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Blood Advances Jul 2024Mantle cell lymphoma (MCL) is dependent on a supportive tumor immune microenvironment (TIME), where infiltration of CD163+ macrophages has a negative prognostic impact....
Mantle cell lymphoma (MCL) is dependent on a supportive tumor immune microenvironment (TIME), where infiltration of CD163+ macrophages has a negative prognostic impact. This study explores how abundance and spatial localization of CD163+ cells are associated with the biology of the MCL TIME. This is achieved through spatial multi-omic investigations of tumor and infiltrating CD163+ and CD3+ cells, respectively. We analyzed diagnostic MCL tissue from 100 patients. Sixty-three proteins were measured by GeoMx® digital spatial profiling in tissue microarrays. Regions of interests (ROIs) were selected in tumor-rich and tumor-sparse tissue regions. Molecular profiling of CD163+ macrophage segments, CD20+ MCL tumor cell segments and CD3+ T-cell segments was performed. To validate protein profiles, 1811 mRNAs were measured in CD20+ cells and two subsets of T-cells. Image analysis was used to extract the phenotype and position of each targeted cell allowing exploration of cell frequencies and cellular neighborhoods. Proteomic investigations revealed that CD163+ cells modulate their immune profile depending on the localization and that the immune inhibitory molecules VISTA and B7-H3 have higher expression in tumor-sparse versus tumor-rich tissue regions and targeting should be explored. We show that MCL tissues with more abundant infiltration of CD163+ cells have a higher expression of key components of the mitogen-activated protein kinase (MAPK) pathway, which was validated by complementary mRNA analyses. Thus, the MAPK pathway may be a feasible therapeutic target in MCL patients with CD163+ cell infiltration. We further show the independent and combined prognostic value of CD11c and CD163 beyond established risk factors.
PubMed: 38959399
DOI: 10.1182/bloodadvances.2023012039 -
Science Advances Jul 2024Pancreatic ductal adenocarcinoma (PDAC) is characterized by increasing fibrosis, which can enhance tumor progression and spread. Here, we undertook an unbiased temporal...
Pancreatic ductal adenocarcinoma (PDAC) is characterized by increasing fibrosis, which can enhance tumor progression and spread. Here, we undertook an unbiased temporal assessment of the matrisome of the highly metastatic KPC (, , ) and poorly metastatic KPC (, , ) genetically engineered mouse models of pancreatic cancer using mass spectrometry proteomics. Our assessment at early-, mid-, and late-stage disease reveals an increased abundance of nidogen-2 (NID2) in the KPC model compared to KPC, with further validation showing that NID2 is primarily expressed by cancer-associated fibroblasts (CAFs). Using biomechanical assessments, second harmonic generation imaging, and birefringence analysis, we show that NID2 reduction by CRISPR interference (CRISPRi) in CAFs reduces stiffness and matrix remodeling in three-dimensional models, leading to impaired cancer cell invasion. Intravital imaging revealed improved vascular patency in live NID2-depleted tumors, with enhanced response to gemcitabine/Abraxane. In orthotopic models, NID2 CRISPRi tumors had less liver metastasis and increased survival, highlighting NID2 as a potential PDAC cotarget.
Topics: Animals; Pancreatic Neoplasms; Proteomics; Mice; Fibrosis; Humans; Carcinoma, Pancreatic Ductal; Cancer-Associated Fibroblasts; Disease Models, Animal; Cell Line, Tumor; Calcium-Binding Proteins; Gemcitabine; Deoxycytidine; Cell Adhesion Molecules
PubMed: 38959305
DOI: 10.1126/sciadv.adl1197 -
PloS One 2024Salmonella infections pose a significant global public health concern due to the substantial expenses associated with monitoring, preventing, and treating the infection....
Salmonella infections pose a significant global public health concern due to the substantial expenses associated with monitoring, preventing, and treating the infection. In this study, we explored the core proteome of Salmonella to design a multi-epitope vaccine through Subtractive Proteomics and immunoinformatics approaches. A total of 2395 core proteins were curated from 30 different isolates of Salmonella (strain NZ CP014051 was taken as reference). Utilizing the subtractive proteomics approach on the Salmonella core proteome, Curlin major subunit A (CsgA) was selected as the vaccine candidate. csgA is a conserved gene that is related to biofilm formation. Immunodominant B and T cell epitopes from CsgA were predicted using numerous immunoinformatics tools. T lymphocyte epitopes had adequate population coverage and their corresponding MHC alleles showed significant binding scores after peptide-protein based molecular docking. Afterward, a multi-epitope vaccine was constructed with peptide linkers and Human Beta Defensin-2 (as an adjuvant). The vaccine could be highly antigenic, non-toxic, non-allergic, and have suitable physicochemical properties. Additionally, Molecular Dynamics Simulation and Immune Simulation demonstrated that the vaccine can bind with Toll Like Receptor 4 and elicit a robust immune response. Using in vitro, in vivo, and clinical trials, our findings could yield a Pan-Salmonella vaccine that might provide protection against various Salmonella species.
