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Genomic Instability: A Stronger Prognostic Marker Than Proliferation for Early Stage Luminal Breast Carcinomas
Anne Vincent-Salomon ,
* E-mail: anne.salomon@curie.net
Affiliations Department of Tumor Biology, Institut Curie, Paris, France, INSERM U830, Institut Curie, Paris, France
Vanessa Benhamo,
Affiliations INSERM U830, Institut Curie, Paris, France, Department of Translational Research, Institut Curie, Paris, France
Eléonore Gravier,
Affiliations Department of Translational Research, Institut Curie, Paris, France, Department of Biostatistics, Institut Curie, Paris, France, INSERMU900, Institut Curie, Paris, France, Ecole des Mines de Paris, Paris, France
Guillem Rigaill,
Affiliations Department of Translational Research, Institut Curie, Paris, France, AgroParisTech, UMR518, Paris, France
Nadège Gruel,
Stéphane Robin,
Affiliation AgroParisTech, UMR518, Paris, France
Yann de Rycke,
Affiliation Department of Biostatistics, Institut Curie, Paris, France
Odette Mariani,
Affiliation Department of Tumor Biology, Institut Curie, Paris, France
Gaëlle Pierron,
David Gentien,
Affiliation Department of Translational Research, Institut Curie, Paris, France
Fabien Reyal,
Affiliation Department of Surgery, Institut Curie, Paris, France
Paul Cottu,
Affiliation Department of Medical Oncology, Institut Curie, Paris, France
Alain Fourquet,
Affiliation Department of Radiation Oncology, Institut Curie, Paris, France
Roman Rouzier,
Xavier Sastre-Garau,
[ ... ],
Affiliation INSERM U830, Institut Curie, Paris, France
[ view less ]
Anne Vincent-Salomon,
David Gentien
Anne Vincent-Salomon Vanessa Benhamo ... Olivier Delattre
The accurate prognosis definition to tailor treatment for early luminal invasive breast carcinoma patients remains challenging.
Two hundred fourteen early luminal breast carcinomas were genotyped with single nucleotide polymorphisms (SNPs) array to determine the number of chromosomal breakpoints as a marker of genomic instability. Proliferation was assessed by KI67 (immunohistochemistry) and genomic grade index (transcriptomic analysis). IHC3 (IHC4 score for HER2 negative tumors) was also determined.
In the training set (109 cases), the optimal cut-off was 34 breakpoints with a specificity of 0.94 and a sensitivity of 0.57 (Area under the curve (AUC): 0.81[0.71; 0.91]). In the validation set (105 cases), the outcome of patients with > 34 breakpoints (11 events / 22 patients) was poorer (logrank test p < 0.001; Relative Risk (RR): 3.7 [1.73; 7.92]), than that of patients with < 34 breakpoints (19 events / 83 patients).Whereas genomic grade and KI67 had a significant prognostic value in univariate analysis in contrast to IHC3 that failed to have a statistical significant prognostic value in this series, the number of breakpoints remained the only significant parameter predictive of outcome (RR: 3.47, Confidence Interval (CI [1.29; 9.31], p = 0.014)) in multivariate analysis .
Genomic instability, defined herein as a high number of chromosomal breakpoints, in early stage luminal breast carcinoma is a stronger prognostic marker than proliferation.
Citation: Vincent-Salomon A, Benhamo V, Gravier E, Rigaill G, Gruel N, Robin S, et al. (2013) Genomic Instability: A Stronger Prognostic Marker Than Proliferation for Early Stage Luminal Breast Carcinomas. PLoS ONE 8(10): e76496. https://doi.org/10.1371/journal.pone.0076496
Editor: William B. Coleman, University of North Carolina School of Medicine, United States of America
Received: February 25, 2013; Accepted: August 27, 2013; Published: October 15, 2013
Copyright: © 2013 vincent-salomon et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Competing interests: The authors declare that no competing interests exist.
A major challenge of breast cancer treatment is to accurately identify patients in whom adjuvant therapy can be safely avoided [1]. Over the past decade, five molecular groups of invasive breast carcinoma have been identified, each associated with a different outcome [2]. Triple-negative carcinomas are recognized as the group associated with the poorest prognosis and efficiently treated with adjuvant chemotherapy [3,4]. Identification of high-risk patients in this group by means of the classical clinicopathological parameters therefore remains difficult. As a result of mammography screening, the majority of breast cancers are now diagnosed at an early luminal stage with no axillary lymph node metastasis, and HER2-negative. The benefit of medical adjuvant treatment in these patients also remains controversial [1]. While luminal carcinoma patients display various outcomes according to their tumor proliferation rate and clinical stage, they harbor a constellation of driver gene mutations and chromosomal alterations [5–9].
Proliferation assessed either by mitotic index according to the Ellis and Elston recommendations [10] or KI67 immunostaining improves the prognostic definition of luminal breast carcinoma patients [11]. However, molecular methods such as genomic grade index (Mapquant®)[12] have been proposed as a more accurate tool to evaluate proliferation. This technique has been developed to classify grade 2 tumors into good and poor outcome groups. IHC4 score, an algorithm inferred from ER, PR, KI67 and HER2 immunostainings has been recently proposed as an interesting alternative tool to refine breast cancers prognostic. Its prognostic value was found to be equivalent to that of the OncotypeDX® for a lower cost [13].
Pangenomic analyses have provided substantial data describing breast carcinoma patterns of genomic alteration [9,14,15]. These analyses, consolidated by recent exome-sequencing results, have also shown that genomic alterations are different according to the molecular or histological types of breast carcinomas [5–7].
The prognostic value of genomic instability for breast cancer has been evaluated either by transcriptomic signature enriched with genes involved in chromosomal integrity maintenance [16–19] or inferred evaluation of ploidy based on fluorescent in situ hybridization [20].
We and others have proposed that the level of genomic complexity within breast carcinomas could contribute to define patient outcome [16,20–23]. In our previous work, we determined that the number of breakpoints had a prognostic power to identify high-risk T1-T2 N0 invasive ductal carcinomas of the breast. We used an in-house array-comparative genomic hybridization (CGH) tool to define a CGH classifier. This classifier was based both on the number of chromosomal breakpoints together with three regions (2p22.2, 3p23 and 8q21-24) to discriminate tumors associated with good and poor outcome. The sensitivity of this classifier was 66%, with a specificity of 84% and an accuracy of 78% [21].
The objective of the present study was to validate, in an independent series, the prognostic value of our previously established genomic signature. In this study, we used a different tool, the SNPs array (SNP 6.0 array, Affymetrix®), as this array has a higher resolution than the array CGH used in our previous study [21] and compared it to proliferation prognostic value. We focused our analysis on early luminal HER2-negative node-negative breast cancers, i.e. in the population of patients in whom prognosis assessment remains challenging, in whom treatment must be adapted to tumor biology and decreased as far as possible to minimize the side effects of chemotherapy.
