tbuckley/cabot-search huggingface dataset:
Cardiac disorders, participation decisions and decision-making under legal uncertainty: a reply to Panhuyzen-Goedkoop and Smeets
Authors: Ryan M Rodenberg
Journal: British Journal of Sports Medicine (2014)

Panhuyzen-Goedkoop and Smeets1 provide an important primer at the intersection of cardiac disorders, decision-making and legal risk in sports medicine. The authors accurately flag the relevant issues and offer concrete suggestions. The purpose of this reply is to elaborate on one of the authors’ key findings and qualify another point through a more textured discussion.

The twin concern of false positives and false negatives permeates the authors’ article. Such an emphasis is well placed. The concern is particularly vexing in the context of cardiac disorders. It was illustrated in the tragic death and legal aftermath involving National Basketball Association player Reggie Lewis, a widely covered event that was recently marked by its 20th anniversary. The past two decades have left a ‘sports law legacy’2—one that all physicians practising in this area should be aware of. …
Cardiovascular Disease, Neuropathy, and Retinopathy
Authors: Zachary T. Bloomgarden
Journal: Diabetes Care (2009)

This is the sixth of a series of six articles based on presentations at the American Diabetes Association Scientific Sessions held 6–10 June 2008 in San Francisco, California.

### Role of glycemia in cardiovascular disease

Jacqueline Dekker (Amsterdam, the Netherlands) discussed the association between hyperglycemia and cardiovascular disease (CVD), particularly addressing A1C measurement in nondiabetic individuals. A1C, she noted, is considered a gold-standard measure of chronic glycemia in diabetic patients. In nondiabetic populations, its implications are somewhat less clear. In a study of 648 apparently healthy individuals, 12% had an elevated total A 1 level (measured in that study) not explained by measurement error or glucose intolerance and remaining in the same range over 3.5 years in 90% of those initially with high and in 68% of those initially with low baseline levels (1). There was no correlation with glucose tolerance, with caloric intake, or with physical activity, but A 1 level was associated with cigarette use and with clinically overt atherosclerosis, leading Dekker to conclude that “factors unrelated to glucose metabolism are the main determinants of A 1” in nondiabetic individuals, perhaps with bearing on risk of what are considered complications of diabetes. A subsequent study of 3,240 nondiabetic individuals showed weak correlation of A1C with fasting and 2-h glucose, cholesterol, and insulin. Weak but significant correlations were also found with erythrocyte characteristics, and cigarette use was associated with higher A1C, again suggesting nonglycemic effects on hemoglobin glycation (2). In the Islington Diabetes Survey, 1,084 participants had glucose tolerance tests and four different A1C assays. The 2-h postload glucose explained 19–41% of the variation in A1C, depending on the assay, and 26–48% of the variation was explained by the fasting glucose, with low and high glycators remaining constant over 4 years (3). If 50–80% is not explained by glycemia, the implication is, again, that although …
Neovascularisation is a prognostic factor of early recurrence in T1/G2 urothelial bladder tumours
Authors: L. Santos, C. Costa, S. Pereira, M. Koch, T. Amaro, F. Cardoso, T. Guimarães, M.J. Bento, F. Lobo, S. Pinto, C. Lopes
Journal: Annals of Oncology (2003)
Reduction of Raf-1 Kinase Inhibitor Protein Expression Correlates with Breast Cancer Metastasis
Authors: Suzanne Hagan, Fahd Al-Mulla, Elizabeth Mallon, Karin Oien, Rhona Ferrier, Barry Gusterson, Jorge J. Curto García, Walter Kolch
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Raf-1 kinase inhibitor protein (RKIP) was originally identified as the first physiologic inhibitor of the Raf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (ERK) pathway. This pathway regulates fundamental cellular functions, including those that are subverted in cancer cells, such as proliferation, transformation, survival, and metastasis. Recently, RKIP has been recognized as a strong candidate for a metastasis suppressor gene in cell and animal model systems. Therefore, we investigated whether RKIP expression is altered in clinical specimens of human primary breast cancers and their lymph node metastases. Experimental Design: Paraffin-embedded tumor samples from 103 breast cancer patients were examined immunohistochemically for the expression of RKIP, activated ERK, and apoptosis. The specificity of the antibodies used was validated by competition experiments with purified recombinant RKIP protein. Results: RKIP expression was high in breast duct epithelia and retained to varying degrees in primary breast tumors. However, in lymph node metastases, RKIP expression was highly significantly reduced or lost (P = 0.000003). No significant correlations were observed between RKIP expression and histologic type, tumor differentiation grade, size, or estrogen receptor status. Conclusion: This is the first study of RKIP expression in a large clinical cohort. It confirms the results of cell culture and animal studies, suggesting that in human breast cancer, RKIP is a metastasis suppressor gene whose expression must be down-regulated for metastases to develop. RKIP expression is independent of other markers for breast cancer progression and prognosis.
Culture of fetal cells from maternal blood for prenatal diagnosis
Authors: H. A. Elicha Gussin
Journal: Human Reproduction Update (2002)

