Acetaminophen Attenuates invasion and alters the expression of extracellular matrix enzymes and vascular factors in human first trimester trophoblast cells.

Acetaminophen is one of the most common medications taken during pregnancy, considered safe for maternal health and fetal development. However, recent epidemiological studies have associated prenatal acetaminophen use with several developmental disorders in offspring. As acetaminophen can freely cross into and through the placenta, epidemiological associations with prenatal acetaminophen use may reflect direct actions on the fetus and/or the impact of altered placental functions. In the absence of rigorous mechanistic studies, our understanding of how prenatal acetaminophen exposure can cause long-term effects in offspring is limited. The objective of this study was to determine whether acetaminophen can alter key functions of a major placental cell type by utilizing immortalized human first trimester trophoblast cells. This study employed a comparative analysis with the nonsteroidal, anti-inflammatory drug aspirin, which has established effects in first trimester trophoblast cells. We report that immortalized trophoblast cells express the target proteins of acetaminophen and aspirin: cyclooxygenase (COX) -1 and -2. Unlike aspirin, acetaminophen significantly repressed the expression of angiogenesis and vascular remodeling genes in HTR-8/SVneo cells. Moreover, acetaminophen impaired trophoblast invasion by over 80%, while aspirin had no effect on invasion. Acetaminophen exposure reduced the expression of matrix metalloproteinase (MMP)-2 and -9 and increased the expression of tissue inhibitors of matrix metalloproteinases 2, leading to an imbalance in the ratio of proteolytic enzymes. Finally, a bioinformatic approach identified novel acetaminophen-responsive gene networks associated with key trophoblast functions and disease. Together these results suggest that prenatal acetaminophen use may interfere with critical trophoblast functions early in gestation, which may subsequently impact fetal development.

Updates on molecular and environmental determinants of luteal progesterone production.

Progesterone, a critical hormone in reproduction, is a key sex steroid in the establishment and maintenance of early pregnancy and serves as an intermediary for synthesis of other steroid hormones. Progesterone production from the corpus luteum is a tightly regulated process which is stimulated and maintained by multiple factors, both systemic and local. Multiple regulatory systems, including classic mediators of gonadotropin stimulation such as the cAMP/PKA pathway and TGFß-mediated signaling pathways, as well as local production of hormonal factors, exist to promote granulosa cell function and physiological fine-tuning of progesterone levels. In this manuscript, we provide an updated narrative review of the known mediators of human luteal progesterone and highlight new observations regarding this important process, focusing on studies published within the last five years. We will also review recent evidence suggesting that this complex system of progesterone production is sensitive to disruption by exogenous environmental chemicals that can mimic or interfere with the activities of endogenous hormones.

Higher odds and rising trends in arrhythmia among young cannabis users with comorbid depression.

BACKGROUND: Cannabis (marijuana) use and depression are known to be strongly interconnected. However, amid alarming rates of mental health problems in the United States young population, the risk of arrhythmia among young cannabis users with comorbid depression has never been studied. METHODS: In-hospital encounters of arrhythmia were identified among young cannabis users (18-39 years) with or without depression using the National Inpatient Sample (2007-2014) databases and apposite ICD-9 codes. Baseline characteristics and trends in prevalence of arrhythmia were evaluated among inpatient young cannabis users with or without depression. A multivariable regression was performed after adjusting for baseline demographics, comorbidities and parallel history of substance abuse. RESULTS: Of 2,011,598 young cannabis users (59.6% male) admitted from 2007-2014, 190,146 (9.5%) of patients had comorbid depression, of which 6.9% of patients experienced arrhythmias with atrial fibrillation being most common. Cannabis users with depression were more likely older, white, females and frequently hospitalized in Midwest and rural hospitals. We observed a steadily rising trend in prevalence of arrhythmia in both groups, but a more rapid rise in cannabis users with depression (4.9% in 2007 to 8.5% in 2014 vs. 3.7% in 2007 to 5.7% in 2014). Correspondingly, young depressed cannabis users had higher odds of arrhythmia compared to non-depressed even after controlling for demographics and comorbidities (OR: 1.41, 95% CI: 1.38-1.44, p<0.001). CONCLUSION: Rampant recreational use of marijuana may increase the risk of arrhythmia by 40% in young cannabis users with depression as compared to non-depressed.

