Relating Lipoprotein(a) Concentrations to Cardiovascular Event Risk After Acute Coronary Syndrome: A Comparison of 3 Tests.

BACKGROUND: Lipoprotein(a) is a risk factor for cardiovascular events and modifies the benefit of PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors. Lipoprotein(a) concentration can be measured with immunoassays reporting mass or molar concentration or a reference measurement system using mass spectrometry. Whether the relationships between lipoprotein(a) concentrations and cardiovascular events in a high-risk cohort differ across lipoprotein(a) methods is unknown. We compared the prognostic and predictive value of these types of lipoprotein(a) tests for major adverse cardiovascular events (MACE). METHODS: The ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) compared the PCSK9 inhibitor alirocumab with placebo in patients with recent acute coronary syndrome. We compared risk of a MACE in the placebo group and MACE risk reduction with alirocumab according to baseline lipoprotein(a) concentration measured by Siemens N-latex nephelometric immunoassay (IA-mass; mg/dL), Roche Tina-Quant turbidimetric immunoassay (IA-molar; nmol/L), and a noncommercial mass spectrometry-based test (MS; nmol/L). Lipoprotein(a) values were transformed into percentiles for comparative modeling. Natural cubic splines estimated continuous relationships between baseline lipoprotein(a) and outcomes in each treatment group. Event rates were also determined across baseline lipoprotein(a) quartiles defined by each assay. RESULTS: Among 11 970 trial participants with results from all 3 tests, baseline median (Q1, Q3) lipoprotein(a) concentrations were 21.8 (6.9, 60.0) mg/dL, 45.0 (13.2, 153.8) nmol/L, and 42.2 (14.3, 143.1) nmol/L for IA-mass, IA-molar, and MS, respectively. The strongest correlation was between IA-molar and MS (r=0.990), with nominally weaker correlations between IA-mass and MS (r=0.967) and IA-mass and IA-molar (r=0.972). Relationships of lipoprotein(a) with MACE risk in the placebo group were nearly identical with each test, with estimated cumulative incidences differing by ≤0.4% across lipoprotein(a) percentiles, and all were incrementally prognostic after accounting for low-density lipoprotein cholesterol levels (all spline P≤0.0003). Predicted alirocumab treatment effects were also nearly identical for each of the 3 tests, with estimated treatment hazard ratios differing by ≤0.07 between tests across percentiles and nominally less relative risk reduction by alirocumab at lower percentiles for all 3 tests. Absolute risk reduction with alirocumab increased with increasing lipoprotein(a) measured by each test, with significant linear trends across quartiles. CONCLUSIONS: In patients with recent acute coronary syndrome, 3 lipoprotein(a) tests were similarly prognostic for MACE in the placebo group and predictive of MACE reductions with alirocumab at the cohort level. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01663402.

Consensus document for lipid profile determination and reporting in Spanish clinical laboratories. What parameters should be included in a basic lipid profile?

Cardiovascular diseases (CVD) continue to be the main cause of death in our country. Adequate control of lipid metabolism disorders is a key challenge in cardiovascular prevention that is far from being achieved in real clinical practice. There is a great heterogeneity in the reports of lipid metabolism from Spanish clinical laboratories, which may contribute to its poor control. For this reason, a working group of the main scientific societies involved in the care of patients at vascular risk, has prepared this document with a consensus proposal on the determination of the basic lipid profile in cardiovascular prevention, recommendations for its realization and unification of criteria to incorporate the lipid control goals appropriate to the vascular risk of the patients in the laboratory reports.

Un caso de hipocolesterolemia a estudio / A case of hypocholesterolemia under study

