Reduced FCGR3B copy number is associated with increased risk of systemic lupus erythematosus (SLE). The five FCGR2/FCGR3 genes are arranged across two highly paralogous genomic segments on chromosome ...1q23. Previous studies have suggested mechanisms for structural rearrangements at the FCGR2/FCGR3 locus and have proposed mechanisms whereby altered FCGR3B copy number predisposes to autoimmunity, but the high degree of sequence similarity between paralogous segments has prevented precise definition of the molecular events and their functional consequences. To pursue the genomic pathology associated with FCGR3B copy-number variation, we integrated sequencing data from fosmid and bacterial artificial chromosome clones and sequence-captured DNA from FCGR3B-deleted genomes to establish a detailed map of allelic and paralogous sequence variation across the FCGR2/FCGR3 locus. This analysis identified two highly paralogous 24.5 kb blocks within the FCGR2C/FCGR3B/FCGR2B locus that are devoid of nonpolymorphic paralogous sequence variations and that define the limits of the genomic regions in which nonallelic homologous recombination leads to FCGR2C/FCGR3B copy-number variation. Further, the data showed evidence of swapping of haplotype blocks between these highly paralogous blocks that most likely arose from sequential ancestral recombination events across the region. Functionally, we found by flow cytometry, immunoblotting and cDNA sequencing that individuals with FCGR3B-deleted alleles show ectopic presence of FcγRIIb on natural killer (NK) cells. We conclude that FCGR3B deletion juxtaposes the 5′-regulatory sequences of FCGR2C with the coding sequence of FCGR2B, creating a chimeric gene that results in an ectopic accumulation of FcγRIIb on NK cells and provides an explanation for SLE risk associated with reduced FCGR3B gene copy number.
To evaluate the ability of a personalized text-message-based intervention to increase weight loss among endometrial cancer survivors with obesity.
In this randomized, controlled trial, endometrial ...cancer survivors with obesity (BMI ≥30 kg/m2) were randomized to a personalized SMS text-message-based weight loss intervention or enhanced usual care. Primary outcome was weight loss at 6 months; secondary outcomes were weight loss at 12 months and changes in psychosocial measures. We also compared clinical characteristics and weight change between trial participants and non-participants.
Between May 18 and December 31, 2017, 80 endometrial cancer survivors with obesity consented to participate in the randomized trial. There were no differences in clinical characteristics between the two arms. Weight changes were similar in the two arms (P = 0.08). At 6 months, no differences in quality of life, physical activity, or body image were noted. Of 358 eligible patients, 80 became trial participants and 278, non-participants. Trial participants were younger (59.3 vs. 63.4 years, P < 0.001), more likely non-white (P = 0.02), on fewer medications (4 vs. 7, P < 0.001), and had a higher median BMI (38.7 vs. 37.6 kg/m2, P = 0.01) than non-participants. Weight change was similar between participants and non-participants (P = 0.85). At 6 months, similar percentages of participants and non-participants (47.7% vs. 44.4%) had gained weight, and similar percentages (9.2% vs. 11.2%) had lost at least 5% of their body weight.
This text-message-based intervention did not increase weight loss among endometrial cancer survivors with obesity, nor did participation in the trial. Other weight management interventions should be promoted to increase weight loss.
Clinical Trial Registration: ClinicalTrials.gov, www.clinicaltrials.gov, NCT03169023.
•A text-message-based intervention did not increase weight loss in endometrial cancer survivors with obesity.•Almost half of participants gained weight after 6 months and they did not lose more weight than non-participants.•Intervention participants were more likely to be younger, non-white and have a higher BMI than non-participants.•Only 22% of eligible endometrial cancer survivors enrolled in this behavioral health intervention trial.•Our negative trial results provide lessons for improving implementation for future weight loss intervention studies.
...many studies reporting on rates of NDD include a large age range or other neurodevelopmental and medical disorders and sensory and motor impairments, which are beyond the scope of this paper and ...our definition of NDD, making age and domain specific information more difficult to obtain 34. ...the workgroup members reviewed 3 case definitions (i.e., ICD-10, ICD-11, DSM-5) in addition to considering common definitions used in research.1.2.1 NDD following maternal immunization In order to identify any reported potential association of maternal immunization with infant neurodevelopmental delay (NDD), separate literature searches were performed using Medline, PubMed, the Cochrane libraries, and Embase.com. ...as previously stated, developmental skill attainment can be variable, such that delays may spontaneously resolve, remit following intervention, or worsen as environmental demands increase and a child fails to acquire the necessary skills to meet these demands 134–137.1.3.4 Influence of treatment on fulfillment of case definition The Working Group decided against using “treatment” or “treatment response” towards fulfillment of the NDD case definition. A domain-specific specialist could also meet gold standard criteria if the delay is identified within that single domain. ...a speech-language therapist with appropriate training/experience in children aged 0–5 would meet gold standard criteria for diagnosing NDD impacting language, while a physical or occupational therapist with appropriate experience could meet such criteria for diagnosing a NDD impacting motor skills.
The development of the jaw joint between the palatoquadrate and proximal part Meckel's cartilage (articular) has recently been shown to involve the gene
Bapx1.
