MDM2 promoter polymorphism and pancreatic cancer risk and prognosis.

PURPOSE: The mouse double minute 2 homologue (MDM2) -309T/G promoter polymorphism has been associated recently with the development and prognosis of a variety of tumors. The G allele is associated with increased affinity for Sp1 binding and higher MDM2 mRNA and protein levels, leading to diminished tumor suppressor activity of the p53 pathway. We hypothesized that the G allele is also associated with increased risk and worse outcome in pancreatic cancer. EXPERIMENTAL DESIGN: We evaluated the association between MDM2 309T/G and the risk of histologically confirmed pancreatic adenocarcinoma at Massachusetts General Hospital using unconditional logistic regression (123 cases and 372 controls). Complete overall survival and progression-free survival data were also available for 109 newly diagnosed patients. RESULTS: The adjusted odds ratios (95% confidence intervals) of pancreatic cancer associated with the MDM2 T/G and G/G genotypes compared with TT were 1.89 (1.20-2.99) and 2.07 (1.03-4.16), respectively (adjusting for age, gender, smoking status, and pack-years of smoking). In Cox proportional hazards model with the wild-type T/T genotype as the reference category and adjusting for stage, treatment, and performance status, both the heterozygous T/G and the homozygous G/G genotypes were associated with decreased progression-free survival [adjusted hazard ratio (95% confidence interval), 1.67 (0.98-2.84) for T/G and 2.28 (1.11-4.71) for G/G] and overall survival [2.64 (1.23-5.67) for T/G and 3.12 (1.22-7.91) for G/G]. CONCLUSIONS: The G allele of the MDM2 -309T/G polymorphism is associated with 2- to 3-fold increase risk and progression of pancreatic adenocarcinoma and a corresponding decrease in survival.     

Myeloperoxidase and superoxide dismutase polymorphisms are associated with an increased risk of developing pancreatic adenocarcinoma

BACKGROUND: Pancreatic cancer risk has been linked to chronic pancreatitis and periodontitis, suggesting a role for inflammation in disease etiology. Myeloperoxidase (MPO) and superoxide dismutase (SOD2) are enzymes that regulate reactive oxygen species and contain recognized single nucleotide polymorphisms (SNPs) that confer altered enzyme activity. METHODS: One hundred twenty-two patients with pancreatic cancer and 331 age- and sex-matched controls were analyzed for polymorphisms of the MPO - guanine 463 adenine (-G463A) and the SOD2 alanine (Ala)-to-valine (Val) polymorphism at codon 16 (Ala16Val) genes. Cases and controls were analyzed for associations between these polymorphisms, adjusting for sex, age, history of alcohol use and smoking history. RESULTS: The variant A allele of MPO -G463A was associated with a lower risk of pancreatic cancer (adjusted odds ratio [OR] for pancreatic cancer, 0.57; 95% confidence interval [95% CI], 0.4-0.9; P = .02). The SOD2 homozygous variant genotype (Val/Val) was associated with a greater risk of pancreatic cancer (adjusted OR, 1.96; 95% CI, 1.0-3.8; P = .04). Compared with individuals who carried both low-risk alleles (A/- and Ala/-), significantly more cases than controls carried both high-risk genotypes (G/G and Val/Val; adjusted OR, 4.31; 95% CI, 1.8-10; P = .001), or 1 high-risk genotype (adjusted OR, 1.96; 95% CI, 1.1-3.4; P = .01). CONCLUSIONS: Polymorphisms of the inflammatory pathway genes MPO -G463A and SOD2 Ala16Val are associated with elevated pancreatic cancer risk. Oxidative stress may play an important role in pancreatic cancer carcinogenesis.     

Genetic associations with sporadic neuroendocrine tumor risk

Genetic risk factors for sporadic neuroendocrine tumors (NET) are poorly understood. We tested risk associations in patients with sporadic NET and non-cancer controls, using a custom array containing 1536 single-nucleotide polymorphisms (SNPs) in 355 candidate genes. We identified 18 SNPs associated with NET risk at a P-value <0.01 in a discovery set of 261 cases and 319 controls. Two of these SNPs were found to be significantly associated with NET risk in an independent replication set of 235 cases and 113 controls, at a P value ≤0.05. An SNP in interleukin 12A (IL12A rs2243123), a gene implicated in inflammatory response, replicated with an adjusted odds ratio (95% confidence interval) (aOR) = 1.47 (1.03, 2.11) P-trend = 0.04. A second SNP in defender against cell death, (DAD1 rs8005354), a gene that modulates apoptosis, replicated at aOR = 1.43 (1.02, 2.02) P-trend = 0.04. Consistent with our observations, a pathway analysis, performed in the discovery set, suggested that genetic variation in inflammatory pathways or apoptosis pathways is associated with NET risk. Our findings support further investigation of the potential role of IL12A and DAD1 in the etiology of NET.     

