tbuckley/cabot-search huggingface dataset:
Homoharringtonine: an effective new drug for remission induction in refractory nonlymphoblastic leukemia.
Authors: R P Warrell, C J Coonley, T S Gee
Journal: Journal of Clinical Oncology (1985)

Homoharringtonine (HHT) is a new plant alkaloid originally isolated in the People's Republic of China. Preliminary studies have suggested antitumor activity in several neoplastic diseases. We treated 49 patients with relapsed or resistant acute leukemia with escalating doses of homoharringtonine administered by continuous infusion. Three dose levels were examined: 5 mg/m2 for seven days, 7 mg/m2 for seven days, and 5 mg/m2 for nine days. Of 28 patients with acute nonlymphoblastic leukemia who received cumulative doses of 45 to 49 mg/m2, seven patients (25%) achieved complete remission. Four of these remissions occurred in a subset of ten patients previously resistant to two or more induction attempts with conventional chemotherapy. There were no remissions in three patients with secondary leukemia or in seven patients with acute lymphoblastic leukemia. Reversible hypotension, fluid retention, diarrhea, and tumor lysis syndrome were the major toxic effects of this treatment. Our results indicate that homoharringtonine is an effective new drug for the treatment of acute nonlymphoblastic leukemia and that this drug does not share cross-resistance with conventional antileukemic agents. The recommended dose is 5 mg/m2/d administered by continuous infusion for nine days.
Defining an optimal referral strategy for patients with a suspicion of axial spondyloarthritis: what is really important? Response to: ‘Evaluating the ASAS recommendations for early referral of axial spondyloarthritis in patients with chronic low back pain; is one parameter present sufficient for primary care practice?’ by van Hoeven <i>et al</i>
Authors: Denis Poddubnyy, Astrid van Tubergen, Robert Landewé, Joachim Sieper, Désirée van der Heijde
Journal: Annals of the Rheumatic Diseases (2015)

We thank van Hoeven et al 1 for their interest in our work2 and for their critical remarks.

The Assessment of SpondyloArthritis international Society (ASAS) referral recommendation3 has been developed as a flexible tool aimed at improving early diagnosis of axial spondyloarthritis (axSpA), which implies that—dependent on the local conditions—parameters from the list shown in box 1 of the original publication could/should be selected. For instance, it does not make sense to ask for human leukocyte antigen (HLA)-B27 positivity in primary care if primary care physicians do not perform this test for whatever reason.

Although the referral strategy should be applied on the level of primary care physician, …
Long-term Risk of Hospitalization for Somatic Diseases in Survivors of Adolescent or Young Adult Cancer
Authors: Kathrine Rugbjerg, Jørgen H. Olsen
Journal: JAMA Oncology (2015)

Survivors of adolescent and young adult cancers are at risk for treatment-induced late adverse effects; however, to our knowledge, the long-term risk of hospitalization in this specific group of cancer survivors has not been thoroughly evaluated.To examine relative and absolute excess risk for hospitalizations up to 34 years after diagnosis of adolescent and young adult cancer compared with population comparisons.This was a cohort study, conducted in Denmark, of 33,555 five-year survivors of adolescent or young adult cancer, diagnosed from 1943 through 2004, when they were 15 to 39 years of age, and 228,447 population comparisons, matched to the survivors by sex and year of birth.Cancer survivors and comparisons were followed up for hospitalizations in the Danish Patient Register through December 2010. Standardized hospitalization rate ratios (RRs) and absolute excess risks (AERs) were calculated.After a median follow-up of 14 years, we identified 53,032 hospitalizations in cancer survivors, whereas 38,423 were expected, resulting in an overall RR of 1.38 (95% CI, 1.37-1.39). The data analysis was started in January 2015 and ended in June 2015. Additional data analyses requested by the reviewers were conducted in August 2015. The highest risks were found for the main diagnostic groups of diseases of blood and blood-forming organs (RR, 2.00; 95% CI, 1.87-2.14), infectious and parasitic diseases (RR, 1.69; 95% CI, 1.61-1.77), and malignant neoplasms (RR, 1.63; 95% CI, 1.59-1.68). The overall AER was 2803 (95% CI, 2712-2893) per 100,000 person-years; the highest AERs were found for malignant neoplasms, diseases of digestive organs, and diseases of the circulatory system (18%, 15%, and 14% of total AER, respectively). Survivors of the 10 most common cancers in adolescents and young adults were at significantly increased risk for diseases in the 12 main diagnostic groups. The highest risks were those of survivors of leukemia (RR, 2.21; 95% CI, 2.02-2.42), brain cancer (RR, 1.93; 95% CI, 1.86-2.00), and Hodgkin lymphoma (RR, 1.87; 95% CI, 1.80-1.94).The large number of survivors and the use of hospital discharge diagnoses made it possible to draw a comprehensive picture of the complex inpatient disease burden experienced by survivors of adolescent and young adult cancer. The findings underscore a great diversity of cancer-related health problems that physicians and patients should be knowledgeable about.
The gut microbiota plays a protective role in the host defence against pneumococcal pneumonia
Authors: Tim J Schuijt, Jacqueline M Lankelma, Brendon P Scicluna, Felipe de Sousa e Melo, Joris J T H Roelofs, J Daan de Boer, Arjan J Hoogendijk, Regina de Beer, Alex de Vos, Clara Belzer, Willem M de Vos, Tom van der Poll, W Joost Wiersinga
Journal: Gut (2015)

