CAR T Cell Membrane Camouflaged Nanocatalyst Augments CAR T Cell Therapy Efficacy Against Solid Tumor.

The immunosuppressive tumor microenvironment (TME) reduces the chimeric antigen receptor (CAR) T-cell therapy against solid tumors. Here, a CAR T cell membrane-camouflaged nanocatalyst (ACSP@TCM) is prepared to augment CAR T cell therapy efficacy against solid tumors. ACSP@TCM is prepared by encapsulating core/shell Au/Cu2- xSe and 3-bromopyruvate with a CAR T cell membrane. It is demonstrated that the CAR T cell membrane camouflaging has much better-targeting effect than the homologous tumors cell membrane camouflaging. ACSP@TCM has an appealing synergistic chemodynamic/photothermal therapy (CDT/PTT) effect that can induce the immunogenic cell death (ICD) of NALM 6 cells. Moreover, 3-bromopyruvate can inhibit the efflux of lactic acid by inhibiting the glycolysis process, regulating the acidity of TME, and providing a more favorable environment for the survival of CAR T cells. In addition, the photoacoustic (PA) imaging and computed tomography (CT) imaging performance can guide the ACSP@TCM-mediated tumor therapy. The results demonstrated that the ACSP@TCM significantly enhanced the CAR T cell therapy efficacy against NALM 6 solid tumor mass, and completely eliminated tumors. This work provides an effective tumor strategy for CAR T cell therapy in solid tumors.

CAIDE Score, Alzheimer's Disease Pathology, and Cognition in Cognitively Normal Adults: The CABLE Study.

Background: Cardiovascular Risk Factors, Ageing and Dementia (CAIDE) risk score serves as a credible predictor of an individual's risk of dementia. However, studies on the link of the CAIDE score to Alzheimer's disease (AD) pathology are scarce. Objective: To explore the links of CAIDE score to cerebrospinal fluid (CSF) biomarkers of AD as well as to cognitive performance. Methods: In the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study, we recruited 600 cognitively normal participants. Correlations between the CAIDE score and CSF biomarkers of AD as well as cognitive performance were probed through multiple linear regression models. Whether the correlation between CAIDE score and cognitive performance was mediated by AD pathology was researched by means of mediation analyses. Results: Linear regression analyses illustrated that CAIDE score was positively associated with tau-related biomarkers, including pTau (p <  0.001), tTau (p <  0.001), as well as tTau/Aß42 (p = 0.008), while it was in negative association with cognitive scores, consisting of MMSE score (p <  0.001) as well as MoCA score (p <  0.001). The correlation from CAIDE score to cognitive scores was in part mediated by tau pathology, with a mediation rate varying from 3.2% to 13.2% . Conclusions: A higher CAIDE score, as demonstrated in our study, was linked to more severe tau pathology and poorer cognitive performance, and tau pathology mediated the link of CAIDE score to cognitive performance. Increased dementia risk will lead to cognitive decline through aggravating neurodegeneration.

Multiomics-based molecular subtyping based on the commensal microbiome predicts molecular characteristics and the therapeutic response in breast cancer.

The gut microbiota has been demonstrated to be correlated with the clinical phenotypes of diseases, including cancers. However, there are few studies on clinical subtyping based on the gut microbiota, especially in breast cancer (BC) patients. Here, using machine learning methods, we analysed the gut microbiota of BC, colorectal cancer (CRC), and gastric cancer (GC) patients to identify their shared metabolic pathways and the importance of these pathways in cancer development. Based on the gut microbiota-related metabolic pathways, human gene expression profile and patient prognosis, we established a novel BC subtyping system and identified a subtype called "challenging BC". Tumours with this subtype have more genetic mutations and a more complex immune environment than those of other subtypes. A score index was proposed for in-depth analysis and showed a significant negative correlation with patient prognosis. Notably, activation of the TPK1-FOXP3-mediated Hedgehog signalling pathway and TPK1-ITGAE-mediated mTOR signalling pathway was linked to poor prognosis in "challenging BC" patients with high scores, as validated in a patient-derived xenograft (PDX) model. Furthermore, our subtyping system and score index are effective predictors of the response to current neoadjuvant therapy regimens, with the score index significantly negatively correlated with both treatment efficacy and the number of immune cells. Therefore, our findings provide valuable insights into predicting molecular characteristics and treatment responses in "challenging BC" patients.

