Recombinant erythropoietin is neuroprotective in a novel mouse oxidative injury model

To identify neuroprotective changes in gene expression, we developed a neonatal mouse model of moderate to severe oxidative brain injury and hypothesized that recombinant erythropoietin (rEpo) would decrease the expression of proapoptotic and proinflammatory genes 24 and 48 h, respectively, after injury and increase the expression of neurogenic and angiogenic genes 168 h after injury. Postnatal day 10 BALB-c mice underwent sham surgery or right common carotid artery occlusion followed by alternating hypoxia and hyperoxia and were then treated with rEpo (5,000 U/kg s.c.) or saline (vehicle) daily for up to three doses. At death, gross brain injury was assessed, then hippocampus, cortex, and thalamus were isolated for RNA or protein extraction. Microarray analysis, real-time polymerase chain reaction, and Bio-Plex suspension array system validation were performed. rEpo decreased both incidence and severity of brain injury (median injury score 3 vs. 0, p < 0.0001) and reduced the injury-induced increases in interleukin-1alpha and interleukin-6 gene expression (p < 0.001), with corresponding effects on protein translation. Similarly, the expression of caspase-1, caspase-4, and caspase-6 and of p53 was increased by brain injury at 24 h, but mitigated by rEpo (p < 0.01). The interleukin-10 expression was higher in the rEpo-treated animals. Apoptotic and proinflammatory gene expression persisted for 168 h. There was no increase in angiogenic gene expression at the time points studied.     

Enhanced phytoremediation of volatile environmental pollutants with transgenic trees

Small, volatile hydrocarbons, including trichloroethylene, vinyl chloride, carbon tetrachloride, benzene, and chloroform, are common environmental pollutants that pose serious health effects. We have developed transgenic poplar (Populus tremula x Populus alba) plants with greatly increased rates of metabolism and removal of these pollutants through the overexpression of cytochrome P450 2E1, a key enzyme in the metabolism of a variety of halogenated compounds. The transgenic poplar plants exhibited increased removal rates of these pollutants from hydroponic solution. When the plants were exposed to gaseous trichloroethylene, chloroform, and benzene, they also demonstrated superior removal of the pollutants from the air. In view of their large size and extensive root systems, these transgenic poplars may provide the means to effectively remediate sites contaminated with a variety of pollutants at much faster rates and at lower costs than can be achieved with current conventional techniques.     

Changes in utilization of axillary dissection in women with invasive breast cancer and sentinel node metastasis after the ACOSOG Z0011 trial

The American College of Surgeons Oncology Group Z0011 (ACOSOG Z0011) trial demonstrated no survival advantage for women with clinical T1–T2 invasive breast cancer with 1–2 positive sentinel lymph nodes (SLN) who received whole-breast radiation, and no further axillary surgery when compared to women who did undergo axillary lymph node dissection (ALND). We used the National Cancer Database (NCDB) to study changes in utilization of ALND after the publication of this trial. NCDB was queried for female patients from 2012 to 2015 who met Z0011 criteria. Patients were divided into four groups based on Commission on Cancer facility accreditation. Outcome measures include the rate of ALND (nonadherence to Z0011) and the average number of nodes retrieved with ALND. 27,635 patients were identified, with no significant differences in T stage and receptor profiles between groups. Overall rate of ALND decreased from 34.0% in 2012 to 22.7% in 2015. Nonadherence was lowest in Academic Programs (decreasing from 30.1% in 2012 to 20.5% in 2015) and was highest in Community Cancer Programs (41.2% in 2012 to 29.1% in 2015). Median number of positive SLN did not differ between groups (p = .563). Median number of nodes retrieved on ALND decreased from 9 (IQR 5–14) in 2012 to 7 (IQR 4–12) in 2015 (p < .001). In patients who met the ACOSOG Z11 trial guidelines, rates of ALND have decreased over time. However, rates of nonadherence to Z0011 are significantly higher in Community Cancer Programs compared to Academic Programs.     

