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1.  Inhibition of Mouse Breast Tumor Initiating Cells by Calcitriol and Dietary Vitamin D 
Molecular cancer therapeutics  2015;14(8):1951-1961.
The anti-cancer actions of vitamin D and its hormonally active form, calcitriol, have been extensively documented in clinical and pre-clinical studies. However, the mechanisms underlying these actions have not been completely elucidated. Here we examined the effect of dietary vitamin D and calcitriol on mouse breast tumor-initiating cells (TICs, also known as cancer stem cells). We focused on MMTV-Wnt1 mammary tumors, for which markers for isolating TICs have previously been validated. We confirmed that these tumors expressed functional vitamin D receptors (VDRs) and estrogen receptors (ERs) and exhibited calcitriol-induced molecular responses including ER down-regulation. Following orthotopic implantation of MMTV-Wnt1 mammary tumor cells into mice, calcitriol injections or a vitamin D-supplemented diet caused a striking delay in tumor appearance and growth while a vitamin D-deficient diet accelerated tumor appearance and growth. Calcitriol inhibited TIC tumor spheroid formation in a dose-dependent manner in primary cultures and inhibited TIC self-renewal in secondary passages. A combination of calcitriol and ionizing radiation inhibited spheroid formation more than either treatment alone. Further, calcitriol significantly decreased TIC frequency as evaluated by in vivo limiting dilution analyses. Calcitriol inhibition of TIC spheroid formation could be overcome by the overexpression of β-catenin, suggesting that the inhibition of Wnt/β-catenin pathway is an important mechanism mediating the TIC inhibitory activity of calcitriol in this tumor model. Our findings indicate that vitamin D compounds target breast TICs reducing tumor-initiating activity. Our data also suggest that combining vitamin D compounds with standard therapies will enhance anti-cancer activity and may improve therapeutic outcomes.
PMCID: PMC4549392  PMID: 25934710
Breast cancer; vitamin D; calcitriol; MMTV-Wnt1; tumor initiating cells (TICs); Wnt/β-catenin
2.  The pathophysiology of thrombocytopenia in chronic liver disease 
Thrombocytopenia is the most common hematological abnormality encountered in patients with chronic liver disease (CLD). In addition to being an indicator of advanced disease and poor prognosis, it frequently prevents crucial interventions. Historically, thrombocytopenia has been attributed to hypersplenism, which is the increased pooling of platelets in a spleen enlarged by congestive splenomegaly secondary to portal hypertension. Over the past decade, however, there have been significant advances in the understanding of thrombopoiesis, which, in turn, has led to an improved understanding of thrombocytopenia in cirrhosis. Multiple factors contribute to the development of thrombocytopenia and these can broadly be divided into those that cause decreased production, splenic sequestration, and increased destruction. Depressed thrombopoietin levels in CLD, together with direct bone marrow suppression, result in a reduced rate of platelet production. Thrombopoietin regulates both platelet production and maturation and is impaired in CLD. Bone marrow suppression can be caused by viruses, alcohol, iron overload, and medications. Splenic sequestration results from hypersplenism. The increased rate of platelet destruction in cirrhosis also occurs through a number of pathways: increased shear stress, increased fibrinolysis, bacterial translocation, and infection result in an increased rate of platelet aggregation, while autoimmune disease and raised titers of antiplatelet immunoglobulin result in the immunologic destruction of platelets. An in-depth understanding of the complex pathophysiology of the thrombocytopenia of CLD is crucial when considering treatment strategies. This review outlines the recent advances in our understanding of thrombocytopenia in cirrhosis and CLD.
PMCID: PMC4847598  PMID: 27186144
cirrhosis; thrombocytopenia; thrombopoietin
3.  Inhibition of Prostaglandin Synthesis and Actions by Genistein in Human Prostate Cancer Cells and by Soy Isoflavones in Prostate Cancer Patients 
International journal of cancer  2009;124(9):2050-2059.
Soy and its constituent isoflavone genistein inhibit the development and progression of prostate cancer (PCa). Our study in both cultured cells and PCa patients reveals a novel pathway for the actions of genistein, namely the inhibition of the synthesis and biological actions of prostaglandins (PGs), known stimulators of PCa growth. In the cell culture experiments, genistein decreased cyclooxygenase-2 (COX-2) mRNA and protein expression in both human PCa cell lines (LNCaP and PC-3) and primary prostate epithelial cells and increased 15-hydroxyprostaglandin dehydrogenase (15-PGDH) mRNA levels in primary prostate cells. As a result genistein significantly reduced the secretion of PGE2 by these cells. EP4 and FP PG receptor mRNA were also reduced by genistein, providing an additional mechanism for the suppression of PG biological effects. Further, the growth stimulatory effects of both exogenous PGs as well as endogenous PGs derived from precursor arachidonic acid were attenuated by genistein. We also performed a pilot randomized double blind clinical study in which placebo or soy isoflavone supplements were given to PCa patients in the neo-adjuvant setting for 2 weeks prior to prostatectomy. Gene expression changes were measured in the prostatectomy specimens. In PCa patients ingesting isoflavones, we observed significant decreases in prostate COX-2 mRNA) and increases in p21 mRNA. There were significant correlations between COX-2 mRNA suppression, p21 mRNA stimulation and serum isoflavone levels. We propose that the inhibition of the PG pathway contributes to the beneficial effect of soy isoflavones in PCa chemoprevention and/or treatment.
