tbuckley/cabot-search huggingface dataset:
Genetic inactivation of<i>Nupr1</i>acts as a dominant suppressor event in a two-hit model of pancreatic carcinogenesis
Authors: Carla E Cano, Tewfik Hamidi, Maria Noé Garcia, Daniel Grasso, Céline Loncle, Stéphane Garcia, Ezequiel Calvo, Gwen Lomberk, Nelson Dusetti, Laurent Bartholin, Raul Urrutia, Juan L Iovanna
Journal: Gut (2013)

Nuclear protein 1 (Nupr1) is a major factor in the cell stress response required for Kras(G12D)-driven formation of pancreatic intraepithelial neoplastic lesions (PanINs). We evaluated the relevance of Nupr1 in the development of pancreatic cancer. We investigated the role of Nupr1 in pancreatic ductal adenocarcinoma (PDAC) progression beyond PanINs in Pdx1-cre;LSL-Kras(G12D);Ink4a/Arf(fl/fl)(KIC) mice. Even in the context of the second tumorigenic hit of Ink4a/Arf deletion, Nupr1 deficiency led to suppression of malignant transformation involving caspase 3 activation in premalignant cells of KIC pancreas. Only half of Nupr1-deficient;KIC mice achieved PDAC development, and incident cases survived longer than Nupr1(wt);KIC mice. This was associated with the development of well-differentiated PDACs in Nupr1-deficient;KIC mice, which displayed enrichment of genes characteristic of the recently identified human classical PDAC subtype. Nupr1-deficient;KIC PDACs also shared with human classical PDACs the overexpression of the Kras-activation gene signature. In contrast, Nupr1(wt);KIC mice developed invasive PDACs with enriched gene signature of human quasi-mesenchymal (QM) PDACs. Cells derived from Nupr1-deficient;KIC PDACs growth in an anchorage-independent manner in vitro had higher aldehyde dehydrogenase activity and overexpressed nanog, Oct-4 and Sox2 transcripts compared with Nupr1(wt);KIC cells. Moreover, Nupr1-deficient and Nurpr1(wt);KIC cells differed in their sensitivity to the nucleoside analogues Ly101-4b and WJQ63. Together, these findings show the pivotal role of Nupr1 in both the initiation and late stages of PDAC in vivo, with a potential impact on PDAC cell stemness. According to Nupr1 status, KIC mice develop tumours that phenocopy human classical or QM-PDAC, respectively, and present differential drug sensitivity, thus becoming attractive models for preclinical drug trials.
American ambivalence toward academic freedom
Authors: Steve Fuller
Journal: Behavioral and Brain Sciences (2006)

Why are U.S. academics, even after tenure and promotion, so timid in their exercise of academic freedom? Part of the problem is institutional – academics are subject to a long probationary period under tight collegial control – but part of the problem is ideological. A hybrid of seventeenth-century British and nineteenth-century German ideals, U.S. academia – and the nation more generally – remains ambivalent toward the value of academic freedom, ultimately inhibiting an unequivocal endorsement.
Role of nitric oxide and angiotensin II in diabetes mellitus-induced glomerular hyperfiltration.
Authors: K M Mathis, R O Banks
Journal: Journal of the American Society of Nephrology (1996)

