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Bioinspired architectural design for composites with much higher fracture resistance than that of individual constituent remains a major challenge for engineers and scientists. Inspired by the survival war between the mantis shrimps and abalones, we design a discontinuous fibrous Bouligand (DFB) architecture, a combination of Bouligand and nacreous staggered structures. Systematic bending experiments for 3D-printed single-edge notched specimens with such architecture indicate that total energy dissipations are insensitive to initial crack orientations and show optimized values at critical pitch angles. Fracture mechanics analyses demonstrate that the hybrid toughening mechanisms of crack twisting and crack bridging mode arising from DFB architecture enable excellent fracture resistance with crack orientation insensitivity. The compromise in competition of energy dissipations between crack twisting and crack bridging is identified as the origin of maximum fracture energy at a critical pitch angle. We further illustrate that the optimized fracture energy can be achieved by tuning fracture energy of crack bridging, pitch angles, fiber lengths, and twist angles distribution in DFB composites.
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The discovery that endoplasmic reticulum (ER) luminal chaperones such as GRP78/BiP can escape to the cell surface upon ER stress where they regulate cell signaling, proliferation, apoptosis, and immunity represents a paradigm shift. Toward deciphering the mechanisms, we report here that, upon ER stress, IRE1α binds to and triggers tyrosine kinase SRC activation, leading to ASAP1 phosphorylation and Golgi accumulation of ASAP1 and Arf1-GTP, resulting in KDEL receptor dispersion from the Golgi and suppression of retrograde transport. At the cell surface, GRP78 binds to and acts in concert with a glycosylphosphatidylinositol-anchored protein, CD109, in blocking TGF-ß signaling by promoting the routing of the TGF-ß receptor to the caveolae, thereby disrupting its binding to and activation of Smad2. Collectively, we uncover a SRC-mediated signaling cascade that leads to the relocalization of ER chaperones to the cell surface and a mechanism whereby GRP78 counteracts the tumor-suppressor effect of TGF-ß.
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Antígenos CD/metabolismo , Estresse do Retículo Endoplasmático/fisiologia , Proteínas de Choque Térmico/metabolismo , Proteínas de Neoplasias/metabolismo , Transdução de Sinais/fisiologia , Fator de Crescimento Transformador beta/metabolismo , Quinases da Família src/metabolismo , Fator 1 de Ribosilação do ADP/genética , Fator 1 de Ribosilação do ADP/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Antígenos CD/genética , Chaperona BiP do Retículo Endoplasmático , Ativação Enzimática/fisiologia , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Células HEK293 , Células HeLa , Proteínas de Choque Térmico/genética , Humanos , Células MCF-7 , Proteínas de Neoplasias/genética , Transporte Proteico/fisiologia , Proteína Smad2/genética , Proteína Smad2/metabolismo , Fator de Crescimento Transformador beta/genéticaRESUMO
Transparent bulk glass is highly demanded in devices and components of daily life to transmit light and protect against external temperature and mechanical hazards. However, the application of glass is impeded by its poor functional performance, especially in terms of thermal isolation and impact resistance. Here, a glass composite integrating the nacre-inspired structure and shear stiffening gel (SSG) material is proposed. Benefiting from the combination of these two elements, this nacre-inspired SSG/glass composite (NSG) exhibits superior thermal insulation and impact resistance while maintaining transparency simultaneously. Specifically, the low thermal conductivity of the SSG combined with the anisotropic heat transfer capability of the nacre-inspired structure enhances the out-of-plane thermal insulation of NSG. The deformations over large volumes in nacre-inspired facesheets promote the deformation region of the SSG core, synergistic effect of tablet sliding mechanism in nacre-inspired structure and strain-rate enhancement in SSG material cause the superior impact resistance of overall panels in a wide range of impact velocities. NSG demonstrates outstanding properties such as transparency, light weight, impact resistance, and thermal insulation, which are major concerns for the application in engineering fields. In conclusion, this bioinspired SSG/glass composite opens new avenues to achieve comprehensive performance improvements for transparent structural materials.
