Ultrasound contrast-enhanced radiomics model for preoperative prediction of the tumor grade of clear cell renal cell carcinoma: an exploratory study.

BACKGROUND: This study aims to explore machine learning(ML) methods for non-invasive assessment of WHO/ISUP nuclear grading in clear cell renal cell carcinoma(ccRCC) using contrast-enhanced ultrasound(CEUS) radiomics. METHODS: This retrospective study included 122 patients diagnosed as ccRCC after surgical resection. They were divided into a training set (n = 86) and a testing set(n = 36). CEUS radiographic features were extracted from CEUS images, and XGBoost ML models (US, CP, and MP model) with independent features at different phases were established. Multivariate regression analysis was performed on the characteristics of different radiomics phases to determine the indicators used for developing the prediction model of the combined CEUS model and establishing the XGBoost model. The training set was used to train the above four kinds of radiomics models, which were then tested in the testing set. Radiologists evaluated tumor characteristics, established a CEUS reading model, and compared the diagnostic efficacy of CEUS reading model with independent characteristics and combined CEUS model prediction models. RESULTS: The combined CEUS radiomics model demonstrated the best performance in the training set, with an area under the curve (AUC) of 0.84, accuracy of 0.779, sensitivity of 0.717, specificity of 0.879, positive predictive value (PPV) of 0.905, and negative predictive value (NPV) of0.659. In the testing set, the AUC was 0.811, with an accuracy of 0.784, sensitivity of 0.783, specificity of 0.786, PPV of 0.857, and NPV of 0.688. CONCLUSIONS: The radiomics model based on CEUS exhibits high accuracy in non-invasive prediction of ccRCC. This model can be utilized for non-invasive detection of WHO/ISUP nuclear grading of ccRCC and can serve as an effective tool to assist clinical decision-making processes.

Coffee Consumption and Incidence of Cardiovascular and Microvascular Diseases in Never-Smoking Adults with Type 2 Diabetes Mellitus.

The relationship between coffee consumption and diabetes-related vascular complications remains unclear. To eliminate confounding by smoking, this study assessed the relationships of coffee consumption with major cardiovascular disease (CVD) and microvascular disease (MVD) in never-smokers with type 2 diabetes mellitus (T2DM). Included were 9964 never-smokers with T2DM from the UK Biobank without known CVD or cancer at baseline (7781 were free of MVD). Participants were categorized into four groups according to daily coffee consumption (0, 0.5-1, 2-4, ≥5 cups/day). CVD included coronary heart disease (CHD), myocardial infarction (MI), stroke, and heart failure (HF). MVD included retinopathy, peripheral neuropathy, and chronic kidney disease (CKD). Cox regression models were used to estimate hazard ratios (HRs) and 95% confidential intervals (CIs) of total CVD and MVD and the component outcomes associated with coffee consumption. During a median of 12.7 years of follow-up, 1860 cases of CVD and 1403 cases of MVD were identified. Coffee intake was nonlinearly and inversely associated with CVD (P-nonlinearity = 0.023) and the component outcomes. Compared with no coffee intake, HRs (95% CIs) associated with a coffee intake of 2 to 4 cups/day were 0.82 (0.73, 0.93) for CVD, 0.84 (0.73, 0.97) for CHD, 0.73 (0.57, 0.92) for MI, 0.76 (0.57, 1.02) for stroke, and 0.68 (0.55, 0.85) for HF. Higher coffee intake (≥5 cups/day) was not significantly associated with CVD outcomes. Coffee intake was linearly and inversely associated with risk of CKD (HR for ≥5 vs. 0 cups/day = 0.64; 95% CI: 0.45, 0.91; P-trend = 0.0029) but was not associated with retinopathy or peripheral neuropathy. Among never-smoking individuals with T2DM, moderate coffee consumption (2-4 cups/day) was associated with a lower risk of various CVD outcomes and CKD, with no adverse associations for higher consumption.

