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Mutation analysis assesses a test suites adequacy by measuring its ability to detect small artificial faults, systematically seeded into the tested program. Mutation analysis is considered one of the strongest test-adequacy criteria. Mutation testing builds on top of mutation analysis and is a testing technique that uses mutants as test goals to create or improve a test suite. Mutation testing has long been considered intractable because the sheer number of mutants that can be created represents an insurmountable problemboth in terms of human and computational effort. This has hindered the adoption of mutation testing as an industry standard. For example, Google has a codebase of two billion lines of code and more than 150,000,000 tests are executed on a daily basis. The traditional approach to mutation testing does not scale to such an environment; even existing solutions to speed up mutation analysis are insufficient to make it computationally feasible at such a scale. To address these challenges, this paper presents a scalable approach to mutation testing based on the following main ideas: (1) mutation testing is done incrementally, mutating only changed code during code review, rather than the entire code base; (2) mutants are filtered, removing mutants that are likely to be irrelevant to developers, and limiting the number of mutants per line and per code review process; (3) mutants are selected based on the historical performance of mutation operators, further eliminating irrelevant mutants and improving mutant quality. This paper empirically validates the proposed approach by analyzing its effectiveness in a code-review-based setting, used by more than 24,000 developers on more than 1,000 projects. The results show that the proposed approach produces orders of magnitude fewer mutants and that context-based mutant filtering and selection improve mutant quality and actionability. Overall, the proposed approach represents a mutation testing framework that seamlessly integrates into the software development workflow and is applicable to industrial settings of any size.

On-board embedded software developed for spaceflight systems (space software) must adhere to stringent software quality assurance procedures. For example, verification and validation activities are typically performed and assessed by third party organizations. To further minimize the risk of human mistakes, space agencies, such as the European Space Agency (ESA), are looking for automated solutions for the assessment of software testing activities, which play a crucial role in this context. Over the years, mutation analysis has shown to be a promising solution for the automated assessment of test suites; it consists of measuring the quality of a test suite in terms of the percentage of injected faults leading to a test failure. A number of optimization techniques, addressing scalability and accuracy problems, have been proposed to facilitate the industrial adoption of mutation analysis. However, to date, two major problems prevent space agencies from enforcing mutation analysis in space software development. In this paper, we enhance mutation analysis optimization techniques to enable their applicability to embedded software and propose a pipeline that successfully integrates them to address scalability and accuracy issues in this context, as described above. Further, we report on the largest study involving embedded software systems in the mutation analysis literature. Our research is part of a research project funded by ESA ESTEC involving private companies (GomSpace Luxembourg and LuxSpace) in the space sector. These industry partners provided the case studies reported in this paper; they include an on-board software system managing a microsatellite currently on-orbit, a set of libraries used in deployed cubesats, and a mathematical library certified by ESA., Accepted for publication on IEEE TRANSACTIONS ON SOFTWARE ENGINEERING

Background : Many recurrent mutations are encountered in core binding factor acute myeloid leukemia (CBF-AML) which may affect the prognosis. Approximately 20-45% of CBF-AML patients have KIT mutations which are having poor prognosis and high incidence of relapse. There is still insufficient data to categorize the patients with c-kit mutation into which risk group and there is a debate around whether Tyrosine kinase inhibitors can decrease the relapse risk and improve the prognosis of those patients . Patients and methods : This study was conducted throughout a period of three years, where 102 CBF-AML were enrolled in our study. We analyzed the incidence of c-KIT exon 8 and 17 D816V mutations in CBF-AML patients and studied the prognosis . Results : The prevalence of CBF-AML was 102/989 (10.3%), 13.7% and 8.7% in pediatrics and adults' groups respectively. c-KIT fragment mutation analysis revealed a mutant form in 27/102 (26.5%) patients. Exon 8 mutation was found in 4/40 pediatric and 2/62 adult patients, while exon 17 mutation was found in 9/40 pediatric and 12/62 adult patients. The c-KIT mutations was more common in t(8;21). There was no significant relationship between c-kit mutation and CR rates, while there was a significant inferior overall, disease free as well as progression free survival in the c-KIT mutant patients as compared to the wild group (p value 0.045, 0.036 and 0.024 respectively) in the pediatric group, however, this significance was not evident in the adults' group . Conclusion : According to our study, the results may suggest c-KIT mutation as a poor risk factor in pediatric CBF-AML.

Mutation testing, a fundamental software testing technique, which is a typical way to evaluate the adequacy of test data. In mutation testing, a set of mutants are generated by seeding the different classes of faults into a program under test. Test data shall be generated in the way that as many mutants can be killed as possible. Thanks to numerous tools to implement mutation testing for different languages, a huge amount of mutants are normally generated even for small-sized programs. However, a large number of mutants not only leads to a high cost of mutation testing, but also make the corresponding test data generation a non-trivial task. In this paper, we make use of intelligent technologies to improve the effectiveness and efficiency of mutation testing from two perspectives. A machine learning technique, namely fuzzy clustering, is applied to categorize mutants into different clusters. Then, a multi-population genetic algorithm via individual sharing is employed to generate test data for killing the mutants in different clusters in parallel when the problem of test data generation as an optimization one. A comprehensive framework, termed as FUZGENMUT, is thus developed to implement the proposed techniques. The experiments based on nine programs of various sizes show that fuzzy clustering can help to reduce the cost of mutation testing effectively, and that the multi-population genetic algorithm improves the efficiency of test data generation while delivering the high mutant-killing capability. The results clearly indicate the huge potential of using intelligent technologies to enhance the efficacy and thus the practicality of mutation testing.

PurposeAnalysis of circulating tumor DNA (ctDNA) in blood could allow noninvasive genetic analysis of primary tumors. Although there have been unmet needs for noninvasive methods in patients with primary central nervous system lymphoma (PCNSL), it is still not determined whether plasma ctDNA analysis could be useful for patients with PCNSL. Materials and MethodsTargeted deep sequencing of 54 genes was performed in cell-free DNA isolated from plasma samples collected pretreatment, during treatment, and at the end of treatment in 42 consecutively diagnosed PCNSL patients between January 2017 and December 2018.ResultsTargeted sequencing of plasma cell-free DNA detected somatic mutations representing ctDNA in 11 cases (11/41, 27%). The detection of ctDNA was not related to the concentration of cell-free DNA or tumor volume. The mutation profiles of these 11 cases varied between patients. The most frequently mutated gene was PIM1 (4/11, 36.4%), whereas KMT2D, PIK3CA, and MYD88 were each observed in three patients (3/11, 27%). The mutations of 13 genes were concordantly found in primary tumor tissue and plasma ctDNA, giving a detection sensitivity of 45%. During the serial tracking of seven patients with complete response, the disappearance of ctDNA mutations was found in four patients, whereas three patients had detected ctDNA mutation at the end of treatment. ConclusionThe plasma ctDNA mutation analysis still has limited value for surveillance and predicting treatment outcomes of PCNSL because the detection efficiency was lower than other systemic lymphomas. Thus, analytical platforms should be improved to overcome anatomical hurdles associated with PCNSL.

