The Functional Assessment of Anorexia/Cachexia Therapy (FAACT) Appetite Scale in veteran cancer patients

Anorexia and appetite assessment is an important priority in supportive oncology. A series of 156 veterans participating in a hematology oncology service completed the Functional Assessment of Anorexia/Cachexia Therapy (FAACT), the Functional Assessment of Cancer Therapy-General scale, the Memorial Symptom Assessment Scale Short Form (MSAS-SF), and the Zung Self-Rating Depression Scale and were followed for survival. The FAACT score correlated well with Karnofsky performance status, quality of life, and symptom distress subscales. A single appetite distress item from the MSAS-SF correlated well with these measures. Both appetite measures correlated with the presence of other symptoms and with concurrently measured hemoglobin, serum sodium, albumin, and cholesterol levels. These self-reported appetite measures were univariate predictors of survival and contributed additional prognostic information to data related to weight-loss distress. In a smaller study, the FAACT score correlated with a visual analogue measure of appetite and with the North Center Cancer Treatment Group appetite instrument.These data support use of these tools for the evaluation of appetite concerns among patients with advanced cancer.     

Emerging drugs for idiopathic pulmonary fibrosis

Pulmonary fibrosis is often the end stage of chronic, persistent, low-level lung injury, either of known or unknown cause. The most severe form of pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF), a disease process of unknown aetiology and one that often leads to respiratory failure and death. At present there are no proven or effective drug therapies for IPF. Recent advances in understanding of disease pathogenesis have focused attention on drug targeting of fibrogenic pathways, as opposed to traditional anti-inflammatory approaches. In this report, the present status of drug development of a number of emerging antifibrotic strategies and agents that may prove more effective in the therapy of this progressive, debilitating and fatal disease are reviewed.     

Geographic information system method for assessing chemo-diversity in medicinal plants

The spatial distribution of wild germplasm of Podophyllum peltatum L. (American mayapple) has been analyzed using the Geographic Information System (GIS) with the objective to develop a method and a database for evaluation of biotic and abiotic factors influencing drug yield, and to map elite genotypes for propagation and improvement. The field assessment followed a standard procedure including geographical coordinates of each accession, leaf biomass randomly harvested, identification of associate species, collection of herbarium specimen, soil sample and digital pictures of the site. By overlaying morphological and chemical data with geomorphic information, a thematic map was created locating the podophyllotoxin-rich accessions and the uniqueness of each site was recorded for post-collection analysis. This work has enabled the establishment of a database of P. peltatum germplasm in Mississippi with drug yield linked to spatial locations for rational utilization of our natural resources. While this method integrates information of well-characterized diverse in situ P. peltatum germplasm, it might become a strategy for curators to reduce cost for establishing and maintaining ex situ collections since the genetic material is geo-referenced.     

Vacuolar degradation of rat liver CYP2B1 in Saccharomyces cerevisiae: further validation of the yeast model and structural implications for the degradation of mammalian endoplasmic reticulum P450 proteins

Mammalian hepatic cytochromes P450 (P450s) are endoplasmic reticulum (ER)-anchored hemoproteins with highly variable half-lives. CYP3A4, the dominant human liver drug-metabolizing enzyme, and its rat liver orthologs undergo ubiquitin (Ub)-dependent 26S proteasomal degradation after suicide inactivation or after heterologous expression in Saccharomyces cerevisiae. In contrast, rat liver CYP2C11 is degraded by the vacuolar "lysosomal" pathway when similarly expressed in yeast. The structural determinants that commit P450s to proteasomal or lysosomal degradation are unknown. To further validate S. cerevisiae as a model for exploring mammalian P450 turnover, the degradation of phenobarbital-inducible liver CYP2B1, an enzyme reportedly degraded via the rat hepatic autophagic-lysosomal pathway, was examined in a yeast strain (pep4delta) deficient in vacuolar degradation and its isogenic wild-type control (PEP4). Although CYP2B1 was equivalently expressed in both strains during early logarithmic growth, its degradation was retarded in pep4delta strain, remaining at a level 5-fold higher than that in PEP4 yeast when monitored at the stationary phase. No comparable CYP2B1 stabilization was detected in yeast genetically deficient in the ER Ub-conjugating enzyme Ubc6p or Ubc7p or defective in 19S proteasomal subunit Hrd2p. Thus, as in the rat liver, CYP2B1 is a target of vacuolar/lysosomal rather than proteasomal degradation in yeast, thereby further validating this model for mammalian P450 turnover. It is intriguing that a chimeric protein, CYP2B1-3A4CT, with the CYP3A4 C-terminal heptapeptide grafted onto the CYP2B1 C terminus, was proteasomally degraded after similar expression. Such diversion of CYP2B1 from its predominantly vacuolar degradation suggests that the CYP3A4 heptapeptide could either actively signal its proteasomal degradation or block its vacuolar proteolysis.     