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Layered inorganic material, with large-area interlayer surface and interface, provides an essential material platform for constructing new configuration of functional materials. Herein, a layered material pillared with nanoclusters realizing high temperature thermal insulation performance is demonstrated for the first time. Specifically, systematic synchrotron radiation spectroscopy and finite element calculation analysis show that ZrOx nanoclusters served as "pillars" to effectively produce porous structures with enough boundary defect while maintaining the layered structure, thereby significantly reducing solid state thermal conductivity (≈0.32 W m-1 K-1 , 298-573 K). Moreover, the layered inorganic silicate material assembled aerogel also exhibits superior thermal insulation performance from room temperature (0.034 W m-1 K-1 , 298 K, air conditions) to high temperature (0.187 W m-1 K-1 , 1073 K, air conditions) and largely enhanced compressive strength (42 kPa at 80% compression), which is the best layered material-based aerogel that has achieved synergistic improvement in thermal and mechanical performance so far. Layered inorganic silicate aerogel pillared by nanoclusters will pave a new avenue for the design of advanced thermal insulation materials under extreme conditions.
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PURPOSE: Our preclinical studies showed that the oncolytic reovirus formulation pelareorep (PELA) has significant immunomodulatory anti-myeloma activity. We conducted an investigator-initiated clinical trial to evaluate PELA in combination with dexamethasone (Dex) and bortezomib (BZ) and define the tumor immune microenvironment (TiME) in patients with multiple myeloma treated with this regimen. PATIENTS AND METHODS: Patients with relapsed/refractory multiple myeloma (n = 14) were enrolled in a phase Ib clinical trial (ClinicalTrials.gov: NCT02514382) of three escalating PELA doses administered on Days 1, 2, 8, 9, 15, and 16. Patients received 40 mg Dex and 1.5 mg/m2 BZ on Days 1, 8, and 15. Cycles were repeated every 28 days. Pre- and posttreatment bone marrow specimens (IHC, n = 9; imaging mass cytometry, n = 6) and peripheral blood samples were collected for analysis (flow cytometry, n = 5; T-cell receptor clonality, n = 7; cytokine assay, n = 7). RESULTS: PELA/BZ/Dex was well-tolerated in all patients. Treatment-emergent toxicities were transient, and no dose-limiting toxicities occurred. Six (55%) of 11 response-evaluable patients showed decreased paraprotein. Treatment increased T and natural killer cell activation, inflammatory cytokine release, and programmed death-ligand 1 expression in bone marrow. Compared with nonresponders, responders had higher reovirus protein levels, increased cytotoxic T-cell infiltration posttreatment, cytotoxic T cells in significantly closer proximity to multiple myeloma cells, and larger populations of a novel immune-primed multiple myeloma phenotype (CD138+ IDO1+HLA-ABCHigh), indicating immunomodulation. CONCLUSIONS: PELA/BZ/Dex is well-tolerated and associated with anti-multiple myeloma activity in a subset of responding patients, characterized by immune reprogramming and TiME changes, warranting further investigation of PELA as an immunomodulator.
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Mieloma Múltiplo , Terapia Viral Oncolítica , Humanos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/etiologia , Terapia Viral Oncolítica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bortezomib/uso terapêutico , Dexametasona/uso terapêutico , Citocinas/uso terapêutico , Microambiente TumoralRESUMO
Nacre is generally regarded as tough body armor, but it was often smashed by predators with a certain striking speed. Nacre-like architectures have been demonstrated to dissipate abundant energy by tablets sliding at static or specific low-speed loads, but whether they're still impact-resistant templates in a wide range of impact velocities remains unclear. Here, we find an anomalous phenomenon that nacre-like structures show superior energy-dissipation ability only in a narrow range of low impact velocities, while they exhibit lower impact resistance than laminated structures when impact velocity exceeds a critical value. This is because the tablets sliding in nacre-like structure occurs earlier and wider at low impact velocities, while it becomes localized at excessive impact velocities. Such anomalous phenomenon remains under different structural sizes and boundary conditions. It further inspires us to propose a hybrid architecture design strategy that achieves optimal impact resistance in a wide range of impact velocities.
