المؤلفون: Hossein J. Sadaei, Aldo Cordova-Palomera, Jonghun Lee, Jaya Padmanabhan, Shang-Fu Chen, Nathan E. Wineinger, Raquel Dias, Daria Prilutsky, Sandor Szalma, Ali Torkamani

المصدر: npj Parkinson's Disease, Vol 8, Iss 1, Pp 1-11 (2022)

مصطلحات موضوعية: Neurology. Diseases of the nervous system, RC346-429

الوصف: Abstract Parkinson’s disease (PD) treatments modify disease symptoms but have not been shown to slow progression, characterized by gradual and varied motor and non-motor changes overtime. Variation in PD progression hampers clinical research, resulting in long and expensive clinical trials prone to failure. Development of models for short-term PD progression prediction could be useful for shortening the time required to detect disease-modifying drug effects in clinical studies. PD progressors were defined by an increase in MDS-UPDRS scores at 12-, 24-, and 36-months post-baseline. Using only baseline features, PD progression was separately predicted across all timepoints and MDS-UPDRS subparts in independent, optimized, XGBoost models. These predictions plus baseline features were combined into a meta-predictor for 12-month MDS UPDRS Total progression. Data from the Parkinson’s Progression Markers Initiative (PPMI) were used for training with independent testing on the Parkinson’s Disease Biomarkers Program (PDBP) cohort. 12-month PD total progression was predicted with an F-measure 0.77, ROC AUC of 0.77, and PR AUC of 0.76 when tested on a hold-out PPMI set. When tested on PDBP we achieve a F-measure 0.75, ROC AUC of 0.74, and PR AUC of 0.73. Exclusion of genetic predictors led to the greatest loss in predictive accuracy; ROC AUC of 0.66, PR AUC of 0.66–0.68 for both PPMI and PDBP testing. Short-term PD progression can be predicted with a combination of survey-based, neuroimaging, physician examination, and genetic predictors. Dissection of the interplay between genetic risk, motor symptoms, non-motor symptoms, and longer-term expected rates of progression enable generalizable predictions.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2373-8057Test

الوصول الحر: https://doaj.org/article/b53df21fcc3248ddb53ea381362d5008Test

المؤلفون: Yainyrette Rivera-Rivera, Mihaela Marina, Shirley Jusino, Miyoung Lee, Jaleisha Vélez Velázquez, Camille Chardón-Colón, Geraldine Vargas, Jaya Padmanabhan, Srikumar P. Chellappan, Harold I. Saavedra

المصدر: Scientific Reports, Vol 11, Iss 1, Pp 1-15 (2021)

مصطلحات موضوعية: Medicine, Science

الوصف: Abstract Nek2 (NIMA‐related kinase 2) is a serine/threonine-protein kinase that localizes to centrosomes and kinetochores, controlling centrosome separation, chromosome attachments to kinetochores, and the spindle assembly checkpoint. These processes prevent centrosome amplification (CA), mitotic dysfunction, and chromosome instability (CIN). Our group and others have suggested that Nek2 maintains high levels of CA/CIN, tumor growth, and drug resistance. We identified that Nek2 overexpression correlates with poor survival of breast cancer. However, the mechanisms driving these phenotypes are unknown. We now report that overexpression of Nek2 in MCF10A cells drives CA/CIN and aneuploidy. Besides, enhanced levels of Nek2 results in larger 3D acinar structures, but could not initiate tumors in a p53+/+ or a p53−/− xenograft model. Nek2 overexpression induced the epithelial-to-mesenchymal transition (EMT) while its downregulation reduced the expression of the mesenchymal marker vimentin. Furthermore, either siRNA-mediated downregulation or INH6’s chemical inhibition of Nek2 in MDA-MB-231 and Hs578t cells showed important EMT changes and decreased invasion and migration. We also showed that Slug and Zeb1 are involved in Nek2 mediated EMT, invasion, and migration. Besides its role in CA/CIN, Nek2 contributes to breast cancer progression through a novel EMT mediated mechanism.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2045-2322Test

