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Susan Sandon, Managing Director of Cornerstone and Jason Arthur, Publisher of William Heinemann have acquired UK and Commonwealth Rights (exc. Canada) in Uncommon Type: Some Stories by Tom Hanks. The deal was struck with Suzanne Smith at Knopf, Penguin Random House in New York.
Uncommon Type will be published this October in hardcover, ebook and in audio with Tom Hanks reading. Publication will be simultaneous with Knopf in the US and in addition, rights have already been sold in Canada, Japan, China, Germany, Italy, Brazil and the Netherlands.
Uncommon Type features seventeen stories, each in some way involving a different typewriter (Hanks is an avid collector of vintage typewriters and owns over one hundred of them). In the book, there is a story about an immigrant arriving in New York City after his family and life have been torn apart by his country's civil war; another about a man who bowls a perfect game (and then another, and another) becoming ESPN's newest celebrity; another about an eccentric billionaire and his faithful executive assistant on the hunt for something larger in America; and another about the junket life of an actor.
"I read a story by Tom in The New Yorker several years ago," said Sonny Mehta, Chairman and Editor-in-Chief of Alfred A. Knopf. , "and was struck by both his remarkable voice and command as a writer. I had hoped there might be more stories in the works. Happily, for readers, it turns out there were."
Hanks began writing the book in 2015. "In the two years of working on the stories," said Hanks, "I made movies in New York, Berlin, Budapest, and Atlanta and wrote in all of them. I wrote in hotels during press tours. I wrote on vacation. I wrote on planes, at home, and in the office. When I could actually make a schedule, and keep to it, I wrote in the mornings from 9 to 1."
Jason Arthur says, "Uncommon Type is uncommonly full of compelling voices and utterly memorable characters. With these astonishingly accomplished, vivid and vital stories, Tom Hanks proves himself to be an exuberant writing talent and an exciting new voice in fiction."
Susan Sandon says, "We read these wonderful stories with mounting excitement and offered within hours of Suzanne's submission. This will be a major publication for us this autumn, indeed a major publishing event."
Notes for editors:
William Heinemann is an imprint of Cornerstone, part of The Random House Group Ltd, a Penguin Random House Company.
Alfred A. Knopf, a flagship imprint of the Knopf Doubleday Publishing Group, which is a division of Penguin Random House, Inc.
Penguin Random House (http://global.penguinrandomhouse.com/) is the world's most global trade book publisher. It was formed on July 1, 2013, upon the completion of an agreement between Bertelsmann and Pearson to merge their respective trade publishing companies, Random House and Penguin, with the parent companies owning 53% and 47%, respectively. Penguin Random House comprises the adult and children's fiction and nonfiction print and digital trade book publishing businesses of Penguin and Random House in the U.S., U.K., Canada, Australia, New Zealand, India and South Africa, and Penguin's trade publishing activity in Asia and Brazil; DK worldwide; and Penguin Random House Group Editorial's Spanish-language companies in Spain, Mexico, Argentina, Uruguay, Colombia, and Chile. Penguin Random House employs more than 10,000 people globally across almost 250 editorially and creatively independent imprints and publishing houses that collectively publish more than 15,000 new titles annually. Its publishing lists include more than 60 Nobel Prize laureates and hundreds of the world's most widely read authors.
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Carriers of germline mutations in DNA mismatch repair (MMR) genes have a high risk of colorectal cancer (CRC), but the modifiers of this risk are not well established. We estimated an association between body mass index (BMI) in early adulthood and subsequent risk of CRC for carriers and, as a comparison, estimated the association for non-carriers.
A weighted Cox regression was used to analyse height and weight at 20 years reported by 1324 carriers of MMR gene mutations (500 MLH1, 648 MSH2, 117 MSH6 and 59 PMS2) and 1219 non-carriers from the Colon Cancer Family Registry.
During 122304 person-years of observation, we observed diagnoses of CRC for 659 carriers (50%) and 36 non-carriers (3%). For carriers, the risk of CRC increased by 30% for each 5kgm–2 increment in BMI in early adulthood (hazard ratio, HR: 1.30; 95% confidence interval, CI: 1.08–1.58; P=0.01), and increased by 64% for non-carriers (HR: 1.64; 95% CI: 1.02–2.64; P=0.04) after adjusting for sex, country, cigarette smoking and alcohol drinking (and the MMR gene that was mutated in carriers). The difference in HRs for carriers and non-carriers was not statistically significant (P=0.50). For MLH1 and PMS2 (MutLα heterodimer) mutation carriers combined, the corresponding increase was 36% (HR: 1.36; 95% CI: 1.05–1.76; P=0.02). For MSH2 and MSH6 (MutSα heterodimer) mutation carriers combined, the HR was 1.26 (95% CI: 0.96–1.65; P=0.09). There was no significant difference between the HRs for MutLα and MutSα heterodimer carriers (P=0.56).
Body mass index in early adulthood is positively associated with risk of CRC for MMR gene mutation carriers and non-carriers.
Lynch syndrome, historically known as hereditary non-polyposis colorectal cancer (Jass, 2006), refers to colorectal and other cancers caused by germline mutations in DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2 (Vasen et al, 1999). Approximately 1 in 3000 people in the general population carry a mutation in an MMR gene (Dunlop et al, 2000). These MMR gene mutation carriers are at substantially increased risk of colorectal cancer (CRC) with an estimated cumulative risk to age 70 years between 40% and 70% depending on the carrier's sex and the MMR gene that is mutated (Chen et al, 2006; Jenkins et al, 2006; Senter et al, 2008; Baglietto et al, 2010). Physical characteristics or environmental exposures of the mutation carriers could also modify their risks of developing CRC (Jenkins et al, 2007). Identifying modifiers of CRC risk for carriers of MMR gene mutations is important for understanding carcinogenesis. Identifying potentially protective or harmful and avoidable risk factors also creates opportunities for mutation carriers to reduce their risks of life-threatening diseases.
