Protein family annotation for the Unified Human Gastrointestinal Proteome by DPCfam clustering.

Technological advances in massively parallel sequencing have led to an exponential growth in the number of known protein sequences. Much of this growth originates from metagenomic projects producing new sequences from environmental and clinical samples. The Unified Human Gastrointestinal Proteome (UHGP) catalogue is one of the most relevant metagenomic datasets with applications ranging from medicine to biology.

T-cell receptor determinants of response to chemoradiation in locally-advanced HPV16-driven malignancies.

Background: The effect of chemoradiation on the anti-cancer immune response is being increasingly acknowledged; however, its clinical implications in treatment responses are yet to be fully understood. Human papillomavirus (HPV)-driven malignancies express viral oncogenic proteins which may serve as tumor-specific antigens and represent ideal candidates for monitoring the peripheral T-cell receptor (TCR) changes secondary to chemoradiotherapy (CRT).

Methods: We performed intra-tumoral and pre- and post-treatment peripheral TCR sequencing in a cohort of patients with locally-advanced HPV16-positive cancers treated with CRT.

Harnessing T cell exhaustion and trogocytosis to isolate patient-derived tumor-specific TCR.

To study and then harness the tumor-specific T cell dynamics after allogeneic hematopoietic stem cell transplant, we typed the frequency, phenotype, and function of lymphocytes directed against tumor-associated antigens (TAAs) in 39 consecutive transplanted patients, for 1 year after transplant. We showed that TAA-specific T cells circulated in 90% of patients but display a limited effector function associated to an exhaustion phenotype, particularly in the subgroup of patients deemed to relapse, where exhausted stem cell memory T cells accumulated. Accordingly, cancer-specific cytolytic functions were relevant only when the TAA-specific T cell receptors (TCRs) were transferred into healthy, genome-edited T cells.

Phase II trial of hypomethylating agent combined with nivolumab for acute myeloid leukaemia relapse after allogeneic haematopoietic cell transplantation-Immune signature correlates with response.

Acute myeloid leukaemia (AML) relapse after allogeneic haematopoietic cell transplantation (allo-HCT) is often driven by immune-related mechanisms and associated with poor prognosis. Immune checkpoint inhibitors combined with hypomethylating agents (HMA) may restore or enhance the graft-versus-leukaemia effect. Still, data about using this combination regimen after allo-HCT are limited.

Preexisting Immunity Drives the Response to Neoadjuvant Chemotherapy in Esophageal Adenocarcinoma.

Unlabelled: Current treatment for patients with locally advanced esophageal adenocarcinoma (EAC) is neoadjuvant chemotherapy (nCT), alone or combined with radiotherapy, before surgery. However, fewer than 30% of treated patients show a pathologic complete response to nCT, which correlates with increased 5-year survival compared with nonresponders. Understanding the mechanisms of response to nCT is pivotal to better stratify patients and inform more efficacious therapies.

DPCfam: Unsupervised protein family classification by Density Peak Clustering of large sequence datasets.

Proteins that are known only at a sequence level outnumber those with an experimental characterization by orders of magnitude. Classifying protein regions (domains) into homologous families can generate testable functional hypotheses for yet unannotated sequences. Existing domain family resources typically use at least some degree of manual curation: they grow slowly over time and leave a large fraction of the protein sequence space unclassified.

Targeting MDM2 enhances antileukemia immunity after allogeneic transplantation via MHC-II and TRAIL-R1/2 upregulation.

Patients with acute myeloid leukemia (AML) often achieve remission after allogeneic hematopoietic cell transplantation (allo-HCT) but subsequently die of relapse driven by leukemia cells resistant to elimination by allogeneic T cells based on decreased major histocompatibility complex II (MHC-II) expression and apoptosis resistance. Here we demonstrate that mouse-double-minute-2 (MDM2) inhibition can counteract immune evasion of AML. MDM2 inhibition induced MHC class I and II expression in murine and human AML cells.

Solution Structure of the BPSL1445 Protein of Reveals the SYLF Domain Three-Dimensional Fold.

The SYLF domain is an evolutionary conserved protein domain with phosphatidylinositol binding ability, whose three-dimensional structure is unknown. Here, we present the solution structure and the dynamics characterization of the SYLF domain of the bacterial BPSL1445 protein. BPSL1445 is a seroreactive antigen and a diagnostic marker of , the etiological agent of melioidosis, a severe infectious disease in the tropics.

Density Peak clustering of protein sequences associated to a Pfam clan reveals clear similarities and interesting differences with respect to manual family annotation.

Background: The identification of protein families is of outstanding practical importance for in silico protein annotation and is at the basis of several bioinformatic resources. Pfam is possibly the most well known protein family database, built in many years of work by domain experts with extensive use of manual curation. This approach is generally very accurate, but it is quite time consuming and it may suffer from a bias generated from the hand-curation itself, which is often guided by the available experimental evidence.

The Immunogenic Potential of Recurrent Cancer Drug Resistance Mutations: An Study.

Cancer somatic mutations have been identified as a source of antigens that can be targeted by cancer immunotherapy. In this work, expanding on previous studies, we analyze the HLA-presentation properties of mutations that are known to drive resistance to cancer targeted-therapies. We survey a large dataset of mutations that confer resistance to different drugs and occur in numerous genes and tumor types.

