Search Results (18)

Objective: Gastric cancer (GC) is characterized by molecular heterogeneity, yet current classifications are largely based on cross-sectional molecular profiles and do not account for the temporal order of mutation accumulation. This study aimed to reconstruct somatic mutation trajectories to identify prognostically distinct subtypes and to examine transcriptomic and microenvironmental features associated with these inferred trajectories. Methods: We applied the Subtype and Stage Inference (SuStaIn) algorithm to TCGA-STAD somatic mutation data to infer the temporal sequence of mutation accumulation. Stage-correlated gene expression analysis was performed to identify genes whose expression levels changed with evolutionary stage. The tumor microenvironment (TME) was characterized using EcoTyper and single-cell RNA sequencing deconvolution, while drug sensitivity was estimated through transcriptome-based IC₅₀ prediction. The clinical relevance of the inferred trajectories was further evaluated in three independent external transcriptomic cohorts. Results: We identified two distinct evolutionary trajectories: the Accelerated Path (AP, 65%) and the Gradual Path (GP, 35%). In the AP, TP53 mutations were positioned at an earlier evolutionary stage (Stage 3) compared to the GP (Stage 8). AP patients had significantly worse overall survival (Hazard Ratio = 1.437, p = 0.044, adjusted for clinical stage and molecular subtypes). The AP was associated with stage-correlated downregulation of the sodium channel gene SCN4A (ρ = −0.36, p < 0.001) and an increase in a squamous-associated gene expression score, while the GP showed stage-correlated expression changes in the mitochondrial gene SDHD (ρ = −0.35, p < 0.001). The AP was further characterized by higher inferred abundance of extracellular matrix CAFs (eCAFs) and lower inferred immune cell scores, whereas the GP was associated with higher inferred signatures of activated B cells and effector memory T cells. Computational drug sensitivity modeling predicted a negative correlation between AP stage and IC₅₀ values for 5-Fluorouracil and Docetaxel. Conclusions: Two distinct mutational ordering patterns identified by SuStaIn are associated with divergent transcriptomic features, TME compositions, and clinical outcomes in gastric cancer. The AP subtype is characterized by early TP53 mutations, SCN4A downregulation, and a stromal-enriched microenvironment, while the GP subtype is associated with later TP53 mutations, SDHD-correlated expression, and higher inferred immune cell scores. The reproducibility of these associations was confirmed in independent cohorts. The computational drug sensitivity predictions and the proposed mechanistic links between gene expression patterns and clinical outcomes should be viewed as hypothesis-generating findings that require prospective and functional validation. Full article

Digestive cancers exhibit high heterogeneity and poor prognosis, yet whether their tumor microenvironments share conserved stromal–immune interactions remains unclear. Here, we performed an integrative multi-omics analysis across seven digestive cancer types and identified a conserved four-gene signature—DCN, COL10A1, CTHRC1, and TREM2—that is consistently enriched in matrix cancer-associated fibroblasts (mCAFs) and myeloid cells. Single-cell RNA sequencing revealed that DCN, COL10A1, and CTHRC1 are predominantly expressed in mCAFs, while TREM2 is enriched in myeloid cells and, to a lesser extent, in antigen-presenting CAFs(apCAFs). Cell–cell communication analysis consistently identified a fibroblast-to-myeloid signaling network centered on ECM-CD44 interactions across all examined cancer types, providing a candidate framework for intercellular crosstalk. Multi-omics profiling further characterized the genomic, epigenetic, and immune correlates of this signature. Collectively, these findings identify a conserved stromal–myeloid gene signature across digestive cancers and provide a candidate gene set for future diagnostic and therapeutic exploration. Full article

