tbuckley/cabot-search huggingface dataset:
Histology as a potential clinical predictor of outcome in advanced non-small cell lung cancer (NSCLC) treated with vinorelbine and mitomycin (VM) combination chemotherapy
Authors: Thomas Wibmer, Thierry Berghmans, Cornelia Kropf, Jean-Jacques Lafitte, Kathrin M. Stoiber, Marianne Paesmans, Stefan Ruediger, Arnaud Scherpereel, Ioanna Blanta, Wolfgang Rottbauer, Jean-Paul Sculier, Christian Schumann
Journal: European Respiratory Journal (2012)

Introduction:  Histology has emerged has an important clinical predictive factor in patients with advanced NSCLC treated with chemotherapy.  Aims:  To analyze combined patient level-data from 2 phase II trials on efficacy and safety of VM in advanced or metastatic NSCLC, in order to determine if histology and other patient and disease characteristics including gender, smoking history and TTF-1 immunohistochemistry (IHC) might be potential clinical predictors of outcome.  Methods:  Response rates, unadjusted survival times and Cox covariate adjusted hazerd ratio estimates (HR) were calculated for each subgroup in each individual trial and in the pooled data set.  Results:  A total of 175 patients were included in this retrospective analysis. Adjusted HRs for both overall survival (OS) and progression free survival (PFS) consistently favored non-adenocarcinoma (non-AC) histology subgroups, achieving statistical significance for OS in the pooled data (n=175; HR 0.677; 95% CI 0.488-0.938; p=0.019) and within one of those two trials (n=65; HR 0.561; 95% CI 0.318-0.988; p=0.045). TTF-1 negative IHC was associated with non-significant favorable OS compared to TTF1 positive subgroup in the cox-adjusted analysis (n=33; HR 1.232; 95% CI 0.555-2.730; p=0.608) and showed a significantly higher response rate (25% vs. 0 %; p=0.040). Gender and smoking history were not strongly related to outcome.  Conclusions:  These results suggest that non-AC histology and TTF-1 negative IHC may be considered as potential predictors of favorable clinical outcome in the treatment with VM. This approach warrants further investiagtion in a phase III study.
Role of Administration Route in the Therapeutic Efficacy of Doxifluridine<xref ref-type="fn" rid="FN2">2</xref>
Authors: F Trave, L Canobbio, J L Au, Y M Rustum
Journal: JNCI Journal of the National Cancer Institute (1987)

Effect of drug administration route on the therapeutic efficacy of the 5-fluorouracil (FUra) analogue doxifluridine [(5'-dFUrd); 5'-deoxy-5-fluorouridine] was investigated in Fischer CDF rats bearing a chemically induced transplantable colon carcinoma sensitive to fluoropyrimidines. The antitumor activities of 5'-dFUrd and of its parent drug FUra were evaluated after 7 days of continuous administration (by iv infusion, iv push, or po route) of doses ranging from 125 to 750 mg 5'-dFUrd/kg/day and from 12.5 to 55 mg FUra/kg/day. At the maximally tolerated dose, 5'-dFUrd (500 mg/kg/day) and FUra (25-35 mg/kd/day) were equally effective in producing cures when treatments were performed by either continuous iv infusion or iv push. 5'-dFUrd was more effective than FUra when these agents were administered orally (82% cures for 5'-dFUrd vs. 30% cures for FUra). Concentrations of 5'-dFUrd and its metabolite FUra in the blood and urine of normal and tumor-bearing rats were determined by high-performance liquid chromatography following administration of 500 mg 5'-dFUrd/kg. Pharmacokinetic studies indicated that at comparable antitumor activity, systemic exposures to FUra derived from 500 mg 5'-dFUrd/kg administered by iv push, orally, or continuous iv infusion were 3.5 +/- 1.0, 3.2 +/- 1.1, and 1.5 +/- 0.3 mM X min, respectively. Antitumor activity and pharmacokinetic results obtained in this model system indicated that 5'-dFUrd is an active agent that can produce cures regardless of the route of administration employed and among the three methods of drug administration tested, comparable tumor-free survival can be achieved by continuous iv infusion of 5'-dFUrd with the concomitant lowest systemic exposure to the cytotoxic metabolite FUra.
General Practitioners’ Attitudes to Sexual Activity in Under-Sixteens
Authors: R Garside, R Ayres, M R Owen, V H Pearson, J Roizen
Journal: Journal of the Royal Society of Medicine (2000)

