tbuckley/cabot-search huggingface dataset:
Abstract 2973: Mouse models of lung cancer mediated by lentiviral gene delivery
Authors: Yifeng Xia, Narayana Yeddula, Eugene Ke, Mathias Leblanc, Inder Verma
Journal: Cancer Research (2014)

Abstract Lung cancer, the leading cause of cancer deaths, is responsible for 1.4 million lives lost worldwide every year. Good animal models that can faithfully recapitulate the human disease are in great need for pre-clinical studies. Based on the different responses to treatment, lung cancer is divided into two major classes: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Adenocarcinoma (AdC) and squamous cell lung cancer (SqCC) are two major sub-types of NSCLC. We have successfully developed a novel lentiviral gene delivery system to study the initiation and development of all these lung cancers. We used CA2Cre-shp53 lentiviral vector to initiate lung adenocarcinoma in LSL-KrasG12D mice and proved the importance of NF-κB/IKK2 pathway in tumor cell proliferation. To search for novel tumor suppressors in lung cancer, we incorporated an shRNA library targeting ∼5000 cell signal genes into our CA2Cre lentivector and did the screening in the mice. We have identified several dozens of candidates and are validating these genes back in animals. SCLC is the most malignant form of lung cancer with a five-year survival less than 6%. A mouse model with p53/Rb deletions activated by Adeno-Cre has been established in Berns lab. To improve the model and study other genes that are frequently mutated in human SCLC, we designed a single lentiviral vector to deliver oncogenes (L-myc etc.) and shRNAs against tumor suppressors (p53, Rb etc) and successfully initiated SCLC in wild-type mice. Furthermore, we included luciferase or fluorescence protein genes in the same vector to follow tumor growth and metastasis in the live animal. Using this new model, we are now studying the crosstalk of multiple mutations in the SCLC development. SqCC has not been well modeled by genetic approaches. Interestingly, when we gave KrasG12D-shp53 lentiviral vector after lung tissue damage induced by naphthalene, the mice quickly developed squamous tumors in the big bronchi other than adenocarcinomas in the peripheral lung. Kras mutations are actually not common in human SqCC patients, so we are now optimizing the model and see if more relevant genetic changes such FGFR1 amplification can also induce this type of lung cancer in mice. We hope that our unique lentiviral tool can simplify and accelerate the lung cancer study to understand the big signal pathway complex leading to tumorigenesis and metastasis in the lung and search for new therapies for this deadly human disease. Citation Format: Yifeng Xia, Narayana Yeddula, Eugene Ke, Mathias Leblanc, Inder Verma. Mouse models of lung cancer mediated by lentiviral gene delivery. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2973. doi:10.1158/1538-7445.AM2014-2973
The blooming of the French lilac
Authors: Lee A. Witters
Journal: Journal of Clinical Investigation (2001)

The history of diabetes mellitus is replete with many therapies, nearly all, including insulin, first given without any knowledge of a mechanism of action. Beginning with early Egyptian physicians who, according to the Ebers Papyrus of 1500 B.C.E., prescribed a mixture of cakes, wheat grains, fresh grits, green lead, earth, and water, up to the more recent introduction of the thiazolidinediones, knowledge of physiologic effects preceded by years or centuries any knowledge as to what the medicament actually did.

In medieval times, a prescription of Galega officinalis was said to relieve the intense urination accompanying the disease that came to have the name of diabetes mellitus. G. officinalis, also known as Goat’s rue, the French lilac or Italian fitch (Figure ​(Figure1),1), was also given during the plague epidemics to promote perspiration and has been used as a galactogogue in cows. The active ingredient in the French lilac that produced the lowering of blood glucose was shown to be galegine or isoamylene guanidine (1). A curious chapter in the history of guanidine-based hypoglycemic agents arose from the mistaken notion that the tetany of hypoparathyroidism was due to the production of increased guanidine following parathyroidectomy, leading to the demonstration that an infusion of guanidine produced lowering of blood glucose (2). While guanidine itself and certain derivatives are too toxic for the treatment of diabetes mellitus, the biguanides (two linked guanidine rings) have proved useful, and three biguanides became available for diabetes therapy in the 1950s. Phenformin and buformin, the former becoming quite popular in the 1960s, were withdrawn from the pharmacopoeia in the early 1970s due to the emergence of frequent lactic acidosis and increased cardiac mortality (1). Metformin, a less lipophilic biguanide, proved safer and, after 20 years of use in Europe, was approved for use in the USA in 1995.



