tbuckley/cabot-search huggingface dataset:
The cost-effectiveness of improving cancer screening compliance.
Authors: Michael S. Broder, Irina Yermilov, Clifford Y. Ko, Melinda Maggard Gibbons, Eunice Chang, Tanya G. Bentley, Dasha Cherepanov, Wendy C. Hsiao, Emmett B. Keeler
Journal: Journal of Clinical Oncology (2012)

6057 Background: Expensive treatments and a growing number of cancer patients have resulted in increased spending on cancer care. Within a framework we developed for measuring the value of quality improvement (QI), we describe the cost-effectiveness of improving compliance with cancer screening measures compared to other quality measures. Methods: We used our framework to examine 18 Healthcare Effectiveness Data and Information Set (HEDIS) 2010 quality measures, synthesize related cost-effectiveness (CE) data and describe measure-specific QI-adjusted incremental cost-effectiveness ratios (ICERs). For each measure we: 1) quantified current compliance; 2) reviewed literature for ICERs; 3) estimated per-person steady state cost and quality-adjusted life years (QALYs); 4) estimated affected population size; 5) estimated the cost of QI; and 6) calculated QI-adjusted ICERs at full compliance, defined as 95%. We assumed per-person QI costs did not change with compliance and varied this in sensitivity analyses. We compared QI-adjusted ICERs for 3 cancer screening measures to the remaining measures. Results: Published ICERs for the cancer screening measures were $43,180/QALY (breast), $5,102/QALY (cervix) and $15,173/QALY (colon) and for other measures from $195/QALY (drug treatment) to $35,616/QALY (flu shots). Incorporating QI costs for cancer screening measures gave QI-adjusted ICERs of $64,549/QALY (breast), $15,463/QALY (cervix) and $22,991/QALY (colon), respectively. Incorporating QI costs for all 18 measures resulted in QI-adjusted ICERs from $195/QALY (drug treatment) to $9,075,868/QALY(antidepressant management), with a median of $15,463/QALY. Reaching 95% compliance with the 3 cancer measures would cost $5.1 billion and add 160,000 QALYs ($32,640/QALY) and with all 18 measures would cost $13.4 billion and add 5.8 million QALYs ($2,313/QALY). Conclusions: Improving compliance with cancer screening may be cost-effective at a threshold of $50k/QALY, although improving care on all HEDIS measures may be even more cost-effective. Accurate assessment of the cost of increasing cancer screening requires integration of both the cost-effectiveness of the screening tests and the cost of the QI programs needed to change practice.
The Path of Most Resistance: Transdifferentiation Underlies Exceptional Nonresponses to Androgen Receptor Pathway Inhibition in Prostate Cancer
Authors: Seema Sinha, Peter S. Nelson
Journal: Cancer Discovery (2017)

Abstract Summary: In this issue of Cancer Discovery, Zou and colleagues describe a mechanism involving cellular transdifferentiation that promotes exceptional resistance to antiandrogen therapy in prostate cancer. A background of coinactivation of Trp53 and Pten increased the frequency of the transdifferentiated neuroendocrine phenotype. These findings have implications for developing approaches to repress cellular plasticity and overcome treatment resistance. Cancer Discov; 7(7); 673–4. ©2017 AACR. See related article by Zou et al., p. 736.
Expanded phase I study of intratumoral Ad-RTS-hIL-12 plus oral veledimex: Tolerability and survival in recurrent glioblastoma.
Authors: E. Antonio Chiocca, John Yu, Surasak Phuphanich, Rimas Vincas Lukas, Priya Kumthekar, Yijun Yang, Qiang (John) Zhou, Jill Y. Buck, Alicia Deary, Hongliang Cai, John A. Barrett, Laurence JN Cooper, Francois M. Lebel
Journal: Journal of Clinical Oncology (2017)

