tbuckley/cabot-search huggingface dataset:
After a Long Illness
Authors: Judith Harris
Journal: JAMA (2020)

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Abstract 38: Prospective Study of Midlife Sedentary Behavior, Physical Activity, and Cognitive Function: The CARDIA Study
Authors: Kara M Whitaker, Kelley Pettee Gabriel, Baojiang Chen, Monica Ahrens, Barbara Sternfeld, Stephen Sidney, David R Jacobs, Priya Palta, Kristine Yaffe
Journal: Circulation (2020)

Introduction: Evidence suggests moderate to vigorous intensity physical activity (MVPA) has beneficial effects on various domains of cognitive function; however, less than half of adults meet MVPA guidelines. Alternate approaches, such as reducing sedentary behavior (SED) with concurrent increases in light-intensity physical activity (LPA) may resonate more strongly with the adult population. Objective: To determine if accelerometer measured SED, LPA, and MVPA at ages 38-50 years is prospectively associated with measures of cognitive function. Methods: We studied 1,842 Black and White men and women enrolled in CARDIA who participated in the year 20 (2005-06) and year 25 (2010-11) and/or year 30 (2015-16) exams. SED, LPA, and MVPA were measured by the ActiGraph 7164 accelerometer at year 20. Cognitive function tests at the year 25 and 30 exams included the Rey Auditory Verbal Learning Test (RAVLT, memory), Digit Symbol Substitution Test (DSST, processing speed), and Stroop Test (executive function). Compositional isotemporal substitution analysis examined associations of SED, LPA, and MVPA at year 20 with repeated measures (unstructured covariance) of the cognitive function raw test scores at years 25 and 30. Results: In men, substituting 30 minutes of SED with 30 minutes of LPA was associated with a decrease in the RAVLT (-0.05) and DSST (-0.76), and increase in Stroop (0.45) scores, indicating worse performance (see Table ). Substituting SED or LPA with MVPA was associated with an increase in RAVLT (0.15, 0.20) and DSST (1.21, 2.00), and decrease in Stroop (-0.68, -1.17) scores, respectively, indicating better performance. In women, who had higher cognitive function scores than men, substituting SED or LPA with MVPA was associated with worse performance on the Stroop test (0.70, 0.63), contrary to our hypothesis. Conclusions: Statistical substitution of time from lower-intensity activities (SED or LPA) with MVPA, but not SED with LPA, resulted in better cognitive performance in men, but not women, over 10 years.
Mammalian target of rapamycin (mTOR) as a target in human breast cancer cells that have acquired resistance to aromatase inhibitor letrozole
Authors: Gauri J. Sabnis, Danijela Jelovac, Brian J. Long, Adam Schayowitz, Aashvini Belosay, Angela M. H. Brodie
Journal: Cancer Research (2006)

2316  Estrogens play an important role in development and progression of breast cancer. Aromatase inhibitors (AIs) such as letrozole, that block the synthesis of estrogen are proving to be superior to antiestrogens (AEs) and may replace tamoxifen as first line treatment for postmenopausal ER positive breast cancer patients. However, resistance to letrozole therapy remains a major concern. To study the mechanisms of this resisitance we have employed a model system designated as Long Term Letrozole Treated (LTLT-Ca). Human MCF-7 breast cancer cells transfected with aromatase were grown as tumors in female ovariectomized nude mice and then treated with letrozole. The tumors regressed initially but later on began to grow. After 56 weeks of treatment the tumors were removed. The cells were isolated from the tumors and the LTLTCa cell line was developed. LTLT-Ca cells were then routinely cultured in the presence of 1μM of letrozole. These cells were completely cross-resistant to other AIs and AEs. Compared to the parental MCF-7Ca cells, up-regulation of growth factor receptors Her-2 (4 fold) and IGF-I β (3 fold) and activation of down-stream targets such as mTOR (3 fold) was observed using western immunoblotting. The overexpression of mTOR was associated with activation of the downstream effectors p70S6K (2 fold) and S6 ribosomal protein (3 Fold). LTLT-Ca cells responded to growth inhibitory effects of rapamycin (IC50= 55.6 nM) and dual EGFR/Her-2 tyrosine kinase inhibitor AEE788 (IC50= 1.5 nM) These cells showed a partial restoration of growth inhibitory effects of letrozole, anastrozole, tamoxifen and fulvestrant after concommitant treatment with AEE788. The cell viability decreased from 83.28% with AEE788 (1nM) alone to 58.21% with AEE (1nM) plus letrozole (1μM). However, rapamycin was unable to restore the responsiveness of these cells to letrozole suggesting that letrozole resistance and mTOR activation may not be connected. Activation of mTOR is usually associated with aberrent activity of Akt. However, LTLT-Ca cells exhibited activation of mTOR inspite of low levels of Akt kinase activity of 0.9 fold compared to MCF-7Ca cells. This suggests that activation of mTOR is independent of Akt activation. It has been hypothesized that when all the erbB activity is blocked, the cells become very sensitive to changes in the mTOR dependent translation. Hence, inhibition of both Her-2 mediated tyrosine kinase signaling and mTOR dependent translation could provide better inhibition of proliferation of breast cancer cells that are refractory to aromatase inhibitor letrozole and may also restore responsiveness to letrozole.
Effect of adjuvant radiotherapy (RT) on overall survival (OS) for node positive head and neck squamous cell carcinoma (HNSCC)
Authors: A. Lavaf, E. Genden, S. Packer, J. Kao
Journal: Journal of Clinical Oncology (2007)

