Longitudinal phosphoproteomics reveals the PI3K-PAK1 axis as a potential target for recurrent colorectal liver metastases.

The resistance of colorectal cancer liver metastases (CRLMs) to 5-fluorouracil (5-FU) chemotherapy remains a significant global health challenge. We investigated the phosphoproteomic dynamics of serial tissue sections obtained from initial metastases and recurrent tumors collected from 24 patients to address this unmet need for innovative therapeutic strategies for patients with CRLM with a poor prognosis. Our analysis revealed the activation of PAK kinase in patients with CRLM with a poor prognosis.

Targeting ErbB and tankyrase1/2 prevent the emergence of drug-tolerant persister cells in ALK-positive lung cancer.

Targeting the drug tolerant persister (DTP) state in cancer cells should prevent further development of resistance mechanisms. This study explored combination therapies to inhibit alectinib-induced DTP cell formation from anaplastic lymphoma kinase-positive non-small cell lung cancer (ALK + NSCLC) patient-derived cells. After drug-screening 3114 compounds, pan-HER inhibitors (ErbB pathway) and tankyrase1/2 inhibitors (Wnt/β-catenin signaling) emerged as top candidates to inhibit alectinib-induced DTP cells growth.

Brexpiprazole treatment for agitation in Alzheimer's dementia: A randomized study.

Introduction: We evaluated the efficacy and safety of brexpiprazole for the treatment of agitation in Alzheimer's dementia (AAD) in Japanese patients.

Methods: This was a phase 2/3 multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Patients with AAD were randomized to receive brexpiprazole 1 mg/day or 2 mg/day, or placebo (3:4:4) for 10 weeks.

An atlas of the aging mouse proteome reveals the features of age-related post-transcriptional dysregulation.

To what extent and how post-transcriptional dysregulation affects aging proteome remains unclear. Here, we provide proteomic data of whole-tissue lysates (WTL) and low-solubility protein-enriched fractions (LSF) of major tissues collected from mice of 6, 15, 24, and 30 months of age. Low-solubility proteins are preferentially affected by age and the analysis of LSF doubles the number of proteins identified to be differentially expressed with age.

Systematic Identification of Kinase-Substrate Relationship by Integrated Phosphoproteome and Interactome Analysis.

The sensitivity of phosphorylation site identification by mass spectrometry (MS)-based phosphoproteomics has improved significantly. However, the lack of kinase-substrate relationship (KSR) data has hindered improvement of the range and accuracy of kinase activity prediction using phosphoproteome data. We herein describe the application of a systematic identification of KSR by integrated phosphoproteome and interactome analysis using doxycycline (Dox)-induced target kinase-overexpressing HEK-293 cells.

QcrC is a potential target for antibody therapy and vaccination to control infection by suppressing its energy metabolism.

Introduction: spp. are a public health concern, yet there is still no effective vaccine or medicine available.

Methods: Here, we developed a -specific antibody and found that it targeted a menaquinol cytochrome reductase complex QcrC.

SFTPB in serum extracellular vesicles as a biomarker of progressive pulmonary fibrosis.

Progressive pulmonary fibrosis (PPF), defined as the worsening of various interstitial lung diseases (ILDs), currently lacks useful biomarkers. To identify novel biomarkers for early detection of patients at risk of PPF, we performed a proteomic analysis of serum extracellular vesicles (EVs). Notably, the identified candidate biomarkers were enriched for lung-derived proteins participating in fibrosis-related pathways.

Proteomic analysis of serum extracellular vesicles reveals Fibulin-3 as a new marker predicting liver-related events in MASLD.

Background: There is a need for novel noninvasive markers for metabolic dysfunction-associated steatotic liver disease (MASLD) to stratify patients at high risk for liver-related events including liver cancer and decompensation. In the present study, we used proteomic analysis of proteins in extracellular vesicles (EVs) to identify new biomarkers that change with fibrosis progression and can predict the development of liver-related events.