Nationwide Frequency, Sequential Trends, and Impact of Co-morbid Mental Health Disorders on Hospitalizations, Outcomes, and Healthcare Resource Utilization in Adult Congenital Heart Disease.

Despite the growing prevalence of adult congenital heart disease (ACHD), data on trends in prevalence of mental health disorders (MHD) among patients with ACHD remain limited. The National Inpatient Sample (2007 to 2014) was queried to identify the frequency and trends of MHD among ACHD hospitalizations (stratification by age, sex, and race); demographics and co-morbidities for ACHD cohorts, with (MHD+) versus without MHD (MHD-); the rate and trends of all-cause in-hospital mortality, disposition, mean length of stay, and hospitalization charges among both cohorts. A total of 11,709 (13.8%, mean age: 49.1 years, 56.0% females, 78.7% white) out of 85,029 ACHD patient encounters had a coexistent MHD (anxiety, depression, mood disorder, or psychosis). ACHD-MHD+ cohort was more often admitted nonelectively (38.1% vs 32.8%, p <0.001) and had a higher frequency of cardiac/extra-cardiac co-morbidities. The trends in prevalence of coexistent MHD increased from 10.3% to 17.5% (70% relative increase) from 2007 to 2014 with a consistently higher prevalence among females (from 13% to 20.3%) compared to males (from 7.6% to 15.5%) (ptrend <0.001). The hospitalization trends with MHD increased in whites (12.1% to 19.8%) and Hispanics (5.9% to 12.7%). All-cause mortality was lower (0.7% vs 1.1%, p = 0.002) in ACHD-MHD+; however, mean length of stay (∼5.7 vs 4.9 days, p <0.001) was higher without significant difference in charges ($97,710 vs $96,058, p = 0.137). ACHD-MHD+ cohort was less often discharged routinely (declining trend) and more frequently transferred to other facilities and required home healthcare (rising trends). In conclusion, this study reveals increasing trends of MHD, healthcare resource utilization and a higher frequency of co-morbidities in patients with ACHD.

Author Correction: At the end of the beginning: immunotherapies as living drugs.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Proceedings: Regenerative Medicine for Lung Diseases: A CIRM Workshop Report.

The mission of the California Institute of Regenerative Medicine (CIRM) is to accelerate treatments to patients with unmet medical needs. In September 2016, CIRM sponsored a workshop held at the University of California, Los Angeles, to discuss regenerative medicine approaches for treatment of lung diseases and to identify the challenges remaining for advancing such treatments to the clinic and market approval. Workshop participants discussed current preclinical and clinical approaches to regenerative medicine in the lung, as well as the biology of lung stem cells and the role of stem cells in the etiology of various lung diseases. The outcome of this effort was the recognition that whereas transient cell delivery approaches are leading the way in the clinic, recent advances in the understanding of lung stem cell biology, in vitro and in vivo disease modeling, gene editing and replacement methods, and cell engraftment approaches raise the prospect of developing cures for some lung diseases in the foreseeable future. In addition, advances in in vitro modeling using lung organoids and "lung on a chip" technology are setting the stage for high quality small molecule drug screening to develop treatments for lung diseases with complex biology. Stem Cells Translational Medicine 2017;6:1823-1828.

In Vivo Cellular Reprogramming: The Next Generation.

