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Abstract Background As a subtype of pulmonary hypertension (PH), pulmonary veno-occlusive disease (PVOD) is devastating and life-threatening disease without effective therapy. Hydrogen has been reported to exhibits antioxidant and anti-inflammatory effects in a rat model induced by monocrotaline of PH. In this study, we investigated the effects of inhaled hydrogen gas on the prevention and treatment of PVOD induced by mitomycin C (MMC) in rats. Methods PVOD was induced in female Sprague-Dawley rats through intraperitoneal injection of MMC at a concentration of 3 mg·kg− 1·wk− 1 for 2 weeks. Inhalation of hydrogen gas (H2) was administered through a designed rat cage concurrently or two weeks after MMC administration. The severity of PVOD was assessed by using hemodynamic measurements and histological analysis. The expression levels of general control nonderepressible 2 (GCN2), nuclear factor erythroid 2-related factor-2 (Nrf2), heme oxygenase-1 (HO-1) and endothelial-to-mesenchymal transition (EndoMT) related proteins in lung tissue were measured. Levels of lipid peroxidation pro-inflammatory cytokines in serum were determined. Results Inhaled H2 improved hemodynamics and right heart function, reversed right ventricular hypertrophy, and prevented pulmonary vessel reconstitution in both prevention and treatment approaches. It decreased malondialdehyde (MDA) levels in the serum and the expression of NADPH oxidase 1 (NOX-1) in lung tissue. It regulated Nrf2/HO-1 signaling pathway and anti-inflammatory factor GCN2 in lung tissue, accompanied by a decrease in macrophages and pro-inflammatory cytokines. Our data suggested that H2 inhalation effectively countered EndoMT induced by MMC, as evidenced by the detection of endothelial markers (e.g., VE-cadherin and CD31) and mesenchymal markers (e.g., vimentin and fibronectin). Further research revealed that H2 preserved p-Smad3 and induced p-Smad1/5/9. Conclusion Inhalation of H2 effectively inhibits the pathogenesis of PVOD induced by MMC in rats. This inhibitory effect may be attributed to the antioxidant and anti-inflammatory properties of H2.

Abstract Interleukin-17A therapeutic inhibitors are among the most effective treatment methods for moderate-to-severe plaque psoriasis (PP). Reflectance confocal microscopy is a non-invasive imaging technique already documented to be beneficial in evaluating the follow-up of PP under treatment with topical actives and phototherapy. This study aimed to assess the epidermal and dermal changes associated with psoriasis and its treatment with RCM during systemic secukinumab treatment in patients with moderate-to-severe PP. A pilot study was conducted to evaluate RCM as a non-invasive tool for monitoring secukinumab treatment in patients with PP. For patients receiving secukinumab treatment, lesional skin was selected for RCM imaging, which were recorded at all scheduled times. The RCM evaluation criteria were established based on the histopathological diagnostic criteria for psoriasis. The clinical severity of psoriasis was assessed utilizing the psoriasis area severity index. A total of 23 patients with PP were included in the study. Each patient received 300 mg of subcutaneous secukinumab as induction therapy at baseline and weeks 1–4, followed by maintenance therapy every four weeks. Microscopic confocal changes were observed during the treatment. The results identified early microscopic evidence of the anti-inflammatory activity of secukinumab, which was not detected during the clinical examination. RCM findings correlating with the PASI were used to observe the patient’s response to treatment and were identified as follows: acanthosis and parakeratosis, presence of epidermal and dermal inflammatory cells, presence of non-edge dermal papillae, and vascularization in the papillary dermis. This study is the first to demonstrate the use of RCM as an effective tool for non-invasive monitoring of secukinumab therapeutic response at a cellular level in a clinical or research setting. Early detection of RCM parameters associated with secukinumab activity may facilitate the identification of an early treatment response. RCM appears to be capable of providing practical and helpful information regarding follow-up in patients with PP undergoing secukinumab treatment. RCM may also provide novel perspectives on the subclinical evaluation of PP’s response to biological therapy.

Abstract Objective This study aimed to evaluate the effect of fence tray matching care (FTMC) in bracket bonding by measuring excess adhesive, as well as linear and angular deviations, and by comparing it with the half-wrapped tray (HWT). Materials and methods An intraoral scanner was used to acquire data on the maxillary dental arch of a patient with periodontitis.Furthermore, 20 maxillary dental arch models were 3D printed. Using 3Shape, PlastyCAD software, and 3D printing technology, 10 FTMC (method I) and HWT (method II) were obtained. By preoperative preparation, intraoperative coordination, and postoperative measurement, the brackets were transferred from the trays to the 3D-printed maxillary dental arch models. Additionally, the bracket’s excess adhesive as well as linear and angular deviations were measured, and the differences between the two methods were analyzed. Results Excess adhesive was observed in both methods, with FTMC showing less adhesive (P

Abstract In diabetes, macrophages and inflammation are increased in the islets, along with β-cell dysfunction. Here, we demonstrate that galectin-3 (Gal3), mainly produced and secreted by macrophages, is elevated in islets from both high-fat diet (HFD)-fed and diabetic db/db mice. Gal3 acutely reduces glucose-stimulated insulin secretion (GSIS) in β-cell lines and primary islets in mice and humans. Importantly, Gal3 binds to calcium voltage-gated channel auxiliary subunit gamma 1 (CACNG1) and inhibits calcium influx via the cytomembrane and subsequent GSIS. β-Cell CACNG1 deficiency phenocopies Gal3 treatment. Inhibition of Gal3 through either genetic or pharmacologic loss of function improves GSIS and glucose homeostasis in both HFD-fed and db/db mice. All animal findings are applicable to male mice. Here we show a role of Gal3 in pancreatic β-cell dysfunction, and Gal3 could be a therapeutic target for the treatment of type 2 diabetes.

