Bioorthogonal Catalysis for Treatment of Solid Tumors Using Thermostable, Self-Assembling, Single Enzyme Nanoparticles and Natural Product Conversion with Indole-3-acetic Acid.

Bioorthogonal catalysis (BC) generates chemical reactions not present in normal physiology for the purpose of disease treatment. Because BC catalytically produces the desired therapy only at the site of disease, it holds the promise of site-specific treatment with little or no systemic exposure or side effects. Transition metals are typically used as catalytic centers in BC; however, solubility and substrate specificity typically necessitate a coordinating enzyme and/or stabilizing superstructure for in vivo application. We report the use of self-assembling, porous exoshells (tESs) to encapsulate and deliver an iron-containing reaction center for the treatment of breast cancer. The catalytic center is paired with indole-3-acetic acid (IAA), a natural product found in edible plants, which undergoes oxidative decarboxylation, via reduction of iron(III) to iron(II), to produce free radicals and bioactive metabolites. The tES encapsulation is critical for endocytic uptake of BC reaction centers and, when followed by administration of IAA, results in apoptosis of MDA-MB-231 triple negative cancer cells and complete regression of in vivo orthotopic xenograft tumors (p < 0.001, n = 8 per group). When Renilla luciferase (rLuc) is substituted for horseradish peroxidase (HRP), whole animal luminometry can be used to monitor in vivo activity.

The Generational Impact Of Racism On Health: Voices From American Indian Communities.

Structural racism toward American Indians and Alaska Natives is found in nearly every policy regarding and action taken toward that population since non-Natives made first contact with the Indigenous peoples of the United States. Generations of American Indians and Alaska Natives have suffered from policies that called for their genocide as well as policies intended to acculturate and dominate them-such as the sentiment from Richard Henry Pratt to "kill the Indian…, save the man." The intergenerational effect is one that has left American Indians and Alaska Natives at the margins of health and the health care system. The effect is devastating psychologically, eroding a value system that is based on community and the sanctity of all creation. Using stories we collected from American Indian people who have experienced the results of racist policies, we describe historical trauma and its links to the health of American Indians and Alaska Natives. We develop two case studies around these stories, including one from a member of the Navajo Nation's experiences during the COVID-19 pandemic, to illustrate biases in institutionalized structures. Finally, we describe how the American Indian and Alaska Native Cultural Wisdom Declaration can help policy makers eliminate the effect of systemic racism on the health of American Indians and Alaska Natives-for instance, by lifting constraints on federal funding for American Indian and Alaska Native initiatives and allowing payment to traditional healers for their health services.

Predicting coronavirus disease (COVID-19) outcomes in the United States early in the epidemic.

By 21 October 2020, the coronavirus disease (COVID-19) epidemic in the United States (US) had infected 8.3 million people, resulting in 61,364 laboratory-confirmed hospitalizations and 222,157 deaths. Currently, policymakers are trying to better understand this epidemic, especially the human-to-human transmissibility of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in relation to social, populational, air travel related and environmental exposure factors. Our study used 50 US states' public health surveillance datasets (January 1-April 1, 2020) to measure associations of confirmed COVID-19 cases, hospitalizations and deaths with these variables. Using the resulting associations and multivariate regression (Negative Binomial and Poisson), predicted cases, hospitalizations and deaths were generated for each US state early in the epidemic. Factors associated with a significantly increased risk of COVID-19 disease, hospitalization and death included: population density, enplanement, Black race and increased sun exposure; in addition, COVID-19 disease and hospitalization were also associated with morning humidity. Although predictions of the number of cases, hospitalizations and deaths due to COVID-19 were not accurate for every state, those states with a combination of large number of enplanements, high population density, high proportion of Black residents, high humidity or low sun exposure may expect more rapid than expected growth in the number of COVID-19 events early in the epidemic.

A general approach to protein folding using thermostable exoshells.

