Nanodrug modified with engineered cell membrane targets CDKs to activate aPD-L1 immunotherapy against liver metastasis of immune-desert colon cancer.

Immunotherapy based on the PD-1/PD-L1 axis blockade has no benefit for patients diagnosed with colon cancer liver metastasis (CCLM) for the microsatellite stable/proficient mismatch repair (MSS/pMMR)) subtype, which is known as an immune-desert cancer featuring poor immunogenicity and insufficient CD8+ T cell infiltration in the tumor microenvironment. Here, a multifunctional nanodrug carrying a cyclin-dependent kinase (CDK)1/2/5/9 inhibitor and PD-L1 antibody is prepared to boost the immune checkpoint blockade (ICB)-based immunotherapy against MSS/pMMR CCLM via reversing the immunosuppressive tumor microenvironment. To enhance the MSS/pMMR CCLM-targeting efficacy, we modify the nanodrug with PD-L1 knockout cell membrane of this colon cancer subtype. First, CDKs inhibitor delivered by nanodrug down-regulates phosphorylated retinoblastoma and phosphorylated RNA polymerase II and meanwhile arrests the G2/M cell cycle in CCLM to promote immunogenic signal release, stimulate dendritic cell maturation, and enhance CD8+ T cell infiltration. Moreover, CDKi suppresses the secretion of immunosuppressive cytokines in tumor-associated myeloid cells sensitizing ICB therapy in CCLM. Notably, the great efficacy to activate immune responses is demonstrated in the patient-derived xenograft model and the patient-derived organoid model as well, revealing a clinical application potential. Overall, our study represents a promising therapeutic approach for targeting liver metastasis, remolding the tumor immune microenvironment (TIME), and enhancing the response of MSS/pMMR CCLM to boost ICB immunotherapy.

Evaluation of Laparoscopic Colorectal Resection Among Elderly Individuals With Colorectal Malignancy: A Single-center Retrospective Analysis.

OBJECTIVE: The purpose of the current study was to statistically clarify the precise risk age in elderly patients undergoing colorectal surgery and to evaluate the safety and efficacy of laparoscopic colorectal resection in these patients. METHODS: Patients' clinical variables were extracted from the database of the Gastrointestinal Surgery Centre, Third Affiliated Hospital of Sun Yat-sen University, from 2015 to 2019. Logistic regression was conducted to identify independent risk factors of postoperative complications and ORs for each age. Curves of odds ratios (ORs) and CIs for each age were fitted by using a locally weighted scatterplot smoother, and a structural breakpoint was determined by the Chow test to identify a precise cutoff risk age for elderly patients. Comparison and subgroup analysis were conducted between surgical approach groups using the Student t test and χ 2 analysis. RESULTS: Locally weighted scatterplot smoother OR analysis manifested that patients aged 69 years old or older suffered a higher possibility of postoperative complications and should be defined as high-risk age. Comparison according to the high-risk age revealed laparoscopic colorectal surgery is better than laparotomic surgery for elderly individuals in terms of hospital stay (9.46 ± 5.96 vs 15.01 ± 6.34, P < 0.05), the incidence of intensive care unit transfer (4 vs 20, P < 0.05), and incidence of surgical site infection (15 vs 20, P < 0.05). Patients who underwent laparotomic surgery had a greater prevalence of Clavien-Dindo II/III complications ( P < 0.05). These findings remained stable even after propensity matching. Furthermore, such superiority was proved especially significant for patients who underwent left-side colorectal resection. In addition, overall survival was improved in the laparoscopic surgery group, whereas no differences were observed in disease-free survival. CONCLUSION: In our study population, age 69 or older was a cutoff point age suggests a higher possibility of postoperative morbidity after colorectal surgery. Laparoscopic colorectal resection should be regarded as a superior therapeutic choice for these elderly individuals, especially for left-side colorectal surgeries.

Preservation versus resection of Denonvilliers' fascia in total mesorectal excision for male rectal cancer: follow-up analysis of the randomized PUF-01 trial.

