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Endoscopic polypectomy is a standard method of treatment of gastrointestinal polyps, but is associated with substantial risk of complications. The most common is hemorrhage, the rate of which varied between 0.3%, and 6%. Various prophylactic techniques have been used to reduce this incidence. The aim of this study was to establish whether the prophylactic injection of adrenaline-saline solution reduces the risk of postpolypectomy bleeding in colonoscopic polypectomy. Between May 2000 and June 2002, patients with colorectal polyps of size > or =1 cm were randomized to receive submucosal epinephrine injection (group A) or no injection (group B). The polypectomies were carried out using the conventional method. In group A, epinephrine (1/10,000) was injected into the stalk or base of the polyp. The patients were observed for complications. A total of 69 patients with 100 polyps were enrolled in this study: n = 50 in group A, and n = 50 in group B, according to randomization. There were a total of nine episodes of postpolypectomy hemorrhage, one in the epinephrine group and eight in the control group (1/50 vs 8/50, p < 0.05). The bleeding correlated with the size of the polyps and the diameter of the stalks. Epinephrine injection prior to colonoscopic polypectomy is effective in preventing bleeding.

With suppressed photon scattering and diminished autofluorescence, in vivo fluorescence imaging in the 1,500- to 1,700-nm range of the near-IR (NIR) spectrum (NIR-IIb window) can afford high clarity and deep tissue penetration. However, there has been a lack of NIR-IIb fluorescent probes with sufficient brightness and aqueous stability. Here, we present a bright fluorescent probe emitting at ∼1,600 nm based on core/shell lead sulfide/cadmium sulfide (CdS) quantum dots (CSQDs) synthesized in organic phase. The CdS shell plays a critical role of protecting the lead sulfide (PbS) core from oxidation and retaining its bright fluorescence through the process of amphiphilic polymer coating and transferring to water needed for imparting aqueous stability and compatibility. The resulting CSQDs with a branched PEG outer layer exhibited a long blood circulation half-life of 7 hours and enabled through-skin, real-time imaging of blood flows in mouse vasculatures at an unprecedented 60 frames per second (fps) speed by detecting ∼1,600-nm fluorescence under 808-nm excitation. It also allowed through-skin in vivo confocal 3D imaging of tumor vasculatures in mice with an imaging depth of ∼1.2 mm. The PEG-CSQDs accumulated in tumor effectively through the enhanced permeation and retention effect, affording a high tumor-to-normal tissue ratio up to ∼32 owing to the bright ∼1,600-nm emission and nearly zero autofluorescence background resulting from a large ∼800-nm Stoke’s shift. The aqueous-compatible CSQDs are excreted through the biliary pathway without causing obvious toxicity effects, suggesting a useful class of ∼1,600-nm emitting probes for biomedical research.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy. Long non‐coding RNAs (lncRNAs) are important regulators in pathological processes, yet their potential roles in PDAC are poorly understood. Here, we identify a fundamental role for a novel lincRNA, linc00511, in the progression of PDAC. Linc00511 levels in PDAC tissue specimens and cell lines were examined by quantitative real‐time PCR. Corresponding adjacent non‐neoplastic tissues were used as controls. The function of linc00511 in PDAC cell lines was determined by RNA interference approach in vitro and in vivo. Fluorescence in situ hybridization (FISH) was used to characterize linc00511 expression in PDAC cells. Insights of the mechanism of competitive endogenous RNAs (ceRNAs) were obtained from bioinformatic analysis, luciferase assays and RIP assays. The association between the linc00511/hsa‐miR29b‐3p axis and VEGFA was verified by Western blotting assay. Immunohistochemistry was performed to evaluate the expression of VEGFA in PDAC samples. The aberrant up‐regulation of linc00511 was detected in PDAC cell lines and patient specimens compared with controls. An increase in linc00511 expression indicates the adverse clinical pathological characteristics and poor prognosis. Functionally, linc00511 depletion in PDAC cells decreased proliferation, migration, invasion and endothelial tube formation. Mechanistically, linc00511 could up‐regulate VEGFA via its competing endogenous RNA (ceRNA) activity on hsa‐miR‐29b‐3p. In summary, our results define an important axis controlling proliferation, invasion and tumour angiogenesis in PDAC. Linc00511 is a novel lncRNA that plays a significant regulatory role in the pathogenesis and progression of PDAC. Thus, Linc00511 represents a new prognostic biomarker to predict clinical outcome of PDAC patients after surgery and may serve as a potential therapeutic target for PDAC treatment.