Patients and tumors
All experiments were performed retrospectively and in accordance with the French Bioethics Law 2004-800, the French National Institute of Cancer (INCa) Ethics Charter and after approval by the Institut Curie review board and ethics committee (Comité de Pilotage of the Groupe Sein). In the French legal context, our institutional review board waived the need for written informed consent from the participants. Moreover, women were informed of the research use of their tissues and did not declare any opposition for such researches. Data were analyzed anonymously.
This analysis was confined to ER-positive, node-negative early (T1-T2 tumor smaller than 30 mm), HER2-negative breast cancers because they now represent the majority of breast carcinomas at diagnosis as a result of systematic screening procedures in western countries [24]. Tumours from the two sets (training and validation) were selected among the 7469 tumor samples from patients treated between 1989 and 1999 with a conservative surgery followed by radiation therapy at the Institut Curie for T1T2 breast carcinoma. The selection criteria for the two sets were small size (
< 3cm), node-negative, invasive ductal breast carcinomas ER + HER2-, node negative. Patients older than 75 years, with previous personal history of cancer, with familial history of breast cancer, with multifocal or bilateral tumours, or with initial metastatic disease were excluded from the study. The final selection was based on the availability and quality of tumor samples in our tumor bank. These samples were collected from fresh surgical specimens by a pathologist within one hour after surgery, flash-frozen in liquid nitrogen and stored at -80°C. The Figure 1 represented the workflow for retrospective tumor selection among available frozen samples collected prospectively between 1989 and 1999. Training set consisted of a case-control group composed of 109 tumors. The median follow-up for the patients of this good prognosis group was 10.9 years, (95% CI: 10.4-11.5). Seventy-nine patients were metastasis-free at five years (A good prognosis group, controls). Thirty patients developed metastasis before four years (Bpoor prognosis group, cases) with a median time to metastasis of 2.3 years (interquartile range: 1.5-3.4). None of the patients had received neoadjuvant or a
djuvant chemotherapy, but six patients had received adjuvant hormone therapy.
Figure 1. Flowshart of patients and tumor's selection and design of the study.
The validation set was composed of 105 tumors samples from 105 patients. Median follow-up was 10.5 years, (95% CI: 10.1-10.9). Tumors were invasive ductal carcinomas smaller than 30 mm, ER-positive, HER2-negative, and node-negative. None of the 105 patients had received neoadjuvant or adjuvant chemotherapy and ten patients had received adjuvant hormone therapy. Thirty out of the 105 patients developed loco-regional or contralateral relapses or experienced a metastatic event (8 out of the 30 patients).
All tumors were retrospectively reviewed by pathologists experienced in breast pathology (XSG and AVS) for the purpose of this study.In particular, histoprognostic grade was assessed retrospectively according to the recommendations of Elston and Ellis [25].
Immunostaining for Estrogen-receptor (ER), progesterone-receptor (PR), HER2 and KI67 determination
ER, progesterone receptor, HER2 receptor and KI67 status were assessed by immunohistochemistry on representative formalin-fixed tumor blocks, according to previously published protocols[26] (see Data S1 for antibody details). The semiquantitative KI67 assessment was performed as previously published [27] and as recommended [28]. A cut-off of 14% was used to define tumors with a high KI67 score (according to St Gallen recommendations [29] and cut-off for molecular classification[30]. Internal (normal glands surrounding the carcinoma) and external controls (for ER, PR and HER2: tissue-microarrays composed of tumors with known ER, PR status, and known numbers of HER2 gene copies together with normal mammary tissue; for KI67: normal lymph node with germinal centers as positive controls) were included in all immunostaining experiments.
Following Cuzick's recommandations, the IHC4 was determined and adapted for HER2 negative tumors (named "IHC3") and, as KI67 was assessed manually, in the formulae, the KI67 value was rescaled [13].
DNA and RNA analyses
All tumor samples contained more than 50% of cancer cells, as assessed by Hematein & Eosin staining of histologic sections of the frozen samples used for nucleic acid extraction. DNA and RNA were extracted according to a previously described phenol-chloroform protocol [27,31].
SNP6.0 analyses for tumor genomic complexity evaluation
The Affymetrix GeneChip Human Mapping 6.0® was normalized using Affymetrix Genotyping Console® (version GTC 3.0.1) (.cel files and data available under accession number GSE48064 in GEO database).The signal from SNP probes was then segmented using Colibri [32]. A first segmentation round was performed to identify and discard outlier probes giving rise to singleton segments. The number of breakpoints was estimated according to the Zhang and Siegmund's BIC-based model selection criterion (Data S2) [33].
The optimal segmentation in terms of least-square fit was recovered via dynamic programming. The pruned version proposed in [[32]] can be used to achieve this optimization step with almost linear complexity. We used the implementation available in the cghseg package [34] via the function segmeanCO. The training set was used to assess the link between the number of breakpoints and the tumor group (A: late onset versus B: early onset metastatic or relapse event). The breakpoint number (assessing the number of chromosomal segmental alterations) cut-off able to accurately identify B tumors (poor prognosis tumors) was determined using the Youden index. This index is defined as the threshold that maximizes the sum of sensitivity and specificity. The number of breakpoints was used as a marker of genomic complexity.
Expression analyses and determination of genomic grade index
After RNA quality control and according to a previously published protocol [27], 94 of the 105 validation cases meeting our selection criteria for node status, tumor size, ER and HER2 status, were hybridized onto U133 plus 2.0 Affymetrix® chips. Transcriptomic data were normalized using RMA (under R software 2.13.2 version). The genomic grade index (GGI), a continuous variable, was calculated using the MapQuant DxM protocol, according to Sotiriou et al [12] and as previously described [27], and was defined as GGI = scale [sum (Probe Sets up in Grade 3 tumors-112 probe sets)- sum (Probe Sets up in Grade 1 tumors-16 probe sets)- offset]. Scale and offset are transformation parameters to standardize the genomic grade index values. The MapQuant® GGI was then standardized by setting the scale and offset parameters so that the mean GGI of histologic Grade 1 tumors was -1 and that of histologic grade 3 tumors was +1. The cut-off was set at 0. Based on the value of the GGI, a genomic grade (Genomic Grade 1 or Genomic Grade 3) was then attributed to each tumor sample.
Detailed patient and tumor characteristics are displayed in Table 1. Training and validation sets comprised a large majority of T1, grade 1 and 2 tumors.
Training set (n=109)
Validation set (n=105)
Means (min-max) 55.6 (36-75) 54.2 (40-69)
>50 74 (68%, 95%CI : 59%-77%) 68 (65%, 95%CI : 56%-74%)
<50 35 (32%, 95%CI : 23%-41%) 37 (35%, 95%CI : 26%-44%)
T1 77 (71%, 95%CI :62%-79%) 77 (73%, 95%CI : 65%-82%)
T2 32 (29%, 95%CI : 20%-38%) 28 (27%, 95%CI : 19%-35%)
Elston-Ellis grade
I 63 (58%, 95% CI:49%-67%) 48 (46%, 95% CI : 36%-55%)
II 35 (32%, 95%CI:23%-41%) 41 (39%, 95%CI : 30%-48%)
III 9 (8%, 95%CI :3%-13%) 16 (15, 95%CI : 8%-22%)
Missing values 2 (2%) 0
Vascular invasion
Yes 10 (9%, 95%CI:4%-14%) 20 (19%, 95%CI :12%-26%))
ER status (IHC)
Positive 109 (100%) 105 (100%)
PR status (IHC)
Positive 83 (76%, 95%CI:68%-84%) 80 (76%, 95%CI:68%-84%)
KI67
< 14% nd 47 (45%, 95%CI:36%-55%)
> 14% nd 58 (55%, 95%CI:46%-64%)
Genomic grade
GGI 1 nd 56 (60%, 95%CI:50%-69%)
Undetermined nd 11 (10.5%)
Table 1. Clinico-biological characteristics of patients and tumors.
