Publications by authors named "Andrew Green"

668 Publications

Untangling the clinicopathological significance of MRE11-RAD50-NBS1 complex in sporadic breast cancers.

NPJ Breast Cancer 2021 Nov 15;7(1):143. Epub 2021 Nov 15.

Nottingham Biodiscovery Institute, School of Medicine, University of Nottingham, University Park, Nottingham, NG7 3RD, UK.

The MRE11-RAD50-NBS1 (MRN) complex is critical for genomic stability. Although germline mutations in MRN may increase breast cancer susceptibility, such mutations are extremely rare. Here, we have conducted a comprehensive clinicopathological study of MRN in sporadic breast cancers. We have protein expression profiled for MRN and a panel of DNA repair factors involved in double-strand break repair (BRCA1, BRCA2, ATM, CHK2, ATR, Chk1, pChk1, RAD51, γH2AX, RPA1, RPA2, DNA-PKcs), RECQ DNA helicases (BLM, WRN, RECQ1, RECQL4, RECQ5), nucleotide excision repair (ERCC1) and base excision repair (SMUG1, APE1, FEN1, PARP1, XRCC1, Pol β) in 1650 clinical breast cancers. The prognostic significance of MRE11, RAD50 and NBS1 transcripts and their microRNA regulators (hsa-miR-494 and hsa-miR-99b) were evaluated in large clinical datasets. Expression of MRN components was analysed in The Cancer Genome Atlas breast cancer cohort. We show that low nuclear MRN is linked to aggressive histopathological phenotypes such as high tumour grade, high mitotic index, oestrogen receptor- and high-risk Nottingham Prognostic Index. In univariate analysis, low nuclear MRE11 and low nuclear RAD50 were associated with poor survival. In multivariate analysis, low nuclear RAD50 remained independently linked with adverse clinical outcomes. Low RAD50 transcripts were also linked with reduced survival. In contrast, overexpression of hsa-miR-494 and hsa-miR-99b microRNAs was associated with poor survival. We observed large-scale genome-wide alterations in MRN-deficient tumours contributing to aggressive behaviour. We conclude that MRN status may be a useful tool to stratify tumours for precision medicine strategies.
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http://dx.doi.org/10.1038/s41523-021-00350-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8593132PMC
November 2021

Stephen Warren.

Authors:
Andrew Green

Lancet 2021 Nov;398(10313):1798

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http://dx.doi.org/10.1016/S0140-6736(21)02404-1DOI Listing
November 2021

Identification of modes of tumor regression in non-small cell lung cancer patients during radiotherapy.

Med Phys 2021 Nov 1. Epub 2021 Nov 1.

Division of Cancer Sciences, University of Manchester, Manchester, UK.

Purpose: Observed gross tumor volume (GTV) shrinkage during radiotherapy (RT) raises the question of whether to adapt treatment to changes observed on the acquired images. In the literature, two modes of tumor regression have been described: elastic and non-elastic. These modes of tumor regression will affect the safety of treatment adaptation. This study applies a novel approach, using routine cone-beam computed tomography (CBCT) and deformable image registration to automatically distinguish between elastic and non-elastic tumor regression.

Methods: In this retrospective study, 150 locally advanced non-small cell lung cancer patients treated with 55 Gray of radiotherapy were included. First, the two modes of tumor regression were simulated. For each mode of tumor regression, one timepoint was simulated. Based on the results of simulated data, the approach used for analysis in real patients was developed. CBCTs were non-rigidly registered to the baseline CBCT using a cubic B-spline algorithm, NiftyReg. Next, the Jacobian determinants were computed from the deformation vector fields. To capture local volume changes, 10 Jacobian values were sampled perpendicular to the surface of the GTV, across the lung-tumor boundary. From the simulated data, we can distinguish elastic from non-elastic tumor regression by comparing the Jacobian values samples between 5 and 12.5 mm inside and 5 and 12.5 mm outside the planning GTV. Finally, morphometric results were compared between tumors of different histologies.

Results: Most patients (92.3%) in our cohort showed stable disease in the first week of treatment and non-elastic shrinkage in the later weeks of treatment. At week 2, 125 patients (88%) showed stable disease, three patients (2.1%) disease progression, and 11 patients (8%) regression. By treatment completion, 91 patients (64%) had stable disease, one patient (0.7%) progression and 46 patients (32%) regression. A slight difference in the mode of tumor change was observed between tumors of different histologies.

Conclusion: Our novel approach shows that it may be possible to automatically quantify and identify global changes in lung cancer patients during RT, using routine CBCT images. Our results show that different regions of the tumor change in different ways. Therefore, careful consideration should be taken when adapting RT.
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http://dx.doi.org/10.1002/mp.15320DOI Listing
November 2021

Silver carboxylate-doped titanium dioxide-polydimethylsiloxane coating decreases Cutibacterium acnes adherence and biofilm formation on polyether ether ketone.

Spine J 2021 Oct 16. Epub 2021 Oct 16.

The Warren Alpert Medical School of Brown University, Providence, RI, USA; Department of Orthopaedic Surgery, Warren Alpert Medical School of Brown University, Providence, RI, USA; Weiss Center for Orthopaedic Trauma Research, Rhode Island Hospital, Providence, RI, USA.

Background Context: Cutibacterium acnes (C. acnes) is a gram-positive facultative anaerobe found in the deep sebaceous follicles of the skin on the shoulder and back. C. acnes has been increasingly recognized as a pathogen in spinal surgical site infection (SSI) especially in the presence of instrumentation.

