tbuckley/cabot-search huggingface dataset:
Angiotensin type 1 receptor antagonist losartan, reduces MPTP-induced degeneration of dopaminergic neurons in substantia nigra
Authors: Tom N Grammatopoulos, Susan M Jones, Ferogh A Ahmadi, Brian R Hoover, Lawrence D Snell, Jesse Skoch, Vimal V Jhaveri, Andy M Poczobutt, James A Weyhenmeyer, W Michael Zawada
Journal: Molecular Neurodegeneration (2007)

Recent attention has focused on understanding the role of the brain-renin-angiotensin-system (RAS) in stroke and neurodegenerative diseases. Direct evidence of a role for the brain-RAS in Parkinson's disease (PD) comes from studies demonstrating the neuroprotective effect of RAS inhibitors in several neurotoxin based PD models. In this study, we show that an antagonist of the angiotensin II (Ang II) type 1 (AT1) receptor, losartan, protects dopaminergic (DA) neurons against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity both in primary ventral mesencephalic (VM) cultures as well as in the substantia nigra pars compacta (SNpc) of C57BL/6 mice (Fig. 1).In the presence of exogenous Ang II, losartan reduced MPP+ (5 muM) induced DA neuronal loss by 72% in vitro. Mice challenged with MPTP showed a 62% reduction in the number of DA neurons in the SNpc and a 71% decrease in tyrosine hydroxylase (TH) immunostaining of the striatum, whereas daily treatment with losartan lessened MPTP-induced loss of DA neurons to 25% and reduced the decrease in striatal TH+ immunostaining to 34% of control.Our study demonstrates that the brain-RAS plays an important neuroprotective role in the MPTP model of PD and points to AT1 receptor as a potential novel target for neuroprotection.
Increased Human Brain Natriuretic Peptide in Congestive Heart Failure
Authors: Masashi Mukoyama, Kazuwa Nakao, Yoshihiko Saito, Yoshihiro Ogawa, Kiminori Hosoda, Shin Ichi Suga, Gotaro Shirakami, Michihisa Jougasaki, Hiroo Imura
Journal: New England Journal of Medicine (1990)
Abstract 4541: Dual targeting of CDK4 and MEK as a combination treatment strategy for metastatic colorectal cancer
Authors: Elizabeth Ziemke, Joseph Dosch, Amrith Shettigar, Shanshan Wan, Theodore Welling, Karin Hardiman, Judith Sebolt-Leopold
Journal: Cancer Research (2014)

Abstract Aberrant hyperactivation of KRAS plays a prominent role in tumor initiation and progression of a broad spectrum of human malignancies. The incidence of KRAS mutations is especially high in colorectal cancers, where it occurs at a frequency of roughly 50%. The present study addresses the hypothesis that dual targeting of CDK4 and MEK represents a viable treatment strategy for the subpopulation of colorectal cancers exhibiting hyperactivated KRAS signaling. We have generated both in vitro and in vivo data in highly passaged colorectal xenograft models to provide compelling support for further exploration of this combination treatment strategy. We have now turned to the study of primary human models that are anticipated to be more predictive of ultimate clinical activity in patients. A heterogeneous panel of low passage colorectal patient-derived xenografts (PDX) has been established from biospecimens procured during patient surgeries conducted at our institution (n=12). All xenograft models have been genomically profiled and their histologies mimicked those observed in the original samples. As anticipated, approximately half of these models harbor an oncogenic KRAS mutation and exhibit widely differing histologies, consistent with the heterogeneity encountered in the clinic. Immunoblotting analysis has further revealed that that the majority (&amp;gt;80%) are positive for both phosphorylated RB and constitutive pERK expression and are therefore candidates for treatment regimens combining inhibitors of CDK4 and MEK. Employing the CDK4 inhibitor palbociclib and multiple MEK inhibitors, in vivo efficacy studies are ongoing against our colorectal PDX panel. Preliminary data have shown a higher frequency of regressions in the combination arm compared to either single agent arm at the respective maximum tolerated doses. Our results therefore suggest that combined inhibition of CDK4 and MEK may provide an attractive therapeutic strategy for the treatment of colorectal cancer. Citation Format: Elizabeth Ziemke, Joseph Dosch, Amrith Shettigar, Shanshan Wan, Theodore Welling, Karin Hardiman, Judith Sebolt-Leopold. Dual targeting of CDK4 and MEK as a combination treatment strategy for metastatic colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4541. doi:10.1158/1538-7445.AM2014-4541
Abstract MP79: Physical Activity Patterns by Data-driven Model-based Clustering Improve Association with Cardiovascular Risk Factors in a Multiethnic Cohort: The Northern Manhattan Study
Authors: Ken Cheung, Joshua Z Willey, Gary Yu, Palma Gervasi-Franklin, Melanie M Wall, Ralph L Sacco, Mitchell S Elkind
Journal: Circulation (2014)

