tbuckley/cabot-search huggingface dataset:
Risk of Hematologic Malignancies After Radioiodine Treatment of Well-Differentiated Thyroid Cancer
Authors: Remco J. Molenaar, Surbhi Sidana, Tomas Radivoyevitch, Anjali S. Advani, Aaron T. Gerds, Hetty E. Carraway, Dana Angelini, Matt Kalaycio, Aziz Nazha, David J. Adelstein, Christian Nasr, Jaroslaw P. Maciejewski, Navneet S. Majhail, Mikkael A. Sekeres, Sudipto Mukherjee
Journal: Journal of Clinical Oncology (2017)

Purpose To investigate the risk and outcomes of second hematologic malignancies (SHMs) in a population-based cohort of patients with well-differentiated thyroid cancer (WDTC) treated or not with radioactive iodine (RAI). Methods Patients with WDTC were identified from SEER registries. Competing risk regression analysis was performed to calculate the risks of SHMs that occurred after WDTC treatment and outcomes after SHM development were assessed. Results Of 148,215 patients with WDTC, 53% received surgery alone and 47% received RAI. In total, 783 patients developed an SHM after a median interval of 6.5 years (interquartile range, 3.3 to 11.2 years) from WDTC diagnosis. In multivariable analysis, compared with those undergoing thyroidectomy alone, RAI treatment was associated with an increased early risk of developing acute myeloid leukemia (AML; hazard ratio, 1.79; 95% CI, 1.13 to 2.82; P = .01) and chronic myeloid leukemia (CML; hazard ratio, 3.44; 95% CI, 1.87 to 6.36; P &lt; .001). This increased risk of AML and CML after RAI treatment was seen even in low-risk and intermediate-risk WDTC tumors. Occurrence of AML but not CML in patients with WDTC was associated with shorter median overall survival compared with matched controls (8.0 years v 31.0 years; P = .001). In addition, AML developing after RAI trended toward inferior survival compared with matched controls with de novo AML (median overall survival, 1.2 years v 2.9 years; P = .06). Conclusion Patients with WDTC treated with RAI had an increased early risk of developing AML and CML but no other hematologic malignancies. AML that arises after RAI treatment has a poor prognosis. RAI use in patients with WDTC should be limited to patients with high-risk disease features, and patients with WDTC treated with adjuvant RAI should be monitored for myeloid malignancies as part of cancer surveillance.
Novel role of prostate apoptosis response-4 tumor suppressor in B-cell chronic lymphocytic leukemia
Authors: Mary K. McKenna, Sunil K. Noothi, Sara S. Alhakeem, Karine Z. Oben, Joseph T. Greene, Rajeswaran Mani, Kathryn L. Perry, James P. Collard, Jacqueline R. Rivas, Gerhard C. Hildebrandt, Roger A. Fleischman, Eric B. Durbin, John C. Byrd, Chi Wang, Natarajan Muthusamy, Vivek M. Rangnekar, Subbarao Bondada
Journal: Blood (2018)
Reply to Shah <i>et al.</i>: Mitochondrial Dysfunction in Bronchopulmonary Dysplasia
Authors: Jegen Kandasamy, Nelida Olave, Scott W. Ballinger, Namasivayam Ambalavanan
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