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Nácar , Nácar/químicaRESUMO
The application of prestresses is a valuable strategy for enhancing the overall mechanical performances of structural materials. Residual stresses, acting as prestresses, exist naturally in biological structural materials, such as the nacre with the 3D "brick-and-mortar" arrangement. Although regulation of the tablets sliding has recently been demonstrated to be vital to improve toughness in synthetic nacre-like structures, the effects of prestresses on the tablets-sliding mechanism in these nacre-like structures remain unclear. Here, by a combination of simulation, additive manufacturing, and drop tower testing the authors reveal that, at a critical prestress, synergistic effects between the prestress-enhanced tablets sliding and prestress-weakened structural integrality result in optimized impact resistance of nacre-like structures. Furthermore, the prestressing strategy is easily implemented to a designed nacre-inspired separator to enhance the impact resistance of lithium batteries. The findings demonstrate that the prestressing strategy combined with bioinspired architectures can be exploited for enhancing the impact resistance of engineering structural materials and energy storage devices.
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Low density, high strength and toughness, together with good environmental stability are always desirable but hardly to achieve simultaneously for man-made structural materials. Replicating the design motifs of natural nacre clearly provides one promising route to obtain such kind of materials, but fundamental challenges remain. Herein, by choosing aramid nanofibers and mica microplatelets as building blocks, we produce a nacreous aramid-mica bulk material with a favorable combination of low density (â¼1.7 g cm-3), high strength (â¼387 MPa) and toughness (â¼14.3 MPa m1/2), and impressive mechanical stability in some harsh environments, including acid/alkali solutions, strong ultraviolet radiation, boiling water, and liquid nitrogen, standing out from previously reported biomimetic bulk composites. Moreover, the obtained material outperforms other bulk nacre-mimetics and most engineering structural materials in terms of its specific strength (227 MPa/[Mg m-3]) and specific toughness (8.4 MPa m1/2/[Mg m-3]), making it a new promising engineering structural material for different technical fields.
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Smart contact lenses attract extensive interests due to their capability of directly monitoring physiological and ambient information. However, previous demonstrations usually lacked efficient sensor modalities, facile fabrication process, mechanical stability, or biocompatibility. Here, we demonstrate a flexible approach for fabrication of multifunctional smart contact lenses with an ultrathin MoS2 transistors-based serpentine mesh sensor system. The integrated sensor systems contain a photodetector for receiving optical information, a glucose sensor for monitoring glucose level directly from tear fluid, and a temperature sensor for diagnosing potential corneal disease. Unlike traditional sensors and circuit chips sandwiched in the lens substrate, this serpentine mesh sensor system can be directly mounted onto the lenses and maintain direct contact with tears, delivering high detection sensitivity, while being mechanically robust and not interfering with either blinking or vision. Furthermore, the in vitro cytotoxicity tests reveal good biocompatibility, thus holding promise as next-generation soft electronics for healthcare and medical applications.
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We previously reported that lacrimal glands (LGs) of male non-obese diabetic (NOD) mice, an established mouse model of autoimmune inflammatory LG disease that displays many features of human LGs in patients afflicted with Sjögren's syndrome (SjS), exhibit significant degradation of extracellular matrix (ECM) structures as well as increased expression of matrix metalloproteinases (MMPs). The purpose of the current study was to expand the spectrum of proteases identified, to clarify their probable origin as well as to identify the contribution of these changes to disease pathogenesis. We explored in depth the changes in ECM structures and ECM protease expression at the onset of disease (6 weeks) versus late stage disease (18 weeks) in male NOD mouse LGs, relative to LGs of age-matched male NODscid, a severely immunocompromised congenic strain, and healthy BALB/c mice. LG tissues were examined using routine histological, immunohistochemical, Western Blot and gene expression analyses novel multiphoton imaging technologies. We further characterized the profile of infiltrating immune cells under each condition using flow cytometry. Our results show that the initial infiltrating cells at 6 weeks of age are responsible for increased MMP and cathepsin H expression and therefore initiate the LG ECM degradation in NOD mice. More importantly, NODscid mice exhibited normal LG ECM structures, indicating the lymphocytes seen in the LGs of NOD mice are responsible for the degradation of the LG ECM. The disease-related remodeling of LG ECM structures may play a crucial role in altering the acinar signaling environment, disrupting the signaling scaffolds within the cells, which are required to mobilize the exocytotic trafficking machinery, ultimately leading to a loss of LG function in patients afflicted with SjS.
