tbuckley/cabot-search huggingface dataset:
Promotion of &lt;italic&gt;N&lt;/italic&gt;-Methyl-&lt;italic&gt;N&lt;/italic&gt;-Nitrosourea-Induced Thyroid Tumors by Iodine Deficiency in F344/NCr Rats&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Masato Ohshima, Jerrold M. Ward
 4
Journal: JNCI Journal of the National Cancer Institute (1984)

Six-week-old male F344 rats were each given an injection once iv of N-methyl-N-nitrosourea [(MNU) CAS: 684-93-5] at a dose of 41.2 mg/kg body weight. Two weeks later, groups of rats were placed on iodine-deficient (ID) or iodine-adequate (IA) diets and then sacrificed at 20 and 33 weeks. Other groups received ID or IA diets without MNU. For localizing thyroid-stimulating hormone (TSH) and prolactin, sections of pituitary glands were stained by the avidin-biotin-peroxidase complex technique with the use of anti-rat TSH or prolactin antibody. At 20 weeks, rats receiving MNU and ID diets had a 100% incidence of diffuse follicular goiter and multiple follicular adenomas of the thyroid. Focal proliferative thyroid follicular lesions including focal hyperplasias and adenomas per square centimeter of thyroid gland were significantly increased in rats given MNU and ID diets in comparison with rats given MNU and IA diets. At 33 weeks, all MNU rats on ID diets had a significantly increased incidence of thyroid carcinoma of the follicular or papillary types and diffuse pituitary thyrotroph hyperplasia, hypertrophy, and vacuolar degeneration. Rats fed ID diets without MNU had diffuse follicular goiter but no tumors at any time period. MNU given alone in rats fed IA diets induced a 10% incidence of single thyroid adenomas at 20 weeks and 70% at 33 weeks and a 10% incidence of thyroid carcinoma at 33 weeks. Tumors induced in other organs by MNU were not affected by the ID diets. Thus this experiment provided evidence that ID diets are potent promoters of thyroid tumors in this system, but the ID diet itself without carcinogen was not carcinogenic under the conditions of the study.
The value of PET-CT (positron emission tomography) in the treatment of metastatic renal cell carcinoma with sorafenib
Authors: U. Stierner, M. Boijsen, M. Suurküla, S. Lundstam
Journal: Journal of Clinical Oncology (2007)

15621 Background: Sorafenib is a new potent multikinase inhibitor directed against both tumour proliferation and angiogenesis. Clinical benefit has been shown in 75% of patients with metastatic renal cell carcinoma. The aim of this study was to evaluate this new treatment with PET-CT with fluorodeoxyglucose (FDG), since the use of only CT measurements has been questioned. Methods: 10 patients (8 male, 2 female, 49–72 years) with metastatic renal cell carcinoma (9 clear cell, 1 chromophobe). All had progressive disease (8 after interferon). Sorafenib 400 mg b.i.d was given orally. FDG-PET-CT scan was performed from head-proximal thigh before treatment and after one month. Up to 6 target lesions in each patient were studied. The sum of the largest diameters was calculated from CT images for each patient. To evaluate the glucose uptake, a region of interest (roi) was designed for each leasion on the initial PET on the transverse section where the lesion appeared to be largest and/or most intense. Using the same roi for subsequent examinations the mean glucose uptake/mean cerebellar uptake was calculated. For each patient the mean change from baseline was calculated. Results: After one month of treatment the sum of tumour diameters measured by CT was mean 85% (53–110%) of the initial value. Measured by PET the mean glucose uptake at one month was mean 73% (29–100%) of the initial value. Seven patients had skeletal lesions. These were often difficult to measure on CT and only small changes were detected. Using PET the mean uptake in skeletal lesions was 77% (62–104%) at one month. Conclusions: Early effects of sorafenib treatment in metastatic renal cell carcinoma can be detected and quantified by PET-CT. Especially in skeletal lesions PET-CT exhibits considerable benefits over CT by visualizing responses otherwise missed. Future studies will reveal if a decrease in tumour glucose uptake at one month correlates with the more clinically relevant endpoints PFS and OS. [Table: see text]
The BET-Bromodomain Inhibitor OTX015 Is Active As a Single Agent and in Combination with Other Targeted Drugs in Preclinical Models of Mantle Cell Lymphoma
Authors: Elena Bernasconi, Chiara Tarantelli, Eugenio Gaudio, Ivo Kwee, Andrea Rinaldi, Luciano Cascione, Anastasios Stathis, Maria Eugenia Riveiro, Emanuele Zucca, Francesco Bertoni
Journal: Blood (2014)
Genomic Analyses Reveal Demographic History and Temperate Adaptation of the Newly Discovered Honey Bee Subspecies<i>Apis mellifera sinisxinyuan</i>n. ssp
Authors: Chao Chen, Zhiguang Liu, Qi Pan, Xiao Chen, Huihua Wang, Haikun Guo, Shidong Liu, Hongfeng Lu, Shilin Tian, Ruiqiang Li, Wei Shi
Journal: Molecular Biology and Evolution (2016)

