tbuckley/cabot-search huggingface dataset:
Association of fatigue and insomnia with inflammatory cytokine and hematopoetic stem cell levels in breast cancer patients undergoing adjuvant radiation therapy.
Authors: Fei-Fei Liu, Willa Wei Shi, M McCusker, Madeline Li, Jie Su, Justin Williams, Tara Spence, Wei Xu, Kathy Chai-Zung Han, Scott Victor Bratman, Kenneth Yip
Journal: Journal of Clinical Oncology (2017)

e12048 Background: Fatigue and insomnia are frequent conditions experienced by breast cancer patients during adjuvant radiation therapy (RT). Our group reported that fatigue correlates with reduced CD34+ circulating hematopoetic stem cell (HSC) levels. Our current study examined the role of inflammatory cytokines in mediating fatigue and insomnia following adjuvant RT. Methods: Phlebotomies were conducted on 148 breast cancer patients undergoing adjuvant RT at five time points: prior to RT (D1), after two (D2) and five (D5) days of treatment, during the final week of RT (Df), and one month post-RT completion (M1). CD34+, CD45+, circulating blood cell (CBC), and 17 inflammatory cytokine levels were assessed. Patients also completed questionnaires at each time point, including the multidimensional fatigue inventory (MIF-21), insomnia severity index (ISI), and hospital anxiety and depression scale (HADS). Results: CD34+, CD45+ and CBC levels decreased during treatment with adjuvant RT, with the lowest levels observed at Df (p&lt;0.001). General fatigue significantly worsened throughout treatment from D1 to Df, returning to baseline at M1, (p&lt;0.001; adjusted for insomnia, depression and anxiety). General fatigue worsened as CD34+ counts, hemoglobin and CBCs increased (p&lt;0.001). Insomnia increased with reduced CD34+, CD45+ and CBCs (p&lt;0.05). TGF-β1, MCP-1, MMP-2, IL-1ra and IFN-α2a cytokine expression varied throughout RT (p&lt;0.01), most significantly at Df. Elevated MCP-1, TNF-RII and TNF-a levels correlated with worsening general fatigue, increased insomnia, and reduced activity and motivation (p&lt;0.001). MMP-2 increased as IL-1ra, CD34+, CD45+ and CBC counts decreased (p&lt;0.001). Further, the 52 patients who received prior adjuvant chemotherapy had elevated levels of fatigue, insomnia and anxiety, which correlated with high HSCs levels. Conclusions: Our findings demonstrate that fatigue and insomnia are associated with reduced HSCs and increased MCP-1, TNF-RII and TNF-a pro-inflammatory cytokines. This examination of the effect of RT on fatigue and insomnia is one of the most comprehensive longitudinal clinical evaluations of its kind.
A phase II single-arm study of pazopanib and paclitaxel as first-line treatment for patients with advanced melanoma.
Authors: John P. Fruehauf, Beverly Alger, James G. Jakowatz, David Hsiang, Leonard S. Sender, Claudette Bettis, Cameron Casey
Journal: Journal of Clinical Oncology (2014)

9036 Background: We designed a phase II single arm, open label clinical trial evaluating pazopanib in combination with metronomic paclitaxel as first line therapy for subjects with unresectable stage III and stage IV melanoma. We collected PK data to determine if pazopanib blood levels were associated with treatment outcomes. Methods: Subjects received paclitaxel at 80mg/m2weekly for 3 weeks in a 4 week cycle and pazopanib at 800mg as a continuous daily oral dose. Patients with treated CNS metastases were eligible. It was predetermined that 44 subjects with measurable disease were sufficient to estimate the response probability to within +/- 15% (95% confidence interval). The primary endpoint was 6-month progression free survival. Secondary endpoints included 1-year survival, TTP and median OS. Outcomes were correlated with pazopanib cycle 2 day 1 pre-dose steady state plasma levels. Results: We enrolled 51% M1c, 34% M1b, 13% M1a, and 1 patient was IIIc. Nine patients had previously treated CNS metastases. Forty six patients were fully evaluable for response. Six of 7 unevaluable patient’s had clinical progression and were considered to have PD. Response rates were: 1 CR, 20 PR’s, 26 SD’s, and 6 PD’s. The overall RR (CR+PR) was 40%. Disease control rate was 89% (CR+PR+SD). Six-month PFS was 70%, 1-year OS was 43%. Median TTP was 210 days and median OS was 403 days. Grade 3-4 AEs included hypertension (25%), transaminitis (23%), and neutropenia (17%). One patient discontinued for grade 4 transaminitis which subsequently resolved completely. Pazopanib was dose reduced in 30% of patient’s. Mean pazopanib serum levels were not significantly different (p=.2) in patients with stable disease (43.43 + 32.3 ug/ml) compared with responding patients (31.96 + 20.58). A linear regression for drug levels and best response yielded an insignificant r = 0.27. Conclusions: This phase II study demonstrated that pazopanib in combination with paclitaxel was well tolerated and resulted in a 40% response rate with 6-month PFS of 70%, indicating that this combination is of further interest. There was no association between pazopanib serum levels and treatment response. Clinical trial information: NCT01107665.
Abstract P245: Loss of Steroid Receptor Coactivator-2 in the Heart Results in a Return to the Fetal Gene Program
Authors: Erin L Reineke, Brian York, Christopher B Newgard, Heinrich Taegtmeyer, George E Taffet, Mark L Entman, Bert W O'Malley
Journal: Circulation Research (2011)

