tbuckley/cabot-search huggingface dataset:
Tissue Collection for Correlative Studies in Childhood Cancer Clinical Trials: Ethical Considerations and Special Imperatives
Authors: Barry D. Anderson, Peter C. Adamson, Susan L. Weiner, Mary S. McCabe, Malcolm A. Smith
Journal: Journal of Clinical Oncology (2004)

Federal regulations prescribe distinct protections for children participating in research studies. Procedures for collecting tissue specimens from children solely for research purposes must pose no more than a minor increase over minimum risk, thereby limiting the approvable correlative biologic studies to evaluate molecularly targeted agents in children with cancer. Ethical issues arise when approvable correlative studies are a mandatory component of an early-phase pediatric clinical trial of new anticancer agents. The National Cancer Institute Cancer Therapy Evaluation Program sponsored a workshop in 2002 to discuss tissue collection for correlative biologic studies in early-phase childhood cancer clinical studies of molecularly targeted agents. Workshop participants recommended the following: (1) tissue specimens for correlative studies should provide vital clinical and scientific results to qualify for early-phase pediatric study consideration; (2) parents should receive a realistic appraisal of the risks, requirements, and potential for benefit of phase I protocol participation; (3) investigators should clearly distinguish clinically necessary procedures from research procedures of no benefit to the child to improve correlative study informed consent; and (4) participation in correlative research studies included in clinical trials generally should be voluntary. The need to acquire important biologic data regarding new molecular agents will challenge the ingenuity of pediatric cancer researchers, necessitating the application of highly sensitive laboratory assay methods, new imaging procedures, and preclinical models of childhood cancer. Such innovative methods can allow necessary scientific information to be obtained while simultaneously respecting the protections appropriately afforded to children participating in research studies and minimizing the burden of research participation for children with cancer and their families.
Nanoparticles of 2-deoxy-d-glucose functionalized poly(ethylene glycol)-co-poly(trimethylene carbonate) for dual-targeted drug delivery in glioma treatment
Authors: Xinyi Jiang, Hongliang Xin, Qiuyue Ren, Jijin Gu, Lingjun Zhu, Fengyi Du, Chunlai Feng, Yike Xie, Xianyi Sha, Xiaoling Fang
Journal: Biomaterials (2013)
Effects of interferon treatment on the antiviral T-cell response in hepatitis C virus genotype 1b- and genotype 2c-infected patients
Authors: G Missale, E Cariani, V Lamonaca, A Ravaggi, A Rossini, R Bertoni, M Houghton, Y Matsuura, T Miyamura, F Fiaccadori, C Ferrari
Journal: Hepatology (1997)

The viral genotype may influence the response to interferon (IFN) treatment in chronic hepatitis C virus (HCV) infection. To characterize potential mechanisms responsible for this effect, we assessed whether IFN modulation of HCV-specific T-cell responses differs in patients infected by different genotypes. The T-cell response to HCV core protein was sequentially analyzed before and during IFN treatment in two groups of patients chronically infected with HCV genotype 1b (eight patients) or 2c (eight patients). Overlapping 20 mer peptides corresponding to the amino acid sequence of the prevalent viral population identified in the serum of each patient were used for the analysis of the T-cell proliferative response to avoid possible problems caused by amino acid differences between infecting virus and HCV proteins used in vitro . Recombinant HCV core antigen was used in parallel. The level of viremia was monitored by competitive polymerase chain reaction (PCR). The T-cell response to HCV peptides and recombinant core protein detected throughout the follow-up was significantly more vigorous in genotype 2c- than in genotype 1b-infected patients. This difference was the result of a greater enhancement of the T-cell response caused by IFN treatment in genotype 2c-compared with genotype 1b-infected patients. The different IFN modulatory effect on T cells from genotype 1b- and genotype 2c-infected patients illustrates an aspect of the virus-host interaction, which may contribute toward the explanation of why different genotypes differ in responsiveness to IFN treatment.
Anandamide induces necrosis in primary hepatic stellate cells
Authors: Sören V. Siegmund, Hiroshi Uchinami, Yosuke Osawa, David A. Brenner, Robert F. Schwabe
Journal: Hepatology (2005)