We read with great interest the study by Kandasamy and colleagues (1), wherein the authors describe the important role of mitochondrial function in the development of bronchopulmonary dysplasia (BPD).We congratulate the authors for conducting this study, in which they concluded that the vascular endothelial mitochondrial dysfunction seen in premature infants contributes to early mortality and the development of BPD.In this excellent study, Kandasamy and colleagues (1) isolated human umbilical vein endothelial cells (HUVECs) from umbilical cords of preterm infants who died or developed BPD, and infants who survived without BPD.They cultured HUVECs and measured mitochondrial bioenergetics (oxygen consumption rate and ATP), mitochondrial reactive oxygen species, and mitochondrial DNA damage.However, they ignored some well-known potential risk factors for mitochondrial dysfunction, such as the mitochondrial membrane potential, peroxisome proliferator-activated receptor-g coactivator 1a (which stimulates mitochondrial biogenesis) (2), and the nicotinamide adenine dinucleotide (NAD)/reduced NAD ratio, all of which are essential for mitochondrial function (3).The measurement of mitochondrial biogenesis may be vital to support the result that there was no difference in the mitochondrial content of HUVECs from infants who died or developed BPD compared with infants who survived without BPD.Further, the authors reported that there was an accumulation of mitochondrial DNA damage in HUVECs from infants who died or developed BPD.This may have been due to impaired mitophagy (the autophagy-dependent degradation of mitochondria), which may lead to the accumulation of reactive oxygen species-producing damaged mitochondria as reported in their study (4).These issues should be resolved in future studies.
Enzastaurin (LY317615.HCl) dramatically enhances the sensitivity of glioblastoma cells and xenografts to temozolomide by blocking signaling through the p90RSK and the AKT pathways and inhibiting CREB transcription factor activation.
Authors: Stephen Parsons, Ann McNulty, Michele Dowless, Bruce Konicek, Spring Weir, Andrew Capen, Phil Schwier, Jennifer Stephens, Robin Goode, Mark Phong, Jaga Virayah, Louis Stancato, James Starling, Jeremy Graff
Journal: Cancer Research (2008)

LB-117   Enzastaurin (ENZ) is an ATP-competitive inhibitor of PKCβ (IC50 = 6nM), other PKCs (α,δ, ϵ, θ, ι, γ, IC50s  in vivo  as well. Our data show that TMZ treatment of GBM cells elicits a substantial increase in the phosphorylation of the transcription factor CREB ser133 , a key transcriptional regulator for pro-survival genes. Accordingly, TMZ treatment elicits an increase in CREB-regulated endogenous gene expression and CREB promoter-reporter activity. CREB S133  phosphorylation can be stimulated by p90RSK and AKT. We show that ENZ directly inhibits p90RSK activity (IC50  ser133  phosphorylation and CREB transcriptional activity. Further, we show that siRNA-mediated reduction of CREB expression sensitizes GBM cells to TMZ-induced apoptosis, indicating that CREB plays a key role in the survival response of GBM cells to TMZ. Collectively, these data suggest that ENZ prevents GBM cells from activating the pro-survival transcription factor CREB in response to the oncolytic insult of TMZ treatment by blocking signaling through p90RSK and the AKT pathway thereby enhancing the efficacy of TMZ for the treatment of glioblastomas.
Combined treatment of bladder cancer cell lines with lapatinib (GW572016) and chemotherapy - evidence of schedule-dependent synergy
Authors: Lynsey McHugh, Marina Kriajevska, J. Kilian Mellon, Tr Leyshon Griffiths
Journal: Cancer Research (2006)

4748   Introduction and Objective In patients with metastatic bladder cancer, cisplatin-based combination chemotherapy has proven benefit in palliating symptoms and prolonging survival. However, the median survival is only one year and toxicity remains a problem. Currently, the gemcitabine and cisplatin (GC) regimen is favoured by many centres. To improve results, a potential strategy is to look for synergistic cooperation between cytotoxic agents and novel targeted therapies. The ErbB family of receptors is frequently dysregulated in bladder cancer, and presents an attractive target for small molecule tyrosine kinase inhibitors (TKIs). In this  in vitro  study, we investigated the effect on cell viability of combining lapatinib (GW572016) [a dual ErbB1/ErbB2 TKI] with GC in varying sequences of application. Methods We chose two bladder cancer cell lines, one (RT112) with high expression of ErbB1 and ErbB2, the other (J82) with low expression of these receptors. These cells were first treated with IC 50  doses of lapatinib and GC. Varying doses of GC were then combined with the IC 50  dose of lapatinib. Cell viability was assessed using the MTT assay performed in triplicate. Results The IC 50  values for RT112 (1.1 μM) and J82 (1.2 μM) following lapatinib were similar. In both cell lines, application of lapatinib before and during or concomitant with GC inhibited cell growth more than GC alone (P 50  of GC gave the same level of cell viability as the full-dose IC 50  of GC alone. Interaction plots of lapatinib before and during GC versus GC alone demonstrated synergy between lapatinib and GC in RT112 and J82 cells. Conclusions In two bladder cancer cell lines, we have shown schedule-dependent synergy between lapatinib and GC. Lapatinib may enable reduced-dose chemotherapy, a potential toxicity-sparing strategy. Lapatinib is a product of GlaxoSmithKline. With thanks to the British Urology Foundation for their generous funding.
Estudio de la introducción de la vacunación antigripal generalizada para personas de la tercera edad en los Países Bajos
Authors: G. A. van Essen
Journal: Eurosurveillance (1998)

