tbuckley/cabot-search huggingface dataset:
Renal Carcinogenic and Nephrotoxic Effects of the Flame Retardant Tris(2,3-dibromopropyl) Phosphate in F344 Rats and (C57BL/6N × C3H/HeN)F&lt;sub&gt;1&lt;/sub&gt; Mice&lt;xref ref-type="fn" rid="fn2"&gt;2&lt;/xref&gt;
Authors: G Reznik, J M Ward, J F Hardisty, A Russfield
Journal: JNCI Journal of the National Cancer Institute (1979)

Tris(2,3-dibromopropyl) phosphate (TBP) was administered in the feed at one of two concentrations to groups of 55 male and 55 female inbred F344 rats and to 50 male and 50 female (C57BL/6N X C3H/HeN)F1 mice. The high and low dietary concentrations of TBP administered orally were 100 and 50 ppm for the rats, respectively, and 1,000 and 500 ppm for the mice, respectively. For each rodent type, 55 animals of each sex were used as contols. In both rodent types, renal epithelial tumors developed at incidences that were significant for male and female rats and mice that received the doses. These tumors included renal tubular cell adenomas and carcinomas that developed from the proximal convoluted tubular epithelium. Among female mice and rats, hyperplasia and/or dysplasia of the proximal convoluted tubular epithelium with or without cystic dilatation of the tubules and increase in the size of cell nuclei were dose dependent and recognized as preneoplastic and/or toxic lesions. The comparative histogenesis of renal tubular neoplasms was discussed.
Mitoxantrone, More than Just Another Topoisomerase II Poison
Authors: Benny J. Evison, Brad E. Sleebs, Keith G. Watson, Don R. Phillips, Suzanne M. Cutts
Journal: Medicinal Research Reviews (2015)

Abstract Mitoxantrone is a synthetic anthracenedione originally developed to improve the therapeutic profile of the anthracyclines and is commonly applied in the treatment of breast and prostate cancers, lymphomas, and leukemias. A comprehensive overview of the drug's molecular, biochemical, and cellular pharmacology is presented here, beginning with the cardiotoxic nature of its predecessor doxorubicin and how these properties shaped the pharmacology of mitoxantrone itself. Although mitoxantrone is firmly established as a DNA topoisomerase II poison within mammalian cells, it is now clear that the drug interacts with a much broader range of biological macromolecules both covalently and noncovalently. Here, we consider each of these interactions in the context of their wider biological relevance to cancer therapy and highlight how they may be exploited to further enhance the therapeutic value of mitoxantrone. In doing so, it is now clear that mitoxantrone is more than just another topoisomerase II poison.
Abstract 13049: Microrna-33, Located Within Srebf2 Intron, Regulate Fatty Acid Synthesis via Targeting SREBP-1 in vivo
Authors: Tomohiro Nishino, Takahiro Horie, Osamu Baba, Yasuhide Kuwabara, Tetsushi Nakao, Masataka Nishiga, Shunsuke Usami, Masayasu Izuhara, Yuya Ide, Fumiko Nakazeki, Satoshi Koyama, Masayuki Yokode, Toru Kita, Takeshi Kimura, Koh Ono
Journal: Circulation (2014)

Introduction: MicroRNAs (miRs) are small non-protein-coding RNAs that bind to specific mRNAs and inhibit translation or promote degradation. Recent reports, including ours, indicated that miR-33 located within the intron of sterol regulatory element binding protein (SREBP) 2 controls cholesterol homeostasis and can be a possible therapeutic target for treating atherosclerosis. Unexpectedly, miR-33 deficient (miR-33 -/- ) mice fed high fat diet (HFD) developed severe fatty liver and the mechanisms were investigated. Methods and Results: The liver weight of miR-33 -/- mice were about 1.5 times heavier than that of miR-33 +/+ mice and histological examination revealed that miR-33 -/- mice developed severe fatty liver under HFD feeding. In order to determine the cause of the fatty liver observed in miR-33 -/- mice fed HFD, we analysed the gene expression profiles using the liver of miR-33 +/+ and miR-33 -/- mice fed normal chow at the age of 16 weeks when they didn’t show fatty liver. As a result, genes involved in fatty acid metabolism were upregulated in miR-33 -/- mice. Among them we found SREBP-1 as a new potential target gene of miR-33 in silico and confirmed that miR-33 targets the 3’UTR of SREBP-1 in vitro . The expression of SREBP-1 and de novo fatty acid production were significantly increased in the liver of miR-33 -/- mice. We further intercrossed miR-33 -/- mice with Srebf1 +/- mice and fed them HFD. Hepatic steatosis was reversed in miR-33 -/- Srebf1 +/- mice compared with miR-33 -/- Srebf1 +/+ mice by histological analysis and measurement of triglyceride levels. The expression levels of genes involved in fatty acid synthesis, including Scd1, Fasn, Acc1 , and Pparg were increased in miR-33 -/- Srebf1 +/+ mice compared with miR-33 +/+ Srebf1 +/+ mice, and those increase were reversed in miR-33 -/- Srebf1 +/- mice. Conclusions: miR-33 regulates lipogenic pathway via regulating SREBP-1 as a novel target in vivo . In sterol-depleted conditions, acetyl-CoA might be preferred as a substrate for cholesterol production and not for fatty acid production by the downregulation of SREBP-1 through the upregulation of miR-33. Conversely, in cholesterol-rich condition, acetyl-CoA might be preferred as a substrate for fatty acid production through the downregulation of miR-33.
The Need for Evidence-Based Medicine
Authors: David L Sackett, William M C Rosenberg
Journal: Journal of the Royal Society of Medicine (1995)

