tbuckley/cabot-search huggingface dataset:
MicroRNA-155 as an inducer of apoptosis and cell differentiation in Acute Myeloid Leukaemia
Authors: Catalina A Palma, Dima Al Sheikha, Teck Khai Lim, Adam Bryant, Thi Thanh Vu, Vivek Jayaswal, David D F Ma
Journal: Molecular Cancer (2014)

Acute myeloid leukaemia (AML) is characterised by the halt in maturation of myeloid progenitor cells, combined with uncontrolled proliferation and abnormal survival, leading to the accumulation of immature blasts. In many subtypes of AML the underlying causative genetic insults are not fully described. MicroRNAs are known to be dysregulated during oncogenesis. Overexpression of miR-155 is associated with some cancers, including haematological malignancies, and it has been postulated that miR-155 has an oncogenic role. This study investigated the effects of modulating miR-155 expression in human AML cells, and its mechanism of action. Analysis of miR-155 expression patterns in AML patients found that Fms-like tyrosine kinase 3 (FLT3)-wildtype AML has the same expression level as normal bone marrow, with increased expression restricted to AML with the FLT3-ITD mutation. Induction of apoptosis by cytarabine arabinoside or myelomonocytic differentiation by 1,23-dihydroxyvitaminD3 in FLT3-wildtype AML cells led to upregulated miR-155 expression. Knockdown of miR-155 by locked nucleic acid antisense oligonucleotides in the FLT3-wildtype AML cells conferred resistance to cytarabine arabinoside induced apoptosis and suppressed the ability of cells to differentiate. Ectopic expression of miR-155 in FLT3-wildtype AML cells led to a significant gain of myelomonocytic markers (CD11b, CD14 and CD15), increase in apoptosis (AnnexinV binding), decrease in cell growth and clonogenic capacity. In silico target prediction identified a number of putative miR-155 target genes, and the expression changes of key transcription regulators of myeloid differentiation and apoptosis (MEIS1, GF1, cMYC, JARID2, cJUN, FOS, CTNNB1 and TRIB2) were confirmed by PCR. Assessment of expression of apoptosis-related proteins demonstrated a marked increase in cleaved caspase-3 expression confirming activation of the apoptosis cascade. This study provides evidence for an anti-leukaemic role for miR-155 in human FLT3-wildtype AML, by inducing cell apoptosis and myelomonocytic differentiation, which is in contrast to its previously hypothesized role as an oncogene. This highlights the complexity of gene regulation by microRNAs that may have tumour repressor or oncogenic effects depending on disease context or tissue type.
Should stroke medicine be a separate subspecialty?
Authors: R L. Hewer, G. J Hankey, R A Rosin
Journal: BMJ (1998)

Introduction: The medical laboratory professional workforce shortage in the United States has been documented through several national survey reports that also describe the use of temporary staffing to fill vacancies. The primary study objectives were to determine the extent of the workforce shortage in Montana and describe the usage of temporary staffing to fill vacancies. Study Objectives: The study objectives were: 1) Identify Montana CLIA laboratories by geographical area classification, 2) Identify usage of temporary medical laboratory professionals based on laboratory type, 3) Determine wage differences between full time/part time permanent employees versus temporary medical laboratory professionals, 4) Determine the usage rates of temporary medical laboratory professionals, 5) Identify the cause(s) for usage of temporary staffing, and 6) Determine the length of time to fill vacancies. Method: An electronic survey comprised of multiple choice, dichotomous, short answer and open-ended questions was developed to collect qualitative and quantitative data and was distributed via email. Results: The survey was sent to 83 facilities, with a 54% (n=45) response rate. Of respondents, 49% (n=22) reported employing temporary staffing, and 51% (n=23) do not employ temporary staffing. The reasons for hiring temporary staffing included: unable to fill the position (62%), medical leave (13%), vacation (10%), and other reasons such as deployment, maternity leave, short-staffed, administrative projects (15%). Of the 22 facilities employing temporary staffing, 45% (n=10) have a temporary staffing budget line item. Conclusion: The survey results indicated there is a medical laboratory professional shortage in Montana, and compared to the national rate, the usage of temporary staffing is higher, and vacancies take longer to fill by up to two years. The usage of temporary staffing is more than twice as high compared to national survey rates. The state specific data obtained from this study provided vital information to the Montana clinical laboratory community and could serve as an impetus to work collaboratively to explore solutions to the shortage based on state specific needs. The survey design can also serve as an example for other states to conduct similar studies to gather state specific information versus national survey aggregate data.
Proteasome β Subunit Pharmacogenomics: Gene Resequencing and Functional Genomics
Authors: Liewei Wang, Shaji Kumar, Brooke L. Fridley, Krishna R. Kalari, Irene Moon, Linda L. Pelleymounter, Michelle A.T. Hildebrandt, Anthony Batzler, Bruce W. Eckloff, Eric D. Wieben, Philip R. Greipp
Journal: Clinical Cancer Research (2008)

