A step towards 6D WAXD tensor tomography.

X-ray scattering/diffraction tensor tomography techniques are promising methods to acquire the 3D texture information of heterogeneous biological tissues at micrometre resolution. However, the methods suffer from a long overall acquisition time due to multi-dimensional scanning across real and reciprocal space. Here, a new approach is introduced to obtain 3D reciprocal information of each illuminated scanning volume using mathematic modeling, which is equivalent to a physical scanning procedure for collecting the full reciprocal information required for voxel reconstruction. The virtual reciprocal scanning scheme was validated by a simulated 6D wide-angle X-ray diffraction tomography experiment. The theoretical validation of the method represents an important technological advancement for 6D diffraction tensor tomography and a crucial step towards pervasive applications in the characterization of heterogeneous materials.

Anisotropic composite aerogel with thermal insulation and flame retardancy from cellulose nanofibers, calcium alginate and boric acid.

With the increasing severity of energy shortages and environmental pollution, there is an urgent need for advanced thermal insulation materials with excellent comprehensive performance, including low thermal conductivity, high flame resistance, and strong compressive strength. Herein, an anisotropic composite aerogel based on cellulose nanofibers (CNF), calcium alginate (CA), and boric acid (BA) is fabricated using a directional freeze-drying strategy. The CA and BA, as double cross-linking agents, associated with oriented porous structure provide the resultant aerogel with good mechanical strength. Additionally, self-flame retardant CA and BA act as synergistic flame retardants that endow the aerogel with excellent flame retardance properties such as a limiting oxygen index value of 44.2 %, UL-94 V-0 rating, and low heat release. Furthermore, this composite aerogel exhibits outstanding thermal insulation performance with a low thermal conductivity of approximately 30 mW m-1 K-1. Therefore, the composite aerogel is expected to have a wide potential application in areas such as construction, automotive industry, batteries, petrochemical pipelines, and high-temperature reaction devices.

Guanidinoacetic acid ameliorates hepatic steatosis and inflammation and promotes white adipose tissue browning in middle-aged mice with high-fat-diet-induced obesity.

Guanidinoacetic acid (GAA) is a naturally occurring amino acid derivative that plays a critical role in energy metabolism. In recent years, a growing body of evidence has emerged supporting the importance of GAA in metabolic dysfunction. Hence, we aimed to investigate the effects of GAA on hepatic and adipose tissue metabolism, as well as systemic inflammatory responses in obese middle-aged mice models and attempted to explore the underlying mechanism. We found that dietary supplementation of GAA inhibited inguinal white adipose tissue (iWAT) hypertrophy in high-fat diet (HFD)-fed mice. In addition, GAA supplementation observably decreased the levels of some systemic inflammatory factors, including IL-4, TNF-α, IL-1ß, and IL-6. Intriguingly, GAA supplementation ameliorated hepatic steatosis and lipid deposition in HFD-fed mice, which was revealed by decreased levels of TG, TC, LDL-C, PPARγ, SREBP-1c, FASN, ACC, FABP1, and APOB and increased levels of HDL-C in the liver. Moreover, GAA supplementation increased the expression of browning markers and mitochondrial-related genes in the iWAT. Further investigation showed that dietary GAA promoted the browning of the iWAT via activating the AMPK/Sirt1 signaling pathway and might be associated with futile creatine cycling in obese mice. These results indicate that GAA has the potential to be used as an effective ingredient in dietary interventions and thus may play an important role in ameliorating and preventing HFD-induced obesity and related metabolic diseases.

KIF5B-mediated internalization of FMDV promotes virus infection.