Purpose: This study assesses whether a silver carboxylate-doped titanium dioxide-polydimethylsiloxane (TiO-PDMS) coating can decrease C. acnes adherence and biofilm formation on PEEK and four other commonly used spinal implant materials, stainless steel, cobalt chromium, titanium, and titanium alloy.

Study Design: We compared the adherence of C. acnes over 24 hours between uncoated, 95:5 TiO to PDMS ratio with 10× silver carboxylate coating and a 100% silver carboxylate coating on each implant material, which were uniformly saw cut and sterilized. Implants were then subjected to scanning electron microscopy (SEM) and confocal scanning laser microscopy (CSLM).

Methods: Samples were coated using 95:5 TiO-PDMS 10× silver carboxylate, 100% silver carboxylate, or left uncoated. C. acnes was applied onto the samples and allowed to adhere for periods of 4, 8, 12, 16, or 20 hours. Nonadherent bacteria were then washed from the samples. These samples were then allowed to continue incubating for a total of 24 hours. SEM and confocal laser scanning microscope were used to visualize all samples for the presence of biofilm and quantification of C. acnes adherence at each time point.

Results: The 95:5 TiO-PDMS 10× silver carboxylate coating was able to significantly decrease C. acnes adherence on PEEK after 8, 12, 16, and 20 hours of adherence. No statistical difference was found between the 95:5 TiO-PDMS 10× silver carboxylate coating and the 100% silver carboxylate positive control. We previously observed extensive C. acnes biofilm formation on uncoated PEEK, but none on PEEK coated with either the 95:5 TiO-PDMS 10× silver carboxylate or 100% Ag coating . Furthermore, no biofilm formation was observed on stainless steel, cobalt chromium, titanium, and titanium alloy coated with 95:5 TiO-PDMS 10× silver carboxylate or 100% Ag coating.

Conclusion: A 95:5 TiO-PDMS 10× silver carboxylate coating decreases C. acnes adhesion and prevents biofilm formation on PEEK and other common orthopedic implant materials.

Clinical Significance: A 95:5 TiO-PDMS 10× silver carboxylate coating may help decrease spinal SSI due to C. acnes, especially in procedures with instrumentation.
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http://dx.doi.org/10.1016/j.spinee.2021.09.011DOI Listing
October 2021

Early prediction of tumour-response to radiotherapy in NSCLC patients.

Phys Med Biol 2021 Nov 5;66(22). Epub 2021 Nov 5.

Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom.

. In this study we developed an automatic method to predict tumour volume and shape in weeks 3 and 4 of radiotherapy (RT), using cone-beam computed tomography (CBCT) scans acquired up to week 2, allowing identification of large tumour changes.. 240 non-small cell lung cancer (NSCLC) patients, treated with 55 Gy in 20 fractions, were collected. CBCTs were rigidly registered to the planning CT. Intensity values were extracted in each voxel of the planning target volume across all CBCT images from days 1, 2, 3, 7 and 14. For each patient and in each voxel, four regression models were fitted to voxel intensity; applying linear, Gaussian, quadratic and cubic methods. These models predicted the intensity value for each voxel in weeks 3 and 4, and the tumour volume found by thresholding. Each model was evaluated by computing the root mean square error in pixel value and structural similarity index metric (SSIM) for all patients. Finally, the sensitivity and specificity to predict a 30% change in volume were calculated for each model.. The linear, Gaussian, quadratic and cubic models achieved a comparable similarity score, the average SSIM for all patients was 0.94, 0.94, 0.90, 0.83 in week 3, respectively. At week 3, a sensitivity of 84%, 53%, 90% and 88%, and specificity of 99%, 100%, 91% and 42% were observed for the linear, Gaussian, quadratic and cubic models respectively. Overall, the linear model performed best at predicting those patients that will benefit from RT adaptation. The linear model identified 21% and 23% of patients in our cohort with more than 30% tumour volume reduction to benefit from treatment adaptation in weeks 3 and 4 respectively.. We have shown that it is feasible to predict the shape and volume of NSCLC tumours from routine CBCTs and effectively identify patients who will respond to treatment early.
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http://dx.doi.org/10.1088/1361-6560/ac2f88DOI Listing
November 2021

Abebech Gobena.

Authors:
Andrew Green

Lancet 2021 Oct;398(10308):1298

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http://dx.doi.org/10.1016/S0140-6736(21)02151-6DOI Listing
October 2021

Prognostic significance of receptor expression discordance between primary and recurrent breast cancers: a meta-analysis.

Breast Cancer Res Treat 2021 Oct 6. Epub 2021 Oct 6.

Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, UK.

Purpose: This meta-analysis aimed to investigate whether receptor (estrogen receptor [ER], progesterone receptor [PR], and human epidermal growth factor receptor 2 [HER2]) discordances between primary and recurrent breast cancers affect patients' survival.

Methods: Search terms contained ER, PR, and HER2 status details in both primary and recurrent tumors (local recurrence or distant metastasis) in addition to survival outcome data (overall survival [OS] or post-recurrence survival [PRS]).

