tbuckley/cabot-search huggingface dataset:
The blood-brain and blood-tumor barriers: A review of strategies for increasing drug delivery
Authors: Dennis R. Groothuis
Journal: Neuro-Oncology (2000)

Drug delivery to brain tumors has been a controversial subject. Some believe the blood-brain barrier is not important, while others believe it is the major obstacle in treatment and have devised innovative approaches to circumvent it. These approaches can be divided into two categories: those that attempt to increase drug delivery of intravascularly administered drugs by manipulating either the drugs or capillary permeability, and those that attempt to increase drug delivery by local administration. Several strategies have been developed to increase the fraction of intravascular drug reaching the tumor, including intra-arterial administration, barrier disruption, new ways of packaging drugs, and, most recently, inhibiting drug efflux from tumor. When given intravascularly, all drugs have a common drawback: the body acts as a sink, and, even in the best situations, only a small fraction of administered drug actually reaches the tumor. A consequence is that systemic toxicity is usually the dose-limiting factor. When given locally, such as into the cerebrospinal fluid or directly into the tumor, 100% of an administered dose is delivered to the target site. However, local delivery is associated with variable and unpredictable spatial distribution and variation in drug concentration. The major dose-limiting factor of most local delivery methods will be neurotoxicity. The relative advantages and disadvantages of the different methods of circumventing the blood-brain barrier are presented in this review, and special attention is given to convection-enhanced delivery, which has particular promise for the local delivery of large therapeutic agents such as monoclonal antibodies, antisense oligonucleotides, or viral vectors.
Association of<i>UBE2L3</i>polymorphisms with diffuse cutaneous systemic sclerosis in a Japanese population: Table 1
Authors: Narumi Hasebe, Aya Kawasaki, Ikue Ito, Manabu Kawamoto, Minoru Hasegawa, Manabu Fujimoto, Hiroshi Furukawa, Shigeto Tohma, Takayuki Sumida, Kazuhiko Takehara, Shinichi Sato, Yasushi Kawaguchi, Naoyuki Tsuchiya
Journal: Annals of the Rheumatic Diseases (2012)

Susceptibility genes to systemic sclerosis (SSc) are substantially shared by other autoimmune diseases.1 UBE2L3 , encoding a ubiquitin-conjugating enzyme, was associated with systemic lupus erythematosus (SLE)2 3 and rheumatoid arthritis (RA).4 In this study, we examined whether UBE2L3 is associated with SSc.

A case–control association study was performed on 391 Japanese patients and 1010 healthy controls recruited at Kanazawa University, the University of Tokyo, Institute of Rheumatology, Tokyo Women's Medical University and Sagamihara Hospital, National Hospital Organisation. All patients and …
Bone Marrow Microvascular and Neuropathic Alterations in Patients With Critical Limb Ischemia
Authors: Martin Teraa, Joost O. Fledderus, Ramil I. Rozbeh, Roos J. Leguit, Marianne C. Verhaar
Journal: Circulation Research (2013)

The impact of severe cardiovascular disease and critical limb ischemia (CLI) on the bone marrow (BM) is largely unknown.To investigate microvascular and neuropathic changes in BM of patients with CLI.BM biopsies were obtained from patients with CLI (n=33) included in the Rejuvenating Endothelial Progenitor Cells via Transcutaneous Intra-arterial Supplementation (JUVENTAS) trial (NCT00371371) and controls (n=12). We performed immunohistochemistry and histomorphometry of the BM to assess microvascular density and to evaluate pan-neuronal and sympathetic innervation, which is involved in progenitor cell mobilization. Microvascular density was reduced significantly in CLI compared with controls (P=0.01), as was sympathetic (P=0.047) and pan-neuronal innervation (P=0.006). No differences in microvascular density and sympathetic or pan-neuronal innervation were observed between patients with CLI with and without diabetes mellitus.CLI is associated with BM microvascular and neuropathic changes, both in patients with and without diabetes mellitus.
Current aspects of spontaneous pneumothorax
Authors: FM Schramel, PE Postmus, RG Vanderschueren
Journal: European Respiratory Journal (1997)

