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1.
Chem Commun (Camb) ; 56(7): 1105-1108, 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31894766

RESUMO

A series of hydrogen-bonded liquid crystals based on resveratrol and resveratrone is reported and investigated with respect to their photo-switchability (at 405 nm) and photo-cyclisation (at 300 nm).

2.
Brief Funct Genomics ; 2019 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-31844895

RESUMO

Chimeric antigen receptor (CAR)-modified T cells have raised among other immunotherapies for cancer treatment, being implemented against B-cell malignancies. Despite the promising outcomes of this innovative technology, CAR-T cells are not exempt from limitations that must yet to be overcome in order to provide reliable and more efficient treatments against other types of cancer. The purpose of this review is to shed light on the field of CAR-T cell gene editing for therapy universalization and further enhancement of antitumor function. Several studies have proven that the disruption of certain key genes is essential to boost immunosuppressive resistance, prevention of fratricide, and clinical safety. Due to its unparalleled simplicity, feasibility to edit multiple gene targets simultaneously, and affordability, CRISPR/CRISPR-associated protein 9 system has been proposed in different clinical trials for such CAR-T cell improvement. The combination of such powerful technologies is expected to provide a new generation of CAR-T cell-based immunotherapies for clinical application.

3.
Blood Rev ; : 100641, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31761379

RESUMO

Due to pioneering in vitro investigations on gene modification, gene engineering platforms have incredibly improved to a safer and more powerful tool for the treatment of multiple blood and immune disorders. Likewise, several clinical trials have been initiated combining autologous hematopoietic stem cell transplantation (auto-HSCT) with gene therapy (GT) tools. As several GT modalities such as lentivirus and gene editing tools have a long developmental path ahead to diminish its negative side effects, it is hard to decide which modality is optimal for treating a specific disease. Gene transfer by lentiviruses is the platform of choice for loss-of-mutation diseases, whereas gene correction/addition or gene disruption by gene editing tools, mainly CRISPR/Cas9, is likely to be more efficient in diseases where tight regulation is needed. Therefore, in this review, we compiled pertinent information about lentiviral gene transfer and CRISPR/Cas9 gene editing, their evolution to a safer platform for HSCT, and their applications on other types of gene disorders based on the etiology of the disease and cell fitness.

4.
Drug Des Devel Ther ; 13: 3439-3451, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31686784

RESUMO

Background: Chemotherapy-induced nausea and vomiting (CINV) are a major burden for patients undergoing emetogenic chemotherapy. International guidelines recommend an antiemetic prophylaxis with corticosteroids, 5-HT3R-antagonists and NK1R-antagonists. The NK1R-antagonist fosaprepitant has shown favorable results in pediatric and adult patients. There is little pediatric experience with fosaprepitant. Methods: This non-interventional observation study analyzed 303 chemotherapy courses administered to 83 pediatric patients with a median age of 9 years (2-17 years), who received antiemetic prophylaxis either with fosaprepitant and granisetron with or without dexamethasone (fosaprepitant group/FG; n=41), or granisetron with or without dexamethasone (control group/CG; n=42), during moderately (CINV risk 30-90%) or highly (CINV risk>90%) emetogenic chemotherapy. The two groups' results were compared with respect to the safety and efficacy of the antiemetic prophylaxis during the acute (0-24hrs after chemotherapy), delayed (>24-120hrs after chemotherapy) and both CINV phases. Laboratory and clinical adverse events were compared between the two cohorts. Results: Adverse events were not significantly different in the two groups (p>0.05). Significantly fewer vomiting events occurred during antiemetic prophylaxis with fosaprepitant in the acute (23 vs 142 events; p<0.0001) and the delayed (71 vs 255 events; p<0.0001) CINV phase. In the control group, the percentage of chemotherapy courses with vomiting was significantly higher during the acute (24%/FG vs 45%/CG; p<0.0001) and delayed CINV phase (28%/FG vs 47%/CG; p=0.0004). Dimenhydrinate (rescue medication) was administered significantly more often in the CG, compared to the FG (114/FG vs 320/CG doses; p<0.0001). Likewise, in the control group, dimenhydrinate was administered in significantly more (p<0.0001) chemotherapy courses during the acute and delayed CINV phases (79 of 150; 52.7%), compared to the fosaprepitant group (45 of 153; 29.4%). Conclusion: Antiemetic prophylaxis with fosaprepitant and granisetron with or without dexamethasone was well tolerated, safe and effective in pediatric patients. However, larger prospective trials are needed to evaluate these findings.

