tbuckley/cabot-search huggingface dataset:
Prognostic Potential of Circulating Tumor DNA Measurement in Postoperative Surveillance of Nonmetastatic Colorectal Cancer
Authors: Yuxuan Wang, Lu Li, Joshua D. Cohen, Isaac Kinde, Janine Ptak, Maria Popoli, Joy Schaefer, Natalie Silliman, Lisa Dobbyn, Jeanne Tie, Peter Gibbs, Cristian Tomasetti, Kenneth W. Kinzler, Nickolas Papadopoulos, Bert Vogelstein, Louise Olsson
Journal: JAMA Oncology (2019)

For patients with resected, nonmetastatic colorectal cancer (CRC), the optimal surveillance protocol remains unclear.To evaluate whether serial circulating tumor DNA (ctDNA) levels detected disease recurrence earlier, compared with conventional postoperative surveillance, in patients with resected CRC.This study included patients (n = 58) with stage I, II, or III CRC who underwent radical surgical resection at 4 Swedish hospitals from February 2, 2007, to May 8, 2013. Eighteen patients received adjuvant chemotherapy at the discretion of their clinicians, who were blinded to the ctDNA results. Blood samples were collected at 1 month after the surgical procedure and every 3 to 6 months thereafter for ctDNA analysis. Patients were followed up until metachronous metastases were detected, or for a median of 49 months. Data analysis was performed from March 1, 2009, to June 23, 2018.Sensitivity and timing of ctDNA positivity were compared with those of conventional surveillance modalities (computed tomographic scans and serum carcinoembryonic antigen tests) for the detection of disease recurrence.This study included 319 blood samples from 58 patients, with a median (range) age of 69 (47-83) years and 34 males (59%). The recurrence rate among patients with positive ctDNA levels was 77% (10 of 13 patients). Positive ctDNA preceded radiologic and clinical evidence of recurrence by a median of 3 months. Of the 45 patients with negative ctDNA throughout follow-up, none (0%; 95% CI, 0%-7.9%) experienced a relapse, with a median follow-up of 49 months. However, 3 (6%; 95% CI, 1.3%-17%) of the 48 patients without relapse had a positive ctDNA result, which subsequently fell to undetectable levels during follow-up.Although these findings need to be validated in a larger, prospective trial, they suggest that ctDNA analysis could complement conventional surveillance strategies as a triage test to stratify patients with resected CRC on the basis of risk of disease recurrence.
Abstract 2490: High <i>AXL</i> promotes migration in non-<i>MYCN</i> amplified neuroblastoma cell lines
Authors: Max M. van Noesel, Floor A.M. Duijkers, Jules P.P. Meijerink, Rob Pieters
Journal: Cancer Research (2012)

Abstract Background: Neuroblastomas (NBL) are tumors with a high rate of metastases (50% of patients). In general, in NBL MYCN amplification (NMA) is the most important prognostic factor. However NMA is infrequent and 70% of NBL are non-NMA tumors and not much is known about the driving oncogenic event. Recently, we identified among 17 NBL cell lines a group of non-NMA NBL cell lines with a distinct gene expression profile (HU133plus2.0 arrays, Affymetrix) and high expression of the AXL gene. AXL is a tyrosine kinase receptor, associated with the metastatic process of several cancers. We hypothesized that AXL contributes to metastsizing potential in non-NMA neuroblastomas and tested if AXL silencing diminishes malignant properties of high AXL expressing cell lines. Results: High expression of AXL was detected in G-IM-EN, SK-N-AS and two subclonal cell lines SH-EP-2 and SH-EP-21N. AXL was silenced (lentiviral AXL shRNA expression plasmids, pLKO.1_shAXL, Sigma-Aldrich) in GI-M-EN and SH-EP-2 with an infection efficiency of &amp;gt;90% and 80-85% AXL-mRNA knockdown. We examined the silencing effect on migration and invasion. A significant reduction of migration (74.7%) and invasion (99.8%) was achieved in GI-M-EN. In the intermediate AXL expressing expressing cell line SH-EP-2 migration reduction was less (41.9%). Furthermore, GI-M-EN and SH-EP-2 were compared for cytoskeletal, morphological changes after silencing. Cells became rounded with small lamellipodia and filopodia and F-actin fluorescent staining showed induction of F-actin positive stress-fibers (17.3%), both most prominent in high AXL expressing GI-M-EN. In SH-EP-2 the number of cells with stress fibers was increased (9.9%). Expression of, matrix metalloproteinase 9 frequent down-stream target of EMT-like processes, was not changed upon silencing of AXL. Also, we observed no effects on cell proliferation, apoptosis or downstream pathways (PI3K-AKT, MAPK-ERK pathway). Conclusion: The AXL gene is highly expressed in a subset of non-NMA NBL cell lines and seems involved in migratory and invasion properties. AXL is a possible mediator of NBL metastasis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2490. doi:1538-7445.AM2012-2490
Abstract P6-18-30: Phase Ib/II study of capecitabine 7/7 schedule with neratinib in patients with HER2-positive metastatic breast cancer (MBC)
Authors: R Wang, J Singh, V Sterlin, M Goldstein, D Lake, S Wong, J Baselga, L Norton, C Dang
Journal: Cancer Research (2019)

