tbuckley/cabot-search huggingface dataset:
Saudi Arabia orders thousands of doctors and medical students to leave Canada within days
Authors: Owen Dyer
Journal: BMJ (2018)

More than 800 doctors from Saudi Arabia who work in Canadian hospitals, plus thousands of Saudi students in Canadian universities and medical schools, have until the end of August to settle their affairs and leave the country, according to peremptory orders from their government.

The kingdom’s de facto ruler, Prince Mohammed bin Salman, is seeking to punish Canada after its foreign minister, Chrystia Freeland, criticised Saudi Arabia’s arrest of a women’s rights campaigner who had advocated for the right to drive. In addition to its action against the students, Saudi Arabia expelled Canada’s ambassador, cut trade ties, and stopped direct flights between the two countries.

Saudi Arabia’s foreign ministry said that it is arranging the immediate transfer to other countries of Saudi patients being treated in Canadian hospitals. The Saudi government sometimes pays for the treatment of favoured subjects in foreign hospitals.

The Saudi government did not elaborate on its plans for these patients, which …
Architecture of the Mouse Brain Synaptome
Authors: Fei Zhu, Mélissa Cizeron, Zhen Qiu, Ruth Benavides-Piccione, Maksym V. Kopanitsa, Nathan G. Skene, Babis Koniaris, Javier DeFelipe, Erik Fransén, Noboru H. Komiyama, Seth G.N. Grant
Journal: Neuron (2018)

Synapses are found in vast numbers in the brain and contain complex proteomes. We developed genetic labeling and imaging methods to examine synaptic proteins in individual excitatory synapses across all regions of the mouse brain. Synapse catalogs were generated from the molecular and morphological features of a billion synapses. Each synapse subtype showed a unique anatomical distribution, and each brain region showed a distinct signature of synapse subtypes. Whole-brain synaptome cartography revealed spatial architecture from dendritic to global systems levels and previously unknown anatomical features. Synaptome mapping of circuits showed correspondence between synapse diversity and structural and functional connectomes. Behaviorally relevant patterns of neuronal activity trigger spatiotemporal postsynaptic responses sensitive to the structure of synaptome maps. Areas controlling higher cognitive function contain the greatest synapse diversity, and mutations causing cognitive disorders reorganized synaptome maps. Synaptome technology and resources have wide-ranging application in studies of the normal and diseased brain.
Cellular Phospholipid and Cholesterol Efflux in High-Density Lipoprotein Deficiency
Authors: MichelMarcil, RachelBissonnette, JérômeVincent, LarbiKrimbou, JacquesGenest
Journal: Circulation (2003)

Background— Prospective studies have examined the relationship between coronary artery disease and low plasma levels of high-density lipoprotein cholesterol (HDL-C). Methods and Results— We investigated the causes of hypoalphalipoproteinemia (HypoA; HDL-C  ≈1.0 mmol/L) of HDL-C. In HypoA subjects, 4 cases of Tangier disease and 6 of familial HDL deficiency (heterozygous Tangier disease) were id...
Abstract 13233: Does Fetal Aortic Valvuloplasty alter the Natural History of Aortic Stenosis?
Authors: AlexanderKovacevic, MatsMellander, GeraldTulzer, UlrikeHerberg, JoannaDangel, AnnikaÖhman, HelenaGardiner
Journal: Circulation (2014)

Introduction: Fetal aortic valvuloplasty (FV) is proposed as therapy to achieve biventricular circulation (BV) in fetuses where univentricular circulation (UV) is likely. Hypothesis: FV cannot alter natural history (NH) outcome. Methods: Hybrid of case-control and repeated samples cohort study. Fetuses with aortic stenosis (AS) were enrolled in a multicenter study (2005-2012). FV was considered in 70 / 214 AS and successful in 59/67 (88.0%) performed. Six salvage cases (hydrops) were excluded and 47 liveborn FV could be matched with 95 controls (NH) by scan closest to 23 +/- 3 weeks and +/- 1 Z-score for MV, LV and AV, producing a best match group for each. Results: Procedure-related death occurred in 7/67 (10.4%). Overall 151/214 (71%) were liveborn, but outcome unknown in 5. Serial left sided growth was similar in FV and NH: Z score differences MV = 0.11, LV = 0.08, AV = 0.11, p>0.90. Hazard ratio for FV survival was similar to NH at 30 d, 1 and 4 yrs after birth [0.68 (95% CI 0.347 - 1.315), p= 0.25]. ...
E-Cadherin/β-Catenin/T-Cell Factor Pathway Is Involved in Smooth Muscle Cell Proliferation Elicited by Oxidized Low-Density Lipoprotein
Authors: AurélieBedel, AnneNègre-Salvayre, SylviaHeeneman, Marie-HélèneGrazide, Jean-ClaudeThiers, RobertSalvayre, FrançoiseMaupas-Schwalm
Journal: Circulation Research (2008)

