tbuckley/cabot-search huggingface dataset:
Clinical relevance of tumor cell ploidy and N-myc gene amplification in childhood neuroblastoma: a Pediatric Oncology Group study.
Authors: A T Look, F A Hayes, J J Shuster, E C Douglass, R P Castleberry, L C Bowman, E I Smith, G M Brodeur
Journal: Journal of Clinical Oncology (1991)

We assessed tumor cell DNA content (ploidy) and N-myc gene copy number as predictors of long-term disease-free survival in 298 children with neuroblastoma. Diploid tumor stem lines were identified in 101 patients (34%), clonal hyperdiploid abnormalities in 194 (65%), and hypodiploid stem lines in three (1%). In children with widely disseminated tumors at diagnosis (stage D), ploidy had a highly age-dependent influence on prognosis. Among infants (less than 12 months) treated with cyclophosphamide-doxorubicin, hyperdiploidy was closely associated with long-term disease-free survival (greater than 90% of cases), while diploidy invariably predicted early treatment failure (P less than .001). Similarly, in children 12 to 24 months of age who were treated with cisplatin-teniposide and cyclophosphamide-doxorubicin, diploidy uniformly predicted early failure, whereas half of the children with hyperdiploidy achieved long-term disease-free survival (P less than .001). There was no relationship between ploidy and treatment outcome in children older than 24 months with stage D tumors who had a very low probability of long-term disease-free survival (less than 10%). N-myc gene amplification was detected in 37 (25%) of the 147 tumors tested, with the remainder showing single-copy levels of the gene. N-myc gene amplification was more frequent in diploid than in hyperdiploid tumors (23 of 57 v 14 of 87, P = .001) and predicted a high likelihood of early treatment failure. In children younger than 2 years with disseminated neuroblastoma, tumor cell ploidy and N-myc gene copy number provide complementary prognostic information that will distinguish patients who can be cured on current regimens from those who require new treatment strategies.
Aiolos Is Required for the Generation of High Affinity Bone Marrow Plasma Cells Responsible for Long-Term Immunity
Authors: Marta Cortés, Katia Georgopoulos
Journal: The Journal of Experimental Medicine (2004)

Antigenic encounter generates long-term immunity sustained by long-lived high affinity plasma cells resident in the bone marrow (BM). Here we show that the Ikaros family member, Aiolos, is specifically required for the generation of these plasma cells. Failure to generate high affinity plasma cells in the BM and to sustain serum antibody titers is apparent after both primary and secondary immunization of Aiolos−/− mice with a range of hapten concentrations. Chimera reconstitutions demonstrate that the BM plasma cell defect is B cell intrinsic. Lack of Aiolos does not alter expression of any of the previously described factors required for general plasma cell differentiation. No defect in somatic hypermutation, the generation of memory B cells, or short-lived high affinity plasma cells in the spleen was observed upon rechallenge. These studies support a model by which the high affinity plasma cell population in the BM undergoes a unique differentiation program that is dependent on Aiolos.
Long-Term Results of a Randomized Trial Comparing Breast-Conserving Therapy With Mastectomy: European Organization for Research and Treatment of Cancer 10801 Trial
Authors: J. A. van Dongen
Journal: JNCI Journal of the National Cancer Institute (2000)

Background: Breast-conserving therapy (BCT) has been shown to be as effective as mastectomy in the treatment of tumors 2 cm or smaller. However, evidence of its efficacy, over the long term, in patients with tumors larger than 2 cm is limited. From May 1980 to May 1986, the European Organization for Research and Treatment of Cancer carried out a randomized, multicenter trial comparing BCT with modified radical mastectomy for patients with tumors up to 5 cm. In this analysis, we investigated whether the treatments resulted in different overall survival, time to distant metastasis, or time to locoregional recurrence. Methods: Of 868 eligible breast cancer patients randomly assigned to the BCT arm or to the modified radical mastectomy arm, 80% had a tumor of 2.1–5 cm. BCT comprised lumpectomy with an attempted margin of 1 cm of healthy tissue and complete axillary clearance, followed by radiotherapy to the breast and a supplementary dose to the tumor bed. The median follow-up was 13.4 years. All P values are two-sided. Results: At 10 years, there was no difference between the two groups in overall survival (66% for the mastectomy patients and 65% for the BCT patients; P = .11) or in their distant metastasis-free rates (66% for the mastectomy patients and 61% for the BCT patients; P = .24). The rate of locoregional recurrence (occurring before or at the same time as distant metastasis) at 10 years did show a statistically significant difference (12% of the mastectomy and 20% of the BCT patients; P = .01). Conclusions: BCT and mastectomy demonstrate similar survival rates in a trial in which the great majority of the patients had stage II breast cancer.
Abstract A15: A phase 2 study of neoadjuvant metformin in prostatic carcinoma
Authors: Anthony Michael Joshua, Neil Fleshner, Michael Pollak, Vanessa Zannella, Barbara Bowes, Marianne Koritzinsky, Joan Sweet, Andrew Evans, John Trachtenberg, Michael Jewett, Antonio Finelli
Journal: Cancer Research (2012)

