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The mechanisms underlying the development and progression of colon cancer are not fully understood. Herein, Src kinase associated phosphoprotein 1 (SKAP1), an immune cell adaptor, is identified as a novel colon cancer‐related gene. SKAP1 expression is significantly increased in colon cancer cells. High SKAP1 levels are independently predictive of poor survival in patients with colon cancer. Notably, SKAP1 expression in colon cancer cells exerted a significant tumor‐promoting effect in vivo rather than in vitro. Screening of tumor‐infiltrating immune cells revealed the involvement of neutrophils in SKAP1‐induced colon tumor promotion. Enhanced formation of neutrophil extracellular traps (NETs) is found to be a key downstream event that contributed to the pro‐tumor role of SKAP1. In colon cancer cells, SKAP1 increased the expression of C‐X‐C motif chemokine ligand 8 (CXCL8) via nuclear factor of activated T cells c1 (NFATc1). The blockade of CXCL8 or NFATc1 largely attenuated neutrophil infiltration, NET formation, and tumor promotion induced by SKAP1. Furthermore, inhibiting SKAP1‐induced NET significantly enhanced the antitumor efficiency of adoptive natural killer cell therapy in colon tumor models. In conclusion, SKAP1 significantly promotes colon cancer growth via the cancer cell/neutrophil NFATc1/CXCL8/NET axis, suggesting that SKAP1 is a potential target for colon cancer therapy. [ABSTRACT FROM AUTHOR]

Three-dimensional (3D) culture is a technique commonly utilized in bioprocessing and biomedical research. Exosomes have been investigated as carriers for medications in numerous studies employing 3D culture methodologies. The objective of this research is to employ 3D cell culture for the isolation and treatment of exosomes targeting colon cancer cells. The isolation of exosomes obtained from HEK293 cells was conducted through the ultracentrifugation technique. Subsequently, exosome treatment was administered to WiDr cells at concentrations of 3.5 µg/ml, 7 µg/ml, and 14 µg/ml.The validation of molecular markers of exosomes (CD9 and CD81), along with BAX, BCL-2, and CD133, was performed using qRT-PCR. The findings revealed the successful isolation of exosomes derived from HEK293 cells, which exhibited the expression of markers CD9 and CD81. Furthermore, the expression of BAX and BCL-2 indicated the potential of exosomes to induce apoptosis, while the expression level of CD133 decreased with treatment at varying concentrations. These results suggest that exosome treatment has the capability to impede the proliferation of WiDr cells and reduce the expression of CD133, thereby signifying the potential application of exosomes as an in-vitro model for investigating cancer therapy in the future. [ABSTRACT FROM AUTHOR]

Introduction: Colon cancer is the second most common cause of death in the United States. With an increasing number of patients diagnosed at younger ages, the disease remains a significant burden. However, recent data on early onset patients admitted with colon cancer are still limited. Methods: We utilized the 2016 to 2021 National Inpatient Sample to investigate trends and characteristics of colon cancer hospitalizations. Nonelective participants were divided into early onset and normal-age groups, with a cut point of 50 years old. In addition, we also investigated factors associated with the risk of inpatient mortality in the study population. Results: There were 26,903 early onset nonelective colon cancer hospitalizations in the population group, amounting to 11.91% of total colon cancer hospitalizations. No significant changes or trends were seen from 2016 to 2021. Compared to the normal-age population group, there was a disproportionate number of Blacks, Hispanics, and Asian Americans, as well as those with obesity and tobacco usage. Conclusion: Some demographic factors and comorbidities disproportionately affect early onset colon cancer patients when compared to the normal-age population group. Further investigations are necessary to combat the growing incidence of early onset colon cancer. [ABSTRACT FROM AUTHOR]

Objective: To elucidate the efficacy of Ginsenoside Rg3 on the reproduction and immigration of HCT-116 cells and its molecular mechanism. Methods: Analysis of the cell cycle along with the colony formation assay, and MTT test were performed to detect the effect of Ginsenoside Rg3 (GRg3) on proliferation of HCT-116 cells. Transwell assay and Cell scratch wound method were carried out to determine the impact on the immigration. The differential expressed genes obtained by RNA-sequencing were intersected with the predicted target genes of GRg3, and PPI was constructed to analyze hub genes. The key target gene expression and its downstream genes were evaluated by western blot assay. Results: The GRg3 can inhibit the reproduction and immigrating ability of colonic carcinoma cells, decrease the ability of colony formation in HCT-116 cells, and arrest the G2 phase. JAK3 was identified as a key target gene. Western blot assay revealed decreased levels of p-STAT5 and JAK3 post-treatment with RG3, while STAT5a and STAT5b did not change significantly. Conclusion: The GRg3 inhibits the phosphorylation of STAT5 but not the expression of total protein by inhibiting the expression of JAK3, and then inhibits the proliferation and migration of HCT-116 cells. [ABSTRACT FROM AUTHOR]

Background: Previous studies employing polymeric micelles and molecular imaging for in vivo nanosystem characterization have led to the development of radionanoprobes (RNPs) designed for diagnosing and monitoring therapeutic interventions in preclinical oncology research, specifically within breast and colon cancer models. These models exhibit high GLUT1 expression on tumor cells and VEGFR expression on the tumor vasculature. We aimed to enhance the tumor-targeting specificity of these RNPs by functionalizing micelles with glucose and bevacizumab. The choice of 99mTc to label the nanoprobes is based on its availability and that direct labeling method is a widespread strategy to prepare radiopharmaceuticals using cold reagents and a 99Mo/99mTc generator. Soluplus® is an attractive polymer for synthesizing micelles that also allows their functionalization. With all the above, the objective of this work was to design, develop and characterize nanoprobes based on polymeric micelles and radiolabeled with 99mTc for the characterization of biological processes associated to the diagnosis, prognosis and monitoring of animal models of breast and colon cancer in preclinical research using molecular images. Results: Four RNPs ([99mTc]Tc-Soluplus®, [99mTc]Tc-Soluplus®+TPGS, [99mTc]Tc-Soluplus®+glucose and [99mTc]Tc-Soluplus®+bevacizumab) were produced with high radiochemical purity (> 95% in all cases) and stability in murine serum for up to 3 h. The RNPs maintained the 100 nm size of the Soluplus® polymeric micelles even when they were functionalized and labeled with 99mTc. The image acquisition protocol enabled the visualization of tumor uptake in two cancer experimental models using the assigned RNPs. In vivo biological characterization showed signal-to-background ratios of 1.7 ± 0.03 for [99mTc]Tc-Soluplus®+TPGS, 1.8 ± 0.02 for [99mTc]Tc-Soluplus®, and 2.3 ± 0.02 for [99mTc]Tc-Soluplus®+glucose in the breast cancer model, and 1.8 ± 0.04 for [99mTc]Tc-Soluplus® and 3.7 ± 0.07 for [99mTc]Tc-Soluplus®+bevacizumab in the colon cancer model. Ex vivo biodistribution, showed that the uptake of the tumors, regardless of the model, is < 2% IA/g while the blood activity concentration is higher, suggesting that the enhanced permeability and retention effect (EPR) would be one of the mechanisms involved in imaging tumors in addition to the active targeting of RNPs. Conclusions: Soluplus®-based polymeric micelles provide a promising nanotechnological platform for the development of RNPs. The functionalization with glucose and bevacizumab enhances tumor specificity enabling effective imaging and monitoring of cancer in animal models. [ABSTRACT FROM AUTHOR]

Objective: To explore the medical significance of methylated septin9 (mSEPT9) in monitoring recurrence and prognostic assessment in individuals with surgically treated colorectal cancer (CRC). Methods: To investigate the role of Septin9 in colorectal cancer, we utilized the TIMER2.0 database to analyze its differential expression between tumor tissues and adjacent normal tissues. Colorectal cancer RNA-seq data from the TCGA database was downloaded and curated. The clinical relevance of mSEPT9 in colorectal cancer was explored by examining the correlation between Septin9 methylation levels and clinical characteristics using UALCAN and MethSurv software. Peripheral blood samples were obtained from 130 CRC subjects who underwent surgery for the detection of mSEPT9 and carcinoembryonic antigen (CEA) expression, along with collection of clinicopathological data such as age, gender, tumor site, TNM stage, and tumor differentiation. Patients were followed up for at least 3 years post-surgery until the death or final follow-up dates (31/12/2022). Additionally, peripheral blood samples were collected from 30 colorectal cancer surgery patients for mSEPT9 detection before and 7 days after surgery. Results: Through bioinformatic database analysis, we identified higher expression levels of SEPT9 mRNA in most tumor tissues compared to normal tissues. Similarly, both paired and unpaired CRC tissues exhibited elevated expression of Septin9 when compared to normal tissues. Following GO and KEGG analysis of Septin9 target genes, we discovered their significant associations with ncRNA metabolic processes, ribonucleoprotein complex biogenesis, spliceosomes, and viral carcinogenesis. Furthermore, the overexpression of mSeptin9 was observed in CRC tissues, and it demonstrated a correlation with colon cancer staging and histologic classification. In our clinical sample study, The positive rate of mSEPT9 in CRC patients 7 days after surgery was 43.44% lower than that of preoperative. The differences in TNM stage, tumor differentiation degree, and preoperative CEA expression level between the preoperative mSEPT9 positive and negative groups of CRC were statistically significant (P < 0.05). Recurrence free survival (RFS) and overall survival (OS) were shorter in the preoperative mSEPT9-positive group, meaning preoperative mSEPT9 status was a risk factor for CRC recurrence and prognosis (P < 0.05). The sensitivity, specificity, and AUC value of preoperative mSEPT9 and CEA levels for predicting postoperative recurrence in CRC patients were 88% vs. 72%, 56.19% vs. 55.24%, and 0.721 vs. 0.636 respectively, well the AUC value of the combined prediction of postoperative recurrence was 0.758. Conclusion: The detection of mSEPT9 combined with CEA in preoperative plasma helps predict recurrence in colorectal cancer patients. [ABSTRACT FROM AUTHOR]