Traditional total mesorectal excision (TME) for rectal cancer requires partial resection of Denonvilliers' fascia (DVF), which leads to injury of pelvic autonomic nerve and postoperative urogenital dysfunction. It is still unclear whether entire preservation of DVF has better urogenital function and comparable oncological outcomes. We conducted a randomized clinical trial to investigate the superiority of DVF preservation over resection (NCT02435758). A total of 262 eligible male patients were randomized to Laparoscopic TME with DVF preservation (L-DVF-P group) or resection procedures (L-DVF-R group), 242 of which completed the study, including 122 cases of L-DVF-P and 120 cases of L-DVF-R. The initial analysis of the primary outcomes of urogenital function has previously been reported. Here, the updated analysis and secondary outcomes including 3-year survival (OS), 3-year disease-free survival (DFS), and recurrence rate between the two groups are reported for the modified intention-to-treat analysis, revealing no significant difference. In conclusion, L-DVF-P reveals better postoperative urogenital function and comparable oncological outcomes for male rectal cancer patients.

Region-specific protection effect of preoperative oral antibiotics combined with mechanical bowel preparation before laparoscopic colorectal resection: a prospective randomized controlled trial.

BACKGROUND: Oral antibiotics (OA) combined with mechanical bowel preparation (MBP) significantly decrease the rate of surgical site infections (SSIs). However, the prophylactic effects in region-specific colorectal surgery have not been assessed. MATERIALS AND METHODS: A single-centre, single-blind, randomized controlled trial was conducted from 2019 to 2022. Patients were eligible if they were diagnosed with nonmetastatic colorectal malignancy, and laparoscopic colorectal surgery was indicated. Participants were randomly assigned (1:1) to the experimental (OA+MBP preparation) or control group (MBP preparation). The randomization was further stratified by resected region. The primary outcome was the incidence of SSIs. Patients were followed up for 1 month postoperatively, and all complications were recorded. RESULT: Between 2019 and 2022, 157 and 152 patients were assigned to the experimental and control groups, respectively, after 51 patients were excluded. The incidence of SSIs in the control group (27/152) was significantly higher than that in the experimental group (13/157; P =0.013), as was the incidence of superficial SSIs (5/157 vs. 14/152, P =0.027) and deep SSIs (7/157 vs. 16/152, P =0.042). After redistribution according to the resected region, the incidence of SSIs was significantly higher in the control group with left-sided colorectal resection (descending, sigmoid colon, and rectum) (9/115 vs. 20/111, P =0.022) but was similar between the groups with right-sided colon resection (ascending colon) (3/37 vs. 7/36, P =0.286). No differences were noted between the groups in terms of other perioperative complications. CONCLUSION: OA+MBP before colorectal surgery significantly reduced the incidence of SSIs. Such a prophylactic effect was particularly significant for left-sided resection. This preparation mode should be routinely adopted before elective left-region colorectal surgeries.

Erratum: Exosomes Released by Bone Marrow Mesenchymal Stem Cells Attenuate Lung Injury Induced by Intestinal Ischemia Reperfusion via the TLR4/NF-κB Pathway: Erratum.

[This corrects the article DOI: 10.7150/ijms.35369.].

New staging systems for left-sided colon cancer based on the number of retrieved and metastatic lymph nodes provide a more accurate prognosis.

Objectives: We aimed to explore reasonable lymph node classification strategies for left-sided colon cancer (LCC) patients. Methods: 48,425 LCC patients from 2010 to 2015 were identified in the US Surveillance, Epidemiology, and End Results database. We proposed an innovative revised nodal (rN) staging of the 8th American Joint Committee on Cancer (AJCC) Tumor/Node/Metastasis (TNM) classification based on the cut-off value of retrieved lymph nodes and survival analyses in patients with LCC. Log odds of positive lymph nodes (LODDS) stage is a numerical classification strategy obtained by a formula that incorporates the numbers of retrieved and positive lymph nodes. To develop the TrN or TLODDS classification, patients with similar survival rates were grouped by combining T and rN or LODDS stage. The TrN or TLODDS classification was further evaluated in a validation set of 12,436 LCC patients from 2016 to 2017 in the same database and a Chinese application set of 958 LCC patients. Results: We developed novel TrN and TLODDS classifications for LCC patients that incorporated 7 stages with reference to the AJCC staging system. In comparison to the 8th AJCC TNM and TrN classifications, TLODDS classification demonstrated significantly better discrimination (area under the receiver operating characteristic curve, 0.650 vs. 0.656 vs. 0.661, p < 0.001), better model-fitting (Akaike information criteria, 309,287 vs. 308,767 vs. 308,467), and superior net benefits. The predictive performance of the TrN and TLODDS classifications was further verified in the validation and application sets. Conclusion: Both the TrN and TLODDS classifications have better discriminatory ability, model-fitting, and net benefits than the existing TNM classification, and represent an alternative to the current TNM classification for LCC patients.

