Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 484
Filtrar
1.
Cell Adh Migr ; 17(1): 20-34, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36656313

RESUMO

The effect of cathelicidin hCAP18/LL-37 in hepatocellular carcinoma (HCC) metastasis remains unclear. Here, we confirmed that LL-37 expression enhanced endothelial-mesenchymal transition (EMT), migration and invasion in HCC cells. And the HER2/EGFR-MAPK/ERK signal participated in the process above. More frequent lung metastases were observed in an LL-37-overexpressing hematogenous metastasis model. Interestingly, 1,25(OH)2D3 together with si-LL-37 significantly enhanced 1,25(OH)2D3-induced inhibition of migration and invasion in PLC/PRF-5 cells, and also enhanced reversion of the EMT process. Therefore, LL-37 is involved in HCC metastases, and may act as an important factor to attenuate the inhibitory activity of 1,25(OH)2D3 on HCC metastasis. Targeting hCAP18/LL-37 may offer a potential strategy to improve the anticancer activity of 1,25(OH)2D3 in HCC therapy.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Camundongos , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Catelicidinas/metabolismo , Catelicidinas/farmacologia , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Movimento Celular
2.
Artif Cells Nanomed Biotechnol ; 51(1): 22-32, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36633420

RESUMO

Human papillomavirus (HPV) infection and related diseases are clinical challenges. The efficacy of 5-aminolevulinic acid photodynamic therapy (ALA-PDT) using red laser (630 ± 5 nm) is remarkable and safe. In this study, we aim to investigate the efficacy of ALA-450 nm PDT comparing with ALA-635 nm PDT. We detected cell proliferation and cell apoptosis through MTT assay and flow cytometry assay respectively. Flow cytometry assay determined the intracellular reactive oxygen species (ROS) generation. Western blotting analysis investigated the protein expression. In vivo, immunohistochemical staining assay and TUNEL assay were performer to detect cell apoptosis. ALA-450 nm PDT inhibited the proliferation of End1 and HeLa cells, promoted cell apoptosis more effectively than ALA-635 nm PDT, and induced cell death probably through increasing the intracellular ROS generation and caspase-dependent apoptosis pathway. In vivo, ALA-450 nm PDT significantly inhibited tumour growth and activated cell apoptosis. The ALA-450 nm PDT had an advantage over ALA-635 nm PDT on inhibiting the proliferation of End1 and HeLa cells and inducing cell apoptosis. The ALA-450 nm PDT might be a promising therapeutic strategy for eradicating the HR-HPV infected cells and promoting the integration of diagnosis and treatment of HR-HPV related diseases.HighlightsWe combined 5-aminolevulinic acid with 450 nm blue laser using as a novel type of photodynamic therapy.The ALA-450 nm PDT had an advantage over ALA-635 nm PDT on inhibition of the proliferation of End1 and HeLa cells and inducing cell apoptosis in vitro and in vivo.The ALA-450 nm PDT may provide a novel alternative therapeutic option in patients with persistent HPV infection and promote the integration of diagnosis and treatment.


Assuntos
Infecções por Papillomavirus , Fotoquimioterapia , Humanos , Ácido Aminolevulínico/farmacologia , Ácido Aminolevulínico/uso terapêutico , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Células HeLa , Espécies Reativas de Oxigênio/metabolismo , Infecções por Papillomavirus/tratamento farmacológico , Linhagem Celular Tumoral , Morte Celular , Apoptose , Lasers
3.
Cell Rep Med ; : 100911, 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36657446

RESUMO

Predicting the clinical response to chemotherapeutic or targeted treatment in patients with locally advanced or metastatic lung cancer requires an accurate and affordable tool. Tumor organoids are a potential approach in precision medicine for predicting the clinical response to treatment. However, their clinical application in lung cancer has rarely been reported because of the difficulty in generating pure tumor organoids. In this study, we have generated 214 cancer organoids from 107 patients, of which 212 are lung cancer organoids (LCOs), primarily derived from malignant serous effusions. LCO-based drug sensitivity tests (LCO-DSTs) for chemotherapy and targeted therapy have been performed in a real-world study to predict the clinical response to the respective treatment. LCO-DSTs accurately predict the clinical response to treatment in this cohort of patients with advanced lung cancer. In conclusion, LCO-DST is a promising precision medicine tool in treating of advanced lung cancer.

