tbuckley/cabot-search huggingface dataset:
Cytokines in chronic inflammatory arthritis. I. Failure to detect T cell lymphokines (interleukin 2 and interleukin 3) and presence of macrophage colony-stimulating factor (CSF-1) and a novel mast cell growth factor in rheumatoid synovitis.
Authors: G S Firestein, W D Xu, K Townsend, D Broide, J Alvaro-Gracia, A Glasebrook, N J Zvaifler
Journal: The Journal of Experimental Medicine (1988)

Because previous studies showed low levels of IFN-gamma in rheumatoid arthritis (RA) synovial fluid (SF) and synovial tissue (ST) explant supernatants, we assayed RA SF and ST for IL-2 and IL-3-like activity. Using an IL-2 dependent murine CTLL line, 6 of 14 RA SF caused increased thymidine uptake (greater than three times control). The activity was distinct from IL-2 because it was not blocked by antibody to IL-2-R. In addition, IL-2 was not detected (less than 50 pg/ml) in 16 joint samples using an ELISA. Multi-colony-stimulating factor (CSF) activity was measured using two assays that can detect murine IL-3 (mast cell proliferation, and bone marrow CSF). In the mast cell assay, [3H]TdR uptake was 493 +/- 67 cpm for medium, 2,910 +/- 329 cpm in the presence of RA SF (p less than 0.001), 1,246 +/- 156 cpm in the presence of SF from patients with seronegative spondyloarthropathies (p less than 0.001), and 736 +/- 100 cpm in the presence of osteoarthritis SF (p greater than 0.1). In the CSF assay, four of five RA SF and five of five RA ST induced colony formation from bone marrow nonadherent cells. Macrophage colonies were most common, although mixed colonies and granulocytes were occasionally observed. The multi-CSF activity in RA is not due to IL-3 since human rIL-3 was not active in either murine assay, and IL-3 mRNA was not detected in RA synovium. Sephadex column chromatography of RA SF revealed that the mast cell growth factor (approximately 6 x 10(3) mol wt) and the CSF (approximately 40 and 100 x 10(3) mol wt) are distinct. The colony-stimulating aspect of the "IL-3-like" activity in RA SF is likely due to CSF-1 because it is the appropriate mol wt and because the activity was neutralized by specific anti-CSF-1 antibody. Finally, an RIA detected 1.6-25 ng/ml of CSF-1 in RA SF and ST and CSF-1 mRNA was detected in four of five RA synovial tissue samples tested.
Anaphylactic bronchospasm during general anesthesia is not related to asthma
Authors: A. Gouel-Chéron, C. Neukirch, B. Aubier, P. Montravers, P. Nicaise, S. Chollet-Martin, P.-M. Mertes, M. Aubier, D. Longrois
Journal: Allergy (2015)

In the general population, a history of asthma (HA) is associated with a higher risk of mortality of anaphylactic shock (AS), but it is unknown whether this association remains valid for intra-operative AS. The goal of this retrospective study was to investigate whether a HA was associated with a higher risk of bronchospasm during intra-operative AS. We analyzed 106 patients (January 2009-December 2012) with intra-operative AS: 57% of them had a confirmed IgE-mediated reaction and 27% had a HA. On logistic regression, the only factor statistically associated with bronchospasm was a neuromuscular blocking drug, with both IgE- or non-IgE-mediated reactions. These results suggest that the mechanisms of bronchospasm in AS may be different from those of asthma and that, in the presence of bronchospasm during anesthesia, AS should be considered to be the most likely cause.
Low-Molecular-Weight Cyclin E Can Bypass Letrozole-Induced G1 Arrest in Human Breast Cancer Cells and Tumors
Authors: Said Akli, Tuyen Bui, Hannah Wingate, Anna Biernacka, Stacy Moulder, Susan L. Tucker, Kelly K. Hunt, Khandan Keyomarsi
Journal: Clinical Cancer Research (2010)