Figure 1

The bloom of the French lilac. This blooming G. officinalis (Goat’s rue; French lilac; Italian fitch) is rich in guanidine. The plant’s long-recognized hypoglycemic properties led eventually to the synthesis of the biguanide compound metformin. ...
Strong Evidence for a Novel Schizophrenia Risk Locus on Chromosome 1p31.1 in Homogeneous Pedigrees From Tamil Nadu, India
Authors: Elizabeth G. Holliday, Dale R. Nyholt, Srinivasan Tirupati, Sujit John, Padmavati Ramachandran, Mangala Ramamurti, Ayankaran Jothi Ramadoss, Anitha Jeyagurunathan, Sowndari Kottiswaran, Heather J. Smith, Cheryl Filippich, Deborah A. Nertney, Derek J. Nancarrow, Nicholas K. Hayward, W. Scott Watkins, Lynn B. Jorde, Rangaswamy Thara, Bryan J. Mowry
Journal: American Journal of Psychiatry (2008)

Objective: The study of ethnically homogeneous populations may help to identify schizophrenia risk loci. The authors conducted a genomewide linkage scan for schizophrenia in an Indian population. Method: Participants were 441 individuals (262 affected probands and siblings) who were recruited primarily from one ethnically homogeneous group, the Tamil Brahmin caste, although individuals from other geographically proximal castes also participated. Genotyping of 124 affected sibling pair pedigrees was performed with 402 short tandem repeat polymorphisms. Linkage analyses were conducted using nonparametric exponential LOD (logarithm of the odds ratio for linkage) scores and parametric heterogeneity LOD scores. Parametric heterogeneity scores were calculated using simple dominant and recessive models, correcting for multiple statistics. The data were examined for evidence of consanguinity. Genomewide significance levels were determined using 10,000 gene dropping simulations. Results: These findings revealed genomewide significant linkage to chromosome 1p31.1, through the use of both exponential and heterogeneity LOD scores, incorporating correction for multiple statistics and mild consanguinity. The estimated sibling recurrence risk associated with this putative locus was 1.95. Analysis for heterogeneity LOD scores also detected suggestive linkage to chromosomes 13q22.1 and 16q12.2. Using 117 tag single nucleotide polymorphisms (SNPs), family-based association analyses of phosphodiesterase 4B ( PDE4B ), the closest schizophrenia candidate gene, detected no convincing evidence of association, suggesting that the chromosome 1 peak represents a novel risk locus. Conclusions: This is the first study—to the authors' knowledge—to report significant linkage of schizophrenia to chromosome 1p31.1. Further investigation of this chromosome region in diverse populations is warranted to identify underlying sequence variants.
Amiodarone toxicity: recurrence of interstitial pneumonitis after withdrawal of the drug
Authors: O Parra, J Ruiz, I Ojanguren, JJ Navas, J Morera
Journal: European Respiratory Journal (1989)

Amiodarone hydrochloride, an iodinated benzofuran derivative, is effective for treatment of supraventricular and ventricular arrhythmias. Pulmonary fibrosis has been reported after treatment with this drug. We present a patient with amiodarone pulmonary toxicity, who initially responded to corticosteroid therapy, but who developed a clinical relapse two months after withdrawal of the drug.
Effects of age upon the mobility of human finger joints.
Authors: C H Barnett, A F Cobbold
Journal: Annals of the Rheumatic Diseases (1968)

Fewmeasurements havebeenmadeofthefrictional forces within living joints. Barnett and Cobbold(1962) recorded thatthecoefficient of friction atthedistal interphalangeal joint ofthe middle finger insixhealthy adults could beaslowas 00075, afigure ofthesameorder asthat inexcised joints (Jones, 1936; Charnley, 1959). Rydell (1965) measured, inapatient fitted withahipprosthesis, thecoefficient offriction between theartificial femoral hipandtheintact acetabulum; hegavea figure 0021± 0-0014. Thepresent paperisconcerned withthevariation observed inthecoefficient offriction, asreflected byjoint mobility, among individuals ofdifferent ages.
Fluticasone propionate/formoterol fumarate improves asthma control and reduces exacerbations compared with fluticasone
Authors: Alberto Papi, David Price, Joaquin Sastre, Kirsten Kaiser, Mark Lomax, Tammy McIver, Sanjeeva Dissanayake
Journal: European Respiratory Journal (2013)

