Pancreatic islet δ-cells produce somatostatin, a paracrine regulator of insulin and glucagon secretion within islets. Although adaptive changes in α- and β-cell populations during pregnancy have been described in both animals and humans, data on δ-cell plasticity are sparse and entirely lacking in human pregnancy. We aimed to determine whether pancreatic islet δ-cell mass undergoes morphological adaptation during human pregnancy. Formalin-fixed paraffin-embedded pancreatic tissue from pregnant (n = 7) and non-pregnant (n = 7) donors was analysed. Sections were immunolabelled for somatostatin to identify δ cells, and whole-slide quantitative analysis was performed using an unbiased automated imaging pipeline. δ-cell area was measured across the entire pancreatic sections and compared between groups. In contrast to previously reported expansion of α- and β-cell populations in pregnancy, δ-cell area was not significantly different between pregnant and non-pregnant donors. No quantitative architectural alterations in δ-cell distribution within islets were observed. Pancreatic δ-cell area does not increase during human pregnancy. These findings demonstrate that endocrine cell plasticity within the maternal pancreas is selective and does not uniformly involve all islet cell subtypes.
Adoptive T cell therapy holds great promise for the treatment of solid tumors but remains constrained by tumor heterogeneity, inefficient neoantigen targeting, and the complexity of T cell manufacturing. Here, we present a patient-specific, broadly applicable platform using physically inactivated tumor organoids (PIOs) to generate tumor-specific cytotoxic T cells ex vivo. Derived from droplet-engineered tumor organoids (DEOs), PIOs preserve the full antigenic repertoire of the patient's tumor without requiring synthetic peptides, antigen-presenting cells, or neoantigen prediction. Using matched tumor tissue and PBMCs from colorectal and liver cancer patients, we show that PIOs activate and expand tumor-specific T cells with enhanced infiltration, selective cytotoxicity, and robust secretion of IFN-γ and IL-2. Multi-round PIO stimulation achieves 80-400-fold expansion of CD8+CD137+ T cells within two weeks. Transcriptomic and epigenetic profiling suggest that PIOs modulate T cell programs linked to migration and persistence. This work redefines tumor organoids as immunotherapeutic materials and establishes a rapid, cost-effective platform for personalized T cell manufacturing. Our findings provide a new translational route for adoptive cell therapy in solid tumors using patient-derived materials.
X-linked inhibitor of apoptosis protein (XIAP) is a multifunctional protein that regulates many cellular functions. Anoikis resistance is necessary for hepatocellular carcinoma (HCC) intrahepatic spread and extrahepatic metastasis. However, limited information is available regarding the mechanism of XIAP underlying the resistance of HCC cells to anoikis. Here we show an increased expression of XIAP in microvascular tumor thrombosis (MVTT) of HCC, which is positively correlated with the expression of extracellular signal-regulated kinases 1/2 (ERK1/2). HCC cells exhibit an increase in XIAP expression when detached, leading to their resistance to anoikis. Furthermore, enhanced phosphorylation of XIAP promotes resistance to anoikis in HCC cells. In addition, the zinc-binding baculovirus IAP repeat (BIR) domains of XIAP, instead of the highly intriguing novel gene (RING) domain, are responsible for conferring resistance to anoikis in HCC cells. Importantly, our findings indicate that ERK1/2 can control the expression of XIAP, leading to the resistance of HCC to anoikis in cell-based and mouse models. The significance of the interaction between XIAP and ERK1/2 in resisting anoikis is emphasized by our discoveries, presenting novel avenues for HCC treatment.
Synthetic cells, assembled from defined molecular components, are designed to mimic the features, form, and function of living cells. Light has emerged as a uniquely precise, biorthogonal, and non-invasive stimulus for regulating and energizing these systems, enabling chemical inhomogeneity and an out-of-equilibrium state central to many cellular processes. This review highlights the biological behaviors and functions that light has helped recreate in synthetic cells, including compartmentalization, energy supply and metabolism, protein synthesis, communication, growth, shape change and division, and motility. We survey the breadth of light-responsive components incorporated into synthetic cells, spanning photoswitchable and photocleavable small molecules, photoswitchable proteins, photocatalysts, nanoparticles, and photosynthetic organelles or organisms. Finally, we offer a perspective on key design considerations such as wavelength, reversibility, integration, biocompatibility, multicolor regulation, and biohybrid strategies. Together, these advances chart promising routes toward more dynamic, energy-autonomous, and programmable synthetic cells that will deepen our understanding of cellular functions and enable emerging biotechnological applications.
