Structural properties and antioxidant capacity of different aminated starch-phenolic acid conjugates.

Different aminated starch (AS) [EEAS (introducing ethylenediamine into starch using cross-linking-etherification-amination method (CEA)), EPAS (introducing o-phenylenediamine using CEA), OEAS (introducing ethylenediamine using cross-linking-oxidation-amination method (COA)), and OPAS (introducing o-phenylenediamine using COA)] were synthesized. The AS-phenolic acids [gallic acid (GA), syringic acid (SA), and vanillic acid (VA)] conjugates were prepared by laccase-catalyzed reaction. The grafting efficiency of EEAS on GA, SA, and VA was 36.59%, 69.71%, and 68.85%, respectively. SA reduced the maximum depolymerization rate of EEAS. The relative crystallinity of EEAS and EPAS grafted phenolic acid increased, and their particles showed severe breakage in appearance. OEAS-phenolic acid conjugates lost its granular structure and behaved as flakes and lumps, while the surface of OPAS-phenolic acid conjugates remained smooth after grafting phenolic acid. GA increased the DPPH· scavenging efficiency of EEAS from 16.12% to 79.92%. The increased antioxidant capacity of the conjugates suggested that AS-phenolic acids conjugates have high potential for applications.

Chidamide combined with a modified Bu-Cy conditioning regimen improves survival in patients with T-cell acute lymphoblastic leukemia/lymphoma undergoing allogeneic hematopoietic stem cell transplantation.

This study aimed to evaluate the efficacy and safety of chidamide (Chi) combined with a modified Busulfan-Cyclophosphamide (mBuCy) conditioning regimen for T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Twenty-two patients received chidamide combined with mBuCy conditioning regimen (Chi group). A matched-pair control (CON) group of 44 patients (matched 1:2) received mBuCy only in the same period. The leukemia-free survival (LFS), overall survival (OS), cumulative incidence of relapse (CIR), and non-relapse-related mortality (NRM) were evaluated. Patients in the Chi group were associated with lower 2-year CIR (19.0 vs. 41.4%, P = 0.030), better 2-year LFS (76.1 vs. 48.1%, P = 0.014), and had no significant difference in 2-year OS (80.5 vs. 66.4%, P = 0.088). Patients with minimal residual disease (MRD) positive before HSCT in the Chi group exhibited an advantage in 2-year LFS and a trend towards better 2-year OS (75.0 vs. 10.2%, P = 0.048; 75.0 vs. 11.4%, P = 0.060, respectively). Multivariable analysis showed that the chidamide intensified regimen was independently associated with better LFS (HR 0.23; 95%CI, 0.08-0.63; P = 0.004), and showed no significant impact with OS for all patients (HR 0.34, 95%CI, 0.11-1.07; P = 0.064). The cumulative incidence rates of grade II-IV aGVHD were similar (36.4 vs. 38.6%, P = 0.858). 20 patients in Chi group evinced an elevation in γ-glutamyltransferase, as compared to the mBuCy group (90.9 vs. 65.9%, P = 0.029). No transplantation-related mortality was documented within the first 100 days after transplantation. The results demonstrate that the chidamide intensified regimen may be an effective and acceptable safety option for T-ALL/LBL undergoing allo-HSCT, and further validation is needed.

Squalene-epoxidase-catalyzed 24(S),25-epoxycholesterol synthesis promotes trained-immunity-mediated antitumor activity.

The importance of trained immunity in antitumor immunity has been increasingly recognized, but the underlying metabolic regulation mechanisms remain incompletely understood. In this study, we find that squalene epoxidase (SQLE), a key enzyme in cholesterol synthesis, is required for ß-glucan-induced trained immunity in macrophages and ensuing antitumor activity. Unexpectedly, the shunt pathway, but not the classical cholesterol synthesis pathway, catalyzed by SQLE, is required for trained immunity induction. Specifically, 24(S),25-epoxycholesterol (24(S),25-EC), the shunt pathway metabolite, activates liver X receptor and increases chromatin accessibility to evoke innate immune memory. Meanwhile, SQLE-induced reactive oxygen species accumulation stabilizes hypoxia-inducible factor 1α protein for metabolic switching into glycolysis. Hence, our findings identify 24(S),25-EC as a key metabolite for trained immunity and provide important insights into how SQLE regulates trained-immunity-mediated antitumor activity.

