Finite-state Markov Chains obey Benford's Law

A sequence of real numbers (x_n) is Benford if the significands, i.e. the fraction parts in the floating-point representation of (x_n) are distributed logarithmically. Similarly, a discrete-time irreducible and aperiodic finite-state Markov chain with probability transition matrix P and limiting matrix P* is Benford if every component of both sequences of matrices (P^n - P*) and (P^{n+1}-P^n) is Benford or eventually zero. Using recent tools that established Benford behavior both for Newton's method and for finite-dimensional linear maps, via the classical theories of uniform distribution modulo 1 and Perron-Frobenius, this paper derives a simple sufficient condition (nonresonant) guaranteeing that P, or the Markov chain associated with it, is Benford. This result in turn is used to show that almost all Markov chains are Benford, in the sense that if the transition probabilities are chosen independently and continuously, then the resulting Markov chain is Benford with probability one. Concrete examples illustrate the various cases that arise, and the theory is complemented with several simulations and potential applications.Comment: 31 pages, no figure

Farsighted Risk Mitigation of Lateral Movement Using Dynamic Cognitive Honeypots

Lateral movement of advanced persistent threats has posed a severe security challenge. Due to the stealthy and persistent nature of the lateral movement, defenders need to consider time and spatial locations holistically to discover latent attack paths across a large time-scale and achieve long-term security for the target assets. In this work, we propose a time-expanded random network to model the stochastic service links in the user-host enterprise network and the adversarial lateral movement. We design cognitive honeypots at idle production nodes and disguise honey links as service links to detect and deter the adversarial lateral movement. The location of the honeypot changes randomly at different times and increases the honeypots' stealthiness. Since the defender does not know whether, when, and where the initial intrusion and the lateral movement occur, the honeypot policy aims to reduce the target assets' Long-Term Vulnerability (LTV) for proactive and persistent protection. We further characterize three tradeoffs, i.e., the probability of interference, the stealthiness level, and the roaming cost. To counter the curse of multiple attack paths, we propose an iterative algorithm and approximate the LTV with the union bound for computationally efficient deployment of cognitive honeypots. The results of the vulnerability analysis illustrate the bounds, trends, and a residue of LTV when the adversarial lateral movement has infinite duration. Besides honeypot policies, we obtain a critical threshold of compromisability to guide the design and modification of the current system parameters for a higher level of long-term security. We show that the target node can achieve zero vulnerability under infinite stages of lateral movement if the probability of movement deterrence is not less than the threshold

From product recommendation to cyber-attack prediction: generating attack graphs and predicting future attacks

Modern information society depends on reliable functionality of information systems infrastructure, while at the same time the number of cyber-attacks has been increasing over the years and damages have been caused. Furthermore, graphs can be used to show paths than can be exploited by attackers to intrude into systems and gain unauthorized access through vulnerability exploitation. This paper presents a method that builds attack graphs using data supplied from the maritime supply chain infrastructure. The method delivers all possible paths that can be exploited to gain access. Then, a recommendation system is utilized to make predictions about future attack steps within the network. We show that recommender systems can be used in cyber defense by predicting attacks. The goal of this paper is to identify attack paths and show how a recommendation method can be used to classify future cyber-attacks in terms of risk management. The proposed method has been experimentally evaluated and validated, with the results showing that it is both practical and effective

Association of Serum Ferritin Levels Before Start of Conditioning With Mortality After alloSCT - A Prospective, Non-interventional Study of the EBMT Transplant Complications Working Party

Elevated serum ferritin levels occur due to iron overload or during inflammation and macrophage activation. A correlation of high serum ferritin levels with increased mortality after alloSCT has been suggested by several retrospective analyses as well as by two smaller prospective studies. This prospective multicentric study aimed to study the association of ferritin serum levels before start of conditioning with alloSCT outcome. Patients with acute leukemia, lymphoma or MDS receiving a matched sibling alloSCT for the first time were considered for inclusion, regardless of conditioning. A comparison of outcomes between patients with high and low ferritin level was performed using univariate analysis and multivariate analysis using cause-specific Cox model. Twenty centers reported data on 298 alloSCT recipients. The ferritin cut off point was determined at 1500 mu g/l (median of measured ferritin levels). In alloSCT recipients with ferritin levels above cut off measured before the start of conditioning, overall survival (HR = 2.5, CI = 1.5-4.1, p = 0.0005) and progression-free survival (HR = 2.4, CI = 1.6-3.8, p <0.0001) were inferior. Excess mortality in the high ferritin group was due to both higher relapse incidence (HR = 2.2, CI = 1.2-3.8, p = 0.007) and increased non-relapse mortality (NRM) (HR = 3.1, CI = 1.5-6.4, p = 0.002). NRM was driven by significantly higher infection-related mortality in the high ferritin group (HR = 3.9, CI = 1.6-9.7, p = 0.003). Acute and chronic GVHD incidence or severity were not associated to serum ferritin levels. We conclude that ferritin levels can serve as routine laboratory biomarker for mortality risk assessment before alloSCT.Peer reviewe

Serum paraoxonase and arylesterase activities in patients with lung cancer in a Turkish population

