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Purpose: Detailed reporting of individually tailored exercise prescriptions (ExRx) used in clinical trials is essential to describe feasibility, tolerability, and efficacy of the intervention and to inform translation to clinical care. This article outlines the methodology used to develop a resistance training (RT) ExRx for people with colon cancer receiving chemotherapy and reports adherence to the randomized controlled trial testing the impact of RT on relative dose intensity of chemotherapy and patient-reported toxicities. Methods: Participants randomized to the exercise arm (n = 90) were included. To promote muscle hypertrophy, the ExRx was twice-weekly, moderate to heavy loads (65%-85% one-repetition maximum), high sets (3-5), and intermediate repetitions (6-10) of five large multijoint movements with adjustable dumbbells. Attendance (achieved frequency) and adherence (achieved volume) were calculated. Group-based trajectory modeling was used to identify clusters of individuals with similar adherence patterns and compared baseline characteristics across adherence groups. Results: The median attendance was 69.1%. Adherence was 60.6% but higher for those receiving 3 versus 6 months of chemotherapy (80.4 vs 47.4%; P < 0.05). Participants engaged in a median of 1.4 d of RT each week, lifting 62% of the one-repetition maximum load, for 3.0 sets and 7.5 repetitions per set. Three distinct adherence groups were identified: 13% "nonstarter," 37% "tapered off," and 50% "consistent exercisers." Females were more likely to be in the nonstarter and tapered-off groups. Conclusions: This article outlines suggested methods for reporting ExRx of RT in oncology clinical trials and provides insight into the tolerance of ExRx of RT during chemotherapy treatment for colon cancer. These findings aim to foster constructive dialogue and offer a premise for designing future research to elucidate the benefits of exercise during chemotherapy. [ABSTRACT FROM AUTHOR]

Background: Colon and breast cancer are the most common types of cancer in cancer patients worldwide. Therefore, health students, especially pharmacy students, should be well-educated about colon and breast cancer. Adequate education and knowledge provide significant benefits from early diagnosis to treatment. Methodology: This study was conducted as a cross-sectional study for 3 months between 1 November 2022, and 31 January 2023, in Northern Cyprus. The aim of this study was to assess pharmacy students' knowledge of breast cancer and colon cancer in North Cyprus Universities. Result: A total of 494 pharmacy students participated in this study. Twenty-three incompletely filled questionnaires were excluded from the study. Regarding Near East University and Cyprus International University pharmacy students' knowledge of colon cancer, 298 out of 494 had good knowledge and 196 out of 494 had poor knowledge. Regarding Near East University and Cyprus International University pharmacy students' knowledge of breast cancer, 317 out of 494 had good knowledge and 177 out of 494 had poor knowledge. The total score of knowledge of Near East University and Cyprus International University pharmacy students about breast cancer was 10 ± 3.43 and 11.40 ± 3.67, respectively. The total score of knowledge of Near East University and Cyprus International University pharmacy students about colon cancer was 7.54 ± 3.67 and 9.19 ± 4.08, respectively. Conclusions: The findings of the study indicate that most of the pharmacy students have good knowledge about the risk factors and symptoms of breast and colon cancer, but are not at the ideal knowledge level expected in the fight against cancer after graduation. [ABSTRACT FROM AUTHOR]

Simple Summary: The research explores the potential of the Wnt receptor ROR1 as a target for cancer treatment, an area gaining significant attention. Despite ongoing therapeutic investigations, the understanding of ROR1's presence in different tissues remains limited. To address this, the study conducted immunohistochemistry analyses on a large variety of tumor types, including sarcomas and carcinomas, revealing a diverse ROR1 expression pattern. Notably, high ROR1 prevalence was observed in mesothelioma, liposarcoma, gastrointestinal stromal tumors, and uterine endometrioid carcinoma. Conversely, other cancers showed lower expression. These findings highlight the potential for ROR1-targeted therapies, particularly in mesothelioma, which exhibits frequent and high ROR1 expression, suggesting a novel therapeutic avenue. This research may inform the development of more effective cancer treatments targeting ROR1. The Wnt receptor ROR1 has generated increased interest as a cancer therapeutic target. Research on several therapeutic approaches involving this receptor is ongoing; however, ROR1 tissue expression remains understudied. We performed an immunohistochemistry analysis of ROR1 protein expression in a large cohort of multiple tumor and histologic types. We analyzed 12 anonymized multi-tumor tissue microarrays (TMAs), including mesothelioma, esophageal and upper gastrointestinal carcinomas, and uterine endometrioid carcinoma, among other tumor types. Additionally, we studied 5 different sarcoma types of TMAs and 6 patient-derived xenografts (PDX) TMAs developed from 19 different anatomic sites and tumor histologic types. A total of 1142 patient cases from different histologic types and 140 PDXs placed in TMAs were evaluated. Pathologists assessed the percentage of tumor cells in each case that were positive for ROR1 and the intensity of staining. For determining the prevalence of staining for each tumor type, a case was considered positive if >1% of its tumor cells showed ROR1 staining. Our immunohistochemistry assays revealed a heterogeneous ROR1 expression profile. A high prevalence of ROR1 expression was found in mesothelioma (84.6%), liposarcoma (36.1%), gastrointestinal stromal tumors (33.3%), and uterine endometrioid carcinoma (28.9%). Other histologic types such as breast, lung, renal cell, hepatocellular, urothelial carcinoma, and colon carcinomas; glioblastoma; cholangiocarcinoma; and leiomyosarcoma showed less ROR1 overall expression, ranging between 0.9 and 13%. No ROR1 expression was seen in mesenchymal chondrosarcoma, rhabdomyosarcoma, or gastric adenocarcinoma cases. Overall, ROR1 expression was relatively infrequent and low in most tumor types investigated; however, ROR1 expression was infrequent but high in selected tumor types, such as gastroesophageal GIST, suggesting that ROR1 prescreening may be preferable for those indications. Further, mesothelioma exhibited frequent and high levels of ROR1 expression, which represents a previously unrecognized therapeutic opportunity. These findings can contribute to the development of ROR1-targeted therapies. [ABSTRACT FROM AUTHOR]

Chromosomal instability is a hallmark of colorectal carcinogenesis and produces an accumulation of different forms of aneuploidies or broad copy number aberrations. Colorectal cancer is characterized by gain-type broad copy number aberrations, specifically in Chr20, Chr8q, Chr13 and Chr7, but their roles and mechanisms in cancer progression are not fully understood. It has been suggested that broad copy number gains might contribute to tumor development through the so-called caricature transcriptomic effect. We intend to investigate the impact of broad copy number gains on long non-coding RNAs' expression in colorectal cancer, given their well-known role in oncogenesis. The influence of such chromosomal aberrations on lncRNAs' transcriptome profile was investigated by SNP and transcriptome arrays in our series of colorectal cancer samples and cell lines. The correlation between aneuploidies and transcriptomic profiles led us to obtain a class of Over-UpT lncRNAs, which are transcripts upregulated in CRC and further overexpressed in colon tumors bearing specific chromosomal aberrations. The identified lncRNAs can contribute to a wide interaction network to establish the cancer driving effect of gain-type aneuploidies. [ABSTRACT FROM AUTHOR]

The identification of targets that are expressed on the cell membrane is a main goal in cancer research. The Lymphocyte Antigen 6 Family Member G6D (LY6G6D) gene codes for a protein that is mainly present on the surface of colorectal cancer (CRC) cells. Therapeutic strategies against this protein like the development of T cell engagers (TCE) are currently in the early clinical stage. In the present work, we interrogated public genomic datasets including TCGA to evaluate the genomic and immunologic cell profile present in tumors with high expression of LY6G6D. We used data from TCGA, among others, and the Tumor Immune Estimation Resource (TIMER2.0) platform for immune cell estimations and Spearman correlation tests. LY6G6D expression was exclusively present in CRC, particularly in the microsatellite stable (MSS) subtype, and was associated with left-side tumors and the canonical genomic subgroup. Tumors with mutations of APC and p53 expressed elevated levels of LY6G6D. This protein was expressed in tumors with an inert immune microenvironment with an absence of immune cells and co-inhibitory molecules. In conclusion, we described clinical, genomic and immune-pathologic characteristics that can be used to optimize the clinical development of agents against this target. Future studies should be performed to confirm these findings and potentially explore the suggested clinical development options. [ABSTRACT FROM AUTHOR]

Based on several clinical observations it was hypothesized that herpesviruses may influence the replication of human bocaviruses, the second known parvoviruses that have been confirmed as human pathogens. While several cell lines support the growth of HSV-1, HBoV-1 was exclusively cultivated on air–liquid interface cultures, the latter being a rather complicated, slow, and low throughput system. One of the cell lines are T84 cells, which are derived from the lung metastasis of a colorectal tumor. In this study, we provide evidence that T84 also supports HBoV replication when cultivated as monolayers, while simultaneously being permissive for HSV-1. The cell culture model thus would enable co-infection studies of both viruses and is worth being optimized for high throughput studies with HBoV-1. Additionally, the study provides evidence for a supporting effect of HSV-1 on the replication and packaging of HBoV-1 progeny DNA into DNase-resistant viral particles. [ABSTRACT FROM AUTHOR]

Background: Stoma prolapse (SP) is a common stoma-related complication, particularly in loop colostomies. This study aimed to investigate potential risk factors for SP development after laparoscopic loop colostomy. Methods: In total, data from 140 patients who underwent laparoscopic loop colostomy were analyzed between September 2016 and March 2022. Risk factors for SP were investigated retrospectively. Results: The median follow-up duration after colostomy was 12.5 months, and SP occurred in 33 (23.6%) patients. Multivariate analysis showed that being overweight (body mass index ≥ 25; odds ratio [OR], 8.69; 95% confidential interval [CI], 1.61–46.72; p = 0.012) and having a thin rectus abdominis penetration of the stoma (< 8.9 mm; OR, 8.22; 95% CI, 2.50–27.05; p < 0.001) were independent risk factors for SP. Other patient characteristics and surgical factors associated with stoma construction were unrelated to SP development. Conclusions: Being overweight and the route penetrating the thinner rectus abdominis during stoma construction was associated with a significantly higher incidence of SP after laparoscopic loop colostomy. Selecting a construction site that penetrates the thicker rectus abdominis muscle may be crucial for preventing SP. [ABSTRACT FROM AUTHOR]

