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• PAK4 inhibition improves PD-1 blockade immunotherapy

  Introduction with rationale and aims for study Immune checkpoint blockade therapies have significantly altered the current landscape of cancer treatment. However, this immunotherapy still fails more often than it succeeds. There are now evidences that the lack of tumour infiltration by immune cells is the main mechanism of primary resistance to PD‐1 blockade therapies for cancer. It has been postulated that cancer cell‐intrinsic mechanisms may actively exclude T cells from tumours, suggesting that the finding of actionable molecules that could be inhibited to increase T cell infiltration may synergize with checkpoint inhibitor immunotherapy. With the idea of finding potential drivers of immune exclusion, we performed RNA sequencing analysis of biopsies from melanoma patients and compared the transcriptomic differences of samples that where infiltrated with those that did not have immune infiltration. Methods RNAseq analysis of gene expressions on biopsies from melanoma patients treated with checkpoint blockade were analysed. We focused on the variable of "infiltration: yes or no,", e.g. tumors that were well infiltrated by immune cells with those that kept immune cells out. Sequencing revealed a list of genes whose expression differed between the infiltrated and noninfiltrated tumors. The kinase PAK4 stood out as a good candidate for inhibition treatment in the future as it was consistently enriched in the samples without immune infiltration. To test whether immunotherapy would work better if we deleted PAK4, we first knocked out PAK4, using CRISPR‐Cas9, in the ‐resistant melanoma cell line, B16. Then they injected the melanoma cells into mice and observed that PAK4 KO tumours now responded to PD‐1 blockade. In order to elucidate whether pharmacological inhibition of PAK4 could recapitulate the results observed in the B16 PAK4 KO tumours, we obtained the PAK4 inhibitor, KPT-9274, from Karyopharm Therapeutics. Indeed, inhibiting PAK4 in combination with anti‐PD‐1 immunotherapy significantly slowed the growth of the B16 melanomas more than either drug alone. Results and Conclusions Transcriptomic analysis of melanoma tumors that were well infiltrated by immune cells with those that kept immune cells out revealed a list of genes whose expression differed between the infiltrated and non-infiltrated tumours. The result suggests that p21 activated kinase 4 (PAK4) is enriched in non-responding tumour biopsies with low T cell and dendritic cell infiltration. In addition, PAK4 decreased WNT activity, a signalling pathway that has previously been involved in immune exclusion. In mouse models, genetic deletion of PAK4 increased T cell infiltration and reversed resistance to PD‐1 blockade in a CD8 T cell-dependent manner. Furthermore, combination of with the PAK4 inhibitor, KPT-9274, improved anti‐tumour responses compared to anti‐PD‐1 alone. Therefore, high PAK4 expression is correlated with low T cell and dendritic cell infiltration and lack of response to PD‐1 blockade, which could be reversed with PAK4 inhibition. The data establish a rationale for targeting this kinase with inhibitors in combination with immune checkpoint inhibitors for patients. Future work and data that we can anticipate for this study Oncogenic signalling pathways and specially the WNT signalling pathway, have been associated with lack of immune infiltration and resistance to PD‐1 blockade therapies. Here, we show that PAK4 overcome resistance to PD‐1 blockade while significantly decreases WNT signalling activity. Therefore, it constitutes the first potential druggable target that is able to reverse oncogenic driven immune cell exclusion. However, the fully mechanism whereby PAK4 sensitizes tumours to immunotherapy remains to be fully elucidated. It is necessary to address whether PAK4 inhibition overcomes resistance through WNT signalling inhibition or if other signalling pathways are involved in the observed phenotype.

  Study phs001919

• Treatment of Pulmonary Hypertension and Sickle Cell Disease with Sildenafil Therapy (Walk-PHaSST)

