tbuckley/cabot-search huggingface dataset:
INTESTINAL AND PULMONARY MUCOSAL T CELLS: Local Heroes Fight to Maintain the Status Quo
Authors: Leo Lefrançois, Lynn Puddington
Journal: Annual Review of Immunology (2006)

Mucosal immunity in the lung and intestine is controlled by complex multifaceted systems. While mucosal T cells are essential for protection against invading pathogens owing to their proximity to the outside world, powerful systems must also be in place to harness ongoing inflammatory processes. In each site, distinct anatomical structures play key roles in mounting and executing both protective and deleterious mucosal T cell responses. Although analogies can be drawn regarding the immune systems of these two organs, there are substantial dissimilarities necessitated by unique physiologic constraints. Here, we discuss how T cell activation and effector function are generated in the mucosae.
Liver target delivery of small interfering RNA to the HCV gene by lactosylated cationic liposome
Authors: Tsunamasa Watanabe, Takuya Umehara, Fumihiko Yasui, Shin-ichiro Nakagawa, Junichi Yano, Tadaaki Ohgi, Satoru Sonoke, Kenichi Satoh, Kazuaki Inoue, Makoto Yoshiba, Michinori Kohara
Journal: Journal of Hepatology (2007)
Vitamin D-3 intestinal absorption in vivo: influence of fatty acids, bile salts, and perfusate pH on absorption.
Authors: D Hollander, K S Muralidhara, A Zimmerman
Journal: Gut (1978)

Intestinal absorption of vitamin D-3 in physiological concentrations was studied in the live unanesthetised rat. In both the jejunum and the ileum a linear relationship was found between the absorption rate of the vitamin and its intraluminal concentration. Increasing the sodium taurocholate concentation in the perfusate above 5mM did not change ileal absorption rate but did decrease jejunal absorption rate. The vitamin's rate of absorption was raised by increases in either the hydrogen ion concentration in vivo is mediated by passive diffusion. The rate of absorption of ttion or the perfusate's flow rate. Addition of 2.5 mM fatty acids of varying chain length and degrees of saturation resulted in a decrease in the rate of vitamin D-3 absorption. These experiments indicate that vitamin D-3 absorption in vivo is mediated by passive diffusion. The rate of absorption of the vitamin is influenced by the composition of the perfusate and the thickness of the unstirred layer.
Marital Status and Survival in Patients With Cancer
Authors: Ayal A. Aizer, Ming-Hui Chen, Ellen P. McCarthy, Mallika L. Mendu, Sophia Koo, Tyler J. Wilhite, Powell L. Graham, Toni K. Choueiri, Karen E. Hoffman, Neil E. Martin, Jim C. Hu, Paul L. Nguyen
Journal: Journal of Clinical Oncology (2013)

To examine the impact of marital status on stage at diagnosis, use of definitive therapy, and cancer-specific mortality among each of the 10 leading causes of cancer-related death in the United States.We used the Surveillance, Epidemiology and End Results program to identify 1,260,898 patients diagnosed in 2004 through 2008 with lung, colorectal, breast, pancreatic, prostate, liver/intrahepatic bile duct, non-Hodgkin lymphoma, head/neck, ovarian, or esophageal cancer. We used multivariable logistic and Cox regression to analyze the 734,889 patients who had clinical and follow-up information available.Married patients were less likely to present with metastatic disease (adjusted odds ratio [OR], 0.83; 95% CI, 0.82 to 0.84; P < .001), more likely to receive definitive therapy (adjusted OR, 1.53; 95% CI, 1.51 to 1.56; P < .001), and less likely to die as a result of their cancer after adjusting for demographics, stage, and treatment (adjusted hazard ratio, 0.80; 95% CI, 0.79 to 0.81; P < .001) than unmarried patients. These associations remained significant when each individual cancer was analyzed (P < .05 for all end points for each malignancy). The benefit associated with marriage was greater in males than females for all outcome measures analyzed (P < .001 in all cases). For prostate, breast, colorectal, esophageal, and head/neck cancers, the survival benefit associated with marriage was larger than the published survival benefit of chemotherapy.Even after adjusting for known confounders, unmarried patients are at significantly higher risk of presentation with metastatic cancer, undertreatment, and death resulting from their cancer. This study highlights the potentially significant impact that social support can have on cancer detection, treatment, and survival.
Management of Chemotherapy-Induced Neutropenia: Measuring Quality, Cost, and Value
Authors: Michaela A. Dinan, Bradford R. Hirsch, Gary H. Lyman
Journal: Journal of the National Comprehensive Cancer Network (2015)

