tbuckley/cabot-search huggingface dataset:
miR-377-dependent BCL-xL regulation drives chemotherapeutic resistance in B-cell lymphoid malignancies
Authors: Sayer Al-harbi, Gaurav S. Choudhary, Jey Sabith Ebron, Brian T. Hill, Nagarajavel Vivekanathan, Angela H. Ting, Tomas Radivoyevitch, Mitchell R. Smith, Girish C. Shukla, Alex Almasan
Journal: Molecular Cancer (2015)

BCL-xL is an anti-apoptotic BCL-2 family protein that inhibits apoptosis and is overexpressed in many cancers. We have reported that acquired resistance to the BCL-2 inhibitor ABT-199 (venetoclax) is associated with increased BCL-xL expression. Yet, how BCL-xL mediates chemoresistance in hematopoietic malignancies is not clear. This finding may help in design of new strategies for therapeutic intervention to overcome acquired chemoresistance mediated by BCL-xL. We now show that the increased BCL-xL expression was inversely correlated with that of miR-377 in ABT-199-resistant cells. This finding was also extended to a panel of B-cell lymphoid lines and primary chronic lymphocytic leukemia (CLL) cells. miR-377 suppressed BCL-xL expression by recognizing two binding sites in the BCL-xL 3'-UTR. Mutation of these two miR-377 consensus-binding sites completely abolished its regulatory effect. Expression of a miR-377 mimic downregulated BCL-xL protein expression and significantly increased apoptotic cell death. Expression of a miR-377 inhibitor restored BCL-xL protein expression and limited cell death caused by the hypomethylating agent 5-azacytidine. Thus, miR-377-dependent BCL-xL regulation drives acquired therapeutic resistance to ABT-199. We further show that CLL patients who received a diverse array of chemotherapy regimens also had significantly higher BCL-xL and lower miR377 expression, indicating that exposure to chemotherapy might trigger transcriptional silencing of miR-377, which results in high levels of BCL-xL. Importantly, CLL patients with high BCL-xL/low miR-377 expression had an advanced tumor stage. Moreover, the high BCL-xL expression correlated with short treatment-free survival in 76 CLL patients. miR-377 is located at 14q32 in the DLK1-DIO3 region, which encodes the largest tumor suppressor miRNA cluster in humans. Examination of five additional 14q32 miRNAs revealed that the majority were significantly down-regulated in most CLL patients as well as in ABT-199-resistant cell lines. Remarkably, four of these miRNAs had significantly decreased expression in chemotherapy-treated CLL patients as compared to those untreated. These findings indicate a reduced expression of multiple miRNAs that may reflect a global silencing of this miRNA cluster in therapy-resistant lymphoid cells. These findings reveal a novel mechanism by which down-regulation of miR-377 increases BCL-xL expression, promoting chemotherapy resistance in B-cell lymphoid malignancies.
Gabexate Mesilate Inhibits Colon Cancer Growth, Invasion, and Metastasis by Reducing Matrix Metalloproteinases and Angiogenesis
Authors: Wan-Hee Yoon, Yeon-Joo Jung, Tae-Dong Kim, Ge Li, Byoung-Jeon Park, Ji-Yeon Kim, Young-Chul Lee, Jin-Man Kim, Jong-Il Park, Hae-Duck Park, Zae-Sung No, Kyu Lim, Byung-Doo Hwang, Young S. Kim
Journal: Clinical Cancer Research (2004)

Abstract Gabexate mesilate (GM), a synthetic protease inhibitor, has an antiproteinase activity on various types of plasma serine proteases. However, its role on matrix metalloproteinases (MMPs) has not been identified. In this study, we investigated the effect of GM on MMPs and on the invasion and metastasis of human colon cancer cell lines and neoangiogenesis. The activities of MMPs secreted from these cells were significantly reduced by GM but unaffected by the serine protease inhibitor aprotinin. GM directly inhibited purified progelatinase A derived from T98G human glioblastoma cells. In vitro, GM significantly reduced the invasive ability of colon cancer cells but not cellular motility, whereas aprotinin affected neither. Liver metastatic ability and tumorigenic potential in nude mice were remarkably reduced on treatment with GM. Immunohistochemical analysis of GM-treated tumors in mice showed a marked increase in apoptosis and a significant reduction in tumor angiogenesis. Human umbilical vein endothelial cell proliferation, tube formation, and neoangiogenesis in the rabbit cornea and Matrigel implanted in mice were significantly inhibited by GM. These results suggest that GM is a novel inhibitor of MMPs and that it may inhibit the invasion and metastasis of human colon cancer cells by blocking MMPs and neoangiogenesis.
Hepatocyte proliferation and gene expression induced by triiodothyroninein vivo andin vitro
Authors: Antonio Francavilla, Brian I. Carr, Alessandro Azzarone, Lorenzo Polimeno, Ziqiu Wang, David H. Van Thiel, Vladimir Subbotin, John G. Prelich, Thomas E. Starzl
Journal: Hepatology (1994)

