tbuckley/cabot-search huggingface dataset:
Deregulation of the PI3K and KRAS signaling pathways in human cancer cells determines their response to everolimus
Authors: Federica Di Nicolantonio, Sabrina Arena, Josep Tabernero, Stefano Grosso, Francesca Molinari, Teresa Macarulla, Mariangela Russo, Carlotta Cancelliere, Davide Zecchin, Luca Mazzucchelli, Takehiko Sasazuki, Senji Shirasawa, Massimo Geuna, Milo Frattini, José Baselga, Margherita Gallicchio, Stefano Biffo, Alberto Bardelli
Journal: Journal of Clinical Investigation (2010)

Personalized cancer medicine is based on the concept that targeted therapies are effective on subsets of patients whose tumors carry specific molecular alterations. Several mammalian target of rapamycin (mTOR) inhibitors are in preclinical or clinical trials for cancers, but the molecular basis of sensitivity or resistance to these inhibitors among patients is largely unknown. Here we have identified oncogenic variants of phosphoinositide-3-kinase, catalytic, alpha polypeptide (PIK3CA) and KRAS as determinants of response to the mTOR inhibitor everolimus. Human cancer cells carrying alterations in the PI3K pathway were responsive to everolimus, both in vitro and in vivo, except when KRAS mutations occurred concomitantly or were exogenously introduced. In human cancer cells with mutations in both PIK3CA and KRAS, genetic ablation of mutant KRAS reinstated response to the drug. Consistent with these data, PIK3CA mutant cells, but not KRAS mutant cells, displayed everolimus-sensitive translation. Importantly, in a cohort of metastatic cancer patients, the presence of oncogenic KRAS mutations was associated with lack of benefit after everolimus therapy. Thus, our results demonstrate that alterations in the KRAS and PIK3CA genes may represent biomarkers to optimize treatment of patients with mTOR inhibitors.
Influenza-Associated Hospitalization in a Subtropical City
Authors: Chit Ming Wong, Lin Yang, King Pan Chan, Gabriel M Leung, Kwok H Chan, Yi Guan, Tai Hing Lam, Anthony Johnson Hedley, Joseph S. M Peiris
Journal: PLoS Medicine (2006)

The impact of influenza on morbidity and hospitalization in the tropics and subtropics is poorly quantified. Uniquely, the Hong Kong Special Administrative Region has computerized hospital discharge diagnoses on 95% of total bed days, allowing disease burden for a well-defined population to be accurately assessed.Influenza-associated morbidity and hospitalization was assessed by Poisson regression models for weekly counts of hospitalizations in Hong Kong during 1996 to 2000, using proportions of positive influenza types A (H1N1 and H3N2) and B isolations in specimens sent for laboratory diagnosis as measures of influenza virus circulation. We adjusted for annual trend, seasonality, temperature, and relative humidity, as well as respiratory syncytial virus circulation. We found that influenza was significantly associated with hospitalization for acute respiratory disease (International Classification of Diseases version 9 codes [ICD9] 460-466 and 480-487) and its subcategory pneumonia and influenza (ICD9 480-487) for all age groups. The annual rates of excess hospitalization per 100,000 population for acute respiratory diseases for the age groups 0-14, 15-39, 40-64, 65-74, and 75+ were 163.3 (95% confidence interval [CI], 135-190), 6.0 (95% CI, 2.7-8.9), 14.9 (95% CI, 10.7-18.8), 83.8 (95% CI, 61.2-104.2), and 266 (95% CI, 198.7-330.2), respectively. Influenza was also associated with hospitalization for cerebrovascular disease (ICD9 430-438) for those aged over 75 y (55.4; 95% CI, 23.1-87.8); ischemic heart disease (ICD9 410-414) for the age group 40-64 y (5.3; 95% CI, 0.5-9.5) and over 75 y (56.4; 95% CI, 21.1-93.4); and diabetes mellitus (ICD9 250) for all age groups older than 40 y.Influenza has a major impact on hospitalization due to cardio-respiratory diseases as well as on cerebrovascular disease, ischemic heart disease, and diabetes mellitus in the tropics and subtropics. Better utilization of influenza vaccine during annual epidemics in the tropics will enhance global vaccine production capacity and allow for better preparedness to meet the surge in demand that is inevitable in confronting a pandemic.
NICKEL DERMATITIS FROM SPECTACLE FRAMES AND WRIST WATCH
Authors: Howard Fox
Journal: JAMA (1933)