Evaluation of artificial intelligent breast ultrasound on lesion detection and characterization compared with hand-held ultrasound in asymptomatic women.

Introduction: To compare the accuracy of Artificial Intelligent Breast Ultrasound (AIBUS) with hand-held breast ultrasound (HHUS) in asymptomatic women and to offer recommendations for screening in regions with limited medical resources. Methods: 852 participants who underwent both HHUS and AIBUS were enrolled between December 2020 and June 2021. Two radiologists, who were unaware of the HHUS results, reviewed the AIBUS data and scored the image quality on a separate workstation. Breast imaging reporting and data system (BI-RADS) final recall assessment, breast density category, quantified lesion features, and examination time were evaluated for both devices. The statistical analysis included McNemar's test, paired t-test, and Wilcoxon test. The kappa coefficient and consistency rate were calculated in different subgroups. Results: Subjective satisfaction with AIBUS image quality reached 70%. Moderate agreements were found between AIBUS with good quality images and HHUS for the BI-RADS final recall assessment (κ = 0.47, consistency rate = 73.9%) and breast density category (κ = 0.50, consistency rate = 74.8%). The lesions measured by AIBUS were statistically smaller and deeper than those measured by HHUS (P < 0.001), though they were not significant in clinical diagnosis (all < 3 mm). The total time required for the AIBUS examination and image interpretation was 1.03 (95% CI (0.57, 1.50)) minutes shorter than that of HHUS per case. Conclusion: Moderate agreement was obtained for the description of the BI-RADS final recall assessment and breast density category. With image quality comparable to that of HHUS, AIBUS was superior for the efficiency of primary screening.

Methylprednisolone for idiopathic granulomatous mastitis: a prospective observational cohort study.

Background: Idiopathic granulomatous mastitis (IGM) is a rare, benign, but locally aggressive breast disease. Steroids are widely used as a breast-conserving option, however, the response rate of steroids varies in reported studies, as well as its different reported usage. This prospective observational cohort study aimed to report the outcomes of methylprednisolone for IGM treatment. Methods: From Aug 2019 to Dec 2021, the clinicopathological information of 156 IGM patients who sought treatment at West China Hospital was prospectively collected. A total of 88 patients treated with methylprednisolone were included in the study. The clinical features, treatment response, and follow-up data were analyzed. Results: The median age at diagnosis was 32 years, and 90.9% of patients were multipara. The predominant symptom at presentation was painful breast mass, with a median size of 4.7 cm. For steroid usage, an initial 20 mg methylprednisolone daily was given until disease stable. The median duration of 20 mg methylprednisolone treatment was 45 (range, 14-376) days. The median duration of whole steroid therapy was 105 (range, 28-381) days. A total of 80.7% of patients (71/88) responded well to steroid treatment. In 63 patients, steroid treatment was successfully withdrawn, and treatment was completed. With an average of 283 days follow-up (range, 0-770 days), relapse was observed in 21 (33.33%) patients. Compared with patients with residual disease as shown by physical examination (PE), those with complete clinical remission (CCR) at the end of treatment had longer relapse-free intervals. Conclusions: Steroids are the preferable breast-conserving option for IGM. Treatment with 20 mg methylprednisolone for an average of 1.5 months is usually required, and full steroid treatment might last for 3 months.

Preoperative high-frequency color Doppler ultrasound assessment of the blood vessels of the fibular myocutaneous flap.

