tbuckley/cabot-search huggingface dataset:
Oxaliplatin, fluorouracil, and leucovorin versus fluorouracil and leucovorin as adjuvant chemotherapy for locally advanced rectal cancer after preoperative chemoradiotherapy (ADORE): an open-label, multicentre, phase 2, randomised controlled trial
Authors: Yong Sang Hong, Byung-Ho Nam, Kyu-Pyo Kim, Jeong Eun Kim, Seong Joon Park, Young Suk Park, Joon Oh Park, Sun Young Kim, Tae-You Kim, Jee Hyun Kim, Joong Bae Ahn, Seok-Byung Lim, Chang Sik Yu, Jin Cheon Kim, Seong Hyeon Yun, Jong Hoon Kim, Jin-Hong Park, Hee Chul Park, Kyung Hae Jung, Tae Won Kim
Journal: The Lancet Oncology (2014)
Mining Methylation for Early Detection of Common Cancers
Authors: Romulo M Brena, Christoph Plass, Joseph F Costello
Journal: PLoS Medicine (2006)

Cancer is one of the most common causes of death worldwide. Lung cancer is the leading cause of cancer-related death worldwide [1], with a five-year survival rate of 10% in Europe and 15% in the United States [2,3]. Strikingly, for lung cancers detected in their early stage, the rate of recurrence within five years is less than 50%. When detected early, current therapies often cure common cancers, including those of the lung, breast, colon, rectum, stomach, and prostate [4]. Therefore, the development of reliable, noninvasive, and cost-effective early detection methods for common cancers is a priority of translational cancer research. Theoretically, a single method that detects multiple common cancer types at an early stage would have the biggest payoff for cancer control.
Cytoglobin, the Newest Member of the Globin Family, Functions as a Tumor Suppressor Gene
Authors: Narayan Shivapurkar, Victor Stastny, Naoki Okumura, Luc Girard, Yang Xie, Clemens Prinsen, Frederik B. Thunnissen, Ignacio I. Wistuba, Bogdan Czerniak, Eugene Frenkel, Jack A. Roth, Triantafillos Liloglou, George Xinarianos, John K. Field, John D. Minna, Adi F. Gazdar
Journal: Cancer Research (2008)

Abstract Cytoglobin (CYGB) is a recently discovered vertebrate globin distantly related to myoglobin with unknown function. CYGB is assigned to chromosomal region 17q25, which is frequently lost in multiple malignancies. Previous studies failed to detect evidence for mutations in the CYGB gene. Recent studies provided preliminary evidence for increased methylation of the gene in lung cancer. Our study was aimed at investigating the role of CYGB as a tumor suppressor gene. By nested methylation-specific DNA sequencing analysis of lung and breast cancer cell lines and bronchial and mammary epithelial cell lines, we identified that methylation of a 110-bp CpG-rich segment of the CYGB promoter was correlated with gene silencing. We specifically targeted this sequence and developed a quantitative methylation-specific PCR assay, suitable for high-throughput analysis. We showed that the tumor specificity of CYGB methylation in discriminating patients with and without lung cancer, using biopsies and sputum samples. We further showed the tumor specificity of this assay with multiple other epithelial and hematologic malignancies. To show tumor suppressor activity of CYGB, we performed the following: (a) RNA interference–mediated knockdown of CYGB gene on colony formation in a CYGB expression–positive lung cancer cell line, resulting in increased colony formation; (b) enforced gene expression in CYGB expression–negative lung and breast cancer cell lines, reducing colony formation; and (c) identification of potential proximate targets down-stream of the CYGB genes. Our data constitute the first direct functional evidence for CYGB, the newest member of the globin family, as a tumor suppressor gene. [Cancer Res 2008;68(18):7448–56]
Comprehending concussion: evolving and expanding our clinical insight
Authors: Michael Makdissi, Jon Patricios
Journal: British Journal of Sports Medicine (2015)

Concussion in sport has been defined as a “complex pathophysiological process affecting the brain, induced by biomechanical factors.”1 The condition is characterised by “a graded set of clinical symptoms that may or may not involve loss of consciousness.”1 

The current consensus definition provides a broad clinicopathological description of concussion. It encompasses the wide range of clinical presentations that result from traumatic forces transmitted to the brain. In its most literal interpretation, any post-traumatic symptom or sign fits the definition of concussion.2 Consequently, the current definition has high sensitivity, but lacks specificity. This issue has been highlighted in recent papers.3 

