Miracle-dz/UniFAR-FTUs huggingface dataset:
Cost-Benefit of Minimally Invasive Staging of Non-small Cell Lung Cancer: A Decision Tree Sensitivity Analysis

Background: Accurate staging of non-small cell lung cancer (NSCLC) is critical for optimal management. Minimally invasive pathologic assessment of mediastinal lymphadenopathy is increasingly being performed. The cost-benefit (minimization of health care costs) of such approaches, in comparison with traditional surgical methods, is yet to be established. Methods: Decision-tree analysis was applied to compare downstream costs of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), conventional TBNA, and surgical mediastinoscopy. Calculations were based on real costs derived from actual patient data at a major teaching hospital in Melbourne, Australia. One- and two-way sensitivity analyses were undertaken to account for potential variation in input parameter values. Results: For the base-case analysis, initial evaluation with EBUS-TBNA (with negative results being surgically confirmed) was the most cost-beneficial approach (AU$2961) in comparison with EBUS-TBNA (negative results not surgically confirmed) ($3344), conventional TBNA ($3754), and mediastinoscopy ($8859). The sensitivity of EBUS-TBNA for detecting disease had the largest impact on cost, whereas the prevalence of mediastinal lymph node metastases determined whether surgical confirmation of negative EBUS-TBNA results remained cost-beneficial. Conclusions: Our study confirms that minimally invasive staging of NSCLC is cost-beneficial in comparison with traditional surgical techniques. EBUS-TBNA was the most cost-beneficial approach for mediastinal staging of patients with NSCLC across all studied parameters.
Induction and maintenance infliximab therapy for the treatment of moderate-to-severe Crohn's disease in children.

BACKGROUND AND AIMS The REACH study evaluated the safety and efficacy of infliximab in children with moderately to severely active Crohn's disease. METHODS Patients (n = 112) with a Pediatric Crohn's Disease Activity Index (PCDAI) score >30 received infliximab 5 mg/kg at weeks 0, 2, and 6. Patients responding to treatment at week 10 were randomized to infliximab 5 mg/kg every 8 or 12 weeks through week 46. A concurrent immunomodulator was required. Clinical response (decrease from baseline in the PCDAI score > or =15 points; total score < or =30) and clinical remission (PCDAI score < or =10 points) were evaluated at weeks 10, 30, and 54. RESULTS At week 10, 99 of 112 (88.4%) patients responded to infliximab (95% confidence interval: [82.5%, 94.3%]) and 66 of 112 (58.9%) patients achieved clinical remission (95% confidence interval: [49.8%, 68.0%]). At week 54, 33 of 52 (63.5%) and 29 of 52 (55.8%) patients receiving infliximab every 8 weeks did not require dose adjustment and were in clinical response and clinical remission, respectively, compared with 17 of 51 (33.3%) and 12 of 51 (23.5%) patients receiving treatment every 12 weeks (P = .002 and P < .001, respectively). CONCLUSIONS Pediatric patients responding to an induction regimen of infliximab were more likely to be in clinical response and remission at week 54 without dose adjustment when their maintenance therapy was given every 8 weeks rather than every 12 weeks. Allowing for dose intensification in the case of relapse, remission rates, but not response rates, at week 54 were superior with every 8-week dosing compared with every 12-week dosing.
Transcriptional Responses toward Diffusible Signals from Symbiotic Microbes Reveal MtNFP- and MtDMI3-Dependent Reprogramming of Host Gene Expression by Arbuscular Mycorrhizal Fungal Lipochitooligosaccharides1[W]

