Background The positive association between obesity and postmenopausal breast cancer has been attributed, in part, to the fact that estrogen, a risk factor for breast cancer, is synthesized in ...adipose tissue. Obesity is also associated with high levels of insulin, a known mitogen. However, no prospective studies have directly assessed associations between circulating levels of insulin and/or insulin-like growth factor (IGF)-I, a related hormone, and the risk of breast cancer independent of estrogen level. Methods We conducted a case–cohort study of incident breast cancer among nondiabetic women who were enrolled in the Women's Health Initiative Observational Study (WHI-OS), a prospective cohort of 93 676 postmenopausal women. Fasting serum samples obtained at study entry from 835 incident breast cancer case subjects and from a subcohort of 816 randomly chosen WHI-OS subjects were tested for levels of insulin, glucose, total IGF-I, free IGF-I, insulin-like growth factor binding protein-3, and estradiol. Multivariable Cox proportional hazards models were used to estimate associations between levels of the serologic factors and baseline characteristics (including body mass index BMI) and the risk of breast cancer. All statistical tests were two-sided. Results Insulin levels were positively associated with the risk of breast cancer (hazard ratio HR for highest vs lowest quartile of insulin level = 1.46, 95% confidence interval CI = 1.00 to 2.13, Ptrend = .02); however, the association with insulin level varied by hormone therapy (HT) use (Pinteraction = .01). In a model that controlled for multiple breast cancer risk factors including estradiol, insulin level was associated with breast cancer only among nonusers of HT (HR for highest vs lowest quartile of insulin level = 2.40, 95% CI = 1.30 to 4.41, Ptrend < .001). Obesity (BMI ≥30 kg/m2) was also associated with the risk of breast cancer among nonusers of HT (HR for BMI ≥30 kg/m2 vs 18.5 to <25 kg/m2 = 2.12, 95% CI = 1.26 to 3.58, Ptrend = .003); however, this association was attenuated by adjustment for insulin (Ptrend = .40). Conclusion These data suggest that hyperinsulinemia is an independent risk factor for breast cancer and may have a substantial role in explaining the obesity–breast cancer relationship.
The follow-up rate, a standard index of the completeness of follow-up, is important for assessing the validity of a cohort study. A common method for estimating the follow-up rate, the "Percentage ...Method", defined as the fraction of all enrollees who developed the event of interest or had complete follow-up, can severely underestimate the degree of follow-up. Alternatively, the median follow-up time does not indicate the completeness of follow-up, and the reverse Kaplan-Meier based method and Clark's Completeness Index (CCI) also have limitations.
We propose a new definition for the follow-up rate, the Person-Time Follow-up Rate (PTFR), which is the observed person-time divided by total person-time assuming no dropouts. The PTFR cannot be calculated directly since the event times for dropouts are not observed. Therefore, two estimation methods are proposed: a formal person-time method (FPT) in which the expected total follow-up time is calculated using the event rate estimated from the observed data, and a simplified person-time method (SPT) that avoids estimation of the event rate by assigning full follow-up time to all events. Simulations were conducted to measure the accuracy of each method, and each method was applied to a prostate cancer recurrence study dataset.
Simulation results showed that the FPT has the highest accuracy overall. In most situations, the computationally simpler SPT and CCI methods are only slightly biased. When applied to a retrospective cohort study of cancer recurrence, the FPT, CCI and SPT showed substantially greater 5-year follow-up than the Percentage Method (92%, 92% and 93% vs 68%).
The Person-time methods correct a systematic error in the standard Percentage Method for calculating follow-up rates. The easy to use SPT and CCI methods can be used in tandem to obtain an accurate and tight interval for PTFR. However, the FPT is recommended when event rates and dropout rates are high.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Integrated microbiome and metabolomics analyses hold the potential to reveal interactions between host and microbiota in relation to disease risks. However, there are few studies evaluating how field ...methods influence fecal microbiome characterization and metabolomics profiling.
Five fecal collection methods immediate freezing at -20°C without preservative, OMNIgene GUT, 95% ethanol, RNA
, and Flinders Technology Associates (FTA) cards were used to collect 40 fecal samples from eight healthy volunteers. We performed gut microbiota 16S rRNA sequencing, untargeted metabolomics profiling, and targeted metabolomics focusing on short chained fatty acids (SCFAs). Metrics included α-diversity and β-diversity as well as distributions of predominant phyla. To evaluate the concordance with the "gold standard" immediate freezing, the intraclass correlation coefficients (ICCs) for alternate fecal collection systems were calculated. Correlations between SCFAs and gut microbiota were also examined.
