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Combinations of Cytochrome P450 Gene Polymorphisms Enhancing the Risk for Sporadic Colorectal Cancer Related to Red Meat Consumption
Sébastien Küry, Bruno Buecher, Sébastien Robiou-du-Pont, Catherine Scoul, Véronique Sébille, Hélène Colman, Claire Le Houérou, Tanguy Le Neel, Jérémie Bourdon, Roger Faroux, Jean Ollivry, Bernard Lafraise, Louis-Dominique Chupin and Stéphane Bézieau
Sébastien Küry
Bruno Buecher
Sébastien Robiou-du-Pont
Catherine Scoul
Véronique Sébille
Hélène Colman
Claire Le Houérou
Tanguy Le Neel
Jérémie Bourdon
Roger Faroux
Jean Ollivry
Bernard Lafraise
Louis-Dominique Chupin
Stéphane Bézieau
Susceptibility to sporadic colorectal cancers (CRC) is generally thought to be the sum of complex interactions between environmental and genetic factors, all of which contribute independently, producing only a modest effect on the whole phenomenon. However, to date, most research has concealed the notion of interaction and merely focused on dissociate analyses of risk factors to highlight associations with CRC. By contrast, we have chosen a combinative approach here to explore the joint effects of several factors at a time. Through an association study based on 1,023 cases and 1,121 controls, we examined the influence on CRC risk of environmental factors coanalyzed with combinations of six single nucleotide polymorphisms located in cytochrome P450 genes (c.−163A>C and c.1548T>C in CYP1A2, g.−1293G>C and g.−1053C>T in CYP2E1, c.1294C>G in CYP1B1, and c.430C>T in CYP2C9). Whereas separate analyses of the SNPs showed no effect on CRC risk, three allelic variant combinations were found to be associated with a significant increase in CRC risk in interaction with an excessive red meat consumption, thereby exacerbating the intrinsic procarcinogenic effect of this dietary factor. One of these three predisposing combinations was also shown to interact positively with obesity. Provided that they are validated, our results suggest the need to develop robust combinative methods to improve genetic investigations into the susceptibility to CRC. (Cancer Epidemiol Biomarkers Prev 2007;16(7):1460–7)
sporadic colorectal cancer
genetic association study
cytochrome P450 genes
Given its high prevalence and poor prognosis, colorectal cancer (CRC) is very much a public health issue in industrialized Western countries. In France, it is the third most frequent cancer (>36,000 new cases were diagnosed in 2000) and the second cause of cancer-related death (16,000 deaths were caused by CRC in 2000 for both sexes; ref. 1). Moreover, the current aging of the French population tends to drastically increase the number of incident cases, which warrants research studies on strategy development for CRC prevention.
The vast majority of CRCs are sporadic disorders, the genesis of which includes both environmental and heritable factors (2). Epidemiologic studies on Western populations have emphasized the large contribution of food and lifestyle to sporadic CRC risk (3-9). High-fat and low-fiber diets, as well as alcohol, tobacco, and red or processed meat consumption, have been shown to produce high levels of polycyclic aromatic hydrocarbons and heterocyclic aromatic amines. These procarcinogenic agents are potentially very harmful and may play a key role in the malignant transformation of cells by interacting with DNA (10, 11). However, their biological deleterious effects cannot be exerted without an oxidative activation by phase I cytochrome P450 (CYP) isoenzymes (12). CYPs are encoded by highly polymorphic genes, which results in a remarkable interindividual variability of enzymatic activity. Therefore, the level of procarcinogens activated by an individual depends on genetic background, which determines the degree of susceptibility to procarcinogen exposure and, consequently, to cancer.
Genetic association studies have reported several examples of single nucleotide polymorphisms (SNP) in CYP genes correlated to modulations of CRC risk, whether alone (13-22) or following interaction with environmental factors such as red meat or cigarette consumption (12, 23-26). Despite laying the foundations for further genetic investigations, these studies still provide too partial a view of the cancer susceptibility phenomenon. In fact, they do not take into account the functional redundancy of CYP enzymes and they usually only analyze the modifications of cancer risk associated with an environmental factor and a unique SNP at a time. In fact, the same alimentary compound can be the substrate of numerous CYP enzymes, the polymorphisms of which may all interfere with CRC risk. Rather than unique genetic polymorphisms, these are combinations of polymorphisms that determine the individual genetic background that will finally potentiate the intrinsic promoting or protective effect of xenobiotics on colorectal carcinogenesis (27). Thus, a clue to the understanding of susceptibility to CRC probably involves an examination of these combinations of polymorphisms conducted in the environmental setting.
This is precisely the target we set ourselves through the population-based case-reference study that we report here. In the present work, we coanalyzed six SNPs of CYP genes—c.−163A>C and c.1548T>C in CYP1A2, g.−1293G>C and g.−1053C>T in CYP2E1, c.1294C>G in CYP1B1, and c.430C>T in CYP2C9—and various environmental factors selected from a bibliographical meta-analysis among the factors presumably the most relevant to colorectal carcinogenesis. We investigated combinations of CYP allelic variants that could serve as biomarkers for CRC prevention and/or prognosis, regarding their possible influence on the relative risk for developing CRC when interacting with environmental factors.
Experimental Design and Assembly of the Cohorts
To investigate potential associations between sporadic CRCs and both environmental and genetic factors, we conducted a case-controlled association study. From December 2002 to March 2006, we assembled two cohorts of 1,023 patients and 1,121 controls. The recruitment of these individuals was carried out in the Pays de la Loire region, which is located in the west of France and incorporates the administrative districts of Loire Atlantique, Maine et Loire, Mayenne, Sarthe, and Vendée. Six public hospitals and five clinics situated within these districts gave their agreement to collaborate in this project, thereby constituting a network of hepatogastroenterologists and oncologists specialized in CRCs. All patients with a personal history of CRC diagnosed at an age ≥40 years were eligible for the case cohort provided that there was no suspicion of major genetic predisposition (familial form of CRC).
Most of the control individuals were selected during a routine check-up by physicians working in one of two Health Examination Centers of region Pays de la Loire. Recruitment of individuals ≥70 years was completed in the departments of internal medicine and hepatogastroenterology of the University Hospital of Nantes. In this way, we made up a control cohort that matched the case cohort according to sex, 5-year age groups, and geographic origins. Control individuals were eligible to be included in the study if they were ≥40 years of age, lived in the study region, spoke French, and were physically and mentally able to participate in a personal interview of ∼15 to 20 min. Unaffected individuals with a familial history of CRC or polyps were noneligible.
To meet the requirements of the local (Comité de Protection des Personnes dans la Recherche Biomédicale) and national (Commission nationale de l'Informatique et des Libertés) ethics committees that approved the study, a written informed consent was obtained from each individual included, after having been clearly explained the research protocol by a physician. During the examination, two venous blood samples of 4 mL each were collected in EDTA tubes from the participant and were used later on for extraction of genomic DNA. All information regarding participants was made anonymous after the collection of blood samples.
In the presence of the physician, each participant answered the same one-page standardized questionnaire that was especially drawn up to provide valuable information on demographic characteristics, regular diet, weight and height, personal history of diabetes mellitus and dyslipidemia, physical activity, and smoking habits (see Fig. 1 ). In this multiple-choice questionnaire, we did not take into account every potential risk factor reported in the literature but we focused more on some of the environmental factors among the most relevant to colorectal carcinogenesis. It is worth noting that we used the grandparents' place of residence—or by default, the parents' place of residence—to define the geographic origin of each participant. Questions about eating habits had been developed with the help of a nutritionist to cover the main categories of food components found in the French diet. Participants were questioned only about the average consumption frequency of foods, whereas quantitative questions were deliberately avoided to keep the questionnaire clear and simple.
Standardized questionnaire on life habits fulfilled by the study participants.
For cases, we additionally requested endoscopy and histology reports from the study oncologist or hepatogastroenterologist. To obtain homogeneous data, a standardized report model designed as a multiple-choice questionnaire was provided to each physician, which notably included questions about tumor aspect and location, presence of metastasis, and tumor infiltration.
All data provided by both the participants and the physicians through the different questionnaires were stored in a common electronic SQL database set up for the sole purpose of the present study. This database also enables the collection of genetic data generated as explained below.
Genotype Analysis
Genomic DNA was extracted from collected blood samples using the Nucleon BACC2 kit (GE Healthcare). DNA concentrations were calculated using Picogreen technology (Molecular Probes) and diluted to 10 ng/μL in 96-well format after a customized automated procedure developed by Microlab Star (Hamilton Robotics).
All study participants were genotyped for six SNPs related to drug-metabolizing enzymes CYP involved in heterocyclic aromatic amines and polycyclic aromatic hydrocarbons carcinogen metabolism: SNPs rs762551 (c.−163A>C; CYP1A2*F) and rs2470890 (c.1548T>C; p.N516N) in CYP1A2, rs3813867 (g.−1293G>C; CYP2E1*5A and CYP2E1*5B) and rs2031920 (g.−1053C>T; CYP2E1*5A and CYP2E1*5B) in CYP2E1, rs1056836 (c.1294C>G; p.V432L; CYP1B1*3) in CYP1B1, and rs1799853 (c.430C>T; p.R144C; CYP2C9*2A, CYP2C9*2B, and CYP2C9*C) in CYP2C9. These six SNPs were selected for their relevance to sporadic CRC according to a bibliographical meta-analysis done through PubMed.
