tbuckley/cabot-search huggingface dataset:
Re: Estimation of Tamoxifen's Efficacy for Preventing the Formation and Growth of Breast Tumors
Authors: Sylvie Ménard, Elda Tagliabue, Manuela Campiglio, Andrea Balsari
Journal: JNCI Journal of the National Cancer Institute (2000)

The recent report by Radmacher and Simon (1) addressed the issue of whether the effect of tamoxifen observed in the National Surgical Adjuvant Breast and Bowel Project’s Breast Cancer Prevention Trial (BCPT) (2) was “mainly due to prevention of newly forming tumors or to treatment of occult disease.” On the basis of analyses in various tumor growth models, those authors (1) concluded that the reduced tumor incidence in the tamoxifen-treated group was probably due to both effects. By contrast, our recent data (3) obtained with the use of a transgenic mice model of spontaneous development of HER2/neu-positive, estrogen-independent tumors suggest that the protective effect observed in the BCPT is due only to treatment of occult disease. Indeed, in our animal model, early treatment with tamoxifen inhibited the formation of terminal buds in the mammary gland and clearly prevented spontaneous tumors. In contrast, late treatment—when subclinical tumors were already present—had no effect, as expected for the treatment of estrogen-independent tumors. In the clinical trial, protection only from estrogen receptor-positive tumors was observed, consistent with the dependence on receptor expression of the therapeutic effect of tamoxifen—if tamoxifen acted to prevent new tumors by reducing the number of normal breast epithelial cells at risk of transformation, then both estrogen receptor-positive and estrogen receptor-negative tumors should have been prevented. Moreover, the reduced incidence of breast cancer associated with tamoxifen was not more pronounced in premenopausal women, in whom tamoxifen is likely to inhibit the hormones that govern homeostasis of the normal epithelial cells during the different phases of the menstrual cycle. Therefore, we think that the protective effect observed in the BCPT is due mainly to the treatment of occult disease. However, it might well be that a longer follow-up period in the BCPT will also reveal a reduced incidence of estrogen receptor-negative tumors after long-term treatment with tamoxifen, indicating the prevention of newly formed tumors.
Quadratus lumborum asymmetry is not isolated to the dominant side in junior cricket fast bowlers
Authors: Alex Kountouris, Marc Portus, Jill Cook
Journal: British Journal of Sports Medicine (2011)

Bowling-side quadratus lumborum (QL) asymmetries have been previously reported on the dominant side in junior cricket fast bowlers using MRI. The aim of this study was to investigate QL asymmetry when measuring with two different methods; first using a small number of images with clear muscle borders and second using a larger number of images with less strict inclusion criteria.MRI was performed on 38 junior (14.9 years) cricket fast bowlers prior to the start of a cricket season. Each MR image slice was evaluated to determine whether the QL muscle contour was visible and was assigned an image-quality rating for inclusion in the study. The cross-sectional area of each included QL image was measured and compared with the corresponding image on the other side of the spine to determine side-to-side difference (asymmetries).Using the main method of including only high-quality MR images, 25% of MR images, where QL was in the field of view, met the inclusion criteria. The mean QL asymmetry was 13%, while 55% of participants had asymmetries greater than 10%. There was no significant difference in the number of participants with dominant and non-dominant side QL asymmetry. However, there was a significant difference in the magnitude of asymmetry between the dominant side (10.5%) and non-dominant (16.4%) asymmetries. The intraclass correlation coefficient for repeated measurements of QL asymmetry for randomly selected images (18%) was excellent (ICC 0.966, 95% CI 0.89 to 0.99). Using the second measurement method, with less strict inclusion criteria for MR images, similar results on the distribution of QL asymmetry were found.Contrary to previous research, this study demonstrated that there was a similar distribution of QL asymmetry between the dominant and non-dominant side. The presence of only dominant side asymmetry must therefore be questioned.
The influence of nitric oxide synthase 2 on cutaneous wound angiogenesis
Authors: L.C. Chin, P. Kumar, J.A. Palmer, J.A. Rophael, J.H. Dolderer, G.P.L. Thomas, W.A. Morrison, A.J. Penington, A.G. Stewart, G.M. Mitchell
Journal: British Journal of Dermatology (2011)