Background: Physical activity is a complex modifiable risk factor (RF) for cardiovascular disease (CVD). Current methods to measure physical activity are limited by the use of summary scores such as total metabolic equivalents score (METS). Hypothesis: Physical activity patterns derived by a data-driven clustering method are associated with CVD RFs independently of METS. Methods: The Northern Manhattan Study is a prospective cohort of older, urban-dwelling, multiethnic, stroke-free individuals. Questionnaires were used to capture multi-dimensions of leisure-time physical activity, which was summarized with METS (total activity minutes х intensity in MET). Participants were grouped into previously defined METS categories (less than 1, greater than 14, and 1-14), and also into clusters by multivariate finite mixture modeling based on activity frequency, duration, energy expenditure, and number of activity types. Bayesian information criterion was used to decide number of clusters. Associations between model-based clusters and 4 RFs (diabetes, hypertension, obesity, high waist circumference) were assessed in the entire cohort and in each METS category; associations between METS and RFs were assessed in each cluster. Chi-squared test was used. Results: Physical activity data were available in 3293, with mean age 69 years, 63% women, and 52% Hispanic. Six clusters were identified and labeled I-VI (Table 1). Model-based clusters were associated with all four RFs (all p≤0.01), with clusters V and VI having lower RFs prevalence than the others: the association with obesity prevailed among those with 1≤METS≤14 (p&lt;0.01); and with hypertension among those with METS&gt;14 (p=0.03). METS categories were associated with all four RFs in the entire cohort (all p≤0.04); METS and RFs became no longer significantly associated within clusters. Conclusions: A data-driven clustering method for depicting physical activity data is a principled, generalizable approach to form subgroups associated with CVD RFs independently of METS.
Abstract #LB-210: Mitoxantrone-amino acid conjugates: novel topoisomerase II-targeting agents with a different drug resistant profile
Authors: Chieh-Hua Lee, Ling-Wei Hsin, Sheng-Fa Yu, Leroy Liu, Tsai-Kun Li
Journal: Cancer Research (2009)

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

The potency and action mechanism of new synthetic mitoxantrone (MTX)-amino acid conjugates (MACs) in killing cancer cells were investigated. It is known that the clinically useful antitumor MTX drugs induce topoisomerase II (TOP2)-mediated DNA breakage and cell death via a proposed \#8220;misalignment\#8221; mechanism, which are correlated with the DNA-intercalating ability of MTXs. In this current study, we show that MACs exhibited nM cytotoxicity against cancer cells rivals with that of clinically used MTXs in tissue culture models. Notably, cellular exposure to MACs induced different levels of chromosomal DNA breakage correlated with cytotoxicity, suggesting that DNA breaks is responsible for MAC-induced cell killing. Further characterization of MAC-induced DNA breakage supports the involvement of TOP2: protein-linked DNA breaks, reversibility, excision of loop-sized chromosomal fragments and antagonizing effect by TOP2 catalytic inhibitors. Moreover, both DNA breakage and cytotoxicity were much reduced in TOP2-deficient conditions created by either mutations or RNA interference. Interestingly, although MACs and MTX have similar binding constants, MACs appear to exhibit lower DNA unwinding ability and \#916;Tm values than those of MTX. In sum, our data are consistent with a mechanistic model where both enzyme- and DNA-drug interactions play important roles for TOP2 targeting by MACs, with amino acid and MTX part interacting with enzyme and DNA, respectively. In addition, we have recently found that, unlike MTXs, MACs are not substrate for drug-resistant transporters. These results therefore suggest that MAC is a promising new class of TOP2-targeting antitumor drug with a different drug resistance profile than MTX.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr LB-210.
V599E B-Raf as the next HSP90 client protein: A novel strategy for selective inhibition of mutated B-Raf
Authors: Olivera M. Grbovic, Andrea Basso, David Solit, Neal Rosen
Journal: Cancer Research (2005)