The tumor heterogeneity that is frequently observed in cancer tissues comprises not only cancer cells but also stromal cells in the tumor microenvironment. One of the major components of tumor stroma, i.e., cancer-associated fibroblasts (CAFs), play crucial roles in tumor progression and the tumor response to chemotherapy. The known subtypes of CAFs are antigen-presenting CAFs (apCAFs), myofibroblastic CAFs (myCAFs), and inflammatory CAFs (iCAFs). It has been speculated that (i) the heterogeneity of CAF subtypes might contribute to tumor progression; (ii) cell-to-cell interactions among CAF subtypes in tumors might be associated with the development of various types of carcinomas, and (iii) juxtracrine and/or paracrine signaling from CAFs may play important roles in this development. A clarification of the mechanisms that underlie the tumoral heterogeneity of CAFs could contribute to cancer treatment as precision medicine. This review explains the significance of CAF heterogeneity in tumor microenvironments, especially concerning the CAF subtypes. Full article

Background: Cancer-associated fibroblasts (CAFs) are key components of the glioblastoma (GBM) microenvironment and contribute to tumor progression, immune evasion, and therapy resistance. However, their heterogeneity and clinical impact in GBM remain poorly defined. Methods: We performed an integrative transcriptomic analysis combining bulk and single-cell RNA sequencing (scRNA-seq) datasets to characterize CAF subtypes in GBM. Four CAF-associated transcriptional programs were defined based on canonical gene signatures: immune CAFs, myofibroblastic CAFs (myoCAFs), inflammatory CAFs (iCAFs), and antigen-presenting CAFs (apCAFs). Prognostic relevance was assessed using survival analyses, and hub genes were identified through network analysis. Results: CAF subtype-specific gene signatures were significantly associated with poor overall survival. Single-cell analysis revealed spatial heterogeneity of CAF activation, with immune and inflammatory CAF markers enriched in low-stemness tumor cells. SYK was identified as a central hub gene shared across CAF subtypes, suggesting its role in stromal signaling. Conclusions: Our study reveals CAF subtype-associated patterns with prognostic and functional relevance in GBM. Targeting CAF subpopulations and key mediators such as SYK may represent a promising therapeutic strategy in GBM. Full article

Underwater debris poses a significant threat to marine ecosystems, fisheries, and the tourism industry, necessitating the development of automated vision-based detection systems. Although recent studies have sought to enhance detection performance through underwater image enhancement, improvements in visual quality do not necessarily translate into higher detection accuracy and may, in some cases, degrade performance. To address this discrepancy between perceptual quality and detection reliability, we propose DiCAF, a dual-input co-attention fusion network built upon the latest You Only Look Once v11 detector. The proposed architecture processes both original and enhanced images in parallel and fuses their complementary features through a co-attention module, thereby improving detection stability and consistency. To mitigate high-frequency noise amplified during the enhancement process, a lightweight Gaussian filter is applied as a post-processing step, enhancing robustness against speckle noise commonly introduced by suspended particles in underwater environments. Furthermore, DiCAF incorporates a non-maximum suppression (NMS)-based ensemble that integrates detection outputs from three branches—original, enhanced, and fused—enabling complementary detection of objects missed by individual models and maximizing overall detection performance. Experimental results demonstrate that the proposed single-model DiCAF with Gaussian post-processing achieves an AP@0.5 of 0.87 and an AP@0.5:0.95 of 0.71 on a marine trash dataset. With the NMS-based ensemble, performance improves to 0.91 and 0.75, respectively. Under artificially injected speckle noise conditions, the proposed method maintains superior robustness, achieving an AP@0.5 of 0.62 and consistently outperforming conventional enhancement-based models. Full article