Abstract Background: Neratinib (N) is a potent irreversible inhibitor of HER1, HER2, and HER4 and has been shown to have antitumor activity in patients (pts) with human epidermal growth factor receptor 2 (HER2) - positive breast cancer. A previous study of combination of neratinib with capecitabine (X) was associated with &amp;gt; G 3 diarrhea in &amp;gt; 20% of patients. Currently, the NALA study is evaluating this combination of N with X at standard schedule against control. X at 7 day on and 7 day off schedule (7/7) has been shown to be well-tolerated with less ≥G3 toxicities. We are conducting a phase Ib/II study of N with X (7/7) in pts with pretreated HER2+ MBC (NCT03377387). Methods: Eligible pts had HER2+ MBC, normal left ventricular ejection fraction (LVEF ≥ 50%); pts can have any and up to 4 prior chemotherapy-based treatments in phase Ib and II portions, respectively. Primary endpoints are to define maximum tolerated dose and efficacy in phase I and phase II portions, respectively. Secondary endpoints include safety and tolerability; exploratory endpoint is to quantify cell-free DNA to correlate with response for phase II portion. There were 4 cohorts for phase Ib with dose level 1 with starting dose of X at 1500 mg BID at 7/7 schedule with N at 240 mg daily. Results: As of July 1, 2018 8 pts have been enrolled in 2 cohorts. The median age is 63y (range: 57-79), and median ECOG is 0 (range: 0-1). 4 patients were treated at dose level 1 and 2 of 4 patients experienced dose-limiting toxicity with G3 diarrhea during cycle 1. Other significant toxicities included G3 hand foot syndrome (n=1), G3 fatigue (n=1) and G3 nausea (n=1). Three pts have now been treated at dose level -1 (X at 1000 mg twice daily 7/7 and N at 240 mg daily) and no ≥ G3 toxicities has been noted. Once MTD is reached, the phase II portion will occur to assess the efficacy and to further establish the safety and tolerability of capecitabine and neratinib at the MTD. Conclusions: The phase Ib/II study combining neratinib and capecitabine 7/7 is ongoing and updated result will be presented. Citation Format: Wang R, Singh J, Sterlin V, Goldstein M, Lake D, Wong S, Baselga J, Norton L, Dang C. Phase Ib/II study of capecitabine 7/7 schedule with neratinib in patients with HER2-positive metastatic breast cancer (MBC) [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 P6-18-30.
Gilead to give up Truvada exclusivity and donate drug to some in US
Authors: Owen Dyer
Journal: BMJ (2019)

Gilead Sciences, the maker of Truvada, will donate enough of the drug to provide pre-exposure HIV prophylaxis (PrEP) to 200 000 people in the US, about a fifth of the population who need it, for at least five years.

Although a year’s supply of Truvada (emtricitabine with tenofovir disoproxil fumarate) costs around $60 to make and is sold in some countries for about $650, in the US it carries a price tag of about $20 000 (£15 400; €17 800). This has been the biggest obstacle to providing PrEP to the estimated 1.1 million people at elevated risk.

The company’s Truvada donation came a day after it said that a generic version of the $3bn a year blockbuster drug will be marketed by Teva Pharmaceutical from 30 September 2020, a year earlier than expected.

In a …
Fruit consumption and risk of type 2 diabetes: results from three prospective longitudinal cohort studies
Authors: Neil Chanchlani, Erin Russell
Journal: BMJ (2013)

The paper

Abstract

Objective To determine whether individual fruits are differentially associated with risk of type 2 diabetes.

Design Prospective longitudinal cohort study.

Setting Health professionals in the United States.

Participants 66 105 women from the Nurses’ Health Study (1984-2008), 85 104 women from the Nurses’ Health Study II (1991-2009), and 36 173 men from the Health Professionals Follow-up Study (1986-2008) who were free of major chronic diseases at baseline in these studies.

