tbuckley/cabot-search huggingface dataset:
Long-Lived Dichotomous Lineages of the Proteasome Subunit Beta Type 8 (PSMB8) Gene Surviving More than 500 Million Years as Alleles or Paralogs
Authors: Kentaro Tsukamoto, Fumi Miura, Naoko T. Fujito, Goro Yoshizaki, Masaru Nonaka
Journal: Molecular Biology and Evolution (2012)

On an evolutionary time scale, polymorphic alleles are believed to have a short life, persisting at most tens of millions of years even under long-term balancing selection. Here, we report highly diverged trans-species dimorphism of the proteasome subunit beta type 8 (PSMB8) gene, which encodes a catalytic subunit of the immunoproteasome responsible for the generation of peptides presented by major histocompatibility complex (MHC) class I molecules, in lower teleosts including Cypriniformes (zebrafish and loach) and Salmoniformes (trout and salmon), whose last common ancestor dates to 300 Ma. Moreover, phylogenetic analyses indicated that these dimorphic alleles share lineages with two shark paralogous genes, suggesting that these two lineages have been maintained for more than 500 My either as alleles or as paralogs, and that conversion between alleles and paralogs has occurred at least once during vertebrate evolution. Two lineages termed PSMB8A and PSMB8F show an A31F substitution that would probably affect their cleaving specificity, and whereas the PSMB8A lineage has been retained by all analyzed jawed vertebrates, the PSMB8F lineage has been lost by most jawed vertebrates except for cartilaginous fish and basal teleosts. However, a possible functional equivalent of the PSMB8F lineage has been revived as alleles within the PSMB8A lineage at least twice during vertebrate evolution in the amphibian Xenopus and teleostean Oryzias species. Dynamic evolution of the PSMB8 polymorphism through long-term persistence, loss, and regaining of dimorphism and conversion between alleles and paralogs implies the presence of strong selective pressure for functional polymorphism of this gene.
Comparison of three physiotherapy regimens for hands with rheumatoid arthritis.
Authors: J Hawkes, G Care, J S Dixon, H A Bird, V Wright
Journal: BMJ (1985)

did not find any relation between inflammatory activity and rheuma- toid factor values.The HLA-B27 associated arthropathies are typically seronegative disorders.We, however, carefully excluded patients with ankylosing spondylitis, reactive arthritis, and psoriatic arthritis, so these arthropathies could not have influenced the results.The biological role of rheumatoid factors is not known.Although seropositivity at the onset of rheumatoid arthritis suggests a poorer prognosis, several studies have failed to detect a relation between IgM rheumatoid factor titres and disease activity.3-5Finding an association of amyloid disease with seronegativity in adult rheumatoid arthritis may be interpreted in favour of some protective role of rheumatoid factors, at least with respect to the development of amyloid; or, more likely, seronegativity and the development of amyloid may be related to similar genetic factors.This study was supported by the Sigrid Juselius Foundation, Finland.1 Maury CPJ.A review of reactive (secondary) amyloidosis and its pathogenesis.
Sex steroids and bone: current perspectives
Authors: Juan Balasch
Journal: Human Reproduction Update (2003)

Although the process of bone remodelling or its control has not yet been fully elucidated there is, at present, sufficient information available to conclude that ovarian steroids (estrogens, androgens, progesterone) play an essential role in skeletal homeostasis. The mechanism of action of sex steroids on the skeleton is still not entirely clear, but it has traditionally included indirect effects on systemic hormones that regulate calcium balance and a direct receptor-mediated action. More recently, changes in cytokine production within the bone marrow, as well as pro-apoptotic and anti-apoptotic effects in the osteoblastic cells, have been proposed as new perspectives on the cellular and molecular mechanisms by which sex steroids influence adult bone homeostasis. Mechanical loading, when combined with estrogens or androgens, results in a greater osteogenic response than either condition separately. Women are especially at risk for osteoporosis if they have had a premature or surgical menopause and have not received hormone replacement therapy (HRT). Other reproductive factors that can help to identify women with osteopenia and emphasize the role of sex steroids in preserving bone mass in premenopausal women include: age at menarche, menstrual history and irregularities (including those associated with excessive exercise), age at menopause, previous hysterectomy, hyperprolactinaemia, anorexia nervosa, scoliosis, ovarian dysgenesis, pregnancy and lactation, and pharmacological ovarian suppression. The prevention of osteoporosis starts with the onset of the menarche. A combination of exercise, appropriate nutrition and a healthy lifestyle all maximize bone mineral accrual and result in optimal peak bone mass; normal ovarian function is essential to this process. Unfortunately, many women actually become aware of the need for osteoporosis prevention much later in life, usually after they have already become menopausal. HRT, however, has important limitations for prevention of fractures in post-menopausal women. Future perspectives for treatment of osteoporosis include androgen therapy and anabolic agents. Specifically, synthetic ligands of the estrogen receptor that can evoke the non-genotrophic but not the genotrophic signal of the receptor may be bone anabolic agents, as opposed to natural estrogens or selective estrogen receptor modulators that are anti-resorptive agents. The same ligands may circumvent the side effects associated with conventional HRT.
Lgr5 expression is absent in human premalignant lesions of the stomach
Authors: Tingting Wang, Khay Guan Yeoh, Manuel Salto-Tellez
Journal: Gut (2012)

