Mutation of the gene PARK2, which encodes an E3 ubiquitin ligase, is the most common cause of early-onset Parkinson's disease1, 2, 3. In a search for multisite tumor suppressors, we identified PARK2 as a frequently targeted gene on chromosome 6q25.2–q27 in cancer. Here we describe inactivating somatic mutations and frequent intragenic deletions of PARK2 in human malignancies. The PARK2 mutations in cancer occur in the same domains, and sometimes at the same residues, as the germline mutations causing familial Parkinson's disease. Cancer-specific mutations abrogate the growth-suppressive effects of the PARK2 protein. PARK2 mutations in cancer decrease PARK2's E3 ligase activity, compromising its ability to ubiquitinate cyclin E and resulting in mitotic instability. These data strongly point to PARK2 as a tumor suppressor on 6q25.2–q27. Thus, PARK2, a gene that causes neuronal dysfunction when mutated in the germline, may instead contribute to oncogenesis when altered in non-neuronal somatic cells.

Tyrosine phosphorylation plays a critical role in regulating cellular function and is a central feature in signaling cascades involved in oncogenesis. The regulation of tyrosine phosphorylation is coordinately controlled by kinases and phosphatases (PTPs). Whereas activation of tyrosine kinases has been shown to play vital roles in tumor development, the role of PTPs is much less well defined. Here, we show that the receptor protein tyrosine phosphatase delta (PTPRD) is frequently inactivated in glioblastoma multiforme (GBM), a deadly primary neoplasm of the brain. PTPRD is a target of deletion in GBM, often via focal intragenic loss. In GBM tumors that do not possess deletions in PTPRD, the gene is frequently subject to cancer-specific epigenetic silencing via promoter CpG island hypermethylation (37%). Sequencing of the PTPRD gene in GBM and other primary human tumors revealed that the gene is mutated in 6% of GBMs, 13% of head and neck squamous cell carcinomas, and in 9% of lung cancers. These mutations were deleterious. In total, PTPRD inactivation occurs in >50% of GBM tumors, and loss of expression predicts for poor prognosis in glioma patients. Wild-type PTPRD inhibits the growth of GBM and other tumor cells, an effect not observed with PTPRD alleles harboring cancer-specific mutations. Human astrocytes lacking PTPRD exhibited increased growth. PTPRD was found to dephosphorylate the oncoprotein STAT3. These results implicate PTPRD as a tumor suppressor on chromosome 9p that is involved in the development of GBMs and multiple human cancers. glioblastoma multiforme ͉ methylation ͉ mutation L oss of tumor suppressor function leads to the initiation and progression of cancer (1, 2). Inactivation of tumor suppressor genes can result from both genetic mechanisms such as mutation and deletion or epigenetic mechanisms such as DNA hypermethylation (3, 4). Identification of these genes has provided insight into the biological processes underlying oncogenesis, but the key tumor suppressors in many cancers, such as glioblastoma multiforme (GBM), remain poorly defined.We previously identified the receptor protein tyrosine phosphatase delta (PTPRD) as a gene that predicts for poor prognosis in breast and colon cancer (4). PTPRD is a member of the highly conserved family of receptor protein tyrosine phosphatases (PTPs), several members of which have been implicated in tumorigenesis (5). The gene encodes a transmembrane protein with a cytoplasmic tyrosine phosphatase domain. The PTPRD gene is located within an area of the genome, chromosome 9p, found to be frequently lost in neuroblastoma, gliomas, lung cancer, and other malignancies (6-9). Some deletions of PTPRD have been noted in several of these studies. However, its close proximity to CDKN2A on chromosome 9p has complicated interpretations. In addition, in independent work during the course of our investigations, PTPRD mutations have been detected in a lung cancer genome study, although no functional validation of the alterations is noted (10-12). Together with thes...

Coordinate control of different classes of cyclins is fundamentally important for cell cycle regulation and tumor suppression, yet the underlying mechanisms are incompletely understood. Here we show that the PARK2 tumor suppressor mediates this coordination. The PARK2 E3 ubiquitin ligase coordinately controls the stability of both cyclin D and cyclin E. Analysis of approximately 5,000 tumor genomes shows that PARK2 is a very frequently deleted gene in human cancer and uncovers a striking pattern of mutual exclusivity between PARK2 deletion and amplification of CCND1, CCNE1 or CDK4—implicating these genes in a common pathway. Inactivation of PARK2 results in the accumulation of cyclin D and acceleration of cell cycle progression. Furthermore, PARK2 is a component of a new class of cullin-RING-containing ubiquitin ligases targeting both cyclin D and cyclin E for degradation. Thus, PARK2 regulates cyclin-CDK complexes, as does the CDK inhibitor p16, but acts as a master regulator of the stability of G1/S cyclins.

