USP15 promotes the progression of papillary thyroid cancer by regulating HMGB1 stability through its deubiquitination.

Purpose: Papillary thyroid cancer (PTC) stands as one of the most prevalent types of thyroid cancers, characterized by a propensity for in-situ recurrence and distant metastasis. The high mobility group protein (HMGB1), a conserved nuclear protein, plays a pivotal role in carcinogenesis by stimulating tumor cell growth and migration. Nevertheless, the underlying mechanism driving aberrant HMGB1 expression in PTC necessitates further elucidation. Materials and methods: Our study unraveled the impact of low and overexpression of USP15 on the proliferation, invasion, and metastasis of PTC cells. Through a comprehensive array of molecular techniques, we uncovered the intricate relationship between HMGB1 and USP15 in the progression of PTC. Results: In this study, we identified USP15, a deubiquitinase in the ubiquitin-specific proteases family, as a true deubiquitylase of HMGB1 in PTC. USP15 was shown to interact with HMGB1 in a deubiquitination activity-dependent manner, deubiquitinating and stabilizing HMGB1. USP15 depletion significantly decreased PTC cell proliferation, migration, and invasion. In addition, the effects induced by USP15 depletion could be rescued by further HMGB1 overexpression. But when HMGB1 is knocked down, even overexpression of USP15 could not promote the progression of PTC cells. Conclusion: In essence, our discoveries shed light on the previously uncharted catalytic role of USP15 as a deubiquitinating enzyme targeting HMGB1, offering a promising avenue for potential therapeutic interventions in the management of PTC.

The prevention of rectovaginal fistula after rectal cancer surgery by packing with laparoscopic dislocated fat flap containing ovarian vascular pedicle anterior to the anastomotic stoma: a parallel group randomized controlled trial protocol.

BACKGROUND: Rectovaginal fistula (RVF) is an abnormal channel formed by epithelial tissue between the anterior wall of the rectum and the posterior wall of the vagina, which manifests as vaginal gassing and defecation. It is one of the common complications of female pelvic surgeries. With the increased number of proctectomies for rectal cancer, the number of postoperative rectovaginal fistulas also increases. Once RVF occurs, the failure rate is still high with various treatments available. RVF causes great suffering to women and is still a major problem in treatment. Therefore, it is significant for female rectal cancer patients to prevent RVF after rectal cancer surgery. In this study, we introduce a new method to prevent RVF during rectal cancer radical operation. METHODS: In this randomized controlled trial (RCT), all operations are performed according to the principle of total mesorectal excision (TME) radical resection in rectal cancer surgery. All eligible participants will be divided into two groups: the experimental group and the control group. Experimental group: the anterior rectal wall of about 1 cm distal to the anastomosis was dislocated. Before the anastomosis of the rectal end, a fat flap (usually left side) containing the ovarian vascular pedicle was dislocated, measured by 10-15 cm in length and 2 cm in width. The fat flap containing the ovarian vascular pedicle was packed and fixed anterior to the anastomotic stoma with fibrin glue. CONTROL GROUP: surgery will be carried out in accordance with the TME principle. Participants will be compared on several variables, including the incidence of RVF after operation (primary outcomes), the occurrence time of postoperative RVF, the occurrence time of RVF after stoma closure, and other postoperative complications, such as anastomotic leakage, chylous leakage, and intestinal obstruction (secondary outcomes). The follow-up data collection will be conducted according to the follow-up time point, and the baseline data will also be collected for follow-up analysis. By comparing the incidence of rectovaginal leakage between the experimental group and the control group, we aim to explore the feasibility of this method for the prevention of postoperative RVF. DISCUSSION: This RCT will explore the feasibility of packing with a laparoscopic dislocated fat flap containing an ovarian vascular pedicle anterior to the anastomotic stoma after rectal cancer surgery to prevent RVF. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR) registration ChiCTR2000031449. Registered on June 26, 2019. All items of the WHO Trial registration data set can be found within the protocol.

