tbuckley/cabot-search huggingface dataset:
Molecular pathologic substaging in 244 stage I non-small-cell lung cancer patients: clinical implications.
Authors: D J Kwiatkowski, D H Harpole, J Godleski, J E Herndon, D B Shieh, W Richards, R Blanco, H J Xu, G M Strauss, D J Sugarbaker
Journal: Journal of Clinical Oncology (1998)

PURPOSE To retrospectively construct a comprehensive multivariate model of cancer recurrence and to design a molecular pathologic substaging system in stage I non-small-cell lung cancer (NSCLC). METHODS All patients with stage I NSCLC resected at Brigham and Women's Hospital (Boston, MA) between 1984 and 1992 with adequate clinical follow-up were studied. The importance of three demographic characteristics, surgical extent, 11 pathologic features, and seven molecular factors on cancer-free survival was examined. RESULTS Two hundred forty-four patients were studied, with 25 noncancer deaths and 80 patients with recurrent disease. Significant univariate predictors (P &lt; .05) of cancer recurrence were age older than 60 years, male sex, wedge resection, World Health Organization (WHO) adenocarcinoma subtype solid tumor with mucin, lymphatic invasion, and p53 expression. Multivariate analysis identified nine independent predictors of recurrence: solid tumor with mucin, a wedge resection, tumor diameter of 4 cm or greater, lymphatic invasion, age older than 60 years, male sex, p53 expression, K-ras codon 12 mutation, and absence of H-ras p21 expression. Multivariate cancer-free survival (CFS) analysis in the 180 patients who underwent lobectomy or pneumonectomy led to the elimination of sex and age, which left six independent factors. CONCLUSION Lobectomy or pneumonectomy should be performed in stage I NSCLC. Using the six independent factors for recurrent disease, we propose a pathologic molecular substaging system. Patients with two factors or less are graded Ia, with a 5-year CFS rate of 87%; those with three factors are graded Ib, with a 5-year CFS rate of 58%; and those with four factors or more are graded Ic, with a 5-year CFS rate of 21%.
CONJUGATION OF SULFOBROMOPHTHALEIN SODIUM WITH GLUTATHIONE IN THIOETHER LINKAGE BY THE RAT *
Authors: Burton Combes, Geneva Sue Stakelum
Journal: Journal of Clinical Investigation (1960)

Most of the sulfobromophthalein sodium (BSP) appearing in the bile of man, rat, dog, sheep and cat differs chromatographically from the free BSP originally administered (1-4).The altered BSP compounds in man, rat and dog appear to be anmino acid conjugates (2)(3)(4).Thus, after hydrolysis of the major BSP compounds with 6 N HC1, several amino acids have been detected by filter paper chromatography.Glycine, glutamic acid and ala- nine were identified in man (2, 3), glycine and glutamic acid in the rat (2) and glycine in the dog (3).Recently, in a preliminary report, Javitt.Wheeler, Baker and Ramiios (5) suggested that BSP appears in bile of the dog as a conjugate of glutathione.These authors found glycine, glu- tamic acid and evidence of free sulfhydryl groups, as miianifested by a positive sodium azide-iodine reaction, after alkaline hydrolysis of the major BSP conjugates.Occasionally, cysteine was de- tectable.BSP conjugates formed in vitro by ad- mixture of BSP and glutathione were identical electrophoretically and chromatographically with conjugates found in bile.Cysteine has also been identified in human BSP conjugates by Grodsky, Carbone and Fanska (4).Cysteine was difficult to detect after hydrolysis with concentrated HCI, but was more clearly demonstrated when the BSP compounds were hydrolyzed with HBr.Glycine and glutamic acid were also detected after hydrolysis of the BSP conjugates.However, these amino acids were found in hydrolysates of control bile processed in the same fashion as BSP bile.There- fore, these authors regarded glycine and glutamic
Fatal Inhalational Anthrax With Unknown Source of Exposure in a 61-Year-Old Woman in New York City
Authors: Bushra Mina, J P Dym, Frank Kuepper, Raymond Tso, Carmina Arrastia, Irina Kaplounova, Hasan Faraj, Agnieszka Kwapniewski, Christopher M Krol, Mayer Grosser, Jeffrey Glick, Steven Fochios, Athena Remolina, Ljiljana Vasovic, Jeffrey Moses, Thomas Robin, Maria DeVita, Michael L Tapper
Journal: JAMA (2002)

