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1.
Micromachines (Basel) ; 15(6)2024 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-38930769

RESUMO

The surface morphology of perovskite films significantly influences the performance of perovskite light-emitting diodes (PeLEDs). However, the thin perovskite thickness (~10 nm) results in low surface coverage on the substrate, limiting the improvement of photoelectric performance. Here, we propose a molecular additive strategy that employs pentafluorophenyl diphenylphosphinate (FDPP) molecules as additives. P=O and Pentafluorophenyl (5F) on FDPP can coordinate with Pb2+ to slow the crystallization process of perovskite and enhance surface coverage. Moreover, FDPP reduces the defect density of perovskite and enhances the crystalline quality. The maximum brightness, power efficiency (PE), and external quantum efficiency (EQE) of the optimal device reached 24,230 cd m-2, 82.73 lm W-1, and 21.06%, respectively. The device maintains an EQE of 19.79% at 1000 cd m-2 and the stability is further enhanced. This study further extends the applicability of P=O-based additives.

3.
NPJ Breast Cancer ; 10(1): 33, 2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38664404

RESUMO

In this post hoc analysis of the ASCENT study, we compared outcomes with sacituzumab govitecan (SG) vs single-agent chemotherapy in clinically important subgroups of patients with metastatic triple-negative breast cancer (mTNBC). Patients with mTNBC refractory to/relapsing after ≥2 prior chemotherapies (≥1 in the metastatic setting) were randomized 1:1 to receive SG or treatment of physician's choice (TPC) until unacceptable toxicity/progression. The primary endpoint was progression-free survival (PFS) per RECIST 1.1 by central review in patients without brain metastases. Patients with brain metastases were allowed if metastases were stable ≥4 weeks. In the intention-to-treat (ITT) population, 19% of patients were age ≥65 years; 12% were Black, and 12% had brain metastases. SG improved PFS and overall survival (OS), respectively, vs TPC in patients age ≥65 years (7.1 vs 2.4 months and 14.7 vs 8.9 months), or of Black race (5.4 vs 2.2 months and 13.8 vs 8.5 months), consistent with outcomes in the ITT population. Patients with brain metastases had numerically higher median PFS with SG vs TPC, but median OS was similar between treatment groups. SG was well tolerated and had a manageable safety profile consistent with the full safety population across all subgroups; neutropenia and diarrhea were the most common treatment-emergent adverse events. These findings confirm the meaningful clinical benefit of SG vs standard chemotherapy in patient subgroups with high unmet needs. SG should be considered an effective and safe treatment option for patients with mTNBC eligible for second-line or later therapy. ClinicalTrials.gov Number: NCT02574455.

4.
Mol Cancer ; 23(1): 5, 2024 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-38184597

RESUMO

BACKGROUND: Cisplatin (CDDP) is the first-line chemotherapeutic strategy to treat patients with ovarian cancer (OC). The development of CDDP resistance remains an unsurmountable obstacle in OC treatment and frequently induces tumor recurrence. Circular RNAs (circRNAs) are noncoding RNAs with important functions in cancer progression. Whether circRNAs function in CDDP resistance of OC is unclear. METHODS: Platinum-resistant circRNAs were screened via circRNA deep sequencing and examined using in situ hybridization (ISH) in OC. The role of circPLPP4 in CDDP resistance was assessed by clone formation and Annexin V assays in vitro, and by OC patient-derived xenografts and intraperitoneal tumor models in vivo. The mechanism underlying circPLPP4-mediated activation of miR-136/PIK3R1 signaling was examined by luciferase reporter assay, RNA pull-down, RIP, MeRIP and ISH. RESULTS: circPLPP4 was remarkably upregulated in platinum resistant OC. circPLPP4 overexpression significantly enhanced, whereas circPLPP4 silencing reduced, OC cell chemoresistance. Mechanistically, circPLPP4 acts as a microRNA sponge to sequester miR-136, thus competitively upregulating PIK3R1 expression and conferring CDDP resistance. The increased circPLPP4 level in CDDP-resistant cells was caused by increased RNA stability, mediated by increased N6-methyladenosine (m6A) modification of circPLPP4. In vivo delivery of an antisense oligonucleotide targeting circPLPP4 significantly enhanced CDDP efficacy in a tumor model. CONCLUSIONS: Our study reveals a plausible mechanism by which the m6A -induced circPLPP4/ miR-136/ PIK3R1 axis mediated CDDP resistance in OC, suggesting that circPLPP4 may serve as a promising therapeutic target against CDDP resistant OC. A circPLPP4-targeted drug in combination with CDDP might represent a rational regimen in OC.


