PROM2 upregulation promotes cancer cell migration and confers a poor prognosis in lung squamous cell carcinoma.

Lung squamous cell carcinoma (LUSC) remains a difficult-to-treat disease with a poor prognosis. While prominin-1 (PROM1/CD-133) is largely investigated in a variety of malignancies, the role of prominin-2 (PROM2), the other member of the prominin family, has not been studied in LUSC. Transcriptomic data derived from matched tumor and adjacent non-tumorous lung tissues of LUSC patients were employed to conduct an in-depth analysis of the genetic and epigenetic regulation of prominin genes within LUSC, utilizing bioinformatic approaches. Furthermore, cellular behavior experiments were executed to discern the biological functions of PROM2. It was observed that PROM2, in contrast to PROM1, exhibited significant upregulation and overexpression at both the mRNA and protein levels in LUSC, and this upregulation was correlated with shortened patient survival. Transcriptomic analysis unveiled DNA methylation as an epigenetic regulatory mechanism associated with PROM2 expression. Notably, two transcription factors, CBFB and NRIP1, were identified as potential regulators of PROM2 expression. Subsequent in vitro investigations demonstrated that knocking down PROM2 led to the inhibition of cancer cell migration and the epithelial-to-mesenchymal transition (EMT). In summary, the pronounced upregulation of PROM2 in LUSC patients was linked to an unfavorable prognosis, possibly attributable to its influence on cancer cell migration and EMT. These findings suggest that PROM2 could serve as a promising diagnostic biomarker and therapeutic target in the management of LUSC. Consequently, further research into the mechanistic aspects and potential therapeutic interventions targeting PROM2 is warranted in the clinical context.

Involvement of ACACA (acetyl-CoA carboxylase α) in the lung pre-metastatic niche formation in breast cancer by senescence phenotypic conversion in fibroblasts.

BACKGROUND: Reprogramming of metabolism is strongly associated with the development of cancer. However, the role of metabolic reprogramming in the remodeling of pre-metastatic niche (PMN), a key step in metastasis, is still unknown. We aimed to investigate the metabolic alternation during lung PMN formation in breast cancer. METHODS: We assessed the transcriptomes and lipidomics of lung of MMTV-PyVT mice by microarray and liquid chromatography-tandem mass mass spectrometry before lung metastasis. The validation of gene or protein expressions was performed by quantitative real-time polymerase chain reaction or immunoblot and immunohistochemistry respectively. The lung fibroblasts were isolated from mice and then co-cultured with breast cancer to identify the influence of cancer on the change of lung fibroblasts in PMN. RESULTS: We demonstrated changes in the lipid profile and several lipid metabolism genes in the lungs of breast cancer-bearing MMTV-PyVT mice before cancer spreading. The expression of ACACA (acetyl-CoA carboxylase α) was downregulated in the lung fibroblasts, which contributed to changes in acetylation of protein's lysine residues and the synthesis of fatty acid. The downregulation of ACACA in lung fibroblasts triggered a senescent and inflammatory phenotypic shift of lung fibroblasts in both in vivo and in vitro models. The senescence-associated secretory phenotype of lung fibroblasts enabled the recruitment of immunosuppressive granulocytic myeloid-derived suppressor cells into the lungs through the production of CXCL1 in the lungs. Knock-in of ACACA prevented lung metastasis in the MMTV-PyVT mouse model, further supporting that ACACA was involved in the remodeling of the lung PMN. CONCLUSIONS: Taken together, these data revealed a mechanism by which ACACA downregulation directed the formation of an immunosuppressive lung PMN in breast cancer.

The Downregulation of LSAMP Expression Promotes Lung Cancer Progression and Is Associated with Poor Survival Prognosis.

