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1.
J Phys Chem Lett ; 2020 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-32155333

RESUMO

Rational control of photoluminescence against temperature change is important for fundamental research and technological applications. Herein, we report anomalous temperature-dependence of upconversion luminescence in Yb/Ho co-doped Sc2Mo3O12 crystals. By leveraging negative thermal expansion of the crystal lattice, energy transfer between the lanthanide do-pants is promoted with increasing temperature from 303 to 573 K, resulting in enhancement of the emission by around 5 folds. Meanwhile, the emission profile is also substantially altered due to the concurrent thermal quenching of selective energy states, corresponding to a clear color shift from green to red. By correlating the red-to-green emission intensity ratio of Ho3+ dopant ions with temperature, a ratiometric luminescence thermometer is constructed with a maximum sensitivity of 2.75% K-1 at 543 K. As the Sc2Mo3O12 crystals are thermally stable and nonhygroscopic, our findings highlight a general approach for highly reversible control of upconversion by temperature in the ambient air.

2.
Adv Mater ; : e1907747, 2020 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-32128925

RESUMO

Actively collecting the mechanical energy by efficient conversion to other forms of energy such as light opens a new possibility of energy-saving, which is of pivotal significance for supplying potential solutions for the present energy crisis. Such energy conversion has shown promising applications in modern sensors, actuators, and energy harvesting. However, the implementation of such technologies is being hindered because most luminescent materials show weak and non-recoverable emissions under mechanical excitation. Herein, a new class of heterojunctioned ZnS/CaZnOS piezophotonic systems is presented, which displays highly reproducible mechanoluminescence (ML) with an unprecedented intensity of over two times higher than that of the widely used commercial ZnS (the state-of-the-art ML material). Density functional theory calculations reveal that the high-performance ML originates from efficient charge transfer and recombination through offset of the valence and conduction bands in the heterojunction interface region. By controlling the ZnS-to-CaZnOS ratio in conjunction with manganese (Mn2+ ) and lanthanide (Ln3+ ) doping, tunable ML across the full spectrum is activated by a small mechanical stimulus of 1 N (10 kPa). The findings demonstrate a novel strategy for constructing efficient ML materials by leveraging interface effects and ultimately promoting practical applications for ML.

3.
BMC Cancer ; 20(1): 195, 2020 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-32143579

RESUMO

BACKGROUND: Donor acute lymphoblastic leukemia with recipient intact is a rare condition. We report a case of donor developing acute lymphoblastic leukemia 8 yrs after donating both bone marrow and peripheral blood hematopoietic stem cells. CASE PRESENTATION: This case report describes a 51-year old female diagnosed with acute lymphoblastic leukemia who donated both bone marrow and peripheral blood stem cells 8 yrs ago for her brother with severe aplastic anemia. Whole exome sequencing revealed leukemic genetic lesions (SF3B1 and BRAF mutation) only appeared in the donor sister, not the recipient, and an unusual type of hematopoietic stem cell transplantation with the recipient's peripheral blood stem cells was done. The patient remained in remission for 3 months before disease relapsed. CD19 CAR-T therapy followed by HLA-identical unrelated hematopoietic stem cell transplantation was applied and the patient remains in remission for 7 months till now. CONCLUSIONS: This donor leukemia report supports the hypothesis that genetic lesions happen randomly in leukemogenesis. SF3B1 combined with BRAF mutation might contribute to the development of acute lymphoblastic leukemia.