Tumor-associated macrophage-specific CD155 contributes to M2-phenotype transition, immunosuppression, and tumor progression in colorectal cancer.

BACKGROUND: Onco-immunogenic molecule CD155 is overexpressed in various tumor microenvironments (TME) including in colorectal cancer (CRC). Tumor-associated macrophages (TAMs) are the most abundant immune cells in CRC TME and play a vital role in CRC progression and metastasis. Most studies have focused on investigating the role of CRC cell-specific CD155 on CRC progression, while the contribution of TAMs-specific CD155 is still unknown. Here, we sought to investigate the expression pattern of CD155 in CRC TAMs and its role in tumor immunity and progression. METHODS: CD155 expression patterns in CRC TAMs and macrophages in paratumor or adjacent normal tissue were analyzed in 50 patients with CRC using flow cytometry and in 141 patients with CRC using immunohistochemistry. The correlation of CD155 expression level in TAMs with M1 and M2 phenotypic transition was analyzed. The role of macrophage-specific CD155 in CRC progression and tumor immune response was investigated in vitro and in vivo. We further analyzed the effect of CRC cells on the regulation of CD155 expression in macrophages. RESULTS: CRC TAMs from clinical samples showed robustly higher expression of CD155 than macrophages from paratumor and adjacent normal tissues. The CD155 expression level was higher in TAMs of CRC at III/IV stages compared with the I/II stages and was negatively associated with the survival of patients with CRC. CD155+ TAMs showed an M2 phenotype and higher expression of interleukin (IL)-10 and transforming growth factor (TGF)-ß. CD155+ macrophages promoted CRC cell migration, invasion, and tumor growth supporting the findings from the clinical tissue analysis. This effect was mainly regulated by TGF-ß-induced STAT3 activation-mediated release of matrix metalloproteinases (MMP)2 and MMP9 in CRC cells. CD155-/- bone marrow transplantation in wild-type mice, as well as CD155- macrophages treatment, promoted the antitumor immune response in the mice ectopic CRC model. Additionally, CRC cells released IL-4 to trigger CD155 expression in macrophages indicating the regulatory role of CRC cells in the development of CD155+ TAMs. CONCLUSIONS: These findings indicated that CD155+ TAMs are responsible for the M2-phenotype transition, immunosuppression, and tumor progression in CRC. The specific localization of CD155+ TAMs in CRC tissue could turn into a potential therapeutic target for CRC treatment.

Bacteroides ovatus-mediated CD27- MAIT cell activation is associated with obesity-related T2D progression.

Type 2 diabetes (T2D) is highly associated with obesity. However, the factors that drive the transition from excessive weight gain to glucose metabolism disruption are still uncertain and seem to revolve around systemic immune disorder. Mucosal-associated invariant T (MAIT) cells, which are innate-like T cells that recognize bacterial metabolites, have been reported to be altered in obese people and to lead to metabolic dysfunction during obesity. By studying the immunophenotypes of blood MAIT cells from a cross-sectional cohort of obese participants with/without T2D, we found an elevation in CD27-negative (CD27-) MAIT cells producing a high level of IL-17 under T2D obese conditions, which could be positively correlated with impaired glucose metabolism in obese people. We further explored microbial translocation caused by gut barrier dysfunction in obese people as a triggering factor of MAIT cell abnormalities. Specifically, accumulation of the bacterial strain Bacteroides ovatus in the peripheral blood drove IL-17-producing CD27- MAIT cell expansion and could be associated with T2D risk in obese individuals. Overall, these results suggest that an aberrant gut microbiota-immune axis in obese people may drive or exacerbate T2D. Importantly, CD27- MAIT cell subsets and Bacteroides ovatus could represent targets for novel interventional strategies. Our findings extend current knowledge regarding the clinical relevance of body mass index (BMI)-associated variation in circulating MAIT cells to reveal the role of these cells in obesity-related T2D progression and the underlying cellular mechanisms.

TIGIT promotes CD8+T cells exhaustion and predicts poor prognosis of colorectal cancer.