Lung cancer has been a leading cause of cancer-related death for decades and therapeutic strategies for non-driver mutation lung cancer are still lacking. A novel approach for this type of lung cancer is an emergent requirement. Here we find that loss of LSAMP (Limbic System Associated Membrane Protein), compared to other IgLON family of proteins NTM (Neurotrimin) and OPCML (OPioid-binding Cell adhesion MoLecule), exhibits the strongest prognostic and therapeutic significance in predicting lung adenocarcinoma (LUAD) progression. Lower expression of LSAMP and NTM, but not OPCML, were found in tumor parts compared with normal parts in six LUAD patients, and this was validated by public datasets, Oncomine® and TCGA. The lower expression of LSAMP, but not NTM, was correlated to shorter overall survival. Two epigenetic regulations, including hypermethylation and miR-143-3p upregulation but not copy number variation, were associated with downregulation of LSAMP in LUAD patients. Pathway network analysis showed that NEGR1 (Neuronal Growth Regulator 1) was involved in the regulatory loop of LSAMP. The biologic functions by LSMAP knockdown in lung cancer cells revealed LSMAP was linked to cancer cell migration via epithelial-mesenchymal transition (EMT) but not proliferation nor stemness of LUAD. Our result showed for the first time that LSAMP acts as a potential tumor suppressor in regulating lung cancer. A further deep investigation into the role of LSAMP in lung cancer tumorigenesis would provide therapeutic hope for such affected patients.

Implications of Continuous Noninvasive Finger Cuff Arterial Pressure Device Use during Cesarean Delivery for Goal-Directed Fluid Therapy Preload Optimization: A Randomized Controlled Trial.

BACKGROUND: Although fixed-volume conventional fluid preloading protocol fails to attenuate postspinal hypotension during cesarean delivery, the effect of goal-directed fluid therapy (GDFT) remains less explored. Continuous noninvasive finger cuff arterial pressure monitoring using devices such as the ClearSight System can provide the noninvasive stroke volume value, enabling clinicians to perform GDFT before spinal anesthesia; however, the efficacy of GDFT requires further elucidation. METHOD: In total, 71 consecutive full-term pregnant women were randomly divided into a control group (n = 34) and a GDFT group (n = 37). Before spinal anesthesia, the control group received a fixed dose (1000 mL) of crystalloid fluid, but the GDFT group received repeated 3 mL/kg body weight of crystalloid fluid challenges within 3 minutes with a 1-minute interval between each fluid challenge based on the stroke volume incremental changes obtained using the ClearSight System (targeting a stroke volume increase of ≥5% after a fluid challenge). The primary outcome was the incidence of postspinal hypotension. The secondary outcomes were total fluid volume, vasopressor dosage, hemodynamic parameter changes, maternal adverse effects, and neonatal profiles. RESULT: Women in the GDFT group received more fluid than did those in the control group (1132 ± 108 vs. 1247 ± 202 mL; p = 0.0044), but the incidence of postspinal hypotension (79.4% vs. 73.0%,; p = 0.5864) and norepinephrine dose (12.5 ± 10.6 vs. 15.1 ± 12.8 mcg, respectively; p = 0.3512) was comparable between the two groups. Fewer women in the GDFT group experienced nausea (61.76% vs. 35.14%; p = 0.0332). Neonatal outcomes (Apgar score and umbilical blood analysis) were comparable and typical in both groups. CONCLUSION: ClearSight-guided GDFT did not ameliorate postspinal hypotension but may reduce nausea. This trial is registered with NCT03013140.

Loss of miR-145-5p Causes Ceruloplasmin Interference with PHD-Iron Axis and HIF-2α Stabilization in Lung Adenocarcinoma-Mediated Angiogenesis.

For decades, lung cancer has been the leading cause of cancer-related death worldwide. Hypoxia-inducible factors (HIFs) play critical roles in mediating lung cancer development and metastasis. The present study aims to clarify how HIF's over-activation affects lung cancer angiogenesis not only in a normoxic condition, but also a hypoxic niche. Our study shows that human lung cancer exhibits elevated levels of ceruloplasmin (CP), which has a negative impact on the prognosis of patients. CP affects the cellular Fe2+ level, which inactivates prolyl hydroxylase (PHD) 1 and 2, resulting in HIF-2α enhancement. Increased HIF-2α leads to vascular endothelial growth factor-A (VEGF-A) secretion and angiogenesis. The expression of CP is under the epigenetic control of miR-145-5p. Restoration of miR-145-5p by miRNA mimics transfection decreases CP expression, increases Fe2+ and PHD1/2 levels and HIF hydroxylation while reduced HIF-2α levels resulting in the inhibition of tumor angiogenesis. In contrast, inhibition of miR-145-5p by miRNA inhibitors increases the expression of CP and VEGF-A in lung cancer cells. Significantly, miR-145-5p expression is lost in the tumor samples of lung cancer patients, and low miR-145-5p expression is strongly correlated with a shorter overall survival time. In conclusion, the current study reveals the clinical importance and prognostic value of miR-145-5p and CP. It identifies a unique mechanism of HIF-2α over-activation, which is mediated by iron imbalance of the iron-PHD coupling that modulates tumor angiogenesis.