Abstract Background: Metformin is an inhibitor of the complex 1 in the respiratory chain, and is widely used in diabetes due to its effect on reducing insulin resistance. It has also been recently described to have effects via AMPK on inhibiting the mTOR kinase. Significant preclinical and epidemiological studies suggest its role in chemoprevention. These actions provide significant rationale to evaluate its utility in prostate cancer. We conducted a phase II single centre study of neoadjuvant metformin in localized prostate cancer. Methods: Men were required to have histologically confirmed prostate cancer involving at least 20% of at least 1 unfragmented biopsy core. Exclusion criteria included patients who on initial assessment are found to be on treatment with any drug used for the treatment of any form of diabetes, or patients that begin treatment for any form of diabetes during the course of the study. Pts were treated with up to 500mg tid of metformin. The primary objectives were to demonstrate safety and tolerability of neoadjuvant metformin administration in men with prostate cancer and to document changes in phospho-AKT signaling indices. Results: 24 patients were enrolled with 22 evaluable; median age was 64 yrs (range, 45-70 yrs). Baseline characteristics included median PSA 6 ng/mL (range, 3.22–36.11 ng/mL). Median duration of drug treatment was 41 days (range 18–81). No grade 3 adverse events were reported, all patients underwent subsequent radical prostatectomy with adverse effects related to metformin. Significant pre-and post changes were noted in serum IGF1 (p=0.02), fasting glucose (p=0.03), BMI (p &amp;lt; 0.01) and waist/hip ratio (p &amp;lt; 0.01). There was a trend for a PSA reduction (p=0.08). There were no correlations between any metabolic, morphometric or cancer-related serum indices. Conclusions: Neoadjuvant metformin is well tolerated prior to radical prostatectomy. Data to date indicates promising effects on metabolic parameters, tissue results will be presented including proliferation indices and signaling pathway assessments. Citation Format: Anthony Michael Joshua, Neil Fleshner, Michael Pollak, Vanessa Zannella, Barbara Bowes, Marianne Koritzinsky, Joan Sweet, Andrew Evans, John Trachtenberg, Michael Jewett, Antonio Finelli. A phase 2 study of neoadjuvant metformin in prostatic carcinoma [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr A15.
Multiple exercise and histamine challenge in asthmatic patients
Authors: R. E Schoeffel, S. D Anderson, I Gillam, D A Lindsay
Journal: Thorax (1980)

We studied the effects of repeated exercise and histamine challenge in asthmatic patients to determine the frequency and degree to which a state of refractoriness was induced by these stimuli. Twenty-nine patients performed three exercise tests, and on a separate day 16 of these patients had three histamine inhalational challenge tests. Forty minutes separated each challenge. Changes in airways resistance were measured using the peak expiratory flow rate (PEFR). The fall in PEFR (expressed as a percentage of the pre-challenge value) was used to quantify the response to challenge. Significant "protection" was defined as a fall in PEFR after a repeated challenge less than 50% of the fall observed on the first challenge. All patients had a fall in PEFR greater than 22% on the first challenge of the day. With repeated exercise 28 out of 29 patients had a fall in PEFR less than that observed on the first test and 12 had significant "protection". The fall in PEFR after the third exercise challenge was not significantly different to the second challenge and a "plateau" effect was observed. There was no significant difference in the fall in PEFR after the first and second histamine challenge although two of the 16 patients were significantly protected. After the third histamine challenge five of the 16 patients were significantly protected from the effects of the same dose of histamine. The degree to which repeated exercise challenge induces a diminished response is variable. With repeated challenge the response to histamine remains relatively constant in most patients though 30% may be expected to be refractory after a third challenge.
STUDIES ON ENDEMIC PNEUMONIA OF THE ALBINO RAT
Authors: John B. Nelson
Journal: The Journal of Experimental Medicine (1951)

