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BLM m RNA and breast cancer (external validation cohort).

Supplementary Figure S1: BLM m RNA and breast cancer (external validation cohort). Supplementary Figure S2: Western blots and immunohistochemistry. Supplementary Figure S3: BLM protein expression and survival. Supplementary Figure S4: BLM-Rad51 co-expression and survival. Supplementary Figure S5: BLM-Rad51 co-expression and survival in ER+ breast cancers.

Bloom syndrome helicase (BLM) has key roles in homologous recombination repair, telomere maintenance, and DNA replication. Germ-line mutations in the BLM gene causes Bloom syndrome, a rare disorder characterized by premature aging and predisposition to multiple cancers, including breast cancer. The clinicopathologic significance of BLM in sporadic breast cancers is unknown. We investigated BLM mRNA expression in the Molecular Taxonomy of Breast Cancer International Consortium cohort (n = 1,950) and validated in an external dataset of 2,413 tumors. BLM protein level was evaluated in the Nottingham Tenovus series comprising 1,650 breast tumors. BLM mRNA overexpression was significantly associated with high histologic grade, larger tumor size, estrogen receptor–negative (ER−), progesterone receptor–negative (PR−), and triple-negative phenotypes (ps < 0.0001). BLM mRNA overexpression was also linked to aggressive molecular phenotypes, including PAM50.Her2 (P < 0.0001), PAM50.Basal (P < 0.0001), and PAM50.LumB (P < 0.0001) and Genufu subtype (ER+/Her2−/high proliferation; P < 0.0001). PAM50.LumA tumors and Genufu subtype (ER+/Her2−/low proliferation) were more likely to express low levels of BLM mRNA (ps < 0.0001). Integrative molecular clusters (intClust) intClust.1 (P < 0.0001), intClust.5 (P < 0.0001), intClust.9 (P < 0.0001), and intClust.10 (P < 0.0001) were also more likely in tumors with high BLM mRNA expression. BLM mRNA overexpression was associated with poor breast cancer–specific survival (BCSS; ps < 0.000001). At the protein level, altered subcellular localization with high cytoplasmic BLM and low nuclear BLM was linked to aggressive phenotypes. In multivariate analysis, BLM mRNA and BLM protein levels independently influenced BCSS. This is the first and the largest study to provide evidence that BLM is a promising biomarker in breast cancer. Mol Cancer Ther; 14(4); 1057–65. ©2015 AACR.

Supplementary Figure S1. RECQL1 and survival in ER+ or ER- breast cancer patients. Supplementary Figure S2. RECQL1-depleted MCF-7 cells exhibit sensitivity to doxorubicin. Supplementary Figure S3. RECQL1 depletion and ERα protein levels.

Supplementary Table S1: Clinicopathological characteristics in the METABRIC cohort Supplementary Table S2: Clinicopathological characteristics of Nottingham Tenovus series Supplemental Table S3: Clinicopathological characteristics of ER- cohort Supplemental Table S4: Clinicopathological characteristics of BRCA germ-line deficient cohort Supplementary Table S5: Antigens, primary antibodies, clone, source, optimal dilution and scoring system used for each immunohistochemical marker Supplementary Table S6. RecQL1 mRNA expression and breast cancer. Supplementary Table S7. RECQL1 protein levels and ER+ breast cancers. Supplementary Table S8. RECQL1 protein levels and ER- breast cancers.

RECQL1 expression and survival in ER+ or ER- breast cancers

Supplementary Tables S1-S9: Supplementary Table S1: Clinicopathological characteristics in the METABRIC cohort Supplementary Table S2: External validation cohorts (pooled n = 2413). Supplementary Table S3: Clinicopathological characteristics of Nottingham cohort Supplementary Table S4: Antigens, primary antibodies, clone, source, optimal dilution and scoring system used for each immunohistochemical marker Supplementary Table S5: BLM (nuclear protein expression) in breast cancer Supplementary Table S6: BLM (cytoplasmic protein expression) in breast cancer Supplementary Table S7: BLM (nuclear and cytoplasmic protein co-expression) in breast cancer Supplementary Table S8. BLM - Rad51 nuclear co-expression and breast cancer Supplementary Table S9: Multivariate analysis in Nottingham cohort.

RECQL1, a key member of the RecQ family of DNA helicases, is required for DNA replication and DNA repair. Two recent studies have shown that germline RECQL1 mutations are associated with increased breast cancer susceptibility. Whether altered RECQL1 expression has clinicopathologic significance in sporadic breast cancers is unknown. We evaluated RECQL1 at the transcriptomic level (METABRIC cohort, n = 1,977) and at the protein level [cohort 1, n = 897; cohort 2, n = 252; cohort 3 (BRCA germline deficient), n = 74]. In RECQL1-depleted breast cancer cells, we investigated anthracycline sensitivity. High RECQL1 mRNA was associated with intClust.3 (P = 0.026), which is characterized by low genomic instability. On the other hand, low RECQL1 mRNA was linked to intClust.8 [luminal A estrogen receptor–positive (ER+) subgroup; P = 0.0455] and intClust.9 (luminal B ER+ subgroup; P = 0.0346) molecular phenotypes. Low RECQL1 expression was associated with shorter breast cancer–specific survival (P = 0.001). At the protein level, low nuclear RECQL1 level was associated with larger tumor size, lymph node positivity, high tumor grade, high mitotic index, pleomorphism, dedifferentiation, ER negativity, and HER-2 overexpression (P < 0.05). In ER+ tumors that received endocrine therapy, low RECQL1 was associated with poor survival (P = 0.008). However, in ER− tumors that received anthracycline-based chemotherapy, high RECQL1 was associated with poor survival (P = 0.048). In RECQL1-depleted breast cancer cell lines, we confirmed doxorubicin sensitivity, which was associated with DNA double-strand breaks accumulation, S-phase cell-cycle arrest, and apoptosis. We conclude that RECQL1 has prognostic and predictive significance in breast cancers. Mol Cancer Ther; 16(1); 239–50. ©2016 AACR.