Introduction:  The combination of fluticasone (FLUT) and formoterol (FORM) in a single inhaler (FLUT/FORM;  flutiform ®) is approved for the maintenance treatment of asthma. This analysis assessed the efficacy of FLUT/FORM versus FLUT in patients who had previously received ICS therapy.   Methods:  Data were pooled from 5 randomized studies in patients with asthma (aged ≥12 years) treated for 8 or 12 weeks with FLUT/FORM (100/10, 250/10 or 500/20 μg b.i.d.; N=528) or FLUT alone (100, 250 or 500 μg b.i.d.; N=527).   Results:  FLUT/FORM significantly ( p    Conclusions:  FLUT/FORM significantly improves lung function and asthma control measures, and is associated with a lower incidence of exacerbations compared with FLUT.
Medically Unexplained Symptoms: Exacerbating Factors in the Doctor-Patient Encounter
Authors: La Page, S Wessely
Journal: Journal of the Royal Society of Medicine (2003)

This paper proposes that well-intentioned actions by medical practitioners can exacerbate or maintain medically unexplained symptoms (MUS)—i.e. physical symptoms that are disproportionate to identifiable physical disease. The term is now used in preference to ‘somatization’.1

Although research has gone some way to explain the predisposing and precipitating causes of MUS, there is little information on the factors that maintain such symptoms and resulting behaviour. We conducted a search of the Medline and Psychinfo databases using ‘iatrogenesis’ and ‘medically unexplained symptoms’ or ‘somatization’ as keywords; however, the yield of references was disappointing, so we supplemented these with papers that included relevant data even if not explicitly about iatrogenesis.

MUS are common. In one study, 30% of new patients attending general medical outpatients had no medical diagnosis to account for their symptoms, whilst a further 22% had a doubtful medical diagnosis.2 Among frequent attenders at secondary care clinics the prevalence of MUS is high,3 and the greater the number of reported symptoms the more disabled the individual is likely to be.4 MUS may or may not be associated with anxiety and depression. Patients with the highest number of MUS are likely to fulfil the psychiatric criteria for somatization disorder—at least 2 years of multiple and various MUS, with persistent refusal to accept advice and reassurance from doctors; functioning impaired. In patients attending general medical clinics the prevalence of either somatization disorder or hypochondriacal disorder is as high as 12%2—in contrast to a community prevalence of 0.1-0.7%.5 The medical specialties employ shorthand descriptions for particular clusters of MUS including irritable bowel syndrome, non-cardiac chest pain, fibromyalgia, chronic fatigue syndrome and repetitive strain injury. They are diagnosed on the basis of symptoms which overlap considerably and have no clear organic aetiology.

Factors predisposing to MUS are female gender,6 childhood experience of parental ill-health (particularly paternal),7 childhood abdominal pain8 and lack of care in childhood.9 High rates of ‘life events’ occur in the period predating the onset of MUS in a pattern similar to that seen before the onset of depressive illness.10 In those with somatization disorder there are high rates of personality disorder.11

What are the factors that lead to persistence of MUS in some individuals? Examples of possible precipitating events include chest pain induced by hyperventilation12 and muscle ache after unaccustomed exercise.13 Some of these mechanisms may become chronic. Additional psychosocial factors may be ‘secondary gain’10 (for example, when chronic pain spares a parent the burden of caring for a difficult child) or maladaptive psychological coping strategies.14 In this paper, we focus on the adverse effects of medical interventions at various stages of the doctor-patient encounter.
Adenosine 3',5'-cyclic-monophosphate-dependent regulation of alpha 1-adrenergic receptor number in rabbit aortic smooth muscle cells.
Authors: W S Colucci
Journal: Circulation Research (1986)

