tbuckley/cabot-search huggingface dataset:
Abstract PR16: Spatio-temporal heterogeneity in the tumor microenvironment influences the evolutionary dynamics of drug resistance
Authors: Shannon Mumenthaler, Jasmine Foo, Nathan Choi, William Pao, David Agus, Franziska Michor, Parag Mallick
Journal: Cancer Research (2015)

Abstract Tumor growth is a complex evolutionary process driven by dynamic feedback between a heterogeneous cell population and selection pressures from the tumor microenvironment. Spatio-temporal heterogeneity in the microenvironment can create physical niches that facilitate cellular adaptation as seen in regions of hypoxia and acidosis where cells may up-regulate glycolysis and become resistant to acid-meditated toxicity in order to survive. In recent studies, using clinically prevalent subtypes of EGFR-related non-small cell lung cancer (NSCLC), we observe that nutrient and drug gradients resulting from a cells' proximity to vasculature, can produce selective pressures driving tumor evolution. We provide a detailed examination of the microenvironmental impact (i.e. oxygen, glucose, and drug) on growth rates of NSCLC cell lines that are either sensitive or resistant to the EGFR TKI, erlotinib. Often we consider drug resistance to be associated with a fitness cost to the cell in the absence of drug. However, here we demonstrate that the situation is more complex, with the local tumor microenvironment influencing the magnitude and the directionality of the selective effect. In fact, the resistant cells actually gain a selective advantage in nutrient-stressed environments compared to the sensitive cells. The resulting growth dynamics were used to inform a stochastic compartment-based tumor model of pre-existing drug resistance where each compartment represents a specific tumor environmental niche. This integrative modeling framework was then used to predict rebound growth kinetics and tumor composition (i.e. % resistance) and in particular, provide insight into the magnitude by which the microenvironment influences these results. These investigations strongly suggest that ignoring the microenvironment or using laboratory environmental conditions to inform tumor dynamics can lead to inaccurate conclusions. Therefore, knowledge of the selective advantage/disadvantage of different cell populations within different regions of the tumor will better guide model predictions, influence overall tumor dynamics, and impact treatment strategies. This abstract is also presented as Poster A80. Citation Format: Shannon Mumenthaler, Jasmine Foo, Nathan Choi, William Pao, David Agus, Franziska Michor, Parag Mallick. Spatio-temporal heterogeneity in the tumor microenvironment influences the evolutionary dynamics of drug resistance. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr PR16. doi:10.1158/1538-7445.CHTME14-PR16
HARMONY 3: 104-Week Randomized, Double-Blind, Placebo- and Active-Controlled Trial Assessing the Efficacy and Safety of Albiglutide Compared With Placebo, Sitagliptin, and Glimepiride in Patients With Type 2 Diabetes Taking Metformin
Authors: Bo Ahrén, Susan L. Johnson, Murray Stewart, Deborah T. Cirkel, Fred Yang, Caroline Perry, Mark N. Feinglos
Journal: Diabetes Care (2014)

OBJECTIVE To compare the efficacy and safety of weekly albiglutide with daily sitagliptin, daily glimepiride, and placebo. Research Design And Methods Patients with type 2 diabetes receiving metformin were randomized to albiglutide (30 mg), sitagliptin (100 mg), glimepiride (2 mg), or placebo. Blinded dose titration for albiglutide (to 50 mg) and glimepiride (to 4 mg) was based on predefined hyperglycemia criteria. The primary end point was change in HbA1c from baseline at week 104. Secondary end points included fasting plasma glucose (FPG), weight, and time to hyperglycemic rescue. RESULTS Baseline characteristics were similar among the albiglutide (n = 302), glimepiride (n = 307), sitagliptin (n = 302), and placebo (n = 101) groups. Baseline HbA1c was 8.1% (65.0 mmol/mol); mean age was 54.5 years. The mean doses for albiglutide and glimepiride at week 104 were 40.5 and 3.1 mg, respectively. At week 104, albiglutide significantly reduced HbA1c compared with placebo (−0.9% [−9.8 mmol/mol]; P &amp;lt; 0.0001), sitagliptin (−0.4% [−4.4 mmol/mol]; P = 0.0001), and glimepiride (−0.3% [−3.3 mmol/mol]; P = 0.0033). Outcomes for FPG and HbA1c were similar. Weight change from baseline for each were as follows: albiglutide −1.21 kg (95% CI −1.68 to −0.74), placebo −1.00 kg (95% CI −1.81 to −0.20), sitagliptin −0.86 kg (95% CI −1.32 to −0.39), glimepiride 1.17 kg (95% CI 0.70–1.63). The difference between albiglutide and glimepiride was statistically significant (P &amp;lt; 0.0001). Hyperglycemic rescue rate at week 104 was 25.8% for albiglutide compared with 59.2% (P &amp;lt; 0.0001), 36.4% (P = 0.0118), and 32.7% (P = 0.1504) for placebo, sitagliptin, and glimepiride, respectively. Rates of serious adverse events in the albiglutide group were similar to comparison groups. Diarrhea (albiglutide 12.9%, other groups 8.6–10.9%) and nausea (albiglutide 10.3%, other groups 6.2–10.9%) were generally the most frequently reported gastrointestinal events. CONCLUSIONS Added to metformin, albiglutide was well tolerated; produced superior reductions in HbA1c and FPG at week 104 compared with placebo, sitagliptin, and glimepiride; and resulted in weight loss compared with glimepiride.
Medical school reunions
Authors: E. McGinley
Journal: BMJ (1997)