Studying the genetic signatures of climate-driven selection can produce insights into local adaptation and the potential impacts of climate change on populations. The honey bee (Apis mellifera) is an interesting species to study local adaptation because it originated in tropical/subtropical climatic regions and subsequently spread into temperate regions. However, little is known about the genetic basis of its adaptation to temperate climates. Here, we resequenced the whole genomes of ten individual bees from a newly discovered population in temperate China and downloaded resequenced data from 35 individuals from other populations. We found that the new population is an undescribed subspecies in the M-lineage of A. mellifera (Apis mellifera sinisxinyuan). Analyses of population history show that long-term global temperature has strongly influenced the demographic history of A. m. sinisxinyuan and its divergence from other subspecies. Further analyses comparing temperate and tropical populations identified several candidate genes related to fat body and the Hippo signaling pathway that are potentially involved in adaptation to temperate climates. Our results provide insights into the demographic history of the newly discovered A. m. sinisxinyuan, as well as the genetic basis of adaptation of A. mellifera to temperate climates at the genomic level. These findings will facilitate the selective breeding of A. mellifera to improve the survival of overwintering colonies.
A retrospective study of anaemia in neonates exposed to thiopurines in utero
Authors: Kate Wiles, Manju Chandiramani, Sabrina Jiwani, Catherine Nelson-Piercy
Journal: Gut (2015)

Thiopurines, including azathioprine and mercaptopurine, have a good safety record in pregnancy.1–3 Meta-analysis shows that maternal thiopurine use is not associated with either congenital abnormality or low birth weight.1 A positive association with preterm delivery has been attributed to the severity of the underlying condition for which thiopurine use acts as a surrogate marker.1 However, Jharap et al suggest that all infants exposed to thiopurines in pregnancy should be routinely tested for anaemia. This conclusion is based on a subgroup analysis of only 16 infants, a median ‘anaemic’ haemoglobin of 14.9 g/dL, which lies within the 95% reference range, and a statistically insignificant correlation between thiopurine metabolite concentration and anaemia.4 

We challenged this recommendation by undertaking a retrospective cohort study of pregnant women receiving thiopurine therapy …
FOXE3 mutations predispose to thoracic aortic aneurysms and dissections
Authors: Shao-Qing Kuang, Olga Medina-Martinez, Dong-chuan Guo, Limin Gong, Ellen S. Regalado, Corey L. Reynolds, Catherine Boileau, Guillaume Jondeau, Siddharth K. Prakash, Callie S. Kwartler, Lawrence Yang Zhu, Andrew M. Peters, Xue-Yan Duan, Michael J. Bamshad, Jay Shendure, Debbie A. Nickerson, Regie L. Santos-Cortez, Xiurong Dong, Suzanne M. Leal, Mark W. Majesky, Eric C. Swindell, Milan Jamrich, Dianna M. Milewicz
Journal: Journal of Clinical Investigation (2016)

The ascending thoracic aorta is designed to withstand biomechanical forces from pulsatile blood. Thoracic aortic aneurysms and acute aortic dissections (TAADs) occur as a result of genetically triggered defects in aortic structure and a dysfunctional response to these forces. Here, we describe mutations in the forkhead transcription factor FOXE3 that predispose mutation-bearing individuals to TAAD. We performed exome sequencing of a large family with multiple members with TAADs and identified a rare variant in FOXE3 with an altered amino acid in the DNA-binding domain (p.Asp153His) that segregated with disease in this family. Additional pathogenic FOXE3 variants were identified in unrelated TAAD families. In mice, Foxe3 deficiency reduced smooth muscle cell (SMC) density and impaired SMC differentiation in the ascending aorta. Foxe3 expression was induced in aortic SMCs after transverse aortic constriction, and Foxe3 deficiency increased SMC apoptosis and ascending aortic rupture with increased aortic pressure. These phenotypes were rescued by inhibiting p53 activity, either by administration of a p53 inhibitor (pifithrin-α), or by crossing Foxe3–/– mice with p53–/– mice. Our data demonstrate that FOXE3 mutations lead to a reduced number of aortic SMCs during development and increased SMC apoptosis in the ascending aorta in response to increased biomechanical forces, thus defining an additional molecular pathway that leads to familial thoracic aortic disease.
Prognostic factors in metastatic melanoma patients treated with biochemotherapy and maintenance immunotherapy
Authors: D. R. Minor, M. Kashani-Sabet, D. Moore, C. Kim, S. S. Venna, W. Wang, P. D. Boasberg, S. O'Day
Journal: Journal of Clinical Oncology (2009)

