Burden of female breast cancer in India: estimates of YLDs, YLLs, and DALYs at national and subnational levels based on the national cancer registry programme.

PURPOSE: Female breast cancer (BC) is the leading cause of cancer incidence and mortality in India, and accounted for 13.5% of new cancer cases and 10% of cancer-related deaths in 2020. This study aims to estimate and report the female BC burden in India at state level from 2012 to 2016 in terms of years of life lost, years lived with disability, and disability-adjusted life years (DALYs), and to project the burden for the year 2025. METHODS: The cancer incidence and mortality data from 28 population-based cancer registries were analysed. The mean mortality to incidence ratio was estimated, and mortality figures were adjusted for underreporting. The burden of female BC was estimated at national and subnational levels using Census data, World Health Organisation's lifetables, disability weights, and the DisMod-II tool. A negative binomial regression is employed to project burden for 2025. RESULTS: The burden of BC among Indian women in 2016 was estimated to be 515.4 DALYs per 100,000 women after age standardization. The burden metrics at state level exhibited substantial heterogeneity. Notably, Tamil Nadu, Telangana, Karnataka, and Delhi had a higher burden of BC than states in the eastern and north-eastern regions. The projection for 2025 indicates to a substantial increase, reaching 5.6 million DALYs. CONCLUSION: The female BC burden in India was significantly high in 2016 and is expected to substantially increase. Undertaking a multidisciplinary, context-specific approach for its prevention and control can address this rising burden.

Spin-glass behavior in a giant unit cell compound Tb117Fe52Ge113.8(1).

In this paper we demonstrate evidence of a cluster spin glass in Tb117Fe52Ge113.8(1) (a compound with a giant cubic unit cell) via ac and dc magnetic susceptibility, magnetization, magnetic relaxation and heat capacity measurements. The results clearly show that Tb117Fe52Ge113.8(1)) undergoes a spin glass phase transition at the freezing temperature, ~38 K. The good fit of the frequency dependence of the freezing temperature to the critical slowing down model and Vogel-Fulcher law strongly suggest the formation of cluster glass in the Tb117Fe52Ge113.8(1) system. The heat capacity data exhibit no evidence for long-range magnetic order, and yield a large value of Sommerfeld coefficient. The spin glass behavior of Tb117Fe52Ge113.8(1) may be understood by assuming the presence of competing interactions among multiple non-equivalent Tb sites present in the highly complex unit cell.

Shape selectivity by guest-driven restructuring of a porous material.

A flexible metal-organic framework selectively sorbs para- (pX) over meta-xylene (mX) by synergic restructuring around pX coupled with generation of unused void space upon mX loading. The nature of the structural change suggests more generally that flexible structures which are initially mismatched in terms of fit and capacity to the preferred guest are strong candidates for effective molecular separations.

Side-chain control of porosity closure in single- and multiple-peptide-based porous materials by cooperative folding.

Porous materials are attractive for separation and catalysis-these applications rely on selective interactions between host materials and guests. In metal-organic frameworks (MOFs), these interactions can be controlled through a flexible structural response to the presence of guests. Here we report a MOF that consists of glycyl-serine dipeptides coordinated to metal centres, and has a structure that evolves from a solvated porous state to a desolvated non-porous state as a result of ordered cooperative, displacive and conformational changes of the peptide. This behaviour is driven by hydrogen bonding that involves the side-chain hydroxyl groups of the serine. A similar cooperative closure (reminiscent of the folding of proteins) is also displayed with multipeptide solid solutions. For these, the combination of different sequences of amino acids controls the framework's response to the presence of guests in a nonlinear way. This functional control can be compared to the effect of single-point mutations in proteins, in which exchange of single amino acids can radically alter structure and function.

Controlling magnetism of a complex metallic system using atomic individualism.

When the complexity of a metallic compound reaches a certain level, a specific location in the structure may be critically responsible for a given fundamental property of a material while other locations may not play as much of a role in determining such a property. The first-principles theory has pinpointed a critical location in the framework of a complex intermetallic compound--Gd(5)Ge(4)--that resulted in a controlled alteration of the magnetism of this compound using precise chemical tools.

Use of microindentation to characterize the mechanical properties of articular cartilage: comparison of biphasic material properties across length scales.

