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The global prevalence of RNA virus infections has presented significant challenges to public health in recent years, necessitating the expansion of its alternative therapeutic library. Due to its evolutional conservation, RNA-dependent RNA polymerase (RdRp) has emerged as a potential target for broad-spectrum antiviral nucleoside analogues. However, after over half a century of structural modification, exploring unclaimed chemical space using frequently-used structural substitution methods to design new nucleoside analogues is challenging. In this study, we explore the use of the "ring-opening" strategy to design new base mimics, thereby using these base mimics to design new nucleoside analogues with broad-spectrum antiviral activities. A total of 29 compounds were synthesized. Their activity against viral RdRp was initially screened using an influenza A virus RdRp high-throughput screening model. Then, the antiviral activity of 38a was verified against influenza virus strain A/PR/8/34 (H1N1), demonstrating a 50% inhibitory concentration (IC50) value of 9.95 µM, which was superior to that of ribavirin (the positive control, IC50 = 11.43 µM). Moreover, 38a also has inhibitory activity against coronavirus 229E with an IC50 of 30.82 µM. In addition, compounds 42 and 46f exhibit an 82% inhibition rate against vesicular stomatitis virus at a concentration of 20 µM and hardly induce cytotoxicity in host cells. This work demonstrates the feasibility of designing nucleoside analogues with "ring-opening" bases and suggests the "ring-opening" nucleosides may have greater polarity, and designing prodrugs is an important aspect of optimizing their antiviral activity. Future research should focus on enhancing the conformational restriction of open-loop bases to mimic Watson-Crick base pairing better and improve antiviral activity.
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Antivirales , Diseño de Fármacos , Nucleósidos , ARN Polimerasa Dependiente del ARN , Antivirales/farmacología , Antivirales/química , Antivirales/síntesis química , Nucleósidos/química , Nucleósidos/farmacología , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , Subtipo H1N1 del Virus de la Influenza A/efectos de los fármacos , Humanos , Animales , Células de Riñón Canino Madin Darby , Perros , Relación Estructura-ActividadRESUMEN
A metal-free and thiol-free organophosphorus-catalyzed method for forming thioethers was disclosed, driven by PIII/PVâO redox cycling. In this work, one-step dehydroxylative thioetherification of alcohols was fulfilled with various hypervalent organosulfur compounds. This established strategy features an excellent functional group tolerance and broad substrate scope, especially inactivated alcohols. The scale-up reaction and further transformation of the product were also successful. Additionally, this method offers a protecting-group-free and step-efficient approach for synthesizing peroxisome proliferator-activated receptor agonists which exhibited promising potential for treating osteoporosis in mammals.
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BACKGROUND: Ischemic necrosis in the distal portion of the flap is a challenging complication in plastic surgery. We hypothesize a novel hybrid flap preconditioning (HFP) device combining foam-mediated external suction and non-surgical delay can promote skin flap survival better than surgical delay. METHOD: Twenty-eight mouse were divided into four groups. Control group: a 4*1.5 dorsal flap was made with no preconditioning. Surgical delay (SD) group: surgical delay was made 7 days before flap elevation. Foam-mediated external suction (FMES) group: foam-mediated external suction at -100mmHg was employed 5 hours per day for 6 days, and the flap was elevated on the seventh day. Hybrid Flap Preconditioning (HFP) group: silicone strips was applied along the contour of the foam interface. Same negative pressure protocol was used as the FMES group. Seven days after flap elevation, macroscopic, histologic, and Western blot analyses were performed. RESULTS: The flap survival rate was 46.25% (8.12%) in the control group, 68.72% (7.00%) in the SD group, 57.03% (8.17%) in the FMES group and 80.66% (3.27%) in the HFP group. Immunohistologic analysis of CD 31+ cell in distal end of viable tissue procured seven days after flap elevation showed a significantly higher angiogenesis in SD group and HFP group. Western Blot results showed an increased expression of VEGF in SD group and HFP group. CONCLUSION: We have developed and fabricated a novel hybrid flap precondition (HFP) device combining foam-mediated external suction and non-surgical delay. The concept of HFP is proved to promote flap survival better than surgical delay.
