tbuckley/cabot-search huggingface dataset:
Sequential Histopathologic Analysis of &lt;italic&gt;α&lt;/italic&gt;-Hexachlorocyclohexane-Induced Hepatic Megalocytosis and Adenoma Formation in the HPB Mouse&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Leander Tryphonas, Frank Iverson
Journal: JNCI Journal of the National Cancer Institute (1983)

A temporal, gross, and histologic analysis of the livers of male HPB black mice maintained on a diet containing 500 ppm α-hexachlorocyclohexane (α-HCH) was performed at 1, 3, 4, 8, 14, 21, 30, 33, 44, and 50 weeks. Grossly, progressive liver enlargement was first noticed at 3 weeks, hepatic nodules at 21 weeks, and emaciation at 30 weeks. Histopathologic liver alterations included universal hypertrophy of centrolobular hepatocytes first seen at 1 week and the merging of adjacent megalocytic zones at 3 weeks. At 21 weeks, microadenomata and macroadenomata were seen in 2 of 7 mice. At 30 weeks, adenomata occurred in 7 of 8 mice and at 33, 44, and 50 weeks in 6 of 6, 5 of 5, and 5 of 5 mice, respectively. Individual adenomata were composed of large well-packed cells with basophilic and acidophilic pale-staining or lipid-laden cytoplasm forming disorganized cords of variable thickness. Depending on the stage of development, adenomata were classified into 4 subtypes. Subtype I, the earliest form seen, arose within megalocytic areas and was composed of a small number of megalocytic cells exhibiting loss of polarity. Subtype II was smaller than a liver lobule. Subtype III was larger and at times resulted from the merging of adjacent subtype II nodules. Subtype IV included the largest adenomata, most of which resulted from coalescing smaller sized subtypes. Under the conditions of this experiment, neither hepatocellular carcinoma nor metastases in the lungs were detected. It was concluded that if α-HCH-induced hepatocellular adenoma is ever to give rise to hepatocellular carcinoma, this transformation must progress very slowly.
Effect of Sodium Thiosulfate on the Pharmacokinetics and Toxicity of Cisplatin
Authors: R. Goel, S. M. Cleary, C. Horton, S. Kirmani, I. Abramson, C. Kelly, S. B. Howell
Journal: JNCI Journal of the National Cancer Institute (1989)

Concurrent administration of sodium thiosulfate (STS) can protect against the nephrotoxic effects of even very-high-dose cisplatin (CDDP) (i.e., 270 mg/m2 given intraperitoneally). The effect of STS on the pharmacology and toxicity of CDDP was investigated in patients receiving at each treatment 90 mg of CDDP/m2 interaperitoneally, with STS given concurrently on alternate cycles by the intravenous route. The patients received a total of 38 courses of therapy, 21 without STS and 17 with STS. STS reduced the total exposure to diethyldithiocarbamate-reactive CDDP for the peritoneal cavity and plasma by 36% and 25%, respectively. When given alone, CDDP caused a statistically significant acute reduction in creatinine clearance levels; this reduction was less evident when STS was given. We conclude that, whereas STS does reduce systemic exposure, the magnitude of this effect was not sufficient to account for the ability of STS to protect against high-dose CDDP. [J Natl Cancer Inst 81:1552–1560, 1989]
Pulmonary hypertension: its assessment and treatment
Authors: S. Brij, A. J. Peacock
Journal: Thorax (1999)