Bone-marrow-derived cell-released extracellular vesicle miR-92a regulates hepatic pre-metastatic niche in lung cancer.

Metastatic tumors have been shown to establish a supportive pre-metastatic niche (PMN) in distant organs, which in turn determines disseminated tumor cells' targeting of such organs. PMN is formed through the recruitment of bone-marrow-derived cells (BMDCs); however, the role of BMDCs in PMN formation is not fully understood. On the basis of RNA-seq data and bioinformatic analysis, secretion of extracellular vesicle (EV) miR-92a by BMDCs of lung cancer-bearing mice contributes to the establishment of liver PMN. Both BMDC-derived EVs and miR-92a mimics potentiate the activation of hepatic stellate cells (HSCs), subsequently increasing extracellular matrix (ECM) deposition in mice. Consequently, remodeling of the liver microenvironment enhanced immunosuppressive cell accumulation and cancer cell attachment. EVs miR-92a directly suppressed its target SMAD7, leading to the enhancement of transforming growth factor-ß signaling in HSC. Elevated levels of circulating miR-92a are found in the sera of lung cancer patients, and EVs isolated from these patients have a similar ability to increase HSCs activation and ECM protein expression. Our study reveals the sequential steps of liver PMN formation in lung cancer, providing critical mediators that prepare PMN in the liver, and identifies new targets that offer valuable options for diagnosis and therapeutic intervention.

The Defective Allele of Aldehyde Dehydrogenase 2 Gene is Associated with Favorable Postoperative Prognosis in Hepatocellular Carcinoma.

Background: The Aldehyde dehydrogenase 2 (ALDH2) mutant genotypes contain an allele encoding defective ALDH2 with reduced efficacy of alcohol metabolism leading to accumulation of highly toxic and carcinogenic acetaldehyde. It can induce unpleasant "Asian flush syndrome" and associate with increased risk of cancers. However, to date, little is known about ALDH2 genotypes in relation to the postoperative prognosis of hepatocellular carcinoma (HCC). Methods: From 2002 to 2012, 419 HCC patients receiving surgical resection of HCC were enrolled for ALDH2-rs671 genotyping and outcome correlation. Results: Of the patients included, 202 were ALDH2-rs671 "GG" (wild type) and 217 were mutant (defective) "AA" + "GA" genotype. Kaplan-Meier analysis indicated that "GG" genotype significantly associated with shorter metastasis-free (P = 0.034) and overall (P = 0.005) survival, but not recurrence-free survival (P = 0.281). Univariate followed by multivariate Cox proportional hazard analysis showed that "GG" genotype was an independent clinical predictor for shorter time-to-distant metastasis (adjusted P = 0.019) and shorter overall survival (adjusted P = 0.001). Subgroup analysis showed that in patients with negative hepatitis B surface antigen, Edmonson's histology grade < 3, and aspartate transaminase > alanine transaminase, the ALDH2-rs671-GG genotype was associated with both shorter time-to-metastasis and shorter overall survival. Conclusions: HCC patients carrying a defective allele of ALDH2 had a favorable postoperative outcome.

Deducting MicroRNA-Mediated Changes Common in Bronchial Epithelial Cells of Asthma and Chronic Obstructive Pulmonary Disease-A Next-Generation Sequencing-Guided Bioinformatic Approach.

