bluuebunny/crossref_metadata_2025_split huggingface dataset:
O27: MICROGLIAL CORRECTION AFTER FETAL THERAPY WITHOUT CONDITIONING IN MICE WITH MUCOPOLYSACCHARIDOSIS TYPE VII
Authors: Nguyen Quoc-Hung , Witt Russell G , Bowen Wang , Eikani Carlo , Shea Jeremy , Smith Lucas K , Boyle Gabrielle , Cadaoas Jaclyn , Sper Renan , MacKenzie John D , Villeda Saul , MacKenzie Tippi C 
Published: April 2021

Abstract

Introduction
Mucopolysaccharidosis type 7 (MPS7) is a lysosomal storage disorder typically fatal in utero. Postnatal enzyme replacement therapy (ERT) to replace missing glucuronidase (GUS) does not penetrate the blood-brain barrier (BBB). We investigated whether in utero ERT (IUERT) specifically targets brain microglia (natural GUS storehouses and key brain inflammation mediators) and whether in utero hematopoietic stem cell transplantation (IUHSCT) results in microglial engraftment as a strategy for permanent correction.

Methods
We performed IUERT by injecting GUS into MPS7 fetuses mid-gestation, and analyzed tissue homogenates (via colorimetric substrate) and brain microglia (via flow cytometry) for enzyme activity after 4-7 days. We performed IUHSCT by transplanting HSCs mid-gestation from CX3CR1-GFP donors. We examined blood, bone marrow, and brain for engraftment. We assessed brain inflammation by staining for CD68. We performed RNA sequencing to characterize engrafted microglia.

Results
IUERT resulted in detectable brain GUS activity. Flow cytometry showed that GUS activity after IUERT was near wild-type levels, and brains harvested in adulthood had decreased inflammation via CD68 immunohistochemistry. IUHSCT resulted in multilineage engraftment of hematopoietic cells in blood and bone. Confocal microscopy revealed multifocal engraftment of donor-derived microglia. RNA sequencing indicated that engrafted microglia were nearly identical to endogenous microglia. MPS7 chimeras had evidence of reduced brain inflammation near donor microglia.

Conclusion
Both IUERT and IUHSCT are complementary treatment modalities that can penetrate the BBB and ameliorate neurologic manifestations of diseases such as MPS7. These results lay the foundation for future studies using in utero molecular therapies for MPS7 as well as other storage disorders.
O50: DEVELOPMENT OF A PATIENT-DERIVED TUMOUR ORGANOIDS FROM METASTATIC BREAST CANCER FOR ASSESSMENT OF NOVEL CLINICALLY ACTIONABLE TARGETS
Authors: Jagust P , Varešlija D , Cocchiglia S , O'Haloran PJ , Dablouk MO , Brett FM , Cryan J , Beausang A , Hudson L , Hill ADK , Young L 
Published: April 2021

Abstract

Introduction
Metastatic breast cancer (MBC) is the main source of mortality in breast cancer patients largely due to lack of effective treatments. Our previous results suggest that tumour transcriptional heterogeneity drives therapy resistance and cancer relapse. While traditional in vitro human cancer cell line models have been widely used for disease modelling, they do not faithfully recapitulate the pathophysiology of MBC.

Method
In this study we developed patient-derived tumour organoid cultures from frozen patient-derived (PDX) models of MBC. Using those models we performed preclinical drug screening of investigational and FDA approved therapeutics previously uncovered by us as potentially clinically actionable in MBC.

Result
Our results reveal high heterogeneity in the responses to various targeted therapies among tested MBC organoids, which makes them a valuable tool for studying intra-tumor heterogeneity and drug response. Moreover, drug screening identified a divergent set of the breast to brain metastatic MBC organoids that showed high sensitivity to a new class of tyrosine kinase receptors, RET.

Conclusion
Taken together, our novel MBC models and methodology applied here provides an important modelling tool to assess the contribution of intra-tumour heterogeneity and microenvironment to drug response as they recapitulate the cellular, structural and biochemical complexity previously observed in our genomic characterisation of MBCs. Application of this type of translational research will enhance the development of new targeted precision medicine strategies and prelude stratification for clinical trials. Abbreviations MBC- Metastatic Breast Cancer; PDX- Patient-Derived Xenografts; FDA- Food and Drug Administration; RET- Receptor Tyrosine Kinase