Aim: This study aimed to investigate the causes and risk factors of colorectal cancer (CRC) in a Turkish population, focusing on various modifiable and nonmodifiable risk factors. Methods: A hospital-based case-control design was employed to compare individuals with CRC (cases) to individuals without CRC (controls). Male and female participants were recruited from the surgery, internal medicine, and outpatient departments. The study encompassed socio-demographic data, clinical information, radiological diagnoses, and biochemical measurements. Univariable and multivariable logistic regressions were used to determine associated risk factors of CRC. Results: The study included 704 individuals with CRC and 704 controls. Significant socio-demographic disparities were observed between the groups, with over 30% of the cases having lower levels of education and income compared to the controls. Lifestyle factors such as obesity, higher rates of smoking (cigarettes and hookah) and alcohol consumption were more prevalent among cases than controls. Further significant associations were identified with intestinal inflammation, obesity, processed food consumption, and symptoms such as abdominal pain, cramps, diarrhea, constipation, blood in stool, bloating, irritable bowel syndrome, nausea/vomiting, anemia, stress, fatigue, weakness, and weight loss. Diet analysis revealed that individuals with CRC consumed more red meat, processed and fast foods along with less pulses and vegetables. Genetic predispositions and exposure to chemicals also correlated strongly with increased CRC risk. Multivariable regression analysis identified, nausea/vomiting, constipation, intestinal disease, genetics factor, hookah-nargileh use, history of any cancer, family history of bowel cancer, constipation, cigarette smoking, stress, milk-yogurt consumption, obesity and red meat consumption as significant determinants for CRC. Conclusion: CRC risk is influenced by dietary, lifestyle, and genetic factors. Awareness of hereditary risk and participation in screening are crucial. Lifestyle changes, such as avoiding smoking, hookah, and alcohol use, and adopting a healthy diet, are essential for prevention. [ABSTRACT FROM AUTHOR]

FOLFOX, composed of 5-FU, oxaliplatin and leucovorin, is a first line chemotherapy regimen for colorectal cancer (CRC) treatment. In this study, we show that 5-FU and oxaliplatin induce DNA damage and activate cGAS/STING signaling leading to enhanced expression of interferon (IFN) b, IFN-stimulated genes and inflammatory cytokines in mouse and human colon cancer cells as well as increased intratumoral CD8+ T cells in mice. Crucially, 5-FU and oxaliplatin increase PD-L1 expression at the mRNA and protein levels, which has been shown to inhibit CD8+ T cell function. Depletion of cGAS, STING, IRF3, or IFNa/b receptor 1 (IFNAR1) abolishes this increase, indicating that 5-FU/oxaliplatin mediated upregulation of PD-L1 expression is dependent on tumor cell intrinsic cGAS/STING signaling. These results imply opposing roles for FOLFOX during cancer treatment. On one hand, 5-FU and oxaliplatin activate the innate immune response to facilitate anti-tumor immunity, and conversely upregulate PD-L1 expression to evade immune surveillance. Analysis of TCGA colon cancer dataset shows a positive correlation between expression of PD-L1 and components of the cGAS/STING pathway, supporting a role for cGAS/STING signaling in upregulating PD-L1 expression in colon cancer patients. Tumor studies in syngeneic immune competent mice demonstrate that the combination of 5-FU/oxaliplatin and anti-PD-1 significantly reduced tumor growth of colon cancer cells compared to 5-FU/oxaliplatin treatment alone. Taken together, our studies have identified a unique pathway leading to chemoresistance and provide a rationale to combine FOLFOX with anti-PD-1/PD-L1 as an effective CRC treatment. [ABSTRACT FROM AUTHOR]

Background: Segmental absence of intestinal musculature (SAIM) is a partial defect of intestinal muscularis propria without diverticulum. Many reports indicate that the increase in intestinal pressure caused by enemas or endoscopic examinations leads to bowel perforation, but there are few reports involving malignant tumors. Moreover, few reports have had good outcomes after performing one-stage intestinal anastomosis. Case presentation: A 60-year-old male came to the office with right-side abdominal pain, and was diagnosed with acute generalized peritonitis caused by ascending colon perforation. Emergency laparotomy was performed, and oval and smooth perforation at the ascending colon was observed, which caused ascites with feces. In addition, there was a tumor on the distal side. The terminal ileum was not dilated, so the cause of the perforation was more likely the SAIM-related thin intestinal wall rather than increased internal intestinal pressure due to obstruction of the tumor. Therefore, a right hemicolectomy with functional end-to-end anastomosis (FEEA) between the ascending colon and ileum was performed, rather than creating a stoma. On pathological examination, the resected bowel segments had a partial defect of intestinal muscularis propria around the perforation, leading to the diagnosis of SAIM. The patient had a favorable postoperative course without anastomotic issues and was discharged safely. Conclusions: This case implies that initial intestinal anastomosis can be performed without creating a stoma when SAIM is suspected from the shape of the perforation and proximal intestine. This case report suggests surgeons should keep SAIM in mind during operations for colon perforations. [ABSTRACT FROM AUTHOR]

Background: Solute Carrier Family 4 Member 4 (SLC4A4) is a membrane protein‐coding gene for a Na+/HCO3− cotransporter and plays a crucial role in regulating pH, bicarbonate secretion and homeostasis. However, the prognostic and immunological role of SLC4A4 in colon cancer remains unknown. Method: In this study, expression profiles of SLC4A4 were retrieved from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, to which a variety of bioinformatic analyses were performed. Sangerbox, Xiantao, ESTIMATE and TIMER online tools were used to delve into the relationship between SLC4A4 expression and immune cell infiltration. The role of SLC4A4 in the proliferation and migration of colon cancer cells was verified by CCK8, EdU and wound healing assays. The related molecules and pathways that SLC4A4 may affect were validated by bioinformatic prediction and western blotting analysis. Results: The expression levels of SLC4A4 were significantly lower in colon cancer tissues than in normal tissues and its low expression was positively correlated with poor prognosis. TIMER and ESTIMATE showed that SLC4A4 broadly influenced immune cell infiltration. Experiments in vitro demonstrated that SLC4A4 inhibited partial epithelial-mesenchymal transition (EMT) phenotypes. Conclusions: To conclude, our study revealed that SLC4A4 is lowly expressed in colon cancer tissues, and SLC4A4 may inhibit the progression of colon cancer via regulating partial EMT phenotypes and immune cell infiltration, which may provide new perspectives for the development of more precise and personalized immune anti-tumor therapies. [ABSTRACT FROM AUTHOR]

Background: The study aimed to compare the clinical outcomes of robotic right colectomy (RRC) versus laparoscopic right colectomy (LRC) in patients diagnosed with right colon cancer, given the increasing adoption of robotic surgical techniques and their potential benefits in oncologic surgery. Methods: This retrospective comparative study included patients who underwent right colectomy at Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, between January 2019 and May 2022. The primary outcomes measured were the number of lymph nodes harvested. Key secondary outcomes included the operation time, intraoperative blood loss, postoperative complications, hospitalization costs, overall survival (OS), and disease-free survival (DFS). Data were analyzed using multivariable Cox proportional hazards regression to adjust for potential confounders. Results: A total of 225 patients (aged 65.23 ± 11.45, 108 males) with right colon cancer were included, with 100 (44.4%) patients underwent RRC. Patients who underwent RRC had significantly more lymph nodes harvested (27.69 ± 12.59 vs. 24.43 ± 9.42, P = 0.028), and incurred higher total hospitalization costs compared to those with LRC (9.68 ± 7.12 vs. 5.28 ± 1.23 ten-thousand-yuan, P < 0.001). The OS and DFS were comparable between RRC and LRC (both P > 0.05) within a median follow-up of 27 (range, 9–44) months. Multivariable cox proportional hazards regression showed that patients underwent RRC had significantly higher risk for all-cause death compared with those underwent LRC [hazards ratio (HR) = 2.303, 95% confidence intervals (CI): 1.625–3.265, P < 0.001]. Conclusion: Patients underwent RRC seemed to have significantly more numbers of lymph nodes harvested and higher risk for all-cause death and higher hospitalization costs compared with those underwent LRC. These findings suggest a need for careful consideration of the benefits and risks associated with robotic versus laparoscopic right colectomy in clinical practice. Trial registration: Not applicable. [ABSTRACT FROM AUTHOR]

The quest to understand the molecular mechanisms of tumour metastasis and identify pivotal biomarkers for cancer therapy is increasing in importance. Single-omics analyses, constrained by their focus on a single biological layer, cannot fully elucidate the complexities of tumour molecular profiles and can thus overlook crucial molecular targets. In response to this limitation, we developed a multiobjective recommendation system (RJH-Metastasis 1.0) anchored in a multiomics knowledge graph to integrate genome, transcriptome, and proteome data and corroborative literature evidence and then conducted comprehensive analyses of colorectal cancer with liver metastasis (CRCLM). A total of 25 key genes significantly associated with CRCLM were recommended by our system, and GNB1, GATAD2A, GBP2, MACROD1, and EIF5B were further highlighted. Specifically, GNB1 presented fewer mutations but elevated RNA transcription and protein expression in CRCLM patients. The role of GNB1 in promoting the malignant behaviours of colon cancer cells was demonstrated via in vitro and in vivo studies. Aberrant expression of GNB1 could be regulated by METTL1-driven m7G modification. METTL1 knockdown decreased m7G modification in the 3' UTR of GNB1, increasing its mRNA transcription and translation during liver metastasis. Furthermore, GNB1 induced the formation of an immunosuppressive microenvironment by promoting the CLEC2C-KLRB1 interaction between memory B cells and KLRB1+PD-1+CD8+ cells. GNB1 expression and the efficacy of PD-1 antibody-based treatment in CRCLM patients were significantly correlated. In summary, our recommendation system can be used for effective exploration of key molecules in colorectal cancer, among which GNB1 was identified as a critical CRCLM promoter and immunotherapy biomarker in colorectal cancer patients. [ABSTRACT FROM AUTHOR]

