•Vitamin D metabolites circulate bound to DBP and, to a lesser extent, albumin.•25OHD binds to DBP with high affinity and is thus strongly influenced by DBP.•For some cells unbound or ‘free’ 25OHD ...may be the most bioavailable form of 25OHD.•DBP may play a pivotal role in the intracrine synthesis of 1,25(OH)2D by immune cells.•Free or bioavailable 25OHD is influenced by DBP concentration and binding affinity.
The last five years have witnessed a remarkable renaissance in vitamin D research and a complete re-evaluation of its benefits to human health. Two key factors have catalyzed these changes. First, it now seems likely that localized, tissue-specific, conversion of 25-hydroxyvitamin D (25OHD) to 1,25-dihydroxyvitamin D (1,25(OH)2D) drives many of the newly recognized effects of vitamin D on human health. The second key factor concerns the ongoing discussion as to what constitutes adequate or optimal serum vitamin D (25OHD) status, with the possibility that vitamin D-deficiency is common to communities across the globe. These two concepts appear to be directly linked when low serum concentrations of 25OHD compromise intracrine generation of 1,25(OH)2D within target tissues. But, is this an over-simplification? Pro-hormone 25OHD is a lipophilic molecule that is transported in the circulation bound primarily to vitamin D binding protein (DBP). While the association between 25OHD and DBP is pivotal for renal handling of 25OHD and endocrine synthesis of 1,25(OH)2D, what is the role of DBP for extra-renal synthesis of 1,25(OH)2D? We hypothesize that binding to DBP impairs delivery of 25OHD to the vitamin D-activating enzyme 1α-hydroxylase in some target cells. Specifically, it is unbound, ‘free’ 25OHD that drives many of the non-classical actions of vitamin D. Levels of ‘free’ 25OHD are dependent on the concentration of DBP and alternative serum binding proteins such as albumin, but will also be influenced by variations in DBP binding affinity for specific vitamin D metabolites. The aim of this review will be to discuss the merits of ‘free 25OHD’ as an alternative marker of vitamin D status, particularly in the context of non-classical responses to vitamin D.
This article is part of a Special Issue entitled ‘16th Vitamin D Workshop’.
BackgroundHuman papillomavirus (HPV) infection is estimated to be the most common sexually transmitted infection; an estimated 6.2 million persons are newly infected every year in the United States. ...There are limited data on HPV infection in heterosexual men MethodsWe conducted a systematic review of the literature by searching MEDLINE using the terms “human papillomavirus,” “HPV,” “male,” “seroprevalence,” and “serology” to retrieve articles published from 1 January 1990 to 1 February 2006. We included studies that had data on population characteristics and that evaluated male genital anatomic sites or specimens for HPV DNA or included assessments of seropositivity to HPV type 6, 11, 16, or 18 in men. We excluded studies that had been conducted only in children or immunocompromised persons (HIV infected, transplant recipients, or elderly) ResultsWe included a total of 40 publications on HPV DNA detection and risk factors for HPV in men; 27 evaluated multiple anatomic sites or specimens, 10 evaluated a single site or specimen, and 3 evaluated risk factors or optimal anatomic sites/specimens for HPV detection. Twelve studies assessed site- or specimen-specific HPV DNA detection. HPV prevalence in men was 1.3%–72.9% in studies in which multiple anatomic sites or specimens were evaluated; 15 (56%) of these studies reported ⩾20% HPV prevalence. HPV prevalence varied on the basis of sampling, processing methods, and the anatomic site(s) or specimen(s) sampled. We included 15 publications reporting HPV seroprevalence. Rates of seropositivity depended on the population, HPV type, and methods used. In 9 studies that evaluated both men and women, all but 1 demonstrated that HPV seroprevalence was lower in men than in women ConclusionHPV infection is highly prevalent in sexually active men and can be detected by use of a variety of specimens and methods. There have been few natural-history studies and no transmission studies of HPV in men. The information that we have reviewed may be useful for future natural-history studies and for modeling the potential impact of a prophylactic HPV vaccine
The development of functional limitations among adults aged 65 or older has profound effects on individual and population resources. Improved understanding of the relationship between functional ...limitations and co-occurring chronic diseases (multimorbidity) is an emerging area of interest. The objective of this study was to investigate the association between multimorbidity and functional limitations among community-dwelling adults 65 or older in the United States and explore factors that modify this association.
