Biomedical subjects

Wenquan Wang

Publications and source records attributed to Wenquan Wang.

18 recordsLinked to original sources

PubMed2006

Comparison of predictive values of two diagnostic tests from the same sample of subjects using weighted least squares.

Screening and diagnostic tests are important in disease prevention or control. The predictive values of positive and negative (PPV and NPV) test results are two of four operational characteristics of a screening test. We review an existing method based on the generalized estimating equation (GEE) methodology for comparing predictive values from the same sample of subjects and propose two Wald test statistics derived from the weighted least squares (WLS) method for the analysis of categorical data. Using these results, we propose sample size calculation formulae for this problem. Simulation studies are conducted to compare the performances of the two Wald test statistics (one based on the difference of two PPVs or NPVs, another based on the logarithm of the ratio of two PPVs or NPVs) and the score/Wald test statistic derived from GEE. We recommend using the difference-based WLS approach.

Angiography↗

PubMed2006

Increased expression of thymidylate synthetase (TS), ubiquitin specific protease 10 (USP10) and survivin is associated with poor survival in glioblastoma multiforme (GBM).

BACKGROUND: The limited success of empirically designed treatment paradigms for patients diagnosed with glioblastoma multiforme (GBM) emphasizes the need for rationally designed treatment strategies based on the molecular profile of tumor samples and their correlation to clinical parameters. METHODS: In the current study, we utilize a novel real-time quantitative low density array (RTQ-LDA) to identify differentially expressed genes in de novo GBM tissues obtained from patients with distinctly different clinical outcomes. Total RNA was isolated from a cohort of 21 GBM specimens obtained from patients with either good (long-term survival (LTS) >36 months post surgery, n = 8) or poor (died of the disease (DOD) <24 months post surgery, n = 13) prognosis. Non-neoplastic brain tissue (n = 5) was obtained from patients who underwent surgery for refractory epilepsy. Demographic data was assessed for correlation with survival using Cox proportional hazards models. Sufficient RNA was available to use RTQ-LDA to quantify the expression of 93 independent genes in 5 LTS, 4 DOD, and 5 non-neoplastic brain samples. The eight differentially expressed genes identified by RTQ-LDA in LTS versus DOD (P <or= 0.050) were subsequently quantified in all 21 GBM samples by real-time quantitative PCR (RTQ). RESULTS: A correlation between younger patients and good prognosis was demonstrated (P <or= 0.05). The combination of RTQ-LDA and RTQ identified thymidylate synthetase (TS), ubiquitin specific protease 10 (USP10), and survivin as significantly over-expressed (P <or= 0.050) in DOD compared to LTS patients. Ribonucleotide reductase subunit M2 (RRM2) was identified as tumor-specific, but not associated with survival. CONCLUSIONS: Taken collectively, TS, USP10, survivin and RRM2 may be useful as prognostic indicators and/or in the development of rationally designed treatment protocols.

Adolescent↗

PubMed2006

A novel technique to quantify glioma tumor invasion using serial microscopy sections.

Here we present a new technique to quantitatively characterize malignant glioma invasion in a syngeneic mouse model. The GL261 mouse malignant glioma cell line was injected intracerebrally into the C57B1/6 black mouse and allowed to propagate for 10 or 17 days, followed by euthanasia of the animal, harvesting of the brain, fixation, and serial sectioning. Histologic examination was performed and the primary tumor mass and discontinuous sites of tumor invasion were traced on digital images of serial microscopy sections, followed by analysis of the invasion characteristics using a custom-written MATLAB program. We found a significant increase in the number of discontinuous tumor invasion sites and in the distance of these sites from the tumor centroid in mice that were euthanized at 17 days post-tumor cell injection, as compared to mice euthanized at 10 days. Furthermore, a scatter plot analyses indicated that the invasion site data could be grouped based on the characteristics of area and distance from the tumor centroid to reveal significant differences between the two experimental groups of mice. This quantitative method will allow a future in vivo analysis of invasion characteristics in glioma cells expressing altered levels or function of invasion genes, and of new therapy targeting invading glioma cells.

Animals↗

PubMed2006

A prospective blinded evaluation of the accuracy of frozen section for the surgical management of endometrial cancer.