Low-molecular-weight cyclin E (LMW-E) in breast cancer cells induces genomic instability and resistance to inhibition by p21, p27, and fulvestrant therapy. Here, we sought to determine if LMW-E renders breast cancer cells unresponsive to aromatase inhibitors (AI), elucidate the mechanism of such resistance, and ascertain if inhibitors of LMW-E-associated kinase activity could overcome this resistance.The antiproliferative effects of the AIs were examined in aromatase-overexpressing MCF-7/Ac1 cells in the presence or absence of full-length cyclin E and LMW-E. Inhibition of LMW cyclin E kinase activity by roscovitine [a cyclin-dependent kinase (CDK) inhibitor] was examined in letrozole-unresponsive MCF-7/Ac1 cells. The role of LMW-E and CDK2 in mediating recurrence following AI treatment was also assessed in breast cancer patients.Overexpression of LMW-E in postmenopausal patients was associated with a poor prognosis. Letrozole, but not exemestane or anastrozole, mediated a pronounced G(1) arrest in MCF-7/Ac1 cells. Androstenedione-induced G(1) exit correlated with increased cyclin E-associated kinase activity and increased CDK2 levels. Letrozole treatment inhibited cyclin E-CDK2 kinase activity by preventing the androstenedione-induced increase in CDK2. LMW-E bypassed this effect and rendered the cells resistant to letrozole inhibition. Roscovitine blocked the androstenedione-induced increase in CDK2, and LMW-E overexpression could not bypass this effect. Lastly, breast cancer patients whose tumors overexpress LMW-E were not responsive to AI treatment.Roscovitine treatment can reverse intrinsic or acquired resistance to letrozole due to LMW-E expression in breast cancer cells. These data support the clinical investigation of CDK2 inhibitor therapy for postmenopausal women with estrogen receptor-positive, LMW-E-expressing breast cancer.
Immunologic Stimuli in Relation to Leukemogenesis. II. Effect of Phytohemagglutinin on Rauscher Viral Leukemogenesis23
Authors: Benjamin V. Siegel, Jane I. Morton
Journal: JNCI Journal of the National Cancer Institute (1973)

A regimen of intraperitoneal (ip) injections in BALB/c mice of 0.5–0.8 mg phytohemagglutinin (PHA) was initiated 2 days before their ip inoculation with Rauscher leukemia virus (RLV) and continued thrice weekly for 8 weeks; this resulted in decreased splenomegaly and fewer deaths. In vitro incubation of PHA with RLV before ip injection prevented leukemia development; similar virus inactivation may have occurred in vivo. However, ip injection of PHA in conjunction with intravenous inoculation of RLV resulted in accelerated leukemogenesis (determined by augmented splenomegaly and viral focus formation) which suggested that PHA might function here to increase host populations of virus-susceptible target cells.
Coexpression of CD25 and CD27 identifies FoxP3+ regulatory T cells in inflamed synovia
Authors: Claudia R. Ruprecht, Marco Gattorno, Francesca Ferlito, Andrea Gregorio, Alberto Martini, Antonio Lanzavecchia, Federica Sallusto
Journal: The Journal of Experimental Medicine (2005)

