tbuckley/cabot-search huggingface dataset:
Histone deacetylase inhibitor down-regulates thymidylate synthase expression: Clinical implication of overcoming 5-fluoruracil resistance in human cancer cells
Authors: Ju-Hee Lee, Yeon-Joo Jung, Jung-Hyun Park, Jee-Hyun Kim, Tae-You Kim, Yung-Jue Bang
Journal: Cancer Research (2005)

1811  Overexpression of thymidylate synthase (TS) has been regarded as a main mechanism of 5-fluorouracil (FU) resistance in human cancer cells. The novel strategy to down-regulate TS appears to be clinically promising in terms of overcoming 5-FU resistance. Here we report that low-dose trichostatin A (TSA) can reverse 5-FU resistance through down-regulation of TS. By using cDNA microarray approaches, we identified that TSA greatly reduced TS gene expression in MDA-MB453 breast cancer cells. We confirmed the down-regulation of TS mRNA expression by RT-PCR. TSA also depleted TS protein expression in both time- and dose-dependent manner. Co-treatment with cycloheximide restored TS expression, suggesting that repression of TS requires new protein synthesis. We found that chaperonic heat shock protein (Hsp) 90 was acetylated following TSA. Along with Hsp90 acetylation, TSA treatment increased the binding of Hsp70 to TS, leading to proteosomal degradation of TS. Thus, TSA seems to effectively down-regulate TS both in gene and protein level. We next tested whether nontoxic low-dose of TSA may affect TS expression and 5-FU sensitivity. We found that 40% of TS basal level was down-regulated by treating 35nM of TSA. Combined treatment with low-dose TSA and 5-FU significantly enhanced 5-FU cytotoxicity in 5-FU resistant gastric cancer cells with down-regulation of TS. Taken together, low-dose TSA is able to reverse 5-FU resistance via down-regulation of TS gene/protein expression. This combinatorial approach using epigenetic therapy may be useful in overcoming chemotherapy resistance for cancer therapy.
Prospective, longitudinal study of risk factors for cancer-related distress in colorectal cancer survivors from prior to surgery until one year after surgery: Results from the ColoCare study.
Authors: Claire J Han, Biljana Gigic, Martin Schneider, Yakup Kulu, Anita Roselyn Peoples, Jennifer Ose, Torsten Koelsch, Paul B. Jacobsen, Graham A. Colditz, Jane C. Figueiredo, William M. Grady, Christopher I. Li, David Shibata, Erin M. Siegel, Adetunji T. Toriola, Alexis B. Ulrich, Cornelia M. Ulrich, Karen L Syrjala
Journal: Journal of Clinical Oncology (2019)

146 Background: Although cancer-related distress is known to persist long after completion of colorectal cancer (CRC) treatment, factors related to distress are largely unexplored in CRC survivors. We examined changes over time and risk factors for distress in CRC patients over the first year after surgery. Methods: We included 212 CRC patients who consented pre-surgery, with data at 6 and 12 months post-surgery from the ColoCare Study in Heidelberg, Germany. Sociodemographic and lifestyle factors, social support and health-related quality of life (QOL) prior to surgery were evaluated as predictors of cancer-related distress. Distress was measured with the Cancer and Treatment Distress instrument (CTXD). Linear regression analyses examined associations between risk factors and distress. Results: Although overall mean of six distress subscales did not change from 6 to 12 months, distress subscale scores varied over time: health burden subscale score increased ( p &lt; .001), while finances ( p = .004), medical demands ( p &lt; .001), and identity ( p &lt; .001) subscale scores decreased from 6 to 12 months. Uncertainty and family strain subscale scores did not change. Younger age, lower income, advanced cancer stage, poorer social support, and poorer baseline QOL scores predicted worse distress at 6 and 12 months. Conclusions: Cancer-related distress continues unresolved at 6 and 12 months post-surgery in this population of CRC survivors. Although some risk factors are difficult to alter, lack of social support may be modifiable and those at risk can be identified early after diagnosis. Screening for risk factors pre-surgery would allow for targeted interventions including strategies to improve resources for those with low support, thereby reducing long-term distress in CRC survivors.
Wearable Sensors: Highly Sensitive and Wearable Liquid Metal‐Based Pressure Sensor for Health Monitoring Applications: Integration of a 3D‐Printed Microbump Array with the Microchannel (Adv. Healthcare Mater. 22/2019)
Authors: Kyuyoung Kim, Jungrak Choi, Yongrok Jeong, Incheol Cho, Minseong Kim, Seunghwan Kim, Yongsuk Oh, Inkyu Park
Journal: Advanced Healthcare Materials (2019)

