Role of miRNA-regulated type H vessel formation in osteoporosis.

Osteoporosis (OP) is a chronic systemic bone metabolism disease characterized by decreased bone mass, microarchitectural deterioration, and fragility fractures. With the demographic change caused by long lifespans and population aging, OP is a growing health problem. The role of miRNA in the pathogenesis of OP has also attracted widespread attention from scholars in recent years. Type H vessels are unique microvessels of the bone and have become a new focus in the pathogenesis of OP because they play an essential role in osteogenesis-angiogenesis coupling. Previous studies found some miRNAs regulate type H vessel formation through the regulatory factors, including platelet-derived growth factor-BB (PDGF-BB), hypoxia-inducible factor 1α (HIF-1α), vascular endothelial growth factor (VEGF), and so on. These findings help us gain a more in-depth understanding of the relationship among miRNAs, type H vessels, and OP to find a new perspective on treating OP. In the present mini-review, we will introduce the role of type H vessels in the pathogenesis of OP and the regulation of miRNAs on type H vessel formation by affecting regulatory factors to provide some valuable insights for future studies of OP treatment.

Study of the Corrosion Behavior of Cathode Current Collector in LiFSI Electrolyte.

Cycling aging is the one of the main reasons affecting the lifetime of lithium-ion batteries and the contribution of aluminum current collector corrosion to the ageing is not fully recognized. In general, aluminum is corrosion resistant to electrolyte since a non-permeable surface film of alumina is naturally formed. However, corrosion of aluminum current collector can still occur under certain conditions such as lithium bis(fluorosulfonyl)imide (LiFSI)-based electrolyte or high voltage. Herein, we investigates the corrosion of aluminum current collector in the electrolyte of 1.2 M LiFSI in ethylene carbonate (EC) and ethyl methyl carbonate (EMC) mixed solvents. The electrochemical results shows that the corrosion current of aluminum is enhanced by cycling time and potential, which is correlated with the surface species and morphology. The formation of AlF3, which is induced by deep penetration of F- anions through surface passivation film, leads to internal volume change and the surface crack in the end. Our work will be inspiring for future development of high-energy-density and high-power-density lithium-ion batteries in which the LiFSI salt will be intensively used.

Lactate dehydrogenase A is implicated in the pathogenesis of B-cell lymphoma through regulation of the FER signaling pathway.

Lactate dehydrogenase A (LDHA) is highly expressed in various tumors. However, the role of LDHA in the pathogenesis of B-cell lymphoma remains unclear. Analysis of data from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases revealed an elevated LDHA expression in diffuse large B-cell lymphoma (DLBC) tissues compared with normal tissues. Similarly, our results demonstrated a significant increase in LDHA expression in tumor tissues from the patients with B-cell lymphoma compared with those with lymphadenitis. To further elucidate potential roles of LDHA in B-cell lymphoma pathogenesis, we silenced LDHA in the Raji cells (a B-cell lymphoma cell line) using shRNA techniques. Silencing LDHA led to reduced mitochondrial membrane integrity, adenosine triphosphate (ATP) production, glycolytic activity, cell viability and invasion. Notably, LDHA knockdown substantially suppressed in vivo growth of Raji cells and extended survival in mice bearing lymphoma (Raji cells). Moreover, proteomic analysis identified feline sarcoma-related protein (FER) as a differential protein positively associated with LDHA expression. Treatment with E260, a FER inhibitor, significantly reduced the metabolism, proliferation and invasion of Raji cells. In summary, our findings highlight that LDHA plays multiple roles in B-cell lymphoma pathogenesis via FER pathways, establishing LDHA/FER may as a potential therapeutic target.

Evaluation of the effectiveness of using flipped classroom in puncture skills teaching.