Take-home message
Patient-derived tumour organoid cultures provide an important modelling tool to assess the contribution of intra-tumour heterogeneity and microenvironment to drug response as they recapitulate the cellular, structural and biochemical complexity previously observed in genomic characterisation of metastatic breast cancer.
SURGICAL EDUCATION AND TRAINING
O58: THE IMPACT OF RADIOTHERAPY ON PATIENT-REPORTED OUTCOMES OF IMMEDIATE IMPLANT-BASED BREAST RECONSTRUCTION: RESULTS OF A PROSPECTIVE MULTICENTRE COHORT STUDY
Authors: Sewart E , Turner N , Conroy EJ , Cutress R , Skillman J , Whisker L , Thrush S , Barnes N , Holcombe C , Potter S 
Published: April 2021

Abstract

Introduction
Post-mastectomy radiotherapy (PMRT) is increasing given to improve breast cancer outcomes but can increase complication rates following implant-based breast reconstruction (IBBR). Little, however, is known about the impact of PMRT on patient-reported outcomes (PROs) of IBBR, especially in the context of mesh-assisted techniques.

Method
2108 consecutive women undergoing IBBR at 81 UK centres were prospectively recruited between 2014 and 2016. Demographic, operative, oncological and 3-month complication data were collected, and patients who consented received post-operative questionnaires. An 18-month questionnaire assessed PROs using the validated BREAST-Q. The effect of IBBR on PROs was investigated using mixed-effects regression models adjusted for clinically relevant confounders and including a random effect to account for potential clustering by centre.

Result
1693 iBRA participants underwent mastectomy for malignancy, of whom 1187 (70%) consented to receive the 18-month questionnaire and 732 (43%) completed it. Patients undergoing PMRT (n=214) reported significantly worse scores across 3 BREAST-Q domains: satisfaction with breasts (-6.27 points, p=0.008, 95% confidence interval (CI)[-10.91,-1.63]), satisfaction with outcome (-7.53 points, p=0.002, CI[-12.20,-2.85]) and physical well-being (-6.55 points, p&lt;0.001, CI[-9.43,-3.67]). Overall satisfaction was worse in the PMRT group (OR 0.497, p=0.002, CI[0.32,0.77]). Use of biological mesh did not ameliorate the impact of PMRT on patient satisfaction (interaction term p-values [0.173 - 0.826]).

Conclusion:
PMRT adversely affects PROs of IBBR. This should be discussed with patients considering IBBR, especially if PMRT is anticipated or indications are borderline, to enable informed decisions regarding oncological and reconstructive options.

Abbrev
PMRT: post-mastectomy radiotherapy, PRO: patient-reported outcome

Take-home message
This multicentre, prospective cohort study of 732 patients undergoing implant-based breast reconstruction demonstrates worse 18-month patient-reported outcomes in women who received post-mastectomy radiotherapy than those who did not. These data should be discussed with patients to help them make informed decisions about reconstructive surgery.
O75: SINGLE CENTRE EXPERIENCE OF SIROLIMUS THERAPY IN HEAD AND NECK VASCULAR MALFORMATIONS
Authors: Pang C , Evans N , Papadopoulou A , Khalifa M , Tsui J , Hamilton G , Lim CS , Brookes J 
Published: April 2021

Abstract

Introduction
To assess the efficacy and safety of Sirolimus in the treatment of low-flow head and neck (H&N) vascular malformations

Method
Patients who presented to our tertiary referral clinic were assessed for eligibility. Suitable patients were commenced on Sirolimus at 0.8 mg/m2, administered orally twice daily, which was approved by our trust Drug and Therapeutic Committee. Patients were reviewed on a monthly basis for a total of six months with an additional one-month review to check for effects upon ceasing treatment. Efficacy and safety were measured through functional and radiological response, laboratory investigations and quality of life questionnaire (36-Item Short Form Health Survey (SF-36), Hospital Anxiety and Depression Scale (HADS) and Visual Analogue Score for Pain (VAS-P)).

Result
Seven patients (mean age 39 years, range 23-65 years) were recruited. One patient did not complete treatment due to intolerable side effects. All patients had a partial response with no patients showing disease progression or complete response. All post-treatment MRI scans showed stable disease with five patients demonstrating a decrease in lesion volume. Five patients reported return of symptoms at one-month post review upon discontinuation of treatment. No statistical significance (P&gt;0.05) in all eight domains of SF-36, HADS, VAS-P and radiological vascular lesion volume between pre- and post-treatment. Most common reported side effects were mouth ulcers (n=2) and metabolic/laboratory abnormality (n=2)

Conclusion
Sirolimus is an effective and safe treatment for patients with complicated low-flow H&N vascular malformations. This provides an alternative treatment where interventional therapy is considered to be limited or challenging.

