Privacy-Preserving Deep Learning NLP Models for Cancer Registries
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60 APPLIED LIFE SCIENCES↗
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Structural Basis for Small G Protein Effector Interaction of Ras-related Protein 1 (Rap1) and Adaptor Protein Krev Interaction Trapped 1 (KRIT1)
Cerebral cavernous malformations (CCMs) affect 0.1-0.5% of the population resulting in leaky vasculature and severe neurological defects. KRIT1 (Krev interaction trapped-1) mutations associate with {approx}40% of familial CCMs. KRIT1 is an effector of Ras-related protein 1 (Rap1) GTPase. Rap1 relocalizes KRIT1 from microtubules to cell membranes to impact integrin activation, potentially important for CCM pathology. We report the 1.95 {angstrom} co-crystal structure of KRIT1 FERM domain in complex with Rap1. Rap1-KRIT1 interaction encompasses an extended surface, including Rap1 Switch I and II and KRIT1 FERM F1 and F2 lobes. Rap1 binds KRIT1-F1 lobe using a GTPase-ubiquitin-like fold interaction but binds KRIT1-F2 lobe by a novel interaction. Point mutagenesis confirms the interaction. High similarity between KRIT1-F2/F3 and talin is revealed. Additionally, the mechanism for FERM domains acting as GTPase effectors is suggested. Finally, structure-based alignment of each lobe suggests classification of FERM domains as ERM-like and TMFK-like (talin-myosin-FAK-KRIT-like) and that FERM lobes resemble domain 'modules.'
59 BASIC BIOLOGICAL SCIENCES↗
Assessment of the Radiation-Equivalent of Chemotherapy Contributions in 1-Phase Radio-chemotherapy Treatment of Muscle-Invasive Bladder Cancer
Purpose: To estimate the radiation equivalent of the chemotherapy contribution to observed complete response rates in published results of 1-phase radio-chemotherapy of muscle-invasive bladder cancer. Methods and Materials: A standard logistic dose–response curve was fitted to data from radiation therapy-alone trials and then used as the platform from which to quantify the chemotherapy contribution in 1-phase radio-chemotherapy trials. Two possible mechanisms of chemotherapy effect were assumed (1) a fixed radiation-independent contribution to local control; or (2) a fixed degree of chemotherapy-induced radiosensitization. A combination of both mechanisms was also considered. Results: The respective best-fit values of the independent chemotherapy-induced complete response (CCR) and radiosensitization (s) coefficients were 0.40 (95% confidence interval −0.07 to 0.87) and 1.30 (95% confidence interval 0.86-1.70). Independent chemotherapy effect was slightly favored by the analysis, and the derived CCR value was consistent with reports of pathologic complete response rates seen in neoadjuvant chemotherapy-alone treatments of muscle-invasive bladder cancer. The radiation equivalent of the CCR was 36.3 Gy. Conclusion: Although the data points in the analyzed radio-chemotherapy studies are widely dispersed (largely on account of the diverse range of chemotherapy schedules used), it is nonetheless possible to fit plausible-looking response curves. The methodology used here is based on a standard technique for analyzing dose-response in radiation therapy-alone studies and is capable of application to other mixed-modality treatment combinations involving radiation therapy.
62 RADIOLOGY AND NUCLEAR MEDICINE↗
Early Tissue Effects of Stereotactic Body Radiation Therapy for Spinal Metastases
Stereotactic body radiation therapy (SBRT) is a highly effective and potentially ablative treatment for complex spinal metastases. Recent data have suggested radiobiologic effects of SBRT that expand beyond the traditional concept of DNA damage. Antitumor immunity, vascular damage leading to tumor necrosis, and increased rates of tumor apoptosis have been implied; however, in-human evidence remains scarce. The present study reports unique pathologic confirmation of SBRT-induced biological effects within spinal metastases treated with preoperative SBRT.
