Linear and Nonlinear Behaviors of the Photoreceptor Coupled Network.

Photoreceptors are electrically coupled to one another, and the spatiotemporal properties of electrical synapses in a two-dimensional retinal network are still not well studied, because of the limitation of the single electrode or pair recording techniques which do not allow simultaneously measuring responses of multiple photoreceptors at various locations in the retina. A multiple electrode recording system is needed. In this study, we investigate the network properties of the two-dimensional rod coupled array of the salamander retina (both sexes were used) by using the newly available multiple patch electrode system that allows simultaneous recordings from up to eight cells and to determine the electrical connectivity among multiple rods. We found direct evidence that voltage signal spread in the rod-rod coupling network in the absence of I h (mediated by HCN channels) is passive and follows the linear cable equation. Under physiological conditions, I h shapes the network signal by progressively shortening the response time-to-peak of distant rods, compensating the time loss of signal traveling from distant rods to bipolar cell somas and facilitating synchronization of rod output signals. Under voltage-clamp conditions, current flow within the coupled rods follows Ohm's law, supporting the idea that nonlinear behaviors of the rod network are dependent on membrane voltage. Rod-rod coupling is largely symmetrical in the 2D array, and voltage-clamp blocking the next neighboring rod largely suppresses rod signal spread into the second neighboring rod, suggesting that indirect coupling pathways play a minor role in rod-rod coupling.

Dihydroartemisinin induces ferroptosis of hepatocellular carcinoma via inhibiting ATF4-xCT pathway.

Management of hepatocellular carcinoma (HCC) remains challenging due to population growth, frequent recurrence and drug resistance. Targeting of genes involved with the ferroptosis is a promising alternative treatment strategy for HCC. The present study aimed to investigate the effect of dihydroartemisinin (DHA) against HCC and explore the underlying mechanisms. The effects of DHA on induction of ferroptosis were investigated with the measurement of malondialdehyde concentrations, oxidised C11 BODIPY 581/591 staining, as well as subcutaneous xenograft experiments. Activated transcription factor 4 (ATF4) and solute carrier family 7 member 11 (SLC7A11 or xCT) were overexpressed with lentiviruses to verify the target of DHA. Here, we confirmed the anticancer effect of DHA in inducing ferroptosis is related to ATF4. High expression of ATF4 is related to worse clinicopathological prognosis of HCC. Mechanistically, DHA inhibited the expression of ATF4, thereby promoting lipid peroxidation and ferroptosis of HCC cells. Overexpression of ATF4 rescued DHA-induced ferroptosis. Moreover, ATF4 could directly bound to the SLC7A11 promoter and increase its transcription. In addition, DHA enhances the chemosensitivity of sorafenib on HCC in vivo and in vitro. These findings confirm that DHA induces ferroptosis of HCC via inhibiting ATF4-xCT pathway, thereby providing new drug options for the treatment of HCC.

Different conformational dynamics of SNARE protein Ykt6 among yeast and mammals.

Ykt6 is one of the most conserved SNARE (N-ethylmaleimide-sensitive factor attachment protein receptor) proteins involved in multiple intracellular membrane trafficking processes. The membrane-anchoring function of Ykt6 has been elucidated to result from its conformational transition from a closed state to an open state. Two ways of regulating the conformational transition were proposed: the C-terminal lipidation and the phosphorylation at the SNARE core. Despite many aspects of common properties, Ykt6 displays differential cellular localizations and functional behaviors in different species, such as yeast, mammals, and worms. The structure-function relationship underlying these differences remains elusive. Here, we combined biochemical characterization, single-molecule FRET measurement, and molecular dynamics simulation to compare the conformational dynamics of yeast and rat Ykt6. Compared to rat Ykt6 (rYkt6), yeast Ykt6 (yYkt6) has more open conformations and could not bind dodecylphosphocholine that inhibits rYkt6 in the closed state. A point mutation T46L/Q57A was shown to be able to convert yYkt6 to a more closed and dodecylphosphocholine-bound state, where Leu46 contributes key hydrophobic interactions for the closed state. We also demonstrated that the phospho-mutation S174D could shift the conformation of rYkt6 to a more open state, but the corresponding mutation S176D in yYkt6 leads to a slightly more closed conformation. These observations shed light on the regulatory mechanism underlying the variations of Ykt6 functions across species.

