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1.
Front Med (Lausanne) ; 8: 720401, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34778286

RESUMO

Background: Laparoscopy is considered to be the gold standard in the evaluation of causes leading to infertility. Hysterosalpingography (HSG) permits indirect visualization of the cervical canal, uterine cavity, and tube patency, which is helpful for evaluating the causes of infertility. Objective: This study aimed to detect tubal abnormalities in infertile women by HSG or laparoscopy and determine the value of HSG in diagnosing fallopian tube status. Methods: The study group consisted of 1,276 patients. HSG was performed as a preliminary test for the evaluation of fallopian tube status. Women were subjected to laparoscopic examination on evidence of HSG abnormalities. Results: The negative predictive value of HSG for detecting patency or occlusion for the right/left tube was 92.08 and 95.44%, respectively. The kappa values for the consistent diagnosis in the right/left tube were 0.470 and 0.574, respectively. In cases of low patency of the right/left tube, there was a greater than a 40% chance for the tube to be patent, and the remaining high probability was pelvic adhesion. The positive predictive value of HSG for detecting patency or occlusion for both tubes was 87.2%. The kappa value was 0.898 [95% CI (0.838, 0.937), p < 0.001], which meant that the diagnostic accuracy of HSG for both tube patency/occlusion was explicit. The kappa value for the diagnosis of hydrosalpinx (especially for bilateral tube hydrosalpinx) was 0.838 [95% CI (0.754, 0.922), p < 0.001], and the diagnostic accuracy for HSG was 79.8, 67.9, and 72.4%, respectively. Conclusion: The current study concluded that HSG is a good diagnostic modality to detect tube abnormalities in infertile patients. HSG and laparoscopy are complementary to each other and whenever the patient is undertaken for diagnosis of infertility. Cost-effective HSG had good predictive value in identifying tubal factor infertility.

2.
Front Mol Biosci ; 8: 727614, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34733887

RESUMO

Oocyte maturation is the foundation for developing healthy individuals of mammals. Upon germinal vesicle breakdown, oocyte meiosis resumes and the synthesis of new transcripts ceases. To quantitatively profile the transcriptomic dynamics after meiotic resumption throughout the oocyte maturation, we generated transcriptome sequencing data with individual mouse oocytes at three main developmental stages: germinal vesicle (GV), metaphase I (MI), and metaphase II (MII). When clustering the sequenced oocytes, results showed that isoform-level expression analysis outperformed gene-level analysis, indicating isoform expression provided extra information that was useful in distinguishing oocyte stages. Comparing transcriptomes of the oocytes at the GV stage and the MII stage, in addition to identification of differentially expressed genes (DEGs), we detected many differentially expressed transcripts (DETs), some of which came from genes that were not identified as DEGs. When breaking down the isoform-level changes into alternative RNA processing events, we found the main source of isoform composition changes was the alternative usage of polyadenylation sites. With detailed analysis focusing on the alternative usage of 3'-UTR isoforms, we identified, out of 3,810 tested genes, 512 (13.7%) exhibiting significant switches of 3'-UTR isoforms during the process of moues oocyte maturation. Altogether, our data and analyses suggest the importance of examining isoform abundance changes during oocyte maturation, and further investigation of the pervasive 3'-UTR isoform switches in the transition may deepen our understanding on the molecular mechanisms underlying mammalian early development.

3.
J Colloid Interface Sci ; 608(Pt 1): 652-661, 2021 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-34628324

RESUMO

The development of functional covalent organic frameworks (COFs) with specific properties is an emerging research field. In the current work, COF-SQ-Ph was synthesized through the aza-Diels-Alder reaction between phenylacetylene and the matrix COF-SQ (triazine-based COF) generated from the organic monomers 2, 4, 6-tris(4-aminophenyl)-1, 3, 5-triazine and 2, 5-dimethoxyterephthalaldehyde in flask. The functionalized COF-SQ-Ph with an extended π-conjugated structure and enhanced structural stability was used as the sulfur loading recipient to prepare sulfur cathodes for lithium-sulfur batteries. Sulfur-impregnated COF-SQ-Ph marked as COF-SQ-Ph-S displayed better cycling stability with a specific capacity of 618 mA h g-1 after 150 cycles due to the lithiophilic interaction between lithium polysulfides and nitrogen atoms from quinoline and triazine moieties in COF-SQ-Ph-S. The functionalization of triazine-based COFs through a cycloaddition reaction in flask could promote the large-scale preparation of tailored COFs and the post-synthesis modification of COF-SQ.

