ABSTRACT
Stacking two-dimensional (2D) van der Waals (vdW) materials in a layered bulk structure provides an appealing platform for the emergence of exotic physical properties. As a vdW crystal with exceptional plasticity, InSe offers the opportunity to explore various effects arising from the coupling of its peculiar mechanical behaviors and other physical properties. Here, we employ neutron scattering techniques to investigate the correlations of plastic interlayer slip, lattice anharmonicity, and thermal transport in InSe crystals. Not only are the interlayer slip direction and magnitude well captured by shifts in the Bragg reflections, but we also observe a deviation from the expected Debye behaviour in the heat capacity and lattice thermal conductivity. Combining the experimental data with first-principles calculations, we tentatively attribute the observed evidence of strong phonon-phonon interactions to a combination of a large acoustic-optical frequency resonance and a nesting effect. These findings correlate the macroscopic plastic slip and the microscopic lattice dynamics, providing insights into the mechano-thermo coupling and modulation in 2D vdW materials.
ABSTRACT
The proliferation and apoptosis of granulosa cells (GCs) affect follicle development and reproductive disorders, with microRNAs playing a crucial regulatory role. Previous studies have shown the differential expression of miR-128-3p at different stages of goat follicle development, which suggests its potential regulatory role in follicle development. In this study, through the Cell Counting Kit-8 assay, the EDU assay, flow cytometry, quantitative real-time polymerase chain reaction, Western blot, and the dual-luciferase reporter assay, we used immortal human ovarian granulosa tumor cell line (KGN) cells as materials to investigate the effects of miR-128-3p and its predicted target gene growth hormone secretagogue receptor (GHSR) on GC proliferation and apoptosis. The results show that overexpression of miR-128-3p inhibited the proliferation of KGN cells, promoted cell apoptosis, and suppressed the expression of proliferating cell nuclear antigen (PCNA) and B-cell lymphoma-2 (BCL2) while promoting that of Bcl-2 associated X protein (BAX). The dual-luciferase reporter assay revealed that miR-128-3p bound to the 3' untranslated region sequence of GHSR, which resulted in the inhibited expression of GHSR protein. Investigation of the effects of GHSR on GC proliferation and apoptosis revealed that GHSR overexpression promoted the expression of PCNA and BCL2, enhanced GC proliferation, and inhibited cell apoptosis, whereas the opposite effects were observed when GHSR expression was inhibited. In addition, miR-128-3p and GHSR can influence the expression of extracellular signal-regulated kinase 1/2 protein. In conclusion, miR-128-3p inhibits KGN cell proliferation and promotes cell apoptosis by downregulating the expression of the GHSR gene.
Subject(s)
MicroRNAs , Receptors, Ghrelin , Female , Humans , Proliferating Cell Nuclear Antigen , MicroRNAs/genetics , Apoptosis/genetics , Cell Proliferation/genetics , Luciferases , Cell Line, TumorABSTRACT
The development of ultrathin, stable ferroelectric materials is crucial for advancing high-density, low-power electronic devices. Nonetheless, ultrathin ferroelectric materials are rare due to the critical size effect. Here, a novel ferroelectric material, magnesium molybdenum oxide (Mg2Mo3O8) is presented. High-quality ultrathin Mg2Mo3O8 crystals are synthesized using chemical vapor deposition (CVD). Ultrathin Mg2Mo3O8 has a wide bandgap (≈4.4 eV) and nonlinear optical response. Mg2Mo3O8 crystals of varying thicknesses exhibit out-of-plane ferroelectric properties at room temperature, with ferroelectricity retained even at a 2 nm thickness. The Mg2Mo3O8 exhibits a relatively large remanent polarization ranging from 33 to 52 µC cm- 2, which is tunable by changing its thickness. Notably, Mg2Mo3O8 possesses a high Curie temperature (>980 °C) across various thicknesses. Moreover, the as-grown Mg2Mo3O8 crystals display remarkable stability under harsh environments. This work introduces nolanites-type crystal into ultrathin ferroelectrics. The scalable synthesis of stable ultrathin ferroelectric Mg2Mo3O8 expands the scope of ferroelectric materials and may prosper applications of ferroelectrics.