OBJECTIVE: Small scale mechanical testing techniques offer new possibilities for defining changes in mechanical properties that accompany the morphological, histological, and biochemical abnormalities of osteoarthritis (OA). The goal of this study was to investigate the use of microindentation in characterizing the biphasic material properties of articular cartilage. Direct comparisons of the biphasic properties (E, k and nu) determined using microindentation were made to those determined on the same specimens using standard macroscale testing techniques. METHODS: Deep-zone bovine articular cartilage specimens (n=10) were tested in macroscale confined and unconfined compression. For microindentation testing, the biphasic properties were determined by conducting finite element simulations of the microindentation experiments for different combinations of values of biphasic properties and identifying the combination yielding the best match to each microindentation curve. Paired t-tests were performed to compare each of E, k and nu between the macro- and microscale. RESULTS: The microscale values for E, k and nu were 0.74 (0.53, 0.95)MPa, 0.66 (0.022, 0.110)x10(-16)m(4)/Ns, and 0.16 (0.08, 0.24), respectively. A significant difference between the macro- and microscale measurements was observed for k (P<0.0001), but not for E or nu (P=0.88, 0.16). CONCLUSIONS: The agreement in Young's modulus and Poisson's ratio between the results of the microindentation and macroscale tests supports the use of microindentation for characterization of some of the biphasic material properties of articular cartilage. The observed differences in permeability between macro- and microscales are consistent with evidence in the literature of a length-scale dependence to this property.

Relationship between markers of activated coagulation, their correlation with inflammation, and association with coronary heart disease (NPHSII).

OBJECTIVE: To determine whether activation of coagulation increases in parallel with inflammation and whether coagulation activation markers (CAMs) are independently associated with coronary heart disease (CHD), in the prospective study, NPHSII. METHODS: Surveillance of 2997 men between 50 and 63 years yielded 314 first CHD events during 36507 person-years of observation. The plasma levels of activated factor XII (FXIIa), the peptides released upon activation of factor X (FXpep) and factor IX (FIXpep), activated factor VII (FVIIa), prothrombin fragment 1 + 2 (F1 + 2) and fibrinopeptide A (FpA) served as indices of activity along the coagulation pathway. C reactive protein (CRP) provided a marker of inflammatory activity. RESULTS: While borderline or significant correlations were identified for each CAM with inflammation, as determined by CRP levels, these did not reach as high a numerical value as was shown for fibrinogen with CRP. FVIIa and FIXpep possessed independent associations with CHD: a one SD increase in adjusted FIXpep and FVIIa level was associated with a relative hazard of 1.20 (95% CI 1.00-1.43) and 0.70 (CI 0.58-0.86), respectively, using a group including all CHD events, compared with 'no-event'. CONCLUSIONS: Inflammation has significant but minimal impact upon CAMs of the extrinsic coagulation pathway. Reduced FVIIa and increased FIXpep levels were found to be significant, independent, predictors of CHD.

The plasma kallikrein-kinin system and risk of cardiovascular disease in men.

BACKGROUND: The plasma kallikrein-kinin system (PKKS) has been implicated in cardiovascular disease, but activation of the PKKS has not been directly probed in individuals at risk of coronary heart disease (CHD) or stroke. OBJECTIVE: To determine the involvement of the PKKS, including factor XI, in cardiovascular disease occurring in a nested case-control study from the Second Northwick Park Heart Study (NPHS-II). METHODS AND RESULTS: After a median follow-up of 10.7 years, 287 cases of CHD and stroke had been recorded and 542 age-matched controls were selected. When FXIIa-C1 esterase inhibitor (C1-inhibitor) concentrations were divided into tertiles (lowest tertile as reference), the odds ratios (ORs) at 95% CIs for CHD were 0.52 (0.34-0.80) in the middle tertile and 0.73 (0.49-1.09) in the highest tertile (P = 0.01 for the overall difference; P = 0.01 for CHD and stroke combined). For kallikrein-C1-inhibitor complexes, the ORs for stroke were 0.29 (0.12-0.72) and 0.67 (0.30-1.52) in the middle and high tertiles, respectively (P = 0.02). FXIIa-C1-inhibitor and kallikrein-C1-inhibitor complexes were negatively related to smoking and fibrinogen (P < 0.005). FXIa-inhibitor complexes correlated strongly with FXIIa-inhibitor complexes. CONCLUSIONS: Lower levels of inhibitory complexes of the PKKS enzymes and particularly of FXIIa contribute to the risk of CHD and stroke in middle-aged men. This observation supports the involvement of the PKKS in atherothrombosis.