Pigs are important intermediate hosts for generating novel influenza viruses. The Eurasian avian-like H1N1 (EAH1N1) swine influenza viruses (SIVs) have circulated in pigs since 1979, and human cases associated with EAH1N1 SIVs have been reported in several countries. However, the biologic properties of EAH1N1 SIVs are largely unknown. Here, we performed extensive influenza surveillance in pigs in China and isolated 228 influenza viruses from 36,417 pigs. We found that 139 of the 228 strains from pigs in 10 provinces in China belong to the EAH1N1 lineage. These viruses formed five genotypes, with two distinct antigenic groups, represented by A/swine/Guangxi/18/2011 and A/swine/Guangdong/104/2013, both of which are antigenically and genetically distinct from the current human H1N1 viruses. Importantly, the EAH1N1 SIVs preferentially bound to human-type receptors, and 9 of the 10 tested viruses transmitted in ferrets by respiratory droplet. We found that 3.6% of children (≤10 y old), 0% of adults, and 13.4% of elderly adults (≥60 y old) had neutralization antibodies (titers ≥40 in children and ≥80 in adults) against the EAH1N1 A/swine/Guangxi/18/2011 virus, but none of them had such neutralization antibodies against the EAH1N1 A/swine/Guangdong/104/2013 virus. Our study shows the potential of EAH1N1 SIVs to transmit efficiently in humans and suggests that immediate action is needed to prevent the efficient transmission of EAH1N1 SIVs to humans.

High-efficiency photocatalysis in metal-organic frameworks (MOF) and MOF nanosheets (NSs) are often limited by their short-lived charge separation as well as selfquenching. Here, we propose to use the energy-transfer process (EnT) to increase charge separation, thus enhancing the catalytic performance of a series of MOF NSs. With the use of NS, the photocatalyst can also be well isolated to reduce selfquenching. Tetrakis(4-carboxyphenyl) porphyrin (H 4 TCPP) and 1,3,6,8-tetrakis(p-benzoic acid)pyrene (H 4 TBAPy) linkers were chosen as the acceptor and donor moieties, respectively. Accounting for the precise spatial design afforded by the MOF NSs, the donor and acceptor moieties could be closely positioned on the NSs, allowing for an efficient EnT process as well as a high degree of site isolation. Two templates, donoron-acceptor NS and acceptor-on-donor NS catalysts, were successfully synthesized, and the results show that the second one has much enhanced catalytic performances over the first one due to site-isolated active photocatalysts.

An important step of phase calculation-based fringe projection systems is 3D calibration, which builds up the relationship between an absolute phase map and 3D shape data. The existing 3D calibration methods are complicated and hard to implement in practical environments due to the requirement of a precise translating stage or gauge block. This paper presents a 3D calibration method which uses a white plate with discrete markers on the surface. Placing the plate at several random positions can determine the relationship of absolute phase and depth, as well as pixel position and X, Y coordinates. Experimental results and performance evaluations show that the proposed calibration method can easily build up the relationship between absolute phase map and 3D shape data in a simple, flexible and automatic way.

The tuning of metal–organic framework (MOF) nanosheet stacking modes from molecular level was rarely explored although it significantly affected the properties and applications of nanosheets. Here, the different stacking modes of Zr‐1, 3, 5‐(4‐carboxylphenyl)‐benzene framework nanosheets were synthesized through the induction of different host–guest noncovalent interactions. The solvents of methyl benzene and ethyl acetate induced twisted stacking of nanosheets with the specific rotation angles of 12°, 18°, 24° and 6°, 18°, 24°, 30°, respectively, which was in agreement with theoretical calculations. Meanwhile, the alkanes were likely to vertically enter the pores of Zr‐BTB nanosheets because of steric hindrance and hydrophobic interactions, resulting in the untwisted stacking of nanosheets. The untwisted ordered nanopores showed the excellent gas chromatographic separations of benzene derivative isomers, which was better than twisted nanosheets stacking and commercial columns. This work uncovers a rational strategy to control the stacking of two‐dimensional MOF nanosheets.

Background Mitochondrial dysfunction is an important component of the aging process and has been implicated in the development of many human diseases. Mitochondrial DNA copy number (mtDNAcn), an indirect biomarker of mitochondrial function, is sensitive to oxidative damage. Few population-based studies have investigated the impact of fruit and vegetable consumption and cigarette smoke (2 major sources of exogenous antioxidants and oxidants) on leukocyte mtDNAcn. Objectives We investigated the association between fruit and vegetable consumption, cigarette smoke, and leukocyte mtDNAcn based on data from the Nurses’ Health Study (NHS). Methods Data from 2769 disease-free women in the NHS were used to examine the cross-sectional associations between dietary sources of antioxidants, cigarette smoke, and leukocyte mtDNAcn. In vitro cell-based experiments were conducted to support the findings from the population-based study. Results In the multivariable-adjusted model, both whole-fruit consumption and intake of flavanones (a group of antioxidants abundant in fruit) were positively associated with leukocyte mtDNAcn (P-trend = 0.005 and 0.02, respectively), whereas pack-years of smoking and smoking duration were inversely associated with leukocyte mtDNAcn (P-trend = 0.01 and 0.007, respectively). These findings are supported by in vitro cell-based experiments showing that the administration of naringin, a major flavanone in fruit, led to a substantial increase in mtDNAcn in human leukocytes, whereas exposure to nicotine-derived nitrosamine ketone, a key carcinogenic ingredient of cigarette smoke, resulted in a significant decrease in mtDNAcn of cells (all P < 0.05). Further in vitro studies showed that alterations in leukocyte mtDNAcn were functionally linked to the modulation of mitochondrial biogenesis and function. Conclusions Fruit consumption and intake of dietary flavanones were associated with increased leukocyte mtDNAcn, whereas cigarette smoking was associated with decreased leukocyte mtDNAcn, which is a promising biomarker for oxidative stress–related health outcomes.