Life and death of circulating cell-free DNA Kustanovich, Anatoli; Schwartz, Ruth; Peretz, Tamar ...
Cancer biology & therapy,
08/2019, Letnik:
20, Številka:
8
Journal Article
Recenzirano
Odprti dostop
Tumor-specific, circulating cell-free DNA in liquid biopsies is a promising source of biomarkers for minimally invasive serial monitoring of treatment responses in cancer management. We will review ...the current understanding of the origin of circulating cell-free DNA and different forms of DNA release (including various types of cell death and active secretion processes) and clearance routes. The dynamics of extracellular DNA in blood during therapy and the role of circulating DNA in pathophysiological processes (tumor-associated inflammation, NETosis, and pre-metastatic niche development) provide insights into the mechanisms that contribute to tumor development and metastases formation. Better knowledge of circulating tumor-specific cell-free DNA could facilitate the development of new therapeutic and diagnostic options for cancer management.
A novel combination of block copolymer (BCP) nano spray‐drying (NSD), solvent annealing, and selective metal oxide growth is utilized to create functional polymer nanoparticles, polymer‐metal‐oxide ...hybrid nanoparticles, and templated metal oxide nanoparticles with tunable composition, internal morphology, and porosity. NSD of BCPs from chloroform and toluene solutions results in porous and nonporous nanoparticles, respectively, with various degrees of phase separation. Further tuning of the nanoparticle internal morphology is performed by solvent annealing the spray‐dried particles with judicious choice of the nonsolvent dispersion medium and the surfactant, yielding assembly of both blocks at the surface of the nanoparticles. Finally, ZnO and Al2O3 are grown inside the polar blocks of phase‐ordered nanoparticles using a sequential infiltration synthesis method, in a post‐assembly process, resulting in hybrid BCP‐ZnO particles and BCP‐templated Al2O3 nanoparticles, as demonstrated by scanning transmission electron microscopy tomography. These structure engineering methods open new ways to direct and template functional nanoparticles.
Diblock copolymer nano and microparticles are fabricated through nano spray‐drying. Particle morphology is controlled by tuning the solution chemistry, spraying conditions, and the following solvent annealing step. Hybrid organic–inorganic particles are fabricated by employing sequential infiltration synthesis, leading to the formation of hybrid block copolymer‐metal oxide particles and porous, block copolymer‐templated metal‐oxide particles.
Nanofabrication is continuously searching for new methodologies to fabricate 3D nanostructures with 3D control over their chemical composition. A new approach for heterostructure nanorod array ...fabrication through spatially controlled–growth of multiple metal oxides within block copolymer (BCP) templates is presented. Selective growth of metal oxides within the cylindrical polymer domains of polystyrene‐block‐poly methyl methacrylate is performed using sequential infiltration synthesis (SIS). Tuning the diffusion of trimethyl aluminum and diethyl zinc organometallic precursors in the BCP film directs the growth of AlOx and ZnO to different locations within the cylindrical BCP domains, in a single SIS process. BCP removal yields an AlOx‐ZnO heterostructure nanorods array, as corroborated by 3D characterization with scanning transmission electron microscopy (STEM) tomography and a combination of STEM and energy‐dispersive X‐ray spectroscopy tomography. The strategy presented here will open up new routes for complex 3D nanostructure fabrication.
A new approach for the design and fabrication of 3D metal oxide heterostructure nanorod arrays is realized through spatially controlled–growth of multiple metal oxides within self‐assembled block copolymer films. Tuning the metal oxide precursor diffusion enables control over the 3D nanorod chemical composition in a simple and precise process.
Applying a next-generation sequencing assay targeting 145 cancer-relevant genes in 40 colorectal cancer and 24 non-small cell lung cancer formalin-fixed paraffin-embedded tissue specimens identified ...at least one clinically relevant genomic alteration in 59% of the samples and revealed two gene fusions, C2orf44-ALK in a colorectal cancer sample and KIF5B-RET in a lung adenocarcinoma. Further screening of 561 lung adenocarcinomas identified 11 additional tumors with KIF5B-RET gene fusions (2.0%; 95% CI 0.8-3.1%). Cells expressing oncogenic KIF5B-RET are sensitive to multi-kinase inhibitors that inhibit RET.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Control over nanopore size and 3D structure is necessary to advance membrane performance in ubiquitous separation devices. Here, inorganic nanoporous membranes are fabricated by combining the ...assembly of cylinder‐forming poly(styrene‐block‐methyl methacrylate) (PS‐b‐PMMA) block copolymer and sequential infiltration synthesis (SIS). A key advance relates to the use of PMMA majority block copolymer films and the optimization of thermal annealing temperature and substrate chemistry to achieve through‐film vertical PS cylinders. The resulting morphology allows for direct fabrication of nanoporous AlOx by selective growth of Al2O3 in the PMMA matrix during the SIS process, followed by polymer removal using oxygen plasma. Control over the pore diameter is achieved by varying the number of Al2O3 growth cycles, leading to pore size reduction from 21 to 16 nm. 3D characterization, using scanning transmission electron microscopy tomography, reveals that the AlOx channels are continuous through the film and have a gradual increase in pore size with depth. Finally, the ultrafiltration performance of the fabricated AlOx membrane for protein separation as a function of protein size and charge is demonstrated.
