tbuckley/cabot-search huggingface dataset:
Isolation, characterization, and in vitro propagation of infantile hemangioma stem cells and an in vivo mouse model
Authors: Dan Xu, Teresa M O, Archil Shartava, Taylor C Fowles, Jianchang Yang, Louis M Fink, David C Ward, Martin C Mihm, Milton Waner, Yupo Ma
Journal: Journal of Hematology & Oncology (2011)

Abstract Background Infantile hemangiomas (IH) are the most common benign tumors of infancy. The typical clinical course consists of rapid growth during the first year of life, followed by natural and gradual involution over a multi-year time span through unknown cellular mechanisms. Some tumors respond to medical treatment with corticosteroids or beta-blockers, however, when this therapy fails or is incomplete, surgical extirpation may be necessary. Noninvasive therapies to debulk or eliminate these tumors would be an important advance. The development of an in vitro cell culture system and an animal model would allow new insights into the biological processes involved in the development and pathogenesis of IH. Results We observed that proliferative stage IH specimens contain significantly more SALL4+ and CD133+ cells than involuting tumors, suggesting a possible stem cell origin. A tumor sphere formation assay was adapted to culture IH cells in vitro . Cells in IH tumor spheres express GLUT1, indicative of an IH cell of origin, elevated levels of VEGF, and various stem/progenitor cell markers such as SALL4, KDR, Oct4, Nanog and CD133. These cells were able to self-renew and differentiate to endothelial lineages, both hallmarks of tumor stem cells. Treatment with Rapamycin, a potent mTOR/VEGF inhibitor, dramatically suppressed IH cell growth in vitro . Subcutaneous injection of cells from IH tumor spheres into immunodeficient NOD-SCID mice produced GLUT1 and CD31 positive tumors with the same cellular proliferation, differentiation and involution patterns as human hemangiomas. Conclusions The ability to propagate large numbers of IH stem cells in vitro and the generation of an in vivo mouse model provides novel avenues for testing IH therapeutic agents in the future.
Targets of enteric motor neurones: smooth muscle cells
Authors: R K Goyal
Journal: Gut (2000)

The cellular targets of enteric motor neurones are gastrointestinal smooth muscle cells, interstitial cells of Cajal (ICC), motor neurones themselves, neuroendocrine cells, mucosal secretory and absorptive cells, secretory glands, blood vessels, and immune cells.1 The effects of motor neurones on smooth muscles, particularly the circular muscle cells and ICCs, are precise in timing whereas their effects on other targets may be somewhat diffuse and long lasting. The enteric motor neurones themselves are targets for intrinsic sensory neurones, enteric interneurones, motor neurones, axons of extrinsic primary afferents, vagal-sacral preganglionic neurones, sympathetic postganglionic neurones, and local and endocrine mediators.

The major physiological neurotransmitters of motor neurones are acetylcholine (ACh), adenosine triphosphate (ATP), tachykinins (substance P and neurokinin (NK) A), vasoactive intestinal peptide (VIP)-pituitary activating cyclic AMP peptide, and nitric oxide (NO).1 Release of neurotransmitter such …
Multiple Patterns of Resistance of Human Leukemia Cell Sublines to Amsacrine Analogues
Authors: G. J. Finlay, B. C. Baguley, K. Snow, W. Judd
Journal: JNCI Journal of the National Cancer Institute (1990)

