOCs, e.g., alpha, beta, gamma, delta, and omicron, to quantify the binding antibody and surrogate neutralizing antibody. Plasmas were collected after two doses of matching AZD1222 (AZx2), two doses of matching mRNA-1273 (Mx2), or mixing AZD1222 and mRNA-1273 (AZ+M). The results showed a significant decrease of surrogate neutralizing antibodies against the receptor-binding domain in all VOCs in AZx2 and Mx2 but not AZ+M. A similar but minor reduction pattern of surrogate neutralizing antibodies against the extracellular domain was observed. While Mx2 exhibited a higher surrogate neutralizing level against all VOCs compared with AZx2, AZ+M showed an even higher surrogate neutralizing level in gamma and omicron compared with Mx2. It is worth noting that the binding antibody displayed a low correlation to the surrogate neutralizing antibody (R-square 0.130-0.382). This study delivers insights into humoral immunities, SARS-CoV-2 mutations, and mixing and matching vaccine strategies, which may provide a more effective vaccine strategy especially in preventing omicron.

Site-Selective C-O Bond Editing of Unprotected Saccharides.

Glucose and its polyhydroxy saccharide analogs are complex molecules that serve as essential structural components in biomacromolecules, natural products, medicines, and agrochemicals. Within the expansive realm of saccharides, a significant area of research revolves around chemically transforming naturally abundant saccharide units to intricate or uncommon molecules such as oligosaccharides or rare sugars. However, partly due to the presence of multiple hydroxyl groups with similar reactivities and the structural complexities arising from stereochemistry, the transformation of unprotected sugars to the desired target molecules remains challenging. One such formidable challenge lies in the efficient and selective activation and modification of the C-O bonds in saccharides. In this study, we disclose a modular 2-fold "tagging-editing" strategy that allows for direct and selective editing of C-O bonds of saccharides, enabling rapid preparation of valuable molecules such as rare sugars and drug derivatives. The first step, referred to as "tagging", involves catalytic site-selective installation of a photoredox active carboxylic ester group to a specific hydroxyl unit of an unprotected sugar. The second step, namely, "editing", features a C-O bond cleavage to form a carbon radical intermediate that undergoes further transformations such as C-H and C-C bond formations. Our strategy constitutes the most effective and shortest route in direct transformation and modification of medicines and other molecules bearing unprotected sugars.

The Promising Potential of Caulerpa microphysa in Dermatology.

In recent years, the search for natural compounds with therapeutic properties has gained momentum, with marine organisms emerging as rich sources of bioactive substances [...].

The Benefit of Hydrogen Gas as an Adjunctive Therapy for Chronic Obstructive Pulmonary Disease.

Background and Objectives: Recent studies suggest that hydrogen gas possesses anti-inflammatory, antioxidant, and anti-apoptotic properties. This study aimed to explore the therapeutic potential of hydrogen gas and assess its safety and tolerability in individuals with chronic obstructive pulmonary disease (COPD). Materials and Methods: Enrolled COPD patients received standard treatments along with additional hydrogen inhalation for 30 min in the morning, afternoon, and evening over a 30-day period. The assessment included changes in the COPD Assessment Test (CAT), the modified Medical Research Council (mMRC) Dyspnea Scale, lung function, sleep quality, inflammation markers, and oxidative stress markers before and after hydrogen inhalation. Results: Six patients participated in this study. Patients 2, 3, 4, 5, and 6 demonstrated improvements in CAT scores following hydrogen gas intervention, with patients 2, 4, 5, and 6 also showing improvements in mMRC scores. Statistically, this study revealed significant improvements in CAT [15.5 (10.5-19.75) vs. 8.5 (3-13.5); p = 0.043] and mMRC scores [2.5 (1-4) vs. 2 (0-3.25); p = 0.046] before and after intervention, respectively. However, no significant differences were observed in lung function, DLCO, sleep quality, and 6 MWT before and after hydrogen therapy. CBC examination showed a significant difference in platelet count before and after treatment [247 (209.75-298.75) vs. 260 (232.75-314.5); p = 0.043], respectively, while other blood tests, inflammation markers, and oxidative stress markers did not exhibit significant differences before and after hydrogen therapy. All patients experienced no obvious side-effects. Conclusions: Adjuvant therapy with hydrogen gas demonstrated symptom improvements in specific COPD patients, and no significant adverse effects were observed in any of the patients. Hydrogen gas may also exert a modulatory effect on platelet count.