Deposition pattern and path-planning deposition strategy have significant impacts on the deformation and residual stress of components during a wire-arc additive manufacturing (WAAM) process. This work comparatively addressed the influence of weaving and non-weaving deposition patterns on the distributions of residual stress and warping deformation during a single-bead-on-plate WAAM process. Further, four path strategies with different deposition sequences (in-out and out-in) and deposition directions (alternate and consistent) were designed for a weaving WAAM process of disc part, and their impacts on temperature history, warping deformation, and residual stress were comparatively analyzed through thermal-mechanical coupling finite element (FE) method. Simulation and experiment results manifest that, compared to the non-weaving pattern, the weaving deposition pattern results in more uniform deformation and lower residual stress on the deposited plate due to wider and shallower molten pool. Comparison results for the four deposition path strategies in the weaving WAAM process of disc part suggest that the out-in deposition sequence exhibits faster heat dissipation and uniform temperature field during the cooling stage, resulting in reduced warping deformation and residual stress on the workpiece. Moreover, uniform deformation is observed across path strategies employing alternate deposition direction. The out-in alternate deposition path strategy was identified as the optimal choice for the weaving WAAM process of disc part. Finally, physical experiments validated the simulated warping deformation of disc parts under different deposition path strategies. This work contributes to the design and optimization of weaving WAAM process for disc-shaped components.

Bigels are two-phase systems made up of oleogel and hydrogel sheared and mixed at a certain temperature. As amphiphilic semi-solid formulations, bigels have attracted wide attention due to their good stability, encapsulation characteristics and processing characteristics. Bigels have great potential in replacing traditional solid fats, improving the nutritional value of composite foods, and delivering bioactive substances. This article reviews the composition, synthesis methods and types of bigels, summarizes the significant progress in the application of bigels in the food field, and give an outlook on future prospects. It is our hope that this review will provide some guidance for further research and application of bigels in the food field.

Abstract β-Cell dysfunction and β-cell loss are hallmarks of type 2 diabetes (T2D). Here, we found that trimethylamine N-oxide (TMAO) at a similar concentration to that found in diabetes could directly decrease glucose-stimulated insulin secretion (GSIS) in MIN6 cells and primary islets from mice or humans. Elevation of TMAO levels impairs GSIS, β-cell proportion, and glucose tolerance in male C57BL/6 J mice. TMAO inhibits calcium transients through NLRP3 inflammasome-related cytokines and induced Serca2 loss, and a Serca2 agonist reversed the effect of TMAO on β-cell function in vitro and in vivo. Additionally, long-term TMAO exposure promotes β-cell ER stress, dedifferentiation, and apoptosis and inhibits β-cell transcriptional identity. Inhibition of TMAO production improves β-cell GSIS, β-cell proportion, and glucose tolerance in both male db/db and choline diet-fed mice. These observations identify a role for TMAO in β-cell dysfunction and maintenance, and inhibition of TMAO could be an approach for the treatment of T2D.

Abstract Inflammation is a common and important pathological process occurring in any part of the body and relating to a variety of diseases. Effective tissue repair is critical for the survival of impaired organisms. Considering the side effects of the currently used anti-inflammatory medications, new therapeutic agents are urgently needed for the improvement of regenerative capacities of inflammatory-impaired tissues. Mesenchymal stromal stem/progenitor cells (MSCs) are characterized by the capabilities of self-renewal and multipotent differentiation and exhibit immunomodulatory capacity. Due to the ability to modulate inflammatory phenotypes and immune responses, MSCs have been considered as a potential alternative therapy for autoimmune and inflammatory diseases. Natural compounds (NCs) are complex small multiple-target molecules mostly derived from plants and microorganisms, exhibiting therapeutic effects in many disorders, such as osteoporosis, diabetes, cancer, and inflammatory/autoimmune diseases. Recently, increasing studies focused on the prominent effects of NCs on MSCs, including the regulation of cell survival and inflammatory response, as well as osteogenic/adipogenic differentiation capacities, which indicate the roles of NCs on MSC-based cytotherapy in several inflammatory diseases. Their therapeutic effects and fewer side effects in numerous physiological processes, compared to chemosynthetic drugs, made them to be a new therapeutic avenue combined with MSCs for impaired tissue regeneration. Here we summarize the current understanding of the influence of NCs on MSCs and related downstream signaling pathways, specifically in pathological inflammatory conditions. In addition, the emerging concepts through the combination of NCs and MSCs to expand the therapeutic perspectives are highlighted. A promising MSC source from oral/dental tissues is also discussed, with a remarkable potential for MSC-based therapy in future clinical applications.

Abstract Background Allergic asthma is a type I allergic reaction mediated by serum Immunoglobulin E (IgE). B cell-mediated humoral immune response to allergens in the pathophysiology of allergic asthma have not been thoroughly elucidated. Peripheral helper T cells (Tph) and follicular helper T cells (Tfh) promote B cell differentiation and antibody production in inflamed tissues. Objective To investigate the roles of B cell subsets, Tph cell subsets and Tfh cell subsets in allergic immune responses. Methods Circulating B cell subsets, Tph cell subsets and Tfh cell subsets in 33 children with allergic asthma and 17 healthy children were analyzed using multicolor flow cytometry. The level of serum total IgE was also assessed. Results Our study found that CD27+CD38+ plasmablasts and CD24hiCD38hi transitional B cells increased and were correlated with serum total IgE level, CD27− naive B cells and CD24hiCD27+ B cells decreased in children with allergic asthma. CXCR5− Tph, CXCR5−ICOS+ Tph, CXCR5−ICOS+PD-1+ Tph, CXCR5+ICOS+ Tfh and CXCR5+ICOS+PD-1+ Tfh increased in children with allergic asthma. Further analysis showed increased Tph2, Tph17, Tfh2 and Tfh17 subtypes while decreased Tph1 and Tfh1 subtypes in children with allergic asthma. Most interestingly, Tph2 or Tfh2 subtypes had a positive correlation with serum total IgE level. Conclusion Overall, these results provide insight into the allergens elicited B, Tph or Tfh cell response and identify heretofore unappreciated CD24hiCD38hi transitional B cells, CD24hiCD27+ B cells, CXCR5− Tph, CXCR5−ICOS+PD-1+ Tph, Tph2 subtypes and Tfh2 subtypes response to allergens.