The construction of a high-quality interface with excellent surface passivation and carrier transport is critical to the device performance of solar cells. Low-dimensional perovskite structures are widely explored for surface passivation due to their effective suppression of interfacial defects and enhanced environmental stability. While terminal molecules for constructing low-dimensional structures provide excellent passivation, they can introduce potential barriers for charge transport if the energy levels are not well-aligned. Herein, a tryptamine molecule is explored as the terminal molecule for the construction of a low-dimensional structure for passivating the buried interface of perovskite solar cells. Based on the inclusion of nitrogen atoms in the aromatic heterocyclic structure, the terminal molecule shows an uplifted HOMO level that aligns well with the perovskite skeleton, giving rise to enhanced orbit coupling. Therefore, this low-dimensional structure enables excellent surface passivation and interfacial carrier transport simultaneously, generating an outstanding open-circuit voltage (VOC) up to 1.266 V and an efficiency of 23.53% for single-junction wide-bandgap (1.68 eV) perovskite solar cells. This improvement enables the fabrication of the perovskite/silicon tandem solar cell with an efficiency of 33.22% (32.88% assessed by a third party) and a VOC of 1.987 V. Moreover, the fast carrier transport at the interface suppressed the halide phase segregation, bringing much enhanced operation stability.
Clear cell renal cell carcinoma (ccRCC) can transition from indolent, low-grade lesions to high-grade, lethal disease through a layered cascade of genomic, epigenomic, metabolic, and immune remodeling. The initiating event in ∼90% of ccRCC is loss of chromosome 3p, enabling biallelic inactivation of VHL and frequent co-loss of chromatin regulators PBRM1, BAP1, and SETD2. The order and combination of genetic alterations shape distinct evolutionary trajectories in ccRCC. PBRM1 loss, observed in approximately 55% of cases, is linked to angiogenic, initially low-grade tumors that may later progress to higher-grade disease. In contrast, BAP1 loss (∼15%) drives early high-grade, inflammatory, immune-enriched phenotypes associated with aggressive behavior and worse prognosis. Progression is further shaped by structural and copy-number events including, chromothripsis coupling 3p loss with 5q gain, and recurrent 9p and 14q losses and 8q gain further promote cell-cycle dysregulation, genomic instability, and metastatic competence. Functionally, VHL loss stabilizes HIF-2α, driving VEGF signaling and Carbonic Anhydrase IX (CA9) expression and coupling pseudohypoxia to metabolic reprogramming and redox protection (glutathione/SLC7A11). Proteogenomic and metabolomic studies further highlight nutrient addiction with GLUT1/ASCT2 upregulation and a stress-resistant metabolic shield linked to grade and therapy resistance. Single-cell and spatial atlases place these programs in anatomic setting. They show that invasive fronts with high epithelial-mesenchymal transition (EMT) activity co-localize with myeloid and regulatory T-cell niches dominated by IL-1β, NF-κB, IL-10, STAT3, and TGF-β, along with exhausted CD8+ T cells, thereby promoting immune escape and invasion. Integrating these layers yields mechanism-based biomarkers and therapeutic nodes for risk-adapted precision treatment.
