tbuckley/cabot-search huggingface dataset:
Abstract B34: Bortezomib induces G2-M arrest through ROS-inducible phosphorylation of ATM-CHK1 in human colon cancer cells
Authors: Hong Seung-Woo, Kim Tae Won, Moon Jai-Hee, Hong Yong-Sang, Jin Dong-Hoon, Shin Jae-Sik, Yoon Dok Hyun, Kim Kyu-pyo, Lee Jae-Lyun, Lee Jung Shin
Journal: Clinical Cancer Research (2012)

Abstract Colorectal cancer (CRC) is one of the most common cancer types, however, newer drug development has reached a plateau at present. Bortezomib (PS-341, Velcade®) is a proteasome inhibitor and approved in the treatment of hematologic malignancies including multiple myeloma. A few trials of bortezomib alone or combination chemotherapy for CRC patients have been reported, however, the results were not so satisfactory, and it might be due to the lack of understanding on the action mechanism. In this report, we suggest the possibility of using bortezomib as a proteasome inhibitor in human colon cancer cells. Although bortezomib has been known to induce apoptosis and cell cycle arrest in various human cancer cells, the inhibitory mechanism of it was not clear. First, bortezomib induced G2-M arrest. Its treatment causes an increase of intracellular reactive oxygen species (ROS) levels and activation of ATM-CHK1 pathway, but not ATR. Also, activation of that pathway led to inactivation of cdc2. Moreover, treatment with NAC, ROS scavenger, inhibited phosphorylation of ATM and subsequent to decrease of cell number at G2-M phase in response to bortezomib indicating that the increased level of ROS after exposure to bortezomib is a result of ATM phosphorylation. In addition, knockdown of endogenous ATM by RNA interference induced the decreased sensitivity to bortezomib. Therefore, these results suggest that bortezomib induces G2-M arrest through ROS-inducible ATM phosphorylation and shows antitumor activity in human colon cancer cells, implying a potential possibility of further investigations in the treatment of CRC patients. Acknowledgement: This study was supported by grants from the Korea Health 21 R&amp;D Project, Ministry of Health and Welfare and Family Affairs, Korea (A062254).
Birth weight and risk of asthma in 3-9-year-old twins: exploring the fetal origins hypothesis
Authors: K. Kindlund, S. F. Thomsen, L. G. Stensballe, A. Skytthe, K. O. Kyvik, V. Backer, H. Bisgaard
Journal: Thorax (2009)

<h3>Aim</h3> To examine the relationship between birth weight and risk of asthma in a population of twins. <h3>Methods</h3> Birth weight of all live twins (8280 pairs) born in Denmark between 1994 and 2000 was linked to information on asthma obtained from parent-completed questionnaires at age 3–9 years. Conditional logistic regression was used to calculate the risk of asthma. <h3>Results</h3> Subjects with a history of asthma at age 3–9 years weighed on average 122 g (95% CI 85 to 160) less at birth than subjects who had not developed asthma, p&lt;0.001. There was a linear increase in asthma risk with decreasing birth weight, OR (per 100 g) 1.04 (95% CI 1.03 to 1.05), p&lt;0.001. Within twin pairs, the lower birthweight twin had a significantly increased risk of asthma compared with the heavier co-twin (11.3% vs 9.9%), OR 1.30 (95% CI 1.10 to 1.54), p=0.002. The result remained significant after adjusting for sex, birth length and Apgar score, OR 1.31 (95% CI 1.03 to 1.65), p=0.027. The risk tended to be higher in monozygotic co-twins compared with dizygotic co-twins, especially for high birth weight differences. <h3>Conclusions</h3> Low birth weight is a risk factor for asthma independently of gestational age, sex, birth length and Apgar score, but this may be due, in part, to residual non-genetic confounding factors. This finding lends support to the "fetal origins hypothesis" suggesting undisclosed prenatal determinants for the risk of asthma.
Histone Deacetylase Inhibitors Induce Growth Arrest and Differentiation in Uveal Melanoma
Authors: Solange Landreville, Olga A. Agapova, Katie A. Matatall, Zachary T. Kneass, Michael D. Onken, Ryan S. Lee, Anne M. Bowcock, J. William Harbour
Journal: Clinical Cancer Research (2011)

