tbuckley/cabot-search huggingface dataset:
UBE3A Suppresses Overnutrition‐Induced Expression of the Steatosis Target Genes of MLL4 by Degrading MLL4
Authors: Janghyun Kim, Bora Lee, Dae‐Hwan Kim, Jae Gwang Yeon, Jeongkyung Lee, Younjung Park, Yuna Lee, Soo‐Kyung Lee, Seunghee Lee, Jae W. Lee
Journal: Hepatology (2018)

Regulation of the protein stability of epigenetic regulators remains ill‐defined despite its potential applicability in epigenetic therapies. The histone H3‐lysine 4‐methyltransferase MLL4 is an epigenetic transcriptional coactivator that directs overnutrition‐induced obesity and fatty liver formation, and Mll4+/‐ mice are resistant to both. Here we show that the E3 ubiquitin ligase UBE3A targets MLL4 for degradation, thereby suppressing high‐fat diet (HFD)‐induced expression of the hepatic steatosis target genes of MLL4. In contrast to Mll4+/‐ mice, Ube3a+/‐ mice are hypersensitive to HFD‐induced obesity and fatty liver development. Ube3a+/‐;Mll4+/‐ mice lose this hypersensitivity, supporting roles of increased MLL4 levels in both phenotypes of Ube3a+/‐ mice. Correspondingly, our comparative studies with wild‐type, Ube3a+/‐ and Ube3a‐/‐ and UBE3A‐overexpressing transgenic mouse livers demonstrate an inverse correlation of UBE3A protein levels with MLL4 protein levels, expression of the steatosis target genes of MLL4, and their decoration by H3‐lysine 4‐monomethylation, a surrogate marker for the epigenetic action of MLL4. Conclusion: UBE3A indirectly exerts an epigenetic regulation of obesity and steatosis by degrading MLL4. This UBE3A‐MLL4 regulatory axis provides a potential therapeutic venue for treating various MLL4‐directed pathogeneses, including obesity and hepatic steatosis.
Hyperthermic pleural lavage for pleural metastasis.
Authors: Patricia L. Thompson
Journal: Journal of Clinical Oncology (2016)

e14569 Background: To evaluate the safety and efficacy of hyperthermic pleural lavage (HTPL) with cisplatin in patients who had undergone cytoreductive surgery pleurectomy/decortication (PD) for isolated chemoresistant pleural metastasis (PM). This may be an alternative treatment for patients with isolated pleural metastasis with controlled primary disease. Methods: After Health System and Cancer Committee approval, 10 patients with unilateral chemoresistant pleural metastasis were registered prospectively. The patients' primary sites of malignancy were under control for a median of 40 months (range, 32 - 61) prior to developing PM. Median time of systemic chemotherapy for PM was 29 months (range, 28 - 76). Patients underwent a unilateral radical P/D and lymph node dissection, 60 minutes pleural lavage (1,500 - 1,700 cc/min) with 225 mg/m2of cisplatin at 42°C. Cisplatin levels drawn at time zero, 1 hour, 4 hours, and 24 hours after completion of HTPL. Results: Median age was 53 years (range, 38 - 64); 7 patients (70%) were women. Primary tumor: breast 5, colon 2, and thymic, renal cell and anal cancer 1 each. Surgical approach was a thoracotomy in 9 patients (90%). Morbidity included atrial fibrillation in 3 (30%), prolonged air leak in 3 (30%), and acute respiratory distress syndrome in 1 (10%). Median hospital stay 7 days (range, 4 - 14). Serum cisplatin levels peaked at 4 hours after lavage; none in the toxic range. Median dose of cisplatin was 386 mg (range, 299 - 450); no patient developed renal insufficiency. Median follow-up was 10 months (range, 1 - 15). 8 patients had no signs of malignant disease at last follow-up; 1 patient (anal cancer – 6 months) developed local recurrence and 1 patient (renal cell cancer - 9 months) developed contralateral pleural disease. All patients experienced improved quality of life, respiratory function, and reduced pleuritic pain. Conclusions: Surgical cytoreduction of chemoresistant PM followed by HTPL with cisplatin was well tolerated with no cisplatin-related toxicities. Early results are promising. This novel treatment for patients with isolated secondary PM represents the first series reported. Longer follow-up is warranted to determine a survival and quality of life advantage as well as defined inclusion and exclusion criteria.
Effect of blinding on completion rate of patient-reported outcome measures in FDA cancer trial submissions, 2007-2017.
Authors: Jessica Roydhouse, Bellinda King-Kallimanis, Lynn Jackson Howie, Harpreet Singh, Paul Gustav Kluetz
Journal: Journal of Clinical Oncology (2018)

