Cell-type specific, inducible and acute degradation of targeted protein in mice by two degron systems.

Despite its broad application in in vitro studies, the application of targeted protein degradation (TPD) to animal models faces considerable challenges. Here, we develop inducible and cell-type specific TPD systems in mice using two degron systems: Oryza sativa TIR1 (OsTIR1)-auxin-inducible degron 2 (AID2) and human cereblon (hCRBN)-SALL4 degron (S4D). Efficient degradation of Satb1 protein by these systems recapitulates phenotypes observed in the Satb1-deficient mice.

Increasing survivors of anthracycline-related cardiomyopathy with breast cancer in trastuzumab era: thirty-one-year trends in a Japanese Community.

Background: Trastuzumab has improved breast cancer (BC) prognosis and reduced anthracycline use. However, the characteristic changes of anthracycline-related cardiomyopathy (ARCM) in patients with BC remain unclear. We aimed to update our understanding of ARCM in the trastuzumab era.

Landscape of homologous recombination deficiency in gastric cancer and clinical implications for first-line chemotherapy.

Background: Homologous recombination deficiency (HRD) is one of the crucial hallmarks of cancer. It is associated with a favorable response to platinum-based chemotherapy. We explored the distinctive clinicopathological features of gastric cancer (GC) with HRD and the clinical significance of HRD in platinum-based first-line chemotherapy for unresectable metastatic GC.

NFκB dynamics-dependent epigenetic changes modulate inflammatory gene expression and induce cellular senescence.

Upregulation of nuclear factor κB (NFκB) signaling is a hallmark of aging and a major cause of age-related chronic inflammation. However, its effect on cellular senescence remains unclear. Here, we show that alteration of NFκB nuclear dynamics from oscillatory to sustained by depleting a negative feedback regulator of NFκB pathway, NFκB inhibitor alpha (IκBα), in the presence of tumor necrosis factor α (TNFα) promotes cellular senescence.

Clinical application of targeted tumour sequencing tests for detecting ERBB2 amplification and optimizing anti-HER2 therapy in gastric cancer.

Background: Evaluation of human epidermal growth factor receptor 2 (HER2) overexpression caused by erb-b2 receptor tyrosine kinase 2 (ERBB2) amplification (AMP) by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) is essential for treating unresectable metastatic gastric cancer (GC). A targeted tumour sequencing test enables comprehensive assessment of alterations in cancer-related genes, including ERBB2. This study aimed to evaluate the concordance between the targeted tumour sequencing test and IHC/FISH for detecting HER2-positive GC and to clarify the significance of ERBB2 AMP and concomitant genetic alterations in HER2 downstream pathways (DPs) in anti-HER2 therapy for unresectable metastatic GC patients.

Quantitative live-cell imaging of secretion activity reveals dynamic immune responses.

Quantification of cytokine secretion has facilitated advances in the field of immunology, yet the dynamic and varied secretion profiles of individual cells, particularly those obtained from limited human samples, remain obscure. Herein, we introduce a technology for quantitative live-cell imaging of secretion activity (qLCI-S) that enables high-throughput and dual-color monitoring of secretion activity at the single-cell level over several days, followed by transcriptome analysis of individual cells based on their phenotype. The efficacy of qLCI-S was demonstrated by visualizing the characteristic temporal pattern of cytokine secretion of group 2 innate lymphoid cells, which constitute less than 0.

Prognostic Significance of NQO1 Expression in Non-neoplastic Esophageal Squamous Epithelium for Patients With Esophageal Cancer.

Background/aim: NAD(P)H dehydrogenase [quinone] 1 (NQO1), an antioxidant enzyme, confers resistance to anticancer agents. NQO1 C609T is a single-nucleotide polymorphism associated with reduced protein expression in the non-neoplastic esophageal squamous epithelium (ESE). This study aimed to investigate immunohistochemical NQO1 expression in non-neoplastic ESE and to elucidate its prognostic significance in patients with esophageal squamous cell carcinoma (ESCC) undergoing neoadjuvant therapy followed by esophagectomy.

