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Cancer Immunology Miniatures
Tumor Mutation Burden and Structural Chromosomal Aberrations Are Not Associated with T-cell Density or Patient Survival in Acral, Mucosal, and Cutaneous Melanomas
Jarem Edwards, Peter M. Ferguson, Serigne N. Lo, Inês Pires da Silva, Andrew J. Colebatch, Hansol Lee, Robyn P.M. Saw, John F. Thompson, Alexander M. Menzies, Georgina V. Long, Felicity Newell, John V. Pearson, Nicola Waddell, Nicholas K. Hayward, Peter A. Johansson, Graham J. Mann, Richard A. Scolyer, Umaimainthan Palendira and James S. Wilmott
Jarem Edwards
1Melanoma Institute Australia, The University of Sydney, North Sydney, New South Wales, Australia.
2Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
3Centenary Institute, The University of Sydney, Camperdown, Sydney, New South Wales, Australia.
4Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia.
Peter M. Ferguson
5Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.
6New South Wales Health Pathology, Sydney, New South Wales, Australia.
ORCID record for Peter M. Ferguson
Serigne N. Lo
ORCID record for Serigne N. Lo
Inês Pires da Silva
Andrew J. Colebatch
Hansol Lee
ORCID record for Hansol Lee
Robyn P.M. Saw
7Mater Hospital, North Sydney, New South Wales, Australia.
ORCID record for Robyn P.M. Saw
John F. Thompson
ORCID record for John F. Thompson
Alexander M. Menzies
8Royal North Shore Hospital, Sydney, New South Wales, Australia.
Georgina V. Long
ORCID record for Georgina V. Long
Felicity Newell
9QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
John V. Pearson
Nicola Waddell
ORCID record for Nicola Waddell
Nicholas K. Hayward
ORCID record for Nicholas K. Hayward
Peter A. Johansson
ORCID record for Peter A. Johansson
Graham J. Mann
10The John Curtin School of Medical Research, Australian National University, Canberra, Australia.
Richard A. Scolyer
ORCID record for Richard A. Scolyer
Umaimainthan Palendira
For correspondence: m.palendira@centenary.org.au James.Wilmott@melanoma.org.au
James S. Wilmott
ORCID record for James S. Wilmott
Tumor mutation burden (TMB) has been proposed as a key determinant of immunogenicity in several cancers, including melanoma. The evidence presented thus far, however, is often contradictory and based mostly on RNA-sequencing data for the quantification of immune cell phenotypes. Few studies have investigated TMB across acral, mucosal, and cutaneous melanoma subtypes, which are known to have different TMB. It is also unknown whether chromosomal structural mutations [structural variant (SV) mutations] contribute to the immunogenicity in acral and mucosal melanomas where such aberrations are common. We stained 151 cutaneous and 35 acral and mucosal melanoma patient samples using quantitative IHC and correlated immune infiltrate phenotypes with TMB and other genomic profiles. TMB and SVs did not correlate with the densities of CD8+ lymphocytes, CD103+ tumor-resident T cells (Trm), CD45RO+ cells, and other innate and adaptive immune cell subsets in cutaneous and acral/mucosal melanoma tumors, respectively, including in analyses restricted to the site of disease and in a validation cohort. In 43 patients with stage III treatment-naïve cutaneous melanoma, we found that the density of immune cells, particularly Trm, was significantly associated with patient survival, but not with TMB. Overall, TMB and chromosomal structural aberrations are not associated with protective antitumor immunity in treatment-naïve melanoma.
Tumor-infiltrating lymphocytes (TIL), particularly cytotoxic CD8+ T cells, have long been recognized as a prognostic factor for patient overall survival in multiple cancers types (1) and are also associated with response to anti–PD-1 and anti–CTLA-4 immunotherapies (2–4). Patient tumors with a higher tumor mutation burden (TMB), the result of increased single-nucleotide variants (SNV), are thought to create a proportionally higher number of neoantigens. These neoantigens are recognized as foreign by the immune system, such that an antitumor response can be generated; hence, the greater the number of neoantigens, the greater the immune infiltrate within the tumor (5, 6). This theory is based on (i) the observation that tumor types displaying a high TMB are generally more immunogenic (able to generate an immune response and have greater TILs) than low TMB tumor types (7), (ii) tumors with higher TMB are generally more responsive to anti–PD-1 checkpoint inhibitor immunotherapy (5, 8, 9), and (iii) neoantigen-specific T cells exist in tumors and are capable of causing tumor regression (10, 11). Despite these observations, data demonstrating a direct relationship between TMB and immune infiltration within specific cancer types are limited, weak, and often contradictory. First, most, if not all, of the studies exploring this relationship have relied on genomic/RNA-sequencing data, in which immune gene expression has been used as a surrogate for measuring immune infiltration (12–16). Second, even within genomic studies, there are mixed results in the literature regarding the relationship between TMB and immune cell presence. Some studies have reported increased immune gene expression in high TMB patients within certain cancer types (13, 17), whereas other studies found no correlation in the majority of cancers (15), including melanoma (14). Yet, some studies reported weak correlations (r < 0.16) to describe the relationship between TMB and TIL densities (12). Some studies have also reported higher immune gene expression within low TMB patients across multiple cancer types (16). Although it is unclear what is the exact contribution TMB and neoantigen numbers have toward the magnitude and type of an antitumor immune response, it is widely assumed that higher TMB is positively correlated with a higher immune infiltrate in tumors of the same cancer type.
In addition to mutations arising from SNV changes, several cancer subtypes harbor other types of mutations. In melanoma, for example, it has been shown that acral and mucosal melanomas contain more chromosomal structural rearrangement mutations, also termed as structural variant (SV) mutations, than cutaneous melanoma (18). Whether or not these types of mutations are immunogenic or correlate with an increased immune infiltrate in acral and mucosal melanoma tumors is unknown. In this study, we explored the relationship between TMB, SVs, and tumor-infiltrating immune cell phenotypes, including tumor-resident CD8+ T cells, in 151 cutaneous and 35 acral and mucosal melanoma tumors using quantitative, multiplex immunofluorescence assays. We also validated our findings in a separate cohort of 67 patients with melanoma. We found that TMB and SVs were not associated with the presence of a broad range of immune cell phenotypes in melanoma tumors, including tumor-resident CD8+ T cells. Although the presence of CD8+ T cells and tumor-resident CD8+ T cells was positively associated with patient overall survival, this was independent of TMB. Our data suggest that TMB and SVs are not determining factors for the presence or absence of immune infiltrates within melanoma tumors.
All patient biopsies were treatment naïve at the time of collection. Fresh-frozen tumor tissues from 186 patients and 67 patients were used in the primary and validation cohorts, respectively, for the generation of genomic data, as described previously (18). Patients with corresponding formalin-fixed, paraffin-embedded (FFPE) tumor tissue were included in the study, and FFPE tumor tissue for each of the patient specimens was stored at room temperature until use for the generation of multiplex IHC data. Patients included in survival analyses did not receive any systemic immune checkpoint or targeted therapy for the duration of their clinical follow-up. The study was conducted in accordance with the National Health and Medical Research Council of Australia's National Statement on Ethical Conduct in Human Research. The study was undertaken with institutional Human Ethics Review Committee approval and patient's written informed consent.
Genomic data
Genomic data were generated previously by Hayward and colleagues (18). SNVs and SVs were defined and analyzed from whole-genome sequencing data as described previously (18). All SNVs represented protein-coding mutations using methods described previously (18). All somatic variants for this study have been deposited in the International Cancer Genome Consortium Data Coordination Centre and are publicly available at https://dcc.icgc.org, under project ID MELA-AU. The BAM files have been deposited in the European Genome-phenome Archive (https://www.ebi.ac.uk/ega/) with accession number EGAS00001001552. Where appropriate, neoantigen load was calculated using the pVAC-Seq (v4.0.10) pipeline (19), whereas the NetMHCpan algorithm (20) was used to estimate binding affinity to HLA genotypes.
Multiplexed immunofluorescence staining
Immunofluorescence staining was carried out on 4-μm thick sections using an Autostainer Plus (Dako – Agilent Technologies) and Opal Multiplex IHC Assay Kit (Akoya Biosciences) with appropriate positive and negative controls, as reported previously (21). Briefly, FFPE tumor specimens were deparaffinized and rehydrated by xylene and an Ethanol gradient (100%, 95%, and 70%; Sigma-Aldrich). Heat-induced antigen retrieval (AR) was performed at 95°C for 20 minutes in pH 9 AR Buffer (Akoya Biosciences). Sections were then cooled and incubated with 3% Hydrogen Peroxide (Sigma-Aldrich) for 10 minutes at room temperature, followed by incubation with a single primary antibody against CD8 (1:500; SP16, Cell Marque), CD103 (1:800; EPR4166, ref. 2, Abcam), PD-L1 (1:2,000; E13LN, Cell Signaling Therapeutics), CD45RO (1:1,000; UCHL-1, Dako), CD11c (1:1,000; EP1347Y, Abcam), CD68 (1:500; Kp-1, Cell Marque), CD4 (1:500; 4B12, Biocare Medical), CD20 (1:250; L26, Biocare Medical), or SOX10 (1:800; BC34, Biocare Medical) for 30 minutes at room temperature. Following this, samples were either incubated with Opal Polymer HRP (Akoya Biosciences) for 30 minutes (CD103) or incubated with the MACH3 Probe/HRP-Polymer Kit (Biocare Medical) for 10 minutes (CD8, PD-L1, CD45RO, and SOX10). Finally, sections were incubated with opal fluorophores at 1:100 dilution made up in Tyramide Signal Amplification Reagent (Opal 7-Color IHC, Akoya Biosciences). The AR step was repeated for subsequent stains on the same slide. On the last staining run, DAPI was added to the sample for 5 minutes. All samples were cover slipped using Vectashield (H-1400) and left overnight to dry at 4°C.
IHC staining
Melanoma paraffin-embedded tissue sections were cut and prepared for staining as described above, with appropriate positive and negative controls. Sections were incubated with a single primary antibody against CD8 (1:200; SP16, Cell Marque) or PD-L1 (1:200; E13LN, Cell Signaling Therapeutics) for 45 minutes at room temperature. Sections were then incubated with a probe antibody (MACH3 Probe, Biocare Medical) specific to the species of the primary antibody for 20 minutes, washed, and then incubated further for 20 minutes with a horseradish peroxidase (HRP)-conjugated antibody (MACH3-HRP, Biocare Medical) specific to the probe. Melanoma sections were then stained with 3,3′-diaminobenzidine (Biocare Medical) for 5 minutes and counterstained with hematoxylin for 5 minutes. All samples were cover slipped with xylene and left to air dry at room temperature.
Imaging and staining quantification
