Outcomes of Left Main Revascularization in Patients with Anemia: Gulf Left Main Registry.

INTRODUCTION: The aim of this study was to evaluate the effects of baseline anemia and anemia following revascularization on outcomes in patients with unprotected left main coronary artery (ULMCA) disease. METHODS: This was a retrospective, multicenter, observational study conducted between January 2015 and December 2019. The data on patients with ULMCA who underwent revascularization through percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) were stratified by the hemoglobin level at baseline into anemic and non-anemic groups to compare in-hospital events. The pre-discharge hemoglobin following revascularization was categorized into very low (<80 g/L for men and women), low (≥80 and ≤119 g/L for women and ≤129 g/L for men), and normal (≥130 g/L for men and ≥120 g/L for women) to assess impact on follow-up outcomes. RESULTS: A total of 2,138 patients were included, 796 (37.2%) of whom had anemia at baseline. A total of 319 developed anemia after revascularization and moved from being non-anemic at baseline to anemic at discharge. There was no difference in hospital major adverse cardiac and cerebrovascular event (MACCE) and mortality between CABG and PCI in anemic patients. At a median follow-up time of 20 months (interquartile range [IQR]: 27), patients with pre-discharge anemia who underwent PCI had a higher incidence of congestive heart failure (CHF) (p < 0.0001), and those who underwent CABG had significantly higher follow-up mortality (HR: 9.85 (95% CI: 2.53-38.43), p = 0.001). CONCLUSION: In this Gulf LM study, baseline anemia had no impact upon in-hospital MACCE and total mortality following revascularization (PCI or CABG). However, pre-discharge anemia is associated with worse outcomes after ULMCA disease revascularization, with significantly higher all-cause mortality in patients who had CABG, and a higher incidence of CHF in PCI patients, at a median follow-up time of 20 months (IQR: 27).

Computed tomography vs. cinefluoroscopy for the assessment of mechanical prosthetic valve leaflet motion.

Evaluation of mechanical prosthetic valve function is based on echocardiography, but adequate assessment of leaflet motion is limited by acoustic shadowing. Cinefluoroscopy is a standard method to assess leaflet motion, while computed tomography (CT) has been suggested as an alternative. We sought to compare the feasibility of leaflet motion assessment by cinefluoroscopy vs. CT. In 35 prospectively enrolled patients, leaflet motion was assessed in 43 bileaflet mechanical prostheses (29 mitral and 14 aortic) by cinefluoroscopy and non-contrast CT. Assessment was considered feasible when the 'in profile' projection (with the radiographic beam parallel to both the valve ring plane and the tilting axis of discs) could be achieved. Overall feasibility of fluoroscopic assessment was 74% (mitral, 66% vs. aortic, 93%; p = 0.071), while feasibility of CT assessment was 100% (p = 0.003). Among prostheses with unfeasible fluoroscopic assessment, CT suggested an extreme C-arm angulation to achieve the "in profile" projection (RAO: 76.0 ± 5.8°, LAO: 122.7 ± 32.5°, CRA: 51.4 ± 16.0°, CAU: 57.0 ± 18.2°). Among prostheses with feasible assessment by both techniques, fluoroscopy and CT yielded similar opening and closing angles (intraclass correlation coefficient, 0.959-0.998) with lower irradiation with CT as compared with fluoroscopy (26.2[21.1-29.3] vs. 289[179-358] mGy, p < 0.001). While CT scan took 8.7 ± 0.5 s, fluoroscopy required 2.64 ± 1.56 min to achieve and record the "in profile" projection. Non-contrast CT provides a higher feasibility and a quicker evaluation of mechanical prosthetic valve leaflet motion with less irradiation than fluoroscopy, especially in mitral valve position.

FOXM1 drives HPV+ HNSCC sensitivity to WEE1 inhibition.

