tbuckley/cabot-search huggingface dataset:
Unfolding the mechanisms of progression of pulmonary emphysema in COPD
Authors: Riccardo Pellegrino, Andrea Antonelli
Journal: European Respiratory Journal (2012)

Until a quarter of a century ago, diagnosing pulmonary emphysema in clinical practice was a very difficult task, as the definition of the disease was based only on the pathological criteria of destruction of the parenchyma distal to the terminal bronchioles in the absence of inflammation and/or fibrosis [1]. Lung function tests could be of help but this was only possible when airflow obstruction was severe, lung volumes increased above normal and diffusing capacity of the lung very low, i.e. too late to identify the disease in the early stages. Similarly, chest radiography could be of help for this purpose but only when lung fields were hyperlucent with blebs and no or few arteries, the diaphragm was flat, and anteroposterior diameters were increased. Again, this was when the disease was too advanced. A major breakthrough occurred with the advent of high-resolution computed tomography (HRCT), a tool that proved to be very sensitive in assessing the pathology on its centrilobular, panlobular and paraseptal features, and its distribution across the lungs [2, 3]. The results were so impressive that the technique was soon widely used in both clinical practice and research. In addition to assisting in the clinical diagnosis of the disease condition, HRCT brought major advancements as for the pathogenesis of the chronic obstructive pulmonary disease (COPD), and nowadays plays a crucial role with respect to lung volume reduction surgery [4] and transplantation [5].

Recent studies have focused on HRCT as a tool to assess the progression of the disease. Most of them have been conducted in α1-antitrypsin deficiency with the aim of identifying the lung densitometry parameters that best reflect the progression of the disease [6] compared with classical functional parameters, such as forced expiratory volume in …
The Long Isoform of Terminal Deoxynucleotidyl Transferase Enters the Nucleus And, Rather than Catalyzing Nontemplated Nucleotide Addition, Modulates the Catalytic Activity of the Short Isoform
Authors: Cindy L. Benedict, Susan Gilfillan, John F. Kearney
Journal: The Journal of Experimental Medicine (2001)

During variable/diversity/joining (V[D]J) recombination, the enzyme terminal deoxynucleotidyl transferase (Tdt) adds random nucleotides at the junctions of the rearranging gene segments, increasing diversity of the antibody (Ab) and T cell receptor repertoires. Two splice variants of Tdt have been described, but only one (short isoform of Tdt [TdtS]) has been convincingly demonstrated to catalyze nontemplated (N) addition in vitro. We have expressed each splice variant of Tdt in transgenic (Tg) mice and found that the TdtS transgene catalyzes N addition on the endogenous Tdt(-/)- background and in fetal liver, but that the long isoform of Tdt (TdtL) transgene does neither. In contrast to previous in vitro results, both TdtS and TdtL are translocated to the nucleus in our model. Furthermore, TdtL/TdtS double Tg mice exhibit less N addition in fetal liver than do TdtS Tg mice. Whereas the TdtS transgene was shown to have functional consequences on the antiphosphorylcholine (PC) B cell repertoire, TdtL Tg mice exhibit a normal PC response, and Tdt(-/)- mice actually exhibit an increase in the PC response and in TEPC 15 idiotype(+) Ab production. We conclude that TdtL localizes to the nucleus in vivo where it serves to modulate TdtS function.
Endothelial dysfunction in young patients with rheumatoid arthritis and low disease activity
Authors: G Vaudo
Journal: Annals of the Rheumatic Diseases (2003)