Methods: We analyzed serum EVs from 50 patients with MASLD assessed for liver fibrosis by biopsy and identified proteins that altered with advanced fibrosis.

Phosphoproteomic Analysis Identified Mutual Phosphorylation of FAK and Src as a Mechanism of Osimertinib Resistance in -Mutant Lung Cancer.

Introduction: Osimertinib is a standard treatment for patients with -mutant NSCLC. Although some osimertinib resistance mechanisms have been identified, nearly 50% of the mechanisms remain to be elucidated. This study was aimed at identifying non-genetic mechanisms underlying osimertinib resistance.

Galectin-10 in serum extracellular vesicles reflects asthma pathophysiology.

Background: Novel biomarkers (BMs) are urgently needed for bronchial asthma (BA) with various phenotypes and endotypes.

Objective: We sought to identify novel BMs reflecting tissue pathology from serum extracellular vesicles (EVs).

Methods: We performed data-independent acquisition of serum EVs from 4 healthy controls, 4 noneosinophilic asthma (NEA) patients, and 4 eosinophilic asthma (EA) patients to identify novel BMs for BA.

Heterogeneity of perivascular astrocyte endfeet depending on vascular regions in the mouse brain.

Astrocytes interact with not only synapses but also brain blood vessels through perivascular astrocyte endfeet (PV-AEF) to form the neurovascular unit (NVU). However, PV-AEF components have not been fully identified. Here, we biochemically isolated blood vessels from mouse brain homogenates and purified PV-AEF.

Phosphotyrosine proteomics in cells synchronized at monopolar cytokinesis reveals EphA2 as functioning in cytokinesis.

Cytokinesis is the final step of the cell division in which cellular components are separated into two daughter cells. This process is regulated through the phosphorylation of different classes of proteins by serine/threonine (Ser/Thr) kinases such as Aurora B and Polo-like kinase 1 (PLK1). Conversely, the role of phosphorylation at tyrosine residues during cytokinesis has not been studied in detail yet.

Rapid and Highly Efficient Purification of Extracellular Vesicles Enabled by a TiO Hybridized Spongy-like Polymer.

We developed a novel purification medium of extracellular vesicles (EVs) by constructing a spongy-like monolithic polymer kneaded with TiO microparticles (TiO-hybridized spongy monolith, TiO-SPM). TiO-SPM was applied in a solid-phase extraction format and enabled simple, rapid, and highly efficient purification of EVs. This is due to the high permeability caused by the continuous large flow-through pores of the monolithic skeleton (median pore size; 5.

An ATR-PrimPol pathway confers tolerance to oncogenic KRAS-induced and heterochromatin-associated replication stress.

Activation of the KRAS oncogene is a source of replication stress, but how this stress is generated and how it is tolerated by cancer cells remain poorly understood. Here we show that induction of KRAS expression in untransformed cells triggers H3K27me3 and HP1-associated chromatin compaction in an RNA transcription dependent manner, resulting in replication fork slowing and cell death. Furthermore, elevated ATR expression is necessary and sufficient for tolerance of KRAS-induced replication stress to expand replication stress-tolerant cells (RSTCs).

Phase-separated nuclear bodies of nucleoporin fusions promote condensation of MLL1/CRM1 and rearrangement of 3D genome structure.

NUP98 and NUP214 form chimeric fusion proteins that assemble into phase-separated nuclear bodies containing CRM1, a nuclear export receptor. However, these nuclear bodies' function in controlling gene expression remains elusive. Here, we demonstrate that the nuclear bodies of NUP98::HOXA9 and SET::NUP214 promote the condensation of mixed lineage leukemia 1 (MLL1), a histone methyltransferase essential for the maintenance of HOX gene expression.

Integrative analysis of cancer dependency data and comprehensive phosphoproteomics data revealed the EPHA2-PARD3 axis as a cancer vulnerability in KRAS-mutant colorectal cancer.