We read with great interest the paper by Nam et al 1 showing that leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5) transcriptionally active cells were not pluripotent progenitor cells in the gastric acid secreting mucosa and that spasmolytic polypeptide-expressing metaplasia was not derived from Lgr5-expressing cells. Here we would like to confirm the relevance of this observation in clinical specimens. Intestinal-type gastric carcinogenesis has been well documented in a stepwise histopathological model, known as Correa pathway, which includes chronic gastritis, intestinal metaplasia, dysplasia and invasive carcinoma.2 We performed Lgr5 immunohistochemistry (IHC) staining on full sections from gastric antral epithelium (n=10), which included intestinal metaplasia and …
Medium term results of lung transplantation for end stage pulmonary sarcoidosis
Authors: S. Walker, G. Mikhail, N. Banner, J. Partridge, A. Khaghani, M. Burke, M. Yacoub
Journal: Thorax (1998)

<h3>BACKGROUND</h3> Lung transplantation is an accepted therapeutic option for patients with end stage pulmonary sarcoidosis. However, the medium term outcome of transplantation in this patient group is unknown. <h3>METHODS</h3> This study was performed to evaluate our experience with lung transplantation for end stage pulmonary sarcoidosis. Between July 1988 and July 1997 12 patients (nine men) underwent lung transplantation for sarcoidosis at our institution. Ten underwent single lung transplantation and two double lung transplantation. <h3>RESULTS</h3> Survival at three and five years was 70% and 56%, respectively. Three patients developed obliterative bronchiolitis at six, 18, and 45 months. One died at the time of retransplantation. Sarcoid granulomas have recurred in the donor organ in three patients. In one the development of granulomas has been associated with clinical deterioration, necessitating retransplantation. Mean (SD) forced expiratory volumes in one second at three and five years were 1.37 (0.67) l and 1.34 (0.13) l, respectively. <h3>CONCLUSIONS</h3> Lung transplantation is a viable option for patients with end stage pulmonary sarcoidosis. The medium term results are comparable with patients undergoing lung transplantation for other indications. Despite histological recurrence of sarcoidosis, the risk of clinically important recurrence is low.
Adrenomedullin Induces Endothelium-Dependent Vasorelaxation via the Phosphatidylinositol 3-Kinase/Akt–Dependent Pathway in Rat Aorta
Authors: Hiroaki Nishimatsu, Etsu Suzuki, Daisuke Nagata, Nobuo Moriyama, Hiroshi Satonaka, Kenneth Walsh, Masataka Sata, Kenji Kangawa, Hisayuki Matsuo, Atsuo Goto, Tadaichi Kitamura, Yasunobu Hirata
Journal: Circulation Research (2001)