Compared with traditional structural test criteria, test data generated based on mutation testing are proved more effective at detecting faults. However, not all test data have the same potence in detecting software faults. If test data are prioritized while generating for mutation testing, the defect detectability of the test suite can be further strengthened. In view of this, we propose a method of test data generation for weak mutation testing via sorting mutant branches based on their dominance degrees. First, the problem of weak mutation testing is transformed into that of covering mutant branches for a transformed program. Then, the dominance relation of mutant branches in the transformed program is analyzed to obtain the non-dominated mutant branches and their dominance degrees. Following that, we prioritize all non-dominated mutant branches in descending order by virtue of their dominance degrees. Finally, the test data are generated in an orderly manner by selecting the mutant branches sequentially. The experimental results on 15 programs show that compared with other methods, the proposed test data generation method can not only improve the error detectability of the test suite, but also has higher efficiency.

Mutation testing has been widely used to assess the fault-detection effectiveness of a test suite, as well as to guide test case generation or prioritization. Empirical studies have shown that, while mutants are generally representative of real faults, an effective application of mutation testing requires “traditional” operators designed for programming languages to be augmented with operators specific to an application domain and/or technology. The case for Android apps is not an exception. Therefore, in this paper we describe the process we followed to create (i) a taxonomy of mutation operations and, (ii) two tools, MDroid+ and MutAPK for mutant generation of Android apps. To this end, we systematically devise a taxonomy of 262 types of Android faults grouped in 14 categories by manually analyzing 2,023 software artifacts from different sources (e.g., bug reports, commits). Then, we identified a set of 38 mutation operators, and implemented them in two tools, the first enabling mutant generation at the source code level, and the second designed to perform mutations at APK level. The rationale for having a dual-approach is based on the fact that source code is not always available when conducting mutation testing. Thus, mutation testing for APKs enables new scenarios in which researchers/practitioners only have access to APK files. The taxonomy, proposed operators, and tools have been evaluated in terms of the number of non-compilable, trivial, equivalent, and duplicate mutants generated and their capacity to represent real faults in Android apps as compared to other well-known mutation tools.

For a nationwide real-word data study on the application of predictive mutation testing of patients with colorectal cancer (CRC) for anti-epidermal growth factor receptor (EGFR) therapy stratification, pathology data were collected from the Dutch Pathology Registry from October 2017 until June 2019 (N=4060) and linked with the Netherlands Cancer Registry. Mutation testing rates increased from 24% at diagnosis of stage IV disease to 60% after 20–23 months of follow-up (pKRAS/NRAS wild-type patients was mainly observed from the third treatment line onwards (65% vs 17% in first/second treatment line (pKRAS/NRAS/BRAF mutation rate was 63.9%, being similar for next-generation sequencing (NGS)-based approaches and single gene tests (64.4% vs 61.2%, p=ns). NGS-based approaches detected more additional potential biomarkers, for example, ERBB2 amplifications (p

Objectives There is an increasing number of driver fusions in NSCLC which are amenable to targeted therapy. Panel testing for fusions is increasingly appropriate but can be costly and requires adequate good quality biopsy material. In light of the typical mutual exclusivity of driver events in NSCLC, the objective of this study was to trial a novel testing pathway, supported by industrial collaboration, in which only patients negative for driver mutations on DNA-NGS were submitted for fusion panel analysis. Materials and methods Over 18 months, all patients from a single centre with non-squamous NSCLC were submitted for DNA-NGS, plus ALK and ROS1 immunohistochemistry +/− FISH. Those which were negative for a driver mutation were then recalled for RNA panel testing. Results 307 samples were referred for DNA-NGS mutation analysis, of which, 10% of cases were unsuitable for or failed DNA-NGS analysis. Driver mutations were detected in 61% (167/275) of all those successfully tested. Of those without a driver mutation and with some remaining tissue available, 28% had insufficient tissue/extracted RNA or failed RNA-NGS. Of those successfully tested, 24% (17/72) had a fusion gene detected involving either ALK, ROS, MET, RET, FGFR or EGFR. Overall, 66% (184/277) of patients had a driver event detected through the combination of DNA and RNA panels. Conclusion Sequential DNA and RNA based molecular profiling increased the efficacy of detecting fusion driven NSCLCs. Continued optimisation of tissue procurement, handling and the diagnostic pathways for gene fusion analysis is necessary to reduce analysis failure rates and improve detection rate for treatment with the next generation of small molecule inhibitors.

BACKGROUND Thyroid nodules with indeterminate cytology represent up to 30% of cases. Molecular testing is now highly recommended to improve management. This study aimed to evaluate the use of the Idylla™ NRAS/BRAF mutation test, a rapid and automated polymerase chain reaction (PCR) assay validated for fixed paraffin-embedded use, on residual thyroid liquid-based fine-needle aspiration (LB-FNA). METHODS Concordance between mutations detected by the Idylla™ assay and the gold-standard qPCR was assessed by splitting in two aliquots 31 BRAF or RAS mutated and 5 non-mutated LB-FNA samples. Samples were obtained either from simulated FNA after thyroidectomy or from FNA obtained during routine care. A third aliquot was used to assess the limit of detection of Idylla™ for five mutated samples. RESULTS The Idylla™ assay showed a sensitivity of 97% and a specificity of 83% as results were concordant for 34 out of 36 samples. One discordant sample concerned a BRAF p.K601E-mutation which is not detected by the Idylla™ cartridge. The other showed a false-positive NRAS p.A146T detection and a weak BRAF p.V600E detection. The limit of detection of the Idylla™ assay was not reached by the dilution assay. CONCLUSION Idylla™ NRAS/BRAF mutation testing can be performed on residual thyroid LB-FNA, using low DNA quantity input, thus not requiring a dedicated sample. The Idylla™ NRAS/BRAF assay offers a quick and easy first step for analyzing the main molecular alterations in indeterminate thyroid nodules, hence improving diagnostic management.

Epidermal growth factor receptor (EGFR) mutation testing in advanced non-small-cell lung cancer (NSCLC) has evolved rapidly over the past decade, largely triggered by the introduction of the targeted EGFR tyrosine kinase inhibitors (TKIs). Initially used to detect common EGFR mutations and determine the most appropriate first-line therapy at diagnosis, testing methodologies have expanded to test for multiple mutations at multiple time points throughout the disease course. Here we review the current mutation testing approaches, including types of biopsies, and the available assays commonly used in the clinic. Specific application of these approaches in advanced NSCLC, including current guideline recommendations, and potential future developments are discussed.