1. Supplementary Figure S1. PCR-SSCP analysis of 21 exons of human RecQL4 gene in human gastric cancer cell lines. 2. Supplementary Figure S2. PCR-SSCP analysis of 21 exons of human RecQL4 gene in human primary gastric tumors and matched gastric tissue controls. 3. Supplementary Figure S3. DNA sequencing result of exons 2-3 of human RecQL4 gene in AGS and HGC-27 cells. 4. Supplementary Figure S4. Coomassie brilliant blue staining images of purified tagged-proteins expressed in E. Coli. 5. Supplementary Figure S5. YB1 domains specifically interacting with RecQL4. 6. Supplementary Figure S6. Level of YB1 and Akt interaction in cytoplasmic(C) and nuclear (N) fractions from MGC-803/Tet-on/Flag-RecQL4 cells with or without RecQL4 induction. 7. Supplementary Figure S7. Effect of YB1 and RecQL4 on MVP promoter activity. 8. Supplementary Figure S8. In vitro direct binding of YB1 and/ RecQL4 proteins to MDR1 promoter region detected by EMSA analysis. 9. Supplementary Table S1. Clinicopathological characteristics of patients with early gastric adenocarcinomas. 10. Supplementary Table S2. Correlation of RecQL4 nuclear and cytoplasmic expression with clinical parameters of gastric cancer patients. 11. Supplementary Table S3. Primer sets of 21 exons of human RecQL4 gene used for PCR-SSCP analysis. 12. Supplementary Table S4. PCR primer sets of drug resistance related genes used for real time RT-PCR analysis.

1. Construction of Tissue Microarray (TMA). 2. Chemicals. 3. Real-time PCR. 4. Dual-Luciferase assay for MVP. 5. In vitro pull-down assay. 6. Co-immunoprecipitation. 7. Protein expression and purification. 8. Chromatin immunoprecipitation analysis 9. Electrophoretic mobility shift assays (EMSAs). 10.PCR-SSCP protocol.

Elevation of the DNA-unwinding helicase RECQL4, which participates in various DNA repair pathways, has been suggested to contribute to the pathogenicity of various human cancers, including gastric cancer. In this study, we addressed the prognostic and chemotherapeutic significance of RECQL4 in human gastric cancer, which has yet to be determined. We observed significant increases in RECQL4 mRNA or protein in >70% of three independent sets of human gastric cancer specimens examined, relative to normal gastric tissues. Strikingly, high RECQL4 expression in primary tumors correlated well with poor survival and gastric cancer lines with high RECQL4 expression displayed increased resistance to cisplatin treatment. Mechanistic investigations revealed a novel role for RECQL4 in transcriptional regulation of the multidrug resistance gene MDR1, through a physical interaction with the transcription factor YB1. Notably, ectopic expression of RECQL4 in cisplatin-sensitive gastric cancer cells with low endogenous RECQL4 was sufficient to render them resistant to cisplatin, in a manner associated with YB1 elevation and MDR1 activation. Conversely, RECQL4 silencing in cisplatin-resistant gastric cancer cells with high endogenous RECQL4 suppressed YB1 phosphorylation, reduced MDR1 expression, and resensitized cells to cisplatin. In establishing RECQL4 as a critical mediator of cisplatin resistance in gastric cancer cells, our findings provide a therapeutic rationale to target RECQL4 or the downstream AKT–YB1–MDR1 axis to improve gastric cancer treatment. Cancer Res; 76(10); 3057–66. ©2016 AACR.

Endodontic retraction is a procedure performed on a tooth that received an earlier attempt at a definitive treatment that resulted in a condition requiring additional new endodontic treatment to achieve a successful outcome. The main cause of treatment failure is insufficient cleaning and inadequate obturation. The objective of this article is to evaluate, through a literature review, the endodontic retreatments with rotary and mechanical files, which is the best efficacy. Experimental and clinical studies were included (case reports, retrospective, prospective and randomized trials) with qualitative and quantitative analysis. The words were included “Endodontic Retreatments” and “Endodontic Treatments”. The conclusion of this article was that with recent technological advances in the area of endodontics, behind the literary reviews we can affirm that the system of instrumentation of the root canals with rotating files maintains the quality of the root preparation.

Dentine hypersensitivity (DHS) is a widespread painful dental problem that is characterized by short sharp pain arising from exposed dentin in response to several different stimuli. This accepted definition, indicates the need to consider a differential diagnosis to rule out other causes of dental pain before the diagnosis of dentin hypersensitivity is made. The management strategy of this dental problem required a good understanding of the complexity of the condition and the variety of the treatment options. The aim of this review is to inform practitioners about dentin hypersensitivity, to provide a brief overview of the diagnosis, etiology and clinical management of dentin hypersensitivity.

Over the past few decades, technological advances in endodontics have taken quantum leaps from conventional hand files to rotary system and from direct vision to magnification. Magnification helps the user not only to see more, but to see well. The application of magnification devices in endodontics is mainly meant for visual enhancement and improved ergonomics. This is crucial especially when long hours are spent in a narrow operating space to treat obscure microanatomy. Magnification aids assist in producing higher quality procedures due to better precision and accuracy. Using the microscope aids improved ergonomics for the operator. Using loupes or microscopes improves the clarity in treatment plan as well as its execution. The magnification aids with camera and video monitor attached, enhance the patient education and better documentation. A strong consideration should be given to adopt using the concept of magnification. Nevertheless, application of magnification in dentistry has yet to be introduced into the mainstream practice due to various influences in behavioural patterns. This review intended to explain the significances of magnification in the field of endodontics as well as use of these tools in dental procedures for better accuracy, handling and thoroughness, which will lead to fewer procedural errors.

SARS-CoV-2 is a member of the family of coronaviruses. The first cases were recorded in Wuhan, China, between December 2019 and January 2020. Italy is one of the most affected countries in Europe. COVID-19 is a new challenge in modern dentistry. New guidelines are required in dental clinics to avoid contagion caused by cross-infections. A narrative review was performed using both primary sources, such as scientific articles and secondary ones, such as bibliographic indexes, web pages, and databases. The main search engines were PubMed, SciELO, and Google Scholar. Twelve articles were selected to develop the bibliographic review by applying pre-established inclusion and exclusion criteria. Precautionary measures should be applied to control COVID-19 in clinical practice. Several authors have highlighted the importance of telephone triage and/or clinic questionnaires, body temperature measurement, usage of personal protective equipment, surface disinfection with ethanol between 62% and 71%, high-speed instruments equipped with an anti-retraction system, four-handed work, and large-volume cannulas for aspiration. Clinically, the use of a rubber dam is essential. FFP2 (or N95) and FFP3 respirators, if compared to surgical masks, provide greater protection for health workers against viral respiratory infections. Further accurate studies are needed to confirm this.

One of the most controversial areas of restorative dentistry is the subject of liners, varnishes and bases. Currently, there is no single protocol, with respect to the use of liners, varnishes and bases, for clinicians to follow. This article is an in-depth literature review that discusses the use of liners, varnishes and bases and the types of materials that are available to the restorative dentist. The new emerging concept of minimally invasive dentistry will require new restorative techniques. These changes will require the clinician to revaluate their use of liners, varnishes and bases. Other clinical considerations and findings from recent research are discussed.