ABSTRACT
The spin Hall effect (SHE), in which an electrical current generates a transverse spin current, plays an important role in spintronics for the generation and manipulation of spin-polarized electrons. The phenomenon originates from spin-orbit coupling. In general, stronger spin-orbit coupling favours larger SHEs but shorter spin relaxation times and diffusion lengths. However, correlated magnetic materials often do not support large SHEs. Achieving large SHEs, long-range spin transport and magnetism simultaneously in a single material is attractive for spintronics applications but has remained a challenge. Here we demonstrate a giant intrinsic SHE coexisting with ferromagnetism in AB-stacked MoTe2/WSe2 moiré bilayers by direct magneto-optical imaging. Under moderate electrical currents with density <1 A m-1, we observe spin accumulation on transverse sample edges that nearly saturates the spin density. We also demonstrate long-range spin Hall transport and efficient non-local spin accumulation that is limited only by the device size (about 10 µm). The gate dependence shows that the giant SHE occurs only near the interaction-driven Chern insulating state. At low temperatures, it emerges after the quantum anomalous Hall breakdown. Our results demonstrate moiré engineering of Berry curvature and electronic correlation for potential spintronics applications.
ABSTRACT
BACKGROUND: Gemcitabine resistance (GR) is a significant clinical challenge in pancreatic adenocarcinoma (PAAD) treatment. Macrophages in the tumor immune-microenvironment are closely related to GR. Uncovering the macrophage-induced GR mechanism could help devise a novel strategy to improve gemcitabine treatment outcomes in PAAD. Therefore, preclinical models accurately replicating patient tumor properties are essential for cancer research and drug development. Patient-derived organoids (PDOs) represent a promising in vitro model for investigating tumor targets, accelerating drug development, and enabling personalized treatment strategies to improve patient outcomes. METHODS: To investigate the effects of macrophage stimulation on GR, co-cultures were set up using PDOs from three PAAD patients with macrophages. To identify signaling factors between macrophages and pancreatic cancer cells (PCCs), a 97-target cytokine array and the TCGA-GTEx database were utilized. The analysis revealed CCL5 and AREG as potential candidates. The role of CCL5 in inducing GR was further investigated using clinical data and tumor sections obtained from 48 PAAD patients over three years, inhibitors, and short hairpin RNA (shRNA). Furthermore, single-cell sequencing data from the GEO database were analyzed to explore the crosstalk between PCCs and macrophages. To overcome GR, inhibitors targeting the macrophage-CCL5-Sp1-AREG feedback loop were evaluated in cell lines, PDOs, and orthotopic mouse models of pancreatic carcinoma. RESULTS: The macrophage-CCL5-Sp1-AREG feedback loop between macrophages and PCCs is responsible for GR. Macrophage-derived CCL5 activates the CCR5/AKT/Sp1/CD44 axis to confer stemness and chemoresistance to PCCs. PCC-derived AREG promotes CCL5 secretion in macrophages through the Hippo-YAP pathway. By targeting the feedback loop, mithramycin improves the outcome of gemcitabine treatment in PAAD. The results from the PDO model were corroborated with cell lines, mouse models, and clinical data. CONCLUSIONS: Our study highlights that the PDO model is a superior choice for preclinical research and precision medicine. The macrophage-CCL5-Sp1-AREG feedback loop confers stemness to PCCs to facilitate gemcitabine resistance by activating the CCR5/AKT/SP1/CD44 pathway. The combination of gemcitabine and mithramycin shows potential as a therapeutic strategy for treating PAAD in cell lines, PDOs, and mouse models.