We conducted a cross-sectional analysis of adults aged 65 or older using data from the National Health and Nutrition Examination Survey (NHANES) from 2005 through 2012. We used negative binomial regression to estimate the association between multimorbidity (≥2 concurrent diseases) and functional limitations and to determine whether the association differed by sex or age.
The prevalence of multimorbidity in this population was 67% (95% confidence interval CI, 65%-68%). Each additional chronic condition was associated with an increase in the number of functional limitations, and the association was stronger among those aged 75 or older than among those aged 65 to 74. For those aged 65 to 74, each additional chronic condition was associated with 1.35 (95% CI, 1.27-1.43) times the number of functional limitations for men and 1.62 times (95% CI, 1.31-2.02) the number of functional limitations for women. For those 75 or older, the associations increased to 1.71 (95% CI, 1.35-2.16) for men and 2.06 (95% CI, 1.51-2.81) for women for each additional chronic condition.
Multimorbidity was associated with increases in functional limitations, and the associations were stronger among women than among men and among adults aged 75 or older than among those aged 65 to 74. These findings underscore the importance of addressing age and sex differences when formulating prevention strategies.
Background
Chemotherapy‐induced toxicities lead to therapy dose reduction or delay, affecting patient outcomes. This systematic review and meta‐analysis evaluated the impact of relative dose ...intensity (RDI) on survival in adult patients with solid tumor cancer on nonadjuvant‐based chemotherapy regimens.
Methods
PubMed, Embase, and Web of Science databases were searched for peer‐reviewed English journal articles or congress s evaluating association between RDI and survival; observational studies, case series of ≥20 patients, and clinical trials published between 2013 and 2020 were eligible. Meta‐analyses were conducted to quantify the association between RDI levels and overall survival (OS) among studies reporting a hazard ratio (HR) for OS by similar tumor types, regimens, and RDI. Forest plots represented summary HR and 95% confidence interval (CI); Cochran's Q and I2 tests evaluated study heterogeneity.
Results
Overall, 919 articles were reviewed and 22 included; seven were eligible for meta‐analysis. Significantly shorter OS at RDI <80% versus ≥80% and <85% versus ≥85% was observed upon meta‐analysis of four carboplatin‐based studies for breast, non‐small cell lung, or ovarian cancer (HR 1.17; 95% CI: 1.07–1.27) and three FOLFOX‐, FOLFIRI‐, or FOLFIRINOX‐based studies for colorectal or pancreatic cancer (HR 1.39; 95% CI: 1.03–1.89). Grade 3 or higher hematologic toxicities were higher for carboplatin‐based regimens (thrombocytopenia: 14%–22%; anemia: 15%–19%; neutropenia: 24%–58%) than FOLFOX‐, FOLFIRI‐, or FOLFIRINOX‐based regimens (thrombocytopenia: 1%–4%; anemia: 5%–19%; neutropenia: 19%–47%).
Conclusion
The results suggested longer OS with RDI ≥80% or ≥85% for both regimens, indicating that management of toxicities across treatment modalities may contribute to maintenance of higher RDI and benefit survival for patients with advanced solid tumors.
Implications for Practice
Chemotherapy‐induced toxicities lead to dose reduction and/or treatment delay, thus affecting patient outcomes. Results of this systematic review and meta‐analysis, evaluating the impact of relative dose intensity (RDI) on survival of patients with solid tumors on nonadjuvant‐based chemotherapy regimens, demonstrate a longer overall survival with RDI levels of at least 80% for patients with solid tumors on carboplatin‐based and FOLFOX‐, FOLFIRI‐, or FOLFIRINOX‐based chemotherapy regimens, suggesting a protective effect of maintaining RDI ≥80% or ≥ ‐85%. Although grade 3 or higher hematologic toxicities occurred more in carboplatin‐based studies, managing toxicities across treatment regimens may contribute to maintenance of higher RDI and ultimately benefit overall survival.