OBJECTIVE: The fibular myocutaneous flap is a classic flap used to reconstruct oral and maxillofacial defects. This study aimed to evaluate the effectiveness of high-frequency color Doppler ultrasound in detecting the blood vessels in the fibular myocutaneous flap, analyze the influence of variations in the peroneal vessels and perforating peroneal arteries on the surgical design, and explore the value of this technology in preoperatively assessing the blood vessels of the fibular myocutaneous flap. METHODS: Twenty-five patients with mandibular disease or defect underwent preoperative evaluation of the blood vessels of the calf by high-frequency color Doppler ultrasound. The inner diameter and peak systolic velocity (PSV) of the peroneal arteries and veins and the perforating peroneal arteries were compared between different groups. The consistency between the perforating peroneal arteries marked by ultrasonography and the intraoperative findings was analyzed. RESULTS: The initial segment of the peroneal artery had a larger inner diameter (p<0.001) and lower PSV (p<0.05) than the middle segment. The perforating peroneal arteries were mainly distributed in the middle of the fibula. The inner diameter of the perforating peroneal artery was larger in men than in women (p<0.05). In comparison with surgical exploration as the gold standard, high-frequency color Doppler ultrasound results showed good consistency (Kappa=0.684, 95% CI: 0.512-0.856, p<0.001), with a sensitivity of 89.36%, specificity of 78.57%, and accuracy of 85.33%. CONCLUSION: High-frequency color Doppler ultrasound can detect, quantitatively evaluate, and accurately mark the peroneal artery and vein and perforating peroneal artery before fibular myocutaneous flap transplantation.

SPARC regulates ferroptosis induced by sorafenib in human hepatocellular carcinoma.

BACKGROUND: Secreted protein acidic and rich in cysteine (SPARC) is implicated in cancer progression, but its role and associated molecular mechanism in the sorafenib sensitivity of hepatocellular carcinoma cells (HCC) remains elusive. METHODS: Human HCC cell lines Hep3B and HepG2 were treated with sorafenib alone or combined with activator or inhibitor of ferroptosis. Cell viability assay, reactive oxygen species (ROS) assay, lactate dehydrogenase (LDH) assay and western blot were used to study the regulatory mechanism of SPARC on HCC cells. RESULTS: Overexpression of SPARC enhanced the cytotoxic effect of sorafenib in Hep3B and HepG2 cells compared with parental cells. Depletion of SPARC decreased the cytotoxic effect of sorafenib in Hep3B and HepG2 cells compared with parental cells. Moreover, overexpression of SPARC significantly induced LDH release, whereas depletion of SPARC suppressed the release of LDH in Hep3B and HepG2 cells. Inhibition of ferroptosis exerted a clear inhibitory role against LDH release, whereas activation of ferroptosis promoted the release of LDH in HCC cells, as accompanied with deregulated expression of ferroptosis-related proteins. Furthermore, overexpression of SPARC induced oxidative stress, whereas depletion of SPARC suppressed the production of ROS. Deferoxamine (DFX)-induced inhibition of ferroptosis suppressed the production of ROS, while activation of ferroptosis promoted the contents of ROS in HCC cells exposed to sorafenib. CONCLUSION: Our findings give a better understanding of ferroptosis and its molecular mechanism in HCC cells that is regulated by SPARC in response to sorafenib.

PTBP3 promotes malignancy and hypoxia-induced chemoresistance in pancreatic cancer cells by ATG12 up-regulation.

Pancreatic ductal adenocarcinoma (PDAC) tumours exhibit a high level of heterogeneity which is associated with hypoxia and strong resistance to chemotherapy. The RNA splicing protein polypyrimidine tract-binding protein 3 (PTBP3) regulates hypoxic gene expression by selectively binding to hypoxia-regulated transcripts. We have investigated the role of PTBP3 in tumour development and chemotherapeutic resistance in human PDAC tissues and pancreatic cancer cells. In addition, we determined the sensitivity of cancer cells to gemcitabine with differential levels of PTBP3 and whether autophagy and hypoxia affect gemcitabine resistance in vitro. PTBP3 expression was higher in human pancreatic cancer than in paired adjacent tissues. PTBP3 overexpression promoted PDAC proliferation in vitro and tumour growth in vivo, whereas PTBP3 depletion had opposing effects. Hypoxia significantly increased the expression of PTBP3 in pancreatic cancer cells in vitro. Under hypoxic conditions, cells were more resistance to gemcitabine. Knockdown of PTBP3 results in decreased resistance to gemcitabine, which was attributed to attenuated autophagy. We propose that PTBP3 binds to multiple sites in the 3'-UTR of ATG12 resulting in overexpression. PTBP3 increases cancer cell proliferation and autophagic flux in response to hypoxic stress, which contributes to gemcitabine resistance.