The E-cadherin/β-catenin/T-cell factor (Tcf) signaling pathway plays a crucial role in embryogenesis and carcinogenesis and has recently emerged in atherosclerosis. The aim of this work was to investigate whether this signaling pathway is involved in smooth muscle cell proliferation induced by oxidized low-density lipoprotein (LDL). In human aortic smooth muscle cells, mitogenic concentration of mildly oxidized LDL induced the activation of β-catenin, as assessed by the dissociation of the β-catenin/cadherin complex, and the concomitant rise of active β-catenin in the cytosol. The oxidized LDL–induced rise of active β-catenin required metalloproteinase activation, as well as epidermal growth factor receptor and Src signaling, as assessed by the use of pharmacological inhibitors and cells overexpressing a SrcK-inactive form. The concomitant phosphatidylinositol 3-kinase/Akt activation and glycogen synthase kinase 3-β phosphorylation induced the inhibition of the proteasomal degradation of β-catenin. Then a...
Abstract 5009: Defined factors overcome T-cell exhaustion via abscopal effect
Authors: Danny Khalil, Luis Felipe Campesato, Sadna Budhu, Yanyun Li, Caitlin Jones, Nathan Suek, Cailian Liu, Billel Gasmi, Rachel Giese, Stephane Pourpe, Taha Merghoub, Jedd D. Wolchok
Journal: Cancer Research (2018)

Abstract Irreversible exhaustion of tumor-associated T cells is an important factor limiting the efficacy of PD-1 blockade in a number of cancers. Recent data suggest that PD-1 blockade functions largely by augmenting T cell costimulation. Given that activated APCs provide necessary T-cell costimulation, we hypothesized that enforced activation of intratumoral APCs would prime tumor-specific T cells and synergize with PD-1 blockade to overcome T-cell exhaustion. After screening various agents in syngeneic murine models, we found that dual CD40/TLR4 activation within a single tumor triggers a systemic tumor-specific CD8 T-cell response that is dependent on BATF3+ dendritic cells. Remarkably, this approach abolishes exhausted PD-1+ intratumoral T cells in treated as well as distant tumors while sparing more proximal T cells outside the tumors. In addition to treating large established tumors, this approach also confers persistent immunity allowing animals to reject reimplanted tumors 90 days after treatment. Dual CD40/TLR4 activation within a single tumor is thus a promising method for overcoming tumor-associated T-cell exhaustion in a manner that may provide durable systemic control of metastatic human cancers while sparing healthy tissues. Citation Format: Danny Khalil, Luis Felipe Campesato, Sadna Budhu, Yanyun Li, Caitlin Jones, Nathan Suek, Cailian Liu, Billel Gasmi, Rachel Giese, Stephane Pourpe, Taha Merghoub, Jedd D. Wolchok. Defined factors overcome T-cell exhaustion via abscopal effect [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5009.
Abstract 315: Cell death of AML blasts induced by cytarabine and enhanced by the Vitamin D2/Carnosic acid cell differentiating combination involves apoptosis signal-regulating kinase 1 (ASK1) activation
Authors: Xuening Wang, Jonathan S. Harrison, George P. Studzinski
Journal: Cancer Research (2018)

