tbuckley/cabot-search huggingface dataset:
Phase I Pharmacokinetic and Pharmacodynamic Study of 17-Allylamino, 17-Demethoxygeldanamycin in Patients With Advanced Malignancies
Authors: Udai Banerji, Anne O'Donnell, Michelle Scurr, Simon Pacey, Sarah Stapleton, Yasmin Asad, Laura Simmons, Alison Maloney, Florence Raynaud, Maeli Campbell, Michael Walton, Sunil Lakhani, Stanley Kaye, Paul Workman, Ian Judson
Journal: Journal of Clinical Oncology (2005)

To study the toxicity and pharmacokinetic-pharmacodynamic profile of 17-allylamino, 17- demethoxygeldanamycin (17-AAG) and to recommend a dose for phase II trials.This was a phase I study examining a once-weekly dosing schedule of 17-AAG. Thirty patients with advanced malignancies were treated.The highest dose level reached was 450 mg/m(2)/week. The dose-limiting toxicities (DLTs) encountered were grade 3 diarrhea in three patients (one at 320 mg/m(2)/week and two at 450 mg/m(2)/week) and grade 3 to 4 hepatotoxicity (AST/ALT) in one patient at 450 mg/m(2)/week. Two of nine DLTs were at the highest dose level. Two patients with metastatic melanoma had stable disease and were treated for 15 and 41 months, respectively. The dose versus area under the curve-relationship for 17-AAG was linear (r(2) = .71) over the dose range 10 to 450 mg/m(2)/week, with peak plasma concentrations of 8,998 mug/L (standard deviation, 2,881) at the highest dose level. After the demonstration of pharmacodynamic changes in peripheral blood leukocytes, pre- and 24 hours post-treatment, tumor biopsies were performed and demonstrated target inhibition (c-RAF-1 inhibition in four of six patients, CDK4 depletion in eight of nine patients and HSP70 induction in eight of nine patients) at the dose levels 320 and 450 mg/m(2)/week. It was not possible to reproducibly demonstrate these changes in biopsies taken 5 days after treatment.It has been possible to demonstrate that 17-AAG exhibits a tolerable toxicity profile with therapeutic plasma concentrations and target inhibition for 24 hours after treatment and some indications of clinical activity at the dose level 450 mg/m(2)/week. We recommend this dose for phase II clinical trials.
Type 2 Diabetes, Muscle Strength, and Impaired Physical Function
Authors: Avan Aihie Sayer, Elaine M. Dennison, Holly E. Syddall, Helen J. Gilbody, David I.W. Phillips, Cyrus Cooper
Journal: Diabetes Care (2005)

There is growing recognition that the complications associated with type 2 diabetes may translate into functional impairment in older people (1). This may reflect a link between the metabolic and mechanical functions of muscle. However, the possibility that the link between glucose tolerance and physical function extends to people without diabetes has not been previously considered. The objective of this study was to determine whether there is a relationship among glucose tolerance, muscle strength, and physical function in men and women with and without type 2 diabetes.

A cross-sectional survey within a cohort study design was used. Information was obtained on self-reported diabetes status cross-checked with medication data, glucose, and insulin levels 2 h after an oral glucose tolerance test (for participants without a previous diagnosis of diabetes) (2), grip strength using a Jamar dynamometer (3), and physical function using the physical function component of the Medical Outcomes Study 36-item short form questionnaire. This is a measure of subjective health status widely validated in both men and women (4,5).

The population-based study sample consisted of 1,391 men and women aged between 60 and 70 years and living in the …
Diagnosis and surgical treatment of coronary artery fistula
Authors: J. P. Roos, H. Hartman, H. Van Der Schaar, A. G. Brom
Journal: Thorax (1970)

Phonocardiography is of great importance in distinguishing coronary artery fistula from other anomalies with a continuous murmur. The presence of this murmur at the apex must be regarded as an important characteristic of a coronary artery fistula, especially when the maximum diastolic murmur is found at the apex. Although coronary artery fistula may be symptomless for a long time, surgical treatment is desirable in most cases. Extracorporeal circulation should be used in all operations for coronary artery fistula to avoid ligation of the wrong artery or failure to close all fistula orifices.
A novel system for navigated endobronchial ultrasound (EBUS)
Authors: Hanne Sorger, Erlend Hofstad, Tore Amundsen, Thomas Lango, Hakon Olav Leira
Journal: European Respiratory Journal (2014)

Introduction 

Endobronchial ultrasound fine needle aspiration (EBUS-FNA) of mediastinal lymph nodes is an essential part of lung cancer staging. In limited disease with presumptive potential to cure, puncturing the wrong node may lead to erroneous clinical decisions. Navigation and multimodal imaging may improve EBUS-FNA efficiency.