The Vectra 3 multispectral slide scanner was used in conjunction with Vectra 3.3 and Phenochart 1.0.4 Software (Akoya Biosciences) to image immunofluorescence staining. Images were then unmixed and analyzed using inForm 2.3.0 Software (Akoya Biosciences). Quantitative analysis was then conducted using the TIBCO Spotfire 3.3.1 from TIBCO. Lymphocyte/leukocyte densities and PD-L1 expression was assessed within tumor only (defined by the presence of SOX10-positive staining). This was performed by a trained pathologist (P.M. Ferguson). In nodal metastases, any residual lymph node tissue, associated structures, and/or cells were annotated out and excluded from downstream analyses. Tumor-resident CD8+ T cells were quantified using the colocalization of CD103 on CD8+ cells. CD4+ T cells were quantified as CD68− CD11c− CD4+ cells. For IHC staining quantification, a trained pathologist (P.M. Ferguson) reviewed each individual case using a conventional upright brightfield microscope and assigned a score to each based on the density of intratumoral CD8 and PD-L1 staining. CD8 staining was quantified using a score from 0 to 3, where 0, absent; 1, sparse (<25%); 2, moderate (25%–75%); and 3, dense (>75%). PD-L1 positivity was determined as the percentage of total cells within the tumor microenvironment (tumor and immune cells, predominantly macrophages) positive for PD-L1 (≥1%) in both immunofluorescence and conventional IHC staining using a continuum scale from 0% to 100%.
Statistical analyses were performed using Prism version 6.0f (GraphPad Software) or TIBCO Spotfire 3.3.1. Patient characteristics were summarized using frequencies and percentages. P values were determined using a nonparametric Dunn multiple comparisons test for comparisons between melanoma subtypes, nonparametric log-rank test for survival data, or Spearman rho test for correlations, where appropriate. P values less than 0.05 were considered significant. Variability in genomic and immune cell density data was expressed in terms of ± 1 SEM. Correlation plots between genomic (including TMB and SVs) and IHC staining data were performed in Prism using a Spearman correlation test. Clinical outcomes analyzed included melanoma-specific survival (MSS). MSS time was calculated as the time from the date of surgical resection of stage III melanoma specimen to date of last follow-up or the date of death from melanoma. Survival curves were generated using Kaplan–Meier method and stratified by expression of a marker using the median staining intensity value (below and above the median as low and high groups, respectively).
Cutaneous melanoma has higher TMB and immune cell infiltration relative to other subtypes
A total of 186 melanoma samples from 186 patients (Supplementary Table S1), including cutaneous (n = 151), acral (n = 30), and mucosal (n = 5) melanomas, of which 51% were nodal metastases, were stained for CD8, CD103, CD45RO, CD4, CD20, CD68, CD11c, and PD-L1 by multiplex immunofluorescence-IHC (mIHC). The number of CD8+ lymphocytes per mm2 within the intratumoral region was significantly higher in cutaneous melanoma (395 ± 50/mm2) compared with acral melanoma (164 ± 61/mm2; P < 0.01) and also showed trends for being higher relative to mucosal melanoma (137 ± 43/mm2), although this difference was not statistically significant (Fig. 1A and B). The densities of tumor-resident CD8+ T cells, a subset of CD8+ T cells expressing the E-cadherin ligand, CD103, and are thought to be enriched for T-cell clones specific to tumor antigens, were also significantly higher in cutaneous melanomas (92 ± 17/mm2) compared with acral melanomas (23 ± 9/mm2; P < 0.01; Fig. 1C). The proportion of tumor-resident cells formed a small subset of the total CD8+ T-cell populations across all melanoma subtypes, cutaneous (26% ± 2%), acral (13% ± 3%), and mucosal (20% ± 5%; Supplementary Fig. S1A). Acral melanoma, but not mucosal melanoma, tended to harbor a smaller proportion of resident CD8+ T cells compared with cutaneous melanoma, which approached significance (P = 0.054; Supplementary Fig. S1A). CD45RO, another marker associated with memory T cells, and PD-L1, the ligand that binds to PD-1 on T cells and is upregulated by IFNγ, were expressed highest in cutaneous melanomas (Fig. 1D; Supplementary Fig. S1B), along with CD68 (Supplementary Fig. S1E). CD4, CD20, and CD11c displayed modest trends for higher expression in cutaneous melanoma (Supplementary Fig. S1C, S1D, and S1F), together indicating that acral and mucosal melanomas are less immunogenic than cutaneous melanomas and contain fewer immune populations associated with antitumor immunity.
Density of immune cell infiltration in cutaneous, acral, and mucosal melanoma tumors. A, Representative single-color images of mIHC staining for CD8, CD103, PD-L1, and CD45RO immune markers in melanoma tumors (images taken at 20× magnification). B, The mean number of CD8+ T cells per mm2 of tumor in cutaneous (n = 151), acral (n = 30), and mucosal (n = 5) melanomas. C, The mean number of CD103+CD8+ tumor-resident T cells (Trm) per mm2 in cutaneous (n = 151), acral (n = 30), and mucosal (n = 5) melanomas. D, The mean number of CD45RO+ cells per mm2 in cutaneous (n = 151), acral (n = 30), and mucosal (n = 5) melanomas. E, The mean number of SNVs in cutaneous (n = 97), acral (n = 28), and mucosal (n = 4) melanomas. Error bars are ± 1 SEM. P values were determined using a nonparametric Dunn multiple comparisons test for comparisons between melanoma subtypes (**, P ≤ 0.01; ***, P ≤ 0.001; ****, P ≤ 0.0001).
No correlation between immune cells and SNV counts in cutaneous or acral/mucosal melanomas
TMB in cutaneous melanomas had higher protein-coding SNV counts (1,281 ± 136) compared with noncutaneous melanomas (acral, 74 ± 11 and mucosal, 59 ± 12; Fig. 1E). However, when we analyzed the effect of TMB on TIL densities in cutaneous melanomas only, no correlative relationship between SNV counts and CD8+ T-cell densities (Spearman r = −0.10; Fig. 2A) or CD103+CD8+ tumor-resident T cells (Spearman r = 0.04) was observed (Fig. 2B), despite increasing evidence that CD103+CD8+ tumor-resident T cells (Trm) represent a subset of T cells specific for tumor antigens (21, 22). We also found no correlation between PD-L1+, CD45RO+, CD4+, CD20+, CD68+, or CD11c+ cells and SNV counts (Supplementary Fig. S1G–S1L). Correlative relationships between immune infiltrates and TMB did not improve when we focused our analysis on the site of disease (Supplementary Table S2). To avoid any bias on representative regions of tissue microarrays, we also stained a subset of cutaneous (n = 17) samples for CD8 and PD-L1 on whole-slide sections and quantified CD8+ T-cell densities and PD-L1 expression in each tumor. Consistent with our main findings, no correlation was observed between CD8+ T-cell density and SNV counts or PD-L1 expression and SNV counts (Supplementary Fig. S2A). Cutaneous tumors with relatively high SNV counts could also simultaneously lack immune infiltration, whereas cutaneous tumors with relatively low SNV counts could show immune infiltrate presence (Supplementary Fig. S2B). We also investigated the effect of TMB and immune infiltrates in acral/mucosal melanomas (n = 32). However, we found no correlative relationship between SNV counts and CD8+ T-cell densities (Spearman r = −0.15), CD103+CD8+ TILs (Spearman r = −0.05), PD-L1 expression (Spearman r = −0.03), CD45RO-positive cells [Spearman r = −0.08, not significant (ns)], or other immune cells (Supplementary Fig. S3). Finally, we sought to determine whether any of the known mutation melanoma subtypes (i.e., BRAF, NF1, and NRAS) were associated with an immune infiltrate presence in cutaneous or acral/mucosal melanomas. No significant trends were found, despite NF1-positive cutaneous tumors showing a higher average SNV count compared with other known melanoma subtypes (Supplementary Fig. S4).
Correlation between CD8+ T cells, CD103+CD8+ T cells, and TMB and SV counts in cutaneous and acral/mucosal melanomas. A, Spearman correlation (r) between SNV counts and number of CD8+ T lymphocytes per mm2 of tumor in (n = 97) cutaneous melanomas. B, Spearman correlation (r) between SNV counts and number of CD103+CD8+ Trm per mm2 of tumor in (n = 97) cutaneous melanomas. C, The mean number of SVs in cutaneous (n = 97), acral (n = 28), and mucosal (n = 4) melanomas. D, Spearman correlation (r) between SV counts and CD8+ T lymphocytes per mm2 of tumor in acral and mucosal melanoma tumors (n = 32). E, Spearman correlation (r) between SV counts and CD103+CD8+ Trm per mm2 of tumor in acral and mucosal melanoma tumors (n = 32). P values were determined using a nonparametric Spearman test [**, P ≤ 0.01; ****, P ≤ 0.0001; ns, not significant (P > 0.05)].
SV counts in acral and mucosal melanomas do not correlate with CD8+ T-cell densities
In our cohort of patient samples, and similar to what has been published previously by our group (18), acral and mucosal melanomas displayed significantly higher SV mutations (acral, 160 ± 3; P < 0.0001 and mucosal, 154 ± 5; P < 0.01) compared with cutaneous melanomas (75 ± 4; Fig. 2C), despite having lower TMB. We, therefore, sought to investigate whether higher SV counts within acral and mucosal melanoma might be correlated with an immune presence. We found no significant correlations between SV counts and densities of CD8+ T lymphocytes (Spearman r = −0.34; Fig. 2D) or CD103+CD8+ tumor-resident T cells (Spearman r = −0.28; Fig. 2E). We also did not found a significant correlation for PD-L1 expression (Spearman r = −0.22), CD4+ T cells (Spearman r = −0.3), CD68+ cells (Spearman r = −0.3), and SV counts (Supplementary Fig. S5A, S5C, and S5E). CD45RO+, CD11c+, and CD20+ immune cells were inversely correlated with SV counts (Supplementary Fig. S5B, S5D, and S5F). We investigated this further for CD8+ T-cell density and PD-L1 expression on whole-slide sections in acral (n = 21) and mucosal (n = 8) melanoma samples containing a higher range of SV counts (52–1,148). Consistent with our findings, no positive correlation was observed between CD8+ T-cell density and SV counts or PD-L1 expression and SV counts (Supplementary Fig. S6A and S6B), indicating that SV mutations are not a driver of immunity in acral/mucosal melanomas.
CD8+ T-cell densities are independent of TMB in a validation cohort
To validate our findings, we stained whole-slide sections for CD8 and PD-L1 using conventional IHC in an independent cohort of patient samples (n = 67; Supplementary Table S3; n = 56, cutaneous melanoma and n = 11, acral/mucosal melanoma) and correlated staining with genomic factors of mutation burden. When we compared average SNV counts by density of CD8 staining (0–3) in cutaneous melanoma samples, we found no significant changes in SNV count between all four levels of CD8 density (Fig. 3A). Cutaneous melanoma tumors with the least (0) and highest (3) CD8+ T-cell infiltration had almost identical average SNV counts (1,647 ± 692 and 1,579 ± 405, respectively). We also explored the predicted neoantigen count from tumor burden in each sample with CD8 density, but found no significant trends (Fig. 3B). PD-L1 expression was weakly correlated with SNV counts (Spearman r = 0.27; P = 0.04; Supplementary Fig. S7A) and with predicted neoantigens (Spearman r = 0.27; P = 0.04; Supplementary Fig. S7B). Although the number of acral/mucosal samples in this cohort was small (n = 11), we found no significant trends between CD8 density and average SV counts (Fig. 3C) or PD-L1 expression and SV counts (Supplementary Fig. S7C), consistent with our previous cohort findings.
Validation cohort. A, Mean SNVs in cutaneous melanoma tumors (n = 56) with varying degrees of intratumoral CD8+ T-lymphocyte infiltration (0–3), where 0, absent CD8 infiltration; 1, sparse CD8 infiltration; 2, moderate CD8 infiltration; and 3, dense CD8 infiltration. B, Mean neoantigen counts in cutaneous melanoma tumors (n = 56) with varying degrees of CD8+ lymphocyte infiltration (0–3). C, Mean SV count in samples with varying CD8 scores (0–2) in acral (n = 8) and mucosal (n = 3) melanomas. Error bars are ± 1 SEM. P values were determined using a Dunn multiple comparisons test (ns, P > 0.05 considered not significant).
MSS for patients with stage III cutaneous melanoma is independent of TMB