Steroid Receptor Coactivator-2 (SRC-2) is an integral transcriptional mediator of metabolism throughout the body with roles in both fatty acid and carbohydrate metabolism. Based on the critical link between cardiac function and cardiac metabolism, which itself has dynamic interplay between both fatty acid and carbohydrate use, we sought to determine if SRC-2 plays a role in controlling cardiac metabolism. Hearts from SRC-2-/- mice were analyzed by extensive gene expression profiling of major metabolic enzymes in fuel usage pathways as well as metabolomic analysis of major metabolites. Our results indicate that under normal conditions, loss of SRC-2 compromises the ability of the adult heart to metabolize fatty acid as its sole fuel source. We observe a gene expression profile that mimics the fetal heart and a metabolomic profile that suggests a reliance on anaerobic conversion of glucose to lactate for energy. This fetal gene switch is paralleled with changes of sarcomeric gene expression, along with several genes altered in response to stress. Interestingly, this long-term adaptive response is adequate to maintain cardiac function under normal conditions. However, SRC-2-/- mice do show impaired cardiac function as compared to SRC-2+/+ mice under hemodynamic stress from aortic banding. Surprisingly, this is accompanied by the absence of hypertrophy, which may be explained by decreased expression of serum response factor (SRF) and several of the transcription factors with which SRF is known to act. Taken together, loss of SRC-2 results in a cardiac phenotype characterized by a return to the fetal gene program that mimics the state of a stressed and/or aging heart. Further investigation of this mouse model may play an important role in understanding the mechanisms underlying the transcriptional events surrounding cardiac metabolic remodeling.
Silencing of Transposable Elements by piRNAs in <i>Drosophila</i>: An Evolutionary Perspective
Authors: Shiqi Luo, Jian Lu
Journal: Genomics Proteomics & Bioinformatics (2017)

Abstract Transposable elements (TEs) are DNA sequences that can move within the genome. TEs have greatly shaped the genomes, transcriptomes, and proteomes of the host organisms through a variety of mechanisms. However, TEs generally disrupt genes and destabilize the host genomes, which substantially reduce fitness of the host organisms. Understanding the genomic distribution and evolutionary dynamics of TEs will greatly deepen our understanding of the TE-mediated biological processes. Most TE insertions are highly polymorphic in Drosophila melanogaster, providing us a good system to investigate the evolution of TEs at the population level. Decades of theoretical and experimental studies have well established “transposition-selection” population genetics model, which assumes that the equilibrium between TE replication and purifying selection determines the copy number of TEs in the genome. In the last decade, P-element-induced wimpy testis (PIWI)-interacting RNAs (piRNAs) were demonstrated to be master repressors of TE activities in Drosophila. The discovery of piRNAs revolutionized our understanding of TE repression, because it reveals that the host organisms have evolved an adaptive mechanism to defend against TE invasion. Tremendous progress has been made to understand the molecular mechanisms by which piRNAs repress active TEs, although many details in this process remain to be further explored. The interaction between piRNAs and TEs well explains the molecular mechanisms underlying hybrid dysgenesis for the I-R and P-M systems in Drosophila, which have puzzled evolutionary biologists for decades. The piRNA repression pathway provides us an unparalleled system to study the co-evolutionary process between parasites and host organisms.
Abstract KP01: UNITED KINGDOM COLLABORATIVE TRIAL OF OVARIAN CANCER SCREENING – (UKCTOCS) – EXPLORING THE RESULTS
Authors: Usha Menon
Journal: Clinical Cancer Research (2017)

