Abstract Objective To analyze the outcomes of patients with high Model for End-Stage Liver Disease (MELD) scores who underwent adult-to-adult live donor liver transplantation (A-A LDLT). Materials ...and Methods From September 2002 to October 2010, a total of 152 adult patients underwent A-A LDLT in our institution. Recipients were stratified into a low MELD score group (Group L; MELD score ≤30) and a high MELD score group (Group H; MELD score >30) to compare short-term and long-term outcomes. Results Of the 152 adult patients who underwent A-A LDLT, 9 were excluded from the analysis because they received ABO-incompatible grafts. Group H comprised 23 and Group L 120 patients. The median follow-up was 21.5 months (range, 3 to 102 m). The mean MELD score was 15.6 in Group L and 36.7 in Group H. There were no significant differences in the mean length of stay in the intensive care unit (Group L: 3.01 days vs Group H: 3.09 days, P = .932) or mean length of hospital stay (Group L: 17.89 days vs. Group H: 19.91 days, P = 0.409). There were no significant differences in 1-, 3-, or 5-year survivals between patients in Groups L versus H (91.5% vs 94.7%; 86.4% vs 94.7%; and 86.4% vs 94.7%; P = .3476, log rank). Conclusion The short-term and long-term outcomes of patients with high MELD scores who underwent A-A LDLT were similar to those of patients with low MELD scores. Therefore, we suggest that high MELD scores are not a contraindication to LDLT.
The landscape of genetic alterations in lung adenocarcinoma derived from Asian patients is largely uncharacterized. Here we present an integrated genomic and transcriptomic analysis of 335 primary ...lung adenocarcinomas and 35 corresponding lymph node metastases from Chinese patients. Altogether 13 significantly mutated genes are identified, including the most commonly mutated gene TP53 and novel mutation targets such as RHPN2, GLI3 and MRC2. TP53 mutations are furthermore significantly enriched in tumours from patients harbouring metastases. Genes regulating cytoskeleton remodelling processes are also frequently altered, especially in metastatic samples, of which the high expression level of IQGAP3 is identified as a marker for poor prognosis. Our study represents the first large-scale sequencing effort on lung adenocarcinoma in Asian patients and provides a comprehensive mutational landscape for both primary and metastatic tumours. This may thus form a basis for personalized medical care and shed light on the molecular pathogenesis of metastatic lung adenocarcinoma.
Mutations of the BRCA1 tumor suppressor gene are the most commonly detected alterations in familial breast and ovarian cancer. Although BRCA1 is required for normal mouse development, the molecular ...basis for its tumor suppressive function remains poorly understood. We show here that BRCA1 increases p53-dependent transcription from the p21WAF1/CIP1 and bax promoters. We also show that BRCA1 and p53 proteins interact both in vitro and in vivo. The interacting regions map, in vitro, to aa 224-500 of BRCA1 and the C-terminal domain of p53. Tumor-derived transactivation-deficient BRCA1 mutants are defective in co-activation of p53-dependent transcription and a truncation mutant of BRCA1 that retains the p53-interacting region acts as a dominant inhibitor of p53-dependent transcription. BRCA1 and p53 cooperatively induce apoptosis of cancer cells. The results indicate that BRCA1 and p53 may coordinately regulate gene expression in their role as tumor suppressors.
The most commonly employed glycosidase assays rely on bulky ultraviolet or fluorescent tags at the anomeric position in potential carbohydrate substrates, thereby limiting the utility of these assays ...for broad substrate characterization. Here we report a qualitative mass spectrometry–based glycosidase assay amenable to high‐throughput screening for the identification of the biochemical functions of putative glycosidases. The assay utilizes a library of methyl glycosides and is demonstrated on a high‐throughput robotic liquid handling system for enzyme substrate screening. Identification of glycosidase biochemical function is achieved through the observation of an appropriate decrease in mass between a potential sugar substrate and its corresponding product by electrospray ionization mass spectrometry (ESI‐MS). In addition to screening known glycosidases, the assay was demonstrated to characterize the biochemical function and enzyme substrate competency of the recombinantly expressed product of a putative glycosidase gene from the thermophilic bacterium Thermus thermophilus.
Losing the right amount of weight: High‐throughput identification of glycosidase biochemical functions, including those from hyperthermophiles, is achieved by observing a correct mass‐loss from individual members of a thermostable library of potential sugar substrates and their corresponding products by using electrospray ionization mass spectrometry (ESI‐MS).
We propose an optical delay line based on differential structure for improving measurement accuracy and extending scanning length of optical coherence domain polarimetry (OCDP). The differential ...delay line is composed of two independent graded refractive index lenses (GRIN) and a double-faced mirror. The OCDP measurement model with loss coefficient and measurement error caused by the GRIN-lens-based delay line is discussed. Compared to the general optical delay line based on a single GRIN lens, the fluctuation of the loss coef cient of differential delay line is reduced to ± 0.1 dB with scanning range of 0.8 m, which corresponds to 80% improvement.
Calmodulin (CaM) is a highly conserved calcium sensor protein associated with chilling tolerance in living organisms. It has four EF-hand domains for binding of four Ca
2+
, two of them located in ...the N-terminus, and the other two in the C-terminus. A notothenioid
CaM
gene fragment (
CaMm
), which only codes for N-terminus of CaM (with two EF-hand domains), was introduced into
Nicotiana benthamiana
. Effects of its overexpression on chilling tolerance in plants were explored. During 4◦C or 0◦C chilling treatment, both
CaMm
and
CaM
transgenic plants showed higher PSII maximum quantum yield, actual quantum yield, and soluble protein content, lower electrolyte leakage and malondialdehyde content than that of the control. The changes in these physiological indices were comparable between the
CaMm
and
CaM
transgenic plants during the treatments. These results indicate that the N-terminus of calmodulin is likely the key functional domain involved in the adaptive response to cold stress.