Purpose: The present study was designed to screen the genetic polymorphisms and expression profiling of CEP-152 and CEP-63 genes in brain tumor patients. Methods: The amplification refractory mutation system PCR technique (ARMS-PCR) was used for mutation analysis using 300 blood samples of brain tumor patients and 300 overtly healthy controls. For expression analysis, 150 brain tumor tissue samples along with adjacent uninvolved/normal tissues (controls) were collected. Results: A significantly higher frequency of the mutant genotype of the CEP-152 single nucleotide polymorphism (rs2169757) and CEP-63 single nucleotide polymorphisms (rs9809619 and rs13060247) was observed in patients versus overtly healthy controls. The authors' results showed highly significant deregulation of CEP-152 (p

Fabry disease (FD) is an inborn X-linked lysosomal storage disorder resulting from α–galactosidase A (α-Gal) activity deficiency in lysosomes. This results in the accumulation of particularly globotriaosylceramide (Gb3) within lysosomes in a wide variety of cells. This study aimed to analyze the clinical presentation, findings and family screenings of index cases, management and outcomes of FD patients in our center. Methods. Data including demographic characteristics, personal history of comorbidities, laboratory findings at the time of diagnosis were recorded. α – Gal activity was measured in all males and females as initial analysis. The cut-off trigger was determined as 1.2 mmol/L per hour. Mutation analysis was performed in males and females with decreased α – Gal activity as a diagnostic assay. In addition, mutation analysis was performed change in females with normal α – Gal providing they have clinical signs or family history for FD. Results. The individuals from nine FD families were presented. Conclusion. Screening for genetic diseases such as FD has crucial conclusions. The detection of FD in an index case leads to appropriate therapy for that patient. Family screening can be started and additional undiagnosed individuals can be detected.

One of the most important and integral components of modern computer security are access control systems. The objective of an access control system (ACS) is often described in terms of protecting system resources against inappropriate or unwanted user access. However, a large degree of sharing can interfere with the protection of resources, so a sufficiently detailed AC policy should allow selective exchange of information when, in its absence, sharing can be considered too risky in general. Erroneous configurations, faulty policies, as well as flaws in the implementation of software can lead to global insecurity. Identifying the differences between policy specifications and their inten ded functions is crucial because the correct implementation and enforcement of the policies of a particular application is based on the premise that the specifications of this policy are correct. As a result of the policy, the specifications presented by the models must undergo rigorous validation and legalization through systematic checks and tests to ensure that the specifications of the policies really correspond to the wishes of the creators. Verifying that access control policies and models are consistent is not a trivial and critical task. And one of the important aspects of such a check is a formal check for inconsistency and incompleteness of the model, and the security requirements of the policy, because the access control model and its implementation do not necessarily express policies that can also be hidden, embedded by mixing with direct access restrictions or another access control model. Одними з найскладніших, важливих та невід'ємних складових сучасної комп'ютерної безпеки є системи керування доступу. Завдання системи керування доступом часто описується з точки зору захисту ресурсів системи проти невідповідного або небажаного доступу користувача. Проте, велика ступінь спільного використання може перешкодити захисту ресурсів, таким чином, досить детальна політика керування доступом повинна дозволяти виборчий обмін інформацією, коли в його відсутність, спільне використання може вважатися занадто ризикованим в цілому. Помилкові конфігурації, несправні політики, а так само недоліки в реалізації програмного забезпечення можуть призвести до глобальної незахищеності. Виявлення відмінностей між специфікаціями політик і їх передбачуваними функціями має вирішальне значення, тому що правильна реалізація і забезпечення дотримання політик конкретного додатка засновані на передумові, що специфікації даної політики є правильними. В результаті політики специфікації, представлені моделями, повинні пройти сувору перевірку і легалізацію шляхом систематичних перевірок і тестувань, щоб гарантувати, що специфікації політик дійсно відповідають бажанням творців. Перевірка відповідності політик і моделей контролю доступу нетривіальна і критична завдання. І одним з важливих аспектів такої перевірки є формальна перевірка на непослідовність і неповноту у моделі, і вимоги безпеки політики, тому що модель контролю доступу та її реалізація не обов'язково явно виражають політики, які також можуть бути приховані, вбудовані шляхом змішування з обмеженнями прямого доступу або іншого доступу моделі управління.

BACKGROUND: The aim of the study was to evaluate familial Mediterranean fever (FMF) mutation analysis in pediatric patients with inflammatory bowel disease (IBD). The relation between MEFV mutations and chronic inflammatory diseases has been reported previously. METHODS: Children with IBD (334 ulcerative colitis (UC), 224 Crohn’s disease (CD), 39 indeterminate colitis (IC)) were tested for FMF mutations in this multicenter study. The distribution of mutations according to disease type, histopathological findings, and disease activity indexes was determined. RESULTS: A total of 597 children (mean age: 10.8 ± 4.6 years, M/F: 1.05) with IBD were included in the study. In this study, 41.9% of the patients had FMF mutations. E148Q was the most common mutation in UC and CD, and M694V in IC (30.5%, 34.5%, 47.1%, respectively). There was a significant difference in terms of endoscopic and histopathological findings according to mutation types (homozygous/heterozygous) in patients with UC (P < .05). There was a statistically significant difference between colonoscopy findings in patients with or without mutations (P = .031, P = .045, respectively). The patients with UC who had mutations had lower Pediatric Ulcerative Colitis Activity Index (PUCAI) scores than the patients without mutations (P = .007). Conclusion: Although FMF mutations are unrelated to CD patients, but observed in UC patients with low PUCAI scores, it was established that mutations do not have a high impact on inflammatory response and clinical outcome of the disease.

Objective: To analyze the clinical, laboratory, and radiological findings and management of patients with clinical pituitary apoplexy and to screen for aryl hydrocarbon receptor-interacting protein (AIP) mutations. Subjects and methods: The clinical findings were collected from the medical records of consecutive sporadic pituitary adenoma patients with clinical apoplexy. Possible precipitating factors, laboratory data, magnetic resonance imaging (MRI) findings and treatment were also analyzed. Peripheral blood samples were obtained for DNA extraction from leukocytes, and the entire AIP coding region was sequenced. Results: Thirty-five patients with pituitary adenoma were included, and 23 (67%) had non-functioning pituitary adenomas. Headache was observed in 31 (89%) patients. No clear precipitating factor was identified. Hypopituitarism was observed in 14 (40%) patients. MRI from 20 patients was analyzed, and 10 (50%) maintained a hyperintense signal in MRI performed more than three weeks after pituitary apoplexy (PA). Surgery was performed in ten (28%) patients, and 25 (72%) were treated conservatively with good outcomes. No AIP mutation was found in this cohort. Conclusion: Patients with stable neuroophthalmological impairments can be treated conservatively if no significant visual loss is present. Our radiological findings suggest that hematoma absorption lasts more than that observed in other parts of the brain. Additionally, our study suggests no benefits of AIP mutation screening in sporadic patients with apoplexy.

