Precisely Inhibiting Excessive Intestinal Epithelial Cell Apoptosis to Efficiently Treat Inflammatory Bowel Disease with Oral Pifithrin-α Embedded Nanomedicine (OPEN).

The increased incidence of inflammatory bowel disease (IBD) has seriously affected the life quality of patients. IBD develops due to excessive intestinal epithelial cell (IEC) apoptosis, disrupting the gut barrier, colonizing harmful bacteria, and initiating persistent inflammation. The current therapeutic approaches that reduce inflammation are limited. Although IBD can be treated significantly by directly preventing IEC apoptosis, achieving this therapeutic approach remains challenging. Accordingly, the authors are the first to develop an oral pifithrin-α (PFTα, a highly specific p53 inhibitor) embedded nanomedicine (OPEN) to effectively treat IBD by inhibiting excessive IEC apoptosis. As a major hub for various stressors, p53 is a central determinant of cell fate, and its inhibition can effectively reduce excessive IEC apoptosis. The tailored OPEN can precisely inhibit the off-target and inactivation resulting from PFTα entry into the bloodstream. Subsequently, it persistently targets IBD lesions with high specificity to inhibit the pathological events caused by excessive IEC apoptosis. Eventually, OPEN exerts a significant curative effect compared with the clinical first-line drugs 5-aminosalicylic acid (5-ASA) and dexamethasone (DEX). Consequently, the OPEN therapeutic strategy provides new insights into comprehensive IBD therapy.

Synergistic photothermal conversion and photocatalysis in 2D/2D MXene/Bi2S3 hybrids for efficient solar-driven water purification.

Plasmonic hybrids are regarded as promising candidates for water purification due to their structure-dependent photocatalysis and photothermal performance. It remains a challenge to develop materials that possess these two characteristics for efficient water purification. Herein, plasmonic Ti3C2Tx/Bi2S3 two-dimensional (2D)/2D hybrids were prepared for efficient solar-driven water purification via the combination of photothermal conversion and photocatalysis. Benefitting from broad light absorption, large 2D/2D interfaces, and efficient charge transfer, the binary hybrids showed high-efficiency photothermal conversion and photothermal-assisted photocatalytic activity. By depositing these 2D/2D hybrids on a hydrophilic and porous cotton piece, the Ti3C2Tx/Bi2S3 membrane displayed a high water evaporation rate and solar-to-vapor efficiency under one-sun irradiation. The solar-driven evaporation of seawater, heavy metal ion solution, and dye solution jointly indicated that the plasmonic membrane shows great potential for drinkable water generation and industrial wastewater treatment. Most importantly, the synergistic effect of photothermal evaporation and photocatalysis of the Ti3C2Tx/Bi2S3 membrane on water purification was demonstrated. The polluted water can not only be treated by evaporation, but also be degraded via photocatalysis under solar light irradiation. This work provides new insight into designing functional materials for water purification based on the combination of photothermal conversion and photocatalysis.

Efficient Therapy of Inflammatory Bowel Disease (IBD) with Highly Specific and Durable Targeted Ta2 C Modified with Chondroitin Sulfate (TACS).

Non-invasive localization of lesions and specific targeted therapy are still the main challenges for inflammatory bowel disease (IBD). Ta, as a medical metal element, has been widely used in the treatment of different diseases because of its excellent physicochemical properties but is still far from being explored in IBD. Here, Ta2 C modified with chondroitin sulfate (CS) (TACS) is evaluated as a highly targeted therapy nanomedicine for IBD. Specifically, TACS is modified with dual targeting CS functions due to IBD lesion-specific positive charges and high expression of CD44 receptors. Thanks to the acid stability, sensitive CT imaging function, and strong reactive oxygen species (ROS) elimination ability, oral TACS can accurately locate and delineate IBD lesions through non-invasive CT imaging, and specifically targeted treat IBD effectively because high levels of ROS are a central factor in the progression of IBD. As expected, TACS has much better imaging and therapeutic effects than clinical CT contrast agent and first-line drug 5-aminosalicylic acid, respectively. The mechanism of TACS treatment mainly involves protection of mitochondria, elimination of oxidative stress, inhibiting macrophage M1 polarization, protection of intestinal barrier, and restoration of intestinal flora balance. Collectively, this work provides unprecedented opportunities for oral nanomedicines to targeted therapy of IBD.

