A burgeoning list of small RNAs with a variety of regulatory functions has been identified in both prokaryotic and eukaryotic cells. However, it remains difficult to identify small RNAs by sequence ...inspection. We used the high conservation of small RNAs among closely related bacterial species, as well as analysis of transcripts detected by high-density oligonucleotide probe arrays, to predict the presence of novel small RNA genes in the intergenic regions of the Escherichia coli genome. The existence of 23 distinct new RNA species was confirmed by Northern analysis. Of these, six are predicted to encode short ORFs, whereas 17 are likely to be novel functional small RNAs. We discovered that many of these small RNAs interact with the RNA-binding protein Hfq, pointing to a global role of the Hfq protein in facilitating small RNA function. The approaches used here should allow identification of small RNAs in other organisms.
Abstract
Context
In an open-label, randomized, controlled, phase 3 trial in 61 children aged 1 to 12 years with X-linked hypophosphatemia (XLH), burosumab improved rickets vs continuing conventional ...therapy with active vitamin D and phosphate.
Objective
We conducted an analysis to determine whether skeletal responses differed when switching to burosumab vs continuing higher or lower doses of conventional therapy.
Methods
Conventional therapy dose groups were defined as higher-dose phosphate greater than 40 mg/kg (HPi), lower-dose phosphate 40 mg/kg or less (LPi), higher-dose alfacalcidol greater than 60 ng/kg or calcitriol greater than 30 ng/kg (HD), and lower-dose alfacalcidol 60 ng/kg or less or calcitriol 30 ng/kg or less (LD).
Results
At week 64, the Radiographic Global Impression of Change (RGI-C) for rickets was higher (better) in children randomly assigned to burosumab vs conventional therapy for all prebaseline dose groups: HPi (+1.72 vs +0.67), LPi (+2.14 vs +1.08), HD (+1.90 vs +0.94), LD (+2.11 vs +1.06). At week 64, the RGI-C for rickets was also higher in children randomly assigned to burosumab (+2.06) vs conventional therapy for all on-study dose groups: HPi (+1.03), LPi (+1.05), HD (+1.45), LD (+0.72). Serum alkaline phosphatase (ALP) also decreased in the burosumab-treated patients more than in the conventional therapy group, regardless of on-study phosphate and active vitamin D doses.
Conclusion
Prior phosphate or active vitamin D doses did not influence treatment response after switching to burosumab among children with XLH and active radiographic rickets. Switching from conventional therapy to burosumab improved rickets and serum ALP more than continuing either higher or lower doses of phosphate or active vitamin D.
Many small, noncoding RNAs in bacteria act as post-transcriptional regulators by basepairing with target mRNAs. While the number of characterized small RNAs (sRNAs) has steadily increased, only a ...limited number of the corresponding mRNA targets have been identified. Here we present a program, TargetRNA, that predicts the targets of these bacterial RNA regulators. The program was evaluated by assessing whether previously known targets could be identified. The program was then used to predict targets for the Escherichia coli RNAs RyhB, OmrA, OmrB and OxyS, and the predictions were compared with changes in whole genome expression patterns observed upon expression of the sRNAs. Our results show that TargetRNA is a useful tool for finding mRNA targets of sRNAs, although its rate of success varies between sRNAs.
Changing to burosumab, a monoclonal antibody targeting fibroblast growth factor 23, significantly improved phosphorus homeostasis, rickets, lower-extremity deformities, mobility, and growth versus ...continuing oral phosphate and active vitamin D (conventional therapy) in a randomized, open-label, phase 3 trial involving children aged 1–12 years with X-linked hypophosphatemia. Patients were randomized (1:1) to subcutaneous burosumab or to continue conventional therapy. We present patient-reported outcomes (PROs) from this trial for children aged ≥ 5 years at screening (
n
= 35), using a Patient-Reported Outcomes Measurement Information System (PROMIS) questionnaire and SF-10 Health Survey for Children. PROMIS pain interference, physical function mobility, and fatigue scores improved from baseline with burosumab at weeks 40 and 64, but changed little with continued conventional therapy. Pain interference scores differed significantly between groups at week 40 (− 5.02, 95% CI − 9.29 to − 0.75;
p
= 0.0212) but not at week 64. Between-group differences were not significant at either week for physical function mobility or fatigue. Reductions in PROMIS pain interference and fatigue scores from baseline were clinically meaningful with burosumab at weeks 40 and 64 but not with conventional therapy. SF-10 physical health scores (PHS-10) improved significantly with burosumab at week 40 (least-squares mean standard error + 5.98 1.79;
p
= 0.0008) and week 64 (+ 5.93 1.88;
p
= 0.0016) but not with conventional therapy (between-treatment differences were nonsignificant). In conclusion, changing to burosumab improved PRO measures, with statistically significant differences in PROMIS pain interference at week 40 versus continuing with conventional therapy and in PHS-10 at weeks 40 and 64 versus baseline.