Durante muchos anos, en los Paises Bajos la vacuna antigripal ha sido administrada por los medicos generalistas, que atienden a la totalidad de la poblacion. Nueve de cada diez consultas utilizan uno de los seis sistemas informaticos aprobados para consultas de medicos generalistas (GPIS). El crecimiento exponencial en el uso de historias medicas informatizadas en paises como los Paises Bajos y el Reino Unido (RU) puede considerarse como uno de los principales avances que, en los ultimos anos, ha experimentado la prevencion de enfermedades en la comunidad. La confeccion de listas de pacientes y la automatizacion convierten a la prevencion sistematica en la medicina general en un concepto viable.
An open-label, multi-center phase I study of the safety and tolerability of the novel immunomodulatory agent PG545 in subjects with advanced solid tumors.
Authors: Keith Dredge, Todd Brennan, Michael Paul Brown, Jason D. Lickliter, Darryn Bampton, Edward Hammond, Liwen Lin, Yiping Yang, Michael Millward
Journal: Journal of Clinical Oncology (2017)

3083 Background: PG545 (pixatimod, pINN) is a novel immunomodulatory agent which stimulates dendritic cells (DC) via TLR9/IL-12 pathway to activate natural killer (NK) cells. It also inhibits tumour-associated macrophages in cancer models. We report on safety, PK, PD, and antitumor activity of PG545 monotherapy. Methods: In this dose escalation (3+3 design) study, eligible pts (ECOG≤1) with advanced solid malignancies who failed standard therapies received PG545 once weekly as a 1-hour i.v. infusion until disease progression or discontinuation due to intolerability. The primary objective was determination of the maximum tolerated dose (MTD). Secondary objectives evaluated safety, antitumor activity based on RECIST (1.1) criteria, PK and PD (plasmacytoid DC &amp; NKp46 + NK cells from PBMC, and plasma cytokines/chemokines). Results: The study recruited 23 subjects across four cohorts (25, 50, 100 &amp; 150 mg). Three dose limiting toxicities (DLTs) - hypertension (2), epistaxis (1) - occurred in the 150 mg cohort, which was identified as a non-tolerated dose level. No DLTs occurred in the 100 mg cohort, which was identified as the MTD. Six SAEs were reported to be possibly or likely related to PG545 treatment. No RECIST 1.1 objective responses were reported; best response was prolonged stable disease up to 24 weeks (mCRC), with disease control rate in evaluable subjects of 38% (6/16) at eight weeks. Exposure (AUC 0-last ) was proportional up to 100mg and mean half-life was 144 hours. At 50 and 100mg dose levels, two subjects in each cohort exhibited up to 4-fold increased numbers of NKp46 + NK cells, IFN-α-producing pDCs, and increases (up to 25-fold) in plasma IFN-γ, TNF-α, IP-10 and MCP-1. Conclusions: PG545 is well tolerated up to 100 mg once-weekly via i.v. infusion. Human exposure data at 50mg and 100mg reach exposures consistent with those required for preclinical efficacy. Preliminary PD data support the proposed mechanism of action, which represents a promising approach to improve the efficacy of existing therapies. These data, and the absence of toxicities associated with chemo- or immunotherapies, support the development of PG545 in combination clinical trials. Clinical trial information: NCT02042781.
Long-term Diet Quality and Risk of Type 2 Diabetes Among Urban Chinese Adults
Authors: Danxia Yu, Wei Zheng, Hui Cai, Yong-Bing Xiang, Honglan Li, Yu-Tang Gao, Xiao-Ou Shu
Journal: Diabetes Care (2017)