Metastasis and recurrence are the main challenges in cancer treatment. Among various therapeutic approaches, immunotherapy holds promise for preventing metastasis and recurrence. In this study, we evaluated the efficacy of treating primary cancer and blocking metastasis and recurrence with photo-immunotherapeutic nanoparticles, which were synthesized using two types of charged polysaccharides. Codium fragile polysaccharide (CFP), which exhibits immune-stimulating properties and carries a negative charge, was combined with positively charged chitosan to synthesize nanoparticles. Additionally, indocyanine green (ICG), a photosensitizer, was loaded inside these particles and was referred to as chitosan-CFP-ICG (CC-ICG). Murine colon cancer cells (CT-26) internalized CC-ICG, and subsequent 808-nanometer laser irradiation promoted apoptotic/necrotic cell death. Moreover, intratumoral injection of CC-ICG, with 808-nanometer laser irradiation eliminated CT-26 tumors in mice. Rechallenged lung metastases of CT-26 cancer were inhibited by dendritic cell activation-mediated cytotoxic T lymphocyte stimulation in mice cured by CC-ICG. These results demonstrated that CC-ICG is a natural tumor therapeutic with the potential to treat primary tumors and suppress metastasis and recurrence. [ABSTRACT FROM AUTHOR]

Background: Cancer and diabetes mellitus are quite common diseases found together worldwide. A considerable amount of evidence is available for the rapid development and presentation of various types of cancer in the type 2 diabetes mellitus (DM2) population as compared with the population without diabetes. The objective of the study is to formulate and evaluate 5-fluorouracil (5-FU) and metformin (MET) nanoparticles (NPs) and to establish the characteristic features of the biodegradable NPs. 5-FU and MET NPs with chitosan as a biodegradable polymer were formulated by the ionotropic cross-linking method. 0.25 gm of MET and 0.25 gm of 5-FU were dissolved in 100 ml of distilled water, and stock solution was prepared. 5 ml of stock solution was slowly mixed into the chitosan solution to obtain the mixture of drugs and chitosan. The tripolyphosphate reserve liquid was dripped slowly into the chitosan solution with constant stirring until the opaline appearance was noticed in the mixture, then filtered, and dried. The NPs were evaluated for their physical properties and drug release kinetics. Cell proliferation assay was done using human colorectal carcinoma cell line (HCT 116). Results: The formulation composed of 1.5 w/v of chitosan, 0.25 w/v of MET, and 5-FU had an average particle diameter of 198.7 nm. The polydispersity index was 0.757. Thermal and infrared spectroscopy results indicated the drugs and polymers selected for the formulation were unique without any identifiable interaction. The NPs were spherical in appearance, with numerous pours on the surface, which was evident when microscopically examined. Uniformity in drug release was observed, and the formulation demonstrated excellent release kinetics. HTC 116 cell line confirmed that the maximum percentage of cell death and minimum viability of cells were observed while using the combination of MET and 5-FU-NPs as compared to the pure MET or 5-FU alone. Conclusion: MET and 5-FU-loaded chitosan NPs were found to have excellent physiochemical properties, particle size, and drug release from the polymer in a controlled manner. Half-maximal inhibitory concentration value (IC50) of MET and 5-FU-NPs was found to be significantly less as compared to MET and 5-FU alone or the combination. [ABSTRACT FROM AUTHOR]

The interplay between gut microbiota and host is crucial for maintaining host health. When this balance is broken, various diseases can arise, including colorectal cancer (CRC). However, the mechanism by which gut microbiota and host interactions mediate CRC development remains unclear. Here, we found that Gasdermin D (GSDMD), an inflammasome effector responsible for forming membrane pores to mediate cell pyroptosis, was upregulated in both human and mouse intestinal tumor samples. GSDMD deficiency significantly suppressed intestinal tumor development in Apcmin/+ mice, a spontaneous CRC mouse model. Apcmin/+Gsdmd−/− mice exhibited reduced IL-1β release in the intestine, and the administration of recombinant mouse IL-1β partially restored intestinal tumor development in Apcmin/+Gsdmd−/− mice. Moreover, 16s rRNA sequencing showed a substantial increase in Lactobacillus abundance in the feces of Apcmin/+Gsdmd−/− mice compared to Apcmin/+ mice. Concurrently, Kynurenine (Kyn), a metabolite derived from host tryptophan (Trp) metabolism, was significantly decreased in the feces of Apcmin/+Gsdmd−/− mice, as shown by metabolite analysis. Additionally, Kyn levels were inversely correlated with Lactobacillus abundance. Furthermore, the administration of exogenous Kyn also promoted intestinal tumor development in Apcmin/+Gsdmd−/− mice. Thus, GSDMD promotes spontaneous CRC development through increasing IL-1β release and Kyn production. Our data suggest an association between GSDMD, gut microbiota, the host Trp/Kyn pathway, and CRC development. [ABSTRACT FROM AUTHOR]

The majority of bispecific costimulatory antibodies in cancer immunotherapy are capable of exerting tumor-specific T-cell activation by simultaneously engaging both tumor-associated targets and costimulatory receptors expressed by T cells. The amount of trimeric complex formed when the bispecific antibody is bound simultaneously to the T cell receptor and the tumor-associated target follows a bell-shaped curve with increasing bispecific antibody exposure/dose. The shape of the curve is determined by the binding affinities of the bispecific antibody to its two targets and target expression. Here, using the case example of FAP-4-1BBL, a fibroblast activation protein alpha (FAP)-directed 4-1BB (CD137) costimulator, the impact of FAP-binding affinity on trimeric complex formation and pharmacology was explored using mathematical modeling and simulation. We quantified (1) the minimum number of target receptors per cell required to achieve pharmacological effect, (2) the expected coverage of the patient population for 19 different solid tumor indications, and (3) the range of pharmacologically active exposures as a function of FAP-binding affinity. A 10-fold increase in FAPbinding affinity (from a dissociation constant [KD] of 0.7 nM-0.07 nM) was predicted to reduce the number of FAP receptors needed to achieve 90% of the maximum pharmacological effect from 13,400 to 4,000. Also, the number of patients with colon cancer that would achieve 90% of the maximum effect would increase from 6% to 39%. In this work, a workflow to select binding affinities for bispecific antibodies that integrates preclinical in vitro data, mathematical modeling and simulation, and knowledge on target expression in the patient population, is provided. The early implementation of this approach can increase the probability of success with cancer immunotherapy in clinical development. [ABSTRACT FROM AUTHOR]

Introduction: Self-antigens abnormally expressed on tumors, such as MUC1, have been targeted by therapeutic cancer vaccines. We recently assessed in two clinical trials in a preventative setting whether immunity induced with a MUC1 peptide vaccine could reduce high colon cancer risk in individuals with a history of premalignant colon adenomas. In both trials, there were immune responders and non-responders to the vaccine. Methods: Here we used PBMC pre-vaccination and 2 weeks after the first vaccine of responders and non-responders selected from both trials to identify early biomarkers of immune response involved in long-term memory generation and prevention of adenoma recurrence. We performed flow cytometry, phosflow, and differential gene expression analyses on PBMCs collected from MUC1 vaccine responders and non-responders pre-vaccination and two weeks after the first of three vaccine doses. Results: MUC1 vaccine responders had higher frequencies of CD4 cells prevaccination, increased expression of CD40L on CD8 and CD4 T-cells, and a greater increase in ICOS expression on CD8 T-cells. Differential gene expression analysis revealed that iCOSL, PI3K AKT MTOR, and B-cell signaling pathways are activated early in response to the MUC1 vaccine. We identified six specific transcripts involved in elevated antigen presentation, B-cell activation, and NFkB1 activation that were directly linked to finding antibody response at week 12. Finally, a model using these transcripts was able to predict non-responders with accuracy. Discussion: These findings suggest that individuals who can be predicted to respond to the MUC1 vaccine, and potentially other vaccines, have greater readiness in all immune compartments to present and respond to antigens. Predictive biomarkers of MUC1 vaccine response may lead to more effective vaccines tailored to individuals with high risk for cancer but with varying immune fitness. [ABSTRACT FROM AUTHOR]

The increasing prevalence of colon and lung cancer presents a considerable challenge to healthcare systems worldwide, emphasizing the critical necessity for early and accurate diagnosis to enhance patient outcomes. The precision of diagnosis heavily relies on the expertise of histopathologists, constituting a demanding task. The health and well‐being of patients are jeopardized in the absence of adequately trained histopathologists, potentially leading to misdiagnoses, unnecessary treatments, and tests, resulting in the inefficient utilization of healthcare resources. However, with substantial technological advancements, deep learning (DL) has emerged as a potent tool in clinical settings, particularly in the realm of medical imaging. This study leveraged the LC25000 dataset, encompassing 25,000 images of lung and colon tissue, introducing an innovative approach by employing a self‐organized operational neural network (Self‐ONN) to accurately detect lung and colon cancer in histopathology images. Subsequently, our novel model underwent comparison with five pretrained convolutional neural network (CNN) models: MobileNetV2‐SelfMLP, Resnet18‐SelfMLP, DenseNet201‐SelfMLP, InceptionV3‐SelfMLP, and MobileViTv2_200‐SelfMLP, where each multilayer perceptron (MLP) was replaced with Self‐MLP. The models' performance was meticulously assessed using key metrics such as precision, recall, F1 score, accuracy, and area under the receiver operating characteristic (ROC) curve. The proposed model demonstrated exceptional overall accuracy, precision, sensitivity, F1 score, and specificity, achieving 99.74%, 99.74%, 99.74%, 99.74%, and 99.94%, respectively. This underscores the potential of artificial intelligence (AI) to significantly enhance diagnostic precision within clinical settings, portraying a promising avenue for improving patient care and outcomes. The synopsis of the literature provides a thorough examination of several DL and digital image processing methods used in the identification of cancer, with a primary emphasis on lung and colon cancer. The experiments use the LC25000 dataset, which consists of 25,000 photos, for the purposes of training and testing. Various techniques, such as CNNs, transfer learning, ensemble models, and lightweight DL architectures, have been used to accomplish accurate categorization of cancer tissue. Various investigations regularly show exceptional performance, with accuracy rates ranging from 96.19% to 99.97%. DL models such as EfficientNetV2, DHS‐CapsNet, and CNN‐based architectures such as VGG16 and GoogleNet variations have shown remarkable performance in obtaining high levels of accuracy. In addition, methods such as SSL and lightweight DL models provide encouraging outcomes in effectively managing large datasets. In general, the research emphasizes the efficacy of DL methods in successfully diagnosing cancer from histopathological pictures. It therefore indicates that DL has the potential to greatly improve medical diagnostic techniques. [ABSTRACT FROM AUTHOR]

