Interactions between the nitrate reductase 2 and catalase 1 fine-tune disease resistance in cassava.

Cassava is one of the most important tuber crops that is used for food, starch and bio-energy. However, cassava is susceptible to a number of diseases, especially cassava bacterial blight (CBB). Nitric oxide (NO) and hydrogen peroxide (H2O2) regulate plant growth and development, as well as stress responses. However, no direct relationships between the enzymes involved in the metabolic enzymes that produce and process these key signaling molecules has been demonstrated. Here, we provide evidence for the interaction between the nitrate reductase 2 (MeNR2) and catalase 1 (MeCAT1) proteins in vitro and in vivo, using yeast two-hybrid (Y2H) and bimolecular fluorescence complementation (BiFC) assays, respectively. MeNR2 is a positive regulator and MeCAT1 is a negative regulator of CBB resistance. MeNR2 was localized in the nucleus, cell membrane and peroxisome, while MeCAT1 was localized in the peroxisomes. The interactions between MeNR2 and MeCAT1 also had effects of their respective enzyme activities. Taken together, the data presented here suggested that there is coordination between H2O2 and NO signaling in cassava disease resistance, through the interactions between MeCAT1 and MeNR2.

Risk factors for initial and recurrent severe infections in first hospitalized patients with systemic lupus erythematosus: A retrospective study of a Chinese cohort.

OBJECTIVE: To evaluate the incidence and associated factors of initial and recurrent severe infections in hospitalized patients with systemic lupus erythematosus (SLE). METHODS: SLE patients that first hospitalized between 2010 and 2021 were studied retrospectively and divided into SLE with and without baseline severe infection groups. The primary outcome was the occurrence of severe infection during follow-up. Cox regression models were used to calculate the hazard ratio (HR) and 95% confidence interval (CI) for initial and recurrent severe infections. RESULTS: Among 1051 first hospitalized SLE patients, 164 (15.6%) had severe infection on admission. During a median follow-up of 4.1 years, 113 (10.8%) patients reached severe infection outcomes, including 27 with reinfection and 86 with initial severe infection (16.5% vs. 9.7%, p = .010). Patients with baseline severe infection had a higher cumulative incidence of reinfection (p = .007). After adjusting for confounding factors, renal involvement, elevated serum creatinine, hypoalbuminemia, cyclophosphamide, and mycophenolate mofetil treatment were associated with an increased risk of severe infection, especially initial severe infection. Low immunoglobulin, anti-dsDNA antibody positivity, and cyclophosphamide use significantly increased the risk of recurrent severe infection, with adjusted HR (95% CI) of 3.15 (1.22, 8.14), 3.60 (1.56, 8.28), and 2.14 (1.01, 5.76), respectively. Moreover, baseline severe infection and low immunoglobulin had a multiplicative interaction on reinfection, with adjusted RHR (95% CI) of 3.91 (1.27, 12.09). CONCLUSION: In this cohort of SLE, patients with severe infection had a higher risk of reinfection, and low immunoglobulin, anti-dsDNA antibody positivity, and cyclophosphamide use were independent risk factors for recurrent severe infection.

Causal association between helicobacter pylori and atherosclerosis: a two-sample Mendelian randomization.

BACKGROUND: Helicobacter pylori (H. pylori), according to a number of recent observational studies, is connected to atherosclerosis (AS). However, the link between H. pylori and AS is debatable. METHODS: In order to calculate the causal relationship between H. pylori and AS, we employed a two-sample Mendelian randomization (MR) analysis. The data for H. pylori were obtained from the IEU GWAS database ( https://gwas.mrcieu.ac.uk/datasets/ ) and the data for AS were obtained from the Finngen GWAS database ( https://r5.finngen.fi/ ). We selected single nucleotide polymorphisms with a threshold of 5 × 10-6 from earlier genome-wide association studies. MR was performed mainly using the inverse variance weighted (IVW) method. To ensure the reliability of the findings, We performed a leave-one-out sensitivity analysis to test for sensitivity. F-value was used to test weak instrument. RESULTS: A positive causal relationship between H. pylori OMP antibody levels and peripheral atherosclerosis was shown by our two-sample MR analysis (odds ratio (OR) = 1.33, 95% confidence interval (CI) = 1.14-1.54, P = 0.26E-03) using IVW. Additionally, there was a causative link between coronary atherosclerosis and H. pylori VacA antibody levels (IVW OR = 1.06, 95% CI = 1.01-1.10, P = 0.016). All the F-values were above 10. CONCLUSIONS: This MR study discovered a causal link between H. pylori and AS. Different antibodies have different effects, so future researches are needed to figure out the exact mechanisms behind this link.