The FTA cards had the highest ICCs compared to the immediate freezing method for α-diversity indices (ICCs = 0.96, 0.96, 0.76 for Shannon index, Simpson's Index, Chao-1 Index, respectively), followed by OMNIgene GUT, RNA
, and 95% ethanol. High ICCs (all >0.88) were observed for all methods for the β-diversity metric. For untargeted metabolomics, in comparison to immediate freezing which detected 621 metabolites at ≥75% detectability level, 95% ethanol showed the largest overlapping set of metabolites (
= 430; 69.2%), followed by FTA cards (
= 330; 53.1%) and OMNIgene GUT (
= 213; 34.3%). Both OMNIgene GUT (ICCs = 0.82, 0.93, 0.64) and FTA cards (ICCs = 0.87, 0.85, 0.54) had acceptable ICCs for the top three predominant SCFAs (butyric acid, propionic acid and acetic acid). Nominally significant correlations between bacterial genera and SCFAs (
< 0.05) were observed in fecal samples collected by different methods. Of note, a high correlation between the genus
(known butyrate producer) and butyric acid was observed for both immediate freezing (
= 0.83) and FTA cards (
= 0.74).
Four alternative fecal collection methods are generally comparable with immediate freezing, but there are differences in certain measures of the gut microbiome and fecal metabolome across methods. Choice of method depends on the research interests, simplicity of fecal collection procedures and ease of transportation to the lab, especially for large epidemiological studies.
Metformin use and endometrial cancer survival Nevadunsky, Nicole S; Van Arsdale, Anne; Strickler, Howard D ...
Gynecologic oncology,
01/2014, Letnik:
132, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Abstract Objective Impaired glucose tolerance and diabetes are risk factors for the development of uterine cancer. Although greater progression free survival among diabetic patients with ovarian and ...breast cancers using metformin has been reported, no studies have assessed the association of metformin use with survival in women with endometrial cancer (EC). Methods We conducted a single-institution retrospective cohort study of all patients treated for uterine cancer from January 1999 through December 2009. Demographic, medical, social, and survival data were abstracted from medical records and the national death registry. Overall survival (OS) was estimated using Kaplan–Meier methods. Cox models were utilized for multivariate analysis. All statistical tests were two-sided. Results Of 985 patients, 114 (12%) had diabetes and were treated with metformin, 136 (14%) were diabetic but did not use metformin, and 735 (74%) had not been diagnosed with diabetes. Greater OS was observed in diabetics with non-endometrioid EC who used metformin than in diabetic cases not using metformin and non-endometrioid EC cases without diabetes (log rank test (p = 0.02)). This association remained significant (hazard ratio = 0.54, 95% CI: 0.30–0.97, p < 0.04) after adjusting for age, clinical stage, grade, chemotherapy treatment, radiation treatment and the presence of hyperlipidemia in multivariate analysis. No association between metformin use and OS in diabetics with endometrioid histology was observed. Conclusion Diabetic EC patients with non-endometrioid tumors who used metformin had lower risk of death than women with EC who did not use metformin. These data suggest that metformin might be useful as adjuvant therapy for non-endometrioid EC.
Objective The objective of the study was to estimate the impact of human immunodeficiency virus (HIV) infection on the incidence of high-grade cervical intraepithelial neoplasia (CIN). Study Design ...HIV-seropositive and comparison seronegative women enrolled in a prospective US cohort study were followed up with semiannual Papanicolaou testing, with colposcopy for any abnormality. Histology results were retrieved to identify CIN3+ (CIN3, adenocarcinoma in situ, and cancer) and CIN2+ (CIN2 and CIN3+). Annual detection rates were calculated and risks compared using a Cox analysis. Median follow-up (interquartile range) was 11.0 (5.4–17.2) years for HIV-seronegative and 9.9 (2.5–16.0) for HIV-seropositive women. Results CIN3+ was diagnosed in 139 HIV-seropositive (5%) and 19 HIV-seronegative women (2%) ( P < .0001), with CIN2+ in 316 (12%) and 34 (4%) ( P < .0001). The annual CIN3+ detection rate was 0.6 per 100 person-years in HIV-seropositive women and 0.2 per 100 person-years in seronegative women ( P < .0001). The CIN3+ detection rate fell after the first 2 years of study, from 0.9 per 100 person-years among HIV-seropositive women to 0.4 per 100 person-years during subsequent follow-up ( P < .0001). CIN2+ incidence among these women fell similarly with time, from 2.5 per 100 person-years during the first 2 years after enrollment to 0.9 per 100 person-years subsequently ( P < .0001). In Cox analyses controlling for age, the hazard ratio for HIV-seropositive women with CD4 counts less than 200/cmm compared with HIV-seronegative women was 8.1 (95% confidence interval, 4.8–13.8) for CIN3+ and 9.3 (95% confidence interval, 6.3–13.7) for CIN2+ ( P < .0001). Conclusion Although HIV-seropositive women have more CIN3+ than HIV-seronegative women, CIN3+ is uncommon and becomes even less frequent after the initiation of regular cervical screening.