MicroRNA 29a therapy for CEACAM6-expressing lung adenocarcinoma.

BACKGROUND: Non-coding microRNAs (miRNAs) play critical roles in tumor progression and hold great promise as therapeutic agents for multiple cancers. MicroRNA 29a (miR-29a) is a tumor suppressor miRNA that inhibits cancer cell growth and tumor progression in non-small cell lung cancer. Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6), which plays an important role in lung cancer progression, has been identified as a target of miR-29a. Here, we evaluated the therapeutic efficacy of a peptide vector capable of delivering miR-29a intracellularly using the acidic tumor microenvironment in a lung adenocarcinoma xenograft mouse model. METHODS: A miRNA delivery vector was constructed by tethering the peptide nucleic acid form of miR-29a to a peptide with a low pH-induced transmembrane structure (pHLIP) to enable transport of the miRNAs across the plasma membrane. Tumor suppressive effects of pHLIP-miR29a on lung adenocarcinoma development in vivo were assessed using a BALB/c xenograft model injected with A549 cells. RESULTS: Incubation of A549 cells with pHLIP-miR-29a at an acidic pH downregulated endogenous CEACAM6 expression and reduced cell viability. Intravenous injection of the mice with pHLIP-miR-29a inhibited tumor growth by up to 18.1%. Intraperitoneal injection of cisplatin reduced tumor volume by 29.9%. Combined pHLIP-miR-29a + cisplatin treatment had an additive effect, reducing tumor volume up to 39.7%. CONCLUSIONS: Delivery of miR-29a to lung adenocarcinoma cells using a pHLIP-mediated method has therapeutic potential as a unique cancer treatment approach.

Molecular Hydrogen: Emerging Treatment for Stroke Management.

Ischemic stroke is a major cause of death and disability worldwide. However, only intravenous thrombolysis using mechanical thrombectomy or tissue plasminogen activator is considered an effective and approved treatment. Molecular hydrogen is an emerging therapeutic agent and has recently become a research focus. Molecular hydrogen is involved in antioxidative, anti-inflammatory, and antiapoptotic functions in normal physical processes and may play an important role in stroke management; it has been evaluated in numerous preclinical and clinical studies in several administration formats, including inhalation of hydrogen gas, intravenous or intraperitoneal injection of hydrogen-enriched solution, or drinking of hydrogen-enriched water. In addition to investigation of the underlying mechanisms, the safety and efficacy of using molecular hydrogen have been carefully evaluated, and favorable outcomes have been achieved. All available evidence indicates that molecular hydrogen may be a promising treatment option for stroke management in the future. This review aimed to provide an overview of the role of molecular hydrogen in the management of stroke and possible further modifications of treatment conditions and procedures in terms of dose, duration, and administration route.

Gut mycobiome dysbiosis and its impact on intestinal permeability in attention-deficit/hyperactivity disorder.

BACKGROUND: Dysbiosis in the gut microbial community might be involved in the pathophysiology of attention-deficit/hyperactivity disorder (ADHD). The fungal component of the gut microbiome, namely the mycobiota, is a hyperdiverse group of multicellular eukaryotes that can influence host intestinal permeability. This study therefore aimed to investigate the impact of fungal mycobiome dysbiosis and intestinal permeability on ADHD. METHODS: Faecal samples were collected from 35 children with ADHD and from 35 healthy controls. Total DNA was extracted from the faecal samples and the internal transcribed spacer regions were sequenced using high-throughput next-generation sequencing (NGS). The fungal taxonomic classification was analysed using bioinformatics tools and the differentially expressed fungal species between the ADHD and healthy control groups were identified. An in vitro permeability assay (Caco-2 cell layer) was used to evaluate the biological effects of fungal dysbiosis on intestinal epithelial barrier function. RESULTS: The ß-diversity (the species diversity between two communities), but not α-diversity (the species diversity within a community), reflected the differences in fungal community composition between ADHD and control groups. At the phylum level, the ADHD group displayed a significantly higher abundance of Ascomycota and a significantly lower abundance of Basidiomycota than the healthy control group. At the genus level, the abundance of Candida (especially Candida albicans) was significantly increased in ADHD patients compared to the healthy controls. In addition, the in vitro cell assay revealed that C. albicans secretions significantly enhanced the permeability of Caco-2 cells. CONCLUSIONS: The current study is the first to explore altered gut mycobiome dysbiosis using the NGS platform in ADHD. The findings from this study indicated that dysbiosis of the fungal mycobiome and intestinal permeability might be associated with susceptibility to ADHD.

