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1.
Mol Genet Genomic Med ; : e1687, 2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-33951332

RESUMO

OBJECTIVE: This study was to report the experiences on the clinical value of noninvasive prenatal testing (NIPT) for the screening of fetal chromosomal deletions/duplications. METHODS: We performed a retrospective analysis of a cohort of 20,439 pregnancies undergoing NIPT from March 2017 to September 2020 at a single center. Patients with positive NIPT results for fetal chromosomal deletions or duplications had options of invasive diagnostic testing or no further testing. The data were complied from all cases with positive NIPT results for chromosomal deletions/duplications. The positive predictive value (PPV) was calculated from tabulated data. RESULTS: In this cohort, positive NIPT results for fetal chromosomal deletions/duplications were found in 60 pregnant women. Of the positive samples, further invasive testing was performed in 39 cases, in which 9 cases were found to be true positive. The overall PPV for chromosomal deletions/duplications was 23.1%. In addition, fetal structural anomaly was found by ultrasound examination in three cases, in which the chromosomal deletions/duplications of three cases were not verified. Moreover, an unexpected pathogenic 8p23.3 deletion was identified by invasive testing in 1 fetus with a false positive NIPT screen for 3q27.3q29 duplication. CONCLUSIONS: In summary, positive NIPT results of chromosomal deletions/duplications were not uncommon in clinical practice, whereas the PPV for the testing was low. Hence, potential risks and high percentage of false positives for these abnormal NIPT results might be informed to pregnant women before the choice made of invasive testing.

2.
Cell Death Differ ; 2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-33953349

RESUMO

The biological function of PRMT5 remains poorly understood in cervical cancer metastasis. Here, we report that PRMT5 physically associates with the transcription factor Snail and the NuRD(MTA1) complex to form a transcriptional-repressive complex that catalyzes the symmetrical histone dimethylation and deacetylation. This study shows that the Snail/PRMT5/NuRD(MTA1) complex targets genes, such as TET1 and E-cadherin, which are critical for epithelial-mesenchymal transition (EMT). This complex also affects the conversion of 5mC to 5hmC. This study demonstrates that the Snail/PRMT5/NuRD(MTA1) complex promotes the invasion and metastasis of cervical cancer in vitro and in vivo. This study also shows that PRMT5 expression is upregulated in cervical cancer and various human cancers, and the PRMT5 inhibitor EPZ015666 suppresses EMT and the invasion potential of cervical cancer cells by disinhibiting the expression of TET1 and increasing 5hmC, suggesting that PRMT5 is a potential target for cancer therapy.

3.
J Hepatol ; 2021 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-33961939

RESUMO

BACKGROUND AND AIM: HEV is a significant cause of acute hepatitis globally. Some genotypes establish persistent infection when immunity is impaired. Adaptive immune mechanisms that mediate resolution of infection have not been identified. Here, the requirement for CD8+ T cells to control HEV infection was assessed in rhesus macaques, a model of acute and persistent HEV infection in humans. METHODS: Rhesus macaques were untreated or treated with depleting anti-CD8α monoclonal antibodies before challenge with an HEV gt3 isolate derived from a chronically infected human subject. HEV replication, ALT, anti-capsid antibody and HEV-specific CD4+ and CD8+ T cell responses were assessed after infection. RESULTS: HEV control in untreated macaques coincided with the onset of a neutralizing IgG response against the ORF2 capsid and liver infiltration of functional HEV-specific CD4+ and CD8+ T cells. Virus control was delayed by 1 week in CD8+ T cell depleted macaques. Infection resolved with onset of a neutralizing IgG antibody response and a much more robust expansion of CD4+ T cells with antiviral effector function. CONCLUSIONS: Liver infiltration of functional CD8+ T cells coincident with HEV clearance in untreated RM, and a 1 week delay in HEV clearance in CD8+ T cell depleted RM, support a role for this subset in timely control of virus replication. Resolution of infection in the absence of CD8+ T cells nonetheless indicates that neutralizing antibodies and/or CD4+ T cells may act autonomously to inhibit HEV replication. HEV susceptibility to multiple adaptive effector mechanisms may explain why persistence occurs only with generalized immune suppression. The findings also suggest that neutralizing antibodies and/or CD4+ T cells should be considered as a component of immunotherapy for chronic infection. LAY ABSTRACT: The hepatitis E virus is a major cause of liver disease globally. Some genetic types (genotypes) of HEV persist in the body if immunity is impaired. Our objective was to identify immune responses that promote clearance of HEV. Findings indicate that HEV may be susceptible to multiple arms of the immune response that can act independently to terminate infection. They also provide a pathway to assess immune therapies for chronic HEV infection.

