Serum autoantibody profiling of oral squamous cell carcinoma patients reveals NUBP2 as a potential diagnostic marker.

Introduction: Oral Squamous Cell Carcinoma (OSCC), a common malignancy of the head and neck region, is frequently diagnosed at advanced stages, necessitating the development of efficient diagnostic methods. Profiling autoantibodies generated against tumor-associated antigens have lately demonstrated a promising role in diagnosis, predicting disease course, and response to therapeutics and relapse. Methods: In the current study, we, for the first time, aimed to identify and evaluate the diagnostic value of autoantibodies in serum samples of patients with OSCC using autoantibody profiling by an immunome protein array. The utility of anti-NUBP2 antibody and tissue positivity in OSCC was further evaluated. Results and discussion: We identified a total of 53 autoantibodies with significant differential levels between OSCC and control groups, including 25 that were increased in OSCC and 28 that were decreased. These included autoantibodies against Thymidine kinase 1 (TK1), nucleotide-binding protein 2 (NUBP2), and protein pyrroline-5-carboxylate reductase 1 (PYCR1), among others. Immunohistochemical validation indicated positive staining of NUBP2 in a large majority of cases (72%). Further, analysis of OSCC data available in TCGA revealed higher NUBP2 expression correlated with better disease-free patient survival. In conclusion, the differential serum autoantibodies identified in the current study, including those for NUBP2, could be used as potential biomarkers for early diagnosis or as screening biomarkers for OSCC pending investigation in a larger cohort.

The Role of FBXW7 in Gynecologic Malignancies.

The F-Box and WD Repeat Domain Containing 7 (FBXW7) protein has been shown to regulate cellular growth and act as a tumor suppressor. This protein, also known as FBW7, hCDC4, SEL10 or hAGO, is encoded by the gene FBXW7. It is a crucial component of the Skp1-Cullin1-F-box (SCF) complex, which is a ubiquitin ligase. This complex aids in the degradation of many oncoproteins, such as cyclin E, c-JUN, c-MYC, NOTCH, and MCL1, via the ubiquitin-proteasome system (UPS). The FBXW7 gene is commonly mutated or deleted in numerous types of cancer, including gynecologic cancers (GCs). Such FBXW7 mutations are linked to a poor prognosis due to increased treatment resistance. Hence, detection of the FBXW7 mutation may possibly be an appropriate diagnostic and prognostic biomarker that plays a central role in determining suitable individualized management. Recent studies also suggest that, under specific circumstances, FBXW7 may act as an oncogene. There is mounting evidence indicating that the aberrant expression of FBXW7 is involved in the development of GCs. The aim of this review is to give an update on the role of FBXW7 as a potential biomarker and also as a therapeutic target for novel treatments, particularly in the management of GCs.

An integrated analysis of microRNAs regulating DNA damage response in triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) remains a clinical challenge due to its aggressive phenotype and limited treatment options for the patients. Many TNBC patients show an inherent defect in the DNA repair capacity primarily by acquiring germline mutations in BRCA1 and BRCA2 genes leading to Homologous Recombination Deficiency (HRD). Epigenetic modifications such as BRCA1 promoter methylation and miRNA expression targeting DNA repair pathway genes have contributed to the HRD phenotype in TNBC. Hence, we aimed to identify microRNAs that are associated with HRD status in the TCGA-BRCA project. MATERIALS AND METHODS: We implemented a miRNA prediction strategy for identifying miRNAs targeting HR pathway genes using an in silico predicted and experimentally validated list from published literature for their association with genomic instability and factors affecting HRD. In silico analysis was performed to study miRNA expression patterns regulated by DNA methylation and TMB status in the TNBC patients from TCGA-BRCA project. Finally, we analysed selected miRNA expression with immune cell infiltration pattern in the TNBC patient cohort. RESULTS: Our study identified miRNAs associated with HRD, tumour mutation burden (TMB), and immune cell infiltration. Identified miRNA signatures were associated with the miR-17 ~ 92 cluster, miR-106b ~ 25 cluster, and miR-200b ~ 429 cluster. Pathway analysis of selected miRNAs suggested their association with altered immune cell infiltration in TNBC. CONCLUSION: Our study identified 6 'HRD associated miRNAs' such as miR-106b, miR-93, miR-17, miR-20a, miR-200b, and miR-429 as novel miRNA-based signatures associated with HR deficiency in TNBC.

