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In our previous study, we reported a series of N-(9,10-anthraquinone-2-carbonyl) amino acid derivatives as novel inhibitors of xanthine oxidase (XO). Recognizing the suboptimal drug-like properties associated with the anthraquinone moiety, we embarked on a nonanthraquinone medicinal chemistry exploration in the current investigation. Through systematic structure-activity relationship (SAR) studies, we identified a series of 4-(isopentyloxy)-3-nitrobenzamide derivatives exhibiting excellent in vitro potency against XO. The optimized compound, 4-isopentyloxy-N-(1H-pyrazol-3-yl)-3-nitrobenzamide (6k), demonstrated exceptional in vitro potency with an IC50 value of 0.13 µM. Compound 6k showed favorable drug-like characteristics with ligand efficiency (LE) and lipophilic ligand efficiency (LLE) values of 0.41 and 3.73, respectively. In comparison to the initial compound 1d, 6k exhibited a substantial 24-fold improvement in IC50, along with a 1.6-fold enhancement in LE and a 3.7-fold increase in LLE. Molecular modeling studies provided insights into the strong interactions of 6k with critical amino acid residues within the active site. Furthermore, in vivo hypouricemic investigations convincingly demonstrated that 6k significantly reduced serum uric acid levels in rats. The MTT results revealed that compound 6k is nontoxic to healthy cells. The gastric and intestinal stability assay demonstrated that compound 6k exhibits good stability in the gastric and intestinal environments. In conclusion, compound 6k emerges as a promising lead compound, showcasing both exceptional in vitro potency and favorable drug-like characteristics, thereby warranting further exploration.
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BACKGROUND: Lupus erythematosus (LE) is a spectrum of autoimmune diseases. Due to the complexity of cutaneous LE (CLE), clinical skin image-based artificial intelligence is still experiencing difficulties in distinguishing subtypes of LE. OBJECTIVES: We aim to develop a multimodal deep learning system (MMDLS) for human-AI collaboration in diagnosis of LE subtypes. METHODS: This is a multi-centre study based on 25 institutions across China to assist in diagnosis of LE subtypes, other eight similar skin diseases and healthy subjects. In total, 446 cases with 800 clinical skin images, 3786 multicolor-immunohistochemistry (multi-IHC) images and clinical data were collected, and EfficientNet-B3 and ResNet-18 were utilized in this study. RESULTS: In the multi-classification task, the overall performance of MMDLS on 13 skin conditions is much higher than single or dual modals (Sen = 0.8288, Spe = 0.9852, Pre = 0.8518, AUC = 0.9844). Further, the MMDLS-based diagnostic-support help improves the accuracy of dermatologists from 66.88% ± 6.94% to 81.25% ± 4.23% (p = 0.0004). CONCLUSIONS: These results highlight the benefit of human-MMDLS collaborated framework in telemedicine by assisting dermatologists and rheumatologists in the differential diagnosis of LE subtypes and similar skin diseases.
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BACKGROUND: Photodynamic therapy is an established treatment option for Bowen's disease. Our meta-analysis was aimed at evaluating the efficacy and recurrence of photodynamic therapy or other topical treatments (5-fluorouracil, cryotherapy) and of photodynamic therapy alone or in combination with other therapies (ablative fractional CO2 laser or plum-blossom needle) for the treatment of Bowen's disease. METHODS: Trials that met our inclusion criteria were identified from PubMed, EMBASE, Web of Science, and Cochrane Library databases, and meta-analyses were conducted with RevMan V.5.4. The risk of bias was estimated with the Cochrane Collaboration's risk of bias tools. Complete response rate, recurrence, pain/visual analogue scale score, cosmetic outcome, and adverse events were considered as outcomes. RESULTS: Of the 2,439 records initially retrieved, 8 randomized controlled trials were included in this meta-analysis. According to our analyses, photodynamic therapy exhibited a significantly higher complete response rate (RR = 1.36, 95% CI [1.01, 1.84], I2 = 86%, p = 0.04), less recurrence (RR = 0.53, 95% CI [0.30, 0.95], I2 = 0%, p = 0.03), and better cosmetic outcome (RR = 1.34, 95% CI [1.15, 1.56], I2 = 0%, p = 0.0002) compared with other treatments. Moreover, there was a significant difference between the complete response rate of photodynamic therapy combined with ablative fractional CO2 laser and that of photodynamic therapy (RR = 1.85, 95% CI [1.38, 2.49], I2 = 0%, p < 0.0001). Photodynamic therapy combined with ablative fractional CO2 laser or plum-blossom needle also showed significantly less recurrence (RR = 0.21, 95% CI [0.09, 0.51], I2 = 0%, p = 0.0005) and a lower visual analogue scale score (RR = 0.51, 95% CI [0.06, 0.96], I2 = 0%, p = 0.03) than photodynamic therapy alone. However, there was no significant difference in the complete response rate between photodynamic therapy combined with ablative continuous CO2 laser and photodynamic therapy combined with ablative fractional CO2 laser (RR = 1.00, 95% CI [0.54, 1.86], I2 not applicable, p = 1.00). CONCLUSIONS: This meta-analysis shows that photodynamic therapy can be used in the treatment of Bowen's disease with better efficacy, less recurrence, and better cosmetic outcomes than cryotherapy and 5-FU. Some methods, including ablative fractional CO2 laser, can be applied in combination with photodynamic therapy to improve efficacy. However, which laser-assisted photodynamic therapy scheme has the most advantages in the treatment of Bowen's disease warrants further exploration.