Successful treatment of a B/T MPAL patient by chemo-free treatment with venetoclax, azacitidine, and blinatumomab.

B/T mixed phenotype acute leukemia (MPAL), which represents only 2-3% of all MPAL cases, is classified as a high-risk leukemia subtype. Adults diagnosed with B/T MPAL have a notably low 3-year survival rate, estimated at 20-40%. The rarity and undercharacterization of B/T MPAL present substantial challenges in identifying an optimal treatment protocol. This report aims to shed light on this issue by presenting a case in which a patient with a complex karyotype was treated using a combination of venetoclax, azacitidine, and blinatumomab. This novel, chemo-free regimen resulted in the patient achieving both hematologic and molecular complete remission, with no severe organ or hematological toxicity observed. Notably, the patient continued to maintain molecular remission for 1 year following the transplantation. Based on these findings, the combination of venetoclax, azacitidine, and blinatumomab could be considered a potential therapeutic approach for B/T MPAL patients, meriting further investigation.

Disparate macrophage responses are linked to infection outcome of Hantan virus in humans or rodents.

Hantaan virus (HTNV) is asymptomatically carried by rodents, yet causes lethal hemorrhagic fever with renal syndrome in humans, the underlying mechanisms of which remain to be elucidated. Here, we show that differential macrophage responses may determine disparate infection outcomes. In mice, late-phase inactivation of inflammatory macrophage prevents cytokine storm syndrome that usually occurs in HTNV-infected patients. This is attained by elaborate crosstalk between Notch and NF-κB pathways. Mechanistically, Notch receptors activated by HTNV enhance NF-κB signaling by recruiting IKKß and p65, promoting inflammatory macrophage polarization in both species. However, in mice rather than humans, Notch-mediated inflammation is timely restrained by a series of murine-specific long noncoding RNAs transcribed by the Notch pathway in a negative feedback manner. Among them, the lnc-ip65 detaches p65 from the Notch receptor and inhibits p65 phosphorylation, rewiring macrophages from the pro-inflammation to the pro-resolution phenotype. Genetic ablation of lnc-ip65 leads to destructive HTNV infection in mice. Thus, our findings reveal an immune-braking function of murine noncoding RNAs, offering a special therapeutic strategy for HTNV infection.

Establishment and characterization of an immortalized bovine intestinal epithelial cell line.

Primary bovine intestinal epithelial cells (PBIECs) are an important model for studying the molecular and pathogenic mechanisms of diseases affecting the bovine intestine. It is difficult to obtain and grow PBIECs stably, and their short lifespan greatly limits their application. Therefore, the purpose of this study was to create a cell line for exploring the mechanisms of pathogen infection in bovine intestinal epithelial cells in vitro. We isolated and cultured PBIECs and established an immortalized BIEC line by transfecting PBIECs with the pCI-neo-hTERT (human telomerase reverse transcriptase) recombinant plasmid. The immortalized cell line (BIECs-21) retained structure and function similar to that of the PBIECs. The marker proteins characteristic of epithelial cells, cytokeratin 18, occludin, zonula occludens protein 1 (ZO-1), E-cadherin and enterokinase, were all positive in the immortalized cell line, and the cell structure, growth rate, karyotype, serum dependence and contact inhibition were normal. The hTERT gene was successfully transferred into BIECs-21 where it remained stable and was highly expressed. The transport of short-chain fatty acids and glucose uptake by the BIECs-21 was consistent with PBIECs, and we showed that they could be infected with the intestinal parasite, Neospora caninum. The immortalized BIECs-21, which have exceeded 80 passages, were structurally and functionally similar to the primary BIECs and thus provide a valuable research tool for investigating the mechanism of pathogen infection of the bovine intestinal epithelium in vitro.