The purpose of ‘casting a large net’ is to capture all possible concussions and manage these injuries conservatively. This position is driven by the lack of reliable and specific diagnostic markers, and concerns related to potential complications associated with concussion. Compounding this, risk factors for complications remain unclear and currently there are few prognostic factors to accurately predict outcomes following concussion.4 

From the athletes’ perspective, a significant downside to the broad definition of concussion is the major time …
Myosin Light Chain Phosphorylation in Neutrophil-Stimulated Coronary Microvascular Leakage
Authors: Sarah Y. Yuan, Mack H. Wu, Elena E. Ustinova, Mingzhang Guo, John H. Tinsley, Primal de Lanerolle, Wenjuan Xu
Journal: Circulation Research (2002)

Neutrophil-induced coronary microvascular leakage represents an important pathophysiological consequence of ischemic and inflammatory heart diseases. The precise mechanism by which neutrophils regulate endothelial barrier function remains to be established. The aim of this study was to examine the microvascular endothelial response to neutrophil activation with a focus on myosin light chain kinase (MLCK)-mediated myosin light chain (MLC) phosphorylation, a regulatory process that controls cell contraction. The apparent permeability coefficient of albumin (Pa) was measured in intact isolated porcine coronary venules. Incubation of the vessels with C5a-activated neutrophils induced a time- and concentration-dependent increase in Pa. The hyperpermeability response was significantly attenuated during inhibition of endothelial MLC phosphorylation with the selective MLCK inhibitor ML-7 and transfection of a specific MLCK-inhibiting peptide. In contrast, transfection of constitutively active MLCK elevated Pa, which was abolished by ML-7. In addition to the vessel study, albumin transendothelial flux was measured in cultured bovine coronary venular endothelial monolayers, which displayed a hyperpermeability response to neutrophils and MLCK in a pattern similar to that in venules. Importantly, neutrophil stimulation caused MLC phosphorylation in endothelial cells in a time course closely correlated with that of the hyperpermeability response. Consistently, the MLCK inhibitors abolished neutrophil-induced MLC phosphorylation. Furthermore, immunohistochemical observation of neutrophil-stimulated endothelial cells revealed an increased staining for phosphorylated MLC in association with contractile stress fiber formation and intercellular gap development. Taken together, the results suggest that endothelial MLCK activation and MLC phosphorylation play an important role in mediating endothelial barrier dysfunction during neutrophil activation.
Rat mesangial cells and matrix metalloproteinase inhibitor
Authors: K Steinmann-Niggli, M Lukes, H P Marti
Journal: Journal of the American Society of Nephrology (1997)

The synthetic inhibitor of matrix metalloproteinases (MMP) Ro 31-9790, a hydroxamic-acid derivative, was investigated for its effect on rat mesangial cells (MC) in culture. For these studies, proliferating MC with a high degree of constitutive expression of a MMP, the 72-kD Type IV collagenase (gelatinase A, MMP-2), were chosen, because they reflect aspects of an inflammatory phenotype that may occur during certain forms of glomerular inflammatory diseases. Ro 31-9790 inhibited activity of the rat MC MMP-2 in a concentration-dependent and competitive fashion, as analyzed by quantitative densitometry and by a continuously recording fluorescent assay. Furthermore, Ro 31-9790 inhibited the proliferation rate of cultured rat MC in a concentration-dependent and at least partially reversible manner without affecting cell viability. It was concluded that the application of synthetic MMP inhibitors may offer a new perspective for the therapy of mesangial cell-derived forms of glomerulonephritis.
Coordinate Activation of Activator Protein 1 and Inflammatory Cytokines in Response to <i>Neisseria gonorrhoeae</i> Epithelial Cell Contact Involves Stress Response Kinases
Authors: Michael Naumann, Thomas Rudel, Björn Wieland, Cornelia Bartsch, Thomas F. Meyer
Journal: The Journal of Experimental Medicine (1998)