The proteasome is a multisubunit cellular organelle that functions as a nonlysosomal threonine protease. Proteasomes play a critical role in the degradation of proteins, regulating a variety of cellular processes, and they are also the target for antineoplastic proteasome inhibitors. Genetic variation in proteasome subunits could influence both proteasome function and response to drug therapy.We resequenced genes encoding the three active proteasome beta subunits using 240 DNA samples from four ethnic groups and the beta 5 subunit gene in 79 DNA samples from multiple myeloma patients who had been treated with the proteasome inhibitor bortezomib. Resequencing was followed by functional studies of polymorphisms identified in the coding region and 3'-flanking region (3'-FR) of PSMB5, the gene encoding the target for clinically useful proteasome inhibitors.Resequencing of 240 DNA samples identified a series of novel ethnic-specific polymorphisms that are not represented in public databases. The PSMB5 3'-FR 1042 G allele significantly increased transcription during reporter gene studies, observations confirmed by genotype-phenotype correlations between single nucleotide polymorphisms (SNP) in PSMB5 and mRNA expression in the 240 lymphoblastoid cell lines from which the resequenced DNA was obtained. Studies with patient DNA samples identified additional novel PSMB5 polymorphisms, including a SNP and an insertion in the 3'-FR. Reporter-gene studies indicated that these two novel polymorphisms might decrease transcription.These results show that nonsynonymous coding SNPs in the PSMB5 gene did not show significant effects on proteasome activity, but SNPs did influence transcription. Future studies might focus on regulatory region polymorphisms.
Vitamin C Antagonizes the Cytotoxic Effects of Antineoplastic Drugs
Authors: Mark L. Heaney, Jeffrey R. Gardner, Nicos Karasavvas, David W. Golde, David A. Scheinberg, Emily A. Smith, Owen A. O'Connor
Journal: Cancer Research (2008)

Abstract Vitamin C is an antioxidant vitamin that has been hypothesized to antagonize the effects of reactive oxygen species–generating antineoplastic drugs. The therapeutic efficacy of the widely used antineoplastic drugs doxorubicin, cisplatin, vincristine, methotrexate, and imatinib were compared in leukemia (K562) and lymphoma (RL) cell lines with and without pretreatment with dehydroascorbic acid, the commonly transported form of vitamin C. The effect of vitamin C on viability, clonogenicity, apoptosis, P-glycoprotein, reactive oxygen species (ROS), and mitochondrial membrane potential was determined. Pretreatment with vitamin C caused a dose-dependent attenuation of cytotoxicity, as measured by trypan blue exclusion and colony formation after treatment with all antineoplastic agents tested. Vitamin C given before doxorubicin treatment led to a substantial reduction of therapeutic efficacy in mice with RL cell–derived xenogeneic tumors. Vitamin C treatment led to a dose-dependent decrease in apoptosis in cells treated with the antineoplastic agents that was not due to up-regulation of P-glycoprotein or vitamin C retention modulated by antineoplastics. Vitamin C had only modest effects on intracellular ROS and a more general cytoprotective profile than N-acetylcysteine, suggesting a mechanism of action that is not mediated by ROS. All antineoplastic agents tested caused mitochondrial membrane depolarization that was inhibited by vitamin C. These findings indicate that vitamin C given before mechanistically dissimilar antineoplastic agents antagonizes therapeutic efficacy in a model of human hematopoietic cancers by preserving mitochondrial membrane potential. These results support the hypothesis that vitamin C supplementation during cancer treatment may detrimentally affect therapeutic response. [Cancer Res 2008;68(19):8031–8]
Abdominal delivery in the 16th century
Authors: H. Reiss
Journal: Journal of the Royal Society of Medicine (2003)

