tbuckley/cabot-search huggingface dataset:
Breast Cancer–Associated <i>PIK3CA</i> Mutations Are Oncogenic in Mammary Epithelial Cells
Authors: Steven J. Isakoff, Jeffrey A. Engelman, Hanna Y. Irie, Ji Luo, Saskia M. Brachmann, Rachel V. Pearline, Lewis C. Cantley, Joan S. Brugge
Journal: Cancer Research (2005)

Abstract Activation of the phosphoinositide 3-kinase (PI3K) pathway has been implicated in the pathogenesis of a variety of cancers. Recently, mutations in the gene encoding the p110α catalytic subunit of PI3K (PIK3CA) have been identified in several human cancers. The mutations primarily result in single amino acid substitutions, with &amp;gt;85% of the mutations in either exon 9 or 20. Multiple studies have shown that these mutations are observed in 18% to 40% of breast cancers. However, the phenotypic effects of these PIK3CA mutations have not been examined in breast epithelial cells. Herein, we examine the activity of the two most common variants, E545K and H1047R, in the MCF-10A immortalized breast epithelial cell line. Both variants display higher PI3K activity than wild-type p110α yet remain sensitive to pharmacologic PI3K inhibition. In addition, expression of p110α mutants in mammary epithelial cells induces multiple phenotypic alterations characteristic of breast tumor cells, including anchorage-independent proliferation in soft agar, growth factor–independent proliferation, and protection from anoikis. Expression of these mutant p110α isoforms also confers increased resistance to paclitaxel and induces abnormal mammary acinar morphogenesis in three-dimensional basement membrane cultures. Together, these data support the notion that the cancer-associated mutations in PIK3CA may significantly contribute to breast cancer pathogenesis and represent attractive targets for therapeutic inhibition.
Dose-Escalation Study of Sonidegib (Lde225) Plus Buparlisib (Bkm120) in Patients (Pts) with Advanced Solid Tumors
Authors: Q.S. Chu, A. Mahipal, M. Schuler, F.G.M. De Braud, L. Dirix, A. Rampersad, J. Zhou, Y. Wu, S. Kalambakas, P.Y. Wen
Journal: Annals of Oncology (2014)
Time-Action Profile of Inhaled Insulin in Comparison With Subcutaneously Injected Insulin Lispro and Regular Human Insulin
Authors: Klaus Rave, Susanne Bott, Lutz Heinemann, Sue Sha, Reinhard H.A. Becker, Susan A. Willavize, Tim Heise
Journal: Diabetes Care (2005)

This study compares the time-action profile of inhaled insulin (INH; Exubera) with that of subcutaneously injected insulin lispro (ILP) or regular human insulin (RHI) in healthy volunteers.In this open-label, randomized, three-way, crossover study, 17 healthy male volunteers were given each of the following treatments in random order: INH (6 mg), ILP (18 units), or RHI (18 units). Glucose infusion rates and serum insulin concentrations were monitored over 10 h.INH had a faster onset of action than both RHI and ILP, as indicated by shorter time to early half-maximal effect (32 vs. 48 and 41 min, respectively; P < 0.001 for IHN vs. RHI and P < 0.05 for IHN vs. ILP). Time to maximal effect was comparable between INH and ILP (143 vs. 137 min; NS) but was shorter for INH than RHI (193 min; P < 0.01). The maximal metabolic effect of INH was comparable with RHI but lower than ILP (8.7 vs. 9.8 vs. 11.2 mg . kg(-1) . min(-1), respectively; P < 0.01 for INH vs. ILP). The duration of action of INH, indicated by time to late half-maximal effect (387 min), was longer than ILP (313 min; P < 0.01) and comparable to RHI (415 min; NS). Total glucodynamic effect after inhalation of INH was comparable to both ILP and RHI (NS). Relative bioefficacy of INH was 10% versus RHI and 11% versus ILP. No drug-related adverse events were observed.INH had a faster onset of action than RHI or ILP and a duration of action longer than ILP and comparable to RHI. These characteristics suggest that inhaled insulin is suitable for prandial insulin supplementation in patients with diabetes.
Increased dietary intake of ω-3-polyunsaturated fatty acids reduces pathological retinal angiogenesis
Authors: Kip M Connor, John Paul SanGiovanni, Chatarina Lofqvist, Christopher M Aderman, Jing Chen, Akiko Higuchi, Song Hong, Elke A Pravda, Sharon Majchrzak, Deborah Carper, Ann Hellstrom, Jing X Kang, Emily Y Chew, Norman Salem, Charles N Serhan, Lois E H Smith
Journal: Nature Medicine (2007)
Molecular Imaging Radiotherapy: Theranostics for Personalized Patient Management of Neuroendocrine Tumors (NETs)
Authors: Kjell Öberg
Journal: Theranostics (2012)