In the UK, under-sixteen-year-olds with some exceptions can be provided with contraceptive care even if unwilling to inform their parents. Nonetheless, many teenagers express doubts about confidentiality in these circumstances, as well as fear of being judged. The attitudes of general practitioners in North and East Devon towards the Gillick ruling regarding the treatment of under sixteens for sexual health matters were assessed. They were asked to indicate their level of agreement or disagreement with a series of statements. 235 (73%) responded, and only 15 (6.5%) rejected the notion that the same duty of confidentiality applies to under-sixteens as to older patients. 76% did, however, prefer parents to know they had been consulted about contraception. Only 7 GPs believed that provision of contraception encourages under-age sex. Despite GPs' general acknowledgment of the importance of confidentiality in relation to sexual activity, teenagers may well be discouraged from seeking advice if they expect strong pressure to tell their parents.
Acidic precursor revealed in human eosinophil granule major basic protein cDNA.
Authors: R L Barker, G J Gleich, L R Pease
Journal: The Journal of Experimental Medicine (1988)

Eosinophil granule major basic protein (MBP), a potent toxin for helminths and various cell types, is a 13.8-kD single polypeptide rich in arginine with a calculated isoelectric point (pI) of 10.9. A cDNA for human MBP was isolated from a gamma GT10 HL-60 cDNA library. The nucleotide sequence of the MBP cDNA indicates that MBP is translated as a 25.2-kD preproprotein. The 9.9-kD pro-portion of proMBP is rich in glutamic and aspartic acids and has a calculated pI of 3.9, while proMBP itself has a calculated pI of 6.2. We suggest that MBP is translated as a nontoxic precursor that protects the eosinophil from damage while the protein is processed through the endoplasmic reticulum to its sequestered site in the granule core toxic MBP, and we present results from the literature suggesting that other cationic toxins, which damage cell membranes, may also be processed from nontoxic precursors containing distinct anionic and cationic regions.
Epicutaneous Application of Toll‐like Receptor 7 Agonists Leads to Systemic Autoimmunity in Wild‐Type Mice: A New Model of Systemic Lupus Erythematosus
Authors: Maki Yokogawa, Mikiro Takaishi, Kimiko Nakajima, Reiko Kamijima, Chisa Fujimoto, Sayo Kataoka, Yoshio Terada, Shigetoshi Sano
Journal: Arthritis & Rheumatology (2013)