In vitro protein folding is a complex process which often results in protein aggregation, low yields and low specific activity. Here we report the use of nanoscale exoshells (tES) to provide complementary nanoenvironments for the folding and release of 12 highly diverse protein substrates ranging from small protein toxins to human albumin, a dimeric protein (alkaline phosphatase), a trimeric ion channel (Omp2a) and the tetrameric tumor suppressor, p53. These proteins represent a unique diversity in size, volume, disulfide linkages, isoelectric point and multi versus monomeric nature of their functional units. Protein encapsulation within tES increased crude soluble yield (3-fold to >100-fold), functional yield (2-fold to >100-fold) and specific activity (3-fold to >100-fold) for all the proteins tested. The average soluble yield was 6.5 mg/100 mg of tES with charge complementation between the tES internal cavity and the protein substrate being the primary determinant of functional folding. Our results confirm the importance of nanoscale electrostatic effects and provide a solution for folding proteins in vitro.

Redefining IL11 as a regeneration-limiting hepatotoxin and therapeutic target in acetaminophen-induced liver injury.

Acetaminophen (N-acetyl-p-aminophenol; APAP) toxicity is a common cause of liver damage. In the mouse model of APAP-induced liver injury (AILI), interleukin 11 (IL11) is highly up-regulated and administration of recombinant human IL11 (rhIL11) has been shown to be protective. Here, we demonstrate that the beneficial effect of rhIL11 in the mouse model of AILI is due to its inhibition of endogenous mouse IL11 activity. Our results show that species-matched IL11 behaves like a hepatotoxin. IL11 secreted from APAP-damaged human and mouse hepatocytes triggered an autocrine loop of NADPH oxidase 4 (NOX4)-dependent cell death, which occurred downstream of APAP-initiated mitochondrial dysfunction. Hepatocyte-specific deletion of Il11 receptor subunit alpha chain 1 (Il11ra1) in adult mice protected against AILI despite normal APAP metabolism and glutathione (GSH) depletion. Mice with germline deletion of Il11 were also protected from AILI, and deletion of Il1ra1 or Il11 was associated with reduced c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) activation and quickly restored GSH concentrations. Administration of a neutralizing IL11RA antibody reduced AILI in mice across genetic backgrounds and promoted survival when administered up to 10 hours after APAP. Inhibition of IL11 signaling was associated with the up-regulation of markers of liver regenerations: cyclins and proliferating cell nuclear antigen (PCNA) as well as with phosphorylation of retinoblastoma protein (RB) 24 hours after AILI. Our data suggest that species-matched IL11 is a hepatotoxin and that IL11 signaling might be an effective therapeutic target for APAP-induced liver damage.

Robust Performance of Potentially Functional SNPs in Machine Learning Models for the Prediction of Atorvastatin-Induced Myalgia.

Statins can cause muscle symptoms resulting in poor adherence to therapy and increased cardiovascular risk. We hypothesize that combinations of potentially functional SNPs (pfSNPs), rather than individual SNPs, better predict myalgia in patients on atorvastatin. This study assesses the value of potentially functional single nucleotide polymorphisms (pfSNPs) and employs six machine learning algorithms to identify the combination of SNPs that best predict myalgia. Methods: Whole genome sequencing of 183 Chinese, Malay and Indian patients from Singapore was conducted to identify genetic variants associated with atorvastatin induced myalgia. To adjust for confounding factors, demographic and clinical characteristics were also examined for their association with myalgia. The top factor, sex, was then used as a covariate in the whole genome association analyses. Variants that were highly associated with myalgia from this and previous studies were extracted, assessed for potential functionality (pfSNPs) and incorporated into six machine learning models. Predictive performance of a combination of different models and inputs were compared using the average cross validation area under ROC curve (AUC). The minimum combination of SNPs to achieve maximum sensitivity and specificity as determined by AUC, that predict atorvastatin-induced myalgia in most, if not all the six machine learning models was determined. Results: Through whole genome association analyses using sex as a covariate, a larger proportion of pfSNPs compared to non-pf SNPs were found to be highly associated with myalgia. Although none of the individual SNPs achieved genome wide significance in univariate analyses, machine learning models identified a combination of 15 SNPs that predict myalgia with good predictive performance (AUC >0.9). SNPs within genes identified in this study significantly outperformed SNPs within genes previously reported to be associated with myalgia. pfSNPs were found to be more robust in predicting myalgia, outperforming non-pf SNPs in the majority of machine learning models tested. Conclusion: Combinations of pfSNPs that were consistently identified by different machine learning models to have high predictive performance have good potential to be clinically useful for predicting atorvastatin-induced myalgia once validated against an independent cohort of patients.

