tbuckley/cabot-search huggingface dataset:
Dinitroazetidines Are a Novel Class of Anticancer Agents and Hypoxia-Activated Radiation Sensitizers Developed from Highly Energetic Materials
Authors: Shoucheng Ning, Mark Bednarski, Bryan Oronsky, Jan Scicinski, Gordon Saul, Susan J. Knox
Journal: Cancer Research (2012)

Abstract In an effort to develop cancer therapies that maximize cytotoxicity, while minimizing unwanted side effects, we studied a series of novel compounds based on the highly energetic heterocyclic scaffold, dinitroazetidine. In this study, we report the preclinical validation of 1-bromoacetyl-3,3-dinitroazetidine (ABDNAZ), a representative lead compound currently in a phase I clinical trial in patients with cancer. In tumor cell culture, ABDNAZ generated reactive free radicals in a concentration- and time-dependent manner, modulating intracellular redox status and triggering apoptosis. When administered to mice as a single agent, ABDNAZ exhibited greater cytotoxicity than cisplatin or tirapazamine under hypoxic conditions. However, compared with cisplatin, ABDNAZ was better tolerated at submaximal doses, yielding significant tumor growth inhibition in the absence of systemic toxicity. Similarly, when combined with radiation, ABDNAZ accentuated antitumor efficacy along with the therapeutic index. Toxicity studies indicated that ABDNAZ was not myelosuppressive and no dose-limiting toxicity was apparent following daily administration for 14 days. Taken together, our findings offer preclinical proof-of-concept for ABDNAZ as a promising new anticancer agent with a favorable toxicity profile, either as a chemotherapeutic agent or a radiosensitizer. Cancer Res; 72(10); 2600–8. ©2012 AACR.
Nailfold video capillaroscopy in psoriasis
Authors: M. Bhushan, T. Moore, A.L. Herrick, C.E.M. Griffiths
Journal: British Journal of Dermatology (2000)

Changes in the microvasculature are considered to play an important part in the pathogenesis of psoriasis and its associated arthritis. The novel method of nailfold video capillaroscopy is an extension of the technique of widefield nailfold microscopy which has been of diagnostic and predictive use in the in vivo study of the microcirculation in systemic sclerosis and other connective tissue disorders. However, similar studies in patients with psoriasis and psoriatic arthritis and/or nail changes have produced conflicting results. We tested the hypothesis that any abnormalities in nailfold capillaries of either a quantitative or qualitative nature might be observed more readily in subjects with pathology adjacent to the nailfold, i.e. distal interphalangeal (DIP) joint changes and/or nail dystrophy, when using this technique. Forty-four patients with psoriasis were recruited (21 males, 23 females). Twelve patients had psoriasis alone, 13 had psoriasis and nail changes, six had DIP joint involvement with changes of psoriasis elsewhere, and 13 had psoriasis, DIP arthritis and nail changes. Capillary density and standard capillary dimensions were studied and compared with those of 44 age- and sex-matched control subjects. There was a significant (P < 0.05) decrease in capillary loop density in patients with either psoriasis plus nail disease (14.5 +/- 5.7 capillaries per 3 mm field) or psoriasis plus nail and DIP joint disease (14.3 +/- 5. 0) when compared with controls (19.2 +/- 3.8). In patients with psoriatic arthritis affecting the DIP joints, there was a statistically significant (P < 0.05) decrease in arterial and venous capillary limb diameters, and this was also seen in those with arthritis associated with nail changes. However, there was no difference in capillary dimensions between patients with psoriasis and/or nail changes when compared with normal controls. Morphological abnormalities previously described in the literature were not noted in any of our four patient groups. Our findings of diminution in both nailfold capillary bed density and dimensions of the arterial and venous capillary limbs suggest that vascular injury, previously noted in ultrastructural studies, may play a part in the pathogenesis of psoriatic arthritis. However, in contrast to previous studies, we found no specific pattern of a morphological nature of nailfold capillaries in patients with psoriasis with or without nail changes, when compared with normal controls.
Peanut allergy is common among hazelnut‐sensitized subjects but is not primarily the result of IgE cross‐reactivity
Authors: L. J. Masthoff, E. van Hoffen, L. Mattsson, J. Lidholm, K. Andersson, L. Zuidmeer‐Jongejan, S. A. Versteeg, C. A. Bruijnzeel‐Koomen, A. C. Knulst, S. G. Pasmans, R. van Ree
Journal: Allergy (2014)