Objective To examine whether topical treatment of wild‐type mice with Toll‐like receptor 7 (TLR‐7) agonists leads to lupus‐like autoimmunity. Methods Wild‐type FVB/N, BALB/c, and C57BL/6 mice were treated with the topical TLR‐7 agonist imiquimod or R848 administered to the ear 3 times weekly. During treatment, the mice were monitored for serum autoantibody and creatinine levels as well as histopathology of the kidneys, spleens, livers, hearts, and skin. Immunologic abnormalities were analyzed by immunohistochemistry, quantitative reverse transcription–polymerase chain reaction, and fluorescence‐activated cell sorting. The role of plasmacytoid dendritic cells (PDCs) in the development of autoimmune disease was validated by in vivo treatment with an anti‐PDC antibody. Diseased mice underwent ultraviolet B irradiation, to evaluate skin photosensitivity. The disease‐causing effect of topical application of imiquimod was compared with that of systemic (intraperitoneal) administration. TLR‐7– and TLR‐9–deficient mice were used to validate the role of TLR‐7. Results Wild‐type mice of different genetic backgrounds developed systemic autoimmune disease following 4 weeks of topical treatment with imiquimod or R848, with elevated levels of autoantibodies to double‐stranded DNA and multiple organ involvement, including glomerulonephritis, hepatitis, carditis, and photosensitivity. Expression of Ifna and Mx1 , the interferon‐α–stimulated gene, was up‐regulated in the organs of imiquimod‐treated mice. However, disease caused by intraperitoneal injection of imiquimod was less severe than that induced by topical application. In vivo depletion of PDCs by a specific antibody protected mice against the autoimmunity induced by topical administration of imiquimod, suggesting a role of PDCs. Furthermore, TLR‐7–deficient mice, but not TLR‐9–deficient mice, were protected against autoimmunity. Conclusion This protocol provides a novel model of inducible systemic lupus erythematosus in wild‐type mice and underscores the skin as the primary organ that allows TLR‐7 agonists to induce SLE.
Differential Response of Malignant BALB/c Mammary Epithelial Cells to the Multiplication-Stimulating Activity of Insulin2
Authors: Bruce A. Voyles, Charles M. McGrath
Journal: JNCI Journal of the National Cancer Institute (1979)

Investigations were done to distinguish normal from malignant BALB/c mammary epithelial cells by growth differences. In a high concentration (15%) of serum, normal epithelial cells (from mice at midterm of first pregnancy) and malignant BALB/c mammary epithelial cells in primary culture divided at the same rate (doubling time = 24 hr) and exhibited an extremely short longevity (three doublings). Insulin did not affect growth rate or longevity. Growth rate of normal and malignant cells was serum-dependent. At serum concentrations limiting for normal cell multiplication, malignant cells showed no proliferative advantage. Insulin complemented but did not replace limiting serum for multiplication of both normal and malignant cells. When allowed to become confluent before three doublings, normal and malignant cells exhibited a contact-mediated (or density-mediated) growth inhibition. Both normal and malignant cells were arrested in the G, phase of the cell cycle at the same density. Near physiologic doses of insulin stimulated DNA synthesis and mitosis in malignant cells but not in normal cells. Approximately 6% of malignant cells were stimulated to divide in the presence of insulin. Maximum DNA synthesis occurred at 24 hours and maximum mitotic activity at 30 hours after addition of insulin. The data suggested that malignant mammary epithelial cells are more sensitive to insulin as an overgrowth-stimulating factor than are normal cells.
Effects of Different Schedules of Dose Fractionation on the Oxygenation Status of a Transplantable Mouse Sarcoma&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: R. F. Kallman, L. J. Jardine, C. W. Johnson
Journal: JNCI Journal of the National Cancer Institute (1970)