Genotypes were determined using high-throughput TaqMan allelic discrimination tests. Primers and dye-labeled MGB-NFQ probes were designed and synthesized by Applied Biosystems (Supplementary Table S1). Reactions were set up in a 384-well plate in a 6 μL final volume, including 2.25 μL of 2× Universal Master Mix, 0.11 μL of 40× Assay Mix, 1.64 μL of water, and 20 ng of genomic DNA (10 ng/μL). Reaction plates were thermocycled in an i-cycler (Bio-Rad Laboratories): An initial 10 min denaturation at 95°C was followed by 45 cycles including a denaturation step at 92°C for 15 s and an annealing/extension step at 60°C for 1 min. After amplification, end-point fluorescence readings were conducted on an Applied Biosystems ABI 7900HT sequence detection system. Genotypes were assigned using the allelic discrimination software SDS v2.1 (Applied Biosystems).
Determination of CRC Risk Associated with Environmental Factors Analyzed Independently. The statistical analysis was done with SAS 9.1 statistical software (SAS Institute, Inc.). Continuous variables were reported as median and range and compared between the case and control groups by Mann-Whitney U test. Categorical variables were reported as number of patients (percentages) and compared by χ2 or Fisher's exact tests when appropriate. P values <0.05 were considered to be statistically significant.
Univariate analyses were done using conditional logistic regression to account for the matching of cases and controls. An appraisal was made on the association between environmental variables adjusting for age followed by an assessment of the odds ratio (OR) of cancer cases together with 95% confidence intervals (95% CI). Multivariate analyses were then done using an iterative stepwise selection procedure to select the variables that were significantly associated with CRC, as assessed by the likelihood ratio test (variable candidates for the model were those associated with CRC in univariate analyses with the P < 0.15 criterion; variables were selected in the model using the P < 0.05 criterion).
Determination of CRC Risk Associated with CYP Allelic Variants Analyzed Independently. To assess the risk of CRC associated with each of the six CYP SNPs listed above, we used SNPStats, a free web-based tool designed for genetic epidemiology purposes (28). SNPStats has a user-friendly interface thanks to the PHP server programming language and uses the free software environment R for statistical computing implemented by the algorithm of the package genetics. As regards our study, the association with cancer was estimated for each SNP by OR of cancer cases along with 95% CI; calculations were adjusted for age and sex, and followed an unconditional logistic regression model. For each SNP, homozygous carriers of the most frequent allele in the cohorts were used as the reference for the analyses. Calculations of ORs were double checked by statistical analysis done with SAS 9.1 statistical software (SAS Institute).
Analyses of gene-environment interactions were then done with SNPStats, which proposes statistical models for calculation of risk associated with one pair of interacting variables. For each of the six CYP SNPs, we investigated all the possible interactions with the environmental covariables of the questionnaire completed by the study participants, and we calculated 95% CI ORs of cancer cases to determine if any "SNP-environmental factor" pair could modify the risk for CRC in our cohorts. A likelihood ratio test was used to investigate interaction among variables of interest.
Analysis of CRC Risk Associated with Multiple-SNPs Combinations. A special option of the software SNPStats is the haplotype analysis done through R package haplo.stats. Using genotypes obtained at different points of polymorphisms (SNPs) located on the same chromosomal region, the software makes it possible to predict and rebuild the haplotypes characterizing a group of individuals through a log-additive model. Although the six CYP SNPs chosen for our study are not all located on the same chromosome and, by definition, cannot belong to a common haplotype, we nevertheless used this SNPStats option to predict preferential combinations of these six SNPs. Based on the genotyping results determined for the six single SNPs in the patient and control cohorts, an evaluation was made of the relative frequencies of multiple-SNP combinations present in the cohorts and the corresponding samples sizes were calculated. Logistic regression was then applied to these data to analyze the associations of the SNP combinations to CRC risk translated into 95% CI ORs.
By use of SNPStats, we investigated the possible SNP combinations interacting with environmental factors and we estimated their associations to CRC risk with 95% CI ORs.
The present work is based on 1,023 patients with sporadic CRC and 1,121 unaffected controls whose main general characteristics are indicated in Table 1 . The mean age is slightly higher for cases than for controls (67 versus 62 years old; P ≤ 0.01), mainly because of the overrepresentation of individuals ≥70 years old in the case cohort [404 individuals (39%) versus 199 (18%) in the control cohort] despite our efforts to match the two cohorts by age. Mean body mass indexes are approximately equal between the two cohorts (26 kg/m2 in patients versus 25 kg/m2 in controls; P ≤ 0.01). As regards gender distribution, males are more numerous in both cohorts but they are slightly underrepresented in the control cohort (62% in patients versus 54% in controls; P ≤ 0.01). Overall, study participants were very compliant as the global response rate to the questionnaire on life habits reached 97.5%; the only relatively weak response rate was in relation to the "method of cooking" item, giving a response of 88.2%.
General characteristics of study patients
Table 2 describes the more significant results obtained with the univariate and multivariate analyses of environmental factors. In the study cohorts, the consequence of red meat consumption on CRC risk was very noticeable and quite distinguishable from those of other environmental factors: Compared with the reference group of moderate eaters, high consumers (≥5 times a week) were at increased risk with an OR of 3.414 (95% CI, 1.93-6.04). To a lesser extent, diabetes status, lack of physical activity, as well as frequent cold cuts and pastry consumption, or, on the contrary, poor-quality fruit intake and low dairy product and fruit consumption were also associated with an increased risk of CRC. Paradoxically, the lack of alcohol consumption was also associated with a decreased CRC risk. By contrast, female gender, dyslipidemia status, and frequent consumption of wholemeal bread decreased the risk of CRC. In addition, we found no effect at all for fish, white meat and cigarette consumption, or cooking methods.
Univariate and multiple variable models of promoting and protective factors independently associated with CRC
From these observations, we also examined combinations of environmental factors found to have a more obvious bearing on CRC risk. As expected, we observed that individuals with the lowest risk of CRC were those who combined the highest consumption of fruit (more than twice a day), vegetables (more than twice a day), dairy products (more than thrice a day), and wholemeal bread. They were associated with an OR of 0.78 (95% CI, 0.62-0.98, P = 0.036) compared with reference individuals who had the same nutritional habits except that they ate white bread instead of wholemeal bread. People with the highest risk of CRC were those eating fruit and vegetables once a day at the most, dairy products twice a day at the most, and white bread (OR, 1.36, 95% CI, 1.15-1.60, P = 0.0004).
Table 3 shows the results of the univariate analyses done with SNPStats for the six single SNPs selected: rs762551 (c.−163A>C) and rs2470890 (c.1548T>C) in CYP1A2, rs3813867 (g.−1293G>C) and rs2031920 (g.−1053C>T) in CYP2E1, rs1056836 (c.1294C>G) in CYP1B1, and rs1799853 (c.430C>T) in CYP2C9. We did not find any association with CRC for any of the allelic variants tested, as ORs never reached statistical significance either for proximal and distal colon, or rectal cancer. Moreover, analyses of interactions between single SNPs and environmental factors of the questionnaire did not show any interacting pair of variables that would modify the risk of CRC (Supplementary Table S2). The results obtained with SNPStats were confirmed with SAS 9.1, by performing univariate analyses adjusted for the covariate SNP of the environmental factors found to be potential risk factors (Table 3). As an example, ORs associated with a high consumption of red meat (more than five times a week) remained steady and statistically significant at about 3.4 (P < 0.001) when adjusted for any of the six SNPs.
Analysis of single-SNP association with CRC (n = 2,131; OR calculations were adjusted by sex and age)
We then analyzed the association between CRC and combinations of multiple SNPs. We tested combinations of two to six SNPs: None was found to be associated with a modification of CRC risk. Therefore, we investigated interactions between these combinations and environmental factors of the questionnaire. The integration of multiple-SNP combinations to the statistical analyses barely changed the ORs calculated above for most environmental factors, especially for the potential risk factors listed in Table 2. However, as summarized in Table 4 , striking results were once again obtained with red meat consumption. Part A of Table 4 indicates that three multiple-SNP combinations—ATGCGT, CCGCGC, and ATGCCC (allelic variants in the combinations are ordered as follows: CYP1A2 c.−163A>C, then CYP1A2 c.1548T>C, CYP2E1 g.−1293G>C, CYP2E1 g.−1053C>T, CYP1B1 c.1294C>G, and CYP2C9 c.430C>T)—were associated with a strong elevation of CRC risk in significant red meat consumers when compared with a common reference group of moderate red meat consumers presenting the most frequent combination ATGCCC. Part B shows that the risk of CRC did not vary significantly between moderate red meat consumers (<4 times a week) whatever SNP combination they exhibited; on the other hand, in significant red meat consumers, the influence of SNP combination was more perceptible as individuals with combination ATGCGT were associated with a significantly increased risk (OR, 2.69; 95% CI, 1.72-4.19) compared with combination ATGCCC; by contrast, combinations of ATGCGC and CCGCCC were at lower risk with ORs dropping to 0.35 (0.17-0.72) and 0.28 (0.12-0.65). Part C of Table 4 takes into account the influence of red meat consumption in the different SNPs combinations; it shows that the intrinsic CRC risk of red meat consumption expressed in Table 2 (OR, 3.414 in great red meat consumers) was slightly increased for combinations (OR, 4.42 and 4.08) ATGCGC and CCGCCC, but considerably enhanced for combinations CCGCGC (OR, 16.34) and ATGCCC (OR, 13.72), and extremely high for combination ATGCGT (OR, 43.78).