The application of immunotherapy for treating colorectal cancer (CRC) is currently a research hotspot, and neoadjuvant immunotherapy has shown initial success in treating CRC. The watch-and-wait (W&W) approach is often used after achieving a clinical complete response (cCR) following preoperative treatment of low rectal cancer. However, thus far, the W&W approach has not been reported for patients with colon cancer. Here, we report the case of a 64-year-old patient with heterogeneous multigenic CRC who achieved cCR after five sessions of neoadjuvant immunotherapy before surgery. A W&W approach was used to spare the patient from surgery. A 64-year-old male presented with intermittent abdominal pain. A colonoscopy examination detected an irregular cauliflower-like mass near the hepatic flexure of the ascending colon. The biopsy results indicated adenocarcinoma of the ascending colon. The patient was administered pembrolizumab (200 mg, ivgtt, q3w). After one cycle of treatment, the intestinal obstruction symptoms disappeared, and the treatment was continued for additional three sessions. After complete clinical remission of the tumor was confirmed, the W&W approach was adopted. Follow-up CT scans and colonoscopy examinations confirmed no local tumor regeneration or metastasis. Neoadjuvant immunotherapy is effective for patients with DNA mismatch repair gene deficiency and/or microsatellite instability high with a high rate of cCR or pathologic complete response. The W&W approach may also be suitable for patients with colon cancer. The safety and feasibility of watch and wait in patients with colon cancer need to be verified by more clinical data. [ABSTRACT FROM AUTHOR]

Background: To prevent local recurrence caused by exfoliated cancer cells caught in the suture line, intraoperative rectal washout during surgery can be performed to eliminate exfoliated cancer cells. However, the impact of neoadjuvant chemoradiotherapy on exfoliated cancer cells is not well known. This study aimed to identify positive rate of malignant cells in rectal washout fluids of neoadjuvant chemoradiotherapy patients and to determine if neoadjuvant chemoradiotherapy could affect exfoliated cancer cells. Methods: A total of 105 patients who underwent rectal washout intraoperatively for distal sigmoid colon and rectal cancer from April 2020 to September 2021 were analyzed. The primary outcome was positive rate of malignant cells in rectal washout fluids of patients who had received neoadjuvant chemoradiotherapy. Results: The positive rate of malignant cells in washout fluids of patients who had received neoadjuvant chemoradiotherapy was 0.0% and those who had not was 32.1%. The overall positive rate was 23.8%. In the positive group, tumor sizes were bigger (4.64 ± 1.68 cm vs. 3.64 ± 2.00 cm, p = 0.026) and more patients had a fungating tumor shown in preoperative colonoscopy (96.0% vs. 71.3%, p = 0.012). Although these factors did not show statistical significance in multivariable logistic regression analysis, fungating tumor showed a trend towards significance (OR: 7.28, 95% CI: 0.90-58.77, p = 0.063). Conclusions: Our study suggests that neoadjuvant chemoradiotherapy could reduce exfoliated cancer cells, and rectal washout for the purpose of eliminating exfoliated cancer cells might be unnecessary in patients who have received neoadjuvant chemoradiotherapy. [ABSTRACT FROM AUTHOR]

Background: Research on circulating tumor cells (CTCs) offers the opportunity to better understand the initial steps of blood‐borne metastasis as main cause of cancer‐related deaths. Here, we have used the colon cancer CTC‐MCC‐41 and breast cancer CTC‐ITB‐01 lines, which were both established from human CTCs as permanent cell lines as models to further study CTC biology with special emphasis on anchorage‐independent survival and growth. Methods and Results: Both cell lines showed a marked intrinsic plasticity to switch between suspension and adherent in vitro growth, in 2D adherent culture conditions, and established an equilibrium of both growth patterns with predominant adherent cells in the CTC‐MCC‐41 line (77%) and suspension cells in the CTC‐ITB‐01 line (85%). Western blot analysis revealed a higher expression of pERK1/2 in CTC‐ITB‐01 adherent cells compared to the suspension counterpart that suggested the involvement of kinases in this process. Subsequent functional kinome profiling identified several serine/threonine as well as tyrosine kinases that were differentially regulated in adherent and suspension CTCs. In the adherent cells of the breast cancer line CTC‐ITB‐01 the activity of MSK1, Src family kinases and the PKG family was increased compared to the suspension counterpart. In adherent cells of the colorectal CTC‐MCC‐41 line, an increased activity of TYRO3 and JAK2 was detected, whereas p38 MAPK was strongly impaired in the suspension CTC‐MCC‐41 cells. Some of the regulated kinases, which include the Src family, TYRO3, MSK1, JAK2 and p38 MAPK, have been associated with crucial cellular processes including proliferation, migration and dormancy in the past. Conclusions: The investigated CTC lines exhibit a high plasticity, similar to the concept of 'adherent‐to‐suspension transition (AST)' that was recently suggested as a new hallmark of tumor biology by Huh et al. Moreover, we identified differentially regulated kinome profiles that may represent potential targets for future studies on therapeutic interventions. [ABSTRACT FROM AUTHOR]

Background: In recent years, the healthcare field has experienced significant advancements. New diagnostic techniques, treatments, and insights into the causes of various diseases have emerged. Despite these progressions, cancer remains a major concern. It is a widespread illness affecting individuals of all ages and leads to one out of every six deaths. Lung and colon cancer alone account for nearly two million fatalities. Though it is rare for lung and colon cancers to co-occur, the spread of cancer cells between these two areas—known as metastasis—is notably high. Early detection of cancer greatly increases survival rates. Currently, histopathological image (HI) diagnosis and appropriate treatment are key methods for reducing cancer mortality and enhancing survival rates. Digital image processing (DIP) and deep learning (DL) algorithms can be employed to analyze the HIs of five different types of lung and colon tissues. Methods: Therefore, this paper proposes a refined DL model that integrates feature fusion for the multi-classification of lung and colon cancers. The proposed model incorporates three DL architectures: ResNet-101V2, NASNetMobile, and EfficientNet-B0. Each model has limitations concerning variations in the shape and texture of input images. To address this, the proposed model utilizes a concatenate layer to merge the pre-trained individual feature vectors from ResNet-101V2, NASNetMobile, and EfficientNet-B0 into a single feature vector, which is then fine-tuned. As a result, the proposed DL model achieves high success in multi-classification by leveraging the strengths of all three models to enhance overall accuracy. This model aims to assist pathologists in the early detection of lung and colon cancer with reduced effort, time, and cost. The proposed DL model was evaluated using the LC25000 dataset, which contains colon and lung HIs. The dataset was pre-processed using resizing and normalization techniques. Results: The model was tested and compared with recent DL models, achieving impressive results: 99.8% for precision, 99.8% for recall, 99.8% for F1-score, 99.96% for specificity, and 99.94% for accuracy. Conclusions: Thus, the proposed DL model demonstrates exceptional performance across all classification categories. [ABSTRACT FROM AUTHOR]

Background: In the present study, we aimed to investigate the association between (EORTC) QLQ-C30 scores and both preoperative somatometric parameters and postoperative outcomes in elderly patients undergoing elective surgery for resectable colorectal cancer. Methods: The 118 elderly consecutive patients who underwent colorectal surgery for cancer in a single university's surgical department between 01/2018 and 12/2018 were prospectively enrolled in the present study. All patients with an age > 65 years, diagnosed with resectable colorectal cancer, without metastatic disease, that underwent elective surgery were included prospectively in the present study. Results: Regarding patients' characteristics, a negative correlation between preoperative QLQ (pQLQ) score and age (p = 0.001) and a positive correlation between body mass index (BMI) and pQLQ score (p = 0.048) were observed. Furthermore, there was a statistically significant difference (p = 0.004) in the mean pQLQ score between patients with rectal or colon cancer. Moreover, assessing pQLQ score was a useful tool in terms of postoperative recovery. Negative correlations between the pQLQ score and time (days) of beginning oral feeding (p < 0.001) and length of hospital stay (p = 0.004) were found. The pQLQ score was statistically significantly lower (p = 0.005) in patients who had any postoperative complication; however, there was no difference in patients with major complications. Conclusions: Advanced age, colon cancer and decreased BMI were negatively associated with preoperative QLQ. The assessment of pQLQ in elderly patients with colorectal cancer can be a useful predictive tool for postoperative complications, length of hospital stay and postoperative rehabilitation. [ABSTRACT FROM AUTHOR]

Patients with chronic myeloid leukemia (CML) respond to tyrosine kinase inhibitors (TKIs); however, CML leukemic stem cells (LSCs) exhibit BCR::ABL kinase-independent growth and are insensitive to TKIs, leading to disease relapse. To prevent this, new therapies targeting CML-LSCs are needed. Rates of mitochondria-mediated oxidative phosphorylation (OXPHOS) in CD34+CML cells within the primitive CML cell population are higher than those in normal undifferentiated hematopoietic cells; therefore, the inhibition of OXPHOS in CML-LSCs may be a potential cure for CML. NK-128 (C33H61NO5S) is a structurally simplified analog of JCI-20679, the design of which was based on annonaceous acetogenins. NK-128 exhibits antitumor activity against glioblastoma and human colon cancer cells by inhibiting OXPHOS and activating AMP-activated protein kinase (AMPK). Here, we demonstrate that NK-128 effectively suppresses the growth of CML cell lines and that the combination of imatinib and NK-128 is more potent than either alone in a CML xenograft mouse model. We also found that NK-128 inhibits colony formation by CD34+ CML cells isolated from the bone marrow of untreated CML patients. Taken together, these findings suggest that targeting OXPHOS is a beneficial approach to eliminating CML-LSCs, and may improve the treatment of CML. [ABSTRACT FROM AUTHOR]