A better understanding of the role of CD4+CD25+ regulatory T cells in disease pathogenesis should follow from the discovery of reliable markers capable of discriminating regulatory from activated T cells. We report that the CD4+CD25+ population in synovial fluid of juvenile idiopathic arthritis (JIA) patients comprises both regulatory and effector T cells that can be distinguished by expression of CD27. CD4+CD25+CD27+ cells expressed high amounts of FoxP3 (43% of them being FoxP3+), did not produce interleukin (IL)-2, interferon-γ, or tumor necrosis factor, and suppressed T cell proliferation in vitro, being, on a per cell basis, fourfold more potent than the corresponding peripheral blood population. In contrast, CD4+CD25+CD27− cells expressed low amounts of FoxP3, produced effector cytokines and did not suppress T cell proliferation. After in vitro activation and expansion, regulatory but not conventional T cells maintained high expression of CD27. IL-7 and IL-15 were found to be present in synovial fluid of JIA patients and, when added in vitro, abrogated the suppressive activity of regulatory T cells. Together, these results demonstrate that, when used in conjunction with CD25, CD27 is a useful marker to distinguish regulatory from effector T cells in inflamed tissues and suggest that at these sites IL-7 and IL-15 may interfere with regulatory T cell function.
Hepatitis B Virus Genotype and DNA Level and Hepatocellular Carcinoma: A Prospective Study in Men
Authors: Ming-Whei Yu, Shiou-Hwei Yeh, Pei-Jer Chen, Yun-Fan Liaw, Chih-Lin Lin, Chun-Jen Liu, Wei-Liang Shih, Jia-Horng Kao, Ding-Shinn Chen, Chien-Jen Chen
Journal: JNCI Journal of the National Cancer Institute (2005)

Although chronic infection with hepatitis B virus (HBV) has been established as a cause of hepatocellular carcinoma (HCC), the roles of viral load and HBV genotype remain unclear.From 1988 through 1992, baseline blood samples were collected from 4841 Taiwanese men who were HBV carriers but had not been diagnosed with HCC. We used real-time polymerase chain reaction assays of plasma DNA samples to quantify HBV DNA levels (a measure of viral load) and determine HBV genotypes for 154 case patients who were diagnosed with HCC during 14 years of follow-up and 316 control subjects. Unconditional logistic regression was used to assess odds ratios (ORs) of HCC for HBV-related factors. All statistical tests were two-sided.The risk of HCC increased with increasing HBV viral load (adjusted OR for the highest versus the lowest quintile of HBV DNA copies/mL = 7.26, 95% confidence interval [CI] = 3.54 to 14.89; P(trend)<.001). Genotype C HBV was associated with an increased risk of HCC compared with other HBV genotypes (adjusted OR = 5.11, 95% CI = 3.20 to 8.18). Both viral load and genotype were positively associated with HCC within 10-year age categories among subjects aged 30 years old to older than 60 years. Genotype C HBV was associated with increased viral load, and associations of HBV genotype and viral load with HCC risk were additive. The adjusted OR of HCC for those carrying genotype C HBV and with viral load in the highest quintile was 26.49 (95% CI = 10.41 to 67.42) compared with HBV carriers with other HBV genotypes and viral load in the lowest two quintiles.Measurements of HBV viral load and genotype may help to define which male HBV carriers aged 30 years or older are at high risk for HCC.
Phase I Dose-Escalation Study of the Pan-HER Inhibitor, PF299804, in Patients with Advanced Malignant Solid Tumors
Authors: Pasi A. Jänne, David S. Boss, D. Ross Camidge, Carolyn D. Britten, Jeffrey A. Engelman, Edward B. Garon, Feng Guo, Steven Wong, Jane Liang, Stephen Letrent, Robert Millham, Ian Taylor, S. Gail Eckhardt, Jan H.M. Schellens
Journal: Clinical Cancer Research (2011)

