Association of single nucleotide polymorphisms at HSPB1 rs7459185 and TGFB1 rs11466353 with radiation esophagitis in lung cancer.

BACKGROUND AND PURPOSE: Radiochemotherapy (RCT) success in lung cancer (LC) can be limited due to the onset of adverse effects in the adjacent normal tissue such as radiation-induced esophageal toxicity (RIET). Therefore, specific biomarkers to customize the RCT dose administration and esophageal toxicity prediction are necessary to improve treatment effectiveness. MATERIALS AND METHODS: 247 LC patients prospectively recruited between 2012 and 2016 from 3 institutions were genotyped for 7 SNPs along TGFB1 and HSPB1 genes seeking an association with RIET risk development. Kaplan-Meier cumulative probability and Cox proportional hazards analyses were used to evaluate the effect of TGFB1 and HSPB1 genotypes on such risk. RESULTS: Multivariate analyses showed that patients carrying the HSPB1 rs7459185 CC genotype were associated with a significantly higher risk of acute grade 3 RIET than those carrying the GG/GC genotypes (HR = 17.73; 95% CI = 2.896-108.49; p = 0.002). LC patients who received higher (>median) volume of esophagus exposed to 30 Gy and harboring the rs7459185 GG/GC genotypes showed a significantly lower RIET incidence (p < 0.001). Additionally, LC patients carrying the TGFB1 rs11466353 GG genotype were found to be associated with a lower risk of late grade 2 RIET compared with those with the TT/TG genotypes (HR = 0.29; 95% CI = 0.103-0.830; p = 0.021). Patients receiving a high (>60 Gy) radiation dose who presented the rs11466353 GG genotype had a significantly lower RIET incidence (p = 0.025). CONCLUSION: The presence of different rs7459185/rs11466353 genotypes in LC patients associated with RIET risk and may be useful biomarkers along with other risk factors for guiding therapy intensity in an individualized therapy.

Vulnerable articulations: the opportunities and challenges of illness and recovery.

Medical anthropology overwhelmingly reveals vulnerability as a problem of powerlessness. Vulnerable groups and individuals are those exposed to the pernicious effects of inequalities, injustices, and oppressive political realities. This largely pejorative stance, we argue, simplifies the place of vulnerability within human experience and in relation to the body, health and illness. By showcasing a range of interlocking vulnerabilities, this paper reveal the spectrum of positive and negative vulnerabilities that affect health and recovery. Through the concept of vulnerable articulations, this paper argues that health and illness experiences simultaneously create and require a range of different interconnected vulnerabilities, some of them harmful, and some of them life affirming. Ethnographically, this paper explore the concept of vulnerable articulations through two contrasting case studies: a group of British and New Zealand nuclear test veterans seeking compensation from the state, and clients of equine therapy in New Zealand. These case studies reveal that understanding human vulnerability requires a close attention to how people navigate between the diverse vulnerabilities that they face, and that attaining well-being often involves harnessing positive vulnerabilities in order to lessen the effects of damaging vulnerabilities.

Lens opacity based modelling of the age-related straylight increase.

This work studies ethnic and geographical differences in the age-related straylight increase by means of a stochastic model and unpublished lens opacity data of 559 residents of Villa Maria (Argentina), as well as data of 912 Indonesian subjects published previously by Husain et al. For both cohorts the prevalence of each type and grade of lens opacity was determined as a function of age, from which a stochastic model was derived capable of simulating the lens opacity prevalence for both populations. These simulated lens opacity data were then converted to estimated straylight by means of an equation derived from previously recorded data of 107 eyes with varying degrees of cataract. Based on these opacity templates 2500 random sets of subject age and lens opacity data were generated by the stochastic model for each dataset, from which estimated straylight could be calculated. For the Argentinian data the estimated straylight was found to closely resemble the published models for age-related straylight increase. For younger eyes the straylight variation of the model was the same as what was previously published (in both cases ±0.200logunits), which doubled in size for older eyes. For the Indonesian data, however, this age-related straylight increase was found to be fundamentally different from the published age model. This suggests that current normative curves for age-related straylight increase may not always be appropriate for non-European populations, and that the inter-individual straylight variations in young, healthy eyes may possibly be due to variations in lens opacities.

A Preliminary Study on Racial Differences in HMOX1, NFE2L2, and TGFß1 Gene Polymorphisms and Radiation-Induced Late Normal Tissue Toxicity.