4.
Lung Cancer ; 175: 68-78, 2022 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-36473332

RESUMO

OBJECTIVES: Transformed small-cell lung cancer (T-SCLC) has an extremely poor prognosis, and no remedies based on immunotherapy have been evaluated among T-SCLC patients. We retrospectively analysed the efficacy and safety of combining atezolizumab with chemotherapy for T-SCLC. METHODS: Forty-seven patients harbouring EGFR mutations who developed T-SCLC were enrolled. Eleven patients who used immunotherapy were defined as the I/O group, and the remaining 36 were defined as the Non-I/O group. Clinical characteristics, pathological data, and survival outcomes were collected. RNA sequencing and whole-exome sequencing (WES) were performed for in-depth analysis. RESULTS: All patients received at least one line of EGFR-TKI before rebiopsy to confirm T-SCLC. Nine patients received atezolizumab-bevacizumab-carboplatin-paclitaxel (albumin-bound) (ABCP), and the remaining 2 received atezolizumab-etoposide-carboplatin (ECT) in the I/O group. The objective response rate was 73 % (8/11). The median progression-free survival (mPFS) of T-SCLC on post-transformation therapy with I/O group and Non-I/O group was 5.1 m and 4.1 m, respectively. The median post-T-SCLC overall survival of the I/O group was significantly longer than that Non-I/O group (20.2 m vs 7.9 m, P < 0.01). T-SCLC harbouring EGFR L858R tended to be longer than EGFR 19del (mPFS: not reached vs 3.7 m, P = 0.11). Positive PD-L1 status was also associated with PFS benefits (mPFS: 6.0 m vs 3.7 m, P = 0.20). Furthermore, RNA sequencing revealed that expression of SFTPA1 is significantly higher in the durable clinical benefit group. WES showed that STC2 mutation is more frequently observed at the time-point immunotherapy acquired resistance. Combination therapy based on a PD-L1 inhibitor was well tolerated, and the safety profile was consistent with previously reported studies. CONCLUSION: Our study first demonstrated that a PD-L1 inhibitor combined with chemotherapy ± bevacizumab could be a potential safe option for specific SCLC-transformed patients. Subsequent studies with more patients are essential to verify the efficacy and potential biomarkers.

5.
BMC Pregnancy Childbirth ; 22(1): 913, 2022 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-36476185

RESUMO

OBJECTIVES: 16p13.11 microdeletion/microduplication are rare genetic diseases with incomplete penetrance, most of which have been reported in adults and children, with ultrasound phenotyping in fetuses rarely described. Here, we have analyzed prenatal ultrasound phenotypic characteristics associated with 16p13.11 microdeletion/microduplication, in order to improve the understanding, diagnosis and monitoring of this disease in the fetus. METHODS: A total of 9000 pregnant women who underwent invasive prenatal diagnosis for karyotyping and SNP-array were retrospectively analyzed in tertiary referral institutions from October 2016 to January 2022. RESULTS: SNP-array revealed that 20 fetuses had copy number variation (CNV) in the 16p13.11 region, out of which 5 had 16p13.11 microdeletion and the rest showed microduplication, along with different ultrasound phenotypes. Furthermore, 4/20 cases demonstrated structural abnormalities, while the remaining 16 cases were atypical in ultrasound. Taken together, 16p13.1 microdeletion was closely related to thickened nuchal translucency, while 16p13.11 microduplication was more closely associated with echogenic bowel. Only 5/15 fetuses were verified by pedigree, with one case of 16p13.11 microdeletion being de novo, and the other cases of 16p13.11 microduplication were inherited from one parent. In 4/20 cases, the pregnancy was terminated. Except for one case with short stature and another one who underwent lung cystadenoma surgery, no abnormalities were reported in the other cases during follow-up. CONCLUSION: Fetuses with 16p13.11 microdeletion/microduplication had no characteristic phenotype of intrauterine ultrasound and was in good health after birth, thus providing a reference for the perinatal management of such cases.


Assuntos
Variações do Número de Cópias de DNA , Resultado da Gravidez , Feminino , Gravidez , Humanos , Estudos Retrospectivos , Pais , Doenças Raras
6.
Clin Transl Oncol ; 2022 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-36512305