PF299804 is a potent, orally available, irreversible inhibitor of tyrosine kinase human epidermal growth factor receptors (HER) 1 (EGFR), HER2, and HER4. This first-in-human study investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of PF299804 in patients with advanced solid malignancies.PF299804 was administered once daily continuously (schedule A) and intermittently (schedule B). Dose escalation proceeded until intolerable toxicities occurred. Skin biopsies were taken predose and after 14 days of treatment to establish a pharmacokinetic/pharmacodynamic relationship. Tumor response was measured once every 2 cycles. Efficacy was correlated with tumor genotypes in non-small cell lung cancer (NSCLC) patients.121 patients were included (111 in schedule A, 10 in schedule B). The maximum tolerated dose (MTD) was 45 mg/d. Dose-limiting toxicities included stomatitis and skin toxicities. Most adverse events were mild and comprised skin toxicities, fatigue, and gastrointestinal side-effects including diarrhea, nausea, and vomiting. Pharmacokinetic analyses revealed dose-dependent increases in PF299804 exposure associated with target inhibition in skin biopsy samples. Fifty-seven patients with non-small cell lung cancer (NSCLC) were treated in this study. Four patients, all previously treated with gefitinib or erlotinib (2 with exon 19 deletions, 1 with exon 20 insertion, 1 mutational status unknown), had a partial response to PF299804.The MTD of PF299804 is 45 mg/d. Both continuous and intermittent treatment schedules were well tolerated, and encouraging signs of antitumor activity were observed in gefitinib/erlotinib treated NSCLC patients.
Antioncogenes and Human Cancer
Authors: David P. Carbone, John D. Minna
Journal: Annual Review of Medicine (1993)

Multiple genetic lesions are thought to transform a normal cell into a malignant one, and both dominant and recessive genetic effects have been identified in this process. Antioncogenes (or tumor suppressor genes) act in a recessive manner, in which both maternal and paternal alleles need to be inactivated to abrogate normal function. The identification of these lesions is giving us insight into the regulatory pathways in the cell and may translate into future improvements in prevention, diagnosis, prognosis, and therapy of human cancer.
Tips for Success As an Academic Clinical Investigator
Authors: Stephanie J. Lee
Journal: Journal of Clinical Oncology (2013)

DOI: 10.1200/JCO.2012.46.8751 When confronted with a new and challenging task, the first thing I have always done is to see how others have succeeded before me. Hearing and reading others’ reflections on their tips, tricks, and pearls has often given me helpful strategies, whether the topic is parenting, traveling, or having a successful career. In hearing the reflections of those who went before, I can benefit from their experiences without any commitment to follow their paths. The advice is free, and I can take what I want and leave the rest behind. So it is in this spirit that I decided to share what I tell aspiring young investigators if they seek my advice about how to achieve success as an academic clinical investigator. After writing down my initial thoughts, I shared the list with my colleagues, who provided many helpful additions and edits. I then circulated it to junior investigators, and the list continued to evolve. Clearly the generalizability of the strategies varies, and the list reflects the lens of my experience. I have been told by some young investigators that the list looks scary, but I wanted to be concrete about how discipline and hard work can enhance your chances for success in academic medicine. My hope is that people reading the list might find some new tactics that resonate with them or, at least, that it will provide a nidus for more discussion about what success as an academic clinical investigator means and how best to achieve it. This article is not about what someone else can do for you—that is mentorship. This article is about what you can do for yourself—the behaviors and skills that you can cultivate to increase your likelihood of success in academic medicine. Although everyone has a unique path that reflects his or her interests, skills, talents, and environment, effective habits can help you achieve your goals and be more successful in whatever career you choose. For fellows and junior faculty who spend less time engaged in research, protected time may be more limited, making focus and efficiency consequently even more critical. A number of benchmarks have been used to quantify success in academic medicine, including number of publications, grants, lectures, research collaborations, and leadership positions. These closely mirror the physician-scientist criteria for promotion, the academic track with which I am most familiar. For the purposes of this article, academic success is defined as a personal sense of accomplishment and external recognition by others in the areas noted. It does not cover many other sources of job satisfaction, including the physicianpatient relationship. Clinician-scholars are also judged on their clinical productivity, clinical reputation, and teaching skills. I have not seen any tips for success published for this academic track but hope to see this gap in the literature filled by someone else. The following tips are organized according to the major challenges for academic clinical investigators:
Acupuncture-Point Stimulation for Chemotherapy-Induced Nausea and Vomiting
Authors: Jeanette Ezzo, Andrew Vickers, Mary Ann Richardson, Claire Allen, Suzanne L. Dibble, Brian Issell, Lixing Lao, Michael Pearl, Gilbert Ramirez, Joseph A. Roscoe, Joannie Shen, Jane Shivnan, Konrad Streitberger, Imad Treish, Grant Zhang
Journal: Journal of Clinical Oncology (2005)