Trial registration
: ClinicalTrials.gov NCT02915705
We present the case of a patient with X-Linked Hypophosphatemia (XLH) and an inflammatory myofibroblastic tumor (IMT) of the bladder which prompted further investigation into the possible ...relationship between XLH and IMT i.e. a case of Occam's Razor or Hickam's Dictum?
In an open label, randomized, controlled, phase 3 trial in 61 children 1 to 12 years old with X-linked hypophosphatemia (XLH), burosumab improved rickets versus continuing conventional therapy with ...active vitamin D and phosphate. Here, we conducted an analysis to determine whether skeletal responses differed when switching to burosumab versus continuing higher or lower doses of conventional therapy.
Conventional therapy dose groups were defined as: higher dose phosphate >40 mg/kg HPi, lower dose phosphate ≤40 mg/kg LPi, higher dose alfacalcidol >60 ng/kg or calcitriol >30 ng/kg HD, and lower dose alfacalcidol ≤60 ng/kg or calcitriol ≤30 ng/kg LD.
At Week 64, the Radiographic Global Impression of Change (RGI-C) for rickets was higher (better) in children randomized to burosumab versus conventional therapy for all pre-baseline dose groups: HPi (+1.72 versus +0.67), LPi (+2.14 versus +1.08), HD (+1.90 versus +0.94), LD (+2.11 versus +1.06). At Week 64, the RGI-C for rickets was also higher in children randomized to burosumab (+2.06) versus conventional therapy for all on-study dose groups: HPi (+1.03), LPi (+1.05), HD (+1.45), LD (+0.72). Serum alkaline phosphatase also decreased in the burosumab treated patients more than in the conventional therapy group, regardless of on-study phosphate and active vitamin D doses.
Prior phosphate or active vitamin D doses did not influence treatment response after switching to burosumab among children with XLH and active radiographic rickets. Switching from conventional therapy to burosumab improved rickets and serum alkaline phosphatase more than continuing either higher or lower doses of phosphate or active vitamin D.
We study the dynamics of a model for the late-type barred-spiral galaxy NGC 3359 by using both observational and numerical techniques. The results of our modelling are compared with photometric and ...kinematical data. The potential used is estimated directly from observations of the galaxy. It describes with a single potential function, a barred-spiral system with an extended spiral structure. Thus, the study of the dynamics in this potential has an interest by itself. We apply orbital theory and response models for the study of the stellar component, and smoothed particle hydrodynamics for modelling the gas. In particular, we examine the pattern speed of the system and the orbital character (chaotic or ordered) of the spiral arms. We conclude that the spiral pattern rotates slowly, in the sense that its corotation is close to or even beyond the end of the arms. Although a single, slow pattern speed could, under certain assumptions, characterize the whole disc, the comparison with the observational data indicates that probably the bar and the spirals have different angular velocities. In our two pattern speeds model, the best fit is obtained with a bar ending close to its 4:1 resonance and a more slowly rotating spiral. Assuming an 11 Mpc distance to the galaxy, a match of our models with the observed data indicates a pattern speed of about 39 km s−1 kpc−1 for the bar and about 15 km s−1 kpc−1 for the spiral. We do not find any indication for a chaotic character of the arms in this barred-spiral system. The flow in the region of the spirals can best be described as a regular ‘precessing-ellipses flow’.
Cyclin-dependent kinase 4/6 (CDK4/6)-specific inhibitors, such as palbociclib, have shown clinical efficacy, but primary or secondary resistance has emerged as a problem. To develop more effective ...therapeutic approaches, investigation is needed into the mechanisms of resistance or adaption. Here, it is demonstrated that CDK2 compensates for loss of CDK4 activity to rescue palbociclib-arrested breast cancer cells, suggesting that inhibition of both kinases is required to achieve durable response. In addition, a novel strategy is described to inhibit tyrosine phosphorylation of p27Kip1 (CDKN1B) and simultaneously inhibit both CDK2 and CDK4. p27Kip1 is a required assembly factor for cyclin-CDK4 complexes, but it must be phosphorylated on residue Y88 to open or activate the complex. The Brk-SH3 peptide, ALT, blocks p27 Y88 phosphorylation, inhibiting CDK4. Nonphosphorylated p27 is no longer a target for ubiquitin-mediated degradation and this stabilized p27 now also inhibits CDK2 activity. Thus, ALT induction inhibits both the kinase that drives proliferation (CDK4) and the kinase that mediates resistance (CDK2), causing a potent and long-lasting cell-cycle arrest. ALT arrests growth of all breast cancer subgroups and synergizes with palbociclib to increase cellular senescence and to cause tumor regression in breast cancer xenograft models. The use of ALT demonstrates that both CDK4 and CDK2 need to be inhibited if long-term efficacy is to be achieved and represents a novel modality to inhibit breast cancer cells.
Modulating tyrosine phosphorylation of p27 impacts both proliferative (CDK4) and resistance (CDK2) mechanisms in breast cancer and suggests that phospho-p27 status may serve as a biomarker for patients that are responsive to CDK4/6 inhibition.
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