Previous studies have provided evidence for the existence of modifiers of CRC risk for MMR gene mutation carriers. For example, CRC risk for carriers is positively associated with alcohol consumption (Watson et al, 2004) and negatively associated with fruit consumption and dietary fibre intake (Diergaarde et al, 2007). For smoking, CRC risk for carriers is positively associated with current smoking (Diergaarde et al, 2007; Pande et al, 2010), but negatively or not associated with former smoking (Diergaarde et al, 2007; Pande et al, 2010). However, the association between body size and CRC risk for MMR gene mutation carriers is yet to be established.
One CRC risk factor for people in the general population is body size, a collective term for body mass index (BMI), waist circumference and height (Dai et al, 2007; Larsson and Wolk, 2007; Moghaddam et al, 2007; Renehan et al, 2008). Previous case–control studies of CRC cases with a family history (therefore, likely to be enriched for MMR gene mutation carriers) compared with population-based controls who were unselected for family history, have shown that current BMI is positively associated with CRC risk (Slattery et al, 2003; Campbell et al, 2007). However, studies that have examined the association between current BMI and the occurrence of tumours with microsatellite instability (MSI), a common characteristic of CRCs caused by MMR defects, have reported no statistically significant associations with this form of disease (Slattery et al, 2000; Campbell et al, 2010). One study that examined the association between BMI and colorectal adenoma risk for MMR gene mutation carriers observed a positive association for males but not females (Botma et al, 2010).
Identifying an association of BMI in early adulthood on subsequent cancer risk would be important for MMR gene mutation carriers who learn their mutation status as adults in their 20s, an increasingly common occurrence because of increased systematic testing in the population, with the consequent opportunity to reduce their risk of disease. In this study, we estimated an association between BMI at age 20 years and CRC risk for MMR gene mutation carriers. As a comparison, we also estimated the association for non-carriers to investigate whether BMI has a differential effect on risk for CRC by mutation status.
Subjects comprised carriers and non-carriers of pathogenic mutations (see below) in the MMR genes MLH1, MSH2, MSH6 and PMS2, recruited and genetically characterised by the Colon Cancer Family Registry (Colon CFR). Study designs and recruitments for the Colon CFR can be found at http://epi.grants.cancer.gov/CFR/ and have been published in detail (Newcomb et al, 2007). Probands were either a recently diagnosed CRC case reported to a population-complete cancer registry or an attendee at a family cancer clinic. They were recruited between 1997 and 2007 and ascertained from family cancer clinics from Australia (Melbourne, Adelaide, Perth, Brisbane and Sydney), New Zealand (Auckland) and the United States (Mayo Clinic, Rochester, Minnesota and Cleveland) or from population-complete cancer registries in the United States (Puget Sound, Washington State; the State of Minnesota; Los Angeles, California; Arizona; Colorado; New Hampshire; North Carolina; and Hawaii), Australia (Victoria) and Canada (Ontario).
Probands were asked for permission to contact their relatives to seek their enrolment in the Colon CFR. For probands ascertained from family cancer clinics, there were pre-specified rules consistent across recruiting centres governing which relatives were to be approached for recruitment (Newcomb et al, 2007). For probands ascertained from population-complete cancer registries, first-degree relatives were recruited at all centres and in some centres, recruitment extended to more distant relatives. Written informed consent was obtained from all study participants, and the study protocol was approved at each Colon CFR centre.
At recruitment, baseline information on demographics, personal characteristics, personal and family history of cancer, cancer screening history, history of polyps, polypectomy and other surgery were obtained from all participants. Participants were followed-up approximately 5 years after baseline to update all this information. The questionnaires are available from http://cfrisc.georgetown.edu/isc/ dd.questionnaires.do. Reported cancer diagnoses and age at diagnoses were confirmed, where possible, using pathology reports, medical records, cancer registry reports and/or death certificates. Blood samples and tumour tissues were collected for genetic testing. The present study was based on all available baseline and follow-up data.
Self-reported height and weight at approximately age 20 years were collected using standardised personal interviews (University of Southern California Consortium), telephone interviews (University of Southern California Consortium, Fred Hutchinson Cancer Research Centre and University of Melbourne) or mailed questionnaires (University of Hawaii, Cancer Care Ontario and Mayo Clinic).
Testing for MLH1, MSH2, MSH6 and PMS2 mutations was performed for all case probands ascertained from family cancer clinics and for all probands from population-based ascertainment who had a colorectal tumour displaying evidence of impaired MMR function as evidenced by either MSI, or by lack of MMR protein expression by immunohistochemistry. Mutation testing was performed by Sanger sequencing or denaturing high-pressure liquid chromatography, followed by confirmatory DNA sequencing. Large insertion and deletion mutations were detected by multiplex ligation-dependent probe amplification according to the manufacturer's instructions (MRC Holland, Amsterdam, The Netherlands) (Southey et al, 2005; Newcomb et al, 2007; Senter et al, 2008). All participants who donated a blood sample, and who were relatives of probands with a pathogenic mutation, underwent testing for the same mutation identified in the proband.
For this study, we included male and female probands and their participating relatives who were confirmed carriers and confirmed non-carriers of an MMR gene mutation. In total, 1468 carriers and 1365 non-carriers were identified. Of these, 144 (10%) carriers and 146 (11%) non-carriers were excluded due to missing data on height or weight at age 20 years, leaving a total of 1324 carriers (252 from population-based sources) and 1219 non-carriers (109 from population-based sources) for the analysis. Excluded subjects did not differ in baseline characteristics from subjects who entered into the analyses (age, sex, country and gene mutated) (data not shown).
