Miracle-dz/UniFAR-FTUs huggingface dataset:
HER‐2/neu antigen loss and relapse of mammary carcinoma are actively induced by T cell‐mediated anti‐tumor immune responses

Induction of tumor‐specific immune responses results in the inhibition of tumor development. However, tumors recur because of the tumor immunoediting process that facilitates development of escape mechanisms in tumors. It is not known whether tumor escape is an active process whereby anti‐tumor immune responses induce loss or downregulation of the target antigen in the antigen‐positive clones. To address this question, we used rat neu‐overexpressing mouse mammary carcinoma (MMC) and its relapsed neu antigen‐negative variant (ANV). ANV emerged from MMC under pressure from neu‐specific T cell responses in vivo. We then cloned residual neu antigen‐negative cells from MMC and residual neu antigen‐positive cells from ANV. We found marked differences between these neu‐negative clones and ANV, demonstrating that the residual neu‐negative clones are probably not the origin of ANV. Since initial rejection of MMC was associated with the presence of IFN‐γ‐secreting T cells, we treated MMC with IFN‐γ and showed that IFN‐γ could induce downregulation of neu expression in MMC. This appears to be due to methylation of the neu promoter. Together, these data suggest that neu antigen loss is an active process that occurs in primary tumors due to the neu‐targeted anti‐tumor immune responses.
Influence of Contraceptive Steroids on the Turnover of Plasma Free Arachidonic and Oleic Acids

The turnover of plasma free oleic and arachidonic acids was determined in five healthy women before and after 3 months contraceptive treatment with a daily dose of 0.05 mg ethinyl estradiol and 0.25 mg d-norgestrel administered in a cyclic manner. The contraceptive steroids did not significantly influence the total plasma free fatty acid (FFA) concentration or the turnover of oleic acid. However, during hormone administration the fractional turnover of arachidonic acid increased by 40 per cent and its arterial concentration fell by 20 per cent. The portion of saturated fatty acids in the FFA fraction decreased during the contraceptive treatment. It is concluded that the treatment with contraceptive steroids (1) had no effect on the turnover of the main part of the FFA fraction, (2) increased the transport of the polyunsaturated arachidonic acid through the plasma pool, possibly as an effect of the estrogen component, and (3) stimulated the desaturation of saturated fatty acids to monoenes.
Brain‐specific ablation of Efr3a promotes adult hippocampal neurogenesis via the brain‐derived neurotrophic factor pathway

Efr3 is a newly identified plasma membrane protein and plays an important role in the phosphoinositide metabolism on the plasma membrane. However, although it is highly expressed in the brain, the functional significance of Efr3 in the brain is not clear. In the present study, we generated Efr3af/f mice and then crossed them with Nestin‐Cre mice to delete Efr3a, one of the Efr3 isoforms, specifically in the brain. We found that brain‐specific ablation of Efr3a promoted adult hippocampal neurogenesis by increasing survival and maturation of newborn neurons without affecting their dendritic tree morphology. Moreover, the brain‐derived neurotrophic factor (BDNF)‐tropomyosin‐related kinase B (TrkB) signaling pathway was significantly enhanced in the hippocampus of Efr3a‐deficient mice, as reflected by increased expression of BDNF, TrkB, and the downstream molecules, including phospho‐MAPK and phospho‐Akt. Furthermore, the number of TUNEL+ cells was decreased in the subgranular zone of dentate gyrus in Efr3a‐deficient mice compared with that of control mice. Our data suggest that brain‐specific deletion of Efr3a could promote adult hippocampal neurogenesis, presumably by upregulating the expression of BDNF and its receptor, TrkB, and therefore provide new insight into the roles of Efr3 in the brain. —Qian, Q. , Liu, Q. , Zhou, D. , Pan, H. , Liu, Z. , He, F. , Ji, S. , Wang, D. , Bao, W. , Liu, X. , Liu, Z. , Zhang, H. , Zhang, X. , Zhang, L. , Wang, M. , Xu, Y. , Huang, F. , Luo, B. , Sun B. Brain‐specific ablation of Efr3a promotes adult hippocampal neurogenesis via the brain‐derived neurotrophic factor pathway. FASEB J. 31, 2104–2113 (2017). www.fasebj. org
Reliability and responsiveness of the shuttle walking test in patients with chronic low back pain.