Embolization with microcoils for urethral hemorrhage: A case report.

RATIONALE: Microcoils are a permanent embolic material, and blood vessels that have been embolized by a microcoil remain occluded for a prolonged period of time. The pudendal artery is an important functional vessel for penile erection. Whether simultaneous embolization of the bilateral pudendal artery using microcoils can seriously affect penile erection has not been sufficiently studied. PATIENT CONCERNS: A 47-year-old male patient, after undergoing brain surgery, accidentally pulled out the Foley catheter causing a urethral hemorrhage. The patient was immediately treated using a new larger Foley catheter inserted under urethroscopic guidance and medication. However, massive bleeding occurred on the tenth day after the procedure. DIAGNOSIS: A right internal iliac angiography performed after the bleeding event demonstrated a rupture at the end of the right internal pudendal artery with the contrast agent flowing out directly from the urethra. A super selective internal pudendal angiogram showed a small amount of hemorrhage at the end of the left internal pudendal artery. INTERVENTIONS: The patient underwent interventional treatment. After the bilateral internal iliac angiography was performed, super-selective internal pudendal artery embolization with microcoils was performed. A subsequent bilateral internal pudendal angiogram did not show any abnormality. OUTCOMES: During the follow up period of 2 months, the patient had no complaints of difficulty in urination or sexual dysfunction. LESSONS: Some doctors do not advocate the use of coils as embolic agents in bilateral pudendal artery lesions because of concerns over erectile dysfunction. There is rich vascular circulation in the perineum. Thus, in arterial embolization for the treatment of penile bleeding, regardless of the type of embolic material used, the key is to ensure accurate embolization to maintain good collateral circulation. This principle can help limit the occurrence of sexual dysfunction to the lowest possible levels after such procedures.

RAMP3 is a prognostic indicator of liver cancer and might reduce the adverse effect of TP53 mutation on survival.

AIM: To assess the prognostic value of RAMP3 expression in terms of overall survival (OS) and recurrence-free survival (RFS) in hepatocellular carcinoma (HCC) patients. MATERIALS & METHODS: Immunochemistry staining was performed to detect RAMP3 expression. Data in the Cancer Genome Atlas-Liver Hepatocellular Cancer were used for secondary analysis. RESULTS: RAMP3 expression was significantly downregulated in HCC tissues than in normal liver tissues. Increased RAMP3 expression was an independent prognostic factor of favorable OS (hazard ratio [HR]: 0.772, 95% CI: 0.689-0.864; p < 0.001) and RFS (HR = 0.719, 95% CI: 0.633-0.817; p < 0.001). High RAMP3 expression was associated with significantly better RFS in both TP53 mutant and wildtype groups. CONCLUSION: High RAMP3 RNA expression is an independent prognostic factor of favorable OS and RFS in patients with HCC.

Plumbagin, a natural naphthoquinone, inhibits the growth of esophageal squamous cell carcinoma cells through inactivation of STAT3.

Although plumbagin, a natural naphthoquinone, has exhibited antiproliferative activity in numerous types of cancer, its anticancer potential in esophageal squamous cell carcinoma (ESCC) remains unclear. In the present study, the effect of plumbagin on the growth of ESCC cells was investigated in vitro and in vivo. ESCC cells were treated with plumbagin and tested for cell cycle distribution and apoptosis. The involvement of STAT3 signaling in the effect of plumbagin was examined. The results demonstrated that plumbagin treatment suppressed ESCC cell viability and proliferation, yet normal esophageal epithelial cell viability was not affected. Plumbagin treatment increased the proportion of cells in the G0/G1 phase of the cell cycle and decreased the proportion of cells in the S phase. Furthermore, plumbagin­treated ESCC cells displayed a significantly greater % of apoptotic cells. Western blot analysis confirmed that plumbagin upregulated tumor protein p53 and cyclin­dependent kinase inhibitor 1A (also known as p21), while it downregulated cyclin D1, cyclin­dependent kinase 4, and induced myeloid leukemia cell differentiation protein Mcl­1. Mechanistically, plumbagin inhibited STAT3 activation, and overexpression of constitutively active STAT3 reversed the plumbagin­mediated growth suppression in ESCC cells. In vivo studies demonstrated that plumbagin delayed the growth of ESCC xenograft tumors and reduced STAT3 phosphorylation. Overall, plumbagin was demonstrated to target STAT3 signaling and to inhibit the growth of ESCC cells both in vitro and in vivo, suggesting that it may represent a potential anticancer agent for ESCC.

