tbuckley/cabot-search huggingface dataset:
Isolation and maintenance of the human pilosebaceous duct: 13-cis retinoic acid acts directly on the duct in vitro
Authors: R. GUY, C. RIDDEN, J. BARTH, T. KEALEY
Journal: British Journal of Dermatology (1993)

The human pilosebaceous duct was isolated and maintained for 7 days in defined medium, and defined medium supplemented with 1 μm 13-cis retinoic acid. Freshly isolated ducts retained their in vivo morphology, showing a stratified squamous keratinizing epithelium. On maintenance there was a loss of basic duct architecture, and a significant reduction in the rate of [methyl-3H] thymidine uptake. The addition of 1 μM 1 3-cis retinoic acid resulted in an improved duct architecture and caused a further signiticant reduction in the rate of [methyl-3H] thymidine uptake. [Methyl-3H] thymidine autoradiography showed that freshly isolated ducts maintained their in situ pattern of cell division. It was difficult to discern the region of celi division in ducts maintained for 7 days, but the degree of graining reflected the measured rates of [methyl-3H] thymidine uptake into PCA precipitable material. The pattern of keratin synthesis of the freshly isolated duct was similar to patterns previously described for the duct in situ. This study reports the successful isolation and maintenance of the human pilosebaceous duct, and demonstrates that 13-cis retinoic acid acts directly at the level of the duct.
Bevacizumab Advanced Melanoma (BEAM) Was a Positive Trial
Authors: David R. Minor
Journal: Journal of Clinical Oncology (2012)

TO THE EDITOR: Bevacizumab Advanced Melanoma (BEAM) by Kim et al was a randomized phase II trial. Cannistra clarified the differences between a phase III trial and a randomized phase II trial in 2009. “Unlike the randomized phase III study, the type I error of a randomized phase II trial is typically high, in the range of 10% to 20%, to keep patient numbers reasonable . . . The typical goal of performing a randomized comparison phase II trial is not to obtain definitive efficacy information, but to identify promising experimental regimens that have a high likelihood of success in the phase III setting.” The BEAM trial showed improvements in response rates, progression-free survival, and overall survival at all time points, with a similar degree of improvement to that seen in other solid tumors in which bevacizumab was added to chemotherapy. The hazard rate for improvement in overall survival at the last time point, 0.79, is the same rate of improvement seen with bevacizumab with the same chemotherapy that led the US Food and Drug Administration to approve bevacizumab for lung cancer. The BEAM trial produced strong evidence that a phase III trial would likely be successful. The statistical design for the BEAM trial was written in 2007, and the desire to keep the patient numbers reasonable together with the desire to use a more traditional type one error of 5% probably led to the hypothesis that the experimental arm would have a 50% improvement in progression-free survival, from 4 to 6 months, despite the fact that rate of improvement has almost never been reported with the addition of bevacizumab to chemotherapy. Because the statistical design of the trial was too ambitious in both the hypothesized improvement and the type one error (P value) sought, “the study did not meet the primary objective.” Our interpretation of the results of the BEAM might be moot if the results of a phase III trial were expected soon. Although there was enthusiasm among both the trial investigators and Genentech personnel in July 2009 for quickly starting a phase III trial, the merger of Genentech into Roche that year led to a change in corporate priorities away from a phase III trial in melanoma. Now with the approval of ipilimumab and vemurafenib, a first-line trial of chemotherapy with bevacizumab would be neither appropriate nor feasible. The BEAM trial was positive, and it will remain our best evidence of the efficacy of antiangiogenic therapy in metastatic melanoma for the near future. Other antivascular endothelial growth factor–targeted agents are being studied for melanoma, and we hope to soon see both phase II and phase III trials of bevacizumab with the new agents that are now our first-line therapy for metastatic melanoma.
Coamplification of DAD-R, SOX5, and EKI1 in human testicular seminomas, with specific overexpression of DAD-R, correlates with reduced levels of apoptosis and earlier clinical manifestation
Authors: Gaetano Zafarana, Ad J. M. Gillis, Ruud J. H. L. M. van Gurp, Per G. Olsson, Fons Elstrodt, Hans Stoop, José Luis Millán, J. Wolter Oosterhuis, Leendert H. J. Looijenga
Journal: Cancer Research (2002)

