Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.330
Filtrar
1.
Nano Lett ; 2019 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-31694380

RESUMO

In recent years, small nanoparticles (NPs) with a diameter of less than 10 nm have aroused considerable interest in biomedical applications. However, their intratumor performance, as well as the antitumor efficacy, has not been well understood due to their size-dependent pharmacokinetics, which presents a formidable challenge for delivering a comparable amount of different small NPs to tumor tissues. Utilizing the multistage delivery strategy, we construct G3-, G5-, and G7-iCluster delivery systems by using poly(amidoamine) (PAMAM) dendrimers of different generations (G3-, G5-, and G7-PAMAM) as building blocks. The iCluster nanoparticles showed comparable pharmacokinetics and similar initial tumor deposition due to their similarity in size and surface chemistry. After accumulating at a tumor site, individual small dendrimers were released, and thus, their intratumor performance was comparatively investigated. Our results indicated that a subtle change in generation markedly affects their intratumor activities. G5-iCluster outperformed G3-iCluster and G7-iCluster in the treatment efficacy in an orthotopic pancreatic tumor model. The mechanistic study revealed that G3-PAMAM showed reduced particle retention in tumor tissue due to its small size and weak cell internalization, while G7-PAMAM was much less penetrative because of its relatively large size and strong particle-cell interaction. In contrast, G5-PAMAM exhibited balanced tumor penetration, cell internalization, and tumor retention. Our finding highlights the huge influence of the subtle difference of small NPs in their intratumor performance.

2.
Neurobiol Dis ; 134: 104669, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31707118

RESUMO

Dysfunction of medial prefrontal cortex (mPFC) in association with imbalance of inhibitory and excitatory neurotransmission has been implicated in depression. However, the precise cellular mechanisms underlying this imbalance, particularly for GABAergic transmission in the mPFC, and the link with the rapid acting antidepressant ketamine remains poorly understood. Here we determined the influence of chronic unpredictable stress (CUS), an ethologically validated model of depression, on synaptic markers of GABA neurotransmission, and the influence of a single dose of ketamine on CUS-induced synaptic deficits in mPFC of male rodents. The results demonstrate that CUS decreases GABAergic proteins and the frequency of inhibitory post synaptic currents (IPSCs) of layer V mPFC pyramidal neurons, concomitant with depression-like behaviors. In contrast, a single dose of ketamine can reverse CUS-induced deficits of GABA markers, in conjunction with reversal of CUS-induced depressive-like behaviors. These findings provide further evidence of impairments of GABAergic synapses as key determinants of depressive behavior and highlight ketamine-induced synaptic responses that restore GABA inhibitory, as well as glutamate neurotransmission.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31781513

RESUMO

This study aimed to design a new method for rapid and accurate detection of carbapenemase phenotypes based on the simplified carbapenem inactivation method (sCIM). We evaluated the sensitivity and specificity of the method, called the rapid carbapenemase detection method (rCDM), for the detection of carbapenemase-producing Enterobacteriaceae and Pseudomonas aeruginosa. A total of 257 Enterobacteriaceae, 236 P. aeruginosa, and 20 Acinetobacter baumannii isolates were tested. Phenotypic evaluations were performed using rCDM, sCIM, and mCIM. For Enterobacteriaceae, the sensitivity of rCDM was 100% and the specificity was 99.6%. For P. aeruginosa, the sensitivity of rCDM was 97.4% and the specificity was 100%. Carbapenemase-producing A. baumannii were not detected by rCDM. The concordance rate of rCDM and sCIM for Enterobacteriaceae and P. aeruginosa was 99.8%, with the exception of one P. aeruginosa isolate that expressed the bla VIM-4 gene. The concordance rate of rCDM and mCIM for Enterobacteriaceae and P. aeruginosa was 100%. rCDM can be used to accurately detect carbapenemase-producing Enterobacteriaceae and P. aeruginosa in 5-6 h and is suitable for routine use in most clinical microbiology laboratories.

