The preventative effects of statin on lung cancer development in patients with idiopathic pulmonary fibrosis using the National Health Insurance Service Database in Korea.

Little is known about the effect of statin use in lung cancer development in idiopathic pulmonary fibrosis (IPF). We analyzed the database of the National Health Insurance Service to further investigate the clinical impacts of statin on lung cancer development and overall survival (OS) in IPF patients. The analysis included 9,182 individuals diagnosed with IPF, of which 3,372 (36.7%) were statin users. Compared to statin non-users, the time from diagnosis of IPF to lung cancer development and OS were longer in statin users in IPF patients. In Cox proportional hazard regression models, higher statin compliance, statin use, and being female had an inverse association with lung cancer risk, while older age at diagnosis of IPF and smoking history were associated with higher risk of lung cancer in IPF patients. For OS, statin use, female sex, higher physical activity frequency, and diabetes were associated with longer survival. In contrast, older age at diagnosis of IPF and smoking history were associated with shorter OS in IPF patients. These data from a large population indicate that statin had an independent protective association with lung cancer development and mortality in IPF patients.

Osteosarcoma and soft-tissue sarcomas with an immune infiltrate express PD-L1: relation to clinical outcome and Th1 pathway activation.

Immune checkpoint proteins, such as PD-L1 and PD-1, are important in several cancers; however, their role in osteosarcoma (OSA) and soft tissue sarcoma (STS) remains unclear. Our aims were to determine whether subsets of OSA/STS harbor tumor-infiltrating lymphocytes (TILs) and express PD-L1, and how PD-L1 expression is related to clinical outcome. Tissue sections of 25 cases each of untreated undifferentiated pleomorphic sarcoma (UPS), myxofibrosarcoma (MFS), liposarcoma (LPS) and 24 of leiomyosarcoma (LMS) were subjected to immunohistochemistry (IHC) for immune cells, PD-L1 and PD-1. RT-qPCR was utilized to quantify levels of PD-L1 mRNA from 33 UPS, 57 MFS and 79 OSA primary-untreated specimens. PD-L1 mRNA levels were tested for their correlation with overall survival in patients presenting without metastases. Transcriptome analysis evaluated biological pathway differences between high and low PD-L1 expressers. A subset of UPS and MFS contained TILs and expressed PD-L1 and PD-1; LMS and LPS did not. PD-L1 levels by IHC and RT-qPCR were positively correlated. PD-L1 over-expression was associated with better survival for UPS and OSA, but not MFS. The Th1 pathway was significantly activated in UPS with high levels of PD-L1 and improved survival. Some sarcoma subtypes harbor TILs and express PD-L1. Patients with UPS and OSA with high levels of PD-L1 had better overall survival than those with low expression levels. Important biological pathways distinguish PD-L1 high and low groups. The stratification of patients with OSA/STS with respect to potential immune therapies may be improved through investigation of the expression of immune cells and checkpoint proteins.

Serum Levels of Growth Factors in Alcohol-dependent Patients according to Comorbid Depressive Symptoms.

OBJECTIVE: This study aims to reveal the relationship of depression with growth factors such as brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and insulin-like growth factor-1 (IGF-1) in inpatients diagnosed with alcohol dependence, and to identify candidate growth factors as biological markers to indicate the comorbid of alcohol dependence and depression. METHODS: This study examined demographic factors in 45 alcohol-dependent patients. The ADS (Korean version of the Alcohol Dependence Scale) and BDI (Korean version of Beck's Depression Inventory) were used. BDNF, NGF, and IGF-1 were measured through ELISA. RESULTS: The average drinking quantity and the ADS score were significantly more severe in alcohol-dependent patients with depression than in those without depression. Linearly comparing BDNF, NGF, and IGF-1 with BDI values, IGF-1 was the growth factor significantly correlated with BDI scores. BDI scores were significantly correlated with ADS scores. IGF-1 was significantly higher in alcohol-dependent patients with depression. Alcohol-dependent patients with depression had greater alcohol use and more severe ADS scores. BDNF and NGF showed no significant difference between alcohol-dependent patients with and without depression, but IGF-1 was significantly higher in those with than in those without depression. CONCLUSION: IGF-1 was found to be associated with depression in alcohol-dependent patients, suggesting that IGF-1 in alcohol- dependent patients could be an important biomarker to indicate whether alcohol-dependence is accompanied by depression.

