tbuckley/cabot-search huggingface dataset:
THE ELABORATION OF SPECIFIC SOLUBLE SUBSTANCE BY PNEUMOCOCCUS DURING GROWTH
Authors: A. R. Dochez, O. T. Avery
Journal: The Journal of Experimental Medicine (1917)

1. A specifically reacting substance of bacterial origin is present in the cell-free fluids of young cultures of pneumococcus. This substance is present when the organisms are growing at their maximum rate and undergoing little or no cell death, and consequently its. presence is not dependent upon cell disintegration but represents the extrusion of bacterial substance by the living organism. 2. The blood and urine of rabbits experimentally infected with pneumococcus contain a similar specific soluble substance during the early hours of the infectious process. 3. Human beings suffering from lobar pneumonia have in their blood and more frequently in their urine a specific soluble substance of pneumococcus origin. The amount of this substance present in the urine varies in different individuals and the presence of a large amount is of unfavorable prognostic import. This specific precipitin reaction in the urine is of diagnostic value. 4. Rabbits injected with soluble pneumococcus material continue to excrete this substance for a considerable period of time. 5. The specifically soluble substance obtained from bacterial cultures and from the urine during infection is not destroyed by boiling, by precipitation with alcohol, acetone, or ether, or by trypsin digestion. 6. Studies are in progress at this time on the degree of toxicity and on the antigenic properties of the substance.
Antioxidant activity in bronchoalveolar lavage fluid from patients with lung cancer.
Authors: B Melloni, M A Lefebvre, F Bonnaud, A Vergnenègre, L Grossin, M Rigaud, A Cantin
Journal: American Journal of Respiratory and Critical Care Medicine (1996)

Glutathione (GSH) is one of the key components of the lung antioxidant defenses. Chronic smokers have higher GSH concentrations in their epithelial lining fluid than do nonsmokers. The aim of this study was to compare antioxidant concentrations in epithelial lining fluid (ELF) from nonsmokers, smokers with, and smokers without non-small-cell lung cancer. The study found that GSH in ELF from patients with lung cancer was significantly greater than in ELF from smokers and nonsmokers, at 1,485.5 +/- 208, 544 +/- 97.6 microM, and 339.3 +/- 112 microM, respectively (p < 0.05). In contrast, superoxide dismutase (SOD) was lower in ELF from patients with lung cancer than in that from smokers and nonsmokers, at 3.52 +/- 0.99, 30.82 +/- 8.2, and 43.91 +/- 10.1 U/ml, respectively (p < 0.05). Spontaneous superoxide anion release by adherent alveolar macrophages (AM) showed no difference between smokers with and without lung cancer. These data indicate that patients with lung cancer have marked modifications in their ELF antioxidant defenses by comparison with those of smokers. It is difficult to distinguish whether changed antioxidant status is a primary disturbance involved in the cancer process or whether it is a consequence of the neoplastic changes in malignancy.
Psychosocial Group Intervention and the Rate of Decline of Immunological Parameters in Asymptomatic HIV-lnfected Homosexual Men
Authors: C.L. Mulder, M.H. Antoni, P.M.G. Emmelkamp, P.J. Veugelers, T.G.M. Sandfort, F.A.J.R. van de Vijver, M.J.J. de Vries
Journal: Psychotherapy and Psychosomatics (1995)

The aim of the study was to determine changes in the rate of decline of immunological parameters after psychosocial group intervention. Subjects were 26 asymptomatic HIV-infected homosexual men who participated in a cognitive-behavioral group therapy (CBT; n = 14), or an experiential group therapy program (ET; n = 12), both of 15 weeks duration. The outcome measures were changes in the decline of CD4 cell counts, and T cell proliferative responses to anti-CD 3 monoclonal antibodies from preintervention to 24 months postintervention. No differences in the rate of decline of CD4 cells or T cell responses between the CBT and ET condition were found, and there were no significant changes in CD4 cell count from pre-to postintervention. However, those subjects who showed larger decreases in distress showed a smaller decline in CD4 cell counts. While the rate of decline in T cell responses was significantly less after both interventions, a similar positive change in T cell responses was found in a comparison group of 149 HIV-infected men with similar demographic, psychosocial and immunological characteristics who did not participate in one of the interventions. We conclude that the psychosocial intervention programs tested here did not cause changes in CD4 cell decline or T cell responses and that decreases in distress were related to increases in CD4 cell counts.
Virus-Directed Enzyme Prodrug Therapy: Intratumoral Administration of a Replication-Deficient Adenovirus Encoding Nitroreductase to Patients With Resectable Liver Cancer
Authors: Daniel H. Palmer, Vivien Mautner, Darius Mirza, Simon Oliff, Winald Gerritsen, Joost R.M. van der Sijp, Stefan Hubscher, Gary Reynolds, Sarah Bonney, Ratna Rajaratnam, Diana Hull, Mark Horne, John Ellis, Andrew Mountain, Simon Hill, Peter A. Harris, Peter F. Searle, Lawrence S. Young, Nicholas D. James, David J. Kerr
Journal: Journal of Clinical Oncology (2004)