<h3>Objective</h3> Pneumonia accounts for more deaths than any other infectious disease worldwide. The intestinal microbiota supports local mucosal immunity and is increasingly recognised as an important modulator of the systemic immune system. The precise role of the gut microbiota in bacterial pneumonia, however, is unknown. Here, we investigate the function of the gut microbiota in the host defence against <i>Streptococcus pneumoniae</i> infections. <h3>Design</h3> We depleted the gut microbiota in C57BL/6 mice and subsequently infected them intranasally with <i>S. pneumoniae</i>. We then performed survival and faecal microbiota transplantation (FMT) experiments and measured parameters of inflammation and alveolar macrophage whole-genome responses. <h3>Results</h3> We found that the gut microbiota protects the host during pneumococcal pneumonia, as reflected by increased bacterial dissemination, inflammation, organ damage and mortality in microbiota-depleted mice compared with controls. FMT in gut microbiota-depleted mice led to a normalisation of pulmonary bacterial counts and tumour necrosis factor-α and interleukin-10 levels 6 h after pneumococcal infection. Whole-genome mapping of alveolar macrophages showed upregulation of metabolic pathways in the absence of a healthy gut microbiota. This upregulation correlated with an altered cellular responsiveness, reflected by a reduced responsiveness to lipopolysaccharide and lipoteichoic acid. Compared with controls, alveolar macrophages derived from gut microbiota-depleted mice showed a diminished capacity to phagocytose <i>S. pneumoniae</i>. <h3>Conclusions</h3> This study identifies the intestinal microbiota as a protective mediator during pneumococcal pneumonia. The gut microbiota enhances primary alveolar macrophage function. Novel therapeutic strategies could exploit the gut–lung axis in bacterial infections.
Prospective validation of ab initio liver transplantation in hepatocellular carcinoma upon detection of risk factors for recurrence after resection
Authors: Joana Ferrer‐Fàbrega, Alejandro Forner, Alexandre Liccioni, Rosa Miquel, Víctor Molina, Miquel Navasa, Constantino Fondevila, Juan Carlos García‐Valdecasas, Jordi Bruix, Josep Fuster
Journal: Hepatology (2015)

A decade ago we proposed to enlist for transplantation those patients with resected hepatocellular carcinoma in whom pathology registered pejorative histological markers (microvascular invasion and/or satellites; ab initio indication) and not wait for the appearance of recurrence. This study evaluates the outcome of this approach. From 1995 to 2012, 164 patients with hepatocellular carcinoma underwent resection. Eighty-five patients were potential candidates for liver transplantation and were considered for it upon detection of pejorative histological markers. Patients without these markers were followed, and salvage liver transplantation was considered upon development of tumor recurrence/liver function impairment. Thirty-seven patients were at high risk and 48 at low risk of recurrence at pathology. Twenty-three out of 37 high-risk patients recurred during follow-up, but in nine of them the tumor burden extent contraindicated liver transplantation. Seventeen were finally transplanted: 10 of them presented recurrence at imaging/explant. After a median posttransplant follow-up of 50.9 months, hepatocellular carcinoma had recurred in two patients and five patients had died, the 5-year survival being 82.4%. Twenty-six of the 48 low-risk patients developed recurrence, and 11 of them were transplanted. After a median posttransplant follow-up of 59 months, two patients developed recurrence and five died, their 5-year survival being 81.8%.Enlistment of patients at high risk of HCC recurrence after resection but before recurrence development seems a valid strategy and is associated with excellent long-term outcome; as early (<6 months) recurrence reflects an aggressive tumor behavior leading to tumor extent exceeding transplant criteria, we propose to wait at least 6 months before enlistment; however, once included on the waiting list, priority strategies should be implemented in order to reach effective transplantation prior to the appearance of recurrence.
VEGF-Induced Expression of miR-17–92 Cluster in Endothelial Cells Is Mediated by ERK/ELK1 Activation and Regulates Angiogenesis
Authors: Aránzazu Chamorro-Jorganes, Monica Y. Lee, Elisa Araldi, Shira Landskroner-Eiger, Marta Fernández-Fuertes, Mahnaz Sahraei, Maria Quiles del Rey, Coen van Solingen, Jun Yu, Carlos Fernández-Hernando, William C. Sessa, Yajaira Suárez
Journal: Circulation Research (2015)