Engineering Oxygen Vacancies in In2O3 with Enhanced Polysulfides Immobilization and Selective Catalytic Capability.

Lithium-sulfur (Li-S) battery is identified as an ideal candidate for next-generation energy storage systems in consideration of its high theoretical energy density and abundant sulfur resources. However, the shuttling behavior of soluble polysulfides (LiPSs) and their sluggish reaction kinetics severely limit the practical application of the current Li-S battery. In this work, a series of In2O3 nanocubes with different oxygen vacancy concentrations are designed and prepared via a facile self-template method. The introduced oxygen vacancy on In2O3 can effectively rearrange the charge distribution and enhance sulfiphilic property. Moreover, the In2O3 with high oxygen vacancy concentration (H-In2O3) can slightly slow down the solid-liquid conversion process and significantly accelerate the liquid-solid conversion process, thus reducing the accumulation of LiPSs in electrolyte and inhibiting the shuttle effect. Contributed by the unique selective catalytic capability, the prepared H-In2O3 exhibits excellent electrochemical performance when used as sulfur host. For instance, a high reversible capacity of 609 mAh g-1 is obtained with only 0.044% capacity decay per cycle over 1000 cycles at 1.0 C. This work presents a typical example for designing advanced sulfur hosts, which is crucial for the commercialization of Li-S battery.

Venetoclax overcomes resistance to all-trans retinoic acid in a variant acute promyelocytic leukemia with TNRC18::RARA fusion.

Acute promyelocytic leukemia (APL) is generally driven by PML::RARA, but approximately 2% of variant APL patients do not contain this fusion gene and pose challenges in diagnosis and treatment. Here, we reported an aggressive APL patient with variant TNRC18::RARA fusion gene, who was resistant to standard differentiation induction therapy consisting of all-trans retinoic acid (ATRA) and arsenic trioxide but achieved complete remission with venetoclax plus ATRA. Mechanistically, venetoclax possesses synergistic effects in ATRA-induced TNRC18::RARA-positive cell differentiation.

Zanubrutinib in relapsed/refractory mantle cell lymphoma: long-term efficacy and safety results from a phase 2 study.

Bruton tyrosine kinase (BTK) inhibitor is an established treatment for relapsed/refractory (R/R) mantle cell lymphoma (MCL). Zanubrutinib, a highly selective BTK inhibitor, is approved for patients with MCL who have received ≥1 prior therapy. We report the long-term safety and efficacy results from the multicenter, open-label, phase 2 registration trial of zanubrutinib. Patients (n = 86) received oral zanubrutinib 160 mg twice daily. The primary endpoint was the overall response rate (ORR), assessed per Lugano 2014. After a median follow-up of 35.3 months, the ORR was 83.7%, with 77.9% achieving complete response (CR); the median duration of response was not reached. Median progression-free survival (PFS) was 33.0 months (95% confidence interval [CI], 19.4-NE). The 36-month PFS and overall survival (OS) rates were 47.6% (95% CI, 36.2-58.1) and 74.8% (95% CI, 63.7-83.0), respectively. The safety profile was largely unchanged with extended follow-up. Most common (≥20%) all-grade adverse events (AEs) were neutrophil count decreased (46.5%), upper respiratory tract infection (38.4%), rash (36.0%), white blood cell count decreased (33.7%), and platelet count decreased (32.6%); most were grade 1/2 events. Most common (≥10%) grade ≥3 AEs were neutrophil count decreased (18.6%) and pneumonia (12.8%). Rates of infection, neutropenia, and bleeding were highest in the first 6 months of therapy and decreased thereafter. No cases of atrial fibrillation/flutter, grade ≥3 cardiac AEs, second primary malignancies, or tumor lysis syndrome were reported. After extended follow-up, zanubrutinib demonstrated durable responses and a favorable safety profile in R/R MCL. The trial is registered at ClinicalTrials.gov as NCT03206970.

