Pseudopeptides with a centrally positioned alkene-based disulphide bridge mimetic stimulate kallikrein-related peptidase 3 activity

Peer reviewe

Comprehensive molecular characterization of adenoid cystic carcinoma reveals tumor suppressors as novel drivers and prognostic biomarkers

© 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Adenoid cystic carcinoma (ACC) is a MYB-driven head and neck malignancy with high rates of local recurrence and distant metastasis and poor long-term survival. New effective targeted therapies and clinically useful biomarkers for patient stratification are needed to improve ACC patient survival. Here, we present an integrated copy number and transcriptomic analysis of ACC to identify novel driver genes and prognostic biomarkers. A total of 598 ACCs were studied. Clinical follow-up was available from 366 patients, the largest cohort analyzed to date. Copy number losses of 1p36 (70/492; 14%) and of the tumor suppressor gene PARK2 (6q26) (85/343; 25%) were prognostic biomarkers; patients with concurrent losses (n = 20) had significantly shorter overall survival (OS) than those with one or no deletions (p < 0.0001). Deletion of 1p36 independently predicted short OS in multivariate analysis (p = 0.02). Two pro-apoptotic genes, TP73 and KIF1B, were identified as putative 1p36 tumor suppressor genes whose reduced expression was associated with poor survival and increased resistance to apoptosis. PARK2 expression was markedly reduced in tumors with 6q deletions, and PARK2 knockdown increased spherogenesis and decreased apoptosis, indicating that PARK2 is a tumor suppressor in ACC. Moreover, analysis of the global gene expression pattern in 30 ACCs revealed a transcriptomic signature associated with short OS, multiple copy number alterations including 1p36 deletions, and reduced expression of TP73. Taken together, the results indicate that TP73 and PARK2 are novel putative tumor suppressor genes and potential prognostic biomarkers in ACC. Our studies provide new important insights into the pathogenesis of ACC. The results have important implications for biomarker-driven stratification of patients in clinical trials. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.info:eu-repo/semantics/publishedVersio

An Overview of the Scala Programming Language

Scala fuses object-oriented and functional programming in a statically typed programming language. It is aimed at the construction of components and component systems. This paper gives an overview of the Scala language for readers who are familar with programming methods and programming language design

The neuroendocrine phenotype, genomic profile and therapeutic sensitivity of GEPNET cell lines

Experimental models of neuroendocrine tumour disease are scarce, and no comprehensive characterisation of existing gastroenteropancreatic neuroendocrine tumour (GEPNET) cell lines has been reported. In this study, we aimed to define the molecular characteristics and therapeutic sensitivity of these cell lines. We therefore performed immunophenotyping, copy number profiling, whole-exome sequencing and a large-scale inhibitor screening of seven GEPNET cell lines. Four cell lines, GOT1, P-STS, BON-1 and QGP-1, displayed a neuroendocrine phenotype while three others, KRJ-I, L-STS and H-STS, did not. Instead, these three cell lines were identified as lymphoblastoid. Characterisation of remaining authentic GEPNET cell lines by copy number rofiling showed that GOT1, among other chromosomal alterations, harboured losses on chromosome 18 encompassing the SMAD4 gene, while P-STS had a loss on 11q. BON-1 had a homozygous loss of CDKN2A and CDKN2B, and QGP-1 harboured amplifications of MDM2 and HMGA2. Whole-exome sequencing revealed both disease-characteristic mutations (e.g. ATRX mutation in QGP-1) and, for patient tumours, rare genetic events (e.g. TP53 mutation in P-STS, BON-1 and QGP-1). A large-scale inhibitor screening showed that cell lines from pancreatic NETs to a greater extent, when compared to small intestinal NETs, were sensitive to inhibitors of MEK. Similarly, neuroendocrine NET cells originating from the small intestine were considerably more sensitive to a group of HDAC inhibitors. Taken together, our results provide a comprehensive characterisation of GEPNET cell lines, demonstrate their relevance as neuroendocrine tumour models and explore their therapeutic sensitivity to a broad range of inhibitors

An Overview of the Scala Programming Language (2. Edition)

Scala fuses object-oriented and functional programming in a statically typed programming language. It is aimed at the construction of components and component systems. This paper gives an overview of the Scala language for readers who are familar with programming methods and programming language design

Efficient Implementation of Concurrent Programming Languages

Dissertation in Computer Science to be publicly examined in Häggsalen, Ångströmlaboratoriet, Uppsala University, on Friday, November 1, 2002 at 1:00 pm for the degree of doctor of philosophy. The examination will be conducted in English. This thesis proposes and experimentally evaluates techniques for efficient implementation of languages designed for high availability concurrent systems. This experimental evaluation has been done while developing the High Performance Erlang (HiPE) system, a native code compiler for SPARC and x86. The two main goals of the HiPE system are to provide efficient execution of Erlang programs, and to provide a research vehicle for evaluating implementation techniques for concurrent functional programming languages. The focus of the thesis is the evaluation of two techniques that enable inter-process optimization through dynamic compilation. The first technique is a fast register allocator called linear scan, and the second is a memory architecture where processes share memory. The main contributions of the thesis are: An evaluation of linear scan register allocation in a different language setting. In addition the performance of linear scan on the register poor x86 architecture is evaluated for the first time. A description of three different heap architectures (private heaps, shared heap, and a hybrid of the two), with a systematic investigation of implementation aspects and an extensive discussion on the associated performance trade-offs of the heap architectures. The description is accompanied by an experimental evaluation of the private vs. the shared heap setting. A novel approach to optimizing a concurrent program, by merging code from a sender with code from a receiver, is presented together with other methods for reducing the overhead of context switching. A description of the implementation aspects of a complete and robust native code Erlang system, which makes it possible to test compiler optimizations on real world programs

Sagonas: On Reducing Interprocess Communication Overhead

We present several different ideas for increasing the performance of highly concurrent programs in general and Erlang programs in particular. These ideas range from simple implementation tricks that reduce communication latency to more thorough code rewrites guided by inlining across process boundaries. We also briefly discuss the impact of different heap architectures on interprocess communication in general and on our proposed optimizations in particular

Separation of positive and disorganization symptoms by prolactin response to 12.5 μg intravenous TRH

Non peer reviewe

On Reducing Interprocess Communication Overhead in Concurrent Programs

We present several di#erent ideas for increasing the performance of highly concurrent programs in general and Erlang programs in particular. These ideas range from simple implementation tricks that reduce communication latency to more thorough code rewrites guided by inlining across process boundaries. We also briefly discuss the impact of different heap architectures on interprocess communication in general and on our proposed optimizations in particular