4.
Aesthetic Plast Surg ; 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32166351

RESUMO

BACKGROUND: The combination of finasteride and topical minoxidil has been used for treating patients with androgenetic alopecia (AGA). However, whether combining these two medications results in greater efficacy than monotherapy is a question worth exploring. OBJECTIVE: This meta-analysis aims to determine the efficacy and safety of combined treatment of finasteride and topical minoxidil. METHODS: A comprehensive search of the Embase, PubMed, and the Cochrane Library databases was performed. Data were extracted and analyzed according to predefined clinical endpoints. RESULTS: Five randomized controlled trials (RCTs) were included in our meta-analysis. All studies compared combined therapy with minoxidil, but only 2 RCTs compared combined therapy with finasteride. Compared with minoxidil or finasteride alone, the combined group had a significantly higher global photographic evaluation score (P < 0.00001), more patients with marked improvement (P < 0.001), and fewer patients with deterioration or no change (P < 0.001). There was no significant difference between the combined group and minoxidil- or finasteride-only groups in the number of patients with moderate and mild improvements, hair density change, or adverse events. CONCLUSIONS: In patients with AGA, the combination treatment of finasteride and topical minoxidil has better therapeutic efficacy than and similar safety as monotherapy. However, the best concentration of combination treatment requires further studies with sound methodological quality. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

5.
Artigo em Inglês | MEDLINE | ID: mdl-32166507

RESUMO

Direct stenting (DS) without pre-dilatation of the culprit lesion might improve myocardial perfusion and prognosis in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (STEMI); however, some studies report conflicting results. We investigated whether DS provides incremental myocardial benefits over conventional stenting (CS) in STEMI patients based on cardiac magnetic resonance imaging (CMR) measures. Reperfused patients who underwent CMR examinations within 1 week of STEMI onset were selected from a multicenter CMR registry of STEMI (NCT: 03768453). Patients were stratified into either a DS or CS group. Each group comprised 137 patients after 1:1 propensity score matching. Major adverse events (MACEs), including death, myocardial re-infarction, re-admission for heart failure, and stroke were noted during a median period of 44 months (interquartile range 32-58 months). DS was associated with larger (p = 0.007) and shorter (p = 0.005) stent sizes than CS. DS and CS achieved comparable angiographic TIMI-3 flow grades (p = 0.86) and myocardial blush grades (p = 0.70). There were no group differences regarding the incidence of CMR manifestations of microvascular dysfunction, including microvascular obstruction (MVO) (p = 0.89) and intramyocardial hemorrhage (p = 0.47), the extent of MVO (p = 0.21), infarction size (p = 0.83), or left ventricular ejection fraction (p = 0.57). Kaplan-Meier analysis revealed similar risks of MACEs (log rank p = 0.909), which occurred in 23.4% of DS and 26.3% of CS patients (p = 0.576). DS did not show any incremental benefits over CS on myocardial impairments as evaluated using CMR.Clinical Trial Registration: Clinicaltrials.gov, NCT: 03768453.

6.
Sci Rep ; 10(1): 4240, 2020 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-32144327

RESUMO

We evaluated the efficacy of second-line hormonal therapy for treatment of metastatic castration-resistant prostate cancer (mCRPC) in a real-world retrospective study. We conducted a population-based real-world cohort study of 258 mCRPC patients between 2014 and 2018 using the Chang Gung Research Database (CGRD) of Taiwan. The second-line hormonal therapy included abiraterone acetate and enzalutamide. The clinical efficacy outcomes were overall survival (OS) and prostate-specific antigen (PSA) doubling time. The median PSA level was also assessed. In total, 223 mCRPC patients who underwent second-line hormonal therapy met all of the inclusion and exclusion criteria for this study. Among them, 65 (29.1%) patients were in the PSA response group and 158 (70.9%) were in the non-response group. The median age was 72.9 years. The median OS was 12.3 months (range: 9.9-19.9 months) and 9.6 months (range: 5.3-15.9 months) in the response and non-response groups, respectively, and the respective PSA doubling times were 9.0 months (range: 4.4-11.6 months) and 3.9 months (range: 2.2-9.1 months), with a median follow-up period of 10.5 months. A significantly longer median OS was seen in the PSA response group. This real-world database study demonstrated that clinical outcomes of second-line hormonal therapy were better in patients with a PSA response. Further studies are warranted to achieve a better understanding of second-line hormonal therapy for mCRPC in Asian populations.

