tbuckley/cabot-search huggingface dataset:
5-Year Results of Dose-Intensive Sequential Adjuvant Chemotherapy for Women With High-Risk Node-Positive Breast Cancer: A Phase II Study
Authors: C. Hudis, M. Fornier, L. Riccio, D. Lebwohl, J. Crown, T. Gilewski, A. Surbone, V. Currie, A. Seidman, B. Reichman, M. Moynahan, G. Raptis, N. Sklarin, M. Theodoulou, L. Weiselberg, R. Salvaggio, K.S. Panageas, T.J. Yao, L. Norton
Journal: Journal of Clinical Oncology (1999)

PURPOSE: We conducted a phase II pilot study of dose-intensive adjuvant chemotherapy with doxorubicin followed sequentially by high-dose cyclophosphamide to determine the safety and feasibility of this dose-dense treatment and to estimate the disease-free and overall survival in breast cancer patients with four or more involved axillary lymph nodes. PATIENTS AND METHODS: Seventy-three patients received adjuvant treatment with four cycles of doxorubicin 75 mg/m 2 as an intravenous bolus every 21 days, followed by three cycles of cyclophosphamide 3,000 mg/m 2 every 14 days with granulocyte colony-stimulating factor support. RESULTS: Seventy-one patients were assessable, and all but two completed all planned chemotherapy. There was no treatment-related mortality. The most common toxicity was neutropenic fever, which occurred in 39% of patients. Median disease-free survival is 66 months (95% confidence interval, 34 to 98 months), and median overall survival has not yet been reached. At 5 years of follow-up, the disease-free survival is 51.7%, and overall survival is 60.0%. There is no long-term treatment-related toxicity, and no cases of acute myelogenous leukemia or myelodysplastic syndrome have been observed. CONCLUSION: Our pilot study of doxorubicin followed by cyclophosphamide demonstrates the safety and feasibility of the sequential dose-dense plan. Long-term follow-up, although noncomparative, is promising. However, this regimen is associated with a higher incidence of toxicity (and also higher costs) than the standard dose and schedule of doxorubicin and cyclophosphamide, and therefore it should not be used as conventional therapy in the absence of demonstrated improvement of outcome. Randomized trials testing the dose-dense approach have been completed but not yet reported. Because the sequential plan can decrease overlapping toxicities, it is an appropriate platform for the addition of newer active agents, such as taxanes or monoclonal antibodies.
Differential inhibition of cellular glutathione reductase activity from isocyanates generated by the antitumor prodrugs Cloretazine and BCNU
Authors: Kevin P. Rice, Philip G. Penketh, Krishnamurthy Shyam, Alan C. Sartorelli
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

1379 

The antitumor, DNA-alkylating agent BCNU (1,3-bis[2-chloroethyl]-2-nitrosourea; Carmustine), which generates chloroethylisocyanate upon decomposition in situ , inhibits cellular glutathione reductase (GR) activity by up to 90% at pharmacological doses. Glutathione reductase requires a cysteine thiol that is susceptible to attack from exogenous electrophiles, particularly carbamoylation from alkylisocyanates, rendering the enzyme unable to catalyze the reduction of oxidized glutathione. Evidence implicates inhibition of GR as a cause of the pulmonary toxicity often seen in high-dose BCNU-treated animals and human cancer patients. Herein we demonstrate that the prodrug Cloretazine™ (1,2-bis[methylsulfonyl]-1-[2-chloroethyl]-2-[(methylamino)carbonyl]hydrazine; VNP40101M), which yields methylisocyanate and chloroethylating species upon activation, does not produce similar inhibition of cellular GR activity, despite BCNU and Cloretazine™ being equally potent inhibitors of purified human GR (IC50 values of 50.8 μM and 54.2 μM, respectively). Human erythrocytes, following exposure to 50 μM BCNU for 1 hour at 37°C, had an 84% decrease in GR activity, whereas 50 μM Cloretazine™ caused less than 1% inhibition under the same conditions. Similar results were found using L1210 murine leukemia cells, with 50 μM BCNU or Cloretazine producing 94% and 28% inhibition of GR, respectively. The disparity between these compounds remained when cells were lysed prior to drug exposure and could be partially recapitulated using purified enzyme when 1 mM reduced glutathione was included during the drug exposure. The superior antineoplastic potential of Cloretazine™ compared to BCNU in animal models could be attributed in part to the contribution of the methylisocyanate, which is synergistic with the co-generated, cytotoxic alkylating species, while at the same time unable to significantly inhibit cellular GR.
Cardiac and Respiratory Dysfunction in Duchenne Muscular Dystrophy and the Role of Second Messengers
Authors: Matias Mosqueira, Ulrike Zeiger, Moritz Förderer, Heinrich Brinkmeier, Rainer HA Fink
Journal: Medicinal Research Reviews (2013)