Min: minimum; max: maximum. GG: genomic grade; ER: estrogen receptors; PR: progesterone receptor; 95%CI: Confidence Interval.
In addition to the Elston and Ellis histoprognostic grade, proliferation was also evaluated by KI67, IHC3 and genomic grade index for 94 of the 105 tumors in the validation set. As shown in Table 1, 45% and 60% of these tumors presented a KI67 index less than 14% of positive cells and a genomic grade index of 1, respectively.
Assessment of genomic complexity with the number of chromosomal breakpoints and definition of a classifier within the training set
According to the segmentation protocol described above, the numbers of breakpoints was determined in group A and group B tumors of the training set and were compared. As shown in Figure 2, the median number of breakpoints in group A tumors was significantly lower (median value=7) than the median number of breakpoints in group B (median value = 40.5)(95% CI: -39.00 ;-14.00, p<0.001, Wilcoxon test).
Figure 2. Boxplot of the number of breakpoints within groups A and B from the training set.
The black line represents the breakpoints median values (median = 7 in A group; median = 40.5 in B group). The bottom and top of the boxes represent the 25th and 75th percentile respectively, whereas the box represents the interquartile range. The whiskers extend to the most extreme data point which is no more than 1.5 times the interquartile range from the box. The single point at the top of each boxplot represents the maximum number of breakpoints within each group A and B respectively.
An optimal cut-off of thirty-four breakpoints was defined to assign each patient to a risk class, as the number of breakpoints ensuring maximum sum of sensitivity (0.57 95% CI: 39%-74%) and specificity (0.94 95% CI: 88%-99%), was 34. A tumor with more than 34 breakpoints was classified in the high-risk complexity group, otherwise it was assigned to the low-risk complexity group. In good prognosis group (no metastatic event within five years), 74 tumors (74/79, 94% 95% CI: 88%-99%) were considered to be low-risk complexity tumors and 5 were considered to be high-risk complexity tumors (5/79, 6% 95% CI: 0%-12%) whereas in poor-prognosis group (metastatic relapse in less than four years), 13 tumors were considered to be low-risk complexity tumors (13/30, 43% 95% CI: 26%-61%) and 17 tumors (17/30, 57% 95% CI: 39%-74%) were considered to be high-risk complexity tumors (Table 2).
Groups Number of breakpoints Specificity Sensitivity
< 34 (%) > 34 (%)
A 74 (94) 5 (6) 0.94
B 13 (43) 17 (57) 0.57
Table 2. Number of tumors with less or more than 34 breakpoints (Threshold) within A and B groups, specificity and sensibility of tumor classification in the training set.
Analysis of the complexity classifier produced a Receiving Operating Characteristics (ROC) curve with a significant area of 0.81 (95% CI: 0.71-0.91) (Figure 3).
Figure 3. Receiving Operating Curve (ROC) curve for the number of breakpoints threshold determination.
Intersection of dotted-lines = Youden index.
Number of breakpoints is linked with histoprognostic grade, genomic grade and KI67 labeling
In the validation set of this series of cases, a link between grade (p<0.001; Kruskal-Wallis test), genomic grade (p<0.001, Wilcoxon test), KI67 (p<0.001, Wilcoxon test) and the number of breakpoints was observed.
The median number of breakpoints in the group of tumors with a KI67 smaller than 14% and greater than or equal to 14% were 5 and 17, respectively, (95% CI:-19-4) (Figure S1).
The Spearman correlation coefficient between genomic grade index and number of breakpoints was 0.54 (p < 0.001) (Figure S2).
Link between the number of breakpoints according to the cut-off chosen and disease-free interval in the validation set
To test the robustness of this cut-off, we determined disease-free interval in the validation set and tested the correlation with the number of breakpoints in univariate and multivariate analyses taking into account clinicopathological and proliferation markers such as grade, KI67 GGI and IHC3 (Table 3).
Multivariate analysis
Relative Risk (95% CI)
Age <=50 vs >50 years 0.94 (0.45-1.98) 0.873
Pathological size >20mm vs <=20mm 1.11 (0.42-2.92) 0.827
Grade II/III vs I 2.12 (0.99-4.5) 0.052 1.39 (0.52-3.70) 0.515
PR status Negative vs Positive 0.9 (0.38-2.1) 0.805
Vascular invasion Yes vs No 1.36 (0.55-3.36) 0.512
KI67(IHC) >14 vs < 14% 2.57 (1.16-5.68) 0.020 1.39 (0.48-4.08) 0.544
Genomic Grade GG3 vs GG1 2.59 (1,17-5.73) 0.019 1.16 (0.39-3.48) 0.788
IHC3 score (continuous) 1.01 (1.00-1.01) 0.204
Number of Breakpoints >34 vs <34 3.7 (1.73-7.92) <0.001 3.47 (1.29-9.31) 0.014
Table 3. Univariate and multivariate analyses for disease free-interval in the validation set.
vs: versus.
Whereas IHC3 score was not found statistically significant in this series of tumors, the three proliferation markers, histopronostic grade, KI67 and genomic grade index together with the number of breakpoints were significantly associated with disease free interval at a significance level of 10% in univariate Cox analysis (Table 3). Interestingly, the number of breakpoints remained the only significant parameter when tested with grade, KI67 and genomic grade index in multivariate Cox analysis (relative risk of 3.47, 95% CI:1.29–9.31, p= 0.014, Wald test). Patients with more than 34 breakpoints experienced a statistically shorter disease-free interval (Log rank test p<0.001), as determined by the Cox model and Kaplan-Meier analyses (Figure 4a).
Figure 4. Disease free-interval (a) and metastasis free-interval (b) analyses (Kaplan Meier analysis and log rank test) in the validation set.
The number of breakpoints was significantly predictive of metastasis-free interval
< 34 breakpoints: 4 events in 83 patients; > 34 breakpoints: 4 events in 22 patients (p=0.009, logrank test; RR: 5.29 [1.32; 21.26]) (Figure 4b).
In this study, we assessed and validated the prognostic power of a genomic complexity signature based on the number of breakpoints determined with a pan-genomic SNP array in early stage node-negative luminal HER2-negative invasive ductal breast cancers. The number of breakpoints in this series outperformed the prognostic value of histoprognostic grade, KI67 index and genomic grade of the tumors.
