tbuckley/cabot-search huggingface dataset:
A Phase I Trial of Lenalidomide in Patients with Recurrent Primary Central Nervous System Tumors
Authors: Howard A. Fine, Lyndon Kim, Paul S. Albert, J. Paul Duic, Hilary Ma, Wei Zhang, Tanyifor Tohnya, William D. Figg, Cheryl Royce
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Inhibition of angiogenesis represents a promising new therapeutic strategy for treating primary malignant brain tumors. Lenalidomide, a potent analogue of the antiangiogenic agent thalidomide, has shown significant activity in several hematologic malignancies, and therefore we chose to explore its tolerability and activity in patients with primary central nervous system tumors. Experimental Design: A phase I interpatient dose escalation trial of lenalidomide in patients with recurrent primary central nervous system tumors was conducted. Results: Thirty-six patients were accrued to the study, of which 28 were evaluable for toxicity, the primary end point of the trial. We show that lenalidomide can be given safely up to doses of 20 mg/m2, with the only toxicity being a probable increased risk of thromboembolic disease. Pharmacokinetic studies reveal good bioavailability, linear kinetics, and no effects of enzyme-inducing antiepileptic drugs on the metabolism of lenalidomide. No objective radiographic responses were seen in any of the treated patients. In the group of 24 patients with recurrent glioblastoma, the median time to tumor progression was &amp;lt;2 months and only 12.5% of patients were progression-free at 6 months. Conclusion: Lenalidomide is well tolerated in patients with recurrent glioma in doses up to 20 mg/m2. Treatment may be associated with an increased risk of thromboembolic disease. Preliminary data suggest that single agent activity may be limited in patients with recurrent glioblastoma at the doses evaluated although larger studies will be needed to confirm these observations.
Effects of Chronic Stress on Memory Decline in Cognitively Normal and Mildly Impaired Older Adults
Authors: Guerry M. Peavy, David P. Salmon, Mark W. Jacobson, Aaron Hervey, Anthony C. Gamst, Tanya Wolfson, Thomas L. Patterson, Sherry Goldman, Paul J. Mills, Srikrishna Khandrika, Douglas Galasko
Journal: American Journal of Psychiatry (2009)

Objective: The literature provides evidence of a strong relationship between greater stress and memory loss, but few studies have examined this relationship with both variables measured over time. The authors sought to determine the prospective association between subjective and objective measures of chronic stress and rate of memory decline in cognitively normal and mildly impaired older adults. Method: This longitudinal study was conducted at a university research center and included 61 cognitively normal subjects and 41 subjects with mild cognitive impairment (ages 65–97). Fifty-two subjects were followed for up to 3 years (mean=2 years) and received repeated stress and cognitive assessments. Exclusion criteria were dementia, significant medical or psychiatric conditions, and medication use (e.g., corticosteroids) that might affect cortisol level or cognitive functioning. The main outcome measure was a regression-based slope reflecting performance change on tests of global cognition and episodic memory as a function of baseline diagnosis, recent life events, and salivary cortisol. Examiners were blind to stress ratings and cortisol levels at the time of cognitive testing. Results: Higher event-based stress ratings collected over the follow-up period were associated with faster cognitive decline in subjects with mild cognitive impairment but not in cognitively normal subjects. In contrast, higher cortisol levels were associated with slower cognitive decline in subjects with mild cognitive impairment but not in cognitively normal subjects. Conclusions: Chronic stress affects cognitive functioning differently in cognitively normal subjects and those with mild cognitive impairment. Cortisol, while likely to have neurotoxic effects over time, may enhance cognitive functioning in older adults compromised by existing cognitive deficits.
Long-Term, Low-Intensity Warfarin Therapy for the Prevention of Recurrent Venous Thromboembolism
Authors: Paul M Ridker, Samuel Z. Goldhaber, Ellie Danielson, Yves Rosenberg, Charles S. Eby, Steven R. Deitcher, Mary Cushman, Stephan Moll, Craig M. Kessler, C. Gregory Elliott, Rolf Paulson, Turnly Wong, Kenneth A. Bauer, Bruce A. Schwartz, Joseph P. Miletich, Henri Bounameaux, Robert J. Glynn
Journal: New England Journal of Medicine (2003)