4.
Biomaterials ; 277: 121128, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34537502

RESUMO

Intratumoral upregulated reactive oxygen species (ROS) has been extensively exploited as exclusive stimulus to activate drug release for tumor-specific therapy. However, insufficient endogenous ROS and tumor heterogeneity severely restrict clinical translation of current ROS-responsive drug delivery systems. Herein, a tailored ROS-activatable self-amplifying supramolecular nanoprodrug was developed for reinforced ROS-responsiveness and highly selective antitumor therapy. A novel ROS-cleavable CA-based thioacetal linker CASOH was synthesized with ROS generator cinnamaldehyde (CA) incorporated into its molecular structure, to skillfully realize self-amplifying positive feedback loop of "ROS-activated CA release with CA-induced ROS regeneration". CASOH was modified with a cytosine analogue gemcitabine (GEM) to obtain ROS-activatable self-immolative prodrug CAG, which could be selectively activated in tumor cells and further achieve self-boosting "snowballing" activation via ROS compensation, while keep inactive in normal cells. Through Watson-Crick nucleobase pairing (G≡C)-like hydrogen bonds, CAG efficiently crosslinked with a matched guanine-rich acyclovir-modified hyaluronic acid conjugate HA-ACV, to self-assemble into pH/ROS dual-responsive supramolecular nanoprodrug HCAG. With high stability, beneficial tumor targeting capacity and pH/ROS-responsiveness, HCAG nanoformulation exhibited remarkable in vivo antitumor efficacy with minimal systemic toxicity. Based on unique tumor-specific self-amplifying prodrug activation and Watson-Crick base pairing-inspired supramolecular self-assembly, this study provides an inspirational strategy of exploiting novel ROS-responsive nanoplatform with reinforced responsiveness and specificity for future clinical translation.


Assuntos
Nanopartículas , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Espécies Reativas de Oxigênio
5.
Eur J Obstet Gynecol Reprod Biol ; 265: 102-106, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34482233

RESUMO

OBJECTIVE: Autoantibodies are associated with worse outcomes in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI), including increasing miscarriage rate, lowering pregnancy rate, and lowering delivery rate. However, little is known about improving IVF/ICSI outcomes for autoantibody-positive women, especially in frozen-thawed embryo transfer (FET) cycles. This study aimed to investigate whether pituitary suppression before FET improves the clinical pregnancy rate (CPR) and live birth rate (LBR) for IVF/ICSI women positive for serum autoantibodies. STUDY DESIGN: A total of 181 infertile women positive for serum autoantibodies were recruited, including 65 women receiving GnRHa and hormone replacement therapy protocols (G-HRT group) and 116 women using modified natural cycles (MNC)/mild stimulated cycles (MSC) as FET protocols (MNC/MSC group). The outcomes were compared between two groups, including CPR, implantation rate (IR), miscarriage rate (MR), ongoing pregnancy rate (OPR), LBR, and gestational age (GA). The primary outcome of the study was CPR. RESULTS: CPR, OPR, and LBR per embryo transferred in the G-HRT groups were significantly higher than those in the MNC/MSC group. No statistically significant differences were observed in the IR and MR. The CPR, IR, MR, OPR, and LBR was 72.23%, 64.00%, 12.77%, 63.07%, and 63.07% in the G-HRT group, respectively, while that was 56.90%, 53.07%, 10.60%, 50.00%, and 50.00% in the MNC/MSC group, respectively. After adjusting for partial potential confounding factors using multiple logistic regression, the type of endometrial preparation is the factor independently associated with enhanced CPR (OR = 0.48, 95%CI: 0.24-0.96, P = 0.039). CONCLUSIONS: The current study showed that prior long-term GnRHa suppression could benefit patients with high serum autoantibody levels during IVF/ICSI FET cycles.