2044 Background: Glioblastoma (GBM) is an aggressive brain tumor affecting ~74,000 people worldwide annually. Recurrent GBM patients have a median OS (mOS) of 6-7 months. OS in patients who have failed temozolomide, bevacizumab or equivalent salvage chemotherapy, is ~3-5 months. New therapies are urgently needed. Ad-RTS-hIL-12 (Ad) is a novel gene therapy expressing IL-12 under the control of an oral activator ligand, veledimex (V), through the RheoSwitch Therapeutic System. Intratumoral administration of Ad results in targeted tumor cytotoxicity and induction of systemic T cell memory. Ad + V is a treatment strategy to extend the IL-12 therapeutic window. Methods: In a multicenter Phase I dose escalation trial and expansion cohort, subjects with recurrent or progressive Grade III or IV glioma undergoing resection were injected intratumorally with Ad 2 x 10 11 viral particles and daily oral V for 15 doses, beginning prior to surgery. The primary endpoint is safety and tolerability of Ad + V; secondary endpoints include OS. Results: 25 subjects were dosed in 3 dose escalation cohorts: 20 mg (n = 7), 30 mg (n = 4), and 40 mg (n = 6) and an expansion cohort of 20 mg (n = 8). Results show V crossed the blood brain-barrier with 35±5% of plasma levels detected in the brain tumor. The 20 mg dose (n = 15) had better drug compliance (86%) than the 30 mg (63%) or 40 mg (52%) cohorts and the 20 mg cohort shows better survival (mOS 12.7 months) compared to other cohorts. The frequency of related ≥Grade (G)3 AEs in the 20 mg cohort was significantly lower: 20% in 20mg, 50% in 30mg and 40 mg. In the 20 mg cohort, the most frequent AEs were transient mild flu-like symptoms seen in 12/15, G3 cytokine release syndrome in 2/15, G3 elevated ALT/AST in 1/15 and G3 lymphopenia in 3/15. All AEs reversed promptly upon discontinuing V. Conclusions: Overall, Ad + 20 mg V is well tolerated; toxicities were predictable and reversible upon discontinuing V. There is a correlation between V dose, BBB penetration and drug related AEs. The tolerability and encouraging survival observed to date warrant further investigation in a pivotal trial. A stereotactic arm and a pediatric trial in diffuse intrinsic pontine glioma patients are planned. Clinical trial information: NCT02026271.
Safety of pulmonary function testing: data from 20 years
Authors: Cara Roberts, Simon Ward, Emil Walsted, James H Hull
Journal: Thorax (2017)

Pulmonary function testing (PFT) is a key investigation in the evaluation of individuals with respiratory symptoms; however, the safety of routine and specialised PFT testing has not been reported in a large data set. Using patient safety incident (PSI) records, we aimed to assess risk of PFT and to characterise these events and any associated risk factors.In this single-centre audit, demographics and PSI data were collected and categorised for PFT performed between 1996 and 2016 and subdivided into cardiopulmonary or non-cardiopulmonary events. The severity of each PSI was rated using the NHS National Patient Safety Agency and any hospital admission reported.There were 119 PSIs reported from 186 000 PFT; that is, 0.6 PSIs per 1000 tests. Cardiopulmonary PSIs were 3.3 times more likely to occur than non-cardiopulmonary (95% CI 2.17 to 5.12). Syncope was the most frequently occurring cardiopulmonary PSI. Cardiopulmonary exercise testing was associated with 2 PSIs per 1000 tests. PSIs necessitating hospital admission and/or emergency department attendance occurred approximately once every 10 000 tests and there was no PFT-associated mortality.Routine and specialised PFT is safe for patients, in the context of established screening preparticipation guidelines. In the event of a PSI, these are likely to be low risk of harm. Our findings highlight the most common PSIs encountered during PFT to facilitate risk reduction.
Randomized double-blind evaluation of dronabinol for the prevention of chemotherapy-induced nausea.
Authors: Steven M. Grunberg, Mark F. Munsell, Phuong Khanh H. Morrow, Jeffrey Kent Giguere, Ulla Jo Ule, Steven J. Saccaro, Adedayo A. Onitilo, Joanna K. Metzner-Sadurski, Michael Fisch
Journal: Journal of Clinical Oncology (2012)

