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1.
Nano Lett ; 2021 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-34061545

RESUMEN

Forming olivine-structured Li(Mn,Fe)PO4 solid solution is theoretically a feasible way to improve the energy density of the solid solutions for lithium ion batteries. However, the Jahn-Teller active Mn3+ in the solid solution restricts their energy density and rate performance. Here, as demonstrated by operando X-ray diffraction, we show that equimolar LiMn0.5Fe0.5PO4 solid solution nanocrystals undergo a single-phase transition during the whole (de)lithiation process, with a feature of zero lithium miscibility gap, which endows the nanocrystals with excellent electrochemical properties. Specifically, the energy density of LiMn0.5Fe0.5PO4 reaches 625 Wh kg-1, which is 16% higher than that of LiFePO4. Moreover, the high-performance LiMn0.5Fe0.5PO4 nanocrystals are prepared by a microwave-assisted hydrothermal synthesis in pure water.

2.
Artículo en Inglés | MEDLINE | ID: mdl-34061727

RESUMEN

Montan resin (MR) is an industrial by-product or solid waste generated during the production of refined montan wax and is not typically reused. In this paper, a bio-modification method using three strains of microorganisms, Acinetobacter venetianus (AV), Pseudomonas aeruginosa (PA), and Phanerochaete chrysosporium (PC), was studied to promote the performance and bio-function of MR so that MR could be recycled. MR can be degraded by these three microorganisms, and their weight loss rates were similar over the treatment period of 15 days. Compared with the original MR, the hydrophilicity of modified MRs was improved, which was related to the increase in apparent oil-water partition coefficients (Kows) and oxygen-containing and hydrophilic groups in modified MRs based on IR and GC-MS analysis. The bio-function of modified MRs by the three strains in terms of promoting maize seed germination and seedling growth was greater compared with untreated MR. Overall, these findings indicate that biomodified MRs might have useful agriculture applications.

3.
Talanta ; 232: 122499, 2021 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-34074451

RESUMEN

In this work, ZnO nanorods (ZnO NRs) with different sizes were hydrothermally grown on the surface of Whatman filter paper for the fabrication of a microfluidic paper-based device (µPAD) for the simultaneous detection of glucose and uric acid. As dual enzymatic reaction was employed for the colorimetric detection in this µPAD, the presence of ZnO NRs promoted the enzyme immobilization thus significantly enhancing the colorimetric signal. The coffee ring effect was effectively conquered by the uniform distribution of ZnO NR as well as a specialized double-layered µPAD design. Meanwhile, two color indicators with distinct colors were used to provide complementary results to better quantify the concentration of the analytes by naked eye. As a result, two linear calibration curves were obtained for the detection of glucose (0.01-10 mmol L-1) and uric acid (0.01-5 mmol L-1), along with a LOD of 3 µmol L-1 for glucose and 4 µmol L-1 for uric acid, respectively. The practical usefulness of the proposed µPAD was further validated by the simultaneous analysis of glucose and uric acid in serum samples and urine samples.


Asunto(s)
Técnicas Analíticas Microfluídicas , Nanotubos , Óxido de Zinc , Microfluídica , Papel
4.
Nature ; 2021 Jun 02.
Artículo en Inglés | MEDLINE | ID: mdl-34079125

RESUMEN

Compartmentalization is a defining characteristic of eukaryotic cells, and partitions distinct biochemical processes into discrete subcellular locations. Microscopy1 and biochemical fractionation coupled with mass spectrometry2-4 have defined the proteomes of a variety of different organelles, but many intracellular compartments have remained refractory to such approaches. Proximity-dependent biotinylation techniques such as BioID provide an alternative approach to define the composition of cellular compartments in living cells5-7. Here we present a BioID-based map of a human cell on the basis of 192 subcellular markers, and define the intracellular locations of 4,145 unique proteins in HEK293 cells. Our localization predictions exceed the specificity of previous approaches, and enabled the discovery of proteins at the interface between the mitochondrial outer membrane and the endoplasmic reticulum that are crucial for mitochondrial homeostasis. On the basis of this dataset, we created humancellmap.org as a community resource that provides online tools for localization analysis of user BioID data, and demonstrate how this resource can be used to understand BioID results better.