DEEP MOVEMENT: Deep learning of movie files for management of endovascular thrombectomy.

OBJECTIVES: Treatment and outcomes of acute stroke have been revolutionised by mechanical thrombectomy. Deep learning has shown great promise in diagnostics but applications in video and interventional radiology lag behind. We aimed to develop a model that takes as input digital subtraction angiography (DSA) videos and classifies the video according to (1) the presence of large vessel occlusion (LVO), (2) the location of the occlusion, and (3) the efficacy of reperfusion. METHODS: All patients who underwent DSA for anterior circulation acute ischaemic stroke between 2012 and 2019 were included. Consecutive normal studies were included to balance classes. An external validation (EV) dataset was collected from another institution. The trained model was also used on DSA videos post mechanical thrombectomy to assess thrombectomy efficacy. RESULTS: In total, 1024 videos comprising 287 patients were included (44 for EV). Occlusion identification was achieved with 100% sensitivity and 91.67% specificity (EV 91.30% and 81.82%). Accuracy of location classification was 71% for ICA, 84% for M1, and 78% for M2 occlusions (EV 73, 25, and 50%). For post-thrombectomy DSA (n = 194), the model identified successful reperfusion with 100%, 88%, and 35% for ICA, M1, and M2 occlusion (EV 89, 88, and 60%). The model could also perform classification of post-intervention videos as mTICI < 3 with an AUC of 0.71. CONCLUSIONS: Our model can successfully identify normal DSA studies from those with LVO and classify thrombectomy outcome and solve a clinical radiology problem with two temporal elements (dynamic video and pre and post intervention). KEY POINTS: • DEEP MOVEMENT represents a novel application of a model applied to acute stroke imaging to handle two types of temporal complexity, dynamic video and pre and post intervention. • The model takes as an input digital subtraction angiograms of the anterior cerebral circulation and classifies according to (1) the presence or absence of large vessel occlusion, (2) the location of the occlusion, and (3) the efficacy of thrombectomy. • Potential clinical utility lies in providing decision support via rapid interpretation (pre thrombectomy) and automated objective gradation of thrombectomy outcomes (post thrombectomy).

Profiling humoral responses to COVID-19 immunization in Kawasaki disease using SARS-CoV-2 variant protein microarrays.