BACKGROUND: The effectiveness of flipped classroom (FC) on puncture skills in medical education is still uncertain. This study aimed to assess the role of the FC model in puncture skills and investigate the acceptance and approval of FC among medical students and instructors. METHODS: A mixed research approach of quasi-experimental research design and descriptive qualitative research was conducted in September 2022 for one month, using an FC teaching method that combined instructional videos and group learning. The study participants were 71 fifth-year medical students from two classes at a Chinese medical school and four instructors. The medical students were randomly divided into two groups: the traditional classroom (TC) group (Group A) and the FC group (Group B). For teaching, Group B used FC, and Group A used PowerPoint-based TC. The effectiveness of the two teaching models was assessed with Objective Structured Clinical Examination (OSCE), and questionnaires were distributed to the medical students and instructors after the assessment. Two independent sample t-tests were used to analyse the differences in demographic data and the OSCE scores of the two groups of medical students. RESULTS: Group B scored higher in puncture skills than Group A, especially regarding abdominal puncture (p = 0.03), thoracentesis (p < 0.001), bone marrow puncture (p < 0.001) and average performance of puncture skills (p < 0.001). For lumbar puncture, no difference in skill scores was observed between groups A and B (p > 0.409). The medical students thought that the FC improved their self-learning ability and helped them acquire knowledge. Regarding the OSCE of their skills, most medical students thought that it was more innovative and objective than traditional examinations and that it was better for assessing their overall abilities. Both the FC and OSCE were supported by the medical students. The instructors were also satisfied with the students' performance in the FC and supported the teaching model, agreeing to continue using it. CONCLUSIONS: This study shows that FC teaching that combines instructional videos and group learning is a reliable and well-received teaching method for puncture skills, which supplements and expands existing teaching methods in the medical field.

Feasibility of anaerobic co-digestion of biodegradable plastics with food waste, investigation of microbial diversity and digestate phytotoxicity.

The effects of biodegradable plastics of different thicknesses (30 and 40 µm) and sizes (20 × 20, 2 × 2, and 1 × 1 mm) on anaerobic digestion of food waste and digestate phytotoxicity were investigated. Methane productions (38 days) for the groups with 20 × 20, 2 × 2, and 1 × 1 mm of 30 µm plastics were 92.46, 138.27, and 259.95 mL/gVSremoval, respectively which are nearly 58 % higher than the control group (58.86 mL/gVSremoval). Methane production in 40 µm plastics groups was lower than in 30 µm groups of equal size. All sizes of 30 µm plastics promoted substrate hydrolysis, acidification, and relative abundance of key hydrolytic bacteria and methanogens. Phytotoxicity tests results showed that seed root elongation was inhibited in groups with 40 µm plastics. In conclusion, 30 µm biodegradable plastics were more suitable for anaerobic digestion with food waste than 40 µm.

Treponema pallidum Promotes the Polarization of M2 Subtype Macrophages to M1 Subtype Mediating the Apoptosis and Inhibiting the Angiogenesis of Human Umbilical Vein Endothelial Cells.

M2 macrophages were related to local immune homeostasis and maternal-fetal tolerance in normal pregnancy; whether M2 macrophages can respond to the stimulation of Treponema pallidum to mediate placental vascular inflammation injury is unclear. In this study, M2 macrophages were constructed to investigate the impact of T. pallidum on macrophage polarization and the underlying signaling pathway involved in this process, and the influence of macrophage polarization triggered by T. pallidum on the apoptosis and angiogenesis of human umbilical vein endothelial cells (HUVEC) was also explored. The results showed that M2 macrophage markers (CD206 and PPARγ) and anti-inflammatory factors (TGFß and CCL18) were decreased, while M1 macrophage marker CD80 and inflammatory cytokines (IL1ß and TNFα) were increased when M2 macrophages were treated with T. pallidum, indicating that T. pallidum promoted the polarization of M2 subtype macrophages to the M1 subtype. Moreover, T. pallidum-induced M1 macrophage polarization was found to be significantly correlated with the activation of Janus kinase 1 (JAK1) and signal transducer and activator of transcription 1 (STAT1). In addition, T. pallidum-induced M1 macrophages were found to promote apoptosis and inhibit the angiogenesis of HUVECs, and JAK1 or STAT1 inhibitors could weaken the apoptosis rate and promote the angiogenesis of HUVECs. These findings revealed that T. pallidum promoted the polarization of M2 macrophages to the M1 subtype through the JAK1-STAT1 signal pathway mediating the apoptosis and inhibiting angiogenesis of HUVECs, which may provide a possible mechanism for T. pallidum-induced adverse pregnancy outcomes.