BACKGROUND AND PURPOSE Walking is an important functional activity and the shuttle walking test has been shown to be a useful test for patients with chronic airways obstruction and heart failure. The test has been used in low back pain research over recent years and has increasingly been used as an outcome measure to investigate treatment efficacy in patients with low back pain. The aim of the present study was to determine the reliability and responsiveness of the shuttle walking test within a group of patients with low back pain (with or without sciatica). METHOD Reliability of the shuttle walking test was determined on a group of patients with low back pain (n = 44) using the Bland and Altman (1986) limits of agreement and the intraclass correlation coefficient (ICC). Responsiveness was assessed using the standardized effect size. The mean distance walked within a patient population (n = 337) was compared with an age- and sex-matched group of healthy subjects (n = 122). RESULTS The shuttle walking test obtained an ICC score of 0.99, whereas the limits of agreement test gave a mean difference of 2.5 m with upper and lower limits of agreement of 52 m and -47 m, respectively. Patients undertaking fitness training reached an effect size of 1.2 compared to a control group of 0.23 and 0.94 for a group undergoing various orthopaedic treatments. CONCLUSIONS The present study has shown that the shuttle walking test is a reliable and responsive test within a group of patients with low back pain, with or without sciatica. It is simple to administer and provides a quick method of measuring one aspect of a patient's physical function.
Blood pressure course in acute ischaemic stroke in relation to stroke subtype

ObjectivesBlood pressure (BP) management in acute stroke remains a matter of little consensus. Data on BP changes during the first hours of ictus are lacking. We aimed to evaluate the early spontaneous time course of BP in different ischaemic stroke (IS) subtypes. MethodsTwenty-four h BP monitoring was performed in 200 first-ever hyper-acute IS patients. The recording was initiated and terminated at 3 h and 27 h of ictus respectively. All IS patients were classified on admission into the following subgroups of different etiology: large artery atherosclerotic stroke (LAA), cardio-embolic stroke (CE), lacunar stroke (LAC) and infarct of undetermined cause (IUC). Statistical comparisons between stroke subgroups were performed using one-way ANOVA and linear regression analyses were used to evaluate the influence of different factors in BP course. ResultsAlthough there were no significant differences in 24 h systolic (SBP) and diastolic (DBP) BP values between IS subgroups, a distinctly different SBP course was observed. The SBP dropped sharply in the LAA and LAC subgroups, while a more gradual decrease was monitored in the CE subgroup. Throughout the BP-recording, a SBP decrease of 10.1% (95% CI: 8.6–11.5) and 10.4% (95% CI: 9.0–11.8) was documented in patients with LAA and LAC respectively, while a milder drop was recorded in CE (3.7%, 95% CI: 2.4–5.0) and IUC (5.5%, 95% CI: 4.1–6.8). Increasing stroke severity (p<0.001) and brain oedema (p=0.013) was independently associated with a milder spontaneous SBP reduction. ConclusionsSpontaneous SBP course varies in acute ischaemic stroke subtypes of different etiology. This may have implications in the optimal management of post-stroke hypertension.
Environmental Regulation, Ideology, and the D. C. Circuit

Richard L. Revesz* S INCE the early 1970s, the United States Court of Appeals for the District of Columbia Circuit has played a central role in the development of environmental law. This role is unique among the courts of appeals in large part because the D.C. Circuit has exclusive venue over challenges to a wide array of environmental regulations. ' As a result, the D.C. Circuit provides a good vehicle for an empirical examination of judicial decisionmaking inenvironmental cases.2 Some commentators have criticized the D.C. Circuit's politicization and have maintained that judges simply vote according to their policy preferences.3 In environmental cases, the allegation
Mechanism of action of PROMOGRAN, a protease modulating matrix, for the treatment of diabetic foot ulcers