Although spontaneous pneumothoraces have been recognized and treated for almost 180 yrs, new aspects have emerged concerning pathogenesis, diagnostic procedures and treatment modalities. In spite of the fact that blebs and bullae are frequently found in patients with primary spontaneous pneumothorax, they seldom seem to be the actual cause of the pneumothorax. Inflammatory changes in the distal airways play an important role in the occurrence of the pneumothorax during transpulmonary pressure changes. The value of the routine use of additional expiratory chest radiographs in diagnosing pneumothoraces has been doubted in previous studies. In this review, the diagnostic yield from additional expiratory chest radiographs is analysed. The role of previous pneumothoraces at presentation and the presence of blebs and bullae are discussed in predicting future recurrences and choosing appropriate treatment for optimal cost-effectiveness. Recommendations are made regarding treatment of primary and secondary spontaneous pneumothorax.
Electrocardiographic Effects of Cortisone and Related Compounds on the Dog
Authors: ROSE LUBSCHEZ, MELVILLE G. MAGIDA, NORMA PlKE
Journal: Circulation Research (1954)

Infusion of cortisone and related compounds in the normal dog under standardized conditions resulted in increased voltage and peaking of the T wave of the electrocardiogram. These alterations were not associated with significant changes in the plasma electrolytes. Plasma inorganic phosphate decreased and urinary phosphate excretion increased. Cortisone appears to alter ventricular repolarization, but the mechanism of the effect is unknown.
Genetics and Pathophysiology of Human Obesity
Authors: David E. Cummings, Michael W. Schwartz
Journal: Annual Review of Medicine (2003)

Obesity has become a leading public health concern. Over 1 billion people are now overweight or obese, and the prevalence of these conditions is rising rapidly. Remarkable new insights into the mechanisms that control body weight are providing an increasingly detailed framework for a better understanding of obesity pathogenesis. Key peripheral signals, such as leptin, insulin, and ghrelin, have been linked to hypothalamic neuropeptide systems, and the anatomic and functional networks that integrate these systems have begun to be elucidated. This article highlights some of these recent findings and their implications for the future of obesity treatment. “Banish plump Jack, and banish all the world.” William Shakespeare, King Henry IV Part 1
Risk of Acute Complications of Diabetes Among People With Schizophrenia in Ontario, Canada
Authors: Taryn Becker, Janet Hux
Journal: Diabetes Care (2010)

Diabetes mellitus (DM) is a complex, chronic disease requiring active self-management and coordinated care. This study aimed to evaluate the relationship between schizophrenia and risk of preventable, acute DM complications.With the use of administrative data, a retrospective study assessed acute DM complications (emergency department [ED] visits or hospitalization for hypo- or hyperglycemia and hospital admissions for infections) among Ontario residents ages 18-50 with schizophrenia and newly diagnosed DM between 1995 and 2005, comparing people with and without pre-existing schizophrenia. Primary outcome was ED visit or hospitalization for hypo- or hyperglycemia. Secondary outcome was the first of either the primary outcome or hospitalization for infection.People with schizophrenia had a 74% greater risk of requiring a hospital visit for hypo- or hyperglycemia (hazard ratio [HR] = 1.74, 95% confidence interval 1.42-2.12) compared with those without schizophrenia. The risk was similar when the outcome included infection (HR = 1.62, 95% CI 1.39-1.89). Outcomes remained significant after adjustment for baseline characteristics.People with schizophrenia are at greater risk for developing an acute complication of DM. Understanding this relationship will direct future studies assessing barriers to care and implementation of individualized approaches to care for this population.
Early Stages in the Development of Collateral Circulation to the Lung in the Rat
Authors: EWALD R. WEIBEL
Journal: Circulation Research (1960)

The early stages of the development of collateral circulation to the lung following experimental ligation of the pulmonary artery were studied in adult rats. Five different types of vessels were found to be involved: 1. The bronchial arteries enlarge. Quantitative gross and microscopic studies indicated that this is first due to hemodynamic factors leading to dilatation of the vessels. After 5 days, true growth of the vessels occurs, associated with proliferative changes in the vessel wall, including mitoses in endothelial and smooth muscle cells. 2. Pre-existing nutrient arteries of the heart muscle coat of the pulmonary veins enlarge by the same processes. 3. New vessels form in the granulation tissue at the ligature. They can grow through the thick vessel wall into the lumen of the main pulmonary artery to form a considerable portal of entry for blood into this vessel. 4. Vessels form in pleural adhesions and can supply blood to the lung from intercostal arteries. 5. New bronchial arteries form in regions where no granulation tissue formation could stimulate their development. The primary anlage consists of a solid cell cord, soon surrounded by an envelope of spindle-shaped cells, representing the anlage of the media. The cell cord differentiates secondarily to an endothelial tube by forming a lumen. The enlarged systemic arteries are directly connected to the lung capillaries by means of multiple small branches, which are also newly formed arteries or arterioles. Arterial bronchopulmouary anastomoses are not as commonly found early in the development of collateral circulation in the rat, as late in this process in dogs. It may be concluded that the enlargement of collateral arteries to the lung following ligation of the pulmonary artery may be initiated by hemodynamic conditions, such as changed pressure gradients. After 5 days, however, other, probably humoral, factors must be responsible for further stimulation of the growth of pre-existing vessels and for the initiation and guidance of new vessel formation.
Trastuzumab duration effects within patient prognostic subgroups in the PHARE trial
Authors: A. Kramar, T. Bachelot, N. Madrange, J.-Y. Pierga, P. Kerbrat, M. Espié, P. Fumoleau, I. Pauporté, D. Khayat, G. Romieu, X. Pivot
Journal: Annals of Oncology (2014)
THE TREATMENT OF PNEUMONIA IN CHILDREN BY SUBCUTANEOUS OXYGEN
Authors: T. M. Montford
Journal: BMJ (1929)