Subject(s)
Adenocarcinoma , Pancreatic Neoplasms , Animals , Mice , Gemcitabine , Pancreatic Neoplasms/metabolism , Deoxycytidine/therapeutic use , Proto-Oncogene Proteins c-akt/metabolism , Coculture Techniques , Adenocarcinoma/pathology , Plicamycin/metabolism , Plicamycin/pharmacology , Plicamycin/therapeutic use , Drug Resistance, Neoplasm/genetics , Cell Line, Tumor , Macrophages/metabolism , RNA, Small Interfering/pharmacology , Organoids/metabolism , Tumor Microenvironment , Pancreatic NeoplasmsABSTRACT
Black phosphorus (BP) exhibits significant potential for clinical applications. However, further research is necessary to uncover the unknown biological functions of BP and broaden its applications across various fields. This study investigates the potential of BP as a targeting PPAR-γ agonist to overcome chemoresistance in the treatment of pancreatic adenocarcinoma (PAAD) using 2D and 3D cell lines, patient-derived organoids (PDOs), and mouse models. RNA-sequencing analysis shows that BP treatment enriches differentially expressed genes in the PPAR pathway, and molecular modeling predicts the potential docking site between BP and PPAR-γ. Transcriptional activity assays are further to verify the activation of PPAR-γ. BP-activated PPAR-γ inhibits cancer stem cell (CSC) properties and expression of biomarkers such as CD44 and c-Myc, which are involved in chemoresistance. Notably, CD44 overexpression in tumor cells renders them susceptible to BP while insensitive to gemcitabine. This indicates that BP preferentially targets stem-like cells, which exhibit heightened resistance to chemotherapeutic drugs. A combination treatment strategy involving BP and gemcitabine is developed, demonstrating enhanced treatment efficacy of PAAD in both in vitro and in vivo models. Thus, BP serves as a PPAR-γ agonist capable of reversing chemoresistance, establishing it as a potent anti-tumor approach for the treatment of PAAD.
Subject(s)
Adenocarcinoma , Pancreatic Neoplasms , Humans , Mice , Animals , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/metabolism , PPAR-gamma Agonists , Drug Resistance, Neoplasm , Adenocarcinoma/drug therapy , Adenocarcinoma/metabolism , Gemcitabine , PPAR gamma/metabolism , PPAR gamma/therapeutic use , Organoids/pathology , Cell Line, Tumor , Pancreatic NeoplasmsABSTRACT
Polycyclic aromatic compounds with an open-shell singlet diradical ground state, namely singlet diradicals, have recently gained attention in the fields of organic electronics, photovoltaics, and spintronics owing to their unique electronic structures and properties. Notably, singlet diradicals exhibit tunable redox amphoterism, which makes them excellent redox-active materials for biomedical applications. However, the safety and therapeutic efficacy of singlet diradicals in biological systems have not yet been explored. Herein, the study presents a newly designed singlet diradical nanomaterial, diphenyl-substituted biolympicenylidene (BO-Ph), exhibiting low cytotoxicity in vitro, non-significant acute nephrotoxicity in vivo, and the ability to induce metabolic reprogramming in kidney organoids. Integrated transcriptome and metabolome analyses reveal that the metabolism of BO-Ph stimulates glutathione (GSH) synthesis and fatty acid degradation, increases the levels of intermediates in the tricarboxylic acid (TCA) and carnitine cycles, and eventually boosts oxidative phosphorylation (OXPHOS) under redox homeostasis. Benefits of BO-Ph-induce metabolic reprogramming in kidney organoids include enhancing cellular antioxidant capacity and promoting mitochondrial function. The results of this study can facilitate the application of singlet diradical materials in the treatment of clinical conditions induced by mitochondrial abnormalities in kidney.