Proteases play a critical role in many of the physiologic processes of wound repair. However, if their activity becomes uncontrolled proteases can mediate devastating tissue damage and consequently they have been implicated in chronic wound pathophysiology. Previous studies have shown that chronic wound fluid contains elevated protease levels that have deleterious effects, degrading de novo granulation tissue and endogenous biologically active proteins such as growth factors and cytokines. Therefore, we have proposed that an effective therapeutic approach for chronic wounds would be to modify this hostile environment and redress this proteolytic imbalance. Using an ex vivo wound fluid model, we show the ability of a proprietary new wound treatment to bind and inactivate proteases. We have shown that the addition of this test material to human chronic wound fluid obtained from diabetic foot ulcer patients resulted in a significant reduction in the activities of neutrophil‐derived elastase, plasmin, and matrix metalloproteinase when compared to wet gauze. This study provides mechanistic evidence to support the hypothesis that this novel treatment modality for chronic wounds physically modifies the wound microenvironment, and thereby promotes granulation tissue formation and stimulates wound repair.
Colonization and Education: Exploring the Legacy of Local Elites in Korea

In this article we examine the impact of pre‐colonial educated elites and colonization on modernization. Using the case of Joseon, as Korea was known before being colonized by Japan in 1910, we investigate how the civil exam system and scholarly traditions, as well as the provision of public schools under Japanese colonial rule, influenced levels of literacy in the colony. We introduce novel data from Joseon's historical court examination archives, colonial education records, and censuses dating back to 1930. Our findings suggest that the spread of Korean literacy during the early colonial period was strongly correlated with the historical presence of civil exam passers from the Joseon Dynasty. Regions with a greater presence of educated elites later had higher numbers of Korean teachers, as well as more private schools established as alternatives to the colonial public schools.
Controlling glycation of recombinant antibody in fed‐batch cell cultures

Protein glycation is a non‐enzymatic glycosylation that can occur to proteins in the human body, and it is implicated in the pathogenesis of multiple chronic diseases. Glycation can also occur to recombinant antibodies during cell culture, which generates structural heterogeneity in the product. In a previous study, we discovered unusually high levels of glycation (>50%) in a recombinant monoclonal antibody (rhuMAb) produced by CHO cells. Prior to that discovery, we had not encountered such high levels of glycation in other in‐house therapeutic antibodies. Our goal here is to develop cell culture strategies to decrease rhuMAb glycation in a reliable, reproducible, and scalable manner. Because glycation is a post‐translational chemical reaction between a reducing sugar and a protein amine group, we hypothesized that lowering the concentration of glucose—the only source of reducing sugar in our fed‐batch cultures—would lower the extent of rhuMAb glycation. When we decreased the supply of glucose to bioreactors from bolus nutrient and glucose feeds, rhuMAb glycation decreased to below 20% at both 2‐L and 400‐L scales. When we maintained glucose concentrations at lower levels in bioreactors with continuous feeds, we could further decrease rhuMAb glycation levels to below 10%. These results show that we can control glycation of secreted proteins by controlling the glucose concentration in the cell culture. In addition, our data suggest that rhuMAb glycation occurring during the cell culture process may be approximated as a second‐order chemical reaction that is first order with respect to both glucose and non‐glycated rhuMAb. The basic principles of this glycation model should apply to other recombinant proteins secreted during cell culture. Biotechnol. Bioeng. 2011;108: 2600–2610. © 2011 Wiley Periodicals, Inc.
Megalencephalic leukoencephalopathy with cysts: the Glialcam‐null mouse model

Megalencephalic leukoencephalopathy with cysts (MLC) is a genetic infantile‐onset disease characterized by macrocephaly and white matter edema due to loss of MLC1 function. Recessive mutations in either MLC1 or GLIALCAM cause the disease. MLC1 is involved in astrocytic volume regulation; GlialCAM ensures the correct membrane localization of MLC1. Their exact role in brain ion‐water homeostasis is only partly defined. We characterized Glialcam‐null mice for further studies.
Intravitreal anti-VEGF therapy blocks inflammatory cell infiltration and re-entry into the circulation in retinal angiogenesis.