In dairy cattle, the intestine is essential for productivity as it contributes nearly 10% of the total metabolizable energy. The intestinal epithelium is at risk of infection from constant exposure to pathogenic microorganisms, which seriously endangers an animal's health, but no bovine intestinal epithelial cell line has been developed so far for research on intestine -related diseases. Thus, the goal of this study was to create an immortalized cell line from isolated primary bovine intestinal epithelial cells. The expression of an exogenous human telomerase reverse transcriptase (hTERT) gene can circumvent the Hayflick limit by maintaining telomere integrity and we used transfection with a plasmid expressing the hTERT gene to convert primary intestinal epithelial cells into an immortalized cell line, which we then characterized. The results showed that the immortalized cell line (BIECs-21) was structurally and functionally similar to the primary bovine intestinal epithelial cells (BIECs) and thus provided a valuable research tool for investigating the mechanism of pathogen infection of the bovine intestinal epithelium in vitro.

Structural and biochemical characterization of Schlafen11 N-terminal domain.

Schlafen11 (SLFN11) is one of the most studied Schlafen proteins that plays vital roles in cancer therapy and virus-host interactions. Herein, we determined the crystal structure of the Sus scrofa SLFN11 N-terminal domain (NTD) to 2.69 Å resolution. sSLFN11-NTD is a pincer-shaped molecule that shares an overall fold with other SLFN-NTDs but exhibits distinct biochemical characteristics. sSLFN11-NTD is a potent RNase cleaving type I and II tRNAs and rRNAs, and with preference to type II tRNAs. Consistent with the codon usage-based translation suppression activity of SLFN11, sSLFN11-NTD cleaves synonymous serine and leucine tRNAs with different efficiencies in vitro. Mutational analysis revealed key determinates of sSLFN11-NTD nucleolytic activity, including the Connection-loop, active site, and key residues essential for substrate recognition, among which E42 constrains sSLFN11-NTD RNase activity, and all nonconservative mutations of E42 stimulated RNase activities. sSLFN11 inhibited the translation of proteins with a low codon adaptation index in cells, which mainly dependent on the RNase activity of the NTD because E42A enhanced the inhibitory effect, but E209A abolished inhibition. Our findings provide structural characterization of an important SLFN11 protein and expand our understanding of the Schlafen family.

Goats with low levels of AAV antibody may serve as candidates for large animal gene therapy.

AAV vector-mediated gene therapy has been proposed as a feasible strategy for several eye diseases. However, AAV antibodies in the serum prior to treatment hinder the transduction efficiency and thus the therapeutic effect. Therefore, it is necessary to evaluate AAV antibodies in the serum before gene therapy. As large animals, goats are more closely related to humans than rodents and more economically available than nonhuman primates. Here, we first evaluated the AAV2 antibody serum level in rhesus monkeys before AAV injection. Then, we optimized a cell-based neutralizing antibody assay for detecting AAV antibodies in the serum of Saanen goats and evaluated the consistency of the cell-based neutralizing antibody assay and ELISA for goat serum antibody evaluation. The cell-based neutralizing antibody assay showed that the percentage of macaques with low antibody levels was 42.86%; however, there were no macaques with low antibody levels when the serum was evaluated by ELISA. The proportion of goats with low antibody levels was 56.67% according to the neutralizing antibody assay and 33. 33% according to the ELISA, and McNemar's test showed that the results of the two assays were not significantly different (P = 0.754), but that their consistency is poor (Kappa = 0.286, P = 0.114). Moreover, longitudinal evaluation of serum antibodies before and after intravitreal injection of AAV2 in goats revealed that the level of AAV antibodies increased and transduction inhibition subsequently increased, as reported in humans, indicating that transduction inhibition should be taken into account at different stages of gene therapy. In summary, starting with an evaluation of monkey serum antibodies, we optimized a detection method of goat serum antibodies, providing an alternative large animal model for gene therapy, and our serum antibody measurement method may be applied to other large animals.

