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

Predicting and Interpreting the Hofmeister Effects of Different Salts with Nucleic Bases and Aromatic Compounds Using Solubility Assay

The interaction between salts and nucleic acid bases or aromatic compounds plays an important role in noncovalent biopolymer assembly processes such as DNA and RNA helix formation and protein-nucleic acid interactions. The project determines effects of five salts contains Hofmeister ions (NaF, K.Br, KSCN, NILiCl, NILiBr) on the solubility of 11 model compounds (nucleic bases, nucleic base derivatives, and naphthalene) to experimentally quantify salt-model compound preferential interactions (chemical potential derivatives designated μ23). Values of μ23 are obtained from the derivative of the logarithm of the model compound solubility with respect to the molal concentration of salt. These data are analyzed to predict interactions of these Hofmeister salts with the five functional groups of nucleic acid bases (aromatic C and N; carbonyl O; Sp3 N, aliphatic C). The results are used to predict the interactions between Hofmeister salts and other organic compounds and effect of Hofmeister salts on nucleic acid processes

X-linked congenital adrenal hypoplasia: a case presentation

Abstract Background Most patients with congenital adrenal hypoplasia (AHC) develop symptoms during infantile and juvenile periods, with varying clinical manifestations. AHC is a disease that is easily misdiagnosed as Addison’s disease or congenital adrenal hyperplasia (CAH). There was also a significant time difference between the age at which patients developed symptoms and the age at which they were diagnosed with AHC. Most patients showed early symptoms during infantile and juvenile periods, but were diagnosed with AHC many years later. Case presentation We are currently reporting a male patient who developed systemic pigmentation at age 2 and was initially diagnosed with Addison’s disease. At 22 years of age, he experienced a slipped capital femoral epiphysis (SCFE), a disease mostly seen in adolescents aged 8–15 years, an important cause of which is endocrine disorder. Testes evaluated using color Doppler Ultrasonography suggested microcalcifications. Further genetic testing and auxiliary examinations revealed that the patient had hypogonadotropic hypogonadism (HH) and DAX-1 gene disorders, at which time he was diagnosed with AHC complicated by HH. He was given hormone replacement therapy, followed by regular outpatient review to adjust the medication. Conclusions The typical early symptoms of AHC are hyperpigmentation and ion disturbance during infantile and juvenile periods, while few patients with AHC develop puberty disorders as early symptoms. AHC is prone to being misdiagnosed as Addison’s disease, and then gradually develops the symptoms of HH in adolescence. The definitive diagnosis of AHC ultimately is based on the patient’s clinical presentation, laboratory results and genetic testing results

Syntheses, Structures, and Luminescent Properties of Dipyridylamine-Functionalized Anthracene and Its Complexes

A novel multidentate ligand with 2,2′-dipyridylamine functionalities, 1,8-bis­[4-(2,2′-dipyridylamino)­phenylacetylenyl]­anthracene (<b>1</b>), has been synthesized through a double Sonogashira coupling reaction and characterized by NMR spectroscopic, elemental, and X-ray diffraction analyses. Compound <b>1</b> can bind to either one metal center as a tetradentate ligand or two metal centers as a double-bidentate ligand. In the double-bidentate mode, the distance between the two metal centers may vary significantly. Compound <b>1</b> displays bright blue luminescence in the solid state and in solution with a quantum efficiency of 64% relative to 9,10-diphenylanthracene. While the dirhodium complex of <b>1</b> shows no luminescence, the two zinc complexes of <b>1</b> display blue luminescence with quantum efficiencies slightly lower than that of <b>1</b>. Organic light-emitting devices (OLEDs) using <b>1</b> as the emitter show a maximum current efficiency of 7 cd/A

Syntheses, Structures, and Luminescent Properties of Dipyridylamine-Functionalized Anthracene and Its Complexes