A colony of albino rats was developed from three breeders (not germ-free) originally delivered by Cesarian section and artificially reared in the laboratories of Professor James A Reyniers. The colony has been maintained under quarantine since June, 1948, in the absence of any demonstrable involvement of the respiratory tract or of the middle ears. At autopsy pleuropneumonia-like organisms, Streptobacillus moniliformis, and the virus-like agent associated with endemic pneumonia were not recoverable from the lungs or the nasal passages of 81 young and adult rats. During the same time interval the morbidity rate of pneumonia in another rat colony known to be free from infectious catarrh was 51 per cent while the incidence of infection with the virus-like agent approached 100 per cent.
Kindlin-3–mediated integrin adhesion is dispensable for quiescent but essential for activated hematopoietic stem cells
Authors: Raphael Ruppert, Markus Moser, Markus Sperandio, Emanuel Rognoni, Martin Orban, Wen-Hsin Liu, Ansgar S. Schulz, Robert A.J. Oostendorp, Steffen Massberg, Reinhard Fässler
Journal: The Journal of Experimental Medicine (2015)

Hematopoietic stem cells (HSCs) generate highly dividing hematopoietic progenitor cells (HPCs), which produce all blood cell lineages. HSCs are usually quiescent, retained by integrins in specific niches, and become activated when the pools of HPCs decrease. We report that Kindlin-3-mediated integrin activation controls homing of HSCs to the bone marrow (BM) and the retention of activated HSCs and HPCs but not of quiescent HSCs in their BM niches. Consequently, Kindlin-3-deficient HSCs enter quiescence and remain in the BM when cotransplanted with wild-type hematopoietic stem and progenitor cells (HSPCs), whereas they are hyperactivated and lost in the circulation when wild-type HSPCs are absent, leading to their exhaustion and reduced survival of recipients. The accumulation of HSPCs in the circulation of leukocyte adhesion deficiency type III patients, who lack Kindlin-3, underlines the conserved functions of Kindlin-3 in man and the importance of our findings for human disease.
High serum concentrations of surfactant protein A in usual interstitial pneumonia compared with non-specific interstitial pneumonia
Authors: H Ishii
Journal: Thorax (2003)

<b>Background:</b> The pathological diagnosis of interstitial lung diseases (ILD) by surgical lung biopsy is important for clinical decision making. There is a need, however, to use serum markers for differentiating usual interstitial pneumonia (UIP) from other ILD. Surfactant protein (SP)-A, SP-D, KL-6, sialyl SSEA-1 (SLX), and sialyl Lewis<sup>a</sup> (CA19-9) are useful markers for the diagnosis and evaluation of activity of ILD. We have investigated the usefulness of these proteins as markers of UIP. <b>Methods:</b> Serum and bronchoalveolar lavage (BAL) fluid levels of the above five markers were measured in 57 patients with various forms of ILD (19 with UIP, 12 with non-specific interstitial pneumonia (NSIP), eight with bronchiolitis obliterans organising pneumonia (BOOP), and 10 with sarcoidosis), eight patients with the control disease (diffuse panbronchiolitis (DPB)), and nine healthy volunteers. <b>Results:</b> Serum levels of SP-A, SP-D, and KL-6 in patients with UIP and NSIP were significantly higher than in healthy volunteers. In particular, the serum levels of SP-A in patients with UIP were significantly higher than in patients with NSIP (p&lt;0.0001, mean difference –58.3 ng/ml, 95% confidence interval –81.6 to –35.0), and BAL fluid levels of SP-D in patients with UIP were significantly lower than in patients with NSIP (p=0.01, mean difference 322.4 ng/ml, 95% confidence interval 79.3 to 565.5). <b>Conclusion:</b> Serum SP-A levels may be clinically useful as a biomarker to differentiate between UIP and NSIP.
Lung Fibrosis, Premature Graying, and Macrocytosis
Authors: Daniel Charles Chambers, Belinda Edith Clarke, Julie McGaughran, Christine Kim Garcia
Journal: American Journal of Respiratory and Critical Care Medicine (2012)

