tbuckley/cabot-search huggingface dataset:
Abstract 2962: Loss of the E3 ubiquitin ligase HACE1 results in enhanced Rac1 signaling contributing to breast cancer progression
Authors: Erik T. Goka, Marc E. Lippman
Journal: Cancer Research (2014)

Abstract The transition from ductal carcinoma in situ (DCIS) to invasive disease is a crucial step in breast cancer progression. The specific alterations that govern this transition have not been elucidated. HER2/neu overexpression is frequently seen (50-60%) at the DCIS stage but is significantly less common in invasive breast cancer (20-30%) suggesting that additional alterations cooperate with HER2/neu to fully transform mammary epithelial cells. We identified novel genes that are capable of cooperating with HER2/neu allowing full malignant transformation, we used a transgenic mouse model that expresses wild-type neu and performed an insertional mutagenesis screen to identify genes whose alterations induce anchorage-independent growth on primary mouse mammary epithelial cells, an in vitro tumor formation assay. We identified the HECT and ankyrin domain containing E3 ligase 1 (HACE1) as a breast cancer tumor suppressor gene whose loss contributes to the transformation process. Loss of HACE1 expression is commonly seen in breast cancer patients and established breast cancer cell lines supporting the role of HACE1 as a breast cancer tumor suppressor gene. HACE1 ubiquitylates the activated GTP-bound form of the Rho family GTPase Rac1, resulting in ubiquitin mediated degradation of Rac1 via the 26S proteasome. The loss of HACE1 results in the accumulation of activated Rac1 leading to enhanced clonogenicity, migration, and invasion of human mammary epithelial cells (HMECs). In addition, the overexpression of HER2 results in activation of Rac1 levels which is further enhanced upon HACE1 loss in HMECs that further enhance colony formation in soft agar, migration, invasion and allows tumor formation in mice. Importantly, knocking down Rac1 using RNA interference or targeting RAC1 using the small molecule inhibitor EHT 1864 can rescue the effects of HACE1 loss mediated transformation. The results establish HACE1 as a breast cancer tumor suppressor gene by attenuating Rac1 signaling. In addition, our work further supports the role of Rac1 as a critical signaling node in breast cancer and that loss of HACE1 leads to enhanced Rac1 signaling that may contribute to breast cancer progression. These results suggest that HACE1 loss may identify precancerous lesions capable of becoming malignant as well as identify cancers susceptible to RAC targeted therapies. Citation Format: Erik T. Goka, Marc E. Lippman. Loss of the E3 ubiquitin ligase HACE1 results in enhanced Rac1 signaling contributing to breast cancer progression. [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 2962. doi:10.1158/1538-7445.AM2014-2962
Web-Based Collaborative Care for Type 2 Diabetes
Authors: James D. Ralston, Irl B. Hirsch, James Hoath, Mary Mullen, Allen Cheadle, Harold I. Goldberg
Journal: Diabetes Care (2008)

OBJECTIVE—To test Web-based care management of glycemic control using a shared electronic medical record with patients who have type 2 diabetes. RESEARCH DESIGN AND METHODS—We conducted a trial of 83 adults with type 2 diabetes randomized to receive usual care plus Web-based care management or usual care alone between August 2002 and May 2004. All patients had GHb ≥7.0%, had Web access from home, and could use a computer with English language–based programs. Intervention patients received 12 months of Web-based care management. The Web-based program included patient access to electronic medical records, secure e-mail with providers, feedback on blood glucose readings, an educational Web site, and an interactive online diary for entering information about exercise, diet, and medication. The primary outcome was change in GHb. RESULTS—GHb levels declined by 0.7% (95% CI 0.2−1.3) on average among intervention patients compared with usual-care patients. Systolic blood pressure, diastolic blood pressure, total cholesterol levels, and use of in-person health care services did not differ between the two groups. CONCLUSIONS—Care management delivered through secure patient Web communications improved glycemic control in type 2 diabetes.
Sleep and work
Authors: C. Gray
Journal: BMJ (1999)

Most of doctors' problems start in bed, or, at least, in getting into and out of bed. Much of medicine consists of doing things we don't want to do when we don't want to do them. Unavoidably, most medical activity takes place on the surface of this difficult planet - it's the only one available so far. Its inescapable period of rotation is 23.93 hours, and the axial tilt of 23.45&#degree; with reference to the solar plane causes the annoying seasonal variation in daylight hours during the 365.25 sidereal days of the solar orbit. Unlike polar bears and bats, who work their rotas according to the actual light and dark cycle, most medics' activity is entrained by the 24 hour based timetables fixed by organisations and computers but not suited to human chronobiology.