Results: Loss of ER or PR in recurrent tumors was significantly associated with shorter OS as compared with receptor-positive concordance (hazard ratio [HR], 1.67; 95% confidence interval [% CI] 1.37-2.04; p < 0.00001 and HR, 1.45; 95% CI 1.21-1.75; p < 0.0001, respectively). Similar trends were observed in groups with only distant metastasis. Gain of ER was a significant predictor of longer PRS as compared with receptor-negative concordance (HR, 0.76; 95% CI 0.59-0.97; p = 0.03). Gain of PR was not a significant predictor of longer survival compared with receptor-negative concordance, but it could be related to better OS at distant metastasis. Both HER2 of loss and gain could be related to poor outcomes.

Conclusion: This meta-analysis showed that receptor conversion in recurrent tumors may affect patient survival as compared with receptor concordance.
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http://dx.doi.org/10.1007/s10549-021-06390-6DOI Listing
October 2021

Nicolaides-Baraitser syndrome in a patient with hypertrophic cardiomyopathy and gene deletion.

Cardiol Young 2021 Sep 15:1-3. Epub 2021 Sep 15.

Department of Paediatric Cardiology, Children's Health Ireland at Crumlin, Dublin, Ireland.

Nicolaides-Baraitser syndrome is a rare, neuro-developmental disorder caused by heterozygous pathogenic variants in the SMARCA2 gene, involved with chromatin regulation. Cardinal features include intellectual disability, short stature, microcephaly, triangular facies, sparse hair, brachydactyly, prominent interphalangeal joints and seizures. Genetic testing demonstrated a loss within SMARCA2 at 9p24.3 inclusive of basepairs 2094861_2141830 (hg19) in our patient. This case highlights a child with Nicolaides-Baraiter syndrome, a SMARCA2 gene deletion and a novel association of hypertrophic obstructive cardiomyopathy.
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http://dx.doi.org/10.1017/S1047951121003826DOI Listing
September 2021

DNA methylation landscapes of 1538 breast cancers reveal a replication-linked clock, epigenomic instability and cis-regulation.

Nat Commun 2021 09 13;12(1):5406. Epub 2021 Sep 13.

Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK.

DNA methylation is aberrant in cancer, but the dynamics, regulatory role and clinical implications of such epigenetic changes are still poorly understood. Here, reduced representation bisulfite sequencing (RRBS) profiles of 1538 breast tumors and 244 normal breast tissues from the METABRIC cohort are reported, facilitating detailed analysis of DNA methylation within a rich context of genomic, transcriptional, and clinical data. Tumor methylation from immune and stromal signatures are deconvoluted leading to the discovery of a tumor replication-linked clock with genome-wide methylation loss in non-CpG island sites. Unexpectedly, methylation in most tumor CpG islands follows two replication-independent processes of gain (MG) or loss (ML) that we term epigenomic instability. Epigenomic instability is correlated with tumor grade and stage, TP53 mutations and poorer prognosis. After controlling for these global trans-acting trends, as well as for X-linked dosage compensation effects, cis-specific methylation and expression correlations are uncovered at hundreds of promoters and over a thousand distal elements. Some of these targeted known tumor suppressors and oncogenes. In conclusion, this study demonstrates that global epigenetic instability can erode cancer methylomes and expose them to localized methylation aberrations in-cis resulting in transcriptional changes seen in tumors.
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http://dx.doi.org/10.1038/s41467-021-25661-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8437946PMC
September 2021

Concordance between core needle biopsy and surgical excision specimens for Ki-67 in breast cancer - a systematic review of the literature.

Histopathology 2021 Sep 2. Epub 2021 Sep 2.

Nottingham Breast Cancer Research Centre, School of Medicine, University of Nottingham, Nottingham, UK.

Aims: The biomarkers oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) are routinely measured in patients with breast cancer with international consensus on how they should be interpreted. There is evidence to support use of other biomarkers to give more detailed predictive and prognostic information. Ki-67 is one example, and measures the proliferative activity of cancer cells. It is important that this can be performed at diagnosis of breast cancer for patients who do not have initial surgical treatment (mainly older women) and those receiving neoadjuvant therapies.

Methods And Results: A systematic review was performed to assess concordance of measurement of Ki-67 between core needle biopsy (CNB) samples and surgical excision (SE) samples in patients with invasive breast cancer. MEDLINE and Embase databases were searched. Studies were eligible if performed within the last 10 years; included quantitative measurement of Ki-67 in both CNB and SE samples with no prior breast cancer treatment; measured concordance between two samples; and had full text available. A total of 22 studies, including 5982 paired CNB and SE samples on which Ki-67 was measured, were appraised. Overall, there appeared to be concordance; however, reliability was unclear. Where given, the Cohen's kappa coefficient (κ) of correlation between samples ranged from 0.261 to 0.712. The concordance rate between CNB and SE where measured as a percentage had a range from 70.3 to 92.7% CONCLUSIONS: Assessment of level of concordance of Ki-67 between CNB and SE samples is hampered by different methodologies. International consensus on Ki-67 measurement is urgently needed.
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http://dx.doi.org/10.1111/his.14555DOI Listing
September 2021

Oestrogen-regulated protein SLC39A6: a biomarker of good prognosis in luminal breast cancer.

Breast Cancer Res Treat 2021 Oct 28;189(3):621-630. Epub 2021 Aug 28.

Division of Cancer and Stem Cells, School of Medicine, The University of Nottingham, University Park, Nottingham, NG7 2RD, England.

Purpose: The outcome of the luminal oestrogen receptor-positive (ER +) subtype of breast cancer (BC) is highly variable and patient stratification needs to be refined. We assessed the prognostic significance of oestrogen-regulated solute carrier family 39 member 6 (SLC39A6) in BC, with emphasis on ER + tumours.