Several lines of evidence indicate that the regulation of microRNA (miRNA) levels by different stimuli may contribute to the modulation of stimulus-induced responses. The miR-17-92 cluster has been linked to tumor development and angiogenesis, but its role in vascular endothelial growth factor-induced endothelial cell (EC) functions is unclear and its regulation is unknown.The purpose of this study was to elucidate the mechanism by which VEGF regulates the expression of miR-17-92 cluster in ECs and determine its contribution to the regulation of endothelial angiogenic functions, both in vitro and in vivo. This was done by analyzing the effect of postnatal inactivation of miR-17-92 cluster in the endothelium (miR-17-92 iEC-KO mice) on developmental retinal angiogenesis, VEGF-induced ear angiogenesis, and tumor angiogenesis.Here, we show that Erk/Elk1 activation on VEGF stimulation of ECs is responsible for Elk-1-mediated transcription activation (chromatin immunoprecipitation analysis) of the miR-17-92 cluster. Furthermore, we demonstrate that VEGF-mediated upregulation of the miR-17-92 cluster in vitro is necessary for EC proliferation and angiogenic sprouting. Finally, we provide genetic evidence that miR-17-92 iEC-KO mice have blunted physiological retinal angiogenesis during development and diminished VEGF-induced ear angiogenesis and tumor angiogenesis. Computational analysis and rescue experiments show that PTEN (phosphatase and tensin homolog) is a target of the miR-17-92 cluster and is a crucial mediator of miR-17-92-induced EC proliferation. However, the angiogenic transcriptional program is reduced when miR-17-92 is inhibited.Taken together, our results indicate that VEGF-induced miR-17-92 cluster expression contributes to the angiogenic switch of ECs and participates in the regulation of angiogenesis.
A tablet of clopidogrel remaining in the lower esophagus after primary percutaneous coronary intervention for acute myocardial infarction
Authors: Tomomi Koizumi, Shigeyuki Nishimura
Journal: Endoscopy (2015)

A 70-year-old woman with ST-segment elevation myocardial infarction (STEMI) underwent primary percutaneous coronary intervention (pPCI). She did not have a past history of either gastrointestinal disease or pemphigoid. Before the pPCI, she received dual antiplatelet therapy (a total of six tablets taken as a loading dose without much water) and maintained a supine position for several hours.
Subclinical Hypothyroidism
Authors: David S. Cooper
Journal: New England Journal of Medicine (2001)

This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the author's clinical recommendations.A 59-year-old woman is found to have a serum thyrotropin level of 7 mU per liter on routine screening. Her only symptoms are mild fatigue, which has been present for more than 10 years, and difficulty losing weight. The results of the physical examination are normal, except for the finding of a small, firm thyroid with a slightly irregular surface. The serum cholesterol level is 220 mg per deciliter (5.69 mmol per liter), the low-density lipoprotein (LDL) cholesterol level is 140 mg per deciliter (3.62 mmol per liter), and a test for antibodies against thyroperoxidase is positive. Should treatment . . .
Adrenocorticotropic hormone in the prevention of cisplatin-induced nausea and vomiting.
Authors: N Colbert, V Izrael, J P Lotz, D Stoppa-Lyonnet, J M Vannetzel, F Pene, M Schlienger, A Laugier
Journal: Journal of Clinical Oncology (1983)