5242  The discovery of frequent mutations in the B-Raf gene in human tumors has generated enormous interest in how this Raf kinase is regulated and how mutations in B-Raf lead to transformation. In this study we provide new insight into these questions by finding that mutational activation of B-Raf is associated with gain of dependence on Hsp90 and its presence in an Hsp90-cdc37 complex. Wild type B-Raf, in contrast, is unaffected by Hsp90 inhibitors and doesn’t require Hsp90 for conformational maturation and stability. The Hsp90 inhibitor 17-allylaminogeldanamycin (17-AAG) causes the targeting of mutated B-Raf to an NP-40 insoluble fraction of the proteasome, where it is degraded. The loss of mutated B-Raf expression results in inhibition of MAP kinase, loss of D-cyclin expression with subsequent G1 arrest and apoptosis. Furthermore, degradation of B-Raf can be induced with Hsp90 inhibitors, in vivo, at non-toxic doses, and this may therefore represent a novel therapeutic strategy for this disease.
Mobile teledermatology for skin tumour screening: diagnostic accuracy of clinical and dermoscopic image tele-evaluation using cellular phones
Authors: S. Kroemer, J. Frühauf, T.M. Campbell, C. Massone, G. Schwantzer, H.P. Soyer, R. Hofmann-Wellenhof
Journal: British Journal of Dermatology (2011)

The ability to diagnose malignant skin tumours accurately and to distinguish them from benign lesions is vital in ensuring appropriate patient management. Little is known about the effects of mobile teledermatology services on diagnostic accuracy and their appropriateness for skin tumour surveillance.To evaluate the diagnostic accuracy of clinical and dermoscopic image tele-evaluation for mobile skin tumour screening.Over a 3-month period up to three clinical and dermoscopic images were obtained of 113 skin tumours from 88 patients using a mobile phone camera. Dermoscopic images were taken with a dermatoscope applied to the camera lens. Clinical and dermoscopic images of each lesion together with clinical information were separately teletransmitted for decision-making. Results were compared with those obtained by face-to-face examination and histopathology as the gold standard.A total of 322 clinical and 278 dermoscopic images were acquired; two (1%) clinical and 18 (6%) dermoscopic pictures were inadequate for decision-making. After excluding inadequate images, the majority of which were dermoscopic pictures, only 104 of the 113 skin tumours from 80 of 88 patients could be tele-evaluated. Among these 104 lesions, 25 (24%) benign nonmelanocytic, 15 (14%) benign melanocytic, 58 (56%) malignant nonmelanocytic and six (6%) malignant melanocytic lesions were identified. Clinical and dermoscopic tele-evaluations demonstrated strong concordance with the gold standard (κ = 0·84 for each) and similar high sensitivity and specificity for all diagnostic categories. With regard to the detailed diagnoses, clinical image tele-evaluation was superior to teledermoscopy resulting in 16 vs. 22 discordant cases.Clinical image tele-evaluation might be the method of choice for mobile tumour screening.
Magnesium Intake, Drinking Water, and Risk of Colorectal Cancer
Authors: Lars Wiklund, Jan Pousette, Mary George
Journal: JAMA (2005)

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Abstract 613: Combining PI3K and 5alpha-reductase inhibitors improves the treatment response in a mouse model of PTEN-deficient prostate cancer
Authors: Yurie Kura, Marco A. De Velasco, Naomi Ando, Emiko Fukushima, Yutaka Yamamoto, Yuji Hatanaka, Nobutaka Shimizu, Masahiro Nozawa, Kazuhiro Yoshimura, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura
Journal: Cancer Research (2014)