Abstract —To study the mechanisms by which adrenomedullin (AM) induces endothelium-dependent vasorelaxation, we examined whether AM-induced endothelium-dependent vasodilation was mediated by the phosphatidylinositol 3-kinase (PI3K)/Akt-dependent pathway in rat aorta, because it was recently reported that PI3K/Akt was implicated in the activation of endothelial NO synthase. AM-induced vasorelaxation in thoracic aorta with intact endothelium was inhibited by pretreatment with PI3K inhibitors to the same level as that in endothelium-denuded aorta. AM elicited Akt phosphorylation in a time- and dose-dependent manner. AM-induced Akt phosphorylation was inhibited by pretreatment with a calmodulin-dependent protein kinase inhibitor as well as with PI3K inhibitors. When an adenovirus construct expressing a dominant-negative Akt mutant (Ad/dnAkt) was injected into abdominal aortas so that the mutant was expressed predominantly in the endothelium layer, AM-induced vasodilation was diminished to the same level as that in endothelium-denuded aortas. Finally, AM-induced cGMP production, which was used as an indicator for NO production, was suppressed by PI3K inhibition or by Ad/dnAkt infection into the endothelium. These results suggested that AM induced Akt activation in the endothelium via the Ca 2+ /calmodulin-dependent pathway and that this was implicated in the production of NO, which in turn induced endothelium-dependent vasodilation in rat aorta.
BLOOD PLASMA PROTEINS AS INFLUENCED BY INTRAVENOUS INJECTION OF GUM ACACIA
Authors: G. P. Heckel, C. C. Erickson, C. L. Yuile, R. E. Knutti
Journal: The Journal of Experimental Medicine (1938)

Lowered plasma protein concentration following single injections of gum acacia in the dog is due in some part to dilution, and in greater part to actual decrease in total circulating protein. The maximum decrease in the total circulating protein does not take place at the same time as the maximum decrease in concentration. Fluctuations in fibrinogen concentration are marked, and are not necessarily proportional to changes in plasma protein concentration. Plasma protein concentration returns to normal limits within 10 to 21 days after the injection, at which time total circulating protein and plasma volume are lower than normal. Loss of protein cannot be accounted for by increase in urinary nitrogen. It is possible to maintain dogs at low levels of plasma protein concentration for several weeks by repeated injections of gum acacia solution. Anatomical changes following such a procedure in a normal dog are most conspicuous in the liver (Fig. A). These observations further implicate the liver as a source of plasma protein. Two mechanisms for the diminution of plasma protein following gum injection are suggested. One of these is based on the possibility that the liver cells being engorged with gum acacia are not able to produce the necessary amount of plasma protein to supply the normal demand. The other possibility is that with the injection of the gum, since there is obviously a greatly increased amount of colloid in the blood, the more readily removable colloid, i.e. plasma protein, is taken out of the blood stream, in an attempt to return plasma volume and colloid osmotic pressure to the normal limits. It is probable that both of these mechanisms are involved. Injection of gum acacia is suggested as a technique for further study of disturbed liver function. It must be obvious that clinical use of gum acacia for intravenous injection is not without danger.
The Tamiflu trials
Authors: E. Loder, D. Tovey, F. Godlee
Journal: BMJ (2014)

Progress towards data sharing but many battles still to fight

This week sees the publication of the updated Cochrane systematic review on the neuraminidase inhibitors oseltamivir and zanamivir.1 The review, which is also reported in two papers published in The BMJ ,2 3 provides the most complete analysis so far of what is known from randomised trials about the effectiveness and safety of these antiviral drugs. It is also the culmination of a four and a half year battle for access to the raw data from industry funded trials of oseltamivir, a drug on which the world has spent billions of dollars.4

Through their exhaustive scrutiny of the data contained in clinical study reports (the lengthy documents held by the drug’s manufacturer Roche and previously seen only in part by drug regulators), the Cochrane authors have set exacting new standards for systematic reviewers and decision makers. Their fight for the data has also shown us, in more detail than ever, that the entire ecosystem of drug evaluation and regulation is deeply flawed.

The Cochrane review and BMJ papers represent a huge amount of work. The authors—Tom Jefferson, Carl Heneghan, and colleagues—are among just a handful of systematic reviewers who have made use of clinical study reports (CSRs) to reach their conclusions. CSRs are intended to provide regulatory authorities with a structured detailed report of a clinical trial.5 In contrast to the abbreviated information about a trial contained in a journal article, one CSR can extend to hundreds of pages. The “compression factor”—the length (in pages) of the CSR of a trial compared with the length of the corresponding journal article—has been found to range from one to an astonishing 8805.6 7