Purpose Assess the effectiveness of acupuncture-point stimulation on acute and delayed chemotherapy-induced nausea and vomiting in cancer patients. Materials and Methods Randomized trials of acupuncture-point stimulation by needles, electrical stimulation, magnets, or acupressure were retrieved. Data were provided by investigators of the original trials and pooled using a fixed-effects model. Results Eleven trials (N = 1,247) were pooled. Overall, acupuncture-point stimulation reduced the proportion of acute vomiting (relative risks [RR] = 0.82; 95% CI, 0.69 to 0.99; P = .04), but not the mean number of acute emetic episodes or acute or delayed nausea severity compared with controls. By modality, stimulation with needles reduced the proportion of acute vomiting (RR = 0.74; 95% CI, 0.58 to 0.94; P = .01), but not acute nausea severity. Electroacupuncture reduced the proportion of acute vomiting (RR = 0.76; 95% CI, 0.60 to 0.97; P = .02), but manual acupuncture did not; delayed symptoms were not reported. Acupressure reduced mean acute nausea severity (standardized mean difference = −0.19; 95% CI, −0.38 to −0.01; P = .03) and most severe acute nausea, but not acute vomiting or delayed symptoms. Noninvasive electrostimulation showed no benefit for any outcome. All trials used concomitant pharmacologic antiemetics, and all, except electroacupuncture trials, used state-of-the-art antiemetics. Conclusion This review complements data on postoperative nausea and vomiting, suggesting a biologic effect of acupuncture-point stimulation. Electroacupuncture has demonstrated benefit for chemotherapy-induced acute vomiting, but studies with state-of-the-art antiemetics as well as studies for refractory symptoms are needed to determine clinical relevance. Acupressure seems to reduce chemotherapy-induced acute nausea severity, though studies did not involve a placebo control. Noninvasive electrostimulation seems unlikely to have a clinically relevant impact when patients are given state-of-the-art pharmacologic antiemetic therapy.
Combination Treatment with TRA-8 Anti–Death Receptor 5 Antibody and CPT-11 Induces Tumor Regression in an Orthotopic Model of Pancreatic Cancer
Authors: Leo Christopher DeRosier, Donald J. Buchsbaum, Patsy G. Oliver, Zhi-Qiang Huang, Jeffrey C. Sellers, William E. Grizzle, Wenquan Wang, Tong Zhou, Kurt R. Zinn, Joshua W. Long, Selwyn M. Vickers
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Evaluate the response of human pancreatic cancer cell lines and orthotopic tumors to TRA-8, an agonistic antibody to death receptor 5, in combination with irinotecan (CPT-11). Experimental Design: MIA PaCa-2 and S2VP10 cells were treated with TRA-8 and/or CPT 11. Cell viability was determined by ATP assay. JC-1 mitochondrial depolarization and Annexin V assays confirmed cell death by apoptosis. Immunoblotting was used to evaluate protein changes. MIA PaCa-2 cells were injected into the pancreas of severe combined immunodeficient mice. Mice underwent abdominal ultrasound to quantitate tumor size before and after treatment with twice weekly injections of 200 μg TRA-8 and/or 25 mg/kg CPT-11 for one or two treatment cycles, each lasting 2 weeks. Results: MIA PaCa-2 cells were more sensitive to TRA-8 and showed additive cytotoxicity, whereas S2VP10 cells showed synergistic cytotoxicity when treated with TRA-8 and CPT-11. Cell death occurred via apoptosis with increased cleavage of caspase-3, caspase-8, and caspase-9 and proapoptotic proteins Bid and poly(ADP)ribose polymerase after combination treatment compared with either agent alone. XIAP and Bcl-XL inhibitors of apoptosis were down-regulated. After a single cycle of in vivo combination therapy, tumor sizes had diminished significantly (P &amp;lt; 0.001) at 8 days posttreatment compared with no treatment, CPT-11, and TRA-8; and there was a 50-day increase in survival with combination treatment over untreated controls (P = 0.0002), 30 days over TRA-8, and a 36-day increase over CPT-11 monotherapy (P = 0.0003). With two cycles of TRA-8/CPT-11 treatment, mean survival time increased significantly (P &amp;lt; 0.001) to 169 days versus untreated controls, TRA-8 or CPT-11 (76, 121, or 108 days, respectively). Conclusions: Combination TRA-8 and CPT-11 therapy produced enhanced cytotoxicity and survival in the MIA PaCa-2 orthotopic model of pancreatic cancer.
Left Ventricular Norepinephrine and Epinephrine Kinetics at Birth in Lambs
Authors: Joseph J. Smolich, Helen S. Cox, Philip J. Berger, Adrian M. Walker, Graeme Eisenhofer, Murray D. Esler
Journal: Circulation Research (1997)

