Investigation of the relationship between obesity, weight cycling, and tumor progression in murine myeloma models

We investigated this relationship in two murine myeloma models with a high fat diet (HFD) to induce obesity, and a diet cycling (DC) regimen to model weight cycling.https://knowledgeconnection.mainehealth.org/lambrew-retreat-2021/1025/thumbnail.jp

Circulating resistin levels and risk of multiple myeloma in three prospective cohorts

BACKGROUND: Resistin is a polypeptide hormone secreted by adipose tissue. A prior hospital-based case-control study reported serum resistin levels to be inversely associated with risk of multiple myeloma (MM). To date, this association has not been investigated prospectively. METHODS: We measured resistin concentrations for pre-diagnosis peripheral blood samples from 178 MM cases and 358 individually matched controls from three cohorts participating in the MM cohort consortium. RESULTS: In overall analyses, higher resistin levels were weakly associated with reduced MM risk. For men, we observed a statistically significant inverse association between resistin levels and MM (odds ratio, 0.44; 95% confidence interval (CI) 0.24-0.83 and 0.54; 95% CI 0.29-0.99, for the third and fourth quartiles, respectively, vs the lowest quartile; Ptrend=0.03). No association was observed for women. CONCLUSIONS: This study provides the first prospective evidence that low circulating resistin levels may be associated with an increased risk of MM, particularly for men

Circulating markers of microbial translocation and host response to bacteria with risk of colorectal cancer: A prospective, nested case-control study in men

BACKGROUND: Gut microbial dysbiosis contributes to colorectal cancer (CRC) pathogenesis, possibly mediated in part by increased intestinal permeability to endotoxin lipopolysaccharide (LPS), microbial translocation, and subsequent endotoxemia and inflammation. However, epidemiologic evidence linking circulating markers of microbial translocation with CRC risk is limited. METHODS: We conducted a prospective, nested case-control study of 261 incident CRC cases and 261 controls (matched on age and time of blood draw) among 18,159 men with pre-diagnostic blood specimens in the Health Professionals Follow-Up Study (1993-2009). We examined three complementary markers of microbial translocation and host response to bacteria, including LPS-binding protein (LBP), soluble CD14 (sCD14), and endotoxincore antibody (EndoCAb) immunoglobulin M (IgM), with subsequent risk of CRC. Unconditional logistic regressions were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). FINDINGS: Pre-diagnostic circulating levels of sCD14 were associated with a higher risk of incident CRC. Compared to men in the lowest quartile, the multivariable OR was 1.90 (95% CI, 1.13-3.22) for men in the highest quartile (OR INTERPRETATION: Microbial translocation and host response to bacteria, as reflected by sCD14, is associated with risk of incident CRC in men. FUNDING: US National Institutes of Health

A prospective analysis of circulating saturated and monounsaturated fatty acids and risk of non-Hodgkin lymphoma

Circulating saturated (SFA) and monounsaturated fatty acids (MUFA), which are predominantly derived from endogenous metabolism, may influence non-Hodgkin lymphoma (NHL) risk by modulating inflammation or lymphocyte membrane stability. However, few biomarker studies have evaluated NHL risk associated with these fats. We conducted a prospective study of 583 incident NHL cases and 583 individually matched controls with archived pre-diagnosis red blood cell (RBC) specimens in the Nurses\u27 Health Study (NHS) and Health Professionals Follow-up Study (HPFS). RBC membrane fatty acid levels were measured using gas chromatography. Using multivariable logistic regression, we estimated odds ratios (OR) and 95% confidence intervals (CI) for risk of NHL and major NHL subtypes including T cell NHL (T-NHL), B cell NHL (B-NHL) and three individual B-NHLs: chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma. RBC SFA and MUFA levels were not associated with NHL risk overall. However, RBC very long chain SFA levels (VLCSFA; 20:0, 22:0, 23:0) were inversely associated with B-NHLs other than CLL/SLL; ORs (95% CIs) per standard deviation (SD) increase in level were 0.81 (0.70, 0.95) for 20:0, 0.82 (0.70, 0.95) for 22:0, and 0.82 (0.70, 0.96) for 23:0 VLCSFA. Also, both VLCSFA and MUFA levels were inversely associated with T-NHL [ORs (95% CIs) per SD: VLCSFA, 0.63 (0.40, 0.99); MUFA, 0.63 (0.40, 0.99)]. The findings of inverse associations for VLCSFAs with B-NHLs other than CLL/SLL and for VLCSFA and MUFA with T-NHL suggest an influence of fatty acid metabolism on lymphomagenesis