Seminomas and nonseminomas represent the invasive stages of testicular (TGCTs) of adolescents and adults. Although TGCTs are characterized by extra copies of the short arm of chromosome 12, the genetic basis for gain of 12p in the pathogenesis of this cancer is not yet understood. We have demonstrated that gain of 12p is related to invasive growth and that amplification of specific 12p sequences, i.e., 12p11.2-p12.1, correlates with reduced apoptosis in the tumors. Here we show that three known genes map within the newly determined shortest region of overlap of amplification (SROA): DAD-R, SOX5, and EKI1. Whereas EKI1 maps close to the telomeric region of the SROA, DAD-R is the first gene at the centromeric region within the 12p amplicon. Although all three genes are amplified to the same level within the SROA, expression of DAD-R is significantly up-regulated in seminomas with the restricted 12p amplification compared with seminomas without this amplicon. DAD-R is also highly expressed in nonseminomas of various histologies and derived cell lines, both lacking such amplification. This finding is of particular interest because seminomas with the restricted 12p amplification and nonseminomas are manifested clinically in the third decade of life and show a low degree of apoptosis. In contrast, seminomas lacking a restricted 12p amplification, showing significantly lower levels of DAD-R with pronounced apoptosis, manifest clinically in the fourth decade of life. A low level of DAD-R expression is also observed in normal testicular parenchyma and in parenchyma containing the precursor cells of this cancer, i.e., carcinoma in situ. Therefore, elevated DAD-R expression in seminomas and nonseminomas correlates with invasive growth and a reduced level of apoptosis associated with an earlier clinical presentation. These data implicate DAD-R as a candidate gene responsible in part for the pathological effects resulting from gain of 12p sequences in TGCTs. In addition, our results also imply differences in expression regulation of DAD-R between seminomas and nonseminomas.
Ly phenotype of cytotoxic T cells for syngeneic tumor.
Authors: H Shiku, T Takahashi, M A Bean, L J Old, H F Oettgen
Journal: The Journal of Experimental Medicine (1976)

Our present and previous findings may be summarized as follows: The phenotype of C57BL/6 (B6) cytotoxic cells for allogeneic target cells is Thy-1+, Ly-1- Ly-2/3+, MSLA+, and Ig-. the phenotype of B6 cytotoxic cells for syngeneic tumor cells is Thy-1+, Ly-1+, Ly-2/3+, MSLA+, and Ig-. The phenotype of B6 cytotoxic cells for syngeneic tumor cells is Thy-1+, Ly-1+, Ly-2/3+, MSLA+, AND Ig-. Thus, differences in Ly phenotype appear to be exhibited not only by cytotoxic T cells as opposed to helper T cells, but also within subcategories of cytotoxic T cells.
Steady-state and nonsteady-state action potentials in fibrillating canine atrium: abnormal rate adaptation and its possible mechanisms
Authors: M Hara
Journal: Cardiovascular Research (1999)

Our goal was to study rate adaptation of atrial action potentials in non-steady and steady states to further our understanding of mechanisms determining inducibility and stability of atrial fibrillation.We used standard microelectrode techniques to examine the characteristics of steady-state action potentials paced at regular cycle lengths (CL) and of nonsteady-state action potentials observed after an abrupt change of CL in atria from canine hearts that had been rapidly paced.We compared action potential characteristics among normal atria, atria in which chronic atrial fibrillation (cAF, lasting more than 3 days) had been induced and atria in which only nonsustained atrial fibrillation (nAF, lasting less than 12 h) had been induced. In steady-state, the rate adaptation of maximum diastolic potential (MDP) and action potential duration (APD) and markedly reduced in both cAF and nAF. Action potential characteristics did not differ between cAF and nAF atria, suggesting that factors other than electrophysiological properties determine the chronicity of AF. The time course of change in APD after an abrupt change of CL was altered in nAF/cAF atria; i.e., when CL was prolonged, APD also prolonged at the first beat, and then shortened during several subsequent beats (initial phase). Thereafter, APD slowly prolonged to a new steady-state (slow phase). In nAF/cAF atria, the initial phase was enhanced (greater shortening of APD) and the slow phase was reduced (less prolongation of APD). This latter phase was modified by ryanodine.Thus the reduced rate adaptation of steady-state APD is explained mainly by the loss of a slow phase of APD adaptation in nAF/cAF which is reversed in the presence of ryanodine. Therefore, in both nAF and cAF atria, rate adaptation of MDP as well as APD are reduced, nonsteady state as well as steady state, AP characteristics are markedly altered and these changes are partially explicable by Ca, -dependent processes.
Sarcoplasmic Reticulum and Nuclear Envelope Are One Highly Interconnected Ca <sup>2+</sup> Store Throughout Cardiac Myocyte
Authors: Xu Wu, Donald M. Bers
Journal: Circulation Research (2006)