The goal of this study was to determine what extent nitric oxide (NO) and/or angiotensin II (AngII) are involved in the hyperfiltration observed in rats with streptozotocin-induced diabetes mellitus. Studies were performed on anesthetized rats 7 to 10 days after the induction of diabetes. Nitro-L-arginine (LNA) was used to inhibit NO synthesis, and losartan was used to block AngII receptors. Three protocols were utilized: (i) control and diabetic rats treated with a constant infusion of LNA; (ii) control and diabetic rats treated first with a constant infusion of losartan and then LNA plus losartan; and (iii) nephrectomized control and diabetic rats treated with LNA (to evaluate the involvement of renal vasoactive factors other than AngII in the systemic response to LNA). Compared with controls, diabetics had a significantly elevated baseline GFR but the same mean arterial pressure (MAP). In Protocol i, LNA caused the same increase in MAP in both groups but only decreased the GFR in controls. In Protocol ii, losartan caused a significant increase in the GFR only in controls. The coinfusion of LNA and losartan caused no change in the GFR in controls but induced a large GFR decrease in diabetics. Losartan had no effect on MAP in either group and did not affect the LNA-induced increase in MAP in either group. The LNA-induced increase in MAP was greater in nephrectomized rats compared with that in intact rats. These data indicate that (1) neither changes in the synthesis of NO nor changes in the actions of AngII, alone, are responsible for the hyperfiltration observed in streptozotocin-induced diabetes; (2) a combined alteration in these two systems may account for diabetes-induced hyperfiltration; (3) the LNA-induced decrease in GFR in control but not in diabetic rats is an AngII-mediated event; and (4) AngII is not involved in the LNA-induced increase in MAP in either control or diabetic rats but other renal factors cannot be ruled out in this response.
Randomized Multicenter Trial of Sentinel Node Biopsy Versus Standard Axillary Treatment in Operable Breast Cancer: The ALMANAC Trial
Authors: Robert E. Mansel, Lesley Fallowfield, Mark Kissin, Amit Goyal, Robert G. Newcombe, J. Michael Dixon, Constantinos Yiangou, Kieran Horgan, Nigel Bundred, Ian Monypenny, David England, Mark Sibbering, Tholkifl I. Abdullah, Lester Barr, Utheshtra Chetty, Dudley H. Sinnett, Anne Fleissig, Dayalan Clarke, Peter J. Ell
Journal: JNCI Journal of the National Cancer Institute (2006)

Background: Sentinel lymph node biopsy in women with operable breast cancer is routinely used in some countries for staging the axilla despite limited data from randomized trials on morbidity and mortality outcomes. We conducted a multicenter randomized trial to compare quality-of-life outcomes between patients with clinically node-negative invasive breast cancer who received sentinel lymph node biopsy and patients who received standard axillary treatment. Methods: The primary outcome measures were arm and shoulder morbidity and quality of life. From November 1999 to October 2003, 1031 patients were randomly assigned to undergo sentinel lymph node biopsy (n = 515) or standard axillary surgery (n = 516). Patients with sentinel lymph node metastases proceeded to delayed axillary clearance or received axillary radiotherapy (depending on the protocol at the treating institution). Intention-to-treat analyses of data at 1, 3, 6, and 12 months after surgery are presented. All statistical tests were two-sided. Results: The relative risks of any lymphedema and sensory loss for the sentinel lymph node biopsy group compared with the standard axillary treatment group at 12 months were 0.37 (95% confidence interval [CI] = 0.23 to 0.60; absolute rates: 5% versus 13%) and 0.37 (95% CI = 0.27 to 0.50; absolute rates: 11% versus 31%), respectively. Drain usage, length of hospital stay, and time to resumption of normal day-to-day activities after surgery were statistically significantly lower in the sentinel lymph node biopsy group (all P <.001), and axillary operative time was reduced ( P = .055). Overall patient-recorded quality of life and arm functioning scores were statistically significantly better in the sentinel lymph node biopsy group throughout (all P ≤.003). These benefits were seen with no increase in anxiety levels in the sentinel lymph node biopsy group ( P >.05). Conclusion: Sentinel lymph node biopsy is associated with reduced arm morbidity and better quality of life than standard axillary treatment and should be the treatment of choice for patients who have early-stage breast cancer with clinically negative nodes.
Rel A Is an Independent Biomarker of Clinical Outcome in Chronic Lymphocytic Leukemia
Authors: Saman Hewamana, Thet Thet Lin, Clare Rowntree, Kamaraj Karunanithi, Guy Pratt, Robert Hills, Chris Fegan, Paul Brennan, Chris Pepper
Journal: Journal of Clinical Oncology (2009)