Osteoarthritis (OA) is a cross-species, multifactorial joint disease characterized by the progressive degeneration of articular cartilage, morphological remodeling of the subchondral bone, and inflammatory and fibrotic changes of the joint capsule. These alterations arise from chronic, often subclinical, inflammatory processes and dysregulated cellular homeostasis, leading to profound shifts in the cellular and extracellular composition of the joint organ. Although the mechanisms driving persistent inflammation are only partially understood, their impact on all joint-associated tissues is well-established. Mesenchymal stromal cells (MSCs) have gained increasing attention as therapeutic candidates for OA due to their immunomodulatory and potentially regenerative capacities. Increasing evidence indicates that MSCs exert their effects predominantly through indirect mechanisms, including paracrine signaling, the release of extracellular vesicles, mitochondrial transfer, and modulation of innate and adaptive immune responses. This review summarizes current insights into how these mechanisms may act within the articular microenvironment to attenuate cartilage degeneration and promote tissue repair in OA. Herein, we consider the effects of MSCs on different cell types and tissues within the joint, and highlight mitochondrial transfer as an emerging mechanism through which MSCs may regenerate and protect them, thereby contributing to the rescue of joint homeostasis.
Despite expanding therapeutic options, the prognosis of lung squamous cell carcinoma (LUSC) remains poor. Immune checkpoint inhibitors benefit only a subset of patients, and epithelial-mesenchymal transition (EMT) has been implicated in invasion, metastasis, treatment resistance, and immune heterogeneity. Therefore, EMT-related biomarkers may offer improved risk stratification. To identify differentially expressed EMT-related genes (DEEMTGs) in LUSC, construct an EMT-based prognostic signature, and evaluate its associations with the tumor microenvironment (TME), tumor mutational burden (TMB), and tissue-level expression patterns. The Cancer Genome Atlas (TCGA) RNA-seq and clinical data were analyzed to obtain DEEMTGs. A prognostic model was built using LASSO and multivariable Cox regression. Survival performance was assessed via Kaplan-Meier, ROC, and Cox analyses. Immune infiltration (CIBERSORT), stromal/immune scores (ESTIMATE), and TMB were compared between risk groups. Exploratory immunohistochemistry (IHC; n = 8) provided orthogonal expression validation. A total of 1,651 DEEMTGs were identified, and a six-gene signature (GAB2, ALDOA, PCDHA3, TMEM92, ERH, IRS4) was established. The risk score independently predicted overall survival and corresponded to distinct TME patterns: low-risk tumors showed higher CD8+ T cells, activated CD4+ memory T cells, and naïve B cells, whereas high-risk tumors had more resting CD4+ memory T cells and M0 macrophages. TMB differences were nonsignificant. IHC provided directional protein-level support while acknowledging transcript-protein variability. We developed a biologically interpretable EMT-based prognostic model that stratifies survival and reflects immune-microenvironment heterogeneity in LUSC. Larger, stage-balanced and immunotherapy-treated cohorts are needed to further validate its clinical utility.
Cartilage regeneration, especially of the temporomandibular joint (TMJ) disc critical for chewing and speech, remains challenging. Key hurdles include its avascular, low-cell structure (impeding repair cell migration) and persistent post-injury compressive/shear stresses (damaging tissue and disrupting new formation). This study designed a sandwich composite hydrogel: GelMA/HAMA loaded with BMSCs, combined with a PVA-bacterial cellulose membrane carrying chondrocyte-derived exosomes. The membrane provides mechanical support and slowly releases exosomes to regulate BMSC proliferation/differentiation. Biomechanical analysis showed reduced stress concentration at perforation edges, protecting regeneration. In vitro experiments confirmed upregulated cartilage matrix genes (e.g., COL1A1, ACAN) in BMSCs. Implantation in a rabbit TMJ disc perforation model for eight weeks led to new cartilage-like tissue and successful repair. This system, optimizing mechanical microenvironment, regulating stem cell fate, and promoting matrix regeneration, offers a novel strategy for functional TMJ disc repair.