We were unable to analyse current BMI in this study, as it was not available 1–2 years prior to diagnosis or censored age for 833 subjects (636 carriers and 197 non-carriers), which is 33% of the total sample size. This was composed of 450 CRC cases (425 carriers and 25 non-carriers), 215 subjects (140 carriers and 75 non-carriers) with another cancer and 164 subjects with a prior polypectomy (70 carriers and 94 non-carriers) and 4 subjects (1 carrier and 3 non-carriers) who did not report current weight at last contact.
A pathogenic mutation was defined to be a variant that was predicted to result in a stop codon, a frameshift mutation, a large insertion or deletion, or a missense mutation previously reported in the scientific literature to be pathogenic. Age at CRC was the age at first diagnosis of CRC. Height and weight were defined as self-reported height and weight at age 20 years, respectively. BMI at age 20 years was calculated as weight as reported at age 20 years in kilograms divided by height in metres squared (kgm–2). Body mass index was categorised as 18.49kgm–2 (underweight), 18.50–24.99kgm–2 (normal weight), 25.00–29.99kgm–2 (overweight) or 30.00kgm–2 (obese) according to World Health Organization criteria (World Health Organization, 1998). T and N staging of CRC was categorised according to the American Joint Committee on Cancer staging (Edge et al, 2009).
Mismatch repair gene mutation carriers and non-carriers were treated as a cohort from birth. A proportional Cox regression model with age as the time scale was used to estimate hazard ratios (HR) relating BMI to CRC risk for carriers and non-carriers. Time at risk started at birth and ended at age of diagnosis of cancer of any site, polypectomy, death or last contact, whichever occurred first. The rationale for censoring at diagnosis of any cancer was that the resultant treatment and surveillance might alter risk of subsequent cancers, including CRC and this would introduce bias if the first cancer was associated with body size. Similarly, as polypectomy may reduce CRC risk, censoring at time of polypectomy was also required to avoid potential bias. Of the total 1324 mutation carriers, observation time ended at age of diagnosis for 659 CRC cases, and was censored at age of polypectomy for 173 subjects, at age of diagnosis of another cancer for 144 subjects, at age of death for 4 subjects and at age of last contact for 344 subjects. Of the total 1219 non-carriers, time of observation ended at the age of diagnosis for 36 CRC cases, at age of polypectomy for 176 subjects, at age of diagnosis of another cancer for 101 subjects, at age of death for 14 subjects and at age of last contact for 892 subjects.
Since some subjects were ascertained because they were from multiple-case CRC families, and CRC cases were preferentially tested for MMR gene mutations, the selection of subjects was not random with respect to disease status. To adjust for this non-random ascertainment, we used the weighted cohort approach described by Antoniou et al (2005), which has been used for modifier studies of cancer risk for carriers of rare genetic mutations (e.g., Andrieu et al, 2006; Antoniou et al, 2008; Win et al, 2011). A simulation study of this approach (Antoniou et al, 2005) showed that allowing for non-random sampling of subjects by using rates from an external referent population removed bias when the external rates were correctly specified, and reduced bias if the external rates were not completely accurate.
Age-specific incidence rates of CRC for MMR gene mutation carriers were previously estimated as described in detail by Pande et al (2010). These age-specific incidence rates were used to calculate sampling fractions to weight the proportion of affected and unaffected carriers in each age stratum, so that the proportion of affected carriers in each age group equalled the population proportions (Supplementary Table S1).
Due to the rarity of mutations in the population, age-specific incidence rates for non-carriers were assumed to equal those for the general population. Data on age-specific (5-year intervals) population cancer incidence rates were obtained from the American Cancer Society Cancer Facts and Figures 2008 (American Cancer Society, 2008). Using these age-specific incidence rates, we calculated sampling fractions to weight the proportion of affected and unaffected non-carriers in each age stratum.
Body mass index was fitted as a continuous variable and as a categorical variable based on WHO BMI classification (World Health Organization, 1998). In order to determine whether a non-linear association with a continuous variable was a superior fit compared with a linear model, we fitted and compared fractional polynomial models. Models were compared using Wald's tests. The proportional hazards assumption was tested by examining the relationship between the scaled Schoenfeld residuals and survival time.
To control for potential confounders present at the age at which BMI was reported (i.e., 20 years old), we adjusted for (i) sex, (ii) country of recruitment, (iii) cigarette smoking at age 20 (never, ever) and (iv) alcohol drinking at age 20 (ever, never) in both carriers and non-carriers, and further adjusted for (v) specific MMR gene that was mutated in carriers. Interactions between (i) mutation carrier status and BMI, (ii) sex and BMI and (iii) the specific MMR gene mutated and BMI were tested by adding an interaction term in a multivariable model. We did not adjust for current BMI because of the well-known bias introduced by adjusting for variables that are in the causal pathway or partly caused by the exposure of interest. The associations between BMI and CRC risk were estimated separately for carriers of mutation in each MMR gene, and carriers of mutations in the MutLα heterodimer (MLH1 and PMS2) and MutSα heterodimer (MSH2 and MSH6) genes.
Two sensitivity analyses were conducted: (i) to determine whether unverified self-reported CRC cases or cases reported by relatives influenced the associations with BMI, we performed analyses after excluding these cases and (ii) to determine whether censoring at polypectomy influenced the associations with BMI, we performed analyses of colorectal neoplasia that is CRC and colorectal polyps combined, as the outcome.