Image preprocessing models are usually employed as the preceding operations of high‐level vision tasks to improve the performance. The adversarial attack technology makes both these models face severe challenges. Prior research is focused solely on attacking single object detection models, without considering the impact of the preprocessing models (multifocus image fusion) on adversarial perturbations within the object detection system. Multifocus image fusion models work in conjunction with the object detection models to enhance the quality of the images and improve the capability of object detection system. Herein, the problem of attacking object detection system that utilizes multifocus image fusion as its preprocessing models is addressed. To retain the attack capabilities of adversarial samples against as many perturbations as possible, new attack method called adaptive retention attack (ARA) is proposed. Additionally, adversarial perturbations concentration mechanism and image selection mechanism, which, respectively, enhance the transferability and attack capability of ARA‐generated adversarial samples. Extensive experiments have demonstrated the feasibility of the ARA. The results confirm that the ARA method can successfully bypass multifocus image fusion models to attack the object detection model.

BackgroundT lymphocytes in tumor microenvironment play a pivotal role in the anti-tumor immunity, and the memory of T cells contributes to the long-term protection against tumor antigens. Compared to solid tumors, studies focusing on the T-cell differentiation in the acute myeloid leukemia (AML) bone marrow (BM) microenvironment remain limited.Patients and methodsFresh BM specimens collected from 103 adult AML patients at diagnosis and 12 healthy donors (HDs) were tested T-cell differentiation subsets by multi-parameter flow cytometry.ResultsCD4 and CD8 T-cell compartments had different constituted profiles of T-cell differentiated subsets, which was similar between AML patients and HDs. Compared to HDs, AML patients as a whole had a significantly higher proportion of CD8 effector T cells (Teff, P = 0.048). Moreover, the T-cell compartment of AML patients with no DNMT3A mutations skewed toward terminal differentiation at the expense of memory T cells (CD4 Teff: P = 0.034; CD8 Teff: P = 0.030; CD8 memory T: P = 0.017), whereas those with mutated DNMT3A had a decrease in CD8 naïve T (Tn) and CD4 effector memory T cells (Tem) as well as an increase in CD4 central memory T cells (Tcm) (P = 0.037, 0.053 and 0.053). Adverse ELN genetic risk correlated with a lower proportion of CD8 Tn. In addition, the low proportions of CD4 Tem and CD8 Tn independently predicted poorer relapse-free survival (RFS, HR [95%CI]: 5.7 (1.4–22.2), P = 0.017 and 4.8 [1.3–17.4], P = 0.013) and event-free survival (EFS, HR [95% CI]: 3.3 (1.1–9.5), P = 0.029; 4.0 (1.4–11.5), P = 0.010), respectively.ConclusionsAML patients had abnormal profiles of BM T-cell differentiation subsets at diagnosis, which was related to DNMT3A mutations. The low proportions of CD4 Tem and CD8 Tn predicted poor outcomes.

BackgroundBrain inflammation plays a key role in ischemia/reperfusion (I/R) injury and is the main cause of “ineffective or futile recanalization” after successful mechanical thrombectomy (MT) in acute ischemic stroke (AIS). One of the primary sources of inflammatory cells after AIS are derived from the spleen. As an innovative and potential neuroprotective strategy after stroke, Remote Administration of Hypothermia (RAH) temporarily suppresses immune activities in the spleen, reduces the release of inflammatory cells and cytokines into blood, and thus reversibly diminishes inflammatory injury in the brain.MethodsThis single-center, prospective, randomized controlled study (RCT) is proposed for AIS patients with anterior circulation large vessel occlusion (LVO). Subjects will be randomly assigned to either the control or intervention groups in a 1:1 ratio (n = 40). Participants allocated to the intervention group will receive RAH on the abdomen above the spleen prior to recanalization until 6 h after thrombectomy. All enrolled patients will receive standard stroke Guideline care. The main adverse events associated with RAH are focal cold intolerance and abdominal pain. The primary outcome will assess safety as it pertains to RAH application. The secondary outcomes include the efficacy of RAH on spleen, determined by spleen volumes, blood inflammatory factor (cells and cytokines), and on brain injury, determined by infarction volumes and poststroke functional outcomes.DiscussionThis study aims to examine the safety and preliminary effectiveness of RAH over the spleen during endovascular therapy in AIS patients. The results of this study are expected to facilitate larger randomized clinical trials and hopefully prove RAH administration confers adjuvant neuroprotective properties in AIS treated with MT.Clinical trial registrationhttps://www.chictr.org.cn/. Identifier ChiCTR 2300077052.

ObjectiveThis study systematically reviews and meta-analyzes existing risk prediction models for diabetic kidney disease (DKD) among patients with type 2 diabetes, aiming to provide references for scholars in China to develop higher-quality risk prediction models.MethodsWe searched databases including China National Knowledge Infrastructure (CNKI), Wanfang Data, VIP Chinese Science and Technology Journal Database, Chinese Biomedical Literature Database (CBM), PubMed, Web of Science, Embase, and the Cochrane Library for studies on the construction of DKD risk prediction models among type 2 diabetes patients, up until 28 December 2023. Two researchers independently screened the literature and extracted and evaluated information according to a data extraction form and bias risk assessment tool for prediction model studies. The area under the curve (AUC) values of the models were meta-analyzed using STATA 14.0 software.ResultsA total of 32 studies were included, with 31 performing internal validation and 22 reporting calibration. The incidence rate of DKD among patients with type 2 diabetes ranged from 6.0% to 62.3%. The AUC ranged from 0.713 to 0.949, indicating the prediction models have fair to excellent prediction accuracy. The overall applicability of the included studies was good; however, there was a high overall risk of bias, mainly due to the retrospective nature of most studies, unreasonable sample sizes, and studies conducted in a single center. Meta-analysis of the models yielded a combined AUC of 0.810 (95% CI: 0.780–0.840), indicating good predictive performance.ConclusionResearch on DKD risk prediction models for patients with type 2 diabetes in China is still in its initial stages, with a high overall risk of bias and a lack of clinical application. Future efforts could focus on constructing high-performance, easy-to-use prediction models based on interpretable machine learning methods and applying them in clinical settings.RegistrationThis systematic review and meta-analysis was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, a recognized guideline for such research.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42024498015.