A network map of macrophage-stimulating protein (MSP) signaling.

Macrophage-stimulating protein (MSP), a serum-derived growth factor belonging to the plasminogen-related kringle domain family, is mainly produced by the liver and released into the blood. MSP is the only known ligand for RON ("Recepteur d'Origine Nantais", also known as MST1R), which is a member of the receptor tyrosine kinase (RTK) family. MSP is associated with many pathological conditions, including cancer, inflammation, and fibrosis. Activation of the MSP/RON system regulates main downstream signaling pathways, including phosphatidylinositol 3-kinase/ AKT serine/threonine kinase/ (PI3-K/AKT), mitogen-activated protein kinases (MAPK), c-Jun N-terminal kinase (JNK) & Focal adhesion kinase (FAK). These pathways are mainly involved in cell proliferation, survival, migration, invasion, angiogenesis & chemoresistance. In this work, we created a pathway resource of signaling events mediated by MSP/RON considering its contribution to diseases. We provide an integrated pathway reaction map of MSP/RON that is composed of 113 proteins and 26 reactions based on the curation of data from the published literature. The consolidated pathway map of MSP/RON mediated signaling events contains seven molecular associations, 44 enzyme catalysis, 24 activation/inhibition, six translocation events, 38 gene regulation events, and forty-two protein expression events. The MSP/RON signaling pathway map can be freely accessible through the WikiPathways Database URL: https://classic.wikipathways.org/index.php/Pathway:WP5353 .

Development of multiple reaction monitoring (MRM) assays to identify Brucella abortus proteins in the serum of humans and livestock.

In the present study, a targeted multiple reaction monitoring-mass spectrometry (MRM-MS) approach was developed to screen and identify protein biomarkers for brucellosis in humans and livestock. The selection of proteotypic peptides was carried out by generating in silico tryptic peptides of the Brucella proteome. Using bioinformatics analysis, 30 synthetic peptides corresponding to 10 immunodominant Brucella abortus proteins were generated. MRM-MS assays for the accurate detection of these peptides were optimized using 117 serum samples of human and livestock stratified as clinically confirmed (45), suspected (62), and control (10). Using high throughput MRM assays, transitions for four peptides were identified in several clinically confirmed and suspected human and livestock serum samples. Of these, peptide NAIYDVVTR corresponding to B. abortus proteins: BruAb2_0537 was consistently detected in the clinically confirmed serum samples of both humans and livestock with 100% specificity. To conclude, a high throughput MRM-MS-based protocol for detecting endogenous B. abortus peptides in serum samples of humans and livestock was developed. The developed protocol will help design sensitive assays to accurately diagnose brucellosis in humans and livestock. The data associated with this study are deposited in Panorama Public (https://panoramaweb.org/rNOZCy.url with ProteomeXchange ID: PXD034407).

Extraterrestrial Gynecology: Could Spaceflight Increase the Risk of Developing Cancer in Female Astronauts? An Updated Review.

Outer space is an extremely hostile environment for human life, with ionizing radiation from galactic cosmic rays and microgravity posing the most significant hazards to the health of astronauts. Spaceflight has also been shown to have an impact on established cancer hallmarks, possibly increasing carcinogenic risk. Terrestrially, women have a higher incidence of radiation-induced cancers, largely driven by lung, thyroid, breast, and ovarian cancers, and therefore, historically, they have been permitted to spend significantly less time in space than men. In the present review, we focus on the effects of microgravity and radiation on the female reproductive system, particularly gynecological cancer. The aim is to provide a summary of the research that has been carried out related to the risk of gynecological cancer, highlighting what further studies are needed to pave the way for safer exploration class missions, as well as postflight screening and management of women astronauts following long-duration spaceflight.

Cancer Stem Cells and Their Possible Implications in Cervical Cancer: A Short Review.