Previous ventricular myocyte studies indicated that ryanodine receptors (RyRs) are in the sarcoplasmic reticulum (SR) and are critical in excitation-contraction coupling, whereas the inositol trisphosphate (InsP(3)) receptors are separately localized on the nuclear envelope (NucEn) and involved in nuclear Ca(2+) signaling. Here, we find that both caffeine and InsP(3) receptor agonists deplete free [Ca(2+)] inside both SR and NucEn. Fluorescence recovery after photobleach (FRAP) was measured using the low-affinity Ca(2+) indicator Fluo-5N trapped inside the SR and NucEn (where its fluorescence is high because [Ca(2+)] is &1 mmol/L). After Fluo-5N photobleach in one end of the cell, FRAP occurred, accompanied by fluorescence decline in the unbleached end with similar time constants (tau&2 minutes) until fluorescence regained spatial uniformity. Notably, SR and NucEn fluorescence recovered simultaneously in the bleached end. Ca(2+) diffusion inside the SR-NucEn was also measured. SR Ca(2+)-ATPase was completely blocked but without acute SR Ca(2+) depletion. Then caffeine was applied locally to one end of the myocyte. In the caffeine-exposed end, free SR [Ca(2+)] ([Ca(2+)](SR)) declined abruptly and recovered partially (tau=20 to 30 seconds). In the noncaffeine end, [Ca(2+)](SR) gradually declined with a similar tau, until [Ca(2+)](SR) throughout the cell equalized. We conclude that the SR and NucEn lumen are extensively interconnected throughout the myocyte. Apparent intrastore diffusion coefficients of Fluo-5N and Ca(2+) were estimated (&8 microm(2) sec(-1) and 60 microm(2) sec(-1)). This rapid luminal communication may maintain homogeneously high luminal [Ca(2+)], ensuring a robust and uniform driving force for local Ca(2+) release events from either SR or NucEn.
Ischemia Modified Albumin Is a Sensitive Marker of Myocardial Ischemia After Percutaneous Coronary Intervention
Authors: Manas K. Sinha, David C. Gaze, John R. Tippins, Paul O. Collinson, Juan Carlos Kaski
Journal: Circulation (2003)

Background— Ischemia modified albumin (IMA; Ischemia Technologies, Inc) blood levels rise in patients who develop ischemia during percutaneous coronary intervention (PCI). It is not known whether IMA elevations correlate with increases in other markers of oxidative stress, ie, 8-iso prostaglandin F2-A (iP). Methods and Results— We compared IMA versus iP plasma levels in 19 patients (mean age 62.8±11.9 years) undergoing PCI and 11 patients (mean age 64±13.6 years) undergoing diagnostic angiography (controls). In the PCI patients, blood samples for IMA and iP were taken from the guide catheter before PCI and after balloon inflations, and from the femoral sheath 30 minutes after PCI. IMA was measured by the albumin cobalt binding (ACB) test and plasma iP by enzyme immunoassay. During PCI, all 19 patients had chest pain and 18 had transient ischemic ST segment changes. IMA was elevated from baseline in 18 of the 19 patients after PCI. Median IMA levels were higher after PCI (101.4 U/mL, 95%CI 82 to 116) compared with baseline (72.8 U/mL, CI 55 to 93; P &lt;0.0001). Levels remained elevated at 30 minutes (87.9 U/mL, CI 78 to 99; P &lt;0.0001) and returned to baseline at 12 hours (70.3 U/mL, CI 65 to 87; P =0.65). iP levels were raised after PCI in 9 of the 19 patients. However, median iP levels were not significantly different immediately ( P =0.6) or 30 minutes after PCI ( P =0.1). In the control group, IMA and iP levels remained unchanged before and after angiography ( P =0.2 and 0.16, respectively). Conclusions— IMA is a more consistent marker of ischemia than iP in patients who develop chest pain and ST segment changes during PCI.
Hair Metabolomics: Identification of Fetal Compromise Provides Proof of Concept for Biomarker Discovery
Authors: Karolina Sulek, Ting-Li Han, Silas Granato Villas-Boas, David Scott Wishart, Shu-E Soh, Kenneth Kwek, Peter David Gluckman, Yap-Seng Chong, Louise Claire Kenny, Philip Newton Baker
Journal: Theranostics (2014)