Two years ago, Lain reported<sup>1</sup>three cases of dermatitis due to spectacle frames made of white gold, an alloy containing nickel. Since then I have seen a patient who had not only a similar dermatitis from spectacle frames but also an eruption due to wearing a nickel-plated wrist watch. E. G., a man, aged 24, a clerk, consulted me, March 10, 1932, for a vesicular and crusted eruption limited to areas where his spectacle frames were in contact with the skin. The affected areas included horizontal streaks along the temples and small patches on the ear lobules, the postauricular region and the left inner canthus. He also presented well defined erythematosquamous patches on the front and back of the right wrist, corresponding to the position where his wrist watch had been in contact with the skin. The patient had worn spectacles since childhood for nearsightedness. He had always used
Chlorosis Lives!— and Slips Through MeSH-Reply
Authors: William H. Crosby
Journal: JAMA (1987)

In Reply.—  In my article, I referred to the work of Gilles et al, 1 who described lost pigmentation in African blacks with hookworm-induced iron deficiency. They made no note of greenish color of palms and soles in the affected patients, but remarked that pallor occurred only in patients with severe deficiency of blood albumin in addition to severe anemia.  I did not state nor imply that melanin overlies hemoglobin in the epidermis. In the microanatomy of the skin, the vascular papillae (containing hemoglobin) protrude into the stratum basale (where most of the melanin resides). Thus, the points of color are not stratified one on the other; they intermingle as in photoengraving, where a mixture of tiny dots of blue and yellow is perceived as green.  I welcome the references provided by Mr Cahan and salute his superior scholarship.
Appropriate Use Criteria For Stress Single-Photon Emission Computed Tomography Sestamibi Studies
Authors: Raymond J. Gibbons, J. Wells Askew, David Hodge, Beth Kaping, Damita J. Carryer, Todd Miller
Journal: Circulation (2011)

We previously reported the application of the 2005 American College of Cardiology Foundation appropriate use criteria for stress single-photon emission computed tomography (SPECT) imaging to patients at Mayo Clinic (Rochester, MN) in 2005 and 2006. A subsequent internal quality improvement project focused on physician education in an attempt to reduce the rate of inappropriate SPECT studies.Our 2008 physician education effort, focused on 4 specific indications that accounted for 88% of the inappropriate SPECT studies, included a presentation at medical grand rounds, a publication in the staff newsletter, meetings with physician administrators, and focused presentations to departments/divisions with many ordering physicians. We then remeasured the appropriateness of SPECT studies using previously published methods. The general categories of study indications, eg, after revascularization, were similar in 273 SPECT patients in 2008 and in our 2005 (n=284) and 2006 (n=284) cohorts. There was a trend suggesting a change in the overall classification of appropriateness over time (P=0.08) and a significant change in the rate of inappropriate studies over time (P=0.018). Inappropriate studies decreased from 14.4% in 2005 to 7.0% in 2006 before initiation of the quality improvement project. After completion of the quality improvement project, inappropriate studies increased to 11.7% (P=0.06). The 95% confidence limits for the 4.7% increase in inappropriate studies after the quality improvement project included a decrease of 0.2% and an increase of 9.6%.This quality improvement project, focused on feedback, physician education, and remeasurement, did not reduce the rate of inappropriate stress SPECT studies in a single academic medical center. Similar limited interventions focused on physician education alone may have limited benefit. More extensive intervention may be necessary to improve the quality of care with appropriateness criteria.
ABC of major trauma. Trauma of the upper urinary tract.
Authors: T Terry
Journal: BMJ (1990)