Subcutaneous injections of hormone triiodothyronine in rats resulted in peak blood levels at 24 hr with return to baseline by 96 hr. The injections stimulated a liver regeneration response that resembled in timing and in magnitude of DNA synthesis (peak, 24 hr) that induced by 40% hepatic resection. The principal proliferation was of hepatocytes. Although there were some temporal differences from the gene expression of transforming growth factor-alpha, transforming growth factor-beta, and c-Ha-ras that are known to follow partial hepatectomy, the overall profile of these changes was similar to those after partial resection. The effect was liver specific and could be reproduced three times with no diminution in response in the same animal with injections at 10-day intervals. No response was detected in kidney or intestine. This effect in intact animals contrasted with the minimal ability of triiodothyronine to stimulate hepatocytes in culture. However, when the culture medium was enriched with epidermal growth factor, there was a dose-related response to triiodothyronine. The totality of these experiments provides a preliminary basis for the creation with pharmacological techniques of an in vivo hyperplastic hepatic condition permissive of transfection of new genes, as an alternative to partial hepatectomy. Although triiodothyronine was the test agent used, other hepatic growth factors singly or in combination could be candidates for this purpose.
Molecular MRI of murine atherosclerotic plaque targeting NGAL: a protein associated with unstable human plaque characteristics
Authors: Bernard C. te Boekhorst, Sandra M. Bovens, Willem E. Hellings, Petra H. van der Kraak, Kees W. van de Kolk, Aryan Vink, Frans L. Moll, Matthijs F. van Oosterhout, Jean P. de Vries, Pieter A. Doevendans, Marie-José Goumans, Dominique P. de Kleijn, Cees J. van Echteld, Gerard Pasterkamp, Joost P. Sluijter
Journal: Cardiovascular Research (2010)

AimsNeutrophil gelatinase-associated lipocalin (NGAL) is an effector molecule of the innate immune system. One of its actions is the prolongation of matrix metalloproteinase-9 (MMP-9) activity by the formation of a degradation-resistant NGAL/MMP-9 complex. We studied NGAL in human atherosclerotic lesions and we examined whether NGAL could act as a target for molecular imaging of atherosclerotic plaques.
FDA Approval: Siltuximab for the Treatment of Patients with Multicentric Castleman Disease
Authors: Albert Deisseroth, Chia-Wen Ko, Lei Nie, Jeanne F. Zirkelbach, Liang Zhao, Julie Bullock, Nitin Mehrotra, Pedro Del Valle, Haleh Saber, Christopher Sheth, Brenda Gehrke, Robert Justice, Ann Farrell, Richard Pazdur
Journal: Clinical Cancer Research (2015)

On April 22, 2014, the FDA granted full approval to siltuximab (SYLVANT for injection; Janssen Biotech, Inc.), a chimeric human-mouse monoclonal antibody to IL6, for the treatment of patients with multicentric Castleman disease (MCD) who are human immunodeficiency virus (HIV) negative and human herpesvirus-8 (HHV-8) negative. The approval was primarily based on the results of a randomized, double-blind trial in which 79 symptomatic patients with MCD were allocated (2:1) to siltuximab plus best supportive care (BSC) or to placebo plus BSC. The primary efficacy endpoint was the proportion of patients in each arm achieving a durable tumor and symptomatic response that persisted for a minimum of 18 weeks without treatment failure. Tumor response was based on independent review of CT scans using the revised Response Criteria for Malignant Lymphoma, and symptomatic response was defined as complete resolution or stabilization of 34 MCD-related signs and symptoms as reported by the investigator. Thirty-four percent of patients in the siltuximab arm and no patients in the placebo arm met the primary endpoint (P = 0.0012). The most common adverse reactions (>10% compared with placebo) during treatment with siltuximab were pruritus, increased weight, rash, hyperuricemia, and upper respiratory tract infection.
Impact of Race on Prostate-Specific Antigen Outcome After Radical Prostatectomy for Clinically Localized Adenocarcinoma of the Prostate
Authors: Chaundre K. Cross, Delray Shultz, S. Bruce Malkowicz, William C. Huang, Richard Whittington, John E. Tomaszewski, Andrew A. Renshaw, Jerome P. Richie, Anthony V. D’Amico
Journal: Journal of Clinical Oncology (2002)