Introduction: A survival paradox between T4N0 (Stage IIB/IIC) and Stage IIIA colon cancer exists, even after adjusting for adequate lymph node (LN) retrieval and receipt of adjuvant chemotherapy (C). We conducted a large hospital-based study to re-evaluate this survival paradox based on the newest 8th edition staging system. Methods: The National Cancer Data Base was queried to evaluate 35,606 patients diagnosed with Stage IIB, IIC, and IIIA colon cancer between 2010 and 2017. The Kaplan–Meier method and log-rank test were used to compare unadjusted overall survival (OS). Multivariable Cox proportional hazards model was used to determine the association of stage with hazard ratios adjusted for relevant demographic and clinical variables including ≥ 12 LNs retrieved and receipt of adjuvant chemotherapy. P value < 0.05 was considered statistically significant. Results: The 5-year OS for optimally treated stage IIIA colon cancer (receipt of C) was 84.3%, which was significantly higher than stage IIB/C (≥ 12 LNs retrieved + C) (72.8%; P < 0.0001). Stage was an independent predictor of OS. Among optimally treated Stage IIIA patients, T1N1 had the best survival (90.6%) while stage T4bN0 (stage IIC) had the worst (70.9%) (P < 0.0001). Compared to stage IIB, stage IIC had a 17% increased risk of overall death while stage IIIA had a 21% reduction in death (P < 0.0001). Conclusion: Stage IIB/C and Stage IIIA survival paradox persists even after accounting for receipt of adjuvant chemotherapy and adequate lymph node retrieval. Future iteration of the TNM system should take this paradox into consideration. [ABSTRACT FROM AUTHOR]

Background: Evidence regarding the outcomes benefits of robotic approach, when compared to a laparoscopic approach, in colectomy remain limited. Objective: This study aimed to analyze the value of robotic approach compared to laparoscopic approach in minimally invasive colectomy. Design: Cohort study of the National Surgical Quality Improvement Program (NSQIP). Setting: This study included data from the NSQIP from 1/2016 to 12/2021. Patient: Adult patients undergoing minimally invasive (laparoscopic or robotic) colorectal surgery. Intervention: Robotic versus laparoscopic colectomy. Outcome measures: Risk ratios for the incidence of medical and surgical morbidity and overall mortality. Results: Compared to laparoscopic, robotic colectomy was associated with a significant decrease in postoperative morbidity [RR 0.84 (95%CI 0.72–0.96), P < 0.001], a significant reduction in postoperative mortality [RR 0.83 (95%CI 0.79–0.90), P 0.010)], and in post operative ileus [RR: 0.80 (95%CI 0.75–0.84), P < 0.001]. Yet, robotic approach was associated with a significant increase in total operative time despite a significant decrease in total length of stay. No benefit was observed regarding anastomotic leak. Limitations: Observational nature of the study cannot exclude residual bias. Conclusions: In this prospective cohort from the NSQIP, robotic colectomy was associated with a significant reduction in postoperative ileus, unplanned conversion to open surgery, morbidity, and overall mortality when compared to laparoscopic colectomy. [ABSTRACT FROM AUTHOR]

High hydrogen sulfide (H2S) expression has been shown to play a crucial role in tumor growth and proliferation in colon cancer. So far, most probes used for monitoring H2S offer single‐modal imaging, which makes the collection of accurate information for tumor diagnosis difficult. In the present study, a novel dual‐modal imaging probe in the second near‐infrared (NIR‐II, 950‐1700) window is proposed and constructed by coating a uniform shell of polydopamine (PDA) on the surface of cuprous oxide (Cu2O)‐conjugated downconversion nanoparticles (DCNPs). Of note, DCNP‐Cu2O@PDA is in the "on" state, with emission centered at 1550 nm (irradiation using a 980nm laser) in non‐neoplastic tissues. Colon tumors with endogenous H2S overexpression can induce the in situ transformation of Cu2O to copper sulfide (Cu2‐XS）. Owing to the competitive absorption between Cu2‐XS and DCNPs at a wavelength of 980 nm, the generated DCNP‐Cu2‐XS@PDA exhibits a quenched NIR‐II fluorescence (FL) signal. Meanwhile, Cu2‐XS exhibits a strong absorbance at 1250 nm, enhancing the NIR‐II photoacoustic (PA) signal accompanied by NIR‐II FL attenuation. The switching in PA and FL signals at the tumor site offered "double assurances" for the accurate monitoring of H2S. [ABSTRACT FROM AUTHOR]

The current study aimed to evaluate Tunisian Tamarix africana Poir biological activities. In this study, novel biological activities of the shoot extracts related to their phenolics investigated. Secondary metabolite contents, antioxidant, anti-inflammatory and cytotoxic activities of four extracts (hexane, dichloromethane, methanol and water) were investigated. Antioxidant activities were assessed via in vitro and ex vivo assays. Besides, anticancer activity was investigated against human lung carcinoma (A-549) and colon adenocarcinoma (DLD-1) cells. The anti-inflammatory ability was evaluated via inhibition of LPS-induced NO production in RAW 264.7 macrophage cell lines. Methanol and water extracts displayed the highest antioxidant (IC50 = 3.3 and 4.3 µg/mL respectively), which are correlated activities correlated with phenolic contents. Hexane extract exhibited an important anti-inflammatory effect inhibiting NO ability by 100% at 80 µg/mL. Besides, T. africana extracts were found to be active against A-549 lung carcinoma cells with IC50 values ranging from 20 to 34 µg/mL. These results suggested that T. africana is considered as a potential source of readily accessible natural molecules with a promising effect on human health and diseases. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the contribution of germline genetics to regulating the briskness and diversity of T cell responses in CRC, we conducted a genome-wide association study to examine the associations between germline genetic variation and quantitative measures of T cell landscapes in 2,876 colorectal tumors from participants in the Molecular Epidemiology of Colorectal Cancer Study (MECC). Methods: Germline DNA samples were genotyped and imputed using genome-wide arrays. Tumor DNA samples were extracted from paraffin blocks, and T cell receptor clonality and abundance were quantified by immunoSEQ (Adaptive Biotechnologies, Seattle, WA). Tumor infiltrating lymphocytes per high powered field (TILs/hpf) were scored by a gastrointestinal pathologist. Regression models were used to evaluate the associations between each variant and the three T-cell features, adjusting for sex, age, genotyping platform, and global ancestry. Three independent datasets were used for replication. Results: We identified a SNP (rs4918567) near RBM20 associated with clonality at a genome-wide significant threshold of 5 × 10− 8, with a consistent direction of association in both discovery and replication datasets. Expression quantitative trait (eQTL) analyses and in silico functional annotation for these loci provided insights into potential functional roles, including a statistically significant eQTL between the T allele at rs4918567 and higher expression of ADRA2A (P = 0.012) in healthy colon mucosa. Conclusions: Our study suggests that germline genetic variation is associated with the quantity and diversity of adaptive immune responses in CRC. Further studies are warranted to replicate these findings in additional samples and to investigate functional genomic mechanisms. [ABSTRACT FROM AUTHOR]

Simple Summary: In this research, we explored the latest advancements in minimally invasive surgery for colon cancer, by comparing laparoscopic surgery to the robotic approach. Our goal was to determine which method has better outcomes in terms of length of surgery, hospital stay, the likelihood of conversion, rate of complications, anastomotic leaks, and the effectiveness of tumor removal by evaluating the number of lymphatic nodes harvested. The findings could help surgeons and patients make more informed decisions related to the surgical options, considering the benefits of each technique. This summary aims to give a straightforward overview of the importance of this research and how it could impact the surgical approach. Background: Minimally invasive surgery in the treatment of colon cancer has significantly advanced over the years. This systematic review and meta-analysis aimed to compare the operative outcomes of robotic and laparoscopic surgery in the treatment of colon cancer, focusing on operative time, hospital stay, conversion rates, anastomotic leak rates, and total number lymph node harvested. Methods: Following PRISMA guidelines, we conducted a systematic search across four databases up to January 2024, registering our protocol with PROSPERO (CRD42024513326). We included studies comparing robotic and laparoscopic surgeries for colon cancer, assessing operative time, hospital length of stay, and other perioperative outcomes. Risk of bias was evaluated using the JBI Critical Appraisal Checklist. Statistical analysis utilized a mix of fixed and random-effects models based on heterogeneity. Results: A total of 21 studies met the inclusion criteria, encompassing 50,771 patients, with 21.75% undergoing robotic surgery and 78.25% laparoscopic surgery. Robotic surgery was associated with longer operative times (SMD = −1.27, p < 0.00001) but shorter hospital stays (MD = 0.42, p = 0.003) compared to laparoscopic surgery. Conversion rates were significantly higher in laparoscopic procedures (OR = 2.02, p < 0.00001). No significant differences were found in anastomotic leak rates. A higher number of lymph nodes was harvested by robotic approach (MD = −0.65, p = 0.04). Publication bias was addressed through funnel plot analysis and Egger's test, indicating the presence of asymmetry (p = 0.006). Conclusions: The choice of surgical method should be individualized, considering factors such as surgeon expertise, medical facilities, and patient-specific considerations. Future research should aim to elucidate long-term outcomes to further guide the clinical decision-making. [ABSTRACT FROM AUTHOR]