62 RADIOLOGY AND NUCLEAR MEDICINE↗
A Comprehensive Urine Proteome Database Generated From Patients With Various Renal Conditions and Prostate Cancer
Urine proteins can serve as viable biomarkers for diagnosing and monitoring various diseases. A comprehensive urine proteome database, generated from a variety of urine samples with different disease conditions, can serve as a reference resource for facilitating discovery of potential urine protein biomarkers. Herein, we present a urine proteome database generated from multiple datasets using 2D LC-MS/MS proteome profiling of urine samples from healthy individuals (HI), renal transplant patients with acute rejection (AR) and stable graft (STA), patients with non-specific proteinuria (NS), and patients with prostate cancer (PC). A total of ~28,000 unique peptides spanning ~2,200 unique proteins were identified with a false discovery rate of <0.5% at the protein level. Over one third of the annotated proteins were plasma membrane proteins and another one third were extracellular proteins according to gene ontology analysis. Ingenuity Pathway Analysis of these proteins revealed 349 potential biomarkers in the literature-curated database. Forty-three percentage of all known cluster of differentiation (CD) proteins were identified in the various human urine samples. Interestingly, following comparisons with five recently published urine proteome profiling studies, which applied similar approaches, there are still ~400 proteins which are unique to this current study. These may represent potential disease-associated proteins. Among them, several proteins such as serpin B3, renin receptor, and periostin have been reported as pathological markers for renal failure and prostate cancer, respectively. Taken together, our data should provide valuable information for future discovery and validation studies of urine protein biomarkers for various diseases.
60 APPLIED LIFE SCIENCES↗
Novel pneumoviruses (PnVs): Evolution and inflammatory pathology
A previous report of a novel pneumovirus (PnV) isolated from the respiratory tract of a dog described its significant homology to the rodent pathogen, pneumonia virus of mice (PVM). The original PnV–Ane4 pathogen replicated in and could be re-isolated in infectious state from mouse lung but elicited minimal mortality compared to PVM strain J3666. Here we assess phylogeny and physiologic responses to 10 new PnV isolates. The G/glycoprotein sequences of all PnVs include elongated amino-termini when compared to the characterized PVMs, and suggest division into groups A and B. While we observed significant differences in cytokine production and neutrophil recruitment to the lungs of BALB/c mice in response to survival doses (50 TCID{sub 50} units) of representative group A (114378-10-29-KY-F) and group B (7968-11-OK) PnVs, we observed no evidence for positive selection (dN>dS) among the PnV/PnV, PVM/PnV or PVM/PVM G/glycoprotein or F/fusion protein sequence pairs. - Highlights: • We consider ten novel isolates of the pneumovirus (PnV) first described by Renshaw and colleagues. • The G/glycoprotein sequences of all PnVs include elongated amino-termini when compared to PVM. • We detect cytokine production and neutrophil recruitment to the lungs of mice in response to PnV. • We observed no evidence for positive selection (dN>dS) among the gene sequence pairs.
60 APPLIED LIFE SCIENCES↗
Red Raspberry Phenols Inhibit Angiogenesis: A Morphological and Subcellular Analysis Upon Human Endothelial Cells
ABSTRACT Polyphenols are a class of natural compounds whose potential as antioxidant, anti‐inflammatory, and anti‐angiogenesis has been reported in many pathological conditions. Red raspberry extract, rich in polyphenols, has been reported to exert anti‐inflammatory effects and prevent cell proliferation in distinct animal models. However, the signaling pathways involved remain unknown. Herein, we used human microvascular endothelial cells (HMVECs) to determine the influence of red raspberry phenolic compound extract concentrations, ranging from 10 to 250 µg gallic acid equivalents (GAE)/mL, on endothelium viability (MTS assay), proliferation (BrdU incorporation), migration (injury assay), and capillary‐like structures formation (Matrigel assay). Protein expression in cell lysates was determined by Western blot analysis. We showed that red raspberry extracts reduced cell viability (GI 50 = 87,64 ± 6,59 μg GAE/mL) and proliferation in a dose‐dependent manner. A significant abrogation of cells ability to migrate to injured areas, even at low concentrations, was observed by injury assay. Cell assembly into capillary‐like structures on Matrigel also decreased in a dose dependent‐manner for higher extract concentrations, as well as the number of branching points per unit of area. Protein expression analysis showed a dose‐dependent decrease in Phospho‐VEGFR2 expression, implying abrogation of VEGF signaling activity. We also showed for the first time that red raspberry phenolic compounds induce the rearrangement of filamentous actin cytoskeleton, with an isotropy increase found for higher testing concentrations. Taken together, our findings corroborate the anti‐angiogenic potential of red raspberry phenolic compounds and provide new insights into their mode of action upon endothelium. J. Cell. Biochem. 117: 1604–1612, 2016. © 2015 Wiley Periodicals, Inc.