Standard therapy to prevent recurrent venous thromboembolism includes 3 to 12 months of treatment with full-dose warfarin with a target international normalized ratio (INR) between 2.0 and 3.0. However, for long-term management, no therapeutic agent has shown an acceptable benefit-to-risk ratio.Patients with idiopathic venous thromboembolism who had received full-dose anticoagulation therapy for a median of 6.5 months were randomly assigned to placebo or low-intensity warfarin (target INR, 1.5 to 2.0). Participants were followed for recurrent venous thromboembolism, major hemorrhage, and death.The trial was terminated early after 508 patients had undergone randomization and had been followed for up to 4.3 years (mean, 2.1). Of 253 patients assigned to placebo, 37 had recurrent venous thromboembolism (7.2 per 100 person-years), as compared with 14 of 255 patients assigned to low-intensity warfarin (2.6 per 100 person-years), a risk reduction of 64 percent (hazard ratio, 0.36 [95 percent confidence interval, 0.19 to 0.67]; P<0.001). Risk reductions were similar for all subgroups, including those with and those without inherited thrombophilia. Major hemorrhage occurred in two patients assigned to placebo and five assigned to low-intensity warfarin (P=0.25). Eight patients in the placebo group and four in the group assigned to low-intensity warfarin died (P=0.26). Low-intensity warfarin was thus associated with a 48 percent reduction in the composite end point of recurrent venous thromboembolism, major hemorrhage, or death. According to per-protocol and as-treated analyses, the reduction in the risk of recurrent venous thromboembolism was between 76 and 81 percent.Long-term, low-intensity warfarin therapy is a highly effective method of preventing recurrent venous thromboembolism.
Reversibility of T-tubule remodelling in heart failure: mechanical load as a dynamic regulator of the T-tubules
Authors: Michael Ibrahim, Cesare M. Terracciano
Journal: Cardiovascular Research (2013)

The T-tubule system in ventricular cardiomyocytes is essential for synchronous Ca2+ handling, and, therefore, efficient contraction. T-tubular remodelling is a common feature of heart disease. In this review, we discuss whether t-tubular remodelling can be reversed and which factors may be implicated in this process. In particular, we focus on the interaction between mechanical load variation and T-tubule structure and function. What is the evidence of this relationship? What is the role of different degrees and durations of mechanical load variation? In what settings might mechanical load variation have detrimental or beneficial effects on T-tubule structure and function? What are the molecular determinants of this interaction? Ultimately this discussion is used to address the question of whether mechanical load variation can provide an understanding to underpin attempts to induce recovery of the T-tubule system. In reviewing these questions, we define what remains to be discovered in understanding T-tubule recovery.
Structural Equation Modeling: Strengths, Limitations, and Misconceptions
Authors: Andrew J. Tomarken, Niels G. Waller
Journal: Annual Review of Clinical Psychology (2004)

Because structural equation modeling (SEM) has become a very popular data-analytic technique, it is important for clinical scientists to have a balanced perception of its strengths and limitations. We review several strengths of SEM, with a particular focus on recent innovations (e.g., latent growth modeling, multilevel SEM models, and approaches for dealing with missing data and with violations of normality assumptions) that underscore how SEM has become a broad data-analytic framework with flexible and unique capabilities. We also consider several limitations of SEM and some misconceptions that it tends to elicit. Major themes emphasized are the problem of omitted variables, the importance of lower-order model components, potential limitations of models judged to be well fitting, the inaccuracy of some commonly used rules of thumb, and the importance of study design. Throughout, we offer recommendations for the conduct of SEM analyses and the reporting of results.
Bevacizumab in Combination With Fluorouracil and Leucovorin: An Active Regimen for First-Line Metastatic Colorectal Cancer
Authors: Herbert I. Hurwitz, Louis Fehrenbacher, John D. Hainsworth, William Heim, Jordan Berlin, Eric Holmgren, Julie Hambleton, William F. Novotny, Fairooz Kabbinavar
Journal: Journal of Clinical Oncology (2005)

