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This article discusses the potential role of gut microbiota in modulating the effectiveness of cancer immunotherapy. The researchers found that the microbial composition of the gut varies in patients with different responses to immunotherapy. They identified a specific strain of Lactobacillus johnsonii (L. johnsonii) that, when administered to mice, increased the efficacy of immunotherapy by promoting CD8+ T cell infiltration. They also discovered that L. johnsonii produces a metabolite called indole-3-propionic acid (IPA), which enhances the responsiveness of immunotherapy by modulating T-cell stemness. The study highlights the complex interactions between gut bacteria and the immune system and suggests that manipulating the gut microbiota could be a potential strategy to improve cancer immunotherapy. [Extracted from the article]

Aging‐induced cognitive impairment is associated with a loss of metabolic homeostasis and plasticity. An emerging idea is that targeting key metabolites is sufficient to impact the function of other organisms. Therefore, more metabolism‐targeted therapeutic intervention is needed to improve cognitive impairment. We first conducted untargeted metabolomic analyses and 16S rRNA to identify the aging‐associated metabolic adaption and intestinal microbiome change. Untargeted metabolomic analyses of plasma revealed L‐arginine metabolic homeostasis was altered during the aging process. Impaired L‐arginine metabolic homeostasis was associated with low abundance of intestinal Akkermansia muciniphila (AKK) colonization in mice. Long‐term supplementation of AKK outer membranes protein‐Amuc_1100, rescued the L‐arginine level and restored cognitive impairment in aging mice. Mechanically, Amuc_1100 acted directly as a source of L‐arginine and enriched the L‐arginine‐producing bacteria. In aged brain, Amuc_1100 promoted the superoxide dismutase to alleviated oxidation stress, and increased nitric oxide, derivatives of L‐arginine, to improve synaptic plasticity. Meanwhile, L‐arginine repaired lipopolysaccharide‐induced intestinal barrier damage and promoted growth of colon organoid. Our findings indicated that aging‐related cognitive impairment was closely associated with the disorders of L‐arginine metabolism. AKK‐derived Amuc_1100, as a potential postbiotic, targeting the L‐arginine metabolism, might provide a promising therapeutic strategy to maintain the intestinal homeostasis and cognitive function in aging. [ABSTRACT FROM AUTHOR]

Emerging evidence has shown that open reading frames inside long noncoding RNAs (lncRNAs) could encode micropeptides. However, their roles in cellular energy metabolism and tumor progression remain largely unknown. Here, we identified a 94 amino acid-length micropeptide encoded by lncRNA LINC00467 in colorectal cancer. We also characterized its conservation across higher mammals, localization to mitochondria, and the concerted local functions. This peptide enhanced the ATP synthase construction by interacting with the subunits a and y (ATP5A and ATP5C), increased ATP synthase activity and mitochondrial oxygen consumption rate, and thereby promoted colorectal cancer cell proliferation. Hence, this micropeptide was termed ATP synthase-associated peptide (ASAP). Furthermore, loss of ASAP suppressed patient-derived xenograft growth with attenuated ATP synthase activity and mitochondrial ATP production. Clinically, high expression of ASAP and LINC00467 predicted poor prognosis of colorectal cancer patients. Taken together, our findings revealed a colorectal cancerassociated micropeptide as a vital player in mitochondrial metabolism and provided a therapeutic target for colorectal cancer., Introduction Colorectal cancer (CRC) is the second leading cause of cancer-related mortality globally (1). The prognosis of patients with early CRC has been greatly improved in the past decade (2). [...]