Colorectal cancer CRC remains one of the leading causes of cancer-related deaths worldwide, with chronic intestinal inflammation identified as a major risk factor. Notably, the tumor suppressor TP53 undergoes mutation at higher rates and earlier stages during human inflammation-driven colon tumorigenesis than in sporadic cases. We investigated whether deleting Trp53 affects inflammation-induced tumor growth and the expression of Lgr5+ cancer stem cells in mice. We examined azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colon tumorigenesis in wild-type Trp53 (+/+), heterozygous (+/−), and knockout (−/−) mice. Trp53−/− mice showed increased sensitivity to DSS colitis and earlier accelerated tumorigenesis with 100% incidence. All groups could develop invasive tumors, but knockouts displayed the most aggressive features. Unlike wild-type CRC, knockouts selectively showed increased populations of Lgr5+ colon cancer stem-like cells. Trp53 loss also boosted laminin, possibly facilitating the disruption of the tumor border. This study highlights how Trp53 deletion promotes the perfect storm of inflammation and stemness, driving colon cancer progression. Trp53 deletion dramatically shortened AOM/DSS latency and improved tumor induction efficiency, offering an excellent inflammation-driven CRC model. [ABSTRACT FROM AUTHOR]

The initial step in pre-mRNA splicing involves formation of a spliceosome commitment complex (CC) or E-complex by factors that serve to bind and mark the exon-intron boundaries that will undergo splicing. The CC component U1 snRNP assembles at the 5′-splice site (ss), whereas SF1, U2AF2, and U2AF1 define the 3′-ss of the intron. A PRP40 protein bridges U1 snRNP with factors at the 3′-ss. To determine how defects in CC components impact cancers, we analyzed human gastrointestinal (GI) cancer patient tissue and clinical data from cBioPortal. cBioPortal datasets were analyzed for CC factor alterations and patient outcomes in GI cancers (bowel, stomach, esophagus, pancreas, and liver). In addition, co-expression datasets were used to determine the splicing targets of the CC. Our analysis found that frequency of genetic changes was low (1%-13%), but when combined with changes in expression levels, there was an overall surprisingly high incidence of CC component (>30%) alterations in GI cancers. Colon cancer patients carrying BRAF driver gene mutations had high incidences of CC alterations (19%-61%), whereas patients with APC, KRAS, or TP53 gene mutations had low (<5%) incidences of CC alterations. Most significantly, patients with mutations in CC genes exhibited a consistent trend of favorable survival rates, indicating that mutations that impair or lower CC component expression favor patient survival. Conversely, patients with high CC expression had worse survival. Pathway analysis indicates that the CC regulates specific metabolic and tumor suppressor pathways. Metabolic pathways involved in cell survival, nutrition, biosynthesis, autophagy, cellular movement (invasion), or immune surveillance pathways correlated with CC factor upregulation, whereas tumor suppressor pathways, which regulate cell proliferation and apoptosis, were inversely correlated with CC factor upregulation. This study demonstrates the versatility of in silico analysis to determine molecular function of large macromolecular complexes such as the spliceosome CC. Furthermore, our analysis indicates that therapeutic lowering of CC levels in colon cancer patients may enhance patient survival. [ABSTRACT FROM AUTHOR]

The food coloring agent E171 raises many questions concerning its negative impact on human health because of the fact that it contains nanoparticle fractions (NPs, diameter < 100 nm). Numerous studies showed its influence on organisms, including the ability to disrupt the intestinal barrier. In the present study, we verified the potential toxicity and pro-inflammatory activity of three different E171 samples (containing NPs fractions) and one TiO2 NPs sample (60–600 µg mL−1) towards Caco-2 colon cancer cells. The experiments revealed no significant changes in terms of the vitality of Caco-2 cells after 24 h of exposure (XTT test). However, after 72 h, a decrease in the proliferation of Caco-2 cells caused by three TiO2 substances was observed. Moreover, deterioration of the metabolic activity of Caco-2 cells (ATP test) by all analyzed substances at 300 and 600 µg mL−1 was seen. While a 24-h exposure to each tested substance resulted in a negligible release of LDH, a prolonged exposure (72 h) indicated an elevated release of LDH, suggesting potential toxicity. All TiO2 samples induced the elevated release of two primary proinflammatory cytokines, i.e., IL-1β and TNF-α, in a dose-independent manner. The discrepancies in the results come from the differences in the share of individual sizes in four TiO2 products. [ABSTRACT FROM AUTHOR]

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Background: Cellular senescence (CS) is believed to be a major factor in the evolution of cancer. However, CS-related lncRNAs (CSRLs) involved in colon cancer regulation are not fully understood. Our goal was to create a novel CSRLs prognostic model for predicting prognosis and immunotherapy and exploring its potential molecular function in colon cancer. Methods: The mRNA sequencing data and relevant clinical information of GDC TCGA Colon Cancer (TCGA-COAD) were obtained from UCSC Xena platform, and CS-associated genes was acquired from the CellAge website. Pearson correlation analysis was used to identify CSRLs. Then we used Kaplan-Meier survival curve analysis and univariate Cox analysis to acquire prognostic CSRL. Next, we created a CSRLs prognosticmodel using LASSO andmultivariate Cox analysis, and evaluated its prognostic power by Kaplan-Meier and ROC curve analysis. Besides, we explored the difference in tumor microenvironment, somatic mutation, immunotherapy, and drug sensitivity between high-risk and low-risk groups. Finally, we verified the functions of MYOSLID in cell experiments. Results: Three CSRLs (AC025165.1, LINC02257 and MYOSLID) were identified as prognostic CSRLs. The prognostic model exhibited a powerful predictive ability for overall survival and clinicopathological features in colon cancer. Moreover, there was a significant difference in the proportion of immune cells and the expression of immunosuppressive point biomarkers between the different groups. The high-risk group benefited from the chemotherapy drugs, such as Teniposide and Mitoxantrone. Finally, cell proliferation and CS were suppressed after MYOSLID knockdown. Conclusion: CSRLs are promising biomarkers to forecast survival and therapeutic responses in colon cancer patients. Furthermore, MYOSLID, one of 3-CSRLs in the prognostic model, could dramatically regulate the proliferation and CS of colon cancer. [ABSTRACT FROM AUTHOR]

Background: Ubiquitination, a major post-translational modification, significantly impacts tumorigenesis, progression, and prognosis. This study aims to classify colon cancer at the molecular level and create a reliable signature using ubiquitination-related genes (URGs) to assess the immune microenvironment and prognosis. Methods: We employed non-negative matrix factorization to subtype colon cancer based on ubiquitination-related gene (URG) expression patterns. Quantitative scores for 28 immune cell infiltrates and the tumor microenvironment were computed using single-sample gene set enrichment analysis (ssGSEA) and the Estimate algorithm. Subtype feature genes were selected through Lasso logistic regression and SVM-RFE algorithm. The ubiquitination-related signature was constructed using univariate Cox, Lasso, and stepwise regression methods to categorize patients into high and low-risk groups. Validation included log-rank tests, receiver operating characteristic (ROC) analysis, decision curve analysis (DCA), and external dataset validation. Immune therapy response was compared using Tumor Immune Dysfunction and Exclusion (TIDE), Immunophenoscore (IPS), and submap analyses. Clinical variables and risk scores were integrated into an enhanced nomogram. The early diagnostic value of four URGs was confirmed via quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry. The cell proliferation was assessed through colony formation, EdU staining, and xenograft tumorigenesis assays. Results: Prognostic ubiquitination-related genes (URGs) stratified patients into subtypes, revealing differences in survival, immune cell infiltration, and pathological staging. A signature of 6 URGs (ARHGAP4, MID2, SIAH2, TRIM45, UBE2D2, WDR72) was identified from 57 subtype-related genes. The high-risk group exhibited characteristics indicative of enhanced epithelial-mesenchymal transition, immune escape, immunosuppressive myeloid-derived suppressor cells, regulatory T cell infiltration, and lower immunogenicity. In contrast, the low-risk group demonstrated the opposite trend but showed a better response to CTLA4 checkpoint inhibitors. The predictive performance of the nomogram significantly improved with the integration of risk score, stage, and age ARHGAP4 and SIAH2 exhibit promising early diagnostic capabilities. Additionally, WDR72 knockdown significantly inhibited CRC cell proliferation both in vitro and in vivo. Conclusion: Our developed ubiquitination-related signature and genes serve as promising biomarkers for colon cancer prognosis, immune microenvironment, and diagnosis. [ABSTRACT FROM AUTHOR]

Death receptor (DR) networks are controlled by the assembly of the Death-Inducing Signaling Complex (DISC) and complex II. The family of small molecules FLIPins (FLIP interactors) were developed to target the caspase-8/c-FLIPL heterodimer. FLIPin compounds were shown to promote apoptosis and caspase-8 activation at the DISC upon stimulation with death ligands (DLs) such as CD95L and TRAIL. To further investigate the role of FLIPin compounds in the DL-mediated cell death response, we analyzed their effects in combination with DLs and SMAC mimetics treatment. FLIPins were found to enhance cell viability loss and cell death induced by DL and SMAC mimetics in acute myeloid leukemia (AML), colon and pancreatic cancer cells. FLIPins enhanced both DL/BV6-induced apoptosis and DL/BV6/zVAD-fmk-induced necroptosis via an increase in complex II formation. Our results indicate that targeting the caspase-8/c-FLIPL heterodimer plays a prominent role in enhancing cell death induced by co-stimulation of DL/SMAC mimetics and opens new therapeutic strategies for targeting DR networks. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to investigate the molecular links and mechanisms between Crohn's disease (CD) and colorectal cancer (CRC). Methods: This study used the Gene Expression Omnibus (GEO) database to identify Differentially expressed genes (DEGs) in CD (GSE112366) and CRC (GSE110224), analyzed by 'edgeR' and 'limma'. The Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes explored DEG functions, and the Search Tool for the Retrieval of Interacting Genes (STRING) informed the protein–protein interaction network construction visualized in Cytoscape (version 3.7.2). Cyto-Hubba identified key genes, whose biomarker potential for CD and CRC was evaluated. Results: The study discovered 61 DEGs, with 44 up- and 17 down-regulated, linked to immune responses and signaling pathways. CXCL1, highly expressed in colon cancer, correlated with better prognosis and lower staging. It also showed associations with immune infiltration and checkpoint molecules, suggesting a role in cancer progression and retreat. Conclusion: CXCL1 may play a role in the development of colorectal cancer from inflammatory bowel disease. [ABSTRACT FROM AUTHOR]

