Miracle-dz/UniFAR-FTUs huggingface dataset:
A randomized phase III trial of biochemotherapy versus interferon-&agr;-2b for adjuvant therapy in patients at high risk for melanoma recurrence

The objective of this study was to compare the clinical benefit of biochemotherapy and interferon-&agr;-2b (IFN) as adjuvant therapy. Biochemotherapy has higher response rates than other regimens in patients with metastatic melanoma. We conducted a randomized phase III study comparing the clinical benefit of biochemotherapy and IFN as adjuvant therapy. Patients who had undergone lymphadenectomy for melanoma metastatic to regional lymph nodes were randomly assigned to either biochemotherapy or IFN, and IFN patients were further randomized to either high-dose IFN (HDI) or intermediate-dose IFN (IDI). The primary end point was relapse-free survival (RFS); the secondary end point was overall survival (OS). The planned enrollment was 200 patients, the number required to have 80% power to detect, at a significance level of 5%, an improvement in median RFS from 18 to 36 months and an improvement in median OS from 40 to 80 months between the IFN and biochemotherapy groups. A futility analysis was performed because of slow accrual. One hundred and thirty-eight patients were enrolled – 71 in the biochemotherapy group, 34 in the HDI subgroup, and 33 in the IDI subgroup. No significant differences in median RFS or OS between the HDI and IDI subgroups were observed. With a median follow-up of 49.3 months, neither the biochemotherapy nor IFN group had reached median RFS or OS, and there were no significant differences in estimated median RFS or OS (P=0.86 and 0.45, respectively) between the two groups. Biochemotherapy is not more effective than IFN as adjuvant therapy for melanoma. These findings support early termination of this trial.
Genetic analysis of protein stability and function.

There is tremendous variability in the importance of individual amino acids in protein sequences. On the one hand, nonconservative residue substitutions can be tolerated with no loss of activity at many residue positions, especially those exposed on the protein surface. On the other hand, destabilizing mutations can occur at a large number of different sites in a protein, and for many proteins such mutations account for more than half of the randomly isolated missense mutations that confer a defective phenotype. At sites that are key determinants of stability or activity, even residue substitutions that are generally considered to be conservative (e.g., Glu in equilibrium Asp, Asn in equilibrium Asp, Ile in equilibrium Leu, Lys in equilibrium Arg and Ala in equilibrium Gly) can have severe phenotypic effects. Unfortunately, this means that there is no simple way to infer the likely effect of an amino acid substitution on the basis of sequence information alone. A nonconservative Gly----Arg substitution could be phenotypically silent at one position while a conservative Asn----Asp change could lead to complete loss of activity at another position. For proteins whose structures are known, it is often possible to predict whether particular residue substitutions will be destabilizing, as long as detailed estimates of the destabilization energy are not required. Substitutions that introduce polar groups, large cavities, or overly large side chains into the hydrophobic core are potentially the most destabilizing. Substitutions that disrupt hydrogen bonding or electrostatic interactions can also have significant effects, although the destabilization caused by these substitutions is smaller than that caused by severe core mutations. Destabilizing substitutions that involve replacing glycines in turns, or introducing prolines into alpha-helices and other disallowed positions are also reasonably common. Finally, most solvent exposed residues can apparently be freely substituted without serious effects on protein stability. Although exceptions may occur, these generalizations serve to summarize a large body of information and can be rationalized in physical and chemical terms. It is an especially encouraging result that proteins appear to tolerate most substitutions, even those that are destabilizing, without significant changes in the native structure. For proteins whose structures are known, this means that it is reasonable to interpret mutant phenotypes in terms of the wild-type structure. For proteins whose structures are not known, it is reasonable to infer that mutations that reduce activity without affecting stability are directly involved in function. (ABSTRACT TRUNCATED AT 400 WORDS)
Assessment of the mutagenic potency of sewage sludges contaminated with polycyclic aromatic hydrocarbons by an Ames sludges for fluctuation assay.