7.
Thyroid ; 2020 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-32188373

RESUMO

BACKGROUND: Iodine is important in both thyroid function and human metabolism. Studies have explored the effect of iodine on metabolic disorders through thyroid function. This study aimed to investigate the relationship between iodine status and metabolic disorders, such as metabolic syndrome, hypertension, impaired glucose metabolism, central obesity and dyslipidemia. METHODS: 51,795 subjects aged ≥18 years from the TIDE (Thyroid Disorders, Iodine Status and Diabetes, a national epidemiological cross-sectional study) program were included. The prevalence of metabolic disorders and its related diseases were calculated based on the level of urinary iodine concentrations (UICs) using the chi-square method. To further explore whether prevalence was associated with UIC, quadratic and UIC-stratified logistic regression models were used. RESULTS: The prevalence of metabolic disorders as a function of UIC was found to be U-shaped with a lower prevalence of 76.0% at a UIC of 300-499 µg/L. Participants with UIC of 300-499 µg/L were associated with metabolic disorders [OR=0.857, 95%CI (0.796-0.922)] and hypertension [OR=0.873, 95%CI (0.814-0.936)]. A UIC of 300-799 µg/L was found to be associated with against the occurrence of metabolic syndrome (MetS) and impaired fasting glucose (IFG). UIC of 500-799 µg/L was associated with the occurrence of prediabetes [OR=0.883, 95%CI (0.797-0.978)]. UIC ≥300 µg/L was associated with the occurrence of hypertriglyceridemia, hypercholesterolemia, and high levels of low density lipoprotein cholesterol (LDL-C). Furthermore, a UIC of <100 µg/L had an association with hypertension [OR=1.097, 95%CI (1.035-1.162)] and hypercholesterolemia [OR=1.178, 95%CI (1.117-1.242)]. CONCLUSIONS: The association between UICs in adults and metabolic disorders and its components is U-shaped. The association between UIC and metabolic disorders disappears in cases of iodine deficiency (<100 µg/L) or excess (>500 µg/L).

8.
Artigo em Inglês | MEDLINE | ID: mdl-32167630

RESUMO

Chromosomal translocations and generating fusion genes are closely associated with disease initiation and progression in acute myeloid leukemia (AML). In this study, we identified a novel t(X;17)(q28;q21) chromosomal rearrangement in a patient with acute monocytic leukemia. Using RNA-sequencing, we identified a KANSL1-MTCP1 and a KANSL1-CMC4 fusion gene. 5'-UTR sequences of the KANSL1 gene were found to become fused upstream of the coding sequence region of the MTCP1 and CMC4 genes, respectively, resulting in an aberrantly high expression of these genes. Functional studies revealed that overexpression of the MTCP1 gene induced an increased cell proliferation and partial blockage of cell differentiation, suggesting that the aberrant expression of MTCP1 is of critical importance in leukemogenesis.

9.
Biomaterials ; 243: 119941, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32172034

RESUMO

After spinal cord injury (SCI), endogenous neural/progenitor stem cells (NSPCs) were activated in neural tissue adjacent to the injured segment, but few cells migrated to the injury epicenter and differentiated into neurons. N-cadherin regulates mechanical adhesion between NSPCs, and also drives NSPCs migration and promotes NSPCs differentiation. In this study, linearly ordered collagen scaffold (LOCS) was modified with N-cadherin through a two-step cross-linking between thiol and amino group. The results indicated that N-cadherin modification improved the adhesion of NSPCs on collagen scaffold and increased the differentiation into neurons. When LOCS-Ncad was transplanted into complete transected rat spinal cords, more NSPCs migrated to the lesion center and more newborn neurons appeared within the injury site. Furthermore, rats transplanted with LOCS-Ncad showed significantly improved locomotor recovery compared with the rats without implants. Collectively, our results suggest that LOCS-Ncad may be a promising treatment option to facilitate SCI repair by recruiting endogenous NSPCs to the lesion center and promoting neuronal differentiation.