Aims and objectives 

We wanted to demonstrate a prototype EBUS-FNA navigation system in a lung phantom, preparing for approved human studies.

Methods 

Using an EBUS bronchoscope with an integrated sensor for position tracking in an electromagnetic (EM) field we performed navigated EBUS in a lung phantom. Preoperative computer tomography (CT) and real-time ultrasound images were integrated into a navigation platform for EM bronchoscopy (CustusX). The coordinates of target lesions in CT and ultrasound volumes were determined in the navigation system, and position deviation was calculated.

Results 

All targets were visualized. Fused CT and ultrasound image positions displayed correctly in the navigation system. Navigation made sonographic target localization easy, and FNA was feasible.

![Figure][1] 



Mean error between ultrasound and CT positions for 11 targets (37 measurements) was 2.8±1.0 mm, maximum error 5.9 mm.

Conclusions 

We successfully demonstrated the feasibility of a new system for navigated ultrasound bronchoscopy, which may increase diagnostic accuracy and provide new opportunities for procedure documentation in EBUS-FNA.

 [1]: pending:yes
Corticotropin-releasing hormone (CRH) regulates macromolecular permeability via mast cells in normal human colonic biopsies in vitro
Authors: C Wallon, P-C Yang, A V Keita, A-C Ericson, D M McKay, P M Sherman, M H Perdue, J D Soderholm
Journal: Gut (2007)

<h3>Objective:</h3> Persistent stress and life events affect the course of ulcerative colitis and irritable bowel syndrome by largely unknown mechanisms. Corticotropin-releasing hormone (CRH) has been implicated as an important mediator of stress-induced abnormalities in intestinal mucosal function in animal models, but to date no studies in human colon have been reported. The aim was to examine the effects of CRH on mucosal barrier function in the human colon and to elucidate the mechanisms involved in CRH-induced hyper-permeability. <h3>Design:</h3> Biopsies from 39 volunteers were assessed for macromolecular permeability (horseradish peroxidise (HRP), <sup>51</sup>Cr-EDTA), and electrophysiology after CRH challenge in Ussing chambers. The biopsies were examined by electron and confocal microscopy for HRP and CRH receptor localisation, respectively. Moreover, CRH receptor mRNA and protein expression were examined in the human mast cell line, HMC-1. <h3>Results:</h3> Mucosal permeability to HRP was increased by CRH (2.8±0.5 pmol/cm<sup>2</sup>/h) compared to vehicle exposure (1.5±0.4 pmol/cm<sup>2</sup>/h), p = 0.032, whereas permeability to <sup>51</sup>Cr-EDTA and transmucosal electrical resistance were unchanged. The increased permeability to HRP was abolished by α-helical CRH (9-41) (1.3±0.6 pmol/cm<sup>2</sup>/h) and the mast cell stabiliser, lodoxamide (1.6±0.6 pmol/cm<sup>2</sup>/h). Electron microscopy showed transcellular passage of HRP through colonocytes. CRH receptor subtypes R1 and R2 were detected in the HMC-1 cell line and in lamina propria mast cells in human colon. <h3>Conclusions:</h3> Our results suggest that CRH mediates transcellular uptake of HRP in human colonic mucosa via CRH receptor subtypes R1 and R2 on subepithelial mast cells. CRH-induced macromolecular uptake in human colon mucosa may have implications for stress-related intestinal disorders.
Effect of folate supplementation on mucosal cell proliferation in high risk patients for colon cancer
Authors: K Khosraviani, H P Weir, P Hamilton, J Moorehead, K Williamson
Journal: Gut (2002)