RESUMO

PURPOSE: The interaction between tumor cells and immune system in hepatocellular carcinoma (HCC) remains unclear. Great clinical achievements have progressed in HCC patients treated with immune checkpoint inhibitors (ICIs) for programmed death-1 and its ligands. However, response efficacy for these therapies is limited, thereby requiring alternative ICI candidates for HCC treatment. B7 homolog 3 protein (B7-H3), an immunoregulatory protein, plays a significant role in tumor immunity and disease progression. In this study, we evaluated the correlation between B7-H3 expression and prognosis of HCC patients, and investigated the therapeutic potential of B7-H3 targeting in HCC. METHODS: B7-H3 expression was analyzed immunohistochemically in HCC patients, and its relationship with tumor-infiltrating lymphocyte infiltration was assessed. The anti-tumor efficacy of anti-B7-H3 antibody therapy was determined using an in vitro co-culture system and a subcutaneous HCC-bearing murine model. RESULTS: We found that B7-H3 overexpressed in tumor cells and positively correlated with poor prognosis in HCC patients. B7-H3 inhibited the infiltration of CD8+ T cells in tumors. Furthermore, co-culture experiment indicated that inhibiting B7-H3 in tumor cells significantly increased T cells-mediated immune activities and tumor cell killing. Consistently, anti-B7-H3 antibody-treated HCC murine model showed decreased tumor size and enhanced anti-tumor immunity mediated by CD8+ T cells. CONCLUSION: Altogether, our findings suggest that B7-H3 inhibition in tumor cells restores the immune cytotoxicity of T cells, which in turn promotes apoptosis of target cells. Therefore, B7-H3 serves as a key negative regulator in tumor immunity and the promising clinical utility of B7-H3-based immunotherapies for HCC treatment could be developed.

7.
Front Endocrinol (Lausanne) ; 13: 1069559, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36531473

RESUMO

Introduction: The COVID lockdown has posted a great challenge to paediatric patients with type 1 diabetes (T1D) and their caregivers on the disease management. This systematic review and meta-analysis sought to compare the glycaemic control among paediatric patients with T1D (aged under 18 years) pre- during, and post-lockdown period. Methods and materials: We did a systematic search of three databases (PubMed, Embase, and the WHO COVID-19 Global literature) for the literature published between 1 Jan 2019 to 10 Sep 2022. Studies meeting the following inclusion criteria were eligible for this study: (1) a COVID-19 related study; (2) inclusion of children aged 18 years old or under with established T1D; (3) comparing the outcomes of interest during or after the COVID lockdown with that before the lockdown. Study endpoints included mean difference (MD) in HbA1c, blood glucose, time in range (TIR, 70-180 mg/dl), time above range (TAR, >180mg/dl), time below range (TBR,<70mg/dl) and glucose variability (coefficient of variation [CV]) between pre-lockdown and during lockdown and/or between pre- and post-lockdown period. The MD and its corresponding 95% CI of each endpoint were pooled using random-effect model considering the potential between-study heterogeneity in COVID restrictions and T1D management. Results: Initial search identified 4488 records and 22 studies with 2106 paediatric patients with T1D were included in the final analysis. Compared with pre-lockdown period, blood glucose was significantly decreased by 0.11 mmol/L (95%CI: -0.18, -0.04) during lockdown period and by 0.42 mmol/L (95%CI: -0.73, -0.11) after lockdown. The improvement was also found for TIR, TAR, TBR, and CV during and post-lockdown (all p values<0.05) except for the post-lockdown TBR (p =0.35). No significant change in HbA1c was observed during and post- lockdown period when compared with the pre-lockdown value. There was moderate to high between-study heterogeneity for most of the analyses. Conclusion: Compared with pre-lockdown period, there was significant improvement in T1D paediatric patients' glucose metrics during and post-lockdown. The underlying reasons for this positive impact warrant further investigation to inform future paediatric diabetes management. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022359213.


Assuntos
COVID-19 , Diabetes Mellitus Tipo 1 , Humanos , Criança , Adolescente , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 1/terapia , Glicemia , Controle Glicêmico , COVID-19/epidemiologia , Controle de Doenças Transmissíveis
8.
Chin J Nat Med ; 20(12): 902-913, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36549804

RESUMO

Curculigo orchioides (CUR) and Epimedium (EPI) are traditional Chinese medicines with estrogen-like biological activity, called Xianmao and Xianlingpi (Er-xian) in Chinese. However, whether Er-xian exerts protective effects on myocardial ischemia-reperfusion injury (MIRI) is unknown. This study aimed to investigate the cardioprotective effects of Er-xian preconditioning against MIRI and the underlying mechanisms. CUR or EPI was administered intragastrically to aged female rats as a monotherapy or combination therapy. 2 weeks later, a rat MIRI model was established. Myocardial infarction size, myocardial morphology, cTnT, cell apoptosis rate, intracellular calcium concentration, mitochondrial permeability transition pore (MPTP) opening and reperfusion injury salvage kinase (RISK) signaling pathway molecules were observed after the surgery. To evaluate the mechanisms of Er-xian, estrogen receptors antagonists ICI 182780 and G15 were used. In this study, Er-xian notably alleviated myocardial tissue damage, maintained mitochondrial morphology, reduced infarct size and cardiac markers, and increased sera levels of E2. Moreover, Er-xian inhibited calcium overload and mPTP opening, and decreased cardiomyocyte apoptosis. We found that the dual therapy of CUR and EPI elicited more noticeable results than CUR or EPI monotherapy. The significant protective effects of Er-xian on ischemia-reperfusion myocardium were attributed to the up-regulation of AKT, ERK1/2 and GSK-3ß phosphorylation levels. The cardioprotective effects of Er-xian were significantly reduced after estrogen receptor blockade, especially GPER30. These results indicate that Er-xian attenuates MIRI through RISK signaling pathway and estrogen receptors are the critical mediators.