Background: Inflammation and subsequent mitochondrial dysfunction and cell death worsen outcomes after revascularization in ischemic stroke. Receptor-interacting protein kinase 1 (RIPK1) activated dynamin-related protein 1 (DRP1) in a NLRPyrin domain containing 3 (NLRP3) inflammasome-dependent fashion and Hypoxia-Inducible Factor (HIF)-1α play key roles in the process. This study determined how phenothiazine drugs (chlorpromazine and promethazine (C + P)) with the hypothermic and normothermic modality impacts the RIPK1/RIPK3-DRP1 and HIF-1α pathways in providing neuroprotection. Methods: A total of 150 adult male Sprague-Dawley rats were subjected to 2 h middle cerebral artery occlusion (MCAO) followed by 24 h reperfusion. 8 mg/kg of C + P was administered at onset of reperfusion. Infarct volumes, mRNA and protein expressions of HIF-1α, RIPK1, RIPK3, DRP-1, NLRP3-inflammation and cytochrome c-apoptosis were assessed. Apoptotic cell death, infiltration of neutrophils and macrophages, and mitochondrial function were evaluated. Interaction between RIPK1/RIPK3 and HIF-1α/NLRP3 were determined. In SH-SY5Y cells subjected to oxygen/glucose deprivation (OGD), the normothermic effect of C + P on inflammation and apoptosis were examined. Results: C + P significantly reduced infarct volumes, mitochondrial dysfunction (ATP and ROS concentration, citrate synthase and ATPase activity), inflammation and apoptosis with and without induced hypothermia. Overexpression of RIPK1, RIPK3, DRP-1, NLRP3-inflammasome and cytochrome c-apoptosis were all significantly reduced by C + P at 33 °C and the RIPK1 inhibitor (Nec1s), suggesting hypothermic effect of C + P via RIPK1/RIPK3-DRP1pathway. When body temperature was maintained at 37 °C, C + P and HIF-1α inhibitor (YC-1) reduced HIF-1α expression, leading to reduction in mitochondrial dysfunction, NLRP3 inflammasome and cytochrome c-apoptosis, as well as the interaction of HIF-1α and NLRP3. These were also evidenced in vitro, indicating a normothermic effect of C + P via HIF-1α. Conclusion: Hypothermic and normothermic neuroprotection of C + P involve different pathways. The normothermic effect was mediated by HIF-1α, while hypothermic effect was via RIPK1/RIPK3-DRP1 signaling. This provides a theoretical basis for future precise exploration of hypothermic and normothermic neuroprotection.

The rapid rise and widespread use of short video applications (SVA) have significantly reshaped our understanding of social media, technology, and human social behavior. Particularly among young users, frequent social media usage and continuous swiping through endless video feeds have become pervasive phenomena. Using dual-process theory, this experimental study explored the psychological consequences of using SVA from two studies. Our findings contributed to the understanding of the cognitive implications of SVA use in young adults in the following ways. Watching short videos predicted less analytic thinking that could go beyond initially flawed intuitions in reasoning (Study 1). Additionally, the process of swiping through the short video feeds, rather than the video content itself, negatively influenced users’ propensity to think analytically; and the decreased positive affect mediated the effect of TikTok usage on analytic thinking (Study 2). These results showed that users should be aware that the common daily leisure activity of using short video applications increases one’s inherent tendency to fast and automatic thinking processing, which can impair their judgment and decision-making in other tasks, such as information discernment. This study indicated the negative implications of artificial intelligence agencies for young adults’ thinking processing in psychological and social domains.

Abstract Background Patients with pulmonary hypertension (PH) and chronic obstructive pulmonary disease (COPD) have an increased risk of disease exacerbation and decreased survival. We aimed to develop and validate a non‐invasive nomogram for predicting COPD associated with severe PH and a prognostic nomogram for patients with COPD and concurrent PH (COPD–PH). Methods This study included 535 patients with COPD–PH from six hospitals. A multivariate logistic regression analysis was used to analyse the risk factors for severe PH in patients with COPD and a multivariate Cox regression was used for the prognostic factors of COPD–PH. Performance was assessed using calibration, the area under the receiver operating characteristic curve and decision analysis curves. Kaplan–Meier curves were used for a survival analysis. The nomograms were developed as online network software. Results Tricuspid regurgitation velocity, right ventricular diameter, N‐terminal pro‐brain natriuretic peptide (NT‐proBNP), the red blood cell count, New York Heart Association functional class and sex were non‐invasive independent variables of severe PH in patients with COPD. These variables were used to construct a risk assessment nomogram with good discrimination. NT‐proBNP, mean pulmonary arterial pressure, partial pressure of arterial oxygen, the platelet count and albumin were independent prognostic factors for COPD–PH and were used to create a predictive nomogram of overall survival rates. Conclusions The proposed nomograms based on a large sample size of patients with COPD–PH could be used as non‐invasive clinical tools to enhance the risk assessment of severe PH in patients with COPD and for the prognosis of COPD–PH. Additionally, the online network has the potential to provide artificial intelligence‐assisted diagnosis and treatment. Highlights A multicentre study with a large sample of chronic obstructive pulmonary disease (COPD) patients diagnosed with PH through right heart catheterisation. A non‐invasive online clinical tool for assessing severe pulmonary hypertension (PH) in COPD. The first risk assessment tool was established for Chinese patients with COPD–PH.

