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Background: Women with HR+ breast cancer experience a persistent risk of distant recurrence (DR) even after completion of 5 years of adjuvant endocrine therapy, with more than 50% of DR occurring after 5 years (late DR). The prognostic genomic signatures currently being used in the clinic were not developed or optimized specifically for late DR. We have previously shown that the Breast Cancer Index (BCI) and BCIN+ prognostic models were significantly prognostic for risk of overall (0-10y) and late (5-10y) distant recurrence (DR) in N0 and N1 HR+ patients in the Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial. Here, the prognostic performance of the BCI and BCIN+ models with alternative cut-points optimized for late DR were evaluated in patients from the TEAM trial, who were free from DR for at least 5 years. Methods: BCI testing was performed blinded to clinical outcome. The pre-specified alternative cut-points 4.4 and 1.8 for BCI and BCIN+ models were determined previously from Trans-aTTom and IDEAL studies, respectively (ESMO 2021). Kaplan-Meier analysis and log-rank test were used to evaluate the prognostic significance of BCI/BCIN+ risk groups based on DR. Univariate and multivariate Cox models were used to estimate hazard ratios (HRs) and the associated 95% confidence intervals (CIs). Results: 1285 HR+ N0 (median age 69.2, 54.2% T1, 92.5% G2-3, 21.3% chemotherapy) and 1762 N1 (median age 68.5, 49.7% T1, 80.8% G2-3, 42.6% chemotherapy) patients who remained free from DR at 5 years post randomization were included in the current analysis. For N0 patients, BCI identified 439 (34%) and 846 (66%) patients as low and high-risk with late 10-year DR rates of 3.8% (95% CI: 1.5-6.0%) and 9.1% (95% CI: 6.8-11.4%), respectively (HR: 2.6, 95% CI: 1.4-5.0; p=0.0025). For N1 patients, BCIN+ identified 287 (16%) and 1475 (84%) patients as low and high-risk with late 10-year DR rates of 3.4% (95% CI: 1.2-5.5%) and 12.3% (95% CI: 10.4-14.2%), respectively (HR: 3.5, 95% CI: 1.8-6.9; p< 0.0001). Similar results were observed in the HER2- patients. Notably, BCI/BCIN+ remained a statistically significant prognostic factor in the multivariate analysis after controlling for age, tumor size, grade, treatment. (Table). Conclusions: Compared to the original BCI/BCIN+ models, the optimized BCI and BCIN+ models showed improved prognostic performance for identifying low-risk patients with a very low risk of late DR (< 4%), for both N0 and N1 patients. These results provide further validation of BCI clinical utility as an aid in the decision-making for extended endocrine therapies for HR+ breast cancer, particularly in patients with N1 disease that may be spared extended endocrine treatment. Table Citation Format: John MS Bartlett, Keying Xu, Jenna Wong, Gregory R. Pond, Yi Zhang, Melanie Spears, Ranelle Salunga, Elizabeth Mallon, Karen J. Taylor, Annette Hasenburg, Christos Markopoulos, Luc Dirix, Caroline Seynaeve, Cornelis J.H. van de Velde, Daniel Rea, Catherine A. Schnabel, Kai Treuner, Jane Bayani. Validation of the Breast Cancer Index (BCI) prognostic models optimized for late distant recurrence in postmenopausal women with early-stage HR+ breast cancer in the TEAM trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-11-10.

This study provides a new record of nitrogen (N) deposition and ecological response at a remote, high-elevation lake within the ecologically fragile Three River Headwaters Region, northwest China, from the early 20thCentury to the past decade. A multi-proxy investigation of a lake sediment core including analyses of chironomids (non-biting midge), lake sediment geochemistry (δ15N, δ13C, TN, TOC, OC:TN), pollen, non-pollen palynomorphs and 210Pb-dating. Results were compared with regional pollution forcings, including fertiliser application, atmospheric nitrate and dust deposition, and a localised multiscale air quality modelling system for N-deposition. Our data reflect a mesotrophic lake for the majority of the 20th Century with minimal anthropogenic impact. A shift in the lake conditions is evident after 1985 with increased nutrient enrichment. Low δ15N, OC:TN and increasing TN values, together with an increase in chironomid taxa associated with eutrophic conditions and macrophytes are exhibited in the record, particularly since 2002. These changes are consistent with nutrient loading causing a change in trophic status. Redundancy analysis (RDA) and partial RDAs verified TN as an important driver behind the shift in chironomid community composition in recent decades, explaining 22.2% of the variance on its own and 16.9% with other environmental variables partialled out. While temperature change since 1960 was not a primary control on the chironomid community of Lake Bander, a step-change increase in summer temperatures since the 1990s coincided with the disappearance of cold stenotherms from the record and seems to have exacerbated the shift to more productive conditions. This study highlights the reach of airborne N from modern agricultural and industrial activity to remote locations, and demonstrates the utility of palaeolimnological techniques as part of modern ecosystem assessment for conservation.