As physicians, whether serving individual patients or populations, we always have sought to base our decisions and actions on the best possible evidence. The ascendancy of the randomized trial heralded a fundamental shift in the way that we establish the clinical bases for diagnosis, prognosis, and therapeutics. The ability to track down, critically appraise (for its validity and usefulness), and incorporate this rapidly growing body of evidence into one's clinical practice has been named ‘evidence-based medicine’ 5,6 (EBM).
Urine Estrogens, Frequency of Ovulation, and Breast Cancer Risk: Case-Control Study in Premenopausal Women&lt;xref ref-type="fn" rid="fn2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="fn3"&gt;3&lt;/xref&gt;
Authors: B MacMahon, P Cole, J B Brown, R Paffenbarger, D Trichopoulos, S Yen
Journal: JNCI Journal of the National Cancer Institute (1983)

Urine specimens from 94 premenopausal women with breast cancer and from 70 control women have been compared with respect to concentration of the three major estrogen fractions and to frequency of ovulation as assessed by urine pregnanediol. The probability of anovulation (0.14 in the breast cancer patients and 0.09 among the controls) was not significantly higher among the women with breast cancer (P approximately 0.30). However, there was a positive association between urine estrogen concentration and breast cancer risk. The association was statistically significant (P less than 0.05) for each of the three estrogens measured and in both the follicular and the luteal phases of the menstrual cycle; the relative risk increased from 1 in the referent category (less than 5 micrograms estrogen/g creatinine) to about 3 in the highest category (greater than or equal to 15 micrograms estrogen/g creatinine). The association between urine estrogens and breast cancer risk was consistently stronger when the comparison was restricted to specimens collected in menstrual cycles during which ovulation occurred.
Treatment and underlying mechanisms of pancreatic cancer cachexia (PANCAX study).
Authors: Jasleen Khanuja, Gillian Gresham, Arsen Osipov, Richard Tuli, Andrew Eugene Hendifar
Journal: Journal of Clinical Oncology (2015)

TPS491 Background: Advanced pancreatic adenocarcinoma is characterized by progressive weight loss and nutritional deterioration, resulting in a cachexia-anorexia syndrome. This wasting has been linked to poorer survival, alterations in host defenses, and decreased functional ability and quality of life. Gut microbiota alterations affect muscle composition and have been demonstrated in mouse models of cancer cachexia. The relationship between pancreatic cancer cachexia and the composition of the fecal microbiome will be investigated. We propose the first prospective study of peptide-based enteral nutritional support in cachectic advanced pancreatic adenocarcinoma patients undergoing chemotherapy. We aim to establish the feasibility and efficacy of enteral nutrition as measured by changes in weight, lean body mass, and hand-grip strength. We will also explore the relationship between anorexia-cachexia with gut hormone changes and alterations in the fecal micro-biome, which may account for resultant malnutrition and muscle loss. Methods: Eligible patients will have a diagnosis of both pancreatic adenocarcinoma and cachexia, defined as greater than 5% unintentional weight loss within the previous 6 months. Peptamen 1.5 will be administered via a jejunal tube for 12 weeks. Lean body mass, evaluated by DEXA, and weight will be assessed at predefined intervals. Oral food intake will measured by 24 hour food recall and a taste and smells alteration survey. Secondary outcomes including, response to chemotherapy, survival, and quality of life will be studied. Fecal microbiome, serum inflammatory markers, and gut hormone levels will be assessed at pre-defined intervals. We have received funding from NIH/NCATS Grant # UL1TR000124 and opened enrollment in September 2014.
EMA/CO for high-risk gestational trophoblastic tumors: results from a cohort of 272 patients.
Authors: M Bower, E S Newlands, L Holden, D Short, C Brock, G J Rustin, R H Begent, K D Bagshawe
Journal: Journal of Clinical Oncology (1997)

