Identification and experimental verification of a biomarker by combining the unfolded protein response with the immune cells in colon cancer.

BACKGROUND: The unfolded protein response (UPR) is associated with immune cells that regulate the biological behavior of tumors. This article aims to combine UPR-associated genes with immune cells to find a prognostic marker and to verify its connection to the UPR. METHODS: Univariate cox analysis was used to screen prognostically relevant UPRs and further screened for key UPRs among them by machine learning. ssGSEA was used to calculate immune cell abundance. Univariate cox analysis was used to screen for prognostically relevant immune cells. Multivariate cox analysis was used to calculate UPR_score and Tumor Immune Microenvironment score (TIME_score). WGCNA was used to screen UPR-Immune-related (UI-related) genes. Consensus clustering analysis was used to classify patients into molecular subtype. Based on the UI-related genes, we classified colon adenocarcinoma (COAD) samples by cluster analysis. Single-cell analysis was used to analyze the role of UI-related genes. We detected the function of TIMP1 by cell counting and transwell. Immunoblotting was used to detect whether TIMP1 was regulated by key UPR genes. RESULTS: Combined UPR-related genes and immune cells can determine the prognosis of COAD patients. Cluster analysis showed that UI-related genes were associated with clinical features of COAD. Single-cell analysis revealed that UI-related genes may act through stromal cells. We defined three key UI-related genes by machine learning algorithms. Finally, we found that TIMP1, regulated by key genes of UPR, promoted colon cancer proliferation and metastasis. CONCLUSIONS: We found that TIMP1 was a prognostic marker and experimentally confirmed that TIMP1 was regulated by key genes of UPR.

Low ligation of the inferior mesenteric artery in robotic mid-low rectal cancer surgery: a comparative study from a single-center.

Laparoscopic total mesorectal excision is the main surgical approach for treating rectal cancer, but there is still no clear consensus on the issue of low ligation of the inferior mesenteric artery during the procedure. Robotic surgery has been shown to have certain advantages over laparoscopic surgery in multiple studies, but further research is needed to better understand the outcomes of robotic surgery in the context of low ligation procedures. In this study, we included 1590 patients with mid-low rectal cancer. Among them, 942 patients underwent low ligation surgery (LL), divided into 138 in the robotic group and 804 in the laparoscopic group. The high ligation surgery (HL) group consisted of 648 patients. The results of LL vs HL showed that the LL group had faster bowel movement recovery (P = 0.003), lower anastomotic leak rate (P = 0.032), and lower International Prostate Symptom Score (IPSS) at 6 months postoperatively (P < 0.001). The results of Rob-LL vs Lap-LL showed that the Rob-LL group had longer operative time (P < 0.001), less blood loss (P = 0.001), more lymph nodes retrieved (P = 0.045), and lower Wexner score at 2 weeks postoperatively (P = 0.029). The concept of low ligation of the inferior mesenteric artery is a promising surgical approach that can accelerate the patient's functional recovery. When combined with robotic technology, it may offer more benefits than laparoscopic techniques.

The battle within: cell death by phagocytosis in cancer.

The process by which living cells are phagocytosed and digested to death is called cell death by phagocytosis, a term that has just recently been generalized and redefined. It is characterized by the phagocytosis of living cells and the cessation of cell death by phagocytosis. Phagocytosis of dead cells is a widely discussed issue in cancer, cell death by phagocytosis can stimulate phagocytosis and stimulate adaptive immunity in tumors, and at the same time, do not-eat-me signaling is an important site for cancer cells to evade recognition by phagocytes. Therefore, we discuss in this review cell death by phagocytosis occurring in cancer tissues and emphasize the difference between this new concept and the phagocytosis of dead tumor cells. Immediately thereafter, we describe the mechanisms by which cell death by phagocytosis occurs and how tumors escape phagocytosis. Finally, we summarize the potential clinical uses of cell death by phagocytosis in tumor therapy and strive to provide ideas for tumor therapy.

Ferroptosis: the balance between death and survival in colorectal cancer.