Oral Administration of Glucosylceramide Suppresses Tumor Growth by Affecting the Ceramide/Sphingosine-1-Phosphate Balance in Breast Cancer Tissue.

Background: Ceramide and sphingosine-1-phosphate (S1P) play opposing roles in cell death and survival, and maintain a dynamic balance called the sphingolipid rheostat. Glucosylceramide is a substrate to generate ceramide but its effect on breast cancer by oral administration was never tested. The purpose of this study was to reveal the anticancer activity of glucosylceramide and its potential as a new therapeutic agent in breast cancer.

Upregulation of IL-4 receptor signaling pathway in circulating ILC2s from asthma patients.

Background: Group 2 innate lymphoid cells (ILC2s) produce type 2 cytokines by stimulation with epithelial cell-derived cytokines and are implicated in the pathogenesis of various allergic diseases, including asthma. However, differences in the molecular characteristics of ILC2s between patients with asthma and healthy subjects remain unclear.

Objective: We sought to evaluate differences in cytokine production capacity and gene expression profile of ILC2s in the peripheral blood of patients with asthma and healthy subjects.

Time-dependent cell-state selection identifies transiently expressed genes regulating ILC2 activation.

The decision of whether cells are activated or not is controlled through dynamic intracellular molecular networks. However, the low population of cells during the transition state of activation renders the analysis of the transcriptome of this state technically challenging. To address this issue, we have developed the Time-Dependent Cell-State Selection (TDCSS) technique, which employs live-cell imaging of secretion activity to detect an index of the transition state, followed by the simultaneous recovery of indexed cells for subsequent transcriptome analysis.

Clinical Significance of Phosphorylated Sphingosine Kinase 1 Expression in Pancreatic Ductal Adenocarcinoma.

Background/aim: Sphingosine-1-phosphate (S1P) is a pleiotropic, bioactive, lipid mediator, produced by sphingosine kinase 1 (SphK1). In this study, we evaluated the expression of phosphorylated SphK1 (pSphK1) in patients with pancreatic ductal adenocarcinoma (PDAC) and investigated its clinical significance.

Materials And Methods: A total of 111 patients who underwent curative-intent resection for PDAC were enrolled.

Annexin A1 is a cell-intrinsic metalloregulator of zinc in human ILC2s.

Group 2 innate lymphoid cells (ILC2s) produce large amounts of type 2 cytokines including interleukin-5 (IL-5) and IL-13 in response to various stimuli, causing allergic and eosinophilic diseases. However, the cell-intrinsic regulatory mechanisms of human ILC2s remain unclear. Here, we analyze human ILC2s derived from different tissues and pathological conditions and identify ANXA1, encoding annexin A1, as a commonly highly expressed gene in non-activated ILC2s.

Identification of a novel enhancer essential for expression in T2 cells and activated ILC2s.

The genome organizer, special AT-rich binding protein-1 (SATB1), functions to globally regulate gene networks during primary T cell development and plays a pivotal role in lineage specification in CD4 helper-, CD8 cytotoxic-, and FOXP3 regulatory-T cell subsets. However, it remains unclear how gene expression is controlled, particularly in effector T cell function. Here, by using a novel reporter mouse strain expressing SATB1-Venus and genome editing, we have identified a -regulatory enhancer, essential for maintaining expression specifically in T2 cells.

Copy number alteration is an independent prognostic biomarker in triple-negative breast cancer patients.

Background: Next-generation sequencing (NGS) has enabled comprehensive genomic profiling to identify gene alterations that play important roles in cancer biology. However, the clinical significance of these genomic alterations in triple-negative breast cancer (TNBC) patients has not yet been fully elucidated. The aim of this study was to clarify the clinical significance of genomic profiling data, including copy number alterations (CNA) and tumor mutation burden (TMB), in TNBC patients.