Characteristics and seasonal variations of cirrus clouds from ground-based lidar and satellite observations over Shouxian Area, China.

This study investigates the macroscopic and optical properties of cirrus clouds in the 32N region from July 2016 to May 2017, leveraging data from ground-based lidar observations and CALIOP to overcome the inconsistencies in detected cirrus cloud samples. Through extensive data analysis, statistical characteristics of cirrus clouds were discerned, revealing lidar ratio values of 28.5 ± 10.8 from ground-based lidar and 27.4 ± 11.2 from CALIOP. Validation with a decade of CALIOP data (2008-2018) confirmed these findings, presenting a consistent lidar ratio of 27.4 ± 12.0. A significant outcome of the analysis was the identification of a positive correlation between the lidar ratio and cloud centroid temperature, indicating a gradual decrease in the lidar ratio as temperatures dropped. The study established a fundamental consistency in their macroscopic properties, including cloud base height, cloud top height, cloud thickness, cloud centroid height, and cloud centroid temperature. The results for ground-based lidar (CALIOP) are: 10.0 ± 2.1 km (10.0 ± 2.2 km), 11.8 ± 2.1 km (11.5 ± 2.3 km), 1.87 ± 0.83 km (1.52 ± 0.71 km), and 10.5 ± 2.2 km, -46.9 ± 9.7°C (-47.1 ± 10.0°C).These properties exhibited seasonal variations, with cirrus clouds reaching higher altitudes in summer and lower in winter, influenced by the height of the tropopause. The optical properties of cirrus clouds were also analyzed, showing an annual average optical depth of 0.31 ± 0.35 for ground-based lidar and 0.32 ± 0.44 for CALIOP. The study highlighted the distribution of subvisible, thin, and thick cirrus clouds, with a notable prevalence of subvisible clouds during summer, suggesting their frequent formation above 14 km. Furthermore, the study observed linear growth in geometric thickness and optical depth up to 2.5 km from CALIOP and 2.9 km from ground-based lidar. Maximum optical depth was observed at cloud centroid temperatures of -35°C for CALIOP and -40°C for ground-based lidar, with optical depth decreasing as temperatures fell. This suggests that fully glaciated cirrus clouds exhibit the highest optical depth at warmer temperatures, within the complete glaciation temperature range of -35°C to -40°C.

Accelerated cortical thinning precedes and predicts conversion to psychosis: The NAPLS3 longitudinal study of youth at clinical high-risk.

Progressive grey matter loss has been demonstrated among clinical high-risk (CHR) individuals who convert to psychosis, but it is unknown whether these changes occur prior to psychosis onset. Identifying illness-related neurobiological mechanisms that occur prior to conversion is essential for targeted early intervention. Among participants in the third wave of the North American Prodrome Longitudinal Study (NAPLS3), this report investigated if steeper cortical thinning was observable prior to psychosis onset among CHR individuals who ultimately converted (CHR-C) and assessed the shortest possible time interval in which rates of cortical thinning differ between CHR-C, CHR non-converters (CHR-NC), and health controls (HC). 338 CHR-NC, 42 CHR-C, and 62 HC participants (age 19.3±4.2, 44.8% female, 52.5% racial/ethnic minority) completed up to 5 MRI scans across 8 months. Accelerated thinning among CHR-C compared to CHR-NC and HC was observed in multiple prefrontal, temporal, and parietal cortical regions. CHR-NC also exhibited accelerated cortical thinning compared to HC in several of these areas. Greater percent decrease in cortical thickness was observed among CHR-C compared to other groups across 2.9±1.8 months, on average, in several cortical areas. ROC analyses discriminating CHR-C from CHR-NC by percent thickness change in a left hemisphere region of interest, scanner, age, age2, and sex had an AUC of 0.74, with model predictive power driven primarily by percent thickness change. Findings indicate that accelerated cortical thinning precedes psychosis onset and differentiates CHR-C from CHR-NC and HC across short time intervals. Mechanisms underlying cortical thinning may provide novel treatment targets prior to psychosis onset.

