tbuckley/cabot-search huggingface dataset:
Phenobarbital induction of cytochrome p-450 b,e genes is dependent on protein synthesis
Authors: Jose Chianale, Leyna Mulholland, Peter G. Traber, Jorge J. Gumucio
Journal: Hepatology (1988)

Phenobarbital induces liver cytochrome P-450 b,e proteins mainly by increasing the rate of transcription of these genes. The mechanism responsible for the phenobarbital increment in the rate of transcription of cytochrome P-450 b,e genes is unknown. The objective of this study was to assess whether active protein synthesis was needed for phenobarbital to induce the liver cytochrome P-450 b,e genes. Cycloheximide (2 mg per kg, i.p.) was administered 90 min prior to a single inductive dose of phenobarbital (80 mg per kg, i.p.) and mRNAS measured at 3, 6 and 12 hr by dot-blot hybridization. While phenobarbital increased cytochrome P-450 b,e mRNAs about 12-fold at 3 hr, this induction was abolished by cycloheximide. To define whether the absence of protein synthesis in hepatocytes inhibited the phenobarbital induction of cytochrome P-450 at the transcriptional level, in vitro transcription rates using isolated nuclei were measured. After phenobarbital administration, there was about a 20-fold increment in transcriptional rate of cytochrome P-450 b,e genes. This increment was abolished by prior injection of cycloheximide. It is proposed that either preexisting regulatory proteins or transacting factors dependent on active protein synthesis participate in the regulation of liver cytochrome P-450 b,e gene transcription after phenobarbital.
The ultrastructure of cardiac myxoma
Authors: W. J. Williams, D. Jenkins, D. Erasmus
Journal: Thorax (1970)

A detailed study has been made of the ultrastructure of a cardiac myxoma from a man aged 41 years. It consists of abundant mucoid stroma in which are scattered single or grouped rounded or stellate cells. The stroma consists mainly of finely granular material with scanty fibrin which is seen predominantly on the surface aspect. No formed collagen is found. The myxoma cells contain numerous mitochondria, Golgi complexes and associated vesicles, moderate amounts of rough endoplasmic reticulum and scanty residual bodies. There is little evidence of pinocytosis. They also contain similar granular material to that found in the stroma. We consider, therefore, that the myxoma cells are biosynthetically active and are responsible for the production of the stroma. Morphologically the lesion does not show the features of a thrombus and we consider that it is most probably a neoplasm, although at present there is no evidence as to the cell of origin.
DNA sequence analysis of NKG2, a family of related cDNA clones encoding type II integral membrane proteins on human natural killer cells.
Authors: J P Houchins, T Yabe, C McSherry, F H Bach
Journal: The Journal of Experimental Medicine (1991)

We have previously described the isolation of a cDNA clone, designated NKG2, that was expressed in all natural killer (NK) cells tested but not in T or B cells. In the present communication, the original isolate, when used to probe a cDNA library prepared from a CD3- NK cell clone, was found to crosshybridize with a family of transcripts that fell into four distinct groups designated NKG2-A, -B, -C, and -D. Full-length cDNA sequences were determined for each group, and the DNA and inferred peptide sequences were analyzed. All four transcripts encode type II membrane proteins of 215-233 amino acids. NKG2-A and -B peptides appear to be alternative splicing products of a single gene. NKG2-C is highly homologous with group A, having 94% homology in the external (COOH-terminal) domain and 56% homology throughout the internal and transmembrane regions. NKG2-D is distantly but significantly related (21% amino acid homology) to the first three groups. Therefore, NKG2-A, -C, and -D appear to be encoded by distinct genes within a family of NK cell-specific genes. Peptide sequence homology searches demonstrate that the NKG2 peptides are members of a supergene family that includes several other type II membrane proteins. This family is characterized by the presence of a C-type animal lectin domain, and several of its members have demonstrated transmembrane signaling capability.
Tumorigenic Heterogeneity in Cancer Stem Cells Evolved from Long-term Cultures of Telomerase-Immortalized Human Mesenchymal Stem Cells
Authors: Jorge S. Burns, Basem M. Abdallah, Per Guldberg, Jørgen Rygaard, Henrik D. Schrøder, Moustapha Kassem
Journal: Cancer Research (2005)