An immunohistochemical study was conducted of 108 papillary carcinoma cases, including 48 cases with intratumoral heterotopic ossification (IHO). In 48 cases, papillary carcinoma with IHO was accompanied by nodular fibrosis. Cases of papillary carcinoma with IHO or nodular fibrosis showed higher incidences of lymph node metastasis, multifocal lesions, and extrathyroidal invasion than those without IHO and nodular fibrosis. A higher number of stromal myofibroblasts was observed in papillary carcinoma with IHO or nodular fibrosis than in that without fibrosis. Expression of both basic fibroblast growth factor (bFGF) and bone morphogenetic protein (BMP)–2 was the highest in papillary carcinoma with IHO. Papillary carcinoma with IHO showed higher vascular invasion and higher numbers of capillaries expressing nestin, which is associated with high expression of vascular endothelial growth factor (VEGF). Papillary carcinoma with IHO is a unique subtype with extensive progression including frequent lymph node metastasis, multifocality, and invasive behavior. Papillary carcinoma with IHO was correlated with expression of bFGF, BMP-2, and VEGF in the carcinoma cells, leading to neovascularization.

Background Pancreatic cancer is the fourth leading cause of cancer death in the United States. Surgery offers the only chance for cure. However, less than twenty percent of patients are considered operative candidates at the time of diagnosis. A common reason for being classified as unresectable is advanced loco-regional disease. A review of the literature indicates that almost nine hundred patients with pancreatic cancer have received regional chemotherapy in the last 15 years. Phase I studies have shown regional administration of chemotherapy to be safe. The average reported response rate was approximately 26%. The average 1-year survival was 39%, with an average median survival of 9 months. Of the patients that experienced a radiographic response to therapy, 78 (78/277, 28%) patients underwent exploratory surgery following regional chemotherapy administration; thirty-two (41%) of those patients were amenable to pancreatectomy. None of the studies performed analyses to identify factors predicting response to regional chemotherapy. Progressive surgical techniques combined with current neoadjuvant chemoradiotherapy strategies have already yielded emerging support for a multimodality approach to treatment of advanced pancreatic cancer. Intravenous gemcitabine is the current standard treatment of pancreatic cancer. However, >90% of the drug is secreted unchanged affecting toxicity but not the cancer per se. Gemcitabine is converted inside the cell into its active drug form in a rate limiting reaction. We hypothesize that neoadjuvant regional chemotherapy with continuous infusion of gemcitabine will be well tolerated and may improve resectability rates in cases of locally advanced pancreatic cancer. Design This is a phase I study designed to evaluate the feasibility and toxicity of super-selective intra-arterial administration of gemcitabine in patients with locally advanced, unresectable pancreatic adenocarcinoma. Patients considered unresectable due to locally advanced pancreatic cancer will receive super-selective arterial infusion of gemcitabine over 24 hours via subcutaneous indwelling port. Three to six patients will be enrolled per dose cohort, with seven cohorts, plus an additional six patients at the maximum tolerated dose; accrual is expected to last 36 months. Secondary objectives will include the determination of progression free and overall survival, as well as the conversion rate from unresectable to potentially resectable pancreatic cancer. Trial Registration ClinicalTrials.gov ID: NCT01294358