The purpose of this study was to determine whether a cyclic adenosine 3',5'-monophosphate-dependent process can be involved in the regulation of vascular smooth muscle alpha 1-adrenergic receptor responsiveness. Experiments were performed in cultured rabbit aortic smooth muscle cells which were characterized previously according to alpha-adrenergic receptor-binding characteristics and receptor-coupled norepinephrine-stimulated 45Ca++ efflux. The addition of dibutyryl-cyclic adenosine monophosphate to the cell culture medium for 24 hours resulted in a concentration-related decrease in maximal [3H]prazosin-binding capacity (41 +/- 4% decrease with 1 mM dibutyryl-cyclic adenosine monophosphate) without an effect on [3H]prazosin-binding affinity. Prostaglandin E1 (10 microM) and forskolin (10 microM) caused similar decreases in maximal [3H]prazosin-binding capacity, whereas butyrate (1 mM) and dibutyryl-guanosine-3',5' cyclic-monophosphate (1 mM) had no effect. Dibutyryl-cyclic adenosine monophosphate (1 mM) caused significant potentiation of the decrease in [3H]prazosin-binding caused by a submaximal (10 nM) but not a maximal (10 microM) concentration of norepinephrine, suggesting that cyclic adenosine monophosphate may act at a distal step in common with norepinephrine to reduce alpha-adrenergic receptor number. Despite the approximately 41% reduction in alpha-adrenergic receptor number following 24-hour incubation of cells with dibutyryl-cyclic adenosine monophosphate, maximal norepinephrine-stimulated 45Ca++ efflux was not reduced, consistent with the markedly nonlinear relationship between alpha-adrenergic receptor occupancy and maximal norepinephrine-stimulated 45Ca++ efflux in this cell system. These data provide evidence for a novel mechanism by which hormones or drugs which increase cyclic adenosine monophosphate levels can modulate alpha-adrenergic responsiveness in vascular smooth muscle.
Characteristics of Placebo Responses in Medical Treatment of Premenstrual Syndrome
Authors: Ellen W. Freeman, Karl Rickels
Journal: American Journal of Psychiatry (1999)

This study characterizes the responses to placebo medication of patients with premenstrual syndrome (PMS) who were randomly assigned in controlled treatment trials. Possible predictors of placebo response were also examined.Subjects from two randomized controlled trials were pooled. The 101 subjects met defined criteria for severe PMS, remained eligible after 1 month of single-blind placebo lead-in treatment, and were randomly assigned to 3 months of double-blind placebo treatment. Improvement in the current study was defined as a decrease of at least 50% in premenstrual symptom score from the pretreatment baseline.At endpoint, 20 (20%) of the placebo-treated subjects showed sustained improvement, 18 of these in at least 3 of the 4 months of placebo medication. Another 42% of subjects partially improved, and 39% were clearly unimproved throughout the study period.Some patients with severe PMS experience significant and sustained improvement with placebo medication, but the majority report only partial or no improvement. Patients who sustain improvement for at least 2 consecutive months are likely to remain improved, indicating the importance of nondrug factors in clinical care.
Postmarketing surveillance studies.
Authors: A. P. Fletcher
Journal: BMJ (1992)

During the trial two subjects failed to don the equipment correctly and one suffered extreme rebreathing, which limited his exercise tolerance in the test atmosphere to less than two minutes.Two volunteers refused to undergo the session in the test atmosphere wearing the hood as they perceived it as too stressful.We have also studied two other commercially available smoke hoods with filters in two volunteers exercising in air at only 75 W.One resulted in a ventilation of 109 /min in one subject, while the other subject was unable to exercise beyond two minutes when his oxygen saturation fell to 87% and his ventilation reached 919 I/min.The other device resulted in ventilations of 103-1 l/min and 107 71/min in the same volunteers.Our subjects represent the healthiest of those who travel by air, whose range of states of health and disease is wide.Tolerance to wearing a smoke hood is probably reduced in less healthy people, elderly people, and children.The hazards of rebreathing while wearing a smokehood and attempting to escape from fire need to be investi- gated further before widespread use of smoke hoods can be recommended.Our study further emphasises the widely held view that people who wear respiratory protection should be specifically trained in its use.Without training, such equipment carries a risk that might limit escape from fire even if the atmosphere is minimally toxic.We believe that existing smoke hoods carry an intrinsic risk to the wearer that in some instances outweighs their potential benefits.
AN INVESTIGATION OF THE BEST METHODS OF DESTROYING LICE AND OTHER BODY VERMIN
Authors: J. P. Kinloch
Journal: BMJ (1916)

