ABSTRACT
GFH009 is a potent, highly selective, small molecule that targets and inhibits the activity of the CDK9/cyclin T1 regulatory complex of P-TEFb. This study aimed to develop and validate a highly selective and sensitive ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method for precise quantification of GFH009 in rat plasma. This method was subsequently employed for conducting toxicokinetic studies of GFH009 in rats. Plasma was prepared using a simple protein precipitation method by acetonitrile. Chromatographic separation of the analytes was achieved on a BEH C18 analytical column with a rapid 3.0 min run time and a flow rate of 0.5 ml/min. The calibration curves for plasma samples exhibited excellent linearity over a wide concentration range of 1.0-1,000 ng/ml for GFH009. Intra- and inter-day accuracies were within 92.7-105.7%, and precisions were no more than 6.7%. Furthermore, the analyte demonstrated stability under four different storage conditions, with variations of <15.0%. This study pioneers a methodological innovation by introducing a highly reliable, specific and sensitive analytical method for GFH009 in rat plasma. The successful application of this method in toxicokinetic studies further underscores its significance, offering valuable insights for the methodology of clinical pharmacokinetic research.
Subject(s)
Liquid Chromatography-Mass Spectrometry , Tandem Mass Spectrometry , Rats , Animals , Tandem Mass Spectrometry/methods , Rats, Sprague-Dawley , Chromatography, Liquid , Toxicokinetics , Chromatography, High Pressure Liquid/methods , Protein Kinase Inhibitors , Reproducibility of ResultsABSTRACT
A novel series of N-aryl-N'-pyrimidin-4-yl ureas has been optimized to afford potent and selective inhibitors of the EGFR L858R/T790M. The most representative compound 28 showed high activity against EGFR L858R/T790M kinase (IC50â¯=â¯4â¯nM) and 22-fold selectivity against wild type EGFR. Moreover, compound 28 potently inhibited EGFR L858R/T790M phosphorylation (IC50â¯=â¯41â¯nM) and cellular proliferation (IC50â¯=â¯37â¯nM) in the H1975 cell line, while being significantly less toxic to A431 cells. Further, compound 28 exhibited a great selectivity in a mini-panel of kinases.
Subject(s)
Antineoplastic Agents/pharmacology , Drug Discovery , Protein Kinase Inhibitors/pharmacology , Urea/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/genetics , ErbB Receptors/metabolism , Humans , Molecular Docking Simulation , Molecular Structure , Mutation , Phosphorylation/drug effects , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Structure-Activity Relationship , Urea/analogs & derivatives , Urea/chemistryABSTRACT
Utilizing the already described 3,4-bi-aryl pyridine series as a starting point, incorporation of a second ring system with a hydrogen bond donor and additional hydrophobic contacts yielded the azaindole series which exhibited potent, picomolar RSK2 inhibition and the most potent in vitro target modulation seen thus far for a RSK inhibitor. In the context of the more potent core, several changes at the phenol moiety were assessed to potentially find a tool molecule appropriate for in vivo evaluation.
Subject(s)
Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Animals , Chromatography, Liquid , Drug Design , Humans , Mass Spectrometry , Phenols/pharmacology , Protein Kinase Inhibitors/chemistry , Proton Magnetic Resonance Spectroscopy , Structure-Activity RelationshipABSTRACT
A series of octahydropyrrolo[3,4-c]pyrroles were synthesized and evaluated by orexin 1 and 2 receptor (OX1 & 2 R) antagonists assays. Compound 14l with potent OXR antagonist activity and suitable pharmacokinetic behavior was chosen to be investigated in an EEG study, which demonstrated effects of sleep promotion comparable to Suvorexant. Furthermore, the di-fluro substituted analogs exhibited reduced hERG inhibition while maintaining moderate potency.