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BACKGROUND: Pancreatic adenocarcinoma (PAAD) is an aggressive solid tumour characterised by few early symptoms, high mortality, and lack of effective treatment. Therefore, it is important to identify new potential therapeutic targets and prognostic biomarkers of PAAD. METHODS: The Cancer Genome Atlas and Genotype-Tissue Expression databases were used to identify the expression and prognostic model of protocadherin 1 (PCDH1). The prognostic performance of risk factors and diagnosis of patients with PAAD were evaluated by regression analysis, nomogram, and receiver operating characteristic curve. Paraffin sections were collected from patients for immunohistochemistry (IHC) analysis. The expression of PCDH1 in cells obtained from primary tumours or metastatic biopsies was identified using single-cell RNA sequencing (scRNA-seq). Real-time quantitative polymerase chain reaction (qPCR) and western blotting were used to verify PCDH1 expression levels and the inhibitory effects of the compounds. RESULTS: The RNA and protein levels of PCDH1 were significantly higher in PAAD cells than in normal pancreatic ductal cells, similar to those observed in tissue sections from patients with PAAD. Aberrant methylation of the CpG site cg19767205 and micro-RNA (miRNA) hsa-miR-124-1 may be important reasons for the high PCDH1 expression in PAAD. Up-regulated PCDH1 promotes pancreatic cancer cell metastasis. The RNA levels of PCDH1 were significantly down-regulated following flutamide treatment. Flutamide reduced the percentage of PCDH1 RNA level in PAAD cells Panc-0813 to < 50%. In addition, the PCDH1 protein was significantly down-regulated after Panc-0813 cells were incubated with 20 µM flutamide and proves to be a potential therapeutic intervention for PAAD. CONCLUSION: PCDH1 is a key prognostic biomarker and promoter of PAAD metastasis. Additionally, flutamide may serve as a novel compound that down-regulates PCDH1 expression as a potential treatment for combating PAAD progression and metastasis.
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Adenocarcinoma , Neoplasias Pancreáticas , Humanos , Pronóstico , Flutamida , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , ARN , Biomarcadores , Regulación Neoplásica de la Expresión Génica , Protocadherinas , Neoplasias PancreáticasRESUMEN
SUMMARY: At present, there is no uniform and quantitative indication standard for periareolar augmentation mastopexy. The authors proposed an indication algorithm and a matched approach to delineate the outer circle, to optimize the result of this operation. Five parameters, including both implant and breast characteristics, were incorporated to form an indication algorithm based on three-dimensional measurement. The indication follows the principle that the circumference of the outer circle should be no more than two times the inner circle. To delineate the outer circle, a "crown" was made on the breast. The above approaches were used on patients who came for periareolar augmentation mastopexy from October of 2015 to January of 2019. Data analyzed included BREAST-Q score, areola diameter, the distance of the sternal notch to the nipple preoperatively and 1 year postoperatively, the distance of nipple elevation 1 year postoperatively, and complication and revision rates. A total of 28 breasts (14 patients) were included in this study. BREAST-Q scores 1-year postoperatively showed significant increases in Satisfaction with Breasts, Psychosocial Well-Being, and Sexual Well-Being ( p = 0.000). The mean areolar diameter preoperatively and postoperatively was 6.7 ± 1.2 cm and 4.6 ± 0.4 cm, respectively ( p = 0.000), and the mean sternal notch-to-nipple distance preoperatively and postoperatively was 22.2 ± 1.9 cm and 18.6 ± 1.0 cm, respectively ( p = 0.000), with an average nipple elevation of 3.2 ± 1.1 cm. The overall complication rate was 7.1 percent ( n = 2); both cases were areolar spreading. The overall revision rate was 0 percent. This preliminary study demonstrated the safety and efficacy of the indication and breast crown approach in reducing complication and revision rates. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.
