Differential expression of angiogenesis-related genes 'VEGF' and 'angiopoietin-1' in metastatic and EMAST-positive colorectal cancer patients.

Abnormal angiogenesis leads to tumor progression and metastasis in colorectal cancer (CRC). This study aimed to elucidate the association between angiogenesis-related genes, including VEGF-A, ANGPT-1, and ANGPT-2 with both metastatic and microsatellite alterations at selected tetranucleotide repeats (EMAST) subtypes of CRC. We conducted a thorough assessment of the ANGPT-1, ANGPT-2, and VEGF-A gene expression utilizing publicly available RNA sequencing and microarray datasets. Then, the experimental validation was performed in 122 CRC patients, considering their disease metastasis and EMAST+/- profile by using reverse transcription polymerase chain reaction (RT-PCR). Subsequently, a competing endogenous RNA (ceRNA) network associated with these angiogenesis-related genes was constructed and analyzed. The expression level of VEGF-A and ANGPT-2 genes were significantly higher in tumor tissues as compared with normal adjacent tissues (P-value < 0.001). Nevertheless, ANGPT-1 had a significantly lower expression in tumor samples than in normal colon tissue (P-value < 0.01). We identified a significantly increased VEGF-A (P-value = 0.002) and decreased ANGPT-1 (P-value = 0.04) expression in EMAST+ colorectal tumors. Regarding metastasis, a significantly increased VEGF-A and ANGPT-2 expression (P-value = 0.001) and decreased ANGPT-1 expression (P-value < 0.05) were established in metastatic CRC patients. Remarkably, co-expression analysis also showed a strong correlation between ANGPT-2 and VEGF-A gene expressions. The ceRNA network was constructed by ANGPT-1, ANGPT-2, VEGF-A, and experimentally validated miRNAs (hsa-miR-190a-3p, hsa-miR-374c-5p, hsa-miR-452-5p, and hsa-miR-889-3p), lncRNAs (AFAP1-AS1, KCNQ1OT1 and MALAT1), and TFs (Sp1, E2F1, and STAT3). Network analysis revealed that colorectal cancer is amongst the 82 significant pathways. We demonstrated a significant differential expression of VEGF-A and ANGPT-1 in colorectal cancer patients exhibiting the EMAST+ phenotype. This finding provides novel insights into the molecular pathogenesis of colorectal cancer, specifically in EMAST subtypes. Yet, the generalization of in silico findings to EMAST+ colorectal cancer warrants future experimental investigations. In the end, this study proposes that the EMAST biomarker could serve as an additional perspective on CMS4 biology which is well-defined by activated angiogenesis and worse overall survival.

Intradermal methylene blue analgesic application in posthemorrhoidectomy pain management: a randomized controlled trial.

Introduction: Unbearable post-hemorrhoidectomy pain is a well-documented challenge, significantly impacting patient well-being and satisfaction after surgery, often influencing patients to decline in undergoing this procedure. It is widely recognized that methylene blue has an effect of reducing inflammation and pain by reduces the production of nitric oxide and inhibiting the action potentials production in nerves. This study aims to explore the potential benefits of postoperative regional administration of methylene blue in providing extended relief from post-hemorrhoidectomy pain. Methods: This study included 97 patients aged 18-75 undergoing hemorrhoidectomy for stage III or IV hemorrhoids. A double-blind, randomized controlled trial compared postoperative intradermal injections of 1% methylene blue to 0.5% Marcaine as the control group. Two-week follow-up assessed pain. Statistical analysis, adherence to ethical standards, and registration were conducted. Result: No significant differences were found in baseline demographics, surgical parameters, or complications between the Methylene Blue and control groups. Intervention group remained lower in mean pain score until the 12th day. Methylene blue group reported significantly lower postoperative pain scores from days 1 to 7, with no significant differences afterward. Conclusion: This ongoing randomized controlled trial reveals the potential analgesic benefits of intradermal injection 1% methylene blue. It demonstrates comparable efficacy in reducing post-hemorrhoidectomy pain, with negligible side effects and complications.

UBE2C: A pan-cancer diagnostic and prognostic biomarker revealed through bioinformatics analysis.