We next explored the relationship between TMB and immune infiltrates in a subset of 43 patients with treatment-naïve stage III cutaneous melanoma to dissect the role of TMB in patient survival. The median follow-up time in this cohort was 24 months (range, 1–156 months). In each case, the median of each variable was used to separate patients into high and low groups for each variable. Survival analysis found that patients with high TMB (average SNV count, 1,494 and median SNV count, 979) had no significant survival advantage compared with patients with low TMB (average SNV count, 282 and median SNV count, 296; P = 0.34; Fig. 4A). Despite this, patients with high CD8+ T-cell densities had significantly longer median MSS (131 months) compared with patients with low CD8+ T-cell densities [21 months; HR, 2.5 (1.12–5.8); P = 0.024; Fig. 4B). Tumor-resident CD8+ T cells most associated with survival of all the prognostic markers evaluated [HR, 4.1 (1.6–10.0); P = 0.001; Fig. 4C]. High PD-L1 expression (>1% cells) also associated with better survival [HR, 2.4 (0.4–1.0); P = 0.035] compared with patients with low PD-L1 expression (Supplementary Fig. S8A). We next investigated whether patient groups with high CD8, CD103+CD8+ Trm, and PD-L1 might have an average increase in TMB compared with CD8, CD103+CD8+ Trm, and PD-L1-low patient groups. We found no differences in the SNV counts between high and low groups (Supplementary Table S4), indicating that the survival advantage associated with high immune cell densities was independent of TMB.
Prognostic effect of TMB relative to CD8+ T cells and Trm in treatment-naïve melanoma patients. A, Kaplan–Meier curve for 43 patients with stage III cutaneous melanoma with high (hi) TMB [greater than the median (76,310); red] and low (lo) TMB (lower than median; black). B, Kaplan–Meier curve for 43 patients with stage III cutaneous melanoma with high numbers of CD8+ T cells (greater than the median = 175 cells/mm2; red) and low numbers of CD8+ T cells (lower than median; black). C, Kaplan–Meier curve for 43 patients with stage III cutaneous melanoma with high numbers of CD103+CD8+ Trm (greater than the median = 8 cells/mm2; red) and low numbers of CD103+CD8+ Trm (lower than median; black). For each curve, the average TMB is given for high and low groups. P values were determined using a nonparametric log-rank test and are indicated in panels.
We showed that TMB does not correlate with immune cell infiltration in cutaneous and acral/mucosal melanoma tumors, including for CD103+CD8+ tumor-resident memory T-cell numbers. These findings remained consistent even when we focused on the site of disease. In melanoma subtypes, where a bias exists for chromosomal structural aberration mutations, we also showed a lack of correlation between these mutation types and the presence of immune cells, likely indicating that these mutations are also not robust elicitors of an antitumor immune response in acral and mucosal melanoma tumors. We also demonstrated that the prognostic effects of immune cell densities, particularly CD103+ tumor-resident CD8+ T cells, are not necessarily associated with TMB in cutaneous melanoma. Although it is possible that increased TMB results in enhanced T-cell receptor diversity and, therefore, improved quality of the immune response, the fact that TMB did not have an impact on melanoma-specific patient survival suggests that it is unlikely to be a key determinant of the protective immunity. Together, our results suggest that immune infiltration in melanomas is independent of TMB, highlighting the importance of other driving factors. Limitations to this study include the moderate sample size of the two patient cohorts, especially the number of acral and mucosal samples with genomic data, and, therefore, it is possible that the study is not powered to detect a significant association between TMB/SVs and immune infiltrates, particularly if those associations are very weak. In addition, no functional characterization of antitumor immunity between high and low TMB tumors was performed. However, despite moderate sample size, known prognostic immune cells/markers, including CD8+ T cells, Trm, and PD-L1, were prognostic in this study, whereas TMB was not. A strength to the study was the use of mIHC, which allowed for an accurate assessment of intratumoral lymphocytes and the characterization of complex phenotypes (CD103+CD8+ Trm). Overall, our data are in-line with the results of a number of other studies (14, 15), including a pan-cancer analysis utilizing The Cancer Genome Atlas database, where no significant correlations were identified between somatic mutation numbers and CD8+ T-cell infiltration scores in the majority of cancers (15).
There are many reasons why TMB may not directly correlate with the magnitude of an antitumor immune response. (i) It is possible that not all the predicted neoantigens from sequencing data are recognizable to the immune system. For example, tumors that have downregulated MHC class I expression may limit the recognition of neoantigens. (ii) It is probable that neoantigens are not equally immunogenic and, therefore, may elicit stronger or weaker immune responses depending on the quality of the neoantigen. Indeed, there is evidence to show that clonal neoantigens, rather than subclonal neoantigens, are more associated with immunity in tumors (11). However, this is unlikely to be a strong confounding variable in melanoma, where the overwhelming majority of neoantigens is classed as clonal (23). (iii) Nonmutated antigens, such as cancer-testis antigens, which can be expressed in melanomas, may also contribute significantly to antitumor immune responses. (iv) It is possible that TMB is only one of many more dominant factors responsible for recruiting and retaining immune cells in tumors, including the presence of Batf3+ dendritic cells, upregulation of the Wnt signaling pathway (24, 25), and the prevalence of myeloid suppressor cells (26), among others. In conclusion, our data indicate that TMB, SV rearrangements, and known melanoma mutation subtypes are not determining factors for the presence or absence of immune infiltrates within melanoma tumors.
S.N. Lo reports grants from National Health and Medical Research Council of Australia (program grant) during the conduct of the study. R.P.M. Saw reports personal fees and other from Novartis (advisory board), Bristol-Myers Squibb (speaking honoraria), MSD (advisory board), and QBiotics (advisory board) outside the submitted work. J.F. Thompson reports grants from National Health and Medical Research Council of Australia (program grant) during the conduct of the study, as well as personal fees from GlaxoSmithKline (honoraria and travel support), BMS Australia (honoraria for advisory board participation), MSD Australia (honoraria for advisory board participation), and Provectus Inc. (honoraria and travel support) outside the submitted work. A.M. Menzies reports personal fees from Bristol-Myers Squibb (advisory board), MSD (advisory board), Novartis (advisory board), Roche (advisory board), and Pierre Fabre (advisory board) outside the submitted work. G.V. Long reports personal fees from Aduro (consultant adviser), Amgen (consultant adviser), Bristol-Myers Squibb (consultant adviser), Highlight Therapeutics S.L (consultant adviser), Mass-Array (consultant adviser), Merck (consultant adviser), MSD (consultant adviser), Novartis (consultant adviser), OncoSec Medical (consultant adviser), Pierre Fabre (consultant adviser), Roche (consultant adviser), QBiotics (consultant adviser), Skyline DX (consultant adviser), and Sandoz (consultant adviser) outside the submitted work. J.V. Pearson reports other from genomiQa PTY LTD (genome analysis company; cofounder, equity holder) outside the submitted work. N. Waddell reports grants from National Health and Medical Research Council of Australia (fellowship) during the conduct of the study and other from genomiQa PTY LTD (cofounder, board member, and equity holder) outside the submitted work. N.K. Hayward reports grants from National Health and Medical Research Council (partial funding of work) during the conduct of the study. R.A. Scolyer reports grants from National Health and Medical Research Council of Australia (program grant and fellowship grant) and nonfinancial support from Melanoma Institute Australia during the conduct of the study, as well as personal fees from Royal Prince Alfred Hospital (salary), Qbiotics, Novartis, MSD Sharp & Dohme, NeraCare, Amgen, Bristol-Myers Squibb, Myriad Genetics, and GlaxoSmithKline outside the submitted work. No potential conflicts of interest were disclosed by the other authors.
J. Edwards: Conceptualization, validation, investigation, visualization, methodology, writing–original draft, project administration, writing–review and editing. P.M. Ferguson: Formal analysis, investigation, methodology. S.N. Lo: Formal analysis. I. Pires da Silva: Visualization, methodology, writing–review and editing. A.J. Colebatch: Investigation, methodology, writing–review and editing. H. Lee: Methodology. R.P.M. Saw: Resources, writing–review and editing. J.F. Thompson: Resources, writing–review and editing. A.M. Menzies: Resources, writing–review and editing. G.V. Long: Conceptualization, resources, supervision, funding acquisition, investigation, visualization, methodology, project administration, writing–review and editing. F. Newell: Resources, data curation, writing–review and editing. J.V. Pearson: Data curation, writing–review and editing. N. Waddell: Data curation, writing–review and editing. N.K. Hayward: Resources, data curation. P.A. Johansson: Resources, data curation, writing–review and editing. G.J. Mann: Resources, data curation. R.A. Scolyer: Conceptualization, resources, supervision, funding acquisition, investigation, visualization, methodology, project administration, writing–review and editing. U. Palendira: Conceptualization, resources, supervision, investigation, visualization, project administration, writing–review and editing. J.S. Wilmott: Conceptualization, resources, software, supervision, funding acquisition, investigation, visualization, methodology, project administration, writing–review and editing.
This work was supported by Melanoma Institute Australia, the New South Wales Department of Health, New South Wales Health Pathology, the National Health and Medical Research Council of Australia (NHMRC), and Cancer Institute NSW. J.S. Wilmott, R.A. Scolyer, and G.V. Long were supported by NHMRC Fellowships. G.V. Long and J.F. Thompson were supported by the Melanoma Foundation of The University of Sydney through The University of Sydney Medical Foundation. U. Palendira was supported by the Cancer Council NSW (RG18-08). J. Edwards was supported by the Research Training Program and Sydney Catalyst scholarships at The University of Sydney and also by a Melanoma Institute Australia PhD scholarship. A.M. Menzies was supported by a Cancer Institute NSW fellowship. R.P.M. Saw and G.V. Long were supported by Melanoma Institute Australia. Support from the Ainsworth Foundation is also gratefully acknowledged.
Cancer Immunol Res 2020;8:1346–53
Received December 19, 2019.
Revision received May 26, 2020.
Accepted September 3, 2020.
Published first September 11, 2020.
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EXCLUSIVE Coronation Street Blog interview with David Neilson (Part 3)
In the third and final part of our exclusive interview with David Neilson, David tells us about the relationship between Roy and Hayley in Coronation Street and what the future may hold for Roy Cropper.
"A Perfect Duet - the Diary of Roy and Hayley Cropper" by Coronation Street Blog Editor, Glenda Young, is available to buy now. More information about how you can pick up a copy is available here.
The first part of our interview with David, in which he talks about how he became an actor and some of his roles before joining Corrie, can be read here. And the second part of our interview, which focuses on David's portrayal of Roy Cropper, can be read here.