9061 Background: Although great progress has been made in the control of chemotherapy-induced vomiting (CIV), prevention of chemotherapy-induced nausea (CIN) has been less successful. Preliminary data suggests that some families of lesser used antiemetic agents, such as the cannabinoids, may have greater efficacy against nausea than against vomiting. Methods: Adult solid tumor patients (pts) receiving cyclophosphamide ≤ 1500 mg/m 2 (C) and/or doxorubicin ≥ 40 mg/m 2 (A) were eligible. Pts could have received prior mildly emetogenic chemotherapy (EC). Pts were not eligible who were receiving other moderately or highly EC, were receiving cranial, abdominal or pelvic radiotherapy, had CIV/CIN with previous chemotherapy, had other causes for nausea/vomiting besides chemotherapy, or were scheduled to receive other antiemetics. Pts with habitual cannabinoid use were not eligible. All pts received palonosetron 0.25 mg (PALO) and dexamethasone 10 mg (DXM) IV before chemotherapy. Patients were randomized double-blind to receive dronabinol 5 mg (D) or matching placebo (P) 3 times a day for 5 days. Nausea, vomiting and toxicity data was collected daily for 5 days. Results: 62 pts were entered on study – female/male 61/1, White/Black/Hispanic/Other 45/14/2/1, median age (range) 58 (29-76). No significant difference was noted in CIV-dependent endpoints (including No Vomiting, Complete Response, or Complete Protection) or in rescue medication use. However pts receiving D had a shorter duration of nausea – Mean number of days of nausea (D vs P) 1.86 days vs 3.10 days (p=0.027) – and a trend toward greater frequency of No Nausea (D vs P) 37% vs 17% (p=0.143). Common toxicities included fatigue (D/P 17/11), headache (D/P 16/16), dizziness (D/P 14/7), constipation (D/P 14/11), and diarrhea (D/P 13/6) No pt discontinued therapy due to mood changes. Conclusions: Low-dose D decreased the duration of CIN and increased the frequency of No Nausea in pts receiving C and/or A. Agents to prevent CIV (such as PALO and DXM) and to prevent CIN (such as D) have complementary activity and result in improved overall control when used together.
A MRI Prospective Survey on Heart and Liver Iron and Cardiac Function in Thalassemia Major Patients Treated with Deferasirox Versus Deferiprone and Desferrioxamine in Monotherapy
Authors: Alessia Pepe, Laura Pistoia, Liana Cuccia, Monica Fortini, Vincenzo Caruso, Rosamaria Rosso, Saveria Campisi, Angelo Peluso, Francesco Sorrentino, Aurelio Maggio, Vincenzo Positano, Giuseppe Peritore, Antonella Meloni
Journal: Blood (2016)
Malignant transformation of teratoma to primitive neuroectodermal tumor (PNET): Outcome analysis with retroperitoneal lymph node dissection and PNET specific chemotherapy
Authors: R. Foster, Y. Ehrlich, T. M. Ulbright, L. Cheng, R. Bihrle, S. D. Beck, M. Andreoiu, M. J. Brames, L. H. Einhorn
Journal: Journal of Clinical Oncology (2009)