The mutagenicity of crude extracts and subfractions of two samples of a reference sewage sludge material and two sewage sludges from two wastewater treatment plants (WWTP), one urban and the other one urban mixed with industrial, was assessed using an Ames fluctuation assay based on 384-well microtiter plates with liquid cultures. Crude extracts of sludges were obtained by ultrasonic extraction with dichloromethane/methanol, and further column fractionation yielded two fractions, one of which containing mutagenic polycyclic aromatic hydrocarbons (PAHs). Quantitative analysis performed by gas chromatography-mass spectrometry gave sum concentrations of the 16 PAHs listed as priority pollutants by the U.S. Environmental Protection Agency at levels between 1,305 and 2,442 microg/kg. Subjecting crude extracts and column fractions to the mutagenicity assay with Salmonella strains TA98 and TA 100 provided good qualitative correlation between the presence of mutagenic PAH and the induction of gene mutations. In general, the crude extracts and the PAH-fractions induced positive responses in the assay with both bacterial strains on metabolic activation by S9 rat-liver homogenate, whereas direct-acting mutagens were not detectable. In the assay with the real sludge samples of two different WWTPs, TA98 proved to be more sensitive than TA100; however, similar sensitivities of the tester strains were observed for two reference sewage sludge materials of the same origin. The outcomes of the Ames fluctuation assay demonstrated its performance as a cost-effective and relatively rapid screening tool to assess the genotoxic potential of complex environmental samples.
Nursing Home Pre-Admission Screening: A Review of State Programs

From January through March of 1981, the Health Care Financing Administration (HCFA) surveyed the agencies of 49 States and the District of Columbia responsible for the administration of the Medicaid program. The purpose of the survey was to determine if the agencies had a nursing home pre-admission screening program for Medicaid patients. Twenty-eight States and the District of Columbia responded that there was a state-wide, pre-admission screening program for Medicaid patients prior to their entry into a nursing home, or that there was a program operating in a portion of the State. HCFA collected information on the scope of the programs, the agencies responsible for conducting pre-admission screening, the composition of the screening teams, and the characteristics of the client assessment instruments. Two States, Virginia and Massachusetts, provided information on program impact. This article presents the findings of the survey and explores several aspects of the Medicaid program influencing the effectiveness of pre-admission screening. It begins with an overview of the policy issues which have influenced the development of pre-admission screening and defines the core components of these programs. We then discuss current Medicaid utilization control mechanisms required of States by statute and the problems associated with these review practices in preventing inappropriate or unnecessary institutionalization. The article then describes and analyzes current State pre-admission screening programs. Finally, we discuss further policy considerations surrounding the effectiveness of pre-admission screening programs in assuring Medicaid patients equitable access to appropriate long-term care services.
Injuries in Runners: A Prospective Study of Alignment

Objective:To determine if measurable lower extremity alignment is a risk factor for overuse running injuries. Design:Prospective cohort study. Setting:Thirty-two week marathon training program. Patients or Participants:Three hundred fifty-five volunteers from the marathon training program began the study; 255 finished the study. Interventions:None. Main Outcome Measures:Past training and injury history was determined by questionnaire, and five lower extremity alignment measures were performed at the beginning of the training program: arch index (AI), heel valgus (HV), knee tubercle-sulcus angle (TSA), knee varus (KV), and leg-length difference (LLD). Overuse injuries, incurred by the runners and categorized by anatomic parts, were recorded during the training period. Results:Ninety subjects experienced overuse injuries. Multivariate analyses with stepwise Poisson regression showed few consistent relationships between alignment and overuse injury rates. Higher AI was protective against overall injuries and knee injuries; higher HV was protective against knee and foot injuries; higher TSA was associated with shin injuries; higher KV was associated with shin injuries; and low LLD was associated with more overall injuries. Conclusions:Minor variations in lower extremity alignment do not appear conclusively to be major risk factors for overuse injuries in runners. Because of the study limitations and the likely multifactorial nature of running injuries, further study is suggested, perhaps in more novice runners.
Measurement of total body water content in horses, using deuterium oxide dilution.