Analysis of association to CRC risk of multiple CYP SNPs combinations interacting with the environmental variable "red meat consumption"
Further analyses of SNPs combinations revealed an interaction between combination ATGCGT and body weight (Supplementary Table S3). Compared with individuals with low to normal weight (body mass index <18.5-24.9; see Table 1), obese individuals (body mass index ≥ 30) were at a statistically significantly increased risk of CRC (OR, 12.55; 95% CI, 6.28-25.09), and overweight individuals (body mass index 25-29.9) were associated with a barely significantly increased risk (OR, 2.24; 95% CI, 0.94-5.31). None of the other most frequent SNP combinations (>4%) showed an interaction with body weight.
Colorectal carcinogenesis has been the subject matter of many studies, all of which confirm an environmental and genetic bicomponent for carcinogenesis of sporadic CRC (2). Numerous population-based studies have underlined associations between risk for CRC and SNPs—notably including the SNPs of the CYP genes we have chosen in our study—interacting with at least one environmental factor. Nevertheless, most of these studies do not produce a sufficient statistical power, and are therefore not reproducible, because they rely upon a too small number of nonhomogeneous or even badly designed cohorts (usually 40-300 individuals; ref. 29). To circumvent this problem, we based our association study on two large cohorts including more than 1,000 individuals each. To date, only a few population-based association studies as large as ours have been reported on genetic susceptibility to CRC and, to our knowledge, none of them have comprised uniquely sporadic cases. Moreover, no comparable studies have been reported on a French population, which highlights the interest and originality of our cohorts, as genetic predisposition is definitively a population-specific phenomenon. In addition, we were especially careful about the quality of the recruitment, whether this was the clinical criteria for patients (every doubtful familial case was excluded systematically) or the homogeneity of both cohorts (i.e., matching as well as possible for age, sex, and geographic origins). We are aware that a weak point of our recruitment resides in the imbalance between patients and controls of over 70 years old; however, simulations of OR calculations on population samples showed that this imbalance did not seem to alter our estimations of CRC risk.
As mentioned in Results, response rate to the questionnaire on life habits was very good, which was translated by a high statistical significance of the results we obtained for the univariate analyses of environmental factors (P < 0.001 for many analyses). These results were consistent with previous descriptions of environmental risk factors in other epidemiologic studies (30-35). Thus, physical activity, fruit, dairy products, and wholemeal bread appeared as protective factors regarding the risk of CRC. However, above all, the most striking result concerned the high consumption of red meat (more than five times a week), which we found associated with a sizable increase in CRC risk (OR, 3.414; 95% CI, 1.93-6.04) compared with a more reasonable consumption (four times a week at the most). Of course, this observation would be moderated by the fact that individuals with this habit constitute only a minor group within both cohorts (69 individuals; i.e., 3.2% of the whole study population). Nevertheless, the procarcinogenic role of red meat is no longer a novelty because it has already been reported several times in the literature and it has been biologically explained by the metabolism of red meat into deleterious polycyclic aromatic hydrocarbons and heterocyclic aromatic amines (36). In any case, the size of the two study cohorts leads us to believe that the number of frequent red meat eaters—although they are small in number—is representative of the local French population we examined. Therefore, the results we obtained may be a little overestimated but they reflect a true tendency.
In the same way, certain other results deserve to be discussed here. For example, the observation of a reduced risk of CRC in patients with dyslipidemia was unexpected. As dysplipidemia was taken into account only in patients requiring medical therapy, we may assume that most of them were treated with inhibitors of hydroxyl-methylglutaryl CoA reductase (also called statins), a widely prescribed class of lipid-lowering agents. This may be a confounding factor as these agents exert a documented protective effect against CRC (37). As regards the lack of effect relating to fish and vegetables, this can be ascribed to an excessively poor representation of the "high consumer categories" for these two covariates. Despite Public Health communications on the virtues of these two products against cancer, they have failed to become essential elements in today's French diet. In contrast, the absence of influence of tobacco on CRC risk is not that surprising because its deleterious effect was essentially described in lung and upper digestive tract cancers (38, 39). Moreover, the participants' answers may have been distorted, notably in patients for whom tobacco consumption appears to be a deliberate risk habit. The same remark could be applied to alcohol consumption, the relative protective effect of which rather contradicted the data reported in the literature and is illogical in terms of detoxification. As regards covariate "cooking methods," the absence of significant results can be correlated to the relatively low response rate (88.2%), which certainly translates the difficulty encountered by the participants to choose a single answer definitively representative of their habits. Indeed, this problem probably comes from the formulation of the question.
The results of the analysis of multiple environmental factor combinations turned out to be extremely logical. Frequent eating of meals rich in fruit, vegetables, dairy products, and wholemeal bread appeared as the most effective combination against CRC. Yet, the relatively weak difference found between single or combined environmental factors underline a barely detectable additive effect or even an independent effect of these covariates on carcinogenesis in the study population.
For the genetic part of our work we focused on six SNPs of four CYP genes that all belong to phase I of the xenobiotic detoxification metabolic pathway, and that are not localized on the same chromosome. We therefore expected to find an additive or rather interactive effect not due to real haplotypes but to variations in the activity of putative interdependent encoded enzymes. According to our bibliographical meta-analysis of previous association studies, five of the six SNPs of CYP genes that we analyzed had already been found to be associated with a rise in risk for colorectal adenomas or cancer, whether alone or in interaction with an environmental factor. In general, the increased risk had been correlated to allelic variants increasing the activity of encoded enzymes, whether for SNPs c.−163A>C (rs762551) in CYP1A2 (13, 19-21, 40), g.−1053C>T (rs2031920) and g.−1293G>C (rs1056836) in CYP2E1 (14, 15), c.1294C>G (rs1056836) in CYP1B1 (17), or c.430C>T (rs1799853) in CYP2C9 (16, 18). However, we were unable to reproduce these results in our cohorts, as we found no association with modulation of CRC risk for any of the six single SNPs analyzed independently or together with environmental factors in our lifestyle questionnaire. An explanation for the divergence with prior studies probably lies in the smaller populations tested: For instance, for CYP1A2 c.−163A>C, 94 individuals (OR, 3.7; 95% CI, 1.3-10.7) in one study (20) and 377 cases/326 controls in yet a second more comprehensive study (OR, 1.53; 95% CI, 1.13-2.08; ref. 21), and 163 patients and 163 controls (OR, 1.91; 95% CI, 1.05-3.52) for CYP2E1 g.−1053C>T (15).
On the other hand, analyses of multiple-SNP combinations showed a strong increase in the intrinsic risk of excessive red meat consumption for three different combinations of allelic variants, ATGCCC, CCGCGC, and ATGCGT, found in 31.6%, 13.4%, and 4.4% of the study individuals respectively (see Table 4). As opposed to these three allelic variant combinations, two other frequent ones, ATGCGC (22.1%) and CCGCCC (9.8%), appeared "neutral" as they barely enhanced the basal CRC risk due to red meat consumption alone (see Table 2). Interaction analyses with other environmental factors revealed that, among the combinations above, ATGCGT was the one that predisposed the most to CRC, as it was the only one found to be additionally associated with a perceptible increase in the risk of CRC in obese individuals (∼14.4% of the study population). This last observation is a good example of gene-environment interaction: In a way, the genetic background seems to exacerbate the procarcinogenic effect of the environmental factor, because, in our cohorts, obesity alone was not found to be associated with an increased CRC risk as reported in the literature (41). On the other hand, genetic expression seems to be influenced by environmental factors, as independent analysis of the ATGCGT combination showed no association with CRC risk. Interestingly, obesity was shown to increase expression and thereby oxidative activities of CYP enzymes, especially CYP1E2, which exacerbates the procarcinogenic effect of xenobiotics (42, 43).
A hypothesis for the marked interaction of combination ATGCGT with obesity and red meat consumption would be that the allelic variants composing this combination contribute to the simultaneous enhancement of the metabolic activities of CYP1A2, CYP2E1, CYP1B1, and CYP2C9 enzymes. Yet, if we postulate from previous works the theoretical combination leading to the greatest enzymatic activity of these four enzymes, we obtain ATGCGC (i.e., a combination we found not to be associated with an effect on CRC risk in our cohorts). In fact, the first four allelic variants of this combination perfectly match the observed ATGCGT combination and they correspond to allelic variants of CYP1A2 (c.−163A and c.1548T) and of CYP2E1 (g.−1293G and g.−1053C) that have been shown to induce an increased enzymatic activity in vitro, and which have been found to be associated with an increase in CRC risk by interacting with red or processed meat (14, 19, 20, 44). This first part of the combination should be associated with an elevated production of polycyclic aromatic hydrocarbons and heterocyclic aromatic amines, and thereby to an increased cancer risk. In the same way, the "neutral" effect on CRC risk observed for combination CCGCCC can be explained as the result of the concomitant decreased activity of CYP1A2 and increased activity of CYP2E1. In fact, the divergence between observed and theoretical predisposing hexanucleotide combinations resides in the last two variants corresponding to c.1294C>G of CYP1B1 and c.430C>T of CYP2C9. Aklillu et al. (45) showed that the allelic variant c.1294C>G of CYP1B1 increases enzymatic activity, but, to date, it has only been found to be associated with lung and head-and-neck cancers (46-48). The allelic variant c.430C>T of CYP2C9 was found to be associated with a decrease in CRC risk (16). However, the size of the population studied in this report was small and the significance of these results may be disputable. Therefore, this divergence between theory and observation does not discredit the predisposing bearing on CRC that we found for the ATGCGT combination. On the contrary, it illustrates the difficulty in extrapolating a general biological model from the combination of independent analyses. This contrasts with environmental factors for which theory perfectly matched observations. It is precisely the very notion of dependence or rather interactivity, between enzymes of the same pathway in this case, which creates all the complexity of the susceptibility phenomenon.