The endogenous cannabinoid anandamide (AEA) is a lipid mediator that blocks proliferation and induces apoptosis in many cell types. Although AEA levels are elevated in liver fibrosis, its role in fibrogenesis remains unclear. This study investigated effects of AEA in primary hepatic stellate cells (HSCs). Anandamide blocked HSC proliferation at concentrations of 1 to 10 μmol/L but did not affect HSC proliferation or activation at nanomolar concentrations. At higher concentrations (25–100 μmol/L), AEA rapidly and dose-dependently induced cell death in primary culture-activated and in vivo-activated HSCs, with over 70% cell death after 4 hours at 25 μmol/L. In contrast to treatment with Fas ligand or gliotoxin, AEA-mediated death was caspase independent and showed typical features of necrosis such as rapid adenosine triphosphate depletion and propidium iodide uptake. Anandamide-induced reactive oxygen species (ROS) formation, and an increase in intracellular Ca2+. Pretreatment with the antioxidant glutathione or Ca2+-chelation attenuated AEA-induced cell death. Although the putative endocannabinoid receptors CB1, CB2, and VR1 were expressed in HSCs, specific receptor blockade failed to block cell death. Depletion of membrane cholesterol by methyl-β-cyclodextrin inhibited AEA binding, blocked ROS formation and intracellular Ca2+-increase, and prevented cell death. In primary hepatocytes, AEA showed significantly lower binding and failed to induce cell death even after prolonged treatment. In conclusion, AEA efficiently induces necrosis in activated HSCs, an effect that depends on membrane cholesterol and a subsequent increase in intracellular Ca2+ and ROS. The anti-proliferative effects and the selective killing of HSCs, but not hepatocytes, indicate that AEA may be used as a potential anti-fibrogenic tool. Supplementary material for this article can be found on the HEPATOLOGY website (http://www.interscience.wiley.com/jpages/0270-9139/suppmat/index.html). (HEPATOLOGY 2005;41:1085–1095.)
QTc Interval Prolongation Is Independently Associated With Severe Hypoglycemic Attacks in Type 1 Diabetes From the EURODIAB IDDM Complications Study
Authors: Gabriella Gruden, Sara Giunti, Federica Barutta, Nish Chaturvedi, Daniel R. Witte, Marinella Tricarico, John H. Fuller, Paolo Cavallo Perin, Graziella Bruno
Journal: Diabetes Care (2011)

OBJECTIVE Our aim was to assess whether severe hypoglycemic attacks were cross-sectionally associated with abnormalities of the QTc interval in type 1 diabetic patients. RESEARCH DESIGN AND METHODS The study included 3,248 type 1 diabetic patients from the EURODIAB IDDM Complications Study. Severe hypoglycemia was defined as an attack serious enough to require the help of another person. A corrected QTc interval (QTc) &amp;gt;0.44 s was considered abnormally prolonged. RESULTS Nineteen percent of patients declared one to two attacks, and 13.2% of patients had three or more attacks. Prevalence of QTc prolongation was greater in patients who experienced three or more hypoglycemic attacks. Logistic regression analysis showed that the frequency of severe hypoglycemia was independently associated with QTc prolongation, even after adjustment for diabetes complications, including autonomic neuropathy (odds ratio 1.27, 95% CI 1.02–1.58). CONCLUSIONS We have provided evidence that severe hypoglycemic attacks are independently associated with a prolonged QTc interval in type 1 diabetic patients from the EURODIAB IDDM Complications Study.
Autoimmune thyroiditis and anti-thyroid antibodies in primary Sjogren's syndrome: a case-control study
Authors: R Tunc
Journal: Annals of the Rheumatic Diseases (2004)

To determine the frequency of antithyroid antibodies and the presence of autoimmune thyroiditis among patients with primary Sjögren's syndrome.A case-control study.53 consecutive patients with primary Sjögren's syndrome, 30 with rheumatoid arthritis, 12 with secondary Sjögren's syndrome associated with rheumatoid arthritis, 17 with autoimmune thyroiditis, and 53 apparently healthy controls were studied for anti-TG and anti-TPO antibodies as well as serum thyroid hormones and TSH levels.The overall frequencies of thyroid antibodies were 6/53 (11%) in primary Sjögren's syndrome, 2/30 (7%) in rheumatoid arthritis, 2/12 (17%) in secondary Sjögren's syndrome, 4/53 (8%) in healthy controls, and 16/17 (94%) in autoimmune thyroiditis. There was no difference in the frequency of the thyroid antibodies among the groups if patients with autoimmune thyroiditis were excluded (p = 0.415 for anti-TPO; p = 0.275 for anti-TG; p = 0.696 for either anti-TG and/or anti-TPO). Only two patients with primary Sjogren's syndrome had clinical hypothyroidism associated with autoimmune thyroiditis.In this Turkish population, no association between primary Sjögren's syndrome and autoimmune thyroiditis was found.
Antigen-driven long term-cultured T cells proliferate in vivo, distribute widely, mediate specific tumor therapy, and persist long-term as functional memory T cells.
Authors: M A Cheever, D B Thompson, J P Klarnet, P D Greenberg
Journal: The Journal of Experimental Medicine (1986)

