A multicenter, randomized, open-label, phase 2 clinical study of telitacicept in adult patients with generalized myasthenia gravis.

BACKGROUND AND PURPOSE: This study aimed to investigate the clinical efficacy and safety of telitacicept in patients with generalized myasthenia gravis (gMG) who tested positive for acetylcholine receptor antibodies or muscle-specific kinase antibodies and were receiving standard-of-care therapy. METHODS: Patients meeting the eligibility criteria were randomly assigned to receive telitacicept subcutaneously once a week for 24 weeks in addition to standard-of-care treatment. The primary efficacy endpoint was the mean change in the quantitative myasthenia gravis (QMG) score from baseline to week 24. Secondary efficacy endpoints included mean change in QMG score from baseline to week 12 and gMG clinical absolute score from baseline to week 24. Additionally, safety, tolerability and pharmacodynamics were assessed. RESULTS: Twenty-nine of the 41 patients screened were randomly selected and enrolled. The mean (± standard deviation [SD]) reduction in QMG score from baseline to week 24 was 7.7 (± 5.34) and 9.6 (± 4.29) in the 160 mg and 240 mg groups, respectively. At week 12, mean reductions in QMG scores for these two groups were 5.8 (± 5.85) and 9.5 (± 5.03), respectively, indicating rapid clinical improvement. Safety analysis revealed no adverse events leading to discontinuation or mortalities. All patients showed consistent reductions in serum immunoglobulin (Ig) A, IgG and IgM levels throughout the study. CONCLUSION: Telitacicept demonstrated safety, good tolerability and reduced clinical severity throughout the study period. Further validation of the clinical efficacy of telitacicept in gMG will be conducted in an upcoming phase 3 clinical trial.

Osmosensor-mediated control of Ca2+ spiking in pollen germination.

Higher plants survive terrestrial water deficiency and fluctuation by arresting cellular activities (dehydration) and resuscitating processes (rehydration). However, how plants monitor water availability during rehydration is unknown. Although increases in hypo-osmolarity-induced cytosolic Ca2+ concentration (HOSCA) have long been postulated to be the mechanism for sensing hypo-osmolarity in rehydration1,2, the molecular basis remains unknown. Because osmolarity triggers membrane tension and the osmosensing specificity of osmosensing channels can only be determined in vivo3-5, these channels have been classified as a subtype of mechanosensors. Here we identify bona fide cell surface hypo-osmosensors in Arabidopsis and find that pollen Ca2+ spiking is controlled directly by water through these hypo-osmosensors-that is, Ca2+ spiking is the second messenger for water status. We developed a functional expression screen in Escherichia coli for hypo-osmosensitive channels and identified OSCA2.1, a member of the hyperosmolarity-gated calcium-permeable channel (OSCA) family of proteins6. We screened single and high-order OSCA mutants, and observed that the osca2.1/osca2.2 double-knockout mutant was impaired in pollen germination and HOSCA. OSCA2.1 and OSCA2.2 function as hypo-osmosensitive Ca2+-permeable channels in planta and in HEK293 cells. Decreasing osmolarity of the medium enhanced pollen Ca2+ oscillations, which were mediated by OSCA2.1 and OSCA2.2 and required for germination. OSCA2.1 and OSCA2.2 convert extracellular water status into Ca2+ spiking in pollen and may serve as essential hypo-osmosensors for tracking rehydration in plants.

Throat microbiota drives alterations in pulmonary alveolar microbiota in patients with septic ARDS.

OBJECTIVES: The translocation of intestinal flora has been linked to the colonization of diverse and heavy lower respiratory flora in patients with septic ARDS, and is considered a critical prognostic factor for patients. METHODS: On the first and third days of ICU admission, BALF, throat swab, and anal swab were collected, resulting in a total of 288 samples. These samples were analyzed using 16S rRNA analysis and the traceability analysis of new generation technology. RESULTS: On the first day, among the top five microbiota species in abundance, four species were found to be identical in BALF and throat samples. Similarly, on the third day, three microbiota species were found to be identical in abundance in both BALF and throat samples. On the first day, 85.16% of microorganisms originated from the throat, 5.79% from the intestines, and 9.05% were unknown. On the third day, 83.52% of microorganisms came from the throat, 4.67% from the intestines, and 11.81% were unknown. Additionally, when regrouping the 46 patients, the results revealed a significant predominance of throat microorganisms in BALF on both the first and third day. Furthermore, as the disease progressed, the proportion of intestinal flora in BALF increased in patients with enterogenic ARDS. CONCLUSIONS: In patients with septic ARDS, the main source of lung microbiota is primarily from the throat. Furthermore, the dynamic trend of the microbiota on the first and third day is essentially consistent.It is important to note that the origin of the intestinal flora does not exclude the possibility of its origin from the throat.