Kawasaki disease (KD) is a form of acute systemic vasculitis syndrome that predominantly occurs in children under the age of 5 years. Its etiology has been postulated due to not only genetic factors but also the presence of foreign antigens or infectious agents. To evaluate possible associations between Kawasaki disease (KD) and COVID-19, we investigated humoral responses of KD patients against S-protein variants with SARS-CoV-2 variant protein microarrays. In this study, plasma from a cohort of KD (N = 90) and non-KD control (non-KD) (N = 69) subjects in categories of unvaccinated-uninfected (pre-pandemic), SARS-CoV-2 infected (10-100 days after infection), and 1-dose, 2-dose, and 3-dose BNT162b2 vaccinated (10-100 days after vaccination) was collected. The principal outcomes were non-KD-KD differences for each category in terms of anti-human/anti-His for binding antibodies and neutralizing percentage for surrogate neutralizing antibodies. Binding antibodies against spikes were lower in the KD subjects with 1-dose of BNT162b2, and mean differences were significant for the P.1 S-protein (non-KD-KD, 3401; 95% CI, 289.0 to 6512; P = 0.0252), B.1.617.2 S-protein (non-KD-KD, 4652; 95% CI, 215.8 to 9087; P = 0.0351) and B.1.617.3 S-protein (non-KD-KD, 4874; 95% CI, 31.41 to 9716; P = 0.0477). Neutralizing antibodies against spikes were higher in the KD subjects with 1-dose of BNT162b2, and mean percentage differences were significant for the 1-dose BNT162b2 B.1.617.3 S-protein (non-KD-KD, -22.89%; 95% CI, -45.08 to -0.6965; P = 0.0399), B.1.1.529 S-protein (non-KD-KD, -25.96%; 95% CI, -50.53 to -1.376; P = 0.0333), BA.2.12.1 S-protein (non-KD-KD, -27.83%; 95% CI, -52.55 to -3.115; P = 0.0195), BA.4 S-protein (non-KD-KD, -28.47%; 95% CI, -53.59 to -3.342; P = 0.0184), and BA.5 S-protein (non-KD-KD, -30.42%; 95% CI, -54.98 to -5.869; P = 0.0077). In conclusion, we have found that KD patients have a comparable immunization response to healthy individuals to SARS-CoV-2 infection and COVID-19 immunization.

Quantitative assessment of cerebrospinal fluid flow and volume in enlargement of the subarachnoid spaces of infancy using MRI.

BACKGROUND: The etiology of enlarged subarachnoid spaces of infancy is unknown; however, there is radiologic similarity with normal pressure hydrocephalus. Adults with normal pressure hydrocephalus have been shown to have altered cerebrospinal (CSF) flow through the cerebral aqueduct. OBJECTIVE: To explore potential similarity between enlarged subarachnoid spaces of infancy and normal pressure hydrocephalus, we compared MRI-measured CSF flow through the cerebral aqueduct in infants with enlarged subarachnoid spaces of infancy to infants with normal brain MRIs. MATERIALS AND METHODS: This was an IRB approved retrospective study. Clinical brain MRI examinations including axial T2 imaging and phase contrast through the aqueduct were reviewed for infants with enlarged subarachnoid spaces of infancy and for infants with a qualitatively normal brain MRI. The brain and CSF volumes were segmented using a semi-automatic technique (Analyze 12.0) and CSF flow parameters were measured (cvi42, 5.14). All data was assessed for significant differences while controlling for age and sex using analysis of covariance (ANCOVA). RESULTS: Twenty-two patients with enlarged subarachnoid spaces (mean age 9.0 months, 19 males) and 15 patients with normal brain MRI (mean age 18.9 months, 8 females) were included. Volumes of the subarachnoid space (P < 0.001), lateral (P < 0.001), and third ventricles (P < 0.001) were significantly larger in infants with enlarged subarachnoid spaces of infancy. Aqueductal stroke volume significantly increased with age (P = 0.005), regardless of group. CONCLUSION: CSF volumes were significantly larger in infants with enlarged subarachnoid spaces of infancy versus infants with a normal MRI; however, there was no significant difference in CSF flow parameters between the two groups.

Diagnosis, Progress, and Treatment Update of Kawasaki Disease.

Kawasaki disease (KD) is an acute inflammatory disorder that primarily affects children and can lead to coronary artery lesions (CAL) if not diagnosed and treated promptly. The original clinical criteria for diagnosing KD were reported by Dr. Tomisaku Kawasaki in 1967 and have been used for decades. However, research since then has highlighted the limitations of relying solely on these criteria, as they might lead to underdiagnosis or delayed diagnosis, potentially increasing the risk of coronary artery complications. This review appears to discuss several important aspects related to KD diagnosis and management. The current diagnostic methods for KD might need updates, especially considering cases that do not fit the typical clinical criteria. Recognizing diagnostic pitfalls and distinguishing KD from other conditions that might have similar clinical presentations is essential. The differences and similarities between KD and Multisystem Inflammatory Syndrome in Children (MIS-C), another inflammatory condition that has been associated with COVID-19, were also reviewed. The review explores the potential role of eosinophil count, new biomarkers, microRNA panels, and scoring systems in aiding the diagnosis of KD. Overall, the review article provides a comprehensive overview of the evolving landscape of KD diagnosis and management, incorporating new diagnostic methods, biomarkers, and treatment approaches to improve patient outcomes and reduce the risk of complications.