Periodontitis Is Associated with Cognitive Impairment in Elderly Koreans: Results from the Yangpyeong Cohort Study.

OBJECTIVES: To investigate the association between periodontitis and cognitive impairment in elderly Koreans. DESIGN: Cross-sectional study with age- and sex-matched case-control selection. SETTING: The Yangpyeong cardiovascular cohort (YCC), a part of the Korean Genome Epidemiologic Study (KoGES), Yangpyeong, South Korea. PARTICIPANTS: Individuals with cognitive impairment (n=65) and cognitively normal controls (n=124) aged 60 and older from the YCC. MEASUREMENTS: Alveolar bone loss was assessed on dental panoramic radiographs to categorize the cumulative history of periodontitis (HOP) into three groups: normal, moderate periodontitis, severe periodontitis. The Mini-Mental State Examination (MMSE) was used to categorize participants as cognitively normal or cognitively impaired. Age- and sex-matched conditional logistic regression models were used for analysis. Confounders considered in the analysis were age, sex, drinking, smoking, exercise, total cholesterol, total protein, body mass index, fasting plasma glucose, intima-media thickness, hypertension medication, and depression. RESULTS: Participants with HOP were more likely to have cognitive impairment than those without (odds ratio=2.14, 95% confidence interval=1.04-4.41). The interaction effect of smoking and exercise on periodontitis highlighted the link. CONCLUSION: Periodontitis was independently associated with cognitive impairment after controlling for various confounders. Further longitudinal research is needed to determine whether periodontitis plays a role in cognitive decline in older adults.

Efficient and anonymous two-factor user authentication in wireless sensor networks: achieving user anonymity with lightweight sensor computation.

A smart-card-based user authentication scheme for wireless sensor networks (hereafter referred to as a SCA-WSN scheme) is designed to ensure that only users who possess both a smart card and the corresponding password are allowed to gain access to sensor data and their transmissions. Despite many research efforts in recent years, it remains a challenging task to design an efficient SCA-WSN scheme that achieves user anonymity. The majority of published SCA-WSN schemes use only lightweight cryptographic techniques (rather than public-key cryptographic techniques) for the sake of efficiency, and have been demonstrated to suffer from the inability to provide user anonymity. Some schemes employ elliptic curve cryptography for better security but require sensors with strict resource constraints to perform computationally expensive scalar-point multiplications; despite the increased computational requirements, these schemes do not provide user anonymity. In this paper, we present a new SCA-WSN scheme that not only achieves user anonymity but also is efficient in terms of the computation loads for sensors. Our scheme employs elliptic curve cryptography but restricts its use only to anonymous user-to-gateway authentication, thereby allowing sensors to perform only lightweight cryptographic operations. Our scheme also enjoys provable security in a formal model extended from the widely accepted Bellare-Pointcheval-Rogaway (2000) model to capture the user anonymity property and various SCA-WSN specific attacks (e.g., stolen smart card attacks, node capture attacks, privileged insider attacks, and stolen verifier attacks).

A provably-secure ECC-based authentication scheme for wireless sensor networks.

A smart-card-based user authentication scheme for wireless sensor networks (in short, a SUA-WSN scheme) is designed to restrict access to the sensor data only to users who are in possession of both a smart card and the corresponding password. While a significant number of SUA-WSN schemes have been suggested in recent years, their intended security properties lack formal definitions and proofs in a widely-accepted model. One consequence is that SUA-WSN schemes insecure against various attacks have proliferated. In this paper, we devise a security model for the analysis of SUA-WSN schemes by extending the widely-accepted model of Bellare, Pointcheval and Rogaway (2000). Our model provides formal definitions of authenticated key exchange and user anonymity while capturing side-channel attacks, as well as other common attacks. We also propose a new SUA-WSN scheme based on elliptic curve cryptography (ECC), and prove its security properties in our extended model. To the best of our knowledge, our proposed scheme is the first SUA-WSN scheme that provably achieves both authenticated key exchange and user anonymity. Our scheme is also computationally competitive with other ECC-based (non-provably secure) schemes.