Here is the final instalment of our exclusive David Neilson interview…
David Neilson with Corrie Blogger, Martin Leay
(Photo by David Doig)
Martin Leay (ML): Did Hayley transform Roy as a character?
David Neilson (DN): When Hayley came in she was going to be the first in a long line of disastrous relationships but because she was so good and we worked well together they went 'hang on, we're going to have to bring her back'.
ML: Was it a surprise when you found out Hayley was transgender?
DN: The way we dealt with it, it was about any kind of prejudice. Roy is very straight – it wasn't ideal for him. It was a big crisis but he was in love with this person, so therefore he had to deal with it. There was always a bit of grit – it wasn't easy. It was outside of his realm. They were both up against society and I think the decency in people identifies with that. And also, we both had immense sympathy for the characters. We always went from the point of view of the integrity of the characters above anything.
ML: Do you think Roy and Hayley helped to shift attitudes in society for the better?
DN: What people related to was their relationship. It was 'we like them, we want them to be together'. That was Roy's thing: 'if I leave this person, I'm less of a person than when we are together' and he discovered something that unfortunately for him wasn't easy. But that's part of development, it is part of growing… life is a struggle. I think people relate to that.
ML: How did you feel when you found out Hayley was going to die?
DN: The writing was fantastic. I got the scripts and it was like wow, this is quite difficult to read, so when we came to doing it – you know it was huge – you get the pay off from a 15 year relationship in real time and you realise you've been in their life. It has a feeling of reality about it, which you can't get in any other kind of show. People have gone through all these experiences with them.
ML: It must have been very difficult to film?
DN: Yes, because you go through it on a daily basis scene after scene and then you get a pile of scripts and go home with it. There is a huge responsibility involved because of what the subject matter is. I had two friends die of cancer during that year and it was quite surreal. The great thing about a human story is that it affects everyone. You can have car crashes, fires and tram crashes but for most people, these things don't happen. This happens and affects people and so it's an everyday human story but immense – devastating. It does feel like a responsibility to the story, to the character and to people watching. It was very difficult to watch. I know a lot of people who couldn't – and that's quite understandable.
ML: Julie Hesmondhalgh says she cried after filming her last scenes. Did you get emotional?
DN: The character cried. It was very upsetting. I just remember feeling completely exhausted by it. I remember the scene we filmed, the actual death; that was quite something. And it had never happened to me before – Kay Patrick, who directed it, didn't have any interruptions. Normally you get retakes but she said 'let them rehearse on their own as much as they want' and then we just did it once. It was a great sense of concentration and everybody, the whole crew and team, was right at the top of their game.
ML: You and Julie are very good friends. It must have been great working with her?
DN: It was such a pleasure to go to work. You might do several episodes one after the other so we'd be on all day and sometimes we'd have such fun and the crew would be laughing and at the end of the day you're knackered but it's such a nice job. It's just messing about for a living. It's great. I actually do for a living what I got told off for at school.
ML: But you're very good at it!
DN: Well, getting away with it. It's finding that little bit of something. That's the skill – and making a living out of it.
ML: You picked up Best Dramatic Performance at last year's British Soap Awards. How does it feel to have your work recognised in this way?
DN: What I have found is that it makes a big impression on other people and that's nice. It does change other people's perception of you. So I realise it's better to win than not to but as far as all the other stuff is concerned… I have been up for Best Actor several times and I've not won it but I've never come away thinking I'm any better or worse than I've ever felt about myself. 'Best Dramatic Performance' – it's who cried the most. And also, it depends on who has had the most lines and who has had the storylines.
ML: Hayley's exit storyline was beautifully written but surely it would have been much less powerful without the wonderful performances from you and Julie?
DN: It comes together. You can look like the character and dress like the character but unless the words are there and the situations are there – you're up against it. I've been very fortunate – with the people I've worked with and with the writing.
ML: Can you tell us what's coming up for Roy?
DN: I actually don't know. It's a choice I make, really. It's like life, it just happens. I'm working with Melanie (Hill). I've done a couple of days with her. She's great – a really good actor and a nice woman. That's the most important thing – that we get on. And we do, so that's fab. It's interesting – it's all wide open, really.
ML: I've read it is not going to be a romantic relationship between Roy and Cathy. Do you think viewers are ready to accept Roy with another woman at some point?
DN: It's a completely new area for him. It depends how it's handled – it's all going to be in the writing. Anything is possible. I think it's the appetite of the writers… and then I deal with it. When it comes through that process, it lands in my pigeonhole and I've got a pile of scripts and I go 'oh, right, OK - what's happening here?' Again, it's like life. I don't know what's going to happen this afternoon.
Whatever did happen that afternoon, I hope David had a very Happy Birthday. It was an honour to meet him and learn about his career and I am very grateful to him for giving so much of his time to speak to the Coronation Street Blog. David is a great actor and, I am pleased to say, a really nice guy - modest, friendly, funny and down-to-earth.
I hope that readers enjoyed these interviews. If you missed Parts One or Two, they are available here and here.
I would like to thank ITV, David Neilson and also Glenda Young for her expert editorial guidance.
Roy Cropper is a character that I have enjoyed watching over the past 20 years – he has made me laugh and he has made me cry. David Neilson has been involved in some of the most interesting and moving Corrie storylines I can remember and never fails to turn in a first class performance.
Long may Roy continue to serve the most competitively priced organic breakfast in Weatherfield (with allotment-grown tomatoes and mushrooms)!
Interview by Martin Leay
You can follow Martin on Twitter @mpleay
You can listen to Martin on Croydon Radio
Posted by Martin Leay at 00:30
Labels: british soap awards 2014, cathy matthews, coronation street, david neilson, hayley cropper, itv, julie hesmondhalgh, melanie hill, newsnow, roy cropper
Great interview Martin! And what a nice man David seems to be!
I also feel priviledged that I'm part of a blog that manages to get these interviews. It shows that we are acknowledged by Corrie and ITV. That's thanks to Glenda and all the rest of the team!
All three excellent pieces! Thanks so much and wow, lucky you to spend quality time with David!
Lovely interview. David's down-to-earth nature comes through very well. Nice to hear from him :)
abbyk said...
Thank you, Martin, for these well written articles about my favorite character.
Really enjoyed these articles, Martin, thank you! Fantastic achievement for your writing, but more for you a fantastic meeting and connecting with a genuine person.
vintgal003 said...
A HUGE thank you Martin for the stellar interview....VERY interesting to read... I'm sure an honour for you to interview David.....thanks again!
Martin Leay said...
Thanks everyone for your comments and feedback. It was indeed a great honour to meet David and to hear so much about his experiences. It was a day I won't forget in a hurry, that's for sure!
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The kingdom combines modern Arab culture and the archaeological legacy of five thousand years of civilisation. The island is home to castles including Qalat Al Bahrain which has been listed by UNESCO as a World Heritage Site. The Bahrain National Museum has artefacts from the country's history dating back to the island's first human inhabitants some 9000 years ago.
Gulf Air is the principal flag carrier of the Kingdom of Bahrain. Headquartered in Muharraq, adjacent to Bahrain International Airport, the airline operates scheduled services to 41 destinations in 30 countries across Africa, Asia and Europe.
Bahrain comprises of a cluster of thirty three islands, which occupies an area of more than seven hundred square kilometers. This archipelago located in the Arabian Gulf, form the eastern shoreline of Saudi Arabia. The local time followed in the country of Bahrain is GMT + 3 hours. The terrain has derived its name from the major and biggest island Bahrain, which occupies more than five hundred and fifty square kilometers. The state is well connected by a route to Muharraq, the international airport and Sitra, the down town area, as well as the country region. A huge gamut of small islands is there near the main island of Bahrain but these islands are mostly abandoned. These islands attract many species of migratory birds which come here in spring and autumn every year. The Arabian Gulf possesses standard deepness of about 36 meters and most of it is in the surrounding area of Bahrain.
In the country of Bahrain though the English language is widely understood and is applied by the majority of business sectors, but Arabic is considered as official language. Coming to religion, Islam is the most eminent religion of Bahrain and is observed by the majority of the population. Besides this the houses of worship of other religions are also found in the country of Bahrain. The climatic condition of the island of Bahrain is influenced by warm summer and cool winter. Usually from November to April the climate is really enjoyable and charming, with temperature ranging from 15 to 24 degree Celsius. Usually the weather becomes coolest between the month of December and March. Months from July to September are dominated by extreme humidity. The yearly standard precipitation is, on an average, 78 millimeters.
This constitutional monarchy in the Gulf region was among the first to discover and benefit from the vast reserves of oil.
Samer Majali is a Jordanian businessman and the current CEO of Gulf Air . Majali has also served as the CEO of Royal Jordanian airlines from 2002-2009, and was credited for transforming the airline into one of the most successful in the region. Under his management, the airline recorded its first ever net profit. Upon his successful management of RJ He was persuade by the Government of Bahrain to assumed the position of CEO of Gulf Air in 2009. His career began in 1979.
Manama (Arabic: المنامة Al Manāma) is the capital and largest city of Bahrain, with an approximate population of 155,000 people. Long an important trading center in the Persian Gulf, Manama is home to a very diverse population. After periods of Portuguese and Persian control and invasions from the Al Sauds and Oman, Bahrain established itself as an independent nation during the 19th century period of British hegemony. In the 20th century, Bahrain's oil wealth helped spur fast growth and in the 1990s a concerted diversification effort led to expansion in other industries and helped transform Manama into an important financial hub in the Middle East.