TIGIT is a lymphocyte surface receptor, which is mainly expressed on the surface of CD8+T cells. The role of TIGIT in colorectal cancer and its expression pattern in colorectal cancer infiltrating lymphocytes are still controversial. This study aimed at identifying the function of TIGIT in colorectal cancer. Patients with colorectal cancer showed significantly higher TIGIT+CD8+T cell infiltration in tumor tissues, metastases compared with paired PBMC and normal tissues through flow cytometry. TIGIT+CD8+T cells showed an exhausted phenotype and expressed low levels of killer cytokines IFN-γ, IL-2, TNF-α. In addition, more inhibitory receptors such as PD-1, LAG-3, and TIM-3 were expressed on the surface of TIGIT+CD8+T cells. TGF-ß1 could promote the expression of TIGIT and inhibit CD8+T cell function in vitro. Moreover, the accumulation of TIGIT+T cells in tumors was associated with advanced disease, predicted early recurrence, and reduced survival rates in colorectal cancer patients. Our results indicate that TIGIT can be a biological marker for the prognosis of colorectal cancer, and TIGIT can be used as a potential target for treatment.

Effect of Denonvilliers' Fascia Preservation Versus Resection During Laparoscopic Total Mesorectal Excision on Postoperative Urogenital Function of Male Rectal Cancer Patients: Initial Results of Chinese PUF-01 Randomized Clinical Trial.

OBJECTIVE: To compare the outcomes of laparoscopic total mesorectal excision (L-TME) with Denonvilliers' fascia (DVF) preservation versus resection on urogenital function of male patients with rectal cancer. BACKGROUND: The protective effect of DVF during L-TME on pelvic autonomic nerves and postoperative urogenital function remains controversial. METHODS: Between August 26, 2015 and July 18, 2019, 253 male patients with cT1-4 (T1-2 for anterior wall) N0-2M0 rectal cancer from 11 institutions were enrolled, and randomly assigned to L-TME with DVF preservation (Exp-group, n = 123) or resection procedures (Con-group, n = 130). Urinary function was assessed by residual urine volume, maximal flow rate, and International Prostate Symptom Score; sexual function was assessed by 5-item version of the International Index of Erectile Function (IIEF-5) and ejaculation grading. RESULTS: The Exp-group patients showed a lower urinary dysfunction rate (6.8% vs 25.4%, P = 0.003), higher maximal flow rate (16.25 ±â€Š8.02 vs 12.40 ±â€Š7.05 mL/s, P = 0.007), and lower International Prostate Symptom Score (6.55 ±â€Š5.86 vs 8.57 ±â€Š5.85, P = 0.026) than the Con-group patients at 2 weeks after surgery. The incidence of erectile dysfunction (IIEF-5 ≤ 11) at 12 months after surgery was lower in the Exp-group than in the Con-group (12.5% vs 34.2%, P = 0.023); Exp-group manifested superior IIEF-5 (16.63 ±â€Š6.28 vs 12.26 ±â€Š6.83, P = 0.018). The incidence of ejaculation dysfunction was lower in the Exp-group than in the Con-group at 12 months after surgery (10.0% vs 29.4%, P = 0.034). CONCLUSIONS: DVF preservation during L-TME revealed protective effects on postoperative urogenital function, and could be a better choice for male rectal cancer patients with specific staging and location. TRIAL REGISTRATION NUMBER: NCT02435758.

The tumor immune microenvironment transcriptomic subtypes of colorectal cancer for prognosis and development of precise immunotherapy.

BACKGROUND: Biomarkers based on immune context may guide prognosis prediction. T-cell inactivation, exclusion, or dysfunction could cause unfavorable tumor microenvironments, which affect immunotherapy and prognosis. However, none of the immuno-biomarkers reported to date can differentiate colorectal-cancer (CRC) patients. Thus, we aimed to classify CRC patients according to the levels of T-cell activation, exclusion, and dysfunction in the tumor microenvironment. METHODS: RNAseq data of 618 CRC patients from The Cancer Genome Atlas and microarray data of 316 CRC patients from Gene Expression Omnibus were analysed using the Tumor Immune Dysfunction and Exclusion algorithm. Unsupervised clustering was used to classify patients. RESULTS: Based on the expression signatures of myeloid-derived suppressor cells, cancer-associated fibroblasts, M2-like tumor-associated macrophages, cytotoxic T-lymphocytes, and PD-L1, all patients were clustered into four subtypes: cluster 1 had a high level of immune dysfunction, cluster 2 had a low level of immune activation, cluster 3 had intense immune exclusion, and cluster 4 had a high level of immune activation and a moderate level of both dysfunction and exclusion signatures. Compared with cluster 1, the hazard ratios and 95% confidential intervals for overall survival were 0.63 (0.35-1.13) for cluster 2, 0.55 (0.29-1.03) for cluster 3, and 0.30 (0.14-0.64) for cluster 4 in multivariate Cox regression. Similar immune clustering and prognosis patterns were obtained upon validation in the GSE39582 cohort. In subgroup analysis, immune clustering was significantly associated with overall survival among stage I/II patients, microsatellite stable/instability-low patients, and patients not treated with adjuvant therapy. CONCLUSIONS: Our findings demonstrated that classifying CRC patients into different immune subtypes serves as a reliable prognosis predictor and may help to refine patient selection for personalized cancer immunotherapy.