Abstract Long-term cultures of telomerase-transduced adult human mesenchymal stem cells (hMSC) may evolve spontaneous genetic changes leading to tumorigenicity in immunodeficient mice (e.g., hMSC-TERT20). We wished to clarify whether this unusual phenotype reflected a rare but dominant subpopulation or if the stem cell origin allowed most cells to behave as cancer stem cells. Cultures of the hMSC-TERT20 strain at population doubling 440 were highly clonogenic (94%). From 110 single-cell clones expanded by 20 population doublings, 6 underwent detailed comparison. Like the parental population, each clone had ≈1.2 days doubling time with loss of contact inhibition. All retained 1,25-(OH)2 vitamin D3–induced expression of osteoblastic markers: collagen type I, alkaline phosphatase, and osteocalcin. All shared INK4a/ARF gene locus deletion and epigenetic silencing of the DBCCR1 tumor suppressor gene. Despite in vitro commonality, only four of six clones shared the growth kinetics and 100% tumorigenicity of the parental population. In contrast, one clone consistently formed latent tumors and the other established tumors with only 30% penetrance. Changing the in vitro microenvironment to mimic in vivo growth aspects revealed concordant clonal heterogeneity. Latent tumor growth correlated with extracellular matrix entrapment of multicellular spheroids and high procollagen type III expression. Poor tumorigenicity correlated with in vitro serum dependence and high p27Kip1 expression. Aggressive tumorigenicity correlated with good viability plus capillary morphogenesis on serum starvation and high cyclin D1 expression. Thus, hMSC-TERT20 clones represent cancer stem cells with hierarchical tumorigenicity, providing new models to explore the stem cell hypothesis for cancer.
Amoxycillin-clavulanate for chronic wet cough in children: cautious interpretation of study findings warranted
Authors: Patrick Stark, Rachel Heenan, Francesca Orsani, Kim Jachno, Tom G Connell
Journal: Thorax (2012)

We read with interest the recent paper by Marchant et al comparing amoxicillin-clavunate to placebo for the treatment of chronic wet cough in children.1 The authors should be commended for attempting a randomised controlled clinical trial in this group of patients that often present paediatricians with a management dilemma. Nevertheless, we have significant concerns regarding several aspects of the study methodology, analysis and interpretation and feel that the authors have overstated their conclusions. We therefore urge caution in interpretation of the study findings.

First, …
Paternity Following Treatment for Testicular Cancer
Authors: Marianne Brydøy, Sophie D. Fosså, Olbjørn Klepp, Roy M. Bremnes, Erik A. Wist, Tore Wentzel-Larsen, Olav Dahl
Journal: JNCI Journal of the National Cancer Institute (2005)

Studies of fertility in men treated for testicular cancer have mainly addressed serum follicle-stimulating hormone levels and sperm parameters. We assessed post-treatment paternity among long-term survivors of testicular cancer.Men (n = 1814) who had been treated for unilateral testicular cancer in Norway during 1980 through 1994 were invited to participate in a national multi-center follow-up survey in 1998 through 2002. The participants were allocated to five groups according to the treatment received after orchiectomy, including treatment at relapse (surveillance, retroperitoneal lymph node dissection, radiotherapy, low-dose chemotherapy [i.e., < or = 850 mg cisplatin], and high-dose chemotherapy [i.e., > 850 mg cisplatin]). Cox proportional hazards analysis was used to assess predictive factors for post-treatment paternity. Statistical tests were two-sided.A total of 1433 men were assessable, of whom 827 were fathers at diagnosis. Post-treatment conception was attempted by 554 men, among whom the overall 15-year actuarial post-treatment paternity rate was 71% (95% confidence interval [CI] = 66% to 75%) without the use of cryopreserved semen. This rate ranged from 48% (95% CI = 30% to 69%) in the high-dose chemotherapy group to 92% (95% CI = 78% to 98%) in the surveillance group (P < .001). The median actuarial time from diagnosis to the birth of the first child after treatment was 6.6 years overall but varied according to treatment. Assisted reproductive technologies were used by 22% of the couples who attempted conception after treatment. Dry ejaculation, treatment group, pretreatment fatherhood, and marital status were statistically significant independent predictors for post-treatment fatherhood, with dry ejaculation as the most important negative factor.Although the overall paternity rate after treatment for testicular cancer was high, the ability to conceive and the time to conception reflected the intensity of treatment. These data may help inform patients about their future ability to father biological children.
Phase II Trial of Sorafenib in Advanced Thyroid Cancer
Authors: Vandana Gupta-Abramson, Andrea B. Troxel, Anoma Nellore, Kanchan Puttaswamy, Maryann Redlinger, Kathy Ransone, Susan J. Mandel, Keith T. Flaherty, Laurie A. Loevner, Peter J. O'Dwyer, Marcia S. Brose
Journal: Journal of Clinical Oncology (2008)