Neisseria gonorrhoeae (Ngo), the etiologic agent of gonorrhea, induce a number of proinflammatory cytokines by contact to epithelial cells. Cytokine genes and a variety of other immune response genes are activated as a result of the regulatory function of immediate early response transcription factors including activator protein 1 (AP-1). Since it is established that phosphorylation of c-Jun, the central component of AP-1, by the stress-activated c-Jun NH2-terminal kinase (JNK) increases the transcriptional activity of AP-1, we studied whether Ngo could induce stress response pathways involving JNK. We found that virulent Ngo strains induce phosphorylation and activation of JNK but not of p38 kinase. Analysis of a nonpathogenic Ngo strain revealed only weak JNK activation. In respect to the molecular components upstream of the JNK signaling cascade, we show that a dominant negative mutant of MAP kinase kinase 4 (MKK4) represses transcription of an AP-1–dependent reporter gene. Regarding upstream stress response factors involved in Ngo-induced MKK4/JNK/AP-1 activation, we identified p21-activated kinase (PAK) but not MAPK/ERK kinase kinase (MEKK1). Inhibition of small GTPases including Rac1 and Cdc42 by Toxin B prevented JNK and AP-1 activation. Our results indicate that Ngo induce the activation of proinflammatory cytokines via a cascade of cellular stress response kinases involving PAK, which directs the signal from the Rho family of small GTPases to JNK/AP-1 activation.
DEMYELINIZATION INDUCED IN THE BRAINS OF MONKEYS BY MEANS OF FAST NEUTRONS
Authors: F. Stephen Vogel, John E. Pickering
Journal: The Journal of Experimental Medicine (1956)

Demyelinization was regularly conspicuous in the white matter of the rostral portions of the brains of 6 monkeys sacrificed 14 to 22 months after exposure of the ocular regions to 850 r.e.p. of 14 mev. neutron radiation and it was not present in the brain of a monkey 2 months after radiation under identical conditions; or in those of 5 non-radiated animals serving as controls. In early lesions, the individual myelin sheaths were varicose and fragmented, while the neurons, axons, and glial cells remained normal in appearance. With the passage of time, the degeneration of myelin became more marked and in later stages was accompanied by a degeneration of the axis cylinders, a proliferation of astrocytes and microglia, and minor cytological changes in the oligodendroglia, the whole process occurring essentially without inflammation or notable changes in the cerebral or meningeal blood vessels. The findings show that neutron radiation has the property of destroying myelin in the living animal and inducing changes that are notably similar in their pathogenesis to those that characterize disseminated encephalomyelitis in human beings.
Induction of specific nonresponsiveness in unprimed human T cells by anti-CD3 antibody and alloantigen.
Authors: C Anasetti, P Tan, J A Hansen, P J Martin
Journal: The Journal of Experimental Medicine (1990)

Fresh peripheral blood mononuclear cells exposed to alloantigen for 3-8 d in the presence of anti-CD3 antibodies showed no response after restimulation with cells from the original donor but remained capable of responding to third-party donors. Antigen-specific nonresponsiveness was induced by both nonmitogenic and mitogenic anti-CD3 antibodies but not by antibodies against CD2, CD4, CD5, CD8, CD18, or CD28. Nonresponsiveness induced by anti-CD3 antibody in mixed leukocyte culture was sustained for at least 34 d from initiation of the culture and 26 d after removal of the antibody. Anti-CD3 antibody also induced antigen-specific nonresponsiveness in cytotoxic T cell generation assays. Anti-CD3 antibody did not induce nonresponsiveness in previously primed cells. Nonresponsiveness induced by anti-CD3 did not appear to be associated with suppressor cell activation. Thus, co-stimulation of the T cell receptor-CD3 complex on unprimed T cells with a fluid phase anti-CD3 antibody and allogenic major histocompatibility complex antigens can induce either clonal anergy or clonal deletion. These results suggest novel approaches for achieving transplantation tolerance.
Exercise and cognition in older adults: is there a role for resistance training programmes?
Authors: T Liu-Ambrose, M G Donaldson
Journal: British Journal of Sports Medicine (2008)

In recent years, there has been a strong interest in physical activity as a primary behavioural prevention strategy against cognitive decline. A number of large prospective cohort studies have highlighted the protective role of regular physical activity in lowering the risk of cognitive impairment and dementia. Most prospective intervention studies of exercise and cognition to date have focused on aerobic-based exercise training. These studies highlight that aerobic-based exercise training enhances both brain structure and function. However, it has been suggested that other types of exercise training, such as resistance training, may also benefit cognition. The purpose of this brief review is to examine the evidence regarding resistance training and cognitive benefits. Three recent randomised exercise trials involving resistance training among seniors provide evidence that resistance training may have cognitive benefits. Resistance training may prevent cognitive decline among seniors via mechanisms involving insulin-like growth factor I and homocysteine. A side benefit of resistance training, albeit a very important one, is its established role in reducing morbidity among seniors. Resistance training specifically moderates the development of sarcopenia. The multifactorial deleterious sequelae of sarcopenia include increased falls and fracture risk as well as physical disability. Thus, clinicians should consider encouraging their clients to undertake both aerobic-based exercise training and resistance training not only for “physical health” but also because of the almost certain benefits for “brain health”.
Allelic Variation of MHC Structure Alters Peptide Ligands to Induce Atypical Partial Agonistic CD8+ T Cell Function
Authors: Dong-Gyun Lim, Jacqueline M. Slavik, Katarzyna Bourcier, Kathrine J. Smith, David A. Hafler
Journal: The Journal of Experimental Medicine (2003)