In article number 1900978 by Yongsuk Oh, Inkyu Park, and co-workers, a liquid metal based-pressure sensor integrated with a rigid microbump array is developed for high sensitivity and electromechanical reliability. In the cover image, not only the epidermal pulse on the wrist but also the body pressures on several body parts are monitored by the proposed sensors for health care applications.
Platelet Activation State Intermixing in a Venous Puncture Model Indicates Novel Patterns of Thrombus Formation
Authors: Brian Storrie, Sung W. Rhee, Irina D Pokrovskaya, Kenny Ling, Yajnesh Vedanaparti, Maria Aronova, Timothy J. Stalker, Lawrence F. Brass, Richard Leapman
Journal: Blood (2019)
Associations between habitual flavonoid intake and hospital admissions for atherosclerotic cardiovascular disease: a prospective cohort study
Authors: Frederik Dalgaard, Nicola P Bondonno, Kevin Murray, Catherine P Bondonno, Joshua R Lewis, Kevin D Croft, Cecilie Kyrø, Gunnar Gislason, Augustin Scalbert, Aedin Cassidy, Anne Tjønneland, Kim Overvad, Jonathan M Hodgson
Journal: The Lancet Planetary Health (2019)

BackgroundFlavonoids, compounds found in plant-based foods and beverages, might ameliorate vascular damage and atherosclerosis. Therefore, our aim was to assess the association between flavonoid intake and hospital admissions due to atherosclerotic cardiovascular disease.MethodsIn this prospective cohort study, participants from the Danish Diet, Cancer, and Health Study were cross-linked with Danish nationwide registries. Eligible participants were aged 50–65 years, had no previous history of atherosclerotic cardiovascular disease, and had completed a food-frequency questionnaire at baseline. We examined associations between flavonoid intake (calculated from food-frequency questionnaires with use of the Phenol-Explorer database) and hospital admissions for atherosclerotic cardiovascular disease, ischaemic heart disease, ischaemic stroke, or peripheral arterial disease. We obtained hazard ratios (HRs) using restricted cubic splines based on Cox proportional hazards models.FindingsOf the participants recruited to the Danish Diet, Cancer, and Health study between 1993 and 1997, our study population was comprised of 53 552 participants, with a median follow-up of 21 years (IQR 15–22). During follow-up, 8773 participants were admitted to hospital for atherosclerotic cardiovascular disease. We observed non-linear associations between flavonoid intake and hospital admissions, plateauing at total flavonoid intakes of approximately 1000 mg per day. Compared with an intake of 175 mg per day, an intake of 1000 mg per day was associated with a 14% lower risk of atherosclerotic cardiovascular disease (HR 0·86, 95% CI 0·81–0·91). For disease subtypes, we observed a 9% lower risk of ischaemic heart disease (0·91, 0·85–0·98), a non-significant 9% lower risk of ischaemic stroke (0·91, 0·82–1·01), and a 32% lower risk of peripheral artery disease (0·68, 0·60–0·78). The overall associations were stronger in smokers than in non-smokers, as well as stronger in consumers of high (>20 g per day) quantities of alcohol than in those consuming low-to-moderate (≤20 g per day) quantities.InterpretationOur results suggest that ensuring an adequate consumption of flavonoid-rich foods, particularly in subpopulations at risk of atherosclerosis such as smokers and consumers of high quantities of alcohol might mitigate some of the risk of atherosclerotic cardiovascular disease. More studies are needed to support and validate these data.FundingDanish Cancer Society.
Effectiveness of a Brief Self-determination Theory–Based Smoking Cessation Intervention for Smokers at Emergency Departments in Hong Kong
Authors: William Ho Cheung Li, Ka Yan Ho, Man Ping Wang, Derek Yee Tak Cheung, Katherine Ka Wai Lam, Wei Xia, Kai Yeung Cheung, Carlos King Ho Wong, Sophia Siu Chee Chan, Tai Hing Lam
Journal: JAMA Internal Medicine (2019)