Accurate segmentation of colorectal polyps is crucial for the early screening and clinical diagnosis of colorectal cancer. However, the diverse morphology of polyps, significant variations in scale, and unstable quality of endoscopic imaging pose serious challenges for existing algorithms in achieving precise boundary segmentation. To address these issues, this study proposes a novel polyp segmentation algorithm, GDCA-Net, which is developed based on the You Only Look Once version 12 segmentation model (YOLOv12-seg). GDCA-Net introduces several architectural innovations. First, a Gather-and-Distribute (GD) mechanism is incorporated to optimize multi-scale feature fusion, while Alterable Kernel Convolution (AKConv) is integrated to enhance the modeling of complex geometric structures. Second, the Convolution and Attention Fusion Module (CAF) and Context-Mixing dynamic convolution (ContMix) modules are designed to strengthen long-range dependency modeling and multi-scale feature extraction for polyp boundary representation. Finally, a Wise Intersection over Union–based (Wise-IoU) loss function is introduced to accelerate model convergence and improve robustness to low-quality samples. Experiments conducted on the PolypDB, Kvasir-SEG, and CVC-ClinicDB datasets demonstrate the superior performance of GDCA-Net in polyp segmentation tasks. On the most challenging PolypDB dataset, GDCA-Net achieved a mean Average Precision at 50% IoU threshold (mAP50) of 85.9% and an F1-score (F1) of 85.5%, representing improvements of 2.2% and 0.7% over YOLOv12-seg, respectively. Moreover, on the Kvasir-SEG dataset, GDCA-Net achieved a leading F1 score of 94.9%. These results clearly demonstrate that GDCA-Net possesses strong performance and generalization capabilities in handling polyps of varying sizes, shapes, and imaging qualities. Full article

Cancer-associated fibroblasts (CAFs) are crucial regulators of the tumor microenvironment (TME), promoting cancer progression, immune suppression, and therapy resistance. Single-cell transcriptomics has identified at least five distinct CAF subtypes: myofibroblastic (myCAFs), inflammatory (iCAFs), antigen-presenting (apCAFs), metabolic (meCAFs), and vascular/developmental (vCAFs/dCAFs), each with unique localization, signaling, and functions. While CAFs are well studied in epithelial cancers, their roles in sarcomas are less understood despite the shared mesenchymal origin of tumor and stromal cells. This overlap blurs the line between malignant and non-malignant fibroblasts, raising fundamental questions about the identity of CAFs in mesenchymal tumors. In this narrative review, we explore the heterogeneity and plasticity of CAFs across solid tumors, focusing on their role in immune evasion, epithelial-to-mesenchymal transition (EMT), and resistance to chemotherapy, targeted therapy, and immunotherapy. We highlight emerging evidence on CAF-like cells in sarcomas and their contribution to tumor invasion, immune exclusion, and metastatic niche formation. We also assess new strategies to target or reprogram CAFs and suggest that CAF profiling may serve as a potential biomarker for patient stratification. Understanding CAF biology across various tumor types, including those with dense stroma and immunologically cold sarcomas, is crucial for developing more effective, personalized cancer treatments. Full article

Tea production and quality are largely determined by the many genetic and biochemical characteristics that occur in tea plant cultivars. Worldwide, tea is consumed for its pleasing and refreshing effects due to its caffeine content. The present study performed transcriptomics analyses of two tea species (Camellia sinensis var. Shuchazao (SCZ) and Camellia ptilophylla (CAF)) and identified diversity in the gene expression levels and major regulatory transcription factors (TFs) for the characterization of purine alkaloids and phenylpropanoid biosynthesis pathways. The RNA-seq analysis of two species (SCZ and CAF) revealed the differences in caffeine and catechins synthesis. In the purine alkaloid biosynthesis pathway, the S-adenosyl methionine (SAM) and adenosine monophosphate (AMP) pathway genes were significantly related to xanthosine synthesis in contrasting purine alkaloids among (Camellia sinensis var. Shuchazao (SCZ) and Camellia ptilophylla (CAF)). The significant expression of SAMS-5, PPAT-2, IMPDH-2, TCS-2, TCS-3, XMT-1, XMT-13, and XDH-4 in the xanthosine degradation pathway in CAF is attributed to higher theobromine content as compared to SCZ. Moreover, the transcription factors (TFs) AP2/ERF (20%), WRKY (12%), NAC (11%), and MYB (8%) were significantly correlated. The upregulated expression of caffeine synthesis genes in SCZ was correlated with MYB and AP2/ERF transcription factors. This study provides the basis for differences in the genetic mechanism in purine alkaloids, phenylpropanoid, and flavonoid biosynthesis pathways, which would be helpful in the development and selection of tea plant species with high or low caffeine concentrations. This study also provides a road map for future genetic improvement in tea species and cultivars. Full article

Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive cancer with striking fibrosis, and its mortality rate is ranked second across human cancers. Cancer-associated fibroblasts (CAFs) play a critical role in PDAC progression, and we reviewed the molecular understanding of PDAC CAFs and novel therapeutic potential at present. CAFs-associated genes (CAFGs) were tentatively classified into three categories by stroma specificity representing stroma/epithelia expression ratios (SE ratios). The recent classification using single cell transcriptome technology clarified that CAFs were composed of myofibroblasts (myCAFs), inflammatory CAFs (iCAFs), and other minor ones (e.g., POSTN-CAFs and antigen presenting CAFs, apCAFs). LRRC15 is a myCAFs marker, and myCAFs depletion by diphtheria toxin induces the rapid accumulation of cytotoxic T lymphocytes (CTLs) and therefore augment PDL1 antibody treatments. This finding proposes that myCAFs may be a critical regulator of tumor immunity in terms of PDAC progression. myCAFs are located in CAFs adjacent to tumor cells, while iCAFs marked by PDPN and/or COL14A1 are distant from tumor cells, where hypoxic and acidic environments being located in iCAFs putatively due to poor blood supply is consistent with HIF1A and GPR68 expressions. iCAFs may be shared with SASP (secretion-associated phenotypes) in senescent CAFs. myCAFs are classically characterized by CAFGs induced by TGFB1, while chemoresistant CAFs with SASP may dependent on IL6 expression and accompanied by STAT3 activation. Recently, it was found that the unique metabolism of CAFs can be targeted to prevent PDAC progression, where PDAC cells utilize glucose, whereas CAFs in turn utilize lactate, which may be epigenetically regulated, mediated by its target genes including CXCR4. In summary, CAFs have unique molecular characteristics, which have been rigorously clarified as novel therapeutic targets of PDAC progression. Full article

Sodium monofluorophosphate (Na₂FPO₃, MFP) is mainly used as an ingredient in fluoride-based dentifrices as it has a high safety profile, with one-third of the toxicity of sodium fluoride (NaF), as well as the ability to reach deep into the dentin. The purpose of this study was to assess the prevention of dentin erosion by MFP upon exposure to citric acid, which has a chelating effect, and to compare the effects to those of the conventional acidulated phosphate fluoride (APF) application method. Bovine dentin was used, and four groups were created: (i) APF (9000 ppmF, pH 3.6) 4 min group; (ii) acidulated phosphate MFP (AP-MFP, 9000 ppmF, pH 3.6) 4 min group; (iii) AP-MFP 2 min + APF 2 min (dual) group; and (iv) no fluoride application (control) group. Compared with the conventional APF application method, the application of AP-MFP was shown to significantly reduce substantial defects, mineral loss, and lesion depth; better maintain Vickers hardness; and promote the homogenous aggregation of fine CaF₂ particles to seal the dentin tubules, enhancing acid resistance in their vicinity. The ΔZ value of the AP-MFP group was 2679 ± 290.2 vol% μm, significantly smaller than the APF group’s 3806 ± 257.5 vol% μm (p < 0.01). Thus, AP-MFP-based fluoride application could effectively suppress citric acid-induced demineralization and could become a new, more powerful, and biologically safer professional-care method for preventing acid-induced dentin erosion than the conventional method. Full article