We applied the Huber–White robust variance estimation by clustering on family membership to allow for any correlation of risk between family members (Rogers, 1993; Williams, 2000). All statistical tests were two sided and, following convention, statistical significance for testing a predetermined null hypothesis was set at P<0.05. All statistical analyses were performed using Stata 10.0 (StataCorp, 2007).
The study comprised 1324 carriers (737 females) of MMR gene mutations (500 in MLH1, 648 in MSH2, 117 in MSH6 and 59 in PMS2) from 498 families contributing a total of 58868 person-years, of which 659 (50%) were diagnosed with CRC, and 1219 non-carriers (712 females) from 287 families contributing 63436 person-years, of which 36 (3%) were diagnosed with CRC. Of all participants, 839 carriers and 983 non-carriers (72%) were recruited in Australia or New Zealand, 367 carriers and 199 non-carriers (22%) in the United States and 118 carriers and 37 non-carriers (6%) in Canada. Baseline characteristics of the study subjects are summarised in Table 1.
Of the 659 CRC cases in carriers, 595 (90%) were confirmed by pathology report or review, SEER or other cancer registries, or hospital or clinical records and 64 (10%) were unconfirmed reports by self or relatives (Table 2). The mean age at CRC diagnosis was 44 (s.d.: 11) years for carriers and 57 (s.d.: 15) years for non-carriers. The mean reported BMI at age 20 years was 22.7 (s.d.: 3.9) kgm–2 for carriers and 22.4 (s.d.: 3.7) kgm–2 for non-carriers. There were no significant differences in mean BMI or the distributions of mutated MMR genes by country (data not shown).
Table 3 shows that carriers who were obese (30kgm–2) had an approximately two-fold (HR: 2.35; 95% confidence interval, CI: 1.30–4.23) increased risk of CRC compared with carriers who had normal BMI (18.5–24.99kgm–2). Colorectal cancer risk for carriers was estimated to be 30% higher for each increment of 5kgm–2 in BMI (adjusted HR: 1.30; 95% CI: 1.08–1.58; P=0.01). The corresponding HR for female carriers was 1.28 (95% CI: 0.98–1.69; P=0.08) and for male carriers was 1.33 (95% CI: 1.01–1.76; P=0.04); there was no statistically significant evidence that these HRs were different between men and women (P=0.97).
The HR per 5kgm–2 in BMI was 1.20 (95% CI: 0.99–1.44; P=0.06) for right-sided colon cancers; 1.03 (95% CI: 0.84–1.27; P=0.76) for left-sided colon and rectosigmoid cancers; and 1.31 (95% CI: 0.84–2.05; P=0.24) for rectal cancers. When a fractional polynomial model was fitted, there was no evidence that the (log) HR was non-linear (P=0.72).
Table 4 presents separate results for carriers of mutations in each MMR gene. There was a positive association between BMI and CRC risk for MLH1 and PMS2 (MutLα heterodimer) mutation carriers combined (HR: 1.36; 95% CI: 1.05–1.76; P=0.02). The HR for MSH2 and MSH6 (MutSα heterodimer) mutation carriers combined was 1.26 (95% CI: 0.96–1.65; P=0.09), and not statistically different from the HR for MutLα heterodimer mutation carriers (P=0.56).
For non-carriers of MMR gene mutations, CRC risk was estimated to be 64% higher for each increment of 5kgm–2 in BMI (adjusted HR: 1.64; 95% CI: 1.02–2.64; P=0.04). The corresponding HR for female carriers was 1.40 (95% CI: 0.67–2.91; P=0.37) and for male carriers was 1.82 (95% CI: 0.93–3.53; P=0.08); the difference between sexes was not statistically significant (P=0.32). When a fractional polynomial model was fitted, there was no evidence that the (log) HR was non-linear (P=0.88).
The HRs for carriers and non-carriers were not statistically different (interaction between mutation status and BMI; P=0.50).
Sensitivity analyses showed that (i) after excluding unverified self-reported cases or cases reported by relatives, the adjusted HR for each 5kgm–2 increment in BMI was 1.37 (95% CI: 1.13–1.66; P=0.002) for carriers and 1.65 (95% CI: 0.97–2.80; P=0.06) for non-carriers and (ii) defining the outcome as colorectal neoplasia (either CRC or polyp), the adjusted HR for each 5kgm–2 increment in BMI was 1.20 (95% CI: 1.00–1.44; P=0.05) for carriers and 1.27 (95% CI: 0.96–1.66; P=0.09) for non-carriers.
We have shown that greater BMI at age 20 years is associated with a higher risk of CRC in later life for both carriers and non-carriers of pathogenic germline mutations in MMR genes. For MMR mutation carriers, we found no statistically significant differences between the strengths of association for men and women, and for carriers of mutations in MutLα or MutSα heterodimer genes. These results suggest that BMI in early adulthood is a potential modifier of CRC risk in later life for MMR gene mutation carriers as a whole.
Our study was based on 1324 carriers and 1219 non-carriers of a confirmed pathogenic mutation in any of four MMR genes, making it the largest study to date of this issue. To overcome bias when subjects are selected on the basis of phenotype, we used a weighted cohort approach (Antoniou et al, 2005), which has been successfully utilised for studies of modifiers of cancer risk of rare genetic mutations (e.g., Andrieu et al, 2006; Antoniou et al, 2008; Win et al, 2011). Familial correlation in the risk of CRC was also accounted for using a robust variance estimation to derive appropriate measure of HR estimate imprecision (Rogers, 1993; Williams, 2000). Another strength was the standardised and uniformly high-quality testing for MMR gene mutations by the Colon CFR (Newcomb et al, 2007).