Consumption of Yoghurt and Other Dairy Products and Risk of Colorectal Cancer in Iran: The IROPICAN Study

Background: There is evidence of an inverse association between yoghurt intake and risk of colorectal cancer (CRC). We aimed at investigating the association between the intake of yoghurt and other dairy foods consumed in Iran and CRC risk. Methods: Our analysis included 4070 subjects within the IROPICAN (Iran Study of Opium and Cancer) study. Detailed information was collected by the use of validated questionnaires. We estimated adjusted odds ratios (OR) and 95% confidence intervals (CI) for the association between the intake of total dairy products, and, separately, of yoghurt, milk, cheese, kashk, dough, cream, ice cream, and other milk products, and CRC using unconditional logistic regression analyses. The intake was categorized in tertiles. Results: Overall, we analyzed 865 cases and 3205 controls. Total dairy products intake was not associated with CRC. The OR for one tertile increase (OR_T) in yoghurt intake was 0.97 (95% CI 0.87–1.08) for CRC and 0.66 (95% CI 0.52–0.84) for proximal colon cancer. Cream intake was associated with CRC (OR_T3 = 1.33, 95% CI 1.08–1.64), colon (OR_T3 = 1.37, 95% CI 1.03–1.81), and proximal cancer (OR_T3 = 1.29, 95% CI 1.04–1.61). The OR of distal colon cancer for ice cream intake was 0.59 (95% CI 0.43–0.82). Other dairy products were not associated with CRC risk.     

Predictors of survival after In vivo split liver transplantation: analysis of 110 consecutive patients

OBJECTIVE: To determine the factors that influence patient survival after in vivo split liver transplantation (SLT). SUMMARY BACKGROUND DATA: Split liver transplantation is effective in expanding the donor pool, and its use reduces the number of deaths in patients awaiting orthotopic liver transplantation. Early SLTs were associated with poor outcomes, and acceptance of the technique has been slow. A better understanding of the factors that influence patient and graft survival would be useful in widening the application of SLT. METHODS: During a 3.5-year period, 55 right and 55 left lateral in vivo split grafts were transplanted in 102 pediatric and adult recipients. The authors' in vivo split technique has been previously described. Median follow-up was 14.5 months. Recipient, donor, and surgical variables were analyzed for their effect on patient survival after SLT. RESULTS: Overall survival rates of patients who received an SLT were not significantly different from those of patients who received whole organ transplants. Survival of left lateral segment recipients, at median follow-up time, was 76% versus 80% in patients receiving a trisegment. Fifty of 102 patients (49%) were high-risk urgent recipients (United Network for Organ Sharing [UNOS] status 1 and 2A) and 52 (51%) were nonurgent recipients (UNOS status 2B, 3). High-risk recipients had a survival rate significantly lower than that of nonurgent recipients. By univariate comparison, two variables-UNOS status and number of transplants per patient-were significantly associated with an increased risk of death. Preoperative recipient mechanical ventilation, preoperative prothrombin time, donor sodium level, donor length of hospital stay, and warm ischemia time approached significance. The type of graft (right vs. left) did not reduce the survival rate after transplantation. Multivariate logistic regression analysis identified UNOS status and length of donor hospital stay as independent predictors of survival. CONCLUSIONS: Patient survival of in vivo SLT is not significantly different from that of whole-organ orthotopic liver transplantation. The variables affecting outcome of in vivo SLT are similar to those in whole-organ transplantation. in vivo SLT should be widely applied to expand a severely depleted donor pool.     

Childhood Brain Tumors,Residential Insecticide Exposure,and Pesticide Metabolism Genes

Background

Insecticides that target the nervous system may play a role in the development of childhood brain tumors (CBTs). Constitutive genetic variation affects metabolism of these chemicals.

Methods

We analyzed population-based case–control data to examine whether CBT is associated with the functional genetic polymorphisms PON1_C–108T, PON1_Q192R, PON1_L55M, BCHE_A539T, FMO1_C–9536A, FMO3_E158K, ALDH3A1_S134A, and GSTT1 (null). DNA was obtained from newborn screening archives for 201 cases and 285 controls, ≤ 10 years of age, and born in California or Washington State between 1978 and 1990. Conception-to-diagnosis home insecticide treatment history was ascertained by interview.

