Gastrointestinal stromal tumors (GISTs) are a rare type of tumor that can develop liver metastasis (LIM), significantly impacting the patient's prognosis. This study aimed to predict LIM in GIST ...patients by constructing machine learning (ML) algorithms to assist clinicians in the decision-making process for treatment. Retrospective analysis was performed using the Surveillance, Epidemiology, and End Results (SEER) database, and cases from 2010 to 2015 were assigned to the developing sets, while cases from 2016 to 2017 were assigned to the testing set. Missing values were addressed using the multiple imputation technique. Four algorithms were utilized to construct the models, comprising traditional logistic regression (LR) and automated machine learning (AutoML) analysis such as gradient boost machine (GBM), deep neural net (DL), and generalized linear model (GLM). We evaluated the models' performance using LR-based metrics, including the area under the receiver operating characteristic curve (AUC), calibration curve, and decision curve analysis (DCA), as well as AutoML-based metrics, such as feature importance, SHapley Additive exPlanation (SHAP) Plots, and Local Interpretable Model Agnostic Explanation (LIME). A total of 6207 patients were included in this study, with 2683, 1780, and 1744 patients allocated to the training, validation, and test sets, respectively. Among the different models evaluated, the GBM model demonstrated the highest performance in the training, validation, and test cohorts, with respective AUC values of 0.805, 0.780, and 0.795. Furthermore, the GBM model outperformed other AutoML models in terms of accuracy, achieving 0.747, 0.700, and 0.706 in the training, validation, and test cohorts, respectively. Additionally, the study revealed that tumor size and tumor location were the most significant predictors influencing the AutoML model's ability to accurately predict LIM. The AutoML model utilizing the GBM algorithm for GIST patients can effectively predict the risk of LIM and provide clinicians with a reference for developing individualized treatment plans.
Oxaliplatin (OHP)-induced peripheral neurotoxicity (OIPN) is a severe clinical problem and potentially permanent side effect of cancer treatment. For the management of OIPN, accurate diagnosis and ...understanding of significant risk factors including genetic vulnerability are essential to improve knowledge regarding the prevalence and incidence of OIPN as well as enhance strategies for the prevention and treatment of OIPN. The molecular mechanisms underlying OIPN are complex, with multi-targets and various cells causing neuropathy. Furthermore, mechanisms of OIPN can reinforce each other, and combination therapies may be required for effective management. However, despite intense investigation in preclinical and clinical studies, no preventive therapies have shown significant clinical efficacy, and the established treatment for painful OIPN is limited. Duloxetine is the only agent currently recommended by the American Society of Clinical Oncology. The present article summarizes the most recent advances in the field of studies on OIPN, the overview of the clinical syndrome, molecular basis, therapy development, and outlook of future drug candidates. Importantly, closer links between clinical pain management teams and oncology will advance the effectiveness of OIPN treatment, and the continued close collaboration between preclinical and clinical research will facilitate the development of novel prevention and treatments for OIPN.
Colorectal cancer is a multifactorial disease involving genetic, environmental, and lifestyle risk factors. Intestinal microbiota plays an important role in the occurrence and development of ...colorectal cancer. Studies have shown that the behavior of intestinal microbiota can lead to pathological changes in the host intestine, which can be divided into epigenetic changes and carcinogenic changes at the gene level, and ultimately promote the formation and development of colorectal cancer. Intestinal microbiota is mainly distributed in the intestinal epithelium, which is composed of a large number of microorganisms interacting with the host intestinal cells. It can affect the immune-inflammation and metabolism of the gastrointestinal tract, and may be used as a biomarker for disease diagnosis. Regulation of gut microbiota is a promising strategy for the prevention and treatment of colorectal cancer. This article reviews the role of intestinal microbiota in the development of colorectal cancer, including the related mechanisms of intestinal microbiota promoting colorectal cancer, the use of intestinal microbiota in the diagnosis of colorectal cancer, and the regulation of intestinal microbiota in the prevention or treatment of colorectal cancer.
Exosomes derived from cancer cells are deemed important drivers of pre-metastatic niche formation at distant organs, but the underlying mechanisms of their effects remain largely unknow. Although the ...role of ADAM17 in cancer cells has been well studied, the secreted ADAM17 effects transported via exosomes are less understood. Herein, we show that the level of exosome-derived ADAM17 is elevated in the serum of patients with metastatic colorectal cancer as well as in metastatic colorectal cancer cells. Furthermore, exosomal ADAM17 was shown to promote the migratory ability of colorectal cancer cells by cleaving the E-cadherin junction. Moreover, exosomal ADAM17 overexpression as well as RNA interference results highlighted its function as a tumor metastasis-promoting factor in colorectal cancer
in vitro
and
in vivo
. Taken together, our current work suggests that exosomal ADAM17 is involved in pre-metastatic niche formation and may be utilized as a blood-based biomarker of colorectal cancer metastasis.