A Nanovaccine Based on Adjuvant Peptide FK-13 and l-Phenylalanine Poly(ester amide) Enhances CD8+ T Cell-Mediated Antitumor Immunity.

Cancer vaccines have shown promise as effective means of antitumor immunotherapy by inducing tumor antigen-specific T cell immunity. In this study, a novel peptide-based tumor nanovaccine that boosts antigen presentation and elicits effective antitumor immunity is developed. The adjuvant characteristics of an antimicrobial peptide-derived core peptide, FK-13, are investigated and used it to generate a fusion peptide named FK-33 with tumor antigen epitopes. l-phenylalanine-based poly(ester amide) (Phe-PEA), 8p4, is also identified as a competent delivery vehicle for the fusion peptide FK-33. Notably, the vaccination of 8p4 + FK-33 nanoparticles (8FNs) in vivo induces dendritic cell activation in the lymph nodes and elicits robust tumor antigen-specific CD8+ T cell response. The nanovaccine 8FNs demonstrate significant therapeutic and prophylactic efficacy against in situ tumor growth, effectively inhibit tumor metastasis, and significantly prolong the survival of tumor-bearing mice. Moreover, 8FNs can incorporate different tumor antigens and exhibit a synergistic therapeutic effect with antiprogrammed cell death protein 1 (PD-1) therapy. In summary, 8FNs represent a promising platform for personalized cancer vaccines and may serve as a potential combinational modality to improve current immunotherapy.

Selective activation of cholinergic neurotransmission from the medial septal nucleus to hippocampal pyramidal neurones improves sepsis-induced cognitive deficits in mice.

BACKGROUND: Sepsis-associated encephalopathy is characterised by cognitive dysfunction, and might be mediated by deficits in neurotransmission. Reduced cholinergic neurotransmission in the hippocampus impairs memory function. We assessed real-time alterations of acetylcholine neurotransmission from the medial septal nucleus to the hippocampus, and explored whether sepsis-induced cognitive deficits can be relieved by activating upstream cholinergic projections. METHOD: Lipopolysaccharide (LPS) injection or caecal ligation and puncture (CLP) was used to induce sepsis and associated neuroinflammation in wild-type and mutant mice. Adeno-associated viruses for calcium and acetylcholine imaging, and for optogenetic and chemogenetic modulation of cholinergic neurones were injected into the hippocampus or medial septum, and a 200-µm-diameter optical fibre was implanted to collect acetylcholine and calcium signals. Cholinergic activity of the medial septum was manipulated and combined with cognitive assessment after LPS injection or CLP. RESULTS: Intracerebroventricular LPS injection reduced postsynaptic acetylcholine (from 0.146 [0.001] to 0.0047 [0.0005]; p=0.004) and calcium (from 0.0236 [0.0075] to 0.0054 [0.0026]; p=0.0388) signals in hippocampal Vglut2-positive glutamatergic neurones, whereas optogenetic activation of cholinergic neurones in the medial septum reversed LPS-induced reductions in these two signals. Intraperitoneal LPS injection decreased acetylcholine concentration in the hippocampus (476 [20] pg ml-1 to 382 [14] pg ml-1; p=0.0001). Reduction in long-term potentiation (238 [23] % to 150 [12] %; p=0.0082) and enhancement of hippocampal pyramidal neurone action potential frequency (5.8 [1.5] Hz to 8.2 [1.8] Hz; p=0.0343) were relieved, and neurocognitive performance was improved by chemogenetic activation of cholinergic innervation of the hippocampus 3 days after LPS injection in septic mice. CONCLUSIONS: Systemic or local LPS reduced cholinergic neurotransmission from the medial septum to hippocampal pyramidal neurones, and their selective activation alleviated defects in hippocampal neuronal function and synaptic plasticity and ameliorated memory deficits in sepsis model mice through enhanced cholinergic neurotransmission. This provides a basis for targeting cholinergic signalling to the hippocampus in sepsis-induced encephalopathy.