OBJECTIVE To measure total body water (TBW) content in horses, using deuterium oxide (D2O) dilution. ANIMALS Six 8- to 10-year-old healthy untrained mixed-breed horses, weighing (mean +/-SD) 503.4 +/- 64.0 kg. PROCEDURE After a 12-hour nonfeeding period, 6 horses were given D2O (0.14 g/kg of body weight) via nasogastric tube. Blood samples were collected from a preplaced indwelling jugular vein catheter prior to and 1 to 8, 10, 12, 14, and 24 hours after administration of D2O. Blood samples were centrifuged immediately, and plasma was collected and stored at -70 C until analysis. The D2O content in plasma was measured by zinc reduction to deuterium gas. The resulting gas was measured, using an isotope ratio mass spectrometer. RESULTS Deuterium oxide was rapidly absorbed from the gastrointestinal tract of all horses, and reached peak (mean +/- SD) plasma concentration (1,454.4 +/- 163 delta D/ml or parts/thousand) 1 hour after administration. Plasma concentration decreased slowly during the next 2 to 3 hours, then remained statistically constant from 2 to 5 hours (early plateau phase) and 3 to 7 hours (late plateau phase) after administration. Mean +/- SEM TBW content was 623.0 +/- 2.2 ml/kg (62.3% of body weight) for the early plateau phase and 630.3 +/- 2.2 ml/kg (63.0% of body weight) for the late plateau phase. CONCLUSION Deuterium oxide dilution appears to be of value for measurement of TBW content in horses, and has a 4-hour plateau effect. Equilibration of D2O with large intestinal water may be the reason for the prolonged equilibrium time and plateau effect seen in these horses. CLINICAL RELEVANCE Deuterium oxide appears safe and efficacious for determining TBW content in horses and may be helpful for determining changes in TBW content during exercise and disease.
Cascade Sliding Mode Torque Control of a Permenant Magnet Synchronous Motor

This paper presents the direct torque control (DTC) of an interior permanent magnet synchronous motor (IPMSM) based on sliding mode technique. Two adaptive sliding mode controllers are designed; one is used for regulating the motor speed and the other is dedicated for controlling the electromagnetic torque. Consequently, the demerits of classical DTC (large torque and current ripples due to sector changes, low speed problems, and sensitivity to uncertainties) could be avoided in the proposed scheme. The control law of each sliding controller has been designed in such a way that the chattering effects associated with the classical sliding mode are reduced to a great extent. Also, the reaching phase could be eliminated using the idea of total sliding mode control. Moreover, a simple adaptive algorithm is used to estimate the upper bound of lumped uncertainty. The stability analysis of the proposed control system is carried out using Lyapunov stability theorem. The feasibility and effectiveness of the proposed system have been demonstrated through computer simulations. A comparison between the proposed system and conventional techniques has been made in order to confirm the validity of the proposed approach. The superiority of the proposed system has been proved through comparative simulation results.
Mechanical transient‐based magnetic resonance elastography

Magnetic resonance elastography (MRE) is a technique for quantifying material properties by measuring cyclic displacements of propagating shear waves. As an alternative to dynamic harmonic wave MRE or quasi‐steady‐state methods, the idea of using a transient impulse for mechanical excitation is introduced. Two processing methods to calculate shear stiffness from transient data were developed. The techniques were tested in phantom studies, and the transient results were found to be comparable to the harmonic wave results. Transient wave based analysis was applied to the brains of six healthy volunteers in order to assess the method in areas of complex wave patterns and geometry. The results demonstrated the feasibility of measuring brain stiffness in vivo using a transient mechanical excitation. Transient and harmonic methods both measure white matter (∼12 kPa) to be stiffer than gray matter (∼8 kPa). There were some anatomic differences between harmonic and transient MRE, specifically where the transient results better depicted the deeper structures of the brain. Magn Reson Med 53:628–639, 2005. © 2005 Wiley‐Liss, Inc.
New capsule with tailored properties for the encapsulation of living cells.