“Are you going? Well, I'll go, if you go.”

I had not attended our 10th anniversary reunion. But our 20th reunion found me beating a path to Peebles Hydro for a gathering of the Glasgow Zeta '76 Club. Here are a few words for the unwary.

Attenders at such reunions are a self selected bunch, and you need to feel that you have achieved some success in at least one major area to brave the self inflicted ordeal. Success can come in many forms–for example, marital status (can you beat the four times married?); number of children (prize given to a happy paediatrician with six children); career status (you …
Babies sleeping with parents: case-control study of factors influencing the risk of the sudden infant death syndrome Commentary: Cot death---the story so far
Authors: P. S Blair, P. J Fleming, I. J Smith, M. W. Platt, J. Young, P. Nadin, P J Berry, J. Golding, None the CESDI SUDI research group, E. Mitchell
Journal: BMJ (1999)

<h3>Abstract</h3> <b>Objective:</b> To investigate the risks of the sudden infant death syndrome and factors that may contribute to unsafe sleeping environments. <b>Design:</b> Three year, population based case-control study. Parental interviews were conducted for each sudden infant death and for four controls matched for age, locality, and time of sleep. <b>Setting:</b> Five regions in England with a total population of over 17 million people. <b>Subjects:</b> 325 babies who died and 1300 control infants. <b>Results:</b> In the multivariate analysis infants who shared their parents9 bed and were then put back in their own cot had no increased risk (odds ratio 0.67; 95% confidence interval 0.22 to 2.00). There was an increased risk for infants who shared the bed for the whole sleep or were taken to and found in the parental bed (9.78; 4.02 to 23.83), infants who slept in a separate room from their parents (10.49; 4.26 to 25.81), and infants who shared a sofa (48.99; 5.04 to 475.60) The risk associated with being found in the parental bed was not significant for older infants (&gt;14 weeks) or for infants of parents who did not smoke and became non-significant after adjustment for recent maternal alcohol consumption (&gt;2 units), use of duvets (&gt;4 togs), parental tiredness (infant slept ≤4 hours for longest sleep in previous 24 hours), and overcrowded housing conditions (&gt;2 people per room of the house). <b>Conclusions:</b> There are certain circumstances when bed sharing should be avoided, particularly for infants under four months old. Parents sleeping on a sofa with infants should always be avoided. There is no evidence that bed sharing is hazardous for infants of parents who do not smoke. <h3>Key messsages</h3> Cosleeping with an infant on a sofa was associated with a particularly high risk of sudden infant death syndrome Sharing a room with the parents was associated with a lower risk There was no increased risk associated with bed sharing when the infant was placed back in his or her cot Among parents who do not smoke or infants older than 14 weeks there was no association between infants being found in the parental bed and an increased risk of sudden infant death syndrome The risk linked with bed sharing among younger infants seems to be associated with recent parental consumption of alcohol, overcrowded housing conditions, extreme parental tiredness, and the infant being under a duvet
Efficacy and safety of celgosivir in patients with dengue fever (CELADEN): a phase 1b, randomised, double-blind, placebo-controlled, proof-of-concept trial
Authors: Jenny G Low, Cynthia Sung, Limin Wijaya, Yuan Wei, Abhay P S Rathore, Satoru Watanabe, Boon Hian Tan, Liying Toh, Lian Tee Chua, Yan'an Hou, Angelia Chow, Shiqin Howe, Wing Ki Chan, Kah Hin Tan, Jasmine S Chung, Benjamin P Cherng, David C Lye, Paul A Tambayah, Lee Ching Ng, John Connolly, Martin L Hibberd, Yee Sin Leo, Yin Bun Cheung, Eng Eong Ooi, Subhash G Vasudevan
Journal: The Lancet Infectious Diseases (2014)
AN UNUSUAL FORM OF MINERAL POISONING AFFECTING THE NERVOUS SYSTEM: MANGANESE?
Authors: LOUIS CASAMAJOR
Journal: JAMA (1913)