Duchenne muscular dystrophy (DMD) affects young boys and is characterized by the absence of dystrophin, a large cytoskeletal protein present in skeletal and cardiac muscle cells and neurons. The heart and diaphragm become necrotic in DMD patients and animal models of DMD, resulting in cardiorespiratory failure as the leading cause of death. The major consequences of the absence of dystrophin are high levels of intracellular Ca2+ and the unbalanced production of NO that can finally trigger protein degradation and cell death. Cytoplasmic increase in Ca2+ concentration directly and indirectly triggers different processes such as necrosis, fibrosis, and activation of macrophages. The absence of the neuronal isoform of nitric oxide synthase (nNOS) and the overproduction of NO by the inducible isoform (iNOS) further increase the intracellular Ca2+ via a hypernitrosylation of the ryanodine receptor. NO overproduction, which further induces the expression of iNOS but decreases the expression of the endothelial isoform (eNOS), deregulates the muscle tissue blood flow creating an ischemic situation. The high levels of Ca2+ in dystrophic muscles and the ischemic state of the muscle tissue would culminate in a positive feedback loop. While efforts continue toward optimizing cardiac and respiratory care of DMD patients, both Ca2+ and NO in cardiac and respiratory muscle pathways have been shown to be important to the etiology of the disease. Understanding the mechanisms behind the fine regulation of Ca2+-NO may be important for a noninterventional and noninvasive supportive approach to treat DMD patients, improving the quality of life and natural history of DMD patients.
Relationship of systemic inflammation and autoimmunity to clinically relevant outcomes in COPD
Authors: Belen Nuñez, Jaume Sauleda, Josep M. Antό, Mª Rosa Julià, Esther Barreiro, Eduard Monsό, Aina Noguera, Joaquim Gea, Federico Gόmez, Judith Garcia-Aymerich, Alvar Agustí
Journal: European Respiratory Journal (2011)

Introduction:  Chronic obstructive pulmonary disease (COPD) is associated with low-grade systemic inflammation and autoinmunity. Their relationship with relevant clinical outcomes is unclear.   Objectives:  To evaluate the relationship of systemic inflammation and markers of autoimmunity with two clinically relevant outcomes, namely number of hospital admissions for respiratory disease and all-cause mortality.   Method:  We studied 342 patients with clinically stable COPD recruited into the PAC-COPD study (68±9 yrs., FEV1 52±16% ref, FEV1/FVC 54±12%, x±SD) who were followed up for 3 years. At recruitment, we determined the serum concentration of C-reactive protein (CRP [nephelometry]), pro-inflammatory cytokines (IL6, IL8 and TNFa, [ELISA]), oxidative stress markers (carboniles, nitrotyrosines, malondialdehyde (MDA) by ELISA) and circulating antinuclear (ANA) and anti-tissue (AT) antibodies (by immunofluorescence).   Results:  We observed that, at recruitment: (1) levels of CRP (9.9±20.6 vs. 7.2±15.5 pg/ml) and IL-8 (5.6±3.9 vs. 4.8±3.4 pg/ml) were higher (p vs  12%) were higher (p   Conclusions:  Systemic inflammation and autoimmunity influence important clinical outcomes in COPD.  Supported in part by FIS 05/2082
Impact of legislation on nursing home care in the United States: lessons for the United Kingdom Commentary: A new script for nursing home care in the United Kingdom?
Authors: C. M Hughes, K. L Lapane, V. Mor, A Turrell, C M Castleden
Journal: BMJ (1999)

