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1.
Nat Commun ; 12(1): 2487, 2021 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-33941784

RESUMO

ARIEL2 (NCT01891344) is a single-arm, open-label phase 2 study of the PARP inhibitor (PARPi) rucaparib in relapsed high-grade ovarian carcinoma. In this post hoc exploratory biomarker analysis of pre- and post-platinum ARIEL2 samples, RAD51C and RAD51D mutations and high-level BRCA1 promoter methylation predict response to rucaparib, similar to BRCA1/BRCA2 mutations. BRCA1 methylation loss may be a major cross-resistance mechanism to platinum and PARPi. Genomic scars associated with homologous recombination deficiency are irreversible, persisting even as platinum resistance develops, and therefore are predictive of rucaparib response only in platinum-sensitive disease. The RAS, AKT, and cell cycle pathways may be additional modulators of PARPi sensitivity.

2.
Chin Med J (Engl) ; 134(9): 1055-1057, 2021 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-33942800
3.
J Parkinsons Dis ; 2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33935105

RESUMO

BACKGROUND: Neurofilament light (NfL) can reflect the extent of neuron/axon damage, thus providing an opportunity to examine the severity and progression of the diseases with such damage. OBJECTIVE: Whether serum NfL can be used as an indicator to monitor the cognitive progress of de novo Parkinson's disease (PD) remains unclear. METHODS: In this research, 144 healthy controls and 301 de novo PD patients from Parkinson's Progression Markers Initiative (PPMI) were recruited. Linear mixed effects models were used to examine the associations of baseline/longitudinal serum NfL with cognitive decline. Cox regression was used to detect cognitive progression in PD participants. RESULTS: We found PD patients had higher serum NfL than controls at baseline (p = 0.031), and NfL increase was faster in PD group (p < 0.001). Both baseline serum NfL and its rate of change predicted measurable cognitive decline in early PD (MoCA, ß= -0.014, p < 0.001; ß= -0.002, p < 0.001, respectively). Additionally, we observed that NfL levels were also able to predict progression in different diagnostic groups and Amyloid- PD and Amyloid+PD groups. After an average follow-up of 6.37±1.84 years, the baseline NfL of the third tertile of high concentrations was associated with a future high risk of PD dementia (adjusted HR 6.33, 95% CI 2.62-15.29, p < 0.001). CONCLUSION: In conclusion, our results indicated that the serum NfL concentration could function as an easily accessible biomarker to monitor the severity and progression of cognitive decline in PD.

4.
Eur J Med Chem ; 220: 113498, 2021 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-33933756

RESUMO

Upon the basis of both possible ligand-binding site interactions and the uniformity of key residues in active sites, a novel class of HIV-1 PR/RT dual inhibitors was designed and evaluated. Cinnamic acids or phenylpropionic acids with more flexible chain and smaller steric hindrance were introduced into the inhibitors, giving rise to significant improvement in HIV-1 RT inhibitory activity by one or two orders of magnitude, with comparable or even improved potency against PR at the same time, compared with coumarin anologues in our previous studies. Among these inhibitors, 38d displayed a 19-fold improvement in anti-PR activity with IC50 value of 0.081 nM compared to the control DRV. In addition, inhibitor 38c exhibited an excellent anti-RT IC50 value of 0.43 µM, only a 4.7-fold less potent activity than the control EFV. More significantly, the disparate ratio between HIV-1 PR and RT inhibition became more reasonable with ratio of 1: 10.4, just as 37b. Furthermore, the assays on HIV-1 late stage and early stage supported the rationality of designing dual inhibitors. The SAR data as well as molecular modeling studies provided new insight for further optimization of more potent HIV-1 PR/RT dual inhibitors.

