Ribosome Newsletter: Navigating the Convergence of Proteomics, AI, Synthetic Biology, and Translational Medicine
Welcome to this week's edition of Ribosome! This week, we explore pivotal biomarkers in pancreatic ductal adenocarcinoma, colorectal cancer diagnosis, and sepsis treatment, offering insights that could transform patient care. Additionally, we feature the impact of dietary choices on the human proteome, and molecular insights into Sudden Infant Death Syndrome. In the Proteomics Innovation section, we highlight cutting-edge mass spectrometry techniques and AI-driven analysis, while our Industry Update keeps you informed about strategic partnerships and advancements in drug development. Join us as we continue to unravel the advances in proteomics and its potential to transform healthcare.
Biomarker Discovery
*Oncology
In this study, researchers conducted a comprehensive analysis on 1,171 patients with resected pancreatic ductal adenocarcinoma (PDAC), uncovering pivotal biomarkers crucial for enhancing adjuvant chemotherapy strategies. Through proteomic profiling of 191 patient samples, the study revealed functional protein modules and established a prognostic risk model for PDAC. Notably, two biomarkers, NDUFB8 and CEMIP2, were identified as significant indicators of patients' overall sensitivity to adjuvant chemotherapy, validated across internal and external cohorts. This research underscores the potential of proteomics in refining prognosis and tailoring adjuvant chemotherapy, offering a significant leap toward personalized medicine in treating PDAC.
*Oncology
This study has utilized longitudinal plasma proteome profiling to identify key biomarkers for diagnosing colorectal cancer (CRC) and predicting responses to cetuximab therapy. By analyzing 641 plasma samples from 147 CRC patients and 90 healthy controls, researchers found distinct proteins, including COL12A1, THBS2, S100A8, and S100A9, effective in distinguishing CRC patients from healthy individuals. Additionally, the study identified biomarkers such as RRAS2, MMP8, FBLN1, RPTOR, and IMPDH2, which could predict initial responses to cetuximab treatment. This comprehensive approach not only enhances our understanding of CRC's molecular landscape but also offers a promising avenue for personalized treatment strategies, highlighting the study's potential to significantly impact CRC management and therapy.
*Infectious diseases
This research has uncovered the potential of Bone Morphogenetic Protein 9 (BMP9) as both a prognostic biomarker and a therapeutic target for sepsis. In two distinct patient cohorts, those with sepsis exhibited significantly lower BMP9 levels compared to healthy individuals, and these levels were closely linked to 28-day mortality rates. Experimental treatments with BMP9 in murine models of sepsis demonstrated improved survival, enhanced macrophage recruitment, and increased bacterial clearance. The study suggests BMP9's vital role in immune response regulation during sepsis, offering a promising avenue for host-directed therapy and patient stratification.
*Nutriproteomics
In a recent study focusing on the effects of dietary choices on the human body, researchers examined how vegan and ketogenic diets impact the proteome, part of a broader investigation into host immunity and the microbiota. This study, involving 20 participants alternating between diets for two-week periods, utilized a comprehensive multiomics approach to dissect dietary impacts. Proteomic analysis revealed that the ketogenic diet induced a broader alteration in plasma protein profiles compared to the vegan diet, highlighting its significant influence on the body's protein composition. Notably, the ketogenic diet was associated with enhanced adaptive immune signatures, while the vegan diet predominantly affected innate immune responses. This research accentuates the profound and distinct effects of dietary interventions on the proteome, offering valuable insights for developing targeted nutritional strategies to modulate immune functions.
*Neonatology
This study examined postmortem samples from 71 Sudden Infant Death Syndrome (SIDS) cases and 20 controls, revealing a subset of SIDS cases with neuroinflammation indicated by elevated CSF neopterin levels. Proteomic and metagenomic analyses identified human parechovirus 3 (HPeV3) in one case, linking occult infection to neuroinflammation in SIDS. Single-nucleus RNA sequencing highlighted brainstem neuroinflammation's molecular signatures associated with HPeV3. This research illustrates how proteomics and next-generation sequencing provide deeper insights into SIDS, potentially guiding future diagnostic and therapeutic strategies.
*Endocrinology
A study on individuals with type 2 diabetes who underwent a weight loss program revealed significant changes in serum levels of nine cancer-related proteins. This intervention, part of the Diabetes Remission Clinical Trial (DiRECT), compared outcomes between participants undergoing the Counterweight-Plus weight-loss program and those receiving standard care. Proteomic analysis identified modifications in proteins such as glycoprotein Nmb and furin, which are implicated in cancer risk. Mendelian randomization analysis further suggested a potential causal relationship between altered protein levels due to weight loss and a reduced risk of breast cancer, though these findings warrant further investigation. This research underscores the impact of weight management in diabetes on biological pathways linked to cancer, highlighting the need for further exploration of these proteins in cancer prevention strategies.