Purpose Virus-directed enzyme prodrug therapy depends on selective delivery of virus encoding a prodrug-activating enzyme to tumor, followed by systemic treatment with prodrug to achieve high levels of the activated cytotoxic at the intended site of action. The use of the bacterial enzyme nitroreductase to activate CB1954 (5-(aziridin-1-yl)-2,4-dinitrobenzamide) to a short lived, highly toxic DNA cross-linking agent has been demonstrated in tumor xenografts. In this study, we report the first clinical trial investigating the feasibility, safety, and transgene expression of a replication-defective adenovirus encoding nitroreductase (CTL102) in patients with liver tumors. Patients and Methods Patients with resectable primary or secondary (colorectal) liver cancer received a single dose of CTL102 delivered by direct intratumoral inoculation 3 to 8 days before surgical resection. Results Eighteen patients were treated with escalating doses of CTL102 (range, 10 8 –5 × 10 11 virus particles). The vector was well tolerated with minimal side effects, had a short half-life in the circulation, and stimulated a robust antibody response. Dose-related increases in tumoral nitroreductase expression measured by immunohistochemical analysis have been observed. Conclusion Direct intratumoral inoculation of CTL102 to patients with primary and secondary liver cancer is feasible and well tolerated. The high level of nitroreductase expression observed at 1 to 5 × 10 11 virus particles mandates further studies in patients with inoperable tumors who will receive CTL102 and CB1954.
Multiple In Vitro Mechanisms of Tumor Cytotoxicity Demonstrated in the Line-l Guinea Pig Hepatoma Model 2
Authors: Robert T. Osteen, Willy F. Piessens, John R. David, W. Hallowell Churchill
Journal: JNCI Journal of the National Cancer Institute (1975)

The line-I guinea pig hepatoma was used to study in vitro tumor cytotoxicity. Cytotoxicity was determined by measurement of the loss of tritiated thymidine-labeled target cells from culture vessels. With this technique, we demonstrated that significant tumor cytotoxicity was caused by lymphoid cells from tumor-immune guinea pigs, by cells from guinea pigs immunized against an antigen unrelated to the tumor target, and by cell-free supernatants rich in lymphocyte mediators. Addition of normal peritoneal exudate cells enhanced the cytotoxic potential of a small number of highly purified immune lymphocytes, which suggested that recruitment of normal cells is an additional mechanism of tumor cell death in this system.
Lung Cancer Risk Prediction: Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial Models and Validation
Authors: C. Martin Tammemagi, Paul F. Pinsky, Neil E. Caporaso, Paul A. Kvale, William G. Hocking, Timothy R. Church, Thomas L. Riley, John Commins, Martin M. Oken, Christine D. Berg, Philip C. Prorok
Journal: JNCI Journal of the National Cancer Institute (2011)

Identification of individuals at high risk for lung cancer should be of value to individuals, patients, clinicians, and researchers. Existing prediction models have only modest capabilities to classify persons at risk accurately. Prospective data from 70 962 control subjects in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) were used in models for the general population (model 1) and for a subcohort of ever-smokers (N = 38 254) (model 2). Both models included age, socioeconomic status (education), body mass index, family history of lung cancer, chronic obstructive pulmonary disease, recent chest x-ray, smoking status (never, former, or current), pack-years smoked, and smoking duration. Model 2 also included smoking quit-time (time in years since ever-smokers permanently quit smoking). External validation was performed with 44 223 PLCO intervention arm participants who completed a supplemental questionnaire and were subsequently followed. Known available risk factors were included in logistic regression models. Bootstrap optimism-corrected estimates of predictive performance were calculated (internal validation). Nonlinear relationships for age, pack-years smoked, smoking duration, and quit-time were modeled using restricted cubic splines. All reported P values are two-sided. During follow-up (median 9.2 years) of the control arm subjects, 1040 lung cancers occurred. During follow-up of the external validation sample (median 3.0 years), 213 lung cancers occurred. For models 1 and 2, bootstrap optimism-corrected receiver operator characteristic area under the curves were 0.857 and 0.805, and calibration slopes (model-predicted probabilities vs observed probabilities) were 0.987 and 0.979, respectively. In the external validation sample, models 1 and 2 had area under the curves of 0.841 and 0.784, respectively. These models had high discrimination in women, men, whites, and nonwhites. The PLCO lung cancer risk models demonstrate high discrimination and calibration.
Levetiracetam and pregabalin for antiepileptic monotherapy in patients with primary brain tumors. A phase II randomized study
Authors: A. O. Rossetti, S. Jeckelmann, J. Novy, P. Roth, M. Weller, R. Stupp
Journal: Neuro-Oncology (2013)