Impact of Nonnative Interactions on the Binding Kinetics of Intrinsically Disordered p53 with MDM2: Insights from All-Atom Simulation and Markov State Model Analysis.

Intrinsically disordered proteins (IDPs) lack a well-defined tertiary structure but are essential players in various biological processes. Their ability to undergo a disorder-to-order transition upon binding to their partners, known as the folding-upon-binding process, is crucial for their function. One classical example is the intrinsically disordered transactivation domain (TAD) of the tumor suppressor protein p53, which quickly forms a structured α-helix after binding to its partner MDM2, with clinical significance for cancer treatment. However, the contribution of nonnative interactions between the IDP and its partner to the rapid binding kinetics, as well as their interplay with native interactions, is not well understood at the atomic level. Here, we used molecular dynamics simulation and Markov state model (MSM) analysis to study the folding-upon-binding mechanism between p53-TAD and MDM2. Our results suggest that the system progresses from the nascent encounter complex to the well-structured encounter complex and finally reaches the native complex, following an induced-fit mechanism. We found that nonnative hydrophobic and hydrogen bond interactions, combined with native interactions, effectively stabilize the nascent and well-structured encounter complexes. Among the nonnative interactions, Leu25p53-Leu54MDM2 and Leu25p53-Phe55MDM2 are particularly noteworthy, as their interaction strength is close to the optimum. Evidently, strengthening or weakening these interactions could both adversely affect the binding kinetics. Overall, our findings suggest that nonnative interactions are evolutionarily optimized to accelerate the binding kinetics of IDPs in conjunction with native interactions.

Integrated Application of Multiomics Strategies Provides Insights Into the Environmental Hypoxia Response in Pelteobagrus vachelli Muscle.

Increasing pressures on aquatic ecosystems because of pollutants, nutrient enrichment, and global warming have severely depleted oxygen concentrations. This sudden and significant lack of oxygen has resulted in persistent increases in fish mortality rates. Revealing the molecular mechanism of fish hypoxia adaptation will help researchers to find markers for hypoxia induced by environmental stress. Here, we used a multiomics approach to identify several hypoxia-associated miRNAs, mRNAs, proteins, and metabolites involved in diverse biological pathways in the muscles of Pelteobagrus vachelli. Our findings revealed significant hypoxia-associated changes in muscles over 4 h of hypoxia exposure and discrete tissue-specific patterns. We have previously reported that P. vachelli livers exhibit increased anaerobic glycolysis, heme synthesis, erythropoiesis, and inhibit apoptosis when exposed to hypoxia for 4 h. However, the opposite was observed in muscles. According to our comprehensive analysis, fishes show an acute response to hypoxia, including activation of catabolic pathways to generate more energy, reduction of biosynthesis to decrease energy consumption, and shifting from aerobic to anaerobic metabolic contributions. Also, we found that hypoxia induced muscle dysfunction by impairing mitochondrial function, activating inflammasomes, and apoptosis. The hypoxia-induced mitochondrial dysfunction enhanced oxidative stress, apoptosis, and further triggered interleukin-1ß production via inflammasome activation. In turn, interleukin-1ß further impaired mitochondrial function or apoptosis by suppressing downstream mitochondrial biosynthesis-related proteins, thus resulting in a vicious cycle of inflammasome activation and mitochondrial dysfunction. Our findings contribute meaningful insights into the molecular mechanisms of hypoxia, and the methods and study design can be utilized across different fish species.

The Variety of Mechanosensitive Ion Channels in Retinal Neurons.