Treatment-associated neutropenia continues to represent the most common dose-limiting toxicity of cancer chemotherapy. It often leads to fever and infection, prompting hospitalization and occasionally resulting in serious morbidity, and even mortality, despite modern broad-spectrum antibiotic treatment and supportive care. Neutropenia and its complications may also lead to chemotherapy dose reductions, treatment delays, or early treatment termination, compromising disease control and the potential for cure. NCCN Clinical Practice Guidelines in Oncology recommend administration of primary prophylaxis with a myeloid growth factor in patients receiving regimens associated with a high risk for febrile neutropenia, and consideration of prophylaxis in patients receiving lower-risk regimens who have other risk factors that might place them at higher risk for febrile neutropenia. Although these agents have been shown to be effective and safe in numerous randomized controlled trials, they are expensive and contribute significantly to increasing health care costs. Regulatory agencies and guideline organizations do not currently address the issue of cost. However, with the relentless increase in health care use and current efforts to reform health care, it has become increasingly important to assess both the cost and the net benefit of interventions related to an episode of care in order to compare the overall value of therapeutic options. This article defines and discusses the intersection of quality, costs, and value in the context of prophylactic myeloid growth factor use in patients with cancer receiving myelosuppressive chemotherapy.
Bone marrow mesenchymal stem cells and TGF-β signaling in bone remodeling
Authors: Janet L. Crane, Xu Cao
Journal: Journal of Clinical Investigation (2014)

During bone resorption, abundant factors previously buried in the bone matrix are released into the bone marrow microenvironment, which results in recruitment and differentiation of bone marrow mesenchymal stem cells (MSCs) for subsequent bone formation, temporally and spatially coupling bone remodeling. Parathyroid hormone (PTH) orchestrates the signaling of many pathways that direct MSC fate. The spatiotemporal release and activation of matrix TGF-β during osteoclast bone resorption recruits MSCs to bone-resorptive sites. Dysregulation of TGF-β alters MSC fate, uncoupling bone remodeling and causing skeletal disorders. Modulation of TGF-β or PTH signaling may reestablish coupled bone remodeling and be a potential therapy.
Blockade of p38α MAPK Ameliorates Acute Inflammatory Renal Injury in Rat Anti-GBM Glomerulonephritis
Authors: Cosimo Stambe, Robert C. Atkins, Greg H. Tesch, Ann M. Kapoun, Prudence A. Hill, George F. Schreiner, David J. Nikolic-Paterson
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. The p38 mitogen-activated protein kinase (MAPK) pathway is a pro-inflammatory signal transduction pathway. The aim of this study was to examine the role of this pathway in acute renal inflammation. Immunostaining localized components of the p38 MAPK pathway (p38α, p-p38, p-ATF-2) in normal glomeruli, to podocytes, and occasional endothelial cells. This study identified an eightfold increase in glomerular activation of p38 MAPK (phosphorylated p38, p-p38) within 3 h of the induction of rat anti–glomerular basement membrane (GBM) glomerulonephritis and localized p-p38 and p-ATF-2 to infiltrating neutrophils, with increased staining of podocytes and endothelial cells. The relevance of these findings to human acute inflammatory renal disease was determined by examination of biopsy specimens. In patients with post-infectious glomerulonephritis, there was an increased number of positive p-p38 glomerular cells, including p-p38 staining of infiltrating neutrophils, compared with normal human kidney. In rats, administration of a specific p38 MAPK inhibitor, NPC 31145, before induction of anti-GBM disease prevented a loss of renal function and substantially reduced proteinuria. The reduction in renal injury was attributed to a 55% reduction in glomerular neutrophil infiltration and a 68% reduction in platelet accumulation. This was associated with an abrogation of glomerular P-selectin immunostaining and inhibition of glomerular P-selectin gene expression. In summary, this study has localized the components of the p38 MAPK pathway to cells in normal and diseased rat and human kidney and identified a number of important mechanisms by which signaling through the p38 MAPK pathway induces inflammatory renal disease. Blockade of the p38 pathway may be a novel therapeutic strategy for the treatment of acute renal inflammation. E-mail: cosimo.stambe@med.monash.edu.au
Camptothecin Analogs (Irinotecan or Topotecan) plus High-Dose Cyclophosphamide as Preparative Regimens for Antibody-Based Immunotherapy in Resistant Neuroblastoma
Authors: Brian H. Kushner, Kim Kramer, Shakeel Modak, Nai-Kong V. Cheung
Journal: Clinical Cancer Research (2004)