4.
J Clin Invest ; 2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31743111

RESUMO

A single sub-anesthetic dose of ketamine, an NMDA receptor (NMDAR) antagonist, produces rapid and sustained antidepressant actions in depressed patients, addressing a major unmet need for the treatment of mood disorders. Ketamine produces a rapid increase in extracellular glutamate and synaptic formation in the prefrontal cortex, but the initial cellular trigger that initiates these and its behavioral actions has not been identified. To address this question, we used a combination of viral shRNA and conditional mutation to produce cell specific knockdown or deletion of a key NMDAR subunit, GluN2B, implicated in the actions of ketamine. The results demonstrate that the antidepressant actions of ketamine were blocked by GluN2B-NMDAR knockdown on GABA (Gad1) interneurons, as well as subtypes expressing somatostatin (Sst), or parvalbumin (Pvalb), but not glutamate principle neurons in the mPFC. Further analysis of GABA subtypes showed that cell specific knockdown or deletion of GluN2B in Sst interneurons blocked or occluded the antidepressant actions of ketamine and revealed sex-specific differences that are associated with excitatory postsynaptic currents on mPFC principle neurons. These findings demonstrate that GluN2B-NMDARs on GABA interneurons are the initial cellular trigger for the rapid antidepressant actions of ketamine and show sex-specific adaptive mechanisms to GluN2B modulation.

5.
Brief Bioinform ; 2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31724702

RESUMO

Although intensive efforts have been devoted to investigating latent tuberculosis (LTB) and active tuberculosis (PTB) infections, the similarities and differences in the host responses to these two closely associated stages remain elusive, probably due to the difficulty in identifying informative genes related to LTB using traditional methods. Herein, we developed a framework known as the consistently differential expression network to identify tuberculosis (TB)-related gene pairs by combining microarray profiles and protein-protein interactions. We thus obtained 774 and 693 pairs corresponding to the PTB and LTB stages, respectively. The PTB-specific genes showed higher expression values and fold-changes than the LTB-specific genes. Furthermore, the PTB-related pairs generally had higher expression correlations and would be more activated compared to their LTB-related counterparts. The module analysis implied that the detected gene pairs tended to cluster in the topological and functional modules. Functional analysis indicated that the LTB- and PTB-specific genes were enriched in different pathways and had remarkably different locations in the NF-κB signaling pathway. Finally, we showed that the identified genes and gene pairs had the potential to distinguish TB patients in different disease stages and could be considered as drug targets for the specific treatment of patients with LTB or PTB.

6.
Molecules ; 24(22)2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31766221

RESUMO

Semiliquidambar cathayensis Chang was a traditional medicinal plant and used to treat rheumatism arthritis and rheumatic arthritis for centuries in China with no scientific validation, while only 15 components were reported. Thus, a rapid, efficient, and precise method based on ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (UHPLC-Q-TOF-MS/MS) was applied in both positive- and negative-ion modes to rapidly analysis the main chemical compositions in S. cathayensis for the first time. Finally, a total of 85 chemical compositions, including 35 alkaloids, 12 flavonoids, 7 terpenoids, 5 phenylpropanoids, 9 fatty acids, 7 cyclic peptides, and 10 others were identified or tentatively characterized in the roots of S. cathayensis based on the accurate mass within 5 ppm error. Moreover, alkaloid, flavonoid, phenylpropanoid, and cyclic peptide were reported from S. cathayensis for the first time. This rapid and sensitive method was highly useful to comprehend the chemical compositions and will provide scientific basis for further study on the material basis, mechanism and clinical application of S. cathayensis roots.

7.
Oncogene ; 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31659254

RESUMO

Discerning oncogenic drivers from passengers remain a major effort in understanding of the essence of the initiation and development of hepatocellular carcinoma (HCC), which is the most common primary liver malignancy and the third leading cause of cancer mortality worldwide. Here we report that ZNF774, a novel zinc-finger protein, inhibits the proliferation and invasion of HCC cells. Molecular characterization of this protein indicated that ZNF774 acts as a transcription repressor, and interrogation of ZNF774 interactome by affinity purification-coupled mass spectrometry revealed that ZNF774 is physically associated with the Mi-2/nucleosome remodeling and deacetylase (NuRD) complex in cells. Genome-wide identification of the transcriptional targets of the ZNF774/NuRD complex by ChIP-seq indicated that ZNF774 represses a cohort of genes including NOTCH2 that are critically involved in the growth and mobility of HCC. We demonstrated that the ZNF774/NuRD complex inhibits the proliferation and invasion of HCC cells in vitro and suppresses HCC growth and metastasis in vivo. Importantly, the expression of ZNF774 is significantly downregulated in HCC, and low ZNF774 expression strongly correlated with high NOTCH2 expression, advanced pathological stages, and poor overall survival of the patients. Together, these results uncover a key role for the ZNF774/NuRD-NOTCH2 axis in hepatocarcinogenesis.