Metastasis is responsible for the death of most cancer patients, yet few therapeutic agents are available which specifically target the molecular events that lead to metastasis. We recently showed that inactivating mutations in the tumor suppressor gene BAP1 are closely associated with loss of melanocytic differentiation in uveal melanoma (UM) and metastasis. The purpose of this study was to identify therapeutic agents that reverse the phenotypic effects of BAP1 loss in UM.In silico screens were done to identify therapeutic compounds predicted to differentiate UM cells using Gene Set Enrichment Analysis and Connectivity Map databases. Valproic acid (VPA), trichostatin A, LBH-589, and suberoylanilide hydroxamic acid were evaluated for their effects on UM cells using morphologic evaluation, MTS viability assays, bromodeoxyuridine incorporation, flow cytometry, clonogenic assays, gene expression profiling, histone acetylation and ubiquitination assays, and a murine xenograft tumorigenicity model.Histone deacetylase (HDAC) inhibitors induced morphologic differentiation, cell-cycle exit, and a shift to a differentiated, melanocytic gene expression profile in cultured UM cells. VPA inhibited the growth of UM tumors in vivo.These findings suggest that HDAC inhibitors may have therapeutic potential for inducing differentiation and prolonged dormancy of micrometastatic disease in UM.
Comparison of methotrexate monotherapy with a combination of methotrexate and etanercept in active, early, moderate to severe rheumatoid arthritis (COMET): a randomised, double-blind, parallel treatment trial
Authors: Paul Emery, Ferdinand C Breedveld, Stephen Hall, Patrick Durez, David J Chang, Deborah Robertson, Amitabh Singh, Ronald D Pedersen, Andrew S Koenig, Bruce Freundlich
Journal: The Lancet (2008)
Assessment of smooth muscle contribution to descending thoracic aortic elastic mechanics in conscious dogs.
Authors: J G Barra, R L Armentano, J Levenson, E I Fischer, R H Pichel, A Simon
Journal: Circulation Research (1993)

Early investigators found contradictory evidence that vascular smooth muscle activation reduces the elastic modulus of the arterial wall under isotonic conditions but increases it under isometric conditions, concomitant with increased pulse-wave velocity. We examined the individual contributions of aortic constituents to the elastic modulus of the aortic wall to determine if isobaric analysis produces an accurate assessment of vascular smooth muscle activation. We used a modified Maxwell model assuming an incremental elastic modulus (Einc) composed of the elastic modulus of elastin fibers (EE), the elastic modulus of collagen fibers (EC) affected by the fraction of collagen fibers (fC) recruited to support wall stress, and the elastic modulus of the vascular smooth muscle (ESM) according to the following formula: Einc = EE+EC x fC+ESM.Einc was assessed in eight conscious dogs using descending thoracic aortic pressure (microtransducer) and diameter (sonomicrometry) measurements. Stress-strain relations in the control state and during activation of smooth muscle by continuous administration of phenylephrine (5 micrograms.kg-1 x min-1) were obtained by transient occlusions of the descending aorta and inferior vena cava. Results were as follows: EE was 4.99 +/- 1.58 x 10(6) dynes/cm2 (mean +/- SD), and EC was 965.8 +/- 399.8 x 10(6) dynes/cm2, assessed during the control state. Phenylephrine administration increased the theoretical pulse-wave velocity (Moens-Korteweg equation) from 5.25 +/- 1.03 m/s during the control state to 7.57 +/- 2.53 m/s (P < .005). Active muscle exhibited a unimodal stress-strain curve with a maximum stress of 0.949 +/- 0.57 x 10(6) dynes/cm2 at a corresponding strain value of 1.299 +/- 0.083. The maximum value observed corresponded, on the pressure-diameter curve of the active artery, to a pressure of 234.28 +/- 46.6 mm Hg and a diameter of 17.94 +/- 1.6 mm. The maximum ESM derived from the stress-strain relation of the active muscle was 8.345 +/- 7.56 x 10(6) dynes/cm2 at a strain value of 1.283 +/- 0.079. This point was located at 208.01 +/- 40.8 mm Hg and 17.73 +/- 1.41 mm on the active pressure-diameter curve. During activation of vascular smooth muscle, Einc decreased (P < .05) when plotted against internal pressure but increased (P < .05) when plotted against strain, over the operative range.(ABSTRACT TRUNCATED AT 400 WORDS)
Chemotherapy of Systemic Fungal Diseases
Authors: P D Hoeprich
Journal: The Annual Review of Pharmacology and Toxicology (1978)