Abstract The continued high case fatality ratio in ovarian cancer has underpinned efforts to develop a screening strategy that could impact on mortality. In the general population randomised control trial - United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) two screening strategies (multimodal MMS and ultrasound USS) were compared to no screening (control C). Of 202,638 women randomised between April 2001-October 2005, 50,624 MMS; 50,623 USS; and 101,299 C were eligible for analysis. By the end of screening (December 2011) 345,570 MMS and 327,775 USS annual screens were performed. At censorship for the initial mortality analysis on 31st December 2014, there was an overall significant stage shift in invasive epithelial ovarian/tubal/peritoneal cancer in the MMS group compared to C in an ‘intention to screen’ analysis. More detailed analysis has shown this stage shift seen in the MMS group was limited to Type II (high grade serous) ovarian cancers. This was associated with a delayed but not yet statistically significant mortality reduction. Disease specific mortality rates in the C arm were continuing to rise while they appeared to have plateaued in the screen arms. Further follow-up is now underway to confirm the mortality reduction and determine its full extent. Meanwhile a focus on detecting low volume disease using cancer specific markers, novel biospecimens such as endocervical samples, targeted imaging and time series algorithms for interpreting marker profile suggest that a new era in ovarian cancer screening is underway. Citation Format: Usha Menon. UNITED KINGDOM COLLABORATIVE TRIAL OF OVARIAN CANCER SCREENING – (UKCTOCS) – EXPLORING THE RESULTS [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr KP01.
Dual Inhibition of HDAC and Tyrosine Kinase Signaling Pathways with CUDC-907 Inhibits Thyroid Cancer Growth and Metastases
Authors: Shweta Kotian, Lisa Zhang, Myriem Boufraqech, Kelli Gaskins, Sudheer Kumar Gara, Martha Quezado, Naris Nilubol, Electron Kebebew
Journal: Clinical Cancer Research (2017)

Abstract Purpose: There is currently no standard therapy for anaplastic thyroid cancer (ATC) and poorly differentiated thyroid cancer (PDTC), which account for two-thirds of thyroid cancer–related deaths. Driver mutations in the PI3K/AKT and RAF/RAS/MEK/ERK pathways are common in ATC and PDTC. Histone deacetylases (HDAC) regulate cancer initiation and progression. Our aim was to determine the therapeutic efficacy of simultaneously targeting these pathways in thyroid cancer with a single agent and to evaluate biomarkers of treatment response. Experimental Design: CUDC-907 is a first-in-class compound, functioning as a dual inhibitor of HDACs and the PI3K/AKT pathway. We investigated its antiproliferative effect in vitro and in vivo. Results: CUDC-907 significantly inhibited cellular proliferation in thyroid cancer cell lines, induced G2–M arrest with decreased levels of the checkpoint regulators cyclin B1, AURKA, AURKB, PLK1, and increased p21 and p27. Treatment induced apoptosis with increased caspase-3/7 activity and decreased survivin levels and decreased cellular migration and invasion. CUDC-907 treatment caused H3 hyperacetylation and decreased HDAC2 expression. HDAC2 was upregulated in ATC and other thyroid cancer histologic subtypes. CUDC-907 treatment reduced both p-AKT and p-ERK1/2 levels. Finally, CUDC-907 treatment, in a metastatic mouse model of thyroid cancer, showed significant inhibition of growth and metastases, and tumors from treated mice had decreased HDAC2 expression, suggesting that this may be a useful biomarker of response. Conclusions: Dual inhibition of HDAC and the tyrosine kinase signaling pathways with CUDC-907 is a promising treatment strategy for advanced, metastatic thyroid cancer. Clin Cancer Res; 23(17); 5044–54. ©2017 AACR.
Adalimumab in Crohn’s disease and symptomatic small bowel strictures
Authors: Yoram Bouhnik, Jean-Yves Mary
Journal: Gut (2017)