Assuntos
Traumatismo por Reperfusão Miocárdica , Ratos , Feminino , Animais , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/metabolismo , Receptores de Estrogênio/metabolismo , Cálcio/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Glicogênio Sintase Quinase 3 beta/farmacologia , Miocárdio/metabolismo , Apoptose , Miócitos Cardíacos
9.
Animals (Basel) ; 12(23)2022 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-36496887

RESUMO

Diarrhea is one of the most common diseases affecting the health of Père David's deer (Elaphurus davidianus). It is believed that an imbalanced intestinal ecology contributes to the etiology of the condition. However, little is known about how the intestinal ecology changes in these diarrheic animals. In this study, 16S rRNA gene sequencing and ultra-high performance liquid chromatography combined with tandem mass spectrometry (UPLC-MS/MS) were used to investigate the gut microbiota and fecal metabolites in five Père David's deer with diarrhea. The results showed that when compared with healthy individuals, considerable changes in the gut microbiome were observed in diarrheic animals, including a significant reduction in microbial diversity and gut microbiota composition alterations. Furthermore, the profiles of numerous fecal metabolites were altered in diarrheic individuals, showing large-scale metabolite dysregulation. Among metabolites, acylcarnitines, lysophosphatidylcholine, bile acids, and oxidized lipids were elevated significantly. Constantly, several metabolic pathways were significantly altered. Interestingly, predicted metabolic pathways based on 16S rRNA gene sequence and differential metabolite analysis showed that lipid metabolism, cofactor, and vitamin metabolism were altered in sick animals, indicating microbiota-host crosstalk in these deer. When combined, the results provide the first comprehensive description of an intestinal microbiome and metabolic imbalance in diarrheic Père David's deer, which advances our understanding and potential future treatment of diarrheic animals.

10.
Front Public Health ; 10: 1004869, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36324439

RESUMO

Background: Sexual behavior is one of the main routes of HIV/AIDS spread. HIV disclosure to sexual partners has been confirmed to be an important strategy for HIV/AIDS prevention and control. We conducted a systematic review and meta-analysis to pool proportions and characteristics of HIV disclosure to sexual partners among people diagnosed with HIV in China. Methods: We searched eight databases and extracted the data on HIV disclosure to partners. Heterogeneity of the data was tested with I 2. Published bias subjectively and objectively analyzed through the funnel plot and Egger's regression test. Subgroup analyses were performed to explore the variation in the proportion by sexual partnership types (unclassified, regular, casual sexual partners), whether being men who have sex with men (MSM), and when to diagnose. The sources of heterogeneity were analyzed. Sensitivity analysis was carried out to evaluate the stability of the results. Results: Out of 3,698 studies, 44 were included in the review; 11 targeted on MSM. The pooled proportion of HIV disclosure to sexual partners was 65% (95% CI: 56%-75%; 34 studies). Sub-group analyses indicated the proportions of HIV disclosure to regular, casual and unclassified sexual partners were 63% (95% CI: 45%-81%; 31 studies), 20% (95% CI: 8%-33%; nine studies), and 66% (95% CI: 59%-73%; 14 studies), respectively. Fifty-seven percent (95% CI: 45%-69%; three studies) disclosed on the day of diagnosis, 62% (95% CI: 42%-82%; four studies) disclosed within 1 month, and 39% (95% CI: 2%-77%; four studies) disclosed 1 month later. Among MSM, the disclosure to regular male partners, regular female sexual partners, spouses, and casual partner were 47% (95% CI: 29%-65%; six studies), 49% (95% CI: 33%-65%; three studies), 48% (95% CI: 18%-78%; seven studies), and 34% (95% CI: 19%-49%; four studies), respectively. Conclusions: The disclosure prevalence of people diagnosed with HIV to sexual partners still need improving in China, and it varies among partner types, key populations, and time being diagnosed. HIV disclosure strategies and procedures need to be developed more detailed and tailored based on the pain points of disclosure status, so as to ultimately prevent HIV transmission through sexual contact. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022291631, identifier: CRD42022291631.