Despite the growing recognition that our ageing population represents a major challenge to the provision of health services,1 2 no major government policy initiative had focused on this topic until the recent establishment of a royal commission. The royal commission was asked to concentrate on funding, but it was also required to define and establish mechanisms to assure the quality of long term care for elderly people, and was instructed to consider "the expectations of elderly people for dignity and security in the way in which their long term needs are met."3 In the United States, where long term care has undergone dramatic changes in the past 10 years, the quality of care continues to be hotly debated. The impetus for changes in the long term care system includes legislation and regulation in the form of the Nursing Home Reform Act of 1987. One aspect of this legislation pertained to the appropriateness of prescribing. We summarise briefly the legislation in respect of prescribing, its implementation, and influence on nursing home care delivery and consider alternative approaches for the United Kingdom. #### Summary points Excessive use of psychotropic medication was commonplace in nursing homes in the United States before the Nursing Home Reform Act 1987 was passed After legislation, psychotropic drugs were used less and a more structured approach to care planning was observed In the United Kingdom, policy relating to nursing home care is unclear and explicit criteria for quality prescribing have not been formulated A combination of structured assessment and review of patients, concerted educational interventions, and greater multidisciplinary working may improve long term care in the United Kingdom Before the Nursing Home Reform Act, psychotropic drugs were used widely in US nursing homes.4–6 These drugs were prescribed for 43%-55% of patients in homes, despite the lack … Correspondence to: A R Turrell
<i>BCR</i> Rearrangement–Negative Chronic Myelogenous Leukemia Revisited
Authors: Razelle Kurzrock, Carlos E. Bueso-Ramos, Hagop Kantarjian, Emil Freireich, Susan L. Tucker, Michael Siciliano, Susan Pilat, Moshe Talpaz
Journal: Journal of Clinical Oncology (2001)

To document the characteristics of patients with major breakpoint cluster region (M-bcr) rearrangement-negative chronic myelogenous leukemia (CML).The hematopathologist, who was blinded to patients' molecular status, reviewed the referral bone marrows and peripheral-blood smears from 26 patients with Philadelphia (Ph) translocation-negative CML who lacked Bcr rearrangement (and other evidence of a Bcr-Abl anomaly) and 14 patients (controls) with chronic-phase Ph-positive CML. Clinical data was ascertained by chart review.Among the 26 M-bcr rearrangement-negative CML patients, three pathologic subtypes emerged: (1) patients indistinguishable from classic CML (n = 9), (2) patients with atypical CML (n = 8), and (3) patients with chronic neutrophilic leukemia (n = 9). Among the 14 patients with Ph-positive CML who were included in the blinded review, 13 were classified as classic CML, and one was classified as atypical CML. The only statistically significant difference between M-bcr rearrangement-negative subgroups was in the proportion of patients having karyotypic abnormalities, an observation common only in patients with atypical CML (P = 0.008). However, the small number of patients in each subgroup limited our ability to differentiate between them. Interferon alfa induced complete hematologic remission in five of 14 patients; four of these remissions lasted more than 5 years. Only one of 26 patients developed blast crisis. The median survival of the 26 patients was 37 months.Patients with M-bcr rearrangement-negative CML fall into three morphologic subgroups. Disease evolution does not generally involve blastic transformation. Instead, patients show progressive organomegaly, leukocytosis, anemia, and thrombocytosis. Some patients in each subgroup can respond to interferon alfa.
Surveillance strategy based on the incidence and patterns of recurrence after curative endoscopic submucosal dissection for early gastric cancer
Authors: Byung-Hoon Min, Eun Kim, Kyoung-Mee Kim, Cheol Park, Jun Lee, Poong-Lyul Rhee, Jae Kim
Journal: Endoscopy (2015)

To suggest an appropriate surveillance strategy after curative endoscopic submucosal dissection (ESD) for early gastric cancers, based on incidence and patterns of local, metachronous, and extragastric recurrence.Between 2003 and 2011, 1497 consecutive patients with 1539 differentiated-type early gastric cancers meeting absolute or expanded indication criteria underwent curative ESD. They were followed up with esophagogastroduodenoscopy (EGD) and abdominal computed tomography (CT) under a standardized surveillance protocol. Long-term outcomes were analyzed for 1306 patients with at least 1 year's follow-up.Incidences of residual and synchronous lesions detected within 1 year were 0.13 % and 0.87 %, respectively. During median 47 months of follow-up, there was 1 local recurrence (0.08 %; early gastric cancer) and 47 cases of metachronous recurrence (3.6 %; 44 early gastric cancers, 3 pT2 advanced gastric cancers); all were curatively treated. During a 5-year surveillance, the cumulative incidence curve of metachronous recurrence increased linearly. Median time from ESD to metachronous recurrence was 30 months. There were 2 extragastric recurrences (0.15 %) in lymph nodes, at 5 and 4 years, respectively, after curative ESD for absolute and expanded indications. The patient with the expanded indications underwent a palliative operation and died of gastric cancer progression.There was a constant incidence rate of metachronous recurrence during a 5-year surveillance period and there was extragastric recurrence at least 4 years after ESD of early gastric cancer even for absolute indications. Therefore, annual or biannual surveillance EGD and abdominal CT might be necessary for at least 5 years after curative ESD for early gastric cancers, with absolute as well as expanded indications.
Identification of low allergenic apple cultivars using skin prick tests and oral food challenges
Authors: B. J. Vlieg‐Boerstra, W. E. van de Weg, S. van der Heide, M. Kerkhof, P. Arens, G. Heijerman‐Peppelman, A. E. J. Dubois
Journal: Allergy (2010)