  Pulmonary arterial hypertension (PAH) is a progressive condition characterized by narrowing or stiffening pulmonary arterioles resulting in increased pulmonary blood pressure and reduced delivery of oxygenated blood to the body. It is a common complication of sickle cell disease and initially presents with the symptom of shortness of breath (dyspnea) on exertion. As the condition worsens, other symptoms such as dizziness, lower extremity edema, and chest pain can develop. The drug, sildenafil, works by relaxing blood vessels in the lungs which reduces pulmonary blood pressure and allows more oxygenated blood to circulate. Increased levels of oxygenated blood allows individuals with PAH to tolerate more activity, but guidelines for using sildenafil in patients with PAH and sickle cell disease were unavailable at the time of the Walk-PHaSST trial.Participants were screened for the existence of pulmonary hypertension with a six minute walk test and a Doppler echocardiogram that assessed TRV, diastolic function, and valvular and systolic function. Subjects with TRV ≥ 2.7 m/s received further clinical evaluation for possible causes of pulmonary hypertension. Other screening data included medical history, a physical exam, and standard laboratory testing. For individuals with moderate to severe pulmonary hypertension (TRV ≥ 3.0), a cardiac catheterization was done at the baseline and week 16 data collection periods.Subjects eligible for the main intervention trial based on screening results were randomized in a 1:1 double blind fashion to receive sildenafil or placebo for 16 weeks. Subjects received 20 mg of oral sildenafil or matching placebo 3 times daily for 6 weeks, followed by 40 mg 3 times daily for 4 weeks, followed by 80 mg 3 times daily for 6 weeks, as tolerated. Participants could also receive other therapies as needed to manage sickle cell and related complications. The primary outcome measure of the trial was change in the six minute walk test, a standard indicator of a person's heart and lung function and exercise capacity, from baseline to week 16. After completing the study treatment (or placebo), participants could choose to be part of the open-label follow-up phase of the study and continue to be assessed for up to one year.The study was intended to screen about 1000 subjects and randomize 132 subjects, however it was terminated early due to the unforeseen increase in adverse events in participants treated with sildenafil as compared to placebo. When the study was stopped, 33 participants had completed the trial. Subjects continued to be monitored, but were instructed to taper sildenafil treatment over three to seven days.There was no evidence that treatment with sildenafil impacted the six minute walk distance from baseline to week 16. In addition, treatment with sildenafil appeared to increase rates of hospitalization due to sickle cell disease pain.Due to in part to the early termination of the trial, the majority of subject data was collected from the screening phase of the study (n=720), as opposed to the main intervention trial (n=74).Instructions for requesting individual-level data are available on BioData Catalyst at https://biodatacatalyst.nhlbi.nih.gov/resources/data/. Apply for data access in dbGaP. Upon approval, users may begin accessing requested data in BioData Catalyst. For questions about availability, you may contact the BioData Catalyst team at https://biodatacatalyst.nhlbi.nih.gov/contact.

  Study phs002383

• A Cancer Cell-Line Titration Series for Evaluating Somatic Classification

  Accurate detection of somatic single nucleotide variants and small insertions and deletions from DNA sequencing experiments of tumour-normal pairs is a challenging task. Tumour samples are often contaminated with normal cells confounding the available evidence for the somatic variants. Furthermore, tumours are heterogeneous so sub-clonal variants are observed at reduced allele frequencies. We present here a cell-line titration series dataset that can be used to evaluate somatic variant calling pipelines with the goal of reliably calling true somatic mutations at low allele frequencies. Cell-line DNA was mixed with matched normal DNA at 8 different ratios to generate samples with known tumour cellularities, and exome sequenced on Illumina HiSeq to depths of >300x. The data was processed with several different variant calling pipelines and verification experiments were performed to assay >1,500 somatic variant candidates using Ion Torrent PGM as an orthogonal technology. By examining the variants called at varying cellularities and depths of coverage, we show that the best performing pipelines are able to maintain a high level of precision at any cellularity. In addition, we estimate the number of true somatic variants undetected as cellularity and coverage decrease. Our cell-line titration series dataset, along with the associated verification results, is effective for this evaluation and will serve as a valuable dataset for future somatic calling algorithm development.

  Study EGAS00001001016

• Antisense long non-coding RNAs are deregulated in skin tissue of patients with systemic sclerosis

  Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of skin and multiple organs of which the pathogenesis is poorly understood. Here we studied differentially expressed coding and non-coding genes in relation to SSc pathogenesis with a specific focus on antisense non-coding RNAs. Skin biopsy-derived RNAs from fourteen early SSc patients and six healthy individuals were sequenced with ion-torrent and analysed using DEseq2. Overall, 4901 genes with a fold change >1.5 and a false discovery rate < 5% were detected in patients versus controls. Upregulated genes clustered in immunological, cell adhesion and keratin-related processes. Interestingly, 676 deregulated non-coding genes were detected, 257 of which were classified as antisense genes. Sense genes expressed opposite of these antisense genes were also deregulated in 42% of the observed sense-antisense gene pairs. The majority of the antisense genes had a similar effect sizes in an independent North American dataset with three genes (CTBP1-AS2, OTUD6B-AS1 and AGAP2-AS1) exceeding the study-wide Bonferroni-corrected ρ-value (PBonf<0.0023, Pcombined = 1.1x10-9, 1.4x10-8, 1.7x10-6, respectively). In this study, we highlight that together with coding genes, (antisense) long non-coding RNAs are deregulated in skin tissue of SSc patients suggesting a novel class of genes involved in pathogenesis of SSc.