Purpose:The Breast Cancer Index (BCI) HOXB13/IL17BR (H/I) ratio predicts benefit from extended endocrine therapy in hormone receptor–positive (HR+) early-stage breast cancer. Here, we report the final analysis of the Trans-aTTom study examining BCI (H/I)'s predictive performance.Experimental Design:BCI results were available for 2,445 aTTom trial patients. The primary endpoint of recurrence-free interval (RFI) and secondary endpoints of disease-free interval (DFI) and disease-free survival (DFS) were examined using Cox proportional hazards regression and log-rank test.Results:Final analysis of the overall study population (N = 2,445) did not show a significant improvement in RFI with extended tamoxifen [HR, 0.90; 95% confidence interval (CI), 0.69–1.16; P = 0.401]. Both the overall study population and N0 group were underpowered due to the low event rate in the N0 group. In a pre-planned analysis of the N+ subset (N = 789), BCI (H/I)-High patients derived significant benefit from extended tamoxifen (9.7% absolute benefit: HR, 0.33; 95% CI, 0.14–0.75; P = 0.016), whereas BCI (H/I)-Low patients did not (−1.2% absolute benefit; HR, 1.11; 95% CI, 0.76–1.64; P = 0.581). A significant treatment-to-biomarker interaction was demonstrated on the basis of RFI, DFI, and DFS (P = 0.037, 0.040, and 0.025, respectively). BCI (H/I)-High patients remained predictive of benefit from extended tamoxifen in the N+/HER2− subgroup (9.4% absolute benefit: HR, 0.35; 95% CI, 0.15–0.81; P = 0.047). A three-way interaction evaluating BCI (H/I), treatment, and HER2 status was not statistically significant (P = 0.849).Conclusions:Novel findings demonstrate that BCI (H/I) significantly predicts benefit from extended tamoxifen in HR+ N+ patients with HER2− disease. Moreover, BCI (H/I) demonstrates significant treatment to biomarker interaction across survival outcomes.

Insights from cell cycle research have led to the hypothesis that tumors may be selectively sensitized to DNA-damaging agents resulting in improved antitumor activity and a wider therapeutic margin. The theory relies on the observation that the majority of tumors are deficient in the G1-DNA damage checkpoint pathway resulting in reliance on S and G2 checkpoints for DNA repair and cell survival. The S and G2 checkpoints are regulated by checkpoint kinase 1, a serine/threonine kinase that is activated in response to DNA damage; thus, inhibition of checkpoint kinase 1 signaling impairs DNA repair and increases tumor cell death. Normal tissues, however, have a functioning G1 checkpoint signaling pathway allowing for DNA repair and cell survival. Here, we describe the preclinical profile of AZD7762, a potent ATP-competitive checkpoint kinase inhibitor in clinical trials. AZD7762 has been profiled extensively in vitro and in vivo in combination with DNA-damaging agents and has been shown to potentiate response in several different settings where inhibition of checkpoint kinase results in the abrogation of DNA damage-induced cell cycle arrest. Dose-dependent potentiation of antitumor activity, when AZD7762 is administered in combination with DNA-damaging agents, has been observed in multiple xenograft models with several DNA-damaging agents, further supporting the potential of checkpoint kinase inhibitors to enhance the efficacy of both conventional chemotherapy and radiotherapy and increase patient response rates in a variety of settings. [Mol Cancer Ther 2008;7(9):2955–66]

Supplementary Figure from Breast Cancer Index Is a Predictive Biomarker of Treatment Benefit and Outcome from Extended Tamoxifen Therapy: Final Analysis of the Trans-aTTom Study

Supplementary Table from AZD7762, a novel checkpoint kinase inhibitor, drives checkpoint abrogation and potentiates DNA-targeted therapies

Supplementary Figure 1 from WWOX Gene Expression Abolishes Ovarian Cancer Tumorigenicity In vivo and Decreases Attachment to Fibronectin via Integrin α3

Supplementary Figure 5 from WWOX Gene Expression Abolishes Ovarian Cancer Tumorigenicity In vivo and Decreases Attachment to Fibronectin via Integrin α3

Supplementary Figure 3 from WWOX Gene Expression Abolishes Ovarian Cancer Tumorigenicity In vivo and Decreases Attachment to Fibronectin via Integrin α3

Supplementary Figure 4 from WWOX Gene Expression Abolishes Ovarian Cancer Tumorigenicity In vivo and Decreases Attachment to Fibronectin via Integrin α3

Supplementary Figure 2 from WWOX Gene Expression Abolishes Ovarian Cancer Tumorigenicity In vivo and Decreases Attachment to Fibronectin via Integrin α3

Supplementary Methods, Legends for Figures 1-5 from WWOX Gene Expression Abolishes Ovarian Cancer Tumorigenicity In vivo and Decreases Attachment to Fibronectin via Integrin α3

