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1.
Cell Biol Int ; 2021 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-33760319

RESUMO

The population decline of the common hippopotamus (Hippopotamus amphibius) has necessitated the preservation of their genetic resources for species conservation and research. Of all actions, cryopreservation of fibroblast cell cultures derived from an animal biopsy is considered a simple but efficient means. Nevertheless, preserving viable cell cultures of the common hippopotamus has not been achieved to our knowledge. To this end, we established and characterized fibroblast cell cultures from the skin sample of a newborn common hippopotamus in this study. By combining the tissue explant direct culture and enzymatic digestion methods, we isolated a great number of cells with typical fibroblastic morphology and high viability. Neither bacteria/fungi nor mycoplasma was detectable in the cell cultures throughout the study. The population doubling time was 34 h according to the growth curve. Karyotyping based on Giemsa staining showed that the cultured cells were diploid with 36 chromosomes in all, one pair of which was sex chromosomes. The amplified mitochondrial cytochrome C oxidase subunit I gene sequence of the cultured cells was 99.26% identical with that of the registered H. amphibius complete mitochondrial DNA, confirming the species of origin of the cells. Flow cytometry and immunofluorescence staining results revealed that the detected cells were positive for fibroblast markers, S100A4, and vimentin. In conclusion, we generated the fibroblast cell cultures from a common hippopotamus and identified their characteristics using multiple techniques. We believe the cryopreserved cells could be useful genetic materials for future research.

2.
Micron ; 145: 103061, 2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-33773439

RESUMO

The gall midge Gephyraulus lycantha (Diptera: Cecidomyiidae) is a serious gall-forming pest that causes devastating damage in the wolfberry, Lycium barbarum (Solanaceae) in Northwest China. In the present study, the external morphology and ultrastructure of the antennae and the antennal sensilla of G. lycantha were examined by scanning electron microscopy. The results show that the moniliform antenna of G. lycantha consisted of a scape, pedicel, and flagellum, and exhibited obvious sexual dimorphism. The male antennae were significantly longer than those of females. Moreover, male flagellomeres were spheroidal nodes separated by slender internodes, whereas those of females were cylindrical with no obvious internodes. There were sex and individual differences in antennal segment number. Male antennae had 10 - 16 flagellomeres, most of which had 15, while female antennae consisted of 8 - 14 flagellomeres, most of which had 12. Moreover, a pair of antennae in the same individual had different numbers of flagellomeres. Four types of sensilla were observed along the surface of the antennae, including sensilla chaetica, sensilla trichodea, sensilla coeloconica, and sensilla circumfila. Among the types of sensilla, sensilla chaetica were the longest and most prominent sensilla discovered on the antennal flagellum in both sexes. Sensilla trichodea were widely distributed over the antennal surface, including the scape, pedicel, and flagellum. Sensilla coeloconica were categorized into four subtypes: sensilla coeloconica Ⅰ, sensilla coeloconica Ⅱ, sensilla coeloconica Ⅲ, and sensilla coeloconica IV; however, sensilla coeloconica IV was absent in females. Sensilla circumfila were found only on cecidomyiidae insect antennae and were attached to the surface by a series of stalks, forming loops around each flagellomere. The numbers of all four types of sensilla on the male antennal windward side were significantly higher than those on the leeward side. The probable biological functions of these sensilla were discussed herein based on their morphology and ultrastructure. These results provide an important basis for further research on chemical communication and strategies for the control of G. lycantha, and it will be able to serve future group Taxonomy studies (species of cecidomyiidae), providing new taxonomic characters (general ultrastructural morphology, number of sensilla and antennal segments, distribution of different types of setae, types and subtypes sensilla), which varies between species and subspecies.

3.
Neurosci Lett ; 750: 135712, 2021 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-33647394

RESUMO

Molecule's mechanism of action interacting with CasL 1 (MICAL1) in spinal cord injury (SCI) is unclear. This study aimed to detect the function of MICAL1 in SCI. Western blot was used to analyze the change of MICAL1 in vivo. Immunofluorescence staining was used to detect the location of MICAL1 expression. Oligodendrocyte cells were treated with H2O2 to induce oxidative injury. Subsequently, siRNA transfection was performed to decrease MICAL1 expression in oligodendrocyte cells. Then, the effects of MICAL1 on oxidative stress, apoptosis, and autophagy were assessed. We found that silencing of MICAL1 could significantly reduce the levels of the nuclear factor erythroid 2-related factor 2 (Nrf2), increase the expression of pro-apoptotic factors (Bax and C-caspase 3), decrease the levels of anti-apoptotic factor (Bcl-2) and pro-autophagy factors (Beclin1 and LC3B). Therefore, MICAL1 is a potential target gene for SCI clinical therapy.