Chemotherapy‐induced toxicities are a challenge to optimal treatments and dosing regimens for cancer patients. This review evaluates the effect of relative dose intensity, including dose delays and reductions, on survival in patients with solid tumors receiving nonadjuvant‐based chemotherapy.
Context:
Total 25-hydroxyvitamin D (25OHD) is a marker of vitamin D status and is lower in African Americans than in whites. Whether this difference holds for free 25OHOD (f25OHD) is unclear, ...considering reported genetic-racial differences in vitamin D binding protein (DBP) used to calculate f25OHD.
Objectives:
Our objective was to assess racial-geographic differences in f25OHD and to understand inconsistencies in racial associations with DBP and calculated f25OHD.
Design:
This study used a cross-sectional design.
Setting:
The general community in the United States, United Kingdom, and The Gambia were included in this study.
Participants:
Men in Osteoporotic Fractures in Men and Medical Research Council studies (N = 1057) were included.
Exposures:
Total 25OHD concentration, race, and DBP (GC) genotype exposures were included.
Outcome Measures:
Directly measured f25OHD, DBP assessed by proteomics, monoclonal and polyclonal immunoassays, and calculated f25OHD were the outcome measures.
Results:
Total 25OHD correlated strongly with directly measured f25OHD (Spearman r = 0.84). Measured by monoclonal assay, mean DBP in African-ancestry subjects was approximately 50% lower than in whites, whereas DBP measured by polyclonal DBP antibodies or proteomic methods was not lower in African-ancestry. Calculated f25OHD (using polyclonal DBP assays) correlated strongly with directly measured f25OHD (r = 0.80–0.83). Free 25OHD, measured or calculated from polyclonal DBP assays, reflected total 25OHD concentration irrespective of race and was lower in African Americans than in US whites.
Conclusions:
Previously reported racial differences in DBP concentration are likely from monoclonal assay bias, as there was no racial difference in DBP concentration by other methods. This confirms the poor vitamin D status of many African-Americans and the utility of total 25OHD in assessing vitamin D in the general population.
We found no racial or genetic differences in serum vitamin D binding protein. Free 25OHD, directly measured or calculated from DBP (using polyclonal antibodies), was low in Afro-Americans, compared to US whites or blacks from The Gambia.
Proteins are an essential part of essentially all biological processes, and there is enormous variation in protein forms and concentrations that is not reflected in DNA or RNA. Recently there have ...been rapid advances in the ability to measure protein sequence, modification and concentration, particularly with methods based in mass spectrometry. Global measures of proteins in tissues or in the circulation provide a broad assessment of the proteome that can be extremely useful for discovery, and targeted proteomic measures can yield specific and sensitive assessments of specific peptides and proteins. While most proteomic measures are directed at the detection of consensus peptide sequences, mass spectrometry based proteomic methods also allow a detailed examination of the peptide sequence differences that result from genetic variants and that may have important effects on protein function. In evaluating proteomic data, a number of analytical considerations are important, including an understanding of missing data, the challenge of multiple testing and replication, and the use of rapidly evolving methods in systems biology. While proteomics has not yet had a major impact in skeletal research, interesting recent research has used these approaches in the study of bone cell biology and the discovery of biomarkers of skeletal disorders. Proteomics can be expected to have an increasing influence in the study of bone biology and pathophysiology.
•Proteomics has not been extensively used in bone research, but these methods are becoming more commonly employed.•Major advances in proteomic measurement approaches have increased the ability to more comprehensively assess protein forms and concentrations.•Global proteomics approaches broadly survey the proteome in tissues or blood, while targeted proteomics assess specific proteins/peptides.•Mass spectrometry proteomics can determine both peptide sequence changes resulting from genetic variation and posttranslational modifications.•Key issues in assessing results include considerations of missing data, multiple testing, replication, and the use of systems biology.•Proteomics has not been extensively used in bone research, but proteomic approaches are becoming more commonly employed.
