Compiler and Software Distributed Shared Memory Support for Irregular Applications

We investigate the use of a software distributed shared memory (DSM) layer to support irregular computations on distributed memory machines. Software DSM supports irregular computation through demand fetching of data in response to memory access faults. With the addition of a very limited form of compiler support, namely the identification of the section of the indirection array accessed by each processor, many of these on-demand page fetches can be aggregated into a single message, and prefetched prior to the access fault. We have measured the performance of this approach for two irregular applications, moldyn and nbf, using the Tread-Marks DSM system on an 8-processor IBM SP2. We find that it has similar performance to the inspector-executor method supported by the CHAOS run-time library, while requiring much simpler compile-time support. For moldyn, it is up to 23% faster than CHAOS, depending on the input problem's characteristics; and for nbf, it is no worse than 14% slower. If we include the execution time of the inspector, the software DSM-based approach is always faster than CHAOS. The advantage of this approach increases as the frequency of changes to the indirection array increases. The disadvantage of this approach is the potential for false sharing overhead when the data set is small or has poor spatial locality

A Portable Kernel Abstraction for Low-Overhead Ephemeral Mapping Management

Modern operating systems create ephemeral virtual-to-physical mappings for a variety of purposes, ranging from the implementation of interprocess communication to the implementation of process tracing and debugging. With succeeding generations of processors the cost of creating ephemeral mappings is increasing, particularly when an ephemeral mapping is shared by multiple processors. To reduce the cost of ephemeral mapping management within an operating system kernel, we introduce the sf_buf ephemeral mapping interface. We demonstrate how in several kernel subsystems—including pipes, memory disks, sockets, execve(), ptrace(), and the vnode pager—the current implementation can be replaced by calls to the sf_buf interface. We describe the implementation of the sf_buf interface on the 32-bit i386 architecture and the 64-bit amd64 architecture. This implementation reduces the cost of ephemeral mapping management by reusing wherever possible existing virtual-to-physical address mappings. We evaluate the sf_buf interface for the pipe, memory disk and networking subsystems. Our results show that these subsystems perform significantly better when using the sf_buf interface. On a multiprocessor platform interprocessor interrupts are greatly reduced in number or eliminated altogether

Adaptive software cache management for distributed shared memory architectures

An adaptive cache coherence mechanism exploits semantic information about the expected or observed access behavior of particular data objects. The authors contend that, in distributed shared-memory systems, adaptive cache coherence mechanisms will outperform static cache coherence mechanisms. They have examined the sharing and synchronization behavior of a variety of shared-memory parallel programs. It is found that the access patterns of a large percentage of shared data objects fall into a small number of categories for which efficient software coherence mechanisms exist. In addition, the authors have performed a simulation study that provides two examples of how an adaptive caching mechanism can take advantage of semantic information

Adaptive Protocols for Software Distributed Shared Memory

We demonstrate the benefits of software shared memory protocols that adapt at run-time to the memory access patterns observed in the applications. This adaptation is automatic, no user annotations are required, and does not rely on compiler support or special hardware. We investigate adaptation between single- and multiple-writer protocols, dynamic aggregation of pages into a larger transfer unit, and adaptation between invalidate and update. Our results indicate that adaptation between single, and multiple-writer and dynamic page aggregation are clearly beneficial. The results for the adaptation between invalid-date and update are less compelling, showing at best gains similar to the dynamic aggregation adaptation and at worst serious performance deterioration

Characterization of human mesothelin transcripts in ovarian and pancreatic cancer

