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Blood cell counting typically requires complex machinery. Flow cytometers used for this purpose involve precise optical alignment, costly detectors, and pretreatment with fluorescent labels. Coulter countertype devices, which monitor ion current, are simpler. However, conventional Coulter counters provide only information about size, making it impossible to distinguish similarly sized lymphocytes from red blood cells (RBCs). Inspired by the fact that RBCs have an exceptionally high propensity to absorb light and convert it to heat, i.e., photothermal effect, this study proposes integrating photothermal phenomena into a microfluidic Coulter counting chip. Photothermal heat selectively amplifies the ion current from RBCs over other components including lymphocytes. The combination of ion current monitoring and the photothermal effect for RBC counting suggests an evolution toward versatile flow cytometers.
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Eritrocitos , Citometría de Flujo , Eritrocitos/citología , Eritrocitos/química , Humanos , Citometría de Flujo/métodos , Iones/químicaRESUMEN
Information encryption strategies have become increasingly essential. Most of the fluorescent security patterns have been made with a lateral configuration of red, green, and blue subpixels, limiting the pixel density and security level. Here we report vertically stacked, luminescent heterojunction micropixels that construct high-resolution, multiplexed anticounterfeiting labels. This is enabled by meniscus-guided three-dimensional (3D) microprinting of red, green, and blue (RGB) dye-doped materials. High-precision vertical stacking of subpixel segments achieves full-color pixels without sacrificing lateral resolution, achieving a small pixel size of â¼µm and a high density of over 13,000 pixels per inch. Furthermore, a full-scale color synthesis for individual pixels is developed by modulating the lengths of the RGB subpixels. Taking advantage of these unique 3D structural designs, trichannel multiplexed anticounterfeiting Quick Response codes are successfully demonstrated. We expect that this work will advance data encryption technology while also providing a versatile manufacturing platform for diverse 3D display devices.
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The functionalities of peptide microstructures and nanostructures can be enhanced by controlling their crystallinity. Gaining control over the crystallinity within the desired structure, however, remains a challenge. We have developed a three-dimensional (3D) printing method that enables spatioselective programming of the crystallinity of diphenylalanine (FF) dipeptide microarchitectures. A femtoliter ink meniscus is used to spatially control reprecipitation self-assembly, enabling the printing of a freestanding FF microstructure with programmed shape and crystallinity. The self-assembly crystallization of FF can be switched on and off at will by controlling the evaporation of the binary solvent. The evaporation-dependent crystallization was theoretically studied by the numerical simulation of supersaturation fields in the meniscus. We found that a 3D-printed FF microarchitecture with spatially programmed crystallinity can carry a 3D digital optical anisotropy pattern, applicable to generating polarization-encoded anticounterfeiting labels. This crystallinity-controlled additive manufacturing will pave the new way for facilitating the creation of peptide-based devices.
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Dipéptidos , Impresión Tridimensional , Dipéptidos/química , Péptidos , Solventes/químicaRESUMEN
Plasmonic nanoparticle clusters promise to support unique engineered electromagnetic responses at optical frequencies, realizing a new concept of devices for nanophotonic applications. However, the technological challenges associated with the fabrication of three-dimensional nanoparticle clusters with programmed compositions remain unresolved. Here, we present a novel strategy for realizing heterogeneous structures that enable efficient near-field coupling between the plasmonic modes of gold nanoparticles and various other nanomaterials via a simple three-dimensional coassembly process. Quantum dots embedded in the plasmonic structures display â¼56 meV of a blue shift in the emission spectrum. The decay enhancement factor increases as the total contribution of radiative and nonradiative plasmonic modes increases. Furthermore, we demonstrate an ultracompact diagnostic platform to detect M13 viruses and their mutations from femtoliter volume, sub-100 pM analytes. This platform could pave the way toward an effective diagnosis of diverse pathogens, which is in high demand for handling pandemic situations.