6572 Background: Patient-reported outcomes (PROs) are commonly included in clinical trial data submitted for FDA review. Open-label designs are frequent in cancer trials. Between-arm differences in PRO missingness have the potential to affect results. We aimed to compare PRO completion rates between study arms pre- and on-treatment in randomized open-label and double-blind cancer trials. Methods: Descriptive analysis of RCTs supporting cancer indications submitted to FDA for regulatory review. We identified trials for malignant disease from 2007 – 2017 using internal FDA databases. Applicant study reports were reviewed to assess PRO use and reporting of completion rates. Completion rates were collected per PRO and compared between arms. Results were summarized at the trial and instrument level using descriptive statistics. Results: Ninety-six of 169 trials (57%) associated with malignant hematology and oncology indications from 2007 – 2017 contained PROs. Fifty-one of the 96 trials (53%) were randomized, controlled trials with useable information on PRO completion. Median completion rates at six months were close to 90%. At six months, 16% of PROs in the double-blind trials had between-arm completion differences of > = 10%, and the median between-arm completion difference was 12%. Furthermore, 8% of PROs had a > = 10% higher completion rate in the control arm of these double-blind trials. However, for open-label trials at 6 months, 20% of PROs had between-arm differences of > = 10%, with a median between-arm completion difference of 25%. For these, completion was better in the experimental arm. Conclusions: PRO completion rates were generally high for those studies that reported them, even for open-label trials. However, between-arm differences in completion rates favoring the experimental arm were larger and more frequent in open-label trials. Imbalances in PRO completion rates between arms affect PRO interpretation. Procedures must be put in place to reduce missingness, and accurate reporting of completion rates upon trial conclusion is critical.
The association between mindfulness and post-operative pain in gynecologic oncology patients undergoing minimally invasive hysterectomy.
Authors: Erica Weston, Christina Raker, David Huang, Cara Amanda Mathews
Journal: Journal of Clinical Oncology (2017)

10079 Background: Studies demonstrate an inverse relationship between mindfulness and chronic pain. However, the relationship between mindfulness and acute post-operative pain has not yet been thoroughly investigated. The objective of this study is to determine if there is an association between pre-operative level of mindfulness and post-operative pain outcomes in women undergoing minimally invasive hysterectomy. Methods: For this prospective cohort study, women planning to undergo laparoscopic or robotic hysterectomy were prospectively recruited at the gynecologic oncology outpatient clinic at our institution. Baseline mindfulness was assessed at the pre-operative clinic visit using the Five Facet Mindfulness Questionnaire (FFMQ). Post-operative pain, using the Visual Numeric Rating Scale (VNRS-11), and opiate pain medication usage were evaluated via chart review and post-operative surveys completed at 1 to 2 week and 4 to 6 week post-operative clinic visits. Results: One hundred twenty four women completed the 6 week post-operative follow-up period, of which 80% were undergoing surgery for malignancy. Baseline mindfulness was inversely correlated with post-operative pain as measured by both the average and highest reported VNRS-11 values during the inpatient stay (r = -0.21, p = 0.019; r = -0.21, p = 0.016). At the 1 to 2 week post-operative visit, self-reported pain score was also inversely correlated with pre-operative mindfulness score (r = -0.24, p = 0.009). This relationship was not observed at the 4 to 6 week post-operative visit (r = -0.08, p = 0.403). Higher pre-operative mindfulness was also associated with lower opiate usage (r = -0.16, p = 0.077), though this relationship was not statistically significant. Conclusions: Higher pre-operative mindfulness is associated with more favorable post-operative pain outcomes, including lower reported numeric pain scores, in gynecologic oncology patients undergoing minimally invasive hysterectomy. This relationship provides an opportunity to target the modifiable personality characteristic of mindfulness, to improve post-operative pain in women planning gynecologic surgery.
Evaluation of the correlations between patient-derived xenograft (PDX) model-based mouse trials and cancer patient-based clinical trials.
Authors: Zhenyu Gu, Jingjing Jiang, Ying Yan, Tingting Tan, Tengfei Yu, Zhenhua Liu, Wei Du, Xuqin Yang, Ling Qiu, X. Katherine Ye
Journal: Journal of Clinical Oncology (2017)