4.
Chem Biol Drug Des ; 2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-33963669

RESUMO

While screening for natural product scaffolds as potential anti Alzheimer's disease (AD), oxymatrine (OMT) was found to relieve symptoms of AD through diminishing death of neuronal cells caused by microglia induced inflammation. In this study, 13 derivatives of OMT were synthesized and their neuroprotective effects were evaluated on Aß1-42 induced PC12 cells using MTT method. In addition, the best neuroprotective potencies were obtained with compounds 4, 6e and 6f, which were selected for evaluation of decrease of IL-1ß and TNF-α in Aß1-42 -treated PC12 cells. Collectively, these data reveal that derivatives 6e and 6f possess best ability of diminish IL-1ß production and reverse cell damage in all compounds, which are possible to developed as therapeutic agents for AD.

5.
Mol Cell ; 2021 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-33930332

RESUMO

A deficient interferon (IFN) response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been implicated as a determinant of severe coronavirus disease 2019 (COVID-19). To identify the molecular effectors that govern IFN control of SARS-CoV-2 infection, we conducted a large-scale gain-of-function analysis that evaluated the impact of human IFN-stimulated genes (ISGs) on viral replication. A limited subset of ISGs were found to control viral infection, including endosomal factors inhibiting viral entry, RNA binding proteins suppressing viral RNA synthesis, and a highly enriched cluster of endoplasmic reticulum (ER)/Golgi-resident ISGs inhibiting viral assembly/egress. These included broad-acting antiviral ISGs and eight ISGs that specifically inhibited SARS-CoV-2 and SARS-CoV-1 replication. Among the broad-acting ISGs was BST2/tetherin, which impeded viral release and is antagonized by SARS-CoV-2 Orf7a protein. Overall, these data illuminate a set of ISGs that underlie innate immune control of SARS-CoV-2/SARS-CoV-1 infection, which will facilitate the understanding of host determinants that impact disease severity and offer potential therapeutic strategies for COVID-19.

6.
Cancer Biomark ; 2021 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-33896819

RESUMO

BACKGROUND: Inflammation-based prognostic scores have been increasingly used for prognosis prediction in malignant tumors. However, no existing study has comprehensively evaluated these scores in combined hepatocellular-cholangiocarcinoma (cHCC-CCA). OBJECTIVE: This study aimed to identify a robust inflammation-based prognostic predictor for cHCC-CCA. METHODS: We retrospectively analyzed 220 patients pathologically confirmed as Allen type C cHCC-CCA. The univariate and multivariate analyses were used to explore the associations between clinical variables and prognosis of cHCC-CCA. The propensity score-matching (PSM) was performed to reduce the effects of potential cofounders and selection bias. Finally, the predictive values of different inflammation-based indices were compared by using time-dependent receiver operating characteristic (ROC) curves. RESULTS: The systemic immune-inflammation index (SII) and aspartate aminotransferase to platelet ratio index (APRI) were identified as independent prognostic predictors in multivariate analysis. After PSM, the survival differences were still significant between SII-high group and SII-low group (P= 0.016 for RFS and P= 0.001 for OS). Further ROC analysis showed that the SII harbored the largest 1-, 3- and 5-year area under the curves (AUC) values as compared with other scores. CONCLUSIONS: The SII may serve as a preferable predictor of both recurrence-free survival (RFS) and overall survival (OS) in patients with cHCC-CCA.