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Nanopartículas del Metal , Nanoestructuras , Puntos Cuánticos , Oro/química , Nanopartículas del Metal/química , Nanoestructuras/química , Puntos Cuánticos/químicaRESUMEN
Photoelectrochemical (PEC) sensors are usually based on a single output signal, that is, the photocurrent change caused by the (photoelectro)chemical reaction between target analytes and photoelectrodes. However, the photocurrent may be influenced by redox species other than the target analyte; therefore, modifying the surface of photoelectrodes with probes that selectively bind to the analyte is essential. Moreover, even though various surface modification methods have been developed, distinguishing molecularly similar chemicals using PEC sensing systems remains a significant challenge. To address these selectivity issues, we proposed a photoanode-based PEC sensor that utilizes a cathodic transient current as a second output signal in addition to the photocurrent, which arises from the back reduction of photo-oxidized species. Factors influencing the back reduction were investigated by observing the transient photocurrent of hematite photoanodes in the presence of model redox probes. The chemical environment around the electrode-electrolyte interface was manipulated by altering the electrolyte composition or modifying the electrode surface. The favorable interaction between the electrode surface and redox species led to an increase in the extent of back reduction and the cathodic transient current. In addition, the extent of back reduction also depends on the chemical identity of the redox species, such as the kinetics of subsequent chemical reactions. Therefore, the synergistic combination of the photocurrent and the cathodic transient current enabled the differentiated detection of various catecholamine neurotransmitters with a single pristine photoelectrode, which has never been achieved using traditional PEC methods. Revisiting the transient photocurrent can complement conventional PEC applications and offers possibilities for more effective semiconductor-based applications.
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Técnicas Biosensibles , Técnicas Electroquímicas , Técnicas Biosensibles/métodos , Electrodos , Oxidación-ReducciónRESUMEN
Obesity and its associated comorbidities (for example, diabetes mellitus and hepatic steatosis) contribute to approximately 2.5 million deaths annually and are among the most prevalent and challenging conditions confronting the medical profession. Neurotensin (NT; also known as NTS), a 13-amino-acid peptide predominantly localized in specialized enteroendocrine cells of the small intestine and released by fat ingestion, facilitates fatty acid translocation in rat intestine, and stimulates the growth of various cancers. The effects of NT are mediated through three known NT receptors (NTR1, 2 and 3; also known as NTSR1, 2, and NTSR3, respectively). Increased fasting plasma levels of pro-NT (a stable NT precursor fragment produced in equimolar amounts relative to NT) are associated with increased risk of diabetes, cardiovascular disease and mortality; however, a role for NT as a causative factor in these diseases is unknown. Here we show that NT-deficient mice demonstrate significantly reduced intestinal fat absorption and are protected from obesity, hepatic steatosis and insulin resistance associated with high fat consumption. We further demonstrate that NT attenuates the activation of AMP-activated protein kinase (AMPK) and stimulates fatty acid absorption in mice and in cultured intestinal cells, and that this occurs through a mechanism involving NTR1 and NTR3 (also known as sortilin). Consistent with the findings in mice, expression of NT in Drosophila midgut enteroendocrine cells results in increased lipid accumulation in the midgut, fat body, and oenocytes (specialized hepatocyte-like cells) and decreased AMPK activation. Remarkably, in humans, we show that both obese and insulin-resistant subjects have elevated plasma concentrations of pro-NT, and in longitudinal studies among non-obese subjects, high levels of pro-NT denote a doubling of the risk of developing obesity later in life. Our findings directly link NT with increased fat absorption and obesity and suggest that NT may provide a prognostic marker of future obesity and a potential target for prevention and treatment.
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Dieta Alta en Grasa/efectos adversos , Neurotensina/metabolismo , Obesidad/inducido químicamente , Obesidad/metabolismo , Proteínas Quinasas Activadas por AMP/metabolismo , Proteínas Adaptadoras del Transporte Vesicular/metabolismo , Animales , Línea Celular , Modelos Animales de Enfermedad , Drosophila melanogaster/citología , Drosophila melanogaster/enzimología , Drosophila melanogaster/metabolismo , Células Enteroendocrinas/metabolismo , Activación Enzimática , Cuerpo Adiposo/metabolismo , Ácidos Grasos/metabolismo , Hígado Graso/metabolismo , Hígado Graso/prevención & control , Femenino , Humanos , Resistencia a la Insulina/fisiología , Mucosa Intestinal/metabolismo , Intestinos/citología , Metabolismo de los Lípidos , Masculino , Ratones , Persona de Mediana Edad , Neurotensina/sangre , Neurotensina/deficiencia , Neurotensina/genética , Obesidad/sangre , Obesidad/prevención & control , Precursores de Proteínas/sangre , Precursores de Proteínas/metabolismoRESUMEN
The driving performance of an off-road vehicle is closely related to soil strength. A bevameter is used to measure the soil strength, and it usually consists of two independent devices: a pressure-sinkage test device and a shear test device. However, its development and measurement processes have not been standardized; thus, researchers apply it in various fields according to their own discretion. In this study, a new bevameter was developed, and experiments were conducted to clarify the factors that affect the measurement performance of the bevameter. The pressure-sinkage test device was tested with circular plates of different sizes, and the results confirmed that the pressure-sinkage parameters decreased with the plate size. For the shear-test device, normal pressure was applied using a dead load to prevent normal-pressure variation due to displacement and speed. In addition, a spline was installed on top of the shaft connected to the shear ring to measure slip sinkage during the shear test. The results showed that the slip sinkage increased in proportion to the normal pressure and slip displacement, but the increase gradually decreased and converged to a certain point.
