Deep Proteomic Analysis on Biobanked Paraffine-Archived Melanoma with Prognostic/Predictive Biomarker Read-Out

SIMPLE SUMMARY: Malignant melanoma is one of the most aggressive cancer types among the solid tumors; therefore, more clinically applicable protein biomarkers predicting survival and therapy response have mandatory importance, impacting patient treatment. The aim of the study was to discover new proteins in biobanked FFPE samples that relate to progression-free survival and response to targeted- and immuno-therapies in patients with melanoma. Protein expressions were detected and quantified by high-resolution mass spectrometry and were integrated with the clinical data and in-depth histopathology characterization. Sample groups with distinct protein expression profiles were connected to longer and shorter survival as well as other clinicopathologic features. In addition, key regulating proteins were assigned, as predictive of progression-free survival in immuno- and/or targeted therapy. Some of the proteins exhibited functionally important correlations to progression and therapy response, which ultimately contributes to a better understanding of melanoma pathology. ABSTRACT: The discovery of novel protein biomarkers in melanoma is crucial. Our introduction of formalin-fixed paraffin-embedded (FFPE) tumor protocol provides new opportunities to understand the progression of melanoma and open the possibility to screen thousands of FFPE samples deposited in tumor biobanks and available at hospital pathology departments. In our retrospective biobank pilot study, 90 FFPE samples from 77 patients were processed. Protein quantitation was performed by high-resolution mass spectrometry and validated by histopathologic analysis. The global protein expression formed six sample clusters. Proteins such as TRAF6 and ARMC10 were upregulated in clusters with enrichment for shorter survival, and proteins such as AIFI1 were upregulated in clusters with enrichment for longer survival. The cohort’s heterogeneity was addressed by comparing primary and metastasis samples, as well comparing clinical stages. Within immunotherapy and targeted therapy subgroups, the upregulation of the VEGFA-VEGFR2 pathway, RNA splicing, increased activity of immune cells, extracellular matrix, and metabolic pathways were positively associated with patient outcome. To summarize, we were able to (i) link global protein expression profiles to survival, and they proved to be an independent prognostic indicator, as well as (ii) identify proteins that are potential predictors of a patient’s response to immunotherapy and targeted therapy, suggesting new opportunities for precision medicine developments

The Human Melanoma Proteome Atlas—Complementing the melanoma transcriptome

The MM500 meta‐study aims to establish a knowledge basis of the tumor proteome to serve as a complement to genome and transcriptome studies. Somatic mutations and their effect on the transcriptome have been extensively characterized in melanoma. However, the effects of these genetic changes on the proteomic landscape and the impact on cellular processes in melanoma remain poorly understood. In this study, the quantitative mass‐spectrometry‐based proteomic analysis is interfaced with pathological tumor characterization, and associated with clinical data. The melanoma proteome landscape, obtained by the analysis of 505 well‐annotated melanoma tumor samples, is defined based on almost 16 000 proteins, including mutated proteoforms of driver genes. More than 50 million MS/MS spectra were analyzed, resulting in approximately 13,6 million peptide spectrum matches (PSMs). Altogether 13 176 protein‐coding genes, represented by 366 172 peptides, in addition to 52 000 phosphorylation sites, and 4 400 acetylation sites were successfully annotated. This data covers 65% and 74% of the predicted and identified human proteome, respectively. A high degree of correlation (Pearson, up to 0.54) with the melanoma transcriptome of the TCGA repository, with an overlap of 12 751 gene products, was found. Mapping of the expressed proteins with quantitation, spatiotemporal localization, mutations, splice isoforms, and PTM variants was proven not to be predicted by genome sequencing alone. The melanoma tumor molecular map was complemented by analysis of blood protein expression, including data on proteins regulated after immunotherapy. By adding these key proteomic pillars, the MM500 study expands the knowledge on melanoma disease

Patienters erfarenheter av att leva med en mekanisk hjärtpump till följd av hjärtsvikt

