Preliminary Study of Radionuclide-Labeled MerTK-Targeting PET Imaging Agents for the Diagnosis of Melanoma.

MerTK PET imaging holds potential as a promising approach for assessing tumor aggressiveness and monitoring treatment response. In this study, we synthesized a series of 18F- and 68Ga-labeled tracers derived from MerTK inhibitors for detection of MerTK expression. Among the synthesized agents, the dimeric compounds [68Ga]10 and [68Ga]12 demonstrated good in vivo and in vitro stability, high affinities to the MerTK receptor, and good MerTK-targeting specificity. Notably, [68Ga]10 exhibited a tumor uptake of 2.6 ± 0.2%ID/g at 1 h p. i. in B16F10 tumor-bearing mice, nearly tripling the uptake of its monomeric counterpart [68Ga]3. A similar enhancement was observed with [68Ga]12 compared to its monomeric analog [68Ga]6. Additionally, [18F]14 achieved a tumor uptake of 7.6 ± 0.5%ID/g at 2 h p. i., outperforming the previously reported [18F]15. Biodistribution analysis further validated the results, highlighting their potential for clinical investigation.

2'3'-cGAMP interactome identifies 2'3'-cGAMP/Rab18/FosB signaling in cell migration control independent of innate immunity.

c-di-GAMP was first identified in bacteria to promote colonization, while mammalian 2'3'-cGAMP is synthesized by cGAS to activate STING for innate immune stimulation. However, 2'3'-cGAMP function beyond innate immunity remains elusive. Here, we report that 2'3'-cGAMP promotes cell migration independent of innate immunity. 2'3'-cGAMP interactome analysis identifies the small GTPase Rab18 as a 2'3'-cGAMP binding partner and effector in cell migration control. Mechanistically, 2'3'-cGAMP binds Rab18 to facilitate GTP loading and subsequent Rab18 activation, which further promotes FosB transcription in facilitating cell migration. Induced synthesis of endogenous 2'3'-cGAMP by intrabreast tumor bacterium S. aureus infection or low-dose doxorubicin treatment facilitates cell migration depending on the cGAS/cGAMP/Rab18/FosB signaling. We find that lovastatin induces Rab18 deprenylation that abolishes 2'3'-cGAMP recognition therefore suppressing cell migration. Together, our study reveals a previously unidentified 2'3'-cGAMP function in cell migration control via the 2'3'-cGAMP/Rab18/FosB signaling that provides additional insights into clinical applications of 2'3'-cGAMP.

Enhancer looping protein LDB1 modulates MYB expression in T-ALL cell lines in vitro by cooperating with master transcription factors.

BACKGROUND: Despite significant progress in the prognosis of pediatric T-cell acute lymphoblastic leukemia (T-ALL) in recent decades, a notable portion of children still confronts challenges such as treatment resistance and recurrence, leading to limited options and a poor prognosis. LIM domain-binding protein 1 (LDB1) has been confirmed to exert a crucial role in various physiological and pathological processes. In our research, we aim to elucidate the underlying function and mechanisms of LDB1 within the background of T-ALL. METHODS: Employing short hairpin RNA (shRNA) techniques, we delineated the functional impact of LDB1 in T-ALL cell lines. Through the application of RNA-Seq, CUT&Tag, and immunoprecipitation assays, we scrutinized master transcription factors cooperating with LDB1 and identified downstream targets under LDB1 regulation. RESULTS: LDB1 emerges as a critical transcription factor co-activator in cell lines derived from T-ALL. It primarily collaborates with master transcription factors (ERG, ETV6, IRF1) to cooperatively regulate the transcription of downstream target genes. Both in vitro and in vivo experiments affirm the essential fuction of LDB1 in the proliferation and survival of cell lines derived from T-ALL, with MYB identified as a significant downstream target of LDB1. CONCLUSIONS: To sum up, our research establishes the pivotal fuction of LDB1 in the tumorigenesis and progression of T-ALL cell lines. Mechanistic insights reveal that LDB1 cooperates with ERG, ETV6, and IRF1 to modulate the expression of downstream effector genes. Furthermore, LDB1 controls MYB through remote enhancer modulation, providing valuable mechanistic insights into its involvement in the progression of T-ALL.