Rheumatoid arthritis (RA) is associated with an increased risk of cardiovascular disease. Endothelial dysfunction represents the earliest stage of atherosclerosis.To evaluate the influence of chronic inflammatory state on endothelial function in patients with RA by measuring endothelial reactivity in young patients with RA with low disease activity and without traditional cardiovascular risk factors.Brachial flow mediated vasodilatation (FMV), assessed by non-invasive ultrasound, was evaluated in 32 young to middle aged patients with RA (age </=59 years), with DAS28 </=3.2 and without overt cardiovascular disease, and in 28 age and sex matched controls.Mean (SD) FMV was significantly lower in patients than in controls (3.2 (1.3)% v 5.7 (2.0)%; p<0.001), inversely related to low density lipoprotein cholesterol (r = -0.45, p<0.05) and C reactive protein (CRP), expressed as the value at the moment of ultrasound evaluation (r = -0.44, p<0.05), as the average of CRP levels evaluated at different times during the disease (r = -0.47, p<0.05), or as the average of >/=4 determinations multiplied by the disease duration (r = -0.40, p<0.05). In a multivariate regression model, a lower brachial flow mediated vasodilatation was independently predicted by low density lipoprotein cholesterol (beta = -0.40, p<0.05), average CRP levels multiplied by the disease duration (beta = -0.44, p<0.05), and brachial artery diameter (beta = -0.28, p<0.05).Young to middle aged patients with RA with low disease activity, free from cardiovascular risk factors and overt cardiovascular disease, have an altered endothelial reactivity that seems to be primarily related to the disease associated chronic inflammatory condition.
BI 6727, A Polo-like Kinase Inhibitor with Improved Pharmacokinetic Profile and Broad Antitumor Activity
Authors: Dorothea Rudolph, Martin Steegmaier, Matthias Hoffmann, Matthias Grauert, Anke Baum, Jens Quant, Christian Haslinger, Pilar Garin-Chesa, Günther R. Adolf
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Antimitotic chemotherapy remains a cornerstone of multimodality treatment for locally advanced and metastatic cancers. To identify novel mitosis-specific agents with higher selectivity than approved tubulin-binding agents (taxanes, Vinca alkaloids), we have generated inhibitors of Polo-like kinase 1, a target that functions predominantly in mitosis. Experimental Design: The first compound in this series, suitable for i.v. administration, has entered clinical development. To fully explore the potential of Polo-like kinase 1 inhibition in oncology, we have profiled additional compounds and now describe a novel clinical candidate. Results: BI 6727 is a highly potent (enzyme IC50 = 0.87 nmol/L, EC50 = 11-37 nmol/L on a panel of cancer cell lines) and selective dihydropteridinone with distinct properties. First, BI 6727 has a pharmacokinetic profile favoring sustained exposure of tumor tissues with a high volume of distribution and a long terminal half-life in mice (Vss = 7.6 L/kg, t1/2 = 46 h) and rats (Vss = 22 L/kg, t1/2 = 54 h). Second, BI 6727 has physicochemical and pharmacokinetic properties that allow in vivo testing of i.v. as well as oral formulations, adding flexibility to dosing schedules. Finally, BI 6727 shows marked antitumor activity in multiple cancer models, including a model of taxane-resistant colorectal cancer. With oral and i.v. routes of administration, the total weekly dose of BI 6727 is most relevant for efficacy, supporting the use of a variety of well-tolerated dosing schedules. Conclusion: These findings warrant further investigation of BI 6727 as a tailored antimitotic agent; clinical studies have been initiated.
Disappearance and appearance of isoenzymes of creatine kinase, lactate dehydrogenase and aspartate aminotransferase in the myocardium undergoing infarction
Authors: Y. MATSUI, H. HASHIMOTO, H. TSUKAMOTO, K. OKUMURA, T. ITO, K. OGAWA, T. SATAKE
Journal: Cardiovascular Research (1989)

Recent investigations have shown that cardiac isoenzymes change with mechanical overload and possibly with myocardial ischaemia. This complicates the interpretation of serum enzyme changes in acute myocardial infarction. We have therefore investigated the rate of release of isoenzymes from necrosing myocardium and the effect of ischaemia per se. Discrete myocardial infarction was produced in 35 male Wistar rats by ligation of left coronary artery. Six (n = 7), 12 (n = 6), 24 (n = 9), 72 (n = 7) h and 3 weeks (n = 6) after surgery, total and isoenzyme activities of creatine kinase (CK), lactate dehydrogenase (LD) and aspartate aminotransferase (AST) were measured in the infarcted myocardium. Untreated rats (n = 12) were used as the control (time 0). Sham operation was performed in 36 rats. During the early period (0 to 12 or 24 h) of infarction, each (iso)enzyme disappeared monoexponentially from the myocardium (mean r = 0.88) with different disappearance rates. Cytosolic isoenzyme fractions decreased more rapidly than mitochondrial fractions. CK MB and the LD-H subunit decreased faster than CK MM and the LD-M subunit. Such differences in the disappearance rate may be related to subcellular localisation of each isoenzyme. In the late period (72 h and 3 weeks), CK BB and the LD-M subunit showed significant reaccumulation in the infarcted myocardium. Although inflammatory cells can be responsible for the reaccumulation of LD-M subunit, the origin of CK BB is unknown.(ABSTRACT TRUNCATED AT 250 WORDS)
Expression of the Defective “S+L−” Type Murine Sarcoma Virus Genome in Human Amnion and Lung Cells
Authors: Alexander G. Papageorge, Paul T. Peebles, Brenda I. Gerwin, Peter J. Fischinger, Carl F. T. Mattern
Journal: JNCI Journal of the National Cancer Institute (1974)