The isolation and analysis of fetal cells from maternal blood would allow non-invasive prenatal genetic screening and diagnosis. Over the past decade, progress has been made towards this goal using various enrichment strategies and analysis by fluorescence in-situ hybridization with chromosome-specific probes and PCR. One method that is currently being explored involves culturing fetal cells. Developing conditions which allow the number of fetal-derived cells to expand in culture and the number of maternally derived cells to be suppressed in culture may lead to a new selection process for obtaining fetal cells. Culturing of fetal cells from maternal blood could make possible conventional metaphase analysis of fetal cells for diagnosis of chromosomal abnormalities.
Early Exercise Training Normalizes Myofilament Function and Attenuates Left Ventricular Pump Dysfunction in Mice With a Large Myocardial Infarction
Authors: Monique C. de Waard, Jolanda van der Velden, Virginie Bito, Semir Ozdemir, Liesbeth Biesmans, Nicky M. Boontje, Dick H.W. Dekkers, Kees Schoonderwoerd, Hans C.H. Schuurbiers, Rini de Crom, Ger J.M. Stienen, Karin R. Sipido, Jos M.J. Lamers, Dirk J. Duncker
Journal: Circulation Research (2007)

The extent and mechanism of the cardiac benefit of early exercise training following myocardial infarction (MI) is incompletely understood, but may involve blunting of abnormalities in Ca 2+ -handling and myofilament function. Consequently, we investigated the effects of 8-weeks of voluntary exercise, started early after a large MI, on left ventricular (LV) remodeling and dysfunction in the mouse. Exercise had no effect on survival, MI size or LV dimensions, but improved LV fractional shortening from 8±1 to 12±1%, and LVdP/dt P30 from 5295±207 to 5794±207 mm Hg/s (both P &lt;0.05), and reduced pulmonary congestion. These global effects of exercise were associated with normalization of the MI-induced increase in myofilament Ca 2+ -sensitivity (ΔpCa 50 =0.037). This effect of exercise was PKA-mediated and likely because of improved β 1 -adrenergic signaling, as suggested by the increased β 1 -adrenoceptor protein (48%) and cAMP levels (36%; all P &lt;0.05). Exercise prevented the MI-induced decreased maximum force generating capacity of skinned cardiomyocytes (F max increased from 14.3±0.7 to 18.3±0.8 kN/m 2 P &lt;0.05), which was associated with enhanced shortening of unloaded intact cardiomyocytes (from 4.1±0.3 to 7.0±0.6%; P &lt;0.05). Furthermore, exercise reduced diastolic Ca 2+ -concentrations (by ∼30%, P &lt;0.05) despite the unchanged SERCA2a and PLB expression and PLB phosphorylation status. Importantly, exercise had no effect on Ca 2+ -transient amplitude, indicating that the improved LV and cardiomyocyte shortening were principally because of improved myofilament function. In conclusion, early exercise in mice after a large MI has no effect on LV remodeling, but attenuates global LV dysfunction. The latter can be explained by the exercise-induced improvement of myofilament function.
Targeting Small Cell Lung Cancer Harboring <i>PIK3CA</i> Mutation with a Selective Oral PI3K Inhibitor PF-4989216
Authors: Marlena Walls, Sangita M. Baxi, Pramod P. Mehta, Kevin K.-C. Liu, JinJiang Zhu, Heather Estrella, Chunze Li, Michael Zientek, Qing Zong, Tod Smeal, Min-Jean Yin
Journal: Clinical Cancer Research (2013)