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Enfermedad de Bowen , Fotoquimioterapia , Neoplasias Cutáneas , Enfermedad de Bowen/tratamiento farmacológico , Humanos , Fotoquimioterapia/métodos , Ensayos Clínicos Controlados Aleatorios como Asunto , Neoplasias Cutáneas/tratamiento farmacológico , Resultado del TratamientoRESUMEN
Worldwide, metastatic melanoma of the skin has an aggressive course with high morbidity and mortality. Therefore, an increased understanding of the pathogenesis of metastatic melanoma has gained increasing attention, including the role of epigenetic modification and competing endogenous RNA (ceRNA). This study aimed to used bioinformatics data to undertake an integrative analysis of long noncoding RNA (lncRNA), microRNA (miRNA) and mRNA expression to construct a ceRNA network in metastatic melanoma. Data from the Cancer Genome Atlas (TCGA), the Gene Ontology (GO) database, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway were analyzed. There were 471 cases that included 103 primary solid tumors and 368 cases of metastatic melanoma that included transcriptome sequencing data (including lncRNA and mRNA); 452 cases had miRNA sequencing data. Analysis of chip data identified 85 6 mRNAs, 67 miRNAs, and 250 lncRNAs that were differentially expressed in cases of metastatic melanoma, of which 25 miRNAs, 18 lncRNAs, and 18 mRNAs participated in the formation of ceRNAs. Survival analysis identified seven differentially expressed mRNAs, five differentially expressed miRNAs (miRNA-29c, miRNA-100, miR-142-3p, miR-150, miR-516a-2), and six differentially expressed lncRNAs (AC068594.1, C7orf71, FAM41C, GPC5-AS1, MUC19, LINC00402) that were correlated with survival time in patients with metastatic melanoma. Bioinformatics data and integrative analysis identified lncRNA, miRNA, and mRNA expression to construct a ceRNA and patient survival network in metastatic melanoma. These findings support the need for further studies on the mechanisms involved in the regulation of metastatic melanoma by ceRNAs.
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Melanoma/genética , MicroARNs/biosíntesis , ARN Mensajero/biosíntesis , Neoplasias Cutáneas/genética , Biología Computacional/métodos , Bases de Datos Genéticas , Ontología de Genes , Redes Reguladoras de Genes , Humanos , Estimación de Kaplan-Meier , Melanoma/metabolismo , MicroARNs/genética , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , ARN Largo no Codificante/genética , ARN Mensajero/genética , Neoplasias Cutáneas/metabolismo , Análisis de Supervivencia , TranscriptomaRESUMEN
BACKGROUND: Provider adherence to the national treatment guidelines for gonorrhea is critical to assuring effective treatment. It is also an important means of limiting antibiotic overuse, which can lead to development of resistant bacteria. The Chinese treatment guidelines recommend the monotherapy with ceftriaxone or spectinomycin in accordance with the World Health Organization guidelines for treatment of uncomplicated gonorrhea. We evaluated adherence to the guidelines among treatment providers in China. METHODS: The study was a nationwide cross-sectional study. In each of the 6 geographic regions in China, at least 1 province was selected. In each selected province, cities with elevated incidence of reported gonorrhea were purposively selected. Using a questionnaire, 2121 physicians recruited from 512 different categories and levels of health sectors from July to September 2017 were investigated. RESULTS: Of the participants, more than 99% diagnosed gonorrhea using one of the laboratory tests including Gram stain, culture, nucleic acid amplification test, or other tests. Culture was the predominant assay of the choice for the diagnosis. Of the 1890 physicians who provided information on prescription behaviors, 62.2% were not adherent to the regimens for treatment of uncomplicated gonorrhea recommended by the National Sexually Transmitted Disease (STD) Treatment Guidelines (National STD Guidelines). Physicians working in the areas located in Northern China (adjusted odds ratio [AOR], 3.06; 95% confidence intervals [CIs], 1.77-5.31), in general hospitals or departments of urology (AOR, 1.54; 95% CIs, 1.08-2.19), diagnosing more cases in the past 6 months (AOR, 1.82; 95% CIs, 1.25-2.67), or unfamiliar with the treatment regimens in the National STD Guidelines (AOR, 3.48; 95% CIs, 2.76-4.37) were significantly more likely to be nonadherent to the National STD Guidelines. CONCLUSIONS: It can be concluded from our study that nonadherence to the national guidelines and empirical treatment with high doses of ceftriaxone occurred frequently in China. Further studies on the impacts of the empirical treatment on antimicrobial resistance of gonorrhea are needed.