Fault localization techniques aim to localize faulty statements using the information gathered from both passed and failed test cases. We present a mutation-based fault localization technique called MuSim. MuSim identifies the faulty statement based on its computed proximity to different mutants. We study the performance of MuSim by using four different similarity metrics. To satisfactorily measure the effectiveness of our proposed approach, we present a new evaluation metric called Mut_Score. Based on this metric, on an average, MuSim is 33.21% more effective than existing fault localization techniques such as DStar, Tarantula, Crosstab, Ochiai.

Next generation sequencing (NGS) technology has revealed the heterogeneity of diffuse large B-cell lymphoma (DLBCL) from a mutation perspective. Accordingly, the conventional cell of origin-based classification of DLBCL has changed to a mutation-based classification. Mutation analysis delineates that B-cell receptor pathway activation, EZH2 mutation, and NOTCH mutations are distinctive drivers of DLBCL. Moreover, the combination of RNA expression data and DNA mutation results suggests similarity between DLBCL subtypes and other non-Hodgkin lymphomas. NGS-based dissection of DLBCL would be the cornerstone for precision treatment in this heterogeneous disease in the near future.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues the pandemic spread of the coronavirus disease 2019 (COVID-19), over 60 million people confirmed infected and at least 1.8 million dead. One of the most known features of this RNA virus is its easiness to be mutated. In late 2020, almost no region of this SARS-CoV-2 genome can be found completely conserved within the original Wuhan coronavirus. Any information of the SARS-CoV-2 variants emerged through as time being will be evaluated for diagnosis, treatment, and prevention of COVID-19. METHODS: We extracted more than two million data of SARS-CoV-2 infected patients from the open COVID-19 dashboard. The sequences of the 38-amino acid putative open reading frame 10 (Orf10) protein within infected patients were gathered output through from National Center for Biotechnology Information and the mutation rates in each position were analyzed and presented in each month of 2020. The mutation rates of A8 and V30 within Orf10 are displayed in selected counties: United States, India, German, and Japan. RESULTS: The numbers of COVID-19 patients are correlated to the death numbers, but not with the death rates (stable and

Test cases are crucial to help developers preventing the introduction of software faults. Unfortunately, not all the tests are properly designed or can effectively capture faults in production code. Some measures have been defined to assess test-case effectiveness: the most relevant one is the mutation score, which highlights the quality of a test by generating the so-called mutants , i.e., variations of the production code that make it faulty and that the test is supposed to identify. However, previous studies revealed that mutation analysis is extremely costly and hard to use in practice. The approaches proposed by researchers so far have not been able to provide practical gains in terms of mutation testing efficiency. This leaves the problem of efficiently assessing test-case effectiveness as still open. In this paper, we investigate a novel, orthogonal, and lightweight methodology to assess test-case effectiveness: in particular, we study the feasibility to exploit production and test-code-quality indicators to estimate the mutation score of a test case. We first select a set of 67 factors and study their relation with test-case effectiveness. Then, we devise a mutation score estimation model exploiting such factors and investigate its performance as well as its most relevant features. The key results of the study reveal that our estimation model only based on static features has 86 percent of both F-Measure and AUC-ROC. This means that we can estimate the test-case effectiveness, using source-code-quality indicators, with high accuracy and without executing the tests. As a consequence, we can provide a practical approach that is beyond the typical limitations of current mutation testing techniques.

Background: BCR-ABL kinase domain(KD) mutations accounts for 60-80% of Imatinib resistance in chronic myeloid leukemia (CML) – chronic phase (CP). Patients with CML who are receiving imatinib treatment, a mutation analysis is required to find out the resistance of imatinib as per European Leukemia Net (ELN) criteria. The present study was carried out to assess for different types of mutations responsible for resistance of imatinib treatment from Western India. Methods: In a retrospective study, the patients who were tested for imatinib resistance were analysed for IRMA testing using direct sequencing of BCR-ABL transcript by Sanger method. Results: A total of 215 patients were tested for Imatinib resistance analysis (IRMA), of which 45 (20.93%) had detectable mutations. The highest frequency of mutation recorded at T315I amino acids site, followed by M244V and G250E sites. Conclusion: The patients who were tested for IRMA showed 20.93 % positive mutations with reference to its resistance are discussed.

Mutation testing is a successful and powerful technique, specifically designed for injecting the artificial faults. Although it is effective at revealing the faults, test suite assessment and its reduction, however, suffer from the expense of executing a large number of mutants. The researchers have proposed different types of cost reduction techniques in the literature. These techniques highly depend on the inspection of mutation operators. Several metrics have been evolved for the same. The selective mutation technique is most frequently used by the researchers. In this paper, the authors investigate different metrics for evaluating the traditional mutation operators for Java. Results on 13 Java programs indicate how grouping few operators can impact the effectiveness of an adequate and minimal test suite, and how this could provide several cost benefits.

Modern software systems, either system or application software, are increasingly being developed on top of virtualized software platforms. They may simply intend to execute on virtual machines or they may be expected to port to physical machines eventually. In either case, the devices, virtual or silicon, in the target virtual or physical machines are expected to conform to the specifications based on which the software systems have been developed. Non-conformance of these devices to the specifications can cause catastrophic failures of the software systems. In this article, we propose a mutation-based framework for effective and efficient conformance checking between virtual/silicon device implementations and their specifications. Based on our defined mutation operators, device specifications can be automatically instrumented with weak mutant-killing constraints to model potential erroneous device behaviors. To kill all feasible mutants, our approach adopts a cooperative symbolic execution mechanism that can efficiently automate the test case generation and conformance checking for virtual/silicon devices. By symbolically executing the instrumented specifications with virtual/silicon device traces obtained from the cooperative execution, our method can accurately measure whether the designs have been sufficiently validated and report the inconsistencies between device specifications and implementations. Comprehensive experiments on two industrial network adapters and their virtual devices demonstrate the effectiveness of our proposed approach in conformance checking for both virtual and silicon devices.

Background: Ongoing clinical trials are investigating poly(ADP-ribose) polymerase (PARP) inhibitors to target the DNA damage repair (DDR) pathway in prostate cancer. DDR mutation screening will guide treatment strategy and assess eligibility for clinical trials. Materials & methods: This systematic review estimated the rate of DDR mutation testing or genetic counseling among men with or at risk of prostate cancer. Results: From 6856 records, one study fulfilled the inclusion criteria and described men undiagnosed with prostate cancer with a family history of BRCA1/2 mutation who received DDR mutation testing. Conclusion: With only one study included in this first systematic review of DDR mutation testing or genetic counseling in men with or at risk of prostate cancer, more research is warranted.

Mutation testing is well known as one of the most effective approaches to create test cases, which can detect software faults. However, its drawback is the low scalability — if no special attention is given to improve efficiency — that directly affects its application in practice. This paper shows a replication study focused on emphasizing evidence in which the use of distributed processing structures can improve mutation testing. For this purpose, an architecture that enables mutation testing concurrent execution was designed. Five load balancing algorithms responsible for controlling the distribution and execution of data while carrying out mutation testing were evaluated. Experiments were conducted in order to evaluate the scalability and performance of the architecture considering homogeneous and heterogeneous setups. A time reduction of 50% was observed when executing mutants in parallel in relation to the conventional sequential application of mutation testing. The performance gain was above 95% when there was a higher number of nodes in the distributed architecture.