6087 Background: Although adjuvant RT is often recommended for locally advanced HNSCC, its effect on OS or cancer-specific survival (CSS) has not been clearly demonstrated. Methods: Within the Surveillance, Epidemiology, and End Results (SEER) Database, we selected patients with locally invasive but node negative (SEER stage 2) or node positive HNSCC (SEER stage 3–4) treated either with surgery alone (S) or surgery and radiation (S+RT). This analysis included 13,145 patients from the SEER 17 database diagnosed between 1988 and 2001. Exclusion criteria included distant metastases, no RT records or death within 3 months of surgery. The median follow-up was 4.7 years. Results: Adjuvant RT was utilized in 55% of patients with stage 2 and 84% of stage 3–4 HNSCC. For Stage 2 HNSCC, adjuvant RT was associated with lower 5 year OS on univariate analysis (46.32% for S+RT vs. 49.76% for S, p=0.016) but not on multivariate analysis (HR 1.00, p=0.93). For Stage 3 HNSCC, RT improved 5 year OS associated with RT on univariate analysis (52% for S + RT vs. 41% for S, p&lt;0.001) and multivariate analysis (HR 0.80, p=0.002). For Stage 4 HNSCC, RT significantly improved 5 year OS on univariate analysis (35% for S + RT vs. 25% for S, p&lt;0.001) and multivariate analysis (HR 0.75, p&lt;0.001). The addition of RT improved 5 year CSS for both stage 3 (59.7% vs. 51.4%) and stage 4 HNSCC (42.1% vs. 32.8%). Conclusions: In the largest reported analysis of adjuvant RT in locally advanced HNSCC, adjuvant RT results in an approximately 10% absolute increase in 5-year CSS and OS for node-positive HNSCC compared to S alone. The absolute benefit of RT is underestimated on univariate analysis because patients with poor prognostic factors are more frequently selected for adjuvant RT. Outcomes in this high-risk population remain suboptimal, emphasizing the need for continued investigation of innovative treatment approaches. No significant financial relationships to disclose.
Endpoints in adjuvant trials: A systematic review of the literature in colon cancer and proposed definitions for future trials
Authors: M. E. Buyse, K. J. Punt, C. H. Köhne, P. Hohenberger, R. Labianca, H. J. Schmoll, L. Pahlman, A. F. Sobrero, J. Y. Douillard
Journal: Journal of Clinical Oncology (2007)