Given the molecular pathophysiology of thyroid cancer and the spectrum of kinases inhibited by sorafenib, including Raf kinase, vascular endothelial growth factor receptors, platelet-derived growth factor receptor, and RET tyrosine kinases, we conducted an open-label phase II trial to determine the efficacy of sorafenib in patients with advanced thyroid carcinoma.Eligible patients with metastatic, iodine-refractory thyroid carcinoma received sorafenib 400 mg orally twice daily. Responses were measured radiographically every 2 to 3 months. The study end points included response rate, progression-free survival (PFS), and best response by Response Evaluation Criteria in Solid Tumors.Thirty patients were entered onto the study and treated for a minimum of 16 weeks. Seven patients (23%; 95% CI, 0.10 to 0.42) had a partial response lasting 18+ to 84 weeks. Sixteen patients (53%; 95% CI, 0.34 to 0.72) had stable disease lasting 14 to 89+ weeks. Seventeen (95%) of 19 patients for whom serial thyroglobulin levels were available showed a marked and rapid response in thyroglobulin levels with a mean decrease of 70%. The median PFS was 79 weeks. Toxicity was consistent with other sorafenib trials, although a single patient died of liver failure that was likely treatment related.Sorafenib has clinically relevant antitumor activity in patients with metastatic, iodine-refractory thyroid carcinoma, with an overall clinical benefit rate (partial response + stable disease) of 77%, median PFS of 79 weeks, and an overall acceptable safety profile. These results represent a significant advance over chemotherapy in both response rate and PFS and support further investigation of this agent in these patients.
Digital Vascular Response to Angiotensin II in Normotensive and Hypertensive Subjects
Authors: PETER GASKELL
Journal: Circulation Research (1967)

The critical opening pressure (COP) of digital vessels after digital nerve block and the change in COP caused by angiotensin at 4 mµg/kilo per min intravenously after the block were compared in 9 normotensive subjects, 8 patients with essential hypertension and 7 patients with various kinds of renal hypertension. The COP after nerve block was less than 20 mm Hg in the normotensives and in 6 renal hypertensives, but more than 20 mm Hg in 7 essential hypertensives. The angiotensin reduced the COP in 7 of the normotensives, increased it substantially in 7 essential hypertensives, but had little effect in 6 renal hypertensives. A significantly greater increase in systemic blood pressure occurred in the essential hypertensives than in the normotensive subjects. In normotensive subjects doses of intravenous angiotensin from 2 to 16 mµg/kilo per min decreased the COP whether preceded by digital nerve block or not. Angiotensin at 8 mµg/kilo per min increased total digital vascular resistance as estimated by venous occlusion plethysmography. The results indicated that angiotensin relaxed smooth muscle in digital vessels of normal subjects but increased vascular resistance. In patients with essential hypertension angiotensin caused contraction of the smooth muscle, a response apparently qualitatively different from normal. In renal hypertensives the smooth muscle had little response to the exogenous angiotensin.
Dog exposure in early childhood reduces atopic dermatitis and wheezing at age 3
Authors: J.D. Bufford, C.L. Reardon, J. Kohls, Z. Li, R. Gangnon, K.A. Roberg, C. Tisler, E. Anderson, D. DaSilva, P.A. Eggleston, R.F. Lemanske, J.E. Gern
Journal: Journal of Allergy and Clinical Immunology (2005)

