Comparative Inhibitory Effects of Tacrolimus, Cyclosporine, and Rapamycin on Human Anti-Pig Xenogeneic Mixed Lymphocyte Reactions.

BACKGROUND: Long-term immunosuppressive maintenance therapy is necessary to prevent the rejection of xenografts. However, it is still unclear which oral immunosuppressant is most suitable for pig-to-human xenotransplantation . METHODS: A xenogeneic mixed lymphocyte reaction (MLR) system was established using peripheral blood mononuclear cells (PBMCs) isolated from wildtype (WT) or GTKO/CMAHKO/ß4GalNT2KO (TKO) pigs as stimulator cells and human PBMCs as responder cells. Various concentrations of tacrolimus (Tac), cyclosporine (CsA), or rapamycin (Rapa) were added to the MLR system as interventions. The inhibitory effects of the three immunosuppressants on the proliferation and cytokine production of human T cells were studied and compared. The inhibitory effect of anti-CD154 mAb alone or in combination with Tac/CsA/Rapa on xenoreactive MLR was also investigated. RESULTS: PBMCs from both WT and TKO pigs stimulated significant proliferation of human T cells. Tac had a strong inhibitory effect on human T-cell proliferation stimulated by pig PBMCs. CsA inhibited human T-cell proliferation in a typical dose-dependent manner. When Tac and CsA concentrations reached 5 and 200 ng/mL, respectively, the proliferation rates of CD3+/CD4+/CD8+ T cells were reduced almost to a negative level. Even at high concentrations, Rapa had only a moderate inhibitory effect on xenogeneic MLR. The inhibitory effects of these three immunosuppressants on xenogeneic T-cell responses were further confirmed by the detection of CD25 expression and supernatant cytokines (IL-2, IL-6, IFN-γ, TNF-α, IL-4, IL-10, and IL-17). Although anti-CD154 mAb monotherapy showed only moderate inhibitory effects on xenoreactive T-cell proliferation, low-dose anti-CD154 mAb combined with low-dose Tac, CSA, or Rapa could produce significant synergistic inhibitory effects. CONCLUSION: Tac is more efficient than CsA or Rapa in inhibiting xenogeneic T-cell responses in vitro. If used in combination with anti-CD154 mAb, all the three immunosuppressants can achieve satisfactory synergistic inhibitory effects.

Improved Charge Injection Balance in Quantum Dot Light-Emitting Diodes through Interface Texture.

The existing methods to improve the charge balance of quantum dot light-emitting diodes (QLEDs) rely on energy-level matching, but these approaches have been limited by material availability and Fermi-level pinning. Here, we propose a solution that does not require changes to the materials' electronic properties. By using nanoimprinting technology to texture the interface between the hole-transporting layer (HTL) and colloidal quantum dot (CQD) layer, we can increase the HTL-CQD contact area. This significantly enhances the hole injection rate while keeping the electron injection rate essentially unchanged. Compared with the conventional planar structure, QLEDs with textured HTL exhibit lower luminance threshold voltage, significantly higher external quantum efficiency at low bias voltages, improved operational stability, and a similar Lambertian factor. Comprehensive measurements confirm that the HTL-CQD interface texture allows more efficient hole injection into CQDs to occur under lower bias, resulting in less CQD charging and more efficient exciton recombination.

Identification and transcriptome analysis of a photosynthesis deficient mutant of Populus davidiana Dode.

Photosynthesis is the main source of energy for plants to sustain growth and development. Abnormalities in photosynthesis may cause defects in plant development. The elaborate regulatory mechanism underlying photosynthesis remains unclear. In this study, we identified a natural mutant from the Greater Khingan Mountains and named it as "1-T". This mutant had variegated leaf with irregular distribution of yellow and green. Chlorophyll contents and photosynthetic capacity of 1-T were significantly reduced compared to other poplar genotypes. Furthermore, a transcriptome analysis revealed 3269 differentially expressed genes (DEGs) in 1-T. The products of the DEGs were enriched in photosystem I and photosystem II. Three motifs were significantly enriched in the promoters of these DEGs. Yeast one-hybrid, Electrophoretic mobility shift assays and tobacco transient transformation experiments indicated that PdGLKs may bind to the three motifs. Further analysis indicated that these photosystem related genes were also significantly down-regulated in PdGLK-RNAi poplars. Therefore, we preliminarily concluded that the down-regulation of PdGLKs in 1-T may affect the expression of photosystem-related genes, resulting in abnormal photosystem development and thus affecting the growth and development. Our results provide new insights into the molecular mechanism of photosynthesis regulating plant growth.