MiR-124 induces autophagy-related cell death in cholangiocarcinoma cells through direct targeting of the EZH2-STAT3 signaling axis.

Cholangiocarcinoma (CCA) is a lethal cancer associated with chronic inflammation that has increased in prevalence in recent decades. The dysregulated expression of microRNAs (miRNAs) has been detected in various types of malignancies, and depending on the target genes this can result in miRNAs functioning as tumor suppressors or oncogenes. In this study, we investigated the role of miR-124 in cholangiocarcinoma (CCA) and found that its expression was significantly downregulated in the tumor tissue of patients and in CCA cell lines. Our results provided evidence that miR-124 induces apoptotic cell death and triggers the autophagic flux in CCA cells. EZH2 and STAT3 were identified as direct targets of miR-124. The effect of miR-124 on EZH2 expression in CCA cells was evaluated using cell transfection, xenotransplantation into nude mice and a luciferase reporter assay. Silencing of EZH2 restored the effects of miR-124, whereas overexpression of EZH2 abrogated the effects of miR-124. Silencing of Beclin1 or ATG5 abrogated the effects of miR-124 or siEZH2. In vivo, overexpression of miR-124 dramatically induced autophagy-related cell death and suppressed tumorigenicity. Taken together, our findings indicated that downregulation of miR-124 expression was associated with disease progression in human CCA and we revealed that miR-124 exerts a tumor suppressive function in CCA by inducing autophagy-related cell death via direct targeting of the EZH2-STAT3 signaling axis.

MiR-4262 promotes cell apoptosis and inhibits proliferation of colon cancer cells: involvement of GALNT4.

A role of microRNA-4262 (miR-4262) in the carcinogenesis of colon cancer remains undetermined. In this study, we studied the effects and mechanisms of miR-4262 to the colon cancer cell proliferation and apoptosis. We found that the levels of miR-4262 significantly down-regulated in colon cancer tissue, compared to the paired adjacent non-tumor colon tissue. The miR-4262 levels in colon cancer cell lines were significantly lower than those in control normal colon tissues. Transfection with the miR-4262 mimic decreased the cell proliferation and increased cell apoptosis in colon cancer cells, while transfection with the antisense of miR-4262 (as-miR-4262) increased cell proliferation and suppressed cell apoptosis in colon cancer cells. Bioinformatics analyses showed that GALNT4 was a potential target gene of miR-4262. The luciferase activities assay and Western blot verified that miR-4262 targeted GALNT4 mRNA to modulate its protein levels. When we treated cells with miR-4262 and GALN4 siRNA, the cell viability was significantly decreased. Together, our study suggests that aberrantly expressed miR-4262 may affect cell apoptosis and proliferation of human colon cancer cells via GALNT4, which appears to be a promising therapeutic target for colon cancer.

Enhanced tumor targeting effects of a novel paclitaxel-loaded polymer: PEG-PCCL-modified magnetic iron oxide nanoparticles.