4.
Pharmacol Res ; 167: 105546, 2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33716167

RESUMO

CONTEXT: The comparative efficacy of gestational diabetes (GDM) treatments lack conclusive evidence for choice of first-line treatment. OBJECTIVES: The aim of this study was to compare the efficacy of metformin and glibenclamide to insulin using a core outcome set (COS) to unify outcomes across trials investigating the treatment of gestational diabetes mellitus. STUDY DESIGN: A network meta-analysis (NMA) was conducted. DATA-SOURCE: PubMed, Embase, and Cochrane Controlled Register of Trials were searched from inception to January 2020. STUDY SELECTION: RCTs that enrolled pregnant women who were diagnosed with GDM and that compared the efficacy of different pharmacological interventions for the treatment of GDM were included. META-ANALYSIS: A generalized pairwise modelling framework was employed. RESULTS: A total of 38 RCTs with 6046 participants were included in the network meta-analysis. Compared to insulin, the estimated effect of metformin indicated improvements for weight gain (WMD -2·39 kg; 95% CI -3·31 to -1·46), maternal hypoglycemia (OR 0.34; 95% CI 0.12 to 0·97) and LGA (OR 0.61; 95% CI 0.38 to 0·98). There were also improvements in estimated effects for neonatal hypoglycemia (OR 0.48; 95% CI 0.19 to 1·25), pregnancy induced hypertension (OR 0.63; 95% CI 0.37 to 1·06), and preeclampsia (OR 0.74; 95% CI 0.538 to 1·04), though with limited evidence against our model hypothesis of equivalence with insulin for these outcomes. CONCLUSION: Metformin is, at least, comparable to insulin for the treatment of GDM. Glibenclamide appears less favorable, in comparison to insulin, than metformin.

5.
BMC Nephrol ; 22(1): 83, 2021 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-33691640

RESUMO

BACKGROUND: Primary hyperoxaluria(PH)is a rare autosomal recessive genetic disease that contains three subtypes (PH1, PH2 and PH3). Approximately 80% of PH patients has been reported as subtype PH1, this subtype of PH has been related to a higher risk of renal failure at any age. Several genetic studies indicate that the variants in gene AGXT are responsible for the occurrence of PH1. However, the population heterogeneity of the variants in AGXT makes the genetic diagnosis of PH1 more challenging as it is hard to locate each specific variant. It is valuable to have a complete spectrum of AGXT variants from different population for early diagnosis and clinical treatments of PH1. CASE PRESENTATION: In this study, We performed high-throughput sequencing and genetic analysis of a 6-year-old male PH1 patient from a Chinese family. Two variants (c.346G > A: p.Gly116Arg; c.864G > A: p.Trp288X) of the gene AGXT were identified. We found a nonsense variant (c.864G > A: p.Trp288X) that comes from the proband's mother and has never been reported previously. The other missense variant (c.346G > A: p.Gly116Arg) was inherited from his father and has been found previously in a domain of aminotransferase, which plays an important role in the function of AGT protein. Furthermore, we searched 110 pathogenic variants of AGXT that have been reported worldwide in healthy local Chinese population, none of these pathogenic variants was detected in the local genomes. CONCLUSIONS: Our research provides an important diagnosis basis for PH1 on the genetic level by updating the genotype of PH1 and also develops a better understanding of the variants in AGXT by broadening the variation database of AGXT according to the Chinese reference genome.