Urinary exosomes: a promising biomarker of drug-induced nephrotoxicity.

Drug-induced nephrotoxicity (DIN) is a big concern for clinical medication, but the clinical use of certain nephrotoxic drugs is still inevitable. Current testing methods make it hard to detect early renal injury accurately. In addition to understanding the pathogenesis and risk factors of drug-induced nephrotoxicity, it is crucial to identify specific renal injury biomarkers for early detection of DIN. Urine is an ideal sample source for biomarkers related to kidney disease, and urinary exosomes have great potential as biomarkers for predicting DIN, which has attracted the attention of many scholars. In the present paper, we will first introduce the mechanism of DIN and the biogenesis of urinary exosomes. Finally, we will discuss the changes in urinary exosomes in DIN and compare them with other predictive indicators to enrich and boost the development of biomarkers of DIN.

Effects of Two Different Proportions of Microbial Formulations on Microbial Communities in Kitchen Waste Composting.

The objective of this research was to investigate the effect of bulking agents on the maturity and gaseous emissions of composting kitchen waste. The composing experiments were carried out by selected core bacterial agents and universal bacterial agents for 20 days. The results demonstrated that the addition of core microbial agents effectively controlled the emission of typical odor-producing compounds. The addition of core and universal bacterial agents drastically reduced NH3 emissions by 94% and 74%, and decreased H2S emissions by 78% and 27%. The application of core microbial agents during composting elevated the peak temperature to 65 °C and in terms of efficient temperature evolution (>55 °C for 8 consecutive days). The organic matter degradation decreased by 65% from the initial values for core microbial agents were added, while for the other treatments the reduction was slight. Adding core microbial agents to kitchen waste produced mature compost with a higher germination index (GI) 112%, while other treatments did not fully mature and had a GI of <70%. Microbial analysis demonstrated that the core microbial agents in composting increased the relative abundances of Weissella, Ignatzschineria, and Bacteroides. Network and redundancy analysis (RDA) revealed that the core microbial agents enhanced the relationship between bacteria and the eight indicators (p < 0.01), thereby improving the bio transformation of compounds during composting. Overall, these results suggest that the careful selection of appropriate inoculation microorganisms is crucial for improved biological transformation and nutrient content composting efficacy of kitchen waste.

Insights into the protective immune response by immunization with full-length recombinant TprK protein: cellular and humoral responses.

Syphilis has resurged in many countries, which has called attention to vaccine development. Based on the immunization-based rabbit model of infection with the Nichols strain, this study explored the protective immune response of a controversial syphilis vaccine candidate, TprK, and found that immunization with full-length rTprK was effective in attenuating lesion development and accelerating lesion resolution, which could reduce the probability of the pathogen spreading to distant tissue sites to prevent the progression of the disease to some extent. Furthermore, the results revealed that immunization with rTprK not only rapidly induced a strong Th1-like cellular response but also elicited a humoral immune response to produce opsonic antibodies to enhance macrophage-mediated opsonophagocytosis. Although complete protection against infection was not achieved, the study provided a comprehensive and in-depth exploration of the immunogenicity of TprK and highlighted the importance of TprK as a promising syphilis vaccine component.

On the correctness of using two-dimensional representations in the analysis of cylindrical peg-hole insertion and withdrawal.