Cervical cancer (CC) is the fourth most common type of gynecological malignancy affecting females worldwide. Most CC cases are linked to infection with high-risk human papillomaviruses (HPV). There has been a significant decrease in the incidence and death rate of CC due to effective cervical Pap smear screening and administration of vaccines. However, this is not equally available throughout different societies. The prognosis of patients with advanced or recurrent CC is particularly poor, with a one-year relative survival rate of a maximum of 20%. Increasing evidence suggests that cancer stem cells (CSCs) may play an important role in CC tumorigenesis, metastasis, relapse, and chemo/radio-resistance, thus representing potential targets for a better therapeutic outcome. CSCs are a small subpopulation of tumor cells with self-renewing ability, which can differentiate into heterogeneous tumor cell types, thus creating a progeny of cells constituting the bulk of tumors. Since cervical CSCs (CCSC) are difficult to identify, this has led to the search for different markers (e.g., ABCG2, ITGA6 (CD49f), PROM1 (CD133), KRT17 (CK17), MSI1, POU5F1 (OCT4), and SOX2). Promising therapeutic strategies targeting CSC-signaling pathways and the CSC niche are currently under development. Here, we provide an overview of CC and CCSCs, describing the phenotypes of CCSCs and the potential of targeting CCSCs in the management of CC.

The Role of Omics Approaches to Characterize Molecular Mechanisms of Rare Ovarian Cancers: Recent Advances and Future Perspectives.

Rare ovarian cancers are ovarian cancers with an annual incidence of less than 6 cases per 100,000 women. They generally have a poor prognosis due to being delayed diagnosis and treatment. Exploration of molecular mechanisms in these cancers has been challenging due to their rarity and research efforts being fragmented across the world. Omics approaches can provide detailed molecular snapshots of the underlying mechanisms of these cancers. Omics approaches, including genomics, transcriptomics, proteomics, and metabolomics, can identify potential candidate biomarkers for diagnosis, prognosis, and screening of rare gynecological cancers and can aid in identifying therapeutic targets. The integration of multiple omics techniques using approaches such as proteogenomics can provide a detailed understanding of the molecular mechanisms of carcinogenesis and cancer progression. Further, omics approaches can provide clues towards developing immunotherapies, cancer recurrence, and drug resistance in tumors; and form a platform for personalized medicine. The current review focuses on the application of omics approaches and integrative biology to gain a better understanding of rare ovarian cancers.

UMP-CMP kinase 2 gene expression in macrophages is dependent on the IRF3-IFNAR signaling axis.

Toll-like receptors (TLRs) are highly-conserved pattern recognition receptors that mediate innate immune responses to invading pathogens and endogenous danger signals released from damaged and dying cells. Activation of TLRs trigger downstream signaling cascades, that culminate in the activation of interferon regulatory factors (IRFs), which subsequently leads to type I interferon (IFN) response. In the current study, we sought to expand the scope of gene expression changes in THP1-derived macrophages upon TLR4 activation and to identify interferon-stimulated genes. RNA-seq analysis led to the identification of several known and novel differentially expressed genes, including CMPK2, particularly in association with type I IFN signaling. We performed an in-depth characterization of CMPK2 expression, a nucleoside monophosphate kinase that supplies intracellular UTP/CTP for nucleic acid synthesis in response to type I IFN signaling in macrophages. CMPK2 was significantly induced at both RNA and protein levels upon stimulation with TLR4 ligand-LPS and TLR3 ligand-Poly (I:C). Confocal microscopy and subcellular fractionation indicated CMPK2 localization in both cytoplasm and mitochondria of THP-1 macrophages. Furthermore, neutralizing antibody-based inhibition of IFNAR receptor in THP-1 cells and BMDMs derived from IFNAR KO and IRF3 KO knockout mice further revealed that CMPK2 expression is dependent on LPS/Poly (I:C) mediated IRF3- type I interferon signaling. In summary, our findings suggest that CMPK2 is a potential interferon-stimulated gene in THP-1 macrophages and that CMPK2 may facilitate IRF3- type I IFN-dependent anti-bacterial and anti-viral roles.

LncRNA MORT (ZNF667-AS1) in Cancer-Is There a Possible Role in Gynecological Malignancies?