Foot-and-mouth disease (FMD) is a highly contagious and economically important disease, which is caused by the FMD virus (FMDV). Although the cell receptor for FMDV has been identified, the specific mechanism of FMDV internalization after infection remains unknown. In this study, we found that kinesin family member 5B (KIF5B) plays a vital role during FMDV internalization. Moreover, we confirmed the interaction between KIF5B and FMDV structural protein VP1 by co-immunoprecipitation (Co-IP) and co-localization in FMDV-infected cells. In particular, the stalk [amino acids (aa) 413-678] domain of KIF5B was indispensable for KIF5B-VP1 interaction. Moreover, overexpression of KIF5B dramatically enhanced FMDV replication; consistently, knockdown or knockout of KIF5B suppressed FMDV replication. Furthermore, we also demonstrated that KIF5B promotes the internalization of FMDV via regulating clathrin uncoating. KIF5B also promotes the transmission of viral particles to early and late endosomes during the early stages of infection. In conclusion, our results demonstrate that KIF5B promotes the internalization of FMDV via regulating clathrin uncoating and intracellular transport. This study may provide a new therapeutic target for developing FMDV antiviral drugs.

Dysregulated fibrinolysis and plasmin activation promote the pathogenesis of osteoarthritis.

Joint injury is associated with risk for development of osteoarthritis (OA). Increasing evidence suggests that activation of fibrinolysis is involved in OA pathogenesis. However, the role of the fibrinolytic pathway is not well understood. Here, we showed that the fibrinolytic pathway, which includes plasminogen/plasmin, tissue plasminogen activator, urokinase plasminogen activator (uPA), and the uPA receptor (uPAR), was dysregulated in human OA joints. Pharmacological inhibition of plasmin attenuated OA progression after a destabilization of the medial meniscus in a mouse model whereas genetic deficiency of plasmin activator inhibitor, or injection of plasmin, exacerbated OA. We detected increased uptake of uPA/uPAR in mouse OA joints by microPET/CT imaging. In vitro studies identified that plasmin promotes OA development through multiple mechanisms, including the degradation of lubricin and cartilage proteoglycans and induction of inflammatory and degradative mediators. We showed that uPA and uPAR produced inflammatory and degradative mediators by activating the PI3K, 3'-phosphoinositide-dependent kinase-1, AKT, and ERK signaling cascades and activated matrix metalloproteinases to degrade proteoglycan. Together, we demonstrated that fibrinolysis contributes to the development of OA through multiple mechanisms and suggested that therapeutic targeting of the fibrinolysis pathway can prevent or slow development of OA.

Vitamin A regulates mitochondrial biogenesis and function through p38 MAPK-PGC-1α signaling pathway and alters the muscle fiber composition of sheep.

BACKGROUND: Vitamin A (VA) and its metabolite, retinoic acid (RA), are of great interest for their wide range of physiological functions. However, the regulatory contribution of VA to mitochondrial and muscle fiber composition in sheep has not been reported. METHOD: Lambs were injected with 0 (control) or 7,500 IU VA palmitate into the biceps femoris muscle on d 2 after birth. At the age of 3 and 32 weeks, longissimus dorsi (LD) muscle samples were obtained to explore the effect of VA on myofiber type composition. In vitro, we investigated the effects of RA on myofiber type composition and intrinsic mechanisms. RESULTS: The proportion of type I myofiber was greatly increased in VA-treated sheep in LD muscle at harvest. VA greatly promoted mitochondrial biogenesis and function in LD muscle of sheep. Further exploration revealed that VA elevated PGC-1α mRNA and protein contents, and enhanced the level of p38 MAPK phosphorylation in LD muscle of sheep. In addition, the number of type I myofibers with RA treatment was significantly increased, and type IIx myofibers was significantly decreased in primary myoblasts. Consistent with in vivo experiment, RA significantly improved mitochondrial biogenesis and function in primary myoblasts of sheep. We then used si-PGC-1α to inhibit PGC-1α expression and found that si-PGC-1α significantly abrogated RA-induced the formation of type I myofibers, mitochondrial biogenesis, MitoTracker staining intensity, UQCRC1 and ATP5A1 expression, SDH activity, and enhanced the level of type IIx muscle fibers. These data suggested that RA improved mitochondrial biogenesis and function by promoting PGC-1α expression, and increased type I myofibers. In order to prove that the effect of RA on the level of PGC-1α is caused by p38 MAPK signaling, we inhibited the p38 MAPK signaling using a p38 MAPK inhibitor, which significantly reduced RA-induced PGC-1α and MyHC I levels. CONCLUSION: VA promoted PGC-1α expression through the p38 MAPK signaling pathway, improved mitochondrial biogenesis, and altered the composition of muscle fiber type.