Asthma and chronic obstructive pulmonary disease (COPD) are chronic airway inflammatory diseases that share some common features, although these diseases are somewhat different in etiologies, clinical features, and treatment policies. The aim of this study is to investigate the common microRNA-mediated changes in bronchial epithelial cells of asthma and COPD. The microRNA profiles in primary bronchial epithelial cells from asthma (AHBE) and COPD (CHBE) patients and healthy subjects (NHBE) were analyzed with next-generation sequencing (NGS) and the significant microRNA changes common in AHBE and CHBE were extracted. The upregulation of hsa-miR-10a-5p and hsa-miR-146a-5p in both AHBE and CHBE was confirmed with quantitative polymerase chain reaction (qPCR). Using bioinformatic methods, we further identified putative targets of these microRNAs, which were downregulated in both AHBE and CHBE: miR-10a-5p might suppress BCL2, FGFR3, FOXO3, PDE4A, PDE4C, and PDE7A; miR-146a-5p might suppress BCL2, INSR, PDE4D, PDE7A, PDE7B, and PDE11A. We further validated significantly decreased expression levels of FOXO3 and PDE7A in AHBE and CHBE than in NHBE with qPCR. Increased serum miR-146a-5p level was also noted in patients with asthma and COPD as compared with normal control subjects. In summary, our study revealed possible mechanisms mediated by miR-10a-5p and miR-146a-5p in the pathogenesis of both asthma and COPD. The findings might provide a scientific basis for developing novel diagnostic and therapeutic strategies.

Hypoxic Lung-Cancer-Derived Extracellular Vesicle MicroRNA-103a Increases the Oncogenic Effects of Macrophages by Targeting PTEN.

Hypoxia, the most commonly observed characteristic in cancers, is implicated in the establishment of an immunosuppressive niche. Recent studies have indicated that extracellular vesicle (EV)-mediated cancer-stroma interactions are considered to play a critical role in the regulation of various cellular biological functions, with phenotypic consequences in recipient cells. However, the mechanisms underlying the relationship between EVs and hypoxia during cancer progression remain largely unknown. In this study, we found that EVs derived from hypoxic lung cancers increased M2-type polarization by miR-103a transfer. Decreased PTEN levels caused by hypoxic cancer-cell-derived EV miR-103a increased activation of AKT and STAT3 as well as expression of several immunosuppressive and pro-angiogeneic factors. In contrast, inhibition of miR-103a by an miRNA inhibitor effectively decreased hypoxic cancer-mediated M2-type polarization, improving the cytokine prolife of tumor infiltration macrophages. Macrophages received cancer-cell-derived EV miR-103a feedback to further enhance cancer progression and tumor angiogenesis. Finally, circulating EV miR-103a levels were higher in patients with lung cancer and closely associated with the M2 polarization. In conclusion, our results delineate a novel mechanism by which lung cancer cells induce immunosuppressive and pro-tumoral macrophages through EVs and inspire further research into the clinical application of EV inhibition or PTEN restoration for immunotherapy.

Montelukast Induces Apoptosis-Inducing Factor-Mediated Cell Death of Lung Cancer Cells.

Developing novel chemo-prevention techniques and advancing treatment are key elements to beating lung cancer, the most common cause of cancer mortality worldwide. Our previous cohort study showed that cysteinyl leukotriene receptor antagonists, mainly montelukast, decreased the lung cancer risk in asthma patients. In the current study, we conducted in vivo and in vitro experiments to demonstrate the inhibiting effect of montelukast on lung cancer and to investigate the underlying mechanisms. Using Lewis lung carcinoma-bearing mice, we showed that feeding montelukast significantly delayed the tumor growth in mice (p < 0.0001). Montelukast inhibited cell proliferation and colony formation and induced the cell death of lung cancer cells. Further investigation showed the down-regulation of B-cell lymphoma 2 (Bcl-2), up-regulation of Bcl-2 homologous antagonist/killer (Bak), and nuclear translocation of apoptosis-inducing factor (AIF) in montelukast-treated lung cancer cells. Montelukast also markedly decreased the phosphorylation of several proteins, such as with no lysine 1 (WNK1), protein kinase B (Akt), extracellular signal-regulated kinase 1/2 (Erk1/2), MAPK/Erk kinase (MEK), and proline-rich Akt substrate of 40-kDa (PRAS40), which might contribute to cell death. In conclusion, montelukast induced lung cancer cell death via the nuclear translocation of AIF. This study confirmed the chemo-preventive effect of montelukast shown in our previous cohort study. The utility of montelukast in cancer prevention and treatment thus deserves further studies.