5081 Background: Malignant transformation of teratoma to PNET is a rare entity. Surgical resection has been the mainstay of therapy because these tumors are not curable with cisplatin based chemotherapy. We report long-term survival and potential cure with retroperitoneal lymph node dissection (RPLND) and PNET specific chemotherapy. Methods: Retrospective review of 75 patients (pts) with PNET in the testis or at distant metastasis treated from Jan 1988 to Dec 2007. 74 had RPLND as part of initial treatment or at relapse. PNET specific chemotherapy consisted of cyclophosphamide, doxorubicin, vincristine alternating with ifosfamide and etoposide. Available PNET specimens were tested for the Ewing's sarcoma (EWS) translocation using a FISH-based method. Results: The median follow-up was 40 months (range 2 to 235). 27 pts presented with clinical stage I disease. 18 underwent primary RPLND with PNET in the retroperitoneum in 5. 4 are dead of disease (DOD). 9 elected surveillance or adjuvant chemotherapy. 8 relapsed with PNET. 4 are DOD. 48 pts presented with metastatic disease. 20 are DOD, 24 have no evidence of disease (NED) and 4 are alive with disease. 50 of 75 pts had PNET documented metastasis with an estimated 5 years disease specific survival of 47%. 10 of these were treated with PNET specific chemotherapy for unresectable disease. 8 of the 10 achieved objective response with the duration of response ranging from 4 to 73 months. 2 pts are NED. 2 additional pts were treated with PNET specific chemotherapy as adjuvant to RPLND. Both are continuously NED. Specimens from 14 pts were tested for the EWS translocation, 2 were positive. Conclusions: Malignant transformation of teratoma to PNET carries an adverse prognosis. RPLND is an integral part of the therapeutic strategy. PNET specific chemotherapy, adjuvant to RPLND or for treatment of unresectable disease followed by surgery, may result in long-term survival and potential cure. No significant financial relationships to disclose.
Right- versus left-side metastatic colorectal cancer: Differences in tumor biology and bevacizumab efficacy
Authors: Paola Ulivi, Emanuela Scarpi, Martina Valgiusti, Andrea Casadei Gardini, Giorgia Marisi, Daniele Calistri, Angela Ragazzini, Elisa Chiadini, Laura Capelli, Luca Frassineti Giovanni, Dino Amadori, Alessandro Passardi
Journal: Annals of Oncology (2017)
Elevated Pre-Treatment Fetal Hemoglobin Predicts Better Outcome in MDS/AML Patients Receiving 5-Aza-2'-Deoxycytidine (DAC)
Authors: Rainer Claus, Gabriele Ihorst, Philipp Sander, Ljudmila Bogatyreva, Heiko Becker, Pierre W Wijermans, Stefan Suciu, Emmanuel Bissé, Michael Lübbert
Journal: Blood (2016)
Impact of Cytopenia Following Unmanipulated Haploidentical Hematopoietic Stem Cell Transplantation Using Post-Transplant Cyclophoshamide
Authors: Villetard Ferdinand, Stefania Bramanti, Samia Harbi, Sabine Fürst, Catherine Faucher, Angela Granata, Faezeh Legrand, Djamel Mokart, Pierre-Jean Weiller, Christian Chabannon, Aude Charbonnier, Anne-Marie Stoppa, Luca Castagna, Didier Blaise, Raynier Devillier
Journal: Blood (2016)
Differential Expression of VEGF-A<sub>xxx</sub> Isoforms Is Critical for Development of Pulmonary Fibrosis
Authors: Shaney L. Barratt, Thomas Blythe, Caroline Jarrett, Khadija Ourradi, Golda Shelley-Fraser, Michael J. Day, Yan Qiu, Steve Harper, Toby M. Maher, Sebastian Oltean, Thomas J. Hames, Chris J. Scotton, Gavin I. Welsh, David O. Bates, Ann B. Millar
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

Rationale: Fibrosis after lung injury is related to poor outcome, and idiopathic pulmonary fibrosis (IPF) can be regarded as an exemplar. Vascular endothelial growth factor (VEGF)-A has been implicated in this context, but there are conflicting reports as to whether it is a contributory or protective factor. Differential splicing of the VEGF-A gene produces multiple functional isoforms including VEGF-A165a and VEGF-A165b, a member of the inhibitory family. To date there is no clear information on the role of VEGF-A in IPF.Objectives: To establish VEGF-A isoform expression and functional effects in IPF.Methods: We used tissue sections, plasma, and lung fibroblasts from patients with IPF and control subjects. In a bleomycin-induced lung fibrosis model we used wild-type MMTV mice and a triple transgenic mouse SPC-rtTA+/−TetoCre+/−LoxP-VEGF-A+/+ to conditionally induce VEGF-A isoform deletion specifically in the alveolar type II (ATII) cells of adult mice.Measurements and Main Results: IPF and normal lung fibroblasts differentially expressed and responded to VEGF-A165a and VEGF-A165b in terms of proliferation and matrix expression. Increased VEGF-A165b was detected in plasma of progressing patients with IPF. In a mouse model of pulmonary fibrosis, ATII-specific deficiency of VEGF-A or constitutive overexpression of VEGF-A165b inhibited the development of pulmonary fibrosis, as did treatment with intraperitoneal delivery of VEGF-A165b to wild-type mice.Conclusions: These results indicate that changes in the bioavailability of VEGF-A sourced from ATII cells, namely the ratio of VEGF-Axxxa to VEGF-Axxxb, are critical in development of pulmonary fibrosis and may be a paradigm for the regulation of tissue repair.
Late-Breaking Basic Science Abstracts From the American Heart Association's Scientific Sessions 2005, Dallas, Texas, November 13-16
Journal: Circulation Research (2005)