Dexmedetomidine alleviated neuropathic pain in dorsal root ganglion neurons by inhibition of anaerobic glycolysis activity and enhancement of ROS tolerance.

Neuropathic pain is a kind of chronic pain that is triggered or caused primarily by damage to the nervous system and neurological dysfunction. It's known that dexmedetomidine is a new type of highly selective alpha2-adrenoceptor agonist with sedation, anti-anxiety, analgesic and other effects. However, the function and mechanism of dexmedetomidine on neuropathic pain are not clear. Rat DRG neurons were isolated and identified using immunofluorescence assay. Following treatment with H2O2, dexmedetomidine or ROS inhibitor (NAC), the apoptosis and ROS levels were examined by flow cytometery; apoptosis- and anaerobic glycolysis-related proteins were determined by Western blot assay; glucose consumption, pyruvic acid, lactic acid and ATP/ADP ratios were also measured. The results revealed that dexmedetomidine inhibited H2O2-induced apoptosis and reactive oxygen species (ROS) in rat DRG neurons and in addition, dexmedetomidine down-regulated the expression levels of anaerobic glycolysis-related proteins, significantly reduced glucose, pyruvic acid and lactic acid levels. It also increased the ATP/ADP ratio in H2O2-treated rat dorsal root ganglion (DRG) neurons. Moreover, we also demonstrated that ROS inhibitor (NAC) also inhibited H2O2-induced apoptosis and anaerobic glycolysis in rat DRG neurons. In conclusion, dexmedetomidine suppressed H2O2-induced apoptosis and anaerobic glycolysis activity by inhibiting ROS, in rat DRG neurons. Therefore, dexmedetomidine might play a pivotal role in neuropathic pain by the inhibition of ROS.

Identification of the surgical indication line for the Denonvilliers' fascia and its anatomy in patients with rectal cancer.

BACKGROUND: The high rate of urogenital dysfunction after traditional total mesorectal excision (TME) has caused doubts among scholars on the standard fashion of dissection. We have proposed the necessity to preserve the Denonvilliers' fascia in patients with rectal cancer. However, how to accurately locate the Denonvilliers' fascia is unclear. This study aimed to explore anatomical features of the Denonvilliers' fascia by comparing autopsy findings and observations of surgical videos so as to propose a dissection method for the preservation of pelvic autonomic nerves during rectal cancer surgery. METHODS: Five adult male cadaver specimens were dissected, and surgical videos of 135 patients who underwent TME for mid-low rectal cancer between January 2009 and February 2019 were reviewed to identify and compare the structure of the Denonvilliers' fascia. RESULTS: The monolayer structure of the Denonvilliers' fascia was observed in 5 male cadaver specimens, and it was located between the rectum, the bottom of the bladder, the seminal vesicles, the vas deferens, and the prostate. The Denonvilliers' fascia was originated from the rectovesical pouch (or rectum-uterus pouch), down to fuse caudally with the rectourethral muscle at the apex of the prostate, and fused to the lateral ligaments on both sides. The fascia was thinner on the midline with a thickness of 1.06 ± 0.10 mm. The crown shape of the Denonvilliers' fascia was slightly triangular, with a height of approximately 5.42 ± 0.16 cm at midline. Nerves were more densely distributed in front of the Denonvilliers' fascia than behind, especially on both sides of it. Under laparoscopic view, the Denonvilliers' fascia was originated at the lowest point of the rectovesical pouch (or rectum-uterus pouch), with a thickened white line which was a good mark for identifying the Denonvilliers' fascia. CONCLUSION: Identification of the surgical indication line for the Denonvilliers' fascia could help us identify the Denonvilliers' fascia, and it would improve our ability to protect the pelvic autonomic function of patients undergoing TME for rectal cancer.

