The DNA damage response in advanced ovarian cancer: functional analysis combined with machine learning identifies signatures that correlate with chemotherapy sensitivity and patient outcome.

BACKGROUND: Ovarian cancers are hallmarked by chromosomal instability. New therapies deliver improved patient outcomes in relevant phenotypes, however therapy resistance and poor long-term survival signal requirements for better patient preselection. An impaired DNA damage response (DDR) is a major chemosensitivity determinant. Comprising five pathways, DDR redundancy is complex and rarely studied alongside chemoresistance influence from mitochondrial dysfunction. We developed functional assays to monitor DDR and mitochondrial states and trialled this suite on patient explants. METHODS: We profiled DDR and mitochondrial signatures in cultures from 16 primary-setting ovarian cancer patients receiving platinum chemotherapy. Explant signature relationships to patient progression-free (PFS) and overall survival (OS) were assessed by multiple statistical and machine-learning methods. RESULTS: DR dysregulation was wide-ranging. Defective HR (HRD) and NHEJ were near-mutually exclusive. HRD patients (44%) had increased SSB abrogation. HR competence was associated with perturbed mitochondria (78% vs 57% HRD) while every relapse patient harboured dysfunctional mitochondria. DDR signatures classified explant platinum cytotoxicity and mitochondrial dysregulation. Importantly, explant signatures classified patient PFS and OS. CONCLUSIONS: Whilst individual pathway scores are mechanistically insufficient to describe resistance, holistic DDR and mitochondrial states accurately predict patient survival. Our assay suite demonstrates promise for translational chemosensitivity prediction.

The impact of obesity and bariatric surgery on the immune microenvironment of the endometrium.

BACKGROUND: The incidence of endometrial cancer is rising in parallel with the obesity epidemic. Obesity increases endometrial cancer risk and weight loss is protective, but the underlying mechanisms are incompletely understood. We hypothesise that the immune microenvironment may influence susceptibility to malignant transformation in the endometrium. The aim of this study was to measure the impact of obesity and weight loss on the immunological landscape of the endometrium. METHODS: We conducted a prospective cohort study of women with class III obesity (body mass index, BMI ≥ 40 kg/m2) undergoing bariatric surgery or medically-supervised low-calorie diet. We collected blood and endometrial samples at baseline, and two and 12 months after weight loss intervention. Serum was analysed for inflammatory markers CRP, IL-6 and TNF-α. Multiplex immunofluorescence was used to simultaneously identify cells positive for immune markers CD68, CD56, CD3, CD8, FOXP3 and PD-1 in formalin-fixed paraffin-embedded endometrial tissue sections. Kruskal-Wallis tests were used to determine whether changes in inflammatory and immune biomarkers were associated with weight loss. RESULTS: Forty-three women with matched serum and tissue samples at all three time points were included in the analysis. Their median age and BMI were 44 years and 52 kg/m2, respectively. Weight loss at 12 months was greater in women who received bariatric surgery (n = 37, median 63.3 kg) than low-calorie diet (n = 6, median 12.8 kg). There were significant reductions in serum CRP (p = 3.62 × 10-6, r = 0.570) and IL-6 (p = 0.0003, r = 0.459), but not TNF-α levels, with weight loss. Tissue immune cell densities were unchanged except for CD8+ cells, which increased significantly with weight loss (p = 0.0097, r = -0.323). Tissue CD3+ cell density correlated negatively with systemic IL-6 levels (p = 0.0376; r = -0.318). CONCLUSION: Weight loss is associated with reduced systemic inflammation and a recruitment of protective immune cell types to the endometrium, supporting the concept that immune surveillance may play a role in endometrial cancer prevention.

Divergence in floral scent and morphology, but not thermogenic traits, associated with pollinator shift in two brood-site-mimicking Typhonium (Araceae) species.