[Efficacy and radiology evaluation of pulpotomy in mature permanent teeth].

OBJECTIVE: To observe the clinical efficacy of pulpotomy in patients of different ages and to explore the occurrence and characteristics of pulpal calcification. METHODS: A total of 77 patients who underwent pulpotomy for mature permanent premolars and molars with caries-derived pulp exposure in the Department of General Dentistry, Peking University School and Hospital of Stomatology from October 2019 to August 2022 were selected. Pulpotomies were performed in a single visit using iRoot BP Plus bioceramic material as pulp capping agent. The patients were divided into three groups according to age: 25 cases in the adolescent group (11-20 years old) with a mean age of (15.88±2.19) years; 27 cases in the middle-aged group (21-50 years old) with a mean age of (34.59±8.67) years; and 25 cases in the elder-aged group (51-83 years old) with a mean age of (63.84±7.40) years. The patients were reviewed 1 year after the operation to evaluate the clinical efficacy and to record the formation of calcified bridge, thickness of calcified bridge, and pulp calcification index (PCI). RESULTS: There was no statistically significant difference between the three groups in terms of gender, dentition, and tooth position (P > 0.05). The 1-year postoperative follow-up rate was 85.71% (66/77), including 88.00% (22/25) in the adolescent group, 85.19% (23/27) in the middle-aged group, and 84.00% (21/25) in the elder-aged group. The 1-year follow-up clinical success rates of the three groups were 95.45% (21/22), 91.30% (21/23), and 95.24% (20/21), respectively, with no statistically significant difference (P>0.05). Among the clinical success cases, calcified bridges appeared in 12 cases (57.14%, 12/21) in the adolescent group, 8 cases (38.10%, 8/21) in the middle-aged group, and 3 cases (15.00%, 3/20) in the elder-aged group, with statistically significant differences (χ2= 7.810, P = 0.020 < 0.05). The difference was statistically significant (F = 4.434, P = 0.020 < 0.05) when comparing the thickness of calcified bridges among the three groups. Calcified bridge thickness was negatively correlated with age (r = -0.516, P < 0.05). The changes in pulpal calcification index ΔPCI were 0.67 ± 0.58, 0.43 ± 0.51, and 0.25 ± 0.52, respectively, with statistically significant differences among the three groups (F = 3.404, P = 0.040 < 0.05). CONCLUSION: Pulpotomy for caries-derived pulp exposure in elderly patients could also achieve a high success rate. The incidence of calcified bri-dges after pulpotomy and the acceleration of pulpal calcification were age-related. The adolescent group was more likely to form calcified bridges and also showed more pronounced accelerated root canal calcification.

Application of near-infrared fluorescence imaging with indocyanine green in mediastinal surgery.

Intraoperative near-infrared (NIR) fluorescence imaging has emerged in recent years and is now used in many surgical procedures. Intraoperative fluorescence imaging can guide surgeons in identifying and localizing specific structures and boundaries, which can facilitate the optimization of surgical procedures. The components of the mediastinum are complex and functionally important, making identifying and locating different structures intraoperatively challenging, and NIR fluorescence imaging has potential clinical value in mediastinal surgery. Here we review the applications of NIR fluorescence imaging technology in mediastinal surgery in recent years.

Novel insights into the role of leaf in the cutting process of Camellia sinensis using physiological, biochemical and transcriptome analyses.