A double-blind trial to evaluate the antiemetic effects of adrenocorticotropic hormone (ACTH) in patients treated with cisplatin was performed. Thirty-seven adults with advanced cancer who were treated with cisplatin were randomly assigned to receive either synthetic long-acting ACTH (1 mg IM given 24 hours, 12 hours, and immediately preceding the administration of cisplatin) or a placebo given under the same conditions. All of the patients received chlorpromazine (50 mg IM) 30 minutes before cisplatin infusion. Patients receiving ACTH and chlorpromazine had significantly fewer episodes of vomiting (p less than 0.01) and shorter periods of nausea (p less than 0.02) than patients receiving placebo and chlorpromazine. Patients receiving ACTH and chlorpromazine were significantly more comfortable than patients receiving placebo and chlorpromazine. No important side effects were observed. ACTH may be an effective agent in preventing nausea and vomiting induced by cisplatin.
The Specificity and Regulation of T-Cell Responsiveness to Allergens
Authors: R E O'Hehir, R D Garman, J L Greenstein, J R Lamb
Journal: Annual Review of Immunology (1991)

Exhausted CD8 T (Tex) cells are a distinct cell lineage that arise during chronic infections and cancers in animal models and humans. Tex cells are characterized by progressive loss of effector functions, high and sustained inhibitory receptor expression, ...Read More
Defining health and disease: setting the boundaries for physiotherapy. Are we undertreating or overtreating? How can we tell?
Authors: J N Baldwin, M J McKay, C E Hiller, E J Nightingale, N Moloney, N Vanicek, P Ferreira, M Simic, K Refshauge, J Burns
Journal: British Journal of Sports Medicine (2015)

Overdiagnosis and overtreatment is rife in medicine and has been identified in the discipline of sports medicine,1 as well as many others. Labelling healthy individuals with mild problems as ‘sick’ is concerning, notwithstanding the risks and costs of unnecessary treatment.2 Clinical decision-making depends on understanding the boundaries between health and disease. However, boundaries are often blurred due to complex and interactive psychosocial and cultural factors.

In the era of patient-centred care, the goal of treatment should be to address the individual as a whole and enable return to usual daily life. Targeting disability, rather than disease alone, must be a priority for clinicians, particularly in the case of diseases such as osteoarthritis that may be considered ‘par for the course’ of ageing. For example, osteoarthritis is a leading cause of disability worldwide, and this burden is set to rise alongside population ageing. Thus, cost-effective interventions are essential. Identifying disease and discerning when to intervene are salient concerns for clinicians, particularly in light of the problems of overdiagnosis and overtreatment. But when does a joint change from being ‘healthy’ to …
Immunology of Syphilis
Authors: G R Cannefax, L C Norins, E J Gillespie
Journal: Annual Review of Medicine (1967)

Many advances have been made in solving microbiological and immu­ nological enigmas since 1905 when Schaudinn & Hoffmann (1) identified the causal organism of syphilis. However, over 60 years later we still are unable to grow virulent Treponema pallidum on artificial media, do not have a vac­ cine, know little about the immunological mechanisms of this disease, and are again seeing syphilis sweep the world in epidemic proportion. Many unanswered questions of host-parasite relationship are of concern to students of the disease. For example, what is the true relationship of the organism and its products to CIutton's joints and interstitial keratitis as seen in congenital syphilis or to the gumma of late syphilis? Nor can we answer why some infected individuals develop cardiovascular or neurosyph­ ilis while others manifest only a reactive serologic test for syphilis. It is not possible to present in the allotted space an extensive treatise on reports of a rather voluminous literature about various immunological as­ pects of naturally acquired and experimental syphilis. We will, instead, pre­ sent selected representative reports and pose further questions on the im­ munology of syphilis by. presenting certain research that we hope will stimu­ late your own interest in the field. Extensive reviews are those of Neisser (2), Chesney (3), Urbach & Beer­ man (4), and Magnuson (5). More recent papers on the subject are those of Wigfield (6) and Cannefax (7). Serologic tests for syphilis are not given detailed coverage in this review. Discussions of serologic tests for syphilis in current use can be found in ar­ ticles by Nicholas & Beerman (8), Wallace (9), and Gillespie & Brown (10).
Erratum to: Comprehensive evaluation of differential gene expression analysis methods for RNA-seq data
Authors: Franck Rapaport, Raya Khanin, Yupu Liang, Mono Pirun, Azra Krek, Paul Zumbo, Christopher E. Mason, Nicholas D. Socci, Doron Betel
Journal: Genome biology (2015)

We previously published a report on the comprehensive evaluation of RNA-seq differential analysis (DE) methods [1] where we compared a number of popular DE tools using a variety of different criteria. Since publication we received valuable feedback and suggestions from the community including from the authors of the algorithms. Here we report on two errors that came to our attention following publication.