text:
require_relative './../../../spec_helper'

describe 'oneview_test::unmanaged_device_add' do
  let(:resource_name) { 'unmanaged_device' }
  include_context 'chef context'

  it 'adds it when it does not exist' do
    allow_any_instance_of(OneviewSDK::UnmanagedDevice).to receive(:exists?).and_return(false)
    expect_any_instance_of(OneviewSDK::UnmanagedDevice).to receive(:add).and_return(true)
    expect(real_chef_run).to add_oneview_unmanaged_device('UnmanagedDevice1')
  end

  it 'updates it when it exists but not alike' do
    allow_any_instance_of(OneviewSDK::UnmanagedDevice).to receive(:exists?).and_return(true)
    allow_any_instance_of(OneviewSDK::UnmanagedDevice).to receive(:retrieve!).and_return(true)
    allow_any_instance_of(OneviewSDK::UnmanagedDevice).to receive(:like?).and_return(false)
    expect_any_instance_of(OneviewSDK::UnmanagedDevice).to receive(:update).and_return(true)
    expect(real_chef_run).to add_oneview_unmanaged_device('UnmanagedDevice1')
  end

  it 'does nothing when it exists and is alike' do
    allow_any_instance_of(OneviewSDK::UnmanagedDevice).to receive(:exists?).and_return(true)
    allow_any_instance_of(OneviewSDK::UnmanagedDevice).to receive(:retrieve!).and_return(true)
    allow_any_instance_of(OneviewSDK::UnmanagedDevice).to receive(:like?).and_return(true)
    expect_any_instance_of(OneviewSDK::UnmanagedDevice).to_not receive(:update)
    expect_any_instance_of(OneviewSDK::UnmanagedDevice).to_not receive(:add)
    expect(real_chef_run).to add_oneview_unmanaged_device('UnmanagedDevice1')
  end
end

redpajama_set_name: RedPajamaGithub


I believe in the imagination. What I cannot see is infinitely more important than what I can see.
I believed in myself. I never imagined myself as just an ordinary player.
Trust that little voice in your head that says 'Wouldn't it be interesting if...'; And then do it.
3 quotes by Duane Michals.