Evaluation of growth, physiological response, and drought resistance of different flue-cured tobacco varieties under drought stress.

Background: In recent years, more severe droughts have occurred frequently in many parts of the world, drought stress is the primary abiotic stress factor restricting the growth and quality of flue-cured tobacco. Therefore, screening dryland cultivation-compatible flue-cured tobacco varieties will help reduce the negative impact of drought. Methods: Tobacco varieties were selected: Qinyan 96 (Q96), Zhongyan 101 (Z101), Yunyan 87 (Y87), and Yunyan 116 (Y116). A pot experiment was conducted with four water supply gradients: sufficient, mild stress, moderate stress, and severe stress. The aim was to analyze inter-varietal differences in agronomic traits, photosynthetic traits, reactive oxygen species (ROS) metabolism, and antioxidant enzyme system under drought stress. Additionally, the drought resistance of four flue-cured tobacco varieties was evaluated using principal component analysis and membership function analysis. Results: The results showed that drought intensification inhibited seedling growth and development across all varieties, with Q96 showing the least decrease and Y116 the greatest. With the increasing degree of drought stress, photosynthetic rates (Pn), transpiration rate (Tr), and stomatal conduction (Gs) have shown gradually decreasing trends, while substomatal cavity CO2 concentration (Ci) showed a growing trend. Severe drought corresponded with lower chlorophyll content and decreased the maximal photochemical efficiency (Fv/Fm), photosystem II (PSII), and photochemical quenching coefficient (qP) in all varieties, while steady-state non-photochemical quenching (NPQ) increased. Increased drought stress led to significantly higher reactive oxygen species (ROS) and malondialdehyde (MDA) content accumulation in tobacco seedlings. The antioxidant enzyme activities in, Q96, Z101, and Y87 increased under mild drought stress, whereas Y116 showed decreased activity. Conclusion: The drought resistance ranking among the four varieties is as follows: Q96 > Z101 > Y87 > Y116. Therefore, Q96 is a promising drought-tolerant breeding material that can be used as a reference for dryland cultivation of flue-cured tobacco.

Iron overload regulates cognitive function in rats with minimal hepatic encephalopathy by inducing an increase in frontal butyrylcholinesterase activity.

Background and aims: This study aimed to investigate the effect of iron overload on acetylcholinesterase activity in the frontal lobe tissue of rats with minimal hepatic encephalopathy (MHE) and its relation to cognitive ability. By elucidating the potential mechanisms of cognitive impairment, this study may offer insights into novel therapeutic targets for MHE. Materials and methods: Twelve Sprague-Dawley rats were purchased and randomly assigned to either the experimental or control group with six rats in each group. Following the induction of MHE, the Morris Water Maze (MWM) was utilized to assess spatial orientation and memory capacity. Subsequently, Magnetic Resonance Imaging (MRI) scans were performed to capture Quantitative Susceptibility Mapping (QSM) images of all rats' heads. Results: Compared to the control group rats, the MHE model rats showed significantly reduced learning and memory capabilities as well as spatial orientation abilities (P < 0.05). Furthermore, the susceptibility values in the frontal lobe tissue of MHE model rats was significantly higher than that of the control group rats (P < 0.05), and the corresponding BuChE activity in the frontal lobe extract of model rats was significantly increased while BuChE activity in the peripheral blood serum was significantly decreased compared to the control group rats (P < 0.05). Meanwhile, our findings indicate a significant positive correlation between latency period and BuChE activity with susceptibility values in the MHE group. Conclusion: The changes in BuChE activity in frontal lobe extract may be related to changes in spatial orientation and behavioral changes in MHE, and iron overload in the frontal lobe tissue may regulate changes in BuChE activity, BuChE levels appear to be iron-dependent.

Azithromycin induces liver injury in mice by targeting the AMPK/Nrf2 pathway.