Subject(s)
Orexin Receptor Antagonists/chemistry , Orexin Receptor Antagonists/pharmacology , Pyrroles/chemistry , Pyrroles/pharmacology , Sleep Initiation and Maintenance Disorders/drug therapy , Animals , Drug Discovery , Electroencephalography , Humans , Male , Orexin Receptor Antagonists/therapeutic use , Pyrroles/pharmacokinetics , Pyrroles/therapeutic use , Rats , Rats, Sprague-Dawley , Sleep Initiation and Maintenance Disorders/physiopathology , Structure-Activity RelationshipABSTRACT
This Letter describes the discovery of a series of potent inhibitors of Human Uric Acid Transporter 1 (hURAT1). Lead generation and optimization via 3D pharmacophore analysis resulted in compound 41. With an IC50 of 33.7nM, 41 also demonstrated good oral bioavailability in rat (74.8%) and displayed a consistent PK profile across all species tested (rat, dog and monkey).
Subject(s)
Cyclobutanes/pharmacology , Gout Suppressants/pharmacology , Organic Anion Transporters/antagonists & inhibitors , Organic Cation Transport Proteins/antagonists & inhibitors , Quinolines/pharmacology , Animals , Cyclobutanes/chemical synthesis , Cyclobutanes/pharmacokinetics , Dogs , Gout Suppressants/chemical synthesis , Gout Suppressants/pharmacokinetics , Humans , Macaca fascicularis , Microsomes, Liver/metabolism , Molecular Docking Simulation , Organic Anion Transporters/chemistry , Organic Cation Transport Proteins/chemistry , Quinolines/chemical synthesis , Quinolines/pharmacokinetics , Rats , Rats, Sprague-Dawley , Structural Homology, Protein , Structure-Activity RelationshipABSTRACT
Alterations in PI3K/AKT signaling are known to be implicated with tumorigenesis. The PI3 kinases family of lipid kinases has been an attractive therapeutic target for cancer treatment. Imidazopyridine compound 1, a potent, selective, and orally available pan-PI3K inhibitor, identified by scaffold morphing of a benzothiazole hit, was further optimized in order to achieve efficacy in a PTEN-deleted A2780 ovarian cancer mouse xenograft model. With a hypothesis that a planar conformation between the core and the 6-heteroaryl ring will allow for the accommodation of larger 5'-substituents in a hydrophobic area under P-loop, SAR efforts focused on 5'-alkoxy heteroaryl rings at the 6-position of imidazopyridine and imidazopyridazine cores that have the same dihedral angle of zero degrees. 6'-Alkoxy 5'-aminopyrazines in the imidazopyridine series were identified as the most potent compounds in the A2780 cell line. Compound 14 with 1,1,1-trifluoroisopropoxy group at 6'-position demonstrated excellent potency and selectivity, good oral exposure in rats and in vivo efficacy in A2780 tumor-bearing mouse. Also, we disclose the X-ray co-crystal structure of one enantiomer of compound 14 in PI3Kα, confirming that the trifluoromethyl group fits nicely in the hydrophobic hot spot under P-loop.
Subject(s)
Phosphoinositide-3 Kinase Inhibitors , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Pyridines/chemistry , Pyridines/pharmacology , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Binding Sites , Cell Line, Tumor , Crystallography, X-Ray , Disease Models, Animal , Drug Evaluation, Preclinical , Enzyme Activation/drug effects , Female , Half-Life , Heterografts , Humans , Mice , Molecular Docking Simulation , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/metabolism , Ovarian Neoplasms/pathology , Phosphatidylinositol 3-Kinases/metabolism , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/therapeutic use , Protein Structure, Tertiary , Pyridines/pharmacokinetics , Pyridines/therapeutic use , Rats , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The Pim proteins (1, 2 and 3) are serine/threonine kinases that have been found to be upregulated in many hematological malignancies and solid tumors. As a result of overlapping functions among the three isoforms, inhibition of all three Pim kinases has become an attractive strategy for cancer therapy. Herein we describe our efforts in identifying potent pan-PIM inhibitors that are derived from our previously reported pyridyl carboxamide scaffold as part of a medicinal chemistry strategy to address metabolic stability.