The abundance and biological contribution of natural killer (NK) cells in cancer are controversial. Here, we aim to uncover clinical relevance and cellular roles of NK cells in colon cancer liver metastasis (CCLM). Here, we integrated single- cell RNA- sequencing, spatial transcriptomics (ST), and bulk RNA- sequencing datasets to investigate NK cells' biological properties and functions in the microenvironment of primary and liver metastatic tumors. Results were validated through an in vitro co- culture experiment based on bioinformatics analysis. Useing single- cell RNA- sequencing and ST, we mapped the immune cellular landscape of colon cancer and well- matched liver metastatic cancer. We discovered that GZMK+ resting NK cells increased significantly in tumor tissues and were enriched in the tumor regions of both diseases. After combining bulk RNA and clinical data, we observed that these NK cell subsets contributed to a worse prognosis. Meanwhile, KIR2DL4+ activated NK cells exhibited the opposite position and relevance. Pseudotime cell trajectory analysis revealed the evolution of activated to resting NK cells. In vitro experiments further confirmed that tumor- cell- co- cultured NK cells exhibited a decidual- like status, as evidenced by remarkable increasing CD9 expression. Functional experiments finally revealed that NK cells exhibited tumoractivating characteristics by promoting the dissociation of SCF (stem cell factor) on the tumor cells membrane depending on cell- to- cell interaction, as the supernatant of the co- culture system enhanced tumor progression. In summary, our findings revealed resting NK cells exhibited a clinical relevance with CCLM, which may be exploited for novel strategies to improve therapeutic outcomes for patients with CCLM. [ABSTRACT FROM AUTHOR]

Oncolytic virotherapy is emerging as a promising therapeutic avenue for cancer treatment, harnessing both innate and tumor-specific immune responses for targeted tumor elimination. In this study, we present a novel oncolytic virus (oHSV1-IL15B) derived from herpes simplex virus-1 (HSV-1), armed with IL-15/IL-15Rα complex, with a focus on treating colon cancer combined with oncolytic HSV-1 expressing anti-PD-1 antibody (oHSV1-aPD1). Results from our study reveal that recombinant oHSV-1 virus equipped with IL-15/IL-15Rα complex exhibited significant anti-tumor effects in a murine CT26 colon adenocarcinoma model. Notably, oHSV1-IL15B combined with oHSV-1-aPD1 demonstrates superior tumor inhibition and prolonged overall survival compared to oHSV1-mock and monotherapy groups. Further exploration highlights the impact of oHSV1-IL15B, oHSV-1-aPD1 and combined group on antitumor capacity, revealing a substantial increase in CD8+ T and CD4+ T cell proportions of CT26-bearing BALB/c mice and promoting apoptosis in tumor tissue. The study emphasizes the pivotal role of cytotoxic CD8+T cells in oncolytic virotherapy, demonstrating that recombinant oHSV1-IL15B combined with oncolytic HSV-1-aPD1 induces a robust tumor-specific T cell response. RNA sequence analysis highlighted oHSV1-IL15B combined with oHSV1-aPD1 improved tumors immune microenvironment on immune response, antiviral response-related genes and apoptosis-related genes, which contributed to anti-tumor immunotherapy. The findings underscore the promising antitumor activity achieved through the combination of IL-15/IL-15Rα complex and anti-PD-1 antibody with oHSV-1. This research opens avenues for diverse therapeutic strategies, suggesting the potential of synergistically utilizing cytokines and anti-PD-1 antibody with oncolytic viruses to enhance immunotherapy for cancer management. [ABSTRACT FROM AUTHOR]

Mitotic Arrest Deficient 1 (gene name MAD1L1), an essential component of the mitotic spindle assembly checkpoint, is frequently overexpressed in colon cancer, which correlates with poor disease-free survival. MAD1 upregulation induces two phenotypes associated with tumor promotion in tissue culture cells–low rates of chromosomal instability (CIN) and destabilization of the tumor suppressor p53. Using CRISPR/Cas9 gene editing, we generated a novel mouse model by inserting a doxycycline (dox)-inducible promoter and HA tag into the endogenous mouse Mad1l1 gene, enabling inducible expression of HA-MAD1 following exposure to dox in the presence of the reverse tet transactivator (rtTA). A modest 2-fold overexpression of MAD1 in murine colon resulted in decreased p53 expression and increased mitotic defects consistent with CIN. After exposure to the colon-specific inflammatory agent dextran sulfate sodium (DSS), 31% of mice developed colon lesions, including a mucinous adenocarcinoma, while none formed in control animals. Lesion incidence was particularly high in male mice, 57% of which developed at least one hyperplastic polyp, adenoma or adenocarcinoma in the colon. Notably, mice expressing HA-MAD1 also developed lesions in tissues in which DSS is not expected to induce inflammation. These findings demonstrate that MAD1 upregulation is sufficient to promote colon tumorigenesis in the context of inflammation in immune-competent mice. Author summary: Worldwide, colorectal cancer is the third most commonly diagnosed cancer and the second-highest cause of cancer-related deaths. A better understanding of the molecular causes of colorectal cancer could provide novel therapeutic targets for this disease. Mitotic Arrest Deficient-1 (MAD1) is commonly overexpressed in colorectal cancers, and elevated expression of MAD1 is associated with worse prognosis. Here we generated a new mutant mouse with inducible, modest overexpression of MAD1. First identified for its role in mitosis, MAD1 is required to ensure proper chromosome segregation. Elevated expression of MAD1 causes chromosome mis-segregation in the colons of these mice. During interphase, overexpressed MAD1 destabilizes the well-known tumor suppressor protein, p53. Consistent with this, mouse colons modestly overexpressing MAD1 show decreased expression of p53. Since inflammation is a risk factor for colorectal cancer, we induced inflammation in the colon using dextran sulfate sodium (DSS) and found that MAD1 overexpression significantly increased the incidence of colon tumors. Like inflammation-mediated colon tumors in humans, in the mice these tumors were more common in males than females. This work shows that MAD1 overexpression can promote colon cancer and suggests that MAD1 may be a novel drug target for this disease. [ABSTRACT FROM AUTHOR]

Previous solid organ transplantation has been associated with worse survival among colorectal cancer (CRC) patients. This study investigates the contribution of CRC characteristics and treatment-related factors to the differential survival. Using the Swedish register-linkage CRCBaSe, all patients with solid organ transplantation before CRC diagnosis were identified and matched with non-transplanted CRC patients. Associations between transplantation history and clinical CRC factors and survival were estimated using the Kaplan-Meier estimator and logistic, multinomial, and Cox regression, respectively. Ninety-eight transplanted and 474 non-transplanted CRC patients were followed for 5 years after diagnosis. Among patients with stage I-III cancer, transplanted patients had lower odds of treatment with abdominal surgery [odds ratio (OR):0.27, 95% confidence interval (CI):0.08-0.90], than non-transplanted patients. Among those treated with surgery, transplanted colon cancer patients had lower odds of receiving adjuvant chemotherapy (OR:0.31, 95% CI:0.11-0.85), and transplanted rectal cancer patients had higher rate of relapse (hazard ratio:9.60, 95% CI:1.84-50.1), than non-transplanted patients. Five-year cancer-specific and overall survival was 56% and 35% among transplanted CRC patients, and 68% and 57% among non-transplanted. Accordingly, transplanted CRC patients were treated less intensely than non-transplanted patients, and had worse cancer-specific and overall survival. These patients might benefit from multidisciplinary evaluation including transplantation specialists. [ABSTRACT FROM AUTHOR]

Background: Colon cancer, a frequently encountered malignancy, exhibits a comparatively poor survival prognosis. Perineural invasion (PNI), highly correlated with tumor progression and metastasis, is a substantial effective predictor of stage II-III colon cancer. Nonetheless, the lack of effective and facile predictive methodologies for detecting PNI prior operation in colon cancer remains a persistent challenge. Method: Pre-operative computer tomography (CT) images and clinical data of patients diagnosed with stage II-III colon cancer between January 2015 and December 2023 were obtained from two sub-districts of Sun Yat-sen Memorial Hospital (SYSUMH). The LASSO/RF/PCA filters were used to screen radiomics features and LR/SVM models were utilized to construct radiomics model. A comprehensive model, shown as nomogram finally, combining with radiomics score and significant clinical features were developed and validated by area under the curve (AUC) and decision curve analysis (DCA). Result: The total cohort, comprising 426 individuals, was randomly divided into a development cohort and a validation cohort as a 7:3 ratio. Radiomics scores were extracted from LASSO-SVM models with AUC of 0.898/0.726 in the development and validation cohorts, respectively. Significant clinical features (CA199, CA125, T-stage, and N-stage) were used to establish combining model with radiomics scores. The combined model exhibited superior reliability compared to single radiomics model in AUC value (0.792 vs. 0.726, p = 0.003) in validation cohorts. The radiomics-clinical model demonstrated an AUC of 0.918/0.792, a sensitivity of 0.907/0.813 and a specificity of 0.804/0.716 in the development and validation cohorts, respectively. Conclusion: The study developed and validated a predictive nomogram model combining radiomics scores and clinical features, and showed good performance in predicting PNI pre-operation in stage II-III colon cancer patients. [ABSTRACT FROM AUTHOR]

Introduction: Colon cancer presents significant surgical challenges that necessitate the development of precise strategies. Standardization with complete mesocolic excision (CME) is common, but some cases require extended resections. This study investigates the use of 3D Image Processing and Reconstruction (3D-IPR) to improve diagnostic accuracy in locally advanced colon cancer (LACC) with suspected infiltration and achieve R0 surgery. Methods: Single-center, prospective, observational, comparative, non-randomized study. •Participants: Patients aged > 18 years undergoing LACC surgery, as indicated by CT scans, confirmed via colonoscopy. Exclusion criteria include neoadjuvant therapy, suspected carcinomatosis on CT, and unresectable tumors. •Interventions: 3D-IPR models are used for surgical planning, providing detailed tumor and surrounding structure metrics. Surgical procedures are guided by CT scans and intraoperative findings, categorized by surgical margins as R0, R1, or R2. •Objective: The primary goal is to evaluate 3D-IPR's utility in achieving R0 resection in LACC with suspected infiltration. Secondary objectives include assessing preoperative surgical strategy, comparing CT reports, detecting adenopathy, and identifying vascularization and anatomical variants. • Outcome: The main outcome is the diagnostic accuracy of 3D-IPR in determining tumor infiltration of neighboring structures compared to conventional CT scans, using definitive pathological reports as the gold standard. Results: •Recruitment and Number Analyzed: The study aims to recruit about 20 patients annually over two years, focusing on preoperative 3D-IPR analysis and subsequent surgical procedures. •Outcome Parameters: These include loco-regional and distant recurrence rates, peritoneal carcinomatosis, disease-free and overall survival, and mortality due to oncologic progression. •Harms: No additional risks from CT scans, as they are mandatory for staging colon tumors. 3D-IPR is derived from these CT scans. Discussion: If successful, this study could provide an objective tool for precise tumor extension delimitation, aiding decision-making for radiologists, surgeons, and multidisciplinary teams. Enhanced staging through 3D-IPR may influence therapeutic strategies, reduce postsurgical complications, and improve the quality of life of patients with LACC. Trial registration: Trial is registered at ISRCTN registry as ISRCTN81005215. Protocol version I (Date 29/06/2023). [ABSTRACT FROM AUTHOR]