9.
Ear Nose Throat J ; : 145561319869608, 2019 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-31566002

RESUMO

BACKGROUND: With the extensive development of endoscopic sinus surgery, iatrogenic medial rectus muscle injury should be treated with caution. Traditional methods to repair a ruptured medial rectus need an anterior orbitotomy approach, with more injury and difficulty in finding the posterior end of the ruptured medial rectus. OBJECTIVE: To explore a new method to repair a ruptured medial rectus. METHODS: Eight cases of iatrogenic medial rectus rupture after endoscopic sinus surgery were reviewed from July 2015 to January 2019. Assisted by image-guided navigation, the ruptured medial rectus was sutured under an endoscopic endonasal orbital approach. Two methods were designed to suture the ruptured medial rectus. Optic nerve and orbital decompression were performed in 5 cases with visual impairment. The extent of exotropia and diplopia were followed up for 5 to 33 months after surgery. RESULTS: With the help of image guidance, the posterior and anterior ends of the ruptured medial rectus of all patients were pinpointed, and operations using medial rectus anastomosis were successfully completed in 7 patients. The exotropia of these patients was corrected, and they have recovered. The vision of 2 patients recovered. There were no minor or major complications intraoperatively or postoperatively. CONCLUSION: Assisted by image-guided navigation, medial rectus anastomosis under an endoscopic endonasal orbital approach is a feasible method. The key to preventing orbital complications is strict professional training, including identification of the Onodi air cell and correct application of powered instrumentation.

10.
Proc Inst Mech Eng H ; 233(12): 1310-1317, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31617820

RESUMO

This study aimed to evaluate the safety and accuracy of mixed reality-based intraoperative three-dimensional navigated pedicle screws in three-dimensional printed model of fractured upper cervical spine. A total of 27 cervical model from patients of upper cervical spine fractures formed the study group. All the C1 and C2 pedicle screws were inserted under mixed reality-based intraoperative three-dimensional image-guided navigation system. The accuracy and safety of the pedicle screw placement were evaluated on the basis of postoperative computerized tomography scans. A total of 108 pedicle screws were properly inserted into the cervical three-dimensional models under mixed reality-based navigation, including 54 C1 pedicle screws and 54 C2 pedicle screws. Analysis of the dimensional parameters of each pedicle at C1/C2 level showed no statistically significant differences in the ideal and the actual entry points, inclined angles, and tailed angles. No screw was misplaced outside the pedicle of the three-dimensional printed model, and no ionizing X-ray radiation was used during screw placement under navigation. It is easy and safe to place C1/C2 pedicle screws under MR surgical navigation. Mixed reality-based navigation is feasible within upper cervical spinal fractures with improved safety and accuracy of C1/C2 pedicle screw insertion.

11.
ACS Appl Mater Interfaces ; 11(46): 43294-43302, 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31661239

RESUMO

Gel electrolytes are important components in flexible solid-state supercapacitors. An urgent need exists for gel electrolytes that can store abundant electrolyte ions and provide high ionic conductivity, with performance characteristics similar to the liquid electrolyte, enabling high-power capability for devices. Herein, we have reported a general and scalable strategy toward various high-performance gel electrolytes including the first freeze of chemical cross-linked poly(vinyl alcohol) followed by infusing with different electrolytes (acid, neutral, and alkaline). The engineering not only endows robust electrolyte ion retention ability and outstanding ion migration rate but also strengthens the mechanical properties for gel electrolytes. As a proof of application, we demonstrate that an all-in-one supercapacitor with a H2SO4 gel electrolyte can deliver excellent rate capability (58.2% retention under the 50-fold increase in current densities), high areal capacitance (644.4 mF cm-2), and long operating lifetime (63.6% retention after 50 000 cycles), representing the best performance among the previously reported all-in-one devices. Thus, we anticipate that the method has a potential application for flexible solid-state energy storage.