Mechanism of direct blunt renal trauma.An external force (F,) may crush the kidney (K) between the 12th rib and the vertebral column, or a force (F2) may crush the kidney against the paravertebral muscles (quadratus lumborum (QL) or psoas major (in position P but deleted from diagram).Penetrating renal trauma occurs in about 7% of patients with abdominal stab wounds.As with blunt renal trauma associated injuries are often present (in up to 80% of cases); these affect the liver, lungs, spleen, small bowel, stomach, pancreas, duodenum, and diaphragm in descending order of frequency.Renal stab wounds are potentially serious, with the possibilities of severed major renal vessels and lacerations to the collecting system or upper ureter.Gunshot wounds that involve the kidney may be caused by a low or high velocity missile.Low velocity missiles cause injury by directly penetrating the tissue whereas high velocity missiles produce direct tissue injury plus damage to adjacent tissue because of the shock wave effect see chapter on blast injuries. Classification of renal trauma Classification of renal injuriesMinor (85%) * Contusions * Superficial lacerations (capsule and pelvicaliceal system intact) Major (10%) * Deep lacerations (capsular tears or pelvicaliceal involvement, or both) Critical (5%) * Renal fragmentation * Pedicle injuries (renal artery thrombosis, vessel avulsion, and pelviureteric rupture) Clinical signs of renal trauma * Regional skin lesions (abrasions, bruising, and entry and exit wounds) * Loin tenderness * Loss of loin contour * Loin mass * Gross haematuria (up to 90% of cases) Findings on intravenous urographyControl film * Fractures (of lower ribs and transverse processes of lumbar vertebrae) * Loss of psoas shadow * Loss of renal outline * Loin mass (displacement of bowel or diaphragm Postcontrast film series * Distortion of caliceal pattern * Contrast extravasation * Non-visualisation of part or whole of caliceal system
Differential effects of chenodeoxycholic and ursodeoxycholic acids on interleukin 1, interleukin 6 and tumor necrosis factor–α production by monocytes
Authors: Yvon Calmus, Jerome Guechot, Philippe Podevin, Marie-Therese Bonnefis, Jacqueline Giboudeau, Raoul Poupon
Journal: Hepatology (1992)

Cell–mediated immunity and macrophage activity, especially that of Kupffer cells, are impaired during cholestasis. Some evidence exists that bile acids play a role in these immune defects. The purpose of this study was to evaluate the effects of individual bile acids on immunity and to determine whether monocytes could be a target. We assessed the effects of chenodeoxycholic acid, an endogenous bile acid, ursodeoxycholic acid, which has been shown to partially correct the immunological abnormalities observed in primary biliary cirrhosis, and their tauroconjugates on the production of interleukin–1, interleukin–6 and tumor necrosis factor-α. Chenodeoxycholic acid had a dose–dependent inhibitory effect on interleukin–1 (inhibitory concentration 50% = 60 m¨mol/L), interleukin–6 (inhibitory concentration 50% = 80 m¨mol/L) and tumor necrosis factor-α (inhibitory concentration 50% = 80 m¨mol/L) production; inhibition was almost complete at 250 m¨mol/L. In contrast, ursodeoxycholic acid had lesser or minimal inhibitory effects (inhibitory concentration 50% = 100 m¨mol/L for interleukin–1 and above 200 m¨mol/L for interleukin–6 and tumor necrosis factor-α). The inhibitory effects of taurochenodeoxycholic acid and tauroursodeoxycholic acid were similar to those of chenodeoxycholic acid and ursodeoxycholic acid, respectively. Ursodeoxycholic acid did not reverse the chenodeoxycholic acid-induced inhibition of interleukin–6 or tumor necrosis factor-α production. In conclusion, chenodeoxycholic acid exerts strong inhibitory effects on monocyte activity in vitro , whereas the effects of ursodeoxycholic acid are minor. (Hepatology 1992;16:719-723.)
Hyperthyroidism and eating disorders.
Authors: V Fonseca, A Wakeling, C W Havard
Journal: BMJ (1990)

having increased activity of i-hydroxybutyrate dehydrogenase.Aspartate aminotransferase activities <42 U/I were found in 84 patients who received streptokinase compared with 70 who received placebo.Similarly, alanine aminotransferase activities >50 U/I were found in 48 who received streptokinase compared with 35 who received placebo.Bilirubin concentrations were routinely measured, and increased concentrations were found in 10 of the patients with increased alanine aminotransferase activity who received streptokinase but none of those who received placebo.The activity of y-glutamyltransferase was not routinely measured, but an increased activity (mean 176 U/1; normal range 11-55 U/i) was seen in six patients who received streptokinase who had an increased activity of alanine aminotransferase.Increased activity of aspartate aminotransferase with no other evidence of infarction occurred in 10 of 16 patients who received streptokinase and in eight of 21 who received placebo (mean activity 118 U/I and 57 U/i respectively).No patients with raised aminotransferase activities after treatment with streptokinase had necropsies.
Ultrastructure of multinucleated giant myeloma cells: Report of one case
Authors: Hitoshi Kurabayashi, Shuichi Miyawaki, Hirokazu Murakami, Kazuo Nemoto, Morio Sawamura, Kazuo Kubota, Takuji Naruse, Jun Tsuchiya
Journal: American Journal of Hematology (1989)