Ferromagnetism in the Mott insulator Ba2NaOsO6.

Results are presented of single crystal structural, thermodynamic, and reflectivity measurements of the double-perovskite Ba2NaOsO6. These characterize the material as a 5d1 ferromagnetic Mott insulator with an ordered moment of approximately 0.2microB per formula unit and TC=6.8(3) K. The magnetic entropy associated with this phase transition is close to Rln2, indicating that the quartet ground state anticipated from consideration of the crystal structure is split, consistent with a scenario in which the ferromagnetism is associated with orbital ordering.

Common adiponectin gene variants show different effects on risk of cardiovascular disease and type 2 diabetes in European subjects.

Alterations in the secretion of adipokines may explain the link between obesity, type 2 diabetes (T2DM) and coronary artery disease (CAD). These conditions have been associated with variation in the adiponectin gene, although evidence for this relationship has been variable, with differences found even in similar samples. This study aims to clarify these inconsistencies by determining the impact of identified adiponectin gene (ADIPOQ) variants (-11391G>A,-1377C>G[promoter] and +45T>G[exon 2] and +276G>T[intron 2]) on the prospective risk of CAD and T2DM in healthy men, and on adverse metabolic markers, in myocardial infarct survivors and controls from different parts of Europe. The hazard ratio for cardiovascular disease varied across the -11391GG/GA/AA(p = 0.03) and -11371CC/CG/GG(p = 0.05) genotypes only. In contrast, only the +45T>G variant (3.80[1.76-8.24]) was associated with T2DM, while two haplotypes GCTT/GCGG (p < 0.05) and +276G>T(p = 0.01) increased risk in interaction with obesity. The variants were associated with a number of biomarkers in Southern but not Northern Europe (p = 0.01), despite no significant differences in allele or haplotype frequencies (p > 0.44). A risk haplotype could not be identified in either sample. Adiponectin gene variants are hence currently poor markers for the development of T2DM and CAD. Their influence on risk depends significantly on interactions that are not currently understood with either genetic variation elsewhere or the environment of the sample studied.

The effect of nucleus pulposus crosslinking and glycosaminoglycan degradation on disc mechanical function.

Altered mechanical loading, secondary to biochemical changes in the nucleus pulposus, is a potential mechanism in disc degeneration. An understanding of the role of this altered mechanical loading is only possible by separating the mechanical and biological effects of early nucleus pulposus changes. The objective of this study was to quantify the mechanical effect of decreased glycosaminoglycans (GAG) and increased crosslinking in the nucleus pulposus using in vitro rat lumbar discs. Following initial mechanical testing the discs were injected according to the four treatment groups: PBS control, chondroitinase-ABC (ChABC) for GAG degradation, genipin (Gen) for crosslinking, or a combination of chondroitinase and genipin (ChABC+Gen). After treatment the discs were again mechanically tested, followed by histology or biochemistry. Neutral zone mechanical properties were changed by approximately 20% for PBS, ChABC, and ChABC+Gen treatments (significant only for PBS in a paired comparison). These trends were reversed with genipin crosslinking alone. With ChABC treatment the effective compressive modulus increased and the GAG content decreased; with the combination of ChABC+Gen the mechanics and GAG content were unchanged. Degradation of nucleus pulposus GAG alters disc axial mechanics, potentially contributing to the degenerative cascade. Crosslinking is unlikely to contribute to degeneration, but may be a potential avenue of treatment.

Increase of plasma fibrinogen levels and variability with age in a sample of middle aged healthy men.