After its discovery in 1953 (1), amphotericin B became the principal antifungal antimicrobic for systemic therapy in humans. Although toxicity proved to be formi­ dable, until recently there were no alternatives for the treatment of systemic mycoses which offered comparable antifungal activity and greater safety. The report of the antifungal activity of 5-fluorocytosine in 1963 (2) led to the availability of an orally administrable, less toxic agent. Unfortunately, the utility of this inhibitory antimicrobic may not extend beyond certain yeasts. Most recently, the antifungally active imidazoles (e.g. miconazole) and the semi­ synthetic polyenes (e.g. amphotericin B methyl ester) have moved from in vitro and experimental in vivo investigations to trials in patients. This review deals with four systemically applicable antifungal antimicrobics: amphotericin B, amphotericin B methyl ester, 5-fiuorocytosine, and miconazole. Some properties of these drugs are summarized in Table 1, and the spectrum of activity against major groups of pathogens is presented in Table 2.
Paws for thought
Authors: A. Johnstone
Journal: BMJ (2003)

Ellie, our family's 2 year old Labrador bitch, jumped into the boot of the car, avulsed a claw, and let out an uncharacteristic wail. An anxious and rather sleepless night was had by all. I put her on a course of dog biscuits (two every four hours) to try to cheer her up. The next morning, after some discussion, I telephoned our local veterinary practice and was soon sitting in the waiting room with time to reflect on the experience.

I had telephoned at 8 40 am and was waiting to be seen at 8 55 am. The receptionist was also the veterinary nurse and was therefore able to triage the problem. She correctly anticipated that an operation might be necessary and, far better, that this should take place as early as possible in the day. The practice is paperless, and …
Mapping the Murine Cardiac 26S Proteasome Complexes
Authors: Aldrin V. Gomes, Chenggong Zong, Ricky D. Edmondson, Xiaohai Li, Enrico Stefani, Jun Zhang, Richard C. Jones, Sheeno Thyparambil, Guang-Wu Wang, Xin Qiao, Fawzia Bardag-Gorce, Peipei Ping
Journal: Circulation Research (2006)

The importance of proteasomes in governing the intracellular protein degradation process has been increasingly recognized. Recent investigations indicate that proteasome complexes may exist in a species- and cell-type–specific fashion. To date, despite evidence linking impaired protein degradation to cardiac disease phenotypes, virtually nothing is known regarding the molecular composition, function, or regulation of cardiac proteasomes. We have taken a functional proteomic approach to characterize 26S proteasomes in the murine heart. Multidimensional chromatography was used to obtain highly purified and functionally viable cardiac 20S and 19S proteasome complexes, which were subjected to electrophoresis and tandem mass spectrometry analyses. Our data revealed complex molecular organization of cardiac 26S proteasomes, some of which are similar to what were reported in yeast, whereas others exhibit contrasting features that have not been previously identified in other species or cell types. At least 36 distinct subunits (17 of 20S and 19 of 19S) are coexpressed and assembled as 26S proteasomes in this vital cardiac organelle, whereas the expression of PA200 and 11S subunits were detected with limited participation in the 26S complexes. The 19S subunits included a new alternatively spliced isoform of Rpn10 (Rpn10b) along with its primary isoform (Rpn10a). Immunoblotting and immunocytochemistry verified the expression of key α and β subunits in cardiomyocytes. The expression of 14 constitutive α and β subunits in parallel with their three inducible subunits (β1i, β2i, and β5i) in the normal heart was not expected; these findings represent a distinct level of structural complexity of cardiac proteasomes, significantly different from that of yeast and human erythrocytes. Furthermore, liquid chromatography/tandem mass spectroscopy characterized 3 distinct types of post-translational modifications including (1) N-terminal acetylation of 19S subunits (Rpn1, Rpn5, Rpn6, Rpt3, and Rpt6) and 20S subunits (α2, α5, α7, β3, and β4); (2) N-terminal myristoylation of a 19S subunit (Rpt2); and (3) phosphorylation of 20S subunits (eg, α7)). Taken together, this report presents the first comprehensive characterization of cardiac 26S proteasomes, providing critical structural and proteomic information fundamental to our future understanding of this essential protein degradation system in the normal and diseased myocardium.
Roles for Insulin Receptor, PI3-Kinase, and <i>Akt</i> in Insulin-Signaling Pathways Related to Production of Nitric Oxide in Human Vascular Endothelial Cells
Authors: Guangyuan Zeng, Frederick H. Nystrom, Lingamanaidu V. Ravichandran, Li-Na Cong, Martha Kirby, Howard Mostowski, Michael J. Quon
Journal: Circulation (2000)