Clinical significance of 206 station lymph node in transverse colon cancer.

BACKGROUND: Lymph node (LN) metastasis is crucial in determining the prognosis and treatment options for colon cancer patients. Our work was to study whether the lymph nodes beyond D3 station in transverse colon cancer, especially 206 LN, should be dissected. METHODS: A total of 225 patients within our department were reviewed. The primary and secondary endpoints were overall survival (OS) and disease-free survival (DFS). We employed Propensity score weighting (PSW) for weighing participants to balance observed confounders between the 206D+ group and the 206D- group. RESULTS: The rate of metastasis in station 206 was 9.3%. Only T stage (OR, 3.009; 95% CI, 1.018-8.892), N stage (OR, 9.818; 95% CI, 1.158-83.227), and M stage (OR, 26.126; 95% CI, 1.274-535.945) were an independent risk factor for 206 station metastasis in multivariate logistic analysis. The 206D+ group had a similarly survival than the 206D- group (3-year DFS, 89.6% v 85.9%; p = 0.389; 3-year OS, 94.6% v 85.3% p = 0.989). PSW further verified it. Metastasis of 206 station LN is not an independent prognostic factor, but a predictive factor of DFS. CONCLUSION: Station 206 LN positive is a predictive factor for DFS. Only the patient with T1-3, N+ who is at a high risk of 206 station LN metastases should consider dissecting 206 station LN.

Preoperative combination score of neutrophils, monocytes, and lymphocytes as a predictor for locally advanced rectal cancer.

OBJECTIVE: The aim of this study was to investigate the prognostic value of baseline peripheral blood neutrophils, monocytes, and lymphocytes on locally advanced rectal cancer (LARC) patients. METHODS: Clinicopathologic data of 317 LARC patients during July 2010 and October 2016 were retrospectively gathered. X-tile software was used to acquire the optimal cutoff values of neutrophils, monocytes, and lymphocytes. Peripheral blood immune score (PBIS) system was proposed and built based on neutrophils, monocytes, and lymphocytes. The Cox model was used to analyze the associations between clinicopathological characteristics and potential outcomes. C-index was used to assess model performance. A nomogram was constructed to predict prognosis, and a calibration plot was used to verify the accuracy of the nomogram prediction model. RESULTS: Cutoff values of neutrophils, lymphocytes, and monocytes were 4.46 (× 109/L), 1.66 (× 109/L), and 0.39 (× 109/L), respectively. PBIS was related to sex (P < 0.001), tumor length (P = 0.003), and tumor thickness (P = 0.014). Multivariate Cox regression analysis revealed that PBIS (HR = 0.707, 95% CI: 0.549-0.912, P = 0.008) was an independent predictor of DFS. High PBIS (HR = 0.697, 95% CI: 0.492-0.988, P = 0.043) and high lymphocyte count (HR = 0.511, 95%CI: 0.273-0.958, P = 0.036) were favorable factors of OS. Both C-index (0.74, 95% CI: 0.549-0.912) and the calibration plot showed good prediction ability of the nomogram for DFS. CONCLUSION: PBIS, composed of baseline peripheral blood neutrophils, monocytes, and lymphocytes, is an independent predictor of the prognosis of LARC. Combination of PBIS and ypTNM stage may be a promising marker to guide adjuvant therapy after the operation.

USP43 directly regulates ZEB1 protein, mediating proliferation and metastasis of colorectal cancer.

