Expression patterns and prognostic role of transketolase-like 1 in muscle-invasive bladder cancer

Purpose

The pentose phosphate pathway (PPP) has been shown to play an important role in the metabolism of cancer cells. The transketolase-like 1 gene (TKTL1) encodes an enzyme representing an essential component of this pathway. Its expression has been demonstrated to correlate with stage and outcome in various tumors. The aim of the present study was to assess expression patterns and the prognostic role of TKTL1 in muscle-invasive bladder cancer (MIBC).

Patients and methods

The expression of TKTL1 was assessed in a tissue microarray consisting of histopathologically benign and malign tissue of 112 patients who underwent radical cystectomy due to MIBC. Cytoplasmatic and nuclear expression were assessed by immunohistochemistry and compared separately with clinicopathologic parameters and outcome.

Results

Cytoplasmatic expression of TKTL1 was exclusively present in tumor tissue. In contrast, the proportion of nuclei positive for TKTL1 was higher in histopathologically benign tissue compared with malign tissue. No correlation was observed between cytoplasmatic or nuclear TKTL1 expression and tumor stage, grade or the presence of metastases. Patients with lymph node involvement showed a decreased frequency of cytoplasmatic expression compared with node-negative patients (p = 0.01). However, no further correlation was observed between the expression of TKTL1 and clinical outcome of patients.

Conclusions

The present study shows that the cytoplasmatic expression of TKTL1 is specific for MIBC tissue compared with histopathologically benign urothelium. This specific expression is present in a subgroup of MIBC potentially identifying patients with activated PPP suitable for a targeted inhibition of sugar metabolism. In contrast to other malignancies, TKTL1 shows no prognostic significance in MIBC.

     

Novel Ranking System for Identifying Efficacious Anti-Influenza Virus PB2 Inhibitors

Through antigenic drift and shifts, influenza virus infections continue to be an annual cause of morbidity in healthy populations and of death among elderly and at-risk patients. The emergence of highly pathogenic avian influenza viruses such as H5N1 and H7N9 and the rapid spread of the swine-origin H1N1 influenza virus in 2009 demonstrate the continued need for effective therapeutic agents for influenza. While several neuraminidase inhibitors have been developed for the treatment of influenza virus infections, these have shown a limited window for treatment initiation, and resistant variants have been noted in the population. In addition, an older class of antiviral drugs for influenza, the adamantanes, are no longer recommended for treatment due to widespread resistance. There remains a need for new influenza therapeutic agents with improved efficacy as well as an expanded window for the initiation of treatment. Azaindole compounds targeting the influenza A virus PB2 protein and demonstrating excellent in vitro and in vivo properties have been identified. To evaluate the in vivo efficacy of these PB2 inhibitors, we utilized a mouse influenza A virus infection model. In addition to traditional endpoints, i.e., death, morbidity, and body weight loss, we measured lung function using whole-body plethysmography, and we used these data to develop a composite efficacy score that takes compound exposure into account. This model allowed the rapid identification and ranking of molecules relative to each other and to oseltamivir. The ability to identify compounds with enhanced preclinical properties provides an opportunity to develop more-effective treatments for influenza in patients.     

Before the onset of interstitial cystitis/bladder pain syndrome,the presence of multiple non-bladder syndromes is strongly associated with a history of multiple surgeries

Objective

Certain functional somatic syndromes (FSSs) such as fibromyalgia and irritable bowel syndrome are accompanied by diffuse pain amplification. Women with interstitial cystitis/bladder pain syndrome (IC/BPS) have numerous FSSs, as well as other non-bladder syndromes (NBSs) that are linked to the FSSs. They also report multiple surgeries. Since pain is a common indication for surgery, we tested the hypothesis that NBSs were associated with surgeries.

Methods

We interviewed 312 incident IC/BPS cases and controls on NBSs and number of surgeries before the index date (for cases, IC/BPS onset date). Poisson and logistic regression analyses adjusted for age, race, educational level, and menopause.

Results

Number of surgeries increased with number of NBSs in both cases and controls whether chronic pelvic pain (CPP), the only NBS generally accepted as an indication for surgery, was present or not. Logistic regression analysis showed that among cases CPP was the only individual NBS associated with a history of multiple surgeries, and then only modestly [odds ratio (OR) 1.9, confidence intervals (CI) 1.06, 3.2]. By far the strongest association was the number of NBSs. The OR for multiple surgeries increased with number of NBSs: for cases with 4–5 NBSs the OR was 14.1 (1.8, 113) and with 6–9 NBSs, 33.1 (3.9, 279). Controls had fewer syndromes and fewer surgeries and this linkage was less prominent.

Conclusion

Among IC/BPS cases, the number of NBSs was strongly correlated with the number of surgeries. Understanding temporal relationships will be necessary to explore causal linkages and may modify surgical practice.