Hazelnut and peanut are botanically unrelated foods, but patients are often sensitized and allergic to both, for reasons that are not well understood.To investigate molecular cosensitization and cross-reactivity to peanut in hazelnut-sensitized individuals, children (n = 81) and adults (n = 80) were retrospectively selected based on sensitization to hazelnut. IgE to hazelnut extract, Cor a 1, 8, 9 and 14, to peanut extract, Ara h 1, 2, 3, 8 and 9, and to Bet v 1 was determined by ImmunoCAP. Allergy to hazelnut and peanut was established by DBPCFC and/or detailed clinical history. Patients were either tolerant or displayed subjective or objective symptoms to either food. IgE cross-reactivity between hazelnut and peanut storage proteins was assessed by reciprocal ImmunoCAP inhibition experiments.Of the 161 hazelnut-sensitized subjects, 109 (68%) were also sensitized to peanut, and 73 (45%) had clinical expression of allergy to peanut that was not associated with the presence or severity of hazelnut allergy. Instead, it was associated with IgE reactivity to peanut storage proteins, in particular Ara h 2. No cross-reactivity could be detected between Ara h 2 and Cor a 14, and 2 of 13 subjects displayed extensive cross-reactivity between 11S globulins; in plasma of both individuals, Ara h 3 almost completely inhibited IgE binding to Cor a 9.Peanut allergy is not primarily the result of IgE cross-reactivity to hazelnut storage proteins. IgE to Cor a 14 and Ara h 2 may serve as useful markers of primary sensitization to hazelnut and peanut, respectively.
Chronic Ischemic Mitral Regurgitation
Authors: Michael A. Borger
Journal: Circulation (2012)

C hronic ischemic mitral regurgitation (cIMR) remains a vexing problem for a large number of patients and their respective clinicians.It is estimated that Ϸ2 million Americans experience cIMR, and this number is likely to increase with an aging general population and improved survival rates for myocardial infarction. 1 Despite the large number of patients with this disease, relatively few patients are referred for surgical therapy.This is reflected in the fact that the largest surgical series to date consist of only a few hundred patients operated on over a several-year interval. 2,
Use of Model for End-Stage Liver Disease Scoring Dynamics in Critically Ill Cirrhotic Trauma Patients
Authors: Timothy A. Pritts
Journal: JAMA Surgery (2015)

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P29 Endothelial cell NF-kB activation is increased in human idiopathic PAH
Authors: L. Price, G. Caramori, P. Dorfmuller, F. Perros, J. Zhu, D. Shao, M. Humbert, I. Adcock, S. Wort
Journal: Thorax (2010)