Decellularized extracellular matrix (dECM) preserves native biochemical and biophysical cues and serves as a functional biomaterial for engineered tissue development. While tissue-specific extracellular matrix (ECM) has been widely studied, regional variation within the same organ remains poorly understood. Here, we investigate chamber-specific roles of ventricular (vtdECM) and atrial (atdECM) dECMs in engineered heart tissue (EHT) formation using induced pluripotent stem cell-derived cardiomyocyte (CM) subtypes. Proteomic analysis revealed distinct compositional profiles, with vtdECM enriched in ventricular development-related proteins and atdECM enriched in structural organization-related proteins. Ventricular CMs exhibited enhanced maturation and function in vtdECM, whereas atrial CMs showed limited responsiveness to ECM composition despite transcriptome-level differences. Encapsulation timing further modulated these effects, with early encapsulation promoting structural maturation and late encapsulation enhancing calcium handling. These findings demonstrate that chamber-specific ECM composition and developmental timing cooperatively regulate subtype-specific CM maturation, providing a framework for designing physiologically relevant EHTs.
Donor-specific HLA antibodies (DSA) occurring prior to or appearing de novo after transplantation play a major role in kidney graft loss, mainly caused by complement activation by DSA. As potential therapeutics, immunologically inert human monoclonal antibodies (mAbs) preventing binding of DSA to HLA-A1 molecules would limit their detrimental effects. In this study, the complement-activating potential of anti-HLA-A1 mAbs (WIM8E5), modified by single amino-acid changes inhibiting C1q binding, Fc-Fc interactions, or FcγR binding, was assessed in the classical crossmatch and by detection of C3d fixation in single antigen Luminex beads. Subsequently, the efficacy of these modified human mAbs was assessed in combination with patient sera to determine whether they could prevent complement-mediated cell lysis and HLA antibodies-induced C3d fixation. Point mutations in anti-HLA-A1-WIM8E5 mAb preventing C1q binding resulted in reduced to absent complement-mediated cell lysis and C3d fixation. Patient sera containing anti-HLA-A1 antibodies are able to activate complement, and WIM8E5-K322A-P329R-S440K (preventing C1q, Fc:Fc interaction and FcyR binding) mAb could prevent cell lysis induced by patient antibodies and inhibit C3d binding to HLA-A1 coated beads. Furthermore, the 109F epitope recognized by the mAb differed from those recognized by patient antibodies, indicating that a single modified mAb can block multiple HLA-A1 recognition sites. In conclusion, single amino-acid mutations in anti-HLA-A1-WIM8E5 directed to inhibit C1q binding, Fc:Fc interactions, or FcγR binding could be used to prevent complement-mediated cell lysis and C3d formation in kidney transplant recipients. Further research is needed to investigate the applicability of modified mAb as potential therapeutics in the clinic.
Vitiligo is an acquired depigmentation disorder caused by melanocyte dysfunction or loss. Oxidative stress is widely considered a key driver to its pathogenesis. Mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2) is implicated in oxidative stress responses, although its role in vitiligo remains uncertain. This study intended to investigate whether epigenetic downregulation of MAPKAPK2 aggravates oxidative stress-induced damage in vitiligo melanocytes. Human melanocyte lines (PIG1 and PIG3V) were used to model normal and vitiligo conditions. The effects of oxidative stress, DNA demethylation (5-aza-DC), and MAPKAPK2 overexpression were assessed using qRT-PCR, Western blot, ELISA, comet assay, TUNEL, and CCK-8. Pharmacological inhibition of MK2 was employed to evaluate the functional requirement of MAPKAPK2 kinase activity, and key antioxidant pathways, including Nrf2 signaling, were investigated. MAPKAPK2 expression was notably downregulated in PIG3V cells compared with PIG1 cells (P < 0.05), and further reduced upon H2O2 exposure (P < 0.01), suggesting stress-related suppression. Exposure to 5-aza-DC partially restored MAPKAPK2 expression (P < 0.01), implicating DNA methylation in its silencing. Functional assays showed that MAPKAPK2 overexpression significantly alleviated H2O2-induced reductions in cell viability, increases in apoptosis, impaired melanogenesis, and oxidative damage (all P < 0.01), while activating the Nrf2/HO-1 antioxidant pathway through suppression of KEAP1 expression and enhancement of Nrf2 nuclear translocation. Genetic knockdown, rescue, and pharmacological inhibition experiments further demonstrated that these cytoprotective effects under oxidative stress were dependent on MAPKAPK2 kinase activity. Epigenetic silencing of MAPKAPK2 aggravates oxidative damage in vitiligo melanocytes, potentially by attenuating Nrf2-associated antioxidant responses. These findings identify MAPKAPK2 as a functionally relevant and targetable factor in the oxidative pathology of vitiligo.