5.
J Adolesc Health ; 2021 May 28.
Artículo en Inglés | MEDLINE | ID: mdl-34059425

RESUMEN

PURPOSE: The objective of this study was to evaluate the feasibility and acceptability of a dynamic, behavioral intervention to optimize medication adherence of adolescents and young adults (AYAs) with HIV newly initiating highly active antiretroviral therapy (HAART) and explore its efficacy on adherence and disease outcomes. METHODS: The two-arm randomized controlled trial piloted a brief, individualized intervention designed for direct integration into standard clinical care. In total, 32 AYAs with a confirmed HIV diagnosis, reportedly horizontally acquired, and recommended to initiate HAART completed a two-week placebo trial before HAART initiation and were subsequently randomized to standard of care or the individualized intervention. Adherence and disease outcomes were measured over the first six months of HAART. RESULTS: Results supported the primary study aim regarding feasibility (recruitment = 89%, attendance = 81%-100%, intervention exercise completion = 100%) and acceptability (average favorable response = 89%). Data also supported the positive effect of the intervention on select HAART adherence measures and disease outcomes. Adherence (by pharmacy refill) declined in both groups; however, adherence declined more slowly in the intervention group versus standard of care (p < .001). In addition, 100% of participants receiving the intervention obtained an undetectable viral load by 3 months and maintained an undetectable viral load at 6 months (vs. 68.8% standard of care). CONCLUSIONS: This is one of the first interventions to target adherence for AYAs with HIV newly initiating HAART and designed for delivery in existing clinical care settings. Future research will help confirm efficacy and the potential utility of the intervention in promoting HAART adherence from medication initiation and preventing the decrease in adherence often observed over time.

6.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(6): 513-520, 2021 Jun 10.
Artículo en Chino | MEDLINE | ID: mdl-34096016

RESUMEN

The use of whole exome sequencing (WES) for the detection of disease-causing variants of genetic diseases and for non-invasive prenatal screening (NIPS) of fetal aneuploidies are two major clinical applications of next generation sequencing (NGS). This article has summarized the official documents developed and updated by the American College of Medical Genetics and Genomics (ACMG) on governing WES and NIPS. These include the development of expert consensus policies and position statements on an ongoing basis to guide clinical application of NGS technology and variant analysis, establish evidence-based practical resources, as well as standards and guidelines to govern diagnosis and screening. These ACMG documents are valuable references to Chinese geneticists, but direct adoption of these standards and guidelines may not be practical due to the differences in disease-associated variant frequencies in Chinese population, socioeconomic status, and medical practice between the two countries. It is hoped that this review could facilitate the development of NGS and NIPS standards and guidelines that are consistent with international standards and concordant with medical genetics practice in China to provide high-quality, efficient and safe clinical services for patients and their families with genetic diseases.


Asunto(s)
Genómica , Secuenciación de Nucleótidos de Alto Rendimiento , China , Consenso , Femenino , Humanos , Embarazo , Tecnología , Estados Unidos
7.
Zhongguo Yi Liao Qi Xie Za Zhi ; 45(3): 315-320, 2021 Jun 08.
Artículo en Chino | MEDLINE | ID: mdl-34096244

RESUMEN

OBJECTIVE: Discuss the working ideas of the dynamic adjustment mechanism of medical device classification in the United States, and provide reference for the construction of medical device related mechanisms in China. METHODS: Collect and interpret the documents of regulatory background, procedures and orders of the dynamic adjustment mechanism of the medical device classification in the United States, and summarize the overall situation and specific cases of the medical device classification adjustment under this mechanism in recent years. RESULTS: The US work idea of the medical device classification dynamic adjustment mechanism is based on the latest valid scientific evidence, conducting risk analysis and identification, and determining the corresponding measures. CONCLUSIONS: During the adjustment process, industry stakeholders have repeatedly discussed and achieved final agreement. Its procedures and working ideas can be used as a reference for China's work.


