tbuckley/cabot-search huggingface dataset:
An atypical pulmonary fibrosis is associated with co-inheritance of mutations in the calcium binding protein genes <i>S100A3</i> and <i>S100A13</i>
Authors: Eid A. Al-Mutairy, Faiga Ahmad Imtiaz, Mohammed Khalid, Somaya Al Qattan, Soad Saleh, Linah Mahmood Mahmoud, Maher Mohammed Al-Saif, Latifa Al-Haj, Azizah Al-Enazi, Abdullah M. AlJebreen, Shamayel Faheem Mohammed, Abdullah Fahad Mobeireek, Khalid Alkattan, Muzamil Amin Chisti, Irina G. Luzina, Mohammed Al-Owain, Ihab Weheba, Abeer Mohamed Abdelsayed, Khushnooda Ramzan, Luke J. Janssen, Walter Conca, Ayodele Alaiya, Kate S. Collison, Brian F. Meyer, Sergei P. Atamas, Khalid S. Khabar, Jeffrey D. Hasday, Futwan Al-Mohanna
Journal: European Respiratory Journal (2019)

Background Pulmonary fibrosis is one of the leading indications for lung transplantation. The disease, which is of unknown aetiology, can be progressive, resulting in distortion of the extracellular matrix (ECM), inflammation, fibrosis and eventual death. Methods 13 patients born to consanguineous parents from two unrelated families presenting with interstitial lung disease were clinically investigated. Nine patients developed respiratory failure and subsequently died. Molecular genetic investigations were performed on patients' whole blood or archived tissues, and cell biological investigations were performed on patient-derived fibroblasts. Results The combination of a unique pattern of early-onset lung fibrosis (at 12–15 years old) with distinctive radiological findings, including 1) traction bronchiectasis, 2) intralobular septal thickening, 3) shrinkage of the secondary pulmonary lobules mainly around the bronchovascular bundles and 4) early type 2 respiratory failure (elevated blood carbon dioxide levels), represents a novel clinical subtype of familial pulmonary fibrosis. Molecular genetic investigation of families revealed a hypomorphic variant in S100A3 and a novel truncating mutation in S100A13 , both segregating with the disease in an autosomal recessive manner. Family members that were either heterozygous carriers or wild-type normal for both variants were unaffected. Analysis of patient-derived fibroblasts demonstrated significantly reduced S100A3 and S100A13 expression. Further analysis demonstrated aberrant intracellular calcium homeostasis, mitochondrial dysregulation and differential expression of ECM components. Conclusion Our data demonstrate that digenic inheritance of mutations in S100A3 and S100A13 underlie the pathophysiology of pulmonary fibrosis associated with a significant reduction of both proteins, which suggests a calcium-dependent therapeutic approach for management of the disease.
Abstract 2099: Apo-10’-lycopenoic acid functions as a peroxisome proliferator-activated receptor gamma activator and inhibits cell growth both in vitro and in vivo ob/ob mice treated with diethylnitrosamine
Authors: Kang-Quan Hu, Yan Wang, Donald E. Smith, Robert M. Russell, Xiang-Dong Wang
Journal: Cancer Research (2008)