PURPOSE To evaluate the results of etoposide, methotrexate, and dactinomycin alternating with cyclophosphamide and vincristine (EMA/CO) chemotherapy in women with high-risk gestational trophoblastic tumors (GTT) and to document the middle- and long-term toxicity of the regimen. PATIENTS AND METHODS A total of 272 consecutive women with high-risk GTT, including 121 previously treated patients, were treated with weekly EMA/CO. The median follow-up duration is 4.5 years (range, 1 to 16). RESULTS The cumulative 5-year survival rate is 86.2% (95% confidence interval, 81.9% to 90.5%). No deaths from GTT have occurred later than 2 years after the end [corrected] of EMA/CO. In a multivariate model, adverse prognostic factors were the presence of liver metastases (P &lt; .0001), interval from antecedent pregnancy (P &lt; .0001), brain metastases (P = .0008), and term delivery of antecedent pregnancy (P = .045). There were 11 (4%) early deaths, while 213 patients (78%) achieved a complete remission. Forty-seven (17%) developed drug resistance to EMA/CO, of whom 33 (70%) were salvaged by further cisplatin-based chemotherapy and surgery. Two women developed acute myeloid leukemia, two cervical malignancy, and one gastric adenocarcinoma after EMA/CO. More than half (56%) of the women who had fertility-conserving surgery and who have been in remission at least 2 years have become pregnant since the completion of EMA/CO, with 112 live births, including three infants with congenital abnormalities. CONCLUSION EMA/CO is an effective and well-tolerated regimen for high-risk GTT. More than half of the women will retain their fertility; however, there is a small but significant risk of second malignancy.
Pathology Prize Evening Polycythaemia following Renal Transplantation
Authors: H P Davis
Journal: Journal of the Royal Society of Medicine (1987)

Polycythaemia has developed in 10 of 59 regularly reviewed patients with renal transplants surviving more than three months. The pathology of the raised haemoglobin level was heterogeneous. Three patients had a picture characterized by a normal red cell mass and reduced plasma volume. Seven patients had a raised red cell mass; in 3 of these this was associated with a period of abnormal liver function and fitted with the state of raised red cell mass in association with hepatic transaminitis. The remaining 4 patients form a unique, previously undefined group with no features to explain the underlying aetiology of the polycythaemia. The patients had a trouble-free post-transplant course with early establishment of graft function. It is proposed, from the data obtained from in vitro culture studies, that the early return of good renal function allows the erythroid compartment to expand in response to circulating erythropoietin. The establishment of an erythron of increased size allows for a persistently raised haemoglobin in the presence of normal erythropoietin levels.
Resistance of AKR Mice to Lymphoid Leukemia Associated With a Chronic Protozoan Infection, &lt;italic&gt;Besnoitia jellisoni&lt;/italic&gt;
Authors: Milford N. Lunde, Albert H. Gelderman
Journal: JNCI Journal of the National Cancer Institute (1971)

To determine the effect of a chronic protozoan infection on the course of spontaneous leukemia, AKR mice congenitally infected with Gross strain A virus were infected with Besnoitia jellisoni, an obligate intracellular parasite. The infected mice survived significantly longer than the mice without B. jellisoni. AKR mice also had a greater resistance than 7 other strains to an acute B. jellisoni challenge. This reciprocal resistance between a chronic protozoan and congenital virus infection is probably due to activated macrophages.
Human metapneumovirus: a new threat?
Authors: A Manuel
Journal: Thorax (2009)

Human metapneumovirus (HMPV) causes illness in both children and adults. Like other viruses, infection produces incomplete immunity and re-infection can occur at all ages. The aim of this research was to identify the incidence and clinical impact of HMPV infection over four consecutive winters in adults in both an inpatient and outpatient setting.