Molecular mechanism of valine and its metabolite in improving triglyceride synthesis of porcine intestinal epithelial cells.

An insufficient energy supply to intestinal epithelial cells decreases production performance in weaned piglets. Triglycerides are the main energy source for intestinal epithelial cells in piglets. The present study aimed to investigate the effects and mechanisms of valine supplementation on triglyceride synthesis in porcine intestinal epithelial (IPEC-J2) cells. Valine supplementation in the medium significantly increased the content of triglycerides, fat droplets, and long-chain fatty acids (C17:0, C18:0, C20:0, C18:1, C20:1, and C22:1) (P < 0.05). Valine metabolite (3-hydroxyisobutyrate [3-HIB]) concentration increased significantly in the valine-supplemented group (P < 0.05). Silencing of the 3-HIB synthase enzyme 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) in IPEC-J2 cells significantly reduced the triglyceride concentration and lipid droplet synthesis. Further studies found that 3-HIB supplementation in the medium significantly increased the concentration of triglycerides, lipid droplets, and unsaturated fatty acids (C16:1, C18:1, C18:2, C18:3, C20:3, C20:4, and C20:5) (P < 0.05) by upregulating the expression of proteins involved in fatty acid transport (CD36) and fatty acid binding protein 3 (FABP3) or triglyceride synthesis (DGAT1) (P < 0.05), indicating that 3-HIB mediates valine-enhanced triglyceride synthesis in IPEC-J2 cells. In conclusion, our results demonstrated that valine enhanced triglyceride synthesis in IPEC-J2 cells via increasing the 3-HIB concentration, which may promote fatty acid transport via upregulation of proteins related to fatty acid transporter. These findings provide new insights into the mechanisms through which valine participates in lipid metabolism.

Case report: Rare persistent complete donor chimerism and GVHD following micro-transplantation from HLA haplotype homozygous donors.

HLA-mismatched hematopoietic stem cell micro-transplantation (MST) is an effective treatment for older patients (≥60 years) with acute myeloid leukemia. Donor selection for MST is broad, ranging from HLA fully mismatched unrelated donors to HLA partially matched related donors. However, the influence of HLA haplotype homozygous donors such donors on MST has not been studied. Such donors has been reported to be associated with a higher risk of graft-versus-host disease (GVHD) in transfusion and cord blood transplantation (CBT). Additionally, sustained complete donor chimerism is rare in MST and usually accompanied by severe acute GVHD and death. Herein, we report the first case of MST using an HLA haplotype homozygous donor. The patient developed persistent complete donor chimerism (donor cells>95%) for 7 months and prolonged isolated thrombocytopenia (PT) for 3 months, after receiving MST from his HLA homozygous son. Grade I acute GVHD presented on day 12 post-MST and it was controlled by timely immunosuppressive treatment. Then he maintained complete molecular remission, complete donor chimerism and mild GVHD for 5 months. However, moderate overlapping GVHD with skin, oral, eyes, and intestinal involvement developed after he self-discontinued Tacrolimus treatment. Fortunately, the GVHD was controlled after intensive anti-rejection therapy and Tacrolimus is now being continued for prophylaxis. This case underscores that HLA haplotype homozygous donors might not be a good choice for MST and GVHD prophylactic should be administrated if such donors have to be selected.

Arenga pinnata Resistant Starch Modulate Gut Microbiota and Ameliorate Intestinal Inflammation in Aged Mice.

