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BACKGROUND: New antifungal agents are required to mitigate against azole-resistant Aspergillus and drug-resistant non-Aspergillus moulds. The novel orotomide, olorofim (F2G, Manchester, UK), has potent fungicidal activity against Aspergillus including azole-resistant Aspergillus fumigatus, Lomentospora prolificans and Scedosporium spp. Development of olorofim-specific clinical breakpoints/epidemiological cut-off values requires reliable MIC data. OBJECTIVES: Determine the in vitro activity of olorofim compared with standard antifungals against mould pathogens at an Australian hospital. MATERIALS AND METHODS: Olorofim MICs were determined for 507 clinical mould isolates using the CLSI M38-A3 standard. MICs of amphotericin B, anidulafungin, posaconazole, voriconazole and isavuconazole were obtained using Sensititre™ YeastOne YO10 and AUSNMRCI panels (Thermo-Fisher Scientific). RESULTS: A. fumigatus sensu stricto was the commonest species (33.3%) followed by L. prolificans (18.3%), Scedosporium (11.4%) and Fusarium (6%) species. Olorofim modal MICs were ≤0.25 mg/L (MIC90 0.25 mg/L) for all Aspergillus except Aspergillus Section Usti (1 mg/L); MICs for nine azole-resistant/non-wild-type A. fumigatus ranged from 0.008 to 0.125 mg/L. The MIC90 of olorofim for L. prolificans was 0.5 mg/L, 0.25-0.5 mg/L for Scedosporium spp. and 8 mg/L for the F. solani complex but with modal MICs of 0.25 and 0.008 mg/L for F. oxysporum and F. proliferatum complexes, respectively. For Verruconis gallopava (nâ=â10), the olorofim MIC90 was 0.06 mg/L (voriconazole MIC90 2 mg/L, isavuconazole MICs of 4->8 mg/L). Olorofim had little activity against other dematiaceous moulds including Exophiala species. CONCLUSIONS: Olorofim was highly active against Aspergillus spp. including azole-resistant A. fumigatus, L. prolificans, Scedosporium spp. and some Fusarium species with the new finding of potent activity against V. gallopava.
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OBJECTIVE: Our objective was to codesign, implement, evaluate acceptability and refine an optimised antenatal education session to improve birth preparedness. DESIGN: There were four distinct phases: codesign (focus groups and codesign workshops with parents and staff); implementation of intervention; evaluation (interviews, questionnaires, structured feedback forms) and systematic refinement. SETTING: The study was set in a single maternity unit with approximately 5500 births annually. PARTICIPANTS: Postnatal and antenatal women/birthing people and birth partners were invited to participate in the intervention, and midwives were invited to deliver it. Both groups participated in feedback. OUTCOME MEASURES: We report on whether the optimised session is deliverable, acceptable, meets the needs of women/birthing people and partners, and explain how the intervention was refined with input from parents, clinicians and researchers. RESULTS: The codesign was undertaken by 35 women, partners and clinicians. Five midwives were trained and delivered 19 antenatal education (ACE) sessions to 142 women and 94 partners. 121 women and 33 birth partners completed the feedback questionnaire. Women/birthing people (79%) and birth partners (82%) felt more prepared after the class with most participants finding the content very helpful or helpful. Women/birthing people perceived classes were more useful and engaging than their partners. Interviews with 21 parents, a midwife focus group and a structured feedback form resulted in 38 recommended changes: 22 by parents, 5 by midwives and 11 by both. Suggested changes have been incorporated in the training resources to achieve an optimised intervention. CONCLUSIONS: Engaging stakeholders (women and staff) in codesigning an evidence-informed curriculum resulted in an antenatal class designed to improve preparedness for birth, including assisted birth, that is acceptable to women and their birthing partners, and has been refined to address feedback and is deliverable within National Health Service resource constraints. A nationally mandated antenatal education curriculum is needed to ensure parents receive high-quality antenatal education that targets birth preparedness.