Unfortunately, humans have large interpersonal variations in effective diurnal cycles; few of us are accurately matched to the actual planetary rotation. Our internal clocks run to a virtual day that may differ widely from the 24 hour standard. Sleep often comes second to work, and, as Evelyn Waugh observed, you need more rest if you don't sleep.

In their seminal paper, environmental epidemiologists Gale and Martyn tested the validity of Benjamin Franklin's maxim “Early to bed and early to rise makes a man healthy, wealthy and wise.”(1) In 1229 men and women aged 65 and over the maxim was not supported: owls were slightly wealthier, but there was no significant difference in health or wisdom. Subjects who spent more than eight hours in bed each night had an increased risk of death for unknown reasons. The authors advised caution in extending their findings to younger people.

Sleep deprivation and disorder are built into the tradition and folklore of medicine, but dysfunctional hours no longer need be …
AN ARTIFICIAL AIRWAY FOR SURGICAL ANESTHESIA
Authors: ROBERT H. FERGUSON
Journal: JAMA (1913)

It seems, therefore, that of the various proteins, carbo¬ hydrates and lipoids which we tested so far, only the complex phosphorus-containing proteins are active.Of oilier substances we found leech extract active and among inorganic substances only colloidal metals.Very young tumors, from two to six days old, do not, seem to be as easily influenced as are those from nine to fourteen days old.Only intravenous injection was effective.We also investigated the action of some of these sub¬ stances on experimentally produced placentomas in the guinea-pig and rabbit.We found, usually, after one injection of casein, some hemorrhages and subsequent necrosis; colloidal copper seemed, SO far, lo be without any marked effect on placentomas.Willi Dr. Leighton we examined Ihe effect of casein and of colloidal copper on wound-healing in white mice.Tlic intravenous injec¬ tion of these substances bad no marked effect on the process of wound-healing.
In vitro and in situ intercellular adhesion molecule-1 (ICAM-1) expression by endothelial cells lining a polyester fabric
Authors: M. Rémy, N. Valli, D. Brethes, C. Labrugère, M.C. Porté-Durrieu, N.B. Dobrova, S.P. Novikova, A.J. Gorodkov, L. Bordenave
Journal: Biomaterials (1999)
Nonionic surfactant vesicular systems for effective drug delivery—an overview
Authors: Gannu P. Kumar, Pogaku Rajeshwarrao
Journal: Acta Pharmaceutica Sinica B (2011)

Vesicular systems are a novel means of drug delivery that can enhance bioavailability of encapsulated drug and provide therapeutic activity in a controlled manner for a prolonged period of time. Liposomes were the first such system but they suffer from a number of drawbacks including high cost and lack of stability at various pHs. Niosomes are a nonionic surfactant vesicular system, which can be easily and reliably made in the laboratory. Many factors affect noisome formation such as the method of manufacture, nature of surfactant and encapsulated drug, temperature at which the lipids are hydrated and the critical packing parameter. This review describes all aspects of niosomes including their different compositions, the various methods of preparation, the effect of changing manufacturing parameters, methods of characterization, factors that affect their stability, their use by various routes of administration, their therapeutic applications and the most important patents. The review also provides detailed information of the various types of niosomes that provide effective drug delivery.
Prevalence, Characteristics, and Publication of Discontinued Randomized Trials
Authors: Benjamin Kasenda, Erik von Elm, John You, Anette Blümle, Yuki Tomonaga, Ramon Saccilotto, Alain Amstutz, Theresa Bengough, Joerg J. Meerpohl, Mihaela Stegert, Kari A. O. Tikkinen, Ignacio Neumann, Alonso Carrasco-Labra, Markus Faulhaber, Sohail M. Mulla, Dominik Mertz, Elie A. Akl, Dirk Bassler, Jason W. Busse, Ignacio Ferreira-González, Francois Lamontagne, Alain Nordmann, Viktoria Gloy, Heike Raatz, Lorenzo Moja, Rachel Rosenthal, Shanil Ebrahim, Stefan Schandelmaier, Sun Xin, Per O. Vandvik, Bradley C. Johnston, Martin A. Walter, Bernard Burnand, Matthias Schwenkglenks, Lars G. Hemkens, Heiner C. Bucher, Gordon H. Guyatt, Matthias Briel
Journal: JAMA (2014)