Colorectal cancer (CRC) is a common malignant tumor associated with high morbidity and mortality. Despite an increase in early screening and treatment options, people with CRC still have a poor prognosis and a low 5-year survival rate. Therefore, mining more therapeutic targets and developing means of early diagnosis and determining prognosis are now imperative in the clinical treatment of CRC. Ferroptosis is a recently identified type of regulated cell death (RCD) characterized, which is identified by the accumulation of iron-dependent lipid peroxidation, thereby causing membrane damage and cell death. Recent studies have shown that ferroptosis is associated with tumors, including CRC, and can be involved in CRC progression; however, the underlying mechanisms are complex and heterogeneous and have not been thoroughly summarized. Therefore, this study reviewed the roles of ferroptosis in CRC progression to target ferroptosis-related factors for CRC treatment. The significance of ferroptosis-related biomarkers and genes in the early diagnosis and prognosis of CRC was also investigated. Furthermore, the limitations of ferroptosis studies in the current treatment of CRC, as well as future research perspectives, are discussed.

The role and molecular mechanism of Trametes Robiniophila Murr(Huaier) in tumor therapy.

ETHNOPHARMACOLOGICAL RELEVANCE: Trametes Robiniophila Murr, commonly known as Huaier, has been extensively documented in ethnopharmacology research in China. Huaier has a long history of clinical usage spanning over 1000 years in China. Traditional clinical application records demonstrate the wide utilization of Huaier for treating various cancers and enhancing the autoimmunity of tumor patients. AIM OF THE REVIEW: The present study provides a comprehensive review of the traditional uses, phytochemical constituents, pharmacological activities, anti-tumor mechanism, and potential applications of Huaier, thereby offering valuable insights for the further development and utilization of this natural product. MATERIALS AND METHODS: This study employed the keywords "Trametes Robiniophila Murr" and "Huaier" to retrieve relevant information on Huaier from various databases, including PubMed, Web of Science, Springer, Science Direct, ACS, Wiley, CNKI, Baidu Scholar, Google Scholar, and ancient materia medica. RESULTS: Trametes Robiniophila Murr (Huaier), a traditional Chinese medicine, has demonstrated significant efficacy in the clinical treatment of various tumors. The primary bioactive constituents of Huaier consist of fungal-derived compounds, including polysaccharides, proteins, ketones, alkaloids, and minerals. The research findings demonstrate that Huaier serves as a reliable adjunctive therapeutic agent by effectively inhibiting cancer cell proliferation, inducing apoptosis in cancer cells, suppressing tumor metastasis, regulating tumor stem cells and immune function. Therefore, it exerts a potent anti-tumor effect when used in conjunction with conventional anti-cancer therapies. CONCLUSIONS: The analysis of traditional uses, phytochemical composition, and pharmacological activity reveals that Huaier exhibits significant potential as a medicinal plant with diverse pharmacological effects. Owing to its numerous advantages, Huaier holds immense promise for application in the domains of tumor prevention and treatment, enhancing both survival time and quality of life among cancer patients.

Hepatitis E virus and SARS-CoV-2 co-infection in an immunocompromised patient: A case report.

Hepatitis E virus (HEV) is a major cause of acute viral hepatitis. Since the coronavirus disease 2019 (COVID-19) pandemic, immunocompromised individuals face an increased risk of HEV and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) co-infection, posing a threat of liver failure and prolonged illness. A 69-year-old male, with a history of chronic lymphocytic leukemia, was co-infected with HEV and SARS-CoV-2. Given the progressive decline in liver function post-admission, steroid therapy was initiated, which led to treatment-related complications. Additionally, the patient experienced an aggravation of COVID-19 symptoms due to persistent SARS-CoV-2 infection, effectively managed through a combination of antiviral medications and corticosteroids. This case describes the intricate clinical trajectory and therapeutic approach for managing HEV and SARS-CoV-2 co-infection, underscoring the potential efficacy of short-term corticosteroid intervention alongside comprehensive antiviral treatment.