In patients with brain tumors, the choice of antiepileptic medication is guided by tolerability and pharmacokinetic interactions. This study investigated the effectiveness of levetiracetam (LEV) and pregabalin (PGB), 2 non-enzyme-inducing agents, in this setting. In this pragmatic, randomized, unblinded phase II trial (NCT00629889), patients with primary brain tumors and epilepsy were titrated to a monotherapy of LEV or PGB. Efficacy and tolerability were assessed using structured questionnaires. The primary composite endpoint was the need to discontinue the study drug, add-on of a further antiepileptic treatment, or occurrence of at least 2 seizures with impaired consciousness during 1 year follow-up. Over 40 months, 25 patients were randomized to LEV, and 27 to PGB. Most were middle-aged men, with a high-grade tumor and at least one generalized convulsion. Mean daily doses were 1125 mg (LEV) and 294 mg (PGB). Retention rates were 59% in the LEV group, and 41% in the PGB group. The composite endpoint was reached in 9 LEV and 12 PGB patients—need to discontinue: side effects, 6 LEV, 3 PGB; lack of efficacy, 1 and 2; impaired oral administration, 0 and 2; add-on of another agent: 1 LEV, 4 PGB; and seizures impairing consciousness: 1 in each. Seven LEV and 5 PGB subjects died of tumor progression. This study shows that LEV and PGB represent valuable monotherapy options in this setting, with very good antiepileptic efficacy and an acceptable tolerability profile, and provides important data for the design of a phase III trial.
NHS reforms could "sabotage" the UK's trend of improved health outcomes, MPs hear
Authors: A. O'Dowd
Journal: BMJ (2011)

The upward trend of improved health outcomes being enjoyed in the UK could be reversed by the NHS reforms, MPs have been told.

Witnesses appearing before MPs on the parliamentary health select committee on 15 March were doubtful that the reforms being proposed under the Health and Social Care Bill would help boost outcomes or make any difference.

As part of their inquiry into commissioning, the MPs referred to the fact that the UK now has the best cardiac surgery outcomes data in Europe and arguably in the world.

This, however, seemed to conflict with what health secretary Andrew Lansley was saying about how the NHS was failing in outcomes in many areas in …
Lack of angiotensin II–facilitated erythropoiesis causes anemia in angiotensin-converting enzyme–deficient mice
Authors: Justin Cole, Dilek Ertoy, Hsinchen Lin, Roy L. Sutliff, Eric Ezan, Tham T. Guyene, Mario Capecchi, Pierre Corvol, Kenneth E. Bernstein
Journal: Journal of Clinical Investigation (2000)

While nephrologists often observe reduced hematocrit associated with inhibitors of angiotensin-converting enzyme (ACE), the basis for this effect is not well understood. We now report that two strains of ACE knockout mice have a normocytic anemia associated with elevated plasma erythropoietin levels. 51Cr labeling of red cells showed that the knockout mice have a normal total blood volume but a reduced red cell mass. ACE knockout mice, which lack tissue ACE, are anemic despite having normal renal function. These mice have increased plasma levels of the peptide acetyl-SDKP, a possible stem cell suppressor. However, they also show low plasma levels of angiotensin II. Infusion of angiotensin II for 2 weeks increased hematocrit to near normal levels. These data suggest that angiotensin II facilitates erythropoiesis, a conclusion with implications for the management of chronically ill patients on inhibitors of the renin-angiotensin system.
Gene Duplication and Loss in a MADS Box Gene Transcription Factor Circuit
Authors: Hae-Lim Lee, Vivian F. Irish
Journal: Molecular Biology and Evolution (2011)