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Grupos Focales , Educación Prenatal , Humanos , Femenino , Embarazo , Grupos Focales/métodos , Adulto , Encuestas y Cuestionarios , Educación Prenatal/métodos , Educación Prenatal/estadística & datos numéricos , Atención Prenatal/métodos , Atención Prenatal/normas , Trabajo de PartoRESUMEN
BACKGROUND: Little is known about the short- and long-term healthcare costs of invasive Scedosporium/Lomentospora prolificans infections, particularly in patient groups without haematological malignancy. This study investigated excess index hospitalization costs and cumulative costs of these infections. The predictors of excess cost and length of stay (LOS) of index hospitalization were determined. These estimates serve as valuable inputs for cost-effectiveness models of novel antifungal agents. METHODS: A retrospective case-control study was conducted at six Australian hospitals. Cases of proven/probable invasive Scedosporium/L. prolificans infections between 2011 and 2021 (n = 34) were matched with controls (n = 66) by predefined criteria. Cost data were retrieved from activity-based costing systems and analysis was performed from the Australian public hospital perspective. All costs were presented in 2022 Australian dollars (AUD). Median regression analysis was used to adjust excess costs of index hospitalization whereas cumulative costs up to 1.5 years follow-up were estimated using interval-partitioned survival probabilities. RESULTS: Invasive Scedosporium/L. prolificans infections were independently associated with an adjusted median excess cost of AUD36 422 (P = 0.003) and LOS of 16.27 days (P < 0.001) during index hospitalization. Inpatient stay was the major cost driver (42.7%), followed by pharmacy cost, of which antifungal agents comprised 23.8% of the total cost. Allogeneic haematopoietic stem cell transplant increased the excess cost (P = 0.013) and prolonged LOS (P < 0.001) whereas inpatient death within ≤28 days reduced both cost (P = 0.001) and LOS (P < 0.001). The median cumulative cost increased substantially to AUD203 292 over 1.5 years in cases with Scedosporium/L. prolificans infections. CONCLUSIONS: The economic burden associated with invasive Scedosporium/L. prolificans infections is substantial.
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Antifúngicos , Scedosporium , Humanos , Antifúngicos/uso terapéutico , Estudios de Casos y Controles , Estudios Retrospectivos , Australia/epidemiologíaRESUMEN
Invasive aspergillosis (IA) is an acute infection affecting patients who are immunocompromised, as a result of receiving chemotherapy for malignancy, or immunosuppressant agents for transplantation or autoimmune disease. Whilst criteria exist to define the probability of infection for clinical trials, there is little evidence in the literature or clinical guidelines on when to change antifungal treatment in patients who are receiving prophylaxis or treatment for IA. To try and address this significant gap, an advisory board of experts was convened to develop criteria for the management of IA for use in designing clinical trials, which could also be used in clinical practice. For primary treatment failure, a change in antifungal therapy should be made: (i) when mycological susceptibility testing identifies an organism from a confirmed site of infection, which is resistant to the antifungal given for primary therapy, or a resistance mutation is identified by molecular testing; (ii) at, or after, 8 days of primary antifungal treatment if there is increasing serum galactomannan, or galactomannan positivity in serum, or bronchoalveolar lavage fluid when the antigen was previously undetectable, or there is sudden clinical deterioration, or a new clearly distinct site of infection is detected; and (iii) at, or after, 15 days of primary antifungal treatment if the patient is clinically stable but with ≥2 serum galactomannan measurements persistently elevated compared with baseline or increasing, or if the original lesions on CT or other imaging, show progression by >25% in size in the context of no apparent change in immune status.
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Aspergilosis , Infecciones Fúngicas Invasoras , Aspergilosis Pulmonar Invasiva , Antifúngicos/uso terapéutico , Aspergilosis/diagnóstico , Aspergilosis/tratamiento farmacológico , Líquido del Lavado Bronquioalveolar/microbiología , Humanos , Huésped Inmunocomprometido , Infecciones Fúngicas Invasoras/diagnóstico , Infecciones Fúngicas Invasoras/tratamiento farmacológico , Aspergilosis Pulmonar Invasiva/diagnóstico , Aspergilosis Pulmonar Invasiva/tratamiento farmacológico , MananosRESUMEN
The photochemistry of (µ2-CRCR')Co2(CO)6 complexes (R = pyrenyl, R' = H; R = pyrenyl, R' = ferrocenyl; R = ferrocenyl, R = H) was investigated by ps-time-resolved infrared spectroscopy at room temperature in dichloromethane solution. The main focus of these studies was to determine the primary photoprocess relevant to the light assisted Pauson-Khand reaction. These studies were supported by spectro-electrochemical investigations and density functional calculations which suggest that the primary process to initiate the Pauson-Khand reaction involves a homolytic cleavage of the Co-Co bond forming a high-spin diradical species and not CO-loss as previously thought.