viously instructed, except that the length of the bars must nIot reach higher than to a position half an inch below the head of the fibula.Fit the bars into slots in thle foot, as inidicated in Fig. 3.Socket.--Procure a piece of strong leather-length, from albove the bulb of the stump to below the head of tlie fibula; bI)eadth equal to the circumference of the stump.Rivet this leathier to the inner sides of the bars.Insert eyelets for lacing th1e socket.The end of the stump, which is not enielosed, rests on a soft pad on the top of the artificial foot.Line the socket down the front with felt, or similar substance.CHOPART'S AMPUTATION.This amputation only requires the patient's boot to be filled up witlh firm stuffing to replace the lost portion of the foot.
Establishment and Characterization of Novel Cell Lines from Sinonasal Undifferentiated Carcinoma
Authors: Yoko Takahashi, Michael E. Kupferman, Diana Bell, Tilahun Jiffar, June Goo Lee, Tong-Xin Xie, Ning-Wei Li, Mei Zhao, Mitchell J. Frederick, Alexander Gelbard, Jeffrey N. Myers, Ehab Y. Hanna
Journal: Clinical Cancer Research (2012)

Abstract Purpose: Sinonasal undifferentiated carcinoma (SNUC) is a rare and aggressive cancer. Despite the use of multimodality treatment, the overall prognosis remains poor. To better understand the biologic features of SNUC and help develop new therapies for the disease, we established SNUC cell lines and characterized their biologic behaviors. Experimental Design: Cell lines were established from a patient with a T4N0M0 SNUC of the right maxillary sinus who was treated with surgical resection at our center. Tumor colonies were harvested and were sequentially replated onto larger plates. Two populations were developed and labeled MDA8788-6 and MDA8788-7. These cell lines were characterized with molecular, biomarker, functional, and histologic analyses. Results: Short tandem repeat genotyping revealed that the cell line is isogenic to the parental tumor, and cytogenetic analysis identified 12 chromosomal translocations. The SNUC cell lines do not form colonies in soft agar but are tumorigenic and nonmetastatic in an orthotopic mouse model of sinonasal cancer. Western blot analysis revealed that both MDA8788 cell lines express epithelial markers but do not express mesenchymal markers or the endocrine marker synaptophysin. Conclusions: This is the first report of the establishment of stable human-derived SNUC cell lines. The lines were highly tumorigenic and maintain the histologic and molecular features of the original tumor. These cell lines should serve as useful tools for the future study of SNUC biology and the development and testing of novel therapies for this deadly disease. Clin Cancer Res; 18(22); 6178–87. ©2012 AACR.
STUDIES IN EXPERIMENTAL SYPHILIS
Authors: Alan M. Chesney, Jarold E. Kemp
Journal: The Journal of Experimental Medicine (1926)

