Increasing Mass Transfer Resistance of MOFs as a Reverse Tuning Strategy to Achieve High-Resolution Gas Chromatographic Separation.

In separation science, precise control and regulation of the MOF stationary phase are crucial for achieving a high separation performance. We supposed that increasing the mass transfer resistance of MOFs with excessive porosity to achieve a moderate mass transfer resistance of the analytes is the key to conducting the MOF stationary phase with a high resolution. Three-dimensional UiO-67 (UiO-67-3D) and two-dimensional UiO-67 (UiO-67-2D) were chosen to validate this strategy. Compared with UiO-67-3D with overfast mass transfer and low retention, the reduced porosity of UiO-67-2D increased the mass transfer resistance of analytes in reverse, resulting in improved separation performance. Kinetic diffusion experiments were conducted to verify the difference in mass transfer resistance of the analytes between UiO-67-3D and UiO-67-2D. In addition, the optimization of the UiO-67-2D thickness for separation revealed that a moderate diffusion length of the analytes is more advantageous in achieving the equilibrium of absorption and desorption.

[Rational design of high performance metal organic framework stationary phase for gas chromatography].

Metal organic frameworks (MOFs) are assembled from metal ions or clusters and organic ligands. The high tunability of these components offers a solid structural foundation for achieving efficient gas chromatography (GC) separation. This review demonstrates that the design of high performance MOFs with suitable stationarity should consider both the thermodynamic interactions provided by these MOFs and the kinetic diffusion of analytes. Thermodynamic parameters are basic indicators for describing the interactions between various analytes and the stationary phase. Thermodynamic parameters such as retention factors, McReynolds constants, enthalpy changes, and entropy changes can reflect the relative intensity of thermodynamic interactions. For example, a larger enthalpy change indicates a stronger thermodynamic interaction between the analytes and stationary phase, whereas a smaller enthalpy change indicates a weaker interaction. In addition, the degree of entropy change reflects the relative degrees of freedom of analytes in the stationary phase. A larger entropy change indicates that the analytes have fewer degrees of freedom in the stationary phase. The higher the degree of restriction, the closer the adsorption of the analytes and, thus, the longer the retention time. Thermodynamic interactions, such as metal affinity, π-π interactions, polarity, and chiral sites, can be rationally introduced into MOF structures by pre- or post-modifications depending on the target analytes. These tailored thermodynamic interactions create a favorable environment with subtle differences for efficient analyte separation. For example, MOF stationarity may require large conjugation centers to provide specific π-π interactions to separate benzenes. Chiral groups may be required in the MOF structure to provide sufficient interactions to separate chiral isomers. The kinetic diffusion rate of the analytes is another critical factor that affects the separation performance of MOFs. The diffusion coefficients of analytes in the stationary phase (Ds) can be used to evaluate their diffusion rates. The chromatographic dynamics equation illustrates that the chromatographic peak of analytes tends to be sharper and more symmetrical when the Ds is large, whereas a wider trailing peak may appear when the Ds is small. The Van Deemter equation also proves that a low Ds may lead to a high theoretical plate height and low column efficiency, whereas a high Ds may lead to a low theoretical plate height and increased column efficiency. Analyte diffusion can be significantly influenced by the pore size, shape, particle size, and packing mode of MOFs. For instance, an excessively small pore size results in increased mass transfer resistance, which affects the diffusion of analytes in the stationary phase, probably leading to serious peak trailing. Thus, a suitable pore size is required to enhance the kinetic diffusion of analytes and improve the separation performance of MOFs. Theoretically, the design of a high performance MOF stationary phase requires the creation of routes for the rapid diffusion of analytes. However, the separation ability of an MOF is determined by not only the kinetic diffusion rate of the analytes but also the thermodynamic interactions it provides. An excessively fast diffusion rate may lead to insufficient interactions between the analytes and MOFs, compromising their ability to effectively separate different analytes. The thermodynamic interactions and kinetic diffusion of analytes are synergistic and mutually essential. Therefore, this review concludes with research on the influence of both the thermodynamic interactions and kinetic diffusion of analytes on the performance of MOF stationary phases. Based on the findings of this review, we propose that high performance MOF stationary phases can be achieved by balancing the thermodynamic interactions and kinetic diffusion of analytes in these phases through the rational design of the MOF structure. We believe that this review provides useful guidelines for the design of high performance MOF stationary phases.