Oral Metal-Free Melanin Nanozymes for Natural and Durable Targeted Treatment of Inflammatory Bowel Disease (IBD).

Oral antioxidant nanozymes bring great promise for inflammatory bowel disease (IBD) treatment. To efficiently eliminate reactive oxygen species (ROS), various metal-based nanozymes have been developed for the treatment of IBD but their practical applications are seriously impaired by unstable ROS-eliminating properties and potential metal ion leakage in the digestive tract. Here, the authors for the first time propose metal-free melanin nanozymes (MeNPs) with excellent gastrointestinal stability and biocompatibility as a favorable therapy strategy for IBD. Moreover, MeNPs have extremely excellent natural and long-lasting characteristics of targeting IBD lesions. In view of the dominant role of ROS in IBD, the authors further reveal that oral administration of MeNPs can greatly alleviate the six major pathological features of IBD: oxidative stress, endoplasmic reticulum stress, apoptosis, inflammation, gut barrier disruption, and gut dysbiosis. Overall, this strategy highlights the great clinical application prospects of metal-free MeNPs via harnessing ROS scavenging at IBD lesions, offering a paradigm for antioxidant nanozyme in IBD or other inflammatory diseases.

CDK4/6 Inhibition Suppresses p73 Phosphorylation and Activates DR5 to Potentiate Chemotherapy and Immune Checkpoint Blockade.

Targeting cyclin-dependent kinases 4 and 6 (CDK4/6) is a successful therapeutic approach against breast and other solid tumors. Inhibition of CDK4/6 halts cell cycle progression and promotes antitumor immunity. However, the mechanisms underlying the antitumor activity of CDK4/6 inhibitors are not fully understood. We found that CDK4/6 bind and phosphorylate the p53 family member p73 at threonine 86, which sequesters p73 in the cytoplasm. Inhibition of CDK4/6 led to dephosphorylation and nuclear translocation of p73, which transcriptionally activated death receptor 5 (DR5), a cytokine receptor and key component of the extrinsic apoptotic pathway. p73-mediated induction of DR5 by CDK4/6 inhibitors promoted immunogenic cell death of cancer cells. Deletion of DR5 in cancer cells in vitro and in vivo abrogated the potentiating effects of CDK4/6 inhibitors on immune cytokine TRAIL, 5-fluorouracil chemotherapy, and anti-PD-1 immunotherapy. Together, these results reveal a previously unrecognized consequence of CDK4/6 inhibition, which may be critical for potentiating the killing and immunogenic effects on cancer cells. SIGNIFICANCE: This work demonstrates how inhibition of CDK4/6 sensitizes cancer cells to chemotherapy and immune checkpoint blockade and may provide a new molecular marker for improving CDK4/6-targeted cancer therapies. See related commentary by Frank, p. 1170.

BET protein degradation triggers DR5-mediated immunogenic cell death to suppress colorectal cancer and potentiate immune checkpoint blockade.

Bromodomain and extra-terminal domain (BET) family proteins are epigenetic readers that play a critical role in oncogenesis by controlling the expression of oncogenes such as c-Myc. Targeting BET family proteins has recently emerged as a promising anticancer strategy. However, the molecular mechanisms by which cancer cells respond to BET inhibition are not well understood. In this study, we found that inducing the degradation of BET proteins by the proteolysis targeting chimeras (PROTAC) approach potently suppressed the growth of colorectal cancer (CRC) including patient-derived tumors. Mechanistically, BET degradation transcriptionally activates Death Receptor 5 (DR5) to trigger immunogenic cell death (ICD) in CRC cells. Enhanced DR5 induction further sensitizes CRC cells with a mutation in Speckle-type POZ protein (SPOP). Furthermore, DR5 is indispensable for a striking antitumor effect of combining BET degradation and anti-PD-1 antibody, which was well tolerated in mice and almost eradicated syngeneic tumors. Our results demonstrate that BET degradation triggers DR5-mediated ICD to potently suppress CRC and potentiate immune checkpoint blockade. These results provide a rationale, mechanistic insights, and potential biomarkers for developing a precision CRC therapy by inducing BET protein degradation.

Intravascular emboli relates to immunosuppressive tumor microenvironment and predicts prognosis in stage III colorectal cancer.

