tbuckley/cabot-search huggingface dataset:
Small studies: strengths and limitations
Authors: A. Hackshaw
Journal: European Respiratory Journal (2008)

A large number of clinical research studies are conducted, including audits of patient data, observational studies, clinical trials and those based on laboratory analyses. While small studies can be published over a short time-frame, there needs to be a balance between those that can be performed quickly and those that should be based on more subjects and hence may take several years to complete. The present article provides an overview of the main considerations associated with small studies.

The definition of “small” depends on the main study objective. When simply describing the characteristics of a single group of subjects, for example the prevalence of smoking, the larger the study the more reliable the results. The main results should have 95% confidence intervals (CI), and the width of these depend directly on the sample size: large studies produce narrow intervals and, therefore, more precise results. A study of 20 subjects, for example, is likely to be too small for most investigations. For example, imagine that the proportion of smokers among a particular group of 20 individuals is 25%. The associated 95% CI is 9–49. This means that the true prevalence in these subjects generally is anywhere between a low or high value, which is not a useful result.

When comparing characteristics between two or more groups of subjects ( e.g. examining risk factors or treatments for disease), the size of the study depends on the magnitude of the expected effect size, which is usually quantified by a relative risk, odds ratio, absolute risk difference, hazard ratio, or difference between two means or medians. The smaller the true-effect size, the larger the study needs to be 1, 2. This is because it is more difficult to distinguish between a real effect and random variation. Consider mortality as the end-point in a …
Host-dependent Lewis (Le) antigen expression in <i>Helicobacter pylori</i> cells recovered from Leb-transgenic mice
Authors: Mary Ann Pohl, Judith Romero-Gallo, Janaki L. Guruge, Doris B. Tse, Jeffrey I. Gordon, Martin J. Blaser
Journal: The Journal of Experimental Medicine (2009)

Variation of surface antigen expression is a mechanism used by microbes to adapt to and persist within their host habitats. Helicobacter pylori, a persistent bacterial colonizer of the human stomach, can alter its surface Lewis (Le) antigen expression. We examined H. pylori colonization in mice to test the hypothesis that host phenotype selects for H. pylori (Le) phenotypes. When wild-type and Leb-expressing transgenic FVB/N mice were challenged with H. pylori strain HP1, expressing Lex and Ley, we found that bacterial populations recovered after 8 mo from Leb-transgenic, but not wild-type, mice expressed Leb. Changes in Le phenotype were linked to variation of a putative galactosyltransferase gene (β-(1,3)galT); mutagenesis and complementation revealed its essential role in type I antigen expression. These studies indicate that H. pylori evolves to resemble the host's gastric Le phenotype, and reveal a bacterial genetic locus that is subject to host-driven selection pressure.
Systemic gene transfer enables optogenetic pacing of mouse hearts
Authors: C. C. Vogt, T. Bruegmann, D. Malan, A. Ottersbach, W. Roell, B. K. Fleischmann, P. Sasse
Journal: Cardiovascular Research (2015)

Optogenetic pacing of the heart has been demonstrated in transgenic animals expressing channelrhodopsin-2 (ChR2). However, for the clinical use of optogenetics to treat cardiac arrhythmias, gene transfer to non-transgenic hearts is required. The aim of this study was to describe a reliable method for gene transfer of ChR2 into a sufficient percentage of cardiomyocytes to overcome the electrical sink of all the coupled non-expressing cardiomyocytes during optical pacing of the whole heart in vivo. Adeno-associated virus (AAV) with cardiac tropism for expression of ChR2 in fusion with mCherry was systemically injected into wild-type mouse hearts. Bright mCherry fluorescence was detected in the whole heart 4–10 weeks later. Single-cell dissociation revealed that on average 58% cardiomyocytes were mCherry-positive. These showed light-induced inward currents, action potentials, and contractions. Pulsed illumination of the left ventricle induced ventricular pacing in vivo in 74% of mice, and higher light intensities were required for reduced pulse duration or size of illumination. Non-responding hearts showed low AAV expression, and the threshold for optical pacing was estimated to be 35–40% ChR2-expressing cardiomyocytes. Optical pacing in vivo was stable over extended periods without negative effects on normal sinus rhythm and ECG parameters after termination of stimulation indicating sufficient cardiac output during pacing. Gene transfer generates sufficient ChR2 photocurrent for reliable optogenetic pacing in vivo and lays out the basis for future optogenetic pacemaker and pain-free defibrillation therapies.
Report on the Pathology of Infantile Marasmus
Authors: W. S. Fenwick
Journal: BMJ (1896)