Asunto(s)
United States Food and Drug Administration , China , Estados Unidos
9.
Chem Commun (Camb) ; 2021 Jun 07.
Artículo en Inglés | MEDLINE | ID: mdl-34096940

RESUMEN

Through a bottom-up strategy, CdS quantum dots (QDs) doped with 12 gold atoms in each nanocrystal (NC) were prepared by cation exchange reactions. The (Au12) dopants inside the CdS matrix were directly observed using Cs-corrected high-angle annular dark-field scanning transmission electron microscopy (HAADF-STEM) images and quantitatively confirmed using the inductively coupled plasma atomic emission spectroscopy (ICP-AES) data. With a photoluminescence quantum yield (PLQY) of 37.5%, the as-prepared (Au12)@CdS QDs emitted light at 635 nm. Due to the injection of excited electrons from the lowest unoccupied molecular orbital (LUMO) of dopants to the conduction band (CB) of CdS, multiple fine peaks were observed in the photoluminescence excitation (PLE) spectra. By using clusters as starting materials, we demonstrate a universal approach for the precise tailoring of dopants and provide a pathway for band energy engineering of doped QDs.

10.
Front Immunol ; 12: 664787, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34093557

RESUMEN

Tuberculosis remains a major health problem. Mycobacterium tuberculosis, the causative agent of tuberculosis, can replicate and persist in host cells. Noncoding RNAs (ncRNAs) widely participate in various biological processes, including Mycobacterium tuberculosis infection, and play critical roles in gene regulation. In this review, we summarize the latest reports on ncRNAs (microRNAs, piRNAs, circRNAs and lncRNAs) that regulate the host response against Mycobacterium tuberculosis infection. In the context of host-Mycobacterium tuberculosis interactions, a broad and in-depth understanding of host ncRNA regulatory mechanisms may lead to potential clinical prospects for tuberculosis diagnosis and the development of new anti-tuberculosis therapies.

11.
Bioengineered ; 12(1): 2364-2376, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-34098829

RESUMEN

Fluoxetine is used to improve cognition, exercise ability, depression, and neurological functions in patients with cerebral ischemic stroke. Circular RNAs (circRNAs) play important regulatory roles in multiple diseases. However, studies regarding the fluoxetine-mediated circRNA-microRNA-messenger RNA (mRNA) axis have not been conducted. This study is aim to investigate the functions of fluoxetine and identification of fluoxetine-mediated circRNAs and mRNAs in cerebral ischemic stroke. The middle cerebral artery occlusion (MCAO) rat models were successfully established at fisrt, and then rats were intraperitoneally injected with 10-mg/kg fluoxetine hydrochloride for 14 d. Afterward, the cerebral infarction area was evaluated using triphenyltetrazolium chloride staining. High-throughput sequencing was adopted to screen the differential circRNAs and mRNAs. The candidate circRNAs, mRNAs, and potential microRNAs were verified using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). In addtion, microRNA and circRNA binding was verified using the dual-luciferase reporter assay. Results revealed that fluoxetine markedly diminished the cerebral infarction area in rats after MCAO. The circRNAs and mRNAs were differentially expressed, which includes 879 circRNAs and 815 mRNAs between sham and MCAO groups, respectively, and 958 circRNAs and 838 mRNAs between MCAO and fluoxetine groups, respectively. In which, circMap2k1 and Pidd1 expression was significantly increased in the MCAO group but suppressed after fluoxetine treatment. Moreover, circMap2k1 directly binds with miR-135b-5p. Taken together, we verified that fluoxetine could improve brain injury after cerebral ischemic stroke. Moreover, the circMap2k1/miR-135b-5p/Pidd1 axis is potentially involved in cerebral ischemic stroke.