Alterations in intraocular and external pressure critically involve the pathogenesis of glaucoma, traumatic retinal injury (TRI), and other retinal disorders, and retinal neurons have been reported to express multiple mechanical-sensitive channels (MSCs) in recent decades. However, the role of MSCs in visual functions and pressure-related retinal conditions has been unclear. This review will focus on the variety and functional significance of the MSCs permeable to K+, Na+, and Ca2+, primarily including the big potassium channel (BK); the two-pore domain potassium channels TRAAK and TREK; Piezo; the epithelial sodium channel (ENaC); and the transient receptor potential channels vanilloid TRPV1, TRPV2, and TRPV4 in retinal photoreceptors, bipolar cells, horizontal cells, amacrine cells, and ganglion cells. Most MSCs do not directly mediate visual signals in vertebrate retinas. On the other hand, some studies have shown that MSCs can open in physiological conditions and regulate the activities of retinal neurons. While these data reasonably predict the crossing of visual and mechanical signals, how retinal light pathways deal with endogenous and exogenous mechanical stimulation is uncertain.

Atomic Level-Macroscopic Structure-Activity of Inhomogeneous Localized Aggregates Enabled Ultra-Low Temperature Hybrid Aqueous Batteries.

The utilization of hybrid aqueous electrolytes has significantly broadened the electrochemical and temperature ranges of aqueous batteries, such as aqueous zinc and lithium-ion batteries, but the design principles for extreme operating conditions remain poorly understood. Here, we systematically unveil the ternary interaction involving salt-water-organic co-solvents and its intricate impacts on both the atomic-level and macroscopic structural features of the hybrid electrolytes. This highlights a distinct category of micelle-like structure electrolytes featuring organic-enriched phases and nanosized aqueous electrolyte aggregates, enabled by appropriate low donor number co-solvents and amphiphilic anions. Remarkably, the electrolyte enables exceptional high solubility, accommodating up to 29.8 m zinc triflate within aqueous micelles. This configuration maintains an intra-micellar salt-in-water setup, allowing for a broad electrochemical window (up to 3.86 V), low viscosity, and state-of-the-art ultralow-temperature zinc ion conductivity (1.58 mS cm-1 at -80°C). Building upon the unique nature of the inhomogeneous localized aggregates, this micelle-like electrolyte facilitates dendrite-free Zn plating/stripping, even at -80°C. The assembled Zn||PANI battery showcases an impressive capacity of 71.8 mAh g-1 and an extended lifespan of over 3000 cycles at -80°C. This study opens up a promising approach in electrolyte design that transcends conventional local atomic solvation structures, broadening the water-in-salt electrolyte concept.

Switching between the [2π+2σ] and Hetero-[4π+2σ] Cycloaddition Reactivity of Bicyclobutanes with Lewis Acid Catalysts Enables the Synthesis of Spirocycles and Bridged Heterocycles.

The exploration of the complex chemical diversity of bicyclo[n.1.1]alkanes and their use as benzene bioisosteres has garnered significant attention over the past two decades. Regiodivergent syntheses of thiabicyclo[4.1.1]octanes (S-BCOs) and highly substituted bicyclo[2.1.1]hexanes (BCHs) using a Lewis acid-catalyzed formal cycloaddition of bicyclobutanes (BCBs) and 3-benzylideneindoline-2-thione derivatives have been established. The first hetero-(4+3) cycloaddition of BCBs, catalyzed by Zn(OTf)2, was achieved with a broad substrate scope under mild conditions. In contrast, the less electrophilic BCB ester undergoes a Sc(OTf)3-catalyzed [2π+2σ] reaction with 1,1,2-trisubstituted alkenes, yielding BCHs with a spirocyclic quaternary carbon center. Control experiments and preliminary theoretical calculations suggest that the diastereoselective [2π+2σ] product formation may involve a concerted cycloaddition between a zwitterionic intermediate and E-1,1,2-trisubstituted alkenes. Additionally, the hetero-(4+3) cycloaddition may involve a concerted nucleophilic ring-opening mechanism.

Differences between migrasome, a 'new organelle', and exosome.