β-Thalassaemia, the most common monogenic disorder, is characterized by genetic heterogeneity at the molecular level. More than 300 mutations of the β globin gene have been characterized all over the world, however, few common mutations account for majority of the cases in various populations. The present study aimed to screen known cases of β-thalassaemia in the Western part of Rajasthan state for five common mutations. The study included 144 known cases of β-thalassaemia of all clinical phenotypes. Cases were diagnosed based on clinical features, haematology investigations including haemogram and Hb-HPLC. Blood samples from cases were taken for mutation analysis. After DNA extraction, mutations were characterized by the polymerase chain reaction method employing allele specific priming technique (AMRS) to study the five mutations including IVS-I-5 (G → C), IVS-I-1 (G → T), CD41/42 (–TCTT), CD 8/9 (+G) and 619 bp deletion from the 3′ end of the β-globin gene using a total of seven different primers. Of all 144 cases, 74 (51.38% of all) cases were of β-thalassaemia major, five (3.4% of all) cases were of β-thalassaemia intermedia and 65 (45.14% of all) cases were of β-thalassaemia minor. Mutation analysis revealed that five common mutations were present in 130 (90.27% of all) cases. Among identified mutations, highest frequency of mutation was of IVS-I-5 (G → C) identified in 73 cases (50.7% of all cases). In 11 (7.63% of all) cases, more than one mutation was identified. β-Thalassaemias are common in Western Rajasthan; however, there is dearth of literature from this part of the country. We observed that five common mutations are common in this part of the country also. These observations are helping us in forming the basis for comprehensive diagnostic database that would not only be useful for genetic counselling but also for prenatal diagnosis.

The genome of the novel coronavirus (COVID-19) disease was first sequenced in January 2020, approximately a month after its emergence in Wuhan, capital of Hubei province, China. COVID-19 genome sequencing is critical to understanding the virus behavior, its origin, how fast it mutates, and for the development of drugs/vaccines and effective preventive strategies. This paper investigates the use of artificial intelligence techniques to learn interesting information from COVID-19 genome sequences. Sequential pattern mining (SPM) is first applied on a computer-understandable corpus of COVID-19 genome sequences to see if interesting hidden patterns can be found, which reveal frequent patterns of nucleotide bases and their relationships with each other. Second, sequence prediction models are applied to the corpus to evaluate if nucleotide base(s) can be predicted from previous ones. Third, for mutation analysis in genome sequences, an algorithm is designed to find the locations in the genome sequences where the nucleotide bases are changed and to calculate the mutation rate. Obtained results suggest that SPM and mutation analysis techniques can reveal interesting information and patterns in COVID-19 genome sequences to examine the evolution and variations in COVID-19 strains respectively.

Angioimmunoblastic T-cell lymphoma (AITL) and peripheral T-cell lymphoma with T follicular helper phenotype (PTCL-TFH) are a group of complex clinicopathological entities that originate from T follicular helper cells and share a similar mutation profile. Their diagnosis is often a challenge, particularly at an early stage, because of a lack of specific histological and immunophenotypic features, paucity of neoplastic T cells and prominent polymorphous infiltrate. We investigated whether the lymphoma-associated RHOA Gly17Val (c.50G>T) mutation, occurring in 60% of cases, is present in the early “reactive” lesions, and whether mutation analysis could help to advance the early diagnosis of lymphoma. The RHOA mutation was detected by quantitative polymerase chain reaction with a locked nucleic acid probe specific to the mutation, and a further peptide nucleic acid clamp oligonucleotide to suppress the amplification of the wild-type allele. The quantitative polymerase chain reaction assay was highly sensitive and specific, detecting RHOA Gly17Val at an allele frequency of 0.03%, but not other changes in Gly17, nor in 61 controls. Among the 37 cases of AITL and PTCL-TFH investigated, RHOA Gly17Val was detected in 62.2% (23/37) of which 19 had multiple biopsies including preceding biopsies in ten and follow-up biopsies in 11 cases. RHOA Gly17Val was present in each of these preceding or follow-up biopsies including 18 specimens that showed no evidence of lymphoma by combined histological, immunophenotypic and clonality analyses. The mutation was seen in biopsies 0-26.5 months (mean 7.87 months) prior to the lymphoma diagnosis. Our results show that RHOA Gly17Val mutation analysis is valuable in the early detection of AITL and PTCL-TFH.

Leptomeningeal metastasis (LM) is a fatal complication of advanced non-small-cell lung cancer (NSCLC). The aim of this study was to evaluate the utility of cerebrospinal fluid (CSF) as a medium for epidermal growth factor receptor (EGFR) mutation testing in clinical practice. We prospectively enrolled patients with EGFR-mutant NSCLC who underwent CSF sampling for suspected LM. The supernatant of CSF after routine cytology examination was collected. The diagnosis of LM was established according to EANO-ESMO criteria. CSF and plasma cell-free DNA (cfDNA) were retrieved for EGFR mutation testing. Fifty-one patients with a median age of 62.7 years were enrolled. The median duration from initial diagnosis to CSF sampling was 23.0 months and most patients (94.1%) had received at least one EGFR-tyrosine kinase inhibitor. Adenocarcinoma cells were found in 37 CSF samples (72.5%), and 48 (94.1%) patients had confirmed or probable LM. Thirty-five of these 48 patients (72.9%) had valid EGFR mutation-testing results using CSF cfDNA and tended to have higher white blood cell counts and positive cytology in their CSF compared to those with invalid mutation testing results. The overall detection rate of EGFR mutation in CSF cfDNA was 68.8%, and the T790M detection rate was 14.6%. In 37 patients with paired CSF and plasma samples, the concordance rate of the EGFR mutation results was 29.7%. For patients with EGFR-mutant NSCLC with LM, CSF supernatant is a valuable source for EGFR mutation testing and may provide important information.