It is a formidable task to sift through this amount of information, which is …
Paclitaxel efficacy and toxicity in older women with metastatic breast cancer: combined analysis of CALGB 9342 and 9840
Authors: S.M. Lichtman, A. Hurria, C.T. Cirrincione, A.D. Seidman, E. Winer, C. Hudis, H.J. Cohen, H.B. Muss
Journal: Annals of Oncology (2011)
Phase II Study of Paclitaxel Given Once per Week Along With Trastuzumab and Pertuzumab in Patients With Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer
Authors: Chau Dang, Neil Iyengar, Farrah Datko, Gabriella D'Andrea, Maria Theodoulou, Maura Dickler, Shari Goldfarb, Diana Lake, Julie Fasano, Monica Fornier, Theresa Gilewski, Shanu Modi, Devika Gajria, Mary Ellen Moynahan, Nicola Hamilton, Sujata Patil, Maxine Jochelson, Larry Norton, José Baselga, Clifford Hudis
Journal: Journal of Clinical Oncology (2014)

The CLEOPATRA (Clinical Evaluation of Trastuzumab and Pertuzumab) study demonstrated superior progression-free survival (PFS) and overall survival when pertuzumab was added to trastuzumab and docetaxel. Paclitaxel given once per week is effective and less toxic than docetaxel. We performed a phase II study to evaluate the efficacy and safety of pertuzumab and trastuzumab with paclitaxel given once per week.Patients with metastatic human epidermal growth factor receptor 2-positive breast cancer with zero to one prior therapy were enrolled. Treatment consisted of paclitaxel 80 mg/m(2) once per week plus trastuzumab (8 mg/kg loading dose → 6 mg/kg) once every 3 weeks plus pertuzumab (840 mg loading dose → 420 mg) once every 3 weeks, all given intravenously. The primary end point was 6-month PFS assessed by Kaplan-Meier methods.From January 2011 to December 2013, we enrolled 69 patients: 51 (74%) and 18 (26%) treated in first- and second-line metastatic settings, respectively. At a median follow-up of 21 months (range, 3 to 38 months), 6-month PFS was 86% (95% CI, 75% to 92%). The median PFS was 19.5 months (95% CI, 14 to 26 months) overall. PFS was 24.2 months (95% CI, 14 months to not reached [NR]) and 16.4 months (95% CI, 8.5 months to NR) for those without and with prior treatment, respectively. At 1 year, Kaplan-Meier PFS was 70% (95% CI, 56% to 79%) overall, 71% (95% CI, 55% to 82%) for those without prior therapy, and 66% (95% CI, 40% to 83%) for those with prior therapy. Treatment was well-tolerated; there was no febrile neutropenia or symptomatic left ventricular systolic dysfunction.Paclitaxel given once per week with trastuzumab and pertuzumab is highly active and well tolerated and seems to be an effective alternative to docetaxel-based combination therapy.
Prospective Study of Falls and Risk Factors for Falls in Adults With Advanced Cancer
Authors: Carol A. Stone, Peter G. Lawlor, George M. Savva, Kathleen Bennett, Rose Anne Kenny
Journal: Journal of Clinical Oncology (2012)

Retrospective studies of inpatients with cancer suggest that a cancer diagnosis confers a high risk of falls. In adults with advanced cancer, we aimed to prospectively document the incidence of falls, identify the risk factors, and determine if falls in this population occur predominantly in older patients.Patients admitted consecutively to community and inpatient palliative care services with metastatic or locoregionally advanced cancer who were mobile without assistance were recruited. Risk-factor assessment was conducted on initial encounter. Patients underwent follow-up via weekly telephone contact for 6 months or until time of fall or death. Relationship between covariates and time to fall was examined using hazard ratios (HRs) derived from univariate and multivariate Cox proportional hazards models.Of 185 participants (52.4% men; mean age 68 ± standard deviation of 12.6 years), 50.3% fell; 35 (53%) of 66 participants age < 65 years and 58 (48.7%) of 119 age ≥ 65 years fell; 61.3% of falls occurred in the community; 42% resulted in injury. Median time to fall was 96 days (95% CI, 64.66 to 127.34). Primary brain tumor or brain metastasis (HR 2.5; P = .002), number of falls in the preceding 3 months (HR, 1.27; P = .005), severity of depression (HR, 1.12; P = .012), benzodiazepine dose (HR, 1.05; P = .004), and cancer-related pain (HR, 1.96; P = .024) were independently associated with time to fall in multivariate analysis.Fifty percent of adults with advanced cancer, regardless of age, will experience a fall associated with high risk of physical injury. There is a compelling need to assess the efficacy of assessment and management of modifiable fall risk factors in patients with advanced cancer.
Refugees: time for moral leadership from the Western democracies
Authors: D. Berger, K. Abbasi
Journal: BMJ (2015)