10.
Sci Rep ; 10(1): 5163, 2020 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-32198390

RESUMO

Epigallocatechin-3-gallate (EGCG), a green tea-derived polyphenol, exhibits antitumor activities. An EGCG nanoemulsion (nano-EGCG) was prepared to improve the stability and reduce the side effects of EGCG for treatment of human lung cancer cells, and the antitumor effects were studied. The possible molecular mechanism underlying its antitumor effects on cultured human lung cancer cells was also elucidated. The antitumor effects of EGCG and nano-EGCG were determined using methylthiazolyldiphenyl-tetrazolium bromide (MTT), colony formation, migration, and invasion assays. In addition, changes in the AMP-activated protein kinase (AMPK) signaling pathway were investigated using Western blot analyses. AMPK inhibitors were used to determine the roles of the AMPK signaling pathway involved in the molecular mechanism of the nano-EGCG. Our results showed that both EGCG and nano-EGCG inhibited the growth of H1299 lung cancer cells, with half-maximal inhibitory concentrations of 36.03 and 4.71 µM, respectively. Additionally, nano-EGCG effectively suppressed lung cancer cell colony formation, migration, and invasion in a dose-dependent manner. Nano-EGCG may inhibit lung cancer cell invasion through matrix metalloproteinase (MMP)-2- and MMP-9-independent mechanisms. Furthermore, the expression of several key regulatory proteins in the AMPK signaling pathway was modulated by nano-EGCG. Nano-EGCG may inhibit lung cancer cell proliferation, colony formation, migration, and invasion through the activation of AMPK signaling pathways. This novel mechanism of nano-EGCG suggests its application in lung cancer prevention and treatment. Our results provide an experimental foundation for further research on its potential activities and effects in vivo.

11.
Blood ; 2020 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-32202636

RESUMO

SETD2, the histone H3 lysine 36 methyltransferase previously identified by us, plays an important role in the pathogenesis of hematologic malignancies, but its role in MDS has been unclear. In this study, we show that low expression of SETD2 correlates with shortened survival in MDS patients and that the SETD2 levels in CD34+ bone marrow (BM) cells of MDS patients can be increased by decitabine. We knock out Setd2 in the NUP98-HOXD13 (NHD13) transgenic mice, which phenocopies human MDS, and demonstrate that loss of Setd2 accelerates the transformation of MDS into acute myeloid leukemia (AML). Loss of Setd2 enhances the ability of NHD13+ HSPCs to self-renew, with increased symmetric self-renewal division and decreased differentiation/cell death. The growth of MDS-associated leukemia cells can be inhibited though increasing H3K36me3 level by using epigenetic modifying drugs. Furthermore, Setd2 deficiency upregulates hematopoietic stem cell (HSC) signaling and downregulates myeloid differentiation pathways in the NHD13+ HSPCs. Our RNA-seq and ChIP-seq analysis indicate that S100a9, the S100 calcium-binding protein, is a target gene of Setd2 and that the addition of recombinant S100a9 weakens the effect of Setd2 deficiency in the NHD13+ HSPCs. In contrast, downregulation of S100a9 leads to decreases of its downstream targets, including IƙBα and Jnk, which influence the self-renewal and differentiation of HSPCs. Therefore, our results demonstrate that SETD2 deficiency predicts poor prognosis in MDS and promotes the transformation of MDS into AML, which provides a potential therapeutic target for MDS-associated acute leukemia.