5.
Eur J Med Chem ; 220: 113450, 2021 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-33906049

RESUMO

A novel class of HIV-1 protease inhibitors with flexible piperidine as the P2 ligand was designed with the aim of improving extensive interactions with the active subsites. Many inhibitors exhibited good to excellent inhibitory effect on enzymatic activity and viral infectivity. In particular, inhibitor 3a with (R)-piperidine-3-carboxamide as the P2 ligand and 4-methoxybenzenesulfonamide as the P2' ligand showed an enzyme Ki value of 29 pM and antiviral IC50 value of 0.13 nM, more than six-fold enhancement of activity compared to DRV. Furthermore, there was no significant change in potency against DRV-resistant mutations and HIV-1NL4-3 variant for 3a. Besides, inhibitor 3a exhibited potent antiviral activity against subtype C variants with low nanomole EC50 values. In addition, the molecular modeling revealed important hydrogen bonds and other favorable van der Waals interactions with the backbone atoms of the protease and provided insight for designing and optimizing more potent HIV-1 protease inhibitors.

6.
Stem Cell Res ; 53: 102305, 2021 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-33813175

RESUMO

Mental retardation autosomal dominant 7 (MRD7), or DYRK1A Related Intellectual Disability Syndrome (OMIM 614104) is a developmental syndrome with microcephaly, intellectual disability, language delay and epileptic seizures. Haploinsufficiency of DYRK1A is the cause of MRD7. Here, we generated an induced pluripotent stem cell (iPSC) line with the mutation (DYRK1Ac.1730T>A) from the Peripheral blood mononuclear cell (PBMC) of a MRD7 patient along with an isogenic gene-corrected control iPSC line by CRISPR/Cas9 genome editing. Both iPSC lines showed full pluripotency, normal karyotype and differentiation capacity without integrating vectors. These DYRK1A mutant and isogenic gene-corrected iPSC control line provides a useful model to study the underlying molecular mechanisms of MRD7.

7.
Pest Manag Sci ; 2021 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-33908141

RESUMO

BACKGROUND: Gypsy moth (Lymantria dispar) is one of the most important pests in the world. Emamectin benzoate (EMB) is widely used in the control of agricultural and forestry pests. Here, we explored the sublethal effects of EMB on gypsy moths in order to better understand the toxicological mechanism of EMB. RESULTS: The sublethal concentration of EMB exposure significantly decreased the larvae body weight. To further explore the mechanism, indicators related to digestion and nutrient metabolism were detected. The results showed that EMB exposure caused the midgut damage, reduced the activities of digestive enzymes and changed the content of sugar and amino acids. Moreover, the expression of insulin/PI3K/FoxO pathway and sugar metabolism-related genes was abnormal. The expression of insulin receptor (InR), chico, PI3K, and protein kinase B (Akt) significantly reduced, and that of phosphatase and tensin homologue (PTEN) and FoxO increased. The expression of glycogen phosphorylase (GP) was upregulation and that of glycogen synthase (GS), trehalase (TRE) and trehalose-phosphate synthase (TPS) were downregulation. All results indicated that EMB inhibits the growth of gypsy moth by inducing midgut injury, digestive dysfunction and nutrient metabolism disorder. In addition, EMB caused midgut injury maybe related to apoptosis or a collateral effect of the damage in other tissues, and more extensive and deeper researches are still needed to investigate the detailed mechanism. CONCLUSION: Our findings strengthen the understanding of the sublethal effect of EMB, and provide a theoretical basis for the application of EMB in the prevention and control of gypsy moth. This article is protected by copyright. All rights reserved.