PMCID: PMC4777303  PMID: 19127598
Genistein; soy; prostaglandins; COX-2; human prostate cells; prostate cancer patients
4.  The Association of Resistin with Cardiovascular Disease in The Multi-Ethnic Study of Atherosclerosis 
Atherosclerosis  2014;239(1):101-108.
To describe the relationship between circulating resistin levels and cardiovascular diseases (CVD) and all-cause death in a multi-ethnic cohort.
Methods and Results
We studied 1,913 participants from the Multi-Ethnic Study of Atherosclerosis with measurements of plasma resistin levels. Absolute proportions experiencing new-onset atrial fibrillation (AF), atherosclerotic CVD (myocardial infarction, angina, resuscitated cardiac arrest, stroke), heart failure (HF), and all-cause death were calculated for each quartile of resistin. We used adjusted Cox proportional regression modeling resistin as a continuous variable per standard deviation of log-transformed resistin and secondarily as a categorical variable using resistin quartiles. Results were stratified by sex and race/ethnicity. The mean age of the population was 64.5 ± 10 years with half being female and a median resistin concentration of 15.1 ng/mL (11.9–19.1). Mean follow-up time was 7.2 ± 1.8 years. There was a graded increase in the occurrence of all outcomes across increasing quartiles of resistin. Modeled as a continuous variable, after adjustment for anthropomorphic measures, traditional risk factors, markers of inflammation, and other adipokines, significant associations were noted for HF (HR 1.4, CI 1.0–2.0), hard and all CVD (HR 1.3, 1.1–1.7 and 1.3, 1.1–1.6, respectively), and CHD (HR 1.31, 1.0–1.6), but not for AF or death. Significant interaction terms were noted between resistin and race, with Hispanic race/ethnicity showing the strongest relationship between resistin and outcomes.
In an ethnically diverse population without known CVD at baseline, there was a strong, independent association between higher resistin levels and incident CVD, CHD and HF.
PMCID: PMC4331252  PMID: 25585029
atherosclerotic heart disease; risk stratification; resistin; adipokines
5.  Relationship Among 25-Hydroxyvitamin D Concentrations, Insulin Action, and Cardiovascular Disease Risk in Patients With Essential Hypertension 
American Journal of Hypertension  2014;28(2):266-272.
Although low plasma 25-hydroxyvitamin D (25(OH)D) concentrations have been shown to predict risk of hypertension and associated cardiovascular disease (CVD), vitamin D repletion has not consistently lowered blood pressure or decreased CVD. One possibility for this discrepancy is the presence of considerable metabolic heterogeneity in patients with hypertension. To evaluate this possibility, we quantified relationships among insulin resistance, 25(OH)D concentration, and CVD risk factor profile in patients with essential hypertension.
Measurements were made of 25(OH)D concentrations, multiple CVD risk factors, and insulin resistance by the steady-state plasma glucose concentration during the insulin suppression test in 140 otherwise healthy patients with essential hypertension.
As a group, the patients were overweight/obese and insulin resistant and had low 25(OH)D concentrations. The more insulin resistant the patients were, the worse the CVD risk profile was. In addition, the most insulin-resistant quartile had significantly lower 25(OH)D concentrations than the most insulin-sensitive quartile (20.3±1.4 vs. 25.8±1.4ng/ml; P = 0.005). In the entire group, 25(OH)D concentration significantly correlated with magnitude of insulin resistance (steady-state plasma glucose concentration; r = −0.20; P = 0.02).
There was considerable metabolic heterogeneity and substantial difference in magnitude of conventional CVD risk factors in patients with similar degrees of blood pressure elevation. The most insulin-resistant quartile of subjects had the lowest 25(OH)D concentration and the most adverse CVD risk profile, and they may be the subset of patients with essential hypertension most likely to benefit from vitamin D repletion.
PMCID: PMC4357801  PMID: 25138785
blood pressure; cardiovascular disease; hypertension; insulin action; vitamin D.
6.  mActive: A Randomized Clinical Trial of an Automated mHealth Intervention for Physical Activity Promotion 
We hypothesized that a fully automated mobile health (mHealth) intervention with tracking and texting components would increase physical activity.
Methods and Results
mActive enrolled smartphone users aged 18 to 69 years at an ambulatory cardiology center in Baltimore, Maryland. We used sequential randomization to evaluate the intervention's 2 core components. After establishing baseline activity during a blinded run‐in (week 1), in phase I (weeks 2 to 3), we randomized 2:1 to unblinded versus blinded tracking. Unblinding allowed continuous access to activity data through a smartphone interface. In phase II (weeks 4 to 5), we randomized unblinded participants 1:1 to smart texts versus no texts. Smart texts provided smartphone‐delivered coaching 3 times/day aimed at individual encouragement and fostering feedback loops by a fully automated, physician‐written, theory‐based algorithm using real‐time activity data and 16 personal factors with a 10 000 steps/day goal. Forty‐eight outpatients (46% women, 21% nonwhite) enrolled with a mean±SD age of 58±8 years, body mass index of 31±6 kg/m2, and baseline activity of 9670±4350 steps/day. Daily activity data capture was 97.4%. The phase I change in activity was nonsignificantly higher in unblinded participants versus blinded controls by 1024 daily steps (95% confidence interval [CI], −580 to 2628; P=0.21). In phase II, participants receiving texts increased their daily steps over those not receiving texts by 2534 (95% CI, 1318 to 3750; P<0.001) and over blinded controls by 3376 (95% CI, 1951 to 4801; P<0.001).