Murine sarcoma virus (MSV) rescued from cloned sarcoma-positive leukemia-negative (S+ L-) mouse cells was used to obtain a single cell clone, S+L− HuACh, from a single-hit terminal focus in human AV-3 amnion cells. Second generation MSV, rescued from S+L− HuACh cells by superinfection with RD-114 virus, was used to generate 3 clones of S+L− cells derived from 3 separate MSV foci in L-132 human lung cells. S+L− human amnion and lung cell clones demonstrated certain characteristics of S+L− mouse cells: All 4 S+L− human cell clones were transformed, expressed the genetically stable murine leukemia virus group-specific antigen marker, and con- tained cryptic MSV rescuable by superinfection with compatible helper-type viruses that conferred host range properties on the rescued MSV pseudotypes. S+L− human cells differed from S+L− mouse cells in that the human cells did not release detectable C-type virus-like particles. S+L− human cells also lacked detectable quantities of the viral core protein reverse transcriptase. Although similar to non producer Kirsten-MSV transformed mouse cells, S+L− human cells failed to release detectable MSV after iododeoxyuridine induction.
Multiple Dicer Genes in the Early-Diverging Metazoa
Authors: D. de Jong, M. Eitel, W. Jakob, H.-J. Osigus, H. Hadrys, R. DeSalle, B. Schierwater
Journal: Molecular Biology and Evolution (2009)

Dicer proteins are highly conserved, are present in organisms ranging from plants to metazoans, and are essential components of the RNA interference pathway. Although the complement of Dicer proteins has been investigated in many "higher" metazoans, there has been no corresponding characterization of Dicer proteins in any early-branching metazoan. We cloned partial cDNAs of genes belonging to the Dicer family from the anthozoan cnidarian Nematostella vectensis and two distantly related haplotypes (species lineages) of the Placozoa (Trichoplax adhaerens 16S haplotype 1 [H1] and Placozoa sp. [H2]). We also identified Dicer genes in the hydrozoan Hydra magnipapillata and the demosponge Amphimedon queenslandica with the use of publicly available sequence databases. Two Dicer genes are present in each cnidarian species, whereas five Dicer genes each are found in the Porifera and Placozoa. Phylogenetic analyses comparing these and other metazoan Dicers suggest an ancient duplication event of a "Proto-Dicer" gene. We show that the Placozoa is the only known metazoan phylum which contains both representatives of this duplication event and that the multiple Dicer genes of the "basal" metazoan phyla represent lineage-specific duplications. There is a striking diversity of Dicer genes in basal metazoans, in stark contrast to the single Dicer gene found in most higher metazoans. This new data has allowed us to formulate new hypotheses regarding the evolution of metazoan Dicer proteins and their possible functions in the early diverging metazoan phyla. We theorize that the multiple placozoan Dicer genes fulfill a specific biological requirement, such as an immune defense strategy against viruses.
Potassium channels and airway function: new therapeutic prospects.
Authors: J L Black, P J Barnes
Journal: Thorax (1990)