e23140 Background: Clinical trial to evaluate the safety and efficacy of an oncology drug candidate in general is a long and expensive process required for regulatory approval in drug development. High failure rates and difficulties to predict the outcome of clinical trials have wasted the resources and hindered the progress to bring more cancer drugs to patients. PDX models have been widely used recently in preclinical efficacy studies of new cancer agents. Comparing with tumor cell line derived xenografts, PDX models showed more similarities to cancer patients in tumor pathological features, molecular changes and drug responses. More importantly, the large number of available PDX models make it feasible to do preclinical tests in large scales which can represent cancer complexity similar to clinical trials with cancer patients. Methods: At GenenDesign, we have established over 1000 PDX tumor models in various cancer types and derived about 200 acquired drug resistance models. In our in house studies, we have tested near 40 treatments with standard of cares (SoCs) and late stage clinical drug candidates either as mono-therapies or combination therapies, and have generated over 3300 drug response datasets. Many tests with targeted drugs are based on cancer gene aberrations as predictive biomarkers. The drug responses were analyzed by Modifying Response Evaluation Criteria in Solid Tumors (mRECIST) method. Results: By comparing the mRECIST scores in mouse trials with results from about two dozens of historical clinical trials at phase 3 or phase 2, we found that there are high correlations in the rates of objective response (OR), stable disease (SD) and progressive disease (PD) between the mouse trials and their counterpart clinical trials. Progression-free survival also showed similar patterns in these analyses. Conclusions: PDX based mouse trials have advantages in flexibility of study design, quickness in testing new drug candidates and direct comparison of multiple drug treatments in the same models. It can provide valuable information on clinical trial outcome prediction and support clinical study design and patient selection.
TCT-160 Attenuated-Signal Plaque and Long-Term Vessel Response after Bioresorbable Scaffold Implantation: IVUS Insights from the ABSORB JAPAN Trial
Authors: Kozo Okada, Yasuhiro Honda, Hideki Kitahara, Ryo Kameda, M Brooke Hollak, Paul G. Yock, Hajime Kusano, Wai-Fung Cheong, Krishna Sudhir, Takeshi Kimura
Journal: Journal of the American College of Cardiology (2018)
Patient characteristics and long-term outcomes beyond the first 6 months after a diagnosis of cancer-associated thrombosis.
Authors: Robert Adam Schmidt, Alaa Alzaki, Nikolas Desilet, Namali Ratnaweera, Erica A. Peterson, Agnes Y. Lee
Journal: Journal of Clinical Oncology (2018)

10057 Background: Cancer associated thrombosis (CAT) is a common complication of malignancies. However, little is known about the clinical course of CAT beyond the initial treatment period of 3 to 6 months. This information is important for clinicians and patients to inform their decision regarding duration of anticoagulation. Methods: Health records from 523 consecutive patients managed at the Vancouver General Hospital Thrombosis clinic for CAT (excluding catheter-related thrombosis) between 2013 and 2015 were reviewed; 327 were alive at 6 months post initial CAT diagnosis. Patient and cancer characteristics, objectively documented recurrent venous thromboembolism (rVTE), clinically relevant bleeding (CRB), and overall mortality of this “survivor” cohort over month 6 to 24 are described. Results: In the 6 month survivor cohort, patients were followed for a median of 605 days (range 1 to 730) and 85.9% had at least 24 months of follow-up or died. Patient characteristics at at 6 months are summarized (Table). Anticoagulation was continued in 68.8%, with a median duration of 93 days; 54.3% of patient-days were on anticoagulation. In the 6 to 24 months after the initial CAT diagnosis, there were 34 rVTE in 30 patients (9.2%; 95% CI 6.3 - 12.8) and 16 CRB in 14 (4.3%; 95% CI 2.4 – 7.1) patients, corresponding to 2.9 rVTE per 100 patient-days and 1.4 CRB per 100 patient-days of follow-up. Twenty-one (61.8%) rVTE events and 11 CRB episodes (68.8%) occurred on therapeutic anticoagulation. Over the 18 months, 141 (43.1%; 95%CI 37.7 – 48.7) patients died. Causes of death were cancer (80.9%), rVTE (1.4%), bleeding (2.8%), other (7.8%), and unknown (7.1%). Three fatal bleeds and 2 fatal rVTE occurred while on anticoagulation. Conclusions: Patients with CAT who are alive at 6 months after VTE diagnosis remain at high risk of rVTE, CRB and death. Patient characteristics at 6 months after initial CAT diagnosis Median Age, year 63.8 Male, % 48.3 ≥2 comorbidities, % 25.1 Cancer Site, % Upper GI 13.5 Hematologic 19.3 Lower GI 15.0 Lung 12.8 Gynecological 13.8 Breast 7.3 GU 4.3 Prostate 4.9 Brain 3.4 Other 5.8 Metastatic disease,* % 56.0 Cancer treatment, % 64.7 *among patients with solid tumours (n = 259).
P05.78 Improving quality of care of meningioma patients: initial evaluation of issues in care trajectories according to the Plan-Do-Study-Act Cycle
Authors: A H Zamanipoor Najafabadi, J P M van de Mortel, D J Lobatto, D Brandsma, W C Peul, M J B Taphoorn, L Dirven, W R van Furth
Journal: Neuro-Oncology (2018)