The formation of root nodules and arbuscular mycorrhizal (AM) roots is controlled by a common signaling pathway including the calcium/calmodulin-dependent kinase Doesn’t Make Infection3 (DMI3). While nodule initiation by lipochitooligosaccharide (LCO) Nod factors is well characterized, diffusible AM fungal signals were only recently identified as sulfated and nonsulfated LCOs. Irrespective of different outcomes, the perception of symbiotic LCOs in Medicago truncatula is mediated by the LysM receptor kinase M. truncatula Nod factor perception (MtNFP). To shed light on transcriptional responses toward symbiotic LCOs and their dependence on MtNFP and Ca2+ signaling, we performed genome-wide expression studies of wild-type, Nod-factor-perception mutant1, and dmi3 mutant roots challenged with Myc- and Nod-LCOs. We show that Myc-LCOs lead to transient, quick responses in the wild type, whereas Nod-LCOs require prolonged incubation for maximal expression activation. While Nod-LCOs are most efficient for an induction of persistent transcriptional changes, sulfated Myc-LCOs are less active, and nonsulfated Myc-LCOs display the lowest capacity to activate and sustain expression. Although all symbiotic LCOs up-regulated a common set of genes, discrete subsets were induced by individual LCOs, suggesting common and specific functions for these in presymbiotic signaling. Surprisingly, even sulfated fungal Myc-LCOs and Sinorhizobium meliloti Nod-LCOs, having very similar structures, each elicited discrete subsets of genes, while a mixture of both Myc-LCOs activated responses deviating from those induced by single treatments. Focusing on the precontact phase, we identified signaling-related and transcription factor genes specifically up-regulated by Myc-LCOs. Comparative gene expression studies in symbiotic mutants demonstrated that transcriptional reprogramming by AM fungal LCOs strictly depends on MtNFP and largely requires MtDMI3.
Vif Overcomes the Innate Antiviral Activity of APOBEC3G by Promoting Its Degradation in the Ubiquitin-Proteasome Pathway*

Viruses must overcome diverse intracellular defense mechanisms to establish infection. The Vif (virion infectivity factor) protein of human immunodeficiency virus 1 (HIV-1) acts by overcoming the antiviral activity of APOBEC3G (CEM15), a cytidine deaminase that induces G to A hypermutation in newly synthesized viral DNA. In the absence of Vif, APOBEC3G incorporation into virions renders HIV-1 non-infectious. We report here that Vif counteracts the antiviral activity of APOBEC3G by targeting it for destruction by the ubiquitin-proteasome pathway. Vif forms a complex with APOBEC3G and enhances APOBEC3G ubiquitination, resulting in reduced steady-state APOBEC3G levels and a decrease in protein half-life. Furthermore, Vif-dependent degradation of APOBEC3G is blocked by proteasome inhibitors or ubiquitin mutant K48R. A mutation of highly conserved cysteines or the deletion of a conserved SLQ(Y/F)LA motif in Vif results in mutants that fail to induce APOBEC3G degradation and produce non-infectious HIV-1; however, mutations of conserved phosphorylation sites in Vif that impair viral replication do not affect APOBEC3G degradation, suggesting that Vif is important for other functions in addition to inducing proteasomal degradation of APOBEC3G. Vif is monoubiquitinated in the absence of APOBEC3G but is polyubiquitinated and rapidly degraded when APOBEC3G is coexpressed, suggesting that coexpression accelerates the degradation of both proteins. These results suggest that Vif functions by targeting APOBEC3G for degradation via the ubiquitin-proteasome pathway and implicate the proteasome as a site of dynamic interplay between microbial and cellular defenses.
Clinical utility of the Behavior Rating Inventory of Executive Function-Self-Report (BRIEF-SR) in adolescents with traumatic brain injury.

OBJECTIVE To evaluate the factor structure and correlates of the Behavior Rating Inventory of Executive Function-Self-Report (BRIEF-SR) in 118 adolescents with traumatic brain injury (TBI). METHOD Cross-sectional study. Maximum-likelihood exploratory, as well as confirmatory, factor analysis. External correlates of factor scores were evaluated. RESULTS Two latent constructs were identified, with notable variation in scale loading pattern compared with standardization sample findings of the BRIEF-SR. These factors covaried inversely with severity of TBI; more severe injuries were associated with lower self-ratings of executive dysfunction, indicating a possible lack of deficit awareness in those with relatively severe injuries. Premorbid ADHD affected both factors, resulting in higher self-ratings of executive dysfunction, suggesting preserved awareness of preexisting difficulties in those with uncomplicated mild injuries. In addition, males reported less executive dysfunction than females. CONCLUSIONS/IMPLICATIONS Findings suggest that the BRIEF-SR measures somewhat different latent constructs after TBI than in typically developing adolescents, and that BRIEF-SR scores need to be considered in concert with objective measures of injury severity and premorbid demographic and historical variables. (PsycINFO Database Record (c) 2013 APA, all rights reserved).
Electromechanical coupling in the membranes of Shaker-transfected HEK cells