Abstract Testosterone is converted to dihydrotestosterone (DHT) by the enzymes 5alpha-reductase types 1 and 2. Inhibition of both 5alpha-reducatase enzymes with dutasteride was effective in reducing the incidence of prostate cancer in high risk patients. This suggests that suppression of DHT with dutasteride may have a potential therapeutic effect on prostate cancer. In this study, we examined the antitumor effects of dutasteride in vivo using a preclinical model of prostate cancer that is based on the PSA-Cre mediated inactivation of PTEN. Our findings show that monotherapy with dutasteride significantly inhibited prostate tumor growth by approximately 25%. Furthermore, the combination of dutasteride with the mTOR inhibitor, everolimus, improved tumor growth suppression compared to monotherapy with either drug. Treatment with dutasteride had a minimal effect on tumor cell proliferation; however, it significantly increased the apoptotic rate in tumors. Interestingly, treatment with dutasteride resulted in increased activation of PI3K/mTOR signaling and a reduction of STAT3 pathway activation. Moreover, increased activation of MAPK, which occurs after treatment with mTOR inhibitors, was effectively reduced with the co-administration of dutasteride. The findings from our study suggest that inhibitors of 5alpha-reductase types 1 and 2 enzymes may have a potential therapeutic value in PTEN deficient prostate cancers, in particular when co-administered with PI3K inhibitors. Citation Format: Yurie Kura, Marco A. De Velasco, Naomi Ando, Emiko Fukushima, Yutaka Yamamoto, Yuji Hatanaka, Nobutaka Shimizu, Masahiro Nozawa, Kazuhiro Yoshimura, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura. Combining PI3K and 5alpha-reductase inhibitors improves the treatment response in a mouse model of PTEN-deficient prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 613. doi:10.1158/1538-7445.AM2014-613
330. Genetic Modification of Murine Embryonic Stem Cells by the Gene Silencing Resistance Retroviral Vector GCDsap
Authors: Sanae Hamanaka, Joichi Usui, Satoru Takahashi, Hisahiro Yoshida, Michio Nagata, Makoto Otsu, Shin Kaneko, Toshiro Nagasawa, Hiromitsu Nakauchi, Masafumi Onodera
Journal: Molecular Therapy (2004)

In the last ASGT meeting, we presented that the retroviral vector GCDsap with high resistance to gene silencing maintained expression of the transgene (EGFP) in mouse embryonic stem (ES) cells over 60 days and the expression was continued even after differentiation of the transduced ES cells into three germ layers of teratomas in NOD/SCID mice. In this study, to assess the ability of the vector to maintain the transgene expression through ontogeny, the transduced ES cells were injected into C57BL/6 mouse 3.5 days blastocytes and chimeric mice were generated. The birth ratio of chimeric mice determined by coat color was 67% (24 out of 36 mice) and 17 out of 24 mice (71%) highly expressed EGFP in their tissues, including hematopoietic cells, neurons, muscles, and intestinal tracts. Furthermore, such high expression of EGFP was transmitted through F1 (47/95 = 49%) to F2 mice (32/56 = 58%) generated by mating with C57BL/6 mice. Although the mean intensity of EGFP varied among the mice, some had 100% of EGFP expressing cells in their peripheral blood. Interestingly, a chimera mouse gave rise to F1 mice that were divided into three groups by the expression patterns in their peripheral blood. Southern blot analyses revealed that the chimeric mouse had 8 copies of proviruses integrated in its chromosomes and each F1 group showed an identical integration pattern of proviruses. This was applicable to F2 mice, in particular, F2 mice borne by F1 mice with the highest EGFP expression also showed high EGFP expression and their integration patterns were identical to that of the F1, suggesting that maintenance of the transgene expression was greatly influenced by the integration sites as well as vector structures. Taken together, it is likely that GCDsap provided a useful tool not only for future regenerative medicine, but also for analysis of epigenetic changes in chromosomes during gonogenesis.
BAY 43-9006 (Sorafenib) is a potent inhibitor of FLT3 tyrosine kinase signaling and proliferation in AML cells
Authors: Daniel Auclair, Donna Miller, Christopher Carter, Yong Chang, Barbara Polony, Xiaomei Zhang, Victoria Yatsula, Walter Pickett, Timothy Housley, Amy Burd, Hong Shi, Sandy Rocks, Richard Gedrich, Laura Abriola, Don Apanovitch, Istvan Enyedy, Jacques Dumas, Bernd Riedl, Pamela A. Trail, Scott M. Wilhelm
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

