Although mutated HLA ligands are considered ideal cancer-specific immunotherapy targets, evidence for their presentation is lacking in hepatocellular carcinomas (HCCs). Employing a unique multi-omics ...approach comprising a neoepitope identification pipeline, we assessed exome-derived mutations naturally presented as HLA class I ligands in HCCs.
In-depth multi-omics analyses included whole exome and transcriptome sequencing to define individual patient-specific search spaces of neoepitope candidates. Evidence for the natural presentation of mutated HLA ligands was investigated through an in silico pipeline integrating proteome and HLA ligandome profiling data.
The approach was successfully validated in a state-of-the-art dataset from malignant melanoma, and despite multi-omics evidence for somatic mutations, mutated naturally presented HLA ligands remained elusive in HCCs. An analysis of extensive cancer datasets confirmed fundamental differences of tumor mutational burden in HCC and malignant melanoma, challenging the notion that exome-derived mutations contribute relevantly to the expectable neoepitope pool in malignancies with only few mutations.
This study suggests that exome-derived mutated HLA ligands appear to be rarely presented in HCCs, inter alia resulting from a low mutational burden as compared to other malignancies such as malignant melanoma. Our results therefore demand widening the target scope for personalized immunotherapy beyond this limited range of mutated neoepitopes, particularly for malignancies with similar or lower mutational burden.
Attention to queer youths' lives in their family homes often centers on their coming out experiences. These experiences are framed as negative, filled with anxiety and even trauma Valentine, G., ...Skelton, T. & Butler, R. (2003). Coming out and outcomes: Negotiating lesbian and gay identities with, and in, the family. Environment and Planning D: Society and Space, 21, 479-499; Valentine, G. & Skelton, T. (2003). Finding oneself, losing oneself: The lesbian and gay 'scene' as a paradoxical space. International Journal of Urban and Regional Research, 27, 849-866. This is not always the case as these experiences can be quite positive and even queer the rest of the family Gorman-Murray, A. (2008). Queering the family home: narratives from gay, lesbian and bisexual youth coming out in supportive family homes in Australia. Gender, Place and Culture, 15, 31-44. For many queer youths, however, coming out to family members can be characterized as neither positive nor negative. Instead, I argue that queer youth experiences in the family home are complex, involving a socio-spatial navigation and negotiation with(in) their family/home. As such, queer youth often must negotiate the closet carefully as they decide to whom, when, and in what capacity to come out. Yet, the experiences of queer youth in the household do not rest solely in coming out. Other factors and family/household arrangements add to the complexity of queer youths' living in the family home - out of the closet or not. Furthermore, this article expands the definition of family by drawing on Sedgwick's concept of the avunculate Sedgwick, E. K. (1993). Tales of the avunculate: Queer tutelage in the importance of being ernest. In E. K. Sedgwick (Ed.), Tendencies, Durham, NC: Duke University Press. I draw upon semi-structured interviews, focus groups and participant observation of LGBT/queer adolescents.
The early steps of photosynthesis involve the photoexcitation of reaction centers (RCs) and light-harvesting (LH) units. Here, we show that the historically overlooked excitonic delocalization across ...RC and LH pigments results in a redistribution of absorption amplitudes that benefits the absorption cross section of the optical bands associated with the RC of several species. While we prove that this redistribution is robust to the microscopic details of the dephasing between these units in the purple bacterium Rhodospirillum rubrum, we are able to show that the redistribution witnesses a more fragile, but persistent, coherent population dynamics which directs excitations from the LH toward the RC units under incoherent illumination and physiological conditions. Even though the redirection does not seem to affect importantly the overall efficiency in photosynthesis, stochastic optimization allows us to delineate clear guidelines and develop simple analytic expressions in order to amplify the coherent redirection in artificial nanostructures.
The rodent vibrissal-trigeminal system is one of the most widely used models for the study of somatosensation and tactile perception, but to date the field has been unable to quantify the complete ...set of mechanical input signals generated during natural whisking behavior. In this report we show that during whisking behavior of awake rats (Rattus norvegicus), the whisker will often bend out of its plane of rotation, generating sizeable mechanical (tactile) signals out of the plane. We then develop a model of whisker bending that allows us to compute the three-dimensional tactile signals at the vibrissal base during active whisking behavior. Considerable information can be lost if whisking motions are considered only in two dimensions, and we offer some suggestions for experimentalists concerned with monitoring the direction of bending. These data represent the first quantification of the physical signals transmitted to the mechanoreceptors in the follicle during active whisking behavior.
Mucosal and acral melanoma respond worse to immune checkpoint inhibitors (ICI) than cutaneous melanoma.
as well as
amplifications are supposed to be associated with hyperprogression on ICI in diverse ...cancers. We therefore investigated the response of metastatic acral and mucosal melanoma to ICI in regard to
or
amplifications and melanoma type.
