Miracle-dz/UniFAR-FTUs huggingface dataset:
Graft survival of pediatric kidney transplant recipients selected for de novo steroid avoidance—a propensity score-matched study

Background Steroid-avoidance protocols have gained popularity in pediatric kidney transplant recipients at low immunologic risk. The long-term safety of steroid avoidance in children with immunologic risk factors remains unknown. Methods Pediatric kidney transplant recipients from 2004 to 2014 in the Organ Procurement and Transplantation Network database who received tacrolimus and mycophenolate immunosuppression were investigated. Propensity score matching was used to compare graft survival in 1624 children who received steroid avoidance with 1624 children who received steroid-based immunosuppression. The effect of steroid avoidance on graft failure among immunologic risk strata was estimated using Cox proportional hazards regression in this propensity score-matched cohort. Results It was observed that 5-year graft survival was mildly improved in children receiving steroid avoidance (84.8% versus 81.2%, P = 0.03). This improvement in graft survival occurred in the first 2 years following transplant, when the hazard ratio (HR) for allograft failure in children receiving steroid avoidance was 0.62 [95% confidence interval (CI) 0.45-0.86]. In contrast, steroid avoidance was not associated with improved allograft survival during Years 2-10 following transplant (HR = 0.93; 95% CI 0.75-1.15). During this time period, HRs (95% CIs) for allograft failure within immunologic risk strata were not significantly different from the null value of 1: repeat kidney transplants, 1.84 (0.84-4.05); African-Americans, 1.02 (0.67-1.56); sensitized recipients, 1.24 (0.63-2.43); recipients of deceased donor kidneys, 1.02 (0.79-1.32); recipients of completely human leukocyte antigen-mismatched kidneys, 0.80 (0.47-1.37); and recipients with pretransplant glomerular disease, 0.94 (0.71-1.23). Conclusions In pediatric kidney transplant recipients receiving tacrolimus- and mycophenolate-based immunosuppression, steroid avoidance can be safely practiced in children with immunologic risk factors.
Pancreatic iron loading in chronically transfused sickle cell disease is lower than in thalassaemia major

Iron endocrinopathy and cardiomyopathy are common in chronically transfused thalassaemia major patients, but relatively rare in chronically transfused patients with sickle cell disease. Since magnetic resonance imaging can demonstrate preclinical organ iron deposition, we hypothesized that pancreas and cardiac R2* would likewise be lower in sickle cell disease patients than thalassaemia major patients having comparable transfusional burdens. To test this hypothesis, we examined pancreatic and cardiac iron in a convenience sample of 100 chronically‐transfused sickle cell disease and 131 thalassaemia major patients. Cardiac R2* (30 ± 9·2 vs. 73 ± 53 Hz, P < 0·0001) and pancreatic R2* (52 ± 62 vs. 253 ± 224 Hz, P < 0·0001) were significantly lower in sickle cell disease than thalassaemia major. Liver iron concentration was similar in both groups (14·9 ± 9·8 vs. 12·3 ± 8·4 mg/g dry weight, P = 0·101). The observed disparity in pancreatic and cardiac iron loading between sickle cell disease and thalassaemia major patients mirrors prior observations of organ toxicity in these patients. Greater cumulative transfusional iron exposure in thalassaemia major patients partially explains these observations but our data also suggest innate differences in labile iron handling between the two diseases.
Peginterferon Treatment In Children: A Review Of Chronic Hepatitis B And Chronic Hepatitis C Treatment

Despite of extensive blood product screening and national immunization programs, chronic hepatitis B and C infections continues to be a global problem with high mortality, morbidity and economic impact. Even though acquisition of these infections mostly occurs in childhood, major problems appear in adulthood. Cirrhosis and HCC are two major expected late events related to chronic hepatitis B and C infections. Rarely, children may also face these complications. To avoid these complications and increase the life expectancy in adults treatment of these two type infections should be started in childhood with appropriate patient selection. In contrast to children, adults are luckier in terms of treatment alternatives. They have the chance to use more potent antivirals with higher genetic barrier and pegylated form of interferons. Recently, the use of pegylated interferon and ribavirin combinations has been approved in children in Chronic HCV infection. However, chronic hepatitis B treatment in children is still dependent on the use of one type antiviral drug and conventional interferon. Treatment in early ages with an antiviral agent that has limited genetic barrier may block the chance of treatment or reduce the response rate in adulthood in chronic hepatitis B infection. This burden indicates the necessity of new therapeutic modalities in children. In this term pegylated interferons may be one of the optiones. In this article we aimed to reviewe the efficacy and safety of conventional and pegylated interferons, for the treatment of Hepatitis C and B infections in children.
Re‐transplantation after bortezomib‐based therapy