Assuntos
Infecções por HIV , Minorias Sexuais e de Gênero , Masculino , Feminino , Humanos , Parceiros Sexuais , Homossexualidade Masculina , Revelação , Infecções por HIV/diagnóstico , Infecções por HIV/epidemiologia , Infecções por HIV/prevenção & controle
11.
Expert Rev Respir Med ; : 1-10, 2022 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-36369876

RESUMO

BACKGROUND: Obstructive sleep apnea (OSA) and hypertension are interrelated diseases linked to gut dysbiosis. This study aimed to investigate the effect of OSA on the gut microbiome in the context of hypertension and vice versa. RESEARCH DESIGN AND METHODS: Of 211 consecutively screened patients, 52 completed polysomnography study, medical history questionnaires, and fecal sample collection. 16S rRNA gene sequencing was performed on fecal samples, and diversity, richness, and microbial taxa were analyzed using bioinformatics. RESULTS: Alpha diversity showed slightly decreased diversity in OSA and hypertension groups without significant difference, and the hypoxia burden index (HBI) showed a weak positive correlation with Chao1 index (r = 0.342, p < 0.05) in OSA patients. Firmicutes-to-Bacteroidetes ratio was higher in patients with than without OSA. In hypertensive patients, those with OSA had higher Ruminococcus_1, Lachnoclostridium, Lachnospira, [Ruminococcus]_torques_group, and unidentified Lachnospiraceae levels than those without OSA. Conversely, in OSA patients, hypertensive patients had lower Faecalibacterium and Lachnospiraceae_NK4A136_group levels. CONCLUSION: The present study suggests a possible compensatory mechanism for gut microbiome changes in sleep apnea pathophysiology. The positive correlation between HBI and alpha diversity, and increase in certain genera of Ruminococcaceae and Lachnospiraceae in OSA patients may represent an adaptive response to hypoxia.

12.
Nat Cancer ; 3(11): 1318-1335, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36357700

RESUMO

Chemokines such as C-C motif ligand 5 (CCL5) regulate immune cell trafficking in the tumor microenvironment (TME) and govern tumor development, making them promising targets for cancer therapy. However, short half-lives and toxic off-target effects limit their application. Oncolytic viruses (OVs) have become attractive therapeutic agents. Here, we generate an oncolytic herpes simplex virus type 1 (oHSV) expressing a secretable single-chain variable fragment of the epidermal growth factor receptor (EGFR) antibody cetuximab linked to CCL5 by an Fc knob-into-hole strategy that produces heterodimers (OV-Cmab-CCL5). OV-Cmab-CCL5 permits continuous production of CCL5 in the TME, as it is redirected to EGFR+ glioblastoma (GBM) tumor cells. OV-Cmab-CCL5 infection of GBM significantly enhances the migration and activation of natural killer cells, macrophages and T cells; inhibits tumor EGFR signaling; reduces tumor size; and prolongs survival of GBM-bearing mice. Collectively, our data demonstrate that OV-Cmab-CCL5 offers a promising approach to improve OV therapy for solid tumors.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Herpesvirus Humano 1 , Terapia Viral Oncolítica , Vírus Oncolíticos , Animais , Camundongos , Imunidade Adaptativa , Neoplasias Encefálicas/terapia , Cetuximab/farmacologia , Receptores ErbB/genética , Glioblastoma/genética , Vírus Oncolíticos/genética , Microambiente Tumoral , Quimiocina CCL5/metabolismo
13.
Acta Otorhinolaryngol Ital ; 42(4): 372-379, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-36254653

RESUMO

Objective: This study aims to assess the frequency, bacteriology, biofilm characteristics and management of skin flap infection (SFI) following cochlear implantation (CI). Methods: The study enrolled 1,251 patients receiving CI in the First Affiliated Hospital of Fujian Medical University between August 2001 and March 2021. Scanning electron microscopy (SEM) was utilised to characterise the aetiology of infection. A proposed classification system was applied to optimise treatments for post-operative skin flap infection. Results: After CI, SFI was reported in 16 patients (1.28%) and occurred more frequently in patients under 6 years of age. Of all SFI cases Staphylococcus aureus was the most common pathogen for flap infection, with 8 cases (50%) and bacterial biofilm was evident within the jelly-like substance on the surface of implanted devices in SFI patients. A two-stage classification was proposed to optimise the treatment schemes. Conservative therapy was recommended for stage I cases and surgical treatment for stage II patients. Conclusions: Paediatric patients are more susceptible to SFI after CI, which may be attributed to the formation of bacterial biofilm. The proposed classification can facilitate the management of SFI.