Exploration on the potential efficacy and mechanism of methyl salicylate glycosides in the treatment of schizophrenia based on bioinformatics, molecular docking and dynamics simulation.

The etiological and therapeutic complexities of schizophrenia (SCZ) persist, prompting exploration of anti-inflammatory therapy as a potential treatment approach. Methyl salicylate glycosides (MSGs), possessing a structural parent nucleus akin to aspirin, are being investigated for their therapeutic potential in schizophrenia. Utilizing bioinformation mining, network pharmacology, molecular docking and dynamics simulation, the potential value and mechanism of MSGs (including MSTG-A, MSTG-B, and Gaultherin) in the treatment of SCZ, as well as the underlying pathogenesis of the disorder, were examined. 581 differentially expressed genes related to SCZ were identified in patients and healthy individuals, with 349 up-regulated genes and 232 down-regulated genes. 29 core targets were characterized by protein-protein interaction (PPI) network, with the top 10 core targets being BDNF, VEGFA, PVALB, KCNA1, GRIN2A, ATP2B2, KCNA2, APOE, PPARGC1A and SCN1A. The pathogenesis of SCZ primarily involves cAMP signaling, neurodegenerative diseases and other pathways, as well as regulation of ion transmembrane transport. Molecular docking analysis revealed that the three candidates exhibited binding activity with certain targets with binding affinities ranging from -4.7 to -109.2 kcal/mol. MSTG-A, MSTG-B and Gaultherin show promise for use in the treatment of SCZ, potentially through their ability to modulate the expression of multiple genes involved in synaptic structure and function, ion transport, energy metabolism. Molecular dynamics simulation revealed good binding abilities between MSTG-A, MSTG-B, Gaultherin and ATP2B2. It suggests new avenues for further investigation in this area.

Unveiling the Twisted Aromatic Donor Effect on the Nonlinear Response of D-π-A Type Malononitrile-Derived Chromophores.

This study presents the design, synthesis, and comprehensive characterization of a novel series of D-π-A type malononitrile-derived chromophores, BTC-1 to BTC-4. Combining various spectroscopic techniques, nonlinear Z-scan measurements, and quantum chemical calculations, we revealed the intricate relationship between nonlinear optical properties and the interplay of molecular structure, intramolecular charge transfer (ICT), and dipole moments (µ). Our experimental and computational findings corroborate that the polarization degree in the ground state, the charge separation in the excited state and ICT collectively dictate the nonlinear optical properties of the compounds. Notably, BTC-1 exhibits an exceptional nonlinear absorption coefficient ß value (2 × 10-8 m W-1), attributed to its optimized charge transfer efficiency and pronounced degree of charge separation. Our findings provide actionable insights for the rational design of high-performance organic NLO materials with potential applications in advanced photonic devices.

TAX1BP1 and FIP200 orchestrate non-canonical autophagy of p62 aggregates for mouse neural stem cell maintenance.