Purpose In a phase III trial, combining bevacizumab (BV)—a recombinant, humanized, monoclonal antibody targeting vascular endothelial growth factor—with irinotecan, bolus fluorouracil (FU), and leucovorin (LV; IFL) increased survival compared with IFL alone in first-line treatment of patients with metastatic colorectal cancer (CRC). Results for the parent study of IFL/BV versus IFL/placebo are reported elsewhere. Here, we describe efficacy and safety results for the third patient cohort in this trial, who received BV combined with FU/LV, and compare them with results for concurrently enrolled patients who received IFL. Methods Patients (N = 923) were randomly assigned to receive IFL/placebo (control), IFL/BV, or FU/LV/BV. Bevacizumab (Avastin; Genentech Inc, South San Francisco, CA) 5 mg/kg was administered intravenously every 2 weeks. Before an interim analysis confirmed acceptable safety for IFL/BV, 313 patients were concurrently randomly assigned to these three arms; after this analysis, the FU/LV/BV arm was discontinued. Results Median overall survivals were 18.3 and 15.1 months with FU/LV/BV (n = 110) and IFL/placebo (n = 100), respectively. Median progression-free survivals were 8.8 and 6.8 months, respectively. Overall response rates were 40.0% and 37.0%, and median response durations were 8.5 and 7.2 months, respectively. Adverse events consistent with those expected from FU/leucovorin- or IFL-based regimens were seen, as were modest increases in hypertension and bleeding in the bevacizumab arm, which were generally easily managed. Conclusion The FU/LV/BV regimen seems as effective as IFL and has an acceptable safety profile. FU/LV/BV is an active alternative treatment regimen for patients with previously untreated metastatic CRC.
Elastography for the non-invasive assessment of liver disease: limitations and future developments
Authors: F. Vizzutti, U. Arena, F. Marra, M. Pinzani
Journal: Gut (2009)

Hepatology is still a relatively young discipline in medicine. The birth of hepatology in the 1950s was largely dependent on the introduction of liver biopsy performed with the Menghini’s needle1 and its modifications. Ever since, diagnosis and staging of chronic liver diseases (CLDs) has been based on the morphological evaluation of liver tissue associated with grading and staging according to established scoring systems.2 3 The introduction of ultrasound scanning, practically the first easily available imaging tool, at the end of the 1970s, provided further diagnostic advantages for the hepatologist, and made liver biopsy a safer procedure. Nowadays, liver biopsy remains an essential tool for the diagnosis of the majority of liver diseases, while its clinical relevance is more limited to the staging of the disease in settings where the diagnosis is based on other established parameters, ie, viral markers in chronic viral hepatitis. Even though the prevalence of biopsy-related complications is very limited in tertiary centres, this procedure still carries a burden of potentially severe events.4 Moreover, sampling error and intra- and inter-observer variability represent major drawbacks.5 6 Overall, liver biopsy should be considered the “best possible reference standard” and does not allow discrimination of adjacent stages of fibrosis (ie, F2 vs F1 or F3 vs F2)6 7 with adequate diagnostic accuracy. Along this trend, hepatologists have started to develop non-invasive systems able to provide a surrogate estimate of disease staging, ie, semi-quantitative assessment of fibrosis. Overall, these attempts are aimed at fulfilling the dream of developing an accurate, easy and cost/effective non-invasive test that allows (1) fast screening, (2) longitudinal follow-up, (3) efficacy of therapeutic treatments; and (4) prognostic evaluation. This assumes a particular relevance in the paediatric setting, where the use of liver biopsy is perceived as bearing higher risks and is less …
PROLAPSE OF THE IRIS. (HERNIA IRIDIS.)— A CASE OF SUCCESSFUL REDUCTION.Read before the Tri-State Medical Society of Alabama, Georgia and Tennessee.
Authors: FRANK TRESTER SMITH
Journal: JAMA (1894)

The case before you, David Lucas, of Chattanooga, came to my office September 20 with a history of having beem struck in the right eye half an hour previously with a piece of steel. Inspection showed a pear-shaped pupil with the point downward and inward, with the iris prolapsing through a linear wound at the margin of the clear cornea. A solution of sulphate of eserin was instilled into the eye and the patient sent home. Two hours later the prolapse was pushed inside the eye with blunt point of a small squint hook. The iris was freed from the wound except a small part which was adherent to its inner side and it was thought that further use of eserin would reduce this more safely than further manipulation. The pupil was almost circular but was still drawn to a point. Eserin was used for several days, the eye was
Predictive Value of Phase I Trials for Safety in Later Trials and Final Approved Dose: Analysis of 61 Approved Cancer Drugs
Authors: Denis L. Jardim, Kenneth R. Hess, Patricia LoRusso, Razelle Kurzrock, David S. Hong
Journal: Clinical Cancer Research (2013)