The choice of a vitamin D–binding protein assay is key in calculating free 25-hydroxyvitamin D levels. The results of this analysis support the use of total 25-hydroxyvitamin D as a marker of vitamin ...D status, regardless of race or GC genotype.
To the Editor:
It is unclear whether circulating free or bioavailable 25-hydroxyvitamin D is a better marker of vitamin D status than is total 25-hydroxyvitamin D, especially in racially diverse populations. Until recently, the only method to compare the levels was to estimate the level of free or bioavailable 25-hydroxyvitamin D from total 25-hydroxyvitamin D, vitamin D–binding protein (also known as gc-globulin, encoded by the
GC
gene), and albumin, with or without the
GC
genotype. Powe et al. reported that levels of vitamin D–binding protein, as measured on a monoclonal enzyme-linked immunosorbent assay (ELISA, R&D Systems), were lower in black . . .
Background.Human papillomavirus (HPV) infection in men contributes to infection and cervical disease in women as well as to disease in men. This study aimed to determine the optimal anatomic site(s) ...for HPV detection in heterosexual men. Methods.A cross-sectional study of HPV infection was conducted in 463 men from 2003 to 2006. Urethral, glans penis/coronal sulcus, penile shaft/prepuce, scrotal, perianal, anal canal, semen, and urine samples were obtained. Samples were analyzed for sample adequacy and HPV DNA by polymerase chain reaction and genotyping. To determine the optimal sites for estimating HPV prevalence, site-specific prevalences were calculated and compared with the overall prevalence. Sites and combinations of sites were excluded until a recalculated prevalence was reduced by <5% from the overall prevalence. Results.The overall prevalence of HPV was 65.4%. HPV detection was highest at the penile shaft (49.9% for the full cohort and 47.9% for the subcohort of men with complete sampling), followed by the glans penis/coronal sulcus (35.8% and 32.8%) and scrotum (34.2% and 32.8%). Detection was lowest in urethra (10.1% and 10.2%) and semen (5.3% and 4.8%) samples. Exclusion of urethra, semen, and either perianal, scrotal, or anal samples resulted in a <5% reduction in prevalence. Conclusions.At a minimum, the penile shaft and the glans penis/coronal sulcus should be sampled in heterosexual men. A scrotal, perianal, or anal sample should also be included for optimal HPV detection.
Objectives
To estimate the risk of thrombocytopenia in various cancers and chemotherapy regimens.
Methods
Structured patient‐level data from the Flatiron Health Electronic Health Record database were ...used to identify adult patients who received chemotherapy for a solid tumor or hematologic malignancy from 2012 to 2017. Three‐month cumulative incidence of thrombocytopenia was assessed based on platelet counts, overall and by grade of thrombocytopenia. Co‐occurrence of anemia, neutropenia, and leukopenia was evaluated.
Results
Of 15,521 patients with solid tumors, 13% had thrombocytopenia within 3 months (platelet count < 100 × 109/L); 4% had grade 3 (25 to < 50 × 109/L), and 2% grade 4 (<25 × 109/L) thrombocytopenia. Of 2537 patients with hematologic malignancies, 28% had any thrombocytopenia, 16% with grade 3, and 12% with grade 4. Among patients with thrombocytopenia, it occurred without another cytopenia in 18% of solid tumors and 7% of hematologic malignancies.
Conclusions
In a large, US‐representative sample of patients undergoing chemotherapy in clinical practice, thrombocytopenia incidence varied across tumor and regimen types. Despite recommendations to alter chemotherapy to avoid severe thrombocytopenia, 4% of patients with solid tumors and 16% with hematologic malignancies experienced grade 3 thrombocytopenia. Prediction and prevention of thrombocytopenia may help oncologists avoid dose modifications and their adverse effects on survival.
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