Using high resolution genome-wide tools from different platforms, Russnes and colleagues [22] showed that, within the different molecular subtypes, qualitative genomic alterations and complex arm aberration index identified tumors associated with breast cancer-specific death. Others groups have shown the prognostic value of chromosomal instability score evaluated as the number of gains and losses assessed on SNP arrays, either in ER positive or negative tumors [16,20,23]. However, these analyses did not focus on early stage (T1 and small T2 N0) luminal tumors.
In our previous work, we have identified a DNA-based genomic signature [21] on T1-T2 breast carcinomas but that encompassed ER and HER2 positive and negative cases. In the present study focused specifically on early stage luminal breast carcinomas, we have further demonstrated the prognostic value of the number of chromosomal breakpoints to assess chromosomal instability using a SNP-based array. ER-positive and HER2-negative, node-negative early stage breast carcinomas are the commonest form of breast cancers in the context of systematic mammography screening. Tailoring treatment for these patients is mandatory but challenging [35]. The challenge is to identify poor prognosis patients when classical anatomical parameters such as size and node status are irrelevant and when the tumors are luminal [36]. The specificity of this new DNA-based signature was increased from 84% to 94%, which means that at initial diagnosis, this signature can contribute to accurate identification of good prognosis breast cancers, i.e. those with 34 breakpoints or less. This signature takes into account the number of breakpoints and not regions of gains or losses. Indeed, luminal invasive carcinomas not otherwise specified demonstrate highly heterogeneous genomic profiles [5] with numerous chromosomal gains and losses, but which are never observed in all cases in the same combination [14,22,34]. We therefore preferred to develop a quantitative signature than a qualitative assessment of the alterations. This approach is more easily reproducible using a standardized bioinformatic tool that can be applied in a customized fashion and is readily accessible [34].
Other authors and we have proposed the use of proliferation as a powerful prognostic tool to identify those tumors with poor outcome [27,28,36]. However, the present study showed that the number of chromosomal breakpoints in multivariate analysis remained the only statistically significant parameter to identify poor prognosis early invasive luminal HER2-negative and node-negative breast cancers, and was more reliable than proliferation assessed by either grade, KI67, IHC3or genomic grade.
Signature such as Oncotype DX® [37] has also been proposed as a robust tool to classify luminal breast carcinomas into three different prognostic groups. However, although the proliferation set of genes is robust and based on five genes encompassing KI67, the HER2 set of genes is more controversial [38], it is of no value in HER2-negative carcinomas. In addition, this test dramatically increases the cost of the diagnostic procedure [39] and it adds little prognostic information compared to the recently proposed cheaper IHC4 test [13,40,41].
In that context, we propose that determination of the number of breakpoints should help to refine the prognosis of early stage breast tumors [21,22]. Even though, the DNA-based signature is correlated with proliferation, it also assesses a different level of biological alterations and provides the global genomic profile of the tumor in a single experiment. It therefore allows an identification of the regions of amplifications, some of which encompass drivers genes that encode for druggable targets [42]. Furthermore, recent developments of Affymetrix® arrays performed with DNA extracted from paraffin-embedded tissue provide promising and robust results like it has been obtained with other arrays [43].
This study demonstrates that genomic complexity assessed by SNPs arrays and determined as the number of breakpoints can be used to predict the outcome of early stage luminal HER2-negative invasive breast carcinomas. But the use of chromosomal breakpoints number in clinical practice will require a prospective validation of its prognostic value in larger and multicentric series of breast cancer patients.
Data S1.
Antibodies used for tumor characterization.
Mathematical analysis for SNP6.0 data segmentation.
Number of breakpoints according to KI67.
Gene expression grade according to number of breakpoints.
The authors thank Dr Anthony Saul for his help in editing the English of our manuscript, Jaydutt Bhalshankhar for his help to deposit transcriptomic and genomic data in a public depository.
Conceived and designed the experiments: AVS OD GP FR PC RR AF XSG. Performed the experiments: VB NG EG DG. Analyzed the data: AVS VB EG YdR SR GR GP. Contributed reagents/materials/analysis tools: AVS XSG AF RR OM FR PC DG. Wrote the manuscript: AVS OD EG. Designed the software used in the analysis to perform the SNP6.0 segmentation analysis: GR SR.
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22. Russnes HG, Vollan HK, Lingjaerde OC, Krasnitz A, Lundin P et al. (2010) Genomic architecture characterizes tumor progression paths and fate in breast cancer patients. Sci Transl Med 2: 38ra47. PubMed: 20592421.
23. Smid M, Hoes M, Sieuwerts AM, Sleijfer S, Zhang Y et al. (2010) Patterns and incidence of chromosomal instability and their prognostic relevance in breast cancer subtypes. Breast Cancer Res Treat 128: 23-30. PubMed: 20632083.
24. Blamey RW, Hornmark-Stenstam B, Ball G, Blichert-Toft M, Cataliotti L et al. (2009) ONCOPOOL - a European database for 16,944 cases of breast cancer. Eur J Cancer 46: 56-71.
25. Elston CW, Ellis IO (1991) Pathological Prognostic Factors in Breast cancer. The value of histological Grade in Breast cancer : experience from a large study with long-term follow-up. Histopathology 19: 403-410. doi:https://doi.org/10.1111/j.1365-2559.1991.tb00229.x. PubMed: 1757079.
26. Vincent-Salomon A, Lucchesi C, Gruel N, Raynal V, Pierron G et al. (2008) Integrated genomic and transcriptomic analysis of ductal carcinoma in situ of the breast. Clin Cancer Res 14: 1956-1965. doi:https://doi.org/10.1158/1078-0432.CCR-07-1465. PubMed: 18381933.
27. Reyal F, Bollet MA, Caly M, Gentien D, Carpentier S et al. (2012) Respective prognostic value of genomic grade and histological proliferation markers in early stage (pN0) breast carcinoma. PLOS ONE 7: e35184. doi:https://doi.org/10.1371/journal.pone.0035184. PubMed: 22529987.
28. Dowsett M, Nielsen TO, A'Hern R, Bartlett J, Coombes RC et al. (2011) Assessment of KI67 in breast cancer: recommendations from the International KI67 in Breast Cancer working group. J Natl Cancer Inst 103: 1656-1664. doi:https://doi.org/10.1093/jnci/djr393. PubMed: 21960707.
29. Goldhirsch A, Wood WC, Coates AS, Gelber RD, Thürlimann B et al. (2011) Strategies for subtypes--dealing with the diversity of breast cancer: highlights of the St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011. Ann Oncol 22: 1736-1747. doi:https://doi.org/10.1093/annonc/mdr304. PubMed: 21709140.
30. Prat A, Cheang MC, Martín M, Parker JS, Carrasco E et al. (2013) Prognostic significance of progesterone receptor-positive tumor cells within immunohistochemically defined luminal A breast cancer. J Clin Oncol 31: 203-209. doi:https://doi.org/10.1200/JCO.2012.43.8150. PubMed: 23233704.
31. Vincent-Salomon A, Raynal V, Lucchesi C, Gruel N, Delattre O (2008) ESR1 gene amplification in breast cancer: a common phenomenon? Nat Genet 40: 802; author reply: 802. doi:https://doi.org/10.1038/ng0708-810. PubMed: 18583967.