  Study EGAS00001002751

• Transcriptome profiling (RNA-seq) of human acute leukemias

  Total RNA-seq of blasts derived from 131 adult T-ALL cases, 7 AML cases and 1 mixed myeloid/lymphoid leukemia with CpG Island Methylator Phenotype (CIMP). The other RNA-seq data used in this study has been previously published and is available at EGAD00001007581 (AML) and EGAD00001007646 (CD34+ cells).

  Dataset EGAD00001011054

• DNA methylation (MCIP-seq) of human acute leukemias and healthy donors

  MCIP-seq of 77 primary samples obtained from human acute leukemias, namely AML, T-ALL and mixed myeloid/lymphoid leukemias with CpG Island Methylator Phenotype (CIMP). Moreover, MCIP-seq of CD34+ HSPCs from 3 healthy donors is included.

  Dataset EGAD00001011052

• Dynamic human admixture histories over the past ~1,300 years at the northern Himalayan frontier

  Archaeological and paleogenomic evidence from the Tibetan Plateau and high-altitude Central Himalayas suggest biocultural connections with each other and with lowland East, Central, and South Asia. However, genetic histories at the northern frontier of the Indian Himalayas, which is geographically more proximal to Central and lowland South Asia, remain underexplored. We analyzed genome-wide data from 7 ancient (~2300 to 100 years old) and 10 present-day individuals from the northern Indian Himalayas and one ~3370-year-old individual from the Central Himalayas in Nepal. Ancient and present-day individuals from the northern Himalayas predominantly have Tibetan-related genetic ancestry, likely the source of high-altitude adaptive variants in these individuals, with substantial Steppe-related genetic ancestry that is observed in all individuals dating between ~1300 years and present day. In addition, some present-day individuals have lowland South Asian admixture. Our analyses reveal a dynamic interplay between genetic admixture and continuity in the northern Himalayas.

  Study EGAS50000001342

• Genetic_profiling_of_mucosal_melanoma

  Primary mucosal melanomas (MMs) arise from melanocytes located in mucosal membranes lining the respiratory, gastrointestinal and urogenital tracts. MMs frequently present late and have a poor prognosis; the 5-year survival rate is only 14%. MM makes up only ~1.4% of all melanomas and it is this rarity that makes knowledge of the genetic changes that contribute to its pathogenesis limited to a small number of exome/genome studies and other targeted studies. Thus to investigate the somatic alterations and mutation spectra in MM genomes, we have extracted genomic DNA from formalin-fixed, paraffin-embedded (FFPE) human MMs, and subjected them to whole exome sequencing. Given the propensity of MM to metastasize, we will also be sequencing metastatic MM lesions; primary and metastatic lesions from the same individual represent an excellent opportunity to identify potential drivers of metastasis in MM. Finally we will sequence ‘normal’ DNA from the same individual, where possible, to exclude germline variations.

  Study EGAS00001001115

• DIME study: Safety, dose-response and efficacy of treatment with Anaerobutyricum soehgenii on glucose metabolism in human subjects with metabolic syndrome

  The intestinal microbiota has been implicated in insulin resistance, although evidence regarding causality in humans is scarce. We herefore performed a phase I/II dose-finding and safety study on the effect of oral intake of the anaerobic butyrogenic Anaerobutyricum soehgenii on glucose metabolism in subjects with metabolic syndrome. We found that treatment with A. soehgenii was safe and observed an overall significant and dose-dependent increase in insulin sensitivity after 4 weeks in all treated subjects. This was accompanied by an altered microbiota composition and a change in bile acid metabolism. Finally, we show that metabolic response upon administration of A. soehgenii (defined as improved insulin sensitivity 4 weeks after A. soehgenii intake) is dependent on microbiota composition at baseline. These data in humans are promising and additional studies are needed to study long-term effects as well as modes of delivery.

  Study EGAS00001003498

• Whole Exome Sequencing Data

  This dataset includes: whole exome sequencing data for a total of 23 BCP-ALL patients - BAM files

  Dataset EGAD50000001519