Background: Histiocytic sarcoma (HS) is a rare disease characterized by the presence of neoplastic histiocytes. We herein report an unusual case of HS that caused massive tumor embolism-related transmural necrosis of the small intestine. Case presentation: A 64-year-old man presented with multiple nodules in the lungs, bone, mediastinum, and subcutaneous tissues that were incidentally detected on preoperative computed tomography for early transverse colon cancer. Approximately two months later, the patient presented with signs of peritoneal irritation suggestive of small intestinal necrosis. Emergency surgery was performed and the necrotic small intestine was resected. Pathological examination revealed small bowel necrosis due to multifocal HS embolism. The postoperative course was uneventful. The patient was unsuccessfully treated with chemotherapy for HS and died 122 days postoperatively. Conclusions: HS can cause massive enteric necrosis due to tumor embolism. Clinicians should be aware of this rare presentation of HS. [ABSTRACT FROM AUTHOR]

Objective(s): Using a quality-by-design methodology, the current research is aimed to prepare and enhance the PEGylated PLGA-loaded regorafenib monohydrate polymeric nanoparticles for enhancing oral bioavailability and biopharmaceutical attributes. The oral multi-kinase inhibitor inhibits VEGFR2-TIE2 tyrosine kinases on two separate targets, which results in anti-angiogenic activity. It also inhibits stromal and oncogenic receptor tyrosine kinases. Materials and Methods: The current study developed nanosized, biocompatible, and PEGylated PLGA polymeric nanoparticles to administer regorafenib monohydrate to patients with metastatic colon cancer. This was accomplished using a modified nanoprecipitation technique to make drug-encapsulated PEGylated PLGA nanoparticles with poloxamer 188 as a stabilizer. Results: The polymeric nanoformulations were characterized for zeta potential, distribution of particle size, entrapment efficiency, DSC, FT-IR, X-RD, and SEM. Both in vitro and in vivo experimental studies were performed for the pure drug and the improved nanoparticle formulation. Conclusion: The nanoparticles obtained from optimization studies were found to have smaller particle sizes, higher entrapment efficiency (%), drug loading capacity, spherical shape particles, amorphous drug embedded matrix, and a biphasic delayed release pattern. These findings suggest that drug-loaded PEGylated PLGA nanoparticles are a potent formulation for the treatment of colon cancer, with improved oral bioavailability and biopharmaceutical properties. [ABSTRACT FROM AUTHOR]

A growing body of evidence indicates the association of dietary advanced glycation end‐products (dAGEs) with the risk of cancer. This systematic review and meta‐analysis aimed to assess the overall association between dAGEs and cancer incidence. An extensive search was carried out through online databases including PubMed, Scopus, and Web of Science up to June 2024. All reported HRs and their 95% CIs for risk of cancer were used to estimate log HRs and their standard errors (SEs). The overall risk estimate was obtained using a random effects model. Inter‐study heterogeneity was determined using Cochrane's Q test and I‐squared. Five prospective cohort studies with a total of 1,220,096 participants and 23,229 incident cancer cases (2193 pancreatic cancers, 11,443 breast cancers, 6162 colorectal cancers, and 3431 total cancers) were included in this meta‐analysis. Compared with the lowest category of dAGEs, the pooled hazard ratio (HR) for overall cancers was 1.04 (95% CI: 0.94, 1.15; I2 = 67.9%) for the highest category of dAGEs. Pooled estimates for different types of cancer showed no significant relationship between dAGEs and risk of breast cancer (HR: 1.119; 95% CI: 0.868, 1.444; I2 = 77.6%; N = 2 studies), pancreatic cancer (HR: 1.242; 95% CI: 0.971, 1.588; I2 = 0.0%; N = 2 studies), colon cancer (HR: 10.985; 95% CI: 0.887, 1.094; I2 = 0.0%; N = 2 studies) and rectal cancer (HR: 0.940; 95% CI: 0.616, 1.433; I2 = 57.7%; N = 2 studies). Dietary AGEs had no significant link with cancer risk. More well‐designed prospective studies are required. [ABSTRACT FROM AUTHOR]

Isothiocyanates (ITCs), prevalent in cruciferous vegetables, are known for their anticarcinogenic properties. Prior research has indicated that heparin can stimulate the growth of colon cancer cells. However, the implications of ITCs in the diet of cancer patients receiving heparin‐based therapies have yet to be fully understood. This exploratory in vitro study examines the proliferative effects of low‐molecular‐weight heparin (LMWH) on human colon cancer cells and assesses the antiproliferative potential of four ITC compounds, exploring possible epidermal growth factor family of receptor tyrosine kinases (Erb‐B) related mechanisms. We evaluated cell viability in HCT‐116 and HT‐29 cell lines following treatment with ITCs alone or combined with LMWH (20 μg/mL) at various concentrations (1–100 μM). Clonogenic and wound‐healing assays were performed after 24 h of treatment with 5 μM ITCs. Additionally, messenger RNA (mRNA) and protein expression of Erb‐B family genes was measured using quantitative polymerase chain reaction (qPCR) and Western blotting. Statistical analysis was conducted using analysis of variance (ANOVA) with Dunnett's post hoc test. Results indicated that the half‐maximal inhibitory concentration (IC50) values for Phenylethyl isothiocyanate (PEITC), Benzyl isothiocyanate (BITC), and Sulforaphane (SFN) were lower than those of Allyl isothiocyanate (AITC) in LMWH‐stimulated HCT‐116 (20.77, 19.10, and 44.05 μM, respectively) and HT‐29 (74.94, 26.77, and 43.49 μM, respectively). PEITC and SFN significantly reduced ErbB1 (epidermal growth factor receptor (EGFR)) and ErbB4 (receptor tyrosine‐protein kinase erbB‐4) expression, while BITC decreased ErbB2 (receptor tyrosine‐protein kinase erbB‐2) and transforming growth factor beta (TGF‐β) expression in HCT‐116 cells (all, p <.05). PEITC, BITC, and SFN also increased proapoptotic Bax expression and decreased the antiapoptotic B‐cell lymphoma 2 (Bcl‐2) expression (all, p <.05). These findings suggest that specific ITCs may mitigate cancer cell proliferation induced by LMWH in cancer therapies, highlighting their potential therapeutic efficacy. [ABSTRACT FROM AUTHOR]

Objective To analyze the differences in the expressions of the total and phosphorylated proteins in human colon cancer HCT116 cells after the knockout (KO) of retinoic acid-induced protein 16 (RAI16) and explore the possible mechanism and related signaling pathways affecting its protein function in HCT116 cells. Methods HCT116 KO and WT cell proteins were collected and extracted, and the protein extraction efficiency was detected via a sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) experiment. After protein digestion, the peptides were labeled with TMT and analyzed via mass spectrometry. We used bioinformatics methods to analyze the identified differential proteins and differentially phosphorylated proteins by using GO, KEGG, and STRING databases. Results The results of SDS-PAGE showed no evident protein degradation. In addition, some key bands were significantly different between the experimental and control groups. A total of 147 up-regulated and 230 down-regulated differential proteins were screened in accordance with the conditions of Foldchange≥1.5 or Foldchange≤1/1.5 and P<0.05. Meanwhile, 106 up-regulated and 217 down-regulated phosphorylation sites were screened. GO enrichment analysis revealed that the differential proteins were mainly enriched in the composition of nucleoplasm, nucleus and cytoplasm, RNA binding, cadherin and chromatin, DNA repair, RNA splicing, and positive regulation of DNA as template transcription. The results of KEGG enrichment indicated that the differential proteins were mainly enriched in nucleocytoplasmic transport, spliceosomes, cell cycle, cell-cell tight junctions, viral carcinogenesis, microRNAs in cancer, etc. The protein interaction network mainly focused on DDX17, NCL, EEF2, CDK1, SSRP1, and SMARCC1. The statistical findings unveiled the up-regulated changes in the two omics of SKP1, ORC1, and BAD and the down-regulated changes in RBL1, RB1, CDK1, CDC6, MCM4, TFDP1, CHD4, and SNW1. Moreover, the phosphorylation differences were more significant than the protein differences. Conclusion RAI16 plays the possible crucial role in multiple biological functions and signaling pathways through key proteins, such as SKP1, ORC1, RB1, and CDK1, which affect the cell cycle and thereby the occurrence and development of cancer [ABSTRACT FROM AUTHOR]

Objective To explore the correlation of RELL1 expression with clinical pathological features and prognosis of patients with colon cancer. Methods Immunohistochemical experiments of the RELL1 protein were performed on tissue chips from 80 colon cancer tissues and 80 adjacent tissues. The relationship between different expression levels of RELL1 protein and clinical pathological parameters was compared. Univariate and multivariate Cox risk proportional regression analyses were conducted on factors affecting the survival of patients with colon cancer. Kaplan-Meier survival curve analysis was conducted on the survival rates of patients with colon cancer and different levels of RELL1 expression. Log rank test was performed to evaluate differences in survival rates. Results The expression of RELL1 in colon cancer tissues was lower than that in adjacent tissues (P<0.05). The expression of RELL1 in cancer tissues is correlated with TNM stage and N stage (P<0.05). The 3-year overall survival (OS) rate of colon cancer patients with high RELL1 expression was higher than that of patients with low RELL1 expression (P<0.05). Multivariate Cox regression analysis showed that low RELL1 expression, advanced age, and high TNM stage were risk factors for poor prognosis in patients with colon cancer (P<0.05). Conclusion The expression of RELL1 is downregulated in colon cancer tissue, and the low RELL1 expression, advanced age, and high TNM stage can lead to adverse outcomes in patients [ABSTRACT FROM AUTHOR]

