CRISPR-Cas9 genome editing technology holds great promise for discovering therapeutic targets in cancer and other diseases. Current screening strategies target CRISPR-Cas9-induced mutations to the 5' ...exons of candidate genes, but this approach often produces in-frame variants that retain functionality, which can obscure even strong genetic dependencies. Here we overcome this limitation by targeting CRISPR-Cas9 mutagenesis to exons encoding functional protein domains. This generates a higher proportion of null mutations and substantially increases the potency of negative selection. We also show that the magnitude of negative selection can be used to infer the functional importance of individual protein domains of interest. A screen of 192 chromatin regulatory domains in murine acute myeloid leukemia cells identifies six known drug targets and 19 additional dependencies. A broader application of this approach may allow comprehensive identification of protein domains that sustain cancer cells and are suitable for drug targeting.
Ramucirumab is the first FDA-approved monotherapy for advanced gastric cancer. In this study, Ramucirumab (Ab) is attached to gold nanoparticles to enhance uptake efficiency. Gold nanoparticles can ...induce direct cytotoxic effects to cancer cells in the presence of Ab, while individual Ab or gold nanoparticles don't have such an effective anticancer effect even at extremely high concentrations. Proteomic and transcriptomic analyses reveal this direct cytotoxicity is derived predominantly from Ab-mediated phagocytosis. High affinity immunoglobulin gamma Fc receptor I shows differential up-regulation in gastric cancer cells treated by these nanodrugs compared with Ab, especially for Ab with gold nanorods. Simplified and powerful designs of smart nanoparticles are highly desired for clinical application. The enhancement of Ab accumulation with a simple composition, combined with direct cytotoxic effects specific to cancer cells brought improved therapeutic effects in vivo compared with Ab, which can promote further clinical application of gold nanomaterials in the diagnosis and therapeutics of gastric cancer.
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•1. Single-atom Co modified g-C3N4 prepared by one-step thermal-polymerization of cobalt phthalocyanine (CoPc) and urea.•2. Strong interaction between Co 3d electrons and C 2p ...electrons of CO2 activate C = O bonds in CO2 molecule.•3. Optimal 1%Co-CN sample exhibits higher CO yield of 94.9 umol/g/h than pure g-C3N4 0.25 umol/g/h.
Using solar energy to realize photoreduction of CO2 into valuable chemicals is a potential way to solve energy crisis and carbon cycle. Due to the extremely stable molecular configuration of CO2, activating CO2 molecule is the key and difficult step in the whole CO2 conversation process. In this work, we used density functional theory (DFT) to calculate the reaction pathways of CO2 to CO on pure g-C3N4 and single-atom cobalt (Co) modified g-C3N4. Theoretical calculation predicts that single-atom Co sites modified g-C3N4 (Co-CN) possess stronger CO2 adsorption ability and lower barrier of CO2 hydrogenation activation than pure g-C3N4. The strong interaction between Co 3d electrons and C 2p electrons of CO2 is the crucial factor to activate C = O bonds of CO2 molecule. Better CO2 adsorption and activation abilities also are proved in Co-CN by CO2 adsorption, temperature programmed desorption (TPD), and sensor tests. As a result, the optimal 1%Co-CN exhibits higher CO yield of 94.9 umol/g/h than pure g-C3N4 (0.25 umol/g/h). This work provides a new insight of the role of single-atom sites in CO2 reduction reactions.
Tumor-targeting peptide-drug conjugates (PDCs) have become a focus of research in recent years. However, due to the instability of peptides and their short in vivo effective half-life, they have ...limited clinical application. Herein, we propose a new DOX PDC based on a homodimer HER-2-targeting peptide and acid-sensitive hydrazone bond, which could enhance the anti-tumor effect of DOX and reduce systemic toxicities. The PDC could accurately deliver DOX into HER2-positive SKBR-3 cells, with it showing 2.9 times higher cellular uptake than free DOX and enhanced cytotoxicity with respect to IC
of 140 nM (vs. 410 nM for free DOX). In vitro assays showed that the PDC had high cellular internalization efficiency and cytotoxicity. In vivo anti-tumor experiments indicated that the PDC could significantly inhibit the growth of HER2-positive breast cancer xenografts in mice and reduce the side effects of DOX. In summary, we constructed a novel PDC molecule targeting HER2-positive tumors, which may overcome some deficiencies of DOX in breast cancer therapy.
Aneuploidy is a ubiquitous feature of human tumors, but the acquisition of aneuploidy typically antagonizes cellular fitness. To investigate how aneuploidy could contribute to tumor growth, we ...triggered periods of chromosomal instability (CIN) in human cells and then exposed them to different culture environments. We discovered that transient CIN reproducibly accelerates the acquisition of resistance to anti-cancer therapies. Single-cell sequencing revealed that these resistant populations develop recurrent aneuploidies, and independently deriving one chromosome-loss event that was frequently observed in paclitaxel-resistant cells was sufficient to decrease paclitaxel sensitivity. Finally, we demonstrated that intrinsic levels of CIN correlate with poor responses to numerous therapies in human tumors. Our results show that, although CIN generally decreases cancer cell fitness, it also provides phenotypic plasticity to cancer cells that can allow them to adapt to diverse stressful environments. Moreover, our findings suggest that aneuploidy may function as an under-explored cause of therapy failure.