Subject(s)
Nanoparticles , Nanostructures , Glutathione , Homeostasis , KidneyABSTRACT
While calcium-overload-mediated therapy (COMT) is a promising but largely untapped therapeutic strategy, combinatory therapy greatly boosts treatment outcomes with integrated merits of different therapies. Herein, a BPQD@CaO2 -PEG-GPC3Ab nanoplatform is formulated by integrating calcium peroxide (CaO2 ) and black phosphorus quantum dot (BPQD, photosensitizer) with active-targeting glypican-3 antibody (GPC3Ab), for combinatory photodynamic therapy (PDT) and COMT in response to acidic pH and near-infrared (NIR) light, wherein CaO2 serves as the reservoir of calcium ions (Ca2+ ) and hydrogen peroxide (H2 O2 ). Navigated by GPC3Ab to tumor cells at acidic pH, the nanoparticle disassembles to CaO2 and BPQD; CaO2 produces COMT Ca2+ and H2 O2 , while H2 O2 makes oxygen (O2 ) to promote PDT; under NIR irradiation BPQD facilitates not only the conversion of O2 to singlet oxygen (1 O2 ) for PDT, but also moderate hyperthermia to accelerate NP dissociation to CaO2 and BPQD, and conversions of CaO2 to Ca2+ and H2 O2 , and H2 O2 to O2 , to enhance both COMT and PDT. After supplementary ionomycin treatment to induce intracellular Ca2+ bursts, the multimodal therapeutics strikingly induce hepatocellular carcinoma apoptosis, likely through the activation of the calpains and caspases 12, 9, and 3, up-regulation of Bax and down-regulation of Bcl-2 proteins. This nanoplatform enables a mutually-amplifying and self-reinforcing synergistic therapy.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Nanoparticles , Photochemotherapy , Humans , Calcium , Photosensitizing Agents/pharmacology , Photosensitizing Agents/therapeutic use , Oxygen , Hydrogen Peroxide , Cell Line, TumorABSTRACT
Layered α-RuCl3 is a promising material to potentially realize the long-sought Kitaev quantum spin liquid with fractionalized excitations. While evidence of this state has been reported under a modest in-plane magnetic field, such behaviour is largely inconsistent with theoretical expectations of spin liquid phases emerging only in out-of-plane fields. These predicted field-induced states have been largely out of reach due to the strong easy-plane anisotropy of bulk crystals, however. We use a combination of tunnelling spectroscopy, magnetotransport, electron diffraction and ab initio calculations to study the layer-dependent magnons, magnetic anisotropy, structure and exchange coupling in atomically thin samples. Due to picoscale distortions, the sign of the average off-diagonal exchange changes in monolayer α-RuCl3, leading to a reversal of spin anisotropy to easy-axis anisotropy, while the Kitaev interaction is concomitantly enhanced. Our work opens the door to the possible exploration of Kitaev physics in the true two-dimensional limit.
Subject(s)
Electrons , Magnetic Fields , AnisotropyABSTRACT
Acquired drug resistance decreases the efficacy of gefitinib after approximately 1 year of treatment in non-small-cell lung cancer (NSCLC). Autophagy is a process that could lead to cell death when it is prolonged. Thus, we investigated a drug combination therapy of gefitinib with rapamycin-a cell autophagy activator-in gefitinib-resistant NSCLC cell line H1975 to improve the therapeutic efficacy of gefitinib in advanced NSCLC cells through acute cell autophagy induction. Cell viability and tumor formation assays indicated that rapamycin is strongly synergistic with gefitinib inhibition, both in vitro and in vivo. Mechanistic studies demonstrated that EGFR expression and cell autophagy decreased under gefitinib treatment and were restored after the drug combination therapy, indicating a potential cell autophagy-EGFR positive feedback regulation. To further optimize the delivery efficiency of the combinational agents, we constructed an anti-EGFR aptamer-functionalized nanoparticle (NP-Apt) carrier system. The microscopic observation and cell proliferation assays suggested that NP-Apt achieved remarkably targeted delivery and cytotoxicity in the cancer cells. Taken together, our results suggest that combining rapamycin and gefitinib can be an efficacious therapy to overcome gefitinib resistance in NSCLC, and targeted delivery of the drugs using the aptamer-nanoparticle carrier system further enhances the therapeutic efficacy of gefitinib.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Nanoparticles , Autophagy , Carcinoma, Non-Small-Cell Lung/pathology , Cell Line, Tumor , Cell Proliferation , Drug Combinations , Drug Resistance, Neoplasm , ErbB Receptors/metabolism , Gefitinib/pharmacology , Gefitinib/therapeutic use , Humans , Lung Neoplasms/metabolism , Protein Kinase Inhibitors/pharmacology , Quinazolines/therapeutic use , Sirolimus/pharmacology , Sirolimus/therapeutic useABSTRACT
Moiré engineering1-3 of van der Waals magnetic materials4-9 can yield new magnetic ground states via competing interactions in moiré superlattices10-13. Theory predicts a suite of interesting phenomena, including multiflavour magnetic states10, non-collinear magnetic states10-13, moiré magnon bands and magnon networks14 in twisted bilayer magnetic crystals, but so far such non-trivial magnetic ground states have not emerged experimentally. Here, by utilizing the stacking-dependent interlayer exchange interactions in two-dimensional magnetic materials15-18, we demonstrate a coexisting ferromagnetic (FM) and antiferromagnetic (AF) ground state in small-twist-angle CrI3 bilayers. The FM-AF state transitions to a collinear FM ground state above a critical twist angle of about 3°. The coexisting FM and AF domains result from a competition between the interlayer AF coupling, which emerges in the monoclinic stacking regions of the moiré superlattice, and the energy cost for forming FM-AF domain walls. Our observations are consistent with the emergence of a non-collinear magnetic ground state with FM and AF domains on the moiré length scale10-13. We further employ the doping dependence of the interlayer AF interaction to control the FM-AF state by electrically gating a bilayer sample. These experiments highlight the potential to create complex magnetic ground states in twisted bilayer magnetic crystals, and may find application in future gate-voltage-controllable high-density magnetic memory storage.