Phase I trials use a small number of patients to define a maximum tolerated dose (MTD) and the safety of new agents. We compared data from phase I and registration trials to determine whether early trials predicted later safety and final dose. We searched the U.S. Food and Drug Administration (FDA) website for drugs approved in nonpediatric cancers (January 1990-October 2012). The recommended phase II dose (R2PD) and toxicities from phase I were compared with doses and safety in later trials. In 62 of 85 (73%) matched trials, the dose from the later trial was within 20% of the RP2D. In a multivariable analysis, phase I trials of targeted agents were less predictive of the final approved dose (OR, 0.2 for adopting ± 20% of the RP2D for targeted vs. other classes; P = 0.025). Of the 530 clinically relevant toxicities in later trials, 70% (n = 374) were described in phase I. A significant relationship (P = 0.0032) between increasing the number of patients in phase I (up to 60) and the ability to describe future clinically relevant toxicities was observed. Among 28,505 patients in later trials, the death rate that was related to drug was 1.41%. In conclusion, dosing based on phase I trials was associated with a low toxicity-related death rate in later trials. The ability to predict relevant toxicities correlates with the number of patients on the initial phase I trial. The final dose approved was within 20% of the RP2D in 73% of assessed trials.
Embolisation of a traumatic aneurysm of the posterior circumflex humeral artery in a volleyball player: Figure 1
Authors: M Vlychou, G Spanomichos, A Chatziioannou, M Georganas, G M Zavras
Journal: British Journal of Sports Medicine (2001)

Repetitive minor vascular injuries caused by physical activity in athletes may lead to ischaemia of the upper extremities. In volleyball players in particular, traumatic aneurysm of the posterior circumflex humeral artery has been reported to be a cause of ischaemia of the arm and hand. Such an aneurysm is described here; it was treated successfully with endovascular embolisation.
Metastatic Struma Ovarii: The Burden of Truth
Authors: I Ross McDougall
Journal: Clinical Nuclear Medicine (2006)

A 58-year-old woman was found to have metastatic thyroid cancer in her liver. This was identified when she was investigated for upper abdominal pain and underwent biopsy of hepatic lesions. She had no palpable thyroid nodule and had a normal ultrasound of the thyroid. Previously, both ovaries had been removed because of tumors. The pathologic findings in one of the ovaries could not be recovered because the procedure was more than 40 years ago, when the patient was a teenager. By a process of elimination, a diagnosis of metastatic struma ovarii was established. Treatment of metastatic thyroid cancer from struma ovarii, including removal of the normal thyroid and administration of I-131, is presented.
THE NATURE OF THE TOXIN-ANTITOXIN FLOCCULATION PHENOMENON
Authors: J. J. Bronfenbrenner, Philip Reichert
Journal: The Journal of Experimental Medicine (1926)

1. Animals immunized with the formalinized filtrates of young toxic cultures of B. botulinus produce an antitoxic serum poor in precipitins. 2. Animals immunized with the formalinized filtrates of old and partly autolyzed toxic cultures produce an antitoxic serum containing precipitins. 3. Animals immunized with toxin-free autolyzed bacteria produce a serum free from antitoxin but rich in specific precipitins. 4. Animals immunized with the filtrates of an atoxic variant produce a serum free from antitoxin but rich in precipitins for the homologous toxin. 5. Animals immunized with the washed bacteria of the atoxic variant produce a serum that contains no antitoxin, but is rich in precipitins for the homologous toxin. 6. Removal of the precipitins by flocculation with a non-toxic antigen does not materially reduce the antitoxic value of a serum. 7. Removal of the proteins of the antigen by add coagulation removes the specific precipitable substance. 8. All the sera that contain precipitins produce the specific flocculus when combined with homologous toxins, anatoxins, or with the filtrates of the atoxic variant. The flocculation is restricted within the type. The amount of the precipitate and the width of the zone vary approximately with the estimated amount of bacterial protein in the antigen that is used for the immunization of animals. We conclude, therefore, that the toxin-antitoxin flocculation is a specific bacterial precipitation phenomenon.
Study on the relationship between skill performance and selected physical fitness variables of hand ball players
Authors: S Ibrahim, K Azeem
Journal: British Journal of Sports Medicine (2010)