الوصول الحر: https://doaj.org/article/349186be6236452795f3845aa7cf9050Test

المؤلفون: John Kornak, Julie Fields, Walter Kremers, Sara Farmer, Hilary W. Heuer, Leah Forsberg, Danielle Brushaber, Amy Rindels, Hiroko Dodge, Sandra Weintraub, Lilah Besser, Brian Appleby, Yvette Bordelon, Jessica Bove, Patrick Brannelly, Christina Caso, Giovanni Coppola, Reilly Dever, Christina Dheel, Bradford Dickerson, Susan Dickinson, Sophia Dominguez, Kimiko Domoto‐Reilly, Kelley Faber, Jessica Ferrall, Ann Fishman, Jamie Fong, Tatiana Foroud, Ralitza Gavrilova, Deb Gearhart, Behnaz Ghazanfari, Nupur Ghoshal, Jill Goldman, Jonathan Graff‐Radford, Neill Graff‐Radford, Ian M. Grant, Murray Grossman, Dana Haley, John Hsiao, Robin Hsiung, Edward D. Huey, David Irwin, David Jones, Lynne Jones, Kejal Kantarci, Anna Karydas, Daniel Kaufer, Diana Kerwin, David Knopman, Ruth Kraft, Joel Kramer, Walter Kukull, Maria Lapid, Irene Litvan, Peter Ljubenkov, Diane Lucente, Codrin Lungu, Ian Mackenzie, Miranda Maldonado, Masood Manoochehri, Scott McGinnis, Emily McKinley, Mario Mendez, Bruce Miller, Namita Multani, Chiadi Onyike, Jaya Padmanabhan, Alexander Pantelyat, Rodney Pearlman, Len Petrucelli, Madeline Potter, Rosa Rademakers, Eliana Marisa Ramos, Katherine Rankin, Katya Rascovsky, Erik D. Roberson, Emily Rogalski‐Miller, Pheth Sengdy, Les Shaw, Adam M. Staffaroni, Margaret Sutherland, Jeremy Syrjanen, Carmela Tartaglia, Nadine Tatton, Joanne Taylor, Arthur Toga, John Trojanowski, Ping Wang, Bonnie Wong, Zbigniew Wszolek, Brad Boeve, Adam Boxer, Howard Rosen, ARTFL/LEFFTDS Consortium

المصدر: Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring, Vol 11, Iss 1, Pp 797-808 (2019)

مصطلحات موضوعية: Generalized additive models, Heterogenous variance modeling, Neuropsychological testing scores, Nonlinear Z‐score correction, Shape constrained additive models, Neurology. Diseases of the nervous system, RC346-429, Geriatrics, RC952-954.6

الوصف: Abstract Introduction Conventional Z‐scores are generated by subtracting the mean and dividing by the standard deviation. More recent methods linearly correct for age, sex, and education, so that these “adjusted” Z‐scores better represent whether an individual's cognitive performance is abnormal. Extreme negative Z‐scores for individuals relative to this normative distribution are considered indicative of cognitive deficiency. Methods In this article, we consider nonlinear shape constrained additive models accounting for age, sex, and education (correcting for nonlinearity). Additional shape constrained additive models account for varying standard deviation of the cognitive scores with age (correcting for heterogeneity of variance). Results Corrected Z‐scores based on nonlinear shape constrained additive models provide improved adjustment for age, sex, and education, as indicated by higher adjusted‐R2. Discussion Nonlinearly corrected Z‐scores with respect to age, sex, and education with age‐varying residual standard deviation allow for improved detection of non‐normative extreme cognitive scores.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2352-8729Test

الوصول الحر: https://doaj.org/article/a6622d356e19452690bcb069ec439d27Test

المؤلفون: Jaya Padmanabhan, Biswarup Saha, Chase Powell, Qianxing Mo, Bradford A. Perez, Srikumar Chellappan

المصدر: Cancers, Vol 13, Iss 15, p 3906 (2021)

مصطلحات موضوعية: transcriptional CDKs, BRD4, EGFR, K-RasG12C, lung cancer organoids, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Non-small cell lung cancer has a 5-year survival rate of less than 12–15%, calling for the development of additional therapeutic strategies to combat this disease. Here we tested the efficacy of inhibiting cyclin-dependent kinase 9 (CDK9) on lung cancer cell lines with K-Ras and EGFR mutations and on lung cancer organoids. Three different CDK9 inhibitors reduced the viability and anchorage-independent growth of lung cancer cell lines at very low nanomolar to micromolar concentrations. CDK9 inhibition suppressed the expression of the anti-apoptotic protein, Mcl1, as well as the embryonic stem cell transcription factors, Sox2 and Sox9, which are pro-tumorigenic. In contrast, treatment with CDK9 inhibitors increased the levels of WT p53 and its downstream target p21 in K-Ras mutant cell lines. Furthermore, the CDK9 inhibitors could markedly reduce the viability of Osimertinib-resistant PC9 and AMG510-resistant H23 and H358 cells with comparable efficacy as the parental cells. CDK9 inhibitors could also significantly reduce the growth and viability of lung cancer organoids with high potency. Taken together, the data presented here strongly suggest that CDK9 inhibitors would be efficacious against K-Ras mutant and EGFR mutant NSCLCs, including those that develop resistance to targeted therapies.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/2072-6694/13/15/3906Test; https://doaj.org/toc/2072-6694Test