Head and neck squamous cell carcinoma (HNSCC) associated with high-risk human papilloma virus (HPV) infection is a growing clinical problem. The WEE1 kinase inhibitor AZD1775 (WEE1i) overrides cell cycle checkpoints and is being studied in HNSCC regimens. We show that the HPV16 E6/E7 oncoproteins sensitize HNSCC cells to single-agent WEE1i treatment through activation of a FOXM1-CDK1 circuit that drives mitotic gene expression and DNA damage. An isogenic cell system indicated that E6 largely accounts for these phenotypes in ways that extend beyond p53 inactivation. A targeted genomic analysis implicated FOXM1 signaling downstream of E6/E7 expression and analyses of primary tumors and The Cancer Genome Atlas (TCGA) data revealed an activated FOXM1-directed promitotic transcriptional signature in HPV+ versus HPV- HNSCCs. Finally, we demonstrate the causality of FOXM1 in driving WEE1i sensitivity. These data suggest that elevated basal FOXM1 activity predisposes HPV+ HNSCC to WEE1i-induced toxicity and provide mechanistic insights into WEE1i and HPV+ HNSCC therapies.

Deep Learning for LiDAR Point Cloud Classification in Remote Sensing.

Point clouds are one of the most widely used data formats produced by depth sensors. There is a lot of research into feature extraction from unordered and irregular point cloud data. Deep learning in computer vision achieves great performance for data classification and segmentation of 3D data points as point clouds. Various research has been conducted on point clouds and remote sensing tasks using deep learning (DL) methods. However, there is a research gap in providing a road map of existing work, including limitations and challenges. This paper focuses on introducing the state-of-the-art DL models, categorized by the structure of the data they consume. The models' performance is collected, and results are provided for benchmarking on the most used datasets. Additionally, we summarize the current benchmark 3D datasets publicly available for DL training and testing. In our comparative study, we can conclude that convolutional neural networks (CNNs) achieve the best performance in various remote-sensing applications while being light-weighted models, namely Dynamic Graph CNN (DGCNN) and ConvPoint.

Polo-like-kinase 1 is a proviral host factor for hepatitis B virus replication.

Chronic hepatitis B virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC) and current treatments for chronic hepatitis B and HCC are suboptimal. Herein, we identified cellular serine/threonine Polo-like-kinase 1 (PLK1) as a positive effector of HBV replication. The aim of this study was to demonstrate the proviral role of PLK1 in HBV biosynthesis and validate PLK1 inhibition a potential antiviral strategy. To this end, we employed physiologically relevant HBV infection models of primary human hepatocytes (PHHs) and differentiated HepaRG cells in conjunction with pharmacologic PLK1 inhibitors, small interfering RNA (siRNA)-mediated knockdown, and overexpression of constitutively active PLK1 (PLK1CA ). In addition, a humanized liver Fah-/- /Rag2-/- /Il2rg-/- (FRG) mouse model was used to determine the antiviral effect of PLK1 inhibitor BI-2536 on HBV infection in vivo. Finally, in vitro PLK1 kinase assays and site-directed mutagenesis were employed to demonstrate that HBV core protein (HBc) is a PLK1 substrate. We demonstrated that HBV infection activated cellular PLK1 in PHHs and differentiated HepaRG cells. PLK1 inhibition by BI-2536 or siRNA-mediated knockdown suppressed HBV DNA biosynthesis, whereas overexpression of PLK1CA increased it, suggesting that the PLK1 effects on viral biosynthesis are specific and that PLK1 is a proviral cellular factor. Significantly, BI-2536 administration to HBV-infected humanized liver FRG mice strongly inhibited HBV infection, validating PLK1 as an antiviral target in vivo. The proviral action of PLK1 is associated with the biogenesis of the nucleocapsid, as BI-2536 leads to its decreased intracellular formation/accumulation. In this respect, our studies identified HBc as a PLK1 substrate in vitro, and mapped PLK1 phosphorylation sites on this protein. CONCLUSION: PLK1 is a proviral host factor that could be envisaged as a target for combined antiviral and antitumoral strategies against HBV infection and HBV-mediated carcinogenesis. (Hepatology 2017;66:1750-1765).

Level I lymph node involvement in patients with N1b papillary thyroid carcinoma: a prospective study.