Background: Immunotherapy has made significant progress in cancer treatment; however, the responsiveness to immunotherapy varies widely among patients. Growing evidence has demonstrated the role of the gut microbiota in the efficacy of immunotherapy. Main body: Herein, we summarise the changes in the microbiota in different cancers under various immunotherapies. The microbial‐host signal transmission on immunotherapeutic responses and mechanisms associated with microbial translocation to tumours in the context of immunotherapy are also discussed. In addition, we have highlighted the clinical application value of methods for regulating the microbiota. Finally, we elaborate on the relationship between the microbiota, host and immunotherapy, and provide potential directions for future research. Conclusion: Different microbiota cause changes in the tumour microenvironment through microbial signals thereby affecting immunotherapy efficacy. Translocation of gut microbiota and the role of extraintestinal microbiota in immunotherapy deserve attention. Microbiota regulation is a novel strategy for combination therapy with immunotherapy. Although there are several aspects that deserve further refinement and exploration with regard to administration and clinical translation. Nevertheless, it is foreseeable that the microbiota will become an integral part of cancer treatment. [ABSTRACT FROM AUTHOR]

Background: The interplay between gut microbiota and tumor microenvironment (TME) in the pathogenesis of colorectal cancer (CRC) is largely unknown. Here, we elucidated the functional role of B. adolescentis and its possible mechanism on the manipulation of Decorin+ macrophages in colorectal cancer. Methods: The relative abundance of B. adolescentis in tumor or para-tumor tissue of CRC patients was analyzed. The role of B. adolescentis was explored in the CRC animal models. The single cell-RNA sequencing (scRNA-seq) was used to investigate the myeloid cells subsets in TME. The expression level of TLR2/YAP axis and its downstream Decorin in macrophages were tested by Western blot and qRT-PCR. Knockdown of Decorin in Raw264.7 was performed to investigate the effect of Decorin+ macrophages on subcutaneous tumor formation. Multi-immunofluorescence assay examined the number of Decorin+ macrophages on the CRC tissue. Results: We found that the abundance of B. adolescentis was significantly reduced in tumor tissue of CRC patients. Supplementation with B. adolescentis suppressed AOM/DSS-induced tumorigenesis in mice. ScRNA-seq and animal experiment revealed that B. adolescentis increased Decorin+ macrophages. Mechanically, Decorin was activated by TLR2/YAP axis in macrophages. The abundance of B. adolescentis was correlated with the number of Decorin+ macrophages and the expression level of TLR2 in tumor tissue of CRC patients. Conclusions: These results highlight that B. adolescentis induced Decorin+ macrophages and provide a novel therapeutic target for probiotic-based modulation of immune microenvironment in CRC. [ABSTRACT FROM AUTHOR]

Forest cover mapping is of paramount importance for environmental monitoring, biodiversity assessment, and forest resource management. In the realm of forest cover mapping, significant advancements have been made by leveraging fully supervised semantic segmentation models. However, the process of acquiring a substantial quantity of pixel-level labelled data is prone to time-consuming and labour-intensive procedures. To address this issue, this paper proposes a novel semi-supervised-learning-based semantic segmentation framework that leverages limited labelled and numerous unlabelled data, integrating multi-level perturbations and model ensembles. Our framework incorporates a multi-level perturbation module that integrates input-level, feature-level, and model-level perturbations. This module aids in effectively emphasising salient features from remote sensing (RS) images during different training stages and facilitates the stability of model learning, thereby effectively preventing overfitting. We also propose an ensemble-voting-based label generation strategy that enhances the reliability of model-generated labels, achieving smooth label predictions for challenging boundary regions. Additionally, we designed an adaptive loss function that dynamically adjusts the focus on poorly learned categories and dynamically adapts the attention towards labels generated during both the student and teacher stages. The proposed framework was comprehensively evaluated using two satellite RS datasets, showcasing its competitive performance in semi-supervised forest-cover-mapping scenarios. Notably, the method outperforms the fully supervised approach by 1–3% across diverse partitions, as quantified by metrics including mIoU, accuracy, and mPrecision. Furthermore, it exhibits superiority over other state-of-the-art semi-supervised methods. These results indicate the practical significance of our solution in various domains, including environmental monitoring, forest management, and conservation decision-making processes. [ABSTRACT FROM AUTHOR]