Abstract Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is involved in controlling metabolism, cell growth, inflammatory responses and tumorigenesis. Specific PPAR-gamma agonists, such as rosiglitazone, inhibit growth and induce differentiation in several different cancer cell lines including liver cancer cells. Lycopene has been shown to decrease the initiation of hepatic preneoplastic foci induced by diethylnitrosamine (DEN) in rats. Recently, we showed that apo-10’-lycopenoic acid, an enzymatic metabolite of lycopene, suppresses carcinogenesis in a mouse model. However, the underlying mechanism(s) is not well defined. In the present study, we examined the effects of apo-10’-lycopenoic acid treatment on cell growth and apoptosis, as well as PPAR-gamma activation in both human liver cells and in livers of ob/ob mice treated with DEN. We reported that apo-10’-lycopenoic acid dose-dependently increased the mRNA expression and protein levels of PPAR-gamma in human THLE-2 liver cells. Apo-10’-lycopenoic acid (from 5 µM to 20 µM) produced concentration-dependent increases in luciferase activity, as compared with PPAR-gamma agonist rosiglitazone in cells co-transfected with constructs containing PPAR-gamma and PPRE-luciferase reporter construct. Additionally, apo-10’-lycopenoic acid dose-dependently inhibited cell growth and induced apoptosis in THLE-2 liver cells by stimulating the cyclin-dependent kinase inhibitor p21 and by reducing activation of c-Jun NH2-terminal kinase (JNK) and cyclin D1 gene expression. However, human HepG2 liver cancer cells were less sensitive to apo-10’-lycopenoic acid treatment, as compared with THLE-2 cells. We further examined the effect of apo-10’-lycopenoic acid treatment (120 mg/Kg diet) in ob/ob mice administered intraperitoneally with a single-dose of DEN (30 mg/Kg body weight). After eight weeks, we found lower expression of PPAR-gamma but higher levels of tumor necrosis factor-alpha and phosphorylated JNK in the liver of ob/ob mice injected with DEN, as compared with controls. Furthermore, apo-10’-lycopenoic acid supplementation prevented DEN-down-regulated expression of PPAR-gamma in the liver of ob/ob mice and significantly inhibited DEN-induced expression of proliferating cell nuclear antigen and cyclinD1. In addition, apo-10’-lycopenoic acid supplementation inhibited DEN-induced tumor necrosis factor-alpha expression and JNK activation in the liver of ob/ob mice. Together, our findings indicate that apo-10’-lycopenoic acid produced from lycopene metabolism may function as a natural ligand of PPAR-gamma and as a potential chemopreventive agent against hepatic tumorigenesis.
Abstract P2-08-48: Features associated with long-term survival in metastatic breast cancer
Authors: NJ Klar, M Rosenzweig, B Diergaarde, A Brufsky
Journal: Cancer Research (2019)

Abstract Background: 5-10% of women with metastatic breast cancer (MBC) survive ≥5 years. Predictors of long-term survival are not clearly elucidated. We used data from 122 long-term MBC survivors (≥5-year survival from date of MBC diagnosis) and 191 short-term MBC survivors (≤2-year survival from date from MBC diagnosis) to identify clinico-pathologic and socioeconomic features associated with MBC survival. Methods: Women initially diagnosed with breast cancer (BC) in or after 1999, and diagnosed with MBC at Magee Women's Cancer Program of UPMC were included (N=313). Data abstracted from medical records included: stage at initial BC diagnosis, body mass index (BMI), Charlson Comorbidity Index (CCI), age, menopausal status at initial BC diagnosis, tumor receptor status at initial BC diagnosis, site of initial metastases, time to recurrence between initial diagnosis and MBC, household income, race, employment status, and partner status. Differences between groups were assessed using t-tests and Chi-square or Fisher's exact tests. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using multivariate logistic regression models. Results: Long-term survivors were significantly (P&amp;lt;0.05) younger, had more ER positive, PR positive, and Her2 positive disease, lower CCI, more often premenopausal at initial diagnosis, lower rates of visceral metastases, higher household income, and more often partnered than short-term survivors. The association of premenopausal status at initial diagnosis with long-term survival remained significant after adjustment for stage at initial diagnosis, tumor receptor status, and CCI (OR: 1.96, 95% CI 1.02- 3.79). Long-term term survivors were also significantly more often diagnosed with de novo MBC compared to short-term survivors. The association of de novo MBC with long-term survival remained significant after adjustment for age, tumor receptor status, and CCI (OR: 3.0, 95% CI 1.6-5.4). Time to recurrence between initial diagnosis and MBC, BMI, race, and employment status were not associated with survival. Conclusions: Diagnosis of de novo MBC, ER-, PR- and/or Her2-positive primary tumor, lower rates of visceral metastases, higher household income, younger age, lower CCI, premenopausal status, and having a partner are associated with long-term survival after diagnosis of MBC. This is one of the first studies to show a survival benefit in MBC for patients with de novo MBC, premenopausal status at initial diagnosis, positive partner status, and higher household income. Citation Format: Klar NJ, Rosenzweig M, Diergaarde B, Brufsky A. Features associated with long-term survival in metastatic breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-08-48.
Abstract P1-09-12: TP53 expression in relation to clinical and etiologic factors in breast cancer subtypes
Authors: XR Yang, M Abubakar, C Guo, H Koka, H Sung, J Guida, J Deng, B Zhou, N Hu, N Lu
Journal: Cancer Research (2019)