Constitutive activation of phosphoinositide 3-kinase (PI3K) occurs frequently in many human tumors via either gene mutation in the p110α catalytic subunit of PI3K or functional loss of tumor suppressor PTEN. Patients with small-cell lung cancer (SCLC) have very poor prognosis and survival rates such that an effective targeted therapy is in strong demand for these patients. In this study, we characterized the highly selective oral PI3K inhibitor, PF-4989216, in preclinical SCLC models to investigate whether targeting the PI3K pathway is an effective targeted therapy option for SCLCs that harbor a PIK3CA mutation.A panel of SCLC cell lines with PIK3CA mutation or PTEN loss were treated with PF-4989216 in several in vitro assays, including PI3K pathway signaling, cell viability, apoptosis, cell-cycle progression, and cell transformation. SCLC cell lines that were sensitive in vitro to PF-4989216 were further evaluated by in vivo animal studies to determine the pharmacokinetic/pharmacodynamic relationship and tumor growth inhibition (TGI) by PF-4989216 treatment.PF-4989216 inhibited PI3K downstream signaling and subsequently led to apoptosis induction, and inhibition in cell viability, transformation, and xenograft tumor growth in SCLCs harboring PIK3CA mutation. In SCLCs with PTEN loss, PF-4989216 also inhibited PI3K signaling but did not induce BCL2-interacting mediator (BIM)-mediated apoptosis nor was there any effect on cell viability or transformation. These results implicate differential tumorigenesis and apoptosis mechanisms in SCLCs harboring PIK3CA mutation versus PTEN loss.Our results suggest that PF-4989216 is a potential cancer drug candidate for patients with SCLC with PIK3CA mutation but not PTEN loss.
Stressing the stepchild: assessing right ventricular contractile reserve in pulmonary arterial hypertension
Authors: Brian A. Houston, Ryan J. Tedford
Journal: European Respiratory Journal (2015)

When Eugene Braunwald addressed the Right Heart Failure Summit in 2012, he echoed the sentiments of cardiologists throughout history by saying that he had "not paid [his] dues to the right ventricle" [1]. For years, the right ventricle was viewed as merely a conduit for transmitting blood to the lungs, a thought buttressed by the relatively preserved cardiac output seen in patients who underwent the Fontan operation [2]. In 1943, Starr et al. [3] found that venous pressure failed to augment after near-complete cauterisation of the right ventricular free wall, again supporting the concept that right ventricular function has very little effect on systemic venous pressure. What Starr et al. [3] failed to realise, but was later demonstrated by Damiano et al. [4], is that his model failed to account for the continued function of the interventricular septum, which was sufficient to propel blood through a pulmonary vascular circuit with normal resistance. Diminished right ventricular contractile reserve may improve prognostic assessment of PAH <http://ow.ly/GVHsg>
Connective Tissue Growth Factor and Regulation of the Mesangial Cell Cycle
Authors: Nadia Abdel Wahab, Benjamin S. Weston, Terry Roberts, Roger M. Mason
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. Connective tissue growth factor (CTGF) is now considered to be one of the important driver molecules for the pathogenesis of diabetic nephropathy (DN) and possibly many other fibrotic disorders. However, the molecular mechanisms by which CTGF functions remain to be established. In an attempt to define these mechanisms, this study was designed to investigate whether CTGF has any effect on the cell cycle of human mesangial cells (HMC), which are known to undergo hypertrophy in DN. This report provides the first evidence that CTGF is a hypertrophic factor for HMC. CTGF stimulates HMC to actively enter the G1 phase from G0, but they do not then progress further through the cell cycle. The molecular mechanisms underlying this G1 phase arrest appear to be due to the induction of the cyclin-dependent kinase inhibitors (CDKI) p15INK4, p21Cip1, and p27Kip1, which are known to bind and inactivate cyclinD/CDK4/6 and the cyclin E/CDK2 kinase complexes. This could account for the maintenance of pRb protein in a non- or very low-phosphorylated state, preventing cell cycle progression. Using CTGF antisense oligonucleotides, the results also indicate that the previously identified transforming growth factor–β (TGF-β)–induced hypertrophy in mesangial cells is CTGF-dependent. Mesangial cell hypertrophy is one of the earliest abnormalities of diabetic nephropathy; therefore, therapeutic strategies targeting CTGF may be beneficial in controlling DN. Email: [email protected]
Pharmacological Ascorbate Radiosensitizes Pancreatic Cancer
Authors: Juan Du, John A. Cieslak, Jessemae L. Welsh, Zita A. Sibenaller, Bryan G. Allen, Brett A. Wagner, Amanda L. Kalen, Claire M. Doskey, Robert K. Strother, Anna M. Button, Sarah L. Mott, Brian Smith, Susan Tsai, James Mezhir, Prabhat C. Goswami, Douglas R. Spitz, Garry R. Buettner, Joseph J. Cullen
Journal: Cancer Research (2015)