The cylindrical peg-hole system is a popular model in the study of assembly and disassembly operations. The analysis of peg-hole systems is customarily performed using simplified two-dimensional representations, viz. a vertical sectional view. However, evidence that this simplification accurately represents the system is lacking. This paper investigates the correctness of using two-dimensional instead of three-dimensional models for peg-hole system analysis, studying their geometrical and kinematic equivalence. Geometrical equivalence implies the contact points between the peg and hole are on a vertical sectional view plane. Kinematic equivalence requires that the forces and torques acting on the peg lie in the same sectional plane. The analysis indicates that while geometrical equivalence can be proven, kinematic equivalence is in general not verified. The severity of the error introduced by the two-dimensional simplification depends on the geometrical configuration and kinematic parameters of the peg-hole system. The effects of kinematic non-equivalence on the boundary conditions of jamming and wedging are discussed. The results of the analysis show that a two-dimensional peg-hole model may give wrong predictions on jamming. Also, the extra lateral error of the three-dimensional model reduces the boundary condition and the possibility of peg-hole wedging.

Treponema pallidum recombinant protein Tp47 enhanced interleukin-6 secretion in human dermal fibroblasts through the toll-like receptor 2 via the p38, PI3K/Akt, and NF-κB signalling pathways.

Interleukin-6 (IL-6) is a multi-effective cytokine involved in multiple immune responses. Whether fibroblasts also turn out to be a cytokine IL-6 factory during interaction with Treponema pallidum is not yet understood. To explore whether fibroblasts participate in inflammation due to syphilis, a series of experiments were performed to explore the role of T. pallidum lipoprotein Tp47 in IL-6 production in human dermal fibroblasts. The Toll-like receptor 2 (TLR2) and participating signalling pathways in this process were also evaluated. The results showed that the expressions of IL-6 and the protein levels of TLR2 in fibroblasts were upregulated after stimulation with Tp47, and this effect was impeded by the TLR2 inhibitor C29. In addition, Tp47 promoted the phosphorylation of p38, PI3K/Akt, and nuclear factor-kappaB (NF-κB), and the translocation of NF-κB in fibroblasts. Moreover, p38, PI3K, and NF-κB inhibitors significantly reduced IL-6 production in fibroblasts stimulated with Tp47. Furthermore, the TLR2 inhibitor C29 inhibited the phosphorylation of p38, Akt, and NF-κB, and the translocation of NF-κB in fibroblasts. In conclusion, our results showed that Tp47 enhanced IL-6 secretion in human dermal fibroblasts through TLR2 via p38, PI3K/Akt, and NF-κB signalling pathways. These findings contribute to our understanding of syphilis inflammation.

Longitudinal Variations in the tprK Gene of Treponema pallidum in an Amoy Strain-Infected Rabbit Model.

Heterogeneous tprK sequences have been hypothesized to be an important factor for persistent infection of Treponema pallidum subsp. pallidum (T. pallidum) in humans. Previous research has only explored tprK diversity using a rabbit model infected with almost clonal isolates, which is inconsistent with the fact that infected human isolates contain multiple heterogeneous tprK sequences. Here, we used the T. pallidum Amoy strain with heterogeneous tprK sequences to establish a rabbit infection model and explore longitudinal variations in the tprK gene under normal infection, immunosuppression treatment, and benzathine penicillin G (BPG) treatment using next-generation sequencing. The diversity of the tprK gene was high in all three groups but was highest in the control group and lowest in the BPG group. Interestingly, the overall diversity of tprK in all three groups decreased during infection, exhibiting a "more to less" trend, indicating that survival selection may be an important factor affecting tprK variation in the later infection stage. BPG treatment appeared to reduce the diversity of tprK but increased the frequency of predominant sequence changes, which might facilitate the escape of T. pallidum from the host immune clearance. Furthermore, the original predominant V region sequence did not disappear with disease progression but retained a relatively high proportion within the population, suggesting a new direction for tprK-related vaccine research. This study provides insights into longitudinal variations within the highly heterogeneous tprK gene sequences of T. pallidum and will contribute to further exploration of the pathogenesis of syphilis. IMPORTANCE The tprK variations are an important factor in persistent T. pallidum infection. A nearly clonal isolate has been used previously to investigate the mechanism of tprK gene variations; however, clinical T. pallidum isolates in infected humans exhibit multiple heterogeneous tprK sequences. Here, we use next-generation sequencing to explore longitudinal variations in the tprK gene under normal infection and immunosuppression and benzathine penicillin G treatment in a rabbit model infected with the Amoy strain with heterogeneous tprK sequences. The overall diversity of tprK in all three groups was high and decreased during infection, exhibiting a "more to less" trend. Benzathine penicillin G treatment reduced the diversity of tprK but increased the frequency of predominant sequence changes. Moreover, the original predominant V region sequence did not disappear as the disease progressed but remained at a relatively high proportion within the population. The research results give us a new understanding about tprK variation.