12.
Chem Commun (Camb) ; 55(87): 13066-13069, 2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31570904

RESUMO

A platinum(ii) complex containing an aminophosphonate ligand preferentially accumulates in the endoplamic reticulum (ER) in association with potent ER stress and reactive oxygen species generation, followed by the activation of damage-associated molecular pattern signals and immune responses. Importantly, the Pt complex exhibits potent anti-tumour activities in two independent mouse models via an immunogenic cell death pathway.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Ésteres/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Organofosfonatos/farmacologia , Compostos Organoplatínicos/farmacologia , Animais , Antineoplásicos Imunológicos/química , Morte Celular/efeitos dos fármacos , Ésteres/química , Humanos , Ligantes , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/patologia , Organofosfonatos/química , Compostos Organoplatínicos/química
13.
J Biol Chem ; 294(47): 17837-17847, 2019 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-31624151

RESUMO

The Krüppel-like factor 5 (KLF5) transcription factor is highly expressed in basal type breast cancer and promotes breast cancer cell proliferation, survival, migration, and tumorigenesis. KLF5 protein stability is regulated by ubiquitination. In this study, ubiquitin-specific protease 3 (USP3) was identified as a new KLF5 deubiquitinase by genome-wide siRNA library screening. We demonstrated that USP3 interacts with KLF5 and stabilizes KLF5 via deubiquitination. USP3 knockdown inhibits breast cancer cell proliferation in vitro and tumorigenesis in vivo, which can be partially rescued by ectopic expression of KLF5. Furthermore, we observed a positive correlation between USP3 and KLF5 protein expression levels in human breast cancer samples. These findings suggest that USP3 is a new KLF5 deubiquitinase and that USP3 may represent a potential therapeutic target for breast cancer.

14.
Curr Alzheimer Res ; 16(8): 732-740, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31470788

RESUMO

BACKGROUND: Upregulation of Cancerous Inhibitor of PP2A (CIP2A) plays an important role in disease-related phosphorylation of tau/APP and tau pathology/Aß overproduction through inhibiting PP2A in AD brain. Genistein has been shown to potently reduce CIP2A in experimental cancer treatment research. Whether Genistein can ameliorate AD pathology through targeting CIP2A needs further investigation. METHODS: The inhibitory effects of Genistein on tau/APP phosphorylation and Aß overproduction in AD cell models have been explored. HEK293-T cells were co-transfected with CIP2A and APP plasmids, or CIP2A and tau plasmids, with Genistein incubation at 0, 30, 60 or 120 µM for 48 h, cell viability and PP2A activities were measured. HEK293-T cells with CIP2A/APP overexpression treated with Genistein at 30 µM for 48 h were collected and lyzed for Western blotting detection of CIP2A, PP2Ac, APP-T668, total APP, PS1, BACE1, sAPPα and sAPPß. Aß40 and Aß42 levels in cell supernatant, soluble fraction (RIPA) and insoluble fraction (formic acid soluble) of cell lysates were measured by ELISA. HEK293-T cells with CIP2A/tau overexpression treated with Genistein at 30 µM for 48 h were collected for Western blotting detection of CIP2A, PP2Ac, tau-S396, tau-S404 and total tau. RESULTS: Genistein effectively reduced CIP2A expression, and restored PP2A activities both in CIP2A/APP, CIP2A/tau co-expressed cells. Genistein reduced APP phosphorylation at T668 site and inhibited Aß production. Meantime, Genistein ameliorated tau hyperphosphorylation through repressing the inhibitory effect of CIP2A on PP2A. CONCLUSION: CIP2A is a target of Genistein in AD therapy. Genistein reduces APP/tau hyperphosphorylation and Aß production through inhibiting the effect of CIP2A on PP2A.