Assuntos
MicroRNAs , Neoplasias Ovarianas , Humanos , Feminino , Cisplatino/farmacologia , Regulação para Cima , RNA Circular/genética , Recidiva Local de Neoplasia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , MicroRNAs/genética , Adenosina , Classe Ia de Fosfatidilinositol 3-Quinase/genética
5.
Micromachines (Basel) ; 14(11)2023 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-38004941

RESUMO

Due to the excellent photonic and electrical properties of metal halide perovskite materials, perovskite light-emitting devices have the potential to replace OLED devices as the next-generation of commercial light-emitting devices. In this article, we controlled the surface morphology of PbBr2 using an in situ dynamic thermal crystallization process, which increased the specific surface area of the films and promoted the solid-state diffusion rate. The CsPbBr3 PeLEDs prepared using this method achieved a maximum current efficiency of 7.1 cd/A at the voltage of 5 V, which was 200% higher than devices prepared using traditional spin-coating processes. These results proved that the in situ thermal dynamic crystallization process effectively improved the film quality of perovskite materials.

6.
Medicine (Baltimore) ; 102(37): e35018, 2023 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-37713874

RESUMO

This retrospective study investigated the effect of auricular acupressure combined with acupuncture for juvenile pseudomyopia (JPM). In this retrospective study, we collected and analyzed a total of 66 eligible records of subjects with JPM. They were allocated into a treatment group (n = 33) and a control group (n = 33). All participants in both groups received auricular acupressure. Additionally, children in the treatment group also underwent acupuncture. The primary outcome was naked visual acuity (VA). It was performed using a standard E visual acuity chart. The secondary outcome was visual fatigue symptoms, as assessed by the College of Optometrists in Vision Development Quality of Life (COVD-QoL) questionnaire. All outcomes were analyzed before and after treatment. There were no significant differences regarding the naked VA and COVD-QoL scores before and after treatment between the 2 groups. However, there were significant differences regarding on naked VA (P < .01) and COVD-QoL scores (P < .01) within 2 groups compared before and after treatment. The findings of this study showed that both APP plus acupuncture and APP alone benefit children with JPM.


Assuntos
Acupressão , Terapia por Acupuntura , Criança , Humanos , Qualidade de Vida , Estudos Retrospectivos , Grupos Controle
7.
Stem Cells Transl Med ; 12(7): 444-458, 2023 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-37311043

RESUMO

Primary and metastatic lung cancer is a leading cause of cancer-related death and novel therapies are urgently needed. Epidermal growth factor receptor (EGFR) and death receptor (DR) 4/5 are both highly expressed in primary and metastatic non-small cell lung cancer (NSCLC); however, targeting these receptors individually has demonstrated limited therapeutic benefit in patients. In this study, we created and characterized diagnostic and therapeutic stem cells (SC), expressing EGFR-targeted nanobody (EV) fused to the extracellular domain of death DR4/5 ligand (DRL) (EVDRL) that simultaneously targets EGFR and DR4/5, in primary and metastatic NSCLC tumor models. We show that EVDRL targets both cell surface receptors, and induces caspase-mediated apoptosis in a broad spectrum of NSCLC cell lines. Utilizing real-time dual imaging and correlative immunohistochemistry, we show that allogeneic SCs home to tumors and when engineered to express EVDRL, alleviate tumor burden and significantly increase survival in primary and brain metastatic NSCLC. This study reports mechanistic insights into simultaneous targeting of EGFR- and DR4/5 in lung tumors and presents a promising approach for translation into the clinical setting.