Subject(s)
Amides/pharmacology , Drug Design , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-pim-1/antagonists & inhibitors , Amides/chemistry , Crystallography, X-Ray , Structure-Activity RelationshipABSTRACT
2-Amino-7-substituted benzoxazole analogs were identified by HTS as inhibitors of RSK2. Molecular modeling and medicinal chemistry techniques were employed to explore the SAR for this series with a focus of improving in vitro and target modulation potency and physicochemical properties.
Subject(s)
Benzoxazoles/chemistry , Protein Kinase Inhibitors/chemistry , Ribosomal Protein S6 Kinases, 90-kDa/antagonists & inhibitors , Benzoxazoles/chemical synthesis , Benzoxazoles/metabolism , Binding Sites , Crystallography, X-Ray , Humans , Molecular Dynamics Simulation , Protein Binding , Protein Kinase Inhibitors/chemical synthesis , Protein Structure, Tertiary , Ribosomal Protein S6 Kinases, 90-kDa/metabolism , Structure-Activity RelationshipABSTRACT
PI3 kinases are a family of lipid kinases mediating numerous cell processes such as proliferation, migration and differentiation. The PI3 Kinase pathway is often de-regulated in cancer through PI3Kα overexpression, gene amplification, mutations and PTEN phosphatase deletion. PI3K inhibitors represent therefore an attractive therapeutic modality for cancer treatment. Herein we describe how the potency of a benzothiazole fragment hit was quickly improved based on structural information and how this early chemotype was further optimized through scaffold hopping. This effort led to the identification of a series of 2-acetamido-5-heteroaryl imidazopyridines showing potent in vitro activity against all class I PI3Ks and attractive pharmacokinetic properties.
Subject(s)
Azo Compounds/chemical synthesis , Phosphoinositide-3 Kinase Inhibitors , Pyridines/chemical synthesis , Pyridines/pharmacology , Azo Compounds/chemistry , Azo Compounds/pharmacology , Benzothiazoles/chemistry , Benzothiazoles/pharmacology , Cell Line, Tumor , Enzyme Activation/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Female , Humans , Imides/chemical synthesis , Imides/chemistry , Imides/pharmacology , Inhibitory Concentration 50 , Models, Molecular , Pyridines/chemistry , Solubility , Structure-Activity RelationshipABSTRACT
To evade cell cycle controls, malignant cells rely upon rapid expression of select proteins to mitigate proapoptotic signals resulting from damage caused by both cancer treatments and unchecked over-proliferation. Cyclin-dependent kinase 9 (CDK9)-dependent signaling induces transcription of downstream oncogenes promoting tumor growth, especially in hyperproliferative 'oncogene-addicted' cancers, such as human hematological malignancies (HHMs). GFH009, a potent, highly selective CDK9 small molecule inhibitor, demonstrated antiproliferative activity in assorted HHM-derived cell lines, inducing apoptosis at IC50 values below 0.2 µM in 7/10 lines tested. GFH009 inhibited tumor growth at all doses compared to controls and induced apoptosis in a dose-dependent manner. Twice-weekly injections of GFH009 maleate at 10 mg/kg significantly prolonged the survival of MV-4-11 xenograft-bearing rodents, while their body weight remained stable. There was marked reduction of MCL-1 and c-MYC protein expression post-drug exposure both in vitro and in vivo. Through rapid 'on-off' CDK9 inhibition, GFH009 exerts a proapoptotic effect on HHM preclinical models triggered by dynamic deprivation of crucial cell survival signals. Our results mechanistically establish CDK9 as a targetable vulnerability in assorted HHMs and, along with the previously shown superior class kinome selectivity of GFH009 vs other CDK9 inhibitors, strongly support the rationale for currently ongoing clinical studies with this agent in acute myeloid leukemia and other HHMs.
