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Epigenetic regulation plays an important role in governing stem cell fate and tumorigenesis. Lost expression of a key DNA demethylation enzyme TET2 is associated with human cancers and has been linked to stem cell traits in vitro; however, whether and how TET2 regulates mammary stem cell fate and mammary tumorigenesis in vivo remains to be determined. Here, using our recently established mammary specific Tet2 deletion mouse model, the data reveals that TET2 plays a pivotal role in mammary gland development and luminal lineage commitment. We show that TET2 and FOXP1 form a chromatin complex that mediates demethylation of ESR1, GATA3, and FOXA1 , three key genes that are known to coordinately orchestrate mammary luminal lineage specification and endocrine response, and also are often silenced by DNA methylation in aggressive breast cancers. Furthermore, Tet2 deletion-PyMT breast cancer mouse model exhibits enhanced mammary tumor development with deficient ERα expression that confers tamoxifen resistance in vivo. As a result, this study elucidates a role for TET2 in governing luminal cell differentiation and endocrine response that underlies breast cancer resistance to anti-estrogen treatments. TET2 loss is associated with human cancers but its role in the mammary gland development and tumorigenesis is unclear. Here, the authors show that TET2–FOXP1 complex mediates demethylation of genes involved in luminal lineage commitment and endocrine response, underlying a role of TET2 loss in endocrine resistant breast cancer.

Oncometabolites are aberrant metabolic byproducts that arise from mutations in enzymes of the tricarboxylic acid (TCA) cycle or related metabolic pathways and play central roles in tumor progression and immune evasion. Among these, 2-hydroxyglutarate (2-HG), succinate, and fumarate are the most well-characterized, acting as competitive inhibitors of α-ketoglutarate-dependent dioxygenases to alter DNA and histone methylation, cellular differentiation, and hypoxia signaling. More recently, itaconate, an immunometabolite predominantly produced by activated macrophages, has been recognized for its dual roles in modulating inflammation and tumor immunity. These metabolites influence cancer development through multiple mechanisms, including epigenetic reprogramming, redox imbalance, and post-translational protein modifications. Importantly, their effects are not limited to cancer cells but extend to various components of the tumor microenvironment, such as T cells, macrophages, dendritic cells, and endothelial cells, reshaping immune responses and contributing to immune suppression. In this review, we highlight the emerging insights into the roles of TCA cycle-associated oncometabolites in cancer biology and immune regulation. We discuss how these metabolites impact both tumor-intrinsic processes and intercellular signaling within the tumor microenvironment. Finally, we examine therapeutic strategies targeting oncometabolite pathways, including mutant IDH inhibitors, α-ketoglutarate mimetics, and immunometabolic interventions, with the goal of restoring immune surveillance and improving cancer treatment outcomes.

Head and Neck squamous cell carcinoma (HNSCC) is a human lethal cancer with clinical, pathological, phenotypical and biological heterogeneity. Caner initiating cells (CICs), which are responsible for tumor growth and coupled with gain of epithelial-mesenchymal transition (EMT), have been identified. Previously, we enriched a subpopulation of head and neck cancer initiating cells (HN-CICs) with up-regulation of CD133 and enhancement of EMT. Others demonstrate that Src kinase interacts with and phosphorylates the cytoplasmic domain of CD133. However, the physiological function of CD133/Src signaling in HNSCCs has not been uncovered. Herein, we determined the critical role of CD133/Src axis modulating stemness, EMT and tumorigenicity of HNSCC and HN-CICs. Initially, down-regulation of CD133 significantly reduced the self-renewal ability and expression of stemness genes, and promoted the differentiation and apoptotic capability of HN-CICs. Additionally, knockdown of CD133 in HN-CICs also lessened both in vitro malignant properties including cell migration/cell invasiveness/anchorage independent growth, and in vivo tumor growth by nude mice xenotransplantation assay. In opposite, overexpression of CD133 enhanced the stemness properties and tumorigenic ability of HNSCCs. Lastly, up-regulation of CD133 increased phosphorylation of Src coupled with EMT transformation in HNSCCs, on the contrary, silence of CD133 or treatment of Src inhibitor inversely abrogated above phenotypic effects, which were induced by CD133 up-regulation in HNSCCs or HN-CICs. Our results suggested that CD133/Src signaling is a regulatory switch to gain of EMT and of stemness properties in HNSCC. Finally, CD133/Src axis might be a potential therapeutic target for HNSCC by eliminating HN-CICs.