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Direct mass-transfer via liquid nanodroplets is one of the most powerful approaches for additive micro/nanofabrication. Electrohydrodynamic (EHD) dispensing has made the delivery of nanosized droplets containing diverse materials a practical reality; however, in its serial form it has insufficient throughput for large-area processing. Here, a parallel, nanoscale EHD method is developed that offers both improved productivity and material diversity in 3D nanoprinting. The method exploits a double-barreled glass nanopipette filled with material inks to parallelize nanodripping ejections, enabling a dual 3D nanoprinting process. It is discovered that an unusual electric field distribution created by cross talk of neighboring pipette apertures can be used to steer the microscopic ejection paths of the ink at will, enabling on-demand control over shape, placement, and material mixing in 3D printed nanostructures. After thorough characterizations of the printing conditions, the parallel fabrication of nanomeshes and nanowalls of silver, CdSe/ZnS quantum dots, and their composites, with programmed designs is demonstrated. This method is expected to advance productivity in the heterogeneous integration of functional 3D nanodevices in a facile manner.
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High-resolution 3D-printed stainless steel metal microreactors (3D-PMRs) with different cross-sectional geometry are fabricated to control ultrafast intramolecular rearrangement reactions in a comparative manner. The 3D-PMR with circular channel demonstrates the improved controllability in rapid Fries-type rearrangement reactions, because of the superior mixing efficiency to rectangular cross-section channels (250 µm × 125 µm) which is confirmed based on the computational flow dynamics simulation. Even in case of very rapid intramolecular rearrangement of sterically small acetyl group occurring in 333 µs of reaction time, the desired intermolecular reaction can outpace to the undesired intramolecular rearrangement using 3D-PMR to result in high conversion and yield.
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Wnt/ß-catenin signaling plays a pivotal role in regulating cell growth and differentiation by activation of the ß-catenin/T-cell factor (TCF) complex and subsequent regulation of a set of target genes that have one or more TCF-binding elements (TBEs). Hyperactivation of this pathway has been implicated in numerous malignancies including human neuroendocrine tumors (NETs). Neurotensin (NT), an intestinal hormone, induces proliferation of several gastrointestinal (GI) cancers including cancers of the pancreas and colon. Here, we analyzed the human NT promoter in silico and found at least four consensus TBEs within the proximal promoter region. Using a combination of ChIP and luciferase reporter assays, we identified one TBE (located â¼900 bp proximal from the transcription start site) that was immunoprecipitated efficiently by TCF4-targeting antibody; mutation of this site attenuated the responsiveness to ß-catenin. We also confirmed that the promoter activity and the mRNA and protein expression levels of NT were increased by various Wnt pathway activators and decreased by Wnt inhibitors in NET cell lines BON and QGP-1, which express and secrete NT. Similarly, the intracellular content and secretion of NT were induced by Wnt3a in these cells. Finally, inhibition of NT signaling suppressed cell proliferation and anchorage-independent growth and decreased expression levels of growth-related proteins in NET cells. Our results indicate that NT is a direct target of the Wnt/ß-catenin pathway and may be a mediator for NET cell growth.
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Tumores Neuroendocrinos/patología , Neurotensina/fisiología , Vía de Señalización Wnt/fisiología , beta Catenina/fisiología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica , Humanos , Neurotensina/antagonistas & inhibidores , Neurotensina/genética , Regiones Promotoras Genéticas , Receptores de Neurotensina/fisiologíaRESUMEN
3D printing of metallic microarchitectures with controlled internal structures is realized at room temperature in ambient air conditions by the manipulation of metal ion concentration and pulsed electric potentials in the electrolyte meniscus during the meniscus-guided electrodeposition. Precise control of the printing nozzle enables the drawing of complex 3D microarchitectures with well-defined geometries and positions.