Assuntos
Infertilidade Feminina , Autoanticorpos , Regulação para Baixo , Transferência Embrionária , Feminino , Humanos , Infertilidade Feminina/terapia , Gravidez , Taxa de Gravidez
6.
Cell Death Dis ; 12(10): 888, 2021 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-34588429

RESUMO

Circular RNAs (circRNAs) are known to act as key regulators in a variety of malignancies. However, the role of circRNAs in cervical cancer (CCa) remains largely unknown. Herein, we demonstrated that a circRNA derived from the TADA2A gene (hsa_circ_0043280) was significantly downregulated in CCa and that this reduction in expression was correlated with a poor prognosis. Furthermore, our results demonstrated that hsa_circ_0043280 functions as a tumor suppressor to inhibit tumor growth and metastasis in CCa. Mechanistically, hsa_circ_0043280 competitively sponges miR-203a-3p and prevents miR-203a-3p from reducing the levels of PAQR3. Collectively, our results demonstrate that hsa_circ_0043280 plays a pivotal role in the development and metastasis of CCa, thus suggesting that hsa_circ_0043280 has significant potential as a prognostic biomarker and a therapeutic target for CCa.

7.
J Med Chem ; 64(18): 13312-13326, 2021 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-34506134

RESUMO

Potent and selective ferroptosis regulators promote an intensive understanding of the regulation and mechanisms underlying ferroptosis, which is highly associated with various diseases. In this study, through a stepwise structure optimization, a potent and selective ferroptosis inducer was developed targeting to inhibit glutathione peroxidase 4 (GPX4), and the structure-activity relationship (SAR) of these compounds was uncovered. Compound 26a exhibited outstanding GPX4 inhibitory activity with a percent inhibition up to 71.7% at 1.0 µM compared to 45.9% of RSL-3. At the cellular level, 26a could significantly induce lipid peroxide (LPO) increase and effectively induce ferroptosis with satisfactory selectivity (the value of 31.5). The morphological analysis confirmed the ferroptosis induced by 26a. Furthermore, 26a significantly restrained tumor growth in a mouse 4T1 xenograft model without obvious toxicity.

8.
Chin Med J (Engl) ; 134(17): 2091-2101, 2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34334630

RESUMO

BACKGROUND: Long non-coding RNA (lncRNA) actin filament-associated protein 1 antisense RNA 1 (AFAP1-AS1) functions as a competing endogenous RNA to regulate target genes expression by sponging microRNAs (miRs) to play cancer-promoting roles in cancer stem cells. However, the regulatory mechanism of AFAP1-AS1 in cervical cancer (CC) stem cells is unknown. The present study aimed to provide a new therapeutic target for the clinical treatment of CC. METHODS: Hyaluronic acid receptor cluster of differentiation 44 variant exon 6 (CD44v6)(+) CC cells were isolated by flow cytometry (FCM). Small interfering RNAs of AFAP1-AS1 (siAFAP1-AS1) were transfected into the (CD44v6)(+) cells. The levels of AFAP1-AS1 were measured by quantitative real-time PCR (qRT-PCR). Sphere formation assay, cell cycle analysis, and Western blotting were used to detect the effect of siAFAP1-AS1. RNA pull-down and luciferase reporter assay were used to verify the relationship between miR-27b-3p and AFAP1-AS1 or vascular endothelial growth factor (VEGF)-C. RESULTS: CD44v6(+) CC cells had remarkable stemness and a high level of AFAP1-AS1. However, AFAP1-AS1 knockdown with siAFAP1-AS1 suppressed the cell cycle transition of G(1)/S phase and inhibited self-renewal of CD44v6(+) CC cells, the levels of the stemness markers octamer-binding transcription factor 4 (OCT4), osteopontin (OPN), and cluster of differentiation 133 (CD133), and the epithelial-mesenchymal transition (EMT)-related proteins Twist1, matrix metalloprotease (MMP)-9, and VEGF-C. In the mechanism study, miR-27b-3p/VEGF-C signaling was demonstrated to be a key downstream of AFAP1-AS1 in the CD44v6(+) CC cells. CONCLUSIONS: LncRNA AFAP1-AS1 knockdown inhibits the CC cell stemness by upregulating miR-27b-3p to suppress VEGF-C.