BACKGROUND: Stage III colorectal cancer (CRC) patients experience varying degrees of prognosis even if receiving standard therapeutic regimes. Intravascular emboli (IVE), a type of vascular invasion, impacts the clinical outcome in CRC. In this study, we confirmed the role of IVE in predicting the prognosis of stage III CRC patients and characterized the tumor microenvironment (TME) of CRC with IVE. METHODS: Data from 220 consecutive patients (cohort 1) with stage III CRC undergoing radical surgery was collected retrospectively between January 2009 to December 2014. According to the presence of IVE, which was confirmed by two independent pathologists, patients were classified into two groups. Univariate and multivariate Cox regression analyses were performed to evaluate the relation of IVE presence to patients' prognosis. The association between IVE and clinicopathological factors was also analyzed. Furthermore, differentially expressed genes (DEGs) and gene set enrichment analyses (GSEA) were performed to describe features of the TME based on microarray data consisting of 6 patients. Tumor tissues from a separate cohort of 73 patients with stage III CRC (cohort 2) collected between June 2014 and December 2015 were used to analyze tumor-infiltrating lymphocyte (TIL) by immunohistochemistry (IHC) staining. RESULTS: IVE was observed in 126 (57.3%) patients and could serve as an unfavorable independent prognostic predictor (P < 0.001) as well as lymph node metastasis (P < 0.05) and tumor location (P < 0.05). Additionally, patients with IVE had a higher neutrophil percentage (P = 0.002) and lower lymphocyte percentage (P = 0.002) relative to those without IVE. CRC with IVE had a significantly different profile of DEGs compared to CRC without IVE, and GSEA showed chronic inflammatory and immunosuppressive TME may promote IVE development. In cohort 2, tumors with IVE had fewer CD3+ TILs in the stromal region, as well as fewer CD8+ TILs in both stromal and tumoral regions relative to those without IVE. CONCLUSION: IVE, which was related closely to a chronic inflammatory and immunosuppressive TME, forecasted a worse prognosis of stage III CRC patients and may be taken into consideration when a therapeutic strategy is decided upon.

A novel risk-scoring system conducing to chemotherapy decision for patients with pancreatic ductal adenocarcinoma after pancreatectomy.

Background: Chemotherapy is suggested to use in all stages of pancreatic cancer. Is it reasonable to recommend chemotherapy for all PDAC patients? It is necessary to distinguish low-risk PDAC patients underwent pancreatectomy, who may not lose survival time due to missed chemotherapy and not need to endure pain, nausea, tiredness, drowsiness, and breath shortness caused by chemotherapy. Methods: Nomograms were constructed with basis from the multivariate Cox regression analysis. X-tile software was utilized to perform risk stratification. Survival curves were used to display the effect of chemotherapy in different risk-stratification. Results: All of the significant variables were used to create the nomograms for overall survival (OS). The total risk score of each patient was calculated by summing the scores related to each variable. X-tile software was utilized to classify patients into high-risk (score >283), median-risk (197

Accurate nomograms with excellent clinical value for locally advanced rectal cancer.

BACKGROUND: Rectal cancer accounts for approximately 30-50% of colorectal cancer. Despite its widespread use and convenience, the American Joint Committee on Cancer (AJCC) staging system for predicting survival is prone to inaccuracy, even including a survival paradox for locally advanced rectal cancer (LARC). An accurate risk stratification of LARC is essential for proper treatment selection and prognostic evaluation. Therefore, we aimed to create prognostic nomograms for LARC capable of assessing overall survival (OS) and cancer-specific survival (CSS) precisely and intuitively. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was accessed. All of the significant variables in the multivariate analysis were integrated to build the nomograms. RESULTS: Data for a total of 23,055 patients with LARC were collected from the SEER database in this study. Based on the multivariate Cox regression analysis, both OS and CSS were significantly associated with 13 variables: age, marital status, race, pathological grade, histological type, T stage, N stage, surgery, radiotherapy, chemotherapy, regional nodes examined (RNE), tumor size, and carcinoembryonic antigen (CEA). These were included in the construction of nomograms for OS and CSS. Time-dependent receiver operating characteristic (ROC) curves, decision curve analysis (DCA), concordance index, and calibration curves demonstrated the discriminative superiority of the nomograms. CONCLUSIONS: The nomograms, which effectively solve the issue of the survival paradox in the AJCC staging system regarding LARC, may act as excellent tools for integrating clinical characteristics and to guiding therapeutic choices for LARC patients.