Background —Previously, we demonstrated that insulin stimulates production of nitric oxide (NO) in endothelial cells. However, specific insulin-signaling pathways mediating production of NO have not been elucidated. Methods and Results —We developed methods for transfection of human umbilical vein endothelial cells (HUVECs) and direct measurement of NO to begin defining insulin-signaling pathways related to NO production. HUVECs were cotransfected with enhanced Green Fluorescent Protein ( eGFP ) and another gene of interest. Transfection efficiencies &gt;95% were obtained by selecting cells expressing eGFP . Overexpression of insulin receptors in HUVECs resulted in an ≈3-fold increase in production of NO in response to insulin. In contrast, HUVECs overexpressing a tyrosine kinase–deficient mutant insulin receptor had a dose-response curve similar to that of control cells. Overexpression of inhibitory mutants of either phosphatidylinositol 3-kinase (PI3K) or Akt resulted in nearly complete inhibition of insulin-stimulated production of NO. Overexpression of an inhibitory mutant of Ras had a much smaller effect. Conclusions —Receptor kinase activity is necessary to mediate production of NO through the insulin receptor. Both PI3K and Akt contribute importantly to this process, whereas the contribution of Ras is small.
Cytotoxicity of Cisplatin and Cisdiammine-1,1-cyclobutane Dicarboxylate in MGH-U1 Cells Grown as Monolayers, Spheroids, and Xenografts&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Charles Erlichman, Danka Vidgen, Anna Wu
Journal: JNCI Journal of the National Cancer Institute (1985)

The cytotoxicity of cisplatin and cisdiammine-1,1-cyclobutane dicarboxylate (CBDCA) was examined using the MGH-U1 human bladder carcinoma cell line, grown as monolayer cultures, multicellular tumor spheroid(s) (MTS), and xenografts in immune-deprived CBA/CaJ mice. The cell survival of exponentially growing monolayers and MTS treated with cisplatin declined in a monoexponential fashion with a concentration of drug resulting in 10% colony survival (D10) of 7.75 micrograms/ml and 9.5 micrograms/ml, respectively. MTS growth delay determination demonstrated a drug concentration-dependent increase in growth delay and a correlation between decreasing surviving fraction and increasing growth delay. In vivo treatment of MGH-U1 xenografts with cisplatin caused a modest decrease in surviving fraction although the xenografted cells treated in vitro demonstrated the same sensitivity to cisplatin as those cells maintained continuously in vitro. The D10 for CBDCA treatment was 246 micrograms/ml for exponentially growing monolayer cells and 196 micrograms/ml for MTS. Growth delay studies with CBDCA showed a concentration-dependent increase in spheroid growth delay and a correlation between decreasing surviving fraction and growth delay similar to cisplatin. The conclusions were that: 1) cisplatin and CBDCA did not have any difficulty penetrating into spheroids, 2) both agents appeared to be active against the noncycling poorly nourished cells found near the necrotic center of spheroids, 3) both cisplatin and CBDCA were cytotoxic toward MGH-U1 cells but cisplatin was 20-30 times more effective, and 4) the limited cytotoxic effect of cisplatin in vivo may be due to the low area under the concentration times the time curve achieved in vivo and not due to intrinsic cell resistance.
Xenogeneic human anti-mouse T cell responses are due to the activity of the same functional T cell subsets responsible for allospecific and major histocompatibility complex-restricted responses.
Authors: S L Swain, R W Dutton, R Schwab, J Yamamoto
Journal: The Journal of Experimental Medicine (1983)

Human T cells respond strongly to mouse major histocompatibility complex (MHC) antigens. The response is directed predominantly to the polymorphic determinants of the MHC antigens and there is little or no response to the nonpolymorphic determinants or to non-MHC antigens. Human cytotoxic T lymphocytes (CTL) are generated specific for the mouse class I MHC antigens and the CTL effectors are blocked by anti-Leu-2a antisera. Human interleukin 2-producing T cells are generated specific for mouse class II antigens and their induction is blocked by anti-Leu-3a antisera. These and other considerations lead us to propose a model for the T cell receptor that provides an explanation for several of the features of T cell recognition. In this model, the recognition of the "class" (I or II) of MHC antigen is separate from the recognition of the polymorphic determinants. We suggest that the initial recognition of the conserved "class" determinants positions another domain of the receptor so that it can only engage with the part of the MHC molecule carrying the polymorphic determinants.
Sodium-Glucose Cotransporter 2 Inhibition and Glycemic Control in Type 1 Diabetes: Results of an 8-Week Open-Label Proof-of-Concept Trial
Authors: Bruce A. Perkins, David Z.I. Cherney, Helen Partridge, Nima Soleymanlou, Holly Tschirhart, Bernard Zinman, Nora M. Fagan, Stefan Kaspers, Hans-Juergen Woerle, Uli C. Broedl, Odd-Erik Johansen
Journal: Diabetes Care (2014)