BACKGROUND: The diverse and complex attributes of cancer have made it a daunting challenge to overcome globally and remains to endanger human life. Detection of critical cancer-related gene alterations in solid tumor samples better defines patient diagnosis and prognosis, and indicates what targeted therapies must be administered to improve cancer patients' outcome. MATERIALS AND METHODS: To identify genes that have aberrant expression across different cancer types, differential expressed genes were detected within the TCGA datasets. Subsequently, the DEGs common to all pan cancers were determined. Furthermore, various methods were employed to gain genetic alterations, co-expression genes network and protein-protein interaction (PPI) network, pathway enrichment analysis of common genes. Finally, the gene regulatory network was constructed. RESULTS: Intersectional analysis identified UBE2C as a common DEG between all 28 types of studied cancers. Upregulated UBE2C expression was significantly correlated with OS and DFS of 10 and 9 types of cancer patients. Also, UBE2C can be a diagnostic factor in CESC, CHOL, GBM, and UCS with AUC = 100% and diagnose 19 cancer types with AUC ≥90%. A ceRNA network constructed including UBE2C, 41 TFs, 10 shared miRNAs, and 21 circRNAs and 128 lncRNAs. CONCLUSION: In summary, UBE2C can be a theranostic gene, which may serve as a reliable biomarker in diagnosing cancers, improving treatment responses and increasing the overall survival of cancer patients and can be a promising gene to be target by cancer drugs in the future.

Guanylate cyclase-C Signaling Axis as a theragnostic target in colorectal cancer: a systematic review of literature.

Introduction: Colorectal cancer (CRC) is a devastating disease that affects millions of people worldwide. Recent research has highlighted the crucial role of the guanylate cyclase-C (GC-C) signaling axis in CRC, from the early stages of tumorigenesis to disease progression. GC-C is activated by endogenous peptides guanylin (GU) and uroguanylin (UG), which are critical in maintaining intestinal fluid homeostasis. However, it has been found that these peptides may also contribute to the development of CRC. This systematic review focuses on the latest research on the GC-C signaling axis in CRC. Methods: According to the aim of the study, a systematic literature search was conducted on Medline and PubMed databases. Ultimately, a total of 40 articles were gathered for the systematic review. Results: Our systematic literature search revealed that alterations in GC-C signaling compartments in CRC tissue have demonstrated potential as diagnostic, prognostic, and therapeutic markers. This research highlights a potential treatment for CRC by targeting the GC-C signaling axis. Promising results from recent studies have explored the use of this signaling axis to develop new vaccines and chimeric antigen receptors that may be used in future clinical trials. Conclusion: The findings presented in this review provide compelling evidence that targeting the GC-C signaling axis may be an advantageous approach for treating CRC.

The molecular biology and therapeutic potential of Nrf2 in leukemia.

NF-E2-related factor 2 (Nrf2) transcription factor has contradictory roles in cancer, which can act as a tumor suppressor or a proto-oncogene in different cell conditions (depending on the cell type and the conditions of the cell environment). Nrf2 pathway regulates several cellular processes, including signaling, energy metabolism, autophagy, inflammation, redox homeostasis, and antioxidant regulation. As a result, it plays a crucial role in cell survival. Conversely, Nrf2 protects cancerous cells from apoptosis and increases proliferation, angiogenesis, and metastasis. It promotes resistance to chemotherapy and radiotherapy in various solid tumors and hematological malignancies, so we want to elucidate the role of Nrf2 in cancer and the positive point of its targeting. Also, in the past few years, many studies have shown that Nrf2 protects cancer cells, especially leukemic cells, from the effects of chemotherapeutic drugs. The present paper summarizes these studies to scrutinize whether targeting Nrf2 combined with chemotherapy would be a therapeutic approach for leukemia treatment. Also, we discussed how Nrf2 and NF-κB work together to control the cellular redox pathway. The role of these two factors in inflammation (antagonistic) and leukemia (synergistic) is also summarized.

Dual Blockade of PD-1 and LAG3 Immune Checkpoints Increases Dendritic Cell Vaccine Mediated T Cell Responses in Breast Cancer Model.