Abstract The ultrastructure of multinucleated giant myeloma cells obtained from an IgAk myeloma patient was investigated. The characteristic findings were marked nucleocytoplasmic asynchrony, irregular nuclear indentation, branched mitochondria, and Golgi apparatus surrounded by nuclei. The patient died of renal failure only 6 months after diagnosis.
Postviral fatigue syndrome.
Authors: D. C. Costa, J. Brostoff, V. Douli, P. J. Ell
Journal: BMJ (1992)

The authors state that all the patients with the postviral fatigue syndrome had characteristic mitochondrial changes, and some had RNA enteroviral sequences, but as the necessary investigations were not applied to the depressed patients or controls it is not possible to tell whether these findings did in fact distinguish the group with the syndrome.Another issue that concerns us is that the authors fail to refer to the considerable body of work suggesting that release of prolactin mediated by 5-hydroxytryptamine is suppressed in depressed patients"4 and that this response is enhanced by antidepressant treatments, including electrocon- vulsive therapy.5There is a non-significant trend in their study for the depressed patients to have a smaller rise in prolactin secretion than controls, with the patients with the postviral fatigue syndrome having a significantly higher response than that of both the other groups.The finding that the prolactin response seems to be changed in opposite directions in the postviral fatigue
Dr Rabelais's 500 year old prescription
Authors: I. MacLean
Journal: BMJ (1994)

initiative to specify the technology required to capture and use patients' clinical records electronically.The existence of these initiatives is due largely to persistent pressure from clinical workers involved with the information management group.Although these links are encouraging, two measures of the group's commitment are less so: firstly, funding of these initiatives seems to be only about £4m, or 2% of the group's total spending to date (though a higher proportion of recent spending).And, secondly, the member- ship of a panel appointed by the NHS Management Executive to undertake a substantial review of staffing in the information management group does not include a single doctor.Only if the information management group is itself con- vinced of the importance of a clinical focus will it be able to convince doctors that it will promote the development of systems that meet their needs and help them to care for patients.Achieving this holds the promise of better care for patients and-for managers, purchasers, the NHS Management Executive, and the Department of Health- accurate and timely data captured as a byproduct of the collection ofgood quality clinical data.
The recellularized liver matrix: A novel way of transplantation?
Authors: Christer Baeck, Konrad Streetz
Journal: Hepatology (2010)

Abstract Orthotopic liver transplantation is the only available treatment for severe liver failure, but it is currently limited by organ shortage. One technical challenge that has thus far limited the development of a tissue-engineered liver graft is oxygen and nutrient transport. Here we demonstrate a novel approach to generate transplantable liver grafts using decellularized liver matrix. The decellularization process preserves the structural and functional characteristics of the native microvascular network, allowing efficient recellularization of the liver matrix with adult hepatocytes and subsequent perfusion for in vitro culture. The recellularized graft supports liver-specific function including albumin secretion, urea synthesis and cytochrome P450 expression at comparable levels to normal liver in vitro. The recellularized liver grafts can be transplanted into rats, supporting hepatocyte survival and function with minimal ischemic damage. These results provide a proof of principle for the generation of a transplantable liver graft as a potential treatment for liver disease.
Morphological Alterations of the Esophagus after Endoscopic Sclerotherapy of Varices
Authors: N. Soehendra, K. de Heer, I. Kempeneers, L. Frommelt
Journal: Endoscopy (1983)

With the combined peri- and intravascular sclerosing technique esophageal varices can be completely eliminated in an average of three treatment sessions. In order to check the success of the procedure, endoscopic and histological findings at the various stages of treatment after sclerosing with 1% Polidocanol were compared. Clinical and autopsy findings are in agreement. After sclerosing, necroses of the mucosa and intramural inflammations occur regularly in the first week. The varices are thrombosed. Later, the inner wall of the esophagus is cicatricially changed. Histologically the fibroses extend transmurally and in some parts even reach the musculature.
Race Joins Host of Unanswered Questions on Early HIV Therapy
Authors: Paul Cotton
Journal: JAMA (1991)