PURPOSE: This study tested whether racial differences in genetic polymorphisms of 4 genes involved in wound repair and response to radiation can be used to predict the occurrence of normal tissue late effects of radiation therapy and indicate potential therapeutic targets. METHODS AND MATERIALS: This prospective study examined genetic polymorphisms that modulate the expression of 4 genes involved in inflammation and fibrosis and response to radiation (HMOX1, NFE2L2, NOS3, and TGFß1). DNA from blood samples of 179 patients (∼ 80% breast and head and neck) collected at the time of diagnosis by their radiation oncologist as exhibiting late normal tissue toxicity was used for the analysis. Patient demographics were as follows: 56% white, 43% African American, 1% other. Allelic frequencies of the different polymorphisms of the participants were compared with those of the general American population stratified by race. Twenty-six additional patients treated with radiation, but without toxicity at 3 months or later after therapy, were also analyzed. RESULTS: Increased frequency of a long GT repeat in the HMOX1 promoter was associated with late effects in both African American and white populations. The single nucleotide polymorphisms (SNP) rs1800469 in the TGFß1 promoter and the rs6721961 SNP in the NFE2L2 promoter were also found to significantly associate with late effects in African Americans but not whites. A combined analysis of these polymorphisms revealed that >90% of African American patients with late effects had at least 1 of these minor alleles, and 58% had 2 or more. No statistical significance was found relating the studied NOS3 polymorphisms and normal tissue toxicity. CONCLUSIONS: These results support a strong association between wound repair and late toxicities of radiation. The presence of these genetic risk factors can vary significantly among different ethnic groups, as demonstrated for some of the SNPs. Future studies should account for the possibility of such ethnic heterogeneity in the late toxicities of radiation.

Ethnic difference in risk of toxicity in prostate cancer patients treated with dynamic arc radiation therapy.

AIMS AND BACKGROUND: The objective of this study was to assess the influence of ethnicity on toxicity in patients treated with dynamic arc radiation therapy (ART) for prostate cancer (PC). METHODS: From June 2006 to May 2012, 162 cT1-T3 cN0 cM0 PC patients were treated with ART (primary diagnosis, n = 125; post-prostatectomy/brachytherapy biochemical recurrence, n = 26; adjuvant post-prostatectomy, n = 11) at 2 institutions. Forty-five patients were Latin Americans and 117 were Europeans. The dose prescribed to the prostate ranged between 68 Gy and 81 Gy. RESULTS: The median age was 69 years (range 43-87 years). The median follow-up was 18 months (range 2-74 months). Overall, only 3 patients died, none due to a cancer-related cause. Biochemical recurrence was seen in 7 patients. The rates of acute grade 2 gastrointestinal (GI) and genitourinary (GU) toxicities were 19.7% and 17%, respectively. Only 1 patient experienced acute grade 3 GI toxicity, whereas 11 patients (6.7%) experienced acute grade 3 GU toxicity. Multivariate analysis showed that undergoing whole pelvic lymph node irradiation was associated with a higher grade of acute GI toxicity (OR: 3.46; p = 0.003). In addition, older age was marginally associated with a higher grade of acute GI toxicity (OR: 2.10; p = 0.074). Finally, ethnicity was associated with acute GU toxicity: Europeans had lower-grade toxicity (OR: 0.27; p = 0.001). CONCLUSIONS: Our findings suggest an ethnic difference in GU toxicity for PC patients treated with ART. In addition, we found that ART is associated with a very low risk of severe toxicity and a low recurrence rate.

Psychosocial and health impacts of uranium mining and milling on Navajo lands.

The uranium industry in the American Southwest has had profoundly negative impacts on American Indian communities. Navajo workers experienced significant health problems, including lung cancer and nonmalignant respiratory diseases, and psychosocial problems, such as depression and anxiety. There were four uranium processing mills and approximately 1,200 uranium mines on the Navajo Nation's over 27,000 square miles. In this paper, a chronology is presented of how uranium mining and milling impacted the lives of Navajo workers and their families. Local community leaders organized meetings across the reservation to inform workers and their families about the relationship between worker exposures and possible health problems. A reservation-wide effort resulted in activists working with political leaders and attorneys to write radiation compensation legislation, which was passed in 1990 as the Radiation Exposure Compensation Act (RECA) and included underground uranium miners, atomic downwinders, and nuclear test-site workers. Later efforts resulted in the inclusion of surface miners, ore truck haulers, and millworkers in the RECA Amendments of 2000. On the Navajo Nation, the Office of Navajo Uranium Workers was created to assist workers and their families to apply for RECA funds. Present issues concerning the Navajo and other uranium-impacted groups include those who worked in mining and milling after 1971 and are excluded from RECA. Perceptions about uranium health impacts have contributed recently to the Navajo people rejecting a resumption of uranium mining and milling on Navajo lands.