Bapx1 is expressed in the developing ...mandibular arch in two distinct caudal, proximal patches, one on either side of the head. These domains coincide later with the position of the developing jaw joint. The mechanisms that result in the restricted expression of
Bapx1 in the mandibular arch were investigated, and two signaling factors that act as repressors were identified. Fibroblast growth factors (Fgfs) expressed in the oral epithelium restrict expression of
Bapx1 to the caudal half of the mandibular arch, while bone morphogenetic proteins (Bmps) expressed in the distal mandibular arch restrict expression of
Bapx1 to the proximal part of the mandible. Application of Fgf8 and Bmp4 beads to the proximal mesenchyme led to loss of
Bapx1 expression and later fusion of the quadrate and articular as the jaw joint failed to form. In addition to fusion of the jaw joint, loss of
Bapx1 lead to loss of the retroarticular process (RAP), phenocopying the defects seen after
Bapx1 function was reduced in the zebrafish. By manipulating these signals, we were able to alter the expression domain of
Bapx1, resulting in a new position of the jaw joint.
•Endometrial cancer (EC) survivors have attempted many methods to lose weight.•EC survivors rarely choose bariatric surgery, physical therapy, or psychologic support services to lose weight.•EC ...survivors without recurrence were more likely to enroll in a weight loss intervention trial than those with recurrence.
We aimed to evaluate obese endometrial cancer (EC) survivors' perceptions of weight loss barriers and previously attempted weight loss methods and to identify characteristics that predicted willingness to enroll in a behavioral intervention trial. We administered a 27-question baseline survey at an academic institution to EC survivors with body mass index ≥ 30 kg/m2. Survivors were asked about their lifestyles, previous weight loss attempts, perceived barriers, and were offered enrollment into an intervention trial. Data was analyzed using Fisher’s Exact, Kruskal-Wallis, and univariate and multivariate regressions. 155 of 358 (43%) eligible obese EC survivors were surveyed. Nearly all (n = 148, 96%) had considered losing weight, and 77% (n = 120) had tried two or more strategies. Few had undergone bariatric surgery (n = 5, 3%), psychologic counseling (n = 2, 1%), or met with physical therapists (n = 9, 6%). Lower income was associated with difficulty in accessing interventions. Survivors commented that negative self-perceptions and difficulties with follow-through were barriers to weight loss, and fear of complications and self-perceived lack of qualification were deterrents to bariatric surgery. 80 (52%) of those surveyed enrolled in the trial. In a multivariate model, adjusting for race and stage, survivors without recurrence were 4.3 times more likely to enroll than those with recurrence. Most obese EC survivors have tried multiple strategies to lose weight, but remain interested in weight loss interventions, especially women who have never experienced recurrence. Providers should encourage weight loss interventions early, at the time of initial diagnosis, and promote underutilized strategies such as psychological counseling, physical therapy, and bariatric surgery.
Fgf8 signalling is known to play an important role during patterning of the first pharyngeal arch, setting up the oral region of the head and then defining the rostral and proximal domains of the ...arch. The mechanisms that regulate the restricted expression of
Fgf8 in the ectoderm of the developing first arch, however, are not well understood. It has become apparent that pharyngeal endoderm plays an important role in regulating craniofacial morphogenesis. Endoderm ablation in the developing chick embryo results in a loss of
Fgf8 expression in presumptive first pharyngeal arch ectoderm.
Shh is locally expressed in pharyngeal endoderm, adjacent to the
Fgf8-expressing ectoderm
, and is thus a candidate signal regulating ectodermal
Fgf8 expression. We show that in cultured explants of presumptive first pharyngeal arch, loss of
Shh signalling results in loss of
Fgf8 expression, both at early stages before formation of the first arch, and during arch formation. Moreover, following removal of the endoderm, Shh protein can replace this tissue and restore
Fgf8 expression. Overexpression of Shh in the non-oral ectoderm leads to an expansion of
Fgf8, affecting the rostral–caudal axis of the developing first arch, and resulting in the formation of ectopic cartilage. Shh from the pharyngeal endoderm thus regulates
Fgf8 in the ectoderm and the role of the endoderm in pharyngeal arch patterning may thus be indirectly mediated by the ectoderm.
Induction of matrix metalloproteinases (MMPs) contributes to adverse remodeling after myocardial infarction (MI). Whether a region- and type-specific distribution of MMPs occurs within the post-MI ...myocardium remained unknown.
Ten sheep were instrumented with a sonomicrometry array to measure dimensions in 7 distinct regions corresponding to the remote, transition, and MI regions. Eight sheep served as reference controls. The relative abundance of representative MMP types and the tissue inhibitors of the MMPs (TIMPs) was quantified by immunoblotting. Segment length increased from baseline in the remote (24.9+/-5.4%), transition (18.0+/-2.9%), and MI (53.8+/-11.0%) regions at 8 weeks after MI (P<0.05) and was greatest in the MI region (P<0.05). Region- and type-specific changes in MMPs occurred after MI. For example, MMP-1 and MMP-9 abundance was unchanged in the remote, fell to 3+/-2% in the transition, and was undetectable in the MI region (P<0.05). MMP-13, MMP-8, and MT1-MMP increased by >300% in the transition and MI regions (P<0.05). TIMP abundance decreased significantly in the transition region after MI and fell to undetectable levels within the MI region.
The unique findings of this study were 2-fold. First, changes in regional geometry after MI were associated with changes in MMP levels. Second, a region-specific portfolio of MMPs was induced after MI and was accompanied by a decline in TIMP levels, indicative of a loss of MMP inhibitory control. Targeting the regional imbalance between specific MMPs and TIMPs within the post-MI myocardium holds therapeutic potential.
Treatment of Organotypic Cultures (OT) and the KPC mouse (LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre) was performed to mimic human chemotherapy regimen cycles with All-Trans Retinoic Acid (ATRA), ...targeting PSC, and the chemotherapeutic agent gemcitabine, targeting pancreatic cancer cells (PCC).
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