We recently demonstrated the biologic importance of the nuclear factor kappa B (NF-kappaB) subunit Rel A in chronic lymphocytic leukemia (CLL) and hypothesized that Rel A DNA binding would have prognostic significance in this disease.Rel A DNA binding was quantified in nuclear extracts derived from 131 unselected CLL patient samples using a quantitative DNA-binding enzyme-linked immunosorbent assay-based method. We then investigated the ability of Rel A to predict for the requirement for treatment and survival and compared our findings with other established prognostic markers.Rel A DNA binding was strongly associated with advanced Binet stage (P < .0001) but did not correlate with immunoglobulin V(H) (IgV(H)) mutation status (P = .25), CD38 expression (P = .87), or zeta-chain-associated protein kinase 70 (ZAP-70) expression (P = .55). It was predictive of time to first treatment (P = .02) and time to subsequent treatment (P = .0001). In addition, Rel A was the most predictive marker of survival both from date of diagnosis (hazard ratio [HR], 9.1; P = .01) and date of entry into the study (HR, 3.9; P = .05) and retained prognostic significance in multivariate analysis for both time to first treatment and overall survival in the presence of Binet stage, IgV(H) mutation status, CD38, and ZAP-70.Rel A is an independent prognostic marker of survival in CLL and seems to have the unique capacity to predict the duration of response to therapy. Prospective assessment of Rel A as a marker of clinical outcome and as a therapeutic target are now warranted.
The characteristics, cellular uptake and intracellular trafficking of nanoparticles made of hydrophobically-modified chitosan
Authors: Ya-Ling Chiu, Yi-Cheng Ho, Yu-Ming Chen, Shu-Fen Peng, Cherng-Jyh Ke, Ko-Jie Chen, Fwu-Long Mi, Hsing-Wen Sung
Journal: Journal of Controlled Release (2010)
Protein S and C antigen levels in proteinuric patients: Dependence on type of glomerular pathology
Authors: Michael Allon, Oved Soffer, Bruce L. Evatt, Gwen Hixon, Carol S. Wideman
Journal: American Journal of Hematology (1989)

Abstract The cause of the thrombotic tendency in nephrotic patients is unknown. Recent reports of thrombotic complications in patients with deficiencies of protein C or protein S (natural inhibitors of coagulation) have raised the possibility that decreased levels of these proteins may play a role in the hypercoagulable state of nephrotic patients. We measured the levels of protein C, total protein S, and free protein S antigens in 42 patients (21 nephrotic and 21 non‐nephrotic) with one of four types of glomerular pathology: diabetic nephropathy (DM), focal glomerular sclerosis (FGS), membranous glomerulonephritis (MGN), and chronic renal failure due to hypertension (CRF). Protein C and total protein S antigen levels were significantly higher in FGS and MGN than they were in DM or CRF. Free protein S levels were lower in DM than they were in MGN. Protein C, total protein S, and free protein S levels did not significantly correlate with either serum albumin or degree of proteinuria. The mean levels of the three proteins did not differ between nephrotic and non‐nephrotic patients. Free protein S and protein C were, however, significantly correlated ( P &lt; .005 and P &lt; .002, respectively) with the type of glomerular pathology, independent of differences in age, sex, serum albumin, or degree of proteinuria. These data suggest that abnormalities of free protein S and protein C are related to the nature of the underlying renal disease, rather than to the degree of proteinuria.
17q21 variants modify the association between early respiratory infections and asthma
Authors: L.A.M. Smit, E. Bouzigon, I. Pin, V. Siroux, F. Monier, H. Aschard, J. Bousquet, F. Gormand, J. Just, N. Le Moual, R. Nadif, P. Scheinmann, D. Vervloet, M. Lathrop, F. Demenais, F. Kauffmann
Journal: European Respiratory Journal (2009)

Single nucleotide polymorphisms (SNPs) at chromosome 17q21 confer an increased risk of early-onset asthma. The objective was to study whether 17q21 SNPs modify associations between early respiratory infections and asthma. Association analysis was conducted in 499 children (268 with asthma, median age 11 yrs) from the Epidemiological Study on the Genetics and Environment of Asthma (EGEA). The 12-yr follow-up data were used to assess persistent or remittent asthma in young adulthood. Respiratory infection before 2 yrs of age was assessed retrospectively. For the 12 17q21 SNPs studied, the odds ratios (OR) for association between infection and early-onset asthma (age at onset ≤4 yrs) were higher in carriers of risk genotypes (OR 3.42–6.36) than in noncarriers (OR 1.84–2.44; p-value for interaction 0.02–0.04 for five SNPs). Risk genotypes also increased the association between infection and childhood asthma that remits in adulthood (OR 4.84–7.16 in carriers and 1.74–2.25 in noncarriers; p-value for interaction 0.008–0.05 for 10 SNPs). In children with 17q21 risk genotypes and early-life environmental tobacco smoke (ETS) exposure, associations between infection and asthma were further enhanced. 17q21 genetic variants and early ETS exposure enhance the association between early respiratory infections and early-onset asthma and childhood asthma that remits in adulthood.
Noninvasive Ventilation With vs Without Early Surfactant to Prevent Chronic Lung Disease in Preterm Infants
Authors: Tetsuya Isayama, Chatree Chai-Adisaksopha, Sarah D. McDonald
Journal: JAMA Pediatrics (2015)