Colorectal cancer (CRC), a common malignant tumour of the gastrointestinal tract, is a life-threatening cancer worldwide. Mutations in KRAS and BRAF, the major driver mutation subtypes in CRC, activate the RAS pathway, contribute to tumorigenesis in CRC and are being investigated as potential therapeutic targets. Despite recent advances in clinical trials targeting KRASG12C or RAS downstream signalling molecules for KRAS-mutant CRC, there is a lack of effective therapeutic interventions.

Rational Supramolecular Strategy via Halogen Bonding for Effective Halogen Recognition in Molecular Imprinting.

Halogen bonding is a highly directional interaction and a potential tool in functional material design through self-assembly. Herein, we describe two fundamental supramolecular strategies to synthesize molecularly imprinted polymers (MIPs) with halogen bonding-based molecular recognition sites. In the first method, the size of the σ-hole was increased by aromatic fluorine substitution of the template molecule, enhancing the halogen bonding in the supramolecule.

Integration of pharmacoproteomic and computational approaches reveals the cellular signal transduction pathways affected by apatinib in gastric cancer cell lines.

Apatinib is known to be a highly selective vascular endothelial growth factor receptor 2 (VEGFR2) inhibitor with anti-angiogenic and anti-tumor properties. In a phase III study, the objective response rate to apatinib was low. It remains unclear why the effectivity of apatinib varies among patients and what type of patients are candidates for the treatment.

In-depth proteomics reveals the characteristic developmental profiles of early lung adenocarcinoma with epidermal growth factor receptor mutation.

Introduction: Lung adenocarcinoma progresses stepwise from atypical adenomatous hyperplasia to adenocarcinoma in situ (AIS), followed by minimally invasive adenocarcinoma (MIA), and then obvious invasive adenocarcinoma. In this study, we examined the protein expression profiles of early and epidermal growth factor receptor (EGFR) mutation-positive lung adenocarcinomas.

Methods: Fifteen cases of small and EGFR mutation-positive adenocarcinomas were collected, including AIS, MIA, and small invasive adenocarcinoma (SIA).

Itraconazole Repolarizes Tumor-associated Macrophages and Suppresses Cervical Cancer Cell Growth.

Background/aim: Itraconazole (ITZ), an antifungal agent, has been reported to have anti-tumor effects in patients with multiple cancer types. We investigated the involvement of tumor-associated macrophages (TAMs) in its tumor-agnostic mechanism.

Materials And Methods: M1 and M2 macrophages were established from human monocyte leukemia cell line (THP-1) and their phenotypes were determined morphologically.

Characterization of Transcriptomic and Proteomic Changes in the Skin after Chronic Fluocinolone Acetonide Treatment.

While topical corticosteroid (TCS) treatment is widely used for many skin diseases, it can trigger adverse side effects, and some of such effects can last for a long time after stopping the treatment. However, molecular changes induced by TCS treatment remain largely unexplored, although transient changes in histology and some major ECM components have been documented. Here, we investigated transcriptomic and proteomic changes induced by fluocinolone acetonide (FA) treatment in the mouse skin by conducting RNA-Seq and quantitative proteomics.

Classification of Extracellular Vesicles Based on Surface Glycan Structures by Spongy-like Separation Media.

Extracellular vesicles (EVs) are lipid bilayer vesicles that enclose various biomolecules. EVs hold promise as sensitive biomarkers to detect and monitor various diseases. However, they have heterogeneous molecular compositions.

Next-generation proteomics of serum extracellular vesicles combined with single-cell RNA sequencing identifies MACROH2A1 associated with refractory COVID-19.

Background: The coronavirus disease 2019 (COVID-19) pandemic is widespread; however, accurate predictors of refractory cases have not yet been established. Circulating extracellular vesicles, involved in many pathological processes, are ideal resources for biomarker exploration.

Methods: To identify potential serum biomarkers and examine the proteins associated with the pathogenesis of refractory COVID-19, we conducted high-coverage proteomics on serum extracellular vesicles collected from 12 patients with COVID-19 at different disease severity levels and 4 healthy controls.