32. Rigaill G (2010). runed dynamic programming for optimal multiple change-point detection. arXiv:10040887v1.
33. Zhang NR, Siegmund DO (2007) A modified Bayes information criterion with applications to the analysis of comparative genomic hybridization data. Biometrics 63: 22-32. doi:https://doi.org/10.1111/j.1541-0420.2006.00662.x. PubMed: 17447926.
34. Picard F, Lebarbier E, Hoebeke M, Rigaill G, Thiam B et al. (2011) Joint segmentation, calling, and normalization of multiple CGH profiles. Biostatistics 12: 413-428. doi:https://doi.org/10.1093/biostatistics/kxq076. PubMed: 21209153.
35. Piccart-Gebhart MJ, Sotiriou C (2007) Adjuvant chemotherapy--yes or no? Prognostic markers in early breast cancer. Ann Oncol 18 Suppl 12: xii2-xii7. doi:https://doi.org/10.1093/annonc/mdm532. PubMed: 18083699.
36. Stuart-Harris R, Caldas C, Pinder SE, Pharoah P (2008) Proliferation markers and survival in early breast cancer: a systematic review and meta-analysis of 85 studies in 32,825 patients. Breast 17: 323-334. doi:https://doi.org/10.1016/j.breast.2008.02.002. PubMed: 18455396.
37. Paik S, Shak S, Tang G, Kim C, Baker J et al. (2004) A Multigene Assay to Predict Recurrence of Tamoxifen-Treated, Node-Negative Breast Cancer. N Engl J Med 351: 2817-2826. doi:https://doi.org/10.1056/NEJMoa041588. PubMed: 15591335.
38. Ignatiadis M, Sotiriou C (2011) Breast cancer: Should we assess HER2 status by Oncotype DX? Nat Rev Clin Oncol 9: 12-14. doi:https://doi.org/10.1038/nrclinonc.2011.188. PubMed: 22143144.
39. Dabbs DJ, Klein ME, Mohsin SK, Tubbs RR, Shuai Y et al. (2011) High false-negative rate of HER2 quantitative reverse transcription polymerase chain reaction of the Oncotype DX test: an independent quality assurance study. J Clin Oncol 29: 4279-4285. doi:https://doi.org/10.1200/JCO.2011.34.7963. PubMed: 21990395.
40. Barton S, Zabaglo L, A'Hern R, Turner N, Ferguson T et al. (2012) Assessment of the contribution of the IHC4+C score to decision making in clinical practice in early breast cancer. Br J Cancer 106: 1760-1765. doi:https://doi.org/10.1038/bjc.2012.166. PubMed: 22531639.
41. Tang G, Cuzick J, Costantino JP, Dowsett M, Forbes JF et al. (2011) Risk of recurrence and chemotherapy benefit for patients with node-negative, estrogen receptor-positive breast cancer: recurrence score alone and integrated with pathologic and clinical factors. J Clin Oncol 29: 4365-4372. doi:https://doi.org/10.1200/JCO.2011.35.3714. PubMed: 22010013.
42. Arnedos M, Scott V, Job B, De La Cruz J, Commo F et al. (2012) Array CGH and PIK3CA/AKT1 mutations to drive patients to specific targeted agents: a clinical experience in 108 patients with metastatic breast cancer. Eur J Cancer 48: 2293-2299. doi:https://doi.org/10.1016/j.ejca.2012.06.014. PubMed: 22840369.
43. Krijgsman O, Israeli D, Haan JC, van Essen HF, Smeets SJ et al. (2011) CGH arrays compared for DNA isolated from formalin-fixed, paraffin-embedded material. Genes Chromosomes Cancer 51: 344-352. PubMed: 22162309.
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Cancers and neoplasms
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Genome complexity
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ON SPECIAL WHILE STOCKS LAST - USUALLY $25!!
This title is a perfect beginner resource outlining the basics in reptile care, and has been priced accordingly.
Should you buy a reptile? Is reptile keeping right for you? These are some of the initial questions presented to the first time keeper.
Before selecting your first reptile one needs to consider suitable housing enclosures or racks, substrates, furnishings such as plants and hides and heating systems—these essentials are all explained. The idea of converting an old TV entertainment unit to a vivarium is interesting.
Feeding details prey items, the preparation of frozen items, food sizes and the transition from different size and types of food items as a reptile develops. How to feed, when to feed where to feed, foods to avoid are all explained as is sloughing and associated problems.
The most popular species available through pet shops and breeders are presented in chapter groups of Pygmy Pythons; medium-sized pythons—the Woma, Bredl's, Carpet, Green Tree, Diamond and Rough-scaled; large pythons—Black-headed, Coastal Carpet and Olive; and lizards—small dragons, Blue-tongued Skinks and the Bearded Dragon.
A chapter on turtles is presented by Dr David Vella and Dr Robert Johnson presented the Reptile Hygiene section.
The title is littered with images of Australian reptile enthusiasts handling their favourite reptile.
Colourful and concise this is an informative basic reference that is will be thumbed through constantly by the reader.


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Home Blockchain Bitcoin Arrives At NFL: Carolina Panthers' Russell Okung to Receive Half of...
Bitcoin Arrives At NFL: Carolina Panthers' Russell Okung to Receive Half of His Salary in BTC
Russell Okung is good at playing sports, but for him, Bitcoin is not a game. That's why he's choosing to receive $6.5 million from his salary in BTC.
Carolina Panthers tackle Russell Okung is doubling up his Bitcoin game. The well-known Bitcoin evangelist announced that he would receive 50% of his total salary in Bitcoin.
This makes Russell Okung the first NFL player to be paid with Bitcoin —or any crypto to be fair, giving BTC a further boost as it keeps making headlines in recent weeks with news of more adoption and interest from institutional investors.
A $6.5 Million Touchdown for BTC
The initiative must be approved by both the NFL and the NFL Players Association, but everything seems to point to everything being ready to move forward. Okung himself confirmed the news on his social media.
Russell Okung had expressed his interest in accepting Bitcoin as payment back in 2019; however, there was nothing official during that year. Today, Okung replied to his own tweet, basically saying that his wish came true.
Russell Okung will receive his Bitcoins thanks to Zap's intermediation. Zap is the startup behind Strike, a platform that converts fiat payments to Bitcoin. The company assured that other top athletes are also interested in BTC.
Doing the maths, Russell Okung would be receiving $6.5 Million in Bitcoin, considering that his 2020 salary is agreed at $13 Million. If he was granted his wish back in 2019, when BTC was hovering around $7400, his current holdings would add up to $29.86 million… Wow!
Okung is joining a list of celebrities that are showing Bitcoin some love. Other stars with the same interest are the rap stars Logic, Nas and Megan Thee Stallion, Maisie Williams, and even the NFL cornerback Richard Sherman.
Bitcoin Is Much More Than Money For Russell Okung
Okung has carried out several campaigns to promote the use of Bitcoin and the philosophy behind Bitcoin as a way to free people from the control exercised by the traditional fiat system. He's co-founder of the BitcoinIs Podcast, which focuses on discussing Bitcoin-related issues.