Background. Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common X-linked inherited erythroenzymopathy in Thailand. The clinical and hematological manifestations of G6PD deficiency are variable. Objective. This study aimed to characterize the genotype-phenotype correlation of G6PD mutations in Thai pediatric patients who were followed-up in Phramongkutklao Hospital, a tertiary center in central Thailand. Material and Method. A total of 102 children including 73 males (71.6%) and 29 females (28.4%) were included in our study. Mutation analysis was performed by direct DNA sequencing of all coding exons of the G6PD gene. Ninety-one patients (89.2%) were presented with neonatal hyperbilirubinemia and 11 patients (10.8%) were presented with acute hemolytic anemia beyond the neonatal period. Results. Molecular analysis of the G6PD gene in 102 G6PD-deficient Thai children identified 12 different mutations. G6PD Viangchan (871G > A) and G6PD Canton (1376G > T) were the first (46.2%) and the second (15.4%) most common identified mutations among both male and female G6PD-deficient individuals, respectively. All affected males were hemizygous for G6PD mutations and had an average G6PD level of 16.7 ± 11.5 (3–76) IU/ml.RBC. Majority of female patients (27 in 29, 93.1%) were heterozygous for G6PD mutations and had an average G6PD level of 133.6 ± 43.4 (9–195) IU/ml.RBC. Two female patients (6.9%) were either homozygous or compound heterozygous for the mutations and had G6PD level in the affected male range (35 and 10 IU/ml.RBC). Only 1 in 27 heterozygous females (3.7%) had G6PD level in the affected male range (9 IU/ml.RBC) which is possibly explained by nonrandom X-chromosome inactivation. The correlation of genotypes, G6PD levels, and clinical phenotypes was not demonstrated in our study in which all of the included G6PD-deficient patients were presented with neonatal hyperbilirubinemia and acute hemolytic anemia, since the genotype-phenotype correlation is normally demonstrated in chronic nonspherocytic hemolytic anemia (CNSHA) G6PD-deficient individuals. Conclusion. This study characterizes the molecular heterogeneity of G6PD variants causing G6PD deficiency in Thai children. Our study demonstrated the efficiency of direct DNA sequencing which can identify 12 missense mutations in Thai children.

Background Epidermolysis bullosa simplex (EBS) is a heterogeneous group of inherited disorders characterized by skin fragility due to intraepidermal separation. Most cases result from heterozygous mutations in KRT5 or KRT14; however, a minority of affected individuals carry mutations in non-keratin genes including DST encoding an epithelial isoform of dystonin. DST-associated EBS is transmitted as an autosomal recessive trait. Here, we report a series of EBS patients carrying bi-allelic DST mutations and review previously reported cases aiming to delineate phenotype-genotype correlations. Methods Whole-exome and direct sequencing were used for variant analysis. Review of previously reported cases was performed. Results Mutation analysis revealed DST mutations in five patients belonging to three families. Two variants have not been previously reported: c.7097dupA (p.Tyr2366X) and c.7429delC (p.Leu2477Serfs*13). We identified an additional six cases in the literature, bringing the total number of individuals affected with EBS due to DST variants to 11. Patients displayed distinctive phenotypes regardless of the causative variant. Conclusions The current study expands the clinical and genetic spectrum of DST-associated EBS subtype.

Background MicroRNAs (miRNAs) are non-coding regulatory molecules 18-25 nucleotides in length that act as post-transcriptional regulators of gene expression. MiRNAs affect various biological processes including carcinogenesis. Deregulation of miRNAa expression has been described in a variety of tumors including papillary thyroid carcinoma (PTC). The aim of the present study was to investigate the role of selected miRNAs in PTC and find associations between miRNA expression and the BRAF (V600E) mutation. Materials and methods The study group comprised a total of 62 patients with surgically treated PTC. The control group consisted of 30 patients with nodular goitre that were surgically treated in the same time period. The expression status of miR-146b, miR-181a, miR-187, miR-221 and miR-222 was determined using quantitative real-time PCR. BRAF mutation analysis was performed by PCR with reverse hybridization. Results MiR-146b, miR-181a, miR-187, miR-221 and miR-222 were up-regulated in PTC compared to normal thyroid gland tissue of the same patient. MiR-146b, miR-187, miR-221 and miR-222 were also up-regulated in PTC compared to nodular goitre. The recurrent tumors were statistically significantly associated with up-regulation of miR-221. The mutation V600E of BRAF gene was significantly associated with up-regulation of miR-146b and with down-regulation of miR-187. Conclusion Over-expression of selected miRNAs in PTC compared to normal thyroid gland tissue and nodular goitre was found. Moreover, miR-221 may serve as a prognostic marker as its over-expression was significantly associated with recurrent tumors.

The society's increasing reliance on web applications with the growing online market and digitization of almost every service, there is an increasing demand for better reliability, security, and interoperability of web applications. Testing becomes an integral part of improving this reliability on web applications. Despite the innumerable number of tools, techniques, methods for testing web applications, there is still scope for expansion in the code coverage of web applications. Mutation testing with its expansive potential to expose vulnerabilities of web applications took a backseat owing to its exhaustive testing cycles. Some mutation operators related to security, performance, and other non-functional attributes of web applications are presented in the current work. In the current work, a thorough analysis of various mutations operators proposed by authors towards the non-existent operators thus far is presented. An augment of 47% of operators occurred in the present work. A concise discussion on the scope of work future direction of work is presented.

The molecular basis of prostate cancer is highly heterogeneous. Our study aimed to perform the mutation analysis ofA total of 24 prostatectomy samples diagnosed with adenocarcinoma were analyzed by microarray hybridization. Also, these samples were IHC stained for EGFR, HER2, P16, and PTEN. The cases were divided into two groups based on low and high Gleason scores. All findings were compared with the clinicopathological parameters of the patients.While

Background/Purpose Occult HBV infection (OBI) could have serious clinical consequences in patients receiving immunosuppressive therapy. We aimed to investigate the prevalence of OBI in Chinese patients with autoimmune hepatitis (AIH) and to analyze its clinical and virological features. Methods 103 AIH cases were enrolled. Hepatitis B virus (HBV) serological markers were screened by chemiluminescence. HBV-DNA were detected by nest-PCR and real-time PCR. HBV genotyping and mutation analysis were performed by Sanger sequencing. Results Twenty-four out of 103 (23.30%) AIH patients had OBI as evidenced by positive HBV-DNA and negative hepatitis B surface antigen (HBsAg). HBV genotype C is the predominant genotype (57.89%), which had more amino acid (AA) substitutions in S region than that of B-genotype group (P = 0.001). The distribution of AA substitution in the ‘α’ determinant region between genotype C and B were significantly different (P = 0.042). In addition to those already reported OBI-associated AA substitutions (e.g., sG145R and sV184A), some new OBI-associated AA substitutions (e.g., sV106A, sC137* and sL176P) were found in AIH patients in our study. Three out of 24 (12.50%) OBI patients were diagnosed as decompensated cirrhosis, one patient with S deletion mutation and two patients with HBV extensive AA substitutions. Conclusions There was a higher proportion of AIH patients with OBI than the general population in China, which can be either seropositive or seronegative-OBI in AIH patients is associated with some specific AA substitutions. The presence of deletion mutations and the extent of AA substitutions in the HBV S region may have predictive clinical implications.

Test-driven development (TDD) is a popular design approach used by the developers with testing being the important software development driving factor. On the other hand, mutation testing is considered one of the most effective testing techniques. However, there is not so much research on combining these two techniques together. In this paper, we propose a novel, hybrid approach called TDD+M which combines test-driven development process together with the mutation approach. The aim was to check whether this modified approach allows the developers to write a better quality code. We verify our approach by conducting a controlled experiment and we show that it achieves better results than the sole TDD technique. The experiment involved 22 computer science students split into eight groups. Four groups (TDD+M) were using our approach, the other four (TDD) – a normal TDD process. We performed a cross-experiment by measuring the code coverage and mutation coverage for each combination (code of group X, tests from group Y). The TDD+M tests achieved better coverage on the code from TDD groups than the TDD tests on their own code (53.3% vs. 33.5% statement coverage and 64.9% vs. 37.5% mutation coverage). The TDD+M tests also found more post-release defects in the TDD code than TDD tests in the TDD+M code. The experiment showed that adding mutation into the TDD process allows the developers to provide better, stronger tests and to write a better quality code.