Clinical Reversion Analysis Identifies Hotspot Mutations and Predicted Neoantigens Associated with Therapy Resistance.

Reversion mutations in or are associated with resistance to PARP inhibitors and platinum. To better understand the nature of these mutations, we collated, codified, and analyzed more than 300 reversions. This identified reversion "hotspots" and "deserts" in regions encoding the and terminus, respectively, of BRCA2, suggesting that pathogenic mutations in these regions may be at higher or lower risk of reversion.

Author Correction: Extreme intratumour heterogeneity and driver evolution in mismatch repair deficient gastro-oesophageal cancer.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Extreme intratumour heterogeneity and driver evolution in mismatch repair deficient gastro-oesophageal cancer.

Mismatch repair deficient (dMMR) gastro-oesophageal adenocarcinomas (GOAs) show better outcomes than their MMR-proficient counterparts and high immunotherapy sensitivity. The hypermutator-phenotype of dMMR tumours theoretically enables high evolvability but their evolution has not been investigated. Here we apply multi-region exome sequencing (MSeq) to four treatment-naive dMMR GOAs.

Identification of single nucleotide variants using position-specific error estimation in deep sequencing data.

Background: Targeted deep sequencing is a highly effective technology to identify known and novel single nucleotide variants (SNVs) with many applications in translational medicine, disease monitoring and cancer profiling. However, identification of SNVs using deep sequencing data is a challenging computational problem as different sequencing artifacts limit the analytical sensitivity of SNV detection, especially at low variant allele frequencies (VAFs).

Methods: To address the problem of relatively high noise levels in amplicon-based deep sequencing data (e.

Genomic and Transcriptomic Determinants of Therapy Resistance and Immune Landscape Evolution during Anti-EGFR Treatment in Colorectal Cancer.

Despite biomarker stratification, the anti-EGFR antibody cetuximab is only effective against a subgroup of colorectal cancers (CRCs). This genomic and transcriptomic analysis of the cetuximab resistance landscape in 35 RAS wild-type CRCs identified associations of NF1 and non-canonical RAS/RAF aberrations with primary resistance and validated transcriptomic CRC subtypes as non-genetic predictors of benefit. Sixty-four percent of biopsies with acquired resistance harbored no genetic resistance drivers.

Microenvironmental niche divergence shapes BRCA1-dysregulated ovarian cancer morphological plasticity.

How tumor microenvironmental forces shape plasticity of cancer cell morphology is poorly understood. Here, we conduct automated histology image and spatial statistical analyses in 514 high grade serous ovarian samples to define cancer morphological diversification within the spatial context of the microenvironment. Tumor spatial zones, where cancer cell nuclei diversify in shape, are mapped in each tumor.

Structure-based analysis of CysZ-mediated cellular uptake of sulfate.

Sulfur, most abundantly found in the environment as sulfate (SO), is an essential element in metabolites required by all living cells, including amino acids, co-factors and vitamins. However, current understanding of the cellular delivery of SO at the molecular level is limited. CysZ has been described as a SO permease, but its sequence family is without known structural precedent.

Homology-Based Annotation of Large Protein Datasets.

Advances in DNA sequencing technologies have led to an increasing amount of protein sequence data being generated. Only a small fraction of this protein sequence data will have experimental annotation associated with them. Here, we describe a protocol for in silico homology-based annotation of large protein datasets that makes extensive use of manually curated collections of protein families.

The Pfam protein families database: towards a more sustainable future.

In the last two years the Pfam database (http://pfam.xfam.org) has undergone a substantial reorganisation to reduce the effort involved in making a release, thereby permitting more frequent releases.

The complexity, challenges and benefits of comparing two transporter classification systems in TCDB and Pfam.

Transport systems comprise roughly 10% of all proteins in a cell, playing critical roles in many processes. Improving and expanding their classification is an important goal that can affect studies ranging from comparative genomics to potential drug target searches. It is not surprising that different classification systems for transport proteins have arisen, be it within a specialized database, focused on this functional class of proteins, or as part of a broader classification system for all proteins.

Structure and sequence analyses of Bacteroides proteins BVU_4064 and BF1687 reveal presence of two novel predominantly-beta domains, predicted to be involved in lipid and cell surface interactions.

Background: N-terminal domains of BVU_4064 and BF1687 proteins from Bacteroides vulgatus and Bacteroides fragilis respectively are members of the Pfam family PF12985 (DUF3869). Proteins containing a domain from this family can be found in most Bacteroides species and, in large numbers, in all human gut microbiome samples. Both BVU_4064 and BF1687 proteins have a consensus lipobox motif implying they are anchored to the membrane, but their functions are otherwise unknown.

Prediction and analysis of intrinsically disordered proteins.

Intrinsically disordered proteins and protein regions (IDPs/IDRs) do not adopt a well-defined folded structure under physiological conditions. Instead, these proteins exist as heterogeneous and dynamical conformational ensembles. IDPs are widespread in eukaryotic proteomes and are involved in fundamental biological processes, mostly related to regulation and signaling.

The InterPro protein families database: the classification resource after 15 years.

The InterPro database (http://www.ebi.ac.