Clinicians have an opportunity to provide smoking cessation interventions to smokers who present to emergency departments (EDs). The effectiveness of a brief intervention based on self-determination theory for smoking cessation is uncertain.To examine the effectiveness of a brief intervention based on self-determination theory for smoking cessation (immediate or progressive) among Chinese smokers presenting at EDs in Hong Kong.This single-blind, multicenter intent-to-treat randomized clinical trial was conducted at the EDs of 4 major acute care hospitals in different districts of Hong Kong. In total, 1571 smokers 18 years or older who presented at 4 major EDs between July 4, 2015, and March 17, 2017, were randomized into an intervention group (n = 787) and a control group (n = 784).The intervention group received brief advice (about 1 minute) and could choose their own quit schedules (immediate or progressive). The control group received a smoking cessation leaflet.Follow-up visits were conducted at 1, 3, 6, and 12 months. The primary outcome measure, by intent to treat, was biochemically validated abstinence at 6 months.Participants (N = 1571) included 1381 men (87.9%); the mean (SD) age at baseline was 47.4 (16.4) years. Among participants who self-reported abstinence at 6 months, 50.3% (85 of 169) had biochemical validation by both an exhaled carbon monoxide test and a saliva cotinine test. Compared with the control group, the intervention group had statistically higher biochemically validated abstinence at 6 months: 6.7% (53 of 787) vs 2.8% (22 of 784) (P < .001), with an adjusted relative risk of 3.21 (95% CI, 1.74-5.93; P < .001). The intervention group also had higher self-reported quit rates at 6 months (12.2% [96 of 787] vs 9.3% [73 of 784], P = .04) and 12 months (13.0% [102 of 787] vs 8.5% [67 of 784], P < .01), as well as higher biochemically validated abstinence at 12 months (7.0% [55 of 787] vs 3.7% [29 of 784], P < .001). The additional cost for each intervention group participant was US $0.47, with an estimated gain of 0.0238 quality-adjusted life-year. The incremental cost per quality-adjusted life-year (US $19.53) fell within acceptable thresholds.This brief, low-cost self-determination theory-based intervention for smokers presenting at EDs effectively increased the biochemically validated quit rate at 6 months. If delivered routinely, such a simple intervention may offer a cost-effective and sustainable approach to help many smokers quit smoking.ClinicalTrials.gov identifier: NCT02660957.
IgM AL amyloidosis: delineating disease biology and outcomes with clinical, genomic and bone marrow morphological features
Authors: Surbhi Sidana, Daniel P. Larson, Patricia T. Greipp, Rong He, Ellen D. McPhail, Angela Dispenzieri, David L. Murray, Surendra Dasari, Stephen M. Ansell, Eli Muchtar, Wilson I. Gonsalves, Taxiarchis V. Kourelis, Marina Ramirez-Alvarado, Prashant Kapoor, S. Vincent Rajkumar, Martha Q. Lacy, Francis K. Buadi, Nelson Leung, Robert A. Kyle, Shaji K. Kumar, Rebecca L. King, Morie A. Gertz
Journal: Leukemia (2019)
Abstract 18911: Relaxin-2 Levels and Early Myocardial Recovery in Peripartum Cardiomyopathy: Results of the Multicenter IPAC Study
Authors: Julie Damp, Michael Givertz, Marc Semigran, Michael Felker, John Boehmer, Hal Skopicki, Biykem Bozkurt, Gregory Ewald, Rami Alharethi, Karen Hanley-Yanez, Indrani Halder, Dennis M McNamara
Journal: Circulation (2015)