EARLY INTERVENTION may harm African Americans infected with the human immunodeficiency virus (HIV), according to a "fragile" new finding. The data, which come from a post hoc subset analysis not in the study's original design, "may be artifactual and not truly result from a biological effect," cautions John D. Hamilton, MD, cochair of the study and chief of infectious disease at the Durham (NC) Veterans Affairs (VA) Medical Center. Progression to acquired immunodeficiency syndrome (AIDS) and death was higher in blacks given zidovudine (Retrovir [commonly called AZT], Burroughs Wellcome Co) when their CD4 counts were between 200 and 500 mm<sup>3</sup>than in patients who were not given the drug until their CD4 counts dropped below 200 mm<sup>3</sup>. Blacks also did not have the "highly significant" CD4 count rise seen in whites when zidovudine therapy is begun, says Hamilton. He presented the findings from the 4-year study, in which
Bisphenol A at Environmentally Relevant Doses Inhibits Adiponectin Release from Human Adipose Tissue Explants and Adipocytes
Authors: Eric R. Hugo, Terry D. Brandebourg, Jessica G. Woo, Jean Loftus, J. Wesley Alexander, Nira Ben-Jonathan
Journal: Environmental Health Perspectives (2008)

The incidence of obesity has risen dramatically over the last few decades. This epidemic may be affected by exposure to xenobiotic chemicals. Bisphenol A (BPA), an endocrine disruptor, is detectable at nanomolar levels in human serum worldwide. Adiponectin is an adipocyte-specific hormone that increases insulin sensitivity and reduces tissue inflammation. Thus, any factor that suppresses adiponectin release could lead to insulin resistance and increased susceptibility to obesity-associated diseases.In this study we aimed to compare a) the effects of low doses of BPA and estradiol (E(2)) on adiponectin secretion from human breast, subcutaneous, and visceral adipose explants and mature adipocytes, and b) expression of putative estrogen and estrogen-related receptors (ERRs) in these tissues.We determined adiponectin levels in conditioned media from adipose explants or adipocytes by enzyme-linked immunosorbant assay. We determined expression of estrogen receptors (ERs) alpha and beta, G-protein-coupled receptor 30 (GPR30), and ERRs alpha, beta, and gamma by quantitative real-time polymerase chain reaction.BPA at 0.1 and 1 nM doses suppressed adiponectin release from all adipose depots examined. Despite substantial variability among patients, BPA was as effective, and often more effective, than equimolar concentrations of E(2). Adipose tissue expresses similar mRNA levels of ERalpha, ERbeta, and ERRgamma, and 20- to 30-fold lower levels of GPR30, ERRalpha, and ERRbeta.BPA at environmentally relevant doses inhibits the release of a key adipokine that protects humans from metabolic syndrome. The mechanism by which BPA suppresses adiponectin and the receptors involved remains to be determined.
Individual Differences in Cancer Susceptibility
Authors: Curtis C. Harris, John J. Mulvihill, Snorri S. Thorgeirsson, John D. Minna
Journal: Annals of Internal Medicine (1980)

The major determinants of cancer risk are environmental carcinogens and predisposing host factors. Interactions between these determinants are now being studied by clinical-laboratory investigations. An individual may be predisposed to cancer by both genetic and acquired conditions. Genes related to malignancy and to carcinogenesis have been mapped to individual chromosomes in several species, including humans. Because most environmental chemical carcinogens require enzymatic activitation and a wide variation in carcinogen metabolism among people has been found, the ratio of metabolic activation to deactivation of carcinogens may ascertain, in part, a person's cancer risk. Additionally, cancer risk of chemical and physical agents can be qualitatively predicted by carcinogenicity tests in experimental animals. The emerging field of cancer ecogenetics is aiding efforts to prevent human cancer.
Accounting for cross boundary flows.
Authors: J Brazier
Journal: BMJ (1987)

RAWP (Resource Allocation Working Party) allows for cross boundary flows by adjusting regional or district health authorities9 (DHAs) targets at an average specialty cost. The previous paper in this series examined problems for an inner city district health authority arising from RAWP cross boundary flow adjustment. This paper examines the likely importance of these and other problems for the National Health Service as a whole. Cross charging has been proposed as an alternative method of funding flows. District health authorities would receive an allocation equivalent to their RAWP target and then all non-emergency flows would be agreed between the authorities where patients live and competing authorities offering treatment at previously negotiated charges based on local estimates of each type of case. The problem of cost estimation is usually cited as a difficulty with this proposed reform, but this paper also discusses other important issues that tend to be neglected.