Sousa, M.↗
Percutaneous CT and Fluoroscopy-Guided Screw Fixation of Pathological Fractures in the Shoulder Girdle: Technical Report of 3 Cases
ObjectiveTo review our initial experience with percutaneous CT and fluoroscopy-guided screw fixation of pathological shoulder-girdle fractures.Materials and MethodsBetween May 2014 and June 2015, three consecutive oncologic patients (mean age 65 years; range 57–75 years) with symptomatic pathological shoulder-girdle fractures unsuitable for surgery and radiotherapy underwent percutaneous image-guided screw fixation. Fractures occurred through metastases (n = 2) or a post-ablation cavity (n = 1). Mechanical properties of osteosynthesis were adjudged superior to stand-alone cementoplasty in each case. Cannulated screws were placed under combined CT and fluoroscopic guidance with complementary radiofrequency ablation or cementoplasty to optimise local palliation and secure screw fixation, respectively, in two cases. Follow-up was undertaken every few weeks until mortality or most recent appointment.ResultsFour pathological fractures were treated in three patients (2 acromion, 1 clavicular, 1 coracoid). Mean size of associated lesion was 2.6 cm (range 1–4.5 cm). Technical success was achieved in all cases (100 %), without complications. Good palliation and restoration of mobility were observed in two cases at 2–3 months; one case could not be followed due to early post-procedural oncologic mortality.ConclusionPercutaneous image-guided shoulder-girdle osteosynthesis appears technically feasible with good short-term efficacy in this complex patient subset. Further studies are warranted to confirm these promising initial results.
62 RADIOLOGY AND NUCLEAR MEDICINE↗
The Prognostic Value of a Pathologic Complete Response After Neoadjuvant Therapy for Digestive Cancer: Systematic Review and Meta-Analysis of 21 Studies
Background: Neoadjuvant therapy (NAT) before radical excision has become the preferred initial option for locally advanced digestive cancers such as esophageal cancer (EC), esophagogastric junction adenocarcinoma (EGJAC), gastric adenocarcinoma (GAC), rectal cancer (RC), and pancreatic cancer (PC). Although some patients reportedly achieve a pathologic complete response (pCR) after neoadjuvant therapy, the published data are inconsistent regarding whether pCR yields a survival benefit. The current meta-analysis was performed to assess the potential prognostic value of pCR after preoperative therapy for patients with digestive cancers. Methods: An extensive electronic search in PubMed, Web of Science, and the Cochrane Library was performed for relevant articles, from which data relative to independent correlations of pCR with overall survival (OS) and disease-free survival (DFS) were extracted for analysis. A random-effects model was used to calculate the pooled hazard ratios (HRs) with their corresponding 95% confidence intervals (CIs). Results: The study identified 6780 patients who met the inclusion and exclusion criteria. The results showed that pCR was significantly correlated with better OS (HR, 0.50; 95% CI, 0.43–0.58; P < 0.001) and DFS (HR, 0.49; 95% CI, 0.40–0.60; P < 0.001) for the digestive cancer patients who achieved pCR than for those who did not achieve pCR. Subgroup analysis showed that the correlation of pCR with OS was significant in EC (HR, 0.57; 95% CI, 0.47–0.69; P < 0.001), EGJAC/GAC (HR, 0.38; 95% CI, 0.17–0.86; P = 0.02), RC (HR, 0.48; 95% CI, 0.28–0.81; P = 0.006), and PC (HR, 0.41; 95% CI, 0.17–0.97; P = 0.04). In addition, the survival benefit for pCR patients was of similar magnitude, irrespective of the type of study, type of NAT, or ethnicity. Conclusions: A pCR is correlated with favorable survival outcomes compared with a non-pCR for digestive cancer patients after NAT.