Analysis of the human metabolome has yielded valuable insights into health, disease and toxicity. However, the metabolic profile of complex biological fluids such as blood is highly dynamic and this has limited the discovery of robust biomarkers. Hair grows relatively slowly, and both endogenous compounds and environmental exposures are incorporated from blood into hair during growth, which reflects the average chemical composition over several months. We used hair samples to study the metabolite profiles of women with pregnancies complicated by fetal growth restriction (FGR) and healthy matched controls. We report the use of GC-MS metabolite profiling of hair samples for biomarker discovery. Unsupervised statistical analysis showed complete discrimination of FGR from controls based on hair composition alone. A predictive model combining 5 metabolites produced an area under the receiver-operating curve of 0.998. This is the first study of the metabolome of human hair and demonstrates that this biological material contains robust biomarkers, which may lead to the development of a sensitive diagnostic tool for FGR, and perhaps more importantly, to stable biomarkers for a range of other diseases.
Molecular profiling of cytomegalovirus-induced human CD8+ T cell differentiation
Authors: Kirsten M.L. Hertoghs, Perry D. Moerland, Amber van Stijn, Ester B.M. Remmerswaal, Sila L. Yong, Pablo J.E.J. van de Berg, S. Marieke van Ham, Frank Baas, Ineke J.M. ten Berge, René A.W. van Lier
Journal: Journal of Clinical Investigation (2010)

CD8+ T cells play a critical role in the immune response to viral pathogens. Persistent human cytomegalovirus (HCMV) infection results in a strong increase in the number of virus-specific, quiescent effector-type CD8+ T cells with constitutive cytolytic activity, but the molecular pathways involved in the induction and maintenance of these cells are unknown. We show here that HCMV infection induced acute and lasting changes in the transcriptomes of virus-reactive T cells collected from HCMV-seropositive patients at distinct stages of infection. Enhanced cell cycle and metabolic activity was restricted to the acute phase of the response, but at all stages, HCMV-specific CD8+ T cells expressed the Th1-associated transcription factors T-bet (TBX21) and eomesodermin (EOMES), in parallel with continuous expression of IFNG mRNA and IFN-γ–regulated genes. The cytolytic proteins granzyme B and perforin as well as the fractalkine-binding chemokine receptor CX3CR1 were found in virus-reactive cells throughout the response. During HCMV latency, virus-specific CD8+ T cells lacked the typical features of exhausted cells found in other chronic infections. Persistent effector cell traits together with the permanent changes in chemokine receptor usage of virus-specific, nonexhausted, long-lived CD8+ T cells may be crucial to maintain lifelong protection from HCMV reactivation.
Use and Abuse of Glucose Reflectance Meters
Authors: Vivienne M Mountier, Russell S Scott, Donald W Beaven
Journal: Diabetes Care (1982)

All diabetic patients who had been using home glucose monitoring devices during the last 2 yr in the area served by the specialist Diabetes Unit in Christchurch, New Zealand were invited to complete a questionnaire designed to provide information on glycemic control, treatment regimen, and patterns of glucose recording. Questionnaires were completed by 111 of 152 patients, of whom 99% were using insulin. The period of use of reflectance meters was between 1 and 18 mo. Forty-three percent used their meters in a manner considered unsatisfactory and 15% failed to write down results. Those patients recording for the longest periods showed a significant trend to more inefficient use of devices. Forty-four percent still relied on their medical supervisor for treatment changes, but most attended infrequently (mode 12 wk; range 1-52 wk). Most frequently, treatment changes were to insulin dose and only one-third had adopted more "physiologic" regimens incorporating rapid-acting insulin. Blood glucose control was not significantly changed from that found in a group of diabetic subjects during the first weeks of monitoring. These results suggest that (1) many patients do not use home glucose monitoring devices in a manner likely to allow rational modification to therapy, (2) neither patients nor family physicians have reacted appropriately to high recorded values, and (3) chronic use of home monitoring has not resulted in good glycemic control for many patients.
The influence of Tigason' (Ro 10–9359) on the serum lipoproteins in man
Authors: G. MICHAELSSON, A. BERGQVIST, A. VAHLQUIST, B. VESSBY
Journal: British Journal of Dermatology (1981)