The toxicity of pharmacologic ascorbate is mediated by the generation of H2O2 via the oxidation of ascorbate. Because pancreatic cancer cells are sensitive to H2O2 generated by ascorbate, they would also be expected to become sensitized to agents that increase oxidative damage such as ionizing radiation. The current study demonstrates that pharmacologic ascorbate enhances the cytotoxic effects of ionizing radiation as seen by decreased cell viability and clonogenic survival in all pancreatic cancer cell lines examined, but not in nontumorigenic pancreatic ductal epithelial cells. Ascorbate radiosensitization was associated with an increase in oxidative stress-induced DNA damage, which was reversed by catalase. In mice with established heterotopic and orthotopic pancreatic tumor xenografts, pharmacologic ascorbate combined with ionizing radiation decreased tumor growth and increased survival, without damaging the gastrointestinal tract or increasing systemic changes in parameters indicative of oxidative stress. Our results demonstrate the potential clinical utility of pharmacologic ascorbate as a radiosensitizer in the treatment of pancreatic cancer.
Matrix metalloproteinase-9 (MMP-9) elevated in serum, but not in bronchial lavage in lung cancer patients
Authors: Melike Koç, Dane Ediger, Ferah Budak, Mehmet Karadag, Barbaros Oral, Esra Uzaslan, Ercument Ege, Oktay Gözü
Journal: European Respiratory Journal (2013)

Matrix metalloproteinase (MMP) family member MMP-9 degrade type IV collagen is one of the main constituents of the basement membrane and closely associated with the invasive and metastatic potential of most types of lung cancer. The first critical phase of malign tumor metastasis is the destruction and penetration of the basement membrane. In this study, we investigated serum and bronchial lavage fluid MMP-9 levels of lung cancer patients and compared them with non-malign patient cohort results. We also attempted to clarify the possible relationship between serum and bronchial lavage fluid MMP-9 levels and histopathology, staging and metastasis of lung cancer. Malign group consisted of 34 patients and non-malign lung disease group consisted of 21 patients as control group. MMP-9 levels in sera and lavage fluids were evaluated with ELISA method. The mean MMP-9 levels of serum samples in the malignant group were significantly higher than in the control group (p 0.05). MMP-9 levels of serum were two-fold higher than of bronchial lavage, but there was no correlation between both fluid in lung cancer and control groups (r=0.18, p>0.05). In malign group, there was significant correlation between the serum MMP-9 levels and local tumor stage in smoker non-small cell lung cancer (NSCLC) patients (r = 0.33,  p  p
Synergistic Effect of Cyclin D1 and c-Myc Leads to More Aggressive and Invasive Mammary Tumors in Severe Combined Immunodeficient Mice
Authors: Yong Wang, Archana Thakur, Yuan Sun, Jack Wu, Hector Biliran, Aliccia Bollig, D. Joshua Liao
Journal: Cancer Research (2007)