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Upregulation of fatty acid synthase (FASN), a key enzyme of de novo lipogenesis, is associated with metastasis in colorectal cancer (CRC). However, the mechanisms of regulation are unknown. Since angiogenesis is crucial for metastasis, we investigated the role of FASN in the neovascularization of CRC. The effect of FASN on tumor vasculature was studied in orthotopic CRCs, the chick embryo chorioallantoic membrane (CAM) and Matrigel plug models using immunohistochemistry, immunofluorescent staining and confocal microscopy. Cell secretion was evaluated by ELISA and antibody arrays. Proliferation, migration and tubulogenesis of endothelial cells (ECs) were assessed in CRC-EC coculture models. In this study, we found that stable knockdown of FASN decreased microvessel density in HT29 and HCT116 orthotopic CRCs and resulted in 'normalization' of tumor vasculature in both orthotopic and CAM models. Furthermore, FASN regulated secretion of pro- and antiangiogenic factors, including vascular endothelial growth factor-A (VEGF-A). Mechanisms associated with the antiangiogenic activity noted with knockdown of FASN included: downregulation of VEGF(189), upregulation of antiangiogenic isoform VEGF(165b) and a decrease in expression and activity of matrix metalloproteinase-9. Furthermore, conditioned medium from FASN knockdown CRC cells inhibited activation of vascular endothelial growth factor receptor-2 and its downstream signaling and decreased proliferation, migration and tubulogenesis of ECs as compared with control medium. Together, these results suggest that cancer cell-associated FASN regulates tumor vasculature through alteration of the profile of secreted angiogenic factors and regulation of their bioavailability. Inhibition of FASN upstream of VEGF-A and other angiogenic pathways can be a novel therapeutic strategy to prevent or inhibit metastasis in CRC.
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Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Células Endoteliales/metabolismo , Ácido Graso Sintasas/genética , Neovascularización Patológica/genética , Animales , Línea Celular Tumoral , Embrión de Pollo , Modelos Animales de Enfermedad , Ácido Graso Sintasas/metabolismo , Regulación de la Expresión Génica , Técnicas de Silenciamiento del Gen , Xenoinjertos , Humanos , Masculino , Metaloproteinasa 9 de la Matriz/metabolismo , Neovascularización Patológica/metabolismo , Transducción de Señal , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Creating hierarchical molecular block heterostructures, with the control over size, shape, optical, and electronic properties of each nanostructured building block can help develop functional applications, such as information storage, nanowire spectrometry, and photonic computing. However, achieving precise control over the position of molecular assemblies, and the dynamics of excitons in each block, remains a challenge. In the present work, the first fabrication of molecular heterostructures with the control of exciton dynamics in each block, is demonstrated. Additionally, these heterostructures are printable and can be precisely positioned using Direct Ink Writing-based (DIW) 3D printing technique, resulting in programable patterns. Singlet excitons with emission lifetimes on nanosecond or microsecond timescales and triplet excitons with emission lifetimes on millisecond timescales appear simultaneously in different building blocks, with an efficient energy transfer process in the heterojunction. These organic materials also exhibit stimuli-responsive emission by changing the power or wavelength of the excitation laser. Potential applications of these organic heterostructures in integrated photonics, where the versatility of fluorescence, phosphorescence, efficient energy transfer, printability, and stimulus sensitivity co-exist in a single nanowire, are foreseen.