Severe anemia in pregnancy in rural Ghana: a case-control study of causes and management

BACKGROUND: Various factors contribute to severe anemia in pregnancy in low-income countries. This study assesses which of these are of importance in rural Ghana, and evaluates management. METHODS: Prospective case-control study in two (sub)district hospitals in rural Ghana among 175 severely anemic pregnant women (Hb < 8.0 g/dl), receiving a comprehensive treatment package; and 152 non-anemic pregnant women (Hb > or = 10.9 g/dl), giving birth at the study hospitals, matched for age and parity. Evaluated characteristics were need for treatment for urinary tract infection and schistosomiasis; sickle cell and HIV status; antenatal care characteristics; and Hb increase after treatment. Statistical analysis included Chi square test and general linear modeling. RESULTS: Associated with severe anemia were multiple pregnancy (OR 8.9; 95%CI 1.1-71.0), urinary tract infection (OR 6.2; 95%CI 3.5-11.0), residence outside study (sub)district (OR 2.7; 95%CI 1.7-4.3), body mass index < 20.0 (OR 2.0; 95%CI 1.2-3.4), and less than 4 antenatal clinic visits (OR 1.9; 95%CI 1.2-3.0). No association was found with sickle cell or HIV status, schistosomiasis treatment, blood loss in pregnancy, or gestational age at antenatal care registration. After treatment, mean Hb in the severe anemia group increased by 3.2 g/dl, significantly more than in the control group (0.2 g/dl; p<0.001). Modeling showed that the number of antenatal visits and the lowest Hb together explained approximately 25% of the variability in Hb prior to childbirth among women with severe anemia. CONCLUSIONS: Treatable causes contribute considerably to severe anemia in pregnancy in low-income countries. Even with limited resources, a substantial increase of Hb can be achieved.     

Genetic variability in the metabolism of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL)

Urinary metabolites of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its glucuronides, termed total NNAL, have recently been shown to be good predictors of lung cancer risk, years before diagnosis. We sought to determine the contribution of several genetic polymorphisms to total NNAL output and inter-individual variability. The study subjects were derived from the Harvard/Massachusetts General Hospital Lung cancer case-control study. We analyzed 87 self-described smokers (35 lung cancer cases and 52 controls), with urine samples collected at time of diagnosis (1992-1996). We tested 82 tagging SNPs in 16 genes related to the metabolism of NNK to total NNAL. Using weighted case status least squares regression, we tested for the association of each SNP with square-root (sqrt) transformed total NNAL (pmol per mg creatinine), controlling for age, sex, sqrt packyears and sqrt nicotine (ng per mg creatinine). After a sqrt transformation, nicotine significantly predicted a 0.018 (0.014, 0.023) pmol/mg creatinine unit increase in total NNAL for every ng/mg creatinine increase in nicotine at p < 10E-16. Three HSD11B1 SNPs and AKR1C4 rs7083869 were significantly associated with decreasing total NNAL levels: HSD11B1 rs2235543 (p = 4.84E-08) and rs3753519 (p = 0.0017) passed multiple testing adjustment at FDR q = 1.13E-05 and 0.07 respectively, AKR1C4 rs7083869 (p = 0.019) did not, FDR q = 0.51. HSD11B1 and AKR1C4 enzymes are carbonyl reductases directly involved in the single step reduction of NNK to NNAL. The HSD11B1 SNPs may be correlated with the functional variant rs13306401 and the AKR1C4 SNP is correlated with the enzyme activity reducing variant rs17134592, L311V.     

Principles and biomechanics of muscle tendon unit transfer: Application in temporalis muscle tendon transposition for smile improvement in facial paralysis

Muscle tendon unit (MTU) transfer is a common procedure performed to restore hand function after peripheral nerve or spinal cord injury. The principles of MTU transfer established for hand surgery can be adopted to optimize the dynamic excursion of the temporalis tendon transfer procedure for facial reanimation. Additionally, the force generating ability of a transferred MTU depends on the ideal length‐tension relationship of the donor muscle. There are unclear guideline for selecting the ideal tension at which a transferred MTU will generate maximum force and excursion and current practice often leads to overstretch and suboptimal actin myosin interaction. The use of intraoperative electrical stimulation is an option for determining the ideal tension to optimize excursion of transferred temporalis tendon units in simile restoration. Understanding the biomechanics and principles of MTU and applying it to the temporalis tendon transfer procedure is necessary to improve its use in facial reanimation.     

Household air pollution and the sustainable development goals

Globally, 41% of households, over 2.8 billion people, rely on solid fuels (coal and biomass) for cooking and heating. In developing countries in Asia and sub-Saharan Africa where these fuels are predominantly used, women who are customarily responsible for cooking, and their young children, are most exposed to the resulting air pollution. Solid fuels are still in widespread use and it appears that intervention efforts are not keeping pace with population growth in developing countries. Here we pinpoint the challenges and identify opportunities for addressing household air pollution while mitigating global climate change and promoting the sustainable development goals. We recommend the following actions: implementation of the WHO indoor air quality guidelines on household fuel combustion; effective promotion and dissemination of improved cookstoves through formation of country alliances for clean cookstoves; expansion of liquefied petroleum gas production facilities and distribution networks; harnessing renewable energy potential; promotion of biogas production at both household and community level; ensuring improved ventilation of homes through education and enforcement of building standards; and exploiting opportunities in the health and other sectors for changing health-damaging cooking behaviour.