Reading view
Mr.LHDR: A Benchmark for Multimodal Real-World Long-Horizon Deep Research Agents
Advances in understanding the mechanisms underlying acquired resistance to third-generation tyrosine kinase inhibitors in non-small cell lung cancer
Front Cell Dev Biol. 2026 Aug 24;14:1867246. doi: 10.3389/fcell.2026.1867246. eCollection 2026.
ABSTRACT
Acquired resistance to third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) presents a formidable challenge in the treatment of non-small cell lung cancer (NSCLC). Despite the remarkable efficacy of these agents, resistance inevitably develops, typically within approximately 10 months of treatment initiation. This review elucidates the multifaceted mechanisms driving this resistance, broadly categorized into on-target EGFR-dependent alterations and off-target EGFR-independent bypass pathway activations. On-target mechanisms include the emergence of tertiary EGFR mutations, most notably C797S, which disrupts TKI binding. Off-target mechanisms encompass the activation of alternative signaling pathways such as MET and HER2/HER3 amplification, as well as histological transformations and complex changes within the tumor microenvironment. Furthermore, recent discoveries highlight the role of epigenetic dysregulation and metabolic reprogramming in fostering resistance. To counter this pervasive adaptability, advanced diagnostic methodologies, including liquid biopsy and high-resolution omics technologies, are crucial for real-time molecular profiling. The field is actively exploring emerging combination therapeutic strategies to circumvent these diverse resistance pathways, aiming to prolong clinical benefits and improve patient outcomes. The persistent emergence of resistance underscores that current targeted therapies, while revolutionary, are primarily disease-modifying rather than curative, necessitating continuous innovation to overcome the inherent biological challenge of tumor adaptability and heterogeneity.
PMID:42707604 | PMC:PMC13547778 | DOI:10.3389/fcell.2026.1867246
An AI system to help scientists write expert-level empirical software
Nature, Published online: 19 May 2026; doi:10.1038/s41586-026-10658-6
An AI system to help scientists write expert-level empirical softwareGranzyme B-based CAR-T cells targeting membrane-bound HSP70 suppress solid tumor growth and metastasis
Oncogene, Published online: 18 April 2026; doi:10.1038/s41388-026-03797-7
Granzyme B-based CAR-T cells targeting membrane-bound HSP70 suppress solid tumor growth and metastasisLearn to Relax with Large Language Models: Solving Constraint Optimization Problems via Bidirectional Coevolution
A high-throughput selection system for fast-acting covalent protein drugs
Integrated transcriptomic and proteomic analyses elucidate the stress tolerance network of <em>Saccharomyces boulardii</em> under gastrointestinal challenge
Food Funct. 2026 Mar 31. doi: 10.1039/d5fo04958j. Online ahead of print.
ABSTRACT
The probiotic yeast Saccharomyces boulardii is renowned for its clinical efficacy, which is intrinsically linked to its exceptional ability to survive the harsh gastrointestinal (GI) environment. However, a comprehensive understanding of the molecular mechanisms and regulatory pathways underlying the stress tolerance of S. boulardii remains limited. This study employed an integrated transcriptomic and proteomic approach to systematically map the dynamic responses of S. boulardii to simulated GI transit. Our analysis revealed that the intestinal phase posed a significantly greater challenge than the gastric phase, triggering extensive molecular reprogramming. A core adaptive strategy was the marked upregulation of the central carbon metabolism, particularly glycolysis, as evidenced by the concerted overexpression of key enzymes at both transcriptional and translational levels, indicating a heightened demand for energy to fuel stress defence mechanisms. Furthermore, significant enrichment was observed in the pathways related to nitrogen and fatty acid metabolism. Integration of the multi-omics datasets highlighted the complexity of the regulatory response, with frequent discordance between mRNA and protein abundance underscoring the importance of post-transcriptional regulation. This study provides a detailed molecular profile of the stress tolerance network in S. boulardii, elucidating the strategic metabolic rewiring and multi-layered regulation that underpin its probiotic resilience. The findings offer valuable insights and a foundational resource for the future development of enhanced probiotic therapies.