The authors used serum and respiratory secretions over a period of four winters from four prospective cohorts. Nasopharyngeal swab specimens were …
Early events in human T cell ontogeny. Phenotypic characterization and immunohistologic localization of T cell precursors in early human fetal tissues.
Authors: B F Haynes, M E Martin, H H Kay, J Kurtzberg
Journal: The Journal of Experimental Medicine (1988)

During early fetal development, T cell precursors home from fetal yolk sac and liver to the epithelial thymic rudiment. From cells that initially colonize the thymus arise mature T cells that populate T cell zones of the peripheral lymphoid system. Whereas colonization of the thymus occurs late in the final third of gestation in the mouse, in birds and humans the thymus is colonized by hematopoietic stem cell precursors during the first third of gestation. Using a large series of early human fetal tissues and a panel of monoclonal antibodies that includes markers of early T cells (CD7, CD45), we have studied the immunohistologic location and differentiation capacity of CD45+, CD7+ cells in human fetal tissues. We found that before T cell precursor colonization of the thymus (7-8 wk of gestation), CD7+ cells were present in yolk sac, neck, upper thorax, and fetal liver, and were concentrated in mesenchyme throughout the upper thorax and neck areas. By 9.5 wk of gestation, CD7+ cells were no longer present in upper thorax mesenchyme but rather were localized in the lymphoid thymus and scattered throughout fetal liver. CD7+, CD2-, CD3-, CD8-, CD4-, WT31- cells in thorax and fetal liver, when stimulated for 10-15 d with T cell-conditioned media and rIL-2, expressed CD2, CD3, CD4, CD8, and WT31 markers of the T cell lineage. Moreover, CD7+ cells isolated from fetal liver contained all cells in this tissue capable of forming CFU-T colonies in vitro. These data demonstrate that T cell precursors in early human fetal tissues can be identified using a mAb against the CD7 antigen. Moreover, the localization of CD7+ T cell precursors to fetal upper thorax and neck areas at 7-8.5 wk of fetal gestation provides strong evidence for a developmentally regulated period in man in which T cell precursors migrate to the epithelial thymic rudiment.
Short interspersed repeats in rabbit DNA can provide functional polyadenylation signals.
Authors: Dan E. Krane, Ross C. Hardison
Journal: Molecular Biology and Evolution (1990)

Analysis of 37 short repetitive elements (SINEs) in rabbit DNA that are known as C repeats has revealed three that contribute functional polyadenylation signals to genes into which they have been inserted. Similar roles have been attributed to particular individual SINEs in rodents and primates before, suggesting that these roles may be common to SINEs in all mammalian orders. Although most SINEs appear to have little influence on the genome individually, the observation that three of 36 rabbit C repeats provide functional sequences suggests a mechanism for the maintenance of SINEs within mammalian genomes.
Abstract 542: Mice with Cardiomyocyte-Restricted IGF-1 Receptor Deletion Exhibit Diminished Cardiomyocyte Size and Resistance to Exercise-Induced Cardiac Hypertrophy
Authors: Jaetaek Kim, Adam R Wende, Crystal Sloan, Benjamin E Wayment, Sheldon E Litwin, Derek LeRoith, E. Dale Abel
Journal: Circulation (2007)