Assuntos
Neoplasias Encefálicas , Carcinoma Pulmonar de Células não Pequenas , Transplante de Células-Tronco Hematopoéticas , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Receptores ErbB/genética , Receptores ErbB/metabolismo , Receptores ErbB/uso terapêutico , Morte Celular , Neoplasias Encefálicas/terapia , Proliferação de Células , Encéfalo/patologia
8.
Nanomaterials (Basel) ; 12(13)2022 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-35808036

RESUMO

Currently, precious metal group materials are known as the efficient and widely used oxygen evolution reaction (OER) and hydrogen evolution reaction (HER) catalysts. The exorbitant prices and scarcity of the precious metals have stimulated scale exploration of alternative non-precious metal catalysts with low-cost and high performance. Layered double hydroxides (LDHs) are a promising precursor to prepare cost-effective and high-performance catalysts because they possess abundant micropores and nitrogen self-doping after pyrolysis, which can accelerate the electron transfer and serve as active sites for efficient OER. Herein, we developed a new highly active NiFeMn-layered double hydroxide (NFM LDH) based electrocatalyst for OER. Through building NFM hydroxide/oxyhydroxide heterojunction and incorporation of conductive graphene, the prepared NFM LDH-based electrocatalyst delivers a low overpotential of 338 mV at current density of 10 mA cm-2 with a small Tafel slope of 67 mV dec-1, which are superior to those of commercial RuO2 catalyst for OER. The LDH/OOH heterojunction involves strong interfacial coupling, which modulates the local electronic environment and boosts the kinetics of charge transfer. In addition, the high valence Fe3+ and Mn3+ species formed after NaOH treatment provide more active sites and promote the Ni2+ to higher oxidation states during the O2 evolution. Moreover, graphene contributes a lot to the reduction of charge transfer resistance. The combining effects have greatly enhanced the catalytic ability for OER, demonstrating that the synthesized NFM LDH/OOH heterojunction with graphene linkage can be practically applied as a high-performance electrocatalyst for oxygen production via water splitting.

10.
NPJ Breast Cancer ; 8(1): 72, 2022 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-35680967

RESUMO

Patients with triple-negative breast cancer (TNBC) who relapse early after (neo)adjuvant chemotherapy have more aggressive disease. In the ASCENT trial, sacituzumab govitecan (SG), an antibody-drug conjugate composed of an anti-Trop-2 antibody coupled to SN-38 via a hydrolyzable linker, improved outcomes over single-agent chemotherapy of physician's choice (TPC) in metastatic TNBC (mTNBC). Of 468 patients without known baseline brain metastases, 33/235 vs 32/233 patients (both 14%) in the SG vs TPC arms, respectively, received one line of therapy in the metastatic setting and experienced disease recurrence ≤12 months after (neo)adjuvant chemotherapy. SG prolonged progression-free survival (median 5.7 vs 1.5 months [HR, 0.41; 95% CI, 0.22-0.76]) and overall survival (median 10.9 vs 4.9 months [HR, 0.51; 95% CI, 0.28-0.91]) vs TPC, with a manageable safety profile in this subgroup consistent with the overall population. In this second-line setting, as with later-line therapy, SG improved survival over conventional chemotherapy for patients with mTNBC.