Comorbidities and the risk of cardiovascular disease mortality among racially diverse patients with breast cancer.

BACKGROUND: Women who have coexisting comorbidities at the time of breast cancer diagnosis have an increased risk of breast cancer and overall mortality. However, the associations between newly diagnosed comorbidities and the risk of cardiovascular disease (CVD) mortality among these patients have not been examined. METHODS: The authors compared the associations between coexisting and newly diagnosed CVD, type 2 diabetes, and hypertension and the risk of CVD mortality among patients with breast cancer identified in the Missouri Cancer Registry. In total, 33,099 women who had incident invasive breast cancer with inpatient and outpatient hospital discharge data within 2 years after breast cancer diagnosis were included: 9.3% were Black. Subdistribution hazard ratios (sdHRs) and 95% CIs were calculated for the risk of CVD-related mortality using adjusted Cox proportional hazards regression models, accounting for a competing risk of breast cancer deaths. RESULTS: Within the first 2 years after breast cancer, the most reported newly diagnosed comorbidity was hypertension (9%), followed by CVD (4%), and type 2 diabetes (2%). CVD mortality was increased in women who had newly diagnosed CVD (sdHR, 2.49; 95% CI, 2.09-2.99), diabetes (sdHR, 2.16; 95% CI, 1.68-2.77), or hypertension (sdHR, 2.06; 95% CI, 1.71-2.48) compared with women who did not have these conditions. Associations were similar by race. The strongest association was among women who received chemotherapy and then developed CVD (sdHR, 3.82; 95% CI, 2.69-5.43). CONCLUSIONS: Monitoring for diabetes, hypertension, and CVD from the time of breast diagnosis may reduce CVD mortality.

Relationship between insurance status and outcomes for patients with breast cancer in Missouri.

BACKGROUND: The cancer stage at diagnosis, treatment delays, and breast cancer mortality vary with insurance status. METHODS: Using the Missouri Cancer Registry, this analysis included 31,485 women diagnosed with invasive breast cancer from January 1, 2007, to December 31, 2015. Odds ratios (ORs) of a late-stage (stage III or IV) diagnosis and a treatment delay (>60 days after the diagnosis) were calculated with logistic regression. The hazard ratio (HR) of breast cancer mortality was calculated with Cox proportional hazards regression. Mediation analysis was used to quantify the individual contributions of each covariate to mortality. RESULTS: The OR of a late-stage diagnosis was higher for patients with Medicaid (OR, 1.72; 95% confidence interval [CI], 1.56-1.91) or no insurance (OR, 2.30; 95% CI, 1.91-2.78) in comparison with privately insured patients. Medicare (OR, 1.21; 95% CI, 1.10-1.37), Medicaid (OR, 1.60; 95% CI, 1.37-1.85), and uninsured patients (OR, 1.58; 95% CI, 1.18-2.12) had higher odds of a treatment delay. The HR of breast cancer-specific mortality was significantly increased in the groups with public insurance or no insurance and decreased after sequential adjustments for sociodemographic factors (HR, 2.39; 95% CI, 1.96-2.91), tumor characteristics (HR, 1.28; 95% CI, 1.05-1.56), and treatment (HR, 1.23; 95% CI, 1.01-1.50). Late-stage diagnoses accounted for 72.5% of breast cancer mortality in the uninsured. CONCLUSIONS: Compared with the privately insured, women with public or no insurance had a higher risk for advanced breast cancer, a >60-day treatment delay, and death from breast cancer. Particularly for the uninsured, Medicaid expansion and increased funding for education and screening programs could decrease breast cancer disparities.

Prioritizing Candidates of Post-Myocardial Infarction Heart Failure Using Plasma Proteomics and Single-Cell Transcriptomics.