Cuttage is the preferred approach for rapid propagation of many species including tea plant (Camellia sinensis). Leaf serves as a key part of nodal cutting, but there is a lack of systematic research on its role in the cutting process. In this study, 24 tea cultivars were employed to prove the necessity of leaf and light during cuttage. Further leaf physiological parameters found that lower net photosynthesis rate probably promoted rooting. Phytohormone content detection showed that auxin content and composition pattern were related to rooting ability. Leaf transcriptome analyses of cuttings from a representative easy-to-root cultivar (cv. Echa 10) revealed that genes involved in carbohydrate metabolism, signal transduction, metabolite biosynthesis and transportation were differentially expressed during the rooting process. CsTSA1, CsYUC10, CsAUX1s, CsPIN3 and CsPIN5 were selected as the candidate genes, which possibly regulate the rooting of nodal cuttings. These results illustrate the necessity of the leaf in cuttage and provide molecular evidence that leaf is an important place for signal transduction, metabolite synthesis and transport during the rooting process.

Melanin-Based Immunoregulatory Nanohybrids Enhance Antitumor Immune Responses in Breast Cancer Mouse Model.

Natural melanin nanoparticles (MNPs) have demonstrated a potential for eliciting antitumor immune responses through inducing immunogenic cell death (ICD); however, the tumor microenvironment (TME) has been shown to inhibit T cell-mediated antitumor immunity. To address this challenge, we designed TME-responsive biodegradable melanin/MnOx nanohybrids via a biomineralization process. Under near-infrared (NIR) light irradiation, the photothermal property of melanin/MnOx nanohybrids triggers ICD and release of tumor-associated antigens (TAAs), while Mn2+ and TAAs induce dendritic cell (DC) maturation to provoke immune responses. Furthermore, the immunoregulatory properties of the nanohybrids themselves are exploited to reshape immunosuppressive TME and downregulate PD-L1 through alleviation of the hypoxic and acidic TME. Although MNPs demonstrate higher photothermal killing efficiency than the nanohybrids in vitro due to their superior photothermal effect, the melanin/MnOx nanohybrids exhibit significantly enhanced antitumor and antimetastatic effects in vivo, benefiting from their ability to reverse immunosuppression and induce DC maturation. Transcriptomics analysis confirmed the successful activation of immune responses. This work presents a promising approach for immunomodulation-enhanced cancer therapy through the intrinsic properties of melanin/MnOx nanohybrids.

Treatment Durations and Whitening Outcomes of Different Tooth Whitening Systems.

Background and Objectives: Tooth whitening is a relatively conservative and effective option to treat discolored teeth. However, questions remain whether in-office or at-home tooth whitening products with short treatment durations are as effective and stable as products with longer treatment durations. Materials and Methods: Forty human third molars with intact enamel surfaces were divided into four groups of ten each, subjected to discoloration challenges with coffee for 60 h, and they were treated with four professional tooth whitening systems: two for take-home use-6% hydrogen peroxide for 30 min/d for a total of 7 h in 14 days (HP6), 10% carbamide peroxide for 10 h/d for 140 h in 14 days (CP10), as well as two for in-office use-35% HP for 10 min × 3 (HP35) for a total of 30 min and 40% HP for 20 min × 3 (HP40) for a total of 60 min. Teeth colors were assessed in the CIE L*a*b* color space with a spectrophotometer immediately and six months after whitening treatments. Surface roughness (Sa) for the treated and untreated enamel surfaces of the teeth in all groups were evaluated with a three-dimensional laser scanning microscope after six months. Results: No significant differences were found between HP6 and CP10 groups immediately after whitening (∆E 10.6 ± 1.6 vs. 11.4 ± 1.7, p > 0.05) and at six months after treatments (∆E 9.0 ± 1.9 vs. 9.2 ± 2.5, p > 0.05), or between HP35 and HP40 groups immediately after whitening (∆E 5.9 ± 1.2 vs. 5.3 ± 1.7, p > 0.05) and at six months after treatments (∆E 7.2 ± 1.6 vs. 7.7 ± 1.3, p > 0.05). The two at-home whitening systems achieved significantly better whitening outcomes than the two in-office products immediately after whitening (p < 0.05). However, at six months after treatments, the differences between at-home and in-office treatments had narrowed significantly (p > 0.05). There were no statistically significant differences with respect to the Sa values between the treated and untreated surfaces (p > 0.05). Conclusions: Tooth whitening products in the same product category have similar whitening efficacies, despite significant differences in treatment durations (7 vs. 140 h, and 30 min vs. 60 min, respectively). Take-home products achieved better whitening outcomes than in-office products, but they needed 14 to 280 times longer treatment durations.

