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Background Exosomal microRNAs (miRNAs or miRs) from bone marrow-derived mesenchymal stem cells (UCMSCs) have emerged as promising therapeutic strategies for cancer treatment. The current study aimed to elucidate the underlying mechanism of human umbilical cord mesenchymal stem cells (hUCMSCs)-derived exosomal miR-375 in esophageal squamous cell carcinoma (ESCC). Methods After determining the expression of miR-375 and its putative target enabled homolog (ENAH) in ESCC tissues and cells, we tested effects of their altered expression on ESCC proliferation, invasion, migration, and tumorsphere formation was subsequently measured. Transfected hUCMSCs-derived exosomes (hUCMSCs-exo) were isolated and co-cultured with ESCC cells to measure the effects of miR-375 delivered by hUCMSCs-exo on ESCC development. Finally, we investigated the effect of miR-375 on tumor growth in vivo. Results The expression of miR-375 was reduced, while the expression of ENAH was elevated in ESCC. ENAH was identified as a target gene of miR-375. Elevated miR-375 or depleted ENAH expression inhibited ESCC cell proliferation, invasion, migration, tumorsphere formation, and promoted apoptosis. Moreover, miR-375 delivered by hUCMSCs-exo could suppress ESCC cell proliferation, invasion, migration, tumorsphere formation, but promoted apoptosis in vitro, as well as inhibiting tumor growth in vivo. Conclusions Taken together, hUCMSCs-exo can deliver miR-375 to suppress ENAH expression and subsequently inhibit the initiation and progression of ESCC.

It is known that one of the main concerns associated with the conventional welding of precipitation-strengthened Al alloys is the formation of softening regions, resulting in the deterioration of mechanical properties. In this study, we show that linear friction welding (LFW) can completely suppress softening regions in precipitation-strengthened AA6061-T6 alloy by introducing a large shear strain and by controlling the interfacial temperature. We found that the LFW process resulted in an extremely low interfacial temperature; it decreased as the applied pressure increased from 50 to 240 MPa. This approach can essentially suppress both softening and hardening regions, leading to uniform hardness distribution in Al joints. The high-pressure LFW process demonstrated here can thus provide an innovated guidance to obtain high-performance Al alloy joints and be extended to other precipitation-strengthened Al alloys, which undergo high-temperature softening.

MicroRNA140-5p has been implicated in temporomandibular joint osteoarthritis (TMJ-OA), though its precise mechanistic role remains unclear. This study investigates the molecular mechanisms underlying microRNA140-5p-mediated inflammatory responses in TMJ-OA. In vitro, mandibular condylar chondrocytes (MCCs) were treated with IL-1β and transfected with small interfering RNA (siRNA) targeting Smad3, a direct target of microRNA140-5p. Expression of inflammatory cytokines was assessed via Western blotting and RT-qPCR. In vivo, a TMJ-OA model was established in Sprague–Dawley (SD) rats, followed by intra-articular injection of antagomir140-5p into the superior joint cavity. Histopathological and immunohistochemical (IHC) analyses were performed using hematoxylin–eosin (HE) staining. Our findings demonstrate that IL-1β treatment upregulated microRNA140-5p expression in MCCs. Overexpression of microRNA140-5p suppressed chondrocyte proliferation and cartilage formation while promoting apoptosis. Conversely, antagomir140-5p administration preserved cartilage integrity in TMJ-OA, restoring expression of SOX9, COL2A1, SMAD3, and TGF-β3, while suppressing inflammatory mediators such as RUNX2 and NF-κB. These findings suggest that the abnormal expression of microRNA-140-5p in condylar cartilage may reflect the pathological progression of temporomandibular joint osteoarthritis, with its potential mechanism likely mediated through regulation of the TGF-β/SMAD/SOX/NF-κB signaling axis.

Mutant KRAS (KRAS MUT ) is often exploited by cancers to shape tumor immunity, but the underlying mechanisms are not fully understood. Here we report that tumor-specific cytotoxic T lymphocytes (CTLs) from KRAS MUT cancers are sensitive to activation-induced cell death (AICD). circATXN7, an NF-κB-interacting circular RNA, governs T cell sensitivity to AICD by inactivating NF-κB. Mechanistically, histone lactylation derived from KRAS MUT tumor cell-produced lactic acid directly activates transcription of circATXN7, which binds to NF-κB p65 subunit and masks the p65 nuclear localization signal motif, thereby sequestering it in the cytoplasm. Clinically, circATXN7 upregulation in tumor-specific CTLs correlates with adverse clinical outcomes and immunotherapeutic resistance. Genetic ablation of circAtxn7 in CD8 + T cells leads to mutant-selective tumor inhibition, while also increases anti-PD1 efficacy in multiple tumor models in female mice. Furthermore, targeting circATXN7 in adoptively transferred tumor-reactive CTLs improves their antitumor activities. These findings provide insight into how lymphocyte-expressed circRNAs contribute to T-cell fate decisions and anticancer immunotherapies. Oncogenic KRAS mutations can dictate the formation of an immune-suppressive tumor microenvironment. Here the authors report that, in KRAS mutant colorectal cancer, the upregulation of circATXN7 in tumor-specific cytotoxic T lymphocytes is associated with increased sensitivity to activation-induced cell death and resistance to immunotherapy.”