BACKGROUND: Heart failure (HF) is the most common long-term complication of acute myocardial infarction (MI). Understanding plasma proteins associated with post-MI HF and their gene expression may identify new candidates for biomarker and drug target discovery. METHODS: We used aptamer-based affinity-capture plasma proteomics to measure 1305 plasma proteins at 1 month post-MI in a New Zealand cohort (CDCS [Coronary Disease Cohort Study]) including 181 patients post-MI who were subsequently hospitalized for HF in comparison with 250 patients post-MI who remained event free over a median follow-up of 4.9 years. We then correlated plasma proteins with left ventricular ejection fraction measured at 4 months post-MI and identified proteins potentially coregulated in post-MI HF using weighted gene co-expression network analysis. A Singapore cohort (IMMACULATE [Improving Outcomes in Myocardial Infarction through Reversal of Cardiac Remodelling]) of 223 patients post-MI, of which 33 patients were hospitalized for HF (median follow-up, 2.0 years), was used for further candidate enrichment of plasma proteins by using Fisher meta-analysis, resampling-based statistical testing, and machine learning. We then cross-referenced differentially expressed proteins with their differentially expressed genes from single-cell transcriptomes of nonmyocyte cardiac cells isolated from a murine MI model, and single-cell and single-nucleus transcriptomes of cardiac myocytes from murine HF models and human patients with HF. RESULTS: In the CDCS cohort, 212 differentially expressed plasma proteins were significantly associated with subsequent HF events. Of these, 96 correlated with left ventricular ejection fraction measured at 4 months post-MI. Weighted gene co-expression network analysis prioritized 63 of the 212 proteins that demonstrated significantly higher correlations among patients who developed post-MI HF in comparison with event-free controls (data set 1). Cross-cohort meta-analysis of the IMMACULATE cohort identified 36 plasma proteins associated with post-MI HF (data set 2), whereas single-cell transcriptomes identified 15 gene-protein candidates (data set 3). The majority of prioritized proteins were of matricellular origin. The 6 most highly enriched proteins that were common to all 3 data sets included well-established biomarkers of post-MI HF: N-terminal B-type natriuretic peptide and troponin T, and newly emergent biomarkers, angiopoietin-2, thrombospondin-2, latent transforming growth factor-ß binding protein-4, and follistatin-related protein-3, as well. CONCLUSIONS: Large-scale human plasma proteomics, cross-referenced to unbiased cardiac transcriptomics at single-cell resolution, prioritized protein candidates associated with post-MI HF for further mechanistic and clinical validation.

Magnetic fields modulate metabolism and gut microbiome in correlation with Pgc-1α expression: Follow-up to an in vitro magnetic mitohormetic study.

Exercise modulates metabolism and the gut microbiome. Brief exposure to low mT-range pulsing electromagnetic fields (PEMFs) was previously shown to accentuate in vitro myogenesis and mitochondriogenesis by activating a calcium-mitochondrial axis upstream of PGC-1α transcriptional upregulation, recapitulating a genetic response implicated in exercise-induced metabolic adaptations. We compared the effects of analogous PEMF exposure (1.5 mT, 10 min/week), with and without exercise, on systemic metabolism and gut microbiome in four groups of mice: (a) no intervention; (b) PEMF treatment; (c) exercise; (d) exercise and PEMF treatment. The combination of PEMFs and exercise for 6 weeks enhanced running performance and upregulated muscular and adipose Pgc-1α transcript levels, whereas exercise alone was incapable of elevating Pgc-1α levels. The gut microbiome Firmicutes/Bacteroidetes ratio decreased with exercise and PEMF exposure, alone or in combination, which has been associated in published studies with an increase in lean body mass. After 2 months, brief PEMF treatment alone increased Pgc-1α and mitohormetic gene expression and after >4 months PEMF treatment alone enhanced oxidative muscle expression, fatty acid oxidation, and reduced insulin levels. Hence, short-term PEMF treatment was sufficient to instigate PGC-1α-associated transcriptional cascades governing systemic mitohormetic adaptations, whereas longer-term PEMF treatment was capable of inducing related metabolic adaptations independently of exercise.

Predicting the Shapes of Protein Complexes through Collision Cross Section Measurements and Database Searches.