Study on the Stability of Low-Carbon Magnesium Cementitious Materials in Sulfate Erosion Environments.

The current investigation focuses on the stability of the magnesium oxide-based cementitious system under the action of sulfate attack and the dry-wet cycle. The phase change in the magnesium oxide-based cementitious system was quantitatively analyzed by X-ray diffraction, combined with thermogravimetry/derivative thermogravimetry and scanning electron microscope, to explore its erosion behavior under an erosion environment. The results revealed that, in the fully reactive magnesium oxide-based cementitious system under the environment of high concentration sulfate erosion, there was only magnesium silicate hydrate gel formation and no other phase; however, the reaction process of the incomplete magnesium oxide-based cementitious system was delayed, but not inhibited, by the environment of high-concentration sulfate, and it tended to turn completely into a magnesium silicate hydrate gel. The magnesium silicate hydrate sample outperformed the cement sample, in terms of stability in a high-concentration sulfate erosion environment, but it tended to degrade considerably more rapidly, and to a greater extent, than Portland cement, in both dry and wet sulfate cycle environments.

Effect of aeration/micro-aeration on lignocellulosic decomposition, maturity and seedling phytotoxicity during full-scale biogas residues composting.

With the accelerated construction of biogas plants, the amount of biogas residues are expanding. Composting has been widely implemented to deal with biogas residues. Aeration regulation is the main factor affecting the post-composting treatment of biogas residues as high-quality fertilizer or soil amendment. Therefore, this study aimed to investigate the impact of different aeration regulations on full-scale biogas residues compost maturity by controlling oxygen concentration under micro-aeration and aeration conditions. Results showed that micro-aerobic extended the thermophilic stage of 17 days at above 55 ℃ and facilitated the mineralization process of organic nitrogen into nitrate nitrogen to retain higher N nutrition levels compared to aerobic treatment. For biogas residues with high moisture, aeration should be regulated at different full-scale composting stages. Total organic carbon (TOC), NH4+-N, NO3--N, total potassium (TK), total phosphorus (TP) and the germination index (GI) could be used to evaluate stabilization, fertilizer efficiency and phytotoxicity of compost with frequent monitoring times. However, seedling growth trials were still necessary in full-scale composting plants when changing of composting process or biogas residues feedstock.

Red Blood Cell Lysis Pretreatment Can Significantly Improve the Yield of Treponema pallidum DNA from Blood.