Eight patients with psoriasis or Darier's disease were studied during 1–3 months of‘Tigason’ treatment (O.7–O.8 mg/kg body weight). The levels of triglycerides and cholesterol in whole serum and in different lipoprotein fractions were repeatedly determined. Before treatment all lipid values were within the normal range. During treatment the values changed gradually and five of the eight patients developed pathological VLDL triglyceride concentrations. A significant increase of VLDL cholesterol and a decrease in the HDL cholesterol was also noted. Until more information is available, prolonged treatment periods with‘Tigason’ should perhaps be avoided, at least in high risk patients.
Protozoa in respiratory pathology: a review
Authors: R. Martinez-Giron, J. G. Esteban, A. Ribas, L. Doganci
Journal: European Respiratory Journal (2008)

Among the micro-organisms that may affect the respiratory apparatus are the protozoa. The diseases they may give rise to constitute a relatively uncommon group of respiratory ailments with, in the majority of cases, an underlying clinical situation corresponding to states of suppressed immunity (AIDS, transplants, malign haemopathies, corticotherapy,<i> etc</i>.). Other factors, such as visits to endemic areas and immigration, also have to be taken into account. In view of the probable increase in the number of cases and the appearance of new emerging diseases, it is the intention of the present work to review the publications available, in different fields of medicine, that refer to the principal kinds of protozoa (Entamoeba, Acanthamoeba, Balamuthia, Leishmania, Trypanosoma, Trichomonas, Lophomonas, Cryptosporidium, Cyclospora, Toxoplasma, Plasmodium, Babesia, Encephalitozoon, Enterocytozoon and Balantidium) and, at the same time, detail and comment on the latest findings on this subject.
Elevation of plasma epinephrine concentrations inhibits proteolysis and leucine oxidation in man via beta-adrenergic mechanisms.
Authors: M E Kraenzlin, U Keller, A Keller, A Thélin, M J Arnaud, W Stauffacher
Journal: Journal of Clinical Investigation (1989)

The role of elevated plasma epinephrine concentrations in the regulation of plasma leucine kinetics and the contribution of beta-receptors were assessed in man. Epinephrine (50 ng/kg per min) was infused either alone or combined with propranolol (beta-blockade) into groups of six subjects fasted overnight; leucine flux, oxidation, and net plasma leucine forearm balance were determined during 180 min. Constant plasma insulin and glucagon concentrations were maintained in all studies by infusing somatostatin combined with insulin and glucagon replacements. Plasma leucine concentrations decreased from baseline during epinephrine infusion by 27 +/- 5 mumol/liter (P less than 0.02) due to a 22 +/- 6% decrease in leucine flux (P less than 0.05 vs. controls receiving saline) and to an increase in the metabolic clearance rate of leucine (P less than 0.02). Leucine oxidation decreased by 36 +/- 8% (P less than 0.01 vs. controls). beta-Blockade abolished the effect of epinephrine on leucine flux and oxidation. Net forearm release of leucine increased during epinephrine (P less than 0.01), suggesting increased muscle proteolysis; the fall of total body leucine flux was therefore due to diminished proteolysis in nonmuscle tissues, such as splanchnic organs. Nonoxidative leucine disappearance as a parameter of protein synthesis was not significantly influenced by epinephrine. Plasma glucose and FFA concentrations increased via beta-adrenergic mechanisms (P less than 0.001). The results suggest that elevation of plasma epinephrine concentrations similar to those observed in severe stress results in redistribution of body proteins and exerts a whole body protein-sparing effect; this may counteract catabolic effects of other hormones during severe stress.
Interleukin-10 and the Interleukin-10 Receptor
Authors: Kevin W. Moore, Rene de Waal Malefyt, Robert L. Coffman, Anne O'Garra
Journal: Annual Review of Immunology (2001)

Interleukin-10 (IL-10), first recognized for its ability to inhibit activation and effector function of T cells, monocytes, and macrophages, is a multifunctional cytokine with diverse effects on most hemopoietic cell types. The principal routine function of IL-10 appears to be to limit and ultimately terminate inflammatory responses. In addition to these activities, IL-10 regulates growth and/or differentiation of B cells, NK cells, cytotoxic and helper T cells, mast cells, granulocytes, dendritic cells, keratinocytes, and endothelial cells. IL-10 plays a key role in differentiation and function of a newly appreciated type of T cell, the T regulatory cell, which may figure prominently in control of immune responses and tolerance in vivo. Uniquely among hemopoietic cytokines, IL-10 has closely related homologs in several virus genomes, which testify to its crucial role in regulating immune and inflammatory responses. This review highlights findings that have advanced our understanding of IL-10 and its receptor, as well as its in vivo function in health and disease.