12.
ACS Nano ; 2020 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-32142248

RESUMO

Anti-polyethylene glycol (PEG) antibodies are present in many healthy individuals as well as in patients receiving polyethylene glycol-functionalized drugs. Antibodies against PEG-coated nanocarriers can accelerate their clearance, but their impact on nanodrug properties including nanocarrier integrity is unclear. Here, we show that anti-PEG IgG and IgM antibodies bind to PEG molecules on the surface of PEG-coated liposomal doxorubicin (Doxil, Doxisome, LC-101, and Lipo-Dox), resulting in complement activation, formation of the membrane attack complex (C5b-9) in the liposomal membrane, and rapid release of encapsulated doxorubicin from the liposomes. Drug release depended on both classical and alternative pathways of complement activation. Doxorubicin release of up to 40% was also observed in rats treated with anti-PEG IgG and PEG-coated liposomal doxorubicin. Our results demonstrate that anti-PEG antibodies can disrupt the membrane integrity of PEG-coated liposomal doxorubicin through activation of complement, which may alter therapeutic efficacy and safety in patients with high levels of pre-existing antibodies against PEG.

13.
Opt Express ; 28(1): 205-215, 2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-32118951

RESUMO

The room-temperature strong plasmon-exciton coupling is first investigated in a metal-insulator-metal (MIM) waveguide-resonator system with WS2 monolayer. Finite-difference time-domain (FDTD) simulated results exhibit that the Fabry-Pérot (F-P) cavity is realized by the MIM plasmonic waveguide with two separated metal bars. When the F-P resonance is tuned to overlap with the A-exciton absorption peak of WS2 monolayer, the strong plasmon-exciton coupling is obtained at visible wavelengths. As a result, the spectral splitting response confirmed by the coupled-mode theory (CMT) appears in the transmission spectrum. Intriguingly, the switching response is handily witnessed by tuning the orientation of WS2 monolayer along the cavity, and the coupling strength is dynamically tuned by changing the position of the WS2 monolayer. Simultaneously, the anticrossing behavior with the Rabi splitting up to 109 meV is achieved by small changes in the length of the F-P cavity and the refractive index of dielectric in the cavity, respectively. The underlying physics is further revealed by the coupled oscillator model (COM). The proposed strong plasmon-exciton coupling can find utility in highly integrated plasmonic circuits for optical switching.

14.
Nat Chem Biol ; 2020 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-32152540

RESUMO

Combination antiretroviral therapy has transformed HIV-1 infection, once a fatal illness, into a manageable chronic condition. Drug resistance, severe side effects and treatment noncompliance bring challenges to combination antiretroviral therapy implementation in clinical settings and indicate the need for additional molecular targets. Here, we have identified several small-molecule fusion inhibitors, guided by a neutralizing antibody, against an extensively studied vaccine target-the membrane proximal external region (MPER) of the HIV-1 envelope spike. These compounds specifically inhibit the HIV-1 envelope-mediated membrane fusion by blocking CD4-induced conformational changes. An NMR structure of one compound complexed with a trimeric MPER construct reveals that the compound partially inserts into a hydrophobic pocket formed exclusively by the MPER residues, thereby stabilizing its prefusion conformation. These results suggest that the MPER is a potential therapeutic target for developing fusion inhibitors and that strategies employing an antibody-guided search for novel therapeutics may be applied to other human diseases.

15.
Biomaterials ; 236: 119825, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32044576

RESUMO

In situ restoration of severely damaged lung remains difficult due to its limited regeneration capacity after injury. Artificial lung scaffolds are emerging as potential substitutes, but it is still a challenge to reconstruct lung regeneration microenvironment in scaffold after lung resection injury. Here, a 3D biomimetic porous collagen scaffold with similar structure characteristics as lung is fabricated, and a novel collagen binding hepatocyte growth factor (CBD-HGF) is tethered on the collagen scaffold for maintaining the biomimetic function of HGF to improve the lung regeneration microenvironment. The biomimetic scaffold was implanted into the operative region of a rat partial lung resection model. The results revealed that vascular endothelial cells and endogenous alveolar stem cells entered the scaffold at the early stage of regeneration. At the later stage, inflammation and fibrosis were attenuated, the microvascular and functional alveolar-like structures were formed, and the general morphology of the injured lung was restored. Taken together, the functional 3D biomimetic collagen scaffold facilitates recovery of the injured lung, alveolar regeneration, and angiogenesis after acute lung injury. Particularly, this is the first study of lung regeneration in vivo guided by biomimetic collagen scaffold materials, which supports the concept that tissue engineering is an effective strategy for alveolar regeneration.