1. Soon after publication we were notified about a discrepancy in table 2. The correction was posted as comment to the main article and now included as erratum. In the last row of table 2 called Runtime for experiments with 3-5 replicates… the values for edgeR and limmaVoom should be Seconds not Minutes.


For completeness, the following table is the runtime performance (in seconds) of six DE analysis methods, comparing the 5 replicates from groups A and B from the SEQC data, as measured on Red Hat Enterprise Linux Server release 5.4, with 12 dual cores Intel Xeon 3.33GHz, and 100G RAM.






2. Zhou and Robinson performed a follow up analysis to our manuscript where they reanalyzed DE when genes are expressed in one condition (see correspondence to Rapaport et al.). They identified a coding error in the calculation of edgeR signal to noise values due to incorrect normalization of edgeR count values. Library size values were not used to scale gene counts. This coding error was fixed and a corrected version is deposited in the source code repository available at: http://bitbucket.org/soccin/seqc.

We redid the analysis for evaluation of genes expressed in only one condition and the main conclusions remain unchanged. The corrected version of Figure 4 in the main manuscript is presented here as Fig. ​Fig.11.



Fig. 1

a edgeR correlation between signal-to-noise and –log10(p-values) using the corrected normalization of gene counts. b ROC analysis of curves for detection of DE at signal-to-noise ratio of ≥3. Note that edgeR AUC has improved from 0.788 ...



We note that our reanalysis is based on the exact same procedure used in the original publication. However, Zhou and Robinson introduce a different version of this analysis where the ROC analysis is based on a common set of genes. Second, most packages used in our original publication have since been updated and in some cases the algorithms revised substantially. Therefore, it is possible that a similar comparison with the latest versions of the packages may result in different conclusions.
Managing risk of hepatitis B after sharps injuries
Authors: Antoon A De Schryver, Wim Van Hooste, Hilde Van Acker, Bieke Claessens, Roger Haenen, Katrien Van Crombrugge, Lode Godderis
Journal: BMJ (2015)

Although Riddell and colleagues' timely update on managing sharps injuries is of great practical use, we have a couple of questions about the hepatitis B management algorithm based on the recipient's vaccination history. 1 The algorithm, based on UK immunisation guidelines, mentions two possible hepatitis B vaccination histories, one of which is two or more doses of vaccine.Does this mean that people who have received two or more doses are considered to be completely vaccinated and that immunisation of healthcare workers against hepatitis B should be restricted to two doses?This seems contrary to the European consensus of 2000, which recommends three doses as a primary course. 2 Secondly, the recommendation is to consider a booster vaccine dose in known vaccine responders (anti-hepatitis B surface antigen >10 mIU/mL) who have received two or more doses of vaccine.Does it mean that known vaccine responders who have received three (or more) doses should be given a booster dose?This also seems contrary to the European Consensus, which recommends no booster if the primary vaccination has been effective. 2It is also not recommended by various European, 3 US, 4 and other national guidelines. 5
Sodium–Glucose Cotransporter Inhibitors: Effects on Renal and Intestinal Glucose Transport
Authors: Sunder Mudaliar, David Polidori, Brian Zambrowicz, Robert R. Henry
Journal: Diabetes Care (2015)

Type 2 diabetes is a chronic disease with disabling micro- and macrovascular complications that lead to excessive morbidity and premature mortality. It affects hundreds of millions of people and imposes an undue economic burden on populations across the world. Although insulin resistance and insulin secretory defects play a major role in the pathogenesis of hyperglycemia, several other metabolic defects contribute to the initiation/worsening of the diabetic state. Prominent among these is increased renal glucose reabsorption, which is maladaptive in patients with diabetes. Instead of an increase in renal glucose excretion, which could ameliorate hyperglycemia, there is an increase in renal glucose reabsorption, which helps sustain hyperglycemia in patients with diabetes. The sodium–glucose cotransporter (SGLT) 2 inhibitors are novel antidiabetes agents that inhibit renal glucose reabsorption and promote glucosuria, thereby leading to reductions in plasma glucose concentrations. In this article, we review the long journey from the discovery of the glucosuric agent phlorizin in the bark of the apple tree through the animal and human studies that led to the development of the current generation of SGLT2 inhibitors.