Background: Adjuvant whole breast radiotherapy (RT) is provided to almost all women with early-stage invasive breast cancer after breast conserving surgery and appropriate systemic therapy. While there is increasing interest to personalize the use of RT based on molecular profiling, to date, there is no molecular signature available to reliably assess the benefit of radiotherapy after surgical resection. Here we assess the ability of a 16-gene signature named Profile for the Omission of Local Adjuvant Radiotherapy (POLAR) to identify who may be suitable candidates for radiotherapy omission in patients of the Scottish Conservation Trial. Methods: The POLAR signature was applied to archival tissue from the Scottish Conservation Trial, which randomized 585 patients with stage I-II breast cancer, tumor size < 4 cm, and age ≤70 years old to receive RT or not. The archival tissue was measured for ER (ER+ >10%), PgR (PgR+ ≥20%), Ki67 (Ki67 high ≥14%), and HER2 (HER2+ defined as HER2 over-expressed or amplified). 26% received adjuvant chemotherapy, the remainder received tamoxifen 20 mg/daily for 5 years. Cox models for the locoregional recurrence (LRR) endpoint tested the association between treatment arms separately for patients with a low and high POLAR score using a pre-specified cut point. Cumulative incidences were computed, with distant metastasis and death without recurrence considered competing events. Results: 224 patients had tissue available and complete clinical data for analysis, 40 (18%) were node-positive. The distribution of clinicopathologic variables between the RT and no RT arms remained balanced. 43% were ER+/PgR+/Ki67 low/HER2-, 31% were ER+/HER2-/Ki67 high or PgR-, 5% were HER2+, and 13% were triple negative. The continuous standardized POLAR score was prognostic for LRR in the no RT arm after adjusting for relevant covariates (HR=1.78 [1.20-2.64], p=0.003). For patients with a POLAR-high score, the 10-year LRR rate was 31% [21%-42%] for patients not receiving RT and 8% [3%-15%] for patients receiving RT (HR 0.36 [0.19-0.69], p=0.0022). For patients with a POLAR low score, the 10-year LRR rates were 20% [10%-33%] for patients not receiving RT and 6% [1%-18%] for patients receiving RT; HR=0.28 [0.08-0.98], p=0.046). In the subgroup of node-negative patients with ER+/HER2-negative tumors (N=137), there was a statistically significant RT benefit for patients with a POLAR high score (HR=0.31 [0.11-0.88], p=0.028) but not for patients with a POLAR low score (HR=0.5 [0.1-2.4], p=0.39). Conclusions: For patients with early-stage invasive breast cancer treated with breast-conserving surgery without RT, POLAR is prognostic for LRR and may refine the selection of “low risk” for omission of RT. Citation Format: Karen J. Taylor, John MS Bartlett, John Bennett, S. Laura Chang, Bradley Arrick, Frederick Baehner, Joseph F. Loane, Tammy Piper, Elizabeth Mallon, Joanna Dunlop, Wilma J. Jack, Jacqueline Caldwell, Ian Kunkler, Linda J. Williams, Corey W. Speers, Felix Y. Feng, Lori Pierce, David A. Cameron. Validation of Profile for the Omission of Local Adjuvant Radiotherapy (POLAR) in early-stage invasive breast cancer patients of the Scottish Conservation Trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-02-12.

Background: There are currently no commercially available tests to identify early stage breast cancer patients treated with breast conserving surgery (BCS) and systemic therapy at low risk of locoregional recurrence (LRR) for whom postoperative radiotherapy (RT) may be safely omitted. Profile for the Omission of Local Adjuvant Radiotherapy (POLAR) is a 16-gene molecular signature developed to identify invasive breast cancer patients who may be candidates for RT omission after BCS. In this work, we seek to validate POLAR in a meta-analysis of three RCTs of BCS +/- RT: SweBCG91RT, Scottish Conservation Trial (SCT) and Princess Margaret Hospital (PMH). Methods: A patient-level meta-analysis was performed in 623 node-negative breast cancer patients with ER+/HER2-negative tumors who were enrolled in the three RCTs and for whom primary tumor material was available for analysis. Contributions from each cohort were as follows: SweBCG91RT N=354 (57%), SCT N=137 (22%), and PMH N=132 (21%). Numbers of LRR events in each cohort were as follows: SweBCG91RT N=72 (20%), SCT N=28 (20%), and PMH N=16 (12%). There was a mix of systemic therapy used (no systemic therapy for SweBCG91RT, chemotherapy or adjuvant endocrine therapy, but not both, in SCT, and tamoxifen but no chemotherapy for PMH). Median follow-up time for the patients who did not have LRR was 13.3 years for SweBCG91RT, 21.1 years for SCT, and 8.6 years for PMH. A multivariable Cox proportional hazards model on time to LRR, including the continuous standardized POLAR score, RT, and interaction, stratified by cohort, was used to test the interaction between the continuous POLAR score and RT. Additional Cox models tested the association between treatment arms separately for patients with a low and high POLAR score using a pre-specified cut point. Cumulative incidences were computed, with distant metastasis and death without recurrence considered as competing events. Results: The test for interaction between RT treatment and POLAR was statistically significant (p = 0.022). Patients with a high POLAR score (N=429 [69%]) had a large benefit from RT (10-year cumulative incidence of LRR: 20% [15%-26%] for those not treated with RT vs 7% [4%-11%] for those treated with RT; hazard ratio for RT vs no RT: 0.37 [0.23-0.60], p < 0.001), whereas there was no evidence of benefit from RT for patients with a low POLAR score (N=194 [31%], 10-year cumulative incidence of LRR: 5% [2%-11%] for those not treated with RT vs 7% [3%-14%] for those treated with RT; hazard ratio for RT vs no RT: 0.92 [0.42-2.02], p = 0.832). Conclusions: To our knowledge, POLAR is the first genomic classifier that is not only prognostic for LRR but also predictive, showing a significant interaction between RT and the classifier. Patients with a high POLAR score should be recommended radiotherapy while patients with a low score may be candidates for omission of radiotherapy after breast conserving surgery. Citation Format: Per Karlsson, Anthony Fyles, S. Laura Chang, Bradley Arrick, Frederick Baehner, Per Malmström, Mårten Fernö, Erik Holmberg, Martin Sjöström, Fei-Fei Liu, David A. Cameron, Linda J. Williams, John MS Bartlett, Joanna Dunlop, Jacqueline Caldwell, Joseph F. Loane, Elizabeth Mallon, Tammy Piper, Wilma J. Jack, Ian Kunkler, Felix Y. Feng, Corey W. Speers, Lori Pierce, John Bennett, Karen J. Taylor. Validation of Profile for the Omission of Local Adjuvant Radiotherapy (POLAR) in a meta-analysis of three randomized controlled trials of breast conserving surgery +/- radiotherapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS4-03.