An X Chromosome Transcriptome Wide Association Study Implicates ARMCX6 in Alzheimer's Disease.

Background: The X chromosome is often omitted in disease association studies despite containing thousands of genes that may provide insight into well-known sex differences in the risk of Alzheimer's disease (AD). Objective: To model the expression of X chromosome genes and evaluate their impact on AD risk in a sex-stratified manner. Methods: Using elastic net, we evaluated multiple modeling strategies in a set of 175 whole blood samples and 126 brain cortex samples, with whole genome sequencing and RNA-seq data. SNPs (MAF > 0.05) within the cis-regulatory window were used to train tissue-specific models of each gene. We apply the best models in both tissues to sex-stratified summary statistics from a meta-analysis of Alzheimer's Disease Genetics Consortium (ADGC) studies to identify AD-related genes on the X chromosome. Results: Across different model parameters, sample sex, and tissue types, we modeled the expression of 217 genes (95 genes in blood and 135 genes in brain cortex). The average model R2 was 0.12 (range from 0.03 to 0.34). We also compared sex-stratified and sex-combined models on the X chromosome. We further investigated genes that escaped X chromosome inactivation (XCI) to determine if their genetic regulation patterns were distinct. We found ten genes associated with AD at p < 0.05, with only ARMCX6 in female brain cortex (p = 0.008) nearing the significance threshold after adjusting for multiple testing (α = 0.002). Conclusions: We optimized the expression prediction of X chromosome genes, applied these models to sex-stratified AD GWAS summary statistics, and identified one putative AD risk gene, ARMCX6.

Mechanochemical synthesis of microscale zero-valent iron/N-doped graphene-like biochar composite for degradation of tetracycline via molecular O2 activation.

In this study, we prepared a micron zero-valent iron/N-doped graphene-like biochar (mZVI/NGB) composite using a mechanochemical method for tetracycline (TC) degradation through O2 activation. The mZVI and NGB components formed a strong coupling catalytic system, with mZVI acting as an electron pool and NGB as a catalyst for H2O2 generation. Under circumneutral pH (5.0-6.8), the mZVI/NGB composite exhibited exceptional TC removal efficiency, reaching nearly 100 % under optimal conditions. It also showed good tolerance to co-existing anions, such as Cl-, SO42-, and humic acid. Further studies found that the TC degradation mechanism was mainly ascribed to the non-radical pathway (1O2 and electron transfer), and the Fe2+/Fe3+ redox cycle on the composite's surface also played a crucial role in maintaining catalytic activity. This research contributes to the development of advanced materials for sustainable and effective water treatment, addressing pharmaceutical pollutant contamination in water sources.

Association between the dietary inflammatory index and pain in US adults from NHANES.

OBJECTIVES: The growing global burden of pain is gradually expanding from the medical field to public health. Dietary inflammatory potential correlates with inflammatory markers, and inflammation is one of the main mechanisms of pain. METHODS: This study explored the association between dietary inflammatory index (DII) and pain from the NHANES database on DII and pain (neck pain, low back pain, joint pain, and headache or migraine) using logistic regression and stratified analysis. RESULTS: The results show a stronger association between DII and joint pain (Q4 of DII adjusted-OR = 1.23, 95% CI = 1.08-1.40, P = 0.003) and headache or migraine (Q4 of DII adjusted-OR = 1.31, 95% CI = 1.15-1.48, P < 0.001), but no association is found in neck pain (Q4 of DII adjusted-OR = 1.03, 95% CI = 0.89-1.20, P = 0.65) and low back pain (Q4 of DII adjusted-OR = 1.04, 95% CI = 0.92-1.17, P = 0.54). After stratifying the data according to demographics, differences in the relationship between DII and pain are found at different levels of the population. DISCUSSION: This study identifies high DII as a risk factor for joint pain and headache or migraine.