Granulocyte‐colony stimulating factor‐producing uterine cervical cancer is a rare aggressive disease, which may be genetically distinct from other uterine cervical cancers.

Substances with good effectiveness that intervene in specific signalling pathways have been used increasingly in recent years in the treatment of patients with advanced breast cancer, and new therapies and approaches have now been added, which actually relate to quite specific changes, such as the treatment of patients with HR+/HER2 tumours with a PIK3CA mutation. The treatment of patients with a BRCA1 or BRCA2 mutation has also been improved by the introduction of PARP inhibitors. Attempts are now being made increasingly to extend treatment indications based on molecular patterns, to identify other patients who could benefit from a treatment and to integrate the newly established treatment methods in existing therapy sequences. This review articles summarises the latest information in this connection.

Introduction Biclonal lymphoid disorders, when two distinct lymphoproliferative disorders (LPD) co-exist, are rare (incidence of 1.4%) and associated with a poor prognosis. NOTCH1 mutations occur in 10% of CLL at diagnosis, associated with a short disease-free interval and increased risk of Richter's transformation. We hypothesised that the incidence of NOTCH1 mutations in CLL with a second LPD may be increased, because the mutation occurs early in leukaemogenesis, permitting clonal divergence. Methods We identified 19 patients with biclonal LPD at diagnosis: 11 with CLL and a second LPD (group A) and 8 with a second distinct CLL (group B). NOTCH1 mutation analysis was performed and clinical outcome investigated. Results Ten of 19 (52%) were NOTCH1 mutated: 5 in group A (45%) and 5 in group B (62.5%) with a favourable clinical outcome observed among this cohort with 28.7 (range 1-99) months of follow-up. Conclusion In conclusion, we identified a significant (52%) incidence of NOTCH1 mutations in CLL in the context of biclonal LPD, associated with an indolent clinical course.

Background EGFR mutant NSCLC patients have leptomeningeal (LM) involvement in more than 9% cases. Material & methods We conducted a study evaluating the diagnostic utility of cfDNA EGFR testing in CSF using DdPCR while comparing it against MRI and CSF cytology. We also looked for known EGFR mutations in the CSF sample. These mutations were also tested in paired plasma samples. We further compared which constituent of CSF (pellet/supernatant) had better yield. Results 21 patients comprised the study. Of these 17 patients were diagnosed to have LM involvement based on conventional criteria. All modalities had 100 % specificity and positive predictive value. However, MRI and CSF cytology had a poor negative predictive value. cfDNA had the highest sensitivity (92.3 %), negative predictive value (75 %), accuracy (94.1 %), and net comparative benefit. Paired plasma samples were available for 19 patients. Primary EGFR mutation was detectable in the CSF sample in 16/19 patients; however, the plasma sample was positive only in 7/19 patients. 3 samples were negative for primary EGFR mutation in both CSF and plasma. None of the CSF samples showed positivity for T790M mutation which could however be observed in two patients in plasma samples. Both supernatant and pellet were analysed for cfDNA mutation analysis in 18/21 patients. The intraclass correlation coefficient regarding the percentage fraction tumor-derived DNA of cfDNA observed was 0.83(95 % CI 0.29 to 0.95) between both samples. Conclusion EGFR detection in CSF has a potential role in diagnosing LM involvement. T790 M resistance mutations are uncommon in CSF post first and second-generation TKIs. Both supernatant and pellet samples can be used for the extraction of cell-free DNA in CSF.

Highlights • High concordance rate in variant calls from tumor biopsies and the corresponding liquid biopsy-derived DNA sample. • ctDNA sequencing allows for unbiased characterization of molecular tumor architecture and reveal the presence of otherwise undetectable resistance-mediating tumor cell clones. • Serial ctDNA analysis allows for monitoring tumor dynamics but limited by tumor cell clonal molecular heterogeneity. • cfDNA methylation analysis using methylation-sensitive restriction enzyme-coupled ddPCR can complement cfDNA mutation scoring to broaden the spectrum of eligible patients for molecular surveillance., Background Radiology is the current standard for monitoring treatment responses in lung cancer. Limited sensitivity, exposure to ionizing radiations and related sequelae constitute some of its major limitation. Non-invasive and highly sensitive methods for early detection of treatment failures and resistance-associated disease progression would have additional clinical utility. Methods We analyzed serially collected plasma and paired tumor samples from lung cancer patients (61 with stage IV, 48 with stages I-III disease) and 61 healthy samples by means of next-generation sequencing, radiological imaging and droplet digital polymerase chain reaction (ddPCR) mutation and methylation assays. Results A 62% variant concordance between tumor-reported and circulating-free DNA (cfDNA) sequencing was observed between baseline liquid and tissue biopsies in stage IV patients. Interestingly, ctDNA sequencing allowed for the identification of resistance-mediating p.T790M mutations in baseline plasma samples for which no such mutation was observed in the corresponding tissue. Serial circulating tumor DNA (ctDNA) mutation analysis by means of ddPCR revealed a general decrease in ctDNA loads between baseline and first reassessment. Additionally, serial ctDNA analyses only recapitulated computed tomography (CT) -monitored tumor dynamics of some, but not all lesions within the same patient. To complement ctDNA variant analysis we devised a ctDNA methylation assay (methcfDNA) based on methylation-sensitive restriction enzymes. cfDNA methylation showed and area under the curve (AUC) of > 0.90 in early and late stage cases. A decrease in methcfDNA between baseline and first reassessment was reflected by a decrease in CT-derive tumor surface area, irrespective of tumor mutational status. Conclusion Taken together, our data support the use of cfDNA sequencing for unbiased characterization of the molecular tumor architecture, highlights the impact of tumor architectural heterogeneity on ctDNA-based tumor surveillance and the added value of complementary approaches such as cfDNA methylation for early detection and monitoring

Ovarian-like epithelial tumors of the testis, including serous borderline tumors, are rare entities. We report the case of a 60-year-old man with a left intratesticular mass who had a radical orchidectomy. Histologically, the tumor was identical to the ovarian counterpart showing a well-delineated cystic lesion characterized by intraluminal papillae. The papillae are lined by atypical cuboidal or ciliated cells and are associated with psammoma bodies. The tumor cells express cytokeratin 7 (CK7), cytokeratin 5-6 (CK5-6), cancer antigen 125 (CA125), estrogen (ER), progesterone (PR), Wilm’s tumor gene (WT1), paired box gene 8 (PAX8), Ber-EP4, and epithelial membrane antigen (EMA). The diagnosis of a serous borderline tumor of the testis was proposed. Mutation testing using next-generation sequencing showed a Q61K KRAS gene mutation. To the best of our knowledge, this is the second case report of a serous borderline tumor of the testis with a Q61K KRAS gene mutation.

