tbuckley/cabot-search huggingface dataset:
Anti-dsDNA Antibodies Bind to Mesangial Annexin II in Lupus Nephritis
Authors: Susan Yung, Kwok Fan Cheung, Qing Zhang, Tak Mao Chan
Journal: Journal of the American Society of Nephrology (2010)

Production of anti-dsDNA antibodies is a hallmark of lupus nephritis, but how these antibodies deposit in organs and elicit inflammatory damage remains unknown. In this study, we sought to identify antigens on the surface of human mesangial cells (HMC) that mediate the binding of human anti-dsDNA antibodies and the subsequent pathogenic processes. We isolated anti-dsDNA antibodies from patients with lupus nephritis by affinity chromatography. We used multiple methods to identify and characterize antigens from the plasma membrane fraction of mesangial cells that crossreacted with the anti-dsDNA antibodies. We found that annexin II mediated the binding of anti-dsDNA antibodies to HMC. After binding to the mesangial cell surface, anti-dsDNA antibodies were internalized into the cytoplasm and nucleus. This also led to induction of IL-6 secretion and annexin II synthesis, mediated through activation of p38 MAPK, JNK, and AKT. Binding of anti-dsDNA antibodies to annexin II correlated with disease activity in human lupus nephritis. Glomerular expression of annexin II correlated with the severity of nephritis, and annexin II colocalized with IgG and C3 deposits in both human and murine lupus nephritis. Gene silencing of annexin II in HMC reduced binding of anti-dsDNA antibody and partially decreased IL-6 secretion. In summary, our data demonstrate that annexin II mediates the binding of anti-dsDNA antibodies to mesangial cells, contributing to the pathogenesis of lupus nephritis. This interaction provides a potential target for therapeutic intervention.
Sports medicine education in Australia
Authors: Peter Fricker
Journal: British Journal of Sports Medicine (2000)

This is recognised as the specialist training programme in sports medicine in both New Zealand and Australia, although government recognition as a medical specialty in Australia is still awaited. In New Zealand, sports medicine has been recognised as a special discipline.

The term “sports physician” is reserved for Fellows of the Australian College of Sports Physicians (ACSP) and “sports medicine practitioner” is used for all other doctors with a qualification—for example, Master of Sports Medicine, Diploma of Sports Medicine—and/or interest in sports medicine.

Fellowship of the ACSP is obtained after a minimum of seven years approved postgraduate medical experience and training. Trainees must be registered to practise in Australia.

An initial three years of internship or hospital residency and perhaps primary care experience is prescribed before a prospective trainee can sit the part 1 fellowship examination of the college. This consists of two three hour multiple choice examination papers which cover physiology, anatomy, pharmacology, and pathology. It is a college specific examination but equivalence has been granted for part 1 examinations of the Royal Australasian College of Physicians and the Royal Australian College of Surgeons.

Successful completion of these papers confers eligibility to apply for a training position with the Advanced Training Program of the ACSP. At the time of writing, there are 11 training posts in Australia and New Zealand. All teaching is carried out by Fellows of the ACSP and fellows of other specialist colleges appointed by the ACSP, and advanced training takes at least four years. The …
Risk of bias from inclusion of patients who already have diagnosis of or are undergoing treatment for depression in diagnostic accuracy studies of screening tools for depression: systematic review
Authors: B. D. Thombs, E. Arthurs, G. El-Baalbaki, A. Meijer, R. C. Ziegelstein, R. J. Steele
Journal: BMJ (2011)

<b>Objectives</b> To investigate the proportion of original studies included in systematic reviews and meta-analyses on the diagnostic accuracy of screening tools for depression that appropriately exclude patients who already have a diagnosis of or are receiving treatment for depression and to determine whether these systematic reviews and meta-analyses evaluate possible bias from the inclusion of such patients. <b>Design</b> Systematic review. <b>Data sources</b> Medline, PsycINFO, CINAHL, Embase, ISI, SCOPUS, and Cochrane databases were searched from 1 January 2005 to 29 October 2009. <b>Eligibility criteria for selecting studies</b> Systematic reviews and meta-analyses in any language that reported on the diagnostic accuracy of screening tools for depression. <b>Results</b> Only eight of 197 (4%) unique publications from 17 systematic reviews and meta-analyses specifically excluded patients who already had a diagnosis of or were receiving treatment for depression. No systematic reviews or meta-analyses commented on possible bias from the inclusion of such patients, even though 10 reviews used quality assessment tools with items to rate risk of bias from composition of the sample of patients. <b>Conclusions</b> Studies of the accuracy of screening tools for depression rarely exclude patients who already have a diagnosis of or are receiving treatment for depression, a potential bias that is not evaluated in systematic reviews and meta-analyses. This could result in inflated estimates of accuracy on which clinical practice and preventive care guidelines are often based, a problem that takes on greater importance as the rate of diagnosed and treated depression in the population increases.
Overall survival benefit for sequential doxorubicin–docetaxel compared with concurrent doxorubicin and docetaxel in node-positive breast cancer—8-year results of the Breast International Group 02-98 phase III trial
Authors: C. Oakman, P.A. Francis, J. Crown, E. Quinaux, M. Buyse, E. De Azambuja, M. Margeli Vila, M. Andersson, B. Nordenskjöld, R. Jakesz, B. Thürlimann, J. Gutiérrez, V. Harvey, L. Punzalan, P. Dell'Orto, D. Larsimont, I. Steinberg, R.D. Gelber, M. Piccart-Gebhart, G. Viale, A. Di Leo
Journal: Annals of Oncology (2013)