PurposeThe aim of this study was investigate the relationship between version and torsional abnormalities of the acetabulum, femur and tibia in patients with symptomatic FAI.MethodsA systematic review was performed according to PRISMA guidelines using the EMBASE, MEDLINE, PubMed and Cochrane databases. Original research articles evaluating the described version and torsional parameters in FAI were included. The MINORS criteria were used to appraise study quality and risk of bias. Mean version and torsion values were displayed using forest plots and the estimated proportion of hips displaying abnormalities in version/torsion were calculated.ResultsA total of 1206 articles were identified from the initial search, with 43 articles, involving 8861 hips, meeting the inclusion criteria. All studies evaluating femoral or acetabular version in FAI reported ‘normal’ mean version values (10–25 °). However, distribution analysis revealed that an estimated 31% and 51% of patients with FAI displayed abnormal central acetabular and femoral version, respectively.ConclusionUp to 51% of patients presenting with symptomatic FAI show an abnormal femoral version, whilst up to 31% demonstrate abnormal acetabular version. This high percentage of version abnormalities highlights the importance of evaluating these parameters routinely during assessment of patients with FAI, to guide clinical decision-making.Level of evidenceIV.

Background: Muscle weakness is common after injury in athletes and in the presence of hip pathology. It will cause abnormal hip biomechanics and can predict future injury. However, objective measurement of hip muscle strength is difficult to perform accurately and reliably. Therefore, it is challenging to determine when an athlete has returned to preinjury levels of strength. In addition, there is currently no standardized method of obtaining measurements, which prevents the data being compared or shared between research centers. Purpose: The purpose of this study is to comprehensively assess the inter- and intraobserver reliability of our standardized muscle strength measurement protocol. Study Design: Descriptive laboratory study. Level of Evidence: Level 3, inception cohort study. Methods: A total of 16 healthy male volunteers (age = 28.3 ± 7.9 years) were recruited. Those with a previous history of hip injuries or disorders were excluded. These volunteers underwent strength testing according to the Cambridge Protocol on 4 separate occasions, performed by 2 independent assessors. Maximal voluntary contractions, fatigue torque fluctuations, and electromyography measurements were recorded. Intra- and interobserver reliability was assessed using intraclass correlation coefficient (ICC). Results: Good-to-excellent correlation was seen for both intra- and interobserver reliability across almost all hip movements for maximal contractions: ICC ranged 0.78 to 0.93 and 0.78 to 0.96, respectively. The standard error of the mean for all hip movements was also extremely low at 2% to 3%. Conclusion: The Cambridge Protocol is a highly reliable method for objective measurement of hip muscle strength. We recommend future studies use this protocol, or the principles underpinning it, to enable data sharing and comparison across different studies. Clinical Relevance: This is a description and analysis of hip muscle strength measurement. If widely used, it will allow for accurate and objective strength assessment and closer monitoring of hip injuries and pathology.

Aim This systematic review aims to understand the relationship between version abnormalities of the femur and acetabulum in patients with primary and secondary femoroacetabular impingement (FAI). Method A systematic review was conducted according to PRISMA guidelines. A computer-based search was performed using the EMBASE, MEDLINE, PubMed and Cochrane databases for articles relating to version and torsional abnormalities in FAI, Legg-Calve-Perthes disease (LCPD) and slipped capital femoral epiphysis (SCFE). The study was registered in the Open Science Framework. Two authors independently performed title/abstract and full text screening according to predetermined inclusion criteria. Results A total of 1206 articles were identified 55 articles, involving 10, 091 hips, met the inclusion criteria. All studies evaluating femoral/acetabular version in FAI reported ‘normal’ mean version values (10o to 25o). However, distribution analysis revealed that an estimated 31.4% and 51.3% of patients with FAI displayed abnormal acetabular and femoral version, respectively. Abnormal femoral version was reported in an estimated 74.5% of hips with LCPD, and abnormal acetabular version in an estimated 20%. Acetabular version was significantly lower in hips with SCFE compared to controls (Z=-3.26, P Conclusions Patients presenting with hip pain attributed to FAI are likely to display an abnormality in femoral or acetabular version. This highlights the importance of evaluating these parameters during assessment of these patients, in order to guide clinical decision making.

IntroductionWerner protein (WRN) plays an important role in DNA repair, replication, transcription, and consequently genomic stability via its DNA-helicase and exonuclease activity. Loss of function of WRN is associated with Werner syndrome (WS), which is characterized by premature aging and cancer predisposition. Malignancies that are commonly linked to WS are thyroid carcinoma, melanoma, breast cancer, meningioma, and soft tissue and bone sarcomas. Currently, the clinicopathologic significance of WRN in breast cancer is largely unknown.Patients and MethodsWe investigated the clinicopathologic and prognostic significance of WRN protein expression in a cohort of clinically annotated series of sporadic (n = 1650) and BRCA-mutated (n = 75) invasive breast cancers. We correlated WRN protein expression to clinicopathologic characteristics, DNA repair protein expression, and survival outcomes.ResultsThere is strong evidence of association between low nuclear and cytoplasmic WRN co-expression and low levels of KU70/KU80, DNA-PK, DNA Pol-B, CKD18, cytoplasmic RECQL4, and nuclear BLM protein expression (adjusted P-values ConclusionsLow WRN protein expression is associated with poor BCSS in patients with breast cancer. This can be used to optimize the risk stratification for personalized treatment.

Elevation of the DNA-unwinding helicase RECQL4, which participates in various DNA repair pathways, has been suggested to contribute to the pathogenicity of various human cancers, including gastric cancer. In this study, we addressed the prognostic and chemotherapeutic significance of RECQL4 in human gastric cancer, which has yet to be determined. We observed significant increases in RECQL4 mRNA or protein in >70% of three independent sets of human gastric cancer specimens examined, relative to normal gastric tissues. Strikingly, high RECQL4 expression in primary tumors correlated well with poor survival and gastric cancer lines with high RECQL4 expression displayed increased resistance to cisplatin treatment. Mechanistic investigations revealed a novel role for RECQL4 in transcriptional regulation of the multidrug resistance gene MDR1, through a physical interaction with the transcription factor YB1. Notably, ectopic expression of RECQL4 in cisplatin-sensitive gastric cancer cells with low endogenous RECQL4 was sufficient to render them resistant to cisplatin, in a manner associated with YB1 elevation and MDR1 activation. Conversely, RECQL4 silencing in cisplatin-resistant gastric cancer cells with high endogenous RECQL4 suppressed YB1 phosphorylation, reduced MDR1 expression, and resensitized cells to cisplatin. In establishing RECQL4 as a critical mediator of cisplatin resistance in gastric cancer cells, our findings provide a therapeutic rationale to target RECQL4 or the downstream AKT–YB1–MDR1 axis to improve gastric cancer treatment. Cancer Res; 76(10); 3057–66. ©2016 AACR.