Potential limitations of this study include the use of self-reported weight and height and the often long period between age 20 years and the interview, meaning that participants often had to recall weight many years in the past. However, other studies have shown that measures of weight taken at age 20–30 years are well correlated with recalled values at age 50–70 years, with correlation coefficients ranging between 0.73 and 0.95 (Stevens et al, 1990; Perry et al, 1995; Troy et al, 1995; Norgan and Cameron, 2000; Tamakoshi et al, 2003). There is a possibility of response bias, where CRC-affected subjects recall their weight at age 20 years differently than unaffected subjects. It is also possible that the recall of weight at age 20 years may have depended on the methods of data collection, which varied by recruitment centre, and, therefore, may have resulted in decreased precision of reported weight data. Since cases with poor survival were less likely to be included in this analysis (as they were unable to provide a blood sample for genetic testing and complete a questionnaire), there is a possibility of survival and selection bias if age at onset and survival of cases were related to BMI and/or mutation status. We acknowledge that exposures such as physical activity and meat consumption that we have not adjusted for in this analysis may be confounders for the observed associations.
One previous study investigated the role of BMI in colorectal neoplasms for MMR gene mutation carriers, but the focus of their study was colorectal adenomas (Botma et al, 2010). They reported that MMR gene mutation carriers who are overweight or obese (current BMI 25kgm–2) had higher risk of adenomas compared with those with normal BMI (<25kgm–2) for men (HR: 8.72; 95% CI: 2.06–36.96), but not for women (HR: 0.75; 95% CI: 0.19–3.07). A case–control study of CRC cases who met the revised Bethesda or Amsterdam criteria for Lynch syndrome and population controls observed both increased BMI at age 20 years and current BMI were associated with increased CRC risk for men, but not for women (Campbell et al, 2007). In our study, we did not observe statistical evidence for a difference between men and women for associations of BMI with CRC risk. Consistent with our results, Slattery et al (2003) found that obese people with a family history of CRC had approximately two-fold increased risk of CRC compared with those with normal BMI for both sexes combined (odds ratio: 1.65, 95% CI: 1.01–2.73).
There have been two population-based case–control studies examining the association between BMI and CRC with and without MSI, a phenotype that indicates loss of MMR function somatically, but not necessarily due to inherited mutations. Approximately 50% of CRCs with MSI diagnosed before age 50 years arise in MMR gene mutation carriers and 12% of cases diagnosed at age 50 years are MMR gene mutation carriers (Hampel et al, 2008). These studies found positive associations between current BMI and microsatellite stable tumours, but no association with MSI-high tumours (Slattery et al, 2000; Campbell et al, 2010). It is difficult to compare these findings with our results because MSI tumours include CRCs caused not by an inherited MMR gene mutation but by methylation of MLH1 (Herman et al, 1998; Poynter et al, 2008), and, therefore, these previous studies are probably not generalisable to MMR gene mutation carriers. Using the population-based cases from the Colon CFR (the same source of data for this analysis), Campbell et al (2010) found some suggestion that obese MMR gene mutation carriers, compared with those with normal BMI, had an increased risk of CRC (odds ratio: 3.96; 95% CI: 0.59–26.48) when MSI-high was further stratified by known MMR gene mutation status. As evidenced by the broad CIs, however, the study had insufficient numbers (only 85 carriers) to adequately investigate the association between BMI and CRC due to MMR gene mutations.
We observed a statistically significant association between BMI in early adulthood and CRC risk for MLH1 and PMS2 mutation carriers, but not for MSH2 and MSH6 mutation carriers. However, the associations were not statistically different from each other (P=0.51). The proteins produced by MSH2 and MSH6 from the MutSα heterodimer are responsible for detecting DNA mismatches occurring during replication, whereas the proteins produced by MLH1 and PMS2 from the MutLα heterodimer are responsible for cleavage (Kadyrov et al, 2006; Hewish et al, 2010). The association we observed with MLH1 and PMS2 mutations is consistent with obesity affecting CRC risk by inducing a second hit in the remaining wild-type allele of MLH1 or PMS2. It is also consistent with obesity being a tumour promoter that is more relevant to tumours induced by MMR defects due to mutations in the MutLα heterodimer.
In this study, as all non-carriers are relatives of mutation carriers and, therefore, in general matched for familial factors that may be risk factors for CRC, the two groups are comparable. Given that we observed similar associations of BMI with CRC risk for carriers and non-carriers, we can surmise that having a mutation in an MMR gene does not alter the degree of increased risk imposed by BMI in early adulthood. In contrast, we have shown, using the same analytical design and data source, that non-carrier women were 74% more likely to develop endometrial cancer for every 5kgm–2 increase in BMI at age 20 (HR: 1.74; 95% CI: 1.27–2.37; P<0.001), while carriers were not more likely to develop endometrial cancer with increased BMI (Win et al, 2011). Given MMR mutation carriers are rare in the general population (Dunlop et al, 2000), the vast majority of the general population are non-carriers and, therefore, our finding for non-carriers will be generalisable to the general population. Our findings for non-carriers are consistent, in terms of direction, with previously published studies that observed a positive association between BMI in early adulthood and subsequent CRC risk for the general population (Le Marchand et al, 1992; Lee and Paffenbarger, 1992; Must et al, 1992; Russo et al, 1998).
The biologic mechanisms underlying an association between body size in early adulthood and increased risk of CRC are not well understood. One theory suggests that obesity, particularly central obesity, increases insulin resistance and hyperinsulinaemia (Giovannucci, 1995; Kahn and Flier, 2000) via alterations in the signalling of endogenous hormones, particularly not only insulin and insulin-like growth factors, but also steroid hormones, and possibly, adipocyte-derived factors such as leptin and adiponectin (Gunter and Leitzmann, 2006; John et al, 2006). High circulating concentrations of insulin and C-peptide, as well as type 2 diabetes, are associated with increased risk of CRC (Kaaks et al, 2000; Larsson et al, 2005). It is of interest that MMR defects frequently result in mutations of the insulin-like growth factor receptor (IGFR), which involves this same insulin signalling system (Duval and Hamelin, 2002). It is not known if the effect of obesity in MMR gene mutation carriers is related to IGFR mutational events.