OBJECTIVE: To prospectively evaluate in a blinded fashion the accuracy of frozen section in endometrial cancer. METHODS: Sixty patients with endometrial cancer or complex atypical hyperplasia were consecutively enrolled. Intraoperatively, a frozen section was obtained, processed, and stored for interpretation by blinded pathologists. Final pathologic diagnosis was conducted in the usual fashion with the pathologists blinded to frozen results. Histologic grade and myometrial invasion on frozen section was correlated with final pathology. RESULTS: Median age was 61 years (range, 39-82 years). Fifty-seven percent of patients were white, and mean body mass index was 40 mg/kg2. Depth of invasion on frozen correlated with final pathology in 67% (95% confidence interval [CI] 55-79%). Twenty-eight percent (95% CI 17-39%) of patients were upstaged from frozen to final. Patients with no invasion on frozen were upstaged in 46% (95% CI 28-64%). Histologic grade on frozen correlated with final pathology in 58% (95% CI 46-70%); 38% (95% CI 26-50%) of patients were upgraded by final grade. Patients with frozen grade 1 histology or less were upgraded in 61% (95% CI 45-77%). Clinically relevant upstaging occurred in 11 patients (18%) (95% CI 8-28%). CONCLUSION: Frozen section for histologic grade and depth of myometrial invasion in endometrial cancer correlates poorly with final pathology. Because a large number of patients are potentially understaged with the use of frozen section with a subsequent risk of over and under treatment, we recommend consideration of comprehensive surgical staging for all patients with endometrial cancer. LEVEL OF EVIDENCE: II-2.

Adult↗

PubMed2006

Cervical intraepithelial neoplasia in adolescent women: incidence and treatment outcomes.

OBJECTIVE: We sought to estimate the incidence of cervical intraepithelial neoplasia (CIN) and treatment outcomes in adolescents with abnormal cytology. METHODS: Adolescent women (ages 14-21 years) referred to colposcopy clinic for abnormal cytology from 1992 to 2004 were identified by computerized database. Only adolescents with biopsy-proven CIN were evaluated. Demographic and risk factor data were obtained from medical records. Referral cytology, histology on biopsy and loop electrosurgical excisional procedure (LEEP), and follow-up cytology were analyzed and compared. Statistical analysis was performed by chi(2) or Fisher exact test, Student t tests, and logistic regression. RESULTS: Of 1,678 adolescents, 517 had biopsy-proven CIN and follow-up. Seventy-seven patients were referred with atypical squamous cells of undetermined significance (ASCUS) cytology; 174 patients were referred with low-grade squamous intraepithelial lesions (LSIL), 258 with high-grade squamous intraepithelial lesions (HSIL) and eight with atypical glandular cells (AGC). The rate of CIN 2/3 in patients with ASCUS, LSIL, and HSIL was 35% (95% confidence interval 24-46%), 36% (29-43%), and 50% (44-56%), respectively. A total of 192 patients with biopsy-proven CIN 2/3 underwent a LEEP. No patients were diagnosed with cervical carcinoma. Fifty-five percent (95% confidence interval 48-62%) of patients had abnormal cytology on follow-up, suggesting recurrence or reinfection. CONCLUSION: Adolescents with abnormal cytology have a high incidence of CIN2/3 and high rates of abnormal cytology after LEEP. Cervical intraepithelial neoplasia 2/3 is common in adolescents with abnormal cytology, yet no cases of cancer were identified. Importantly, LEEP fails to meet its therapeutic goals given a high incidence of abnormal follow-up cytology and may represent overly aggressive therapy because the majority of human papillomavirus infections are transient with high regression rates. LEVEL OF EVIDENCE: III.

Adolescent↗

PubMed2006

Multiple gene expression analyses in paraffin-embedded tissues by TaqMan low-density array: Application to hedgehog and Wnt pathway analysis in ovarian endometrioid adenocarcinoma.