<h3>Background</h3> Pulmonary arterial hypertension (PAH) is associated with pulmonary vascular inflammation, and several of the inflammatory genes involved are regulated by nuclear factor-kB (NF-kB). NF-kB is a heterodimer of p65 and p50 subunits which, upon activation, translocate into the nucleus and binds to target gene promoters. NF-kB activation in PAH has not been examined in detail to date. We assessed NF-kB activation by immunohistochemical analysis of nuclear p65. <h3>Methods</h3> Samples were obtained from South Paris University from patients with severe idiopathic PAH (IPAH) following lung transplantation (n=10) and from control subjects undergoing lobectomy or pneumonectomy (n=10). Tissue blocks were fixed and paraffin-embedded, 4-mm thick sections underwent immunoperoxidase double staining for macrophage (CD68+)/p65, using mouse anti-human CD68 (Dako; 1:100 dilution) and rabbit anti human p65 (Santa Cruz Biotechnology; 1:50 dilution), before detection with chromogen fast red and counterstaining with haematoxylin. Vessels of interest were defined and quantitative scoring of nuclear p65 immunostaining of ten randomly selected pulmonary arteries per slide performed by a researcher blinded to the groups. Data are expressed as median and IQR, and the groups were compared by the Kruskal–Wallis or Mann–Whitney U test. <h3>Results</h3> (1) PAH specimens showed co-localisation of p65 within CD68+ macrophages in 75.4 (64.8–84.6)% of samples. Airway epithelium, neutrophils and lymphocytes were also positive for p65. (2) Pulmonary arterial medial thickness was increased in PAH compared to controls, at 33.7 (18.8–67.9)% in vessels 100–250 mm external diameter (E.D.) and 27.2 (14.8–44.2)% in vessels 250–500 mm ED, vs 17.7 (11.2–30.3)% and 14.9 (11.8–17.8)% in controls (p&lt;0.0001 between groups). (3) Nuclear p65 was present in pulmonary artery endothelial cells (EC) but not other vascular cells including pulmonary artery smooth muscle cells in PAH: 53.9 (0–100)% of vessels 100–250 mm E.D. and 53.1 (0–100)% of those 250–500 mm E.D. scored EC p65 positivity in PAH compared to 7.5 (0–25.0)% in 100–250 mm ED and 4.7 (0–21.1)% in 250–500 mm ED in controls (p&lt;0.0001 between groups) (Abstract P29 Figure 1). <h3>Conclusion</h3> NF-kB activation is present in macrophages and pulmonary arterial endothelial cells in pulmonary arteries of 100–500 mm ED in patients with PAH.
Identification of a PAX-FKHR Gene Expression Signature that Defines Molecular Classes and Determines the Prognosis of Alveolar Rhabdomyosarcomas
Authors: Elai Davicioni, Friedrich Graf Finckenstein, Violette Shahbazian, Jonathan D. Buckley, Timothy J. Triche, Michael J. Anderson
Journal: Cancer Research (2006)

Alveolar rhabdomyosarcomas (ARMS) are aggressive soft-tissue sarcomas affecting children and young adults. Most ARMS tumors express the PAX3-FKHR or PAX7-FKHR (PAX-FKHR) fusion genes resulting from the t(2;13) or t(1;13) chromosomal translocations, respectively. However, up to 25% of ARMS tumors are fusion negative, making it unclear whether ARMS represent a single disease or multiple clinical and biological entities with a common phenotype. To test to what extent PAX-FKHR determine class and behavior of ARMS, we used oligonucleotide microarray expression profiling on 139 primary rhabdomyosarcoma tumors and an in vitro model. We found that ARMS tumors expressing either PAX-FKHR gene share a common expression profile distinct from fusion-negative ARMS and from the other rhabdomyosarcoma variants. We also observed that PAX-FKHR expression above a minimum level is necessary for the detection of this expression profile. Using an ectopic PAX3-FKHR and PAX7-FKHR expression model, we identified an expression signature regulated by PAX-FKHR that is specific to PAX-FKHR-positive ARMS tumors. Data mining for functional annotations of signature genes suggested a role for PAX-FKHR in regulating ARMS proliferation and differentiation. Cox regression modeling identified a subset of genes within the PAX-FKHR expression signature that segregated ARMS patients into three risk groups with 5-year overall survival estimates of 7%, 48%, and 93%. These prognostic classes were independent of conventional clinical risk factors. Our results show that PAX-FKHR dictate a specific expression signature that helps define the molecular phenotype of PAX-FKHR-positive ARMS tumors and, because it is linked with disease outcome in ARMS patients, determine tumor behavior.
Targeting Bone Metastasis in Prostate Cancer with Endothelin Receptor Antagonists
Authors: Michael A. Carducci, Antonio Jimeno
Journal: Clinical Cancer Research (2006)