Dr Loudon (May 2003 JRSM1), discussing the operation on Marguerite of Vienna after a 5-year pregnancy, proposes that it was an abdominal delivery rather than a caesarean section. The concept that some of the early so-called caesarean sections were in fact abdominal deliveries of an advanced extrauterine pregnancy is mentioned by O'Dowd and Philipp2 in their comprehensive chapter on the history of the operation, and the subject was discussed by Gordon King in an oration 50 years ago. 3 King, who was professor of obstetrics and gynaecology from 1939 to 1954 at the University of Hong Kong, detailed the history and classification of advanced extrauterine pregnancies and of abdominal delivery, and reported his personal experience of 12 cases. Before the advent of modern diagnostic techniques, the history of malpresentation, false labour, abdominal delivery, survival of the mother (and occasionally the baby) and subsequent normal deliveries was all important. Often there had been severe abdominal pain or bleeding in early pregnancy. The history of Elizabeth, wife of the Austrian swineherd Jacob Nufer, in the year 1500 fits these criteria. Used to gelding pigs, Nufer delivered his wife with the tools of his trade, by abdominal section, after ineffectual labour and lack of help from 13 midwives and several lithotomists. This report of abdominal delivery predates Dr Loudon's case by some 50 years. Moreover, it is the first case in which the baby survived as well as the mother, who subsequently gave birth normally to one set of twins and four singletons. Even if a woman had escaped death from haemorrhage or infection to survive caesarean section in those days, it is inconceivable that she could have had so many subsequent vaginal deliveries without uterine rupture.
Region-specific dendritic simplification induced by Aβ, mediated by tau via dysregulation of microtubule dynamics: a mechanistic distinct event from other neurodegenerative processes
Authors: Nataliya Golovyashkina, Lorène Penazzi, Carlo Ballatore, Amos B. Smith, Lidia Bakota, Roland Brandt
Journal: Molecular Neurodegeneration (2015)

Dendritic simplification, a key feature of the neurodegenerative triad of Alzheimer's disease (AD) in addition to spine changes and neuron loss, occurs in a region-specific manner. However, it is unknown how changes in dendritic complexity are mediated and how they relate to spine changes and neuron loss. To investigate the mechanisms of dendritic simplification in an authentic CNS environment we employed an ex vivo model, based on targeted expression of enhanced green fluorescent protein (EGFP)-tagged constructs in organotypic hippocampal slices of mice. Algorithm-based 3D reconstruction of whole neuron morphology in different hippocampal regions was performed on slices from APPSDL-transgenic and control animals. We demonstrate that induction of dendritic simplification requires the combined action of amyloid beta (Aβ) and human tau. Simplification is restricted to principal neurons of the CA1 region, recapitulating the region specificity in AD patients, and occurs at sites of Schaffer collateral input. We report that γ-secretase inhibition and treatment with the NMDA-receptor antagonist, CPP, counteract dendritic simplification. The microtubule-stabilizing drug epothilone D (EpoD) induces simplification in control cultures per se. Similar morphological changes were induced by a phosphoblocking tau construct, which also increases microtubule stability. In fact, low nanomolar concentrations of naturally secreted Aβ decreased phosphorylation at S262 in a cellular model, a site which is known to directly modulate tau-microtubule interactions. The data provide evidence that dendritic simplification is mechanistically distinct from other neurodegenerative events and involves microtubule stabilization by dendritic tau, which becomes dephosphorylated at certain sites. They imply that treatments leading to an overall decrease of tau phosphorylation might have a negative impact on neuronal connectivity.
Personal Views: Rugby union should ban contested scrums
Authors: James B Bourke
Journal: BMJ (2006)

For 30 years I have been an honorary medical officer to Nottingham Rugby Football Club. In this time I have attended about 25 games a season and on many occasions have been the “duty doctor,” either officially or unofficially. In that time four players have been removed from the field of play at Nottingham with serious neck injuries. Three of the injuries were associated with scrums, and one occurred in a tackle. All four players had initial sensory and motor impairment. Two recovered within minutes or hours; one recovered in days; and one became paraplegic. Three needed an operation for fracture. Another three Nottingham players injured their necks in scrums while playing away from home and needed to be removed from the pitch. One player needed an operation and is paraplegic. Therefore I have experience of seven serious spinal cord injuries, five of which have required an operation. Two of the players are wheelchair dependent. Six of the seven injuries were related to the scrum, and in all cases the scrums were of the contested type—in which each set of forwards tries to shove the opponents off the ball—and that is more dangerous than the uncontested scrum, in which the players are not allowed to push their opponents away from the spot where the scrum occurs.
Role of Vα 14 NKT cells in the development of impaired liver regeneration in vivo
Authors: H Ito
Journal: Hepatology (2003)