In structural biology, collision cross sections (CCSs) from ion mobility mass spectrometry (IM-MS) measurements are routinely compared to computationally or experimentally derived protein structures. Here, we investigate whether CCS data can inform about the shape of a protein in the absence of specific reference structures. Analysis of the proteins in the CCS database shows that protein complexes with low apparent densities are structurally more diverse than those with a high apparent density. Although assigning protein shapes purely on CCS data is not possible, we find that we can distinguish oblate- and prolate-shaped protein complexes by using the CCS, molecular weight, and oligomeric states to mine the Protein Data Bank (PDB) for potentially similar protein structures. Furthermore, comparing the CCS of a ferritin cage to the solution structures in the PDB reveals significant deviations caused by structural collapse in the gas phase. We then apply the strategy to an integral membrane protein by comparing the shapes of a prokaryotic and a eukaryotic sodium/proton antiporter homologue. We conclude that mining the PDB with IM-MS data is a time-effective way to derive low-resolution structural models.

Patients with acute and chronic coronary syndromes have elevated long-term thrombin generation.

Coronary artery disease is a leading cause of morbidity and mortality worldwide. Despite significant advances in revascularization strategies and antiplatelet therapy with aspirin and/or P2Y12 receptor antagonist, patients with acute coronary syndrome (ACS) continue to be at long-term risk of further cardiovascular events. Besides platelet activation, the role of thrombin generation (TG) in atherothrombotic complications is widely recognized. In this study, we hypothesized that there is an elevation of coagulation activation persists beyond 12 months in patients with ACS and chronic coronary syndrome (CCS) when compared with healthy controls. We measured TG profiles of patients within 72 h after percutaneous coronary intervention, at 6-month, 12-month and 24-month. Our results demonstrated that TG of patients with ACS (n = 114) and CCS (n = 40) were persistently elevated when compared to healthy individuals (n = 50) in peak thrombin (ACS 273.1 nM vs CCS 287.3 nM vs healthy 234.3 nM) and velocity index (ACS 110.2 nM/min vs CCS 111.0 nM/min vs healthy 72.9 nM/min) at 24-month of follow-up. Our results suggest a rationale for addition of anticoagulation to antiplatelet therapy in preventing long-term ischemic events after ACS. Further research could clarify whether the use of TG parameters to enable risk stratification of patients at heightened long-term procoagulant risk who may benefit most from dual pathway inhibition.

Usability Assessment of the Missouri Cancer Registry's Published Interactive Mapping Reports: Round Two.

BACKGROUND: Health-related data's users have trouble understanding and interpreting combined statistical and mapping information. This is the second round of a usability study conducted after we modified and simplified our tested maps based on the first round's results. OBJECTIVE: To explore if the tested maps' usability improved by modifying the maps according to the first round's results. METHODS: We recruited 13 cancer professionals from National American Central Cancer registries (NACCR) 2016 conference. The study involved three phases per participant: A pretest questionnaire, the multi-task usability test, and the System Usability Scale (SUS). Software was used to record the computer screen during the trial and the users' spoken comments. We measured several qualitative and quantitative usability metrics. The study's data was analyzed using spreadsheet software. RESULTS: In the current study, unlike the previous round, there was no significant statistical relationship between the subjects' performance on the study test and the experience in GIS tools (P = .17 previously was .03). Three out of the four (75%) of our subjects with a bachelor's degree or less accomplished the given tasks effectively and efficiently. This study developed a comparable satisfaction results to the first round study, despite that the previous round's participants were highly educated and more experienced with GIS. CONCLUSION: By considering the round one's results and by updating our maps, we made the tested maps simpler to be used by subjects who have little experience in using GIS technology, and have little spatial and statistical knowledge.

G Protein-Coupled Estrogen Receptor Production Using an Escherichia coli Cell-Free Expression System.

Heterologous expression of the G protein-coupled estrogen receptor (GPER) comes with a suite of challenges intrinsic to membrane proteins. This receptor's low expression levels and tendency to form insoluble aggregates in Escherichia coli and yeast make it a difficult receptor-target to study. In this unit, we detail steps to produce monomeric GPER using a precipitation-based cell-free system. We provide information on the DNA construct for expression, the pipetting scheme for the reaction supplements to generate a master mix, and the cell-free reaction setup. In the last portion of this unit, we outline steps for solubilization and purification, and we provide a viable method for qualitatively observing functionality by liquid chromatography-mass spectrometry detection. © 2019 by John Wiley & Sons, Inc.

