tbuckley/cabot-search huggingface dataset:
Spontaneous Transformation of Rat Ovarian Surface Epithelial Cells: Association With Cytogenetic Changes and Implications of Repeated Ovulation in the Etiology of Ovarian Cancer
Authors: A. K. Godwin, J. R. Testa, L. M. Handel, Z. Liu, L. A. Vanderveer, P. A. Tracey, T. C. Hamilton
Journal: JNCI Journal of the National Cancer Institute (1992)

Background: Ovarian surface epithelial cells undergo several rounds of division to repair the wound created by follicular rupture at the time of ovulation. This cyclical requirement for cell division, when not interrupted by the long anovulatory rest periods that occur during pregnancy and lactation, may contribute to the development of ovarian cancer. Purpose and Methods: To test this hypothesis, we isolated rat ovarian surface epithelial cells from 10 adult female Fisher rats, initiated two mixed-population and seven clonal cell lines, and repeatedly subcultured these cells in vitro for more than 20 passages. We then tested them for the acquisition of the following four features associated with transformation: 1) the loss of contact inhibition, 2) the capacity for substrate-independent growth, 3) the ability to form tumors when injected subcutaneously and/or in-traperitoneally into athymic mice, and 4) cytogenetic abnormalities. Results: Loss of contact inhibition was observed in all nine late-passage cell lines. Six of the nine late-passage, but none of the early-passage, cell lines tested exhibited a capacity for substrate-independent growth that was augmented in a dose-dependent manner by epidermal growth factor. Two late-passage cell lines (clone 2 and mixed-population 2) generated tumors in athymic BALB/c mice within 3 weeks following subcutaneous injection of 5 ×10 6 cells, whereas similar numbers of early-passage cells from the same cell lines failed to generate palpable tumors. Late-passage clone 7 cells were tumorigenic when 5 × 10 7 cells were injected intraperitoneally. Two of the cell lines analyzed exhibited alterations involving losses of part or all of one member of the chromosome 5 pair. Clone 2 possessed an interstitial deletion, del(5)(q21.3q24), consistent with the loss of an uncloned putative tumor suppressor gene at 5q22q23 previously reported to reside near the loci for the interferon a, interferon (β;, and c-jun genes. Early-passage clone 7 cells exhibited chromosome 5 monosomy, while late-passage cells contained one normal chromosome 5 and a derivative (5ql2q). Southern analysis of the three cell lines revealed no consistent loss of loci for the interferon and c-jun genes, although early-passage clone 7 cells had one half the gene copy number for the interferon β and c-jun genes and both early- and late-passage clone 7 cells lacked DNA sequences hybridizing with the probe for interferon α Conclusion: This pattern of passage-dependent spontaneous transformation of rat ovarian surface epithelial cells in vitro supports the hypothesis that repetitious ovulation contributes to the etiology of human ovarian cancer. [J Natl Cancer Inst 84: 592–601, 1992]
Cyclin D1 overexpression and p53 inactivation immortalize primary oral keratinocytes by a telomerase-independent mechanism
Authors: Oliver G. Opitz, Yasir Suliman, William C. Hahn, Hideki Harada, Hubert E. Blum, Anil K. Rustgi
Journal: Journal of Clinical Investigation (2001)

The immortalization of human cells is a critical step in multistep carcinogenesis. Oral-esophageal carcinomas, a model system to investigate molecular mechanisms underlying squamous carcinogenesis, frequently involve cyclin D1 overexpression and inactivation of the p53 tumor suppressor. Therefore, our goal was to establish the functional role of cyclin D1 overexpression and p53 inactivation in the immortalization of primary human oral squamous epithelial cells (keratinocytes) as an important step toward malignant transformation. Cyclin D1 overexpression alone was found to induce extension of the replicative life span of normal oral keratinocytes, whereas the combination of cyclin D1 overexpression and p53 inactivation led to their immortalization. This study also demonstrates that immortalization of oral keratinocytes can be independent of telomerase activation, involving an alternative pathway of telomere maintenance (ALT).
Recruitment of Beneficial M2 Macrophages to Injured Spinal Cord Is Orchestrated by Remote Brain Choroid Plexus
Authors: Ravid Shechter, Omer Miller, Gili Yovel, Neta Rosenzweig, Anat London, Julia Ruckh, Ki-Wook Kim, Eugenia Klein, Vyacheslav Kalchenko, Peter Bendel, Sergio A. Lira, Steffen Jung, Michal Schwartz
Journal: Immunity (2013)
Soluble tumour necrosis factor receptors p55 and p75 in the urine monitor disease activity and the efficacy of treatment of inflammatory bowel disease.
Authors: F Hadziselimovic, L R Emmons, H Gallati
Journal: Gut (1995)