Membranes flex with changes in transmembrane potential as a result of changes in interfacial tension, the Lippman effect. We studied the membrane electromotility of Shaker K+-transfected HEK-293 cells in real time by using combined patch-clamp atomic force microscopy. In the voltage range where the channels were closed, Shaker expression had little effect on electromotility relative to wild-type cells. Depolarization between −120 and −40 mV resulted in a linear upward cantilever deflection equivalent to an increase in membrane tension. However, when depolarized sufficiently for channel opening, the electromotility saturated and only recovered over 10 s of milliseconds. This remarkable loss of motility was associated with channel opening, not ionic flux or movement of the voltage sensors. The IL mutant of Shaker, in which the voltage dependence of channel opening but not sensor movement is shifted to more positive potentials, caused the loss of electromotility saturation also to shift to more positive potentials. The temporary loss of electromotility associated with channel opening is probably caused by local buckling of the bilayer as the inner half of the channel expands as expected from X-ray structural data.
Reticuloendothelial System Response to Hyperlipidemia in Rhesus and Cynomolgus Monkeys

A detailed study of the effect of various periods of hyperlipidemia on the reticuloendothelial system (RES) lipid accumulation in rhesus and cynomolgus monkeys was conducted. The cynomolgus serum cholesterol and triglyceride levels were on the average more elevated than the rhesus levels throughout a 12‐month period when both species were fed a diet containing 12.5% coconut oil, 12.5% butter fat, and 2% cholesterol. After cynomolgus monkeys were fed this diet, their reticuloendothelial system became more lipid laden than that of the rhesus monkeys, in both the liver and the spleen. This was also true for the circulating monocytes. Furthermore, the parenchymal cells of the cynomolgus livers also become more fat filled, and chemical analyses demonstrated more cholesterol (total, free, and esterified) and triglycerides in the liver and the spleen. Xanthomata development in the cynomolgus, although similar in type and distribution, was more extensive than that in the rhesus monkey after similar periods of experimental diet feeding. Therefore, the RES of two species of macaque monkeys are affected differently when challenged with the same high fat, high cholesterol diet, with the cynomolgus RES being much more involved with lipid and cholesterol storage than the rhesus RES.
Evidence for degradation of gastrointestinal mucin by Candida albicans secretory aspartyl proteinase

A zone of extracellular digestion of the mucin layer around Candida albicans blastoconidia was observed by transmission electron microscopy in the jejunum of mice inoculated intragastrically (G. T. Cole, K. R. Seshan, L. M. Pope, and R. J. Yancey, J. Med. Vet. Mycol. 26:173-185, 1988). This observation prompted the hypothesis that a putative mucinolytic enzyme(s) may contribute to the virulence of C. albicans by facilitating penetration of the mucus barrier and subsequent adherence to and invasion of epithelial cells. Mucinolytic activity was observed as zones of clearing around colonies of C. albicans LAM-1 grown on agarose containing yeast nitrogen base, glucose, and hog gastric mucin. In addition, concentrated culture filtrate obtained after growth for 24 h in yeast nitrogen base, supplemented with glucose and mucin as the sole nitrogen source, contained proteolytic activity against biotin-labelled mucin which was inhibited by pepstatin A. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the culture filtrate revealed two components of 42 and 45 kDa, with pIs of 4.1 and 5.3, respectively. A zymogram showed that mucin was degraded only by the 42-kDa component, which was also recognized by immunoblotting with an anti-secretory aspartyl proteinase (anti-Sap) 2p monoclonal antibody. The N-terminal sequence of the first 20 amino acids matched that reported for Sap2p. These results demonstrate that Sap2p is responsible for proteolysis of mucin by C. albicans in vitro and may be involved as a virulence factor in the breakdown of mucus and penetration of the mucin barrier by C. albicans.
Transfection of Rat Cells With Proopiomeranocortin Gene, Precursor of Endogenous Endorphin, Using Radial Shock Waves Suppresses Inflammatory Pain