RAD54 and BLM helicase play pivotal roles during homologous recombination repair (HRR) to ensure genome maintenance. BLM amino acids (aa 181-212) interact with RAD54 and enhance its chromatin remodeling activity. Functionally, this interaction heightens HRR, leading to a decrease in residual DNA damage in colon cancer cells. This contributes to chemoresistance in colon cancer cells against cisplatin, camptothecin, and oxaliplatin, eventually promoting tumorigenesis in preclinical colon cancer mouse models. ChIP-Seq analysis and validation revealed increased BLM and RAD54 corecruitment on the MRP2 promoter in camptothecin-resistant colon cancer cells, leading to BLM-dependent enhancement of RAD54- mediated chromatin remodeling. We screened the Prestwick small-molecule library, with the intent to revert camptothecinand oxaliplatin-induced chemoresistance by disrupting the RAD54-BLM interaction. Three FDA/European Medicines Agency-approved candidates were identified that could disrupt this interaction. These drugs bound to RAD54, altered its conformation, and abrogated RAD54-BLM-dependent chromatin remodeling on G5E4 and MRP2 arrays. Notably, the small molecules also reduced HRR efficiency in resistant lines, diminished anchorage-independent growth, and hampered the proliferation of tumors generated using camptothecin- and oxaliplatin-resistant colon cancer cells in both xenograft and syngeneic mouse models in BLM-dependent manner. Therefore, the 3 identified small molecules can serve as possible viable candidates for adjunct therapy in colon cancer treatment. [ABSTRACT FROM AUTHOR]

Gas gangrene is a rare, severe gas-producing infection that can be related to colorectal cancer. Gas gangrene can be confirmed by radiologic findings and crepitation on touch. Spontaneous gas gangrene can be associated with colorectal cancer. An 80-year-old female complaint about a sudden abdominal pain, accompanied with progressive swelling pain in thigh and fever. Diagnosis based on assessment findings were gas gangrene and descending colonic cancer perforation. Emergency surgery was performed for debridement and drainage, followed by vacuum sealing drainage (VSD) with polyurethane (PU). Two more surgical interventions were given before the colonic tumor surgery. The patient recovered well in the long-term follow-up. This report demonstrates the diagnosis, treatment, and management of a successful case of gas gangrene caused by perforation of descending colonic cancer. Accurate preoperative diagnosis and reasonable use of VSD (PU) material played an important role in the treatment of this case. [ABSTRACT FROM AUTHOR]

BACKGROUND: We hypothesized that tumor- and hospital-level factors, compared with surgeon characteristics, are associated with the majority of variation in the 12 or more lymph nodes (LNs) examined quality standard for resected colon cancer. STUDY DESIGN: A dataset containing an anonymized surgeon identifier was obtained from the National Cancer Database for stage I to III colon cancers from 2010 to 2017. Multilevel logistic regression models were built to assign a proportion of variance in achievement of the 12 LNs standard among the following: (1) tumor factors (demographic and pathologic characteristics), (2) surgeon factors (volume, approach, and margin status), and (3) facility factors (volume and facility type). RESULTS: There were 283,192 unique patient records with 15,358 unique surgeons across 1,258 facilities in our cohort. Achievement of the 12 LNs standard was high (90.3%). Achievement of the 12 LNs standard by surgeon volume was 88.1% and 90.7% in the lowest and highest quartiles, and 86.8% and 91.6% at the facility level for high and low annual volume quartiles, respectively. In multivariate analysis, the following tumor factors were associated with meeting the 12 LNs standard: age, sex, primary tumor site, tumor grade, T stage, and comorbidities (all p < 0.001). Tumor factors were responsible for 71% of the variation in 12 LNs yield, whereas surgeon and facility characteristics contributed 17% and 12%, respectively. CONCLUSIONS: Twenty-nine percent of the variation in the 12 LNs standard is linked to modifiable factors. The majority of variation in this quality metric is associated with non-modifiable tumor-level factors. [ABSTRACT FROM AUTHOR]

Simple Summary: This study explored a potentially significant player in the spread of metastatic cancer: "hybrid cells" (HCs) combining features of both epithelial (common in tissues) and immune cells (such as macrophages). HCs were found in more than one type of tumor (THC) and showed a unique transcriptional profile including the activation of functional pathways, potentially explaining their mobility, dissemination into circulation, and metastatic progression. Normal healthy tissue also showed hybrid cells (NHC), but they were rare and could be easily distinguished from THCs based on their gene expression profile. The study also developed a way to identify HCs in large datasets generated at the single-cell level, paving the way for further research on their function and as potential therapeutic targets. Metastatic cancer is a leading cause of death in cancer patients worldwide. While circulating hybrid cells (CHCs) are implicated in metastatic spread, studies documenting their tissue origin remain sparse, with limited candidate approaches using one–two markers. Utilizing high-throughput single-cell and spatial transcriptomics, we identified tumor hybrid cells (THCs) co-expressing epithelial and macrophage markers and expressing a distinct transcriptome. Rarely, normal tissue showed these cells (NHCs), but their transcriptome was easily distinguishable from THCs. THCs with unique transcriptomes were observed in breast and colon cancers, suggesting this to be a generalizable phenomenon across cancer types. This study establishes a framework for HC identification in large datasets, providing compelling evidence for their tissue residence and offering comprehensive transcriptomic characterization. Furthermore, it sheds light on their differential function and identifies pathways that could explain their newly acquired invasive capabilities. THCs should be considered as potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Simple Summary: Glycolysis and oxidative phosphorylation play important roles in the progression and growth of cancers. The development of natural products and their semisynthetic derivatives for cancer treatment is a longstanding focus of our research interests. We developed compounds known as diaminobutoxy-substituted isoflavonoids (DBIs) that effectively stimulated Adenosine 5′ Monophosphate-activated Protein Kinase (AMPK) and suppressed the growth of colorectal cancer cells by specifically targeting mitochondrial complex I. We now report a new DBI analog, namely, DBI-2, with promising properties for cancer treatment. The combination of DBI-2 and BAY-876, a glucose transporter 1 inhibitor, exhibited synergistic effects on colorectal cancer cells. Furthermore, the therapeutic effectiveness of DBI-2 in colorectal cancer cell xenograft mouse models was enhanced by implementing a ketogenic diet, an outcome that indicated this drug/diet combination is a potentially promising combination strategy for cancer therapy. Cancer cells undergo a significant level of "metabolic reprogramming" or "remodeling" to ensure an adequate supply of ATP and "building blocks" for cell survival and to facilitate accelerated proliferation. Cancer cells preferentially use glycolysis for ATP production (the Warburg effect); however, cancer cells, including colorectal cancer (CRC) cells, also depend on oxidative phosphorylation (OXPHOS) for ATP production, a finding that suggests that both glycolysis and OXPHOS play significant roles in facilitating cancer progression and proliferation. Our prior studies identified a semisynthetic isoflavonoid, DBI-1, that served as an AMPK activator targeting mitochondrial complex I. Furthermore, DBI-1 and a glucose transporter 1 (GLUT1) inhibitor, BAY-876, synergistically inhibited CRC cell growth in vitro and in vivo. We now report a study of the structure–activity relationships (SARs) in the isoflavonoid family in which we identified a new DBI-1 analog, namely, DBI-2, with promising properties. Here, we aimed to explore the antitumor mechanisms of DBIs and to develop new combination strategies by targeting both glycolysis and OXPHOS. We identified DBI-2 as a novel AMPK activator using an AMPK phosphorylation assay as a readout. DBI-2 inhibited mitochondrial complex I in the Seahorse assays. We performed proliferation and Western blotting assays and conducted studies of apoptosis, necrosis, and autophagy to corroborate the synergistic effects of DBI-2 and BAY-876 on CRC cells in vitro. We hypothesized that restricting the carbohydrate uptake with a KD would mimic the effects of GLUT1 inhibitors, and we found that a ketogenic diet significantly enhanced the therapeutic efficacy of DBI-2 in CRC xenograft mouse models, an outcome that suggested a potentially new approach for combination cancer therapy. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) screening relies primarily on stool analysis to identify occult blood. However, its sensitivity for detecting precancerous lesions is limited, requiring the development of new tools to improve CRC screening. Carcinogenesis involves significant alterations in mucosal epithelium glycocalyx that decisively contribute to disease progression. Building on this knowledge, we examined patient series comprehending premalignant lesions, colorectal tumors, and healthy controls for the T-antigen—a short-chain O-glycosylation of proteins considered a surrogate marker of malignancy in multiple solid cancers. We found the T-antigen in the secretions of dysplastic lesions as well as in cancer. In CRC, T-antigen expression was associated with the presence of distant metastases. In parallel, we analyzed a broad number of stools from individuals who underwent colonoscopy, which showed high T expressions in high-grade dysplasia and carcinomas. Employing mass spectrometry-based lectin-affinity enrichment, we identified a total of 262 proteins, 67% of which potentially exhibited altered glycosylation patterns associated with cancer and advanced pre-cancerous lesions. Also, we found that the stool (glyco)proteome of pre-cancerous lesions is enriched for protein species involved in key biological processes linked to humoral and innate immune responses. This study offers a thorough analysis of the stool glycoproteome, laying the groundwork for harnessing glycosylation alterations to improve non-invasive cancer detection. [ABSTRACT FROM AUTHOR]

