Elevated expression of cyclooxygenase-2 is a negative prognostic factor for overall survival in intrahepatic cholangiocarcinoma

The production of prostaglandins is regulated by cyclooxygenases (COXs), which also have a role in tumour development and progression in various human malignancies, including cholangiocarcinoma. Limited information is available of the correlation of COX-2 protein expression and prognosis in intrahepatic cholangiocarcinoma (ICC). The aim of the present study was to determine the clinical significance of COX-2 expression in ICC. In addition the correlation of COX-2 expression and apoptosis/proliferation was analysed. COX-2 expression was determined immunohistochemically in 62 resected ICCs. Proliferation was assessed using Ki67-immunohistochemistry, and apoptosis was measured with the TdT-mediated dUTP nick-end-labelling technique. COX-2 was identified as an independent prognostic factor (P = 0.028) in resected ICC by survival analysis. High levels of COX-2 expression were found to be associated both with reduced apoptosis and increased proliferation of tumour cells. This study demonstrates the independent prognostic value of the COX-2 expression in resected ICC, thus, offering a potential additional adjuvant therapeutic approach with COX-2 inhibitors

Performance of the CMS muon trigger system in proton-proton collisions at √s = 13 TeV

The muon trigger system of the CMS experiment uses a combination of hardware and software to identify events containing a muon. During Run 2 (covering 2015-2018) the LHC achieved instantaneous luminosities as high as 2 × 10 cm s while delivering proton-proton collisions at √s = 13 TeV. The challenge for the trigger system of the CMS experiment is to reduce the registered event rate from about 40 MHz to about 1 kHz. Significant improvements important for the success of the CMS physics program have been made to the muon trigger system via improved muon reconstruction and identification algorithms since the end of Run 1 and throughout the Run 2 data-taking period. The new algorithms maintain the acceptance of the muon triggers at the same or even lower rate throughout the data-taking period despite the increasing number of additional proton-proton interactions in each LHC bunch crossing. In this paper, the algorithms used in 2015 and 2016 and their improvements throughout 2017 and 2018 are described. Measurements of the CMS muon trigger performance for this data-taking period are presented, including efficiencies, transverse momentum resolution, trigger rates, and the purity of the selected muon sample. This paper focuses on the single- and double-muon triggers with the lowest sustainable transverse momentum thresholds used by CMS. The efficiency is measured in a transverse momentum range from 8 to several hundred GeV

Well-Typed Programs Can Go Wrong: A Study of Typing-Related Bugs in JVM Compilers

Despite the substantial progress in compiler testing, research endeavors have mainly focused on detecting compiler crashes and subtle miscompilations caused by bugs in the implementation of compiler optimizations. Surprisingly, this growing body of work neglects other compiler components, most notably the front-end. In statically-typed programming languages with rich and expressive type systems and modern features, such as type inference or a mix of object-oriented with functional programming features, the process of static typing in compiler front-ends is complicated by a high-density of bugs. Such bugs can lead to the acceptance of incorrect programs (breaking code portability or the type system's soundness), the rejection of correct (e.g. well-typed) programs, and the reporting of misleading errors and warnings. We conduct, what is to the best of our knowledge, the first empirical study for understanding and characterizing typing-related compiler bugs. To do so, we manually study 320 typing-related bugs (along with their fixes and test cases) that are randomly sampled from four mainstream JVM languages, namely Java, Scala, Kotlin, and Groovy. We evaluate each bug in terms of several aspects, including their symptom, root cause, bug fix's size, and the characteristics of the bug-revealing test cases. Some representative observations indicate that: (1) more than half of the typing-related bugs manifest as unexpected compile-time errors: the buggy compiler wrongly rejects semantically correct programs, (2) the majority of typing-related bugs lie in the implementations of the underlying type systems and in other core components related to operations on types, (3) parametric polymorphism is the most pervasive feature in the corresponding test cases, (4) one third of typing-related bugs are triggered by non-compilable programs. We believe that our study opens up a new research direction by driving future researchers to build appropriate methods and techniques for a more holistic testing of compilers

Well-typed programs can go wrong: A study of typing-related bugs in JVM compilers