Gynecological cancers (GCs) are currently among the major threats to female health. Moreover, there are different histologic subtypes of these cancers, which are defined as 'rare' due to an annual incidence of <6 per 100,000 women. The majority of these tend to be associated with a poor prognosis. Long non-coding RNAs (lncRNAs) play a critical role in the normal development of organisms as well as in tumorigenesis. LncRNAs can be classified into tumor suppressor genes or oncogenes, depending on their function within the cellular context and the signaling pathways in which they are involved. These regulatory RNAs are potential therapeutic targets for cancer due to their tissue and tumor specificity. However, there still needs to be a deeper understanding of the mechanisms by which lncRNAs are involved in the regulation of numerous biological functions in humans, both in normal health and disease. The lncRNA Mortal Obligate RNA Transcript (MORT; alias ZNF667-AS1) has been identified as a tumor-related lncRNA. ZNF667-AS1 gene, located in the human chromosome region 19q13.43, has been shown to be silenced by DNA hypermethylation in several cancers. In this review, we report on the biological functions of ZNF667-AS1 from recent studies and describe the regulatory functions of ZNF667-AS1 in human disease, including cancer. Furthermore, we discuss the emerging insights into the potential role of ZNF667-AS1 as a biomarker and novel therapeutic target in cancer, including GCs (ovarian, cervical, and endometrial cancers).

Comparative Proteomic Analysis Reveals Varying Impact on Immune Responses in Phorbol 12-Myristate-13-Acetate-Mediated THP-1 Monocyte-to-Macrophage Differentiation.

Macrophages are sentinels of the innate immune system, and the human monocytic cell line THP-1 is one of the widely used in vitro models to study inflammatory processes and immune responses. Several monocyte-to-macrophage differentiation protocols exist, with phorbol 12-myristate-13-acetate (PMA) being the most commonly used and accepted method. However, the concentrations and duration of PMA treatment vary widely in the published literature and could affect the probed phenotype, however their effect on protein expression is not fully deciphered. In this study, we employed a dimethyl labeling-based quantitative proteomics approach to determine the changes in the protein repertoire of macrophage-like cells differentiated from THP-1 monocytes by three commonly used PMA-based differentiation protocols. Employing an integrated network analysis, we show that variations in PMA concentration and duration of rest post-stimulation result in downstream differences in the protein expression and cellular signaling processes. We demonstrate that these differences result in altered inflammatory responses, including variation in the expression of cytokines upon stimulation with various Toll-like receptor (TLR) agonists. Together, these findings provide a valuable resource that significantly expands the knowledge of protein expression dynamics with one of the most common in vitro models for macrophages, which in turn has a profound impact on the immune as well as inflammatory responses being studied.

Molecular alterations in oral cancer between tobacco chewers and smokers using serum proteomics.

BACKGROUND: Tobacco exposure (through smoking or chewing) is one of the predominant risk factors associated with the development of oral squamous cell carcinoma (OSCC). Despite the growing number of patients diagnosed with OSCC, there are few circulating biomarkers for identifying individuals at a higher risk of developing the disease. Successful identification of candidate molecular markers for risk assessment could aid in the early detection of oral lesions and potentially be used for community screening of high-risk populations. OBJECTIVE: Identification of differentially expressed proteins in the serum of oral cancer patients which can serve as biomarkers for the diagnosis of the onset of oral cancer among tobacco users. METHODS: We employed a tandem mass tag (TMT)-based quantitative proteomics approach to study alterations in the serum proteomes of OSCC patients based on their tobacco exposure habits (chewing and smoking) compared to healthy individuals with no history of using any form of tobacco or any symptoms of the disease. RESULTS: Mass spectrometry-based analysis resulted in the identification of distinct signatures in the serum of OSCC patients who either chewed or smoked tobacco. Pathway analysis revealed opposing effects of dysregulated proteins enriched in the complement-coagulation signaling cascades with a high expression of the Serpin family of proteins observed in OSCC patients who chewed tobacco compared to healthy individuals whereas these proteins showed decreased levels in OSCC patients who smoked. ELISA-based validation further confirmed our findings revealing higher expression of SERPINA6 and SERPINF1 across serum of OSCC patients who chewed tobacco compared to healthy individuals. CONCLUSIONS: This study serves as a benchmark for the identification of serum-based protein markers that may aid in the identification of high-risk patients who either chew tobacco or smoke tobacco.