Recent studies have shown the hedgehog and Wnt families of signaling proteins to be associated with tumor initiation, growth, and survival. However, these pathways remain unexplored in ovarian endometrioid adenocarcinoma (OEA). Here, we describe a novel TaqMan low-density array to examine the expression of 26 and 20 genes in the hedgehog and Wnt pathways, respectively, in six matched snap-frozen and formalin-fixed, paraffin-embedded (FPE) OEA specimens. Expression values were normalized to uninvolved ovarian epithelium. Gene expression in matched frozen and FPE tissues demonstrated significant concordance (r = 0.92, P < 0.0001). However, comparison of amplified and unamplified RNA from frozen OEA tissues revealed an altered molecular profile in amplified RNA. Amplification of RNA from FPE tissues was not successful. The expression of Desert hedgehog (DHH), Indian hedgehog (IHH), Hedge-hog interacting protein (HHIP), Wnt10B, Wnt9B, and Wnt inhibitory factor (WIF1) were tumor-specific with no detectable expression in normal ovarian epithelium. In addition, several genes were significantly (P < 0.025) down-regulated in OEA, including cyclin E2, Porcupine, c-Myc, and Axin 2 (4.8-, 3.6-, 2.9-, and 1.9-fold, respectively). TaqMan low-density array provides an effective multivariate technique for examining gene expression in RNA isolated from either snap-frozen or archival FPE tissues and can identify tumor-specific genes, possibly leading to novel treatments.

Animals↗

PubMed2005

Anti-tumor activity of TRA-8 anti-death receptor 5 (DR5) monoclonal antibody in combination with chemotherapy and radiation therapy in a cervical cancer model.

OBJECTIVES: There is substantial evidence that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) causes apoptosis via activation of death receptors 4 and 5 (DR4 and DR5). We sought to determine the therapeutic potential of TRA-8 (anti-DR5 monoclonal antibody) in combination with chemotherapy and radiation therapy in a cervical cancer model. METHODS: DR5 expression in 7 human cervical cancer cell lines was analyzed by indirect immunofluorescence using murine TRA-8 in combination with flow cytometry. Cell lines were treated with TRA-8 alone or in combination with cisplatin, topotecan, or radiation, and cytotoxicity assays were performed. Mice were inoculated with ME-180 cancer cells and treated with different combinations of therapy. Animals receiving antibody were injected intraperitoneally with 200 microg of TRA-8. Animals received 9 Gy 60Co radiation divided into 3 fractions and 3 intraperitoneal doses of cisplatin (6 mg/kg) 1 h before radiation. A similar experiment was performed using topotecan (2 mg/kg) as the chemotherapeutic agent. RESULTS: DR5 was expressed to a varying degree on the cervical cancer cell lines. Combination treatment with TRA-8 and chemotherapy or radiation resulted in synergistic cytotoxicity in vitro. In vivo, combination therapy with TRA-8, cisplatin, and radiation produced tumor growth inhibition that was significantly greater than the other groups. Similar results were seen in combination studies with topotecan. CONCLUSIONS: These data suggest that DR5 is a good target for activation of the apoptotic pathway. Monoclonal antibodies such as TRA-8 may play an important role in the development of an effective treatment strategy for patients with advanced cervical cancer.

Animals↗

PubMed2005

Lyn kinase activity is the predominant cellular SRC kinase activity in glioblastoma tumor cells.

Cellular Src activity modulates cell migration, proliferation, and differentiation, and recent reports suggest that individual members of the Src family may play specific roles in these processes. As we have found that Lyn, but not Fyn, activity promotes migration of glioblastoma cells in response to the cooperative signal generated by platelet-derived growth factor receptor beta and integrin alpha(v)beta3, we compared the activity and expression of Lyn and Fyn in glioblastoma (grade IV) tumor biopsy samples with that in anaplastic astrocytoma (grade III) tumors, nonneoplastic brain, and normal autopsy brain samples. Lyn kinase activity was significantly elevated in glioblastoma tumor samples. Notably, the Lyn kinase activity accounted for >90% of pan-Src kinase activity in glioblastoma samples but only approximately 30% of pan-Src kinase activity in the other groups. The levels of phosphorylation of the autophosphorylation site were consistent with significantly higher Lyn activity in glioblastoma tumor tissue than nonneoplastic brain. Although the normalized levels of Lyn protein and the relative levels of Lyn message were significantly higher in glioblastoma samples than nonneoplastic brain, the normalized levels of Lyn protein did not correlate with Lyn activity in the glioblastoma samples. There was no significant difference in the normalized levels of c-Src and Fyn protein and message in the glioblastoma and nonneoplastic brain. Immunostaining revealed that Lyn is located primarily in the glioblastoma cells in the tumor biopsies. These data indicate that Lyn kinase activity is significantly elevated in glioblastoma tumors and suggest that it is the Lyn activity that promotes the malignant phenotype in these tumors.

Astrocytoma↗

PubMed2005

Antigenic conservation and immunogenicity of the HIV coreceptor binding site.