Background In women with node-positive breast cancer, the Breast International Group (BIG) 02-98 tested the incorporation of docetaxel (Taxotere) into doxorubicin (Adriamycin)-based chemotherapy, and compared sequential and concurrent docetaxel. At 5 years, there was a trend for improved disease-free survival (DFS) with docetaxel. We present results at 8-year median follow-up and exploratory analyses within biologically defined subtypes. Methods Patients were randomly assigned to one of four treatments: (i) sequential control: doxorubicin (A) (75 mg/m(2)) × 4 →classical cyclophosphamide, methotrexate, 5-fluorouracil (CMF); (ii) concurrent control: doxorubicin, cyclophosphamide (AC)(60/600 mg/m(2)) × 4 →CMF; (iii) sequential docetaxel: A (75 mg/m(2)) × 3 → docetaxel (T) (100 mg/m(2)) × 3 → CMF and (iv) concurrent docetaxel: AT(50/75 mg/m(2)) × 4 →CMF. The primary comparison evaluated docetaxel efficacy regardless of the schedule. Exploratory analyses were undertaken within biologically defined subtypes. Results Two thousand eight hundred and eighty-seven patients were enrolled. After 93.4 months of median follow-up, there were 916 DFS events. For the primary comparison, there was no significant improvement in DFS from docetaxel [hazard ratio (HR) = 0.91, 95% confidence interval (CI) = 0.80-1.05, P = 0.187]. In secondary comparisons, sequential docetaxel significantly improved DFS compared with sequential control (HR = 0.81, 95% CI = 0.67-0.99, P = 0.036), and significantly improved DFS (HR = 0.84, 95% CI = 0.72-0.99, P = 0.035) and overall survival (OS) (HR = 0.79, 95% CI = 0.65-0.98, P = 0.028) compared with concurrent doxorubicin-docetaxel. Luminal-A disease had the best prognosis. HRs favored addition of sequential docetaxel in all subtypes, except luminal-A; but this observation was not statistically supported because of limited numbers. Conclusion With further follow-up, the sequential docetaxel schedule resulted in significantly better OS than concurrent doxorubicin-docetaxel, and continued to show better DFS than sequential doxorubicin-based control.
Nonatopic Children with Multitrigger Wheezing Have Airway Pathology Comparable to Atopic Asthma
Authors: Graziella Turato, Angelo Barbato, Simonetta Baraldo, Maria Elena Zanin, Erica Bazzan, Kim Lokar-Oliani, Fiorella Calabrese, Cristina Panizzolo, Deborah Snijders, Piero Maestrelli, Renzo Zuin, Leonardo M Fabbri, Marina Saetta
Journal: American Journal of Respiratory and Critical Care Medicine (2008)