Topics: Proteomics; Epitopes, T-Lymphocyte; Salmonella; Computational Biology; Humans; Genomics; Molecular Docking Simulation; Salmonella Vaccines; Animals; Bacterial Proteins; Molecular Dynamics Simulation; Salmonella Infections; Epitopes, B-Lymphocyte; Immunoinformatics
PubMed: 38959229
DOI: 10.1371/journal.pone.0292413 -
Proceedings of the National Academy of... Jul 2024Phoresy is an interspecies interaction that facilitates spatial dispersal by attaching to a more mobile species. Hitchhiking species have evolved specific traits for...
Phoresy is an interspecies interaction that facilitates spatial dispersal by attaching to a more mobile species. Hitchhiking species have evolved specific traits for physical contact and successful phoresy, but the regulatory mechanisms involved in such traits and their evolution are largely unexplored. The nematode displays a hitchhiking behavior known as nictation during its stress-induced developmental stage. Dauer-specific nictation behavior has an important role in natural populations, which experience boom-and-bust population dynamics. In this study, we investigated the nictation behavior of 137 wild strains sampled throughout the world. We identified species-wide natural variation in nictation and performed a genome-wide association mapping. We show that the variants in the promoter of , encoding a putative steroidogenic enzyme, underlie differences in nictation. This difference is due to the changes in expression in glial cells, which implies that glial steroid metabolism regulates phoretic behavior. Population genetic analysis and geographic distribution patterns suggest that balancing selection maintained two haplotypes that existed in ancestral populations. Our findings contribute to further understanding of the molecular mechanism of species interaction and the maintenance of genetic diversity within natural populations.
Topics: Animals; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Neuroglia; Genome-Wide Association Study; Behavior, Animal; Genetic Variation; Promoter Regions, Genetic; Steroids
PubMed: 38959036
DOI: 10.1073/pnas.2320796121 -
JAMA Cardiology Jul 2024There is no consensus regarding the best method for prediction of hypertensive disorders of pregnancy (HDP), including gestational hypertension and preeclampsia.
IMPORTANCE
There is no consensus regarding the best method for prediction of hypertensive disorders of pregnancy (HDP), including gestational hypertension and preeclampsia.
OBJECTIVE
To determine predictive ability in early pregnancy of large-scale proteomics for prediction of HDP.
DESIGN, SETTING, AND PARTICIPANTS
This was a nested case-control study, conducted in 2022 to 2023, using clinical data and plasma samples collected between 2010 and 2013 during the first trimester, with follow-up until pregnancy outcome. This multicenter observational study took place at 8 academic medical centers in the US. Nulliparous individuals during first-trimester clinical visits were included. Participants with HDP were selected as cases; controls were selected from those who delivered at or after 37 weeks without any HDP, preterm birth, or small-for-gestational-age infant. Age, self-reported race and ethnicity, body mass index, diabetes, health insurance, and fetal sex were available covariates.
EXPOSURES
Proteomics using an aptamer-based assay that included 6481 unique human proteins was performed on stored plasma. Covariates were used in predictive models.
MAIN OUTCOMES AND MEASURES
Prediction models were developed using the elastic net, and analyses were performed on a randomly partitioned training dataset comprising 80% of study participants, with the remaining 20% used as an independent testing dataset. Primary measure of predictive performance was area under the receiver operating characteristic curve (AUC).
RESULTS
This study included 753 HDP cases and 1097 controls with a mean (SD) age of 26.9 (5.5) years. Maternal race and ethnicity were 51 Asian (2.8%), 275 non-Hispanic Black (14.9%), 275 Hispanic (14.9%), 1161 non-Hispanic White (62.8% ), and 88 recorded as other (4.8%), which included those who did not identify according to these designations. The elastic net model, allowing for forced inclusion of prespecified covariates, was used to adjust protein-based models for clinical and demographic variables. Under this approach, no proteins were selected to augment the clinical and demographic covariates. The predictive performance of the resulting model was modest, with a training set AUC of 0.64 (95% CI, 0.61-0.67) and a test set AUC of 0.62 (95% CI, 0.56-0.68). Further adjustment for study site yielded only minimal changes in AUCs.