Oxaliplatin is a widely used chemotherapy drug for patients with advanced colorectal cancer (CRC); however, frequent drug resistance limits its therapeutic efficacy in patients. Here, this work identifies cyclin‐dependent kinase 1 (CDK1) as a critical contributor to oxaliplatin resistance via in vitro and in vivo CRISPR/Cas9 screening. CDK1 is highly expressed in oxaliplatin‐resistant cells and tissues due to the loss of N6‐methyladenosine modification. Genetic and pharmacological blockade of CDK1 restore the susceptibility of CRC cells to oxaliplatin in vitro and in cell/patient‐derived xenograft models. Mechanistically, CDK1 directly binds to and phosphorylates Acyl‐CoA synthetase long‐chain family 4 (ACSL4) at S447, followed by recruitment of E3 ubiquitin ligase UBR5 and polyubiquitination of ACSL4 at K388, K498, and K690, which leads to ACSL4 protein degradation. Reduced ACSL4 subsequently blocks the biosynthesis of polyunsaturated fatty acid containing lipids, thereby inhibiting lipid peroxidation and ferroptosis, a unique iron‐dependent form of oxidative cell death. Moreover, treatment with a ferroptosis inhibitor nullifies the enhancement of CRC cell sensitivity to oxaliplatin by CDK1 blockade in vitro and in vivo. Collectively, the findings indicate that CDK1 confers oxaliplatin resistance to cells by suppressing ferroptosis. Therefore, administration of a CDK1 inhibitor may be an attractive strategy to treat patients with oxaliplatin‐resistant CRC. Oxaliplatin resistance is a thorny issue in the clinical treatment of colorectal cancer (CRC). The current study demonstrates that CDK1 facilitates oxaliplatin resistance in a cell cycle‐independent manner. CDK1 directly phosphorylates and ubiquitinates ACSL4 protein, resulting in ACSL4 degradation, thereby inhibiting ferroptosis and promoting oxaliplatin resistance. CDK1 blockade may be an attractive strategy to treat CRC patients with oxaliplatin resistance.

Inflammation is a common medical complication in colorectal cancer (CRC) patients, which plays significant roles in tumor progression and immunosuppression. However, the influence of inflammatory conditions on the tumor response to immune checkpoint inhibitors (ICI) is incompletely understood. Here we show that in a patient with high microsatellite instability (MSI-H) CRC and a local inflammatory condition, the primary tumor progresses but its liver metastasis regresses upon Pembrolizumab treatment. In silico investigation prompted by this observation confirms correlation between inflammatory conditions and poor tumor response to PD-1 blockade in MSI-H CRCs, which is further validated in a cohort of 62 patients retrospectively enrolled to our study. Inhibition of local but not systemic immune response is verified in cultures of paired T cells and organoid cells from patients. Single-cell RNA sequencing suggests involvement of neutrophil leukocytes via CD80/CD86-CTLA4 signaling in the suppressive immune microenvironment. In concordance with this finding, elevated neutrophil-to-lymphocyte ratio indicates inhibited immune status and poor tumor response to ICIs. Receiver operating characteristic curve further demonstrates that both inflammatory conditions and a high NLR could predict a poor response to ICIs in MSI- CRCs, and the predictive value could be further increased when these two predictors are combined. Our study thus suggests that inflammatory conditions in MSI-H CRCs correlate with resistance to ICIs through neutrophil leukocyte associated immunosuppression and proposes both inflammatory conditions and high neutrophil-to-lymphocyte ratio as clinical features for poor ICI response. Inflammatory conditions often affect colorectal cancer patients, and their effect on their ongoing treatment is a pressing medical question. Here authors show that inflammation interferes with local anti-tumour immune response and inhibits response to immune checkpoint blockade therapy via immunosuppressive neutrophil leukocytes.

Thalassemia is an autosomal recessive genetic disorder and a common form of Hemoglobinopathy. It is classified into α-thalassemia and β-thalassemia. This disease is mainly prevalent in tropical and subtropical regions, including southern China. Severe α-thalassemia and intermediate α-thalassemia are among the most common birth defects in southern China. Intermediate α-thalassemia, also known as Hb H disease, is characterized by moderate anemia. Severe α-thalassemia, also known as Hb Bart’s Hydrops fetalis syndrome, is a fatal condition. Infants with severe β-thalassemia do not show symptoms at birth but develop severe anemia later, requiring expensive treatment. Most untreated patients with severe β-thalassemia die in early childhood. Screening for thalassemia carriers and genetic diagnosis in high-prevalence areas significantly reduce the incidence of severe thalassemia. This review aims to summarize the genetic diagnostic approaches for thalassemia. Conventional genetic testing methods can identify 95–98% of thalassemia carriers but may miss rare thalassemia genotypes. Third-Generation Sequencing offers significant advantages in complementing other genetic diagnostic approaches, providing a basis for genetic counseling and prenatal diagnosis.