Novel therapeutic perspectives for wet age-related macular degeneration: RGD-modified liposomes loaded with 2-deoxy-D-glucose as a promising nanomedicine.

Choroidal neovascularization (CNV), characterized as a prominent feature of wet age-related macular degeneration (AMD), is a primary contributor to visual impairment and severe vision loss globally, while the prevailing treatments are often unsatisfactory. The development of conventional treatment strategies has largely been based on the understanding that the angiogenic switch of endothelial cells is dictated by angiogenic growth factors alone. Even though treatments targeting vascular endothelial growth factor (VEGF), like Ranibizumab, are widely administered, more than half of the patients still exhibit inadequate or null responses, emphasizing the imperative need for solutions to this problem. Here, aiming to explore therapeutic strategies from a novel perspective of endothelial cell metabolism, a biocompatible nanomedicine delivery system is constructed by loading RGD peptide-modified liposomes with 2-deoxy-D-glucose (RGD@LP-2-DG). RGD@LP-2-DG displayed good targeting performance towards endothelial cells and excellent in vitro and in vivo inhibitory effects on neovascularization were demonstrated. Moreover, our mechanistic studies revealed that 2-DG interfered with N-glycosylation, leading to the inhibition of vascular endothelial growth factor receptor 2 (VEGFR2) and its downstream signaling. Notably, the remarkable inhibitory effect on neovascularization and biocompatibility of RGD@LP-2-DG render it a highly promising and clinically translatable therapeutic candidate for the treatment of wet AMD and other angiogenic diseases, particularly in patients who are unresponsive to currently available treatments.

CXCL1/IGHG1 signaling enhances crosstalk between tumor cells and tumor-associated macrophages to promote MC-LR-induced colorectal cancer progression.

Microcystin-leucine arginine (MC-LR) is a common cyantotoxin produced by hazardous cyanobacterial blooms, and eutrophication is increasing the contamination level of MC-LR in drinking water supplies and aquatic foods. MC-LR has been linked to colorectal cancer (CRC) progression associated with tumor microenvironment, however, the underlying mechanism is not clearly understood. In present study, by using GEO, KEGG, GESA and ImmPort database, MC-LR related differentially expressed genes (DEGs) and pathway- and gene set-enrichment analysis were performed. Of the three identified DEGs (CXCL1, GUCA2A and GDF15), CXCL1 was shown a positive association with tumor infiltration, and was validated to have a dominantly higher upregulation in MC-LR-treated tumor-associated macrophages (TAMs) rather than in MC-LR-treated CRC cells. Both CRC cell/macrophage co-culture and xenograft mouse models indicated that MC-LR stimulated TAMs to secrete CXCL1 resulting in promoted proliferation, migration, and invasion capability of CRC cells. Furtherly, IP-MS assay found that interaction between TAMs-derived CXCL1 and CRC cell-derived IGHG1 may enhance CRC cell proliferation and migration after MC-LR treatment, and this effect can be attenuated by silencing IGHG1 in CRC cell. In addition, molecular docking analysis, co-immunoprecipitation and immunofluorescence further proved the interactions between CXCL1 and IGHG1. In conclusion, CXCL1 secreted by TAMs can trigger IGHG1 expression in CRC cells, which provides a new clue in elucidating the mechanism of MC-LR-mediated CRC progression.

[Spatiotemporal Evolution and Influencing Factors of Ecosystem Service Value in the Yellow River Basin].

The external spatiotemporal evolution and intrinsic impact mechanisms of ecosystem service value are of great significance for understanding regional ecosystem issues and enhancing human ecological well-being. Based on grid data, this study used the equivalent factor method and NDVI to measure the ecosystem service value of the Yellow River Basin, analyzed the spatial-temporal evolution of urban ecosystem service value along the basin, and established a GWR model to explore the spatial heterogeneity of each influencing factor on the basis of determining the main influencing factors via geographic detector. The results showed that:① The ecosystem service value of the Yellow River Basin increased first, then decreased, and finally increased from 2000 to 2020, showing a spatial distribution pattern of "the south was higher than the north;" "the lower reaches were lower, and the upper and middle reaches were higher;" and the regulation service contributed the most to the ecosystem service value of the basin. ② The results of geographical exploration showed that the degree of influence of various factors was different. Social factors played the strongest role in explaining the ecosystem service value of the Yellow River Basin, followed by economic factors, and natural factors played the weakest role. The high value areas in the upper reaches were mainly related to rivers and lakes, and the high value areas in the middle reaches were mainly related to mountains. ③ The results of the GWR model showed that population density and land reclamation rate were negatively correlated with ecosystem service value, whereas average annual precipitation was positively correlated, and the effects increased from east to west. The GDP per unit area was negatively correlated with the overall ecosystem service value but positively correlated in the upstream region.