The Relationship between Primary Gross Tumor Volume and Tumor Response of Locally Advanced Rectal Cancer: pGTV as a More Accurate Tumor Size Indicator.

Purpose: To identify the clinical predictive factors of tumor response and to evaluate the significance of primary gross tumor volume (pGTV), obtained from radiotherapy planning, in predicting tumor response. Materials and Methods: We retrospectively analyzed data of consecutive locally advanced rectal cancer (LARC) patients who were treated with neoadjuvant chemoradiotherapy (nCRT) followed by radical surgery at our institution between March 2009 and December 2017. We identify independent predictors of tumor response to nCRT by statistical analysis. Disease-free survival (DFS) starting from the time of surgery was calculated by the Kaplan-Meier method, and log-rank tests were performed to compare DFS between patients with superior and inferior tumor response. Results: Overall, 185 LARC patients received nCRT, of whom 89 (48.11%) achieved superior tumor response. Diminutive pGTV (p = 0.038) and distance from the anal verge (DAV) (p = 0.006) were independent predictive factors of superior tumor response. Meanwhile, pGTV can be regarded as an independent predictor of pathologic complete response (pCR) (p = 0.036). The log-rank test revealed that DFS was longer in the diminutive pGTV group than in the giant pGTV group (p = 0.001). Conclusions: pGTV, as a measure of tumor size, is not only an important prognostic indicator but also an independent predictive factor of tumor response, even pCR.

Stage migration resulting from inadequate number of examined lymph nodes impacts prognosis in stage II colon cancer after radical surgery.

PURPOSE: We evaluated the impact of examined lymph node (ELN) number on the prognosis of stage II colon cancer after radical surgery and developed a novel prognostic scoring system by combining primary tumor extension (pT) and ELN number for reclassification of stage II colon cancer. METHODS: Three cohorts of patients diagnosed with colon cancer between 2004 and 2010 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate analyses were performed to evaluate the relationship between factors and patients' survival including cause-specific survival (CSS) and overall survival (OS). Survival curves from subgroups were plotted by the Kaplan-Meier method and compared by the log-rank test. RESULTS: Cohort 1 and cohort 2 consisted of 13,960 and 5312 stage II colon cancer patients, respectively. Cohort 3 consisted of 4713 stage III patients. Factors including ELN, age, and pT were found to be associated with patients' survival in cohorts 1 and 2. Patients who were older or with smaller tumors were more likely to experience inadequate ELN. Patients with a higher score, as calculated by the novel scoring system, showed worse survival. Compared with stage III colon cancer patients, stage II patients with high scores had a comparable or even worse survival than stage IIIA and IIIB patients. CONCLUSION: Inadequate ELN leads to understaging in stage II colon cancer and predicts inferior prognosis. Our analyses show that the novel prognostic scoring system, consisting of combined pT and ELN, quantified stage migration effect and can be applied to the reclassification of stage II colon cancer.

Development and validation of prognostic nomograms for early-onset locally advanced colon cancer.

BACKGROUND: The incidence of colorectal cancer in patients younger than 50 years has been increasing in recent years. OBJECTIVE: Develop and validate prognostic nomograms predicting overall survival (OS) and cancer-specific survival (CSS) for early-onset locally advanced colon cancer (EOLACC) based on the Surveillance, Epidemiology, and End Results (SEER) database. RESULTS: The entire cohort comprised 13,755 patients with EOLACC. The nomogram predicting OS for EOLACC displayed that T stage contributed the most to prognosis, followed by N stage, regional nodes examined (RNE) and surgery. The nomogram predicting CSS for EOLACC demonstrated similar results. Various methods identified the discriminating superiority of the nomograms. X-tile software was used to classify patients into high-risk, medium-risk, and low-risk according to the risk score of the nomograms. The risk stratification effectively avoided the survival paradox. CONCLUSIONS: We established and validated nomograms for predicting OS and CSS based on a national cohort of almost 13,000 EOLACC patients. The nomograms could effectively solve the issue of survival paradox of the AJCC staging system and be an excellent tool to integrate the clinical characteristics to guide the therapeutic choice for EOLACC patients. METHODS: Nomograms were constructed based on the SEER database and the Cox regression model.