In conclusion, we observed three combinations of CYP allelic variants that strongly predispose to CRC by interacting and enhancing the intrinsic predisposing potential of excessive red meat consumption. One of these combinations, ATGCGT, has a particularly strong effect on CRC risk and also interacts positively with obesity, another known promoting factor of CRC. Our present work illustrates the need to go beyond the analysis of single SNPs proposed in most of the current studies on genetic predisposition for complex diseases like cancer. Studies on predisposition to colorectal and prostate cancer have already started to show the power of combinative approaches (49-52). In addition, our present data highlight the very interest of analyzing SNP combinations in connection with environmental risk factors to a better appreciation of the complexity of in vivo events accounting for cancer susceptibility.
We are aware that our approach can be considerably improved. The most significant results presented here relate indeed to a small subgroup of the cohort [69 great red meat consumers (3.2%) of 2,144 individuals], and they would need to be reproduced and confirmed on larger cohorts. In addition, investigation of a more comprehensive panel of SNPs would certainly lead to even more conclusive observations. Therefore, we now plan to examine additional polymorphic genes involved in the metabolic pathway of xenobiotic detoxification, such as genes of glutathione S-transferases, UDP-glucuronosyl transferases, or sulfotransferases. Nevertheless, in the present work, we deliberately reduced the number of studied SNPs in a didactical perspective to better illustrate the phenomenon of interaction between genes.
Although our combinative approach contains room for improvement, we believe that it is more meaningful than association studies dealing with one risk factor at a time. The identification of SNP combinations modulating CRC risk cancer in a precise environmental context is a first step toward the determination of genetic profiles of susceptibility, which should enable the establishment of personal nutritional recommendations for patients.
We thank all the patients, control individuals, and physicians who participated in this work and made it possible.
Grant support: Regional Hospital Clinical Research Program and the Groupement des Entreprises Françaises dans la LUtte contre le Cancer, the Association Anne de Bretagne Génétique, and the Ligue Régionale Contre le Cancer.
Note: Supplementary data for this article are available at Cancer Epidemiology Biomakers and Prevention Online (http://cebp.aacrjournals.org/).
S. Küry, B. Buecher, and S. Robiou-du-Pont contributed equally to this work.
Accepted May 10, 2007.
Revision received April 30, 2007.
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Sachse C, Bhambra U, Smith G, et al. Polymorphisms in the cytochrome P450 CYP1A2 gene (CYP1A2) in colorectal cancer patients and controls: allele frequencies, linkage disequilibrium and influence on caffeine metabolism. Br J Clin Pharmacol 2003;55:68–76.
Moonen H, Engels L, Kleinjans J, Kok T. The CYP1A2-164A→C polymorphism (CYP1A2*1F) is associated with the risk for colorectal adenomas in humans. Cancer Lett 2005;229:25–31.
Landi S, Gemignani F, Moreno V, et al. A comprehensive analysis of phase I, phase II. metabolism gene polymorphisms and risk of colorectal cancer. Pharmacogenomics 2005;15:535–46.
Rodriguez-Antona C, Ingelman-Sundberg M. Cytochrome P450 pharmacogenetics and cancer. Oncogene 2006;25:1679–91.
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Roberts-Thomson IC, Butler WJ, Ryan P. Meat, metabolic genotypes and risk for colorectal cancer. Eur J Cancer Prev 1999;8:207–11.
Le Marchand L, Hankin JH, Wilkens LR, et al. Combined effects of well-done red meat, smoking, and rapid N-acetyltransferase 2 and CYP1A2 phenotypes in increasing colorectal cancer risk. Cancer Epidemiol Biomarkers Prev 2001;10:1259–66.
Tranah GJ, Chan AT, Giovannucci E, Ma J, Fuchs C, Hunter DJ. Epoxide hydrolase and CYP2C9 polymorphisms, cigarette smoking, and risk of colorectal carcinoma in the Nurses' Health Study and the Physicians' Health Study. Mol Carcinog 2005;44:21–30.
Bartsch H, Nair U, Risch A, Rojas M, Wikman H, Alexandrov K. Genetic polymorphism of CYP genes, alone or in combination, as a risk modifier of tobacco-related cancers. Cancer Epidemiol Biomarkers Prev 2000;9:3–28.
Sole X, Guino E, Valls J, Iniesta R, Moreno V. SNPStats: a web tool for the analysis of association studies. Bioinformatics 2006;22:1928–9.
Brennan P. Gene-environment interaction and aetiology of cancer: what does it mean and how can we measure it? Carcinogenesis 2002;23:381–7.
Bingham SA, Day NE, Luben R, et al. Dietary fibre in food and protection against colorectal cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC): an observational study. Lancet 2003;361:1496–501.
Peters U, Sinha R, Chatterjee N, et al. Dietary fibre and colorectal adenoma in a colorectal cancer early detection programme. Lancet 2003;361:1491–5.
Sanjoaquin MA, Appleby PN, Thorogood M, Mann JI, Key TJ. Nutrition, lifestyle and colorectal cancer incidence: a prospective investigation of 10998 vegetarians and non-vegetarians in the United Kingdom. Br J Cancer 2004;90:118–21.
Soerjomataram I, de Vries E, Pukkala E, Coebergh JW. Excess of cancers in Europe: A study of eleven major cancers amenable to lifestyle change. Int J Cancer 2007;120:1336–43.
Alvarez-Leon EE, Roman-Vinas B, Serra-Majem L. Dairy products and health: a review of the epidemiological evidence. Br J Nutr 2006;96 Suppl 1:S94–9.
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Home / Boat News Races & Regatta / Sydney to Auckland Ocean Race
© 2023 ALL RIGHTS RESERVED BY RPAYC
Posted by: YachtBoatNews in Boat News Races & Regatta 11 days ago Comments Off on Sydney to Auckland Ocean Race 47 Views
The first entries have been received for the Royal Prince Alfred Yacht Club (RPAYC), and Royal New Zealand Yacht Squadron (RNZYS) hosted inaugural Sydney to Auckland Ocean Race, due to start on Saturday, 7 October 2023, at 1pm.
Postponed in 2021 due to Covid, this challenging 1250 nautical mile race starts on Sydney Harbour and finishes off the RNZYS in Auckland. It is open to racing and cruising yachts, superyachts and ocean-racing multihulls.
Entries already received come from RPAYC's Mark Griffith with the DK46, LCE Old School Racing and lnity, Marc Depret's Figaro 3. Dare Devil, the Cookson 47 owned by Sibby Ilzhofer from Newcastle Cruising Yacht Club in NSW, is also entered.
Griffith commented, "I think it's going to be a premier race, the longest (from Australia) and an international race. This is the first time anyone gets to do it, so there should be quite a bit of interest and a strong fleet."
On the dynamics of the race, the yachtsman says, "It will probably be six or seven days. The Sydney Hobart and Melbourne to Hobart are a sprint by comparison. We will have to pace ourselves more with the various conditions."
LCE Old School on the way to third overall in the Pittwater to Coffs race © Andrea Francolini
The LCE Old School Racing crew plans to take full advantage of the New Zealand end of the race.
'We've got plans to stay over," Griffith says. "The Coastal Classic is only a week later and gets around 160 entries. We don't want to miss that. We also plan to cruise to the Bay of Islands (one of the most spectacular places on the planet) and that's on the way home, so we might leave the boat there and do the Bay of Islands Regatta.
"This is not something we get to do every day, so we want to go hard at it," Griffith ends.
On being the first entry in, Sibby Ilzhofer says, "Like the Sydney Noumea (1064 nautical miles), it'll be challenging. It's a new race, so it starts our hearts beating again. I think It'll also bind Australia and New Zealand as sailing nations."
Inity – Sydney to Auckland Ocean Race – photo © Robert McClelland
Ilzhofer continues, "I love New Zealand. Some of my crew from other races in the past are from there. Not only that, Dare Devil is a Cookson boat built in New Zealand. We have a new mast and rigging, also from New Zealand. It's ready to go in the boat, which has been painted black, has a new black mast and black sails (like the All Blacks)," she laughs. "So, the boat will be heading home in a way."
On preparing, the yachtswoman says, "It's not easy, but the Alfreds have been so helpful. I had a call to see if I needed any help. You don't get much of that these days. To have internal support makes you feel connected."
New paint job and mast for Dare Devil – photo © Sibby Ilzhofer
On her expectations, she says, "From a racing perspective, I'd like to see us repeat our fifth over the line behind the big boats in the Sydney Noumea race.
"From a crew perspective, I want a cohesive team that works well together. I like to run a calm crew with good teamwork and I'll be building that team over the next six months."
The inaugural Sydney to Auckland Ocean Race has been timed to allow prospective competitors to compete on the northern circuit in Queensland beforehand and to be back in Australia in time for the Rolex Sydney Hobart and Melbourne to Hobart yacht races.
Alternatively, entrants can stay in New Zealand to take advantage of the famous Coastal Classic in late October. There is also the option of staying longer to cruise and take in the Bay of Islands Sailing Week in late January 2024.
Entries for the Category 1 Sydney to Auckland Ocean Race close on 1 September 2023. For all information, including entry and Notice of Race, please visit: www.sydneytoauckland.com
The race finishes off Royal New Zealand Yacht Squadron – photo © RNZYS
by Di Pearson / Sydney to Auckland media
Previous: The Ocean Race
Next: Cup Spy.. Kiwis AC40 test
45th Wooden Boat Festival
Gulf Regatta 2019 ~ Overall
America's Cup Rialto