Potential role of the intratumoral microbiota in colorectal cancer immunotherapy.

Colorectal cancer (CRC) has been one of the most common malignancies worldwide. Despite the advances in current therapies, the mortality rate of CRC remains high. Among them, immunotherapy has achieved satisfactory results in some CRC patients, however, how to expand the use of immunotherapy in CRC patients remains an urgent challenge. Surprisingly, the intratumoral microbiota has been found in multiple tumor tissues, including CRC. It has been demonstrated that the intratumoral microbiota is associated with the progression and treatment of CRC, and is able to enhance or decrease anti-tumor immune responses via different mechanisms as well as influence the immunotherapy efficacy, providing new potential therapeutic targets for CRC immunotherapy. In this review, we focus on the characteristics of the intratumoral microbiota, its roles in the genesis and development of CRC, its modulation of anti-tumor immune responses and immunotherapy, and propose potential applications of the intratumoral microbiota in CRC immunotherapy. Additionally, we propose possible directions for future research on the intratumoral microbiota related to CRC immunotherapy.

Microbes in the tumor microenvironment: New additions to break the tumor immunotherapy dilemma.

Immunotherapies currently used in clinical practice are unsatisfactory in terms of therapeutic response and toxic side effects, and therefore new immunotherapies need to be explored. Intratumoral microbiota (ITM) exists in the tumor environment (TME) and reacts with its components. On the one hand, ITM promotes antigen delivery to tumor cells or provides cross-antigens to promote immune cells to attack tumors. On the other hand, ITM affects the activity of immune cells and stromal cells. We also summarize the dialog pathways by which ITM crosstalks with components within the TME, particularly the interferon pathway. This interaction between ITM and TME provides new ideas for tumor immunotherapy. By analyzing the bidirectional role of ITM in TME and combining it with its experimental and clinical status, we summarized the adjuvant role of ITM in immunotherapy. We explored the potential applications of using ITM as tumor immunotherapy, such as a healthy diet, fecal transplantation, targeted ITM, antibiotics, and probiotics, to provide a new perspective on the use of ITM in tumor immunotherapy.

The value of intratumoral microbiota in the diagnosis and prognosis of tumors.

Intratumoral microbiota (ITM) are microorganisms present in tumor cells. ITM participate in tumor development by affecting tumor cells directly and the tumor microenvironment (TME), indirectly. Alterations in ITM instigate changes in tumor DNA, activate oncogenic pathways, induce tumor inflammatory responses, disrupt normal immune activity, and facilitate the secretion of effectors leading to tumor progression, metastasis, or diminished therapeutic effects. ITM varies significantly in different types of cancer cells and disease states. The presence of certain ITM serves as a predictor of various disease states. Thus, ITM predicts tumorigenesis, tumor grade, treatment efficacy, and prognosis, making it a potential tumor biomarker. The present study aimed to determine the mechanisms by which ITM affects tumor development, especially through the TME; highlight the significant potential of ITM in enhancing tumor diagnosis and prognosis; and outline future directions for ITM research, with a focus on the development of innovative tumor markers.

Tumor size impact on TNM staging which define post-operative complications in rectal cancer.

The purpose of this study was to see how accurate tumor size was at predicting T and N stages in rectal malignancies. Tumor sizes of 40 mm and greater than 40 mm were used to assess post-operative challenges in related to T1-T2 and T3-T4 stages, as well as between node N0 and node N1 and N2 patients. A total of 131 patients were treated for colorectal cancer, with 54 patients < 40 mm and 77 patients > 40 mm receiving Da Vinci colorectal surgery. Conferring to the Clavien-Dindo classification grade III, there's an increase in the percentage of tumors > 40 mm, which also impacts the percentage of intestinal obstruction, anastomotic leakage, GERD, and sepsis with a P < 0.05. A tumor size of more than 40 mm is strongly associated with advanced pT stages. Tumor size may serve in addition to clinical staging and improve the management of rectal cancer.

FANCA facilitates G1/S cell cycle advancement, proliferation, migration and invasion in gastric cancer.