Mesenchymal stem cell-derived exosomes (MSC-Exos) have emerged as key mediators of intercellular communication within the tumor microenvironment. However, a comprehensive synthesis of their paradoxical roles in digestive system tumors remains absent. This review provides an in-depth analysis of the molecular mechanisms by which MSC-Exos regulate tumor progression, with a focus on how they transfer specific non-coding RNAs and proteins to target cells, thereby modulating angiogenesis, epithelial-mesenchymal transition, immune evasion, and drug resistance. We highlight the functional heterogeneity of MSC-Exos in colorectal, liver, gastric, and pancreatic cancers, and examine how signals from the tumor microenvironment remodel their molecular cargo, establishing complex feedback loops. Furthermore, we discuss emerging translational frontiers, including the engineering of MSC-Exos as targeted drug delivery vehicles. By integrating mechanistic insights with clinical challenges, this review aims to elucidate the complex biology of MSC-Exos and pave new avenues for their application in precision oncology for digestive system tumors.
Fangchinoline, a bisbenzylisoquinoline alkaloid derived from Stephaniae tetrandrine, is known for its antioxidant and anticancer potential. This study aimed to explore fangchinoline's anticancer targets in silico and evaluate its effects on human epidermal growth receptor-2 (HER-2) overexpressing MCF-7 breast cancer cells. Potential molecular targets were identified using GeneCards and DisGeNET, with intersecting genes analysed via DAVID and Cytoscape. Molecular docking and 50-nanosecond molecular dynamics simulations were conducted against ERBB2, IGF1R, and ADRB2 proteins. Cytotoxicity was evaluated through 3-(4,5-dimethylthiazole-2-yl)-2,5- diphenyl tetrazolium bromide assay, while flow cytometry assessed cell cycle distribution, apoptosis, expression of PI3K, Akt, mTOR, p53, HER-2, and reactive oxygen species (ROS) levels. A total of 256 overlapping genes were identified, and ERBB2 emerged as the most promising target with a binding affinity of -8.57 kcal/mol. Fangchinoline exhibited cytotoxicity against MCF-7/HER-2 cells with an IC50 of 9.67 ±0.14 µM. Fangchinoline induced G2-M arrest and significantly increased apoptosis. Flow cytometry revealed downregulation of PI3K (-42.1%), Akt (-38.6%), and mTOR (-45.3%), with a corresponding upregulation of p53 (+59.8%) compared to controls. Reactive oxygen species production was elevated by +48.5% after treatment. Fangchinoline exhibits promising anticancer activity by targeting ERBB2 and modulating critical oncogenic and apoptotic pathways. Its ability to upregulate p53 and ROS while suppressing PI3K/Akt/mTOR signalling suggests its strong potential as a HER-2-targeted therapeutic agent.