Main outcome measure Incident cases of type 2 diabetes, identified through self report and confirmed by supplementary questionnaires.

Results During 3 464 641 person years of follow-up, 12 198 participants developed type 2 diabetes. After adjustment for personal, lifestyle, and dietary risk factors of diabetes, the pooled hazard ratio of type 2 diabetes for every three servings/week of total whole fruit consumption was 0.98 (95% confidence interval 0.96 to 0.99). With mutual adjustment of individual fruits, the pooled hazard ratios of type 2 diabetes for every three servings/week were 0.74 (0.66 to 0.83) for blueberries, 0.88 (0.83 to 0.93) for grapes and raisins, 0.89 (0.79 to 1.01) for prunes, 0.93 (0.90 to 0.96) for apples and pears, 0.95 (0.91 to 0.98) for bananas, 0.95 (0.91 to 0.99) for grapefruit, 0.97 (0.92 to 1.02) for peaches, plums, and apricots, 0.99 (0.95 to 1.03) for oranges, 1.03 (0.96 to 1.10) for strawberries, and 1.10 (1.02 to 1.18) for cantaloupe. The pooled hazard ratio for the same increment in fruit juice consumption was 1.08 (1.05 to 1.11). The associations with risk of type 2 diabetes differed significantly among individual fruits (P<0.001 in all cohorts).

Conclusion Our findings suggest the presence of heterogeneity in the associations between individual fruit consumption and risk …
Sudden loss of sensation
Authors: Kathryn Harrison, Omar Kouzel, Sarkar Haider, Antal Szabo
Journal: BMJ (2012)

A 33 year old female teacher presented to hospital with a 10 day history of reduced sensation in both legs. She reported tingling in the left lower leg progressing overnight to involve both legs reaching mid-thigh level. Over the following 24 hours, the sensory loss had ascended to the level of the umbilicus and she was unable to feel her underwear. Her symptoms progressed throughout the next seven days until the reduced sensation extended to just beneath her breasts. She denied any visual disturbance, limb stiffness or weakness, or urinary or faecal incontinence. She developed a shuffling gait because of reduced sensation in her feet.

On examination, she had no meningeal signs such as neck stiffness or photophobia, and examination of her cranial nerves, motor system, and coordination were normal. She had brisk lower limb reflexes and down going plantars. Sensation to soft touch and pinprick was reduced bilaterally below the level of T5. She had normal anal tone on rectal examination. An urgent magnetic resonance imaging (MRI) scan of her spine was arranged (figure).⇓



MRI spine (whole) with gadolinium



(1) What is …
PGC1α Inhibits Polyamine Synthesis to Suppress Prostate Cancer Aggressiveness
Authors: Lisa Kaminski, Stéphanie Torrino, Maeva Dufies, Zied Djabari, Romain Haider, François-René Roustan, Emilie Jaune, Kathiane Laurent, Nicolas Nottet, Jean-François Michiels, Maeva Gesson, Stéphane Rocchi, Nathalie M. Mazure, Matthieu Durand, Jean-François Tanti, Damien Ambrosetti, Stephan Clavel, Issam Ben-Sahra, Frédéric Bost
Journal: Cancer Research (2019)

Abstract Although tumorigenesis is dependent on the reprogramming of cellular metabolism, the metabolic pathways engaged in the formation of metastases remain largely unknown. The transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) plays a pleiotropic role in the control of cancer cell metabolism and has been associated with a good prognosis in prostate cancer. Here, we show that PGC1α represses the metastatic properties of prostate cancer cells via modulation of the polyamine biosynthesis pathway. Mechanistically, PGC1α inhibits the expression of c-MYC and ornithine decarboxylase 1 (ODC1), the rate-limiting enzyme for polyamine synthesis. Analysis of in vivo metastases and clinical data from patients with prostate cancer support the proposition that the PGC1α/c-MYC/ODC1 axis regulates polyamine biosynthesis and prostate cancer aggressiveness. In conclusion, downregulation of PGC1α renders prostate cancer cells dependent on polyamine to promote metastasis. Significance: These findings show that a major regulator of mitochondrial metabolism controls polyamine synthesis and prostate cancer aggressiveness, with potential applications in therapy and identification of new biomarkers.
Students 4 Best Evidence: the future of evidence based healthcare
Authors: Katy Bettany, Matthew Billingsley
Journal: BMJ (2014)

Students 4 Best Evidence (S4BE) is a project set up by the Cochrane Centre. It consists of a growing network of students from a variety of disciplines from around the world who are interested in evidence based healthcare (EBH). We interviewed Martin Burton, director of UK Cochrane Centre, and David Carroll, medical student at Queen’s University Belfast, about the project. Martin is also a consultant otolaryngologist at the Oxford University Hospitals NHS Trust, and a senior clinical lecturer at the University of Oxford. David is one of S4BE’s contributors and editors, an avid tweeter, cat fan, and one of the founders of the Open Access Button (www.openaccessbutton.org).