Detection of Labile Conformations of Elastin's Prolines by Solid-State Nuclear Magnetic Resonance and Fourier Transform Infrared Techniques.

Samples of native elastin are prepared with high levels of enrichment at its prolines, which are believed to play a major role in the elasticity of elastin. Major and minor populations of trans and cis isomers at the Xaa-Pro imide bonds are detected in two-dimensional 13C nuclear magnetic resonance (NMR) experiments. One- and two-dimensional 13C NMR and isotope-edited Fourier transform infrared experiments are also used to identify the prolines' folded and unfolded states, type II ß-turn and random coil, respectively, at physiological temperatures. This study provides new details about elastin's conformational ensemble. In addition, the cis-trans isomerization of its abundant prolines provides an additional mechanism of fiber elongation in tissue.

Surface protein engineering increases the circulation time of a cell membrane-based nanotherapeutic.

Mammalian cell membranes are often incompatible with chemical modifications typically used to increase circulation half-life. Using cellular nanoghosts as a model, we show that proline-alanine-serine (PAS) peptide sequences expressed on the membrane surface can extend the circulation time of a cell membrane derived nanotherapeutic. Membrane expression of a PAS 40 repeat sequence decreased protein binding and resulted in a 90% decrease in macrophage uptake when compared with non-PASylated controls (P ≤ 0.05). PASylation also extended circulation half-life (t1/2 = 37 h) compared with non-PASylated controls (t1/2 = 10.5 h) (P ≤ 0.005), resulting in ~7-fold higher in vivo serum concentrations at 24 h and 48 h (P ≤ 0.005). Genetically engineered membrane expression of PAS repeats may offer an alternative to PEGylation and provide extended circulation times for cellular membrane-derived nanotherapeutics.

Five Fruit and Vegetable a Day Does Not Reflect the Upward Trend of Obesity in the U.S.

OBJECTIVE: After almost three decades of U.S. surveillance in fruit and vegetable (F&V) intake and obesity, it is important to evaluate their usefulness for monitoring prevention and health promotion efforts in public health. We used U.S. surveillance data to evaluate whether the 16-year trends of F&V intake, measured by the prevalence of eating five or more servings of fruits and vegetables a day (FV5/day) is related to obesity trend as measured by its prevalence in the same period. We also evaluated whether trends in the prevalence of FV5/day by important sociodemographic factors (age, race/ethnicity, etc.) could explain the findings. STUDY DESIGN: A secondary analysis of U.S. adults (≥ 18 years) from the Behavioral Risk Factor Surveillance System (BRFSS) (1994-2009). METHODS: We categorized survey subjects for their F&V intake derived from the BRFSS six-question food frequency questionnaire into two groups: < FV5/day vs. ≥ FV5/day. Obesity was defined as BMI ≥ 30. We used logistic regressions to compute predicted prevalence of FV5/day and obesity, and to estimate the odds ratio of FV5/day by obesity and levels of sociodemographic, stratified by year. RESULTS: Between 1994 and 2009, the prevalence of FV5/day hovered around 25% among U.S. adults, while the obesity prevalence steadily increased from 14.8% to 27.4%. As measured through odds ratio, an inverse association between FV5/day and obesity was only observed in 55+, but not in other age, racial/ethnic or education groups. CONCLUSIONS: Between 1994 and 2009, we could not confirm a decrease in the prevalence of FV5/day associated with an increase in obesity prevalence, except for age 55+ group. Known disparities in FV5/day and obesity across sociodemographic factors persisted over the study period. FV5/day may be an inappropriate measure of total calories derived from eating fruits and vegetables. Its use to measure impact of public health strategies to improve nutrition and prevent obesity may be questionable.

The effect of metabolic risk factors on cancer mortality among blacks and whites.