<b>Aims:</b> Intracellular folate deficiency has been implicated in colonic carcinogenesis in epidemiological studies and animal and human cancer models. Our aim was to determine the effect of folate supplementation on patients with recurrent adenomatous polyps using rectal mucosal cell proliferation as a biomarker. <b>Patients and methods:</b> Eleven patients with recurrent adenomatous polyps of the colon were randomised into a treatment group (n=6) receiving a dietary supplement of 2 mg folic acid per day for three months and a control group (n=5) receiving a placebo. Rectal biopsies where taken at 10 cm from the anal verge prior to supplementation and repeated at four, 12, and 18 weeks from the start of the supplementation. Each biopsy was immediately incubated in culture medium enriched with bromodeoxyuridine (BrdU). The S phase cells which incorporated BrdU into their DNA were identified following immunohistochemical staining. Twenty five orientated crypts were identified for each time point and the number and position of BrdU positive and BrdU negative cells were counted. BrdU labelling indices (LIs) were calculated for the entire crypt and for each of five equal compartments running consequently from the base to the luminal surface. <b>Results:</b> The LI of the treatment group (9.1 (6.7, 12.3)) and the control group (9.3 (7.8, 10.3)) were comparable at the start. Over the duration of the supplementation period, LI in the control group did not alter significantly (9.3 (7.8, 10.3) <i>v</i> 9.6 (8.9, 10.4)). However, LI of the folate treated group was lowered after 12 weeks of supplementation (9.1 (6.7, 12.3) <i>v</i> 7.4 (5.3, 9.6)). Analysis of the LI for compartments within the crypt showed that the most significant drop in number of proliferating cells was in the upper most regions of the crypt. <b>Conclusion:</b> These data indicate that (a) folate supplementation decreases colonic mucosal cell proliferation in a high risk group for colon cancer and (b) the most significant reduction takes place at the luminal aspect of the crypt.
Multiple Successful Desensitizations to Brentuximab Vedotin: A Case Report and Literature Review
Authors: Michael D. DeVita, Andrew M. Evens, Steven T. Rosen, Paul A. Greenberger, Adam M. Petrich
Journal: Journal of the National Comprehensive Cancer Network (2014)

Brentuximab vedotin is an antibody-drug conjugate FDA-approved for the treatment of systemic anaplastic large-cell lymphoma (ALCL) that has relapsed after multiagent chemotherapy. At least 2 cases of hypersensitivity reactions to brentuximab vedotin have been reported, without attempted desensitization. This report describes a morbidly obese 32-year-old woman with ALCL that relapsed after autologous stem cell transplantation, who was treated on a phase II clinical study with brentuximab vedotin. After 1 dose, she experienced near-complete remission, but therapy was stopped because of severe drug-related toxicity. She then received 5 cytotoxic treatments and radiation, and ultimately experienced disease progression. The patient was rechallenged with brentuximab vedotin approximately 28 months after initial exposure and tolerated the dose well, but experienced a significant allergic reaction with the next dose. High-dose steroid and antihistamine prophylaxis administered 50 minutes before the subsequent brentuximab vedotin infusion was unsuccessful in mitigating this reaction. Brentuximab vedotin was successfully infused according to a rapid desensitization protocol. With progressive dose titration and supportive care, the patient tolerated this therapy. She received 11 doses through a rapid desensitization protocol and experienced a durable disease remission.
What role for MRI in hamstring strains? An argument for a difference between recreational and professional athletes
Authors: John Orchard
Journal: British Journal of Sports Medicine (2014)

It is tempting to read the Moen et al 1 study and conclude that MRI is not very useful in assessing prognosis of hamstring strains. Previous studies have found a reasonable correlation between MRI severity and clinical outcome,2–4 but no previous study has compared such a multitude of clinical parameters with a similar number of MRI parameters head to head with a blinded methodology. That is the strength of Moen's study.

The clinical parameters proved to be at least as good as the MRI parameters and some were clearly superior. The best predictive MRI parameter found that injuries closer to the ischial tuberosity had a worse prognosis, but as a predictive variable it was almost identical to simply recording where tenderness started in relation to the ischial tuberosity on clinical assessment.1

With these MRI data, the authors are in a good position to conclude that MRI investigation is not justified for the average non-professional athlete suffering an average hamstring strain. The exception, though, is probably one of the types of hamstring injury excluded from this study—hamstring tendon rupture. If there is strong clinical suspicion of hamstring tendon rupture, for which surgery may …
Combined Delivery and Magnetic Resonance Imaging of Neural Cell Adhesion Molecule–Targeted Doxorubicin-Containing Liposomes in Experimentally Induced Kaposi's Sarcoma
Authors: Cristina Grange, Simonetta Geninatti-Crich, Giovanna Esposito, Diego Alberti, Lorenzo Tei, Benedetta Bussolati, Silvio Aime, Giovanni Camussi
Journal: Cancer Research (2010)

