SEARCH · Search PubMed

Results for “Overall”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

SourceResearch connectionFrom yearThrough year

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 757 records · Page 42Linked to original sources

PubMed2026

Prolonged Cytopenia After Idecabtagene Vicleucel for Multiple Myeloma is Associated with Poor Overall Survival.

Cytopenias are well-recognized toxicities of idecabtagene vicleucel (ide-cel), a chimeric antigen receptor T cell (CAR-T) therapy approved for the treatment of relapsed, refractory multiple myeloma (RRMM). However, little is known of prognostic implications of cytopenias that persist 30 to 100 days after CAR-T infusion. We report the duration, incidence, and impact on outcomes of post-CAR-T cytopenias at Day 30 and Day 100, defined as an absolute neutrophil count of <500 cells/mm3 and/or platelet count <20 × 109 cells/L, per the recent definitions of immune effector cell-associated hematotoxicity for neutropenia (N-ICAHT) and thrombocytopenia (T-ICAHT). Using observational data from the Center for International Blood and Marrow Transplant Research, we identified 821 patients treated during 2021 to 2023. The cumulative incidence of cytopenias at Day 30 was 25% and at Day 100 was 2%. Patients with Day 30 cytopenias had inferior progression-free survival (PFS) (39% versus 45%, P = .01) and overall survival (OS) at 12 months (57% versus 76%, P < .01). While there was no significant difference in PFS in patients who had Day 100 cytopenias (42% versus 53%, P = .12), compared to those who did not, patients with Day 100 cytopenias had significantly inferior OS at 12 months (55% versus 82%, P < .01). High (≥2) chimeric antigen receptor cell-mediated hematotoxicity score was associated with cytopenias at Day 30 (hazard ratio 5.26, P < .001). Cytopenias at Day 30 after ide-cel were associated with inferior PFS and OS. In addition, cytopenias at Day 100 after ide-cel are rare and are associated with inferior OS.

CAR-T↗

PubMed2006

Use of a novel assay based on intact recombinant viruses expressing green (EGFP) or red (DsRed2) fluorescent proteins to examine the contribution of pol and env genes to overall HIV-1 replicative fitness.

Multiple studies have described a reduction in the replicative fitness of HIV-1 isolates harboring mutations that confer resistance to antiretroviral drugs. Contradictory results, however, have been obtained depending on the methodology used in each study (Quinones-Mateu, M.E., Arts, E.J., 2002. Fitness of drug resistant HIV-I: methodology and clinical implications. Drug Resist. Update 5, 224-233), affecting our understanding of the potential relationship of viral replicative fitness with HIV-1 disease. It has been demonstrated previously that both pol and env genes play a major role in HIV-1 replicative fitness of clinical isolates. Therefore, measuring clinically relevant replicative fitness using recombinant viruses where a single mutation and/or viral gene have been introduced does not seem like a reasonable approach in this era of multi-target antiretroviral therapy. A novel method was developed to measure HIV-1 replicative fitness based on recombinant viruses expressing the enhanced green fluorescent (EGFP) or the Discosoma sp. red fluorescent (DsRed2) proteins in a HIV-1NL4-3 backbone. Contrary to previous designs to analyze HIV-1 fitness, these replication competent viruses were created in an intact viral genetic background (without deleting or affecting the expression of any viral gene). This new system was used to evaluate the contribution of drug-resistance mutations in the pol and env genes to overall viral replicative fitness (in the presence and absence of drug pressure) using direct growth competition experiments. Mutations in pol showed a stronger effect on HIV-1 replicative fitness than mutations in the env gene associated with resistance to enfuvirtide, corroborating the plasticity of the later gene to accept mutations and the sensibility of the protease and reverse transcriptase enzymes to drug-associated primary mutations. In conclusion, a new protocol was used to measure HIV-1 replicative fitness in either the presence or absence of antiretroviral drugs, which may be used as a high-throughput assay to help us understand the clinical significance of viral fitness.

