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Immune checkpoint blockade is effective for some patients with cancer, but most are refractory to current immunotherapies and new approaches are needed to overcome resistance1,2. 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 immunity3-6. 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.
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Inmunoterapia , Neoplasias , Proteína Tirosina Fosfatasa no Receptora Tipo 1 , Proteína Tirosina Fosfatasa no Receptora Tipo 2 , Animales , Humanos , Ratones , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Modelos Animales de Enfermedad , Resistencia a Antineoplásicos , Inhibidores de Puntos de Control Inmunológico , Inmunoterapia/métodos , Interferones/inmunología , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/inmunología , Neoplasias/tratamiento farmacológico , Neoplasias/enzimología , Neoplasias/inmunología , Proteína Tirosina Fosfatasa no Receptora Tipo 1/antagonistas & inhibidores , Proteína Tirosina Fosfatasa no Receptora Tipo 2/antagonistas & inhibidores , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunologíaRESUMEN
Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are the most frequently mutated metabolic genes across human cancers. These hotspot gain-of-function mutations cause the IDH enzyme to aberrantly generate high levels of the oncometabolite, R-2-hydroxyglutarate, which competitively inhibits enzymes that regulate epigenetics, DNA repair, metabolism, and other processes. Among epithelial malignancies, IDH mutations are particularly common in intrahepatic cholangiocarcinoma (iCCA). Importantly, pharmacological inhibition of mutant IDH (mIDH) 1 delays progression of mIDH1 iCCA, indicating a role for this oncogene in tumor maintenance. However, not all patients receive clinical benefit, and those who do typically show stable disease rather than significant tumor regressions. The elucidation of the oncogenic functions of mIDH is needed to inform strategies that can more effectively harness mIDH as a therapeutic target. This review will discuss the biology of mIDH iCCA, including roles of mIDH in blocking cell differentiation programs and suppressing antitumor immunity, and the potential relevance of these effects to mIDH1-targeted therapy. We also cover opportunities for synthetic lethal therapeutic interactions that harness the altered cell state provoked by mIDH1 rather than inhibiting the mutant enzyme. Finally, we highlight key outstanding questions in the biology of this fascinating and incompletely understood oncogene.
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Neoplasias de los Conductos Biliares , Colangiocarcinoma , Neoplasias de los Conductos Biliares/genética , Conductos Biliares Intrahepáticos/metabolismo , Biología , Colangiocarcinoma/genética , Humanos , Isocitrato Deshidrogenasa/genética , MutaciónRESUMEN
The emergence of SARS-CoV-2 has profoundly impacted global society and various aspects of human life. While the pandemic has resulted in disruptions and challenges, it has also accelerated scientific research on viruses and immunology, leading to remarkable progress in vaccine technology and immunization strategies. This review examines the impact of SARS-CoV-2 on pre-existing neuromuscular disorders, and neuromuscular events following SARS-CoV-2 infection, including immune-mediated and critical illness status-related disorders. Furthermore, the review discusses the relationship between SARSCoV- 2 vaccination and neuromuscular complications. The findings highlight the need for further research and understanding to improve patient outcomes. Keywords: SARS-CoV-2, neuromuscular diseases, vaccine.
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COVID-19 , Enfermedades Neuromusculares , Humanos , SARS-CoV-2 , COVID-19/complicaciones , Enfermedades Neuromusculares/complicaciones , Inmunización , PandemiasRESUMEN
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.
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Instituciones de Salud/estadística & datos numéricos , Estudios de Cohortes , Femenino , Humanos , Masculino , Taiwán , Revisión de Utilización de RecursosRESUMEN
Metabolic reprogramming is key for cancer development, yet the mechanism that sustains triple-negative breast cancer (TNBC) cell growth despite deficient pyruvate kinase M2 (PKM2) and tumor glycolysis remains to be determined. Here, we find that deficiency in tumor glycolysis activates a metabolic switch from glycolysis to fatty acid ß-oxidation (FAO) to fuel TNBC growth. We show that, in TNBC cells, PKM2 directly interacts with histone methyltransferase EZH2 to coordinately mediate epigenetic silencing of a carnitine transporter, SLC16A9. Inhibition of PKM2 leads to impaired EZH2 recruitment to SLC16A9, and in turn de-represses SLC16A9 expression to increase intracellular carnitine influx, programming TNBC cells to an FAO-dependent and luminal-like cell state. Together, these findings reveal a new metabolic switch that drives TNBC from a metabolically heterogeneous-lineage plastic cell state to an FAO-dependent-lineage committed cell state, where dual targeting of EZH2 and FAO induces potent synthetic lethality in TNBC.