<h3>Importance</h3> The discontinuation of randomized clinical trials (RCTs) raises ethical concerns and often wastes scarce research resources. The epidemiology of discontinued RCTs, however, remains unclear. <h3>Objectives</h3> To determine the prevalence, characteristics, and publication history of discontinued RCTs and to investigate factors associated with RCT discontinuation due to poor recruitment and with nonpublication. <h3>Design and Setting</h3> Retrospective cohort of RCTs based on archived protocols approved by 6 research ethics committees in Switzerland, Germany, and Canada between 2000 and 2003. We recorded trial characteristics and planned recruitment from included protocols. Last follow-up of RCTs was April 27, 2013. <h3>Main Outcomes and Measures</h3> Completion status, reported reasons for discontinuation, and publication status of RCTs as determined by correspondence with the research ethics committees, literature searches, and investigator surveys. <h3>Results</h3> After a median follow-up of 11.6 years (range, 8.8-12.6 years), 253 of 1017 included RCTs were discontinued (24.9% [95% CI, 22.3%-27.6%]). Only 96 of 253 discontinuations (37.9% [95% CI, 32.0%-44.3%]) were reported to ethics committees. The most frequent reason for discontinuation was poor recruitment (101/1017; 9.9% [95% CI, 8.2%-12.0%]). In multivariable analysis, industry sponsorship vs investigator sponsorship (8.4% vs 26.5%; odds ratio [OR], 0.25 [95% CI, 0.15-0.43];<i>P</i> &lt; .001) and a larger planned sample size in increments of 100 (−0.7%; OR, 0.96 [95% CI, 0.92-1.00];<i>P</i> = .04) were associated with lower rates of discontinuation due to poor recruitment. Discontinued trials were more likely to remain unpublished than completed trials (55.1% vs 33.6%; OR, 3.19 [95% CI, 2.29-4.43];<i>P</i> &lt; .001). <h3>Conclusions and Relevance</h3> In this sample of trials based on RCT protocols from 6 research ethics committees, discontinuation was common, with poor recruitment being the most frequently reported reason. Greater efforts are needed to ensure the reporting of trial discontinuation to research ethics committees and the publication of results of discontinued trials.
Risk of Worsening Renal Function With Nesiritide in Patients With Acutely Decompensated Heart Failure
Authors: Jonathan D. Sackner-Bernstein, Hal A. Skopicki, Keith D. Aaronson
Journal: Circulation (2005)

Background— Renal function is an important prognostic factor for patients with acutely decompensated heart failure (ADHF). We investigated the renal effects of nesiritide as treatment for ADHF. Methods and Results— Randomized clinical trials comparing nesiritide with either placebo or active control for ADHF were identified by electronic and manual searches and thorough review of US Food and Drug Administration files available via the website. Worsening renal function was defined as an increase in serum creatinine &gt;0.5 mg/dL. Relative risk across all studies was determined by meta-analysis with Mantel-Haenszel fixed-effects models (RR MH ). Risk of dialysis and medical intervention for worsening renal function were compared between therapies. Frequency of worsening renal function was determined from 5 randomized studies that included 1269 patients. Use of Food and Drug Administration–approved doses of nesiritide (≤0.03 μg · kg −1 · min −1 ) significantly increased the risk of worsening renal function compared with non–inotrope-based control (RR MH , 1.52; 95% CI, 1.16 to 2.00; P =0.003) or any control therapy, including non–inotrope- and inotrope-based therapies (RR MH , 1.54; 95% CI, 1.19 to 1.98; P =0.001). Even low-dose nesiritide (≤0.015 μg · kg −1 · min −1 ) significantly increased risk ( P =0.012 and P =0.006 compared with non–inotrope- and inotrope-based controls, respectively), as did nesiritide administered at any dose up to 0.06 μg · kg −1 · min −1 ( P =0.002 and P =0.001, respectively). There was no difference in the need for dialysis between therapies. Conclusions— Nesiritide significantly increases the risk of worsening renal function in patients with ADHF. Whether worsening renal function reflects hemodynamic effect or renal injury is unknown, but the prognostic importance of worsening renal function suggests the need for further investigation in appropriately powered clinical trials.
A Study of the Antibody Response to a Booster of Tetanus Toxoid
Authors: Sidney Goldsmith, Elliott Rosenberg, Eric H. Pollaczek
Journal: New England Journal of Medicine (1962)