Introduction: Relaxin-2 is a polypeptide hormone which is elevated in peripartum women. Recombinant relaxin-2 is under investigation as a therapy for acute heart failure. Whether endogenous relaxin influences myocardial function in peripartum cardiomyopathy (PPCM) has not been previously investigated. We investigated the impact of relaxin-2 on recovery in PPCM in the multicenter Investigations of Pregnacy Associated Cardiomyopathy (IPAC) study. Methods: 98 women with PPCM were enrolled and serum obtained at entry. LVEF was assessed by echocardiography at entry, 2 months, 6 months and 12 months. Relaxin-2 levels were measured by ELISA. Myocardial recovery was evaluated by tertiles of relaxin at entry for the entire cohort (n=98). Given that relaxin-2 levels were most elevated early, we then reevaluated the impact of relaxin specifically in subjects enrolled in the first quartile based on days postpartum to entry. Results: Overall the cohort was 30% black 65% white and 5% other. Mean age was 30 + 6 years, LVEF 0.35 + 0.10 and time to entry 31 + 25 days post-partum. The mean relaxin level was 29 + 110 pg/ml and dropped rapidly postpartum (correlation r= -0.42, p&lt;0.001, mean relaxin2 for post postpartum quartiles=97 + 203 (0 to 11 days), 10 + 31 (12 to 24), 4 + 2(25 to 51), 5 + 7 (51 to 95),p=0.004. For relaxin tertiles analysis for the overall cohort, subjects with the highest levels at entry had the highest mean LVEF at 2 months postpartum, (LVEF high/intermediate/low relaxin= 0.47 + 0.10/0.44 + 0.10/0.39 + 0.10,p=0.01). When reevaluated only in women presenting in the first quartile( n=25, days postpartum 6.5 +3.2 , range 0 -11 days), LVEF at 2 months was again higher in those with the highest relaxin levels (relaxin tertiles high/intermediate/low =0.53 + 0.10/ 0.45 + 0.09/0.38 + 0.11, p=0.02) with a trend at 6 months (p=0.09) and 12 months(12 month LVEF tertiles=0.55 + 0.08/ 0.53 + 0.09/0.47 + 0.14, p=0.19). Conclusions: In women with PPCM, higher relaxin-2 levels were associated with early myocardial recovery and higher LVEF at 2 months.Endogenous relaxin appears play a cardio protective role in PPCM. The role of treatment with recombinant relaxin to facilitate myocardial recovery in PPCM remains to be determined.
Pension reprieve: will the new scheme work for you?
Authors: Abi Rimmer
Journal: BMJ (2019)

Earlier this month NHS England announced a temporary scheme to allow doctors to work extra hours over winter, with the promise that the NHS would reimburse them for any additional tax they accrued on their pension as a result.1

Under the scheme, hospital doctors and GPs who reach the annual allowance limit in 2019-20 can choose a “scheme pays” option.

Mark Skellum, a partner at chartered accountants Ballards LLP, explains what the scheme could mean for doctors.

