Design, synthesis and antiproliferative activity of raloxifene/histone deacetylase inhibitor hybrids in breast cancer.

Antiestrogen/histone deacetylase inhibitor (HDACi) hybrids were designed by merging structures of raloxifene with suberoylanilide hydroxamic acid, incorporating the HDACi unit into the phenolic ring of the antiestrogen. These hybrids were synthesized with a range of HDACi chain lengths and assessed for bifunctionality. Four hybrids, 21 (YW471), 22 (YW490), 27(YW486), and 28 (YW487) showed good potency both as antiestrogens in a BRET assay and in a fluorometric HDACi assay.

Phase locking of hippocampal CA3 neurons to distal CA1 theta oscillations selectively predicts memory performance.

How the coordination of neuronal spiking and brain rhythms between hippocampal subregions supports memory function remains elusive. We studied the interregional coordination of CA3 neuronal spiking with CA1 theta oscillations by recording electrophysiological signals along the proximodistal axis of the hippocampus in rats that were performing a high-memory-demand recognition memory task adapted from humans. We found that CA3 population spiking occurs preferentially at the peak of distal CA1 theta oscillations when memory was tested but only when previously encountered stimuli were presented.

The ERK inhibitor LY3214996 augments anti-PD-1 immunotherapy in preclinical mouse models of BRAFV600E melanoma brain metastasis.

Background: Immune checkpoint inhibitors (ICI) have revolutionized cancer treatment; however, only a subset of patients with brain metastasis (BM) respond to ICI. Activating mutations in the mitogen-activated protein kinase signaling pathway are frequent in BM. The objective of this study was to evaluate whether therapeutic inhibition of extracellular signal-regulated kinase (ERK) can improve the efficacy of ICI for BM.

Recalling gist memory depends on CA1 hippocampal neurons for lifetime retention and CA3 neurons for memory precision.

Why some of us remember events more clearly than others and why memory loses precision over time is a major focus in memory research. Here, we show that the recruitment of specific neuroanatomical pathways within the medial temporal lobe (MTL) of the brain defines the precision of the memory recalled over the lifespan. Using optogenetics, neuronal activity mapping, and studying recent to very remote memories, we report that the hippocampal subfield CA1 is necessary for retrieving the gist of events and receives maximal support from MTL cortical areas (MEC, LEC, PER, and POR) for recalling the most remote memories.

Inhibitory temporo-parietal effective connectivity is associated with explicit memory performance in older adults.

Successful explicit memory encoding is associated with inferior temporal activations and medial parietal deactivations, which are attenuated in aging. Here we used dynamic causal modeling (DCM) of functional magnetic resonance imaging data to elucidate effective connectivity patterns between hippocampus, parahippocampal place area (PPA), and precuneus during encoding of novel visual scenes. In 117 young adults, DCM revealed pronounced activating input from the PPA to the hippocampus and inhibitory connectivity from the PPA to the precuneus during novelty processing, with both being enhanced during successful encoding.