62 RADIOLOGY AND NUCLEAR MEDICINE↗
Arrhythmia mutations in calmodulin cause conformational changes that affect interactions with the cardiac voltage-gated calcium channel
Calmodulin (CaM) represents one of the most conserved proteins among eukaryotes and is known to bind and modulate more than a 100 targets. Recently, several disease-associated mutations have been identified in the CALM genes that are causative of severe cardiac arrhythmia syndromes. Although several mutations have been shown to affect the function of various cardiac ion channels, direct structural insights into any CaM disease mutation have been lacking. Here we report a crystallographic and NMR investigation of several disease mutant CaMs, linked to long-QT syndrome, in complex with the IQ domain of the cardiac voltage-gated calcium channel (Ca V 1.2). Surprisingly, two mutants (D95V, N97I) cause a major distortion of the C-terminal lobe, resulting in a pathological conformation not reported before. Furthermore, these structural changes result in altered interactions with the Ca V 1.2 IQ domain. Another mutation (N97S) reduces the affinity for Ca 2+ by introducing strain in EF hand 3. A fourth mutant (F141L) shows structural changes in the Ca 2+ -free state that increase the affinity for the IQ domain. These results thus show that different mechanisms underlie the ability of CaM disease mutations to affect Ca 2+ -dependent inactivation of the voltage-gated calcium channel.
59 BASIC BIOLOGICAL SCIENCES↗
Endogenous 3, 4- Dihydroxyphenylalanine and Dopaquinone Modifications on Protein Tyrosine: links to mitochondrially derived oxidative stress via hydroxyl radical
Oxidative modifications of protein tyrosines have been implicated in multiple human diseases. Among these modifications, elevations in levels of 3, 4-dihydroxyphenylalanine (DOPA), a major product of hydroxyl radical addition to tyrosine, has been observed in a number of pathologies. Here we report the first global proteome survey of endogenous site-specific modifications, i.e, DOPA and its further oxidation product dopaquinone (DQ) in mouse brain and heart tissues. Results from LC-MS/MS analyses included 203 and 71 DOPA-modified tyrosine sites identified from brain and heart, respectively, with a false discovery rate of ~1%; while only a few nitrotyrosine containing peptides, a more commonly studied marker of oxidative stress, were detectable, suggesting the much higher abundance for DOPA modification as compared with tyrosine nitration. Moreover, 57 and 29 DQ modified peptides were observed from brain and heart, respectively; nearly half of these peptides were also observed with DOPA modification on the same sites. For both tissues, these modifications are preferentially found in mitochondrial proteins with metal-binding properties, consistent with metal catalyzed hydroxyl radical formation from mitochondrial superoxide and hydrogen peroxide. These modifications also link to a number of mitochondria-associated and other signaling pathways. Furthermore, many of the modification sites were common sites of previously reported tyrosine phosphorylation suggesting potential disruption of signaling pathways. Structural aspects of DOPA-modified tyrosine sequences are distinct from those of nitrotyrosines suggesting that each type of modifications provides a marker for different in vivo reactive chemistries and can be used to predict sensitive protein targets. Collectively, the results suggest that these modifications are linked with mitochondrially-derived oxidative stress, and may serve as sensitive markers for disease pathologies.