The aim of the study was to discover if soluble tumour necrosis factor receptors (sTNF-R p55 and p75) in the urine of patients with inflammatory bowel disease (IBD) could be used to monitor the different stages of the activity of the diseases. Twenty five patients with either Crohn9s disease or ulcerative colitis were followed up during a longterm study. The 16 patients who become acutely ill with either Crohn9s disease or ulcerative colitis had significantly higher concentrations of sTNF-R p55 and p75 in their urine compared with those who were in remission, or those who were normal controls. There was a significant correlation between increased concentrations (&gt; 20 ng/ml) of both sTNF-R p55 and p75 in the urine and a high Crohn9s disease activity index (CDAI) and colitis activity index (CAI). Therefore, determination of sTNF-R is a good non-invasive parameter that can be used to assess the activity of disease and the efficacy of treatment.
Involvement of Interleukin (IL) 8 receptor in negative regulation of myeloid progenitor cells in vivo: evidence from mice lacking the murine IL-8 receptor homologue.
Authors: H E Broxmeyer, S Cooper, G Cacalano, N L Hague, E Bailish, M W Moore
Journal: The Journal of Experimental Medicine (1996)

Expansion of mature neutrophils has been observed in mice lacking the murine interleukin (IL) 8 receptor homolog [mIL-8Rh(-/-)], and human (hu) IL-8 suppresses proliferation of primitive myeloid cells in vitro and in vivo. To evaluate involvement and relevance of murine IL-8 receptor homolog (mIL-8Rh) in negative regulation of myelopoiesis, we studied mIL-8Rh(-/-) and (+/+) mice raised in a normal or germ-free environment. Immature myeloid progenitors from mIL-8Rh(+/+) mice bred under normal or germ-free conditions were significantly suppressed in vitro by recombinant huIL-8, macrophage inflammatory protein (MIP)-1 alpha, platelet factor (PF) 4, interferon inducible protein (IP) 10, monocyte chemotactic peptide (MCP) 1, and H-ferritin. In contrast, progenitors from mIL-8Rh(-/-) mice were insensitive to inhibition by IL-8, but not to these other chemokines and H-ferritin. Mouse MIP-2, a ligand for mIL-8Rh, suppressed progenitors from normal but not mIL-8Rh(-/-) mice. Under normal environmental conditions, enhanced numbers of myeloid progenitors were found in femur, spleen, and blood of mIL-8Rh(-/-) compared with mIL-8Rh(+/+) mice. Numbers of myeloid progenitors were greatly decreased in mIL-8Rh(-/-)and (+/+) mice in germ-free conditions, and were either not significantly enhanced in mIL-8Rh(-/-) mice compared with (+/+) mice or were only moderately so. Differences in progenitors/organ between a germ-free and normal environment were greater for the mIL-8Rh(-/-) mice. These results document selective insensitivity of myeloid progenitor cells from mIL-8Rh(-/-) mice to inhibition by huIL-8 and mouse MIP-2 and a large expansion of myeloid progenitors in these mice, the latter effect being environmentally inducible. This provides strong support for a negative myeloid regulatory role played by the mIL-8Rh in vivo, whose active ligand may be MIP-2.
The Discovery of the Leukotrienes
Authors: BENGT SAMUELSSON
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