Cellular reprogramming technology has created new opportunities in understanding human disease, drug discovery, and regenerative medicine. While a combinatorial code was initially found to reprogram somatic cells to pluripotency, a "second generation" of cellular reprogramming involves lineage-restricted transcription factors and microRNAs that directly reprogram one somatic cell to another. This technology was enabled by gene networks active during development, which induce global shifts in the epigenetic landscape driving cell fate decisions. A major utility of direct reprogramming is the potential of harnessing resident support cells within damaged organs to regenerate lost tissue by converting them into the desired cell type in situ. Here, we review the progress in direct cellular reprogramming, with a focus on the paradigm of in vivo reprogramming for regenerative medicine, while pointing to hurdles that must be overcome to translate this technology into future therapeutics.

Pluripotent stem cells progressing to the clinic.

Basic experimental stem cell research has opened up the possibility of many diverse clinical applications; however, translation to clinical trials has been restricted to only a few diseases. To broaden this clinical scope, pluripotent stem cell derivatives provide a uniquely scalable source of functional differentiated cells that can potentially repair damaged or diseased tissues to treat a wide spectrum of diseases and injuries. However, gathering sound data on their distribution, longevity, function and mechanisms of action in host tissues is imperative to realizing their clinical benefit. The large-scale availability of treatments involving pluripotent stem cells remains some years away, because of the long and demanding regulatory pathway that is needed to ensure their safety.

Challenging Regeneration to Transform Medicine.

UNLABELLED: The aging population in the U.S. and other developed countries has led to a large increase in the number of patients suffering from degenerative diseases. Transplantation surgery has been a successful therapeutic option for certain patients; however, the availability of suitable donor organs and tissues significantly limits the number of patients who can benefit from this approach. Regenerative medicine has witnessed numerous recent and spectacular advances, making the repair or replacement of dysfunctional organs and tissues an achievable goal. Public-private partnerships and government policies and incentives would further catalyze the development of universally available donor tissues, resulting in broad medical and economic benefits. This article describes a Regenerative Medicine Grand Challenge that the Alliance for Regenerative Medicine recently shared with the White House's Office of Science and Technology Policy in response to a White House call to action in scientific disciplines suggesting that the development of "universal donor tissues" should be designated as a Regenerative Medicine Grand Challenge. Such a designation would raise national awareness of the potential of regenerative medicine to address the unmet needs of many diseases and would stimulate the scientific partnerships and investments in technology needed to expedite this goal. Here we outline key policy changes and technological challenges that must be addressed to achieve the promise of a major breakthrough in the treatment of degenerative disease. A nationalized effort and commitment to develop universal donor tissues could realize this goal within 10 years and along the way result in significant innovation in manufacturing technologies. SIGNIFICANCE: Regenerative therapies, in which dysfunctional or degenerating cells, tissues, or organs are repaired or replaced, have the potential to cure chronic degenerative diseases. Such treatments are limited by a shortage of donor organs and tissues and the need for immune suppression to prevent rejection. This article proposes a 21st Century Grand Challenge that would address this significant medical need by coordinating a national effort to convene the multidisciplinary expertise needed to manufacture functional and engraftable cells, tissues, or organs that could be made available to any patient without significant risk of rejection-so-called universal donor tissues.

Proceedings: human leukocyte antigen haplo-homozygous induced pluripotent stem cell haplobank modeled after the california population: evaluating matching in a multiethnic and admixed population.

The development of a California-based induced pluripotent stem cell (iPSC) bank based on human leukocyte antigen (HLA) haplotype matching represents a significant challenge and a valuable opportunity for the advancement of regenerative medicine. However, previously published models of iPSC banks have neither addressed the admixed nature of populations like that of California nor evaluated the benefit to the population as a whole. We developed a new model for evaluating an iPSC haplobank based on demographic and immunogenetic characteristics reflecting California. The model evaluates haplolines or cell lines from donors homozygous for a single HLA-A, HLA-B, HLA-DRB1 haplotype. We generated estimates of the percentage of the population matched under various combinations of haplolines derived from six ancestries (black/African American, American Indian, Asian/Pacific Islander, Hispanic, and white/not Hispanic) and data available from the U.S. Census Bureau, the California Institute for Regenerative Medicine, and the National Marrow Donor Program. The model included both cis (haplotype-level) and trans (genotype-level) matching between a modeled iPSC haplobank and the recipient population following resampling simulations. We showed that serving a majority (>50%) of a simulated California population through cis matching would require the creation, redundant storage, and maintenance of almost 207 different haplolines representing the top 60 most frequent haplotypes from each ancestry group. Allowances for trans matching reduced the haplobank to fewer than 141 haplolines found among the top 40 most frequent haplotypes. Finally, we showed that a model optimized, custom haplobank was able to serve a majority of the California population with fewer than 80 haplolines.