Analysis of Intra-Tumoral Macrophages and T Cells in Non-Small Cell Lung Cancer (NSCLC) Indicates a Role for Immune Checkpoint and CD200-CD200R Interactions.

Non-small cell lung carcinoma (NSCLC) is one of the most commonly diagnosed cancers and a leading cause of cancer-related deaths. Immunotherapy with immune checkpoint inhibitors shows beneficial responses, but only in a proportion of patients. To improve immunotherapy in NSCLC, we need to map the immune checkpoints that contribute immunosuppression in NSCLC-associated immune cells and to identify novel pathways that regulate immunosuppression. Here, we investigated the gene expression profiles of intra-tumoral immune cells isolated from NSCLC patients and compared them to the expression profiles of their counterparts in adjacent healthy tissue. Transcriptome analysis was performed on macrophages, CD4+ and CD8+ T cells. The data was subjected to Gene Ontology (GO) term enrichment and weighted correlation network analysis in order to identify mediators of immunosuppression in the tumor microenvironment in NSCLC. Immune cells from NSCLC revealed a consistent differential expression of genes involved in interactions between myeloid cells and lymphocytes. We further identified several immunosuppressive molecules and pathways that may be activated in tumor-associated macrophages in NSCLC. Importantly, we report novel data on immune cell expression of the newly described CD200/CD200R1 pathway, and the leukocyte immunoglobulin-like receptors (LILRs), which may represent novel innate immune checkpoints, dampening the anti-tumor T cell immune response in NSCLC. Our study substantiates the importance of tumor-associated macrophages as a mediator of immunosuppression and a promising target for immunotherapy.

Molecular alterations in oral cancer using high-throughput proteomic analysis of formalin-fixed paraffin-embedded tissue.

Loss of cell differentiation is a hallmark for the progression of oral squamous cell carcinoma (OSCC). Archival Formalin-Fixed Paraffin-Embedded (FFPE) tissues constitute a valuable resource for studying the differentiation of OSCC and can offer valuable insights into the process of tumor progression. In the current study, we performed LC-MS/MS-based quantitative proteomics of FFPE specimens from pathologically-confirmed well-differentiated, moderately-differentiated, and poorly-differentiated OSCC cases. The data were analyzed in four technical replicates, resulting in the identification of 2376 proteins. Of these, 141 and 109 were differentially expressed in moderately-differentiated and poorly differentiated OSCC cases, respectively, compared to well-differentiated OSCC. The data revealed significant metabolic reprogramming with respect to lipid metabolism and glycolysis with proteins belonging to both these processes downregulated in moderately-differentiated OSCC when compared to well-differentiated OSCC. Signaling pathway analysis indicated the alteration of extracellular matrix organization, muscle contraction, and glucose metabolism pathways across tumor grades. The extracellular matrix organization pathway was upregulated in moderately-differentiated OSCC and downregulated in poorly differentiated OSCC, compared to well-differentiated OSCC. PADI4, an epigenetic enzyme transcriptional regulator, and its transcriptional target HIST1H1B were both found to be upregulated in moderately differentiated and poorly differentiated OSCC, indicating epigenetic events underlying tumor differentiation. In conclusion, the findings support the advantage of using high-resolution mass spectrometry-based FFPE archival blocks for clinical and translational research. The candidate signaling pathways identified in the study could be used to develop potential therapeutic targets for OSCC.

The Proteomic Landscape of Resting and Activated CD4+ T Cells Reveal Insights into Cell Differentiation and Function.