4018 Background: Disease-free survival (DFS) is the primary endpoint of most trials testing adjuvant treatments. However many other endpoints are used. There is much confusion about these endpoints since different definitions were used among trials, or no definitions were provided at all. Moreover there is no consensus on either the definition of each endpoint or on the most relevant among these endpoints. This creates difficulties when comparing the results of various trials. Methods: Adjuvant trials in colon cancer were used as a model. A systematic review was performed on published adjuvant studies in colon cancer from 1997–2006, and the definitions of endpoints other than overall survival (OS) were recorded. A panel of medical oncologists, surgical oncologists, and a statistician, all with expertise in randomised trials in colorectal cancer, aimed to reach consensus on the definition of the various endpoints as well as to select the most relevant among these. Results: A total of 52 studies were identified. In addition to overall survival 8 other endpoints were used, and both the definition of these endpoints as well as the starting point differed considerably among these studies. No definition was provided for the endpoint in 19 (37%) studies and for the starting point in 30 (58%) studies. The panel reached consensus on the definition of each endpoint ( table ), and agreed that DFS, defined as the time from randomisation to any event irrespective of cause was considered to be the most relevant endpoint for adjuvant studies. The date of randomisation was considered to be the most appropriate starting point. Conclusions: The proposed guideline will help in the design of future adjuvant studies in colon cancer, and will achieve the uniformity required to facilitate cross-study comparisons. It may serve as a model for adjuvant studies in other solid tumors. [Table: see text] No significant financial relationships to disclose.
Abstract P355: Development and Validation of a Nutrient Density Score That Includes Foods Groups
Authors: Jessica D Smith, Victor Fulgoni, Adam Drewnowski
Journal: Circulation (2020)

Introduction: There has been considerable work performed on nutrient profiling to assess the nutritional contribution of a food to a healthy dietary pattern. Most profiling approaches have focused on nutrients to limit and nutrients to encourage. A few profiling approaches have also included certain food groups in the profiling algorithm. Objectives: The objective of this study was to develop a nutrient density score, based on the Nutrient Rich Food Index (NRF) 6.3, that includes food groups and validate the score against a gold-standard marker of diet quality, the Healthy Eating Index (HEI) 2015. Methods: Stepwise regression was used to develop a nutrient density score based on the day 1 total dietary intake of the U.S. population 2 years and older (excluding pregnant and lactating women) from the National Health and Nutrition Examination Survey (NHANES) 2011-2016 (n=23,743). Intake of food groups was taken from the Food Patterns Equivalent Database (FPED) 2011-2016. Sixteen nutrients (as a percent of the Daily Value) as well as five food groups (as a percentage of recommended intake in 2015-2020 Dietary Guidelines) were considered in the score. Results: When only the 16 nutrients were included in the score, 66% of the variability in the HEI 2015 could be accounted for (R 2 = 0.66). When only the five food groups were considered, the maximum R 2 with the HEI 2015 was 0.50. However, when both nutrients and foods groups were considered, the model explained 74% of the variability in the HEI 2015 (Table). The increase in the R 2 begins to plateau after the inclusion of 10 elements: 3 nutrients to encourage (fiber, potassium and unsaturated fat), 4 food groups (dairy, fruit, whole grains, and nuts and seeds) and 3 nutrients to limit (added sugar, saturated fat, sodium). Conclusion: A nutrient density score that includes both nutrients and foods groups best predicts diet quality as measured by the HEI 2015.
A case-control study examining the role of recent chemotherapy in causing <i>Clostridium difficile</i> infection among cancer patients
Authors: P. Thapaliya, A. Donato, K. Curl
Journal: Journal of Clinical Oncology (2007)

19563 Background: Clostridium difficle infection is a major cause of morbidity and mortality in hospitalized patients. The recent use of cancer chemotherapy agents is a frequently cited risk factor but there is a paucity of evidence to this regard. Objective: To determine if an association exists between C. difficile infection requiring hospitalization and recent chemotherapy in patients with cancer. Design: A retrospective case control study. Setting: Community Teaching Hospital Participants: 357 cancer patients admitted with diarrhea or developed diarrhea during their hospital stay that were tested for C. difficile diarrhea via toxin assay over a 2 year period. Outcome Measurements: C. difficile infection using tests for toxin A and or B in stool. Results: Eighty-nine cases had stool positive for C. difficile toxin whereas 267 controls were negative. 30/89 (33%) cases and 90/268 (33%) controls were found to have chemotherapy in the six weeks before collection of stool for toxin assay (Odds Ratio (OR) 1.09, p=1.0 using Pearson Chi square). Factors associated with infection on logistic regression analysis included recent antibiotic usage (OR 1.99, 95% CI 1.01- 3.93),hospitalization in preceding 2 wks with OR 4.1 (95%CI 2.39–7.05) and institutionalization with OR 2.13 (95 % CI 1.03–4.39). Conclusions: C .difficile infection in cancer patients is more likely in recently institutionalized or hospitalized patients who have received recent antibiotics, but not patients with recent chemotherapy. No significant financial relationships to disclose.
Phase II study of adjuvant gemcitabine plus docetaxel (GD) for completely resected stage I-IV high grade uterine leiomyosarcoma (HGuLMS)
Authors: M. L. Hensley, J. Larkin, N. Ishill, N. Abu-Rustum, P. Sabbatini, J. Konner, W. Tew, D. Spriggs, C. A. Aghajanian
Journal: Journal of Clinical Oncology (2007)