Abstract TP53 is a well-known tumor suppressor gene and mutations in TP53 are the most frequent genomic event in most cancers including breast cancer. Recent studies have shown that the frequency, spectrum, timing, and clinical implications of TP53 mutations varied in different molecular subtypes of breast cancer. For example, the frequency of TP53 mutations is the highest in basal-like subtype and lowest in luminal A tumors. However, the evaluation of TP53 protein expression, as a surrogate for TP53 mutations, in large studies in the context of tumor subtypes is limited. In addition, the etiologic relevance of TP53 expression is yet to be investigated. The goal of this study is to evaluate the association of clinical and breast cancer risk factors with TP53 expression, measured using immunohistochemistry (IHC), in breast cancer molecular subtypes. The analysis included 7,226 women with invasive breast cancer who were diagnosed and treated in a tertiary hospital in Beijing, China. Subtypes were defined as Luminal A: ER+ and PR+, HER2–, and low grade (grades 1 or 2); luminal B/HER2–: ER+ and/or PR+, HER2–, and high grade (grade 3); luminal B/HER2+: ER+ and/or PR+, HER2+ (regardless of grade); HER2-enriched: ER–, PR–, and HER2+; Triple-negative (TN): ER–, PR–, and HER2–. As expected, positive TP53 staining showed the lowest frequency in the luminal A (46%) and highest in the TN (61%) and HER2-enriched (63%) subtypes (P-value &amp;lt;0.001). Overall and particularly in luminal A patients, positive TP53 staining was associated with higher frequencies of aggressive tumor features such as higher grade, larger tumor size, higher proliferative index, and EGFR expression. Compared with TP53– patients, TP53+ patients were more likely to have younger ages at onset and increased parity, but these associations were largely driven by the luminal A subtype [OR (95% CI) vs nulliparity = 2.67 (1.59, 4.51); 2.63 (1.52, 4.55); 3.68 (2.01, 6.72) for 1, 2, and ≥3 children, respectively (P-trend = 0.006)]. Luminal A/TP53+ patients were also more likely to have breastfed [OR (95% CI) ever vs never = 1.38 (1.03, 1.85)] than luminal A/TP53– patients. These findings suggest that TP53 IHC staining might be used to further refine the classification of luminal A breast cancer into subgroups with distinct clinical and etiologic relevance. Citation Format: Yang XR, Abubakar M, Guo C, Koka H, Sung H, Guida J, Deng J, Zhou B, Hu N, Lu N. TP53 expression in relation to clinical and etiologic factors in breast cancer subtypes [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-09-12.
Abstract P3-08-21: Not presented
Authors: L Stanek, P Tesarova, M Vocka, L Petruzelka, Z Musil
Journal: Cancer Research (2019)

Abstract This abstract was not presented at the conference. Citation Format: Stanek L, Tesarova P, Vocka M, Petruzelka L, Musil Z. Not presented [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-08-21.
Abstract LB-138: <i>In vivo</i> imaging of DNA damage and repair
Authors: Yanming Wang, Lili Liu, Chunying Wu, Alina Bulgar, Wenxia Zhu, Eduardo Somoza, Stanton Gerson
Journal: Cancer Research (2010)

Abstract Objectives: To directly quantify abasic sites induced by DNA-targeted chemotherapeutic agents for in vivo studies of base excision repair pathway. Background: Current cancer treatments rely heavily on chemotherapeutic agents to induce cytotoxic DNA damages and programmed cell death in ancer cells. However, the efficacy of DNA-targeted agents such as temozolomide is often compromised by intrinsic cellular responses such as DNA base excision repair (BER). Previous studies have shown that BER pathway results in formation of abasic or apurinic/apyrimidinic (AP) sites and inhibition of AP sites leads to significant reduction of drug resistance and enhancement of drug sensitivity. Thus, AP-site formation has been identified as an important biomarker in DNA-targeted chemotherapies. Methods: Design, synthesis, and evaluation of PET imaging agents that bind to AP sites with high affinity and specificity. We date, we have developed positron-emitting [11C]methoxyamine for positron emission tomography (PET) that allows for quantification of AP sites in vivo. Results: [11C]methoxyamine has been synthesized with high radiochemical yield and purity. Following radiolabelling, microPET studies have been conducted to evaluate their pharmacokinetic profiles in melanoma and glioma xenograft tumor mouse models that are pre-treated with temozolomide to induce AP-site formation. Subsequent quantitative analysis showed that the radioactivity concentration were elevated in proportion to the AP sites induced in tumor regions pre-treated with temozolomide relative to tumor regions without any treatment. In vivo blocking studies based on microPET also showed that the agents bound to AP sites with high specificity. Conclusion: our studies demonstrated that PET imaging can be used to monitor BER pathway and evaluate efficacy of DNA-targeted therapeutic treatments in cancer. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-138.
Performing a literature review
Authors: Gulraj S Matharu, Christopher D Buckley
Journal: BMJ (2012)