Design and Discovery of Water-Soluble Benzooxaphosphole-Based Ligands for Hindered Suzuki-Miyaura Coupling Reactions with Low Catalyst Load.

We report a new class of highly effective, benzooxaphosphole-based, water-soluble ligands in the application of Suzuki-Miyaura cross-coupling reactions for sterically hindered substrates in aqueous media. The catalytic activities of the coupling reactions were greatly enhanced by the addition of catalytic amounts of organic phase transfer reagents, such as tetraglyme and tetrabutylammonium bromide. The optimized general protocol can be conducted with a low catalyst load, thereby providing a practical solution for these reactions. The viability of this new Suzuki-Miyaura protocol was demonstrated with various substrates to generate important building blocks, including heterocycles, for the synthesis of biologically active compounds.

Tannic acid modified microscale zero valent iron (TA-mZVI) with enhanced anti-passivation capability for Cr(VI) removal.

The removal of Cr(VI) from aqueous solutions using microscale zerovalent iron (mZVI) shows promising potential. However, the surface passivation of mZVI particles hinders its widespread application. In this study, we prepared tannic acid (TA) modified mZVI composite (TA-mZVI) by a simple sonication method. The introduction of TA allowing TA-mZVI composite to adsorb Cr(VI) rapidly under electrostatic forces attraction, guarantying TA-mZVI exhibited remarkable Cr(VI) removal capacity with a maximum adsorption capacity of 106.1 mg⋅g-1. At an initial pH of 3, it achieved a rapid removal efficiency of 96.2% within just 5 min, which was 7.7 times higher than that of mZVI. Various characterizations, including XPS and CV analysis, indicated that the formation of TA-Fe complexes accelerates electron transfer. In addition, TA endows functional groups to TA-mZVI, raising the dispersion and stability and serves as a protective layer hindering passivation. Further mechanistic analysis revealed that Cr(VI) removal by TA-mZVI followed an adsorption-reduction-precipitation mechanism, with TA mitigating the surface passivation of mZVI and facilitating the reduction of most Cr(VI) to Cr(III). Batch cyclic experiments revealed that TA-mZVI exhibited satisfactory performance, maintaining over 85% Cr(VI) removal even after five cycles and minimally affected by various coexisting ions. With notable advantages in cost-effectiveness, ease-synthesis and recovery, this work provides a great promise for developing efficient reactive adsorbent for addressing Cr(VI) contamination in aqueous solutions.

Factors associated with 25-hydroxyvitamin D level in Chinese hospitalized patients with systemic lupus erythematosus: a retrospective cohort study.

We aimed to investigate the factors associated with vitamin D deficiency and changes in 25 (OH)D levels, as well as the impact of those changes on disease activity and renal function among SLE patients. This retrospective cohort study was based on the medical records of SLE patients hospitalized between 2010 and 2021. We collected relevant information from this patient population. Logistic regression analysis was employed to determine the factors associated with vitamin D deficiency and increased 25 (OH)D levels, and we calculated the odds ratios (ORs) and 95% confidence intervals (CIs) accordingly. At baseline, among the 1257 SLE patients, the median and interquartile range of 25 (OH)D levels were 14 (9, 20) ng/ml, with 953 (75.8%) patients exhibiting 25 (OH)D deficiency (< 20 ng/ml). The presence of 25 (OH)D deficiency was found to be associated with renal involvement and a high glucocorticoid (GC) maintenance dose. Among the 383 patients who were followed up for an average of 18 months, an increase of at least 100% in 25 (OH)D levels was positively associated with a decreased GC maintenance dose and vitamin D3 supplementation, with adjusted odds ratios(OR) (95% confidence interval [CI]) of 2.16 (1.02, 4.59) and 1300 (70, 22300), respectively. Furthermore, an increased level of 25 (OH)D was significantly associated with a decrease in the Disease Activity Index 2000 score and the urinary protein/creatinine ratio. Patients with SLE have low vitamin D levels, especially those with impaired kidney function. Increased 25 (OH)D levels can be achieved through supplementation with high doses of vitamin D3 and are associated with improvements in disease activity and the urinary protein/creatinine ratio.