Pancreatic cancer is one of the deadliest forms of cancer with one of the lowest 5-year survival rates of all cancer types. A defining characteristic of pancreatic cancer is the existence of dense desmoplastic stroma that, when exposed to stimuli such as cytokines, growth factors, and chemokines, generate a tumor-promoting environment. Cancer-associated fibroblasts (CAFs) are activated during the progression of pancreatic cancer and are a crucial component of the tumor microenvironment (TME). CAFs are primarily pro-tumorigenic in their activated state and function as promoters of cancer invasion, proliferation, metastasis, and immune modulation. Aided by many signaling pathways, cytokines, and chemokines in the tumor microenvironment, CAFs can originate from many cell types including resident fibroblasts, mesenchymal stem cells, pancreatic stellate cells, adipocytes, epithelial cells, endothelial cells, and other cell types. CAFs are a highly heterogeneous cell type expressing a variety of surface markers and performing a wide range of tumor promoting and inhibiting functions. Single-cell transcriptomic analyses have revealed a high degree of specialization among CAFs. Some examples of CAF subpopulations include myofibrotic CAFs (myCAFs), which exhibit a matrix-producing contractile phenotype; inflammatory CAFs (iCAF) that are classified by their immunomodulating, secretory phenotype; and antigen-presenting CAFs (apCAFs), which have antigen-presenting capabilities and express Major Histocompatibility Complex II (MHC II). Over the last several years, various attempts have been undertaken to describe the mechanisms of CAF–tumor cell interaction, as well as CAF–immune cell interaction, that contribute to tumor proliferation, invasion, and metastasis. Although our understanding of CAF biology in cancer has steadily increased, the extent of CAFs heterogeneity and their role in the pathobiology of pancreatic cancer remains elusive. In this regard, it becomes increasingly evident that further research on CAFs in pancreatic cancer is necessary. Full article

Over recent years, many researchers have supported the autoimmune theory of sarcoidosis. The presence of uncontrolled inflammatory response on local and system levels in patients with sarcoidosis did not define that the immunoregulatory mechanisms could be affected. The aim of this study was to evaluate the distribution and the disturbance circulating Treg cell subsets in the peripheral blood in patients with sarcoidosis. Materials and methods: A prospective comparative study was performed in 2016–2018 (34 patients with sarcoidosis (men (67.6%), women (32.3%)) were examined). Healthy subjects—the control group (n = 40). The diagnosis of pulmonary sarcoidosis was performed according to the standard criteria. We used two ten-color combinations of antibodies for Treg immunophenotyping. The first one contained CD39–FITC, CD127–PE, CCR4–PE/Dazzle™ 594, CD25–PC5.5, CD161–PC7, CD4–APC, CD8–APC–AF700, CD3–APC/Cy7, HLA–DR–PacBlue, and CD45 RA–BV 510™, while the second consisted of CXCR3–Alexa Fluor 488, CD25–РЕ, CXCR5–РЕ/Dazzle™ 594, CCR4–PerСP/Сy5.5, CCR6–РЕ/Cy7, CD4–АPC, CD8 АPC–AF700, CD3–АPC/Cy7, CCR7–BV 421, and CD45 RA–BV 510. The flow cytometry data were analyzed by using Kaluza software v2.3. A statistical analysis was performed with Statistica 7.0 and GraphPad Prism 8 software packages. Results of the study: Primarily, we found that patients with sarcoidosis had decreased absolute numbers of Treg cells in circulation. We noted that the level of CCR7-expressing Tregs decreased in patients with sarcoidosis vs. the control group (65.55% (60.08; 70.60) vs. 76.93% (69.59; 79.86) with p < 0.001). We noticed that the relative numbers of CD45RA–CCR7+ Tregs decreased in patients with sarcoidosis (27.11% vs. 35.43%, p < 0.001), while the frequency of CD45 RA–CCR7– and CD45RA+ CCR7– Tregs increased compared to the control group (33.3% vs. 22.73% and 0.76% vs. 0.51% with p < 0.001 and p = 0.028, respectively). CXCR3-expressing Treg cell subsets—Th1-like CCR60078CXCR3+ Tregs and Th17.1-like CCR6+ CXCR3+ Tregs—significantly increased in patients with sarcoidosis vs. the control group (14.4% vs. 10.5% with p < 0.01 and 27.9% vs. 22.8% with p < 0.01, respectively). Furthermore, the levels of peripheral blood EM Th17-like Tregs significantly decreased in the sarcoidosis group vs. the control group (36.38% vs. 46.70% with p < 0.001). Finally, we found that CXCR5 expression was increased in CM Tregs cell subsets in patients with sarcoidosis. Conclusions: Our data indicated a decrease in circulating Tregs absolute numbers and several alterations in Treg cell subsets. Moreover, our results highlight the presence of increased levels of CM CXCR5+ follicular Tregs in the periphery that could be linked with the imbalance of follicular Th cell subsets and alterations in B cell, based on the immune response. The balance between the two functionally distinct Treg cell populations—Th1-like and Th17-like Tregs—could be used in sarcoidosis diagnosis and the determination of prognosis and disease outcomes. Furthermore, we want to declare that analysis of Treg numbers of phenotypes could fully characterize their functional activity in peripherally inflamed tissues. Full article