Systemic therapy has improved outcomes in advanced hepatocellular carcinoma (HCC), but the risk of esophagogastric variceal (EGV) bleeding remains a concern. This study investigated the incidence and risk factors for EGV bleeding and mortality in cirrhotic HCC patients receiving systemic therapy. This single-center retrospective study included cirrhotic patients with intermediate to advanced HCC who initially received systemic therapy with tyrosine kinase inhibitors (TKIs) alone or in combination with anti-programmed cell death-1 antibodies (anti-PD-1). HCC was diagnosed based on histology or typical radiological findings and staged according to the Barcelona Clinic Liver Cancer (BCLC) classification system. EGV bleeding was confirmed by oesophagogastroduodenoscopy. The treatment efficacy was evaluated using the modified Response Evaluation Criteria in Solid Tumors. A total of 263 patients were included, predominantly male (85.9%), with a median age of 59 years. BCLC stages B and C accounted for 59.3% and 40.7% of cases, respectively. The 1-year and 2-year cumulative incidence of EGV bleeding were 16.7% and 21.6%, respectively. Portal vein thrombosis (PVT), ascites, and severe varices were independently associated with 1-year EGV bleeding. The 1-year mortality rate was 6.1%. The mortality was independently associated with EGV bleeding, AFP levels >400 ng/mL, type of portal vein tumor thrombus, and tumor progression. The overall objective response rate (ORR) was 32.0%, with TKIs plus anti-PD-1 achieving higher ORR than TKIs alone (39.5% vs. 27.7%, P=0.017) without increasing the bleeding risk or mortality (all P>0.05). Among 162 HBV-related HCC patients receiving long-term antiviral therapy, HBV DNA negative conversion (37.5% vs. 29.6%, P=0.739) and HBsAg decline (-15.1% vs. -14.3%, P=0.883) were comparable between TKIs plus anti-PD-1 and TKIs alone group. In cirrhotic patients with advanced HCC, PVT, ascites and high-risk EGV were predictors of variceal bleeding, regardless of the tumor response. TKIs plus anti-PD-1 achieved higher ORR than TKIs alone without increasing EGV bleeding risk or mortality, supporting their use in selected patients with careful assessment of EGV bleeding risk.
Radiodensity of subcutaneous adipose tissue (SAT), measurable on routine computed tomography (CT), may reflect metabolic status and cachexia, both of which influence cancer outcomes. However, its prognostic role in metastatic non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICI) remains unclear. This study aimed to evaluate the prognostic value of SAT radiodensity in this patient population. The retrospective analysis included 92 patients with stage IV NSCLC receiving ICI. Subcutaneous adipose tissue radiodensity (Hounsfield units) was measured from pre-treatment CT at the L3 level and categorized into quartiles. Kaplan- Meier analysis, log-rank test, and Cox proportional hazards models were used. Nonlinear associations were assessed using restricted cubic splines. Cox models were? adjusted for demographic, clinical, and treatment factors. A p-value < 0.05 was considered statistically significant. Median overall survival for Q1, Q2, Q3, and Q4 was 13.4, 26.3, 18.4, and 14.2 months, respectively (log-rank p = 0.0226). Compared with Q1, Q2 showed a significantly reduced mortality risk across all models (fully adjusted hazard ratios = 0.32, 95% CI: 0.15-0.64, p = 0.002). Q3 and Q4 were not significantly different from Q1. Restricted cubic spline analysis revealed a mild U-shaped relationship (p for nonlinearity = 0.0094), with intermediate SAT density linked to best outcomes. Programmed death ligand 1 expression significantly modified the SAT-survival association (p for interaction < 0.0001). Moderate SAT radiodensity was associated with improved survival in metastatic NSCLC patients on ICI, potentially reflecting an optimal metabolic-immune balance. Subcutaneous adipose tissue density, easily obtained from routine imaging, warrants further prospective validation as a scalable prognostic biomarker.
The deletion of tumor suppressor genes often occurs in a tumor-specific manner and is accompanied by the unintended loss of adjacent genes. Nicotinamide adenine dinucleotide kinase (NADK), located at a tumor suppressive locus on chromosome 1p36, plays a pivotal role in the biosynthesis of NADP and NADPH and has a closely related paralog, NADK2, in human cells. Although synthetic lethality between NAD kinases was reported in yeast, the relationship between NADK and NADK2 in human cells remains unclear. Here, we investigated alterations of the NADK gene expression across various tumor types and assessed whether there is a synthetic lethal relationship between these NAD kinases in human cells. Analysis of The Cancer Genome Atlas dataset revealed NADK gene deletion in multiple tumor types. Depletion of both NADK and NADK2 using siRNA decreased cellular NADP(H) levels and inhibited cell proliferation, resulting in the induction of apoptosis. Notably, NADK2 knockdown alone markedly impaired cell proliferation and NADP(H) production in NADK homozygous-deleted tumor cells, and also reduced proliferation in NADK heterozygous-deleted tumor cells, whereas in NADK-intact tumor cells only de novo NADP synthesis, but not its intracellular levels or proliferation, was affected. These findings suggest that loss of the NADK gene in tumor cells confers vulnerability to NADK2 depletion.