OBJECTIVE Little evidence exists regarding long-term diet quality and the risk of type 2 diabetes among Asian populations, who have undergone a nutrition transition and a diabetes epidemic. RESEARCH DESIGN AND METHODS A total of 117,919 Chinese men and women, 40–74 years old, free of diabetes, cardiovascular disease, and cancer at baseline, were followed from 1996 to 2015. Diet quality was assessed by a healthy diet score (HDS) based on eight commonly consumed food groups previously suggested to be related to diabetes. Long-term diet quality and its changes were assessed by repeated surveys using food-frequency questionnaires. RESULTS We identified 6,111 incident diabetes cases during a mean follow-up of 11.5 years. Higher HDS was associated with lower diabetes risk (hazard ratio [HR] 0.85 [95% CI 0.78–0.92] in the highest vs. lowest quintile, Pcontinuous &amp;lt;0.0001) after adjustment for potential confounders including BMI. Maintaining a high HDS during follow-up was associated with 26% lower risk compared with a consistently low HDS (HR 0.74 [95% CI 0.63–0.85]). The inverse association between HDS and diabetes was observed regardless of participants’ age, sex, smoking and exercise habits, obesity status, and metabolic disease status but was more prominent among those who participated in leisure-time exercise (Pinteraction = 0.004). When considered jointly, a sustained high HDS plus exercise was associated with a 45% reduced risk of diabetes (HR 0.55 [95% CI 0.45–0.67]). CONCLUSIONS A high-quality diet, especially maintained over the long term and in conjunction with leisure-time exercise, is associated with lower risk of type 2 diabetes among urban Chinese adults.
Clinical importance of CD44v9 expression and relationships between CD44v9 expression and effect of neoadjuvant chemotherapy and the prognosis in triple negative breast cancer.
Authors: Sayuri Akiyoshi, Mayumi Ishida, Chinami Koga, Yoshiaki Nakamura, Aya Fujita, Kenichi Taguchi, Eriko Tokunaga
Journal: Journal of Clinical Oncology (2016)

e12555 Background: CD44 variant 9 (CD44v9), a splicing variant of CD44, has emerged as a novel marker of cancer stemness in a variety of solid tumors. CD44v9 has been shown to be correlated with the resistance the cancer treatment and the prognosis in various type of malignancies including gastric cancer and the head and neck squamous cell carcinoma. Triple negative breast cancers (TNBCs) are biologically more aggressive than other subtypes, and the treatment of patients with TNBC has been challenging due to the absence of molecular targets and the heterogeneity of the disease. Patients with TNBC are usually treated with adjuvant or neoadjuvant chemotherapy (NAC). The pathogical CR (pCR) after NAC is significantly associated with better prognosis in TNBCs than no-pCR, therefore, the development of the new strategies for the patients without pCR is needed.The aim of this study is to analyze the expression of CD44v9 and investigate the relationships between CD44v9 and the efficacy of NAC and the prognosis in TNBC. Methods: Among the 67 cases of TNBC who treated with NAC between 2002 and 2014, samples of both pre- and post-NAC were available in 33 cases. The CD44v9 expression was analyzed with immunohistochemistry. Results: Eleven of 33 (33.3%) cases achieved pCR. There were no relationships between the pre-NAC CD44v9 expression and the clinical stage and the pathological responses to NAC. The prognosis of the patients with high CD44v9 expression in pre-NAC samples was significantly poorer in terms of disease-free survival and overall survival, especially in no-pCR group. In addition, high expression of CD44v9 in pre-NAC samples was associated with high histological and nuclear grade of the tumor in the post-NAC samples, suggesting the relationship between high CD44v9 and the resistance to NAC. The post-NAC CD44v9 expression in no-pCR samples did not correlate with the prognosis. Conclusions: This study suggests that the CD44v9 expression in pre-NAC samples is useful to predict the prognosis of the patients the TNBC, which did not achieve pCR. CD44v9 might be the therapeutic target to improve the prognosis of TNBC.
Abstract 14038: Impact of Total Stent Length After Sirolimus-Eluting Stent Implantation on 10-Year Clinical Outcomes
Authors: Takashi Hiromasa, Shoichi Kuramitsu, Hiroyuki Jinnouchi, Mizuki Miura, Yukiko Matsumura, Yuhei Yamaji, Takenori Domei, Kyohei Yamaji, Makoto Hyodo, Yoshimitsu Soga, Shinichi Shirai, Kenji Ando
Journal: Circulation (2016)