Adjunctive-to-insulin therapy with sodium-glucose cotransporter 2 (SGLT2) inhibition may improve glycemic control in type 1 diabetes (T1D).We evaluated the glycemic efficacy and safety of empagliflozin 25 mg daily in 40 patients treated for 8 weeks in a single-arm open-label proof-of-concept trial (NCT01392560).Mean A1C decreased from 8.0 ± 0.9% (64 ± 10 mmol/mol) to 7.6 ± 0.9% (60 ± 10 mmol/mol) (P < 0.0001), fasting glucose from 9.0 ± 4.3 to 7.0 ± 3.2 mmol/L (P = 0.008), symptomatic hypoglycemia (<3.0 mmol/L) from 0.12 to 0.04 events per patient per day (P = 0.0004), and daily insulin dose from 54.7 ± 20.4 to 45.8 ± 18.8 units/day (P < 0.0001). Mean urinary excretion of glucose increased from 19 ± 19 to 134 ± 61 g/day (P < 0.0001). Weight decreased from 72.6 ± 12.7 to 70.0 ± 12.3 kg (P < 0.0001), and waist circumference decreased from 82.9 ± 8.7 to 79.1 ± 8.0 cm (P < 0.0001).This proof-of-concept study strongly supports a randomized clinical trial of adjunctive-to-insulin empagliflozin in patients with T1D.
Raloxifene Prevails in STAR Trial, May Face Easier Road to Acceptance Than Previous Drugs
Authors: Brian Vastag
Journal: JNCI Journal of the National Cancer Institute (2006)

Raloxifene and Tamoxifen were pitted head to head in the STAR trial. Raloxifene Prevails in STAR Trial, May Face Easier Road to Acceptance Than Previous DrugsRaloxifene seems to have won the contest with tamoxifen to prevent breast cancer in high-risk postmenopausal women, providing equal cancer-preventing benefi ts with fewer serious side effects.The fi nding clears the way for possibly wider use of the osteoporosis drug.Results from the 20,000-woman Study of Tamoxifen and Raloxifene (STAR) were released in April, more than a year ahead of schedule.Raloxifene's greatest advantage appears to be fewer serious side effects, including uterine cancer, blood clots, and cataracts." The study was designed to compare the drugs head to head, and raloxifene was the winner, " said Larry Wickerham, M.D., associate director of the National Surgical Adjuvant Breast and Bowel Project, which announced the results with the National Cancer Institute " This is good news for women, " added Leslie Ford, M.D., associate director of clinical research for NCI's Division of Cancer Prevention.Roughly the same number of women taking each drug developed breast cancer -167 in the raloxifene group and 163 in the tamoxifen group, a difference that wasn't statistically signifi cant.The fi ndings have prompted raloxifene maker Eli Lilly to petition the Food and Drug Administration for permission to market raloxifene for breast cancer
Folic Acid Supplements During Pregnancy in Specific Clinical Settings
Authors: Andrea Romigi, Fabio Placidi, Francesca Izzi
Journal: JAMA Pediatrics (2015)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Pediatrics HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Pediatrics journal
Abscess Incision and Drainage
Authors: Michael T. Fitch, David E. Manthey, Henderson D. McGinnis, Bret A. Nicks, Manoj Pariyadath
Journal: New England Journal of Medicine (2007)

Incision and drainage is the primary therapy for cutaneous abscess management, as antibiotic treatment alone is inadequate for treating many of these loculated collections of infectious material. Most localized skin abscesses without associated cellulitis can be managed with simple incision and drainage and do not require antibiotic treatment. Cutaneous abscesses have been described in all areas of the body, but are most commonly found in the axillae, buttocks, and extremities. This outpatient procedure is appropriate for many office settings, as well as for urgent care and emergency department practice environments. Diagnosis of a skin abscess is the first step . . . .