Abstract Purpose: We used high-dose cyclophosphamide plus topotecan/vincristine (CTV) or irinotecan (C/I) in patients with resistant neuroblastoma. The aim was to use a regimen with little risk to major organs to (a) achieve or consolidate remission in heavily treated patients and to (b) induce an immunological state conducive to passive immunotherapy with the murine 3F8 antibody. Experimental Design: CTV and C/I included cyclophosphamide 140 mg/kg (∼4200 mg/m2). With CTV, topotecan 2 mg/m2 was infused i.v. (30 min) on days 1–4 (total, 8 mg/m2), and vincristine 0.067 mg/kg was injected on day 1. With C/I, irinotecan, 50 mg/m2 was infused i.v. (1 h) on days 1–5 (total, 250 mg/m2). Mesna and granulocyte colony-stimulating factor were used. Results: Twenty-nine patients received 38 courses of CTV, and 26 patients received 38 courses of C/I. All patients had previously received topotecan, a hemopoietic stem-cell transplant, and/or high-dose cyclophosphamide. CTV and C/I caused myelosuppression of comparably prolonged duration as follows: absolute neutrophil counts &amp;lt;500/μl lasted 5–12 days in patients who had not previously received transplant and 7–21 days in patients who were post-transplant. Other significant toxicities included typhlitis (two CTV-treated patients, one C/I-treated patient) and hemorrhagic cystitis (one C/I-treated patient). Major responses were seen in 4 (15%) of 26 CTV and 4 (17%) of 24 C/I-treated patients with assessable disease. Bone marrow disease resolved in 5 (28%) of 18 CTV-treated patients and in 4 (27%) of 15 C/I-treated patients. 3F8 after CTV or C/I was not blocked by neutralizing antibodies, consistent with the desired immunosuppressive effect of high-dose cyclophosphamide. Conclusions: CTV and C/I require transfusional and antibiotic support but otherwise entail tolerable morbidity. They have modest antineuroblastoma activity in heavily treated patients and are good preparative regimens for passive immunotherapy with monoclonal antibodies.
Morphology of Interleukin-2-Stimulated Human Peripheral Blood Mononuclear Effector Cells Killing Glioma-Derived Tumor Cells In Vitro
Authors: G. R. Hook, M. A. Greenwood, D. Barba, B. Ikejiri, S. N. Chen, E. H. Oldfield, R. J. Weber, L. M. Muul
Journal: JNCI Journal of the National Cancer Institute (1988)

This is the first morphological study of interleukin-2-stimulated human peripheral blood mononuclear(PBM) cells resulting in lympokine-activated killer(LAK) cell activity against human glioma-derived tumorcells in vitro, in which high-resolution differential interference video light microscopy, scanning electron microscopy, and transmission electron microscopy were used. A subset of cells within the LAK cell population are the effector cells and have an asymmetric cellulararchitecture characteristic of cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. Upon binding to target cells, the LAK effector cell nucleus is positioned away from the target cell, whereas the granules, Golgi apparatus, and microtubules orient toward the target cell. These LAK-glioma cell conjugates form very tight plasma membrane bonds with numerous interdigitations, and vesicles were found in the small extracellular spaces between the cells. This morphology was not observed in unstimulated PBM-glioma cell co-cultures. Glioma-derived cells react to LAK effector cells by blebbing, becoming round, and rapidly detaching from the substracte. The injured glioma-derived cells had a highly condensed cytoplasm and chromatin, lobular nucleus, and severe plasma membrane blebs, which are consistent with an apoptotic rather than an osmotic lysis mechanism of cell death. This study provides morphological evidence that supports a common cytotoxic mechanism for CTLs, NK cells, and LAK effector cells. The cytotoxic mechanism is based on the local exocytosis of vesicles by the effector cell into the small extracellular space between the effector-target cell conjugate. Granules found in CTLs, NK cells, and LAK cells contain a pore-forming protein that inserts holes in the target cell's plasma membrane through which a lethal substance(s) not yet identified is thought to enter the cell. [J Natl Cancer Inst 1988;80:171–177]
Phase 2 study of T138067-sodium in patients with malignant glioma: Trial of the National Cancer Institute of Canada Clinical Trials Group
Authors: Sarah Kirby, Stan Z. Gertler, Warren Mason, Christopher Watling, Peter Forsyth, Jacinta Aniagolu, Robert Stagg, Matthew Wright, Jean Powers, Elizabeth A. Eisenhauer
Journal: Neuro-Oncology (2005)