Immunogenic, broadly reactive epitopes of the HIV-1 envelope glycoprotein could serve as important targets of the adaptive humoral immune response in natural infection and, potentially, as components of an acquired immune deficiency syndrome vaccine. However, variability in exposed epitopes and a combination of highly effective envelope-cloaking strategies have made the identification of such epitopes problematic. Here, we show that the chemokine coreceptor binding site of HIV-1 from clade A, B, C, D, F, G, and H and circulating recombinant form (CRF)01, CRF02, and CRF11, elicits high titers of CD4-induced (CD4i) antibody during natural human infection and that these antibodies bind and neutralize viruses as divergent as HIV-2 in the presence of soluble CD4 (sCD4). 178 out of 189 (94%) HIV-1-infected patients had CD4i antibodies that neutralized sCD4-pretreated HIV-2 in titers (50% inhibitory concentration) as high as 1:143,000. CD4i monoclonal antibodies elicited by HIV-1 infection also neutralized HIV-2 pretreated with sCD4, and polyclonal antibodies from HIV-1-infected humans competed specifically with such monoclonal antibodies for binding. In vivo, variants of HIV-1 with spontaneously exposed coreceptor binding surfaces were detected in human plasma; these viruses were neutralized directly by CD4i antibodies. Despite remarkable evolutionary diversity among primate lentiviruses, functional constraints on receptor binding create opportunities for broad humoral immune recognition, which in turn serves to constrain the viral quasispecies.

Amino Acid Sequence↗

PubMed2005

Patient-specific dosimetry of pretargeted radioimmunotherapy using CC49 fusion protein in patients with gastrointestinal malignancies.

UNLABELLED: Pretargeted radioimmunotherapy (RIT) using CC49 fusion protein, comprised of CC49-(scFv)4 and streptavidin, in conjunction with 90Y/111In-DOTA-biotin (DOTA = dodecanetetraacetic acid) provides a new opportunity to improve efficacy by increasing the tumor-to-normal tissue dose ratio. To our knowledge, the patient-specific dosimetry of pretargeted 90Y/111In-DOTA-biotin after CC49 fusion protein in patients has not been reported previously. METHODS: Nine patients received 3-step pretargeted RIT: (a) 160 mg/m2 of CC49 fusion protein, (b) synthetic clearing agent (sCA) at 48 or 72 h later, and (c) 90Y/111In-DOTA-biotin 24 h after the sCA administration. Sequential whole-body 111In images were acquired immediately and at 2-144 h after injection of 90Y/111In-DOTA-biotin. Geometric-mean quantification with background and attenuation correction was used for liver and lung dosimetry. Effective point source quantification was used for spleen, kidneys, and tumors. Organ and tumor 90Y doses were calculated based on 111In imaging data and the MIRD formalism using patient-specific organ masses determined from CT images. Patient-specific marrow doses were determined based on radioactivity concentration in the blood. RESULTS: The 90Y/111In-DOTA-biotin had a rapid plasma clearance, which was biphasic with <10% residual at 8 h. Organ masses ranged from 1,263 to 3,855 g for liver, 95 to 1,009 g for spleen, and 309 to 578 g for kidneys. The patient-specific mean 90Y dose (cGy/37 MBq, or rad/mCi) was 0.53 (0.32-0.78) to whole body, 3.75 (0.63-6.89) to liver, 2.32 (0.58-4.46) to spleen, 7.02 (3.36-11.2) to kidneys, 0.30 (0.09-0.44) to lungs, 0.22 (0.12-0.34) to marrow, and 28.9 (4.18-121.6) to tumors. CONCLUSION: Radiation dose to normal organs from circulating radionuclide is substantially reduced using pretargeted RIT. Tumor-to-normal organ dose ratios were increased about 8- to 11-fold compared with reported patient-specific mean dose to liver, spleen, marrow, and tumors from 90Y-CC49.

Aged↗

PubMed2005

Clinical significance of unsatisfactory conventional pap smears owing to inadequate squamous cellularity defined by the Bethesda 2001 criterion.