Exosomes are nanometer-scale extracellular vesicles secreted by cells with a diameter of approximately 30-100 nanometers. Serving as essential messengers for intercellular communication, they play significant roles in both physiological and pathological processes. Their low immunogenicity, excellent tissue penetrability, and high biocompatibility have positioned them as a research focus for disease diagnostic biomarkers and drug delivery vehicles. Spinal cord injury (SCI) is a severe traumatic disorder of the nervous system, often leading to neuronal death, axonal disruption, glial scar formation, and dysregulated inflammatory responses, ultimately resulting in irreversible sensory and motor dysfunction. This review systematically elucidates the pivotal roles of exosomes derived from various cell sources in the repair of SCI. It focuses on how these exosomes target key cellular components including neurons, glial cells, vascular endothelial cells, and immune cells. This interaction modulates core pathological processes such as neuroinflammation, glial scar formation, axonal regeneration, angiogenesis, and apoptosis. By synthesizing current evidence, we aim to unravel the complex regulatory networks mediated by exosomes as intercellular signaling hubs within the SCI microenvironment. Furthermore, this review provides a theoretical foundation for their future development as novel diagnostic tools, regenerative therapeutic vectors, and targeted intervention strategies for SCI.
Abnormal cellular metabolism is one of the characteristics of tumour cells. However, the differences in the global metabolomics between normal and tumour tissues remain unclear. In this study, we have proposed a diagnostic and prognostic model for colorectal cancer (CRC) based on metabolomics and genomics. Metabolomics data of CRC patients was obtained from the MetaboLights repository, and identified the characteristic metabolites of CRC cells through orthogonal partial least squares discriminant analysis (OPLS-DA). Then we performed differential analysis of these metabolites between normal and tumour tissues. Subsequent enrichment analysis was used to analyse the signalling pathways related to the differential metabolites. Finally, we combined metabolomics and genomics to construct a prognostic model, and detected the expression of key metabolites and genes in CRC cell lines by using ELISA and western blot. Based on the variable important in projection values of OPLS-DA, we identified 318 characteristic metabolites. By conducting differential analysis of these metabolites, we identified 30 downregulated and 42 upregulated metabolites in colorectal cancer. The combined analysis of enrichment pathways revealed that 5 pathways were enriched in both metabolomics and transcriptomics. We established a prognostic model through univariate Cox and least absolute shrinkage and selection operator regression, and then verified the excellent application value of the model for patient prognosis through receiver operating characteristic curves and survival analysis. Finally, ELISA and western blot experiments showed that compared with normal colorectal epithelial cells, the levels of estradiol and formimidoyltransferase cyclodeaminase proteins were increased, while the levels of methionine and SLC5A1 proteins were decreased in CRC cells.
The ascent of novel alternative methods in drug development spotlights the dual needs for improved biological fidelity to in vivo, along with reproducibility, especially in regulatory applications. The need for pre-clinical models of patient-derived endometriosis lesions motivates the development of a vascularizable, completely synthetic extracellular matrix (v-CS-ECM) that supports morphogenesis of perfusable microvasculature in a microfluidic device, in the context of relevant lesion cells. This paper describes v-CS-ECM, a peptide-modified polyethylene glycol-based hydrogel crosslinked with a cell-degradable peptide that achieves these dual goals. Vessels form by morphogenesis after the liquid v-CS-ECM precursor, containing endothelial cells and fibroblasts, is injected into the tissue compartment to encapsulate cells. Vessel formation is influenced by ECM biochemical and biophysical properties, the source of vascular cells, and microphysiological system operating conditions. The v-CS-ECM also supports the co-culture of endometrial epithelial organoids and fibroblasts, and formation of microvascularized endometriosis lesion-like structures when all cell types are co-encapsulated in a microfluidic device with constant flow. Hence, v-CS-ECM has the potential to improve preclinical evaluation of endometriosis drug efficacy by enabling microvascularized patient-derived lesion models.