CD4+ T cells (T helper cells) are cytokine-producing adaptive immune cells that activate or regulate the responses of various immune cells. The activation and functional status of CD4+ T cells is important for adequate responses to pathogen infections but has also been associated with auto-immune disorders and survival in several cancers. In the current study, we carried out a label-free high-resolution FTMS-based proteomic profiling of resting and T cell receptor-activated (72 h) primary human CD4+ T cells from peripheral blood of healthy donors as well as SUP-T1 cells. We identified 5237 proteins, of which significant alterations in the levels of 1119 proteins were observed between resting and activated CD4+ T cells. In addition to identifying several known T-cell activation-related processes altered expression of several stimulatory/inhibitory immune checkpoint markers between resting and activated CD4+ T cells were observed. Network analysis further revealed several known and novel regulatory hubs of CD4+ T cell activation, including IFNG, IRF1, FOXP3, AURKA, and RIOK2. Comparison of primary CD4+ T cell proteomic profiles with human lymphoblastic cell lines revealed a substantial overlap, while comparison with mouse CD+ T cell data suggested interspecies proteomic differences. The current dataset will serve as a valuable resource to the scientific community to compare and analyze the CD4+ proteome.

A comprehensive pathway map of IL-18-mediated signalling.

Interleukin-18 (IL-18) is a member of the IL-1 family of cytokines and was initially described as an IFN-γ-inducing factor derived from anti-CD3-stimulated T-helper (Th)1 cells. IL-18 plays a significant role in the activation of hematopoietic cell types mediating both Th1 and Th2 responses and is the primary inducer of interferon-γ in these cells. The biological activity of IL-18 is mediated through its binding to the IL-18 receptor complex and activation of nuclear factor-κB (NF-κB), culminating in the production and release of several cytokines, chemokines, and cellular adhesion molecules. In certain cell types, IL-18 also activates mitogen-activated protein kinases (MAPKs) and phosphoinositide 3-kinase/ AKT serine/threonine kinase (PI3K/AKT) signaling modules leading to the production and release of proinflammatory cytokines. IL-18-mediated signaling acts as one of the vital components of the immunomodulatory cytokine networks involved in host defense, inflammation, and tissue regeneration. Albeit its biomedical importance, a comprehensive resource of IL-18 mediated signaling pathway is currently lacking. In this study, we report on the development of an integrated pathway map of IL-18/IL-18R signaling. The pathway map was developed through literature mining from published literature based on manual curation guidelines adapted from NetPath and includes information on 16 protein-protein interaction events, 38 enzyme-catalysis events, 12 protein translocation events, 26 activations/inhibition events, transcriptional regulators, 230 gene regulation events and 84 induced protein expression events. The IL-18 signaling pathway can be freely accessed through the WikiPathways database (https://www.wikipathways.org/index.php/Pathway:WP4754).

Omics data-driven analysis identifies laminin-integrin-mediated signaling pathway as a determinant for cell differentiation in oral squamous cell carcinoma.

BACKGROUND: In recent years, high-throughput omics technologies have been widely used globally to identify potential biomarkers and therapeutic targets in various cancers. However, apart from large consortiums such as The Cancer Genome Atlas, limited attempts have been made to mine existing datasets pertaining to cancers. METHODS AND RESULTS: In the current study, we used an omics data analysis approach wherein publicly available protein expression data were integrated to identify functionally important proteins that revealed consistent dysregulated expression in head and neck squamous cell carcinomas. Our analysis revealed members of the integrin family of proteins to be consistently altered in expression across disparate datasets. Additionally, through association evidence and network analysis, we also identified members of the laminin family to be significantly altered in head and neck cancers. Members of both integrin and laminin families are known to be involved in cell-extracellular matrix adhesion and have been implicated in tumor metastatic processes in several cancers. To this end, we carried out immunohistochemical analyses to validate the findings in a cohort (n = 50) of oral cancer cases. Laminin-111 expression (composed of LAMA1, LAMB1, and LAMC1) was found to correlate with cell differentiation in oral cancer, showing a gradual decrease from well differentiated to poorly differentiated cases. CONCLUSION: This study serves as a proof-of-principle for the mining of multiple omics datasets coupled with selection of functionally important group of molecules to provide novel insights into tumorigenesis and cancer progression.

Dissecting Alzheimer's Disease Molecular Substrates by Proteomics and Discovery of Novel Post-translational Modifications.