The antileukemia drug amsacrine and seven analogues were tested for in vitro activity against five multidrug-resistant human leukemia cell sublines (two derived from each of two Jurkat parent lines and one from the K562 line) and the corresponding parent lines (Jurkat, K562, and P388 leukemia). Resistant cell lines were derived by exposure to either amsacrine or doxorubicin. The resistance factor was calculated as the ratio of the mean IC 50 value for the resistant cell line to that for the parent line. IC 50 was defined as the concentration of drug inhibiting cell growth to 50% of that in control (drug-free) cultures. Patterns of cross-resistance were visualized by plotting the deviations of resistance factors from the mean resistance factor, on a logarithmic scale. Considerable variations in resistance factors were noted for each cell subline as the amsacrine substituents were altered. Four main patterns were evident: a transport-related multidrug-resis-tance pattern (three sublines), a pattern similar to that for a murine P388 leukemia subline resistant to amsacrine, and two patterns not observed previously. Since some of the sublines tested showed evidence of altered topoisomerase II activity, it appears that changes in the resistance pattern in these lines may reflect changes in the stability of the ternary complexes formed by the drug, the altered enzyme, and the DNA. The resistance factor was reduced from more than 100-fold to about 13-fold in three of the sublines tested and from eightfold to twofold in two others. This finding suggests that appropriate drug design may overcome several forms of multidrug resistance in human leukemia and other types of cancer. [J Natl Cancer Inst 82:662–667,1990]
Patient-Reported Symptoms and Quality of Life During Treatment With Tamoxifen or Raloxifene for Breast Cancer Prevention
Authors: Stephanie R Land, D Lawrence Wickerham, Joseph P Costantino, Marcie W Ritter, Victor G Vogel, Myoungkeun Lee, Eduardo R Pajon, James L Wade, Shaker Dakhil, James B Lockhart, Norman Wolmark, Patricia A Ganz
Journal: JAMA (2006)

Tamoxifen has been approved for breast cancer risk reduction in high-risk women, but how raloxifene compares with tamoxifen is unknown.To compare the differences in patient-reported outcomes, quality of life [QOL], and symptoms in Study of Tamoxifen and Raloxifene (STAR) participants by treatment assignment.STAR was a double-blind, randomized phase 3 prevention trial designed to evaluate the relative efficacy of raloxifene vs tamoxifen in reducing the incidence of invasive breast cancer in high-risk postmenopausal women. Between July 1, 1999, and November 4, 2004, 19,747 participants were enrolled at centers throughout North America, with a median potential follow-up time of 4.6 years (range, 1.2-6.5 years). Patient-reported symptoms were collected from all participants using a 36-item symptom checklist. Quality of life was measured with the Medical Outcomes Study Short-Form Health Survey (SF-36), the Center for Epidemiologic Studies-Depression (CES-D), and the Medical Outcomes Study Sexual Activity Questionnaire in a substudy of 1983 participants, median potential follow-up 5.4 years (range, 4.6-6.0 years). Questionnaires were administered before treatment, every 6 months for 60 months and at 72 months.Primary QOL end points were the SF-36 physical (PCS) and mental (MCS) component summaries.Among women in the QOL analysis, mean PCS, MCS, and CES-D scores worsened modestly over the study's 60 months, with no significant difference between the tamoxifen (n = 973) and raloxifene (n = 1010) groups (P>.2). Sexual function was slightly better for participants assigned to tamoxifen (age-adjusted repeated measure odds ratio, 1.22%; 95% CI, 1.01-1.46). Of the women in the symptom assessment analyses, the 9769 in the raloxifene group reported greater mean symptom severity over 60 months of assessments than the 9743 in the tamoxifen group for musculoskeletal problems (1.15 vs 1.10, P = .002), dyspareunia (0.78 vs 0.68, P<.001), and weight gain (0.82 vs 0.76, P<.001). Women in the tamoxifen group reported greater mean symptom severity for gynecological problems (0.29 vs 0.19, P<.001), vasomotor symptoms (0.96 vs 0.85, P<.001), leg cramps (1.10 vs 0.91, P<.001), and bladder control symptoms (0.88 vs 0.73, P<.001).No significant differences existed between the tamoxifen and raloxifene groups in patient-reported outcomes for physical health, mental health, and depression, although the tamoxifen group reported better sexual function. Although mean symptom severity was low among these postmenopausal women, those in the tamoxifen group reported more gynecological problems, vasomotor symptoms, leg cramps, and bladder control problems, whereas women in the raloxifene group reported more musculoskeletal problems, dyspareunia, and weight gain.clinicaltrials.gov Identifier: NCT00003906.
Gpx5 protects the family jewels
Authors: R. John Aitken
Journal: Journal of Clinical Investigation (2009)