PROGRESSIVE wasting of the tissues of the body in infancy may be due to many different causes.In some cases the symptom arises from some constitutional affection, such as rickets or syphilis.In other instances tuberculosis is directly responsible for the loss of flesh; while in others, again, actual want of food, or starvation, is the sole cause of the emaciation.But perhaps the most interesting variety of infantile atrophy is that which ensues from the habitual administration of certain deleterious substances, miscalled
A Phase Ib Open Label Clinical Trial of Continuous Once Daily Oral Afatinib (A) Plus Sirolimus (S) in Patients (Pts) with Egfr Mutation Positive (Egfr M+) Nsclc and/or Disease Progression Following Prior Erlotinib (E) or Gefitinib (G)
Authors: T. Moran, R. Palmero, M. Provencio, A. Insa, M. Majem, N. Reguart, J. Bosch-Barrera, D. Isla, C.P. Lee, S. Kraemer, D. Schnell, R. Rosell
Journal: Annals of Oncology (2014)
Thymic negative selection is functional in NOD mice
Authors: Michael Mingueneau, Wenyu Jiang, Markus Feuerer, Diane Mathis, Christophe Benoist
Journal: The Journal of Experimental Medicine (2012)

Based on analyses of multiple TCR transgenic (tg) models, the emergence of pathogenic T cells in diabetes-prone NOD mice has been ascribed to a failure to censure autoreactive clones in the thymus. In contrast, using isolated and preselected thymocytes, we show that nonobese diabetic (NOD) genetic variation impairs neither clonal deletion nor downstream transcriptional programs. However, we find that NOD genetic variation influences αβ/γδ-lineage decisions promoted by early expression of tg αβ-TCRs at the double-negative (DN) stage. In B6 and other genetic backgrounds, tg αβ-TCRs behave like γδ-TCRs and commit a large fraction of DNs toward the γδ-lineage, thereby decreasing the size of the double-positive (DP) pool, which is efficiently positively and negatively selected. In NOD DNs, αβ-TCR signalosomes instead behave like pre-TCRs, resulting in high numbers of DPs competing for limited selection niches, and poor positive and negative selection. Once niche effects are neutralized in mixed bone marrow chimeras, positive and negative selection are equally efficient on B6 and NOD backgrounds. Biochemical analysis revealed a selective defect in the activation of Erk1/2 downstream of NOD αβ-TCR signalosomes. Therefore, NOD genetic variation influences αβ/γδ-lineage decisions when the αβ-TCR heterodimer is prematurely expressed, but not the process of negative selection.
Nitric oxide in primary ciliary dyskinesia
Authors: Woolf T. Walker, Claire L. Jackson, Peter M. Lackie, Claire Hogg, Jane S. Lucas
Journal: European Respiratory Journal (2012)

Nitric oxide is continually synthesised in the respiratory epithelium and is upregulated in response to infection or inflammation. Primary ciliary dyskinesia (PCD) is characterised by recurrent sinopulmonary infections due to impaired mucociliary clearance. Despite chronic infections, nasal nitric oxide in such patients is markedly reduced and is used as a screening test for this condition. These low levels were first described &gt;15 yrs ago but the underlying mechanisms have yet to be fully elucidated. We review epithelial nitric oxide synthesis, release and measurement in the upper airways with particular reference to PCD. The key hypotheses that have been proposed to explain the low nitric oxide levels in this condition are explored and the potential benefits of augmenting airway nitric oxide levels are considered. Further work in these patients clarifying both whether the respiratory epithelium is able to biosynthesise normal levels of nitric oxide and the role played by abnormalities in the anatomy of the paranasal sinuses is essential. While nitric oxide augmentation is unlikely to be beneficial in common PCD phenotypes, it has potential in the treatment of secondary dyskinesias and may also improve treatment of bacterial infections, particularly where biofilms are implicated.
Complementary and Alternative Medicine Among Advanced Cancer Patients Enrolled on Phase I Trials: A Study of Prognosis, Quality of Life, and Preferences for Decision Making
Authors: Fay J. Hlubocky, Mark J. Ratain, Ming Wen, Christopher K. Daugherty
Journal: Journal of Clinical Oncology (2007)