George Mekhail, Co-Founder of BitcoinIs told Cryptopotato that Russell's decision would be one more way to promote the use of Bitcoin and the podcast's philosophy:
"The Bitcoin circular economy is something BitcoinIs was focused on for much of 2020 and 2021 will be even bigger now thanks to the great work of Russell Okung and Strike App."
A circular economy is a form of behavior that seeks to reduce as much waste as possible by maximizing efficiency. Bitcoin can solve that problem because of its non-inflationary, electronic, and decentralized characteristics. Just as a reference, the cost of producing a $100 bill is almost 20 cents, and the Federal Reserve can print infinite amounts of money, which decreases people's purchasing power.
On the other hand, there's a predetermined amount of Bitcoins issued every 10 minutes, and every four years, the rate decreases to 50%. This eventually appreciates the purchasing power of hodlers and is one of the reasons that helped Bitcoin go up in price in 2020.
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redpajama_set_name: RedPajamaCommonCrawl


text:
Request for information concerning ownership of- Re: Land adjacent 34 Elmhurst, Tadley, Hampshire, RG26 3LE
Request for information concerning ownership of- Re: Land adjacent 34 Elmhurst, Tadley, Hampshire, RG26 3LE Notice is hereby given that we,
Request for information concerning ownership of:- Re: Land adjacent 33 Elmhurst, Tadley, Hampshire, RG26 3LE
Request for information concerning ownership of:- Re: Land adjacent 33 Elmhurst, Tadley, Hampshire, RG26 3LE Notice is hereby given that we,
Borough of Basingstoke and Deane Town and Country Planning Act 1990 Planning (Listed Buildings and Conservation Areas) Act 1990
Borough of Basingstoke and Deane Town and Country Planning Act 1990 Planning (Listed Buildings and Conservation Areas) Act 1990 The applications
Notice effective from Thu 10 Oct 19 to Sat 9 Nov 19
SUSAN ELIZABETH WILSHIN Deceased
SUSAN ELIZABETH WILSHIN Deceased Pursuant to the Trustee Act 1925 anyone having a claim against or an interest in the Estate of the deceased,
DAPHNE JOAN BUCKINGHAM (Deceased)
DAPHNE JOAN BUCKINGHAM (Deceased) Pursuant to the Trustee Act 1925 anyone having a claim against or an interest in the Estate of the deceased,
Notice effective from Wed 20 Dec 17 to Fri 19 Jan 18
RUTH MARY LEMCKE (Deceased)
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PAULINE ELIZABETH HARVEY Deceased
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Notice effective from Tue 16 Feb 21 to Thu 18 Mar 21
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Sooner or later I'm going to run out of post titles - that is, if I'm not allowed to use the same name twice. Obviously this one isn't finished, and I didn't spend much time on it to begin with, but here it is. Reference is a photo by Marcus J. Ranum.
Dreadfully sleepy, but didn't want to go to bed, so I pulled a random picture up and tried to draw it. I've come to the realization that I'm locking myself into lines instead of shaping with value. Need to work on that. Leaving it this rough mostly 'cause it's nearly five in the morning and I need to go to sleep.
I feel like it's been a while since I've painted anything to completion. I have been doodling (largely vacating my bowels on a canvas and saving it off never to speak of it again), but my last painting was done over two months ago. Anyways, I felt a little inspired last night and started doodling - although this time, with a bit more of an idea in mind. Kind of. Here's the rough sketch and my progress on the value study.


text:
Weekly Rewind: Tinder for celebrities, Star Wars app launches, and more
By Karen Tumbokon	 July 12, 2015
In the tech world, a lot happens in a week. Too much, in fact, for mere mortals with real lives to keep track of everything. That's why we've compiled a quick and dirty list of the top 10 tech stories from this week. From major glitches halting all NYSE trading and grounding United Airlines flights, to Tinder introducing verified accounts for celebrities and Disney launching the official Star Wars app for iOS and Android devices, it's all here.
Take selfies with Darth Vader in the official Star Wars app
With San Diego Comic-Con right around the corner, it's no surprise that Disney and Lucasfilm launched an official Star Wars app for iOS and Android devices. By downloading the app, Star Wars fans can take and share selfies in iconic costumes, get Star Wars themed weather forecasts, and play sound effects from their favorite characters. The app also provides Star Wars news and blogs from StarWars.com, movie trailers, and behind-the-scenes features.
Tinder adds verified profiles for celebrities you will never date
Tinder announced in a blog post on Tuesday that it's introducing verified profiles for "notable public figures, celebrities, and athletes." If you see a Tinder profile with a blue check mark icon, that means the profile has been through the verification process, which is similar to the ones used by Facebook and Twitter. Over the past few months, it's been rumored that celebrities such as Leonardo DiCaprio and Hilary Duff have been using the dating platform.
Here are all the places that support Apple Pay, including 300+ banks and credit unions
At the time of its launch, Apple Pay had more than 220,000 participating vendors. Now that Apple Pay is compatible with the iPhone 6 and iPhone 6 Plus, banks and retail locations are looking to show their support for Apple Pay. Since new partners are being added to the list every day, we've compiled a list of all of the major brands and countries that support Apple Pay.
Microsoft slashes 7,800 jobs from its phone business
Microsoft announced on Wednesday that it will be laying off up to 7,800 employees over the next few months, most of which are based in its phone division. Microsoft also stated that it will write off $7.6 billion for its acquisition of Nokia's devices and services business, but it admits the deal to acquire Nokia was indeed a failure. The new round of layoffs come in addition to the 18,000 employees Microsoft let go last year.
Major glitches halt NYSE trading and ground United Airlines flights
Ronnie Chua/Shutterstock
United Airlines flights were halted on Wednesday morning after the FFA said it was experiencing "automation issues," which forced planes to be grounded for more than two hours. United said in a statement: "We experienced a network connectivity issue this morning. We are working to resolve this and apologize to our customers for any inconvenience."
The New York Stock Exchange was also halted for nearly four hours on Wednesday after what was described as an "internal problem." The NYSE blames an internal computer glitch for the issues and reports it wasn't a cyberattack.
Next page: 5 more tech stories you might have missed this week
YouTube star PewDiePie made a whopping $7 million in 2014
YouTube's biggest star Felix Kjellberg, also known as PewDiePie, has revealed he earned $7.4 million from recording himself playing video games. Since launching his YouTube channel in 2010, Kjellber's videos received more than 37.7 million subscribers and 9.4 billion views. After Swedish paper Expressen released his earnings, the news began to spread on various social networks.
This app shows you who deleted you on Facebook
2nix Studio/Shutterstock
Keeping up with your friends is tough, and while your Facebook News Feed my appear busy most of the time, missing updates from a certain someone may go unnoticed. As days, or weeks or months go by, you might begin to realize that this person is no longer interacting with your updates, so you check that person's profile and to your surprise, you're no longer friends on Facebook! Every day, Facebook members are blindly "unfriended." While Facebook doesn't provide a feature to notify its users every time they are removed from someone's friends list, an app called Who Deleted Me plans to fill that gap.