Pterygium in an aged Mongolian population: a population-based study in China.

AIMS: To determine the prevalence and identify associated risk factors for pterygium in an elderly Mongolian population at high altitude in Henan County, China. METHODS: A population-based survey was conducted from June 2006 to September 2006. A stratified, clustered, random sampling procedure was used to select 2486 Mongolian people aged 40 years and older. Pterygium was diagnosed and graded clinically as grade 1 (transparent), 2 (intermediate), and 3 (opaque). Risk factors associated with pterygium were evaluated with logistic regression models. RESULTS: From 2486 eligible subjects, 2112 (84.9%) were examined. There were 378 people with either unilateral (n=228) or bilateral (n=150) pterygia, equivalent to an overall prevalence of 17.9% (95% confidence interval (CI) 16.3, 19.5). The prevalence increased with older age (chi (2)-test of trend P<0.001). Visual acuity decreased with higher group of pterygium (chi (2)=97.759, P<0.0001). Pterygium was independently associated with Schirmer's test (< or =5 mm) (odds ratio (OR) 2.4; 95% CI, 1.9, 3.1), tear breakup time (< or =10 s) (OR 2.3; 95% CI, 1.8, 2.9), lower education level (<3 years) (OR 2.1; 95% CI, 1.4, 3.2), increasing age (OR 2.0; 95% CI, 1.4, 2.8) for persons 70-79, compared with 40-49, and other risk factors. CONCLUSIONS: The prevalence of pterygium in an older Mongolian population at high altitude is high, primarily because of ocular sun exposure and the other effects of the unique plateau climate, and representing an important health problem. People should be strongly encouraged to wear a wide-brimmed hat and/or sunglasses whenever they are outside.

Nuclear energy in postwar Japan and anti-nuclear movements in the 1950s.

The atomic bombings of Hiroshima and Nagasaki in August 1945 revealed the most destructive power to-date of man-made weapons. Their impact was so great that Japanese scientists thought that a bigger disaster could be prevented only if war was abolished. Thus they welcomed the international control of atomic energy. It was, however, only after the occupation that the Japanese general public began to learn about the horror of these atomic disasters due to the censorship imposed by the occupational forces. The hydrogen bomb test by the US in the Bikini atoll on March 1, 1954 renewed fears of nuclear weapons. The crew of a Japanese fishing vessel, the "Daigo Fukuryu Maru" (Lucky Dragon No. 5) suffered from exposure to radiation from the test. Even after the incident the US did not stop nuclear tests which continued to radioactively contaminate fish and rains in Japan. As a result, the petition movement for the ban of nuclear trials suddenly spread all over the country. By the summer of 1955 the number of the signatures grew to more than one third of Japan's population at the time. Under the strong influence of anti-nuclear Japanese public opinion the Science Council of Japan announced the so-called three principles of atomic energy: "openness," "democracy," and "independence" to ensure atomic energy was used for peaceful uses only. These principles were included in the Atomic Energy Basic Law established in December 1955. With this law, military uses of nuclear energy were strictly forbidden.

One minute after the detonation of the atomic bomb: the erased effects of residual radiation.

The U.S. Government's official narrative denies the effects of residual radiation which appeared one minute after the atomic bomb detonations in Hiroshima and Nagasaki. This paper explores declassified documents from the U.S. Atomic Energy Commission, the Atomic Bomb Casualties Commission, and others and shows that these documents actually suggested the existence of serious effects from residual radiation.

Korean atomic bomb victims.