Recent advances in the understanding of prostate cancer biology and its progression to bone metastasis have led to the development of drugs directed against precise molecular alterations in the prostate tumor cell and host cells in the normal bone environment such as osteoclasts and osteoblasts. Endothelins (ETs) and their receptors have emerged as a potential target in prostate cancer bone metastasis. By activating the ETA receptor, ET-1 is pathogenically involved in facilitating several aspects of prostate cancer progression, including proliferation, escape from apoptosis, invasion, and new bone formation, processes that are general to many malignancies. Notwithstanding, there are a number of features specifically driven by the ET axis in prostate cancer, such as creating and perpetuating a unique interaction between the metastatic prostate cancer cell and the bone microenvironment (osteoblast, osteoclast, and stroma) or altering the equilibrium in pain modulation. These features have led to the preferential clinical evaluation of atrasentan (ABT-627) as a biological therapy in prostate carcinoma, first in hormone-refractory prostate cancer. Biological activity of atrasentan in patients with prostate cancer has been shown by the suppression of biochemical markers of prostate cancer progression in bone, and clinical activity is evidenced by a consistent trend demonstrating a delay in time to disease progression when compared with placebo, especially in patients with bone metastases. Further studies of atrasentan and other selective ET-1 antagonists (ZD4054) are ongoing.
Leukocyte Migration Inhibition Among Breast Cancer Patients in Response to Various Oncogenic Viruses&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Mamoru Fukuda, Harold J. Wanebo, Lillian Tsuei, Roy Ashikari, Nurul H. Sarkar
Journal: JNCI Journal of the National Cancer Institute (1980)

The direct leukocyte migration inhibition (LMI) test was done with leukocytes from healthy women and from patients with primary operable breast cancer, benign breast disease, or head and neck cancer. Purified preparations of murine mammary tumor virus (MuMTV), Mason-Pfizer monkey virus (MPMV), and murine leukemia virus (MuLV) were used. For each virus, the lowest 10th percentile of the LMI responses of controls was used to discriminate positive from negative responses. Leukocytes from 46 of 94 (49%) breast cancer patients responded to MuMTV, which was significantly different from each of the other test groups: Positive reactions were observed in only 9 of 67 (13%) healthy persons, 2 of 32 (6%) patients with benign breast tumors, and 2 of 20 (10%) patients with head and neck cancer. Although leukocytes from 29% of the breast cancer patients responded to MPMV, this response did not significantly differ from that observed in healthy women (14%), in patients with benign disease (20%), or in patients with head and neck cancer (20%). The leukocytes from the breast cancer patients were not reactive to MuLV. LMI tests to both MuMTV and extracts of MCF-7 cultured breast cancer cells were done in 36 breast cancer patients and 40 healthy women simultaneously. Of the breast cancer patients, 75% responded to MuMTV and/or MCF-7 antigen as compared to 18% of the controls (P less than 0.005). These data suggest that leukocytes from breast cancer patients are presensitized to MuMTV and antigen(s) present in MCF-7 breast cancer cell line, but not to MPMV or MuLV.
Developing an injury tracking software system specific for volleyball: a case example
Authors: K R Yasher, K Liller, S Wong, S Jang, B J Morris, J G Konin
Journal: British Journal of Sports Medicine (2011)

Background Injury tracking systems are becoming increasingly popular in the realm of sports medicine. Identifying the prevalence and types of injuries can contribute to the identification of risk factors associated with sport specific injuries, as well as lead to the development of injury prevention programs, educational material, rule changes, and improved protective equipment. Objective To describe the process of creating an injury tracking system for volleyball in an effort to track variables associated with injury patterns. Design A software program containing over 1000variables was developed by certified athletic trainers and public health experts. Variables included demographic information, environmental factors, and sport specific movements. Standardized definitions (ie, ‘injury’) were established and pilot tested for reliability and validity purposes using internally developed case studies. Setting Data was collected via a web-based software program through the university academic program. Participants Participants included female volleyball players between 14–18 years of age. Results Analysis of the results identified common injuries associated with volleyball and their associated mechanisms. These findings directly led to the implementation of educational programs designed to prevent such injuries from occurring in the future. Furthermore, internal assessments of the program development noted the requirement of frequent variable modifications, standardized training necessities, and ongoing discussion to assure accurate data input. Conclusions The development of an injury tracking system specific to volleyball requires time, funding, ongoing re-evaluation, standardized terms, training for data collectors, and plans for implementing the findings into practical information for coaches, players, parents, and health care providers. When developed successfully, the information collected can prove to be valuable.
Effect of vasoactive intestinal polypeptide and somatostatin on secretion of epidermal growth factor and bicarbonate from Brunner's glands.
Authors: P Kirkegaard, P S Olsen, E Nexo, J J Holst, S S Poulsen
Journal: Gut (1984)