Gradual deterioration of fatty liver disease to liver cancer via inhibition of AMPK signaling pathways involved in energy-dependent disorders, cellular aging, and chronic inflammation.

Introduction: Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer kind. According to recent research, a fatty liver increases the risk of hepatocellular cancer. Nevertheless, the AMPK signaling pathway is crucial. In addition, 5'-AMP-activated protein kinase (AMPK) is strongly linked to alterations in the tumor microenvironment, such as inflammation, hypoxia, and aging. The objective of this study is to evaluate the impact of the AMPK signaling pathway on the progression of fatty liver to HCC. Methods: In this study, we established a mouse liver cancer model using high-fat diets and nano-nitrosamines (nano-DEN). In addition, we employed a transcriptomic technique to identify all mRNAs detected in liver samples at the 25th weekexpression of proteins linked with the LKB1-AMPK-mTOR signaling pathway, inflammation, aging, and hypoxia was studied in microarrays of liver cancer tissues from mice and humans. These proteins included p-AMPK, LKB1, mTOR, COX-2, ß-catenin, HMGB1, p16, and HIF-1α. Results: Data were collected at different times in the liver as well as in cancerous and paracancerous regions and analyzed by a multispectral imaging system. The results showed that most of the genes in the AMPK signaling pathway were downregulated. Prakk1 expression was upregulated compared to control group but downregulated in the cancerous regions compared to the paracancerous regions. Stk11 expression was downregulated in the cancerous regions. Mtor expression was upregulated in the cancerous regions. During liver cancer formation, deletion of LKB1 in the LKB1-AMPK-mTOR signaling pathway reduces phosphorylation of AMPK. It contributed to the upregulation of mTOR, which further led to the upregulation of HIF1α. In addition, the expression of ß-catenin, COX-2, and HMGB1 were upregulated, as well as the expression of p16 was downregulated. Discussion: These findings suggest that changes in the AMPK signaling pathway exacerbate the deterioration of disrupted energy metabolism, chronic inflammation, hypoxia, and cellular aging in the tumor microenvironment, promoting the development of fatty liver into liver cancer.

Development and Validation of a Nomogram for Predicting Radial Artery Spasm During Coronary Angiography.

This study describes an attempt to develop a user-friendly nomogram incorporating psychological factors to individually predict the risk of radial artery spasm. Patients consecutively recruited between June 2020 and June 2021 constituted the development cohort for retrospective analysis of the development of a prediction model. Least absolute shrinkage and selection operator regression combined with clinical significance was employed to screen out appropriate independent variables. The model's discrimination and calibration were subsequently evaluated and calibrated by using the C-index, receiver operating characteristic (ROC) curve, and calibration plot. Decision curve analysis was also performed to evaluate the net benefit with the nomogram, and internal validation was assessed using bootstrapping validation. The predictors included in the risk nomogram included "body mass index ," "anxiety score," "duration of interventional surgery," "latency time (time spent waiting in the catheterization laboratory)," "vascular circuity (substantial changes in the curvature of vessels)," and "puncture number." The derived model showed good discrimination with an area under the ROC curve of .77, a C-index of .771 (95% CI: .72-.822) and good calibration. Decision curve analysis indicated that the nomogram provided a better net benefit than the alternatives.

[Application of gas chromatography separation based on metal-organic framework material as stationary phase].