Nomograms predicting Overall Survival and Cancer-specific Survival for Synchronous Colorectal Liver-limited Metastasis.

Background: Colorectal cancer (CRC) ranks as the third most frequent cancer type and the second leading cause of cancer-related death worldwide. The liver is the most common metastatic site of CRC with 20%-34% of patients suffering synchronous liver metastasis. Patients with colorectal liver-limited metastasis account for one-third of deaths from colorectal cancer. Moreover, some evidence indicated that CRC patients with synchronous liver disease encounter a worse prognosis and more disseminated disease state comparing with metastatic liver disease that develops metachronously. Methods: Data in this retrospective analysis were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Nomograms were constructed with basis from a multivariate Cox regression analysis. The prognostic nomograms were validated by C-index, time-dependent receiver operating characteristic (ROC) curve, decision curve analysis (DCA) and calibration curves. Results: A total of 9,958 CRC patients with synchronous liver-limited metastasis were extracted from the SEER database during 2010-2016. Both overall survival (OS) and cancer-specific survival (CSS) were significantly correlated with age, marital status, race, tumor location, pathological grade, histologic type, T stage, N stage, surgery for primary tumor, surgery for liver metastasis, chemotherapy and CEA. All of the significant variables were used to create the nomograms predicting OS and CSS. C-index values, time-dependent ROC curves, DCA curves and calibration curves, proved the superiority of the nomograms. Conclusions: Our research investigated a national cohort of almost 10,000 patients to create and verify nomograms based on pathological, therapeutic and demographic features to predict OS and CSS for synchronous colorectal liver-limited metastasis (SCLLM). The nomograms may act as an excellent tool to integrate clinical characteristics to guide the therapeutic choice for SCLLM patients.

Structure-Adjustable Gold Nanoingots with Strong Plasmon Coupling and Magnetic Resonance for Improved Photocatalytic Activity and SERS.

Au nanoingots, on which an Au nanosphere is accurately placed in an open Au shell, are synthesized through a controllable hydrothermal method. The prepared Au nanoingots exhibit an adjustable cavity structure, strong plasmon coupling, tunable magnetic plasmon resonance, and prominent photocatalytic and SERS performances. Au nanoingots exhibit two resonance peaks in the extinction spectrum, one (around 550 nm) is ascribed to electric dipole resonance coming from the central Au, and the other one (650-800 nm) is ascribed to the magnetic dipole resonance originating from the open Au shell. Numerical simulations verify that the intense electric and magnetic fields locate in the bowl-shaped nanogap between the Au nanosphere and shell, and they can be further optimized by changing the size of the outer Au shell. Au nanoingots with the largest shell have the strongest electric field because of large-area plasmon coupling, while Au nanoingots with the largest shell opening size have the strongest magnetic field. As a result, the structure-adjustable Au nanoingots show a high tunability and enhancement of catalytic reduction of p-nitrophenol and SERS detection of Rhodamine B. Specially, Au nanoingots with the largest shell size exhibit the highest catalytic activity and Raman signals at 532 nm excitation. However, Au nanoingots with the largest shell opening size have the highest photocatalytic activity with light irradiation (λ > 420 nm) and exhibit the best SERS performance at 785 nm excitation.

A bibliometric analysis of 23,492 publications on rectal cancer by machine learning: basic medical research is needed.

BACKGROUND AND AIMS: The aim of this study was to analyse the landscape of publications on rectal cancer (RC) over the past 25 years by machine learning and semantic analysis. METHODS: Publications indexed in PubMed under the Medical Subject Headings (MeSH) term 'Rectal Neoplasms' from 1994 to 2018 were downloaded in September 2019. R and Python were used to extract publication date, MeSH terms and abstract from the metadata of each publication for bibliometric assessment. Latent Dirichlet allocation was applied to analyse the text from the articles' abstracts to identify more specific research topics. Louvain algorithm was used to establish a topic network resulting in identifying the relationship between the topics. RESULTS: A total of 23,492 papers published were identified and analysed in this study. The changes of research focus were analysed by the changing of MeSH terms. Studied contents extracted from the publications were divided into five areas, including surgical intervention, radiotherapy and chemotherapy intervention, clinical case management, epidemiology and cancer risk as well as prognosis studies. CONCLUSIONS: The number of publications indexed on RC has expanded rapidly over the past 25 years. Studies on RC have mainly focused on five areas. However, studies on basic research, postoperative quality of life and cost-effective research were relatively lacking. It is predicted that basic research, inflammation and some other research fields might become the potential hotspots in the future.