Cell Line↗

PubMed2006

An intention-to-treat by endovascular repair policy may reduce overall mortality in ruptured abdominal aortic aneurysm.

OBJECTIVE: The use of endovascular aneurysm repair (EVAR) for ruptured abdominal aortic aneurysm (AAA) has been restricted to a small number of specialized units on a selected group of patients. The aim of this study is to assess if the overall mortality in these patients with ruptured AAA may be reduced in a unit where all patients with ruptured AAA are considered first for EVAR. METHODS: During a 24-month period beginning in July 2002, 51 patients admitted with ruptured AAA were considered for EVAR as the treatment of choice and comprised the study group. EVAR was performed in 17 patients. Open repair was performed in 34 patients: 13 patients had hemodynamic instability and 16 patients had an unsuitable aortic neck anatomy. The study group was compared with a historical control group of 41 patients with ruptured AAA who were treated by open repair from July 2000 to June 2002. RESULTS: Mortality rate was 39% in the study group compared with 59% in the control group (P = .065). The duration of stay in the intensive care unit was significantly lower in the study group than in the control group (P = .01), although the total in-hospital stay was similar (17 days vs 14 days, P = .83). Within the study group, EVAR patients had a mortality rate of 24% compared with 47% in the open group (P = .14). CONCLUSION: Although the number of patients was small, offering EVAR to as many patients as possible with ruptured AAA has resulted in a 20% reduction in mortality, albeit statistically insignificant. However, it is in the unstable patients that EVAR will need to improve survival before it may be hailed to supersede the conventional approach.

Acute Kidney Injury↗

PubMed2006

Considering the major mental disorders as clinical expressions of periodic pathological oscillations of the overall operating mode of brain function.

The consideration of the collective significance of the shared characteristics and overlaps in the clinical expression and pharmacological responses of the major mental disorders (namely, schizophrenia, bipolar disorders, obsessive compulsive disorder, anxieties/phobias, borderline syndrome and possibly others) supports the following: (1) These disorders have a common, initial neurodevelopmental origin. (2) They occur probabilistically on some of "at-risk" individuals whose pre-existing, extreme, temperamental/structural variance confers vulnerability for such occurrence. (3) Lastly, each of these syndromes can be considered as a clinical expression of oscillations (i.e., a switch to a pathologically ordered phase) of the overall, common operating mode of brain function. This mode based on a particular-for-our-brain, emergent quality of complexity, normally ensures the synchrony, coordination, subtlety and robust flexibility in the expression of the components of each of the various higher faculties of the brain, namely, the faculty of: (1) mood modulation; (2) coordination of feelings, thoughts and the responses to the external world; and (3) keeping constrain and limited but appropriate input of primitive drives. The conclusions in this paper have important ramifications in rethinking the current nosological procrustean flawed classification and the neurodevelopmental origin of the major mental disorders as well as the biases shown in selecting subjects for research. It also opens opportunities in the future development of novel, effective, economical and harmless therapies that will restore and maintain the normal phase of the operating mode of brain function. For example, the patient can wear an appropriate electronic device that sends a particular type of signal to the brain which will affect remission and prevent relapses without harm. We can thus avoid the use of pharmacological agents which have limited effectiveness, severe, long-term side-effects and financial burden to the patient.

Brain↗

PubMed2004

Overall distribution of GLYT2 mRNA-containing versus GAD67 mRNA-containing neurons and colocalization of both mRNAs in midbrain, pons, and cerebellum in rats.