Background: Trigger transposable element-derived 1 (TIGD1) is a human-specific gene, but no studies have been conducted to determine its mechanism of action. Our aim is to ascertain the function and mode of action of TIGD1 in the development of colon cancer. Materials and Methods: The authors used bioinformatics to analyze the relationship between TIGD1 and the clinical characteristics of colon cancer, as well as its prognosis. A series of cell assays were conducted to assess the function of TIGD1 in the proliferation and migration of colon cancer, and flow cytometry was used to explore its effects on apoptosis and the cell cycle. Results: The authors discovered that the expression of TIGD1 was remarkably elevated in colon cancer. Clinical correlation analysis demonstrated that TIGD1 expression was elevated in the tissues of advanced-stage patients, and it was remarkably elevated in individuals with both lymph node and distant metastasis. Further, the authors found that individuals showing elevated TIGD1 expression levels had a shortened survival time. Univariate and multivariate Cox regression analyses revealed that TIGD1 was an independent prognostic factor. Overexpression of the TIGD1 gene remarkedly enhances the proliferation and metastasis of colon cancer cells and suppresses apoptosis. In addition, the overexpression of TIGD1 can enhance the transition of tumor cells from the G1 toward the S phase. Western blot results suggested that TIGD1 may promote the malignant activity of colon cancer cells via the Wnt/β-catenin signaling pathway, Bcl-2, N-cadherin, BAX, E-cadherin, CDK6, and CyclinD1. Conclusions:TIGD1 may be an independent prognostic factor in the advancement of colon cancer, and therefore function as a therapeutic target. [ABSTRACT FROM AUTHOR]

Background Monoallelic germline MBD4 pathogenic variants were recently reported to cause a predisposition to uveal melanoma, associated with a specific tumor mutational signature and good response to immunotherapy. Monoallelic tumor pathogenic variants have also been described in brain tumors, breast cancers, and myxofibrosarcomas, whereas biallelic germline MBD4 pathogenic variants have been involved in a recessive hereditary adenomatous polyposis and a specific type of acute myeloid leukemia. Methods We analyzed MBD4 for all patients with a diagnosis of uveal melanoma at Institut Curie since July 2021 and in the 3240 consecutive female probands explored at the Institut Curie for suspicion of predisposition to breast cancer between July 2021 and February 2023. Results We describe 25 families whose probands carry a monoallelic germline pathogenic variant in MBD4. Eighteen of these families presented with uveal melanoma (including a case patient with multiple uveal melanoma), and 7 families presented with breast cancer. Family histories showed the first familial case of uveal melanoma in monoallelic MBD4 pathogenic variant carriers and other various types of cancers in relatives, especially breast, renal, and colorectal tumors. Conclusions Monoallelic MBD4 pathogenic variant may explain some cases of familial and multiple uveal melanoma as well as various cancer types, expanding the tumor spectrum of this predisposition. Further genetic testing in relatives combined with molecular tumor analyses will help define the tumor spectrum and estimate each tumor's risk. [ABSTRACT FROM AUTHOR]

Neutrophil (PMN) tissue accumulation is an established feature of ulcerative colitis (UC) lesions and colorectal cancer (CRC). To assess the PMN phenotypic and functional diversification during the transition from inflammatory ulceration to CRC we analyzed the transcriptomic landscape of blood and tissue PMNs. Transcriptional programs effectively separated PMNs based on their proximity to peripheral blood, inflamed colon, and tumors. In silico pathway overrepresentation analysis, proteinnetwork mapping, gene signature identification, and gene-ontology scoring revealed unique enrichment of angiogenic and vasculature development pathways in tumor-associated neutrophils (TANs). Functional studies utilizing ex vivo cultures, colitis-induced murine CRC, and patient-derived xenograft models demonstrated a critical role for TANs in promoting tumor vascularization. Spp1 (OPN) and Mmp14 (MT1-MMP) were identified by unbiased -omics and mechanistic studies to be highly induced in TANs, acting to critically regulate endothelial cell chemotaxis and branching. TCGA data set and clinical specimens confirmed enrichment of SPP1 and MMP14 in high-grade CRC but not in patients with UC. Pharmacological inhibition of TAN trafficking or MMP14 activity effectively reduced tumor vascular density, leading to CRC regression. Our findings demonstrate a niche-directed PMN functional specialization and identify TAN contributions to tumor vascularization, delineating what we believe to be a new therapeutic framework for CRC treatment focused on TAN angiogenic properties. [ABSTRACT FROM AUTHOR]

Background. Tumor budding is a poor prognostic factor in colorectal adenocarcinoma, but the underlying mechanism remains unclear. Interleukin-6 (IL6) is one of the main cytokines produced by cancer-associated fibroblasts. IL6 is linked with cancer progression and poor prognosis by activating cancer cells and modifying the cancer microenvironment. However, little is known about the expression of IL6 in tumor budding and its association with tumor budding in colorectal adenocarcinoma. Methods. The clinicopathological and prognostic significance of IL6 in tumor budding was examined using a tissue microarray consisting of 36 patient samples of tumor budding in colorectal adenocarcinoma. IL6 mRNA was detected by RNAscope. Patients were stratified into negative and positive IL6 expression groups. Results. IL6 expression was overwhelmingly observed in cancer stroma but was negligible in cancer cells. Tumor budding grade was higher in the IL6-positive group in cancer stroma than in the IL6-negative group (P =.0161), while the IL6-positive group significantly exhibited the epithelial–mesenchymal transition phenotype compared with the IL6-negative group in cancer stroma (P =.0301). There was no significant difference in overall survival between colorectal adenocarcinoma patients in the IL6-positive and -negative groups in cancer stroma. Conclusion. Tumor budding may be affected by IL6 expression, and IL6 expression in cancer stroma at tumor budding may be an important prognostic marker. [ABSTRACT FROM AUTHOR]

The core–shell nanobombs integrating azo bonds (N N) and tetrasulfide bonds (S S S S) have been constructed and exhibit photothermal-thermodynamic effects, therapeutic H 2 S production, and biodegradation under the sensitive ignition by both near-infrared laser and tumor microenvironments, achieving a high efficacy against colorectal tumors. [Display omitted] • Rational design of nanobombs integrating azo and tetrasulfide bonds. • High and stable photothermal conversion due to the passivation of organosilica shell. • Photothermal-ignited nanobombs with the release of alkyl radicals. • Glutathione-ignited simultaneous H 2 S production and biodegradation due to tetrasulfide breaking. Reactive chemical bonds are associated with the generation of therapeutic radicals and gases under internal-external stimuli, which are highly attractive for cancer treatments. However, designing multifunctional nanostructures that incorporate multiple chemical bonds remains a significant challenge. Herein, novel core–shell nanobombs integrating azo (N N) and tetrasulfide bonds (S S S S) have been constructed with sensitive ignition by both near-infrared (NIR) laser and tumor microenvironments (TME) for treating colorectal tumors. The nanobombs (GNR/AIPH@MON@PVP, GAMP) were prepared by the in-situ growth of tetrasulfide-contained mesoporous organosilica nanoshell (MON) on gold nanorods (GNR) as the photothermal initiator, the load of azo compound (AIPH) as the radical producer and polymer modification. Upon NIR irradiation, the GNR core exhibits stable and high photothermal effects because of the passivation of the MON shell, leading to the thermal ablation of cancer cells. Simultaneously, the local hyperthermia ignites AIPH to release alkyl radicals to cause extensive oxidative stress without oxygen dependence. Moreover, the MON shell can be gradually decomposed in a reduced environment and release therapeutic H 2 S gas because of the cleavage of S S S S bonds by the glutathione (GSH) overexpressed in TME, causing mitochondrial injury. Owing to multifunctional functions, the GAMP significantly inhibits the growth rate of tumors upon NIR irradiation and achieves the highest efficacy among treatments. Therefore, this study presents activatable nanoagents containing multiple chemical bonds and provides insights into developing comprehensive antitumor strategies. [ABSTRACT FROM AUTHOR]

Resistance to immunotherapy in colorectal cancer (CRC) is associated with obstruction of FAS (Apo‐1 or CD95)‐dependent apoptosis, a hallmark of cancer. Here it is demonstrated that the upregulation of pirin (PIR) protein in colon cancers promotes tumorigenesis. Knockout or inhibition of PIR dramatically increases FAS expression, FAS‐dependent apoptosis and attenuates colorectal tumor formation in mice. Specifically, NFκB2 is a direct transcriptional activator of FAS and robustly suppressed by PIR in dual mechanisms. One is the disruption of NFκB2 complex (p52‐RELB) association with FAS promoter, the other is the inhibition of NIK‐mediated NFκB2 activation and nuclear translocation, leading to the inability of active NFκB2 complex toward the transcription of FAS. Furthermore, PIR interacts with FAS and recruits it in cytosol, preventing its membrane translocation and assembling. Importantly, knockdown or knockout of PIR dramatically sensitizes cells to FAS mAb‐ or active CD8+ T cells‐triggered cell death. Taken together, a PIR‐NIK‐NFκB2‐FAS survival pathway is established, which plays a key role in supporting CRC survival. [ABSTRACT FROM AUTHOR]

Polyphyllin VII is a biologically active herbal monomer extracted from the traditional Chinese herbal medicine Chonglou. Many studies have demonstrated the anticancer activity of polyphyllin VII against various types of cancers, such as colon, liver, and lung cancer, but its effect on breast cancer has not been elucidated. In this study, we demonstrate that polyphyllin VII inhibited proliferation, increased production of intracellular reactive oxygen species, and decreased mitochondrial membrane potential in breast cancer cells. Notably, polyphyllin VII also induced apoptosis via the mitochondrial pathway. Transcriptome sequencing was used to analyze the targets of PPVII in regulating breast cancer cells. Mechanistic studies showed that polyphyllin VII downregulated Son of Sevenless1 (SOS1) and inhibited the MAPK/ERK pathway. Furthermore, PPVII exerted strong antitumor effects in vivo in nude mice injected with breast cancer cells. Our results suggest that PPVII may promote apoptosis through regulating the SOS1/MAPK/ERK pathway, making it a possible candidate target for the treatment of breast cancer. [ABSTRACT FROM AUTHOR]