The migrasome is a new organelle discovered by Professor Yu Li in 2015. When cells migrate, the membranous organelles that appear at the end of the retraction fibres are migrasomes. With the migration of cells, the retraction fibres which connect migrasomes and cells finally break. The migrasomes detach from the cell and are released into the extracellular space or directly absorbed by the recipient cell. The cytoplasmic contents are first transported to the migrasome and then released from the cell through the migrasome. This release mechanism, which depends on cell migration, is named 'migracytosis'. The main components of the migrasome are extracellular vesicles after they leave the cell, which are easy to remind people of the current hot topic of exosomes. Exosomes are extracellular vesicles wrapped by the lipid bimolecular layer. With extensive research, exosomes have solved many disease problems. This review summarizes the differences between migrasomes and exosomes in size, composition, property and function, extraction method and regulation mechanism for generation and release. At the same time, it also prospects for the current hotspot of migrasomes, hoping to provide literature support for further research on the generation and release mechanism of migrasomes and their clinical application in the future.

Robust hierarchically organized whole-brain patterns of dysconnectivity in schizophrenia spectrum disorders observed after personalized intrinsic network topography.

BACKGROUND: Spatial patterns of brain functional connectivity can vary substantially at the individual level. Applying cortical surface-based approaches with individualized rather than group templates may accelerate the discovery of biological markers related to psychiatric disorders. We investigated cortico-subcortical networks from multi-cohort data in people with schizophrenia spectrum disorders (SSDs) and healthy controls (HC) using individualized connectivity profiles. METHODS: We utilized resting-state and anatomical MRI data from n = 406 participants (n = 203 SSD, n = 203 HC) from four cohorts. Functional timeseries were extracted from previously defined intrinsic network subregions of the striatum, thalamus, and cerebellum as well as 80 cortical regions of interest, representing six intrinsic networks using (1) volume-based approaches, (2) a surface-based group atlas approaches, and (3) Personalized Intrinsic Network Topography (PINT). RESULTS: The correlations between all cortical networks and the expected subregions of the striatum, cerebellum, and thalamus were increased using a surface-based approach (Cohen's D volume vs. surface 0.27-1.00, all p < 10-6 ) and further increased after PINT (Cohen's D surface vs. PINT 0.18-0.96, all p < 10-4 ). In SSD versus HC comparisons, we observed robust patterns of dysconnectivity that were strengthened using a surface-based approach and PINT (Number of differing pairwise-correlations: volume: 404, surface: 570, PINT: 628, FDR corrected). CONCLUSION: Surface-based and individualized approaches can more sensitively delineate cortical network dysconnectivity differences in people with SSDs. These robust patterns of dysconnectivity were visibly organized in accordance with the cortical hierarchy, as predicted by computational models.

Increased expression of OPN contributes to idiopathic pulmonary fibrosis and indicates a poor prognosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is fibrotic lung disease with no effective treatment. It is characterized by destruction of alveolar structure and pulmonary interstitial fibrosis, leading to dyspnea and even asphyxia death of patients. Epithelial-mesenchymal transition (EMT) is considered to be a driving factor in the pathogenesis of IPF. Osteopontin (OPN) is a secreted protein widely present in the extracellular matrix and involved in the occurrence and development of a variety of diseases. METHODS: The original datasets were obtained from NCBI GEO databases analyzed with the online tool GEO2R and EasyGEO. Bleomycin induced mouse pulmonary fibrosis model and OPN/OPN-biotin treated mouse model were established to investigate the role of OPN in mouse pulmonary fibrosis and the target cells of OPN. A549 cells and HBE cells were used to explore the mechanism of OPN-induced epithelial-mesenchymal transition (EMT) in epithelial cells and mass spectrometry was used to detect OPN downstream receptors. Precision-cut lung slices and lentivirus-treated mice with pulmonary fibrosis were used to examine the therapeutic effect of OPN and its downstream pathways on pulmonary fibrosis. RESULTS: We demonstrate that the content of OPN in IPF bronchoalveolar lavage fluid (BALF) is high compared to the normal groups, and its expression level is correlated with prognosis. At the animal level, OPN was highly expressed at all stages of pulmonary fibrosis in mice, and the bronchoalveolar lavage fluid (BALF) could accurately reflect its expression in the lung. Next, we reveal that OPN was mainly expressed by macrophages and the main target cells of OPN were epithelial cells. Mice developed pulmonary fibrosis accompanied after treating the mice with OPN. Both in vitro and in vivo experiments confirmed that OPN could induce EMT of alveolar epithelial cells. Mechanistically, OPN binding triggered phosphorylation of FAK by CD44, thus activating snail1-mediated profibrotic protein synthesis. Inhibition of FAK phosphorylation and its downstream pathways can effectively alleviate pulmonary fibrosis in precision sections of lung tissue (PCLS) assay. OPN knockdown in bleomycin-induced lung fibrosis mice led to significantly less fibrosis. CONCLUSION: Our data suggest that OPN mediates lung fibrosis through EMT, implicating its potential therapeutic target and prognostic indicator role for IPF. OPN may be a target for the diagnosis and treatment of IPF.