7.
PLoS Pathog ; 17(4): e1009561, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33905456

RESUMO

The H7N9 avian influenza virus (AIV) that emerged in China have caused five waves of human infection. Further human cases have been successfully prevented since September 2017 through the use of an H7N9 vaccine in poultry. However, the H7N9 AIV has not been eradicated from poultry in China, and its evolution remains largely unexplored. In this study, we isolated 19 H7N9 AIVs during surveillance and diagnosis from February 2018 to December 2019, and genetic analysis showed that these viruses have formed two different genotypes. Animal studies indicated that the H7N9 viruses are highly lethal to chicken, cause mild infection in ducks, but have distinct pathotypes in mice. The viruses bound to avian-type receptors with high affinity, but gradually lost their ability to bind to human-type receptors. Importantly, we found that H7N9 AIVs isolated in 2019 were antigenically different from the H7N9 vaccine strain that was used for H7N9 influenza control in poultry, and that replication of these viruses cannot, therefore, be completely prevented in vaccinated chickens. We further revealed that two amino acid mutations at positions 135 and 160 in the HA protein added two glycosylation sites and facilitated the escape of the H7N9 viruses from the vaccine-induced immunity. Our study provides important insights into H7N9 virus evolution and control.

8.
Nature ; 2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33727703

RESUMO

The COVID-19 pandemic is the third outbreak this century of a zoonotic disease caused by a coronavirus, following the emergence of severe acute respiratory syndrome (SARS) in 20031 and Middle East respiratory syndrome (MERS) in 20122. Treatment options for coronaviruses are limited. Here we show that clofazimine-an anti-leprosy drug with a favourable safety profile3-possesses inhibitory activity against several coronaviruses, and can antagonize the replication of SARS-CoV-2 and MERS-CoV in a range of in vitro systems. We found that this molecule, which has been approved by the US Food and Drug Administration, inhibits cell fusion mediated by the viral spike glycoprotein, as well as activity of the viral helicase. Prophylactic or therapeutic administration of clofazimine in a hamster model of SARS-CoV-2 pathogenesis led to reduced viral loads in the lung and viral shedding in faeces, and also alleviated the inflammation associated with viral infection. Combinations of clofazimine and remdesivir exhibited antiviral synergy in vitro and in vivo, and restricted viral shedding from the upper respiratory tract. Clofazimine, which is orally bioavailable and comparatively cheap to manufacture, is an attractive clinical candidate for the treatment of outpatients and-when combined with remdesivir-in therapy for hospitalized patients with COVID-19, particularly in contexts in which costs are an important factor or specialized medical facilities are limited. Our data provide evidence that clofazimine may have a role in the control of the current pandemic of COVID-19 and-possibly more importantly-in dealing with coronavirus diseases that may emerge in the future.

9.
Acad Radiol ; 2021 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-33653656

RESUMO

OBJECTIVE: This study aimed to assess the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) with modified FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) as an alternative treatment option in advanced hepatocellular carcinoma (HCC) patients with failed or unsuitability for transarterial chemoembolization (TACE). MATERIALS AND METHODS: From September 2018 to January 2020, 87 advanced HCC patients who progressed on TACE or were not eligible for TACE received HAIC treatment with modified FOLFOX. The primary endpoint was overall survival (OS) and secondary endpoints included progression-free survival (PFS), tumor response assessed by Response Evaluation Criteria in Solid Tumors 1.1, and adverse events graded according to CTCAE 5.0. Based on prognostic factors determined by multivariate analysis, a nomogram was developed to predict patient survival. RESULTS: The median OS and PFS were 9.0 months (95%CI 7.6-10.4) and 3.7 months (95%CI 3.1-4.3), respectively. The objective response rate was 13.8%, with a disease control rate of 48.3%. Grade 3 adverse events were observed, such as infection (9.2%), thrombocytopenia (5.7%), hyperbilirubinemia (3.4%), abdominal pain (2.3%) and alanine aminotransferase increase (2.3%). Albumin, AST, and extrahepatic metastasis were incorporated to construct a new nomogram that could stratify patients into three prognostic subgroups, including low-, intermediate-, and high-risk groups, with significant differences in 9-month OS rates (71%, 42% and 6%, respectively; p< 0.001). The nomogram was better than the Okuda, AJCC, and CLIP staging systems for OS prediction. CONCLUSION: These findings support the feasibility of HAIC with modified FOLFOX as an alternative treatment strategy for advanced HCC when TACE is ineffective or unsuitable.