Security enhanced anonymous multiserver authenticated key agreement scheme using smart cards and biometrics.

An anonymous user authentication scheme allows a user, who wants to access a remote application server, to achieve mutual authentication and session key establishment with the server in an anonymous manner. To enhance the security of such authentication schemes, recent researches combined user's biometrics with a password. However, these authentication schemes are designed for single server environment. So when a user wants to access different application servers, the user has to register many times. To solve this problem, Chuang and Chen proposed an anonymous multiserver authenticated key agreement scheme using smart cards together with passwords and biometrics. Chuang and Chen claimed that their scheme not only supports multiple servers but also achieves various security requirements. However, we show that this scheme is vulnerable to a masquerade attack, a smart card attack, a user impersonation attack, and a DoS attack and does not achieve perfect forward secrecy. We also propose a security enhanced anonymous multiserver authenticated key agreement scheme which addresses all the weaknesses identified in Chuang and Chen's scheme.

Provably-secure (Chinese government) SM2 and simplified SM2 key exchange protocols.

We revisit the SM2 protocol, which is widely used in Chinese commercial applications and by Chinese government agencies. Although it is by now standard practice for protocol designers to provide security proofs in widely accepted security models in order to assure protocol implementers of their security properties, the SM2 protocol does not have a proof of security. In this paper, we prove the security of the SM2 protocol in the widely accepted indistinguishability-based Bellare-Rogaway model under the elliptic curve discrete logarithm problem (ECDLP) assumption. We also present a simplified and more efficient version of the SM2 protocol with an accompanying security proof.

Password-only authenticated three-party key exchange proven secure against insider dictionary attacks.

While a number of protocols for password-only authenticated key exchange (PAKE) in the 3-party setting have been proposed, it still remains a challenging task to prove the security of a 3-party PAKE protocol against insider dictionary attacks. To the best of our knowledge, there is no 3-party PAKE protocol that carries a formal proof, or even definition, of security against insider dictionary attacks. In this paper, we present the first 3-party PAKE protocol proven secure against both online and offline dictionary attacks as well as insider and outsider dictionary attacks. Our construct can be viewed as a protocol compiler that transforms any 2-party PAKE protocol into a 3-party PAKE protocol with 2 additional rounds of communication. We also present a simple and intuitive approach of formally modelling dictionary attacks in the password-only 3-party setting, which significantly reduces the complexity of proving the security of 3-party PAKE protocols against dictionary attacks. In addition, we investigate the security of the well-known 3-party PAKE protocol, called GPAKE, due to Abdalla et al. (2005, 2006), and demonstrate that the security of GPAKE against online dictionary attacks depends heavily on the composition of its two building blocks, namely a 2-party PAKE protocol and a 3-party key distribution protocol.

On the security of a simple three-party key exchange protocol without server's public keys.

Authenticated key exchange protocols are of fundamental importance in securing communications and are now extensively deployed for use in various real-world network applications. In this work, we reveal major previously unpublished security vulnerabilities in the password-based authenticated three-party key exchange protocol according to Lee and Hwang (2010): (1) the Lee-Hwang protocol is susceptible to a man-in-the-middle attack and thus fails to achieve implicit key authentication; (2) the protocol cannot protect clients' passwords against an offline dictionary attack; and (3) the indistinguishability-based security of the protocol can be easily broken even in the presence of a passive adversary. We also propose an improved password-based authenticated three-party key exchange protocol that addresses the security vulnerabilities identified in the Lee-Hwang protocol.

Association rule extraction from XML stream data for wireless sensor networks.

With the advances of wireless sensor networks, they yield massive volumes of disparate, dynamic and geographically-distributed and heterogeneous data. The data mining community has attempted to extract knowledge from the huge amount of data that they generate. However, previous mining work in WSNs has focused on supporting simple relational data structures, like one table per network, while there is a need for more complex data structures. This deficiency motivates XML, which is the current de facto format for the data exchange and modeling of a wide variety of data sources over the web, to be used in WSNs in order to encourage the interchangeability of heterogeneous types of sensors and systems. However, mining XML data for WSNs has two challenging issues: one is the endless data flow; and the other is the complex tree structure. In this paper, we present several new definitions and techniques related to association rule mining over XML data streams in WSNs. To the best of our knowledge, this work provides the first approach to mining XML stream data that generates frequent tree items without any redundancy.