Immature spermatozoa are vulnerable to oxidative stress after their release from the testes, due in part to an innate deficiency in antioxidant enzymes. The male reproductive tract compensates for this deficiency by secreting antioxidant enzymes such as glutathione peroxidase 5 (Gpx5) into the epididymal lumen. In this issue of the JCI, Chabory et al. examined the phenotype of Gpx5–/– mice and found that while deletion of this gene did not seem to affect fertility per se, it did influence the incidence of miscarriage and embryonic defects in mated wild-type female mice (see the related article beginning on page 2074). Importantly, the appearance of these problems was age dependent and associated with signs of oxidative stress in the spermatozoa. These results demonstrate the key importance of Gpx5 as an extracellular antioxidant designed to protect maturing mammalian spermatozoa from oxidative stress.
Correlation between level of heparinization and patency of the infarct-related coronary artery after treatment of acute myocardial infarction with alteplase (rt-PA)
Authors: Jef Arnout, Maarten Simoons, David de Bono, Hans J. Rapold, Désiré Collen, Marc Verstraete
Journal: Journal of the American College of Cardiology (1992)
A Novel One-Armed Anti-c-Met Antibody Inhibits Glioblastoma Growth <i>In vivo</i>
Authors: Tobias Martens, Nils-Ole Schmidt, Carmen Eckerich, Regina Fillbrandt, Mark Merchant, Ralph Schwall, Manfred Westphal, Katrin Lamszus
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Expression of the receptor tyrosine kinase c-Met and its ligand scatter factor/hepatocyte growth factor (SF/HGF) are strongly increased in glioblastomas, where they promote tumor proliferation, migration, invasion, and angiogenesis. We used a novel one-armed anti-c-Met antibody to inhibit glioblastoma growth in vivo. Experimental Design: U87 glioblastoma cells (c-Met and SF/HGF positive) or G55 glioblastoma cells (c-Met positive and SF/HGF negative) were used to generate intracranial orthotopic xenografts in nude mice. The one-armed 5D5 (OA-5D5) anti-c-Met antibody was infused intratumorally using osmotic minipumps. Following treatment, tumor volumes were measured and tumors were analyzed histologically for extracellular matrix (ECM) components and proteases relevant to tumor invasion. Microarray analyses were done to determine the effect of the antibody on invasion-related genes. Results: U87 tumor growth, strongly driven by SF/HGF, was inhibited &amp;gt;95% with OA-5D5 treatment. In contrast, G55 tumors, which are not SF/HGF driven, did not respond to OA-5D5, suggesting that the antibody can have efficacy in SF/HGF-activated tumors. In OA-5D5-treated U87 tumors, cell proliferation was reduced &amp;gt;75%, microvessel density was reduced &amp;gt;90%, and apoptosis was increased &amp;gt;60%. Furthermore, OA-5D5 treatment decreased tumor cell density &amp;gt;2-fold, with a consequent increase in ECM deposition and increased immunoreactivity for laminin, fibronectin, and tenascin. Microarray studies showed no incresae in these ECM factors, rather down-regulation of urokinase-type plasminogen activator and matrix metalloproteinase 16 in glioblastoma cells treated with OA-5D5. Conclusions: Local treatment with OA-5D5 can almost completely inhibit intracerebral glioblastoma growth when SF/HGF is driving tumor growth. The mechanisms of tumor inhibition include antiproliferative, antiangiogenic, and proapoptotic effects.
Attenuation of WNT signaling by DKK-1 and -2 regulates BMP2-induced osteoblast differentiation and expression of OPG, RANKL and M-CSF
Authors: Ken-ichi Fujita, Siegfried Janz
Journal: Molecular Cancer (2007)