redpajama_set_name: RedPajamaCommonCrawl


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Predicting protein-protein interactions
Tufts University and MIT research team develop a deep-learning model that predicts interaction between two proteins with high accuracy.
image: Tufts University Department of Computer Science and Massachusetts Institute of Technology (MIT) collaborated to design a structurally-motivated deep learning method built from recent advances in neural language modeling. The team's deep-learning model, called D-SCRIPT, was able to predict protein-protein interactions (PPIs) from primary amino acid sequences. view more
Credit: Courtesy of researcher Rohit Singh of MIT.
In research published in the journal Cell Systems, Professor Lenore Cowen of the Tufts Department of Computer Science and colleagues from Massachusetts Institute of Technology (MIT) collaborated to design a structurally-motivated deep learning method built from recent advances in neural language modeling. The team's deep-learning model, called D-SCRIPT, was able to predict protein-protein interactions (PPIs) from primary amino acid sequences.
Those predictions allow researchers to model PPI networks with a clustering method and enable the detection of functional subnetworks, or modules. Scientists study organisms' PPI networks as a means of understanding their signaling circuitry, which could lead to better prediction of cell behavior and gene functions, while finding functional modules in PPI networks could help researchers reach stronger understandings of cellular functional organization.
Cowen along with researchers Sam Sledzieski, Rohit Singh, and renowned computational biologist Bonnie Berger from MIT's Computer Science and Artificial Intelligence Lab found that the D-SCRIPT model, trained on more than 38,000 human PPIs, was better able to generalize when compared to the current state-of-the-art approach (the deep-learning method PIPR), and therefore could characterize fly proteins. They also applied D-SCRIPT to screen for PPIs related to cow digestion and identified functional gene modules that related to immune response and metabolism.
The researchers concluded that the D-SCRIPT model trained on human PPI data could be applied to many species of interest – critically, even those that have been rarely studied or that lack PPI data.
Cell Systems
https://doi.org/10.1016/j.cels.2021.08.010
D-SCRIPT translates genome to phenome with sequence-based, structure-aware, genome-scale predictions of protein-protein interactions
Article Publication Date
Kalimah Knight
kalimah.knight@tufts.edu
/Life sciences/Biochemistry/Protein functions/Protein interactions
/Applied sciences and engineering/Computer science/Computer modeling
https://www.cell.com/cell-systems/fulltext/S2405-4712(21)00333-1


The Director of Development assumes responsibility for designing and implementing the fundraising programs of the AFP Foundation for Philanthropy in annual giving, major and planned giving, and corporate philanthropy. The Director of Development is accountable for achieving the Foundation's fundraising goals and ensures implementation of best practice in cultivation, solicitation, acknowledgment, and stewardship of current and potential donors. Fundamental to this position is leveraging resources and building relationships that engage and motivate external funders to support AFP's strategic initiatives to promote ethical and effective fundraising in the interest of the public good.
Increase the size and number of annual AFP Foundation gifts for BE the CAUSE Campaign and Chapter Impact.
Cultivate and engage qualified AFP Chapters as major donors to support strategic initiatives.
Serve as staff liaison to AFP Foundation's fundraising board and committees.
Maintain security and quality controls to ensure compliance with all regulatory requirements in fundraising.
Oversee external grant administration and ensure timely submission of interim and final grant reports.
Participate in board meetings and conference events as required.
Experience with fundraising using the Internet, social networking and digital innovations.
Bachelor's degree or equivalent prior experience.
Strong verbal communications skills and demonstrated ability to write clearly and persuasively and ability to think quickly.
Commitment to donor satisfaction and customer service.
Creativity, flexibility and, upbeat "can-do" attitude.
Sound judgment, impeccable ethical principles with an ability to maintain discretion and respect confidences.
Ability to function independently and think strategically, simultaneously function as an effective team player with the ability to collaborate with the AFP Foundation and AFP staff.
Skilled at prioritizing workload, managing multiple tasks and meeting tight deadlines.
Since 1960, AFP has inspired global change and supported efforts that generated over $1 trillion. AFP's 33,000 individual and organizational members raise over $100 billion annually, equivalent to one-third of all charitable giving in North America and millions more around the world.


President Benigno Aquino has served notice to Environment Secretary Ramon Paje that no new mining applications should be approved in Palawan province, home to �world wonder� Puerto Princesa Underground River.
In an accompanying memorandum to his new order on mining, the President ordered Paje to �desist from processing mining applications� in Palawan.
PUERTO PRINCESA CITY, April 25 (PNA) -- This city of natural wonders is offering a new tourism attraction with a steady low humming sound that is slowly reverberating and intriguing many who are in search of a different kind of adventure.
Honey bee culture was introduced here almost eight years ago as a livelihood project for low-income earners under the office of Mayor Edward S. Hagedorn. The Puerto Princesa City Beekeeping Project (PPCBP) has now opened its farm in Barangay Irawan to local guests and tourists interested in apiculture, or the maintenance and study of honey bee colonies.
�Life begins at 40�. This old adage will be the maxim of the participants in the Veterans event of the 2012 FIM Asia Motocross Championship, the continent�s premiere motocross series which will unfold in Puerto Princesa City on April 12-15. Aptly titled the Asian Veterans class, the event is open to all physically fit and able senior riders (40-55 years of age) from the FIM Asia member federations. The Veterans are allowed to use bikes with a displacement of up to 450cc (4-stroke).
This year marks the ninth straight year that Mayor Edward S. Hagedorn and his constituents are hosting the country�s biggest annual spectator motorsport event. The event which coincides with one round of the Philippine national motocross series has never failed to thrill and excite the thousands who troop to the city�s world-class racetrack in Barangay Sta. Monica each year since it was launched in 2004. Sponsors of this year event are the City of Puerto Princesa, Asia Brewery, Polisport, Repsol, Kia Palawan and Shakeys. The event is also supported by the Department of Tourism and recognized by the Philippine Sports Commission and Philippine Olympic Committee.