Las hipocolesterolemias primarias (o hipobetalipoproteinemias) constituyen un trastorno infrecuente del metabolismo de las lipoproteínas que pueden obedecer a una predisposición poligénica o a una enfermedad monogénica. Entre estas, es posible diferenciar entre formas sintomáticas y asintomáticas, en las que, en ausencia de causas secundarias, la sospecha clínica inicial son concentraciones plasmáticas de ApoB por debajo del percentil 5 de la distribución por edad y sexo. En esta nota clínica describimos del diagnóstico diferencial de un caso de hipocolesterolemia asintomática. Estudiamos los datos clínicos de la paciente índice, así como su perfil lipídico y el de los familiares junto con los datos clínicos de estos que son relevantes para realizar el diagnóstico diferencial. Se realizó un estudio genético como prueba diagnóstica. El diagnóstico diferencial realizado sugirió una hipobetalipoproteinemia heterocigota por variantes de pérdida de función en PCSK9. La prueba diagnóstica puso de manifiesto, en la paciente índice, la presencia de una variante de cambio de pauta de lectura en PCSK9, en heterocigosis, de origen materno. Las concentraciones plasmáticas de colesterol de LDL y PCSK9 de la paciente y los familiares, fueron compatibles con la segregación de dicha variante. En conclusión, la prueba diagnóstica realizada permitió confirmar el diagnóstico de sospecha en el caso estudiado de hipobetalipoproteinemia familiar asintomática a causa de una variante de pérdida de función en el gen PCSK9. (AU)

Primary hypocholesterolemia (or hypobetalipoproteinemia) is a rare disorder of lipoprotein metabolism that may be due to a polygenic predisposition or a monogenic disease. Among these, it is possible to differentiate between symptomatic and asymptomatic forms, in which, in the absence of secondary causes, the initial clinical suspicion is plasma ApoB levels below the 5th percentile of the distribution by age and sex. Here we describe the differential diagnosis of a case of asymptomatic hypocholesterolemia. We studied proband's clinical data, the lipid profile of the proband and her relatives and the clinical data of the family relevant to carry out the differential diagnosis. We performed a genetic study as the diagnostic test. The information obtained from the differential diagnosis suggested a heterozygous hypobetalipoproteinemia due to PCSK9 loss-of-function variants. The diagnostic test revealed, in the proband, the presence of a heterozygous PCSK9 frame-shift variant of a maternal origin. Plasma levels of LDL cholesterol and PCSK9 of the patient and her relatives were compatible with the segregation of the variant revealed. In conclusion, the diagnostic test performed confirmed the suspected diagnosis of the proband as asymptomatic familial hypobetalipoproteinemia due to a loss-of-function variant in the PCSK9 gene. (AU)

Assessment of Apolipoprotein(a) Isoform Size Using Phenotypic and Genotypic Methods.

Apolipoprotein(a) (apo(a)) is the protein component that defines lipoprotein(a) (Lp(a)) particles and is encoded by the LPA gene. The apo(a) is extremely heterogeneous in size due to the copy number variations in the kringle-IV type 2 (KIV2) domains. In this review, we aim to discuss the role of genetics in establishing Lp(a) as a risk factor for coronary heart disease (CHD) by examining a series of molecular biology techniques aimed at identifying the best strategy for a possible application in clinical research and practice, according to the current gold standard.

Documento de consenso para la determinación e informe del perfil lipídico en laboratorios clínicos españoles / Consensus document for lipid profile determination and reporting in Spanish clinical laboratories. What parameters should be included in a basic lipid profile?

Las enfermedades cardiovasculares (ECV) siguen siendo la principal causa de muerte en nuestro país. El control adecuado de las alteraciones del metabolismo lipídico es un reto clave en prevención cardiovascular que está lejos de alcanzarse en la práctica clínica real. Existe una gran heterogeneidad en los informes del metabolismo lipídico de los laboratorios clínicos españoles, lo que puede contribuir al mal control del mismo. Por ello, un grupo de trabajo de las principales sociedades científicas implicadas en la atención de los pacientes de riesgo vascular hemos elaborado este documento con una propuesta básica de consenso sobre la determinación del perfil lipídico básico en prevención cardiovascular, recomendaciones para su realización y unificación de criterios para incorporar los objetivos de control lipídico adecuados al riesgo vascular de los pacientes en los informes de laboratorio (AU)

Cardiovascular diseases (CVD) continue to be the main cause of death in our country. Adequate control of lipid metabolism disorders is a key challenge in cardiovascular prevention that is far from being achieved in real clinical practice. There is a great heterogeneity in the reports of lipid metabolism from Spanish clinical laboratories, which may contribute to its poor control. For this reason, a working group of the main scientific societies involved in the care of patients at vascular risk, has prepared this document with a consensus proposal on the determination of the basic lipid profile in cardiovascular prevention, recommendations for its realization and unification of criteria to incorporate the lipid control goals appropriate to the vascular risk of the patients in the laboratory reports (AU)

Documento de consenso para la determinación e informe del perfil lipídico en laboratorios clínicos españoles / Consensus document for lipid profile determination and reporting in Spanish clinical laboratories. What parameters should be included in a basic lipid profile?