Whilst the use of high dose alkylating agents and autologous stem cell transplantation (ASCT) has a fundamental role in consolidating initial anti-tumour induction therapy, its role in salvage therapy consolidation remains to be determined. Bortezomib has been shown to be an effective agent at first and subsequent relapse, with responses equivalent or better than the response to previously used conventional therapies in first-line therapy (Richardson et al, 2005; Laubach et al, 2009). Combining bortezomib re-induction with a second ASCT after maximal anti-tumour response is, therefore, an attractive concept. Accordingly, we undertook a retrospective review of patients proceeding to a second ASCT after bortezomib-based re-induction therapy. Patients undergoing a second ASCT after progression from an initial ASCT and subsequent bortezomib re-induction therapy in 12 centres were identified (n = 40). Detailed information on the patients was obtained through anonymized clinical data retrieval forms, capturing critical patient and disease-specific factors including response to initial induction therapy, response to first ASCT, time to progression, subsequent therapies, bortezomib-based re-induction therapy and response to second ASCT (including the type of transplant and stem cell source). Response to therapy was categorized according to the International Myeloma Working Group criteria (Durie et al, 2006). Kaplan Meier plots were made using the Statistical Package for the Social Sciences (spss) IBM, Chicago, Illinois, USA. There were insufficient cytogenetic data for analysis. A total of 40 patients were identified in this retrospective study. Two patients had planned reduced intensity allogeneic (RIC-Allo) transplants after their second autologous transplant and weren excluded from further analysis. Patient characteristics including age, sex, type of myeloma, therapy prior to their first and second transplants are shown in Table Ia. One patient who relapsed 10 months after their bortezomib therapy was transplanted in relapse. All other patients were transplanted prior to disease progression. Twenty-six patients were treated with a combination of bortezomib and dexamethasone, eight patients had PAD chemotherapy (bortezomib, adriamycin and dexamethasone (Oakervee et al, 2005). Two patients had bortezomib monotherapy, one patient had bortezomib plus intravenous melphalan and one patient had bortezomib plus cyclophosphamide, dexamethasone and idarubicin. The median number of cycles of bortezomib therapy was 4 (range 2–12). Patients receiving PAD chemotherapy also had a median of four cycles
Classroom Research: Implementing the Scholarship of Teaching

Introduction to Classroom Research. The Leslies? Learning Issues: Prerequisite Knowledge Metacognition and Learning Strategies Self--Confidence and Motivation. The Captive Audience? Learning Issues: Learning Goals Deep and Surface Learning, Student Ratings of Instruction. But Is It Working? Learning Issues: Peer Learning and Intellectual Development, Critical Thinking. The Challenge? Designing Your Own Classroom Research.
A C⋅As lyase for degradation of environmental organoarsenical herbicides and animal husbandry growth promoters