9051 Background: Patients with stage IV metastatic melanoma are usually felt to be incurable with a median survival of 6.4 months and a 5-year survival of only 2%. Biochemotherapy has shown promise with long-term survival in selected patients. We felt the study of prognostic factors would determine which patients might benefit the most from this intensive therapy. Methods: 135 consecutive patients with stage IV melanoma treated with decrescendo biochemotherapy followed by maintenance immunotherapy at one melanoma treatment center were studied to determine the most important prognostic factors; these factors were then validated by analysis of 133 patients treated in a multi-center trial at other institutions. Patients were treated using the inpatient regimen of O'Day (JCO23:710s,2005 abstract). Results: Median overall survival (OS) was 16.6 months with 1-year survival of 70% and 5-year survival of 28%. Median progression-free survival (PFS) was 7.6 months with 15% progression-free at 5 years. PFS curves showed no relapses after 30 months, so remissions were durable. For OS performance status 0, normal LDH, stage M1a, and non-visceral sites of metastases were favorable prognostic factors. For PFS performance status 0, normal LDH, female sex, age &lt;50 and stage M1a were favorable prognostic factors Multivariate analysis demonstrated two important prognostic factors for survival: normal serum LDH and the presence of either skin or nodes as one of the sites of metastatic disease. The group with normal LDH and skin or node metastases had a relatively good prognosis with median survival of 44 months and a 5-year survival of 38%. Conversely patients with elevated LDH without any skin or nodal metastases had a poor prognosis, with no long-term survivors. Conclusions: Metastatic melanoma patients treated with biochemotherapy and maintenance immunotherapy that have either a normal LDH or skin or nodes as one of their metastatic sites may have durable remissions of their disease, and this therapy should be studied further in these groups. [Table: see text]
Derivation and Validation of a Quality Indicator to Benchmark In-Hospital Complications Among Injury Admissions
Authors: Lynne Moore, François Lauzier, Henry T. Stelfox, John Kortbeek, Richard Simons, Simon Berthelot, Julien Clément, Gilles Bourgeois, Alexis F. Turgeon
Journal: JAMA Surgery (2016)

The rate of complications among injury admissions has been estimated to be more than 3 times that observed for general admissions, and complications have been targeted as an important quality-of-care metric. Despite the negative effect of complications on resource use and patient mortality and morbidity, there is no standardized method to benchmark trauma centers in terms of in-hospital complications, to our knowledge.To develop a quality indicator (QI) for in-hospital complications that can be used to evaluate the quality of acute injury care and to assess its validity.Multicenter retrospective cohort study. The setting was a well-established inclusive trauma system in Canada. Participants included all 66 048 moderate or major injury admissions to an adult trauma center between April 1, 2006, and March 31, 2012. The dates of the analysis were January to April 2015.The primary outcome was the occurrence of at least 1 in-hospital complication. We selected risk-adjustment variables by expert consultation and bootstrap resampling. We evaluated internal validity using measures of discrimination, construct validity, and forecasting.The study cohort comprised 66 048 patients. Their mean (SD) age was 59 (22) years, and 48.0% were female. Fifteen percent of patients had at least 1 in-hospital complication. The risk-adjustment model has excellent discrimination (area under the curve, 0.81) and calibration. The QI was correlated with the risk-adjusted incidence of mortality (r = 0.71), unplanned readmission (r = 0.43), and mean length of stay (r = 0.68). Hospital performance on the QI from 2007 to 2009 was predictive of performance from 2010 to 2012 (r = 0.82).We developed a QI to benchmark trauma centers on in-hospital complications among injury admissions. The QI is based on data that are routinely collected in most trauma systems and demonstrates good internal validity. The integration of this QI in trauma quality improvement programs will facilitate the identification of quality problems, the implementation of solutions, and the evaluation of their effectiveness. Therefore, the QI has the potential to lead to reductions in mortality, morbidity, and resource use after injury.
The Neuroimmune Axis in the Kidney: Role in Hypertension.
Authors: Rhian M. Touyz
Journal: Circulation Research (2015)