Werner syndrome protein (WRN) is a RecQ helicase that participates in DNA repair, genome stability and cellular senescence. The five human RecQ helicases, RECQL1, Bloom, WRN, RECQL4 and RECQL5 play critical roles in DNA repair and cell survival after treatment with the anticancer drug camptothecin (CPT). CPT derivatives are widely used in cancer chemotherapy to inhibit topoisomerase I and generate DNA double-strand breaks during replication. Here we studied the effects of CPT on the stability and expression dynamics of human RecQ helicases. In the cells treated with CPT, we observed distinct effects on WRN compared to other human RecQ helicases. CPT altered the cellular localization of WRN and induced its degradation by a ubiquitin-mediated proteasome pathway. WRN knockdown cells as well as CPT treated cells became senescent and stained positive for senescence-associated β-galactosidase at a higher frequency compared to control cells. However, the senescent phenotype was attenuated by ectopic expression of WRN suggesting functional implication of WRN degradation in CPT treated cells. Approximately 5-23% of breast cancer tumors are known to respond to CPT-based chemotherapy. Interestingly, we found that the extent of CPT-induced WRN degradation correlates with increasing sensitivity of breast cancer cells to CPT. The abundance of WRN decreased in CPT-treated sensitive cells; however, WRN remained relatively stable in CPT-resistant breast cancer cells. In a large clinical cohort of breast cancer patients, we find that WRN and topoisomerase I expression correlate with an aggressive tumor phenotype and poor prognosis. Our novel observations suggest that WRN abundance along with CPT-induced degradation could be a promising strategy for personalizing CPT-based cancer chemotherapeutic regimens.

RECQL4 helicase is a molecular motor that unwinds DNA, a process essential during DNA replication and DNA repair. Germ-line mutations in RECQL4 cause type II Rothmund–Thomson syndrome (RTS), characterized by a premature ageing phenotype and cancer predisposition. RECQL4 is widely considered to be a tumour suppressor, although its role in human breast cancer is largely unknown. As the RECQL4 gene is localized to chromosome 8q24, a site frequently amplified in sporadic breast cancers, we hypothesized that it may play an oncogenic role in breast tumourigenesis. To address this, we analysed large cohorts for gene copy number changes (n = 1977), mRNA expression (n = 1977) and protein level (n = 1902). Breast cancer incidence was also explored in 58 patients with type II RTS. DNA replication dynamics and chemosensitivity was evaluated in RECQL4-depleted breast cancer cells in vitro. Amplification or gain in gene copy number (30.6%), high-level mRNA expression (51%) and high levels of protein (23%) significantly associated with aggressive tumour behaviour, including lymph node positivity, larger tumour size, HER2 overexpression, ER-negativity, triple-negative phenotypes and poor survival. RECQL4 depletion impaired the DNA replication rate and increased chemosensitivity in cultured breast cancer cells. Thus, although recognized as a ’safe guardian of the genome’, our data provide compelling evidence that RECQL4 is tumour promoting in established breast cancers.

Background Access to rehabilitation to prevent disability and optimise function is recommended for patients with cancer, including following cancer diagnosis. Models to integrate rehabilitation within oncology services as cancer treatment commences are required, but must be informed by those they are intended to support. We aimed to identify views of patients, carers and clinicians to develop and refine a rehabilitation model to be tested in a feasibility trial for people newly diagnosed with lung cancer or mesothelioma. Methods We conducted a focus group study with people affected by lung cancer or mesothelioma, their carers and clinicians providing their care to identify priorities for rehabilitation in this period. We sought views on core intervention components, processes and outcomes and integration with oncology services. Data were analysed using thematic analysis. Results Fifteen clinicians (oncologists, nurse specialists, physiotherapists and occupational therapists), nine patients and five carers participated. A proposed outline rehabilitation model was perceived as highly relevant for this population. Participants recommended prompt and brief rehabilitation input, delivered whilst people attend for hospital appointments or at home to maximise accessibility and acceptability. Participants recognised variation in need and all prioritised tailored support for symptom self-management, daily activities and the involvement of carers. Clinicians also prioritised achieving fitness for oncology treatment. Patients and carers prioritised a sensitive manner of approach, positivity and giving hope for the future. Participant’s recommendations for outcome measurement related to confidence in usual daily activities, symptom control and oncology treatment completion rates over objective measures of cardiorespiratory fitness. Conclusion The importance of providing tailored rehabilitation around the time of diagnosis for people with lung cancer or mesothelioma was affirmed by all participants. The refined model of rehabilitation recommended for testing in a feasibility trial is flexible, tailored and short-term. It aims to support people to self-manage symptoms, tolerate cancer treatments and to remain active and independent in daily life. It is delivered alongside scheduled hospital appointments or at home by an expert practitioner sensitive to the psycho-social sequelae that follow a diagnosis of thoracic cancer. Electronic supplementary material The online version of this article (10.1186/s40814-018-0350-0) contains supplementary material, which is available to authorized users.

Bloom syndrome helicase (BLM) has key roles in homologous recombination repair, telomere maintenance, and DNA replication. Germ-line mutations in the BLM gene causes Bloom syndrome, a rare disorder characterized by premature aging and predisposition to multiple cancers, including breast cancer. The clinicopathologic significance of BLM in sporadic breast cancers is unknown. We investigated BLM mRNA expression in the Molecular Taxonomy of Breast Cancer International Consortium cohort (n = 1,950) and validated in an external dataset of 2,413 tumors. BLM protein level was evaluated in the Nottingham Tenovus series comprising 1,650 breast tumors. BLM mRNA overexpression was significantly associated with high histologic grade, larger tumor size, estrogen receptor–negative (ER−), progesterone receptor–negative (PR−), and triple-negative phenotypes (ps < 0.0001). BLM mRNA overexpression was also linked to aggressive molecular phenotypes, including PAM50.Her2 (P < 0.0001), PAM50.Basal (P < 0.0001), and PAM50.LumB (P < 0.0001) and Genufu subtype (ER+/Her2−/high proliferation; P < 0.0001). PAM50.LumA tumors and Genufu subtype (ER+/Her2−/low proliferation) were more likely to express low levels of BLM mRNA (ps < 0.0001). Integrative molecular clusters (intClust) intClust.1 (P < 0.0001), intClust.5 (P < 0.0001), intClust.9 (P < 0.0001), and intClust.10 (P < 0.0001) were also more likely in tumors with high BLM mRNA expression. BLM mRNA overexpression was associated with poor breast cancer–specific survival (BCSS; ps < 0.000001). At the protein level, altered subcellular localization with high cytoplasmic BLM and low nuclear BLM was linked to aggressive phenotypes. In multivariate analysis, BLM mRNA and BLM protein levels independently influenced BCSS. This is the first and the largest study to provide evidence that BLM is a promising biomarker in breast cancer. Mol Cancer Ther; 14(4); 1057–65. ©2015 AACR.

