Verification of full functional correctness for imperative linked data structures

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 2010.Cataloged from PDF version of thesis.Includes bibliographical references (p. 207-222).We present the verification of full functional correctness for a collection of imperative linked data structures implemented in Java. A key technique that makes this verification possible is a novel, integrated proof language that we have developed within the context of the Jahob program verification system. Our proof language allows us to embed proof commands directly within the program, making it possible to reason about the behavior of the program in its original context. It also allows us to effectively leverage Jahob's integrated reasoning system. Unlike conventional program verification systems that rely on a single monolithic prover, Jahob includes interfaces to a diverse collection of specialized automated reasoning systems-automated theorem provers, decision procedures, and program analyses-that work together to prove the verification conditions that the system automatically generates. Our proof language enables the developer to direct the efforts of these automated reasoning systems to successfully verify properties that the system is unable to verify without guidance. Our specifications characterize the behavior of the data structures in terms of their abstract state, resulting in verified interfaces that can be used to reason about the behavior of the data structures without revealing the underlying representation. The results demonstrate the effectiveness of our proof language and integrated reasoning approach, and provide valuable insight into the specification and verification of imperative linked data structures.by Karen K. Zee.Ph.D

Predicate Abstraction for Linked Data Structures

We present Alias Refinement Types (ART), a new approach to the verification of correctness properties of linked data structures. While there are many techniques for checking that a heap-manipulating program adheres to its specification, they often require that the programmer annotate the behavior of each procedure, for example, in the form of loop invariants and pre- and post-conditions. Predicate abstraction would be an attractive abstract domain for performing invariant inference, existing techniques are not able to reason about the heap with enough precision to verify functional properties of data structure manipulating programs. In this paper, we propose a technique that lifts predicate abstraction to the heap by factoring the analysis of data structures into two orthogonal components: (1) Alias Types, which reason about the physical shape of heap structures, and (2) Refinement Types, which use simple predicates from an SMT decidable theory to capture the logical or semantic properties of the structures. We prove ART sound by translating types into separation logic assertions, thus translating typing derivations in ART into separation logic proofs. We evaluate ART by implementing a tool that performs type inference for an imperative language, and empirically show, using a suite of data-structure benchmarks, that ART requires only 21% of the annotations needed by other state-of-the-art verification techniques

Photoluminescence and Electron Spin Resonance of ilicon Dioxide Crystal with Rutile Structure (Stishovite)

This work was supported by ERANET MYND. Also, financial support provided by Scientific Research Project for Students and Young Researchers Nr. SJZ/2017/2 realized at the Institute of Solid State Physics, University of Latvia is greatly acknowledged. The authors express our gratitude to R.I. Mashkovtsev for help in ESR signal interpretation. The authors are appreciative to T.I. Dyuzheva, L.M. Lityagina, N.A. Bendeliani for stishovite single crystals and to K. Hubner and H.-J. Fitting for stishovite powder of Barringer Meteor Crater.An electron spin resonance (ESR) and photoluminescence signal is observed in the as grown single crystal of stishovite indicating the presence of defects in the non‐irradiated sample. The photoluminescence of the as received stishovite single crystals exhibits two main bands – a blue at 3 eV and an UV at 4.75 eV. Luminescence is excited in the range of optical transparency of stishovite (below 8.75 eV) and, therefore, is ascribed to defects. A wide range of decay kinetics under a pulsed excitation is observed. For the blue band besides the exponential decay with a time constant of about 18 μs an additional ms component is revealed. For the UV band besides the fast component with a time constant of 1–3 ns a component with a decay in tens μs is obtained. The main components (18 μs and 1–3 ns) possess a typical intra‐center transition intensity thermal quenching. The effect of the additional slow component is related to the presence of OH groups and/or carbon molecular defects modifying the luminescence center. The additional slow components exhibit wave‐like thermal dependences. Photo‐thermally stimulated creation–destruction of the complex comprising host defect and interstitial modifiers explains the slow luminescence wave‐like thermal dependences.ERANET MYND; ISSP UL Nr. SJZ/2017/2 ; Institute of Solid State Physics, University of Latvia as the Center of Excellence has received funding from the European Union’s Horizon 2020 Framework Programme H2020-WIDESPREAD-01-2016-2017-TeamingPhase2 under grant agreement No. 739508, project CAMART

Survivorship: sleep disorders, version 1.2014.