Although many models have been proposed that could lead to the maintenance of gene duplicates, the ways in which interacting gene duplicates influence each other's evolution and function remain poorly understood. Here, we focus on duplication and loss of the B class MADS box transcription factor genes in the euasterids I and the ramifications of such changes on paralog evolution and their encoded functions. In core eudicots, the B class genes belong to two paralogous lineages whose products form obligate heterodimers. Based on comparative genomic and phylogenetic analyses, we show that five stepwise B class MADS box gene gain or loss events occurred during the radiation of the euasterids I within core eudicots. Gene loss in one sublineage was correlated with a deficit of other sublineage genes. We also show that the gain or loss of B class MADS box gene paralogs were associated with altered protein-protein interactions among the remaining copies. These altered protein interactions were correlated with asymmetric patterns of sequence diversification and selection, suggesting that compensatory changes were driving the evolution of such genes. Furthermore, these B class MADS box gene gain or loss events were associated with the evolutionary divergence of floral morphology in the euasterids I. Together, these observations point to a cooperative strategy by which gene networks evolve, with selection maintaining the overall logic of a network despite changes in individual components.
Identification of Patients with (Atypical) <i>MUTYH</i>-Associated Polyposis by <i>KRAS2</i> c.34G &amp;gt; T Prescreening Followed by <i>MUTYH</i> Hotspot Analysis in Formalin-Fixed Paraffin-Embedded Tissue
Authors: Marjo van Puijenbroek, Maartje Nielsen, Carli M.J. Tops, Hans Halfwerk, Hans F.A. Vasen, Marjan M. Weiss, Tom van Wezel, Frederik J. Hes, Hans Morreau
Journal: Clinical Cancer Research (2008)

Abstract Purpose: To assess the feasibility of identifying patients with (atypical) MUTYH-associated polyposis (MAP) by KRAS2 c.34G &amp;gt; T prescreening followed by MUTYH hotspot mutation analysis in formalin-fixed paraffin-embedded tissue (FFPE). Methods: We collected 210 colorectal FFPE tumors from 192 individuals who presented with &amp;lt;10 adenomas or familial mismatch repair proficient colorectal carcinomas with &amp;lt;10 concomitant adenomas. The tissues were tested for somatic KRAS2 mutations and for three Dutch hotspot MUTYH germ line mutations (p.Tyr165Cys, p.Gly382Asp, and p.Pro391Leu) by sequencing analysis. Results: The c.34G &amp;gt; T, KRAS2 transversion was detected in 10 of 210 tumors. In one of these 10 cases, a monoallelic p.Gly382Asp MUTYH mutation was found and a full MUTYH analysis in leukocyte DNA revealed an unclassified variant p.Met269Val. This was in a 61-year-old patient with a cecum carcinoma and three adenomas. After further requests, her family case history revealed that her brother had had between 10 and 15 adenomas and turned out to carry both MUTYH germ line mutations. MUTYH hotspot mutation screening in 182 patients without the somatic c.34G &amp;gt; T KRAS2 mutation led to the detection of three monoallelic germ line MUTYH mutation carriers. Conclusion: KRAS2 c.34G &amp;gt; T somatic prescreening, followed by MUTYH hotspot mutation analysis when positive, can identify patients with (atypical) MAP. If heterozygous hotspot MUTYH mutations are identified, a complete germ line MUTYH mutation screening should be carried out if possible. Immediate MUTYH hotspot mutation analysis is a practical alternative in patients with &amp;gt;10 adenomas or in cases of multiple colorectal carcinomas in one generation for which only FFPE tissue is available.
RETRACTED: Valsartan in a Japanese population with hypertension and other cardiovascular disease (Jikei Heart Study): a randomised, open-label, blinded endpoint morbidity-mortality study
Authors: Seibu Mochizuki, Björn Dahlöf, Mitsuyuki Shimizu, Katsunori Ikewaki, Makoto Yoshikawa, Ikuo Taniguchi, Makoto Ohta, Taku Yamada, Kazuhiko Ogawa, Kiyoshi Kanae, Makoto Kawai, Shingo Seki, Fumiko Okazaki, Masayuki Taniguchi, Satoru Yoshida, Naoko Tajima
Journal: The Lancet (2007)
Down-regulation of PPARgamma1 suppresses cell growth and induces apoptosis in MCF-7 breast cancer cells
Authors: Yekaterina Y Zaytseva, Xin Wang, R Chase Southard, Natalie K Wallis, Michael W Kilgore
Journal: Molecular Cancer (2008)