Neuroendocrine tumors (NETs) possess unique features including expression of peptide hormone receptors as well as the capacity to concentrate and take up precursor forms of amines and peptides making hormones that are stored in secretory granules within the tumor cells (APUD). The expression of somatostatin receptors on tumor cells have been widely explored during the last two decades starting with (111)In-DTPA-Octreotide as an imaging agent followed by (68)Ga-DOTATOC/TATE positron emission tomography scanning. The new generation of treatment includes (90)Yttrium-DOTATOC/DOTATATE as well as (177)Lutetium-DOTATOC/DOTATATE/DOTANOC treatment of various subtypes of NETs. The objective response rate by these types of PRRT is in the range of 30-45% objective responses with 5-10% grade 3/4 toxicity mainly hematologic and renal toxicity. The APUD mechanism is another unique feature of NETs which have generated an interest over the last two decades to develop specific tracers including (11)C-5HTP, (18)F-DOPA and (11)C-hydroxyefedrin. These radioactive tracers have been developed in centres with specific interest in NETs and are not available everywhere. (111)In-DTPA-Octreotide is still the working horse in diagnosis and staging of metastatic NETs, but will in the future be replaced by (68)Ga-DOTATOC/DOTATATE PET/CT scanning which provide higher sensitivity and specificity and is also more convenient for the patient because it is a one-stop-procedure. Both (90)Yttrium-DOTATOC/DOTATATE as well as (177)Lutetium-DOTATOC/DOTATATE are important new therapies for malignant metastatic NETs. However, the precise role in the treatment algorithm has to be determined in forthcoming randomized trials.
Consensus and Future Directions on the Definition of High On-Treatment Platelet Reactivity to Adenosine Diphosphate
Authors: Laurent Bonello, Udaya S. Tantry, Rossella Marcucci, Ruediger Blindt, Dominick J. Angiolillo, Richard Becker, Deepak L. Bhatt, Marco Cattaneo, Jean Philippe Collet, Thomas Cuisset, Christian Gachet, Gilles Montalescot, Lisa K. Jennings, Dean Kereiakes, Dirk Sibbing, Dietmar Trenk, Jochem W. Van Werkum, Franck Paganelli, Matthew J. Price, Ron Waksman, Paul A. Gurbel
Journal: Journal of the American College of Cardiology (2010)
Is continuous positive airway pressure necessarily an everyday therapy in patients with obstructive sleep apnoea?
Authors: Valentina A. Rossi, Esther I. Schwarz, Konrad E. Bloch, John R. Stradling, Malcolm Kohler
Journal: European Respiratory Journal (2014)

There are limited data on the evolution of obstructive sleep apnoea (OSA) during continuous positive airway pressure (CPAP) therapy and whether this treatment is required every night. 125 OSA patients with an original oxygen desaturation index (ODI) &gt;10 events per hour, established on CPAP, were asked to withdraw CPAP for four nights and performed ambulatory nocturnal pulse oximetry on the fourth night of CPAP withdrawal. An ODI &gt;10 events per hour during pulse oximetry was considered to indicate persistent OSA. Patients not experiencing recurrence of OSA underwent repeat ambulatory pulse oximetry after a further 2-week period off CPAP. In 71% of the patients, OSA recurred after four nights of CPAP withdrawal (group 1); thus, OSA did not recur in 29% (group 2). 55% of group 2 had an ODI &gt;10 events per hour after 2 weeks off CPAP; thus, 45% remained without a recurrence. In multivariate analysis, higher original ODI, longer duration of CPAP therapy, current smoking status and larger neck circumference were independently associated with a higher ODI after four nights of CPAP withdrawal (all p&lt;0.05). Following CPAP withdrawal, a third of CPAP-treated patients do not experience significant recurrence of oxygen desaturations after 4 days and ∼10% do not after 2 weeks. Thus, a significant proportion of patients may be able to stop CPAP for short periods.
Systematic identification of personal tumor-specific neoantigens in chronic lymphocytic leukemia
Authors: Mohini Rajasagi, Sachet A. Shukla, Edward F. Fritsch, Derin B. Keskin, David DeLuca, Ellese Carmona, Wandi Zhang, Carrie Sougnez, Kristian Cibulskis, John Sidney, Kristen Stevenson, Jerome Ritz, Donna Neuberg, Vladimir Brusic, Stacey Gabriel, Eric S. Lander, Gad Getz, Nir Hacohen, Catherine J. Wu
Journal: Blood (2014)
Fanconi anemia type C and p53 cooperate in apoptosis and tumorigenesis
Authors: Brian Freie, Xiaxin Li, Samantha L. M. Ciccone, Kathy Nawa, Scott Cooper, Catherine Vogelweid, Laurel Schantz, Laura S. Haneline, Attilio Orazi, Hal E. Broxmeyer, Suk-Hee Lee, D. Wade Clapp
Journal: Blood (2003)
Forbidden synonymous substitutions in coding regions.
Authors: R J Britten
Journal: Molecular Biology and Evolution (1993)