We aimed to clarify the overall distribution of glycinergic neurons in the midbrain, pons, and cerebellum in rats, using in situ hybridization for mRNA encoding glycine transporter 2 (GLYT2), which reliably detects glycinergic cell bodies. We combined this method with in situ hybridization for mRNA encoding glutamic acid decarboxylase isoform 67 (GAD67), and have presented for the first time global and detailed views of the distribution of glycinergic neurons in relation to GABAergic neurons. In addition to this single-detection study, we performed double-detection of GLYT2 mRNA and GAD67 mRNA to determine the distribution of neurons co-expressing these mRNAs. We have shown that many areas of the brainstem and cerebellum, not only areas where previous immunohistochemical studies have specified, involve double-labeled neurons with GLYT2 and GAD67 mRNAs. In particular, when lightly labeled GLYT2 mRNA-positive neurons were distributed within the area of GAD67 mRNA-positive neurons, almost all such GLYT2 mRNA-positive neurons were GAD67 mRNA-positive. Areas or neuron groups expressing exclusively GLYT2 mRNA or GAD67 mRNA were rather limited, such as the superior colliculus, nucleus of the trapezoid body, and Purkinje cells. The present study suggests that the corelease of glycine and GABA from single neurons is more widespread than has been reported.

Amino Acid Transport Systems, Neutral↗

PubMed2026

A novel neoadjuvant immunotherapy confers improved overall survival in oral cancer patients with low tumor PD-L1 expression The IT-MATTERS Clinical trial - Prognostic role of tumor PD-L1 expression.

OBJECTIVE: Five-year overall survival (OS) remains < 50% for patients with resectable, locally advanced (LA) primary oral squamous cell carcinoma (OSCC) and soft palate, receiving current standard of care (SOC). The aim of our study was to examine neoadjuvant Leukocyte Interleukin Injection (LI) with CIZ (intravenous low dose cyclophosphamide, indomethacin and zinc multivitamins) effect on OS, in low-risk (LR) OSCC patients. PATIENTS AND METHODS: In a randomized, controlled Phase 3 trial, treatment-naïve locally advanced patients, with stage III/IVa OSCC and soft-palate cancer, had surgical tumor samples assessed for pre-defined thresholds of PD-L1 tumor proportion score (TPS). OS was analyzed using proportional hazard models for LI + CIZ + SOC vs SOC, in the intention-to-treat (ITT) population. RESULTS: OS was superior in low risk (LR) patients receiving LI + CIZ + SOC compared to SOC; OS advantage hazard ratio (HR) 0.64, p = 0.0569 (without selecting for N0, PD-L1 TPS < 10%), and the Kaplan-Meier (K-M) lifetable achieved significance (log rank p = 0.0340) favoring LI + CIZ + SOC vs SOC. Applying the selection criteria (cN0 and TPS < 10%) to ITT, OS reached HR 0.34p = 0.0012, Kaplan-Meier log rank p = 0.0015. The ITT LR cohort (cN0 and TPS < 10%) achieved a HR 0.26 (p = 0.0023), Kaplan-Meier log rank p = 0.0013, supported by progression free survival (PFS) HR 0.43, p = 0.0178, Kaplan-Meier log rank p = 0.0431, with 32% absolute survival advantage over control at 60 months. CONCLUSIONS: Significant OS prolongation was observed in ITT population for LI + CIZ + SOC vs SOC, in LR and in ITT LR cN0, PD-L1TPS < 10% cohort having locally advanced squamous cell carcinoma tumors in oral cavity/soft-palate. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT01265849; EudraCT (Identifier: 2010-019952-35).

Humans↗

PubMed2005

Predicting the overall management outcome in patients with a subarachnoid hemorrhage accompanied by a massive intracerebral or full-packed intraventricular hemorrhage: a 15-year retrospective study.

