tbuckley/cabot-search huggingface dataset:
Clinical, functional and radiographic consequences of achieving stable low disease activity and remission with adalimumab plus methotrexate or methotrexate alone in early rheumatoid arthritis: 26-week results from the randomised, controlled OPTIMA study
Authors: Arthur Kavanaugh, Roy M Fleischmann, Paul Emery, Hartmut Kupper, Laura Redden, Benoit Guerette, Sourav Santra, Josef S Smolen
Journal: Annals of the Rheumatic Diseases (2012)

To assess the efficacy and safety of adalimumab plus methotrexate (ADA+MTX) compared with methotrexate monotherapy in achieving stable low disease activity (LDA; disease activity score (DAS28(CRP)) <3.2 at weeks 22 and 26) and clinical, radiographic and functional outcomes in methotrexate-naive patients with early rheumatoid arthritis (RA).1032 patients with active RA were randomly assigned 1:1 to ADA+MTX or placebo plus methotrexate (PBO+MTX) for 26 weeks. Treatment modifications were to be made in a subsequent study period based on the achievement of DAS28(CRP) <3.2 at weeks 22 and 26. Post-hoc analyses compared patients achieving stable remission using DAS28 and 2010 ACR/EULAR criteria with those achieving LDA but not remission.Among patients completing 6 months, 44% (207/466) ADA+MTX versus 24% (112/460) PBO+MTX patients achieved stable LDA at weeks 22 and 26 (p<0.001). Combination therapy was statistically superior to methotrexate in obtaining higher ACR20/50/70 responses, more clinical remissions, greater mean reductions in DAS28(CRP), no radiographic progression, and normal functional status at week 26 (p<0.001 for all). The only factor predicting stable LDA was disease activity at week 12. Patients achieving ACR/EULAR remission, particularly in the PBO+MTX group, had some advantage in radiographic outcomes compared with patients who only achieved LDA (but not remission). The overall frequency of adverse events was comparable between groups. There were more serious infections and deaths in the ADA+MTX group, with a possible age effect.Treatment with ADA+MTX was significantly superior to methotrexate alone with respect to clinical, radiographic and functional outcomes in patients with early active RA. Before initiating treatment with adalimumab, individual patient evaluation of the benefit/risk ratio should be carefully considered.
Temozolomide in Children with progressive low-grade glioma1
Authors: Sridharan Gururangan, Michael J. Fisher, Jeffrey C. Allen, James E. Herndon, Jennifer A. Quinn, David A. Reardon, James J. Vredenburgh, Annick Desjardins, Peter C. Phillips, Melody A. Watral, Jeanne M. Krauser, Allan H. Friedman, Henry S. Friedman
Journal: Neuro-Oncology (2007)

We conducted a phase II study to assess the efficacy of oral temozolomide (TMZ) in children with progressive low-grade glioma. Thirty eligible patients were enrolled on this study. Median age at enrollment was 10 years (range, 4-18 years). Eligible patients received TMZ (200 mg/m(2) per day) by mouth for five days every four weeks. Patients received a median of nine cycles (range, 2-12 cycles) of treatment. Best responses in the 26 patients (86%) with optic pathway glioma (OPG)/pilocytic astrocytoma (PA) included partial response in 3 patients (11%), minor response in 1 (4%), stable disease in 10 (38%), and progressive disease in 12 (46%). Only one of four patients with fibrillary astrocytoma had stable disease for 29 months after TMZ. The overall disease stabilization rate in patients with OPG/PA was 54%, and disease control was maintained for a median interval of 34 months. Seventeen of 26 patients had progressive disease either on or off therapy, and three have died of disease. The two-year progression-free and overall survivals in patients with OPG/PA were 49% (95% CI, 30%-67%) and 96% (95% CI, 89%-100%), respectively. Worst toxicity related to TMZ in all 30 patients included grade 2-4 thrombocytopenia in seven patients, grade 2-4 neutropenia in seven, grade 2 skin rash in one, and intratumor hemorrhage in one. TMZ given in this schedule was successful in stabilizing disease in a significant proportion of the patients with OPG/PA, with manageable toxicity.
RNA-guided CRISPR-Cas technologies for genome-scale investigation of disease processes
Authors: Sean E Humphrey, Andrea L Kasinski
Journal: Journal of Hematology & Oncology (2015)