5.
Langmuir ; 35(51): 16679-16692, 2019 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-31614087

RESUMO

The molecular-scale structure and dynamics of confined liquids has increasingly gained relevance for applications in nanotechnology. Thus, a detailed knowledge of the structure of confined liquids on molecular length scales is of great interest for fundamental and applied sciences. To study confined structures under dynamic conditions, we constructed an in situ X-ray surface forces apparatus (X-SFA). This novel device can create a precisely controlled slit-pore confinement down to dimensions on the 10 nm scale by using a cylinder-on-flat geometry for the first time. Complementary structural information can be obtained by simultaneous force measurements and X-ray scattering experiments. The in-plane structure of liquids parallel to the slit pore and density profiles perpendicular to the confining interfaces are studied by X-ray scattering and reflectivity. The normal load between the opposing interfaces can be modulated to study the structural dynamics of confined liquids. The confinement gap distance is tracked simultaneously with nanometer precision by analyzing optical interference fringes of equal chromatic order. Relaxation processes can be studied by driving the system out of equilibrium by shear stress or compression/decompression cycles of the slit pore. The capability of the new device is demonstrated on the liquid crystal 4'-octyl-4-cyano-biphenyl (8CB) in its smectic A (SmA) mesophase. Its molecular-scale structure and orientation confined in 100 nm to 1.7 µm slit pores was studied under static and dynamic nonequilibrium conditions.

6.
Macromolecules ; 52(12): 4483-4491, 2019 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-31274929

RESUMO

Fully saturated, aliphatic polymers containing adamantane moieties evenly distributed along the polymer backbone are of great interest due to their exceptional thermal stability, yet more synthetic strategies toward these polymers would be desirable. Herein, we report for the first time the synthesis of poly(1,3-adamantylene alkylene)s based on α,ω-dienes containing bulky 1,3-adamantylene defects precisely located on every 11th, 17th, 19th, and 21st chain carbon via acyclic diene metathesis polycondensation. All saturated polymers revealed excellent thermal stabilities (452-456 °C) that were significantly higher compared to those of structurally similar polyolefins with aliphatic or aromatic ring systems in the backbone of polyethylene (PE). Their crystallinity increases successively from shorter to longer CH2 chains between the adamantane defects. The adamantanes were located in the PE crystals distorting the PE unit cell by the incorporation of the adamantane defect at the kinks of a terrace arrangement. Precise positioning of structural defects within the polymeric backbone provides various opportunities to customize material properties by "defect engineering" in soft polymeric materials.

7.
Bone Marrow Transplant ; 54(11): 1847-1858, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31089287

RESUMO

Although allogeneic hematopoietic stem-cell transplantation (HSCT) provides high cure rates for children with high-risk acute lymphoblastic leukaemia (ALL), relapses remain the main cause of treatment failure. Whereas donor killer cell immunoglobulin-like receptor (KIR) genotype was shown to impact on relapse incidence in adult myeloid leukaemia similar studies in paediatric ALL are largely missing. Effect of donor KIR genotype on transplant outcome was evaluated in 317 children receiving a first myeloablative HSCT from an HLA-matched unrelated donor or sibling within the prospective ALL-SCT-BFM-2003 trial. Analysis of donor KIR gene polymorphism revealed that centromeric presence and telomeric absence of KIR B haplotypes was associated with reduced relapse risk. A centromeric/telomeric KIR score (ct-KIR score) integrating these observations correlated with relapse risk (hazard ratio (HR) 0.58; P = 0.002) while it had no impact on graft-versus-host disease or non-relapse mortality. In multivariable analyses ct-KIR score was associated with reduced relapse risk (HR 0.58; P = 0.003) and a trend towards improved event-free survival (HR 0.76; P = 0.059). This effect proved independent of MRD level prior to HSCT. Our data suggest that in children with ALL undergoing HSCT after myeloablative conditioning, donor selection based on KIR genotyping holds promise to improve clinical outcome by decreasing relapse risk and prolonged event-free survival.