Resmetirom, a liver-directed, orally active agonist of THR-β, could play a favorable role in treating NASH, but little is known about the underlying mechanism. A NASH cell model was established to test the preventive effect of resmetirom on this disease in vitro. RNA-seq was used for screening, and rescue experiments were performed to validate the target gene of the drug. A NASH mouse model was used to further elucidate the role and the underlying mechanism of resmetirom. Resmetirom effectively eliminated lipid accumulation and decreased triglyceride (TG) levels. In addition, repressed RGS5 in the NASH model could be recovered by resmetirom treatment. The silencing of RGS5 effectively impaired the role of resmetirom. In the NASH mouse model, obvious gray hepatization, liver fibrosis and inflammation, and increased macrophage infiltration were observed in liver tissues, while resmetirom almost returned them to normal conditions as observed in the control group. Pathological experimental data also confirmed that resmetirom has great potential in NASH treatment. Finally, RGS5 expression was suppressed in the NASH mouse model, but it was upregulated by resmetirom treatment, while the STAT3 and NF-κB signaling pathways were activated in NASH but inhibited by the agent. Resmetirom could improve NASH by recovering RGS5 expression and subsequently inactivating the STAT3 and NF-κB signaling pathways. [ABSTRACT FROM AUTHOR]

Microbiota-host interactions play critical roles in colorectal cancer (CRC) progression, however, the underlying mechanisms remain elusive. Here, we uncover that Fusobacterium nucleatum (F. nucleatum) induces a dramatic decline of m6A modifications in CRC cells and patient-derived xenograft (PDX) tissues by downregulation of an m6A methyltransferase METTL3, contributing to inducation of CRC aggressiveness. Mechanistically, we characterized forkhead box D3 (FOXD3) as a transcription factor for METTL3. F. nucleatum activates YAP signaling, inhibits FOXD3 expression, and subsequently reduces METTL3 transcription. Downregulation of METTL3 promotes its target kinesin family member 26B (KIF26B) expression by reducing its m6A levels and diminishing YTHDF2-dependent mRNA degradation, which contributes to F. nucleatum-induced CRC metastasis. Moreover, METTL3 expression is negatively correlated with F. nucleatum and KIF26B levels in CRC tissues. A high expression of KIF26B is also significantly correlated with a shorter survival time of CRC patients. Together, our findings provide insights into modulating human m6A epitranscriptome by gut microbiota, and its significance in CRC progression. Fusobacterium nucleatum contributes to host epitranscriptomic modifications and colorectal cancer (CRC) development. Here, the authors show that Fusobacterium nucleatum reduces global m6A modifications to promote CRC metastasis through a YAP/FOXD3/METTL3/KIF26B axis. [ABSTRACT FROM AUTHOR]

Aim: Chemoresistance to 5-fluorouracil (5-Fu) is common in colorectal cancer (CRC). Programmed necrosis (necroptosis) is an alternative form of programmed cell death regulated by receptor-interacting protein kinase (RIPK) 1 and 3, assumed as a novel target of cancer therapy. In this study, we aimed to explore whether a novel small molecular agent GDC-0326 could facilitate the effect of 5-Fu through necroptosis. Main Methods: Cell Counting Kit-8 (CCK-8) assay and colony formation were performed to confirm the function of GDC-0326 in CRC cells. Western blot and immunofluorescence were conducted to measure the altered expressions of RIPK1/RIPK3 induced by GDC-0326. Subcutaneous tumor models were used to evaluate the chemotherapeutic effects and concomitant side effects of GDC-0326 in vivo. Key Findings: We found that GDC-0326 effectively suppressed the growth of CRC cells in a dose-dependent manner. The induction of necroptosis by GDC-0326 was correlated with the modulation of RIPK1 and RIPK3. Necrostatin-1 and GSK-872, inhibitors of RIPK1 and RIPK3, respectively, could rescue the cell death induced by GDC-0326. In addition, in vitro and in vivo studies showed that 5-Fu plus GDC-0326 evinced a better antitumor efficacy by suppressing tumor growth and increasing tumor necrosis with no increased toxicity. Significance: This study demonstrates that GDC-0326 plus 5-Fu has augmented antitumor efficacy and acceptable safety, which might be a promising therapeutic strategy for CRC patients in the future. [ABSTRACT FROM AUTHOR]