In a subset of patients with primary pulmonary hypertension (PPH), high doses of oral calcium-channel blockers (CCB) produce a sustained clinical and haemodynamic improvement.However, significant sideeffects have been reported during acute testing with CCB.Therefore, to identify accurately patients who may benefit from long-term CCB therapy, there is a need for a safe, potent and short-acting vasodilator.The aim of this study was to compare the acute response to inhaled nitric oxide (NO) and oral high doses of CCB in 33 consecutive patients with PPH.A significant acute vasodilator response was defined by a fall in both mean pulmonary artery pressure and total pulmonary resistance by >20%.Ten patients responded acutely to NO, nine of whom responded acutely to CCB, without any complications.The 23 other patients failed to respond to NO and CCB.In these non-responders, nine serious adverse events were observed with CCB (38%).There was no clinical or baseline haemodynamic feature predicting acute vasodilator response.Long-term oral treatment with CCB was restricted to the nine acute responders and a sustained clinical and haemodynamic improvement was observed in only six patients.In primary pulmonary hypertension, the acute response rate to high doses of calciumchannel blockers is low (27%).Serious adverse reactions to high doses of calcium-channel blockers during acute testing are frequently observed in non-responders.It is concluded that nitric oxide may be used as a screening agent for safely identifying patients with primary pulmonary hypertension who respond acutely to calcium-channel blockers and may benefit from long-term treatment with these agents.
Suppression of orthotopically implanted hepatocarcinoma in mice by umbilical cord-derived mesenchymal stem cells with sTRAIL gene expression driven by AFP promoter
Authors: Cihui Yan, Ming Yang, Zhenzhen Li, Shuangjing Li, Xiao Hu, Dongmei Fan, Yanjun Zhang, Jianxiang Wang, Dongsheng Xiong
Journal: Biomaterials (2014)
Dietary Calcium and Magnesium, Major Food Sources, and Risk of Type 2 Diabetes in U.S. Black Women
Authors: Rob M. van Dam, Frank B. Hu, Lynn Rosenberg, Supriya Krishnan, Julie R. Palmer
Journal: Diabetes Care (2006)

OBJECTIVE—Inverse associations between magnesium and calcium intakes and risk of type 2 diabetes have been reported for studies in predominantly white populations. We examined magnesium, calcium, and major food sources in relation to type 2 diabetes in African-American women. RESEARCH DESIGN AND METHODS—This is a prospective cohort study including 41,186 participants of the Black Women’s Health Study without a history of diabetes who completed validated food frequency questionnaires at baseline. During 8 years of follow-up (1995–2003), we documented 1,964 newly diagnosed cases of type 2 diabetes. RESULTS—The multivariate-adjusted hazard ratio of type 2 diabetes for the highest compared with the lowest quintile of intake was 0.69 (95% CI 0.59–0.81; P trend &amp;lt;0.0001) for dietary magnesium and 0.86 (0.74–1.00; P trend = 0.01) for dietary calcium. After mutual adjustment, the association for calcium disappeared (hazard ratio 1.04 [95% CI 0.88–1.24]; P trend = 0.88), whereas the association for magnesium remained. Daily consumption of low-fat dairy (0.87 [0.76–1.00]; P trend = 0.04) and whole grains (0.69 [0.60–0.79]; P trend &amp;lt;0.0001) were associated with a lower risk of type 2 diabetes compared with a consumption less than once a week. After mutual adjustment, the hazard ratio was 0.81 (0.68–0.97; P trend = 0.02) for magnesium and 0.73 (0.63–0.85; P trend &amp;lt;0.0001) for whole grains. CONCLUSIONS—These findings indicate that a diet high in magnesium-rich foods, particularly whole grains, is associated with a substantially lower risk of type 2 diabetes in U.S. black women.
Bcl3 Selectively Promotes Metastasis of ERBB2-Driven Mammary Tumors
Authors: Alison Wakefield, Jitka Soukupova, Amelie Montagne, Jill Ranger, Rhiannon French, William J. Muller, Richard W. E. Clarkson
Journal: Cancer Research (2012)

