MALDI imaging–based identification of prognostically relevant signals in bladder cancer using large-scale tissue microarrays

ObjectiveAlthough most patients with urinary bladder cancer present with noninvasive and low-malignant stages of the disease, about 20% eventually develop life-threatening metastatic tumors. This study was designed to evaluate the potential of matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) to identify molecular markers predicting the clinical course of bladder cancer.Materials and methodsWe employed MALDI-MSI to a bladder cancer tissue microarray including paraffin-embedded tissue samples from 697 patients with clinical follow-up data to search for prognostically relevant associations.ResultsAnalysis of our MALDI imaging data revealed 40 signals in the mass spectra (m/z signals) associated with epithelial structures. The presence of numerous m/z signals was statistically related to one or several phenotypical findings including tumor aggressiveness (stage, grade, or nodal status; 30 signals), solid (5 signals) or papillary (3 signals) growth patterns, and increased (6 signals) or decreased (12 signals) cell proliferation, as determined by Ki-67 immunohistochemistry. Two signals were linked with tumor recurrence in noninvasive (pTa category) tumors, of which one was also related to progression from pTa-category to pT1-category disease. The absence of one m/z signal was linked with decreased survival in the subset of 102 muscle-invasive cancers.ConclusionOur data demonstrate the suitability of combining MSI and large-scale tissue microarrays to simultaneously identify and validate clinically useful molecular markers in urinary bladder cancer.     

Structure‐Based Design and Synthesis of a Small Molecule that Exhibits Anti‐inflammatory Activity by Inhibition of MyD88‐mediated Signaling to Bacterial Toxin Exposure

Both Gram‐positive and Gram‐negative pathogens or pathogen‐derived components, such as staphylococcal enterotoxins (SEs) and endotoxin (LPS) exposure, activate MyD88‐mediated pro‐inflammatory cellular immunity for host defense. However, dysregulated MyD88‐mediated signaling triggers exaggerated immune response that often leads to toxic shock and death. Previously, we reported a small molecule compound 1 mimicking BB‐loop structure of MyD88 was capable of inhibiting pro‐inflammatory response to SEB exposure in mice. In this study, we designed a dimeric structure compound 4210 covalently linked with compound 1 by a non‐polar cyclohexane linker which strongly inhibited the production of pro‐inflammatory cytokines in human primary cells to SEB (IC₅₀ 1–50 μm ) or LPS extracted from Francisella tularensis, Escherichia coli, or Burkholderia mallei (IC₅₀ 10–200 μm ). Consistent with cytokine inhibition, in a ligand‐induced cell‐based reporter assay, compound 4210 inhibited Burkholderia mallei or LPS‐induced MyD88‐mediated NF‐kB‐dependent expression of reporter activity (IC₅₀ 10–30 μm ). Furthermore, results from a newly expressed MyD88 revealed that 4210 inhibited MyD88 dimer formation which is critical for pro‐inflammatory signaling. Importantly, a single administration of compound 4210 in mice showed complete protection from lethal toxin challenge. Collectively, these results demonstrated that compound 4210 inhibits toxin‐induced inflated pro‐inflammatory immune signaling, thus displays a potential bacterial toxin therapeutic.     

Blood pressure crisis following withdrawal of clonidine (Catapres, Catapresan), with special reference to arterial and urinary catecholamine levels, and suggestions for acute management

In five patients with severe essential hypertension, placebo was substituted after 24 to 48 months of treatment with clonidine and a diuretic. In the present study, four of the patients developed a marked blood pressure rise following withdrawal of clonidine which was rapidly reversed by intravenous administration of propranolol 0.2 mg. per kilogram of body weight and phentolamine 20 to 30 mg. The fifth patient was pretreated with reserpine 2.0 mg. intramuscularly for three days prior to withdrawal of clonidine, and the blood pressure rise which he experienced was far less impressive. All patients experienced similar “withdrawal” symptoms, consisting of headaches, insomnia, restlessness, tremor, and nausea.Catecholamines were determined in arterial blood and urine, before and during the overshoot. They revealed a marked increase, particularly in the urine samples, consistent with the appearance of a hyperadrenergic state.     

Religious involvement and cigarette smoking in young adults: the CARDIA study (Coronary Artery Risk Development in Young Adults)study (

BACKGROUND: Results of previous studies have suggested that involvement in religious activities may be associated with lower rates of smoking. We sought to determine whether frequent attendance at religious services is associated with less smoking among young adults. METHODS: This prospective cohort study of 4569 adults aged 20 to 32 years included approximately equal numbers of blacks and whites and men and women from 4 cities in the United States who attended the 1987/1988 examination of the Coronary Artery Risk Development in Young Adults (CARDIA) study. Frequency of attendance at religious services and denominational affiliation were determined by self-report questionnaire in 1987/1988. Cigarette smoking was determined by interview at this time and again 3 years later. RESULTS: Of 4544 participants who completed the tobacco questionnaire in 1987/1988, 34% (891/2598) who attended religious services less than once per month or never and 23% (451/1946) who attended religious services at least once per month reported current smoking (odds ratio [OR], 1.7; 95% confidence interval [CI], 1.5-2.0; P<.001). This association between less frequent attendance at religious services and current smoking was found in most denominations and remained significant after adjusting for potential confounding variables (OR, 1.5; 95% CI, 1.3-1.8; P<.001). During 3-year follow-up, nonsmokers who reported little or no religious involvement had an increased risk of smoking initiation (adjusted OR, 1.9; 95% CI, 1.3-2.7; P<.001). CONCLUSIONS: Young adults who attend religious services have lower rates of current and subsequent cigarette smoking. The potential health benefits associated with religious involvement deserve further study.     