Background Liver metastasis is the leading cause of death in patients with colorectal cancer (CRC). Emerge evidence suggests that circular RNA (circRNA) is a pivotal player in cancer progression. However, its role in CRC liver metastasis remains largely unknown. Methods Circ-YAP expression was detected by qRT-PCR and in situ hybridization. The function of circ-YAP was tested by wound healing, transwell and CCK-8 assays. RNA immunoprecipitation, pull-down, luciferase reporter, chromatin immunoprecipitation assays were used to investigate the mechanism underlying circ-YAP promoting CRC liver metastasis. CRC liver metastasis animal model was established to assess the effect of circ-YAP in vivo. Results Circ-YAP was notably upregulated in CRC with liver metastasis, which was associated with dismal prognosis. Circ-YAP promoted CRC cell migration and invasion in vitro, and facilitated liver metastasis in patient-derived xenografts (PDX) models in vivo. Mechanistically, circ-YAP encoded a novel truncated protein containing 220 amino acids, termed as YAP-220aa, which competitively bound to LATS1, resulting in YAP dephosphorylation and nuclear translocation, thereby activating a cohort of metastasis-promoting genes. Importantly, N 6 -methyladenosine (m 6 A) modification orchestrated efficient initiation of circ-YAP translation, requiring m 6 A reader YTHDF3 and eIF4G2 translation initiation complex. Intriguingly, circ-YAP was transcriptionally enhanced by YAP/TEAD complex, thus forming a positive regulatory feed-forward loop. Conclusions Our findings reveal a previously uncharacterized oncoprotein encoded by circ-YAP, implying a promising biomarker and therapeutic target for CRC patients with liver metastasis.

In the contemporary big data era, data-driven prognostic and health management (PHM) methodologies have emerged as indispensable tools for ensuring the secure and reliable operation of complex equipment systems. Central to these methodologies is the accurate prediction of remaining useful life (RUL), which serves as a pivotal cornerstone for effective maintenance and operational decision-making. While significant advancements in computer hardware and artificial intelligence (AI) algorithms have catalyzed substantial progress in AI-based RUL prediction, extant research frequently exhibits a narrow focus on specific algorithms, neglecting a comprehensive and comparative analysis of AI techniques across diverse equipment types and operational scenarios. This study endeavors to bridge this gap through the following contributions: (1) A rigorous analysis and systematic categorization of application scenarios for equipment RUL prediction, elucidating their distinct characteristics and requirements. (2) A comprehensive summary and comparative evaluation of several AI algorithms deemed suitable for RUL prediction, delineating their respective strengths and limitations. (3) An in-depth comparative analysis of the applicability of AI algorithms across varying application contexts, informed by a nuanced understanding of different application scenarios and AI algorithm research. (4) An insightful discussion on the current challenges confronting AI-based RUL prediction technology, coupled with a forward-looking examination of its future prospects. By furnishing a meticulous and holistic understanding of the traits of various AI algorithms and their contextual applicability, this study aspires to facilitate the attainment of optimal application outcomes in the realm of equipment RUL prediction.

Background Brucellosis shows pronounced spatiotemporal heterogeneity in China, with changing epidemiological patterns as traditionally non-endemic southern regions experience increasing incidence. This study analyzes the spatiotemporal distribution and influencing factors of brucellosis in China to inform differentiated prevention strategies. Methods Using human brucellosis data from 31 Chinese provinces (2004–2021), combined with meteorological, socioeconomic, and livestock husbandry indicators, we developed Bayesian spatiotemporal models to analyze provincial-level spatial effects, temporal effects, spatiotemporal interactions, and quantify the impact of multiple factors on brucellosis incidence risk at the provincial scale. Richardson classification was applied for hotspot analysis, and average annual percentage change (AAPC) evaluated incidence trends. Results China reported 687,529 brucellosis cases (2004–2021). Spatial distribution showed a “high north, low south” pattern, with Inner Mongolia having the highest incidence (45.81/100,000) and Shanghai the lowest (0.01/100,000). Northern regions contained most hotspots (41.94%), while southern areas comprised most coldspots (51.61%). Temporal analysis revealed increasing risk (2004–2016), brief decline (2016–2018), and subsequent increase (post-2018). Spatiotemporal interaction effects indicated provincial-level risk pattern shifts from northern to central-southern regions, with Gansu, Hubei, Yunnan, and Hunan showing highest growth (AAPCs: 64.42%, 53.80%, 53.61%, 50.47%). Ecological regression identified six significant factors: mean temperature, sunshine duration, NDVI, population density, and medical institutions density negatively correlated with risk; dairy production positively associated with risk. Conclusions At the provincial level, brucellosis risk patterns in China show shifts from traditional northern high-incidence provinces to central-southern provinces. Environmental, socioeconomic, and livestock factors significantly influence disease risk. Prevention strategies should implement region-specific approaches while strengthening multi-departmental coordination.