Abstract Bcl3 is a putative proto-oncogene deregulated in hematopoietic and solid tumors. Studies in cell lines suggest that its oncogenic effects are mediated through the induction of proliferation and inhibition of cell death, yet its role in endogenous solid tumors has not been established. Here, we address the oncogenic effect of Bcl3 in vivo and describe how this Stat3-responsive oncogene promotes metastasis of ErbB2-positive mammary tumors without affecting primary tumor growth or normal mammary function. Deletion of the Bcl3 gene in ErbB2-positive (MMTV-Neu) mice resulted in a 75% reduction in metastatic tumor burden in the lungs with a 3.6-fold decrease in cell turnover index in these secondary lesions with no significant effect on primary mammary tumor growth, cyclin D1 levels, or caspase-3 activity. Direct inhibition of Bcl3 by siRNA in a transplantation model of an Erbb2-positive mammary tumor cell line confirmed the effect of Bcl3 in malignancy, suggesting that the effect of Bcl3 was intrinsic to the tumor cells. Bcl3 knockdown resulted in a 61% decrease in tumor cell motility and a concomitant increase in the cell migration inhibitors Nme1, Nme2, and Nme3, the GDP dissociation inhibitor Arhgdib, and the metalloprotease inhibitors Timp1 and Timp2. Independent knockdown of Nme1, Nme2, and Arhgdib partially rescued the Bcl3 motility phenotype. These results indicate for the first time a cell-autonomous disease-modifying role for Bcl3 in vivo, affecting metastatic disease progression rather than primary tumor growth. Cancer Res; 73(2); 745–55. ©2012 AACR.
Engineered fibroblast growth factor 19 reduces liver injury and resolves sclerosing cholangitis in Mdr2‐deficient mice
Authors: Mei Zhou, R. Marc Learned, Stephen J. Rossi, Alex M. DePaoli, Hui Tian, Lei Ling
Journal: Hepatology (2015)

Defects in multidrug resistance 3 gene (MDR3), which encodes the canalicular phospholipid flippase, cause a wide spectrum of cholangiopathy phenotypes in humans. Mice deficient in Mdr2 (murine ortholog of MDR3) develop liver diseases that closely reproduce the biochemical, histological, and clinical features of human cholangiopathies such as progressive familial intrahepatic cholestasis and primary sclerosing cholangitis. We hypothesized that modulating bile acid metabolism by the gut hormone fibroblast growth factor 19 (FGF19) may represent a novel approach for treating cholangiopathy and comorbidities. We introduced adeno-associated virus carrying the gene for either the endocrine hormone FGF19 or engineered FGF19 variant M70 to 12-week old Mdr2-deficient mice with fully established disease. Effects on serum levels of liver enzymes, liver histology, and bile acid homeostasis were evaluated. FGF19 and M70 rapidly and effectively reversed liver injury, decreased hepatic inflammation, attenuated biliary fibrosis, and reduced cholecystolithiasis in Mdr2-deficient mice. Mechanistically, FGF19 and M70 significantly inhibited hepatic expression of Cyp7a1 and Cyp27a1, which encode enzymes responsible for the rate-limiting steps in the classic and alternate bile acid synthetic pathways, thereby reducing the hepatic bile acid pool and blood levels of bile acids. Importantly, prolonged exposure to FGF19, but not M70, led to the formation of hepatocellular carcinomas in the Mdr2-deficient mice. Furthermore, M70 ameliorated the hepatosplenomegaly and ductular proliferation that are associated with cholangiopathy.These results demonstrate the potential for treating cholangiopathy by safely harnessing FGF19 biology to suppress bile acid synthesis.
Vascular Endothelial Growth Factor–Targeted Therapy in Renal Cell Carcinoma: Current Status and Future Directions
Authors: Brian I. Rini
Journal: Clinical Cancer Research (2007)