Abstract Little is known about the changes in the left ventricular (LV) kinetics of the catecholamines norepinephrine and epinephrine occurring at birth and their relationship to perinatal alterations in LV function and whole-body catecholamine kinetics. To address this issue, whole-body and LV catecholamine kinetics (radiotracer dilution methodology) and fetal LV output and myocardial blood flow (radioactive microspheres) were measured in chronically instrumented near-term fetuses and in the same animals 1 and 4 hours after birth. Between fetal and 1-hour lambs, LV external work increased 115% ( P &lt;.005); carotid arterial plasma norepinephrine concentration, 148% ( P &lt;.01); carotid arterial plasma epinephrine concentration, 546% ( P &lt;.005); LV norepinephrine spillover, a measure of LV sympathetic activity, 4.1-fold ( P &lt;.005); LV epinephrine spillover, 3-fold ( P &lt;.05); total-body spillover of norepinephrine, 52% ( P &lt;.025); and total-body spillover of epinephrine, 460% ( P &lt;.005). Arterial catecholamine concentrations and total-body catecholamine spillovers were unchanged between 1- and 4-hour lambs, but LV external work fell ( P &lt;.05) to a level still 77% greater than in fetal lambs ( P &lt;.005); LV norepinephrine spillover returned to near-fetal levels, and LV epinephrine spillover became undetectable. These results suggest that (1) a transient increase in LV sympathetic activity occurs at birth and may contribute to the immediate postnatal augmentation of LV performance, (2) organ differences in the pattern of sympathetic activation occur at birth, and (3) birth-related increases in LV sympathetic activity are accompanied by release of epinephrine from the heart.
A Study of α1-Fetoprotein Levels during Exposure to 3′-Methyl-4-dimethylaminoazobenzene and Its Analogs
Authors: Frederick F. Becker, Allan A. Horland, Alan Shurgin, Stewart Sell
Journal: Cancer Research (1975)

The serum concentration of α1-fetoprotein (α1F) was determined in rats following exposure to the hepatocarcinogen, 3′-methyl-4-dimethylaminoazobenzene, and its analogs. Small quantities of the carcinogen caused a rapid and significant elevation of α1F. Neither 2-methyl-4-dimethylaminoazobenzene nor p -aminoazobenzene resulted in any elevation of α1F. Further, under circumstances wherein 2-methyl-4-dimethylaminoazobenzene is reported to become carcinogenic, i.e. , when administered at the time of 70% hepatectomy, neither elevation of α1F nor histological alteration of the liver was noted.

The increase in α1F after 3′-methyl-4-dimethylaminoazobenzene exposure is the result of a highly selective interaction. The possible contribution of hepatocyte mitosis to the elevation of α1F seen during chemical carcinogenesis is emphasized.