Ineffective implementation of emergency reduction measures against high concentrations of particulate matter in Seoul, Republic of Korea.

Since December 30, 2017, the Seoul Metropolitan Government, Republic of Korea, has been implementing emergency reduction measures (ERMs) restricting the operation of industrial sites, thermal power plants, and vehicles when air quality is expected to deteriorate. ERMs are implemented when the present observed concentration of particulate matter (PM) of aerodynamic diameter less than 2.5 µm (PM2.5) and/or the predicted values for the following day exceed a threshold value. In this study, the effectiveness of ERMs was evaluated for 33 days with and 6 days without ERM implementation but where the PM2.5 concentration exceeded the threshold value, until March 15, 2021. Of the 33 days of ERM implementation, on 7 days it was executed despite the thresholds not being met. The ERM on these days might have been properly executed because the pre-notice and implementation of ERM might have reduced the local emissions of air pollutants. Our major findings are that even on days of ERM implementation, there were marginal reductions in vehicle traffic, thermal power generation, and industrial emissions. Second, the concentrations of PM2.5 and related air pollutants in Seoul were almost unchanged for most ERM implementation episodes. Third, most of the 39 (= 33 + 6) days when the air quality worsened were caused by the transboundary transport of air pollutants from China. In conclusion, it was revealed that the currently executed ERM law is insufficient for effectively reducing PM2.5. To achieve the required reductions, it is necessary to undertake stricter policies in Seoul and its neighboring regions.

Assessing pulsatile waveforms of paravascular cerebrospinal fluid dynamics within the glymphatic pathways using dynamic diffusion-weighted imaging (dDWI)

Cerebrospinal fluid (CSF) in the paravascular spaces of the surface arteries (sPVS) is a vital pathway in brain waste clearance. Arterial pulsations may be the driving force of the paravascular flow, but its pulsatile pattern remains poorly characterized, and no clinically practical method for measuring its dynamics in the human brain is available. In this work, we introduce an imaging and quantification framework for in-vivo non-invasive assessment of pulsatile fluid dynamics in the sPVS. It used dynamic Diffusion-Weighted Imaging (dDWI) at a lower b-values of 150s/mm2 and retrospective gating to detect the slow flow of CSF while suppressing the fast flow of adjacent arterial blood. The waveform of CSF flow over a cardiac cycle was revealed by synchronizing the measurements with the heartbeat. A data-driven approach was developed to identify sPVS and allow automatic quantification of the whole-brain fluid waveforms. We applied dDWI to twenty-five participants aged 18-82 y/o. Results demonstrated that the fluid waveforms across the brain showed an explicit cardiac-cycle dependency, in good agreement with the vascular pumping hypothesis. Furthermore, the shape of the CSF waveforms closely resembled the pressure waveforms of the artery wall, suggesting that CSF dynamics is tightly related to artery wall mechanics. Finally, the CSF waveforms in aging participants revealed a strong age effect, with a significantly wider systolic peak observed in the older relative to younger participants. The peak widening may be associated with compromised vascular compliance and vessel wall stiffening in the older brain. Overall, the results demonstrate the feasibility, reproducibility, and sensitivity of dDWI for detecting sPVS fluid dynamics of the human brain. Our preliminary data suggest age-related alterations of the paravascular pumping. With an acquisition time of under six minutes, dDWI can be readily applied to study fluid dynamics in normal physiological conditions and cerebrovascular/neurodegenerative diseases.

MRI Radiogenomics of Pediatric Medulloblastoma: A Multicenter Study.