Mice bearing disseminated syngeneic FBL-3 leukemia were treated with cyclophosphamide plus long term-cultured T cells immune to FBL-3. The cultured T cells for therapy had been induced to grow in vitro for 62 d by intermittent stimulation with irradiated FBL-3. At the time of therapy, such antigen-driven long term-cultured T cells were greatly expanded in number, proliferated in vitro in response to FBL-3, and were specifically cytotoxic. Following adoptive transfer, donor T cells persisting in the host were identified and counted using donor and host mice congenic for the T cell marker Thy-1. The results show that antigen-driven long term-cultured T cells proliferated rapidly in vivo, distributed widely in host lymphoid organs, and were effective in tumor therapy. Moreover, the already rapid in vivo growth rate of donor T cells could be augmented by administration of exogenous IL-2. When cured mice were examined 120 d after therapy, donor L3T4+ T cells and donor Lyt-2+ T cells could be found in large numbers in host ascites, spleen, and mesenteric and axillary lymph nodes. The persisting donor T cells proliferated in vitro, and became specifically cytotoxic in response to FBL-3, demonstrating that antigen-driven long term-cultured T cells can persist long term in vivo and provide immunologic memory.
Cholinergic and nitrergic interneurones in the myenteric plexus of the human colon
Authors: A J Porter, D A Wattchow, S J H Brookes, M Costa
Journal: Gut (2002)

<b>Background:</b> Myenteric interneurones are involved in the reflexes that control the motility of the human colon. <b>Aims:</b> The distribution of choline acetyltransferase (ChAT) and nitric oxide synthase (NOS) immunoreactivity in myenteric interneurones was investigated in this study. <b>Methods:</b> DiI (1,1`- didodecyl 3,3,3`,3`-indocarbocyanine perchlorate) was applied to the myenteric plexus of the human colon followed by organotypic culture. Retrogradely labelled neurones, with projections longer than motor neurones (&gt;10 mm), were studied to exclude motor neurone populations. ChAT and NOS immunoreactivity was then determined in the interneurones. <b>Results:</b> We found that 90% of interneurones projecting orally contained ChAT and none contained NOS. Ninety five per cent of descending interneurones were labelled with ChAT and/or NOS antisera; 46% contained NOS immunoreactivity alone, 20% contained ChAT immunoreactivity alone, and 29% contained both ChAT and NOS. Anally directed interneurones had significantly longer projections than orally projecting interneurones. <b>Conclusions:</b> Nearly all interneurones contain either NOS or ChAT immunoreactivity. Orally projecting interneurones are of two types: 90% contain ChAT alone and the remainder contain immunoreactivity for neither ChAT nor NOS. There are three main types of anally projecting interneurones: the largest, which contains NOS but not ChAT, and the two smaller classes which contain ChAT and NOS, and CHAT alone.
Trimethylaminuria: the use of choline as an aid to diagnosis
Authors: ROBIN MARKS, M.W. GREAVES, C. PROTTEY, P.J. HARTOP
Journal: British Journal of Dermatology (1977)

Trimethylamine metabolism can be studied by means of choline loading. The value and some limitations of the method are illustrated by results obtained in normal subjects, a patient with the Fish Odour syndrome and his kindred.
Overexpression of Platelet-Derived Growth Factor-BB Increases Tumor Pericyte Content via Stromal-Derived Factor-1α/CXCR4 Axis
Authors: Nan Song, Yujie Huang, Hubing Shi, Shaopeng Yuan, Yanping Ding, Xiaomin Song, Yan Fu, Yongzhang Luo
Journal: Cancer Research (2009)