BACKGROUND: Azithromycin is an antibacterial and anti-inflammatory drug widely used for the treatment of various diseases, including those caused by atypical pathogens, bacterial or viral infections, chronic sinusitis, and bronchial asthma, particularly in pediatric patients. However, concerns have emerged regarding its hepatotoxicity and its precise mechanism of action remains unclear. OBJECTIVE: To investigate the molecular mechanisms responsible for azithromycin-induced acute liver injury to advance our understanding of the progression and pathogenesis of antibiotic-induced liver damage, and to improve prevention and treatment strategies. MATERIALS AND METHODS: C57BL/6 mice, Nrf2-/- mice, and primary hepatocytes were used. Primary hepatocytes from mice were isolated using a two-step perfusion method and cultured in vitro via the 'sandwich' culture model. RESULTS: The exposure to azithromycin resulted in increased apoptosis and reactive oxygen species (ROS) levels. In mouse models, intraperitoneal administration of azithromycin at varying concentrations and time points substantially induced hepatic disarray, swelling, and dysfunction. Azithromycin markedly upregulated the mRNA and protein levels of phosphorylated adenosine-activated protein kinase (AMPK) while downregulating nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase 1 (HO-1), and NADPH: quinone oxidoreductase 1 (NQO-1). Moreover, HO-1 and NQO-1 protein levels remained largely unaffected in primary hepatocytes co-cultured with azithromycin in Nrf2-/- mice. CONCLUSIONS: Our findings suggest that azithromycin-induced acute liver injury is mediated by suppression of Nrf2 activation and ROS production. This sheds light on the potential mechanisms involved in azithromycin-induced liver damage, underscoring the importance of exploring targeted interventions to mitigate the hepatotoxic effects.

Treatment of acromioclavicular joint dislocation with looped steel plate and clavicular hook steel plate: recent therapeutic observation.

Objectives: To compare the clinical efficacy of Endobutton-looped steel plate and clavicular hook steel plate in the treatment of acromioclavicular joint dislocation. METHODS: The retrospective case-control study was conducted at the Baoding Forensic Hospital, Hebei University, China and comprised data from January 2022 to June 2023 of adult inpatients of either gender with acromioclavicular joint dislocation. The data was divided into intervention group A and control group B. Group A patients had been treated with Endobutton-looped steel plate, while those in group B had been treated using clavicular hook steel plate. Clinical efficacy, clinical indicators, Karlsson score for shoulder joint function, range of motion of the shoulder, and complications during 6-month follow-up were compared between the groups. Data was analysed using SPSS 26. RESULTS: Of the 50 patients, there were 25(50%) in group A; 15(60%) males and 10(40%) females with mean age 37.75±6.24 years (range: 19-58 years) and mean dislocation-to-visit time 2.52±0.61 days (range: 0-7 days). There were 25(50%) patients in group B; 16(64%) males and 9(36%) females with mean age 38.24±6.30 years (range: 18- 59 years) and mean dislocation-to-visit time 2.47±0.58 days (range: 0-6 days). The groups showed no significant differences (p>0.05). Clinical efficacy of group A was higher than that of group B (p<0.05). Group A showed shorter surgical duration and incisional length, and lower average treatment cost compared to group B(p<0.05). The shoulder joint function in group A was significantly better than group B (p<0.05). Post-treatment, the range of motion of abduction, external rotation and internal rotation in group A were superior to group B (p<0.05). Complications in the two groups showed no significant difference (p>0.05). CONCLUSIONS: Compared to clavicular hook steel plate, Endobutton-looped steel plate presented higher clinical efficacy, shorter surgical duration, smaller incision and lower treatment cost, which promoted the recovery of shoulder joint function and contributed to high therapeutic safety.

Integrating MXene Film With Recyclable Polyethylene Glycol-co-Polyphosphazene Copolymer as Solid-Solid Phase Change Material for Versatile Applications.