Study Design. The effect of proopiomelanocortin (POMC) gene transfer with radial shock waves (RSW) was investigated in vitro and in vivo rat pain models. Objective. To examine the efficacy of POMC gene transfer with RSW, efficiency of &bgr;-endorphin production in transfected cells, and its effects and side effects in pain models. Summary of Background Data. Opioids have been used to treat chronic pain originating from knee osteoarthritis and the lower back; however, several side effects have been reported. Endogenous opioids are safe, but they are not used for clinical treatment because their metabolism is very fast. Methods. POMC plasmid was produced from pretransformed rat brain cDNA. POMC gene was added to the muscle of rat in vitro and in vivo with RSWs. We assessed &bgr;-endorphin activity using immunohistochemistry. For assessment of pain behavior, we evaluated change in pain score and the level of the inflammatory neuropeptide, calcitonin gene-related peptide (CGRP), after transfection of the POMC gene in an adjuvant induced pain model for 28 days after treatment. Results. POMC transfected using RSW expressed &bgr;-endorphin at a significantly increased level in muscle cells compared with non-RSW transfection and controls in vitro and in vivo (P < 0.05). Animals showed significant pain sensitivity and increased CGRP expression in dorsal root ganglia neurons in this model; however, these findings decreased for 14 days after transfection of POMC into muscle. There was no significant difference in side effects, such as a change in the level of food pellet intake or constipation, between POMC-treated animals and untreated animals. Conclusion. POMC transfection with RSW increased &bgr;-endorphin expression in muscle for 14 days, and suppressed pain behavior and CGRP expression in dorsal root ganglia neurons without side effects. This suggested that transfer of POMC by RSW is an effective treatment for inflammatory pain.
The role of echocardiography in hemodynamic monitoring

Purpose of reviewEchocardiography has become more widely available to noncardiologists because of the technological advances in smaller, multipurpose ultrasound units with basic cardiac capabilities. In this review, we discuss the type of clinical information a trained intensivist can hope to obtain from bedside echocardiography and suggest the ways in which this complements traditional hemodynamic monitoring. Recent findingsFollowing a 10-h hands-on course, intensivists are able to perform and interpret a goal-oriented echocardiogram in approximately 10 min with good accuracy. Bedside echocardiography can aid in determining fluid status and qualitative cardiac ejection fraction, which can then be used immediately to guide therapy. SummaryIntensivists can safely and accurately perform goal-oriented echocardiography. Although not yet proven to influence clinical outcome, we suggest that the major utility of echocardiography is for those with distributive or mixed shock in whom target central venous pressure has been achieved without evidence of adequate tissue perfusion. In this subset of patients, echocardiography can aid in selecting those most likely to benefit from further fluid or inotropic support.
Some Effects of High Temperature on Polyploidy and Other Variations in Maize.

7 Davidson and Bogert, forthcoming publication. 8 Davidson and Bogert, forthcoming publication. 9 Behrend, Ann. Chem., 245, 213 (1888); Behrend and Ernert, Ibid., 258, 347 (1890). 10 Angeli, Atti. accad. Lincei, [5] 3, II, 72 (1894). 11 Johnson, Baudisch, and Hoffmann, loc. cit. 12 Levene, Bass, and Simms, J. Biol. Chem., 70, 229 (1926). 13 Behrend and Roosen, Ann. Chem., 251, 235 (1889). 14 Behrend and Osten, Ann. Chem., 343, 133 (1905); Behrend and Beer, Ibid., 362, 115 (1908). 15 Levene, J. Biol. Chem., 63, 653 (1925). 16 Behrend and Koch, Ann. Chem., 315, 246 (1901); Behrend and von Vogel, Ibid., 259 (1901). 17 This reaction suggests a mechanism for the formation of 5-phenylhydrazinouracil from the action of phenylhydrazine on 5,5-dibromo-6-hydroxy-5,6-dihydrouracil which was observed by Levene: namely, the formation of uracil-5-azobenzene (much as given above) followed by its reduction to the hydrazo compound by the excess of phenylhydrazine present.
Neighborhood environment and self-reported health status: a multilevel analysis.

OBJECTIVES This study examined whether neighborhood socioeconomic environment helps to explain the proportion of community members with self-reported poor health status. METHODS A random sample of 9240 persons aged 25 to 74 years were interviewed during 1988 and 1989. The socioeconomic environment of each respondent's neighborhood was measured with the Care Need Index (CNI) and the Townsend score. The data were analyzed with a multilevel model adjusted for the independent variables. The second-level variables were the 2 neighborhood scores. RESULTS There was a clear gradient for poor health and education within every CNI interval so that with an increasing CNI (indicating more deprivation), the prevalence of poor health increased in all 3 education groups (P = .001). In the full model, decreasing educational level, obesity, length and frequency of smoking, physical inactivity, and increasing CNI were associated with poor health. Persons living in the most deprived neighborhoods had a prevalence ratio of 1.69 (95% confidence interval = 1.44, 1.98) for poor health compared with those living in the most affluent areas. CONCLUSIONS Both neighborhood socioeconomic environment and individual educational status are associated with self-reported poor health.
Increased dietary salt accelerates chronic allograft nephropathy in rats.