Showtime standalone streaming debuts on multiple devices
CBS announced last month its plans for a new a la carte subscription service for Showtime to compete against similar services from HBO and others. Earlier this week, the network launched the new venture, making it available on several platforms including the Apple TV and other Apple devices, Roku boxes, Sony's PlayStation Vue streaming service, and the Web. By downloading the Showtime app, you can catch up on hit shows like Dexter, Weeds, Californication, and more. After the 30-day free trial, you will need to subscribe to Showtime for $11 a month.
T-Mobile's 'Mobile without Borders' ends roaming fees in Mexico and Canada
T-Mobile announced on Thursday it's getting rid of roaming fees for all U.S. users who travel to Mexico and Canada for no extra charge starting July 15. In other words, when T-Mobile users travel to Mexico or Canada, they'll get calls, texts, and data with speeds up to 4G LTE from Mexican and Canadian networks through their Simple Choice plans at no extra cost. The 'Mobile without Borders' feature allows users to call to landlines and mobile phones in both countries.
U.S. Government data breach affected 21.5 million people
Back in April 2015, the Office of Personnel Management discovered that 4.2 million former employees' personal data had been hacked. The government agency revealed that 19.7 million were individuals who applied for background checks, as well as 1.8 million others, who weren't even applicants at all.
What is Signal? How to use the encrypted messaging app
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The best Windows apps
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Common iOS 13 problems and how to fix them (iOS 13.7 update)
What is Apple CarPlay?
How to replace lost or broken AirPods, AirPods Pro, or their charging case
The best cloud storage services for 2021
The best GIF-maker apps and websites for 2021
How to take a screenshot on your Samsung Galaxy S21
The best Apple iPhone deals for January 2021


I've been out and about this week meeting interesting people from the world of "Sustainability". Generally a very pro-active collection of thought leaders and scientists, engineers, consumer activists and the heads of brands who hold the keys to a lot of the immediate doorways to solutions for many of the resource issues that are being grappled with. That said I got to thinking just how complicated it is to come to grips with the full gamut of what being 'sustainable' entails.
In the urgent drive towards becoming, and being part of, a sustainable entity, a lot of bandwagons are being jumped on. The 'green' bandwagon is claiming a lot of passengers at present with brands making bold statements about how 'green' they are or declaring how many major steps are being taken to get them 'greener'.
The other bandwagon is the grand 'natural' one with its passengers, 'eco friendly', 'organic' and the champions of biodiversity. Somehow the passengers are viewed with deep suspicion, and GM agriculture is leading the attack against their global arrival. The quest to return to sound, earth-based principles that allow for respect, rest and regeneration in order to generate abundance is not yet on the big boy's radar.
Then there is the wagon of 'economic development' and its gargantuan passenger, 'energy needs'. If all of these wagons trundle off in different directions there won't be any crash. However, on this journey, there is only one road – the one called earth. Crisscross it all you like, you eventually end up where you started.
The journey towards sustainability is going to require a powerful commitment from all of us in order to reach. The web of interconnectivity can no longer be broken up into single compartments without consideration of the other pieces of the whole. Supply chains are vital in rectifying the pollution and waste issues our society faces, as well as the (excuse the pun) drain on water resources. Reduced access to water leads directly to economic contraction. Suddenly the basics become the most fundamental of all and the balance sheets will require serious amendments.
Green is the colour of the heart chakra. The heart chakra is the love centre of our human energy field and if there is a stagnation of energy in this region, the body manifests various heart related diseases. My granny used to say she suffered from heart trouble and advise on tonics for the heart. The universal panacea is love, of course. Miraculous healing occurs in the presence of love. So no matter which wagon you decide to get on, make sure you take some love with you and see if it spurs you ever faster on the journey.


The beauty dish helps to reduce the scattering of light and obtain a soft diffusion.
Provided with the honeycomb to create a directional light and eliminate harsh shadows.
The silver interior results in higher specularity.
A light soft cloth for creating the soft effect.Compatible with GODOX WITSTRO AD-180 / AD-360 flash.


Icing Designs: Tis the Season for chocolate covered marshmallow snowmen!
Tis the Season for chocolate covered marshmallow snowmen!
We are quickly approaching the holidays! As we all know this month can be so overwhelming. It is almost a hassle to walk through the mall to buy all those gifts on your list. We have learned over the years that some of the best gifts are handmade and from your heart. I have been making homemade sweet trays for years to give to some of my favorite people on my list, including Kellie! I love finding a gorgeous platter and filling it with beautiful sweets and wrapping it up festively! I always include my chocolate covered marshmallow snowmen on the trays and they are always the first thing people comment on. They are so easy to make and are so cute! Today we are really excited to share them with you, along with the easy DIY instructions so that you can make them too! Even if you just make a few and wrap them up sweetly, they make a great little gift to give to someone you love!
These are so easy that even your kids can help! One of my twins, Maia helped me and she did such a great job...and had so much fun! Just use lollipop sticks and put three marshmallows on each stick.
After you are done setting them up you just dip them in white chocolate, shake off the excess and lay them to dry on a parchment lined cookie sheet. As they are drying, add an orange sprinkle for a carrot nose and sprinkle some edible glitter on them to give them some snowy sparkle!
After they are dry put some melted chocolate in a pipping bag and make little half moons for eyes. I like to take a tooth pick and drag some chocolate down to make eye lashes.
Then use some melted pink chocolate to create a ruffled scarf!
If you want to make a snow "man" You can cut a marshmallow in half and instead of letting the chocolate drip off, put it on the parchment paper and move it in a circular motion to create a hat brim.
You can use some melted chocolate to "glue" it on to the top of the snowman!
We hope you try these...your friends and family will love them!
So adorable and yummy! I can't wait to try it! Thanks!!
That is it! We are so going to make these! Love them!
Okay, that are just toooooo stinkin' cute!! Love em and I bet they're soooo tasty! :) Following your fabulous blog now!!
I saw this on Love the Day and I just thought it was the cutest idea!
I am just loving how cute & simple these are. Thank you for sharing!
I also shared them on my blog, I hope you don't mind.
Great idea-you guys are so creative!
They are just amazing !!!!! I would love to make them but I can't figure out out to make the scarf look like that with the chocolate.
Cant wait to try making these with my kids! I was at a craft show today and they were selling them for $3.00! Thanks so much!
Hi I wish i could do NOTHING but make every idea you give us! Wondering how the pink chocolate scarf is applied, How long ahead can they be made and do we store them in the fridge? Thanks.


Focuses on unarmed national movements of resistance to imperial, dictatorial or semi-authoritarian rule in relation to the theories and experience of guerrilla warfare, revolution, concepts of power and links between people power and electoral processes. The discussion, which draws on a range of literatures (including theories of nonviolent action, political thought and democratization) is then set in a global context.
Examines a range of justifications for nonviolent direct action and civil disobedience in liberal parliamentary states, and shows the shifts in debate both within protest movements and in response to them. Also discusses unarmed resistance to corporate exploitation and neoliberal economic policies in a global context.