11.
Breast Cancer Res Treat ; 195(2): 127-139, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35545724

RESUMO

PURPOSE: Sacituzumab govitecan (SG) is an antibody-drug conjugate composed of an anti-Trop-2 antibody coupled to SN-38 via a proprietary hydrolyzable linker. In the ASCENT study, SG improved survival versus single-agent treatment of physician's choice (TPC) in pre-treated metastatic triple-negative breast cancer (mTNBC). Hormone/HER2 receptor changes are common, particularly at relapse/metastasis. This subanalysis assessed outcomes in patients who did/did not have TNBC at initial diagnosis, before enrollment. METHODS: TNBC diagnosis was only required at study entry. Patients with mTNBC refractory/relapsing after ≥ 2 prior chemotherapies were randomized 1:1 to receive SG or TPC. Primary endpoint was progression-free survival (PFS) in patients without brain metastases. RESULTS: Overall, 70/235 (30%) and 76/233 (33%) patients who received SG and TPC, respectively, did not have TNBC at initial diagnosis. Clinical benefit with SG versus TPC was observed in this subset. Median PFS was 4.6 versus 2.3 months (HR 0.48; 95% CI 0.32-0.72), median overall survival was 12.4 versus 6.7 months (HR 0.44; 95% CI 0.30-0.64), and objective response rate (ORR) was 31% versus 4%; those who also received prior CDK4/6 inhibitors had ORRs of 21% versus 5%. Efficacy and safety for patients with TNBC at initial diagnosis were generally similar to those who did not present with TNBC at initial diagnosis. CONCLUSION: Patients without TNBC at initial diagnosis had improved clinical outcomes and a manageable safety profile with SG, supporting SG as a treatment option for mTNBC regardless of subtype at initial diagnosis. Subtype reassessment in advanced breast cancer allows for optimal treatment. Clinical trial registration number NCT02574455, registered October 12, 2015.


Assuntos
Neoplasias da Mama , Imunoconjugados , Neoplasias de Mama Triplo Negativas , Anticorpos Monoclonais Humanizados , Neoplasias da Mama/tratamento farmacológico , Camptotecina/análogos & derivados , Feminino , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/diagnóstico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico
12.
J Hepatol ; 77(3): 607-618, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35439567

RESUMO

BACKGROUND & AIMS: Non-alcoholic steatohepatitis (NASH) is associated with increased risk of liver-related and cardiovascular morbidity and mortality. Given the complex pathophysiology of NASH, combining therapies with complementary mechanisms may be beneficial. This trial evaluated the safety and efficacy of semaglutide, a glucagon-like peptide-1 receptor agonist, alone and in combination with the farnesoid X receptor agonist cilofexor and/or the acetyl-coenzyme A carboxylase inhibitor firsocostat in patients with NASH. METHODS: This was a phase II, open-label, proof-of-concept trial in which patients with NASH (F2-F3 on biopsy, or MRI-proton density fat fraction [MRI-PDFF] ≥10% and liver stiffness by transient elastography ≥7 kPa) were randomised to 24 weeks' treatment with semaglutide 2.4 mg once weekly as monotherapy or combined with once-daily cilofexor (30 or 100 mg) and/or once-daily firsocostat 20 mg. The primary endpoint was safety. All efficacy endpoints were exploratory. RESULTS: A total of 108 patients were randomised to semaglutide (n = 21), semaglutide plus cilofexor 30 mg (n = 22), semaglutide plus cilofexor 100 mg (n = 22), semaglutide plus firsocostat (n = 22) or semaglutide, cilofexor 30 mg and firsocostat (n = 21). Treatments were well tolerated - the incidence of adverse events was similar across groups (73-90%) and most events were gastrointestinal in nature. Despite similar weight loss (7-10%), compared with semaglutide monotherapy, combinations resulted in greater improvements in liver steatosis measured by MRI-PDFF (least-squares mean of absolute changes: -9.8 to -11.0% vs. -8.0%), liver biochemistry, and non-invasive tests of fibrosis. CONCLUSIONS: In patients with mild-to-moderate fibrosis due to NASH, semaglutide with firsocostat and/or cilofexor was generally well tolerated. In exploratory efficacy analyses, treatment resulted in additional improvements in liver steatosis and biochemistry vs. semaglutide alone. Given this was a small-scale open-label trial, double-blind placebo-controlled trials with adequate patient numbers are warranted to assess the efficacy and safety of these combinations in NASH. CLINICAL TRIAL REGISTRATION NUMBER: NCT03987074. LAY SUMMARY: Non-alcoholic fatty liver disease and its more severe form, non-alcoholic steatohepatitis (NASH), are serious liver conditions that worsen over time if untreated. The reasons people develop NASH are complex and combining therapies that target different aspects of the disease may be more helpful than using single treatments. This trial showed that the use of 3 different types of drugs, namely semaglutide, cilofexor and firsocostat, in combination was safe and may offer additional benefits over treatment with semaglutide alone.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Azetidinas , Método Duplo-Cego , Fibrose , Peptídeos Semelhantes ao Glucagon , Humanos , Isobutiratos , Ácidos Isonicotínicos , Hepatopatia Gordurosa não Alcoólica/complicações , Oxazóis , Pirimidinas , Resultado do Tratamento
13.
Cell Rep Med ; 2(11): 100449, 2021 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-34841295