6.
Sci Total Environ ; 776: 145731, 2021 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-33647664

RESUMO

In this study, 17 legacy and emerging PFASs were investigated in soil and plant leaves near a valley-type landfill, which has been in operation for over 20 years. ΣPFASs concentrations ranged from 5.31 to 108 ng/g dw and 11.9 to 115 ng/g dw in the soil and leaf samples, respectively, and perfluorobutanoic acid (PFBA) was dominant in both soil and leaves. The concentrations of hexafluoropropylene oxide dimer acid (HFPO-DA), 6:2 chlorinated polyfluorinated ether sulfonic acid (F-53B) and 6:2 fluorotelomer sulfonic acid (6:2 FTS) were significantly higher than those of legacy PFOA and PFOS, indicating emerging alternatives were widely applied in the region. The integrated approach of PCA analysis, field investigation of relevant industrial activities in the study area, along with the Unmix model analysis quantitatively revealed that factories producing consumer products and the landfill were the major sources of PFASs in soil, accounting for 57% of total PFASs detected. Bioaccumulation factors (BAFs) of ΣPFASs in leaves varied from 0.37 to 8.59, and higher BAFs were found in camphor leaves. The log10BAFs in all plant leaves showed a linear decrease with increasing carbon chain lengths for individual PFCAs (C4-C8). The BAF values of HFPO-DA, F-53B and 6:2 FTS were 0.01-3.39, 0.04-6.15 and 0.01-6.33, respectively. The human health risk assessment of EDIs showed a decreasing trend with the increasing carbon chain lengths of PFCAs (C4-C9), and the PFASs EDI indicated further study on the human health risk via vegetable consumption be warranted.

7.
Ying Yong Sheng Tai Xue Bao ; 32(2): 591-600, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33650369

RESUMO

Accurate spatial distribution information of soil properties would be helpful for improving the accuracy of soil organic carbon storage estimation. In this study, terrain factors were used as predictors, and the fuzzy C-means (FCM) clustering method was used to make digital soil prediction mapping for soil organic carbon content, soil bulk density, soil depth, and soil gravel content in Nanshan forest farm in Jiyuan City of Henan Province. Based on the digital mapping results, the prediction mapping of soil organic carbon density and the estimation of soil organic carbon storage were realized. The results showed that the average soil organic carbon density in the study area based on the digital soil mapping method was 4.24 kg·m-2, the mean error (ME), mean absolute error (MAE) and root mean square error (RMSE) of the prediction map were 0.08, 2.80 and 5.03 kg·m-2, respectively. The accuracy, stability and reliability of the prediction results were higher than the tradiation methods. The soil organic carbon storage in the study area was estimated to be 3.08×108 kg. Based on the digital soil mapping technology, only a small number of soil samples could be used to map and estimate the soil organic carbon density with high accuracy, which could characterize the spatial distribution characteristics of soil organic carbon density. This study provided a new way to estimate soil organic carbon storage, which would help to improve the accuracy and efficiency of soil organic carbon storage estimation.


Assuntos
Carbono , Solo , Carbono/análise , China , Florestas , Reprodutibilidade dos Testes
8.
Microsc Res Tech ; 2021 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-33655696

RESUMO

Pseudotorymus jaapiellae is an important ectoparasitoid of the larvae of Gephyraulus lycantha, a serious gall-forming pest that devastates wolfberry, Lycium barbarum, in Northwest China. To provide requisite background for our ongoing research on the mechanisms of P. jaapiellae's host location and subsequent oviposition, we used scanning electron microscopy to describe the external morphologies and distributions of sensilla on their antennae and ovipositors. The geniculate antennae of both male and female P. jaapiellae were each composed of a scape with a basal radiculum, a pedicel, an anellum and a flagellum. We identified nine morphological sensilla types on the antennae of both sexes, including three sensilla trichodea (ST), one sensillum basiconicum (SB), two sensilla chaetica (SCh), one sensillum placodeum (SP), one sensillum coeloconicum (SCo), and one sensillum campaniformia (SCa). Females had significantly more ST I and SP than males had, but males had more ST III than did females. We observed six types of sensilla on the ovipositor, including three ST, one SB, and two SCa. ST II, ST IV and SB II were on the sheath, whereas ST V and the SCa were on the stylus. Finally, the possible biological functions of these sensilla were discussed according to their morphology and ultrastructure. These results provide an important basis for further study on chemical communication between P. jaapiellae and their host, and contribute to the development of a biological control program for G. lycantha, using the parasitoid, P. jaapiellae.

