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      The PEMDAC phase 2 study of pembrolizumab and entinostat in patients with metastatic uveal melanoma

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          Abstract

          Preclinical studies have suggested that epigenetic therapy could enhance immunogenicity of cancer cells. We report the results of the PEMDAC phase 2 clinical trial ( n = 29; NCT02697630) where the HDAC inhibitor entinostat was combined with the PD-1 inhibitor pembrolizumab in patients with metastatic uveal melanoma (UM). The primary endpoint was objective response rate (ORR), and was met with an ORR of 14%. The clinical benefit rate at 18 weeks was 28%, median progression free survival was 2.1 months and the median overall survival was 13.4 months. Toxicities were manageable, and there were no treatment-related deaths. Objective responses and/or prolonged survival were seen in patients with BAP1 wildtype tumors, and in one patient with an iris melanoma that exhibited a UV signature. Longer survival also correlated with low baseline ctDNA levels or LDH. In conclusion, HDAC inhibition and anti-PD1 immunotherapy results in durable responses in a subset of patients with metastatic UM.

          Trial registration ClinicalTrials.gov registration number: NCT02697630 (registered 3 March 2016). EudraCT registration number: 2016–002114-50.

          Abstract

          The authors report the results of the phase II PEMDAC clinical study testing the combination of the HDAC inhibitor entinostat with the anti- PD-1 antibody pembrolizumab in uveal melanoma. Low tumor burden, a wildtype BAP1 gene in the tumor or iris melanoma correlates with response and longer survival.

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          The Sequence Alignment/Map format and SAMtools

          Summary: The Sequence Alignment/Map (SAM) format is a generic alignment format for storing read alignments against reference sequences, supporting short and long reads (up to 128 Mbp) produced by different sequencing platforms. It is flexible in style, compact in size, efficient in random access and is the format in which alignments from the 1000 Genomes Project are released. SAMtools implements various utilities for post-processing alignments in the SAM format, such as indexing, variant caller and alignment viewer, and thus provides universal tools for processing read alignments. Availability: http://samtools.sourceforge.net Contact: rd@sanger.ac.uk
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            STAR: ultrafast universal RNA-seq aligner.

            Accurate alignment of high-throughput RNA-seq data is a challenging and yet unsolved problem because of the non-contiguous transcript structure, relatively short read lengths and constantly increasing throughput of the sequencing technologies. Currently available RNA-seq aligners suffer from high mapping error rates, low mapping speed, read length limitation and mapping biases. To align our large (>80 billon reads) ENCODE Transcriptome RNA-seq dataset, we developed the Spliced Transcripts Alignment to a Reference (STAR) software based on a previously undescribed RNA-seq alignment algorithm that uses sequential maximum mappable seed search in uncompressed suffix arrays followed by seed clustering and stitching procedure. STAR outperforms other aligners by a factor of >50 in mapping speed, aligning to the human genome 550 million 2 × 76 bp paired-end reads per hour on a modest 12-core server, while at the same time improving alignment sensitivity and precision. In addition to unbiased de novo detection of canonical junctions, STAR can discover non-canonical splices and chimeric (fusion) transcripts, and is also capable of mapping full-length RNA sequences. Using Roche 454 sequencing of reverse transcription polymerase chain reaction amplicons, we experimentally validated 1960 novel intergenic splice junctions with an 80-90% success rate, corroborating the high precision of the STAR mapping strategy. STAR is implemented as a standalone C++ code. STAR is free open source software distributed under GPLv3 license and can be downloaded from http://code.google.com/p/rna-star/.
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              Fast and accurate short read alignment with Burrows–Wheeler transform

              Motivation: The enormous amount of short reads generated by the new DNA sequencing technologies call for the development of fast and accurate read alignment programs. A first generation of hash table-based methods has been developed, including MAQ, which is accurate, feature rich and fast enough to align short reads from a single individual. However, MAQ does not support gapped alignment for single-end reads, which makes it unsuitable for alignment of longer reads where indels may occur frequently. The speed of MAQ is also a concern when the alignment is scaled up to the resequencing of hundreds of individuals. Results: We implemented Burrows-Wheeler Alignment tool (BWA), a new read alignment package that is based on backward search with Burrows–Wheeler Transform (BWT), to efficiently align short sequencing reads against a large reference sequence such as the human genome, allowing mismatches and gaps. BWA supports both base space reads, e.g. from Illumina sequencing machines, and color space reads from AB SOLiD machines. Evaluations on both simulated and real data suggest that BWA is ∼10–20× faster than MAQ, while achieving similar accuracy. In addition, BWA outputs alignment in the new standard SAM (Sequence Alignment/Map) format. Variant calling and other downstream analyses after the alignment can be achieved with the open source SAMtools software package. Availability: http://maq.sourceforge.net Contact: rd@sanger.ac.uk
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                Author and article information