Potassium (K+) channels have long been associated with recovery of excitable cells after depolarisation and drugs that block these channels, such as tetraethylammonium and 4- aminopyridine, cause an increase in excita- bility.In airway smooth muscle these K+ channel blocking drugs result in spontaneous action potentials and a reduced threshold of excitation,'2 which may be similar to the elec- trophysiological changes described in asth- matic airways.'The recent development of drugs that open K+ channels in smooth muscle has reawakened interest in potassium channels because such drugs relax airway smooth muscle and may reduce the hyperreactivity of asthma.It is now clear that there is great diversity ofK+ channels in different cells, raising the possibility that selective drugs may be developed for specific cell types, with therapeutic benefit.We review here some ofthe recent developments in under- standing K+ channels in airways and the therapeutic prospects for new K+ channel activators. Potassium channels and their typesRecent electrophysiological studies and the use of new pharmacological agents have shown that K+ channels are present on cells of several types, including nerves, secretory cells, and skeletal and smooth muscle cells.45K+ channels are now seen to be diverse and may be modulated by changes in membrane potential, ion concentration, or receptor activation.All cells in the body are likely to have K+ channels and they may have more than one type.
Future Directions in the Treatment of Neuroendocrine Tumors: Consensus Report of the National Cancer Institute Neuroendocrine Tumor Clinical Trials Planning Meeting
Authors: Matthew H. Kulke, Lillian L. Siu, Joel E. Tepper, George Fisher, Deborah Jaffe, Daniel G. Haller, Lee M. Ellis, Jacqueline K. Benedetti, Emily K. Bergsland, Timothy J. Hobday, Eric Van Cutsem, James Pingpank, Kjell Oberg, Steven J. Cohen, Mitchell C. Posner, James C. Yao
Journal: Journal of Clinical Oncology (2011)

Neuroendocrine tumors (NETs) arise from a variety of anatomic sites and share the capacity for production of hormones and vasoactive peptides. Because of their perceived rarity, NETs have not historically been a focus of rigorous clinical research. However, the diagnosed incidence of NETs has been increasing, and the estimated prevalence in the United States exceeds 100,000 individuals. The recent completion of several phase III studies, including those evaluating octreotide, sunitinib, and everolimus, has demonstrated that rigorous evaluation of novel agents in this disease is both feasible and can lead to practice-changing outcomes. The NET Task Force of the National Cancer Institute GI Steering Committee convened a clinical trials planning meeting to identify key unmet needs, develop appropriate study end points, standardize clinical trial inclusion criteria, and formulate priorities for future NET studies for the US cooperative group program. Emphasis was placed on the development of well-designed clinical trials with clearly defined efficacy criteria. Key recommendations include the evaluation of pancreatic NET separately from NETs of other sites and the exclusion of patients with poorly differentiated histologies from trials focused on low-grade histologies. Studies evaluating novel agents for the control of hormonal syndromes should avoid somatostatin analog washout periods when possible and should include quality-of-life end points. Because of the observed long survival after progression of many patients, progression-free survival is recommended as a feasible and relevant primary end point for both phase III studies and phase II studies where a delay in progression is expected in the absence of radiologic responses.
Patients with delusional infestation (delusional parasitosis) often require prolonged treatment as recurrence of symptoms after cessation of treatment is common: an observational study
Authors: S. Wong, A. Bewley
Journal: British Journal of Dermatology (2011)

Delusional infestation (DI) is an uncommon psychiatric disorder in which patients present with the false and fixed belief of infestation. Numerous studies have demonstrated improvement with pharmacological treatment; however, recurrence rates on cessation of treatment remain unknown.To assess the clinical response and recurrence rates following treatment for DI.All patients with DI seen in our combined dermatology/psychiatry clinic to date (n=73) were offered pharmacological therapy. Patients were contacted to complete a telephone questionnaire to assess clinical outcomes, including remission and recurrence rates following treatment.Fifty-nine of 73 (81%) patients with DI received treatment, of whom 40/59 (68%) reported improvement or resolution of symptoms, and the remaining 19/59 (32%) failed to respond. Fifteen of 40 patients with DI completed a course of treatment, 12/40 patients are still undergoing treatment, and outcomes are unknown for 13/40. Of those who completed treatment, 11/15 (73%) reported total remission for at least 9months after discontinuing treatment (range 9months-2·5years). Recurrence of symptoms occurred in 4/15 (27%) within 4months of stopping treatment.Pharmacological treatment of DI can be effective, particularly in a combined dermatology/psychiatry clinic. Most treated patients have a good prognosis, and a remission period can be expected. However, more than 25% of patients may relapse on stopping treatment, with the greatest risk being within the first few months of discontinuation. These patients may require longer treatment courses, or long-term maintenance therapy for symptom control, although further studies are needed to provide recommended guidelines on drug and dosing regimen.
Prevalence and prognostic value of CSF markers of Alzheimer's disease pathology in patients with subjective cognitive impairment or mild cognitive impairment in the DESCRIPA study: a prospective cohort study
Authors: Pieter Jelle Visser, Frans Verhey, Dirk L Knol, Philip Scheltens, Lars-Olof Wahlund, Yvonne Freund-Levi, Magda Tsolaki, Lennart Minthon, Åsa K Wallin, Harald Hampel, Katharina Bürger, Tuula Pirttila, Hilkka Soininen, Marcel Olde Rikkert, Marcel M Verbeek, Luiza Spiru, Kaj Blennow
Journal: The Lancet Neurology (2009)
New Routes to Old Places: <i>PIK3R1</i> and <i>PIK3R2</i> Join <i>PIK3CA</i> and <i>PTEN</i> as Endometrial Cancer Genes
Authors: Sandra Herrero-Gonzalez, Antonio Di Cristofano
Journal: Cancer Discovery (2011)