To cite this article: Vlieg‐Boerstra BJ, van de Weg WE, van der Heide S, Kerkhof M, Arens P, Heijerman‐Peppelman G, Dubois AEJ. Identification of low allergenic apple cultivars using skin prick tests and oral food challenges. Allergy 2011; 66 : 491–498. Abstract Background: As oral allergy syndrome (OAS) symptoms to apple are frequent, we aimed to identify low allergenic apple cultivars and to validate the prick‐to‐prick skin prick test (SPT) as a suitable screening method. Methods: Sixty‐eight apple cultivars were tested by SPTs in 33 Dutch adults with OAS, before and during the birch pollen season in 2006 and 2007, respectively. Three cultivars yielding the largest number of negative SPTs (Elise, Santana and Pink Lady ® ) and one reference cultivar (Golden Delicious) were subsequently tested by single‐blind oral food challenges (SBFC) just after picking in fall 2007 (fresh) and in spring 2008 (stored), outside the birch pollen season and preceded by SPTs. In spring, Santana was replaced by Modi ® . Results: In fresh apples, OAS symptoms of Elise, as measured by cumulative scores on a Visual Analogue Scale VASt, were significantly lower than those of Santana, Pink Lady and Golden Delicious ( P = 0.021; 0.040 and 0.005, respectively). VASt scores of Santana were significantly lower than those of Golden Delicious ( P = 0.049). In stored apples, VASt scores of Elise were significantly lower than that of Golden Delicious ( P = 0.038). VASt scores of fresh apples did not differ significantly from stored apples, except in Golden Delicious (spring &lt; fall: P = 0.021). The SPTs did not predict the severity of OAS. Conclusion: SPTs are not useful to assess the allergenicity of apple cultivars. By using SBFC, Elise and Santana were identified as low allergenic apple cultivars in patient with OAS. Our data on the effect of storage are inconclusive.
Effects of a Functional Variant c.353T&gt;C in <i>Snai1</i> on Risk of Two Contextual Diseases. Chronic Obstructive Pulmonary Disease and Lung Cancer
Authors: Lei Yang, Xiaorong Yang, Weidong Ji, Jieqiong Deng, Fuman Qiu, Rongrong Yang, Wenxiang Fang, Lisha Zhang, Dongsheng Huang, Chenli Xie, Haibo Zhang, Nanshan Zhong, Pixin Ran, Yifeng Zhou, Jiachun Lu
Journal: American Journal of Respiratory and Critical Care Medicine (2014)

Rationale: Epithelial–mesenchymal transition (EMT) plays a key role in the development of chronic obstructive pulmonary disease (COPD) and lung cancer.Objectives: There are five major EMT regulatory genes (Snai1, Slug, Zeb1, Zeb2, and Twist1) involved in EMT. We hypothesized that germline variants in these genes may influence the development of both diseases.Methods: Seven genetic variants were genotyped in two two-stage case-control studies with 2,072 lung cancer cases and 2,077 control subjects, and 1,791 patients with COPD and 1,940 control subjects to show their associations with development of both diseases.Measurements and Main Results: An exon variant c.353T>C(p.Val118Ala) of Snai1 harbored decreased risks of lung cancer (CT/CC vs. TT: odds ratio [OR], 0.76; 95% confidence interval [CI], 0.65–0.90) and COPD (CC vs. CT vs. TT: OR, 0.75; 95% CI, 0.63–0.89), and c.353T>C affected lung cancer risk indirectly through COPD (COPD accounted for 6.78% of effect that the variant had on lung cancer). Moreover, c.353T>C was correlated with lung cancer stages in smoking patients (P = 0.013), and those with the c.353C genotypes were less likely to have metastasis at diagnosis than those with the c.353TT genotype (OR, 0.60; 95% CI, 0.41–0.88). The c.353C allele encoding p.118Ala attenuated Snai1’s ability to up-regulate mesenchymal biomarkers (i.e., fibronectin and vimentin) expression, and to promote EMT-like changes, including morphologic changes, cell migration, and invasion. However, these effects were not observed for the other variants.Conclusions: The functional germline variant c.353T>C (p.Val118Ala) of Snai1 confers consistently decreased risks of lung cancer and COPD, and this variant affects lung cancer risk through a mediation effect of COPD.
Corruption impairs discussion on long term use of psychiatric drugs
Authors: R. Whitaker, L. Cosgrove
Journal: BMJ (2015)