PURPOSE: To compare prostate-specific antigen (PSA) outcome after radical prostatectomy (RP) for prostate cancer in African-American and white men using previously established risk groups. PATIENTS AND METHODS: Between 1989 and 2000, 2,036 men (n = 162 African-American men, n = 1,874 white men) underwent RP for clinically localized prostate cancer. Using pretreatment PSA, Gleason score, clinical T stage, and percentage of positive biopsy specimens, patients were stratified into low- and high-risk groups. For each risk group, PSA outcome was estimated using the actuarial method of Kaplan and Meier. Comparisons of PSA outcome between African-American and white men were made using the log-rank test. RESULTS: The median age and PSA level for African-American and white men were 60 and 62 years old and 8.8 and 7.0 ng/mL, respectively. African-Americans had a statistically significant increase in PSA (P = .002), Gleason score (P = .003), clinical T stage (P = .004), and percentage of positive biopsy specimens (P = .04) at presentation. However, there was no statistical difference in the distribution of PSA, clinical T stage, or Gleason score between racial groups in the low- and high-risk groups. The 5-year estimate of PSA outcome was 87% in the low-risk group for all patients (P = .70) and 28% versus 32% in African-American and white patients in the high-risk group (P = .28), respectively. Longer follow-up is required to confirm if these results are maintained at 10 years. CONCLUSION: Even though African-American men presented at a younger age and with more advanced disease compared with white men with prostate cancer, PSA outcome after RP when controlled for known clinical predictive factors was not statistically different. This study supports earlier screening in African-American men.
Physical and Functional Interactions between the Wwox Tumor Suppressor Protein and the AP-2γ Transcription Factor
Authors: Rami I. Aqeilan, Alexey Palamarchuk, Ronald J. Weigel, Juan J. Herrero, Yuri Pekarsky, Carlo M. Croce
Journal: Cancer Research (2004)

Abstract The WWOX gene encodes a tumor suppressor WW domain-containing protein, Wwox. Alterations of WWOX have been demonstrated in multiple types of cancer, and introduction of Wwox into Wwox-negative tumor cells has resulted in tumor suppression and apoptosis. The Wwox protein contains two WW domains that typically bind proline-rich motifs and mediate protein–protein interactions. Recently, we have described functional cross-talk between the Wwox protein and the p53 homologue, p73. To further explore the biological function of Wwox, we investigated other interacting candidates. In this report, we demonstrate a physical and functional association between AP-2γ transcription factor and the Wwox protein. AP-2γ at 20q13.2 encodes a transcription factor and is frequently amplified in breast carcinoma. We show that Wwox binds to the PPPY motif of AP-2γ via its first WW domain. Alterations of tyrosine 33 in the first WW domain of Wwox or the proline-rich motif in AP-2γ dramatically reduce this interaction. In addition, our results demonstrate that Wwox expression triggers redistribution of nuclear AP-2γ to the cytoplasm, hence suppressing its transactivating function. Our results suggest that Wwox tumor suppressor protein inhibits AP-2γ oncogenic activity by sequestering it in the cytoplasm.
Pharmacologic Modulators of Nitric Oxide Exacerbate Tubulointerstitial Inflammation in Proteinuric Rats
Authors: GOPALA K. RANGAN, YIPING WANG, DAVID C. H. HARRIS
Journal: Journal of the American Society of Nephrology (2001)