5991 

Activating mutations of the protein tyrosine kinase (PTK) FLT3 can be found in approximately 30% of patients with acute myeloid leukemia (AML) thereby representing the most frequent genetic alterations in AML. Activating internal tandem duplication (ITD) mutations in the FLT3 juxtamembrane domain have been shown to be an independent negative prognostic factor for survival. BAY 43-9006 is a novel dual action RAF kinase and VEGFR inhibitor that targets tumor cell proliferation and tumor angiogenesis. We show that BAY 43-9006 potently inhibits FLT3 wild type (FLT3-WT) and FLT3-ITD enzymatic activity in cell free assays. BAY 43-9006 at single digit nanomolar concentrations inhibited the proliferation of MV4;11 and EOL-1 leukemic cells that express FLT3-ITD in vitro , whereas the growth of the FLT-3 independent RS4-11 leukemic cell line was only weakly inhibited (IC50 = 12 μM). Cell cycle arrest and induction of apoptosis were observed upon treatment with BAY 43-9006 in MV4;11 and EOL-1 cells. In HEK293 cells stably transfected with FLT3-WT or FLT3-ITD, BAY 43-9006 at nanomolar concentrations (5-50 nM) blocked basal and ligand (FL) dependent FLT3-mediated tyrosine autophosphorylation as well as ERK1/2 and Stat5 transphosphorylation. Inhibition of FLT3-mediated signaling was also observed in MV4;11 cells treated with nanomolar doses of BAY 43-9006. The anti-tumor efficacy of BAY 43-9006 was evaluated against the MV4;11 leukemia grown subcutaneously in NCr nu/nu mice. Doses of 3 and 10 mg/kg administered orally for 14 days induced complete regression of 60% and 90% of MV4;11 tumors, respectively. Modeling of the binding of BAY 43-9006 to FLT3 showed that it interacts with FLT3 in a similar binding mode as reported for BRAF. The demonstration that BAY 43-9006 exhibits potent target inhibition and efficacy in FLT3-ITD models suggests that this compound may have biologic activity in AML patients with FLT3 mutations.
Angiokeratomas, Fabry disease and enzyme replacement therapy: still a challenge
Authors: M. Möhrenschlager, V. Henkel, J. Ring
Journal: British Journal of Dermatology (2005)

Journal Article Angiokeratomas, Fabry disease and enzyme replacement therapy: still a challenge Get access M. Möhrenschlager, M. Möhrenschlager Department of Dermatology and Allergy Biederstein, Technical University of Munich, Biedersteiner Str. 29, D‐80802 Munich, Germany *Department of Psychiatry, Ludwig‐Maximilians‐University Munich, Nussbaumstr. 7, D‐80336 Munich, Germany E‐mail: moehrenschlager@lrz.tum.de Search for other works by this author on: Oxford Academic Google Scholar V. Henkel, V. Henkel Department of Dermatology and Allergy Biederstein, Technical University of Munich, Biedersteiner Str. 29, D‐80802 Munich, Germany *Department of Psychiatry, Ludwig‐Maximilians‐University Munich, Nussbaumstr. 7, D‐80336 Munich, Germany E‐mail: moehrenschlager@lrz.tum.de Search for other works by this author on: Oxford Academic Google Scholar J. Ring J. Ring Department of Dermatology and Allergy Biederstein, Technical University of Munich, Biedersteiner Str. 29, D‐80802 Munich, Germany *Department of Psychiatry, Ludwig‐Maximilians‐University Munich, Nussbaumstr. 7, D‐80336 Munich, Germany E‐mail: moehrenschlager@lrz.tum.de Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 152, Issue 1, 1 January 2005, Pages 177–178, https://doi.org/10.1111/j.1365-2133.2005.06359.x Published: 01 January 2005
Modification of Characteristics of an &lt;italic&gt;In Vitro&lt;/italic&gt; Mouse Cell Line After an Increase of Its Tumor-Producing Capacity&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: G. Barski, J. L. Biedler, Fr. Cornefert
Journal: JNCI Journal of the National Cancer Institute (1961)

Three of nearly a hundred normal C3H mice, receiving subcutaneous injections of large inoculums of cells from the low-cancer NCTC 2555 clone (Sanford et al.), developed sarcomas at the inoculation site after long latent periods. Two cell strains established in vitro from these tumors were analyzed and compared with the parental clone and a constantly high-cancer NCTC 2472 clone. The two “derived” cell strains maintained a relatively high tumor-producing capacity during at least 8 to 9 months in vitro. The karyotype of each was like the parental line, especially in respect to biarmed chromosomes. The rate of cell multiplication remained unchanged, but morphological modifications, such as cytoplasmic ramifications and increase of mobility, were noted. No striking antigenic alterations of the “derived” cell lines could be evidenced by cross inoculations in mice. However, implantations on chick chorio-allantoic and chick mesonephros organ cultures allowed us to demonstrate a gradation of invasive capacity of different cell lines studied, parallel to their malignancy for isologous mice.