Objective To explore the causal relationship between the characteristics of glycemic traits (fasting blood glucose, fasting insulin, glycosylated hemoglobin, and insulin resistance) and benign colorectal neoplasm (colorectal adenomas, benign rectal neoplasm, and benign colon neoplasm). Methods The instrumental variables of blood glucose characteristics were extracted from MAGIC and GLGCL alliance, and the genome-wide data of colorectal benign tumors came from Finn-Gen alliance. In this study, random effect inverse-variance weighted method (IVW), MR-Egger regression, and weighted median method (WMM) were used to analyze the causal relationship between four glycemic traits and benign colorectal neoplasm. Results The results of IVW model showed that there was no causal relationship between fasting blood glucose (OA =0.999, 95%CI: 0.997-1.001), fasting insulin (OA=1.002, 95&lowbar;CI: 0.998-1.006), glycosylated hemoglobin (CI=1.001, 95%CI: 0.999-1.004), insulin resistance (OA=0.999, 95%CI: 0.997-1.002), and colorectal adenoma. There was no causal relationship between fasting blood glucose (OA =0.909, 95%CI: 0.684-1.209), fasting insulin (OA=1.220, 95%CI: 0.706-2.107), glycosylated hemoglobin (0A=0.678, 95&lowbar;CI: 0.440-1.046), insulin resistance (OA=1.161, 95 CI: 0.810-1.663) and rectal benign tumor. There was no causal relationship between fasting blood glucose (OA =0.966, 95%CI: 0.836-1.116), fasting insulin (OA=1.318, 95%CI: 0.906-1.916), glycosylated hemoglobin (OA=1.124, 95%CI: 0.882-1.431), insulin resistance (OA=1.071, 95%CI: 0.875-1.311) and benign tumors of colon. Conclusion There is no evidence of causal relationships of fasting blood glucose, fasting insulin, glycosy- lated hemoglobin, and insulin resistance with colorectal adenomas, benign rectal neoplasm, and benign colon neoplasm. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer is the most common malignancy in Saudi males and third most common in females. Patients with locally advanced colon cancer may eventually develop metastatic disease if not treated promptly and according to guidelines. The recent National Comprehensive Cancer Network guideline recommends tumor resection followed by adjuvant chemotherapy for stage III and high-risk stage II tumors. Therefore, the objective of this study was to characterize patients with locally advanced colon cancer and identify factors associated with the use of adjuvant chemotherapy and the addition of oxaliplatin in locally advanced colon cancer patients. Methods: All patients diagnosed with locally advanced colon cancer at National Guard Health Affairs (NGHA) during 2016-2021 were investigated. Patients' characteristics were compared using Chi-square and Fisher exact test, whereas predictors of adjuvant chemotherapy/Oxaliplatin use were identified using univariate and multivariate logistic regression. Results: Out of 222 patients diagnosed with locally advanced colon cancer, 133 received adjuvant chemotherapy. Factors associated with adjuvant chemotherapy administration were age and smoking status. In the multivariable analysis, older patients were less likely to receive oxaliplatin than younger patients. Stage III patients diagnosed during 2019-2021 had 5.61 times higher odds of receiving oxaliplatin. Conclusion: The findings of this study show that older patients and smokers are less likely to be treated with adjuvant chemotherapy. Moreover, age as well as diagnosis year were important determinants of oxaliplatin administration in stage III locally advanced colon cancer patients. [ABSTRACT FROM AUTHOR]

BACKGROUND: Colorectal cancer (CRC) is a digestive tract malignancy microRNAs (miRNAs) have attracted much attention as biomarkers in tumor studies. OBJECTIVE: This work focused on the predictive potential and mechanism of miR-4310 in CRC. METHODS: The miRNA expression profile sets were obtained from the Gene Expression Omnibus (GEO) database, and the appropriate miRNA was screened by GEO2R. The CRC tissues and control tissues of 88 patients with CRC were collected, and the expression of miR-4310 was detected by quantitative real-time PCR, and the efficacy of miR-4310 in diagnosing CRC was evaluated by the receiver operating characteristic curve (ROC). The effects of miR-4310 on the proliferation, migration, and invasion of CRC cells were explored by Cell Counting Kit-8 (CCK-8) and Transwell experiments. Predicting the potential binding sites of miR-4310 and Runt-related transcription factor 1 (RUNX1) by four predictive websites. The relationship between miR-4310 and RUNX1 was confirmed by a double luciferase reporter gene experiment. RESULTS: The bioinformatics analysis found that miR-4310 was differentially expressed in CRC tissues and this finding was certified by the expression of miR-4310 in CRC tissues of collected patients and cultured CRC cell lines. The expression of miR-4310 had a predictive possibility for CRC patients. MiR-4310/RUNX1 pathway had effects on CRC viability, migration, and invasion. CONCLUSION: MiR-4310 had the potential to be a biomarker for early screening of CRC. MiR-4310 and RUNX1 participated in the regulation of CRC cells. [ABSTRACT FROM AUTHOR]

Background/Aims: Colonoscopy is commonly used for colorectal cancer screening; therefore, the detection of colon subepithelial tumors (SETs) has also increased. Several research studies have been undertaken to diagnose and treat stomach and rectal SETs. The purpose of this study was to determine a diagnostic point for colon SETs by comparing histological findings with the endoscopic characteristics of colon SETs discovered by chance. Methods: A total 194 patients underwent an endoscopic ultrasound (EUS) for suspicious colon SETs during a colonoscopy from May 2014 to December 2021. A total of 105 colon SETs, which were histologically diagnosed, were finally included. Fisher's exact test was used to determine the factors associated with malignant SETs. Results: Colon SETs were predominantly present in the right colon (n = 73, 69.5%), particularly in the transverse colon (n = 32, 30.5%). The majority were smaller than 10 mm (n = 88, 83.8%), and they had hard consistencies (n = 84, 80%) and exhibited no surface changes (n = 96, 91.4%). Most of them were found in the submucosal layers (n = 54, 51.4%) and had a hypoechoic pattern (n = 56, 53.3%) in the EUS. Of the histologically confirmed cases, only three (3/105, 2.9%) were malignant. Most benign lesions were lipomas, suspected parasitic infections, or lesions caused by various inflammatory reactions, including fibrous/fibrocalcific lesions and necrotic nodules. All soft lesions were benign. Two of the three malignant lesions were adenocarcinomas, and the other was lymphoma. For the malignant SETs, there was a statistically significant alteration in the surface of the tumors (p < 0.001), and they were located where the muscularis mucosa layer was included (p = 0.008). The potential malignant SETs, granular cell tumors, and neuroendocrine tumors (NETs) had similar features, such as yellowish hypoechoic masses. Colon NETs were only found in the rectosigmoid junction. Parasitic infections and lesions, resulting in various inflammatory reactions, were observed as pale and hard SETs and mostly revealed as mixed echogenic masses located in the muscularis mucosa, submucosa, or multi-layers in the EUS. Conclusion: This study showed that small colon SETs were mostly benign lesions. Despite its rarity, pathological confirmation is crucial in cases where the SET has surface changes and has been located in a position where the muscularis mucosa layer was included on the EUS, due to the risk of malignancy. [ABSTRACT FROM AUTHOR]

Simple Summary: The prognosis of patients with metastatic colon cancer remains very poor. A minority of patients, mostly those with liver-restricted disease, are eligible for intentionally curative surgery. In most cases, however, the presence of extra-hepatic metastases precludes curative treatment. The aim of this study was to gain insight into the processes governing multi-organ metastasis. We applied the microsurgical transplantation of mouse colon tumor organoids into the caecum or into the liver of syngeneic immunocompetent mice. Colon tumors growing in the liver seeded distant metastases to the lungs and to the peritoneal cavity more efficiently than those growing in the caecum. This was associated with the formation of hotspots of macrophage-surrounded vitronectin-positive blood vessels, specifically in liver tumors. Thus, 'onward spread' from liver metastases plays a major role in multi-organ metastasis, potentially through liver-specific vascular hotspots. The therapeutic targeting of these signals may help achieve the containment of the disease within the liver, thus preventing multi-organ metastasis. Colorectal cancer metastasizes predominantly to the liver but also to the lungs and the peritoneum. The presence of extra-hepatic metastases limits curative (surgical) treatment options and is associated with very poor survival. The mechanisms governing multi-organ metastasis formation are incompletely understood. Here, we tested the hypothesis that the site of tumor growth influences extra-hepatic metastasis formation. To this end, we implanted murine colon cancer organoids into the primary tumor site (i.e., the caecum) and into the primary metastasis site (i.e., the liver) in immunocompetent mice. The organoid-initiated liver tumors were significantly more efficient in seeding distant metastases compared to tumors of the same origin growing in the caecum (intra-hepatic: 51 vs. 40%, p = 0.001; peritoneal cavity: 51% vs. 33%, p = 0.001; lungs: 30% vs. 7%, p = 0.017). The enhanced metastatic capacity of the liver tumors was associated with the formation of 'hotspots' of vitronectin-positive blood vessels surrounded by macrophages. RNA sequencing analysis of clinical samples showed a high expression of vitronectin in liver metastases, along with signatures reflecting hypoxia, angiogenesis, coagulation, and macrophages. We conclude that 'onward spread' from liver metastases is facilitated by liver-specific microenvironmental signals that cause the formation of macrophage-associated vascular hotspots. The therapeutic targeting of these signals may help to contain the disease within the liver and prevent onward spread. [ABSTRACT FROM AUTHOR]

