Integration of ERα-PELP1-HER2 signaling by LSD1 (KDM1A/AOF2) offers combinatorial therapeutic opportunities to circumventing hormone resistance in breast cancer

Accumulating evidence indicates that psychological stress can have deleterious influences on cancer development and progression, but the mechanisms responsible remain unclear. One possible mechanism is suggested by emerging evidence that DNA damage is increased by exposure to stress and stress hormones (for example, cortisol, catecholamines). Possible molecular mechanisms for such effects were the subject of a recent paper by Hara and colleagues, which suggests that chronic stress, through ??-adrenergic stimulation, can induce two synergistic pathways that result in accumulation of DNA damage. Herein, we discuss the potential implications of these findings for breast cancer etiology, progression, and treatment response.     

Cardiac repolarization instability during normal postnatal development

Long QT syndrome is a disease characterized by abnormal lengthening of the QT interval and by sudden cardiac death. It is a disease of development, with the incidence of a sudden event increasing during childhood. Repolarization instability during postnatal development could make the substrate susceptible to a fatal arrhythmia. Dynamic changes in repolarization that occur on a beat-to-beat basis, known as alternans, are a hallmark of electrical instability. T-wave alternans (TWA) in the electrocardiogram correlates with arrhythmia risk and long-term survival in adults. We determined TWA properties longitudinally in vivo in 7 propofol-sedated New Zealand white rabbits using transesophageal pacing weekly from 2 to 10 weeks of age. Furthermore, TWA induction after the onset of rapid pacing was characterized in vitro in 6 infant (2 weeks) and 6 adolescent (7 weeks) isolated, arterially perfused rabbit hearts. In vivo, TWA amplitude was maximum at 2 weeks and declined with age. Isoproterenol increased TWA at 8 weeks (adolescence). In vitro, large-amplitude TWA was induced with rapid pacing in both infant and adolescents but decreased to low, steady-state levels in infants. We conclude that TWA properties are age dependent in rabbit. Significant TWA is induced in rabbit at the onset of rapid pacing.     

IRAK2 is associated with systemic lupus erythematosus risk

Clinical Rheumatology - Interleukin-1 receptor-associated kinases (IRAKs) are serine-threonine kinases involved in toll-like receptor and interleukin-1 signaling pathways. They play a key role in...     

A simplified radiosynthesis of [18F]MK‐6240 for tau PET imaging

[¹⁸F]MK‐6240 (6‐(fluoro)‐3‐(1H‐pyrrolo[2,3‐c]pyridin‐1‐yl)isoquinolin‐5‐amine) is a highly selective PET radiotracer for the in vivo imaging of neurofibrillary tangles (NFTs). [¹⁸F]MK‐6240 was synthesized in one step from its bis‐Boc protected precursor N‐[(tert‐butoxy)carbonyl]‐N‐(6‐nitro‐3‐[1H‐pyrrolo[2,3‐c]pyridin‐1‐yl]isoquinolin‐5‐yl) carbamate in DMSO using [¹⁸F] fluoride with TEA HCO₃ with step‐wise heating up to 150°C, resulting in an isolated radiochemical yield of 9.8% ± 1.8% (n = 3) calculated from the end of bombardment (5.2% ± 1.0% calculated from the end of synthesis). This new synthetic approach eliminates the acidic deprotection of the bis‐Boc ¹⁸F‐labeled intermediate, which reduces the number of operations necessary for the synthesis as well as losses, which occur during deprotection and neutralization of the crude product mixture prior to the HPLC purification. The synthesis was performed automatically with a single‐use cassette on an IBA Synthera+ synthesis module. This synthesis method affords the radioligand with a reliable radiochemical yield, high radiochemical purity, and a high molar activity. [¹⁸F]MK‐6240 synthesized with this method has been regularly (n > 60) used in our ongoing human and animal PET imaging studies.     

PET/CT Imaging of 89Zr-N-sucDf-Pembrolizumab in Healthy Cynomolgus Monkeys

Molecular Imaging and Biology - Programmed cell death-1 receptor (PD-1) and its ligand (PD-L1) are the targets for immunotherapy in many cancer types. Although PD-1 blockade has therapeutic...