Nanoporous inorganic membranes are fabricated from cylinder‐forming block copolymer templates. Sequential infiltration synthesis followed by oxygen plasma etching converses polymer domains into uniform alumina pores with tunable pore size. The resulting cylindrical channels are continuous through the film thickness. The created membrane shows excellent protein separation ability. This fabrication route holds great promise in making multifunctional membranes.
Accomplishing on‐demand molecular separation with a high selectivity and good permeability is very desirable for pollutant removal and chemical and pharmaceutical processing. The major challenge for ...sub‐10 nm filtration of particles and molecules is the fabrication of high‐performance membranes with tunable pore size and designed functionality. Here, a versatile top‐down approach is demonstrated to produce such a membrane using isoporous block copolymer membranes with well‐defined pore sizes combined with growth of metal oxide using sequential infiltration synthesis and atomic layer deposition (SIS and ALD). The pore size of the membranes is tuned by controlled metal oxide growth within and onto the polymer channels, enabling up to twofold pore diameter reduction. Following the growth, the distinct functionalities are readily incorporated along the membrane nanochannels with either hydrophobic, cationic, or anionic groups via straightforward and scalable gas/liquid–solid interface reactions. The hydrophilicity/hydrophobicity of the membrane nanochannel is significantly changed by the introduction of hydrophilic metal oxide and hydrophobic fluorinated groups. The functionalized membranes exhibit a superior selectivity and permeability in separating 1–2 nm organic molecules and fractionating similar‐sized proteins based on size, charge, and hydrophobicity. This demonstrates the great potential of organic–inorganic–organic isoporous membranes for high‐performance molecular separation in numerous applications.
Novel hybrid organic–inorganic–organic isoporous membranes are fabricated via sequential infiltration synthesis and atomic layer deposition within block copolymer membranes followed by addition of functional organic molecules. The membrane pore sizes are controlled by metal oxide growth in a predictive manner. The hybrid membranes exhibit superior selectivity and permeability in separating 1–2 nm organic molecules and similar‐sized proteins.
Inorganic–organic mesophase materials provide a wide range of tunable properties, which are often highly dependent on their nano‐, micro‐, or meso‐scale compositions and structures. Among these are ...macroscopic orientational order and corresponding anisotropic material properties, the adjustability of which are difficult to achieve. This is due to the complicated transient and coupled transport, chemical reaction, and surface processes that occur during material syntheses. By understanding such processes, general criteria are established and used to prepare diverse mesostructured materials with highly aligned channels with uniform nanometer dimensions and controllable directionalities over macroscopic dimensions and thicknesses. This is achieved by using a micropatterned semipermeable poly(dimethylsiloxane) stamp to manage the rates, directions, and surfaces at which self‐assembling phases nucleate and the directions that they grow. This enables mesostructured surfactant‐directed silica and titania composites, including with functional guest species, and mesoporous carbons to be prepared with high degrees of hexagonal order, as well as controllable orthogonal macroscopic orientational order. The resulting materials exhibit novel anisotropic properties, as demonstrated by the example of direction‐dependent photocurrent generation, and are promising for enhancing the functionality of inorganic–organic nanocomposite materials in separations, catalysis, and energy conversion applications.
High and controllable degrees of macroscopic orientational ordering are demonstrated for mesostructured silica, titania, and carbon films. Judicious selection of synthesis conditions enables the control of the directions and relative rates of solvent removal, surfactant self‐assembly, inorganic‐oxide cross‐linking, and the surfaces at which mesophases grow. The materials exhibit anisotropic properties for applications in separations, catalysis, and energy conversion.