From its discovery as an adaptive bacterial and archaea immune system, the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas system has quickly been developed into a powerful and groundbreaking programmable nuclease technology for the global and precise editing of the genome in cells. This system allows for comprehensive unbiased functional studies and is already advancing the field by revealing genes that have previously unknown roles in disease processes. In this review, we examine and compare recently developed CRISPR-Cas platforms for global genome editing and examine the advancements these platforms have made in guide RNA design, guide RNA/Cas9 interaction, on-target specificity, and target sequence selection. We also explore some of the exciting therapeutic potentials of the CRISPR-Cas technology as well as some of the innovative new uses of this technology beyond genome editing.
Early Penguin Fossils, Plus Mitochondrial Genomes, Calibrate Avian Evolution
Authors: Kerryn E. Slack, Craig M. Jones, Tatsuro Ando, G. L.(Abby) Harrison, R. Ewan Fordyce, Ulfur Arnason, David Penny
Journal: Molecular Biology and Evolution (2006)

Testing models of macroevolution, and especially the sufficiency of microevolutionary processes, requires good collaboration between molecular biologists and paleontologists. We report such a test for events around the Late Cretaceous by describing the earliest penguin fossils, analyzing complete mitochondrial genomes from an albatross, a petrel, and a loon, and describe the gradual decline of pterosaurs at the same time modern birds radiate. The penguin fossils comprise four naturally associated skeletons from the New Zealand Waipara Greensand, a Paleocene (early Tertiary) formation just above a well-known Cretaceous/Tertiary boundary site. The fossils, in a new genus (Waimanu), provide a lower estimate of 61-62 Ma for the divergence between penguins and other birds and thus establish a reliable calibration point for avian evolution. Combining fossil calibration points, DNA sequences, maximum likelihood, and Bayesian analysis, the penguin calibrations imply a radiation of modern (crown group) birds in the Late Cretaceous. This includes a conservative estimate that modern sea and shorebird lineages diverged at least by the Late Cretaceous about 74 +/- 3 Ma (Campanian). It is clear that modern birds from at least the latest Cretaceous lived at the same time as archaic birds including Hesperornis, Ichthyornis, and the diverse Enantiornithiformes. Pterosaurs, which also coexisted with early crown birds, show notable changes through the Late Cretaceous. There was a decrease in taxonomic diversity, and small- to medium-sized species disappeared well before the end of the Cretaceous. A simple reading of the fossil record might suggest competitive interactions with birds, but much more needs to be understood about pterosaur life histories. Additional fossils and molecular data are still required to help understand the role of biotic interactions in the evolution of Late Cretaceous birds and thus to test that the mechanisms of microevolution are sufficient to explain macroevolution.
Earlier Puberty as a Predictor of Later Onset of Schizophrenia in Women
Authors: R Z Cohen, M V Seeman, A Gotowiec, L Kopala
Journal: American Journal of Psychiatry (1999)

OBJECTIVE: The aim of this study was to determine whether puberty plays a mediating role in onset of schizophrenia. The hypothesis was that there is an inverse relation between age at puberty (menarche) and age at onset in women. METHOD: Competent and consenting individuals with DSM-IV-defined schizophrenia or schizoaffective disorder and their mothers underwent a 45-minute interview to ascertain age at first odd behavior, age at first psychotic symptoms, age at first hospitalization, and ages at various indices of puberty. Information about substance use, head injury, perinatal trauma, and first-degree family history of schizophrenia was also obtained. RESULTS: In the women (N=35), the earlier the age at menarche, the later the ages at both the first psychotic symptoms and the first hospitalization. There was no significant association between puberty and onset in the men (N=45). Other than gender, none of the examined variables played a role in the interaction of puberty and onset of illness. CONCLUSIONS: In women, early puberty (whether through hormonal or social influence) was associated with later onset of schizophrenia. This effect was not found in men; in fact, the trend was in the opposite direction.
Timing of antiepileptic drug withdrawal and long-term seizure outcome after paediatric epilepsy surgery (TimeToStop): a retrospective observational study
Authors: Kim Boshuisen, Alexis Arzimanoglou, J Helen Cross, Cuno SPM Uiterwaal, Tilman Polster, Onno van Nieuwenhuizen, Kees PJ Braun
Journal: The Lancet Neurology (2012)
Combining Genome-Wide Methods to Investigate the Genetic Complexity of Courtship Song Variation in Drosophila melanogaster
Authors: Thomas L. Turner, Paige M. Miller, Veronica A. Cochrane
Journal: Molecular Biology and Evolution (2013)