ABSTRACT
Electron correlation and topology are two central threads of modern condensed matter physics. Semiconductor moiré materials provide a highly tuneable platform for studies of electron correlation1-12. Correlation-driven phenomena, including the Mott insulator2-5, generalized Wigner crystals2,6,9, stripe phases10 and continuous Mott transition11,12, have been demonstrated. However, non-trivial band topology has remained unclear. Here we report the observation of a quantum anomalous Hall effect in AB-stacked MoTe2 /WSe2 moiré heterobilayers. Unlike in the AA-stacked heterobilayers11, an out-of-plane electric field not only controls the bandwidth but also the band topology by intertwining moiré bands centred at different layers. At half band filling, corresponding to one particle per moiré unit cell, we observe quantized Hall resistance, h/e2 (with h and e denoting the Planck's constant and electron charge, respectively), and vanishing longitudinal resistance at zero magnetic field. The electric-field-induced topological phase transition from a Mott insulator to a quantum anomalous Hall insulator precedes an insulator-to-metal transition. Contrary to most known topological phase transitions13, it is not accompanied by a bulk charge gap closure. Our study paves the way for discovery of emergent phenomena arising from the combined influence of strong correlation and topology in semiconductor moiré materials.
ABSTRACT
Nanosafety is a major concern for nanotechnology development. Evaluation of the transcriptome and the DNA methylome is proposed for nanosafety assessments. RNA m6A modification plays a crucial role in development, disease, and cell fate determination through regulating RNA stability and decay. Here, since black phosphorus quantum dots (BPQDs), among many other types of QDs, increase the global m6A level and decrease the demethylase ALKBH5 level in lung cells, the epitranscriptome is taken into consideration for the first time to evaluate nanosafety. Both the transcriptome and m6A epitranscriptome analyses show that BPQDs alter many biological processes, such as the response to selenium ions and the lipoxygenase pathway, indicating possible ferroptosis activation. The results further show that BPQDs cause lipid peroxidation, mitochondrial dysfunction, and iron overload. Recognition of these modified mRNAs by YTHDF2 leads to mRNAs' decay and eventually ferroptosis. This study shows that RNA m6A modification not only is a more sophisticated indicator for nanosafety assessment but also provides novel insight into the role of RNA m6A in regulating BPQD-induced ferroptosis, which may be broadly applicable to understanding the functions of RNA m6A under stress.
Subject(s)
Ferroptosis , Quantum Dots , Ferroptosis/genetics , Phosphorus/metabolism , Quantum Dots/toxicity , RNA, Messenger/metabolism , RNA-Binding Proteins/geneticsABSTRACT
The evolution of a Landau Fermi liquid into a non-magnetic Mott insulator with increasing electronic interactions is one of the most puzzling quantum phase transitions in physics1-6. The vicinity of the transition is believed to host exotic states of matter such as quantum spin liquids4-7, exciton condensates8 and unconventional superconductivity1. Semiconductor moiré materials realize a highly controllable Hubbard model simulator on a triangular lattice9-22, providing a unique opportunity to drive a metal-insulator transition (MIT) via continuous tuning of the electronic interactions. Here, by electrically tuning the effective interaction strength in MoTe2/WSe2 moiré superlattices, we observe a continuous MIT at a fixed filling of one electron per unit cell. The existence of quantum criticality is supported by the scaling collapse of the resistance, a continuously vanishing charge gap as the critical point is approached from the insulating side, and a diverging quasiparticle effective mass from the metallic side. We also observe a smooth evolution of the magnetic susceptibility across the MIT and no evidence of long-range magnetic order down to ~5% of the Curie-Weiss temperature. This signals an abundance of low-energy spinful excitations on the insulating side that is further corroborated by the Pomeranchuk effect observed on the metallic side. Our results are consistent with the universal critical theory of a continuous Mott transition in two dimensions4,23.