Background Radiogenomics of pediatric medulloblastoma (MB) offers an opportunity for MB risk stratification, which may aid therapeutic decision making, family counseling, and selection of patient groups suitable for targeted genetic analysis. Purpose To develop machine learning strategies that identify the four clinically significant MB molecular subgroups. Materials and Methods In this retrospective study, consecutive pediatric patients with newly diagnosed MB at MRI at 12 international pediatric sites between July 1997 and May 2020 were identified. There were 1800 features extracted from T2- and contrast-enhanced T1-weighted preoperative MRI scans. A two-stage sequential classifier was designed-one that first identifies non-wingless (WNT) and non-sonic hedgehog (SHH) MB and then differentiates therapeutically relevant WNT from SHH. Further, a classifier that distinguishes high-risk group 3 from group 4 MB was developed. An independent, binary subgroup analysis was conducted to uncover radiomics features unique to infantile versus childhood SHH subgroups. The best-performing models from six candidate classifiers were selected, and performance was measured on holdout test sets. CIs were obtained by bootstrapping the test sets for 2000 random samples. Model accuracy score was compared with the no-information rate using the Wald test. Results The study cohort comprised 263 patients (mean age ± SD at diagnosis, 87 months ± 60; 166 boys). A two-stage classifier outperformed a single-stage multiclass classifier. The combined, sequential classifier achieved a microaveraged F1 score of 88% and a binary F1 score of 95% specifically for WNT. A group 3 versus group 4 classifier achieved an area under the receiver operating characteristic curve of 98%. Of the Image Biomarker Standardization Initiative features, texture and first-order intensity features were most contributory across the molecular subgroups. Conclusion An MRI-based machine learning decision path allowed identification of the four clinically relevant molecular pediatric medulloblastoma subgroups. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Chaudhary and Bapuraj in this issue.

Effects of virtual reality-based motor control training on inflammation, oxidative stress, neuroplasticity and upper limb motor function in patients with chronic stroke: a randomized controlled trial.

BACKGROUND: Immersive virtual reality (VR)-based motor control training (VRT) is an innovative approach to improve motor function in patients with stroke. Currently, outcome measures for immersive VRT mainly focus on motor function. However, serum biomarkers help detect precise and subtle physiological changes. Therefore, this study aimed to identify the effects of immersive VRT on inflammation, oxidative stress, neuroplasticity and upper limb motor function in stroke patients. METHODS: Thirty patients with chronic stroke were randomized to the VRT or conventional occupational therapy (COT) groups. Serum biomarkers including interleukin 6 (IL-6), intracellular adhesion molecule 1 (ICAM-1), heme oxygenase 1 (HO-1), 8-hydroxy-2-deoxyguanosine (8-OHdG), and brain-derived neurotrophic factor (BDNF) were assessed to reflect inflammation, oxidative stress and neuroplasticity. Clinical assessments including active range of motion of the upper limb and the Fugl-Meyer Assessment for upper extremity (FMA-UE) were also used. Two-way mixed analyses of variance (ANOVAs) were used to examine the effects of the intervention (VRT and COT) and time on serum biomarkers and upper limb motor function. RESULTS: We found significant time effects in serum IL-6 (p = 0.010), HO-1 (p = 0.002), 8-OHdG (p = 0.045), and all items/subscales of the clinical assessments (ps < 0.05), except FMA-UE-Coordination/Speed (p = 0.055). However, significant group effects existed only in items of the AROM-Elbow Extension (p = 0.007) and AROM-Forearm Pronation (p = 0.048). Moreover, significant interactions between time and group existed in item/subscales of FMA-UE-Shoulder/Elbow/Forearm (p = 0.004), FMA-UE-Total score (p = 0.008), and AROM-Shoulder Flexion (p = 0.001). CONCLUSION: This was the first study to combine the effectiveness of immersive VRT using serum biomarkers as outcome measures. Our study demonstrated promising results that support the further application of commercial and immersive VR technologies in patients with chronic stroke.

Effect of abdominal weight training with and without cough machine assistance on lung function in the patients with prolonged mechanical ventilation: a randomized trial.