Martin Burton: One of the key things about S4BE is that it is designed for students in any healthcare discipline, or potentially for students studying a non-healthcare discipline. So although we started out working with medical students, we’re hoping that nursing students, physiotherapy students, pharmacy students, etcetera will be interested. For example, we’ve recently had a blog from a post-doctoral chemistry student who’s now got an interest in EBH. We …
Abstract LB-246: A Phase I and first time in human study of the centromere associated protein E (CENP-E) inhibitor GSK923295A in patients with advanced solid tumors
Authors: Vincent Chung, Ronald A Fleming, Brendan M. Johnson, Jennifer L.s. Gauvin, Emily Lu, Joanne J. Lager, Dona B. Alberti, Brenda Williams, Barbara L. Weber, Kyle D. Holen
Journal: Cancer Research (2008)

Abstract Background: CENP-E plays a critical role in maintaining and silencing mitotic checkpoint signaling. CENP-E mRNA is overexpressed in a variety of human tumors relative to adjacent normal tissue, suggesting that it may have an important role in tumor cell proliferation. GSK923295A is a potent and selective small molecule inhibitor of CENP-E with broad preclinical activity against solid and hematologic cancer cells in vitro and in murine tumor xenograft models. The purpose of this Phase I study is to determine the maximally tolerated dose, dose-limiting toxicities (DLTs), pharmacokinetics (PK), and pharmacodynamics of GSK923295A in patients with advanced solid tumors. Methods: Adult patients with refractory advanced solid tumors are administered GSK923295A by a 1-hour intravenous infusion on days 1, 8, and 15 of 28-day treatment cycles. Doses are escalated in cohorts of 2 patients using an accelerated titration scheme. Transition to a standard (40% or 33%) dose escalation scheme is planned if 2 grade 2 toxicities or 1 DLT are observed in the first treatment cycle. Blood samples are collected on days 1 and 15 over 48 hours to determine the plasma PK of GSK923295A. Pre- and post-treatment FDG-PET and tumor biopsies are performed in selected patients. Results: Eight patients [4 males, 4 females; median age 54.5 years; cancers of pancreas (2), lung (2), stomach (1), colon (1), parotid gland (1), and liver (1)] have been treated at 10, 20, 40, and 80 mg/m2 (median of 1.5 and total of 15 cycles completed). One DLT (AST elevation) has been reported at 80 mg/m2. We have expanded this dose level to 3 patients. At the 4 dose levels studied thus far, PK appears dose proportional with low intrapatient variability, modest interpatient variability, and no apparent accumulation or time-dependent PK. Conclusions: One DLT has been observed at the 80 mg/m2 dose level. Evaluation of GSK923295A continues at a dose level of 80 mg/m2. Dose Level (mg/m2)NDayCmax* (ng/mL)AUC(0-¥)* (ng.h/mL)Clearance* (L/h/m2)Half-life* (h)1021279-377413-61516.3-24.22.72-3.7610215228-409377-76613.1-26.55.22-6.772021546-767992-156012.8-20.19.02-9.7020215499-889927-189010.6-21.68.11-8.9640211300-25302130-71305.61-18.84.50-13.6402151690-24202290-72705.50-17.55.64-20.580212090-25005210-655012.2-15.412.4-13.0*Denotes range from 2 patients.
Abstract 5297: A novel role of cdc-family genePFTK1in the control of liver cancer cell motility
Authors: Wilson K-C Leung, Arthur KK Ching, Anthony WH Chan, Terence CW Poon, Ka-Fai To, Alice ST Wong, Nathalie Wong
Journal: Cancer Research (2010)