Adult stem cells with the pluripotency of embryonic stem cells (ESCs) would be ideal for organ regeneration strategies.Previous studies in neonatal mice suggest that the germline lineage may retain the ability to generate pluripotent cells.We aimed to evaluate the pluripotency and plasticity of adult spermatogonial stem cells (SSCs), which are responsible for maintaining spermatogenesis throughout life in the male.Using a genetic approach we established the culture condition for isolation of SSCs from adult mouse testis (success rate ϭ 27% of mice).These isolated SSCs respond to the culture conditions and acquire ESC properties.They are able to spontaneously (without co-culture) differentiate into functional cardiomyocytes expressing cardiac-specific genes (isl1, GATA4, Nkx2.5, MEF2C, ␣-MHC, MLC2v, ANF, SERCA2a and NCX) and proteins (sarcomeric MHC, cardiac troponin T and connexin 43).Four major types of action potentials (APs) characteristic for specialized cells of the ventricle, sinus node, Purkinje fibers and atrium are found in these cardiomyocytes.Functional maturity of ventricle-like cells (n ϭ 11 from 3 independent experiments) is shown by AP characteristics: upstroke velocity (dV/dt max ) being 55.8Ϯ4.8V/s, amplitude (APA) being 115.8Ϯ3.3 mV, duration at 90% of repolarisation (APD 90 ) being 288.9Ϯ55.5 ms and maximum diastolic potential (MDP) being -48.3Ϯ3.0 mV.The amplitudes of calcium transients (fluo4) measured in SSC-derived ventricle-like cardiomyocytes (n ϭ 10) are similar to those measured in ESC-derived cardiomyocytes (n ϭ 6; 464Ϯ77 nM vs. 287Ϯ69 nM , respectively).This is also comparable to adult cardiac myocytes.Besides cardiomyocytes, SSCs give rise to vascular smooth muscle (expressing smooth muscle-␣-actin, vascular smooth muscle MHC) and endothelial cells (expressing PECAM-1, VEGFR2, and vWF).SSCs also differentiate into other somatic cell types in vitro.Furthermore, we show that SSCs are able to differentiate into cardiac cells and most other somatic cells in vivo after blastocyst microinjection.Thus, adult spermatogonal stem cells exhibit pluripotency like embryonic stem cells and may offer new possibilities in cell based cardiac regeneration strategies.
Working night shifts reduces repair of DNA damage, study suggests
Authors: Susan Mayor
Journal: BMJ (2017)

Working at night is associated with reduced repair of DNA damage, shows an observational study of healthcare shift workers that suggests that this effect was driven by suppression of melatonin.1

The study investigated a subgroup of people working shifts in healthcare taken from a previous larger study of 223 shift workers, which showed that sleeping during the day was associated with decreased urinary excretion of 8-hydroxydeoxyguanosine (8-OH-dG),2 the most common mutagenic DNA lesion induced …
Abstract 430: Circadian Control of Heart Rate
Authors: Alicia D’souza, Sven Wegner, Anne Berit Johnsen, Eleanor Gill, Charlotte Cox, Halina Dobrzynski, Ulrik Wisløff, George Hart, Hugh D Piggins, Mark R Boyett
Journal: Circulation Research (2015)