Take-home message
Sirolimus is an effective and safe treatment option for patients with complicated low-flow head and neck vascular malformations where interventional therapy is limited or challenging.
O77: DOES MESH IMPROVE PATIENT SATISFACTION AND HEALTH-RELATED QUALITY OF LIFE AFTER IMPLANT-BASED BREAST RECONSTRUCTION? A MULTICENTRE PROSPECTIVE COHORT STUDY
Authors: Sewart E , Turner N , Conroy EJ , Cutress R , Skillman J , Whisker L , Thrush S , Barnes N , Holcombe C , Potter S 
Published: April 2021

Abstract

Introduction
Biological and synthetic meshes may improve outcomes of immediate IBBR by facilitating single-stage direct-to-implant procedures. However, high-quality supporting evidence is limited, particularly regarding PROs.

Method
2108 consecutive women undergoing IBBR at 81 centres were prospectively recruited between 2014-2016. Demographic, operative, oncological and 3-month complication data were collected. An 18-month questionnaire assessed PROs using the validated BREAST-Q and a five-point Likert scale rating of overall reconstructive outcome.
The impacts of different IBBR techniques on PROs were explored using mixed-effects regression models adjusted for clinically-relevant confounders and including a random effect to account for clustering by centre. The reference group was two- stage submuscular reconstruction without mesh.

Result
1470 participants consented to receive the questionnaire and 891 completed it. 67 patients underwent two-stage submuscular reconstruction; 764 patients received subpectoral reconstructions with biological mesh (n=495) synthetic mesh (n=95) or dermal sling (n=174). 14 patients underwent prepectoral reconstructions (introduced late in the study).
Compared with two-stage reconstructions, no differences in PROs were seen in biological or synthetic mesh-assisted or dermal sling procedures (p&gt;0.05). However, prepectoral IBBR patients reported better satisfaction with breasts (difference=6.63, 95% confidence interval[1.65–11.61], p=0.009). Outcomes were similar to those in the NMBRA 2008/9 cohort, which included submuscular procedures only.

Conclusion
This study does not suggest that mesh improves PROs of IBBR. It provides early data supporting improved satisfaction with breasts following prepectoral reconstructions. Future trials are needed to robustly evaluate prepectoral techniques.

Abbrev
IBBR: implant-based breast reconstruction, PRO: patient-reported outcome, NMBRA: National Mastectomy and Breast Reconstruction Audit

Take-home message
Although mesh-assisted techniques have become widely adopted, this large, prospective, multicentre cohort study does not suggest that mesh improves patient-reported outcomes of implant-based breast reconstruction compared with standard submuscular techniques. However, it provides early data to support improved satisfaction with breasts in the prepectoral setting, which now requires robust evaluation.
P9: MANAGEMENT OF ESOPHAGEAL FOOD BOLUS OBSTRUCTION AT A UNIVERSITY TEACHING HOSPITAL – A RETROSPECTIVE ANALYSIS
Authors: Hashmi ZZ , Ahmed R , Alijarad F , Madanur M , Razzaq Z , Majeed M , Bughio M , Cagney D , Aakif M , Mustafa H , Amin A , Khan A , Aftab F , Corrigan M , Redmond HP 
Published: April 2021

Abstract

Introduction
Despite the fact that esophageal food bolus obstruction is a common surgical problem, there are no clear guidelines on its management. Medical treatment with Buscopan and Glucagon is mostly in-effective, requiring a therapeutic Oesophago-Gastro-Duodenoscopy (OGD).

Method
All consecutive cases of food bolus obstructions (FBO) presenting to the Emergency Department (ED) for 18 month period between 01/01/2018 and 30/06/2019 were retrospectively reviewed.

Result
A total of 30 patients were admitted with food bolus obstruction via ED (1.67 per month). Females (67%) constituted most of these patients. Average age was 55 with range of 19-83. 84% of patients presented with Dysphagia, while Odynophagia (10%) and chest pain (6%) were other presenting symptoms. Average duration of symptoms was 17 hours (Range 2 – 48 hours). 44% of patients had OGD done under sedation while others (56%) had under General Anaesthesia (GA). In 70% of cases, food bolus was pushed into stomach, while it was retrieved out in 20%. In 10%, it had already spontaneously passed in stomach on OGD. The etiology of FBO was inflammatory in 60% cases, while an esophageal stricture was seen in 10% only. In 30% cases no cause of FBO was identified. Post-OGD length of stay was on average 1.15 days (range 12 hours – 7 days). 2 patients had aspiration pneumonia prolonging their hospital stay, there was no esophageal perforation or mortality.