Introduction:  We sought to assess the relationship between total stent length (TSL) and long-term clinical outcomes after sirolimus-eluting stent (SES) implantation.   Methods:  From April 2004 and March 2008, a total of 985 consecutive patients with 1304 lesions undergoing percutaneous coronary intervention only with SES implantation were analyzed. Patients and lesions were divided into tertile group: TSL per patient (PA group [13-23 mm], n=466; PB group [24-41 mm], n=164; and PC group [42-196 mm], n=355), and TSL per lesion (LA group [8-18 mm], n=508; LB group [19-28 mm], n=317; and LC group [29-125 mm], n=479). We assessed the cumulative 10-year incidence of clinically driven target-lesion revascularization (CD-TLR) and definite stent thrombosis (ST) based on TSL per patient (TSL-P) and lesion (TSL-L) groupings, and cardiac death and myocardial infarction in the TSL-P groupings.   Results:  The cumulative 10-year incidence of CD-TLR for the TSL-P and TSL-L were higher in the PC and LC groups than in the other groups (19.0% vs. 17.4% vs. 28.2%, p=0.02 and 19.3% vs. 19.7% vs. 24.1%, p=0.04, respectively). No significant differences in the cumulative 10-year incidence of definite ST were observed in both TSL-P and TSL-L groups (2.2% vs. 0.79% vs. 4.0%, p=0.08 and 1.9% vs. 3.7% vs. 2.0%, p=0.61, respectively). No significant differences in the cumulative 10-year incidence of cardiac death and myocardial infarction were also observed in TSL-P groups.   Conclusions:  TSL after SES implantation has significantly impact on CD-TLR rate through 10 years, but it is not associated with an increased incidence of definite ST.
Impact of Distinct Genetic and Epigenetic Aberrations on Survival and Response in Acute Myeloid Leukemia Patients Receiving Epigenetic Therapy
Authors: Jan K. Hiller, Claudia Schmoor, Verena I. Gaidzik, Charlotte Schmidt-Salzmann, Arzu Yalcin, Mahmoud Abdelkarim, Nadja Blagitko-Dorfs, Konstanze Döhner, Lars Bullinger, Justus Duyster, Michael Lübbert, Björn Hackanson
Journal: Blood (2016)
Effect of Different Doses of Galcanezumab vs Placebo for Episodic Migraine Prevention
Authors: Vladimir Skljarevski, Tina M. Oakes, Qi Zhang, Margaret B. Ferguson, James Martinez, Angelo Camporeale, Kirk W. Johnson, Qiuling Shan, Jeffrey Carter, Aaron Schacht, Peter J. Goadsby, David W. Dodick
Journal: JAMA Neurology (2017)