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Antibacterianos/administración & dosificación , Ceftriaxona/administración & dosificación , Gonorrea/tratamiento farmacológico , Adhesión a Directriz/estadística & datos numéricos , Neisseria gonorrhoeae/efectos de los fármacos , Espectinomicina/administración & dosificación , China , Estudios Transversales , Quimioterapia Combinada , Gonorrea/microbiología , Hospitales , Humanos , Incidencia , Médicos/estadística & datos numéricos , Guías de Práctica Clínica como Asunto , Encuestas y CuestionariosRESUMEN
BACKGROUND: Parenteral penicillin is the first-line regimen for treating syphilis, but unsuitable for some patients due to penicillin allergy and lacking health resources. Unfortunately, the efficacy of penicillin alternatives remains poorly understood. This study aimed to assess the efficacy of ceftriaxone and doxycycline/tetracycline in treating early syphilis relative to that of penicillin, and thereby to determine which antibiotic is a better replacement for penicillin. METHOD: By searching literature from PubMed, Cochrane Central Register of Controlled Trials, Embase, the Web of Science, and ClinicalTrials.gov and systematically screening relevant studies, eligible randomized controlled trials (RCTs) and observational studies on treatments with penicillin, doxycycline/tetracycline, and ceftriaxone for early syphilis were identified and combined in this systematic review. Estimated risk ratios (RRs) and 95% confidence intervals (CIs) were utilized to compare their serological response and treatment failure rates. At 12-month follow up, serological response rates were compared by a direct meta-analysis and network meta-analysis (NMA), while treatment failure rates were compared with a direct meta-analysis. RESULT: Three RCTs and seven cohort studies were included in this research. The results of NMA demonstrated that no significant differences existed in serological response rate at 12-month follow-up between any two of the three treatments (doxycycline/tetracycline vs. penicillin RR = 1.01, 95%CI 0.89-1.14; ceftriaxone vs. penicillin RR = 1.00, 95%CI 0.89-1.13; ceftriaxone vs. doxycycline/tetracycline RR = 0.99, 95%CI 0.96-1.03), which was consistent with the outcomes of the direct meta-analysis. In addition, the direct meta-analysis indicated that, at 12-month follow-up, penicillin and ceftriaxone treatment groups had similar treatment failure rates (RR = 0.92, 95%CI 0.12-6.93), while treatment failure rate was significantly lower among penicillin recipients than among doxycycline/tetracycline recipients (RR = 0.58, 95%CI 0.38-0.89). CONCLUSION: Ceftriaxone is as effective as penicillin in treating early syphilis with regard to serological response and treatment failure rate. Compared with doxycycline/tetracycline, ceftriaxone appears to be a better choice as the substitution of penicillin.
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Antibacterianos/uso terapéutico , Sífilis/tratamiento farmacológico , Ceftriaxona/administración & dosificación , Ceftriaxona/uso terapéutico , Quimioterapia Combinada , Humanos , Estudios Observacionales como Asunto , Penicilinas/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Tetraciclina/administración & dosificación , Tetraciclina/uso terapéutico , Resultado del TratamientoRESUMEN
OBJECTIVE: To investigate the operative technique and the clinical value of retroperitoneal laparoscopic enucleation of the renal hamartoma. METHODS: Twenty-five patients of renal hamartoma received retroperitoneal laparoscopic enucleation. The patients were placed in lateral decubitus position. All laparoscopic surgical procedures were performed retroperitoneally using 3 port-sites. The tumor was exposed and resected along the edge, and the tumor clipped out with a lithotomy forceps. The renal hamartoma was confirmed through a pathological diagnosis during the operation. The resection surface was sutured with fibrin and absorbable hemostatic gauze. RESULTS: The operations were finished successfully in all patients. The diameter of tumors ranged from 1.8 cm x 2.0 cm to 4.5 cm x 4.9 cm. The operative time was 50 - 90 (mean=70) min. The blood loss was 30 - 80 (mean=55) mL. The hospital stay was 7 - 9 (mean=8) days. CONCLUSION: Retroperitoneal laparoscopic enucleation of the renal hamartoma is safe and effective, whose advantages include minimal invasive, less blood loss, short hospital stay, and rapid convalescence.