Assuntos
Implante Coclear , Implantes Cocleares , Infecções Estafilocócicas , Bactérias , Biofilmes , Criança , Implantes Cocleares/efeitos adversos , Implantes Cocleares/microbiologia , Humanos , Complicações Pós-Operatórias/etiologia , Staphylococcus aureus
14.
Hum Mol Genet ; 2022 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-36255739

RESUMO

Spinal muscular atrophy (SMA) is a fatal neuromuscular disease caused by homozygous deletions or mutations of the SMN1 gene. SMN2 is a paralogous gene of SMN1 and a modifying gene of SMA. A better understanding of how SMN2 exon 7 splicing is regulated helps discover new therapeutic targets for SMA therapy. Based on an antisense walk method to map exonic and intronic splicing silencers (ESSs and ISSs) in SMN2 exon 7 and the proximal regions of its flanking introns, we identified one ISS (ISS6-KH) at upstream of the branch point site in intron 6. By using mutagenesis-coupled RT-PCR with SMN1/2 minigenes, immunochromatography, over-expression, and siRNA-knockdown, we found this ISS consists of a bi-partite hnRNP A1 binding cis-element and a poly-U sequence located between the proximal hnRNP A1 binding site (UAGCUA) and the branch site. Both HuR and hnRNP C1 proteins promote exon 7 skipping through the poly-U stretch. Mutations or deletions of these motifs lead to efficient SMN2 exon 7 inclusion comparable to SMN1 gene. Furthermore, we identified an optimal antisense oligonucleotide (ASO) that binds the intron 6 ISS and causes striking exon 7 inclusion in the SMN2 gene in patient fibroblasts and SMA mouse model. Our findings demonstrate that this novel ISS plays an important role in SMN2 exon 7 skipping and highlight a new therapeutic target for SMA therapy.

15.
Microbiol Spectr ; : e0214322, 2022 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-36287010

RESUMO

The pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has posed an enormous burden on the global public health system and has had disastrous socioeconomic consequences. Currently, single sampling tests, 20-in-1 pooling tests, nucleic acid point-of-care tests (POCTs), and rapid antigen tests are implemented in different scenarios to detect SARS-CoV-2, but a comprehensive evaluation of them is scarce and remains to be explored. In this study, 3 SARS-CoV-2 inactivated cell culture supernatants were used to evaluate the analytical performance of these strategies. Additionally, 5 recombinant SARS-CoV-2 nucleocapsid (N) proteins were also used for rapid antigen tests. For the wild-type (WT), Delta, and Omicron strains, the lowest inactivated virus concentrations to achieve 100% detection rates of single sampling tests ranged between 1.28 × 102 to 1.02 × 103, 1.28 × 102 to 4.10 × 103, and 1.28 × 102 to 2.05 × 103 copies/mL. The 20-in-1 pooling tests ranged between 1.30 × 102 to 1.04 × 103, 5.19 × 102 to 2.07 × 103, and 2.59 × 102 to 1.04 × 103 copies/mL. The nucleic acid POCTs were all 1.42 × 103 copies/mL. The rapid antigen tests ranged between 2.84 × 105 to 7.14 × 106, 8.68 × 104 to 7.14 × 106, and 1.12 × 105 to 3.57 × 106 copies/mL. For the WT, Delta AY.2, Delta AY.1/AY.3, Omicron BA.1, and Omicron BA.2 recombinant N proteins, the lowest concentrations to achieve 100% detection rates of rapid antigen tests ranged between 3.47 to 142.86, 1.74 to 142.86, 3.47 to 142.86, 3.47 to 142.86, and 5.68-142.86 ng/mL, respectively. This study provided helpful insights into the scientific deployment of tests and recommended the full-scale consideration of the testing purpose, resource availability, cost performance, result rapidity, and accuracy to facilitate a profound pathway toward the long-term surveillance of coronavirus disease 2019 (COVID-19). IMPORTANCE In the study, we reported an evaluation of 4 detection strategies implemented in different scenarios for SARS-CoV-2 detection: single sampling tests, 20-in-1 pooling tests, nucleic acid point-of-care tests, and rapid antigen tests. 3 SARS-CoV-2-inactivated SARS-CoV-2 cell culture supernatants and 5 recombinant SARS-CoV-2 nucleocapsid proteins were used for evaluation. In this analysis, we found that for the WT, Delta, and Omicron supernatants, the lowest concentrations to achieve 100% detection rates of single sampling tests ranged between 1.28 × 102 to 1.02 × 103, 1.28 × 102 to 4.10 × 103, and 1.28 × 102 to 2.05 × 103 copies/mL. The 20-in-1 pooling tests ranged between 1.30 × 102 to 1.04 × 103, 5.19 × 102 to 2.07 × 103, and 2.59 × 102 to 1.04 × 103 copies/mL. The nucleic acid POCTs were all 1.42 × 103 copies/mL. The rapid antigen tests ranged between 2.84 × 105 to 7.14 × 106, 8.68 × 104 to 7.14 × 106, and 1.12 × 105 to 3.57 × 106 copies/mL. For the WT, Delta AY.2, Delta AY.1/AY.3, Omicron BA.1, and Omicron BA.2 recombinant N proteins, the lowest concentrations to achieve 100% detection rates of rapid antigen tests ranged between 3.47 to 142.86, 1.74 to 142.86, 3.47 to 142.86, 3.47 to 142.86, and 5.68 to 142.86 ng/mL, respectively.