Meningioma are common benign intracranial tumours, that can cause severe neurological and daily functional problems, sometimes requiring lifelong care and support. Current practice and guidelines lack focus on these long-term sequelae. Value-Based Healthcare (VBHC) initiatives aim to increase the value of care for patients, but continuous evaluation and improvement of these initiatives is required. According to the Plan-Do-Study-Act (PDSA) cycle, a model for continuous healthcare evaluation and improvement, we explored issues in meningioma care trajectories, possible high impact initiatives to improve these issues, and the implementability of these initiatives. Previously, issues in the meningioma care trajectories were identified through a survey by The Netherlands Comprehensive Cancer Organisation. Using a grounded theory approach, a thematic framework was constructed based on this data and used for further data collection through three semi-structured interviews with patient-partner dyads (i.e. pairs) and four focus groups with patient-partner dyads and healthcare providers (both two focus groups). Issues in meningioma care trajectories reported by patient-partner dyads and healthcare providers were related to information, care and support, logistics, and diagnostics and treatment. Most important issues were lack of information about intervention and outcomes, and lack of support after treatment. A reported solution for many issues was the incorporation of a case manager. Other possible solutions were implementation of routine use of patient-reported outcome measures (PROMs) or a rehabilitation program, and formalization of these care trajectories. The most important barriers for these solutions were budget, capacity, ICT infrastructure, qualified personnel, and know-how. Implementation of a few simple solutions (e.g. case manager) may improve the majority of experienced issues in meningioma care trajectories. Information on the identified barriers and facilitators can be used to ensure successful implementation of these practice changing initiatives, which need iterative evaluation in PDSA cycles.
Live-cell phenotypic-biomarker microfluidic assay for the risk stratification of cancer patients via machine learning
Authors: Michael S. Manak, Jonathan S. Varsanik, Brad J. Hogan, Matt J. Whitfield, Wendell R. Su, Nikhil Joshi, Nicolai Steinke, Andrew Min, Delaney Berger, Robert J. Saphirstein, Gauri Dixit, Thiagarajan Meyyappan, Hui-May Chu, Kevin B. Knopf, David M. Albala, Grannum R. Sant, Ashok C. Chander
Journal: Nature Biomedical Engineering (2018)
Abstract MP11: Serum Metabolites Associate With Kidney Function Among Bogalusa Heart Study Participants
Authors: Jovia L Nierenberg, Jiang He, Changwei Li, Shengxu Li, Lydia A Bazzano, Wei Chen, Tanika N Kelly
Journal: Circulation (2018)

Chronic kidney disease (CKD) is an important public health challenge due to its high prevalence, potential for progression to end-stage renal disease, and associated increases in risks of cardiovascular disease morbidity and mortality. While traditional risk factors for reduced kidney function have been identified, the biological pathways underlying this complex phenotype remain largely unknown. A metabolome-wide association study was conducted among 825 white and 436 African-American participants of the Bogalusa Heart Study (BHS) to identify metabolites associated with kidney function. Estimated glomerular filtration rate (eGFR) was calculated among BHS participants using the CKD Epidemiology Collaboration (CKD-EPI) equation. Untargeted, ultra-high performance liquid chromatography tandem-mass spectroscopy was used to quantify 1,466 metabolites. A total of 1,202 metabolites passing rigorous quality control were tested for association with eGFR in race stratified and combined multiple regression analyses that adjusted for age, sex, education, cigarette smoking, alcohol drinking, physical activity, body mass index, and race (in combined analyses). Significant metabolites were identified as those achieving Bonferroni corrected significance (P&lt;4.16х10 -5 ) in one race group and the entire cohort, with a similar trend observed in the other race group. Results of these analyses are presented in the Figure . Among 302 significant metabolites, 89 were novel and in known metabolic pathways, 106 were novel and in unknown metabolic pathways, and 107 were previously reported. The 89 novel metabolites were classified into the following pathways: 40 in amino acids, 3 in carbohydrates, 7 in cofactors, 1 in energy, 6 in nucleotides, 9 in peptides, and 14 in xenobiotics. In conclusion, the current analysis not only validated previous findings, but identified novel metabolites associated with kidney function. These data provide important insights into the biological pathways underlying this complex phenotype.
Expression and clinical significance of antigen presentation components beta-2 microglobulin, HLA class I heavy chains, and HLA class II in non-small cell lung cancer (NSCLC).
Authors: Ila Datar, Franz Villarroel-Espindola, Brian S. Henick, Konstantinos N. Syrigos, Maria Toki, David L. Rimm, Soldano Ferrone, Roy S. Herbst, Kurt A. Schalper
Journal: Journal of Clinical Oncology (2018)