Little is currently known about the genetic complexity of quantitative behavioral variation, the types of genes involved, or their effects on intermediate phenotypes. Here, we conduct a genome-wide association study of Drosophila melanogaster courtship song variation using 168 sequenced inbred lines, and fail to find highly significant associations. However, by combining these data with results from a well-powered Evolve and Resequence (E&R) study on the same trait, we provide statistical evidence that some power to associate genotype and phenotype is available. Genes that are significant in both analyses are enriched for expression in the nervous system, and affect neural development and synaptic growth when perturbed. Quantitative complementation at one of these loci, Syntrophin-like 1, supports a hypothesis that variation at this locus affects variation in the inter-pulse interval of courtship song. These results suggest that experimental evolution may provide an approach for genome-scale replication in Drosophila.
Somatostatin effect on TNFA receptors in Kupffer cells
Authors: M. Georgiadou, G. Notas, I. Drigiannakis, O. Sfakianaki, M. Frangaki, E. Kouroumalis
Journal: Gut (2011)

<h3>Introduction</h3> Somatostatin is a mediator of immune functions and has been used as an antineoplastic agent in animal models and human neoplasias. We have demonstrated that octreotide-a somatostatin analogue- inhibits only LPS-induced secretion of pro-inflammatory cytokines including tumour necrosis factor (TNF) α by Kupffer cells.12 We therefore tested the hypothesis that somatostatin modulates the expression of TNFα receptors and apoptosis of Kupffer cells. <h3>Methods</h3> Rat Kupffer cells were isolated by centrifugal elutriation. TNFR1 and TNFR2 expression was studied by RT-PCR, quantitative PCR, Western Blot and immunofluorescence before and after octreotide pre-incubation. Apoptosis was assessed by quantitative measurement of cytoplasmic histone-associated DNA fragments (Roche). TNFα mRNa expression was assessed by a semiquantitative PCR and TNFα was measured in cell supernatants by ELISA. <h3>Results</h3> TNFR1 and TNFR2 m RNA are constitutively expressed in Kupffer cells. Octreotide incubation increased both receptors expression with a peak at 6 h and return to basal levels at 24 h. TNFR1 was mostly influenced. However only TNFR2 protein increase was identified by Western blot, while a band at 90 kD was present instead of a band at 55 kD as expected for TNFR1. TNFa mRNA expression and protein secretion was not influenced by octreotide at 24 h. However a significant inhibition was observed at 48 h. TNF had no effect on Kupffer cell apoptosis while octreotide significantly increased their apoptosis and this effect was not influenced by co-incubation with TNFα. <h3>Conclusion</h3> TNFR1 and TNFR2 are constitutively expressed in Kupffer cells and their expression is strongly increased by somatostatin. Moreover somatostatin increases Kupffer cell apoptosis. These findings may in part explain the antineoplasmatic effect of somatostatin.
MUC16 provides immune protection by inhibiting synapse formation between NK and ovarian tumor cells
Authors: Jennifer AA Gubbels, Mildred Felder, Sachi Horibata, Jennifer A Belisle, Arvinder Kapur, Helen Holden, Sarah Petrie, Martine Migneault, Claudine Rancourt, Joseph P Connor, Manish S Patankar
Journal: Molecular Cancer (2010)

Cancer cells utilize a variety of mechanisms to evade immune detection and attack. Effective immune detection largely relies on the formation of an immune synapse which requires close contact between immune cells and their targets. Here, we show that MUC16, a heavily glycosylated 3-5 million Da mucin expressed on the surface of ovarian tumor cells, inhibits the formation of immune synapses between NK cells and ovarian tumor targets. Our results indicate that MUC16-mediated inhibition of immune synapse formation is an effective mechanism employed by ovarian tumors to evade immune recognition.Expression of low levels of MUC16 strongly correlated with an increased number of conjugates and activating immune synapses between ovarian tumor cells and primary naïve NK cells. MUC16-knockdown ovarian tumor cells were more susceptible to lysis by primary NK cells than MUC16 expressing controls. This increased lysis was not due to differences in the expression levels of the ligands for the activating receptors DNAM-1 and NKG2D. The NK cell leukemia cell line (NKL), which does not express KIRs but are positive for DNAM-1 and NKG2D, also conjugated and lysed MUC16-knockdown cells more efficiently than MUC16 expressing controls. Tumor cells that survived the NKL challenge expressed higher levels of MUC16 indicating selective lysis of MUC16(low) targets. The higher csMUC16 levels on the NKL resistant tumor cells correlated with more protection from lysis as compared to target cells that were never exposed to the effectors.MUC16, a carrier of the tumor marker CA125, has previously been shown to facilitate ovarian tumor metastasis and inhibits NK cell mediated lysis of tumor targets. Our data now demonstrates that MUC16 expressing ovarian cancer cells are protected from recognition by NK cells. The immune protection provided by MUC16 may lead to selective survival of ovarian cancer cells that are more efficient in metastasizing within the peritoneal cavity and also at overcoming anti-tumor innate immune responses.
Cytokine patterns in the pathogenesis of human leishmaniasis.
Authors: C Pirmez, M Yamamura, K Uyemura, M Paes-Oliveira, F Conceição-Silva, R L Modlin
Journal: Journal of Clinical Investigation (1993)