PURPOSE: The patients with prolonged mechanical ventilation (PMV) have the risk of ineffective coughing and infection due to diaphragm weakness. This study aimed to explore the effect of abdominal weight training (AWT) intervention with/without cough machine (CM) assistance on lung function, respiratory muscle strength and cough ability in these patients. METHODS: Forty patients with PMV were randomly assigned to three groups: AWT group (n = 12), AWT + CM group (n = 14) and control group (n = 14). Change of maximum inspiratory pressure (MIP), Maximum expiratory pressure (MEP) and peak cough flow (PCF) between 1 day before and 2 weeks after the intervention were compared among these three groups. RESULTS: MIP before and after intervention in AWT group (30.50 ± 11.73 vs. 36.00 ± 10.79; p < 0.05) and AWT + CM group (29.8 ± 12.14 vs. 36.14 ± 10.42; p < 0.05) compared with control group (28.43 ± 9.74 vs 26.71 ± 10.77; p > 0.05) was significantly improved. MEP before and after intervention in AWT group (30.58 ± 15.19 vs. 41.50 ± 18.33; p < 0.05) and AWT + CM group (27.29 ± 12.76 vs 42.43 ± 16.96; p < 0.05) compared with control group (28.86 ± 10.25 vs. 29.57 ± 14.21; p > 0.05) was significantly improved. PCF before and after intervention in AWT group in AWT group (105.83 ± 16.21 vs. 114.17 ± 15.20; p < 0.05) and AWT + CM group (108.57 ± 18.85 vs. 131.79 ± 38.96; p < 0.05) compared to control group (108.57 ± 19.96 vs. 109.86 ± 17.44; p > 0.05) showed significant improvements. AWT + CM group had significantly greater improvements than control group in MIP and peak cough flow than control group (13.71 ± 11.28 vs 19.64 ± 29.90, p < 0.05). CONCLUSION: AWT can significantly improve lung function, respiratory muscle strength, and cough ability in the PMV patients. AWT + CM can further improve their expiratory muscle strength and cough ability. Trial registration ClinicalTrials.gov registry (registration number: NCT0529538 retrospectively registered on March 3, 2022).

Active Targeting of P-Selectin by Fucoidan Modulates the Molecular Profiling of Metastasis in Docetaxel-Resistant Prostate Cancer.

The standard of care for prostate cancer (PCa) is androgen deprivation therapy (ADT). Although hormone-sensitive PCa is curable by ADT, most conditions progress to castration-resistant prostate cancer (CRPCa) and metastatic CRPCa (mCRPCa). Front-line docetaxel has been administered to patients with CRPCa and mCRPCa. Nevertheless, docetaxel resistance after half a year of therapy has emerged as an urgent clinical concern in patients with CRPCa and mCRPCa. We verified the mechanism by which docetaxel-resistant PCa cells (DU/DX50) exhibited significant cell migration and expression of malignant tumor-related proteins. Our study shows that the biological activity of fucoidan has an important application for docetaxel-resistant PCa cells, inhibiting IL-1R by binding to P-selectin and reducing the expression levels of NF-κB p50 and Cox2 in this metastasis-inhibiting signaling pathway. Furthermore, the combined treatment of fucoidan and docetaxel showed significant anticancer and synergistic effects on the viability of DU/DX50 cells, which is relevant for overcoming the current limitations and improving treatment outcomes. Overall, fucoidan-based combination chemotherapy may exert beneficial effects and facilitate the treatment of docetaxel-resistant PCa.

Expression of Eosinophilic Subtype Markers in Patients with Kawasaki Disease.