In a study of the transformation of polyunsaturated fatty acids in rabbit polymorphonuclear leukocytes in 1976 it was discovered that arachidonic acid is oxygenated at C-5 (1). Subsequently a number of derivatives, including leukotriene B 4  (LTB 4 ), were identified (2-4). Extension of these studies led in 1979 to the discovery of the pivot epoxide intermediate, LTA 4  (5), and the elucidation of the structure of SRS-A (slow-reacting substance of anaphylaxis) as a group of cysteinyl-leukotrienes, namely LTC 4 , LTD 4 , and LTE 4  (6-10). Earlier work had shown that the prostaglandins are formed by oxygenation and further transformation of arachidonic acid and other polyunsaturated fatty acids (11). The first intermediate in the formation of prostaglandins, the endoperoxide PGG 2 , was isolated and identified in 1974 (12). At the same time we introduced the name cyclooxygenase for the enzyme catalyzing the transformation of arachidonic acid into PGG 2  (12). However, the endoperoxides, PGG 2  and PGH 2 , had some biological effects that could not be explained by their conversion to the known prostaglandins (12). This finding eventually led to the discovery of thromboxane A 2 , an unstable platelet-aggregating and vasoconstrictor substance (13). Subsequent work showed that the endoperoxide can also be converted into a derivative, prostacyclin (PGI 2 ), with opposite biological effects (14). Prostaglandins E 2  and I 2  have strong proinflammatory effects. Aspirin and other nonsteroidal antiinflammatory drugs (NSAIDs) inhibit the enzyme (cyclooxygenase) responsible for conversion of arachidonic acid into prostaglandins and thromboxanes (15). An induced form of the cyclooxygenase (COX-2) seems to play an important role in inflammation, thus opening the possibility of developing antiinflammatory NSAIDs that lack the side effects of the previous generation of such drugs (16, 17). In 1975 antiinflammatory steroids were proposed to inhibit prostaglandin formation by blocking of the release of the precursor acid from phospholipid stores (18). Since steroids and NSAIDs have significantly different antiinflammatory effects it seemed conceivable that some of these differences might be explained by the formation of proinflammatory derivatives of arachidonic acid by cyclooxygenase-independent reactions. Our studies of the metabolism of arachidonic acid in leukocytes unraveled a new metabolic pathway and led to the discovery of the leukotrienes (8). These compounds play a role in allergy and asthma and have pronounced proinflammatory effects (19, 20).
A co-clinical approach identifies mechanisms and potential therapies for androgen deprivation resistance in prostate cancer
Authors: Andrea Lunardi, Ugo Ala, Mirjam T Epping, Leonardo Salmena, John G Clohessy, Kaitlyn A Webster, Guocan Wang, Roberta Mazzucchelli, Maristella Bianconi, Edward C Stack, Rosina Lis, Akash Patnaik, Lewis C Cantley, Glenn Bubley, Carlos Cordon-Cardo, William L Gerald, Rodolfo Montironi, Sabina Signoretti, Massimo Loda, Caterina Nardella, Pier Paolo Pandolfi
Journal: Nature Genetics (2013)
Annular Geometry in Patients With Chronic Ischemic Mitral Regurgitation
Authors: Shuichiro Kaji, Michihiro Nasu, Atsushi Yamamuro, Kazuaki Tanabe, Kunihiko Nagai, Tomoko Tani, Koichi Tamita, Kenichi Shiratori, Makoto Kinoshita, Michio Senda, Yukikatsu Okada, Shigefumi Morioka
Journal: Circulation (2005)

Background— Although animal studies showed that annular remodeling may be related to the pathogenesis of chronic ischemic mitral regurgitation (CIMR), little was known in humans. A better understanding of the precise 3D geometry of the mitral valvular-ventricular complex in CIMR is needed to devise a better surgical technique. The purpose of the study was to elucidate mitral annular geometry in patients with CIMR using cardiac MRI. Methods and Results— Thirty-eight patients with previous inferior or posterior myocardial infarction were studied. With the 3D reconstruction of the mitral annulus and subvalvular apparatus from a series of longitudinal cine MRIs, end-systolic mitral annulus dimensions and 3D geometry were calculated. Patients were grouped by mitral regurgitation grade using echocardiography (≥2+, n=15 versus ≤1+, n=23). Both septal-lateral and commissure-commissure mitral annular diameters were significantly greater in CIMR(+) patients (35±5 versus 30±4 mm, P =0.005; 46±6 versus 39±4 mm, P &lt;0.001, respectively). The length of the fibrous annulus was significantly larger in CIMR(+) patients (28±3 versus 24±3 mm; P &lt;0.001). The height of the annular “saddle horn” above a best-fit plane was lower in CIMR(+) patients (4.2±1.2 versus 6.0±1.8 mm; P =0.002), and the annular height to commissural width ratio was significantly lower in CIMR(+) patients (12±3 versus 21±5%; P &lt;0.001). Conclusions— Patients with CIMR had greater septal-lateral and commissure-commissure mitral annular dimension, larger intertrigonal distance, and flattened saddle shape of mitral annulus. These associated geometric alterations may be important in the pathogenesis of CIMR.
Effect of Vitamin D Supplementation on Glycemic Control in Patients With Type 2 Diabetes (SUNNY Trial): A Randomized Placebo-Controlled Trial
Authors: Yvonne H.M. Krul-Poel, Sanne Westra, Edwin ten Boekel, Marieke M. ter Wee, Natasja M. van Schoor, Hans van Wijland, Frank Stam, Paul T.A.M. Lips, Suat Simsek
Journal: Diabetes Care (2015)