Most of the studies on the incidence, pattern, and predictive factors of lymph node (LN) metastasis with papillary thyroid carcinoma (PTC) have been performed retrospectively and no common consensus has been reached regarding the predictors for the involvement of level I LNs. This study was conducted prospectively to determine the incidence and the possible predictors of level I involvement in N1b PTC patients. The study included 30 consecutive patients with N1b stage of PTC. All the patients underwent neck dissection (ND) including level I. The relation between involvement of level I LNs and various clinicopathological variables was studied. Unilateral neck dissection was performed in 24 patients and bilateral neck dissection in six patients leading to 36 NDs. Level I was excised in all patients, with five specimens (14%) positive for metastasis. Levels II, III, IV, V, VI, and VII were positive in 52.8, 58.3, 58.3, 33.3, 63, and 22.2%, respectively. Level I involvement was significantly related to the number of lymph node levels affected (p = 0.003) and macroscopic extranodal invasion (p = 0.04). It was not related to the involvement of other individual levels, gender, age, size of the largest thyroid nodule, size of the largest LN involved, or histo-pathological variant of the tumor. This study suggests that including level I in therapeutic neck dissection for N1b PTC patients might be recommended in selected cases of multiple level involvement and macroscopic extranodal invasion requiring sacrifice of internal jugular vein, spinal accessory nerve, or sternomastoid muscle.

EpCAM-regulated intramembrane proteolysis induces a cancer stem cell-like gene signature in hepatitis B virus-infected hepatocytes.

BACKGROUND & AIMS: Hepatocytes in which the hepatitis B virus (HBV) is replicating exhibit loss of the chromatin modifying polycomb repressive complex 2 (PRC2), resulting in re-expression of specific, cellular PRC2-repressed genes. Epithelial cell adhesion molecule (EpCAM) is a PRC2-repressed gene, normally expressed in hepatic progenitors, but re-expressed in hepatic cancer stem cells (hCSCs). Herein, we investigated the functional significance of EpCAM re-expression in HBV-mediated hepatocarcinogenesis. METHODS: Employing molecular approaches (transfections, fluorescence-activated cell sorting, immunoblotting, qRT-PCR), we investigated the role of EpCAM-regulated intramembrane proteolysis (RIP) in HBV replicating cells in vitro, and in liver tumors from HBV X/c-myc mice and chronically HBV infected patients. RESULTS: EpCAM undergoes RIP in HBV replicating cells, activating canonical Wnt signaling. Transfection of Wnt-responsive plasmid expressing green fluorescent protein (GFP) identified a GFP + population of HBV replicating cells. These GFP+/Wnt+ cells exhibited cisplatin- and sorafenib-resistant growth resembling hCSCs, and increased expression of pluripotency genes NANOG, OCT4, SOX2, and hCSC markers BAMBI, CD44 and CD133. These genes are referred as EpCAM RIP and Wnt-induced hCSC-like gene signature. Interestingly, this gene signature is also overexpressed in liver tumors of X/c-myc bitransgenic mice. Clinically, a group of HBV-associated hepatocellular carcinomas was identified, exhibiting elevated expression of the hCSC-like gene signature and associated with reduced overall survival post-surgical resection. CONCLUSIONS: The hCSC-like gene signature offers promise as prognostic tool for classifying subtypes of HBV-induced HCCs. Since EpCAM RIP and Wnt signaling drive expression of this hCSC-like signature, inhibition of these pathways can be explored as therapeutic strategy for this subtype of HBV-associated HCCs. LAY SUMMARY: In this study, we provide evidence for a molecular mechanism by which chronic infection by the hepatitis B virus results in the development of poor prognosis liver cancer. Based on this mechanism our results suggest possible therapeutic interventions.

Refining perforator selection for deep inferior epigastric perforator flap: the impact of the dominant venous perforator.

INTRODUCTION: This article aims to investigate the critical role of the venous-perforator in the decision-making process of choosing the best suitable perforator-complex in a deep inferior epigastric perforator (DIEP) flap. METHODS: Forty consecutive DIEP breast reconstructions were pre-operatively evaluated by CT-Angiography to identify the dominant and centrally located abdominal wall perforators. The CTA results were used as a guide to conduct a Color-Duplex-Ultrasound examination that was mainly focused on investigating the accompanying venous-perforator. In group-A (n = 20) perforator-complex selection was based on the size of the arterial-perforator, whilst in group-B (n = 20) it was based on the size of the venous-perforator. RESULTS: All single perforator-complex DIEP flaps survived. No significant differences were recorded concerning the size of arterial-perforator between the two groups; however the size of venous-perforator was significantly larger in group-B (P < 0.05). In group-A, four flaps showed vascular compromise intraoperative that was salvaged by flap supercharge with the superficial inferior epigastric system. In contrast, in group-B, all flaps were re-vascularized uneventfully (P < 0.05). Physical examination revealed a palpable mass in one patient and ultrasound investigation added three cases with a firm area of scar tissue in group-A, but no fat necrosis was detected in group-B (P < 0.05). CONCLUSIONS: The CTA-guided duplex ultrasonography could direct the perforator-complex selection according to the size of the venous-perforator, and may reduce the intraoperative problems and the incidence of fat necrosis.