A 42-year-old woman with an 8-year history of unexplained macrocytosis (MCV 114) and mild thrombocytopaenia (105) presented with dry cough and dyspnea. She was noted to have fine inspiratory crepitations on auscultation of the chest and gray eyebrows and hair roots (Figure 1). The patient admitted to coloring her hair since she went completely gray at the age of 17. A thin section computed tomography scan of the chest demonstrated subpleural and basal predominant reticular changes and early honeycombing (Figure 2, arrowheads), and open lung biopsy confirmed usual interstitial pneumonia (Figure 3, hematoxylin and eosin, ×20) with fibroblastic foci (arrow, inset ×100) and early honeycomb change. Her peripheral blood mononuclear cell telomere length was well below the 1st percentile for her age, and Sanger sequencing confirmed a novel mutation resulting in a change from alanine to aspartic acid at position 678 in the TERT gene (Figure 4). There was no family history of lung disease; however, details were limited because the patient was adopted. Telomerase deficiency leads to progressive shortening of telomere length and premature cellular senescence, and is a recently identified cause of familial and sporadic pulmonary fibrosis, with which premature graying and hematologic abnormalities are often associated (1–4).



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Crystal Structures of Prostaglandin D2 11-Ketoreductase (AKR1C3) in Complex with the Nonsteroidal Anti-Inflammatory Drugs Flufenamic Acid and Indomethacin
Authors: Andrew L. Lovering, Jon P. Ride, Christopher M. Bunce, Julian C. Desmond, Stephen M. Cummings, Scott A. White
Journal: Cancer Research (2004)

Abstract It is becoming increasingly well established that nonsteroidal anti-inflammatory drugs (NSAID) protect against tumors of the gastrointestinal tract and that they may also protect against a variety of other tumors. These activities have been widely attributed to the inhibition of cylooxygenases (COX) and, in particular, COX-2. However, several observations have indicated that other targets may be involved. Besides targeting COX, certain NSAID also inhibit enzymes belonging to the aldo-keto reductase (AKR) family, including AKR1C3. We have demonstrated previously that overexpression of AKR1C3 acts to suppress cell differentiation and promote proliferation in myeloid cells. However, this enzyme has a broad tissue distribution and therefore represents a novel candidate for the target of the COX-independent antineoplastic actions of NSAID. Here we report on the X-ray crystal structures of AKR1C3 complexed with the NSAID indomethacin (1.8 Å resolution) or flufenamic acid (1.7 Å resolution). One molecule of indomethacin is bound in the active site, whereas flufenamic acid binds to both the active site and the β-hairpin loop, at the opposite end of the central β-barrel. Two other crystal structures (1.20 and 2.1 Å resolution) show acetate bound in the active site occupying the proposed oxyanion hole. The data underline AKR1C3 as a COX-independent target for NSAID and will provide a structural basis for the future development of new cancer therapies with reduced COX-dependent side effects.
Statin Use and Breast Cancer: Prospective Results From the Women's Health Initiative
Authors: Jane A. Cauley, Anne McTiernan, Rebecca J. Rodabough, Andrea LaCroix, Douglas C. Bauer, Karen L. Margolis, Electra D. Paskett, Mara Z. Vitolins, Curt D. Furberg, Rowan T. Chlebowski
Journal: JNCI Journal of the National Cancer Institute (2006)