BACKGROUND: Flowers which imitate insect oviposition sites probably represent the most widespread form of floral mimicry, exhibit the most diverse floral signals and are visited by two of the most speciose and advanced taxa of insect - beetles and flies. Detailed comparative studies on brood-site mimics pollinated exclusively by each of these insect orders are lacking, limiting our understanding of floral trait adaptation to different pollinator groups in these deceptive systems. METHODS: Two closely related and apparent brood-site mimics, Typhonium angustilobum and T. wilbertii (Araceae) observed to trap these distinct beetle and fly pollinator groups were used to investigate potential divergence in floral signals and traits most likely to occur under pollinator-mediated selection. Trapped pollinators were identified and their relative abundances enumerated, and thermogenic, visual and chemical signals and morphological traits were examined using thermocouples and quantitative reverse transcription-PCR, reflectance, gas chromatography-mass spectrometry, floral measurements and microscopy. KEY RESULTS: Typhonium angustilobum and T. wilbertii were functionally specialized to trap saprophagous Coleoptera and Diptera, respectively. Both species shared similar colour and thermogenic traits, and contained two highly homologous AOX genes (AOX1a and AOX1b) most expressed in the thermogenic tissue and stage (unlike pUCP). Scent during the pistillate stage differed markedly - T. angustilobum emitted a complex blend of sesquiterpenes, and T. wilbertii, a dung mimic, emitted high relative amounts of skatole, p-cresol and irregular terpenes. The species differed significantly in floral morphology related to trapping mechanisms. CONCLUSIONS: Functional specialization and pollinator divergence were not associated with differences in anthesis rhythm and floral thermogenic or visual signals between species, but with significant differences in floral scent and morphological features, suggesting that these floral traits are critical for the attraction and filtering of beetle or fly pollinators in these two brood-site mimics.

Analysis of EURADOS neutron intercomparison results according to new ISO standards criteria.

The European Radiation Dosimetry Group has carried out several different types of intercomparison (IC) exercises in the past that qualify as proficiency tests for different dosimetry systems and types of radiation. The first neutron dosemeter IC was held in 2012 (IC2012n) and was followed by a second in 2017/2018 (IC2017n). In sum, 31 Individual Monitoring Services (IMSs) entered 34 dosimetry systems in IC2012n, and 32 IMSs entered 33 dosimetry systems for IC2017n. Such exercises provided a rare opportunity to see how neutron dosemeters perform. For the IC2012n exercise, there were no applicable performance standards for neutron personal dosemeters. ISO/TC85/SC2 updated the ISO Standard 14146 in 2018 (ISO 14146:2018. Radiation protection-Criteria and performance limits for the periodic evaluation of dosimetry services) to include neutron dosimetry. It was thus possible to analyse the IC2017n exercise in accordance with the requirements given by this new standard. It is now of interest to reanalyse the results of IC2012n to quantify any modifications to the conclusions.

Immune checkpoint inhibitors efficacy across solid cancers and the utility of PD-L1 as a biomarker of response: a systematic review and meta-analysis.

Background: Immune checkpoint inhibitors (ICPI) are a tumor agnostic treatment. However, trials of their use have been site specific. Here we summarize the trial data and explore the utility of programmed death-ligand 1 (PD-L1) expression as a biomarker to direct their pan-cancer use. Method: A systematic review of literature, following PRISMA guidelines, was performed. Medline, Embase, Cochrane CENTRAL, NHS Health and Technology, and Web of Science were searched from their conception to June 2022 limited to the English language. The search terms and method were devised by a specialist medical librarian. Studies were limited to adults with solid cancers (excluding melanomas) treated with ICPIs. Only phase III randomized control trials (RCT) were included. The primary outcome was overall survival and secondary outcomes were progression free survival, PD-L1 expression, quality of life outcomes and adverse event data. Where present in eligible clinical trials, hazard ratios (HR), risk ratios (RR), standard error (SE) and 95% confidence intervals (CI) were extracted or calculated. Heterogeneity across studies was described with the use of an I2 score (Low: 25, 50%: moderate, 75% low heterogeneity). HR pools inverse variance methods were adopted by Random Effects (RE). Means were standardized across any heterogenous scale limits. Results: In total 46,510 participants were included in the meta-analysis. Overall, meta-analysis favored the use of ICPIs with an overall survival (OS) HR of 0.74 (95% CI 0.71 to 0.78). Lung cancers showed the most benefit in OS [HR 0.72 (95% 0.66-0.78)] followed by head and neck cancers [HR 0.75 (95% CI 0.66-0.84)] and gastroesophageal junction cancers [HR 0.75 (95% CI 0.61-0.92)]. ICPIs seem to be efficacious at both primary presentation and recurrence [OS HR 0.73 (95% CI 0.68-0.77)] vs. [OS HR 0.79 (95% CI 0.72 to 0.87)] respectively. Interestingly, subgroup analysis comparing studies in which most cancers demonstrated PD-L1 expression vs. those studies in which a minority of cancer demonstrated PD-L1 expression reported similar effect of ICPI use on OS; oddly the data favored ICPI use in studies with a minority of PD-L1 expression. Specifically, studies with minority PD-L1 expression had an HR 0.73 (95% CI 0.68-0.78) vs. studies with majority PD-L1 expression HR 0.76 (95% CI 0.70-0.84). This was maintained even when studies exploring the same cancer site were directly compared. Subgroup analysis was performed comparing the impact on OS subdivided by the specific ICPI used. Where meta-analysis was performed, Nivolumab led to the greatest impact [HR 0.70 (95% CI 0.64-0.77)] with Avelumab failing to reach significance [HR 0.93 (95% CI 0.80-1.06)]. However, overall heterogenicity was high (I2 = 95%). Finally, the use of ICPIs led to an improved side effect profile when compared with standard chemotherapy [RR 0.85 (95% CI 0.73-0.98)]. Conclusion: ICPIs improve survival outcomes in all cancer types. These effects are seen in the primary, recurrent, chemotherapy sensitive, chemotherapy resistant disease. These data support their use as a tumor agnostic therapy. Furthermore, they are well tolerated. However, PD-L1 as a biomarker for the targeting of ICPI use seems problematic. Other biomarkers such as mismatch repair or tumor mutational burden should be explored in randomized trials. In addition, there are still limited trials looking at ICPI use outside of lung cancer.