OBJECTIVE Low vitamin D status has been associated with impaired glycemic control in patients with type 2 diabetes. The purpose of our study was to evaluate the effect of vitamin D supplementation on glycemic control in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS This randomized, double-blind, placebo-controlled trial was conducted in 275 adult patients with type 2 diabetes without insulin treatment. Patients were randomly assigned to receive either vitamin D3 (50,000 IU/month) or placebo for 6 months. To assess the primary outcome of the study, change in HbA1c, we performed a linear regression analysis. RESULTS Mean baseline serum 25-hydroxyvitamin D [25(OH)D] increased from 60.6 ± 23.3 to 101.4 ± 27.6 nmol/L and 59.1 ± 23.2 to 59.8 ± 23.2 nmol/L in the vitamin D and placebo group, respectively. Mean baseline HbA1c was 6.8 ± 0.5% (51 ± 6 mmol/mol) in both groups. After 6 months, no effect was seen on HbA1c (mean difference: β = 0.4 [95% CI −0.6 to 1.5]; P = 0.42) and other indicators of glycemic control (HOMA of insulin resistance, fasting insulin, and glucose) in the entire study population. Subgroup analysis in patients with a serum 25(OH)D &amp;lt;50 nmol/L or an HbA1c level &amp;gt;7% (53 mmol/mol) did not differ the results. CONCLUSIONS In a well-controlled group of patients with type 2 diabetes, intermittent high-dose vitamin D supplementation did not improve glycemic control.
Identification of the hemangioblast in postnatal life
Authors: Elvira Pelosi, Mauro Valtieri, Simona Coppola, Rosanna Botta, Marco Gabbianelli, Valentina Lulli, Giovanna Marziali, Barbara Masella, Robert Müller, Cecilia Sgadari, Ugo Testa, Giuseppina Bonanno, Cesare Peschle
Journal: Blood (2002)
Effect of a Rapid Response Team on Hospital-wide Mortality and Code Rates Outside the ICU in a Children’s Hospital
Authors: Paul J Sharek, Layla M Parast, Kit Leong, Jodi Coombs, Karla Earnest, Jill Sullivan, Lorry R Frankel, Stephen J Roth
Journal: JAMA (2007)

ContextIntroduction of a rapid response team (RRT) has been shown to decrease mortality and cardiopulmonary arrests outside of the intensive care unit (ICU) in adult inpatients. No published studies to date show significant reductions in mortality or cardiopulmonary arrests in pediatric inpatients.ObjectiveTo determine the effect on hospital-wide mortality rates and code rates outside of the ICU setting after RRT implementation at an academic children's hospital.Design, Setting, and ParticipantsA cohort study design with historical controls at a 264-bed, free-standing, quaternary care academic children's hospital. Pediatric inpatients who spent at least 1 day on a medical or surgical ward between January 1, 2001, and March 31, 2007, were included. A total of 22 037 patient admissions and 102 537 patient-days were evaluated preintervention (before September 1, 2005), and 7257 patient admissions and 34 420 patient-days were evaluated postintervention (on or after September 1, 2005).InterventionThe RRT included a pediatric ICU–trained fellow or attending physician, ICU nurse, ICU respiratory therapist, and nursing supervisor. This team was activated using standard criteria and was available at all times to assess, treat, and triage decompensating pediatric inpatients.Main Outcome MeasuresHospital-wide mortality rates and code (respiratory and cardiopulmonary arrests) rates outside of the ICU setting. All outcomes were adjusted for case mix index values.ResultsAfter RRT implementation, the mean monthly mortality rate decreased by 18% (1.01 to 0.83 deaths per 100 discharges; 95% confidence interval [CI], 5%-30%; P = .007), the mean monthly code rate per 1000 admissions decreased by 71.7% (2.45 to 0.69 codes per 1000 admissions), and the mean monthly code rate per 1000 patient-days decreased by 71.2% (0.52 to 0.15 codes per 1000 patient-days). The estimated code rate per 1000 admissions for the postintervention group was 0.29 times that for the preintervention group (95% likelihood ratio CI, 0.10-0.65; P = .008), and the estimated code rate per 1000 patient-days for the postintervention group was 0.28 times that for the preintervention group (95% likelihood ratio CI, 0.10-0.64; P = .007).ConclusionImplementation of an RRT was associated with a statistically significant reduction in hospital-wide mortality rate and code rate outside of the pediatric ICU setting.
Factors associated with menstrual dysfunction and self-reported bone stress injuries in female runners in the ultra- and half-marathons of the Two Oceans
Authors: L K Micklesfield, J Hugo, C Johnson, T D Noakes, E V Lambert
Journal: British Journal of Sports Medicine (2007)