The present study explores the function of FANCA gene, a pivotal member of the Fanconi anaemia (FA) pathway crucial for preserving genomic stability and preventing cancer, particularly in the context of gastric cancer (GC). Using immunohistochemistry, quantitative real-time PCR, and western blot analysis, we evaluate FANCA mRNA and protein expressions in GC cell lines. The relationship between FANCA expression and clinicopathological characteristics is also explored. Various assays, including CCK8, colony formation, wound healing, and Transwell assays, are used to assess functional changes in cells associated with FANCA. Flow cytometry is utilized to evaluate alterations in the cell cycle resulted from FANCA knockdown and overexpression. Our findings show elevated FANCA expression in GC cell lines, with levels correlated with pathologic stage and lymphatic metastasis. FANCA knockdown impedes cell proliferation, migration, and invasion and induces G1/S phase cell cycle arrest. Conversely, FANCA overexpression stimulates cell proliferation, migration, and invasion. In vivo xenograft experiments confirm the promotional role of FANCA in GC tumor progression. Moreover, FANCA overexpression is associated with the activation of cell cycle. Collectively, our results suggest that FANCA drives malignant cell behaviors in GC through the cell cycle pathway, highlighting its potential as a therapeutic target for the treatment of GC.

Multi-omics data-based analysis characterizes molecular alterations of the vesicle genes in human colorectal cancer.

The role of vesicular genes in the development of colorectal cancer (CRC) is crucial. Analyzing alterations in these genes at multi-omics can aid in understanding the molecular pathways behind colorectal carcinogenesis and identifying potential treatment targets. However, studies on the overall alteration of vesicular genes in CRC are still lacking. In this study, we aimed to investigate the relationship between vesicle genetic alterations and CRC progression. To achieve this, we analyzed molecular alterations in CRC vesicle genes at eight levels, including mRNA, protein, and epigenetic levels. Additionally, we examined CRC overall survival-related genes that were obtained from a public database. Our analysis of chromatin structural variants, DNA methylation, chromatin accessibility, and proteins (including phosphorylation, ubiquitination, and malonylation), along with RNA-seq data from the TCGA database, revealed multiple levels of alterations in CRC vesicle genes in the collected tissue samples. We progressively examined the alterations of vesicle genes in mRNA and protein levels in CRC and discovered the hub genes. Further investigation identified the probable essential transcription factors. This study contributes to a thorough knowledge of the connection between vesicle gene alterations at multiple levels and the development of CRC and offers a theoretical framework for the identification of novel treatment targets.

Role of imbalanced gut microbiota in promoting CRC metastasis: from theory to clinical application.

Metastasis poses a major challenge in colorectal cancer (CRC) treatment and remains a primary cause of mortality among patients with CRC. Recent investigations have elucidated the involvement of disrupted gut microbiota homeostasis in various facets of CRC metastasis, exerting a pivotal influence in shaping the metastatic microenvironment, triggering epithelial-mesenchymal transition (EMT), and so on. Moreover, therapeutic interventions targeting the gut microbiota demonstrate promise in enhancing the efficacy of conventional treatments for metastatic CRC (mCRC), presenting novel avenues for mCRC clinical management. Grounded in the "seed and soil" hypothesis, this review consolidates insights into the mechanisms by which imbalanced gut microbiota promotes mCRC and highlights recent strides in leveraging gut microbiota modulation for the clinical prevention and treatment of mCRC. Emphasis is placed on the considerable potential of manipulating gut microbiota within clinical settings for managing mCRC.

Identification and validation of the clinical prediction model and biomarkers based on chromatin regulators in colon cancer by integrated analysis of bulk- and single-cell RNA sequencing data.