Las enfermedades cardiovasculares (ECV) siguen siendo la principal causa de muerte en nuestro país. El control adecuado de las alteraciones del metabolismo lipídico es un reto clave en prevención cardiovascular que está lejos de alcanzarse en la práctica clínica real. Existe una gran heterogeneidad en los informes del metabolismo lipídico de los laboratorios clínicos españoles, lo que puede contribuir al mal control del mismo. Por ello, un grupo de trabajo de las principales sociedades científicas implicadas en la atención de los pacientes de riesgo vascular hemos elaborado este documento con una propuesta básica de consenso sobre la determinación del perfil lipídico básico en prevención cardiovascular, recomendaciones para su realización y unificación de criterios para incorporar los objetivos de control lipídico adecuados al riesgo vascular de los pacientes en los informes de laboratorio. (AU)

Cardiovascular diseases (CVD) continue to be the main cause of death in our country. Adequate control of lipid metabolism disorders is a key challenge in cardiovascular prevention that is far from being achieved in real clinical practice. There is a great heterogeneity in the reports of lipid metabolism from Spanish clinical laboratories, which may contribute to its poor control. For this reason, a working group of the main scientific societies involved in the care of patients at vascular risk, has prepared this document with a consensus proposal on the determination of the basic lipid profile in cardiovascular prevention, recommendations for its realization and unification of criteria to incorporate the lipid control goals appropriate to the vascular risk of the patients in the laboratory reports. (AU)

Associations of Serum Apolipoprotein A1 and High Density Lipoprotein Cholesterol With Glucose Level in Patients With Coronary Artery Disease.

This study determined the associations of apolipoprotein A1 (ApoA1), high-density lipoprotein cholesterol (HDL-C), and HDL-C/ApoA1 ratio with fasting blood glucose (FBG) and evaluated the mediating effects of high-sensitivity C-reactive protein (hsCRP) and body mass index (BMI). A cross-sectional study with 4805 coronary artery disease (CAD) patients was performed. In multivariable analyses, higher ApoA1, HDL-C, and HDL-C/ApoA1 ratio were associated with significantly lower FBG level (Q [quartile] 4 vs Q1: 5.67 vs 5.87 mmol/L for ApoA1; 5.64 vs 5.98 mmol/L for HDL-C; 5.63 vs 6.01 mmol/L for HDL-C/ApoA1 ratio). Moreover, inverse associations of ApoA1, HDL-C, and HDL-C/ApoA1 ratio with abnormal FBG (AFBG) were found with odd ratios (95% confidence interval) of .83 (.70-.98), .60 (.50-.71), and .53 (.45-.64) in Q4 compared with Q1. Path analyses indicated that "ApoA1 (or HDL-C)-FBG" associations were mediated by hsCRP and "HDL-C-FBG" association was mediated by BMI. Our data suggested that higher ApoA1, HDL-C, and HDL-C/ApoA1 ratio were favorably associated with a lower FBG level in CAD patients and these associations might be mediated by hsCRP or BMI. Collectively, higher concentrations of ApoA1, HDL-C, and HDL-C/ApoA1 ratio might decrease the risk of AFBG.

Associations of apolipoproteinA1, high density lipoprotein cholesterol with hemoglobin glycation index and triglyceride-glucose index in Chinese adults with coronary artery disease.