To determine the incidence of clinically significant lesions in long-term follow-up after a diagnosis of inadequate squamous cellularity using former and new criteria, we reviewed conventional Papanicolaou (Pap) smears (January-December 1998) for adequacy based on the Bethesda System 2001 criterion. Of 23,302 Pap smears evaluated in our laboratory, 114 (0.489%) were classified as unsatisfactory and 245 (1.051%) as "satisfactory but limited by" based on the 10% rule. Follow-up information for 5 years was obtained for 172 patients without a concurrent cervical epithelial abnormality: 25 (14.5%) had squamous abnormalities (atypical squamous cells, 22; low-grade squamous intraepithelial lesion, 2; and high-grade squamous intraepithelial lesion, 1). With the Bethesda System 2001 criterion, 167 (97.1%) of 172 smears had inadequate squamous cellularity and 5 (2.9%) were adequate. No differences in the incidence of squamous abnormalities detected on follow-up were noted between patients with unsatisfactory Pap smears owing to inadequate squamous cellularity and patients with satisfactory and negative smears. Our findings raise the question whether patients with unsatisfactory Pap smears and a negative history of gynecologic diseases require repeated Pap smears within 2 to 4 months as suggested by the American Society for Colposcopy and Cervical Pathology guideline.

False Negative Reactions↗

PubMed2004

Work, leisure-time physical activity, and risk of preeclampsia and gestational hypertension.

Few studies of preeclampsia have assessed physical activity level, yet recent evidence suggests that the pathologic mechanisms in preeclampsia are similar to those in cardiovascular disease, for which physical activity is shown to be protective. The authors assessed the independent and combined effects of work and regular leisure-time physical activity (LTPA) during early pregnancy on risk of de novo preeclampsia (n = 44) and gestational hypertension (n = 172) among women recruited from 13 obstetric practices in the New Haven, Connecticut, area between 1988 and 1991. Control subjects were normotensive throughout pregnancy (n = 2,422). Information on time at work spent sitting, standing, and walking and on LTPA before and during pregnancy was collected via face-to-face interviews. Logistic regression analyses suggested that women who engaged in any regular LTPA regardless of caloric expenditure (adjusted odds ratio (aOR) = 0.66, 95% confidence interval (CI): 0.35, 1.22), were unemployed (aOR = 0.64, 95% CI: 0.21, 2.00), or had nonsedentary jobs (aOR = 0.71, 95% CI: 0.37, 1.36) were at decreased risk of preeclampsia. Analyses of gestational hypertension showed no indication of a protective effect of workplace activity, LTPA, or unemployment. Consistent with other studies, these data suggest that regular physical activity during pregnancy may reduce preeclampsia risk.

Adult↗

PubMed2004

Placebo-controlled, double-blind trial of intravenous ribavirin for the treatment of hantavirus cardiopulmonary syndrome in North America.

UNLABELLED: BACKGROUND. Ribavirin is active in vitro against hantaviruses, but the findings of an open trial of the use of intravenous ribavirin for the treatment of hantavirus cardiopulmonary syndrome (HCPS) were inconclusive. METHODS: Subjects with suspected HCPS in the prodrome or cardiopulmonary phase but without shock were eligible for randomization to receive either intravenous ribavirin (33 mg/kg [<or=2 g], followed by 16 mg/kg [<or=1 g] given every 6 h for 4 days and by 8 mg/kg [<or=.5 g] given every 8 h for 3 days) or placebo (administered for 7 days or until the initial Sin Nombre virus antibody test result was confirmed to be negative). The primary outcome was survival at day 28 of the study without the need for extracorporeal membrane oxygenation (ECMO). RESULTS: Thirty-six subjects were enrolled in the trial from March 1996 through July 2001, at which point the study was terminated prematurely because of both the slow rate of accrual of subjects and the findings of a futility analysis. Of the 36 subjects enrolled, 23 (all of whom were enrolled during the cardiopulmonary stage of HCPS) had HCPS confirmed by serologic testing. The severity of illness at entry into the study was similar among the 10 subjects with HCPS who received ribavirin and the 13 subjects with HCPS who received placebo. The proportion of subjects who survived and who did not require ECMO was similar among ribavirin recipients and placebo recipients (70% vs. 62%, respectively); 2 ribavirin recipients and 2 placebo recipients died, including 3 of 7 subjects treated with ECMO. The frequency of adverse events, including anemia, was similar between treatment groups. CONCLUSIONS: The rate of accrual of subjects in the present study was inadequate to clearly assess the safety or efficacy of ribavirin in the treatment of HCPS. However, ribavirin was well tolerated, and the lack of trends supporting the use of intravenous ribavirin suggests that it is probably ineffective in the treatment of HCPS in the cardiopulmonary stage.

Adult↗

PubMed2004

Over 20% of human transcripts might form sense-antisense pairs.