Significance Organoarsenicals are used as herbicides, pesticides, antimicrobial growth promoters, and chemical warfare agents. Environmental organoarsenicals are microbially degraded, but the molecular mechanisms of breakdown are unknown. We previously identified a two-step pathway of degradation involving sequential reduction and C⋅As bond cleavage. Here we report cloning of the gene and characterization of the gene product for a C⋅As lyase, ArsI, a member of the family of type I extradiol dioxygenases. ArsI is the only enzyme shown to be involved in degradation of the reduced forms of the herbicide monosodium methylarsonic acid and the antimicrobial growth promoter roxarsone. As arsI genes are widely distributed in bacteria, ArsI-catalyzed organoarsenic degradation is proposed to have an impact on the arsenic biogeocycle. Arsenic is the most widespread environmental toxin. Substantial amounts of pentavalent organoarsenicals have been used as herbicides, such as monosodium methylarsonic acid (MSMA), and as growth enhancers for animal husbandry, such as roxarsone (4-hydroxy-3-nitrophenylarsonic acid) [Rox(V)]. These undergo environmental degradation to more toxic inorganic arsenite [As(III)]. We previously demonstrated a two-step pathway of degradation of MSMA to As(III) by microbial communities involving sequential reduction to methylarsonous acid [MAs(III)] by one bacterial species and demethylation from MAs(III) to As(III) by another. In this study, the gene responsible for MAs(III) demethylation was identified from an environmental MAs(III)-demethylating isolate, Bacillus sp. MD1. This gene, termed arsenic inducible gene (arsI), is in an arsenic resistance (ars) operon and encodes a nonheme iron-dependent dioxygenase with C⋅As lyase activity. Heterologous expression of ArsI conferred MAs(III)-demethylating activity and MAs(III) resistance to an arsenic-hypersensitive strain of Escherichia coli, demonstrating that MAs(III) demethylation is a detoxification process. Purified ArsI catalyzes Fe2+-dependent MAs(III) demethylation. In addition, ArsI cleaves the C⋅As bond in trivalent roxarsone and other aromatic arsenicals. ArsI homologs are widely distributed in prokaryotes, and we propose that ArsI-catalyzed organoarsenical degradation has a significant impact on the arsenic biogeocycle. To our knowledge, this is the first report of a molecular mechanism for organoarsenic degradation by a C⋅As lyase.
Abrogation of α-synuclein–mediated dopaminergic neurodegeneration in LRRK2-deficient rats

Significance Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common known genetic cause of late-onset Parkinson disease, but the mechanisms underlying LRRK2 action in neurodegeneration are not clear. We demonstrate that rats deficient in LRRK2 expression are protected from dopaminergic neurodegeneration caused by overexpression of α-synuclein or exposure to LPS. LRRK2 expression is induced in proinflammatory brain myeloid cells under pathological conditions. Our results suggest that LRRK2 inhibition may have important neuroprotective effects by critically modulating neuroinflammatory responses. LRRK2 inhibition may therefore be a potentially efficacious approach to slow or stop the progression of brain disorders where myeloid cell activation drives aspects of dysfunction. Missense mutations in the leucine-rich repeat kinase 2 (LRRK2) gene can cause late-onset Parkinson disease. Past studies have provided conflicting evidence for the protective effects of LRRK2 knockdown in models of Parkinson disease as well as other disorders. These discrepancies may be caused by uncertainty in the pathobiological mechanisms of LRRK2 action. Previously, we found that LRRK2 knockdown inhibited proinflammatory responses from cultured microglia cells. Here, we report LRRK2 knockout rats as resistant to dopaminergic neurodegeneration elicited by intracranial administration of LPS. Such resistance to dopaminergic neurodegeneration correlated with reduced proinflammatory myeloid cells recruited in the brain. Additionally, adeno-associated virus-mediated transduction of human α-synuclein also resulted in dopaminergic neurodegeneration in wild-type rats. In contrast, LRRK2 knockout animals had no significant loss of neurons and had reduced numbers of activated myeloid cells in the substantia nigra. Although LRRK2 expression in the wild-type rat midbrain remained undetected under nonpathological conditions, LRRK2 became highly expressed in inducible nitric oxide synthase (iNOS)-positive myeloid cells in the substantia nigra in response to α-synuclein overexpression or LPS exposures. Our data suggest that knocking down LRRK2 may protect from overt cell loss by inhibiting the recruitment of chronically activated proinflammatory myeloid cells. These results may provide value in the translation of LRRK2-targeting therapeutics to conditions where neuroinflammation may underlie aspects of neuronal dysfunction and degeneration.
Physical and virtual water transfers for regional water stress alleviation in China