According to predictions from the current theoretical models for ageing the heterogeneity of the population is increasing with increasing age. Although the direct observation of such changes in humans is extremely difficult, supporting evidence should be identifiable in key biomarkers associated with health and mortality. Using data from the Northwick Park Heart Study II of 3052 healthy middle-aged men (mean 56 years of age, range 49-69 years), with 5 annual measures of CHD risk factors, ageing effects were tested for plasma fibrinogen, cholesterol and triglycerides. Fibrinogen levels increased with age (p < 0.0001), while cholesterol showed a decrease, and triglycerides did not show any change with age. There was a significant increase in the variance of fibrinogen with age (p < 0.0007) but not for cholesterol or triglycerides. The raising effect on fibrinogen levels associated with the A allele of the FIBB - 455G>A promoter variant also decreased with age (p = 0.005). The age-associated changes observed in the fibrinogen variability and the association of phenotype to genotype are discussed in light of the evolutionary theory, and their implications are considered.

Refined association mapping for a quantitative trait: weight in the H19-IGF2-INS-TH region.

Previous analyses have provided evidence for one or more loci affecting body weight in the H19-IGF2-INS-TH region on chromosome 11p15. To identify the location of a possible causal locus or loci we applied association analysis by composite likelihood to a large cohort under the Malecot model for body weight. A random sample of 2731 men in the UK were typed for eleven single nucleotide polymorphisms (SNPs) in IGF2, two SNPs in H19, one SNP in INS and one microsatellite marker in the TH genes. Using F tests appropriate to small marker sets, the superiority of regression over correlation was confirmed. All the evidence for association came from IGF2, with P= 0.007 for height-adjusted weight and P= 0.019 for weight additionally adjusted for smoking and alcohol drinking. Although the estimated point location for the suspected causal variant was close to IGF2 ApaI, the 95% confidence and support intervals covered most of IGF2 but none of the other loci. Identification of the causal SNP or SNPs within IGF2 will require typing of more variants in this region.

The apolipoprotein A-V genotype and plasma apolipoprotein A-V and triglyceride levels: prospective risk of type 2 diabetes. Results from the Northwick Park Heart Study II.

AIMS/HYPOTHESIS: We sought to establish the relationship between plasma apolipoprotein A-V (APOA5, previously known as apoA-V) and triglyceride levels and to determine the impact of the APOA5 genotype on APOA5 levels and development of type 2 diabetes in a 15-year follow-up study of healthy UK men. MATERIALS AND METHODS: APOA5 -1131T>C and S19W genotypes were determined in 2,490 men, of whom 145 subsequently developed type 2 diabetes. In a subset of 299 men, we also determined APOA5 levels. RESULTS: Plasma APOA5 levels positively correlated with triglycerides (r=0.18, p<0.002) and were not different in men who subsequently developed type 2 diabetes compared with healthy men (p=0.7). Carriers of either APOA5 W19 or -1131C had, as expected, higher plasma triglycerides. However, while W19 carriers had significantly higher APOA5 levels (p=0.0003), APOA5 levels were not associated with -1131T>C (p=0.63), reinforcing the idea that the reported -1131C association with triglycerides levels is due to linkage disequilibrium with variants in the APOC3 gene, and not due to the direct effect on APOA5 levels. Overall no effect of APOA5 -1131T>C or S19W was found on type 2 diabetes risk. CONCLUSIONS/INTERPRETATION: In contrast to animal studies, in man, plasma APOA5 positively correlates with plasma triglyceride levels. In prospective analysis, with the caveat that numbers were small, APOA5 genotypes do not appear to have an impact on risk of development of type 2 diabetes.

EPCR Ser219Gly: elevated sEPCR, prothrombin F1+2, risk for coronary heart disease, and increased sEPCR shedding in vitro.

