Malignant peripheral nerve sheath tumors (MPNST) are highly invasive soft tissue sarcomas that arise within the peripheral nerve and frequently metastasize. To identify molecular events contributing ...to malignant transformation in peripheral nerve, we compared eight cell lines derived from MPNSTs and seven normal human Schwann cell samples. We found that MPNST lines are heterogeneous in their in vitro growth rates and exhibit diverse alterations in expression of pRb, p53, p14(Arf), and p16(INK4a) proteins. All MPNST cell lines express the epidermal growth factor receptor and lack S100beta protein. Global gene expression profiling using Affymetrix oligonucleotide microarrays identified a 159-gene molecular signature distinguishing MPNST cell lines from normal Schwann cells, which was validated in Affymetrix microarray data generated from 45 primary MPNSTs. Expression of Schwann cell differentiation markers (SOX10, CNP, PMP22, and NGFR) was down-regulated in MPNSTs whereas neural crest stem cell markers, SOX9 and TWIST1, were overexpressed in MPNSTs. Previous studies have implicated TWIST1 in apoptosis inhibition, resistance to chemotherapy, and metastasis. Reducing TWIST1 expression in MPNST cells using small interfering RNA did not affect apoptosis or chemoresistance but inhibited cell chemotaxis. Our results highlight the use of gene expression profiling in identifying genes and molecular pathways that are potential biomarkers and/or therapeutic targets for treatment of MPNST and support the use of the MPNST cell lines as a primary analytic tool.
Aim: A field experiment was conducted during rabi season to determine the effect of biofertilizers and split application of vermicompost on biological properties (microbial biomass carbon and ...nitrogen, microbial populations and enzyme activities) in rhizosphere of wheat. Results: The experiment results indicated that among biofertilizers treatments, seed inoculation with Azotobacter + PSB + KMB + ZnSB (Bs) resulted in a significant higher soil microbial biomass carbon, microbial biomass nitrogen, population of bacteria, fungi and actinomycetes, dehydrogenase activity and acid phosphatase enzyme activity in comparison to control. Similarly, application of vermicompost as 50 % VC at sowing + 50 % VC at tillering (V3) were obtained improved microbial biomass carbon and nitrogen, microbial population, dehydrogenase activity and acid phosphatase enzyme activity while remaining at par with 75 % VC at sowing + 25 % VC at tillering (V4) proved superior in comparison to rest of the treatments due to continuous supply of nutrients throughout the crop cycle. Grain and straw yield of wheat also increased due to the application of biofertilizers and vermicompost over the control. Interpretation: Biofertilizers (Azotobacter, PSB, KMB and ZnSB) and split application of vermicompost enhanced the soil microbial population and enzymatic activities which sustained the soil health for better wheat production. Methodology: The experiment was laid out in factorial randomized block design with three replications consisting of twenty treatment combinations. Soil samples were collected from the plots at 0-15 cm depth after harvest of wheat crop and soil biological properties analyzed using standard. analytical procedure.
Background
The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 Physical Functioning subscale is a widely used patient‐reported outcome measure ...that quantifies cancer patients' physical functioning. Strong floor/ceiling effects can affect a scale's sensitivity to change. The aim of this study was to characterize floor/ceiling effects of the physical functioning domain in patients with advanced/metastatic breast cancer enrolled in commercial clinical trials and a community‐based trial.
Methods
The clinical trial cohort comprised patients from 5 registrational trials submitted to the Food and Drug Administration for review (2010‐2017). The community cohort comprised a subgroup of patients from the Alliance Patient Reported Outcomes to Enhance Cancer Treatment (PRO‐TECT) trial. The distribution of patient responses to Physical Functioning items and the summed score were assessed at the baseline and 3‐month follow‐up for both cohorts. Descriptive statistics were used to determine floor/ceiling effects at the item and scale levels.
Results
The clinical trial cohort and the community cohort consisted of 2407 and 178 patients, respectively. Twenty‐four percent or more of the respondents reported “not at all” for having trouble/needing help with each Physical Functioning item across both cohorts and measurement time points. Fourteen to twenty percent of the patients scored perfectly (100 of 100) on the Physical Functioning subscale summary measure (where higher scores indicated better physical functioning) across both cohorts and time points.
Conclusions
Minor floor effects and notable ceiling effects were found at the item and scale levels of the Physical Functioning subscale, regardless of cohort, and this creates some uncertainty about its ability to detect changes in physical functioning among high‐functioning patients. Investigators may consider adding additional high‐functioning items from the EORTC's item library to more accurately describe the impact of anticancer treatment on patients' physical functioning.
Abstract
We present a multiwavelength analysis using the Submillimeter Array (SMA), James Clerk Maxwell Telescope, NOEMA, JWST, the Hubble Space Telescope (HST), and the Spitzer Space Telescope of ...two dusty strongly star-forming galaxies, 850.1 and 850.2, seen through the massive cluster lens A 1489. These SMA-located sources both lie at
z
= 4.26 and have bright dust continuum emission, but 850.2 is a UV-detected Lyman-break galaxy, while 850.1 is undetected at ≲ 2
μ
m, even with deep JWST/NIRCam observations. We investigate their stellar, interstellar medium, and dynamical properties, including a pixel-level spectral energy distribution analysis to derive subkiloparsec-resolution stellar-mass and
A
V
maps. We find that 850.1 is one of the most massive and highly obscured,
A
V
∼ 5, galaxies known at
z
> 4 with
M
*
∼10
11.8
M
⊙
(likely forming at
z
> 6), and 850.2 is one of the least massive and least obscured,
A
V
∼ 1, members of the
z
> 4 dusty star-forming population. The diversity of these two dust-mass-selected galaxies illustrates the incompleteness of galaxy surveys at
z
≳ 3–4 based on imaging at ≲ 2
μ
m, the longest wavelengths feasible from HST or the ground. The resolved mass map of 850.1 shows a compact stellar-mass distribution,
R
e
mass
∼1 kpc, but its expected evolution means that it matches both the properties of massive, quiescent galaxies at
z
∼ 1.5 and ultramassive early-type galaxies at
z
∼ 0. We suggest that 850.1 is the central galaxy of a group in which 850.2 is a satellite that will likely merge in the near future. The stellar morphology of 850.1 shows arms and a linear bar feature that we link to the active dynamical environment it resides within.