BACKGROUND: Patients with a subarachnoid hemorrhage (SAH) accompanied by a massive intracerebral hemorrhage (ICH) or a full-packed intraventricular hemorrhage (IVH) have poor outcomes. We evaluated the clinical factors to predict the overall outcome in such patients. METHODS: Data on nontraumatic SAH patients were collected and classified into 3 groups: the pure SAH group (SAH accompanied with neither ICH nor IVH), the ICH group (SAH accompanied with a massive ICH; hematoma 30 mL), and the IVH group (SAH and all ventricles were full-packed with hematoma). One hundred seventy-nine patients were in the ICH group and 109 in the IVH group. We evaluated clinical factors, such as the Hunt & Hess (H&H) score on admission, age, sex, history, rebleeding ratio, and the computerized tomography findings (SAH score). RESULTS: The result of multivariate logistic regression analysis of clinical variables in the ICH group, good and intermediate H&H grades, younger age (<70), no rebleeding, and lower SAH score were associated with a favorable outcome. In the result of the multivariate logistic regression analysis of clinical variables in the IVH group, only a higher SAH score was associated with an unfavorable outcome. CONCLUSIONS: In the ICH group, factors that could be used to predict a favorable outcome included good and intermediate H&H scores (1, 2, and 3) on admission, younger age (<70), and a lower SAH score. In the IVH group, the main factor that could be used to predict a favorable outcome was a lower SAH score.

Adult↗

PubMed2004

Aggressive treatment for bladder cancer is associated with improved overall survival among patients 80 years old or older.

OBJECTIVES: To examine the impact of various treatment modalities on survival among patients with bladder cancer who were 80 years old or older compared with younger patients. A compendium of evidence suggests that bladder cancer surgery is safe among octogenarians; however, the benefit of such treatment in a population with limited life expectancy has not been well documented. METHODS: Subjects with the primary diagnosis of bladder cancer were identified from the National Cancer Institute's Surveillance, Epidemiology, and End Results cancer registry between 1988 and 1999. Of the 13,796 patients diagnosed with bladder cancer, 24% were older than 80 years of age. Proportional hazards regression modeling was performed to determine the independent association of treatment strategy on overall and bladder cancer survival while adjusting for multiple covariates. RESULTS: Of patients 80 years old or older, bladder cancer management included watchful waiting (7%), radiotherapy alone (1%), full or partial cystectomy (12%), and transurethral resection (79%). Patients 80 years old or older were less likely to be treated with extirpative surgery than their younger counterparts (P <0.0001). Cox proportional hazards models demonstrated that, among patients 80 years old or older, radical cystectomy/partial cystectomy had the greatest risk reduction in death from bladder cancer (hazard ratio 0.3) and death from any cause (hazard ratio 0.4) among the primary treatment modalities (both P <0.0001). CONCLUSIONS: Disparities in practice patterns between younger and geriatric patients with bladder cancer exist. We provide compelling evidence that aggressive surgical management of bladder cancer in these patients may improve survival. Risk adjustment tools should be used to identify patients (young and old) who would be better served by less aggressive management.

Age Factors↗

PubMed2004

(Un)certainty of overall binding constants of Al with dissolved organic matter determined by the Scatchard approach.

One of the best approaches to date to obtain overall binding constants (Ko) for Al and dissolved organic matter (DOM) from acidic soil solutions is to collect 'free' Al data with diffusive gradients in thin films (DGT) and to infer the Ko values by fitting a continuous distribution model based on Scatchard plots. Although there is clear established literature demonstrating the usefulness of the Scatchard approach, relatively little attention has been given to a realistic assessment of the uncertainties associated with the final fitted Ko values. In this study we present an uncertainty analysis of the fitted Ko values using a synthetic dataset with different levels of random noise and a real data set using DGT data from an acidic soil solution. The parameters in the continuous distribution model and their corresponding upper and lower 95% uncertainty bounds were determined using the Shuffled Complex Evolution Metropolis (SCEM) algorithm. Although reasonable fits of the distribution model to the experimental data were obtained in all cases, an appreciable uncertainty in the resulting Ko values was found due to three main reasons. Firstly, obtaining 'free' Al data even with the DGT method is relatively difficult, leading to uncertainty in the data. Secondly, before Scatchard plots can be constructed, the maximum binding capacity (MBC) must be estimated. Any uncertainty in this MBC propagates into uncertainty associated with the final plots. Thirdly, as the final fitted Ko values are largely based on extrapolation, a small uncertainty in the fit of the binding data results in an appreciable uncertainty in the obtained Ko. Therefore, while trends in Ko for Al and DOM could easily be discerned and compared, the uncertainty in the Ko values hinders the application in quantitative speciation calculation. More comprehensive speciation models that avoid the use of Ko seem to fit better for this purpose.