As a follow-up on the earlier finding that sarcoma KHT in C3H/Km mice contained, on the average, 14–16% anoxic cells, and that the anoxic fraction was not altered significantly 3 days after 5 daily fractional doses of 190 rads, the same tumor line was subjected to additional fractionation schedules to determine their relative effects on the anoxic fraction. The same conditioning dose, 950 rads, was administered as 2 × 475 rods, 3 × 317 rads, or as a single dose. On the Monday after the week of conditioning irradiation, representative tumors were irradiated in situ with 950–2850 rads either in nitrogen-asphyxiated or in living, air-breathing mice. After final irradiation, the tumors were removed from the mice, their cells were suspended, and survival was determined by an endpoint-dilution method. The terminal slopes of the pairs of dose-survival curves obtained for cells irradiated in killed and living mice were approximately parallel. Anoxic fractions were computed for tumors irradiated after the different fractionation regimens by the calculation of the ratio, TD50(anoxic—irradiation in killed mice)/TD50(mixed—irradiation in living mice). This ratio is equivalent to the anoxic fraction if one assumes that the dosesurvival curves for high test doses (≧950 rads) were parallel for tumors irradiated under anoxic conditions (in dead mice) and under different degrees of oxygenation (in living, air-breathing mice). Thus the latter curve was displaced according to the proportion of sensitive (adequately oxygenated) and resistant (severely hypoxic) cells when the tumors were irradiated; the TD50 was used as the quantitative criterion of cell survival. Except for 2 × 475 rads given 48 hours apart (Wed., Fri.), the anoxic fractions for all other conditioning regimens did not differ significantly from those of unirradiated tumors. The regimen of 2 × 475 rads/48 hours produced a significantly (P<0.05) lower mean anoxic fraction of 5.0%. Contrasted with other schedules, this particular regimen of conditioning irradiation results in a tumor that becomes better oxygenated. Thus the number, size, and spacing of fractional doses vary in efficacy with respect to tumor reoxygenation. Additional evidence suggests that these differences in reoxygenation are independent of intracellular recovery.
Merkel Cell Carcinoma, Version 1.2014
Authors: Christopher K. Bichakjian, Thomas Olencki, Murad Alam, James S. Andersen, Daniel Berg, Glen M. Bowen, Richard T. Cheney, Gregory A. Daniels, L. Frank Glass, Roy C. Grekin, Kenneth Grossman, Alan L. Ho, Karl D. Lewis, Daniel D. Lydiatt, William H. Morrison, Kishwer S. Nehal, Kelly C. Nelson, Paul Nghiem, Clifford S. Perlis, Ashok R. Shaha, Wade L. Thorstad, Malika Tuli, Marshall M. Urist, Timothy S. Wang, Andrew E. Werchniak, Sandra L. Wong, John A. Zic, Karin G. Hoffmann, Nicole R. McMillian, Maria Ho
Journal: Journal of the National Comprehensive Cancer Network (2014)

Merkel cell carcinoma is a rare, aggressive cutaneous tumor that combines the local recurrence rates of infiltrative nonmelanoma skin cancer with the regional and distant metastatic rates of thick melanoma. The NCCN Guidelines for Merkel Cell Carcinoma provide recommendations on the diagnosis and management of this aggressive disease based on clinical evidence and expert consensus. This version includes revisions regarding the use of PET/CT imaging and the addition of a new section on the principles of pathology to provide guidance on the analysis, interpretation, and reporting of pathology results.
DNA Synthesis Index: Higher for Human Gallbladders With Cholesterol Gallstones Than With Pigment Gallstones&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;
Authors: J Lamote, P Putz, M Francois, G Willems
Journal: JNCI Journal of the National Cancer Institute (1983)

[3H]dThd uptake by the gallbladder epithelium was estimated in 33 patients with cholesterol stones, in 13 patients with pigment stones, and in 12 gallbladders without stones. Proliferative parameters were estimated by autoradiography after in vitro incubation with [3H]-dThd. Stones were identified by quantitative infrared spectroscopy. The degree of inflammation of the gallbladder wall was estimated by a histologic scoring method. In the gallbladders containing cholesterol stones the DNA synthesis index (1.39 +/- 0.28%) was higher (P less than .01) than in the gallbladders without stones (0.19 +/- 0.04%). No significant increase in proliferative parameters was found in the gallbladders with pigment stones (0.24 +/- 0.06%). No correlation was found between total stone number, weight or volume, and the DNA synthesis index. No evidence was observed that inflammation could influence the epithelial cell proliferation. Something in the bile of patients with cholesterol stones rather than the physical presence of stones may be the cause of the variations observed.
Screening, Monitoring, and Treatment of Stage 1 to 3 Chronic Kidney Disease: A Clinical Practice Guideline From the Clinical Guidelines Committee of the American College of Physicians
Authors: Amir Qaseem, Robert H. Hopkins, Donna E. Sweet, Melissa Starkey, Paul Shekelle
Journal: Annals of Internal Medicine (2013)