Materials And Methods: SLC39A6 mRNA expression and copy number alterations were assessed using the METABRIC cohort (n = 1980). SLC39A6 protein expression was evaluated in a large (n = 670) and annotated series of early-stage (I-III) operable BC using tissue microarrays and immunohistochemistry. The associations between SLC39A6 expression and clinicopathological parameters, patient outcomes and other ER-related markers were evaluated using Chi-square tests and Kaplan-Meier curves.

Results: High SLC39A6 mRNA and protein expression was associated with features characteristic of less aggressive tumours in the entire BC cohort and ER + subgroup. SLC39A6 protein expression was detected in the cytoplasm and nuclei of the tumour cells. High SLC39A6 nuclear expression and mRNA levels were positively associated with ER + tumours and expression of ER-related markers, including the progesterone receptor, forkhead box protein A1 and GATA binding protein 3. In the ER + luminal BC, high SLC39A6 expression was independently associated with longer BC-specific survival (BCSS) (P = 0.015, HR 0.678, 95% CI 0.472‒0.972) even in those who did not receive endocrine therapy (P = 0.001, HR 0.701, 95% CI 0.463‒1.062).

Conclusion: SLC39A6 may be prognostic for a better outcome in ER + luminal BC. Further functional studies to investigate the role of SLC39A6 in ER + luminal BC are warranted.
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http://dx.doi.org/10.1007/s10549-021-06336-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8505289PMC
October 2021

The Biological and Clinical Significance of Glutaminase in Luminal Breast Cancer.

Cancers (Basel) 2021 Aug 6;13(16). Epub 2021 Aug 6.

Nottingham Breast Cancer Research Centre, Academic Unit for Translational Medical Sciences, School of Medicine, University of Nottingham Biodiscovery Institute, University Park, Nottingham NG7 2RD, UK.

The glutamine metabolism has a key role in the regulation of uncontrolled tumour growth. This study aimed to evaluate the expression and prognostic significance of glutaminase in luminal breast cancer (BC). The glutaminase isoforms (GLS/GLS2) were assessed at genomic/transcriptomic levels, using METABRIC ( = 1398) and GeneMiner datasets ( = 4712), and protein using immunohistochemistry in well-characterised cohorts of Oestrogen receptor-positive/HER2-negative BC patients: ductal carcinoma in situ (DCIS; = 206) and invasive breast cancer (IBC; = 717). Glutaminase expression was associated with clinicopathological features, patient outcome and glutamine-metabolism-related genes. In DCIS, GLS alone and GLS+/GLS2- expression were risk factors for shorter local recurrence-free interval ( < 0.0001 and = 0.001, respectively) and remained prognostic factors independent of tumour size, grade and comedo necrosis ( = 0.0008 and = 0.003, respectively). In IBC, gene copy number gain with high mRNA expression was associated with poor patient outcome ( = 0.011), whereas high GLS2 protein was predictive of a longer disease-free survival ( = 0.006). Glutaminase plays a role in the biological function of luminal BC, particularly GLS in the early non-invasive stage, which could be used as a potential biomarker to predict disease progression and a target for inhibition. Further validation is required to confirm these observations, and functional assessments are needed to explore their specific roles.
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http://dx.doi.org/10.3390/cancers13163963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8391318PMC
August 2021

Multi-Organ Dysfunction in Cerebral Palsy.

Front Pediatr 2021 9;9:668544. Epub 2021 Aug 9.

Discipline of Pediatrics, School of Medicine, Trinity College Dublin, The University of Dublin, Dublin, Ireland.

Cerebral Palsy (CP) describes a heterogenous group of non-progressive disorders of posture or movement, causing activity limitation, due to a lesion in the developing brain. CP is an umbrella term for a heterogenous condition and is, therefore, descriptive rather than a diagnosis. Each case requires detailed consideration of etiology. Our understanding of the underlying cause of CP has developed significantly, with areas such as inflammation, epigenetics and genetic susceptibility to subsequent insults providing new insights. Alongside this, there has been increasing recognition of the multi-organ dysfunction (MOD) associated with CP, in particular in children with higher levels of motor impairment. Therefore, CP should not be seen as an unchanging disorder caused by a solitary insult but rather, as a condition which evolves over time. Assessment of multi-organ function may help to prevent complications in later childhood or adulthood. It may also contribute to an improved understanding of the etiology and thus may have an implication in prevention, interventional methods and therapies. MOD in CP has not yet been quantified and a scoring system may prove useful in allowing advanced clinical planning and follow-up of children with CP. Additionally, several biomarkers hold promise in assisting with long-term monitoring. Clinicians should be aware of the multi-system complications that are associated with CP and which may present significant diagnostic challenges given that many children with CP communicate non-verbally. A step-wise, logical, multi-system approach is required to ensure that the best care is provided to these children. This review summarizes multi-organ dysfunction in children with CP whilst highlighting emerging research and gaps in our knowledge. We identify some potential organ-specific biomarkers which may prove useful in developing guidelines for follow-up and management of these children throughout their lifespan.
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http://dx.doi.org/10.3389/fped.2021.668544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8382237PMC
August 2021

Shoulder Hemiarthroplasty with Nonprosthetic Glenoid Arthroplasty: The Ream-and-Run Procedure.

JBJS Rev 2021 08 25;9(8). Epub 2021 Aug 25.