An automated tracking‐texting intervention increased physical activity with, but not without, the texting component. These results support new mHealth tracking technologies as facilitators in need of behavior change drivers.
Clinical Trial Registration
URL: Unique identifier: NCT01917812.
PMCID: PMC4845232  PMID: 26553211
accelerometer; activity tracker; automation; cardiovascular disease; digital health; eHealth; health technology; mHealth; mobile phone; pedometer; physical activity; prevention; smartphone; text messages; texting; wearable device; wearable sensor
7.  Mesenchymal Precursor Cells as Adjunctive Therapy in Recipients of Contemporary LVADs 
Circulation  2014;129(22):2287-2296.
Allogeneic mesenchymal precursor cells (MPC) injected during left ventricular assist device (LVAD) implantation may contribute to myocardial recovery. This trial explores the safety and efficacy of this strategy.
Methods and Results
In this multi-center, double-blind, sham-procedure controlled trial, 30 patients were randomized (2:1) to intramyocardial injection of 25M MPCs or medium during LVAD implantation. The primary safety endpoint was incidence of infectious myocarditis, myocardial rupture, neoplasm, hypersensitivity reaction, and immune sensitization (90 days post-randomization). Key efficacy endpoints were functional status and ventricular function, while temporarily weaned from LVAD support (90 days post-randomization). Patients were followed until transplant or 12 months post-randomization, whichever came first. Mean age was 57.4 (±13.6) years, mean LVEF 18.1%, and 66.7% were destination therapy LVADs. No safety events were observed. Successful temporary LVAD weaning was achieved in 50% of MPC and 20% of control patients at 90 days (p=0.24); the posterior probability that MPCs increased the likelihood of successful weaning is 93%. At 90 days, 3 deaths occurred in control and none in MPC patients. Mean LVEF following successful wean was 24.0% (MPC=10) and 22.5% (Control=2) (p=0.56). At 12 months, 30% of MPC and 40% of control patients were successfully temporarily weaned from LVAD support (p=0.69) and 6 deaths occurred in MPC patients. Donor-specific HLA sensitization developed in 2 MPC and 3 control patients and resolved by 12 months.
In this preliminary trial, administration of MPCs appeared to be safe and there was a potential signal of efficacy. Future studies will evaluate the potential for higher or additional doses to enhance the ability to wean LVAD recipients off support.
Clinical Trial Registration Information Identifier: NCT01442129.
PMCID: PMC4243683  PMID: 24682346
Left Ventricular Assist Device; Heart Failure; Mesenchymal precursor cell; Stem cells; Placebo; Randomized controlled trial
8.  MiR-1 Overexpression Enhances Ca2+ release and Promotes Cardiac Arrhythmogenesis by Targeting PP2A Regulatory Subunit B56α and Causing CaMKII-Dependent Hyperphosphorylation of RyR2 
Circulation research  2009;104(4):514-521.
MicroRNAs are small endogenous noncoding RNAs that regulate protein expression by hybridization to imprecise complementary sequences of target mRNAs. Changes in abundance of muscle-specific microRNA, miR-1, have been implicated in cardiac disease, including arrhythmia and heart failure. However, the specific molecular targets and cellular mechanisms involved in the action of miR-1 in the heart are only beginning to emerge. In this study we investigated the effects of increased expression of miR-1 on excitation-contraction coupling and Ca2+ cycling in rat ventricular myocytes using methods of electrophysiology, Ca2+ imaging and quantitative immunoblotting. Adenoviral-mediated overexpression of miR-1 in myocytes resulted in a marked increase in the amplitude of the inward Ca2+ current, flattening of Ca2+ transients voltage dependency and enhanced frequency of spontaneous Ca2+ sparks while reducing the sarcoplasmic reticulum Ca2+ content as compared with control. In the presence of isoproterenol, rhythmically paced, miR-1-overexpressing myocytes exhibited spontaneous arrhythmogenic oscillations of intracellular Ca2+, events that occurred rarely in control myocytes under the same conditions. The effects of miR-1 were completely reversed by the CaMKII inhibitor KN93. Although phosphorylation of phospholamban was not altered, miR-1 overexpression increased phosphorylation of the ryanodine receptor (RyR2) at S2814 (CaMKII) but not at S2808 (PKA). Overexpression of miR-1 was accompanied by a selective decrease in expression of the protein phosphatase PP2A regulatory subunit B56α involved in PP2A targeting to specialized subcellular domains. We conclude that miR-1 enhances cardiac excitation-contraction coupling by selectively increasing phosphorylation of the L-type and RyR2 channels via disrupting localization of PP2A activity to these channels.
PMCID: PMC4394868  PMID: 19131648
Ryanodine receptor; miR-1; CaMKII; PP2A; arrhythmia
9.  Mutations in the vitamin D receptor and hereditary vitamin D-resistant rickets 
BoneKEy Reports  2014;3:510.