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Proteínas da Matriz Extracelular/metabolismo , Matriz Extracelular/metabolismo , Linfócitos/fisiologia , Metaloproteinases da Matriz/metabolismo , Síndrome de Sjogren/metabolismo , Animais , Western Blotting , Catepsina H/genética , Catepsina H/metabolismo , Movimento Celular/fisiologia , Regulação para Baixo , Proteínas da Matriz Extracelular/genética , Citometria de Fluxo , Técnica Indireta de Fluorescência para Anticorpo , Aparelho Lacrimal , Masculino , Metaloproteinases da Matriz/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Functional atrophy and accompanying lymphocytic infiltration and destruction of the lacrimal gland (LG) are characteristics of Sjögren's Syndrome (SjS). The male NOD mouse is an experimental model for the autoimmune exocrinopathy that develops in the LG of SjS patients. Acinar cells in LG of male NOD mice aged 3-4 months were previously shown to accumulate lipid droplets. In the current study, analysis of lipid components revealed that the accumulated lipids were mostly cholesteryl esters (CE). Gene expression microarray analysis followed by real-time RT-PCR revealed alterations in the expression of several genes involved in lipid homeostasis in LG of 12-week-old male NOD mice relative to matched BALB/c controls. A series of upregulated genes including apolipoprotein E, apolipoprotein F, hepatic lipase, phosphomevalonate kinase, ATP-binding cassette D1 and ATP-binding cassette G1 were identified. Comparison of liver mRNAs to LG mRNAs in BALB/c and NOD mice revealed that the differential expressions were LG-specific. Gene expression profiles were also characterized in LGs of female mice, younger mice and immune-incompetent NOD SCID mice. Investigation of the cellular distribution of Apo-E and Apo-F proteins suggested that these proteins normally coordinate to mediate lipid efflux from the acinar cells but that dysfunction of these processes due to missorting of Apo-F may contribute to CE deposition. Finally, the initiation and extent of lipid deposition were correlated with lymphocytic infiltration in the LG of male NOD mice. We propose that impaired lipid efflux contributes to lipid deposition, an event that may contribute to the development and/or progression of dacryoadenitis in the male NOD mouse.
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Regulação da Expressão Gênica/fisiologia , Aparelho Lacrimal/metabolismo , Metabolismo dos Lipídeos/genética , Síndrome de Sjogren/genética , Envelhecimento/genética , Envelhecimento/metabolismo , Animais , Apolipoproteínas/metabolismo , Apolipoproteínas E/metabolismo , Feminino , Perfilação da Expressão Gênica/métodos , Homeostase/genética , Humanos , Aparelho Lacrimal/imunologia , Linfócitos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Síndrome de Sjogren/imunologia , Síndrome de Sjogren/metabolismo , Especificidade da EspécieRESUMO
GRP78 conducts protein folding and quality control in the ER and shows elevated expression and cell surface translocation in advanced tumors. However, the underlying mechanisms enabling GRP78 to exert novel signaling functions at cell surface are just emerging. CD44 is a transmembrane protein and an important regulator of cancer metastasis, and isoform switch of CD44 through incorporating additional variable exons to the extracellular juxtamembrane region is frequently observed during cancer progression. Using super-resolution dual-color single-particle tracking, we report that GRP78 interacts with CD44v in plasma membrane nanodomains of breast cancer cells. We further show that targeting cell surface GRP78 by the antibodies can effectively reduce cell surface expression of CD44v and cell spreading of tamoxifen-resistant breast cancer cells. Our results uncover new functions of GRP78 as an interacting partner of CD44v and as a regulator of CD44v membrane homeostasis and cell spreading. This study also provides new insights into anti-CD44 therapy in tamoxifen-resistant breast cancer.