A new capsule for the encapsulation and transplantation of pancreatic islets has been developed. Five active ingredients are involved in the capsule formation process: high viscosity sodium alginate (SA-HV), cellulose sulfate (CS), poly(methylene-co-guanidine) hydrochloride (PMCG), calcium chloride, and sodium chloride. Complexation reaction exhibits several unique features: (1) solution of SA-HV with CS represents a physical mixture of two entangled polyanions that provide both pH-sensitive (carboxylic) and permanently charged (sulfate) groups; (2) presence of CaCl2 in the cation solution ensures formation of the gelled bead after the drop of polyanion solution is immersed in the cation solution; (3) character of the polycation (PMCG), i.e., low molecular weight and unusually high charge density, combines both high mobility and reactivity; (4) presence of PMCG in cation solution, together with CaCl2, gives rise to the competitive binding of these two cations based on their diffusion and affinity towards the anion groups; and (5) NaCl provides the anti-gelling sodium ions that significantly affect the reaction of CaCl2 with the polyanion matrix, thus altering the final properties of the capsule surface, shape, and permeability. The capsule size, mechanical strength, membrane thickness, and permeability can be precisely adjusted and quantified. Detailed information on the permeability aspects is given in another paper by Brissová et al. [J. Biomed. Mater. Sci., 39, 61 (1998)]. The new features concerning capsule processing and testing are presented. We believe that the capsule characteristics can be optimized in the next step to meet the biological criteria. The initial transplantation results suggest that this capsule is biocompatible and noncytotoxic and is a promising candidate for the immunoisolation of cells such as pancreatic islets.
MAGE, BAGE and GAGE gene expression in human rhabdomyosarcomas

MAGE, BAGE and GAGE genes encode tumor‐associated antigens that are presented by HLA class I molecules and recognized by CD8+ cytolytic T lymphocytes. These antigens are currently regarded as promising targets for active, specific tumor immunotherapy because MAGE, BAGE and GAGE genes are expressed in many human cancers of different histotype and are silent in normal tissues, with the exception of spermatogonia and placental cells. MAGE, BAGE and GAGE gene expression has been extensively studied in different tumors of adults but is largely unknown in many forms of pediatric solid cancer. Using RT‐PCR, we analyzed MAGE‐1, MAGE‐2, MAGE‐3, MAGE‐4, MAGE‐6, BAGE, GAGE‐1,‐2 or ‐8 and GAGE‐3,‐4,‐5,‐6 or ‐7b gene expression in 31 samples of pediatric rhabdomyosarcoma, the most frequent form of malignant soft tissue tumor in children. MAGE genes were expressed in a substantial proportion of patients (MAGE‐1, 38%; MAGE‐2, 51%; MAGE‐3, 35%; MAGE‐4, 22%; MAGE‐6, 35%), while expression of BAGE (6%); GAGE‐1, GAGE‐2 and GAGE‐8 (9%); and GAGE‐3, GAGE‐4, GAGE‐5, GAGE‐6 and GAGE‐7B (16%) was less frequent. Overall, 58% of tumors expressed at least 1 gene, and 35% expressed 3 or more genes simultaneously. Our data suggest that a subset of rhabdomyosarcoma patients could be eligible for active, specific immunotherapy directed against MAGE, BAGE and GAGE antigens. © 2001 Wiley‐Liss, Inc.
Transplantation of human embryonic stem cell‐derived neural precursor cells and enriched environment after cortical stroke in rats: cell survival and functional recovery

Cortical stem cell transplantation may help replace lost brain cells after stroke and improve the functional outcome. In this study, we transplanted human embryonic stem cell (hESC)‐derived neural precursor cells (hNPCs) or vehicle into the cortex of rats after permanent distal middle cerebral artery occlusion (dMCAO) or sham‐operation, and followed functional recovery in the cylinder and staircase tests. The hNPCs were examined prior to transplantation, and they expressed neuroectodermal markers but not markers for undifferentiated hESCs or non‐neural cells. The rats were housed in either enriched environment or standard cages to examine the effects of additive rehabilitative therapy. In the behavioral tests dMCAO groups showed significant impairments compared with sham group before transplantation. Vehicle groups remained significantly impaired in the cylinder test 1 and 2 months after vehicle injection, whereas hNPC transplanted groups did not differ from the sham group. Rehabilitation or hNPC transplantation had no effect on reaching ability measured in the staircase test, and no differences were found in the cortical infarct volumes. After 2 months we measured cell survival and differentiation in vivo using stereology and confocal microscopy. Housing had no effect on cell survival or differentiation. The majority of the transplanted hNPCs were positive for the neural precursor marker nestin. A portion of transplanted cells expressed neuronal markers 2 months after transplantation, whereas only a few cells co‐localized with astroglial or oligodendrocyte markers. In conclusion, hESC‐derived neural precursor transplants provided some improvement in sensorimotor function after dMCAO, but did not restore more complicated sensorimotor functions.
Halomonas zincidurans sp. nov., a heavy-metal-tolerant bacterium isolated from the deep-sea environment.