Heterogeneous loss of function mutations in the vitamin D receptor (VDR) interfere with vitamin D signaling and cause hereditary vitamin D-resistant rickets (HVDRR). HVDRR is characterized by hypocalcemia, secondary hyperparathyroidism and severe early-onset rickets in infancy and is often associated with consanguinity. Affected children may also exhibit alopecia of the scalp and total body. The children usually fail to respond to treatment with calcitriol; in fact, their endogenous levels are often very elevated. Successful treatment requires reversal of hypocalcemia and secondary hyperparathyroidism and is usually accomplished by administration of high doses of calcium given either intravenously or sometimes orally to bypass the intestinal defect in VDR signaling.
PMCID: PMC4015455  PMID: 24818002
10.  Vitamin D Receptor Mutations in Patients with Hereditary 1,25-Dihydroxyvitamin D-Resistant Rickets 
Hereditary vitamin D resistant rickets (HVDRR), also known as vitamin D-dependent rickets type II, is an autosomal recessive disorder characterized by the early onset of rickets with hypocalcemia, secondary hyperparathyroidism and hypophosphatemia and is caused by mutations in the vitamin D receptor (VDR) gene. The human gene encoding the VDR is located on chromosome 12 and comprises eight coding exons and seven introns.
Objectives, Patients, and Methods
We analyzed the VDR gene of 5 previously unreported patients, two from Singapore and one each from Macedonia (former Yugoslav Republic), Saudi Arabia and Turkey. Each patient had clinical and radiographic features of rickets, hypocalcemia, and the 4 cases that had the measurement showed elevated serum concentrations of 1,25-dihydroxyvitamin D (1,25(OH)2D). Mutations were re-created in the WT VDR cDNA and examined for 1,25(OH)2D3-mediated transactivation in COS-7 monkey kidney cells.
Direct sequencing identified four novel mutations and two previously described mutations in the VDR gene. The novel mutations included a missense mutation in exon 3 causing the amino acid change C60W; a missense mutation in exon 4 causing the amino acid change D144N; a missense mutation in exon 7 causing the amino acid change N276Y; and a 2 bp deletion in exon 3 5’-splice site (IVS3Δ+4–5) leading to a premature stop.
These 4 unique mutations add to the previous 45 mutations identified in the VDR gene in patients with HVDRR.
PMCID: PMC3933290  PMID: 24246681
Vitamin D; rickets; hypocalcemia; mutations; vitamin D receptor; HVDRR
11.  Equivalent anticancer activities of dietary vitamin D and calcitriol in an animal model of breast cancer: importance of mammary CYP27B1 for treatment and prevention 
Calcitriol [1,25(OH)2D3], the hormonally active form of vitamin D exerts anti-proliferative, pro-apoptotic, anti-inflammatory effects and other anticancer actions in breast cancer (BCa) cell cultures and animal models of BCa. Our research is focused on investigating the potential beneficial effects of dietary vitamin D3 compared to calcitriol and the underlying mechanisms in BCa treatment and chemoprevention. We recently found that dietary vitamin D3 exhibits significant tumor inhibitory effects in xenograft models of BCa that are equivalent to those elicited by the administration of the active hormone calcitriol. At the easily achievable dose tested in our studies, dietary vitamin D3 exhibited substantial tumor inhibitory activity and, unlike calcitriol, did not cause hypercalcemia demonstrating its relative safety. We found elevations in circulating calcitriol as well as increased CYP27B1 expression in the tumor and the intestine in tumor-bearing mice ingesting a vitamin D3-supplemented diet. We hypothesize that the elevation in circulating 25(OH)D induced by dietary vitamin D3 supplements stimulates local synthesis of calcitriol in the mammary tumor microenvironment and the ensuing paracrine/autocrine actions play a major role in the anticancer activity of dietary vitamin D3. Our findings suggest that the endocrine activity of calcitriol derived from tumor and other extra-renal sources such as the intestine, probably also plays a role in mediating the anticancer effects of dietary vitamin D3. Thus it appears that multiple sites of 1α-hydroxylation contribute to the anticancer effects of dietary vitamin D3. Our data strongly suggest that dietary vitamin D will be useful in the chemoprevention and treatment of BCa since it is a safe, economical and easily available nutritional agent that is equivalent to calcitriol in exerting anticancer effects, at least in mouse models. Furthermore, adequate vitamin D nutrition and avoidance of vitamin D deficiency appear to be important in reducing BCa risk. These findings warrant clinical trials in BCa patients and in women at high risk for BCa to evaluate the benefits of dietary vitamin D3 supplementation.