A 61-year-old woman who was a New York City hospital employee developed fatal inhalational anthrax, but with an unknown source of anthrax exposure. The patient presented with shortness of breath, malaise, and cough that had developed 3 days prior to admission. Within hours of presentation, she developed respiratory failure and septic shock and required mechanical ventilation and vasopressor therapy. Spiral contrast-enhanced computed tomography of the chest demonstrated large bilateral pleural effusions and hemorrhagic mediastinitis. Blood cultures, as well as DNA amplification by polymerase chain reaction of the blood, bronchial washings, and pleural fluid specimens, were positive for Bacillus anthracis. The clinical course was complicated by liver failure, renal failure, severe metabolic acidosis, disseminated intravascular coagulopathy, and cardiac tamponade, and the patient died on the fourth hospital day. The cause of death was inhalational anthrax. Despite epidemiologic investigation, including environmental samples from the patient's residence and workplace, no mechanism for anthrax exposure has been identified.
Tumor necrosis factor is a critical mediator in hapten induced irritant and contact hypersensitivity reactions.
Authors: P F Piguet, G E Grau, C Hauser, P Vassalli
Journal: The Journal of Experimental Medicine (1991)

We examined the role of cytokines in the cutaneous response to the application of trinitrochlorobenzene (TNCB) in both nonsensitized and sensitized mice, i.e., in the irritant reaction (IR) and contact hypersensitivity reactions (CH). When administered immediately before challenge, anti-tumor necrosis factor (TNF) antibody abrogated the ear swelling response in CH; antibody directed against interferon gamma or antibodies to both granulocyte/macrophage colony-stimulating factor and interleukin 3 (IL-3) had a partial inhibitory effect; anti-IL-2 receptor antibody had no effect. Anti-TNF prevented the various features of the CH, as seen on histological sections, e.g., leukocyte infiltration and hemorrhages within the dermis and keratinocytes necrosis. Anti-TNF antibody also prevented the IR. The presence of TNF mRNA was evaluated on Northern blots; TNF-alpha mRNA was detectable in an untreated ear, increased after the application of TNCB in nonsensitized mice, and was highest in sensitized mice. TNF mRNA accumulation, which was evident 0.5 h after hapten application and lasted greater than 72 h, was abolished by treatment with anti-TNF antibody, thus suggesting an auto-amplification of TNF production. The cellular origin of TNF mRNA was explored by in situ hybridization; basal keratinocytes showed the highest labeling, but TNF mRNA was also detectable in cells of the dermal infiltrate. After hapten (TNCB) application at sites susceptible (the ear) or resistant (the foot pad) to CH or IR, a close correlation was observed between TNF mRNA accumulation and the intensity of the inflammatory reaction. The major role played by TNF in both the CH and the IR explains the histologically similar aspects of these reactions and the extreme variability of these reactions at various anatomical sites.
Intestinal antibody pattern of coeliac disease: association with gamma/delta T cell receptor expression by intraepithelial lymphocytes, and other indices of potential coeliac disease.
Authors: E Arranz, J Bode, K Kingstone, A Ferguson
Journal: Gut (1994)

Patients with coeliac disease have IgM antibodies and IgA anti-gliadin antibody in gut secretions, and also high counts of intraepithelial lymphocytes (IEL) that express the gamma/delta T cell receptor. These features of intestinal immunity may be markers of latent coeliac disease. Their occurrence was examined in 77 patients referred for jejunal biopsy, in whom biopsy histology was normal, to establish the extent to which these, and other candidate markers (high total IEL count, serum IgA anti-gliadin antibody (AGA), and increased permeability) coexist in the same patient. Twelve patients had high serum anti-gliadin antibody titres and nine increased permeability. The gamma/delta IEL count was high (> 5.5 per mm villus epithelium) in nine patients, the intestinal antibody pattern was positive in 21, and the total IEL count was high (> 40 per 100 enterocytes) in 13. Overall, 31 patients had positive indices, but in 19 only a single test was abnormal. High gamma/delta IEL counts were found in six of 21 intestinal antibody positive patients, but in only two of 56 who were intestinal antibody negative (p < 0.001); there were no other significant associations. Clinical tests of gluten sensitivity will be required to establish the prevalence of latent gluten sensitive enteropathy in the 40% of patients referred for jejunal biopsy in whom one or more of the immunological indices of potential coeliac disease is present.
Inhibition of Melanoma Growth and Metastasis by ATF2-Derived Peptides
Authors: Anindita Bhoumik, Lisa Gangi, Ze’ev Ronai
Journal: Cancer Research (2004)