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Neoplasias de la Mama Triple Negativas , Humanos , Neoplasias de la Mama Triple Negativas/metabolismo , Línea Celular Tumoral , Mutaciones Letales Sintéticas , Glucólisis , CarnitinaRESUMEN
Fibrolamellar carcinoma (FLC) is a liver cancer of adolescents and young adults characterized by fusions of the genes encoding the protein kinase A catalytic subunit, PRKACA, and heat shock protein, DNAJB1. The chimeric DNAJB1-PRKACA protein has increased kinase activity and is essential for FLC xenograft growth. Here, we explore the critical oncogenic pathways controlled by DNAJB1-PRKACA using patient-derived FLC models, engineered systems, and patient samples. We show that a core function of DNAJB1-PRKACA is the phosphorylation and inactivation of Salt-inducible kinases (SIKs). This leads to deregulation of the CRTC2 transcriptional co-activator and p300 acetyltransferase, resulting in transcriptional reprogramming and increased global histone acetylation, driving malignant growth. Our studies establish a central oncogenic mechanism of DNAJB1-PRKACA and suggest the potential of targeting CRTC2/p300 in FLC. Notably, these findings link this rare cancer's signature fusion oncoprotein to more common cancer gene alterations involving STK11 and GNAS, which also function via SIK suppression.
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Isocitrate dehydrogenase 1 (IDH1) is the most commonly mutated metabolic gene across human cancers. Mutant IDH1 (mIDH1) generates the oncometabolite (R)-2-hydroxyglutarate, disrupting enzymes involved in epigenetics and other processes. A hallmark of IDH1-mutant solid tumors is T cell exclusion, whereas mIDH1 inhibition in preclinical models restores antitumor immunity. Here, we define a cell-autonomous mechanism of mIDH1-driven immune evasion. IDH1-mutant solid tumors show selective hypermethylation and silencing of the cytoplasmic double-stranded DNA (dsDNA) sensor CGAS, compromising innate immune signaling. mIDH1 inhibition restores DNA demethylation, derepressing CGAS and transposable element (TE) subclasses. dsDNA produced by TE-reverse transcriptase (TE-RT) activates cGAS, triggering viral mimicry and stimulating antitumor immunity. In summary, we demonstrate that mIDH1 epigenetically suppresses innate immunity and link endogenous RT activity to the mechanism of action of a US Food and Drug Administration-approved oncology drug.
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Evasión Inmune , Inmunidad Innata , Isocitrato Deshidrogenasa , Neoplasias , Animales , Humanos , Ratones , Línea Celular Tumoral , ADN/metabolismo , Desmetilación del ADN , Metilación de ADN , Elementos Transponibles de ADN , Epigénesis Genética , Glutaratos/metabolismo , Inmunidad Innata/genética , Isocitrato Deshidrogenasa/genética , Isocitrato Deshidrogenasa/metabolismo , Mutación , Neoplasias/inmunología , Neoplasias/genética , Nucleotidiltransferasas/genética , Escape del Tumor , Evasión Inmune/genéticaRESUMEN
Biliary tract cancers (BTCs) are a group of deadly malignancies encompassing intrahepatic and extrahepatic cholangiocarcinoma, gallbladder carcinoma, and ampullary carcinoma. Here, we present the integrative analysis of 63 BTC cell lines via multi-omics clustering and genome- scale CRISPR screens, providing a platform to illuminate BTC biology and inform therapeutic development. We identify dependencies broadly enriched in BTC compared to other cancers as well as dependencies selective to the anatomic subtypes. Notably, cholangiocarcinoma cell lines are stratified into distinct lineage subtypes based on biliary or dual biliary/hepatocyte marker signatures, associated with dependency on specific lineage survival factors. Transcriptional analysis of patient specimens demonstrates the prognostic significance of these lineage subtypes. Additionally, we delineate strategies to enhance targeted therapies or to overcome resistance in cell lines with key driver gene mutations. Furthermore, clustering based on dependencies and proteomics data elucidates unexpected functional relationships, including a BTC subgroup with partial squamous differentiation. Thus, this cell line atlas reveals potential therapeutic targets in molecularly defined BTCs, unveils biologically distinct disease subtypes, and offers a vital resource for BTC research.
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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.