RESUMO

Cell-based immunotherapy has become the new-generation cancer medicine, and "off-the-shelf" cell products that can be manufactured at large scale and distributed readily to treat patients are necessary. Invariant natural killer T (iNKT) cells are ideal cell carriers for developing allogeneic cell therapy because they are powerful immune cells targeting cancers without graft-versus-host disease (GvHD) risk. However, healthy donor blood contains extremely low numbers of endogenous iNKT cells. Here, by combining hematopoietic stem cell (HSC) gene engineering and in vitro differentiation, we generate human allogeneic HSC-engineered iNKT (AlloHSC-iNKT) cells at high yield and purity; these cells closely resemble endogenous iNKT cells, effectively target tumor cells using multiple mechanisms, and exhibit high safety and low immunogenicity. These cells can be further engineered with chimeric antigen receptor (CAR) to enhance tumor targeting or/and gene edited to ablate surface human leukocyte antigen (HLA) molecules and further reduce immunogenicity. Collectively, these preclinical studies demonstrate the feasibility and cancer therapy potential of AlloHSC-iNKT cell products and lay a foundation for their translational and clinical development.


Assuntos
Células Alógenas/imunologia , Engenharia Celular , Células-Tronco Hematopoéticas/imunologia , Imunoterapia , Células T Matadoras Naturais/imunologia , Neoplasias/imunologia , Neoplasias/terapia , Células Alógenas/metabolismo , Animais , Linhagem Celular Tumoral , Perfilação da Expressão Gênica , Antígenos HLA/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Humanos , Camundongos Endogâmicos NOD , Camundongos SCID , Células T Matadoras Naturais/metabolismo , Fenótipo , Receptores de Antígenos Quiméricos/metabolismo , Transcriptoma/genética
14.
J Cosmet Laser Ther ; 23(5-6): 142-148, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35083965

RESUMO

Microneedle fractional radiofrequency (MFR) and non-ablative 1565 nm fractional laser (NAFL) have recently been introduced as new techniques to address the growing concern of facial photoaging. In this prospective randomized split-face study, we wanted to compare the safety and efficacy of MFR with that of NAFL for the treatment of facial photoaging in Asian patients. Fifteen healthy Chinese patients were enrolled for this randomized split-face study. Each patient underwent three sessions of treatment with MFR and NAFL on opposite sides of their face, one month apart. A blinded outcome assessment of the photoaging severity was performed by two independent plastic surgeons on a 5-point visual analogue scale (VAS, 0-4). Patient satisfaction was also scored based on a 5-point VAS (0 = dissatisfaction, 4 = extremely satisfied). Sagging of the nasolabial groove was evaluated using the Antera 3D camera, facial wrinkles and pores using the VISIA skin analysis system. Any adverse events that occurred during the study were also evaluated. Based on the VAS scores and results from the Antera 3D and VISIA, it was noted that there was a significant improvement in facial skin laxity, wrinkles, and pores, and lesser sagging of the nasolabial groove on both the MFR and NAFL sides of the face, compared with that of the baseline. Most patients were satisfied with the treatment and reported tolerable pain and crusting. Although no significant differences were observed between the MFR and NAFL treatments, the NAFL treatment resulted in a shorter downtime(4.56 ± 2.72d) than the MFR treatment(6.96 ± 3.27d). This study confirms the efficacy of MFR and NAFL treatments for facial skin rejuvenation in Asian patients. Furthermore, the therapies were found to be safe and well-tolerated. Our findings suggest that NAFL may be a more convenient treatment modality for facial photoaging because of its shorter downtime. However, sagging of the nasolabial groove was more improved by the MFR treatment than by the NAFL treatment.