Galcanezumab (LY2951742), a monoclonal antibody against calcitonin gene-related peptide (CGRP), is one of a novel class of new medicines for migraine prevention.To assess whether at least 1 dose of galcanezumab was superior to placebo for episodic migraine prevention.A randomized clinical trial was conducted in the United States (July 7, 2014, to August 19, 2015) in clinics of 37 licensed physicians with a specialty including, but not limited to, psychiatry, neurology, internal medicine, and primary care. Subcutaneous injections of galcanezumab, 5, 50, 120, or 300 mg, or placebo were given monthly during the 3-month treatment period. A total of 936 patients were assessed; 526 did not meet study entry or baseline criteria and 410 patients were randomly assigned to receive placebo or galcanezumab. Analyses were conducted on an intent-to-treat population, which included all patients who were randomized and received at least 1 dose of study drug.Short-term migraine treatments were allowed as needed except for opioids or barbiturates.To determine if at least 1 of the 4 doses of galcanezumab tested was superior to placebo for migraine prevention measured by the mean change from baseline in the number of migraine headache days 9 weeks to 12 weeks after randomization.Of the 936 patients assessed, 410 met entry criteria (aged 18-65 years with 4-14 migraine headache days per month and migraine onset prior to age 50 years) and were randomized to receive placebo or galcanezumab. For the primary end point, galcanezumab, 120 mg, significantly reduced migraine headache days compared with placebo (99.6% posterior probability -4.8 days; 90% BCI, -5.4 to -4.2 days vs 95% superiority threshold [Bayesian analysis] -3.7 days; 90% BCI, -4.1 to -3.2 days). Adverse events reported by 5% or more of patients in at least 1 galcanezumab dose group and more frequently than placebo included injection-site pain, upper respiratory tract infection, nasopharyngitis, dysmenorrhea, and nausea.Monthly subcutaneous injections of galcanezumab, both 120 mg and 300 mg, demonstrated efficacy (repeated-measures analysis) for the preventive treatment of migraine and support further development in larger phase 3 studies. All dosages were safe and well tolerated for the preventive treatment of episodic migraine.clinicaltrials.gov Identifier: NCT02163993.
Comparison Of Exhaled Breath Fraction Temperature (frEBT) In Patients With Respiratory Allergy
Authors: Rosa Ivett Guzman-Avilan, Sandra Nora González- Diaz, Alfredo Arias Cruz, Alejandra Macias-Weinmann, Barbara Elizondo Villarreal, Carlos Macouzet-Sanchez, Rosalaura Virginia Villarreal-Gonzalez, Cindy Elizabeth de Lira-Quezada, Katia Guzman Avilan, Daniel Sanchez-Guerra
Journal: Journal of Allergy and Clinical Immunology (2018)
Морфологічні основи оцінки стеатозу, стеатогепатиту та фіброзу у хворих на неалкогольну жирову хворобу печінки в поєднанні з ожирінням і патологією біліарного тракту
Authors: Yu.M. Stepanov, A.Yu. Filippova
Journal: GASTROENTEROLOGY (2017)

Мета. Вивчення гістопатологічних особливостей стеатозу, стеатогепатиту та фіброзу печінки (ФП) при жировій хворобі печінки (ЖХП) неалкогольної етіології та встановлення наявності взаємозалежності між ступенем стеатозу печінки, гістологічними маркерами фіброзу та збільшенням показників індексу маси тіла (ІМТ) у пацієнтів з неалкогольним стеатозом печінки (НАСП) і неалкогольним стеатогепатитом (НАСГ) у поєднанні з ожирінням (ОЖ) та патологією біліарного тракту. Матеріали та методи. Під спостереженням перебувало 70 хворих з неалкогольною ЖХП (НАЖХП), у тому числі: 48 хворих із НАСП у поєднанні з ОЖ (1 група), 22 хворі із НАСГ з ОЖ (2 група). Залежно від ступеня збільшення ІМТ кожна з груп хворих із НАСП і НАСГ та супутнім ОЖ була розподілена на три підгрупи: з ІМТ 25–29,9 кг/м2 — надлишкова маса тіла (НМТ); з ІМТ 30–34,9 кг/м2 — ОЖ І ступеня; з ІМТ 35–39,9 кг/м2 — ОЖ ІІ ступеня. В гістологічній діагностиці НАСП/НАСГ, а також для визначення стадії ФП використовували критерії МЕТАVIR і BRUNT. Результати. Виявлено залежність вираженості стеатозу печінки у хворих із різними клінічними формами ЖХП від ІМТ, що було підтверджено і результатами кореляційного аналізу: при НАСП — rs = 0,798 (p &lt; 0,001), при НАСГ — rs = 0,678 (p &lt; 0,001). При збільшенні ІМТ у хворих поглиблюються фібротичні процеси з наявністю F0 стадії при НМТ у хворих із НАСП до F3 стадії при ОЖ ІІ ступеня у пацієнтів з НАСГ. Коефіцієнти кореляції між ІМТ і стадією ФП при НАСП дорівнюють rs = 0,464 (p &lt; 0,001), при НАСГ — rs = 0,759 (p &lt; 0,001). Висновки. У більшості випадків НАСП (58,3 %) та НАСГ (45,4 %) було встановлено макровезикулярний стеатоз. У хворих із НАСП частіше спостерігалися F1 та F2 стадії фіброзу (50,0 %), у той час як у пацієнтів з НАСГ частіше були зареєстровані F2 та F3 стадії фіброзу (77,3 %). При коморбідному перебігу НАЖХП характерним є змішаний тип ФП.