This study aimed to compare the regulatory effects of Arenga pinnata retrograded starch (APRS), Arenga pinnata starch (APS), and whole Arenga pinnata flour (APF) on gut microbiota and improvement of intestinal inflammation in aged mice. APF, APS, and APRS altered gut microbiota composition and exhibited different prebiotic effects. Bifidobacterium showed the greatest increase in feces of aged mice fed APF. The abundance of genus Lachnospiraceae_NK4A136 was highest in the APS group. APRS supplementation led to a greatest increasement in abundance of Lactobacillus, Roseburia, and Faecalibacterium prausnitzii. APRS induced significantly more short-chain fatty acid (SCFAs) production than APF and APS. APF, APS, and APRS treatments improved intestinal inflammation in aged mice and the order of ameliorative effect was APRS > APS > APF. APRS significantly decreased relative mRNA expression of pro-inflammatory cytokines (IL-6, IL-1ß, and TNF-α) and increased anti-inflammatory cytokines (IL-10). In addition, APF, APS, and APRS significantly downregulated the relative mRNA expression of senescence-associated gene p53 and upregulated the expression of anti-aging gene Sirt1. These results provide potentially useful information about the beneficial effects of Arenga pinnata products on human health.

CD7-directed CAR T-cell therapy: a potential immunotherapy strategy for relapsed/refractory acute myeloid leukemia.

Relapsed/refractory acute myeloid leukemia (AML) patients generally have a dismal prognosis and the treatment remains challenging. Due to the expression of CD7 on 30% AML and not on normal myeloid and erythroid cells, CD7 is an attractive target for immunotherapy of AML. CD7-targeted CAR T-cells had demonstrated encouraging efficacy in xenograft models of AML. We report here on the use of autologous CD7 CAR T-cells in the treatment of a relapsed/refractory AML patient with complex karyotype, TP53 deletion, FLT3-ITD mutation, and SKAP2-RUNX1 fusion gene. Before the CAR T-cell therapy, the patient achieved partial remission with IA regimen and attained complete remission after reinduction therapy (decitabine and venentoclax). Relapse occurred after consolidation (CLAG regimen). Then she failed CLIA regimen combined with venetoclax and exhibited resistance to FLT3 inhibitors. Bone marrow showed 20% blasts (CD7+ 95.6%). A total dose of 5 × 106/kg CD7 CAR T-cells was administered after the decitabine +FC regimen. Seventeen days after CAR T-cells infusion, she achieved morphologic leukemia-free state. The patient developed grade 3 cytokine release syndrome. No severe organ toxicity or immune effector cell-associated neurotoxicity syndrome was observed. In summary, the autologous CD7 CAR T-cell therapy could be considered a potential approach for AML with CD7 expression (NCT04762485).Trial registration Clinical Trials.gov, NCT04762485. Registered on February 21, 2021, prospectively registered.

Advances in mRNA vaccines.

mRNA vaccines have been increasingly recognized as a powerful vaccine platform since the FDA approval of two COVID-19 mRNA vaccines, which demonstrated outstanding prevention efficacy as well as great safety profile. Notably, nucleoside modification and lipid nanoparticle-facilitated delivery has greatly improved the immunogenicity, stability, and translation efficiency of mRNA molecule. Here we review the recent progress in mRNA vaccine development, including nucleoside modification, in vitro synthesis and product purification, and lipid nanoparticle vectors for in vivo delivery and efficient translation. We also briefly introduce the clinical application of mRNA vaccine in preventing infectious diseases and treating inflammatory diseases including cancer.

Protective effect of Ulinastatin on acute lung injury in diabetic sepsis rats.