Indirect comparisons of efficacy of zanubrutinib versus orelabrutinib in patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma or relapsed or refractory mantle cell lymphoma.

We conducted two indirect comparisons to estimate the efficacy of zanubrutinib versus orelabrutinib in Chinese patients with relapsed or refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) or R/R mantle cell lymphoma (MCL). An unanchored matching-adjusted indirect comparison (MAIC) was performed in R/R CLL/SLL patients. Individual patient data from zanubrutinib trial (BGB-3111-205) were adjusted to match the aggregated data from the orelabrutinib trial (ICP-CL-00103). A naïve comparison was performed in R/R MCL for the different response assessment methodology and efficacy analysis set between the zanubrutinib (BGB-3111-206) and orelabrutinib (ICP-CL-00102) trials. Efficacy outcomes included ORR and PFS. In R/R CLL/SLL patients, after matching, IRC-assessed ORR was comparable (86.6% vs. 92.5%; risk difference, -5.9% [95% CI: -15.8%-3.8%]); IRC-assessed PFS was similar with a favorable trend in zanubrutinib over orelabrutinib (HR, 0.74 [95% CI: 0.37-1.47]) and the 18-month PFS rate was numerically higher in zanubrutinib (82.9% vs. 78.7%). In R/R MCL patients, naïve comparison showed investigator-assessed ORR was similar (83.7% vs. 87.9%; risk difference, -4.2% [95% CI: -14.8%-6.0%]), and CR rate was significantly higher in zanubrutinib over orelabrutinib (77.9% vs. 42.9%; risk difference, 35.0% [95% CI: 14.5%, 53.7%]). Investigator-assessed PFS was similar with a favorable trend (HR, 0.77 [95% CI: 0.45-1.32]) in zanubrutinib over orelabrutinib and the 12-month PFS rate was numerically higher in zanubrutinib (77.5% vs. 70.8%). MAIC result showed zanubrutinib demonstrated favorable PFS over orelabrutinib for R/R CLL/SLL patients. The naïve comparison showed zanubrutinib had favorable PFS and higher CR rate than orelabrutinib for R/R MCL patients.

Hsa_circ_0012919 promotes pyroptosis in CD4+T cells of systemic lupus erythematous by miR-125a-3p/GSDMD axis.

The etiology of systemic lupus erythematous (SLE) remains unclear. Pyroptosis, a new model of programmed cell death, was poorly explored in the pathogenesis of SLE. We found cell pyroptosis in CD4+T cells of SLE patients and kidneys from MRL/lpr mice by examining caspase-1 and gasdermin D (GSDMD) in by RT-PCR, Western blot, and levels of IL-1ß, IL-18 and TNF-α were detected by RT-PCR and Elisa. Expression of caspase-1 and GSDMD and levels of IL-1ß, IL-18, TNF-α decreased significantly after downregulation of hsa_circ_0012919 (p < 0.05). Inhibition of miR-125a-3p enhanced expression of caspase-1 and GSDMD (p < 0.05), and increased the release of IL-1ß, IL-18 and TNF-α (p < 0.05), thereby counteracting the effect of hsa_circ_0012919 knockdown on pyroptosis. Finally, we identified GSDMD as the target gene of miR-125a-3p. Silencing GSDMD reversed the effect of 5-aza-deoxycytidine in increasing release of IL-1ß, IL-18, TNF-α and activating caspase-1, but it could be reversed by miR-125a-3p inhibitor. In conclusion, hsa_circ_0012919 regulated the pyroptosis in the CD4+ T cells of SLE patients by miR-125a-3p/GSDMD axis.