Poloxamer (Pluronic®) nonionic surfactant vehicles are a series of chemically-related block copolymers finding widespread use in parenteral formulations as solubilizing and wetting agents for traditional, low-molecular weight organic drug molecules, as well as stabilizing agents for proteins and polypeptide drugs. We report the effects of poloxamer 407 (Pluronic® F-127) on plasma cholesterol and triglyceride concentrations in rats. Poloxamer 407 injected into rats by intraperitoneal injection (dose = 1.5 gm/kg) resulted in sustained (greater than 96 hour) hypercholesterolemia and hypertriglyceridemia. A larger dose of poloxamer 407 was required to elevate plasma triglyceride relative to total cholesterol. Ingestion of commercial rat chow had a negligible effect on plasma cholesterol and triglycerides levels in control (no poloxamer injection) animals, but consumption of food by animals that received an intraperitoneal injection of poloxamer 407 (30% w/w) resulted in significantly (p
Abstract P3-08-16: Age's importance in early breast cancer: Oncotype Dx results in patients ≤40 years
Authors: R Ruiz, F Namuche, Z Morante, A Aguilar, D Urrunaga, G Ziegler, M Chavez Mac Gregor, M Leon, H Gomez
Journal: Cancer Research (2019)

Abstract Background The 21-gene recurrence score (RS) predicts the benefit of adjuvant chemotherapy (CT) in ER-positive HER2-negative breast cancer (BC) and has been validated in population where women under 40 are underrepresented.Young BC pts are more likely to receive adjuvant chemotherapy (CT) in addition to endocrine therapy (ET). Our objective was to assess the RS results in young (≤40 yo) vs older (&amp;gt;40 yo) pts and evaluate the impact of age on clinical decision-making according to RS categories. Methods We retrospectively reviewed electronic medical files of all patients with early stage hormone receptor BC for whom RS was available between 2007 and 2017 in 3 specialized cancer centers. We used the Mann-Whitney and Chi-squared tests to assess differences between age group. Similarly, we evaluated the association between age groups and treatment, within each ODx category. To determine if age was associated with CT use in the low risk category, a logistic regression model was constructed. Results A total of 551 pts were included, 53 (9.6%) ≤40 yo and 498 (90.4%) &amp;gt;40 yo. No statistical differences were found between the younger and older groups in T (p=0.874), N (p=0.794), stage (p=0.188), or grade (p=0.791). Young patients underwent radical surgery more frequently than their older counterparts (41.5 vs 25.7%, p=0.014). Statistically significant differences were also observed in ER mean, which was lower in the younger group (80 vs 90%, p&amp;lt;0.001). The median RS result was significantly higher in the younger group (19 vs 16, p=0.009). Also, high-risk recurrence score category was significantly more frequent in the younger group (22.6 vs 9.2%, p=0.009). In the intermediate-risk category there were no differences in the proportion of patients who received CT according to age groups (p=0.484). In the low-risk category, 28.0% of patients ≤40 years vs 11.3% of patients &amp;gt;40 years received CT (p=0.037). Conclusions Our results indicate that RS tends to be higher in patients with BC ≤ 40 yo and that the frequency of high-risk RS is significantly higher in the younger group, suggesting biological differences between groups. 28% of young patients with low-risk RS from our cohort are overtreated. Based on these results, it should be considered to develop a test adjusted to the age of the patients. Citation Format: Ruiz R, Namuche F, Morante Z, Aguilar A, Urrunaga D, Ziegler G, Chavez Mac Gregor M, Leon M, Gomez H. Age's importance in early breast cancer: Oncotype Dx results in patients ≤40 years [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-08-16.
Abstract LB-333: Antagonistic interaction effects of aspirin and folic acid on inflammatory markers
Authors: Gloria Y Ho, Xiaonan Xue, Fred Saibil, Thomas Rohan, John Baron
Journal: Cancer Research (2008)