Short-term antigen presentation and single clonal burst limit the magnitude of the CD8(+) T cell responses to malaria liver stages

Malaria sporozoites induce swift activation of antigen-specific CD8(+) T cells that inhibit the intracellular development of liver-stage parasites. The length of time of functional in vivo antigen presentation, estimated by monitoring the activation of antigen-specific CD8(+) T cells, is of short duration, with maximum T cell activation occurring within the first 8 h after immunization and lasting approximately 48 h. Although the magnitude of the CD8(+) T cell response closely correlates with the number of parasites used for immunization, increasing the time of antigen presentation by daily immunizations does not enhance the magnitude of this response. Thus, once a primary clonal burst is established, the CD8(+) T cell response becomes refractory or unresponsive to further antigenic stimulation. These findings strongly suggest that the most efficient strategy for the induction of primary CD8(+) T cell responses is the delivery of a maximal amount of antigen in a single dose, thereby ensuring a clonal burst that involves the largest number of precursors to become memory cells.     

"White coat" versus "sustained" borderline hypertension in Tecumseh, Michigan

During a survey of young subjects not receiving treatment for hypertension in Tecumseh, Michigan, clinic and self-monitored blood pressures taken at home (14 readings in 7 days) were obtained in 737 subjects (387 men, 350 women, average age 31.5 years). Hypertension in the clinic was diagnosed if the clinic blood pressure exceeded 140 mm Hg systolic or 90 mm Hg diastolic. In the absence of firm criteria for what constitutes hypertension at home, subjects whose average home blood pressure was in the upper decile of the whole population were considered to have hypertension at home. By these criteria, 7.1% of the whole population had "white coat" hypertension (i.e., high clinic but not elevated home readings). The prevalence of "sustained" hypertension (i.e., high readings in the clinic and at home) was 5.1%. Subjects with white coat and sustained borderline hypertension in Tecumseh were very similar. Both groups showed, at previous examinations (at ages 5, 8, 21, and 23 years), significantly higher blood pressure readings than the normotensive subjects. As young adults (average age 33.3 years), the parents of both hypertensive groups had significantly higher blood pressure readings than the parents of normotensive subjects. Both hypertensive groups had faster heart rates, higher systemic vascular resistance, and higher minimal forearm vascular resistance. Both hypertensive groups were more overweight, had higher plasma triglycerides, insulin, and insulin/glucose ratios than normotensive subjects. The white coat hypertensive group also had lower values of high density lipoprotein than the normotensive group. White coat hypertension is a frequent condition.(ABSTRACT TRUNCATED AT 250 WORDS)     

Primary linitis plastica of the rectum

Five cases of primary linitis plastica of the rectum are presented. The clinical, radiologic, and pathologic features of the disease are described with emphasis on the difficulty in establishing a correct preoperative diagnosis. Because the histologic features of primary and secondary linitis plastica are indistinguishable and because secondary involvement is twice as common as primary, it is mandatory that other sites of origin are excluded and that both the proximal and distal margins of the resected area be free of tumor. Read at the joint meeting of the American Society of Colon and Rectal Surgeons and the Royal Society of Medicine, London, England, June 18 to 20, 1979.     

Transcapillary protein leakage and fluid movement: Effect of venous pressure

The effect of elevating venous pressure (ΔP_v) on the transcapillary escape of albumin (Q_T) in control and papverinized gracilis muscles perfused at constant flow was determined by means of direct monitoring of the rate of accumulation of tissue ¹²⁵I-labeled albumin radioactivity. Simultaneously, transcapillary fluid movement (FM) was assessed volumetrically. Under control isovolumetric conditions, Q_T = 2.25 mg/min · 100 g. In addition to causing an FM of 0.03 ml/min · 100 g · mm Hg, increasing P_v enhanced Q_T by 0.06 mg/min · 100 g · mm Hg. Papverinization itself decreased Q_T to 2.0 mg/min · 100 g and affected FM only slightly. However, the superposition of P_v elevation caused a FM of 0.008 ml/min · 100 g · mm Hg and resulted in Q_T increasing by 0.29 mg/min · 100 g · mm Hg. The results of this study indicate that Q_T is sensitive to changes in microvascular hemodynamics, and thus changes in microvascular pressure may affect FM in two ways, first by increasing the transcapillary pressure gradient and second by augmenting Q_T which may superimpose an oncotic adjunct to FM.