Controversy exists regarding which of the 2 major strategies currently used to prevent chronic lung disease (CLD) in preterm infants is optimal: noninvasive continuous positive airway pressure (NCPAP) or intubate-surfactant-extubate (INSURE). Preterm infants often require surfactant administration because of respiratory distress syndrome.To evaluate whether early INSURE or NCPAP alone is more effective in preventing CLD, death, or both.We searched the MEDLINE, EMBASE, Cochrane Controlled Trials Register, and Cumulative Index to Nursing and Allied Health Literature databases from their inception to January 2, 2015, along with conference proceedings and trial registrations.Randomized clinical trials that compared early INSURE with NCPAP alone in preterm infants who had never been intubated before the study entry were selected. Among 1761 initially identified articles, 9 trials (1551 infants) were included.Duplicate study selection and data extraction were performed. Meta-analysis was conducted using random-effects models with quality-of-evidence assessment according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system.Seven main outcomes were selected a priori to be assessed according to GRADE, including a composite outcome of CLD and/or death, CLD alone, death alone, air leakage, severe intraventricular hemorrhage, neurodevelopmental impairment, and a composite outcome of death and/or neurodevelopmental impairment.There were no statistically significant differences between early INSURE and NCPAP alone for all outcomes assessed. However, the relative risk (RR) estimates appeared to favor early INSURE over NCPAP alone, with a 12% RR reduction in CLD and/or death (RR, 0.88; 95% CI, 0.76-1.02; risk difference [RD], -0.04; 95% CI, -0.08 to 0.01; moderate quality of evidence), a 14% decrease in CLD (RR, 0.86; 95% CI, 0.71-1.03; RD, -0.03; 95% CI, -0.06 to 0.01; moderate quality of evidence), and a 50% decrease in air leakage (RR, 0.50; 95% CI, 0.24-1.07; RD, -0.03; 95% CI, -0.06 to 0.00; very low quality of evidence). The sample size was less than the optimal information size.Currently, no evidence suggests that either early INSURE or NCPAP alone is superior to the other. INSURE does not appear to increase CLD and/or death, CLD alone, and air leakage and may reduce these adverse outcomes compared with NCPAP alone. Further adequately powered trials are required.
Anti-interleukin 17A therapy inhibits tumour necrosis factor-mediated bone loss by modulation of T cell balance
Authors: K Polzer, M Koenders, W Baum, A Patakas, I Mcinnes, L Joosten, G Schett, W van den Berg, J Zwerina
Journal: Annals of the Rheumatic Diseases (2010)

Immune activation is the major driver of local and systemic bone loss. Pro-inflammatory cytokines, in particular tumour necrosis factor (TNF), link immune activation with bone loss. Recently, T cells have been implicated as regulators of bone turnover. Th1 and Th2 associated lymphokines such as interleukin 12 (IL12), interferon γ and IL4 …
Abstract P6-07-12: Akt2 expression is associated with good long-term prognosis in estrogen receptor positive breast cancer
Authors: H Fohlin, G Pérez-Tenorio, T Fornander, L Skoog, B Nordenskjöld, J Carstensen, O Stål
Journal: Cancer Research (2012)