Somatic cell nuclear transfer in Oregon: expanding the pluripotent space and informing research ethics.

In May, Oregon Health and Science University (OHSU) announced the successful derivation, by the Mitalipov laboratory, of embryonic stem cells by somatic cell nuclear transfer. This experiment was recognized as a "formidable technical feat" and potentially a key step toward developing cell-based therapies. The OHSU report is also an example of how a scientific breakthrough can inform research ethics. This article suggests ways that nuclear transfer embryonic stem cell lines may contribute to research ethics by adding rigor to studies addressing pressing research questions important to the development of cell-based therapies.

Pluripotent stem cells from cloned human embryos: success at long last.

Recently in Cell, Mitalipov and colleagues report an advance that has eluded scientists for over a decade-the successful derivation of embryonic stem cell lines using somatic cell nuclear transfer, or SCNT (Tachibana et al., 2013).

The Alpha Stem Cell Clinic: a model for evaluating and delivering stem cell-based therapies.

Cellular therapies require the careful preparation, expansion, characterization, and delivery of cells in a clinical environment. There are major challenges associated with the delivery of cell therapies and high costs that will limit the companies available to fully evaluate their merit in clinical trials, and will handicap their application at the present financial environment. Cells will be manufactured in good manufacturing practice or near-equivalent facilities with prerequisite safety practices in place, and cell delivery systems will be specialized and require well-trained medical and nursing staff, technicians or nurses trained to handle cells once delivered, patient counselors, as well as statisticians and database managers who will oversee the monitoring of patients in relatively long-term follow-up studies. The model proposed for Alpha Stem Cell Clinics will initially use the capacities and infrastructure that exist in the most advanced tertiary medical clinics for delivery of established bone marrow stem cell therapies. As the research evolves, they will incorporate improved procedures and cell preparations. This model enables commercialization of medical devices, reagents, and other products required for cell therapies. A carefully constructed cell therapy clinical infrastructure with the requisite scientific, technical, and medical expertise and operational efficiencies will have the capabilities to address three fundamental and critical functions: 1) fostering clinical trials; 2) evaluating and establishing safe and effective therapies, and 3) developing and maintaining the delivery of therapies approved by the Food and Drug Administration, or other regulatory agencies.

Human disease modeling with induced pluripotent stem cells.

In the past few years, cellular programming, whereby virtually all human cell types, including those deep within the brain or internal organs, can potentially be produced and propagated indefinitely in culture, has opened the door to a new type of disease modeling. Importantly, many diseases or disease predispositions have genetic components that vary from person to person. Now cells from individuals can be readily reprogrammed to form pluripotent cells, and then directed to differentiate into the lineage and the cell type in which the disease manifests. Those cells will contain the genetic contribution of the donor, providing an excellent model to delve into human disease at the level of individuals and their genomic variants. To date, over fifty such disease models have been reported, and while the field is young and hurdles remain, these tools promise to inform scientists about the cause and cellular-molecular mechanisms involved in pathology, unravel the role of environmental versus hereditary factors driving disease, and provide an unprecedented tool for screening therapeutic agents that might slow or halt disease progression.

Stem cell biology: Towards the reality of cell therapeutics.

Although the road to cell therapeutics is rife with uncertainties ­ scientific, clinical and economic ­ its success could transform medicine. Five years into its mission, the California Institute of Regenerative Medicine is laying a foundation for this new form of medical treatment.