Colorectal cancer is one of the most common malignant tumors of the digestive tract. In this study, we had examined the biological role of USP43 in colorectal cancer. USP43 protein and mRNA abundance in clinical tissues and five cell lines were analyzed with quantitative real-time PCR test (qRT-PCR) and western blot. USP43 overexpression treated DLD1 cells and USP43 knockdown treated SW480 cells were used to study cell proliferation, migration, colony formation, invasion, and the expression of epithelial-mesenchymal transformation (EMT) biomarkers. Moreover, ubiquitination related ZEB1 degradation was studied with qRT-PCR and western blot. The relationships between USP43 and ZEB1 were investigated with western blot, co-immunoprecipitation, migration, and invasion. USP43 was highly expressed in colorectal cancer tissues. USP43 overexpression and knockdown treatments could affect cell proliferation, colony formation, migration, invasion, and the expression of EMT associated biomarkers. Moreover, USP43 can regulate ZEB1 degradation through ubiquitination pathway. USP43 could promote the proliferation, migration, and invasion of colorectal cancer. Meanwhile, USP43 can deubiquitinate and stabilize the ZEB1 protein, which plays an important role in the function of colorectal cancer.

A nomogram for predicting rectovaginal fistula after low anterior resection for rectal cancer.

PURPOSE: Rectovaginal fistula (RVF) is a complicated and troublesome complication of low anterior resection (LAR) for rectal cancer. We aimed to investigate the risk factors for post-LAR RVF and develop a predictive nomogram. METHODS: We performed a retrospective analysis of 821 female patients with rectal cancer who underwent LAR between October 2010 and October 2018. Logistic regression was performed to identify risk factors. A nomogram was developed to predict RVF. RESULTS: The incidence of post-LAR RVF was 3.4% (28/821). A multivariate analysis showed that the preoperative serum hemoglobin level (OR 2.449, 95% CI 1.144-5.239), the distance between the tumor and anal verge (OR 4.158, 95% CI 1.392-12.418), surgical procedure (OR 2.369, 95% CI 1.117-5.027), hysterectomy (OR 2.996, 95% CI 1.106-8.833), and bilateral oophorectomy (OR 5.823, 95% CI 1.639-20.689) were significantly associated with the development of RVF. A nomogram was developed, which showed a C-index of 0.824 (95% CI 0.730-0.918) and an adjusted C-index of 0.790. CONCLUSION: This study identified the preoperative serum hemoglobin level, the distance between the tumor and the anal verge, the type of surgical procedure, hysterectomy, and bilateral oophorectomy as predictors of post-LAR RVF. A nomogram was successfully developed. It could aid in the prediction of RVF in patients undergoing LAR.

The Expressions of Keratins and P63 in Primary Squamous Cell Carcinoma of the Thyroid Gland: An Application of Raman Spectroscopy.

PURPOSE: Primary squamous cell carcinoma is a rare malignancy in the thyroid gland (SCCTh). The overall prognosis of this carcinoma is poor. This study aimed to explore the application of Raman spectroscopy in investigating the expression of CK5/6 and P63 in SCCTh. PATIENTS AND METHODS: Tissues of the SCCTh and adjacent normal thyroid, as well as blood serum, were collected from a patient with pathology-confirmed SCCTh. Whole genome sequencing analysis was performed with the tissue of the SCCTh. The expressions of keratins and TP53 family gene were investigated by the Raman spectroscopy in tissues of the SCCTh and adjacent normal thyroid. The serum was also investigated by the Raman spectroscopy for the expression of keratins and TP53 family gene. RESULTS: The whole genome sequencing analysis identified the mutation of the TP53 gene (42%) in the tissues of SCCTh. Accordingly, the Raman spectra analyses showed higher expression of keratins and TP53 family gene in the tissues of SCCTh compared with that in the adjacent normal thyroid. Raman spectra analyses of the serum of the patient also showed the expressions of the keratins and TP53 family gene. CONCLUSION: The expressions of the keratins and TP53 are different in the tissues of SCCTh and adjacent normal thyroid, and the difference could be identified with high sensitivity by the Raman spectra analyses.

A 3-circular RNA signature as a noninvasive biomarker for diagnosis of colorectal cancer.