Scheme pays is a way to defer an annual allowance liability until you draw your pension. Rather than having to pay the tax through your tax return, the scheme pays option means that the NHS pension scheme settles the liability …
Lessons learnt from treatment of foot sarcomas: Analysis from dedicated sarcoma clinic in North India
Authors: S.J. Pawar, S. Rastogi, E. Dhamija, A. Barwad, V. Kumar, R. Pandey, S. Shishak, K. Kalra, A. Aggarwal, A. Garg, A.R. Mridha, J. Chaubey, S.A. Khan
Journal: Annals of Oncology (2019)
Admissions from care homes are a symptom of bad policy leadership
Authors: Clive E Bowman
Journal: BMJ (2019)

Hospital admissions from care homes1 are often due to a clinician being unable or unavailable to “do something,” such as make the difficult decision that admission would be futile. The PEACH study joins an increasing litany of well crafted studies identifying the potential for supportive interventions.2 These generally ignore the realities of staff availability.

Care home residents do not fit the …
Antitumor effects of sorafenib, bevacizumab and cetuximab as single agents or in combination with an MEK, mTOR or bcl-2 inhibitor, in a SNU-398 human hepatocellular tumor xenograft model.
Authors: Jordi Rodon, Gunjan Malik, Wang-Hong Wu, Kamalesh Sankhala, Michael Wick, Janet Dancey, Kyriakos Papadoupolos
Journal: Cancer Research (2008)

1332  Current therapy for advanced hepatocellular carcinoma (HCC) is still limited. Both surface receptors like EGFR and VEGFR, as well as intracellular molecules can be targeted with new therapies. Early clinical trials in HCC investigating the efficacy of anti-EGFR agents like cetuximab, or anti-angiogenic agents including sorafenib and bevacizumab show single agent activity in HCC. Recent results of a phase III trial of sorafenib vs. placebo have shown an increase in time-to-progression of 3 months which granted approval by the FDA and EMEA. A phase II trial of the MEK inhibitor AZD6244 in HCC is ongoing. The combination of targeted therapies has been shown to be feasible in phase I studies and have entered phase II testing in many solid tumors.  The goal of this study was to test different combinations of approved and novel targeted therapies, using both a rational and empirical approach. We combined inhibitors of the surface receptors EGFR (cetuximab) and VEGFR (sorafenib, or bevacizumab) with either an apoptosis activator (the bcl-2 inhibitor GX15-070) or with downstream signaling inhibitors (the mTOR inhibitor temsirolimus, or the MEK inhibitor AZD6244) in the human SNU-398 human HCC model.  Measured endpoints for these studies included tumor growth inhibition (TGI), partial or complete tumor regression, and agent toxicity as measured by weight loss, deaths, and gross observation.  Significant single agent activity was observed with sorafenib (42% TGI), suggesting some correlation with clinical observations. Combined inhibition of the EGF or VEGF receptor with mTOR or MEK inhibition produced significant additive or synergistic effects. Sorafenib combined with either AZD6244 or temsirolimus respectively produced a 69% and 79% TGI and were considered the most active in this model. No drug-related deaths were observed and no significant weight loss was seen in any combination groups when compared to single agent treatment. Additional pharmacodynamic studies evaluating the effect of these combinations on the intracellular feedback loops are underway.  Overall, these studies confirms SNU-398 as a useful model for testing of potential HCC treatments. In addition, these data strongly support further investigation of the combination of sorafenib with either AZD6244 or temsirolimus in HCC. AZD6244 and GX15-070 were obtained through collaboration with the NCI-CTEP.
Not just a bad metaphor, but a little piece of a big bad metaphor
Authors: George N Reeke
Journal: Behavioral and Brain Sciences (2019)

Abstract Besides failing for the reasons Brette gives, codes fail to help us understand brain function because codes imply algorithms that compute outputs without reference to the signals' meanings. Algorithms cannot be found in the brain, only manipulations that operate on meaningful signals and that cannot be described as computations, that is, sequences of predefined operations.
Telemedicine: A new survivorship visit model.
Authors: Stacie Corcoran, Sheila Kenny
Journal: Journal of Clinical Oncology (2019)