BACKGROUND: Multifunctional magnetic nanoparticles (MNP) have been newly developed for tumor-targeted drug carriers. To address challenges including biocompatibility, stability, nontoxicity, and targeting efficiency, here we report the novel drug deliverer poly(ethylene glycol) carboxyl-poly(ɛ-caprolactone) modified MNP (PEG-PCCL-MNP) suitable for magnetic targeting based on our previous studies. METHODS: Their in vitro characterization and cytotoxicity assessments, in vivo cytotoxicity assessments, and antitumor efficacy study were elaborately investigated. RESULTS: The size of PEG-PCCL-MNP was 79.6 ± 0.945 nm. PEG-PCCL-MNP showed little in vitro or in vivo cytotoxicity and good biocompatibility, as well as effective tumor-specific cell targeting for drug delivery with the presence of external magnetic field. DISCUSSION: PEG-PCCL-MNP is a potential candidate of biocompatible and tumor-specific targeting drug vehicle for hydrophobic drugs.

Different imaging techniques for the detection of pelvic lymph nodes metastasis from gynecological malignancies: a systematic review and meta-analysis.

OBJECTIVE: This study aimed to evaluate the diagnostic performance of different imaging techniques and the corresponding diagnostic criteria for preoperative detection of pelvic lymph node metastasis from gynecological carcinomas. METHODS: Six databases were systematically searched for retrieving eligible studies. Study inclusion, data extraction and risk of bias assessment were performed by 2 reviewers independently. STATA 14.0 was used to perform the meta-analysis. RESULTS: Eighty eligible studies were collected. The pooled sensitivity, specificity, and area under curve (AUC) of CT, MRI and DWI were 47%, 93%, 0.7424; 50%, 95%, 0.8039 and 84%, 95%, 0.9523 respectively. As regards PET, PET-CT and US, the pooled sensitivity, specificity and AUC were 56%, 97%, 0.9592; 68%, 97%, 0.9363 and 71%, 99%, 0.9008 respectively. The summary receiver operating characteristic (SROC) curve indicated that the systematic diagnostic performances of PET, PET-CT, DWI were superior to other imaging modalities. CONCLUSIONS: The present work demonstrated that DWI, PET, PET-CT were the top-priority consideration of imaging modalities for detecting metastatic pelvic lymph node in gynecological carcinoma. DWI was recommended as the first choice for metastasis exclusion and all the other imaging techniques including CT and MRI were suitable for metastasis conformation. However, for the early stage lymph node malignancy, PET or PET-CT could represent a better choice. More studies exploring the diagnostic efficacy of detailed criteria are required in the future.

Tumor-associated macrophage-derived CCL20 enhances the growth and metastasis of pancreatic cancer.

Pancreatic cancer is an aggressive malignancy with a high metastatic potential that results in a high mortality rate worldwide. Although macrophages have the potential to kill tumor cells and elicit immune responses against tumors, there is evidence that tumor-associated macrophages (TAMs) promote tumor progression and suppress T-cell responses. CC-chemokine ligand 20 (CCL20) and its unique receptor CC-chemokine receptor 6 (CCR6) are exploited by cancer cells for migration and metastasis and play important roles in the development and progression of cancer. Recent studies have shown that the expression of CCL20 is upregulated in pancreatic cancer; however, the mechanism of action of CCL20 remains to be fully elucidated. In this study, the aberrant expression of CCL20 in TAMs of pancreatic cancer tissue, including metastatic pancreatic cancer tissue, was detected. CCL20 expression was considerably higher in macrophages than in pancreatic cancer cell lines, particularly in interleukin-4-treated (M2) macrophages. Using Boyden chamber assays of pancreatic cancer cells, we found that CCL20 secreted by M2 macrophages promoted the migration, epithelial-mesenchymal transition, and invasion of pancreatic cancer cells. RNA interference results showed that CCR6 is a receptor for CCL20 in pancreatic cancer cells, mediating the increased invasive properties of these cells promoted by CCL20. Using a mouse model, we confirmed the roles of CCR6/CCL20 in promoting pancreatic cancer growth and liver metastasis in vivo Our findings provide insight into the important role of macrophage-secreted CCL20 in pancreatic cancer and implicate CCR6/CCL20 as potential therapeutic targets.