5591 Background: Patients (pts) with completely resected stage I-IV HGuLMS are at high risk for recurrence, with reported 2-year progression-free survival ranging from 19–30% (Dinh, Gyn Onc 2004; Major, Cancer 1993). No adjuvant treatment has been shown to improve survival, although prospective data are limited. GD achieves objective responses in metastatic uLMS. We sought to determine whether 4 cycles GD given after complete resection of stage I-IV HGuLMS would yield a 2-year PFS of at least 40%, in order to determine whether GD was worth pursuing as an adjuvant strategy in a randomized trial. Methods: Eligible pts with completely resected HGuLMS within 8 weeks of surgery, no prior GD, no evidence of disease on post-resection CT, KPS = 80, and adequate organ function were treated with G 900 mg/m 2 over 90 minutes days 1 and 8 + D 75 mg/m 2 d8, with GCSF or pegfilgrastim, every 3 weeks for 4 cycles. CT was performed at baseline, after cycle 4, and every 3 months. Progression defined as new evidence of disease on CT. Results: 25 pts (median age 49, range 37–73) enrolled; 23 evaluable (1-never treated, 1-ineligible). Grade 3 related toxicities were: neutropenia (2/23) 8.7%, febrile neutropenia (2/23) 8.7%, anemia (2/23) 8.7%, thrombocytopenia (1/23) 4.3%, diarrhea (1/23) 4.3%, hyperglycemia (2/23) 8.7%, pulmonary (2/23) 8.7%; there were no ≥ grade 4 toxicities. With median follow-up of 29 months (range 0.5 to 45 months) for all pts, PFS at 2 y and 3 y is 45%, and median OS is not yet reached. For the 18 pts with stage I or II uLMS 2-y and 3-y PFS is 58%, and median PFS is 38 months (95%C.I. 6 months to not yet reached). Sites of first recurrence were: lung only-3/23 (13%); pelvis only-5/23 (22%); both-5 (22%). Treatment of recurrence was at physician discretion and included resection, resection plus pelvic radiation, and/or chemotherapy. Conclusions: Pts treated with post-resection GD for stage I-IV HGuLMS had 2-y and 3-y PFS that appears superior to historical rates of PFS. Incorporation of GD into a randomized trial of adjuvant chemotherapy vs adjuvant pelvic radiation for resected stage I and II uLMS is planned. No significant financial relationships to disclose.
The molecular basis underpinning the potency and specificity of MAIT cell antigens
Authors: Wael Awad, Geraldine J. M. Ler, Weijun Xu, Andrew N. Keller, Jeffrey Y. W. Mak, Xin Yi Lim, Ligong Liu, Sidonia B. G. Eckle, Jérôme Le Nours, James McCluskey, Alexandra J. Corbett, David P. Fairlie, Jamie Rossjohn
Journal: Nature Immunology (2020)
Targeting cancer-associated fibroblasts by dual-responsive lipid-albumin nanoparticles to enhance drug perfusion for pancreatic tumor therapy
Authors: Qianwen Yu, Yue Qiu, Jianping Li, Xian Tang, Xuhui Wang, Xingli Cun, Shanshan Xu, Yayuan Liu, Man Li, Zhirong Zhang, Qin He
Journal: Journal of Controlled Release (2020)
Sex Differences in Salaries of Department Chairs at Public Medical Schools
Authors: Michael Mensah, Whitney Beeler, Lisa Rotenstein, Reshma Jagsi, Joanne Spetz, Eleni Linos, Christina Mangurian
Journal: JAMA Internal Medicine (2020)

Author(s): Mensah, Michael; Beeler, Whitney; Rotenstein, Lisa; Jagsi, Reshma; Spetz, Joanne; Linos, Eleni; Mangurian, Christina
Mature results of a phase II study of intraperitoneal topotecan as consolidation therapy in ovarian cancer
Authors: T. W. Malpass, K. McGonigle, M. Roberston, P. Weiden, H. G. Muntz
Journal: Journal of Clinical Oncology (2007)