领英推荐
Proteomics Innovation
*pQTL Mapping
This study demonstrated the utility of mass-spectrometry-based proteomics, specifically using the Proteograph? Product Suite, in identifying protein-altering variants associated with peptides. By analyzing over 18,000 unique peptides from nearly 3,000 proteins in more than 320 blood samples from a diverse cohort, the research successfully pinpointed 184 significant protein-altering variants across 137 genes. This approach confirmed the target specificity of co-associated affinity binders, highlighted putatively causal cis-encoded proteins, and provided evidence for proteins' presence in blood, including those potentially elusive to affinity-based proteomics. The findings underscore the advantage of mass spectrometry in overcoming the limitations of affinity-based methods, offering precise protein quantification and variant identification for drug target prioritization.
*DIA Proteomics
A recent study introduced a novel mass spectrometry (MS) approach termed narrow-window data-independent acquisition (nDIA), leveraging high-resolution MS1 scans alongside parallel tandem MS (MS/MS) scans at about 200 Hz using 2-Th isolation windows. This method, executed on a quadrupole Orbitrap mass spectrometer integrated with an Astral analyzer, achieves unprecedented MS/MS scanning speed, sensitivity, and accuracy. The nDIA technique allows for the profiling of over 100 full yeast proteomes per day or 48 human proteomes, reaching depths of approximately 10,000 human protein groups in just half an hour. Compared to existing state-of-the-art MS methodologies, nDIA offers three times the coverage, significantly enhancing protein quantification and identification in complex biological samples. This advancement opens new avenues for high-throughput proteomics, promising deeper insights into biological processes and disease mechanisms with its superior speed and coverage capabilities.
*Protein Identification
This study demonstrated significant advancements in proteomic analysis through the use of micropillar array columns (μPACs), wide-window acquisition, and AI-driven CHIMERYS search engine. This combination increased peptide and protein identifications by up to 50% and 24%, respectively, across bulk, affinity purification, and single-cell proteomics, outperforming traditional methods. Moreover, it identified 92% more potential interactors in protein-protein interaction studies, including new binding partners for the chromatin remodeler Smarca5/Snf2h. This enhanced platform offers greater precision, accuracy, and throughput, marking a substantial improvement in proteomic research capabilities.
*Protein Aggregation
This study has delved into the intricate relationship between N-glycosylation and protein aggregation, revealing how this posttranslational modification acts as a proteomic shield against aggregation. By employing proteome-wide computational analysis and biophysical techniques, researchers discovered that N-glycosylation, unlike most posttranslational modifications, is strategically enriched near aggregation-prone regions in proteins prone to misfolding. This enrichment is evolutionarily selected, indicating a fundamental role in maintaining proteome integrity. The study further demonstrated, through in vitro experiments, that N-glycosylation effectively hinders peptide aggregation by steric hindrance, showcasing its pivotal function in higher eukaryotes' defense against protein aggregation. This discovery not only sheds light on N-glycosylation's protective mechanism but also opens new avenues for understanding and potentially mitigating aggregation-related disorders.
Industry Update
*Partnership
Takeda Pharmaceutical has secured a licensing agreement with Protagonist Therapeutics, paying $300 million upfront for the rights to a promising blood disorder treatment, rusfertide, outside the U.S. The collaboration, aimed at advancing the drug through Phase 3 trials for polycythemia vera, a condition that leads to excess red blood cell production, could see Protagonist receiving up to $1.7 billion in total, depending on future milestones and sales. This partnership not only infuses Protagonist with significant funds to progress its research but also leverages Takeda's global commercialization expertise for the drug's potential market launch.
*Partnership
Gilead Sciences is intensifying its involvement with Arcus Biosciences by investing an additional $320 million to increase its ownership to 33%, aiming to expedite the development of domvanalimab, a promising immunotherapy targeting the TIGIT protein. This strategic move includes accelerating two cancer trials while discontinuing a lung cancer study to reallocate resources more effectively. Despite the high expectations surrounding TIGIT inhibitors, the decision to focus on trials combining immunotherapies with chemotherapy marks a pivotal strategy in harnessing the potential of TIGIT pathways in cancer treatment.
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