Alzheimer's disease (AD) is a common complex disease and a major public health burden in both developed and developing countries. Postgenomic technologies such as proteomics and intelligent mining of multi-omics Big Data offer new prospects for diagnostics and therapeutics innovation for AD. In this context, it is noteworthy that mass spectrometry (MS) data are often searched against proteomics databases to unravel the identity of protein biomarkers. In contrast, only a fraction of the MS data can be matched to known proteins, while a large portion of such raw data remains underutilized. Furthermore, the spectral data can be mined for multiple high-confidence post-translational modifications (PTMs) without a priori enrichment. Thus, AD research stands to gain by greater attention to the biological mechanisms regulated by PTMs. Protein modifications may serve as diagnostic biomarkers or as novel molecular targets for drug discovery. We report here novel PTMs discovered in relation to the AD from MS/MS-based proteomic datasets. Publicly available label-free proteomics data were searched for select PTMs using SEQUEST-HT. Only high-confidence PTMs were analyzed using bioinformatics analysis. We identified 4961 unique modified peptides corresponding to 1856 proteins from AD datasets. Of these, 52 proteins were known to be involved in Alzheimer's pathway. Importantly, 3164 PTMs reported in this study are novel in the context of AD. Furthermore, protein quantification revealed expression of 13 high-abundant secretary proteins across multiple studies, which can be potentially harnessed in the future to develop biomarkers. In summary, this study identifies novel PTMs which might help develop new insights on the molecular substrates of AD and thus inform future development of novel diagnostics and treatments for this highly prevalent disease.

Dynamics of Dual Specificity Phosphatases and Their Interplay with Protein Kinases in Immune Signaling.

Dual specificity phosphatases (DUSPs) have a well-known role as regulators of the immune response through the modulation of mitogen-activated protein kinases (MAPKs). Yet the precise interplay between the various members of the DUSP family with protein kinases is not well understood. Recent multi-omics studies characterizing the transcriptomes and proteomes of immune cells have provided snapshots of molecular mechanisms underlying innate immune response in unprecedented detail. In this study, we focus on deciphering the interplay between members of the DUSP family with protein kinases in immune cells using publicly available omics datasets. Our analysis resulted in the identification of potential DUSP-mediated hub proteins including MAPK7, MAPK8, AURKA, and IGF1R. Furthermore, we analyzed the association of DUSP expression with TLR4 signaling and identified VEGF, FGFR, and SCF-KIT pathway modules to be regulated by the activation of TLR4 signaling. Finally, we identified several important kinases including LRRK2, MAPK8, and cyclin-dependent kinases as potential DUSP-mediated hubs in TLR4 signaling. The findings from this study have the potential to aid in the understanding of DUSP signaling in the context of innate immunity. Further, this will promote the development of therapeutic modalities for disorders with aberrant DUSP signaling.

A network map of netrin receptor UNC5B-mediated signaling.

UNC-5 Homolog B (UNC5B) is a member of the dependence receptor family. This family of receptors can induce two opposite intracellular signaling cascades depending on the presence or absence of the ligand and is thus capable of driving two opposing processes. UNC5B signaling has been implicated in several cancers, where it induces cell death in the absence of its ligand Netrin-1 and promotes cell survival in its presence. In addition, inhibition of Netrin-1 ligand has been reported to decrease invasiveness and angiogenesis in tumors. UNC5B signaling pathway has also been reported to be involved in several processes such as neural development, developmental angiogenesis and inflammatory processes. However, literature pertaining to UNC5B signaling is scarce and scattered. Considering the importance of UNC5B signaling, we developed a resource of signaling events mediated by UNC5B. Using data mined from published literature, we compiled an integrated pathway map consisting of 88 UNC5B-mediated signaling events and 55 proteins. These signaling events include 27 protein-protein interaction events, 33 catalytic events involving various post-translational modifications, 9 events of UNC5B-mediated protein activation/inhibition, 27 gene regulation events and 2 events of translocation. This pathway resource has been made available to the research community through NetPath ( http://www.netpath.org /), a manually curated resource of signaling pathways (Database URL: http://www.netpath.org/pathways?path_id=NetPath_172 ). The current resource provides a foundation for the understanding of UNC5B-mediated cellular responses. The development of resource will serve researchers to explore the mechanisms of UNC-5B signaling in cancers.