59 BASIC BIOLOGICAL SCIENCES↗
Rutin is a potent senomorphic agent to target senescent cells and can improve chemotherapeutic efficacy
Aging is a major risk factor for most chronic disorders, for which cellular senescence is one of the central hallmarks. Senescent cells develop the pro-inflammatory senescence-associated secretory phenotype (SASP), which significantly contributes to organismal aging and age-related disorders. Development of senotherapeutics, an emerging class of therapeutic agents to target senescent cells, allows to effectively delay aging and alleviate chronic pathologies. Here we report preliminary outputs from screening of a natural medicinal agent (NMA) library for senotherapeutic candidates and validated several agents with prominent potential as senomorphics. Rutin, a phytochemical constituent found in a number of plants, showed remarkable capacity in targeting senescent cells by dampening expression of the full spectrum SASP. Further analysis indicated that rutin restrains the acute stress-associated phenotype (ASAP) by specifically interfering with the interactions of ATM with HIF1α, a master regulator of cellular and systemic homeostasis activated during senescence, and of ATM with TRAF6, part of a key signaling axis supporting the ASAP development toward the SASP. Conditioned media produced by senescent stromal cells enhanced the malignant phenotypes of prostate cancer cells, including in vitro proliferation, migration, invasion, and more importantly, chemoresistance, while rutin remarkably downregulated these gain-of-functions. Although classic chemotherapy reduced tumor progression, the treatment outcome was substantially improved upon combination of a chemotherapeutic agent with rutin. Our study provides a proof of concept for rutin as an emerging natural senomorphic agent, and presents an effective therapeutic avenue for alleviating age-related pathologies including cancer.
60 APPLIED LIFE SCIENCES↗
Improving preoperative detection of synchronous liver metastases in pancreatic cancer with combined contrast-enhanced and diffusion-weighted MRI
Purpose: To explore the value of gadolinium-enhanced MRI combined with diffusion-weighted MRI (Gd-enhanced MRI with DWI) in addition to contrast-enhanced CT (CECT) for detection of synchronous liver metastases for potentially resectable pancreatic cancer. Methods: By means of a retrospective cohort study we included patients with potentially resectable pancreatic cancer on CECT, who underwent Gd-enhanced MRI with DWI between January 2012 and December 2016. A single observer evaluated MRI and CT and was blinded to imaging, pathology, and surgery reports. Liver lesions were scored in both modalities, using a 3-point scale: 1-benign, 2-indeterminate, 3- malignant (i.e., metastasis). The primary outcome parameters were the presence of liver metastases on Gd-enhanced MRI with DWI and the sensitivity of Gd-enhanced MRI with DWI for synchronous liver metastases. Results: We included 66 patients (42 men, 24 women; median age 65 years, range 36–82 years). In 19 patients, liver metastases were present, which were confirmed by histopathology (n = 12), {sup 18}FDG-PET (n = 6), or surgical inspection (n = 1). Gd-enhanced MRI with DWI showed metastases in 16/19 patients (24%), which resulted in a sensitivity of 84% (95% CI 60–97%). Contrast-enhanced MRI showed 156 and DWI 397 metastases (p = 0.051), and 339 were particularly small (< 5 mm). Conclusions: In this study, Gd-enhanced MRI with DWI detected synchronous liver metastases in 24% of patients with potentially resectable pancreatic cancer on CECT with a sensitivity of 84%. Diffusion-weighted MRI showed a greater number of metastases than any other sequence, particularly small metastases (< 5 mm).
62 RADIOLOGY AND NUCLEAR MEDICINE↗
Basal Subtype of Invasive Breast Cancer Is Associated With a Higher Risk of True Recurrence After Conventional Breast-Conserving Therapy
Purpose: To determine whether breast cancer subtype is associated with patterns of ipsilateral breast tumor recurrence (IBTR), either true recurrence (TR) or elsewhere local recurrence (ELR), among women with pT1-T2 invasive breast cancer (IBC) who receive breast-conserving therapy (BCT). Methods and Materials: From Jan 1998 to Dec 2003, 1,223 women with pT1-T2N0-3 IBC were treated with BCT (lumpectomy plus whole-breast radiation). Ninety percent of patients received adjuvant systemic therapy, but none received trastuzumab. Biologic cancer subtypes were approximated by determining estrogen receptor-positive (ER+), progesterone receptor-positive (PR+), and human epidermal growth factor receptor-2-positive (HER-2+) expression, classified as luminal A (ER+ or PR+ and HER-2 negative [HER-2-]), luminal B (ER+ or PR+ and HER-2+), HER-2 (ER- and PR- and HER-2+), and basal (ER- and PR- and HER-2- ) subtypes. Imaging, pathology, and operative reports were reviewed by two physicians independently, including an attending breast radiologist. Readers were blinded to subtype and outcome. TR was defined as IBTR within the same quadrant and within 3 cm of the primary tumor. All others were defined as ELR. Results: At a median follow-up of 70 months, 24 patients developed IBTR (5-year cumulative incidence of 1.6%), including 15 TR and 9 ELR patients. At 5 years, basal (4.4%) and HER-2 (9%) subtypes had a significantly higher incidence of TR than luminal B (1.2%) and luminal A (0.2%) subtypes (p < 0.0001). On multivariate analysis, basal subtype (hazard ratio [HR], 4.8, p = 0.01), younger age at diagnosis (HR, 0.97; p = 0.05), and increasing tumor size (HR, 2.1; p = 0.04) were independent predictors of TR. Only younger age (HR, 0.95; p = 0.01) significantly predicted for ELR. Conclusions: Basal and HER-2 subtypes are significantly associated with higher rates of TR among women with pT1-T2 IBC after BCT. Younger age predicts for both TR and ELR. Strategies to reduce TR in basal breast cancers, such as increased boost doses, concomitant radiation and chemotherapy, or targeted therapy agents, should be explored.