Abstract Cyclin D1 is one of the most commonly overexpressed oncogenes in breast cancer; yet, it is not clear whether cyclin D1 alone is capable of causing malignant transformation of mammary epithelial cells. Here, we show that ectopic expression of cyclin D1 in benign mouse mammary epithelial cells promotes cell proliferation, anchorage-independent growth in soft agar, and tumorigenesis in severe combined immunodeficient mice. To address the possible interaction of cyclin D1 and c-myc in malignant transformation, we used cyclin D1/c-myc dual-expressing clones, which displayed more aggressive and invasive phenotype than cyclin D1–expressing clones. These data provide evidence that overexpression of cyclin D1 or coexpression with c-myc could cause invasive malignant transformation of benign mouse mammary epithelial cells. Furthermore, microarray analysis of cyclin D1 and cyclin D1/c-myc clones showed that these two tumor-producing clones might use distinct invasive pathways. In summary, overexpression of cyclin D1 may commit mammary epithelia to a tumor-prone phenotype in which cooperation with other genes, such as synergy with c-myc, may lead to a more aggressive phenotype. [Cancer Res 2007;67(8):3698–707]
Gene expression of matrix metalloproteinases 1, 3, and 9 by chondrocytes in osteoarthritic human knee articular cartilage is zone and grade specific
Authors: A J Freemont, V Hampson, R Tilman, P Goupille, Y Taiwo, J A Hoyland
Journal: Annals of the Rheumatic Diseases (1997)

<h3>OBJECTIVES</h3> Matrix metalloproteinases (MMPs) are thought to be major mediators of cartilage destruction. Osteoarthritis (OA) is characterised by cartilage degradation. This study explores gene expression of three MMPs in articular chondrocytes during the histological development of the cartilage lesion of OA. <h3>METHODS</h3> Biopsy specimens of human normal and OA cartilage, classified into four grades on the basis of histology, were probed for MMPs 1, 3, and 9 using <sup>35</sup>S-labelled cDNA probes. The signal was measured at four different depths (zones) using an automated image analyser and compared with signal from sections probed with λDNA. Rheumatoid synovium was used as a positive control for MMP gene expression. <h3>RESULTS</h3> Rheumatoid tissue contained mRNA for all three MMPs. Expression in chondrocytes varied with the depth of the chondrocyte in the cartilage and the histomorphological extent of the OA changes. There was no detectable mRNA signal for these three MMPs in normal cartilage. In general, in OA, MMP-1 gene expression was greatest in the superficial cartilage in established disease. By contrast mRNAs for MMP-3 and 9 were expressed deeper in the cartilage, MMP-9 early in disease and MMP-3 with a biphasic pattern in early and late stage disease, most pronounced in the latter. This was a consequence of differential expression in single cells and chondrocyte clusters in late disease. <h3>CONCLUSION</h3> The data indicate that expression of genes for MMPs 1, 3, and 9 is differentially regulated in human articular chondrocytes and, in individual cells, is related to the depth of the chondrocyte below the cartilage surface and the nature and extent of the cartilage lesion.
ELECTROENCEPHALOGRAPHIC STUDIES IMMEDIATELY FOLLOWING HEAD INJURY
Authors: ROBERT S. DOW, GEORGE ULETT, JOHN RAAF
Journal: American Journal of Psychiatry (1944)

1. If mild cerebral trauma such as we were investigating produced changes in the electroencephalographic tracing the abnormality disappeared within a period of minutes in the vast majority of cases. 2. Patients who gave a history of amnesia following cerebral trauma, but were clear mentally at the time the EEG was taken, showed only a slight increase in the percentage of abnormal records as compared to the control series. This was true even when the records were taken within a few hours of the accident. 3. If there was an impairment of consciousness of any degree at the time the EEG was taken, abnormality in the EEG was the rule. 4. Electroencephalographic records taken within 30 minutes after patients sustained head injury showed a greater percentage of abnormality than those taken after 30 minutes had elapsed. The rapid disappearance of abnormal electroencephalographic findings points, in our opinion, to some mechanism in concussion other than petechial hemorrhage, cerebral contusion, embolic phenomenon, or any other histopathological change which must of necessity require several days to disappear. 5. In the patients with abnormal electroencephalographic records the average velocity of the striking object or of the falling head at the time of impact was greater than the velocity necessary to produce concussion in experimental animals as determined by others. The average velocity of the striking object or falling head in patients who showed normal or borderline electroencephalographic records was less than the velocity necessary to produce concussion in experimental animals. 6. The study of the electroencephalographic records taken immediately following mild head injury was less reliable than clinical judgment in predicting time loss from work. An ultimate opinion of the value of EEGs in this respect will depend upon a study of a group of more severely injured patients.