12.
Int J Clin Oncol ; 2021 Jun 04.
Artículo en Inglés | MEDLINE | ID: mdl-34086111

RESUMEN

BACKGROUND: Non-coding RNAs have emerged as important regulators in human cancers. In this work, we investigated the role of long intergenic non-protein-coding RNA 943 (LINC00943) in gastric cancer (GC). METHODS: LINC00943 expression was evaluated in GC patient tissues and cell lines. In SNU-5 and MKN-45 cells, LINC00943 was knocked down to investigate its roles in regulating GC cell proliferation, 5-FU chemosensitivity and in vivo explant growth. Possible downstream target of LINC00943, human mature microRNA-101-3p (hsa-miR-101-3p) was also evaluated. RESULTS: LINC00943 was aberrantly overexpressed in in situ GC tumors and immortal GC cell lines. LINC00943 overexpression was associated with GC patients' poor prognosis. LINC00943 knockdown reduced GC cell proliferation, 5-FU resistance and in vivo explant growth. Hsa-miR-101-3p was found to be regulated by LINC00943 in GC. Hsa-miR-101-3p downregulation reversed the tumor-suppressing functions of LINC00943 knockdown in GC cells. CONCLUSION: In summary, our results indicated that LINC00943 was correlated with gastric cancer and regulates cancer cell proliferation and chemosensitivity via hsa-miR-101-3p.

13.
J Food Biochem ; : e13752, 2021 Jun 04.
Artículo en Inglés | MEDLINE | ID: mdl-34086366

RESUMEN

Fructus Gardeniae (FG) is medicine food widely used for the treatment and prevention of various diseases. However, in recent years, research has suggested that high doses of FG can cause hepatotoxicity and nephrotoxicity. To assess this potential toxicity in more depth, this study investigated the effects of decocted FG and two of its bioactive constituents (geniposide and genipin) on liver and kidney function in rats. Rats were intragastrically administered FG (330 mg/kg body weight), geniposide (50 mg/kg body weight), or genipin (50 mg/kg body weight) for 12 weeks. Changes in body weight, liver and kidney indices, biochemical indices, and inflammatory factors were monitored. In addition, pathological sections were assessed and the expression of caspase-3, NF-κBp65, COX-2, and iNOS was detected by immunohistochemistry and Western blot. It was found that the levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, creatinine, and urea nitrogen increased following administration of FG, geniposide, and genipin. Furthermore, the activities of superoxide dismutase and reduced glutathione decreased following treatment, while malondialdehyde levels increased. Pathological and immunohistochemical evaluations further confirmed that FG and its constituents may cause damage to the liver and kidneys. The mechanism study revealed that the protein level of inflammatory pathway increased and further promoted apoptosis, suggesting that it should not be taken orally for extended periods of time. PRACTICAL APPLICATIONS: Chinese medicine and food safety have always been public health concerns. Fructus Gardeniae (FG) is a plant with a dual-purpose as it is used as both a medicine and food. Medicinally, it has the effects of heat-clearing and detoxification. However, its adverse effects and related mechanisms are not clear, and this has potential safety implications. In this study, rats were treated with FG for 12 weeks and found that the long-term administration of FG or high dosing can lead to damage to liver and kidney function. Therefore, close attention must be paid to the dosage of FG in order to achieve a therapeutic effect and avoid adverse reactions. Thus, this study lays a foundation for the safety evaluation and clinical application of FG.

14.
Glob Chang Biol ; 2021 Jun 06.
Artículo en Inglés | MEDLINE | ID: mdl-34091981

RESUMEN

Methane (CH4 ) emissions from northern peatlands are projected to increase due to climate change, primarily because of projected increases in soil temperature. Yet, the rates and temperature responses of the two CH4 emission-related microbial processes (CH4 production by methanogens and oxidation by methanotrophs) are poorly known. Further, peatland sites within a fen-bog gradient are known to differ in the variables that regulate these two mechanisms, yet the interaction between peatland type and temperature lacks quantitative understanding. Here, we investigated potential CH4 production and oxidation rates for 14 peatlands in Finland located between c. 60 and 70 °N latitude, representing bogs, poor fens and rich fens. Potentials were measured at three different temperatures (5, 17.5 and 30 °C) using the laboratory incubation method. We linked CH4 production and oxidation patterns to their methanogen and methanotroph abundance, peat properties, and plant functional types. We found that the rich fen-bog gradient related nutrient availability and methanogen abundance increased the temperature response of CH4 production, with rich fens exhibiting the greatest production potentials. Oxidation potential showed a steeper temperature response than production, which was explained by aerenchymous plant cover, peat water holding capacity, peat nitrogen and sulphate content. The steeper temperature response of oxidation suggests that, at higher temperatures, CH4 oxidation might balance increased CH4 production. Predicting net CH4 fluxes as an outcome of the two mechanisms is complicated due to their different controls and temperature responses. The lack of correlation between field CH4 fluxes and production/oxidation potentials, and the positive correlation with aerenchymous plants points towards the essential role of CH4 transport for emissions. The scenario of drying peatlands under climate change, which is likely to promote Sphagnum-establishment over brown mosses in many places, will potentially reduce the predicted warming-related increase in CH4 emissions by shifting rich fens to Sphagnum-dominated systems.