Enhanced osteoblast-dependent osteoclastogenesis due to inhibition of Wnt/β-catenin signaling in bone morphogenic protein (BMP)-driven osteoprogenitors has been repeatedly implicated in the natural history of cancer-associated osteolytic lesions, but the mechanism of this bone loss is poorly understood. We examined the impact of secreted Wnt inhibitors from the Dickkopf (Dkk) family on pluripotent mesenchymal cells undergoing BMP2-induced osteoblastic differentiation. We found that Dkk1 and -2 restored the Wnt3a-dependent reduction of alkaline phosphatase (ALP), Osterix and p53, indicating that mitigated Wnt/β-catenin signaling promotes certain aspects of early osteoblastogenesis through the BMP-p53-Osterix-ALP axis. Dkk1 and -2 increased the expression of the osteoclast differentiation factors, receptor activator of NF-κB ligand (RANKL) and macrophage-colony stimulating factor (M-CSF), upon stimulation with Wnt3a/1,25-dihydroxyvitamine D3 and Wnt3a/BMP2, respectively. The decoy receptor of RANKL, osteoprotegerin (OPG), was down regulated under the latter conditions. These findings indicated that Dkk1 and -2 facilitate osteoclastogenesis by enhancing RANKL/RANK and M-CSF/c-Fms interactions. Dkk4 weakly shared activities of Dkk-1 and -2, whereas Dkk3 was ineffective. Our results suggest that inhibited Wnt/β-catenin signaling in BMP2-induced osteoprogenitors in vivo promotes, on balance, the heightened formation of osteoclasts. Focally increased Dkk1 production by tumor cells in the bone may thus lead to focal bone loss.
Anti-threonyl-tRNA synthetase, a second myositis-related autoantibody.
Authors: M B Mathews, M Reichlin, G R Hughes, R M Bernstein
Journal: The Journal of Experimental Medicine (1984)

An autoantibody known as PL-7 was found in the serum of four patients with myositis and one with a systemic lupus erythematosus-like syndrome. The PL-7 antigen is an 80,000 dalton polypeptide that coprecipitates with transfer RNA. In aminoacylation reactions, PL-7 IgG inhibited the charging of tRNA with threonine but had little or no effect on charging with other amino acids. Experimental antibodies raised against purified threonyl-tRNA synthetase recognized the same 80,000 dalton polypeptide, but tRNA was not coprecipitated. We conclude that PL-7 antibody is directed at threonyl-tRNA synthetase, and that different antigenic sites are recognized by the human and experimental autoantibodies. Our findings emphasize the link between myositis and autoimmunity to tRNA-related structures.
The effect of inhaling a dry powder of sodium chloride on the airways of asthmatic subjects
Authors: SD Anderson, J Spring, B Moore, LT Rodwell, N Spalding, I Gonda, K Chan, A Walsh, AR Clark
Journal: European Respiratory Journal (1997)

Wet aerosols of 4.5% sodium chloride (NaCl) are often used to assess the bronchial responsiveness associated with asthma. We questioned whether dry NaCl could be used as an alternative. Dry powder NaCl was inhaled from capsules containing either 5, 10, 20 or 40 mg to a cumulative dose of 635 mg. The powder was delivered via an Inhalator or Halermatic. The airway sensitivity to the dry and wet NaCl was compared in 24 patients with asthma aged 19-39 yrs. All subjects responded to both preparations and the geometric mean (95% confidence intervals) for the provocative dose of NaCl causing forced expiratory volume in one second (FEV1) to fall 20% from baseline (PD[20,NaCl]) for dry NaCl was 103 mg (68-157) versus 172 mg (102-292), p&lt;0.03 for the wet NaCl. The response to dry NaCl was reproducible and on repeat challenge the PD20 was 108 mg (75-153). The mean maximum fall in FEV1 was approximately 25% on each of the two test days. Spontaneous recovery occurred within 60 min after challenge with dry NaCl and within 5 min after bronchodilator. There were no serious side-effects requiring medical attention, however some patients coughed on inhalation of the 40 mg dose and three gagged. Arterial oxygen saturation remained within normal limits. We conclude that a suitably prepared dry powder of sodium chloride could potentially replace wet sodium chloride to assess bronchial responsiveness in patients with asthma, but further studies are required to establish the long-term stability of the dry powder preparation.
Life Versus Death
Authors: Arthur J. Moss
Journal: Circulation (2008)