Phase-change materials (PCMs) stand a pivotal advancement in thermal energy storage and management due to their reversible phase transitions to store and release an abundance of heat energy. However, conventional solid-liquid PCMs suffer from fluidity and leakage in their molten state, limiting their applications at advanced levels. Herein, a novel Zn2+-crosslinked polyethylene glycol-co-polyphosphazene copolymer (PCEPN-Zn) as a solid-solid PCM through dynamic metal-ligand coordination is first designed and synthesized. The as-synthesized PCEPN-Zn is further integrated with an MXene film to construct a double-layered phase-change composite through layer-by layer adhesion. Owing to the introduction of MXene film with low emissivity, good light absorptivity, and nonflammability, the resultant phase-change composite not only presents a high latent-heat capacity, good thermal stability, high thermal reliability, and excellent shape stability, but also exhibits a superior self-healing ability, good recyclability, high adhesivity, and good flame-retardant performance. It can be easily adhered to on most objects for various application scenarios. With a combination of the excellent functions derived from PCEPN-Zn and MXene film, the developed phase-change composite exhibits broad prospects for versatile applications in the thermal management of CPUs and Li-ion batteries, thermal infrared stealth of high-temperature objects, heat therapy in the clinic, and fire-safety for various scenarios.

Analysis of the correlation between defunctioning stoma and postoperative low anterior resection syndrome in rectal cancer: a prospective cohort study.

BACKGROUND: To evaluate the effect of stoma-related factors (stoma or no stoma, stoma type, and stoma reversal time) on the occurrence of low anterior resection syndrome (LARS), a highly prevalent condition that can develop after anal sphincter-sparing surgery for rectal cancer and impair quality of life, which includes fecal incontinence, fecal urgency and frequent defecation. METHODS: Patients who underwent radical rectal cancer surgery from July 2018 to July 2022 in a tertiary hospital were included. Baseline data, tumor condition, operation condition and postoperative recovery were obtained by clinical observation. Follow-up data were collected by telephone follow-up. The chi-square and Fisher exact tests were used to analyse differences, coefficient of contingency was used to determine correlations, and independent risk factors for the occurrence of LARS (Patients with a score of 21 or more points were defined as having LARS using the LARS score) were further determined by binary logistic regression. RESULTS: A total of 480 patients met the inclusion criteria, of which 267 used a defunctioning stoma and 213 did not use a defunctioning stoma. There was a positive correlation between defunctioning stoma (P < 0.001, P < 0.001, P < 0.05) and the occurrence of LARS at 3, 6, and 12 months postoperatively, and there was no significant correlation between the stoma type or stoma reversal time and the occurrence of LARS at 3, 6 and 12 months postoperatively (P > 0.05). In binary logistic regression analysis, high BMI (Exp(B) = 1.072, P = 0.039), tumor closer to dentate line (Exp(B) = 0.910, P = 0.016), and ultra-low anterior resection (Exp(B) = 2.264, P = 0.011) increased the possibility of LARS at 3 months postoperatively; high BMI, proximity of the tumor to the dentate line, and ultra-low anterior resection were not independent risk factors for LARS at 6 months postoperatively (P > 0.05). However, proximity of the tumor to the dentate line (Exp(B) = 0.880, P = 0.035) increased the likelihood of LARS at 12 months postoperatively, while high BMI and ultra-low anterior resection remained non-significant as independent risk factors for LARS at 12 months postoperatively (P > 0.05). CONCLUSIONS: Defunctioning stoma was not an independent risk factor for the occurrence of LARS, whereas high BMI, tumor closer to dentate line, and ultra-low anterior resection were independent risk factors for the occurrence of LARS. TRIAL REGISTRATION: Not applicable.

Cesarean hysterectomy in pregnancies complicated with placenta previa accreta: a retrospective hospital-based study.