Mcl-1 inhibition overcomes intrinsic and acquired regorafenib resistance in colorectal cancer.

Intrinsic and acquired resistance to targeted therapies is a significant clinical problem in cancer. We previously showed that resistance to regorafenib, a multi-kinase inhibitor for treating colorectal cancer (CRC) patients, can be caused by mutations in the tumor suppressor FBW7, which block degradation of the pro-survival Bcl-2 family protein Mcl-1. We tested if Mcl-1 inhibition can be used to develop a precision combination therapy for overcoming regorafenib resistance. METHODS: Small-molecule Mcl-1 inhibitors were tested on CRC cells with knock-in (KI) of a non-degradable Mcl-1. Effects of Mcl-1 inhibitors on regorafenib sensitivity were determined in FBW7-mutant and -wild-type (WT) CRC cells and tumors, and in those with acquired regorafenib resistance due to enriched FBW7 mutations. Furthermore, translational potential was explored by establishing and analyzing FBW7-mutant and -WT patient-derived organoid (PDO) and xenograft (PDX) tumor models. RESULTS: We found that highly potent and specific Mcl-1 inhibitors such as S63845 overcame regorafenib resistance by restoring apoptosis in multiple regorafenib-resistant CRC models. Mcl-1 inhibition re-sensitized CRC tumors with intrinsic and acquired regorafenib resistance in vitro and in vivo, including those with FBW7 mutations. Importantly, Mcl-1 inhibition also sensitized FBW7-mutant PDO and PDX models to regorafenib. In contrast, Mcl-1 inhibition had no effect in FBW7-WT CRCs. CONCLUSIONS: Our results demonstrate that Mcl-1 inhibitors can overcome intrinsic and acquired regorafenib resistance in CRCs by restoring apoptotic response. FBW7 mutations might be a potential biomarker predicting for response to the regorafenib/Mcl-1 inhibitor combination.

Establishment and Verification of Synchronous Metastatic Nomogram for Gastrointestinal Stromal Tumors (GISTs): A Population-Based Analysis.

AIM: Assess the risk of synchronous metastasis and establish a nomogram in patients with GISTs. METHODS: Surveillance, Epidemiology and End Results database (2004-2014) was accessed. With the logistic regression model as the basis, a nomogram was constructed. RESULTS: 7,256 target patients were contained in our study. The nomogram discrimination for mGIST prediction revealed that tumor size contributed most to synchronous metastasis, followed by lymph nodes, extension, pathologic grade, tumor location, and mitotic count. C-index values of predictions were 0.821 (95% CI, 0.805-0.836) and 0.815 (95% CI, 0.800-0.831), and Brier score were 0.109 and 0.112 in training and validation group, respectively. The value of area under the ROCs were 0.813 (p < 0.001) in the primary cohort and 0.819 (p < 0.001) in the validation cohort. Through the calibration curves (as seen in the figures), nomogram prediction proved to have excellent agreement with actual metastatic diseases. CONCLUSION: A new nomogram was created that can evaluate synchronous metastatic diseases in patients with GISTs.

Is abdominal vascular calcification score valuable in predicting the occurrence of colorectal anastomotic leakage? A meta-analysis.

OBJECTIVE: Anastomotic leakage (AL) is a catastrophic surgical complication affecting the prognosis of patients after colorectal surgery. We aimed to determine the value of the arterial calcification (AC) score in predicting AL. METHODS: Medline and Embase were searched through November 2019. The odds ratio (OR) and 95% confidence interval (CI) were used to estimate the association between AC and AL after colorectal surgery. The fixed-effects model or random-effects model was adopted for data pooling. Subgroup analyses were conducted to assess the effect of different aortoiliac trajectories. RESULTS: Four studies involving 496 patients were included. The calcium volume and calcium score measurements of different trajectories revealed a significant difference with regard to the left and right common iliac arteries, the superior mesenteric artery, and the left common iliac artery. Calcification of the internal iliac artery significantly increased the risk of AL compared with no AL (OR = 1.005; 95% CI 1.002-1.009; P = 0.005), as did calcification of the left internal iliac artery (OR = 1.009; 95% CI 1.002-1.016; P = 0.011), but not of the common iliac artery (OR = 1.001; 95% CI 1.000-1.001; P = 0.317) or common and internal iliac artery (OR = 1.000; 95% CI 1.000-1.000; P = 1.000). CONCLUSIONS: AC is associated with increased risk of AL following colorectal surgery. TRIAL REGISTRATION: CRD42019141236.