8.
JAMA Netw Open ; 4(4): e214103, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33877311

RESUMO

Importance: Elevated expression of AURKA adversely affects prognosis in estrogen receptor (ER)-positive and ERBB2 (formerly HER2)-negative and triple-negative breast cancer and is associated with resistance to taxanes. Objective: To compare paclitaxel alone vs paclitaxel plus alisertib in patients with ER-positive and ERBB2-negative or triple-negative metastatic breast cancer (MBC). Design, Setting, and Participants: In this randomized clinical trial conducted with the US Oncology Network, participants were randomized to intravenous (IV) paclitaxel 90 mg/m2 on days 1, 8, and 15 on a 28-day cycle or IV paclitaxel 60 mg/m2 on days 1, 8, and 15 plus oral alisertib 40 mg twice daily on days 1 to 3, 8 to 10, and 15 to 17 on a 28-day cycle. Stratification was by prior neo or adjuvant taxane and by line of metastatic therapy. Eligible patients were those who had undergone endocrine therapy, 0 or 1 prior chemotherapy regimens for MBC, more than 12 months treatment-free interval from neo or adjuvant taxane therapy, and with measurable or evaluable lytic bone-disease. Data were analyzed from March 2019 through May 2019. Main Outcomes and Measures: The main outcome was progression-free survival (PFS) with secondary end points of overall survival (OS), overall response rate, clinical benefit rate, safety, and analysis of archival breast cancer tissues for molecular markers associated with benefit from alisertib. Results: A total of 174 patients were randomized, including with 86 randomized to paclitaxel and 88 patients randomized to paclitaxel plus alisertib, and 169 patients received study treatment. The final cohort included 139 patients with a median (interquartile range [IQR]) age of 62 (27-84) years with ER-positive and ERBB2-negative MBC, with 70 randomized to paclitaxel and 69 randomized to paclitaxel plus alisertib. The TNBC cohort closed with only 35 patients enrolled due to slow accrual and were not included in efficacy analyses. The median (IQR) follow-up was 22 (10.6-25.1) months, and median (IQR) PFS was 10.2 (3.8-15.7) months with paclitaxel plus alisertib vs 7.1 (3.8-10.6) months with paclitaxel alone (HR, 0.56; 95% CI, 0.37-0.84; P = .005). Median (IQR) OS was 26.3 (12.4-37.2) months for patients who received paclitaxel plus alisertib vs 25.1 (11.0-31.4) months for paclitaxel alone (HR, 0.89; 95% CI, 0.58-1.38; P = .61). Grade 3 or 4 adverse events occurred in 56 patients (84.8%) receiving paclitaxel plus alisertib vs 34 patients (48.6%) receiving paclitaxel alone. The main grade 3 or 4 adverse events with paclitaxel plus alisertib vs paclitaxel alone were neutropenia (50 patients [59.5%] vs 14 patients [16.4%]), anemia (8 patients [9.5%] vs 1 patient [1.2%]), diarrhea (9 patients [10.7%] vs 0 patients), and stomatitis or oral mucositis (13 patients [15.5%] vs 0 patients). One patient receiving paclitaxel plus alisertib died of sepsis. Conclusions and Relevance: This randomized clinical trial found that the addition of oral alisertib to a reduced dose of weekly paclitaxel significantly improved PFS compared with paclitaxel alone, and toxic effects with paclitaxel plus alisertib were manageable with alisertib dose reduction. These data support further evaluation of alisertib in patients with ER-positive, ERBB2-negative MBC. Trial Registration: ClinicalTrials.gov Identifier: NCT02187991.

9.
Signal Transduct Target Ther ; 6(1): 167, 2021 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-33895773

RESUMO

The ongoing 2019 novel coronavirus disease (COVID-19) caused by SARS-CoV-2 has posed a worldwide pandemic and a major global public health threat. The severity and mortality of COVID-19 are associated with virus-induced dysfunctional inflammatory responses and cytokine storms. However, the interplay between host inflammatory responses and SARS-CoV-2 infection remains largely unknown. Here, we demonstrate that SARS-CoV-2 nucleocapsid (N) protein, the major structural protein of the virion, promotes the virus-triggered activation of NF-κB signaling. After binding to viral RNA, N protein robustly undergoes liquid-liquid phase separation (LLPS), which recruits TAK1 and IKK complex, the key kinases of NF-κB signaling, to enhance NF-κB activation. Moreover, 1,6-hexanediol, the inhibitor of LLPS, can attenuate the phase separation of N protein and restrict its regulatory functions in NF-κB activation. These results suggest that LLPS of N protein provides a platform to induce NF-κB hyper-activation, which could be a potential therapeutic target against COVID-19 severe pneumonia.