PMCID: PMC3554854  PMID: 22939886
12.  Direct Renin Inhibition Prevents Cardiac Dysfunction in a Diabetic Mouse Model: Comparison with an Angiotensin Receptor Antagonist and Angiotensin Converting Enzyme Inhibitor 
Hyperglycemia upregulates intracellular angiotensin II production in cardiac myocytes, effects of which are blocked more effectively by renin inhibition than angiotensin receptor blockers (ARBs) or ACE inhibitors. Here we determined whether renin inhibition is more effective at preventing diabetic cardiomyopathy than an ARB or ACE inhibitor. Diabetes was induced in adult mice for 10 wks by streptozotocin. Diabetic mice were treated with insulin, aliskiren (renin inhibitor), benazeprilat (ACE inhibitor), or valsartan (ARB) via subcutaneous minipumps. Significant impairment in diastolic and systolic cardiac function was observed in diabetic mice, which was completely prevented by all three RAS inhibitors. Hyperglycemia significantly increased cardiac oxidative stress and circulating inflammatory cytokines, which were blocked by aliskiren and benazeprilat, while valsartan was partially effective. Diabetes increased cardiac (pro)renin receptor (PRR) expression and nuclear translocation of promyelocytic zinc finger protein (PLZF), which was completely prevented by aliskiren and valsartan, and partially by benazeprilat. Renin inhibition provided similar protection of cardiac function as ARBs and ACE inhibitors. Activation of PLZF by PRR represented a novel mechanism in diabetic cardiomyopathy. Differential effects of the three agents on oxidative stress, cytokines, and PRR expression suggested subtle differences in their mechanism of action.
PMCID: PMC3982397  PMID: 23116220
Diabetic cardiomyopathy; intracrine; prorenin receptor
13.  Combination of Calcitriol and Dietary Soy Exhibits Enhanced Anticancer Activity and Increased Hypercalcemic Toxicity in a Mouse Xenograft Model of Prostate Cancer 
The Prostate  2012;72(15):1628-1637.
The potential role of vitamin D and soy in prostate cancer (PCa) prevention/treatment has gained much attention in recent years. In this study, we evaluated the anticancer activity of calcitriol, the active form of vitamin D, dietary soy, and their combinations in a mouse model of PCa.
Athymic male nude mice bearing PC-3 human PCa xenografts received diets containing 10 kcal% or 20 kcal% soy, calcitriol injections, or a combination of dietary soy and calcitriol. Changes in tumor growth, serum levels of 1,25(OH)2D and calcium, and regulation of tumor gene expression were examined.
The combination treatments resulted in substantially greater inhibition of tumor growth than either agent alone. Soy diets alone caused a modest elevation in serum 1,25(OH)2D, whereas the calcitriol-soy combinations led to substantially elevated serum 1,25(OH)2D, hypercalcemia, and in some cases lethal toxicity. The combinations enhanced calcitriol activity in regulating target gene expression, including greater up-regulation of anti-proliferative (p21, IGFBP-3) and pro-apoptotic (Bax) genes, increased inhibition of anti-apoptotic (Bcl-2) and cell cycle promoting (cyclin D1) genes, and suppression of prostaglandin (PG) synthesis and signaling (COX-2, 15-PGDH, PG receptors). Increases in serum calcium were accompanied by elevated expression of intestinal calcium absorption genes (TRPV6, calbindin-9k).
Soy increases the bioavailability of endogenous and administered calcitriol, thereby enhancing its anticancer effects and risk of hypercalcemia. Since both agents are easily available as dietary supplements, the increased potential for hypercalcemic toxicity becomes an important factor when considering the combined use of vitamin D and soy in PCa therapy.
PMCID: PMC3389566  PMID: 22457201
Vitamin D; calcitriol; soy; prostate cancer; CYP24A1; hypercalcemia
14.  The Potential Therapeutic Benefits of Vitamin D in the Treatment of Estrogen Receptor Positive Breast Cancer 
Steroids  2012;77(11):1107-1112.
Calcitriol (1,25-dihydroxyvitamin D3), the hormonally active form of vitamin D, inhibits the growth of many malignant cells including breast cancer (BCa) cells. The mechanisms of calcitriol anticancer actions include cell cycle arrest, stimulation of apoptosis and inhibition of invasion, metastasis and angiogenesis. In addition we have discovered new pathways of calcitriol action that are especially relevant in inhibiting the growth of estrogen receptor positive (ER+) BCa cells. Calcitriol suppresses COX-2 expression and increases that of 15-PGDH thereby reducing the levels of inflammatory prostaglandins (PGs). Our in vitro and in vivo studies show that calcitriol decreases the expression of aromatase, the enzyme that catalyzes estrogen synthesis selectively in BCa cells and in the mammary adipose tissue surrounding BCa, by a direct repression of aromatase transcription via promoter II as well as an indirect effect due to the reduction in the levels of PGs, which are major stimulator of aromatase transcription through promoter II. Calcitriol down-regulates the expression of ERα and thereby attenuates estrogen signaling in BCa cells including the proliferative stimulus provided by estrogens. Thus the inhibition of estrogen synthesis and signaling by calcitriol and its anti-inflammatory actions will play an important role in inhibiting ER+ BCa. We hypothesize that dietary vitamin D would exhibit similar anticancer activity due to the presence of the enzyme 25-hydroxyvitamin D-1α-hydroxylase (CYP27B1) in breast cells ensuring conversion of circulating 25-hydroxyvitamin D to calcitriol locally within the breast micro-environment where it can act in a paracrine manner to inhibit BCa growth. Cell culture and in vivo data in mice strongly suggest that calcitriol and dietary vitamin D would play a beneficial role in the prevention and/or treatment of ER+ BCa in women.