Department of Orthopaedics and Sports Medicine, University of Washington, Seattle, Washington.

»: Glenoid component wear and loosening are the principal failure modes of anatomic total shoulder arthroplasty (aTSA).

»: The ream-and-run (RnR) procedure is an alternative glenohumeral arthroplasty for patients who wish to avoid the risks and limitations of a prosthetic glenoid component.

»: During the RnR procedure, the arthritic glenoid is conservatively reamed to a single concavity, while the prosthetic humeral component and soft tissues are balanced to provide both mobility and stability of the joint.

»: The success of the RnR procedure depends on careful patient selection, preoperative education and engagement, optimal surgical technique, targeted rehabilitation, and close postoperative communication between the surgeon and the patient.

»: While the RnR procedure allows high levels of shoulder function in most patients, the recovery can be longer and more arduous than with aTSA.

»: Patients who have undergone an RnR procedure occasionally require a second closed or open procedure to address refractory shoulder stiffness, infection, or persistent glenoid-sided pain. These second procedures are more common after the RnR than with aTSA.
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http://dx.doi.org/10.2106/JBJS.RVW.20.00243DOI Listing
August 2021

Spatial distribution and consequences of contaminants in harbour sediments - A case study from Richards Bay Harbour, South Africa.

Mar Pollut Bull 2021 Nov 20;172:112764. Epub 2021 Aug 20.

University of Greifswald, Institute for Geography and Geology, F.L.-Jahn Str. 16, 17489 Greifswald, Germany.

Richards Bay Harbour (RBH) is situated in the industrialized area on the northeast coast of South Africa. To decipher recent human activities and accompanying environmental degradation, surface sediment was collected across RBH and analysed for granulometric and elemental composition, microfaunal assemblages, and microplastics. Microplastics occur most abundantly near recreational areas, whereas metal contamination relates to activities at bulk goods terminals from which they are imported or exported. In particular, Cr and Cu concentrations in surface sediment near bulk goods terminals exceed South African sediment quality guidelines. In metal contaminated sediment, bioindicators reflected stress and were noticeably impacted. A transect of short sediment cores reflects spatial and historical metal contamination and allows quantification of the load of metals within the sediment column. The volume of metal (Cr) contaminated sediment was estimated at almost 2 million m.
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http://dx.doi.org/10.1016/j.marpolbul.2021.112764DOI Listing
November 2021

The frequency and clinical significance of DNA polymerase beta (POLβ) expression in breast ductal carcinoma in situ (DCIS).

Breast Cancer Res Treat 2021 Nov 18;190(1):39-51. Epub 2021 Aug 18.

Division of Cancer and Stem Cells, School of Medicine, The University of Nottingham, Nottingham, UK.

Background: The prediction of clinical behaviour of breast ductal carcinoma in situ (DCIS) and its progression to invasive disease remains a challenge. Alterations of DNA damage repair mechanisms are associated with invasive breast cancer (BC). This study aims to assess the role of base excision repair (BER) DNA Polymerase Beta (POLβ) in DCIS.

Methods: A cohort of DCIS comprising pure DCIS (n = 776) and DCIS coexisting with invasive BC (n = 239) were prepared as tissue microarrays. POLβ protein expression was assessed using immunohistochemistry and correlated with clinicopathological parameters and patient outcome. Preclinically, we investigated the impact of POLβ depletion on stem cell markers in representative DCIS cell line models.

Results: Reduced POLβ expression was associated with aggressive DCIS features including high nuclear grade, comedo necrosis, larger tumour size, hormonal receptor negativity, HER2 overexpression and high Ki67 index. Combined low nuclear/low cytoplasmic POLβ expression showed the strongest association with the features' characteristics of aggressive behaviour. There was a gradual reduction in the POLβ expression from normal breast tissue, to DCIS, with the lowest expression observed in the invasive BC. Low POLβ expression was an independent predictor of recurrence in DCIS patients treated with breast conserving surgery (BCS). POLβ knockdown was associated with a significant increase in cell stemness markers including SOX2, NANOG and OCT4 levels in MCF10-DCIS cell lines.

Conclusion: Loss of POLβ in DCIS is associated with aggressive behaviour and it can predict recurrence. POLβ expression in DCIS provides an additional feature for patients' risk stratification for personalised therapy.
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http://dx.doi.org/10.1007/s10549-021-06357-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8557137PMC
November 2021

Barbara Murphy.

Authors:
Andrew Green

Lancet 2021 07;398(10298):384

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http://dx.doi.org/10.1016/S0140-6736(21)01660-3DOI Listing
July 2021

SLC1A5 co-expression with TALDO1 associates with endocrine therapy failure in estrogen receptor-positive breast cancer.

Breast Cancer Res Treat 2021 Sep 19;189(2):317-331. Epub 2021 Jul 19.

Nottingham Breast Cancer Research Centre, Academic Unit for Translational Medical Sciences, School of Medicine, University of Nottingham Biodiscovery Institute, University of Nottingham, University Park, Nottingham, NG7 2RD, UK.

Purpose: Identification of effective biomarkers for the benefit of endocrine treatment and understanding the molecular pathways that contribute to the development of resistance are of crucial importance to the management of luminal breast cancer. The amino acid transporter SLC1A5 has emerging importance as a prognostic marker and potential therapeutic target in various types of cancer. This study aims to investigate its role in luminal breast cancer as a potential predictive marker for endocrine treatment.