Background: Several biomarkers such as estrogen receptor (ER), progesterone receptor (PR), androgen receptor (AR) and Ki67 have been implicated in the pathogenesis and/or as prognostic biomarkers of breast cancer, and are utilized to determine treatment. Given the heterogeneity of response to endocrine therapy, however, predictive biomarkers are critical to better individualize patient care. Previous results from the Trans-aTTom study demonstrated that the Breast Cancer Index HOXB13/IL17BR [BCI (H/I)] biomarker significantly predicts extended endocrine benefit from 10 vs 5y of tamoxifen. In this correlative study, the predictive activity of BCI (H/I) was compared with ER, PR, AR and Ki67 protein expression in node positive patients treated in the aTTom trial. Methods: Patients with available tumor tissue and biomarker analyses were included. ER, PR, AR and Ki67 were centrally assessed by immunohistochemistry (IHC) utilizing tissue microarrays. BCI gene expression analysis by RT-PCR was performed blinded to clinical outcome. Multivariate Cox models adjusting for age, tumor size, tumor grade and HER2 status were used to assess the significance of the interaction between treatment and each biomarker as continuous variables. 17-year risk of recurrence, as a function of each continuous biomarker, was estimated from Cox models in each of the 2 treatment arms. Results: Analysis of 789 HR+, N+ patients showed a weak negative correlation between BCI (H/I) and ER, PR, and AR expression whereas Ki67 and the AR/ER ratio showed no correlation (ER, cor=−0.18; PR, cor=−0.25; AR, cor=−0.14; Ki67, cor=0.04; AR/ER ratio, cor=0.02). The interaction between BCI (H/I) and extended tamoxifen treatment was significant (p=0.014). In addition, analysis of risk of recurrence as a function of continuous BCI (H/I) demonstrated that the magnitude in the reduction in recurrence risk with extended tamoxifen correlated with increasing H/I levels. In contrast, interaction P values were nonsignificant (ER, p=0.829; PR, p=0.659; AR, p=0.783; Ki67, p=0.865; AR/ER ratio, p=0.835) and the magnitude of endocrine benefit did not correlate with expression levels of any of other biomarkers. Conclusion: Results from this post-hoc analysis of the Trans-aTTom study demonstrated that whereas BCI(H/I) is a significant predictive biomarker of endocrine response, analysis of ER, PR, AR, Ki67 and AR/ER expression showed no interaction with treatment, and lacked the ability to predict benefit of extended tamoxifen in HR+ early stage breast cancer. These results add to the growing body of evidence that BCI (H/I) is distinct in its ability to predict benefit from therapy and interrogates distinct tumor biology that is not captured by other traditional biomarkers. Citation Format: Dennis C Sgroi, Kai Treuner, Yi Zhang, Tammy Piper, Ranelle Salunga, Ikhlaaq Ahmed, Lucy Doos, Sarah Thornber, Karen J Taylor, Elena F Brachtel, Sarah Pirrie, Catherine A Schnabel, Daniel W Rea, John MS Bartlett. Correlative studies of the breast cancer index (HOXB13/IL17BR) and ER, PR, AR, AR/ER ratio and Ki67 for prediction of extended endocrine benefit: A trans-aTTom study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS4-09.