Rationale: Epidemiologic studies have shown that, in atopic children, wheezing is more likely to persist into adulthood, eventually becoming asthma, whereas it appears to resolve by adolescence in nonatopic children.Objectives: To investigate whether among children with multitrigger wheeze responsive to bronchodilators the airway pathology would be different in nonatopic wheezers, who are often considered nonasthmatic, compared with atopic wheezers, who are more frequently diagnosed as having asthma.Methods: Bronchial biopsies were obtained from 55 children undergoing bronchoscopy for appropriate clinical indications: 18 nonatopic children with multitrigger wheeze (median age, 5 yr; range, 2–10 yr), 20 atopic children with multitrigger wheeze (medan age, 5 yr; range, 2–15 yr), and 17 control children with no atopy or wheeze (median age, 4; range, 2–14 yr). By histochemistry and immunohistochemistry, we quantified epithelial loss, basement membrane thickness, angiogenesis, inflammatory cells, IL-4+, and IL-5+ cells in subepithelium.Measurements and Main Results: Unexpectedly, all pathologic features examined were similar in atopic and nonatopic wheezing children. Compared with control subjects, both nonatopic and atopic wheezing children had increased epithelial loss (P = 0.03 and P = 0.002, respectively), thickened basement membrane (both P < 0.0001), and increased number of vessels (P = 0.003 and P = 0.03, respectively) and eosinophils (P < 0.0001 and P = 0.002, respectively). Moreover, they had increased cytokine expression, which was highly significant for IL-4 (P = 0.002 and P = 0.0001, respectively) and marginal for IL-5 (P = 0.02 and P = 0.08, respectively).Conclusions: This study shows that the airway pathology typical of asthma is present in nonatopic wheezing children just as in atopic wheezing children. These results suggest that, when multitrigger wheezing responsive to bronchodilators is present, it is associated with pathologic features of asthma even in nonatopic children.
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First- or Second-Line Therapy in Patients With Metastatic Renal Cell Cancer
Authors: Jared A. Gollob, W. Kimryn Rathmell, Tina M. Richmond, Christine B. Marino, Elizabeth K. Miller, Gayle Grigson, Catharine Watkins, Lin Gu, Bercedis L. Peterson, John J. Wright
Journal: Journal of Clinical Oncology (2007)

We undertook this study to determine the activity and tolerability of sorafenib administered with interferon alfa-2b (IFN-alpha-2b) as first- or second-line therapy in metastatic renal cell cancer (RCC).Between November 2004 and October 2006, 40 patients at two sites were enrolled onto a phase II trial of sorafenib plus IFN-alpha-2b. Treatment consisted of 8-week cycles of sorafenib 400 mg orally bid plus IFN-alpha-2b 10 million U subcutaneously three times a week followed by a 2-week break. Patients were eligible to receive additional cycles of therapy until disease progression. Dose reduction of both drugs by 50% was permitted once for toxicity.The response rate was 33% (95% CI, 19% to 49%; 13 of 40 patients), including 28% partial responses (n = 11) and 5% complete responses (n = 2). Responses were seen in treatment-naïve and interleukin-2 (IL-2) -treated patients within the first two cycles. The median duration of response was 12 months. With a median follow-up time of 14 months, median progression-free survival time was 10 months (95% CI, 8 to 18 months), and median overall survival time has not yet been reached. Fatigue, anorexia, anemia, diarrhea, hypophosphatemia, rash, nausea, and weight loss were the most common toxicities. Grade 3 toxicities were uncommon but included hypophosphatemia, neutropenia, rash, fatigue, and anemia. Dose reductions were required in 65% of patients.The combination of sorafenib and IFN-alpha-2b has substantial activity in treatment-naïve and IL-2-treated patients with RCC. The toxicity exceeded that of either drug alone, but dose reductions and breaks between cycles allowed for chronic therapy. A larger, randomized trial would determine whether there is any advantage to this regimen compared with sorafenib alone.
Antitumor Activity of YM155, a Selective Small-Molecule Survivin Suppressant, Alone and in Combination with Docetaxel in Human Malignant Melanoma Models
Authors: Kentaro Yamanaka, Takahito Nakahara, Tomohiro Yamauchi, Aya Kita, Masahiro Takeuchi, Fumiko Kiyonaga, Naoki Kaneko, Masao Sasamata
Journal: Clinical Cancer Research (2011)

Abstract Purpose: Aggressive cell growth and chemoresistance are notorious obstacles in melanoma therapy. Accumulating evidence suggests that survivin is preferentially expressed in cancer cells and plays a crucial role in cell division and apoptosis dysfunction. Here, we evaluated the therapeutic potential of YM155, a selective survivin suppressant, alone and in combination with docetaxel using human melanoma models. Experimental Design: A375 and SK-MEL-5 human malignant melanoma cells were treated with siRNA, YM155, and/or docetaxel, and cell viability, mRNA and protein expression levels, cell-cycle distribution, and immunohistochemical staining were then evaluated. Furthermore, the efficacy of YM155 combined with docetaxel was further examined in established xenograft models. Results: Survivin suppression was sufficient to induce spontaneous apoptosis of melanoma cells. YM155 showed nanomolar antiproliferative effects and induced tumor regression in established melanoma xenograft models. Docetaxel showed antitumor activity against melanoma cells, although it also induced survivin upregulation and G2/M mitotic arrest; however, cotreatment with YM155 decreased survivin expression below basal levels. Combination treatment of YM155 and docetaxel induced a greater rate of apoptosis than the sum of the single-treatment rates and promoted tumor regression without enhanced body weight loss in the melanoma xenograft models. Conclusions: Survivin is responsible for the inherent low levels of spontaneous apoptosis in melanoma cells. The concomitant combination of YM155 with docetaxel diminished the accumulation of survivin in G2/M mitotic arrest, and induced more intense apoptosis compared with each single treatment. YM155 in combination with docetaxel is well tolerated and shows greater efficacy than either agent alone in mouse xenograft models. Clin Cancer Res; 17(16); 5423–31. ©2011 AACR.
A Potentially Functional Mariner Transposable Element in the Protist Trichomonas vaginalis
Authors: J. C. Silva
Journal: Molecular Biology and Evolution (2004)