Assuntos
MicroRNAs , RNA Longo não Codificante , Neoplasias do Colo do Útero , Linhagem Celular Tumoral , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/genética , RNA Longo não Codificante/genética , Neoplasias do Colo do Útero/genética , Fator A de Crescimento do Endotélio Vascular/genética , Fator C de Crescimento do Endotélio Vascular
9.
Angew Chem Int Ed Engl ; 60(44): 23651-23655, 2021 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-34428331

RESUMO

Gathering information on the atomic nature of reactive sites and trap states is key to fine tuning catalysis and suppressing deleterious surface voltage losses in photoelectrochemical technologies. Here, spectroelectrochemical and computational methods were combined to investigate a model photocathode from the promising chalcopyrite family: CuIn0.3 Ga0.7 S2 . We found that voltage losses are linked to traps induced by surface Ga and In vacancies, whereas operando Raman spectroscopy revealed that catalysis occurred at Ga, In, and S sites. This study allows establishing a bridge between the chalcopyrite's performance and its surface's chemistry, where avoiding formation of Ga and In vacancies is crucial for achieving high activity.

10.
Sheng Wu Gong Cheng Xue Bao ; 37(6): 2039-2049, 2021 Jun 25.
Artigo em Chinês | MEDLINE | ID: mdl-34227293

RESUMO

Triptolide has wide clinical applications due to its anti-inflammatory, anti-tumor and immunosuppressive activities. In this study, we investigated the effect of blocking isopentenyl pyrophosphate (IPP) translocation on the biosynthesis of triptolide by exogenously adding D,L-glyceraldehyde (DLG) to the suspension cells of Ttripterygium wilfordii at different stages (7 d, 14 d). Subsequently, the cell viability, biomass accumulation, triptolide contents, as well as the profiles of the key enzyme genes involved in the upstream pathway of triptolide biosynthesis, were analyzed. The results showed that IPP translocation is involved in the biosynthesis of triptolide. IPP is mainly translocated from the plastid (containing the MEP pathway) to the cytoplasm (containing the MVA pathway) in the early stage of the culture, but reversed in the late stage. Blocking the translocation of IPP affected the expression of key enzyme genes involved in the upstream pathway of triptolide, which in turn affected the accumulation of triptolide. Understanding the characteristics and mechanism of IPP translocation provides a theoretical basis for further promoting triptolide biosynthesis through synthetic biology.


Assuntos
Diterpenos , Fenantrenos , Compostos de Epóxi , Hemiterpenos , Compostos Organofosforados
11.
Exp Biol Med (Maywood) ; : 15353702211033247, 2021 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-34308657

RESUMO

Atherosclerotic plaque destabilization is a dominating cause of acute cardiovascular events such as myocardial infarction and stroke. This study aims to identify genetic biomarkers related to atherosclerotic plaque destabilization using bioinformatics. Three transcriptome datasets of human carotid atherosclerotic plaque samples were downloaded from ArrayExpress and Gene Expression Omnibus databases, including E-MATB-2055, E-TABM-190, and GSE120521. With Robust Rank Aggregation analysis, we documented 46 differentially expressed genes between stable and unstable/ruptured plaques. Functional enrichment analysis using DAVID tool demonstrated that these genes were mainly related to biological functions such as extracellular matrix disassembly, collagen catabolic process, response to mechanical stimulus, and PPAR signaling pathway. A protein-protein interaction network for the differentially expressed genes was constructed, and eight pivotal genes (ITGAM, MMP9, PLAUR, CCR1, CD163, CD36, ADAM8, and IL1RN) were obtained from the network with a connective degree > 5. The expression patterns of these hub differentially expressed genes could be verified in atherosclerotic plaque samples with intraplaque hemorrhage. Using gene set variation analysis, the eight genes were integrated to generate an atherosclerotic plaque destabilization score, which showed a high performance in not only discriminating individuals with myocardial infarction from those with stable coronary illness, but also in predicting future acute cardiovascular events in atherosclerotic patients. In conclusion, the findings of this study will enhance our knowledge on the pathological mechanisms involved in atherosclerotic plaque destabilization, and provide potential gene biomarkers for risk stratification of patients with atherosclerotic cardiovascular disease.