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Neoplasias da Mama/metabolismo , Resistencia a Medicamentos Antineoplásicos , Proteínas de Choque Térmico/metabolismo , Receptores de Hialuronatos/metabolismo , Actinas/metabolismo , Membrana Celular/metabolismo , Chaperona BiP do Retículo Endoplasmático , Feminino , Regulação Neoplásica da Expressão Gênica , Homeostase , Humanos , Receptores de Hialuronatos/química , Células MCF-7 , Células Neoplásicas Circulantes/metabolismo , Transdução de Sinais , TamoxifenoRESUMO
The commercial ceramic nanoparticle coated microporous polyolefin separators used in lithium batteries are still vulnerable under external impact, which may cause short circuits and consequently severe safety threats, because the protective ceramic nanoparticle coating layers on the separators are intrinsically brittle. Here, a nacre-inspired coating on the separator to improve the impact tolerance of lithium batteries is reported. Instead of a random structured ceramic nanoparticle layer, ion-conductive porous multilayers consisting of highly oriented aragonite platelets are coated on the separator. The nacre-inspired coating can sustain external impact by turning the violent localized stress into lower and more uniform stress due to the platelet sliding. A lithium-metal pouch cell using the aragonite platelet coated separator exhibits good cycling stability under external shock, which is in sharp contrast to the fast short circuit of a lithium-metal pouch cell using a commercial ceramic nanoparticle coated separator.
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Lacrimal glands (LGs) of male non-obese diabetic (NOD) mice display many features of human LGs in patients afflicted with the autoimmune disease Sjögren's syndrome (SS), including the loss of secretory functions and a lymphocytic infiltration into the glands by 4 months of age. So far, research has mainly focused on the intracellular events that are involved in initiating LG dysfunction; however, the impact of SS on extracellular matrix (ECM) structures of the diseased LGs has not yet been determined. In this study we identified and compared LG ECM formation and integrity of age-matched male healthy (BALB/c) and diseased (NOD) mice. LG tissues were examined using routine histological, biochemical, immunohistochemical and gene expression analysis. Multiphoton imaging and second-harmonic generation (SHG) microscopy permitted the non-invasive analysis of major LG ECM structures including collagen- and elastin-containing fibers. Biochemical testing demonstrated a significant loss of collagen, glycosaminoglycans and desmosine in NOD LGs when compared to healthy BALB/c LGs. Immunohistochemical staining and gene expression analysis confirmed this disease-related alteration of LG ECM structures. Furthermore, laser-induced autofluorescence and SHG microscopy revealed dramatic changes in the structural organization of most collagenous and elastic fibers of the diseased LG tissues that were more pronounced than those displayed by histological analysis. Our results clearly show an enhanced degradation of ECM proteins accompanied by the severe disorganization and deformation of ECM structures of diseased LG tissues. These new insights into the involvement of ECM degradation in SS may lead to novel therapies for patients suffering from dry eye disease.