Subject(s)
Antineoplastic Agents , Cyclin-Dependent Kinase 9 , Hematologic Neoplasms , Humans , Antineoplastic Agents/pharmacology , Apoptosis , Cyclin-Dependent Kinase 9/antagonists & inhibitors , Hematologic Neoplasms/drug therapy , OncogenesABSTRACT
KRAS inhibitor AMG510 covalently modifies the G12C residue and inactivates the KRAS/G12C function. Because there are many reactive cysteines in the proteome, it is important to characterize AMG510 on-target modification and off-targets. Here, we presented a streamlined workflow to measure abundant AMG510 modified peptides including that of KRAS/G12C by direct profiling, and a pan-AMG510 antibody peptide IP workflow to profile less abundant AMG510 off-targets. We identified over 300 off-target sites with three distinct kinetic patterns, expanding the AMG510 modified proteome involved in the nucleocytoplasmic transport, response to oxidative stress, adaptive immune system, and glycolysis. We found that AMG510 covalently modified cys339 of ALDOA and inhibited its enzyme activity. Moreover, AMG510 modified KEAP1 cys288 and induced NRF2 accumulation in the nuclear of NSCLC cells independent of KRAS/G12C mutation. Our study provides a comprehensive resource of protein off-targets of AMG510 and elucidates potential toxicological sideeffects for this covalent KRASG12C inhibitor.
ABSTRACT
Overexpression of PIM 1, 2, and 3 kinases is frequently observed in many malignancies. Previously, we discovered a potent and selective pan-PIM kinase inhibitor, compound 2, currently in phase I clinical trials. In this work, we were interested in replacing the amino group on the cyclohexane ring in compound 2 with a hydroxyl group. Structure-based drug design led to cellularly potent but metabolically unstable tetra-substituted cyclohexyl diols. Efforts on the reduction of Log D by introducing polar heterocycles improved metabolic stability. Incorporating fluorine to the tetra-substituted cyclohexyl diol moiety further reduced Log D, resulting in compound 14, a cellularly potent tetra-substituted cyclohexyl diol inhibitor with moderate metabolic stability and good permeability. We also describe the development of efficient and scalable synthetic routes toward synthetically challenging tetra-substituted cyclohexyl diol compounds. In particular, intermediate 36 was identified as a versatile intermediate, enabling a large-scale synthesis of highly substituted cyclohexane derivatives.
Subject(s)
Cyclohexanols/pharmacology , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-pim-1/antagonists & inhibitors , Cell Line, Tumor , Cyclohexanols/chemical synthesis , Cyclohexanols/metabolism , Humans , Microsomes, Liver/metabolism , Molecular Docking Simulation , Molecular Structure , Protein Binding , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/metabolism , Proto-Oncogene Proteins c-pim-1/metabolism , Structure-Activity RelationshipABSTRACT
Symmetric continuously tunable three-dimensional (3D) liquid photonic crystals have been investigated using self-organized blue-phase liquid crystal films. The photonic band gap in the overall visible spectrum can be tuned continuously, reversibly, and rapidly as the applied electric field changes. After driven by the applied field, four-time enhancement of the reflectivity results in more vivid reflection colors. A lasing emission of tuning working wavelength has been demonstrated by using the dye-doped blue-phase liquid crystal film. With the advantages of fast response speed, no alignment layer, large-scale electrically shift of the photonic band gap, and macro optical isotropy, this self-assembled soft material has many potential applications in high-performance reflective full-color display, 3D tunable lasers, and nonlinear optics.