Conclusion
Esophageal food bolus obstruction is a common surgical problem, OGD under GA is a safe recommended procedure, which often picks up an underlying pathology.

Take-home message
Esophageal food bolus obstruction is a common surgical problem, OGD under GA is a safe recommended procedure, which often picks up an underlying pathology.
Populism in an Identity Framework: A Feedback Model
Authors: Reveilhac Maud , Morselli Davide 
Published: April 2021

Abstract
Drawing upon the social psychology concept of identity entrepreneurs (Haslam et al., 2010), we develop a feedback model between politicians and the public that strongly emphasizes the circumstances in which public opinion may facilitate populist discursive elements and politics. We thus consider the success of populism as neither inherently driven by political leaders nor primarily driven by increasing populist attitudes in the public and acknowledge the fragmented nature of the populist discourse emphasized by recent studies. We raise the question of whether there is a populist collective identity, which is accountable in terms of populist rhetorical elements, and how it changes over time. To answer this question, we apply the proposed framework to the case of the rise and development of the populist discourse in Switzerland while accounting for its dynamic adaptation to raising public concerns and for the influence of its core rhetorical elements on individual voting behavior.
quemao, a Drosophila Bristle Locus, Encodes Geranylgeranyl Pyrophosphate Synthase
Authors: Lai Chaoqiang , McMahon Robert , Young Chi , Mackay Trudy F C , Langley Charles H 
Published: April 2021

Abstract
The quemao (qm) locus of Drosophila melanogaster is characterized by a P-element-associated mutant lacking most of the large bristles on the thorax and by several EMS-induced recessive lethals. quemao was cloned using a transposon tagging strategy. P-element-mediated transformation demonstrated that the cloned qm DNA sequence (from the 65F cytological region) rescues the mutant phenotype. A 2.3-kb qm transcript was identified by Northern blot analysis by sequencing of the isolated qm cDNA clones and by 5′ rapid amplification cDNA end (RACE). The predicted amino acid sequence (338 residues) of the coding region of the qm transcript shares 42, 31, 13, 20, and 12% identical amino acid sequences with the geranylgeranyl pyrophosphate synthase (GGPPS) of fungi, yeast, plants, archaebacteria, and eubacteria, respectively. It also contains five highly conserved domains common among all known isoprenyl pyrophosphate synthases. The P element associated with the original qm mutant is inserted in the 5′ untranslated region of the transcript. An EMS-induced qm nonsense mutation at the 12th codon leads to recessive lethality at the first larval instar, indicating the essential role of qm in the isoprenoid biosynthesis of insects.
Possible Assortment of a1 and a2 Region Gene Segments in Human MHC Class I Molecules
Authors: Johnson George , Wu Tai T 
Published: April 2021

AbstractUsing pair-wise comparison of aligned nucleotide sequences of distinct and complete human MHC class I molecules, we have constructed triangular tables to study the similarities and differences of various a1 (exon 2) and a2 (exon 3) region sequences. There are two HLA-A (A*6901 and A*6601) and 13 HLA-B (B*4201, B*8101, B*4102, B*4801, B*4007, B*4001, B*4802, Dw53, B*4406, B*4402, B*3901, B*1514 and B*3702) sequences that have identical a1 sequences with other known MHC class I molecules, while their a2 sequences are the same as those of different ones. Of these 15, A*6901, B*4001 and B*4802 have previously been suggested as the results of recombination between A*6801 and A*0201, B*4101 and B*8101, and B*4801 and B*3501, respectively. However, many other sequences can also be used to generate them by recombination. Furthermore, their reciprocal products have never been identified. Thus, gene conversion has subsequently been suggested as an alternative. Another possible genetic mechanism for generating these nucleotide sequence similarities can be assortment, or that some gene segments can be duplicated or multiplicated to be used in different human MHC class I molecules. Interestingly, this genetic mechanism is probably absent for the generation of different mouse MHC class I molecules.
The Maize Regulatory Gene B-Peru Contains a DNA Rearrangement That Specifies Tissue-Specific Expression Through Both Positive and Negative Promoter Elements
Authors: Selinger David A , Lisch Damon , Chandler Vicki L 
Published: April 2021