Purpose: The Breast Cancer Index (BCI) HOXB13/IL17BR (H/I) ratio predicts benefit from extended endocrine therapy in hormone receptor–positive (HR+) early-stage breast cancer. Here, we report the final analysis of the Trans-aTTom study examining BCI (H/I)'s predictive performance. Experimental Design: BCI results were available for 2,445 aTTom trial patients. The primary endpoint of recurrence-free interval (RFI) and secondary endpoints of disease-free interval (DFI) and disease-free survival (DFS) were examined using Cox proportional hazards regression and log-rank test. Results: Final analysis of the overall study population (N = 2,445) did not show a significant improvement in RFI with extended tamoxifen [HR, 0.90; 95% confidence interval (CI), 0.69–1.16; P = 0.401]. Both the overall study population and N0 group were underpowered due to the low event rate in the N0 group. In a pre-planned analysis of the N+ subset (N = 789), BCI (H/I)-High patients derived significant benefit from extended tamoxifen (9.7% absolute benefit: HR, 0.33; 95% CI, 0.14–0.75; P = 0.016), whereas BCI (H/I)-Low patients did not (−1.2% absolute benefit; HR, 1.11; 95% CI, 0.76–1.64; P = 0.581). A significant treatment-to-biomarker interaction was demonstrated on the basis of RFI, DFI, and DFS (P = 0.037, 0.040, and 0.025, respectively). BCI (H/I)-High patients remained predictive of benefit from extended tamoxifen in the N+/HER2− subgroup (9.4% absolute benefit: HR, 0.35; 95% CI, 0.15–0.81; P = 0.047). A three-way interaction evaluating BCI (H/I), treatment, and HER2 status was not statistically significant (P = 0.849). Conclusions: Novel findings demonstrate that BCI (H/I) significantly predicts benefit from extended tamoxifen in HR+ N+ patients with HER2− disease. Moreover, BCI (H/I) demonstrates significant treatment to biomarker interaction across survival outcomes.

A comprehensive database of paleoclimate records is needed to place recent warming into the longer-term context of natural climate variability. We present a global compilation of quality-controlled, published, temperature-sensitive proxy records extending back 12,000 years through the Holocene. Data were compiled from 679 sites where time series cover at least 4000 years, are resolved at sub-millennial scale (median spacing of 400 years or finer) and have at least one age control point every 3000 years, with cut-off values slackened in data-sparse regions. The data derive from lake sediment (51%), marine sediment (31%), peat (11%), glacier ice (3%), and other natural archives. The database contains 1319 records, including 157 from the Southern Hemisphere. The multi-proxy database comprises paleotemperature time series based on ecological assemblages, as well as biophysical and geochemical indicators that reflect mean annual or seasonal temperatures, as encoded in the database. This database can be used to reconstruct the spatiotemporal evolution of Holocene temperature at global to regional scales, and is publicly available in Linked Paleo Data (LiPD) format. Fil: Kaufman, Darrell. Northern Arizona University.; Estados Unidos Fil: McKay, Nicholas. Northern Arizona University.; Estados Unidos Fil: Routson, Cody. Northern Arizona University.; Estados Unidos Fil: Erb, Michael. Northern Arizona University.; Estados Unidos Fil: Davis, Basil. University Of Lausanne; Suiza Fil: Heiri, Oliver. University Of Basel; Suiza Fil: Jaccard, Samuel. University Of Bern; Suiza Fil: Tierney, Jessica. University of Arizona; Estados Unidos Fil: Dätwyler, Christoph. University Of Bern; Suiza Fil: Axford, Yarrow. Northwestern University; Estados Unidos Fil: Brussel, Thomas. University of Utah; Estados Unidos Fil: Cartapanis, Olivier. University Of Bern; Suiza Fil: Chase, Brian. Universite de Montpellier; Francia Fil: Dawson, Andria. Mount Royal University; Canadá Fil: de Vernal, Anne. Université du Québec a Montreal; Canadá Fil: Engels, Stefan. University of London; Reino Unido Fil: Jonkers, Lukas. University Of Bremen; Alemania Fil: Marsicek, Jeremiah. University of Wisconsin-Madison; Estados Unidos Fil: Moffa Sánchez, Paola. University of Durham; Reino Unido Fil: Morrill, Carrie. University of Colorado; Estados Unidos Fil: Orsi, Anais. Université Paris-Saclay; Francia Fil: Rehfeld, Kira. Heidelberg University; Alemania Fil: Saunders, Krystyna. Australian Nuclear Science And Technology Organisation; Australia Fil: Sommer, Philipp. University Of Lausanne; Suiza Fil: Thomas, Elizabeth. University At Buffalo; Estados Unidos Fil: Tonello, Marcela Sandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones Marinas y Costeras. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Instituto de Investigaciones Marinas y Costeras; Argentina Fil: Tóth, Mónika. Balaton Limnological Institute; Hungría Fil: Vachula, Richard. Brown University; Estados Unidos Fil: Andreev, Andrei. Alfred Wegener Institut Helmholtz Centre for Polar and Marine Research; Alemania Fil: Bertrand, Sebastien. Ghent University; Bélgica Fil: Massaferro, Julieta. Administración de Parques Nacionales. Parque Nacional "Nahuel Huapi"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina

A comprehensive database of paleoclimate records is needed to place recent warming into the longer-term context of natural climate variability. We present a global compilation of quality-controlled, published, temperature-sensitive proxy records extending back 12,000 years through the Holocene. Data were compiled from 679 sites where time series cover at least 4000 years, are resolved at sub-millennial scale (median spacing of 400 years or finer) and have at least one age control point every 3000 years, with cut-off values slackened in data-sparse regions. The data derive from lake sediment (51%), marine sediment (31%), peat (11%), glacier ice (3%), and other natural archives. The database contains 1319 records, including 157 from the Southern Hemisphere. The multi-proxy database comprises paleotemperature time series based on ecological assemblages, as well as biophysical and geochemical indicators that reflect mean annual or seasonal temperatures, as encoded in the database. This database can be used to reconstruct the spatiotemporal evolution of Holocene temperature at global to regional scales, and is publicly available in Linked Paleo Data (LiPD) format., Measurement(s)climateTechnology Type(s)digital curationFactor Type(s)temporal interval • geographic location • proxy typeSample Characteristic - Environmentclimate systemSample Characteristic - LocationEarth (planet) Machine-accessible metadata file describing the reported data: https://www.ncdc.noaa.gov/paleo/study/27330

This study provides the first mid to late Holocene chironomid-inferred temperature (C-IT) model for northwest Ireland, creating a valuable climatic context for the development of Irish society during the Neolithic and Bronze Age. Using a lake sediment core from an isolated catchment, Lough Meenachrinna in northwest Ireland, a multi-proxy approach of chironomid (Diptera: Chironomidae) subfossils, sediment geochemistry (δ13C, δ15N, C:N) and pollen analysis was used to assess any potential limnological impact from prehistoric human activity in the region and provide a quantitative summer temperature estimate for the late Mesolithic to the Iron Age (7050–2050 cal yr BP). The pollen record provides a local signal of human activity, showing low levels of pastoral indicators in the early Neolithic, with increased evidence for pastoral and arable farming during the Bronze Age and in particular the Iron Age. Human activity does not appear to be a driving force in lake system change at Lough Meenachrinna, as peaks in farming indicators (e.g. pastoral pollen indicators and increased δ15N values) were not concurrent with major fluctuations in the chironomid assemblages. C-ITs provide evidence of multiple fluctuations in temperature during the mid to late Holocene with a cold phase during the late Mesolithic (6800–5890 cal yr BP), followed by a warming period during the early Neolithic (5890–5570 cal yr BP). C-ITs reflect a relatively warm climate during the middle Neolithic, with a substantial warming from the late Neolithic into the early Bronze Age (4630–3810 cal yr BP). C-ITs show a general cooling trend from the Bronze Age into the Iron Age, with a cold event occurring at 3340 cal yr BP during the middle Bronze Age and second cold event at 2430 cal yr BP during the Iron Age. The multi-proxy approach has proven an effective strategy for untangling human and climate influences on the chironomid record, and is recommended as a methodological approach in future Holocene climatic reconstructions where prehistoric human influence is a factor.

This study explored the utility and performance of chironomid (Diptera: Chironomidae) autecology in the investigation of prehistoric farming impacts on freshwater lake systems. Chironomid subfossils, lake sediment geochemistry (δ13C, δ15N and C:N), pollen and macroscopic charcoal analyses were used in a comparative limnological assessment of three archaeologically rich study sites in northwest Ireland. At all three study sites, pastoral farming and its associated nutrient inputs, as represented by non-arboreal pollen indicative of grassland/pasture (NAPp) and lake sediment geochemistry, are concomitant with increases in eutrophic chironomid taxa. Redundancy analysis (RDA) and partial RDAs established that δ15N and NAPp were controlling factors of chironomid community compositional change during the Neolithic (4000–2500 BC) and Bronze Age (2500–600 BC). Bronze Age farming had a considerably greater impact on the lake systems than Neolithic farming, as indicated by a higher proportion of eutrophic taxa and increases in δ15N, C:N and δ13C values, consistent with increased erosion and agricultural inputs. Findings emphasise the importance of identifying the natural, pre-impacted state of a lake system to determine the extent of agricultural impact accurately. The timing and magnitude of change show that Neolithic and Bronze Age farming exhibited a strong control over chironomid communities at all three sites.