ABSTRACT
BACKGROUND: Recently, pine wood nematode (PWN, Bursaphelenchus xylophilus) has been found in the extreme cold area of northeast China. The third-stage dispersal juvenile (DJ3) of PWN, which is a long-lived stress-resistant stage, plays an important role in the process of PWN spreading to low-temperature areas, as this stage can survive under unfavorable conditions. RESULTS: Weighted correlation network analysis (WGCNA) was used to analyze the expression patterns of 15,889 genes included in 21 RNA-Seq results of PWN at DJ3 and the other 6 different stages, and a total of 12 coexpression modules were obtained. Among them, the magenta module has the highest correlation with DJ3, which included a total of 652 genes. KEGG enrichment analysis showed that most of the genes in the magenta module were involved in metabolic processes, which were related to autophagy and longevity regulation. These pathways included starch and sucrose metabolism, which contains trehalose metabolism. To explore the function of trehalose in DJ3 formation and survival under - 20 °C, a trehalose-6-phosphate synthase encoding gene (Bx-tps), a trehalose-6-phosphate phosphatase encoding gene (Bx-tpp) and 7 trehalase encoding genes (Bx-tres) were identified and investigated. The expression of these 9 genes was related to the formation of DJ3. A treatment under - 20 °C induced the accumulation of trehalose. The survival rate of DJ3 at -20 °C reduced after silencing of any of these trehalose metabolism genes. Further analysis suggested that two trehalose synthesis genes were highly correlated with DJ3 and might be involved in autophagy by regulating with energy conversion related genes. CONCLUSIONS: The above results indicated that trehalose metabolism promotes DJ3 formation and helps DJ3 survive at -20 °C. Although trehalose accumulation is favorable for DJ3 to cope with low-temperature stress, multiple trehalose metabolism genes need to work together. There may be a multi-path regulated physiological process involving trehalose synthesis genes under low-temperature stress resistance. This physiological process may regulate the formation and maintenance of DJ3 through autophagy and energy conversion.
Subject(s)
Pinus , Tylenchida , Animals , China , Temperature , TrehaloseABSTRACT
Two-dimensional (2D) magnetic materials have attracted much recent interest with unique properties emerging at the few-layer limit. Beyond the reported impacts on the static magnetic properties, the effects of reducing the dimensionality on the magnetization dynamics are also of fundamental interest and importance for 2D device development. In this report, we investigate the spin dynamics in atomically thin antiferromagnetic FePS3 of varying layer numbers using ultrafast pump-probe spectroscopy. Following the absorption of an optical pump pulse, the time evolution of the antiferromagnetic order parameter is probed by magnetic linear birefringence. We observe a strong divergence in the demagnetization time near the Néel temperature. The divergence can be characterized by a power-law dependence on the reduced temperature, with an exponent decreasing with sample thickness. We compare our results to expectations from critical slowing down and a two-temperature model involving spins and phonons and discuss the possible relevance of spin-substrate phonon interactions.
ABSTRACT
The strong excitonic effect in monolayer transition metal dichalcogenide (TMD) semiconductors has enabled many fascinating light-matter interaction phenomena. Examples include strongly coupled exciton-polaritons and nearly perfect atomic monolayer mirrors. The strong light-matter interaction also opens the door for dynamical control of mechanical motion through the exciton resonance of monolayer TMDs. Here, we report the observation of exciton-optomechanical coupling in a suspended monolayer MoSe2 mechanical resonator. By moderate optical pumping near the MoSe2 exciton resonance, we have observed optical damping and antidamping of mechanical vibrations as well as the optical spring effect. The exciton-optomechanical coupling strength is also gate-tunable. Our observations can be understood in a model based on photothermal backaction and gate-induced mirror symmetry breaking in the device structure. The observation of gate-tunable exciton-optomechanical coupling in a monolayer semiconductor may find applications in nanoelectromechanical systems (NEMS) and in exciton-optomechanics.