5570 Background: Previous studies with intraperitoneal (IP) topotecan have shown 20 mg/m 2 to be well tolerated. This study evaluated the feasibility, safety, and effectiveness of IP topotecan as consolidation therapy for ovarian cancer. Methods: Patients with stage III/IV ovarian (or primary peritoneal) cancer in clinical complete response after cytoreduction and IV chemotherapy with carboplatin and paclitaxel who had benign findings or minimal persistent disease (&lt;= 1 cm diameter) documented at second-look surgery were eligible. IP topotecan 20 mg/m 2 was administered once every 21 days for 4 to 6 cycles. Dose reduction was based on grade 3–4 toxicities. Hematopoietic growth factors were used at the discretion of the treating physician. Results: Twenty patients were enrolled (18 ovarian and 2 peritoneal cancers). Sixteen patients received 4 cycles, 3 patients received 6 cycles, and 1 patient withdrew by personal request after 1 cycle. Of the total 83 cycles, 10 (12%) were delayed due to slow recovery of neutropenia, and 22 (27%) were administered with does reductions due to prior grade 3–4 myelosuppression. Mean delivered dose was 18 mg/m 2 . Major toxicities included episodes of neutropenia (6 grade 3; 3 grade 4) and thrombocytopenia (7 grade 3; 2 grade 4). Filgrastim was administered to 75% of patients in 51 (61%) cycles, and epoetin alfa was administered to 30% of patients in 20 (24%) cycles. Other adverse events (grade 1 or 2) that occurred in approximately half of patients included nausea and abdominal distension. Median progression-free survival was 24 months from second-look surgery (Kaplan-Meier, 95% CI 14–34 months). Sixteen patients (80%) are alive after median of 42 months from second look surgery (range, 29 to 62 months), with 4.5 year estimated overall survival of 84% (95% CI 68–100%) measured from original diagnosis. Conclusion: Consolidation IP topotecan 20 mg/m 2 every 3 weeks for 4–6 cycles is feasible and well tolerated. Progression-free and overall survival in this pilot study compare favorably with results expected for advanced ovarian cancer. Future investigation of IP topotecan is warranted, both as consolidation therapy and salvage therapy for advanced ovarian cancer. No significant financial relationships to disclose.
Effects of drugs on cellular dynamics visualized in live cells labeled with GFP in the nucleus and RFP in the cytoplasm
Authors: Ping Jiang, Meng Yang, Mingxu Xu, A. R. Moossa, Robert M. Hoffman
Journal: Cancer Research (2005)

3337   Analysis of the effects of targeted drugs is usually made on cells  in vitro  or  in vivo  after they have been fixed or extracted under various conditions. Considerably greater information on the mechanism of specific drug targeting could be obtained in studies where analysis is made on living cells  in vitro  and  in vivo . Toward this goal, we have labeled cancer cells with the green fluorescent protein (GFP) linked to histone H2B in the nucleus and with red fluorescent protein (RFP) on a retrovirus in the cytoplasm. Both cytoplasmic and nuclear dynamics can be visualized in these cells in the living state due to the differential labeling of nucleus and cytoplasm with fluorescent proteins. Human PC-3 prostate cancer cells were labeled with GFP in the nucleus and RFP in the cytoplasm as described above. These cells were used as a model system to determine the specific nuclear-cytoplasmic effects of various agents. When the dual-labeled PC-3 cells were treated with Taxol, the GFP-labeled nucleus was found to undergo dramatic early changes. The nucleoplasm appeared to attach to the nuclear membrane, resulting in the nucleus assuming a ring-like structure. This event preceded the cells entering apoptosis. In contrast to the effect of Taxol, which inhibits tubulin depolymerization, vinblastin, which inhibits tubulin polymerization, resulted in the contraction of the GFP-labeled nuclei. High dose thymidine also resulted in the nucleus assuming ring-like structures prior to entering apoptosis. The tumor cells labeled with GFP in the nucleus and RFP in the cytoplasm can also be readily analyzed in the living state for their cell cycle position as shown by the nuclear-cytoplasmic ratio. Therefore, cell cycle arrest by specific agents can be readily visualized in living dual-color cells. The various stages of apoptosis are also readily visualized in the dual-color cells. These observations can be made  in vivo  as well as  in vitro . Thus, the cells labeled with GFP in the nucleus and RFP in the cytoplasm can be highly useful to establish the mechanism of drug targeting in the living state.