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Carcinoid tumors are rare neuroendocrine tumors (NETs) that are increasing in incidence. Mutation and altered expression of Wnt/ß-catenin signaling components have been described in many tumors but have not been well-studied in NETs. Here, we observed accumulation of ß-catenin in the cytoplasm and/or nucleus in 25% of clinical NET tissues. By mutational analysis, the mutations of ß-catenin (I35S) and APC (E1317Q, T1493T) were identified in NET cells and the tissues. Expression of representative Wnt inhibitors was absent or markedly decreased in BON, a human pancreatic carcinoid cell line; treatment with 5-aza-2'-deoxycytidine (5-aza-CdR) increased expression levels of the Wnt inhibitors. Methylation analyses demonstrated that CpG islands of SFRP-1 and Axin-2 were methylated, whereas the promoters of DKK-1, DKK-3 and WIF-1 were unmethylated in four NET cells. Aberrant methylation of SFRP-1 was particularly observed in most of clinical NET tissues. In addition, the repression of these unmethylated genes was associated with histone H3 lysine 9 dimethylation (H3K9me2) in BON cells. Together, 5-aza-CdR treatment inhibited cell proliferation and decreased the protein levels of H3K9me2 and G9a. Moreover, a novel G9a inhibitor, UNC0638, suppressed BON cell proliferation through inhibition of Wnt/ß-catenin pathway. Overexpression of the inhibitory genes, particularly SFRP-1 and WIF-1 in BON cells, resulted in suppression of anchorage-independent growth and inhibition of tumor growth in mice. Our findings suggest that aberrant Wnt/ß-catenin signaling, through either mutations or epigenetic silencing of Wnt antagonists, contributes to the pathogenesis and growth of NETs and have important clinical implications for the prognosis and treatment of NETs.
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Tumores Neuroendocrinos/genética , Tumores Neuroendocrinos/metabolismo , Transducción de Señal/genética , Proteínas Wnt/genética , Proteínas Wnt/metabolismo , beta Catenina/genética , beta Catenina/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Proteína Axina/genética , Proteína Axina/metabolismo , Línea Celular Tumoral , Núcleo Celular/genética , Núcleo Celular/metabolismo , Islas de CpG , Citoplasma/genética , Citoplasma/metabolismo , Metilación de ADN , Análisis Mutacional de ADN/métodos , Epigénesis Genética , Epigenómica/métodos , Expresión Génica/genética , Genes APC , Genes Supresores de Tumor , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Ratones Desnudos , Mutación , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Factores de Transcripción TCF/genética , Factores de Transcripción TCF/metabolismo , Transcripción Genética/genéticaRESUMEN
Viruses have unique coat proteins that are genetically modifiable. Their surface can serve as a nano-template on which electroactive molecules are immobilized. In this study, we report filamentous bacteriophage as a backbone to which redox mediators are covalently and densely tethered, constructing redox nanowire, i.e. an electron conducting biomaterial. The highly ordered coat proteins of a filamentous bacteriophage provide flexible and biocompatible platform to constitute a biohybrid redox nanowire. Incorporating bacteriophage and redox molecules form an entangled assembly of nanowires enabling facile electron transfer. Electron transfer among the molecular mediators in the entangled assembly originates apparent electron diffusion of which the electron transfer rate is comparable to that observed in conventional redox polymers. Programming peptide terminals suggests further enhancement in electron mediation by increasing redox species mobility. In addition, the redox nanowire film functions as a favorable matrix for enzyme encapsulation. The stability of the enzymes entrapped in this unique matrix is substantially improved.
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Bacteriófagos , Técnicas Biosensibles , Nanocables , Nanocables/química , Oxidación-Reducción , Transporte de Electrón , ElectrodosRESUMEN
Mixed-halide perovskites show tunable emission wavelength across the visible-light range, with optimum control of the light color. However, color stability remains limited due to the notorious halide segregation under illumination or an electric field. Here, a versatile path toward high-quality mixed-halide perovskites with high emission properties and resistance to halide segregation is presented. Through systematic in and ex situ characterizations, key features for this advancement are proposed: a slowed and controllable crystallization process can promote achievement of halide homogeneity, which in turn ensures thermodynamic stability; meanwhile, downsizing perovskite nanoparticle to nanometer-scale dimensions can enhance their resistance to external stimuli, strengthening the phase stability. Leveraging this strategy, devices are developed based on CsPbCl1.5 Br1.5 perovskite that achieves a champion external quantum efficiency (EQE) of 9.8% at 464 nm, making it one of the most efficient deep-blue mixed-halide perovskite light-emitting diodes (PeLEDs) to date. Particularly, the device demonstrates excellent spectral stability, maintaining a constant emission profile and position for over 60 min of continuous operation. The versatility of this approach with CsPbBr1.5 I1.5 PeLEDs is further showcased, achieving an impressive EQE of 12.7% at 576 nm.