Investigating Power Density and the Degree of Nonlinearity in Intrinsic Components of Anesthesia EEG by the Hilbert-Huang Transform: An Example Using Ketamine and Alfentanil.

Empirical mode decomposition (EMD) is an adaptive filter bank for processing nonlinear and non-stationary signals, such as electroencephalographic (EEG) signals. EMD works well to decompose a time series into a set of intrinsic mode functions with specific frequency bands. An IMF therefore represents an intrinsic component on its correspondingly intrinsic frequency band. The word of 'intrinsic' means the frequency is totally adaptive to the nature of a signal. In this study, power density and nonlinearity are two critical parameters for characterizing the amplitude and frequency modulations in IMFs. In this study, a nonlinearity level is quantified using degree of waveform distortion (DWD), which represents the characteristic of waveform distortion as an assessment of the intra-wave modulation of an IMF. In the application of anesthesia EEG analysis, the assessments of power density and DWD for a set of IMFs represent dynamic responses in EEG caused by two different anesthesia agents, Ketamine and Alfentanil, on different frequency bands. Ketamine causes the increase of power density and the decrease of nonlinearity on γ-band neuronal oscillation, which cannot be found EEG responses of group B using Alfentanil. Both agents cause an increase of power density and a decrease of nonlinearity on ß-band neuronal oscillation accompany with a loss of consciousness. Moreover, anesthesia agents cause the decreases of power density and nonlinearity (i.e. DWD) for the low-frequency IMFs.

Laricitrin ameliorates lung cancer-mediated dendritic cell suppression by inhibiting signal transducer and activator of transcription 3.

Natural polyphenolic compounds of grapes and their seeds are thought to be therapeutic adjuvants in a variety of diseases, including cancer prevention. This study was carried out to investigate the effect of grape phenolic compounds on the regulation of cancer-mediated immune suppression. Laricitrin exhibits the greatest potential to ameliorate the suppressive effects of lung cancer on dendritic cells' (DCs') differentiation, maturation and function. Human lung cancer A549 and CL1-5 cells change the phenotype of DCs that express to high levels of IL-10 and prime T cells towards an immune suppression type-2 response (Th2). Laricitrin treatment stimulated DC differentiation and maturation in the condition media of cancer cells, a finding supported by monocyte marker CD14's disappearance and DC marker CD1a's upregulation. Laricitrin decreases expression of IL-10 in cancer-conditioned DCs, and subsequently switches CD4+ T cell response from Th2 to Th1 in vitro and in vivo. Reversal of laricitrin on lung cancer-induced DCs' paralysis was via inhibiting the phosphorylation of signal transducer and activator of transcription 3 (STAT3). Laricitrin also potentiated the anticancer activity of cisplatin in mouse models. Thus, laricitrin could be an efficacious immunoadjuvant and have a synergistic effect when combined with chemotherapy.

Lung cancer-derived galectin-1 contributes to cancer associated fibroblast-mediated cancer progression and immune suppression through TDO2/kynurenine axis.

Communication between cancer cells and their microenvironment plays an important role in cancer development, but the precise mechanisms by which cancer-associated fibroblasts (CAF) impact anti-cancer immunity and cancer progression in lung cancer are poorly understood. Here, we report that lung fibroblasts when activated by lung cancer cells produce tryptophan metabolite kynurenine (Kyn) that inhibits dendritic cells' differentiation and induces cancer growth as well as migration. We identified TDO2 (tryptophan 2,3-dioxygenase) as the main enzyme expressed in fibroblasts capable of tryptophan metabolism. Mechanistically, condition medium of CAF or exogenous kynurenine stimulated AKT, with no lysine 1 (WNK1) and cAMP response element-bindingprotein (CREB) phosphorylation in lung cancer cells. Inhibition of the AKT/CREB pathway prevents cancer proliferation, while inhibition of the AKT/ WNK1 reverted epithelial-to-mesenchymal transition and cancer migration induced by kynurenine. Moreover, we also demonstrate that lung cancer-derived galectin-1 contributes to the upregulation of TDO2 in CAF through an AKT-dependent pathway. Immunohistochemical analysis of lung cancer surgical specimens revealed increased TDO2 expression in the fibroblasts adjacent to the cancer. Furthermore, in vivo studies showed that administration of TDO2 inhibitor significantly improves DCs function and T cell response, and decreases tumor metastasis in mice. Taken together, our data identify the feedback loop, consisting of cancer-derived galectin-1 and CAF-producing kynurenine, that sustains lung cancer progression. These findings suggest that targeting this pathway may be a promising therapeutic strategy.