Abstract Cancer metastasis remains a major cause of cancer morbidity and mortality in individuals diagnosed with hepatocellular carcinoma (HCC). We previously reported on regional chromosome 7q21-q22 gains in close association with HCC progression, and discerned a candidate proto-oncogene PFTK1 within this region by array-based CGH mapping. The PFTK1 protein, PFTAIRE protein kinase 1, is a novel member of the Cdc2-related serine/threonine protein kinases. Our earlier investigations by ectopic expression and gene knockdown of PFTK1 confirmed a functional role for the PFTAIRE protein kinase in the motile phenotype of HCC cells, yet the biological basis remained to be determined. The aims of this study are therefore to establish the clinicopathologic significance of PFTK1 in HCC, and to define the PFTK1-modulated mechanisms in the control of HCC cell motility. Recent Tissue Microarray Analysis (TMA) on 180 paired primary HCC and their adjacent non-tumoral liver suggested common up-regulated PFTK1 compared to non-malignant counterpart (76.1%; p&amp;lt;0.0001). Correlative analysis further indicated PFTK1 over-expression in association with advanced tumor grading (P&amp;lt;0.0001) and the presence of microvascular invasion (P=0.05). By 2D-PAGE coupled with mass spectrometry, comparative proteomic profiling for phosphorylated proteins in PFTK1-suppressed HCC cells highlighted 5 differentially down-regulated spots, which included β-actin (ACTB), transgelin2 (TAGLN2), heat shock protein 70, mitochondrial aldehyde dehydrogenase and 14-3-3 gamma protein. Western blot analysis further verified a consistent reduction on ACTB phosphorylation and the serine phosphorylation of the TAGLN2 protein in the absence of PFTK1 protein kinase. Immunofluorescence analysis for cytoskeletal organizations indicated marked reduction on the actin stress fibers in PFTK1 knockdown cells. In conclusion, our results suggested that PFTK1 can affect the actin cytoskeletal organization and thus a motile phenotype in HCC cells through phosphorylation of ACTB and TAGLN2 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 5297.
Abstract ES8-3: Does breast cancer prevention need an 18th amendment? New evidence on alcohol and breast cancer
Authors: M Terry
Journal: Cancer Research (2019)

Abstract Epidemiological studies have consistently supported an association between alcohol consumption and breast cancer risk for many years. Breast cancer guidelines from many societies, including the American Cancer Society, have also discussed reducing alcohol consumption to help prevent breast cancer. So why aren't more women aware of this association? This talk will review the latest evidence, including more recent mechanistic studies, about the association between alcohol intake and breast cancer as well as newer data about the lack of cardio protective benefit of modest alcohol intake. What evidence do we now have about whether the association with breast cancer risk and outcomes after diagnosis varies by time in life and intensity of drinking patterns? Citation Format: Terry M. Does breast cancer prevention need an 18th amendment? New evidence on alcohol and 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 ES8-3.
Two-view digital breast tomosynthesis versus digital mammography in a population-based breast cancer screening programme (To-Be): a randomised, controlled trial
Authors: Solveig Hofvind, Åsne S Holen, Hildegunn S Aase, Nehmat Houssami, Sofie Sebuødegård, Tron A Moger, Ingfrid S Haldorsen, Lars A Akslen
Journal: The Lancet Oncology (2019)
The mechanism(s) of action of antioxidants: From scavenging reactive oxygen/nitrogen species to redox signaling and the generation of bioactive secondary metabolites
Authors: Attila Hunyadi
Journal: Medicinal Research Reviews (2019)

Abstract Small molecule, dietary antioxidants exert a remarkably broad range of bioactivities, and many of these can be explained by the influence of antioxidants on the redox homeostasis. Such compounds help to modulate the levels of harmful reactive oxygen/nitrogen species, and therefore participate in the regulation of various redox signaling pathways. However, upon ingestion, antioxidants usually undergo extensive metabolism that can generate a wide range of bioactive metabolites. This makes it difficult, but otherwise a need, to identify the ones responsible for the different activities of antioxidants. By better understanding their ways of action, the use of antioxidants in therapy can be improved. This review provides a summary on the role of the in vivo metabolic changes and the oxidized metabolites on the mechanisms behind the bioactivity of antioxidants. A special attention is given to metabolites described as products of biomimetic oxidative chemical reactions, which can be considered as models of free radical scavenging. During such reactions a wide variety of metabolites are formed, and they can exert completely different specific bioactivities as compared to their parent antioxidants. This implies that exploring the free radical scavenging‐related metabolite fingerprint of each antioxidant molecule, collectively defined here as the scavengome, will lead to a deeper understanding of the bioactivity of these compounds. Furthermore, this paper aims to be a working tool for systematic studies on oxidized metabolic fingerprints of antioxidants, which will certainly reveal an often‐neglected segment of chemical space that is a treasury of bioactive compounds.