AIMS: Scarce data explored the associations of apolipoproteins with hemoglobin glycation index (HGI) and triglyceride-glucose (TyG) index. This study determined associations of serum apolipoproteinA1 (ApoA1) and high density lipoprotein cholesterol (HDL-C) with HGI and TyG index in coronary artery disease (CAD) patients. METHODS: A total of 10,803 CAD patients were included in this cross-sectional pilot study. Serum concentrations of ApoA1 and HDL-C were measured. Analyses of covariance were used to compare the mean differences in glucose metabolism indices (e.g., HGI, TyG index, hemoglobin glycation [HbA1c], fasting blood glucose [FBG]) among the quartiles of ApoA1, HDL-C and HDL-C/ApoA1 ratio. RESULTS: In multivariate analysis, higher ApoA1, HDL-C and HDL-C/ApoA1 ratio were associated with significantly lower HGI (Quartile [Q]4 vs. Q1: -0.032 % vs. 0.017 % for ApoA1; -0.072 % vs. 0.079 % for HDL-C; -0.083 % vs. 0.085 % for HDL-C/ApoA1 ratio). Intermediate ApoA1 level was inversely associated with TyG index (Q2 vs. Q1: 296.278 vs. 306.794). The mean TyG index were significantly decreased with increased HDL-C and HDL-C/ApoA1 ratio (Q4 vs. Q1: 298.584 vs. 309.221 for HDL-C; 300.405 vs. 315.218 for HDL-C/ApoA1 ratio). Moreover, the inverse associations of ApoA1, HDL-C and HDL-C/ApoA1 ratio with HbA1c and FBG also were observed. In path analysis, the associations of HDL-C and HDL-C/ApoA1 ratio with TyG index were mediated by obesity. CONCLUSION: This study provided further support for the hypoglycemic effects of ApoA1 and HDL-C in patients with CAD. Replication of these findings is warranted in further longitudinal studies in different populations.

Consensus document for lipid profile testing and reporting in Spanish clinical laboratories.

Cardiovascular diseases (CVD) continue to be the main cause of death in our country. Adequate control of lipid metabolism disorders is a key challenge in cardiovascular prevention that is far from being achieved in real clinical practice. There is a great heterogeneity in the reports of lipid metabolism from Spanish clinical laboratories, which may contribute to its poor control. For this reason, a working group of the main scientific societies involved in the care of patients at vascular risk, has prepared this document with a consensus proposal on the determination of the basic lipid profile in cardiovascular prevention, recommendations for its realization and unification of criteria to incorporate the lipid control goals appropriate to the vascular risk of the patients in the laboratory reports.

Consensus document for lipid profile testing and reporting in Spanish clinical laboratories: What parameters should a basic lipid profile include?

Cardiovascular diseases (CVD) continue to be the main cause of death in our country. Adequate control of lipid metabolism disorders is a key challenge in cardiovascular prevention that is far from being achieved in real clinical practice. There is a great heterogeneity in the reports of lipid metabolism from Spanish clinical laboratories, which may contribute to its poor control. For this reason, a working group of the main scientific societies involved in the care of patients at vascular risk, has prepared this document with a consensus proposal on the determination of the basic lipid profile in cardiovascular prevention, recommendations for its realization and unification of criteria to incorporate the lipid control goals appropriate to the vascular risk of the patients in the laboratory reports.

A case of hypocholesterolemia under study. / Un caso de hipocolesterolemia a estudio.

Primary hypocholesterolemia (or hypobetalipoproteinemia) is a rare disorder of lipoprotein metabolism that may be due to a polygenic predisposition or a monogenic disease. Among these, it is possible to differentiate between symptomatic and asymptomatic forms, in which, in the absence of secondary causes, the initial clinical suspicion is plasma ApoB levels below the 5th percentile of the distribution by age and sex. Here we describe the differential diagnosis of a case of asymptomatic hypocholesterolemia. We studied proband's clinical data, the lipid profile of the proband and her relatives and the clinical data of the family relevant to carry out the differential diagnosis. We performed a genetic study as the diagnostic test. The information obtained from the differential diagnosis suggested a heterozygous hypobetalipoproteinemia due to PCSK9 loss-of-function variants. The diagnostic test revealed, in the proband, the presence of a heterozygous PCSK9 frame-shift variant of a maternal origin. Plasma levels of LDL cholesterol and PCSK9 of the patient and her relatives were compatible with the segregation of the variant revealed. In conclusion, the diagnostic test performed confirmed the suspected diagnosis of the proband as asymptomatic familial hypobetalipoproteinemia due to a loss-of-function variant in the PCSK9 gene.

Lipoprotein(a): cardiovascular risk and emerging therapies.