Insulin-like growth factor 1 (IGF-1) and IGF-1 receptors are expressed in murine hearts, and IGF-1 receptor signaling in cardiac muscle has been proposed to play a role in growth, differentiation, and cell survival, but mechanisms by which IGF-1 modulates myocardial structure and function are only partially understood. To investigate the role of IGF-1 signaling on cardiac development and physiology, we generated mice with cardiomyocyte-restricted knockout of the IGF-1receptor (IGF-1R −/−) by crossing α-MHC-Cre mice with mice containing a floxed exon 3 of the IGF-1R gene. Ablation of IGF-1 receptors in cardiomyocytes did not alter baseline heart weight to tibia length (HW/TL) ratios at 8 weeks or 12 weeks of age. However, wheat germ agglutinin (WGA-FITC) staining revealed that myocyte cross-sectional area was reduced by 18.8% (P &lt; 0.05). To define the contribution of IGF-1 receptor signaling in the development of physiological hypertrophy; mice [WT (n = 7) or IGF-1R −/− (n = 9)] were subjected to 4 weeks swim (Sw) training and compared with Sedentary (Sed) wild type (WT) (n = 5) or IGF-1R −/− (n = 7) mice. HW/TL ratios increased by 19.2% in WT animals after swim training (5.19 ± 0.26 vs. 6.18 ± 0.2, P &lt; 0.05), but only by 5.5% in Sw IGF-1R −/− mice (5.58 ± 0.18 vs. 5.89 ± 0.22, P = 0.32) and the fold increase in HW/TL was significantly greater in Sw WT vs. Sw IGF-1R −/− (P &lt; 0.05). Despite resistance to hypertrophy, cardiac systolic function assessed by ejection fraction was preserved in Sw IGF-1R −/− (before Sw 0.71 ± 0.02 vs. after Sw 0.67 ± 0.02, P = 0.12). Phosphorylation of Akt was significantly increased in both trained WT and IGF-1R−/− mice at Ser473 [fold-change 1.61 ± 0.09 (P &lt; 0.05) and 2.11 ± 0.19 (P &lt; 0.01), respectively] and Thr308 [2.42 ± 0.24 and 2.61 ± 0.59 (P &lt; 0.01), respectively] vs. Sed. Surprisingly Ser (473) Akt phosphorylation was greater in Sw IGF-1R−/− vs. Sw WT (P &lt; 0.05). These data define an essential role for IGF-1 signaling in mediating physiologic cardiomyocyte hypertrophy, and indicate that although Akt signaling might be necessary for mediating physiological cardiac hypertrophy it is not sufficient in the absence of myocardial IGF-1R signaling.
Evaluation of whole lung 3D dynamic oxygen-enhanced MRI
Authors: Jose Ulloa, Alexandra Morgan, Geoff Parker
Journal: European Respiratory Journal (2014)

RATIONALE: Dynamic oxygen-enhanced MRI (dOEMRI) provides imaging biomarkers of regional lung ventilation and perfusion1. Previously, dOEMRI has been limited to single slice imaging. Capturing the whole lung within a single breathing cycle increases the utility of dOEMRI in identifying regional alterations in lung function. In this work, we evaluate a novel quantitative whole lung 3D dOEMRI protocol based on a single-shot 3D MPRAGE sequence available on many scanners2.

METHODS: Sequence parameters were optimised to maximise contrast in the lung when switching from air to O2 during free breathing. The protocol was evaluated on a 1.5T Philips Achieva scanner in 4 healthy volunteers (3 which had repeat scans). Baseline T1 maps were acquired while subjects breathed medical air. This was followed by a 15min dynamic scan (temporal resolution 10s), during which gas supply was switched from air to 100% O2, and back to air. Dynamic data were converted to ΔPO2 maps and parameterised with an exponential model of O2 wash-in and wash-out1.

RESULTS: Figure 1 shows an image volume overlaid with a map of O2 wash-in and ΔPO2 time series of all the subjects scanned. The same exponential model was applied to the group average ΔPO2.

CONCLUSIONS: These results are the first to show the feasibility of volumetric whole lung dynamic OEMRI.

REFERENCES: 1 Kershaw et al. MRM 64:1838-1842;2010. 2 Deichmann et al. Neuroimage 12:112-127;2000.

Thanks to University of Manchester, MRIF. 

![Figure][1]  [1]: pending:yes
Novel, Long-Acting Drug May Help Prevent and Treat Malaria
Authors: Tracy Hampton
Journal: JAMA (2015)

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Design Issues in Randomized Clinical Trials of Maintenance Therapies
Authors: Boris Freidlin, Richard F Little, Edward L Korn
Journal: JNCI Journal of the National Cancer Institute (2015)

A potential therapeutic strategy for patients who respond (or have stable disease) on a fixed-duration induction therapy is to receive maintenance therapy, typically given for a prolonged period of time. To enable patients and clinicians to make informed treatment decisions, the designs of phase III randomized clinical trials (RCTs) assessing maintenance strategies need to be such that their results will provide clear assessment of the relevant risks and benefits of these strategies. We review the key aspects of maintenance RCT designs. Important design considerations include choice of first-line and second-line therapies, minimizing between-arm differences in follow-up schedules, and choice of the primary endpoint. In order to change clinical practice, RCTs should be designed to accurately isolate and quantify the clinical benefit of maintenance as compared with the standard approach of fixed-duration induction followed by the second-line treatment at progression. To accomplish this, RCTs need to utilize an overall survival (or quality of life) endpoint or, in settings where this is not feasible, endpoints that incorporate the effects of the subsequent line of therapy (eg, time from randomization to second progression or death). Toxicity and symptom information over both the study treatment (maintenance) and the second-line treatment should also be collected and reported.