Assuntos
Lasers de Estado Sólido , Envelhecimento da Pele , Érbio , Humanos , Lasers de Estado Sólido/efeitos adversos , Satisfação do Paciente , Estudos Prospectivos , Rejuvenescimento , Resultado do Tratamento
15.
Int J Pharm ; 587: 119688, 2020 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-32717281

RESUMO

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor-in-Chief. Significant similarities were noticed post-publication between this article and an article submitted to the Journal of Drug Delivery Science and Technology on the same day, by an apparently unrelated research group: Tong Zhang, Tianhui Zhu, Fanyin Wang, Ling Peng and Mingying Lai 60 (2020) 101949 https://doi.org/10.1016/j.jddst.2020.101949 Moreover, the authors did not respond to the journal request to comment on these similarities and to provide the raw data, and the Editor-in-Chief decided to retract the article. One of the conditions of submission of a paper for publication is that authors declare explicitly that their work is original and genuine. As such this article represents a severe abuse of the scientific publishing system.


Assuntos
Lentes de Contato , Nanopartículas , Preparações Farmacêuticas , Animais , Sistemas de Liberação de Medicamentos , Lipídeos , Tamanho da Partícula , Poloxâmero , Coelhos , Retina , Rodanina/análogos & derivados , Tiazolidinas
16.
Medicine (Baltimore) ; 99(20): e20109, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32443320

RESUMO

To assess the prevalence and causes of visual impairment (VI) in the elderly Chinese rural population in Shaanxi Province.A population-based, cross-sectional study design was used to determine the extent of VI in Chinese people over the age of 50 years in Shaanxi Province. Visual acuity and best-corrected visual acuity were measured using the logarithm of minimum angle of resolution chart. Blindness and low vision were defined according to WHO criteria. The major cause of VI was identified for all participants who were visually impaired.A total of 1912 residents completed a standard questionnaire and underwent a detailed eye examination, and the response rate was 90%. The overall prevalence of blindness and low vision were 1.5% and 8.2%. There was no statistically significant differences between genders in the prevalence of blindness and low vision (P > .05). The prevalence of blindness and low vision was higher among older individuals (P < .05) and lower (P < .05) among those with the highest education level. Cataract, corneal opacity, and glaucoma were considered as the main causes of blindness, which accounted for 67.9%, 10.7%, and 7.1%, respectively. Cataract, refractive error, and age-related macular degeneration were always considered as the leading causes of low vision, which accounted for 66%, 14.7%, and 5.8%, respectively.Cataract, corneal opacity, and glaucoma were the main causes of blindness and low vision in the population aged 50 years or more. The prevalence of these diseases that causes blindness and low vision was higher than that reported in other studies.


Assuntos
Transtornos da Visão/epidemiologia , Transtornos da Visão/etiologia , Idoso , Idoso de 80 Anos ou mais , China/epidemiologia , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , População Rural , Acuidade Visual
17.
J Hepatol ; 73(1): 26-39, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32147362