Drugs frequently require interactions with multiple targets—via a process known as polypharmacology—to achieve their therapeutic actions. Currently, drugs targeting several serotonin receptors, ...including the 5-HT2C receptor, are useful for treating obesity, drug abuse, and schizophrenia. The competing challenges of developing selective 5-HT2C receptor ligands or creating drugs with a defined polypharmacological profile, especially aimed at G protein-coupled receptors (GPCRs), remain extremely difficult. Here, we solved two structures of the 5-HT2C receptor in complex with the highly promiscuous agonist ergotamine and the 5-HT2A-C receptor-selective inverse agonist ritanserin at resolutions of 3.0 Å and 2.7 Å, respectively. We analyzed their respective binding poses to provide mechanistic insights into their receptor recognition and opposing pharmacological actions. This study investigates the structural basis of polypharmacology at canonical GPCRs and illustrates how understanding characteristic patterns of ligand-receptor interaction and activation may ultimately facilitate drug design at multiple GPCRs.
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•Agonist ergotamine and inverse agonist ritanserin-bound 5-HT2C structures solved•Conformational changes uncover key features of two distinct ligand-bound states•Structural basis for ligand promiscuity versus subtype selectivity revealed
Understanding how one drug can bind to many similar targets and have different functional outcomes will inform drug design with desired efficacy profiles.
SUMMARY
Objectives
To analyse anti‐D alloimmunisation in pregnant women with D‐elute (DEL) phenotype in China, for developing a predictive model to evaluate whether a person with the DEL phenotype ...can receive RhD‐positive blood.
Background
Alloanti‐D acquired by pregnancy or transfusion is one of the major causes of both haemolytic disease among newborns and haemolytic transfusion reactions. To date, there is little data available about the antigenic properties and immunogenicity of extremely weak D variants known as DEL.
Methods
RHD genotyping and D epitope mapping were performed using gene sequencing and comprehensive immunohaematological methods, respectively. DEL pregnant women carrying an RhD‐positive fetus were tested for the presence of alloanti‐D.
Results
A total of 130 of 142 (91·5%) pregnant women with a DEL phenotype were confirmed to carry the RHD (K409K) allele. Among 12 DEL women who appeared to have RHD‐CE‐D hybrid alleles, there were 1 RHD‐CE (4–7)‐D, 7 RHD‐CE(4–9)‐D, and 4 RHD‐CE (2–5)‐D alleles. Alloanti‐D antibodies were detected in 6 of 142 DEL women, and all the six women had the partial DEL phenotype.
Conclusion
The data indicate that partial DEL women appear at risk of alloimmunization to the D antigen. RhD immune globulin prophylaxis is necessary for partial DEL women. Partial DEL patients should receive only RhD‐negative RBCs, whereas DEL patients with complete expression of antigen can safely receive RhD‐positive RBCs.
To summarize the experience of diagnosis and treatment of congenital choledochal cyst in the past 20 years (1980-2000).
The clinical data of 108 patients admitted from 1980 to 2000 were analyzed ...retrospectively.
Abdominal pain,jaundice and abdominal mass were presented in most child cases. Clinical symptoms in adult cases were non-specific, resulting in delayed diagnosis frequently. Fifty-seven patients (52.7%) had coexistent pancreatiobiliary disease. Carcinoma of the biliary duct occurred in 18 patients (16.6%). Ultrasonic examination was undertaken in 94 cases, ERCP performed in 46 cases and CT in 71 cases. All of the cases were correctly diagnosed before operation. Abnormal pancreatobiliary duct junction was found in 39 patients. Before 1985 the diagnosis and classification of congenital choledochal cyst were established by ultrasonography preoperatively and confirmed during operation, the main procedures were internal drainage by cyst enterostomy. After 1985, the diagnosis was established by ERCP and CT, and cystectomy with Roux-en-Y hepaticojejunostomy was the conventional procedures.In 1994, we reported a new and simplified operative procedure in order to reduce the risk of choledochal cyst malignancy. Postoperative complication was mainly retrograde infection of biliary tract, which could be controlled by the administration of antibiotics, there was no perioperative mortality.
The concept in diagnosis and treatment of congenital choledochal cyst has obviously been changed greatly.CT and ERCP were of great help in the classification of the disease.Currently, cystectomy with Roux-en-Y hepaticojejunostomy is strongly recommended as the choice for patients with type I and type IV cysts. Piggyback orthotopic liver transplantation is indicated in type V cysts (Caroli's disease) with frequently recurrent cholangitis.
The mean life of the positive muon has been measured to a precision of 11 ppm using a low-energy, pulsed muon beam stopped in a ferromagnetic target, which was surrounded by a scintillator detector ...array. The result, tau(micro)=2.197 013(24) micros, is in excellent agreement with the previous world average. The new world average tau(micro)=2.197 019(21) micros determines the Fermi constant G(F)=1.166 371(6)x10(-5) GeV-2 (5 ppm). Additionally, the precision measurement of the positive-muon lifetime is needed to determine the nucleon pseudoscalar coupling g(P).
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