This study provides the first decadally resolved chironomid and organic geochemistry record of the Irish Neolithic from a small lake adjacent to the Carrowkeel-Keshcorran complex in County Sligo, Ireland. Chironomid (non-biting midge fly) sub-fossils and lake sediment geochemistry (δ13C, δ15N and C:N) from the Templevanny Lough core were used to assess the timing and magnitude of within-lake responses to Neolithic farming activity. When compared with decadally resolved pollen and macroscopic charcoal records from the same core, the limnological data show a direct influence of prehistoric farming on a freshwater lake system through nutrient loading and lake eutrophication. Elevated nutrient levels, suggesting a more productive lake system, and a subsequent turnover in the chironomid community indicate a period of intensive farming activity from c. 3790–3620 BC in the early Neolithic. This was followed by a decline in farming with short periods of small-scale human activity, exemplified through nutrient loading and short-lived increases in eutrophic chironomid taxa during the middle to late Neolithic. A return of farming activity can be seen in all proxy data in the late Neolithic ( c. 2720–2480 BC). The chironomid community composition typically lagged land-use change by c. 10–20 years and exhibited predictable and proportional responses to agricultural activity. The timing and magnitude of limnological changes show that land-use, rather than climate, is the main control on chironomids at Templevanny Lough, thus showing the potential prominence of the anthropogenic signal during the Neolithic.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Background: Taxanes are an established part of the treatment regime for early and metastatic breast cancer. However acquired chemoresistance remains a major factor in therapeutic failure in these patients. Treatment options thereafter are limited. It is key that the underlying molecular mechanisms of the taxane resistance are elucidated to drive the development of novel targeted therapies to treat chemorefractory disease. Methods: In vitro models of taxane resistance in breast cancer were developed through continuous exposure of MDA-MB-231 and MCF7 cell lines to either paclitaxel or docetaxel. Differential gene expression analysis was performed comparing the resistant cells to chemosensitive parent lines using the Nanostring PanCancer Pathway panel. Further, RPPA analysis was utilised to investigate the proteomic signature of the chemoresistant lines and Western blotting performed to confirm key changes. A small molecule kinase screen was performed to identify candidate inhibitors with activity in the taxane resistant models. Results: Nanostring gene expression analysis resulted in the identification of 204 significantly altered mRNA in MDA-MB-231 PACR, 231 mRNA altered in MDA-MB-231 DOCR and 88 mRNA significantly altered in MCF7 PACR (1.5 fold, p-value Table 1: Sensitivity of taxane resistant cell lines models to BKM-120 and PIK-75Cell line modelBKM-120 IC50 (µM)PIK-75 IC50 (µM)MDA-MB-231 Parent3.284 ± 0.5820.033 ± 0.008MDA-MB-231 PACR1.512 ± 0.5240.076 ± 0.018MDA-MB-231 DOCR2.267 ± 0.8160.064 ± 0.01MCF7 Parent0.421 ± 0.0440.022 ± 0.015MCF7 PACR0.289 ± 0.0410.01 ± 0.003 Conclusion: Candidate resistance-associated pathways were identified by differential gene expression analysis and proteomic analysis by RPPA. Western blotting confirmed alterations in the PI3K/Akt and MAPK pathways. PI3K inhibitors were found to have potent activity against the taxane resistant cell line models. Further investigations to confirm their potential as a therapeutic in the treatment of chemoresistant breast cancer is required. Citation Format: Karen J Taylor, Nicola Lyttle, Linda Lao, Charlie Gourley, David A Cameron, John MS Bartlett, Melanie Spears. Identification of mechanisms driving acquired chemoresistance in preclinical breast cancer models of taxane resistance [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-03-21.

This study provides a unique method of inquiry for archaeological investigation with an aim to assess the intensity and effects of Neolithic and Bronze Age farming practices at Lough Dargan, northwest Ireland, through a multi-proxy analysis of a lake sediment core. Chironomid (non-biting midge fly) subfossils and lake sediment geochemistry (δ13C, δ15N and C:N ratios) were used to assess changes in limnological conditions through time. The limnological data were compared with macroscopic charcoal concentration and pollen data to examine the potential influence that early farmers had on a freshwater lake system within a prehistorically active catchment. Results from the chironomid analysis show that the first substantial period of agricultural activity in the early Neolithic (c. 3730–3190 BC) resulted in a temporary shift to more eutrophic lake conditions. There is evidence of animal husbandry with substantial levels of animal waste reaching the lake, leaving an imprint in the geochemical record of increased δ15N values and decreased δ13C values and C:N ratios during this time. The chironomid community reverted back to its pre-impacted state c. 3190 BC in response to a period of reduced farming (c. 3390–3000 BC) which eventually led to a distinct lull in activity, with possible cessation of farming from 3000 to 2700 BC. A return to eutrophic conditions coincided with the gradual return of agriculture, with more permanently altered lake conditions dominating from 2400 BC, even during a 250-year period of reduced human activity commencing at c. 1440 BC. Increased sedimentation rate, along with increases in δ13C, δ15N and C:N, the presence of chironomid taxa indicative of erosion, more eutrophic lake conditions and high concentrations of macroscopic charcoal all point to more intensive land use practices during the Bronze Age. Palaeolimnological data exhibited an immediate response to intensified farming during this time, and were especially responsive to pastoral farming due either to scale of activity or proximity to the lakeside. The success of this study demonstrates the effectiveness of palaeolimnological analysis in the investigation of prehistoric farming. This approach will help inform Neolithic and Bronze Age land-use practice and human–environment relations in the region, and highlights the potential for chironomid-based archaeological research.

Reducing medication errors is a topic of national concern and action. Nursing students participated in a healthcare organization's continuous quality improvement project targeting patient safety. Students were actively involved in chart review and became acutely aware of safety issues related to medication administration, order transcription and implementation, and documentation. Both the students and the hospital realized expected and unexpected benefits.