Specific targeting of tumors by combined delivery of drugs and of imaging agents represents an attractive strategy for treatment of cancer. The aim of the present study was to investigate whether neural cell adhesion molecule (NCAM)-targeted liposomes may enhance drug delivery and allow magnetic resonance imaging (MRI) in a severe combined immunodeficient mouse model of NCAM-positive Kaposi's sarcoma. NCAM-binding peptide-coated liposomes loaded with both doxorubicin and a lipophilic gadolinium (Gd) derivative were generated. NCAM-targeted liposomes induced an enhanced in vitro doxorubicin internalization within Kaposi's cells as detected by MRI with respect to untargeted polyethylene glycol liposomes. Internalization resulted in enhanced apoptosis. In vivo weekly administration of NCAM-targeted liposomes containing 5 mg/kg doxorubicin for 4 consecutive weeks induced a significant reduction of tumor mass and vascularization and enhanced cell necrosis and apoptosis with respect to untargeted liposomes. These effects were associated with an enhanced concentration of doxorubicin within the tumor and a reduced systemic toxicity of doxorubicin. By electron microscopy, NCAM-targeted liposomes were detected mainly within tumor cells whereas the untargeted liposomes were mainly accumulated in the extracellular space. Gd-labeled liposomes allowed the MRI visualization of drug delivery in the tumor region. The intensity of MRI signal was partially hampered by the "quenching" of the attainable relaxation enhancement on endosomal entrapment of the Gd-labeled liposomes. In conclusion, targeting NCAM may be a suitable strategy for specific drug delivery and imaging by liposomes in NCAM-expressing tumors. Moreover, treatment with NCAM-targeted liposomes showed enhanced therapeutic effect and reduced toxicity with respect to untargeted liposomes.
Dopamine D3 Receptors and Salt-Dependent Hypertension
Authors: GERD LUIPPOLD, CLAUDIA ZIMMERMANN, MATTHIAS MAI, DORIS KLOOR, DOROTHEA STARCK, GERHARD GROSS, BERND MÜHLBAUER
Journal: Journal of the American Society of Nephrology (2001)

Alterations in the dopaminergic system may contribute to the pathogenesis of hypertension. Dopamine D3 receptors have been shown to be involved in the regulation of sodium balance and hemodynamics in rodents. For determining the role of D3 receptors in salt-dependent hypertension, clearance experiments were performed in anesthetized salt-sensitive (DS) and salt-resistant (DR) Dahl rats that were fed a standard diet with either normal (0.2%) or high (4%) sodium content for 21 to 26 d, which induced hypertension in DS but not in DR rats. The D3 receptor agonist R(+)-7-hydroxydipropyl-aminotetralin (7-OH-DPAT) increased GFR by up to 35% and urinary sodium excretion by up to 4.4-fold in DR rats that were on both normal and high-sodium diet. 7-OH-DPAT-induced natriuresis also was observed in DS rats that were on normal diet but not in hypertensive DS rats that were on high-salt diet. No GFR response to 7-OH-DPAT was found in DS rats, irrespective of sodium diet. The diminished functional response to D3 receptor stimulation in DS rats was associated with a significantly lower [3H]-7-OH-DPAT binding to renal membrane protein when comparing DS with DR rats. Consequently, DR rats were treated with BSF 135170, a novel, highly selective D3 receptor antagonist, for 29 d. Whereas no change in systolic BP was observed during normal diet, high sodium intake significantly increased BP by almost 40 mmHg. In summary, both expression and function of the renal dopamine D3 receptor are impaired in salt-sensitive Dahl rats. Together with the induction of salt-dependent hypertension in genetically salt-resistant Dahl rats by D3 receptor blockade, the data strongly suggest that the deficiency in dopamine D3 receptors represents an important pathophysiological factor in the development of salt-dependent hypertension.
Novel venom gene discovery in the platypus
Authors: Camilla M Whittington, Anthony T Papenfuss, Devin P Locke, Elaine R Mardis, Richard K Wilson, Sahar Abubucker, Makedonka Mitreva, Emily SW Wong, Arthur L Hsu, Philip W Kuchel, Katherine Belov, Wesley C Warren
Journal: Genome biology (2010)