ABSTRACT
OBJECTIVE: Organoids have recently been used as in vitro models to screen chemotherapy drugs in combination with hyperthermia treatment in colorectal cancer. Our research aimed to establish a library of patient-derived colorectal cancer organoids to evaluate synergism between chemotherapy drugs and hyperthermia; validate an index of the hyperthermia chemotherapy sensitization enhancement ratio (HCSER) to identify the chemotherapeutics most enhanced by hyperthermia; and recommend chemotherapy drugs for hyperthermic intraperitoneal treatment. METHODS: Organoids were grown from cells extracted from colorectal cancer patient samples or colorectal cancer cell lines. Cells from both sources were encapsulated in 3D Matrigel droplets, which were formulated in microfluidics and phase-transferred into identical cell-laden Matrigel microspheres. The microspheres were seeded in 96-well plates, with each well containing a single microsphere that developed into an organoid after 7 days. The organoids were used to evaluate the efficacy of chemotherapy drugs at both 37°C as a control and 43°C for 90 min to examine hyperthermia synergism. Cell viability was counted with 10% CCK8. RESULTS: We successfully established a library of colorectal cancer organoids from 22 patient parental tumors. We examined the hyperthermia synergism of 7 commonly used hyperthermic intraperitoneal chemotherapy drugs. In 11 of the 22 patient organoids, raltitrexed had significant hyperthermia synergism, which was indexed as the highest HCSER score within each patient group. CONCLUSIONS: Our results primarily demonstrated the use of patient-derived colorectal cancer organoids as in vitro models to evaluate hyperthermia synergistic chemotherapeutics. We found that hyperthermia enhanced the effect of raltitrexed the most among the common anti-colorectal cancer drugs.
ABSTRACT
Current organoid technologies require intensive manual manipulation and lack uniformity in organoid size and cell composition. We present here an automated organoid platform that generates uniform organoid precursors in high-throughput. This is achieved by templating from monodisperse Matrigel droplets and sequentially delivering them into wells using a synchronized microfluidic droplet printer. Each droplet encapsulates a certain number of cells (e.g., 1,500 cells), which statistically represent the heterogeneous cell population in a tumor section. The system produces >400-µm organoids within 1 week with both inter-organoid homogeneity and inter-patient heterogeneity. This enables automated organoid printing to obtain one organoid per well. The organoids recapitulate 97% gene mutations in the parental tumor and reflect the patient-to-patient variation in drug response and sensitivity, from which we obtained more than 80% accuracy among the 21 patients investigated. This organoid platform is anticipated to fulfill the personalized medicine goal of 1-week high-throughput screening for cancer patients.
Subject(s)
Automation , Neoplasms/pathology , Organoids/pathology , Precision Medicine , Animals , Automation/methods , Biometry/methods , High-Throughput Screening Assays/methods , Humans , Mice , Microfluidics/methods , Precision Medicine/methods , Printing, Three-DimensionalABSTRACT
We report measurements of current-induced thermoelectric and spin-orbit torque effects within devices in which multilayers of the semiconducting two-dimensional van der Waals magnet Cr2Ge2Te6 (CGT) are integrated with Pt and Ta metal overlayers. We show that the magnetic orientation of the CGT can be detected accurately either electrically (using an anomalous Hall effect) or optically (using magnetic circular dichroism) with good consistency. The samples exhibit large thermoelectric effects, but nevertheless, the spin-orbit torque can be measured quantitatively using the angle-dependent second harmonic Hall technique. For CGT/Pt, we measure the spin-orbit torque efficiency to be similar to conventional metallic-ferromagnet/Pt devices with the same Pt resistivity. The interfacial transparency for spin currents is therefore similar in both classes of devices. Our results demonstrate the promise of incorporating semiconducting 2D magnets within spin-orbitronic and magneto-thermal devices.