Isolinderalactone enhances the inhibition of SOCS3 on STAT3 activity by decreasing miR-30c in breast cancer.

Development of an efficient treatment for triple-negative breast cancer is an urgent issues. Compounds from plant extracts are a potential source of novel cancer treatment. Isolinderalactone, a kind of sesquiterpenoids compound, was purified from the root of Lindera strychnifolia and Neolitsea daibuensis and shows anti-inflammatory and anticancer capacity. In the present study, isolinderalactone induced apoptosis in MDA-MB-231 cells which is a kind of triple-negative breast cancer cell line through induction of an intrinsic mitochondria-mediated and caspase-independent cell death. Treatment of isolinderalactone increased the protein level of the suppressor of cytokine signaling 3 (SCOS3), decreased phosphorylation of the signal transducer and activator of transcription 3 (STAT3), and suppressed expression of the down-stream genes of the X-linked inhibitor of apoptosis protein in MDA-MB-231 cells. Our results further showed that the level of SOCS3 expression was induced by isolinderalactone due to inhibiting the microRNA hsa-miR-30c-5p (miR-30c) expression. In addition, intraperitoneal injection of isolinderalactone induced apoptosis in a xenograft breast tumor while it did not significantly affect the histology of liver, kidney and lung of the treated mice. In conclusion, isolinderalactone induces apoptosis in MDA-MB­231 cells and suppresses STAT3 signaling pathway through regulation of SOCS3 and miR-30c. It may become a novel treatment for triple-negative breast cancer in the future.

S100P interacts with integrin α7 and increases cancer cell migration and invasion in lung cancer.

S100P, a Ca2+ binding protein, has been shown to be overexpressed in various cancers. However, its functional character in lung cancer remains largely unknown. In this study, we show that S100P increases cancer migration, invasion and metastasis in lung cancer cells. Ectopic expression of S100P increases migration, invasion and EMT in less invasive CL1-0 lung cancer cells. Conversely, knockdown of S100P suppressed migration and invasion, and caused a reversion of EMT in highly invasive lung cancer cells. These effects were transduced by increasing the interaction of S100P with integrin α7, which activated focal adhesion kinase (FAK) and AKT. Blocking FAK significantly decreased S100P-induced migration by decreasing Src and AKT activation, whereas inhibiting AKT reduced S100P upregulation on ZEB1 expression. Further study has indicated that S100P knockdown prevents the spread of highly metastatic human lung cancer in animal models. This study therefore suggests that S100P represents a critical activator of lung cancer metastasis. Detection and targeted treatment of S100P-expressing cancer is an attractive therapeutic strategy in treating lung cancer.

Aryl hydrocarbon receptor agonists upregulate VEGF secretion from bronchial epithelial cells.

UNLABELLED: Chronic airway diseases, such as asthma and chronic obstructive pulmonary disease, are characterized by airway remodeling. Vascular endothelial growth factor (VEGF) is a critical regulator of angiogenesis and vascular remodeling, important components of airway remodeling. The aryl hydrocarbon receptor (AhR) is the principle receptor for many environmental toxicants, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which may contribute to the pathogenesis of asthma and chronic obstructive pulmonary disease. However, the regulatory role of AhR on the expression of VEGF in bronchial epithelial cells (BECs) remains elusive. This study was conducted to determine the role of AhR in regulating bronchial epithelial VEGF expression, which might contribute to angiogenesis of airway remodeling. The plasma VEGF levels of asthmatic patients and healthy subjects were compared. By treating HBE-135, Beas-2B, and primary human BECs with AhR agonists, the mechanisms through which AhR modulated VEGF expression in human BECs were investigated. The plasma VEGF level was significantly higher in asthmatic patients than in healthy subjects. AhR agonists significantly upregulated VEGF secretion from human BECs, which promoted the migratory and tube-forming ability of human umbilical vein endothelial cells. The secretion of VEGF was increased via a canonical AhR pathway, followed by the 15-LOX/15-HETE/STAT3 pathway. C57BL/6JNarl mice treated with TCDD intratracheally also showed increased VEGF expression in BECs. This hitherto unrecognized pathway may provide a potential target for the treatment of airway remodeling in many pulmonary diseases, especially those related to environmental toxicants. KEY MESSAGE: AhR agonists increase VEGF secretion from bronchial epithelial cells. The mechanism involves the canonical AhR pathway and 15-LOX/15-HETE/STAT3 pathway. Asthmatic patients have higher plasma VEGF level. Mice treated with intratracheal TCDD show increased VEGF expression in BECs. This novel regulatory pathway is a potential target for treating asthma and COPD.