15.
Acta Trop ; 200: 105186, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31542371

RESUMO

The small blood flukes of genus Schistosoma, which cause one of the most prevalent and serious parasitic zoonosis schistosomiasis, are dependent on immune-related factors of their mammalian host to facilitate their growth and development, and the formation of granulomatous pathology caused by eggs deposited in host's liver and intestinal wall. Schistosome development is hampered in the mice lacking just T cells, and is even more heavily retarded in the severe combined immunodeficient (SCID) mice lacking both T and B lymphocytes. Nevertheless, it's still not clear about the underlying regulatory molecular mechanisms of schistosome growth and development by host's immune system. This study, therefore, detected and compared the serum metabolic profiles between the immunodeficient mice and immunocompetent mice (SCID mice vs. BALB/c mice) before and after S. japonicum infection (on the thirty-fifth day post infection using liquid chromatography-mass spectrometry (LC-MS). Totally, 705 ion features in electrospray ionization in positive-ion mode (ESI+) and 242 ion features in ESI- mode were identified, respectively. First, distinct serum metabolic profiles were identified between SCID mice and BALB/c mice without S. japonicum worms infection. Second, uniquely perturbed serum metabolites and their enriched pathways were also obtained between SCID mice and BALB/c mice after S. japonicum infection, which included differential metabolites due to both species differences and differential responses to S. japonicum infection. The metabolic pathways analysis revealed that arachidonic acid metabolism, biosynthesis of unsaturated fatty acids, linoleic acid metabolism, glycosylphosphatidylinositol (GPI)-anchor biosynthesis, alpha-linolenic acid metabolism, glycerophospholipid metabolism, sphingolipid metabolism and purine metabolism were enriched based on the differential serum metabolites between SCID mice and BALB/c mice after S. japonicum infection, which was addressed to be related to the retarded growth and development of S. japonicum in SCID mice. These findings provide new clues to the underlying molecular events of host's systemic metabolic changes on the growth and development of S. japonicum worms, and also provide quite promising candidates for exploitation of drugs or vaccines against schistosome and schistosomiasis.

16.
Anal Biochem ; 587: 113446, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31545947

RESUMO

The effect of sample containers made of different materials on the MS-based analysis of oligonucleotides remains unknown. Here, we evaluated five types of sample containers on the MS signal stability of oligonucleotide, and they were normal glass insert, silanized glass insert with three different silanization techniques, and polypropylene sample vial. Also, we attempted to tackle signal stability issue by varying modifiers in dissolution solvent. Our results showed that sample containers made of different materials can significantly influence the MS signal stability of oligonucleotide at low concentration. Triethylamine (TEA) evidently improved both the signal stability and intensity of oligonucleotide.

17.
J Hepatobiliary Pancreat Sci ; 26(11): 517-523, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31532908

RESUMO

BACKGROUND: With the advancement of robotic pancreaticoduodenectomy (RPD), several reconstruction methods have been advocated to make RPD more effective and safer. In this study, we investigated the safety and effectiveness of RPD using a left retrocolic (L-port) technique and compared it with those of RPD using an antecolic technique. METHODS: Between October 2015 and August 2016, we retrospectively reviewed consecutive cases of RPD before and after introducing the L-port technique for gastrointestinal reconstruction. The L-port technique was mainly performed for retrocolic gastrojejunal reconstruction and some cases of duodenojejunal reconstruction. The perioperative and postoperative outcomes were compared in the two groups. RESULTS: Eighty-three cases of RPD were retrieved for statistical analysis. Compared with the antecolic group, the L-port group was significantly associated with a shorter operative time (median time [IQR] 345 [307-384] min vs. 390 [370-455] min, P < 0.001), reconstruction time (54 [48-59] min vs. 84 [75-98] min, P < 0.001) and lower incidence of delayed gastric emptying. There were no cases of re-operation due to internal herniation, colonic ischemia, or bowel volvulus in the L-port group during the 1-year follow-up period. CONCLUSIONS: Our results demonstrated that the L-port technique of RPD is a safe and feasible technique for gastrointestinal reconstruction.