NAT2*5/*5 genotype (341T>C) is a potential risk factor for schistosomiasis-associated bladder cancer in Egyptians

Arylamine N-acetyl transferase (NAT2) displays extensive genetic polymorphisms that affect the rates of acetylation of drugs and genotoxic compounds such as amine carcinogens. To investigate whether the slow acetylator genotype is a risk factor for development of bladder cancer following schistosomal infection of the urinary tract, the authors determined the frequencies of 3 common polymorphisms in the NAT2 gene (341T>C, 590G>A, and 282C>T), which are associated with impaired acetylation activity, in control subjects (n=61; mean age 34.3+/-9.2 years) and in schistosomiasis-associated bladder cancer patients (n=55; 52+/-10.9 years) from the Egyptian population. Genotyping was carried out using rapid cycle PCR on the LightCycler, and subjects were assigned to a slow, intermediate, or rapid acetylator phenotype on the basis of the genotypes. The frequencies of the mutant alleles observed in the controls from the present study were similar to those reported previously for both the Egyptian population and other Arab populations. Patients showed a higher prevalence (78.2%) of slow acetylator phenotype than controls (67.2%), but this did not reach statistical significance (P=0.19). However, there were significantly more individuals who were carriers of 2 mutant 341T>C alleles (NAT2*5/*5 genotype) in the patient group compared with controls (odds ratio 2.6, CI 1.02-6.67, P=0.026). The alloenzyme encoded by this allele has been shown to display a large reduction in its catalytic activity. In conclusion, these data suggest that the NAT2*5/*5 genotype is a potential risk factor for development of urinary bladder cancer in patients with prior schistosomiasis infection.     

Integration of gene expression profiling and clinical variables to predict prostate carcinoma recurrence after radical prostatectomy

BACKGROUND: Gene expression profiling of prostate carcinoma offers an alternative means to distinguish aggressive tumor biology and may improve the accuracy of outcome prediction for patients with prostate carcinoma treated by radical prostatectomy. METHODS: Gene expression differences between 37 recurrent and 42 nonrecurrent primary prostate tumor specimens were analyzed by oligonucleotide microarrays. Two logistic regression modeling approaches were used to predict prostate carcinoma recurrence after radical prostatectomy. One approach was based exclusively on gene expression differences between the two classes. The second approach integrated prognostic gene variables with a validated postoperative predictive model based on standard variables (nomogram). The predictive accuracy of these modeling approaches was evaluated by leave-one-out cross-validation (LOOCV) and compared with the nomogram. RESULTS: The modeling approach using gene variables alone accurately classified 59 (75%) tissue samples in LOOCV, a classification rate substantially higher than expected by chance. However, this predictive accuracy was inferior to the nomogram (concordance index, 0.75 vs. 0.84, P = 0.01). Models combining clinical and gene variables accurately classified 70 (89%) tissue samples and the predictive accuracy using this approach (concordance index, 0.89) was superior to the nomogram (P = 0.009) and models based on gene variables alone (P < 0.001). Importantly, the combined approach provided a marked improvement for patients whose nomogram-predicted likelihood of disease recurrence was in the indeterminate range (7-year disease progression-free probability, 30-70%; concordance index, 0.83 vs. 0.59, P = 0.01). CONCLUSIONS: Integration of gene expression signatures and clinical variables produced predictive models for prostate carcinoma recurrence that perform significantly better than those based on either clinical variables or gene expression information alone.