9.
Life Sci ; 274: 119325, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33713665

RESUMO

AIMS: The emergence of antibiotic tolerance was a tricky problem in the treatment of chronic Pseudomonas aeruginosa-infected cystic fibrosis and burn victims. The quorum sensing (QS) inhibitor may serve as a new tactic for the bacterial resistance by inhibiting the biofilm formation and the production of virulence factors. This study explored the potential of luteolin as a QS inhibitor against P. aeruginosa and the molecular mechanism involved. MAIN METHODS: Crystal violet staining, CLSM observation, and SEM analysis were carried out to assess the effect of luteolin on biofilm formation. The motility assays and the production of virulence factors were determined to evaluate the QS-inhibitory activity of luteolin. Acyl-homoserine lactone, RT-PCR, and molecular docking assays were conducted to explain its anti-QS mechanisms. KEY FINDINGS: The biofilm formation, the production of virulence factors, and the motility of P. aeruginosa could be efficiently inhibited by luteolin. Luteolin could also attenuate the accumulation of the QS-signaling molecules N-(3-oxododecanoyl)-L-homoserine lactone (OdDHL) and N-butanoyl-L-homoserine lactone (BHL) (P < 0.01) and downregulate the transcription levels of QS genes (lasR, lasI, rhlR, and rhlI) (P < 0.01). Molecular docking analysis indicated that luteolin had a greater docking affinity with LasR regulator protein compared with OdDHL. SIGNIFICANCE: This study is important as it reports the molecular mechanisms involved in the anti-biofilm formation activity of luteolin against P. aeruginosa. This study also indicated that luteolin could be helpful when used for the treatment of clinical drug-resistant infections of P. aeruginosa.

10.
PLoS Comput Biol ; 17(3): e1008848, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33750948

RESUMO

Our sense of touch helps us encounter the richness of our natural world. Across a myriad of contexts and repetitions, we have learned to deploy certain exploratory movements in order to elicit perceptual cues that are salient and efficient. The task of identifying optimal exploration strategies and somatosensory cues that underlie our softness perception remains relevant and incomplete. Leveraging psychophysical evaluations combined with computational finite element modeling of skin contact mechanics, we investigate an illusion phenomenon in exploring softness; where small-compliant and large-stiff spheres are indiscriminable. By modulating contact interactions at the finger pad, we find this elasticity-curvature illusion is observable in passive touch, when the finger is constrained to be stationary and only cutaneous responses from mechanosensitive afferents are perceptible. However, these spheres become readily discriminable when explored volitionally with musculoskeletal proprioception available. We subsequently exploit this phenomenon to dissociate relative contributions from cutaneous and proprioceptive signals in encoding our percept of material softness. Our findings shed light on how we volitionally explore soft objects, i.e., by controlling surface contact force to optimally elicit and integrate proprioceptive inputs amidst indiscriminable cutaneous contact cues. Moreover, in passive touch, e.g., for touch-enabled displays grounded to the finger, we find those spheres are discriminable when rates of change in cutaneous contact are varied between the stimuli, to supplant proprioceptive feedback.

11.
J Clin Epidemiol ; 135: 70-78, 2021 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-33592277

RESUMO

OBJECTIVE: In evidence synthesis practice, researchers often face the problem of how to deal with zero-events. Inappropriately dealing with zero-events studies may lead to research waste and mislead healthcare practice. We propose a framework to guide researchers to better deal with zero-events in meta-analysis. STUDY DESIGN AND SETTING: We used two dimensions, one with respect to the total events count across all studies in the comparative arms in a meta-analysis, and a second with respect to whether included studies have single or both arms with zero-events, to establish the framework for the classification of meta-analysis with zero-events studies. A dataset from Cochrane systematic reviews was used to evaluate the classification. RESULTS: The proposed framework classifies meta-analysis with zero-events studies into six subtypes. The classification matched well to the large real-world dataset. The applicability of existing methods for zero-events were then presented under each meta-analysis subtype based on this framework, with a 5-step principle to help researchers in evidence synthesis practice. CONCLUSIONS: The proposed framework should be considered by researchers when making decisions on the selection of the synthesis methods in a meta-analysis. It also provides a reasonable basis for the development of methodological guidelines to deal with zero-events in meta-analysis.