TLR2 promotes human intrahepatic cholangiocarcinoma cell migration and invasion by modulating NF-κB pathway-mediated inflammatory responses.

Intrahepatic cholangiocarcinoma (ICC) is a rare and aggressive malignancy that is often diagnosed at advanced stages, which limits treatment options. Despite its increasing incidence and mortality worldwide, the pathogenesis of ICC is not well understood. Here, we examined the effect of the dysregulation of innate immune responses on carcinogenesis by investigating the role of toll-like receptor (TLR)2 in the pathogenesis and invasiveness of ICC and explored the underlying mechanisms. Immunohistochemical analysis, real-time PCR, and western blotting showed higher TLR2 levels in ICC tissues and cell lines. Silencing and overexpression experiments indicated that TLR2 promotes ICC migration and invasion, induces the expression of epithelial-to-mesenchymal transition (EMT) markers, and upregulates the proinflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1ß concomitant with the activation of NF-κB signaling. Inhibition of NF-κB activity abolished the effect of TLR2 on EMT, invasion and migration, and the TLR2-induced upregulation of proinflammatory cytokines, and suppressed the effect of exogenous TNF-α and IL-6 on restoring EMT, migration and invasion in the presence of TLR2. Taken together, our results indicate that TLR2 has protumorigenic and prometastatic effects in ICC through the upregulation of inflammatory cytokines induced by the activation of NF-κB signaling, suggesting potential novel therapeutic targets for the treatment of ICC.

Diet-induced obese mice exhibit altered immune responses to acute lung injury induced by Escherichia coli.

OBJECTIVE: Obesity has been associated with impaired immunity and increased susceptibility to bacterial infection. It also exerts protective effects against mortality secondary to acute lung injury. The effects of obesity on immune responses to acute lung injury induced by Escherichia coli were investigated to determine if the above-mentioned differences in its effects were related to infection severity. METHODS: Diet-induced obesity (DIO) and lean control mice received intranasal instillations of 10(9) or 10(10) CFUs of E. coli. The immune responses were examined at 0 h (uninfected), 24 h, and 96 h postinfection. RESULTS: Following infection, the DIO mice exhibited higher leukocyte, interleukin (IL)-10, IL-6, and tumor necrosis factor-α levels and more severe lung injury than the lean mice. Following inoculation with 10(10) CFUs of E. coli, the DIO mice exhibited higher mortality and more severe inflammation-induced injury than the lean mice, but no differences in E. coli counts were noted between the two groups. However, inoculated with 10(9) CFUs of E. coli, the DIO mice exhibited smaller E. coli burdens at 24 h and 96 h after infection, as well as lower concentrations of IL-10 and tumor necrosis factor-α and less severe lung injury at 96 h after infection. CONCLUSIONS: The results support the emerging view that obesity may be beneficial in the setting of milder infection but detrimental in the setting of more severe infection.

Overexpression of Phosphoserine Aminotransferase 1 (PSAT1) Predicts Poor Prognosis and Associates with Tumor Progression in Human Esophageal Squamous Cell Carcinoma.

BACKGROUND/AIMS: Phosphoserine aminotransferase 1 (PSAT1) is over-expressed in many carcinoma tissues, however little is known regarding its expression and function in esophageal carcinogenesis. This study investigated the expression of PSAT1 in human esophageal squamous cell carcinoma (ESCC) tissues to determine the relationship between PSAT1 expression and clinicopathological factors. METHODS: The expression of PSAT1 in 64 surgical resections from esophageal carcinogenesis patients was examined by quantitative RT-PCR and immunohistochemistry and the results were compared with clinicopathological factors. In vitro experiments were performed in ESCC cells overexpressing PSAT1 to measure cell viability and invasion. Tumor formation in vivowas examined by injection of tumor cells into immunocompromised mice subcutaneously. RESULTS: PSAT1 expression was elevated in ESCC tissues compared to normal esophageal tissues. Increased PSAT1 expression was significantly associated with stage of disease, lymph node metastasis, distant metastasis and poor prognosis. In vitro, PSAT1 overexpression promoted ESCC cell proliferation and matrigel invasion. In vivo, injection of mice with ECSS cells overexpressing PSAT1 enhanced tumor formation. Western blot analysis revealed that PSAT1 upregulated the expression and/or activity of GSK3ß/Snail. CONCLUSION: PSAT1 plays a crucial role in the development of ESCC and predicts poor survival. Therefore, PSAT1 may be a promising novel anticancer therapeutic target.

