Genetics of ABCB1 in Cancer.

ABCB1, also known as MDR1, is a gene that encodes P-glycoprotein (P-gp), a membrane-associated ATP-dependent transporter. P-gp is widely expressed in many healthy tissues-in the gastrointestinal tract, liver, kidney, and at the blood-brain barrier. P-gp works to pump xenobiotics such as toxins and drugs out of cells. P-gp is also commonly upregulated across multiple cancer types such as ovarian, breast, and lung. Overexpression of ABCB1 has been linked to the development of chemotherapy resistance across these cancers. In vitro work across a wide range of drug-sensitive and -resistant cancer cell lines has shown that upon treatment with chemotherapeutic agents such as doxorubicin, cisplatin, and paclitaxel, ABCB1 is upregulated. This upregulation is caused in part by a variety of genetic and epigenetic mechanisms. This includes single-nucleotide variants that lead to enhanced P-gp ATPase activity without increasing ABCB1 RNA and protein levels. In this review, we summarize current knowledge of genetic and epigenetic mechanisms leading to ABCB1 upregulation and P-gp-enhanced ATPase activity in the setting of chemotherapy resistance across a variety of cancers.

The safety of pediatric use of paracetamol (acetaminophen): a narrative review of direct and indirect evidence.

Paracetamol (acetaminophen) use during pregnancy and early childhood was accepted as safe in the 1970s, but is now a subject of considerable concern. Careful analysis shows that initial acceptance of the drug was based on the false assumption that drug interactions in babies and adults are the same, and on a complete absence of knowledge regarding the impact of the drug on brain development. At least fourteen epidemiological studies now indicate that prenatal exposure to paracetamol is associated with neurodevelopmental problems. Based on these studies, it can be concluded that prenatal exposure to paracetamol causes statistically significant risks of developmental delays, attention deficit hyperactivity disorder, and a subtype of autism spectrum disorder (ASD) associated with hyperkinetic behavior. In contrast, data regarding postnatal exposure to paracetamol are limited, and several factors impede a classic multivariate analysis of epidemiologic data to resolve the issue. However, circumstantial evidence regarding postnatal exposure to the drug is abundant, and includes at least three otherwise unexplained temporal relationships, data from laboratory animal studies, several miscellaneous and otherwise unexplained correlations, and a lack of alternative suspects that fit the evidence-derived profile. Based on this evidence, it can be concluded without any reasonable doubt that oxidative stress puts some babies and children at risk of paracetamol-induced neurodevelopmental injury, and that postnatal exposure to paracetamol in those susceptible babies and children is responsible for many if not most cases of ASD.

Paracetamol (acetaminophen) use in infants and children was never shown to be safe for neurodevelopment: a systematic review with citation tracking.

Although widely believed by pediatricians and parents to be safe for use in infants and children when used as directed, increasing evidence indicates that early life exposure to paracetamol (acetaminophen) may cause long-term neurodevelopmental problems. Furthermore, recent studies in animal models demonstrate that cognitive development is exquisitely sensitive to paracetamol exposure during early development. In this study, evidence for the claim that paracetamol is safe was evaluated using a systematic literature search. Publications on PubMed between 1974 and 2017 that contained the keywords "infant" and either "paracetamol" or "acetaminophen" were considered. Of those initial 3096 papers, 218 were identified that made claims that paracetamol was safe for use with infants or children. From these 218, a total of 103 papers were identified as sources of authority for the safety claim.   Conclusion: A total of 52 papers contained actual experiments designed to test safety, and had a median follow-up time of 48 h. None monitored neurodevelopment. Furthermore, no trial considered total exposure to drug since birth, eliminating the possibility that the effects of drug exposure on long-term neurodevelopment could be accurately assessed. On the other hand, abundant and sufficient evidence was found to conclude that paracetamol does not induce acute liver damage in babies or children when used as directed. What is Known: • Paracetamol (acetaminophen) is widely thought by pediatricians and parents to be safe when used as directed in the pediatric population, and is the most widely used drug in that population, with more than 90% of children exposed to the drug in some reports. • Paracetamol is known to cause liver damage in adults under conditions of oxidative stress or when used in excess, but increasing evidence from studies in humans and in laboratory animals indicates that the target organ for paracetamol toxicity during early development is the brain, not the liver. What is New: • This study finds hundreds of published reports in the medical literature asserting that paracetamol is safe when used as directed, providing a foundation for the widespread belief that the drug is safe. • This study shows that paracetamol was proven to be safe by approximately 50 short-term studies demonstrating the drug's safety for the pediatric liver, but the drug was never shown to be safe for neurodevelopment. Paracetamol is widely believed to be safe for infants and children when used as directed, despite mounting evidence in humans and in laboratory animals indicating that the drug is not safe for neurodevelopment. An exhaustive search of published work cited for safe use of paracetamol in the pediatric population revealed 52 experimental studies pointing toward safety, but the median follow-up time was only 48 h, and neurodevelopment was never assessed.

Evolution of the hygiene hypothesis into biota alteration theory: what are the paradigms and where are the clinical applications?

For thousands of years, changes in human cultures have altered the biota associated with the human body, and those alterations have strongly influenced human health. The hygiene hypothesis has evolved over the past 30 years into a nuanced biota alteration theory, but modern medical priorities and regulatory policies have resulted in tragic underutilization of the acquired knowledge.