While debating the important question of whether long term psychiatric drugs cause more harm than good,1 we must remember that results from longer term government funded studies of psychiatric drugs have often been reported in a manner that protects psychiatry’s guild interests, rather than being consistent with the dictates of good science. Here are two …
Prognostic Value of Angiopoietin-2 for Overall Survival in Patients with Metastatic Colorectal Carcinoma Treated By Chemotherapy and Bevacizumab
Authors: M. Jary, D. Vernerey, E. Dobi, F. Monnien, Y. Godet, S. Kim, O. Bouché, S. Fratte, F. Ghiringhelli, A. Goncalvez, T. Lecomte, J. Leger, L. Queiroz, O. Adotevi, F. Bonnetain, C. Borg
Journal: Annals of Oncology (2014)
Animals can tell us more
Authors: Norbert Sachser, S. Helene Richter
Journal: Behavioral and Brain Sciences (2015)

Abstract From a behavioural biologist's point of view, we argue: (1) The study of resilience in animals should not be restricted to neuronal mechanisms. Rather, questions of ontogeny, function, and evolution also should be addressed to achieve a comprehensive understanding. (2) Implementing new paradigms from animal welfare research in studies of resilience would allow an assessment of appraisal styles in animals.
NCCN Task Force: Clinical Utility of PET in a Variety of Tumor Types
Authors: Donald A. Podoloff, Douglas W. Ball, Edgar Ben-Josef, Al B. Benson, Steven J. Cohen, R. Edward Coleman, Dominique Delbeke, Maria Ho, David H. Ilson, Gregory P. Kalemkerian, Richard J. Lee, Jay S. Loeffler, Homer A. Macapinlac, Robert J. Morgan, Barry Alan Siegel, Seema Singhal, Douglas S. Tyler, Richard J. Wong
Journal: Journal of the National Comprehensive Cancer Network (2009)

Use of PET is widespread and increasing in the United States, mainly for oncologic applications. In November 2006, the National Comprehensive Cancer Network (NCCN) gathered a panel of experts to review the literature and develop clinical recommendations for using PET scans in lymphoma and non–small cell lung, breast, and colorectal cancers. However, because its use is not restricted to these diseases, and evidence is accumulating for its application in other types of cancers, NCCN convened a second meeting in December 2008 to expand on the initial report. A multidisciplinary panel met to discuss the current data on PET application for various tumor types, including genitourinary, gynecologic, pancreatic, hepatobiliary, thyroid, brain, small cell lung, gastric, and esophageal cancers, and sarcoma and myeloma. This report summarizes the proceedings of this meeting, including discussions of the background of PET, the role of PET in oncology, principles of PET use, emerging applications, and possible future developments.
Variations in Etiology of Ventilator-associated Pneumonia across Four Treatment Sites
Authors: JORDI RELLO, MARCIO SA-BORGES, HUMBERTO CORREA, SANTIAGO-RAMON LEAL, JORGE BARAIBAR
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

This retrospective multicenter study compared microorganisms documented by quantitative cultures from bronchoscopic samples in episodes of ventilator-associated pneumonia (VAP) from three different institutions in Barcelona (B), Montevideo (M), and Seville (S). The observations were compared with the findings reported by Trouillet and coworkers (AJRCCM 1998;157:531–539) in Paris (P). The objective was to evaluate whether a classification of etiologies of VAP in four groups, based on the number of ventilation days and previous antimicrobial use, might contribute to establishing generalized guidelines for empirical therapy. Significant variations in etiologies (p < 0.05) were found in all of the microorganisms isolated from VAP episodes across three treatment sites when compared with the reference site (P). In Group 1 ( < 7 d and absence of antibiotics), Pseudomonas aeruginosa remained extremely infrequent (3 of 89, 3.3%) in the joint category, whereas the incidence of Acinetobacter baumannii was significantly higher, owing to M findings. On the other hand, one site (B) had a significantly lower incidence of multiresistant pathogens (Methicillin-resistant Staphylococcus aureus [MRSA] and nonfermenters other than P. aeruginosa), even in Group 2 ( < 7 d and antibiotics), Group 3 ( ⩾ 7 d and absence of antibiotics), and Group 4 (antibiotics and ⩾ 7 days). Similar findings were documented when episodes were grouped according to Groups 1 and 3 of the ATS guidelines. We conclude that causes of VAP varied markedly across four treatment sites, resulting in the need for large-scale variations in antimicrobial prescribing practices. Instead of following general recommendations, antimicrobial prescribing practices for VAP should be based on up-to-date information of the pattern of multiresistant isolates from each institution.