Abstract Background Peroxisome proliferator-activated receptor gamma (PPARγ) is a member of the nuclear hormone receptor superfamily and is highly expressed in many human tumors including breast cancer. PPARγ has been identified as a potential target for breast cancer therapy based on the fact that its activation by synthetic ligands affects the differentiation, proliferation, and apoptosis of cancer cells. However, the controversial nature of current studies and disappointing results from clinical trials raise questions about the contribution of PPARγ signaling in breast cancer development in the absence of stimulation by exogenous ligands. Recent reports from both in vitro and in vivo studies are inconsistent and suggest that endogenous activation of PPARγ plays a much more complex role in initiation and progression of cancer than previously thought. Results We have previously demonstrated that an increase in expression of PPARγ1 in MCF-7 breast cancer cells is driven by a tumor-specific promoter. Myc-associated zinc finger protein (MAZ) was identified as a transcriptional mediator of PPARγ1 expression in these cells. In this study, using RNA interference (RNAi) to inhibit PPARγ1 expression directly or via down-regulation of MAZ, we report for the first time that a decrease in PPARγ1 expression results in reduced cellular proliferation in MCF-7 breast cancer cells. Furthermore, we demonstrate that these changes in proliferation are associated with a significant decrease in cell transition from G 1 to the S phase. Using a dominant-negative mutant of PPARγ1, Δ462, we confirmed that PPARγ1 acts as a pro-survival factor and showed that this phenomenon is not limited to MCF-7 cells. Finally, we demonstrate that down-regulation of PPARγ1 expression leads to an induction of apoptosis in MCF-7 cells, confirmed by analyzing Bcl-2 expression and PARP-1 cleavage. Conclusion Thus, these findings suggest that an increase in PPARγ1 signaling observed in breast cancer contributes to an imbalance between proliferation and apoptosis, and may be an important hallmark of breast tumorigenesis. The results presented here also warrant further investigation regarding the use of PPARγ ligands in patients who are predisposed or already diagnosed with breast cancer.
Reciprocal Regulation of Hepatic and Adipose Lipogenesis by Liver X Receptors in Obesity and Insulin Resistance
Authors: Simon W. Beaven, Aleksey Matveyenko, Kevin Wroblewski, Lily Chao, Damien Wilpitz, Tu Wen Hsu, Jacob Lentz, Brian Drew, Andrea L. Hevener, Peter Tontonoz
Journal: Cell Metabolism (2013)
Phase I and Pharmacokinetic Study of Gimatecan Given Orally Once a Week for 3 of 4 Weeks in Patients with Advanced Solid Tumors
Authors: Andrew X. Zhu, Neal Ready, Jeffrey W. Clark, Howard Safran, Antonino Amato, Nadia Salem, Silvia Pace, Xiaoying He, Nela Zvereva, Thomas J. Lynch, David P. Ryan, Jeffrey G. Supko
Journal: Clinical Cancer Research (2008)

Abstract Purpose: A phase I study was conducted to determine the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) of gimatecan, a lipophilic camptothecin analogue, administered orally once a week for 3 weeks. Experimental Design: Adult patients with advanced solid tumors with good performance status and adequate hematologic, hepatic, and renal function were eligible for the study. The plasma pharmacokinetics of the drug was characterized during the initial 28-day cycle. Results: A total of 33 patients were evaluated at 7 dose levels ranging from 0.27 to 3.20 mg/m2/wk. Anemia, fatigue, neutropenia, nausea, and vomiting were the principal toxicities. DLTs experienced by 3 of 7 patients in dose level 7 (3.20 mg/m2) were grade 2 hyperbilirubinemia and grade 3 to 4 fatigue. DLT (anorexia and nausea) occurred in only 1 of 11 patients evaluated at the MTD of 2.40 mg/m2. There were no objective responses, although disease stabilization was observed in 4 patients. Gimatecan has a very long apparent biological half-life (mean ± SD, 77 ± 37 h) and exists in plasma almost entirely as the pharmacologically active intact lactone form. At the MTD, mean peak concentrations of the drug in plasma ranged from 67 to 82 ng/mL for the 3 weekly doses and the mean concentration 7 days after dosing was 15 ± 18 ng/mL. Conclusions: Administration of gimatecan orally once a week at doses that are well tolerated provides continuous exposure to potentially effective plasma concentrations of the biologically active form of the drug. This regimen deserves further evaluation to define its antitumor activity in specific tumor types either alone or in combination with other agents.