In the evolution of highly conserved genes, a few "synonymous" substitutions at third bases that would not alter the protein sequence are forbidden or very rare, presumably as a result of functional requirements of the gene or the messenger RNA. Another 10% or 20% of codons are significantly less variable by synonymous substitution than are the majority of codons. The changes that occur at the majority of third bases are subject to codon usage restrictions. These usage restrictions control sequence similarities between very distant genes. For example, 70% of third bases are identical in calmodulin genes of man and trypanosome. Third-base similarities of distant genes for conserved proteins are mathematically predicted, on the basis of the G+C composition of third bases. These observations indicate the need for reexamination of methods used to calculate synonymous substitutions.
Imaging Microdomain Ca <sup>2+</sup> in Muscle Cells
Authors: Shi-Qiang Wang, Chaoliang Wei, Guiling Zhao, Didier X.P. Brochet, Jianxin Shen, Long-Sheng Song, Wang Wang, Dongmei Yang, Heping Cheng
Journal: Circulation Research (2004)

Ca2+ ions passing through a single or a cluster of Ca2+-permeable channels create microscopic, short-lived Ca2+ gradients that constitute the building blocks of cellular Ca2+ signaling. Over the last decade, imaging microdomain Ca2+ in muscle cells has unveiled the exquisite spatial and temporal architecture of intracellular Ca2+ dynamics and has reshaped our understanding of Ca2+ signaling mechanisms. Major advances include the visualization of "Ca2+ sparks" as the elementary events of Ca2+ release from the sarcoplasmic reticulum (SR), "Ca2+ sparklets" produced by openings of single Ca2+-permeable channels, miniature Ca2+ transients in single mitochondria ("marks"), and SR luminal Ca2+ depletion transients ("scraps"). As a model system, a cardiac myocyte contains a 3-dimensional grid of 104 spark ignition sites, stochastic activation of which summates into global Ca2+ transients. Tracking intermolecular coupling between single L-type Ca2+ channels and Ca2+ sparks has provided direct evidence validating the local control theory of Ca2+-induced Ca2+ release in the heart. In vascular smooth muscle myocytes, Ca2+ can paradoxically signal both vessel constriction (by global Ca2+ transients) and relaxation (by subsurface Ca2+ sparks). These findings shed new light on the origin of Ca2+ signaling efficiency, specificity, and versatility. In addition, microdomain Ca2+ imaging offers a novel modality that complements electrophysiological approaches in characterizing Ca2+ channels in intact cells.
Loss-of-Function Polymorphism of the Human Kallikrein Gene with Reduced Urinary Kallikrein Activity
Authors: Rola Slim, Florence Torremocha, Thierry Moreau, Anne Pizard, Steven C. Hunt, Albert Vuagnat, Gordon H. Williams, Francis Gauthier, Xavier Jeunemaitre, Franc[COMBINING CEDILLA]ois Alhenc-Gelas
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. Kallikrein is synthesized in the distal tubules and produces kinins, which are involved in the regulation of vascular tone in the kidney. Urinary kallikrein activity has been reported to be partly inherited and to be reduced in essential hypertension. In a systematic search for molecular variants of the human kallikrein gene, nine single-nucleotide polymorphisms were identified. Five of those polymorphisms, including two nonsynonymous substitutions in exon 3, i.e., Arg53His (allelic frequency in Caucasian subjects, 0.03) and Gln121Glu (allelic frequency, 0.33), were studied in a normotensive group and two independent hypertensive groups for which 24-h urinary kallikrein activity had been measured. A significant decrease in urinary kallikrein activity was observed for the subjects who were heterozygous for the Arg53His polymorphism, compared with the other subjects. This finding was consistent in the two hypertensive groups and was observed with several kallikrein enzymatic assays. The Gln121Glu polymorphism and the other polymorphisms were not associated with changes in urinary kallikrein activity. None of the polymorphisms was associated with hypertension. Recombinant kallikrein variants were synthesized and enzymatically characterized, using native kininogen and kininogen-derived synthetic peptide substrates. No important effect was observed after Gln121 mutation, but there was a major decrease in enzyme activity when Arg53 was replaced by histidine. A model of kallikrein derived from crystallographic data suggested that Arg53 can affect substrate binding. The identification of a subset of subjects with genetically reduced kallikrein activity as a result of an amino acid mutation could facilitate analysis of the role of the kallikrein-kinin system in renal and vascular diseases.
MORAL INSANITY IN THE UNITED STATES 1835-1866
Authors: NORMAN DAIN, ERIC T. CARLSON
Journal: American Journal of Psychiatry (1962)