Assuntos
/metabolismo , NF-kappa B/metabolismo , RNA Viral/metabolismo , Transdução de Sinais , Células A549 , Acrilatos/farmacologia , Animais , /patologia , Chlorocebus aethiops , Células HEK293 , Células HeLa , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Fosfoproteínas/metabolismo , Células Vero
10.
Exp Lung Res ; 47(5): 250-259, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33896314

RESUMO

Purpose: To delve into the related molecular mechanism of ACTL6A on non-small cell lung cancer (NSCLC) cell growth and apoptosis.Methods: Quantitative real-time polymerase chain reaction, immunohistochemical staining, and western blot assays were employed to examine ACTL6A mRNA and protein expression in four NSCLC cell line (NCI-H2170, LTEP-s, NCI-H1703, and PC-9) and normal lung cell line (BEAS-2B). CCK-8 cell viability assays and clone formation assay were applied to verify the cell proliferation of NCI-H2170 cell line after knockdown of ACTL6A. Flow cytometry assays were applied to check the role of ACTL6A in the apoptosis of NSCLC cells. The western blot assays were employed to examine the protein expression of WWC1, YAP, TAZ, and CYR61 in NCI-H2170 after knockdown of ACTL6A. Finally, xenograft tumor was taken out and checked the tumor volumes and weight. Immunohistochemical staining and western blot assays were employed to examine cell proliferation and apoptosis of NSCLC in vivo.Results: In this study, the results showed that the mRNA and protein expression level of ACTL6A was higher in four NSCLC cell line than normal lung cell line, respectively. Suppression of ACTL6A inhibited the growth and promoted apoptosis of NSCLC cells. Meanwhile, ACTL6A promotes tumor growth and inhibits apoptosis of NSCLC in vivo via Hippo/YAP signaling pathway.Conclusion: ACTL6A promotes the proliferation in NSCLC by regulating Hippo/YAP pathway.

11.
Medicine (Baltimore) ; 100(16): e25569, 2021 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-33879714

RESUMO

BACKGROUND: Studies comparing data between the high-power short-duration radiofrequency (HPSR) and low power longer duration therapy were limited and inconsistent. Therefore, we conduct a high-quality systematic review and meta-analysis to assess the efficacy and safety of HPSR on outcomes for patients with atrial fibrillation (AF). METHODS: The online literature is searched using the following combination of medical subject heading terms: "high-power" OR "high power" AND "radiofrequency" AND "atrial fibrillation." MEDLINE (PubMed), EMBASE (OVID), Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science (ISI database) will be searched without any language restrictions. All clinical trials to assess the efficacy and safety of HPSR in the treatment of atrial fibrillation will be considered eligible for analysis. The present study will be performed by Review Manager Software (RevMan Version 5.3, The Cochrane Collaboration, Copenhagen, Denmark). Ethical approval and patient consent are not required because this study is a literature-based study. RESULTS: This study expects to provide credible and scientific evidence for the efficacy and safety of HPSR on outcomes for patients with AF. REGISTRATION NUMBER: 10.17605/OSF.IO/WAEBN.


Assuntos
Fibrilação Atrial/cirurgia , Ablação por Radiofrequência/métodos , Ensaios Clínicos como Assunto , Humanos , Metanálise como Assunto , Projetos de Pesquisa , Revisões Sistemáticas como Assunto , Resultado do Tratamento
12.
Biochem Biophys Res Commun ; 555: 182-189, 2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-33823364

RESUMO

Autophagy and apoptosis, as major modes of cell death, play critical roles in cellular homeostasis. Our previous study demonstrated that the cross-talk between autophagy and apoptosis regulated cadmium-induced testicular injury and self-recovery, influencing male fertility. However, the underlying mechanism remains blurry. Herein, our subfertility rat model indicated that cadmium-induced autophagy and apoptosis were ameliorated by the activation of SIRT3 and blunted by the inhibition of SIRT3 in rat testis. Further, generating SIRT3 overexpression and knockdown models in TM3 mouse Leydig cells, we found that melatonin (SIRT3 activator) and overexpression of SIRT3 rescued cadmium-induced autophagy and apoptosis in TM3 cells. Knockdown of SIRT3 induced autophagy and apoptosis, which failed to be reversed by melatonin in TM3 cells. Taken together, SIRT3 functions as a pivotal protective factor in testicular Leydig cells injury, and melatonin regulates the cross-talk between autophagy and apoptosis by SIRT3, ameliorating cadmium-induced testicular injury.

