Fraziersahl9541
Cathepsin D (Cath D) has been evidenced as a potential target for cancer therapy. Our previous studies revealed that TB-9, a tasiamide B derivative, exhibited highly potent inhibition against Cath D with satisfactory selectivity over Cath E and BACE1. But this compound was inactive on cell level possibly due to poor membrane permeability. Herein, we report the design, synthesis, and evaluation of two novel Cath D inhibitors (2 and 3) which combining tasiamide B scaffold with a cell penetrating peptide (CPP) specifically targeting the endolysosomal compartment. The results revealed that 2 and 3 not only retained highly potent inhibition against Cath D, but also were active against MDA-MB-231 cell lines.Neuraminidase (NA) is an important target in the development of anti-influenza virus drugs. Compounds containing 1,3, 4-oxadiazole heterocycles have good biological activity and have been proved to have wide applications in antibacterial and antiviral drugs. In this paper, a series of novel 1, 3, 4-oxadiazole neuraminidase inhibitors (6a-6l) were designed and synthesized and their inhibitory activities of NA was tested in vitro. The results displayed that compound 6d exerts the best inhibitory activity (IC50 = 0.027 µM), which was obviously lower than that of oseltamivir carboxylate (OSC) (IC50 = 0.082 µM). Molecular docking analysis showed that the 1, 3, 4-oxadiazole heterocycle plays crucial part in compound 6d, and it can interact with the key arginine triad (Arg118, Arg292 and Arg 371) at the NA S1 site. The good efficacy of 6d may also be attributed to the extension of the substituted aniline ring to the 150-cavitiy. The theoretical and experimental results may provide reference for development of new anti-influenza drugs.
To assess the anatomical relationships and variations in the pretracheal space and to guide tracheotomy procedures in a safe manner with image-based evidence.
A retrospective study was conducted on unirradiated patients requiring elective tracheotomies. Preoperative contrast-enhanced CT (CECT)/CT venography (CTV) was applied for an anatomical evaluation of the pretracheal region. Vascular morphologies were compared for three vessels the anterior jugular vein (AJV), the innominate artery (IA) and the inferior thyroid vascular plexus (ITVP). The relationships between the thyroid isthmus and the 2nd-4th tracheal rings were also analyzed.
A total of 120 patients were identified, most of whom (n=110, 91.7%) had head and neck squamous cell carcinomas. Patients with recognizable AJVs (n=118) were divided into 3 groups single-branch (n=11, 9.2%), double-branch (n=105, 87.5%), and multibranch (n=2, 1.7%). In addition, IAs were categorized as low-bifurcation (n=51, 42.5%), high-bifurcation (n=40, 33.3%), platform (n=27, 22.5%) and variant types (n=2, 1.7%). Within the platform types, high-lying IAs (n=15, 8.3%) might have interfered with the standard tracheal incisions due to possible IA-tracheal overlay. This interference was also related to the height of intraoperative tracheal incisions (r
=0.364, P=0.001). Within ITVPs, independent-trunk types were found in 71 cases (59.2%), while common-trunk types were found in 45 (37.5%). Epinephrine bitartrate manufacturer In addition, a low thyroid isthmus (suprasternal-isthmus distance <3cm) was found in 83 cases (69.2%).
CT image-based evidence can prepare junior practitioners with important pretracheal anatomical information, thereby facilitating safer tracheotomy procedures. Our results shed light on vascular relationships for emergent tracheotomy.
CT image-based evidence can prepare junior practitioners with important pretracheal anatomical information, thereby facilitating safer tracheotomy procedures. Our results shed light on vascular relationships for emergent tracheotomy.
Surgical resection of the maxilla impairs aesthetics, speech, swallowing, and mastication. Maxillary reconstruction is increasingly performed with virtual surgical planning (VSP) to enhance functional dental rehabilitation with a conventional denture or osseointegrated implants. The aim of this study was to determine whether dental status and VSP is associated with health-related quality of life (HRQOL) and function in patients who have undergone maxillectomy.
A cross-sectional study was conducted among patients who underwent free flap reconstruction or obturation of the maxilla between July 2009 and December 2020. The FACE-Q Head and Neck Cancer (FACE-Q) module, M.D. Anderson Dysphagia Inventory (MDADI), and Speech Handicap Index (SHI) were used to evaluate HRQOL.
Forty-three patients (response rate 59%) completed questionnaires and 48% underwent dental rehabilitation. In Okay Class II and III defects, adjusting for the effect of radiotherapy and time from surgery, there was a positive association between denture status and FACE-Q smiling (p=0.020), eating (p=0.012), smiling (p=0.015), and MDADI global (p=0.015), emotional (p=0.027), functional (p=0.028), and composite (p=0.029) scores. VSP was associated with FACE-Q swallowing (p=0.005), drooling (p=0.030), eating (p=0.008), smiling (p=0.021), MDADI global (p=0.017), emotional (p=0.041), functional (p=0.040), composite (p=0.038), and SHI total scores (p=0.042).
Dentoalveolar rehabilitation and VSP were associated with higher HRQOL scores relating to eating and drinking, smiling, and speaking.
Dentoalveolar rehabilitation and VSP were associated with higher HRQOL scores relating to eating and drinking, smiling, and speaking.
To propose a refined M1 classification in de novo metastatic nasopharyngeal carcinoma (NPC) based on pooled data from two academic institutions.