We have progressively analysed three studies of coronary heart disease (CHD) for a variant in EPCR (Ser219Gly). Initially, in a prospective study, NPHSII, while no overall CHD-risk was identified in heterozygotes, homozygotes for 219Gly exhibited a three-fold elevated risk (HR 3.3, CI 1.22-8.96). In diabetics within NPHSII, there was a suggestion that 219Gly+ was associated with elevated CHD-risk (HR 1.89, CI 0.39-9.06) although numbers were small. To further assess the effect of the variant in diabetes, a case-control study of MI, HIFMECH, was used, in which previous analysis had defined a group with metabolic syndrome, by factor analysis. A significant CHD-risk interaction was identified between genotype and the 'metabolic syndrome' factor (interaction p=0.009). To further assess CHD-risk for this variant in type-2 diabetes and to assess the effect of the variant upon thrombin generation and plasma levels of soluble EPCR, a cross-sectional study of type-2 diabetes was used. A significant CHD-risk was identified for European Whites (OR 2.84, CI 1.38-5.85) and Indian Asians in this study (OR 1.6, CI 1.00-2.57) and the frequency of 219Gly was two-fold higher in Indian Asians. Soluble EPCR levels were strongly associated with genotype, with homozygotes for 219Gly having four-fold higher levels (p<0.0001). In vitro studies of EPCR-transfected cells suggested increased basal release of sEPCR from cells expressing the 219Gly EPCR phenotype. Furthermore, in base-line samples from NPHSII and in the diabetic study, a significant increase in prothrombin F1+2 level was observed for 219Gly. The increased CHD-risk and thrombin generation appears to be acting through increased shedding of the Gly allele from the cell surface.

Cholesteryl ester transfer protein TaqIB variant, high-density lipoprotein cholesterol levels, cardiovascular risk, and efficacy of pravastatin treatment: individual patient meta-analysis of 13,677 subjects.

BACKGROUND: Several studies have reported that the cholesteryl ester transfer protein (CETP) TaqIB gene polymorphism is associated with HDL cholesterol (HDL-C) levels and the risk of coronary artery disease (CAD), but the results are inconsistent. In addition, an interaction has been implicated between this genetic variant and pravastatin treatment, but this has not been confirmed. METHODS AND RESULTS: A meta-analysis was performed on individual patient data from 7 large, population-based studies (each >500 individuals) and 3 randomized, placebo-controlled, pravastatin trials. Linear and logistic regression models were used to assess the relation between TaqIB genotype and HDL-C levels and CAD risk. After adjustment for study, age, sex, smoking, body mass index (BMI), diabetes, LDL-C, use of alcohol, and prevalence of CAD, TaqIB genotype exhibited a highly significant association with HDL-C levels, such that B2B2 individuals had 0.11 mmol/L (0.10 to 0.12, P<0.0001) higher HDL-C levels than did B1B1 individuals. Second, after adjustment for study, sex, age, smoking, BMI, diabetes, systolic blood pressure, LDL-C, and use of alcohol, TaqIB genotype was significantly associated with the risk of CAD (odds ratio=0.78 [0.66 to 0.93]) in B2B2 individuals compared with B1B1 individuals (P for linearity=0.008). Additional adjustment for HDL-C levels rendered a loss of statistical significance (P=0.4). Last, no pharmacogenetic interaction between TaqIB genotype and pravastatin treatment could be demonstrated. CONCLUSIONS: The CETP TaqIB variant is firmly associated with HDL-C plasma levels and as a result, with the risk of CAD. Importantly, this CETP variant does not influence the response to pravastatin therapy.

Increased incidence of neoplasia of the digestive tract in men with persistent activation of the coagulant pathway.

BACKGROUND: Thrombin promotes angiogenesis and cell proliferation in cancer. Whether thrombin turnover influences cancer incidence is unknown. OBJECTIVES: To explore the relation between the status of the coagulant pathway and cancer incidence by population survey. METHODS: Of 4,009 middle-aged men clinically free of malignancy, 3052 (76.1%) were recruited. Measurements of hemostatic status were made annually for 4 years, and follow-up for morbidity and mortality was maintained thereafter. Persistent activation of the coagulant pathway was diagnosed when prothrombin fragment 1+2 and fibrinopeptide A concentrations exceeded the upper quartiles of the population distribution in two consecutive annual examinations. Cancer incidence rates in men developing persistent activation (taking the time of onset of activation as baseline) were compared with those in men remaining free of this condition. RESULTS: Persistent activation of the hemostatic pathway was a distinct entity found in 111 men [43 expected by chance alone (P <0.001)], and associated with activation throughout the coagulation pathway. Total mortality (/1000 person-years) was higher in those with persistent activation than in others (17.1 and 9.7, respectively, P=0.015), owing to a higher mortality from all cancers (11.3 and 5.1, respectively, P=0.01), due in turn largely to a higher mortality from cancers of the digestive tract (6.3 and 1.9, respectively, P=0.004). Trends were similar for non-fatal cancers. CONCLUSIONS: Persistent activation of the coagulant pathway plays a role in the preclinical phase of cancer and is associated with an increased incidence of clinical malignancy, especially of the digestive tract.