12.
Stem Cells Int ; 2021: 6550388, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34306095

RESUMO

Cancer stem cells are a key population participating in the promotion of the cervical cancer progression through interacting with cancer cells. Existing studies have preliminary revealed that cervical cancer stem cells contribute to tumor recurrence and chemotherapy resistance. However, the specific mechanisms involved in regulating cell functions remain largely unknown. Here, we analyzed published data from public databases and our global transcriptome data, thus identifying cancer-related signaling pathways and molecules. According to our findings, upregulated TAB2 was correlated to stem cell-like properties of cervical cancer. Immunohistochemistry staining of TAB2 in normal and cervical cancer tissues was performed. The cell function experiments demonstrated that knockdown of TAB2 reduced the stemness of cervical cancer cells and, importantly, prevented cervical cancer progression. Collectively, the therapeutic scheme targeting TAB2 may provide an option for overcoming tumor relapse and chemoresistance of cervical cancer via obstructing stemness maintenance.

13.
Nat Prod Bioprospect ; 11(5): 545-555, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34061296

RESUMO

One novel spirolactone, aquilarisinolide (1), three new sesquiterpenoids, (2R,4S,5R,7R)-2-hydroxyeremophila-9,11-dien-8-one (2), (1R,4S,5S,7R,11R)-13-hydroxyepidaphnauran-9-en-8-one (3), and (4R,5S,7R,8S,10S,13R)-8,13-dihydroxyrotunda-1,11-dien-3-one (4), together with 13 known compounds (5-17) were isolated from the resinous heartwood of Aquilaria sinensis (Thymelaeaceae). The structures of the new compounds were elucidated based on the analysis of NMR and MS data and theoretical calculations their ECD spectra. The isolated compounds were evaluated for their protective activities against PC12 cell injury induced by corticosterone (CORT) and 1-methyl-4-phenylpyridine ion (MPP+), as well as inhibitory activities against BACE1. Compound 4, 5,6-dihydroxy-2-(2-phenylethyl)chromone (5), daphnauranol B (7), 6-methoxy-2-[2-(3-methyoxyphenyl)ethyl]chromone (10), isoagarotetrol (14), and 1-hydroxy-1,5-diphenylpentan-3-one (16) showed significant protective effects on CORT-induced injury in PC12 cells at a concentration of 20 µM (P < 0.001). Isoagarotetrol (14) showed a significant protective effect on MPP+-induced injury in PC12 cells at a concentration of 20 µM (P < 0.001), while compound 4 showed a moderate activity (P < 0.01). The BACE1-inhibitory activities of all tested compounds were very weak with less than 30% inhibition at a concentration of 20 µM.

14.
Front Cardiovasc Med ; 8: 661709, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34095251

RESUMO

Background: Regulatory T cells (Tregs) have shown to be protective against the development of atherosclerosis, a major pathological cause for cardiovascular events. Here, we aim to explore the roles of Tregs-related genes in atherosclerosis deterioration. Methods and Results: We downloaded the gene expression profile of 29 atherosclerotic samples from the Gene Expression Omnibus database with an accession number of GSE28829. The abundance of Tregs estimated by the CIBERSORT algorithm was negatively correlated with the atherosclerotic stage. Using the limma test and correlation analysis, a total of 159 differentially expressed Tregs-related genes (DETregRGs) between early and advanced atherosclerotic plaques were documented. Functional annotation analysis using the DAVID tool indicated that the DETregRGs were mainly enriched in inflammatory responses, immune-related mechanisms, and pathways such as complement and coagulation cascades, platelet activation, leukocyte trans-endothelial migration, vascular smooth muscle contraction, and so on. A protein-protein interaction network of the DETregRGs was then constructed, and five hub genes (PTPRC, C3AR1, CD53, TLR2, and CCR1) were derived from the network with node degrees ≥20. The expression patterns of these hub DETregRGs were further validated in several independent datasets. Finally, a single sample scoring method was used to build a gene signature for the five DETregRGs, which could distinguish patients with myocardial infarction from those with stable coronary disease. Conclusion: The results of this study will improve our understanding about the Tregs-associated molecular mechanisms in the progression of atherosclerosis and facilitate the discovery of novel biomarkers for acute cardiovascular events.