62 RADIOLOGY AND NUCLEAR MEDICINE↗
Anastomosing hemangioma of the liver: a case series
Purpose: To report imaging and pathologic features of five pathologically proven anastomosing hemangiomas of the liver (AHL). Methods: A retrospective review for AHL was conducted using our institutional database from 6/2004 to 3/2018. Histology proven AHL with radiologic imaging available for review were included. A total of five patients who met our criteria were identified from our institutional database. Computed tomography, ultrasound, and magnetic resonance imaging findings, including location, size, attenuation/signal intensity, enhancement characteristics, and additional imaging data were reviewed. The clinical and pathological data were also reviewed. Results: The imaging characteristics of AHL are variable, but features such as peripheral or diffuse hyperintensity on diffusion weighted imaging, arterial hyperenhancement without globular interrupted enhancement, and persistent enhancement without complete filling in the delayed phases were more characteristic of AHL. Imaging also demonstrated a lack of aggressive features. Conclusions: AHL present a diagnostic dilemma as they can mimic more malignant lesions, such as angiosarcoma, both on imaging and at pathology. While the imaging characteristics of AHL are variable, there are some features which can help distinguish AHL from other liver lesions. When the diagnosis of anastomosing hemangioma is known, the management of choice is primarily surveillance, as intervention can cause unnecessary morbidity, and no degeneration to malignancy has been identified to date.
62 RADIOLOGY AND NUCLEAR MEDICINE↗
Treating and Downstaging Hepatocellular Carcinoma in the Caudate Lobe with Yttrium-90 Radioembolization
Purpose: This study was designed to determine the technical feasibility, safety, efficacy, and potential to downstage patients to within transplantation criteria when treating patients with hepatocellular carcinoma (HCC) of the caudate lobe using Y90 radioembolization. Methods: During a 4-year period, 8 of 291 patients treated with radioembolization for unresectable HCC had disease involving the caudate lobe. All patients were followed for treatment-related clinical/biochemical toxicities, serum tumor marker response, and treatment response. Imaging response was assessed with the World Health Organization (WHO) and European Association for the Study of the Liver (EASL) classification schemes. Pathologic response was reported as percent necrosis at explantation. Results: Caudate lobe radioembolization was successfully performed in all eight patients. All patients presented with both cirrhosis and portal hypertension. Half were United Network for Organ Sharing (UNOS) stage T3 (n = 4, 50%). Fatigue was reported in half of the patients (n = 4, 50%). One (13%) grade 3/4 bilirubin toxicity was reported. One patient (13%) showed complete tumor response by WHO criteria, and three patients (38%) showed complete response using EASL guidelines. Serum AFP decreased by more than 50% in most patients (n = 6, 75%). Four patients (50%) were UNOS downstaged from T3 to T2, three of who underwent transplantation. One specimen showed histopathologic evidence of 100% complete necrosis, and two specimens demonstrated greater than 50% necrosis. Conclusions: Radioembolization with yttrium-90 appears to be a feasible, safe, and effective treatment option for patients with unresectable caudate lobe HCC. It has the potential to downstage patients to transplantation.