Background Inducible nitric oxide synthase (nitric oxide synthase 2, NOS 2) inhibition significantly suppresses chronically ischaemic skin flap survival, possibly because of reduced angiogenesis. Objectives To investigate the effect of genetic NOS 2 inhibition on cutaneous wound angiogenesis in two in vivo murine models. The impact of NOS 2 manipulation on vascular endothelial growth factor (VEGF)‐A stimulated and fibroblast growth factor (FGF)‐2 stimulated angiogenesis was also investigated in the Matrigel® plug assay. Methods (i) Matrigel plugs/incisional wounds: two groups of NOS 2−/− mice and two groups of wild‐type (WT) mice had bilateral Matrigel plugs containing 500 ng mL−1 VEGF‐A or 1000 ng mL−1 FGF‐2 injected subcutaneously in the abdomen. A 2·5 cm long dorsal incisional skin wound was created and sutured closed in the same animals. Wounds and plugs were explored at 7 or 12 days. (ii) Excisional wounds: dorsal 0·5 × 1·0 cm excisional skin wounds were created in four groups (two NOS 2−/− and two WT) and explored at 7 or 14 days. Wounds and Matrigel plugs were examined histologically and morphometrically for determination of percentage vascular volume (PVV). Results The PVV in NOS 2−/− incisional wounds and excisional wounds was significantly less than in WT wounds (P =0·05 and P <0·001, respectively). The PVV was significantly less in VEGF‐A stimulated Matrigel plugs compared with FGF‐2 stimulated plugs in NOS 2−/− mice (P <0·01), but not in WT mice. Conclusions NOS 2 is significantly involved in angiogenic signalling in healing skin wounds, particularly within the first 7 days. However, Matrigel plug vascularization suggests that the role of NOS 2 in angiogenesis is related to VEGF‐A but not FGF‐2 stimulated angiogenesis.
Phase II Study of Belagenpumatucel-L, a Transforming Growth Factor Beta-2 Antisense Gene-Modified Allogeneic Tumor Cell Vaccine in Non–Small-Cell Lung Cancer
Authors: John Nemunaitis, Robert O. Dillman, Paul O. Schwarzenberger, Neil Senzer, Casey Cunningham, Jodi Cutler, Alex Tong, Padmasini Kumar, Beena Pappen, Cody Hamilton, Edward DeVol, Phillip B. Maples, Lily Liu, Terry Chamberlin, Daniel L. Shawler, Habib Fakhrai
Journal: Journal of Clinical Oncology (2006)