Mariner transposable elements encoding a D,D34D motif-bearing transposase are characterized by their pervasiveness among, and exclusivity to, animal phyla. To date, several hundred sequences have been obtained from taxa ranging from cnidarians to humans, only two of which are known to be functional. Related transposons have been identified in plants and fungi, but their absence among protists is noticeable. Here, we identify and characterize Tvmar1, the first representative of the mariner family to be found in a species of protist, the human parasite Trichomonas vaginalis. This is the first D,D34D element to be found outside the animal kingdom, and its inclusion in the mariner family is supported by both structural and phylogenetic analyses. Remarkably, Tvmar1 has all the hallmarks of a functional element and has recently expanded to several hundred copies in the genome of T. vaginalis. Our results show that a new potentially active mariner has been found that belongs to a distinct mariner lineage and has successfully invaded a nonanimal, single-celled organism. The considerable genetic distance between Tvmar1 and other mariners may have valuable implications for the design of new, high-efficiency vectors to be used in transfection studies in protists.
Nonuniform and Variable Arrangements of Ryanodine Receptors Within Mammalian Ventricular Couplons
Authors: Parisa Asghari, David R.L. Scriven, Shubhayan Sanatani, Sanjiv K. Gandhi, Andrew I.M. Campbell, Edwin D.W. Moore
Journal: Circulation Research (2014)

Single-tilt tomograms of the dyads in rat ventricular myocytes indicated that type 2 ryanodine receptors (RYR2s) were not positioned in a well-ordered array. Furthermore, the orientation and packing strategy of purified type 1 ryanodine receptors in lipid bilayers is determined by the free Mg2+ concentration. These observations led us to test the hypothesis that RYR2s within the mammalian dyad have multiple and complex arrangements.To determine the arrangement of RYR2 tetramers in the dyads of mammalian cardiomyocytes and the effects of physiologically and pathologically relevant factors on this arrangement.We used dual-tilt electron tomography to produce en-face views of dyads, enabling a direct examination of RYR2 distribution and arrangement. Rat hearts fixed in situ; isolated rat cardiomyocytes permeabilized, incubated with 1 mmol/L Mg2+, and then fixed; and sections of human ventricle, all showed that the tetramer packing within a dyad was nonuniform containing a mix of checkerboard and side-by-side arrangements, as well as isolated tetramers. Both phosphorylation and 0.1 mmol/L Mg2+ moved the tetramers into a predominantly checkerboard configuration, whereas the 4 mmol/L Mg2+ induced a dense side-by-side arrangement. These changes occurred within 10 minutes of application of the stimuli.The arrangement of RYR2 tetramers within the mammalian dyad is neither uniform nor static. We hypothesize that this is characteristic of the dyad in vivo and may provide a mechanism for modulating the open probabilities of the individual tetramers.
Calcium cycling in heart failure: how the fast became too furious
Authors: A ARMAND
Journal: Cardiovascular Research (2004)

After them, the (scientific) philosophers appear. ..who proclaim that only they are wise and all other mortals are but shadows flapping about. . . .[The philosophers] build uncountable worlds as . ..they hypothesize without hesitation causes for . ..unexplainable things, as if they were secretaries of Nature, architects of all things, as if they appeared among us from a meeting of gods.Meanwhile, Nature laughs at them and their speculations, because that they have uncovered nothing is demonstrated by the fact that they immediately cross their swords on each single issue without results. . .
Correlation between pancreatic polypeptide response to secretin and ERCP findings in chronic pancreatitis.
Authors: I Stern, I C Roberts-Thomson, J Hansky
Journal: Gut (1982)