Although we have previously demonstrated that IL-12 stimulation increases the number of hepatic natural killer (NK) T (NKT) cells and enhances liver injury during the early phase of liver regeneration, the role of NKT cells has remained unknown. We therefore evaluated the influence of NKT cells activated by IL-12 or by alpha-galactosylceramide (alpha-GalCer) on murine liver regeneration using Valpha 14 NKT knockout (Jalpha 281(-/-)) mice. Levels of serum alanine aminotransferase (sALT) 24 hours after partial hepatectomy were enhanced in Jalpha 281(+/+) but not in Jalpha 281(-/-) mice by both procedures. Hepatic NKT cells expressed considerably more interferon (IFN) gamma and tumor necrosis factor alpha (TNF-alpha) messenger RNA (mRNA) after stimulation with both factors in Jalpha 281(+/+) mice. Either anti-IFN-gamma or TNF-alpha antibody inhibited the enhancement of liver injury. Furthermore, recombinant TNF-alpha injection similarly caused injury in hepatectomized livers of both Jalpha 281(+/+) and Jalpha 281(-/-) mice; indeed, adoptively transferred TNF-alpha(+/+) NKT cells enhanced liver injury after hepatectomy in TNF-alpha knockout mice. TNF receptor expressions on hepatocytes increased and peaked 24 hours after partial hepatectomy. In conclusion, simultaneous TNF-alpha synthesis and high levels of TNF receptor expression on hepatocytes cause severe liver damage by activated NKT cells during liver regeneration.
EpiGRAPH: user-friendly software for statistical analysis and prediction of (epi)genomic data
Authors: Christoph Bock, Konstantin Halachev, Joachim Büch, Thomas Lengauer
Journal: Genome biology (2009)

The EpiGRAPH web service http://epigraph.mpi-inf.mpg.de/ enables biologists to uncover hidden associations in vertebrate genome and epigenome datasets. Users can upload sets of genomic regions and EpiGRAPH will test multiple attributes (including DNA sequence, chromatin structure, epigenetic modifications and evolutionary conservation) for enrichment or depletion among these regions. Furthermore, EpiGRAPH learns to predictively identify similar genomic regions. This paper demonstrates EpiGRAPH's practical utility in a case study on monoallelic gene expression and describes its novel approach to reproducible bioinformatic analysis.
Epidermal Growth Factor Impairs the Cytochrome C/Caspase-3 Apoptotic Pathway Induced by Transforming Growth Factorβ in Rat Fetal Hepatocytes Via a Phosphoinositide 3-Kinase–Dependent Pathway
Authors: Isabel Fabregat, Blanca Herrera, Margarita Fernández, Alberto M. Álvarez, Aránzazu Sánchez, César Roncero, Juan-José Ventura, Ángela M. Valverde, Manuel Benito
Journal: Hepatology (2000)

Transforming growth factor β (TGF-β)-mediated apoptosis is one of the major death processes in the liver. We have previously shown that epidermal growth factor (EGF) is an important survival signal for TGF-β-induced apoptosis in fetal hepatocytes (Fabregat et al., FEBS Lett 1996;384:14-18). In this work we have studied the intracellular signaling implicated in the protective effect of EGF. We show here that EGF activates p42 and p44 mitogen-activated protein kinases (MAPK). However, mitogen extracellular kinase (MEK) inhibitors do not block the survival effect of EGF. EGF also activates phosphoinositide 3-kinase (PI 3-kinase) and protein kinase B (PKB/AKT) in these cells. The presence of PI 3-kinase inhibitors blocks the protective effect of EGF on cell viability, DNA fragmentation, and caspase-3 activity. We have found that TGF-β disrupts the mitochondrial transmembrane potential (ΔΨ m ) and activates the release of cytochrome c, this effect being blocked by EGF, via a PI 3-kinase-dependent pathway. A detailed study on bcl-2 superfamily gene expression shows that TGF-β produces a decrease in the messenger RNA (mRNA) and protein levels of bcl-x L , an antiapoptotic member of this family, capable of preventing cytochrome c release. EGF is able to maintain bcl-x L levels even in the presence of TGF-β. PI 3-kinase inhibitors completely block the protective effect of EGF on TGF-β-induced bcl-x L down-regulation. We conclude that PI 3-kinase mediates the survival effect of EGF on TGF-β-induced death by acting upstream from the mitochondrial changes, i.e., preventing bcl-x L down-regulation, cytochrome c release, and activation of caspase-3.
Biosimilars in rheumatology: the wind of change
Authors: Christian K Schneider
Journal: Annals of the Rheumatic Diseases (2013)