Abstract Acute Myeloid Leukemia (AML) is a disease with a grim prognosis and limited curative treatment options. The principal agent used to induce disease remissions is Cytarabine (AraC), typically combined with an anthracycline, though multiple other combinations have been explored. We have previously reported that the exposure of AML blasts, in which the DNA is already damaged by AraC, to the Vitamin D2 analog Doxercalciferol combined with Carnosic Acid (D2/CA) enhances AraC cytotoxicity, resulting in an increased cell kill of the blasts. To obtain an understanding of the underlying mechanisms, and thus facilitate the translation of this finding to the clinic, we conducted in vitro studies on HL60, U937 cell lines and on AML blasts in primary culture. The initial findings were that the kinases BRAF and JNK1 and the pro-apoptotic protein BIM participate in the enhancement of AraC action. We now report that the kinase activity of ASK1 (MAP3K5) is upregulated by both AraC and D2/CA, and this appears to be additive thus increasing the apoptosis by this sequential combination regimen. Interestingly, we also noted that BRAF directly binds to ASK1, and since it is a kinase, this raises the possibility that it activates ASK1 in this experimental system. This possibility is strengthened by the report that JNK activation which leads to apoptosis is dependent on BRAF. The ongoing investigation of additional details of the molecular events responsible for enhanced cell death may provide clues for the improvement of the therapy of AML. (Supported by NIH grant R01CA044722-26 from NCI). Citation Format: Xuening Wang, Jonathan S. Harrison, George P. Studzinski. Cell death of AML blasts induced by cytarabine and enhanced by the Vitamin D2/Carnosic acid cell differentiating combination involves apoptosis signal-regulating kinase 1 (ASK1) activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 315.
Abnormal Cardiac Autonomic Nervous Activity After Right Ventricular Outflow Tract Reconstruction
Authors: HideoOhuchi, HiroshiSuzuki, KeikoToyohara, KimikoTatsumi, YasuoOno, YoshioArakaki, ShigeyukiEchigo
Journal: Circulation (2000)

Background—There are few studies of cardiac autonomic nervous activity (CANA) in patients with congenital heart disease. Methods and Results—We evaluated CANA in 54 patients after closure of an atrial/ventricular septal defect (group A), 54 patients after successful right ventricular outflow tract reconstruction (RVOTR) (group B1), 35 RVOTR patients with residual stenosis (group B2), and 47 controls. Cardiac parasympathetic nervous activity (PSNA) was estimated by heart rate (HR) change after cholinergic blockade, HR variability, and arterial baroreflex sensitivity (BRS). Cardiac sympathetic nervous activity was estimated by the heart-to-mediastinum 123I-metaiodobenzylguanidine activity ratio (H/M) and HR increase after isoproterenol infusion (β). HR response (ΔHR) and peak oxygen uptake (Vo2) were measured by exercise test. There was no difference in β among study groups. Group A exhibited mildly impaired PSNA, which recovered 1 year after surgery, and no change in H/M. Impaired PSNA and low H/M were fo...
Abstract 103: Expression and regulation of MMP9 and RECK in human oral squamous cell carcinoma progression and invasion
Authors: Kamdeo Kumar Pramanik, Basabi Rana, Ajay Rana, Rajakishore Mishra
Journal: Cancer Research (2018)

Abstract Purpose: Matrix metalloproteinase-9 (MMP-9), a Zn-dependent endopeptidase is known to play a central role in oral cancer pathogenesis. Recently we observed differential function of MMP-9 and reversion-inducing cysteine-rich protein with Kazal motifs (RECK) respectively in OSCC invasion. We hypothesize that the downregulation of MMP-9 via RECK promotes human oral cancer progression and invasion. Experimental procedure: The mRNA expression, protein expression and activity of MMP-9/2, expression of transcription factors like Snail, c-Myc, β-catenin and protein-protein interaction of TIMP1/RECK with MMP9 and promoter methylation of RECK gene were assessed by using RT-PCR, immunohistochemistry (IHC), Western blotting, co-immunoprecipitation, gelatin zymography, and bisulphate modification-PCR analyses. Wnt5a and LPA mediated MMP-9 regulation as well as the MMP-9 regulation by the exogenously expression of RECK, GSK3β (WT) or non phosphoryable active GSK3β (S9A) was also performed in oral tongue SCC derived SCC-9 cells. Summary: We observed up-regulation/activation of MMP-9 was associated with decreased expression of RECK and progression and invasion of OSCC. MMP-9 expression/ activity was positively correlated with inactivation of GSK3β signaling. Conversely, a link between inactivation of GSK3 signaling and the progressive silencing of RECK gene through promoter hypermethylation was observed. Finally, Wnt5a and LPA mediated increased MMP-9 and decreased RECK expressions were observed. Conclusion: Taken together, these results demonstrated the influence of a novel signaling axis GSK3β-RECK-MMP-9 to drive OSCC progression and invasion. Thus, targeting this pathway may be exploited for treating OSCC. Citation Format: Kamdeo Kumar Pramanik, Basabi Rana, Ajay Rana, Rajakishore Mishra. Expression and regulation of MMP9 and RECK in human oral squamous cell carcinoma progression and invasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 103.
Polymeric biomaterials for biophotonic applications
Authors: Dingying Shan, Ethan Gerhard, Chenji Zhang, John William Tierney, Daniel Xie, Zhiwen Liu, Jian Yang
Journal: Bioactive Materials (2018)

With the growing importance of optical techniques in medical diagnosis and treatment, there exists a pressing need to develop and optimize materials platform for biophotonic applications. Particularly, the design of biocompatible and biodegradable materials with desired optical, mechanical, chemical, and biological properties is required to enable clinically relevant biophotonic devices for translating in vitro optical techniques into in situ and in vivo use. This technological trend propels the development of natural and synthetic polymeric biomaterials to replace traditional brittle, nondegradable silica glass based optical materials. In this review, we present an overview of the advances in polymeric optical material development, optical device design and fabrication techniques, and the accompanying applications to imaging, sensing and phototherapy.
Abstract 19302: Surgical Approach to Continuous Flow Left Ventricular Assist Device Explantation: a Comparison of Outcomes
Authors: Andrew C Baldwin, Steve K Singh, Elena Sandoval, Jatin Anand, William E Cohn, Hari R Mallidi, O.H. Frazier
Journal: Circulation (2014)

Objective:  Weaning and explanation of selected patients with continuous flow left ventricular assist devices (CF LVADs) has been shown to be feasible. Clinical outcomes are poorly described regarding the various operative approaches employed, which differ primarily in the degree of retained pump material. We evaluate the impact of CF LVAD explant surgical approach on early and late clinical events.   Methods:  A single-center, retrospective review was performed, evaluating all patients who underwent explanation of a CF LVAD (2006-2014). Descriptive univariate statistics, multivariate regression and survival analysis were performed. Patients were stratified by surgical approach, and censored by transplant, device re-implantation or death.   Results:  A total of 27 patients were identified (25 HeartMateII, 2 HeartWare); characteristics and outcomes are listed in Figure 1a. Four approaches were used: complete pump and outflow excision with ventriculotomy closure (n=13 ; 48%), pump excision and ligation of inflow and outflow grafts (n=7 ; 26%), ligation of outflow graft and driveline transection (n=5 ; 19%), or driveline transection alone (n=2 ; 7%). Primary incisions were subcostal (n=19, 70%) or subxiphoid (n=5, 19%), with 1 conversion to sternotomy (n=1, 7%). Mean duration of CF support prior to explant was 532±424 days (range 42-1937 days), while post-explant survival (defined as time preceding transplant, device re-implantation, or death) was 1116±927 days (range 127-2877 days). Survival stratified by surgical approach is shown in Figure 1b. Overall time-to-event and survival analyses showed no significant difference in postoperative length of stay (p=0.7), stroke (p=0.12), reoperation (p=0.4), or total survival (p=0.12) between surgical approaches.   Conclusions:  This is the largest description of CF LVAD explantation by surgical approach. While technical difficulty varies, all are feasible with similar early and late survival and clinical outcomes.
Pioglitazone Prevents Acute and Chronic Cardiac Allograft Rejection
Authors: HisanoriKosuge, GoHaraguchi, NoritakaKoga, YasuhiroMaejima, Jun-ichiSuzuki, MitsuakiIsobe
Journal: Circulation (2006)

Background— Peroxisome proliferator–activated receptor-γ plays an important role in regulating inflammation. Although cardiac transplantation is an established therapy for patients with end-stage heart disease, allograft rejection is a major concern for long-term survival. We investigated the role of pioglitazone in acute and chronic rejection in a murine cardiac transplantation model. Methods and Results— We performed heterotopic murine cardiac transplantation in total allomismatch or major histocompatibility complex class II–mismatched combinations. Recipient mice were given standard chow or chow containing pioglitazone (3 mg · kg−1 · d−1) beginning 1 day before cardiac transplantation. In acute rejection, animals given pioglitazone showed significantly longer cardiac allograft survival than control mice (mean survival time, 34.6±7.8 versus 8.4±0.4 days; P<0.003). Treatment with pioglitazone significantly suppressed graft expression of interferon-γ and monocyte chemoattractant protein-1. In chronic reje...
Abstract 3712: Optimizing design parameters of a VLA-4-targeted liposomal nanoparticle in a multiple myeloma disease model
Authors: Basar Bilgicer, Tanyel Kiziltepe, David Omstead, Peter Deak
Journal: Cancer Research (2018)

Abstract Ligand-targeted liposomes have garnered interest as drug delivery vehicles for cancer therapy, however they have not consistently produced successful outcomes. These inconsistencies likely arise from differences in disease models and target receptors, as well as from nanoparticle design parameters which can significantly influence therapeutic efficacy. We systematically evaluated the role that peptide-linker length, peptide hydrophilicity, peptide density, and nanoparticle size play on tumor targeting using a multifaceted synthetic strategy to prepare highly controlled and consistent peptide-targeted liposomes. We analyzed these parameters in a VLA-4-expressing multiple myeloma model system where liposomes were functionalized with a VLA-4-antagonist peptide to evaluate in vitro targeting efficiency and in vivo biodistribution and tumor cell uptake. Our studies demonstrated that by increasing the hydrophilicity of the targeting peptide sequence via addition of an oligolysine chain and simultaneously optimizing the EG peptide-linker length, cellular uptake of targeted liposomes was significantly enhanced in vitro. Specifically, the cellular uptake was greatly enhanced for 50-100 nm size liposomes with shorter peptide-linker lengths of EG6 when compared to the industry standard EG45 linker. For in vivo applications, although targeted formulations did not enhance tumor accumulation directly relative to non-targeted formulations, liposomes designed with EG6 linker and an oligolysine chain provided a significant advantage by demonstrating significantly enhanced tumor cell uptake relative to non-targeted liposomes. These results highlighted the importance of creating a comprehensive understanding of the effect of each liposome design parameter on multifactorial biological endpoints in determining the therapeutic potential of peptide-targeted liposomes. Citation Format: Basar Bilgicer, Tanyel Kiziltepe, David Omstead, Peter Deak. Optimizing design parameters of a VLA-4-targeted liposomal nanoparticle in a multiple myeloma disease model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3712.
Abstract 1153: Development and validation of a novel in vitro model of the tumor immune microenvironment
Authors: RUOLAN ZHOU, Rachel Weathered, Luis Alonzo, Renata Mezyk-Kopec, Melody Swartz
Journal: Cancer Research (2018)

Abstract Tumor-associated lymphatics and their connection to the tumor-draining lymph node (TDLN) play important roles in cancer metastasis as well as in modulating the immune microenvironment. They bathe the TDLN in cytokines, exosomes, antigens, and suppressive factors from the tumor microenvironment to alter the anti-tumor immune response. These interactions are difficult to study in vivo, yet currently, these interactions cannot be readily explored in vitro. Here, we developed a perfused paper-based cell culture platform which can recreate the 3-dimensional architecture, stromal component and physiological levels of interstitial flow of the native tissue environment, while keeping the device high-throughput, easy to use, and inexpensive. This platform can sustain the long-term cultures (&amp;gt;3 weeks) of a number of tumor cell lines, which form complex architectures reminiscent of actual tumors, as well as of excised tumor tissue. The platform also supports the function and viability of immune cells (such as T lymphocytes and dendritic cells) and stromal cells (such as lymphatic endothelial cells and fibroblasts). To model the tumor interaction with its TDLN, we created a model in which tumor cells and lymph node stromal cells (LNSC) are cultured in separate but connected compartments under perfusion. To validate this, we have demonstrated preferential tumor migration to preconditioned (vs. unconditioned) LN stroma. The LN stroma compartment also supports co-culture of dendritic cells and T lymphocytes. To validate the modeling of the crosstalk between the tumor and TDLN, we show that tumor conditionioning of the LN primes the LN microenvironment to dampen cytotoxic T cell function. Together, these data highlight the potential of this system for studying complex tumor-host cell interactions in the tumor microenvironment over long periods of time, and paves the way towards an in vitro screening platform for drug screening for drugs that target cells or factors in the tumor microenvironment that serve as barriers to both chemotherapy as well as immunotherapies. Citation Format: RUOLAN ZHOU, Rachel Weathered, Luis Alonzo, Renata Mezyk-Kopec, Melody Swartz. Development and validation of a novel in vitro model of the tumor immune microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1153.