Preoperative mechanical bowel preparation with oral antibiotics reduces surgical site infection after elective colorectal surgery for malignancies: results of a propensity matching analysis.

BACKGROUND: Surgical site infections (SSIs) are a major postoperative complication after colorectal surgery. Current study aims to evaluate prophylactic function of oral antibiotic (OA) intake in combination with mechanical bowel preparation (MBP) relative to MBP alone with respect to postoperative SSI incidence. METHODS: A retrospective analysis of eligible patients was conducted using the databases of the Gastrointestinal Surgery Centre, Third Affiliated Hospital of Sun Yat-sen University from 2011 to 2017. Data pertaining to postoperative hospital stay length, expenses, SSI incidence, anastomotic fistula incidence, and rates of other complications were extracted and compared. A propensity analysis was conducted to minimize bias associated with demographic characteristics. Subgroup analyses were performed to further explore protective effects of OA in different surgical sites. RESULTS: The combination of OAs and MBP was related to a significant decrease in the incidence of overall SSIs, superficial SSI, and hospitalization expenses. The MBP + OA modality was particularly beneficial for patients undergoing left-side colon or rectum resections, with clear prophylactic efficacy. The combination of MPB + OA did not exhibit significant prophylactic efficacy in patients undergoing right hemi-colon resection. Age, surgical duration, and application of OA were all independent factors associated with the occurrence of SSIs. CONCLUSION: These results suggest that the combination of OA + MBP should be recommended for patients undergoing elective colorectal surgery, particularly for operations on the left side of the colon or rectum. TRIAL REGISTRATION: NCT04258098. Retrospectively registered.

Laparoscopic colorectal resection combined with simultaneous thermal ablation or surgical resection of liver metastasis: a retrospective comparative study.

Objective: Colorectal liver metastasis is a critical cause of mortality. However, the safety and long-term prognosis of simultaneous colorectal tumor resection along with hepatic lesion ablation are debated. The current analysis was conducted to further clarify the controversy.Methods: In this retrospective study, we collected data of 68 patients who underwent ablation or resection for liver lesions combined with simultaneous laparoscopic primary colorectal tumor resection between September 2011 and October 2016 at the Third Affiliated Hospital of Sun Yat-sen University. Perioperative outcomes and long-term follow-up data were compared between patients in the resection and ablation groups.Results: Both groups had similar surgical duration (286.70 ± 78.33 vs. 313.67 ± 80.90 min), conversion rate (2 vs. 0), total expenses (81.51 ± 20.20 vs. 82.21 ± 27.81 kRMB, p = .914) and morbidities (11 vs. 24, p = .667). However, the postoperative hospital stays (12.82 ± 9.25 vs. 8.40 ± 2.38 d) and transfusion rates (56.52% vs. 8.89%) were significantly lower in the ablation group. The long-term overall survival (p = .714), disease-free survival (p = .680) and intra-hepatic recurrent-free survival (p = .496) were comparable between both groups.Conclusion: With respect to simultaneous treatment for both primary colorectal cancer and liver metastasis, hepatic lesion ablation was associated with lower blood loss and hospital stay duration than liver resection, without compromising the surgical safety and long-term prognosis.

Risk factors analysis for surgical site infection following elective colorectal resection: a retrospective regression analysis.