This study explored the protective effect and its possible mechanism of ulinastatin (UTI) on acute lung injury (ALI) in type 2 diabetes mellitus (DM) sepsis rats. Following treatment with UTI, the wet/dry weight (W/D) ratio, pathological changes, hypoxia-inducible factor-1ɑlpha (HIF-1ɑ) protein and Toll-like receptor 4 (TLR4) mRNA expression of lung tissues, the expression levels of interleukin-1beta (IL-1ß), IL-18, and tumor necrosis factor-alpha (TNF-ɑ), the contents of malondialdehyde (MDA) and superoxide dismutase (SOD) in serum were detected in type 2 DM sepsis rats. It was found that rats with type 2 DM and sepsis showed obvious damage in lung tissues with significantly increased inflammatory cells, necrosis, and swelling of alveolar epithelial cells, but UTI decreased the lung damage induced by DM and sepsis. In addition, compared with the control, the W/D ratio, serum IL-1ß, IL-18 and TNF-ɑ contents, HIF-1ɑ protein expression, TLR4 mRNA expression, pulmonary microvascular permeability, MDA content in serum in type 2 DM and sepsis groups were significantly increased in type 2 DM sepsis rats (p < 0.05). However, compared with the groups with type 2 DM sepsis, the W/D ratio, serum IL-1ß, IL-18, TNF-ɑ contents, HIF-1ɑ protein expression, TLR4 mRNA expression, and pulmonary microvascular permeability in UTI-treated group were significantly decreased, but the activity of SOD increased (p < 0.05). This study indicates that UTI can effectively reduce ALI induced by diabetic sepsis in rats through inhibiting inflammatory response, reducing oxidative stress, regulating hypoxia response pathway, and improving pulmonary microvascular permeability.

SeMet attenuates AFB1-induced intestinal injury in rabbits by activating the Nrf2 pathway.

The aim of this study was to investigate the role of selenomethionine (SeMet) in alleviating AFB1 induced intestinal injury by inhibiting intestinal oxidative stress. Forty 35-day-old rabbits were divided randomly into 4 groups (control group, AFB1 group, 0.2 mg/kg Se + AFB1 group, 0.4 mg/kg Se + AFB1 group). From the first day of the experiment, the two treatment groups were fed 0.2 mg/kg SeMet or 0.4 mg/kg SeMet daily for 21 days. On the 17th day, all rabbits in the model group and the two treatment groups were given intragastric AFB1 daily for 5 days. The ADG, ADFI and FCR of the rabbits were examined. Rabbit jejunum tissue was collected for hematoxylin- eosin staining (HE), PCNA detection, immunofluorescence and WB. Intestinal tissue IL-1ß, IL-6 and TNF-α were examined by enzyme-linked immunosorbent assay (ELISA). The results showed that the production performance was decreased, the levels of ROS and MDA were increased in intestinal tissues, the activity of antioxidant enzymes was decreased and the expression levels of Nrf2 and HO-1 were decreased in AFB1-exposed rabbits. In addition, AFB1 induces an inflammatory response in the jejunum and promotes the expression of TNF-α, IL-6 and IL-1ß. SeMet pretreatment significantly improved the performance of the rabbits, alleviated intestinal oxidative stress and the inflammatory response. Therefore, we confirmed that SeMet protects against AFB1 induced oxidative damage and improves productivity in rabbits by activating the Nrf2/HO-1 signaling pathway.

Optic chiasmatic potential by endoscopically implanted skull base microinvasive biosensor: a brain-machine interface approach for anterior visual pathway assessment.

Background: Visually evoked potential (VEP) is widely used to detect optic neuropathy in basic research and clinical practice. Traditionally, VEP is recorded non-invasively from the surface of the skull over the visual cortex. However, its trace amplitude is highly variable, largely due to intracranial modulation and artifacts. Therefore, a safe test with a strong and stable signal is highly desirable to assess optic nerve function, particularly in neurosurgical settings and animal experiments. Methods: Minimally invasive trans-sphenoidal endoscopic recording of optic chiasmatic potential (OCP) was carried out with a titanium screw implanted onto the sphenoid bone beneath the optic chiasm in the goat, whose sphenoidal anatomy is more human-like than non-human primates. Results: The implantation procedure was swift (within 30 min) and did not cause any detectable abnormality in fetching/moving behaviors, skull CT scans and ophthalmic tests after surgery. Compared with traditional VEP, the amplitude of OCP was 5-10 times stronger, more sensitive to weak light stimulus and its subtle changes, and was more repeatable, even under extremely low general anesthesia. Moreover, the OCP signal relied on ipsilateral light stimulation, and was abolished immediately after complete optic nerve (ON) transection. Through proof-of-concept experiments, we demonstrated several potential applications of the OCP device: (1) real-time detector of ON function, (2) detector of region-biased retinal sensitivity, and (3) therapeutic electrical stimulator for the optic nerve with low and thus safe excitation threshold. Conclusions: OCP developed in this study will be valuable for both vision research and clinical practice. This study also provides a safe endoscopic approach to implant skull base brain-machine interface, and a feasible in vivo testbed (goat) for evaluating safety and efficacy of skull base brain-machine interface.