Abstract Cheung and colleagues identify PIK3R1 and PIK3R2, the genes encoding the α and β isoforms of the phosphatidylinositol 3-kinase (PI3K) p85 regulatory subunit, as additional mutation targets in endometrial cancer, and describe a novel mechanism leading to PTEN loss. Cancer Discovery; 1(2); 106–7. ©2011 AACR. Commentary on Cheung et al., p. 170
Emerging trends in the epidemiology of melanoma
Authors: V. Nikolaou, A.J. Stratigos
Journal: British Journal of Dermatology (2013)

Cutaneous melanoma (CM) is one of the most rapidly growing cancers worldwide, with a consistent increase in incidence among white populations over the past four decades. Despite the early detection of primarily thin melanomas and the improved survival rates observed in several countries, the rate of thick melanomas has remained constant or continues to increase, especially in the older age group. Current considerations in the epidemiology of melanoma focus on the observed survival benefit of females vs. males, the contributing role of indoor tanning in melanoma risk and the diverse effect of sun exposure in the development of different types of melanoma with respect to their clinical and mutational profile. Certain well-known risk factors, such as skin, hair and eye pigmentation and melanocytic naevi have been validated in large-scale association studies, while additional lifestyle factors and iatrogenic exposures, such as immunosuppressive agents and nonsteroidal anti-inflammatory drugs are being investigated. In addition, genome-wide association studies have revealed genetic loci that underlie the genetic susceptibility of melanoma, some of which are related to known risk factors. Recently, an interesting association of melanoma with Parkinson disease has been noted, with a higher than expected frequency of melanoma in patients with Parkinson disease and vice versa. This review article provides an update in the epidemiology of cutaneous melanoma and discusses recent developments in the field.
Social Norm Processing in Adult Social Phobia: Atypically Increased Ventromedial Frontal Cortex Responsiveness to Unintentional (Embarrassing) Transgressions
Authors: Karina S. Blair, Marilla Geraci, Nick Hollon, Marcela Otero, Jeffrey DeVido, Catherine Majestic, Madeline Jacobs, R.J.R. Blair, Daniel S. Pine
Journal: American Journal of Psychiatry (2010)

Objective: Little is known about the neural underpinnings of generalized social phobia, which is defined by a persistent heightened fear of social disapproval. Using event-related functional MRI (fMRI), the authors examined whether the intent of an event, which mediates the neural response to social disapproval in healthy individuals, differentially affects response in generalized social phobia. Method: Sixteen patients with generalized social phobia and 16 healthy comparison subjects group-matched on age, gender, and IQ underwent fMRI scans while reading stories that involved neutral social events, unintentional social transgressions (e.g., choking on food at a party and coughing it up), or intentional social transgressions (e.g., disliking food at a party and spitting it out). Results: Significant group-by-transgression interactions were observed in ventral regions of the medial prefrontal cortex. Healthy individuals tended to show increased blood-oxygen-level-dependent responses to intentional relative to unintentional transgressions. Patients with generalized social phobia, however, showed significantly increased responses to the unintentional transgressions. They also rated the unintentional transgressions as significantly more embarrassing than did the comparison subjects. Results also revealed significant group main effects in the amygdala and insula bilaterally, reflecting elevated generalized social phobia responses in these regions to all event types. Conclusions: These results further implicate the medial prefrontal cortex in the pathophysiology of generalized social phobia, specifically through its involvement in distorted self-referential processing. These results also further underscore the extended role of the amygdala and insula in the processing of social stimuli more generally in generalized social phobia.