Before the 1860s many leading American psychiatrists accepted the concept of moral insanity as defined by Prichard. These men also emphasized the psychological element in the etiology, pathology, and treatment of mental illness and were in advance of their colleagues on most psychiatric questions. They tried to take a purely clinical and scientific view of mental illness and to broaden its confines to include largely emotional disorders. Some psychiatrists, however, had reservations about the theory of moral insanity, and a few, like Gray, condemned it outright. Fear of public opinion, reluctance to take an independent stand on controversial issues, and attachment to conventional moral precepts, combined with an increasing stress on somaticism, led a growing number of American psychiatrists eventually to reject the concept of moral insanity. This trend reflected the passing of the first and more venturesome generation of the new profession. The problems that moral insanity dealt with and the controversy that it inspired, however, remain with us to this day.
Measures of reversibility in response to bronchodilators in chronic airflow obstruction: relation to airway calibre.
Authors: D. C. Weir, P. Sherwood Burge
Journal: Thorax (1991)

A study was carried out to examine the independence from starting prebronchodilator FEV1 of four indices commonly used to express airflow (FEV1) reversibility in response to bronchodilators. In 121 patients with chronic airflow obstruction with a mean prebronchodilator FEV1 of 1.81 (43.9% of predicted values) the change in FEV1 expressed as a percentage of the patient9s predicted FEV1 was the least dependent on starting FEV1. Reversibility, expressed as a percentage of the prebronchodilator value or as a percentage of the maximal possible increase (predicted minus starting FEV1) was correlated with starting FEV1.
Treating Helicobacter pylori infection in primary care patients with uninvestigated dyspepsia: the Canadian adult dyspepsia empiric treatment---Helicobacter pylori positive (CADET-Hp) randomised controlled trial
Authors: N. Chiba
Journal: BMJ (2002)

<h3>Abstract</h3> <b>Objective:</b> To determine whether a "test for <i>Helicobacter pylori</i> and treat" strategy improves symptoms in patients with uninvestigated dyspepsia in primary care. <b>Design:</b> Randomised placebo controlled trial. <b>Setting:</b> 36 family practices in Canada. <b>Participants:</b> 294 patients positive for <i>H</i><i>pylori</i> (<sup>13</sup>C- urea breath test) with symptoms of dyspepsia of at least moderate severity in the preceding month. <b>Intervention:</b> Participants were randomised to twice daily treatment for 7 days with omeprazole 20 mg, metronidazole 500 mg, and clarithromycin 250 mg or omeprazole 20 mg, placebo metronidazole, and placebo clarithromycin. Patients were then managed by their family physicians according to their usual care. <b>Main outcome measures:</b> Treatment success defined as no symptoms or minimal symptoms of dyspepsia at the end of one year. Societal healthcare costs collected prospectively for a secondary evaluation of actual mean costs. <b>Results:</b> In the intention to treat population (n=294), eradication treatment was significantly more effective than placebo in achieving treatment success (50% <i>v</i> 36%; P=0.02; absolute risk reduction=14%; number needed to treat=7, 95% confidence interval 4 to 63). Eradication treatment cured <i>H pylori</i> infection in 80% of evaluable patients. Treatment success at one year was greater in patients negative for <i>H pylori</i> than in those positive for <i>H pylori</i> (54% <i>v</i> 39%; P=0.02). Eradication treatment reduced mean annual cost by $C53 (86 to 180) per patient. <b>Conclusions:</b> A "test for <i>H pylori</i> with <sup>13</sup>C-urea breath test and eradicate" strategy shows significant symptomatic benefit at 12 months in the management of primary care patients with uninvestigated dyspepsia. <h3>What is already known on this topic</h3> Dyspepsia is a common problem in primary health care, although controversy exists about its definition Studies of <i>H pylori</i> eradication in patients with uninvestigated dyspepsia have shown reduced need for endoscopy and thus significant cost savings compared with a strategy of prompt endoscopy The "test for <i>H pylori</i> and treat" strategy has been recommended for uninvestigated dyspepsia, but there have been no randomised controlled trials showing improvement in symptoms <h3>What this study adds</h3> When given eradication treatment in primary care, <i>H pylori</i> positive patients with uninvestigated dyspepsia show improvement in overall dyspepsia symptoms at 12 months This supports the "test for <i>H pylori</i> and treat" strategy
High effectiveness of short treatment with bupropion for smoking cessation in general care
Authors: L P Breitling, D Twardella, H Brenner
Journal: Thorax (2008)