Cell-free DNA (cfDNA) in human plasma provides access to molecular information about the pathological processes in the organs or tumors from which it originates. These DNA fragments are derived from ...fragmented chromatin in dying cells and retain some of the cell-of-origin histone modifications. In this study, we applied chromatin immunoprecipitation of cell-free nucleosomes carrying active chromatin modifications followed by sequencing (cfChIP-seq) to 268 human samples. In healthy donors, we identified bone marrow megakaryocytes, but not erythroblasts, as major contributors to the cfDNA pool. In patients with a range of liver diseases, we showed that we can identify pathology-related changes in hepatocyte transcriptional programs. In patients with metastatic colorectal carcinoma, we detected clinically relevant and patient-specific information, including transcriptionally active human epidermal growth factor receptor 2 (HER2) amplifications. Altogether, cfChIP-seq, using low sequencing depth, provides systemic and genome-wide information and can inform diagnosis and facilitate interrogation of physiological and pathological processes using blood samples.
Background.
Disulfiram, an alcohol aversion agent, has been in use for >50 years. Numerous authors have reported an anticancer effect of this drug in vitro and in mouse models. More recently, several ...reports have claimed that disulfiram also possesses anti‐stem cell activity. We set out to obtain initial data regarding the safety of combining this drug with chemotherapy and the possible effectiveness of disulfiram in a combination regimen in non‐small cell lung cancer (NSCLC).
Methods.
This phase II, multicenter, randomized, double‐blinded study assessed the safety and efficacy of adding of disulfiram to cisplatin and vinorelbine for six cycles. Newly diagnosed NSCLC patients were recruited. Patients with either stage IV or what was considered at the time “wet IIIb” (since 2009, these patients have been considered stage IV) were recruited. The patients were treated with only chemotherapy, and none were treated with either surgery or chemoradiation. Disulfiram was administered at a dose of 40 mg three times daily.
Results.
Forty patients were treated for more than two cycles, half with and half without disulfiram, which was well tolerated. An increase in survival was noted for the experimental group (10 vs. 7.1 months). Interestingly, there were only two long‐term survivors, both in the disulfiram group.
Conclusion.
The addition of disulfiram to a combination regimen of cisplatin and vinorelbine was well tolerated and appeared to prolong survival in patients with newly diagnosed non‐small cell lung cancer. The results from this small study seem encouraging enough for assessment in larger trials. Disulfiram is an inexpensive and safe drug; if its addition to chemotherapy could be shown to prolong survival, an effective regimen could be established and used widely, even in resource‐poor countries.
摘要
背景. 双硫仑为酒精厌恶疗法的戒酒药物，迄今已应用50余年。 很多作者报告了该制剂在体外和小鼠模型中的抗癌作用。近年来，几项报告指出双硫仑还具有抗干细胞活性。本研究获得了非小细胞肺癌（NSCLC）中该药联合化疗的原始安全性数据，以及联合方案中双硫仑的可能疗效。
方法. 本项多中心、随机、双盲II期研究评估了双硫仑联合顺铂与长春瑞滨治疗6周期的安全性和有效性。评估对象为新确诊的IV期或“wet IIIb”期（自2009年起，这些患者被视为IV期）NSCLC患者。这些患者仅接受化疗，无一例进行手术或化放疗。双硫仑给药剂次为40 mg，每日3次。
结果. 40例患者接受了2个周期以上治疗，50%联合使用双硫仑，50%则未联合双硫仑。两种治疗均耐受良好。我们观察到研究组生存期延长（10个月vs. 7.1 个月）。值得注意的是，仅有2例长期生存患者，均在双硫仑组。
结论. 对于新确诊的非小细胞肺癌患者，顺铂和长春瑞滨联合方案基础上添加双硫仑后，不但能够被很好地耐受，而且似乎可延长患者生存期。本次小规模研究结果很令人鼓舞，应在此基础上开展更大规模的试验。双硫仑费用不高，且安全性好；若在化疗中加入双硫仑证实具有生存获益，那么这种有效方案应该确立并广泛应用，包括资源贫乏的国家。The Oncologist 2015;20:366–367
The presence of tumor-infiltrating Natural Killer (NK) within a tumor bed may be indicative of an ongoing immune response toward the tumor. However, many studies have shown that an intense NK ...infiltration, is associated with advanced disease and may even facilitate cancer development. The exact role of the tumor infiltrating NK cells and the correlation between their presence and poor prognosis remains unclear. Interestingly, during pregnancy high numbers of a specific NK subset, CD56(bright)CD16(dim), are accumulated within first trimester deciduas. These decidual NK (dNK) cells are unique in their gene expression pattern secret angiogenic factors that induce vascular growth. In the present study we demonstrate a significant enrichment of a CD56(brigh)CD16(dim) NK cells within tumors. These NK cells express several dNK markers including VEGF. Hence, this study adds new insights into the identity of tumor residual NK cells, which has clear implications for the treatment of human cancer.
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