PCR can be a supplement to Treponema serological testing. However, its sensitivity is not satisfactory for blood sample testing. The aim of this study was to investigate whether pretreatment with red blood cell (RBC) lysis could enhance the yield of Treponema pallidum subsp. pallidum DNA extraction from blood. We developed and verified the efficacy of a quantitative PCR (qPCR) assay that utilizes TaqMan technology to specifically detect T. pallidum DNA by targeting the polA gene. Simulation media with 106 to 100 treponemes/mL were prepared in normal saline (NS), whole blood, plasma, and serum, and RBC lysis pretreatment was performed on a portion of whole blood. Then, blood samples drawn from 50 syphilitic rabbits were divided in parallel into five groups, labeled whole blood, whole blood/lysed RBCs, plasma, serum, and blood cells/lysed RBCs. DNA extraction and qPCR detection were performed. The detection rate and copy number were compared among different groups. The polA assay showed good linearity and an excellent amplification efficiency of 102%. In the simulated blood samples, the detection limit of the polA assay reached 1 × 102 treponemes/mL in whole blood/lysed RBCs, plasma, and serum. However, the detection limit was only 1 × 104 treponemes/mL in NS and whole blood. Among the blood samples from syphilitic rabbits, whole blood/lysed RBCs showed the best detection rate (82.0%), while the detection rate for whole blood was only 6%. The copy number of whole blood/lysed RBCs was higher than that of whole blood. RBC lysis pretreatment can significantly improve the yield of T. pallidum DNA from whole blood, and the yield is better than that from whole blood, plasma, serum, and blood cells/lysed RBCs. IMPORTANCE Syphilis is a sexually transmitted disease caused by T. pallidum that can spread into the blood. T. pallidum DNA can be detected in blood by PCR but with low sensitivity. Few studies have applied RBC lysis pretreatment to blood T. pallidum DNA extraction. This study shows that the detection limit, detection rate, and copy number of whole blood/lysed RBCs were better than those of whole blood, plasma, and serum. After RBC lysis pretreatment, the yield of low concentrations of T. pallidum DNA was improved, and the low sensitivity of blood-based T. pallidum PCR was improved. Therefore, whole blood/lysed RBCs are the ideal sample for acquiring blood T. pallidum DNA.

A Two-Stage Screw Detection Framework for Automatic Disassembly Using a Reflection Feature Regression Model.

For remanufacturing to be more economically attractive, there is a need to develop automatic disassembly and automated visual detection methods. Screw removal is a common step in end-of-life product disassembly for remanufacturing. This paper presents a two-stage detection framework for structurally damaged screws and a linear regression model of reflection features that allows the detection framework to be conducted under uneven illumination conditions. The first stage employs reflection features to extract screws together with the reflection feature regression model. The second stage uses texture features to filter out false areas that have reflection features similar to those of screws. A self-optimisation strategy and weighted fusion are employed to connect the two stages. The detection framework was implemented on a robotic platform designed for disassembling electric vehicle batteries. This method allows screw removal to be conducted automatically in complex disassembly tasks, and the utilisation of the reflection feature and data learning provides new ideas for further research.

Electronic nose application for detecting different odorants in source water: Possibility and scenario.

The problem of taste and odor (T&O) in drinking water is a widespread societal concern and highlights substantial challenges related to the detection and evaluation of odor in water. In this study, the portable electronic nose PEN3, which is equipped with ten different heated metal sensors, was applied to analyze its applicability, feasibility and application scenarios for the detection of typical odorants, such as 2-methylisobornel (2-MIB), geosmin (GSM), ß-cyclocitral, ß-ionone, and other T&O compounds in source water, while avoiding uncertainties and instability related to manual inspection. All the T&O compounds could be effectively differentiated by principal component analysis (PCA). Linear discriminant analysis (LDA) showed that the odors varied greatly between different samples and could be effectively distinguished. As the odorant concentration increased, the sensor response intensity of the primary identification sensors R6 and R8 increased with a significant positive correlation. For Microcystis aeruginosa, an algae that produces odorants, PCA could distinguish the odors of algae at a series of densities at different concentrations. The responses of R10 showed a significant increase with increasing algae density, implying the production of more aliphatic hydrocarbons and other odor compounds. The results indicated that the electronic nose could provide a promising alternative to traditional unstable and complex detection methods for the detection of odorous substances in surface water and early warning of odor events. This study aimed to provide technical support for rapid monitoring and early warning of odorants in source water management.

Response and duration of serum anti-SARS-CoV-2 antibodies induced by the third dose of an inactivated vaccine: A prospective longitudinal cohort study at 21 serial time points over 641 days.