Abstract The resistance of melanoma to apoptosis, as well as its growth and metastasis capabilities, can be overcome by expression of a peptide derived from amino acid (aa) 51 to 100 of ATF2. Here we show that expression of ATF2(51–100) in human melanoma cells reduced their growth in nude mice, which was additionally inhibited upon treatment with protein kinase inhibitors UCN-01 or SB203580. Injection of a fusion protein consisting of HIV-TAT and aa 51 to 100 of ATF2 into SW1 melanomas efficiently inhibits their growth and their metastasis up to complete regression. Additionally, expression of a 10aa peptide that corresponds to aa 51 to 60 of ATF2 sensitizes melanoma cells to spontaneous apoptosis, which coincides with activation of caspase 9 and poly(ADP-ribose) polymerase cleavage, and inhibit their growth in vivo. The 10aa peptide increases the association of c-Jun NH2-terminal kinase with c-Jun but not with ATF2, resulting in concomitant increase in TRE-mediated transcription. Our study points to mechanisms underlying the activities of the ATF2 peptide while highlighting its possible use in drug design.
Histaminase release from human granulocytes.
Authors: R S Zeiger, F J Twarog, H R Colten
Journal: The Journal of Experimental Medicine (1976)

Histaminase (EC-1.4.3.6), one of the two catabolic enzymes for histamine, is contained in human granulocytes. Opsonized zymosan or the calcium ionophore A-23187 induce a dose-dependent release of histaminase from human granulocytes in vitro. Release is completed within 30 min, is temperature dependent, and requires divalent cations. Opsonized zymosan-induced histaminase release was maximal in the presence of both calcium and magnesium, whereas ionophore release was magnesium independent. The total cellular content of histaminase could be released by both opsonized zymosan and ionophore. In contrast, only 25% of the cellular beta glucuronidase, a lysosomal enzyme, was released after maximal stimulation with opsonized zymosan; there was minimal release of beta glucuronidase with ionophore. Zymosan- and ionophore-induced histaminase release was inhibited by agents that are presumed to interfere with cell metabolism and disrupt microtubules. Human granulocytes therefore may modulate the effect of histamine by releasing histaminase at a site of inflammation. Studies of granulocyte histaminase release in vitro may also provide a new model to explore granulocyte function and secretion.
Spatial patterns of transcriptional activity in the chromosome of Escherichia coli.
Authors: Kyeong Soo Jeong, Jaeyong Ahn, Arkady B Khodursky
Journal: Genome biology (2004)

Abstract Background Although genes on the chromosome are organized in a fixed order, the spatial correlations in transcription have not been systematically evaluated. We used a combination of genomic and signal processing techniques to investigate the properties of transcription in the genome of Escherichia coli K12 as a function of the position of genes on the chromosome. Results Spectral analysis of transcriptional series revealed the existence of statistically significant patterns in the spatial series of transcriptional activity. These patterns could be classified into three categories: short-range, of up to 16 kilobases (kb); medium-range, over 100-125 kb; and long-range, over 600-800 kb. We show that the significant similarities in gene activities extend beyond the length of an operon and that local patterns of coexpression are dependent on DNA supercoiling. Unlike short-range patterns, the formation of medium and long-range transcriptional patterns does not strictly depend on the level of DNA supercoiling. The long-range patterns appear to correlate with the patterns of distribution of DNA gyrase on the bacterial chromosome. Conclusions Localization of structural components in the transcriptional signal revealed an asymmetry in the distribution of transcriptional patterns along the bacterial chromosome. The demonstration that spatial patterns of transcription could be modulated pharmacologically and genetically, along with the identification of molecular correlates of transcriptional patterns, offer for the first time strong evidence of physiologically determined higher-order organization of transcription in the bacterial chromosome.
Correlation between [5-3H]glucose and [U-14C]deoxyglucose as markers of glycolysis in reperfused myocardium.
Authors: A J Liedtke, B Renstrom, S H Nellis
Journal: Circulation Research (1992)