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An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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Extracellular matrix (ECM) deposition and resultant scar play a major role in the pathogenesis and progression of liver fibrosis. Identifying core regulators of ECM deposition may lead to urgently needed diagnostic and therapetic strategies for the disease. The transcription factor Sex determining region Y box 9 (SOX9) is actively involved in scar formation and its prevalence in patients with liver fibrosis predicts progression. In this study, transcriptomic approaches of Sox9-abrogated myofibroblasts identified >30% of genes regulated by SOX9 relate to the ECM. Further scrutiny of these data identified a panel of highly expressed ECM proteins, including Osteopontin (OPN), Osteoactivin (GPNMB), Fibronectin (FN1), Osteonectin (SPARC) and Vimentin (VIM) as SOX9 targets amenable to assay in patient serum. In vivo all SOX-regulated targets were increased in human disease and mouse models of fibrosis and decreased following Sox9-loss in mice with parenchymal and biliary fibrosis. In patient serum samples, SOX9-regulated ECM proteins were altered in response to fibrosis severity, whereas comparison with established clinical biomarkers demonstrated superiority for OPN and VIM at detecting early stages of fibrosis. These data support SOX9 in the mechanisms underlying fibrosis and highlight SOX9 and its downstream targets as new measures to stratify patients with liver fibrosis.
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Proteínas de la Matriz Extracelular/metabolismo , Matriz Extracelular/metabolismo , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Factor de Transcripción SOX9/metabolismo , Animales , Biomarcadores/metabolismo , Estudios de Cohortes , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Humanos , Ratones , Ratones Endogámicos C57BL , Miofibroblastos/metabolismo , Índice de Severidad de la EnfermedadRESUMEN
Near-UV excitation of non-heme FeIV[double bond, length as m-dash]O complexes results in light intensity dependent increase in reaction rates for the oxidation of C-H bonds even at low temperature (-30 °C). The enhancement of activity is ascribed to the ligand-to-[FeIV[double bond, length as m-dash]O] charge transfer character of the near-UV bands to generate a highly reactive [(L+) FeIII-O*] species. The enhancement is not observed with visible/NIR excitation of the d-d absorption bands.
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Cardiosphere-derived cell (CDC) infusion into damaged myocardium has shown some reparative effect; this could be improved by better selection of patients and cell subtype. CDCs isolated from patients with ischemic heart disease are able to support vessel formation in vitro but this ability varies between patients. The primary aim of our study was to investigate whether the vascular supportive function of CDCs impacts on their therapeutic potential, with the goal of improving patient stratification. A subgroup of patients produced CDCs which did not efficiently support vessel formation (poor supporter CDCs), had reduced levels of proliferation and increased senescence, despite them being isolated in the same manner and having a similar immunophenotype to CDCs able to support vessel formation. In a rodent model of myocardial infarction, poor supporter CDCs had a limited reparative effect when compared to CDCs which had efficiently supported vessel formation in vitro. This work suggests that not all patients provide cells which are suitable for cell therapy. Assessing the vascular supportive function of cells could be used to stratify which patients will truly benefit from cell therapy and those who would be better suited to an allogeneic transplant or regenerative preconditioning of their cells in a precision medicine fashion. This could reduce costs, culture times and improve clinical outcomes and patient prognosis. Stem Cells Translational Medicine 2017;6:1399-1411.