Abstract. Nitric oxide (NO) regulates inflammatory responses partly by cell-specific inhibition of the transcription factor nuclear factor κB (NF-κB). This study investigated the effect of continuous oral administration of an NO donor (molsidomine [Mol]), NO precursor (L-arginine [L-arg]), or selective inhibitors of inducible NO synthase (iNOS; aminoguanidine [AG], L- N 6 -(1-iminoethyl)lysine [L-NIL]) on the progression of tubulointerstitial inflammation and NF-κB activation in a non-immune model of chronic glomerular disease (Adriamycin nephropathy [AN]), from day 8 until day 30 after disease induction. On day 30, rats with AN had heavy proteinuria, reduced creatinine clearance, and tubulointerstitial disease. Treatment with both AG and L-NIL exacerbated the progression of AN as evidenced by ( 1 ) increased renal cortical malondialdehyde; ( 2 ) reduced creatinine clearance; and ( 3 ) increased tubular atrophy, interstitial volume, and monocyte infiltration. Unexpectedly, Mol also increased renal malondialdehyde and worsened tubular injury, whereas L-arg had no effect. The increase in renal cortical NF-κB activation in AN was not altered by AG, L-NIL, or Mol, but the mRNA expression of monocyte chemoattractant protein-1, interleukin-10, and osteopontin were elevated in these groups. Nitrite release from kidney slices reduced in AN. Treatment with Mol restored renal nitrite release to normal, whereas neither L-arg nor the NOS inhibitors had an effect. It is concluded that endogenous iNOS-derived NO has a protective role against tubulointerstitial injury and cytokine production in AN. However, the pro-oxidant activity of NO donors may limit their potential benefit in proteinuric renal disease.
Runx3 controls the axonal projection of proprioceptive dorsal root ganglion neurons
Authors: Ken-ichi Inoue, Shigeru Ozaki, Takashi Shiga, Kosei Ito, Tomoyuki Masuda, Nobuo Okado, Tsutomu Iseda, Saburo Kawaguchi, Masaharu Ogawa, Suk-Chul Bae, Namiko Yamashita, Shigeyoshi Itohara, Norio Kudo, Yoshiaki Ito
Journal: Nature Neuroscience (2002)
The effect of chronic digitoxin administration on the contractile state of normal and nonfailing hypertrophied myocardium.
Authors: J F Williams, R D Potter
Journal: Journal of Clinical Investigation (1975)

To determine the effect of prolonged digitoxin administration on contractile function of nonfailing myocardium, right ventricular papillary muscle mechanics were examined after 6 or 24 wk of glycoside administration to control and pulmonary artery banded cats. Resting length-tension relations were not affected by digitoxin; however, isometrically developed force and the maximal rate of force development at the peak of the length-tension curve were increased in all treated groups. In untreated animals, banding resulted in a 28% incidence of deaths from heart failure. 6 wk after constriction, contractile function was depressed whereas normal function was observed 24 wk after banding. Digitoxin significantly reduced mortality from heart failure and enhanced the recovery of contractile function; contractile function in the 6 wk banded treated group approached that of untreated control and 24-wk banded groups. The long-term effects of digitoxin on contractile function were not importantly related to the temporal association between banding and institution of glycoside administration. Development of myocardial hypertrophy was comparable in treated and untreated banded groups.These results demonstrate that a significant positive inotropic effect persists in both normal and nonfailing hypertrophied myocardium during chronic digitoxin administration.
Synergistic Interaction between the HDAC Inhibitor, MPT0E028, and Sorafenib in Liver Cancer Cells <i>In Vitro</i> and <i>In Vivo</i>
Authors: Chun-Han Chen, Mei-Chuan Chen, Jing-Chi Wang, An-Chi Tsai, Ching-Shih Chen, Jing-Ping Liou, Shiow-Lin Pan, Che-Ming Teng
Journal: Clinical Cancer Research (2014)

To investigate the antitumor activities of a histone deacetylase (HDAC) inhibitor, MPT0E028, plus sorafenib in liver cancer cells in vitro and in vivo.Different liver cancer cell lines were exposed to sorafenib in the presence or absence of MPT0E028, and cell viability was determined by MTT assay. Effects of combined treatment on cell cycle and intracellular signaling pathways were assessed by flow cytometry and Western blot analysis. The Hep3B xenograft model was used to examine the antitumor activity in vivo.Our data indicate that sorafenib and MPT0E028 synergistically reduced cell viability in liver cancer cells, and also markedly induced apoptotic cell death in these cells, as evidenced by the cleavage of caspase-3, PARP, and DNA fragmentation. MPT0E028 altered the global modifications of histone and nonhistone proteins regardless of the presence of sorafenib. However, sorafenib blocked MPT0E028-induced Erk activation and its downstream signaling cascades, such as Stat3 phosphorylation (Ser(727)) and Mcl-1 upregulation. Ectopic expression of constitutively active Mek successively reversed the apoptosis triggered by the combined treatment. Pharmacologic inhibition of Mek by PD98059 potentiated MPT0E028-induced apoptosis, suggesting that the synergistic interaction between MPT0E028 and sorafenib occurs at least partly through inhibition of Erk signaling. The data demonstrated that transcriptional activation of fibroblast growth factor receptor 3 (FGFR3) contributes to MPT0E028-mediated Erk phosphorylation. Finally, MPT0E028 plus sorafenib significantly improved the tumor growth delay (TGD) in a Hep3B xenograft model.These findings suggest that MPT0E028 in combination with sorafenib has significant anti-hepatocellular carcinoma activity in preclinical models, potentially suggesting a novel therapeutic strategy for patients with advanced hepatocellular carcinoma.
Metabolism and Disposition Kinetics of Nicotine
Authors: Janne Hukkanen, Pleyton Jacob, Neal L. Benowitz
Journal: Pharmacological Reviews (2005)