To date, the definition that the off-label usage of drugs refers to the unapproved use of approved drugs, which covers unapproved indications, patient populations, doses, and/or routes of administration, has been in existence for many years. Currently, there is a limited frequency and prevalence of research on the off-label use of antineoplastic drugs, mainly due to incomplete definition and classification issues. It is time to embrace new categories for the off-label usage of anticancer drugs. This review provided an insight into an updated overview of the concept and categories of the off-label use of anticancer drugs, along with illustrating specific examples to establish the next studies about the extent of the off-label usage of anticancer drugs in the oncology setting. The scope of the off-label use of current anticancer drugs beyond the previous definitions not only includes off-label uses in terms of indications, patient populations, doses, and/or routes of administration but also off-label use in terms of medication course, combination, sequence of medication, clinical purpose, contraindications scenarios, etc. In addition, the definition of the off-label usage of anticancer drugs should be added to the condition at a given time, and it varies from approval authorities. We presented a new and relatively comprehensive classification, providing extensive analysis and illustrative examples of the off-label usage of antineoplastic drugs for the first time. Such a classification has the potential to promote practical adoption and enhance management strategies for the off-label use of antitumor drugs.

Early molecular response (EMR) at 3 months is predictive of improved overall survival (OS) and progression-free survival (PFS) in patients with chronic myeloid leukemia in the chronic phase (CML-CP). Although about one-third of patients treated with first-line imatinib do not achieve EMR, long-term OS and PFS are still observed in most patients. DASCERN (NCT01593254) is a prospective, phase IIb, randomized trial evaluating a switch to dasatinib in patients who have not achieved EMR after 3 months of treatment with first-line imatinib. Early analysis demonstrated an improved major molecular response (MMR) rate at 12 months with dasatinib versus imatinib (29% vs. 13%, P=0.005). Here, we report results from the final 5-year follow-up. In total, 174 patients were randomized to dasatinib and 86 to remain on imatinib. Forty-six (53%) patients who remained on imatinib but subsequently experienced failure were allowed to cross over to dasatinib per protocol. At a minimum follow-up of 60 months, the cumulative MMR rate was significantly higher in patients randomized to dasatinib versus imatinib (77% vs. 44%, P

Objective: Bendamustine was approved for treating chronic lymphocytic leukemia and indolent B-cell non-Hodgkin lymphoma. Despite its therapeutic benefits, the long-term safety of bendamustine in a large population remains inadequately understood. This study evaluates the adverse events (AEs) associated with bendamustine, using a real-world pharmacovigilance database to support its clinical application.Methods: We conducted a post-marketing risk analysis to assess the association between bendamustine and its AEs. Data were extracted from the US FDA’s Adverse Event Reporting System (FAERS), covering the period from January 2017 to September 2023. The characteristics of bendamustine-associated AEs and the onset time were further analyzed. Statistical analysis was performed using MYSQL 8.0, Navicat Premium 15, Microsoft EXCEL 2016, and Minitab 21.0.Results: 9,461,874 reports were collected from the FAERS database, 9,131 identified bendamustine as the “primary suspected” drug. We identified 331 significant disproportionality preferred terms (PTs). Common AEs included pyrexia, neutropenia, infusion site reaction, progressive multifocal leukoencephalopathy (PML), injection site vasculitis, and pneumonia—all documented on bendamustine’s label. Notably, 16 unexpected and significant AEs were discovered, including hypogammaglobulinemia, which is concerning due to its potential to increase infection susceptibility following bendamustine treatment. Other significant findings were anaphylactic reactions, PML, and cutaneous malignancies, suggesting updates to the drug’s label may be necessary. Physicians should monitor for neurological and skin changes in patients and discontinue treatment if PML is suspected. Moreover, the median onset time for bendamustine-associated AEs was 13 days, with an interquartile range [IQR] of 0–59 days, predominantly occurring on the first day post-initiation. The β of bendamustine-related AEs suggested risk reduction over time.Conclusion: Our study uncovered some potential pharmacovigilance signals for bendamustine, providing important insights for its safe and effective clinical use.

The evolution of inclusions in molten steel in tundish before and after vacuum treatment during the production of GCr15 bearing steel in a steel plant is analyzed， the results showed that total oxygen content in molten steel increased greatly in tundish. Magnesium aluminum Spinel inclusions increased in RH soft blowing and tundish to varying degrees， and the number increased significantly in tundish. The MgO aggregate particles in the working layer of the tundish coating are greatly reduced， and some MgO particles are dissolved in the molten steel， resulting in the increase of oxygen content in the molten steel.The effect of different SiO2 content on the phase of tundish coating was discussed by thermodynamic simulation analysis. It was proposed that the control of SiO2 content at range 4%~6% and the strengthening of tundish masonry management can reduce the formation of high temperature low melting phase in tundish coating and effectively improve the flaw detection eligibility rate of bearing steel GCr15 head slab.

Abstract Objective To develop a Risk Assessment Tool for Cancer-related Venous Thrombosis in China. Methods A modified two-round Delphi method was employed to establish consensus within a field to reach an agreement via a questionnaire or by interviewing a multidisciplinary panel of experts by collecting their feedback to inform the next round, exchanging their knowledge, experience, and opinions anonymously, and resolving uncertainties. Furthermore, The AHP (Analytic Hierarchy Process) was used to determine the final quality indicators’ relative importance. Results The expert’s positive coefficient was 85.19% in the first round and 82.61% in the second round, with authoritative coefficients of 0.89 and 0.92 in the respective surveys. The P-value of Kendall’s W test was all less than 0.001 for each round, and the W-value for concordance at the end of the two rounds was 0.115. The final Risk Assessment Tool for Cancer-related Venous Thrombosis consisted of three domains, ten subdomains, and 39 indicators, with patient factors weighing 0.1976, disease factors weighing 0.4905, and therapeutic factors weighing 0.3119. Conclusion The tool is significantly valid and reliable with a strong authority and coordination degree, and it can be used to assess the risk of cancer-related VTE and initiate appropriate thrombophylactic interventions in China.