Primary membranous nephropathy in two siblings with one combined with anti-glomerular basement membrane disease: a case report.

BACKGROUND: The phospholipase A2 receptor (PLA2R) associated with membranous nephropathy (MN) is an organ-specific autoimmune disease associated with PLA2R and human leukocyte antigen (HLA) genes. Familial PLA2R-related MN is rarely reported. The combination of anti-GBM disease and MN has been well documented, though the mechanism behind it remains unclear. CASE PRESENTATION: We describe two siblings diagnosed with pathology-confirmed PLA2R-related MN 1 year apart. And one of the two siblings developed an anti-GBM disease. The high-resolution HLA typing showed identical alleles in both siblings, specifically heterozygotes of DRB1*15:01/*03:01. CONCLUSION: We describe a familial case of PLA2R-related MN supporting the role of genetic factors that HLA-DRB1*15:01 and DRB1*03:01 predispose patients in the development of PLA2R-related MN in the Han Chinese population. The combination of MN and anti-GBM disease may also partially be associated with the same susceptible HLA allele DRB1*15:01.

The Effect of Manual Lymph Drainage and Compression Bandaging for Stage 2 Breast Cancer-Related Lymphedema: A Randomized Controlled Trial.

Aim: To explore the effect of manual lymph drainage (MLD), compression bandaging (CB), or combined decongestive therapy (CDT), including MLD and CB, on stage 2 breast cancer-related lymphedema (BCRL). Methods: Sixty women with stage 2 BCRL were enrolled. They were randomly divided into the MLD group, the CB group or the CDT group. Each group, respectively, received MLD alone, CB alone, or CDT composed of MLD and CB, for 2 weeks. The volume and the local tissue water (LTW) of affected arms were measured before and after treatment. Arm circumferences were measured at 4 cm interval starting from the wrist to the shoulder with a tape measure. LTW was detected using the (tissue dielectric constant, TDC) method and was expressed as TDC value in two sites on the ventral midpoint of upper arm and forearm. Results: The volume of affected arms in each group after 2-weeks' treatment was lower than their baseline and the difference was statistically significant (p < 0.05). But there was no significant difference in volume change among three groups. The TDC value of the upper arm and forearm in the group CB and the group CDT decreased distinctly compared with baseline (p < 0.05). But the TDC value of the upper arm and forearm after MLD did not change (p > 0.05). Compared with the group MLD and the group CDT, the reduction of the TDC value in the group CB was more significant (p < 0.05). Conclusions: MLD or CB alone could effectively reduce the volume of affected arms for patients with stage 2 BCRL, and CB also could reduce the LTW more significantly. CDT did not seem to show an extra advantage. Therefore, CB may be the first choice for stage 2 BCRL. But for patients who are unwilling or intolerant to CB, MLD can be selected.

Rough Nanovaccines Boost Antitumor Immunity Through the Enhancement of Vaccination Cascade and Immunogenic Cell Death Induction.