18.
Artigo em Inglês | MEDLINE | ID: mdl-31527040

RESUMO

Hepatitis C virus (HCV) genotype (GT) 2 represents approximately 9% of all viral infections globally. While treatment outcomes for GT2-infected patients have improved substantially with direct-acting antiviral agents (DAAs) compared to interferon-α, the presence of polymorphisms in NS5A can impact efficacy of NS5A inhibitor-containing regimens. Thus, pathways of NS5A resistance were explored in GT2 subtypes using elbasvir, an NS5A inhibitor with broad genotype activity. Resistance selection studies, resistance analysis in NS5A-inhibitor treated virologic failures, antiviral activities in replicons bearing a panel of GT2 subtype sequences and amino acid substitutions introduced by site-directed mutagenesis were performed to define determinants of inhibitor susceptibility. Elbasvir showed differential antiviral activity in replicons bearing GT2 sequences. The EC50 values for replicons bearing reference NS5A sequences for GT2a and GT2b were 0.003 and 3.4 nanomolar (nM) respectively. Studies with recombinant replicons demonstrated crosstalk between amino acid positions 28 and 31. The combination of phenylalanine and methionine at positions 28 and 31 respectively, conferred the highest potency reduction for elbasvir in GT2a and GT2b. This combination was observed in failures from the C-SCAPE trial. Addition of grazoprevir, an NS3/4A protease inhibitor, to elbasvir more effectively suppressed the emergence of resistance in GT2 at modest inhibitor concentrations (3X EC90). Ruzasvir, a potent, pan-genotype NS5A inhibitor successfully inhibited replicons bearing GT2 resistance-associated substitutions (RASs) at positions 28 and 31. The studies demonstrate crosstalk between amino acids at positions 28 and 31 in NS5A modulate inhibitor potency and may impact treatment outcomes in some HCV GT2-infected patients.

19.
Luminescence ; 2019 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-31495065

RESUMO

A new compound, ethyl 5-phenyl-2-(p-tolyl)-2H-1,2,3-triazole-4-carboxylate was successfully introduced and synthesized as a novel rhodamine B derivative named REPPC, and characterized by 1 H nuclear magnetic resonance (NMR), 13 C NMR, and high resolution mass spectrometry (HRMS). It showed an obvious fluorescence and UV-visible light absorption enhancement towards Hg2+ ion without interference from common metal ions in N,N-dimethylformamide-H2 O (pH 7.4). The spirolactam ring moiety of rhodamine in REPPC was converted to the open-ring form generating a 1:1 complex with the intervention of a mercury ion, verified by electrospray ionization-mass spectroscopy testing and density functional theory calculation. REPPC was used to visualize the level of mercury ions in living HeLa cells with encouraging results.

20.
Target Oncol ; 14(5): 591-601, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31502117

RESUMO

BACKGROUND: Fibroblast growth factor receptor (FGFR) 2 is overexpressed in several tumor types, including triple-negative breast cancer and gastric cancer, both of which have a high unmet medical need. Aprutumab ixadotin (BAY 1187982) is the first antibody-drug conjugate (ADC) to target FGFR2 and the first to use a novel auristatin-based payload. OBJECTIVE: This first-in-human trial was conducted to determine the safety, tolerability, and maximum tolerated dose (MTD) of aprutumab ixadotin in patients with advanced solid tumors from cancer indications known to be FGFR2-positive. PATIENTS AND METHODS: In this open-label, multicenter, phase I dose-escalation trial (NCT02368951), patients with advanced solid tumors received escalating doses of aprutumab ixadotin (starting at 0.1 mg/kg body weight), administered intravenously on day 1 of every 21-day cycle. Primary endpoints included safety, tolerability, and the MTD of aprutumab ixadotin; secondary endpoints were pharmacokinetic evaluation and tumor response to aprutumab ixadotin. RESULTS: Twenty patients received aprutumab ixadotin across five cohorts, at doses of 0.1-1.3 mg/kg. The most common grade ≥ 3 drug-related adverse events were anemia, aspartate aminotransferase increase, proteinuria, and thrombocytopenia. Dose-limiting toxicities were thrombocytopenia, proteinuria, and corneal epithelial microcysts, and were only seen in the two highest dosing cohorts. The MTD was determined to be 0.2 mg/kg due to lack of quantitative data following discontinuations at 0.4 and 0.8 mg/kg doses. One patient had stable disease; no responses were reported. CONCLUSIONS: Aprutumab ixadotin was poorly tolerated, with an MTD found to be below the therapeutic threshold estimated preclinically; therefore, the trial was terminated early. CLINICALTRIALS. GOV IDENTIFIER: NCT02368951.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA