tbuckley/cabot-search huggingface dataset:
Syntheses and Discovery of a Novel Class of Cinnamic Hydroxamates as Histone Deacetylase Inhibitors by Multimodality Molecular Imaging in Living Subjects
Authors: C.T. Chan, J. Qi, W. Smith, R. Paranol, R. Mazitschek, N. West, R. Reeves, G. Chiosis, S.L. Schreiber, J.E. Bradner, R. Paulmurugan, S.S. Gambhir
Journal: Cancer Research (2014)

Abstract Histone deacetylases (HDAC) that regulate gene expression are being explored as cancer therapeutic targets. In this study, we focused on HDAC6 based on its ability to inhibit cancerous Hsp90 chaperone activities by disrupting Hsp90/p23 interactions. To identify novel HDAC6 inhibitors, we used a dual-luciferase reporter system in cell culture and living mice by bioluminescence imaging (BLI). On the basis of existing knowledge, a library of hydrazone compounds was generated for screening by coupling cinnamic hydroxamates with aldehydes and ketones. Potency and selectivity were determined by in vitro HDAC profiling assays, with further evaluation to inhibit Hsp90(α/β)/p23 interactions by BLI. In this manner, we identified compound 1A12 as a dose-dependent inhibitor of Hsp90(α/β)/p23 interactions, UKE-1 myeloid cell proliferation, p21waf1 upregulation, and acetylated histone H3 levels. 1A12 was efficacious in tumor xenografts expressing Hsp90(α)/p23 reporters relative to carrier control–treated mice as determined by BLI. Small animal 18F-FDG PET/CT imaging on the same cohort showed that 1A12 also inhibited glucose metabolism relative to control subjects. Ex vivo analyses of tumor lysates showed that 1A12 administration upregulated acetylated-H3 by approximately 3.5-fold. Taken together, our results describe the discovery and initial preclinical validation of a novel selective HDAC inhibitor. Cancer Res; 74(24); 7475–86. ©2014 AACR.
Management of uninvestigated dyspepsia: review and commentary
Authors: A Axon
Journal: Gut (2002)

Up to 40% of individuals complain of dyspepsia but only 25% of these present to their general practitioner. If symptoms have been present for a relatively short period the majority can be managed by reassurance and symptomatic treatment. Those with a longer history require empirical treatment with more powerful medication, endoscopy, testing for <i>Helicobacter pylori</i>, or a combination of these approaches. There is some debate about whether the treatment of <i>Helicobacter pylori</i> infection is an appropriate strategy for patients with dyspepsia. It is the general practitioner who determines how the uninvestigated patient with dyspepsia will be managed because those referred to hospital usually undergo endoscopy at an early stage.
World-class performance in lightweight rowing: is it genetically influenced? A comparison with cyclists, runners and non-athletes: Table 1
Authors: Carlos A Muniesa, Marta González-Freire, Catalina Santiago, José I Lao, Amaya Buxens, Juan C Rubio, Miguel A Martín, Joaquín Arenas, Felix Gomez-Gallego, Alejandro Lucia
Journal: British Journal of Sports Medicine (2008)

In this study, genotype frequencies of several polymorphisms that are candidates to influence sports performance (ie, ACTN3 R577X, ACE ID, PPARGC1A Gly482Ser, AMPD1 C34T, CKMM 985bp/1170bp and GDF8 (myostatin) K153R) were compared in 123 nonathletic controls, 50 professional cyclists, 52 Olympicclass runners and 39 world-class rowers (medallists in world championships, lightweight category). Significant differences in genotype distributions among the groups were not found except for the ACE gene, that is, lower (p&lt;0.05) proportion of II in rowers (10.3%) than in the total subject population (22.3%). In summary, sports performance is likely polygenic with the combined effect of hundreds of genetic variants, one possibly being the ACE ID polymorphism (at least in the sports studied here), but many others remain to be identified.
Epithelial barrier formation by airway basal cells
Authors: J. S. Erjefalt, F. Sundler, C. G. Persson
Journal: Thorax (1997)

BACKGROUND: Epithelial shedding processes in airway inflammation and defence may produce damaged areas where basal cells are the main remaining epithelial cell type. The present study examines the capacity of basal cells to form an epithelial barrier structure after loss of columnar epithelial cells. METHODS: A technique was developed which allows selective removal of columnar epithelial cells from isolated airways. A drop of tissue adhesive glue was applied on the mucosal surface shortly after excision of guinea pig trachea and human bronchus. Gentle removal of the glue, together with attached columnar cells, left a single layer of cobbled, solitary basal cells. The tissue was kept in culture media. Morphological changes of the basal cells were monitored by immuno-histochemistry and scanning and transmission electron microscopy at several time points. RESULTS: After 20 minutes the basal cells had undergone extensive flattening and established contact with each other. The basement membrane thus became covered by a poorly differentiated epithelium in both guinea pig and human airways. Abundant interdigitating cytoplasmic protrusions were observed at cell borders. CONCLUSIONS: Basal cells promptly flatten out to cover the basement membrane at loss of neighbouring columnar cells. These data may explain why the epithelial barrier function may be uncompromised in desquamative airway diseases. Furthermore, they suggest the possibility that sacrificial release of columnar epithelial cells and prompt creation of a barrier structure constitute important roles of basal cells in airway defence against severe insults.
In Reference to Maschio et al. (Neuro-Oncology. 2008;10:106–107)
Authors: Ingeborg Bosma, Jan J. Heimans, Martin Klein
Journal: Neuro-Oncology (2008)

nitive function in the course of the disease.Patients were included irrespective of having epilepsy or of the type of AED they were using.Inclusion took place in six centers in the Netherlands, where at the time of inclusion the use of these newer AEDs was not common practice.This means that all of our included patients were receiving mono-or polytherapy treatment with the older AEDs such as valproic acid, carbamazepine, and phenytoin.Because evaluation of the effects of AED treatment was not our primary objective, patients used different dosages of mono-or polytherapy; and because our sample size was rather small, we did not further specify the AED regimes of each patient.On the other hand, it was interesting to find that impaired neurocognitive function in the patients with tumor progression, compared to those without progression, was indeed influenced by the use of AEDs.By adding the sentence in the abstract "the possibility of the deleterious effects is important to consider when prescribing an AED(s)" we do emphasize that this is an important issue in the treatment of brain tumor patients.Recently, we started a longitudinal multicenter trial on the effect of levetiracetam in glioma patients and its effect on neurocognitive function and health-related quality of life.We strongly support the efforts that teams like Maschio and colleagues are making to further investigate the effects of AED treatment in brain tumor patients.We therefore thank Maschio and her team for once more making it clear in their letter that further investigation is needed.
The Probable Destruction of Bacteria in Polluted River Water by Infusoria
Authors: D. H. Attfield
Journal: BMJ (1893)

BACTERIA BY INFUSORIA..JurSE 17, 189& The fact has been assumed-and quite correctly, as the analysis I now submit shows.I happened to be called to a lingering labour, in which I delivered the child with forceps (low operation).The child was a healthy full-time male and was born head first.Im- mediately the breech was expelled, and before any attempt to breathe was made, the child began to micturate.I seized the-penis with one hand and a clean cup with the other, and then caught the remainder of the urine-just over half an ounce.This urine was carefully preserved and analysed.For comparison I obtained another specimen of urine from the same child-6 drachms, passed eight and a half hours later.TABLE I.-Qualitative Analysie.specimen 1.-I ounce.Specimen Il.-6 drachms.Passed immediately after birth, and Eight and a-half hours after before inspiration.birth.Examination showed-EXaMination showed- No sugar.No sugar.No albumen.No albumen.No phosphates.No phosphates.No sulphates.Sulphates present
SIGNS OF MILD TRAUMATIC BRAIN INJURY IN ACTIVE DUTY US MARINES CAN BE MEASURED WITH BRAIN MRI MAGNETO-ENCEPHALOGRAPHY
Authors: E Britt, M Diwaker, D Baker, D Chang, M Huang
Journal: British Journal of Sports Medicine (2014)

Background Concussions are a leading cause of sustained physical, cognitive and emotional impairment in both athletes and military personnel. A pathological feature is disinhibited brain frontal and temporal lobe function, with impaired attention, memory, judgment, emotional regulation and decision-making. Objective Conventional neuroimaging has limited ability to detect structural abnormalities in mTBI. Alternatively, a neuroimaging biomarker using MRI magneto-encephalograpy (MEG) is capable of mapping brain wave activity in mTBI. The objective was to use MEG technology to study brain function during a computerized “Go-No Go” vigilance and reaction test in military personnel. Design Prospective, case series clinical study. Setting Active duty infantrymen from the US Marine Corps explosive ordnance disposal program (high concussion risk). Participants 37 male subjects, tested (summer of 2013) during pre-deployment training at Camp Pendleton, CA. Assessment of risk factors The subjects completed neuroimaging, neurocognitive assessment and clinical interviews. Each provided data on mTBI, post-traumatic stress disorder (PTSD) symptoms, and had a MEG scan while performing the neurocognitive Go-NoGo test. Main outcome measurements 1) Motor cortex, frontal and temporal lobe activation, 2) commission errors (reacting when not supposed to), 3) PTSD and mTBI scoring. Results The Go stimulus activated the motor cortex exclusively, while the NoGo stimulus activated the dorsolateral prefrontal cortex (DLPFC) and left mediolateral temporal lobe (MLTL) exclusively. There were statistically significant negative correlations between: DLPFC and commission errors, and MLTL and Clinican-Administered PTSD scale. Conclusions MEG imaging showed regional brain activation patterns during functional tests requiring the individual to act, or to repress action. Lower activation of the frontal and temporal lobes was associated with more errors of inhibition, and greater fear symptoms. These structure-function relationships of the brain may be useful to predict concussion risk or monitor recovery. The subjects were deployed overseas (Fall 2013), and will be retested post-deployment (expected Spring 2015).
Circulating and Urinary Transforming Growth Factor β1, Amadori Albumin, and Complications of Type 1 Diabetes
Authors: Nish Chaturvedi, Casper G. Schalkwijk, Heidemarie Abrahamian, John H. Fuller, Coen D.A. Stehouwer
Journal: Diabetes Care (2002)

OBJECTIVE—Transforming growth factor (TGF)-β1 is overexpressed in diabetes as a consequence of hyperglycemia and the creation of early glycated end products and may be responsible for the characteristic structural renal changes associated with diabetes. We sought to examine the role of both urinary and circulating TGF-β1 and its promoter Amadori albumin in the vascular complications of type 1 diabetes. RESEARCH DESIGN AND METHODS—The present article reports on a nested case-control study from the EURODIAB Prospective Complications Study of Europeans with type 1 diabetes. Case subjects (n = 356) were all individuals with one or more complications of diabetes; control subjects (n = 185) were all individuals with no evidence of complications. RESULTS—Urinary TGF-β1 and Amadori albumin were elevated in patients with micro- or macroalbuminuria. Standardized regression effects (SREs) for macroalbuminuria versus normoalbuminuria were 2.45 (95% CI 1.88–3.18, P = 0.0001 for urinary TGF-β1) and 1.67 (1.34–2.07, P = 0.001 for Amadori albumin). The SRE for urinary TGF-β1 remained statistically significant when adjusted for HbA1c, Amadori albumin, and blood pressure. Circulating TGF-β1 was elevated in individuals with proliferative retinopathy compared with individuals without retinopathy (SRE 1.29 [1.07–1.550], P = 0.007). This result was attenuated to 1.16 (0.95–1.43, P = 0.2) in the multivariate model, largely because of HbA1c. CONCLUSIONS—Elevated levels of urinary TGF-β1 in macroalbuminuria were associated with elevations in Amadori albumin and HbA1c and also in blood pressure. In contrast, only circulating TGF-β1 was related to proliferative retinopathy, and HbA1c largely accounted for this. These findings may indicate novel pathways for understanding mechanisms and therapeutic interventions.
Walter Graham Harris
Authors: N G. Graham
Journal: BMJ (2005)

Consultant general surgeon Huddersfield Hospitals 1966-88 (b Swindon Village, Gloucestershire, 1928; q St Bartholomew's Hospital 1955; FRCS), died from cerebrovascular disease on 29 April 2005.​2005.




Figure 1




Graham was senior registrar at the Leeds and Bradford teaching hospitals from 1961 to 1966 and then a progressive general surgeon in Huddersfield, embracing all aspects of general surgery, with a particular interest and expertise in breast surgery. He created a specialist breast surgical clinic in Huddersfield in 1966 and was chosen to lead one of the four breast screening units in the United Kingdom during the 1970s, which were subsequently “rolled out” through the NHS. In 1970 he was elected president of the Honley Male Voice Choir. He took early retirement after a heart attack but continued to enjoy his music and developed his hobby as a caterer. He leaves a wife, Patricia; five children; and 11 grandchildren.
Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial
Authors: George D Demetri, Peter Reichardt, Yoon-Koo Kang, Jean-Yves Blay, Piotr Rutkowski, Hans Gelderblom, Peter Hohenberger, Michael Leahy, Margaret von Mehren, Heikki Joensuu, Giuseppe Badalamenti, Martin Blackstein, Axel Le Cesne, Patrick Schöffski, Robert G Maki, Sebastian Bauer, Binh Bui Nguyen, Jianming Xu, Toshirou Nishida, John Chung, Christian Kappeler, Iris Kuss, Dirk Laurent, Paolo G Casali
Journal: The Lancet (2012)
Single-cell genotyping demonstrates complex clonal diversity in acute myeloid leukemia
Authors: Amy L. Paguirigan, Jordan Smith, Soheil Meshinchi, Martin Carroll, Carlo Maley, Jerald P. Radich
Journal: Science Translational Medicine (2015)

Clonal evolution in cancer-the selection for and emergence of increasingly malignant clones during progression and therapy, resulting in cancer metastasis and relapse-has been highlighted as an important phenomenon in the biology of leukemia and other cancers. Tracking mutant alleles to determine clonality from diagnosis to relapse or from primary site to metastases in a sensitive and quantitative manner is most often performed using next-generation sequencing. Such methods determine clonal frequencies by extrapolation of allele frequencies in sequencing data of DNA from the metagenome of bulk tumor samples using a set of assumptions. The computational framework that is usually used assumes specific patterns in the order of acquisition of unique mutational events and heterozygosity of mutations in single cells. However, these assumptions are not accurate for all mutant loci in acute myeloid leukemia (AML) samples. To assess whether current models of clonal diversity within individual AML samples are appropriate for common mutations, we developed protocols to directly genotype AML single cells. Single-cell analysis demonstrates that mutations of FLT3 and NPM1 occur in both homozygous and heterozygous states, distributed among at least nine distinct clonal populations in all samples analyzed. There appears to be convergent evolution and differential evolutionary trajectories for cells containing mutations at different loci. This work suggests an underlying tumor heterogeneity beyond what is currently understood in AML, which may be important in the development of therapeutic approaches to eliminate leukemic cell burden and control clonal evolution-induced relapse.
Generation of idiotype-specific T cell help through network perturbation.
Authors: K Gleason, S Pierce, H Köhler
Journal: The Journal of Experimental Medicine (1981)

Different manipulations of BALB/c mice were used to generate idiotype-specific help: neonatally induced suppression of the T 15 idiotype and low-dose priming with anti-T15 antibody. The splenic foci culture system was used to study T15-idiotype-recognizing helper T cells under limiting-cell-dose conditions. These treatments induced T15 idiotype-specific help for B cells responding to TNP-T15. Normal or hemocyanin-primed BALB/c mice did not supply T15 idiotype-specific help. The helper cells were sensitive to anti-Thy-1.2 and complement treatment and can distinguish T15 from an idiotype-different, PC-binding myeloma protein, M167, and the TNP binding myeloma protein, M460. These data show that idiotype-specific T helper cells can be induced by at least two different manipulations of the idiotype network. These manipulations presumably do not act directly on the T15-recognizing T cells, but must involve complementary idiotypic circuits that stimulate anti-T15 specific T cells. Furthermore, this study demonstrates that the splenic-fragment culture technique provides a general method to investigate, at the single cell level, idiotypic T-B cell interactions induced by perturbations of the immune network.
Listening to music helps reduce pain and anxiety after surgery, review shows:
Authors: Susan Mayor
Journal: BMJ (2015)