Comprehensive analysis of optimal power flow using recent metaheuristic algorithms.

This paper provides six metaheuristic algorithms, namely Fast Cuckoo Search (FCS), Salp Swarm Algorithm (SSA), Dynamic control Cuckoo search (DCCS), Gradient-Based Optimizer (GBO), Northern Goshawk Optimization (NGO), Opposition Flow Direction Algorithm (OFDA) to efficiently solve the optimal power flow (OPF) issue. Under standard and conservative operating settings, the OPF problem is modeled utilizing a range of objectives, constraints, and formulations. Five case studies have been conducted using IEEE 30-bus and IEEE 118-bus standard test systems to evaluate the effectiveness and robustness of the proposed algorithms. A performance evaluation procedure is suggested to compare the optimization techniques' strength and resilience. A fresh comparison methodology is created to compare the proposed methodologies with other well-known methodologies. Compared to previously reported optimization algorithms in the literature, the obtained results show the potential of GBO to solve various OPF problems efficiently.

GLUT1 inhibitor BAY-876 induces apoptosis and enhances anti-cancer effects of bitter receptor agonists in head and neck squamous carcinoma cells.

Head and neck squamous cell carcinomas (HNSCCs) are cancers that arise in the mucosa of the upper aerodigestive tract. The five-year patient survival rate is ~50%. Treatment includes surgery, radiation, and/or chemotherapy and is associated with lasting effects even when successful in irradicating the disease. New molecular targets and therapies must be identified to improve outcomes for HNSCC patients. We recently identified bitter taste receptors (taste family 2 receptors, or T2Rs) as a novel candidate family of receptors that activate apoptosis in HNSCC cells through mitochondrial Ca2+ overload and depolarization. We hypothesized that targeting another component of tumor cell metabolism, namely glycolysis, may increase the efficacy of T2R-directed therapies. GLUT1 (SLC2A1) is a facilitated-diffusion glucose transporter expressed by many cancer cells to fuel their increased rates of glycolysis. GLUT1 is already being investigated as a possible cancer target, but studies in HNSCCs are limited. Examination of immortalized HNSCC cells, patient samples, and The Cancer Genome Atlas revealed high expression of GLUT1 and upregulation in some patient tumor samples. HNSCC cells and tumor tissue express GLUT1 on the plasma membrane and within the cytoplasm (perinuclear, likely co-localized with the Golgi apparatus). We investigated the effects of a recently developed small molecule inhibitor of GLUT1, BAY-876. This compound decreased HNSCC glucose uptake, viability, and metabolism and induced apoptosis. Moreover, BAY-876 had enhanced effects on apoptosis when combined at low concentrations with T2R bitter taste receptor agonists. Notably, BAY-876 also decreased TNFα-induced IL-8 production, indicating an additional mechanism of possible tumor-suppressive effects. Our study demonstrates that targeting GLUT1 via BAY-876 to kill HNSCC cells, particularly in combination with T2R agonists, is a potential novel treatment strategy worth exploring further in future translational studies.

Proteomic Associations of Adverse Outcomes in Human Heart Failure.