15.
Artículo en Inglés | MEDLINE | ID: mdl-34092625

RESUMEN

Hyperthyroidism is a common disease mainly manifested by hyperexcitability of multiple systems and hypermetabolism. Currently, antithyroid drugs (ATDs), radioiodine therapy (RIT), and surgery are mainly used in the clinical treatment for primary hyperthyroidism. We reported a case of a 28-year-old female who received a novel treatment for primary hyperthyroidism. This patient had poor control of thyroid function while taking ATD, and her oral Methimazole (MMI) dose varied repeatedly between 20 mg qd and 15 mg qd, failing to maintain a stable status. To minimize the possible complication and to achieve drug reduction or withdrawal, she refused RIT and surgery and showed up in our department. The patient, diagnosed with Graves' disease (GD) and met the surgical indication after systematic clinical evaluation, was subject to ultrasound-guided percutaneous microwave ablation (MWA) of the partial thyroid gland with continuous oral administration of 20 mg qd MMI. The post-ablation condition was stable and the patient was discharged 2 days after the operation. Thyroid ultrasound and serum thyroid function test were examined regularly after ablation and the MMI dosage was gradually reduced according to the results of the biochemical examination. Five weeks after the operation, the patient completely discontinued the medication. Ultrasound-guided percutaneous microwave ablation is minimally invasive, safe, and effective, and has potential to be an alternative treatment besides the 3 classical treatments of hyperthyroidism.

16.
Adv Healthc Mater ; : e2100546, 2021 Jun 03.
Artículo en Inglés | MEDLINE | ID: mdl-34081401

RESUMEN

Herein, a collaborative precise antibacterial wound healing therapy nanoplatform integrating drug-food homologous bioactive molecule (cinnamaldehyde, CA) with photothermal therapy (PTT) is presented. Copper-gallic acids-cinnamaldehyde-polydopamine nanorods (Cu-GA-CA-PDA NRs) with near-infrared light (NIR)-controlled CA release property are fabricated, which also integrate CA and photothermal synergistic sterilization, as well as antioxidant, anti-inflammatory, and anti-infection capacities. The characteristics of NIR-mediated CA release and photothermal response of Cu-GA-CA-PDA NRs support their excellent sterilization performance in vitro/in vivo. In addition, under the guidance of NIR, Cu-GA-CA-PDA NRs can hinder the formation of inflammatory cells, reduce oxidative stress damage, accelerate the regeneration of skin tissues in S. aureus-infected wound sites, and achieve the goal of promoting wound healing. Therefore, NIR-mediated Cu-GA-CA-PDA NRs with multifunctional biological activities provide a highly competitive strategy for curing bacteria-infected wounds.

17.
Shanghai Kou Qiang Yi Xue ; 30(2): 201-205, 2021 Apr.
Artículo en Chino | MEDLINE | ID: mdl-34109363

RESUMEN

PURPOSE: The objective of this study was to detect and analyze the existence of differential metabolites from saliva of patients with oral squamous cell carcinoma(OSCC) by metabonomics method, and to evaluate its application value on clinical diagnosis or screening of OSCC. METHODS: The collected saliva samples for OSCC patients, oral leukoplakiac(OLK) patients who were pathologically diagnosed and met the inclusion criteria were analyzed using metabonomics methods (GC-TOF-MS). The results were analyzed by principal component analysis and orthogonal partial least squares discriminant analysis using SIMCA software. RESULTS: The metabolic profiles of OSCC, OLK and healthy control group showed significant differences (P<0.05). In total, 15 typical differential metabolites among the three groups were detected. Further study focusing on metabolic pathway revealed imbalance of protein, energy and lipid metabolism between OSCC and OLK patients. Abnormal tricarboxylic acid cycle was detected as well. CONCLUSIONS: Metabonomics methods is feasible for differential metabolites analysis,15 differential metabolites were detected in OSCC,OLK patients and healthy people. These findings will contribute to the early screening of oral squamous cell carcinoma.


Asunto(s)
Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Neoplasias de la Boca , Biomarcadores de Tumor , Humanos , Leucoplasia Bucal , Metabolómica , Saliva , Carcinoma de Células Escamosas de Cabeza y Cuello
18.
J Exp Bot ; 2021 Jun 11.
Artículo en Inglés | MEDLINE | ID: mdl-34115862

RESUMEN

Plant and animal intracellular nucleotide-binding and leucine-rich repeat (NLR) receptors play important roles in sensing pathogens and activating defense signaling. However, the molecular mechanisms underlying the activation of host defense signaling by NLR proteins remain largely unknown. Many previous studies have determined that the coil-coil (CC) or Toll and interleukin-1 receptor/resistance protein (TIR) domain of NLR proteins and their dimerization/oligomerization are critical for activating downstream defense signaling. In this study, we demonstrated that the nucleotide-binding (NB) domain of the tomato Sw-5b NLR alone can activate downstream defense signaling, leading to elicitor-independent cell death. Sw-5b NB domains can self-associate, and this self-association is crucial for activating cell death signaling. The self-association was strongly compromised after the introduction of a K568R mutation into the P-loop of the NB domain. Consequently, the NB K568R mutant induced cell death very weakly. The NB CΔ20 mutant lacking the C-terminal 20 amino acids can self-associate but cannot activate cell death signaling. The NB CΔ20 mutant also interfered with wild-type NB domain self-association, leading to compromised cell death induction. By contrast, the NB K568R mutant did not interfere with wild-type NB domain self-association and its ability to induce cell death. Structural modeling of Sw-5b suggests that NB domains associate with one another and likely participate in oligomerization. As Sw-5b-triggered cell death is dependent on helper NLR proteins, we propose that the Sw-5b NB domain acts as a nucleation point for the assembly of an oligomeric resistosome, probably by recruiting downstream helper partners, to trigger defense signaling.

19.
Lancet Oncol ; 2021 Jun 09.
Artículo en Inglés | MEDLINE | ID: mdl-34118197

RESUMEN

BACKGROUND: Oncogenic alterations in RET have been identified in multiple tumour types, including 1-2% of non-small-cell lung cancers (NSCLCs). We aimed to assess the safety, tolerability, and antitumour activity of pralsetinib, a highly potent, oral, selective RET inhibitor, in patients with RET fusion-positive NSCLC. METHODS: ARROW is a multi-cohort, open-label, phase 1/2 study done at 71 sites (community and academic cancer centres) in 13 countries (Belgium, China, France, Germany, Hong Kong, Italy, Netherlands, Singapore, South Korea, Spain, Taiwan, the UK, and the USA). Patients aged 18 years or older with locally advanced or metastatic solid tumours, including RET fusion-positive NSCLC, and an Eastern Cooperative Oncology Group performance status of 0-2 (later limited to 0-1 in a protocol amendment) were enrolled. In phase 2, patients received 400 mg once-daily oral pralsetinib, and could continue treatment until disease progression, intolerance, withdrawal of consent, or investigator decision. Phase 2 primary endpoints were overall response rate (according to Response Evaluation Criteria in Solid Tumours version 1·1 and assessed by blinded independent central review) and safety. Tumour response was assessed in patients with RET fusion-positive NSCLC and centrally adjudicated baseline measurable disease who had received platinum-based chemotherapy or were treatment-naive because they were ineligible for standard therapy. This ongoing study is registered with ClinicalTrials.gov, NCT03037385, and enrolment of patients with treatment-naive RET fusion-positive NSCLC was ongoing at the time of this interim analysis. FINDINGS: Of 233 patients with RET fusion-positive NSCLC enrolled between March 17, 2017, and May 22, 2020 (data cutoff), 92 with previous platinum-based chemotherapy and 29 who were treatment-naive received pralsetinib before July 11, 2019 (efficacy enrolment cutoff); 87 previously treated patients and 27 treatment-naive patients had centrally adjudicated baseline measurable disease. Overall responses were recorded in 53 (61%; 95% CI 50-71) of 87 patients with previous platinum-based chemotherapy, including five (6%) patients with a complete response; and 19 (70%; 50-86) of 27 treatment-naive patients, including three (11%) with a complete response. In 233 patients with RET fusion-positive NSCLC, common grade 3 or worse treatment-related adverse events were neutropenia (43 patients [18%]), hypertension (26 [11%]), and anaemia (24 [10%]); there were no treatment-related deaths in this population. INTERPRETATION: Pralsetinib is a new, well-tolerated, promising, once-daily oral treatment option for patients with RET fusion-positive NSCLC. FUNDING: Blueprint Medicines.