Our results suggest that BMI in early adulthood is a potential modifier of CRC risk for carriers of an MMR gene mutation. Currently, the only methods available for MMR gene mutation carriers to reduce their risk for CRC are screening by colonoscopy (de Jong et al, 2006), prophylactic subtotal colectomy (Smith and Rodriguez-Bigas, 2009) and aspirin chemoprevention (Burn et al, 2009). Avoiding obesity in early adulthood might also reduce the risk of CRC for MMR gene mutation carriers.
This work was supported by the National Cancer Institute, National Institutes of Health under RFA #CA-95-011 and through cooperative agreements with members of the Colon CFR and Principal Investigators. Collaborating centres include Australasian Colorectal Cancer Family Registry (U01 CA097735), the USC Familial Colorectal Neoplasia Collaborative Group (U01 CA074799), Mayo Clinic Cooperative Family Registry for Colon Cancer Studies (U01 CA074800), Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783), Seattle Colorectal Cancer Family Registry (U01 CA074794) and University of Hawaii Colorectal Cancer Family Registry (U01 CA074806). This work was also supported by a grant from NHMRC Australia (ID 400160). The content of this manuscript neither necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centres in the CFRs, nor does mention of trade names, commercial products or organisations implies endorsement by the US Government or the CFR. We had full responsibility for the design of the study, the collection of the data, the analysis and interpretation of the data, the decision to submit the manuscript for publication and the writing of the manuscript. We thank Dr Elizabeth Williamson from Murdoch Childrens Research Institute, Melbourne, Australia for statistical advice. We thank all study participants of the Colon Cancer Family Registry and staff for their contributions to this project.
The authors declare no conflict of interest.
Supplementary Information accompanies the paper on British Journal of Cancer website (http://www.nature.com/bjc)
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Tag: Ravana
Latest stories
A visit to Hatu Mata Temple near Shimla is Full of Blissful Adventure
Located at about 65 km distance from Shimla, is a destination called Hatu Peak, also famous as the highest peak in the Shimla region. The famous Hatu Mata Temple of the Narkanda region is believed to be a temple of Ravana's wife as per the local belief of the Narkanda Tribe. Situated at 8 km […]
Shiva Tandava Stotram and its meaning – Written by Ravana
Shiva Tandava Stotram is written by Ravana. He is a scholar in Navavyakarana (the 9 types of Sanskrit grammar). Shiv Tandava Stotram is one of his many works. Shiva Tandava Stotram describes how Lord Shiva's hair moves, how the water of river Ganga splashes when he performs a Tandava dance, how his drums sound as […]
The Untold Story of Ravana's sister Surpanakha
Not many of us know about the life story of Ravana's sister Surpanakha.If there had been no Surpanakha, there would have been no Ramayana. This sentence marks the utmost importance of her character as only after her unreciprocated seduction of both Rama and Lakshman resulting in chopping away of her nose and ears by the […]
The Tale of Kartavirya Arjuna – The king who defeated Ravana
History is full of mighty heroes who met an end pitfall because they got to carried away, drunk in power and lost touch with the humanity. One such tale is that of the mighty of Haihayas (In the Mahabharata epic, the Heheya Kingdom (also known as Haihaya, Haiheya, Heiheya, etc.) is one of the kingdoms ruled […]
Shiva Tandava Stotram describes the power and dance of lord Shiva
Shiva Tandava Stotram describes how Lord shiva's hair moves, how the water of river Ganga splashes when he performs a Tandava dance, how his drums sound as he dances, how his ornaments move along with him and more. Story behind Shiva Tandava Stotram Naarad Muni advised Ravana to bring Shiva to his place in Lanka. […]
Was Ravana Kidnapping Sita A Pre-decided Act?
Even the youngest member of the Indian families knows that Sita was abducted by Ravana and the reason we have told them shapes kidnapping of Sita into a revenge taken by Ravana on behalf of his sister. The question that frames here is that whether the chopping of nose and ears of Shurpanakha by Lakshmana […]
Sita was a Daughter of Ravana according to some versions of Ramayana
Goddess Sita's birth is disputed and vague as she was said to be found in a furrow in a plowed field, and for that reason is regarded as a daughter of Bhumi Devi. It is believed that her birthplace to be Janakpur in the Eastern-Madhesh of Nepal or Sitamarhi in Mithila region of present-day Bihar. […]
How did Lord Rama travel from Lanka to Ayodhya in Just 18 days?
Every Hindu is acquainted with the story of Ramayana in one way or the other. It's the story of how Lord Rama saves his wife from Ravana's – the demon king's – abduction. Before that, he and his brother Laxman was exiled from the palace by his father Dasharatha. The war between the two extreme […]
9 Unknown Truths You Probably Didn't Know About Ravana
Ravana is often considered as an evil character in the Ramayana. However, the truth is we can't really classify him as completely good or bad. Like every other mortal being, even he had his shades of gray. Although, it's quite true that he was the most dexterous, but he was one of the most interesting […]
Was the idea of modern satellite really made in the ancient times by Hindus?
If you look at graphical interpretations of Hindu mythology, you might see some cool stuff which seems to be impossible according to modern science. As we already know, the first artificial satellite ever launched by humans was on 1975. It was the Russian satellite Sputnik that hit the news then and is considered to be […]
If KARMA works, why are many corrupt people successful?
