tbuckley/cabot-search huggingface dataset:
Signs of Obstruction of the Superior Longitudinal Sinus following Closed Head Injuries (Traumatic Hydrocephalus)
Authors: J. P. Martin
Journal: BMJ (1955)

<h3>ABSTRACT</h3> The 22q11.2 deletion syndrome (22q11.2DS), associated with congenital and neuropsychiatric anomalies, is the most common copy number variant (CNV)-associated syndrome. Patient-derived, induced pluripotent stem cell (iPS) models have provided important insight into the mechanisms of phenotypic features of this condition. However, patient-derived iPS models may harbor underlying genetic heterogeneity that can confound analysis of pathogenic CNV effects. Furthermore, the ∼1.5 Mb “A-B” deletion at this locus is inherited at higher frequency than the more common ∼3 Mb “A-D” deletion, but remains under-studied due to lack of relevant models. To address these issues, here we leveraged a CRISPR-based strategy in Cas9-expressing iPS cells to engineer novel isogenic models of the 22q11.2 “A-B” deletion. After <i>in vitro</i> differentiation to excitatory neurons, integrated transcriptomic and cell surface proteomics identified deletion-associated alterations in surface adhesion and cell signaling. Furthermore, implantation of iPS-derived neuronal progenitor cells into the cortex of neonatal mice found accelerated neuronal maturation within a relevant microenvironment. Taken together, our results suggest pathogenic mechanisms of the 22q11.2 “A-B” deletion in driving neuronal and neurodevelopmental phenotypes, both <i>in vitro</i> and <i>in vivo</i>. We further propose that the isogenic models generated here will provide a unique resource to study this less-common variant of the 22q11.2 microdeletion syndrome.
New Strategies in Neuroblastoma: Therapeutic Targeting of MYCN and ALK
Authors: Giuseppe Barone, John Anderson, Andrew D.J. Pearson, Kevin Petrie, Louis Chesler
Journal: Clinical Cancer Research (2013)

Clinical outcome remains poor in patients with high-risk neuroblastoma, in which chemoresistant relapse is common following high-intensity conventional multimodal therapy. Novel treatment approaches are required. Although recent genomic profiling initiatives have not revealed a high frequency of mutations in any significant number of therapeutically targeted genes, two exceptions, amplification of the MYCN oncogene and somatically acquired tyrosine kinase domain point mutations in anaplastic lymphoma kinase (ALK), present exciting possibilities for targeted therapy. In contrast with the situation with ALK, in which a robust pipeline of pharmacologic agents is available from early clinical use in adult malignancy, therapeutic targeting of MYCN (and MYC oncoproteins in general) represents a significant medicinal chemistry challenge that has remained unsolved for two decades. We review the latest approaches envisioned for blockade of ALK activity in neuroblastoma, present a classification of potential approaches for therapeutic targeting of MYCN, and discuss how recent developments in targeting of MYC proteins seem to make therapeutic inhibition of MYCN a reality in the clinic.
Comparison of measured exhaled nitric oxide at varying flow rates
Authors: D Menzies
Journal: Thorax (2005)

Altered levels of exhaled nitric oxide (FeNO) have been well documented in a number of conditions, although it is in asthma that this phenomenon has been most extensively investigated.1 Raised FeNO levels in patients with asthma have been correlated not only with other markers of airway inflammation (including induced sputum eosinophil count), but also with airway hyperresponsiveness and response to inhaled corticosteroids.2 Furthermore, the detection of a raised FeNO level has been shown to have a positive predictive value of up to 95% for the diagnosis of asthma.3

A number of …
Effects of nicotinamide and intravenous insulin therapy in newly diagnosed type 1 diabetes.
Authors: J Vidal, M Fernández-Balsells, G Sesmilo, E Aguilera, R Casamitjana, R Gomis, I Conget
Journal: Diabetes Care (2000)