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Enfermedad de la Arteria Coronaria/terapia , Isquemia Miocárdica/terapia , Células Madre/citología , Apoptosis/fisiología , Western Blotting , Movimiento Celular/fisiología , Citometría de Flujo , Humanos , InmunohistoquímicaRESUMEN
Fibrosis due to extracellular matrix (ECM) secretion from myofibroblasts complicates many chronic liver diseases causing scarring and organ failure. Integrin-dependent interaction with scar ECM promotes pro-fibrotic features. However, the pathological intracellular mechanism in liver myofibroblasts is not completely understood, and further insight could enable therapeutic efforts to reverse fibrosis. Here, we show that integrin beta-1, capable of binding integrin alpha-11, regulates the pro-fibrotic phenotype of myofibroblasts. Integrin beta-1 expression is upregulated in pro-fibrotic myofibroblasts in vivo and is required in vitro for production of fibrotic ECM components, myofibroblast proliferation, migration and contraction. Serine/threonine-protein kinase proteins, also known as P21-activated kinase (PAK), and the mechanosensitive factor, Yes-associated protein 1 (YAP-1) are core mediators of pro-fibrotic integrin beta-1 signalling, with YAP-1 capable of perpetuating integrin beta-1 expression. Pharmacological inhibition of either pathway in vivo attenuates liver fibrosis. PAK protein inhibition, in particular, markedly inactivates the pro-fibrotic myofibroblast phenotype, limits scarring from different hepatic insults and represents a new tractable therapeutic target for treating liver fibrosis.
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Proteínas Adaptadoras Transductoras de Señales/metabolismo , Integrina beta1/metabolismo , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Miofibroblastos/metabolismo , Miofibroblastos/patología , Fosfoproteínas/metabolismo , Transducción de Señal , Quinasas p21 Activadas/metabolismo , Animales , Células Estrelladas Hepáticas , Humanos , Masculino , Ratones Endogámicos C57BL , Cadenas Ligeras de Miosina/metabolismo , Fenotipo , Ratas Sprague-Dawley , Factores de Transcripción , Proteínas Señalizadoras YAPRESUMEN
External adherens junction-based cell-cell contacts involving E-cadherin interactions function to sense planar cell status and modulate epithelial cell proliferation through Hippo (Hpo) and non-canonical Wnt pathways signaling. We hypothesized these regulatory processes should also be sensitive to a similar cell-cell contact sensor associated with apical-basal polarity events at epithelial surfaces. We used 2 human pancreatic cancer cell lines to explore this hypothesis: one with the capacity to form functional tight junction structures and polarize (HPAFII) and one lacking this capacity (AsPc1). Occludin (Ocln), a tetraspanning protein associated with TJ structures and capable of establishing external cell-cell contacts, was observed to partially co-localize with Hpo elements YAP (c-yes associated protein) and TEAD (TEA-dependent), which function to drive a proliferative transcription program. Treatment with dobutamine, known to affect YAP, was shown to suppress proliferation in an Ocln-dependent manner. Blockade of protein kinase C-zeta (PKC-ζ) diminished transepithelial electrical resistance (TER) of HPAFII monolayers that was not corrected by dobutamine treatment while the loss of TER resulting from inhibition of ROCK1 could be partially recovered. Examination of normal and cancerous human pancreatic biopsies showed that the cellular localization of Ocln, c-Yes, YAP, and TEAD were similar to HPAFII for normal cells and AsPc1 for cancerous cells. Together, these results suggest a link between Hpo and signals emanating from cell-cell contacts involving Ocln that may regulate pancreatic cell proliferation through the coordination of planar cell polarity with apical-basal polarity events.
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Heart failure (HF) is the major cause of mortality worldwide. For more than a decade, cell-based therapies have been developed as treatment for heart disease as an alternative to current therapies. Trials and systematic reviews have assessed the safety and efficacy of cell therapies in a diverse number of participants and clinical settings. The present study collated and synthesized evidence from all systematic reviews related to cell-based therapies and HF. A total of 11 systematic reviews were identified through searches of electronic databases up to June 2014. We set out to answer 2 key questions on the efficacy of cell therapies in HF: (1) What is the overall effect of cell therapies on primary outcomes such as left ventricular ejection fraction (LVEF) and mortality? (2) How important is it to define the clinical setting and length of follow-up when assessing cell therapies and HF? There seems to be enough evidence to suggest that cell therapies have a moderate, long-lasting effect on LVEF, but the reduction on the risk of mortality observed by some systematic reviews needs to be confirmed in larger, statistically powered clinical trials. Additionally, and in order to strengthen conclusions, it is important to assess clinical evidence for defined clinical settings and to standardize the length of follow-up when comparing outcome data across several trials and systematic reviews.