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Thermometry, the process of measuring temperature, is one of the most fundamental tasks not only for understanding the thermodynamics of basic physical, chemical, and biological processes but also for thermal management of microelectronics. However, it is a challenge to acquire microscale temperature fields in both space and time. Here, a 3D printed micro-thermoelectric device that enables direct 4D (3D Space + Time) thermometry at the microscale is reported. The device is composed of freestanding thermocouple probe networks, fabricated by bi-metal 3D printing with an outstanding spatial resolution of a few µm. It shows that the developed 4D thermometry can explore dynamics of Joule heating or evaporative cooling on microscale subjects of interest such as a microelectrode or a water meniscus. The utilization of 3D printing further opens up the possibility to freely realize a wide range of on-chip, freestanding microsensors or microelectronic devices without the design restrictions by manufacturing processes.
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Structural colors are produced by the diffraction of light from microstructures. The collective arrangement of substructures is a simple and cost-effective approach for structural coloration represented by colloidal self-assembly. Nanofabrication methods enable precise and flexible coloration by processing individual nanostructures, but these methods are expensive or complex. Direct integration of desired structural coloration remains difficult because of the limited resolution, material-specificity, or complexity. Here, we demonstrate three-dimensional printing of structural colors by direct writing of nanowire gratings using a femtoliter meniscus of polymer ink. This method combines a simple process, desired coloration, and direct integration at a low cost. Precise and flexible coloration is demonstrated by printing the desired structural colors and shapes. In addition, alignment-resolved selective reflection is shown for displayed image control and color synthesis. The direct integration facilitates structural coloration on various substrates, including quartz, silicon, platinum, gold, and flexible polymer films. We expect that our contribution can expand the utility of diffraction gratings across various disciplines such as surface-integrated strain sensors, transparent reflective displays, fiber-integrated spectrometers, anticounterfeiting, biological assays, and environmental sensors.
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Pervasive mechanical force in nature and human activities is closely related to intriguing physics and widespread applications. However, describing stress distribution timely and precisely in three dimensions to avoid "groping in the dark" is still a formidable challenge, especially for nonplanar structures. Herein, we realize three-dimensional (3D) stress imaging for sharp arbitrary targets via advanced 3D printing, owing to the use of fluoride nanocrystal(NC)-based ink. Notably, a fascinating mechano-luminescence (ML) is observed for the homogeneously dispersed NaLuF4:Tb3+ NCs (â¼25 nm) with rationally designed deep traps (at 0.88 and 1.02 eV) via incorporating Cs+ ions and using X-ray irradiation. Carriers captured in the corresponding traps are steadily released under mechanical stimulations, which enables a ratio metric luminescence intensity based on the applied force. As a result, a significant mechano-optical conversion and superior optical waveguide of the corresponding transparent printed targets demonstrate stress in 3D with a high spatial and temporal resolution based on stereovision. These results highlight the optical function of the 3D-printed fluoride NCs, which cast light into the black boxes of stress described in space, benefiting us in understanding the ubiquitous force relevant to most natural and engineering processes.
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Activation of phosphatidylinositol 3-kinase (PI3K)/Akt signaling is associated with tumorigenesis and metastasis of colorectal cancer (CRC). The mammalian target of rapamycin (mTOR) kinase, a downstream effector of PI3K/Akt signaling, regulates tumorigenesis and metastasis of CRCs, indicating that mTOR inhibition may have therapeutic potential. Notwithstanding, many cancers, including CRC, demonstrate resistance to the antitumorigenic effects of rapamycin. In this study, we show that inhibition of mTORC1 with rapamycin leads to feedback activation of PI3K/Akt and Ras-MAPK signaling, resulting in cell survival and possible contribution to rapamycin resistance. Combination with the multikinase inhibitor, sorafenib, abrogates rapamycin-induced activation of PI3K/Akt and Ras-MAPK signaling pathways. Combination of rapamycin with sorafenib synergistically inhibits proliferation of CRC cells. CRCs harboring coexistent KRAS and PIK3CA mutations are partially sensitive to either rapamycin or sorafenib monotherapy, but highly sensitive to combination treatment with rapamycin and sorafenib. Combination with sorafenib enhances therapeutic efficacy of rapamycin on induction of apoptosis and inhibition of cell-cycle progression, migration and invasion of CRCs. We demonstrate efficacy and safety of concomitant treatment with rapamycin and sorafenib at inhibiting growth of xenografts from CRC cells with coexistent mutations in KRAS and PIK3CA. The efficacy and tolerability of combined treatment with rapamycin and sorafenib provides rationale for use in treating CRC patients, particularly those with tumors harboring coexistent KRAS and PIK3CA mutations.