Modula-2*: An extension of Modula-2 for highly parallel programs

Parallel programs should be machine-independent, i.e., independent of properties that are likely to differ from one parallel computer to the next. Extensions are described of Modula-2 for writing highly parallel, portable programs meeting these requirements. The extensions are: synchronous and asynchronous forms of forall statement; and control of the allocation of data to processors. Sample programs written with the extensions demonstrate the clarity of parallel programs when machine-dependent details are omitted. The principles of efficiently implementing the extensions on SIMD, MIMD, and MSIMD machines are discussed. The extensions are small enough to be integrated easily into other imperative languages

Latency hiding in parallel systems: a quantitative approach

In many parallel applications, network latency causes a dramatic loss in processor utilization. This paper examines software pipelining as a technique for network latency hiding. It quantifies the potential improvements with detailed,instruction-level simulations. The benchmarks used are the Livermore Loop kernels and BLAS Level 1. These were parallelized and run on the instruction-level RISC simulator DLX, extended with both a blocking and a pipelined network. Our results show that prefetch in a pipelined network improves performance by a factor of 2 to 9, provided the network has sufficient bandwidth to accept at least 10 requests per processor

Efficient parallel computation on workstation clusters

We present novel hard- and software that efficiently implements communication primitives for parallel execution on Workstation clusters. We provide low communication latencies, minimal protocol, zero operating system overhead, and high throughput. With this technology, it is possible to build effective parallel systems using off-the-shelf workstations. Our goal is to develop a standard interfaceboard and the necessary software for interfacing any number of computers, from a workstation to a cabinet full of workstation-boards

MODULA-2* and its compilation

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A Novel Approach for Quantifying the Pharmacological Activity of T-Cell Engagers Utilizing In Vitro Time Course Experiments and Streamlined Data Analysis

CD3-bispecifc antibodies are a new class of immunotherapeutic drugs against cancer. The pharmacological activity of CD3-bispecifcs is typically assessed through in vitro assays of cancer cell lines co-cultured with human peripheral blood mononuclear cells (PBMCs). Assay results depend on experimental conditions such as incubation time and the efector-to-target cell ratio, which can hinder robust quantifcation of pharmacological activity. In order to overcome these limitations, we developed a new, holistic approach for quantifcation of the in vitro dose–response relationship. Our experimental design integrates a time-independent analysis of the dose–response across diferent time points as an alternative to the static, “snap-shot” analysis based on a single time point commonly used in dose–response assays. We show that the potency values derived from staticin vitro experiments depend on the incubation time, which leads to inconsistent results across multiple assays and compounds. We compared the potency values from the time-independent analysis with a model-based approach. We fnd comparably accurate potency estimates from the model-based and time-independent analyses and that the timeindependent analysis provides a robust quantifcation of pharmacological activity. This approach may allow for an improved head-to-head comparison of diferent compounds and test systems and may prove useful for supporting frst-in-human dose selection

Ibrutinib-based therapy reinvigorates CD8 T cells compared to chemoimmunotherapy: immune-monitoring from the E1912 trial

Bruton's tyrosine kinase Inhibitors (BTKis) that target B cell receptor signaling have led to a paradigm shift in CLL treatment. BTKis have been shown to reduce abnormally high CLL-associated T cell counts and the expression of immune checkpoint receptors concomitantly with tumor reduction. However, the impact of BTKi therapy on T cell function has not been fully characterized. Here, we performed longitudinal immunophenotypic and functional analysis of pre- and on-treatment (6- and 12-months) peripheral blood samples from patients in the phase 3 E1912 trial comparing ibrutinib-rituximab to fludarabine, cyclophosphamide and rituximab (FCR). Intriguingly, we report that despite reduced overall T cell counts, higher numbers of T cells including effector CD8+ subsets at baseline and at the 6-month time-point associated with no infections and favorable progression-free survival (PFS) in the ibrutinib-rituximab arm. Assays demonstrated enhanced anti-CLL T cell killing function during ibrutinib-rituximab, including a switch from predominantly CD4+ T-cell:CLL immune synapses at baseline to increased CD8+ lytic synapses on-therapy. Conversely, in the FCR arm, higher T cell numbers correlated with adverse clinical responses and showed no functional improvement. We further demonstrate the potential of exploiting rejuvenated T cell cytotoxicity during ibrutinib-rituximab using the bispecific antibody glofitamab - supporting combination immunotherapy approaches

A RAS-Independent Biomarker Panel to Reliably Predict Response to MEK Inhibition in Colorectal Cancer

Background: In colorectal cancer (CRC), mutations of genes associated with the TGF-β/BMP signaling pathway, particularly affecting SMAD4, are known to correlate with decreased overall survival and it is assumed that this signaling axis plays a key role in chemoresistance. Methods: Using CRISPR technology on syngeneic patient-derived organoids (PDOs), we investigated the role of a loss-of-function of SMAD4 in sensitivity to MEK-inhibitors. CRISPR-engineered SMAD4R361H PDOs were subjected to drug screening, RNA-Sequencing, and multiplex protein profiling (DigiWest®). Initial observations were validated on an additional set of 62 PDOs with known mutational status. Results: We show that loss-of-function of SMAD4 renders PDOs sensitive to MEK-inhibitors. Multiomics analyses indicate that disruption of the BMP branch within the TGF-β/BMP pathway is the pivotal mechanism of increased drug sensitivity. Further investigation led to the identification of the SFAB-signature (SMAD4, FBXW7, ARID1A, or BMPR2), coherently predicting sensitivity towards MEK-inhibitors, independent of both RAS and BRAF status. Conclusion: We identified a novel mutational signature that reliably predicts sensitivity towards MEK-inhibitors, regardless of the RAS and BRAF status. This finding poses a significant step towards better-tailored cancer therapies guided by the use of molecular biomarkers