Advanced Stage Is a Risk for Severe Neutropenia in Breast Cancer Patients Undergoing Neoadjuvant Adriamycin/Cyclophosphamide/Docetaxel Chemotherapy.

Background: Severe neutropenia, including febrile neutropenia, is a major toxicity of systemic chemotherapy that leads to delays in treatment, higher costs, and mortality. Severe neutropenia may occur during neoadjuvant chemotherapy even when the patients are free from known risk factors. Pegfilgrastim, a covalent conjugant of filgrastim that stimulate the production of neutrophils, is used for prevention.

Crossing the valley of death: Toward translational research regarding ILC2.

Group 2 innate lymphoid cells (ILC2s) are tissue-resident innate lymphoid cells that express the transcription factor GATA3 as a master regulator, which leads to the production of large amounts of type 2 cytokines, such as IL-5 and IL-13. ILC2s are activated by epithelial cell-derived cytokines, including IL-33 and IL-25, and play a key role in parasite expulsion, allergic responses, tissue repair, and metabolism. In the first five years after the discovery of ILC2s, research mainly focused on their function through cytokine receptors.

A hairy situation for ILC2s.

The overall contribution of type 2 immunity to cutaneous barrier integrity is poorly understood. In this issue of Immunity, Ricardo-Gonzalez et al. demonstrate the mechanisms by which type 2 cytokines and group 2 innate lymphoid cells (ILC2s) regulate Demodex mite colonization and maintain skin homeostasis.

Tissue-Specific Diversity of Group 2 Innate Lymphoid Cells in the Skin.

Since the discovery of group 2 innate lymphoid cells (ILC2s), their developmental pathways, mechanisms of activation and regulation, and immunological roles in the steady state and in disease have been reported in various organs. ILC2s, which produce large amounts of IL-5 and IL-13 in response to tissue-derived factors and are essential in inducing and promoting allergic inflammation, have also been found to play multifaceted roles in maintaining tissue homeostasis. While T cells respond to foreign antigens, the activation of ILC2s is regulated by various tissue-derived factors, including cytokines, lipids, hormones, and neurotransmitters, and ILC2s show different phenotypes depending on the tissue in which they are present.

ILCs and Allergy.

The recent discovery of new innate lymphoid cells (ILCs) has revolutionized the field of allergies. Since most allergic diseases induce a type 2 immune response, Th2 cells, which produce IL-4, IL-5, and IL-13 in an antigen-dependent manner, in addition to basophils and mast cells which are activated by antigen-specific IgE, are thought to play a major role in the pathogenesis. However, since group 2 innate lymphoid cells (ILC2s) produce type 2 cytokines (i.

[A Case of HER2-Positive Recurrent Breast Cancer and Liver Metastases of GIST Treated with Combined Anti-HER2 Therapy and Imatinib].

A 70-year-old female with liver metastases from gastrointestinal stromal tumor(GIST)that were found 3 months after partial gastrectomy for the primary GIST underwent Auchincloss operation for left breast cancer with ipsilateral axillary lymph node metastases. The diagnosis was microinvasive ductal cancer that was pT1miN1M0, pStage ⅡA, hormone receptor negative, and HER2 positive. Given the impact of this cancer on the prognosis of liver metastases of GIST, imatinib therapy, but not adjuvant chemotherapy, was started promptly for breast cancer after surgery.

Plasma Sphingosine-1-Phosphate Levels Are Associated with Progression of Estrogen Receptor-Positive Breast Cancer.

Although numerous experiments revealed an essential role of a lipid mediator, sphingosine-1-phosphate (S1P), in breast cancer (BC) progression, the clinical significance of S1P remains unclear due to the difficulty of measuring lipids in patients. The aim of this study was to determine the plasma concentration of S1P in estrogen receptor (ER)-positive BC patients, as well as to investigate its clinical significance. We further explored the possibility of a treatment strategy targeting S1P in ER-positive BC patients by examining the effect of FTY720, a functional antagonist of S1P receptors, on hormone therapy-resistant cells.