R andomized clinical trials have clearly shown that the implanted cardiac defibrillator (ICD) saves lives [1][2][3] and that cardiac resynchronization therapy (CRT) and combined ICD and CRT devices reduce both heart failure and mortality. 4 -6 However, during long-term follow-up of patients with these implanted devices, only a minority will use appropriate ICD therapy for life-threatening ventricular tachyarrhythmic events.For example, in the Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II), only 35% of the patients in the ICD arm received appropriate ICD therapy (shock or antitachycardia pacing) during 3-year follow-up. 7he challenge facing the medical profession is how to better identify and select patients who will benefit from implanted ICD or combined ICD and CRT devices so as to achieve greater therapeutic efficacy without losing patients.During recent years, several noninvasive and invasive electrophysiological tests have been evaluated, including signal-averaged ECG, heart rate variability, heart rate turbulence, T-wave alternans, and programmed electrophysiological testing, but the risk-stratification results from these tests have not been very encouraging.Recently, Goldenberg et al demonstrated that the ICD:conventional therapy hazard ratio in patients with advanced renal disease (blood urea nitrogen Ͼ50 mg/ dL) and in good-risk patients without adverse clinical factors such as heart failure, atrial fibrillation, older age, and wide QRS complex, renal dysfunction was close to 1.0 in 35% of the ICD-treated patients, with no evident benefit from the ICD. 8The remaining 65% of the at-risk ICD-treated patients received considerably enhanced benefit from the ICD, with a 50% or greater reduction in mortality.These findings are encouraging, but we should be able to do better.
Comparative Analysis of Micrometastasis to the Bone Marrow and Lymph Nodes of Node-Negative Breast Cancer Patients Receiving No Adjuvant Therapy
Authors: Stephan Braun, B. Semeni Cevatli, Cyamak Assemi, Wolfgang Janni, Christina R.M. Kentenich, Christian Schindlbeck, Dorothea Rjosk, Florian Hepp
Journal: Journal of Clinical Oncology (2001)

PURPOSE: In node-negative patients, of whom up to 30% will recur within 5 years after diagnosis, markers are still needed that identify patients at high enough risk to warrant further adjuvant treatment. In the present study we analyzed whether a correlation exists between microscopic tumor cell spread to bone marrow and to lymph nodes and attempted to determine which route is clinically more important. PATIENTS AND METHODS: According to a prospective design, bone marrow aspirates and axillary lymph nodes of level I (n = 1,590) from 150 node-negative patients with stage I or II breast cancer were analyzed immunocytochemically with monoclonal anticytokeratin (CK) antibodies. We investigated associations with prognostic factors and the effect of micrometastasis on patients’ prognosis. RESULTS: CK-positive cells in bone marrow aspirates were present in 44 (29%) of 150 breast cancer patients, whereas only 13 patients (9%) had such positive findings in lymph nodes; simultaneous microdissemination to bone marrow and lymph nodes was seen in merely two patients. No correlation of bone marrow micrometastases with other risk factors was assessed. Reduced 4-year distant disease-free and overall survival were each associated with a positive bone marrow finding (P = .032 and P = .014, respectively) but not with lymph node micrometastasis. Multivariate analysis revealed an independent prognostic effect of bone marrow micrometastasis on survival, with a hazards ratio of 6.1 (95% confidence interval, 1.2 to 31.3) for cancer-related death (P = .031) in our series. CONCLUSION: Immunocytochemical detection of micrometastatic cells in bone marrow but not in lymph nodes is an independent prognostic risk factor in node-negative breast cancer that may have implications for surgery and stratification into adjuvant therapy trials.
Absence of Adverse Effects of Severe Hypoglycemia on Cognitive Function in School-Aged Children With Diabetes Over 18 Months
Authors: Tim Wysocki, Michael A. Harris, Nelly Mauras, Larry Fox, Alexandra Taylor, S. Craig Jackson, Neil H. White
Journal: Diabetes Care (2003)