BACKGROUND: Placenta previa accreta (PPA) is a severe obstetric condition that can cause massive postpartum hemorrhage and transfusion. Cesarean hysterectomy is necessary in some severe cases of PPA to stop the life-threatening bleeding, but cesarean hysterectomy can be associated with significant surgical blood loss and major complications. The current study is conducted to investigate the potential risk factors of excessive blood loss during cesarean hysterectomy in women with PPA. METHODS: This is a retrospective study including singleton pregnancies after 28 weeks of gestation in women with placenta previa and pathologically confirmed placenta accreta spectrum who received hysterectomy during cesarean sections. A total of 199 women from January 2012 to August 2023 were included in this study and were divided into Group 1 (estimated surgical blood loss (EBL) ≤ 3500 mL, n = 103) and Group 2 (EBL > 3500 mL, n = 96). The primary outcome was defined as an EBL over 3500 mL. Baseline characteristics and surgical outcomes were compared between the two groups. A multivariate logistic regression model was applied to find potential risk factors of the primary outcome. RESULTS: Massive surgical blood loss was prevalent in our study group, with a median EBL of 3500 mL. The multivariate logistic analysis showed that emergency surgery (OR 2.18, 95% CI 1.08-4.41, p = 0.029), cervical invasion of the placenta (OR 2.70, 95% CI 1.43-5.10, p = 0.002), and intraoperative bladder injury (OR 5.18, 95% CI 2.02-13.28, p = 0.001) were all associated with the primary outcome. Bilateral internal iliac arteries balloon occlusion (OR 0.57, 95% CI 0.34-0.97) and abdominal aortic balloon occlusion (OR 0.33, 95% CI 0.19-0.56) were negatively associated with the primary outcome. CONCLUSIONS: Emergency surgery, cervical invasion of the placenta, and intraoperative bladder injury were potential risk factors for additional EBL during cesarean hysterectomy in women with PPA. Future prospective studies are needed to confirm the effect of intra-arterial balloon occlusion in cesarean hysterectomy of PPA.

GLO1 regulates hepatocellular carcinoma proliferation and migration through the cell cycle pathway.

BACKGROUND: Hepatocellular carcinoma (HCC) is a malignant tumor characterized by a high mortality rate. The occurrence and progression of HCC are linked to oxidative stress. Glyoxalase-1 (GLO1) plays an important role in regulating oxidative stress, yet the underlying mechanism remains unclear. GLO1 may serve as a prognostic biomarker and therapeutic target for HCC. METHODS: Based on TCGA database hepatocellular carcinoma samples, we conducted a bioinformatics analysis to explore the correlation between GLO1 expression and HCC cell proliferation and viability. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed that differentially expressed genes (DEGs) were mainly enriched in the cell cycle pathway. We analyzed the relationships between GLO1 and 24 genes enriched in the cell cycle pathway using a protein-protein interaction (PPI) network. Finally, experimental validation was performed to assess GLO1's impact on the distribution of cells at different cell cycle stages and on the proliferation and migration of HCC cells. RESULTS: Our study demonstrated that GLO1 was overexpressed in HCC tissues and was associated with a poor prognosis. Data analysis indicated that overexpression of GLO1 activated the cell cycle pathway and positively correlated with expression of the majority of key cell cycle genes. Experimental validation showed that GLO1 expression affects the number of HCC cells in G2 and S phases and regulates HCC cell proliferation and migration. CONCLUSIONS: GLO1 represents a promising therapeutic target for HCC, providing valuable insights into its role in the viability and proliferation of HCC cells.

Super-Enhancer-Driven IRF2BP2 is Activated by Master Transcription Factors and Sustains T-ALL Cell Growth and Survival.

Super enhancers (SEs) are large clusters of transcriptional enhancers driving the expression of genes crucial for defining cell identity. In cancer, tumor-specific SEs activate key oncogenes, leading to tumorigenesis. Identifying SE-driven oncogenes in tumors and understanding their functional mechanisms is of significant importance. In this study, a previously unreported SE region is identified in T-cell acute lymphoblastic leukemia (T-ALL) patient samples and cell lines. This SE activates the expression of interferon regulatory factor 2 binding protein 2 (IRF2BP2) and is regulated by T-ALL master transcription factors (TFs) such as ETS transcription factor ERG (ERG), E74 like ETS transcription factor 1 (ELF1), and ETS proto-oncogene 1, transcription factor (ETS1). Hematopoietic system-specific IRF2BP2 conditional knockout mice is generated and showed that IRF2BP2 has minimal impact on normal T cell development. However, in vitro and in vivo experiments demonstrated that IRF2BP2 is crucial for T-ALL cell growth and survival. Loss of IRF2BP2 affects the MYC and E2F pathways in T-ALL cells. Cleavage under targets and tagmentation (CUT&Tag) assays and immunoprecipitation revealed that IRF2BP2 cooperates with the master TFs of T-ALL cells, targeting the enhancer of the T-ALL susceptibility gene recombination activating 1 (RAG1) and modulating its expression. These findings provide new insights into the regulatory network within T-ALL cells, identifying potential new targets for therapeutic intervention.