BACKGROUND: Circular RNAs (circRNAs), a novel type of noncoding RNAs, play critical roles in the initiation and progression of cancer. Emerging studies also shows that circRNAs may function as potential markers for cancer diagnosis and treatment. However, the diagnostic value of circRNAs in colorectal cancer (CRC) remains need to be unearthed. METHODS: CircRNA microarray was performed to detect the differentially expressed circRNAs in eight plasma samples, including four colorectal cancer (CRC) and four normal samples. Besides, the results of microarray were validated by quantitative real-time polymerase chain reaction (qRT-PCR). Moreover, ROC curve evaluation was performed to calculate the diagnostic value of significantly dysregulated circRNAs. In order to predict the potential mechanism of the significant circRNAs, circRNA-miRNA-mRNA network was constructed based on the TargetScan, miRTarBase and MIRDB database, as well as CircInteractome online software. Furthermore, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to further predict the function of meaningful circRNAs. RESULTS: Totally three differentially expressed circRNAs were identified in CRC plasma compared to normal plasma by circRNA microarray analysis, and the results was validated by qRT-PCR. Hsa_circ_0082182, hsa_circ_0000370 and hsa_circ_0035445 were identified and ROC curves analysis was used to calculate the single and joint diagnostic value. Furthermore, GO and KEGG analyses revealed that functions were mainly cancer-related, which indicated that the circRNAs were meaningfully associated with CRC cell proliferation and metastasis. CONCLUSION: In conclusion, we have identified three circRNAs that are dysregulated in CRC plasma, including hsa_circ_0082182, hsa_circ_0000370 and hsa_circ_0035445. ROC curves showed that these circRNAs might have diagnostic value for colorectal cancer. Furthermore, bioinformatics analysis indicated that the above-mentioned circRNAs might be involved in the development of CRC.

Survival outcome of adjuvant radiotherapy after local excision for T2 early rectal cancer: An analysis based on the surveillance, epidemiology, and end result registry database.

BACKGROUND: Major resection (MR) is recommended for cases with T2 finding after local excision (LE) of early rectal cancer, but the revision procedure is accompanied with high morbidity. We evaluated the oncological safety of LE followed by adjuvant radiotherapy as a rectum-preserving alternative to MR for T2 early rectal cancer. METHODS: A total of 3786 patients with T2N0M0 rectal adenocarcinoma between 1998 and 2013 were included from the SEER database. Survival rates were compared using the Kaplan-Meier method with a log-rank test, and multivariate analyses were performed using Cox proportional regression models. RESULTS: Of these patients included, 429 (11.3%) treated with LE alone (LE group), 3067 (81.0%) treated with MR (MR group), and 290 (7.7%) treated with LE followed by adjuvant radiotherapy (LE + adjuvant RT group). The 5-year cancer specific survival (CSS) rate and 5-year overall survival (OS) rate were significantly lower in LE patients group than those in MR patients group (70.5% vs. 81.8%, P < 0.001; 57.3% vs. 72.3%, P < 0.001). The 5-year CSS rate and 5-year OS rate were similar between LE + adjuvant RT and MR groups (78.4% vs. 81.8%, P = 0.975, and 70.7% vs. 72.3%, P = 0.311, respectively). Multivariate Cox regression revealed that treatment strategies, age and CEA status were independently associated with CSS and OS. After age adjustment, LE was associated with reduced CSS (using MR as a reference, HR, 1.784; P < 0.001) and reduced OS (HR, 1.739; P < 0.001). However, CSS and OS related to LE + adjuvant RT of T2 rectal cancer group weren't be affected (HR, 0.994; P = 0.962 and HR, 0.904; P = 0.302, respectively). CONCLUSIONS: When MR is inappropriate for T2 early rectal cancer patients because of patients refusal or co-morbidities, LE + adjuvant RT can provide acceptable levels of long-term survival.

Risk Factors for Early Postoperative Small Bowel Obstruction after Elective Colon Cancer Surgery: An Observational Study of 1,244 Consecutive Patients.