INTRODUCTION: There is abundant evidence that elevated lipoprotein(a) [LP(a)] associates with cardiovascular risk. Most lipid modifying therapies don't reduce Lp(a), but new technologies are emerging that act upstream, such as antisense oligonucleotides (ASO) and small interfering RNAs (siRNAs) that inhibit the translation of mRNA for proteins specifically involved in lipid metabolism. AREAS COVERED: Despite the benefit of therapies for the prevention of atherosclerotic cardiovascular disease (ASCVD), Lp(a) is one of the 'residual risks,' established by observational and Mendelian randomization studies. Although current established lipid modifying therapies targeting low-density-lipoprotein cholesterol, such as statins and ezetimibe, do not lower Lp(a), ASOs and siRNAs demonstrated significant reduction of Lp(a) by -98 to -101% in recent clinical trials. However, we still don't know if specifically lowering Lp(a) reduced cardiovascular events, how much Lp(a) lowering is required to produce clinical benefit, and whether diabetes and inflammation have any impact. This review summarizes Lp(a), the knowns and unknowns about Lp(a), and focus emerging treatments. EXPERT OPINION: New Lp(a) lowering therapies have the potential to contribute to the personalized prevention of ASCVD.

Apolipoprotein†E Recognizes Alzheimer's Disease Associated 3-O Sulfation of Heparan Sulfate.

Apolipoprotein E (ApoE)'s ϵ4 alle is the most important genetic risk factor for late onset Alzheimer's Disease (AD). Cell-surface heparan sulfate (HS) is a cofactor for ApoE/LRP1 interaction and the prion-like spread of tau pathology between cells. 3-O-sulfo (3-O-S) modification of HS has been linked to AD through its interaction with tau, and enhanced levels of 3-O-sulfated HS and 3-O-sulfotransferases in the AD brain. In this study, we characterized ApoE/HS interactions in wildtype ApoE3, AD-linked ApoE4, and AD-protective ApoE2 and ApoE3-Christchurch. Glycan microarray and SPR assays revealed that all ApoE isoforms recognized 3-O-S. NMR titration localized ApoE/3-O-S binding to the vicinity of the canonical HS binding motif. In cells, the knockout of HS3ST1-a major 3-O sulfotransferase-reduced cell surface binding and uptake of ApoE. 3-O-S is thus recognized by both tau and ApoE, suggesting that the interplay between 3-O-sulfated HS, tau and ApoE isoforms may modulate AD risk.

Documento de consenso para la determinación e informe del perfil lipídico en laboratorios clínicos españoles / Consensus document for lipid profile determination and reporting in Spanish clinical laboratories. What parameters should be included in a basic lipid profile?

Las enfermedades cardiovasculares (ECV) siguen siendo la principal causa de muerte en nuestro país. El control adecuado de las alteraciones del metabolismo lipídico es un reto clave en prevención cardiovascular que está lejos de alcanzarse en la práctica clínica real. Existe una gran heterogeneidad en los informes del metabolismo lipídico de los laboratorios clínicos españoles, lo que puede contribuir al mal control del mismo. Por ello, un grupo de trabajo de las principales sociedades científicas implicadas en la atención de los pacientes de riesgo vascular hemos elaborado este documento con una propuesta básica de consenso sobre la determinación del perfil lipídico básico en prevención cardiovascular, recomendaciones para su realización y unificación de criterios para incorporar los objetivos de control lipídico adecuados al riesgo vascular de los pacientes en los informes de laboratorio.(AU)

Cardiovascular diseases (CVD) continue to be the main cause of death in our country. Adequate control of lipid metabolism disorders is a key challenge in cardiovascular prevention that is far from being achieved in real clinical practice. There is a great heterogeneity in the reports of lipid metabolism from Spanish clinical laboratories, which may contribute to its poor control. For this reason, a working group of the main scientific societies involved in the care of patients at vascular risk, has prepared this document with a consensus proposal on the determination of the basic lipid profile in cardiovascular prevention, recommendations for its realization and unification of criteria to incorporate the lipid control goals appropriate to the vascular risk of the patients in the laboratory reports.(AU)

Consensus document for lipid profile determination and reporting in Spanish clinical laboratories. What parameters should be included in a basic lipid profile? / Documento de consenso para la determinación e informe del perfil lipídico en laboratorios clínicos españoles: ¿Qué parámetros debe incluir un perfil lipídico básico?