13.
Antiviral Res ; 190: 105078, 2021 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-33894278

RESUMO

Antiviral therapeutics is one effective avenue to control and end this devastating COVID-19 pandemic. The viral RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 has been recognized as a valuable target of antivirals. However, the cell-free SARS-CoV-2 RdRp biochemical assay requires the conversion of nucleotide prodrugs into the active triphosphate forms, which regularly occurs in cells yet is a complicated multiple-step chemical process in vitro, and thus hinders the utility of this cell-free assay in the rapid discovery of RdRp inhibitors. In addition, SARS-CoV-2 exoribonuclease provides the proof-reading capacity to viral RdRp, thus creates relatively high resistance threshold of viral RdRp to nucleotide analog inhibitors, which must be examined and evaluated in the development of this class of antivirals. Here, we report a cell-based assay to evaluate the efficacy of nucleotide analog compounds against SARS-CoV-2 RdRp and assess their tolerance to viral exoribonuclease-mediated proof-reading. By testing seven commonly used nucleotide analog viral polymerase inhibitors, Remdesivir, Molnupiravir, Ribavirin, Favipiravir, Penciclovir, Entecavir and Tenofovir, we found that both Molnupiravir and Remdesivir showed the strong inhibition of SARS-CoV-2 RdRp, with EC50 value of 0.22 µM and 0.67 µM, respectively. Moreover, our results suggested that exoribonuclease nsp14 increases resistance of SARS-CoV-2 RdRp to nucleotide analog inhibitors. We also determined that Remdesivir presented the highest resistance to viral exoribonuclease activity in cells. Therefore, we have developed a cell-based SARS-CoV-2 RdRp assay which can be deployed to discover SARS-CoV-2 RdRp inhibitors that are urgently needed to treat COVID-19 patients.

14.
Inflammopharmacology ; 2021 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-33797658

RESUMO

BACKGROUND: This study aimed to compare the efficiency regarding postoperative pain control, consumption of rescue drug, patients' satisfaction and the safety of preoperative analgesia versus postoperative analgesia using non-steroidal anti-inflammatory drugs (NSAIDs) in patients who received arthroscopic knee surgery (AKS). METHODS: Four hundred and sixty-four patients who received AKS were recruited in this multicenter, randomized, controlled study. Subsequently, they were randomized into PRE group (N = 232) and POST group (N = 232). In PRE group, patients received celecoxib, meloxicam or rofecoxib from 2 h pre-operation (Pre (- 2 h)) to 48 h post-operation for analgesia. In POST group, patients received celecoxib, meloxicam or rofecoxib from 4 to 48 h post-operation for analgesia. RESULTS: h and 12 h; pain VAS at passive movement was reduced in PRE group than POST group at 6 h, 12 h and 24 h. Additionally, consumption of rescue drug (pethidine) was decreased, while overall satisfaction was increased in PRE group compared to POST group. As for adverse events, the incidences of nausea, vomiting, constipation, drowsiness and dizziness were similar between PRE group and POST group. In subgroup analysis, the pain VAS score at passive movement at 6 h and nausea and constipation incidences were distinctive among subgroups categorized by meloxicam, celecoxib and rofecoxib administration. However, no difference of other assessments was found among subgroups categorized by meloxicam, celecoxib and rofecoxib administration. CONCLUSION: Preoperative analgesia using NSAIDs is more efficient and equivalently tolerable compared to postoperative analgesia using NSAIDs in patients who receive AKS.