Sleep disorders, including insomnia and excessive sleepiness, affect a significant proportion of patients with cancer and survivors, often in combination with fatigue, anxiety, and depression. Improvements in sleep lead to improvements in fatigue, mood, and quality of life. This section of the NCCN Guidelines for Survivorship provides screening, diagnosis, and management recommendations for sleep disorders in survivors. Management includes combinations of sleep hygiene education, physical activity, psychosocial interventions, and pharmacologic treatments

Survivorship: cognitive function, version 1.2014.

Cognitive impairment is a common complaint among cancer survivors and may be a consequence of the tumors themselves or direct effects of cancer-related treatment (eg, chemotherapy, endocrine therapy, radiation). For some survivors, symptoms persist over the long term and, when more severe, can impact quality of life and function. This section of the NCCN Guidelines for Survivorship provides assessment, evaluation, and management recommendations for cognitive dysfunction in survivors. Nonpharmacologic interventions (eg, instruction in coping strategies; management of distress, pain, sleep disturbances, and fatigue; occupational therapy) are recommended, with pharmacologic interventions as a last line of therapy in survivors for whom other interventions have been insufficient

NCCN Guidelines Insights: Survivorship, Version 2.2019.

The NCCN Guidelines for Survivorship provide screening, evaluation, and treatment recommendations for consequences of cancer and cancer treatment to aid healthcare professionals who work with survivors of adult-onset cancer. Guidance is also provided to help promote physical activity, weight management, and proper immunizations in survivors and to facilitate care coordination to ensure that all needs are addressed. These NCCN Insights summarize some of the topics discussed by the NCCN Survivorship Panel during the 2019 update of the guidelines, including the survivorship population addressed, ways to improve care coordination, and pain management

NCCN Guidelines Insights: Survivorship, Version 2.2020.

The NCCN Guidelines for Survivorship provide screening, evaluation, and treatment recommendations for consequences of adult-onset cancer and its treatment, with the goal of helping healthcare professionals who work with survivors, including those in primary care. The guidelines also provide recommendations to help clinicians promote physical activity, weight management, and proper immunizations in survivors and facilitate care coordination to ensure that all of the survivors needs are addressed. These NCCN Guidelines Insights summarize additions and changes made to the guidelines in 2020 regarding cardiovascular disease risk assessment and screening for subsequent primary malignancies

Variation in Coronary Atherosclerosis Severity Related to a Distinct LDL (Low-Density Lipoprotein) Profile Findings From a Familial Hypercholesterolemia Pig Model

OBJECTIVE: In an adult porcine model of familial hypercholesterolemia (FH), coronary plaque development was characterized. \nTo elucidate the underlying mechanisms of the observed inter-individual variation in disease severity, detailed lipoprotein \nprofiles were determined. \nAPPROACH AND RESULTS: FH pigs (3 years old, homozygous LDLR R84C mutation) received an atherogenic diet for 12 months. \nCoronary atherosclerosis development was monitored using serial invasive imaging and histology. A pronounced difference \nwas observed between mildly diseased pigs which exclusively developed early lesions (maximal plaque burden, 25% [23%\xe2\x80\x93 \n34%]; n=5) and advanced-diseased pigs (n=5) which developed human-like, lumen intruding plaques (maximal plaque burden, \n69% [57%\xe2\x80\x9377%]) with large necrotic cores, intraplaque hemorrhage, and calcifications. Advanced-diseased pigs and mildly \ndiseased pigs displayed no differences in conventional risk factors. Additional plasma lipoprotein profiling by size-exclusion \nchromatography revealed 2 different LDL (low-density lipoprotein) subtypes: regular and larger LDL. Cholesterol, sphingosine1-phosphate, ceramide, and sphingomyelin levels were determined in these LDL-subfractions using standard laboratory \ntechniques and high-pressure liquid chromatography mass-spectrometry analyses, respectively. At 3 months of diet, regular \nLDL of advanced-diseased pigs contained relatively more cholesterol (LDL-C; regular/larger LDL-C ratio 1.7 [1.3\xe2\x80\x931.9] versus \n0.8 [0.6\xe2\x80\x930.9]; P=0.008) than mildly diseased pigs, while larger LDL contained more sphingosine-1-phosphate, ceramides, and \nsphingomyelins. Larger and regular LDL was also found in plasma of 3 patients with homozygous FH with varying LDL-C ratios. \nCONCLUSIONS: In our adult FH pig model, inter-individual differences in atherosclerotic disease severity were directly related to \nthe distribution of cholesterol and sphingolipids over a distinct LDL profile with regular and larger LDL shortly after the diet \nstart. A similar LDL profile was detected in patients with homozygous FH