This is it: the tight that is getting glowing reviews from magazine testers all over the world and is also the favorite among the Castelli test crew. The comments that keep coming up are the great fit along with exceptional comfort down to very cold temperatures or even when the thermometer rises. The secret to the great fit is the mixture of Thermoflex Core2 along with our standard Thermoflex, which lets us create just enough stretch but with enough support to keep everything in place.
The wide temperature range is thanks to the inner layer of Thermoflex Cure Due, with its hollow-core polyester for great moisture management and insulation. All that plus the Progetto X2 Air seat pad, GIRO++ bib straps and Camlock ankle zips with reflective overlays. It will get glowing reviews from you too.


text:
Image courtesy of the Department of Mathematics, University of Edinburgh
BORN 9th April 1903 Edinburgh, Scotland, UK
DIED 3rd January 1994 Edinburgh, Scotland, UK
WORKED Edinburgh and Rosyth, UK
HONOURS Elected as a Fellow of the Royal Society of Edinburgh in 1951, only 2 years after women were allowed to be Fellows; Has a physics prize named after her; One of the roads within the science campus at Edinburgh University commemorates her.
Photograph of Marion Ross Road within the campus of Edinburgh University
Royal Festival Hall Auditorium,1951.
Author: Robin and Lucienne Day Foundation
Marion Ross always took a keen interest in music, especially organ music, inspired by her father. He had designed the organ for the Holy Rude Church in Stirling, and composed organ music. Marion founded a trust so that a prize for composition could be awarded to encourage the work of Scottish church musicians. The prize continued to be awarded after her death.
As Assistant Lecturer at Edinburgh University, Marion Ross set up a course in acoustics for music students. She took a keen interest in the construction of the Royal Festival Hall in London, one of the first concert halls to be designed for its acoustical qualities, not entirely successfully!
Title: Physics is for me……and Marion Ross!
Music by: Canal View Primary School P6 Physics Group
Words by: Canal View Primary School P6 Physics Group & the Audience
For: Mixed Voices
Recorded Live at: AK Bell Library, Perth (Nov 11th 2019) and Beacon Arts Centre Greenock (March 8th 2019) as part of our Echoes Minerva Scientifica Tour of Scotland
Performed by: electric voice theatre (Frances M Lynch & Margaret Cameron) and the AUDIENCE!
First Performed by: Canal View Primary School P6 Physics Group, Edinburgh Napier University, June 2017
Marion Ross was the focus for this group during their Minerva Scientifica workshops in 2017. Her story – told to them by Catherine Booth from the National Library of Scotland – inspired them to think of all the amazing things in the world that they would like to investigate – just as she did.
Years later we still perform this music at every single Minerva Scientifica show, but it has been transformed into an audience participation sing-a-long-a-physics song! Do join in and see if you can answer the questions asked during the performance by children from All Saints Primary School!
Marion Ross was educated at Edinburgh Ladies College then Edinburgh University. She trained as a teacher of mathematics in Cambridge. She gained her PhD back at Edinburgh University.
Marion Ross taught mathematics for several years, both in Woking, Surrey, and in Falkirk, Scotland
Crystallographer
For one year in the 1930s, she worked as a crystallographer in Manchester University collaborating with Dr C A Beevers, under the guidance of Sir W. Lawrence Bragg. Sir Lawrence had been awarded a Nobel prize for his work in crystallography in 1915.
Wartime Researcher
During WW2, Marion Ross spent 4 years working with the Admiralty at Rosyth, Fife, and became Head of the Research Group. Their investigations involved underwater acoustics and hydrodynamics
CC BY-SA 3.0, Link Sound Waves in Water
After the war, Dr Marion Ross became a lecturer in the Physics Department at Edinburgh University, where she remained for the rest of her career, specializing in areas such as nuclear and X-ray physics and fluid dynamics.
Beta-alumina diagram
During her year as a crystallographer, Ross and Beevers investigated the crystal structure of a molecule, 'beta-alumina' and published their results in a German journal in 1937. They found a problem anomaly in the structure where sodium ions were present, and these locations became known as 'Beevers-Ross', or 'anti-Beevers-Ross' sites. The two scientists could not see any practical application for these, and simply noted them as interesting. Years later, it was discovered that the mobile sodium ions form efficient fast ion conductors, important in battery technology.
Photographic plate, exposed to billion-volt protons (Brookhaven National Laboratory. c. 1957)
At Edinburgh University, Marion Ross set up a laboratory to conduct experiments in nuclear physics. These included the detection of charged particles on photographic plates. X-ray imaging is a familiar medical application of this branch of science, though digital technologies have now taken over.
Fluid dynamics – the flows of liquids and gases – was a continuing scientific interest for Marion Ross, and she set up a Fluid Dynamics unit within the University. Experiments to investigate smooth and turbulent flows were undertaken using a low-speed wind tunnel, but also required mathematical calculations using the properties of the gas or liquid under consideration, such as its pressure and temperature.
Model of a wind tunnel (NASA)
Marion Ross was the eldest daughter in a family of 5 girls. Her father, William Baird Ross, was a well-known organist and composer of organ music.
She once told a young student that she enjoyed playing table tennis, and if she didn't have a bat to hand, she would hit the ping-pong ball with a text book! This either shows her sense of fun or her inventiveness – perhaps both!
Science requires careful observation and recording of results. Sometimes the implications of a discovery are not immediately obvious at the time, but noted for future study. Marion Ross and her colleague were in just that position when they spotted the properties of the beta-alumina crystal. Fortunately they wrote and published a description of it, and scientists working in a different field much later, followed up this work, and realized its importance.
Marion Ross encouraged and supervised many young and advanced students in her time. These days she inspires many working with us on Minerva Scientifica, particularly the children of Canal View Primary School who wrote a song about her (see Music above).
Royal Society of Edinburgh Obituary
'Beevers-Ross' sites in crystal


text:
Home / News / Chapman Tripp acts in proceedings against Athletics New Zealand and NZ Olympic Committee
Chapman-Tripp-acts-in-proceedings-against-Athletics-New-Zealand-and-NZ-Olympic-Committee
18 July 2016 | Article
Leading law firm Chapman Tripp is acting for London-based New Zealand marathon runner Paul Martelletti in Sports Tribunal proceedings against Athletics New Zealand and the
New Zealand Olympic Committee.
Over the weekend, Athletics New Zealand reconsidered its non-nomination of Mr Martelletti, announced last Tuesday (July 12) after a notice of appeal against non-nomination was filed by Chapman Tripp partner Daniel Kalderimis last Thursday (July 14). The national body presented its final decision on Mr Martelletti's nomination at 12:30pm on Saturday (July 16), confirming that it would not nominate him for the Olympic Team.
A notice of appeal will be filed to the Sports Tribunal today (July 18). "Mr Martelletti is New Zealand's leading men's marathon runner, the holder of the Oceania marathon title, and the only International Association of Athletics Federations (IAAF) qualifying athlete for the Rio Olympics Men's Marathon event from New Zealand," Kalderimis says. "Here, there is no competition for places. For New Zealand, it is Mr Martelletti or no-one."
To qualify for Rio, marathon runners must complete a time of 2:19 under IAAF standards. Mr Martelletti has done so twice. "The overall test in New Zealand is whether Mr Martelletti is capable of a Top 16 placing. He is. Despite being ill when competing in the recent London marathon, Mr Martelletti completed in 2:17:26, finishing in 21st place overall, indicating that a time of under 2:14 was likely to be achieved. This was from a field of 39,000 competitors, which was not limited to three entries per nation as is the Rio 2016 marathon," says Mr Kalderimis.
Grounds for his Sports Tribunal appeal include that the Nomination Criteria were improperly applied and that evidence of Mr Martelletti's illnesses during key events was not accorded sufficient weight.
Mr Martelletti's coach, Nick Anderson, a former UK Athletics head coach, strongly supports Mr Martelletti's contention that he is capable of a Top 16 placing in Rio, pointing to his recent training in Kenya, strong results in races prior to the London marathon indicating the likelihood of a 2:14 time if he had not been hampered by illness, as well as the difficulty of predicting championship marathon placings based on personal best results.
"Mr Martelletti is eligible, qualified and determined. We should not lightly deny competitive athletes a chance to represent and inspire their country, especially in a popular event such as the marathon," says Mr Kalderimis. "If Mr Martelletti were the only qualified Australian runner, there is no question but that he would be at the Games. The result need be no different here," Mr Kalderimis says.
New Zealand has not been represented by a male marathon runner in the Olympic Games since 2004.
Related topics: Litigation & dispute resolution
Daniel Kalderimis; Jeremy Upson
Litigation & dispute resolution