We studied the activity of T138067-sodium in patients with malignant gliomas. T138067-sodium is a unique new chemotherapy agent that inhibits microtubule formation by binding irreversibly and specifically to beta(1), beta(2)and beta(4) isotypes of 3-tubulin, causing cell arrest at G(2)/M and inducing apoptosis. Patients with recurrent anaplastic astrocytoma or glioblastoma multiforme were treated intravenously with 330 mg/m(2) of T138067-sodium weekly. Treatment was continued until the patient experienced either unacceptable toxicity or progressive disease. Patients had to have histologically proven glioma, have bidimensionally measurable disease at least 1 cm x 1 cm, and have received no more than one prior adjuvant chemotherapy. No chemotherapy or radiotherapy for recurrent disease was permitted. Nineteen patients entered the trial. One patient was found to be ineligible. There were two patients with anaplastic astrocytoma and 16 with glioblastoma multiforme. Only two patients had received prior adjuvant chemotherapy. The first seven patients had full pharmacokinetic sampling. No dose-limiting toxicity was seen, and pharmacokinetic results were consistent with those from nonglioma patients. The most common drug-related effects were fatigue (33%), nausea (28%), neutropenia (28%), and anorexia (17%). No patients stopped the study because of toxicity. No responses were seen in the 15 eligible patients who completed at least one cycle. Three patients had stable disease with a median duration of 2.6 months. Our results suggest that given in this dose and schedule T138067-sodium does not have activity in this population of anaplastic astrocytoma and glioblastoma multiforme.
Competitive Binding of Bilirubin and Drugs to Human Serum Albumin Studied by Enzymatic Oxidation
Authors: R. Brodersen
Journal: Journal of Clinical Investigation (1974)

The mechanism of drug-induced displacement of bilirubin from the blood into tissues was studied. A model of simple, competitive binding of bilirubin and drug to one site on serum albumin was established. Variations of the free bilirubin concentration after addition of drugs were studied in vitro by measuring velocities of oxidation with hydrogen peroxide and horseradish peroxidase. In all cases, the results were in agreement with the model. The competitive effects of 20 drugs were measured and expressed quantitatively as binding constants to the bilirubin site on human serum albumin. Several drugs caused changes of the bilirubin-albumin light absorption spectrum, indicating simultaneous binding of both ligands, without an effect on the free bilirubin concentration. Noncompetitive site-to-site effects on bilirubin binding could not be demonstrated. An equation is proposed for calculation of the maximal displacing effect of a drug from knowledge of its plasma concentration, the above-determined binding constant, and the degree of protein binding of the drug. Comparison of these results with previous observations of bilirubin displacement in newborn humans and in experimental animals indicates a general agreement with a simple competitive mechanism of binding of bilirubin and drug to one site on the albumin molecule. Binding of drugs to other, noncompetitive sites is common.
The Right Care by the Right Clinician
Authors: Mitchell H. Katz
Journal: JAMA Internal Medicine (2014)