Nanovaccines have attracted intense interests for efficient antigen delivery and tumor-specific immunity. It is challenging to develop a more efficient and personalized nanovaccine to maximize all steps of the vaccination cascade by exploiting the intrinsic properties of nanoparticles. Here, biodegradable nanohybrids (MP) composed of manganese oxide nanoparticles and cationic polymers are synthesized to load a model antigen ovalbumin to form MPO nanovaccines. More interestingly, MPO could serve as autologous nanovaccines for personalized tumor treatment taking advantage of in situ released tumor-associated antigens induced by immunogenic cell death (ICD). The intrinsic properties of MP nanohybrids including morphology, size, surface charge, chemical, and immunoregulatory functions are fully exploited to enhance of all steps of the cascade and induce ICD. MP nanohybrids are designed to efficiently encapsulate antigens by cationic polymers, drain to lymph nodes by appropriate size, be internalized by dendritic cells (DCs) by rough morphology, induce DC maturation through cGAS-STING pathway, and enhance lysosomal escape and antigen cross-presentation through the "proton sponge effect". The MPO nanovaccines are found to efficiently accumulate in lymph nodes and elicit robust specific T-cell immune responses to inhibit the occurrence of ovalbumin-expressing B16-OVA melanoma. Furthermore, MPO demonstrate great potential to serve as personalized cancer vaccines through the generation of autologous antigen depot through ICD induction, activation of potent antitumor immunity, and reversal of immunosuppression. This work provides a facile strategy for the construction of personalized nanovaccines by exploiting the intrinsic properties of nanohybrids.

Injectable Hydrogels Encapsulating Dual-Functional Au@Pt Core-Shell Nanoparticles Regulate Infarcted Microenvironments and Enhance the Therapeutic Efficacy of Stem Cells through Antioxidant and Electrical Integration.

Injectable functional biomaterials have made significant progress in cardiac regenerative. In addition, how to adjust the abominable infarction microenvironment and introduce therapeutic stem cells to improve the healing effect has become a hotspot. Herein, injectable stem cell vector is prepared by combining natural alginate hydrogel and Au@Pt nanoparticles (Au@Pt/Alg hydrogel) to encapsulate brown adipose stem cells (BASCs). Au@Pt nanoparticles with both antioxidative and conductive properties could effectively eliminate reactive oxygen species, enhance the frequency of action potential release of cardiomyocytes, and further reduce the inflammatory factors of macrophage in vitro. The Au@Pt/Alg hydrogel enhances the antioxidant, differentiation, and paracrine capability of BASCs. The effect of BASCs loaded Au@Pt/Alg hydrogel is evaluated in a rat myocardial infarction (MI) model. The antioxidant, anti-inflammatory, and heart electrical integration are showed in the MI model. More interestingly, Au@Pt/Alg hydrogel can effectively maintain the paracrine efficiency and pro-angiogenesis effects of BASCs in the infarcted area. This study led us to recognize the great value of Au@Pt/Alg hydrogels for their ability to actively regulate the microenvironment and carry stem cells for MI treatment.

Higher Pelvic Incidence Was Associated with a Higher Risk of Sagittal Malposition of Femoral Component and Poor Outcomes of Primary Total Knee Arthroplasty: A Retrospective Cohort Analysis.