Association Between Mycophenolate Mofetil Use and Subsequent Infections Among Hospitalized Patients with Systemic Lupus Erythematosus: A Nested Case-Control Study.

INTRODUCTION: The association between mycophenolate mofetil (MMF) and infection in patients with systemic lupus erythematosus (SLE) has not been clarified. This study evaluated the degree and factors in effect of MMF use on infection in patients with SLE. METHODS: A hospitalized-based observational study was conducted to collect medical records on patients with SLE during 2010-2021. A nested case-control study was performed among 3339 patients with SLE, including 1577 cases and 1762 controls by whether they developed any type of infection. The exposure of MMF use was determined within 1 year before diagnosed infection or the end of follow-up. Logistic regression was used to estimate the odds ratio (OR) and 95% confidence interval (CI) for association between MMF and subsequent infection. RESULTS: MMF was significantly associated with the risk of overall infection (adjusted OR 1.90, 95% CI 1.48-2.44) and different types of infections, including bacterial infection (adjusted OR 2.07, 95% CI 1.55-2.75), viral infection (adjusted OR 1.92, 95% CI 1.23-3.01), and opportunistic infection (adjusted OR 2.13, 95% CI 1.31-3.46). The top three risks of specific types of infections were bacteremia/septicemia, urinary tract infection/pyelonephritis, and herpes zoster. Stratification analysis showed risk of overall infection increased especially in MMF users with age over 55 years, diabetes, central nervous system involvement, and thrombocytopenia. Moreover, the risk of infection increased with increasing dosage and duration of MMF use. Additionally, the combination of MMF with CYC and other immunosuppressants significantly increases the risk of infections compared to using a single one. CONCLUSIONS: MMF use is associated with various type of infections in patients with SLE, particularly in those with longer use, older age, complications with comorbidities, and concomitant use of CYC or other immunosuppressants.

Aqueous Stability of Metal-Organic Frameworks Using ReaxFF-Based Metadynamics Simulations.

Aqueous stability is a critical property for the application of metal-organic framework (MOF) materials in humid conditions. The sampling of the free energy surface for a water reaction is challenging due to a lack of a reactive force field. Here, we developed a ReaxFF force field for simulating the reaction of zeolitic imidazole frameworks (ZIFs) with water. We carried out metadynamics simulations based on ReaxFF to study the reaction of water with a few different types of MOFs. We also conducted an experimental water immersion test and characterized the XRD, TG, and gas adsorption properties of the MOFs before and after the immersion test. By considering the energy barrier for a hydrolysis reaction, the simulation results are in good agreement with the experiments. MOFs with open structures and large pores are found to be unstable in metadynamics simulations, where the water molecule can attack or bond with the metallic node relatively easily. In contrast, it is more difficult for water to attack the Zn atom in the ZnN4 tetrahedral structure of ZIFs. We also found that ZIFs with the -NO2 functional groups have higher water stability. Discrepancies between the metadynamics simulation and gas adsorption experiments have been accounted for from the phase/crystallinity change of the structure reflected in the X-ray diffraction and thermogravimetry analysis of the MOF samples.

An overview of 3D printed metal implants in orthopedic applications: Present and future perspectives.