A Gram-stain-negative, aerobic, rod-like, motile by peritrichous flagella and moderately halophilic bacterium, designated strain B6(T), was isolated a deep-sea sediment collected from the South Atlantic Ocean. The isolate grew with 0.5-15 % (w/v) NaCl, at 4-37 °C and pH 5.0-8.5 and showed a high tolerance to zinc, manganese, cobalt and copper ions. The major fatty acids were C16 : 0, C19 : 0 cyclo ω8c, C12 : 0 3-OH and C12 : 0. The predominant ubiquinone was Q-9. The genomic DNA G+C content was 61.1 mol%. Phylogenetic analysis based on 16S rRNA gene comparisons indicated that strain B6(T) belonged to the genus Halomonas, and the closest relative was Halomonas xinjiangensis TRM 0175(T) (96.1 %). Based upon the phenotypic, chemotaxonomic and genetic data, strain B6(T) represents a novel species from the genus Halomonas, for which the name Halomonas zincidurans sp. nov. is proposed. The type strain is B6(T) ( = CGMCC 1.12450(T) = JCM 18472(T)).
Induction of lef1 during zebrafish fin regeneration

Because the transcription factor Lef1 is important for development of several vertebrate organs but has not been investigated for involvement in epimorphic regeneration, we examined its expression during regeneration of amputated adult zebrafish caudal fins. We found that lef1 is markedly up‐regulated in the newly formed wound epidermis of the fin regenerate and is maintained in the basal epidermal layer during formation of the regeneration blastema. During regenerative outgrowth, lef1 expression is strongest in epidermal cells adjacent to newly aligned scleroblasts that secrete bone matrix, while it is low or undetectable in epidermis adjacent to mesenchymal areas with either mature bone or proliferative distal blastema cells. This localization is similar to that of the putative fin ray patterning signal Shh. In addition, brief treatments of fin regenerates with retinoic acid or the synthetic Fgfr1 inhibitor SU5402 down‐regulate epidermal lef1, similar to their effects on shh. These results suggest a role for Lef1 in scleroblast alignment analogous to that proposed for Shh. Other Wnt signaling pathway members wnt3a, wnt5, and β‐catenin are also expressed in the fin regenerate. Our data suggest that Lef1 has specific roles in inducing and patterning vertebrate regenerating tissue. © 2000 Wiley‐Liss, Inc.
Ligand-induced EGF Receptor Oligomerization Is Kinase-dependent and Enhances Internalization*

The current activation model of the EGF receptor (EGFR) predicts that binding of EGF results in dimerization and oligomerization of the EGFR, leading to the allosteric activation of the intracellular tyrosine kinase. Little is known about the regulatory mechanism of receptor oligomerization. In this study, we have employed FRET between identical fluorophores (homo-FRET) to monitor the dimerization and oligomerization state of the EGFR before and after receptor activation. Our data show that, in the absence of ligand, ∼40% of the EGFR molecules were present as inactive dimers or predimers. The monomer/predimer ratio was not affected by deletion of the intracellular domain. Ligand binding induced the formation of receptor oligomers, which were found in both the plasma membrane and intracellular structures. Ligand-induced oligomerization required tyrosine kinase activity and nine different tyrosine kinase substrate residues. This indicates that the binding of signaling molecules to activated EGFRs results in EGFR oligomerization. Induction of EGFR predimers or pre-oligomers using the EGFR fused to the FK506-binding protein did not affect signaling but was found to enhance EGF-induced receptor internalization. Our data show that EGFR oligomerization is the result of EGFR signaling and enhances EGFR internalization.