Autophagy plays a pivotal role in diverse biological processes, including the maintenance and differentiation of neural stem cells (NSCs). Interestingly, while complete deletion of Fip200 severely impairs NSC maintenance and differentiation, inhibiting canonical autophagy via deletion of core genes, such as Atg5, Atg16l1, and Atg7, or blockade of canonical interactions between FIP200 and ATG13 (designated as FIP200-4A mutant or FIP200 KI) does not produce comparable detrimental effects. This highlights the likely critical involvement of the non-canonical functions of FIP200, the mechanisms of which have remained elusive. Here, utilizing genetic mouse models, we demonstrated that FIP200 mediates non-canonical autophagic degradation of p62/sequestome1, primarily via TAX1BP1 in NSCs. Conditional deletion of Tax1bp1 in fip200 hGFAP conditional knock-in (cKI) mice led to NSC deficiency, resembling the fip200 hGFAP conditional knockout (cKO) mouse phenotype. Notably, reintroducing wild-type TAX1BP1 not only restored the maintenance of NSCs derived from tax1bp1-knockout fip200 hGFAP cKI mice but also led to a marked reduction in p62 aggregate accumulation. Conversely, a TAX1BP1 mutant incapable of binding to FIP200 or NBR1/p62 failed to achieve this restoration. Furthermore, conditional deletion of Tax1bp1 in fip200 hGFAP cKO mice exacerbated NSC deficiency and p62 aggregate accumulation compared to fip200 hGFAP cKO mice. Collectively, these findings illustrate the essential role of the FIP200-TAX1BP1 axis in mediating the non-canonical autophagic degradation of p62 aggregates towards NSC maintenance and function, presenting novel therapeutic targets for neurodegenerative diseases.

[Spatiotemporal Coupling Analysis of Urbanization and Ecosystem Services in Southeastern Fujian].

Revealing the spatiotemporal coupling relationship between urbanization and ecosystem services can help to clarify regional development differences, optimize the implementation path of urbanization, and improve the quality of ecosystem services. Taking southeastern Fujian, a region with a good ecological foundation and strong urbanization potential, as a case study, the levels of multidimensional urbanization systems and typical ecosystem services of this region in the years 2000, 2010, and 2020 were quantified using the index comprehensive evaluation method and the InVEST model. The Pearson correlation coefficient and the coupling coordination degree model were used to analyze the spatiotemporal coupling relationship between urbanization and ecosystem services, and suggestions for improving regional coordinated development were proposed. The results showed that： ① The comprehensive urbanization level in southeastern Fujian increased continuously, with an average annual growth rate of 7.3%, of which social urbanization was the fastest, followed by economic urbanization and population urbanization, and spatial urbanization was relatively backward. Ecosystem services tended to decline, especially food and water provision services, which decreased by 61.9% and 46.9%, respectively. The spatial distribution showed a mismatch pattern of "high urbanization level and weak ecosystem services" in the southeast coastal area and "low urbanization level and strong ecosystem services" in the northwest inland area. ② The correlation between urbanization and ecosystem services was mainly negative. The negative effect of economic and social urbanization on ecosystem services was weaker than that of population and spatial urbanization, with a clear weakening tendency. As population and spatial urbanization slowed down sharply and economic and social urbanization accelerated, the driving force of urbanization development gradually shifted from "quantitative increase" to "qualitative improvement." Thus, the decline of ecosystem services was alleviated. ③ Comprehensive urbanization and various ecosystem services experienced three stages of "imbalance-transition-reconciliation," with an average increase of 60.5% to 120.6% in the coupling coordination degree. However, highly coordinated regions remained scarce, indicating that there is still significant room for improvement. The relative relationship between urbanization and ecosystem services evolved from urbanization lag to ecosystem services lag. The fluctuation problem of backward coupling coordination level caused by excessive urbanization had initially appeared in the southeastern coastal area. Therefore, in future construction, southeastern Fujian should improve economic quality and social benefits； strengthen the overall management, protection, and restoration of ecological space； and enhance the order and stability of the coordinated development of urbanization and ecosystem services.

Human umbilical cord mesenchymal stem cells derived-exosomes on VEGF-A in hypoxic-induced mice retinal astrocytes and mice model of retinopathy of prematurity.