PMCID: PMC3429709  PMID: 22801352
Calcitriol; breast cancer; anti-proliferative effects; anti-inflammatory effects; aromatase; prostaglandins; aromatase inhibitors; estrogen receptor; dietary vitamin D
15.  The Role of Vitamin D Receptor Mutations in the Development of Alopecia 
Hereditary Vitamin D Resistant Rickets (HVDRR) is a rare disease caused by mutations in the vitamin D receptor (VDR). The consequence of defective VDR is the inability to absorb calcium normally in the intestine. This leads to a constellation of metabolic abnormalities including hypocalcemia, secondary hyperparathyroidism and hypophosphatemia that cause the development of rickets at an early age in affected children. An interesting additional abnormality is the presence of alopecia in some children depending on the nature of the VDR mutation. The data indicate that VDR mutations that cause defects in DNA binding, RXR heterodimerization or absence of the VDR cause alopecia while mutations that alter VDR affinity for 1,25(OH)2D3 or disrupt coactivator interactions do not cause alopecia. The cumulative findings indicate that hair follicle cycling is dependent on unliganded actions of the VDR. Further research is ongoing to elucidate the role of the VDR in hair growth and differentiation.
PMCID: PMC3196847  PMID: 21693169
16.  Vitamin D Metabolism and Action in the Prostate: Implications for Health and Disease 
Prostate cancer (PCa) is the second most common cancer in men worldwide. Epidemiological, molecular, and cellular studies have implicated vitamin D deficiency as a risk factor for the development and/or progression of PCa. Studies using cell culture systems and animal models suggest that vitamin D acts to reduce the growth of PCa through regulation of cellular proliferation and differentiation. However, although pre-clinical studies provide a strong indication for anti-cancer activity, proof of therapeutic benefits in men is still lacking. The anti-proliferative and pro-differentiating properties of vitamin D have been attributed to calcitriol [1,25(OH)2D3], the hormonally active form of vitamin D, acting through the vitamin D receptor (VDR). Metabolism of vitamin D in target tissues is mediated by two key enzymes: 1α-hydroxylase (CYP27B1), which catalyzes the synthesis of calcitriol from 25(OH)D and 24-hydroxylase (CYP24), which catalyzes the initial step in the conversion of calcitriol to less active metabolites. Many factors affect the balance of calcitriol synthesis and catabolism and several maneuvers, like combination therapy of calcitriol with other drugs, have been explored to treat PCa and reduce its risk. The current paper is an overview addressing some of the key factors that influence the biological actions of vitamin D and its metabolites in the treatment and/or prevention of PCa.
PMCID: PMC3189327  PMID: 21664249
Prostate cancer; vitamin D; calcitriol; vitamin D receptor (VDR); 1α-hydroxylase; 24-hydroxylase; combination therapy
17.  Calcium Plus Vitamin D Supplementation and the Risk of Nonmelanoma and Melanoma Skin Cancer: Post Hoc Analyses of the Women's Health Initiative Randomized Controlled Trial 
Journal of Clinical Oncology  2011;29(22):3078-3084.
In light of inverse relationships reported in observational studies of vitamin D intake and serum 25-hydroxyvitamin D levels with risk of nonmelanoma skin cancer (NMSC) and melanoma, we evaluated the effects of vitamin D combined with calcium supplementation on skin cancer in a randomized placebo-controlled trial.
Postmenopausal women age 50 to 79 years (N = 36,282) enrolled onto the Women's Health Initiative (WHI) calcium/vitamin D clinical trial were randomly assigned to receive 1,000 mg of elemental calcium plus 400 IU of vitamin D3 (CaD) daily or placebo for a mean follow-up period of 7.0 years. NMSC and melanoma skin cancers were ascertained by annual self-report; melanoma skin cancers underwent physician adjudication.
Neither incident NMSC nor melanoma rates differed between treatment (hazard ratio [HR], 1.02; 95% CI, 0.95 to 1.07) and placebo groups (HR, 0.86; 95% CI, 0.64 to 1.16). In subgroup analyses, women with history of NMSC assigned to CaD had a reduced risk of melanoma versus those receiving placebo (HR, 0.43; 95% CI, 0.21 to 0.90; Pinteraction = .038), which was not observed in women without history of NMSC.
Vitamin D supplementation at a relatively low dose plus calcium did not reduce the overall incidence of NMSC or melanoma. However, in women with history of NMSC, CaD supplementation reduced melanoma risk, suggesting a potential role for calcium and vitamin D supplements in this high-risk group. Results from this post hoc subgroup analysis should be interpreted with caution but warrant additional investigation.
PMCID: PMC3157967  PMID: 21709199
18.  The Anti-Cancer and Anti-Inflammatory Actions of 1,25(OH)2D3 
Various epidemiological studies have shown an aetiological link between vitamin D deficiency and cancer incidence. The active metabolite of vitamin D, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], has potent anti-cancer activities both in vitro and in vivo. These anti-cancer effects are attained by regulating the transcription of numerous genes that are involved in different pathways to reduce tumorigenesis and are dependent on the cancer cell type. Besides reducing cell growth and inducing apoptosis, 1,25(OH)2D3 also inhibits angiogenesis and metastasis. Moreover, its potency to inhibit inflammation also contributes to its anti-tumoral activity. Here, we report the different ways in which 1,25(OH)2D3 interferes with the malignant processes that are activated in cancer cells.
PMCID: PMC3164534  PMID: 21872801
Vitamin D; Cancer; Proliferation; Apoptosis; Metastasis; Angiogenesis; Inflammation
19.  Pelvic Positioning Creates Error in CT Acetabular Measurements 
CT allows for accurate measurement of acetabular orientation and shape, but malpositioning of the pelvis may lead to measurement variance.