Bakgrund: Hjärtsvikt är en åldersrelaterad sjukdom och eftersom människor lever allt längre ökar förekomsten. Relaterat till detta kan behandlingsalternativ som en mekaniska hjärtpump i framtiden öka. För att kunna ge patienter med en mekanisk hjärtpump god vård, bör sjuksköterskan arbeta inom ramen för kärnkompetenserna, framför allt med evidensbaserad- och personcentrerad vård. Syfte: Syftet med denna litteraturstudie var att belysa patienters erfarenheter av att leva med en mekanisk hjärtpump till följd av hjärtsvikt. Metod: Denna studie var en litteraturstudie med kvalitativ design baserad på tio vetenskapliga artiklar. Databassökningarna utfördes i CINAHL och PubMed. De utvalda artiklarna kvalitetsgranskades och en innehållsanalys genomfördes för att kunna besvara studiens syfte. Resultat: Innehållsanalysen resulterade i två huvudkategorier och sju underkategorier. Huvudkategorierna var Ny fas i livet och Anpassning i vardagen. Underkategorierna var livskvalitet, sexualitet och intimitet, förändringar i livet, socialt nätverk, hanteringsstrategier, rutiner och anpassning samt acceptans. Resultatet visade att majoriteten av patienterna upplevde en bättre livskvalitet efter att ha fått en mekanisk hjärtpump, dock kände de sig inte botade och nya utmaningar framkom i det nya livet med den mekaniska hjärtpumpen. Konklusion: Resultatet visade att patienternas erfarenheter av att ha en mekanisk hjärtpump var individuella. Majoriteten av patienterna fick en bättre livskvalitet, genom stöd från sjukhuset och ett bra socialt nätverk. Det är viktigt att sjukvården arbetar personcentrerat, för att kunna ge bästa möjliga vård till patienten.Background: Heart failure is an age-related disese and while people geting older the incidence increases. Related to this a mechanical heart pump as treatment option may increase in the future. In order to give the patient with a mechanical heart assist device good care, the nurse should work within the framework of nurses core competencies, evidence-based and person-centred care. Aim: to illustrate what experiences patients have with the mechanical heart assist device related to their heart failure. Method: This study is a literature study with a qualitative design, based on ten articles. The searches was done in database, CINAHL and PubMed. The articles were analyzed to find relevant data of similarities and differences. Result: Two categories and seven subcategories where found. The categories was a new phase in life and adaption in life. The subcategories was quality of life, sexuality and intimacy, change in life, social network, managment strategies, routine and adjustments and accaptance. From these categories and subcategories it emerged that the majority of patients had a better quality of life, but that they did not feel cured, new challenges emerged in the new life with the mechanical heart assist device. Conclusion: The results of the literature study revealed that the patients’ experience of having a mechanical heart assist device was individual. The majority of patients had better quality of life through support from the healthcare staff and a good social network. It is important for the healthcare system to work person-centered, in order to provide the best possible care to the patient

Patienters erfarenheter av att leva med en mekanisk hjärtpump till följd av hjärtsvikt

Bakgrund: Hjärtsvikt är en åldersrelaterad sjukdom och eftersom människor lever allt längre ökar förekomsten. Relaterat till detta kan behandlingsalternativ som en mekaniska hjärtpump i framtiden öka. För att kunna ge patienter med en mekanisk hjärtpump god vård, bör sjuksköterskan arbeta inom ramen för kärnkompetenserna, framför allt med evidensbaserad- och personcentrerad vård. Syfte: Syftet med denna litteraturstudie var att belysa patienters erfarenheter av att leva med en mekanisk hjärtpump till följd av hjärtsvikt. Metod: Denna studie var en litteraturstudie med kvalitativ design baserad på tio vetenskapliga artiklar. Databassökningarna utfördes i CINAHL och PubMed. De utvalda artiklarna kvalitetsgranskades och en innehållsanalys genomfördes för att kunna besvara studiens syfte. Resultat: Innehållsanalysen resulterade i två huvudkategorier och sju underkategorier. Huvudkategorierna var Ny fas i livet och Anpassning i vardagen. Underkategorierna var livskvalitet, sexualitet och intimitet, förändringar i livet, socialt nätverk, hanteringsstrategier, rutiner och anpassning samt acceptans. Resultatet visade att majoriteten av patienterna upplevde en bättre livskvalitet efter att ha fått en mekanisk hjärtpump, dock kände de sig inte botade och nya utmaningar framkom i det nya livet med den mekaniska hjärtpumpen. Konklusion: Resultatet visade att patienternas erfarenheter av att ha en mekanisk hjärtpump var individuella. Majoriteten av patienterna fick en bättre livskvalitet, genom stöd från sjukhuset och ett bra socialt nätverk. Det är viktigt att sjukvården arbetar personcentrerat, för att kunna ge bästa möjliga vård till patienten.Background: Heart failure is an age-related disese and while people geting older the incidence increases. Related to this a mechanical heart pump as treatment option may increase in the future. In order to give the patient with a mechanical heart assist device good care, the nurse should work within the framework of nurses core competencies, evidence-based and person-centred care. Aim: to illustrate what experiences patients have with the mechanical heart assist device related to their heart failure. Method: This study is a literature study with a qualitative design, based on ten articles. The searches was done in database, CINAHL and PubMed. The articles were analyzed to find relevant data of similarities and differences. Result: Two categories and seven subcategories where found. The categories was a new phase in life and adaption in life. The subcategories was quality of life, sexuality and intimacy, change in life, social network, managment strategies, routine and adjustments and accaptance. From these categories and subcategories it emerged that the majority of patients had a better quality of life, but that they did not feel cured, new challenges emerged in the new life with the mechanical heart assist device. Conclusion: The results of the literature study revealed that the patients’ experience of having a mechanical heart assist device was individual. The majority of patients had better quality of life through support from the healthcare staff and a good social network. It is important for the healthcare system to work person-centered, in order to provide the best possible care to the patient

Patienters erfarenheter av att leva med en mekanisk hjärtpump till följd av hjärtsvikt