Nicotine is of importance as the addictive chemical in tobacco, pharmacotherapy for smoking cessation, a potential medication for several diseases, and a useful probe drug for phenotyping cytochrome P450 2A6 (CYP2A6). We review current knowledge about the metabolism and disposition kinetics of nicotine, some other naturally occurring tobacco alkaloids, and nicotine analogs that are under development as potential therapeutic agents. The focus is on studies in humans, but animal data are mentioned when relevant to the interpretation of human data. The pathways of nicotine metabolism are described in detail. Absorption, distribution, metabolism, and excretion of nicotine and related compounds are reviewed. Enzymes involved in nicotine metabolism including cytochrome P450 enzymes, aldehyde oxidase, flavin-containing monooxygenase 3, amine <i>N</i>-methyltransferase, and UDP-glucuronosyltransferases are represented, as well as factors affecting metabolism, such as genetic variations in metabolic enzymes, effects of diet, age, gender, pregnancy, liver and kidney diseases, and racial and ethnic differences. Also effects of smoking and various inhibitors and inducers, including oral contraceptives, on nicotine metabolism are discussed. Due to the significance of the CYP2A6 enzyme in nicotine clearance, special emphasis is given to the effects and population distributions of <i>CYP2A6</i> alleles and the regulation of CYP2A6 enzyme.
Whole-Exome Sequencing Identifies MDH2 as a New Familial Paraganglioma Gene
Authors: Alberto Cascón, Iñaki Comino-Méndez, María Currás-Freixes, Aguirre A de Cubas, Laura Contreras, Susan Richter, Mirko Peitzsch, Veronika Mancikova, Lucía Inglada-Pérez, Andrés Pérez-Barrios, María Calatayud, Sharona Azriel, Rosa Villar-Vicente, Javier Aller, Fernando Setién, Sebastian Moran, Juan F Garcia, Ana Río-Machín, Rocío Letón, Álvaro Gómez-Graña, María Apellániz-Ruiz, Giovanna Roncador, Manel Esteller, Cristina Rodríguez-Antona, Jorgina Satrústegui, Graeme Eisenhofer, Miguel Urioste, Mercedes Robledo
Journal: JNCI Journal of the National Cancer Institute (2015)

Disruption of the Krebs cycle is a hallmark of cancer. IDH1 and IDH2 mutations are found in many neoplasms, and germline alterations in SDH genes and FH predispose to pheochromocytoma/paraganglioma and other cancers. We describe a paraganglioma family carrying a germline mutation in MDH2, which encodes a Krebs cycle enzyme. Whole-exome sequencing was applied to tumor DNA obtained from a man age 55 years diagnosed with multiple malignant paragangliomas. Data were analyzed with the two-sided Student's t and Mann-Whitney U tests with Bonferroni correction for multiple comparisons. Between six- and 14-fold lower levels of MDH2 expression were observed in MDH2-mutated tumors compared with control patients. Knockdown (KD) of MDH2 in HeLa cells by shRNA triggered the accumulation of both malate (mean ± SD: wild-type [WT] = 1±0.18; KD = 2.24±0.17, P = .043) and fumarate (WT = 1±0.06; KD = 2.6±0.25, P = .033), which was reversed by transient introduction of WT MDH2 cDNA. Segregation of the mutation with disease and absence of MDH2 in mutated tumors revealed MDH2 as a novel pheochromocytoma/paraganglioma susceptibility gene.
A phase III trial of pemetrexed plus gemcitabine versus gemcitabine in patients with unresectable or metastatic pancreatic cancer. Ann Oncol 2005; 16: 1639–1645
Authors: H. Oettle, D. Richards, R.K. Ramanathan, J.L. van Laethem, M. Peeters, M. Fuchs, A. Zimmermann, W. John, D. Von Hoff, M. Arning, H.L. Kindler
Journal: Annals of Oncology (2006)