BACKGROUND: Identifying novel molecular drivers of disease progression in heart failure (HF) is a high-priority goal that may provide new therapeutic targets to improve patient outcomes. The authors investigated the relationship between plasma proteins and adverse outcomes in HF and their putative causal role using Mendelian randomization. METHODS AND RESULTS: The authors measured 4776 plasma proteins among 1964 participants with HF with a reduced left ventricular ejection fraction enrolled in PHFS (Penn Heart Failure Study). Assessed were the observational relationship between plasma proteins and (1) all-cause death or (2) death or HF-related hospital admission (DHFA). The authors replicated nominally significant associations in the Washington University HF registry (N=1080). Proteins significantly associated with outcomes were the subject of 2-sample Mendelian randomization and colocalization analyses. After correction for multiple testing, 243 and 126 proteins were found to be significantly associated with death and DHFA, respectively. These included small ubiquitin-like modifier 2 (standardized hazard ratio [sHR], 1.56; P<0.0001), growth differentiation factor-15 (sHR, 1.68; P<0.0001) for death, A disintegrin and metalloproteinase with thrombospondin motifs-like protein (sHR, 1.40; P<0.0001), and pulmonary-associated surfactant protein C (sHR, 1.24; P<0.0001) for DHFA. In pathway analyses, top canonical pathways associated with death and DHFA included fibrotic, inflammatory, and coagulation pathways. Genomic analyses provided evidence of nominally significant associations between levels of 6 genetically predicted proteins with DHFA and 11 genetically predicted proteins with death. CONCLUSIONS: This study implicates multiple novel proteins in HF and provides preliminary evidence of associations between genetically predicted plasma levels of 17 candidate proteins and the risk for adverse outcomes in human HF.

Effective hybrid search technique based constraint mixed-integer programming for smart home residential load scheduling.

In this paper, the problem of scheduling smart homes (SHs) residential loads is considered aiming to minimize electricity bills and enhance the user comfort. The problem is addressed as a multi-objective constraint mixed-integer optimization problem (CP-MIP) to model the constrained load operation. As the CP-MIP optimization problem is non-convex, a novel hybrid search technique, that combines the Relaxation and Rounding (RnR) approach and metaheuristic algorithms to enhance the accuracy and relevance of decision variables, is proposed. This search technique is implemented through two stages: the relaxation stage in which a metaheuristic technique is applied to get the optimal rational solution of the problem. Whereas, the second stage is the rounding process which is applied via stochastic rounding approach to provide a good-enough feasible solution. The scheduling process has been done under time-of-use (ToU) dynamic electricity pricing scheme and two powering modes (i.e., powering from the main grid only or powering from a grid-tied photovoltaic (PV) residential power system), in addition, four metaheuristics [i.e., Binary Particle Swarm Optimization (BPSO), Self-Organizing Hierarchical PSO (SOH-PSO), JAYA algorithm, and Comprehensive Learning JAYA algorithm (CL-JAYA)] have been utilized. The results reported in this study verify the effectiveness of the proposed technique. In the 1st powering mode, the electricity bill reduction reaches 19.4% and 20.0% when applying the modified metaheuristics, i.e. SOH-PSO and CL-JAYA, respectively, while reaches 56.1%, and 54.7% respectively in the 2nd powering scenario. In addition, CL-JAYA superiority is also observed with regard to the user comfort.

Sustained alternate-day fasting potentiates doxorubicin cardiotoxicity.

Fasting strategies are under active clinical investigation in patients receiving chemotherapy. Prior murine studies suggest that alternate-day fasting may attenuate doxorubicin cardiotoxicity and stimulate nuclear translocation of transcription factor EB (TFEB), a master regulator of autophagy and lysosomal biogenesis. In this study, human heart tissue from patients with doxorubicin-induced heart failure demonstrated increased nuclear TFEB protein. In mice treated with doxorubicin, alternate-day fasting or viral TFEB transduction increased mortality and impaired cardiac function. Mice randomized to alternate-day fasting plus doxorubicin exhibited increased TFEB nuclear translocation in the myocardium. When combined with doxorubicin, cardiomyocyte-specific TFEB overexpression provoked cardiac remodeling, while systemic TFEB overexpression increased growth differentiation factor 15 (GDF15) and caused heart failure and death. Cardiomyocyte TFEB knockout attenuated doxorubicin cardiotoxicity, while recombinant GDF15 was sufficient to cause cardiac atrophy. Our studies identify that both sustained alternate-day fasting and a TFEB/GDF15 pathway exacerbate doxorubicin cardiotoxicity.

Apolipoprotein M Attenuates Anthracycline Cardiotoxicity and Lysosomal Injury.

Apolipoprotein M (ApoM) binds sphingosine-1-phosphate (S1P) and is inversely associated with mortality in human heart failure (HF). Here, we show that anthracyclines such as doxorubicin (Dox) reduce circulating ApoM in mice and humans, that ApoM is inversely associated with mortality in patients with anthracycline-induced heart failure, and ApoM heterozygosity in mice increases Dox-induced mortality. In the setting of Dox stress, our studies suggest ApoM can help sustain myocardial autophagic flux in a post-transcriptional manner, attenuate Dox cardiotoxicity, and prevent lysosomal injury.