With the ability to produce components with complex and precise structures, additive manufacturing or 3D printing techniques are now widely applied in both industry and consumer markets. The emergence of tissue engineering has facilitated the application of 3D printing in the field of biomedical implants. 3D printed implants with proper structural design can not only eliminate the stress shielding effect but also improve in vivo biocompatibility and functionality. By combining medical images derived from technologies such as X-ray scanning, CT, MRI, or ultrasonic scanning, 3D printing can be used to create patient-specific implants with almost the same anatomical structures as the injured tissues. Numerous clinical trials have already been conducted with customized implants. However, the limited availability of raw materials for printing and a lack of guidance from related regulations or laws may impede the development of 3D printing in medical implants. This review provides information on the current state of 3D printing techniques in orthopedic implant applications. The current challenges and future perspectives are also included.

Allogenic Umbilical Cord-Derived Mesenchymal Stromal Cells Sustain Long-Term Therapeutic Efficacy Compared With Low-Dose Interleukin-2 in Systemic Lupus Erythematosus.

OBJECTIVES: Mesenchymal stromal cells (MSCs) and low-dose interleukin-2 (IL-2) both have demonstrated efficacy in treating systemic lupus erythematosus (SLE). The aim of this study is to conduct a head-to-head comparison between the 2 treatments and provide insights for clinical applications. METHODS: Lupus-prone mice were treated with umbilical cord-derived MSCs (UC-MSCs), IL-2, or a combination of UC-MSCs and IL-2, respectively. The lupus-like symptoms, renal pathology, and T-cell response were assessed 1 or 4 weeks later. Modulation of IL-2 production by MSCs on immune cells was investigated by the coculture assay. Disease activity and serum IL-2 of SLE patients were determined before and after receiving UC-MSCs. RESULTS: Both UC-MSCs and IL-2 improved lupus symptoms in lupus-prone mice 1 week after treatment, while the effects of UC-MSCs lasted up to 4 weeks. Moreover, the UC-MSC-treated group showed better renal pathology improvement. Importantly, UC-MSCs combined with IL-2 did not provide better efficacy than UC-MSCs alone. Consistent with this, UC-MSCs alone and UC-MSCs + IL-2 resulted in similar levels of serum IL-2 and frequencies of Tregs. Neutralization of IL-2 partly reduced the promotion of Tregs by UC-MSCs, suggesting that IL-2 was involved in the upregulation of Tregs by UC-MSCs. Lastly, an increase in serum IL-2 positively correlated with the reduction of disease activity of SLE patients by UC-MSCs. CONCLUSION: Both the single injection of UC-MSCs and repeated IL-2 administration exerted comparable efficacy in alleviating SLE manifestations, but UC-MSCs provided sustained alleviation and showed better improvement in renal pathology.

An X Chromosome Transcriptome Wide Association Study Implicates ARMCX6 in Alzheimer's Disease.

Background: The X chromosome is often omitted in disease association studies despite containing thousands of genes which may provide insight into well-known sex differences in the risk of Alzheimer's Disease. Objective: To model the expression of X chromosome genes and evaluate their impact on Alzheimer's Disease risk in a sex-stratified manner. Methods: Using elastic net, we evaluated multiple modeling strategies in a set of 175 whole blood samples and 126 brain cortex samples, with whole genome sequencing and RNA-seq data. SNPs (MAF>0.05) within the cis-regulatory window were used to train tissue-specific models of each gene. We apply the best models in both tissues to sex-stratified summary statistics from a meta-analysis of Alzheimer's disease Genetics Consortium (ADGC) studies to identify AD-related genes on the X chromosome. Results: Across different model parameters, sample sex, and tissue types, we modeled the expression of 217 genes (95 genes in blood and 135 genes in brain cortex). The average model R2 was 0.12 (range from 0.03 to 0.34). We also compared sex-stratified and sex-combined models on the X chromosome. We further investigated genes that escaped X chromosome inactivation (XCI) to determine if their genetic regulation patterns were distinct. We found ten genes associated with AD at p 0.05, with only ARMCX6 in female brain cortex (p = 0.008) nearing the significance threshold after adjusting for multiple testing (α = 0.002). Conclusions: We optimized the expression prediction of X chromosome genes, applied these models to sex-stratified AD GWAS summary statistics, and identified one putative AD risk gene, ARMCX6.