T cell receptors recognize small changes in peptide ligands leading to different T cell responses. Here, we analyzed a panel of HLA-A2–Tax11-19 reactive T cell clones to examine how small allelic variations of MHC molecules could alter the functional outcome of antigen recognition. Similar to the effects induced by antigenic altered peptide ligands, weak or partial agonistic T cell functions were identified in individual T cell clones with the recognition of MHC-altered peptide ligands (MAPLs). Interestingly, one subtype of HLA-A2 molecules induced an unusual type of partial agonistic function; proliferation without cytotoxicity. Modeling of crystallographic data indicated that polymorphic amino acids in the HLA-A2 peptide binding groove, especially the D-pocket, were responsible for this partial agonism. Reciprocal mutations of the Tax peptide side chain engaging the D-pocket indeed restored the agonist functions of the MHC–peptide complex. Whereas early intracellular signaling events were not efficiently induced by these MAPLs, phosphorylated c-Jun slowly accumulated with sustained long-term expression. These data indicate that MAPLs can induce atypical partial agonistic T cell function through structural and biochemical mechanisms similar to altered peptide ligands.
Insights into the Evolution of Mitochondrial Genome Size from Complete Sequences of Citrullus lanatus and Cucurbita pepo (Cucurbitaceae)
Authors: A. J. Alverson, X. Wei, D. W. Rice, D. B. Stern, K. Barry, J. D. Palmer
Journal: Molecular Biology and Evolution (2010)

The mitochondrial genomes of seed plants are unusually large and vary in size by at least an order of magnitude. Much of this variation occurs within a single family, the Cucurbitaceae, whose genomes range from an estimated 390 to 2,900 kb in size. We sequenced the mitochondrial genomes of Citrullus lanatus (watermelon: 379,236 nt) and Cucurbita pepo (zucchini: 982,833 nt)—the two smallest characterized cucurbit mitochondrial genomes—and determined their RNA editing content. The relatively compact Citrullus mitochondrial genome actually contains more and longer genes and introns, longer segmental duplications, and more discernibly nuclear-derived DNA. The large size of the Cucurbita mitochondrial genome reflects the accumulation of unprecedented amounts of both chloroplast sequences (>113 kb) and short repeated sequences (>370 kb). A low mutation rate has been hypothesized to underlie increases in both genome size and RNA editing frequency in plant mitochondria. However, despite its much larger genome, Cucurbita has a significantly higher synonymous substitution rate (and presumably mutation rate) than Citrullus but comparable levels of RNA editing. The evolution of mutation rate, genome size, and RNA editing are apparently decoupled in Cucurbitaceae, reflecting either simple stochastic variation or governance by different factors.
Specific antimononuclear phagocyte monoclonal antibodies. Application to the purification of dendritic cells and the tissue localization of macrophages.
Authors: W C Van Voorhis, R M Steinman, L S Hair, J Luban, M D Witmer, S Koide, Z A Cohn
Journal: The Journal of Experimental Medicine (1983)

3C10 and 1D9 are two related monoclonal antibodies that specifically identify human mononuclear phagocytes in a large number of sites, including blood monocytes, alveolar macrophages, and macrophages in tissue sections of spleen, lymph node, and skin. The antigen persists on monocytes cultured for greater than 4 wk, but it is not found on giant cells. The 3C10-1D9 determinant is carried by a 55 kD polypeptide, is expressed at approximately 40,000 copies per monocyte, and is protease sensitive. The antigen is clearly different from HLA-class II or Ia-like antigens that have been studied with a new monoclonal 9.3F10. The 9.3F10 antigen is found on B cells, dendritic cells and monocytes; is protease resistant, and occurs on a 33-29 kD doublet typical of class II products. The 3C10 monoclonal provides a clear distinction between human mononuclear phagocytes and dendritic cells. First, monocytes and lymphocytes can be eliminated from plastic-adherent mononuclear cells using 3C10, complement, and two previously described cytotoxic antibodies, BA-1 (anti-B cell) and Leu-1 (anti-T cell). As a result, the trace dendritic cell component of blood can be enriched to considerable purity (65-75%) and yield. Second, immunocytochemical staining of tissue sections reveals that 3C10+ macrophages are anatomically segregated from dendritic cells. Large numbers of 3C10+ cells are found in red pulp of spleen and in regions surrounding lymphatic channels of lymph node. However, 3C10+ macrophages are scarce in white pulp of spleen and the lymphocyte-rich cortex of node that are the sites where dendritic cells are localized. 3C10+ cells in skin are found in the dermis, particularly in leprosy infiltrates, but the Langerhans' cells of epidermis are 3C10-. The distinctive localization of macrophages and dendritic cells is consistent with their respective functions as effector and accessory cells in the immune response.
Case number 31: Nodular panniculitis as expression of Munchausen's syndrome (panniculitis artefacta)
Authors: A-K Tausche
Journal: Annals of the Rheumatic Diseases (2004)