Given the prevalence of low-pathogenic but highly infectious Omicron variants, a cohort study was conducted to assess the response and duration of novel coronavirus-inactivated vaccine-induced antibodies 1 year after the third dose (Day 641). Blood samples were collected and anti-spike neutralizing antibodies (neutralizing antibody), total antibodies against the receptor-binding domain of the spike protein (total antibody), and immunoglobulin G antibodies against the spike protein (IgG antibody) were determined. Antibody kinetics and attenuation were evaluated. The results showed that the levels of neutralizing, total, and IgG antibodies on Day 641 were 98.05 IU/mL, 152.8 AU/mL, and 7.68 S/CO, respectively. Levels of anti-SARS-CoV-2 antibodies were higher in the younger subgroup than in the older subgroup at several time points after the second and third doses. The seropositive rate of neutralizing antibodies providing protection from infection or severe infection was 46.87% and 87.5%, and the seropositive rates of total antibody and IgG antibody were maintained at 100% and 90.63%, respectively. The half-lives of neutralizing, total, and IgG antibodies were 186.89, 363.04, and 417.50 days, respectively. Collectively, anti-SARS-CoV-2 antibodies may provide a certain degree of protection from infection 1 year after the third dose and high protection from severe infection.

Safety and efficacy of PD-1 and PD-L1 inhibitors in relapsed and refractory Hodgkin's lymphoma: a systematic review and meta-analysis of 20 prospective studies.

BACKGROUND: Inhibitors of programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) have been used in the treatment of relapsed and refractory Hodgkin's lymphoma (R/R HL) recently. To further understand the safety and efficacy of PD-1/PD-L1 inhibitors in R/R HL, we conducted this meta-analysis. METHODS: Databases and the Clinical Registration Platforms have been systematically searched for related studies by March 2022. For safety analysis, the incidence and exhibition of any grade and grade 3 or higher adverse effects (AEs) were evaluated. Besides, severe AEs (SAEs), treatment-related deaths, and AEs leading to treatment discontinuation were summarized. The overall response rate (ORR), complete response (CR) rate, partial response (PR) rate, progression-free survival (PFS), overall survival (OS), and duration of response (DOR) were calculated for efficacy analysis. All processes were implemented mainly through the package Meta and MetaSurv of software R 4.1.2. RESULTS: Overall 20 studies and 1440 patients were enrolled. The pooled incidence of any grade and grade 3 or higher AEs were 92% and 26%, respectively. The pooled ORR, CR rate and PR rate were 79%, 44% and 34%, respectively. The most common AEs were neuropathy (29%), nausea (27%), pyrexia (26%), and leukopenia (25%), and the most common grade 3 or higher AEs included leukopenia (10%), infusion reaction (8%), weight gain (3%), and neutropenia (2.7%). In survival analysis, pembrolizumab monotherapy appeared to perform better compared to nivolumab monotherapy. CONCLUSIONS: PD-1/PD-L1 inhibitors show promising efficacy and tolerable AEs in the treatment of R/R HL.

GSK-3ß/ß-catenin pathway plays crucial roles in the regulation of NK cell cytotoxicity against myeloma cells.

The plasma cell malignancy, multiple myeloma (MM), has significantly improved by the application of new drugs and autologous hematopoietic stem cell transplantation. However, MM remains incurable. A number of studies have revealed an anti-MM effect of natural killer (NK) cells; however, their clinical efficacy is limited. Furthermore, glycogen synthase kinase (GSK)-3ß inhibitors show an antitumor function. In this study, we aimed to evaluate the potential roles of a GSK-3ß inhibitor (TWS119) in the regulation of NK cell cytotoxicity against MM. Our results showed that, in the presence of TWS119, the NK cell line, NK-92, and in vitro-expanded primary NK cells exhibited a significantly higher degranulation activity, expression of activating receptors, cellular cytotoxicity, and cytokine secretion when they were exposed to MM cells. Mechanistic studies indicated that TWS119 treatment markedly upregulated RAB27A expression, a key molecule for NK cell degranulation, and induced the colocalization of ß-catenin with NF-κB in the nucleus of NK cells. More importantly, GSK-3ß inhibition combined with the adoptive transfer of TWS119-treated NK-92 cells significantly reduced tumor volume and prolonged the survival time of myeloma-bearing mice. In summary, our novel findings suggest that targeting GSK-3ß through the activation of ß-catenin/NF-κB pathway may be an important approach to improve therapeutic efficacy of NK cell transfusion for MM.