RATIONALE: Exposure to dogs in the first year of life is associated with increased production of IL-10 and a decreased risk of atopic dermatitis (AD) and allergic sensitization at age 1. The effect of pet exposure on subsequent immune development and atopic diseases has not been well studied. METHODS: Pet ownership at birth was recorded for 285 children enrolled in the COAST study (Childhood Origins of ASThma). PHA-induced cytokine responses from peripheral blood mononuclear cells were obtained at annual visits. Can f 1 levels were determined in settled dust from 101 homes at age 3. RESULTS: Dog exposure was associated with decreased AD (14% vs. 38%; p<0.001) and wheezing (19% vs. 35%; p=0.005) in year 3, but not with allergic sensitization at age 3 (35% vs. 45%; p=0.14). Although dog ownership was not significantly associated with PHA-induced cytokine responses at age 3, Can f1 levels in bedroom dust were positively associated with IL-10 (rs=0.33; p=0.001), IL-5 (rs=0.34, p=0.001) and IL-13 (rs=0.35, p<0.001) responses at age 1, and IL-5 (rs=0.23; p=0.03) and IL-13 (rs=0.23, p=0.03) responses at age 3. Can f 1 levels were not significantly associated with IL-10 responses at age 3 (rs=0.07, p=0.51). CONCLUSIONS: Dose-dependent exposure to Can f1 in early childhood is associated with changes in immune development. While alterations in cytokine responses seen at age 1 are less significant by age 3, protection against the clinical manifestations of atopic disease persist.
Estimation of Left Ventricular Residual Volume in the Dog by a Thermodilution Method
Authors: Elliot Rapaport, Bernard D. Wiegand, J. David Bristow
Journal: Circulation Research (1962)

Thermodilution was used to estimate left ventricular volumes by the indicator-dilution principle. The results of multiple determinations in the same animal were in close agreement. Average values determined in 16 dogs anesthetized with a chloralose-urethane mixture were SV 18 ml., ESV 37 ml., EDV 56 ml., and CO 2.54 L./min. The ratio ESV/EDV averaged 66 per cent, which was significantly less than the ESV to EDV ratio of 79 per cent observed in 14 other dogs anesthetized with sodium pentobarbital and studied in a comparable fashion. This difference was attributed primarily to the myocardial depressant effects of the barbiturate anesthetic. The ability to perform multiple determinations without "indicator" accumulation, to record the time-temperature curve directly at the base of the aorta without sampling through a catheter system, to avoid introducing substances into the circulation which may produce significant circulatory effects, and to perform calibration quickly and easily suggests that the thermodilution technique offers a simple, rapid, and reproducible method for estimating ventricular volumes.
Macrophage oxygen-dependent antimicrobial activity. IV. Role of endogenous scavengers of oxygen intermediates.
Authors: H W Murray, C F Nathan, Z A Cohn
Journal: The Journal of Experimental Medicine (1980)

The activities of the endogenous O2- and H2O2 scavenging enzymes, superoxide dismutase (SOD), glutathionine peroxidase (GP), and catalase, were measured in lysates of the intracellular parasite, Toxoplasma gondii, and in various macrophage populations. During 72 h of cultivation in standard medium alone, the catalase activity of in vivo-activated toxoplasma-immune macrophages (IM) and immune-boosted macrophages (IB) progressively increased by eight- to ninefold, and correlated with the previously observed parallel decline in these cells' antitoxoplasma activity and capacity to release H2O2. SOD and GP activities either remained constant or decreased during this 3-d period. Lymphokine exposure, which preserved the antitoxoplasma activity and oxidative capacity of 48- and 72-h cultures of IB and IM cells, blunted the rise in catalase levels and had no effect on SOD or GP. Inhibition of IB and IM macrophage catalase by aminotriazole maintained toxoplasmastatic activity otherwise lost after 48 h of cultivation. In addition, IB and IM cells from acatalasemic mice contained 20- to 30-fold less catalase, and showed comparatively little decline in either H2O2 release or antitoxoplasma activity during 72 h in culture. In vitro-(lymphokine) activated resident macrophages from normal mice had the highest levels of SOD, GP, and catalase, and these cells failed to kill or inhibit T. gondii despite enhanced extracellular release of O2- and H2O2. Toxoplasmas were also found to contain all three enzymatic scavengers. Aminotriazole inhibition of lymphokine-activated cells' catalase or of toxoplasma catalase was effective in inducing these macrophages to display antitoxoplasma activity. Moreover, and in contrast to normocatalasemic resident cells, those from acatalesemic mice were readily induced by lymphokine to inhibit the replication of untreated virulent toxoplasmas. These results suggest that endogenous O2- and H2O2 scavenging enzymes, which function within both T. gondii and activated macrophages as host cell antioxidant protective mechanisms, may reduce the effectiveness of phagocyte antimicrobial activity. Thus, the presence of SOD, GP, and especially catalase within both target and effector cell may be important determinants of macrophage oxygen-dependent processes.
Classification of antiarrhythmic agents and the two laws of pharmacology
Authors: L Hondeghem
Journal: Cardiovascular Research (2000)

In a standard textbook of pharmacology [1] there are 50 (three-column, 69-line) pages in the index (50×3×69=10 350). In order to render this vast information somewhat manageable the chemicals are grouped in about 50 chapters, one of which is “Agents used in cardiac arrhythmias” [2]. Antiarrhythmic agents are in turn subdivided in four classes plus a group of miscellaneous agents (containing those that do not fit in any of the four standard classes). At times it is desirable to subdivide these classes into subclasses (main topic of this paper).