Bakgrund: Hjärtsvikt är en åldersrelaterad sjukdom och eftersom människor lever allt längre ökar förekomsten. Relaterat till detta kan behandlingsalternativ som en mekaniska hjärtpump i framtiden öka. För att kunna ge patienter med en mekanisk hjärtpump god vård, bör sjuksköterskan arbeta inom ramen för kärnkompetenserna, framför allt med evidensbaserad- och personcentrerad vård. Syfte: Syftet med denna litteraturstudie var att belysa patienters erfarenheter av att leva med en mekanisk hjärtpump till följd av hjärtsvikt. Metod: Denna studie var en litteraturstudie med kvalitativ design baserad på tio vetenskapliga artiklar. Databassökningarna utfördes i CINAHL och PubMed. De utvalda artiklarna kvalitetsgranskades och en innehållsanalys genomfördes för att kunna besvara studiens syfte. Resultat: Innehållsanalysen resulterade i två huvudkategorier och sju underkategorier. Huvudkategorierna var Ny fas i livet och Anpassning i vardagen. Underkategorierna var livskvalitet, sexualitet och intimitet, förändringar i livet, socialt nätverk, hanteringsstrategier, rutiner och anpassning samt acceptans. Resultatet visade att majoriteten av patienterna upplevde en bättre livskvalitet efter att ha fått en mekanisk hjärtpump, dock kände de sig inte botade och nya utmaningar framkom i det nya livet med den mekaniska hjärtpumpen. Konklusion: Resultatet visade att patienternas erfarenheter av att ha en mekanisk hjärtpump var individuella. Majoriteten av patienterna fick en bättre livskvalitet, genom stöd från sjukhuset och ett bra socialt nätverk. Det är viktigt att sjukvården arbetar personcentrerat, för att kunna ge bästa möjliga vård till patienten.Background: Heart failure is an age-related disese and while people geting older the incidence increases. Related to this a mechanical heart pump as treatment option may increase in the future. In order to give the patient with a mechanical heart assist device good care, the nurse should work within the framework of nurses core competencies, evidence-based and person-centred care. Aim: to illustrate what experiences patients have with the mechanical heart assist device related to their heart failure. Method: This study is a literature study with a qualitative design, based on ten articles. The searches was done in database, CINAHL and PubMed. The articles were analyzed to find relevant data of similarities and differences. Result: Two categories and seven subcategories where found. The categories was a new phase in life and adaption in life. The subcategories was quality of life, sexuality and intimacy, change in life, social network, managment strategies, routine and adjustments and accaptance. From these categories and subcategories it emerged that the majority of patients had a better quality of life, but that they did not feel cured, new challenges emerged in the new life with the mechanical heart assist device. Conclusion: The results of the literature study revealed that the patients’ experience of having a mechanical heart assist device was individual. The majority of patients had better quality of life through support from the healthcare staff and a good social network. It is important for the healthcare system to work person-centered, in order to provide the best possible care to the patient

The Human Melanoma Proteome Atlas-Complementing the melanoma transcriptome

The MM500 meta-study aims to establish a knowledge basis of the tumor proteome to serve as a complement to genome and transcriptome studies. Somatic mutations and their effect on the transcriptome have been extensively characterized in melanoma. However, the effects of these genetic changes on the proteomic landscape and the impact on cellular processes in melanoma remain poorly understood. In this study, the quantitative mass-spectrometry-based proteomic analysis is interfaced with pathological tumor characterization, and associated with clinical data. The melanoma proteome landscape, obtained by the analysis of 505 well-annotated melanoma tumor samples, is defined based on almost 16 000 proteins, including mutated proteoforms of driver genes. More than 50 million MS/MS spectra were analyzed, resulting in approximately 13,6 million peptide spectrum matches (PSMs). Altogether 13 176 protein-coding genes, represented by 366 172 peptides, in addition to 52 000 phosphorylation sites, and 4 400 acetylation sites were successfully annotated. This data covers 65% and 74% of the predicted and identified human proteome, respectively. A high degree of correlation (Pearson, up to 0.54) with the melanoma transcriptome of the TCGA repository, with an overlap of 12 751 gene products, was found. Mapping of the expressed proteins with quantitation, spatiotemporal localization, mutations, splice isoforms, and PTM variants was proven not to be predicted by genome sequencing alone. The melanoma tumor molecular map was complemented by analysis of blood protein expression, including data on proteins regulated after immunotherapy. By adding these key proteomic pillars, the MM500 study expands the knowledge on melanoma disease

The human melanoma proteome atlas—Defining the molecular pathology

The MM500 study is an initiative to map the protein levels in malignant melanoma tumor samples, focused on in‐depth histopathology coupled to proteome characterization. The protein levels and localization were determined for a broad spectrum of diverse, surgically isolated melanoma tumors originating from multiple body locations. More than 15,500 proteoforms were identified by mass spectrometry, from which chromosomal and subcellular localization was annotated within both primary and metastatic melanoma. The data generated by global proteomic experiments covered 72% of the proteins identified in the recently reported high stringency blueprint of the human proteome. This study contributes to the NIH Cancer Moonshot initiative combining detailed histopathological presentation with the molecular characterization for 505 melanoma tumor samples, localized in 26 organs from 232 patients