ABSTRACT
OBJECTIVE: To genotype the RHCE gene of Hans, Xinjiang's Uigurs and Kazakstans in China, and to compare the results of RHCE genotyping with that of RhCc/Ee phenotyping. METHODS: RHCE genes of 98 Hans with RhD positive and 230 Hans, 72 Uigurs and 18 Kazakstans with RhD/RHD negative were genotyped with PCR-sequence specific primer (SSP) technique. RESULTS: The results of RHE/RHe genotyping from samples with RhD positive and negative were in accord with that of phenotyping. It would result in 4.44% error using C-->G polymorphism at nt48 of RHCE gene to genotype RHCE, and 4.05% failure of detection using the 109 bp insertion to detectRHCE gene in Chinese Hans. The results of RHE/RHe genotyping in unrelated 72 Uigurs and 18 Kazakstans with RhD phenotype were consistent with that of phenotyping, and false positive and false negative were not found in genotyping in Uigurs and Kazakstans tested. CONCLUSION: The results of RHE/RHe and RHc genotyping were correct with PCR-SSP and accordant with that of phenotyping. Using the C48G polymorphism in exon 1 of RHCE to genotype RHC gene would result in false positive resulting from RHc mutation at this locus, and using the 109 bp insertion to genotype RHC gene would result in false negative because of the absence of the 109 bp. Therefore it is necessary to genotype RHC gene using more than two polymorphic loci.
Subject(s)
Phenotype , Rh-Hr Blood-Group System/genetics , Serologic Tests/methods , Ethnicity/genetics , Genotype , Humans , Polymorphism, Genetic , Rh-Hr Blood-Group System/bloodABSTRACT
OBJECTIVE: Through researching preoperative coagulation function in the case of ABO-identical blood insufficient for emergency rescue transfusion according to recommended programs of special emergency rescue transfusion was carried out, the relationship between volume of blood products and coagulation function was analyzed. METHODS: The surgical cases of blood transfusion more than 1 600 ml during operation were collected in our hospitals from Aug 2015 to Dec 2016ï¼n=218ï¼, these cases were divided into the normal coagulation groupï¼Group Aï¼ and abnormal coagulation groupï¼Group Bï¼, and the patients of emergency rescue transfusion O type blood groupï¼Group Cï¼. The basic information of cases, the infused volume of red blood cellï¼RBCï¼, virus-inactivated frozen plasmaï¼VIFPï¼, fresh frozen plasmaï¼FFPï¼, cryoprecipitateï¼Cï¼and plateletsï¼Pï¼, prothrombin timeï¼PTï¼, activated partial thromboplastin timeï¼APTTï¼, fibrinogenï¼FIBï¼and international normalized ratioï¼INRï¼were analyzed, the relationship between volume of blood transfusion and coagulation function were also analysed. At the same time, the efficiency and safety index were compared before and after transfusion. These indexes, such as hemoglobinï¼Hbï¼, indirect bilirubinï¼IBiLï¼, direct antiglobulin testï¼DATï¼and irregular antibody were determined at the time-paints of 24 h, 3 d and 7 d after blood transfusion. RESULTS: The differences of age and blood type between group A and B was not statistically significantï¼P>0.05ï¼. Proportion of A and AB typeï¼transfusion volume of RBC, FFP, C and Plt all were significantly higher in group C ï¼P<0.05ï¼. PT, APTT, FIB and INR in group B and C were significantly differentï¼P<0.05ï¼, which related with the transfusion volume of RBC, FFP and Cï¼P<0.05ï¼. DAT and irregular antibody in every group was all negative before transfusion, No any new irregular antibodies had been detected after transfusion. Hb after blood transfusion was not statistically different before and after transfusion in group C, the IBiL level also was not significantly increased after blood transfusionï¼P > 0.05ï¼. All those showed that emergency rescue transfusion was safe and effective. CONCLUSION: Preoperative coagulation function is one of factors inflnencing blood products transfusion volume during operation, which also is the basis for evaluating bleeding and blood transfusion. Emergency O type blood and ABO-matched blood transfusions show the same efficiency and safety.