Password-only authenticated three-party key exchange with provable security in the standard model.

Protocols for password-only authenticated key exchange (PAKE) in the three-party setting allow two clients registered with the same authentication server to derive a common secret key from their individual password shared with the server. Existing three-party PAKE protocols were proven secure under the assumption of the existence of random oracles or in a model that does not consider insider attacks. Therefore, these protocols may turn out to be insecure when the random oracle is instantiated with a particular hash function or an insider attack is mounted against the partner client. The contribution of this paper is to present the first three-party PAKE protocol whose security is proven without any idealized assumptions in a model that captures insider attacks. The proof model we use is a variant of the indistinguishability-based model of Bellare, Pointcheval, and Rogaway (2000), which is one of the most widely accepted models for security analysis of password-based key exchange protocols. We demonstrated that our protocol achieves not only the typical indistinguishability-based security of session keys but also the password security against undetectable online dictionary attacks.

Security enhanced user authentication protocol for wireless sensor networks using elliptic curves cryptography.

Wireless sensor networks (WSNs) consist of sensors, gateways and users. Sensors are widely distributed to monitor various conditions, such as temperature, sound, speed and pressure but they have limited computational ability and energy. To reduce the resource use of sensors and enhance the security of WSNs, various user authentication protocols have been proposed. In 2011, Yeh et al. first proposed a user authentication protocol based on elliptic curve cryptography (ECC) for WSNs. However, it turned out that Yeh et al.'s protocol does not provide mutual authentication, perfect forward secrecy, and key agreement between the user and sensor. Later in 2013, Shi et al. proposed a new user authentication protocol that improves both security and efficiency of Yeh et al.'s protocol. However, Shi et al.'s improvement introduces other security weaknesses. In this paper, we show that Shi et al.'s improved protocol is vulnerable to session key attack, stolen smart card attack, and sensor energy exhausting attack. In addition, we propose a new, security-enhanced user authentication protocol using ECC for WSNs.

Accept or refuse? A pilot study of patients' perspective on participating as imaginary research subjects in schizophrenia.

OBJECTIVE: The goal of the present study was to evaluate demographic and clinical factors that affect the intention to participate in commonly-conducted research in patients with schizophrenia. METHODS: Thirty-four outpatients with a diagnosis of schizophrenia were enrolled in this study. They were asked whether they would have any intention to participate in four imaginary studies: a simple questionnaire, a genetic study, a study of complex tasks and a risky study. We analyzed the differences in general psychopathology, insight and demographic characteristics of the participants according to their responses (acceptance or refusal) to the four proposed studies. RESULTS: Younger and better-educated patients tended to decline participation in a risky study. Patients with a longer duration of regular psychiatric follow-ups tended to willingly participate in the simple questionnaire. There were no overall statistical differences in general psychopathology and insight between patients who agreed or declined to participate in studies. CONCLUSION: Age and education level may be factors that influence decisions to participate in schizophrenia studies. Further research is needed to confirm and expand on the current findings.

Matrix metalloproteinase-9 promoter polymorphisms in Korean patients with systemic lupus erythematosus.