Identification of PANoptosis-related predictors for prognosis and tumor microenvironment by multiomics analysis in glioma.

PANoptosis is a newly described inflammatory programmed cell death, that highlights coordination between pyroptosis, apoptosis and necroptosis. However, the functions of PANoptosis-related genes in glioma progression still remain to be explored. This study aims to identify PANoptosis-related predictors that may be utilized for prognosis prediction and development of new therapeutic targets. Firstly, bulk and single-cell RNA-seq (scRNA-seq) data of glioma patients were extracted from TCGA, CGGA and GEO database. Genetic analysis indicates a considerably high mutation frequency of PANoptosis-related genes (PANRGs) in glioma. Consensus clustering was applied to reveal different subtypes of glioma based on PANRGs. Two PANoptosis subtypes with distinct prognostic and TME characteristics were identified. Then, with LASSO-Cox regression analysis, four PANoptosis-related predictors (MYBL2, TUBA1C, C21orf62 and KCNIP2) were determined from bulk and scRNA-seq analysis. Predictive PANRG score model was established with these predictors and its correlation with tumor microenvironment (TME) was investigated. The results showed that patients with low PANRG score, had higher infiltration of anti-tumor immune cells, higher MSI score and lower TIDE score, which are more likely to benefit from immunotherapy. Further analysis identified 16 potential drugs associated with PANoptosis-related predictors. Moreover, the expression levels of four PANoptosis-related predictors were examined in clinical samples and the results were consistent with those analyzed in the database. Besides, we also confirmed the biological functions of two oncogenic predictors (MYBL2 and TUBA1C) by cell experiments, which revealed that knockdown of MYBL2 or TUBA1C could significantly inhibit the proliferation and migration of glioma cells. These findings highlight the prognostic value and biological functions of PANRGs in glioma, which may provide valuable insights for individualized treatment.

Whole transcriptome sequencing identifies a competitive endogenous RNA network that regulates the immunity of bladder cancer.

Several types of non-coding RNAs such as circRNAs, lncRNAs, and miRNAs have been identified to regulate mRNAs through the mechanism known as the competitive endogenous RNA (ceRNA) network. To explore the role of the ceRNA regulatory network in the immune microenvironment of bladder cancer, whole-transcriptome sequencing of bladder tumor and its peritumoral tissues from 38 bladder cancer patients, with a total of 63 samples, was performed to screen differentially expressed circ-, lnc-, mi-, and mRNAs to construct a circ/lnc-mi-mRNA regulatory network with pruning algorithms. We excavated a key immune-related gene BDNF to build the final ceRNA network as hsa-miR-107 sponged by hsa-circ-000211, AC108488.1, and LINC00163. Finally, a meta-analysis of 7 public datasets demonstrated that low expression of BDNF and high expression of hsa-miR-107 were associated with longer survival. Our study identified a ceRNA regulatory network as a potentially new prognostic marker and molecular therapeutic target of bladder cancer.

Identification of AURKA as a Biomarker Associated with Cuproptosis and Ferroptosis in HNSCC.

Cuproptosis and ferroptosis represent copper- and iron-dependent forms of cell death, respectively, and both are known to play pivotal roles in head and neck squamous cell carcinoma (HNSCC). However, few studies have explored the prognostic signatures related to cuproptosis and ferroptosis in HNSCC. Our objective was to construct a prognostic model based on genes associated with cuproptosis and ferroptosis. We randomly assigned 502 HSNCC samples from The Cancer Genome Atlas (TCGA) into training and testing sets. Pearson correlation analysis was utilized to identify cuproptosis-associated ferroptosis genes in the training set. Cox proportional hazards (COX) regression and least absolute shrinkage operator (LASSO) were employed to construct the prognostic model. The performance of the prognostic model was internally validated using single-factor COX regression, multifactor COX regression, Kaplan-Meier analysis, principal component analysis (PCA), and receiver operating curve (ROC) analysis. Additionally, we obtained 97 samples from the Gene Expression Omnibus (GEO) database for external validation. The constructed model, based on 12 cuproptosis-associated ferroptosis genes, proved to be an independent predictor of HNSCC prognosis. Among these genes, the increased expression of aurora kinase A (AURKA) has been implicated in various cancers. To further investigate, we employed small interfering RNAs (siRNAs) to knock down AURKA expression and conducted functional experiments. The results demonstrated that AURKA knockdown significantly inhibited the proliferation and migration of HNSCC cells (Cal27 and CNE2). Therefore, AURKA may serve as a potential biomarker in HNSCC.

miR-122-3p targets UBE2I to regulate the immunosuppression of liver cancer and the intervention of Liujunzi formula.