Insights from cell cycle research have led to the hypothesis that tumors may be selectively sensitized to DNA-damaging agents resulting in improved antitumor activity and a wider therapeutic margin. The theory relies on the observation that the majority of tumors are deficient in the G1-DNA damage checkpoint pathway resulting in reliance on S and G2 checkpoints for DNA repair and cell survival. The S and G2 checkpoints are regulated by checkpoint kinase 1, a serine/threonine kinase that is activated in response to DNA damage; thus, inhibition of checkpoint kinase 1 signaling impairs DNA repair and increases tumor cell death. Normal tissues, however, have a functioning G1 checkpoint signaling pathway allowing for DNA repair and cell survival. Here, we describe the preclinical profile of AZD7762, a potent ATP-competitive checkpoint kinase inhibitor in clinical trials. AZD7762 has been profiled extensively in vitro and in vivo in combination with DNA-damaging agents and has been shown to potentiate response in several different settings where inhibition of checkpoint kinase results in the abrogation of DNA damage-induced cell cycle arrest. Dose-dependent potentiation of antitumor activity, when AZD7762 is administered in combination with DNA-damaging agents, has been observed in multiple xenograft models with several DNA-damaging agents, further supporting the potential of checkpoint kinase inhibitors to enhance the efficacy of both conventional chemotherapy and radiotherapy and increase patient response rates in a variety of settings. [Mol Cancer Ther 2008;7(9):2955–66]

The relative contributions of the hippocampus and the perirhinal cortex to recognition memory are currently the subject of intense debate. Whereas some authors propose that both structures play a similar role in recognition memory, others suggest that the hippocampus might mediate recollective and/or associative aspects of recognition memory, whereas the perirhinal cortex may mediate item memory. Here we investigate an alternative functional demarcation between these structures, following reports of stimulus-specific perceptual deficits in amnesics with medial temporal lobe (MTL) lesions. Using a novel recognition memory test for faces and scenes, participants with broad damage to MTL structures, which included the hippocampus and the perirhinal cortex, were impaired on both face and scene memory. By contrast, participants with damage limited to the hippocampus showed deficits only in memory for scenes. These findings imply that although both the hippocampus and surrounding cortex contribute to recognition memory, their respective roles can be distinguished according to the type of material to be remembered. This interaction between lesion site and stimulus category may explain some of the inconsistencies present in the literature.

In recent years, a number of studies have demonstrated an important role for functional neuroimaging in the identification of residual cognitive function in persistent vegetative state. Such studies, when successful, may be particularly useful where there is concern about the accuracy of the diagnosis and the possibility that residual cognitive function has remained undetected. Unfortunately, functional neuroimaging in persistent vegetative state is extremely complex and subject to numerous methodological, clinical and theoretical difficulties. Here, we describe the strategy used to study residual auditory and speech processing in a single patient with a clinical diagnosis of persistent vegetative state. Identical positron emission tomography studies, conducted nine months apart, revealed preserved and consistent responses in predicted regions of auditory cortex in response to intelligible speech stimuli. Moreover, a preliminary functional magnetic resonance imaging examination at the time of the second session revealed partially intact responses to semantically ambiguous stimuli, which are known to tap higher aspects of speech comprehension. In spite of the multiple logistic and procedural problems involved, these results have major clinical and theoretical implications and provide a strong basis for the systematic study of possible residual cognitive function in patients diagnosed as being in a persistent vegetative state.

Speech comprehension is resistant to acoustic distortion in the input, reflecting listeners' ability to adjust perceptual processes to match the speech input. For noise-vocoded sentences, a manipulation that removes spectral detail from speech, listeners' reporting improved from near 0% to 70% correct over 30 sentences (Experiment 1). Learning was enhanced if listeners heard distorted sentences while they knew the identity of the undistorted target (Experiments 2 and 3). Learning was absent when listeners were trained with nonword sentences (Experiments 4 and 5), although the meaning of the training sentences did not affect learning (Experiment 5). Perceptual learning of noise-vocoded speech depends on higher level information, consistent with top-down, lexically driven learning. Similar processes may facilitate comprehension of speech in an unfamiliar accent or following cochlear implantation.

Microcell-mediated transfer of normal chromosome 11 (chr 11) to a clonal derivative of the ovarian cancer cell line, OVCAR3, was performed and generated independent hybrids with a common set of phenotypes: inhibition of cell growth and of cellular migration in vitro; and inhibition of tumor growth in vivo. Differential display reverse transcriptase-PCR (RT-PCR), cDNA-representational difference analysis, and hybridization of cDNA high-density filter arrays identified altered mRNAs associated with these phenotypic alterations. Quantitative RT-PCR-based validation of each altered mRNA eliminated false positives to identify a reduced set of expression differences. Twelve products were confirmed as up-regulated and 4 as down-regulated upon introduction of chr 11. Strikingly, 4 of the 12 up-regulated genes were located on chr 11. Expression analysis of selected products by quantitative RT-PCR in a series of 18 human primary ovarian tumors revealed several associations with clinicopathological features. Importantly, low expression of two products, the lysosomal protease CTSD and the lens crystallin CRYAB, was significantly associated with adverse patient survival. Immunohistochemical analysis of CTSD in a larger independent panel of 58 primary ovarian tumors confirmed that low CTSD was associated with poor survival. Furthermore, low CTSD was significantly associated with serous histology and advanced tumor stage. The combined approach of microcell-mediated chromosome transfer and expression difference analysis has identified several altered mRNAs in a model of chr 11-mediated ovarian tumor suppression. The detailed contextual characterization of these genes will determine the extent of their involvement in neoplastic development.