Adalimumab in Crohn's disease and symptomatic small bowel stricturesWe thank Sonambekar et al 1 for their pertinent remarks, which raised the problem of some errors in our manuscript 2 and gave us the opportunity to correct them: (1) the length of the strictures on MRI is in centimetres and not in millimetres (table 3); (2) it is noted that among the 97 patients, three had L2 diseases (table 2).After checking each case, two patients had L3 disease and one patient had L1 disease.(3) Among the causes of failure of treatment, a part of sentence was cut-off in the part 'primary and secondary endpoints'.The complete sentence goes as follows: thirty-five patients failed to achieve success for the following reasons: 14 needed corticosteroids after week 8, two patients were switched to infliximab, eight patients underwent an intestinal resection, two patients had an endoscopic dilation, 10 patients had a severe adverse effect leading to adalimumab discontinuation, two patients interrupted adalimumab treatment and five patients withdrew from the study (four were lost to follow-up and one withdrew consent).Thus, only two patients were switched to infliximab.We also agree with the authors that the Crohn's disease obstructive score is not yet validated and requires validation and simplification, and the first aspect was underlined in the manuscript.
New Opportunities for Evidence in Fetal Alcohol Spectrum Disorder
Authors: Carol Bower, Gareth Baynam
Journal: JAMA Pediatrics (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Pediatrics HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Pediatrics journal
Dioctyl sodium sulfosuccinate (DOSS; CAS #577-11-7) a major component of the dispersant COREXIT is an obesogen
Authors: Alexis M. Temkin, Robert R. Bowers, Margaret E. Magaletta, Steven Holshouser, Adriana Maggi, Paolo Ciana, Louis J. Guillette, John Bowden, John E. Baatz, Demetri D. Spyropoulos, John R. Kucklick
Journal: Environmental Health Perspectives (2016)
Phase I study of preoperative continuous 5-FU and sorafenib with external radiation therapy in locally advanced rectal adenocarcinoma.
Authors: Gopi Kesaria Prithviraj, Kun Jiang, Xiuhua Zhao, Dung-Tsa Chen, Brian Morse, Ravi Shridhar, Sarah E. Hoffe, David Shibata, Richard D. Kim
Journal: Journal of Clinical Oncology (2014)

3636^ Background: Preoperative treatment with fluoropyrimidine-based chemoradiotherapy is the standard of care in locally advanced rectal cancer (T3, T4 or N1). Sorafenib inhibits of ras/raf, PDFGR and VEGFR with synergistic activity with radiation (RT). This phase I study evaluated the safety and efficacy of sorafenib with infusional 5-FU and RT in patients with locally advanced rectal cancer. Methods: Patients with stage II or III rectal cancer, confirmed by endoscopic ultrasound (EUS) and CT scan, were recruited in 4 cohorts of 3 patients per dose level (DL), with an expansion cohort at the MTD. A 3+3 dose escalation design was used. RT was given in 25 fractions at 1.8Gy (45Gy) day 1-5 at all dose levels. Patients underwent surgery 6-10 weeks following neoadjuvant therapy. Results: 14 patients were enrolled at Moffitt Cancer Center, including 8 females and 6 males with a median age of 55 years (range: 40-72). After observing toxicity in the first cohort (2 patients with G2 and G3 skin toxicity and 1 patient with G2 mucositis) requiring dose interruptions, an amendment was made to change the schedule of chemotherapy and sorafenib to days 1-5 instead of daily. Following this, hypertension was the only G3 toxicity seen. 2 patients had G3 hypertension at 200mg adjusted dose(day1-5); 1 patient had G3 hypertension at the 400 mg PO BID dose level, and no grade IV toxicities were observed. No perioperative complications were seen. One patient is awaiting surgery. Due to patient refusal, 2 patients did not undergo surgery. KRAS status was available for 10 patients. The pCR rate was 36% and downstaging was observed in 81.8% of patients. The pCR was 50% in those with KRAS mutant tumors (2/4 pts). Conclusions: After changing the dosing schedule, this regimen was very well tolerated. The pCR and downstaging rate of the tumor is encouraging. Accrual to the expansion cohort is ongoing. Clinical trial information: NCT01376453.
Predicting sensitivity to palbociclib with early circulating tumor DNA dynamics in the PALOMA-3 trial.
Authors: Ben O'Leary, Sarah Hrebien, James P Morden, Matthew Beaney, Yuan Liu, Cynthia Huang Bartlett, Maria Koehler, Massimo Cristofanilli, Isaac Garcia-Murillas, Judith Bliss, Nicholas C. Turner
Journal: Journal of Clinical Oncology (2017)