10.
Zhongguo Gu Shang ; 34(1): 80-5, 2021 Jan 25.
Artigo em Chinês | MEDLINE | ID: mdl-33666025

RESUMO

OBJECTIVE: To investigate the clinical effect of anterior cervical Hybrid surgery in the treatment of cervical degenerative diseases (CDD) and observe the incidence of heterotopic ossification of disc replacement segment at 1 year after surgery. METHODS: From January 2015 to April 2018, 35 patients who received anterior cervical hybrid surgery met the inclusion and exclusion criteria and the complete clinical follow up data were analyzed retrospectively. Complete imaging follow-up data were obtained from 24 patients. There were 15 males and 20 females, aged from 39 to 70(55.57±7.73) years old. The amount of bleeding was for 20 to 100 (40.29±18.39) ml, and the hospitalstay was for 4 to 28(11.03±4.63) days, and the follow-up time was(12.97±1.36) months. Clinical outcomes were assessed by the Tanaka Yasushi cervical spondylitis symptom scale 20 score (YT20), and Japanese Orthopaedic Association (JOA) score. The occurrence of heterotopic ossification after Hybrid surgery was evaluated by X-ray according to McAfee standard one year after operation. Patients with or without heterotopic ossificationwere divided into two groups and their clinical effects were compared. RESULTS: At the final follow up, the mean YT20 score and JOA score were significantly higher than those before operation (P <0.05), and the average improvement rate of JOA was (70.66 ±0.44)%. One year after operation, the heterotopic ossification occurred in 10 of 24 segments, with incidence of 41.70%(10/24), including 29.20% in gradeⅠand 12.50% in gradeⅡ. The results of clinical efficacy comparison between patients with and without heterotopic ossification were as follows:there was no significant difference in JOA score before and after operation (P>0.05);there was no significant difference in YT20 score before operation (P>0.05), and YT20 score in patients with heterotopic ossification was significantly lower than that in patients without heterotopic ossification(P<0.05). CONCLUSION: The short-term clinical effect of Hybrid surgery is satisfactory for cervical degenerative diseases, and the cause of heterotopic ossification still needs tobe further explored.


Assuntos
Degeneração do Disco Intervertebral , Substituição Total de Disco , Adulto , Idoso , Vértebras Cervicais/cirurgia , Feminino , Seguimentos , Humanos , Degeneração do Disco Intervertebral/cirurgia , Masculino , Pessoa de Meia-Idade , Amplitude de Movimento Articular , Estudos Retrospectivos , Resultado do Tratamento
11.
Int J Food Microbiol ; 342: 109044, 2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33529874