الوصول الحر: https://doaj.org/article/9e5dc96753204b53b36ee82347a50164Test

المؤلفون: Courtney Schaal, Jaya Padmanabhan, Srikumar Chellappan

المصدر: Cancers, Vol 7, Iss 3, Pp 1447-1471 (2015)

مصطلحات موضوعية: nicotine, tobacco carcinogens, calcium channels, beta-adrenergic receptors, epithelial mesenchymal transition, metastasis, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Pancreatic cancer shows a strong correlation with smoking and the current therapeutic strategies have been relatively ineffective in improving the survival of patients. Efforts have been made over the past many years to understand the molecular events that drive the initiation and progression of pancreatic cancer, especially in the context of smoking. It has become clear that components of tobacco smoke not only initiate these cancers, especially pancreatic ductal adenocarcinomas (PDACs) through their mutagenic properties, but can also promote the growth and metastasis of these tumors by stimulating cell proliferation, angiogenesis, invasion and epithelial-mesenchymal transition. Studies in cell culture systems, animal models and human samples have shown that nicotinic acetylcholine receptor (nAChR) activation enhances these tumor-promoting events by channeling signaling through multiple pathways. In this context, signaling through calcium channels appear to facilitate pancreatic cancer growth by itself or downstream of nAChRs. This review article highlights the role of nAChR downstream signaling events and calcium signaling in the growth, metastasis as well as drug resistance of pancreatic cancer.

وصف الملف: electronic resource

العلاقة: http://www.mdpi.com/2072-6694/7/3/0845Test; https://doaj.org/toc/2072-6694Test

الوصول الحر: https://doaj.org/article/95be290b834e469bb5a2e69068267307Test

المؤلفون: Ethika Tyagi, Tina Fiorelli, Michelle Norden, Jaya Padmanabhan

المصدر: International Journal of Alzheimer's Disease, Vol 2013 (2013)

مصطلحات موضوعية: Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Geriatrics, RC952-954.6

الوصف: The association of inflammatory proteins with neuritic plaques in the brains of Alzheimer’s disease (AD) patients has led to the hypothesis that inflammation plays a pivotal role in the development of pathology in AD. Earlier studies have shown that alpha 1-antichymotrypsin (ACT) enhances amyloid beta fibrillization and accelerated plaque formation in APP transgenic mice. Later studies from our laboratory have shown that purified ACT induces tau hyperphosphorylation and degeneration in neurons. In order to understand the mechanisms by which inflammatory proteins enhance tau hyperphosphorylation, we injected interleukin-1β (IL-1β) intracerebroventricularly into mice expressing human ACT, human tau, or both transgenes. It was found that the hyperphosphorylation of tau in ACT and ACT/htau mice after IL-1β injection correlated with increased phosphorylation of c-Jun N-terminal kinase (JNK). We verified the involvement of JNK in ACT-induced tau phosphorylation by utilizing JNK inhibitors in cultured primary neurons treated with ACT, and we found that the inhibitor showed complete prevention of ACT-induced tau phosphorylation. These results indicate that JNK is one of the major kinases involved in the ACT-mediated tau hyperphosphorylation and suggest that inhibitors of this kinase may protect against inflammation-induced tau hyperphosphorylation and neurodegeneration associated with AD.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2090-8024Test; https://doaj.org/toc/2090-0252Test

الوصول الحر: https://doaj.org/article/497b15bb62d147d6bdaf55f501e8adb6Test

المؤلفون: Tina Fiorelli, Lisa Kirouac, Jaya Padmanabhan

المصدر: PLoS ONE, Vol 8, Iss 2, p e57979 (2013)