Studies were conducted in extracorporeally perfused, intact, working pig hearts to determine whether, in heart muscle, trace-labeled deoxyglucose serves as an accurate marker of glycolytic flux in reperfusion after exposures to mild to moderate regional ischemia. In the main study, two groups of hearts were compared, as distinguished by levels of glucose in the whole-blood perfusate (euglycemic hearts [group I], blood glucose of 7.4 +/- 0.2 mumol/ml, n = 7; hyperglycemic hearts [group II], blood glucose of 12.9 +/- 0.5 mumol/ml, n = 8). Both groups were subjected to a 60% reduction in anterior descending coronary flow for 30 minutes followed by reperfusion for 40 minutes. Modest and comparable regional mechanical stunning during reflow was noted in both groups. Glucose utilization, as estimated from the release of 3H2O from the steady-state infusion of [5-3H]glucose during aerobic perfusion, was modest but during reperfusion was noted to increase significantly above aerobic values in each of the two groups, with a doubling of rates in group II hearts compared with group I hearts (p less than 0.041 or p less than 0.090). Net lactate extraction was comparable in reflow in both groups, suggesting in this specific instance a preferential enhancement of glucose oxidation in hyperglycemic group II hearts. Shifts in accumulation of tissue radioactivity of [U-14C]2-deoxyglucose in reperfused myocardium were not able to track these trends. The variability of 14C-labeled radioactivity among animals was marked and essentially masked any ability to discern trends in glycolysis as described by tritiated glucose between the aerobic and reperfusion intervals. When the data were arrayed by linear regression analysis, the slopes derived from 14C-labeled deoxyglucose were either discordant or insensitive to those described by 3H-labeled glucose. Tissue glycogen levels were slow to recover in early reflow and at end reperfusion were still significantly depressed from aerobic levels. The present data indicate that coronary reperfusion and hyperglycemia have influence in determining glycolytic flux in myocardium. Labeled deoxyglucose, considered solely as a marker of exogenous glucose utilization, appears to be an insensitive agent in describing these events at conditions of relatively low glucose flux.
Acute Pain Management for Patients Receiving Maintenance Methadone or Buprenorphine Therapy
Authors: Daniel P. Alford, Peggy Compton, Jeffrey H. Samet
Journal: Annals of Internal Medicine (2006)

More patients with opioid addiction are receiving opioid agonist therapy (OAT) with methadone and buprenorphine. As a result, physicians will more frequently encounter patients receiving OAT who develop acutely painful conditions, requiring effective treatment strategies. Undertreatment of acute pain is suboptimal medical treatment, and patients receiving long-term OAT are at particular risk. This paper acknowledges the complex interplay among addictive disease, OAT, and acute pain management and describes 4 common misconceptions resulting in suboptimal treatment of acute pain. Clinical recommendations for providing analgesia for patients with acute pain who are receiving OAT are presented. Although challenging, acute pain in patients receiving this type of therapy can effectively be managed.
Implementation and dissemination research: the time has come!
Authors: Caroline F Finch
Journal: British Journal of Sports Medicine (2011)

In a provocative statement in a very recent issue of the American Journal of Preventive Medicine , Kessler and Glasgow have called for a 10-year moratorium on efficacy randomised controlled trials (RCTs) in health and health services research.1 The authors argue that much intervention research has had minimal impact on both policy and practice because the very nature of efficacy studies means that focus has had to be on a limited number of specific causal and preventive factors; this ignores both the complexity of real-world implementation and the multilevel ecological context in which interventions need to be conducted. I have also previously discussed those same limitations as they apply to sports injury prevention studies,2 3 most recently as part of my keynote address at the 2011 International Olympic Committee World Conference on The Prevention of Injury and Illness in Sport, to be published in a forthcoming issue of BJSM .4

Compared with other areas of medical and behavioural research, sports medicine is in its infancy and intervention research of any a kind, efficacy or effectiveness, is relatively scarce, though the former dominates.5 It would not, therefore, be appropriate to halt all sports medicine efficacy studies or those using RCT designs. Recent reviews in BJSM have highlighted clear gaps in current knowledge that could be useful for the prioritising of such work.6 7

Having said this, there is no doubt that unless we fully embrace the challenges of conducting implementation and translation/dissemination studies, our sports medicine prevention efforts …
Unhurried NK cells
Authors: Heather L. Van Epps
Journal: The Journal of Experimental Medicine (2006)

Naive T cells race around lymph nodes in search of their specific antigens but, according to a study on page 619, natural killer (NK) cells are in less of a hurry. Bajenoff and colleagues provide the first glimpse of NK cells in live lymph nodes, revealing slow moving cells that form long-lasting contacts with dendritic cells (DCs).