Sickle Cell Hemoglobin in the Ferryl State Promotes ßCys-93 Oxidation and Mitochondrial Dysfunction in Epithelial Lung Cells (E10).

Polymerization of intraerythrocytic deoxyhemoglobin S (HbS) is the primary molecular event that leads to hemolytic anemia in sickle cell disease (SCD). We reasoned that HbS may contribute to the complex pathophysiology of SCD in part due to its pseudoperoxidase activity. We compared oxidation reactions and the turnover of oxidation intermediates of purified human HbS and HbA. Hydrogen peroxide (H2O2) drives a catalytic cycle that includes the following three distinct steps: 1) initial oxidation of ferrous (oxy) to ferryl Hb; 2) autoreduction of the ferryl intermediate to ferric (metHb); and 3) reaction of metHb with an additional H2O2 molecule to regenerate the ferryl intermediate. Ferrous and ferric forms of both proteins underwent initial oxidation to the ferryl heme in the presence of H2O2 at equal rates. However, the rate of autoreduction of ferryl to the ferric form was slower in the HbS solutions. Using quantitative mass spectrometry and the spin trap, 5,5-dimethyl-1-pyrroline-N-oxide, we found more irreversibly oxidized ßCys-93in HbS than in HbA. Incubation of the ferric or ferryl HbS with cultured lung epithelial cells (E10) induced a drop in mitochondrial oxygen consumption rate and impairment of cellular bioenergetics that was related to the redox state of the iron. Ferryl HbS induced a substantial drop in the mitochondrial transmembrane potential and increases in cytosolic heme oxygenase (HO-1) expression and mitochondrial colocalization in E10 cells. Thus, highly oxidizing ferryl Hb and heme, the product of oxidation, may be central to the evolution of vasculopathy in SCD and may suggest therapeutic modalities that interrupt heme-mediated inflammation.

MicroRNA-340 Inhibits Esophageal Cancer Cell Growth and Invasion by Targeting Phosphoserine Aminotransferase 1.

BACKGROUND/AIMS: Emerging evidence indicates that microRNA (miR)-340 is downregulated in various human cancers, suggesting that it acts as a tumor suppressor. The aim of the present study was to evaluate the expression and role of miR-340 in human esophageal squamous cell carcinoma (ESCC). METHODS: The expression of miR-340 was examined in 64 paired ESCC and adjacent non-tumor tissues by quantitative real time PCR. The effects of miR-340 on ESCC cell proliferation and metastasis were examined by MTT and Matrigel invasion assays. Tumor growth was assessed by subcutaneous inoculation of cells into BALB/c nude mice. Targets of miR-340 were identified by bioinformatics and verified by luciferase reporter assays, quantitative real-time PCR, and western blotting. RESULTS: MiR-340 was significantly downregulated in ESCC tumor tissues compared to adjacent non-tumor tissues and in ESCC cell lines compared to esophageal endothelial cells. Overexpression of miR-340 inhibited ESCC cell growth, colony formation, and invasion, and tumor growth in a xenograft mouse model. PSAT1 was identified as a direct target of miR-340 and its ectopic expression partially reversed the miR-340 mediated inhibition of viability, invasion and EMT in ESCC cells. The expression of miR-340 was negatively correlated with that of PSAT1 in human ESCC samples. CONCLUSION: MiR-340 functions as a tumor suppressor by modulating the expression of PSAT1 and may contribute to the progression and invasiveness of ESCC.