ETHNOPHARMACOLOGICAL RELEVANCE: Liujunzi formula has been used to treat liver cancer in China for many years, but its underlying mechanism remains unclear. We previously found that decreased expression of miR-122-3p was associated with liver cancer. In this study, we aimed to explore the target of miR-122-3p and the effect of the Liujunzi formula on miR-122-3p and its downstream events in liver cancer. MATERIAL AND METHODS: Bioinformatics pinpointed potential targets of miR-122-3p. The actual target was confirmed by miRNA mimic/inhibitor transfections and a dual-luciferase reporter assay. RNA-seq looked at downstream genes impacted by this target. Flow cytometry checked for changes in T cell apoptosis levels after exposing them to liver cancer cells. Gene expression was measured by RT-qPCR, western blotting, and immunofluorescence staining. RESULTS: Cell experiments found the Liujunzi extract (LJZ) upregulated miR-122-3p and in a dose-dependent manner. Bioinformatics analysis found UBE2I was a potential target of miR-122-3p, which was validated through experiments using miRNA mimics/inhibitors and a dual-luciferase reporter assay. RNA-seq data implicated the NF-κB pathway as being downstream of the miR-122-3p/UBE2I axis, further confirmed by forcing overexpression of UBE2I. Bioinformatic evidence suggested a link between UBE2I and T cell infiltration in liver cancer. Given that the NF-κB pathway drives PD-L1 expression, which can inhibit T cell infiltration, we investigated whether PD-L1 is a downstream effector of miR-122-3p/UBE2I. This was corroborated through mining public databases, UBE2I overexpression studies, and tumor-T cell co-culture assays. In addition, we also confirmed that LJZ downregulates UBE2I and NF-κB/PD-L1 pathways through miR-122-3p. LJZ also suppressed SUMOylation in liver cancer cells and protected PD-1+ T cells from apoptosis induced by co-culture with tumor cells. Strikingly, a miR-122-3p inhibitor abrogated LJZ's effects on UBE2I and PD-L1, and UBE2I overexpression rescued the LJZ-mediated effects on NF-κB and PD-L1. CONCLUSIONS: miR-122-3p targets UBE2I, thereby suppressing the NF-κB signaling cascade and downregulating PD-L1 expression, which potentiates anti-tumor immune responses. LJZ bolsters anti-tumor immunity by modulating the miR-122-3p/UBE2I/NF-κB/PD-L1 axis in liver cancer cells.

Clinical features and genetic spectrum of a multicenter Chinese cohort with myotonic dystrophy type 1.

BACKGROUND: As the most common subtype of adult muscular dystrophy worldwide, large cohort reports on myotonic dystrophy type I (DM1) in China are still lacking. This study aims to analyze the genetic and clinical characteristics of Chinese Han DM1 patients. METHODS: Based on the multicenter collaborating effort of the Pan-Yangtze River Delta Alliance for Neuromuscular Disorders, patients with suspected clinical diagnoses of DM1 were genetically confirmed from January 2020 to April 2023. Peak CTG repeats in the DMPK gene were analyzed using triplet repeat-primed PCR (TP-PCR) and flanking PCR. Time-to-event analysis of onset age in females and males was performed. Additionally, detailed clinical features and longitudinal changes from the disease onset in 64 DM1 patients were retrospectively collected and analyzed. The Epworth Sleepiness Scale and Fatigue Severity Scale were used to quantify the severity of daytime sleepiness and fatigue. RESULTS: Among the 211 genetically confirmed DM1 patients, the mean age at diagnosis was 40.9 ± 12.2 (range: 12-74) with a male-to-female ratio of 124:87. The average size of CTG repeats was 511.3 (range: 92-1945). Among the DM1 patients with comprehensive clinical data (n = 64, mean age 41.0 ± 12.0), the age at onset was significantly earlier in males than in females (4.8 years earlier, p = 0.026). Muscle weakness (92.2%), myotonia (85.9%), and fatigue (73.4%) were the most prevalent clinical features. The predominant involved muscles at onset are hands (weakness or myotonia) (52.6%) and legs (walking disability) (42.1%). Of them, 70.3% of patients had daytime sleepiness, 14.1% had cataract surgery, 7.8% used wheelchairs, 4.7% required ventilatory support, and 1.6% required gastric tubes. Regarding the comorbidities, 4.7% of patients had tumors, 17.2% had diabetes, 23.4% had dyspnea, 28.1% had intermittent insomnia, 43.8% experienced dysphagia, and 25% exhibited cognitive impairment. Chinese patients exhibited smaller size of CTG repeats (468 ± 139) than those reported in Italy (613 ± 623), the US (629 ± 386), and Japan (625 [302, 1047]), and milder phenotypes with less multisystem involvement. CONCLUSION: The Chinese Han DM1 patients presented milder phenotypes compared to their Caucasian and Japanese counterparts. A male predominance and an early age of onset were identified in male Chinese Han DM1 patients.

Boundary-Sensitive Segmentation of Small Liver Lesions.

Early diagnosis plays a pivotal role in handling the global health challenge posed by liver diseases. However, early-stage lesions are typically quite small, presenting significant difficulties due to insufficient regions for developing effective features, indistinguishable boundaries of small lesions, and a lack of tiny liver lesion masks. To address these issues, we approach the solution in two-fold: an efficient model and a high-quality dataset. The model is built upon the advantages of path signature and camouflaged object detection. The path signature narrows down the ambiguous boundaries between lesions and other tissues while the camouflaged object detection achieves high accuracy in detecting inconspicuous lesions. The two are seamlessly integrated to ensure high accuracy and fidelity. For the dataset, we collect more than ten thousand liver images with over four thousand lesions, approximately half of which are small. Experiments on both an established dataset and our newly constructed one show that the proposed model outperforms state-of-the-art semantic segmentation and camouflaged object detection models, particularly in detecting small lesions. Moreover, the decisive and faithful salience maps generated by the model at the boundary regions demonstrate its strong robustness.

Large language models assisted multi-effect variants mining on cerebral cavernous malformation familial whole genome sequencing.

Cerebral cavernous malformation (CCM) is a polygenic disease with intricate genetic interactions contributing to quantitative pathogenesis across multiple factors. The principal pathogenic genes of CCM, specifically KRIT1, CCM2, and PDCD10, have been reported, accompanied by a growing wealth of genetic data related to mutations. Furthermore, numerous other molecules associated with CCM have been unearthed. However, tackling such massive volumes of unstructured data remains challenging until the advent of advanced large language models. In this study, we developed an automated analytical pipeline specialized in single nucleotide variants (SNVs) related biomedical text analysis called BRLM. To facilitate this, BioBERT was employed to vectorize the rich information of SNVs, while a deep residue network was used to discriminate the classes of the SNVs. BRLM was initially constructed on mutations from 12 different types of TCGA cancers, achieving an accuracy exceeding 99%. It was further examined for CCM mutations in familial sequencing data analysis, highlighting an upstream master regulator gene fibroblast growth factor 1 (FGF1). With multi-omics characterization and validation in biological function, FGF1 demonstrated to play a significant role in the development of CCMs, which proved the effectiveness of our model. The BRLM web server is available at http://1.117.230.196.

Study on the expression changes of lncRNA in patients with systemic lupus erythematosus and its correlation with Treg cells.

OBJECTIVES: We initially explored the link between the differentially expressed long non-coding RNAs (lncRNAs) and the number of regulatory T (Treg) cells by detecting the lncRNA expression profiles in patients with systemic lupus erythematosus (SLE), then analyzed the correlation between Treg-related lncRNAs and the clinical features of SLE patients, predicting the mechanism by which lncRNAs regulate the differentiation and development of Treg cells, and provided new ideas for the treatment of SLE. METHODS: Peripheral blood of 9 active SLE patients were collected and mononuclear cells (PBMCs) were extracted; the lncRNA expression profiles of PBMCs were analyzed by whole transcriptome sequencing. Nine healthy people were used as controls to screen the differentially expressed lncRNAs, to analyze the correlation between lncRNAs and Treg cell number. Pearson test was used to analyze the correlation between lncRNAs and the number of Treg cell, and the correlation between Treg-associated lncRNA and SLEDAI score, ESR, C3, and C4 in SLE patients. The targeted genes of Treg-associated lncRNAs were predicted with miRcode and Targetscan databases and coexpression network. RESULTS: There were 240 differentially expressed lncRNAs in SLE patients compared with healthy controls, including 134 highly expressed lncRNAs (p < 0.05) and 106 lowly expressed lncRNAs (p < 0.05). The expression of ANKRD44-AS1 (r = 0.7417, p = 0.0222), LINC00200 (r = 0.6960, p = 0.0373), AP001363.2 (r = 0.7766, p = 0.0138), and LINC02824 (r = 0.7893, p = 0.0114) were positively correlated with the number of Treg cell, and the expression of AP000640.1 (r = - 0.7225, p = 0.0279), AC124248.1 (r = - 0.7653, p = 0.0163), LINC00482 (r = - 0.8317, p = 0.0054), and MIR503HG (r = - 0.7617, p < 0.05) were negatively correlated with the number of Treg cell. Among these Treg-associated lncRNAs, the expression of LINC00482 (r = - 0.7348, p < 0.05) and MIR503 HG (r = - 0.7617, p < 0.05) were negatively correlated with C3. LINC00200, ANKRD44 - AS1, and AP000640.1 related to Treg cells regulate the expression of signal transducer and activator of transcription 5 (STAT5), phospholipase D1 (PLD1), homeodomain-only protein X (HOPX), and runt-related transcription factor 3 (RUNX3) through competitive binding of miRNA or trans-regulatory mechanism, thereby regulating the differentiation and development of Treg cell. CONCLUSIONS: The lncRNA expression profiles were changed in SLE patients, the differentially expressed lncRNAs were associated with abnormal number and function of Treg cells in SLE, and Treg-associated lncRNAs were associated with SLE-disease activity, which may affect the expression of STAT5, PLD1, HOPX, RUNX3 and regulate Treg cell function and participate in the pathogenesis and progression of SLE by competitively binding to miRNAs or trans-regulatory mechanism. Key points • Systemic lupus erythematosus (SLE) is an autoimmune disease involving multiple organs and systems. lncRNAs may affect Treg cells function by regulating genes expression, which may be an important pathogenesis of SLE. • This study, taking SLE as an example, preliminarily analyzed the correlation between lncRNA and Treg cells in SLE patients, analyzed the correlation between Treg-related lncRNA and the clinical characteristics of SLE, and speculated that lncRNA could regulate the differentiation and development of Treg cells through competitive combination with miRNA or trans-regulatory mechanisms. • It is possible to target epigenetic therapy for SLE.

A Convenient and Effective Preoxygenation Technique for Prolonging Deep Inspiration Breath-Hold Duration With a Venturi Mask With a 50% Oxygen Concentration.

PURPOSE: Voluntary deep inspiration breath-hold (DIBH) is commonly used in radiation therapy (RT), but the short duration of a single breath-hold, estimated to be around 20 to 40 seconds, is a limitation. This prospective study aimed to assess the feasibility and safety of using a simple preoxygenation technique with a Venturi mask to prolong voluntary DIBH. METHODS AND MATERIALS: The study included 33 healthy volunteers and 21 RT patients. Preoxygenation was performed using a Venturi mask with a 50% oxygen concentration. Paired t tests compared the duration of a single DIBH in room air and after 5, 15, and 30 minutes of preoxygenation in healthy volunteers. Sustainability of breath-hold and tolerability of heart rate and blood pressure were assessed for multiple DIBH durations in both volunteers and patients. RESULTS: In healthy volunteers, a 15-minute preoxygenation significantly prolonged the duration of a single DIBH by 24.95 seconds compared with 5-minute preoxygenation (89 ± 27.76 vs 113.95 ± 30.63 seconds; P < .001); although there was a statistically significant increase in DIBH duration after 30-minute preoxygenation, it was only extended by 4.95 seconds compared with 15-minute preoxygenation (113.95 ± 30.63 vs 118.9 ± 29.77 seconds; P < .01). After 15-minute preoxygenation, a single DIBH lasted over 100 seconds in healthy volunteers and over 80 seconds in RT patients, with no significant differences among 6 consecutive cycles of DIBH. Furthermore, there were no significant differences in heart rate or blood pressure after DIBHs, including DIBH in room air and 6 consecutive DIBHs after 15-minute preoxygenation (all P > .05). CONCLUSIONS: Preoxygenation with a 50% oxygen concentration for 15 minutes effectively prolongs the duration of 6 cycles of DIBH both in healthy volunteers and RT patients. The utilization of a Venturi mask to deliver 50% oxygen concentration provides a solution characterized by its convenience, good tolerability, and effectiveness.

[Application of analgesia and sedation under BIS monitoring combined with hydraulic coupling intracranial pressure monitoring in severe craniocerebral injury].