Metal-organic frameworks (MOFs) are a new class of porous materials, which are synthesized using organic ligands and inorganic metal ions or metal clusters. MOFs possess tunable structures through the self-assembly of a large number of organic linkers and metal nodes, which is beyond the scope of conventional porous materials. In addition, MOFs have excellent properties, including the lowest density (as low as 0.13 g/cm), highest specific surface area (as high as 10400 m2/g), and largest pore aperture (as large as 9.8 nm) among all porous materials reported till date. Because of their high porosity, large surface area, tunable apertures, as well as high chemical and thermal stabilities, MOFs have been widely applied in the fields of adsorption, separation, and catalysis. In addition, MOFs have been successfully applied as stationary phases for isomer separation in gas chromatography (GC). Since the use of the first MOF (MOF-508) packed column for the separation of alkane isomers in GC, several other MOFs (e. g., MIL-47, MOF-5, and ZIF-8) have been employed for the GC separation of isomers. However, packed-column-type separation not only requires gram-scale quantities of MOFs, thereby increasing the analysis cost, but also results in poor separation efficiency. The first MOF (MIL-101) capillary column designed toward cost reduction allowed for the baseline separation of xylene and ethylbenzene isomers within 100 s under constant-temperature conditions. Since then, the capillary-type column has been widely utilized in the MOF-based stationary phase for GC separation.Alkanes, xylene isomers and ethyl toluene, oxy-organics and organic pollutants are not only important chemicals in industry but also harmful environmental pollutants. Thus, the separation of these analytes is of practical importance environmental monitoring and industrial quality control. However, it is difficult to realize the efficient separation and detection of these isomers or racemates because of their similar boiling points and molecular sizes. In the past decades, GC was utilized as a rapid and efficient technique for the separation of the abovementioned analytes. The stationary phase used in GC plays a dominant role in the separation processes. This review summarizes the MOF-based GC separation of the abovementioned targets based on the different classification of analytes, including alkanes, xylenes, racemates, oxy-organics and persistent organic pollutants.The separation mechanisms of different analytes are also discussed according to the structural benefits of MOFs. The separation mechanisms mainly involve van der Waals forces between the MOFs and analytes, interactions between the unsaturated metal sites and different functional groups of the analytes, molecular sieve effect or shape selectivity, and hydrogen-bond or π-π interactions. In addition, the chiral recognition abilities of MOFs possibly depend on the interactions between the chiral active sites in chiral MOFs and racemates.Furthermore, efficient GC separation is influenced by thermodynamic and kinetic factors. The thermodynamic factor is mainly the difference between the partition coefficients of the separated components, which also reflects the properties of the analytes as well as the interactions between the stationary phase and the analytes. The kinetic factor also affects the column efficiency and chromatographic peak shape. Compared with traditional inorganic porous materials, MOFs with tunable structures are more favorable for optimizing the separation of isomers from both thermodynamic and kinetic standpoints. Therefore, this review summarizes the separation mechanism when using MOFs as stationary phases for isomer separation via thermodynamic and kinetic analyses. We hope the review would aid the state-of-art design of MOF stationary phases for high efficient isomer separations in GC.

Ultramicroporous metal-organic frameworks for capillary gas chromatographic separation.

Fine-tuning of the SiF62--containing metal-organic frameworks (SIFSIX) through the substitution of metal centers and ligands changed the apertures from 8.3 Å to 3.8 Å, resulting in ultramicropores and notably improving the separation performance of alkane isomers. Herein, we reported SIFSIX-1-Zn, SIFSIX-1-Cu and SIFSIX-3-Zn as representative stationary phases for capillary gas chromatography (GC). The capillary column coated with ultramicroporous SIFSIX-3-Zn efficiently separated the alkane isomers and benzene homologues, which outperformed SIFSIX-1-Zn and SIFSIX-1-Cu. This resulted from size matching between the window of the ultramicroporous SIFSIX-3-Zn and the analytes, which was also supported by McReynolds constants, column efficiency and peak tailing effect. It opened up a new avenue for ultramicroporous materials in the chromatography separation of isomers.

The role of late reperfusion in ST-segment elevation myocardial infarction: a real-world retrospective cohort study.