A combination of two common thrombomodulin gene variants (-1208-1209TTdelTT and A455V) influence risk of coronary heart disease: a prospective study in men.

In a previous case control study of myocardial infarction (MI), we identified risk associated with the combination of two variants in the thrombomodulin (TM) gene (-1208-1209TTdelTT and A455V) and an interaction with increased body mass index (BMI). The rare alleles at these two common variant sites in the TM gene occur in most individuals on the same allele (V/delTT) and are in strong linkage disequilibrium (Delta=0.67, P <0.0005). We have extended these findings in a prospective study of 2700 UK middle age men; the second Northwick Park Heart Study (NPHSII), in which 227 coronary heart disease (CHD) events have been reported to date. Risk was analysed by tertile of BMI, systolic blood pressure (SBP) and triglyceride. The strongest risk for the V/delTT haplotype was in the mid- and top-tertile of triglyceride; RR 1.95 (CI 1.12-3.40) and 1.77 (CI 1.02-3.09), respectively, compared to non-carriers in the lowest tertile (after adjusting for age, practice, smoking, SBP, BMI; interaction P=0.016). No significant risk was identified for increased triglyceride levels in those with the common TM haplotype. There was a suggestion for greater inflammatory response (C-reactive protein levels, CRP) in those with V/delTT compared to those with the common allele, as triglyceride levels increased. Overall, these findings may suggest that the common TM allele confers protection against the adverse CHD effect of either plasma triglyceride-containing lipoproteins, or the underlying atherosclerotic mechanism of the metabolic syndrome, and that this process is defective in carriers of V/delTT.

The -344T>C promoter variant of the gene for aldosterone synthase (CYP11B2) is not associated with cardiovascular risk in a prospective study of UK healthy men.

INTRODUCTION: The tissue renin-angiotensin system is implicated in the pathogenesis of coronary artery disease (CAD). As locally synthesised aldosterone is a potential mediator of CAD, we have sought an association of the -344T>C variant of the aldosterone synthase (CYP11B2) gene with CAD events. METHODS: Subjects comprised of the Second Northwick Park Heart Study (NPHSII), a prospective study of unrelated, healthy middle-aged Caucasian males. CAD events were recorded in 2490 subjects, and defined as a sudden cardiac death, myocardial infarction or coronary artery revascularisation procedure. Mean follow-up was 10.8 years. Aldosterone synthase genotype was determined in 2490 subjects. Power calculation suggests that we have 80% power (at a significance level of 0.05) to detect a difference in hazard ratio (HR) between homozygote groups of 0.45. RESULTS: One hundred and eighty-seven CAD events were recorded in 2490 subjects. In the group overall, CAD events were independent of genotype with adjusted hazard ratios being 1.00 versus 1.25 versus 0.80 for TT versus TC versus CC genotypes, respectively, P = 0.07. Genotype interactions with smoking and blood pressure were sought. Whilst CAD events were independent of genotype amongst non-smokers, CC genotype in smokers was associated with a reduced risk HR 2.02 versus 2.28 versus 0.82 for TT versus TC versus CC genotypes, P = 0.05 (HR for TT + TC versus CC were 1.77 versus 0.67, P = 0.02). This apparent interaction remained after adjustment for conventional risk factors. No such interaction was found with blood pressure. CONCLUSIONS: Aldosterone synthase genotype is unrelated to overall CAD events risk. A possible interaction with smoking requires confirmation.

Decoupling of the magnetic and structural transformations in Er5Si4.

Er5Si4 is a member of the R5(Si(4-x)Gex) family of alloys, where R=rare earth metal. Many of these compounds display a strong coupling between the magnetic and crystal lattices. In the naturally layered R5(Si(4-x)Gex) materials, inter- and intralayer interactions can be controlled by chemical and physical means; thus their physical properties can be tailored within wide limits. The Er5Si4 is unique in that the temperature dependent structural sequence is opposite that of other representatives of this family. The magnetism of Er5Si4 is reflective of its exceptional place within the series.