AIM: To observe the effect of human umbilical cord mesenchymal stem cells (hUCMSCs) secretions on the relevant factors in mouse retinal astrocytes, and to investigate the effect of hUCMSCs on the expression of vascular endothelial growth factor-A (VEGF-A) and to observe the therapeutic effect on the mouse model of retinopathy of prematurity (ROP). METHODS: Cultured hUCMSCs and extracted exosomes from them and then retinal astrocytes were divided into control group and hypoxia group. MTT assay, flow cytometry, reverse transcription-polymerase chain reaction (RT-PCR) and Western blot were used to detect related indicators. Possible mechanisms by which hUCMSCs exosomes affect VEGF-A expression in hypoxia-induced mouse retinal astrocytes were explored. At last, the efficacy of exosomes of UCMSCs in a mouse ROP model was explored. Graphpad6 was used to comprehensively process data information. RESULTS: The secretion was successfully extracted from the culture supernatant of hUCMSCs by gradient ultracentrifugation. Reactive oxygen species (ROS) and hypoxia inducible factor-1α (HIF-1α) of mice retinal astrocytes under different hypoxia time and the expression level of VEGF-A protein and VEGF-A mRNA increased, and the ROP cell model was established after 6h of hypoxia. The secretions of medium and high concentrations of hUCMSCs can reduce ROS and HIF-1α, the expression levels of VEGF-A protein and VEGF-A mRNA are statistically significant and concentration dependent. Compared with the ROP cell model group, the expression of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signal pathway related factors in the hUCMSCs exocrine group is significantly decreased. The intravitreal injection of the secretions of medium and high concentrations of hUCMSCs can reduce VEGF-A and HIF-1α in ROP model tissues. HE staining shows that the number of retinal neovascularization in ROP mice decreases with the increase of the dose of hUCMSCs secretion. CONCLUSION: In a hypoxia induced mouse retinal astrocyte model, hUCMSCs exosomes are found to effectively reduce the expression of HIF-1α and VEGF-A, which are positively correlated with the concentration of hUCMSCs exosomes. HUCMSCs exosomes can effectively reduce the number of retinal neovascularization and the expression of HIF-1α and VEGF-A proteins in ROP mice, and are positively correlated with drug dosage. Besides, they can reduce the related factors on the PI3K/AKT/mTOR signaling pathway.

Construction of V2O5@MXene Cathodes toward a High Specific Capacity Aqueous Aluminum-Ion Battery.

Aqueous aluminum-ion batteries (AAIBs) are considered a strong candidate for the new generation of energy storage devices. The lack of suitable cathode materials has been a bottleneck factor hindering the future development of AAIBs. In this work, we design and construct a highly effective cathode with dual morphologies. Two-dimensional (2D) layered MXene materials possessed good conductivity and hydrophilicity, which are used as the substrates to deposit rod-shaped vanadium oxides (V2O5) to form a three-dimensional (3D) cathode. The cathode design provides a strong boost for the rapid electrochemical activities of rod-shaped V2O5 by embedding/extracting both protons (H+) and aluminum-ion (Al3+). As a result, the V2O5@MXene cathode based AAIB delivers an ultrahigh initial specific capacity of 626 mAh/g at 0.1 A/g with a stable cycle performance up to 100 cycles. This work is a breakthrough for the development of cathode materials for AAIBs.

Development and evaluation of interpretable machine learning regressors for predicting femoral neck bone mineral density in elderly men using NHANES data.

Osteoporotic femoral neck fractures (OFNFs) pose a significant orthopedic challenge in the elderly population, accounting for up to 40% of all osteoporotic fractures and leading to considerable health deterioration and increased mortality. In addressing the critical need for early identification of osteoporosis through routine screening of femoral neck bone mineral density (FNBMD), this study developed a user-friendly prediction model aimed at men aged 50 years and older, a demographic often overlooked in osteoporosis screening. Utilizing data from the National Health and Nutrition Examination Survey (NHANES), the study involved outlier detection and handling, missing value imputation via the K nearest neighbor (KNN) algorithm, and data normalization and encoding. The dataset was split into training and test sets with a 7:3 ratio, followed by feature screening through the least absolute shrinkage and selection operator (LASSO) and the Boruta algorithm. Eight different machine learning algorithms were then employed to construct predictive models, with their performance evaluated through a comprehensive metric suite. The random forest regressor (RFR) emerged as the most effective model, characterized by key predictors such as age, body mass index (BMI), poverty income ratio (PIR), serum calcium, and race, achieving a coefficient of determination (R²) of 0.218 and maintaining robustness in sensitivity analyses. Notably, excluding race from the model resulted in sustained high performance, underscoring the model's adaptability. Interpretations using Shapley additive explanations (SHAP) highlighted the influence of each feature on FNBMD. These findings indicate that our predictive model effectively aids in the early detection of osteoporosis, potentially reducing the incidence of OFNFs in this high-risk population.