We therefore sought to determine: (1) whether acetabular anteversion measurements using the femoral head centers differed from those using the posterior ischia, and (2) the extent to which changing obliquity, rotation, and tilt of a pelvis in a CT scanner affected the measurement of acetabular variables.
A radiopaque human pelvis model with articulated hips was suspended from a plastic sheet as part of an adjustable frame. Changes in the transverse and sagittal planes created rotation and tilt, while rotating the frame in the coronal plane created obliquity. CT scans were obtained, varying the combinations of obliquity, rotation, and tilt by intervals of 5°, up to 20°. Acetabular anteversion (AA), anterior acetabular sector angle (AASA), posterior acetabular sector angle (PASA), and horizontal acetabular sector angle (HASA) were measured.
The two methods for measuring AA yielded values differing by 1° to 4° but correlated (r = 0.981) across the spectrum of pelvis positioning. Pelvic obliquity and tilt were linearly associated with changes in the measurements. For each 1°-increase in pelvic obliquity, AA changed −0.4°, and AASA, PASA, and HASA changed 1.93°, 0.99°, and 2.80°, respectively. For each 1°-increase in pelvic tilt, AA changed 0.8°, and AASA, PASA, and HASA changed −1.07°, 0.52°, and −0.51°, respectively. Rotation had no affect on the variables.
Small changes in pelvic obliquity and tilt were associated with variances in acetabular measurements. The measured changes were directly proportional to the changes in obliquity and tilt, and were additive. Pelvic rotation created no changes in measurement.
Clinical Relevance
Incorrect interpretation of acetabular anteversion and coverage may lead to unsatisfactory acetabular fragment positioning during reorientational surgery. Although intraoperative positioning of an acetabular fragment may not be as precise as the tools for preoperative planning, it is important for a surgeon to have the most precise data available for planning a procedure, and know where error can occur in collecting the data.
PMCID: PMC3094628  PMID: 21365336
20.  Inhibitory Effects of Calcitriol on the Growth of MCF-7 Breast Cancer Xenografts in Nude Mice: Selective Modulation of Aromatase Expression in vivo 
Hormones & cancer  2011;2(3):190-202.
Calcitriol (1,25-dihydroxyvitamin D3), the hormonally active metabolite of vitamin D, exerts many anticancer effects in breast cancer (BCa) cells. We have previously shown using cell culture models that calcitriol acts as a selective aromatase modulator (SAM) and inhibits estrogen synthesis and signaling in BCa cells. We have now examined calcitriol effects in vivo on aromatase expression, estrogen signaling, and tumor growth when used alone and in combination with aromatase inhibitors (AIs). In immunocompromised mice bearing MCF-7 xenografts, increasing doses of calcitriol exhibited significant tumor inhibitory effects (~50% to 70% decrease in tumor volume). At the suboptimal doses tested, anastrozole and letrozole also caused significant tumor shrinkage when used individually. Although the combinations of calcitriol and the AIs caused a statistically significant increase in tumor inhibition in comparison to the single agents, the cooperative interaction between these agents appeared to be minimal at the doses tested. Calcitriol decreased aromatase expression in the xenograft tumors. Importantly, calcitriol also acted as a SAM in the mouse, decreasing aromatase expression in the mammary adipose tissue, while increasing it in bone marrow cells and not altering it in the ovaries and uteri. As a result, calcitriol significantly reduced estrogen levels in the xenograft tumors and surrounding breast adipose tissue. In addition, calcitriol inhibited estrogen signaling by decreasing tumor ERα levels. Changes in tumor gene expression revealed the suppressive effects of calcitriol on inflammatory and growth signaling pathways and demonstrated cooperative interactions between calcitriol and AIs to modulate gene expression. We hypothesize that cumulatively these calcitriol actions would contribute to a beneficial effect when calcitriol is combined with an AI in the treatment of BCa.
PMCID: PMC3114631  PMID: 21686077
Calcitriol; Selective aromatase modulator; Estrogen synthesis; Aromatase; Aromatase inhibitors; Breast cancer; Xenografts
21.  Genetic Disorders and Defects in Vitamin D Action 
PMCID: PMC2879401  PMID: 20511055
1α-hydroxylase deficiency; hereditary vitamin D resistant rickets; vitamin D receptor; mutations; rickets; alopecia
22.  Improved Characterization of Focal Liver Lesions With Liver-Specific Gadoxetic Acid Disodium–Enhanced Magnetic Resonance Imaging: A Multicenter Phase 3 Clinical Trial 
To evaluate the safety of gadoxetic acid disodium (Gd-EOB-DTPA) magnetic resonance imaging (MRI) and its efficacy in characterizing liver lesions.
Lesion characterization and classification using combined (unenhanced and Gd-EOB-DTPA–enhanced) MRI were compared with those using unenhanced MRI and contrast-enhanced spiral computed tomography (CT) using on-site clinical and off-site blinded evaluations for patients with focal liver lesions.