Lewisy promotes migration of oral cancer cells by glycosylation of epidermal growth factor receptor.

Aberrant glycosylation changes normal cellular functions and represents a specific hallmark of cancer. Lewisy (Ley) carbohydrate upregulation has been reported in a variety of cancers, including oral squamous cell carcinoma (OSCC). A high level of Ley expression is related to poor prognosis of patients with oral cancer. However, it is unclear how Ley mediates oral cancer progression. In this study, the role of Ley in OSCC was explored. Our data showed that Ley was upregulated in HSC-3 and OC-2 OSCC cell lines. Particularly, glycosylation of epidermal growth factor receptor (EGFR) with Ley was found in OC-2 cells, and this modification was absent upon inhibition of Ley synthesis. The absence of Ley glycosylation of EGFR weakened phosphorylation of AKT and ERK in response to epidermal growth factor (EGF). Additionally, EGF-triggered cell migration was reduced, but cell proliferation was not affected. Ley modification stabilized EGFR upon ligand activation. Conversely, absence of Ley glycosylation accelerated EGFR degradation. In summary, these results indicate that increased expression of Ley in OSCC cells is able to promote cell migration by modifying EGFR which in turn stabilizes EGFR expression and downstream signaling. Targeting Ley on EGFR could have a potential therapeutic effect on oral cancer.

Transcatheter aortic valve implantation: Anesthetic experience of retrograde transfemoral approach with CoreValve ReValving System.

OBJECTIVES: Valvular aortic stenosis (AS) is a major cardiac valvular disease in geriatric people. Conventional treatment for severe AS is aortic valve replacement through surgery. However, many geriatric patients are considered inoperable due to higher risks for surgery and anesthesia. Transcatheter aortic valve implantation (TAVI), a less invasive procedure, has rapidly developed in recent years as an alternative management option for high-risk AS patients. Herein, we describe our anesthetic experience in the TAVI procedure. METHODS: We included 11 patients who consecutively received transfemoral TAVI in the period from September 2010 to January 2011. All patients received general anesthesia with endotracheal intubation; arterial line placement and central venous catheter insertion were carried out for monitoring hemodynamics. Transesophageal echocardiography was applied for valve evaluation, hemodynamic monitoring, and intraoperative guidance. Patients were transferred to the intensive care unit for further care after surgery. The periprocedural events were recorded. RESULTS: The mean age of these patients was 82 years. Morphology of the aortic valve in all patients was tricuspid, and the etiology of AS was degenerative calcification. During TAVI, all patients received bolus injections of 5-10 µg norepinephrine just before the rapid pacing stage in order to increase the mean arterial pressure. Only one patient needed continuous infusion of dopamine because of severe preoperative congestive heart failure, and another patient needed continuous infusion of norepinephrine due to relatively old age and suspected low systemic vascular resistance. After TAVI, all patients had the endotracheal tube extubated within 7 hours, except one because of preoperative ventilator dependence. Another male patient stayed in the intensive care unit for 8 days due to postoperative complete atrioventricular block, and he received permanent pacemaker implantation. There was no early mortality. CONCLUSION: TAVI is another choice for AS patients who have a high perioperative risk. General anesthesia with endotracheal intubation and application of transesophageal echocardiography can facilitate the use of this new technique by cardiologists. Complete preprocedural evaluation and good intraprocedural cooperation are still the gold standards to achieve successful TAVI and patient safety.