Colorectal cancer stem cell (CSC) has been regarded to be the root of colorectal cancer progression. However, there is still no effective therapeutic method targeting colorectal CSC in clinical application. Here, we investigated the effects of dichloroacetate (DCA) on colorectal cancer cell stemness. We showed that DCA could reduce colorectal cancer cell stemness in a dose‐dependent manner, which is evident by the decreased expression of stemness markers, tumor cell sphere‐formation and cell migration ability. In addition, it was found that DCA trigerred the ferroptosis of colorectal CSC, which is characterized as the upregulation of iron concentration, lipid peroxides, and glutathione level, and decreased cell viability. Mechanistic studies demonstrated that DCA could sequester iron in lysosome and thus trigger ferroptosis, which is necessary for DCA‐mediated attenuation on colorectal cancer cell stemness. Taken together, this work suggests that DCA might be a colorectal CSC‐killer. [ABSTRACT FROM AUTHOR]

Abstract Background ZIC1, a vital transcription factor with zinc finger domains, has been implicated in the process of neural development. We previously showed that ZIC1 may function as a tumour suppressor in gastrointestinal cancers. However, the molecular mechanism underlying ZIC1 participation in tumour progression remains unknown. Methods The role of ZIC1 on cell proliferation and migration was examined. The regulation of sonic hedgehog (Shh), phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling pathways after ectopic expression of ZIC1 in gastric cancer cells were evaluated. Results Overexpression of ZIC1 contributes to the inhibition of cell proliferation migration and cell-cycle distribution in gastric cancer. The modulation of G1/S checkpoint by ZIC1 is mainly mediated through the regulation of cyclin-dependent kinases (p21 Waf1/Cip1, p27 Kip1 and cyclin D1). In addition, ZIC1 can inactivate the level of phospholated Akt and Erk1/2, and transcriptionally regulate sonic hedgehog (Shh) signaling, thus leading to regulate the expression of p21 Waf1/Cip1 and cyclin D1. Finally, we have systemically identified ZIC1 downstream targets by cDNA microarray analysis and revealed that 132 genes are down-regulated and 66 genes are up-regulated after transfection with ZIC1 in gastric cancer cells. These candidate genes play critical roles in cell proliferation, cell cycle and cell motility. Conclusions Overexpression of ZIC1 results in inactivation of Shh, PI3K and MAPK signaling pathways, as well as regulation of multiple downstream targets which are essential for the development and progression of gastric cancer. ZIC1 serves as a potential therapeutic target for gastric cancer.

Most cancer cells employ overexpression of glucose transports (GLUTs) to satisfy glucose demand ("Sweet Tooth") for increased aerobic glycolysis rates. GLUT1, one of the most widely expressed GLUTs in numerous cancers, was identified as a prognosis-related biomarker of gastric cancer via tissue array analysis. Herein, a "Sweet Tooth"-oriented SN38 prodrug delivery nanoplatform (Glu-SNP) was developed for targeted gastric cancer therapy. For this purpose, a SN38-derived prodrug (PLA-SN38) was synthesized by tethering 7-ethyl-10-hydroxycamptothecin (SN38) to biocompatible polylactic acid (PLA) with the appropriate degree of polymerization (n = 44). The PLA-SN38 conjugate was further assembled with glycosylated amphiphilic lipid to obtain glucosamine-decorated nanoparticles (Glu-SNP). Glu-SNP exhibited potent antitumor efficiency both in vitro and in vivo through enhanced cancer cell-specific targeting associated with the overexpression of GLUT1, which provides a promising approach for gastric cancer therapy. [ABSTRACT FROM AUTHOR]