Figure 1

Lymph node NK cells (green) form long-lasting contacts with dendritic cells (red).




In recent years, intravital imaging has shown that T cells dart rapidly around lymph nodes in search of their rare cognate antigens, making fleeting contacts with DCs as they go. An encounter with a cognate antigen delivers a stop signal that triggers stable T cell–DC interactions, during which the T cell presumably receives activating signals.

Bajenoff and colleagues used the same technology to show that NK cells move at a more leisurely pace than T cells—a pace that is unaltered by infection. The reason for this lethargy is a matter of speculation, but might reflect both the clonal nature of NK cells and the diversity of ligands that activate these cells. In other words, unlike T cells, NK cells needn't look far for their activating signals.

Also unlike T cells, NK cells form long-lasting contacts with DCs in the absence of antigen. These prolonged interactions, the authors suggest, might provide the NK cells with survival signals. Indeed, recent studies showed that interleukin (IL)-15—an essential NK cell survival factor—must be presented in trans, with the cytokine binding to its receptor on one cell type (the DC) and acting on another (the NK cell).

Infection with Leishmania major caused lymph node NK cells to secret the T helper type 1 (Th1)-promoting cytokine interferon-γ (IFN-γ) and congregate with CD4+ T cells—a positioning consistent with the requirement for NK cell–derived IFN-γ in the development of a protective Th1 response against L. major.
Inherited Disorders of Renal Magnesium Handling
Authors: DAVID E. C. COLE, GARY A. QUAMME
Journal: Journal of the American Society of Nephrology (2000)

The genetic basis and cellular defects of a number of primary magnesium wasting diseases have been elucidated over the past decade. This review correlates the clinical pathophysiology with the primary defect and secondary changes in cellular electrolyte transport. The described disorders include (1) hypomagnesemia with secondary hypocalcemia, an earlyonset, autosomal-recessive disease segregating with chromosome 9q12-22.2; (2) autosomal-dominant hypomagnesemia caused by isolated renal magnesium wasting, mapped to chromosome 11q23; (3) hypomagnesemia with hypercalciuria and nephrocalcinosis, a recessive condition caused by a mutation of the claudin 16 gene (3q27) coding for a tight junctional protein that regulates paracellular Mg(2+) transport in the loop of Henle; (4) autosomal-dominant hypoparathyroidism, a variably hypomagnesemic disorder caused by inactivating mutations of the extracellular Ca(2+)/Mg(2+)-sensing receptor, CASR: gene, at 3q13.3-21 (a significant association between common polymorphisms of the CASR: and extracellular Mg(2+) concentration has been demonstrated in a healthy adult population); and (5) Gitelman syndrome, a recessive form of hypomagnesemia caused by mutations in the distal tubular NaCl cotransporter gene, SLC12A3, at 16q13. The basis for renal magnesium wasting in this disease is not known. These inherited conditions affect different nephron segments and different cell types and lead to variable but increasingly distinguishable phenotypic presentations. No doubt, there are in the general population other disorders that have not yet been identified or characterized. The continued use of molecular techniques to probe the constitutive and congenital disturbances of magnesium metabolism will increase the understanding of cellular magnesium transport and provide new insights into the way these diseases are diagnosed and managed.
<i>BRAF</i> V600E Mutation in Two Distinct Meningeal Melanocytomas Associated With a Nevus of Ota
Authors: Lisandra Muñoz-Hidalgo, Concha Lopez-Gines, Lara Navarro, Robert C. Callaghan, Teresa San Miguel, Rosario Gil-Benso, Vicent Quilis, Laura Botella, Jose Gonzalez-Darder, Miguel Cerda-Nicolas
Journal: Journal of Clinical Oncology (2014)
Blockade of Specific NOTCH Ligands: A New Promising Approach in Cancer Therapy
Authors: Anaïs Briot, M. Luisa Iruela-Arispe
Journal: Cancer Discovery (2015)

The signaling specificity conveyed by distinct combination of NOTCH receptors/ligands has remained elusive. In this issue of Cancer Discovery, through the development of ligand-specific NOTCH inhibitors, Kangsamaksin and colleagues uncovered unique signaling outcomes downstream of DLL- and JAG-receptor activation and demonstrated their effects in the suppression of tumor angiogenesis.