The major challenge to identifying natural sense- antisense (SA) transcripts from public databases is how to determine the correct orientation for an expressed sequence, especially an expressed sequence tag sequence. In this study, we established a set of very stringent criteria to identify the correct orientation of each human transcript. We used these orientation-reliable transcripts to create 26 741 transcription clusters in the human genome. Our analysis shows that 22% (5880) of the human transcription clusters form SA pairs, higher than any previous estimates. Our orientation-specific RT-PCR results along with the comparison of experimental data from previous studies confirm that our SA data set is reliable. This study not only demonstrates that our criteria for the prediction of SA transcripts are efficient, but also provides additional convincing data to support the view that antisense transcription is quite pervasive in the human genome. In-depth analyses show that SA transcripts have some significant differences compared with other types of transcripts, with regard to chromosomal distribution and Gene Ontology-annotated categories of physiological roles, functions and spatial localizations of gene products.

Base Pairing↗

PubMed2004

Treatment for cervical intraepithelial neoplasia and risk of preterm delivery.

CONTEXT: It is unclear whether treatments for cervical intraepithelial neoplasia (CIN) increase the subsequent risk of preterm delivery. Most studies have lacked sufficient sample size, mixed heterogeneous subtypes of preterm delivery, and failed to control for confounding factors. OBJECTIVE: To determine whether cervical laser and loop electrosurgical excision procedure (LEEP) treatments increase risk of preterm delivery and its subtypes. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study conducted among women evaluated at a colposcopy clinic serving Auckland, New Zealand (1988-2000), comparing delivery outcomes of untreated women (n = 426) and those treated (n = 652) with laser conization, laser ablation, or LEEP. Record linkage using unique health identifiers identified women who had subsequent deliveries. MAIN OUTCOME MEASURES: Total preterm delivery and its subtypes, spontaneous labor and premature rupture of membranes before 37 weeks' gestation (pPROM). RESULTS: The overall rate of preterm delivery was 13.8%. The rate of pPROM was 6.2% and the rate of spontaneous preterm delivery was 3.8%. Analyses showed no significant increase in risk of total preterm delivery (adjusted relative risk [aRR], 1.1; 95% confidence interval [CI], 0.8-1.5) or spontaneous preterm delivery (aRR, 1.3; 95% CI, 0.7-2.6) for any treatment. Risk of pPROM was significantly increased following treatment with laser conization (aRR, 2.7; 95% CI, 1.3-5.6) or LEEP (aRR, 1.9; 95% CI, 1.0-3.8), but not laser ablation (aRR, 1.1; 95% CI, 0.5-2.4). Moreover, risk of pPROM and total preterm delivery increased significantly with increasing height of tissue removed from the cervix in conization. Women in the highest tertile of cone height (> or =1.7 cm) had a greater than 3-fold increase in risk of pPROM compared with untreated women (aRR, 3.6; 95% CI, 1.8-7.5). CONCLUSIONS: LEEP and laser cone treatments were associated with significantly increased risk of pPROM. Careful consideration should be given to treatment of CIN in women of reproductive age, especially when treatment might reasonably be delayed or targeted to high-risk cases.

Cervix Uteri↗

PubMed2004

Prognostic value of 1p, 19q, 9p, 10q, and EGFR-FISH analyses in recurrent oligodendrogliomas.

Although 1p/19q codeletions define "genetically favorable" oligodendrogliomas, eventual tumor progression and patient death remain constant. Genetic testing is often performed at the time of recurrence, though it is unclear whether these or other genetic alterations provide useful prognostic information. We characterized 138 of 189 (73%) available primary and recurrent oligodendroglial neoplasms from 80 patients, utilizing paired FISH probes for 1p32/1q42, 19p13/19q13, CEP7/EGFR, CEP9/p16, and PTEN/DMBT1. Patients were followed until death (49%), or a median follow-up of 8.9 years. Patients with 1p/19q codeleted tumors (71%) had an estimated overall median survival of 14.9 years with an estimated 3.9 years from first recurrence. In contrast, those lacking deletions had significantly lower estimated overall median survivals of 4.7 years and 1.0 year after first recurrence (both p < 0.001). This increased survival in patients with 1p/19q codeleted tumors remained significant when adjustments were made for age, tumor grade, type of surgical procedure, and treatment with radiation or chemotherapy. Only 1 recurrence showed focal EGFR amplification, while 5 developed 10q deletions, mostly in high-grade mixed oligoastrocytomas lacking 1p/19q deletions. In contrast, p16 (9p21) deletions were common and associated with both high grade (p < 0.001) and recurrence (p = 0.002). Our data suggest that in classic oligodendrogliomas: 1) 1p/19q tumor status is a powerful predictor of patient survival, even after recurrence; 2) p16 deletions are common progression-associated alterations; and 3) 10q deletions and EGFR amplifications are sufficiently rare to suggest the possibility of alternate diagnoses.