                Contributors
                lars.ny@oncology.gu.se
                jonas.nilsson@perkins.org.au
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                27 August 2021
                27 August 2021
                2021
                : 12
                : 5155
                Affiliations
                [1 ]GRID grid.8761.8, ISNI 0000 0000 9919 9582, Sahlgrenska Cancer Center, Department of Oncology, Institute of Clinical Sciences, , University of Gothenburg and Sahlgrenska University Hospital, ; Gothenburg, Sweden
                [2 ]GRID grid.411279.8, ISNI 0000 0000 9637 455X, Department of Oncology, , Akershus University Hospital, ; Lørenskog, Norway
                [3 ]GRID grid.8761.8, ISNI 0000 0000 9919 9582, Sahlgrenska Cancer Center, Department of Surgery, Institute of Clinical Sciences, , University of Gothenburg and Sahlgrenska University Hospital, ; Gothenburg, Sweden
                [4 ]GRID grid.1012.2, ISNI 0000 0004 1936 7910, Harry Perkins Institute of Medical Research, , University of Western Australia, ; Perth, WA Australia
                [5 ]GRID grid.8761.8, ISNI 0000 0000 9919 9582, Department of Laboratory Medicine, Wallenberg Centre for Molecular and Translational Medicine, Department of Clinical Genetics and Genomics, Sahlgrenska Cancer Center, Institute of Biomedicine, , University of Gothenburg and Sahlgrenska University Hospital, ; Gothenburg, Sweden
                [6 ]GRID grid.416386.e, ISNI 0000 0004 0624 1470, Department of Oncology, , St. Erik Eye Hospital, ; Stockholm, Sweden
                [7 ]GRID grid.1649.a, ISNI 000000009445082X, Department of Clinical Immunology and Transfusion Medicine, , Sahlgrenska University Hospital, ; Gothenburg, Sweden
                [8 ]GRID grid.4514.4, ISNI 0000 0001 0930 2361, Department of Hematology Oncology and Radiation Physics, , Skåne University Hospital, and Institute of Clinical Sciences, Lund University, ; Lund, Sweden
                [9 ]GRID grid.24381.3c, ISNI 0000 0000 9241 5705, Department of Oncology, , Karolinska University Hospital, ; Stockholm, Sweden
                [10 ]GRID grid.412215.1, ISNI 0000 0004 0623 991X, Department of Oncology, , Norrlands University Hospital, ; Umeå, Sweden
                [11 ]GRID grid.412354.5, ISNI 0000 0001 2351 3333, Department of Oncology, , Uppsala University Hospital, ; Uppsala, Sweden
                Author information
                http://orcid.org/0000-0002-6543-5369
                http://orcid.org/0000-0002-5994-6699
                http://orcid.org/0000-0003-4243-0191
                http://orcid.org/0000-0003-0346-6837
                Article
                25332
                10.1038/s41467-021-25332-w
                8397717
                34453044
                0a0d9e67-5905-491a-95e7-0b1cb5909192
                © The Author(s) 2021

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 28 March 2021
                : 5 August 2021
                Funding
                Funded by: FundRef https://doi.org/10.13039/100004334, Merck (Merck & Co., Inc.);
                Funded by: FundRef https://doi.org/10.13039/501100004063, Knut och Alice Wallenbergs Stiftelse (Knut and Alice Wallenberg Foundation);
                Funded by: FundRef https://doi.org/10.13039/501100002794, Cancerfonden (Swedish Cancer Society);
                Funded by: FundRef https://doi.org/10.13039/501100004359, Vetenskapsrådet (Swedish Research Council);
                Funded by: FundRef https://doi.org/10.13039/100007436, Familjen Erling-Perssons Stiftelse (Erling-Persson Family Foundation);
                Categories
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                © The Author(s) 2021

                Uncategorized
                phase ii trials,molecular medicine,cancer genomics,cancer immunotherapy,melanoma
                Uncategorized
                phase ii trials, molecular medicine, cancer genomics, cancer immunotherapy, melanoma

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