Programme costs for introducing age/gestation-based universal influenza vaccine schedules for young children and pregnant women in Hong Kong.

BACKGROUND: Hong Kong experiences year-round influenza activity with winter and summer peaks. The government's Vaccination Subsidy Scheme (VSS) provides vaccine to high-risk groups prior to the larger winter peak. The VSS is predominantly administered through the private sector. This study aimed to cost the two theoretical routine influenza vaccination schedules using both northern and southern hemisphere vaccines, administered according to child's age and women's gestation, from a governmental perspective; and compare these costs to the costs of government's seasonal VSS assuming equivalent coverage estimates to determine the budget impacts of these influenza vaccination programmes in Hong Kong. METHODS: We used the World Health Organization's Flutool Plus to estimate the incremental annual costs for immunising young children aged 6 months to 2 years and pregnant women with influenza vaccine during 2021, assuming the latter group accesses the public system for some antenatal care. Inputs were based on literature review, publicly available data and expert opinions. Sensitivity analyses were done with various coverage rates and vaccine costs. RESULTS: The annual incremental cost (including vaccine price) to vaccinate young children with three doses of influenza vaccine during the first two years of life was estimated at USD 1,175,146 (per-dose-cost of USD 10.55) at 75% coverage while that to vaccinate pregnant women with one dose at 60% coverage was estimated at USD 398,555 (per-dose-cost of USD 13.39). Across a range of sensitivity analyses we predict that routine year-round schedules could be cost-saving to the government compared to the VSS. Implementing routine immunisation to both risk groups equates to USD 1,573,701, i.e., 0.012% of Hong Kong's annual healthcare spending. CONCLUSION: Proposed year-round universal schedules providing influenza immunisation according to the child's age or the woman's gestation are predicted to be cost-saving compared to the current seasonally administered subsidised vaccine programme.

Histological and Somatic Mutational Profiles of Mismatch Repair Deficient Endometrial Tumours of Different Aetiologies.