Abstract Renal cell carcinoma is a highly vascular tumor associated with expression of vascular endothelial growth factor (VEGF). Recently, VEGF-targeted therapies have been identified as a promising therapeutic approach. Three agents targeting the VEGF pathway have shown clinical activity as monotherapy in metastatic renal cell carcinoma: the anti-VEGF monoclonal antibody, bevacizumab, and small-molecule VEGF receptor tyrosine kinase inhibitors, sorafenib and sunitinib. This article explores these agents in terms of their mechanisms of action, clinical efficacy, and toxicity profiles. This article also reviews future development strategies, including combination regimens and drug sequencing, trial design considerations, and patient selection opportunities.
Phase I Study of RO4929097, a Gamma Secretase Inhibitor of Notch Signaling, in Patients With Refractory Metastatic or Locally Advanced Solid Tumors
Authors: Anthony W. Tolcher, Wells A. Messersmith, Stanislaw M. Mikulski, Kyriakos P. Papadopoulos, Eunice L. Kwak, Darlene G. Gibbon, Amita Patnaik, Gerald S. Falchook, Arvind Dasari, Geoffrey I. Shapiro, John F. Boylan, Zhi-Xin Xu, Ka Wang, Astrid Koehler, James Song, Steven A. Middleton, Jonathan Deutsch, Mark DeMario, Razelle Kurzrock, Jennifer J. Wheler
Journal: Journal of Clinical Oncology (2012)

To determine the maximum-tolerated dose (MTD) and assess safety, pharmacokinetics, pharmacodynamics, and evidence of antitumor activity of RO4929097, a gamma secretase inhibitor of Notch signaling in patients with advanced solid malignancies.Patients received escalating doses of RO4929097 orally on two schedules: (A) 3 consecutive days per week for 2 weeks every 3 weeks; (B) 7 consecutive days every 3 weeks. To assess reversible CYP3A4 autoinduction, the expanded part of the study tested three dosing schedules: (B) as above; modified A, 3 consecutive d/wk for 3 weeks; and (C) continuous daily dosing. Positron emission tomography scans with [(18)F]fluorodeoxyglucose (FDG-PET) were used to assess tumor metabolic effects.Patients on schedule A (n = 58), B (n = 47), and C (n = 5; expanded cohort) received 302 cycles of RO4929097. Common grade 1 to 2 toxicities were fatigue, thrombocytopenia, fever, rash, chills, and anorexia. Transient grade 3 hypophosphatemia (dose-limiting toxicity, one patient) and grade 3 pruritus (two patients) were observed at 27 mg and 60 mg, respectively; transient grade 3 asthenia was observed on schedule A at 80 mg (one patient). Tumor responses included one partial response in a patient with colorectal adenocarcinoma with neuroendocrine features, one mixed response (stable disease) in a patient with sarcoma, and one nearly complete FDG-PET response in a patient with melanoma. Effect on CYP3A4 induction was observed.RO4929097 was well tolerated at 270 mg on schedule A and at 135 mg on schedule B; the safety of schedule C has not been fully evaluated. Further studies are warranted on the basis of a favorable safety profile and preliminary evidence of clinical antitumor activity.
High-dose methotrexate with or without whole brain radiotherapy for primary CNS lymphoma (G-PCNSL-SG-1): a phase 3, randomised, non-inferiority trial
Authors: Eckhard Thiel, Agnieszka Korfel, Peter Martus, Lothar Kanz, Frank Griesinger, Michael Rauch, Alexander Röth, Bernd Hertenstein, Theda von Toll, Thomas Hundsberger, Hans-Günther Mergenthaler, Malte Leithäuser, Tobias Birnbaum, Lars Fischer, Kristoph Jahnke, Ulrich Herrlinger, Ludwig Plasswilm, Thomas Nägele, Torsten Pietsch, Michael Bamberg, Michael Weller
Journal: The Lancet Oncology (2010)
Age-Specific Effectiveness of the Nijmegen Population-Based Breast Cancer-Screening Program: Assessment of Early Indicators of Screening Effectiveness
Authors: P. G. M. Peer, R. Holland, J. H. C. L. Hendriks, M. Mravunac, A. L. M. Verbeek
Journal: JNCI Journal of the National Cancer Institute (1994)