Despite extensive research, the 5-year survival rate of pancreatic cancer (PDAC) patients remains at only 9%. Patients often show poor treatment response, due partly to a highly complex tumor microenvironment (TME). Cancer-associated fibroblast (CAF) heterogeneity is characteristic of the pancreatic TME, where several CAF subpopulations have been identified, such as myofibroblastic CAFs (myCAFs), inflammatory CAFs (iCAFs), and antigen presenting CAFs (apCAFs). In PDAC, cancer cells continuously adapt their metabolism (metabolic switch) to environmental changes in pH, oxygenation, and nutrient availability. Recent advances show that these environmental alterations are all heavily driven by stromal CAFs. CAFs and cancer cells exchange cytokines and metabolites, engaging in a tight bidirectional crosstalk, which promotes tumor aggressiveness and allows constant adaptation to external stress, such as chemotherapy. In this review, we summarize CAF diversity and CAF-mediated metabolic rewiring, in a PDAC-specific context. First, we recapitulate the most recently identified CAF subtypes, focusing on the cell of origin, activation mechanism, species-dependent markers, and functions. Next, we describe in detail the metabolic crosstalk between CAFs and tumor cells. Additionally, we elucidate how CAF-driven paracrine signaling, desmoplasia, and acidosis orchestrate cancer cell metabolism. Finally, we highlight how the CAF/cancer cell crosstalk could pave the way for new therapeutic strategies. Full article

Cancer-associated fibroblasts (CAFs) play a major role in the progression and drug resistance of pancreatic cancer. Recent studies suggest that CAFs exhibit functional heterogeneity and distinct transcriptomic signatures in pancreatic cancer. Pancreatic fibroblasts also form an integral component in pancreatic diseases such as chronic pancreatitis named disease-associated fibroblasts (DAFs). However, intra-tumoral heterogeneity of CAFs in pancreatic cancer patients and their pivotal role in cancer-related mechanisms have not been fully elucidated. Further, it has not been elucidated whether CAF subtypes identified in pancreatic cancer also exist in chronic pancreatitis. In this study, we used primary isolated fibroblasts from pancreatic cancer and chronic pancreatitis patients using the outgrowth method. Single-cell RNA sequencing (scRNA-seq) was performed, and bioinformatics analysis identified highly variable genes, including factors associated with overall survival of pancreatic cancer patients. The majority of highly variable genes are involved in the cell cycle. Instead of previously classified myofibroblastic (myCAFs), inflammatory (iCAFs), and antigen-presenting (ap) CAFs, we identified a myCAFs-like subtype in all cases. Most interestingly, after cell cycle regression, we observed 135 highly variable genes commonly identified in chronic pancreatitis and pancreatic cancer patients. This study is the first to conduct scRNAseq and bioinformatics analyses to compare CAFs/DAFs from both chronic pancreatitis and pancreatic cancer patients. Further studies are required to select and identify stromal factors in DAFs from chronic pancreatitis cases, which are commonly expressed also in CAFs potentially contributing to pancreatic cancer development. Full article

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related morbidity and mortality in the western world, with limited therapeutic strategies and dismal long-term survival. Cancer-associated fibroblasts (CAFs) are key components of the pancreatic tumor microenvironment, maintaining the extracellular matrix, while also being involved in intricate crosstalk with cancer cells and infiltrating immunocytes. Therefore, they are potential targets for developing therapeutic strategies against PDAC. However, recent studies have demonstrated significant heterogeneity in CAFs with respect to their origins, spatial distribution, and functional phenotypes within the PDAC tumor microenvironment. Therefore, it is imperative to understand and delineate this heterogeneity prior to targeting CAFs for PDAC therapy. Full article