We conducted a query of our melanoma registry, looking for patients with metastatic acral or mucosal melanoma treated by ICI. Whole exome sequencing, FISH and immunohistochemistry on melanoma tissue could be performed on 45 of the total cohort of 51 patients. Data were correlated with patients` responses to ICI and survival.
22 out of 51 patients had hyperprogressive disease (an increase in tumor load of >50% at the first staging). Hyperprogression occurred more often in case of
or
amplification or <1% PD-L1 positive tumor cells. Nevertheless, this association was not significant. Interestingly, the anorectal melanoma type and the presence of liver metastases were significantly associated with worse survival.
So far, we found no reliable predictive marker for patients who develop hyperprogression on ICI, specifically with regard to
or
amplifications. Nevertheless, patients with anorectal melanoma, liver metastases or melanoma with amplified
seem to have an increased risk of not benefitting from ICI.
Quality control (QC) is an important part of all NGS data analysis stages. Many available tools calculate QC metrics from different analysis steps of single sample experiments (raw reads, mapped ...reads and variant lists). Multi-sample experiments, as sequencing of tumor-normal pairs, require additional QC metrics to ensure validity of results. These multi-sample QC metrics still lack standardization. We therefore suggest a new workflow for QC of DNA sequencing of tumor-normal pairs. With this workflow well-known single-sample QC metrics and additional metrics specific for tumor-normal pairs can be calculated. The segmentation into different tools offers a high flexibility and allows reuse for other purposes. All tools produce qcML, a generic XML format for QC of -omics experiments. qcML uses quality metrics defined in an ontology, which was adapted for NGS.
All QC tools are implemented in C ++ and run both under Linux and Windows. Plotting requires python 2.7 and matplotlib. The software is available under the 'GNU General Public License version 2' as part of the ngs-bits project: https://github.com/imgag/ngs-bits.
christopher.schroeder@med.uni-tuebingen.de.
Supplementary data are available at Bioinformatics online.
The detection of somatic driver mutations by next-generation sequencing (NGS) is becoming increasingly important in the care of advanced melanoma patients. In our study, we evaluated the NGS results ...of 82 melanoma patients from clinical routine in 2017. Besides determining the tumor mutational burden (TMB) and annotation of all genetic driver alterations, we investigated their potential as a predictor for resistance to immune checkpoint inhibitors (ICI) and as a distinguishing feature between melanoma subtypes. Melanomas of unknown primary had a similar mutation pattern and TMB to cutaneous melanoma, which hints at its cutaneous origin. Besides the typical hotspot mutation in BRAF and NRAS, we frequently observed CDKN2A deletions. Acral and mucosal melanomas were dominated by CNV alterations affecting PDGFRA, KIT, CDK4, RICTOR, CCND2 and CHEK2. Uveal melanoma often had somatic SNVs in GNA11/Q and amplification of MYC in all cases. A significantly higher incidence of BRAF V600 mutations and EGFR amplifications, PTEN and TP53 deletions was found in patients with disease progression while on ICI. Thus, NGS might help to characterize melanoma subtypes more precisely and to identify possible resistance mechanisms to ICI therapy. Nevertheless, NGS based studies, including larger cohorts, are needed to support potential genetic ICI resistance mechanisms.
Follicular lymphoma (FL) is characterized genetically by a significant intraclonal diversity of rearranged immunoglobulin heavy chain (IGH) genes and a substantial cell migration activity (follicular ...trafficking). Recently, in situ follicular neoplasia (ISFN), characterized by accumulations of immunohistochemically strongly BCL2-positive, t(14;18)+ clonal B cells confined to germinal centers in reactive lymph nodes, has been identified as a precursor lesion of FL with low risk of progression to manifest FL. The extent of ongoing somatic hypermutation of rearranged IGH genes and interfollicular trafficking in ISFN is not known. In this study we performed an in depth analysis of clonal evolution and cell migration patterns in a case of pure ISFN involving multiple lymph nodes. Using laser microdissection and next generation sequencing (NGS) we documented significant intraclonal diversity of the rearranged IGH gene and extensive interfollicular migration between germinal centers of the same lymph node as well as between different lymph nodes. Furthermore, we identified N-glycosylation motifs characteristic for FL in the CDR3 region.
Metastatic uveal melanoma (UM) is a rare form of melanoma differing from cutaneous melanoma by etiology, prognosis, driver mutations, pattern of metastases and poor response rate to immune checkpoint ...inhibitors (ICI). Recently, a bispecific gp100 peptide-HLA-directed CD3 T cell engager, tebentafusp, has been approved for the treatment of HLA-A*02:01 metastatic or unresectable UM. While the treatment regime is complex with weekly administrations and close monitoring, the response rate is limited. Only a few data exist on combined ICI in UM after previous progression on tebentafusp. In this case report, we present a patient with metastatic UM who first suffered extensive progression under treatment with tebentafusp but in the following had an excellent response to combined ICI. We discuss possible interactions that could explain responsiveness to ICI after pretreatment with tebentafusp in advanced UM.
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