Case-cohort studies have become common in epidemiological studies of rare disease, with Cox regression models the principal method used in their analysis. However, no appropriate procedures to assess ...the assumption of proportional hazards of case-cohort Cox models have been proposed.
We extended the correlation test based on Schoenfeld residuals, an approach used to evaluate the proportionality of hazards in standard Cox models. Specifically, pseudolikelihood functions were used to define "case-cohort Schoenfeld residuals", and then the correlation of these residuals with each of three functions of event time (i.e., the event time itself, rank order, Kaplan-Meier estimates) was determined. The performances of the proposed tests were examined using simulation studies. We then applied these methods to data from a previously published case-cohort investigation of the insulin/IGF-axis and colorectal cancer.
Simulation studies showed that each of the three correlation tests accurately detected non-proportionality. Application of the proposed tests to the example case-cohort investigation dataset showed that the Cox proportional hazards assumption was not satisfied for certain exposure variables in that study, an issue we addressed through use of available, alternative analytical approaches.
The proposed correlation tests provide a simple and accurate approach for testing the proportional hazards assumption of Cox models in case-cohort analysis. Evaluation of the proportional hazards assumption is essential since its violation raises questions regarding the validity of Cox model results which, if unrecognized, could result in the publication of erroneous scientific findings.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Adiposity is an established risk factor for postmenopausal breast cancer. Recent data suggest that high insulin levels in overweight women may play a major role in this relationship, due to insulin's ...mitogenic/antiapoptotic activity. However, whether overweight women who are metabolically healthy (i.e., normal insulin sensitivity) have elevated risk of breast cancer is unknown. We investigated whether overweight women with normal insulin sensitivity i.e., homeostasis model assessment of insulin resistance (HOMA-IR) index, or fasting insulin level, within the lowest quartile (q1) have increased breast cancer risk. Subjects were incident breast cancer cases (N = 497) and a subcohort (N = 2,830) of Women's Health Initiative (WHI) participants with available fasting insulin and glucose levels. In multivariate Cox models, metabolically healthy overweight women, defined using HOMA-IR, were not at elevated risk of breast cancer compared with metabolically healthy normal weight women HRHOMA-IR, 0.96; 95% confidence interval (CI), 0.64-1.42. In contrast, the risk among women with high (q3-4) HOMA-IRs was elevated whether they were overweight (HRHOMA-IR, 1.76; 95% CI, 1.19-2.60) or normal weight (HRHOMA-IR, 1.80; 95% CI, 0.88-3.70). Similarly, using fasting insulin to define metabolic health, metabolically unhealthy women (insulin q3-4) were at higher risk of breast cancer regardless of whether they were normal weight (HRinsulin, 2.06; 95% CI, 1.01-4.22) or overweight (HRinsulin, 2.01; 95% CI, 1.35-2.99), whereas metabolically healthy overweight women did not have significantly increased risk of breast cancer (HRinsulin, 0.96; 95% CI, 0.64-1.42) relative to metabolically healthy normal weight women. Metabolic health (e.g., HOMA-IR or fasting insulin) may be more biologically relevant and more useful for breast cancer risk stratification than adiposity per se.