Syphilitic rabbits inoculated intratesticularly and treated with arsphenamine before the 69th day of the disease, when reinoculated with the same strain of treponemata and in a manner identical with that of the first inoculation) are capable of responding to the infection in at least five different ways. In addition to exhibiting a local lesion at the site of reinoculation, accompanied by dissemination of the virus, they may show no local lesion at all but present evidence of dissemination of the virus together with the development of a positive Wassermann reaction. In some instances the virus may be recovered from the reinoculation site although no local lesion is produced there and no dissemination of the virus can be shown to take place. An occasional animal treated before the 69th day of the disease remains completely refractory to a second infection. When treatment is postponed to 6 months or more after the original inoculation, reinfection carried out by intratesticular injection is almost always impossible and such animals appear to be entirely refractory. However, if rabbits treated late are reinoculated with the homologous strain by depositing the virus upon a granulating wound on the back, successful reinfections can be accomplished in at least 50 per cent of the test animals. The resistance which develops in rabbits in the course of syphilitic infection is, then, not absolute but relative. It is pointed out that these results cast discredit upon the validity of the reinoculation method as a test of cure in syphilitic infection. It is also suggested upon the basis of these experiments, that the subsequent occurrence of a positive Wassermann reaction in patients with early syphilis in whom the Wassermann reaction has become negative under treatment may not always represent a relapse in the the disease but possibly in some instances a new infection without clinical signs.
Inflammatory cell populations and cytokine mRNA expression in the nasal mucosa in aspirin-sensitive rhinitis
Authors: E.m. Varga, M.r. Jacobson, K Masuyama, S. Rak, S.j. Till, Y. Darby, Q Hamid, V. Lund, G.k. Scadding, S.r. Durham
Journal: European Respiratory Journal (1999)

Aspirin-sensitive rhinitis is characterized by severe perennial nasal congestion and discharge. The study questioned whether this disease, like immunoglobulin E-mediated rhinitis, might be associated with local recruitment and activation of T-lymphocytes, mast cells and eosinophils with parallel increases in "T-helper2-type" cytokines. Nasal biopsies from 10 patients with aspirin-sensitive rhinitis and 12 healthy controls subjects were studied. Nasal mucosal sections were examined by immunohistochemistry in order to determine cell phenotypes and by in situ hybridization to detect cells expressing messenger ribonucleic acid (mRNA) for cytokines. In aspirin-sensitive rhinitis there were increases in total (CD3+) (p=0.05) and activated (CD25+) T-cells (p=0.007), total (major basic protein (MBP) positive) (p=0.004) and activated (monoclonal antibody which recognizes the cleaved form of eosinophil cationic protein (EG2) positive) eosinophils (p=0.003), tryptase+ mast cells (p=0.04) and CD68+ macrophages (p=0.002). Neutrophils and cells expressing human leukocyte antigen-DR were no different. Marked increases were observed in the numbers of interleukin (IL)-5 mRNA+ cells (p=0.004) in aspirin-sensitive patients, whereas lower numbers of IL-4 mRNA+ cells were observed, with a trend for a difference from controls (p=0.07). No differences were observed for either IL-2 or interferon-gamma. In conclusion, in aspirin-sensitive rhinitis there is intense inflammation of the nasal mucosa characterised by T-lymphocytes, eosinophils and mast cells. The predominance of macrophages and disproportionate increase in interleukin-5 compared to interleukin-4 messenger ribonucleic acid expression suggests that factors other than "allergic" mechanisms may be important in this disease.
Schedule-Dependent Effect of Phase-Specific Cytotoxic Agents on Production of Hemolytic Plaque-Forming Cells 2
Authors: Hsiu-san Lin
Journal: JNCI Journal of the National Cancer Institute (1976)

The proliferative phase of the primary response of mice to sheep red blood cells (SRBC) was used to study quantitatively the schedule-dependent effect of four phase-specific cytotoxic agents: 1-μ-d-arabinofuranosylcytosine (ARA-C), methotrexate (MTX), 5-fluorodeoxyuridine (5-FUDR), and 5-fluorouracil (5-FU). The multiple injections of ARA-C given 24–60 hours after SRBC injection caused a 100-fold greater inhibition in the production of direct hemolytic plaque-forming cells (PFC) on day 4 than the maximum inhibition obtained by a single injection. A similar, but lesser, enhancing effect was observed with 5-FUDR. Although a single injection of either MTX or 5-FU given 24 or 48 hours after the immunization alone was effective in suppressing PFC production, multiple injections of MTX at 6-hour intervals could cause the same degree of inhibition with a smaller total dose. In contrast, there was no difference for 5-FU, whether given as a single injection or in a divided dose. When only two doses of cytotoxic agents were used, 8- and 14-hour intervals with ARA-C and MTX, respectively, gave the maximum degree of inhibition.
Somatisation in functional dyspepsia: integrating gastric physiology with psychological state
Authors: F. Creed
Journal: Gut (2008)

Functional dyspepsia is considered to be the result of a complex interaction between biological, psychological and social factors. In this issue of the journal, Van Oudenhove and colleagues1 ( see page 1666 ) are the first to (1) present a study reporting these three aspects simultaneously in a large sample of patients attending a tertiary clinic and (2) identify whether the symptoms of functional dyspepsia are more closely associated with measures of gastric function or psychological state. The study suggests strongly it is the latter.