Abstract Platelet-derived growth factor-BB (PDGF-BB) is a well-characterized growth factor displaying potent biological effects on angiogenesis. Recent studies reveal that overexpression of PDGF-BB within tumors results in increased pericyte coverage, suggesting that PDGF-BB signaling is also essential for the cancerous pericyte recruitment process. However, the molecular mechanism underlying this regulation remains obscure. In the current study, we show that tumor-derived PDGF-BB induces SDF-1α expression in endothelial cells (EC), resulting in the formation of SDF-1α chemotaxis gradient, which coincides with the PDGF-BB–induced pericyte recruitment during angiogenesis. PDGF-BB dramatically up-regulates SDF-1α secretion through the activation of PDGFRβ in tumor-associated ECs, whereas this up-regulation can be substantially inhibited by either blockade of the phosphatidylinositol 3-kinase/Akt/mTOR pathway with chemical inhibitors or the inactivation of HIF-1α through small interfering RNA interference. On the other hand, we reveal that SDF-1α can increase pericytes motility in vitro. Blockade of the SDF-1α/CXCR4 axis prevents the PDGF-BB–induced pericyte recruitment not only in three in vitro recruitment models but also in the PDGF-BB–overexpressing tumor xenograft models. These results highlight that the involvement of SDF-1α/CXCR4 axis is essential for the pericyte recruitment within the PDGF-BB–overexpressing tumors and raise the possibility that blockade of the SDF-1α/CXCR4 axis may provide a therapeutic synergy with antiangiogenic molecules that selectively target ECs. [Cancer Res 2009;69(15):6057–64]
Pharmacodynamic response in a phase 1 clinical study of the potent Hedgehog pathway antagonist GDC-0449 using a GLI1 qRT-PCR assay
Authors: Walter Darbonne, Edward Kadel, Bob Yauch, Bert Lum, Jim Marsters, Howard Mackey, Kelly Dupree, William Manning, Jorge DiMartino, Frederic de Sauvage, Paul Fielder, Jennifer Low
Journal: Clinical Cancer Research (2008)

B29   The Hedgehog (Hh) signaling pathway is an important regulator of organ patterning during embryonic development and is restricted to a few post-embryonic tissues, including hair follicles. However, the Hh pathway has been shown to be re-activated in a subset of tumors, including basal cell carcinomas (BCC) and medulloblastomas, as a result of somatic mutations in genes encoding the cell surface receptors Patched-1 ( PTCH1 ) and/or Smoothened ( SMO ). Hh pathway activation results in the activation of the GLI transcription factors, which induce the transcriptional upregulation of hedgehog target genes, including  GLI1  itself. We have developed a well-characterized qRT-PCR assay from hair pluck and skin punch biopsy (SPB) samples for normalized  GLI1  that is greater than 95 percent efficient, is quantitative over a 61-fold range of input RNA, and has an intra-donor variability of 1.24-fold, which easily allows for the measurement of a two-fold or higher change in normalized  GLI1  expression between samples (the minimum down-modulation of  GLI1  observed in pre-clinical efficacy models).  GDC-0449 is a potent antagonist of the Hh pathway tested in a phase 1 clinical study to evaluate its safety, tolerability, MTD, PK, and pharmacodynamics (PD) in patients with solid tumors. Hair pluck and SPB samples were collected from patients for PD analysis, assessing changes in expression levels of  GLI1  mRNA, prior to dosing and after eight and 21 days of continuous daily dosing in the dose escalation cohorts (150, 270 and 540 mg), a safety cohort and in a BCC cohort (both 150 mg). PD samples were collected at the day eight timepoint only for the 150 mg GDC-0449 DE cohort. Plasma GDC-0449 concentrations coincident with PD sample collection times were all above the targeted trough concentration of 5uM, based on pre-clinical murine efficacy models.  Whereas measured post-dose  GLI1  expression from hair pluck samples collected in the phase 1 study showed a variable PD response compared to pre-dose  GLI1  mRNA levels, a 2-14-fold decrease in  GLI1  expression was observed in SPB samples from 18 of 23 (78%) patients, across all dose cohorts. Similar intra-patient changes in  GLI1  expression were observed in SPB samples collected after 8 and 21 days of daily dosing. These PD data, utilizing a well-characterized qRT-PCR assay, provide evidence that GDC-0449 is modulating the hedgehog pathway in relevant tissue. These data supported the selection of a phase 2 dose.
Living-Donor Kidney Transplantation
Authors: Connie L. Davis, Francis L. Delmonico
Journal: Journal of the American Society of Nephrology (2005)

The first successful living-donor kidney transplant was performed 50 yr ago. Since then, in a relatively brief period of medical history, living kidney transplantation has become the preferred treatment for those with ESRD. Organ replacement from either a live or a deceased donor is preferable to dialysis therapy because transplantation provides a better quality of life and improved survival. The advantages of live versus deceased donor transplantation now are readily apparent as it affords earlier transplantation and the best long-term survival. Live kidney donation has also been fostered by the technical advance of laparoscopic nephrectomy and immunologic maneuvers that can overcome biologic obstacles such as HLA disparity and ABO or cross-match incompatibility. Congressional legislation has provided an important model to remove financial disincentives to being a live donor. Federal employees now are afforded paid leave and coverage for travel expenses. Candidates for renal transplantation are aware of these developments, and they have become less hesitant to ask family members, spouses, or friends to become live kidney donors. Living donation as practiced for the past 50 yr has been safe with minimal immediate and long-term risk for the donor. However, the future experience may not be the same as our society is becoming increasingly obese and developing associated health problems. In this environment, predicting medical futures is less precise than in the past. Even so, isolated abnormalities such as obesity and in some instances hypertension are no longer considered absolute contraindications to donation. These and other medical risks bring additional responsibility in such circumstances to track the unknown consequences of a live-donor nephrectomy.
Intensive Insulin Therapy in the Medical ICU
Authors: Greet Van den Berghe, Alexander Wilmer, Greet Hermans, Wouter Meersseman, Pieter J. Wouters, Ilse Milants, Eric Van Wijngaerden, Herman Bobbaers, Roger Bouillon
Journal: New England Journal of Medicine (2006)