To investigate factors associated with menstrual dysfunction, self-reported bone stress injuries and energy balance in women runners.613 runners were randomly sampled during the registration period for an endurance event. Demographic information, including self-reported height and weight, training and injury history and menstrual history, was collected by questionnaire.Ultra-marathon (ULTRA) participants (n = 276) were significantly older (mean (SD) 39 (8.2) vs 34 (10.5) years; p<0.001), lighter (58.2 (6.6) vs 59.6 (8.3) kg; p<0.05) and reported a higher training volume (p<0.001) than half-marathon (HALF) participants (n = 337). Significantly more ULTRA subjects than HALF subjects reported a previous bone stress injury (21% vs 14%; p<0.05). There was no difference between the groups for menstrual status, but age at menarche was later (p<0.01) in the ULTRA group. Data were combined according to the absence (REG; n = 368/602 (61%)) or presence (IRREG; n = 234/602 (39%)) of a history of menstrual irregularity. Subject morphology was similar between groups, but the IRREG group had a higher self-reported measure on the self-loathing subscale (SLSS; p<0.01). The whole group was then classified according to current menstrual status, with 165 women being classified as currently irregular. (OLIGO/AMEN; 11.6%) and 445 women as currently regular (EUMEN; 88.4%). There were no morphological differences between the groups, however the OLIGO/AMEN group had a later age of menarche (p<0.01) than the EUMEN group. Further, women who reported a previous bone stress injury had higher SLSS scores than those who did not (2.91 (0.98) vs 2.68 (0.84); p<0.05).There may be two independent mechanisms associated with energy balance, which are related to bone stress injuries, but may not necessarily be related to menstrual dysfunction.
Low-dose irradiation promotes tissue revascularization through VEGF release from mast cells and MMP-9–mediated progenitor cell mobilization
Authors: Beate Heissig, Shahin Rafii, Haruyo Akiyama, Yuichi Ohki, Yayoi Sato, Tejada Rafael, Zhenping Zhu, Daniel J. Hicklin, Ko Okumura, Hideoki Ogawa, Zena Werb, Koichi Hattori
Journal: The Journal of Experimental Medicine (2005)

Mast cells accumulate in tissues undergoing angiogenesis during tumor growth, wound healing, and tissue repair. Mast cells can secrete angiogenic factors such as vascular endothelial growth factor (VEGF). Ionizing irradiation has also been shown to have angiogenic potential in malignant and nonmalignant diseases. We observed that low-dose irradiation fosters mast cell–dependent vascular regeneration in a limb ischemia model. Irradiation promoted VEGF production by mast cells in a matrix metalloproteinase-9 (MMP-9)–dependent manner. Irradiation, through MMP-9 up-regulated by VEGF in stromal and endothelial cells, induced the release of Kit-ligand (KitL). Irradiation-induced VEGF promoted migration of mast cells from the bone marrow to the ischemic site. Irradiation-mediated release of KitL and VEGF was impaired in MMP-9–deficient mice, resulting in a reduced number of tissue mast cells and delayed vessel formation in the ischemic limb. Irradiation-induced vasculogenesis was abrogated in mice deficient in mast cells (steel mutant, Sl/Sld mice) and in mice in which the VEGF pathway was blocked. Irradiation did not induce progenitor mobilization in Sl/Sld mice. We conclude that increased recruitment and activation of mast cells following irradiation alters the ischemic microenvironment and promotes vascular regeneration in an ischemia model. These data show a novel mechanism of neovascularization and suggest that low-dose irradiation may be used for therapeutic angiogenesis to augment vasculogenesis in ischemic tissues.
Scalp Dysesthesia Related to Cervical Spine Disease
Authors: Laura A. Thornsberry, Joseph C. English
Journal: JAMA Dermatology (2012)

Scalp dysesthesia is characterized by abnormal sensations of the scalp in the absence of any other unusual physical examination findings. The pathogenesis of this condition is unknown but has been reported in the setting of underlying psychiatric disorders. Other localized pruritic syndromes, including brachioradial pruritus and notalgia paresthetica, have been associated with pathologic conditions of the spine and have been successfully treated with gabapentin.Among 15 women identified in a retrospective review of medical records as having been seen with scalp dysesthesia, 14 patients had cervical spine disease confirmed by imaging. The most common finding on imaging was degenerative disk disease, with 10 of 14 patients having these changes at C5-C6. Other abnormal imaging findings included anterolisthesis, osteophytic spurring, lordosis, kyphosis, and nerve root impingement. A gabapentin regimen (topical or oral) had been recommended to 14 patients; of 7 patients who were followed up, 4 patients noted improvement in symptoms when taking gabapentin.Patients with scalp dysesthesia also had abnormal cervical spine images. Chronic muscle tension placed on the pericranial muscles and scalp aponeurosis secondary to the underlying cervical spine disease may lead to the symptoms of scalp dysesthesia.