Methods: SLC1A5 expression was assessed at the transcriptomic and proteomic levels in large, well-characterized cohorts of luminal breast cancer. The sensitivity to endocrine therapy after SLC1A5 knockdown was investigated in vitro, using MCF7 and MDA-MB-175 cell lines. Bioinformatic analyses were performed to study the interacting networks of SLC1A5 and to identify a key co-expressed gene with SLC1A5.

Results: Here, we showed that patients with tumors that highly expressed SLC1A5 associated with a high risk of relapse after endocrine treatment. In vitro, depletion of SLC1A5 increases the sensitivity of luminal breast cancer cells to tamoxifen. TALDO1 was identified as key co-expressed gene with SLC1A5, and in vitro knockdown of SLC1A5 showed reduction in TALDO1 expression. Indeed, TALDO1 was associated with poor clinical outcomes in patients who were subject to endocrine therapy.

Conclusion: These findings suggest that metabolic alterations, particularly the interaction between the key amino acid transporter SLC1A5 and metabolic enzyme TALDO1, could affect the sensitivity of endocrine therapy. This study demonstrated the prognostic value of both SLC1A5 and TALDO1 as biomarkers in luminal breast cancer.
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http://dx.doi.org/10.1007/s10549-021-06298-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357718PMC
September 2021

Smarajit Jana.

Authors:
Andrew Green

Lancet 2021 07;398(10296):206

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http://dx.doi.org/10.1016/S0140-6736(21)01561-0DOI Listing
July 2021

A review of the racial heterogeneity of breast cancer stem cells.

Gene 2021 Sep 29;796-797:145805. Epub 2021 Jun 29.

University of Cape Coast, School of Medical Sciences, Department of Surgery, Cape Coast, Ghana.

Breast Cancer Stem Cells has become the toast of many breast cancer investigators in the past two decades owing to their crucial roles in tumourigenesis, progression, differentiation, survival and chemoresistance. Despite the growing list of research data in this field, racial or ethnic comparison studies on these stem cells remain scanty. This study is a comparative racial analysis of putative breast cancer stem cells. Research articles on the clinicopathological significance of breast cancer stem cells within a period of 17 years (2003-2020) were reviewed across 5 major races (African/Black American, Asian, Caucasian/White, Hispanic/Latino, and American). The associations between the stem cells markers (CD44+/CD24/low, BMI1, ALDH1, CD133, and GD2) and clinicopathological and clinical outcomes were analysed. A total of 40 studies were included in this study with 50% Asian, 25% Caucasian, 10% African, 5% American and 2.5% Hispanic/Latino, and 7.5% other mixed races. CD44/CD24 has been associated with TNBC/Basal like phenotype across all races. It is generally associated with poor clinicopathological features such as age, tumour size, lymph node metastasis and lymphovascular invasion. In Asians, CD44/CD24 was associated with DFS and OS but not in Caucasians. ALDH1 was the most studied breast CSC marker (40% of all studies on breast cancer stem cell markers) also associated with poor clinicopathological features including size, age, stage, lymph node metastasis and Nottingham Prognostic Index. ALDH1 was also associated with DFS and OS in Asians but not Caucasians. Racial variations exist in breast cancer stem cell pattern and functions but ill-defined due to multiple factors. Further research is required to better understand the role of breast CSC.
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http://dx.doi.org/10.1016/j.gene.2021.145805DOI Listing
September 2021

Sindisiwe van Zyl.

Authors:
Andrew Green

Lancet 2021 Jun;397(10292):2330

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http://dx.doi.org/10.1016/S0140-6736(21)01322-2DOI Listing
June 2021

The prognostic significance of Flap Endonuclease 1 (FEN1) in breast ductal carcinoma in situ.

Breast Cancer Res Treat 2021 Jul 12;188(1):53-63. Epub 2021 Jun 12.

Nottingham Breast Cancer Research Centre, Division of Cancer and Stem Cells, School of Medicine, The University of Nottingham, Nottingham, UK.

Background: Impaired DNA repair mechanism is one of the cancer hallmarks. Flap Endonuclease 1 (FEN1) is essential for genomic integrity. FEN1 has key roles during base excision repair (BER) and replication. We hypothesised a role for FEN1 in breast cancer pathogenesis. This study aims to assess the role of FEN1 in breast ductal carcinoma in situ (DCIS).

Methods: Expression of FEN1 protein was evaluated in a large (n = 1015) well-characterised cohort of DCIS, comprising pure (n = 776) and mixed (DCIS coexists with invasive breast cancer (IBC); n = 239) using immunohistochemistry (IHC).

Results: FEN1 high expression in DCIS was associated with aggressive and high-risk features including higher nuclear grade, larger tumour size, comedo type necrosis, hormonal receptors negativity, higher proliferation index and triple-negative phenotype. DCIS coexisting with invasive BC showed higher FEN1 nuclear expression compared to normal breast tissue and pure DCIS but revealed significantly lower expression when compared to the invasive component. However, FEN1 protein expression in DCIS was not an independent predictor of local recurrence-free interval.

Conclusion: High FEN1 expression is linked to features of aggressive tumour behaviour and may play a role in the direct progression of DCIS to invasive disease. Further studies are warranted to evaluate its mechanistic roles in DCIS progression and prognosis.
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http://dx.doi.org/10.1007/s10549-021-06271-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8233293PMC
July 2021

Comparison of Postoperative Anatomy Using Anatomic Total Shoulder Arthroplasty Versus Soft-Tissue Balancing Total Shoulder Arthroplasty.