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Alquilantes , Neoplasias Hepáticas , Humanos , Sulfotransferasas , Neoplasias Hepáticas/tratamiento farmacológico , ArilsulfotransferasaRESUMEN
Immunometabolism considers the relationship between metabolism and immunity. Typically, researchers focus on either the metabolic pathways within immune cells that affect their function or the impact of immune cells on systemic metabolism. A more holistic approach that considers both these viewpoints is needed. On September 5-8, 2022, experts in the field of immunometabolism met for the Keystone symposium "Immunometabolism at the Crossroads of Obesity and Cancer" to present recent research across the field of immunometabolism, with the setting of obesity and cancer as an ideal example of the complex interplay between metabolism, immunity, and cancer. Speakers highlighted new insights on the metabolic links between tumor cells and immune cells, with a focus on leveraging unique metabolic vulnerabilities of different cell types in the tumor microenvironment as therapeutic targets and demonstrated the effects of diet, the microbiome, and obesity on immune system function and cancer pathogenesis and therapy. Finally, speakers presented new technologies to interrogate the immune system and uncover novel metabolic pathways important for immunity.
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Neoplasias , Humanos , Neoplasias/metabolismo , Sistema Inmunológico , Redes y Vías Metabólicas , Obesidad/terapia , Obesidad/metabolismo , Microambiente TumoralRESUMEN
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.
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FGFR inhibitors are approved for the treatment of advanced cholangiocarcinoma harboring FGFR2 fusions. However, the response rate is moderate, and resistance emerges rapidly due to acquired secondary FGFR2 mutations or due to other less-defined mechanisms. Here, we conducted high-throughput combination drug screens, biochemical analysis, and therapeutic studies using patient-derived models of FGFR2 fusion-positive cholangiocarcinoma to gain insight into these clinical profiles and uncover improved treatment strategies. We found that feedback activation of EGFR signaling limits FGFR inhibitor efficacy, restricting cell death induction in sensitive models and causing resistance in insensitive models lacking secondary FGFR2 mutations. Inhibition of wild-type EGFR potentiated responses to FGFR inhibitors in both contexts, durably suppressing MEK/ERK and mTOR signaling, increasing apoptosis, and causing marked tumor regressions in vivo. Our findings reveal EGFR-dependent adaptive signaling as an important mechanism limiting FGFR inhibitor efficacy and driving resistance and support clinical testing of FGFR/EGFR inhibitor therapy for FGFR2 fusion-positive cholangiocarcinoma. SIGNIFICANCE: We demonstrate that feedback activation of EGFR signaling limits the effectiveness of FGFR inhibitor therapy and drives adaptive resistance in patient-derived models of FGFR2 fusion-positive cholangiocarcinoma. These studies support the potential of combination treatment with FGFR and EGFR inhibitors as an improved treatment for patients with FGFR2-driven cholangiocarcinoma. This article is highlighted in the In This Issue feature, p. 1171.
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Neoplasias de los Conductos Biliares , Colangiocarcinoma , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Neoplasias de los Conductos Biliares/genética , Neoplasias de los Conductos Biliares/metabolismo , Conductos Biliares Intrahepáticos/metabolismo , Conductos Biliares Intrahepáticos/patología , Colangiocarcinoma/tratamiento farmacológico , Colangiocarcinoma/genética , Colangiocarcinoma/metabolismo , Receptores ErbB/genética , Humanos , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/farmacología , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genética , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/metabolismoRESUMEN
Isocitrate dehydrogenase 1 mutations (mIDH1) are common in cholangiocarcinoma. (R)-2-hydroxyglutarate generated by the mIDH1 enzyme inhibits multiple α-ketoglutarate-dependent enzymes, altering epigenetics and metabolism. Here, by developing mIDH1-driven genetically engineered mouse models, we show that mIDH1 supports cholangiocarcinoma tumor maintenance through an immunoevasion program centered on dual (R)-2-hydroxyglutarate-mediated mechanisms: suppression of CD8+ T-cell activity and tumor cell-autonomous inactivation of TET2 DNA demethylase. Pharmacologic mIDH1 inhibition stimulates CD8+ T-cell recruitment and interferon γ (IFNγ) expression and promotes TET2-dependent induction of IFNγ response genes in tumor cells. CD8+ T-cell depletion or tumor cell-specific ablation of TET2 or IFNγ receptor 1 causes treatment resistance. Whereas immune-checkpoint activation limits mIDH1 inhibitor efficacy, CTLA4 blockade overcomes immunosuppression, providing therapeutic synergy. The findings in this mouse model of cholangiocarcinoma demonstrate that immune function and the IFNγ-TET2 axis are essential for response to mIDH1 inhibition and suggest a novel strategy for potentiating efficacy. SIGNIFICANCE: Mutant IDH1 inhibition stimulates cytotoxic T-cell function and derepression of the DNA demethylating enzyme TET2, which is required for tumor cells to respond to IFNγ. The discovery of mechanisms of treatment efficacy and the identification of synergy by combined CTLA4 blockade provide the foundation for new therapeutic strategies. See related commentary by Zhu and Kwong, p. 604. This article is highlighted in the In This Issue feature, p. 587.