62 RADIOLOGY AND NUCLEAR MEDICINE↗
Long noncoding RNA H19-derived miR-675 aggravates restenosis by targeting PTEN
Highlights: • LncRNA H19 and miR-675 are positively correlated with restenosis. • LncRNA H19 promotes VSMCs proliferation. • LncRNA H19-derived miR-675 directly targets on PTEN. • LncRNA H19 aggravates restenosis in a miR-675-dependent manner. Restenosis is mainly attributed to excessive proliferation of vascular smooth muscle cells (VSMCs). Noncoding RNAs have been identified as key regulators of diverse pathological processes. We reported that the long noncoding RNA H19 (LncRNA H19) and LncRNA H19-derived microRNA (miR-675) are overexpressed in neointima of balloon-injured artery. Thus, the present study aims to evaluate the role of LncRNA H19 on VSMCs proliferation. To determine the changes of LncRNA H19 and miR-675 expression in the injured arterial wall, the standard rat carotid artery balloon injury model was used. In vivo studies demonstrated that both LncRNA H19 and miR-675 were upregulated after vascular injury. Correlation analysis revealed a positive relationship between LncRNA H19/miR-675 and the ratio of intima to media. Gain-of-function studies showed that the overexpression of LncRNA H19 accelerated T/G HA-VSMC proliferation in vitro. We further validated that PTEN is the target gene of miR-675 as demonstrated by luciferase assay. Finally, the results of the rescue experiment indicated that LncRNA H19 promoted the proliferation of T/G HA-VSMC in a miR-675-dependent manner. This finding not only reveal a novel function of LncRNA H19, but also has important diagnostic and therapeutic implications in the setting of restenosis and perhaps other vascular proliferative disorders as well.
60 APPLIED LIFE SCIENCES↗
3-(Naphthalen-2-yl(propoxy)methyl)azetidine hydrochloride attenuates NLRP3 inflammasome-mediated signaling pathway in lipopolysaccharide-stimulated BV2 microglial cells
Highlights: • KHG26792 attenuated LPS-induced TNF-α, IL-1β, and IL-6 level in BV2 cells. • KHG26792 attenuated LPS-induced ROS and nitrotyrosine level. • KHG26792 attenuated LPS-induced damage in mitochondrial potential. • KHG26792 attenuated LPS-induced expression of NLRP3, activated caspase-1, and ASC. • KHG26792 attenuated LPS-induced ATP level through P2X7 receptor. The nucleotide-binding and oligomerization domain-like receptor containing a pyrin domain 3 (NLRP3) inflammasome is a multiprotein complex with a role in innate immune responses. NLRP3 inflammasome dysfunction is a common feature of chronic inflammatory diseases. Microglia activation is also associated with neuroinflammatory pathologies. We previously reported that 3-(naphthalen-2-yl(propoxy)methyl)azetidine hydrochloride (KHG26792) reduced hypoxia-induced toxicity by modulating inflammation. However, no studies have elucidated the precise mechanisms for the anti-inflammatory action of KHG26792, in particular via inflammasome mediation. This study investigated the effects of KHG26792 on the inflammasome-mediated signaling pathway in lipopolysaccharide (LPS)-stimulated BV2 microglial cells. KHG26792 significantly attenuated several inflammatory responses including tumor necrosis factor-α, interleukin-1β, interleukin-6, reactive oxygen species, and mitochondrial potential in these cells. KHG26792 also suppressed LPS-induced increase NLRP3, activated caspase-1, and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) levels. Furthermore, KHG26792 successfully blocked LPS-activated adenosine triphosphate (ATP) level, likely through the purinergic receptor P2X ligand-gated ion channel 7 (P2X7) receptor. Our results suggest that the anti-inflammatory functions of KHG26792 may be, at least in part, due to regulation of the P2X7R/NLRP3-mediated signaling pathway during microglial activation.
60 APPLIED LIFE SCIENCES↗