J Am Acad Orthop Surg 2021 Oct;29(19):848-854

From the Department of Orthopaedics, Stanford University Hospitals, Redwood City, CA (Truntzer), the Department of Orthopaedics, University of Kansas Medical Center, Kansas City, KS (Vopat, Barnds), the Department of Orthopaedics, Brown University, Providence, RI (Schwartz, Anavian, Green), and the Department of Orthopaedic Surgery, Yale University, New Haven, CT (Blaine).

Background: The importance of anatomic reconstruction of the proximal humerus on shoulder biomechanics and kinematics after anatomic total shoulder replacement (aTSR) has been highlighted by a number of investigations. The humeral head designs of current-generation shoulder arthroplasty emphasize either anatomic or soft-tissue balancing total shoulder arthroplasty (sbTSR) philosophies. The purpose of this study was to compare the postoperative anatomy of TSR systems used to treat primary glenohumeral osteoarthritis.

Methods: This was a matched cohort study of 60 patients treated with either press-fit aTSR or sbTSR by two shoulder surgeons. The analysis of postoperative true AP radiographs was performed to calculate multiple representative anatomic parameters of the TSR.

Results: A significant difference was observed in the average measurements between the sbTSR and aTSR designs about the humeral head center offset (5.2 ± 0.4 mm versus 3.9 ± 0.3 mm; P = 0.02), implant-humeral shaft angle (0.3 ± 0.3 varus versus 1.7 ± 0.3 valgus, P < 0.001), and humeral head to tuberosity height (8.8 ± 0.4 mm versus 6.2 ± 0.4, P < 0.001), respectively. No significant difference was observed in the average measurements between the two systems' designs regarding the head-shaft angle (133.4° ± 0.8° versus 135.0° ± 1.0°, P = 0.16) and the relation of humeral head to lateral humeral cortex (0.15 ± 0.6 mm inside the lateral cortex versus 0.19 ± 0.6 outside the lateral cortex; P = 0.69), respectively.

Conclusions: Despite differing design philosophies of these systems, and some notable differences, the absolute differences between the measured anatomic parameters were small and not likely clinically relevant. Anatomic and soft-tissue balancing humeral arthroplasty implants can both reliably reconstruct proximal humeral anatomy.
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http://dx.doi.org/10.5435/JAAOS-D-20-00782DOI Listing
October 2021

Flogging a Dead Salmon? Reduced Dose Posterior to Prostate Correlates With Increased PSA Progression in Voxel-Based Analysis of 3 Randomized Phase 3 Trials.

Int J Radiat Oncol Biol Phys 2021 07 20;110(3):696-699. Epub 2021 Apr 20.

Division of Cancer Science, University of Manchester, Manchester, United Kingdom. Electronic address:

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http://dx.doi.org/10.1016/j.ijrobp.2021.01.017DOI Listing
July 2021

PP1, PKA and DARPP-32 in breast cancer: A retrospective assessment of protein and mRNA expression.

J Cell Mol Med 2021 06 15;25(11):5015-5024. Epub 2021 May 15.

Division of Cancer and Stem Cells, Nottingham Breast Cancer Research Centre, School of Medicine, University of Nottingham Biodiscovery Institute, Nottingham, UK.

Cyclic AMP-dependent protein kinase A (PKA) and protein phosphatase 1 (PP1) are proteins involved in numerous essential signalling pathways that modulate physiological and pathological functions. Both PP1 and PKA can be inhibited by dopamine- and cAMP-regulated phosphoprotein 32 kD (DARPP-32). Using immunohistochemistry, PKA and PP1 expression was determined in a large primary breast tumour cohort to evaluate associations between clinical outcome and clinicopathological criteria (n > 1100). In addition, mRNA expression of PKA and PP1 subunits was assessed in the METABRIC data set (n = 1980). Low protein expression of PKA was significantly associated with adverse survival of breast cancer patients; interestingly, this relationship was stronger in ER-positive breast cancer patients. PP1 protein expression was not associated with patient survival. PKA and PP1 subunit mRNA was also assessed; PPP1CA, PRKACG and PRKAR1B were associated with breast cancer-specific survival. In patients with high expression of DARPP-32, low expression of PP1 was associated with adverse survival when compared to high expression in the same group. PKA expression and PP1 expression are of significant interest in cancer as they are involved in a wide array of cellular processes, and these data indicate PKA and PP1 may play an important role in patient outcome.
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http://dx.doi.org/10.1111/jcmm.16447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178272PMC
June 2021

Nawal El Saadawi.

Authors:
Andrew Green

Lancet 2021 May;397(10285):1618

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http://dx.doi.org/10.1016/S0140-6736(21)00941-7DOI Listing
May 2021

Stuart Saunders.

Authors:
Andrew Green

Lancet 2021 Apr;397(10281):1258

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http://dx.doi.org/10.1016/S0140-6736(21)00725-XDOI Listing
April 2021

Intratumoural Cytochrome P450 Expression in Breast Cancer: Impact on Standard of Care Treatment and New Efforts to Develop Tumour-Selective Therapies.

Biomedicines 2021 Mar 12;9(3). Epub 2021 Mar 12.

Institute of Cancer Therapeutics, School of Pharmacy and Medical Sciences, Faculty of Life Sciences, University of Bradford, Bradford BD7 1DP, UK.