Subject(s)
Blood Coagulation , Blood Coagulation Tests , Blood Transfusion , Humans , Partial Thromboplastin Time , Prothrombin TimeABSTRACT
The discovery and optimization of a series of 2-morpholino-pyrimidine derivatives containing various sulfonyl side chains at the C4 position led to the identification of compound 26 as a potent dual PI3K/mTOR inhibitor. It exhibited high inhibitory activity against PI3Kα/ß/γ/δ (IC50 = 20/376/204/46 nM) and mTOR (IC50 = 189 nM), potent functional suppression of AKT phosphorylation (IC50 = 196 nM), and excellent antiproliferative effects on a panel of cancer cells. Enzymic data and modeling simulation indicate that a cyclopropyl ring on the C4 sulfone chain and a fluorine on the C6 aminopyridyl moiety are responsible for its maintained PI3K activity and enhanced mTOR potency, respectively. Furthermore, compound 26 exhibited higher efficiency in the HT-29 colorectal carcinoma xenograft model at the daily dose of 3.75 and 7.5 mg/kg relative to BKM120 at the dose of 15 and 30 mg/kg.
ABSTRACT
OBJECTIVE: To investigate the safety and effectiveness of neonatal ABO or Rh(D) by using compatible blood transfusion through retrospective analysis of data from cases received compatible blood transfusion and type matched blood transfusion. METHODS: The clinical data of 26 cases of neonatal compatible blood transfusion in Chinese Nanchang area from January 2014 to October 2016 were collected, and 26 cases of neonatal type-matched blood transfusion were selected according to ratio of 1:1 cases. The efficiency and safety index of 26 patients compatible blood transfusion were compared with that of type-matched blood transfusion. The efficiency indexes included: patients' basic characteristics, red blood cell (RBC) count, hemoglobin (Hb) level, hematocrit (Hct), and the safety indexes contain Hb level and indirect bilirubin (IBiL) value before and after blood transfusion, irregular antibody screening, direct antiglobulin test (DAT) results and the adverse reactions of blood transfusion. RESULTS: The age, sex, days of hospitalization between compatible blood transfusion and type matched blood transfusion were not statistically significantly different (P>0.05). The Hb level before transfusion, blood transfusion volume and the increase of Hb, Hct and RBC were not statistically significantly different between two groups (P>0.05). The values of Hb, Hct and RBC in 2 groups significantly increased at the day 1 after blood transfusion (P<0.05). No blood transfusion adverse reaction occurred in 2 groups. The IBiL value significantly decreased in compatible blood transfusion patients at the day 1 after blood transfusion (P<0.05). No new irregular antibodies had been detected after transfusion in all patients, and the others' DAT and screening for irregular antibodies were negative except 22 patients with neonatal hemolysis. The values of Hb and IBiL statistically significantly differenence were not in 12 patients between 1d, 3d, 7d after blood transfusion (P>0.05). CONCLUSION: The efficiency and safety between compatible blood transfusion and type matched blood transfusion are the same in neonatal blood transfusion. Compatible blood transfusion is a safe and effective in clinical blood transfusion.
Subject(s)
ABO Blood-Group System , Blood Transfusion , Antibodies , Coombs Test , Erythrocyte Transfusion , Hemolysis , Humans , Infant , Infant, Newborn , Retrospective StudiesABSTRACT
A bromotyrosine alkaloid family of antimicrobial agents was synthesized using the known structure of a natural inhibitor of the mycobacterial mycothiol S-conjugate amidase (MCA) as a template. This series of compounds represents a novel class of anti-infective agents against Gram-positive pathogens, including mycobacteria and meticillin- and vancomycin-resistant Staphylococcus aureus. The fact that these compounds are active against mycobacterial strains in which the MCA gene is deleted and against Gram-positive bacteria lacking mycothiol suggests the existence of an alternative target for these compounds. One member of this family, EXEG1706, was identified as the lead compound possessing low MICs (2.5-25 microg ml(-1)) for several clinical isolates, whilst having low toxicity for THP-1 monocytes and macrophages.