Background: Chromatin regulators (CRs) are implicated in the development of cancer, but a comprehensive investigation of their role in colon adenocarcinoma (COAD) is inadequate. The purpose of this study is to find CRs that can provide recommendations for clinical diagnosis and treatment, and to explore the reasons why they serve as critical CRs. Methods: We obtained data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Weighted Gene Co-Expression Network Analysis (WGCNA) screened tumor-associated CRs. LASSO-Cox regression was used to construct the model and to screen key CRs together with support vector machine (SVM), the univariate Cox regression. We used single-cell data to explore the expression of CRs in cells and their communication. Immune infiltration, immune checkpoints, mutation, methylation, and drug sensitivity analyses were performed. Gene expression was verified by quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR). Pan-cancer analysis was used to explore the importance of hub CRs. Results: We finally obtained 32 tumor-associated CRs. The prognostic model was constructed based on RCOR2, PPARGC1A, PKM, RAC3, PHF19, MYBBP1A, ORC1, and EYA2 by the LASSO-Cox regression. Single-cell data revealed that the model was immune-related. Combined with immune infiltration analysis, immune checkpoint analysis, and tumor immune dysfunction and exclusion (TIDE) analysis, the low-score risk group had more immune cell infiltration and better immune response. Mutation and methylation analysis showed that multiple CRs may be mutated and methylated in colon cancer. Drug sensitivity analysis revealed that the low-risk group may be more sensitive to several drugs and PKM was associated with multiple drugs. Combined with machine learning, PKM is perhaps the most critical gene in CRs. Pan-cancer analysis showed that PKM plays a role in the prognosis of cancers. Conclusions: We developed a prognostic model for COAD based on CRs. Increased expression of the core gene PKM is linked with a poor prognosis in several malignancies.

Akkermania muciniphila: a rising star in tumor immunology.

Tumor is accompanied by complex and dynamic microenvironment development, and the interaction of all its components influences disease progression and response to treatment. Once the tumor microenvironment has been eradicated, various mechanisms can induce the tumors. Microorganisms can maintain the homeostasis of the tumor microenvironment through immune regulation, thereby inhibiting tumor development. Akkermania muciniphila (A. muciniphila), an anaerobic bacterium, can induce tumor immunity, regulate the gastrointestinal microenvironment through metabolites, outer membrane proteins, and some cytokines, and enhance the curative effect through combined immunization. Therefore, a comprehensive understanding of the complex interaction between A. muciniphila and human immunity will facilitate the development of immunotherapeutic strategies in the future and enable patients to obtain a more stable clinical response. This article reviews the most recent developments in the tumor immunity of A. muciniphila.

A new strategy for immunotherapy of microsatellite-stable (MSS)-type advanced colorectal cancer: Multi-pathway combination therapy with PD-1/PD-L1 inhibitors.

Colorectal cancer (CRC) is a frequent gastrointestinal malignancy with high rates of morbidity and mortality; 85% of these tumours are proficient mismatch repair (pMMR)-microsatellite instability-low (MSI-L)/microsatellite stable (MSS) CRC known as 'cold' tumours that are resistant to immunosuppressive drugs. Monotherapy with programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors is ineffective for treating MSS CRC, making immunotherapy for MSS CRC a bottleneck. Recent studies have found that the multi-pathway regimens combined with PD-1/PD-L1 inhibitors can enhance the efficacy of anti-PD-1/PD-L1 in MSS CRC by increasing the number of CD8+ T cells, upregulating PD-L1 expression and improving the tumour microenvironment. This paper reviews the research progress of PD-1/PD-L1 inhibitors in combination with cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitors, oncolytic virus, intestinal flora, antiangiogenic agents, chemotherapy, radiotherapy and epigenetic drugs for the treatment of pMMR-MSI-L/MSS CRC.

Wogonoside Ameliorates Airway Inflammation and Mucus Hypersecretion via NF-κB/STAT6 Signaling in Ovalbumin-Induced Murine Acute Asthma.