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Tratamiento Basado en Trasplante de Células y Tejidos , Bases de Datos Factuales , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/terapia , Volumen Sistólico , Ensayos Clínicos como Asunto , Insuficiencia Cardíaca/mortalidad , HumanosRESUMEN
A general method for the preparation of N-protected ß-amino aldehydes from allylic amines or linear allylic alcohols is described. Here the Pd(II)-catalyzed oxidation of N-protected allylic amines with benzoquinone is achieved in tBuOH under ambient conditions with excellent selectivity toward the anti-Markovnikov aldehyde products and full retention of configuration at the allylic carbon. The method shows a wide substrate scope and is tolerant of a range of protecting groups. Furthermore, ß-amino aldehydes can be obtained directly from protected allylic alcohols via palladium-catalyzed autotandem reactions, and the application of this method to the synthesis of ß-peptide aldehydes is described. From a mechanistic perspective, we demonstrate that tBuOH acts as a nucleophile in the reaction and that the initially formed tert-butyl ether undergoes spontaneous loss of isobutene to yield the aldehyde product. Furthermore, tBuOH can be used stoichiometrically, thereby broadening the solvent scope of the reaction. Primary and secondary alcohols do not undergo elimination, allowing the isolation of acetals, which subsequently can be hydrolyzed to their corresponding aldehyde products.
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Aldehídos/síntesis química , Compuestos Alílicos/química , Amidas/química , Compuestos Organometálicos/química , Paladio/química , Aldehídos/química , Catálisis , Estructura Molecular , Oxidación-ReducciónRESUMEN
Multimodal photo, thermal and electrochemical approaches toward CO release from the amino carbene complex [(CO)5CrC(NC4H8)CH3] is reported. Picosecond time resolved infrared spectroscopy was used to probe the photo-induced early state dynamics leading to CO release, and DFT calculations confirmed that CO release occurs from a singlet excited state.
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Monóxido de Carbono/química , Cromo/química , Técnicas Electroquímicas , Metano/análogos & derivados , Compuestos Organometálicos/química , Temperatura , Metano/química , Procesos Fotoquímicos , Teoría CuánticaRESUMEN
The photochemistry and photophysics of three model "half-sandwich" complexes (η(6)-benzophenone)Cr(CO)3, (η(6)-styrene)Cr(CO)3, and (η(6)-allylbenzene)Cr(CO)3 were investigated using pico-second time-resolved infrared spectroscopy and time-dependent density functional theory methods. The (η(6)-benzophenone)Cr(CO)3 complex was studied using two excitation wavelengths (470 and 320 nm) while the remaining complexes were irradiated using 400 nm light. Two independent excited states were detected spectroscopically for each complex, one an unreactive excited state of metal-to-arene charge-transfer character and the other with metal-to-carbonyl charge transfer character. This second excited state leads to an arrested release of CO on the pico-second time-scale. Low-energy excitation (470 nm) of (η(6)-benzophenone)Cr(CO)3 populated only the unreactive excited state which simply relaxes to the parent complex. Higher energy irradiation (320 nm) induced CO-loss. Irradiation of (η(6)-styrene)Cr(CO)3, or (η(6)-allylbenzene)Cr(CO)3 at 400 nm provided evidence for the simultaneous population of both the reactive and unreactive excited states. The efficiency at which the unreactive excited state is populated depends on the degree of conjugation of the substituent with the arene π-system and this affects the efficiency of the CO-loss process. The quantum yield of CO-loss is 0.50 for (η(6)-allylbenzene)Cr(CO)3 and 0.43 for (η(6)-styrene)Cr(CO)3. These studies provide evidence for the existence of two photophysical routes to CO loss, a minor ultrafast route and an arrested mechanism involving the intermediate population of a reactive excited state. This reactive excited state either relaxes to reform the parent species or eject CO. Thus the quantum yield of the CO-loss is strongly dependent on the excitation wavelength. Time-dependent density functional theory calculations confirm that the state responsible for ultrafast CO-loss has significant metal-centred character while the reactive state responsible for the arrested CO-loss has significant metal-to-carbonyl charge-transfer character. The CO-loss product (η(6)-allylbenzene)Cr(CO)2 formed following irradiation of (η(6)-allylbenzene)Cr(CO)3 reacts further with the pendent alkenyl group to form the chelate product (η(6),η(2)-allylbenzene)Cr(CO)2.