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•Periods of chromosomal instability can accelerate acquisition of drug resistance•Drug-resistant cancer cells frequently harbor recurrent aneuploidies•Recapitulation of an aneuploidy in drug-naive cells is sufficient for resistance•Chromosomal instability correlates with poor therapeutic responses in human tumors
Chromosomal instability (CIN) is a hallmark of cancer and is frequently found to correlate with aggressive disease. However, the role of CIN in driving tumor progression is poorly understood. Here, Lukow et al. demonstrate a role for CIN in promoting therapeutic resistance through the acquisition of specific aneuploidies.
Whole exome sequencing has proven to be a powerful tool for understanding the genetic architecture of human disease. Here we apply it to more than 2,500 simplex families, each having a child with an ...autistic spectrum disorder. By comparing affected to unaffected siblings, we show that 13% of de novo missense mutations and 43% of de novo likely gene-disrupting (LGD) mutations contribute to 12% and 9% of diagnoses, respectively. Including copy number variants, coding de novo mutations contribute to about 30% of all simplex and 45% of female diagnoses. Almost all LGD mutations occur opposite wild-type alleles. LGD targets in affected females significantly overlap the targets in males of lower intelligence quotient (IQ), but neither overlaps significantly with targets in males of higher IQ. We estimate that LGD mutation in about 400 genes can contribute to the joint class of affected females and males of lower IQ, with an overlapping and similar number of genes vulnerable to contributory missense mutation. LGD targets in the joint class overlap with published targets for intellectual disability and schizophrenia, and are enriched for chromatin modifiers, FMRP-associated genes and embryonically expressed genes. Most of the significance for the latter comes from affected females.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Computational fluid dynamics (CFD) and population balance models (PBM) were coupled together for the first time to simulate the synthesis of zirconia nanoparticles in a continuous hydrothermal flow ...synthesis (CHFS) system with a self-designed confined impinging jet mixing (CJM) reactor. The hydrodynamic and thermodynamic behaviors within the CJM reactor strongly influenced the formation of the ZrO
nanoparticles. Crucial parameters, such as velocities, temperatures, mixing conditions, and reaction rates, were analyzed under various supercritical conditions. Temperature and velocity measurements as functions of distance were also investigated. Normal particle size distribution (PSD) patterns were observed in all cases. The mean particle sizes in this study were calculated and compared using PBM aggregation analysis.
In vivo molecular imaging of tumors targeting a specific cancer cell marker is a promising strategy for cancer diagnosis and imaging guided surgery and therapy. While targeted imaging often relies on ...antibody‐modified probes, peptides can afford targeting probes with small sizes, high penetrating ability, and rapid excretion. Recently, in vivo fluorescence imaging in the second near‐infrared window (NIR‐II, 1000–1700 nm) shows promise in reaching sub‐centimeter depth with microscale resolution. Here, a novel peptide (named CP) conjugated NIR‐II fluorescent probe is reported for molecular tumor imaging targeting a tumor stem cell biomarker CD133. The click chemistry derived peptide‐dye (CP‐IRT dye) probe afforded efficient in vivo tumor targeting in mice with a high tumor‐to‐normal tissue signal ratio (T/NT > 8). Importantly, the CP‐IRT probes are rapidly renal excreted (≈87% excretion within 6 h), in stark contrast to accumulation in the liver for typical antibody‐dye probes. Further, with NIR‐II emitting CP‐IRT probes, urethra of mice can be imaged fluorescently for the first time noninvasively through intact tissue. The NIR‐II fluorescent, CD133 targeting imaging probes are potentially useful for human use in the clinic for cancer diagnosis and therapy.
One novel peptide (CP)‐conjugated NIR‐II targeting fluorescent probe for molecular tumor imaging is developed toward a tumor stem cell receptor CD133. The peptide–dye probe shows efficient in vivo tumor targeting behaviors in mice with a high tumor‐to‐normal tissue signal ratio and can be renally excreted rapidly, in contrast to accumulation in the liver for typical protein–dye probes.
Exosomes are naturally occurring nanoscale vesicles that are released and received by almost all cells in the body. Exosomes can be transferred between cells and contain various molecular constitutes ...closely related to their origin and function, including proteins, lipids, and RNAs. The importance of exosomes in cellular communication makes them important vectors for delivering a variety of drugs throughout the body. Exosomes are ubiquitous in the circulatory system and can reach the site of injury or disease through a variety of biological barriers. Due to its unique structure and rich inclusions, it can be used for the diagnosis and treatment of diseases. Mesenchymal stem-cell-derived exosomes (MSCs-Exo) inherit the physiological functions of MSCs, including repairing and regenerating tissues, suppressing inflammatory responses, and regulating the body's immunity; therefore, MSCs-Exo can be used as a natural drug delivery carrier with therapeutic effects, and has been increasingly used in the treatment of cardiovascular diseases and neurodegenerative diseases. Here, we summarize the research progress of MSCs-Exo as drug delivery vectors and their application for various drug deliveries, providing ideas and references for the study of MSCs-Exo in recent years.
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