PURPOSE Anti-VEGF-A antibody (Ab) (e.g., bevacizumab, ranibizumab) is widely used as a treatment against retinal angiogenesis and edema. The purpose of this study was to evaluate whether intravitreal anti-VEGF Ab injection modulates inflammatory cells in retinal angiogenesis. METHODS To investigate whether intravitreal bevacizumab injections affect the number of inflammatory cells in proliferative diabetic retinopathy (PDR) membranes in patients, immunohistochemical staining with CD45 Ab (pan-leukocyte marker) was performed using the surgically obtained membranes in pars plana vitrectomy with or without pretreatment with bevacizumab. To check whether anti-VEGF-A Ab affects leukocytes going in and out of blood vessels during retinal angiogenesis, the authors performed their novel leukocyte transmigration assay and CD45 immunostaining in a mouse model of oxygen-induced retinopathy (OIR). RESULTS The authors' new imaging approach revealed that intravitreal injection of anti-VEGF-A Ab blocks leukocyte infiltration as well as angiogenesis. The Ab injection inhibited leukocyte transmigration before affecting the angiogenenic area. CD45 staining showed no significant difference in the leukocyte number in the angiogenic retina or the human PDR membranes between the anti-VEGF-A Ab injected group and the control group. Furthermore, VEGF-A inhibition also affected leukocytes going out from the retina. CONCLUSIONS Intravitreal injection of anti-VEGF-A Ab could inhibit leukocyte trafficking in the retina, suggesting that anti-VEGF-A therapy could serve as a treatment in retinal inflammation.
Serum Glucan Levels Are Not Specific for Presence of Fungal Infections in Intensive Care Unit Patients

ABSTRACT Fungal infections in the critically ill patient are difficult to diagnose and are associated with a high mortality rate. A major obstacle to managing fungal infection is the lack of a reliable clinical assay that will rapidly identify patients with fungal sepsis. Glucans are polymers of glucose that are found in the cell wall of fungi and certain bacteria. Glucans are also released from the fungal cell wall into the extracellular milieu. Several studies have reported that detection of fungal glucan in serum or plasma is useful in the diagnosis of mycoses. However, recent studies have questioned the clinical utility of this assay. In this study, we examined serum glucan levels in intensive care unit (ICU) patients and attempt to correlate serum glucan levels with the presence of fungal infection. Following attainment of informed consent, serum was harvested from 46 ICU patients with confirmed fungal infections, confirmed bacterial infections, or no evidence of infection. Sera from eight healthy volunteers served as control. Serum glucan was assayed with a glucan-specific Limulus assay. Serum glucan levels were increased (69.6 ± 17 pg/ml; P < 0.001) in ICU patients versus the normal (11.5 ± 1.3 pg/ml) and noninfected ICU (27.4 ± 17 pg/ml) controls. However, serum glucan levels were not different in patients with confirmed fungal infections versus those with confirmed bacterial infections. Thus, serum glucan levels did not show a correlation with the presence of fungal infections and do not appear to be specific for fungal infections. However, the assay may be useful as a negative predictor of infection.
Ambient Particulate Matter and Health Effects: Publication Bias in Studies of Short-Term Associations

Background: Time-series studies have shown short-term temporal associations between low levels of ambient particulate air pollution and adverse health effects. It is not known whether or to what extent this literature is affected by publication bias. Methods: We obtained effect estimates from time-series studies published up to January 2002. These were summarized and examined for funnel plot asymmetry. We compared summary estimates between single-city and prospective multicity studies. Using 1 multicity study, we examined the sensitivity of summary estimates to alternative lag selection policies. Results: We found evidence for publication bias among single-city studies of daily mortality, hospital admissions for chronic obstructive lung disease (COPD), and incidence of cough symptom, but not for studies of lung function. Statistical correction for this bias reduced summary relative risk estimates for a 10 μg/m3 increment of particulate matter less than 10 μm aerodynamic diameter (PM10) as follows: daily mortality from 1.006 to 1.005 and admissions for COPD from 1.013 to 1.011; and odds ratio for cough from 1.025 to 1.015. Analysis of results from a large multicity study suggested that selection of positive estimates from a range of lags could increase summary estimates for PM10 and daily mortality by up to 130% above those based on nondirectional approaches. Conclusion: We conclude that publication bias is present in single-city time-series studies of ambient particles. However, after correcting for publication bias statistically, associations between particles and adverse health effects remained positive and precisely estimated. Differential selection of positive lags may also inflate estimates.
Vaginal Misoprostol Administration for Cervical Ripening and Labor Induction