8.
Acc Chem Res ; 52(4): 1006-1015, 2019 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-30925035

RESUMO

The ice premelt, often called the quasi-liquid layer (QLL), is key for the lubrication of ice, gas uptake by ice, and growth of aerosols. Despite its apparent importance, in-depth understanding of the ice premelt from the microscopic to the macroscopic scale has not been gained. By reviewing data obtained using molecular dynamics (MD) simulations, sum-frequency generation (SFG) spectroscopy, and laser confocal differential interference contrast microscopy (LCM-DIM), we provide a unified view of the experimentally observed variation in quasi-liquid (QL) states. In particular, we disentangle three distinct types of QL states of disordered layers, QL-droplet, and QL-film and discuss their nature. The topmost ice layer is energetically unstable, as the topmost interfacial H2O molecules lose a hydrogen bonding partner, generating a disordered layer at the ice-air interface. This disordered layer is homogeneously distributed over the ice surface. The nature of the disordered layer changes over a wide temperature range from -90 °C to the bulk melting point. Combined MD simulations and SFG measurements reveal that the topmost ice surface starts to be disordered around -90 °C through a process that the topmost water molecules with three hydrogen bonds convert to a doubly hydrogen-bonded species. When the temperature is further increased, the second layer starts to become disordered at around -16 °C. This disordering occurs not in a gradual manner, but in a bilayer-by-bilayer manner. When the temperature reaches -2 °C, more complicated structures, QL-droplet and QL-film, emerge on the top of the ice surface. These QL-droplets and QL-films are inhomogeneously distributed, in contrast to the disordered layer. We show that these QL-droplet and QL-film emerge only under supersaturated/undersaturated vapor pressure conditions, as partial and pseudopartial wetting states, respectively. Experiments with precisely controlled pressure show that, near the water vapor pressure at the vapor-ice equilibrium condition, no QL-droplet and QL-film can be observed, implying that the QL-droplet and QL-film emerge exclusively under nonequilibrium conditions, as opposed to the disordered layers formed under equilibrium conditions. These findings are connected with many phenomena related to the ice surface. For example, we explain how the disordering of the topmost ice surface governs the slipperiness of the ice surface, allowing for ice skating. Further focus is on the gas uptake mechanism on the ice surface. Finally, we note the unresolved questions and future challenges regarding the ice premelt.

9.
Bone Marrow Transplant ; 54(12): 1940-1950, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30903024

RESUMO

Allogeneic hematopoietic stem cell transplantation (HSCT) is a standard therapeutic intervention for hematological malignancies and several monogenic diseases. However, this approach has limitations related to lack of a suitable donor, graft-versus-host disease and infectious complications due to immune suppression. On the contrary, autologous HSCT diminishes the negative effects of allogeneic HSCT. Despite the good efficacy, earlier gene therapy trials with autologous HSCs and viral vectors have raised serious safety concerns. However, the CRISPR/Cas9-edited autologous HSCs have been proposed to be an alternative option with a high safety profile. In this review, we summarized the possibility of CRISPR/Cas9-mediated autologous HSCT as a potential treatment option for various diseases supported by preclinical gene-editing studies. Furthermore, we discussed future clinical perspectives and possible clinical grade improvements of CRISPR/cas9-mediated autologous HSCT.