The host response to infection appears to be regulated by spe- cific patterns of local cytokine production.In the mouse, resis- tance to many pathogens including Leishmania is associated with a THl cytokine profile, IL-2 and IFN-,y; whereas suscepti- bility to infection is associated with production of TH2 cyto- kines, IL4, IL-5, and IL-10.To determine the cytokine patterns of the local immune response to Leishmania infection in humans, we used the polymerase chain reaction to compare cytokine mRNAs in biopsy specimens of American cutaneous leishmaniasis.In localized cutaneous leishmaniasis and the Montenegro delayed-type hypersensitivity reaction, type 1 cytokine mRNAs such as IL-2, IFN-y, and lymphotoxin were relatively predominant.In the chronic and destructive mucocu- taneous form of leishmaniasis, there was a mixture of type 1 and type 2 cytokines, with a striking abundance of IL4 mRNA in lesions.These results suggest that clinical course of infection with Leishmania braziliensis in man is associated with specific local patterns of cytokine production.(J.Clin.Invest. 1993. 9:1390-1395.)Key words: cytokines -interleukin 4 * leish- maniasis * polymerase chain reaction * T lymphocytes recur or progress as a more chronic form.This scenario is exemplified in the human response to the parasite Leishmania braziliensis.The most common clinical form ofdisease caused by L. braziliensis is localized cutaneous leishmaniasis (LCL),' characterized by single or multiple ulcerated dermal lesions that usually heal spontaneously.However, in 2-5% of LCL patients in Brazil, a chronic mucocutaneous (MCL) form arises in which there is severe and progressive destruction ofthe nasal, oral, and/or pharyngeal mucous membranes.
Chief medical officer post goes to woman for first time
Authors: A. O'Dowd
Journal: BMJ (2011)

The post of chief medical officer for England has been given to Sally Davies, the first time a woman has held the post.

Professor Davies, who has been interim chief medical officer since May last year after Liam Donaldson stepped down, is the 16th person to hold the post since it was created in 1855.

The role, which has a salary of between £205 000 (€240 000; $335 000) and £209 000 a year, is to serve as the government’s most senior medical adviser and to be responsible for providing expert advice on a wide range of issues …
Haptoglobin Synthesis. I. In Vivo Studies of the Production of Haptoglobin, Fibrinogen, and γ-Globulin by the Canine Liver*
Authors: Chester A. Alper, John H. Peters, Alan G. Birtch, Frank H. Gardner
Journal: Journal of Clinical Investigation (1965)

Haptoglobin is an a2 plasma glycoprotein that forms a stable complex with hemoglobin (1-5). The complex is cleared from the plasma much more rapidly than free haptoglobin so that marked hypoor anhaptoglobinemia is a concomitant of hemolysis (6, 7). Since free hemoglobin passes readily into the urine, whereas the complex, perhaps owing to its much greater size, does not, haptoglobin may play a role in the conservation of iron by the body (5, 7). Haptoglobin concentration increases markedly in man (8-12) and animals (13-15) in the presence of inflammation or tissue necrosis. Estrogen administration depresses the haptoglobin concentration in the serum of man (10). The site of synthesis of this protein is unknown although the liver has been suggested (16), for it is known that in some instances of parenchymatous liver disease haptoglobin concentration is reduced (10, 17). At least theoretically this might be the result of decreased synthesis by a damaged organ. However, increased hemoglobin
Recurrent Positive Selection of the Drosophila Hybrid Incompatibility Gene Hmr
Authors: S. Maheshwari, J. Wang, D. A. Barbash
Journal: Molecular Biology and Evolution (2008)