Aim: The aim of this study was to evaluate the apical transportation, centering ability and cyclic fatigue resistance of Hero shaper, Twisted file, Hyflex file and RACE rotary file systems. Methods: Mesiobuccal roots of eighty maxillary molars were divided into four groups and instrumented with Hero shaper, Twisted file, Hyflex file and RACE rotary file systems with a final apical size being 25/.04. Apical deviation was assessed by the radiographic platform method that enables obtaining superimposed images of the first and last instrument used in root canal preparation in the same radiograph. Apical transportation was measured in millimeters with the aid of the AUTOCAD 2008 software. Forty canals were sectioned at 7mm from the apex and stereomicroscopic Images were taken at 6x magnification before and after instrumentation for evaluation of centering ability. The cyclic fatigue testing was conducted with the instrumentrotating freely at angles of curvature of 45 degree. Total 10 instruments were tested in each group. The instruments were rotated at 400rpm using the X-smart motor (Dentsply, Maillefer) until fracture occurred. Results: There was no statistically significant difference between the four groups in apical transportation and centering ability whereas twisted files showed the maximum cyclic fatigue resistance. Conclusion: The different rotary file systems provided minimum canal transportation and the twisted file performed significantly better in terms of cyclic fatigue resistance.

The spectrum sensing methods have been incorporated in an essence to fulfill the sensing requirements associated with the detection of primary user in cognitive radio (CR) networks. Energy detection (ED) is the simplest and most commonly employed method to sense the licensed spectrum so that secondary user can make proficient use of it. The conventional energy detector has predefined value of sensing threshold due to which its targeted performance deteriorates considerably with noise uncertainty under severe fading environment at low SNR province. In this paper, we have proposed a novel approach for the adaptation of sensing threshold based on the imperfect knowledge of channel state information (CSI) so that it must be chosen approximately to meet tradeoff between probability of detection and false alarm probability under severe fading. The simulated results are presented to validate that proposed scheme is more robust against noise vagueness. We have compared the performance efficiency of proposed methodology with imperfect CSI, the conventional methodology with full CSI and conventional scheme with imperfect CSI. It has shown that the proposed scheme significantly outperforms the conventional schemes.

RECQL1, a key member of the RecQ family of DNA helicases, is required for DNA replication and DNA repair. Two recent studies have shown that germline RECQL1 mutations are associated with increased breast cancer susceptibility. Whether altered RECQL1 expression has clinicopathologic significance in sporadic breast cancers is unknown. We evaluated RECQL1 at the transcriptomic level (METABRIC cohort, n = 1,977) and at the protein level [cohort 1, n = 897; cohort 2, n = 252; cohort 3 (BRCA germline deficient), n = 74]. In RECQL1-depleted breast cancer cells, we investigated anthracycline sensitivity. High RECQL1 mRNA was associated with intClust.3 (P = 0.026), which is characterized by low genomic instability. On the other hand, low RECQL1 mRNA was linked to intClust.8 [luminal A estrogen receptor–positive (ER+) subgroup; P = 0.0455] and intClust.9 (luminal B ER+ subgroup; P = 0.0346) molecular phenotypes. Low RECQL1 expression was associated with shorter breast cancer–specific survival (P = 0.001). At the protein level, low nuclear RECQL1 level was associated with larger tumor size, lymph node positivity, high tumor grade, high mitotic index, pleomorphism, dedifferentiation, ER negativity, and HER-2 overexpression (P < 0.05). In ER+ tumors that received endocrine therapy, low RECQL1 was associated with poor survival (P = 0.008). However, in ER− tumors that received anthracycline-based chemotherapy, high RECQL1 was associated with poor survival (P = 0.048). In RECQL1-depleted breast cancer cell lines, we confirmed doxorubicin sensitivity, which was associated with DNA double-strand breaks accumulation, S-phase cell-cycle arrest, and apoptosis. We conclude that RECQL1 has prognostic and predictive significance in breast cancers. Mol Cancer Ther; 16(1); 239–50. ©2016 AACR.

Objectives The aim of this study was to systematically review the literature on measurement of muscle strength in patients with femoroacetabular impingement (FAI) and other pathologies and to suggest guidelines to standardise protocols for future research in the field. Methods The Cochrane and PubMed libraries were searched for any publications using the terms ‘hip’, ‘muscle’, ‘strength’, and ‘measurement’ in the ‘Title, Abstract, Keywords’ field. A further search was performed using the terms ‘femoroacetabular’ or ‘impingement’. The search was limited to recent literature only. Results A total of 29 articles were reviewed to obtain information on a number of variables. These comprised the type of device used for measurement, rater standardisation, the type of movements tested, body positioning and comparative studies of muscle strength in FAI versus normal controls. The studies found that hip muscle strength is lower in patients with FAI; this is also true for the asymptomatic hip in patients with FAI. Conclusions Current literature on this subject is limited and examines multiple variables. Our recommendations for achieving reproducible results include stabilising the patient, measuring isometric movements and maximising standardisation by using a single tester and familiarising the participants with the protocol. Further work must be done to demonstrate the reliability of any new testing method. Cite this article: E. Mayne, A. Memarzadeh, P. Raut, A. Arora, V. Khanduja. Measuring hip muscle strength in patients with femoroacetabular impingement and other hip pathologies: A systematic review. Bone Joint Res 2017;6:66–72. DOI: 10.1302/2046-3758.61.BJR-2016-0081.