Previous studies have shown an impaired pancreatic polypeptide response to secretin in most patients with advanced chronic pancreatitis, but the sensitivity of the investigation in milder degrees of chronic pancreatitis remains unclear. In the present study the pancreatic polypeptide response to secretin was evaluated in 32 patients categorised as having advanced, moderate, or minimal chronic pancreatitis on the basis of the degree of abnormality of the retrograde pancreatogram. The pancreatic polypeptide response was abnormal (peak:basal pancreatic polypeptide ratio less than 5) in 17 of 19 patients (90%) with advanced or moderate chronic pancreatitis, but was normal in patients with minimal disease. The simple and non-invasive nature of this test makes it an attractive investigation for evaluation of the severity of pancreatic damage.
Targeting Activated Akt with GDC-0068, a Novel Selective Akt Inhibitor That Is Efficacious in Multiple Tumor Models
Authors: Jie Lin, Deepak Sampath, Michelle A. Nannini, Brian B. Lee, Michael Degtyarev, Jason Oeh, Heidi Savage, Zhengyu Guan, Rebecca Hong, Robert Kassees, Leslie B. Lee, Tyler Risom, Stefan Gross, Bianca M. Liederer, Hartmut Koeppen, Nicholas J. Skelton, Jeffrey J. Wallin, Marcia Belvin, Elizabeth Punnoose, Lori S. Friedman, Kui Lin
Journal: Clinical Cancer Research (2013)

We describe the preclinical pharmacology and antitumor activity of GDC-0068, a novel highly selective ATP-competitive pan-Akt inhibitor currently in clinical trials for the treatment of human cancers.The effect of GDC-0068 on Akt signaling was characterized using specific biomarkers of the Akt pathway, and response to GDC-0068 was evaluated in human cancer cell lines and xenograft models with various genetic backgrounds, either as a single agent or in combination with chemotherapeutic agents.GDC-0068 blocked Akt signaling both in cultured human cancer cell lines and in tumor xenograft models as evidenced by dose-dependent decrease in phosphorylation of downstream targets. Inhibition of Akt activity by GDC-0068 resulted in blockade of cell-cycle progression and reduced viability of cancer cell lines. Markers of Akt activation, including high-basal phospho-Akt levels, PTEN loss, and PIK3CA kinase domain mutations, correlate with sensitivity to GDC-0068. Isogenic PTEN knockout also sensitized MCF10A cells to GDC-0068. In multiple tumor xenograft models, oral administration of GDC-0068 resulted in antitumor activity ranging from tumor growth delay to regression. Consistent with the role of Akt in a survival pathway, GDC-0068 also enhanced antitumor activity of classic chemotherapeutic agents.GDC-0068 is a highly selective, orally bioavailable Akt kinase inhibitor that shows pharmacodynamic inhibition of Akt signaling and robust antitumor activity in human cancer cells in vitro and in vivo. Our preclinical data provide a strong mechanistic rationale to evaluate GDC-0068 in cancers with activated Akt signaling.
A Mycoplasma Peptide Elicits Heteroclitic CD4+ T Cell Responses against Tumor Antigen MAGE-A6
Authors: Lazar Vujanovic, Maja Mandic, Walter C. Olson, John M. Kirkwood, Walter J. Storkus
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Although T-helper (Th) epitopes have been previously reported for many tumor antigens, including MAGE-A6, the relevant HLA-DR alleles that present these peptides are expressed by only a minority of patients. The identification of tumor antigenic epitopes presented promiscuously by many HLA-DR alleles would extend the clinical utility of these peptides in vaccines and for the immunomonitoring of cancer patients. Experimental Design: A neural network algorithm and in vitro sensitization assays were employed to screen candidate peptides for their immunogenicity. Results: The MAGE-A6140-170, MAGE-A6172-187, and MAGE-A6280-302 epitopes were recognized by CD4+ T cells isolated from the majority of normal donors and melanoma patients evaluated. Peptide-specific CD4+ T cells also recognized autologous antigen-presenting cell pulsed with recombinant MAGE-A6 (rMAGE) protein, supporting the natural processing and MHC presentation of these epitopes. Given the strong primary in vitro sensitization of normal donor CD4+ T cells by the MAGEA6172-187 epitope, suggestive of potential cross-reactivity against an environmental stimulus, we identified a highly homologous peptide within the Mycoplasma penetrans HF-2 permease (MPHF2) protein. MPHF2 peptide–primed CD4+ T cells cross-reacted against autologous APC pulsed with the MAGE-A6172-187 peptide or rMAGE protein and recognized HLA-matched MAGE-A6+ melanoma cell lines. These responses seemed heteroclitic in nature because the functional avidity of MPHF2 peptide-primed CD4+ T cells for the MAGE-A6172-187 peptide was ∼1,000 times greater than that of CD4+ T cells primed with the corresponding MAGE-A6 peptide. Conclusions: We believe that these novel “promiscuous” MAGE-A6/MPHF2 Th epitopes may prove clinically useful in the treatment and/or monitoring of a high proportion of cancer patients.