The American College of Physicians (ACP) developed this guideline to present the evidence and provide clinical recommendations on the screening, monitoring, and treatment of adults with stage 1 to 3 chronic kidney disease.This guideline is based on a systematic evidence review evaluating the published literature on this topic from 1985 through November 2011 that was identified by using MEDLINE and the Cochrane Database of Systematic Reviews. Searches were limited to English-language publications. The clinical outcomes evaluated for this guideline included all-cause mortality, cardiovascular mortality, myocardial infarction, stroke, chronic heart failure, composite vascular outcomes, composite renal outcomes, end-stage renal disease, quality of life, physical function, and activities of daily living. This guideline grades the evidence and recommendations by using ACP's clinical practice guidelines grading system.ACP recommends against screening for chronic kidney disease in asymptomatic adults without risk factors for chronic kidney disease. (Grade: weak recommendation, low-quality evidence)ACP recommends against testing for proteinuria in adults with or without diabetes who are currently taking an angiotensin-converting enzyme inhibitor or an angiotensin II-receptor blocker. (Grade: weak recommendation, low-quality evidence)ACP recommends that clinicians select pharmacologic therapy that includes either an angiotensin-converting enzyme inhibitor (moderate-quality evidence) or an angiotensin II-receptor blocker (high-quality evidence) in patients with hypertension and stage 1 to 3 chronic kidney disease. (Grade: strong recommendation)ACP recommends that clinicians choose statin therapy to manage elevated low-density lipoprotein in patients with stage 1 to 3 chronic kidney disease. (Grade: strong recommendation, moderate-quality evidence).
<i>ITGB4</i>-associated non-Herlitz junctional epidermolysis bullosa: report of two new cases carrying two novel<i>ITGB4</i>mutations
Authors: W.Y. Yuen, R.J. Sinke, M.F. Jonkman
Journal: British Journal of Dermatology (2012)

Funding sources: This work was supported by Vlinderkind (Dutch Butterfly Child Foundation) and the J.P. Nater Foundation. Conflicts of interests: None declared. Madam, Epidermolysis bullosa (EB) is a genetic, trauma‐induced, blistering disease consisting of 29 subtypes.1 Mutations in ITGB4, the gene coding for the hemidesmosomal protein integrin β4 (β4), cause the rare subtype EB with pyloric atresia that can be lethal in childhood.2, 3,ITGB4 mutations have also been associated with nonpyloric atresia cases of EB. We previously described a case of EB simplex caused by ITGB4 mutations.4 Furthermore, three cases of non‐Herlitz junctional EB (JEB‐nH), which is usually caused by mutations in the genes coding for laminin‐332 (LM‐332: LAMA3, LAMB3, LAMC2) or for type XVII collagen (Col17: COL17A1), have been associated with ITGB4 mutations.3, 5 We found two more JEB‐nH cases carrying pathogenic ITGB4 mutations, corresponding with an incidence of 6·5% in the Dutch JEB‐nH cohort (two ITGB4‐associated JEB‐nH families out of a total of 31 families). Here we report these two new JEB‐nH cases carrying two novel ITGB4 mutations.
High level IL-12 production by murine dendritic cells: upregulation via MHC class II and CD40 molecules and downregulation by IL-4 and IL-10.
Authors: F Koch, U Stanzl, P Jennewein, K Janke, C Heufler, E Kämpgen, N Romani, G Schuler
Journal: The Journal of Experimental Medicine (1996)