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BACKGROUND AND AIMS: Liver fibrosis is a major cause of morbidity and mortality. It is characterised by excessive extracellular matrix (ECM) deposition from activated hepatic stellate cells (HSCs). Although potentially reversible, treatment remains limited. Understanding how ECM influences the pathogenesis of the disease may provide insight into novel therapeutic targets for the disease. The extracellular protein Epimorphin (EPIM) has been implicated in tissue repair mechanisms in several tissues, partially, through its ability to manipulate proteases. In this study, we have identified that EPIM modulates the ECM environment produced by activated hepatic stellate cells (HSCs), in part, through down-regulation of pro-fibrotic Sex-determining region Y-box 9 (SOX9). METHODS: Influence of EPIM on ECM was investigated in cultured primary rat HSCs. Activated HSCs were treated with recombinant EPIM or SOX9 siRNA. Core fibrotic factors were evaluated by immunoblotting, qPCR and chromatin immunoprecipitation (ChIP). RESULTS: During HSC activation EPIM became significantly decreased in contrast to pro-fibrotic markers SOX9, Collagen type 1 (COL1), and α-Smooth muscle actin (α-SMA). Treatment of activated HSCs with recombinant EPIM caused a reduction in α-SMA, SOX9, COL1 and Osteopontin (OPN), while increasing expression of the collagenase matrix metalloproteinase 13 (MMP13). Sox9 abrogation in activated HSCs increased EPIM and MMP13 expression. CONCLUSION: These data provide evidence for EPIM and SOX9 functioning by mutual negative feedback to regulate attributes of the quiescent or activated state of HSCs. Further understanding of EPIM's role may lead to opportunities to modulate SOX9 as a therapeutic avenue for liver fibrosis.
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Células Estrelladas Hepáticas/metabolismo , Metaloproteinasa 13 de la Matriz/metabolismo , Glicoproteínas de Membrana/genética , Factor de Transcripción SOX9/metabolismo , Animales , Secuencia de Bases , Sitios de Unión , Colágeno/metabolismo , Modelos Animales de Enfermedad , Expresión Génica , Regulación de la Expresión Génica , Técnicas de Silenciamiento del Gen , Cirrosis Hepática/genética , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Metaloproteinasa 13 de la Matriz/genética , Glicoproteínas de Membrana/metabolismo , Motivos de Nucleótidos , Péptido Hidrolasas/genética , Péptido Hidrolasas/metabolismo , Unión Proteica , Proteolisis , Ratas , Factor de Transcripción SOX9/genéticaRESUMEN
The c-Jun N-terminal protein kinase (JNK) and its two direct activators, namely the mitogen-activated protein kinase (MAPK) kinase 4 (MKK4) and MKK7, constitute a signaling node frequently mutated in human pancreatic ductal adenocarcinoma (PDAC). Here we demonstrate the cooperative interaction of endogenous expression of Kras(G12D) with loss-of-function mutations in mkk4 or both, mkk4 and mkk7 genes in the pancreas. More specifically, impaired JNK signaling in a subpopulation of Pdx1-expressing cells dramatically accelerated the appearance of Kras(G12D)-induced acinar-to-ductal metaplasia and pancreatic intraepithelial neoplasias, which rapidly progressed to invasive PDAC within 10 weeks of age. Furthermore, inactivation of mkk4/mkk7 compromised acinar regeneration following acute inflammatory stress by locking damaged exocrine cells in a permanently de-differentiated state. Therefore, we propose that JNK signaling exerts its tumor suppressive function in the pancreas by antagonizing the metaplastic conversion of acinar cells toward a ductal fate capable of responding to oncogenic stimulation.