Spine-pelvis-lower extremity sagittal alignment is regarded as a global sagittal balance. Currently, there are few studies evaluating the pelvic and femoral sagittal alignment during total knee arthroplasty (TKA). This retrospective study aims to elucidate how pelvic and femoral sagittal alignment affect clinical outcomes of primary TKA for osteoarthritis (OA) and determine the proper range of femoral sagittal alignment. Patient-reported outcome measures (PROMs), including the Knee Society Score (KSS), Western Ontario and McMaster Universities (WOMAC), and patient satisfaction scores, and clinician-reported outcomes (CROs), including range of motion (ROM) and pelvic and femoral sagittal parameters, of 67 cases were evaluated (89 knees) before and 1 year after TKA. The angle between the distal femur anterior cortex line and flange of the femoral component (FC) was defined as the α angle. Correlations between the α angle and PROM and CRO were investigated using multivariate and secondary regression analyses. Patients were further divided into four cohorts (A, B, C, and D) according to the α angle, and comparisons of their postoperative PROM and ROM scores were performed. Postoperative PROM and ROM scores improved significantly compared with the preoperative scores (p < 0.01). Only the α angle was significantly associated with postoperative knee extension among all PROM and CRO indexes (p = 0.001). Secondary regression demonstrated a convex upward function, and the scores were the highest at α angles of 0.57, 0.96, and -1.42 degrees for postoperative KSS, satisfaction, and range of knee extension, respectively (p < 0.01). However, the concave upward degree was the lowest at an α angle of 0.33 degrees for pelvic incidence (p < 0.001). Bonferroni's paired comparisons indicated that postoperative KSS and satisfaction of the cohort B (0 degrees ≤ α angle ≤ 3 degrees) were better than those of other cohorts (p < 0.0125). The results indicate that surgeons should pay more attention to the sagittal alignment of FC in patients with increased pelvic incidence, the distal femoral anterior cortex is recommended as an anatomic landmark, and 0 to 3 degrees might be "safe zones" of the sagittal flexion of FC in TKA. This study reflects the level of evidence III.

Clinicopathological and prognostic characteristics of idiopathic membranous nephropathy with dual antigen positivity.

Background: Idiopathic membranous nephropathy (IMN) is the most common pathological type in adults with nephrotic syndrome. Many target antigens have been discovered. However, dual antigen-positive IMN patients are very rare, with only a few such cases being briefly described in various studies. There is no specific study on the clinicopathological and prognostic characteristics of dual antigen-positive IMN patients, and the disease characteristics of such patients remain unclear. Methods: Immunohistochemical staining of PLA2R, THSD7A, and NELL-1 was conducted on kidney tissue samples obtained from patients diagnosed with IMN. Simultaneously, the presence of corresponding serum antibodies was determined. Patients exhibiting positivity for dual antigens were included in the study, identified either through tissue staining or serum antibody detection. We retrospectively collected their clinical, pathological, and follow-up data and measured their serum antibody levels at multiple time points. Additionally, the same type of dual antigen-positive IMN cases reported in the literature were reviewed to extract clinical, pathological, and prognostic information. We compared the data for all of the above dual antigen-positive and PLA2R single-positive IMN cases at our center. Results: We identified 6 IMN patients with dual antigen positivity at our center, approximately 0.7% of whole MN series; the previous literature reports 43 IMN patients with dual antigen positivity, the proportion ranged from 0.2% to 2.8%. The IgG1 positivity rate in the renal tissue of the dual antigen-positive patients at our center was significantly lower than that of dual antigen-positive patients previously reported (16.7% vs. 100.0%, p=0.015), but there was no significant difference in clinical or prognostic aspects. Patients with dual antigen positivity reported at our center and in the literature were combined and compared with PLA2R single-positive IMN reported at our center. Compared with PLA2R single-positive IMN patients, dual antigen-positive IMN patients had a higher renal tissue IgG1 positivity rate (58.3% vs. 22.3%, p=0.016), and the time required to achieve remission was longer [13.5 (3.3,35.0) vs. 3.0 (1.0,8.0), p=0.052]. Overall, The changes in urine protein were consistent with the changes in serum PLA2R antibody levels in dual antigen-positive IMN patients. Conclusions: For patients with primary membranous nephropathy who did not attain remission following prolonged treatment, multiple target antigen staining should still be actively performed, even with positivity for the PLA2R target antigen.

Tumor microenvironment-responsive delivery nanosystems reverse immunosuppression for enhanced CO gas/immunotherapy.