CONCLUSIONS AND RELEVANCE
In this case-control study with detailed clinical data and stored plasma samples available in the first trimester, an aptamer-based proteomics panel did not meaningfully add to predictive utility over and above clinical and demographic factors that are routinely available.
PubMed: 38958943
DOI: 10.1001/jamacardio.2024.1621 -
Purinergic Signalling Jul 2024Snake bites are a severe problem in the countryside of Brazil and are usually attributed to snakes of the genera Bothrops, Crotalus, and Lachesis. Snake venom can...
Snake bites are a severe problem in the countryside of Brazil and are usually attributed to snakes of the genera Bothrops, Crotalus, and Lachesis. Snake venom can release ectoenzymes and nucleotidases that modulate the purinergic system. In addition to serum therapy against snake poisoning, medicinal plants with anti-inflammatory activities, such as Tabebuia aurea, is empirically applied in accidents that occur in difficult-to-access areas. This study aimed was to verify the presence and activity of nucleotidases in the crude venom of Bothrops mattogrossensis (BmtV) in vitro and characterize the modulation of purinergic components, myeloid differentiation, and inflammatory/oxidative stress markers by BmtV in vivo and in vitro. Moreover, our study assessed the inhibitory activities of specioside, an iridoid isolated from Tabebuia aurea, against the effects of BmtV. Proteomic analysis of venom content and nucleotidase activity confirm the presence of ectonucleotidase-like enzymes in BmtV. In in vivo experiments, BmtV altered purinergic component expression (P2X7 receptor, CD39 and CD73), increased neutrophil numbers in peripheral blood, and elevated oxidative stress/inflammatory parameters such as lipid peroxidation and myeloperoxidase activity. BmtV also decreased viability and increased spreading index and phagocytic activity on macrophages. Specioside inhibited nucleotidase activity, restored neutrophil numbers, and mediate the oxidative/inflammatory effects produced by BmtV. We highlight the effects produced by BmtV in purinergic system components, myeloid differentiation, and inflammatory/oxidative stress parameters, while specioside reduced the main BmtV-dependent effects.
PubMed: 38958820
DOI: 10.1007/s11302-024-10032-z -
Planta Jul 2024Millets' protein studies are lagging behind those of major cereals. Current status and future insights into the investigation of millet proteins are discussed. Millets... (Review)
Review
Millets' protein studies are lagging behind those of major cereals. Current status and future insights into the investigation of millet proteins are discussed. Millets are important small-seeded cereals majorly grown and consumed by people in Asia and Africa and are considered crops of future food security. Although millets possess excellent climate resilience and nutrient supplementation properties, their research advancements have been lagging behind major cereals. Although considerable genomic resources have been developed in recent years, research on millet proteins and proteomes is currently limited, highlighting a need for further investigation in this area. This review provides the current status of protein research in millets and provides insights to understand protein responses for climate resilience and nutrient supplementation in millets. The reference proteome data is available for sorghum, foxtail millet, and proso millet to date; other millets, such as pearl millet, finger millet, barnyard millet, kodo millet, tef, and browntop millet, do not have any reference proteome data. Many studies were reported on stress-responsive protein identification in foxtail millet, with most studies on the identification of proteins under drought-stress conditions. Pearl millet has a few reports on protein identification under drought and saline stress. Finger millet is the only other millet to have a report on stress-responsive (drought) protein identification in the leaf. For protein localization studies, foxtail millet has a few reports. Sorghum has the highest number of 40 experimentally proven crystal structures, and other millets have fewer or no experimentally proven structures. Further proteomics studies will help dissect the specific proteins involved in climate resilience and nutrient supplementation and aid in breeding better crops to conserve food security.
Topics: Millets; Plant Proteins; Proteome; Proteomics; Droughts; Stress, Physiological; Crops, Agricultural; Sorghum
PubMed: 38958760
DOI: 10.1007/s00425-024-04478-z -
TAG. Theoretical and Applied Genetics.... Jul 2024Transcriptomics and proteomics information collected on a platform can predict additive and non-additive effects for platform traits and additive effects for field...