Asthma is recognized as a chronic respiratory illness characterized by airway inflammation and airway hyperresponsiveness. Wogonoside, a flavonoid glycoside, is reported to significantly alleviate the inflammation response and oxidative stress. Herein, this study aimed to investigate the therapeutic effect and underlying mechanism of wogonoside on airway inflammation and mucus hypersecretion in a murine asthma model and in human bronchial epithelial cells (16HBE). BALB/c mice were sensitized and challenged with ovalbumin (OVA). Pulmonary function and the number of cells in the bronchoalveolar lavage fluid (BALF) were examined. Pathological changes in lung tissue in each group were evaluated via hematoxylin and eosin and periodic acid-Schiff staining, and changes in levels of cytokines in BALF and of immunoglobulin E in serum were determined via an enzyme-linked immunosorbent assay. The expression of relevant genes in lung tissue was analyzed via real-time PCR. Western blotting and immunofluorescence were employed to detect the expression of relevant proteins in lung tissue and 16HBE cells. Treatment with 10 and 20 mg/kg wogonoside significantly attenuated the OVA-induced increase of inflammatory cell infiltration, mucus secretion, and goblet cell percentage and improved pulmonary function. Wogonoside treatment reduced the level of T-helper 2 cytokines including interleukin (IL)-4, IL-5, and IL-13 in BALF and of IgE in serum and decreased the mRNA levels of cytokines (IL-4, IL-5, IL-6, IL-13, and IL-1ß and tumor necrosis factor-α), chemokines (CCL-2, CCL-11, and CCL-24), and mucoproteins (MUC5AC, MUC5B, and GOB5) in lung tissues. The expression of MUC5AC and the phosphorylation of STAT6 and NF-κB p65 in lung tissues and 16HBE cells were significantly downregulated after wogonoside treatment. Thus, wogonoside treatment may effectively decrease airway inflammation, airway remodeling, and mucus hypersecretion via blocking NF-κB/STAT6 activation.

The engineered exosomes targeting ferroptosis: A novel approach to reverse immune checkpoint inhibitors resistance.

Immune checkpoint inhibitors (ICIs) have been extensively used in immunological therapy primarily due to their ability to prolong patient survival. Although ICIs have achieved success in cancer treatment, the resistance of ICIs should not be overlooked. Ferroptosis is a newly found cell death mode characterized by the accumulation of reactive oxygen species (ROS), glutathione (GSH) depletion, and glutathione peroxidase 4 (GPX4) inactivation, which has been demonstrated to be beneficial to immunotherapy and combining ferroptosis and ICIs to exploit new immunotherapies may reverse ICIs resistance. Exosomes act as mediators in cell-to-cell communication that may regulate ferroptosis to influence immunotherapy through the secretion of biological molecules. Thus, utilizing exosomes to target ferroptosis has opened up exciting possibilities for reversing ICIs resistance. In this review, we summarize the mechanisms of ferroptosis improving ICIs therapy and how exosomes regulate ferroptosis through adjusting iron metabolism, blocking the ROS accumulation, controlling ferroptosis defense systems, and influencing classic signaling pathways and how engineered exosomes target ferroptosis and improve ICIs efficiency.

Exosomal non-coding RNA: A new frontier in diagnosing and treating pancreatic cancer: A review.

Pancreatic cancer is the most fatal malignancy worldwide. Once diagnosed, most patients are already at an advanced stage because of their highly heterogeneous, drug-resistant, and metastatic nature and the lack of effective diagnostic markers. Recently, the study of proliferation, metastasis, and drug resistance mechanisms in pancreatic cancer and the search for useful diagnostic markers have posed significant challenges to the scientific community. Exosomes carry various biomolecules (DNA, non-coding RNAs (ncRNAs), proteins, and lipids) that mediate communication between tumors and other cells. ncRNAs can be transported through exosomes to numerous relevant receptor cells and regulate local epithelial-mesenchymal transition (EMT) in tumor tissue, proliferation, drug resistance, and the establishment of pre-metastatic ecological niches in distant organs. In summary, exosomal ncRNAs promote tumor cell proliferation, invasion, and metastasis through multiple EMT, immunosuppression, angiogenesis, and extracellular matrix remodeling pathways. Moreover, we discuss the significant therapeutic significance of exosomal ncRNAs as PC biomarkers.