Despite significant advances in treatment strategies over the past decade, selective treatment of breast cancer with limited side-effects still remains a great challenge. The cytochrome P450 (CYP) family of enzymes contribute to cancer cell proliferation, cell signaling and drug metabolism with implications for treatment outcomes. A clearer understanding of CYP expression is important in the pathogenesis of breast cancer as several isoforms play critical roles in metabolising steroid hormones and xenobiotics that contribute to the genesis of breast cancer. The purpose of this review is to provide an update on how the presence of CYPs impacts on standard of care (SoC) drugs used to treat breast cancer as well as discuss opportunities to exploit CYP expression for therapeutic intervention. Finally, we provide our thoughts on future work in CYP research with the aim of supporting ongoing efforts to develop drugs with improved therapeutic index for patient benefit.
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http://dx.doi.org/10.3390/biomedicines9030290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998590PMC
March 2021

Age-Related Biology of Early-Stage Operable Breast Cancer and Its Impact on Clinical Outcome.

Cancers (Basel) 2021 Mar 19;13(6). Epub 2021 Mar 19.

School of Medicine, University of Nottingham, Derby DE22 3DT, UK.

As age advances, breast cancer (BC) tends to change its biological characteristics. This study aimed to explore the natural progression of such changes. The study included 2383 women with clinically T0-2N0-1M0 BC, managed by primary surgery and optimal adjuvant therapy in a dedicated BC facility. Tissue micro-arrays were constructed from their surgical specimens and indirect immunohistochemistry was used for analysis of a large panel ( = 16) of relevant biomarkers. There were significant changes in the pattern of expression of biomarkers related to luminal (oestrogen receptor (ER), progesterone receptors (PgR), human epidermal growth factor receptor (HER-2), E-cadherin, MUC1, bcl2 CK7/8, CK18 and bcl2) and basal (CK5/6, CK14, p53 and Ki67) phenotypes, lymph node stage, histological grade and pathological size when decade-wise comparison was made ( < 0.05). The ages of 40 years and 70 years appeared to be the milestones marking a change of the pattern. There were significantly higher metastasis free and breast cancer specific survival rates among older women with ER positive tumours while there was no significant difference in the ER negative group according to age. Biological characteristics of BC show a pattern of change with advancing age, where 40 years and 70 years appear as important milestones. The pattern suggests <40 years as the phase with aggressive phenotypes, >70 years as the less aggressive phase and 40-70 years being the transitional phase.
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http://dx.doi.org/10.3390/cancers13061417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8003777PMC
March 2021

RANK signaling increases after anti-HER2 therapy contributing to the emergence of resistance in HER2-positive breast cancer.

Breast Cancer Res 2021 03 30;23(1):42. Epub 2021 Mar 30.

Oncobell, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.

Background: Around 15-20% of primary breast cancers are characterized by HER2 protein overexpression and/or HER2 gene amplification. Despite the successful development of anti-HER2 drugs, intrinsic and acquired resistance represents a major hurdle. This study was performed to analyze the RANK pathway contribution in HER2-positive breast cancer and anti-HER2 therapy resistance.

Methods: RANK and RANKL protein expression was assessed in samples from HER2-positive breast cancer patients resistant to anti-HER2 therapy and treatment-naive patients. RANK and RANKL gene expression was analyzed in paired samples from patients treated with neoadjuvant dual HER2-blockade (lapatinib and trastuzumab) from the SOLTI-1114 PAMELA trial. Additionally, HER2-positive breast cancer cell lines were used to modulate RANK expression and analyze in vitro the contribution of RANK signaling to anti-HER2 resistance and downstream signaling.

Results: RANK and RANKL proteins are more frequently detected in HER2-positive tumors that have acquired resistance to anti-HER2 therapies than in treatment-naive ones. RANK (but not RANKL) gene expression increased after dual anti-HER2 neoadjuvant therapy in the cohort from the SOLTI-1114 PAMELA trial. Results in HER2-positive breast cancer cell lines recapitulate the clinical observations, with increased RANK expression observed after short-term treatment with the HER2 inhibitor lapatinib or dual anti-HER2 therapy and in lapatinib-resistant cells. After RANKL stimulation, lapatinib-resistant cells show increased NF-κB activation compared to their sensitive counterparts, confirming the enhanced functionality of the RANK pathway in anti-HER2-resistant breast cancer. Overactivation of the RANK signaling pathway enhances ERK and NF-κB signaling and increases lapatinib resistance in different HER2-positive breast cancer cell lines, whereas RANK loss sensitizes lapatinib-resistant cells to the drug. Our results indicate that ErbB signaling is required for RANK/RANKL-driven activation of ERK in several HER2-positive cell lines. In contrast, lapatinib is not able to counteract the NF-κB activation elicited after RANKL treatment in RANK-overexpressing cells. Finally, we show that RANK binds to HER2 in breast cancer cells and that enhanced RANK pathway activation alters HER2 phosphorylation status.

Conclusions: Our data support a physical and functional link between RANK and HER2 signaling in breast cancer and demonstrate that increased RANK signaling may contribute to the development of lapatinib resistance through NF-κB activation. Whether HER2-positive breast cancer patients with tumoral RANK expression might benefit from dual HER2 and RANK inhibition therapy remains to be elucidated.
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http://dx.doi.org/10.1186/s13058-021-01390-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008631PMC
March 2021
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