ABSTRACT
The origin of cancer is related to the dysregulation of multiple signal pathways and of physiological processes. Bromodomain-containing protein 4 (BRD4) has become an attractive target for the development of anticancer and anti-inflammatory agents since it can epigenetically regulate the transcription of growth-promoting genes. The synthesized BRD4 inhibitors with new chemical structures can reduce the drug resistance, but their binding modes and the inhibitory mechanism remain unclear. Here, we initially constructed robust QSAR models based on 68 reported tetrahydropteridin analogues using topomer CoMFA and HQSAR. On the basis of QSAR results, we designed 16 novel tetrahydropteridin analogues with modified structures and carried out docking studies. Instead of significant hydrogen bondings with amino acid residue Asn140 as reported in previous research, the molecular docking modelling suggested a novel docking pose that involves the amino acid residues (Trp81, Pro82, Val87, Leu92, Leu94, Cys136, Asp144, and Ile146) at the active site of BRD4. The MD simulations, free energy calculations, and residual energy contributions all indicate that hydrophobic interactions are decisive factors affecting bindings between inhibitors and BRD4. The current study provides new insights that can aid the discovery of BRD4 inhibitors with enhanced anti-cancer ability.
Subject(s)
Cell Cycle Proteins/antagonists & inhibitors , Drug Design , Pteridines/pharmacology , Quantitative Structure-Activity Relationship , Transcription Factors/antagonists & inhibitors , Cell Cycle Proteins/chemistry , Molecular Docking Simulation , Molecular Dynamics Simulation , Pteridines/chemistry , Transcription Factors/chemistryABSTRACT
We investigated the prognostic effects of high-flux hemodialysis (HFHD) and low-flux hemodialysis (LFHD) in patients with chronic kidney disease (CKD). Both an electronic and a manual search were performed based on our rigorous inclusion and exclusion criteria to retrieve high-quality, relevant clinical studies from various scientific literature databases. Comprehensive meta-analysis 2.0 (CMA 2.0) was used for the quantitative analysis. We initially retrieved 227 studies from the database search. Following a multi-step screening process, eight high-quality studies were selected for our meta-analysis. These eight studies included 4967 patients with CKD (2416 patients in the HFHD group, 2551 patients in the LFHD group). The results of our meta-analysis showed that the all-cause death rate in the HFHD group was significantly lower than that in the LFHD group (OR=0.704, 95%CI=0.533-0.929, P=0.013). Additionally, the cardiovascular death rate in the HFHD group was significantly lower than that in the LFHD group (OR=0.731, 95%CI=0.616-0.866, P<0.001). The results of this meta-analysis clearly showed that HFHD decreases all-cause death and cardiovascular death rates in patients with CKD and that HFHD can therefore be implemented as one of the first therapy choices for CKD.
Subject(s)
Kidney Failure, Chronic/therapy , Renal Dialysis/methods , Bias , Cardiovascular Diseases/mortality , Case-Control Studies , Cause of Death , Disease Progression , Humans , Kidney Failure, Chronic/mortality , Prognosis , Publication Bias/statistics & numerical data , Regression Analysis , Renal Insufficiency, Chronic/mortality , Sensitivity and SpecificityABSTRACT
We investigated the prognostic effects of high-flux hemodialysis (HFHD) and low-flux hemodialysis (LFHD) in patients with chronic kidney disease (CKD). Both an electronic and a manual search were performed based on our rigorous inclusion and exclusion criteria to retrieve high-quality, relevant clinical studies from various scientific literature databases. Comprehensive meta-analysis 2.0 (CMA 2.0) was used for the quantitative analysis. We initially retrieved 227 studies from the database search. Following a multi-step screening process, eight high-quality studies were selected for our meta-analysis. These eight studies included 4967 patients with CKD (2416 patients in the HFHD group, 2551 patients in the LFHD group). The results of our meta-analysis showed that the all-cause death rate in the HFHD group was significantly lower than that in the LFHD group (OR=0.704, 95%CI=0.533-0.929, P=0.013). Additionally, the cardiovascular death rate in the HFHD group was significantly lower than that in the LFHD group (OR=0.731, 95%CI=0.616-0.866, P<0.001). The results of this meta-analysis clearly showed that HFHD decreases all-cause death and cardiovascular death rates in patients with CKD and that HFHD can therefore be implemented as one of the first therapy choices for CKD.