Background: ATR-Chk1 signalling network is critical for genomic stability. ATR-Chk1 may be deregulated in breast cancer and have prognostic, predictive and therapeutic significance. Patients and methods: We investigated ATR and phosphorylated CHK1Ser345 protein (pChk1) expression in 1712 breast cancers (Nottingham Tenovus series). ATR and Chk1 mRNA were evaluated in 1950 breast cancers (METABRIC cohort). Pre-clinically, biological consequences of ATR gene knockdown or ATR inhibition by small molecule inhibitor (VE-821) were investigated in MCF-7 and MDA-MB-231 breast cancer cell lines and in non-tumorigenic breast epithelial cells (MCF10A). Results: High ATR and high cytoplasmic pChk1 expression was significantly associated with higher tumour stage, higher mitotic index, pleomorphism and lymphovascular invasion. In univariate analysis, high ATR and high cytoplasmic pChk1 protein expression was associated with shorter breast cancer specific survival (BCSS). In multivariate analysis, high ATR remains an independent predictor of adverse outcome. At the mRNA level, high Chk1 remains associated with aggressive phenotypes including lymph node positivity, high grade, Her-2 overexpression, triple-negative phenotype and molecular classes associated with aggressive behaviour and shorter survival.. Pre-clinically, Chk1 phosphorylation at serine 345 following replication stress (induced by gemcitabine or hydroxyurea treatment) was impaired in ATR knockdown and in VE-821 treated breast cancer cells. Doxycycline inducible knockdown of ATR suppressed growth, which was restored when ATR was re-expressed. Similarly, VE-821 treatment resulted in a dose dependent suppression of cancer cell growth and survival (MCF7 and MDA-MB-231) but had no effect on non-tumorigenic breast epithelial cells (MCF10A). Conclusions: We provides evidence that ATR and Chk1 are promising biomarkers and rational drug target for personalized therapy in breast cancer.

ATM-Chk2 network is critical for genomic stability, and its deregulation may influence breast cancer pathogenesis. We\ud investigated ATM and Chk2 protein levels in two cohorts [cohort 1 (n = 1650) and cohort 2 (n = 252)]. ATM and Chk2\ud mRNA expression was evaluated in the Molecular Taxonomy of Breast Cancer International Consortium cohort (n =\ud 1950). Low nuclear ATM protein level was significantly associated with aggressive breast cancer including larger tumors,\ud higher tumor grade, higher mitotic index, pleomorphism, tumor type, lymphovascular invasion, estrogen receptor (ER)−,\ud PR−, AR−, triple-negative, and basal-like phenotypes (Ps b .05). Breast cancer 1, early onset negative, low XRCC1, low\ud SMUG1, high FEN1, high MIB1, p53 mutants, low MDM2, low Bcl-2, low p21, low Bax, high CDK1, and low Chk2 were\ud also more frequent in tumors with low nuclear ATM level (Ps b .05). Low ATM protein level was significantly associated\ud with poor survival including in patients with ER-negative tumors who received adjuvant anthracycline or cyclophosphamide,\ud methotrexate, and 5-fluorouracil–based adjuvant chemotherapy (Ps b .05). Low nuclear Chk2 protein was\ud likely in ER−/PR−/AR−; HER-2 positive; breast cancer 1, early onset negative; low XRCC1; low SMUG1; low APE1; low\ud polβ; low DNA-PKcs; low ATM; low Bcl-2; and low TOPO2A tumors (P b .05). In patients with ER+ tumors who received\ud endocrine therapy or ER-negative tumors who received chemotherapy, nuclear Chk2 levels did not significantly influence\ud survival. In p53 mutant tumors, low ATM (P b .000001) or high Chk2 (P b .01) was associated with poor survival. When\ud investigated together, low-ATM/high-Chk2 tumors have the worst survival (P = .0033). Our data suggest that ATM-Chk2\ud levels in sporadic breast cancer may have prognostic and predictive significance.

BRCA1, a key factor in homologous recombination (HR) repair may also regulate base excision repair (BER). Targeting BRCA1?BER deficient cells by blockade of ATM and DNA?PKcs could be a promising strategy in breast cancer. We investigated BRCA1, XRCC1 and pol ? protein expression in two cohorts (n = 1602 sporadic and n = 50 germ?line BRCA1 mutated) and mRNA expression in two cohorts (n = 1952 and n = 249). Artificial neural network analysis for BRCA1?DNA repair interacting genes was conducted in 249 tumours. Pre?clinically, BRCA1 proficient and deficient cells were DNA repair expression profiled and evaluated for synthetic lethality using ATM and DNA?PKcs inhibitors either alone or in combination with cisplatin. In human tumours, BRCA1 negativity was strongly associated with low XRCC1, and low pol ? at mRNA and protein levels (p < 0.0001). In patients with BRCA1 negative tumours, low XRCC1 or low pol ? expression was significantly associated with poor survival in univariate and multivariate analysis compared to high XRCC1 or high pol ? expressing BRCA1 negative tumours (ps < 0.05). Pre?clinically, BRCA1 negative cancer cells exhibit low mRNA and low protein expression of XRCC1 and pol ?. BRCA1?BER deficient cells were sensitive to ATM and DNA?PKcs inhibitor treatment either alone or in combination with cisplatin and synthetic lethality was evidenced by DNA double strand breaks accumulation, cell cycle arrest and apoptosis. We conclude that XRCC1 and pol ? expression status in BRCA1 negative tumours may have prognostic significance. BRCA1?BER deficient cells could be targeted by ATM or DNA?PKcs inhibitors for personalized therapy.

Background: DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a serine threonine kinase belonging to the PIKK family (phosphoinositide 3-kinase-like-family of protein kinase), is a critical component of the non-homologous end joining (NHEJ) pathway required for the repair of DNA double strand breaks. DNA-PKcs may be involved in breast cancer pathogenesis. Methods: We evaluated clinicopathological significance of DNA-PKcs protein expression in 1161 tumours and DNA-PKcs mRNA expression in 1950 tumours. We correlated DNA-PKcs to other markers of aggressive phenotypes, DNA repair, apoptosis and cell cycle regulation. Results: Low DNA-PKcs protein expression was associated with higher tumour grade, higher mitotic index, tumour de-differentiation and tumour type (ps