Increased demand for primary care has resulted in the increased use of advanced practice clinicians (nurse practitioners and physician assistants) to supplement the physician workforce. It is natural to ask how the care delivered by these advanced practice clinicians differs from the care provided by physicians. In this article, Hughes et al1 find that advanced practice clinicians order modestly more radiologic tests (0.3%) than primary care physicians among Medicare patients. However, this overall percentage difference obscures a more important finding. When the investigators focused on a common problem in primary care, lower back pain, they found that advanced practice clinicians ordered no more imaging tests than physicians, and when the investigators limited the sample to patients with acute respiratory illness, advance practice clinicians actually ordered fewer imaging tests. Advancedpracticeclinicianshavesubstantially feweryears of training than physicians, and it is not surprising that when confrontingunfamiliar conditions theymayordermore tests. At the same time, using advanced practice clinicians to care for patients with conditions for which they are familiar may produce the same or superior care, as theymay bemore willing to follow standardized protocols than physicians. In this regard, advanced practice clinicians may be better suited for practices that specialize in care of patients with a particular complex disease, such as patients with human immunodeficiencyvirus or hepatitis C virus, forwhich the issues aremore circumscribed than in general medicine settings where patientsmayhave awide andunpredictable range of symptoms and illnesses. It is all about putting the right clinician in the right position to provide the right care.
Cognitive and Adaptive Outcome in Extracerebellar Low-Grade Brain Tumors in Children: A Report From the Children's Oncology Group
Authors: M. Douglas Ris, Dean W. Beebe, F. Daniel Armstrong, John Fontanesi, Emi Holmes, Robert A. Sanford, Jeffrey H. Wisoff
Journal: Journal of Clinical Oncology (2008)

Purpose To determine whether pediatric patients treated with surgery only for low-grade tumors in the cerebral hemispheres, supratentorial midline, and exophytic brainstem evidence neurocognitive, academic, adaptive, or emotional/behavioral sequelae. Patients and Methods Ninety-three patients from a natural history study of low-grade astrocytomas were tested an average of 111 days after surgery. Rates of below average (≤ 25th percentile) scores in this sample were compared with test norms, and performances were compared across anatomic sites. Finally, the relationships of pre-, peri-, and postsurgical complications to outcome were investigated. Results For the entire sample, there was a significantly elevated rate of below average scores across intelligence quotient, achievement, and adaptive behavior, but not behavioral/emotional adjustment measures. Patients with hemispheric, midline, and brainstem tumors did not differ significantly. Patients with left hemisphere tumors generally performed worse than those with right hemisphere tumors. Finally, neurobehavioral outcome was unrelated to pre-, peri-, or postsurgery complications. Conclusion After surgery for low-grade brain tumors, a significant number of patients was found to function below average, by as much as 55% compared with 25% in the normative population. Moreover, these results suggest greater risk for patients with lesions situated in the left cerebral hemisphere. Routine neuropsychological follow-up of children after treatment for low-grade tumors is recommended.
Global surveillance of cancer survival 1995–2009: analysis of individual data for 25 676 887 patients from 279 population-based registries in 67 countries (CONCORD-2)
Authors: Claudia Allemani, Hannah K Weir, Helena Carreira, Rhea Harewood, Devon Spika, Xiao-Si Wang, Finian Bannon, Jane V Ahn, Christopher J Johnson, Audrey Bonaventure, Rafael Marcos-Gragera, Charles Stiller, Gulnar Azevedo e Silva, Wan-Qing Chen, Olufemi J Ogunbiyi, Bernard Rachet, Matthew J Soeberg, Hui You, Tomohiro Matsuda, Magdalena Bielska-Lasota, Hans Storm, Thomas C Tucker, Michel P Coleman
Journal: The Lancet (2014)

Worldwide data for cancer survival are scarce. We aimed to initiate worldwide surveillance of cancer survival by central analysis of population-based registry data, as a metric of the effectiveness of health systems, and to inform global policy on cancer control.
Mechanisms of fetal origins of health problems in adults need to be investigated
Authors: J. Seckl
Journal: BMJ (1998)

EDITOR–Stanner et al found that maternal starvation during pregnancy during the siege of Leningrad was not associated with alterations in birth variables or cardiovascular or metabolic pathophysiology in infants.1 In their commentary on the paper Rich-Edwards and Gillman call for animal studies to determine the underlying mechanisms for the hypothesis of fetal origins that was proposed by Barker et al. …