Simple Summary: The success of cancer immunotherapy is largely associated with immunologically hot tumors. Oncolytic viruses can transform cold tumors into hot tumors. In this study, we found that an oncolytic vaccinia virus (oVV) expressing interleukin-9 (IL-9) can transform cold tumors into hot tumors and that it elicited effective antitumor effects. The antitumor effects can be enhanced in combination with an immune checkpoint blockade, indicating a potential translation of the IL-9-expressing oncolytic virus into a clinical trial to enhance the antitumor effects elicited by immune checkpoint blockades for cancer immunotherapy. The success of cancer immunotherapy is largely associated with immunologically hot tumors. Approaches that promote the infiltration of immune cells into tumor beds are urgently needed to transform cold tumors into hot tumors. Oncolytic viruses can transform the tumor microenvironment (TME), resulting in immunologically hot tumors. Cytokines are good candidates for arming oncolytic viruses to enhance their function in this transformation. Here, we used the oncolytic vaccinia virus (oVV) to deliver interleukin-9 (IL-9) into the tumor bed and explored its antitumor effects in colon and lung tumor models. Our data show that IL-9 prolongs viral persistence, which is probably mediated by the up-regulation of IL-10. The vvDD-IL-9 treatment elevated the expression of Th1 chemokines and antitumor factors such as IFN-γ, granzyme B, and perforin. IL-9 expression increased the percentages of CD4+ and CD8+ T cells in the TME and decreased the percentage of oVV-induced immune suppressive myeloid-derived suppressor cells (MDSC), leading to potent antitumor effects compared with parental virus treatment. The vvDD-IL-9 treatment also increased the percentage of regulatory T cells (Tregs) in the TME and elevated the expression of immune checkpoint molecules such as PD-1, PD-L1, and CTLA-4, but not GITR. The combination therapy of vvDD-IL-9 and the anti-CTLA-4 antibody, but not the anti-GITR antibody, induced systemic tumor-specific antitumor immunity and significantly extended the overall survival of mice, indicating a potential translation of the IL-9-expressing oncolytic virus into a clinical trial to enhance the antitumor effects elicited by an immune checkpoint blockade for cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Personalized cancer medicine is based on the right classification of patients that can, then, be treated according to their specific characteristics. This is accomplished by the use of biological markers, so the identification of reliable biomarkers is a primary goal of clinical research. Here, we present two RNA molecules (named MDL1 and MDL1AS) that are generated in the mitochondria and have been heretofore neglected due to a glitch in the official human genome. Both molecules are good prognostic biomarkers in rectal cancer, meaning that their expression can predict which patients will survive more than 5 years after treatment. In addition, MDL1AS is also a good diagnostic biomarker (can distinguish people with/without the disease) for diverse cancers, including those of the colon, rectum, breast, and larynx. Experiments in cancer cells in culture show that these RNAs regulate several hallmarks of cancer, such as mitochondrial function, cell growth, and migration. Non-coding RNAs provide new opportunities to identify biomarkers that properly classify cancer patients. Here, we study the biomarker status of the mitochondrial long non-coding RNAs, MDL1 and MDL1AS. Expression of these genes was studied in public transcriptomic databases. In addition, a cohort of 69 locally advanced rectal cancer (LARC) patients with a follow-up of more than 5 years was used to determine the prognostic value of these markers. Furthermore, cell lines of colorectal (HCT116) and breast (MDA-MB-231) carcinoma were employed to study the effects of downregulating MDL1AS in vitro. Expression of MDL1AS (but not MDL1) was significantly different in tumor cells than in the surrounding tissue in a tumor-type-specific context. Both MDL1 and MDL1AS were accurate biomarkers for the 5-year survival of LARC patients (p = 0.040 and p = 0.007, respectively) with promising areas under the curve in the ROC analyses (0.820 and 0.930, respectively). MDL1AS downregulation reduced mitochondrial respiration in both cell lines. Furthermore, this downregulation produced a decrease in growth and migration on colorectal cells, but the reverse effects on breast cancer cells. In summary, MDL1 and MDL1AS can be used as reliable prognostic biomarkers of LARC, and MDL1AS expression provides relevant information on the diagnosis of different cancers. [ABSTRACT FROM AUTHOR]

Background: Aberrant DNA methylation is prevalent in colorectal serrated lesions. We previously reported that the CpG island of SMOC1 is frequently methylated in traditional serrated adenomas (TSAs) and colorectal cancers (CRCs) but is rarely methylated in sessile serrated lesions (SSLs). In the present study, we aimed to further characterize the expression of SMOC1 in early colorectal lesions. Methods: SMOC1 expression was analyzed immunohistochemically in a series of colorectal tumors (n = 199) and adjacent normal colonic tissues (n = 112). Results: SMOC1 was abundantly expressed in normal colon and SSLs while it was significantly downregulated in TSAs, advanced adenomas and cancers. Mean immunohistochemistry scores were as follows: normal colon, 24.2; hyperplastic polyp (HP), 18.9; SSL, 23.8; SSL with dysplasia (SSLD)/SSL with early invasive cancer (EIC), 15.8; TSA, 5.4; TSA with high grade dysplasia (HGD)/EIC, 4.7; non-advanced adenoma, 21.4; advanced adenoma, 11.9; EIC, 10.9. Higher levels SMOC1 expression correlated positively with proximal colon locations and flat tumoral morphology, reflecting its abundant expression in SSLs. Among TSAs that contained both flat and protruding components, levels of SMOC1 expression were significantly lower in the protruding components. Conclusion: Our results suggest that reduced expression of SMOC1 is associated with progression of TSAs and conventional adenomas and that SMOC1 expression may be a biomarker for diagnosis of serrated lesions and risk prediction in colorectal tumors. [ABSTRACT FROM AUTHOR]

Background: Patients with familial adenomatous polyposis (FAP) have an increased risk of developing gastric neoplasms. However, the clinical course of FAP with these gastric lesions has not yet been fully clarified. The present study aimed to clarify the changes in the incidence risk of developing gastric adenoma or gastric cancer during the lifespan of patients with FAP. Methods: Four hundred forty-three patients with data regarding gastric adenoma and gastric cancer retrospectively registered in a nationwide Japanese multicenter study were enrolled. The cumulative incidences and hazard rates (HRs) of gastric neoplasms were evaluated. Results: The cumulative incidence rates in 50-year-old patients with FAP were 22.8% for gastric adenoma and 7.6% for gastric cancer, respectively. No significant association was found between gastric neoplasms and the colonic phenotype. The peak age for the HR of gastric adenoma was 65 years, with the highest HR (0.043). Regarding the incidence of gastric cancer, the HR increased moderately up to the age of 40 years, but the increase accelerated from the age of 50 years (HR = 0.0067). Conclusion: Careful surveillance of the upper gastrointestinal tract in elderly patients with FAP, such as shortening the interval of follow-up according to age, may be helpful for early diagnosis of gastric cancer. [ABSTRACT FROM AUTHOR]

Background: Iatrogenic colonoscopy perforation (ICP) is a rare but most serious complication during colonoscopy investigation. However, endoscopic closure plays an important role in the dealing with ICP with the development of endoscopic techniques presently, there are still some portion of patients transferred to surgery. Methods: Once a perforation was detected, endoclips were used to closed the defect of the colon. Then a colonic TET was planted inside the colon. The terminal end of the TET was put proximally to or near the location of the perforation. Then gas and fluid was sucked out through the TET with a syringe every 4 h. Results: Three cases were treated with endoclip closure and colonic TET drainage. Case 1 was caused by urgent immediate perforation during routine colonoscopy, case 2 was delayed perforation after snare resection, and case 3 was ESD-related perforation. All patients got healed, no one transferred to surgery. Conclusions: A combination of endoclip closure and colonic TET drainage might be an easy and potential method in the dealing with different types of ICP. This study may offer a novel paradigm for addressing endoscopy-related intestinal perforations. [ABSTRACT FROM AUTHOR]

Background: Colon cancer is a disease with a worldwide spread. Surgery is the best option for the treatment of advanced colon cancer, but some aspects are still debated, such as the extent of lymphadenectomy. In Japanese guidelines, the gold standard was D3 dissection to remove the central lymph nodes (203, 213, and 223), but in 2009, Hoenberger et al. introduced the concept of complete mesocolic excision, in which surgical dissection follows the embryological planes to remove the mesentery entirely to prevent leakage of cancer cells and collect more lymph nodes. Our study describes how lymphadenectomy is currently performed in major Italian centers with an unclear indication on the type of lymphadenectomy that should be performed during right hemicolectomy (RH). Methods: CoDIG 2 is an observational multicenter national study that involves 76 Italian general surgery wards highly specialized in colorectal surgery. Each center was asked not to modify their usual surgical and clinical practices. The aim of the study was to assess the preference of Italian surgeons on the type of lymphadenectomy to perform during RH and the rise of any new trends or modifications in habits compared to the findings of the CoDIG 1 study conducted 4 years ago. Results: A total of 788 patients were enrolled. The most commonly used surgical technique was laparoscopic (82.1%) with intracorporeal (73.4%), side-to-side (98.7%), or isoperistaltic (96.0%) anastomosis. The lymph nodes at the origin of the vessels were harvested in an inferior number of cases (203, 213, and 223: 42.4%, 31.1%, and 20.3%, respectively). A comparison between CoDIG 1 and CoDIG 2 showed a stable trend in surgical techniques and complications, with an increase in the robotic approach (7.7% vs. 12.3%). Conclusions: This analysis shows how lymphadenectomy is performed in Italy to achieve oncological outcomes in RH, although the technique to achieve a higher lymph node count has not yet been standardized. Trial registration (ClinicalTrials.gov) ID: NCT05943951. [ABSTRACT FROM AUTHOR]

Despite the introduction of new molecular classifications, advanced colorectal cancer (CRC) is treated with chemotherapy supplemented with anti-EGFR and anti-VEGF targeted therapy. In this study, 552 CRC cases with different primary tumor locations (250 left side, 190 rectum, and 112 right side) were retrospectively analyzed by next generation sequencing for mutations in 50 genes. The most frequently mutated genes were TP53 in left-sided tumors compared to right-sided tumors and BRAF in right-sided tumors compared to left-sided tumors. Mutations in KRAS, NRAS, and BRAF were not detected in 45% of patients with left-sided tumors and in 28.6% of patients with right-sided tumors. Liver metastases were more common in patients with left-sided tumors. Tumors on the right side were larger at diagnosis and had a higher grade (G3) than tumors on the left. Rectal tumors exhibit distinctive biological characteristics when compared to left-sided tumors, including a higher absence rate of KRAS, NRAS, and BRAF mutations (47.4% in rectal versus 42.8% in left-sided tumors). These rectal tumors are also unique in their primary metastasis site, which is predominantly the lungs, and they have varying mutation rates, particularly in genes such as BRAF, FBXW7, and TP53, that distinguish them from tumors found in other locations. Primary tumor location has implications for the potential treatment of CRC with anti-EGFR therapy. [ABSTRACT FROM AUTHOR]