A novel multidentate ligand with 2,2′-dipyridylamine functionalities, 1,8-bis­[4-(2,2′-dipyridylamino)­phenylacetylenyl]­anthracene (<b>1</b>), has been synthesized through a double Sonogashira coupling reaction and characterized by NMR spectroscopic, elemental, and X-ray diffraction analyses. Compound <b>1</b> can bind to either one metal center as a tetradentate ligand or two metal centers as a double-bidentate ligand. In the double-bidentate mode, the distance between the two metal centers may vary significantly. Compound <b>1</b> displays bright blue luminescence in the solid state and in solution with a quantum efficiency of 64% relative to 9,10-diphenylanthracene. While the dirhodium complex of <b>1</b> shows no luminescence, the two zinc complexes of <b>1</b> display blue luminescence with quantum efficiencies slightly lower than that of <b>1</b>. Organic light-emitting devices (OLEDs) using <b>1</b> as the emitter show a maximum current efficiency of 7 cd/A

Pan-cancer proteogenomics connects oncogenic drivers to functional states

Cancer driver events refer to key genetic aberrations that drive oncogenesis; however, their exact molecular mechanisms remain insufficiently understood. Here, our multi-omics pan-cancer analysis uncovers insights into the impacts of cancer drivers by identifying their significant cis-effects and distal trans-effects quantified at the RNA, protein, and phosphoprotein levels. Salient observations include the association of point mutations and copy-number alterations with the rewiring of protein interaction networks, and notably, most cancer genes converge toward similar molecular states denoted by sequence-based kinase activity profiles. A correlation between predicted neoantigen burden and measured T cell infiltration suggests potential vulnerabilities for immunotherapies. Patterns of cancer hallmarks vary by polygenic protein abundance ranging from uniform to heterogeneous. Overall, our work demonstrates the value of comprehensive proteogenomics in understanding the functional states of oncogenic drivers and their links to cancer development, surpassing the limitations of studying individual cancer types

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

Proteogenomic Characterization Reveals Therapeutic Vulnerabilities in Lung Adenocarcinoma

To explore the biology of lung adenocarcinoma (LUAD) and identify new therapeutic opportunities, we performed comprehensive proteogenomic characterization of 110 tumors and 101 matched normal adjacent tissues (NATs) incorporating genomics, epigenomics, deep-scale proteomics, phosphoproteomics, and acetylproteomics. Multi-omics clustering revealed four subgroups defined by key driver mutations, country, and gender. Proteomic and phosphoproteomic data illuminated biology downstream of copy number aberrations, somatic mutations, and fusions and identified therapeutic vulnerabilities associated with driver events involving KRAS, EGFR, and ALK. Immune subtyping revealed a complex landscape, reinforced the association of STK11 with immune-cold behavior, and underscored a potential immunosuppressive role of neutrophil degranulation. Smoking-associated LUADs showed correlation with other environmental exposure signatures and a field effect in NATs. Matched NATs allowed identification of differentially expressed proteins with potential diagnostic and therapeutic utility. This proteogenomics dataset represents a unique public resource for researchers and clinicians seeking to better understand and treat lung adenocarcinomas

Proteogenomic and metabolomic characterization of human glioblastoma

Glioblastoma (GBM) is the most aggressive nervous system cancer. Understanding its molecular pathogenesis is crucial to improving diagnosis and treatment. Integrated analysis of genomic, proteomic, post-translational modification and metabolomic data on 99 treatment-naive GBMs provides insights to GBM biology. We identify key phosphorylation events (e.g., phosphorylated PTPN11 and PLCG1) as potential switches mediating oncogenic pathway activation, as well as potential targets for EGFR-, TP53-, and RB1-altered tumors. Immune subtypes with distinct immune cell types are discovered using bulk omics methodologies, validated by snRNA-seq, and correlated with specific expression and histone acetylation patterns. Histone H2B acetylation in classical-like and immune-low GBM is driven largely by BRDs, CREBBP, and EP300. Integrated metabolomic and proteomic data identify specific lipid distributions across subtypes and distinct global metabolic changes in IDH-mutated tumors. This work highlights biological relationships that could contribute to stratification of GBM patients for more effective treatment