OBJECTIVE—Some children with type 1 diabetes may be at risk of cognitive impairments, but mechanisms of this effect have not been confirmed. The objective of this study was to determine whether severe hypoglycemia (SH) in children with type 1 diabetes is associated with cognitive decline over 18 months. RESEARCH DESIGN AND METHODS—A sample of 142 6- to 15-year-old children with type 1 diabetes (mean age 11.6 ± 2.7 years) enrolled in a trial of intensive therapy (IT) or usual care (UC) were tested with the Das-Naglieri Cognitive Assessment System at baseline and after 9 and 18 months. Episodes of SH were recorded by parents and reported promptly for verification by study nurses. HbA1c was measured quarterly. RESULTS—Over 18 months, 58 of 142 patients (41%) experienced 111 SH episodes, with a RR of SH of 1.12 for IT over UC. Neither occurrence nor frequency of SH was associated with decline in full-scale intelligence quotient (IQ), standard scores for planning, attention, simultaneous processing, or successive processing, or scaled scores on any of eight subtests. The same findings emerged when only patients who had experienced hypoglycemic seizures or coma were included in the SH group for analyses. These effects persisted when the child’s age, sex, type 1 diabetes duration, and age at diagnosis were controlled statistically. HbA1c during the trial was not associated with cognitive changes. CONCLUSIONS—SH did not induce adverse changes in the measures of cognitive function administered to 6- to 15-year-old children with type 1 diabetes in this study. Although SH should be avoided in all children with diabetes, these episodes did not have adverse effects on cognition in this age-group over 18 months.
Lepr <sup>db</sup> Diabetic Mouse Bone Marrow Cells Inhibit Skin Wound Vascularization but Promote Wound Healing
Authors: Vesna Stepanovic, Ola Awad, Chunhua Jiao, Martine Dunnwald, Gina C. Schatteman
Journal: Circulation Research (2003)

Bone marrow stem cells participate in tissue repair processes and may have roles in skin wound repair. Diabetes is characterized by delayed and poor wound healing, and type 1 diabetes seems to lead to stem cell dysfunction. Hence, stem cell dysfunction could contribute to poor healing, and stem cell–based therapies may be efficacious in diabetic wounds. We investigated the potential of exogenous stem cells to promote skin healing and possible effects of type 2 diabetes on stem cell function. Mouse bone marrow cells from nondiabetic and diabetic mice were enriched for putative stem cells and injected under skin wounds of nondiabetic or type 2 diabetic Lepr db mice. Using histology and morphometry, vascularization and healing in treated and untreated mice were analyzed. We anticipated a correlation between improved wound healing and vascularization, because therapies that increase tissue vascularization tend to enhance wound healing. Our data indicate that exogenous nondiabetic bone marrow–derived cells increase vascularization and improve wound healing in Lepr db mice but have little effect on nondiabetic controls. In contrast, Lepr db -derived marrow cells inhibit vascularization but promote wound healing in Lepr db mice. Thus, adult stem cell function may be impaired by type 2 diabetes; the ability to promote vascularization and wound healing are distinct functions of bone marrow cells; and neovascularization and wound healing may not be tightly coupled. Additionally, we observed little incorporation of injected cells into wound structures, suggesting that improved healing is mediated through mechanisms other than direct differentiation and incorporation of the cells.