Guyton suggested over 40 years ago that the kidney, by regulating volume homeostasis and sodium reabsorption, is critically involved in maintaining normal blood pressure through the pressure natriuresis response and that alterations in these processes lead to hypertension.1 The importance of the kidney in the pathophysiology of hypertension is also evidenced by kidney transplantation studies in rodents, where grafting of kidneys from normotensive rats normalized blood pressure in bilaterally nephrectomized hypertensive rats, and vice versa.2 These data suggest that the blood pressure trait follows the kidney phenotype and may relate to the nephron number, where fewer nephrons are associated with impaired pressure natriuresis and predisposition to hypertension.3 To further support a role for the kidney in hypertension are human genetic studies, which demonstrated that the majority of inherited monogenetic forms of hypertension affect the distal nephron and volume and sodium homeostasis.4 Moreover, increased renal sympathetic nerve activity causes an increase in blood pressure, whereas renal sympathectomy lowers blood pressure in experimental models of hypertension5 and in human hypertensive patients, indicating the importance of the sympathetic nervous system in renal function in hypertension.6

Article, see p 547 

The functional significance of the renal sympathetic nerves in the kidney became more apparent when it was shown anatomically that nerve fibers are in direct contact with tubular segments and that they directly influence renal tubular function through norepinephrine-containing renal sympathetic nerve terminals.7 Activation of the renal sympathetic system increases norepinephrine release with increased sodium and water reabsorption by renal tubular epithelial cells, smooth muscle contraction, and renin release from granular cells of the juxtaglomerular apparatus,1 processes that contribute to blood pressure elevation. In addition, growing evidence indicates that activation of renal sympathetic nerves promotes renal inflammation through adaptive and innate immune mechanisms. In hypertension, T …
Novel Biomarker of Oxidative Stress Is Associated With Risk of Death in Patients With Coronary Artery Disease
Authors: Riyaz S. Patel, Nima Ghasemzadeh, Danny J. Eapen, Salman Sher, Shawn Arshad, Yi-an Ko, Emir Veledar, Habib Samady, A. Maziar Zafari, Laurence Sperling, Viola Vaccarino, Dean P. Jones, Arshed A. Quyyumi
Journal: Circulation (2015)

Free radical scavengers have failed to improve patient outcomes, promoting the concept that clinically important oxidative stress may be mediated by alternative mechanisms. We sought to examine the association of emerging aminothiol markers of nonfree radical mediated oxidative stress with clinical outcomes.Plasma levels of reduced (cysteine and glutathione) and oxidized (cystine and glutathione disulphide) aminothiols were quantified by high performance liquid chromatography in 1411 patients undergoing coronary angiography (mean age 63 years, male 66%). All patients were followed for a mean of 4.7 ± 2.1 years for the primary outcome of all-cause death (n=247). Levels of cystine (oxidized) and glutathione (reduced) were associated with risk of death (P<0.001 both) before and after adjustment for covariates. High cystine and low glutathione levels (>+1 SD and <-1 SD, respectively) were associated with higher mortality (adjusted hazard ratio [HR], 1.63; 95% confidence interval [CI], 1.19-2.21; HR, 2.19; 95% CI, 1.50-3.19; respectively) compared with those outside these thresholds. Furthermore, the ratio of cystine/glutathione was also significantly associated with mortality (adjusted HR, 1.92; 95% CI, 1.39-2.64) and was independent of and additive to high-sensitivity C-reactive protein level. Similar associations were found for other outcomes of cardiovascular death and combined death and myocardial infarction.A high burden of oxidative stress, quantified by the plasma aminothiols, cystine, glutathione, and their ratio, is associated with mortality in patients with coronary artery disease, a finding that is independent of and additive to the inflammatory burden. Importantly, these data support the emerging role of nonfree radical biology in driving clinically important oxidative stress.
A prognostic index for natural killer cell lymphoma after non-anthracycline-based treatment: a multicentre, retrospective analysis
Authors: Seok Jin Kim, Dok Hyun Yoon, Arnaud Jaccard, Wee Joo Chng, Soon Thye Lim, Huangming Hong, Yong Park, Kian Meng Chang, Yoshinobu Maeda, Fumihiro Ishida, Dong-Yeop Shin, Jin Seok Kim, Seong Hyun Jeong, Deok-Hwan Yang, Jae-Cheol Jo, Gyeong-Won Lee, Chul Won Choi, Won-Sik Lee, Tsai-Yun Chen, Kiyeun Kim, Sin-Ho Jung, Tohru Murayama, Yasuhiro Oki, Ranjana Advani, Francesco d'Amore, Norbert Schmitz, Cheolwon Suh, Ritsuro Suzuki, Yok Lam Kwong, Tong-Yu Lin, Won Seog Kim
Journal: The Lancet Oncology (2016)
Association of vitamin D receptor (Fok-I) polymorphism with asthma in Tunisian children
Authors: Haifa Maalmi, Hanadi Abid, Jamel Ammar, Anissa Berraies, Kamel Hamzaoui, Agnes Hamzaoui
Journal: European Respiratory Journal (2011)