Predictive value of PAR and PNI for the acute complicated course of pediatric acute hematogenous osteomyelitis

Abstract Objective Platelet to albumin ratio (PAR) and prognostic nutritional index (PNI) are potential indicators for evaluating nutritional and inflammatory status. This study aimed to examine the relationship between PAR and PNI and the acute complicated course of acute hematogenous osteomyelitis (AHO). Methods AHO patients were divided into the simple course group and the acute complicated course group. The patient's gender, age, site of infection, body temperature, laboratory results, and pathogen culture results were collected and compared. Multivariate logistic regression analysis was used to determine the independent risk factors of the acute complicated course group. The receiver operating characteristic curve was applied to determine the optimal cut-off value. Results In total, 101 AHO patients with a median age of 7.58 years were included. There were 63 cases (62.4 %) in the simple course group and 38 cases (37.6 %) in the complicated course group. Binary logistic regression analysis revealed that PAR and PNI were independent risk factors for predicting the acute complicated course of AHO (p = 0.004 and p < 0.001, respectively). Receiver operating characteristic curve analysis demonstrated that the combination of PAR and PNI had an area under the curve of 0.777 (95 % CI: 0.680-0.873, p < 0.001) with a cut-off value of 0.51. Conclusions The incidence of acute complicated courses was significantly higher in patients with high PAR and low PNI. A combined factor greater than 0.51, derived from PAR and PNI measurements within 24 h of admission, may be useful for predicting AHO patients who are likely to develop severe disease.

MERTK inhibition selectively activates a DC - T-cell axis to provide anti-leukemia immunity.

TAM-family tyrosine kinases (TYRO3, AXL and MERTK) are potential cancer therapeutic targets. In previous studies MERTK inhibition in the immune microenvironment was therapeutically effective in a B-cell acute leukemia (B-ALL) model. Here, we probed anti-leukemia immune mechanisms and evaluated roles for TYRO3 and AXL in the leukemia microenvironment. Host Mertk knock-out or MERTK inhibitor MRX-2843 increased CD8α+ dendritic cells (DCs) with enhanced antigen-presentation capacity in the leukemia microenvironment and inhibited leukemogenesis. High MERTK or low DC gene expression were associated with poor prognosis in pediatric ALL patients, indicating the clinical relevance of these findings. MRX-2843 increased CD8+ T-cell numbers and prevented induction of exhaustion markers, implicating a DC - T-cell axis. Indeed, combined depletion of CD8α+ DCs and CD8+ T-cells was required to abrogate anti-leukemia immunity in Mertk-/- mice. Tyro3-/- mice were also protected against B-ALL, implicating TYRO3 as an immunotherapeutic target. In contrast to Mertk-/- mice, Tyro3-/- did not increase CD8α+ DCs with enhanced antigen-presentation capacity and therapeutic activity was less dependent on DCs, indicating a different immune mechanism. Axl-/- did not impact leukemogenesis. These data demonstrate differential TAM kinase roles in the leukemia microenvironment and provide rationale for development of MERTK and/or TYRO3-targeted immunotherapies.

Multi-Spectral Radiation Temperature Measurement: A High-Precision Method Based on Inversion Using an Enhanced Particle Swarm Optimization Algorithm with Multiple Strategies.

Multi-spectral temperature measurement technology has been found to have extensive applications in engineering practice. Addressing the challenges posed by unknown emissivity in multi-spectral temperature measurement data processing, this paper adds emissivity constraints to the objective function. It proposes a multi-spectral radiation temperature measurement data processing model realized through a particle swarm optimization algorithm improved based on multiple strategies. This paper simulates six material models with distinct emissivity trends. The simulation results indicate that the algorithm calculates an average relative temperature error of less than 0.3%, with an average computation time of merely 0.24 s. When applied to the temperature testing of silicon carbide and tungsten, experimental data further confirmed its accuracy: the absolute temperature error for silicon carbide (tungsten) is less than 4 K (7 K), and the average relative error is below 0.4% (0.3%), while two materials maintain an average computation time of 0.33 s. In summary, the improved particle swarm optimization algorithm demonstrates strong performance and high accuracy in multi-spectral radiation thermometry, making it a feasible solution for addressing multi-spectral temperature measurement challenges in practical engineering applications. Additionally, it can be extended to other multi-spectral systems.