PURPOSE: Increasing the efficiency of unsuccessful immunotherapy methods is one of the most important research fields. Therefore, the use of combination therapy is considered as one of the ways to increase the effectiveness of the dendritic cell (DC) vaccine. In this study, the inhibition of immune checkpoint receptors such as LAG3 and PD-1 on T cells was investigated to increase the efficiency of T cells in response to the DC vaccine. METHODS: We used trimethyl chitosan-dextran sulfate-lactate (TMC-DS-L) nanoparticles (NPs) loaded with siRNA molecules to quench the PD-1 and LAG3 checkpoints' expression. RESULTS: Appropriate physicochemical characteristics of the generated NPs led to efficient inhibition of LAG3 and PD-1 on T cells, which was associated with increased survival and activity of T cells, ex vivo. Also, treating mice with established breast tumors (4T1) using NPs loaded with siRNA molecules in combination with DC vaccine pulsed with tumor lysate significantly inhibited tumor growth and increased survival in mice. These ameliorative effects were associated with increased anti-tumor T cell responses and downregulation of immunosuppressive cells in the tumor microenvironment and spleen. CONCLUSION: These findings strongly suggest that TMC-DS-L NPs loaded with siRNA could act as a novel tool in inhibiting the expression of immune checkpoints in the tumor microenvironment. Also, combination therapy based on inhibition of PD-1 and LAG3 in combination with DC vaccine is an effective method in treating cancer that needs to be further studied.

Targeting Wee1 kinase as a therapeutic approach in Hematological Malignancies.

Hematologic malignancies include various diseases that develop from hematopoietic stem cells of bone marrow or lymphatic organs. Currently, conventional DNA-damage-based chemotherapy drugs are approved as standard therapeutic regimens for these malignancies. Although many improvements have been made, patients with relapsed or refractory hematological malignancies have a poor prognosis. Therefore, novel and practical therapeutic approaches are required for the treatment of these diseases. Interestingly several studies have shown that targeting Wee1 kinase in the Hematological malignancies, including AML, ALL, CML, CLL, DLBCL, BL, MCL, etc., can be an effective therapeutic strategy. It plays an essential role in regulating the cell cycle process by abrogating the G2-M cell-cycle checkpoint, which provides time for DNA damage repair before mitotic entry. Consistently, Wee1 overexpression is observed in various Hematological malignancies. Also, in healthy normal cells, repairing DNA damages occurs due to G1-S checkpoint function; however, in the cancer cells, which have an impaired G1-S checkpoint, the damaged DNA repair process depends on the G2-M checkpoint function. Thus, Wee1 inhibition could be a promising target in the presence of DNA damage in order to potentiate multiple therapeutic drugs. This review summarized the potentials and challenges of Wee1 inhibition combined with other therapies as a novel effective therapeutic strategy in Hematological malignancies.

Endoscopic pilonidal sinus treatment: A minimally invasive surgical technique.

INTRODUCTION: Pilonidal sinus disease (PSD) is a common skin and subcutaneous disease that is mainly seen in men (mean age, 30 years); its incidence rate is 26 cases per 100 000. PSD greatly affects quality of life. Ideally, a surgical procedure to treat PSD should involve a minimal hospital stay and require minimal time off work, discomfort, operative time, and cost; it should also limit recurrence. In this study, we present a new minimally invasive technique for pilonidal sinus surgery known as endoscopic pilonidal sinus treatment (EPSiT). METHODS: From February 2017 to April 2019, 100 patients diagnosed with PSD were treated with the EPSiT method at the Department of General Surgery, Imam Reza Hospital. Patient information was recorded prospectively. During the operation, the fistula cavity and tracts were ablated by an electrode that was introduced through the operative channel. All the epithelial and granulation tissues were removed by a brush inserted into the operative channel or by a Volkmann spoon. RESULTS: None of the patients had postoperative complications, such as hematoma, seroma, or wound infection, during the follow-up period. Recurrence was seen four patients (4%). At 1 week postoperatively, the visual analog scale score was 3 for 37 patients (37%) and 2 for 28 patients (28%). The maximal cosmetic satisfaction rate was reported in 85 patients (85%). CONCLUSION: As a minimally invasive procedure, EPSiT is effective for treating PSD. Compared with excision and primary closure techniques, EPSiT has a very low recurrence rate after the procedure and a short hospital stay.