Transforming acidic acid coiled-coil protein 3 (TACC3) and cytoskeleton associated protein 5 (cKAP5; or colonic hepatic tumor overexpressed gene, chTOG) are vital for spindle assembly and stabilization initiated through TACC3 Aurora-A kinase interaction. Here, TACC3 and cKAP5/chTOG localization with monospecific antibodies is investigated in eGFP-centrin-2- expressing mouse meiotic spermatocytes. Both proteins bind spermatocyte spindle poles but neither kinetochore nor interpolar microtubules, unlike in mitotic mouse fibroblasts or female meiotic oocyte spindles. Spermatocytes do not display a liquid-like spindle domain (LISD), although fusing them into maturing oocytes generates LISD-like TACC3 condensates around sperm chromatin but sparse microtubule assembly. Microtubule inhibitors do not reduce TACC3 and cKAP5/chTOG spindle pole binding. MLN 8237 Aurora-A kinase inhibitor removes TACC3, not cKAP5/chTOG, disrupting spindle organization, chromosome alignment, and impacting spindle pole γ-tubulin intensity. The LISD disruptor 1,6-hexanediol abolished TACC3 in spermatocytes, impacting spindle bipolarity and chromosome organization. Cold microtubule disassembly and rescue experiments in the presence of 1,6-hexanediol reinforce the concept that spermatocyte TACC3 spindle pole presence is not required for spindle pole microtubule assembly. Collectively, meiotic spermatocytes without a LISD localize TACC3 and cKAP5/chTOG exclusively at spindle poles to support meiotic spindle pole stabilization during male meiosis, different from either female meiosis or mitosis. [ABSTRACT FROM AUTHOR]

Despite the introduction of new molecular classifications, advanced colorectal cancer (CRC) is treated with chemotherapy supplemented with anti-EGFR and anti-VEGF targeted therapy. In this study, 552 CRC cases with different primary tumor locations (250 left side, 190 rectum, and 112 right side) were retrospectively analyzed by next generation sequencing for mutations in 50 genes. The most frequently mutated genes were TP53 in left-sided tumors compared to right-sided tumors and BRAF in right-sided tumors compared to left-sided tumors. Mutations in KRAS, NRAS, and BRAF were not detected in 45% of patients with left-sided tumors and in 28.6% of patients with right-sided tumors. Liver metastases were more common in patients with left-sided tumors. Tumors on the right side were larger at diagnosis and had a higher grade (G3) than tumors on the left. Rectal tumors exhibit distinctive biological characteristics when compared to left-sided tumors, including a higher absence rate of KRAS, NRAS, and BRAF mutations (47.4% in rectal versus 42.8% in left-sided tumors). These rectal tumors are also unique in their primary metastasis site, which is predominantly the lungs, and they have varying mutation rates, particularly in genes such as BRAF, FBXW7, and TP53, that distinguish them from tumors found in other locations. Primary tumor location has implications for the potential treatment of CRC with anti-EGFR therapy. [ABSTRACT FROM AUTHOR]

The spleen is a key source of circulating and tumor-infiltrating immune cells. However, the effect of splenectomy on tumor growth remains unclear. At 3 weeks after splenectomy, we subcutaneously injected LuM1 cells into BALB/c mice and evaluated the growth of primary tumors and lung metastases at 4 weeks after tumor inoculation. In addition, we examined the phenotypes of immune cells in peripheral blood by using flow cytometry and in tumor tissue by using multiplex immunohistochemistry. The growth of primary tumors was reduced in splenectomized mice compared with the sham-operated group. Conversely, splenectomized mice had more lung metastases. Splenectomized mice had fewer CD11b+cells, especially monocytic MDSCs (CD11b+Gr-1neg-lowLy6chigh), and NK cells (CD49b+CD335+). The proportion of NK cells was inversely correlated with the number of lung metastases. In splenectomized mice, the density of CD3+ and granzyme B+ CD8+ T cells was increased, with fewer M2-type macrophages in primary tumors, but NK cells were decreased markedly in lung. Splenectomy concurrently enhances T cell-mediated acquired immunity by reducing the number of monocytic MDSCs and suppresses innate immunity by decreasing the number of NK cells. Splenectomy has opposite effects on primary and metastatic lesions through differential regulation on these two immune systems. [ABSTRACT FROM AUTHOR]

Simple Summary: The adrenal gland is often the site of metastasis coming from different primary tumors, including lung, kidney, breast, gastrointestinal cancer and melanoma. Metastasis-directed therapy is not yet well standardized and a multidisciplinary assessment is relevant for planning adequate management. Minimally invasive adrenalectomy is the most common treatment option, and many reports are available in the literature, demonstrating its feasibility. Previous studies showed increased survival in selected patients treated who had an adrenalectomy for metastasis, but all these findings remained inconsistent due to heterogeneous baseline clinical conditions, primary histology and tumor staging. Therefore, further investigations are needed to define the ideal candidate for adrenal metastasectomy in case of oligometastatic diseases. In the present report, we present the oncological outcome of a minimally invasive adrenalectomy for isolated adrenal metastasis, and the impact of primary histology on cancer-specific survival probability. Adrenalectomy is commonly considered a curative treatment in case of adrenal gland as site of metastasis. In the present study, we evaluated the impact of primary tumor histology on survival outcomes after a minimally invasive adrenal mastectomy for a solitary metachronous metastasis. From May 2004 to August 2020, we prospectively collected data on minimally invasive adrenalectomies whose pathological examination showed a metastasis. All patients only received metastasectomies that were performed with curative intent, or to achieve non-evidence of disease status. Adjuvant systemic therapy was not administered in any case. Cancer-specific survival (CSS) was assessed using the Kaplan–Meier method. Univariable and multivariable Cox regression analyses were applied to identify independent predictors of CSS. Out of 235 laparoscopic and robotic adrenalectomies, the pathologic report showed metastases in 60 cases. The primary histologies included 36 (60%) renal cell carcinoma (RCC), 9 (15%) lung cancer, 6 (10%) colon cancer, 4 (6.7%) sarcoma, 3 (5%) melanoma and 2 (3.3%) bladder cancer. RCC displayed significantly longer survival rates with a 5-year CSS of 55.9%, versus 22.8% for other histologies (log-rank p = 0.01). At univariable analysis, disease-free interval (defined as the time from adrenalectomy to evidence of disease progression) < 12 months and histology were predictors of CSS (p = 0.003 and p < 0.001, respectively). At multivariable Cox analysis, the only independent predictor of CSS was primary tumor histology (p = 0.005); patients with adrenal metastasis from colon cancer and bladder cancer showed a 5.3- and 75.5-fold increased risk of cancer death, respectively, compared to patients who had RCC as primary tumor histology. Oncological outcomes of adrenal metastasectomies are strongly influenced by primary tumor histology. A proper discussion of the role of surgery in a multidisciplinary context could provide optimal treatment strategies. [ABSTRACT FROM AUTHOR]

Simple Summary: This research studied how three types of proteins, called interleukins (namely 8, 17A and 33), are present in the blood of healthy people and people with colon cancer. Colon cancer is a disease that affects the large intestine. The paper looked at 82 people, 42 of whom had colon cancer and 40 of whom did not. The researchers divided the cancer patients into four groups based on how severe their cancer was. The study measured the amount of interleukins in the blood of each person using a special test. The paper analyzed the results of the test, considering the age, gender, and cancer stage of each person. The results showed that younger people, and those with less severe cancer had more interleukins in their blood. The paper also found that two of the interleukins (8 and 17A) were higher in the cancer group, while one of them (33) was higher in the healthy group. The study also found that the interleukins were related to each other in both groups. This research concluded that the interleukins might help detect colon cancer and predict how it will progress. This paper could help improve the diagnosis and treatment of colon cancer. This research investigated the serum levels of three interleukins (IL8, IL17A, and IL33) and the possible relationships between them in healthy people and colon cancer patients at different stages. This study involved 82 participants, 42 of whom had colon cancer and 40 were healthy individuals. The cancer patients were classified into four groups according to the TNM staging classification of colon and rectal cancer. Serum levels of the interleukins were measured by the ELISA test. The data were analyzed statistically to compare the demographic characteristics, the interleukin levels across cancer stages, and the correlation between interleukins in both groups. The results showed that women had more early-stage colon cancer diagnoses, while men had more advanced-stage cancer diagnoses. Stage two colon cancer was more common in older people. Younger people, men, and those with early-stage colon cancer had higher levels of interleukins. The levels of IL8 and IL17A were higher in the cancer group, while the level of IL33 was higher in the healthy group. There was a strong correlation between IL8 and IL17A levels in both groups (p = 0.001). IL17A influenced the level of IL33 in the cancer group (p = 0.007). This study suggested that cytokine variation profiles could be useful for detecting colon cancer and predicting its outcome. [ABSTRACT FROM AUTHOR]