BACKGROUND: Mismatch repair deficient (MMRd) tumours may arise from somatic events acquired during carcinogenesis or in the context of Lynch syndrome (LS), an inherited cancer predisposition condition caused by germline MMR pathogenic variants. Our aim was to explore whether sporadic and hereditary MMRd endometrial cancers (EC) display distinctive tumour biology. METHODS: Clinically annotated LS-EC were collected. Histological slide review was performed centrally by two specialist gynaecological pathologists. Mutational analysis was by a bespoke 75- gene next-generation sequencing panel. Comparisons were made with sporadic MMRd EC. Multiple correspondence analysis was used to explore similarities and differences between the cohorts. RESULTS: After exclusions, 135 LS-EC underwent independent histological review, and 64 underwent mutational analysis. Comparisons were made with 59 sporadic MMRd EC. Most tumours were of endometrioid histological subtype (92% LS-EC and 100% sporadic MMRd EC, respectively, p = NS). Sporadic MMRd tumours had significantly fewer tumour infiltrating lymphocytes (p ≤ 0.0001) and showed more squamous/mucinous differentiation than LS-EC (p = 0.04/p = 0.05). PTEN mutations were found in 88% sporadic MMRd and 61% LS-EC, respectively (p < 0.001). Sporadic MMRd tumours had significantly more mutations in PDGFRA, ALK, IDH1, CARD11, CIC, MED12, CCND1, PTPN11, RB1 and KRAS, while LS-EC showed more mutations affecting SMAD4 and ARAF. LS-EC showed a propensity for TGF-ß signalling disruption. Cluster analysis found that wild type PTEN associates predominantly with LS-EC, whilst co-occurring mutations in PTEN, PIK3CA and KRAS predict sporadic MMRd EC. CONCLUSIONS: Whilst MMRd EC of hereditary and sporadic aetiology may be difficult to distinguish by histology alone, differences in infiltrating immune cell counts and mutational profile may predict heterogenous responses to novel targeted therapies and warrant further study.

Analysis of human total antibody repertoires in TIF1γ autoantibody positive dermatomyositis.

We investigate the accumulated microbial and autoantigen antibody repertoire in adult-onset dermatomyositis patients sero-positive for TIF1γ (TRIM33) autoantibodies. We use an untargeted high-throughput approach which combines immunoglobulin disease-specific epitope-enrichment and identification of microbial and human antigens. We observe antibodies recognizing a wider repertoire of microbial antigens in dermatomyositis. Antibodies recognizing viruses and Poxviridae family species are significantly enriched. The identified autoantibodies recognise a large portion of the human proteome, including interferon regulated proteins; these proteins cluster in specific biological processes. In addition to TRIM33, we identify autoantibodies against eleven further TRIM proteins, including TRIM21. Some of these TRIM proteins share epitope homology with specific viral species including poxviruses. Our data suggest antibody accumulation in dermatomyositis against an expanded diversity of microbial and human proteins and evidence of non-random targeting of specific signalling pathways. Our findings indicate that molecular mimicry and epitope spreading events may play a role in dermatomyositis pathogenesis.

Redox-active tetrathiafulvalene and dithiolene compounds derived from allylic 1,4-diol rearrangement products of disubstituted 1,3-dithiole derivatives.

We present a series of compounds by exploiting the unusual 1,4-aryl shift observed for electron-rich 1,3-dithiole-2-thione and tetrathiafulvalene (TTF) derivatives in the presence of perchloric acid. The mechanistic features of this rearrangement are discussed since this synthetic strategy provides an alternative route for the synthesis and functionalisation of sulfur rich compounds including redox active compounds of TTFs, and a Ni dithiolene.

Controlling the conformational changes in donor-acceptor [4]-dendralenes through intramolecular charge-transfer processes.

The synthesis of two [4]-dendralene compounds incorporating thiophene-(p-nitrophenyl) donor-acceptor units is presented. The dendralenes adopt two different conformers in solution and solid state and the transformation between the structures can be controlled by light and heat. The electron-donating components of the dendralenes are represented by bromothienyl (in 13) and ethylenedioxythiophene(EDOT)-thienyl (in 15) end-groups. The most facile transformation involves the isomerisation of donor-acceptor conjugated systems (a conformers) into structures in which only the thiophenes are conjugated (b conformers), and this process is driven by ambient light. The structures of the two conformers of compound 13 are confirmed by single-crystal X-ray diffraction studies and the structural changes in both compounds have been monitored by 1H NMR spectroscopy and absorption studies. The transformations were found to be first-order processes with rate constants of k=0.0027 s(-1) and k=0.00022 s(-1) for 13 and 15, respectively. Density functional theory calculations at the B3LYP/6-31G* level give credence to the proposed mechanism for the a-->b conversion, which involves photoinduced intramolecular charge transfer (ICT) as the key step. The EDOT derivative (15) can be polymerised by electrochemical oxidation and a combination of cyclic voltammetry and UV/Vis spectroelectrochemical experiments indicate that the a conformer can be trapped and stabilised in the solid state.

Blocks of limited haplotype diversity revealed by high-resolution scanning of human chromosome 21.