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Neoplasias de los Conductos Biliares , Colangiocarcinoma , Dioxigenasas , Animales , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Neoplasias de los Conductos Biliares/genética , Conductos Biliares Intrahepáticos/metabolismo , Antígeno CTLA-4/genética , Colangiocarcinoma/tratamiento farmacológico , Colangiocarcinoma/genética , Proteínas de Unión al ADN/genética , Dioxigenasas/genética , Humanos , Interferón gamma/genética , Isocitrato Deshidrogenasa , Ratones , MutaciónRESUMEN
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 (memGRP78+) exerted cancer stemness properties of self-renewal, differentiation and radioresistance. Of note, xenotransplantation assay indicated merely 100 memGRP78+ 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, memGRP78 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.
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Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Neoplasias de Cabeza y Cuello/metabolismo , Neoplasias de Cabeza y Cuello/patología , Proteínas de Choque Térmico/metabolismo , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Transducción de Señal , Animales , Carcinoma de Células Escamosas/genética , Línea Celular , Movimiento Celular/genética , Movimiento Celular/fisiología , Chaperón BiP del Retículo Endoplásmico , Citometría de Flujo , Perfilación de la Expresión Génica , Neoplasias de Cabeza y Cuello/genética , Proteínas de Choque Térmico/genética , Humanos , Inmunohistoquímica , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Análisis de Secuencia por Matrices de Oligonucleótidos , Interferencia de ARNRESUMEN
Hydrogels have extended applications across multiple fields. A novel hydrogel material is often evaluated for its properties and applications in either a wet or dry state, but not both. In this study, we investigated a protein-based, composite hydrogel system in both its wet and dry states. Bovine serum albumin (BSA) was used as the hydrogel base. With the assistance of organosilanes, BSA solutions became hydrogels under facile reaction conditions. In the first part, the wet gel was prepared in situ in a syringe; upon injecting through a needle, the gel retained its structure. The use of the nascent gel system as an injectable drug-delivery vehicle is of particular interest. We therefore developed a microplate platform that allows a "one-plate" study-i.e. gel preparation, payload loading and release-all being performed in a single plate. This one-plate method further enables a systematic study of various controlling parameters for drug release. For example, we can tune the release rate by simply adjusting the phosphate content in the hydrogel formulation. Besides, for low-releasing compounds, the release profile was also tunable while using the one-plate method. In the second part, we further demonstrate the versatility of our composite hydrogels. By simply varying the feed ratio of two organosilanes, (3-mercaptopropyl)methyldimethoxysilane and (3-mercaptopropyl)trimethoxysilane, and phosphate concentrations, dry gels exhibiting various absorption capacities towards water, organic solvents, and oil can be prepared. Further characterizations using SEM and 29Si NMR spectroscopy revealed porous structures and hybrid siloxane bridges within the composite material.
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Sistemas de Liberación de Medicamentos , Hidrogeles/química , Animales , Bovinos , Doxorrubicina/administración & dosificación , Doxorrubicina/química , Liberación de Fármacos , Fluoresceína/administración & dosificación , Fluoresceína/química , Azul de Metileno/administración & dosificación , Azul de Metileno/química , Compuestos de Organosilicio , Porosidad , Rodaminas/administración & dosificación , Rodaminas/química , Albúmina Sérica Bovina/química , Silanos/químicaRESUMEN
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.
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Diferenciación Celular , Proteínas de Unión al ADN/metabolismo , Estradiol/metabolismo , Estrógenos/metabolismo , Glándulas Mamarias Animales/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Animales , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/fisiopatología , Linaje de la Célula , Metilación de ADN , Proteínas de Unión al ADN/genética , Dioxigenasas , Sistema Endocrino/metabolismo , Epigénesis Genética , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/metabolismo , Femenino , Humanos , Glándulas Mamarias Animales/fisiopatología , Ratones , Ratones Noqueados , Proteínas Proto-Oncogénicas/genéticaRESUMEN
Reactions involving hydrophobic reactants in water can be much accelerated in organic solvent-free solutions containing amphiphiles at neutral pH and room temperature. Previously, we demonstrated that organosilica colloidal particles could be conveniently synthesized by a versatile salt-catalysis method in solutions modified with various amphiphilic molecules. The method precludes the use of any solvent, any added form of energy (thermal or mechanical), and any strong (or hazardous) acids/bases. Herein, the kinetic properties of the reaction were systematically investigated for fluoride-catalysed synthesis of colloidal organosilica from a thiol-functionalized organosilane precursor, (3-mercaptopropyl)trimethoxysilane. Continuous, real-time ATR-FTIR measurements allowed probing the time evolution of organosilica condensation in different reaction systems, containing one of the following: non-ionic surfactants (Tween 20, Tween 40, Tween 60, Tween 80, Triton X-100), anionic surfactant (sodium dodecyl sulphate; SDS), cationic surfactant (cetyltrimethylammonium bromide; CTAB), and amphiphilic polymers (polyvinyl alcohol and polyvinylpyrrolidone). Overall, while some amphiphile-specific properties were revealed, fluoride-catalysed synthesis was ultrafast with a universal two-phase kinetic scheme (e.g. transition within 5-10 min) for all amphiphiles studied.