We sought to describe complementary and alternative medicine (CAM) usage among phase I trial participants and to describe these patients' treatment decision-making preferences, awareness of prognosis, survival, and quality of life.Advanced cancer patients enrolling onto phase I trials were surveyed regarding biologically based CAM use. Decision-making preferences and awareness of prognosis were assessed using validated and/or standardized instruments. The Functional Assessment of Cancer Therapy-General instrument was used to assess quality of life. Univariate and multivariate analyses were performed to detect differences between CAM users and nonusers.Of 212 interviewed patients, 34% (n = 72) described taking biologically based CAM. Median age of those taking biologically based CAM was 55 years, compared with 62 years for nonusers (P < .005). There were no statistically significant differences found between CAM usage and preferences for degree of patient involvement in medical decision making. Those patients who acknowledged that their deaths were likely to occur within 1 year were more likely to admit to prior CAM use (70% v 34%; P = .02). CAM users had poorer overall quality of life compared with nonusers (87.0 +/- 12.4 v 91.2 +/- 14.7; P = .007). No differences in survival were identified.Prior CAM use among phase I cancer trial patients studied was common and associated with age, stated acknowledgment of prognosis, and quality of life. Patients enrolling onto early-phase trials should be questioned about CAM use. Additional study is needed to determine the frequency of use of those biologically based CAM agents that threaten the accuracy of early-phase cancer trial data.
Metastatic tumor evolution and organoid modeling implicate TGFBR2as a cancer driver in diffuse gastric cancer
Authors: Lincoln D Nadauld, Sarah Garcia, Georges Natsoulis, John M Bell, Laura Miotke, Erik S Hopmans, Hua Xu, Reetesh K Pai, Curt Palm, John F Regan, Hao Chen, Patrick Flaherty, Akifumi Ootani, Nancy R Zhang, James M Ford, Calvin J Kuo, Hanlee P Ji
Journal: Genome biology (2014)

Abstract Background Gastric cancer is the second-leading cause of global cancer deaths, with metastatic disease representing the primary cause of mortality. To identify candidate drivers involved in oncogenesis and tumor evolution, we conduct an extensive genome sequencing analysis of metastatic progression in a diffuse gastric cancer. This involves a comparison between a primary tumor from a hereditary diffuse gastric cancer syndrome proband and its recurrence as an ovarian metastasis. Results Both the primary tumor and ovarian metastasis have common biallelic loss-of-function of both the CDH1 and TP53 tumor suppressors, indicating a common genetic origin. While the primary tumor exhibits amplification of the Fibroblast growth factor receptor 2 ( FGFR2 ) gene, the metastasis notably lacks FGFR2 amplification but rather possesses unique biallelic alterations of Transforming growth factor-beta receptor 2 ( TGFBR2 ), indicating the divergent in vivo evolution of a TGFBR2 -mutant metastatic clonal population in this patient. As TGFBR2 mutations have not previously been functionally validated in gastric cancer, we modeled the metastatic potential of TGFBR2 loss in a murine three-dimensional primary gastric organoid culture. The Tgfbr2 shRNA knockdown within Cdh1 -/- ; Tp53 -/- organoids generates invasion in vitro and robust metastatic tumorigenicity in vivo , confirming Tgfbr2 metastasis suppressor activity. Conclusions We document the metastatic differentiation and genetic heterogeneity of diffuse gastric cancer and reveal the potential metastatic role of TGFBR2 loss-of-function. In support of this study, we apply a murine primary organoid culture method capable of recapitulating in vivo metastatic gastric cancer. Overall, we describe an integrated approach to identify and functionally validate putative cancer drivers involved in metastasis.
Sorafenib in Renal Cell Carcinoma
Authors: Keith T. Flaherty
Journal: Clinical Cancer Research (2007)

Abstract Sorafenib is an orally available inhibitor of vascular endothelial growth factor receptors, platelet-derived growth factor receptor-β, and RAF kinases. A dose of 400 mg twice daily administered continuously was selected for phase 2 testing, although 600 mg twice daily formally met criteria for a maximum tolerated dose. It is well tolerated compared with cytokine therapy. Antitumor activity was shown clearly in the context of a randomized discontinuation phase 2 trial. In this setting, even disease stabilization was established as a treatment-related phenomenon. A phase 3 trial with sorafenib confirmed a benefit of therapy across the vast majority of patients treated with sorafenib as opposed to placebo. Limited investigations into the mechanism of action of sorafenib in renal cell carcinoma support vascular endothelial growth factor receptor antagonism as the primary mediator of effect. The toxicity profile of sorafenib allows for its use in combination regimens. The focus of efforts to improve on the efficacy of sorafenib is on use with IFN, bevacizumab, or temsirolimus. Preliminary evidence with this approach is promising and will be the subject of the next generation of randomized trials in renal cell carcinoma.
Nephronophthisis
Authors: Friedhelm Hildebrandt, Massimo Attanasio, Edgar Otto
Journal: Journal of the American Society of Nephrology (2009)