Indoor Volatile Organic Compounds: Concentration Characteristics and Health Risk Analysis on a University Campus.

Volatile organic compounds (VOCs) are major indoor air pollutants that contain several toxic substances. However, there are few studies on health risk assessments of indoor VOCs in China. This study aimed to determine the concentration characteristics of VOCs on college campuses by collecting VOC samples from different locations on campus during different seasons combined with the exposure times of college students in each location obtained from a questionnaire survey to assess the possible health risks. The highest total VOC concentration (254 ± 101 µg/m3) was in the dormitory. The seasonal variation of TVOC concentrations was related to the variation of emission sources in addition to temperature. Health risk assessments of VOCs were evaluated using non-carcinogenic and carcinogenic risk values, represented by hazard quotient (HQ) and lifetime cancer risk (LCR), respectively. The non-carcinogenic risks at all sampling sites were within the safe range (HQ < 1). Dormitories had the highest carcinogenic risk, whereas the carcinogenic risk in the other three places was low (with LCR < 1.0 × 10-6). Moreover, 1,2-dichloroethane was identified as a possible carcinogenic risk substance in the dormitory due to its high LCR (1.95 × 10-6). This study provides basic data on health risks in different locations on campus and a basis for formulating measures to improve people's living environments.

Impact of α-tocopherol and EGCG on the oxidative stability of margarine: Exploring the possible synergistic effect mechanism.

Margarine is a typical water-in-oil (W/O) emulsion fat product. Due to the presence of a water-oil interface, the oil oxidation in the emulsion system is the interface reaction, which is much faster than that in bulk oil and shows different oxidation mechanisms. The analysis of Rancimat and electron spin resonance indicated that α-tocopherol and EGCG show synergistic antioxidant effects in the margarine. After 20 days of accelerated oxidation storage, the antioxidant effect of the compound antioxidant (50 mg/kg α-tocopherol + 350 mg/kg EGCG) on the margarine was significantly higher than that of the single antioxidant α-tocopherol and EGCG. Based on the results of antioxidants partitioning, electrochemistry, fluorescence spectroscopy, and the oxidative decomposition of antioxidants, the possible mechanisms of interaction were the promotion of α-tocopherol regeneration by EGCG, and the fact that α-tocopherol and EGCG could act at different stages and positions of oxidation. This work will contribute to studying antioxidant interactions and can provide valuable suggestions for practical production. PRACTICAL APPLICATION: This study aims to improve the oxidative stability of margarine by adding α-tocopherol and epigallocatechin-gallate (EGCG) individually and in blends. The mechanism of compound antioxidant synergistic inhibition of margarine oxidation was analyzed, providing theoretical basis and scientific basis for the research and practical application of natural antioxidant synergistic mechanism.

Alerting trends in epidemiology for calcific aortic valve disease, 1990-2019: An age-period-cohort analysis for the Global Burden of Disease Study 2019.

AIMS: To assess the trends in calcific aortic valve disease (CAVD) epidemiology, with an emphasis on CAVD mortality, leading risk factors, and their associations with age, period, and birth cohort. METHODS AND RESULTS: Prevalence, disability-adjusted life years, and mortality were derived from the Global Burden of Disease Study 2019. The age-period-cohort model was employed to study the detailed trends of CAVD mortality and its leading risk factors. Globally, CAVD showed unsatisfactory results from 1990 to 2019, with the CAVD deaths of 127 000 in 2019. CAVD mortality was substantially reduced in high socio-demographic index (SDI) countries [-1.45%, 95% confidence interval (CI) (-1.61 to -1.30)], mildly increased in high-middle SDI countries [0.22%, 95% CI (0.06-0.37)], and unchanged in other SDI quintiles. There was a noticeable transition in CAVD deaths from younger to older populations globally. The CAVD mortality increased exponentially with age, and the male had higher mortality than the female before 80 years old. Favourable period [0.69, 95% CI (0.66-0.72)] and birth effects [0.30, 95% CI (0.22-0.43)] were mainly observed in high SDI countries, while unfavourable effects were mostly noticed in high-middle SDI countries. High systolic blood pressure was the leading risk factor of CAVD deaths globally, and it showed favourable trends in high SDI regions. CONCLUSION: Although CAVD mortality reduction was observed globally, unfavourable period, and cohort effects were found in many countries. Increase of mortality rate among the population ≥85 years was the common challenge across all SDI quintiles, stressing the necessity to further improve health care for CAVD patients worldwide.