Subject(s)
Humans , Renal Dialysis/methods , Kidney Failure, Chronic/therapy , Prognosis , Cardiovascular Diseases/mortality , Bias , Case-Control Studies , Regression Analysis , Cause of Death , Sensitivity and Specificity , Publication Bias/statistics & numerical data , Disease Progression , Renal Insufficiency, Chronic/mortality , Kidney Failure, Chronic/mortalityABSTRACT
We investigated a possible person-to-person transmission within a family cluster of two confirmed influenza A(H7N9) patients in Guangzhou, China. The index case, a man in his late twenties, worked in a wet market that was confirmed to be contaminated by the influenza A(H7N9) virus. He developed a consistent fever and severe pneumonia after 4 January 2014. In contrast, the second case, his five-year-old child, who only developed a mild disease 10 days after disease onset of the index case, did not have any contact with poultry and birds but had unprotected and very close contact with the index case. The sequences of the haemagglutinin (HA) genes of the virus stains isolated from the two cases were 100% identical. These findings strongly suggest that the second case might have acquired the infection via transmission of the virus from the sick father. Fortunately, all 40 close contacts, including the other four family members who also had unprotected and very close contact with the cases, did not acquire influenza A(H7N9) virus infection, indicating that the person-to-person transmissibility of the virus remained limited. Our finding underlines the importance of carefully, thoroughly and punctually following-up close contacts of influenza A(H7N9) cases to allow detection of any secondary cases, as these may constitute an early warning signal of the virus's increasing ability to transmit from person-to-person.
Subject(s)
Genome, Viral/genetics , Influenza A Virus, H5N1 Subtype/pathogenicity , Influenza in Birds/transmission , Influenza, Human/transmission , Adult , Animals , Child, Preschool , China , Contact Tracing , Environmental Exposure , Family , Female , Humans , Influenza A Virus, H5N1 Subtype/isolation & purification , Influenza in Birds/virology , Influenza, Human/virology , Male , Phylogeny , Population Surveillance , Poultry , Sequence Analysis, DNAABSTRACT
OBJECTIVE: The aim of this paper was to investigate the changes in cyclic 3'5'-guanosine monophosphate (cGMP) before and after hemodialysis to estimate the value of cGMP to the dry boby-weight. METHODS: Plasma cGMP levels (by radioimmunoassay), cardiothoracic ratio (CTR), and the body weight (BW) before and after hemodialysis were determined in chronic hemodialysis patients and clinical signs and symptoms were observed at the same time. RESULTS: 1. The predialytic cGMP value of the patients was significantly higher than that of healthy controls (P < 0.05). 2. The postdialytic cGMP level was significantly lower than the predialytic cGMP level (P < 0.01). 3. Postdialytic CTR and BW values were significantly lower than predialytic values (P < 0.01). 4. Compared to those of predialysis, postdialytic clinic signs and symptoms of the patients were significantly relieved. CONCLUSIONS: 1. The plasma cGMP level can sensitively reflect the hydration state and is a reliable marker for dry body-weight estimation. 2. The measurement of plasma cGMP combined with clinical parameters and radiological indexes permit a more accurate dry body-weight estimation.
Subject(s)
Body Weight , Cyclic GMP/blood , Kidney Failure, Chronic/therapy , Adolescent , Adult , Aged , Female , Humans , Kidney Failure, Chronic/blood , Male , Middle Aged , Renal DialysisABSTRACT
The localization of some enzyme in adult worms of Clonorchis sinensis was studied by histochemical method in this paper. Acid phosphatase was detected mainly in digestive duct, subtegument and the walls of testis, uterus and ovary; acetylcholinesterase was found in oral sucker, ventral sucker, pharynx; and ATPase was found to exist in oral sucker, ventral sucker, pharynx and muscle layer in the subtegument. The eggs of C. sinensis possessed the above three enzymes.