Subject(s)
Alkaloids/pharmacology , Anti-Bacterial Agents/pharmacology , Tyrosine/analogs & derivatives , Alkaloids/chemistry , Anti-Bacterial Agents/chemistry , Bacteria/drug effects , Cell Line , Fluoroacetates , Humans , Macrophages/drug effects , Models, Chemical , Molecular Structure , Monocytes/drug effects , Tyrosine/chemistry , Tyrosine/pharmacologyABSTRACT
OBJECTIVE: To research comparatively on the RHD gene structures in unrelated RhD negative individuals of Chinese Uigur and Han population. METHODS: The upstream, downstream, hybrid box and 10 exons of RHD gene were detected with sequence specific primer-PCR technique. RESULTS: The results showed the genotypes of RhD negative individuals to have the significant difference between Chinese Uigur and Han population, that 94.44% Uigur individuals were with RHD(-)/RHD(-) genotype but just 61.40% Han population were with this genotype(94.44% versus 61.40%, P<0.01); 2.78% Uigur individuals were with RHD(+)/RHD(-) genotype but 34.21% Han population were with this genotype(2.78% versus 34.21%, P<0.01). However, there was significantly no RHD(+)/RHD(+) genotype difference between Chinese Uigur and Han population(2.78% versus 4.39%, P>0.05). In 78 cases of RhD negative Chinese Hans with single RHD gene, of which the RHD gene structure showed that 53(67.95%) cases were RHD(1-10) allele(of 53 RHD(1-10) alleles, 14 alleles were unexpressed); 15(19.23%) were RHD-CE(2-9)-D(2) allele; 5(6.41%) cases were RHD-CE(2-7)-D(2) allele; 2(2.56%) were similar to RHD-CE(3-6)D allele; 1(1.28%) case was RHD-CE(5-6)-D allele; and 2(2.56%) were RHD-CE(6)-D or point mutation respectively. Of 2 RhD negative Chinese Uigurs with RhD(-)/RHD(+) genotype, one carried RHD(1-10) allele, another carried RHD-CE(2-9)-D(2) allele. CONCLUSION: The most frequently unexpressed RHD alleles were RHD-CE(2-9)-D(2), RHD(1-10) and RHD-CE(2-7)-D(2) respectively in Chinese Han population who carried single RHD allele with RHD(-) phenotype and RHD(+) genotype. It showed the confluent character of RH gene in Chinese Han and Uigur population that there existed unexpressed RHD-CE(2-9)-D(2) allele in Chinese Uigur nationality, which was infrequent in Chinese Uigur population but frequent in Chinese Han population.
Subject(s)
Alleles , Asian People/genetics , Ethnicity/genetics , Rh-Hr Blood-Group System/genetics , China/ethnology , Ethnicity/ethnology , Exons/genetics , Genotype , Humans , Polymerase Chain Reaction , Polymorphism, Genetic , Population GroupsABSTRACT
OBJECTIVE: To study the difference and similarity between Hans and Uighurs in regard to Rhesus box and its significance. METHODS: The sequence specific primers of upstream, downstream and hybrid Rhesus boxes were designed on the basis of RHD gene sequence. The upstream, downstream and hybrid Rhesus boxes were determined by polymerase chain reaction-sequence specific primer(PCP-SSP) and mismatched PCR. RESULTS: The percentage of RHD-/RHD-, RHD+/RHD- and RHD+/RHD+ genotypes ascertained in the unrelated Hans with RhD(-) were 61.40%, 34.21% and 4.39% respectively, while those in the unrelated Chinese Uighurs with RhD(-) were 94.44%, 2.78% and 2.78% respectively. Furthermore, all 6 cases of some other minorities were RHD-/RHD- types. The percentage of RHD-/RHD- and RHD+/RHD- genotypes ascertained in the unrelated Chinese Uighurs were significantly higher than those in Chinese Hans (P < 0.01), whereas no statistically significant difference in the percentage of RHD+/RDH+ genotype between the two groups was observed (P > 0.05). CONCLUSION: The Rh blood group of Uighurs in Xingjiang possesses both Oriental and Caucasian characteristics, which embodies a special ethnical aspect of the Chinese nation and is in accord with the anthropologic research results.