After colonizing Korea, Japan invaded China, and subsequently initiated the Pacific War against the United States, Britain, and their allies. Towards the end of the war, U.S. warplanes dropped atomic bombs on Hiroshima and Nagasaki, which resulted in a large number of Koreans who lived in Hiroshima and Nagasaki suffering from the effects of the bombs. The objective of this paper is to examine the history of Korea atomic bomb victims who were caught in between the U.S., Japan, the Republic of Korea (South Korea) and the Democratic People's Republic of Korea (North Korea).

Possession of ATM sequence variants as predictor for late normal tissue responses in breast cancer patients treated with radiotherapy.

PURPOSE: The ATM gene product is a central component of cell cycle regulation and genomic surveillance. We hypothesized that DNA sequence alterations in ATM predict for adverse effects after external beam radiotherapy for early breast cancer. METHODS AND MATERIALS: A total of 131 patients with a minimum of 2 years follow-up who had undergone breast-conserving surgery and adjuvant radiotherapy were screened for sequence alterations in ATM using DNA from blood lymphocytes. Genetic variants were identified using denaturing high performance liquid chromatography. The Radiation Therapy Oncology Group late morbidity scoring schemes for skin and subcutaneous tissues were applied to quantify the radiation-induced effects. RESULTS: Of the 131 patients, 51 possessed ATM sequence alterations located within exons or in short intron regions flanking each exon that encompass putative splice site regions. Of these 51 patients, 21 (41%) exhibited a minimum of a Grade 2 late radiation response. In contrast, of the 80 patients without an ATM sequence variation, only 18 (23%) had radiation-induced adverse responses, for an odds ratio of 2.4 (95% confidence interval, 1.1-5.2). Fifteen patients were heterozygous for the G-->A polymorphism at nucleotide 5557, which causes substitution of asparagine for aspartic acid at position 1853 of the ATM protein. Of these 15 patients, 8 (53%) exhibited a Grade 2-4 late response compared with 31 (27%) of the 116 patients without this alteration, for an odds ratio of 3.1 (95% confidence interval, 1.1-9.4). CONCLUSION: Sequence variants located in the ATM gene, in particular the 5557 G-->A polymorphism, may predict for late adverse radiation responses in breast cancer patients.

Psychosocial effects of the Chernobyl nuclear disaster.

The psychological factors surrounding the Chernobyl disaster include the sudden trauma of evacuation, long-term effects of being a refugee, disruption of social networks, illness, separation and its effects on families, children's perception and effects on their development and the threat of a long-term consequence with an endless future. Added to this was the breakdown of the Soviet Union with consequent collapse of health services, increasing poverty and malnutrition. These complexities made necessary new individual and social treatment methods developed in UNESCO Community Centres, within which some positives have resulted, such as the development of individual and group self help and the professions of counselling, social work and community development, practices which did not previously exist in the Soviet Union.

Prevalence of pterygium and cataract in indigenous populations of the Brazilian Amazon rain forest.

PURPOSE: To compare the prevalence of pterygium and cataract in four indigenous populations of the Brazilian Amazonian rain forest (Arawak, Tukano, Maku, and Yanomami) with different ethnic and social behaviour backgrounds. METHODS: A cross-sectional pterygium and cataract survey was performed in 624 adult Indians of the Brazilian rain forest belonging to four different ethnic groups. The Indians were classified according to their social behaviour in two groups: Arawak and Tukano (group 1) and Maku and Yanomami (group 2). Slit-lamp biomicroscopy was employed to examine the entire sample. All subjects were classified as 1 or 0 according to the presence or absence pterygium and cataract. Sex and age were also recorded. RESULTS: chi(2)-tests revealed that the prevalence of pterygium and cataract differed significantly between groups 1 and 2. For pterygia: 36.6% (97/265) and 5.0% (18/359), respectively (chi(2)=101.2, P<0.0001), and for cataracts: 24.5% (65/265) and 13.7% (49/359) respectively (chi(2)=12.09, P=0.0005). Gender was not associated with pterygium (P=0.1326) and cataract (P=0.2263) in both groups. Elderly subjects showed a significantly higher prevalence of cataract (P<0.0001). The prevalence of pterygia did not increase with age (P=0.8079) in both groups. CONCLUSION: Indians of group 1 have higher prevalence of pterygia and cataract than Indians of group 2. Social behaviour, especially the rate of sun exposure, appears to be the main factor for the different rates of pterygium and cataract displayed by these indigenous people of the Brazilian rain forest.