BACKGROUND: Previous data showed that metabolic syndrome (MS) and its components are associated with cancer mortality. However, whether the association varies by race is unclear. To examine the association between metabolic risk factors and cancer death in non-Hispanic whites (whites) and non-Hispanic blacks (blacks) in the US. METHODS: We used data from National Health and Nutrition Examination Survey III (NHANES III) [1988-1994], a nationwide survey conducted by the National Center for Health Statistics of the Centers for Disease Control and Prevention in the US. We included a total of 18,001 participants aged ≥20 years in the study. We ascertained cancer death from NHANES III mortality follow-up study, which linked with the National Death Index and provides follow-up from the date of baseline NHANES III [1988-1994] through December 2006. MS was defined as the presence of at least three of five risk factors [i.e., elevated triglycerides (TG) (≥150 mg/dL), impaired fasting blood glucose (≥100 mg/dL), increased waist circumference (≥88 cm for women and ≥102 cm for men), elevated blood pressure (BP) (≥130 mmHg systolic BP or ≥85 mmHg diastolic BP) and, reduced high density lipoprotein (HDL) cholesterol (<50 mg/dL)]. The interaction between race and MS and its components against total cancer mortality was first tested. Cox proportional hazards regression was then used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) for total cancer mortality in relation to each MS individual component, and a MS composite score in whites and blacks, separately. RESULTS: We found a statistically significant interaction between MS and race as well as MS components and race in their effect on cancer death. In adjusted models, elevated BP was significantly associated with a 41% increased risk of total cancer death in blacks (HR 1.41; 95% CI, 1.10-1.80) while in whites, the risk of cancer death increased 29% with central obesity (HR 1.29; 95% CI, 1.05-1.59), 26% with low HDL (HR 1.26; 95% CI, 1.04-1.52), and 45% with impaired fasting glucose (HR 1.45; 95% CI, 1.19-1.76). CONCLUSIONS: The relationship between metabolic risk factors and total cancer mortality differed by race in the US. In blacks, high BP was associated with an increased risk for cancer death while in whites, central obesity, low HDL, and especially impaired fasting glucose were positively associated with cancer death.

Zirconia dental implants: A clinical and radiographic evaluation.

OBJECTIVE: Limited clinical evidence has been reported in dental literature regarding zirconia dental implants. The aim of the present retrospective consecutive case series was to evaluate the clinical outcome of zirconia dental implants with 1 to 5 years of follow-up. CLINICAL CONSIDERATIONS: The clinical outcome of 24 implants in 12 consecutive patients (male 5, female 7) with a mean age of 55 years (range 27-86) is reported. Radiographic crestal bone level was assessed by the use of "ImageJ" software program. Gingival and plaque indices were recorded at baseline and latest follow-up. CONCLUSION: The overall success rate of zirconia implants was 92%. Within the limitations of the present clinical evaluation, zirconia implants provided excellent clinical results and esthetic outcomes. A mean periimplant bone loss of 0.3 mm was measured in 33.3% of the implants and 66.7% were not affected by radiographic detectable periimplant bone loss. Two implants in two patients failed. Low gingival and plaque indices were predominant values for both interim and final restorations. The apparent less affinity to plaque accumulation may favor soft tissue health around zirconia dental implants and decrease the risk of inflammation or infection. Zirconia dental implant merits further investigation. CLINICAL SIGNIFICANCE: Zirconia dental implants are emerging as an option in clinical practice of implant dentistry providing stable clinical results and esthetic outcomes.

Sources of variability in quantifying circulating thymosin beta-4: literature review and recommendations.

INTRODUCTION: Thymosin beta-4 (TB4) is an endogenous peptide with protective and regenerative effects in models of cellular and organ injury. TB4 is increasingly measured as a potential plasma or serum biomarker in human cardiovascular, liver, infectious, and autoimmune disease. AREAS COVERED: The focus of this review is the quantification of TB4 in clinical cohort studies and whether reported TB4 concentrations differ with respect to method of sample preparation. We survey current literature for studies measuring TB4 in human serum or plasma and compare reported concentrations in healthy controls. EXPERT OPINION: We find substantial intra- and inter- study variability in healthy controls, and a lack of protocol standardization. We further highlight three factors that may confound TB4 clinical measurements and should be considered in future study design: 1) residual platelets remaining in suspension after centrifugation, 2) TB4 release following ex vivo platelet activation, and 3) specificity of assays towards posttranslational modifications. Accordingly, we put forth our recommendations to minimize residual and activated platelets during sample collection, and to cross-validate TB4 measurements using both antibody-based and mass spectrometry-based methods.