Background: Bradyarrhythmias occur more frequently at night. On the basis of heart rate variability this is attributed to high vagal tone. Here we tested the alternative hypothesis that an intrinsic circadian clock-driven remodelling of pacemaking ion channels underlies fluctuations in heart rate (HR). Methods and results: The occurrence of a circadian rhythm in HR was tested by placing nocturnal C57BL6/J mice under a strict 12/12h light-dark cycle and telemetry-based ECG intervals measured every 2 h for 48 h. Under these conditions, the R-R interval was rhythmic (n=10). To test whether this is caused by circadian rhythms in the expression of ion channels controlling HR, sinus node (SAN) biopsies were collected at time points corresponding to the minima (ZT0, subjective day) and maxima (ZT12, subjective night) of HR, as determined by ECG recordings. Real-time PCR normalised to 28s demonstrated an elevated expression of the key pacemaking ion channel HCN4 that carries the pacemaker current I f and genes encoding the Ca 2+ -handling proteins SERCA2a and RYR2 at ZT12 ( P &lt;0.05, n=10). Presence of clock machinery (essential transcription factors involved in setting intrinsic circadian rhythms) as potential regulators of ion channel oscillation were investigated in the SAN of mPer1 Luc mice which carry the 5’ upstream region of the mPer1 gene (a key core clock component) fused to a luciferase gene. mPer1-luc bioluminescence was recorded in the isolated SAN using a light-tight photomultiplier tube assembly to reveal a circadian rhythm with a periodicity of 24 h (n=3). Disruption of the molecular clock by global knockout of core clock components Cry1 and Cry2 abrogated the circadian cycling of mPer1-luc in the SN of Cry1 -/- /Cry2 -/- double knockout mice (n=3). Examination of 10[[Unable to Display Character: &amp;#8201;]]kb of the Hcn4 promoter revealed a conserved consensus binding site for CLOCK and its heterodimer BMAL1, other essential transcription factors involved in setting intrinsic circadian rhythms. Conclusions: This is the first demonstration of a peripheral circadian clock in the cardiac pacemaker and circadian oscillations in key pacemaker mechanisms. Data reveal a novel regulator of SN function and the occurrence of bradyarrythmias at night.
Abstract 344: FNDC5, a PGC1-a-Dependent Myokine, Increases Glucose Utilization and Fatty-Acid Oxidation by AMPK Signaling Pathway
Authors: Ling Tao, Yi Liu, Chao Xin, Weidong Huang, Lijian Zhang, Di Zhu, Lu Sun, Haichang Wang
Journal: Circulation Research (2013)

FNDC5 is a hormone secreted by myocytes that could reduce obesity and insulin resistance, However, the exact effect of FNDC5 on glucose and lipid metabolism remain poorly identified; More importantly, the signaling pathways that mediate the metabolic effects of FNDC5 is completely unknown. Here we showed that FNDC5 stimulates β-oxidation and glucose uptake in C2C12 cells in a dose- and time-dependent fashion in vitro (n=8, all P&lt;0.01). In vivo study revealed that FNDC5 also enhanced glucose tolerance in diabetic mice and increased the glucose uptake evidenced by increased [18F] FDG accumulation in hearts by PET scan (n=6, all P&lt;0.05). FNDC5 decreased the expression of gluconeogenesis related molecules (PEPCK and G6Pase) and increased the phosphorylation of ACC, a key modulator of fatty-acid oxidation, both in hepatocytes and C2C12 cells (n=3, all P&lt;0.05). In parallel with its stimulation of β-oxidation and glucose uptake, FNDC5 increased the phosphorylation of AMPK both in hepatocytes and C2C12 cells in a dose- and time-dependent fashion in vitro and in vivo. More importantly, the β-oxidation and glucose uptake, the expression of PEPCK and G6Pase and the phosphorylation of ACC induced by FNDC5 were attenuated by AMPK inhibitor in hepatocytes and C2C12 cells (P&lt;0.05). Most importantly, the FNDC5 induced glucose uptake and phosphorylation of ACC were attenuated in AMPK-DN mice (n=6, all P&lt;0.05). The glucose-lowering effect of FNDC5 in diabetic mice was also attenuated by AMPK inhibitor. Our data presents the direct evidence that FNDC5 stimulates glucose utilization and fatty-acid oxidation by AMPK signaling pathway, suggesting that FNDC5 be a novel pharmacological approach for type 2 diabetes.