To investigate the association between functional promoter polymorphisms of matrix metalloproteinase-9 (MMP-9) and systemic lupus erythematosus (SLE), we analyzed MMP-9 promoter -1562 C>T and MMP-9 -90 (CA)(n) repeat polymorphisms in 135 Korean SLE patients (mean age, 34.7 years; 124 female and 11 male) and in 135 gender- and age-matched healthy controls (mean age, 35.4 years). Clinical and laboratory findings were collected during the follow-up period (mean, 63.5 months; range, 3-252 months), and Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Indexes were calculated. The levels of total MMP-9 were measured in sera of SLE patients and controls by enzyme-linked immunoabsorbent assay. The serum levels of MMP-9 in SLE patients were significantly lower than those of controls (mean +/- standard error of the mean, 1421.6+/-177.4 vs 3731.4+/-441.4 ng/ml, p=1.2 x 10(-5) by t test). Both functional polymorphisms were under the Hardy-Weinberg equilibrium state except (CA)(n) repeat polymorphisms in SLE patients (p=2.6 x 10(-5) by chi(2) goodness-of-fit test). The distribution of the MMP-9 promoter polymorphisms or haplotypes was not significantly different in SLE patients and controls. However the frequency of alleles with low numbers of CA repeats (n<21, 11.9% vs 7.0%, p=0.06 by the chi(2) test; odds ratio=1.78, 95% confidence interval=0.99-3.20) and the prevalence of low CA repeats homozygote tended to be higher in patients than in controls (5.2% vs 0.7%, p=0.07 by logistic regression, odds ratio=7.29, 95% confidence interval=0.88-60.10) in the recessive model. No relationship was found between MMP-9 polymorphisms and clinical features or damage as indicated by SLICC/ACR Damage Index in the study subjects. These results suggest that genetic polymorphisms of the MMP-9 promoter regions are not associated with the development of SLE in Korea.

AK2 activates a novel apoptotic pathway through formation of a complex with FADD and caspase-10.

Mitochondrial proteins function as essential regulators in apoptosis. Here, we show that mitochondrial adenylate kinase 2 (AK2) mediates mitochondrial apoptosis through the formation of an AK2-FADD-caspase-10 (AFAC10) complex. Downregulation of AK2 attenuates etoposide- or staurosporine-induced apoptosis in human cells, but not that induced by tumour-necrosis-factor-related apoptosis-inducing ligand (TRAIL) or Fas ligand (FasL). During intrinsic apoptosis, AK2 translocates to the cytoplasm, whereas this event is diminished in Apaf-1 knockdown cells and prevented by Bcl-2 or Bcl-X(L). Addition of purified AK2 protein to cell extracts first induces activation of caspase-10 via FADD and subsequently caspase-3 activation, but does not affect caspase-8. AFAC10 complexes are detected in cells undergoing intrinsic cell death and AK2 promotes the association of caspase-10 with FADD. In contrast, AFAC10 complexes are not detected in several etoposide-resistant human tumour cell lines. Taken together, these results suggest that, acting in concert with FADD and caspase-10, AK2 mediates a novel intrinsic apoptotic pathway that may be involved in tumorigenesis.

Clinical implications of matrix metalloproteinase-1, -3, -7, -9, -12, and plasminogen activator inhibitor-1 gene polymorphisms in colorectal cancer.

BACKGROUND AND AIM: Overexpression of matrix metalloproteinase (MMP)-1, -3, -7, -9, and plasminogen activator inhibitor-1 (PAI-1) are implicated in the invasion and metastasis of colorectal cancer, while MMP-12 provides a protective role against colorectal cancer. The promoter and exon polymorphisms of their genes, which are known to affect the transcription of these genes, were assessed to correlate with colorectal cancer susceptibility. METHODS: MMP1, 3, 7, 9, 12 and PAI1 were assayed in 185 colorectal cancer patients and 304 healthy controls using polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) analysis. Respective genotypes and haplotypes were compared between the population groups and also between clinicopathological characteristics in the colorectal cancer patients. RESULTS: The homozygous MMP1-1,607 dupG genotype was significantly more frequent in colorectal cancer patients than in healthy controls. The frequency of MMP1-1,607 dupG homozygotes was also greater in patients of less than or equal to 50 years of age, and in patients with 10 or more metastatic lymph nodes, compared with those of older age or with fewer lymph nodes. The frequency of MMP9-1,562 C homozygotes was significantly greater in colorectal cancer patients than in healthy controls. However, the genotype and allele frequencies of MMP3-1,171dupA, MMP7-181A > G, MMP12-82A > G, MMP9-90(CA)(14-27), and R279Q did not differ between the population groups or clinicopathological parameters. The MMP7-181A-MMP1-1,607dupG-MMP3-1,171A-MMP12-82A and MMP9-1,562C-90(CA)(20)+ 279Q haplotypes were significantly more frequent in colorectal cancer patients than in healthy controls. The genotype and allele frequencies of PAI1-675 G were similar between patients and healthy controls, but the frequency of PAI1-675 G homozygotes was significantly greater in patents over 50 years of age. CONCLUSIONS: MMP1-1,607 dupG and MMP9-1,562 C homozygotes demonstrated an increased risk of colorectal cancer regardless of ethnic differences, whereas other MMP and PAI1 polymorphisms did not. Nevertheless, specific MMP haplotypes on 11q22.1-23.3 and 20q12-13 seem to be implicated in susceptibility to colorectal cancer.