BACKGROUND: Lung cancer (LC) is the leading cause of cancer-related deaths. Oxidative DNA damage may contribute to the cancer risk. The antioxidant paraoxonase (PON1) is an endogenous free radical scavenger in the human body. The aim of this study was to determine serum PON1 and arylesterase (ARE) activities in patients with newly diagnosed LC. METHODS: This case control study involved a total of 39 patients with newly diagnosed LC (untreated) and same number of age- and sex-matched healthy individuals. Serum PON1 and ARE activities in addition to lipid parameters were measured in both groups. RESULTS: Serum PON1 and ARE activities were found to be lower in patients with LC compared to the controls (p = 0.001 and p = 0.018, respectively). The ratio of PON1/high density lipoprotein (HDL) was significantly lower in the LC group compared to the control one (p = 0.009). There were positive correlations between the serum levels of HDL and PON1 in both the control (r = 0.415, p = 0.009) and the LC groups (r = 0.496, p = 0.001), respectively. PON1 enzyme activity was calculated as three different phenotypes in both groups. In regard to lipid parameters, total cholesterol levels were significantly lower (p = 0.014) in the LC group whereas the other lipid parameters such as HDL, LDL, and triglyceride levels were not significantly different among groups. CONCLUSION: Serum PON1 activity is significantly low in the LC group compared with the healthy controls. Metastasis status and cigarette smoking do not affect serum PON1 activity in the LC patients

Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia

Background: chronic lymphocytic leukemia (CLL) primarily affects older persons who often have coexisting conditions in addition to disease-related immunosuppression and myelosuppression. We conducted an international, open-label, randomized phase 3 trial to compare two oral agents, ibrutinib and chlorambucil, in previously untreated older patients with CLL or small lymphocytic lymphoma. Methods: we randomly assigned 269 previously untreated patients who were 65 years of age or older and had CLL or small lymphocytic lymphoma to receive ibrutinib or chlorambucil. The primary end point was progression-free survival as assessed by an independent review committee. Results: the median age of the patients was 73 years. During a median follow-up period of 18.4 months, ibrutinib resulted in significantly longer progression-free survival than did chlorambucil (median, not reached vs. 18.9 months), with a risk of progression or death that was 84% lower with ibrutinib than that with chlorambucil (hazard ratio, 0.16; P<0.001). Ibrutinib significantly prolonged overall survival; the estimated survival rate at 24 months was 98% with ibrutinib versus 85% with chlorambucil, with a relative risk of death that was 84% lower in the ibrutinib group than in the chlorambucil group (hazard ratio, 0.16; P=0.001). The overall response rate was higher with ibrutinib than with chlorambucil (86% vs. 35%, P<0.001). The rates of sustained increases from baseline values in the hemoglobin and platelet levels were higher with ibrutinib. Adverse events of any grade that occurred in at least 20% of the patients receiving ibrutinib included diarrhea, fatigue, cough, and nausea; adverse events occurring in at least 20% of those receiving chlorambucil included nausea, fatigue, neutropenia, anemia, and vomiting. In the ibrutinib group, four patients had a grade 3 hemorrhage and one had a grade 4 hemorrhage. A total of 87% of the patients in the ibrutinib group are continuing to take ibrutinib. Conclusions: ibrutinib was superior to chlorambucil in previously untreated patients with CLL or small lymphocytic lymphoma, as assessed by progression-free survival, overall survival, response rate, and improvement in hematologic variables. (Funded by Pharmacyclics and others; RESONATE-2 ClinicalTrials.gov number, NCT01722487.)

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure fl ux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defi ned as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (inmost higher eukaryotes and some protists such as Dictyostelium ) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the fi eld understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation it is imperative to delete or knock down more than one autophagy-related gene. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways so not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field

Identification and Validation of Novel Cerebrospinal Fluid Biomarkers for Staging Early Alzheimer's Disease

Ideally, disease modifying therapies for Alzheimer disease (AD) will be applied during the 'preclinical' stage (pathology present with cognition intact) before severe neuronal damage occurs, or upon recognizing very mild cognitive impairment. Developing and judiciously administering such therapies will require biomarker panels to identify early AD pathology, classify disease stage, monitor pathological progression, and predict cognitive decline. To discover such biomarkers, we measured AD-associated changes in the cerebrospinal fluid (CSF) proteome.CSF samples from individuals with mild AD (Clinical Dementia Rating [CDR] 1) (n = 24) and cognitively normal controls (CDR 0) (n = 24) were subjected to two-dimensional difference-in-gel electrophoresis. Within 119 differentially-abundant gel features, mass spectrometry (LC-MS/MS) identified 47 proteins. For validation, eleven proteins were re-evaluated by enzyme-linked immunosorbent assays (ELISA). Six of these assays (NrCAM, YKL-40, chromogranin A, carnosinase I, transthyretin, cystatin C) distinguished CDR 1 and CDR 0 groups and were subsequently applied (with tau, p-tau181 and Aβ42 ELISAs) to a larger independent cohort (n = 292) that included individuals with very mild dementia (CDR 0.5). Receiver-operating characteristic curve analyses using stepwise logistic regression yielded optimal biomarker combinations to distinguish CDR 0 from CDR>0 (tau, YKL-40, NrCAM) and CDR 1 from CDR<1 (tau, chromogranin A, carnosinase I) with areas under the curve of 0.90 (0.85-0.94 95% confidence interval [CI]) and 0.88 (0.81-0.94 CI), respectively.Four novel CSF biomarkers for AD (NrCAM, YKL-40, chromogranin A, carnosinase I) can improve the diagnostic accuracy of Aβ42 and tau. Together, these six markers describe six clinicopathological stages from cognitive normalcy to mild dementia, including stages defined by increased risk of cognitive decline. Such a panel might improve clinical trial efficiency by guiding subject enrollment and monitoring disease progression. Further studies will be required to validate this panel and evaluate its potential for distinguishing AD from other dementing conditions