PMID:41914832 | DOI:10.1039/d5fo04958j
Integrated transcriptomic and proteomic analyses elucidate the stress tolerance network of <em>Saccharomyces boulardii</em> under gastrointestinal challenge
Food Funct. 2026 Mar 31. doi: 10.1039/d5fo04958j. Online ahead of print.
ABSTRACT
The probiotic yeast Saccharomyces boulardii is renowned for its clinical efficacy, which is intrinsically linked to its exceptional ability to survive the harsh gastrointestinal (GI) environment. However, a comprehensive understanding of the molecular mechanisms and regulatory pathways underlying the stress tolerance of S. boulardii remains limited. This study employed an integrated transcriptomic and proteomic approach to systematically map the dynamic responses of S. boulardii to simulated GI transit. Our analysis revealed that the intestinal phase posed a significantly greater challenge than the gastric phase, triggering extensive molecular reprogramming. A core adaptive strategy was the marked upregulation of the central carbon metabolism, particularly glycolysis, as evidenced by the concerted overexpression of key enzymes at both transcriptional and translational levels, indicating a heightened demand for energy to fuel stress defence mechanisms. Furthermore, significant enrichment was observed in the pathways related to nitrogen and fatty acid metabolism. Integration of the multi-omics datasets highlighted the complexity of the regulatory response, with frequent discordance between mRNA and protein abundance underscoring the importance of post-transcriptional regulation. This study provides a detailed molecular profile of the stress tolerance network in S. boulardii, elucidating the strategic metabolic rewiring and multi-layered regulation that underpin its probiotic resilience. The findings offer valuable insights and a foundational resource for the future development of enhanced probiotic therapies.
PMID:41914832 | DOI:10.1039/d5fo04958j
Scalable single-cell total RNA sequencing unifies coding and noncoding transcriptomics
Nature Biotechnology, Published online: 31 March 2026; doi:10.1038/s41587-026-03068-6
Simultaneous profiling of adenylated and non-adenylated RNAs reveals regulatory programs across diverse cell types.Integrated Machine Learning and Multi-Omics Identifies a Novel Molecular Signature for Improving the Prognosis of Hepatocellular Carcinoma
J Hepatocell Carcinoma. 2026 Mar 11;13:574690. doi: 10.2147/JHC.S574690. eCollection 2026.
ABSTRACT
BACKGROUND: Hepatocellular carcinoma (HCC) exhibits significant molecular heterogeneity and complex immune microenvironment, which to some extent limits the accuracy of prognosis assessment and the formulation of individualized treatment strategies. This study aims to identify immune-derived molecular signatures based on multi-omics data and machine learning methods for the prognosis prediction and risk stratification of HCC.
METHODS: Based on weighted gene co-expression network analysis(WGCNA) and differential gene analysis,immune-derived molecular signature (IDMS) were screened in both single-cell and bulk transcriptomes. Prognostic model was constructed by multi-machine learning approachs. Subsequently, we investigated the differences in mutations, biological functions, and immune cell infiltration within the tumor microenvironment between the high- and low-risk groups.In addition, we comprehensively analyzed the drug sensitivity of IDMS and predicted potential drugs.
RESULTS: We identified seven hub genes at the single-cell and bulk transcriptome levels. Based on multiple machine learning, we constructed a prognostic model that demonstrated excellent performance in predicting overall survival for patients with HCC. IDMS -integrated normograms provide a promising and quantitative tool for clinical risk management.Notably, a significant difference in microsatellite instability (MSI) was observed between the high- and low-risk groups. This indicates that patients in the high-risk group might have a better response to immunotherapy. Additionally, we predicted potential drugs targeting to these risk subgroups.
CONCLUSION: Our research developed an IDMS that could serve as an effective tool for patient stratification management and prognosis prediction. This signature could provide a reference for immunotherapy for patients with HCC and improve their prognosis.
PMID:41847219 | PMC:PMC12991065 | DOI:10.2147/JHC.S574690