Microbial diversity and oil biodegradation potential of northern Barents Sea sediments.

The Arctic, an essential ecosystem on Earth, is subject to pronounced anthropogenic pressures, most notable being the climate change and risks of crude oil pollution. As crucial elements of Arctic environments, benthic microbiomes are involved in climate-relevant biogeochemical cycles and hold the potential to remediate upcoming contamination. Yet, the Arctic benthic microbiomes are among the least explored biomes on the planet. Here we combined geochemical analyses, incubation experiments, and microbial community profiling to detail the biogeography and biodegradation potential of Arctic sedimentary microbiomes in the northern Barents Sea. The results revealed a predominance of bacterial and archaea phyla typically found in the deep marine biosphere, such as Chloroflexi, Atribacteria, and Bathyarcheaota. The topmost benthic communities were spatially structured by sedimentary organic carbon, lacking a clear distinction among geographic regions. With increasing sediment depth, the community structure exhibited stratigraphic variability that could be correlated to redox geochemistry of sediments. The benthic microbiomes harbored multiple taxa capable of oxidizing hydrocarbons using aerobic and anaerobic pathways. Incubation of surface sediments with crude oil led to proliferation of several genera from the so-called rare biosphere. These include Alkalimarinus and Halioglobus, previously unrecognized as hydrocarbon-degrading genera, both harboring the full genetic potential for aerobic alkane oxidation. These findings increase our understanding of the taxonomic inventory and functional potential of unstudied benthic microbiomes in the Arctic.

Relationship between plasma TNF-α levels and agitation symptoms in first episode patients with schizophrenia.

BACKGROUND: Increasing evidence suggested that immune abnormalities involved in the pathophysiology of schizophrenia. However, the relationship between immunity and clinical features has not been clarified. The aim of this study was to measure the plasma levels of tumor necrosis factor alpha (TNF-α) and soluble TNF-α receptor 1 (sTNF-α R1) and to investigate their association with agitation in first episode patients with schizophrenia (FEPS). METHODS: The plasma TNF-α and sTNF-α R1 levels were measured using sandwich enzyme-linked immunosorbent assay (ELISA) in the FEPS with (n = 36) and without agitation (n = 49) symptoms, and healthy controls (HCs, n = 54). The psychopathology was assessed by the Positive and Negative Syndrome Scale (PANSS), and the agitation symptoms were evaluated by the PANSS excitatory component (PANSS-EC). RESULTS: The plasma TNF-α levels in patients with and without agitation symptoms were significantly higher than those in HCs. The patients with agitation had significantly higher plasma TNF-α levels compared to the patients without agitation. There were no significant differences in the sTNF-α R1 levels among the three groups. Furthermore, the plasma TNF-α levels were positively correlated with the PANSS total score, Positive and General psychopathological subscores, and PANSS-EC score in the FEPS, but the relationships were not found for the plasma sTNF-α R1 levels. CONCLUSIONS: These results suggested that TNF-α might play an important role in the onset and development of agitation symptoms of schizophrenia.

Language-aware multiple datasets detection pretraining for DETRs.

Pretraining on large-scale datasets can boost the performance of object detectors while the annotated datasets for object detection are hard to scale up due to the high labor cost. What we possess are numerous isolated filed-specific datasets, thus, it is appealing to jointly pretrain models across aggregation of datasets to enhance data volume and diversity. In this paper, we propose a strong framework for utilizing Multiple datasets to pretrain DETR-like detectors, termed METR, without the need for manual label spaces integration. It converts the typical multi-classification in object detection into binary classification by introducing a pre-trained language model. Specifically, we design a category extraction module for extracting potential categories involved in an image and assign these categories into different queries by language embeddings. Each query is only responsible for predicting a class-specific object. Besides, to adapt our novel detection paradigm, we propose a Class-wise Bipartite Matching strategy that limits the ground truths to match queries assigned to the same category. Extensive experiments demonstrate that METR achieves extraordinary results on either multi-task joint training or the pretrain & finetune paradigm. Notably, our pre-trained models have high flexible transferability and increase the performance upon various DETR-like detectors on COCO val2017 benchmark. Our code is publicly available at: https://github.com/isbrycee/METR.

