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Preeclampsia is a potentially fatal pregnancy disorder affecting millions of women around the globe. Dysregulation in gene and protein expression within key biological pathways controlling angiogenesis has been implicated in the development of preeclampsia. Altered CpG methylation, a type of epimutation, may underlie this pathway dysregulation. In the present study, placental tissue from preeclamptic cases and normotensive controls was analyzed for genome-wide differential CpG methylation and concomitant changes in gene expression. A set of 123 genes, representing 19.9% of all genes with altered CpG methylation, was associated with functional changes in transcript levels. Underscoring the complex relationships between CpG methylation and gene expression, here hypermethylation was never associated with gene silencing, nor was hypomethylation always associated with gene activation. Moreover, the genomic region of the CpG mark was important in predicting the relationship between CpG methylation and gene expression. The 123 genes were enriched for their involvement in the transforming growth factor beta (TGF-β) signaling pathway, a known regulator of placental trophoblast invasion and migration. This is the first study to identify CpG hypomethylation as an activator of TGF-β-associated gene expression in the preeclamptic placenta. The results suggest functional epimutations are associated with preeclampsia disease status and the identified genes may represent novel biomarkers of disease.

We report that long double-stranded DNA confined to quasi-1D nanochannels undergoes superdiffusive motion under the action of the enzyme T4 DNA ligase in the presence of necessary co-factors. Inside the confined environment of the nanochannel, double-stranded DNA molecules stretch out due to self-avoiding interactions. In absence of a catalytically active enzyme, we see classical diffusion of the center of mass. However, cooperative interactions of proteins with the DNA can lead to directed motion of DNA molecules inside the nanochannel. Here we show directed motion in this configuration for three different proteins (T4 DNA ligase, MutS, E. coli DNA ligase) in the presence of their energetic co-factors (ATP, NAD + ).

Preeclampsia is a potentially fatal pregnancy disorder affecting millions of women around the globe. Dysregulation in gene and protein expression within key biological pathways controlling angiogenesis has been implicated in the development of preeclampsia. Altered CpG methylation, a type of epimutation, may underlie this pathway dysregulation. In the present study, placental tissue from preeclamptic cases and normotensive controls was analyzed for genome-wide differential CpG methylation and concomitant changes in gene expression. A set of 123 genes, representing 19.9% of all genes with altered CpG methylation, was associated with functional changes in transcript levels. Underscoring the complex relationships between CpG methylation and gene expression, here hypermethylation was never associated with gene silencing, nor was hypomethylation always associated with gene activation. Moreover, the genomic region of the CpG mark was important in predicting the relationship between CpG methylation and gene expression. The 123 genes were enriched for their involvement in the transforming growth factor beta (TGF-[beta]) signaling pathway, a known regulator of placental trophoblast invasion and migration. This is the first study to identify CpG hypomethylation as an activator of TGF-[beta]-associated gene expression in the preeclamptic placenta. The results suggest functional epimutations are associated with preeclampsia disease status and the identified genes may represent novel biomarkers of disease.

The EU, the USA, and Japan account for the majority of biological pharmacotherapy use worldwide. Biosimilar regulatory approval pathways were authorised in the EU (2006), in Japan (2009), and in the USA (2015), to facilitate approval of biological drugs that are highly similar to reference products and to encourage market competition. Between 2007 and 2020, 33 biosimilars for oncology were approved by the European Medicines Agency (EMA), 16 by the US Food and Drug Administration (FDA), and ten by the Japan Pharmaceuticals and Medical Devices Agency (PMDA). Some of these approved applications were initially rejected because of manufacturing concerns (four of 36 [11%] with the EMA, seven of 16 [44%] with the FDA, none of ten for the PMDA). Median times from initial regulatory submission before approval of oncology biosimilars were 1·5 years (EMA), 1·3 years (FDA), and 0·9 years (PMDA). Pharmacists can substitute biosimilars for reference biologics in some EU countries, but not in the USA or Japan. US regulation prohibits substitution, unless the biosimilar has been approved as interchangeable, a designation not yet achieved for any biosimilar in the USA. Japan does not permit biosimilar substitution, as prescribers must include the product name on each prescription and that specific product must be given to the patient. Policy Reviews published in 2014 and 2016 in The Lancet Oncology focused on premarket and postmarket policies for oncology biosimilars before most of these drugs received regulatory approval. In this Policy Review from the Southern Network on Adverse Reactions, we identify factors preventing the effective launch of oncology biosimilars. Introduction to the market has been more challenging with therapeutic than for supportive care oncology biosimilars. Addressing region-specific competition barriers and educational needs would improve the regulatory approval process and market launches for these biologics, therefore expanding patient access to these products in the EU, the USA, and Japan.