Previously untreated de novo M1 NPC patients prospectively treated at The University of Hong Kong (N=69) and Fujian Cancer Hospital (N=114) between 2007 and 2016 were recruited and randomized in a 21 ratio to generate training (N=120) and validation (N=63) cohorts, respectively. Multivariable analysis (MVA) was performed for the training and validation cohorts to identify anatomic prognostic factors for overall survival (OS). Recursive partitioning analysis (RPA) was performed which incorporated the anatomic prognostic factors identified in the MVA to derive Anatomic-RPA groups which stratified OS in the training cohort, and were then validated in the validation cohort.
Median follow-up for the training and validation cohorts was 27.2 and 30.2months with 3-year OS of 51.6% and 51.1%, respectively. MVA revealed that co-existing liver-bone metastases was the only factor prognostic for OS in both the training and validation cohorts. Anatomic-RPA separated M1 disease into M1a (no co-existing liver-bone metastases) and M1b (co-existing liver-bone metastases) with median OS 39.5 and 23.7months, respectively (p=0.004) in the training cohort. RPA for the validation cohort also confirmed good segregation with co-existing liver-bone metastases with median OS 47.7 and 16.0months, respectively (p=0.008).
Our proposal to subdivide de novo M1 NPC into M1a (no co-existing liver-bone metastases) vs. M1b (co-existing liver-bone metastases) provides better OS segregation.
Our proposal to subdivide de novo M1 NPC into M1a (no co-existing liver-bone metastases) vs. M1b (co-existing liver-bone metastases) provides better OS segregation.
Senescence leads to permanent cell-cycle arrest and is a potential target for cancer therapy. Andrographolide (AD) is a diterpene lactone isolated from Traditional Chinese Medicine (TCM) Andrographis paniculate, which has been used as an anti-inflammatory drug in clinical practice with the potential to target senescence in recalcitrant lung cancer.
To determine whether AD can induce senescence in human lung adenocarcinoma in vitro and in vivo and to elucidate the underlying mechanisms.
SA-β-Gal staining was used to detect the expression of senescence-associated β-galactosidase (SA-β-Gal) in human lung adenocarcinoma cells A549 and NCI-H1795. DNA damage was examined by the detection of γH2AX foci. Cell cycle was analyzed by flow cytometry. Cancer cell proliferation was determined by ATPlite assay and clonogenic survival assay in vitro. Tumor growth was determined in a mouse model of A549. The expression level of proteins and mRNA was estimated by Western blotting and Quantitative RT-PCR, respectively. Smtherapeutic for recalcitrant human lung adenocarcinoma.
In the present study, we found that the primary anti-inflammatory drug AD could have a potential antitumor effect in lung cancer. We demonstrated that AD induced lung adenocarcinoma senescence in vitro and in vivo via p53/p21 and Skp2/p27 for the first time. AD is therefore a promising senescence-inducing therapeutic for recalcitrant human lung adenocarcinoma.
The quality of traditional Chinese medicines (TCMs) has been closely related to their growth regions. The geo-herbalism of TCMs is just like the protected destination of origin on foodstuffs and wines, telling us the specific geographic regions could yield TCMs with superior quality. However, the impact of habitat on TCMs could hardly been indicated in current quality evaluation, defects were as follows (1) few studies involved the effect of environmental factors, (2) more attentions were paid to several abundant compounds, while global components especially water-soluble compounds were prone to be ignored.
A new integrated metabolomics analysis based on global and water-soluble components was proposed aiming to explore habitat-related chemomarkers for TCMs combined with correlation analysis to environmental factors. The geo-herbalism of Magnoliae officinalis cortex (MOC) was studied as an example.
Multi-metabolomics approach based on UPLC/Q-TOF-MS and GC-MS combined with LC-2ECD were employed to analyz well prediction performance with an accuracy of 96.97%. Most markers belong to water-soluble compounds and temperature and precipitation contributed to such chemical differences.
The proposed strategy based on multi-metabolomics analysis could aid exploration of habitat-related chemomarkers for TCMs. Meanwhile, the screened out water-soluble compounds could perform equivalent functions in recognition of Daodi medicinal materials (DMMs) and non-DMM samples compared to the global components to some extent.
The proposed strategy based on multi-metabolomics analysis could aid exploration of habitat-related chemomarkers for TCMs. Meanwhile, the screened out water-soluble compounds could perform equivalent functions in recognition of Daodi medicinal materials (DMMs) and non-DMM samples compared to the global components to some extent.
Ulcerative colitis (UC) is a type of inflammatory bowel disease (IBD) characterized by an overactive immune response and destruction of the colorectal epithelium with intricate pathological factors. Shenlingbaizhu (SLBZ) formula, included in the Chinese Pharmacopoeia 2020, has been widely utilized to treat UC.
The present study was designed to uncover the underlying molecular mechanisms of SLBZ formula against UC.
A murine model of experimental colitis was established by orally feeding 2% dextran sodium sulfate (DSS) to mice for 7 days, followed by SLBA treatment for the next 15 days. Network pharmacology analysis was performed to predict the pharmacological mechanisms. High-throughput 16S rRNA sequencing integrated with liquid chromatography-mass spectrometry (LC-MS) was conducted on mouse stool in order to determine alterations in the composition of the intestinal microbiota and metabolites. Western blotting, immunofluorescence, and flow cytometry were performed to examine the anti-inflammatory role of SLBZ.