16.
J Am Chem Soc ; 144(42): 19410-19416, 2022 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-36223688

RESUMO

Trace water in organic solvents can play a crucial role in the construction of supramolecular assemblies, which has not gained enough attention until very recent years. Herein, we demonstrate that residual water in organic solvents plays a decisive role in the regulation of the evolution of assembled structures and their functionality. By adding Mg(ClO4)2 into a multi-component organic solution containing terpyridine-based ligand 3Tpy and monodentate imidazole-based ligand M2, the system underwent an unexpected kinetic evolution. Metallo-supramolecular polymers (MSP) formed first by the coordination of 3Tpy and Mg2+, but they subsequently decomposed due to the interference of M2, resulting in a transient MSP system. Further investigation revealed that this occurred because residual water in the solvent and M2 cooperatively coordinated with Mg2+. This allowed M2 to capture Mg2+ from MSP, which led to depolymerization. However, owing to the slow reaction between trace water/M2/Mg2+, the formation of MSP still occurred first. Therefore, water regulated both the thermodynamics and kinetics of the system and was the key factor for constructing the transient MSP. Fine-tuning the water content and other assembly motifs regulated the assembly evolution pathway, tuned the MSP lifetime, and made the luminescent color of the system undergo intriguing transition processes over time.


Assuntos
Imidazóis , Água , Água/química , Ligantes , Solventes/química , Polímeros/química
17.
Front Med (Lausanne) ; 9: 990538, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36186798

RESUMO

Objective: Primary orbital lymphoma (POL) accounts for an essential part of adult orbital malignancies. Nevertheless, it remains a relatively rare lymphoid malignancy, accounting for <1% of all non-Hodgkin's lymphoma (NHL) cases. Orbital diffuse large B-cell lymphoma (DLBCL) is one of the most prevalent subtypes of POL that confers the worst outcomes. The prognostic determinants of orbital DLBCL remain unknown. Therefore, a retrospective analysis was conducted by investigating the Surveillance, Epidemiology, and End Results (SEER) database for independent predictive factors for the prognosis of orbital DLBCL. Materials and methods: Using the SEER program, we acquired patient data including demographics, clinical characteristics, and treatment strategies. Our cohort included cases of primary orbital DLBCL diagnosed from 2000 to 2017. We conducted Kaplan-Meier analyses to visualize the overall survival (OS) and cause-specific survival (CSS). The Cox proportional hazard regression models were applied to assess the effects of these prognostic factors on OS and CSS. Results: The present cohort included 332 patients with orbital DLBCL. Age was the most impacted variable by orbital DLBCL. Three independent prognostic variables of orbital DLBCL were identified on diagnosis: advanced age, no radiation treatment, and late-stage (Stage IV). Moreover, patients who underwent chemotherapy demonstrated a greater OS when compared with those who did not. In orbital DLBCL, being unmarried was also a poor prognostic factor. Conclusion: The current study is the largest population-based case series of orbital DLBCL. The age at the time of diagnosis, marital status, absence of chemotherapy or radiotherapy, and tumor stage were all found to be correlated with worse prognosis.