RESUMO

BACKGROUND & AIMS: Apoptosis signal-regulating kinase 1 (ASK1) plays a key role in hepatocyte injury, inflammation, and fibrosis in non-alcoholic steatohepatitis (NASH). We evaluated the safety and antifibrotic effect of selonsertib, a selective inhibitor of ASK1, in patients with advanced fibrosis due to NASH. METHODS: We conducted 2 randomized, double-blind, placebo-controlled, phase III trials of selonsertib in patients with NASH and bridging fibrosis (F3, STELLAR-3) or compensated cirrhosis (F4, STELLAR-4). Patients were randomized 2:2:1 to receive selonsertib 18 mg, selonsertib 6 mg, or placebo once daily for 48 weeks. Liver biopsies were performed at screening and week 48 and non-invasive tests of fibrosis (NITs) were evaluated. The primary efficacy endpoint was the proportion of patients with ≥1-stage improvement in fibrosis without worsening of NASH at week 48. Additional endpoints included changes in NITs, progression to cirrhosis (in STELLAR-3), and liver-related clinical events. RESULTS: Neither trial met the primary efficacy endpoint. In STELLAR-3, fibrosis improvement without worsening of NASH was observed in 10% (31/322, p = 0.49 vs. placebo), 12% (39/321, p = 0.93 vs. placebo), and 13% (21/159) of patients in the selonsertib 18 mg, selonsertib 6 mg, and placebo groups, respectively. In STELLAR-4, the primary endpoint was achieved in 14% (51/354; p = 0.56), 13% (45/351; p = 0.93), and 13% (22/172) of patients, respectively. Although selonsertib led to dose-dependent reductions in hepatic phospho-p38 expression indicative of pharmacodynamic activity, it had no significant effect on liver biochemistry, NITs, progression to cirrhosis, or adjudicated clinical events. The rates and types of adverse events were similar among selonsertib and placebo groups. CONCLUSIONS: Forty-eight weeks of selonsertib monotherapy had no antifibrotic effect in patients with bridging fibrosis or compensated cirrhosis due to NASH. LAY SUMMARY: Patients with non-alcoholic steatohepatitis (NASH) can develop scarring of the liver (fibrosis), including cirrhosis, which increases the risks of liver failure and liver cancer. We tested whether 48 weeks of treatment with selonsertib reduced fibrosis in patients with NASH and advanced liver scarring. We did not find that selonsertib reduced fibrosis in these patients. TRIAL REGISTRATION DETAILS: Clinicaltrials.gov numbers NCT03053050 and NCT03053063.


Assuntos
Benzamidas , Imidazóis , Cirrose Hepática , Fígado/patologia , Hepatopatia Gordurosa não Alcoólica , Piridinas , Benzamidas/administração & dosagem , Benzamidas/efeitos adversos , Biópsia/métodos , Progressão da Doença , Relação Dose-Resposta a Droga , Método Duplo-Cego , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Imidazóis/administração & dosagem , Imidazóis/efeitos adversos , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/etiologia , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , MAP Quinase Quinase Quinase 5/antagonistas & inibidores , MAP Quinase Quinase Quinase 5/metabolismo , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Resultado do Tratamento
18.
Exp Ther Med ; 19(2): 999-1005, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32010262

RESUMO

The aim of the present study was to determine the role of long intergenic non-protein coding RNA 858 (LINC00858) in retinoblastoma (RB) and investigate the underlying molecular mechanisms. RB tissues and paracancerous tissues of 27 RB cases were obtained. RB cell lines (SO-RB50, Y79, HXO-RB44 and WERI-Rb1) and a normal retinal epithelial cell line (ARPE-19) were cultured for in vitro experiments. Batches of SO-RB50 and Y79 cells were assigned to groups transfected with small interfering RNA targeting LINC00858 (si-LINC00858 group), microRNA (miR)-3182 mimics or inhibitor, or the respective controls. A Cell Counting Kit-8 and Transwell assays were performed to assess the effect of the transfections on the proliferation, migration and invasion of SO-RB50 and Y79 cells. A luciferase reporter assay was performed using SO-RB50 cells to demonstrate the direct binding of LINC00858 and miR-3182. Reverse transcription-quantitative PCR was employed to detect LINC00858 and miR-3182 expression. Pearson correlation analysis was used to assess the correlation between the expression of LINC00858 and miR-3182. The results indicated that RB tissues and cells exhibited aberrantly elevated LINC00858 expression (P<0.05). Compared with those in the control-transfected group, SO-RB50 and Y79 cells of the si-LINC00858 group had a lower cell proliferation, as well as a lower number of migrated and invaded cells (all P<0.05). miR-3182 was proven to be a target gene of LINC00858, to be abnormally downregulated in RB tissues and cells (P<0.05) and to be negatively correlated with LINC00858 expression. Compared with those in the si-LINC00858 + inhibitor-negative control group, SO-RB50 and Y79 cells of the si-LINC00858 + miR-3182 inhibitor group exhibited a significantly higher relative proliferation, migration and invasion (all P<0.05). In conclusion, LINC00858 promoted RB cell proliferation, migration and invasion, at least partially by inhibiting miR-3182.