OBJECTIVE: To investigate the clinical value of analgesia and sedation under bispectral index (BIS) monitoring combined with hydraulic coupled intracranial pressure (ICP) monitoring in severe craniocerebral injury (sTBI). METHODS: (1) A prospective self-controlled parallel control study was conducted. A total of 32 patients with sTBI after craniotomy admitted to the intensive care unit (ICU) of the First People's Hospital of Huzhou from December 2020 to July 2021 were selected as the research objects. ICP was monitored by Codman monitoring system and hydraulically coupled monitoring system, and the difference and correlation between them were compared. (2) A prospective randomized controlled study was conducted. A total of 108 sTBI patients admitted to the ICU of the First People's Hospital of Huzhou from August 2021 to August 2022 were selected patients were divided into 3 groups according to the random number table method. All patients were given routine treatment after brain surgery. On this basis, the ICP values of the patients in group A (35 cases) were monitored by Codman monitoring system, the ICP values of the patients in group B (40 cases) were monitored by hydraulic coupling monitoring system, and the ICP values of the patients in group C (33 cases) were monitored combined with hydraulic coupling monitoring system, and the analgesia and sedation were guided by BIS. The ICP after treatment, cerebrospinal fluid drainage time, ICP monitoring time, ICU stay time, complications and Glasgow outcome score (GOS) at 6 months after surgery were compared among the 3 groups. In addition, patients in group B and group C were further grouped according to the waveforms. If P1 = P2 wave or P2 and P3 wave were low, they were classified as compensatory group. If the round wave or P2 > P1 wave was defined as decompensated group, the GOS scores of the two groups at 6 months after operation were compared. RESULTS: (1) There was no significant difference in ICP values measured by Codman monitoring system and hydraulic coupling monitoring system in the same patient (mmHg: 11.94±1.76 vs. 11.88±1.90, t = 0.150, P = 0.882; 1 mmHg≈0.133 kPa). Blan-altman analysis showed that the 95% consistency limit (95%LoA) of ICP values measured by the two methods was -4.55 to 4.68 mmHg, and all points fell within 95%LoA, indicating that the two methods had a good correlation. (2) There were no significant differences in cerebrospinal fluid drainage time, ICP monitoring time, ICU stay time, and incidence of complications such as intracranial infection, intracranial rebleeding, traumatic hydrocephalus, cerebrospinal fluid leakage, and accidental extubation among the 3 groups of sTBI patients (P > 0.05 or P > 0.017). The ICP value of group C after treatment was significantly lower than that of group A and group B (mmHg: 20.94±2.37 vs. 25.86±3.15, 26.40±3.09, all P < 0.05), the incidence of pulmonary infection (9.1% vs. 45.7%, 42.5%), seizure (3.0% vs. 31.4%, 30.0%), reoperation (3.0% vs. 31.4%, 40.0%), and poor prognosis 6 months after operation (33.3% vs. 65.7%, 65.0%) were significantly lower than those in group A and group B (all P < 0.017). According to the hydraulic coupling waveform, GOS scores of 35 patients in the compensated group were significantly higher than those of 38 patients in the decompensated group 6 months after operation (4.03±1.18 vs. 2.39±1.50, t = 5.153, P < 0.001). CONCLUSIONS: The hydraulic coupled intracranial pressure monitoring system has good accuracy and consistency in measuring ICP value, and it can better display ICP waveform changes than the traditional ICP monitoring method, and has better prediction value for prognosis evaluation, which can replace Codman monitoring to accurately guide clinical work. In addition, analgesia and sedation under BIS monitoring combined with hydraulic coupled ICP monitoring can effectively reduce ICP, reduce the incidence of complications, and improve the prognosis, which has high clinical application value.

Enterogenic Stenotrophomonas maltophilia migrates to the mammary gland to induce mastitis by activating the calcium-ROS-AMPK-mTOR-autophagy pathway.

BACKGROUND: Mastitis is an inflammatory disease of the mammary gland that has serious economic impacts on the dairy industry and endangers food safety. Our previous study found that the body has a gut/rumen-mammary gland axis and that disturbance of the gut/rumen microbiota could result in 'gastroenterogenic mastitis'. However, the mechanism has not been fully clarified. Recently, we found that long-term feeding of a high-concentrate diet induced mastitis in dairy cows, and the abundance of Stenotrophomonas maltophilia (S. maltophilia) was significantly increased in both the rumen and milk microbiota. Accordingly, we hypothesized that 'gastroenterogenic mastitis' can be induced by the migration of endogenous gut bacteria to the mammary gland. Therefore, this study investigated the mechanism by which enterogenic S. maltophilia induces mastitis. RESULTS: First, S. maltophilia was labelled with superfolder GFP and administered to mice via gavage. The results showed that treatment with S. maltophilia promoted the occurrence of mastitis and increased the permeability of the blood-milk barrier, leading to intestinal inflammation and intestinal leakage. Furthermore, tracking of ingested S. maltophilia revealed that S. maltophilia could migrate from the gut to the mammary gland and induce mastitis. Subsequently, mammary gland transcriptome analysis showed that the calcium and AMPK signalling pathways were significantly upregulated in mice treated with S. maltophilia. Then, using mouse mammary epithelial cells (MMECs), we verified that S. maltophilia induces mastitis through activation of the calcium-ROS-AMPK-mTOR-autophagy pathway. CONCLUSIONS: In conclusion, the results showed that enterogenic S. maltophilia could migrate from the gut to the mammary gland via the gut-mammary axis and activate the calcium-ROS-AMPK-mTOR-autophagy pathway to induce mastitis. Targeting the gut-mammary gland axis may also be an effective method to treat mastitis.