Early growth response-1 ( EGR1 ) is a transcription factor correlated with prostate cancer (PC) progression in a variety of contexts. For example, EGR1 levels increase in response to suppressed androgen receptor signaling or loss of the tumor suppressor, PTEN. EGR1 has been shown to regulate genes influencing proliferation, apoptosis, immune cell activation, and matrix degradation, among others. Despite this, the impact of EGR1 on PC metastatic colonization is unclear. We demonstrate using a PC model (DU145/RasB1) of bone and brain metastasis that EGR1 expression regulates angiogenic and osteoclastogenic properties of metastases. We have shown previously that FN14 (TNFRSF12A) and downstream NF-κB signaling is required for metastasis in this model. Here we demonstrate that FN14 ligation also leads to NF-κB-independent, MEK-dependent EGR1 expression. EGR1- depletion in DU145/RasB1 cells reduced both the number and size of metastases but did not affect primary tumor growth. Decreased EGR1 expression led to reduced blood vessel density in brain and bone metastases as well as decreased osteolytic bone lesion area and reduced numbers of osteoclasts at the bone–tumor interface. TWEAK (TNFSF12) induced several EGR1- dependent angiogenic and osteoclastogenic factors (e.g., PDGFA, TGFB1, SPP1, IL6, IL8, and TGFA, among others). Consistent with this, in clinical samples of PC, the level of several genes encoding angiogenic/osteoclastogenic pathway effectors correlated with EGR1 levels. Thus, we show here that EGR1 has a direct effect on prostate cancer metastases. EGR1 regulates angiogenic and osteoclastogenic factors, informing the underlying signaling networks that impact autonomous and microenvironmental mechanisms of cancer metastases.

Angiogenesis is closely associated with tumor growth and metastasis, and microvascular density (MVD) is currently the clinical standard for evaluating tumor angiogenesis. Thus, the detection of intratumoral MVD is of great significance for understanding disease progression and predicting patient prognosis. Tumor tissue sections of 238 patients with lung adenocarcinoma (LUAD) who underwent radical surgery were retrospectively analyzed. Immunohistochemical (IHC) staining was carried out using a CD34 polyclonal antibody to determine intratumoral MVD, and the relationship of CD34-MVD with the clinicopathological characteristics and survival time of LUAD patients was analyzed. CD34-MVD was associated with tumor size, lymph node metastasis, tumor recurrence, and patient survival status; patients with tumor size ≤3 cm ( = 0.015), negative for lymph node metastasis ( = 0.049), no tumor recurrence ( = 0.021), and survival ( = 0.042) had higher MVD. Survival analysis suggested that patients with high MVD had higher disease-free survival (log-rank = 0.005) and overall survival (log-rank = 0.004) compared to patients with low MVD. The Cox proportional hazards model showed that a high MVD ( = 0.022) reduced the risk of postoperative tumor recurrence in patients with LUAD. Decreased intratumoral CD34 positive microvessels were associated with tumor development in patients with LUAD. CD34-MVD is an independent risk factor affecting postoperative tumor recurrence in patients with LUAD and can be used as a prognostic indicator for this group of patients.

In lung cancer, antiangiogenic strategies targeting tumor-derived endothelial cells (TECs) afford a survival advantage, but the characteristics of TECs have not been comprehensively elucidated. Herein, high-purity (> 98%) TECs were obtained, and these cells retained expression of EC markers and exhibited high viability. ITRAQ-2DLC-MS/MS was performed to profile the proteome and the heterogeneity of ECs. Only 31 of 1820 identified proteins were differentially expressed between adenocarcinoma (ADC)- and squamous cell carcinoma (SCC)-derived TECs (TEC-A and TEC-S, respectively), and cadherin-2 (CDH2) was the most significantly upregulated protein in TEC-A samples. Positive immunostaining for CDH2 (score > 3) was significantly more frequent in the endothelium of ADC tissues than in that of SCC tissues. Loss- or gain-of-function analysis showed that CDH2 significantly promoted in vitro and in vivo angiogenesis and sensitivity to the antagonist exherin. The MAPK/ERK and MAPK/JNK signaling pathways may play crucial roles in CDH2-induced HIF-1α/VEGF-mediated angiogenesis. Moreover, high CDH2 expression in TECs was significantly associated with tumor stage, visceral pleural metastasis, and decreased overall survival in patients with ADC but not SCC. Together, these data indicate the importance of CDH2 in angiogenesis and highlight its potential both for antiangiogenic therapy and as a candidate prognostic marker for ADC.

