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Pinkus, Jack

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Pinkus

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Jack

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Pinkus, Jack

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2008 - 200912010 - 20131

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Author's Publications: search.filters.isAuthorOfPublication.f1072e30-6489-46fb-8f79-e9013e99d457

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    Prion-like domain mutations in hnRNPs cause multisystem proteinopathy and ALS
    (2013) Kim, Hong Joo; Kim, Nam Chul; Wang, Yong-Dong; Scarborough, Emily A.; Moore, Jennifer; Diaz, Zamia; MacLea, Kyle S.; Freibaum, Brian; Li, Songqing; Molliex, Amandine; Kanagaraj, Anderson P.; Carter, Robert; Boylan, Kevin B.; Wojtas, Aleksandra M.; Rademakers, Rosa; Pinkus, Jack; Greenberg, Steven; Trojanowski, John Q.; Traynor, Bryan J.; Smith, Bradley N.; Topp, Simon; Gkazi, Athina-Soragia; Miller, Jack; Shaw, Christopher E.; Kottlors, Michael; Kirschner, Janbernd; Pestronk, Alan; Li, Yun R.; Ford, Alice Flynn; Gitler, Aaron D.; Benatar, Michael; King, Oliver D.; Kimonis, Virginia E.; Ross, Eric D.; Weihl, Conrad C.; Shorter, James; Taylor, J. Paul
    Summary Algorithms designed to identify canonical yeast prions predict that ~250 human proteins, including several RNA-binding proteins associated with neurodegenerative disease, harbor a distinctive prion-like domain (PrLD) enriched in uncharged polar amino acids and glycine. PrLDs in RNA-binding proteins are essential for the assembly of ribonucleoprotein granules. However, the interplay between human PrLD function and disease is not understood. Here, we define pathogenic mutations in PrLDs of hnRNPA2/B1 and hnRNPA1 in families with inherited degeneration affecting muscle, brain, motor neuron and bone, and a case of familial ALS. Wild-type hnRNPA2 and hnRNPA1 display an intrinsic tendency to assemble into self-seeding fibrils, which is exacerbated by the disease mutations. Indeed, the pathogenic mutations strengthen a ‘steric zipper’ motif in the PrLD, which accelerates formation of self-seeding fibrils that cross-seed polymerization of wild-type hnRNP. Importantly, the disease mutations promote excess incorporation of hnRNPA2 and hnRNPA1 into stress granules and drive the formation of cytoplasmic inclusions in animal models that recapitulate the human pathology. Thus, dysregulated polymerization caused by a potent mutant ‘steric zipper’ motif in a PrLD can initiate degenerative disease. Related proteins with PrLDs must be considered candidates for initiating and perhaps propagating proteinopathies of muscle, brain, motor neuron and bone.
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    Immunohistochemical Markers Associated With Brain Metastases in Patients with Nonsmall Cell Lung Carcinoma
    (Wiley, 2008-10-15) Saad, Ali G.; Yeap, Beow; Thunnissen, Frederik B. J. M.; Pinkus, Geraldine; Pinkus, Jack; Loda, Massimo; Sugarbaker, David J.; Johnson, Bruce; Chirieac, Lucian
    BACKGROUND There are no reliable markers able to identify patients with non-small cell lung cancer (NSCLC) likely to metastasize to the brain. We investigated associations between immunohistochemical markers and development of brain metastases in patients with NSCLC. METHODS We performed a hospital-based, case-control study of patients with newly diagnosed NSCLC between 1989 and 2003 that developed brain metastases who had available pathology material from both primary NSCLC and brain metastases. The control patients had NSCLC and no evidence of brain metastases. We examined NSCLC for expression of Ki-67, caspase-3, VEGF-A, VEGF-C, E-cadherin and EGFR in 54 surgical pathology specimens using immunohistochemistry and evaluated associations with development of brain metastases. RESULTS Brain metastases developed after a median time of 12.5 months (range 1.7-89.4 months) from the diagnosis of NSCLC. A significantly increased risk of developing brain metastases was associated with patients who had high Ki-67 (adjusted odds ratio 12.2, 95% CI, 2.4 to 70.4, P<0.001), low caspase-3 (adjusted odds ratio 43.0, 95% CI, 5.3 to >100, P<0.001), high VEGF-C (adjusted odds ratio 14.6, 95% CI, 2.0 to >100, P<0.001), and low E-cadherin (adjusted odds ratio 3.6, 95% CI, 0.9 to 16.4, P=0.05), in the primary NSCLC. No significant risk was observed with VEGF-A and EGFR. A high Ki-67 was also associated with a shorter overall survival (P=0.04). CONCLUSIONS Patients with NSCLC and high Ki-67, low caspase-3, high VEGF-C, and low E-cadherin in their tumors may benefit from close surveillance since they may have an increased risk of developing brain metastases.