Role of SSH1 in colorectal cancer prognosis and tumor progression.

BACKGROUND AND AIM: Slingshot 1 protein (SSH1) plays a critical role in cytoskeleton dynamic regulation. Increasing evidence suggest that SSH1 expression is upregulated in several cancers and relates to tumor progression and drug resistance. Here, we evaluated the role of SSH1 in colorectal cancer (CRC) development and its prognostic value in patients with CRC. METHODS: SSH1 expression was examined by quantitative real-time polymerase chain reaction, western blot analysis, or immunohistochemistry. The association between SSH1 expression and clinical characteristics and prognosis was evaluated. Stable SSH1 knockdown cells were used for in vitro assays and xenograft models. Correlation between SSH1 expression and epithelial-mesenchymal transition (EMT) was analyzed by western blot and online data analysis. RESULTS: SSH1 expression was upregulated in cancer tissue compared with paired non-cancerous tissue in patients with CRC. SSH1 expression level in CRC tissue was associated with tumor stage, lymph node metastasis, and correlated with poor prognosis as indicated by univariate and multivariate analyses. In vitro, loss of SSH1 impaired colony formation, migration, and invasion of CRC cells. In vivo data suggest that SSH1 could promote the progression and metastasis of CRC. Interestingly, E-cadherin, ZEB1, and Snail, which are markers of EMT, had a significant expression correlation with SSH1. CONCLUSIONS: SSH1 expression is associated with CRC progression and predicts poor prognosis. SSH1 may promote CRC tumor progression by regulating EMT.

High Loading of Hydrophobic and Hydrophilic Agents via Small Immunostimulatory Carrier for Enhanced Tumor Penetration and Combinational Therapy.

Development of small-sized nanoformulations for effective tumor penetration, particularly for those tumors with dense stroma is a major challenge in cancer nanomedicine. It is even more challenging to achieve effective co-loading of both hydrophobic and hydrophilic anticancer agents through a small-sized nanocarrier. In this work, we designed a novel redox-responsive gemcitabine (GEM)-conjugated polymer POEG-co-PVDGEM (PGEM) as a small-sized nanocarrier to co-deliver hydrophilic GEM and hydrophobic paclitaxel (PTX). Methods: The in vitro physicochemical and biological properties of PTX/PGEM NPs were characterized. The efficiency of the PGEM carrier in selective codelivery of GEM and PTX in two murine tumor models as well as a patient derived xenograft model (PDX) was also evaluated. In addition, we investigated the changes in tumor immune microenvironment after treatment with PTX/PGEM nanoparticles. Results: We discovered that GEM conjugation could significantly decrease the nanoparticle size from 160 nm to 13 nm. Moreover, different from most reported GEM-conjugated polymers, PGEM polymer could serve as a prodrug carrier to load a wide variety of hydrophobic agents with high drug loading capacity and excellent stability. More importantly, our strategy could be extended to various nucleotides-based drugs such as azacytidine, decitabine and cytarabine, suggesting a new platform for co-delivery of various first line hydrophilic and hydrophobic anticancer agents. Imaging showed that our small-sized carrier was much more effective in tumor accumulation and penetration compared to the relatively large-sized drug carrier. The PGEM prodrug-based carrier not only well retained the pharmacological activity of GEM, but also boosted T-cell immune response. Furthermore, delivery of PTX via PGEM led to significantly improved antitumor activity in several murine cancer models and a PDX model of colon cancer. Conclusion: This work not only provided a small-sized carrier platform that was able to load multiple hydrophilic and hydrophobic drugs with high loading capacity, but also provided an effective regimen for enhanced tumor penetration and improved anti-tumor immunity.