Intensive insulin therapy reduces morbidity and mortality in patients in surgical intensive care units (ICUs), but its role in patients in medical ICUs is unknown.
Dermatitis herpetiformis: diagnosis, diet and demography.
Authors: D J Gawkrodger, J N Blackwell, H M Gilmour, E A Rifkind, R C Heading, R S Barnetson
Journal: Gut (1984)

We describe a long term study of 76 patients with dermatitis herpetiformis. Unlike patients with coeliac disease, where the peak incidence was during the first and fourth decades, no dermatitis herpetiformis patients presented in the first decade; also, there was a male preponderance in dermatitis herpetiformis which contrasts with the excess of females in coeliac disease. The apparent prevalence of dermatitis herpetiformis was 11 per 100 000 in our population; approximately one fifth of that of coeliac disease. Jejunal villous atrophy was present in 78% of our dermatitis herpetiformis patients, and a single jejunal biopsy was as effective at detecting this as the multiple biopsy technique. A majority of patients were able to stop, or radically reduce their dapsone or sulphapyridine treatment after the institution of a gluten free diet. Spontaneous remission of the skin lesion occurred in only two patients not receiving a gluten free diet. Gastric parietal or thyroid antibodies were detected in 38% of patients, and three cases of thyroid disease and two cases of pernicious anaemia were detected. Lymphoma developed in two patients, one being intestinal in origin. We conclude that a gluten free diet is of therapeutic benefit in dermatitis herpetiformis and that spontaneous remission is uncommon in those not on a diet. Despite patchiness of the enteropathy, a single jejunal biopsy is quite adequate to diagnose the presence of upper intestinal villous atrophy.
Consistent loss of the D5S89 locus mapping telomeric to the interleukin gene cluster and centromeric to EGR-1 in patients with 5q- chromosome
Authors: L Nagarajan, J Zavadil, D Claxton, X Lu, J Fairman, JA Warrington, JJ Wasmuth, AC Chinault, CE Sever, ML Slovak
Journal: Blood (1994)
Telomerase Activity in Benign and Malignant Breast Lesions: a Pilot Prospective Study on Fine-Needle Aspirates
Authors: Raffaella Villa, Nadia Zaffaroni, Marco Folini, Maria Grazia Daidone, Rosella Silvestrini, Gabriele Martelli, Giuseppe De Palo
Journal: JNCI Journal of the National Cancer Institute (1998)
Carbon Nanotube Thin Film Biosensors for Sensitive and Reproducible Whole Virus Detection
Authors: Himadri S. Mandal, Zhengding Su, Andrew Ward, Xiaowu (Shirley) Tang
Journal: Theranostics (2012)

Here, we report the label-free, sensitive, and real-time electrical detection of whole viruses using carbon nanotube thin film (CNT-TF) field effect devices. Selective detection of approximately 550 model viruses, M13-bacteriophage, is demonstrated using a simple two-terminal (no gate electrode) configuration. Chemical gating through specific antibody-virus binding on CNT surface is proposed to be the sensing mechanism. Compared to electrical impedance sensors with identical microelectrode dimensions (no CNT), the CNT-TF sensors exhibit sensitivity 5 orders higher. We believe the reported approach could lead to a reproducible and cost-effective solution for rapid viral identification.
Low-dose tamoxifen in the treatment of breast ductal intraepithelial neoplasia: results of a large observational study
Authors: A. Guerrieri-Gonzaga, E. Botteri, M. Lazzeroni, N. Rotmensz, A. Goldhirsch, C. Varricchio, D. Serrano, M. Cazzaniga, F. Bassi, A. Luini, V. Bagnardi, G. Viale, S. Mora, G. Bollani, E. Albertazzi, B. Bonanni, A. Decensi
Journal: Annals of Oncology (2009)