Background The Royal Marsden Hospital (RMH) and Gustave Roussy Institute (GRIm) have prospectively validated prognostic scores to aide patient selection for phase I immunotherapy trials in many tumour sites, including NSCLC. These include number of metastatic sites, LDH, Albumin and Neutrophil-to-Lymphocyte Ratio (NLR). GRIm score stratified 155 patients to high-risk and low-risk categories, according to LDH, Albumin and NLR, with median OS of 4 months in high-risk cohort and 17 months in low-risk group. NSCLC was the predominant tumour site in this analysis including 30 stage IV patients. This score had similar design to RMH score, except for number of metastatic sites instead of NLR. Methods 165 consecutive Nottinghamshire patients with stage IIIB/IV NSCLC on PD1/PDL1 immune-checkpoint inhibitors from December 2015 to December 2018 have been retrospectively analysed. At data cut-off in April 2019, 148 - 151 patients were censored for median TTF, PFS and OS, according to GRIm - RMH scores respectively: 17 patients were unclassified into GRIm (10.3%) and 14, into RMH (8.5%) for LDH unavailability; 70 patients remain alive (42.4%), 31 of whom still receiving immunotherapy (18.8%). Results Table . 1508P mTTF (cycles) mPFS (months) mOS (months) GRIm score 0-1 80 patients (95% CI) Pembrolizumab-61 p Atezolizumab-13 p Nivolumab-3 p 9 (9-13) 9 (7.5-11) 7 (4.6-10.5) 6 7 (6.9-10) 7 (7.5-11) 6 (3.6-7.3) 3 10 (10-13.5) 11 (11-15) 7.5 (5.2-9.1) 6 2-3 68 patients (95% CI) Pembrolizumab-59 p Atezolizumab-6 p Nivolumab-3 p 3 (3.8-7) 3 (4-7.5) 3.5 (0.3-8.1) 1 2 (3-5.7) 2 (3-6.1) 3 (0.04 - 5.4) 1 4 (5.1-8.6) 5 (5-9.1) 6 (1.3-10) 1 RMH score 0-1 93 patients (95% CI) Pembrolizumab-78 p Atezolizumab-12 p Nivolumab-3 p 9 (8.6-12.4) 8 (8.8-13.2) 11 (4.7-12.1) 6 7 (6.9-9.9) 6.5 (7.2-10.7) 7 (3.3-8) 3 10 (10-13.5) 11 (10.6-14.6) 8 (5.5-9.5) 6 2-3 58 patients (95% CI) Pembrolizumab-46 p Atezolizumab-9 p Nivolumab-3 p 2.5 (3.4-7) 3 (3.7-8.1) 2 (1.35-4.2) 1 2 (2.6-5.4) 2.5 (2.8-6.2) 3 (0.9-3.4) 1 3 (4.5-7.9) 4 (4.8-9) 3 (1.7-7.3) 1 Conclusions GRIm / RMH scores on our population have consistently shown predictive and prognostic relevance, with more favourable TTF, PFS and OS in low-risk groups across any immunotherapy. On treatment stratification, Atezolizumab outcomes show better correlation with RMH score and Nivolumab remains underrepresented at our centre. Our results are consistent with international multi-institutional studies at Gustave Roussy (France) on Lung Immune Prognostic Index (LIPI) and Princess Alexandra Hospital (Australia) on modified LIPI. Disease control has been observed when immune-related adverse events have occurred, suggesting baseline autoimmune antibodies may be predictive of response and immune-related toxicity, a currently open line of observational prospective research. Legal entity responsible for the study Nottingham University Hospitals NHS Trust at UK. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

4003 Background: Level A evidence supports use of CisGem as first-line chemotherapy for ABC; no robust evidence is available for second-line chemotherapy. Methods: Pts diagnosed with ABC with disease progression after prior CisGem were randomised (1:1) to either ASC+mFOLFOX or ASC. Randomisation was stratified by serum albumin levels ( < 35 vs ≥35 g/L), platinum sensitivity (determined from first-line CisGem) and disease extent (locally advanced vs metastatic). Pts with ECOG PS0-1, adequate haematological, renal and liver function, and adequate biliary drainage were eligible. Primary end-point was overall survival (OS) (multivariable Cox regression adjusted for stratification factors); sample size: 162 pts delivering 148 events were required (80% power; 5% two-sided alpha) for a hypothesised hazard ratio (HR) of 0.63. Assumed median survival for ASC was 4 months. Results: 162 pts (81 in each arm) were randomised (27 March ‘14 - 04 Jan ‘18); median age 65 yrs (range 26-84); sex: 80 (49%) male, 82 (51%) female; primary site: intrahepatic 72 (44%), extrahepatic 45 (28%), gallbladder 34 (21%) and ampullary 11 (7%). Baseline characteristics were balanced between arms except platinum sensitivity (ASC+mFOLFOX 27 pts (33%); ASC 34 pts (42%)). After 150 OS events, the adjusted HR was 0.69 (95% CI 0.50-0.97; p = 0.031; ASC+mFOLFOX vs ASC). Median OS (months (m)), 6m and 12m OS-rate (%) were 6.2m, 50.6% and 25.9% for the ASC+mFOLFOX and 5.3m, 35.5%, 11.4% for the ASC arm, respectively. Grade 3/4 toxicities were reported in 48 (59%) and 32 (39%) pts in the ASC+mFOLFOX and ASC arm, respectively; these were balanced between arms except for fatigue and neutropenia (more frequent in ASC+mFOLFOX arm); data cleaning is ongoing. No chemotherapy-related deaths were reported. Conclusion: Survival with ASC was greater than assumed; ASC+mFOLFOX improved OS after progression to CisGem with a clinically meaningful increase in 6m and 12m OS rate. ASC+mFOLFOX should become standard of care in second-line for ABC. Clinical trial information: NCT01926236.

Context: Advanced osteoarthritis of knee joint if bilateral, severely restricts patient mobility. This acts as an aggravating factor for pre existing comorbid elements of metabolical syndrome (MS) like Type II diabetes mellitus and hypertension as patients are unable to carry out therapeutic walks. Successfully implanted total knee arthroplasty (TKA) increases physical activity and enables to carry out therapeutic walks thus may help in better control of type II diabetes mellitus and hypertension. The objective of this prospective study was to find whether TKA for osteoarthritis knee had any effect to improve blood glucose levels and reduce blood pressure. Materials and Methods: A prospective study was done in which patients operated for tricompartmental osteoarthritis of knee with associated comorbidities like Type II diabetes mellitus or hypertension during a period of 2008 and 2009 were studied. One hundred and twenty patients were enrolled (55 diabetics, 65 hypertensives) who met our inclusion criteria. Preoperative knee society score, lower extremity activity scale fasting blood glucose level and systolic and diastolic blood pressure were compared with one year followup values. The KSS and LEAS scores were analysed by the Wilcoxon signed ranked test, while the fasting blood glucose (FBG) levels and systolic and diastolic blood pressure levels were analysed by paired ′t′ test. Results: The reduction of systolic blood pressure by 8 mmHg (t = 5.6, P value < 0.05) and diastolic blood pressure by 6 mmHg ( t = 7.6, P value < 0.05) was recorded which was statistically significant. However, no statistically significant effect on fasting blood glucose levels was observed ( t = -0.77, P value = 0.442). KSS improved in DM from preoperative 29 to 86 and LEAS improved from 6.7 to 11.3. Conclusions: Authors are of the opinion that successful total knee replacement results in increased physical activity and reduces blood pressure (systolic and diastolic) in hypertensives. However, the same is not seen in blood glucose level. Increased physical activity and reduced dependence on NSAIDS postoperatively, may be contributing in reduction of systolic and diastolic blood pressure. Further studies in this aspect are necessary.