Despite experimental observations suggesting that 3-hydroxy-3-methylglutaryl coenzyme A inhibitors (statins) have antitumor activity, clinical studies have reached mixed conclusions about the relationship between statin use and breast cancer risk.To investigate associations between potency, duration of use, and type of statin used and risk of invasive breast cancer, we examined data for 156,351 postmenopausal women who were enrolled in the Women's Health Initiative. Information was collected on breast cancer risk factors and on the use of statins and other lipid-lowering drugs. Cox proportional hazards regression was used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs). Statistical tests were two-sided.Over an average follow-up of 6.7 years, 4383 invasive breast cancers were confirmed by medical record and pathology report review. Statins were used by 11,710 (7.5%) of the cohort. Breast cancer incidence was 4.09 per 1000 person-years (PY) among statin users and 4.28 per 1000 PY among nonusers. In multivariable models, the hazard ratio of breast cancer among users of any statin, compared with nonusers, was 0.91 (95% CI = 0.80 to 1.05, P = .20). There was no trend in risk by duration of statin use, with HR = 0.80 (95% CI = 0.63 to 1.03) for < 1 year of use, HR = 0.99 (95% CI = 0.80 to 1.23) for 1- < 3 years of use, and HR = 0.94 (95% CI = 0.75 to 1.18) for > or = 3 years of use. Hydrophobic statins (i.e., simvastatin, lovastatin, and fluvastatin) were used by 8106 women, and their use was associated with an 18% lower breast cancer incidence (HR = 0.82, 95% CI = 0.70 to 0.97, P = .02). Use of other statins (i.e., pravastatin and atorvastatin) or nonstatin lipid-lowering agents was not associated with breast cancer incidence.Overall statin use was not associated with invasive breast cancer incidence. Our finding that use of hydrophobic statins may be associated with lower breast cancer incidence suggests possible within-class differences that warrant further evaluation.
Cultural Differences in Access to Care
Authors: Lonnie R. Snowden, Ann-Marie Yamada
Journal: Annual Review of Clinical Psychology (2004)

As high-profile reviews have appeared and international interest has grown, sophisticated studies of the U.S. population continue to document racial and ethnic disparities in initiation of mental health care and in continuity of care. Many explanations focus on cultural factors: trust and treatment receptiveness, stigma, culturally distinctive beliefs about mental illness and mental health, culturally sanctioned ways of expressing mental health-related suffering and coping styles, and client preferences for alternative interventions and treatment-seeking pathways, as well as unresponsive programs and providers. The research itself has become more rigorous and informative, but it continues to lack theoretical focus and does not yet yield cumulative findings. Too few studies have addressed community and regional differences or differences between mental health treatment programs and systems, or considered mental health-related policies that are very likely linked to disparities. Theoretically well-formulated studies on representative samples can provide a comprehensive explanation of access disparities in cultural and culture-related terms that inform a broad-based plan of remedial intervention.
Prediction of Postoperative Recurrence-Free Survival in Non–Small Cell Lung Cancer by Using an Internationally Validated Gene Expression Model
Authors: Ranjana Mitra, Jinseon Lee, Jisuk Jo, Monica Milani, Jeanette N. McClintick, Howard J. Edenberg, Kenneth A. Kesler, Karen M. Rieger, Sunil Badve, Oscar W. Cummings, Ahmed Mohiuddin, Dafydd G. Thomas, Xianghua Luo, Beth E. Juliar, Lang Li, Clementina Mesaros, Ian A. Blair, Anjaiah Srirangam, Robert A. Kratzke, Clement J. McDonald, Jhingook Kim, David A. Potter
Journal: Clinical Cancer Research (2011)

This study was performed to discover prognostic genomic markers associated with postoperative outcome of stage I to III non-small cell lung cancer (NSCLC) that are reproducible between geographically distant and demographically distinct patient populations.American patients (n = 27) were stratified on the basis of recurrence and microarray profiling of their tumors was performed to derive a training set of 44 genes. A larger Korean patient validation cohort (n = 138) was also stratified by recurrence and screened for these genes. Four reproducible genes were identified and used to construct genomic and clinicogenomic Cox models for both cohorts.Four genomic markers, DBN1 (drebrin 1), CACNB3 (calcium channel beta 3), FLAD1 (PP591; flavin adenine dinucleotide synthetase), and CCND2 (cyclin D2), exhibited highly significant differential expression in recurrent tumors in the training set (P < 0.001). In the validation set, DBN1, FLAD1 (PP591), and CACNB3 were significant by Cox univariate analysis (P ≤ 0.035), whereas only DBN1 was significant by multivariate analysis. Genomic and clinicogenomic models for recurrence-free survival (RFS) were equally effective for risk stratification of stage I to II or I to III patients (all models P < 0.0001). For stage I to II or I to III patients, 5-year RFS of the low- and high-risk patients was approximately 70% versus 30% for both models. The genomic model for overall survival of stage I to III patients was improved by addition of pT and pN stage (P < 0.0013 vs. 0.010).A 4-gene prognostic model incorporating the multivariate marker DBN1 exhibits potential clinical utility for risk stratification of stage I to III NSCLC patients.