10.
Phys Chem Chem Phys ; 21(7): 3734-3741, 2019 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-30462119

RESUMO

The interfacial premelting in ice/clay nano composites was studied by high energy X-ray diffraction. Below the melting point of bulk water, the formation of liquid water was observed for the ice/vermiculite and ice/kaolin systems. The liquid fraction is gradually increasing with temperature. For both minerals, similar effective premelting layer thicknesses of 2-3 nm are reached 3 K below the bulk melting point. For the quantitative description of the molten water fraction in wet clay minerals we developed a continuum model for short range interactions and arbitrary pore size distributions. This model quantitatively describes the experimental data over the entire temperature range. Model parameters were obtained by fitting using a maximum entropy (MaxEnt) approach. Pronounced differences in the deviation from Antonow's rule relating interfacial free energy between ice, water, and clay are observed for the charged vermiculite and uncharged kaolin minerals. The resultant parameters are discussed in terms of their ice nucleation efficiency. Using well defined and characterized ice/clay nano composite samples, this work bridges the gap between studies on single crystalline ice/solid model interfaces and naturally occurring soils and permafrost.

11.
Mol Cell Pediatr ; 5(1): 9, 2018 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-30430274

RESUMO

BACKGROUND: ß-Thalassemia is an inherited hematological disorder caused by mutations in the human hemoglobin beta (HBB) gene that reduce or abrogate ß-globin expression. Although lentiviral-mediated expression of ß-globin and autologous transplantation is a promising therapeutic approach, the risk of insertional mutagenesis or low transgene expression is apparent. However, targeted gene correction of HBB mutations with programmable nucleases such as CRISPR/Cas9, TALENs, and ZFNs with non-viral repair templates ensures a higher safety profile and endogenous expression control. METHODS: We have compared three different gene-editing tools (CRISPR/Cas9, TALENs, and ZFNs) for their targeting efficiency of the HBB gene locus. As a proof of concept, we studied the personalized gene-correction therapy for a common ß-thalassemia splicing variant HBBIVS1-110 using Cas9 mRNA and several optimally designed single-stranded oligonucleotide (ssODN) donors in K562 and CD34+ hematopoietic stem cells (HSCs). RESULTS: Our results exhibited that indel frequency of CRISPR/Cas9 was superior to TALENs and ZFNs (P < 0.0001). Our designed sgRNA targeting the site of HBBIVS1-110 mutation showed indels in both K562 cells (up to 77%) and CD34+ hematopoietic stem cells-HSCs (up to 87%). The absolute quantification by next-generation sequencing showed that up to 8% site-specific insertion of the NheI tag was achieved using Cas9 mRNA and a chemically modified ssODN in CD34+ HSCs. CONCLUSION: Our approach provides guidance on non-viral gene correction in CD34+ HSCs using Cas9 mRNA and chemically modified ssODN. However, further optimization is needed to increase the homology directed repair (HDR) to attain a real clinical benefit for ß-thalassemia.

12.
Langmuir ; 34(44): 13375-13386, 2018 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-30350703

RESUMO

We have investigated the formation of lamellar crystals of poly(vinylidene fluoride) (PVDF) in the presence of oriented clay particles with different aspect ratios (ARs) and surface properties. Hot-melt screw extrusion of PVDF with 5 wt % of montmorillonite (AR ≈ 12) or fluoromica (AR ≈ 27) resulted in formation of phase-separated blends. Replacing the clays with their organoclay derivatives, organomontmorillonite or organofluoromica, resulted in the corresponding intercalated nanocomposites. The organoclays induced formation of polar ß- and γ-polymorphs of PVDF in contrast to the α-polymorph, which dominates in the pure PVDF and the PVDF/clay blends. Solid-state nuclear magnetic resonance revealed that the content of the α-phase in the nanocomposites was never higher than 7% of the total crystalline phase, whereas the ß/γ mass ratio was close to 1:2, irrespective of the AR or crystallization conditions. X-ray diffraction showed that the oriented particles with a larger AR caused orientation of the polar lamellar crystals of PVDF. In the presence of the organofluoromica, PVDF formed a chevron-like lamellar nanostructure, where the polymer chains are extended along the extrusion direction, whereas the lamellar crystals were slanted from normal to the extrusion direction. Time-resolved X-ray diffraction experiments allowed the identification of the formation mechanism of the chevron-like nanostructure.

