Epithelial–mesenchymal transformation markers E-cadherin and survivin predict progression of stage pTa urothelial bladder carcinoma

Purpose

To determine whether the immunohistochemical markers survivin and E-cadherin can predict progress at initially diagnosed Ta bladder cancer.

Methods

We retrospectively searched for every initially diagnosed pTa urothelial bladder carcinoma having been treated at our single-center hospital in Germany from January 1992 up to December 2004. Follow-up was recorded up to June 2010, with recurrence or progress being the endpoints. Immunohistochemical staining and analysis of survivin and E-cadherin of the TURB specimens were performed. Outcome dependency of progression and no progression with immunohistochemical staining was analyzed using uni- and multivariate regression analysis, Kaplan–Meier analysis and uni- and multivariate Cox regression analysis.

Results

Overall, 233 patients were included. Forty-two percent of those were tumor free in their follow-up TURBs, 46 % had at least one pTa recurrence and 12 % even showed progress to at least pT1 bladder cancer. Aberrant staining of E-cadherin was found within 71 % of patients with progression in contrast to only 40 % in cases without progression (p = 0.004). Of all progressed patients, 92 % showed overexpression of survivin in their initial pTa specimen compared to 61 % without progression (p = 0.001). Kaplan–Meier analysis revealed aberrant E-cadherin staining to be associated with worse progression-free survival (PFS) (p = 0.005) as well as overexpression of survivin (p = 0.003). In multivariate Cox regression analysis, strong E-cadherin staining was an independent prognosticator for better PFS (p = 0.033) and multifocality (p = 0.046) and tumor size over 3 cm (p = 0.042) were prognosticators for worse PFS.

Conclusion

Adding the immunohistochemical markers survivin and E-cadherin could help to identify patients at risk of developing a progressive disease in initial stage pTa bladder cancer.

     

Prophylactic antibiotics to prevent surgical site infections in Botswana: findings and implications

Objectives: Antibiotic prophylaxis in surgery is known to reduce the rate of surgical site infections (SSI) as well as shorten hospital stay. However, there is currently a scarcity of data on antibiotic prophylaxis and SSIs among African countries including Botswana. Consequently, this study aimed to address this.

Methods: A prospective study involving 400 patients was carried out at a leading tertiary hospital in Botswana from 2014–2015. Patients’ demographic information, type of surgery performed and peri-operative use of antibiotics were documented. All enrolled patients were followed-up for 30 days post discharge to fully document the incidence of SSIs.

Results: Median age of patients was 35.5 (25 – 50) years, with 52% female. There were 35.8% emergency and 64.2% elective surgeries. The most common operations were exploratory laparotomy (25%), appendectomy (18.3%), excision, and mastectomy (8%). Antibiotics were given in 73.3% of patients, mainly postoperatively (58.3%). The most commonly prescribed antibiotics were cefotaxime (80.7%), metronidazole (63.5%), cefradine (13.6%) and amoxicillin/clavulanate (11.6%). The incidence of SSI was 9%. The most common organisms were Pseudomonas aeruginosa, Staphylococcus aureus, and coagulase-negative staphylococci.

Conclusion: The rate of SSI is a concern, and may be related to inappropriate antibiotic prophylaxis given post operatively. Interventions are in place to decrease SSI rates to acceptable levels in this leading hospital by improving for instance infection prevention practices including the timing of antibiotic prophylaxis. Research is also ongoing among other hospitals in Botswana to reduce SSI rates building on these findings.     

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.     

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.