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site: media | arena: nba | pageType: stories | section: | slug: if-lakers-need-rajon-rondo-to-go-nuclear-rockets-should-feel-good-about-their-chances-moving-forward | sport: basketball | route: article_single.us | 6-keys: media/spln/nba/reg/free/stories
If Lakers need Rajon Rondo to go nuclear, Rockets should feel good about their chances moving forward
Even with LeBron and Anthony Davis dominating, Houston still has the horses to win this series
By Brad Botkin
Sep 9, 2020 at 10:44 am ET 4 min read
That the Houston Rockets were even within striking distance of the Los Angeles Lakers in the fourth quarter Tuesday night is remarkable. They only made 12 3-pointers, two more than the Lakers, and that's a stat they need to -- and usually do -- dominate. They only scored 38 points in the entire second half. LeBron James and Anthony Davis combined for 62 points on 61 percent shooting, and the Lakers shot 55 percent to Houston's 46 percent overall. Rajon Rondo -- Rajon Rondo! -- scored 21 points on 8-of-11 shooting, including 3 of 5 from 3-point land. Danuel House Jr., who has been great for the Rockets, didn't play, and the Lakers' bench outscored Houston's 42-16.
You look at these numbers, and the Rockets shouldn't have had a chance to win Game 3. But they did. They lost 112-102, a close enough final, but even that is deceiving. The game was tied after three quarters. The Rockets had a fourth-quarter lead until Rondo sparked a 13-2 run with two 3-pointers and a steal and finish.
"Playoff Rondo" might still be a thing, but if him hitting 3s and generally throwing it back to his Boston days is what it takes for the Lakers to gain even a sliver of separation from Houston, on a night when LeBron and Davis were about as dominant as you can expect them to be no less, the Rockets have to like their chances to tie this series 2-2 with a win in Game 4, don't they?
The unfortunate thing for Houston is that all of these things -- perhaps with the exception of Rondo playing out of his mind -- feel sustainable. LeBron was nothing short of breathtaking, finishing with 36 points on 57 percent shooting while tallying four 3-pointers and four blocks, the latter coming as part of a virtuoso third-quarter defensive showing -- and if we're being honest, it still feels like he can pull these performances out of his bag on demand.
At this point, marveling at LeBron performing like this at 35 years old, as if to imply there has to be an expiration date on him being the best player in the world, is sort of pointless. Sure, this can't keep up forever, but it's not going anywhere in this series, or for the rest of these playoffs, or probably for at least a few more seasons. The Rockets have to accept his dominance as inevitable and try to win in spite of it.
The same goes for Davis, who is just too big and too great for the miniature Rockets to handle. When he's got his touch going from the mid-range like he does right now, forget about it.
But Houston's defense has been superb in the postseason. The switching and rotating is a real problem for offenses, including the Lakers, LeBron and Davis' excellence notwithstanding. You have to think Mike D'Antoni will make some adjustments heading into Game 4, starting with packing the paint with more bodies to at least show LeBron some congestion on his drives and hopefully have to kick out to shooters.
The Lakers are not a great shooting team. Again, if Rondo is going to be hitting 3s, and combining with Kyle Kuzma to shoot 15 of 21 from the field, the Rockets are in massive trouble. But that's a variable the Rockets can reasonably expect to regress. So what it really comes down to is Houston flipping its own 3-point shooting script. Part of that will be, hopefully, getting House back for Game 4. He missed Game 3 for personal reasons. He's shooting 36 percent from deep in the playoffs. He made 3 of 7 from 3 in Game 2. Even one more threat in a short Houston rotation can make a big difference.
The bigger issue for Houston isn't making 3-pointers, but taking them. They only attempted 30 on Tuesday. They averaged 45 in the regular season. You have to credit the Lakers' defense for a lot of this. They were rotating like crazy in Game 4, particularly in the second half, running guys off the line and recovering with discipline and throwing surprise, quick, late-clock traps at Harden after guarding him straight up for the most part in the first half.
You wonder if D'Antoni will limit Harden's pick-and-rolls moving forward and instead just let him attack one-on-one. The Rockets are looking for advantageous switches, but they're also bringing a second defender to Harden on a conveyor belt. At least make the double come from farther away.
Either way, the Rockets can better force the 3-point shooting issue, and it starts with Russell Westbrook, who finished with 30 points in Game 3, but was pretty terrible in the second half. He's back to settling for way too many mid-range pull-ups. He's fallen back in love with his little bank shot from 15 feet. The Lakers chuckle every time he takes one of those shots, perhaps even more when he makes one or two, because then he'll keep firing.
When the Rockets are clicking, Westbrook is attacking the numbers and space provided by the Harden doubles and either getting to the rim, getting fouled or kicking to shooters. Stop pulling up for jumpers! If Westbrook is disciplined enough to redirect those attempts to better shooters behind the 3-point line, and Houston merely shoots to its averages, there is every reason to believe the Rockets can win Game 4 and still make this a long series, if not win it outright. It's still there for the taking.
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Haslem not surprised Heat didn't pursue Harden
McCollum has broken foot; out at least four weeks
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Q: Tcp server only taking one command. Need to flush recv buffer? I am able to send the command "insert data" to the tcp server and it will do what is suppose to. I would like the server to take multiple commands one after the other. At the moment if i send "insert data" and then hit enter and then send "bob" which should not do anything the server responds as if i sent "insert data" again. If you think i should post full source code up let me know in comments.. Screenshot: http://imgur.com/UNRFb5n
#define buf 2000
void *connection_handler(void *socket_desc)
{
    //Get the socket descriptor
    int sock = *(int*)socket_desc;
    ssize_t read_size;
    char *message , client_message[buf];
    //char *contents;
    //contents = "hello";
    //strcpy(mess,contents);
    //Send some messages to the client
    message = "Greetings! I am your connection handler\n";
    write(sock , message , strlen(message));

    message = "Now type something and i shall repeat what you type \n";
    write(sock , message , strlen(message));

    //Receive a message from client
    while( (read_size = recv(sock , client_message , buf , 0 )) > 0 )
    {
        //write(sock , client_message , strlen(client_message));
        char start_char[] = "start";
        char insert_demo_char[] = "insert_demo";
        char *inserting = "Inserting Data\n";
        char *complete = "Task Complete\n";
        if(strcmp(message, start_char))
        {
            printf("Starting...\n");
            //start();
            //printf("it works");
            //fflush( stdout );
        }
        if(strcmp(message, insert_demo_char))
        {
            write(sock , inserting , strlen(inserting));
            printf("Inserting data\n");
            insert_demo();
            write(sock, complete, strlen(complete));
            printf("Finished Inserting Data\n");
        }
    }
    if(read_size == 0)
    {
        puts("Client disconnected");
        fflush(stdout);
    }
    else if(read_size == -1)
    {
        perror("recv failed");
    }

    //Free the socket pointer
    free(socket_desc);

    return 0;
}

A: while( (read_size = recv(sock , client_message , buf , 0 )) > 0 )
{
    [...]
    if(strcmp(message, start_char))

After you receive data into client_message, you are checking the buffer named message instead.  Since you didn't recv() into that buffer, of course it has not changed.
Also note that strcmp() returns 0 if the two strings are equal, and non-zero if the two strings are different; you may have that backwards in your if(strcmp()) tests (I'm not sure what behavior you intended).

A: Since TCP is an octet streaming service, and cannot send application level messages longer than one byte, sending 'insert data' from the client may result in the recv() call loading the buffer with any of:
i
in
ins
inse
inser
insert
insert
insert d
insert da
insert dat
insert data

In the cases of incomplete application-level messages, more calls to recv() will be required to receive the remaining bytes of the message.
Note that sending 'insert data\0' will only result in a null-terminated char array in the buffer if recv() happens to return all that data in one call, which is why the 'read_size' returned by recv() is the ONLY way to determine how many bytes were loaded when transferring binary data: using strXXX calls on such a buffer is UB.  You can use 'read_size' when transferring text to ensure that the text is null terminated, so preventing UB if the null terminator is not in the  buffer:
while( (read_size = recv(sock , client_message , buf-1 , 0 )) > 0 )
client_message[read_size]:=\0;

..will at least give you a 'client_message' that is guaranteed null-terminated, though it will not help with strcmp() failing to identify partial application-level messages in the buffer.
To transfer application messages larger than one byte, you need a protocol on top of TCP that can parse the messages out from the byte stream.

redpajama_set_name: RedPajamaStackExchange


James serves as Lead Pastor and primary communicator on Sunday mornings. James came to Christ through the investment of a friend in high school, and he is passionate about leveraging the relationships we have with the 8-15 (or so) people we each connect with on a weekly basis. James has served at Christ First since 2010 in various roles including Worship Leader and Groups Director. He and his wife, Shanna, enjoy living in the Covina area and keeping up with their three children.
Thiago gives leadership to all three worship services here at Christ First, mainly leading worship in the Modern Service, with an occasional Sunday in the Classic and Spanish services. Thiago has been at Christ First since 2014 and is proud to call this his church home. His love for modern worship music, his classical training, and his Spanish church upbringing equips him with what he needs to be an effective Worship Pastor for our entire church.
Jennifer has called Christ First home since 2004. She served in a variety of roles before coming on staff: drama director, in youth ministries, and in the college/young adult group. Her desire is to see families grow together and thrive. Jennifer enjoys bringing family and friends together, which is why she believes in the power of groups. Life is better when it's shared. She lives with her husband, Bert, and they cherish time with their three grown children.
The title says Business Manager, but it's a fancy way to say, "Does it All"! If you have questions on giving, want Outreach information, or want to volunteer to work on special/creative projects, Jyl's the one to call. Jyl grew up at Christ First and knows just about everything there is to know about the church. She and her husband, Doug, have two awesome teenagers whom they love spending time with.
Cameron has had the pleasure of calling Christ First his home since he was in preschool. His passion for working with students stems from the impact that the youth programs at Christ First played in his personal walk with God. He and his wife, Emily, have three canine children they currently enjoy raising.
Jennifer has served in the field of Child Development for 25 years and is thankful for the opportunity to serve here at Christ First. She leads an amazing staff of teachers who put their hearts and souls into guiding children. Our preschool provides quality academic and spiritual growth for children ages 2-5. Please contact Jennifer if you have any questions or would like a tour of our Preschool.
Tom is passionate about leading the Chancel Choir at Christ First. He directs the weekly choral performances along with 3-4 Holiday musicals per year. He is a joy to be around and you can always hear him leading a joyful noise.
Brian is passionate about local and international missions. He leads the Embrace Covina campaign and leverages local service opportunities to get our people outside the walls of the church. Brian also gives leadership to short-term mission trips and keeps our church family connected with missionaries on the foreign mission field.
Pastor Marco has been married to his wife, Maria, for 27 years. God has blessed them with two children--Isaiah, who is 25 years old, and Smyrna, who is 18. They are here to serve The Lord Jesus and our Spanish community.
Born and raised in Texas, Amber and her son have called Christ First Covina home since 2017. She is passionate about clearly and effectively communicating the Gospel of Jesus Christ to as many people as possible. In a multi-generational church, this means taking care of everything from social media, to bulletins, to personal phone calls in order to make sure that the ministries and events at Christ First are known--so that Jesus can be known!
Copyright © 2018 Christ First Covina, All rights reserved.