16.
Int J Nanomedicine ; 15: 521-536, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32021192

RESUMO

Introduction: The myelodysplastic syndromes (MDS) are a very heterogeneous group of myeloid disorders characterized by peripheral blood cytopenias and increase risk of transformation to acute myeloid leukemia (AML). Daunorubicin (DNR) is an indispensable drug for the treatment of MDS and AML. However, its side effects including cardiac toxicity and bone marrow suppression severely limit clinical application. Many researches reported high expression of CD123 antigen on high-risk MDS cells, so we constructed a novel drug delivery system comprising daunorubicin-loaded CdTe QDs conjugated with anti-CD123 mAbs (DNR-CdTe-CD123) to develop targeted combination chemotherapy for MDS. Methods: CdTe conjugated antiCD123 through amide bond, co-loaded with DNR with electrostatic bonding. Then, we determined characterization and release rate of DNR-CdTe-CD123. The therapeutic effect and side effect of drug delivery system were evaluated through in vitro and in vivo experiments. Results: CdTe showed appropriate diameter and good dispersibility and DNR was loaded into CdTes with high encapsulation efficiency and drug loading. The maximum drug loading and encapsulation efficiency were 42.08 ± 0.64% and 74.52 ± 1.81%, respectively, at DNR concentration of 0.2mg/mL and anti-CD123 mAbs volume of 5ul (100ug/mL). Flow cytometry (FCM) showed that CD123 antigen was highly expressed on MUTZ-1 cells, and its expression rate was 72.89 ± 10.67%. In vitro experiments showed that the inhibition rate and apoptosis rate of MUTZ-1 cells treated with DNR-CdTe-CD123 were higher than those in the other groups (P<0.05). Compared with the other groups, the level of apoptosis-related protein (P53, cleaved caspase-9, Bax and cleaved caspase-3) were upregulated in DNR-CdTe-CD123 group (P<0.05). In vivo experiments, DNR-CdTe-CD123 can effectively inhibit the tumor growth of MDS-bearing nude mice and reduce the side effects of DNR on myocardial cells. Conclusion: The system of DNR-CdTe-CD123 enhances the therapeutic effects and reduce the side effects of DNR, thus providing a novel platform for MDS treatment.

17.
Drug Deliv ; 27(1): 309-322, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32037895

RESUMO

Amentoflavone, robustaflavone, 2″,3″-dihydro-3',3‴-biapigenin, 3',3‴-binaringenin, and delicaflavone are five major hydrophobic components in the total biflavonoids extract from Selaginella doederleinii (TBESD) that display favorable anticancer properties. The purpose of this study was to develop a new oral delivery formulation to improve the solubilities, dissolution rates, and oral bioavailabilities of the main ingredients in TBESD by the solid dispersion technique. Solid dispersions of TBESD with various hydrophilic polymers were prepared, and different technologies were applied to select the suitable carrier and method. TBESD amorphous solid dispersion (TBESD-ASD) with polyvinylpyrrolidone K-30 was successfully prepared by the solvent evaporation method. The physicochemical properties of TBESD-ASD were investigated by scanning electron microscopy, differential scanning calorimetry, and Fourier-transform infrared spectroscopy. As a result, TBESD was found to be molecularly dispersed in the amorphous carrier. The solubilities and dissolution rates of all five ingredients in the TBESD-ASD were significantly increased (nearly 100% release), compared with raw TBESD. Meanwhile, TBESD-ASD showed good preservation stability for 3 months under accelerated conditions of 40 °C and 75% relative humidity. A subsequent pharmacokinetic study in rats revealed that Cmax and AUC0-t of all five components were significantly increased by the solid dispersion preparation. An in vivo study clearly revealed that compared to raw TBESD, a significant reduction in tumor size and microvascular density occurred after oral administration of TBESD-ASD to xenograft-bearing tumor mice. Collectively, the developed TBESD-ASD with the improved solubility, dissolution rates and oral bio-availabilities of the main ingredients could be a promising chemotherapeutic agent for cancer treatment.