text:
EU's Michel Barnier unveils powers to fine banks up to 10pc of turnover
The European Union's top financial regulator has set out harsh new rules for the banking industry that could see banks being fined as much as 10pc of their entire annual turnover if they fail to comply.
European banks will be required to maintain a core tier one capital ratio of 8pc, of which common equity will have to make up 4.5 percentage points of the total Photo: EPA
By Harry Wilson, Banking Correspondent
6:29PM BST 20 Jul 2011
Banks will be forced to hold more capital of a higher quality as part of the package of reforms that will hand the EU sweeping powers to intervene in the financial system to prevent a future crisis.
Among the sanctions at the disposal of the authorities will be the ability to hand out "administrative fines" that could amount to up to 10pc of an institution's annual turnover as well as the power to temporarily ban managers at any one of the 8,000 banks operating within the EU.
Michel Barnier, EU internal markets commissioner, said regulations were a "tremendously important step forward in learning the lessons from the crisis".
"The financial crisis has hit European families and businesses hard. We cannot let such a crisis occur again and we cannot allow the actions of a few in the financial world to jeopardise our prosperity," he added.
In line with the Basel III capital agreements, European banks will be required to maintain a core tier one capital ratio of 8pc, of which common equity will have to make up 4.5 percentage points of the total, up from two percentage points. In addition, banks will in good years be expected to set aside an undetermined additional store of capital as a "countercyclical buffer" and the largest banks will also face an additional surcharge.
The magnificent strength of the euro
Only Germany can save EMU
Angela Merkel: can she rescue the euro?
IMF: eurozone risks global contagion
Santander's Ana Botin to meet ICB on bank reforms
Banks cannot argue 'behind closed doors' - MPs
In what could prove to be contentious, national regulators are limited in their ability to impose extra capital requirements on their domestic banks, with the EU saying it wanted to prevent countries from "distorting" the market.
"Financial stability can only be achieved by the EU acting together; not by each member state on its own," said the EU.
"The apparent aim of the Commission is that, by creating uniform prudential standards, those jurisdictions that would struggle to impose higher standards will not be perceived as less safe, and capital requirements will not become a basis for inter-state competition," said Jeremy Jennings-Mares, a capital markets partner at law firm Morrison & Foerster.
"It is frankly extraordinary that the UK has to fight in Europe to retain this discretion for national supervisors," said Ash Saluja, at law firm CMS Cameron McKenna.
Senior British regulators, including Lord Turner, the chairman of the Financial Services Authority, have argued that higher capital requirements could be imposed in future.
David Miles, a member of the Bank of England's Monetary Policy Committe, has said a capital ratio of 20pc could be appropriate.
News by Sector »
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text:
Restricted visibility: yacht has close quarters situation with bulk carrier
admin | 30th June 2014
Report Text:
A 30ft cutter (CL) and a 33ft sloop (D) were sailing in company across the English Channel. Both vessels had radar and radar reflectors, but not AIS. Crew of (CL) included an Ocean Yacht Master and two Day Skippers, one with a Royal Naval bridge watchkeeping certificate and on (D) a Yacht Master and Day Skipper. Again the latter held a Royal Naval bridge watchkeeping certificate.
We left Alderney at 0600 with a forecast of light/moderate westerly winds and moderate locally poor visibility, improving later, bound for the Needles. Initially we proceeded under power with visibility of one to two miles. Our planned course was to the east of the Casquets TSS. We crossed the east bound shipping lane (not a Traffic Separation Scheme) uneventfully although we did use radar having only one contact which passed at a range of two to three miles without being seen visually. Visibility then improved to three to four miles with a fair wind and we had a pleasant sail without engine for a couple of hours. As the radar is a heavy user of current and visibility was good, we shut it down.
At about 1400 we were approaching the west bound shipping lane when the wind dropped and within the space of less than ten minutes we entered fog with visibility of 100 yards or less. The headsail was furled and we started to motor again and switched on the radar.
Although reasonably experienced yachtsmen we had not had recent experience of radar plotting for collision avoidance. CL's radar was more reliable than D's, which only worked intermittently, so CL took the lead with D in station just visible astern, and in VHF communication on channel 6 dual watch channel 16.
We had seen no shipping before the fog but on switching on the radar at 8 miles range there were 6 – 7 contacts, ships proceeding westwards in the shipping lane. One of CL's crew kept radar watch; the screen was visible to the helmsman and other crew. It was soon evident that most of the contacts were passing clear but one 3 –4 miles away on the starboard bow was a cause for concern. After plotting this contact for five minutes or so we decided that risk of collision existed and that we should alter course to starboard. We made a bold alteration of 90 degrees from a course of roughly north to one of east, when the contact on a westerly course was between two to three miles away.
CL's radar was set with course up (not the more convenient north up) and so when we altered course all the tracks of radar contacts changed and in the next few minutes it was not clear if the true courses of any of the contacts had changed. However we felt confident that from the previous plot we should be safe. We then suddenly saw a large indistinct visual contact on our port beam at a range of two to three cables. At first we thought this was a ship heading west but after a few moments we saw a bow wave and realised it was a large ship heading straight for us. Seconds later the helmsman saw that we were very fine on the ship's starboard bow and altered course violently to port reversing our course from east to west, D following. A large, Chinese registered bulk carrier (BC) just passed us at a distance of less than 100 yards (see photo attached, taken from D). This was too close for comfort.
We altered back to our northerly course and had no further worrying incidents although we kept a close visual and radar watch. The fog did not clear until we were within two miles of the Needles lighthouse at about 1900. It took a little time and thought to work out what had happened.
Overview: We had altered course from north to east to avoid the BC, which we had plotted as steering west. However as we came into close quarters she was steering south so she had clearly altered course. Our radar plotting on CL was not accurate enough to have seen this although on D they had just noticed this but did not have time to notify CL. It seems clear that BC had altered course to port and to a course of south at the same time as we had altered to a course of east. We had both altered from one set of converging courses to another at the same time!
Who was to blame for this incident, which clearly could have resulted in a collision with serious, possibly fatal consequences? On CL and on D we felt we had made the right decision to alter course to starboard to avoid BC. She had however altered course to port at the same time to try and avoid us. The International Regulations for Preventing Collisions at Sea (IRPCS or "Colregs") Rule 19. Conduct of vessels in restricted visibility paragraph (d) states: –
A vessel, which detects by radar alone the presence of another vessel shall determine if a close quarters situation is developing and/or risk of collision exists. If so she shall take avoiding action in ample time, provided that when such action consists of an alteration of course, so far as possible the following shall be avoided:
(i) an alteration of course to port for a vessel forward of the beam, other than for a vessel being overtaken;
(ii) an alteration of course towards a vessel abeam or abaft the beam.
It seems clear that BC had contravened this rule. CL's radar plotting was weak being 'head up'. This was perfectly adequate to cope with CL being on a steady course, but with 6-7 contacts and a major alteration of course, it proved inadequate. However CL / D complied with Rule 19 by altering course to starboard when we considered that a risk of collision existed whereas BC contravened Rule 19 by altering course to port for a vessel forward of the beam.
One of us (the Ocean Yacht master) has discussed this incident with a very experienced professional Merchant Marine Captain and Extra Master who is currently an Officer with the Government Agency. He agrees with this assessment that we were right and BC was wrong although he did point out that we should have kept a better radar plot and that in fog there are no "stand on" and "give way" vessels; all vessels should keep clear of others following Rule 19.
Lessons Learned: The following arise from a discussion between both crews that evening in port:
1. Radar is reassuring and useful in fog but must be used actively. A plot of all contacts should be kept either on a plotting sheet or with a china graph pen on the radar screen.
2. North up stabilised radar is easier to interpret than course up. The Colregs require that "Proper use shall be made be made of radar equipment if fitted and operational". This does not mean that the latest most refined radar set or AIS is essential but it does mean that the equipment available must be used to the best advantage.
3. Commercial shipping cannot be relied upon to follow the Colregs and so close visual, auditory, and radar watch is essential. We did not hear sound signals from BC; we did not use our own foghorn, although it was available, as we felt it was unlikely to be heard on a large merchant ship and if we used it routinely we were at risk of exhausting the aerosol canister so that it should be conserved for emergency use only.
4. Do not alter course to port, except for a vessel on the starboard quarter, without careful consideration of all other options, except as in our second alteration, as a last resort.
5. An alternative to an alteration of course is to reduce speed or stop which should always be considered. In this case if we had stopped we should still have been at risk when BC altered course towards us. We felt that a substantial alteration of course of 90 degrees was more likely to have been evident to BC than a reduction of speed of five knots.
Fog at sea is always a cause for concern and sometimes frightening. I hope these comments may help others when faced with this difficult situation.
CHIRP requested further information for clarity of their understanding and was advised by the reporter, they didn't hear any fog signals before the incident, but did afterwards, as they approached the fog bank they heard nothing. They were very surprised when they switched the radar on to have seven/eight contacts in the fog bank, and not a sound from any of them. They now assume everybody relies on AIS. Also whilst BC had a significant bow wave, they didn't notice much wash after she passed us. In retrospect they believe BC must have slowed. Their feeling was the BC didn't see their alteration and thought that BC had avoided the collision by BC actions, whereas in reality it was a Stockholm/Andrea Doria collision type situation.
The quality of this recreational seafarers' end of passage review and their in-depth sharing of lessons learned is commendable.
Seafarers are warned, AIS is not a substitute for radar or for use as a vessel plotting device, it is simply a method whereby vessels can be identified and basic information about them received. The International Maritime Organisation (IMO) in Resolution A.917(22) 'Guidelines for the onboard operational use of shipbourne automatic identification systems (AIS)' states AIS are designed to be capable of providing information about the ship to other ships and to coastal authorities automatically; they are not a device to be used for collision avoidance purposes. Also be aware of the risk of human error and the use/ set up of equipment causing an AIS signal not to be detected by another station. Many recreational craft are fitted with class B systems, vessels over 300gt are fitted with class A systems and research has shown that in some circumstances AIS-B transmissions may not be detected by AIS-A equipment and they can even turn off AIS-B reception.
In addition to the lessons learned by the reporter, recreational seafarers should be aware, even when a large vessel has eased off its propulsion, a significant bow wave will still occur until it has almost stopped in the water. It is also prudent to review the boat's inventory of safety equipment and allow for redundancy. As there was concern of their air supply for the horn, the crew could have used a hand operated or mouth operated horn as a back up.
Categories: Complacency, Culture, Error Enforcing Conditions, Human Element Analysis, Latent Failures, Procedures, Situation Awareness, Training