Lethality in hybrids between Drosophila melanogaster and its sibling species Drosophila simulans is caused in part by the interaction of the genes Hybrid male rescue (Hmr) and Lethal hybrid rescue (Lhr). Hmr and Lhr have diverged under positive selection in the hybridizing species. Here we test whether positive selection of Hmr is confined only to D. melanogaster and D. simulans. We find that Hmr has continued to diverge under recurrent positive selection between the sibling species D. simulans and Drosophila mauritiana and along the lineage leading to the melanogaster subgroup species pair Drosophila yakuba and Drosophila santomea. Hmr encodes a member of the Myb/SANT-like domain in ADF1 (MADF) family of transcriptional regulators. We show that although MADF domains from other Drosophila proteins have predicted ionic properties consistent with DNA binding, the MADF domains encoded by different Hmr orthologs have divergent properties consistent with binding to either the DNA or the protein components of chromatin. Our results suggest that Hmr may be functionally diverged in multiple species.
Integrating genotypic and expression data in a segregating mouse population to identify 5-lipoxygenase as a susceptibility gene for obesity and bone traits
Authors: Margarete Mehrabian, Hooman Allayee, Jirina Stockton, Pek Yee Lum, Thomas A Drake, Lawrence W Castellani, Michael Suh, Christopher Armour, Stephen Edwards, John Lamb, Aldons J Lusis, Eric E Schadt
Journal: Nature Genetics (2005)
Abdominal pain following obesity treatment
Authors: Kamal V Patel, Joanne Ooi, Shuvra Ray, Nyree Griffin, Jude A Oben
Journal: Gut (2013)

A 61-year-old woman presented to the emergency department with a 3-day history of vomiting, abdominal distension and pain plus anorexia. This was on a background of morbid obesity, non-alcoholic fatty liver disease and previous laparoscopic cholecystectomy. An elective procedure to enhance weight loss had been performed 5 months before the acute admission, without complication before presentation.

On examination her abdomen was soft, tender and with a palpable epigastric mass. Blood tests and vital signs were unremarkable. Chest radiography revealed no subdiaphragmatic free air but abdominal radiography revealed a significant abnormality (figure 1).



Figure 1 
Emergency abdominal x-ray.



What is the diagnosis and next management step?

CT findings (figures 2 and 3) were reported …
Androgen Receptor Inhibits Estrogen Receptor-α Activity and Is Prognostic in Breast Cancer
Authors: Amelia A. Peters, Grant Buchanan, Carmela Ricciardelli, Tina Bianco-Miotto, Margaret M. Centenera, Jonathan M. Harris, Shalini Jindal, Davendra Segara, Li Jia, Nicole L. Moore, Susan M. Henshall, Stephen N. Birrell, Gerhard A. Coetzee, Robert L. Sutherland, Lisa M. Butler, Wayne D. Tilley
Journal: Cancer Research (2009)

Abstract There is emerging evidence that the balance between estrogen receptor-α (ERα) and androgen receptor (AR) signaling is a critical determinant of growth in the normal and malignant breast. In this study, we assessed AR status in a cohort of 215 invasive ductal breast carcinomas. AR and ERα were coexpressed in the majority (80-90%) of breast tumor cells. Kaplan-Meier product limit analysis and multivariate Cox regression showed that AR is an independent prognostic factor in ERα-positive disease, with a low level of AR (less than median of 75% positive cells) conferring a 4.6-fold increased risk of cancer-related death (P = 0.002). Consistent with a role for AR in breast cancer outcome, AR potently inhibited ERα transactivation activity and 17β-estradiol–stimulated growth of breast cancer cells. Transfection of MDA-MB-231 breast cancer cells with either functionally impaired AR variants or the DNA-binding domain of the AR indicated that the latter is both necessary and sufficient for inhibition of ERα signaling. Consistent with molecular modeling, electrophoretic mobility shift assays showed binding of the AR to an estrogen-responsive element (ERE). Evidence for a functional interaction of the AR with an ERE in vivo was provided by chromatin immunoprecipitation data, revealing recruitment of the AR to the progesterone receptor promoter in T-47D breast cancer cells. We conclude that, by binding to a subset of EREs, the AR can prevent activation of target genes that mediate the stimulatory effects of 17β-estradiol on breast cancer cells. [Cancer Res 2009;69(15):6131–40]