BACKGROUND: Mesothelin is an attractive target for cancer immunotherapy due to its restricted expression in normal tissues and high level expression in several tumor types including ovarian and pancreatic adenocarcinomas. Three mesothelin transcript variants have been reported, but their relative expression in normal tissues and tumors has been poorly characterized. The goal of the present study was to clarify which mesothelin transcript variants are commonly expressed in human tumors. METHODS: Human genomic and EST nucleotide sequences in the public databases were used to evaluate sequences reported for the three mesothelin transcript variants in silico. Subsequently, RNA samples from normal ovary, ovarian and pancreatic carcinoma cell lines, and primary ovarian tumors were analyzed by reverse transcription-polymerase chain reaction (RT-PCR) and nucleotide sequencing to directly identify expressed transcripts. RESULTS: In silico comparisons of genomic DNA sequences with available EST sequences supported expression of mesothelin transcript variants 1 and 3, but there were no sequence matches for transcript variant 2. Newly-derived nucleotide sequences of RT-PCR products from tissues and cell lines corresponded to mesothelin transcript variant 1. Mesothelin transcript variant 2 was not detected. Transcript variant 3 was observed as a small percentage of total mesothelin amplification products from all studied cell lines and tissues. Fractionation of nuclear and cytoplasmic RNA indicated that variant 3 was present primarily in the nuclear fraction. Thus, mesothelin transcript variant 3 may represent incompletely processed hnRNA. CONCLUSION: Mesothelin transcript variant 1 represents the predominant mature mRNA species expressed by both normal and tumor cells. This conclusion should be important for future development of cancer immunotherapies, diagnostic tests, and gene microarray studies targeting mesothelin

Liquid biopsies in lung cancer: The new ambrosia of researchers

In the last decades the approach to cancer patient management has been deeply revolutionized. We are moving from a "one-fits-all" strategy to the "personalized medicine" based on the molecular characterization of the tumor. In this new era it is becoming more and more clear that the monitoring of the disease is fundamental for the success of the treatment, thus there is the need of new biomarker discovery. More precisely in the last years the scientific community has started to use the term "liquid biopsy". A liquid biopsy is a liquid biomarker that can be easily isolated from many body fluids (blood, saliva, urine, ascites, pleural effusion, etc.) and, as well as a tissue biopsy, a representative of the tissue from which it is spread. In this review we will focus our attention on circulating tumor cells, circulating tumor DNA, exosomes and secretomes with the aim to underlie their usefulness and potential application in a clinical setting for lung cancer patient management

ALK and crizotinib: After the honeymoon...what else? Resistance mechanisms and new therapies to overcome it

none13The last few decades have witnessed a silent revolution in the war against NSCLC, thanks to the discovery of "oncogenic drivers" and the subsequent development of targeted therapies. The discovery of the EML4-ALK fusion gene in a subgroup of patients with NSCLC and the subsequent clinical development of crizotinib has been an amazing success story in lung cancer translational-research, and its accelerated approval [only 4 years from the discovery of ALK rearrangement in NSCLC to the approval by the Food and Drug Administration (FDA)] marked the beginning of the new decade of targeted therapy. However, common to all targeted therapies, despite an initial benefit, patients inevitably experience tumor progression, due to the development of resistance. Several molecular mechanisms are responsible for acquired resistance, such as secondary mutations of ALK kinase domain or amplification of ALK fusion gene, or the activation of other oncogenic drivers, which may cause resistance independently of ALK genetic alterations. Pre-clinical data and early clinical trials showed the promising efficacy of a new class of ALK-inhibitors in overcoming acquired resistance. The inhibition of the molecular chaperone, HSP90, represents another promising strategy to overcome crizotinib resistance in ALK-rearranged NSCLC. Several molecules are currently under investigation in order to establish their specific role in the treatment of ALK-rearranged NSCLC.openRolfo C.; Passiglia F.; Castiglia M.; Raez L.E.; Germonpre P.; Gil-Bazo I.; Zwaenepoel K.; De Wilde A.; Bronte G.; Russo A.; Van Meerbeeck J.P.; Van Schil P.; Pauwels P.Rolfo, C.; Passiglia, F.; Castiglia, M.; Raez, L. E.; Germonpre, P.; Gil-Bazo, I.; Zwaenepoel, K.; De Wilde, A.; Bronte, G.; Russo, A.; Van Meerbeeck, J. P.; Van Schil, P.; Pauwels, P