Modulation of radiation-induced cytokine elevation associated with esophagitis and esophageal stricture by manganese superoxide dismutase-plasmid/liposome (SOD2-PL) gene therapy.

Radiation of the esophagus of C3H/HeNsd mice with 35 or 37 Gy of 6 MV X rays induces significantly increased RNA transcription for interleukin 1 (Il1), tumor necrosis factor alpha (Tnf), interferon gamma inducing factor (Ifngr), and interferon gamma (Ifng). These elevations are associated with DNA damage that is detectable by a comet assay of explanted esophageal cells, apoptosis of the esophageal basal lining layer cells in situ, and micro-ulceration leading to dehydration and death. The histopathology and time sequence of events are comparable to the esophagitis in humans that is associated with chemoradiotherapy of non-small cell lung carcinoma (NSCLC). Intraesophageal injection of clinical-grade manganese superoxide dismutase-plasmid/liposome (SOD2-PL) 24 h prior to irradiation produced an increase in SOD2 biochemical activity in explanted esophagus. An equivalent therapeutic plasmid weight of 10 microgram ALP plasmid in the same 500 microliter of liposomes, correlated to around 52-60% of alkaline phosphatase-positive cells in the squamous layer of the esophagus at 24 h. Administration of SOD2-PL prior to irradiation mediated a significant decrease in induction of cytokine mRNA by radiation and decreased apoptosis of squamous lining cells, micro-ulceration, and esophagitis. Groups of mice receiving 35 or 37 Gy esophageal irradiation by a technique protecting the lungs and treating only the central mediastinal area were followed to assess the long-term effects of radiation. SOD2-PL-treated irradiated mice demonstrated a significant decrease in esophageal wall thickness at day 100 compared to irradiated controls. Mice with orthotopic thoracic tumors composed of 32D-v-abl cells that received intraesophageal SOD2-PL treatment showed transgenic mRNA in the esophagus at 24 h, but no detectable human SOD2 transgene mRNA in explanted tumors by nested RT-PCR. These data provide support for translation of this strategy of SOD2-PL gene therapy to studies leading to a clinical trial in fractionated irradiation to decrease the acute and chronic side effects of radiation-induced damage to the esophagus.

Prevalence and risks of dementia in the Japanese population: RERF's adult health study Hiroshima subjects. Radiation Effects Research Foundation.

OBJECTIVES: To study the prevalence rate of dementia and its subtypes in Japan and to investigate the relationship of risk factors, such as demographic features and disease history, to the prevalence of Alzheimer's disease or vascular dementia. DESIGN: A prevalence study within a longitudinal cohort study. SETTING: The original Adult Health Study (AHS) cohort consisted of atomic-bomb survivors and their controls selected from residents in Hiroshima and Nagasaki using the 1950 national census supplementary schedules and the Atomic Bomb Survivors Survey. Since 1958, the AHS subjects have been followed through biennial medical examinations. PARTICIPANTS: Subjects were 637 men and 1585 women aged 60 years or older in the AHS cohort. Forty-eight subjects resided in hospitals and institutions. MEASUREMENTS: In addition to the biennial medical examinations ongoing since 1958, a screening test for cognitive impairment (CASI) was conducted by trained nurses between September 1992 and September 1996. The prevalence of dementia and its subtypes was assessed in 343 subjects suspected to have dementia and in 272 subjects with high CASI scores who were selected randomly. RESULTS: The prevalence of dementia based on DSM III/R criteria, using neurological examination, the IQCODE, and CDR > or = 1, was 7.2%. The prevalence of Alzheimer's disease was 2.0% in men and 3.8% in women, and the prevalence of vascular dementia was 2.0% in men and 1.8% in women. The relationship of risk factors to Alzheimer's disease or vascular dementia was investigated by the multivariate logistic linear regression analysis. Odds ratios of Alzheimer's disease for age (in 10-year increments), attained education (in 3-year increments), history of head trauma, and history of cancer are 6.3, 0.6, 7.4, and 0.3, respectively. Odds ratios of vascular dementia for age, history of stroke, and history of hypertension are 2.0, 35.7, and 4.0, respectively. Neither type of dementia showed any significant effect of sex or radiation exposure. CONCLUSION: This study is the first study of Japanese dementia rates carried out with a protocol similar enough to that of a US study to allow meaningful comparisons. The prevalence rates demonstrated are more similar to US rates than were found in many previous reports in Japan.