In a sound, cross-sectional study of 201 patients the authors correlated responses to gastric distension with measures of past and recent stress, anxiety, depression and a measure of somatisation with the gastrointestinal items removed. In multivariate analysis, including all these independent measures, somatisation was the only significant correlate of number and severity of dyspeptic symptoms. Somatisation and reported childhood abuse were the only significant correlates of weight loss. These relationships were similar in people who were, or were not, hypersensitive to gastric distension.

Has this study really advanced our knowledge of the aetiology of functional dyspepsia? There are several difficulties with the design of this study which limit its usefulness in this respect, even though it was executed well. These include the choice of endpoints, the cross-sectional design and the dualistic approach.

No specific theoretical basis is provided for choosing the outcomes …
Serial Electrocardiographic Changes in Treated Hypertensive Patients with Reference to Voltage Criteria, Mean QRS Vectors, and the QRS-T Angle
Authors: PHILIP L. DERN, RAY PRYOR, STROTHER H. WALKER, DONALD T. SEARLS
Journal: Circulation (1967)

Serial changes in voltage, QRS vectors, and QRS-T angles were studied in 44 patients who had shown improvement in their electrocardiograms during treatment for hypertension. Changes were observed in a number of electrocardiographic voltage criteria often used in the study of left ventricular hypertrophy. This is consistent with a change in the magnitude of the mean QRS vector and its reflection on a variety of ECG leads even if pretreatment records were normal. Improvement also occurred in the mean T vectors and the QRS-T angle. It is proposed that serial changes in the ECG might be of greater value than pretreatment abnormalities in diagnosing the disorder of cardiac structure or function that occurs in hypertension.
BET Bromodomain Inhibition of<i>MYC</i>-Amplified Medulloblastoma
Authors: Pratiti Bandopadhayay, Guillaume Bergthold, Brian Nguyen, Simone Schubert, Sharareh Gholamin, Yujie Tang, Sara Bolin, Steven E. Schumacher, Rhamy Zeid, Sabran Masoud, Furong Yu, Nujsaubnusi Vue, William J. Gibson, Brenton R. Paolella, Siddhartha S. Mitra, Samuel H. Cheshier, Jun Qi, Kun-Wei Liu, Robert Wechsler-Reya, William A. Weiss, Fredrik J. Swartling, Mark W. Kieran, James E. Bradner, Rameen Beroukhim, Yoon-Jae Cho
Journal: Clinical Cancer Research (2013)

Abstract Purpose: MYC-amplified medulloblastomas are highly lethal tumors. Bromodomain and extraterminal (BET) bromodomain inhibition has recently been shown to suppress MYC-associated transcriptional activity in other cancers. The compound JQ1 inhibits BET bromodomain-containing proteins, including BRD4. Here, we investigate BET bromodomain targeting for the treatment of MYC-amplified medulloblastoma. Experimental Design: We evaluated the effects of genetic and pharmacologic inhibition of BET bromodomains on proliferation, cell cycle, and apoptosis in established and newly generated patient- and genetically engineered mouse model (GEMM)-derived medulloblastoma cell lines and xenografts that harbored amplifications of MYC or MYCN. We also assessed the effect of JQ1 on MYC expression and global MYC-associated transcriptional activity. We assessed the in vivo efficacy of JQ1 in orthotopic xenografts established in immunocompromised mice. Results: Treatment of MYC-amplified medulloblastoma cells with JQ1 decreased cell viability associated with arrest at G1 and apoptosis. We observed downregulation of MYC expression and confirmed the inhibition of MYC-associated transcriptional targets. The exogenous expression of MYC from a retroviral promoter reduced the effect of JQ1 on cell viability, suggesting that attenuated levels of MYC contribute to the functional effects of JQ1. JQ1 significantly prolonged the survival of orthotopic xenograft models of MYC-amplified medulloblastoma (P &amp;lt; 0.001). Xenografts harvested from mice after five doses of JQ1 had reduced the expression of MYC mRNA and a reduced proliferative index. Conclusion: JQ1 suppresses MYC expression and MYC-associated transcriptional activity in medulloblastomas, resulting in an overall decrease in medulloblastoma cell viability. These preclinical findings highlight the promise of BET bromodomain inhibitors as novel agents for MYC-amplified medulloblastoma. Clin Cancer Res; 20(4); 912–25. ©2013 AACR.