text:
Contemporary R&B soloist Bobii Lewis has been announced to join Craig David and Rita Ora when they perform at The County Ground, home of Northamptonshire County Cricket on Saturday 01 September 2018.
Having already supported Craig David at his recent O2 Academy Brixton show, Tottenham born Bobii has grown into one of the biggest names in UK underground contemporary R&B.
Since releasing his debut mixtape Blind In The Summer, which saw collaborations with Stefflon Don and WSTRN, he is currently working on his highly anticipated debut album
which promises to masterfully fuse his influences of R&B, hip-hop and reggae and feature some high-level collaborations.
**Bobii has evolved into a transcendent R&B talent – CLASH**
**Make sure you get yourself acquainted with this rising talent – Complex** **'Drifting' is the perfect proof of the young R&B musician's undeniable talent – Wonderland** **A gem of an artist - GRM Daily**
Tickets for Craig David and Rita Ora with special guest Bobii Lewis at The County Ground, Northampton County Cricket Club are available to purchase now.
www.ticketmaster.co.uk
www.lhgtickets.com
www.nccc.co.uk
Tickets are priced at: £39.50 + booking fee (General Admission), £45.00 + booking fee (Silver) and £60.00 (Golden Circle)
Children under the age of 16 must be accompanied by an adult, Under 5's go free
Tickets are all standing
This concert is outdoors
Accessible Tickets Purchase Information
Twitter: https://twitter.com/CraigDavid Facebook: https://www.facebook.com/CraigDavid Instagram: https://www.instagram.com/craigdavid


Total Government Net Lending/ Borrowing (% of GDP) for Burundi in year 2015 is -6.914 %.
This makes Burundi No. 159 in world rankings according to Total Government Net Lending/ Borrowing (% of GDP) in year 2015. The world's average Total Government Net Lending/ Borrowing (% of GDP) value is -3.65 %; Burundi is 3.26 less than the average.
In the previous year, 2014, Total Government Net Lending/ Borrowing (% of GDP) for Burundi was -3.68 % Total Government Net Lending/ Borrowing (% of GDP) for Burundi in 2015 was or will be 87.78% more than it was or will be in 2014.
In the following or forecasted year, 2016, Total Government Net Lending/ Borrowing (% of GDP) for Burundi was or will be -3.33 %, which is 51.82% less than the 2015 figure.


New Delhi: The Supreme Court Monday halted the criminal trial of auction portal eBay India and its chief Avinash Bajaj for an alleged sale of an obscene video clip showing two Delhi students.
A bench of Justice Altmas Kabir suspended a Delhi High Court ruling, which had scrapped their prosecution under penal laws but had allowed it under the new information technology law.
The apex court bench halted the trial on a lawsuit by Bajaj who challenged the high court ruling. The high court allowed his prosecution under section 85 of the Information Technology Act, 2000, for violating section 67 of the law, which prohibits publishing obscene information in electronic form.
Delhi Police had registered a criminal case against Bajaj and his erstwhile firm Baazee.Com India Pvt Ltd, now eBay India Pvt Ltd, for illegally displaying the video clip on the portal as merchandise for sale.
Bajaj, a US citizen, subsequently sold Bazee.Com to eBay in 2004.
Challenging the Delhi High Court ruling, Bajaj contended in his petition that mere listing of a product for sale could not be termed as crime under the IT Act.
Bajaj in his petition also argued that the term "obscenity" is not defined in the IT Act and accordingly no liability can be fixed on him for listing the 2.37-minute video clip even if it was obscene.
On Bajaj's petition, the bench issued notices to the Delhi government and Delhi Police, seeking their response to his contentions.


text:
Round 2 - Vs VUW Beavers, Nairnville Park, 11 April
Elite v Vic Uni (11/04/2015)
The weather leading up to the 2nd game of the season was pretty dire, leading many to question whether the game would actually take place. Thankfully, the gods at Capital Football decided Cap 7 was to be spared that unhappy fate, and the game was to go ahead, versus the Vic Uni Beavers. Talk during the week was dominated by Adam and Dave's "controversial" line-up and the naming of 7 substitutes. After being dropped for his rubbish performance in Round 1, one unnamed (Pete) Elite player said on Friday night "F*ck Adam and Dave, I'm on the bench so I'm going to get totally wasted tonight". That player (Pete) will obviously remain anonymous, but from looking at a few other lads on the sidelines, that attitude was catching.
After completing their usual pre-game warm-up, the Elite had the usual team talk from the gaffer and got pumped to get things underway. Sadly, like Tinder Todd, we were a bit too premature and excited in front of a bunch of Beavers, as the game was not due to kick off for another 10 minutes.
Finally we got underway, with the Elite kicking off. Damo clearly forgot which team he was playing, as his first touch was a through-ball to the opposition striker. Thankfully, they managed to mess up the chance and no damage was done. Vic Uni were definitely the more confident team starting though, and created a few more chances. One particular one-on-one looked as though it was a goal for all money, but thankfully Dave had stopped going to see his Personal Trainer and the ball deflected to safety (via the post). Turns out that can do more than just pick the ball out of the net (yay Dave).
Around about this time, someone turned up with a chilli bin full of beers on the sideline.
That chance seemed to be the wake-up call that the Elite needed and we started to play much more confidently. After generating a few chances, Stu got a loose ball at the edge of the box and calmly slotted the ball into the corner of the net. Elite 1-0. After that we continued to play all the football, although Vic Uni's "late 80's Wimbledon" style of football continued to cause us issues. After 1 long-ball too many, they won a free kick on the edge of the box and scored with a free header from 1 yard out. 1-1. With half-time approaching the Elite were gaining the ascending. After finally agreeing to come on (and play at his less favoured wing back role), Crespo was causing significant difficulties down their wing. We managed to work a cross into the box, where Greg rose above the defender and majestically powered it into the top corner with his head. A brilliant goal and a wonderful personal moment for Greg as he took a one goal lead in the battle of England's South Coast. 2-1 Elite at Half-time.
The half time team talk centred around continuing to play our game and not gobbing off at the ref. Changes were made. We kick off.
I'm going to be honest and I can't remember anything about this half, other than Webby giving us a 3-1 lead with a header from 1-yard. We then let them back into the game, with 2 goals of dubious legality and the game finished 3-3. Another draw against the Beavers.
MVP points always hard to distribute, but I'm going with:
3 points - Crespo. Looked dangerous a lot when attacking his defender. Showed his potential as the Elite's premier wing back, probably cementing his position there for the season.
2 points – CJ. Played wing-back and did not complain. Held the ball up well when we went short.
1 point – Ganes. Lots of cracking tackles in the first half.
Impartial Onlooker
Great write-up. Completely accurate version of events.


Another Faturan update - from 1913!
Using the French search engine Gallica, I found an older mention of Faturan, in a 1913 publication called Les Temps Nouveaux. Under the "Help Us" heading, the text says, "A friend asks for information on a product imitating amber called Faturan".
So, within 3 years of the first Bakelite plant opening in Germany, a competitive product was on the market. In the US, the same thing happened and Baekeland successfully sued for patent infringement. Not sure how things went in Europe but there were dozens of European phenolic products by the early 1920s, before the original patents ran out.


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