89 Background: The number of cancer survivors in the United States is expected to approach 22 million by the year 2029. With an annual Survivorship Program visit volume exceeding 16,000, this comprehensive cancer center developed an innovative approach to delivering survivorship care to meet the growing demand for comprehensive follow up care. Institutional space, patient convenience and visit compliance are also factors in considering alternatives to traditional ‘brick and mortar’ visits. Methods: Patients are seen in our Autologous Bone Marrow Transplant (BMT) Survivorship Clinic at 6, 12- and 24-months post-transplant. A pilot was developed targeting patients scheduled for a 6-month visit, where patients are often struggling with treatment sequelae, managing other medical appointments, and returning to work and life after transplant. Patients were offered a telemedicine visit instead of an in-person clinic visit with the survivorship advanced practice provider (APP). The Survivorship APP and administrative staff were trained on the use of monitors and technologic means to connect patient to provider. Eligible patients had to have an institutional portal account and speak English. They were contacted by phone to assess interest, and if they agreed, instructions were provided via secure institutional portal reviewing device and connectivity requirements. Results: The telemedicine visit components included: review of home medication list, interval history and review of systems, screen for late treatment effects, lab result review, treatment summary and care plan review including risk of secondary cancer and screening recommendations, health promotion counseling, primary care physician recommendations and immunization status. Of 26 visits scheduled, 22 were successfully completed. Challenges to completing the visit will be described and include poor connectivity and patient location at the time of the scheduled visit. Conclusions: Despite some minor challenges, patients described good satisfaction with telemedicine citing visit comprehensiveness and convenience. As a result of the successful pilot, telemedicine visits are being expanded to include survivorship patients who are 24 months post BMT.
CD73 immune checkpoint defines regulatory NK cells within the tumor microenvironment
Authors: Shi Yong Neo, Ying Yang, Julien Record, Ran Ma, Xinsong Chen, Ziqing Chen, Nicholas P. Tobin, Emily Blake, Christina Seitz, Ron Thomas, Arnika Kathleen Wagner, John Andersson, Jana de Boniface, Jonas Bergh, Shannon Murray, Evren Alici, Richard Childs, Martin Johansson, Lisa S. Westerberg, Felix Haglund, Johan Hartman, Andreas Lundqvist
Journal: Journal of Clinical Investigation (2019)

High levels of ecto-5′-nucleotidase (CD73) have been implicated in immune suppression and tumor progression, and have also been observed in cancer patients who progress on anti–PD-1 immunotherapy. Although regulatory T cells can express CD73 and inhibit T cell responses via the production of adenosine, less is known about CD73 expression in other immune cell populations. We found that tumor-infiltrating NK cells upregulate CD73 expression and the frequency of these CD73-positive NK cells correlated with larger tumor size in breast cancer patients. In addition, the expression of multiple alternative immune checkpoint receptors including LAG-3, VISTA, PD-1, and PD-L1 was significantly higher in CD73-positive NK cells than in CD73-negative NK cells. Mechanistically, NK cells transport CD73 in intracellular vesicles to the cell surface and the extracellular space via actin polymerization–dependent exocytosis upon engagement of 4-1BBL on tumor cells. These CD73-positive NK cells undergo transcriptional reprogramming and upregulate IL-10 production via STAT3 transcriptional activity, suppressing CD4-positive T cell proliferation and IFN-γ production. Taken together, our results support the notion that tumors can hijack NK cells as a means to escape immunity and that CD73 expression defines an inducible population of NK cells with immunoregulatory properties within the tumor microenvironment.
Neural coding: The bureaucratic model of the brain
Authors: Romain Brette
Journal: Behavioral and Brain Sciences (2019)

Abstract The neural coding metaphor is so ubiquitous that we tend to forget its metaphorical nature. What do we mean when we assert that neurons encode and decode? What kind of causal and representational model of the brain does the metaphor entail? What lies beneath the neural coding metaphor, I argue, is a bureaucratic model of the brain.