1018 Background: Palbociclib improves progression free survival (PFS) in patients with advanced, hormone receptor positive, HER2-negative breast cancer. There are currently no biomarkers to predict sensitivity to palbociclib. We investigated if early circulating tumour DNA (ctDNA) dynamics could predict clinical outcome on palbociclib (Palbo) and fulvestrant (F) in the PALOMA-3 trial. Methods: Plasma samples were prospectively collected in PALOMA-3 for ctDNA analysis at baseline, cycle 1 day 15 (D15) and end of treatment (EOT), and were screened for PIK3CA and ESR1 mutations using digital PCR. The primary objective was to assess whether early dynamic changes in PIK3CA mutations would predict PFS in patients treated with Palbo + F. Suppression of PIK3CA ctDNA levels below an optimised cut-off at cycle 1 D15, relative to baseline levels, was termed a ‘circulating DNA ratio (CDR) response. Results: PIK3CA mutations were identified in 22.0% (100/455) of screened baseline samples with 52 of these randomised to Palbo + F and having matched D15 samples. Patients on Palbo + F with a CDR response had a median PFS of 11.2 months (95%CI 11.1 – undefined) whereas patients on Palbo + F without a CDR response had a median PFS of 4.1 months (95%CI 3.6 – 5.5) (HR for no CDR response 4.92, 95% CI 1.98 – 12.26, p = 0.0002). Overall, Palbo + F suppressed D15 PIK3CA ctDNA levels to a greater extent than placebo + F (p&lt;0.0001). ESR1 mutations were identified in 25.6% (114/445) of screened baseline samples, 65 having matched D15 samples. ESR1 mutations showed greater ctDNA suppression than PIK3CA mutations, and were more frequently undetectable at EOT (25.8% ESR1 undetectable 8/31, v 2.6% for PIK3CA, 1/38, p=0.004). Clearance of ESR1 mutation at EOT was associated with early loss of ESR1at D15 (p = 0.027). Conclusions: Early circulating tumor DNA assessment may predict sensitivity to palbociclib and fulvestrant, and if validated by further analysis may allow treatment to be adapted prior to progression. ESR1 mutations are frequently lost after treatment with palbociclib and fulvestrant.
Toxicity of extended adjuvant aromatase inhibitors therapy in postmenopausal breast cancer patients: A systematic review and meta-analysis.
Authors: Hadar Goldvaser, Domen Ribnikar, Tristan Alexandra Barnes, David W. Cescon, Alberto Ocana, Eitan Amir
Journal: Journal of Clinical Oncology (2017)

549 Background: Aromatase inhibitors (AI) are a gold standard adjuvant endocrine therapy for postmenopausal women with breast cancer. A number of randomized trials (RCTs) have reported modest improvements in breast cancer outcomes from extending treatment with AI beyond the initial 5 years after diagnosis. However, less in known about the toxicity of extended AI compared with no therapy. Methods: We conducted a systematic review of MEDLINE to identify RCTs that compared extended AI to placebo or no treatment. The search was supplemented by a review of abstracts from the American Society of Clinical Oncology and San Antonio Breast Cancer Symposium meetings between 2013 and 2016. Odds ratios (ORs), 95% confidence intervals (CI), absolute risks, and the number needed to harm (NNH) associated with one adverse event were computed for prespecified safety and tolerability outcomes including cardiovascular disease, bone fractures, second cancers (excluding new breast cancer), treatment discontinuation due to adverse events and death without recurrence. Results: Seven trials comprising 16349 patients met the inclusion criteria. Longer treatment with AI was associated with increased odds of cardiovascular disease (OR = 1.18, 95% CI 1.00-1.40, P=0.05; NNH = 122) and bone fractures (OR = 1.34, 95% CI 1.16 - 1.55, P &lt; 0.001; NNH = 72). Compared to control, longer AI therapy was associated with a higher odds of treatment discontinuation due to adverse events (OR = 1.45, 95% CI 1.25 - 1.68, P &lt; 0.001; NNH = 20). Longer AI therapy did not influence the odds of second cancers (OR = 0.93, 95% CI 0.73-1.18, P = 0.56). There was a numerical excess of death without recurrence with longer AI therapy, but this was not statistically significant (OR = 1.11, 95% CI 0.9 - 1.36, P = 0.34). Conclusions: Longer durations of AI use are associated with increased cardiovascular events and bone fracture. There is a numerical, but non-statistically significant excess of deaths without breast cancer recurrence among patients receiving longer AI therapy. These data should be taken into account when considering extended adjuvant AI therapy for breast cancer patients.