UNTIL recently, it was thought that five years after the basic immunization was the limit beyond which booster doses of tetanus toxoid would be ineffective. However, in recent years Stafford et al.1 2 3 and Looney and his associates4 have reported good results after giving booster doses to persons who had received their basic immunization as much as ten years previously. They found an excellent antibody response, with increases in titers from a prebooster level of approximately 0.05 unit per milliliter to a postbooster level of 10 or more units per milliliter in the majority of subjects tested. Peterson and his co-workers . . .
Multiple Organ Failure Syndrome-Reply
Authors: Frank B. Cerra
Journal: JAMA (1994)

<h3>In Reply.</h3> —Systemic capillary leak syndrome is clearly a physical manifestation of the systemic inflammatory organ dysfunction response to infection and tissue injury and in patients who develop the progressive form of MOF. Beyond this physical sign, however, the role of this physical manifestation in tissue oxygenation remains largely in the experimental research domain. Clinical studies documenting this expression of the inflammatory response as a pathogenic mechanism of ischemic injury that affects outcomes in patients seem to be only in the early research phase. This is different than correlating this physical sign with an outcome or validating it as a predictor of an outcome. A review of the clinical studies indicates that this point of view also pertains to the clinical use of the various volume expanders. I would concur that more research is necessary and that appropriately designed and executed clinical studies with suitable endpoints that focus on these
A Distinctive Exanthem
Authors: Frederick A. J. Kingery
Journal: JAMA (1965)

I followed your advice and used the ringworm medicine for the spot on my hip. Now look at me, the sweet young thing said, displaying a torso covered with hundreds of oval scaling lesions. The herald plaque of pityriasis rosea (Fig 1) precedes the generalized eruption and resembles a superficial ringworm infection enough to result in frequent misdiagnosis. The patient then interprets the subsequent exanthem (Fig 2) as an unexpected result of the initial treatment.  Little is known about pityriasis rosea a century after Gilbert's description of the disease. Seasonal variations in incidence, with peaks in the spring and fall, account for periodic epidemics. Cases do not cluster in families, houses, or dormitories, so contagion is apparently not a factor. The frequent occurrence during pregnancy is unexplained, unless there is merit in the unproved idea that new clothing acts as a precipitating factor. The disease develops most commonly in young
Using the infrastructure of a conditional cash transfer program to deliver a scalable integrated early child development program in Colombia: cluster randomized controlled trial
Authors: O. P. Attanasio, C. Fernandez, E. O. A. Fitzsimons, S. M. Grantham-McGregor, C. Meghir, M. Rubio-Codina
Journal: BMJ (2014)

<b>Objective</b> To assess the effectiveness of an integrated early child development intervention, combining stimulation and micronutrient supplementation and delivered on a large scale in Colombia, for children’s development, growth, and hemoglobin levels. <b>Design</b> Cluster randomized controlled trial, using a 2×2 factorial design, with municipalities assigned to one of four groups: psychosocial stimulation, micronutrient supplementation, combined intervention, or control. <b>Setting</b> 96 municipalities in Colombia, located across eight of its 32 departments. <b>Participants</b> 1420 children aged 12-24 months and their primary carers. <b>Intervention</b> Psychosocial stimulation (weekly home visits with play demonstrations), micronutrient sprinkles given daily, and both combined. All delivered by female community leaders for 18 months. <b>Main outcome measures</b> Cognitive, receptive and expressive language, and fine and gross motor scores on the Bayley scales of infant development-III; height, weight, and hemoglobin levels measured at the baseline and end of intervention. <b>Results</b> Stimulation improved cognitive scores (adjusted for age, sex, testers, and baseline levels of outcomes) by 0.26 of a standard deviation (P=0.002). Stimulation also increased receptive language by 0.22 of a standard deviation (P=0.032). Micronutrient supplementation had no significant effect on any outcome and there was no interaction between the interventions. No intervention affected height, weight, or hemoglobin levels. <b>Conclusions</b> Using the infrastructure of a national welfare program we implemented the integrated early child development intervention on a large scale and showed its potential for improving children’s cognitive development. We found no effect of supplementation on developmental or health outcomes. Moreover, supplementation did not interact with stimulation. The implementation model for delivering stimulation suggests that it may serve as a promising blueprint for future policy on early childhood development. <b>Trial registration</b> Current Controlled trials ISRCTN18991160.
Dynamics of trajectory formation and speed/accuracy trade-offs
Authors: Reinoud J. Bootsma, Denis Mottet
Journal: Behavioral and Brain Sciences (1997)