Elucidating under-studied aspects of the link between obesity and multiple myeloma: Weight pattern, body shape trajectory, and body fat distribution

BACKGROUND: Although obesity is an established modifiable risk factor for multiple myeloma (MM), several nuanced aspects of its relation to MM remain unelucidated, limiting public health and prevention messages. METHODS: We analyzed prospective data from the Nurses\u27 Health Study and Health Professionals Follow-Up Study to examine MM risk associated with 20-year weight patterns in adulthood, body shape trajectory from ages 5 to 60 years, and body fat distribution. For each aforementioned risk factor, we report hazard ratios (HRs) and 95% confidence intervals (CIs) for incident MM from multivariable Cox proportional-hazards models. RESULTS: We documented 582 incident MM cases during 4 280 712 person-years of follow-up. Persons who exhibited extreme weight cycling, for example, those with net weight gain and one or more episodes of intentional loss of at least 20 pounds or whose cumulative intentional weight loss exceeded net weight loss with at least one episode of intentional loss of 20 pounds or more had an increased MM risk compared with individuals who maintained their weight (HR = 1.71, 95% CI = 1.05 to 2.80); the association was statistically nonsignificant after adjustment for body mass index. We identified four body shape trajectories: lean-stable, lean-increase, medium-stable, and medium-increase. MM risk was higher in the medium-increase group than in the lean-stable group (HR = 1.62, 95% CI = 1.22 to 2.14). Additionally, MM risk increased with increasing hip circumference (HR per 1-inch increase: 1.03, 95% CI = 1.01 to 1.06) but was not associated with other body fat distribution measures. CONCLUSIONS: Maintaining a lean and stable weight throughout life may provide the strongest benefit in terms of MM prevention

Pre-diagnosis plasma immune markers and risk of non-Hodgkin lymphoma in two prospective cohort studies

Inflammation and B-cell hyperactivation have been associated with non-Hodgkin lymphoma development. This prospective analysis aimed to further elucidate pre-diagnosis plasma immune marker profiles associated with non-Hodgkin lymphoma risk. We identified 598 incident lymphoma cases and 601 matched controls in Nurses\u27 Health Study and Health Professionals Follow-up Study participants with archived pre-diagnosis plasma samples and measured 13 immune marker levels with multiplexed immunoassays. Using multivariable logistic regression we calculated odds ratios and 95% confidence intervals per standard deviation unit increase in biomarker concentration for risk of non-Hodgkin lymphoma and major histologic subtype, stratifying additional models by years ( \u3c 5, 5 to \u3c 10, \u3e /=10) after blood draw. Soluble interleukin-2 receptor-alpha, CXC chemokine ligand 13, soluble CD30, and soluble tumor necrosis factor receptor-2 were individually positively associated, and B-cell activating factor of the tumor necrosis factor family inversely associated, with all non-Hodgkin lymphoma and one or more subtypes. The biomarker combinations associated independently with lymphoma varied somewhat by subtype and years after blood draw. Of note, the unexpected inverse association between B-cell activating factor and chronic lymphocytic leukemia/small lymphocytic lymphoma risk (odds ratio: 95% confidence interval: 0.51, 0.43-0.62) persisted more than 10 years after blood draw (odds ratio: 0.70; 95% confidence interval: 0.52-0.93). In conclusion, immune activation precedes non-Hodgkin lymphoma diagnosis by several years. Decreased B-cell activating factor levels may denote nascent chronic lymphocytic leukemia many years pre-diagnosis