مصطلحات موضوعية: Medicine, Science

الوصف: Altered proteolysis of amyloid precursor protein is an important determinant of pathology development in Alzheimer's disease. Here, we describe the detection of two novel fragments of amyloid precursor protein in H4 neuroglioma cells undergoing apoptosis. Immunoreactivity of these 25-35 kDa fragments to two different amyloid precursor protein antibodies suggests that they contain the amyloid-β region and an epitope near the C-terminus of amyloid precursor protein. Generation of these fragments is associated with cleavage of caspase-3 and caspase-7, suggesting activation of these caspases. Studies in neurons undergoing DNA damage-induced apoptosis also showed similar results. Inclusion of caspase inhibitors prevented the generation of these novel fragments, suggesting that they are generated by a caspase-dependent mechanism. Molecular weight prediction and immunoreactivity of the fragments generated suggested that such fragments could not be generated by cleavage at any previously identified caspase, secretase, or calpain site on amyloid precursor protein. Bioinformatic analysis of the amino acid sequence of amyloid precursor protein revealed that fragments fitting the observed size and immunoreactivity could be generated by either cleavage at a novel, hitherto unidentified, caspase site or at a previously identified matrix metalloproteinase site in the extracellular domain. Proteolytic cleavage at any of these sites leads to a decrease in the generation of α-secretase cleaved secreted APP, which has both anti-apoptotic and neuroprotective properties, and thus may contribute to neurodegeneration in Alzheimer's disease.

وصف الملف: electronic resource

العلاقة: http://europepmc.org/articles/PMC3585261?pdf=renderTest; https://doaj.org/toc/1932-6203Test

الوصول الحر: https://doaj.org/article/24cc2708da8a4c0d89fc194f3a8472c6Test

المؤلفون: Jose F Abisambra, Tina Fiorelli, Jaya Padmanabhan, Peter Neame, Inge Wefes, Huntington Potter

المصدر: PLoS ONE, Vol 5, Iss 1, p e8556 (2010)

مصطلحات موضوعية: Medicine, Science

الوصف: BACKGROUND: Alzheimer's disease (AD) is a chronic neurodegenerative disorder and the most common form of dementia. The major molecular risk factor for late-onset AD is expression of the epsilon-4 allele of apolipoprotein E (apoE), the major cholesterol transporter in the brain. The low-density lipoprotein receptor (LDLR) has the highest affinity for apoE and plays an important role in brain cholesterol metabolism. METHODOLOGY/PRINCIPAL FINDINGS: Using RT-PCR and western blotting techniques we found that over-expression of APP caused increases in both LDLR mRNA and protein levels in APP transfected H4 neuroglioma cells compared to H4 controls. Furthermore, immunohistochemical experiments showed aberrant localization of LDLR in H4-APP neuroglioma cells, Abeta-treated primary neurons, and in the PSAPP transgenic mouse model of AD. Finally, immunofluorescent staining of LDLR and of gamma- and alpha-tubulin showed a change in LDLR localization preferentially away from the plasma membrane that was paralleled by and likely the result of a disruption of the microtubule-organizing center and associated microtubule network. CONCLUSIONS/SIGNIFICANCE: These data suggest that increased APP expression and Abeta exposure alters microtubule function, leading to reduced transport of LDLR to the plasma membrane. Consequent deleterious effects on apoE uptake and function will have implications for AD pathogenesis and/or progression.

وصف الملف: electronic resource

العلاقة: http://europepmc.org/articles/PMC2797391?pdf=renderTest; https://doaj.org/toc/1932-6203Test

الوصول الحر: https://doaj.org/article/21c355055680449696141c40328db022Test

المؤلفون: Jaya Padmanabhan, Elena Ratti, Polyna Khudyakov, Wei Yin, Stephen Zicha, Olga Golonzhka, Tairmae Kangarloo, Brian Harel, Nancy Goodman, Emmanuelle Magueur, Craig Shering, Thor Ostenfeld, Antonio Laurenza, Arthur Simen

المصدر: Tuesday, April 25.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::261966b3c44c6a73808d8a3590adb1e2Test
https://doi.org/10.1212/wnl.0000000000201834Test

المؤلفون: Srikumar Chellappan, Domenico Coppola, Jaya Padmanabhan, Durairaj Mohankumar, Biswarup Saha, Namrata Bora-Singhal

الوصف: Transient transfection data

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8372dee8b719ac6d9fc7eb53f4e43da3Test
https://doi.org/10.1158/2767-9764.22545255Test