Aluminum↗

PubMed2006

CA125 level as a predictor of progression-free survival and overall survival in ovarian cancer patients with surgically defined disease status prior to the initiation of intraperitoneal consolidation therapy.

OBJECTIVES: Recent data suggest that differences in CA125 levels within the normal range may predict progression-free survival (PFS), but limited information is available regarding the value of these differences in predicting overall survival (OS) in patients with epithelial ovarian cancer. The objective of this study was to determine whether CA125 is an independent predictor of OS in patients with surgically defined disease status at the end of primary therapy prior to intraperitoneal (IP) consolidation chemotherapy. A secondary objective was to assess the relationship of CA125 level to PFS. METHODS: Using data from a retrospective cohort of 433 patients who received intraperitoneal (IP) therapy following primary treatment for ovarian cancer between 1984 and 1998, we identified 241 patients with a complete clinical response and CA125 data at the time of second-look surgery prior to IP chemotherapy. Patient demographics and updated follow-up status were abstracted from medical records. Kaplan-Meier survival curves were compared using the log-rank test, and Cox regression models were used for multivariate analysis. RESULTS: The majority of patients had advanced stage III or IV disease (n=201, 83%) and high-grade histology (n=163, 68%). Taxane was used as part of primary platinum-based therapy in 56% (n=134) of patients, and subsequent IP chemotherapy was platinum-based in 85% (n=206). When considered as a continuous variable, CA125 was a predictor of OS (P=0.029). Using the median CA125 level in our study group as a cut-off, OS was increased in patients with CA125 < or =12 U/ml (median 5.8 years) compared with >12 (3.7 years) (P=0.0027). CA125 level was an independent predictor of OS (HR: 1.410; 95% CI, 1.044, 1.904, P=0.0248) in a multivariate model that included stage (P=0.0166), grade (P=0.0001), and findings at second-look surgery (P=0.0003). CA125 level was also a predictor of clinical PFS (radiographic or CA125 elevation criteria alone) in a subset of 161 patients as a continuous variable (P=0.0036), and when divided at the median (< or = or >12; median 2.8 years vs. 1.7 years; P=0.0017). CONCLUSIONS: In our study population, CA125 level at the end of primary therapy was a predictor of OS and PFS when considered as a continuous variable, or when divided at the median (< or = or >12 U/ml). Further prospective study is required to optimize clinically significant cut-off values within the normal range of CA125 levels for both OS and PFS endpoints.

Adult↗

PubMed2006

The environmental risk assessment of human pharmaceuticals in the overall EU regulatory affairs process.

The approval of new human pharmaceutical products in the EU requires an assessment of potential environmental risks related to the use by patients, besides the evaluation of the human safety, efficacy, and quality evaluation. The current guidance by the European Medicines Agency (EMEA), describing the process of the environmental risk assessment for human drugs, covers a two-tiered assessment programme with a modelling step for an environmental exposure scenario and a subsequent step of environmental fate and effects testing. The following paper describes ways how the requirements of the environmental risk assessment can be sensibly incorporated in the overall approval process of a pharmaceutical product including the risk/benefit analysis for the patient. The resources for environmental testing and assessment programmes can be employed economically, if the pharmacological, toxicological, and pharmacokinetic information obtained during the development programme of a human pharmaceutical is used to develop substance-specific test programmes and to evaluate the environmental risk assessment taking into account the pharmacodynamic properties and the use pattern by patients. Finally, we suggest that the environmental risk evaluation process as part of drug approvals should adhere to a focussed assessment strategy considering existing knowledge and the therapeutic needs.