Results

We observed no biologically plausible main effects for any of the metabolic polymorphisms with CBT risk. However, we observed strong interactions between genotype and insecticide exposure during childhood. Among exposed children, CBT risk increased per PON1_–108T allele [odds ratio (OR) = 1.8; 95% confidence interval (CI), 1.1–3.0] and FMO1_–9536A (*6) allele (OR = 2.7; 95% CI, 1.2–5.9), whereas among children never exposed, CBT risk was not increased (PON1: OR = 0.7; 95% CI, 0.5–1.0, interaction p = 0.005; FMO1: OR = 1.0; 95% CI, 0.6–1.6, interaction p = 0.009). We observed a similar but statistically nonsignificant interaction between childhood exposure and BCHE_A539T (interaction p = 0.08). These interactions were present among both Hispanic and non-Hispanic white children.

Conclusion

Based on known effects of these variants, these results suggest that exposure in childhood to organophosphorus and perhaps to carbamate insecticides in combination with a reduced ability to detoxify them may be associated with CBT. Confirmation in other studies is required.     

The clinical significance of MAGEA3 expression in pancreatic cancer

The MAGEA gene family that encodes cancer testis antigens is differentially expressed in many cancers. Though MAGEA3 expression has been detected in gastrointestinal malignancies, its role in pancreatic ductal adenocarcinoma (PDAC) has not been well established. We assessed 57 patients who underwent intent-to-cure surgery for PDAC. Total RNA from paraffin-embedded pancreatic tumors was extracted and assessed for MAGEA3 gene expression by an optimized probe-based quantitative real-time RT-PCR (qRT) assay. MAGEA3 gene expression was detected by qRT in 25 (44%) patients. For the entire cohort, detection of MAGEA3 expression was associated with significantly decreased overall survival (median, 16 vs 33 months; log-rank, p = 0.032). When clinicopathologic factors, including age, gender, stage, tumor extent, lymph node metastasis, tumor grade, perineural invasion and lymphovascular invasion were assessed by univariate analysis, MAGEA3 gene expression and tumor grade were significant prognostic factors for poor survival (HR 2.1, 95% CI: 1.0-4.4, p = 0.041; and HR 3.7, 95% CI: 1.8-7.6, p = 0.0004, respectively). Immunohistochemistry (IHC) was performed and confirmed MAGEA3 protein in PDAC specimens. In conclusion, MAGEA3 is differentially expressed in patients with PDAC; its expression correlates with significantly worse survival. Molecular assessment for MAGEA3 should be considered to improve prognostic evaluation and to identify eligible patients for potential immune-based therapy.     

Genetic polymorphisms in three Iranian populations with different risks of esophageal cancer, an ecologic comparison

The age-standardized incidence of esophageal cancer (EC) varies from 3 to >100/100,000 per year in different provinces of Iran. This striking variation of incidence is associated with differences in ethnic backgrounds, raising the possibility that genetic factors are involved in the pathogenesis of EC. We compared the frequencies of polymorphisms in ten genes that have been hypothesized to have a role in risk of EC (CYP1A1, CYP2A6, CYP2E1, GSTM1, GSTP1, GSTT1, ADH2, ADH3, ALDH2, and O6-MGMT) among three Iranian ethnic groups with highly varying rates of EC. These three groups included high-risk Turkomans, medium-risk Turks, and low-risk Zoroastrian Persians. Compared to Zoroastrians, Turkomans had higher frequency of four alleles that are speculated to favor carcinogenesis (CYP1A1 m1, CYP1A1 m2, CYP2A6*9, and ADH2*1); these results are consistent with an influence of these allele variants on the population risk of EC. However, none of these four alleles had a high enough prevalence in Turkomans to explain the high rates of EC in this group. Three of these four alleles (CYP1A1 m1, CYP1A1 m2, CYP2A6*9) were less frequent among Turkomans than in some Asian populations with lower risks of EC. We conclude that it is unlikely that variations in these polymorphic genes are major contributors to the high incidence of EC among Turkomans in Iran.