This study examined the relationship between skill performance and selected physical fitness variables of hand ball players of Osmania University, Hyderabad, India. 30 handball players aged 18-11 years were randomly selected from players undergoing rigorous training camp for the All India Inter-University tournament. Defensive ability, passing ability and dribbling ability were assessed by defence movement test, passing test and control dribbling test. The tests selected for the physical fitness variables were: speed, 50 m run; explosive power, sergeant jump; agility, 6×10 m shuttle run; cardiorespiratory endurance, 12 min run/walk test; flexibility, bend and reach test. The statistical tool used was Pearson product moment correlation. Defensive ability was positively correlated with speed (r=0.72) and agility (r=0.61), whereas explosive power, cardiorespiratory endurance and flexibility were negatively correlated. Passing ability was negatively correlated with speed and agility, and positively correlated with explosive power (r=0.38), cardiorespiratory endurance (r=0.79) and flexibility (r=0.69). The skill of dribbling was positively correlated with speed (r=0.87) and agility (r=0.95), and negatively correlated with explosive power; it was not significantly correlated with cardiorespiratory endurance or flexibility. The results showed that defensive ability performance can be improved by good speed and agility. A player can excel in passing if he has good explosive power, cardiorespiratory endurance and flexibility. The skill of dribbling can be taken care of if a player has speed and agility.
Activation of the Hedgehog pathway in pilocytic astrocytomas
Authors: Sarah Z. Rush, Ty W. Abel, Juan G. Valadez, Matthew Pearson, Michael K. Cooper
Journal: Neuro-Oncology (2010)

Pilocytic astrocytoma is commonly viewed as a benign lesion. However, disease onset is most prevalent in the first two decades of life, and children are often left with residual or recurrent disease and significant morbidity. The Hedgehog (Hh) pathway regulates the growth of higher WHO grade gliomas, and in this study, we have evaluated the activation and operational status of this regulatory pathway in pilocytic astrocytomas. Expression levels of the Hh pathway transcriptional target PTCH were elevated in 45% of tumor specimens analyzed (ages 1–22 years) and correlated inversely with patient age. Evaluation of a tissue array revealed oligodendroglioma-like features, pilomyxoid features, infiltration, and necrosis more commonly in specimens from younger patients (below the median patient age of 10 years). Immunohistochemical staining for the Hh pathway components PTCH and GLI1 and the proliferation marker Ki67 demonstrated that patients diagnosed before the age of 10 had higher staining indices than those diagnosed after the age of 10. A significant correlation between Ki67 and PTCH and GLI1 staining indices was measured, and 86% of Ki67-positive cells also expressed PTCH. The operational status of the Hh pathway was confirmed in primary cell culture and could be modulated in a manner consistent with a ligand-dependent mechanism. Taken together, these findings suggest that Hh pathway activation is common in pediatric pilocytic astrocytomas and may be associated with younger age at diagnosis and tumor growth.
Evolution of matrix metalloprotease and tissue inhibitor expression during heart failure progression in the infarcted rat
Authors: J Peterson
Journal: Cardiovascular Research (2000)

Objective: Characterize the timecourse of matrix metalloproteinase (MMP-1, -2, -3, -7, -9, -11, -12, -13, and -14) and endogenous tissue inhibitors of MMPs (TIMP-1, -2, -3, and -4) upregulation during left ventricular (LV) remodeling following myocardial infarction (MI) in rats. Methods: The descending left coronary artery of male rats (Rattus norvegicus) was ligated to produce a MI. LV function and dilation were assessed from 1 day to 16 weeks post-MI. Protein and mRNA extraction was done on LV samples containing scar and myocardium together. Gelatinase activity was measured by zymography. Westerns were run on the MMPs known to cleave fibrillar collagen in the rat (MMP-8, -13, and -14) as well as TIMP-1, -2, and -4. Results: Average infarct size was 38.6±1.1%, and produced LV dysfunction and progressive LV dilation. Thoracic ascites, a marker of congestive heart failure (HF), was not present until 12 weeks post-MI. Upregulation of MMP-2, -8, -9, -13, and -14 and TIMP-1 and TIMP-2 was detected at different timepoints during HF progression. Increased MMP protein levels occurred sometimes without a corresponding elevation in mRNA levels, and increased TIMP mRNA levels without increased protein levels. MMP-13 active form was elevated during the first 2 weeks post-MI while TIMP-1 and TIMP-2 protein levels were not significantly elevated until 2 weeks post-MI. MMP-8 and MMP-14 protein levels increased later during heart failure progression. Conclusion: MMP/TIMP upregulation evolves over time following infarction in the rat LV. Some MMPs were significantly elevated during the first week post-MI (MMP-13, -2, and -9) and another was not until 16 weeks post-MI (MMP-14). The dissociation between LV MMP/TIMP mRNA and protein levels shows that post-translation processing occurs in the rat heart.