Belagenpumatucel-L is a nonviral gene-based allogeneic tumor cell vaccine that demonstrates enhancement of tumor antigen recognition as a result of transforming growth factor beta-2 inhibition.We performed a randomized, dose-variable, phase II trial involving stages II, IIIA, IIIB, and IV non-small-cell lung cancer patients. Each patient received one of three doses (1.25, 2.5, or 5.0 x 10(7) cells/injection) of belagenpumatucel-L on a monthly or every other month schedule to a maximum of 16 injections. Immune function, safety, and anticancer activity were monitored.Seventy-five patients (two stage II, 12 stage IIIA, 15 stage IIIB, and 46 stage IV patients) received a total of 550 vaccinations. No significant adverse events were observed. A dose-related survival difference was demonstrated in patients who received > or = 2.5 x 10(7) cells/injection (P = .0069). Focusing on the 61 late-stage (IIIB and IV) assessable patients, a 15% partial response rate was achieved. The estimated probabilities of surviving 1 and 2 years were 68% and 52%, respectively for the higher dose groups combined and 39% and 20%, respectively, for the low-dose group. Immune function was explored in the 61 advanced-stage (IIIB and IV) patients. Increased cytokine production (at week 12 compared with patients with progressive disease) was observed among clinical responders (interferon gamma, P = .006; interleukin [IL] -6, P = .004; IL-4, P = .007), who also displayed an elevated antibody-mediated response to vaccine HLAs (P = .014). Furthermore, positive enzyme-linked immunospot reactions to belagenpumatucel-L showed a correlation trend (P = .086) with clinical responsiveness in patients achieving stable disease or better.Belagenpumatucel-L is well tolerated, and the survival advantage justifies further phase III evaluation.
Clinical outcomes according to QRS duration and morphology in the Eplerenone in Mild Patients: Hospitalization and SurvIval Study in Heart Failure (EMPHASIS‐HF)
Authors: Jane A. Cannon, Timothy J. Collier, Li Shen, Karl Swedberg, Henry Krum, Dirk J. Van Veldhuisen, John Vincent, Stuart J. Pocock, Bertram Pitt, Faiez Zannad, John J.V. McMurray
Journal: European Journal of Heart Failure (2015)
A phase I study of rhizoxin (NSC 332598) by 72-hour continuous intravenous infusion in patients with advanced solid tumors
Authors: A.W. Tolcher, C. Aylesworth, J. Rizzo, E. Izbicka, E. Campbell, J. Kuhn, G. Weiss, D.D. Von Hoff, E.K. Rowinsky
Journal: Annals of Oncology (2000)
Tissue and Cellular Localization of a Novel Polycystic Kidney Disease–Like Gene Product, Polycystin-L
Authors: Nuria Basora, Hideki Nomura, Urs V. Berger, Cherie Stayner, Lei Guo, Xiaohua Shen, Jing Zhou
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. Polycystin-L (PCL), the third member of the polycystin family of proteins, functions as a Ca2+-modulated nonselective cation channel when expressed in Xenopus oocytes. Polycystin-1 and -2 are mutated in autosomal-dominant polycystic kidney disease (ADPKD), but the role of PCL in disease has not been determined. In this study, an anti-peptide polyclonal antiserum was generated against the carboxyl terminal domain of human PCL and used to determine the patterns of expression and distribution of PCL by indirect immunofluorescence in both developing and adult mice. The results show that PCL is predominantly expressed in adult mouse tissues and has a more restricted pattern of expression than either polycystin-1 or -2. In the kidney, PCL expression was first detected at E16, and levels increased into adulthood. Localization of PCL was predominantly found in the apical region of the principal cells of inner medullary collecting ducts. PCL was also found in discrete cell types of the retina, testis, liver, pancreas, heart, and spleen, but it was not detected in the lung. These data in combination with evidence of PCL channel activity are crucial for elucidating the physiologic role of this novel cation channel and may shed light on the function of inner medullary collecting ducts and polycystins. The expression pattern of PCL suggests that it is unlikely to be a candidate gene for ADPKD, but it remains a potential candidate for other as yet unmapped human cystic disorders.
Genome-wide identification of microRNAs regulating cholesterol and triglyceride homeostasis
Authors: Alexandre Wagschal, S Hani Najafi-Shoushtari, Lifeng Wang, Leigh Goedeke, Sumita Sinha, Andrew S deLemos, Josh C Black, Cristina M Ramírez, Yingxia Li, Ryan Tewhey, Ida Hatoum, Naisha Shah, Yong Lu, Fjoralba Kristo, Nikolaos Psychogios, Vladimir Vrbanac, Yi-Chien Lu, Timothy Hla, Rafael de Cabo, John S Tsang, Eric Schadt, Pardis C Sabeti, Sekar Kathiresan, David E Cohen, Johnathan Whetstine, Raymond T Chung, Carlos Fernández-Hernando, Lee M Kaplan, Andre Bernards, Robert E Gerszten, Anders M Näär
Journal: Nature Medicine (2015)
Plasma renin activity during exercise in the dog.
Authors: M D Lifschitz, L D Horwitz
Journal: Circulation Research (1976)

Previous workers have suggested that a rise in plasma renin activity (PRA) may mediate some of the hemodynamic changes associated with exercise. To test this hypothesis in nine dogs chronically instrumented for measurement of aortic pressure (catheter) or cardiac output (ascending aorta electromagnetic flow probe) PRA was measured by radioimmunoassay in blood samples drawn before and during running on a level treadmill at 4-8 miles per hour. Exercise caused increases in heart rate from 96 +/- 5 (SE) to 186 +/- 7 beats/min, cardiac output from 2.8 +/- 0.3 to 6.2 +/- 0.6 liters/min, and mean aortic pressure from 115 +/- 5 to 132 +/- 5 mm Hg (P less than 0.01). Mean PRA was 6.6 +/- 0.7 (SE) ng of angiotensin 1/ml per 3 hours before and 7.6 +/- 1.2 ng Ang I during exercise, values that are not different statistically. Propranolol reduced PRA at rest from 8.6 +/- 1.1 to 5.9 +/- 1.1 ng Ang 1 (P less than 0.05), but there was no significant difference between resting and exercise levels, although the increments in heart rate, cardiac output, and mean aortic pressure were reduced. Standing on hindlimbs for 5 minutes did not cause a change in mean aortic pressure or PRA. However, administration of pentolinium reduced mean aortic pressure, and PRA rose from 6.0 +/- 1.1 to 9.8 +/- 1.5 ng Ang I. Exercise, with or without beta-adrenergic blockade, does not cause increased PRA in conscious dogs in which the renin-angiotensin system is normally responsive.
PET Study of [<sup>18</sup>F]6-Fluoro-<scp>l</scp>-Dopa Uptake in Neuroleptic- and Mood-Stabilizer-Naive First-Episode Nonpsychotic Mania: Effects of Treatment With Divalproex Sodium
Authors: Lakshmi N Yatham, Peter F Liddle, I-Shin Shiah, Raymond W Lam, Elton Ngan, Gayle Scarrow, Miguel Imperial, Jon Stoessl, Vesna Sossi, Thomas J Ruth
Journal: American Journal of Psychiatry (2002)