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HYPOTHESIS: Protein hydrogels are water-rich structure of cross-linked protein networks. The preparation of dry gels is conceptually simple. However, reports on innovative use of dry protein hydrogels are scarce, possibly because water removal would diminish intended properties. Here, an oil-like thiol-organosilane is proposed as a protein hydrogel-promoting agent that mediates the formation of hydrophobic composite gel networks with promising properties upon drying. EXPERIMENTS: 3-Mercaptopropyltrimethoxylsilane (MPTMS) was used to transform aqueous albumin solutions into hydrogels. The gelation conditions were systematically investigated and optimized by varying various parameters, including temperature, pH, and the concentrations of MPTMS, albumin, and phosphate. The hydrogels were freeze-dried to obtain dry gel monoliths. The morphology of gel structure was evaluated using FE-SEM. The following properties of the dry monoliths were further evaluated: water uptake, floatability, drug loading and release, water contact angles, bulk densities, and oil adsorption. Mechanistic investigation included FTIR and fluorescence quenching determinations, and the study of emulsion properties. FINDINGS: An unprecedented protein-organosilane composite hydrogel was synthesized in a one-step reaction, at neutral pH and ambient conditions. Freeze-dried gel monoliths exhibited excellent hydrophobicity and floatability (immediate floating and lasting for >7â¯days on water). The proposed material may find novel applications in floating drug delivery and environmental clean-up of oil spills.
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Mitochondria are dynamic organelles that have been linked to stem cell homeostasis. However, the mechanisms involved in mitochondrial regulation of stem cell fate determination remain elusive. Here we discover that epithelial-mesenchymal transition (EMT), a key process in cancer progression, induces mitochondrial fusion through regulation of the miR200c-PGC1α-MFN1 pathway. EMT-activated MFN1 forms a complex with PKCζ and is required for PKCζ-mediated NUMB phosphorylation and dissociation from the cortical membrane to direct asymmetric division of mammary stem cells, where fused mitochondria are tethered by MFN1-PKCζ to the cortical membrane and asymmetrically segregated to the stem cell-like progeny with enhanced glutathione synthesis and reactive oxygen species scavenging capacities, allowing sustaining of a self-renewing stem cell pool. Suppression of MFN1 expression leads to equal distribution of the fragmented mitochondria in both progenies that undergo symmetric luminal cell differentiation. Together, this study elucidates an essential role of mitofusin in stem cell fate determination to mediate EMT-associated stemness.
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Polaridad Celular , Transición Epitelial-Mesenquimal , GTP Fosfohidrolasas/metabolismo , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Células Madre/citología , Células Madre/metabolismo , Animales , Línea Celular , Femenino , Humanos , Ratones , Ratones Noqueados , MicroARNs/metabolismo , Mitocondrias/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismoRESUMEN
PURPOSE: We report a case of spontaneous resolution of donor disk partial dislocation after deep lamellar endothelial keratoplasty (DLEK). DESIGN: Case report. METHODS: A 70-year-old male with right pseudophakia bullous keratopathy underwent DLEK. Postoperatively, a partial dislocation of inferior donor disk was noted. Repositioning surgery with gas tamponade was performed. RESULTS: The interfacial separation remained after gas tamponade. Two weeks later, corneal edema subsided, and there was a reduction in interfacial separation. One month after DLEK, donor disk spontaneously attached to recipient corneal bed. At the six-month follow-up, astigmatism was 1.75 diopters. Specular microscopy showed endothelial counts of 1520 cells/mm(2). Spectacle-corrected visual acuity improved to 6/15. CONCLUSIONS: Partial dislocation of donor disk after DLEK has a possibility of spontaneous resolution, even after a failed attempt at gas tamponade.