12.
Artigo em Inglês | MEDLINE | ID: mdl-33555101

RESUMO

OBJECTIVE: Although hydroxychloroquine/chloroquine (HCQ/CQ) form the cornerstone of systemic lupus erythematosus (SLE) treatment, not all patients receive this, which may contribute to disparities in outcomes. We investigated factors associated with first dispensing of HCQ/CQ. METHODS: Using Medicaid insurance claims from 2000-2010, we identified individuals age 18-65 years with incident SLE (≥3 SLE ICD-9 codes separated by ≥30 days without prior SLE codes or HCQ/CQ use for 24 months.) The primary outcome was first dispensing of HCQ/CQ within 24 months of the first SLE code. We used Cox proportional hazards regression models to examine the association between sociodemographic factors, comorbidities, health care utilization and medication use and HCQ/CQ dispensing within 24 months of diagnosis. RESULTS: We identified 9560 Medicaid beneficiaries with incident SLE; 41% received HCQ (N=3949) or CQ (N=14) within 24 months of diagnosis. Younger patients were more likely to receive HCQ/CQ. Black, Asian, Hispanic and American Indian/Alaska Native individuals were more likely to receive HCQ/CQ than White individuals. Alcohol, opioid, and nicotine use, diabetes, and end-stage renal disease were associated with lower dispensing. Outpatient appointments and preventive care services were associated with higher rates; more hospitalizations with lower rates. CONCLUSION: Only 41% of Medicaid beneficiaries with SLE received HCQ/CQ within 24 months of diagnosis. Greater outpatient and preventive care increased receipt. All non-White race/ethnicities had higher rates of first dispensing. Time to initial HCQ/CQ dispensing may not explain racial/ethnic disparities in adverse outcomes, highlighting the need to consider other care quality-related issues and medication adherence challenges.

13.
J Phys Chem A ; 2021 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-33595311

RESUMO

As the first thermal stable molecule with a B≡B bond, the diboryne complex protected by N-heterocyclic carbene ligands (NHC-B≡B-NHC) has attracted much interest. Researchers point out that π-back-donation highly stabilizes the B≡B bond besides σ-donation, both of which are induced by NHC ligands. In this work, details of the π-back-donation are revisited by using DFT calculations. There are two delocalized π* orbitals in NHC, and the symmetry of one π* orbital is highly adaptive to the π orbitals in B≡B bond, whereas the other cannot be involved in the π-back-donation. In staggered configuration, two orthogonal π orbitals of B≡B interact with this π* orbital in each NHC ligand, respectively, to form π-back-donations in both sides. This interaction has proven to be more intensive than π-conjunction, resulting in the lower energy of the staggered isomer compared with the eclipsed one containing greater π-conjunction. Moreover, intensity of the π-back-donation can be enhanced by reducing the energy levels of the matched π* orbitals in ligands, which gives references for the design of stable diborynes.

14.
J Int Med Res ; 49(2): 300060520986677, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33528281

RESUMO

We describe herein a 37-year-old woman with a 2-week history of melena who was eventually diagnosed with ileal haemolymphangioma, a rare benign tumour. Local mucosal congestion and swelling were found through single-balloon enteroscopy, which showed an irregular protuberance approximately 10 cm long, located 3.2 m from the Treitz ligament. We performed a laparoscopic-assisted partial resection of the small intestine combined with intestinal adhesiolysis. According to postoperative pathology, the final diagnosis was ileal haemolymphangioma with haemorrhage.

15.
Comput Stand Interfaces ; : 103520, 2021 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-33584007

RESUMO

The current pandemic situation due to COVID-19 is seriously affecting our daily work and life. To block the propagation of infectious diseases, an effective contact tracing mechanism needs to be implemented. Unfortunately, existing schemes have severe privacy issues that jeopardize the identity-privacy and location-privacy for both users and patients. Although some privacy-preserving systems have been proposed, there remain several issues caused by centralization. To mitigate this issues, we propose a Privacy-preserving contact Tracing scheme in 5G-integrated and Blockchain-based Medical applications, named PTBM. In PTBM, the 5G-integrated network is leveraged as the underlying infrastructure where everyone can perform location checking with his mobile phones or even wearable devices connected to 5G network to find whether they have been in possible contact with a diagnosed patient without violating their privacy. A trusted medical center can effectively trace the patients and their corresponding close contacts. Thorough security and performance analysis show that the proposed PTBM scheme achieves privacy protection, traceability, reliability, and authentication, with high computation & communication efficiency and low latency.

16.
Surg Endosc ; 2021 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-33591448

RESUMO

BACKGROUND: Thoracoscopic lobectomy is widely accepted for the treatment of congenital lung malformations (CLM), owing to its advantages. However, severe incomplete interlobar fissure may lead to a high rate of conversion to thoracotomy and postoperational complications. Thoracoscopic lobectomy utilizing the pulmonary hilum approach may be an effective and safe method to resolve these problems. This retrospective study was conducted to estimate the safety and efficiency of this approach. METHODS: A retrospective review of medical records was performed in our institution, from January 2014 to December 2019, and 432 patients with CLM who underwent thoracoscopic lobectomy through the pulmonary hilum approach were included in this study. Patients were divided into the incomplete fissure (IF) group and complete fissure (CF) group according to the level of fissure, which was proposed by an anatomical classification of pulmonary fissures. RESULTS: Patients in the IF and CF groups were 131 and 301, respectively. In univariate analysis, there were statistical significances between the two groups in terms of intraoperative blood loss (P = 0.04), surgical time (P = 0.01), the number of chest tube drainages (P < 0.01), and the total length of hospital stay (P = 0.03). However, no patients experienced bronchopleural fistula, postoperative pneumonia, or conversion to thoracotomy in either group. Five patients experienced prolonged air leakage in the IF group, and no prolonged air leakage occurred in the CF group. CONCLUSION: An IF would certainly increase the difficulty of CLM surgery, and thoracoscopic lobectomy using the pulmonary hilum approach is an effective and safe method for CLM patients.