Though capable of reproducing experimentally observed velocity profiles, the model proposed by Plamondon &amp; Alimi (P&amp;A) does not provide a viable theoretical framework for the understanding of trajectory formation and speed/accuracy trade-offs. The issues of variation and stability can be better understood by considering movement as resulting from an underlying dynamic rather than from an impulse-response of the system.
Treating Depression in Predominantly Low-Income Young Minority Women
Authors: Jeanne Miranda, Joyce Y. Chung, Bonnie L. Green, Janice Krupnick, Juned Siddique, Dennis A. Revicki, Tom Belin
Journal: JAMA (2003)

<h3>Context</h3> Impoverished minority women experience a higher burden from depression than do white women because they are less likely to receive appropriate care. Little is known about the effectiveness of guideline-based care for depression with impoverished minority women, most of whom do not seek care. <h3>Objective</h3> To determine the impact of an intervention to deliver guideline-based care for depression compared with referral to community care with low-income and minority women. <h3>Design, Setting, and Participants</h3> A randomized controlled trial conducted in the Washington, DC, suburban area from March 1997 through May 2002 of 267 women with current major depression, who attended county-run Women, Infants, and Children food subsidy programs and Title X family planning clinics. <h3>Outcomes</h3> Hamilton Depression Rating Scale measured monthly from baseline through 6 months; instrumental role functioning (Social Adjustment Scale) and social functioning (Short Form 36-Item Health Survey) measured at baseline and 3 and 6 months. <h3>Interventions</h3> Participants were randomly assigned to an antidepressant medication intervention (trial of paroxetine switched to bupropion, if lack of response) (n = 88), a psychotherapy intervention (8 weeks of manual-guided cognitive behavior therapy) (n = 90), or referral to community mental health services (n = 89). <h3>Results</h3> Both the medication intervention (<i>P</i>&lt;.001) and the psychotherapy intervention (<i>P</i>= .006) reduced depressive symptoms more than the community referral did. The medication intervention also resulted in improved instrumental role (<i>P</i>= .006) and social (<i>P</i>= .001) functioning. The psychotherapy intervention resulted in improved social functioning (<i>P</i>= .02). Women randomly assigned to receive medications were twice as likely (odds ratio, 2.04; 95% confidence interval, 0.98-4.27;<i>P</i>= .057) to achieve a Hamilton Depression Rating Scale score of 7 or less by month 6 as were those referred to community care. <h3>Conclusions</h3> Guideline-concordant care for major depression is effective for these ethnically diverse and impoverished patients. More women engaged in a sufficient duration of treatment with medications compared with psychotherapy, and outcome gains were more extensive and robust for medications.
Acute Glaucoma After General Surgery
Authors: Boardman C. Wang
Journal: JAMA (1961)

Among approximately 25,000 patients, 5 developed acute glaucoma following general surgery. The possible etiological factors considered include (1) a preexisting narrow ocular filtration angle; (2) mydriasis induced by stress through endogenous catecholamine: (3) elevation of intraocular tension from succinylcholine; and (4) pupillary dilatation caused by scopolamine. An adequate history regarding prior eye disease and evaluation of anterior chamber depth preoperatively are advisable. Where shallow chambers are present, 2% pilocarpine eye drops should be used before operation. Scopolamine and succinylcholine are best avoided in these cases. In the early postoperative period, proper attention should be paid to the eyes for the symptoms and signs of acute glaucoma, i.e., ocular pain, dilated pupil, cloudy cornea, pericorneal vascular congestion, and blurred vision.