RESUMO

Antimicrobial resistance (AMR) in non-typhoidal Salmonella from poultry is a public health concern. Injudicious use of antibiotics in humans and agriculture fuels the emergence of resistance. The objective of this study was to characterize the prevalence, antibiotic susceptibility profiles and genetic resistance mechanisms of Salmonella isolated from US retail poultry meat samples with and without antibiotic-related claims. We reviewed data from 46,937 poultry meat samples collected from 2008 to 2017 through the FDA NARMS retail meat program. Antibiotic usage claims on the poultry packaging were used to categorize the sample as 'conventionally raised' or 'reduced or no antibiotic use'. The results show that the prevalence of Salmonella in conventional poultry samples (8.6%) was higher than reduced or no antibiotic use poultry samples (5.1%). The odds of resistance to three or more antimicrobial classes (multi-drug resistant) were 2.61 times higher for Salmonella isolates from conventional samples, compared to isolates from reduced antibiotic use samples. The frequency of the aminoglycoside resistance gene, strB, and the beta-lactam resistant gene, blaCMY-2, were higher in isolates from conventional meat. This study suggests that conventionally raised poultry meat was more likely to be contaminated with multi-drug resistant Salmonella, and those Salmonella are more likely to carry genes for antibiotics resistance.


Assuntos
Agricultura/métodos , Antibacterianos/uso terapêutico , Farmacorresistência Bacteriana , Aves Domésticas/microbiologia , Salmonella/efeitos dos fármacos , Animais , Antibacterianos/farmacologia , Farmacorresistência Bacteriana/efeitos dos fármacos , Farmacorresistência Bacteriana/genética , Genes Bacterianos , Testes de Sensibilidade Microbiana , Salmonella/genética , Salmonella/isolamento & purificação , Salmonelose Animal/tratamento farmacológico , Salmonelose Animal/microbiologia , Estados Unidos
12.
J Antibiot (Tokyo) ; 74(5): 317-323, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33558649

RESUMO

Fungi are important resources for drug development, as they have a diversity of genes, that can produce novel secondary metabolites with effective bioactivities. Here, five depsidone-based analogs were isolated from the rice media of Chaetomium brasiliense SD-596. Their structures were elucidated using NMR and mass spectrometry analysis. Five compounds, including three new depsidone analogs, mollicellin S (1), mollicellin T (2), and mollicellin U (3), and two known compounds, mollicellin D (4) and mollicellin H (5), exhibited significant inhibition against Staphylococcus aureus and methicillin-resistant Staphylococcus aureus (MRSA), with MIC values ranging from 6.25 to 12.5 µg ml-1. Herein, we identified the predicted plausible biosynthetic cluster of the compounds and discussed the structure-activity relationship. Finally, we found that the introduction of aldehyde and methoxyl groups provide marked improvement for the inhibition against MRSA.

13.
Neurosurg Focus ; 50(2): E9, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33524950

RESUMO

OBJECTIVE: The aim of this study was to demonstrate the in vivo safety and antitumor effect of a novel recombinant vesicular stomatitis virus (VSV): G protein less (GLESS)-fusion-associated small transmembrane (FAST)-VSV. METHODS: Viral infection efficiency and cell proliferation were detected using an inverted fluorescence microscope and alarmaBlue assay, respectively. To evaluate the safety of the virus, different doses of GLESS-FAST-VSV and a positive control virus (VSV∆M51) were injected into normal F344 rats and C57BL/6 mice, and each animal's weight, survival time, and pathological changes were examined on the following day. To evaluate the efficacy of the virus, RG2 and GL261 cells were used to construct rat and mouse glioma models, respectively, via a stereotactic method. After multiple intratumoral injections of the virus, tumor growth (size) and the survival time of the animals were observed. RESULTS: In vitro experiments showed that GLESS-FAST-VSV could infect and kill brain tumor cells and had less toxic effects on normal cells. After direct injection of GLESS-FAST-VSV into the animal brains, all animals tolerated the virus well, and no animal death, encephalitis, or ventriculitis was observed. In contrast, all animals that received brain injections of VSV∆M51 in the brain died. Moreover, multiple injections of GLESS-FAST-VSV in brain tumors significantly prolonged the survival of normal-immunity animals harboring brain tumors. CONCLUSIONS: GLESS-FAST-VSV exhibited little neurotoxicity and could be injected directly into the tumor to effectively inhibit tumor growth and prolong the survival of normal-immunity animals, laying a theoretical foundation for the early application of such viruses in clinical trials.