Global patterns of human DNA sequence variation (haplotypes) defined by common single nucleotide polymorphisms (SNPs) have important implications for identifying disease associations and human traits. We have used high-density oligonucleotide arrays, in combination with somatic cell genetics, to identify a large fraction of all common human chromosome 21 SNPs and to directly observe the haplotype structure defined by these SNPs. This structure reveals blocks of limited haplotype diversity in which more than 80% of a global human sample can typically be characterized by only three common haplotypes.

The UCSC genome browser database: update 2007.

The University of California, Santa Cruz Genome Browser Database contains, as of September 2006, sequence and annotation data for the genomes of 13 vertebrate and 19 invertebrate species. The Genome Browser displays a wide variety of annotations at all scales from the single nucleotide level up to a full chromosome and includes assembly data, genes and gene predictions, mRNA and EST alignments, and comparative genomics, regulation, expression and variation data. The database is optimized for fast interactive performance with web tools that provide powerful visualization and querying capabilities for mining the data. In the past year, 22 new assemblies and several new sets of human variation annotation have been released. New features include VisiGene, a fully integrated in situ hybridization image browser; phyloGif, for drawing evolutionary tree diagrams; a redesigned Custom Track feature; an expanded SNP annotation track; and many new display options. The Genome Browser, other tools, downloadable data files and links to documentation and other information can be found at http://genome.ucsc.edu/.

Aphids Influence Soil Fungal Communities in Conventional Agricultural Systems.

Arbuscular mycorrhizal fungi (AMF) form symbioses with the roots of most plant species, including cereals. AMF can increase the uptake of nutrients including nitrogen (N) and phosphorus (P), and of silicon (Si) as well as increase host resistance to various stresses. Plants can simultaneously interact with above-ground insect herbivores such as aphids, which can alter the proportion of plant roots colonized by AMF. However, it is unknown if aphids impact the structure of AMF communities colonizing plants or the extent of the extraradical mycelium produced in the soil, both of which can influence the defensive and nutritional benefit a plant derives from the symbiosis. This study investigated the effect of aphids on the plant-AMF interaction in a conventionally managed agricultural system. As plants also interact with other soil fungi, the non-AMF fungal community was also investigated. We hypothesized that aphids would depress plant growth, and reduce intraradical AMF colonization, soil fungal hyphal density and the diversity of AM and non-AM fungal communities. To test the effects of aphids, field plots of barley enclosed with insect proof cages were inoculated with Sitobion avenae or remained uninoculated. AMF specific and total fungal amplicon sequencing assessed root fungal communities 46 days after aphid addition. Aphids did not impact above-ground plant biomass, but did increase the grain N:P ratio. Whilst aphid presence had no impact on AMF intraradical colonization, soil fungal hyphal length density, or AMF community characteristics, there was a trend for the aphid treatment to increase vesicle numbers and the relative abundance of the AMF family Gigasporaceae. Contrary to expectations, the aphid treatment also increased the evenness of the total fungal community. This suggests that aphids can influence soil communities in conventional arable systems, a result that could have implications for multitrophic feedback loops between crop pests and soil organisms across the above-below-ground interface.

Distinct Immunological Landscapes Characterize Inherited and Sporadic Mismatch Repair Deficient Endometrial Cancer.