Vitamin D receptor (VDR) polymorphisms have been implicated in several immune and inflammatory disorders characterized by an imbalance in Th1/Th2 cell activity. Because asthma is characterized by a shift of Th cell responses toward type2, VDR presents itself to be a candidate gene for asthma susceptibility.  In the present study, we investigated the associations of the VDR-Fok-I (F/f) polymorphism with risk of childhood asthma, severity, passive smoke and atopy in Tunisia using case-control study.  Our population consisted in 212 asthmatic children and 152 healthy paediatric controls. Genotyping of VDR-Fok-I (F/f) polymorphism was performed using PCR -Restriction Length Polymorphism (RFLP) analysis.  The case-control study revealed a protective effect of VDR-Fok-I “f” allele in childhood asthma: The VDR-Fok-I (f/f) genotype were less frequent in children with asthma than in healthy individuals (P=0.01; χ 2 =8.12). And therefore the VDR-Fok-I (f) allele was less frequent in the case than in the control subjects (p=0.006; OR=0.64; 95% CI= 0.46-0.89; χ 2 =7.42). No association was demonstrated with VDR-Fok-I (F/f) polymorphism with severity, atopy or passive smoke.  These data suggest a strong association of VDR-Fok-I polymorphism with asthma in Tunisia. Therefore, the VDR and vitamin D may be involved in the pathogenesis of childhood asthma disease in our population.
Safety and radiation dosimetry profiles of intrathecal I-131 sodium iodide (NaI) in patients with leptomeningeal metastasis (LM)
Authors: F. C. Wong, M. Groves, S. Hsu, C. Conrad, A. Kumar, A. Fonnegra, Y. Wang, N. Pappadopoulus, R. B. Sparks, D. A. Podoloff
Journal: Journal of Clinical Oncology (2005)

3107 Background: Loregional/intrathecal radionuclide therapy of leptomeningeal metastasis (LM) using beta-emitters may provide effective means to ablate meningeal tumor deposits. Use of short-range isotopes will lower underlying neural damages. I-131 NaI possess these desirable features and has known low systemic toxicity (except thyroid). This project involves 2 phase I studies to evaluate toxicity (or lack of) and radiation dosimetry after I-131 NaI is injected intrathecally via intralumbarly (IL) or intraventricularly (IVent) for LM treatment. Methods: Under thyroid protection with Lugol’s solution, eligible patients with LM received intrathecal (IL or IVent) injection of 15, 30 or 60 mCi of I-131 NaI after undergoing cisternogram to ensure patency of CSF. Serial whole-body anterior and posterior images were acquired using a dual-head Seimens ECAM DUET gamma camera at 1, 2, 4, 6, 24, 30 and 48 Hours after injection. Whole-body and organ radiation dosimetry were derived from scintigrams, urine and blood activities. Serial CSF cytology, neuropsychology, ophthalmology, CBC and TSH levels were monitored up to 6 months. Results: Eighteen patients (9+9) were studied on 2 IRB-approved protocols (IL and IVent). No acute toxicity (NCI creteria) were attributed to I-131 NaI. There was fast clearance of I-131 from the CSF and the body with residence time of 2 and 4 hours, respectively. No thyrotoxicity nor hematotoxicity related to I-131 NaI was observed in either protocol. Transient CSF conversion was found in 4/18 patients and improvement in neuropsychology scores were noted in 4/16 evaluable patients. Effective dose equivalents (whole-body) were 0.44 and 0.27 cGy/mCi for the IVent and IL I-131 NaI respectively. Toxicity studies at 90 and 120 mCi are ongoing without gamma imaging. Conclusions: Diffuse meningeal tumor deposits were geographically targetted with I-131 NaI ablation up to 60 mCi with no toxicity. These therapies make use of pharmcokinetic advantages of locoregional therapy- high initial delivery and low system toxicity after dilution to the body. Locoregional application of I-131 NaI may be a safe route for internal irradiation of human tumors, whether diffuse or solitary. No significant financial relationships to disclose.