14.
Sci Total Environ ; 771: 144751, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33545472

RESUMO

This study investigated the effects of applying different biochars to soil on shifts in the bacterial community, the biodegradation of antibiotics, and their relationships. In total, nine biochars were applied to agricultural soil contaminated with 16 antibiotics. Clustering analysis showed that the responses of bacteria at the genus level to biochars were highly dependent on the biochar feedstock rather than the pyrolysis temperature. Among the antibiotics tested in the study, the biodegradation percentage was lower for tetracyclines (TCs, 6-14%) than sulfonamides (SAs, 8-26%) and quinolones (QLs, 8-24%). For specific individual antibiotics from the same class with similar structures, the high adsorption affinity of soil particles for antibiotics due to hydrophobic interactions (logKow) and electrostatic interactions (pKa) resulted in low biodegradation percentages for antibiotics in the soil. The biodegradation of TCs was affected more by the biochar type (effect size: -10% to 42%) than those of QLs (-26% to 14%) and SAs (-24% to 22%). According to the relationships determined between the bacterial taxonomic composition and biodegradation of antibiotics, Steroidobacter from the phylum Proteobacteria has significant positive correlations with the biodegradation of all SAs (p < 0.01), thereby indicating that Steroidobacter had a high capacity for biodegrading SAs. Significant positive correlations were also detected (p < 0.05) between specific genera (Iamia, Parviterribacter, and Gaiella) from the phylum Actinobacteria and the biodegradation of SAs. No significant positive correlations were found between bacterial genera and the biodegradation percentages for QLs and TCs, possibly due to the specific microorganisms involved in these biodegradation processes. The results in this study provide insights into the biodegradation mechanisms of antibiotics in soil and they may facilitate the development of strategies for the bioremediation of antibiotic-contaminated soil.


Assuntos
Poluentes do Solo , Solo , Antibacterianos , Bactérias , Biodegradação Ambiental , Carvão Vegetal , Poluentes do Solo/análise
15.
Aging (Albany NY) ; 13(4): 5824-5844, 2021 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-33612482

RESUMO

Gastric cancer (GC) is a heterogeneous disease with different clinical manifestations and prognoses. Alternative splicing (AS) is a determinant of gene expression and contributes to protein diversity from a rather limited gene transcript in metazoans. AS events are associated with different aspects of cancer biology, including cell proliferation, apoptosis, invasion, etc. Here, we present a comprehensive analysis of the prognostic AS profile in GC. GC-specific AS (GCAS) events were analyzed, and overall survival-associated GCAS (OS-GCAS) events were verified among the genome-wide AS events identified in The Cancer Genome Atlas (TCGA) database. In total, 1,287 GCAS events of 837 genes and 173 OS-GCAS events of 130 genes were identified. The parental genes of OS-GCAS events were significantly enriched in the development of GC. Protein-protein interaction (PPI) and OS-GCAS-associated splicing factor (SF) interaction networks were constructed. Multivariate Cox regression analysis with least absolute shrinkage and selection operator (LASSO) penalty was performed to establish a prognostic risk formula, representing 23 OS-GCAS events. The low-risk group had better OS than the high-risk group and lower immune and stromal scores. Cox proportional hazard regression was applied to generate an AS-clinical integrated prognostic model with a considerable area under the curve (AUC) value in both the training and validation datasets. Our study provides a profile of OS-GCAS events and an AS-clinical nomogram to predict the prognosis of GC.