20.
Artículo en Inglés | MEDLINE | ID: mdl-34118198

RESUMEN

BACKGROUND: Oncogenic alterations in RET represent important therapeutic targets in thyroid cancer. We aimed to assess the safety and antitumour activity of pralsetinib, a highly potent, selective RET inhibitor, in patients with RET-altered thyroid cancers. METHODS: ARROW, a phase 1/2, open-label study done in 13 countries across 71 sites in community and hospital settings, enrolled patients 18 years or older with RET-altered locally advanced or metastatic solid tumours, including RET-mutant medullary thyroid and RET fusion-positive thyroid cancers, and an Eastern Co-operative Oncology Group performance status of 0-2 (later limited to 0-1 in a protocol amendment). Phase 2 primary endpoints assessed for patients who received 400 mg once-daily oral pralsetinib until disease progression, intolerance, withdrawal of consent, or investigator decision, were overall response rate (Response Evaluation Criteria in Solid Tumours version 1.1; masked independent central review) and safety. Tumour response was assessed for patients with RET-mutant medullary thyroid cancer who had received previous cabozantinib or vandetanib, or both, or were ineligible for standard therapy and patients with previously treated RET fusion-positive thyroid cancer; safety was assessed for all patients with RET-altered thyroid cancer. This ongoing study is registered with clinicaltrials.gov, NCT03037385, and enrolment of patients with RET fusion-positive thyroid cancer was ongoing at the time of this interim analysis. FINDINGS: Between Mar 17, 2017, and May 22, 2020, 122 patients with RET-mutant medullary and 20 with RET fusion-positive thyroid cancers were enrolled. Among patients with baseline measurable disease who received pralsetinib by July 11, 2019 (enrolment cutoff for efficacy analysis), overall response rates were 15 (71%) of 21 (95% CI 48-89) in patients with treatment-naive RET-mutant medullary thyroid cancer and 33 (60%) of 55 (95% CI 46-73) in patients who had previously received cabozantinib or vandetanib, or both, and eight (89%) of nine (95% CI 52-100) in patients with RET fusion-positive thyroid cancer (all responses confirmed for each group). Common (≥10%) grade 3 and above treatment-related adverse events among patients with RET-altered thyroid cancer enrolled by May 22, 2020, were hypertension (24 patients [17%] of 142), neutropenia (19 [13%]), lymphopenia (17 [12%]), and anaemia (14 [10%]). Serious treatment-related adverse events were reported in 21 patients (15%), the most frequent (≥2%) of which was pneumonitis (five patients [4%]). Five patients [4%] discontinued owing to treatment-related events. One (1%) patient died owing to a treatment-related adverse event. INTERPRETATION: Pralsetinib is a new, well-tolerated, potent once-daily oral treatment option for patients with RET-altered thyroid cancer. FUNDING: Blueprint Medicines.

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