Constructed Risk Prognosis Model Associated with Disulfidptosis lncRNAs in HCC.

Disulfidptosis is a novel cell death mode in which the accumulation of disulfide bonds in tumor cells leads to cell disintegration and death. Long-stranded noncoding RNAs (LncRNAs) are aberrantly expressed in hepatocellular carcinoma (HCC) and have been reported to carry significant potential as a biomarker for HCC prognosis. However, lncRNA studies with disulfidptosis in hepatocellular carcinoma have rarely been reported. Therefore, this study aimed to construct a risk prognostic model based on the disulfidptosis-related lncRNA and investigate the mechanisms associated with disulfidptosis in hepatocellular carcinoma. The clinical and transcriptional information of 424 HCC patients was downloaded from The Cancer Genome Atlas (TCGA) and divided into test and validation sets. Furthermore, 1668 lncRNAs associated with disulfidptosis were identified using Pearson correlation. Six lncRNA constructs were finally identified for the risk prognostic model using one-way Cox proportional hazards (COX), multifactorial COX, and lasso regression. Kaplan-Meier (KM) analysis, principal component analysis, receiver operating characteristic curve (ROC), C-index, and column-line plot results confirmed that the constructed model was an independent prognostic factor. Based on the disulfidptosis risk score, risk groups were identified as potential predictors of immune cell infiltration, drug sensitivity, and immunotherapy responsiveness. Finally, we confirmed that phospholipase B domain containing 1 antisense RNA 1 (PLBD1-AS1) and muskelin 1 antisense RNA (MKLN1-AS) were highly expressed in hepatocellular carcinoma and might be potential biomarkers in HCC by KM analysis and quantitative real-time PCR (RT-qPCR). This study demonstrated that lncRNA related to disulfidptosis could serve as a biomarker to predict prognosis and treatment targets for HCC.

Persulfate catalyst synthesized with waterworks sludge for degrading Safranine T in the presence of boron.

Energy conservation and emission reduction are the general trend of the present world. In this study, a catalyst of 3WSH based on the waste recycle of waterworks sludge (WS) and Chinese herbs was prepared using one-step calcination treatment and then characterized by SEM, XRD, XPS, FTIR and BET. The catalytic performance of 3WSHB for activating potassium persulfate (PDS) was evaluated through the degradation of Safranine T (ST) in the presence of boron powder (B). The effects of vital parameters on ST removal were systematically studied, including PDS concentration, 3WSHB dosage, initial solution pH, B dosage, temperature and coexisting cations. The highest efficiency of ST removal was up to 93.0% under the optimal condition with 1.85 mM of PDS, 0.3 g/L of 3WSHB, 0.35g/L of B, 7 of pH. EPR and free radical quenching experiments demonstrated that •OH was the dominant reactive oxygen species for ST degradation in the PDS/3WSHB/B system. Moreover, the intermediates determined by HPLC-MS indicated that the oxidization of benzene ring substituents in ST and a hydrogen abstraction by electron transfer might occur during ST degradation. The dissatisfied reuse performance of 3WSHB might be attributed to its low Fe content and simple reusing way. The results demonstrate the effectiveness of WS recycling and reuse in the field of pollutant remediation.

Peripheral Blood Th1/Th17 Immune Cell Shift is Associated with Disease Activity and Severity of AQP4 Antibody Sero-Positive Neuromyelitis Optica Spectrum Disorder.

Purpose: Neuromyelitis optica spectrum disorder (NMOSD) is a rare recurrent autoimmune disease of the central nervous system. However, to date, the peripheral blood profile of the T helper cell subsets in NMOSD remains controversial and poorly understood. This study aimed to compare the levels of helper T cell subsets in the peripheral blood from patients with NMOSD in different phases of the disease and studied their correlation with the clinical severity of the disease. Patients and methods: We used flow cytometry with cellular membrane surface staining to measure the levels of helper T cell subsets in 50 patients with NMOSD during the attack (n = 25) and remission (n = 25) phases and in 21 healthy controls. Results: Patients with NMOSD had higher levels of Th1 and Th17 cells in the attack phase compared to parallel populations in the remission phase and healthy controls. Th1/Th2 and Th17/Treg ratios were positively correlated with the severity of the disease in the attack phase of NMOSD. In contrast, Treg cell levels were negatively correlated with the severity of the disease in the attack phase in patients with NMOSD. Conclusion: The peripheral blood immune profile in NMOSD towards a Th1/Th17 cell-mediated pro-inflammatory immune response, which is associated with disease activity and severity of neuromyelitis optica spectrum disorder.