PURPOSE: Eosinophils may rise to a higher level in the acute phase of Kawasaki disease (KD) both before and after intravenous immunoglobulin (IVIG) therapy. A substantial body of research was carried out on the association between KD and allergic diseases. Eosinophils play an important role in type 2 inflammation. Recent studies have shown that there are two distinct subtypes of eosinophils. In addition to their role in inflammation, lung-resident eosinophils (rEOS) also regulate homeostasis. Inflammatory eosinophils (iEOS) reflect type 2 inflammation in tissues. iEOS were considered the primary eosinophils in non-severe allergic asthma, while rEOS were thought to be the primary eosinophils in severe non-allergic eosinophilic asthma. This case-control study aimed to investigate the marker expression of eosinophilic subtypes in KD patients. MATERIALS AND METHODS: The marker expressions of eosinophilic subtypes in the leukocytes of patients with KD were evaluated by the recently established KDmarkers online tool, a web server including gene expression data. Finally, the results were validated with a quantitative reverse transcriptase polymerase chain reaction (RT-PCR). We analyzed the mRNA expression levels of SELL and IL10RA in leukocytes from KD patients and febrile children. RESULTS: Included in our screening tools were transcriptome arrays, which provided clues showing the importance of rEOS, whose role was identified by three genes (lower IL10RA, higher SELL, and SERPINB1 than controls). In contrast, the iEOS representative gene CD101 was not elevated in KD. It was found that the gene IL10RA, a marker of inflammatory eosinophilic leukocytes, was more highly expressed in the leukocytes of KD patients (n = 43) than febrile controls (n = 32), especially those without coronary artery lesions (CAL) (n = 26). Before treatment, SELL expression was higher in leukocytes of CAL patients (CAL, 1.33 ± 0.18, n = 39; non-CAL, 0.87 ± 0.12, n = 55; p = 0.012). SELL was significantly higher after half a year compared to febrile controls. CONCLUSIONS: To our knowledge, this is the first study to demonstrate that KD patients have increased SELL than febrile controls after 6 months of treatment. We present evidence here that dynamically different eosinophilic involvement exists between KD patients with and without CAL. The role of eosinophilic subtypes in KD patients warrants further investigation.

Telomere Dysfunction Activates p53 and Represses HNF4α Expression Leading to Impaired Human Hepatocyte Development and Function.

BACKGROUND AND AIMS: Telomere attrition is a major risk factor for end-stage liver disease. Due to a lack of adequate models and intrinsic difficulties in studying telomerase in physiologically relevant cells, the molecular mechanisms responsible for liver disease in patients with telomere syndromes remain elusive. To circumvent that, we used genome editing to generate isogenic human embryonic stem cells (hESCs) harboring clinically relevant mutations in telomerase and subjected them to an in vitro, stage-specific hepatocyte differentiation protocol that resembles hepatocyte development in vivo. APPROACH AND RESULTS: Using this platform, we observed that while telomerase is highly expressed in hESCs, it is quickly silenced, specifically due to telomerase reverse transcriptase component (TERT) down-regulation, immediately after endoderm differentiation and completely absent in in vitro-derived hepatocytes, similar to what is observed in human primary hepatocytes. While endoderm derivation is not impacted by telomere shortening, progressive telomere dysfunction impaired hepatic endoderm formation. Consequently, hepatocyte derivation, as measured by expression of specific hepatic markers as well by albumin expression and secretion, is severely compromised in telomerase mutant cells with short telomeres. Interestingly, this phenotype was not caused by cell death induction or senescence. Rather, telomere shortening prevents the up-regulation and activation of human hepatocyte nuclear factor 4 alpha (HNF4α) in a p53-dependent manner. Both reactivation of telomerase and silencing of p53 rescued hepatocyte formation in telomerase mutants. Likewise, the conditional expression (doxycycline-controlled) of HNF4α, even in cells that retained short telomeres, accrued DNA damage, and exhibited p53 stabilization, successfully restored hepatocyte formation from hESCS. CONCLUSIONS: Our data show that telomere dysfunction acts as a major regulator of HNF4α during hepatocyte development, pointing to a target in the treatment of liver disease in telomere-syndrome patients.

Chemical and Biochemical Aspects of Molecular Hydrogen in Treating Kawasaki Disease and COVID-19.

Kawasaki disease (KD) is a systemic vasculitis and is the most commonly acquired heart disease among children in many countries, which was first reported 50 years ago in Japan. The 2019 coronavirus disease (COVID-19, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)) has been a pandemic in most of the world since 2020, and since late 2019 in China. Kawasaki-like disease caused by COVID-19 shares some symptoms with KD, referred to as multisystem inflammatory syndrome in children, and has been reported in the United States, Italy, France, England, and other areas of Europe, with an almost 6-10 times or more increase compared with previous years of KD prevalence. Hydrogen gas is a stable and efficient antioxidant, which has a positive effect on oxidative damage, inflammation, cell apoptosis, and abnormal blood vessel inflammation. This review reports the chemical and biochemical aspects of hydrogen gas inhalation in treating KD and COVID-19.