13.
Phys Chem Chem Phys ; 20(37): 24494-24495, 2018 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-30207340

RESUMO

Correction for 'Surface induced smectic order in ionic liquids - an X-ray reflectivity study of [C22C1im]+[NTf2]-' by Julian Mars et al., Phys. Chem. Chem. Phys., 2017, 19, 26651-26661.

14.
Macromol Rapid Commun ; 39(15): e1800282, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29900622

RESUMO

Supramolecular gels made from 2D building blocks are emerging as one of the novel multifunctional soft materials for various applications. This study reports on a class of supramolecular nanosheet gels formed through a reversible self-assembly process involving both intramolecular folding and intermolecular self-assembly of poly[oligo(ethylene glycol)-co-(phenyl-capped bithiophenes)]. Such hierarchical self-assembled structure allows the gels to switch between sol and gel states under either redox or thermostimulus. Moreover, the gels illustrate high Young's moduli, compared to their controls that are made from the same oligo(ethylene glycol) and phenyl-capped bithiophenes blocks but have highly covalent-crosslinked structures. The example might open a window for emerging supramolecular 2D materials to develop mechanically robust and stimuli-responsive soft materials without compromising their intrinsic functions.


Assuntos
Nanoestruturas/química , Polímeros/química , Temperatura Ambiente , Módulo de Elasticidade , Géis/química , Substâncias Macromoleculares/síntese química , Substâncias Macromoleculares/química , Estrutura Molecular , Oxirredução , Tamanho da Partícula , Polímeros/síntese química , Propriedades de Superfície
15.
Soft Matter ; 14(30): 6214-6221, 2018 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-29932197

RESUMO

The impact of the linking group in hydrogen-bonded liquid crystals is systematically studied by a modular approach. POM and DSC results exhibited tremendous differences in the mesomorphic behaviour of the assemblies, due to the versatile linkages of the side chains, which were correlated with structural features and the elctronical nature of the side chains.

19.
J Invest Dermatol ; 138(5): 1157-1165, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29203359

RESUMO

Inherited forms of epidermolysis bullosa are blistering diseases of the skin and mucosa resulting from various gene mutations. Transplantation of bone marrow-derived stem cells might be a promising systemic treatment for severe dystrophic or junctional epidermolysis bullosa, but many key questions remain unresolved. Two open questions of clinical interest are whether systemically transplanted bone marrow-derived stem cells of mesodermal origin might be able to transdifferentiate into keratinocytes with an ectodermal phenotype and whether these cells are also capable of repairing a specific intraepidermal gene defect. To address these questions, we transplanted bone marrow-derived stem cells into mice with a blistering disease exclusively localized to the epidermis resulting from a functional knockout of desmoglein-3 (Dsg3). We found that Dsg3+ donor-derived cells migrate into the recipient epidermis. However, these cells failed to restore the missing Dsg3 mRNA and DSG3 protein expression in the transplanted Dsg3-/- mice. The donor-derived cells found in the epidermis preserved their CD45+ hematopoietic origin, and no transdifferentiation into integrin α6+ keratinocytes or integrin α6+/CD34+ epidermal stem cells occurred. Our results indicate that bone marrow-derived stem cells preserve their mesodermal fate after systemic transplantation and are not capable of treating patients with epidermolysis bullosa with an intraepidermal skin defect.


Assuntos
Células da Medula Óssea/fisiologia , Desmogleína 3/fisiologia , Epidermólise Bolhosa/terapia , Transplante de Células-Tronco Hematopoéticas , Mesoderma/citologia , Pele/patologia , Animais , Diferenciação Celular , Movimento Celular , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
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