No matter your feelings toward the current state of the NFL, from its safety to anthem protests, it's nearly impossible not to love Larry Fitzgerald. The Arizona Cardinals star wide receiver is as real as it gets, a genuine leader in the community, and his latest act of kindness is incredibly special.
Less than a month after reading a tribute at the funeral of Senator John McCain, his longtime friend, Fitzgerald helped pick up the tab at a family-owned Scottsdale deli to support the owner, who has terminal cancer.
This past Tuesday, from 12 p.m. to 5 p.m., Fitzgerald paid for every single tab at Casella's Italian Delicatessen and collected donations for deli owner Joe Casella, his wife, Tina Casella, and their family.
Casella's Italian Delicatessen has been opened since 1977, and the 79-year old Joe Casella is facing terminal cancer. Fitzgerald is leading the community to rally around the family.
There were plenty of people who showed up to the restaurant, too.
FREE FOOD: brought to you by @LarryFitzgerald, he wants to help out his longtime friend & family-run business in the valley. Owner of Casella's Deli, Joe is battling terminal cancer, they're accepting donations to help pay for his medical bills.
Cardinals teammates Christian Kirk and D.J. Foster, who went to nearby Saguaro High School, were expected to attend the event on Granite Reef Road.
Since being drafted No. 3 overall by the Arizona Cardinals in the 2004 NFL Draft, the University of Pittsburgh alum and unanimous All-American has been the face of the franchise at the University of Phoenix Stadium and a leader in the community. He was named the Walter Payton NFL Man of the Year in 2016.
Fitzgerald, an 11-time Pro Bowl selection, has 1,244 receptions for 15,649 yards and 110 touchdowns during his career.
It's hard telling how long the 35-year-old will keep playing in the NFL, but his impact in the local area, such as picking up a local deli tab and providing free meals and free food for the public to support the Casella family, is a legacy that will continue long after his playing days and something people will never forget.


text:
East of the Jordan
East of the Jordan: a record of travel and observation in the countries of Moab, Gilead, and Bashan : 70 illustrations and a map
Merrill, Selah (Author)
Hitchcock, Roswell D. (Writer of introduction)
London Richard Bentley and son 1881
Merrill, Selah, East of the Jordan. A record of travel and observation in the countries of Moab, Gilead and Bashan during the years 1875 - 1877 (1882) (Socin, Albert, 1844 - 1899)
by: Merrill, Selah
Galilee in the time of Christ
Galilee in the time of the Christ: By Selah Merrill. With an introd. by A. P. Peabody
East of the Jordan: territories and sites of the Hebrew scriptures
by: MacDonald, Burton 1939-
"East of the Jordan": territories and sites of the Hebrew scriptures
Bioarchaeology east of the Jordan
by: Judd, Margaret
The Neolithic of Jordan (East Bank)
by: Kafafi, Zeidan Abdel-Kafi 1950-
Mosques east and west of the Jordan Valley: from the Arab conquest to the end of the Mamluk period
by: Raphael, Kate
The sanctuaries of the baptism on the east bank of the Jordan river
by: Piccirillo, Michele 1944-2008
Historical imagery of desert kites in Eastern Jordan
by: Hammer, Emily, et al.
Traditional systems of water conservation in the eastern Badiya of Jordan
by: Lancaster, William, et al.
Recent Discoveries Relating to the Neolithic Periods in Eastern Jordan
by: Betts, A. V. G.
The Significance of the Mycenaean Pottery Found East of the Jordan River
by: Leonard, Albert Jr.
The later prehistory of the Badia excavations and surveys in Eastern Jordan
by: Betts, A. V. G., et al.
Archaeological explorations on the Roman frontier in North-East Jordan: the Roman and Byzantine military installations and road network on the ground and from the air
by: Kennedy, D. L. 1948-
The East Jordan Valley during Iron Age I
by: Ji, Chang-Ho C.
Ammon, Moab and Edom. Gods and kingdoms east of the Jordan
by: Burnett, Joel S. 1968-
Late prehistoric aggregation patterns in Jordan's eastern Badia
by: Rollefson, Gary O. 1942-


Tomorrow marks my daughter, E's, eighth birthday. I never realized how emotional children's birthdays are for their parents until she was born. Every day I am grateful for her, but especially on this day. While motherhood does not solely define me, it has changed everything about my life and how I view the world. I am a better person because of her.
Eight years ago the most glorious little firecracker entered the world. From the start, she burst with energy and a remarkable zest for life. "Congratulations! A beautiful little girl!" Dr. P pronounced. A great surprise–almost everyone predicted a boy, and though we all say we just want a healthy baby, truth is, I secretly longed for a healthy girl.
Little Miss E was eager to learn what life was like out here, like she'd been tapping her toes waiting at the starting line for the race to begin already. The medical students who had suddenly piled into the delivery room gasped at her ready responses to the Apgar test.
All children are special in their own ways. Early on, E displayed intelligence, curiosity, and verbal capacity beyond her years. She spoke her first word at seven months; by a year, she was stringing together short phrases. Paragraphs would soon follow. When she was almost two, returning from day care one afternoon, she plopped herself in the driveway and pointed at the darkening sky. "Moon, please!" She wanted me to bring the moon to her so she could get a better look, make it hers. Walking didn't come until nearly eighteen months, our first clue of her penchant for perfectionism. At three, she could recite "Horton Hears a Who" and "Thidwick, The Big Hearted Moose" verbatim, but one day she stopped doing it. "I'm mad," she said. "Mad at who?" "Mad at the book!" She was angry she couldn't actually read it yet.
Today, I honor her and the incredible person she is and will continue to become. My fiance, B, once remarked that next to the word, "spunky," in the dictionary, there should be a picture of E. Of all the things I admire about her, I am most grateful for this attribute. Just as much as all of the love and support she received from friends and family, I am convinced that her indomitable spirit–her courage, tenacity, feistiness, and pluck, like a protective hard shell protecting her tender heart–is what got her through the troughs of her illness without succumbing to despair.
I cannot bring her the moon. But I can offer lots of love. And help guide her to become the best E that she can be, channeling her mercurial nature and helping her lean into her strengths. I expect great things from her, but not in the traditional sense. With her learning capabilities, inner drive and dogged work ethic, I know she will be an achiever in whatever she chooses to pursue professionally. But more importantly, to me at least, I am certain that she will do so with kindness and empathy. She will infect others with her zest for living, and in so doing, will bring more hope into world. God bless the child.


Author's note: Written for Cassievalentine as part of the "Five Things" meme. Spoilers for seasons 1 and 2 through the season 2finale.
Disclaimer: Characters and places belong to Shonda Rimes. No profit or infringement intended.
5. The third night in a row he comes in after midnight, Addison doesn't say hello or ask him if she can fix him a sandwich. It's not so much that she's tired of the fighting -- at least the fighting means there's some energy left in their marriage -- but the fact is, Derek doesn't really look at her anymore when he's yelling. She watches from her perch on the sofa as Derek takes off his shoes, drops his blazer on the kitchen table, and unsnaps his wrist watch. She opens her mouth to ask where he's been, and she doesn't just mean physically, but before she can get the words out, he's kneeling in front of her, his hands on her knees, as if he were a supplicant. His palms are hot against her skin, and he leans towards her, his lips pressing hard against any words she might have to say. For the third night in a row, Addison forgives him.
4. The bar is dank and dusty, and it's the last place Addison would ever set foot in. The bartender is burly guy, wearing a gray t-shirt, and his accent gives him away as a native Bostonian, most probably from the North Shore. In other circumstances, Derek would ask what brought the guy down to New York City, but as he takes another gulp of his beer, Derek decides he doesn't care.
"Last call," the bartender says. "You okay?"
"You ought to go home. Aren't you a doctor?"
"You sound like my wife."
"More reason to go home."
"Not tonight," Derek says. He sighs heavily. "I've already been home."
There's a moment of silence, and the neon glow from the Budweiser sign reflects streaks of red and blue on the wall. The bartender puts some newly washed glasses away, each one settling into the crate with a clink.
"There's nothing you can't fix," the bartender says with all the confidence of someone who's never been there, never done that.
"I found her in bed with my best friend."
More silence, more clinking. Derek picks at an imaginary piece of lint on his blazer jacket. He thinks about Addison, sitting up in bed, clutching the flannel sheet to her chest, her red hair falling around her face, and the way the early evening light cut through the slats of the blinds, criss-crossing her body. He wonders if she meant for him to find them, because after all, they -- Addison and Mark -- could have gone to a hotel.
"That's rough, man. I'm sorry," the bartender says. "What are you going to do?"
The bartender leans on the counter, his weight on his forearms. "Go home," he says. "Ask her why. There are two sides to every story." He straightens up and resumes tidying up. "You can decide in the morning. When you're rested, when your head is cleared, when your anger isn't set on slow burn."
Derek nods slowly. He pushes a couple of twenties across the bar. He can afford to be generous tonight, his last night in New York City.
"Go home," the bartender says. "Talk to her."
"Yeah," Derek says. "Thanks." He shoves his hands in his pockets and walks out into the night.
3. The problem with the trailer, Addison decides, is that it's not large enough for two egos, a dog (which she keeps tripping over), and Meredith Grey. She admits there's a certain efficiency in being able to be able to reach for a piece of toast while in the shower, but she also hates the fact there's nowhere to put her vast collection of shoes (currently stored beneath the bed and the tiny table in the breakfast 'room'; it's also starting to really annoy her how Derek refers to each segment of the trailer as a 'room'). Plus, given the size, she knows there's nowhere Meredith Grey hasn't been.
The only good thing about the trailer, she thinks, is the fact when Derek starts to descend into moodiness, his eyes growing dark with anger (or more likely, resentment, but Addison doesn't like to think he resents her), Addison can flee into the wide open spaces, turning her face up to the sky, and letting the wind ruffle through her hair. Addison is starting to develop a love for nature.
Still there are times, when she stands on the porch, watching Derek (always in flannel plaid and blue jeans when at home) firing up the grill, when she wants to say, "How about we look into buying a house? I hear they have them here in Seattle." But she's afraid of his answer, because there are times when she thinks he loves the trailer (and what it represents) more than her.
2. Addison tilts her face towards the night sky. Out here, well away from the lights of the city, she can see the Milky Way. It's been years since she's seen the stars quite like this -– diamonds thrown up against velvet in a haphazard embarrassment of riches -- and she has to admit, she likes it. The air is sticky sweet with the smell of spring rain, and the symphony of crickets, owls, and other creatures of the night is strangely beautiful. Addison steals a sideways glance at Derek, who is sitting on the porch, brooding, his fingers wrapped around a sweating bottle of beer. He doesn't need to know, Addison decides, that Seattle is growing on her.
1. She hears the way he says 'Meredith' and she shivers. She hates the fact of not knowing when the elevator doors open, when she turns a corner, when she enters the cafeteria, whether she'll see Derek there. With Meredith. She hates the way he says 'Meredith' and she's running out of snappy, witty sayings to make them think she doesn't care when she sees them together, but as she walks away from them, she'll twist her engagement and wedding rings around her fingers.
On the rare occasions she and Derek share a meal together, Addison desperately wants to ask him what he's thinking, what he's feeling. But she knows the response -- it's been the same for years: "Not now, Addison" or worse, because she knows it's not true, "I'm fine, Addison." She hates the way he says her name, with the emphasis on the last syllable, as if he's scolding her. There's no softness to his voice when he speaks to her, no rounded syllables, no gentleness, and she hates hearing the formality of 'Addison'. She thinks she could bear this assault on her name if she didn't have to see him on a daily basis speaking to Meredith, knowing so well that there's a difference in tone, in cadence, in emotion.
So for this dinner, just before the prom, they're sitting in a fancy French restaurant, their silverware blinking against the china plates. Derek is wearing his tux, she's wearing red because he once told her he liked her best in red. She reaches forward, brushes his hand with the tips of her fingers. Derek lifts his hand, smiles wanly at her, and she decides not to ask if he is willing to let Meredith go. She lifts her wine glass, the merlot swirling at the bottom of the goblet.
"To us," she says, her voice scratchy with emotion.
Derek hesitates and then he nods slowly. His glass taps gently against hers. "To us." He draws back, clears his throat. He has that faraway look in his eyes, the one that makes her afraid of what he's going to say. "You look beautiful tonight, Addie."
She smiles. Yes, she was right not to ask him how he truly feels about Meredith.
Feedback always appreciated at seemag1@yahoo.com or in my LJ.