Nephronophthisis (NPHP), a recessive cystic kidney disease, is the most frequent genetic cause of end-stage kidney disease in children and young adults. Positional cloning of nine genes (NPHP1 through 9) and functional characterization of their encoded proteins (nephrocystins) have contributed to a unifying theory that defines cystic kidney diseases as "ciliopathies." The theory is based on the finding that all proteins mutated in cystic kidney diseases of humans or animal models are expressed in primary cilia or centrosomes of renal epithelial cells. Primary cilia are sensory organelles that connect mechanosensory, visual, and other stimuli to mechanisms of epithelial cell polarity and cell-cycle control. Mutations in NPHP genes cause defects in signaling mechanisms that involve the noncanonical Wnt signaling pathway and the sonic hedgehog signaling pathway, resulting in defects of planar cell polarity and tissue maintenance. The ciliary theory explains the multiple organ involvement in NPHP, which includes retinal degeneration, cerebellar hypoplasia, liver fibrosis, situs inversus, and mental retardation. Positional cloning of dozens of unknown genes that cause NPHP will elucidate further signaling mechanisms involved. Nephrocystins are highly conserved in evolution, thereby allowing the use of animal models to develop future therapeutic approaches.
Von Willebrand's disease with spontaneous platelet aggregation induced by an abnormal plasma von Willebrand factor.
Authors: H R Grainick, S B Williams, L P McKeown, M E Rick, P Maisonneuve, C Jenneau, Y Sultan
Journal: Journal of Clinical Investigation (1985)

We have investigated and characterized the abnormalities in four unrelated patients with von Willebrand's disease (vWd) who have (a) enhanced ristocetin-induced platelet aggregation (RIPA) at low ristocetin concentrations, (b) absence of the largest plasma von Willebrand factor (vWf) multimers, and (c) thrombocytopenia. The platelet-rich plasma of these patients aggregates spontaneously without the addition of any agonists. When isolated normal platelets are resuspended in patient plasma spontaneous aggregation occurs; however, the patients' plasmas did not induce platelet aggregation of normal washed formalinized platelets. When the patients' platelets are suspended in normal plasma, spontaneous aggregation is not observed. The spontaneous platelet aggregation (SPA) is associated with dense granule secretion as measured by ATP release and alpha granule release as measured by beta-thromboglobulin and platelet factor 4 release. The SPA is totally inhibited by 5 mM EDTA, prostaglandin I2, and dibutryl cyclic AMP, while it is only partially inhibited by 1 mM EDTA, acetylsalicylic acid, or apyrase. A monoclonal antibody directed against glycoprotein Ib (GPIb) and/or a monoclonal antibody against the glycoprotein IIb/IIIa (GPIIb/IIIa) complex totally inhibits the SPA. The vWf was isolated from the plasma of one of these patients. The purified vWf induced platelet aggregation of normal platelets resuspended in either normal or severe vWd plasma, but the vWf did not induce platelet aggregation of normal platelets resuspended in afibrinognemic plasma. Sialic acid and galactose quantification of the patient's vWf revealed approximately a 50% reduction compared with normal vWf. These studies indicate that a form of vWd exists, which is characterized by SPA that is induced by the abnormal plasma vWf. The SPA is dependent on the presence of plasma fibrinogen, and the availability of the GPIb and the GPIIb/IIIa complex. In this variant form of vWd the abnormal vWf causes enhanced RIPA, SPA, and thrombocytopenia.
Appearance of the Novel Activating F1174S ALK Mutation in Neuroblastoma Correlates with Aggressive Tumor Progression and Unresponsiveness to Therapy
Authors: Tommy Martinsson, Therese Eriksson, Jonas Abrahamsson, Helena Caren, Magnus Hansson, Per Kogner, Sattu Kamaraj, Christina Schönherr, Joel Weinmar, Kristina Ruuth, Ruth H. Palmer, Bengt Hallberg
Journal: Cancer Research (2010)