Since the appearance of the seminal publication on sustained release bupropion versus placebo for smoking cessation exactly 10 years ago,1 bupropion has become a mainstay of nicotine addiction therapy.2 Some concerns relating to increased risk of seizures remain, in particular as exclusion of predisposed patients may be suboptimal in general practice.3 Furthermore, the cost of about €135 or US$180 for a pack of 100 pills required for a standard course of treatment of at least 7 weeks represents a substantial barrier to wider use.4 We present data suggesting that much shorter treatments with bupropion may be as effective as standard regimens.

In a cluster randomised trial in …
Intrinsic Regulation of Skeletal Muscle Blood Flow
Authors: RICHARD D. JONES, ROBERT M. BERNE
Journal: Circulation Research (1964)

Isolated, innervated and acutely or chronically denervated resting skeletal muscle of the dog exhibited high intrinsic vascular tone. Sustained alteration of perfusion pressure or venous pressure evoked autoregulatory responses; vascular resistance increased at elevated driving pressures and decreased at reduced driving pressures. Comparable changes of resistance were observed after sustained alteration of blood flow during pump perfusion. Autoregulation was consistently observed during muscle contractions with constant pressure or constant flow perfusion. In resting and contracting skeletal muscle a low venous blood oxygen saturation (VO 2 ) was characteristic of preparations exhibiting a high degree of autoregulation. In innervated resting muscle autoregulation was concealed by reflex or local stimuli and its disappearance was associated with a decreased vascular resistance and an increased VO 2 . In resting chronically denervated muscle or in contracting muscle, whether innervated or denervated, such stimuli failed to affect the autoregulatory response. A schema has been proposed to define the "states" of skeletal muscle blood flow and some of the factors responsible for the presence or absence of autoregulation.
B cell dependence on and response to accessory signals in murine lupus strains.
Authors: G J Prud'homme, R S Balderas, F J Dixon, A N Theofilopoulos
Journal: The Journal of Experimental Medicine (1983)

B cell hyperactivity, a feature common to all lupus-prone murine strains, may be caused by hyperresponsiveness to, overproduction of, or bypassing of certain signals required for B cell activation, proliferation, and differentiation. In this study, we have compared the responses of B cells from three lupus-prone strains of mice (BXSB males, MRL and NZB/W females) and normal strains in a number of assays for which two or more signals are required to obtain a response. In medium to low density cultures of B cells from BXSB and NZB/W but not MRL/l lupus mice, the cells' proliferation induced by bacterial lipopolysaccharide (LPS) or anti-mu antibody was much higher than that of B cells from normal controls. At low B cell density, polyclonal activation by these substances and subsequent Ig secretion were dependent on accessory signals present in supernatants of concanavalin A-treated normal lymphocytes (CAS) or on the MRL/l proliferating T cell-derived B cell differentiation factor (L-BCDF) in both lupus-prone and immunologically normal mice. However, the responses of B cells from BXSB and NZB/W, but not MRL/l, mice to these accessory signals were higher than those of normal mice. Ig synthesis by fresh B cells of BXSB and NZB/W mice cultured in the absence of mitogens but in the presence of CAS or L-BCDF was higher than by similar cells from other strains, suggesting an increased frequency of B cells activated in vivo in these two autoimmune strains of mice. The patterns of IgG subclass secretion in response to LPS (without added CAS or L-BCDF) were abnormal in all lupus strains, with a predominance of IgG2b and/or IgG2a and low levels of IgG3, contrary to normal B cells for which IgG3 synthesis predominated. However, IgG1 synthesis in vitro by autoimmune and normal B cells alike was highly dependent on T cell-derived soluble mediators. Antigen-specific responses to SRBC in vitro of B cells from all lupus strains, like those of B cells from normal strains, required a minimum of three signals (antigen, LPS, T cell-derived antigen nonspecific helper factors). Yet, once triggered, B cells of BXSB and NZB/W mice gave higher responses than those of the other strains. We conclude that B cells of lupus mice have signal requirements similar to those of normal mice. Nevertheless, B cells of BXSB and NZB/W, but not MRL/l, lupus mice hyperrespond or process some accessory signals abnormally.