18.
Molecules ; 25(3)2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-32012928

RESUMO

PEGylated nanomedicines are known to induce infusion reactions (IRs) that in some cases can be life-threatening. Herein, we report a case study in which a patient with rare mediastinal and intracardiac IgG4-related sclerosing disease received 8 treatments of intravenously administered PEGylated liposomal methylprednisolone-succinate (NSSL-MPS). Due to the ethical requirements to reduce IRs, the patient received a cocktail of premedication including low dose of steroids, acetaminophen and H2 blockers before each infusion. The treatment was well-tolerated in that IRs, complement activation, anti-PEG antibodies and accelerated blood clearance of the PEGylated drug were not detected. Prior to the clinical study, an in vitro panel of assays utilizing blood of healthy donors was used to determine the potential of a PEGylated drug to activate complement system, elicit pro-inflammatory cytokines, damage erythrocytes and affect various components of the blood coagulation system. The overall findings of the in vitro panel were negative and correlated with the results observed in the clinical phase.

19.
Molecules ; 25(3)2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-32041334

RESUMO

Biodegradation of contaminants is extremely complicated due to unpredictable microbial behaviors. Monitoring of microbial biodegradation drives us to determine (1) the amounts of specific degrading microbes, (2) the abundance, and (3) expression level of relevant functional genes. To this endeavor, the cultivation independent polymerase chain reaction (PCR)-based monitoring technique develops from endpoint PCR, real-time quantitative PCR, and then into novel digital PCR. In this review, we introduce these three categories of PCR techniques and summarize the timely applications of digital PCR and its superiorities than qPCR for biodegradation monitoring. Digital PCR technique, emerging as the most accurately absolute quantification method, can serve as the most promising and robust tool for monitoring of microbial biodegradation.

20.
Int J Mol Sci ; 21(4)2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-32093290

RESUMO

Prodrug activator gene therapy mediated by murine leukemia virus (MLV)-based retroviral replicating vectors (RRV) was previously shown to be highly effective in killing glioma cells both in culture and in vivo. To avoid receptor interference and enable dual vector co-infection with MLV-RRV, we have developed another RRV based on gibbon ape leukemia virus (GALV) that also shows robust replicative spread in a wide variety of tumor cells. We evaluated the potential of GALV-based RRV as a cancer therapeutic agent by incorporating yeast cytosine deaminase (CD) and E. coli nitroreductase (NTR) prodrug activator genes into the vector. The expression of CD and NTR genes from GALV-RRV achieved highly efficient delivery of these prodrug activator genes to RG-2 glioma cells, resulting in enhanced cytotoxicity after administering their respective prodrugs 5-fluorocytosine and CB1954 in vitro. In an immune-competent intracerebral RG-2 glioma model, GALV-mediated CD and NTR gene therapy both significantly suppressed tumor growth with CB1954 administration after a single injection of vector supernatant. However, NTR showed greater potency than CD, with control animals receiving GALV-NTR vector alone (i.e., without CB1954 prodrug) showing extensive tumor growth with a median survival time of 17.5 days, while animals receiving GALV-NTR and CB1954 showed significantly prolonged survival with a median survival time of 30 days. In conclusion, GALV-RRV enabled high-efficiency gene transfer and persistent expression of NTR, resulting in efficient cell killing, suppression of tumor growth, and prolonged survival upon CB1954 administration. This validates the use of therapeutic strategies employing this prodrug activator gene to arm GALV-RRV, and opens the door to the possibility of future combination gene therapy with CD-armed MLV-RRV, as the latter vector is currently being evaluated in clinical trials.

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