17.
J Agric Food Chem ; 69(6): 1942-1952, 2021 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-33533595

RESUMO

Neonicotinoids are the most widely used insecticides in modern agriculture, and their residues have been found in the environment and food. Previous studies reported that neonicotinoids exert toxic effects in various tissues, but whether they interfered with the female reproductive process remains unknown. In our present research, thiamethoxam was selected as a representative neonicotinoid to establish a mouse toxicity model with gavage. We found that thiamethoxam decreased the ovarian coefficient and disrupted the expression of female hormone receptors, subsequently affecting follicle development. Ovarian granulosa cells from the thiamethoxam exposure group underwent a high level of apoptosis. Using transcriptome analysis, we showed that thiamethoxam exposure altered the expression of multiple oocyte genes related to inflammation, apoptosis, and endoplasmic reticulum stress. Thiamethoxam also adversely affected oocyte and embryo development. Western blotting and fluorescence staining results confirmed that thiamethoxam affected the integrity of DNA, triggered apoptosis, promoted oxidative stress and endoplasmic reticulum stress, and impaired mitochondrial function. Collectively, our results indicated that thiamethoxam exposure disrupts ovarian homeostasis and decreases oocyte quality via endoplasmic reticulum stress and apoptosis induction.

18.
J Exp Clin Cancer Res ; 40(1): 61, 2021 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-33557912

RESUMO

BACKGROUND: ONC201 is a dopamine receptor D2 (DRD2) antagonist that inhibits tumor growth in preclinical models through ClpP activation to induce integrated stress response pathway and mitochondrial events related to inhibition of cell growth, which is being explored in clinical trials for solid tumors and hematological malignancies. In this study, we investigated the anti-tumorigenic effect of ONC201 in endometrial cancer cell lines and a genetically engineered mouse model of endometrial cancer. METHODS: Cell proliferation was assessed by MTT and colony formation assays. Cell cycle and apoptosis were evaluated by Cellometer. Invasion capacity was tested using adhesion, transwell and wound healing assays. LKB1fl/flp53fl/fl mouse model of endometrial cancer were fed a control low fat diet versus a high fat diet to mimic diet-induced obesity. Following tumor onset, mice were treated with placebo or ONC201. Metabolomics and lipidomics were used to identify the obesity-dependent effects of ONC201 in the mouse endometrial tumors. DRD2 expression was analyzed by immunohistochemistry in human endometrioid and serous carcinoma specimens. DRD2 mRNA expression from the Cancer Genome Atlas (TCGA) database was compared between the four molecular subtypes of endometrial cancer. RESULTS: Increasing DRD2 expression in endometrial cancer was significantly associated with grade, serous histology and stage, as well as worse progression free survival and overall survival. Higher expression of DRD2 mRNA was found for the Copy Number High (CNH) subtype when compared to the other subtypes. ONC201 inhibited cell proliferation, induced cell cycle G1 arrest, caused cellular stress and apoptosis and reduced invasion in endometrial cancer cells. Diet-induced obesity promoted endometrial tumor growth while ONC201 exhibited anti-tumorigenic efficacy in the obese and lean LKB1fl/fl/p53fl/fl mice. Metabolomic analysis demonstrated that ONC201 reversed the obesity-driven upregulation of lipid biosynthesis and reduced protein biosynthesis in obese and lean mice. CONCLUSION: ONC201 has anti-tumorigenic effects in endometrial cancer cells and a transgenic mouse model of endometrial cancer, and DRD2 expression was documented in both human serous and endometrioid endometrial cancer. These studies support DRD2 antagonism via ONC201 as a promising therapeutic strategy for endometrial cancer that has already demonstrated pharmacodynamic activity and clinical benefit in both serous and endometrioid endometrial cancer patients.

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