We have shown previously that dendritic cells (DC) produce IL-12 upon interaction with CD4+ T cells. Here we ask how this IL-12 production is induced and regulated. Quantitative PCR and in situ hybridization for IL-12 p40 and an ELISA specific for the p70 heterodimer were used to determine IL-12 production. We demonstrate that ligation of either CD40 or MHC class II molecules independently trigger IL-12 production in DC, and that IL-12 production is downregulated by IL-4 and IL-10. The levels of bioactive IL-12 that can be released by triggering with an anti-CD40 mAb or with a T cell hybridoma are high (range 260-4700 pg/ml from 1 X 10(6) DC in 72 h). The CD40-mediated pathway indicates that IL-12 production is induced in DC upon interaction with activated, CD40 ligand-expressing helper T cells, even in the absence of cognate antigen recognition. Side-by-side comparison of IL-12 production, and blocking experiments employing an anti-CD40 ligand mAb, suggest that the CD40-mediated pathway is quantitatively more significant than induction via the MHC class II molecule. The importance of the CD40/CD40 ligand interaction for IL-12 induction in DC likely contributes to the recent finding that mice lacking the CD40 ligand are impaired in mounting Th1 type cell-mediated immune responses.
Use of Acupuncture in the Control of Chemotherapy-Induced Nausea and Vomiting
Authors: Ting Bao
Journal: Journal of the National Comprehensive Cancer Network (2009)

Chemotherapy-induced nausea and vomiting (CINV) is one of the most common and feared side effects of chemotherapy. Despite recent advances in pharmacologic antiemetic therapy, additional treatment for breakthrough CINV is needed. Acupuncture is a safe medical procedure with minimal side effects; several randomized controlled clinical trials have suggested its efficacy in controlling this side effect. A recent meta-analysis of those trials demonstrated that acupuncture significantly reduced the proportion of patients experiencing acute chemotherapy-induced vomiting. Those trials, however, did not show that acupuncture significantly alleviated acute chemotherapy-induced nausea or delayed CINV. The clinical relevance of these results were limited by the fact that they predated the use of aprepitant and that only 1 or 2 acupuncture points were stimulated during acupuncture treatment. More clinical trials to study the effect of acupuncture with additional antiemetic acupuncture points in adjunct to modern pharmacologic antiemetic therapy are needed.
Ondansetron Plus Metopimazine Compared With Ondansetron Plus Metopimazine Plus Prednisolone as Antiemetic Prophylaxis in Patients Receiving Multiple Cycles of Moderately Emetogenic Chemotherapy
Authors: T. Sigsgaard, J. Herrstedt, J. Handberg, M. Kjær, P. Dombernowsky
Journal: Journal of Clinical Oncology (2001)

PURPOSE: To compare the antiemetic efficacy and tolerability of ondansetron plus metopimazine with ondansetron plus metopimazine plus prednisolone during nine cycles of moderately emetogenic chemotherapy. PATIENTS AND METHODS: A total of 221 women with stage I or II breast cancer and no prior chemotherapy who were scheduled to receive adjuvant chemotherapy with intravenous cyclophosphamide, fluorouracil and methotrexate or cyclophosphamide, epirubicin, and fluorouracil given every 3 weeks were included in a double-blind parallel trial. Patients were randomized to 3 days of oral treatment with ondansetron plus metopimazine, or ondansetron plus metopimazine plus prednisolone. Ondansetron was administered as 8 mg bid, metopimazine as 30 mg qid, and prednisolone as 50 mg qd. RESULTS: In all, 216 patients (97.7%) were assessable for efficacy during a total of 1,462 cycles. In cycle 1, complete protection from emetic episodes/nausea day 1, days 2 through 5, and days 1 through 5 was achieved in 84.4%/51.4%, 82.6%/41.3%, and 79.8%/34.9% with ondansetron plus metopimazine and in 84.1%/57.0%, 86.8%/53.8%, and 79.4%/43.0% with ondansetron plus metopimazine plus prednisolone, respectively. In cycle 1, the three-drug combination was superior only in the treatment of nausea on days 2 through 5 (P = .0497). The cumulative emetic protection rate after nine cycles was 0.52 with ondansetron plus metopimazine and 0.75 with ondansetron plus metopimazine plus prednisolone. Side effects were generally few and mild with both treatments. Constipation was the only adverse event significantly more frequent with the three-drug combination (P = .029). CONCLUSION: Ondansetron plus metopimazine plus prednisolone is highly effective and superior to ondansetron plus metopimazine during nine cycles of moderately emetogenic chemotherapy.