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Atherosclerosis has been effectively avoided with many therapies that lower low-density lipoprotein cholesterol. However, significant cardiovascular burden remains. The effect of raising high-density lipoprotein (HDL) has been confounded by other factors (such as lowering triglycerides or LDL) and unsuccessful when attempting to solely increase HDL. Reviewing the available data, the failures of previous strategies may reflect the complexity of HDL in human metabolism and the heterogeneity of human genetics. dal-GenE (NCT02525939) represents the first large cardiovascular outcomes study to use a selective genomic test to identify the target population most likely to receive therapeutic benefit and uses a cholesterol ester transfer protein inhibitor, dalcetrapib. Both the cholesterol ester transfer protein target and the ADCY9 polymorphism identified by the diagnostic test are based on inheritance and an evolving understanding of inborn risk. Selective treatment of subpopulations may be the key to the conundrum of HDL as an actionable risk factor.

The purpose of this article is to review the current landscape of new therapeutic targets, advances in biomarkers and imaging technologies, regulatory sciences, and their collective potential impact on the development of novel anti-atherosclerosis drugs. Current development challenges such as the design of pharmacodynamic (indicative or surrogate biomarker) and ‘‘hard’ end point studies are reviewed. The reader can also expect to learn about advanced collaborative efforts that will likely have an impact on future initiatives.

Objectives. This study compared the efficacy and safety of atorvastatin, fluvastatin, lovastatin, and simvastatin in patients with documented atherosclerosis treated to U.S. National Cholesterol Education Program (NCEP) recommended low-density-lipoprotein (LDL) cholesterol concentration (≤100 mg/dl [2.59 mmol/liter]).

Background:High levels of total and LDL-cholesterol are associated with an increased risk of atherosclerotic vascular disease. Lowering of serum cholesterol levels by pharmacologic intervention with inhibitors of cholesterol synthesis, the so-called statins, reduces the incidence of cardiovascular events in subjects with and without atherosclerotic manifestations. In a 16-week, multicenter, randomized, open-label cross-over study we compared the efficacy and safety of the new compound atorvastatin for reducing LDL-cholesterol with simvastatin or pravastatin.

The arguments for a warning on foodstuffs open new ground in product liability. Some of the dangers of fat-laden foods have been apparent for many years and are widely known to the public. Other aspects of fat consumption, specifically hidden fats, such as saturated fats, have only recently been explored, and are known to a limited segment of the population at risk. Negligence and warranty theories are too narrow to encompass this situation, wherein the benefits and risks of a product are not well defined and not easily separable. Some warning about the dangers resulting from fat ingestion is necessary, but may be adequately dispensed by ingredient labeling. If consumers are aware of the potential for harm, then they are assuming a substantial portion of the risk. How risk-free can we, or should we, make our society?

NM23 is a candidate tumor suppressor protein and has recently been identified as an NDP kinase. The expression of NM23 is inversely related to the metastatic potential of tumor cells. Two NM23 genes, NME1 and NME2, that code for the A and B chains of the kinase, respectively, have been cloned. To determine the human chromosomal location of the NME2 gene, we have analyzed DNA from rodent-human cell lines and hybrid cell lines containing portions of chromosome 17 by a combination of PCR amplification and Southern hybridization. The NME2 gene was mapped to the chromosome region 17q21-q22, the same region in which the NME1 gene has been localized. This region is linked to the early onset breast/ovarian locus (BRCA1) and allelic deletions of NME1 have been associated with metastatic potential of colorectal carcinomas.

In mouse mammary tumors, the Wnt-3 gene can be activated by proviral insertion. Here we report on the isolation of a human homolog, WNT3. A genomic clone was isolated by use of mouse Wnt-3 sequences as a probe, after which cDNA containing most of the protein-encoding domain of the human gene was obtained by PCR. Comparison between the deduced mouse and human WNT-3 protein sequences showed four changes in 333 amino acids. WNT3 is located on chromosome 17q21. The gene was not found to be amplified or rearranged in a collection of human breast tumors.

Human upstream binding factor (hUBF) is a sequence-specific DNA-binding protein that is essential for the activation of human 18s and 28s rRNA gene transcription. We have isolated and localized the gene (UBTF) encoding hUBF to the DI7S183 locus on chromosome 17q21 by analyzing a cosmid from the region and carrying out Southern analysis on a previously constructed chromosome 17 somatic cell hybrid mapping panel using a probe from the hUBF cDNA. Confirmation of its location at this region was obtained from the results of pulsed-field gel electrophoresis analysis of genomic DNA using the hUBF cDNA and other probes from the region. These data also enabled the construction of a long-range restriction map of the region. Copyright 1995, 1999 Academic Press

• OBJECTIVE. —We followed the clinical course of four patients with type I hyperlipidemia from two kindreds who presented at an early age. PATIENTS. —Two propositi presented with severe abdominal pain and bloody diarrhea at 8 and 10 weeks of age. They also exhibited delayed growth. We compared their course with that of two siblings (one sibling of each proband) who also have familial hyperchylomicronemia but were diagnosed and have subsequently shown normal growth. MAIN RESULTS. —Although each sibling pair possesses the same lipoprotein lipase gene defect and resides in a similar environment, significant differences in stature are apparent. CONCLUSION. —Specific structural defects in the lipoprotein lipase gene alone do not define phenotypic presentation. However, severity of clinical presentation may influence future growth characteristics.(AJDC. 1993;147:60-62)

A gene for early-onset familial breast cancer has recently been mapped to the chromosome 17q12–23 region. In order to confirm the gene location, we have tested an extensive early-onset breast cancer family with 4 markers in this chromosome region. Linkage was negative with all 4 markers. This study suggests that there is genetic heterogeneity among early-onset breast cancer families.