To date, few peptides in the complex mixture of platypus venom have been identified and sequenced, in part due to the limited amounts of platypus venom available to study. We have constructed and sequenced a cDNA library from an active platypus venom gland to identify the remaining components. We identified 83 novel putative platypus venom genes from 13 toxin families, which are homologous to known toxins from a wide range of vertebrates (fish, reptiles, insectivores) and invertebrates (spiders, sea anemones, starfish). A number of these are expressed in tissues other than the venom gland, and at least three of these families (those with homology to toxins from distant invertebrates) may play non-toxin roles. Thus, further functional testing is required to confirm venom activity. However, the presence of similar putative toxins in such widely divergent species provides further evidence for the hypothesis that there are certain protein families that are selected preferentially during evolution to become venom peptides. We have also used homology with known proteins to speculate on the contributions of each venom component to the symptoms of platypus envenomation. This study represents a step towards fully characterizing the first mammal venom transcriptome. We have found similarities between putative platypus toxins and those of a number of unrelated species, providing insight into the evolution of mammalian venom.
Insulin Analogs—Is There a Compelling Case to Use Them? No!
Authors: Mayer B. Davidson
Journal: Diabetes Care (2014)

The availability of insulin analogs has offered insulin replacement strategies that are proposed to more closely mimic normal human physiology. Specifically, there are a considerable number of reports demonstrating that prandial insulin analogs (lispro, aspart, glulisine) have pharmacokinetic and pharmacodynamic profiles closer to normal, with resulting faster onset and offset of insulin effect when compared with regular human insulin. In addition, basal insulin analogs (glargine, detemir) have been reported to offer longer duration of action, less variability, more predictability, less hypoglycemia (especially nocturnal), and a favorable effect on weight. However, an argument against use of analog insulins as compared with use of regular or NPH insulin is one that states that the effectiveness and risk of hypoglycemia are the only two valid clinical outcomes that should be used to compare the analog and human insulins. Thus, there remains a debate in some circles that analog insulins are no more effective than human insulins, yet at a much higher financial cost. To provide an in-depth understanding of both sides of the argument, we provide a discussion of this topic as part of this two-part point-counterpoint narrative. In the counterpoint narrative presented here, Dr. Davidson provides his argument and defends his opinion that outside of a few exceptions, analog insulins provide no clinical benefit compared with human insulins but cost much more. In the preceding point narrative, Dr. Grunberger provides a defense of analog insulins and their value in clinical management and suggests that when evaluating the “cost” of therapy, a much more global assessment is needed. —William T. Cefalu Editor in Chief, Diabetes Care
The Early Reactions of Non-Neuronal Cells to Brain Injury
Authors: D M D Landis
Journal: Annual Review of Neuroscience (1994)

The brain's default mode network consists of discrete, bilateral and symmetrical cortical areas, in the medial and lateral parietal, medial prefrontal, and medial and lateral temporal cortices of the human, nonhuman primate, cat, and rodent brains. Its ...Read More
Gene Expression Profiling of Bronchoalveolar Lavage Cells in Acute Lung Rejection
Authors: Vincent J. Gimino, Jeffrey D. Lande, Todd R. Berryman, Richard A. King, Marshall I. Hertz
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

Lung transplantation is effective for many diseases that are unresponsive to other therapy. However, long-term survival of recipients is limited by the development of bronchiolitis obliterans syndrome. Acute rejection is a major risk factor for bronchiolitis obliterans syndrome, but noninvasive biomarkers have not been identified. To address this deficiency, gene expression microarrays were performed using bronchoalveolar lavage cells of lung transplant recipients with acute rejection (n = 7) and with no rejection (n = 27). The cell and differential counts were similar. Signal values for genes between groups were compared using t tests. One hundred thirty-five genes were upregulated in the acute-rejection group, including genes involved in acute rejection, immune response genes with an unknown role in rejection, genes not known to have a role in rejection, and genes of unknown function. Two-dimensional hierarchical clustering grouped all acute rejection samples into one cluster and the majority of the no-rejection samples into a second cluster. The acute-rejection samples showed significant changes in gene expression for seven biological pathways. Bronchoalveolar lavage cells are a reliable RNA source for microarray analysis, which is powerful in identifying acute-rejection genes. The individual genes, patterns of gene expression, or biologic pathways identified may represent novel biomarkers for acute rejection.
Intermittent axillary vein obstruction in a competitive canoeist.
Authors: J R Livesey
Journal: British Journal of Sports Medicine (1990)

The case is reported of a competitive canoeist with intermittent axillary vein obstruction secondary to shoulder girdle muscle hypertrophy. The anatomy of the axilla, pathology of the axillary vein, and reported cases of sports injuries involving the axillary vein are discussed. This would appear to be the first report of such an occurrence in a canoeist.