Coordination engineering for iron-based hexacyanoferrate as a high-stability cathode for sodium-ion batteries.

Iron-based hexacyanoferrate (Fe-HCF) are promising cathode materials for sodium-ion batteries (SIBs) due to their unique open-channel structure that facilitates fast ion transport and framework stability. However, practical implementation of SIBs has been hindered by low initial Coulombic efficiency (ICE), poor rate performance, and short lifespan. Herein, we report a coordination engineering to synthesize sodium-rich Fe-HCF as cathodes for SIBs through a uniquely designed 10-kg-scale chemical reactor. Our study systematically investigated the relationship between coordination surroundings and the electrochemical behavior. Building on this understanding, the cathode delivered a reversible capacity of 99.3 mAh g-1 at 5 C (1 C = 100 mA g-1), exceptional rate capability (51 mAh g-1 even at 100 C), long lifespan (over 15,000 times at 50 C), and a high ICE of 92.7%. A full cell comprising the Fe-HCF cathode and hard carbon (HC) anode exhibited an impressive cyclic stability with a high-capacity retention rate of 98.3% over 1,000 cycles. Meanwhile, this material can be readily scaled to the practical levels of yield. The findings underscore the potential of Fe-HCF as cathodes for SIBs and highlight the significance of controlling nucleation and morphology through coordination engineering for a sustainable energy storage system.

Dynamic regulation of stem cell adhesion and differentiation on degradable piezoelectric poly (L-lactic acid) (PLLA) nanofibers.

Degradable piezoelectric materials possess significant potential for application in the realm of bone tissue regeneration. However, the correlation between cell regulation mechanisms and the dynamic variation caused by material degradation has not been explained, hindering the optimization of material design and its in vivo application. Herein, piezoelectric poly (L-lactic acid) (PLLA) nanofibers with different molecular weights (MW) were fabricated, and the effects of their piezoelectric properties, structural morphology, and material products during degradation on the adhesion and osteogenic differentiation of mesenchymal stem cells (MSCs) were investigated. Our results demonstrated that cell adhesion-mediated piezoelectric stimulation could significantly enhance cell spreading, cell orientation, and upregulate the expression of calmodulin, which further triggers downstream signaling cascade to regulate osteogenic differentiation markers of type I collagen and runt-related transcription factor 2. Additionally, during the degradation of the nanofibers, the piezoelectric properties of PLLA weakened, the fibrous structure gradually diminished, and pH levels in the vicinity decreased, which resulting in reduced osteogenic differentiation capability of MSCs. However, nanofibers with higher MW (280 kDa) have the ability to maintain the fibrous morphology and piezoelectricity for a longer time, which can regulate the osteogenic differentiation of stem cells for more than 4 weeks. These findings have provide a new insight to correlate cell behavior with MW and the biodegradability of piezopolymers, which revealed an active method for cell regulation through material optimization for bone tissue engineering in near future.

Metabolic stress induces a double-positive feedback loop between AMPK and SQSTM1/p62 conferring dual activation of AMPK and NFE2L2/NRF2 to synergize antioxidant defense.