15.
Cell Rep ; 34(9): 108802, 2021 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-33657377

RESUMO

Human brain development is a complex process involving neural proliferation, differentiation, and migration that are directed by many essential cellular factors and drivers. Here, using the NetBID2 algorithm and developing human brain RNA sequencing dataset, we identify synaptotagmin-like 3 (SYTL3) as one of the top drivers of early human brain development. Interestingly, SYTL3 exhibits high activity but low expression in both early developmental human cortex and human embryonic stem cell (hESC)-derived neurons. Knockout of SYTL3 (SYTL3-KO) in human neurons or knockdown of Sytl3 in embryonic mouse cortex markedly promotes neuronal migration. SYTL3-KO causes an abnormal distribution of deep-layer neurons in brain organoids and reduces presynaptic neurotransmitter release in hESC-derived neurons. We further demonstrate that SYTL3-KO-accelerated neuronal migration is modulated by high expression of matrix metalloproteinases. Together, based on bioinformatics and biological experiments, we identify SYTL3 as a regulator of cortical neuronal migration in human and mouse developing brains.

16.
Virol Sin ; 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33723808

RESUMO

The CREB-regulated transcriptional co-activators (CRTCs), including CRTC1, CRTC2 and CRTC3, enhance transcription of CREB-targeted genes. In addition to regulating host gene expression in response to cAMP, CRTCs also increase the infection of several viruses. While human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR) promoter harbors a cAMP response element and activation of the cAMP pathway promotes HIV-1 transcription, it remains unknown whether CRTCs have any effect on HIV-1 transcription and HIV-1 infection. Here, we reported that CRTC2 expression was induced by HIV-1 infection, but CRTC2 suppressed HIV-1 infection and diminished viral RNA expression. Mechanistic studies revealed that CRTC2 inhibited transcription from HIV-1 LTR and diminished RNA Pol II occupancy at the LTR independent of its association with CREB. Importantly, CRTC2 inhibits the activation of latent HIV-1. Together, these data suggest that in response to HIV-1 infection, cells increase the expression of CRTC2 which inhibits HIV-1 gene expression and may play a role in driving HIV-1 into latency.

17.
Cell Mol Neurobiol ; 2021 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-33694132

RESUMO

Tumor necrosis factor receptor-associated factor 6 (TRAF6) has been reported to be expressed in spinal astrocytes and is involved in neuropathic pain. In this study, we investigated the role and mechanism of TRAF6 in complete Freund's adjuvant (CFA)-evoked chronic inflammatory hypersensitivity and the effect of docosahexaenoic acid (DHA) on TRAF6 expression and inflammatory pain. We found that TRAF6 was dominantly increased in microglia at the spinal level after intraplantar injection of CFA. Intrathecal TRAF6 siRNA alleviated CFA-triggered allodynia and reversed the upregulation of IBA-1 (microglia marker). In addition, intrathecal administration of DHA inhibited CFA-induced upregulation of TRAF6 and IBA-1 in the spinal cord and attenuated CFA-evoked mechanical allodynia. Furthermore, DHA prevented lipopolysaccharide (LPS)-caused increase of TRAF6 and IBA-1 in both BV2 cell line and primary cultured microglia. Finally, intrathecal DHA reduced LPS-induced upregulation of spinal TRAF6 and IBA-1, and alleviated LPS-induced mechanical allodynia. Our findings indicate that TRAF6 contributes to pain hypersensitivity via regulating microglial activation in the spinal dorsal horn. Direct inhibition of TRAF6 by siRNA or indirect inhibition by DHA may have therapeutic effects on chronic inflammatory pain.

18.
Clin Exp Rheumatol ; 2021 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-33734971

RESUMO

OBJECTIVES: To identify valuable ultrasonography findings combined with clinical markers for predicting carotid progression of Takayasu's arteritis (TAK) on imaging during a 1-year follow-up period. METHODS: From May 2016 to June 2019, 77 Chinese TAK patients with carotid artery involvement were enrolled in the present study. The patients' clinical characteristics and serological test and carotid ultrasonography results were recorded at baseline and each visit. Carotid progression was evaluated by ultrasonography every 3 months during the 1-year follow-up. Baseline clinical characteristics and ultrasonography results for predicting progression on imaging were identified. RESULTS: Sixteen (20.8%) patients presented with carotid progression on imaging during the 1-year follow-up period. The patients in the progressive group were younger (23.4±3.7 vs. 32.3±9.8 years, p<0.01) than those in the non-progressive group. At baseline, the vessel wall was thicker in the progressive group than in the non-progressive group (2.4±0.8 vs. 1.9±0.5 mm, p=0.041). Furthermore, the proportion of patients with refractory disease (87.5% vs. 16.4%, p<0.01) was higher in the progressive group than in the non-progressive group. Patients with a thickened carotid wall (≥1.9 mm), refractory disease, and younger age (≤30 years) might be at a high risk of carotid progression on imaging (75%, AUC: 0.93, sensitivity: 75%, specificity: 93.4%). CONCLUSIONS: Younger patients with early vascular structural changes at baseline as well as refractory disease seemed more likely to show carotid progression on imaging.