16.
Theranostics ; 11(5): 2058-2076, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33500709

RESUMO

Histone deacetylases (HDACs) are involved in key cellular processes and have been implicated in cancer. As such, compounds that target HDACs or drugs that target epigenetic markers may be potential candidates for cancer therapy. This study was therefore aimed to identify a potential epidrug with low toxicity and high efficiency as anti-tumor agents. Methods: We first screened an epigenetic small molecule inhibitor library to screen for an epidrug for breast cancer. The candidate was identified as PCI-24781 and was characterized for half maximal inhibitory concentration (IC50), for specificity to breast cancer cells, and for effects on carcinogenesis and metastatic properties of breast cancer cell lines in vitro. A series of in silico and in vitro analyses were further performed of PCI-24781 to identify and understand its target. Results: Screening of an epigenetic inhibitor library in MDA-MB-231 cells, a malignant cancer cell line, showed that PCI-24781 is a potential anti-tumor drug specific to breast cancer. Ca2+ related pathways were identified as a potential target of PCI-24781. Further analyses showed that PCI-24781 inhibited Gαq-PLCß3-mediated calcium signaling by activating the expression of regulator of G-protein signaling 2 (RGS2) to reduce cell proliferation, metastasis, and differentiation, resulting in cell death in breast cancer. In addition, RGS2 depletion reversed anti-tumor effect and inhibition of calcium influx induced by PCI-24781 treatment in breast cancer cells. Conclusions: We have demonstrated that PCI-24781 is an effective anti-tumor therapeutic agent that targets calcium signaling by activating RGS2. This study also provides a novel perspective into the use of HDAC inhibitors for cancer therapy.

17.
Cell Rep ; 34(2): 108628, 2021 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-33440148

RESUMO

Recent studies have profiled the innate immune signatures in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and suggest that cellular responses to viral challenge may affect disease severity. Yet the molecular events that underlie cellular recognition and response to SARS-CoV-2 infection remain to be elucidated. Here, we find that SARS-CoV-2 replication induces a delayed interferon (IFN) response in lung epithelial cells. By screening 16 putative sensors involved in sensing of RNA virus infection, we found that MDA5 and LGP2 primarily regulate IFN induction in response to SARS-CoV-2 infection. Further analyses revealed that viral intermediates specifically activate the IFN response through MDA5-mediated sensing. Additionally, we find that IRF3, IRF5, and NF-κB/p65 are the key transcription factors regulating the IFN response during SARS-CoV-2 infection. In summary, these findings provide critical insights into the molecular basis of the innate immune recognition and signaling response to SARS-CoV-2.


Assuntos
Imunidade Inata , Helicase IFIH1 Induzida por Interferon/metabolismo , /fisiologia , /patologia , Linhagem Celular , Células Epiteliais/citologia , Células Epiteliais/imunologia , Células Epiteliais/virologia , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Fator Regulador 3 de Interferon/genética , Fator Regulador 3 de Interferon/metabolismo , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/metabolismo , Interferons/genética , Interferons/metabolismo , RNA Helicases/metabolismo , Interferência de RNA , RNA de Cadeia Dupla/metabolismo , RNA Interferente Pequeno/metabolismo , /isolamento & purificação , Transdução de Sinais , Fator de Transcrição RelA/metabolismo , Replicação Viral
18.
Cancer Med ; 10(3): 1103-1119, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33410261

RESUMO

BACKGROUND: Inflammatory indexes are considered to be potential prognostic biomarkers for patients with gastric cancer (GC). However, little evidence has defined the prognostic significance of inflammatory indexes for GC with different Lauren classification. METHODS: A total of 852 patients with GC were randomly selected consecutively into intestinal type and diffuse/mixed type groups. Group bias was reduced by propensity score matching. The cutoff values of inflammatory indexes were analyzed by receiver operating characteristic curve. The Kaplan-Meier method and log-rank test were used to analyze the overall survival (OS). The chi-square test was used to analyze the association between inflammatory indexes and clinical characteristics. The independent risk factor for prognosis in each group was analyzed by univariate and multivariate analyses based on logistic regression. The nomogram models were constructed by R studio. RESULTS: Intestinal type GC patients (p < 0.05) had a lower percentage of neutrophils in stage I, higher percentage of neutrophils and higher platelet count in stage Ⅲ (p < 0.05). Systemic immune-inflammation index (SII) (p < 0.001), pTNM stage (p < 0.001), and postoperative chemotherapy (p = 0.002) were independent risk factors for prognosis in the intestinal type group. Platelet-lymphocyte ratio (PLR) (p < 0.001) and pTNM stage (p = 0.001) were independent risk factors for prognosis in the diffuse/mixed type group. The area under the curve of the nomogram model in predicting 5-year prognosis in the intestinal type group and diffuse/mixed type group were 0.807 and 0.788, respectively. CONCLUSION: SII combined with postoperative chemotherapy and pTNM stage were used to construct a nomogram model to predict the prognosis of intestinal type GC. PLR combined with pTNM stage can be used to construct a nomogram model for diffuse/mixed type GC patients.