Journal Article Age-Specific Effectiveness of the Nijmegen Population-Based Breast Cancer-Screening Program: Assessment of Early Indicators of Screening Effectiveness Get access Petronella G. M. Peer, Petronella G. M. Peer Department of Epidemiology, Medical Informatics, and Statistics, University of NijmegenThe Netherlands Search for other works by this author on: Oxford Academic PubMed Google Scholar Roland Holland, Roland Holland Department of Pathology, University Hosptial, University of NijmegenNijmegen Search for other works by this author on: Oxford Academic PubMed Google Scholar Jan H. C. L. Hendriks, Jan H. C. L. Hendriks Department of Diagnostic Radiology, University Hosptial, University of NijmegenNijmegen Search for other works by this author on: Oxford Academic PubMed Google Scholar Marcel Mravunac, Marcel Mravunac Department of Pathology, Canisius Wilhelmina HospitalNijmegen Search for other works by this author on: Oxford Academic PubMed Google Scholar André L. M. Verbeek André L. M. Verbeek * Department of Epidemiology, Medical Informatics, and Statistics, University of NijmegenThe Netherlands * Correspondence to: Petronella G. M. Peer. M.S., Department of Epidemiology. Medical Informatics, and Statistics. University of Nijmegen. P. O. Box 9101, 6500 HB Nijmegen. The Netherlands. Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 86, Issue 6, 16 March 1994, Pages 436–441, https://doi.org/10.1093/jnci/86.6.436 Published: 16 March 1994 Article history Received: 12 June 1993 Revision received: 15 November 1993 Accepted: 05 January 1994 Published: 16 March 1994
Ofatumumab, a Novel Anti-CD20 Monoclonal Antibody for the Treatment of B-Cell Malignancies
Authors: Bruce D. Cheson
Journal: Journal of Clinical Oncology (2010)

The availability of safe and effective monoclonal antibodies (mAbs) has dramatically altered treatment strategies for B-cell malignancies. Rituximab, a type I chimeric anti-CD20 mAb, not only has activity against a broad range of CD20-positive B-cell malignancies but also, when combined with chemotherapy or other biologic agents, has improved response rates; in addition, in certain situations, progression-free survival and even overall survival may be prolonged. Recently, other anti-CD20 mAbs have been developed to improve on the activity achieved with rituximab or to demonstrate efficacy in patients whose diseases are resistant to rituximab. The most extensively studied of these is ofatumumab, a type I human antibody that binds to a different epitope of CD20 than rituximab. Preclinical data suggest improved complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity compared with rituximab. In early clinical trials, ofatumumab demonstrated single-agent activity against chronic lymphocytic leukemia (CLL) and a number of histologies of B-cell non-Hodgkin's lymphomas. This antibody was recently approved by the US Food and Drug Administration for the treatment of CLL that is resistant to both fludarabine and alemtuzumab. Additional study is ongoing with ofatumumab in combination with chemotherapy and biologic agents to further enhance its efficacy. Ofatumumab offers another effective agent with which to improve the outcome of patients with B-cell malignancies.
Intracellular K+ activity, intracellular Na+ activity and maximum diastolic potential of canine subendocardial Purkinje cells from one-day-old infarcts.
Authors: K P Dresdner, R P Kline, A L Wit
Journal: Circulation Research (1987)