Significance Freshwater resources are unevenly distributed in China. This situation drives a significant amount of water flow both physically and virtually across China. Here, we report on our quantification of China’s physical and virtual water flows and associated water stress at the provincial level. In 2007, interprovincial physical water flows amounted to only a small part of China’s total water supply, but virtual water flows amounted to over one-third of supply. We found that both physical and virtual water flows exacerbated water stress for the main water-exporting provinces. The results highlight the need for more emphasis to be placed on water demand management rather than the current focus on supply-oriented management. Water can be redistributed through, in physical terms, water transfer projects and virtually, embodied water for the production of traded products. Here, we explore whether such water redistributions can help mitigate water stress in China. This study, for the first time to our knowledge, both compiles a full inventory for physical water transfers at a provincial level and maps virtual water flows between Chinese provinces in 2007 and 2030. Our results show that, at the national level, physical water flows because of the major water transfer projects amounted to 4.5% of national water supply, whereas virtual water flows accounted for 35% (varies between 11% and 65% at the provincial level) in 2007. Furthermore, our analysis shows that both physical and virtual water flows do not play a major role in mitigating water stress in the water-receiving regions but exacerbate water stress for the water-exporting regions of China. Future water stress in the main water-exporting provinces is likely to increase further based on our analysis of the historical trajectory of the major governing socioeconomic and technical factors and the full implementation of policy initiatives relating to water use and economic development. Improving water use efficiency is key to mitigating water stress, but the efficiency gains will be largely offset by the water demand increase caused by continued economic development. We conclude that much greater attention needs to be paid to water demand management rather than the current focus on supply-oriented management.
Highly Conductive, Air‐Stable Silver Nanowire@Iongel Composite Films toward Flexible Transparent Electrodes

A new type of flexible transparent electrode is designed, by employing wettability-induced selective electroless-welding of silver nanowire (AgNW) networks, together with a thin conductive iongel as the protective layer. The obtained electrode exhibits high optical transmittance, and excellent air-stability without sacrificing conductivity.
A multi‐centre study of therapeutic efficacy and safety of platelet components treated with amotosalen and ultraviolet A pathogen inactivation stored for 6 or 7 d prior to transfusion

Bacteria in platelet components (PC) may result in transfusion‐related sepsis (TRS). Pathogen inactivation of PC with amotosalen (A‐PC) can abrogate the risk of TRS and hence facilitate storage to 7 d. A randomized, controlled, double‐blinded trial to evaluate the efficacy and safety of A‐PC stored for 6–7 d was conducted. Patients were randomized to receive one transfusion of conventional PC (C‐PC) or A‐PC stored for 6–7 d. The primary endpoint was the 1 h corrected count increment (CCI) with an acceptable inferiority of 30%. Secondary endpoints included 1‐ and 24‐h count increment (CI), 24‐h CCI, time to next PC transfusion, red blood cell (RBC) use, bleeding and adverse events. 101 and 100 patients received A‐PC or C‐PC respectively. The ratio of 1‐h CCI (A‐PC:C‐PC) was 0·87 (95% confidence interval: 0·73, 1·03) demonstrating non‐inferiority (P = 0·007), with respective mean 1‐h CCIs of 8163 and 9383; mean 1‐h CI was not significantly different. Post‐transfusion bleeding and RBC use were not significantly different (P = 0·44, P = 0·82 respectively). Median time to the next PC transfusion after study PC was not significantly different between groups: (2·2 vs. 2·3 d, P = 0·72). Storage of A‐PCs for 6–7 d had no impact on platelet efficacy.
Combination of bexarotene and the retinoid CD1530 reduces murine oral-cavity carcinogenesis induced by the carcinogen 4-nitroquinoline 1-oxide

Significance Oral-cavity squamous-cell carcinoma is one of the most common human cancers in the world. About 60–70% of oral-cavity carcinoma cases are diagnosed only after the tumors have become locally advanced. Therefore, in addition to treatment, prevention of oral cancer is a very important goal. In this study, we found that the combination of the drugs bexarotene and CD1530 was more effective than either drug alone in preventing oral carcinogenesis in our mouse model of human oral and esophageal cancers. We envision that the combination of bexarotene and CD1530 could potentially be applied to humans at a high risk for oral cancer, as a very effective strategy for the prevention and treatment of human oral cancer. We investigated the effects of bexarotene (a retinoid X receptor agonist), CD1530 (a retinoic acid receptor γ selective agonist), and the combination of these two drugs for the prevention of oral carcinogenesis induced by the carcinogen 4-nitroquinoline 1-oxide (4-NQO) in a mouse model of human oral-cavity and esophageal squamous-cell carcinoma previously generated in our laboratory. We observed decreased numbers of neoplastic tongue lesions and reduced lesion severity in the 4-NQO plus CD1530 (4N+C) and 4-NQO plus bexarotene plus CD1530 (4N+B+C) groups compared with the 4-NQO group. RNA-Seq analyses showed increases in transcripts in cell proliferation/cell cycle progression pathways in the 4-NQO vs. the untreated group. In addition, β-catenin and matrix metallopeptidase 9 (MMP9) protein levels and reactive oxygen species (ROS), as assessed by 4-hydroxynonenal (4-HNE) staining, were elevated in tongue tissues 17 wk after the termination of the 4-NQO treatment. The 4N+B, 4N+C, and 4N+B+C groups showed dramatically lower levels of β-catenin, MMP9, and 4-HNE staining compared with the 4-NQO group. The major reduction in 4-HNE staining in the retinoid treatment groups suggests a novel mechanism of action, reduction of ROS, by which bexarotene and CD1530 inhibit carcinogenesis.
Role of immune responses in the pathogenesis of low‐risk MDS and high‐risk MDS: implications for immunotherapy