12015 Background: Defective antigen presenting machinery (APM) limits tumor recognition by cognate T cells mediating resistance to immune checkpoint inhibitors (ICIs). The expression frequency, biological context and prognostic value of major APM components in NSCLC are poorly characterized. Methods: Using multiplexed quantitative immunofluorescence we measured levels of Beta-2 microglobulin (B2M, clone-D8P1H), HLA-B, C heavy chains (HLA-I, clone HC10), HLA Class-II (HLA-II, clone LGII-612.14) and pancytokeratin (CK, clone AE1/AE3) protein in 754 stage I-IV immunotherapy-naïve NSCLCs represented in tissue microarrays: Cohort#1 Yale (n = 423), Cohort#2 Greece (n = 284) and cohort# 3 Yale (n = 137) with molecularly annotated lung adenocarcinomas (ADCs). Targets were measured in tumor/stroma by fluorescence colocalization with tumor-specific CK. Associations with clinicopathological variables, T-cell infiltration, driver mutations and survival were studied. Results: B2M, HLA-I heavy chains (HCs) and HLA-II were expressed in tumor cells in 86.7%, 83.1% and 77.9% of NSCLCs, respectively. The markers showed significant positive association with each other in CK- stromal cells (R2= 0.27-0.33, P < 0.05) but not in CK+ tumor cells (R2= 0.002-0.14, P > 0.05). Tumors lacking B2M had significantly lower HLA-I, -II and CD3+ infiltrating T cells than cases with B2M expression. No consistent association was seen between the targets and major clinicopathological variables across cohorts. Comparable levels of the markers were seen in KRAS/EGFR mutant and wild type lung ADCs. Tumor B2M downregulation was associated with worse outcome in both cohorts, but was significant only in cohort#1 and showed clear trend in #2. Conclusions: B2M, HLA-I HCs and HLA-II are downregulated in 12-22% of primary, immunotherapy-naïve NSCLCs. Reduced B2M expression associates with an immune “cold” phenotype characterized by low HLA-I, -II levels, low T cell infiltration and poor prognosis. Our results support an immunomodulatory role of APM downregulation in NSCLC and underscore its possible involvement in primary resistance to ICIs and potential as a biomarker.
DNA recognition patterns of the multi-zinc-finger protein CTCF: a mutagenesis study
Authors: Jingjing Guo, Ni Li, Jiexiong Han, Fei Pei, Tianyu Wang, Duo Lu, Jiandong Jiang
Journal: Acta Pharmaceutica Sinica B (2018)

CCCTC-binding factor (CTCF) is a zinc-finger protein, serving an important part in the genome architecture as well as some biochemical processes. Over 70,000 CTCF binding DNA sites have been detected genome-wide, and most anchors of chromatin loops are demarcated with the CTCF binding. Various protein or RNA molecules interact with DNA-bound CTCF to conduct different biological functions, and potentially the interfaces between CTCF and its cofactors can be targets for drug development. Here we identify the effective region of CTCF in DNA recognition, which defines the exposed CTCF surface feature for the interaction of cofactors. While the zinc-finger region contributes the most in DNA association, its binding affinity varies based on different DNA sequences. To investigate the effectiveness of individual zinc-fingers, the key residues are mutated to inactivate the DNA binding ability, while the finger configuration and the spacing between fingers are preserved. The strategy is proved to be successful, while clear differences are observed in the DNA binding affinities among the 11 finger mutants and the result is consistent to previous studies in general. With the help of inactivated finger mutants, we identify the ineffective fingers and the dominant effective fingers, which form distinctive patterns on different DNA targets.