Globular Antifreeze Protein-Inspired Nanoparticle-Based Large-Scale T-Cell Cryoprotection System for Lymphoma Immunotherapy.

Large-scale biosafe T-cell cryopreservation is required to bring T-cell therapies to the market, but it remains challenging due to the cytotoxicity of common cryoprotectants [e.g., dimethyl sulfoxide (DMSO)] and unavoidable ice injuries to cells. Herein, inspired by natural globular antifreeze proteins, we establish a biocompatible zwitterionic magnetic nanoparticle (ZMNP)-based cryoprotection system, achieving large-scale cryopreservation of T cells for lymphoma immunotherapy. ZMNPs could form a globular hydration shell to inhibit water molecule aggregation as well as ice growth, and the surficial hydration strength-antifreeze performance relationship of ZMNPs was investigated. During the thawing process, ZMNPs possessed a magnetic field-mediated nanowarming property that enabled rapid heating and also facilitated easy magnetic separation for cell recovery. These combined effects resulted in a high post-thaw viability (>80%) of large-scale T-cell cryopreservation (20 mL). Notably, post-thaw T cells exhibited similar transcript profiles to fresh cells, while up- or downregulation of 1050 genes was found in the DMSO group. In a mouse E.G7-OVA lymphoma model, ZMNP-system-cryopreserved T cells achieved a tumor suppression rate of 77.5%, twice as high as the DMSO group. This work holds great promise for the application of advanced cryopreservation techniques in the development of therapeutic cellular products.

Efficacy and safety of hepatic arterial infusion chemotherapy combined with fruquintinib and tislelizumab for patients with microsatellite stable colorectal cancer liver metastasis following failure of multiple-line therapy.

Background and aim: The prognosis of microsatellite stable (MSS)-colorectal cancer liver metastasis (CRCLM) following failure of multi-line therapy remains dismal. The aim of this study is to evaluate the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) plus fruquintinib and tislelizumab (HAIC-F-T treatment) for MSS-CRCLM which failed from multiple-line therapy. Methods: From February 2021 to June 2023, 45 patients with MSS-CRCLM after failure of multiple-line therapy who received HAIC combined with fruquintinib and tislelizumab (HAIC-F-T triple treatment) were enrolled. The combination therapy included HAIC regimens with oxaliplatin and 5-fluorouracil or irinotecan, oxaliplatin, and 5-fluorouracil on days 1-2, intravenous tislelizumab (200 mg) before HAIC on day 1, and oral fruquintinb (3 mg/d) on day 3-21, every 4 weeks. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. Results: The follow-up ended on June 22, 2024, with a median follow-up time of 17.5 months. The objective response rate was 42.2%, and the disease control rate was 82.2%. The median OS was 15.3 months (95% confidence interval [CI]:12.634-17.966), and the median PFS was 7.5 months (95% CI:5.318-9.682). The independent risk factors related to worse OS were previous PD-1 immunotherapy (P = 0.021) and the number of HAIC-F-T triple treatment cycles of ≤ 2 (P = 0.007). The incidence of grade 3 or higher adverse events (AEs) was 20%, with the most frequent grade 3 or higher AEs being abdominal pain (3/45, 6.7%). Conclusion: HAIC combined with fruquintinib and tislelizumab may be an alternative salvage treatment for patients with MSS-CRCLM following failure of multiple-line therapy.

Metabolic profiling and spatial metabolite distribution in wild soybean (G. soja) and cultivated soybean (G. max) seeds.