Abstract Extracellular vesicles (EVs) have gained increasing recognition as significant regulators of intercellular communication in various physiological and pathological processes. These vesicles play a pivotal role in cancer progression by facilitating the transfer of diverse cargoes, including lipids, proteins, and nucleic acids. Regulated cell death (RCD), the orderly and autonomous death of cells, is controlled by a variety of biomacromolecules and, in turn, influences various biological processes and cancer progression. Recent studies have demonstrated that EV cargoes regulate diverse oncogenes and tumor suppressors to mediate different nonapoptotic forms of RCD, notably ferroptosis, pyroptosis, and necroptosis. Nevertheless, comprehensive exploration of EV-mediated nonapoptotic RCD forms in the context of cancer has not been performed. This review summarizes the progress regarding the biological functions and underlying mechanisms of EVs in mediating nonapoptotic RCD by delivery of cargoes to regulate tumor progression. Additionally, the review delves into the potential clinical applications of EV-mediated cell death and its significance in the areas of cancer diagnosis and therapy.

In this paper, large-scale energy storage system(ESS) is taken as the research object to conduct study of business models on the participation of ESS in electricity spot market with liberalization. First, based on the typical market clearing mechanism at home and abroad, the clearing method, clearing calculation process and so on in day-ahead market and real-time balance market are analyzed, and a joint clearing mechanism suitable for large-scale ESS to participate in the spot market is proposed, including bidding method, billing method and clearing method, etc. Then, in order to fully explore the market value and other added value of large-scale ESS, to enhance cluster effect and to solve the problem of idle ESS capacity, business models suitable for large-scale ESS to participate in the spot market are proposed, including independent (single investment entity, single service model), alliance (diversified investment entities, single service model), and shared (diversified investment entities, diversified service models) models. The game relationship in the market transaction chain is analyzed, of which the electric energy value, the ancillary service value, and other added value are quantified. On this basis, a bilevel clearing model paradigm for ESS to participate in the spot joint market of different business models is constructed based on the master-slave game. In the upper-level model, large-scale ESS is the leader to participate in market competition with the goal of maximizing profits, while the dispatching and trading center in the lower-level model are followers to jointly clear the market with the goal of maximizing social welfare. Finally, the validity and feasibility of the proposed business models are verified by taking typical transaction scenarios as examples based on the improved IEEE30 node system.

Abstract Background Effective exercise for the frail elderly has been found to contribute to healthy aging; the corresponding relationship between intensity and volume of exercise and health effects remains unclear. The present study aimed to investigate the dose–response effects of resistance training on muscle strength and physical fitness in frail older adults. Methods In this randomized controlled trial, participants were randomized into seven groups: moderate‐volume low‐intensity, moderate‐volume moderate‐intensity, moderate‐volume high‐intensity, high‐volume low‐intensity, high‐volume moderate‐intensity, high‐volume high‐intensity and routine care, receiving 12 weeks of resistance training of different intensities and volumes of exercise. The outcomes were muscle strength (assessed by ergonomics force gauges) and physical fitness function (assessed by the 6‐min walking test [6MWT], the 30‐s sit‐to‐stand test [30sSTST] and the 8‐foot up‐and‐go test [8‐FUGT]) before and at 6 and 12 weeks of intervention. Results A total of 161 participants completed the exercise intervention. There were no significant differences in age, sex, height, body weight and body mass index among the seven groups. The exercise volume of resistance training showed linear relationships with muscle strength of the lower limbs, 30sSTST and 6MWT results and a non‐linear relationship with 8‐FUGT. Resistance training intensity was found to have a linear relationship with muscle strength of the lower limbs and 6MWT and non‐linear relationships with 30sSTST and 8‐FUGT. The mixed linear model analysis revealed that the lower limb muscle strength differed significantly before and during the intervention (W = 8571.5, Padj

Piglets are particularly susceptible to oxidative stress, which causes inferior growth performance and intestinal damage. Squalene (SQ), a natural bioactive substance enriched in shark liver oil, shows excellent antioxidant properties and can currently be obtained at a low cost from deodorizer distillate during the production of plant oil. This study aimed to evaluate the effects of plant-derived SQ supplementation on the growth performance of piglets and explore the beneficial roles of SQ against oxidative stress and intestinal injury in diquat-challenged piglets. Forty piglets were randomly divided into five groups and fed a basal diet supplemented with SQ at 0, 500, 1000, or 2000 mg/kg for 5 weeks. Acute oxidative stress was induced in the piglets with diquat (10 mg/kg BW) at the fourth week of the experiment, followed by a 7-d recovery period. Results showed that before the diquat challenge, SQ supplementation significantly improved growth performance (average daily gain and feed conversion ratio) and serum antioxidant status, and after the diquat challenge, SQ supplementation significantly mitigated diquat-induced growth arrest, intestinal villous atrophy, intestinal epithelial cell apoptosis, intestinal hyperpermeability, and deficiency of intestinal epithelial tight junction proteins (zonula occludens-1, occludin, and claudin-3). Under oxidative stress induced by diquat, SQ supplementation consistently improved the antioxidant status of the small intestine, liver, and muscle. In vitro, SQ was shown to alleviate hydrogen peroxide (H2O2)-induced increase of the levels of intracellular reactive oxygen species and apoptosis of porcine intestinal epithelial cells. Taken together, SQ supplementation improves growth performance and effectively alleviates acute oxidative stress-induced growth retardation and intestinal injury via improving antioxidant capacity in piglets. Our findings may provide an efficient strategy for alleviating oxidative stress-induced inferior growth performance and intestinal damage in piglets.