Listening to music before, during, or after surgery notably decreases patients’ pain and anxiety and reduces their use of analgesic drugs, a review published in the Lancet has shown.1

Use of music has a long history of improving patients’ experience of being in hospital, and studies have shown positive effects on postoperative recovery. But no comprehensive review has previously studied its use in different types of …
Werner Syndrome Helicase Has a Critical Role in DNA Damage Responses in the Absence of a Functional Fanconi Anemia Pathway
Authors: Monika Aggarwal, Taraswi Banerjee, Joshua A. Sommers, Chiara Iannascoli, Pietro Pichierri, Robert H. Shoemaker, Robert M. Brosh
Journal: Cancer Research (2013)

Werner syndrome is genetically linked to mutations in WRN that encodes a DNA helicase-nuclease believed to operate at stalled replication forks. Using a newly identified small-molecule inhibitor of WRN helicase (NSC 617145), we investigated the role of WRN in the interstrand cross-link (ICL) response in cells derived from patients with Fanconi anemia, a hereditary disorder characterized by bone marrow failure and cancer. In FA-D2(-/-) cells, NSC 617145 acted synergistically with very low concentrations of mitomycin C to inhibit proliferation in a WRN-dependent manner and induce double-strand breaks (DSB) and chromosomal abnormalities. Under these conditions, ataxia-telangiectasia mutated activation and accumulation of DNA-dependent protein kinase, catalytic subunit pS2056 foci suggested an increased number of DSBs processed by nonhomologous end-joining (NHEJ). Rad51 foci were also elevated in FA-D2(-/-) cells exposed to NSC 617145 and mitomycin C, suggesting that WRN helicase inhibition interferes with later steps of homologous recombination at ICL-induced DSBs. Thus, when the Fanconi anemia pathway is defective, WRN helicase inhibition perturbs the normal ICL response, leading to NHEJ activation. Potential implication for treatment of Fanconi anemia-deficient tumors by their sensitization to DNA cross-linking agents is discussed.
Secreted Semaphorin 5A Activates Immune Effector Cells and Is a Biomarker for Rheumatoid Arthritis
Authors: Christiane Gras, Britta Eiz‐Vesper, Yarua Jaimes, Stephan Immenschuh, Roland Jacobs, Torsten Witte, Rainer Blasczyk, Constança Figueiredo
Journal: Arthritis & Rheumatology (2014)

To investigate the role of the multifunctional protein semaphorin 5A (Sema5A) in modulating cellular immune responses and as a biomarker in rheumatoid arthritis (RA).A soluble form of recombinant Sema5A was used to assess its effect on the functions of primary T cells and natural killer (NK) cells isolated from the peripheral blood of healthy donors. Cell proliferation and expression of transcription factors were determined by flow cytometry. Cytokine secretion was analyzed using Luminex technology. Serum samples obtained from 145 patients with RA and control serum samples obtained from healthy individuals or patients with non-RA rheumatic diseases were analyzed for the presence of secreted Sema5A, using enzyme-linked immunosorbent assays and immunoblotting.Soluble Sema5A strongly increased T cell and NK cell proliferation and induced the secretion of proinflammatory Th1/Th17 cytokines. Accordingly, Sema5A stimulation caused significant up-regulation of T-bet and retinoic acid receptor-related orphan nuclear receptor γt levels in T cells. In addition, significantly elevated levels of secreted Sema5A were detected in the serum of patients with RA compared with control serum. Sema5A levels were highest in patients with RA who were positive for the RA biomarker anti-cyclic citrullinated peptide (P < 0.001 versus patients with systemic lupus erythematosus and patients with Sjögren's syndrome) and correlated with the levels of rheumatoid factor.Soluble Sema5A is a potent activator of T cells and NK cells in vitro, and high serum levels of Sema5A are associated with RA. Taken together, the results indicate that Sema5A contributes to the pathogenesis of RA through antigen-independent T cell and NK cell activation. Hence, Sema5A is a promising complementary biomarker for the diagnosis of RA.