BACKGROUND: Early reperfusion of the coronary artery has become the first choice for patients with ST-segment elevation myocardial infarction (STEMI). How to deal with patients who miss the time window for early reperfusion is still controversial. Based on real-world data, this study was conducted to explore whether percutaneous coronary intervention (PCI) has an advantage over standard drug therapy in patients who miss the optimal treatment window. METHODS: Consecutive patients who were diagnosed with STEMI and met the inclusion criteria between 2009 and 2018 in our center were retrospectively included in this cohort study. The primary endpoint events were major adverse cardiac events (MACEs), including heart failure, sudden cardiac death, malignant arrhythmia, thrombi and bleeding events during the period of admission. Secondary endpoint events were components of MACEs. At the same time, we also evaluated angina pectoris at admission and discharge through Canadian Cardiovascular Society (CCS) grading. RESULTS: This study enrolled 417 STEMI patients and divided them into four groups (PCI < 3 days, 14.87%; 3 days 7 days, 34.29%; MED, 29.74%). During the period of admission, MACEs occurred in 52 cases. The incidence of MACEs was 11.29, 7.95, 4.20 and 25.81% in the four respective groups (p < 0.0001). The MED group had higher rates of MACEs (OR = 3.074; 95% CI 0.1.116-8.469, p = 0.03) and cardiac death (OR = 3.027; 95% CI 1.121-8.169, p = 0.029) compared to the PCI group. Although both treatments were effective in improving CCS grade at discharge, the PCI group improved more significantly (p < 0.0001). CONCLUSIONS: In the real world, delayed PCI can be more effective in patients with angina symptoms at discharge and reduce the incidence of MACEs and cardiac death during hospitalization. The timing of intervention was independent of the occurrence of MACEs during hospitalization and of improvement in symptoms.

Translational Inhibition of α-Neurexin 2.

Neurexins are extensively investigated presynaptic cell-adhesion molecules which play important roles in transmitting signals and processing information at synapses that connect neurons into a vast network of cellular communications. Synaptic transmission of information is a fast and dynamic process which relies on rapid and tight regulation of synaptic protein expression. However, the mechanism underlying those regulation is still not fully understood. Therefore, we explore how the expression of NRXN2α, one of encoding genes for neurexins, is regulated at the translational level. NRXN2α transcript has a long and conserved 5'-untranslated region (5'UTR) suggestive of the rapid regulation of protein expression at the translational level. We first demonstrate that the 5'UTR has negative effects on the expression of the NRXN2α and find a critical subregion responsible for the major inhibitory function. Then we identify a particular secondary structure of G-quadruplex in the 5'UTR. Moreover, we find that the synergistic roles of G-quadruplex and upstream AUGs are responsible for most of NRXN2α-5'UTR inhibitory effects. In conclusion, we uncovered 5' UTR of neurexin2 potentially inhibits neurexin2 translation by multiple mechanisms. In addition, this study underscores the importance of direct protein quantitation in experiments rather than using mRNA as an indirect estimate of protein expression.

Fruit and vegetable consumption, cigarette smoke, and leukocyte mitochondrial DNA copy number.

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.

Pre-diagnostic leukocyte mitochondrial DNA copy number and skin cancer risk.

No previous study has examined the association between mitochondrial DNA copy number (mtCN) and skin cancer risk prospectively. We examined the associations between peripheral blood leukocytes mtCN level and the risks of skin cancers in a case-control study nested within the Nurses' Health Study of non-Hispanic White women, including 272 melanoma cases and 293 controls, 508 squamous cell carcinoma (SCC) cases and 550 controls, and 515 basal cell carcinoma (BCC) cases and 536 controls. Relative mtCN in peripheral blood leukocytes was measured by quantitative PCR-based assay. Unconditional logistic regression models were used to examine the associations between mtCN and skin cancer risks. Compared with those with high mtCN, the risk for melanoma was 1.06 [95% confidence interval (CI) = 0.70-1.62] in the median group and 1.19 (95% CI = 0.78-1.81) for the low group. There was suggestive evidence that increased risk for melanoma was apparent among low constitutional susceptibility group [odds ratio (OR)low versus high = 1.80, 95% CI = 0.95-3.39, P for trend = 0.07, P for interaction = 0.06]. The increased risk of melanoma was also apparent among high cumulative UV exposure group (ORlow versus high = 3.40, 95% CI = 1.46-7.92, P for trend = 0.004, P for interaction = 0.01). For non-melanoma skin cancers, compared with high-mtCN group, low-mtCN group had an increased risk for SCC (OR = 1.26, 95% CI = 0.93-1.71) and BCC (OR = 1.35; 95% CI = 1.00-1.82). Because some of the associations were marginally significant, the results only provided suggestive evidence. Further studies are warranted to replicate these findings and better understand the underlying mechanisms.