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Carcinoma Ductal Pancreático/metabolismo , MAP Quinasa Quinasa 4/genética , MAP Quinasa Quinasa 7/genética , Neoplasias Pancreáticas/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/genética , Células Acinares/enzimología , Animales , Carcinogénesis/metabolismo , Carcinoma Ductal Pancreático/genética , Desdiferenciación Celular , MAP Quinasa Quinasa 4/metabolismo , MAP Quinasa Quinasa 7/metabolismo , Sistema de Señalización de MAP Quinasas , Ratones , Ratones Transgénicos , Mutación Missense , Páncreas/enzimología , Páncreas/patología , Páncreas/fisiopatología , Neoplasias Pancreáticas/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , RegeneraciónRESUMEN
An efficient and simple method for selective oxidation of secondary alcohols and oxidation of alkanes to ketones is reported. An in situ prepared catalyst is employed based on manganese(II) salts, pyridine-2-carboxylic acid, and butanedione, which provides good-to-excellent conversions and yields with high turnover numbers (up to 10 000) with H2 O2 as oxidant at ambient temperatures. In substrates bearing multiple alcohol groups, secondary alcohols are converted to ketones selectively and, in general, benzyl C-H oxidation proceeds in preference to aliphatic C-H oxidation.
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Alcoholes/química , Carbono/química , Peróxido de Hidrógeno/química , Hidrógeno/química , Cetonas/química , Manganeso/química , Catálisis , Oxidación-Reducción , Especificidad por SustratoRESUMEN
UNLABELLED: Osteopontin (OPN) is an important component of the extracellular matrix (ECM), which promotes liver fibrosis and has been described as a biomarker for its severity. Previously, we have demonstrated that Sex-determining region Y-box 9 (SOX9) is ectopically expressed during activation of hepatic stellate cells (HSC) when it is responsible for the production of type 1 collagen, which causes scar formation in liver fibrosis. Here, we demonstrate that SOX9 regulates OPN. During normal development and in the mature liver, SOX9 and OPN are coexpressed in the biliary duct. In rodent and human models of fibrosis, both proteins were increased and colocalized to fibrotic regions in vivo and in culture-activated HSCs. SOX9 bound a conserved upstream region of the OPN gene, and abrogation of Sox9 in HSCs significantly decreased OPN production. Hedgehog (Hh) signaling has previously been shown to regulate OPN expression directly by glioblastoma (GLI) 1. Our data indicate that in models of liver fibrosis, Hh signaling more likely acts through SOX9 to modulate OPN. In contrast to Gli2 and Gli3, Gli1 is sparse in HSCs and is not increased upon activation. Furthermore, reduction of GLI2, but not GLI3, decreased the expression of both SOX9 and OPN, whereas overexpressing SOX9 or constitutively active GLI2 could rescue the antagonistic effects of cyclopamine on OPN expression. CONCLUSION: These data reinforce SOX9, downstream of Hh signaling, as a core factor mediating the expression of ECM components involved in liver fibrosis. Understanding the role and regulation of SOX9 during liver fibrosis will provide insight into its potential modulation as an antifibrotic therapy or as a means of identifying potential ECM targets, similar to OPN, as biomarkers of fibrosis.
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Cirrosis Hepática/diagnóstico , Cirrosis Hepática/etiología , Osteopontina/fisiología , Factor de Transcripción SOX9/fisiología , Animales , Progresión de la Enfermedad , Humanos , Masculino , Osteopontina/biosíntesis , Ratas , Ratas Sprague-Dawley , Factor de Transcripción SOX9/biosíntesisRESUMEN
The photochemistry of (η(6)-anisole)Cr(CO)(3) and (η(6)-thioanisole)Cr(CO)(3) was investigated by picosecond time-resolved infrared spectroscopy in n-heptane solution at 298 K. Two independent excited states are populated following 400 nm excitation of each of these complexes. An excited state with some metal-to-CO charge-transfer character is responsible for the CO-loss process, which is slow compared to CO-loss from Cr(CO)(6). Observed first order rate constants of 1.8 × 10(10) s(-1) and 2.5 × 10(10) s(-1) were obtained for the anisole and thioanisole complexes, respectively. The second excited state has metal-to-arene charge transfer character and results in a haptotropic shift of the thioanisole ligand. DFT calculations characterized the excited states involved and the nature of the haptotropic shift intermediate observed for the thioanisole species.