Background Head and neck squamous cell carcinoma (HNSCC) is a highly lethal cancer that contains cellular and functional heterogeneity. Previously, we enriched a subpopulation of highly tumorigenic head and neck cancer initiating cells (HN-CICs) from HNSCC. However, the molecular mechanisms by which to govern the characteristics of HN-CICs remain unclear. GRP78, a stress-inducible endoplasmic reticulum chaperone, has been reported to play a crucial role in the maintenance of embryonic stem cells, but the role of GRP78 in CICs has not been elucidated. Results Initially, we recognized GRP78 as a putative candidate on mediating the stemness and tumorigenic properties of HN-CICs by differential systemic analyses. Subsequently, cells with GRP78 anchored at the plasma membrane ( mem GRP78 + ) exerted cancer stemness properties of self-renewal, differentiation and radioresistance. Of note, xenotransplantation assay indicated merely 100 mem GRP78 + HNSCCs resulted in tumor growth. Moreover, knockdown of GRP78 significantly reduced the self-renewal ability, side population cells and expression of stemness genes, but inversely promoted cell differentiation and apoptosis in HN-CICs. Targeting GRP78 also lessened tumorigenicity of HN-CICs both in vitro and in vivo . Clinically, co-expression of GRP78 and Nanog predicted the worse survival prognosis of HNSCC patients by immunohistochemical analyses. Finally, depletion of GRP78 in HN-CICs induced the expression of Bax, Caspase 3, and PTEN. Conclusions In summary, mem GRP78 should be a novel surface marker for isolation of HN-CICs, and targeting GRP78 signaling might be a potential therapeutic strategy for HNSCC through eliminating HN-CICs.

Muscle biopsy is a fundamental procedure to assist the final diagnosis of myopathy. With the recent advances in molecular diagnosis, serology tests, and mechanism-based classification in myopathy, the précised diagnosis for myopathy required the applications of multiple tools. This study intends to reappraise the benefit of muscle biopsy in adult-onset myopathy under the setting of an optimized muscle biopsy protocol and comprehensive serology tests. A one-group pretest-posttest study design was used. The pre- and post-biopsy diagnoses and treatments in 69 adult patients were compared. Muscle biopsy yielded 85.5% of definitive diagnoses, including changes in pre-biopsy diagnoses (40.6%) and narrowing down the suspicious myopathies (49.3%). The demographic data and clinical parameters between the group “with change” and “without change” after biopsy were not different. Among those with changes in diagnosis, 39.3% also had a corresponding shift in treatment, which benefits the patients significantly. Regarding the most common adult-onset myopathy, idiopathic inflammatory myopathy (IIM), 41% of patients with pre-biopsy diagnosis as IIM had changes in their IIM subtype diagnosis, and 53% was finally not IIM after muscle biopsy. Although there have been advances in molecular diagnosis recently, muscle biopsy still undoubtedly critically guided the diagnosis and treatment of adult-onset myopathy in the era of precision medicine.

Immune checkpoint blockade is effective for some patients with cancer, but most are refractory to current immunotherapies and new approaches are needed to overcome resistance 1 , 2 . The protein tyrosine phosphatases PTPN2 and PTPN1 are central regulators of inflammation, and their genetic deletion in either tumour cells or immune cells promotes anti-tumour immunity 3 – 6 . However, phosphatases are challenging drug targets; in particular, the active site has been considered undruggable. Here we present the discovery and characterization of ABBV-CLS-484 (AC484), a first-in-class, orally bioavailable, potent PTPN2 and PTPN1 active-site inhibitor. AC484 treatment in vitro amplifies the response to interferon and promotes the activation and function of several immune cell subsets. In mouse models of cancer resistant to PD-1 blockade, AC484 monotherapy generates potent anti-tumour immunity. We show that AC484 inflames the tumour microenvironment and promotes natural killer cell and CD8 + T cell function by enhancing JAK–STAT signalling and reducing T cell dysfunction. Inhibitors of PTPN2 and PTPN1 offer a promising new strategy for cancer immunotherapy and are currently being evaluated in patients with advanced solid tumours (ClinicalTrials.gov identifier NCT04777994 ). More broadly, our study shows that small-molecule inhibitors of key intracellular immune regulators can achieve efficacy comparable to or exceeding that of antibody-based immune checkpoint blockade in preclinical models. Finally, to our knowledge, AC484 represents the first active-site phosphatase inhibitor to enter clinical evaluation for cancer immunotherapy and may pave the way for additional therapeutics that target this important class of enzymes. An orally bioavailable small-molecule active-site inhibitor of the phosphatases PTPN2 and PTPN1, ABBV-CLS-484, demonstrates immunotherapeutic efficacy in mouse models of cancer resistant to PD-1 blockade.