Despite the substantial progress in compiler testing, research endeavors have mainly focused on detecting compiler crashes and subtle miscompilations caused by bugs in the implementation of compiler optimizations. Surprisingly, this growing body of work neglects other compiler components, most notably the front-end. In statically-typed programming languages with rich and expressive type systems and modern features, such as type inference or a mix of object-oriented with functional programming features, the process of static typing in compiler front-ends is complicated by a high-density of bugs. Such bugs can lead to the acceptance of incorrect programs (breaking code portability or the type system's soundness), the rejection of correct (e.g. well-typed) programs, and the reporting of misleading errors and warnings. We conduct, what is to the best of our knowledge, the first empirical study for understanding and characterizing typing-related compiler bugs. To do so, we manually study 320 typing-related bugs (along with their fixes and test cases) that are randomly sampled from four mainstream JVM languages, namely Java, Scala, Kotlin, and Groovy. We evaluate each bug in terms of several aspects, including their symptom, root cause, bug fix's size, and the characteristics of the bug-revealing test cases. Some representative observations indicate that: (1) more than half of the typing-related bugs manifest as unexpected compile-time errors: the buggy compiler wrongly rejects semantically correct programs, (2) the majority of typing-related bugs lie in the implementations of the underlying type systems and in other core components related to operations on types, (3) parametric polymorphism is the most pervasive feature in the corresponding test cases, (4) one third of typing-related bugs are triggered by non-compilable programs. We believe that our study opens up a new research direction by driving future researchers to build appropriate methods and techniques for a more holistic testing of compilers. Software Engineerin

Metallothionein overexpression and its prognostic relevance in intrahepatic cholangiocarcinoma and extrahepatic hilar cholangiocarcinoma (Klatskin tumors)

Metallothionein is a group of small molecular weight cysteine-rich proteins with a broad variety of functions. Metallothionein has been shown to regulate apoptosis and proliferation. Overexpression of metallothionein frequently occurs in human tumors and is related to prognosis as well as therapy response. However, metallothionein expression and its clinical relevance in cholangiocarcinoma have not been investigated. The present study aimed to analyze metallothionein over-expression and its possible prognostic impact in intrahepatic cholangiocarcinoma and hilar extrahepatic cholangiocarcinoma (Klatskin tumors). We investigated the relationship of immunohistochemically demonstrated metallothionein expression with various clinicopathological parameters in a series of 56 intrahepatic and 56 extrahepatic cholangiocarcinoma. In noncancerous bile duct epithelia metallothionein was only occasionally weakly expressed; strong metallothionein overexpression (>50% metallothionein -positive tumor cells) was noted in 7 (12.5%) of 56 intrahepatic cholangiocarcinoma and 14 (25%) of 56 Klatskin tumors, which was associated with poor clinical outcome in univariate Kaplan-Meier testing in both intrahepatic cholangiocarcinoma (P = .002) and Klatskin tumors (P = .034). Moreover, strong metallothionein expression was identified as an independent prognostic parameter in multivariate Cox regression analysis in both intrahepatic cholangiocarcinoma (P = .005) and Klatskin tumors (P = .035). In contrast, cholangiocarcinoma with a papillary phenotype (8/112; 7.1%) exhibited a significant lack of strong metallothionein expression in all 8 of 8 cases. Strong metallothionein expression is identified as an independent poor prognostic parameter, and determination of the metallothionein expression may serve as an additional tool for the therapeutic management of patients with cholangiocarcinoma. In comparison, lack of metallothionein expression seems to be associated with cholangiocarcinoma with a papillary phenotype, which is generally recognized to have a better prognosis

Comparison of the sixth and the seventh editions of the UICC classification for intrahepatic cholangiocarcinoma

Abstract Background The current seventh edition of the TNM classification for intrahepatic cholangiocarcinoma (ICC) includes tumor number, vascular invasion, lymph node involvement but no longer the tumor size as compared to the sixth edition. The impact of the seventh edition on stage-based prognostic prediction for patients with ICC was evaluated. Methods Between 03/2001 and 02/2013, 98 patients with the diagnosis of an ICC were surgically treated at our center. Median survival times were calculated for these patients after separate classification by both sixth and seventh editions. Results Median overall survival was increased in patients classified to the lower tumor stages I and II using the seventh as compared to the sixth edition: stage I (54.9 vs. 47.3 months), stage II (19.9 vs. 18.9 months), stage III (17.2 vs. 19.9 months), and stage IV (23.2 vs. 15.3 months), respectively. The seventh edition definition of the T category resulted in an increased median survival regarding the T1 (50.4 vs. 47.3 months) as well as the T2 category (19.9 vs. 15.6 months) and revealed a reduced median survival of patients within the T3 (21.6 vs. 24.8 months) as well as the T4 category (19.9 vs. 27.0 months). Conclusions The UICC seventh edition TNM classification for ICC improves separation of patients with intermediate stage tumors as compared to the sixth edition. The prognostic value of the UICC staging system has been improved by the seventh edition. Trial registration The data for this study have been retrospectively registered and the study has been approved by the ethic committee of the medical faculty of the University Hospital of Essen, Germany (license number 15-6353-BO)