OBJECTIVE: Although dopaminergic hyperactivity has been implicated in mania, the precise location in the brain of the abnormality is unclear. This study assessed presynaptic dopamine function in neuroleptic- and mood-stabilizer-naive nonpsychotic first-episode manic patients before and after treatment with divalproex sodium by measuring [18F]6-fluoro-l-dopa ([18F]DOPA) uptake in the striatum with positron emission tomography (PET). METHOD: Thirteen patients with DSM-IV bipolar I disorder, manic episode, and 13 healthy comparison subjects underwent [18F]DOPA PET scans. Ten of the 13 patients had repeat PET scans 2–6 weeks after beginning treatment with divalproex sodium monotherapy. [18F]DOPA uptake rate constants (Ki values) in the striatum were calculated by using graphical analysis with activity from the occipital cortex as the input function. RESULTS: No significant differences in [18F]DOPA uptake rate constants in the striatum were found between the manic patients and the comparison subjects. After treatment with divalproex sodium, [18F]DOPA rate constants were significantly reduced in the patients and were lower in the patients than in the comparison subjects. CONCLUSIONS: Although presynaptic dopamine function as reflected by [18F]DOPA uptake is not altered in mania, presynaptic dopamine function in manic patients was lower after treatment with divalproex sodium.
The Formation of Bile Canaliculi in Human Hepatoma Cell Lines
Authors: Jen-Hwey Chiu, Cheng-Po Hu, Wing-Yiu Lui, Szecheng J. Lo, Chungming Chang
Journal: Hepatology (1990)

Hepatocytes, known as polarized epithelial cells, are composed of sinusoid, basolateral and bile canalicular domains. Each domain contains proteins specific for it. Our studies indicate that the well-differentiated human hepatoma cell lines HepG2 and HuH-7 formed bile canaliculi in tissue culture, whereas the poorly differentiated hepatoma cell lines HA22T/VGH and SK-HEP-1 did not. We also used the 9B2 monoclonal antibody, previously shown to be specific for the human bile canalicular domain, to study formation of bile canaliculi in these human hepatoma cell lines. All four cell lines synthesize the 140-kD 9B2 antigen. Studies using peroxidase-antiperoxidase staining and immunoelectron microscopy revealed that the 9B2 antigen was first detected in cytoplasm and packaged in microvilli-lined vesicles, then vectorially transported to the cell surface and eventually fused with microvilli-lined vesicles from neighboring cells to form bile canaliculi in well-differentiated hepatoma cell lines. However, the 9B2 antigen of poorly differentiated lines was synthesized in cytoplasm, then transported directly to and evenly distributed on the cell membrane. These results lead us to conclude that human hepatoma cell lines could serve as a good in vitro model to study the formation of bile canaliculi in human hepatocytes. The bile canaliculi of human hepatocytes may be preformed and assembled in the intracellular, microvilli-lined vesicles, then vectorially transported to the cell surface, where they form the bile canaliculi through vesicles fusion. Finally, formation of bile canaliculi and transport of 9B2 antigen may be related to the differentiation of hepatocytes or progression stages of human hepatoma cells.
Detoxification and Treating Opioid Dependence—Reply
Authors: Patrick G. O’Connor
Journal: JAMA (2006)

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Primary airway epithelial cultures from children are highly permissive to respiratory syncytial virus infection
Authors: A M Fonceca, B F Flanagan, R Trinick, R L Smyth, P S McNamara
Journal: Thorax (2011)