Cardiac radiation improves ventricular function in mice and humans with cardiomyopathy.

BACKGROUND: Rapidly dividing cells are more sensitive to radiation therapy (RT) than quiescent cells. In the failing myocardium, macrophages and fibroblasts mediate collateral tissue injury, leading to progressive myocardial remodeling, fibrosis, and pump failure. Because these cells divide more rapidly than cardiomyocytes, we hypothesized that macrophages and fibroblasts would be more susceptible to lower doses of radiation and that cardiac radiation could therefore attenuate myocardial remodeling. METHODS: In three independent murine heart failure models, including models of metabolic stress, ischemia, and pressure overload, mice underwent 5 Gy cardiac radiation or sham treatment followed by echocardiography. Immunofluorescence, flow cytometry, and non-invasive PET imaging were employed to evaluate cardiac macrophages and fibroblasts. Serial cardiac magnetic resonance imaging (cMRI) from patients with cardiomyopathy treated with 25 Gy cardiac RT for ventricular tachycardia (VT) was evaluated to determine changes in cardiac function. FINDINGS: In murine heart failure models, cardiac radiation significantly increased LV ejection fraction and reduced end-diastolic volume vs. sham. Radiation resulted in reduced mRNA abundance of B-type natriuretic peptide and fibrotic genes, and histological assessment of the LV showed reduced fibrosis. PET and flow cytometry demonstrated reductions in pro-inflammatory macrophages, and immunofluorescence demonstrated reduced proliferation of macrophages and fibroblasts with RT. In patients who were treated with RT for VT, cMRI demonstrated decreases in LV end-diastolic volume and improvements in LV ejection fraction early after treatment. CONCLUSIONS: These results suggest that 5 Gy cardiac radiation attenuates cardiac remodeling in mice and humans with heart failure. FUNDING: NIH, ASTRO, AHA, Longer Life Foundation.

HDL Composition, Heart Failure, and Its Comorbidities.

Although research on high-density lipoprotein (HDL) has historically focused on atherosclerotic coronary disease, there exists untapped potential of HDL biology for the treatment of heart failure. Anti-oxidant, anti-inflammatory, and endothelial protective properties of HDL could impact heart failure pathogenesis. HDL-associated proteins such as apolipoprotein A-I and M may have significant therapeutic effects on the myocardium, in part by modulating signal transduction pathways and sphingosine-1-phosphate biology. Furthermore, because heart failure is a complex syndrome characterized by multiple comorbidities, there are complex interactions between heart failure, its comorbidities, and lipoprotein homeostatic mechanisms. In this review, we will discuss the effects of heart failure and associated comorbidities on HDL, explore potential cardioprotective properties of HDL, and review novel HDL therapeutic targets in heart failure.

Finite-time and sampled-data synchronization of complex dynamical networks subject to average dwell-time switching signal.

This study deals with the finite-time synchronization problem of a class of switched complex dynamical networks (CDNs) with distributed coupling delays via sampled-data control. First, the dynamical model is studied with coupling delays in more detail. The sampling system is then converted to a continuous time-delay system using an input delay technique. We obtain some unique and less conservative criteria on exponential stability using the Lyapunov-Krasovskii functional (LKF), which is generated with a Kronecker product, linear matrix inequalities (LMIs), and integral inequality. Furthermore, some sufficient criteria are derived by an average dwell-time method and determine the finite-time boundedness of CDNs with switching signal. The proposed sufficient conditions can be represented in the form of LMIs. Finally, numerical examples are given to show that the suggested strategy is feasible.

Global and context-specific transcriptional consequences of oncogenic Fbw7 mutations.