Particular focus on European and North American movements against nuclear weapons in the 1950s-60s and 1980s and East European responses in the 1980s. But other nuclear disarmament protests, peace campaigns on other issues and nonviolent initiatives in other parts of the world are indicated more briefly.
On a transnational expedition in 1959-60 attempting to prevent French nuclear tests in the Algerian Sahara.
Account of four transnational teams going to Warsaw Pact capitals to protest against the 1968 Warsaw Pact invasion.
the site associated with this Guide. As well as offering both editions of this bibliography, it includes updates and offers access to several books on nonviolence.


This hard cello case is basically the lightest case in the land! It is significantly lighter than the rest of the cases in the Gewa range and for those traveling constantly the hefty price-tag is well worth the investment. The case is very easy to carry rucksack style with the two padded straps supplied, the weight of course makes a significant difference to your back as well as it being much easier to maneuver across train platforms, onto buses, into taxis etc.
Internally the case is similar to other Gewa cases, moulded to fit the cello snugly whilst suspending the cello in the centre of the case which gives fantastic impact protection.


Senators Mark R. Warner and Tim Kaine are accepting applications for the position of judge in the US District Court for the Eastern District of Virginia.
Effective immediately, the Supreme Court of Virginia has approved Legal Ethics Opinion 1887: Duties when a lawyer over whom no one has supervisory authority is impaired.
Supreme Court of Virginia Chief Justice Donald W. Lemons has recommended and is seeking comments on the Conference to the National Task Force on Lawyer Well-Being's report, The Path to Lawyer Well-Being: Practical Recommendations for Positive Change.
Attorneys who would like to assist low-income victims of Hurricane Harvey with their legal issues via the ABA's Free Legal Answers program may do so by following the instructions found here.
The Mandatory Continuing Legal Education Board is seeking comment on proposed changes to Opinion 16 regarding the standards for MCLE courses presented remotely. Comment deadline is September 15, 2017.
Anthem, Aetna, and United Healthcare have announced that they will stop selling individual policies in virtually all Virginia localities effective January 1, 2018. Five insurers remain in Virginia's marketplace: Optima, Kaiser, Piedmont, Cigna, and CareFirst. VSB members with questions concerning coverage may contact their brokers or the Virginia State Bar Members' Insurance Center (877-214-5239) about establishing a group health insurance plan (if they have a full-time non-spousal employee).
At its meeting on May 5, 2017, the Virginia State Bar Clients' Protection Fund Board awarded $66,392.99 in reimbursement to former clients of four Virginia attorneys.
The Virginia State Bar Access to Justice Committee and the Old Dominion Bar Association are sponsoring a seminar with three MCLE hours pending entitled Bridging the Justice Gap through Pro Bono on September 12, 2017, in Richmond.
Registration is open for the 2nd Annual Government Contracting Seminar 2017, September 12, 2017, at the Waterford at Fair Oaks, Fairfax.
Registration is open for the Virginia Academy of Elder Law Attorneys Annual Meeting, September 18, 2017, at the Boar's Head, Charlottesville.
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text:
IPPIS: 96,090 out of about 137,016 lecturers already enrolled – FG
It's disruptive intrusion - ASUU
Juliana Taiwo-Obalonye, Abuja
The Federal Government has disclosed that over 96,090 (70 percent) out of about 137,016 (less than 30 percent) of university lecturers have already enrolled in the Integrated Payroll and Personnel Information System (IPPIS), urging ASUU to encourage the remaining 40,926 members to comply with the process.
This is even as Academic Staff Union of Universities (ASUU) has described IPPIS as "disruptive intrusion", adding "IPPIS violates the laws of the federation, violates university statutes, and violates agreements between the Federal Government and ASUU."
This was disclosed at a meeting presided over President Muhammadu Buhari at the State House in Abuja.
In her remarks at the meeting, the Minister of Finance, Budget and National Planning, Zainab Ahmed, said a desk had been opened in the Office of the Accountant General of the Federation for registration of university staff, assuring that peculiarities of the tertiary institutions will be accommodated.
The minister pointed out that many anomalies were discovered in the university structures that had contributed to the increased cost burden, which include staff working and earning pay in more than one university, contract staff on payroll of the government, tax reductions on PAYEE and multiple employments.
Ahmed said some universities had rushed to recruit more staff before the IPPIS registration commenced, which was then detected.
"While it is clear that ASUU has peculiarities, it should be recognised and rightly accommodated, and the allowances will be made, and not leaving the university out of IPPIS because of the peculiarities," she added.
Secretary to the Government of the Federation, Boss Mustapha, urged ASUU to comply with IPPIS in national interest as his office was already in the process of streamlining all issues of human resources in government.
On IPPIS and university operations, the ASUU President, Prof. Biodun Ogunyemi, said the Federal Government's visitor initiative to the universities, at least once in five years, was the best guarantee for monitoring accountability processes that include internal and external audit processes.
He said the IPPIS will be a "disruptive intrusion", adding: "IPPIS violates the laws of the federation, violates university statutes, and violates agreements between the Federal Government and ASUU.
"The government should welcome ASUU's ongoing innovation of a robust system of human resource management and compensation, called the University Transparency and Accountability Solution, which will address peculiarities of universities and end inappropriate recruitments."
In a statement by the Special Adviser on Media and Publicity, Femi Adesina, quoted President Buhari as saying the Federal Government will give more attention to improving personnel and infrastructure of universities to produce quality graduates, assuring that education will, henceforth, be a top priority in development goals of the country.
He said effective and efficient operations of universities will go a long way in improving the economy, especially with focus on science and technology.
He urged members of ASUU to assist the Federal Government in realising the target of improved education and credible certificates by complying with ongoing verification and validation of human resources in the universities, which will guarantee optimum output.
"The future of the country depends on quality education and our certificates must be credible to inspire confidence," he said.
President Buhari said constitutional provisions should be carefully studied and adhered to for more harmonious relationships, and standards that will promote efficiency.
The president directed the Ministry of Education to put in more effort in ensuring that Nigerian universities are properly funded, with adequate infrastructure and staffing.
The President of ASUU, Ogunyemi, also said the educational sector needed more Federal Government attention, noting that implementation of agreements over the years will go a long way in improving the quality of education in the universities.
He said: "Nigerian universities can make meaningful contributions to addressing the challenges of the country (economy, security and corruption) if given the opportunities. Appropriate funding level, competitive conditions of service, university autonomy and academic freedom are critical to creating such an atmosphere.
"With adequate and effective education, particularly university education, Nigerians will be less susceptible to manipulation, our economy will grow and problems of insecurity and corruption will be drastically reduced," he said.
The ASUU president said Nigeria could learn from countries like China, Malaysia and Singapore that have encouraged universities to drive their educational development through tripartite linkages of government, industries and universities called Triple Helix Principle.
The Minister of Education, Adamu Adamu and Labour and Employment , Dr Chris Ngige, assured that the Federal Government was committed to improving the educational sector, promising to work closely with ASUU.
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