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Matriz Extracelular/metabolismo , Aparelho Lacrimal/citologia , Aparelho Lacrimal/patologia , Síndrome de Sjogren/patologia , Animais , Colágeno/genética , Colágeno/metabolismo , Desmosina/metabolismo , Matriz Extracelular/química , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Glicosaminoglicanos/metabolismo , Humanos , Aparelho Lacrimal/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Análise de Sequência com Séries de Oligonucleotídeos , Síndrome de Sjogren/fisiopatologiaRESUMO
Exploration of graphene-based artificial nacres with excellent mechanical properties demonstrates the potential to surpass natural nacre. Recent experimental studies report that optimal crosslink density defined as concentration of the surface functional groups is usually observed in these artificial nacres towards superb mechanical performance. A hybrid model integrating a nonlinear shear-lag model and atomistic simulations reveals the emergence of an optimal crosslink density at which the maximum strength and toughness are achieved. The origin is due to the balance among the reduction of in-plane tensile properties of the graphene sheets, the enhancement of the shear strength of the interlayer and the reduction of interface plasticity. In addition, our results also reveal that the size insensitivity of the graphene sheet appears when the shear stress of the interlayer is highly localized, the increase of the crosslink density intensifies the nonuniformity of the shear stress and the optimal mechanical properties of the artificial nacre cannot be further enhanced by tuning the size of the graphene sheets. Three kinds of interface molecular interactions with their optimal crosslink densities are also proposed to simultaneously maximize the strength and toughness of graphene-based artificial nacres.
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Over 400 million years ago, the evolution of vertebrates gave rise to a life cycle in which the organism began to live longer particularly as an adult. To accommodate such a longer lifespan, the organism underwent adaptation, developing a mechanism for long-lived cellular homeostasis. This adaptation required a population of long-lived relatively quiescent somatic stem cells (SSCs) along with a more proliferative differentiated daughter cell population, and was necessary to safeguard the genetic attributes with which SSCs were endowed. Intriguingly, cAMP response element binding protein (CREB)-binding protein (CBP) and E1A-binding protein, 300 kDa (p300), the highly homologous Kat3 coactivators had diverged, through duplication of ancestral Kat3, immediately preceding the evolution of vertebrates, given that both CBP and p300 have been detected in nearly all vertebrates versus non-vertebrates. We now demonstrate that a relatively small, highly evolutionarily conserved, amino terminal 9 amino acid deletion in CBP versus p300, plays a critical role in allowing for both robust maintenance of genomic integrity in stem cells and the initiation of a feed-forward differentiation mechanism by tightly controlling the interaction of the nuclear receptor family with the Wnt signaling cascade in either an antagonistic or synergistic manner.
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Proteína de Ligação a CREB , Evolução Molecular , Instabilidade Genômica/fisiologia , Via de Sinalização Wnt/fisiologia , beta Catenina , Fatores de Transcrição de p300-CBP , Animais , Proteína de Ligação a CREB/genética , Proteína de Ligação a CREB/metabolismo , Linhagem Celular Tumoral , Camundongos , beta Catenina/genética , beta Catenina/metabolismo , Fatores de Transcrição de p300-CBP/genética , Fatores de Transcrição de p300-CBP/metabolismoRESUMO
BACKGROUND AND OBJECTIVE: The development of the tyrosine kinase inhibitor Imatinib (IM) represents a milestone in CML (Chronic Myeloid Leukemia) treatment. However, it is not curative and patients develop IM resistance. IM resistance has been previously correlated with the emergence of drug-resistant LIC/LSC (Leukemia Initiating Cell/Leukemia Stem Cell) and increased nuclear catenin levels and enhanced Wnt signaling. It has been demonstrated previously that drug resistant CML LIC/LSC can be safely eliminated both in vitro and in vivo via disruption of the CBP/catenin interaction, utilizing the highly biochemically selective small molecule CBP/catenin antagonist ICG- 001. METHODS: Here, we utilized an in vitro IM selection of primary CML patients' samples to identify drug-resistant LIC/LSC populations. In this report, we characterized the drug-resistant CML LIC/LSC population using FACS, Smartchip qPCR and colony assays to analyze cell surface markers, transcriptomics and function. RESULTS: As opposed to previous characterization of the CML leukemic stem cell population as being either CD34+CD38- or CD34+CD38+, the in vitro selected Imatinib resistant (IM-R) CML LSC population was consistently CD34-CD38-. In Long-Term Culture Initiating Cell assay (LTC-IC, a surrogate assay for long term repopulating stem cells), our results suggest that the CBP/catenin antagonist ICG- 001 sensitizes LIC/LSC to IM treatment by forced differentiative elimination of the CML LIC/LSC population. CONCLUSION: In vitro selected IM resistant cells are negative for both CD34 and CD38 by FACS analysis. These cells acquire CD34/CD38 expression after co-culture with stromal cells. CBP/catenin antagonist ICG-001 facilitates IM function in eliminating these cells.