text:
New members of the Wafilin Systems family
Wafilin's tremendous growth in recent months has resulted in many new projects. To ensure we continue to deliver top-quality service to all our customers, we must respond to this growth by continually attracting new talent into our team. In the past few months, we have been pleased to welcome three new colleagues. All three bring specific specialist skills and experience, which they will dedicate to delivering the best possible service to our customers. This month, we are delighted to introduce you to our latest new joiners.
Experienced mechanical engineer chooses Wafilin Systems
Our first new appointment is Harry van der Wal, our new Project Engineer. Harry brings many years of engineering experience in the food industry, having worked at companies including Friesland Campina and Sanco Processing. "At Wafilin, I'm responsible for technical design development, procurement, dispatch and process monitoring". With the benefit of Harry's experience, our work will be even more project-driven and efficient, and we can increase and monitor the quality and reliability of our systems.
Harry was quickly persuaded that he wanted to become part of the Wafilin team. "I could tell straight away that this was a line-up of good, capable people – with a strong commitment to process technology. It's really important to me to be able to work with colleagues, customers and suppliers in a positive and enjoyable way. This is a core value for Wafilin too, so I think we're perfectly in tune in this regard". Wafilin's dynamic nature as a growing company also attracted Harry. "Ultimately, my goal is to work with a motivated group of people to deliver great projects and contribute to the company's growth".
Former intern with a passion for dairy technology
Last August, Jelmer de Wal – a former intern at Wafilin Systems – officially joined us as Junior Technical Sales Engineer. After his internship, Jelmer completed his graduation project in the dairy industry and then came straight back to Wafilin. "The great thing about Wafilin is that it's a small company, so it's easy to approach people and get to know them. It's a nice environment to work in too" says Jelmer.
Jelmer is a dairy technologist in heart and soul, and engineering is his great passion. This combination made him the perfect candidate for his role within Wafilin. With his knowledge and commitment to the industry, he is already helping to deliver the best of service to Wafilin customers. "At present, I'm focusing on R&D activities and carrying out pilot testing for our customers. In the process, I'm hoping to take on greater responsibility so that eventually I'll be able to execute my own projects".
With the benefit of Jelmer's knowledge, we can deliver an even better service to our customers in the dairy industry. We are delighted that this young and talented dairy technologist is joining us as another shoulder to the wheel!
Food technologist newly appointed to the Wafilin Systems team
Last but not least, Marte Roorda is another new addition to the Wafilin Systems team. Marte recently graduated as a food technologist and she brings extensive practical and theoretical knowledge of the dairy industry. She is taking up the role of Junior Technical Sales Engineer within Wafilin Systems.
Despite being in discussion with a number of large companies that interested her, Wafilin was the one she opted for. "Huge draws for me were the knowledge and expertise of the colleagues I'll work with on various projects, as well as the goals we share – for instance in relation to sustainability. My aim is to help Wafilin grow and develop within the dairy market."
Marte's ambitions and competencies in dairy process technology lie mainly in the areas of process improvement and development, innovation and sustainability. "I came into contact with the dairy industry through my internship. I then became so passionate about this field of work that I decided to make it a focus of my studies. As a result, I graduated with a specialisation in dairy process technology." We look forward to working with Marte on new and innovative solutions.
New colleagues add value for customers
We are thrilled to have our new colleagues on-board, together with the experience and skills they bring. Their input makes us even better equipped to service our customers on all fronts – from engineering to the provision of relevant information. At Wafilin, we are always willing to go the extra mile for our valued customers and, with our new colleagues, we will continue to do so!
Interested to meet Harry, Jelmer or Marte? You are welcome to drop into the Wafilin Systems office. Contact Henk Schonewille, CEO of Wafilin Systems: make a appointment


text:
Free Access to Law from Malawi
Supreme Court of Appeal
High Court: General Division
High Court: Commercial Division
Industrial Relations Court
Magistrate Court Lilongwe
Magistrate Court Zomba
Laws of Malawi
Numbered Acts
Malawi Law Journal
Home » Kapiye v Lapken & Anor. (Civil Appeal Cause No. 102 of 2017) [2018] MWHC 1101 (23 July 2018);
Kapiye v Lapken & Anor. (Civil Appeal Cause No. 102 of 2017) [2018] MWHC 1101 (23 July 2018);
Myson Kapiye-Vs- Delunde Lapken and John Mamison Civil Appeal No. 102 of 2017.pdf
This was an appeal against a decision of a magistrate to dismiss the appellant's claim over a piece of customary land which he claimed was unlawfully in the possession of the second respondent, his son. The appellant had left the village for a long time and upon returning found that the first respondent had constructed a home on his land. The appellant instructed the first respondent to vacate land but he refused and proceeded to sell the land to the second respondent. The appellant told the court below that he inherited the piece of land from his father. The lower court found that the appellant had failed to adduce enough evidence to show that the land belonged to him.
The court had to determine the following: which party had the right of occupation of the land; whether the land was lawfully transferred to the second respondent and whether a permanent injunction could be granted restraining the appellant or the respondents from interfering with the land in question.
The court held that although the land had been given to the first respondent customarily, chiefs must be guided by the law specifically, the Constitution and it was against the law to deprive any person the right to use and occupy customary land without any justification at law. It held that indefinite individual usage and occupation of customary land was therefore permissible under the laws of Malawi and the subsequent transfer was legal. Accordingly, the court upheld the lower court ruling.
Flynote tags:
Cultural and heritage values in the environment
African customary law and rights of indigenous peoples
https://old.malawilii.org/system/files/judgment/high-court-general-division/2018/1101/Myson%20%20Kapiye-Vs-%20Delunde%20%20Lapken%20%20and%20%20John%20%20Mamison%20%20Civil%20%20Appeal%20%20No.%20102%20%20of%20%202017.pdf
Malawi Judiciary
Malawi Law Society
Legal Information from Africa
Legal Information from the UK
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It Is Outright Best For Modern Girls Having Rectangular Body Shape.


Major sacrilege of Guru Sahib occurred at village Rayya at street Vishkarma which is near a government school. In one of the houses, pothis of Guru Sahib and Gutka Sahib's were found allegedly burnt.
The incident occurred on August 15, 2015 and Sikhs worldwide expressed outrage over the incident. Just this year alone, 14 causes of Guru Saroop's being burnt have come to light from Punjab alone.
The Satkar Committee along with many other Singhs arrived at the village calling the police to arrest the suspect. The suspect was arrested and taken into custody.
Next post Pictures & Videos – Landslide at Gurdwara Manikaran Sahib, Himachal Pradesh. Multiple deaths reported.