Background HIV-seropositive women face high risk for infection with oncogenic human papillomavirus (oncHPV) types, abnormal Pap test results, and precancer, but cervical cancer risk is only modestly ...increased. Human papillomavirus (HPV)16 is highly oncogenic but only weakly associated with HIV status and immunosuppression, suggesting HPV16 may have a greater innate ability to evade host immune surveillance than other oncHPV types, which in turn should result in a greater relative increase in the prevalence of other oncHPV types among women with cervical precancer. Objective We sought to assess whether the underrepresentation of HPV16 among HIV-seropositive relative to HIV-seronegative women remains among those with cervical precancers. Study Design HIV-seropositive and HIV-seronegative women in the Women’s Interagency HIV Study were screened for cervical intraepithelial neoplasia (CIN) grade ≥3 (CIN3+ ). DNA from >40 HPV types was detected by polymerase chain reaction in cervicovaginal lavage specimens obtained at the visit at which CIN3+ was diagnosed. Results HPV16 was detected in 13 (62%) of 21 HIV-seronegative women with CIN3+ but only 44 (29%) of 154 HIV-seropositive women with CIN3+ ( P = .01). The lower prevalence of HPV16 in CIN3+ among HIV-seropositive women persisted after controlling for covariates (odds ratio OR, 0.25; 95% confidence interval CI, 0.08–0.78). The prevalence of other members of the HPV16-related alpha-9 oncHPV clade as a group was similar in HIV-infected and uninfected women with CIN3+ (OR, 1.02; 95% CI, 0.53–1.94). The prevalence of non-alpha-9 oncHPV types was increased in HIV-seropositive vs HIV-seronegative women with CIN3+ (OR, 3.9; 95% CI, 1.3–11.8). Conclusion The previously demonstrated increase in CIN3+ incidence among HIV-seropositive women is associated with lower HPV16 and higher non-alpha-9 oncHPV prevalence. This is consistent with prior reports that HIV has a weak effect on infection by HPV16 relative to other oncHPV and supports use of nonavalent HPV vaccine in HIV-seropositive women.
BACKGROUND:CD4 T cells play an important role in atherosclerosis, but their antigen specificity is poorly understood. Immunization with apolipoprotein B (ApoB, core protein of low density ...lipoprotein) is known to be atheroprotective in animal models. Here, we report on a human APOB peptide, p18, that is sequence-identical in mouse ApoB and binds to both mouse and human major histocompatibility complex class II molecules.
METHODS:We constructed p18 tetramers to detect human and mouse APOB-specific T cells and assayed their phenotype by flow cytometry including CD4 lineage transcription factors, intracellular cytokines, and T cell receptor activation. Apolipoprotein E–deficient (Apoe) mice were vaccinated with p18 peptide or adjuvants alone, and atherosclerotic burden in the aorta was determined.
RESULTS:In human peripheral blood mononuclear cells from donors without cardiovascular disease, p18 specific CD4 T cells detected by a new human leukocyte antigen-antigen D related-p18 tetramers were mostly Foxp3 regulatory T cells (Tregs). Donors with subclinical cardiovascular disease as detected by carotid artery ultrasound had Tregs coexpressing retinoic acid-related orphan receptor gamma t or T-bet, which were both almost absent in donors without cardiovascular disease. In Apoe mice, immunization with p18 induced Tregs and reduced atherosclerotic lesions. After peptide restimulation, responding CD4 T cells identified by Nur77-GFP (green fluorescent protein) were highly enriched in Tregs. A new mouse I-A-p18 tetramer identified the expansion of p18-specific CD4 T cells on vaccination, which were enriched for interleukin-10–producing Tregs.
CONCLUSIONS:These findings show that APOB p18–specific CD4 T cells are mainly Tregs in healthy donors, but coexpress other CD4 lineage transcription factors in donors with subclinical cardiovascular disease. This study identifies ApoB peptide 18 as the first Treg epitope in human and mouse atherosclerosis.
Summary Oncogenic human papillomavirus (HPV) is a common genital infection that has the potential to develop into cervical cancer in some women. This Review summarises current knowledge on the ...mechanisms of host immunity that help prevent and control HPV infection and the viral factors that exist to avoid immune surveillance. Although most women clear the infection within a few months, the virus induces a shift towards immune tolerance that can facilitate persistence and permit tumorigenesis. Mechanisms used by HPV to avoid immune surveillance and control include infecting only the basal layer of the cervical epithelium, limiting expression of viral proteins until later stages of epithelial differentiation, undergoing non-lytic replication, and downregulating the expression of important receptors on cells of the innate immune system. Furthermore, HPV suppresses the expression of several proinflammatory proteins that are crucial in clearing infection and activating the cytotoxic T lymphocytes involved in killing virus-infected cells. Interestingly, neutralising antibodies, although of uncertain effectiveness in preventing infection or reinfection after natural exposure (prior infection), are highly protective after immunisation with HPV virus-like-particle-based vaccines. Understanding what is known and unknown about the interaction between the immune system and HPV is important in the assessment of the potential contribution of prophylactic vaccination in reducing the incidence of cervical cancer. However, despite our growing understanding, many aspects of the interactions between HPV and the host immune system remain unknown, and this Review draws attention to several of these unresolved issues and their implications.
PDF