Mutations in the kinase domain of the ALK kinase have emerged recently as important players in the genetics of the childhood tumor neuroblastoma. Here, we report the appearance of a novel ALK mutation in neuroblastoma, correlating with aggressive tumor behavior. Analyses of genomic DNA from biopsy samples initially showed ALK sequence to be wild type. However, during disease progression, mutation of amino acid F1174 to a serine within the ALK kinase domain was observed, which correlated with aggressive neuroblastoma progression in the patient. We show that mutation of F1174 to serine generates a potent gain-of-function mutant, as observed in 2 independent systems. First, PC12 cell lines expressing ALK(F1174S) display ligand-independent activation of ALK and further downstream signaling activation. Second, analysis of ALK(F1174S) in Drosophila models confirms that the mutation mediates a strong, rough eye phenotype upon expression in the developing eye. Thus, we report a novel ALK(F1174S) mutation that displays ligand-independent activity in vivo, correlating with rapid and treatment-resistant tumor growth. The study also shows that initial screening in the first tumor biopsy of a patient may not be sufficient and that further molecular analysis, in particular in tumor progression and/or tumor relapse, is warranted for better understanding of the treatment of neuroblastoma patients.
Comparison between percutaneous ethanol injection (PEI) and transarterial chemoembolization (TACE) in patients with small hepatocellular carcinoma (HCC)
Authors: G. Cioni, F. Turrini, E. Baraldi, P.G. Pedrazzini, E. Ventura, A. Ferrari, P. D'Alimonte, P. Ariosi, M. De Santis
Journal: Journal of Hepatology (2000)
New Aspects in the Pathophysiology of Preeclampsia
Authors: John M. Davison, Volker Homuth, Arun Jeyabalan, Kirk P. Conrad, S. Ananth Karumanchi, Susan Quaggin, Ralf Dechend, Friedrich C. Luft
Journal: Journal of the American Society of Nephrology (2004)

Preeclampsia, the de novo occurrence of hypertension and proteinuria after the 20th week of gestation, continues to exert an inordinate toll on mothers and children alike. Recent clinical trials, new physiologic insights, and novel observations on pathogenesis have altered the thinking about preeclampsia. The mechanisms surrounding relaxin and its effects on the circulation and on matrix metalloproteinases have been elucidated. The growth factor's receptor, fms-like tyrosine kinase 1, has been shown to exist in a soluble form that is able to inactivate vascular endothelial-derived growth factor and human placental growth factor. Compelling evidence has been brought forth suggesting that fms-like tyrosine kinase 1 is a circulating factor that can cause preeclampsia. Preeclamptic women have high circulating levels of asymmetric dimethyl arginine that could account for the generalized endothelial dysfunction observed in preeclampsia. Preeclamptic women also produce novel autoantibodies that may serve to activate angiotensin receptors. These new observations raise the possibility that the treatment of preeclamptic women will soon be improved.
Mining the pre-diagnostic antibody repertoire of TgMMTV-neu mice to identify autoantibodies useful for the early detection of human breast cancer
Authors: Sasha E Stanton, Jianning Mao, John Ladd, Lauren Rastedder, Ekram Gad, Samir Hanash, Mary L Disis
Journal: Journal for ImmunoTherapy of Cancer (2013)

Meeting abstracts Breast cancer has been shown to be immunogenic and can stimulate an antibody immune response. Because of this immunogenicity, identification of early breast tumor antigens could allow identification of autoantibodies for the early detection of breast cancer. In this study, the
American Cancer Society Guidelines for Breast Cancer Screening: Update 2003
Authors: R. A. Smith, D. Saslow, K. Andrews Sawyer, W. Burke, M. E. Costanza, W. P. Evans, R. S. Foster, E. Hendrick, H. J. Eyre, S. Sener
Journal: CA A Cancer Journal for Clinicians (2003)

In 2003, the American Cancer Society updated its guidelines for early detection of breast cancer based on recommendations from a formal review of evidence and a recent workshop. The new screening recommendations address screening mammography, physical examination, screening older women and women with comorbid conditions, screening women at high risk, and new screening technologies.
Some Properties of Contractile Proteins of the Heart as Studied on the Extracted Heart Muscle Preparation
Authors: MAX TAESCHLER, R. J. BING
Journal: Circulation Research (1953)

The physiologic properties of the contractile elements (actomyosin) have been studied on the extracted heart muscle of the dog. It was found that many properties of fresh heart muscle are due to inherent qualities of the contractile proteins. For example, the speed of contraction decreased with increasing loads, the work increased with rising tension up to an optimal value, and increased fiber length resulted in greater muscle work.