Carbon monoxide (CO) gas therapy demonstrates great potential to induce cancer cell apoptosis and antitumor immune responses, which exhibits tremendous potential in cancer treatment. However, the therapeutic efficacy of CO therapy is inhibited by the immunosuppressive tumor microenvironment (TME). Herein, a facile strategy is proposed to construct hollow-structured rough nanoplatforms to boost antitumor immunity and simultaneously reverse immunosuppression by exploring intrinsic immunomodulatory properties and morphological optimization of nanomaterials. The TME-responsive delivery nanosystems (M-RMH) are developed by encapsulating the CO prodrug within hollow rough MnO2 nanoparticles and the subsequent surface functionalization with hyaluronic acid (HA). Rough surfaces are designed to facilitate the intrinsic properties of HA-functionalized MnO2 nanoparticles (RMH) to induce dendritic cell maturation and M1 macrophage polarization by STING pathway activation and hypoxia alleviation through enhanced cellular uptake. After TME-responsive degradation of RMH, controlled release of CO is triggered at the tumor site for CO therapy to activate antitumor immunity. More importantly, RMH could modulate immunosuppressive TME by hypoxia alleviation. After the combination with aPD-L1-mediated checkpoint blockade therapy, robust antitumor immune responses are found to inhibit both primary and distant tumors. This work provides a facile strategy to construct superior delivery nanosystems for enhanced CO/immunotherapy through efficient activation of antitumor immune responses and reversal of immunosuppression.

An Integrated Study on the Differential Expression of the FOX Gene Family in Cancer and Their Response to Chemotherapy Drugs.

The Forkhead-box (FOX) transcription factors, as one of the largest gene families in humans, play key roles in cancer. Although studies have suggested that several FOX transcription factors have a significant impact on cancer, the functions of most of the FOX genes in cancer remain elusive. In the study, the expression of 43 FOX genes in 63 kinds of cancer diseases (including many subtypes of same cancer) and in response to 60 chemical substances was obtained from the Gene Expression Atlas database of the European Bioinformatics Institute. Based on the high degree of overlap in FOXO family members differentially expressed in various cancers and their particular responses to chemotherapeutic drugs, our data disclosed the FOX genes that played an important role in the development and progression of cancer. More importantly, we predicted the role of one or several combinatorial FOX genes in the diagnosis and prognostic assessment of a specific cancer and evaluated the potential of a certain anticancer drug therapy for this type of cancer by integrating patterns of FOX genes expression with anticancer drugs sensitivity.

RNA-seq characterization of histamine-releasing mast cells as potential therapeutic target of osteoarthritis.

OBJECTIVE: Mast cells in the osteoarthritis (OA) synovium correlate with disease severity. This study aimed to further elucidate the role of mast cells in OA by RNA-Seq analysis and pharmacological blockade of the activity of histamine, a key mast cell mediator, in murine OA. METHODS: We examined OA synovial tissues and fluids by flow cytometry, immunostaining, single-cell and bulk RNA-Seq, qPCR, and ELISA. Cetirizine, a histamine H1 receptor (H1R) antagonist, was used to treat the destabilization of the medial meniscus (DMM) mouse model of OA. RESULTS: Flow cytometry and immunohistology analysis of OA synovial cells revealed KIT+ FcεRI+ and TPSAB1+ mast cells. Single-cell RNA-Seq of OA synovial cells identified the expression of prototypical mast cell markers KIT, TPSAB1, CPA3 and HDC, as well as distinctive markers HPGD, CAVIN2, IL1RL1, PRG2, and CKLF, confirmed by bulk RNA-Seq and qPCR. A mast cell prototypical marker expression score classified 40 OA patients into three synovial pathotypes: mast cell-high, -medium, and -low. Additionally, we detected mast cell mediators including histamine, tryptase AB1, CPA3, PRG2, CAVIN2, and CKLF in OA synovial fluids. Elevated H1R expression was detected in human OA synovium, and treatment of mice with the H1 receptor antagonist cetirizine reduced the severity and OA-related mediators in DMM. CONCLUSION: Based on differential expression of prototypical and distinct mast cell markers, human OA joints can be stratified into mast cell-high, -medium, and -low synovial tissue pathotypes. Pharmacologic blockade of histamine activity holds the potential to improve OA disease outcome.