Background Angiogenesis is a critical step in colorectal cancer growth, progression and metastasization. CT are routine imaging examinations for preoperative clinical evaluation in colorectal cancer patients. This study aimed to investigate the predictive value of preoperative CT enhancement rate (CER) and CT perfusion parameters on angiogenesis in colorectal cancer, as well as the association of preoperative CER and CT perfusion parameters with serum markers. Methods This retrospective analysis included 42 patients with colorectal adenocarcinoma. Median of microvessel density (MVD) as the cut-off value, it divided 42 patients into high-density group (MVD ≥ 35/field, n  = 24) and low-density group (MVD < 35/field, n  = 18), and 25 patients with benign colorectal lesions were collected as the control group. Statistical analysis of CER, CT perfusion parameters, serum markers were performed in all groups. Receiver operating curves (ROC) were plotted to evaluate the diagnostic efficacy of relevant CT perfusion parameters for tumor angiogenesis; Pearson correlation analysis explored potential association between CER, CT perfusion parameters and serum markers. Results CER, blood volume (BV), blood flow (BF), permeability surface (PS) and carbohydrate antigen 19 − 9 (CA19-9), carbohydrate antigen 125 (CA125), carcinoembryonic antigen (CEA), trefoil factor 3 (TFF3), vascular endothelial growth factor (VEGF) in colorectal adenocarcinoma were significantly higher than those in the control group, the parameters in high-density group were significantly higher than those in the low-density group ( P  < 0.05); however, the time to peak (TTP) of patients in colorectal adenocarcinoma were significantly lower than those in the control group, and the high-density group showed a significantly lower level compared to the low-density group ( P  < 0.05). The combined parameters BF + TTP + PS and BV + BF + TTP + PS demonstrated the highest area under the curve (AUC), both at 0.991. Pearson correlation analysis showed that the serum levels of CA19-9, CA125, CEA, TFF3, and VEGF in patients showed positive correlations with CER, BV, BF, and PS ( P  < 0.05), while these indicators exhibited negative correlations with TTP ( P  < 0.05). Conclusions Some single and joint preoperative CT perfusion parameters can accurately predict tumor angiogenesis in colorectal adenocarcinoma. Preoperative CER and CT perfusion parameters have certain association with serum markers.

Oncolytic viruses (OVs) have been engineered or selected for cancer cell-specific infection however, we have found that following intravenous administration of vesicular stomatitis virus (VSV), tumor cell killing rapidly extends far beyond the initial sites of infection. We show here for the first time that VSV directly infects and destroys tumor vasculature in vivo but leaves normal vasculature intact. Three-dimensional (3D) reconstruction of infected tumors revealed that the majority of the tumor mass lacks significant blood flow in contrast to uninfected tumors, which exhibit relatively uniform perfusion. VSV replication in tumor neovasculature and spread within the tumor mass, initiates an inflammatory reaction including a neutrophil-dependent initiation of microclots within tumor blood vessels. Within 6 hours of intravenous administration of VSV and continuing for at least 24 hours, we observed the initiation of blood clots within the tumor vasculature whereas normal vasculature remained clot free. Blocking blood clot formation with thrombin inhibitors prevented tumor vascular collapse. Our results demonstrate that the therapeutic activity of an OV can go far beyond simple infection and lysis of malignant cells.