Adult↗

PubMed2002

[Comparison of morphology, physiology and mineral element contents among genotypes of sesame with different tolerance to waterlogging under anaerobic condition].

The morphological and physiological indexes and the mineral element contents in different organs of 4 genotypes of sesame were examined under controlled oxygen supply. The number of adventitious roots of flooding tolerant varieties, Wild No. 7 and Yuzhi No. 1, increased 4-5 fold, the activity of ADH enhanced about twice, but the net photosynthetic rate (Pn) decreased slightly. There were significant increase in Ca and P and little decrease in K in roots, and decrease in other elements in roots and 8 elements in stems and leaves. As for less flooding-tolerant genotypes, Danbackaggce and Suiping Xiaozhihuang, however, the number of adventitious roots increased little, the activity of ADH enhanced 5-9 folds, and Pn decreased by 50-60%. An increase in Ca and P, and a significant reduction in K was found in roots. It was concluded that the waterlogging tolerance of sesame depended firstly on the structural adaptation, then on the anoxia metabolism, and that Ca and P may play an important role in the metabolic adaptation to the anaerobic environment for plant survival.

Adaptation, Biological↗

PubMedDate not supplied

Site-specifically traced drug release and biodistribution of a paclitaxel-antibody conjugate toward improvement of the linker structure.

Tumor-directed drug delivery is a promising strategy in cancer treatment, and in this field, monoclonal antibodies constitute an important class of targeting vehicles. A critical issue in the design of targeting conjugates is the timing of the release of the cytotoxic payload, with the ideal situation being the release at the maximum tumor uptake of the targeting molecule. A site-specific radiolabeling technique was used to elucidate the biodistribution and in vivo drug release pattern of an antibody conjugate of paclitaxel (PTX, 1, Figure 1) in which the drug and the antibody moieties were connected by a succinate (SX) linker. In this new method, a metabolite of PTX, 3'-(4-hydroxyphenyl)paclitaxel (3'-OH-PTX, 2, Figure 1) was used as a tyrosine mimic for the synthesis of the drug site-labeled conjugate (DSL, [(125)I]-3'-OH-PTXSXC225). This was achieved by iodogen (125)I-labeling of 3'-OH-PTXSX and subsequent conjugation to C225. The antibody site-labeled conjugate (ASL, PTXSX-[(125)I]-C225) was prepared by direct radioiodination of PTXSXC225. Biodistribution of these compounds was studied in Balb/c nude mice bearing DU-145 human prostate carcinoma xenografts. While the 4 and 24 h tumor uptake (in percent injected dose per gram of tissue, %ID/g) for [(125)I]-3'-OH-PTXSXC225 were 3.3 +/- 1.5 and 1.7 +/- 0.6%ID/g, the PTXSX-[(125)I]-C225 showed tumor uptake values of 3.8 +/- 4.2 and 14.8 +/- 4.2%ID/g at these time points. This difference in the tumor uptake over time indicates an early cleavage of the drug with respect to the antibody tumor localization. This was further confirmed by an in vitro drug release kinetics study leading to a half-life of about 2 h for PTXSXC225 under physiological conditions. To increase the stability of the PTX-MAb bond, a new conjugate (PTXGLC225) with glutaric acid (GL) as the linker was synthesized. Under the same conditions, the PTXGLC225 showed a 16-fold increase in the half-life (t(1/2)) of the drug release. The effect of the increased t(1/2) of this compound on the antitumor activity of the conjugate was tested in a DU-145 human prostate tumor-implanted mouse model. In comparison to a previous similar experiment with PTXSXC225, better antitumor activity was observed for the PTXGLC225 conjugate as compared to controls. These results demonstrated the first time use of radioiodinated 3'-OH-PTX for in vivo tracing of a paclitaxel conjugate and application of the resulting information to the design of a therapeutically more useful PTX-MAb linker.

Animals↗