The Fbw7 ubiquitin ligase targets many proteins for proteasomal degradation, which include oncogenic transcription factors (TFs) (e.g., c-Myc, c-Jun, and Notch). Fbw7 is a tumor suppressor and tumors often contain mutations in FBXW7, the gene that encodes Fbw7. The complexity of its substrate network has obscured the mechanisms of Fbw7-associated tumorigenesis, yet this understanding is needed for developing therapies. We used an integrated approach employing RNA-Seq and high-resolution mapping (cleavage under target and release using nuclease) of histone modifications and TF occupancy (c-Jun and c-Myc) to examine the combinatorial effects of misregulated Fbw7 substrates in colorectal cancer (CRC) cells with engineered tumor-associated FBXW7 null or missense mutations. Both Fbw7 mutations caused widespread transcriptional changes associated with active chromatin and altered TF occupancy: some were common to both Fbw7 mutant cell lines, whereas others were mutation specific. We identified loci where both Jun and Myc were coregulated by Fbw7, suggesting that substrates may have synergistic effects. One coregulated gene was CIITA, the master regulator of MHC Class II gene expression. Fbw7 loss increased MHC Class II expression and Fbw7 mutations were correlated with increased CIITA expression in TCGA colorectal tumors and cell lines, which may have immunotherapeutic implications for Fbw7-associated cancers. Analogous studies in neural stem cells in which FBXW7 had been acutely deleted closely mirrored the results in CRC cells. Gene set enrichment analyses revealed Fbw7-associated pathways that were conserved across both cell types that may reflect fundamental Fbw7 functions. These analyses provide a framework for understanding normal and neoplastic context-specific Fbw7 functions.

Proteomic Analysis of Effects of Spironolactone in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: The TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial) suggested clinical benefits of spironolactone treatment among patients with heart failure with preserved ejection fraction enrolled in the Americas. However, a comprehensive assessment of biologic pathways impacted by spironolactone therapy in heart failure with preserved ejection fraction has not been performed. METHODS: We conducted aptamer-based proteomic analysis utilizing 5284 modified aptamers to 4928 unique proteins on plasma samples from TOPCAT participants from the Americas (n=164 subjects with paired samples at baseline and 1 year) to identify proteins and pathways impacted by spironolactone therapy in heart failure with preserved ejection fraction. Mean percentage change from baseline was calculated for each protein. Additionally, we conducted pathway analysis of proteins altered by spironolactone. RESULTS: Spironolactone therapy was associated with proteome-wide significant changes in 7 proteins. Among these, CARD18 (caspase recruitment domain-containing protein 18), PKD2 (polycystin 2), and PSG2 (pregnancy-specific glycoprotein 2) were upregulated, whereas HGF (hepatic growth factor), PLTP (phospholipid transfer protein), IGF2R (insulin growth factor 2 receptor), and SWP70 (switch-associated protein 70) were downregulated. CARD18, a caspase-1 inhibitor, was the most upregulated protein by spironolactone (-0.5% with placebo versus +66.5% with spironolactone, P<0.0001). The top canonical pathways that were significantly associated with spironolactone were apelin signaling, stellate cell activation, glycoprotein 6 signaling, atherosclerosis signaling, liver X receptor activation, and farnesoid X receptor activation. Among the top pathways, collagens were a consistent theme that increased in patients receiving placebo but decreased in patients randomized to spironolactone. CONCLUSIONS: Proteomic analysis in the TOPCAT trial revealed proteins and pathways altered by spironolactone, including the caspase inhibitor CARD18 and multiple pathways that involved collagens. In addition to effects on fibrosis, our studies suggest potential antiapoptotic effects of spironolactone in heart failure with preserved ejection fraction, a hypothesis that merits further exploration.

Endoscopic transorbital ligation of the maxillary artery through the inferior orbital fissure.

OBJECTIVE: Determine the feasibility of accessing the internal maxillary artery (IMA) through a transorbital endoscopic assisted approach through the inferior orbital fissure (IOF). MATERIALS AND METHODS: Six adult cadaveric specimens were injected intravascularly with colored latex and dissected on 12 sides. A transorbital endoscopic approach was used to expose the IOF and reach the IMA. RESULTS: The average length and width of the anterolateral segment of the IOF were 7.3 and 4 mm, respectively, on the right side and 6.7 and 3.8 mm, respectively, on the left side. Surgical exposure and modification of the IOF allowed the exposure and control of the IMA in all 12 sides. CONCLUSIONS: The IOF is a feasible portal to the IMA. The benefits of this approach include vascular control of the distal segment of the maxillary artery. It may provide access in clinical scenarios where endonasal access is not possible (e.g., extensive tumors) or serve as an alternative or complementary surgical route (e.g., control during a total or radical maxillectomy).