Optimization Modeling of Anti - breast Cancer Candidate Drugs.

To explore how to control the estrogen level in vivo by regulating the activity of the estrogen receptor in the development of breast cancer drugs, multiple-featured evaluation methods were first applied to screen the molecular descriptors of compounds according to the information of antagonist ERα provided in this study. Combining the methods of Extreme Gradient Boost (XGBoost), Light Gradient Boosting Machine (LightGBM) and Random Forest (RF), a stacking-integrated regression model for quantitatively predicting the ERα (estrogen receptors alpha) activity of breast cancer candidate drug was constructed, which considered the compounds acting on the target and their biological activity data, a series of molecular structure descriptors as the independent variables, and the biological activity values as the dependent variables. Then, three classification methods of XGBoost, LightGBM, and Gradient Boosting Decision Tree (GBDT) were selected and the voting strategy was applied to build five ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) classification prediction models. Finally, two schemes based on genetic algorithm (GA) were used to optimize the model and provide predictions for optimizing the biological activity and ADMET properties of ERα antagonists simultaneously. Results showed that the model prediction has strong practical significance, which can guide the structural optimization of existing active compounds and improve the activity of anti-breast cancer candidate drugs.

Pharmacogenomic and Statistical Analysis.

Genetic variants can alter response to drugs and other therapeutic interventions. The study of this phenomenon, called pharmacogenomics, is similar in many ways to other types of genetic studies but has distinct methodological and statistical considerations. Genetic variants involved in the processing of exogenous compounds exhibit great diversity and complexity, and the phenotypes studied in pharmacogenomics are also more complex than typical genetic studies. In this chapter, we review basic concepts in pharmacogenomic study designs, data generation techniques, statistical analysis approaches, and commonly used methods and briefly discuss the ultimate translation of findings to clinical care.

CD56brightCD16- to CD57+CD56dimCD16+ NK cell ratio discriminates disease activity and renal involvement in patients with systemic lupus erythematosus.

OBJECTIVES: We aimed to discriminate subpopulations of peripheral natural killer (NK) cells of patients with systemic lupus erythematosus (SLE) and evaluate their usability in monitoring disease activity. METHODS: The total number of NK cells and their subpopulations were determined by flow cytometry in 68 patients with SLE and 35 healthy controls. Clinical data were extracted from medical records, including serum anti-double-stranded-DNA (anti-dsDNA), complement C3 and C4, and urine protein. Disease activity in patients with SLE was assessed using the SLE Disease Activity Index-2000 (SLEDAI-2K). RESULTS: The percentages and absolute numbers of NK cells decreased, and the proportions of three major NK cell subsets defined by cell maturation status altered in SLE patients. The frequency of CD56brightCD16- NK (immature, Im NK) cells increased, while that of the CD57+CD56dimCD16- subset (mature, more differentiated, MD NK) decreased in patients with high-activity SLE, resulting in a significant increase in the Im NK-to-MD NK ratio as compared with that in patients with low-activity SLE. The area under the receiver operating characteristic curve indicated that the ratio was 0.722 in severe SLE and 0.773 in lupus nephritis, with optimal cut-off levels of 0.075 and 0.108, respectively. The ratio correlated positively with the SLEDAI-2K score, proteinuria, and serum anti-dsDNA antibody levels but negatively with C3 and C4 levels. CONCLUSIONS: Our data indicate that the imbalance in Im NK and MD NK cells may play a role in lupus development and serve as a predictive biomarker to assess disease activity and renal involvement in patients with SLE.