Fractal analysis of EEG in hypnosis and its relationship with hypnotizability.

Fractal analysis was applied to study the trends of EEG signals in the hypnotic condition. The subjects were 19 psychiatric outpatients. Hypnotizability was measured with the Hypnotic Induction Profile (HIP). Fifty-four sets of EEG data were analyzed by detrended fluctuation analysis (DFA), a well-established fractal analysis technique. The scaling exponents, which are the results of fractal analysis, are reduced toward white noise during the hypnotic condition, which differentiates the hypnotic condition from the waking condition. Further, the decrease in the scaling exponents during hypnosis was solely associated with the eye-roll sign within specific cortical areas (F3, C4, and O1/2) closely related to eye movements and attention. In conclusion, the present study has found that the application of the fractal analysis technique can demonstrate the electrophysiological correlations with hypnotic influence on cerebral activity.

Association of TNFA promoter region haplotype in Behçet's Disease.

Although the etiology of Behçet's Disease (BD; MIM 109650) remains to be clearly elucidated, levels of tumor necrosis factor alpha (TNF-alpha) have been reported to be significantly elevated in BD patients, and TNF-alpha blockers have been demonstrated to exhibit some degree of therapeutic efficacy for a certain subset of BD sufferers. In this study, we have conducted an analysis of the TNFA haplotypes in the promoter response element that affect the binding affinity of specific transcription factors, in order to characterize their association with the clinical features of BD. Six polymorphisms in the promoter region of TNFA were genotyped in 254 BD patients and 344 control subjects, via the PCR-RFLP technique. TNFA -1031*C, -863*A and -308*G alleles were associated with an increased risk of BD (p=0.030, OR=1.4; p=0.008, OR=1.5; p=0.010, OR=1.8, respectively). The sole TNFA haplotype -1031C-863A-857C-376G-308G-238G, was associated with a 1.6 fold increase in the risk of BD, whereas the TNFA haplotype -1031T-863C-857C-376G-308A-238G was associated with a 0.6 decreased risk of BD. The TNFA -1031*C, -863*A, -857*C and -308*G alleles were significantly associated with BD. The findings of this study, collectively, indicate that TNFA haplotypes in the promoter response elements may exert significant influence on susceptibility to BD.

Start codon polymorphisms in the vitamin D receptor and colorectal cancer risk.

The expression of the nuclear vitamin D receptor (VDR), which is involved in regulating cell growth and proliferation, may contribute to the development of colorectal cancer. Polymorphisms in the VDR gene (OMIM 601769) may influence the expression or function of the VDR protein. A population-based, case-control study of VDR start codon, intron, and exon polymorphisms, haplotypes for these polymorphisms, and the relationships between these polymorphisms and clinicopathological parameters in 190 colorectal cancer patients and 318 controls was conducted. The start codon variant VDR 27823*C/*C genotype was associated with an increased risk for colorectal cancer, while the 27823*T/*T genotype was associated with a decreased risk. In addition, the VDR 61888*G/*G genotype was associated with reduced colorectal cancer risk. The intron 8 60880G>A and exon 9 61968T>C polymorphisms were not associated with colorectal cancer risk. The VDR 27823*C-60890*G-61888*T-61968*T haplotype was associated with an increased risk of colorectal cancer, whereas the VDR 27823*T-60890*G-61888*G-61968*T haplotype was associated with a decreased risk of colorectal cancer. Moreover, the 27823*C/*C genotype was more frequently identified in patients with preoperative serum carcinoembryonic antigen (CEA) levels over 6ng/mL. These results suggest that the VDR start codon 27823*C allele may be linked to high risk for colorectal cancer, especially in a subset of colorectal cancers showing specific biological behaviors.