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Proteína de Ligação a CREB/antagonistas & inibidores , Cateninas/antagonistas & inibidores , Mesilato de Imatinib/farmacologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Células-Tronco Neoplásicas/patologia , Antígenos CD/metabolismo , Biomarcadores Tumorais/metabolismo , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Proteína de Ligação a CREB/metabolismo , Cateninas/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Proteínas de Neoplasias/metabolismo , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Fenótipo , Pirimidinonas/farmacologia , Ensaio Tumoral de Célula-TroncoRESUMO
BACKGROUND: Although canonical Wnt signaling is known to promote tumorigenesis in pancreatic ductal adenocarcinoma (PDAC), a cancer driven principally by mutant K-Ras, the detailed molecular mechanisms by which the Wnt effector ß-catenin regulates such tumorigenesis are largely unknown. We have previously demonstrated that ß-catenin's differential usage of the Kat3 transcriptional coactivator cyclic AMP-response element binding protein-binding protein (CBP) over its highly homologous coactivator p300 increases self-renewal and suppresses differentiation in other types of cancer. AIM/METHODS: To investigate Wnt-mediated carcinogenesis in PDAC, we have used the specific small molecule CBP/ß-catenin antagonist, ICG-001, which our lab identified and has extensively characterized, to examine its effects in human pancreatic cancer cells and in both an orthotopic mouse model and a human patient-derived xenograft (PDX) model of PDAC. RESULTS/CONCLUSION: We report for the first time that K-Ras activation increases the CBP/ß-catenin interaction in pancreatic cancer; and that ICG-001 specific antagonism of the CBP/ß-catenin interaction sensitizes pancreatic cancer cells and tumors to gemcitabine treatment. These effects were associated with increases in the expression of let-7a microRNA; suppression of K-Ras and survivin; and the elimination of drug-resistant cancer stem/tumor-initiating cells.
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There is currently no FDA approved therapeutic agent for ARS mitigation post radiation exposure. Here we report that the small molecule YH250, which specifically antagonizes p300/catenin interaction, stimulates hematopoiesis in lethally or sublethally irradiated mice. A single administration of YH250 24 hours post irradiation can significantly stimulate HSC proliferation, improve survival and accelerate peripheral blood count recovery. Our studies suggest that promotion of the expansion of the remaining HSC population via stimulation of symmetric non-differentiative proliferation is at least part of the mechanism of action.
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Cateninas/antagonistas & inibidores , Hematopoese/efeitos dos fármacos , Compostos Heterocíclicos com 2 Anéis/farmacologia , Compostos Heterocíclicos com 2 Anéis/uso terapêutico , Lesões por Radiação/tratamento farmacológico , Fatores de Transcrição de p300-CBP/antagonistas & inibidores , Animais , Células Cultivadas , Camundongos , Camundongos TransgênicosRESUMO
Lacrimal glands of male NOD and BALB/c mice have very small, pleomorphic acinar lumens. Acini contain isolated zones of highly complex cell surface interdigitations at the basal surface, sometimes occurring between acinar and myoepithelial cells. In NOD mice, cytological abnormalities, including mitochondrial deterioration, pleomorphic and heterogeneous cytoplasmic vacuoles, and lipid accumulation are evident within acinar cells at 1 month. Accumulation of lipid is further increased as the animal ages, accompanied by lymphocytic infiltration and destruction of acini. These results demonstrate alterations from normal cytology as early as 1 month in NOD mice, well before detection of clinical signs of Sjögren syndrome.