18.
Artigo em Inglês | MEDLINE | ID: mdl-36159574

RESUMO

Objective: To compare the clinical efficacy of different insulin administration methods and blood glucose monitoring methods in treating type 1 diabetes mellitus in children. Methods: Patients were divided into four groups: multiple daily injection (MDI) + fingertip blood glucose detection, continuous subcutaneous insulin infusion (CSII) + fingertip blood glucose detection, MDI + continuous glucose monitoring system (CGMS), and CSII + CGMS. After six months of treatment, followed by telephone and at least once a month in an outpatient clinic, insulin doses were adjusted according to the children's blood glucose levels. Blood glucose control and the daily dose of insulin were compared among the four groups after treatment, and the incidence of hypoglycemia in each group was recorded during the treatment. We also compare the incidence of the adverse event among the four groups. Results: 6 months later, the levels of HbA1c, FBG, and two h PG in each group were lower than those before treatment. There were significant differences in HbA1c, two h PG, and the daily insulin dose among the four groups. There were differences in the frequency of hypoglycemia among all the groups. The frequency of hypoglycemia in groups C and D was lower than in group A. Conclusions: CSII was better than MDI, and the blood glucose monitoring effect of CGMS was better than the fingertip blood glucose detection. The patients treated with CSII combined with CGMS had the best clinical efficacy. The patients treated with CSII combined with CGMS had the lowest adverse events incidence.

19.
Pharmaceutics ; 14(9)2022 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-36145553

RESUMO

Cationic cell-penetrating peptides (CPPs), such as transactivator of transcription (TAT) peptide, have been proposed as effective drug carriers to improve intracellular delivery of biological macromolecules. Amphibian skin-derived Kunitz-type trypsin inhibitors (KTIs), short counterparts of KTIs from plant sources, were found to possess potent serine protease inhibitory activity. However, poor transmembrane permeability of these molecules has largely hindered the study of the full spectrum of their biological actions. As a result, this study aimed to extend the biological activities of amphibian KTIs by their conjugation to cationic CPPs. Herein, a novel peptide (kunitzin-OV2) and its phenylalanine-substituted analogue F9-kunitzin-OV2 (F9-KOV2) were evaluated for inhibition of trypsin/chymotrypsin and showed weak antibacterial activity against Escherichia coli (E. coli). As expected, the conjugation to TAT peptide did not increase membrane lysis compared with the original kunitzin-OV2, but effectively assisted this complex to enter cells. TAT-kunitzin-OV2 (TAT-KOV2) exhibited a 32-fold increase in antibacterial activity and an enhanced bactericidal rate against E. coli. In addition, the conjugation enabled the parent peptides to exhibit antiproliferative activity against cancer cells. Interestingly, TAT-F9-kunitzin-OV2 (TAT-F9-KOV2) showed stronger antiproliferative activity against human breast cancer (MCF-7) and human glioblastoma (U251MG) cell lines, which TAT-KOV2 did not possess. Moreover, TAT-F9-KOV2 showed a 20-25-fold increase in antiproliferative capacity against human lung cancer (H157, H460) cell lines compared with TAT-KOV2. Therefore, the conjugation of CPPs effectively solves the problem of cell penetration that short KTIs lack and provides evidence for new potential applications for their subsequent development as new antibacterial and anticancer agents.

20.
ACS Nano ; 16(9): 15273-15285, 2022 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-36075101

RESUMO

Flexible solid-state zinc-air batteries (ZABs) with low cost, excellent safety, and high energy density has been considered as one of ideal power sources for portable and wearable electronic devices, while their practical applications are still hindered by the kinetically sluggish cathodic oxygen reduction and oxygen evolution reactions (ORR/OER). Herein, a Janus-structured flexible free-standing bifunctional oxygen electrocatalyst, with OER-active O, N co-coordinated Ni single atoms and ORR-active Co3O4@Co1-xS nanosheet arrays being separately integrated at the inner and outer walls of flexible hollow carbon nanofibers (Ni-SAs/HCNFs/Co-NAs), is reported. Benefiting from the sophisticated topological structure and atomic-level-designed chemical compositions, Ni-SAs/HCNFs/Co-NAs exhibits outstanding bifunctional catalytic activity with the ΔE index of 0.65 V, representing the current state-of-the-art flexible free-standing bifunctional ORR/OER electrocatalyst. Impressively, the Ni-SAs/HCNFs/Co-NAs-based liquid ZAB show a high open-circuit potential (1.45 V), high capacity (808 mAh g-1 Zn), and extremely long life (over 200 h at 10 mA cm-2), and the assembled flexible all-solid-state ZABs have excellent cycle stability (over 80 h). This work provides an efficient strategy for developing high-performance bifunctional ORR/OER electrocatalysts for commercial applications.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...