Biological oncology products are integral to cancer treatment, but their high costs pose challenges to patients, families, providers, and insurers. The introduction of biosimilar agents—molecules that are similar in structure, function, activity, immunogenicity, and safety to the original biological drugs—provide opportunities both to improve health-care access and outcomes, and to reduce costs. Several international regulatory pathways have been developed to expedite entry of biosimilars into global marketplaces. The first wave of oncology biosimilar use was in Europe and India in 2007. Oncology biosimilars are now widely marketed in several countries in Europe, and in Australia, Japan, China, Russia, India, and South Korea. Their use is emerging worldwide, with the notable exception of the USA, where several regulatory and cost barriers to biosimilar approval exist. In this Review, we discuss oncology biosimilars and summarise their regulatory frameworks, clinical experiences, and safety concerns.

Oxidative stress is implicated in the pathogenesis and progression of several disease states. In order to prevent oxidative stress related toxicity, the cell mounts an effective antioxidant defense response. This response consists of enzymes that reduce levels of reactive oxygen species (ROS). Therefore, in order to mount an effective antioxidant defense, transcriptional regulation of antioxidant genes must be tightly regulated. Elucidating the molecular pathways of antioxidant gene transcription will aid in designing therapeutic strategies for oxidative stress related diseases. Promoters of antioxidant genes such as heme oxygenase-1 (HO-1) feature an upstream enhancer element that regulates transcriptional activation. This antioxidant response element (ARE) is activated in response to oxidative stress, and while activation of the ARE by the transcription factor NF-E2-related factor 2 (Nrf2) has been studied, the role of chromatin remodeling in activation of the ARE has been relatively unexplored. Post-translational modification of histones plays a key role in chromatin-mediated regulation of gene transcription. However, the role of histone phosphorylation in gene transcription has not been fully elucidated. We sought to determine the role of histone phosphorylation in ARE activation and in the transcriptional regulation of ARE-containing genes by employing the environmental contaminant arsenite, a known inducer of oxidative stress, which potently stimulates histone H3 serine 10 phosphorylation (H3S10P) and HO-1 expression. We report that arsenite induces H3S10P enrichment of the HO-1 AREs and HO-1 expression in an oxidative stress-dependent manner. We also observed that the c-Jun N-terminal kinase (JNK) contributes to arsenite-mediated induction of H3S10P and HO-1 expression. Furthermore, we demonstrate that Nrf2 regulates H3S10P enrichment at the HO-1 AREs. We also found that arsenite induces histone H3 threonine 11 phosphorylation (H3T11P), both at the global level and at the HO-1 AREs. Additionally, we demonstrate that the DNA damage-responsive kinase Chk1 mediates H3T11P in response to arsenite, as well as regulating arsenite induction of HO-1. Collectively, these results suggest that histone H3 S10 and T11 phosphorylation may play a role in HO-1 transcription in response to arsenite.

Discerning cellular responses to environmental contaminants requires a basic understanding of the molecular processes of the cell. Metabolomic, transcriptomic, epigenomic, and proteomic responses can be analyzed in tandem to develop a comprehensive working model that predicts how complex biological systems respond to toxicant exposure. These quantitative outputs are the measurable alterations in metabolite levels, gene expression profiles, epigenetic signatures, and the protein expression patterns of the cell. This chapter provides a brief overview of the constituents, organization, and homeostatic processes of the eukaryotic cell, with a focus on the molecular mechanisms that provide quantitative inputs useful for a systems biological perspective. A working knowledge of molecular biology will facilitate an understanding of the molecular processes disrupted by toxicants and an understanding of the biological implications of toxicant exposure.