The basis for the reduced maximum diastolic potential of canine cardiac subendocardial Purkinje fibers surviving one day after extensive transmural infarction was investigated, using double-barrel potassium and sodium ion-sensitive microelectrodes. The maximum diastolic potential of Purkinje fibers in infarct preparations from the left ventricular apex measured during the first hour of superfusion in a tissue bath was -50.1 +/- 13.7 mV, a value markedly reduced from the value in control Purkinje fibers from noninfarcted preparations (-85.0 +/- 4.5 mV). The intracellular potassium ion activity was reduced by 50.4 mM during this time (intracellular potassium ion activity equals 61.6 +/- 16.1 mM, as compared to control intracellular potassium ion activity of 112 +/- 19.8 mM). The potassium equilibrium potential was reduced by 16.0 mV (from -97.2 +/- 4.7 mV in controls to -81.2 +/- 6.9 mV), thus accounting for about one half of the reduction in the maximum diastolic potential. After 6 hours of superfusion, the maximum diastolic potential increased to -78.9 +/- 8.7 mV (still significantly less than control). The potassium equilibrium potential had largely recovered (-93.8 +/- 5.9 mV). The intracellular sodium ion activity of Purkinje fibers in the infarcts (15.6 +/- 6.9 mM) was elevated during the first hour of superfusion by 6.2 mM compared to control (9.4 +/- 2.6 mM), and this was only 12% as much as the initial intracellular potassium ion activity decrease. Sodium ion activity after 3-6 hours of superfusion was not significantly different than normal (12.1 +/- 4.9 mM). In conclusion, only a portion of the maximum diastolic potential changes can be explained by a reduction of the potassium equilibrium potential. It is likely that change(s) in the cell membrane sodium-potassium pump's function and in the membrane conductance are also involved. Furthermore, the lack of a compensatory increase in intracellular sodium ion activity accompanying the large reduction of intracellular potassium ion activity may be a consequence of the cellular acidosis, which is known to occur during myocardial ischemia.
Postconditioning attenuates myocardial ischemia–reperfusion injury by inhibiting events in the early minutes of reperfusion
Authors: H Kin
Journal: Cardiovascular Research (2004)

Objective: We previously showed that brief intermittent ischemia applied during the onset of reperfusion (i.e., postconditioning) is cardioprotective in a canine model of ischemia–reperfusion. This study tested the hypothesis that the early minutes of reperfusion (R) during which postconditioning (Post-con) is applied are critical to its cardioprotection. Methods: In anesthetized open-chest rats, the left coronary artery (LCA) was occluded for 30 min and reperfused for 3 h. All rats were randomly divided into six groups: Control (n=8): no intervention at R; Ischemic preconditioning (IPC) (n=8): the LCA was occluded for 5 min followed by 10 min of R before the index occlusion; Post-con 1 (n=8): after LCA occlusion, three cycles of 10 s R followed by 10 s LCA re-occlusion were applied during the first minute of R; Post-con 2 (n=8): Six cycles of 10 s R and 10 s re-occlusion were applied during the first 2 min of R; Delayed Post-con (n=8): the ligature was loosened for full reflow for the first minute of R, after which the three-cycle Post-con algorithm was applied; Sham (n=6): the surgical procedure was identical to other groups, but the LCA ligature was not ligated. Results: Infarct size (TTC staining) was 23% smaller in Post-con 1 (40±2%*) than in Control (52±3%), confirmed by plasma creatine kinase activity (18±2* vs. 46±6 IU/g protein). There was no further reduction in infarct size with 6 cycles of Post-con (40±2.9%, p>0.05 vs. Post-con 1). Meanwhile, infarct size reduction was significantly greater in the IPC group (17±3%) than in Post-con1 (p<0.01). The plasma lipid peroxidation product malondialdehyde (MDA, μM/ml) was less after R in IPC and Post-con 1 (0.8±0.07* and 0.8±0.06*) vs. Control (1.21±0.08), consistent with a visual decrease in superoxide anion generation (dihydroethidium staining) in the AAR myocardium after 3 h of reperfusion. Neutrophil accumulation (myeloperoxidase activity, MPO, U/100 g tissue) in the AAR was less in IPC (1.4±0.3*) and Post-con 1 (2.5±0.3*) vs. Control (5.5±0.6). The reductions in infarct size, creatine kinase, MDA and DHE staining were lost with delayed Post-con, while MPO activity remained lower than in Control (3.2±0.4*). Conclusions: (1) Post-con at onset of R reduces myocardial injury; (2) cardioprotection may be mediated, in part, by inhibiting oxidant generation and oxidant mediated injury; (3) the first minute of R in the rat model is critical to cardioprotection by Post-con; and (4) cardioprotection by Post-con may be independent of neutrophil accumulation in AAR. *p<0.05 Post-con vs. Control.