RECQL5 is a member of the RecQ family of DNA helicases and has key roles in homologous recombination, base excision repair, replication and transcription. The clinicopathological significance of RECQL5 expression in breast cancer is unknown. In this study, we have evaluated RECQL5 mRNA expression in 1977 breast cancers, and RECQL5 protein level in 1902 breast cancers [Nottingham Tenovus series ( n = 1650) and ER− cohort ( n = 252)]. Expression levels were correlated to aggressive phenotypes and survival outcomes. High RECQL5 mRNA expression was significantly associated with high histological grade ( P = 0.007), HER2 overexpression ( P = 0.032), ER+/HER2−/high proliferation genefu subtype ( P < 0.0001), integrative molecular clusters (intClust 1and 9) ( P < 0.0001) and poor survival ( P < 0.0001). In subgroup analysis, high RECQL5 mRNA level remains significantly associated with poor BCSS in ER+ cohort ( P < 0.0001) but not in ER− cohort ( P = 0.116). At the protein level, in tumours with low RAD51, high RECQL5 level was significantly associated with high histological grade ( P < 0.0001), higher mitotic index ( P = 0.008), dedifferentiation ( P = 0.025), pleomorphism ( P = 0.027) and poor survival ( P = 0.003). In subgroup analysis, high RECQL5/low RAD51 remains significantly associated with poor BCSS in ER+ cohort ( P = 0.010), but not in ER− cohort ( P = 0.628). In multivariate analysis, high RECQL5 mRNA and high RECQL5/low RAD51 nuclear protein coexpression independently influenced survival ( P = 0.022) in whole cohort and in the ER+ subgroup. Preclinically, we show that exogenous expression of RECQL5 in MCF10A cells can drive proliferation supporting an oncogenic function for RECQL5 in breast cancer. We conclude that RECQL5 is a promising biomarker in breast cancer.

This study reports results from the first International Body Project (IBP-I), which surveyed 7,434 individuals in 10 major world regions about body weight ideals and body dissatisfaction. Participants completed the female Contour Drawing Figure Rating Scale (CDFRS) and self-reported their exposure to Western and local media. Results indicated there were significant cross-regional differences in the ideal female figure and body dissatisfaction, but effect sizes were small across high-socioeconomic-status (SES) sites. Within cultures, heavier bodies were preferred in low-SES sites compared to high-SES sites in Malaysia and South Africa ( ds = 1.94-2.49) but not in Austria. Participant age, body mass index (BMI), and Western media exposure predicted body weight ideals. BMI and Western media exposure predicted body dissatisfaction among women. Our results show that body dissatisfaction and desire for thinness is commonplace in high-SES settings across world regions, highlighting the need for international attention to this problem.

Radiation-induced DNA damage activates the DNA damage response (DDR). DDR up-regulation may predict radio-resistance and increase the risk of early local recurrence despite radiotherapy in early stage breast cancers. In 1755 early stage breast cancers, DDR signalling [ATM, ATR, total Ckh1, Chk1 phosphorylated at serine(345) (pChk1), Chk2, p53], base excision repair [PARP1, POLβ, XRCC1, FEN1, SMUG1], non-homologous end joining (Ku70/Ku80, DNA-PKcs) and homologous recombination [RAD51, BRCA1, γH2AX, BLM, WRN, RECQL5, PTEN] protein expression was correlated to time to early local recurrence. Pre-clinically, radio-sensitization by inhibition of Chk1 activation by ATR inhibitor (VE-821) and inhibition of Chk1 (V158411) were investigated in MDA-MB-231 (p53 mutant) and MCF-7 (p53 wild-type) breast cancer cells. In the whole cohort, 208/1755 patients (11.9%) developed local recurrence of which 126 (61%) developed local recurrence within 5 years of initiation of primary therapy. Of the 20 markers tested, only pChk1 and p53 significantly associated with early local recurrence (p value = 0.015 and 0.010, respectively). When analysed together, high cytoplasmic pChk1-nuclear pChk1 (p = 0.039), high cytoplasmic pChk1-p53 (p = 0.004) and high nuclear pChk1-p53 (p = 0.029) co-expression remain significantly linked to early local recurrence. In multivariate analysis, cytoplasmic pChk1 level independently predicted early local recurrence (p = 0.025). In patients who received adjuvant local radiotherapy (n = 949), p53 (p = 0.014) and high cytoplasmic pChk1-p53 (p = 0.017) remain associated with early local recurrence. Pre-clinically, radio-sensitisation by VE-821 or V158411 was observed in both MCF-7 and MDA-MB-231 cells and was more pronounced in MCF-7 cells. We conclude that pChk1 is a predictive biomarker of radiotherapy resistance and early local recurrence.

Stratification of oestrogen receptor (ER) negative and triple negative breast cancers (TNBCs) is urgently needed. In the current study, a cohort of 880 ER- (including 635 TNBCs) was immuno-profiled for a panel of DNA repair proteins including: Pol β, FEN1, APE1, XRCC1, SMUG1, PARP1, BRCA1, ATR, ATM, DNA-PKcs, Chk1, Chk2, p53, and TOPO2. Multivariate Cox proportional hazards models (with backward stepwise exclusion of these factors, using a criterion of p < 0.05 for retention of factors in the model) were used to identify factors that were independently associated with clinical outcomes. XRCC1 (p = 0.002), pol β (p = 0.032) FEN1 (p = 0.001) and BRCA1 (p = 0.040) levels were independently associated with poor BCSS. Subsequently, DNA repair index prognostic (DRPI) scores for breast cancer specific survival (BCSS) were calculated and two prognostic groups (DRPI-PGs) were identified. Patients in prognostic group 2 (DRPI-PG2) have higher risk of death (p < 0.001). Furthermore, in DRPI-PG2 patients, exposure to anthracycline reduced the risk of death [(HR (95% CI) = 0.79 (0.64–0.98), p = 0.032) by 21–26%. In addition, DRPI-PG2 patients have adverse clinicopathological features including higher grade, lympho-vascular invasion, Her-2 positive phenotype, compared to those in DRPI-PG1 (p < 0.01). Receiver operating characteristic (ROC) curves indicated that the DRPI outperformed the currently used prognostic factors and adding DRPI to lymph node stage significantly improved their performance as a predictor for BCSS [p < 0.00001, area under curve (AUC) = 0.70]. BER strongly influences pathogenesis of ER- and TNBCs. The DRPI accurately predicts BCSS and can also serve as a valuable prognostic and predictive tool for TNBCs.