Karma is a concept that explains the effects that our actions have up on our lives. The underlying hypothesis is "As you sow, so shall you reap". Karma is based law of returns of energy – and the energy can be of many types-mechanical/physical, emotional/moral, mental/intellectual or spiritual. Karma is a working of energy, not […]


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Body Bar Fitness & Spa
9365 Mcknight Rd Ste 100, Pittsburgh, PA 15237
(412) 364-8500
9365 Mcknight Rd Ste 100, Pittsburgh, PA 15237
(412) 364-8500
2014 Babcock Blvd, Pittsburgh, PA 15209
Regular Hours
Fax: (412) 364-6770
American Massage Therapy Association
Associated Bodywork and Massage Professionals
Smart Tan International
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I started using the Body Bar for prenatal massage about four years ago. Since then, I've gone for facials, massage, tanning, and became a member of their fitness facility. They offer so much and the prices are unbeatable for the professional, clean atmosphere. I left to try the new, big gym down the road and was back at Body Bar in no time. New and big does not measure up to friendly, clean, and quality.
The prices are amazing for the services offered! Went for a massage, the front seemed busy with tanning, but the massage part was quiet and relaxing! Will definitely be back!
I get regular massages here & I am never disappointed! All their therapists are great & the girls at the front desk are so nice!
I am at the Body Bar almost every day, and I have never been disappointed! I have used their massage, tanning, and waxing services and would recommend them to anyone. The staff is very friendly and knowledgable. The tanning beds are nicer than any I've come across (and there are always specials)! On top of their great service, the Body Bar is extremely clean and welcoming.
I absolutely loved the Body Bar! I just received my first Airbrush Tan and it came out beautifully!! The technician and the front desk staff were so friendly, and I got a ton of compliments on my tan. There are a variety of colors the technician is able to pick from so it was customized to my skin tone, not to mention they keep track of the color combination they use so you can do the same thing every time you go in :) I would definitely recommend the Body Bar to any friend of mine!! It was a great experience!
It's been awhile since I last went for a facial service. I stop going for them regularly because I didn't feel these services did anything dramatic for my skin and when I do go for them, it's more like a pampering session for myself. After talking with Jessica the esthetician she educated me on a few little thing I change in my daily routine at home as well as getting facials at least once every three months my skin changed dramatically. I would also like to add the staff there was very friendly and helpful.
The service at The Body Bar is amazing! When I first walked in, I thought it seemed kind of busy because the fitness center and classes are held in the front. The spa is in the rear of the facillity in its own private area. It was very relaxing back there, and very clean. I was impressed to see the staff cleaning the rooms after each service and chaging the linens. Everyone was very friendly and attentive and I loved hoe personable they were w/o talking too much! They provideyou with really good coupons for future visits and although it's a hike from where I live, I'll definitely be back.


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Two Hours in Tallinn
My experience in Tallinn was very limited...2 hours. I was fortunate enough to be able to step on land while working for a cruise line and being docked at Tallinn. Hopefully my brief time in Estonia will give you an idea of what you'd like to see (hopefully in a longer period of time).
Tallinn's old town center is approximately a 15 minute walk from the cruise terminal. Upon arrival at the city walls, I started following a self-guided tour from my guidebook. It gave me a good overview of the city with a brief description of things of note while walking around.
The town hall square was your usual bustling center plaza with restaurants and stalls to purchase mementos (more on that later).
I continued my walk by heading to the upper part of the town to get a glimpse of my first Russian orthodox cathedral, Alexander Nevsky.
If you stay uphill and walk back towards the cruise terminal you'll come across some great viewpoints to overlook the city.
With my available time coming to a close, I started back towards the cruise ship terminal. Stopping to survey the stalls set up outside the terminal for trinkets. Usually I would avoid making purchases right on the pier, but if you fancy yourself some amber jewelry, it's much cheaper to buy it in Tallinn than in Russia, (at least it was during my visit).
My mother who was traveling with me, was able to spend more time in the city center than I was. She reported that there was great woolen items for sale including gorgeous sweaters. She also had the chance to stop into a local restaurant (saying to avoid the places right on the market square which appeared to have a poor quality) and enjoyed some Russian influenced fare.
Tallinn would definitely be worth spending a day in if you weren't arriving by ship, but as a stop on your voyage, it does make a lovely day...even if you only have 2 hours off of work.


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Coreas is a member of the Goddards Group of Companies, Corea & Co. is well established as being the most respected shipping agency and shore excursion operator in St Vincent and the Grenadines serving 70% of the cruise and cargo vessels that visit our shores.
Corea & Co's Cruise Division represents:-Princess Cruises, Festival Cruises, Celebrity Cruises, Silverssea Cruises, Cunard/Seabourn line, Sun Cruises, Costa Cruises, P&O Cruises, Clipper Cruise Lines, Crystal Cruises, Hapg-Lloyd Kreufahrten GmbH, Hansa Touristik, Sea Cloud Cruises, Marine Universal Shipping Co, Royal Olympic Cruises, Holland America, Aida Cruises as well as special Expeditions.
Website designed by: Wyllie Design.