OBJECTIVE: To investigate the effect of intravenous insulin therapy combined with nicotinamide in the metabolic control and beta-cell function of newly diagnosed type 1 diabetic subjects in comparison with intensive insulin therapy and nicotinamide alone. RESEARCH DESIGN AND METHODS: A total of 34 newly diagnosed type 1 diabetic patients were included. After the correction of initial metabolic disturbances, subjects were randomly assigned to the following three groups within 72 h after admission: 1) intensive insulin therapy + placebo (C) (n = 12); 2) intensive insulin therapy + nicotinamide, 700 mg three times a day (NIC) (n = 11); and 3) 72-h intravenous insulin followed by intensive insulin therapy + nicotinamide, 700 mg three times a day (NIV) (n = 11). The subjects were monitored for 12 months. GAD, tyrosine phosphatase antibodies, and insulin autoantibodies were measured. C-peptide was measured basally and after 2, 4, 6, 8, and 10 min of 1 mg intravenous glucagon. HbA1c, glucagon, and antibody measurements were determined initially and at 1, 3, 6, 9, and 12 months. RESULTS: HbA1c values declined to normal after treatment was initiated in all groups and remained not significantly different during the follow-up period. We did not find differences between experimental (NIC and NIV) and placebo (C) groups in terms of beta-cell function, considering basal or glucagon-stimulated C-peptide (maximal stimulated C-peptide and area under the curve [AUC] of C-peptide) values during the follow-up period. After pooling data from the NIC and NIV groups (both including nicotinamide) and comparing it with data from the C group, the results remained unchanged. At diagnosis, GAD positivity was observed in 10 of 12, 8 of 11, and 10 of 11 subjects (NS) in the C, NIC, and NIV groups, respectively, and IA2 positivity was observed in 3 of 12, 4 of 11, and 4 of 11 subjects (NS) in the C, NIC, and NIV groups, respectively. Antibody titers displayed a similar behavior in all groups during the follow-up period. CONCLUSIONS: Our pilot study failed to demonstrate that the addition of 72-h intravenous insulin and nicotinamide to conventional intensive insulin therapy produces any beneficial effect in newly diagnosed type 1 diabetic subjects in terms of beta-cell function and metabolic control.
Self–class I MHC molecules support survival of naive CD8 T cells, but depress their functional sensitivity through regulation of CD8 expression levels
Authors: Kensuke Takada, Stephen C. Jameson
Journal: The Journal of Experimental Medicine (2009)

Previous studies have suggested that naive CD8 T cells require self-peptide–major histocompatability complex (MHC) complexes for maintenance. However, interpretation of such studies is complicated because of the involvement of lymphopenic animals, as lymphopenia drastically alters naive T cell homeostasis and function. In this study, we explored naive CD8 T cell survival and function in nonlymphopenic conditions by using bone marrow chimeric donors and hosts in which class I MHC expression is absent or limited to radiosensitive versus radioresistant cells. We found that long-term survival of naive CD8 T cells (but not CD4 T cells) was impaired in the absence of class I MHC. However, distinct from this effect, class I MHC deprivation also enhanced naive CD8 T cell responsiveness to low-affinity (but not high-affinity) peptide–MHC ligands. We found that this improved sensitivity was a consequence of up-regulated CD8 levels, which was mediated through a transcriptional mechanism. Hence, our data suggest that, in a nonlymphopenic setting, self-class I MHC molecules support CD8 T cell survival, but that these interactions also attenuate naive T cell sensitivity by dynamic tuning of CD8 levels.
Temporal regulation of expression of immediate early and second phase transcripts by endothelin-1 in cardiomyocytes
Authors: Timothy E Cullingford, Thomais Markou, Stephen J Fuller, Alejandro Giraldo, Sampsa Pikkarainen, Georgia Zoumpoulidou, Ali Alsafi, Collins Ekere, Timothy J Kemp, Jayne L Dennis, Laurence Game, Peter H Sugden, Angela Clerk
Journal: Genome biology (2008)

Endothelin-1 stimulates Gq protein-coupled receptors to promote proliferation in dividing cells or hypertrophy in terminally differentiated cardiomyocytes. In cardiomyocytes, endothelin-1 rapidly (within minutes) stimulates protein kinase signaling, including extracellular-signal regulated kinases 1/2 (ERK1/2; though not ERK5), with phenotypic/physiological changes developing from approximately 12 h. Hypertrophy is associated with changes in mRNA/protein expression, presumably consequent to protein kinase signaling, but the connections between early, transient signaling events and developed hypertrophy are unknown. Using microarrays, we defined the early transcriptional responses of neonatal rat cardiomyocytes to endothelin-1 over 4 h, differentiating between immediate early gene (IEG) and second phase RNAs with cycloheximide. IEGs exhibited differential temporal and transient regulation, with expression of second phase RNAs within 1 h. Of transcripts upregulated at 30 minutes encoding established proteins, 28 were inhibited >50% by U0126 (which inhibits ERK1/2/5 signaling), with 9 inhibited 25-50%. Expression of only four transcripts was not inhibited. At 1 h, most RNAs (approximately 67%) were equally changed in total and polysomal RNA with approximately 17% of transcripts increased to a greater extent in polysomes. Thus, changes in expression of most protein-coding RNAs should be reflected in protein synthesis. However, approximately 16% of transcripts were essentially excluded from the polysomes, including some protein-coding mRNAs, presumably inefficiently translated. The phasic, temporal regulation of early transcriptional responses induced by endothelin-1 in cardiomyocytes indicates that, even in terminally differentiated cells, signals are propagated beyond the primary signaling pathways through transcriptional networks leading to phenotypic changes (that is, hypertrophy). Furthermore, ERK1/2 signaling plays a major role in this response.
Wnt3a protects SH-SY5Y cells against 6-hydroxydopamine toxicity by restoration of mitochondria function
Authors: Lei Wei, Li Ding, Ming-shu Mo, Ming Lei, Limin Zhang, Kang Chen, Pingyi Xu
Journal: Translational Neurodegeneration (2015)

Wnt/β-catenin signal has been reported to exert cytoprotective effects in cellular models of several diseases, including Parkinson's disease (PD). This study aimed to investigate the neuroprotective effects of actived Wnt/β-catenin signal by Wnt3a on SH-SY5Y cells treated with 6-hydroxydopamine (6-OHDA).Wnt3a-conditioned medium (Wnt3a-CM) was used to intervene dopaminegic SH-SY5Y cells treated with 6-OHDA. Cell toxicity was determined by cell viability and lactate dehydrogenase leakage (LDH) assay. The mitochondria function was measured by the mitochondrial membrane potential, while oxidative stress was monitored with intracellular reactive oxygen species (ROS). Western blot analysis was used to detect the expression of GSK3β, β-catenin as well as Akt.Our results showed that 100 μM 6-OHDA treated for 24 h significantly decreased cell viability and mitochondrial transmembrane potential, reduced the level of β-catenin and p-Akt, increased LDH leakage, ROS production and the ratio of p-GSK3β (Tyr216) to p-GSK3β (Ser9). However, Wnt3a-conditioned medium reversing SH-SY5Y cells against 6-OHDA-induced neurotoxicity by reversing these changes.Activating of Wnt/β-catenin pathway by Wnt3a-CM attenuated 6-OHDA-induced neurotoxicity significantly, which related to the inhibition of oxidative stress and maintenance of normal mitochondrial function.
Reply
Authors: Phillip Hylemon, Masayuki Nagahashi, Kazuaki Takabe, Huiping Zhou
Journal: Hepatology (2015)

Potential conflict of interest: Nothing to report. Author names in bold designate shared co‐first authorship. We thank Carulli et al. for their great interest in our recent study and insightful comments on bile acid–mediated regulation of lipid metabolism.1 Our study clearly shows that sphingosine‐1 phosphate receptor 2 (S1PR2), which is activated by conjugated bile acids, regulates nuclear sphingosine kinase 2, allowing for the up‐regulation of genes involved in lipid and sterol metabolism by an epigenetic mechanism.1 Conjugated bile acid–mediated activation of S1PR2 may allow for up‐regulation of lipid secretion through very low‐density lipoprotein and increase oxidation of fatty acids (Fig. 1). Intriguingly, S1PR2 also activates the extracellular signal–regulated kinase and AKT signaling pathways, probably through epidermal growth factor receptor.2 Activation of pyruvate dehydrogenase kinase and protein kinase Cζ, a branch of the AKT pathway, is necessary for maximum induction of small heterodimer partner (SHP).3 Watanabe et al. reported that SHP represses sterol regulatory element binding protein 1c, down‐regulating fatty acid and triglyceride synthesis.4 Our study indicated that S1PR2 may function to both increase output of lipids from the liver and decrease lipid synthesis through farnesoid X receptor–SHP induction. Also, S1PR2 appears to help coordinately regulate glucose metabolism as bile acids have been shown to be as potent as insulin in activating AKT and glycogen synthase and down‐regulating gluconeogenesis genes.5 In a feed/fast cycle, conjugated bile acids returning from the intestines probably rapidly activate sphingosine kinase 2, which is required for the induction of genes involved in lipid metabolism and secretion through an epigenetic mechanism. Activation of AKT:pyruvate dehydrogenase kinase:protein kinase Cζ increases the phosphorylation of farnesoid X receptor and allows maximal induction of SHP, a nuclear receptor involved in repressing genes by associating with other nuclear receptors (hepatocyte nuclear factor 4α, liver X receptor, others) and possibly chromatin modifying cofactors. Hence, S1PR2 may play a role in both the induction and the repression of hepatic gene expression, depending upon the time in the feed/fast cycle. Inflammation, which inhibits the insulin signaling pathway (AKT), may disrupt these tightly regulated metabolic regulatory mechanisms, allowing for lipid accumulation and increased risk for nonalcoholic fatty liver disease.Figure 1: Role of sphingosine 1‐phosphate receptor 2 in the regulation of hepatic metabolism. Abbreviations: CBA, conjugated bile acid; ERK, extracellular signal–regulated kinase; FXR, farnesoid X receptor; PDK, pyruvate dehyrdrogenase kinase; PKC, protein kinase C; SHP, small heterodimer partner; SphK2, sphingosine kinase 2; S1PR2, sphingosine‐1 phosphate receptor 2; VLDL, very low‐density lipoprotein.
C-terminally truncated kindlin-1 leads to abnormal adhesion and migration of keratinocytes
Authors: C. Has, R.J. Ludwig, C. Herz, J.S. Kern, S. Ussar, F.R. Ochsendorf, R. Kaufmann, H. Schumann, J. Kohlhase, L. Bruckner-Tuderman
Journal: British Journal of Dermatology (2008)

Background The Kindler syndrome (KS) protein kindlin-1 is a member of a protein complex that links cortical actin to integrins on the surface of basal keratinocytes. Loss of kindlin-1 leads to abnormalities of cell adhesion and motility, and to skin blistering and progressive poikiloderma as clinical symptoms. Objectives Here we investigated a severely affected patient, disclosed the mutation that caused the disease and delineated its biological consequences. Methods Mutation screening of the kindlin-1 gene, KIND1 (now called FERMT1), was performed with polymerase chain reaction (PCR) amplification of all exons and sequencing. Mutated kindlin-1 was characterized by reverse transcriptase (RT)-PCR and immunoblotting, and genotype–phenotype correlations were analysed using immunohistochemical staining of skin biopsies and keratinocytes from the patient’s skin. Cell adhesion and motility were assessed with functional tests. Results We disclosed a splice site mutation in the first position of intron 13 of the FERMT1 gene, which caused skipping of exon 13. The short transcript partially escaped nonsense-mediated mRNA decay and was translated into a truncated protein. Conclusion A C-terminally truncated kindlin-1 in keratinocytes could not function correctly even if it were expressed.
Trigger Activity More Than Three Years After Left Atrial Linear Ablation Without Pulmonary Vein Isolation in Patients With Atrial Fibrillation
Authors: Hildegard Tanner, Gerhard Hindricks, Richard Kobza, Anja Dorszewski, Petra Schirdewahn, Christopher Piorkowski, Jin-Hong Gerds-Li, Hans Kottkamp
Journal: Journal of the American College of Cardiology (2005)
Formation of lipoxins and leukotrienes during receptor-mediated interactions of human platelets and recombinant human granulocyte/macrophage colony-stimulating factor-primed neutrophils.
Authors: S Fiore, C N Serhan
Journal: The Journal of Experimental Medicine (1990)

The generation of lipoxygenase products of arachidonic acid is considered an important event in inflammation. This study demonstrates the levels of both lipoxins and leukotrienes (LTC4, LTD4, LTB4, and omega-oxidized LTB4) generated from endogenous sources of arachidonate by PMN primed with recombinant human granulocyte/macrophage colony-stimulating factor and in coincubations with platelets (1:1 to 1:100 ratio). Upon exposure to receptor-mediated stimuli (FMLP and thrombin), the levels of lipoxins generated were within the range of both LTB4 and LTC4. Co-incubation of [1-14C]arachidonate-labeled platelets with primed polymorphonuclear leukocytes (PMN) followed by addition of thrombin and FMLP led to the formation of both 5- and 15-LO products that carried 14C label. Thus, in addition to the transcellular conversion of LTA4 to platelet-derived lipoxins and LTC4, PMN can use platelet-derived arachidonate to generate lipoxygenase products. These results are the first to document the relationship between the levels of lipoxins and leukotrienes generated by receptor-mediated activation of cytokineprimed PMN interacting with platelets. Moreover, they indicate that PMN-platelet interactions utilize bidirectional transcellular routes to contribute to lipoxin formation.
Regional variation in gene expression in the healthy colon is dysregulated in ulcerative colitis
Authors: C L Noble, A R Abbas, J Cornelius, C W Lees, G-T Ho, K Toy, Z Modrusan, N Pal, F Zhong, S Chalasani, H Clark, I D Arnott, I D Penman, J Satsangi, L Diehl
Journal: Gut (2008)

<h3>Objective:</h3> To investigate differential intestinal gene expression in patients with ulcerative colitis and in controls. <h3>Design:</h3> Genome-wide expression study (41 058 expression sequence tags, 215 biopsies). <h3>Setting:</h3> Western General Hospital, Edinburgh, UK, and Genentech, San Francisco, USA. <h3>Patients:</h3> 67 patients with ulcerative colitis and 31 control subjects (23 normal subjects and 8 patients with inflamed non-inflammatory bowel disease biopsies). <h3>Interventions:</h3> Paired endoscopic biopsies were taken from 5 specific anatomical locations for RNA extraction and histology. The Agilent microarray platform was used and confirmation of results was undertaken by real time polymerase chain reaction and immunohistochemistry. <h3>Results:</h3> In healthy control biopsies, cluster analysis showed differences in gene expression between the right and left colon. (χ<sup>2</sup> = 25.1, p&lt;0.0001). Developmental genes, homeobox protein A13 (HOXA13), (p = 2.3×10<sup>−16</sup>), HOXB13 (p&lt;1×10<sup>−45</sup>), glioma-associated oncogene 1 (GLI1) (p = 4.0×10<sup>−24</sup>), and GLI3 (p = 2.1×10<sup>−28</sup>) primarily drove this separation. When all ulcerative colitis biopsies and control biopsies were compared, 143 sequences had a fold change of &gt;1.5 in the ulcerative colitis biopsies (0.01&gt;p&gt;10<sup>−45</sup>) and 54 sequences had a fold change of &lt;−1.5 (0.01&gt;p&gt;10<sup>−20</sup>). Differentially upregulated genes in ulcerative colitis included serum amyloid A1 (SAA1) (p&lt;10<sup>−45</sup>) the alpha defensins 5 and 6 (DEFA5 and 6) (p = 0.00003 and p = 6.95×10<sup>−7</sup>, respectively), matrix metalloproteinase 3 (MMP3) (p = 5.6×10<sup>−10</sup>) and MMP7 (p = 2.3×10<sup>−7</sup>). Increased DEFA5 and 6 expression was further characterised to Paneth cell metaplasia by immunohistochemistry and in situ hybridisation. Sub-analysis of the inflammatory bowel disease 2 (IBD2) and IBD5 loci, and the ATP-binding cassette (ABC) transporter genes revealed a number of differentially regulated genes in the ulcerative colitis biopsies. <h3>Conclusions:</h3> Key findings are the expression gradient in the healthy adult colon and the involvement of novel gene families, as well as established candidate genes in the pathogenesis of ulcerative colitis.
Genotype-Dependent Induction of Transmissible Chromosomal Instability by γ-Radiation and the Benzene Metabolite Hydroquinone
Authors: I. Duncan Gowans, Sally A. Lorimore, Joanne M. McIlrath, Eric G. Wright
Journal: Cancer Research (2005)

Abstract Although it is well established that ionizing radiation and benzene are epidemiologically linked to acute myeloid leukemia (AML), the underlying mechanisms are not understood. We have shown that γ-radiation can induce a persisting genomic instability in the clonal descendants of hemopoietic stem cells manifested as a high frequency of nonclonal chromosome and chromatid aberrations. A strikingly similar instability is shown after exposure to the benzene metabolite hydroquinone. The CBA/Ca but not the C57BL/6 genotype is susceptible to the induction of instability by both ionizing radiation and hydroquinone and exposure of CBA/Ca, but not C57BL/6, mice to either agent is known to be associated with the development of AML. The results are consistent with the proposal that chromosomal instability induced by either agent may contribute to AML development by increasing the number of genetic lesions in hemopoietic cells. Genotype-dependent chromosomal instability can be induced by hydroquinone doses that are not acutely stem cell toxic and this may have important implications for current assessment of safe levels of exposure to benzene as well as for mechanistic understanding of the hemotoxic and leukemogenic effects.
A pilot study on the effects of pre-event manipulation on jump height and running velocity
Authors: I Shrier, D Macdonald, G Uchacz
Journal: British Journal of Sports Medicine (2006)

Purpose: To compare changes in jump height and running velocity with and without pre-event high-velocity, low-amplitude manipulation (HVLA). Methods: A crossover study design with elite healthy athletes was used. After a 15 min warm-up, the subjects were tested for countermovement jump height (CMJ) and flying 40 m sprint time (SPRINT). A sport chiropractor then evaluated each subject. Subjects were randomised to either HVLA (applied to joints based on examination) or placebo (simulated performance-enhancement stickers). They then rested for 60 min, performed another 15 min warm-up, and were retested. The protocol was repeated 48 h later with the alternative intervention. The mean of two sprints and three jumps were analysed, as well as peak performances. The sample size was based on prior results from the effects of stretching. Results: 19 subjects involved in sprint sports were enrolled; two were too sore to participate on day 2, and one could only participate in the jump (all had HVLA on day 1). Of the 17 participants analysed, seven were female, age range was 19–35, and 17 were national or world-class athletes. The ranges for baseline measures were: SPRINT 4.1–5.5 s; CMJ 47.4–92.7 cm. Overall, the greater than expected variability in this pilot study led to the study being underpowered. Subjects tended to perform better after HVLA for both CMJ and SPRINT (both mean and peak results), but none of the results were statistically significant (p = 0.30–0.61). Conclusion: Although the larger than expected variability in the pilot study means that the observed clinically relevant differences were not statistically significant, the direction and magnitude of the changes associated with HVLA suggest that it may be beneficial. That said, the increased soreness after HVLA suggests that it may be detrimental. HVLA warrants further study.