Cardiovascular diseases (CVD) continue to be the main cause of death in our country. Adequate control of lipid metabolism disorders is a key challenge in cardiovascular prevention that is far from being achieved in real clinical practice. There is a great heterogeneity in the reports of lipid metabolism from Spanish clinical laboratories, which may contribute to its poor control. For this reason, a working group of the main scientific societies involved in the care of patients at vascular risk, has prepared this document with a consensus proposal on the determination of the basic lipid profile in cardiovascular prevention, recommendations for its realization and unification of criteria to incorporate the lipid control goals appropriate to the vascular risk of the patients in the laboratory reports.

Documento de consenso para la determinación e informe del perfil lipídico en laboratorios clínicos españoles ¿Qué parámetros debe incluir un perfil lípido básico? / Consensus document to determine and report the lipid profile in spanish clinical laboratories. Which parameters should a basic lipid profile include?

Las enfermedades cardiovasculares (ECV) siguen siendo la principal causa de muerte en nuestro país. El control adecuado de las alteraciones del metabolismo lipídico es un reto clave en prevención cardiovascular que está lejos de alcanzarse en la práctica clínica real. Existe una gran heterogeneidad en los informes del metabolismo lipídico de los laboratorios clínicos españoles, lo que puede contribuir al mal control del mismo. Por ello, un grupo de trabajo de las principales sociedades científicas implicadas en la atención de los pacientes de riesgo vascular, hemos elaborado este documento con una propuesta básica de consenso sobre la determinación del perfil lipídico básico en prevención cardiovascular, recomendaciones para su realización y unificación de criterios para incorporar los objetivos de control lipídico adecuados al riesgo vascular de los pacientes en los informes de laboratorio.(AU)

Cardiovascular diseases (CVD) continue to be the main cause of death in Spain. Adequate control of lipid metabolism disorders is a key challenge in cardiovascular prevention that is far from achieved in real clinical practice. There is a major heterogeneity in the reports of lipid metabolism from Spanish clinical laboratories, which may contribute to its poor monitoring. For this reason, a working group of the main scientific societies involved in the care of patients at vascular risk, has drawn up this document with a consensus proposal on the determination of the basic lipid profile in cardiovascular prevention, recommendations for its implementation and combining the criteria to incorporate the lipid monitoring goals suitable for the vascular risk of the patients in the laboratory reports.(AU)

Consumption of Policosanol (Raydel®) Improves Hepatic, Renal, and Reproductive Functions in Zebrafish: In Vivo Comparison Study among Cuban, Chinese, and American Policosanol.

The current study compared three policosanols from Cuba (sugarcane, Raydel®, policosanol (1), China (rice bran, Shaanxi, policosanol (2), and the USA (sugarcane, Lesstanol®, policosanol (3) in the treatment of dyslipidemia and protection of the liver, ovary, and testis in hypercholesterolemic zebrafish. After twelve weeks of supplementation of each policosanol (PCO, final 0.1% in diet, w/w) with a high cholesterol diet (HCD, final 4%, w/w), the Raydel policosanol (PCO1) group showed the highest survivability, approximately 89%. In contrast, Shaanxi policosanol (PCO2) and Lesstanol policosanol (PCO3) produced 73% and 87% survivability, respectively, while the HCD alone group showed 75% survivability. In the 12th week, the PCO1 group demonstrated the most modest increase in body weight along with significantly lower levels of total cholesterol (TC) and triglycerides (TG) in comparison to the HCD control group. Additionally, the PCO1 group exhibited the highest proportion of high-density lipoprotein (HDL)-cholesterol within TC. Notably, the PCO1 group displayed the lowest level of aspartate aminotransferase and alanine aminotransferase, minimal infiltration of inflammatory cells, reduced interleukin (IL)-6 production in the liver, a notable decline in reactive oxygen species (ROS) generation and mitigated fatty liver changes. HCD supplementation induced impairment of kidney morphology with the greatest extent of ROS production and apoptosis. On the other hand, the PCO 1 group showed a remarkably improved morphology with the least ROS generation and apoptosis. Within the ovarian context, the PCO1 group exhibited the most substantial presence of mature vitellogenic oocytes, accompanied by minimal levels of ROS and apoptosis. Similarly, in the testicular domain, the PCO1 group showcased optimal morphology for spermatogenesis, characterized by the least interstitial area and diminished production of ROS in testicular cells. At week 8, the PCO1 group showed the highest egg-laying ability, with around 244 eggs produced per mating. In contrast, the HCD alone, PCO2, and PCO3 groups showed significantly lower egg-laying ability (49, 59, and 86 eggs, respectively). The embryos from the PCO1 group exhibited the highest survivability with the fastest swimming ability and developmental speed. These results suggest that PCO1 consumption significantly enhanced the reproduction system, egg-laying ability, and embryo survivability. In conclusion, among the three policosanols, Cuban (Raydel®) policosanol had the strongest effect on survivability, improving dyslipidemia, liver protection, kidney, ovary, and testis with a restoration of the cell morphology, and the least ROS production and apoptosis-induced by HCD supplementation.