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A German man was charged with drug trafficking. The prosecution accused him of selling 11 kilograms of marijuana. The defendant also ordered narcotics from the dark web for his personal use. Law enforcement authorities stopped a 39-year-old's car because of his suspicious Hanoverian license plate. The suspect, 39, of Brunswick, Lower Saxony, Germany was arrested on the scene since the ... Read More »
Tag Archives: facing
Darknet Vendors Behind "FinestDrugsDE" Facing 15 Years in Prison
In November 2016, police raided numerous apartments in Thuringia, Germany. During the raids, law enforcement made discoveries that they called the biggest blow against online drug trafficking, at the time. They found notebooks of recorded data, phones, hard drives, kilograms of drugs, and two suspects: 31-year-old Philipp H. and 19-year-old Stefanie W. Those two suspects now face 15 years in ... Read More »
Operation Tiger: 13 Arrested And Facing Drug Charges In New Zealand
New Zealander authorities announced the arrest of 13 individuals who were arrested in a nationwide police operation. The suspects are facing drug-related charges. All of the cases against the defendants are related to the dark web narcotic trade. On August 4, Detective Sergeant Tim Williams of the Waitemata Police informed the public in a press release about the arrest of ... Read More »
German Weapon And Narcotic Dealer Facing 68 Charges
A man in his 30s from Lüdenscheid, Germany is facing 68 charges, including the illegal sale of weapons and drugs on a darknet forum. According to the court documents, the prosecution is currently preparing a comprehensive case against the 33-year-old defendant. A cybercrime specialist from the Cologne public prosecutor's office reported that the family father had allegedly traded drugs and ... Read More »
Germany Facing Record Levels of Internet Fraud
A recent case in Germany revealed just how common fraudulent online storefronts have become. The Munich District Court heard a case that exemplified the fraud issues in Germany. And Matthias Huber, public prosecutor, explained the reason similar shops kept causing problems for the general public—and the police. The biggest issue that victims often face, he explained, was that fraudsters usually ... Read More »
Swiss Cantonal Police Facing Difficulties In The Prosecution Of Dark Net Criminals
According to a report, the cantonal police in Bern, Switzerland is confronted with new challenges when they are investigating cybercrime-related cases. The Swiss cantonal police published a crime report on Monday, in which they only gave a few words to cybercrime. According to them, the investigations against internet criminals are "very complex and elaborate". Law enforcement authorities admitted that they ... Read More »
Gladstone Man Facing Jail For Possessing Ice
Buddy Lipczynski (26) from Gladstone, has been arrested by police for possessing 1.9 grams of methylamphetamine (meth/ice). The man was on suspended jail sentence since he pleaded guilty last August to possession of a document on a flash drive that held instructions on the manufacturing of methylamphetamine. Lipcynski has stood before court several times for multiple drug-related charges and for ... Read More »
Wendelstein Man Facing Court For Ordering Drugs From Dark Web
Franz K. (26), from Wendelstein, is facing charges for ordering several different drugs from dark net markets, such as hash, marijuana, and even viagra. According to the Swabach District Court, the amount of the illegal substances were around 203 grams and were delivered to the man by the German postal service. The man watched a documentary about the dark web, ... Read More »
Hackers Carrying Out Largest Theft Of Customer Data In US. History Facing Prison
Gery Shalon, Joshua Samuel Aaron, two hackers have been charged with arranging and executing massive cyber attacks against financial institutions, brokerage firms, financial news publishers in the United States. This includes the largest theft of customer data from a U.S. financial institution in history, which is the U.S. Financial Sector Hacks. The two man were also charged with the manipulation ... Read More »
Silk Road 2.0 Vendor Arrested in Onymous May Be Facing Jail (UK)
As it was published in walesonline: A drug dealer caught as part of an international clampdown on the so-called "dark net" platform Silk Road 2.0 has been warned he could face jail. Cei William Owens, was arrested with six other Britons last year by the National Crime Agency (NCA), hours after the FBI swooped on the controversial website's alleged creator. ... Read More »


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Software Development Engineer II
Since its founding in 2002, Big Fish has been the world's largest producer and distributor of casual games, with titles which continuously land us at the top of app store charts. Today, we're bounding into the mid-core space, exploring new and exciting forms of gameplay, and producing more fun than ever! Big Fish is home to six individual studios, each with its own unique style of game-play. Together, we're united under a common goal: to produce and develop the very best in mobile gaming, and bring fun and entertainment to our millions of customers across the globe!
Tired of playing the wrong kinds of "games"? Join the Pond!
Do you have a passion for developing highly scalable, highly available software that provides key game features to millions of users? Are you eager to work in the fast growing, dynamic, and challenging mobile games space?
The Game Platform Team is looking for a mid-level software engineer to join our team. We support a number of back-end services that drive game features and user experience. We solve complex problems and deliver highly customized solutions for our mobile business lines.
If you're looking for an opportunity to develop highly performant, highly available, scalable systems that provide key features to millions of users across hundreds of different games, this is the team for you!
- Build and maintain mission critical back-end services that handle high volume of traffic
- Research, design and prototype solutions to complex business problems
- Deliver high quality, extensible and maintainable software
- Collaborate with other engineering teams to ensure integrity of end-to-end functionality
- Solid understanding of web development and client-server technologies
- Excellent problem solving, debugging and troubleshooting skills
- Strong verbal and written communication skills
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- Desire and ability to learn quickly and be part of a world-class team
- Bachelors of Science degree in Computer Science, Computer Engineering or Electrical Engineering
- 3 years of progressive, post-baccalaureate experience as a Software Engineer or a related occupation
- 3 years of experience working with object oriented programming language (Java or C#) and dependency management
- 3 years of experience in programming with Python or PHP scripting language
- 3 years of experience building highly scalable, highly available, distributed systems with service oriented architecture (RESTful, RPC)
- 3 years of experience in data persistence technologies, both relational (SQL) and non-relational (Memcached, Redis, MongoDB)
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Want to discover more about life at Big Fish? Check us out on TheMuse.com!
Be the next Big Fish in the Pond!
Meet Some of Big Fish Games's Employees
Meg C.
Senior Game Producer
Meg works to assemble and develop a talented mid-core team with cohesive skills sets to create Big Fish Games titles together far into the future.
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