In this study, Japan's multifunctional materials company was used to provide the phytosanitary materials jointly developed by Yamaguchi University, and the red soil of the National Pingtung University of Science and Technology Soil and Water Conservation Experimental Zone was used as the experimental soil matrix to test the densities (SP45 and SP60) and slopes (25, 35 and 45degree) of different paving under the rainfall simulating test (with I=80mm/hr). The analysis found that uses the multifunctional planting net can effectively reduce runoff and soil loss. The steeper the slope, the more runoff and soil loss it produces. Multifunctional planting nets with higher density can reduce the effect of runoff and soil loss, this statistics have not yet reached significant variance levels. This experiment is discussing the slope commonly used in engineering. These results can be used as a reference for further experiment planning.

Doctor shopping is a common phenomenon in many countries. However, patterns of switching healthcare facilities on the same day were little known. The data were obtained from the longitudinal cohort datasets (LHID2010) of Taiwan’s National Health Insurance Research Database in 2010. Of 1,000,000 persons of the cohort with 13,276,928 nonemergent visits, 185,347 patients had visited different healthcare facilities within one day, with a total of 672,478 visits and 337,260 switches between facilities in 329,073 patient-days. While 63.0% (n=212,590) of all switches occurred between facilities of the same accreditation level, 14.1% (n=47,664) moved from lower to higher level, and 22.8% (n=77,006) moved in the opposite direction. In 33,689 switches, patients moved to the same specialty of another facility. In 48,324 switches, patients moved to another facility with the same diagnosis, and the most frequent diagnoses were diseases of the digestive system (11,148) and diseases of the respiratory system (10,393). In a densely populated country without strict referral regulation, a high percentage of Taiwanese people had the experience of visiting different healthcare facilities on the same day. The system of family physicians as personal doctors and gatekeepers to healthcare might ameliorate the harmful impact.

Head and neck squamous cell carcinoma (HNSCC) is a highly lethal cancer. Previously, we identify head and neck cancer initiating cells (HN-CICs), which are highly tumorigenic and resistant to conventional therapy. Therefore, development of drug candidates that effectively target HN-CICs would benefit future head and neck cancer therapy. In this study, we first successfully screened for an active component, named YMGKI-1, from natural products of Antrodia cinnamomea Mycelia (ACM), which can target the stemness properties of HNSCC. Treatment of YMGKI-1 significantly downregulated the aldehyde dehydrogenase (ALDH) activity, one of the characteristics of CIC in HNSCC cells. Additionally, the tumorigenic properties of HNSCC cells were attenuated by YMGKI-1 treatment in vivo. Further, the stemness properties of HN-CICs, which are responsible for the malignancy of HNSCC, were also diminished by YMGKI-1 treatment. Strikingly, YMGKI-1 also effectively suppressed the cell viability of HN-CICs but not normal stem cells. Finally, YMGKI-1 induces the cell death of HN-CICs by dysregulating the exaggerated autophagic signaling pathways. Together, our results indicate that YMGKI-1 successfully lessens stemness properties and tumorigenicity of HN-CICs. These findings provide a new drug candidate from purified components of ACM as an alternative therapy for head and neck cancer in the future.

Adult liver malignancies, including intrahepatic cholangiocarcinoma and hepatocellular carcinoma, are the second leading cause of cancer-related deaths worldwide. Most individuals are treated with either combination chemotherapy or immunotherapy, respectively, without specific biomarkers for selection. Here using high-throughput screens, proteomics and in vitro resistance models, we identify the small molecule YC-1 as selectively active against a defined subset of cell lines derived from both liver cancer types. We demonstrate that selectivity is determined by expression of the liver-resident cytosolic sulfotransferase enzyme SULT1A1, which sulfonates YC-1. Sulfonation stimulates covalent binding of YC-1 to lysine residues in protein targets, enriching for RNA-binding factors. Computational analysis defined a wider group of structurally related SULT1A1-activated small molecules with distinct target profiles, which together constitute an untapped small-molecule class. These studies provide a foundation for preclinical development of these agents and point to the broader potential of exploiting SULT1A1 activity for selective targeting strategies. Shi et al. report a sulfonation-dependent vulnerability of liver tumors expressing the sulfotransferase SULT1A1 by showing their sensitivity to the small molecule YC-1 and identifying structurally related compounds that can be modified by SULT1A1.