Mendelian randomization (MR) is an established approach for assessing the causal effects of heritable exposures on outcomes. Outcomes of interest often include binary clinical endpoints, but may also include censored survival times. We explore the implications of both the Cox proportional hazard model and the additive hazard model in the context of MR, with a specific emphasis on two‐stage methods. We show that naive application of standard MR approaches to censored survival times may induce significant bias. Through simulations and analysis of data from the Women's Health Initiative, we provide practical advice on modeling survival outcomes in MRs. 相似文献
Akt/protein kinase B (PKB) plays an important role in cell survival. However, the role of Akt in the biology of gastric cancer has not been well studied. We sought to investigate the expression of Akt or phosphorylated Akt (pAkt) in human gastric carcinomas and to analyze the relationship between Akt or pAkt and the clinicopathologic parameters. The expressions of Akt and pAkt were evaluated immunohistochemically in 311 gastric carcinomas using the tissue array method. Akt expression was detected in 74% of the tumors and pAkt expression in 78%. pAkt was highly expressed in the early stage of pTNM (p=0.011). We also found an inverse association between pAkt and lymphatic invasion (p=0.01) or lymph node metastasis (p=0.008). pAkt expression was significantly correlated with a higher survival in patients with stage I carcinomas (p=0.0003). Interestingly, combined evaluation revealed that the group with pAkt-positive and lymph node-negative carcinomas showed a better prognosis than the other groups (p<0.0001). In addition, pAkt was shown to correlate positively with APC (p=0.002) and Smad4 (p<0.0001) expression. These findings suggest that pAkt expression may help to predict the clinical outcome of gastric cancer patients. 相似文献
The presence of immunoglobulins and antibodies were investigated in the fertile hen's egg during embryogenesis. The egg yolk, egg albumin, amniotic and allantoic fluids, chick embryo serum and intestinal contents were examined for the presence of immunoglobulin and level of antibodies.
Immunoglobulin G was not detected in fresh egg albumin, but appeared in the albumin from the 4th day of embryogenesis and persisted through the 16th day. The antibody profile of egg albumin during embryogenesis attained two peaks, which were separated by a trough on the 8th day of embryogenesis. The immunoelectrophoretic pattern of albumin IgG was different from that of egg yolk IgG.
The IgG of chick embryo serum was of γ2 mobility on the 12th day of incubation and shifted gradually to the full range of γ1 and γ2 mobilities on the 20th day of incubation. Egg-transmitted antibodies appeared on the 12th day of incubation and attained peak values on the 16th day of incubation.
Moderate antibody levels were detected in the amniotic and allantoic fluids from the 12th to the 18th days of incubation.
We review here the 10-year experience at the University of Michigan with 35 patients with gastrin hypersecretion who underwent transhepatic venous sampling (THVS) for tumor localization. Since 1978 THVS has been done routinely in all patients with gastrinoma syndrome considered for operation. Thirty-one patients had proved gastrinomas--21 benign sporadic tumors and 10 tumors associated with multiple endocrine neoplasia type-I (MEN I) syndrome. The correlation between the site of the maximal gradient and location of a sporadic tumor was poor. Overall sensitivity was only 35%, specificity 89%, and negative predictive value 89%. If gradients were regionalized to three areas--body and tail, gastrinoma triangle, and hepatic lobes--then sensitivity was 94%, positive predictive value 94%, and specificity 97%, with a negative predictive value of 97%. The maximal gastrin gradient above the mean for other values gave the greatest sensitivity and specificity. In MEN I syndrome, only four of eight patients with macroadenomas had their tumors correctly localized, a sensitivity of 50% and specificity and negative predictive value of 75%. In 19 patients who had operative localization of sporadic gastrinoma, computed tomography had a sensitivity of 31%, specificity of 66%, positive predictive value of 83%, and negative predictive value of 15%. Selective angiography was better, with a sensitivity of 29%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 100%. Regionalization to the triangle proved valuable for detection of microgastrinomas, as was measurement of hepatic vein gastrins for identification of intrahepatic tumors. In MEN I syndrome, if regionalization was achieved (50%), tumor resection appeared to offer hope of "cure." We conclude that THVS is the best tool for tumor regionalization to the pancreatic tail and body, gastrinoma triangle, and hepatic lobes. It has allowed us to achieve surgical cure in 19 of 21 patients with sporadic gastrinomas and improvement in four of eight patients with MEN I syndrome. 相似文献
From January 1979 to October 1986, 86 patients with surgically resectable adenocarcinoma of the rectum or rectosigmoid were treated with adjuvant radiotherapy consisting of preoperative 2,400 cGy (22 patients), preoperative 4,000 cGy (14 patients), "sandwich" technique (27 patients), and postoperative irradiation (23 patients). Average follow-up was 42.9 months. The local recurrence rate was 4.5%, 9.1%, 7.4%, and 34.8%, respectively. The distant metastasis rate was 18.2%, 18.2%, 7.4%, and 30.4%, respectively. Preoperative radiotherapy with adequate surgical resection appears more effective in reducing the incidence of local recurrence. 相似文献