A certain indication of the humanitarian trend of modern times is the ever-increasing interest in the accidents, intoxications and diseases coincident with various trades. The ill effects that arsenic, lead and phosphorus have on workers started this line of investigation, and these intoxications have been so well studied that their clinical pictures are well known. Undoubtedly the most serious and permanent of trade diseases are those which affect the nervous system. Up to within recent years, only peripheral nervous system poisonings were recognized in workers in metallic and other poisons. Peripheral neuritis is the commonest form of occupational nervous system disorder, and it has for its commonest causative agents lead and arsenic. Other substances which produce neuritis in workers are copper, mercury, carbon bisulphid, anilin oil and the cyanids. In the central nervous system, on the other hand, conditions are different. Of all the substances mentioned, lead alone is known
Thyrotoxicosis Due to Functioning Metastatic Follicular Thyroid Carcinoma After Twelve I-131 Therapies
Authors: Jian Tan, Guizhi Zhang, Wengui Xu, Zhaowei Meng, Feng Dong, Fuhai Zhang, Qiang Jia, Xuehui Liu
Journal: Clinical Nuclear Medicine (2009)

We present a case of functioning metastatic follicular thyroid carcinoma (FTC) causing severe thyrotoxicosis despite four years 12 iodine-131 therapies (1.461 Ci cumulatively). Initially, the patient had ostalgia and fracture in the right femur. Surgery-confirmed metastatic bone FTC and thyroidectomy-confirmed FTC. One month later, iodine-131 treatment commenced. During the follow-up, different metastatic sites showed different outcomes. Lung metastases disappeared, a thigh metastasis persisted, a new metastasis in the head occurred and pelvic metastases deteriorated into a huge mass elevating thyroglobulin and causing thyrotoxicosis within 3 months. Presurgical PET/CT also demonstrated the massiveness of the pelvic metastases. Thyrotoxicosis disappeared after surgical removal of the pelvic lesion.
OT3-01-16: A Phase 2 Study of Ridaforolimus (RIDA) and Dalotuzumab (DALO) in Estrogen Receptor Positive (ER+) Breast Cancer.
Authors: BD Lu, JL Blum, J Cortes, HS Rugo, C Swanton, L Eaton, Y Song, T Zhang, SW Ebbinghaus, J Baselga
Journal: Cancer Research (2011)

Abstract Background: Activation of the PI3K/AKT/mTOR pathway is common in breast cancer. Preclinical studies indicate that the dual inhibition of IGFR and mTOR may be additive or synergistic and abrogates the feedback activation of AKT due to rapamycin analog mTOR inhibitors. A phase 1 study of the mTOR inhibitor RIDA and the anti-IGFR antibody DALO demonstrated that the combination was feasible and well-tolerated at doses that were nearly those used for the two single agents and with dose limiting toxicity of stomatitis, similar to RIDA as monotherapy. A preliminary signal of anti-tumor activity, including partial responses and prolonged progression free survival, was observed in ER+ breast cancer, especially in high proliferation tumors. This observation is supported by data from tumor profiling and preclinical data suggesting that ER+ high proliferation breast cancer may be responsive to the RIDA-DALO combination. Methods: This is a two-part, adaptive design study intended to first test the combination of RIDA-DALO against a standard agent, exemestane, for ER+ positive breast cancer that has progressed after aromatase inhibitors. The trial is a multi-center, international, randomized study with PFS as the primary endpoint. Patients (pts) are stratified into high and low proliferation strata based on baseline Ki67, and the low proliferation stratum is capped to ensure adequate enrollment of high proliferation pts. If Part A shows a PFS benefit for RIDA-DALO, Part B is intended to show the PFS benefit of the combination over the single agents by comparing RIDA-DALO to RIDA and DALO. Part B will be further adapted based on whether the PFS benefit in Part A is observed in all-comers or the high proliferation subset. Tumor tissue is collected for molecular profiling and analysis of intrinsic subtype, with an efficacy analysis based on classification of tumors using the genomic grade index (GGI) as an exploratory objective. This trial design is intended to establish proof of concept that RIDA-DALO can prolong PFS in ER+ breast cancer in all-comers or a high proliferation subset by Ki67, while efficiently addressing the development of two investigational agents in combination and leading to a two-arm Phase 3 design. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT3-01-16.
Characterisation of bronchoconstrictor responses to sodium metabisulphite aerosol in atopic subjects with and without asthma.
Authors: G M Nichol, A Nix, K F Chung, P J Barnes
Journal: Thorax (1989)