Abstract
The B-Peru allele of the maize b regulatory gene is unusual relative to most b alleles in that it is expressed in the aleurone layer of the seed. It is also expressed in a subset of plant vegetative tissues. Transgenic maize plants containing the B-Peru gene with the first 710 bases of upstream sequence conferred the same levels of aleurone expression as nontransgenic B-Peru plants, but no pigment was made in vegetative tissues. Transient transformation assays in aleurone tissue localized the aleurone-specific promoter to the first 176 bases of the B-Peru upstream region and identified two critically important regions within this fragment. Mutation of either region alone reduced expression greater than fivefold. Surprisingly, the double mutation actually increased expression to twice the native promoter level. Our results suggest that these two critical sequences, which lie close together in the promoter, may form a negative regulatory element. Several lines of evidence suggest that the B-Peru promoter arose through the translocation of an existing aleurone-specific promoter to the b locus. Immediately upstream of the aleurone-specific promoter elements and in the opposite orientation to the b coding sequence is a pseudogene sequence with strong similarity to a known class of proteins. Our findings that novel aleurone-specific promoter sequences of the B-Peru transcription factor are found adjacent to part of another gene in a small insertion are quite unexpected and have interesting evolutionary implications.
Genetic Analysis of Organ Fusion in Arabidopsis thaliana
Authors: Lolle Susan J , Hsu Wendy , Pruitt Robert E 
Published: April 2021

Abstract
Postgenital organ fusion occurs most commonly during reproductive development and is important in many angiosperms during genesis of the carpel. Although a number of mutants have been described that manifest ectopic organ fusion, little is known about the genes involved in regulating this process. In this article we describe the characterization of a collection of 29 Arabidopsis mutants showing an organ fusion phenotype. Mapping and complementation analyses revealed that the mutant alleles define nine different loci distributed throughout the Arabidopsis genome. Multiple alleles were isolated for the four complementation groups showing the strongest organ fusion phenotype while the remaining five complementation groups, all of which show only weak floral organ fusion, have a single representative allele. In addition to fusion events between aerial parts of the shoot, some mutants also show abnormal ovule morphology with adjacent ovules joined together at maturity. Many of the fusion mutants isolated have detectable differences in the rate at which chlorophyll can be extracted; however, in one case no difference could be detected between mutant and wild-type plants. In three mutant lines pollen remained unresponsive to contact with the mutant epidermis, demonstrating that organ fusion and pollen growth responses can be genetically separated from one another.
Activation of Latent Transgenes in Arabidopsis Using a Hybrid Transcription Factor
Authors: Guyer Dave , Tuttle Ann , Rouse Sabrina , Volrath Sandra , Johnson Marie , Potter Sharon , Görlach Jörn , Goff Steve , Crossland Lyle , Ward Eric 
Published: April 2021

Abstract
A hybrid transcription factor comprising a fusion of the DNA-binding domain of Saccharomyces cerevisiae GAL4 and the transcription activation domain of maize C1 was expressed in stably transformed Arabidopsis. Additional transgenic lines were created containing test genes controlled by a synthetic promoter consisting of concatemeric copies of the cis-acting site recognized by GAL4 (UASG) fused to a minimal promoter. The GAL4/C1 effector line was crossed to two lines containing a synthetic promoter/GUS fusion. Both histochemical staining and GUS activity assays indicate strong activation of GUS expression was achieved only after crossing. The GAL4/C1 effector line was also crossed to 15 lines containing a synthetic promoter/antisense adenylosuccinate synthetase gene. Severely retarded growth, and in some cases lethality, was observed in 40% of the F1 lines. This system of activation by crossing is generally useful for activating expression of test transgenes.
Members of the Arabidopsis Actin Gene Family Are Widely Dispersed in the Genome
Authors: McKinney E C , Meagher R B 
Published: April 2021

Abstract
Plant genomes are subjected to a variety of DNA turnover mechanisms that are thought to result in rapid expansion and presumable contraction of gene copy number. The evolutionary history of the 10 actin genes in Arabidopsis thaliana is well characterized and can be traced to the origin of vascular plant genomes. Knowledge about the genomic position of each actin gene may be the key to tracing landmark genomic duplication events that define plant families or genera and facilitate further mutant isolation. All 10 actin genes were mapped by following the segregation of cleaved amplified polymorphisms between two ecotypes and identifying actin gene locations among yeast artificial chromosomes. The Arabidopsis actin genes are widely dispersed on four different chromosomes (1, 2, 3, and 5). Even the members of three closely related and recently duplicated pairs of actin genes are unlinked. Several other cytoskeletal genes (profilins, tubulins) that might have evolved in concert with actins were also mapped, but showed few patterns consistent with that evoulutionary history. Thus, the events that gave rise to the actin gene family have been obscured either by the duplication of very small genic fragments or by extensive rearrangement of the genome.