Co-occurring mutations in KEAP1 in STK11/LKB1-mutant NSCLC activate NFE2L2/NRF2 to compensate for the loss of STK11-AMPK activity during metabolic adaptation. Characterizing the regulatory crosstalk between the STK11-AMPK and KEAP1-NFE2L2 pathways during metabolic stress is crucial for understanding the implications of co-occurring mutations. Here, we found that metabolic stress increased the expression and phosphorylation of SQSTM1/p62, which is essential for the activation of NFE2L2 and AMPK, synergizing antioxidant defense and tumor growth. The SQSTM1-driven dual activation of NFE2L2 and AMPK was achieved by inducing macroautophagic/autophagic degradation of KEAP1 and facilitating the AXIN-STK11-AMPK complex formation on the lysosomal membrane, respectively. In contrast, the STK11-AMPK activity was also required for metabolic stress-induced expression and phosphorylation of SQSTM1, suggesting a double-positive feedback loop between AMPK and SQSTM1. Mechanistically, SQSTM1 expression was increased by the PPP2/PP2A-dependent dephosphorylation of TFEB and TFE3, which was induced by the lysosomal deacidification caused by low glucose metabolism and AMPK-dependent proton reduction. Furthermore, SQSTM1 phosphorylation was increased by MAP3K7/TAK1, which was activated by ROS and pH-dependent secretion of lysosomal Ca2+. Importantly, phosphorylation of SQSTM1 at S24 and S226 was critical for the activation of AMPK and NFE2L2. Notably, the effects caused by metabolic stress were abrogated by the protons provided by lactic acid. Collectively, our data reveal a novel double-positive feedback loop between AMPK and SQSTM1 leading to the dual activation of AMPK and NFE2L2, potentially explaining why co-occurring mutations in STK11 and KEAP1 happen and providing promising therapeutic strategies for lung cancer.Abbreviations: AMPK: AMP-activated protein kinase; BAF1: bafilomycin A1; ConA: concanamycin A; DOX: doxycycline; IP: immunoprecipitation; KEAP1: kelch like ECH associated protein 1; LN: low nutrient; MAP3K7/TAK1: mitogen-activated protein kinase kinase kinase 7; MCOLN1/TRPML1: mucolipin TRP cation channel 1; MEFs: mouse embryonic fibroblasts; MTORC1: mechanistic target of rapamycin kinase complex 1; NAC: N-acetylcysteine; NFE2L2/NRF2: NFE2 like bZIP transcription factor 2; NSCLC: non-small cell lung cancer; PRKAA/AMPKα: protein kinase AMP-activated catalytic subunit alpha; PPP2/PP2A: protein phosphatase 2; ROS: reactive oxygen species; PPP3/calcineurin: protein phosphatase 3; RPS6KB1/p70S6K: ribosomal protein S6 kinase B1; SQSTM1/p62: sequestosome 1; STK11/LKB1: serine/threonine kinase 11; TCL: total cell lysate; TFEB: transcription factor EB; TFE3: transcription factor binding to IGHM enhancer 3; V-ATPase: vacuolar-type H+-translocating ATPase.

Neoadjuvant sintilimab plus chemotherapy in EGFR-mutant NSCLC: Phase 2 trial interim results (NEOTIDE/CTONG2104).

The clinical efficacy of neoadjuvant immunotherapy plus chemotherapy remains elusive in localized epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). Here, we report interim results of a Simon's two-stage design, phase 2 trial using neoadjuvant sintilimab with carboplatin and nab-paclitaxel in resectable EGFR-mutant NSCLC. All 18 patients undergo radical surgery, with one patient experiencing surgery delay. Fourteen patients exhibit confirmed radiological response, with 44% achieving major pathological response (MPR) and no pathological complete response (pCR). Similar genomic alterations are observed before and after treatment without influencing the efficacy of subsequent EGFR-tyrosine kinase inhibitors (TKIs) in vitro. Infiltration and T cell receptor (TCR) clonal expansion of CCR8+ regulatory T (Treg)hi/CXCL13+ exhausted T (Tex)lo cells define a subtype of EGFR-mutant NSCLC highly resistant to immunotherapy, with the phenotype potentially serving as a promising signature to predict immunotherapy efficacy. Informed circulating tumor DNA (ctDNA) detection in EGFR-mutant NSCLC could help identify patients nonresponsive to neoadjuvant immunochemotherapy. These findings provide supportive data for the utilization of neoadjuvant immunochemotherapy and insight into immune resistance in EGFR-mutant NSCLC.