BACKGROUND: Early postoperative small bowel obstruction (EPSBO) is a common complication following colon cancer surgery. EPSBO is associated with increased hospital stays, mortality rates, and healthcare costs. The purpose of this study was to identify risk factors for EPSBO following elective colon cancer surgery. STUDY DESIGN: We retrospectively reviewed the clinicopathological variables of 1,244 patients with colon cancer who underwent partial colectomy from January 2000 to December 2014. A multivariable logistic regression model was used to identify risk factors for EPSBO. RESULTS: The EPSBO rate was 3.5%. In multivariate analysis, preoperative bowel obstruction (OR 2.378; 95% CI 0.986-5.735, p = 0.054), weight loss >10% of body weight (OR 3.029; 95% CI 1.000-9.178, p = 0.05), albumin level (in g/L; OR 0.966; 95% CI 0.937-0.996, p = 0.024), and surgical duration (in min; OR 1.008; 95% CI 1.003-1.012, p = 0.003) were significant predictors of EPSBO. CONCLUSION: EPSBO is more likely to develop in the presence of poor systemic conditions (e.g., weight loss >10% of body weight, hypoalbuminemia, and preoperative bowel obstruction) and following operations of longer duration. These predictors may facilitate the stratification of patients at risk for EPSBO following surgery for elective colon cancer.

A scoring system basing pathological parameters to predict regional lymph node metastasis after preoperative chemoradiotherapy for locally advanced rectal cancer: implication for local excision.

Local excision is an alternative to radical surgery that is indicated in patients with locally advanced rectal cancer (LARC) who have a good response to chemoradiotherapy (CRT). Regional lymph node status is a major uncertainty during local excision of LARC following CRT. We retrospectively reviewed clinicopathologic variables for 244 patients with LARC who were treated at our institute between December 2000 and December 2013 in order to identify independent predictors of regional lymph node metastasis. Multivariate analysis of the training sample demonstrated that histopathologic type, tumor size, and the presence of lymphovascular invasion were significant predictors of regional nodal metastasis. These variables were then incorporated into a scoring system in which the total scores were calculated based on the points assigned for each parameter. The area under the curve in the receiver operating characteristic analysis was 0.750, and the cutoff value for the total score to predict regional nodal metastasis was 7.5. The sensitivity of our system was 73.2% and the specificity was 69.4%. The sensitivity was 77.8% and the specificity was 51.2% when the scoring system was applied to the testing sample. Using this system, we could accurately predict regional nodal metastases in LARC patients following CRT, which may be useful for stratifying patients in clinical trials and selecting potential candidates for organ-sparing surgery following CRT for LARC.

Laparoscopic transabdominal approach partial intersphincteric resection for low rectal cancer: surgical feasibility and intermediate-term outcome.

BACKGROUND: Traditionally, conventional intersphincteric resection requires a combined abdominal and perineal approach and a handsewn coloanal anastomosis procedure, which is difficult to accomplish via the perineal approach. A completely abdominal approach partial intersphincteric resection (APISR) with laparoscopy can simplify the anastomosis procedure. This study evaluated the intermediate-term oncological and functional results of laparoscopic versus open APISR for low rectal cancer. METHODS: A total of 137 consecutive patients with low rectal cancer who underwent APISR from January 2006 to August 2013 were retrospectively evaluated. Patient groups were classified into as open surgery (OP, n = 48) group and laparoscopy (LAP, n = 89). The primary endpoint was 3-year disease-free survival and the Wexner score for anal function. RESULTS: The LAP group had longer operating time, less intraoperative blood loss, and shorter hospital stay after surgery compared with the OP group. Median follow-up was 32.3 months. The local recurrence rates were similar in the two groups (LAP 3.2% vs. OP 6.1%; P = 0.652). The combined 3-year disease-free survival rate was 83.2% in the LAP group and 83.8% in the OP group (P = 0.857). Wexner scores were similar in the two groups (LAP 2.9 ± 4.5 vs. OP 3.1 ± 5.0). In the LAP group, 89.7% of patients had good continence compared with 91.4% in the OP group (P = 0.311). CONCLUSIONS: Laparoscopic APISR can be performed safely and offers similar intermediate-term oncological and functional outcome compared with the open procedure. The oncological adequacy requires long-term follow-up data.