Although such classification renders the pharmacological information more manageable, it is frequently difficult or impossible to fit a chemical in a class. For example, while beta blockers certainly belong as a chapter in the section on autonomic drugs, they also form an important class in the antiarrhythmic agents (see below). In addition, they also need to be described in the sections on angina, congestive heart failure and hypertension (among others). This problem follows directly from the first law of pharmacology: no drug has a single effect.

A group of investigators has tried to remedy this problem for classification of antiarrhythmic agents by proposing an alternative: the Sicilian gambit [3]. Basically, they list all the chemicals with antiarrhythmic properties as rows in a table, while describing all possible actions in columns. The advantage of this system is that it can be very accurate and complete: as new chemicals emerge new rows are added, while new mechanisms are added as new columns. Unfortunately, as progress is made the complexity of the table grows nearly quadratically and soon the entries exceed the retention capacity of ordinary souls… so that its usefulness is reduced to an encyclopedic nature, i.e., to be consulted when full details are needed.

As a result, the only practical classification …
In non-transplant patients with multiple myeloma, the pre-treatment level of clonotypic cells predicts event-free survival
Authors: Kyle J Thulien, Andrew R Belch, Tony Reiman, Linda M Pilarski
Journal: Molecular Cancer (2012)

In multiple myeloma (MM), the immunoglobulin heavy chain VDJ gene rearrangement is a unique clonotypic signature that identifies all members of the myeloma clone independent of morphology or phenotype. Each clonotypic MM cell has only one genomic copy of the rearranged IgH VDJ.Pre-treatment bone marrow aspirates from myeloma patients at diagnosis or in relapse were evaluated for the number of clonotypic cells using real time quantitative PCR (RPCR). RPCR measured the level of clonal cells, termed VDJ%, in 139 diagnosis and relapse BM aspirates from MM patients.Patients with a VDJ% below the median had a significantly longer event free survival (EFS) then those with a VDJ% higher than the median (p=0.0077, HR=0.57). Further, although the VDJ% from non-transplant patients predicted EFS (p=0.0093), VDJ% failed to predict outcome after autologous stem cell transplant (p=0.53).Our results suggest that for non-transplant patients, the tumor burden before treatment, perhaps reflecting cancer stem cell progeny/output, is an indirect measure that may indicate the number of MM cancer stem cells and hence event free survival.
Reply to K.-P. Dieckmann et al
Authors: Sally P. Stenning, Tim Oliver, Ben Mead, Rhian Gabe
Journal: Journal of Clinical Oncology (2011)

or, alternatively, cisplatin-based multidrug chemotherapy.Notably, a subset of 15 patients with seminoma and contralateral TIN underwent treatment with carboplatin at a dosage of 7 ϫ area under the curve, according to European guidelines. 4 Strikingly, eight patients showed persistence of TIN on a repeat testicular biopsy, and two other patients developed a second seminoma after 4.5 and 11 years, respectively.Only two patients were found to be TIN-free when the repeat biopsy was performed.The three remaining patients had no repeat biopsy performed and are still under observation; no second tumor has developed in any of the three patients after a median observation time of 50 months.In comparison, another subset of the study population comprised 11 patients who underwent surveillance with no particular treatment for TIN.Of this group, six patients developed invasive seminoma during follow-up.Thus, the presumed cancer-preventing efficacy of carboplatin was not demonstrated in two thirds of patients, and this result is practically identical to the outcome that could be expected if no treatment were administered.Our experience is at odds with the observations of Oliver et al. 1 Although we are deeply convinced with respect to the benefits of carboplatin in the adjuvant management of stage I seminoma, we must raise serious doubts regarding the presumed efficacy of this drug in the prevention of contralateral testicular cancer.