BACKGROUND Chronic allograft nephropathy (CAN), a major problem in renal transplantation, is related to both alloantigen-dependent and -independent processes. Because dietary salt intake modulated glomerular production of transforming growth factor-beta, which has been shown to play an important role in CAN, we hypothesized that dietary salt would directly enhance renal injury in a rodent model of CAN. METHODS Dietary NaCl was increased from 1.0% (normal) to 8.0% in a group of Fisher/Lewis rats 25 days following orthotopic renal transplantation and was continued until 16 weeks after transplantation. RESULTS Blood pressure, which was recorded using radiotelemetry in the first eight-weeks post-transplantation, did not differ between the groups, but allograft recipients on the 8.0% NaCl diet rapidly demonstrated increased urinary albumin excretion. Renal function determined by dynamic functional imaging was worse in allograft recipients on the 8.0% NaCl diet by six weeks following transplantation. Histologic examination at 16 weeks confirmed a significant increase in allograft damage in the 8.0% NaCl group compared with allografts from rats on 1.0% NaCl diet. These findings included glomerulosclerosis and tubulointerstitial injury that consisted of fibrosis, tubular atrophy and dilation, intratubular casts, and tubular epithelial cell damage. Small arteries and arterioles did not show evidence of damage from hypertension or other abnormality. CONCLUSIONS In this model of CAN, renal allograft dysfunction preceded hypertension and was accelerated significantly by an increase in dietary salt.
Design and synthesis of pH-sensitive polymeric micelles for oral delivery of poorly water-soluble drugs

Abstract pH-sensitive polymer poly (polylactide-co-methacrylic acid)–b-poly (acrylic acid) was synthesized using atom transfer radical polymerization and ring-opening polymerization and characterized by gel permeation chromatography and 1H NMR. The polymers can self-assemble to form micelles in aqueous medium, which respond rapidly to pH change within the gastrointestinal relevant pH range. Critical micelle concentrations and pH response behavior of the polymeric micelle were investigated. Water-insoluble drug nifedipine was loaded and the drug-loading content can be controlled by tuning the composition of the polymers. The in vitro release studies indicate pH sensitivity enabled rapid drug release at the environment of simulated intestinal fluid (pH 7.36), the cumulative released amount of NFD reached more than 80% within 24 h, while only 35% in the simulated gastric fluid (pH 1.35). All the results showed that the pH-sensitive P(PLAMA-co-MAA)–b-PAA micelle may be a prospective candidate as oral drug delivery carrier for hydrophobic drugs with controlled release behavior.
Recruitment of Replication Protein A by the Papillomavirus E1 Protein and Modulation by Single-Stranded DNA

ABSTRACT With the exception of viral proteins E1 and E2, papillomaviruses depend heavily on host replication machinery for replication of their viral genome. E1 and E2 are known to recruit many of the necessary cellular replication factors to the viral origin of replication. Previously, we reported a physical interaction between E1 and the major human single-stranded DNA (ssDNA)-binding protein, replication protein A (RPA). E1 was determined to bind to the 70-kDa subunit of RPA, RPA70. In this study, using E1-affinity coprecipitation and enzyme-linked immunosorbent assay-based interaction assays, we show that E1 interacts with the major ssDNA-binding domain of RPA. Consistent with our previous report, no measurable interaction between E1 and the two smaller subunits of RPA was detected. The interaction of E1 with RPA was substantially inhibited by ssDNA. The extent of this inhibition was dependent on the length of the DNA. A 31-nucleotide (nt) oligonucleotide strongly inhibited the E1-RPA interaction, while a 16-nt oligonucleotide showed an intermediate level of inhibition. In contrast, a 10-nt oligonucleotide showed no observable effect on the E1-RPA interaction. This inhibition was not dependent on the sequence of the DNA. Furthermore, ssDNA also inhibited the interaction of RPA with papillomavirus E2, simian virus 40 T antigen, human polymerase alpha-primase, and p53. Taken together, our results suggest a potential role for ssDNA in modulating RPA-protein interactions, in particular, the RPA-E1 interactions during papillomavirus DNA replication. A model for recruitment of RPA by E1 during papillomavirus DNA replication is proposed.