<h3>Background</h3> Respiratory syncytial virus (RSV) infection of airway epithelial cells (AECs) is an important initial event in RSV bronchiolitis. AEC immunological responses are thought to be critical in driving the subsequent inflammation in the airway. This study examined viral replication, cytotoxicity and cytokine production in cultures of primary AECs from children compared with responses to RSV infection in an immortalised epithelial cell line and to those from infants with RSV bronchiolitis. <h3>Methods</h3> RSV replication, proinflammatory cytokine responses and cytotoxicity in RSV-infected primary AEC cultures derived from bronchial brushings from the lungs of children were compared with those seen in BEAS-2B cultures, as well as AECs and bronchoalveolar lavage fluid collected from children with and without RSV bronchiolitis. <h3>Results</h3> Viral replication, cytotoxicity and inflammatory cytokine production were greater in primary AEC cultures than in BEAS-2B cells. Different response patterns were observed, with RSV infection of primary AEC cultures causing distinct peaks of viral replication and matched cytotoxic responses. Some primary AEC culture immunological responses, such as interleukin 8, were similar in magnitude to those seen in clinical samples from the lungs of children with RSV bronchiolitis. Although variable amounts of RSV were detected by PCR in freshly isolated primary AECs, RSV was not detected by immunocytochemistry. <h3>Conclusion</h3> This is one of the first studies to examine comprehensively the responses to RSV infection in primary AEC cultures from children and shows marked differences from those of a commercially available immortalised human cell line but reassuring similarities to results found in vivo. This suggests that future work investigating responses of AECs to RSV infection should use primary AEC cultures.
Dual Blockade of the PI3K/AKT/mTOR (AZD8055) and RAS/MEK/ERK (AZD6244) Pathways Synergistically Inhibits Rhabdomyosarcoma Cell Growth <i>In Vitro</i> and <i>In Vivo</i>
Authors: Jane Renshaw, Kathryn R. Taylor, Ryan Bishop, Melanie Valenti, Alexis De Haven Brandon, Sharon Gowan, Suzanne A. Eccles, Ruth R. Ruddle, Louise D. Johnson, Florence I. Raynaud, Joanna L. Selfe, Khin Thway, Torsten Pietsch, Andrew D. Pearson, Janet Shipley
Journal: Clinical Cancer Research (2013)

To provide rationale for using phosphoinositide 3-kinase (PI3K) and/or mitogen-activated protein kinase (MAPK) pathway inhibitors to treat rhabdomyosarcomas, a major cause of pediatric and adolescent cancer deaths.The prevalence of PI3K/MAPK pathway activation in rhabdomyosarcoma clinical samples was assessed using immunohistochemistry. Compensatory signaling and cross-talk between PI3K/MAPK pathways was determined in rhabdomyosarcoma cell lines following p110α short hairpin RNA-mediated depletion. Pharmacologic inhibition of reprogrammed signaling in stable p110α knockdown lines was used to determine the target-inhibition profile inducing maximal growth inhibition. The in vitro and in vivo efficacy of inhibitors of TORC1/2 (AZD8055), MEK (AZD6244), and P13K/mTOR (NVP-BEZ235) was evaluated alone and in pairwise combinations.PI3K pathway activation was seen in 82.5% rhabdomyosarcomas with coactivated MAPK in 36% and 46% of alveolar and embryonal subtypes, respectively. p110α knockdown in cell lines over the short and long term was associated with compensatory expression of other p110 isoforms, activation of the MAPK pathway, and cross-talk to reactivate the PI3K pathway. Combinations of PI3K pathway and MAP-ERK kinase (MEK) inhibitors synergistically inhibited cell growth in vitro. Treatment of RD cells with AZD8055 plus AZD6244 blocked reciprocal pathway activation, as evidenced by reduced AKT/ERK/S6 phosphorylation. In vivo, the synergistic effect on growth and changes in pharmacodynamic biomarkers was recapitulated using the AZD8055/AZD6244 combination but not NVP-BEZ235/AZD6244. Pharmacokinetic analysis provided evidence of drug-drug interaction with both combinations.Dual PI3K/MAPK pathway activation and compensatory signaling in both rhabdomyosarcoma subtypes predict a lack of clinical efficacy for single agents targeting either pathway, supporting a therapeutic strategy combining a TORC1/2 with a MEK inhibitor.
Changes in amount and intracellular distribution of androgen receptor in human foreskin as a function of age.
Authors: C G Roehrborn, J L Lange, F W George, J D Wilson
Journal: Journal of Clinical Investigation (1987)

To provide insight into the factors that control growth of the penis we measured the amount and intracellular distribution of specific high affinity androgen receptor in foreskins obtained at circumcision from 49 males varying in age from newborn to 59 yr. Total (cytosolic plus nuclear extract) androgen receptor decreased from approximately 40 fmol/g tissue weight in newborn foreskins to approximately 25 fmol/g by 1 yr of age. The amount of receptor rose in childhood to approximately 180 fmol/g in the late teenage years and fell thereafter to approximately 20-40 fmol/g in men older than 40 yr. The amount of receptor in the nuclear fraction increased at the time of puberty and subsequently decreased in parallel with the decline in total receptor level. These changes in androgen-receptor amount are similar when expressed per milligram DNA or per milligram protein.