19.
Int J Hyperthermia ; 38(1): 1-10, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33400889

RESUMO

OBJECTIVE: Albumin-to-alkaline phosphatase ratio (AAPR), a newly developed blood biomarker, has been reported to have prognostic value in several types of cancer. This study aimed to investigate the predictive value of AAPR in patients with early-stage hepatocellular carcinoma (HCC) undergoing radiofrequency ablation (RFA) as initial therapy. METHODS: This retrospective study analyzed 445 patients with newly diagnosed HCC undergoing RFA as initial therapy. A series of survival analyses were performed to evaluate the prognostic value of AAPR. Univariate and multivariate analyses were performed to identify independent prognostic factors. An AAPR-based nomogram was constructed, and its predictive performance was validated. RESULTS: Patients with a low AAPR had a significantly reduced recurrence-free survival (RFS) and overall survival (OS) compared with those with a high AAPR. AAPR was found to be an independent prognostic indicator and showed superior discrimination efficacy than other liver function indices. The AAPR-based nomogram had a concordance index value of 0.72 (95% confidence interval [CI]: 0.65-0.79) in the training cohort and 0.72 (95% CI: 0.63-0.81) in the validation cohort, which significantly outperformed other existing staging systems. CONCLUSIONS: AAPR serves as a promising indicator of prognosis in patients with early-stage HCC undergoing RFA. The AAPR-based nomogram might contribute to individualized prognosis prediction and clinical decision making.

20.
Medicine (Baltimore) ; 100(2): e24045, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33466156

RESUMO

RATIONALE: Drug-induced liver injury (DILI) has a relatively low incidence, whereas the incidence of herb-induced liver injury (HILI) is still under investigation. As a special type of DILI, the diagnosis of drug-induced autoimmune-like hepatitis presents a persistent challenge, because this condition has partial characteristics of both DILI and autoimmune hepatitis (AIH), such as a certain history of medication use and histology that similar is to AIH. Thus, the differential diagnosis between DILI and AIH can be confusing. PATIENT CONCERNS: A 67-year-old woman taking xiang-tian-guo for 6 months was admitted to our hospital with a complaint of experiencing jaundice for 2 weeks. DIAGNOSIS: A liver biopsy exhibited interface inflammation, foam cells, and "rosette" -like hepatocytes. She was diagnosed with herb-induced liver injury (hepatocellular and acute), a RUCAM score of 7 (probable), a severity for grade 4 liver injury, and accompanied autoimmune-like changes. INTERVENTIONS: The patient was instructed to cease the administration of suspicious drugs. The patient also received liver protection and albumin transfusion. OUTCOMES: After 25 days of hospitalization, the patients aminotransferase levels returned to normal. No recurrence was observed after the administration of the treatments and a close follow-up. LESSONS: We must to be vigilant about the safety of xiang-tian-guo as a herbal medicine. When faced with the difficulty of distinguishing between AIH and DILI, long-term follow-up observations for recurrence can aid clinicians in making a judgment.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Medicamentos de Ervas Chinesas/efeitos adversos , Meliaceae/efeitos adversos , Idoso , Biópsia , Diagnóstico Diferencial , Feminino , Hepatite Autoimune/diagnóstico , Humanos , Testes de Função Hepática
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