Drug-Related Side Effects and Adverse Reactions↗

PubMed2003

Overall injury risk to different drivers: combining exposure, frequency, and severity models.

Traffic crash risk assessments should incorporate appropriate exposure data. However, existing US nationwide crash data sets, the NASS General Estimates System (GES) and the Fatality Analysis Reporting System (FARS), do not contain information on driver or vehicle exposure. In order to obtain appropriate exposure data, this work estimates vehicle miles driven (VMD) by different drivers using the Nationwide Personal Transportation Survey (NPTS). These results are combined with annual crash rates and injury severity information from the GES for a comprehensive assessment of overall risk to different drivers across vehicle classes. Data are distinguished by driver age, gender, vehicle type, crash type (rollover versus non-rollover), and injury severity. After correcting for drivers' crash exposure, results indicate that young drivers are far more crash prone than other drivers (per VMD) and that drivers of sports utility vehicles (SUVs) and pickups (PUs) are more likely to be involved in rollover crashes than those driving passenger cars. Although, the results suggest that drivers of SUVs are generally much less crash prone than drivers of passenger cars, the rollover propensity of SUVs and the severity of that crash type offset many of the incident benefits for SUV drivers.

Accidents, Traffic↗

PubMed1999

Overall cardiovascular profile of sildenafil citrate.

Sildenafil, a selective inhibitor of phosphodiesterase type 5 (PDE5), is the first in a new class of orally effective treatments for erectile dysfunction. During sexual stimulation, the cavernous nerves release nitric oxide (NO), which induces cyclic guanosine monophosphate (cGMP) formation and smooth muscle relaxation in the corpus cavernosum. Sildenafil facilitates the erectile process during sexual stimulation by inhibiting PDE5 and thus blocking the breakdown of cGMP. Sildenafil alone can cause mean peak reductions in systolic/diastolic blood pressure of 10/7 mm Hg that are not dose related, whereas the heart rate is unchanged. Sildenafil and nitrates both increase cGMP levels in the systemic circulation but at different points along the NO-cGMP pathway. The combination is contraindicated because they synergistically potentiate vasodilation and may cause excessive reductions in blood pressure. Erectile dysfunction is a significant medical condition that shares numerous risk factors with ischemic heart disease, and hence a substantial overlap exists between these patient groups. From extensive clinical trials, the most commonly reported cardiovascular adverse events in patients treated with sildenafil were headache (16%), flushing (10%), and dizziness (2%). The incidences of hypotension, orthostatic hypotension, and syncope and the rate of discontinuation of treatment due to adverse events were <2% and were the same in patients taking sildenafil and those taking placebo. Retrospective analysis of the concomitant use of antihypertensive medications (beta blockers, alpha blockers, diuretics, angiotensin-converting enzyme inhibitors, and calcium antagonists) in patients taking sildenafil did not indicate an increase in the reports of adverse events or significant episodes of hypotension compared with patients treated with sildenafil alone. In clinical trials, the incidence of serious cardiovascular adverse events, including stroke and myocardial infarction, was the same for patients treated with sildenafil or placebo. Concurrent disease states, such as renal or hepatic impairment, or concomitant use of inhibitors of the cytochrome P450 isozyme CYP3A4 could increase systemic exposure to sildenafil. Since the US market launch in April 1998, monitoring of spontaneous adverse event reports in association with sildenafil has demonstrated a pattern that is generally consistent with the experience observed during clinical development, with the exception of infrequent reports of priapism. In conclusion, extensive clinical testing has shown that overall treatment with sildenafil for up to 1 year is well tolerated and is associated with a low incidence of adverse events that result in discontinuation of treatment in <3% of patients.

3',5'-Cyclic-GMP Phosphodiesterases↗

PubMed1995

Body fat distribution, rather than overall adiposity, influences serum lipids and lipoproteins in healthy men independently of age.