Association between Periodontitis and Hematologic Cancer: An NHIRD Cohort Study in Taiwan.

BACKGROUND: Chronic periodontitis, an inflammation-related disorder affecting global populations, has been revealed to be linked to diverse cancers. Numerous epidemiological studies have not shown a link between chronic periodontitis and blood cancers in Taiwan. METHODS: This study included 601,628 patients, diagnosed with newly chronic periodontitis by the ICD-9-CM classification, who were enrolled from 2001 to 2021 in the National Health Insurance Research Database (NHIRD) in Taiwan. In this study, we employed comprehensive statistical analyses to investigate the association between chronic periodontitis and hematologic cancers. Initially, we calculated incidence density and used a Poisson regression to analyze relative risk. Subsequently, we compared the cumulative incidence of hematological cancer in both chronic and non-chronic periodontitis groups using the Kaplan-Meier method. RESULTS: The results revealed a significantly lower cumulative incidence of hematologic cancer in individuals with non-chronic periodontitis over a 12-year follow-up period. To further explore the risk factors, a Cox proportional hazard regression analysis was conducted. Being male (adjusted hazard ratio [aHR] = 1.21, 95% CI: 1.04 to 1.42; p = 0.014) and having hypertension (aHR = 1.34, 95% CI: 1.06 to 1.69; p = 0.015) were demonstrated to be associated with an increased risk of hematologic cancers, respectively. In addition, in a subtype multivariate analysis for categorizing hematologic cancers into lymphoma and leukemia, the aHR for leukemia was 1.48 (95% CI: 1.13 to 1.93; p = 0.004) and aHR for lymphoma was 1.15 (95% CI: 0.96 to 1.37; p = 0.140). CONCLUSIONS: This study found that being male and having hypertension were the significant risk factors for hematological malignancies. Moreover, the association between chronic periodontitis and specific subtypes of hematologic cancers was confirmed.

Dual targeting total saponins of Pulsatilla of natural polymer crosslinked gel beads with multiple therapeutic effects for ulcerative colitis.

Oral colon targeted drug delivery system (OCTDDS) is desirable for the treatment of ulcerative colitis (UC). In this study, we designed a partially oxidized sodium alginate-chitosan crosslinked microsphere for UC treatment. Dissipative particle dynamics (DPD) was used to study the formation and enzyme response of gel beads from a molecular perspective. The formed gel beads have a narrow particle size distribution, a compact structure, low cytotoxicity and great colon targeting in vitro and in vivo. Animal experiments demonstrated that gel beads promoted colonic epithelial barrier integrity, decreased the level of pro-inflammatory factors, accelerated the recovery of intestinal microbial homeostasis in UC rats and restored the intestinal metabolic disorders. In conclusion, our gel bead is a promising approach for the treatment of UC and significant for the researches on the pathogenesis and treatment mechanism of UC.

Single-cell analysis of anti-BCMA CAR T cell therapy in patients with central nervous system autoimmunity.

Chimeric antigen receptor (CAR) T cell immunotherapy for the treatment of neurological autoimmune diseases is promising, but CAR T cell kinetics and immune alterations after treatment are poorly understood. Here, we performed single-cell multi-omics sequencing of paired cerebrospinal fluid (CSF) and blood samples from patients with neuromyelitis optica spectrum disorder (NMOSD) treated with anti-B cell maturation antigen (BCMA) CAR T cells. Proliferating cytotoxic-like CD8+ CAR T cell clones were identified as the main effectors in autoimmunity. Anti-BCMA CAR T cells with enhanced features of chemotaxis efficiently crossed the blood-CSF barrier, eliminated plasmablasts and plasma cells in the CSF, and suppressed neuroinflammation. The CD44-expressing early memory phenotype in infusion products was potentially associated with CAR T cell persistence in autoimmunity. Moreover, CAR T cells from patients with NMOSD displayed distinctive features of suppressed cytotoxicity compared with those from hematological malignancies. Thus, we provide mechanistic insights into CAR T cell function in patients with neurological autoimmune disease.

The relationship of KRAS expression with KRAS status, prognosis, and tumor-infiltrated T lymphocytes in colorectal cancer.

Background: The significance of Kirsten rat sarcoma viral oncogene (KRAS) mutation in colorectal cancer (CRC) is well established; yet, its association with KRAS expression and prognosis warrants further investigation. While high KRAS expression is commonly linked with poorer prognosis in other cancers, its role in CRC remains relatively understudied. Objective: To explore the correlation between KRAS expression, KRAS status, prognosis, and tumor-infiltrating T lymphocyte density in CRC. Design: Single-center retrospective study. Methods: Conducted between 2010 and 2020, this study utilized tumor samples to assess KRAS expression and quantify CD3+/CD8+ T lymphocytes. The Cox proportional hazards model and linear regression analysis were employed to examine the relationship between KRAS expression, prognosis, and tumor-infiltrating T lymphocytes. Results: This study included 265 CRC patients who underwent radical surgery. No significant association was observed between KRAS expression and KRAS status (p > 0.05). High KRAS expression was associated with poorer overall survival and disease-free survival (p < 0.05). Subgroup analysis revealed that high KRAS expression remained indicative of a worse prognosis in the group with mismatch repair-deficient (dMMR) and KRAS mutant type (p < 0.05). Multivariate analysis confirmed KRAS expression as an unfavorable prognostic factor (p < 0.05). However, the significance of KRAS expression was lost in the dMMR and KRAS mutant-type group regarding overall survival (p > 0.05). Notably, KRAS expression showed a negative correlation with the density of CD8+ T lymphocytes in tumor tissue (p < 0.05), a finding also observed in the dMMR group (p < 0.05). Conclusion: No association was found between KRAS expression and KRAS mutation status in CRC. Higher KRAS expression was indicative of poorer prognosis for CRC patients, except for those with proficient mismatch repair and KRAS wild type. In addition, in patients with dMMR, KRAS expression was associated with a lower density of CD8+ T lymphocytes in tumor tissue.

Exploring the link between KRAS gene expression and outcomes in colorectal cancer patients: impact on survival, mutation status, and T lymphocyte levels 1. KRAS gene: A gene that, when mutated, can lead to the development and growth of colorectal cancer. The KRAS gene is part of a family of genes that help control cell growth and death. 2. T lymphocytes: A type of immune cell that plays a crucial role in the body's defense against infections and cancer. They can identify and kill cancer cells. 3. The study found that the level of activity of the KRAS gene in colorectal cancer patients did not change based on whether the KRAS gene was mutated or what type of mutation it had. 4. For patients with a specific type of colorectal cancer (dMMR) and those with mutations in the KRAS gene, high levels of KRAS gene activity were linked to a poorer outlook. Essentially, these patients had a harder time fighting the disease, and KRAS gene activity served as a warning sign for more challenging outcomes. 5. In patients with dMMR colorectal cancer, higher KRAS gene activity was associated with fewer CD8+ T lymphocytes in the tumor. CD8+ T lymphocytes are crucial immune cells that help fight cancer by attacking cancer cells. This means that in these patients, the body's natural defense against the tumor was weaker.

Drawing as a window to emotion with insights from tech-transformed participant images.

This study delves into expressing primary emotions anger, happiness, sadness, and fear through drawings. Moving beyond the well-researched color-emotion link, it explores under-examined aspects like spatial concepts and drawing styles. Employing Python and OpenCV for objective analysis, we make a breakthrough by converting subjective perceptions into measurable data through 728 digital images from 182 university students. For the prominent color chosen for each emotion, the majority of participants chose red for anger (73.11%), yellow for happiness (17.8%), blue for sadness (51.1%), and black for fear (40.7%). Happiness led with the highest saturation (68.52%) and brightness (75.44%) percentages, while fear recorded the lowest in both categories (47.33% saturation, 48.78% brightness). Fear, however, topped in color fill percentage (35.49%), with happiness at the lowest (25.14%). Tangible imagery prevailed (71.43-83.52%), with abstract styles peaking in fear representations (28.57%). Facial expressions were a common element (41.76-49.45%). The study achieved an 81.3% predictive accuracy for anger, higher than the 71.3% overall average. Future research can build on these results by improving technological methods to quantify more aspects of drawing content. Investigating a more comprehensive array of emotions and examining factors influencing emotional drawing styles will further our understanding of visual-emotional communication.

Biogenic volatile organic compounds in forest therapy base: A source of air pollutants or a healthcare function?

Air pollution poses a significant threat to public health, while biogenic volatile organic compounds (BVOCs) play a crucial role in both aspects. However, the unclear relationship between BVOCs and air pollutants in the under-canopy space limits the accuracy of air pollution control and the exploitation of forest healthcare functions. To clarify the variation of BVOCs in forest therapy bases, and their impacts on ozone (O3) and fine particulate matter (PM2.5) at nose height, total VOCs (TVOCs) in the forest were collected during typical sunny days, while air pollutants and meteorological factors were observed simultaneously. The results showed that the branch-level emissions of P. tabuliformis were dominated by healthcare-effective monoterpenoids, with only α-pinene having relative air concentrations of over 5 % in forest air samples. The correlation between concentrations of under-canopy TVOCs and emission rates of BVOCs from P. tabuliformis was weak (p > 0.09) in all seasons. However, the correlation between concentrations of TVOCs and the concentrations of O3 and PM2.5 showed clear seasonal differences. In spring, TVOCs only showed a significant negative correlation with PM2.5 in the forest (p < 0.01). In summer and autumn, TVOCs were significantly negatively correlated with both O3 (p < 0.001) and PM2.5 (p < 0.01). Specifically, the negative linear relationships were more pronounced for O3 and oxygenated VOCs in autumn (R2 = 0.40, p < 0.001) than for other relationships. The relationship between air pollutant concentrations inside and outside the forest also showed significant seasonal differences, generally characterized by a weaker correlation between them during seasons of strong emissions. Therefore, BVOCs in coniferous forests are health functions as they can provide healthcare effects and mitigate the concentration of air pollutants in the forest, and the establishment of forest therapy bases in rural areas with low NOx can be a sensible approach to promote good health, well-being, and sustainable development.

Chitosan catechol-tannic acid composite hydrogel and cryogel with antimicrobial and hemostatic properties.

Hydrogels containing catechol group have received attention in the biomedical field due to their robust adhesive/cohesive capabilities, biocompatibility, and hemostatic abilities. Catechol-functionalized chitosan holds promise for preparing self-assembly hydrogels. However, issues of inefficient gelation and instability still persist in these hydrogels. In the current study, we synthesized chitosan catechol (CC) of high catechol substitution (~28 %) and combined CC with tannic acid (TA, which also contains catechol) to form self-healing CC-TA hydrogels. The catechol-enriched CC-TA composite hydrogels showed rapid gelation and mechanical reinforcement (shear modulus ~110 Pa). In situ coherent small-angle X-ray scattering (SAXS) coupled with rheometry revealed a morphological feature of mesoscale clusters (~20 nm) within CC-TA hydrogel. The clusters underwent dynamic destruction under large-amplitude oscillatory shear, corresponding with the strain-dependent and self-healing behavior of the CC-TA hydrogel. The composite hydrogel had osmotic-responsive and notable adhesive properties. Meanwhile, CC-TA composite cryogel prepared simply through freeze-thawing procedures exhibited distinctive macroporous structure (~200 µm), high water swelling ratio (~7000 %), and favorable compressive modulus (~8 kPa). The sponge-like cryogel was fabricated into swabs, demonstrating hemostatic capacity. The CC-TA composites, in both hydrogel and cryogel forms, possessed ROS scavenging ability, antimicrobial activity, and cell compatibility with potentials in biological applications.

Ultra-broadband TM-pass polarizer based on anisotropic metamaterials in lithium niobate on an insulator.

An ultra-broadband TM-pass polarizer is designed, fabricated, and experimentally demonstrated based on subwavelength grating (SWG) metamaterials in a lithium niobate on an insulator (LNOI) platform. According to our simulation, the designed device is predicted to work at a 220 nm wavelength range from 1460 to 1680 nm, covering the S-, C-, L-, U-bands of optical fiber communication. By depositing and subsequently etching a silicon nitride thin film atop the LNOI chip, the SWG structures are formed successfully by using complementary metal-oxide semiconductor (CMOS)-compatible fabrication processes. The measured results show a high polarization extinction ratio larger than 20 dB and a relatively low insertion loss below 2.5 dB over a 130 nm wavelength range from 1500 to 1630 nm, mainly limited by the operation bandwidth of our laser source.

BmATAD3A mediates mitochondrial ribosomal protein expression to maintain the mitochondrial energy metabolism of the silkworm, Bombyx mori.

ATAD3A is a mitochondrial membrane protein belonging to the ATPase family that contains the AAA+ domain. It is widely involved in mitochondrial metabolism, protein transport, cell growth, development and other important life processes. It has previously been reported that the deletion of ATAD3A causes growth and development defects in humans, mice and Caenorhabditis elegans. To delve into the mechanism underlying ATAD3A defects and their impact on development, we constructed a Bombyx mori ATAD3A (BmATAD3A) defect model in silkworm larvae. We aim to offer a reference for understanding ATAD3A genetic defects and elucidating the molecular regulatory mechanisms. The results showed that knockout of the BmATAD3A gene significantly affected the weight, survival rate, ATPase production and mitochondrial metabolism of individuals after 24 h of incubation. Combined metabolomics and transcriptomics analysis further demonstrated that BmATAD3A knockout inhibits amino acid biosynthesis through the regulation of mitochondrial ribosomal protein expression. Simultaneously, our findings indicate that BmATAD3A knockout impeded mitochondrial activity and ATPase synthesis and suppressed the mitochondrial oxidative phosphorylation pathway through B. mori mitochondrial ribosomal protein L11 (BmmRpL11). These results provide novel insights into the molecular mechanisms involved in the inhibition of development caused by ATAD3A deficiency, offering a potential direction for targeted therapy in diseases associated with abnormal ATAD3A expression.

Cost-Effective Rechargeable Magnesium Battery Based on a Fluorinated Alkoxyaluminate Electrolyte and a Carbonyl Polymer Cathode.

Rechargeable magnesium batteries (RMBs) are one of the most promising "post-lithium" battery technologies, but the electrochemical performance is still far from expectation due to the sluggish reaction kinetics of divalent Mg2+ ions. Herein, we report a low-cost, high-performance Mg-organic battery based on the combination of a fluorinated alkoxyaluminate electrolyte and a carbonyl polymer cathode material. First, the one-pot synthesized Mg[Al(HFIP)4]2 (HFIP = hexafluoro-2-propanol) is proved superior to the Mg[B(HFIP)4]2 analogue in both Mg anode compatibility and electrochemical window, as the electrolyte salt in the G2-DME (G2 = diethylene glycol dimethyl ether; DME = 1,2-dimethoxyethane) mixture solvent. Second, a simple wet grinding method is proposed to effectively improve the dispersion uniformity of the poly(benzoquinone-pyrrole) (PBQPy) active material in the cathode. Third, the elaborate Mg-PBQPy battery exhibits superior electrochemical performance within 0.4-3.0 V, including a high reversible capacity of 197 mA h g-1, a high average discharge voltage of 1.6 V, and a high capacity retention of 71% after 500 cycles. Finally, based on various electrochemical analysis and ex situ characterization results, we propose a general microscopic structure evolution model to reveal the electrochemical behaviors of carbonyl polymer cathode in RMBs, including the swelling of polymer active material, trapping of Mg2+ ions, and reversible redox reaction.

Zinc alleviates thermal stress-induced damage to the integrity and barrier function of cultured chicken embryonic primary jejunal epithelial cells via the MAPK and PI3K/AKT/mTOR signaling pathways.

Zinc (Zn) could alleviate the adverse effect of high temperature (HT) on intestinal integrity and barrier function of broilers, but the underlying mechanisms remain unclear. We aimed to investigate the possible protective mechanisms of Zn on primary cultured broiler jejunal epithelial cells exposed to thermal stress (TS). In Exp.1, jejunal epithelial cells were exposed to 40℃ (normal temperature, NT) and 44℃ (HT) for 1, 2, 4, 6, or 8 h. Cells incubated for 8 h had the lowest transepithelial resistance (TEER) and the highest phenol red permeability under HT. In Exp.2, the cells were preincubated with different Zn sources (Zn sulfate as iZn and Zn proteinate with the moderate chelation strength as oZn) and Zn supplemental levels (50 and 100 µmol/L) under NT for 24 h, and then continuously incubated under HT for another 8 h. TS increased phenol red permeability, lactate dehydrogenase (LDH) activity and p-PKC/PKC level, and decreased TEER, cell proliferation, mRNA levels of claudin-1, occludin, zona occludens-1 (ZO-1), PI3K, AKT and mTOR, protein levels of claudin-1, ZO-1 and junctional adhesion molecule-A (JAM-A), and the levels of p-ERK/ERK, p-PI3K/PI3K and p-AKT/AKT. Under HT, oZn was more effective than iZn in increasing TEER, occludin, ZO-1, PI3K, and AKT mRNA levels, ZO-1 protein level, and p-AKT/AKT level; supplementation with 50 µmol Zn/L was more effective than 100 µmol Zn/L in increasing cell proliferation, JAM-A, PI3K, AKT, and PKC mRNA levels, JAM-A protein level, and the levels of p-ERK/ERK and p-PI3K/PI3K; furthermore, supplementation with 50 µmol Zn/L as oZn had the lowest LDH activity, and the highest ERK, JNK-1, and mTOR mRNA levels. Therefore, supplemental Zn, especially 50 µmol Zn/L as oZn, could alleviate the TS-induced integrity and barrier function damage of broiler jejunal epithelial cells possibly by promoting cell proliferation and tight junction protein expression via the MAPK and PI3K/AKT/mTOR signaling pathways.

Prevalence of coccidia in lagomorphs in China between 1981 and 2023: A systematic review and meta-analysis.

Lagomorpha coccidiosis, caused by coccidia, is a prevalent disease affecting rabbits, hares and pikas. This meta-analysis aimed to estimate the pooled prevalence of coccidia infection in lagomorphs and identify potential risk factors. A systematic search of six databases yielded 102 studies published between 1981 and 2023. The pooled prevalence of Eimeriidae, Sarcocystidae and Cryptosporidiidae in lagomorphs was 76.4%, 6.2% and 3.9%, respectively. Rabbits had the highest prevalence of Eimeriidae (76.8%) and Sarcocystidae (7.4%), while pikas had the highest prevalence of Cryptosporidiidae (6.2%). Juvenile rabbits exhibited the highest prevalence of Eimeriidae (84.6%) and Cryptosporidiidae (9.9%). Northwest China had the highest prevalence of Eimeriidae (87.8%). Over time, the prevalence of Eimeriidae declined (Coefficient: -0.0062; P<0.05), but remained high (65.0%) in the past five years. Our findings highlight the prevalence of Eimeriidae infection in lagomorphs and the need for further research on Sarcocystidae and Cryptosporidiidae infections. We emphasize the importance of developing lagomorpha coccidia vaccines and implementing vaccination schedules for juvenile rabbits to mitigate coccidia infections.

Frontline combination of dasatinib and low-intensity chemotherapy in adults with de novo Philadelphia chromosome-positive acute lymphoblastic leukemia.

BACKGROUND: Studies on dasatinib-based low-intensity induction regimens and post-remission strategies are limited in China. Therefore, we conducted a single-center phase 2 trial in newly diagnosed adult patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) to establish the efficacy and safety of this treatment approach. RESEARCH DESIGN AND METHODS: Patients received one month of dasatinib plus low-intensity chemotherapy and two months of dasatinib monotherapy for induction, followed by a single course of high-dose methotrexate for consolidation. Subsequently, they underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) or tyrosine kinase inhibitor (TKI)-based treatment for maintenance therapy between October 2015 and August 2022. RESULTS: Twenty-two patients were enrolled. Median age was 45 years (range, 20-71). The rates of major and complete molecular responses in the third month were 18.2% and 40.9% respectively. With a median follow-up of 15 months (range, 5-89), the estimated 3-year disease-free survival (DFS) and overall survival (OS) were 52.4% and 73.2%, respectively. The TKI-based cohort had a significantly poorer DFS (p = 0.014) and OS (p = 0.008) than the allo-HSCT cohort. CONCLUSIONS: Our results suggest that dasatinib-based low-intensity chemotherapy is safe and effective as an induction strategy in the Chinese population. Allo-HSCT plays a crucial role in the long-term outcomes of patients with Ph+ ALL. CLINICAL TRIAL REGISTRATION: The trial was registered at ClinicalTrials.gov as NCT02690922.

Combination of chidamide and PD-1 blockade in Refractory/Relapsed aggressive large B-cell lymphomas with high risk of failing CAR-T therapy.

BACKGROUND: Refractoriness and relapse after chimeric antigen receptor T-cell therapy have emerged as major challenges for immunotherapy of aggressive large B-cell lymphoma. Thus far, there is no consensus on how to address treatment failure and whether to administer maintenance therapy following CAR-T cell therapy. METHODS: From August 2017 through November 2022, 52 patients with refractory/relapsed aggressive LBCL who had a high risk of resistance to CAR-T cell therapy were given chidamide in combination with a PD-1 inhibitor as maintenance therapy following either CAR19/22 T-cell cocktail therapy or CAR19/22 T-cell cocktail therapy plus autologous stem cell transplantation (ASCT). Another 52 aggressive LBCL patients who had comparable baseline characteristics and received similar therapeutic regimens but did not receive any interventions following CAR-T cell therapy or CAR-T cell therapy plus ASCT were regarded as the control group to evaluate the efficacy and safety of the combination of chidamide and a PD-1 inhibitor. RESULTS: Among the 52 patients who received chidamide and a PD-1 inhibitor as maintenance therapy, with a median follow-up of 26.5 months (range: 1.1-53.8), neither the median progression-free survival (PFS) nor overall survival (OS) was reached, and the expected 2-year OS and PFS rates were 89 % and 77 %, respectively, which were superior to those of the control group (p < 0.001). Long-term chidamide administration and a specific genetic subtype of EZB were strongly associated with a better response after chidamide plus PD-1 blockade therapy. Additionally, long-term chidamide administration was significantly associated with prolonged persistence and reactivation of CD19-directed CAR-T cells in the peripheral blood. Adverse effects (AEs) were moderate and reversible, and no treatment-related deaths occurred. CONCLUSION: Our results indicate that the combination of chidamide and PD-1 blockade as maintenance therapy could improve the outcomes of aggressive LBCL patients at high risk of failing CAR-T cell therapy.

Identification of hyperthermophilic D-allulose 3-epimerase from Thermotoga sp. and its application as a high-performance biocatalyst for D-allulose synthesis.

D-Allulose 3-epimerase (DAE) is a vital biocatalyst for the industrial synthesis of D-allulose, an ultra-low calorie rare sugar. However, limited thermostability of DAEs hinders their use at high-temperature production. In this research, hyperthermophilic TI-DAE (Tm = 98.4 ± 0.7 ℃) from Thermotoga sp. was identified via in silico screening. A comparative study of the structure and function of site-directed saturation mutagenesis mutants pinpointed the residue I100 as pivotal in maintaining the high-temperature activity and thermostability of TI-DAE. Employing TI-DAE as a biocatalyst, D-allulose was produced from D-fructose with a conversion rate of 32.5%. Moreover, TI-DAE demonstrated excellent catalytic synergy with glucose isomerase CAGI, enabling the one-step conversion of D-glucose to D-allulose with a conversion rate of 21.6%. This study offers a promising resource for the enzyme engineering of DAEs and a high-performance biocatalyst for industrial D-allulose production.

Differential Susceptibility to Propofol and Ketamine in Primary Cultures of Young and Senesced Astrocytes.

The adverse effects of general anesthesia on the long-term cognition of young children and senior adults have become of concern in recent years. Previously, mechanistic and pathogenic investigations focused on neurons, and little is known about the effect of commonly used intravenous anesthetics such as propofol and ketamine on astrocytes. Recently, astrocyte dysfunction has been implicated in a wide range of age-related brain diseases. In this study, we examined the survival and viability of both young and senescent astrocytes in culture after adding propofol and ketamine to the media at varying strengths. Oxidative stimulus was applied to commercially available fetal cell lines of human astrocytes in vitro to induce morphological changes in cellular senescence. Our results indicate that propofol reduces the survival of young astrocytes as compared to controls, as well as to ketamine. These effects were seen in comparisons of total cell count and at both high and low dose concentrations. High doses of propofol also significantly reduced cell viability compared to those exposed to baseline controls and ketamine. Senescent astrocytes, on the other hand, demonstrated cell count reductions as compared to baseline controls and ketamine when exposed to either DMSO or propofol. The data show differential susceptibility of young astrocytes to propofol than to ketamine. The observed cell count reduction may be related to the adverse effects of propofol on mitochondrial function and free radical production, as described in previous studies. We speculate that ketamine may have a more favorable safety profile in infants and young children.

Accurate Simulation for 2D Lubricating Materials in Realistic Environments: From Classical to Quantum Mechanical Methods.

2D materials such as graphene, MoS2, and hexagonal BN are the most advanced solid lubricating materials with superior friction and anti-wear performance. However, as a typical surface phenomenon, the lubricating properties of 2D materials are largely dependent on the surrounding environment, such as temperature, stress, humidity, oxygen, and other environmental substances. Given the technical challenges in experiment for real-time and in situ detection of microscopic environment-material interaction, recent years have witnessed the acceleration of computational research on the lubrication behavior of 2D materials in realistic environments. This study reviews the up-to-date computational studies for the effect of environmental factors on the lubrication performance of 2D materials, summarizes the theoretical methods in lubrication from classical to quantum-mechanics ones, and emphasizes the importance of quantum method in revealing the lubrication mechanism at atomic and electronic level. An effective simulation method based on ab initio molecular dynamics is also proposed to try to provide more ways to accurately reveal the friction mechanisms and reliably guide the lubricating material design. On the basis of current development, future prospects, and challenges for the simulation and modeling in lubrication with realistic environment are outlined.