Transcriptomics and proteomics information collected on a platform can predict additive and non-additive effects for platform traits and additive effects for field traits. The effects of climate change in the form of drought, heat stress, and irregular seasonal changes threaten global crop production. The ability of multi-omics data, such as transcripts and proteins, to reflect a plant's response to such climatic factors can be capitalized in prediction models to maximize crop improvement. Implementing multi-omics characterization in field evaluations is challenging due to high costs. It is, however, possible to do it on reference genotypes in controlled conditions. Using omics measured on a platform, we tested different multi-omics-based prediction approaches, using a high dimensional linear mixed model (MegaLMM) to predict genotypes for platform traits and agronomic field traits in a panel of 244 maize hybrids. We considered two prediction scenarios: in the first one, new hybrids are predicted (CV-NH), and in the second one, partially observed hybrids are predicted (CV-POH). For both scenarios, all hybrids were characterized for omics on the platform. We observed that omics can predict both additive and non-additive genetic effects for the platform traits, resulting in much higher predictive abilities than GBLUP. It highlights their efficiency in capturing regulatory processes in relation to growth conditions. For the field traits, we observed that the additive components of omics only slightly improved predictive abilities for predicting new hybrids (CV-NH, model MegaGAO) and for predicting partially observed hybrids (CV-POH, model GAOxW-BLUP) in comparison to GBLUP. We conclude that measuring the omics in the fields would be of considerable interest in predicting productivity if the costs of omics drop significantly.
Topics: Zea mays; Genotype; Phenotype; Proteomics; Plant Breeding; Models, Genetic; Genomics; Transcriptome; Linear Models; Multiomics
PubMed: 38958724
DOI: 10.1007/s00122-024-04679-w -
Arquivos Brasileiros de Cirurgia... 2024Molecular medicine opened new horizons in understanding disease mechanisms and discovering target interventions. The wider availability of DNA and RNA sequencing,... (Review)
Review
Molecular medicine opened new horizons in understanding disease mechanisms and discovering target interventions. The wider availability of DNA and RNA sequencing, immunohistochemical analysis, proteomics, and other molecular tests changed how physicians manage diseases. The gastric cancer molecular classification proposed by The Cancer Genome Atlas Program divides gastric adenocarcinomas into four subtypes. However, the available targets and/or immunotherapies approved for clinical use seem to be dissociated from these molecular subtypes. Until a more reliable interpretation of the stupendous amount of data provided by the molecular classifications is presented, the clinical guidelines will rely on available actionable targets and approved therapies to guide clinicians in conducting cancer management in the era of molecular therapies.
Topics: Stomach Neoplasms; Humans; Adenocarcinoma; Molecular Targeted Therapy
PubMed: 38958347
DOI: 10.1590/0102-6720202400018e1811 -
Journal of Drug Targeting Jul 2024Exosome therapy has garnered significant attention due to its natural delivery capabilities, low toxicity, high biocompatibility, and potential for personalised...
Exosome therapy has garnered significant attention due to its natural delivery capabilities, low toxicity, high biocompatibility, and potential for personalised treatment through engineering modifications. Recent studies have highlighted the ability of tumour cell-derived exosomes (TDEs) to interact with immune cells or modify the immune microenvironment to suppress host immune responses, as well as their unique homing ability to parental cells. The core question of this study is whether this immunomodulatory property of TDEs can be utilised for the immunotherapy of inflammatory diseases. In our experiments, we prepared exosomes derived from murine colon cancer cells CT26 (CT26 exo) using ultracentrifugation, characterised them, and conducted proteomic analysis. The therapeutic potential of CT26 exo was evaluated in our dextran sulphate sodium salt (DSS)-induced inflammatory bowel disease (IBD) mouse model. Compared to the control and 293 T exo treatment groups, mice treated with CT26 exo showed a reduction in the disease activity index (DAI) and colon shortening rate, with no noticeable weight loss. Haematoxylin and eosin (H&E) staining of colon paraffin sections revealed reduced inflammatory infiltration and increased epithelial goblet cells in the colons of CT26 exo-treated group. Furthermore, we conducted preliminary mechanistic explorations by examining the phenotyping and function of CD4 T cells and dendritic cells (DCs) in the colonic lamina propria of mice. The results indicated that the ameliorative effect of CT26 exosomes might be due to their inhibition of pro-inflammatory cytokine secretion by colonic DCs and selective suppression of Th17 cell differentiation in the colon. Additionally, CT26 exo exhibited good biosafety. Our findings propose a novel exosome-based therapeutic approach for IBD and suggest the potential application of TDEs in the treatment of inflammatory diseases.
PubMed: 38958251
DOI: 10.1080/1061186X.2024.2369876