Aims
Tralokinumab, an investigational human immunoglobulin G4 monoclonal antibody, potently and specifically neutralizes interleukin‐13, a central mediator of asthma. Tralokinumab has shown ...improvements in clinical endpoints in adults with uncontrolled asthma. The present study explored the pharmacokinetics (PK) and safety of a single tralokinumab dose, and utilized a population PK modelling and simulation approach to evaluate the optimal dosing strategy for adolescents.
Methods
Adolescent subjects with asthma, using daily controller medication, received a single subcutaneous dose of tralokinumab 300 mg. Safety, immunogenicity and PK data were collected during a 57‐day follow‐up. A population PK model was developed using data from the present study and prior studies in adults. Simulations were performed to evaluate dose adjustment requirements for adolescents.
Results
Twenty adolescents (12–17 years) were enrolled; all completed the study. No clinically relevant safety findings or antidrug antibodies were detected. PK parameters were similar to those observed in adults. PK modelling showed that body weight was a minor predictor of tralokinumab PK; after incorporating body weight into the PK model, a 15% (nonparametric 95% confidence interval 5%, 26%) lower clearance was found in adolescents compared with adults 173 (151, 209) vs. 204 (191, 229) ml day–1. Simulations showed no therapeutically relevant differences in exposures between adolescent and adult populations, and similar PK profiles for weight‐based (4 mg kg–1) and fixed (300 mg) fortnightly subcutaneous doses of tralokinumab.
Conclusion
Single‐dose administration of tralokinumab 300 mg in adolescents was well tolerated, with a PK profile similar to that in adults. Exposure predictions suggest that dose adjustment is not required for adolescents.
Autosomal recessive forms of pseudohypoaldosteronism are caused by genetic defects in the epithelial sodium channel. Little is known about the long-term outcome and medication needs during childhood ...and adolescence.
This study reports a single-centre experience of children affected with this ultra-rare condition over a 37-year period.
We report the clinical presentation, growth, neuro-development, associated conditions, mortality and medication dosing and administration for 12 affected children from eight families.
All children were presented within the first 2 weeks of life with life-threatening, severe hyperkalaemia and hyponatraemia. All parents were consanguineous and of South Asian, Middle Eastern or African ethnic origin. Eight children had homozygous mutations in the SCNN1A and SCNN1G genes, encoding the epithelial sodium channel subunits alpha and gamma, respectively, including one novel mutation. Three children died (25%) and two (16%) had severe neurological impairment post-cardiac arrest secondary to hyperkalaemia. One affected female had a successful pregnancy at the age of 28 years.
Despite high mortality and morbidity in this condition, survival with normal physical and neurological outcome is possible, justifying intensive management to prevent electrolyte imbalance.
Raised C-reactive protein (CRP) is a risk factor for type 2 diabetes. According to the Mendelian randomization method, the association is likely to be causal if genetic variants that affect CRP level ...are associated with markers of diabetes development and diabetes. Our objective was to examine the nature of the association between CRP phenotype and diabetes development using CRP haplotypes as instrumental variables.
We genotyped three tagging SNPs (CRP + 2302G > A; CRP + 1444T > C; CRP + 4899T > G) in the CRP gene and measured serum CRP in 5,274 men and women at mean ages 49 and 61 y (Whitehall II Study). Homeostasis model assessment-insulin resistance (HOMA-IR) and hemoglobin A1c (HbA1c) were measured at age 61 y. Diabetes was ascertained by glucose tolerance test and self-report. Common major haplotypes were strongly associated with serum CRP levels, but unrelated to obesity, blood pressure, and socioeconomic position, which may confound the association between CRP and diabetes risk. Serum CRP was associated with these potential confounding factors. After adjustment for age and sex, baseline serum CRP was associated with incident diabetes (hazard ratio = 1.39 95% confidence interval 1.29-1.51, HOMA-IR, and HbA1c, but the associations were considerably attenuated on adjustment for potential confounding factors. In contrast, CRP haplotypes were not associated with HOMA-IR or HbA1c (p = 0.52-0.92). The associations of CRP with HOMA-IR and HbA1c were all null when examined using instrumental variables analysis, with genetic variants as the instrument for serum CRP. Instrumental variables estimates differed from the directly observed associations (p = 0.007-0.11). Pooled analysis of CRP haplotypes and diabetes in Whitehall II and Northwick Park Heart Study II produced null findings (p = 0.25-0.88). Analyses based on the Wellcome Trust Case Control Consortium (1,923 diabetes cases, 2,932 controls) using three SNPs in tight linkage disequilibrium with our tagging SNPs also demonstrated null associations.
Observed associations between serum CRP and insulin resistance, glycemia, and diabetes are likely to be noncausal. Inflammation may play a causal role via upstream effectors rather than the downstream marker CRP.
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