Intravaginal misoprostol has been shown to be an effective agent for cervical ripening and induction of labor. Vaginal application of misoprostol has been reported in over 9000 women worldwide and seems to have safety profile similar to that of endocervically and intravaginally administered dinoprostone. Concern arises with the use of higher doses of intravaginal misoprostol (50 mcg or more) and the association with uterine contractile abnormalities and for this reason, use of low-dose misoprostol regimen has been recommended by the American College of Obstetricians and Gynecologists. The recommendation is use of a 25-mcg dose of misoprostol inserted into the posterior vaginal fornix and repeated every 3 to 6 hours as needed. Misoprostol administration to women with prior cesarean births seems to increase the likelihood of uterine scar disruption and should not be used in these women. There are reports of uterine rupture in women with unscarred uteri treated with vaginally applied misoprostol. Therefore, all patients need to be monitored adequately after misoprostol administration. Although there is a growing body of data regarding the ambulatory use of intravaginal misoprostol for cervical ripening, its use for this purpose cannot be recommended outside of investigational protocols at this time because of concerns for maternal and neonatal safety.
Academic achievement and emotional status of children with ADHD treated with long-term methylphenidate and multimodal psychosocial treatment.

OBJECTIVE To test the hypothesis that intensive multimodal psychosocial intervention (that includes academic assistance and psychotherapy) combined with methylphenidate significantly enhances the academic performance and emotional status of children with attention-deficit/hyperactivity disorder (ADHD) compared with methylphenidate alone and with methylphenidate combined with nonspecific psychosocial treatment (attention control). METHOD One hundred three children with ADHD (ages 7-9), free of conduct and learning disorders, who responded to short-term methylphenidate were randomized for 2 years to receive one of three treatments: (1) methylphenidate alone, (2) methylphenidate plus psychosocial treatment that included academic remediation, organizational skills training, and psychotherapy as well as parent training and counseling and social skills training, or (3) methylphenidate plus attention control treatment. Children's function was assessed through academic testing, parent ratings of homework problems, and self-ratings of depression and self-esteem. RESULTS No advantage was found on any measure of academic performance or emotional status for the combination treatment over methylphenidate alone and over methylphenidate plus attention control. Significant improvement occurred across all treatments and was maintained over 2 years. CONCLUSIONS In stimulant-responsive young children with ADHD without learning and conduct disorders, there is no support for academic assistance and psychotherapy to enhance academic achievement or emotional adjustment. Significant short-term improvements were maintained over 2 years.
Four Essays on the Determinants of Human Capital Accumulation in Norway

Do biased perceptions and behaviors affect teachers’ assessment of students? To investigate this question, a number of studies use data on two different scores for the same individuals: one non-blind score based on classroom tests assessed by the student’s own teacher and one blind test score based on a national exam marked externally and anonymously. In the absence of bias in teachers’ assessments, it is argued, there should not be significant differences in the gaps in blind and non-blind scores between different groups. This article present a parsimonious econometric framework that distills out the assumptions necessary to identify group bias in teachers’ assessment from such a comparison of blind and non-blind scores. This framework lays the foundation for our empirical analysis, where data from the Norwegian school system are employed to estimate and interpret differences between nonblind and blind assessments. The results suggest that the relationship between the subject ability and non-blind results tends to be different from the relationship between subject ability and blind results. Evidence of this is found both when grades are recorded when teachers grade the same test and when they grade based on different assessments that are meant to test the same skill. The difference between non-blind and blind will therefore be a function of the skill tested. This leads to different estimates of the group bias when holding ability fixed.