The effect of VIP and somatostatin on secretion of epidermal growth factor and bicarbonate from Brunner9s glands was investigated in the rat. Vasoactive intestinal polypeptide infused in doses of 10 and 100 ng/kg/h significantly increased epidermal growth factor and bicarbonate output, but the concentrations did not change. Somatostatin infused at doses of 1, 10, 100 and 1000 ng/kg/h against a background of VIP 100 ng/kg/h inhibited in dose-dependent fashion the stimulated epidermal growth factor and bicarbonate outputs from rat Brunner9s gland pouches. Also basal secretion was inhibited by somatostatin. Infusion of antisomatostatin serum stimulated Brunner9s gland secretion. By immunohistochemical studies of rat duodena, it was found that epidermal growth factor, is almost exclusively present in the secretory cells of Brunner9s glands. It is concluded that VIP stimulates secretion of epidermal growth factor and bicarbonate from Brunner9s glands, an effect which is inhibited by somatostatin. A possible role for somatostatin in the control of Brunner9s gland secretion is suggested.
Evolution of the Cation Chloride Cotransporter Family: Ancient Origins, Gene Losses, and Subfunctionalization through Duplication
Authors: Anna-Maria Hartmann, David Tesch, Hans Gerd Nothwang, Olaf R.P. Bininda-Emonds
Journal: Molecular Biology and Evolution (2013)

The cation chloride cotransporter (CCCs) family comprises of four subfamilies—K+-Cl− cotransporters (KCCs), Na+-K+-2Cl− cotransporters (NKCCs), and Na+-Cl− cotransporters (NCCs)—and possibly two additional members—CCC interacting protein (CIP1) and polyamine transporters (CCC9)—as well. Altogether, CCCs can play essential physiological roles in transepithelial ion reabsorption and secretion, cell volume regulation, and inhibitory neurotransmission and so are present across all domains of life. To gain insight into the evolution of this family, we performed a comprehensive phylogenetic analysis using publically available genomic information. Our results clearly support CIP1 as being a true CCC based on shared evolutionary history. By contrast, the status of CCC9 in this regard remains equivocal. We also reveal the existence of a single ancestral CCC gene present in Archaea, from which numerous duplication events at the base of archaeans and eukaryotes lead to the divergence and subsequent neofunctionalization of the paralogous CCC subfamilies. A diversity of ensuing gene-loss events resulted in the complex distribution of CCCs present across the different taxa. Importantly, the occurrence of KCCs in "basal" metazoan taxa like sponges would allow an early formation of fast hyperpolarizing neurotransmission in metazoans. Gene duplications within the CCC subfamilies in vertebrates (in particular, KCCs, NKCCs, and NCCs) lend further evidence to the 2R hypothesis of two rounds of genome duplication at the base of the vertebrate lineage, especially in concert with our syntenic cluster analyses. This increased number of KCCs, NKCCs, and NCCs isoforms facilitates their further, important subfunctionalization in the vertebrate lineage.
PROPERTIES OF THE CAUSATIVE AGENT OF A CHICKEN TUMOR
Authors: Albert Claude
Journal: The Journal of Experimental Medicine (1937)

1. The agent causing Chicken Tumor I can be separated from the other constituents of the tumor filtrate by means of high speed centrifugation. The separation was practically complete when a filtrate of average viscosity (0.018 poise) was submitted to a centrifugal field of 14,000 times gravity for 2 hours. 2. Relative purification of the agent was obtained by means of differential centrifugation and washing in Tyrode's solution or in distilled water. The washed sediment gave opalescent solutions composed of minute particles of approximately, but not exactly, the same size. The dry weight of the active material separated by high speed centrifugation was 0.0008 mg. per cc. of filtrate, or about 1 part per 2800 parts of the total filtrate. 3. The tumor-producing activity of the washed sediment was significantly greater than that of the entire original filtrate. It is suggested that the gain in tumor-producing power was effected by the removal of an inhibiting factor, known to occur normally in chicken tumor extracts.