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Implantes de Mama , Mamoplastia , Mama/cirugía , Humanos , Mamoplastia/métodos , Pezones/cirugía , Estudios Retrospectivos , Resultado del TratamientoAsunto(s)
Modelos Teóricos , Neovascularización Patológica , Animales , Células Cultivadas , Humanos , RatonesRESUMEN
BACKGROUND: This study aims to put forward a new classification of breast asymmetry based on the relative position of the nipple and inframammary fold (IMF) and propose a surgical algorithm of determining new IMF to address breast asymmetry in patients undergoing transaxillary augmentation mammaplasty, which is named as NIMF (nipple inframammary) classification and surgical algorithm. METHODS: Three hundred and forty-five patients received transaxillary augmentation mammaplasty with anatomical implants. Preoperative breast asymmetry was classified into four types. I: asymmetrical nipple with asymmetrical IMF in the same direction; II: symmetrical nipple with asymmetrical IMF; III: asymmetrical nipple with symmetrical IMF; IV: asymmetrical nipple with unapparent IMF. Surgical plans (3 plans for type I, II, IV while 5 plans for type III) to set the new IMF were provided for each patient, who chose one of them as the final surgical plan. Breast-Q and Likert scale were used to evaluate patient satisfaction and symmetry of breast preoperatively and 6 months postoperatively. RESULTS: The incidence of type I, II, III, IV was 30%, 15%, 13%, and 4%, respectively. Ninety-seven percent of patients with breast asymmetry chose plan C, which aimed to balance the relative position of nipple and IMF. Postoperative Breast-Q scores showed a significant rise compared with preoperative scores, but no statistical difference between plan C V.S. other plans. Patients with symmetrical preoperative breasts (Group A) had significantly higher postoperative Breast-Q scores than patients with asymmetrical preoperative breasts (Group B). In breast symmetry assessment, Group A had a significantly higher postoperative score than Group B, but the postoperative score was significantly lowered compared with the preoperative score in both Group A and B. CONCLUSION: The NIMF classification and surgical algorithm provide a systematic and scientific way to analyze and improve breast asymmetry, to achieve optimized patient satisfaction in transaxillary augmentation mammaplasty with anatomical implants. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine Ratings, please refer to Table of Contents or online Instructions to Authors www.springer.com/00266 .
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Implantación de Mama , Implantes de Mama , Mamoplastia , Algoritmos , Estética , Femenino , Humanos , Pezones/cirugía , Estudios Retrospectivos , Resultado del TratamientoAsunto(s)
Acetilcisteína , Trasplantes , Acetilcisteína/farmacología , Tejido Adiposo , Humanos , Proyectos Piloto , Trasplante AutólogoRESUMEN
Lymphedema is a chronic, progressive disease caused by primary or secondary reasons. It is currently uncurable and conservative compression therapy is generally applied. Lymphovenous anastomosis and vascularized lymph node transfer (VLNT) are two main surgical treatment that are used in addition to conservative therapy. Lymphovenous anastomosis involves the anastomosing remaining functional lymphatic vessels to vein. When the lymphatic vessels are greatly damaged and in no case can they be used for anastomosis, VLNT provide the affected area with lymph nodes from elsewhere to restore the drainage function. During all these procedures, a clear image to identify related lymphatic structures and venous vessels can be greatly useful for preoperative planning, intraoperative navigation, and postoperative evaluation. Lymphoscintigraphy used to be the gold standard in evaluating lymphedema and mapping lymphatic systems. But due to the downside of radiation, invasive operation and complication, other modalities are gaining attention. In this article, we reviewed the application of Indocyanine green (ICG) lymphography, ultrasound, magnetic resonance lymphography (MRL), and single-photon emission computed tomography-computed tomography (SPECT-CT) in the field of surgical therapy in lymphedema.