BACKGROUND: A surgical site infection (SSI) is a major post-operative complication from elective colorectal surgery; however, few studies have focused on evaluating the risk factors for SSI. This study aimed to analyze the relative correlation of medical and environmental factors as well as patient-related factors that contribute to the incidence of all types of SSI. METHODS: A retrospective search for eligible patients was conducted using the patient database of the Gastrointestinal Surgery Center of the Third Affiliated Hospital of Sun Yat-sen University from January 2011 to August 2017. Pre-operative demographic and surgical data were extracted and recoded according to the study protocol. Univariate and multivariate analyses were performed to clarify factors affecting the incidence of SSI. Propensity analysis was conducted to minimize bias in the demographic characteristics to explore the prophylactic effect of pre-operative administration of oral antibiotics. RESULTS: Univariate analysis of the baseline characteristics revealed that younger age (odds ratio [OR]: 0.378; 95% confidence interval [CI]: 0.218-0.657) and pre-operative oral antibiotic use (OR: 0.465; 95% CI: 0.255-0.850) were protective factors, while pre-operative anemia (OR: 4.591; 95% CI: 2.567-8.211), neoadjuvant chemotherapy history (OR: 2.398; 95% CI: 1.094-5.256), and longer surgical duration (OR: 2.393; 95% CI: 1.349-4.246; P = 0.002) were identified as risk factors for SSI. Multivariate analysis indicated that age (P = 0.003), surgical duration (P = 0.001), and pre-operative oral antibiotic use (P < 0.001) were independent factors that affect the incidence of SSI. Furthermore, a propensity-matched analysis confirmed the protective effect of oral antibiotic use, with a 1-day course of oral antibiotic producing a similar effect to a 3-day course. CONCLUSIONS: Age, surgical duration, and pre-operative oral antibiotic use were associated with the incidence of SSI. However, pre-operative oral antibiotic use was the only controllable factor. From the results of our study, pre-operative oral antibiotic use is recommended before elective colorectal surgery and a 1-day course is enough to provide the protective effect.

Endothelial progenitor cells promote viability and nerve regenerative ability of mesenchymal stem cells through PDGF-BB/PDGFR-ß signaling.

Denervation-induced erectile dysfunction (ED) is a prevailing health problem. Our previous study revealed that endothelial progenitor cells (EPCs) promoted the effect of mesenchymal stem cells (MSCs) on restoration of denervation-induced ED in rats. However, underling mechanisms are still largely elusive. In this study, EPCs and MSCs were co-cultured and resorted to co-EPCs and co-MSCs. EPCs-derived paracrine factors containing PDGF-BB (platelet-derived growth factor) were detected, and MSCs were pre-treated with PDGF-BB, while co-MSCs were pre-treated with PDGFR inhibitor AG1296. Either viability or nerve regenerative ability of MSCs was evaluated. In addition, inhibition of either PI3K/Akt or MEK/Erk pathway was performed to evaluate the role of PI3K/Akt and MEK/Erk pathway in PDGF-BB-induced viability of MSCs. The results revealed that PDGF-BB significantly increased the proportion of PDGFR-ß+ MSCs, and promoted both in-vitro and in-vivo viability, as well as nerve regenerative capacity and erectile function restoration of MSCs in rats. Inhibition of PI3K/Akt, MEK/Erk pathway or mTOR led to decrease of PDGF-BB/PDGFR-ß induced viability of MSCs. To our knowledge, our study first demonstrates that EPCs promote viability and potential nerve regenerative ability of MSCs through PDGF-BB/PDGFR-ß signaling and its downstream PI3K/Akt and MEK/Erk pathways. mTOR acts as a co-mediator in PI3K/Akt and MEK/Erk pathways.

Exosomes Released by Bone Marrow Mesenchymal Stem Cells Attenuate Lung Injury Induced by Intestinal Ischemia Reperfusion via the TLR4/NF-κB Pathway.

Purpose: Acute lung injury (ALI) is a primary component of multiple organ dysfunction syndromes triggered by intestinal ischemia-reperfusion (IIR) which results in high mortality. Existing treatment options remain unsatisfactory. Mesenchymal stem cells (MSCs) have shown considerable promise as a biological therapy for ALI in preclinical studies. However, there are many limitations to stem cell treatment. This study aimed to investigate whether MSC-derived exosomes, a non-cellular alternative, are able to act in a protective capacity similar to that of MSCs for ALI triggered by IIR in a rat model and to explore the underlying mechanisms. Methods: The IIR model involved occlusion of the superior mesenteric artery of a rat for 75 min then reperfusion for 20 h. Rats then received an intravenous injection of either bone marrow-derived MSCs or MSC-derived exosomes. Pathologic alteration of lung tissue, levels of pro-inflammatory cytokines, apoptotic proteins and TLR4/NF-κB signaling were measured to evaluate the therapeutic effect of treatment with either MSCs or exosomes. Results: Manifestations of acute lung injury after IIR were observed as edema and hemorrhage of alveoli and mesenchyme, and inflammatory cell infiltration. MSCs and MSC-derived exosomes both attenuated IIR-induced lung damage by decreased apoptosis and inflammation accompanied by down-regulation of TLR4 and NF-κB expression. Conclusions: MSC-derived exosomes provide protection similar to that of MSCs against IIR-induced ALI via inhibition of TLR4/NF-κB signaling, suggesting that a potential strategy against IIR-mediated acute lung injury could be therapy with exosomes as a non-cellular alternative to MSC transplantation.

