Transient titin-dependent ventricular defects during development lead to adult atrial arrhythmia and impaired contractility.

Developmental causes of the most common arrhythmia, atrial fibrillation (AF), are poorly defined, with compensation potentially masking arrhythmic risk. Here, we delete 9 amino acids (Δ9) within a conserved domain of the giant protein titin's A-band in zebrafish and human-induced pluripotent stem cell-derived atrial cardiomyocytes (hiPSC-aCMs). We find that zebrafish embryos' cardiac morphology is perturbed and accompanied by reduced functional output, but ventricular function recovers within days.

Engineered cocultures of iPSC-derived atrial cardiomyocytes and atrial fibroblasts for modeling atrial fibrillation.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia treatable with antiarrhythmic drugs; however, patient responses remain highly variable. Human induced pluripotent stem cell-derived atrial cardiomyocytes (iPSC-aCMs) are useful for discovering precision therapeutics, but current platforms yield phenotypically immature cells and are not easily scalable for high-throughput screening. Here, primary adult atrial, but not ventricular, fibroblasts induced greater functional iPSC-aCM maturation, partly through connexin-40 and ephrin-B1 signaling.

Reanalysis of Trichloroethylene and Tetrachloroethylene Metabolism to Glutathione Conjugates Using Human, Rat, and Mouse Liver Models to Improve Precision in Risk Characterization.

Background: Both trichloroethylene (TCE) and tetrachloroethylene (PCE) are high-priority chemicals subject to numerous human health risk evaluations by a range of agencies. Metabolism of TCE and PCE determines their ultimate toxicity; important uncertainties exist in quantitative characterization of metabolism to genotoxic moieties through glutathione (GSH) conjugation and species differences therein.

Objectives: This study aimed to address these uncertainties using novel liver models, interspecies comparison, and a sensitive assay for quantification of GSH conjugates of TCE and PCE, -(1,2-dichlorovinyl)glutathione (DCVG) and -(1,2,2-trichlorovinyl) glutathione (TCVG), respectively.

Mutant ANP induces mitochondrial and ion channel remodeling in a human iPSC-derived atrial fibrillation model.

Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) can model heritable arrhythmias to personalize therapies for individual patients. Although atrial fibrillation (AF) is a leading cause of cardiovascular morbidity and mortality, current platforms to generate iPSC-atrial (a) CMs are inadequate for modeling AF. We applied a combinatorial engineering approach, which integrated multiple physiological cues, including metabolic conditioning and electrical stimulation, to generate mature iPSC-aCMs.

LIGHT enhanced bispecific antibody armed T-cells to treat immunotherapy resistant colon cancer.

Increased tumor infiltrating lymphocytes (TIL) are associated with improved patient responses to immunotherapy. As a result, there is interest in enhancing lymphocyte trafficking particularly to colon cancers since the majority are checkpoint blockade-resistant and microsatellite stable. Here, we demonstrate that activated T-cells (ATC) armed with anti-CD3 x anti-EGFR bispecific antibody increases TIL and mediate anti-tumor cytotoxicity while decreasing tumor cell viability.

Latest impact of engineered human liver platforms on drug development.

Drug-induced liver injury (DILI) is a leading cause of drug attrition, which is partly due to differences between preclinical animals and humans in metabolic pathways. Therefore, human liver models are utilized in biopharmaceutical practice to mitigate DILI risk and assess related mechanisms of drug transport and metabolism. However, liver cells lose phenotypic functions within 1-3 days in two-dimensional monocultures on collagen-coated polystyrene/glass, which precludes their use to model the chronic effects of drugs and disease stimuli.

Bioengineering approaches to mature induced pluripotent stem cell-derived atrial cardiomyocytes to model atrial fibrillation.

Induced pluripotent stem cells (iPSCs) serve as a robust platform to model several human arrhythmia syndromes including atrial fibrillation (AF). However, the structural, molecular, functional, and electrophysiological parameters of patient-specific iPSC-derived atrial cardiomyocytes (iPSC-aCMs) do not fully recapitulate the mature phenotype of their human adult counterparts. The use of physiologically inspired microenvironmental cues, such as postnatal factors, metabolic conditioning, extracellular matrix (ECM) modulation, electrical and mechanical stimulation, co-culture with non-parenchymal cells, and 3D culture techniques can help mimic natural atrial development and induce a more mature adult phenotype in iPSC-aCMs.

ERRATUM.

Testing drugs in isogenic rodent strains to satisfy regulatory requirements is insufficient for derisking organ toxicity in genetically diverse human populations; in contrast, advances in mouse genetics can help mitigate these limitations. Compared to the expensive and slower in vivo testing, in vitro cultures enable the testing of large compound libraries toward prioritizing lead compounds and selecting an animal model with human-like response to a compound. In the case of the liver, a leading cause of drug attrition, isolated primary mouse hepatocytes (PMHs) rapidly decline in function within current culture platforms, which restricts their use for assessing the effects of longer-term compound exposure.

Long-Term Engineered Cultures of Primary Mouse Hepatocytes for Strain and Species Comparison Studies During Drug Development.

Testing drugs in isogenic rodent strains to satisfy regulatory requirements is insufficient for derisking organ toxicity in genetically diverse human populations; in contrast, advances in mouse genetics can help mitigate these limitations. Compared to the expensive and slower in vivo testing, in vitro cultures enable the testing of large compound libraries toward prioritizing lead compounds and selecting an animal model with human-like response to a compound. In the case of the liver, a leading cause of drug attrition, isolated primary mouse hepatocytes (PMHs) rapidly decline in function within current culture platforms, which restricts their use for assessing the effects of longer-term compound exposure.

Microfabrication of liver and heart tissues for drug development.

Drug-induced liver- and cardiotoxicity remain among the leading causes of preclinical and clinical drug attrition, marketplace drug withdrawals and black-box warnings on marketed drugs. Unfortunately, animal testing has proven to be insufficient for accurately predicting drug-induced liver- and cardiotoxicity across many drug classes, likely due to significant differences in tissue functions across species. Thus, the field of human tissue engineering has gained increasing importance over the last 10 years.

Cutaneous erosions: a herald for impending pancytopenia in methotrexate toxicity.

Psoriatic plaque erosion is a rare toxic side effect of low-dose methotrexate (LDMTX) that has been reported during the treatment of psoriasis and described as a herald for impending pancytopenia. Fatalities from this have rarely been reported. Even rarer is methotrexate (MTX)-induced erosions of clinically normal skin in patients without a history of psoriasis.

Autoimmune clustering: sweet syndrome, Hashimoto thyroiditis, and psoriasis.

Acute febrile neutrophilic dermatosis (AFND; Sweet syndrome) is characterized by a constellation of symptoms and findings: fever, neutrophilia, and tender erythematous skin lesions that typically show an upper dermal infiltrate of mature neutrophils. Whereas some cases are idiopathic, others have been associated with a variety of disorders. In this report, we describe the occurrence of AFND with chronic lymphocytic thyroiditis (Hashimoto thyroiditis) and preexisting psoriasis.