Inhalation of sodium metabisulphite is thought to induce bronchoconstriction by release of sulphur dioxide. We sought to establish the reproducibility of the airway response to inhaled sodium metabisulphite given in increasing doubling concentrations (0.3 to 160 mg/ml) to 13 asthmatic and five atopic non-asthmatic subjects and the contribution of cholinergic mechanisms to this response. In 15 of the 18 subjects bronchoconstriction was sufficient to allow calculation of the dose of metabisulphite causing a 20% reduction in the forced expiratory volume in one second (FEV1) from baseline values (PD20 metabisulphite). The 95% confidence limit for the difference between this and a second PD20 metabisulphite determined 2-14 days later was 2.5 doubling doses. The difference between repeat PD20 metabisulphite measurements was unrelated to the number of days between challenges or change in baseline FEV1. Ten subjects returned for a third study 3-120 days after the second challenge; variability in PD20 metabisulphite did not differ from that seen between the first and second challenges. PD20 methacholine was determined between the two metabisulphite challenges and found to correlate with PD20 metabisulphite (r = 0.71). Inhaled ipratropium bromide 200 micrograms given in a randomised, placebo controlled, crossover study to 10 subjects increased PD20 methacholine 42 fold but had no significant effect on the response to metabisulphite. A single inhalation of the PD20 metabisulphite in five subjects induced maximal bronchoconstriction 2-3 minutes after inhalation, with a plateau in FEV1 lasting a further four minutes before recovery. A further single inhalation of the same PD20 dose 43 minutes later produced a 27% (SEM 4%) smaller fall in FEV1 than the first inhalation. These results show that metabisulphite PD20 values measured over days and weeks show similar reproducibility to those reported for histamine inhalation and that PD20 metabisulphite correlates with methacholine responsiveness. Most of the bronchoconstriction is not inhibited by antimuscarinic agents; the underlying mechanisms require further investigation.
Bedside Measurement of Alveolar Carbon Dioxide Tension
Authors: Herbert A. Ravin, Myron Stein
Journal: New England Journal of Medicine (1958)

ABNORMALITIES of pulmonary excretion of carbon dioxide often become clinically evident only when the patient is no longer able to respond to respiratory stimuli. Recently described syndromes of carbon dioxide retention1 usually remain unrecognized until the underlying pulmonary disease is far advanced. Determinations of alveolar or arterial carbon dioxide tension (pCO2), however, are generally limited to specially equipped laboratories. It is the purpose of this report to describe a simple method for measuring alveolar pCO2 in the hope that it will facilitate wider clinical application of this useful determination.Apparatus§A pulmonary gas sample is collected in . . .
Allergen reduction measures in houses of allergic asthmatic patients: effects of air-cleaners and allergen-impermeable mattress covers
Authors: S van der Heide, HF Kauffman, AE Dubois, JG de Monchy
Journal: European Respiratory Journal (1997)

Recommendations for allergen avoidance or allergen reduction measures play an important part in the treatment of allergic asthmatic patients. The purpose of this study was to test recently developed air-cleaners with respect to their capacity to capture airborne allergen particles and to improve clinical parameters of asthmatic patients sensitized to aeroallergens. Forty five allergic asthmatic patients were studied in a double-blind procedure for 6 months. The patients were divided into three groups of 15 patients. In Group 1, the intervention consisted of the application of active air-cleaners in living-rooms and bedrooms. In Group 2, placebo air-cleaners were used in combination with allergen-impermeable mattress covers. In Group 3, the same intervention was performed as in Group 2 but with active air-cleaners. Allergen levels in mattress and floor dust were measured before, and 3 and 6 months after the interventions. After 6 months, the air-cleaners were dismantled and the filters were analysed for the amount of dust collected and allergen content. Immunological and lung function parameters were measured before, and 3 and 6 months after the interventions. Considerable amounts of airborne dust and allergenic particles were captured in the filters of the air-cleaners. Up to the 18.9 g of dust, 4,513 ng of house dust mite allergen, Der p 1, and 50,000 mU of cat allergen, Fel d 1, (in houses with cats) were collected by air-cleaners in living-rooms. Only in Group 3 (in which both active air-cleaners and mattress covers were used) was a small (less than 1 doubling dose) but statistically significant improvement of provocative concentration of histamine causing a 20% fall in forced expiratory volume in one second (PC20) observed (from 5.96 to 9.02 mg x mL(-1)). The amount of dust and house dust mite allergen collected in the filters was significantly correlated with an improvement of peak flow variation. In combination with other allergen avoidance measures, the examined air-cleaners can contribute to diminished allergen exposure and improvement of airway hyperresponsiveness in asthmatic patients.
Successful use of vancomycin hydrochloride in the treatment of lactulose resistant chronic hepatic encephalopathy.
Authors: K Tarao, T Ikeda, K Hayashi, A Sakurai, T Okada, T Ito, H Karube, T Nomoto, T Mizuno, K Shindo
Journal: Gut (1990)