Australia sets a disgraceful example in its treatment of refugees 

Any observer of today’s spiraling refugee crises in Africa, the Middle East, and Asia must agree with Hegel that “The only thing we learn from history is that we learn nothing from history.” At the Evian conference of 1938, the US encouraged representatives of 32 nations to find a solution to the Jewish refugee crisis in Europe but refused to relax its own, severely limited refugee quotas, as did Britain.1 2 The other participating nations followed suit, except the Dominican Republic, which agreed to take 100 000. In the summer of 1939, in the first act of a “stop the boats” doctrine that still plays out today, the St Louis , a German luxury liner carrying over 900 German Jewish refugees, was refused entry by Cuba, the US, and Canada and returned to Europe, where a large number of the would-be refugees were subsequently murdered in the Holocaust.3 This hypocrisy sent a clear message to Hitler that no one else cared about the Jews, or at least not enough to do anything, and he correctly concluded he was able to act with impunity.

Today’s failure of moral leadership by …
Association Between Genetic Variants on Chromosome 15q25 Locus and Objective Measures of Tobacco Exposure
Authors: Marcus R. Munafò, Maria N. Timofeeva, Richard W. Morris, David Prieto-Merino, Naveed Sattar, Paul Brennan, Elaine C. Johnstone, Caroline Relton, Paul C. D. Johnson, Donna Walther, Peter H. Whincup, Juan P. Casas, George R. Uhl, Paolo Vineis, Sandosh Padmanabhan, Barbara J. Jefferis, Antoinette Amuzu, Elio Riboli, Mark N. Upton, Paul Aveyard, Shah Ebrahim, Aroon D. Hingorani, Graham Watt, Tom M. Palmer, Nicholas J. Timpson, George Davey Smith
Journal: JNCI Journal of the National Cancer Institute (2012)

BackgroundTwo single-nucleotide polymorphisms, rs1051730 and rs16969968, located within the nicotinic acetylcholine receptor gene cluster on chromosome 15q25 locus, are associated with heaviness of smoking, risk for lung cancer, and other smoking-related health outcomes. Previous studies have typically relied on self-reported smoking behavior, which may not fully capture interindividual variation in tobacco exposure.
Response to Letter Regarding Article, “External Carotid Artery–Internal Jugular Vein Fistula: A Complication of Internal Jugular Cannulation”
Authors: Vijay K. Sharma, Ashok W. Pereira, Benjamin K.C. Ong, Rahul Rathakrishnan, Bernard P.L. Chan, Hock Luen Teoh
Journal: Circulation (2006)
Induction of the Early Growth Response (Egr) Family of Transcription Factors during Thymic Selection
Authors: Hui Shao, Dwight H. Kono, Ling-Yu Chen, Elyssa M. Rubin, Jonathan Kaye
Journal: The Journal of Experimental Medicine (1997)

There is little known about the regulation of gene expression during TCR-mediated differentiation of immature CD4+8+ (double positive) thymocytes into mature T cells. Using the DPK CD4+8+thymocyte precursor cell line, we demonstrate that the early growth response-1 gene (Erg-1), encoding a zinc finger transcription factor, is rapidly upregulated after TCR stimulation. We also report that Egr-1 is expressed by a subset of normal double positive thymocytes in the thymic cortex, as well by a majority of medullary single positive thymocytes. Expression of Egr-1 is dramatically reduced in the thymus of major histocompatibility complex knockout mice, but can be induced by anti-CD3 antibody stimulation of isolated thymocytes from these animals. These and other data suggest that high level expression of Egr-1 in the thymus is a consequence of selection. A similar pattern of expression is found for family members Egr-2 and Egr-3. Using the DPK cell line, we also demonstrate that expression of Egr-1, 2, and 3 is dependent upon ras activation, as is the initiation of differentiation to a single positive cell. In contrast, the calcineurin inhibitor cyclosporin A, which inhibits DPK cell differentiation as well as positive selection, inhibits expression of Egr-2 and Egr-3, but not Egr-1. The identification of the Egr family in this context represents the first report of a link between the two known signaling pathways involved in positive selection and downstream transcriptional regulators.