Management of oxaliplatin-induced peripheral neuropathy (OIPN) has proven challenging owing to the concern that any OIPN-preventing agents may also decrease the efficacy of the chemotherapeutic agent ...and fail to reverse established neuronal damage. Nevertheless, targeting redox signaling pathways constitutes a promising therapy in OIPN and we have previously demonstrated the protective role of nuclear factor erythroid-2 related factor 2 (NRF2) in this disorder. Here, we investigated the protective properties of formononetin (FN), a clinical preparation extract, in OIPN. RNA interference experiments revealed that FN protects against OIPN directly through activation of the NRF2 pathway. Further expression profile sequencing showed that FN exerts its protective effect via the NRF2 downstream-oxaliplatin metabolism enzyme, GSTP1. We also demonstrated that FN does not influence the chemotherapeutic function of oxaliplatin, as NRF2 exhibits a different drug metabolic enzyme activation state downstream in colorectal cell lines than that in neurons. Following synthesis of Bio-FN to screen the target binding proteins, we found that FN selectively binds to His129 and Lys131 in the BTB domain of KEAP1. In vivo experiments revealed that FN-induced activation of the NRF2 signaling pathway alleviated the nociceptive sensations in mice. Our findings highlight a new binding mechanism between KEAP1 and isoflavones for activation of the NRF2 system and suggest that pharmacological or therapeutic activation of the NRF2-GSTP1 axis may serve as an effective strategy to prevent or attenuate the progression of OIPN.
Display omitted
•FN prevents oxaliplatin-induced peripheral neuropathy via KEAP1-NRF2-GSTP1 axis.•FN retains oxaliplatin in vitro antitumor activity in cancer cells.•FN selectively binds His129 and Lys131 in the Keap1 BTB domain.
Disulfidptosis, a regulated form of cell death, has been recently reported in cancers characterized by high SLC7A11 expression, including invasive breast carcinoma, lung adenocarcinoma, and ...hepatocellular carcinoma. However, its role in colon adenocarcinoma (COAD) has been infrequently discussed. In this study, we developed and validated a prognostic model based on 20 disulfidptosis-related genes (DRGs) using LASSO and Cox regression analyses. The robustness and practicality of this model were assessed via a nomogram. Subsequent correlation and enrichment analysis revealed a relationship between the risk score, several critical cancer-related biological processes, immune cell infiltration, and the expression of oncogenes and cell senescence-related genes. POU4F1, a significant component of our model, might function as an oncogene due to its upregulation in COAD tumors and its positive correlation with oncogene expression. In vitro assays demonstrated that POU4F1 knockdown noticeably decreased cell proliferation and migration but increased cell senescence in COAD cells. We further investigated the regulatory role of the DRG in disulfidptosis by culturing cells in a glucose-deprived medium. In summary, our research revealed and confirmed a DRG-based risk prediction model for COAD patients and verified the role of POU4F1 in promoting cell proliferation, migration, and disulfidptosis.
Hematological metastasis has been recognized as a crucial factor contributing to the high rates of metastasis and mortality observed in colorectal cancer (CRC). Notably, exosomes derived from cancer ...cells participate in the formation of CRC pre-metastatic niches; however, the mechanisms underlying their effects are largely unknown. While our preliminary research revealed the role of exosome-derived disintegrin and metalloproteinase 17 (ADAM17) in the early stages of CRC metastasis, the role of exosomal ADAM17 in CRC hematogenous metastasis remains unclear.
In the present study, we isolated and purified exosomes using ultracentrifugation and identified exosomal proteins through quantitative mass spectrometry. In vitro, co-culture assays were conducted to evaluate the impact of exosomal ADAM17 on the permeability of the blood vessel endothelium. Vascular endothelial cell resistance, the cell index, membrane protein separation, flow cytometry, and immunofluorescence were employed to investigate the mechanisms underlying exosomal ADAM17-induced vascular permeability. Additionally, a mouse model was established to elucidate the role of exosomal ADAM17 in the modulation of blood vessel permeability and pre-metastatic niche formation in vivo.
Our clinical data indicated that ADAM17 derived from the circulating exosomes of patients with CRC could serve as a blood-based biomarker for predicting metastasis. The CRC-derived exosomal ADAM17 targeted vascular endothelial cells, thus enhancing vascular permeability by influencing vascular endothelial cadherin cell membrane localization. Moreover, exosomal ADAM17 mediated the formation of a pre-metastatic niche in nude mice by inducing vascular leakage, thereby promoting CRC metastasis. Nonetheless, ADAM17 selective inhibitors effectively reduced CRC metastasis in vivo.
Our results suggest that exosomal ADAM17 plays a pivotal role in the hematogenous metastasis of CRC. Thus, this protein may serve as a valuable blood-based biomarker and potential drug target for CRC metastasis intervention.