15.
Cell Rep ; 35(6): 109101, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33979616

RESUMO

Depleting the microenvironment of important nutrients such as arginine is a key strategy for immune evasion by cancer cells. Many tumors overexpress arginase, but it is unclear how these cancers, but not T cells, tolerate arginine depletion. In this study, we show that tumor cells synthesize arginine from citrulline by upregulating argininosuccinate synthetase 1 (ASS1). Under arginine starvation, ASS1 transcription is induced by ATF4 and CEBPß binding to an enhancer within ASS1. T cells cannot induce ASS1, despite the presence of active ATF4 and CEBPß, as the gene is repressed. Arginine starvation drives global chromatin compaction and repressive histone methylation, which disrupts ATF4/CEBPß binding and target gene transcription. We find that T cell activation is impaired in arginine-depleted conditions, with significant metabolic perturbation linked to incomplete chromatin remodeling and misregulation of key genes. Our results highlight a T cell behavior mediated by nutritional stress, exploited by cancer cells to enable pathological immune evasion.

16.
Zhongguo Zhong Yao Za Zhi ; 46(9): 2197-2206, 2021 May.
Artigo em Chinês | MEDLINE | ID: mdl-34047121

RESUMO

The chromatic values of the broken-fried and single-fried Gardeniae Fructus Praeparatus(GFP) were measured by the color analyzer to analyze the color variation rule, and the contents of 10 main components were determined by ultra-high performance liquid chromatography(UPLC). The multivariate statistical analysis, Pearson correlation analysis, and discriminant analysis were conducted to investigate the color and components of GFP samples. The experimental results revealed that L~*, a~*, b~*, and E~*ab decreased continuously during processing, and the color of samples gradually deepened. The trend and range of chromatic values during broken-frying and single-frying processes were basically identical. Gardenoside, crocin-Ⅰ(C-Ⅰ), and crocin-Ⅱ(C-Ⅱ) showed an obviously downward trend, while the contents of geniposidic acid and 5-hydroxymethylfurfural(5-HMF) increased significantly. Shanzhiside, deacetyl-asperulosidic acid methyl ester, and geniposide(G2) showed a downward trend. Scandoside methyl ester rose first and fell later. Genipin-1-O-gentiobioside(G1) went through a decrease-increase-decrease trend. The change trends of component contents during broken-frying and single-frying processes were generally consistent, but the change range was different. Among all the components, scandoside methyl ester and G1 showed obvious change. Because of different stir-frying time, the change rate of each component content in the process of broken-frying was higher than that in single-frying process. Additionally, geniposidic acid, gardenoside, scandoside methyl ester, C-Ⅰ, C-Ⅱ, and 5-HMF exhibited a higher correlation with apparent color. On the basis of above findings, the discriminant function of two frying processes was established, which could be applied to the discrimination of broken-fried and single-fried samples. This study analyzed the dynamic quality change rule of GFP during broken-frying and single-frying processes based on color-component correlation analysis, and found the two methods showed consistent change trend, yet with slight difference in the quality of samples. This study can provide data support for the processing of GFP.


Assuntos
Medicamentos de Ervas Chinesas , Gardenia , Cromatografia Líquida de Alta Pressão , Frutas
17.
Adv Sci (Weinh) ; 8(10): 2001978, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-34026427

RESUMO

Neoadjuvant chemotherapy (NACT) remains an attractive alternative for controlling locally advanced cervical cancer. However, approximately 15-34% of women do not respond to induction therapy. To develop a risk stratification tool, 56 patients with stage IB-IIB cervical cancer are included in 2 research centers from the discovery cohort. Patient-specific somatic mutations led to NACT non-responsiveness are identified by whole-exome sequencing. Next, CRISPR/Cas9-based library screenings are performed based on these genes to confirm their biological contribution to drug resistance. A 15-gene classifier is developed by generalized linear regression analysis combined with the logistic regression model. In an independent validation cohort of 102 patients, the classifier showed good predictive ability with an area under the curve of 0.80 (95% confidence interval (CI), 0.69-0.91). Furthermore, the 15-gene classifier is significantly associated with patient responsiveness to NACT in both univariate (odds ratio, 10.8; 95% CI, 3.55-32.86; p = 2.8 × 10-5) and multivariate analysis (odds ratio, 17.34; 95% CI, 4.04-74.40; p = 1.23 × 10-4) in the validation set. In conclusion, the 15-gene classifier can accurately predict the clinical response to NACT before treatment, representing a promising approach for guiding the selection of appropriate treatment strategies for locally advanced cervical cancer.