A pilot study of cord blood-derived natural killer cells as maintenance therapy after autologous hematopoietic stem cell transplantation.

Natural killer (NK) cell based immunotherapy is an emerging strategy in hematologic malignancies because allogeneic NK cells can provide potent antitumor immunity without inducing graft-versus-host disease. Thus, we expanded cord blood-derived NK (CB-NK) cells ex vivo from random (MHC mismatched and KIR mismatched) donors, and investigate the feasibility and efficacy of repeated infusions CB-NK cells as maintenance therapy after autologous hematopoietic stem cell transplantation (ASCT). Thirty-one patients with acute myeloid leukemia and high-risk lymphoma received ASCT and the adoptive CB-NK cell multiple infusions for maintenance therapy. Patients received a median dose of 5.98 × 107/kg (range, 1.87-17.69 × 107/kg) CB-NK cells and 23 patients completed four infusions, 8 patients received three infusions. Only mild infusion reactions occurred in 15.5% of 116 infusions. Compared to a contemporaneous cohort of 90 patients who did not receive NK cell therapy, the adoptive transfer of CB-NK cells as maintenance treatment showed a tendency of difference in decreasing the relapse rate between CB-NK group and control group (9.7% vs 24.4%). The patients who receiving NK cell infusions had a better PFS and OS than controls (4 year PFS, 84.4 ± 8.3% vs 73.5 ± 5.4%; and 4 year OS, 100% vs 78.1 ± 5.4%) . These findings demonstrate safety and validity of maintenance therapy using CB-NK cells multiple infusions after ASCT, and it is worthy of further clinical trial verification.

The MAGIC algorithm probability (MAP)-guided preemptive therapy of acute graft versus host disease with methylprednisolone: A randomized controlled trial.

Acute graft versus host disease (aGvHD) is a severe complication that arises in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) and remains the primary cause of nonrelapse mortality (NRM). The MAGIC algorithm probability (MAP) has been proposed to identify patients at intermediate and high risk of developing aGvHD. The levels of suppression of tumorigenicity 2 (ST2) and regenerating islet-derived 3α (Reg3α) were assessed, and MAP was calculated on days 7, 14, 21, and 28 after allo-HSCT. Based on the MAP results, patients were classified into low-, intermediate-, or high-risk groups for the development of aGvHD. Random assignment was performed to allocate intermediate- or high-risk patients to receive preemptive therapy with methylprednisolone or not. The 100-day cumulative incidences of grade 2 or higher (35.5% ± 8.6%) and grade 3 or higher (12.9% ± 6.0%) aGvHD in the methylprednisolone group were significantly lower than those in the control group (66.7% ± 7.9%, p = .01; 42.9% ± 8.4%, p = .01), and similar to those observed in the low-risk group (31.7% ± 7.3%, p = .75; 2.4% ± 2.4%, p = .08). The 6-month cumulative incidences of NRM were 14.1% ± 6.6%, 22.7% ± 7.1%, and 2.4% ± 2.4% in the methylprednisolone, control, and low-risk groups, respectively, with no significant difference between the methylprednisolone and control groups (p = .29). Methylprednisolone did not increase infections (p = .34). The 100-day cumulative incidences of cytomegalovirus (CMV) reactivation were 67.7% ± 8.4%, 65.6% ± 8.4%, and 46.3% ± 7.8% (p = .08), and those of grade 2 or higher hemorrhagic cystitis were 29.0% ± 8.2%, 45.2% ± 8.9% and 22.0% ± 6.5% (p = .11) in the methylprednisolone, control, and low-risk groups, respectively. MAP-guided preemptive therapy for aGvHD is promising. The long-term efficacy and safety remain to be investigated.