Altered Host Immunity, Human T Lymphotropic Virus Type I Replication, and Risk of Adult T-Cell Leukemia/Lymphoma: A Prospective Analysis from the ATL Cohort Consortium

Background: Adult T-cell leukemia/lymphoma (ATL) is a rare and often fatal outcome of infection with human T-lymphotropic virus type I (HTLV-I). Altered host immunity in HTLV-I carriers has been postulated as a risk factor for ATL, but is not well understood. Methods: We prospectively examined well-validated serologic markers of HTLV-I pathogenesis and host immunity in 53 incident ATL cases and 150 carefully matched asymptomatic HTLV-I carriers from eight population-based studies in Japan, Jamaica, the United States and Brazil. We used multivariable conditional logistic regression, conditioned on the matching factors (cohort/race, age, sex, and sample collection year), to evaluate the biomarkers’ associations with ATL in all subjects and by years (≤5, >5) from blood draw to ATL diagnosis. Results: In the pooled population, above-median soluble interleukin-2-receptor-alpha levels (sIL2R, v. ≤ median; odds ratio (OR), 95% confidence interval (CI)=4.08, 1.47-11.29) and anti-Tax seropositivity (anti-Tax; OR, 95% CI=2.97, 1.15-7.67), which indicate T cell activation and HTLV-I replication, respectively, were independently associated with an increased ATL risk. Above-median total immunoglobulin E levels (v. ≤ median; OR, 95% CI=0.45, 0.19-1.06), which indicate type 2 (B cell) activation, predicted a lower ATL risk. The sIL2R and anti-Tax associations with ATL were stronger in samples collected ≤5 years pre-diagnosis. Conclusions: The biomarker profile predictive of ATL risk suggests a role for heightened T cell activation and HTLV-I replication and diminished type 2 immunity in the etiology of ATL in HTLV-I carriers. Translation of these findings to clinical risk prediction or early ATL detection requires further investigation. Acknowledgements: This abstract is presented on behalf of the ATL Cohort Consortium

Genetically inferred birthweight, height, and puberty timing and risk of osteosarcoma

INTRODUCTION: Several studies have linked increased risk of osteosarcoma with tall stature, high birthweight, and early puberty, although evidence is inconsistent. We used genetic risk scores (GRS) based on established genetic loci for these traits and evaluated associations between genetically inferred birthweight, height, and puberty timing with osteosarcoma. METHODS: Using genotype data from two genome-wide association studies, totaling 1039 cases and 2923 controls of European ancestry, association analyses were conducted using logistic regression for each study and meta-analyzed to estimate pooled odds ratios (ORs) and 95% confidence intervals (CIs). Subgroup analyses were conducted by case diagnosis age, metastasis status, tumor location, tumor histology, and presence of a known pathogenic variant in a cancer susceptibility gene. RESULTS: Genetically inferred higher birthweight was associated with an increased risk of osteosarcoma (OR =1.59, 95% CI 1.07-2.38, P = 0.02). This association was strongest in cases without metastatic disease (OR =2.46, 95% CI 1.44-4.19, P = 9.5 ×10-04). Although there was no overall association between osteosarcoma and genetically inferred taller stature (OR=1.06, 95% CI 0.96-1.17, P = 0.28), the GRS for taller stature was associated with an increased risk of osteosarcoma in 154 cases with a known pathogenic cancer susceptibility gene variant (OR=1.29, 95% CI 1.03-1.63, P = 0.03). There were no significant associations between the GRS for puberty timing and osteosarcoma. CONCLUSION: A genetic propensity to higher birthweight was associated with increased osteosarcoma risk, suggesting that shared genetic factors or biological pathways that affect birthweight may contribute to osteosarcoma pathogenesis