18.
Cytogenet Genome Res ; 161(3-4): 167-177, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33951625

RESUMO

The barrier-to-autointegration factor (BAF) is widely expressed in most human tissues and plays a critical role in chromatin organization, nuclear envelope assembly, gonadal development, and embryonic stem cell self-renewal. Complete loss of BAF has been shown to lead to embryonic lethality and gonadal defects. The BAF paralog, namely, barrier-to-autointegration factor 2 (BANF2), exhibits a testis-predominant expression pattern in both humans and mice. Unlike BAF, it may cause isolated male infertility. Therefore, we used the CRISPR/Cas9 system to generate Banf2-knockout mice to further study its function in spermatogenesis. Unexpectedly, knockout mice did not show any detectable abnormalities in histological structure of the testis, epididymis, ovary, and other tissues, and exhibited normal fertility, indicating that Banf2 is not essential for mouse spermatogenesis and fertility.


Assuntos
Fertilidade/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas Nucleares/genética , Espermatogênese/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Sistemas CRISPR-Cas , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Genes Essenciais , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Nucleares/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Espermatozoides/metabolismo , Testículo/citologia , Testículo/metabolismo
19.
J Immunother ; 44(7): 264-275, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-33928928

RESUMO

LY3381916 is an orally available, highly selective, potent inhibitor of indoleamine 2,3-dioxygenase 1. This study explored the safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of LY3381916 monotherapy and in combination with a programmed death-ligand 1 (PD-L1) inhibitor (LY3300054) in patients with advanced solid tumors. During dose escalation, patients received escalating doses of LY3381916 at 60-600 mg once daily (qd) and 240 mg twice daily in monotherapy (n=21) and in combination with PD-L1 inhibitor at 700 mg every 2 weeks (n=21). A modified toxicity probability interval method was used to guide dose escalation. Dose-limiting toxicities occurred in 3 patients; 1 at LY3381916 240 mg twice daily (alanine aminotransferase/aspartate aminotransferase increase and systemic inflammatory response syndrome) and 2 at LY3381916 240 mg qd in combination with PD-L1 inhibitor (fatigue and immune-related hepatitis). LY3381916, at the recommended phase II dose, 240 mg qd, in combination with PD-L1 inhibitor, produced maximal inhibition of indoleamine 2,3-dioxygenase 1 activity in plasma and tumor tissue, and led to an increase of CD8 T cells in tumor tissue. In the combination dose expansion cohorts, 14 triple-negative breast cancer and 4 non-small cell lung cancer patients were enrolled. Treatment-related liver toxicity (grade ≥2 alanine aminotransferase/aspartate aminotransferase increase or immune-related hepatitis) was the most prominent adverse event in triple-negative breast cancer patients (n=5, 35.7%). Best response was stable disease. These preliminary data suggest an alternative dose level of LY3381916 is needed for the combination with PD-L1 inhibitor. The combination clinical activity was limited in this study.

20.
J Biomater Sci Polym Ed ; 32(12): 1548-1563, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33902402

RESUMO

Nowadays, great effort has been devoted to fabricate flexible wearable sensor with high stretchability, moderate modulus, favorable durability, excellent transparency, and satisfactory sensitivity. In this work, we report the preparation of a hybrid double-network (DN) hydrogel by a simple one-pot method. First, chitosan was added into an AlCl3 solution to form Al3+-chitosan complex (CS-Al3+). Second, the hybrid CS/Al3+-poly(acrylamide) (PAM) DN hydrogels were constructed via in situ polymerization of acrylamide (AM) in present of Al3+-chitosan complex. Thanks to the existence of electrically conductive CS-Al3+ networks, the resulting hybrid DN hydrogel exhibits excellent stretchability, fatigue resistance, transparency, and conductivity. Furthermore, the CS/Al3+-PAM DN hydrogel could be used as strain sensor, and demonstrates many desired virtues, including satisfactory sensitivity (gauge factors of 1.7-12.1), wide detection range (up to 1500%), low limit of discernment (1% strain), high reliability, and excellent durability (1000 cycles). More significantly, the manufactured hydrogel-based strain sensor can be employed as wearable devices to precisely detect various human movements.


Assuntos
Quitosana , Dispositivos Eletrônicos Vestíveis , Condutividade Elétrica , Humanos , Hidrogéis , Reprodutibilidade dos Testes
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