<h3>PURPOSE</h3> We hypothesized that antibiotic overuse for acute cough illness (ACI) is in part due to a mismatch between patients' expectations and the natural history of ACI. <h3>METHODS</h3> We performed a population-based random digit dialing survey of 493 adults in Georgia to determine their expectations regarding the duration of ACI. We also performed a systematic review of observational studies and the placebo or untreated control groups of randomized controlled trials to determine the duration of ACI from the published medical literature. We included studies of otherwise healthy adults with undifferentiated ACI, no clear bacterial cause, data on at least 1 cough outcome, and at least 1 week of follow-up. <h3>RESULTS</h3> The mean duration of cough in the published literature was 17.8 days. Survey respondents reported a median duration of 5 to 7 days and a mean duration of 7.2 to 9.3 days depending on the specific scenario. Patients expecting a longer duration of illness were more likely to be white, female, and have self-reported asthma or chronic lung disease. Independent predictors of the belief that antibiotics are always helpful included nonwhite race (OR = 1.82, 95% CI, 1.14–2.92), some college education or less (OR = 2.08, 95% CI, 1.26–3.45), and previous antibiotics for ACI (OR = 2.20, 95% CI, 1.34–3.55). <h3>CONCLUSIONS</h3> There is a mismatch between patients' expectations regarding the duration of ACI and the actual duration based on the best available evidence. Efforts to reduce inappropriate antibiotic use should target this discrepancy.
Letter from Chicago: Hearts from monkeys and machines
Authors: G. Dunea
Journal: BMJ (1985)

The British Medical Journal's "man in Chicago" presents a tongue-in-cheek view of the attitude of various segments of the American public to the Baby Fae baboon heart transplant and the mechanical heart implant at the Humana Heart Institute. Dunea ties these events to a recent report from the Office of Technology Assessment concerned with the high costs of medical care, especially care involving complex technologies, and with the potential impact of new Medicare reimbursement policies. He concludes with several anecdotes about the mass media and sex surveys and takes a final jab at Americans' worship of British pomp and tradition.
CARDIAC DISEASE IN SOLDIERS AND RECRUITS
Authors: C. W. Scarisbrick
Journal: BMJ (1917)

Settenth Day.-A fast day.Eighth Day.-30 grams of cooked fat bacon replace 30 grams of lean meat.Ninth Day.-30 grams cooked fat bacon replace 15 grams of lean meat, 15 grams of boiled potato added.Tenth Day.-30 grams of fat added.Elevenlth Day.-Breakfast: Weak coffee 300 c.cm., thin cream 15 c.cm., one egg, cooked fat bacon 30 grams, raw lettuce 200 grams.Lunch: Cooked lean meat 20 grams, fat 15 grams, oooked French beans or their equivalent 120 grams, boiled potato 60 grams, butter 15 grams.Tea: Weak tea 300 c.cm., cream 15 c.cm., boiled potato 30 grams, butter 15 grams.D)inner: Clear broth 200 c.cm., one egg, cooked cabbage 100 grams, cooked French beans 100 grams, butter 30 grams.Twvelfth Day.-Add fat 30 grams.T7hir-teentth Day.-Add white bread 15 grams, subtract raw lettuce 120 grams.Add white bread 15 grams at tea, and subtract 30 grams of potato at lunch.Add butter 15 grams, Foltrteenth Bay.-A fast day.Fifteenth Day.-Breakfast: Coffee 300 c.cm., cream 20 c.cm., one egg, cooked fat bacon 30 grams, raw lettuce 100 grams, white bread 15 grams, butter 15 grams.Lunch: Cooked lean meat 60 grams, fat 30 grams, cooked French beans 120 grams, boiled potato 30 grams, butter 60 grams.Tea: Tea 300 grams, white bread 15 grams, one egg, butter 30 grams.Dinner: Clear broth 200 c.cm., one egg, cooked cabbage 120 grams, boiled potato 30 grams, butter 60 grams.The diet on the fiftee'nth day represents carbohydrate 42 grams, protein 54 grams, fat 192 grams.: Note that the carbolhydrate is fairlv well divided: Breakfast 12 grams lunch 8 grams, tea 9 grams, dinner 13grams.The energy