A Missense Variant in PTPN22 is a Risk Factor for Drug-induced Liver Injury

Background & Aims We performed genetic analyses of a multiethnic cohort of patients with idiosyncratic drug-induced liver injury (DILI) to identify variants associated with susceptibility. Methods We performed a genome-wide association study of 2048 individuals with DILI (cases) and 12,429 individuals without (controls). Our analysis included subjects of European (1806 cases and 10,397 controls), African American (133 cases and 1,314 controls), and Hispanic (109 cases and 718 controls) ancestry. We analyzed DNA from 113 Icelandic cases and 239,304 controls to validate our findings. Results We associated idiosyncratic DILI with rs2476601, a nonsynonymous polymorphism that encodes a substitution of tryptophan with arginine in the protein tyrosine phosphatase, nonreceptor type 22 gene (PTPN22) (odds ratio [OR] 1.44; 95% confidence interval [CI] 1.28–1.62; P = 1.2 × 10–9 and replicated the finding in the validation set (OR 1.48; 95% CI 1.09–1.99; P = .01). The minor allele frequency showed the same effect size (OR > 1) among ethnic groups. The strongest association was with amoxicillin and clavulanate-associated DILI in persons of European ancestry (OR 1.62; 95% CI 1.32–1.98; P = 4.0 × 10–6; allele frequency = 13.3%), but the polymorphism was associated with DILI of other causes (OR 1.37; 95% CI 1.21–1.56; P = 1.5 × 10–6; allele frequency = 11.5%). Among amoxicillin- and clavulanate-associated cases of European ancestry, rs2476601 doubled the risk for DILI among those with the HLA risk alleles A*02:01 and DRB1*15:01. Conclusions In a genome-wide association study, we identified rs2476601 in PTPN22 as a non-HLA variant that associates with risk of liver injury caused by multiple drugs and validated our finding in a separate cohort. This variant has been associated with increased risk of autoimmune diseases, providing support for the concept that alterations in immune regulation contribute to idiosyncratic DILI

Shortened Telomere Length Is Associated with Increased Risk of Cancer: A Meta-Analysis

BACKGROUND: Telomeres play a key role in the maintenance of chromosome integrity and stability, and telomere shortening is involved in initiation and progression of malignancies. A series of epidemiological studies have examined the association between shortened telomeres and risk of cancers, but the findings remain conflicting. METHODS: A dataset composed of 11,255 cases and 13,101 controls from 21 publications was included in a meta-analysis to evaluate the association between overall cancer risk or cancer-specific risk and the relative telomere length. Heterogeneity among studies and their publication bias were further assessed by the χ(2)-based Q statistic test and Egger's test, respectively. RESULTS: The results showed that shorter telomeres were significantly associated with cancer risk (OR = 1.35, 95% CI = 1.14-1.60), compared with longer telomeres. In the stratified analysis by tumor type, the association remained significant in subgroups of bladder cancer (OR = 1.84, 95% CI = 1.38-2.44), lung cancer (OR = 2.39, 95% CI = 1.18-4.88), smoking-related cancers (OR = 2.25, 95% CI = 1.83-2.78), cancers in the digestive system (OR = 1.69, 95% CI = 1.53-1.87) and the urogenital system (OR = 1.73, 95% CI = 1.12-2.67). Furthermore, the results also indicated that the association between the relative telomere length and overall cancer risk was statistically significant in studies of Caucasian subjects, Asian subjects, retrospective designs, hospital-based controls and smaller sample sizes. Funnel plot and Egger's test suggested that there was no publication bias in the current meta-analysis (P = 0.532). CONCLUSIONS: The results of this meta-analysis suggest that the presence of shortened telomeres may be a marker for susceptibility to human cancer, but single larger, well-design prospective studies are warranted to confirm these findings