Specification and Implementation of Dynamic Web Site Benchmarks

The absence of benchmarks for Web sites with dynamic content has been a major impediment to research in this area. We describe three benchmarks for evaluating the performance of Web sites with dynamic content. The benchmarks model three common types of dynamic content Web sites with widely varying application characteristics: an online bookstore, an auction site, and a bulletin board. For the online bookstore, we use the TPCW specification. For the auction site and the bulletin board, we provide our own specification, modeled after ebay.com and slahdot.org, respectively. For each benchmark we describe the design of the database and the interactions provided by the Web server. We have implemented these three benchmarks with a variety of methods for building dynamic-content applications, including PHP, Java servlets and EJB (Enterprise Java Beans). In all cases, we use commonly used open-source software. We also provide a client emulator that allows a dynamic content Web server to be driven with various workloads. Our implementations are available freely from our Web site for other researchers to use. These benchmarks can be used for research in dynamic Web and application server design. In this paper, we provide one example of such possible use, namely discovering the bottlenecks for applications in a particular server configuration. Other possible uses include studies of clustering and caching for dynamic content, comparison of different application implementation methods, and studying the effect of different workload characteristics on the performance of servers. With these benchmarks we hope to provide a common reference point for studies in these areas

Staining Performance of ALK and ROS1 Immunohistochemistry and Influence on Interpretation in Non–Small-Cell Lung Cancer

Selection of nonesmall-cell lung cancer patients for treatment relies on the detection of expression of anaplastic lymphoma kinase (ALK) and ROS proto-oncogene 1 (ROS1) protein by immunohistochemistry (IHC). We evaluated staining performance for different IHC protocols and laboratory characteristics, and their influence on ALK and ROS1 interpretation during external quality assessment schemes between 2015 and 2018. Participants received five formalin-fixed, paraffin-embedded cases for staining by their routine protocol, whereafter at least two pathologists scored them simultaneously under a multihead microscope and awarded a graded expert staining score (ESS) from 1 to 5 points based on staining quality. European Conformity in Vitro Diagnostic kits (such as D5F3) revealed a better ALK ESS compared with laboratory-developed tests. ESS was indifferent to the applied antibody dilution or a recent protocol change. Lower ESSs were observed for higher antibody incubation times and temperatures. ESS for various ROS1 protocols were largely similar. Overall, for both markers, ESS improved over time and for repeated external quality assessment participation but was independent of laboratory setting or experience. Except for ROS1, ESS positively correlated with laboratory accreditation. IHC stains with lower ESS correlated with increased error rates in ALK and ROS1 interpretation and analysis failures. Laboratory characteristics differently affected staining quality and interpretation, and laboratories should assess both aspects, and less common protocols need improvement in staining performanc

External Quality Assessment on Molecular Tumor Profiling with Circulating Tumor DNA-Based Methodologies Routinely Used in Clinical Pathology within the COIN Consortium

BackgroundIdentification of tumor-derived variants in circulating tumor DNA (ctDNA) has potential as a sensitive and reliable surrogate for tumor tissue-based routine diagnostic testing. However, variations in pre(analytical) procedures affect the efficiency of ctDNA recovery. Here, an external quality assessment (EQA) was performed to determine the performance of ctDNA mutation detection work flows that are used in current diagnostic settings across laboratories within the Dutch COIN consortium (ctDNA on the road to implementation in The Netherlands).MethodsAliquots of 3 high-volume diagnostic leukapheresis (DLA) plasma samples and 3 artificial reference plasma samples with predetermined mutations were distributed among 16 Dutch laboratories. Participating laboratories were requested to perform ctDNA analysis for BRAF exon 15, EGFR exon 18–21, and KRAS exon 2–3 using their regular circulating cell-free DNA (ccfDNA) analysis work flow. Laboratories were assessed based on adherence to the study protocol, overall detection rate, and overall genotyping performance.ResultsA broad range of preanalytical conditions (e.g., plasma volume, elution volume, and extraction methods) and analytical methodologies (e.g., droplet digital PCR [ddPCR], small-panel PCR assays, and next-generation sequencing [NGS]) were used. Six laboratories (38%) had a performance score of >0.90; all other laboratories scored between 0.26 and 0.80. Although 13 laboratories (81%) reached a 100% overall detection rate, the therapeutically relevant EGFR p.(S752_I759del) (69%), EGFR p.(N771_H773dup) (50%), and KRAS p.(G12C) (48%) mutations were frequently not genotyped accurately.ConclusionsDivergent (pre)analytical protocols could lead to discrepant clinical outcomes when using the same plasma samples. Standardization of (pre)analytical work flows can facilitate the implementation of reproducible liquid biopsy testing in the clinical routine