Lung and colon cancer (LCC) is a dominant life-threatening disease that needs timely attention and precise diagnosis for efficient treatment. The conventional diagnostic techniques for LCC regularly encounter constraints in terms of efficiency and accuracy, thus causing challenges in primary recognition and treatment. Early diagnosis of the disease can immensely reduce the probability of death. In medical practice, the histopathological study of the tissue samples generally uses a classical model. Still, the automated devices that exploit artificial intelligence (AI) techniques produce efficient results in disease diagnosis. In histopathology, both machine learning (ML) and deep learning (DL) approaches can be deployed owing to their latent ability in analyzing and predicting physically accurate molecular phenotypes and microsatellite uncertainty. In this background, this study presents a novel technique called Lung and Colon Cancer using a Swin Transformer with an Ensemble Model on the Histopathological Images (LCCST-EMHI). The proposed LCCST-EMHI method focuses on designing a DL model for the diagnosis and classification of the LCC using histopathological images (HI). In order to achieve this, the LCCST-EMHI model utilizes the bilateral filtering (BF) technique to get rid of the noise. Further, the Swin Transformer (ST) model is also employed for the purpose of feature extraction. For the LCC detection and classification process, an ensemble deep learning classifier is used with three techniques: bidirectional long short-term memory with multi-head attention (BiLSTM-MHA), Double Deep Q-Network (DDQN), and sparse stacked autoencoder (SSAE). Eventually, the hyperparameter selection of the three DL models can be implemented utilizing the walrus optimization algorithm (WaOA) method. In order to illustrate the promising performance of the LCCST-EMHI approach, an extensive range of simulation analyses was conducted on a benchmark dataset. The experimentation results demonstrated the promising performance of the LCCST-EMHI approach over other recent methods. [ABSTRACT FROM AUTHOR]

Weizmannia coagulans has been shown to have anticancer properties. However, there is limited research on the effects of postbiotic W. coagulans on colorectal cancer cell proliferation. Additionally, the exact mechanisms through which it influences apoptosis- and autophagy-related signaling pathways are yet to be thoroughly elucidated. This study explored the role of W. coagulans MZY531 as a postbiotic in inhibiting tumor growth by modulating apoptosis and autophagy in tumor cells. During the experimental period in the model group, tumors proliferated, tumor markers increased significantly, and immunofluorescence results showed that caspase-3 and terminal deoxynucleotidyl transferase dUTP nick-end labeling were significantly decreased. Conversely, supplementation with W. coagulans MZY531 postbiotics significantly reduced the levels of tumor markers carcinoembryonic antigen, colon cancer antigen, and extracellular protein kinase A and promoted cell apoptosis by increasing the caspase-3-positive count and terminal deoxynucleotidyl transferase dUTP nick-end labeling-positive cells in tumor tissue. Mechanistically, W. coagulans MZY531 postbiotics inhibit tumor growth through the modulation of the Bax/Bcl-2/caspase-3 and JAK2/STAT3 apoptosis pathways and PI3K/AKT/mTOR and TGF-β/SMAD4 cell autophagy pathways. W. coagulans MZY531 postbiotics had a more significant effect than that of W. coagulans MZY531 alone. Probiotics are expected to become effective natural functional foods for the treatment of colorectal cancer. [ABSTRACT FROM AUTHOR]

Parasporin PS2Aa1, recently renamed Mpp46Aa1, is an anti-cancer protein known for its selectivity against various human cancer cell lines. We genetically modified native PS2Aa1 to create a library of approximately 100 mutants. From this library, we selected promising mutants based on their half-maximal inhibitory concentration (IC50) and sequence variations. In this study, Variant 3–35, with the G257V substitution, demonstrated increased cytotoxicity and selectivity against the colon cancer cell line SW480. Conversely, Variant N65, featuring substitutions N92D, K175R, and S218G, yielded the most favorable results against the cancer cell lines SW-620, MOLT-4, and Jurkat. The caspase 3/7 and 9, Annexin V-Cy3 and 6-GFDA activities, and, most notably, mitochondrial membrane permeabilization assays confirmed the apoptotic marker elevation. These findings indicate that residues 92, 175, 218, and 257 may play a critical role in the cytotoxic activity and selectivity. We successfully obtained genetically improved variants with substitutions at these key amino acid positions. Additionally, we conducted molecular dynamic simulations to explore the potential interactions between PS2Aa1 and the CD59 GPI-anchored protein. The simulation results revealed that residues 57, 92, and 101 were consistently present, suggesting their possible significance in the interactions between parasporin and the CD59 protein. [ABSTRACT FROM AUTHOR]

Background/Objectives: An inhibitor of small Rho GTPase Cdc42, CASIN, has been shown to reduce cancer cell proliferation, migration, and invasion, yet it has several limitations, including rapid drug elimination and low bioavailability, which prevents its systemic administration. In this study, we designed and characterized a nanoparticle-based delivery system for CASIN encapsulated within poly(lactide-co-glycolide)-block-poly(ethylene glycol)-carboxylic acid endcap nanoparticles (PLGA-PEG-COOH NPs) for targeted inhibition of Cdc42 activity in colon cancer. Methods: We applied DLS, TEM, and UV–vis spectroscopy methods to characterize the size, polydispersity index, zeta potential, encapsulation efficiency, loading capacity, and in vitro drug release of the synthesized nanoparticles. The CCK-8 cell viability test was used to study colorectal cancer cell growth in vitro. Results: We showed that CASIN-PLGA-PEG-COOH NPs were smooth, spherical, and had a particle size of 86 ± 1 nm, with an encapsulation efficiency of 66 ± 5% and a drug-loading capacity of 5 ± 1%. CASIN was gradually released from NPs, reaching its peak after 24 h, and could effectively inhibit the proliferation of HT-29 (IC50 = 19.55 µM), SW620 (IC50 = 9.33 µM), and HCT116 (IC50 = 10.45 µM) cells in concentrations ranging between 0.025–0.375 mg/mL. CASIN-PLGA-PEG-COOH NPs demonstrated low hemolytic activity with a hemolytic ratio of less than 1% for all tested concentrations. Conclusion: CASIN-PLGA-PEG-COOH NPs have high encapsulation efficiency, sustained drug release, good hemocompatibility, and antitumor activity in vitro. Our results suggest that PLGA-PEG-COOH nanoparticles loaded with CASIN show potential as a targeted treatment for colorectal cancer and could be recommended for further in vivo evaluation. [ABSTRACT FROM AUTHOR]

Background/Objectives: Brazilian red propolis has attracted attention for its pharmacological properties. However, signs of toxicity were recently observed in long-term studies using the hydroalcoholic extract of red propolis (RPHE), likely due to polyprenylated benzophenones. This study aimed to develop a benzophenone-free red propolis extract (BFRP) and validate an HPLC-PDA method to quantify its main constituents: isoliquiritigenin, vestitol, neovestitol, medicarpine, and 7-O-methylvestitol. Methods: BFRP's toxicity was assessed in zebrafish larvae through a vibrational startle response assay (VSRA) and morphological analysis. Genotoxicity was evaluated using the micronucleus test in rodents, and the extract's effects on chemically induced preneoplastic lesions in rat colon were studied. An HPLC-PDA method was used to quantify BFRP's main compounds. Results: BFRP primarily contained vestitol (128.24 ± 1.01 μg/mL) along with isoliquiritigenin, medicarpin, neovestitol, and 7-O-methylvestitol. Zebrafish larvae exposed to 40 µg/mL of BFRP exhibited toxicity, higher than the 10 µg/mL for RPHE, though no morphological differences were found. Fluorescent staining in the notochord, branchial arches, and mouth was observed in larvae treated with both BFRP and RPHE. No genotoxic or cytotoxic effects were observed up to 2000 mg/kg in rodents, with no impact on hepatotoxicity or nephrotoxicity markers. Chemoprevention studies showed a 41.6% reduction in preneoplastic lesions in rats treated with 6 mg/kg of BFRP. Conclusions: These findings indicate that BFRP is a safe, effective propolis-based extract with potential applications for human health, demonstrating reduced toxicity and chemopreventive properties. [ABSTRACT FROM AUTHOR]

Introduction: This study aimed to evaluate the short‑ and long‑term outcomes of single‑incision laparoscopic colectomy (SILC) for right‑sided colon cancer (CC) using a craniocaudal approach. Patients and Methods: The data of patients who underwent SILC for right‑sided CC at our hospital between January 2013 and December 2022 were retrospectively collected. Surgery was performed using a craniocaudal approach. Short‑ and long‑term operative outcomes were analysed. Results: In total, 269 patients (127 men, 142 women; median age 74 years) underwent SILC for right‑sided CC. The cases included ileocaecal resection (n = 138) and right hemicolectomy (n = 131). The median operative time was 154 min, and the median operative blood loss was 0 ml. Twenty‑seven cases (10.0%) required an additional laparoscopic trocar, and 9 (3.3%) were converted to open surgery. The Clavien–Dindo classification Grade III post‑operative complications were detected in 7 (2.6%) cases. SILC was performed by 25 surgeons, including inexperienced surgeons, with a median age of 34 years. The 5‑year cancer‑specific survival (CSS) was 96.1% (95% confidence interval [CI] 91.3%–98.2%), and CSS per pathological disease stage was 100% for Stages 0–I and II and 86.2% (95% CI 71.3%–93.7%) for Stage III. The 5‑year recurrence‑free survival (RFS) was 90.6% (95% CI 85.7%–93.9%), and RFS per pathological disease stage was 100% for Stage 0–I, 91.7% (95% CI 80.5%–96.6%) for Stage II and 76.1% (95% CI 63.0%–85.1%) for Stage III. Conclusions: SILC for right‑sided CC can be safely performed with a craniocaudal approach, with reasonable short‑ and long‑term outcomes. [ABSTRACT FROM AUTHOR]