Pre-diagnostic leukocyte mitochondrial DNA copy number and risk of lung cancer.

We prospectively investigated the relationship between mtCN and the risk of lung cancer in 463 case-control pairs from two prospective cohort studies, the Nurses' Health Study (NHS) and the Health Professionals Follow-Up Study (HPFS). The adjusted least-squares means of log-transformed mtCN (log_mtCN) by smoking status were estimated by generalized linear models. Multivariable conditional logistic regression model adjusting for confounders was used to obtain the odds ratios (ORs) and 95% confidence intervals (CIs) for the association between log_mtCN and lung cancer risk. The adjusted least-squares mean of log_mtCN in heavy smokers was significantly lower than that in never smokers (P = 0.05). Compared to the high log_mtCN group, the risk of lung cancer was 1.29 (95% CI = 0.89-1.87) for the median group, and 1.11 (95% CI = 0.75-1.64) for the low group. Among current smokers, compared to participants with high levels of log_mtCN, those with median levels had a significantly higher risk of lung cancer (OR = 2.09; 95% CI = 1.12-3.90), but not those with low levels (OR = 1.37; 95% CI = 0.75-2.48). Further studies are warranted to confirm these findings.

Overexpression of MCPH1 inhibits uncontrolled cell growth by promoting cell apoptosis and arresting the cell cycle in S and G2/M phase in lung cancer cells.

Microcephalin (MCPH1/BRIT1) is a large nuclear protein that is involved in the early cellular response to DNA damage, the expression of which is reduced in a variety of types of human tumors. A recent study by our group demonstrated that MCPH1 expression is markedly decreased in lung cancer. However, it remains unclear whether inducing the expression of MCPH1 may ameliorate lung cancer, and, if so, which mechanisms underlie this process. The results of the present study demonstrated that MCPH1 expression was downregulated in lung cancer tissues compared with that in normal lung tissues. Furthermore, MCPH1 overexpression in A549 non-small cell lung carcinoma cells, successfully inhibited cell proliferation via arrest of the cell cycle in the S and G2/M phases. In addition, MCPH1 overexpression promoted cell apoptosis, in association with a significant increase in the quantities of Bax and active caspase-3, as well as a decrease in the level of Bcl-2. In conclusion the present results indicated that MCPH1 is involved in the regulation of apoptosis and entry into mitosis, suggesting that MCPH1 may function as a tumor suppressor and that it may be important in the pathogenesis of lung cancer.

Pan-cancer genetic analysis identifies PARK2 as a master regulator of G1/S cyclins.

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.

No association between garlic intake and risk of colorectal cancer.

BACKGROUND: Although experimental studies suggested beneficial role of garlic intake on colorectal carcinogenesis, limited prospective cohort studies have evaluated garlic intake in relation to colorectal cancer (CRC) incidence. METHODS: We followed 76,208 women in the Nurses' Health Study and 45,592 men in the Health Professionals Follow-up Study for up to 24 years and examined garlic intake and garlic supplement use in relation to CRC risk. Information on garlic intake and supplement use was assessed using a validated food frequency questionnaire and a Cox proportional hazard regression model was used to estimate the multivariable hazard ratio (MV-HR) and 95% confidence intervals (95% CIs). RESULTS: We documented 2368 (1339 women and 1029 men) incident CRC cases and fo und no association between garlic intake and CRC risk; the MV-HRs (95% CIs) associated with garlic (1 clove or 4 shakes per serving) intake ≥ 1/day compared with < 1/month were 1.21 (0.94-1.57; p-trend = 0.14) for women and 1.00 (0.71-1.42; p-trend = 0.89) for men. The MV-HRs (95% CIs) of CRC for garlic supplement use, which was used in 6% of the participants in each study, were 0.72 (0.48-1.07) for women and 1.22 (0.83-1.78) for men. CONCLUSION: Our prospective data do not support an important role of garlic intake or garlic supplement use in colorectal carcinogenesis.