Trans-anal or trans-abdominal total mesorectal excision? A systematic review and meta-analysis of recent comparative studies on perioperative outcomes and pathological result.

BACKGROUND: Trans-anal total mesorectal resection (TaTME) is a novel approach for rectal cancer. However, the perioperative and pathological outcomes of this procedure remain controversial. METHOD: A systematic literature search was performed using PubMed, Embase, Wanfang (China) and the Cochrane Library databases without restriction to regions or languages. We included 17 trials comparing TaTME with Laparoscopic TME (LaTME) for meta-analysis (MA). Fixed and random-effect models were used to measure the pooled estimates. RESULTS: A total of 17 trials including 1346 patients were eligible for this MA. Pooled perioperative data using TaTME was associated with a significant reduction in estimated blood loss (WMD: 41.40, CI: 76.83 to -5.97; p = 0.02), hospital stay (WMD: 1.27, CI: 2.32 to -0.23; p = 0.02), conversion (OR: 0.28 CI: 0.15-0.52; p < 0.0001), readmission rates (OR: 0.42, CI: 0.25-0.69; p = 0.0007) and overall postoperative complications (OR: 0.73, CI: 0.56-0.95; p = 0.02). TaTME did not compromise surgical duration (WMD: 11.61, CI: 26.62-3.41; p = 0.13) or enhance complications including anastomotic leakage, ileus, urinary dysfunction, wound infection and pelvic abscess. Concerning pathological outcomes, the TaTME group demonstrated longer circumferential resection margins (CRM) (WMD: 0.91, CI: 0.58-1.24; p < 0.00001) and reduced CRM involvement (OR: 0.47, CI: 0.29-0.75; p = 0.002), whilst the distal resection margin (DRM) quality of the mesorectum and harvested lymph node were comparable. CONCLUSION: TaTME achieves similar surgical outcomes to LaTME, with the added advantage of a safe CRMs, reduced blood loss, shorter hospital stay, lower conversion and readmission rates, and lower postoperative morbidity. Long-term oncological and functional data are now required to confirm these findings.

Predictive models of adjuvant chemotherapy for patients with stage ii colorectal cancer: A retrospective study.

BACKGROUND: It remains controversial whether patients with Stage II colorectal cancer would benefit from adjuvant chemotherapy after radical resection. The aim of this study was to establish two mathematical models to identify the suitable patients for adjuvant chemotherapy. METHODS: The current study comprised of two steps. In the first step, 353 patients with Stage II colorectal cancer who underwent surgical procedures at the Third Affiliated Hospital of Sun Yat-sen University between June 2006 and December 2015 were entered and followed up for 6-120 months. Their clinical data were collected and enrolled into the database. We established two mathematical models by univariate and multivariate Cox regression analysis to identify the target patients; in the second step, 230 patients under the same standard between January 2012 and December 2016 were entered and followed up for 3-62 months to verify the two models' validation. RESULTS: In the first step, totally 340 surgical patients with Stage II colorectal cancer were finally enrolled in this study. Statistical analysis showed that tumor differentiation (TD) (P < 0.001), lymphovascular invasion (LVI) (P < 0.001), uncertain or positive margins (UPM) (P < 0.001), and fewer lymph nodes (LNs) (<12) retrieved (P < 0.001) were correlated with the overall survival (OS) and disease free survival (DFS). We obtained two models: (1) OS risk score = 1.116 × TD + 2.202 × LVI + 3.676 × UPM + 1.438 × LN - 0.493; (2) DFS risk score = 0.789 × TD + 2.074 × LVI + 3.183 × UPM + 1.329 × LN - 0.432. According to the models and cutoff points [(0.07, 1.33) and (-0.04, 1.30), respectively], patients can be divided into three groups: low-risk, moderate-risk, and high-risk. Moreover, the high-risk group patients could benefit from adjuvant chemotherapy. In the second step, totally 221 patients were finally used to verify the models' validation. The results proved that the models were accurate and feasible (P< 0.05). CONCLUSIONS: According to the predictive models, patients with Stage II colorectal cancer in the high-risk group are strongly recommended for adjuvant chemotherapy, thus facilitating the individualized and precise treatment.