Objective. To characterise cancer diagnosis in Scottish primary care in 2018/19 and draw comparisons with diagnostic activity in 2014. Methods. A national audit of cancer diagnosis undertaken in Scottish general practices. Participating GPs collected diagnostic pathway data on patients diagnosed with cancer in 2018/19 from medical records. These data were supplemented by linkage to the Scottish Cancer Registry and previous audit data from 2014. Analyses explored and compared patient demographics, presentation, diagnostic routes, and intervals. Results. Seventy-three practices submitted data on 2,014 cases in 2014 and 90 practices submitted data on 2,318 cases in 2018/2019. Individual demographics and types of cancer were similar. There was a higher proportion of USC (urgent suspected cancer) referrals in 2019 than 2014 (42.9% vs 38.1%, p = 0.008) but a similar proportion of emergency presentations (19.2% vs 20.4%). Primary care (median 4 (IQR 0–22) vs 5 (0–23)) and diagnostic intervals (27 (10–59) vs 30 (13–68)) were similar in both periods. Significantly fewer (24.5% vs 28.3, p = 0.015) had a diagnostic interval >60 days in 2019 than 2014. Harder to diagnose cancers were more likely to present as emergencies and be subject to prolonged delays in both cohorts. Conclusions. The 2014 and 2018/19 cohorts were broadly similar. There is limited evidence that USC use had increased between 2014 and 2018/19. Harder to diagnose cancers are still most likely to present as emergencies and be subject to delays. Overall, it seems there were small improvements in cancer diagnosis prepandemic and a further audit could examine evidence for a postpandemic recovery. [ABSTRACT FROM AUTHOR]

Chemotherapy is widely used to treat colorectal cancer (CRC). Despite its substantial benefits, the development of drug resistance and adverse effects remain challenging. This study aimed to elucidate a novel role of glucagon in anti‐cancer therapy. In a series of in vitro experiments, glucagon inhibited cell migration and tube formation in both endothelial and tumor cells. In vivo studies demonstrated decreased tumor blood vessels and fewer pseudo‐vessels in mice treated with glucagon. The combination of glucagon and chemotherapy exhibited enhanced tumor inhibition. Mechanistic studies demonstrated that glucagon increased the permeability of blood vessels, leading to a pronounced disruption of vessel morphology. Signaling pathway analysis identified a VEGF/VEGFR‐dependent mechanism whereby glucagon attenuated angiogenesis through its receptor. Clinical data analysis revealed a positive correlation between elevated glucagon expression and chemotherapy response. This is the first study to reveal a role for glucagon in inhibiting angiogenesis and vascular mimicry. Additionally, the delivery of glucagon‐encapsulated PEGylated liposomes to tumor‐bearing mice amplified the inhibition of angiogenesis and vascular mimicry, consequently reinforcing chemotherapy efficacy. Collectively, the findings demonstrate the role of glucagon in inhibiting tumor vessel network and suggest the potential utility of glucagon as a promising predictive marker for patients with CRC receiving chemotherapy. [ABSTRACT FROM AUTHOR]

Tissue polarimetry has been gaining importance in extracting useful diagnostic information from the structural attributes of tissues, which vary in response to the tissue health status and hence find great potential in cancer diagnosis. However, the complexities associated with cancer make it challenging to isolate the characteristic changes as the tumor progresses using polarimetry. This study attempts to experimentally characterize the polarimetric behavior in colon cancer associated with various stages of development. Bulk and unstained sections of normal and tumor colon tissue were imaged in the reflection and transmission polarimetry configurations at low and high imaging resolutions using an in-house developed Mueller polarimeter. Through this study, we observed that the information about the major contributors of scattering in colon tissue, manifesting in depolarization and retardance, can be obtained from the bulk tissue and unstained sections. These parameters aid in characterizing the polarimetric changes as the colon tumor progresses. While the unstained colon section best indicated the depolarization contrast between normal and tumor, the contrast through the retardance parameter was more pronounced in the bulk colon tissue. The results suggest that the polarimetric "digitally stained" images obtained by Mueller polarimetry are comparable with the bulk tissue counterparts, making it useful for characterizing colon cancer tissues across different stages of development. [ABSTRACT FROM AUTHOR]

The photosensitizing ability of a boron difluoride beta-diketonate derivative has been studied. The spectral and luminescent properties of the dye and the spectral-kinetic characteristics of its triplet state have been established. The quantum efficiency of singlet oxygen formation has been determined. The in vitro photosensitizing activity of the dye against tumor cells of colon adenocarcinoma was demonstrated, and the values of dark and photoinduced cytotoxicity were obtained. [ABSTRACT FROM AUTHOR]

BACKGROUND: Advances in surgical practices have decreased hospital length of stay (LOS) after surgery. This study aimed to determine the safety of short-stay (≤24-hour) left colectomy for colon cancer patients in the US. STUDY DESIGN: Adult colon cancer patients who underwent elective left colectomies were identified using the American College of Surgeons NSQIP database (2012 to 2021). Patients were categorized into 4 LOS groups: LOS 1 day or less (≤24-hour short stay), 2 to 4, 5 to 6, and 7 or more. Primary outcomes were 30-day postoperative overall and serious morbidity. Secondary outcomes were 30-day mortality and readmission. Multivariable logistic regression was performed to explore the association between LOS and overall and serious morbidity. RESULTS: A total of 15,745 patients who underwent left colectomies for colon cancer were identified with 294 (1.87%) patients undergoing short stay. Short-stay patients were generally younger and healthier with lower 30-day overall morbidity rates (LOS ≤1 day: 3.74%, 2 to 4: 7.38%, 5 to 6: 16.12%, and ≥7: 37.64%, p < 0.001). Compared with patients with LOS 2 to 4 days, no differences in mortality and readmission rates were observed. On adjusted analysis, there was no statistical difference in the odds of overall (LOS 2 to 4 days: odds ratio 1.90, 95% CI 1.01 to 3.60, p = 0.049) and serious morbidity (LOS 2 to 4 days: odds ratio 0.86, 95% CI 1.42 to 1.76, p = 0.672) between the short-stay and LOS 2 to 4 days groups. CONCLUSIONS: Although currently performed at low rates in the US, short-stay left colectomy is safe for a select group of patients. Attention to patient selection, refinement of clinical pathways, and close follow-up may enable short-stay colectomies to become a more feasible reality. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) exhibits pronounced heterogeneity and is categorized into four widely accepted consensus molecular subtypes (CMSs) with unique tumor microenvironments (TMEs). However, the intricate landscape of the microbiota and host-microbiota interactions within these TMEs remains elusive. Using RNA-sequencing data from The Cancer Genome Atlas, we analyzed the host transcriptomes and intratumoral microbiome profiles of CRC samples. Distinct host genes and microbial genera were identified among the CMSs. Immune microenvironments were evaluated using CIBERSORTx and ESTIMATE, and microbial coabundance patterns were assessed with FastSpar. Through LASSO penalized regression, we explored hostmicrobiota associations for each CMS. Our analysis revealed distinct host gene signatures within the CMSs, which encompassed ferroptosis-related genes and specific immune microenvironments. Moreover, we identified 293, 153, 66, and 109 intratumoral microbial genera with differential abundance, and host-microbiota associations contributed to distinct TMEs, characterized by 829, 1,270, 634, and 1,882 robust gene-microbe associations for each CMS in CMS1–CMS4, respectively. CMS1 featured inflammation-related HSF1 activation and gene interactions within the endothelin pathway and Flammeovirga. Integrin-related genes displayed positive correlations with Sutterella in CMS2, whereas CMS3 spotlighted microbial associations with biosynthetic and metabolic pathways. In CMS4, genes involved in collagen biosynthesis showed positive associations with Sutterella, contributing to disruptions in homeostasis. Notably, immune-rich subtypes exhibited pronounced ferroptosis dysregulation, potentially linked to tissue microbial colonization. This comprehensive investigation delineates the diverse landscapes of the TME within each CMS, incorporating host genes, intratumoral microbiota, and their complex interactions. These findings shed light on previously uncharted mechanisms underpinning CRC heterogeneity and suggest potential therapeutic targets. NEW & NOTEWORTHY This study determined the following: 1) providing a comprehensive landscape of consensus molecular subtype (CMS)-specific tumor microenvironments (TMEs); 2) constructing CMS-specific networks, including host genes, intratumoral microbiota, and enriched pathways, analyzing their associations to uncover unique patterns that demonstrate the intricate interplay within the TME; and 3) revealing a connection between immune-rich subtypes and ferroptosis activation, suggesting a potential regulatory role of the microbiota in ferroptosis dysregulation of the colorectal cancer TME. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer (CRC) has consistently shown a global rise in incidence. p53 exerts regulatory function in signaling processes, with the p53 mutation accelerating the late stage of colorectal carcinogenesis. Programmed death ligand 1 (PD-L1) is an immune checkpoint regulator whose role in targeted therapy of CRCs needs to be evaluated. Beta-catenin plays a fundamental role in cell adhesion, with long-term effects on disease progression and survival. A detailed evaluation of all these factors is essential to tailoring new therapeutic approaches in advanced-stage cases. Aims and Objectives: To study the immunohistochemical (IHC) expression of p53, PD-L1, and beta-catenin in different histologic grades and stages of colorectal carcinomas. Materials and Methods: A total of 29 cases of segmental colectomy were included in the study population. Tumor sections were sent for IHC study of p53, PD-L1, and beta-catenin and interpreted as per standard protocol. Findings were tabulated against the histologic grade and stages of CRCs. Statistical analysis was done using SPSS 25.0 to test for statistical significance at P<0.05. Results: The study population predominantly consisted of males (66%), mainly in the age group of 46-60 years. p53 was significantly more expressed in left colonic tumors. PD-L1 expression was also significantly associated with histologic grade and nodal metastasis. High beta-catenin expression was seen in well-differentiated adenocarcinomas and lower T and N-stage disease. Positive p53 also correlated with positive PD-L1 expression. However, expression of p53 was also high in tumors with low beta-catenin expression. Conclusion: p53, PD-L1, and beta-catenin may have a role in prognostication and predicting long-term survival outcomes in CRC cases. These may also act as potential therapeutic targets with a more detailed evaluation and a larger sample size of CRC cases. [ABSTRACT FROM AUTHOR]