PURPOSE: We investigated the relationships between the amount and distribution of body fat and fasting serum lipids and lipoproteins to explore whether coronary artery disease (CAD) risk may be mediated through effects on the serum lipid profile. PATIENTS AND METHODS: We determined serum total cholesterol and triglyceride, low-density lipoprotein cholesterol, high-density lipoprotein (HDL) cholesterol, and HDL subfractions 2 and 3 in 103 healthy men, aged 21 to 77 years (mean 48.7). The amount and distribution of fat were determined directly by dual energy X-ray absorptiometry. Adiposity was determined as the ratio between total body fat tissue and total body lean tissue, while fat distribution was taken as the ratio between the mass of fat tissue in the android (central) and gynoid (hip and thigh) regions. RESULTS: Univariate analysis showed both adiposity and fat distribution to be correlated with total serum cholesterol and triglyceride concentrations (adiposity r = .20, .21; both P < 0.05: fat distribution r = .25, .38; P < 0.05, P < 0.001, respectively). Fat distribution was also negatively correlated with HDL2 cholesterol (r = -.20, P < 0.05). In multiple linear regression analysis, neither age nor adiposity was significantly correlated with any serum lipid or lipoprotein concentration, while increasing android-to-gynoid ratio was independently associated with elevated total serum triglyceride (r = .40, P < 0.01) and decreased HDL2 (r = -.25, P < 0.05) concentrations. CONCLUSIONS: The association of both age and overall adiposity with the fasting serum lipid profile are mediated via their correlations with body fat distribution. In men, the distribution, rather than the amount, of body fat is related to adverse changes in serum lipids and lipoproteins, and hence potentially to increased CAD risk.

Absorptiometry, Photon↗

PubMed2002

A short mutational hot spot in the first intron of BCL-6 is associated with increased BCL-6 expression and with longer overall survival in large B-cell lymphomas.

BCL-6 somatic mutations have been described in normal and tumoral B lymphocytes, associated with germinal center transit. We analyzed mutations in the major mutation cluster of BCL-6 in a series of 45 large B-cell lymphomas (LBCLs) and 15 Burkitt's lymphomas, and their relation to the level of BCL-6 expression and clinical outcome. Mutations in LBCL cases revealed the existence of two distinct, short mutational hot spots, spanning positions 106 to 127 and 423 to 443, in which the mutation frequency was higher than expected (P < 0.001). Mutations in the 423 to 443 subcluster were associated with an increased level of expression, although this was not the case with the 106 to 127 cluster. Additionally, LBCL cases characterized by the presence of mutations in the 423 to 443 cluster showed an increased overall survival (P < 0.05) when compared with the nonmutated LBCL cases in these positions. Burkitt's lymphoma cases showed a slightly lower frequency of mutations with a nonclustered distribution and lacked any relationship with the level of expression or any clinical characteristic. Findings from LBCLs suggest that the 423 to 443 cluster includes a regulatory region that is of importance for BCL-6 expression. Deregulation of BCL-6 expression caused by these mutations could play an important role in lymphoma genesis or progression.

DNA-Binding Proteins↗

PubMed2001

Specific spin labelling of the sugar-H(+) symporter, GalP, in cell membranes of Escherichia coli: site mobility and overall rotational diffusion of the protein.

The D-galactose-H(+) symport protein (GalP) of Escherichia coli is a homologue of the human glucose transport protein, GLUT1. After amplified expression of the GalP transporter in E. coli, other membrane proteins were prereacted with N-ethylmaleimide in the presence of excess D-galactose to protect GalP. Inner membranes were then specifically spin labelled on Cys(374) of GalP with 4-maleimide-2,2,6,6-tetramethylpiperidine-1-oxyl. The electron paramagnetic resonance (EPR) spectra are characteristic of a single labelling site in which the mobility of the spin label is very highly constrained. This is confirmed with other nitroxyl spin labels, which are derivatives of iodoacetamide and indanedione. Saturation transfer EPR spectra indicate that the overall rotation of the GalP protein in the membrane is slow at low temperatures (approx. 2 degrees C), but considerably more rapid and highly anisotropic at physiological temperatures. The rate of rotation about the membrane normal at 37 degrees C is consistent with predictions for a 12-transmembrane helix assembly that is less than closely packed.