Background Plasma cell myeloma (PCM) is a genetically heterogeneous disease. The genetic spectrum of PCM has been expanded to mutations such as KRAS, NRAS, and BRAF genes in the RAS-RAF-MAPK pathway. In this study, we have evaluated the frequency of these mutations and their significance, including baseline characteristics and clinical outcomes. Methods We explored 50 patients who were newly diagnosed with PCM between 2009 and 2012 at a single Korean institute. Clinical and laboratory parameters were gathered through careful review of medical records. Mutation analysis was carried out using DNA from the bone marrow at the time of diagnosis. Pyrosequencing was performed to detect KRAS G12V, KRAS G13D, and NRAS G61R. BRAF V600E was analyzed by allele-specific real- time PCR. Comparison of clinical and laboratory parameters was carried out according to those mutations. Results We identified 14 patients (28%) with activating mutations in the RAS-RAF-MAPK pathway (RAS/RAF mutations): KRAS (N=3), NRAS (N=4), BRAF (N=7), and both KRAS and BRAF (N=1). RAS/RAF mutations were more frequently observed in patients with complex karyotypes and showed poorer progression free survival (PFS). Specifically, the BRAF V600E mutation had a significantly negative impact on median PFS. Conclusion We first showed the frequency of RAS/RAF mutations in Korean patients with PCM. Screening of these mutations could be considered as a routine clinical test at the time of diagnosis and follow-up due to their influence on clinical outcome, as well as its potential as a therapeutic target.

Y. Sasaki, Y. Higo, S. Matsumoto and S. Kusumoto, "SBFL-Suitability: A Software Characteristic for Fault Localization," 2020 IEEE International Conference on Software Maintenance and Evolution (ICSME), Adelaide, Australia, 2020, pp. 702-706, doi: 10.1109/ICSME46990.2020.00076., 2020 IEEE International Conference on Software Maintenance and Evolution (ICSME) [28 Sept.-2 Oct. 2020, Adelaide, Australia, Australia], Spectrum-Based Fault Localization (in short, SBFL) is one of the popular techniques to localize faulty code fragments of a given program. SBFL utilizes the information about which statements are executed by each of the success or failure test cases. There are various implementation ways for the same functionality if we use high-level programming languages. The authors consider that differences in these implementation ways may affect the efficiency of localizing faults using SBFL. In this paper, we define a characteristic to what extent a program is suitable for SBFL as SBFL-Suitability, and we propose a technique for measuring SBFL-Suitability. The proposed technique generates many slightly-variant programs from a given program with Mutation Testing, and then it measures how accurately SBFL detects the changed program statements in the variant programs. We conducted an experiment to investigate how SBFL-Suitability differs depending on the differences in source code structures. As a result, we found that (1) the fewer statements in the same nesting level, the higher SBFL-Suitability tends to be, and (2) the presence of Early Return improves SBFL-Suitability.

An intraductal papillary mucinous neoplasm (IPMN) is a common pancreatic precursor lesion, and it often harbors mutations in KRAS, GNAS, and RNF43. To clarify the molecular profiles of IPMNs, we conducted mutation analysis of KRAS, GNAS, and RNF43 in 61 IPMN formalin-fixed, paraffin-embedded (FFPE) specimens. The mutation rates of codons 12, 13, and 61 in KRAS and codon 201 in GNAS were detected by Sanger sequencing. Next-generation sequencing was performed on RNF43, and the results were further verified by Sanger sequencing. We identified KRAS and GNAS mutations in 35 (57%) and 40 (66%) IPMN cases, respectively. GNAS mutations were significantly correlated with the morphologic subtype (P<0.001) and were more prevalent in the intestinal subtype (93%) than in the gastric (55%) and pancreatobiliary subtypes (44%) but were absent in the oncocytic subtype. RNF43 mutations were found in 5 cases (8%), all of which occurred in high-grade dysplasia and invasive lesions (2/5 and 3/5). All 5 cases harboring RNF43 mutations also exhibited GNAS mutations. RNF43 mutations were associated with a worse prognosis in invasive IPMN patients (P=0.002), while KRAS and GNAS mutations did not affect the prognosis of patients.

Sarcomatoid melanoma is an extremely rare pattern of malignant melanoma, and only few cases have been described throughout the literature. We herein report a case of a patient with newly diagnosed, metastatic giant sarcomatoid melanoma of the arm. The patient underwent surgical removal of the huge mass, and NGS sequencing demonstrated BRAF V600E mutation. In view of histological, immunohistochemical and molecular findings, a combined BRAF/MEK inhibitor (BRAF/MEK-i) therapy was prescribed as first line treatment. A complete response (over one year) to targeted therapy was obtained, and no adverse events have been reported. The patient maintained a full range of shoulder and elbow movements, and she is able to live independently and resume her daily activities. We therefore recommend that all patients with undifferentiated melanomas, sarcomatoid cutaneous malignancies or other mesenchymal tumours, should undergo BRAFV600E mutation testing.

Objective: Although the prognostic role of BRAFV600E mutation in papillary thyroid carcinoma (PTC) is controversial, the American Thyroid Association (ATA) includes the mutational status in their risk stratification system. To evaluate the impact of the BRAFV600E mutation status on PTC risk stratification. Subjects and methods: PTC patients attending a university-based hospital who had the analysis of the BRAFV600E mutation were included. Persistent disease was defined as the presence of biochemical or structural disease. The performance of the ATA risk stratification system on predicting persistent disease with or without the BRAFV600E mutation status information was evaluated. Results: Of the 134 patients evaluated, 44 (32.8%) carried BRAFV600E mutation. The median tumor size was 1.7 cm (P25-75 1.0-3.0), 64 (47.8%) patients had lymph node, and 11 (8.2%) distant metastases. According to the ATA risk stratification system, patients were classified as low, intermediate, and high risk in 55 (41%), 59 (44%), and 20 (14%) patients, respectively.The data on BRAFV600E mutation reclassified 12 (8.9%) patients from low to intermediate risk. After a median follow-up of 8.5 years, the prevalence of persistent disease was similar in patients with and without BRAFV600E mutation (P = 0.42). Multivariate analysis failed to demonstrate an association between the BRAFV600E mutation and persistent disease status (RR 0.96; 95%CI 0.47-1.94). Notably, none of the patients reclassified from low to intermediate risk showed persistent disease on follow-up. Conclusion: Inclusion of BRAFV600E mutational status has a limited impact on risk stratification and does not add to the prediction of outcomes in PTC patients. Arch Endocrinol Metab. 2020;64(6):751-7., SCOPUS: ar.j, info:eu-repo/semantics/published