Current opportunities and challenges: genome-wide association studies on pigmentation and skin cancer.

Genome-wide association studies (GWAS) have become a widely used approach for genetic association studies of various human traits. A few GWAS have been conducted with the goal of identifying novel loci for pigmentation traits, melanoma, and non-melanoma skin cancer. Nevertheless, the phenotype variation explained by the genetic markers identified so far is limited. In this review, we discuss the GWAS study design and its application in pigmentation and skin cancer research. Furthermore, we summarize recent developments in post-GWAS activities such as meta-analysis, pathway analysis, and risk prediction.

No association between Parkinson disease alleles and the risk of melanoma.

BACKGROUND: Recent data showed that melanoma was more common among patients with Parkinson disease than individuals without Parkinson disease and vice versa. It has been hypothesized that these two diseases may share common genetic and environmental risk factors. METHODS: We evaluated the association between single-nucleotide polymorphisms (SNP) selected on the basis of recent genome-wide association studies (GWAS) on Parkinson disease risk and the risk of melanoma using 2,297 melanoma cases and 6,651 controls. RESULTS: The Parkinson disease SNP rs156429 in the chromosome 7p15 region was nominally associated with melanoma risk with P value of 0.04, which was not significant after the Bonferroni correction for multiple comparisons. No association was observed between the remaining 31 Parkinson disease SNPs and the risk of melanoma. The genetic score based on the number of Parkinson disease risk allele was not associated with melanoma risk [OR for the highest genetic score quartile (30-35) vs. the lowest (15-20), 1.13, 95% confidence interval (CI), 0.47-2.70]. CONCLUSION: The Parkinson disease SNPs identified in published GWAS do not seem to play an important role in melanoma development. IMPACT: The Parkinson disease susceptibility loci discovered by GWAS contribute little to the observed epidemiologic association between the Parkinson disease and melanoma.

Somatic mutations of the Parkinson's disease-associated gene PARK2 in glioblastoma and other human malignancies.

Mutation of the gene PARK2, which encodes an E3 ubiquitin ligase, is the most common cause of early-onset Parkinson's disease. 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.

14-3-3sigma and p21 synergize to determine DNA damage response following Chk2 inhibition.

DNA damage checkpoints are critical for preventing tumorigenesis and regulating the response of cells to genotoxic agents. It is believed that the coordinated actions of a number of effectors underlie proper checkpoint function. The kinase Chk2, p21 and 14-3-3sigma have each been shown to be independent effectors of the G(2) DNA damage checkpoint. However, the relative roles of these proteins remain unclear. To help elucidate this question, we have perturbed each of these 3 genes in combination in human cells. We show that Chk2 depletion causes markedly increased sensitivity to DNA damage in p21(-/-), 14-3-3sigma(-/-) cells but not in cells lacking only one or none of these genes. This greater sensitivity was due to an increase in apoptosis following DNA damage and not due to exacerbation of G(2) checkpoint defects. Pharmacologic inhibition of Chk2 in p21(-/-), 14-3-3sigma(-/-) cells also resulted in greater sensitivity to DNA damage. Our data indicates that p21 and 14-3-3sigma synergize as molecular determinants of sensitivity to DNA damage following Chk2 inhibition, and Chk2 modulates the biological rheostat that determines whether a cancer cell undergoes arrest versus death after treatment with a chemotherapeutic agent. These findings have implications for the targeting of Chk2 in human cancers.

The tyrosine phosphatase PTPRD is a tumor suppressor that is frequently inactivated and mutated in glioblastoma and other human cancers.

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.