Amino Acid Sequence↗

PubMed1997

Overall and internal dynamics of DNA as monitored by five-atom-tethered spin labels.

Electron paramagnetic resonance (EPR) spectra of the two-atom-tethered six-membered ring thymidylate spin label (DUMTA) incorporated into duplexes of different sizes were found to display a helix length dependence and a local-order parameter S = 0.32 +/- 0.01 for B-DNA based on the dynamic cylinder model (Keyes, R. S., and A. M. Bobst. 1995. Detection of internal and overall dynamics of a two-atom-tethered spin-labeled DNA. Biochemistry. 34:9265-9276). This sensitivity to size, which reflects global tumbling, is now reported for the more flexible five-atom-tethered five-membered ring thymidylate spin label (DUAP) that can be readily incorporated enzymatically and sequence specifically into nucleic acids of different sizes. The DUAPs containing B-DNA systems were simulated with the same dynamic cylinder model, giving S = 0.20 +/- 0.01 for the more flexibly tethered spin label. This shows that S is dependent on tether length but not on global motion. An analysis with the same motional model of the B-Z transition in a (dG-dC)n polymer containing the five-atom-tethered six-membered ring cytidylate spin label (DCAT) (Strobel, O. K., R. S. Keyes, and A. M. Bobst. 1990b. Base dynamics of local Z-DNA conformations as detected by electron paramagnetic resonance with spin-labeled deoxycytidine analogues. Biochemistry. 29:8522-8528) revealed an increase in S from 0.15 +/- 0.01 to 0.26 +/- 0.01 in response to the B- to Z-DNA transition. This indicates that S is not only sensitive to tether length, but also to conformational changes in DNA. Both the DUAP- and the DCAT-labeled systems were also simulated with a base disk model. From the DUAP spectral series, the perpendicular component of the correlation time tau perpendicular describing the spin-labeled base diffusion was found to be sensitive to global tumbling, confirming earlier results obtained with DUMTA. The DCAT polymer results demonstrated that tau perpendicular monitors a conformational change from B- to Z-DNA, indicating that tau perpendicular is also sensitive to local base dynamics. These results confirm that the dynamics of five-atom-tethered nitroxides are coupled to the nucleic acid dynamics and, as with two-atom-tethered spin labels, can be characterized by S and tau perpendicular. The analyses of both spin-labeled systems provide good evidence for spin-labeled base motions within double-stranded DNA occurring on the nanosecond time scale, and establish that both labels can be used to monitor changes in global tumbling and local order parameter due to variations in DNA conformation and protein-DNA interactions.

Base Sequence↗

PubMed2000

Analysis of linear and cyclic oligomers in polyamide-6 without sample preparation by liquid chromatography using the sandwich injection method. II. Methods of detection and quantification and overall long-term performance.

By separating the first six linear and cyclic oligomers of polyamide-6 on a reversed-phase high-performance liquid chromatographic system after sandwich injection, quantitative determination of these oligomers becomes feasible. Low-wavelength UV detection of the different oligomers and selective post-column reaction detection of the linear oligomers with o-phthalic dicarboxaldehyde (OPA) and 3-mercaptopropionic acid (3-MPA) are discussed. A general methodology for quantification of oligomers in polymers was developed. It is demonstrated that the empirically determined group-equivalent absorption coefficients and quench factors are a convenient way of quantifying linear and cyclic oligomers of nylon-6. The overall long-term performance of the method was studied by monitoring a reference sample and the calibration factors of the linear and cyclic oligomers.

Caprolactam↗