A novel sandwich impedimetric immunosensor for detection of apolipoprotein-A1 based on the gold nanoparticle-hybridized mercapto-ß-cyclodextrin-Pb(II) metal-organic framework.

A novel sandwich electrochemical impedimetric immunosensor was proposed to detect apolipoprotein-A1 (Apo-A1), a common biomarker for bladder cancer. The molybdenum disulfide/graphene quantum dot (MoS2/GQD) nanocomposites were modified on the surface of a glassy carbon electrode (GCE) and used to immobilize the biotinylated antibody (Ab1) with the help of chitosan and glutaraldehyde (denoted as BSA/Ab1/CHIT/MoS2/GQD/GCE). Pb(II)-thiol-ß-cyclodextrin metal-organic framework (denoted as Pb-MOF) was synthesized with lead metal ions and thiol-ß-cyclodextrin ligands by a one-pot solvothermal method, and then, gold nanoparticles were modified on the surface of Pb-MOF (Pb-MOF-AuNPs) by Au-S bond, which was used as signal label for the recombinant antibody (Ab2). When the immunosensor of BSA/Ab1/CHIT/MoS2/GQD/GCE reacted with Apo-A1, Pb-MOF-AuNPs-Ab2/BSA was connected to the electrode when immunoreaction occurred, and an immune sandwich structure was formed, which led to significantly increased charge transfer resistance of electrochemical probe for ferrocyanide (II)/(III) within the frequency range 10-1 ~ 105 Hz at 5 mV amplitude and the potential of 0.180 V (vs. SCE). Based on this principle, the quantitative detection of Apo-A1 was established. The relative change of electrochemical resistance and the logarithmic value of Apo-A1 concentration showed a linear relationship with a linear coefficient of 0.9989 in the range 1.00 pg mL-1 and 1.00 µg mL-1 with the limit of detection of 0.30 pg mL-1. The selectivity, repeatability, and other performance of the proposed immunosensor were also investigated. The immunosensor was successfully applied to the detection of real serum and urine samples with recovery in the range 96.4 ~ 109.1% (RSD < 3.8%), indicating that it could be helpful for the clinical diagnosis of bladder cancer.

LPA disruption with AAV-CRISPR potently lowers plasma apo(a) in transgenic mouse model: A proof-of-concept study.

Lipoprotein(a) (Lp(a)) represents a unique subclass of circulating lipoprotein particles and consists of an apolipoprotein(a) (apo(a)) molecule covalently bound to apolipoprotein B-100. The metabolism of Lp(a) particles is distinct from that of low-density lipoprotein (LDL) cholesterol, and currently approved lipid-lowering drugs do not provide substantial reductions in Lp(a), a causal risk factor for cardiovascular disease. Somatic genome editing has the potential to be a one-time therapy for individuals with extremely high Lp(a). We generated an LPA transgenic mouse model expressing apo(a) of physiologically relevant size. Adeno-associated virus (AAV) vector delivery of CRISPR-Cas9 was used to disrupt the LPA transgene in the liver. AAV-CRISPR nearly completely eliminated apo(a) from the circulation within a week. We performed genome-wide off-target assays to determine the specificity of CRISPR-Cas9 editing within the context of the human genome. Interestingly, we identified intrachromosomal rearrangements within the LPA cDNA in the transgenic mice as well as in the LPA gene in HEK293T cells, due to the repetitive sequences within LPA itself and neighboring pseudogenes. This proof-of-concept study establishes the feasibility of using CRISPR-Cas9 to disrupt LPA in vivo, and highlights the importance of examining the diverse consequences of CRISPR cutting within repetitive loci and in the genome globally.