19.
Cell Stem Cell ; 25(4): 542-557.e9, 2019 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-31495780

RESUMO

Invariant natural killer T (iNKT) cells are potent immune cells for targeting cancer; however, their clinical application has been hindered by their low numbers in cancer patients. Here, we developed a proof-of-concept for hematopoietic stem cell-engineered iNKT (HSC-iNKT) cell therapy with the potential to provide therapeutic levels of iNKT cells for a patient's lifetime. Using a human HSC engrafted mouse model and a human iNKT TCR gene engineering approach, we demonstrated the efficient and long-term generation of HSC-iNKT cells in vivo. These HSC-iNKT cells closely resembled endogenous human iNKT cells, could deploy multiple mechanisms to attack tumor cells, and effectively suppressed tumor growth in vivo in multiple human tumor xenograft mouse models. Preclinical safety studies showed no toxicity or tumorigenicity of the HSC-iNKT cell therapy. Collectively, these results demonstrated the feasibility, safety, and cancer therapy potential of the proposed HSC-iNKT cell therapy and laid a foundation for future clinical development.


Assuntos
Células-Tronco Hematopoéticas/fisiologia , Imunoterapia Adotiva/métodos , Células T Matadoras Naturais/fisiologia , Neoplasias/terapia , Animais , Células Cultivadas , Engenharia Genética , Humanos , Camundongos , Camundongos SCID , Células T Matadoras Naturais/transplante , Neoplasias/imunologia , Receptores de Antígenos de Linfócitos T/genética , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Int Ophthalmol ; 39(10): 2223-2235, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30607864

RESUMO

OBJECTIVE: To understand the involvement of the mGluR5-mediated JNK signaling pathway in rats with diabetic retinopathy (DR). METHODS: This study established rat models of diabetes mellitus (DM), which were divided into Normal, DM, DM + CHPG (mGluR5 agonist CHPG), and DM + MTEP (mGluR5 antagonist MTEP) groups. The blood glucose and weight of rats were recorded. EB staining was used for observation of blood-retinal barrier (BRB) damage. Neural retina function was measured by pattern electroretinogram (ERG). PAS and NG2 immunohistochemistry were conducted to evaluate the retinal vascular morphology. The TUNEL assay and active caspase-3 immunohistochemistry were performed to detect retinal cell apoptosis. Additionally, the expression levels of superoxide dismutase (SOD) and methylenedioxyamphetamine (MDA) were measured. Moreover, expression levels of mGluR5 and JNK pathway-related proteins were detected by western blot. RESULTS: When compared with control rats, rats in the DM group showed decreased amplitude and latency of the peak times in the ERG test; further, DM group rats presented increases in blood glucose, BRB permeability, a retinal capillary area density, retinal cell apoptosis with an increased number of active caspase-3-positive cells, MDA level, mGluR5 levels, and the ratio of p-JNK/JNK, and they showed reductions in body weight and SOD activity, as well as in the number of pericytes and in the pericyte coverage (all P < 0.05). However, rats in DM + CHPG group had stronger negative effects than those in DM group (all P < 0.05). Rats from DM + MTEP group showed an opposite trend compared with the DM rats (all P < 0.05). CONCLUSION: The level of mGluR5 in DR rats was upregulated, whereas inhibition of mGluR5 alleviated retinal pathological damage and decreased cell apoptosis to improve DR via suppression of the JNK signaling pathway, which provided a scientific theoretical basis for the clinical treatment of DR.


Assuntos
Retinopatia Diabética/fisiopatologia , Sistema de Sinalização das MAP Quinases/fisiologia , Receptor de Glutamato Metabotrópico 5/fisiologia , Animais , Glicemia/metabolismo , Barreira Hematorretiniana/patologia , Diabetes Mellitus Experimental , Retinopatia Diabética/metabolismo , Eletrorretinografia , Masculino , Ratos , Ratos Sprague-Dawley , Receptor de Glutamato Metabotrópico 5/metabolismo , Retina/fisiopatologia , Vasos Retinianos/patologia
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