Overall survival benefits provided by lenalidomide maintenance after chimeric antigen receptor T cell therapy in patients with refractory/relapsed diffuse large B-cell lymphoma.

Background: Chimeric antigen receptor T cell (CAR-T) therapy has achieved remarkable effects in refractory/relapsed (R/R) diffuse large B-cell lymphoma (DLBCL). However, many patients receiving CAR-T therapy still eventually die of disease recurrence or progression due to target antigen loss or exhaustion of CAR-T cells. Therefore, maintaining the efficacy of CAR-T has become a particular research focus. As lenalidomide can regulate T cell function, we conducted a study to evaluate the efficacy of lenalidomide maintenance after CAR-T therapy in R/R DLBCL patients. Methods: Seven R/R DLBCL patients who received lenalidomide maintenance after CAR-T therapy and nine DLBCL patients that underwent CAR-T treatment alone were included. The clinical data of all subjects were collected to evaluate the efficacy of lenalidomide maintenance. In order to understand the possible mechanisms of lenalidomide in CAR-T therapy, CAR-T copies of peripheral blood were regularly detected by quantitative real-time polymerase chain reaction, and an in vitro test was also conducted. Results: Overall survival (OS) was significantly prolonged in the lenalidomide maintenance group. Furthermore, one case responding to CAR-T therapy initially but suffering a relapse shortly achieved complete remission again after lenalidomide exposure, with an increase in the number of CAR-T copies detected. The in vitro test showed that lenalidomide could delay the exhaustion of CAR-T cells. Conclusions: Lenalidomide maintenance after CAR-T therapy is a safe and effective choice for R/R DLBCL patients. We confirmed that lenalidomide maintenance can improve patients' OS, and the delayed exhaustion of CAR-T cells may contribute to this OS benefit.

Dexmedetomidine improved one-lung ventilation-induced cognitive dysfunction in rats.

BACKGROUND: One-lung ventilation (OLV) is widely used in thoracic surgery. However, OLV may also increase CERO2 and aggravate delayed cognitive recovery. Here, we aimed to investigate the effect of dexmedetomidine (DEX) on cognitive function in rats undergoing OLV. METHODS: Sprague-Dawley rats were randomly divided into two-lung ventilation (TLV) group, OLV group and OLV treated with DEX group. Group DEX received 25 µg/kg DEX i.p. 30 min before induction. After mechanical ventilation (MV), Morris water maze (MWM) test was carried out to examine spatial memory function. Western blotting was used to detect pERK1/2, pCREB, Bcl-2 and BAX in hippocampal tissues. Transmission electron microscopy (TEM) was used to observe the hippocampal CA1 region. RESULTS: Post-MV, compared with group OLV, group DEX showed increases in percentage of target quadrant time (P < 0.05), platform crossings (P < 0.05), a reduction in CERO2 (P < 0.05), and pERK1/2, pCREB, and Bcl-2 significantly increased (P < 0.01 or P < 0.05), while BAX significantly decreased (P < 0.01), besides, a less damaged synaptic structure was observed in group DEX. CONCLUSIONS: DEX improved post-MV cognitive function in rats undergoing OLV, reduced cerebral oxygen consumption, protected synaptic structure and upregulated ERK1/2-CREB anti-apoptotic signaling pathway in hippocampal CA1 region.