Tryptophan (Trp) is an essential amino acid that cannot be synthesized by animals. It has been characterized into two different isomers, levorotation-Trp (L-Trp) and dextrorotation-Trp (D-Trp), based on their distinct molecule orientation. Intestinal epithelial cells and gut microbiota are involved in metabolizing L-Trp in the gut via the activation of the kynurenine, serotonin, and indole pathways. However, knowledge regarding D-Trp metabolism in the gut remains unclear. In this review, we briefly update the current understanding of intestinal L/D-Trp metabolism and the function of their metabolites in modulating the gut physiology and diseases. Finally, we summarize the effects of Trp nutrition on swine production at different stages, including growth performance in weaned piglets and growing pigs, as well as the reproduction performance in sows.

Deoxynivalenol (DON), a toxic secondary metabolite produced by Fusarium species that mainly infect cereals, causes huge economic loss to the agricultural industry. Biodegradation has emerged as a promising method owing to its high efficiency, specificity, and environment-friendly. The present study reports the procedures for obtaining a bacterial consortium YM-1 from the intestines of free-range chickens by anaerobic culture in Luria-Bertani (LB) and 96-well plates. The YM-1, mainly composed of Proteus_vulgaris, Tissierella_praeacuta, Fusobacterium_varium, uncultured_bacterium_g_Peptoniphilus, Bacteroides_uniformis, Bacteroides_vulgatus, Bacteroides_thetaiotaomicron, Clostridium_cochlearium, and Eubacterium_limosum, was able to effectively de-epoxidize 50 μg/mL DON by 99.2 % within 24 h under an anaerobic condition. The viability of the intestinal porcine epithelial cell line-J2 (IPEC-J2) was significantly damaged under 0.5 μg/mL, 1 μg/mL, or 2 μg/mL DON exposure. The products of DON degraded by YM-1, mainly consisting of de-epoxy-deoxynivalenol (DOM-1), were validated to be non-toxic to the IPEC-J2 cells. These results indicate the potential use of bacterial consortium YM-1 as a bio-agent for DON decontamination in foods and feeds.

Background:Depressive disorder is a common disease characterized by depressed mood and loss of pleasure, which often brings a great grief to patients and a huge burden to the society. Currently, the therapeutic strategy has made a rapid progress, but even the most well-studied and commonly used antidepressants will take weeks to produce a desired effect and have some side-effects. Besides, the objective and specific diagnostic indexes are still absent. Many important hypotheses have been proposed and inflammation is one of them. Among the inflammatory cytokines that might be closely related to depression, HMGB1 is a novel and vital one.Methods:We reviewed and analyzed literature on PubMed and web of science using the relevant key words ( "depression/MDD" in conjunction with "HMGB1/high mobility group box 1).Results:We found that both clinical and laboratory studies demonstrated pro-inflammatory role of HMGB1 in depressive disorder, while conditional knockout or inhibition of HMGB1 could alleviate inflammation and depression.Conclusion:Therefore, in this review we will talk about the possible role of HMGB1 in the development of depressive disorder and the underlying mechanisms with the hope of providing evidence for a novel and effective therapy for depressive disorder.

Abstract Background Cervical cancer (CC) is the fourth most common cancer in women worldwide. Although immunotherapy has been applied in clinical practice, its therapeutic efficacy remains far from satisfactory, necessitating further investigation of the mechanism of CC immune remodeling and exploration of novel treatment targets. This study aimed to investigate the mechanism of CC immune remodeling and explore potential therapeutic targets. Methods We conducted single‐cell RNA sequencing on a total of 17 clinical specimens, including normal cervical tissues, high‐grade squamous intraepithelial lesions, and CC tissues. To validate our findings, we conducted multicolor immunohistochemical staining of CC tissues and constructed a subcutaneous tumorigenesis model in C57BL/6 mice using murine CC cell lines (TC1) to evaluate the effectiveness of combination therapy involving indoleamine 2,3‐dioxygenase 1 (IDO1) inhibition and immune checkpoint blockade (ICB). We used the unpaired two‐tailed Student's t‐test, Mann‐Whitney test, or Kruskal‐Wallis test to compare continuous data between two groups and one‐way ANOVA with Tukey's post hoc test to compare data between multiple groups. Results Malignant cervical epithelial cells did not manifest noticeable signs of tumor escape, whereas lysosomal‐associated membrane protein 3‐positive (LAMP3+) dendritic cells (DCs) in a mature state with immunoregulatory roles were found to express IDO1 and affect tryptophan metabolism. These cells interacted with both tumor‐reactive exhausted CD8+ T cells and CD4+ regulatory T cells, synergistically forming a vicious immunosuppressive cycle and mediating CC immune escape. Further validation through multicolor immunohistochemical staining showed co‐localization of neoantigen‐reactive T cells (CD3+, CD4+/CD8+, and PD‐1+) and LAMP3+ DCs (CD80+ and PD‐L1+). Additionally, a combination of the IDO1 inhibitor with an ICB agent significantly reduced tumor volume in the mouse model of CC compared with an ICB agent alone. Conclusions Our study suggested that a combination treatment consisting of targeting IDO1 and ICB agent could improve the therapeutic efficacy of current CC immunotherapies. Additionally, our results provided crucial insights for designing drugs and conducting future clinical trials for CC.