19.
Gynecol Oncol ; 2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-33752918

RESUMO

OBJECTIVE: To evaluate correlations between rucaparib exposure and selected efficacy and safety endpoints in patients with recurrent ovarian carcinoma using pooled data from Study 10 and ARIEL2. METHODS: Efficacy analyses were limited to patients with carcinomas harboring a deleterious BRCA1 or BRCA2 mutation who had received ≥2 prior lines of chemotherapy. Safety was evaluated in all patients who received ≥1 rucaparib dose. Steady-state daily area under the concentration-time curve (AUCss) and maximum concentration (Cmax,ss) for rucaparib were calculated for each patient and averaged by actual dose received over time (AUCavg,ss and Cmax,avg,ss) using a previously developed population pharmacokinetic model. RESULTS: Rucaparib exposure was dose-proportional and not associated with baseline patient weight. In the exposure-efficacy analyses (n = 121), AUCavg,ss was positively associated with independent radiology review-assessed RECIST response in the subgroup of patients with platinum-sensitive recurrent disease (n = 75, p = 0.017). In the exposure-safety analyses (n = 393, 40 mg once daily to 840 mg twice daily [BID] starting doses), most patients received a 600 mg BID rucaparib starting dose, with 27% and 21% receiving 1 or ≥2 dose reductions, respectively. Cmax,ss was significantly correlated with grade ≥2 serum creatinine increase, grade ≥3 alanine transaminase/aspartate transaminase increase, platelet decrease, fatigue/asthenia, and maximal hemoglobin decrease (p < 0.05). CONCLUSION: The exposure-response analyses provide support for the approved starting dose of rucaparib 600 mg BID for maximum clinical benefit with subsequent dose modification only following the occurrence of a treatment-emergent adverse event in patients with BRCA-mutated recurrent ovarian carcinoma.

20.
Int J Mol Sci ; 22(4)2021 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-33671452

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a fatal and age-related pulmonary disease. Nintedanib is a receptor tyrosine kinase inhibitor, and one of the only two listed drugs against IPF. Regorafenib is a novel, orally active, multi-kinase inhibitor that has similar targets to nintedanib and is applied to treat colorectal cancer and gastrointestinal stromal tumors in patients. In this study, we first identified that regorafenib could alleviate bleomycin-induced pulmonary fibrosis in mice. The in vivo experiments indicated that regorafenib suppresses collagen accumulation and myofibroblast activation. Further in vitro mechanism studies showed that regorafenib inhibits the activation and migration of myofibroblasts and extracellular matrix production, mainly through suppressing the transforming growth factor (TGF)-ß1/Smad and non-Smad signaling pathways. In vitro studies have also indicated that regorafenib could augment autophagy in myofibroblasts by suppressing TGF-ß1/mTOR (mechanistic target of rapamycin) signaling, and could promote apoptosis in myofibroblasts. In conclusion, regorafenib attenuates bleomycin-induced pulmonary fibrosis by suppressing the TGF-ß1 signaling pathway.


Assuntos
Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/metabolismo , Compostos de Fenilureia/uso terapêutico , Piridinas/uso terapêutico , Transdução de Sinais , Fator de Crescimento Transformador beta1/metabolismo , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Bleomicina , Movimento Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células NIH 3T3 , Compostos de Fenilureia/farmacologia , Piridinas/farmacologia , Proteínas Smad/metabolismo , Serina-Treonina Quinases TOR/metabolismo
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