The wind of change is blowing in rheumatology -rheumatologists may soon be exposed to "biosimilars" of the medicines they routinely use, since the European Medicines Agency (EMA) has recently issued its final guideline on biosimilar monoclonal antibodies (mAbs),[1] -a product class of utmost importance for rheumatologists -and a biosimilar infliximab is currently under evaluation for marketing authorisation in Europe, [2], and more will come.Rheumatologists, as it appears, are especially challenged these days since many of their patients are already successfully put on a longterm treatment with individualized drug regimens, including biologicals like for example Tumour Necrosis Factor (TNF)-alpha inhibitors.Apparently, introduction of "copy" versions of the medicines they already know may be seen as a critical issue, although economical considerations suggest major cost savings in healthcare, [3]."Concerns", "challenges" and "critical issues": These are terms with which the term "biosimilar" is often combined in papers written by clinicians and discussions at conferences (see for example, [4][5][6]).We read about the "complexity" of biological medicines, and that it is difficult to replicate their exact structure.Also in clinical literature in rheumatology, we read about "small variations" that can impact the activity and function of a biosimilar, and "major safety and efficacy concerns" that have to be addressed before clinicians can use biosimilars, [7].In their review in this issue of the Annals of the Rheumatic Diseases, Thomas Dörner and colleagues report on a roundtable discussion on the advent of biosimilars in rheumatology recently held at the Charité in Berlin (Germany), [8].I note at least one aspect in this review that is worth emphasizingthe paper puts scientific facts into perspective: For example, it reports about the complexities and
Unrecognised ringside concussive injury in amateur boxers
Authors: James M Moriarity, Robert H Pietrzak, Jeffrey S Kutcher, Margaretha Helen Clausen, Kevin McAward, David G Darby
Journal: British Journal of Sports Medicine (2012)

Concussion is common in contact sports such as boxing. Diagnosis of concussion depends on symptom report or recognition of clinical features, and true incidence may be underestimated. Persistent morbidity is a possible risk of repeated or unrecognised concussion. This study aimed to evaluate pre and postbout cognitive performance in motivated amateur boxers in order to detect objective evidence of unrecognised cognitive impairment suggestive of concussive injury.The study employed a prospective and observational design. Participants were amateur boxers who won at least one bout in a single elimination competition. Optimal preparticipation performance using a computerised cognitive assessment tool (CCAT, Axon Sports) and no significant deterioration in cognitive performance within 24 h postbout were required to compete. All boxers were screened for clinical evidence of concussion by a ringside physician.Of approximately 200 competing boxers, 96 were eligible having won at least one of the total 160 bouts. Mean age was 21.3 (SD 1.9) years (range 18.5-29.7). Of these, 17 (10.6%) failed their first postbout CCAT, with 12 (71%) passing a repeat test. Of the five remaining boxers, there were two boxers (1.3% of bouts) not suspected of a concussion after their bouts, who showed evolving slowing in cognitive performance typical of a concussion.Cognitive impairment, as detected by subtle deterioration in reaction time measures, can occur in amateur boxers postbout that is not recognised at ringside. Although the vast majority of bouts were conducted safely, unrecognised injury may occur and be detectable using objective computerised cognitive assessment.
A Phase I Study of Eribulin and Gemcitabine in Patients with Avanced Solid Tumours. a Study of the Princess Margaret Phase Ii Consortium
Authors: R. Goel, S. Lheureux, S.A. Laurie, R.A. Halford, D. Jonker, E.X. Chen, D. Keller, V. Bourada, L. Wang, L.A. Doyle, L.L. Siu, A.M. Oza
Journal: Annals of Oncology (2014)