The myelodysplastic syndromes (MDS) constitute a group of heterogeneous clonal haemopoietic stem cell disorders, characterized by ineffective and dysplastic haematopoiesis with varying degrees of peripheral cytopenia. Low‐risk MDS is characterized by increased apoptosis in the bone marrow (BM) with autoimmune characteristics whereas the advanced or high‐risk stages involve immune evasion and secondary DNA damage, giving cells growth potential to progress into acute myeloid leukaemia (AML). Nevertheless, the causes of MDS remain poorly defined and it is not clear how the disease progresses from an early stage to advanced MDS and AML. Although there are clear indications for a role of the immune system, the exact mechanism by which the immune response contributes to the progression is not yet clear. New insights into the pathophysiology of MDS with regard to the immune system will be instrumental for the development of novel patient‐oriented therapies. This review is focused on the role of immune responses in MDS and the implications for the development of novel immune therapies.
The Preuss Foundation Seminar on vaccine therapy for malignant primary brain tumors. February 15-17, 1998, La Jolla, Calif.

The 28th Preuss Foundation Seminar, held at the Salk Institute for Biological Studies in La Jolla, California, during February 25–27, 1998, focused on the issues surrounding the development of a vaccine therapy for MPBT. 2 The invited participants present at the seminar consisted of a prestigious group of basic scientists, neuropathologists, and medical and surgical neuro-oncologists. The meeting Chairmen, Glenn Dranoff (Boston, Mass.) and Darell Bigner (Durham, N.C.), began by defining two overall goals for the seminar. The first goal was to present and evaluate available data in the context of the following questions:
Effects of geometry and chemistry on hydrophobic solvation

Significance The solvation free energy of a molecule includes the free energy required to remove solvent from what will become the molecular interior and the free energy gained from dispersive interactions between the solute and solvent. Traditionally, these free energies have been assumed to be proportional to the surface area of the molecule. However, we computed these free energies for a series of alkanes and four configurations of decaalanine and showed that although these free energies were linear in the surface area for each set of molecules, each atom’s contributions to these energies depended on correlations with its surrounding atoms. The atomic contributions to these energies were therefore not additive. This finding suggests that most current hydrophobic models are unsatisfactory. Inserting an uncharged van der Waals (vdw) cavity into water disrupts the distribution of water and creates attractive dispersion interactions between the solvent and solute. This free-energy change is the hydrophobic solvation energy (ΔGvdw). Frequently, it is assumed to be linear in the solvent-accessible surface area, with a positive surface tension (γ) that is independent of the properties of the molecule. However, we found that γ for a set of alkanes differed from that for four configurations of decaalanine, and γ = −5 was negative for the decaalanines. These findings conflict with the notion that ΔGvdw favors smaller A. We broke ΔGvdw into the free energy required to exclude water from the vdw cavity (ΔGrep) and the free energy of forming the attractive interactions between the solute and solvent (ΔGatt) and found that γ < 0 for the decaalanines because −γatt > γrep and γatt < 0. Additionally, γatt and γrep for the alkanes differed from those for the decaalanines, implying that none of ΔGatt, ΔGrep, and ΔGvdw can be computed with a constant surface tension. We also showed that ΔGatt could not be computed from either the initial or final water distributions, implying that this quantity is more difficult to compute than is sometimes assumed. Finally, we showed that each atom’s contribution to γrep depended on multibody interactions with its surrounding atoms, implying that these contributions are not additive. These findings call into question some hydrophobic models.