Gadoxetic acid disodium was well tolerated in this study. For the clinical evaluation, more lesions were correctly characterized using combined (unenhanced and Gd-EOB-DTPA–enhanced) MRI than using unenhanced MRI and spiral CT (96% vs 84% and 85%, respectively; P ≤ 0.0008). For the blinded evaluation, more lesions were correctly characterized using combined MRI compared with using unenhanced MRI (61%–76% vs 48%–65%, respectively; P ≤ 0.0012 for 2/3 readers); when compared with spiral CT, a similar proportion of lesions were correctly characterized.
Gadoxetic acid disodium–enhanced MRI is of clinical benefit relative to unenhanced MRI and spiral CT for a radiological diagnosis of liver lesions.
PMCID: PMC3036163  PMID: 20351497
liver lesion; magnetic resonance; computed tomography; contrast agent; Gd-EOB-DTPA
23.  Hereditary 1,25-dihydroxyvitamin D-resistant rickets with alopecia resulting from a novel missense mutation in the DNA-binding domain of the vitamin D receptor 
The rare genetic recessive disease, hereditary vitamin D resistant rickets (HVDRR), is caused by mutations in the vitamin D receptor (VDR) that result in resistance to the active hormone 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3 or calcitriol). In this study, we examined the VDR from a young boy with clinical features of HVDRR including severe rickets, hypocalcemia, hypophosphatemia and partial alopecia. The pattern of alopecia was very unusual with areas of total baldness, adjacent to normal hair and regions of scant hair. The child failed to improve on oral calcium and vitamin D therapy but his abnormal chemistries and his bone x-rays normalized with intravenous calcium therapy. We found that the child was homozygous for a unique missense mutation in the VDR gene that converted valine to methionine at amino acid 26 (V26M) in the VDR DNA-binding domain (DBD). The mutant VDR was studied in the patient’s cultured skin fibroblasts and found to exhibit normal [3H]1,25-(OH)2D3 binding and protein expression. However, the fibroblasts were unresponsive to treatment with high concentrations of 1,25(OH)2D3 as demonstrated by their failure to induce CYP24A1 gene expression, a marker of 1,25(OH)2D3 responsiveness. We recreated the V26M mutation in the WT VDR and showed that in transfected COS-7 cells the mutation abolished 1,25(OH)2D3-mediated transactivation. The mutant VDR exhibited normal ligand-induced binding to RXRα and to the coactivator DRIP205. However, the V26M mutation inhibited VDR binding to a consensus vitamin D response element (VDRE).
In summary, we have identified a novel V26M mutation in the VDR DBD as the molecular defect in a patient with HVDRR and an unusual pattern of alopecia.
PMCID: PMC2794978  PMID: 19815438
calcitriol; resistance; calcium; intravenous; hairless; retinoid X receptor
24.  Cardiomyopathy: An Overview 
American family physician  2009;79(9):778-784.
Cardiomyopathy is an anatomic and pathologic diagnosis associated with muscle or electrical dysfunction of the heart. Cardiomyopathies represent a heterogeneous group of diseases that often lead to progressive heart failure with signifcant morbidity and mortality. Cardiomyopathies may be primary (i.e., genetic, mixed, or acquired) or secondary (e.g., infltrative, toxic, infammatory). Major types include dilated cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, and arrhythmogenic right ventricular cardiomyopathy. Although cardiomyopathy is asymptomatic in the early stages, symptoms are the same as those characteristically seen in any type of heart failure and may include shortness of breath, fatigue, cough, orthopnea, paroxysmal nocturnal dyspnea, and edema. Diagnostic studies include B-type natriuretic peptide levels, baseline serum chemistries, electrocardiography, and echocardiography. Treatment is targeted at relieving the symptoms of heart failure and reducing rates of heart failure–related hospitalization and mortality. Treatment options include pharmacotherapy, implantable cardioverter-defbrillators, cardiac resynchronization therapy, and heart transplantation. Recommended lifestyle changes include restricting alcohol consumption, losing weight, exercising, quitting smoking, and eating a low-sodium diet.
PMCID: PMC2999879  PMID: 20141097
25.  Hereditary Vitamin D Resistant Rickets 
Bone  2009;45(4):743-746.
To study the vitamin D receptor (VDR) gene in a young girl with severe rickets and clinical features of hereditary vitamin D resistant rickets, including hypocalcemia, hypophosphatemia, partial alopecia, and elevated serum levels of 1,25-dihydroxyvitamin D.
Study design
We amplified and sequenced DNA samples from blood for the patient, her mother, and the patient’s two siblings. We amplified and sequenced the VDR cDNA from RNA isolated from the patient’s blood.
DNA sequence analyses of the VDR gene showed that the patient was homozygous for a novel guanine to thymine substitution in the 5′-splice site in the exon 8-intron J junction. Analysis of the VDR cDNA using reverse transcriptase-polymerase chain reaction showed that exons 7 and 9 were fused, and that exon 8 was skipped. The mother was heterozygous for the mutation and the two siblings were unaffected.
A novel splice site mutation was identified in the VDR gene that caused exon 8 to be skipped. The mutation deleted amino acids 303-341 in the VDR ligand-binding domain, which is expected to render the VDR non-functional. Nevertheless, successful outpatient treatment was achieved with frequent high doses of oral calcium. (190 words)
PMCID: PMC2782671  PMID: 19523546
Hereditary Vitamin D Resistant Rickets; Vitamin D Receptor; 1,25-dihydroxyvitamin D; Bone; Alopecia

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