Around 30% of endometrial cancers (EC) are mismatch repair (MMR) deficient, mostly as a consequence of mutations acquired during tumorigenesis, but a significant minority is caused by Lynch syndrome (LS). This inherited cancer predisposition syndrome primes an anti-cancer immune response, even in healthy carriers. We sought to explore the intra-tumoral immunological differences between genetically confirmed LS-associated MMR-deficient (MMRd), sporadic MMR-deficient, and MMR-proficient (MMRp) EC. Endometrial tumors from women with known LS were identified (n = 25). Comparator tumors were recruited prospectively and underwent microsatellite instability (MSI) testing, immunohistochemistry (IHC) for MMR expression and MLH1 methylation testing. Those found to have MLH1 hypermethylation formed the sporadic MMR-deficient group (n = 33). Those found to be mismatch repair proficient and microsatellite stable formed the MMR-proficient group (n = 35). A fully automated monoplex IHC panel was performed on sequential formalin-fixed paraffin-embedded tumor sections to identify CD3+, CD8+, CD45RO+, FoxP3+, and PD-1+ immune cells, and PD-L1 expression by tumor/immune cells. Two independent observers quantified immune marker expression at the tumor center and invasive margin. Mean and overall compartmental T-cell counts generated standard (binary: Low/High) and higher resolution (quaternary: 0-25, 25-50, 50-75, 75-100%) immune scores, which were used as explanatory features in neural network, support vector machine, and discriminant predictive modeling. Overall T-cell counts were significantly different between the three cohorts: CD3+ (p = <0.0001), CD8+ (p = <0.0001), CD45RO+ (<0.0001), FoxP3+ (p = <0.0001), and PD1+ (p = <0.0001), with LS-associated MMR-deficient tumors having highest infiltrations. There were significant differences in CD8+ (p = 0.02), CD45RO+ (p = 0.007), and PD-1+ (p = 0.005) T-cell counts at the invasive margin between LS-associated and sporadic MMR-deficient tumors, but not between sporadic MMR-deficient and MMR-proficient tumors. Predictive modeling could accurately determine MMR status based on CD8+ T-cell counts within the tumor center alone. This study shows that LS-associated and sporadic MMR-deficient EC are distinct immunological entities, which has important implications for treatment and prognosis.

The UCSC Genome Browser Database: update 2006.

The University of California Santa Cruz Genome Browser Database (GBD) contains sequence and annotation data for the genomes of about a dozen vertebrate species and several major model organisms. Genome annotations typically include assembly data, sequence composition, genes and gene predictions, mRNA and expressed sequence tag evidence, comparative genomics, regulation, expression and variation data. The database is optimized to support fast interactive performance with web tools that provide powerful visualization and querying capabilities for mining the data. The Genome Browser displays a wide variety of annotations at all scales from single nucleotide level up to a full chromosome. The Table Browser provides direct access to the database tables and sequence data, enabling complex queries on genome-wide datasets. The Proteome Browser graphically displays protein properties. The Gene Sorter allows filtering and comparison of genes by several metrics including expression data and several gene properties. BLAT and In Silico PCR search for sequences in entire genomes in seconds. These tools are highly integrated and provide many hyperlinks to other databases and websites. The GBD, browsing tools, downloadable data files and links to documentation and other information can be found at http://genome.ucsc.edu/.

ADDITIONAL CHARACTERISATION OF THE THERMAL NEUTRON PILE AT THE NATIONAL PHYSICAL LABORATORY, UK.

As part of its wide-ranging neutron metrology capabilities, the National Physical Laboratory in the UK has a thermal neutron facility in which accelerator-produced neutrons are moderated within a large assembly or pile of graphite bricks. The neutron field has previously been well characterised in terms of the fluence rate and energy spectrum at various irradiation positions. However, recent changes to the structure (e.g. enlarging the central irradiation cavity) have prompted a renewal and extension of this work. We have also used Monte Carlo modelling to improve our understanding of the pile's performance.

Results of field trials using the NPL simulated reactor neutron field facility.

The NPL simulated reactor neutron field facility provides neutron spectra similar to those found in the environs of UK gas-cooled reactors. Neutrons are generated by irradiating a thick lithium-alloy target with monoenergetic protons between 2.5 and 3.5 MeV (depending on the desired spectrum), and then moderated by a 40-cm diameter sphere of heavy water. This represents an extremely soft workplace field, with a mean neutron energy of 25 keV and, more significantly, a mean fluence to ambient dose equivalent conversion coefficient of the order of 20 pSv cm(2), approximately 20 times lower than those of the ISO standard calibration sources (252)Cf and (241)Am-Be. Results of field trials are presented, including readings from neutron spectrometers, personal dosimeters (active and passive) and neutron area survey meters, and issues with beam monitoring are discussed.

Measurement and calculation of the emission anisotropy of an X1 252Cf neutron source.

The authors have measured the emission anisotropy from a (252)Cf spontaneous fission neutron source in an X1 encapsulation. The measurements were made in a large low-scatter laboratory using a long counter, and data were taken at angles varying in 10 degrees steps from 0 degrees to 180 degrees relative to the cylindrical axis of the source. Corrections were made for room scatter, loss of neutrons due to air scatter and detector dead time. Calculations corresponding to these measurements were subsequently carried out using the two Monte Carlo codes MCNP and MCBEND, and the results are compared with the measurements and with each other.