A 45 year old woman presented with a 4 year history of fever attacks, generalised fatigue, arthralgias, and recurring painful nodules of the subcutaneous tissue in different localisations. Extensive diagnostic procedures had been carried out in several rheumatological and dermatological departments of university hospitals (13 admissions). Under the diagnosis of nodular panniculitis and because of the deep infiltration, incisions and surgical debridement were often necessary. At the physical examination she had a temperature over 39°C, an approximately plum sized painful nodule in the subcutaneous tissue of the left shoulder, and ulcerations of the left hand and elbow (after surgical debridement) (fig 1).



 Figure 1  
 Painful deep nodule—left shoulder.



Laboratory tests showed a raised white cell count of 11.6×109 …
Risk factors for hypoglycaemia in neurocritical care patients
Authors: Freya M. van Iersel, Arjen J. C. Slooter, Renee Vroegop, Annemiek E. Wolters, Charlotte A. M. Tiemessen, Rik H. J. Rösken, Johannes G. van der Hoeven, Linda M. Peelen, Cornelia W. E. Hoedemaekers
Journal: Intensive Care Medicine (2012)
Strong Evidence of a Genetic Determinant for Mammographic Density, a Major Risk Factor for Breast Cancer
Authors: Celine M. Vachon, Thomas A. Sellers, Erin E. Carlson, Julie M. Cunningham, Christopher A. Hilker, Regenia L. Smalley, Daniel J. Schaid, Linda E. Kelemen, Fergus J. Couch, V. Shane Pankratz
Journal: Cancer Research (2007)

Abstract Increased mammographic density (MD), the proportion of dense tissue visible on a mammogram, is a strong risk factor for breast cancer, common in the population and clusters in families. We conducted the first genome-wide linkage scan to identify genes influencing MD. DNA was obtained from 889 relatives (756 women, 133 men) from 89 families. Percent MD was estimated on 618 (82%) female family members using a validated computer-assisted thresholding method. The genome-wide scan included 403 microsatellite DNA markers with an average spacing of 9 cM. Fine mapping of a region of chromosome 5p (5p13.1-5p15.1) was done using 21 additional closely spaced DNA markers. Linkage analyses were conducted to quantify the evidence for a gene responsible for MD across the genome. The maximum log odds for linkage (LOD) score from the genome-wide scan was on chromosome 5p (LOD = 2.9, supporting linkage by a factor of 102.9 or 794 to 1) with a 1-LOD interval spanning 28.6 cM. Two suggestive regions for linkage were also identified on chromosome 12 (LOD = 2.6, 1-LOD interval of 14.8 cM; and LOD = 2.5, 1-LOD interval of 17.2 cM). Finer mapping of the region surrounding the maximum LOD on chromosome 5p resulted in stronger and statistically significant evidence for linkage (LOD = 4.2) and a narrowed 1-LOD interval (13.4 cM). The putative locus on chromosome 5p is likely to account for up to 22% of variation in MD. Hence, 1 or more of the 45 candidate genes in this region could explain a large proportion of MD and, potentially, breast cancer. [Cancer Res 2007;67(17):8412–8]
Cold and hot cognition: Quantum probability theory and realistic psychological modeling
Authors: Philip J. Corr
Journal: Behavioral and Brain Sciences (2013)

Abstract Typically, human decision making is emotionally “hot” and does not conform to “cold” classical probability (CP) theory. As quantum probability (QP) theory emphasises order, context, superimposition states, and nonlinear dynamic effects, one of its major strengths may be its power to unify formal modeling and realistic psychological theory (e.g., information uncertainty, anxiety, and indecision, as seen in the Prisoner's Dilemma).