Bempedoic acid, an ATP citrate lyase inhibitor, reduces low-density lipoprotein (LDL) cholesterol levels and is associated with a low incidence of muscle-related adverse events; its effects on cardiovascular outcomes remain uncertain. We conducted a double-blind, randomized, placebo-controlled trial involving patients who were unable or unwilling to take statins owing to unacceptable adverse effects (\"statin-intolerant\" patients) and had, or were at high risk for, cardiovascular disease. The patients were assigned to receive oral bempedoic acid, 180 mg daily, or placebo. The primary end point was a four-component composite of major adverse cardiovascular events, defined as death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization. A total of 13,970 patients underwent randomization; 6992 were assigned to the bempedoic acid group and 6978 to the placebo group. The median duration of follow-up was 40.6 months. The mean LDL cholesterol level at baseline was 139.0 mg per deciliter in both groups, and after 6 months, the reduction in the level was greater with bempedoic acid than with placebo by 29.2 mg per deciliter; the observed difference in the percent reductions was 21.1 percentage points in favor of bempedoic acid. The incidence of a primary end-point event was significantly lower with bempedoic acid than with placebo (819 patients [11.7%] vs. 927 [13.3%]; hazard ratio, 0.87; 95% confidence interval [CI], 0.79 to 0.96; P = 0.004), as were the incidences of a composite of death from cardiovascular causes, nonfatal stroke, or nonfatal myocardial infarction (575 [8.2%] vs. 663 [9.5%]; hazard ratio, 0.85; 95% CI, 0.76 to 0.96; P = 0.006); fatal or nonfatal myocardial infarction (261 [3.7%] vs. 334 [4.8%]; hazard ratio, 0.77; 95% CI, 0.66 to 0.91; P = 0.002); and coronary revascularization (435 [6.2%] vs. 529 [7.6%]; hazard ratio, 0.81; 95% CI, 0.72 to 0.92; P = 0.001). Bempedoic acid had no significant effects on fatal or nonfatal stroke, death from cardiovascular causes, and death from any cause. The incidences of gout and cholelithiasis were higher with bempedoic acid than with placebo (3.1% vs. 2.1% and 2.2% vs. 1.2%, respectively), as were the incidences of small increases in serum creatinine, uric acid, and hepatic-enzyme levels. Among statin-intolerant patients, treatment with bempedoic acid was associated with a lower risk of major adverse cardiovascular events (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization). (Funded by Esperion Therapeutics; CLEAR Outcomes ClinicalTrials.gov number, NCT02993406.).

But even the best doctor in what is the world's most technologically advanced health-care system with the most highly skilled doctors is limited by how much the medical profession as a whole knows, and for many procedures -- even for some of the most common ones -- it does not know enough. There will always be uncertainty, because medicine is an art as well as a science. Doctors have different practice styles and patients have differing needs and expectations. However, the areas of uncertainty are larger than most of us realize -- and larger than they need to be. At a time of rapidly rising costs, too many common treatments lack adequate evaluation. And what we do know -- from the good assessments that are available and from studies of wide variations in utilization of care -- is that there is overuse of a number of services and underuse of others. Indeed, Arnold Relman, editor of The New England Journal of Medicine, has said that in his opinion at least 20% to 30% of all medical procedures done even in good hospitals are not worthwhile. We need to know more about new and old technologies and we need better systems to turn tested research results into practice and remove that which is obsolete or harmful. A good example of an operation done too frequently, generating excessive risk and costs, is the Caesarean section. One out of four deliveries in the U.S. today is by Caesarean, and the rate is increasing rapidly. The American College of Obstetricians and Gynecologists believes that the percentage should be lower, and that the only way to reduce the number of operations is through a massive education campaign. There is no need, for example, with today's operating techniques, for many women who have had one Caesarean to deliver their subsequent babies that way. Yet 38% of these operations are on women who have had previous sections and have not had an adequate trial labor, so clearly the message has not gotten through. In California, an effort to remove inappropriate incentives that might tilt borderline decisions calls for third-party payers to pay the same for a normal delivery as for a Caesarean.