Wild soybeans retain many substances significantly reduced or lost in cultivars during domestication. This study utilized LC-MS to analyze metabolites in the seed coats and embryos of wild and cultivated soybeans. 866 and 815 metabolites were identified in the seed extracts of both soybean types, with 35 and 10 significantly differing metabolites in the seed coat and embryos, respectively. The upregulated metabolites in wild soybeans are linked to plant defense, stress responses, and nitrogen cycling. MALDI-MSI results further elucidated the distribution of these differential metabolites in the cotyledons, hypocotyls, and radicles. In addition to their role in physiological processes like growth and response to environmental stimuli, the prevalent terpenoids, lipids, and flavonoids present in wild soybeans exhibit beneficial bioactivities, including anti-inflammatory, antibacterial, anticancer, and cardiovascular disease prevention properties. These findings underscore the potential of wild soybeans as a valuable resource for enhancing the nutritional and ecological adaptability of cultivated soybeans.

A novel spherical GelMA-HAMA hydrogel encapsulating APET×2 polypeptide and CFIm25-targeting sgRNA for immune microenvironment modulation and nucleus pulposus regeneration in intervertebral discs.

METHODS: Single-cell transcriptomics and high-throughput transcriptomics were used to screen factors significantly correlated with intervertebral disc degeneration (IDD). Expression changes of CFIm25 were determined via RT-qPCR and Western blot. NP cells were isolated from mouse intervertebral discs and induced to degrade with TNF-α and IL-1ß. CFIm25 was knocked out using CRISPR-Cas9, and CFIm25 knockout and overexpressing nucleus pulposus (NP) cell lines were generated through lentiviral transfection. Proteoglycan expression, protein expression, inflammatory factor expression, cell viability, proliferation, migration, gene expression, and protein expression were analyzed using various assays (alcian blue staining, immunofluorescence, ELISA, CCK-8, EDU labeling, transwell migration, scratch assay, RT-qPCR, Western blot). The GelMA-HAMA hydrogel loaded with APET×2 polypeptide and sgRNA was designed, and its effects on NP regeneration were assessed through in vitro and mouse model experiments. The progression of IDD in mice was evaluated using X-ray, H&E staining, and Safranin O-Fast Green staining. Immunohistochemistry was performed to determine protein expression in NP tissue. Proteomic analysis combined with in vitro and in vivo experiments was conducted to elucidate the mechanisms of hydrogel action. RESULTS: CFIm25 was upregulated in IDD NP tissue and significantly correlated with disease progression. Inhibition of CFIm25 improved NP cell degeneration, enhanced cell proliferation, and migration. The hydrogel effectively knocked down CFIm25 expression, improved NP cell degeneration, promoted cell proliferation and migration, and mitigated IDD progression in a mouse model. The hydrogel inhibited inflammatory factor expression (IL-6, iNOS, IL-1ß, TNF-α) by targeting the p38/NF-κB signaling pathway, increased collagen COLII and proteoglycan Aggrecan expression, and suppressed NP degeneration-related factors (COX-2, MMP-3). CONCLUSION: The study highlighted the crucial role of CFIm25 in IDD and introduced a promising therapeutic strategy using a porous spherical GelMA-HAMA hydrogel loaded with APET×2 polypeptide and sgRNA. This innovative approach offers new possibilities for treating degenerated intervertebral discs.

Podocan unraveled: Understanding its role in tumor proliferation and smooth muscle regulation.

Podocan, a small leucine-rich repeat protein, is expressed in HIV-associated nephropathy, the cardiovascular system, and smooth muscle. Studies have linked PODN and PODNL to cancers such as osteosarcoma, glioma, and stomach cancer. Research has primarily focused on podocan's role in renal podocytes, injured smooth muscle cells, and various tumor cells. Bioinformatics studies have examined the role of PODN as a biomarker in tumors. Our research summarizes the modulatory role of podocan in smooth muscle and tumor proliferation through its suppression of cell proliferation and promotion of cell differentiation via various signaling pathways, including Wnt/ß-catenin, TGF-ß, and Akt/mTOR. We aim to provide a comprehensive overview of PODN's involvement in smooth muscle, cardiovascular system, and tumors by integrating current and past research. This review aims to enhance understanding and inform in the diagnosis, prognosis, and treatment of various diseases.