Medicinal herbs can be used for the development of antioxidant and anticancer platforms. However, the mechanisms by which the bioactive materials show these properties remain largely unclear. Also, a detailed understanding of the interaction between small compounds and carrier proteins like albumin can provide useful information about the regulation of their stability and circulation time properties. In this paper, the interaction of rhamnazin (C17H14O7), an O-methylated flavonol exists in Rhamnus petiolaris, with human serum albumin (HSA) was investigated. Also, the antioxidant and anti-lung cancer effects of rhamnazin were assessed. The results showed that a static rhamnazin-HSA complex was formed by the contribution of hydrophobic forces, which led to an increase in the content of the α-helix structure of HSA. Cellular assays revealed that rhamnazin (10 µM) recovered cell viability in human proximal renal tubular epithelial cells (HK2) reduced by H2O2 (0.5 mM) through reduction of ROS, restoration of CAT and SOD activities and GSH content, regulation of Bax, Bcl-2, and caspase-3. Moreover, the anti-lung cancer data demonstrated that rhamnazin induced apoptosis on lung adenocarcinoma A549 cells associated with a p53-dependent manner via overexpression of apoptotic Bax and caspase-3 and down-regulation of anti-apoptotic Bcl-2. To summarize, the potential binding of rhamnazin and HSA, as well as its antioxidant/anticancer properties, are critical for understanding the solubility and stability of this bioactive compound in plasma, as well as its therapeutic implications.

Current treatments for neurodegenerative diseases and neural injuries face major challenges, primarily due to the diminished regenerative capacity of neurons in the mammalian CNS as they mature. Here, we investigated the role of Ezh2, a histone methyltransferase, in regulating mammalian axon regeneration. We found that Ezh2 declined in the mouse nervous system during maturation but was upregulated in adult dorsal root ganglion neurons following peripheral nerve injury to facilitate spontaneous axon regeneration. In addition, overexpression of Ezh2 in retinal ganglion cells in the CNS promoted optic nerve regeneration via both histone methylation-dependent and -independent mechanisms. Further investigation revealed that Ezh2 fostered axon regeneration by orchestrating the transcriptional silencing of genes governing synaptic function and those inhibiting axon regeneration, while concurrently activating various factors that support axon regeneration. Notably, we demonstrated that GABA transporter 2, encoded by Slc6a13, acted downstream of Ezh2 to control axon regeneration. Overall, our study underscores the potential of modulating chromatin accessibility as a promising strategy for promoting CNS axon regeneration., Introduction Axon degeneration and neuronal cell death are common consequences of neurodegenerative diseases and neural injuries. Unfortunately, current clinical therapeutics for neural injuries and neurodegenerative diseases still fall short of [...]

A fundamental vision technique for industrial robots involves the six degrees of freedom pose estimation of target objects from a single image. However, the direct estimation of the six degrees of freedom object pose solely from a single image is subject to limited accuracy. Various refinement approaches have been proposed to improve the accuracy by utilizing rendered images from a 3D model. Nevertheless, balancing speed and accuracy in an industrial setting remains a challenge for these methods. In this study, we propose a novel six degrees of freedom pose refinement approach centered around matching real image patches. Unlike previous approaches, our method does not rely on a 3D model, resulting in increased speed and accuracy. In the offline phase, we construct an offline database using image patches obtained from real images. During the inference phase, our method initially identifies the image patch within the offline database that is closest to the initial pose. Subsequently, we refine the six degrees of freedom pose by matching the corresponding image patches from the offline database. Experimental results indicate that our six degrees of freedom pose refinement method achieves real-time capability with a frame rate of 71 Frames Per Second (FPS), along with high precision. When the threshold is set to 0.5% of the object diameter, the average distance of dots score on the test data surpasses 70%. Moreover, experiments involving gripping and assembling tasks on an industrial robot demonstrate the ability of our method to autonomously select appropriate grasping angles and positions in real time. It further generates suitable motion paths, ultimately ensuring production efficiency.

Background: Previous studies have shown that MCM3 plays a key role in initiating DNA replication. However, the mechanism of MCM3 function in most cancers is still unknown. The aim of our study was to explore the expression, prognostic role, and immunological characteristics of MCM3 across cancers.Methods: We explored the expression pattern of MCM3 across cancers. We subsequently explored the prognostic value of MCM3 expression by using univariate Cox regression analysis. Spearman correlation analysis was performed to determine the correlations between MCM3 and immune-related characteristics, mismatching repair (MMR) signatures, RNA modulator genes, cancer stemness, programmed cell death (PCD) gene expression, tumour mutation burden (TMB), microsatellite instability (MSI), and neoantigen levels. The role of MCM3 in predicting the response to immune checkpoint blockade (ICB) therapy was further evaluated in four immunotherapy cohorts. Single-cell data from CancerSEA were analysed to assess the biological functions associated with MCM3 in 14 cancers. The clinical correlation and independent prognostic significance of MCM3 were further analysed in the TCGA and CGGA lower-grade glioma (LGG) cohorts, and a prognostic nomogram was constructed. Immunohistochemistry in a clinical cohort was utilized to validate the prognostic utility of MCM3 expression in LGG.Results: MCM3 expression was upregulated in most tumours and strongly associated with patient outcomes in many cancers. Correlation analyses demonstrated that MCM3 expression was closely linked to immune cell infiltration, immune checkpoints, MMR genes, RNA modulator genes, cancer stemness, PCD genes and the TMB in most tumours. There was an obvious difference in outcomes between patients with high MCM3 expression and those with low MCM3 expression in the 4 ICB treatment cohorts. Single-cell analysis indicated that MCM3 was mainly linked to the cell cycle, DNA damage and DNA repair. The expression of MCM3 was associated with the clinical features of LGG patients and was an independent prognostic indicator. Finally, the prognostic significance of MCM3 in LGG was validated in a clinical cohort.Conclusion: Our study suggested that MCM3 can be used as a potential prognostic marker for cancers and may be associated with tumour immunity. In addition, MCM3 is a promising predictor of immunotherapy responses.

The injection of early dark energy (EDE) before the recombination, a possible resolution of the Hubble tension, will not only shift the scalar spectral index ns towards ns=1, but also be likely to tighten the current upper limit on tensor-to-scalar ratio r. In this work, with the latest CMB datasets (Planck PR4, ACT, SPT and BICEP/Keck), as well as BAO and SN, we confirm this result, and discuss its implication on inflation. We also show that if we happen to live with EDE, how the different inflation models currently allowed would be distinguished by planned CMB observations, such as CMB-S4 and LiteBIRD.