Transport of 14C-labeled acetic, propionic (PA), butyric, valeric, heptanoic (HA), and octanoic (OA) acids across the Madin Darby canine kidney (MDCK) epithelial cell monolayer grown on a porous polycarbonate membrane was studied in Hanks' balanced salt solution (HBSS) at 37°C in both apical-to-basolateral and basolateral-to-apical directions. At micromolar concentrations of solutes, metabolic decomposition was significant as evidenced by [14C]CO2 production during the OA transport. The apparent permeability (Pe) indicates that as lipophilicity increases, diffusion across the unstirred boundary layer becomes rate limiting. In support of this notion, transport of OA and HA was enhanced by agitation, showed an activation energy of 3.7 kcal/mol for OA, and resulted in identical Pe values for both transport directions. Analysis of Pe changes with varying alkyl chain length resulted in a G of –0.68 ± 0.09 kcal/mol for –CH2-group transfer from an aqueous phase to the MDCK cells. When the intercellular tight junctions were opened by the divalent chelator EGTA in Ca2+/Mg2+ -free HBSS, transport of the fluid-phase marker Lucifer yellow greatly increased because of paracellular leakage. PA transport also showed a significant increase, but OA transport was independent of EGTA. Although albumin also undergoes paracellular transport in the presence of EGTA and OA binds strongly to albumin, OA transport in EGTA solution was unchanged by albumin. These observations indicate that transmembrane transport is the major mechanism for lipophilic substances. The present study, together with earlier work on the transport of polar substances, shows that the MDCK cell monolayer is an excellent model of the transepithelial transport barrier. 相似文献
AB-type amphiphilic copolymers (abbreviated as LE) composed of poly (L-leucine) (PLL) as the A component and poly (ethylene
oxide) (PEO) as the B component were synthesized by the ring-opening polymerization of L-leucine N-carboxy-anhydride initiated
by methoxy polyoxyethylene amine (Me-PEO-NH2) and characterized. Core-shell type nanoparticles were prepared by the diafiltration method. Particle size distribution obtained
by dynamic light scattering was dependent on PLL composition and the size for LE-1, LE-2 and LE-3 was 369.6±267, 523.4±410
and 561.2±364 nm, respectively. Shapes of the nanoparticles observed by transmission electron microscope (TEM) were almostly
spherical. The critical micelle concentration (CMC) of the nanoparticles determined by a fluorescence probe technique was
dependent on the composition of hydrophobic PLL, and the CMC for LE-1, LE-2 and LE-3 was 2. 0×10−6, 1.7×10−6 and 1.5×10−6 (mol/l), respectively. Clonazepam release from core-shell type nanoparticles in vitro was dependent on PLL composition and
drug loading content. 相似文献
Induction of an adaptive response to ionizing radiation in mouse lymphoma (EL4) cells was studied by using cell survival fraction
and apoptotic nucleosomal DNA fragmentation as biological end points. Cells in early log phase were pre-exposed to low dose
of γ-rays (0.01 Gy) 4 or 20 hrs prior to high dose γ-ray (4, 8 and 12 Gy for cell survival fraction analysis; 8 Gy for DNA
fragmentation analysis) irradiation. Then cell survival fractions and the extent of DNA fragmentation were measured. Significant
adaptive response, increase in cell survival fraction and decrease in the extent of DNA fragmentation were induced when low
and high dose γ-ray irradiation time interval was 4 hr. Addition of protein or RNA synthesis inhibitor, cycloheximide or 5,6-dichloro-1-β-d-ribofuranosylbenzimidazole
(DRFB), respectively during adaptation period, the period from low dose γ-ray irradiation to high dose γ-ray irradiation,
was able to inhibit the induction of adaptive response, which is the reduction of the extent DNA fragmentation in irradiated
EL4 cells. These data suggest that the induction of adaptive response to ionizing radiation in EL4 cells required both protein
and RNA synthesis. 相似文献
Purpose. This study is concerned with cellular delivery/generation of 2′-azido-2′-deoxyuridine and -deoxycytidine diphosphate (N3UDP or N3CDP), potent inhibitors of ribonucleotide reductase. It characterizes the phosphorylation steps involved in the conversion of 2′-azido-2′-deoxyuridine (N3Urd) and 2′-azido-2′-deoxycytidine (N3Cyd) to the corresponding diphosphates and explores a prodrug approach in cellular delivery of the inhibitor which circumvents the requirement of deoxynucleoside kinases. Methods. Cell growth of CHO and 3T6 cells of known deoxycytidine kinase level was determined in the presence of N3Urd and N3Cyd. Activity of ribonucleotide reductase was determined in the presence of the azidonucleosides as well as their mono- or di-phosphates in a Tween 80-containing permeabilizing buffer. A prodrug of 5′-monophosphate of N3Urd was prepared and its biological activity was evaluated with CHO cells as well as with cells transfected with deoxycytidine kinase. Results. N3Urd failed to inhibit the growth of both cell lines, while N3Cyd was active against 3T6 cells and moderately active against CHO cells. These results correlate with the deoxycytidine kinase levels found in the cells. Importance of the kinase was further established with the finding that the nucleoside analogs were inactive as reductase inhibitors in a permeabilized cell assay system while their mono- and di-phosphates were equally active. The prodrug was active in cell growth inhibition regardless of the deoxycytidine kinase level. Conclusions. The azidonucleosides become potent inhibitors of the reductase by two sequential phosphorylation steps. The present study indicates that the first step to monophosphate is rate-limiting, justifying a prodrug approach with the monophosphate. 相似文献
An analytic formalism utilizing a convolution technique is presented for the incorporation of anisotropy corrections into the dynamic (or transit) dose calculations in high dose rate (HDR) brachytherapy. A simple numerical implementation of the suggested formalism is also presented. Two calculational examples are provided in order to show some effects of anisotropy corrections on the dynamic dose calculations. Based on the results from these examples and published literature, the absence of anisotropy corrections in the dynamic dose calculations could result in a dosimetric error up to the order of 0.1 Gy during the full course of HDR brachytherapy treatments depending on fractionation and geometrical arrangement. Therefore, the incorporation of anisotropy corrections into dynamic dose calculations could eliminate this kind of error in HDR brachytherapy. 相似文献