Although numerous studies have demonstrated the effects of fire on the total amount of soil organic carbon (SOC), much remains unknown. In Autumn 2009, a well-controlled fire experiment was conducted ...in the boreal forest of Daxing'an Mountains, China. Over the next three years, repeated samplings were performed at settled points, taking the pre-fire state as the reference base (control). All soil samples were collected at a fixed sampling depth (0–10cm). Soil organic carbon content (SOCC) and soil organic carbon density (SOCD) were examined simultaneously. A paired-samples T-test was employed to ascertain any possible significant changes after the fire. The total amount of SOC in 0–10cm soil was dynamic after fire disturbance, and the direction and magnitude of the changes largely depended on the burning severity and the post-fire period. The spatial patterns of SOC changes and their temporal succession were closely associated with the primitive pattern of fire severity. For low- and medium-severity fires, no significant immediate change in SOCC or SOCD was detected. After one or two leaching seasons, a statistically significant increase (less than +5% on average for SOCC, less than +10% on average for SOCD) was observed in low- and medium-severity burning areas due to incorporation of fire-derived forest debris and semi-decomposed dead roots, but this minor increase was diminished or offset by the third year. High-severity fire caused significant immediate C loss in topsoil through direct combustion, while the subsequent changes varied: either rapidly and continually decreased until the third year (from approximately −10% to −60% for SOCC, and from −5% to −40% for SOCD) as a result of subsequent erosion, or increased dramatically (from +40% to more than +100% for SOCC) due to deposition of burnt OM and/or organic soil, depending on the convex or concave microtopography. The sensitivities of SOCC and SOCD to fire disturbance were inconsistent due to changes in soil bulk density. SOCD was relatively sensitive to the temporary increase after medium-severity fire, while SOCC was more sensitive to the prolonged decrease following high-severity burning. Factors affecting changes in SOC were more complicated than previously reported. In particular, the collapse, burning and erosion of topsoil all contributed to the downward-shift of actual sampling depth, which resulted in a “dilution effect” on SOCC and a “superaddition effect” on SOCD. This effect was an underlying reason for the sensitivity differentiation of the two indices and further complicated the characterization of changes in SOC.
•Spatiotemporal changes in total soil organic carbon (SOC) after fire were monitored.•SOC content (SOCC) and SOC density (SOCD) differed after fire damage.•Topsoil collapse, burning and erosion caused a shift-down of actual sampling depth.•This resulted in a “dilution effect” for SOCC and “superadditive effect” for SOCD.•Burnt organic matter was deposited in concave areas, increasing SOC markedly.
GSTpi is a Phase II metabolic enzyme which is originally considered as an important facilitator of cellular detoxification. Here, we found that GSTpi stabilized VE-cadherin in endothelial cell ...membrane through inhibiting VE-cadherin phosphorylation and VE-cadherin/catenin complex dissociation, and consequently maintained endothelial barrier function. Our findings demonstrated a novel mechanism that GSTpi inhibited VE-cadherin phosphorylation through suppressing the activation of Src/VE-cadherin pathway. Mass spectrometry analysis and molecular docking showed that GSTpi enhanced Src S-glutathionylation at Cys185, Cys245, and Cys400 of Src. More important, we found that GSTpi promoted S-glutathionylation of Src was essential for GSTpi to inhibit Src phosphorylation and activation. Furthermore, in vivo experiments indicated that AAV-GSTpi exerted the protective effect on pulmonary vessel permeability in the animal model of acute lung injury. This study revealed a novel regulatory effect of GSTpi on vascular endothelial barrier function and the importance of S-glutathionylation of Src induced by GSTpi in the activation of Src/VE-cadherin pathway.
Display omitted
•GSTpi regulates endothelial barrier function in response to pro-inflammatory stress.•GSTpi inhibits the destabilization of membrane VE-cadherin through suppressing the activation of Src/VE-cadherin pathway.•GSTpi selectively inhibits Src phosphorylation by S-glutathionylating novel cysteines of Src.•GSTpi exerts the protective effect on pulmonary vessel permeability in the animal model of acute lung injury.
Immune function is an important indicator for assessing postoperative recovery and long-term survival in patients with malignancy, and laparoscopic surgery is thought to have a less suppressive ...effect on the immune response than open surgery. This study aimed to investigate this effect in a retrospective clinical study.
In this retrospective clinical study, we enrolled 63 patients with colorectal cancer in the Department of General Surgery of the First Affiliated Hospital of Soochow University and assessed the changes in their postoperative immune function by measuring CD3
T, CD4
T, CD8
T lymphocytes, and CD4
/CD8
ratio.
Compared with open surgery, laparoscopic colorectal surgery was effective in improving the postoperative decline in immune function. We determined that the number of CD4
, CD8
T lymphocytes, and the CD4
/CD8
ratio was not significantly reduced in the laparoscopic group.
Laparoscopic-assisted colorectal resection can reduce the inhibition of immune functions compared with conventional open surgery.
PDF