Abstract This ancillary study to the Aspirin/Folate Polyp Prevention Trial examined the effects of low dose aspirin and folic acid (FA) supplementation on reducing the levels of inflammatory markers- CRP, IL-6, and TNF-α. The Aspirin/Folate Trial was a randomized, double-blind trial of aspirin and folate to prevent recurrent colorectal adenomas. In a 3x2 factorial design, patients were randomized to receive 81 mg/d or 325 mg/d of aspirin or placebo, and to receive 1 mg/d of FA or placebo. In this ancillary study, blood samples collected at baseline and year 3 were assayed for the 3 inflammation markers. Marker levels at year 3 were analyzed by linear regression, with main effects of the randomization groups and interaction between aspirin and FA modeled as independent variables. In the FA-placebo stratum, mean CRP at year 3 decreased with increasing dosage of aspirin, and it was 0.58 μg/mL lower in the aspirin-325 mg group than aspirin-placebo group (P=0.048). However, in the FA-1 mg stratum, the aspirin-325 mg group actually had a higher mean CRP than aspirin-placebo. Similarly, among individuals not given aspirin, the FA-1 mg group had a 0.58 μg/mL reduction in mean CRP as compared to the FA-placebo group (P=0.045), but in individuals who were also given 325 mg of aspirin, mean CRP was higher in FA-1 mg than FA-placebo. Therefore, 325 mg of aspirin or FA alone decreased CRP levels, but together they attenuated the effects of each single regimen (P=0.033 for interaction). There were also antagonistic interaction effects on TNF-α (P=0.019) and the overall proinflammatory index (P=0.009) calculated by combining the levels of the 3 markers. Similar results were obtained when adjusting for other covariates, including baseline marker levels. Long-term use of low dose aspirin or FA supplementation alone has a modest anti-inflammatory effect, but the two regimens together eliminate such beneficial effects, and the mechanism needs to be elucidated. Table 1.Geometric mean of inflammation markers at year 3 by randomization groupAspirin: PlaceboAspirin: 81 mgAspirin: 325 mgFolic Acid: PlaceboCRP (μg/mL)2.452.141.87*IL-6 (pg/mL)2.102.012.01TNF-α (pg/mL)2.161.511.63Folic Acid: 1 mgCRP (μg/mL)1.87**2.172.15IL-6 (pg/mL)1.942.112.15TNF-α (pg/mL)1.661.652.42*P=0.048, mean CRP levels between aspirin-325 mg and aspirin-placebo in the FA-placebo subgroup. **PP=0.045, mean CRP levels between FA-1 mg and FA-placebo in the aspirin-placebo subgroup.
Abstract PD4-06: A clinical model for assessing the individual breast cancer risk in mammography screening
Authors: M Eriksson, K Czene, Y Pawitan, P Hall
Journal: Cancer Research (2019)

Abstract Background. Mammography screening reduces breast cancer mortality, but is suboptimal for the breast cancers that are not detected by the screening. These women are identified as symptomatic interval cancers with more aggressive tumors and worse pronosis. To efficiently screen for breast cancer the individual breast cancer risk should be determined. We describe a model that is suited for bi-annual screening programs and estimates the 2-year risk of breast cancer. The risk model could be used at most mammography screening units without adding substantial cost. Methods. The study was based on the population based prospective KARMA cohort including 70,877 participants. Mammograms were collected up to five years following baseline mammogram. A prediction model was developed using mammographic features (density, microcalcifications and masses), use of hormone replacement therapy (HRT), family history of breast cancer, menopausal status, and body mass index. Relative risks were calculated using conditional logistic regression and 2-year absolute risks were calculated Results. Comparing women at highest and lowest mammographic density yielded a 5-fold higher risk of breast cancer for women at highest density. When adding microcalcifications and masses to the model, high-risk women had a nearly 9-fold higher risk of breast cancer compared to those at lowest risk. In the full model, taking HRT use, family history of breast cancer and menopausal status into consideration, area under the curve (AUC) reached 0.73. We calculated the absolute 2-year risk of breast cancer based on national incidence and mortality rates. We also stratified women into risk groups using the NICE guidelines adapted to 2-year risks. The 20% women with moderate or high breast cancer risk were 7.6 times more likely to develop breast cancer compared to the general risk. Also 18% of the women showed 4 times reduced risk compared to the average population. Conclusions. This risk model can improve mammography screening by identifying women that are in need of additional examination procedures. There is also a substantial proportion of women with low breast cancer risk who will have little benefit from screening. Citation Format: Eriksson M, Czene K, Pawitan Y, Hall P. A clinical model for assessing the individual breast cancer risk in mammography screening [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD4-06.