Clinically, a considerable portion of patients with early T stage who were supposed to have a low distant metastatic probability were diagnosed with metastatic liver colorectal cancer (CRLM). Our study aims to evaluate the prognostic value of the T stage for metastatic patients and establish a convenient individual assessment model for clinicians to explore preoperative predictors. The mRNA profiles of colorectal tumors (N = 19) were obtained by microarray at our clinical center. A total of 5,618 patients with CRLM from 2010 to 2015 were enrolled for the Surveillance, Epidemiology, and End Results (SEER) database. The cDNA microarray analyses showed that gene expression pattern in the T2N0M1 subgroup was significantly different from the T3/4N0M0 subgroup. In the survival analysis, metastatic patients with T1 stage surprisingly had much poorer prognosis than those with T3/T4 stage. Specifically, metastatic patients with early T stage were observed with higher frequency occurring at the rectum, better differentiation, less metastases in the lymph nodes, and a higher CEA level. Further survival analysis indicated that early T classification was an independent prognostic factor for a poor survival. When the lymph node (N) status was taken into consideration, patients with T1/2N+ had better survival than T1/2N0 patients. A clinical nomogram was constructed based on preoperative factors. The calibration curves showed a good concordance between nomogram prediction and actual observation. In conclusion, CRLM with early T stage had a different biological background. The prognosis of patients at T1/2M1 was poorer than at T3/4M1. More attention should be paid to the surveillance of high-risk factors and the screening of early T stage. [ABSTRACT FROM AUTHOR]

Senescent microenvironments play an important role in tumor progression. Here, we report that doxorubicin (DOX)‐pretreated or replicative senescent stromal cells (WI‐38 and HUVEC) promote colorectal cancer (CRC) cell growth and invasion in vitro and in vivo. These pro‐tumorigenic effects were attenuated by exogenous administration of Klotho, an anti‐aging factor. We subsequently identified several senescence‐associated secretory phenotype (SASP)‐associated genes, including CCL2, which were significantly upregulated in both types of senescent stromal cells during replication and DNA damage‐induced senescence. Importantly, we found that the secretion of CCL2 by senescent stromal cells was significantly higher than that seen in nonsenescent cells or in senescent cells pretreated with Klotho. Notably, CCL2 was found to accelerate CRC cell proliferation and invasion, while this effect could be blocked by administration of a specific CCR2 antagonist. We further show that Klotho can suppress NF‐κB activation during DOX‐induced senescence and thus block CCL2 transcription. Low expression of Klotho, or high expression of CCL2 in patient tumor tissues, correlated with poor overall survival of CRC patients. Collectively, our findings suggest that senescent stromal cells are linked to progression of CRC. Klotho can suppress the senescent stromal cell‐associated triggering of CRC progression by inhibiting the expression of SASP factors including CCL2. The identification of key SASP factors such as CCL2 may provide potential therapeutic targets for improving CRC therapy. [ABSTRACT FROM AUTHOR]

Computer-aided polyp detection in gastric gastroscopy has been the subject of research over the past few decades. However, despite significant advances, automatic polyp detection in real time is still an unsolved problem. In this paper, we report on a convolutional neural network (CNN) for polyp detection that is constructed based on Single Shot MultiBox Detector (SSD) architecture and which we call SSD for Gastric Polyps (SSD-GPNet). To take full advantages of feature maps’ information from the feature pyramid and to acquire higher accuracy, we re-use information that is abandoned by Max-Pooling layers. In other words, we reuse the lost data from the pooling layers and concatenate that data as extra feature maps to contribute to classification and detection. Meanwhile, in the feature pyramid, we concatenate feature maps of the lower layers and feature maps that are deconvolved from upper layers to make explicit relationships between layers and to effectively increase the number of channels. The results show that our enhanced SSD for gastric polyp detection can realize real-time polyp detection with 50 frames per second (FPS) and can improve the mean average precision (mAP) from 88.5% to 90.4%, with only a little loss in time-performance. And the further experiment shows that SSD-GPNet has excellent performance in improving polyp detection recalls over 10% (p = 0.00053), especially in small polyp detection. This can help endoscopic physicians more easily find missed polyps and decrease the gastric polyp miss rate. It may be applicable in daily clinical practice to reduce the burden on physicians. [ABSTRACT FROM AUTHOR]