The tumour suppressor Fat1 is dispensable for normal murine hematopoiesis.

Loss and overexpression of FAT1 occurs among different cancers with these divergent states equated with tumor suppressor and oncogene activity, respectively. Regarding the latter, FAT1 is highly expressed in a high proportion of human acute leukemias relative to normal blood cells, with evidence pointing to an oncogenic role. We hypothesized that this occurrence represents legacy expression of FAT1 in undefined hematopoietic precursor subsets that is sustained following transformation, predicating a role for FAT1 during normal hematopoiesis. We explored this concept by using the Vav-iCre strain to construct conditional knockout (cKO) mice where Fat1 expression was deleted at the hematopoietic stem cell stage. Extensive analysis of precursor and mature blood populations using multi-panel flow cytometry revealed no ostensible differences between Fat1 cKO mice and normal littermates. Further functional comparisons involving colony forming unit and competitive bone marrow transplantation assays support the conclusion that Fat1 is dispensable for normal murine hematopoiesis.

Mechanism of PTPN18 for regulating the migration and invasion of endometrial cancer cells via the MYC/PI3K/AKT pathway.

OBJECTIVE: Endometrial cancer (EC) is a prevalent gynecologic malignancy. The critical role of PTPN18 in EC has been reported, while its role in the aerobic glycolysis of EC cells remains unclear. Our current study focused on the mechanism of PTPN18 in the regulation of aerobic glycolysis in EC. METHODS: PTPN18 expression levels in endometrial stromal cells (KC02-44D) and EC cells (KLE, HEC-1-A, HEC-1B, and HEC-50) were determined. Following transfection of sh-PTPN18 in HEC-1-A cells, the changes in cell migratory and invasive abilities were assessed by the Transwell assay, and the changes in glucose consumption, lactic acid secretion, and ATP levels were detected using kits. The expression levels of glycolysis-related proteins HIF-1α, PKM2, and LDHA and the activation of the MYC/PI3K/AKT pathway were detected by Western blot. Additionally, sh-PTPN18 and pcDNA3.1-MYC were transfected into HEC-1-A cells to further explore their roles in the changes in aerobic glycolysis, migration, and invasion ability of EC cells. RESULTS: Expression of PTPN18 in EC cells was up-regulated (HEC-1-A>HEC-1B>HEC-50>KLE). PTPN18 knockdown suppressed EC cell migration and invasion. Additionally, PTPN18 knockdown reduced glucose consumption, lactate production, ATP levels, and glycolysis-related protein levels (HIF-1α, PKM2, LDHA). PTPN18 knockdown inhibited the activation of the MYC/PI3K/AKT pathway in EC cells. MYC overexpression partially annulled the inhibitory effects of PTPN18 knockdown on aerobic glycolysis, migration, and invasion of EC cells. CONCLUSION: Our present study provided evidence that the knockdown of PTPN18 inhibited the aerobic glycolysis, migration, and invasion of EC cells by suppressing the MYC/PI3K/AKT pathway.

Blockage of TMEM189 induces G2/M arrest and inhibits the growth of breast tumors.

Cancer is the major cause of premature death in humans worldwide, demanding more efficient therapeutics. Aberrant cell proliferation resulting from the loss of cell cycle regulation is the major hallmark of cancer, so targeting cell cycle is a promising strategy to combat cancer. However, the molecular mechanism underlying the dysregulation of cell cycle of cancer cells remains poorly understood. TMEM189, a newly identified protein, plays roles in the biosynthesis of ethanolamine plasmalogen and the regulation of autophagy. Here, we demonstrated that the expression level of TMEM189 was negatively correlated with the survival rate of the cancer patients. TMEM189 deficiency significantly suppresses the cancer cell proliferation and migration, and causes cell cycle G2/M arrest both in vitro and in vivo. Furthermore, TMEM189 depletion suppressed the growth of breast tumors in vivo. Taken together, our work indicated that TMEM189 promotes cancer progression by regulating cell cycle G2/M transition, suggesting that it is a promising target in cancer therapy.