Abstract Introduction: Akt is a signaling modulator for many cellular processes, including metabolism, cell proliferation, cell survival and cell growth. Three isoforms of Akt have been identified, but only a few studies have concerned the isoform-specific roles in the prognosis of breast cancer patients. The aim of this study was to investigate the prognostic value of Akt1 and Akt2 in estrogen receptor positive (ER+) and estrogen receptor negative (ER−) breast cancer with long-term follow-up. Material and Methods: The expression of Akt in tumor tissue was analyzed with immunohistochemistry in a cohort of 272 postmenopausal patients with stage II breast cancer. Hazard ratios and 95% confidence intervals were estimated using the Cox's proportional hazards model. Results: The risk of distant recurrence was reduced for patients with ER+ tumors expressing Akt2 compared to patients with no Akt2 expression (HR = 0.49, 95% CI 0.29–0.82, p = 0.007). When adjusting for important clinical tumor characteristics and treatment, Akt2 was still an independent prognostic factor (HR = 0.38, 95% CI 0.21–0.68, p = 0.001) and the association remained long-term. After more than five years since diagnosis the risk reduction was 57% for patients with Akt2 positive tumors. The prognostic value of Akt2 increased with higher estrogen receptor levels from no effect among patients with ER− tumors to 68% risk reduction for the group with high ER-levels (P for trend= 0.042). Akt1 showed no significant prognostic information. Conclusion: Our results indicate that Akt2 expression is associated with a lower distant recurrence rate for patients with ER+ tumors and that this association remains long-term. The prognostic value of Akt2 increases with higher estrogen receptor expression, motivating further mechanistic studies on the role of Akt2 in ER+ breast cancer. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-07-12.
Genetically Altered Fields as Origin of Locally Recurrent Head and Neck Cancer
Authors: Maarten P. Tabor, Ruud H. Brakenhoff, Henrique J. Ruijter-Schippers, J. Alain Kummer, C. René Leemans, Boudewijn J. M. Braakhuis
Journal: Clinical Cancer Research (2004)

Surgeons treating patients with head and neck squamous cell carcinoma (HNSCC) rely heavily on histology to decide whether the resection margins are tumor free and subsequent adjuvant treatments can be omitted. However, despite the presence of tumor-free margins, 10-30% of HNSCC patients still develop a locally recurrent tumor. Evidence is available that recurrent cancer develops from either (a). outgrowth of a relatively small number of tumor cells that have not been detected by the pathologist or (b). a precursor lesion in which additional genetic alterations have led again to invasive cancer.In a retrospective study on 13 HNSCC cases, we analyzed the primary tumor, its surrounding histologically tumor-free resection margins, and local recurrences for loss of heterozygosity (22 microsatellite markers on 6 chromosomes) and TP53 mutations to determine the origin of the recurrent cancer.A precursor lesion was absent in 5 of 13 (39%) cases, and the genetic similarity of the primary and recurrent cancer was high, providing evidence that residual cancer cells were the origin of recurrence. For the remaining eight cases (61%) a genetically related precursor lesion (field) was detected, and for five of these cases, evidence was found that both the primary and recurrent carcinoma originated from this field. The remaining three cases were less conclusive.This study explains the pathobiology of locally recurrent HNSCC in patients with histologically tumor-free resection margins and indicates that the development of novel therapies to decrease the local recurrence rates in HNSCC should not only be focused on eradicating residual cancer cells but also on the precursor lesions that are left behind.
Prognostic Relevance of AGR2 Expression in Breast Cancer
Authors: Florian Rudolf Fritzsche, Edgar Dahl, Stefan Pahl, Mick Burkhardt, Jun Luo, Empar Mayordomo, Tserenchunt Gansukh, Anja Dankof, Ruth Knuechel, Carsten Denkert, Klaus-Jürgen Winzer, Manfred Dietel, Glen Kristiansen
Journal: Clinical Cancer Research (2006)

We aimed to evaluate the expression of the human anterior gradient-2 (AGR2) in breast cancer on RNA and protein level and to correlate it with clinicopathologic data, including patient survival.AGR2 mRNA expression was assessed by reverse transcription-PCR in 25 breast cancer samples and normal tissues. A polyclonal rabbit AGR antiserum was used for immunohistochemistry on 155 clinicopathologically characterized cases. Statistical analyses were applied to test for prognostic and diagnostic associations.Immunohistochemical detection of AGR2 was statistically significantly associated with positive estrogen receptor status and lower tumor grade. AGR2-positive tumors showed significantly longer overall survival times in univariate analyses. For the subgroup of nodal-negative tumors, an independent prognostic value of AGR2 was found.The expression of AGR2 in breast cancer is strongly associated with markers of tumor differentiation (estrogen receptor positivity, lower tumor grade). A prognostic effect of AGR2 for overall survival could be shown, which became independently significant for the group of nodal-negative tumors.