ODY VERMIN.[I MricOA greater egg-carrying capacity.than those of the head louse.Tlhe eggs ar6 slightly larger and the number laid was greater, wlhile tlle habits associated with egglaying differ, althouglh by transposing the conditions suit- able for other species a, considerable degree of uniformity may be produced.It is probable that in nature tlleir egglaying lhabits are quite distinct.Cross pairings between the insects are easily brought about and miglht, under exceptional circumstances, occur naturally.Hybrid strains resulting from pairings of P. capitis males with P. humanl'Us females, and vice versa, were maintained without trouble until the F3 generation, and there seemed no reason why such strains could not be continiued indefinitely.Nevertheless, the marked dis- parity in the sexes of the F1 generation of some crosses between P. capitis male and P. humnanus female was sug- gestive of the specific ratlher than the racial rank of the two insects.The mortality of females of P. capitis crossed with P. humanus males points in the same direction, but there was no such obvious disparity in thle sexes of the first generation of hybrids from this cross, nor was tlhere any muarked disparity in the proportion of the sexes in the following hybrid generations.In size the hybrid insects are approximately interinediate, but inclining in form, activity and habits towards P. capitis.Extreme disparity in tlle size of some indi- viduals of citlher sex was noted in some of the broods of the F3 generation; very large males and small females being observed.Habits.The body louse exhibits habits of gregariousness, espe- cially durinig the mou-lting phases, and a preference for retiring to a particular spot to oviposit, which leads to the clustering of eggs; botlh of these habits are shown, though in a less marked degree, by P. capitis, and it is possible that they mighit be partly due to the conditions of captivity, thlough it seems more probable that tile diver- gence in its lhabitat is accentuating botlh tendencies in P. hurnanuts.
Cross sectional evaluation of biochemical markers of bone, cartilage, and synovial tissue metabolism in patients with knee osteoarthritis: relations with disease activity and joint damage
Authors: P Garnero
Journal: Annals of the Rheumatic Diseases (2001)

<h3>OBJECTIVE</h3> To analyse the relations between the urinary levels of type II collagen C-telopeptide (CTX-II) and glucosyl-galactosyl pyridinoline (Glc-Gal-PYD)—two newly developed biochemical markers of type II collagen and synovial tissue destruction respectively—disease activity and the severity of joint destruction in patients with knee osteoarthritis (OA). The clinical performance of these two new markers was compared with that of a panel of other established biochemical markers of connective tissue metabolism. <h3>METHODS</h3> The following biochemical markers were measured in a group of 67 patients with knee OA (mean age 64 years, median disease duration eight years ) and in 67 healthy controls: for bone, serum osteocalcin, serum and urinary C-telopeptide of type I collagen (CTX-I); for cartilage, urinary CTX-II, serum cartilage oligomeric matrix protein (COMP), and serum human cartilage glycoprotein 39 (YKL-40); for synovium, urinary Glc-Gal-PYD, serum type III collagen N-propeptide (PIIINP), serum hyaluronic acid (HA); and for inflammation, serum C reactive protein. Biochemical markers were correlated with pain and physical function (WOMAC index) and with quantitative radiographic evaluation of the joint space using the posteroanterior view of the knees flexed at 30°. <h3>RESULTS</h3> All bone turnover markers were decreased in patients with knee OA compared with controls (−36%, −38%, and −52%, p&lt;0.0001 for serum osteocalcin, serum CTX-I and urinary CTX-I, respectively). Serum COMP (+16%, p=0.0004), urinary CTX–II (+25%, p=0.0009), urinary Glc-Gal-PYD (+18%, p=0.028), serum PIIINP (+33%, p&lt;0.0001), and serum HA (+ 233%, p&lt;0.0001) were increased. By univariate analyses, increased urinary Glc-Gal-PYD (<i>r</i>=0.41, p=0.002) and decreased serum osteocalcin (<i>r</i>=−0.30, p=0.025) were associated with a higher total WOMAC index. Increased urinary CTX–II (<i>r</i>=−0.40, p=0.0002) and Glc-Gal-PYD (<i>r</i>=−0.30, p=0.0046) and serum PIIINP (<i>r</i>=−0.29, p=0.0034) were the only markers which correlated with joint surface area. By multivariate analyses, urinary Glc-Gal-PYD and CTX-II were the most important predictors of the WOMAC index and joint damage, respectively. <h3>CONCLUSION</h3> Knee OA appears to be characterised by a systemic decrease of bone turnover and increased cartilage and synovial tissue turnover. CTX-II, Glc-Gal-PYD, and PIIINP may be useful markers of disease severity in patients with knee OA.