Human pallial MGE-type GABAergic interneuron cell therapy for chronic focal epilepsy.

Mesial temporal lobe epilepsy (MTLE) is the most common focal epilepsy. One-third of patients have drug-refractory seizures and are left with suboptimal therapeutic options such as brain tissue-destructive surgery. Here, we report the development and characterization of a cell therapy alternative for drug-resistant MTLE, which is derived from a human embryonic stem cell line and comprises cryopreserved, post-mitotic, medial ganglionic eminence (MGE) pallial-type GABAergic interneurons. Single-dose intrahippocampal delivery of the interneurons in a mouse model of chronic MTLE resulted in consistent mesiotemporal seizure suppression, with most animals becoming seizure-free and surviving longer. The grafted interneurons dispersed locally, functionally integrated, persisted long term, and significantly reduced dentate granule cell dispersion, a pathological hallmark of MTLE. These disease-modifying effects were dose-dependent, with a broad therapeutic range. No adverse effects were observed. These findings support an ongoing phase 1/2 clinical trial (NCT05135091) for drug-resistant MTLE.

Old drugs, new tricks: leveraging known compounds to disrupt coronavirus-induced cytokine storm.

A major complication in COVID-19 infection consists in the onset of acute respiratory distress fueled by a dysregulation of the host immune network that leads to a run-away cytokine storm. Here, we present an in silico approach that captures the host immune system's complex regulatory dynamics, allowing us to identify and rank candidate drugs and drug pairs that engage with minimal subsets of immune mediators such that their downstream interactions effectively disrupt the signaling cascades driving cytokine storm. Drug-target regulatory interactions are extracted from peer-reviewed literature using automated text-mining for over 5000 compounds associated with COVID-induced cytokine storm and elements of the underlying biology. The targets and mode of action of each compound, as well as combinations of compounds, were scored against their functional alignment with sets of competing model-predicted optimal intervention strategies, as well as the availability of like-acting compounds and known off-target effects. Top-ranking individual compounds identified included a number of known immune suppressors such as calcineurin and mTOR inhibitors as well as compounds less frequently associated for their immune-modulatory effects, including antimicrobials, statins, and cholinergic agonists. Pairwise combinations of drugs targeting distinct biological pathways tended to perform significantly better than single drugs with dexamethasone emerging as a frequent high-ranking companion. While these predicted drug combinations aim to disrupt COVID-induced acute respiratory distress syndrome, the approach itself can be applied more broadly to other diseases and may provide a standard tool for drug discovery initiatives in evaluating alternative targets and repurposing approved drugs.

Analysis of PPARγ Signaling Activity in Psoriasis.

In our previous work, we built the model of PPARγ dependent pathways involved in the development of the psoriatic lesions. Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor and transcription factor which regulates the expression of many proinflammatory genes. We tested the hypothesis that low levels of PPARγ expression promote the development of psoriatic lesions triggering the IL17-related signaling cascade. Skin samples of normally looking and lesional skin donated by psoriasis patients and psoriatic CD3+ Tcells samples (n = 23) and samples of healthy CD3+ T cells donated by volunteers (n = 10) were analyzed by real-time PCR, ELISA and immunohistochemistry analysis. We found that the expression of PPARγ is downregulated in human psoriatic skin and laser treatment restores the expression. The expression of IL17, STAT3, FOXP3, and RORC in psoriatic skin before and after laser treatment were correlated with PPARγ expression according to the reconstructed model of PPARγ pathway in psoriasis.In conclusion, we report that PPARγ weakens the expression of genes that contribute in the development of psoriatic lesion. Our data show that transcriptional regulation of PPARγ expression by FOSL1 and by STAT3/FOSL1 feedback loop may be central in the psoriatic skin and T-cells.

The Model of PPARγ-Downregulated Signaling in Psoriasis.

Interactions of genes in intersecting signaling pathways, as well as environmental influences, are required for the development of psoriasis. Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor and transcription factor which inhibits the expression of many proinflammatory genes. We tested the hypothesis that low levels of PPARγ expression promote the development of psoriatic lesions. We combined experimental results and network functional analysis to reconstruct the model of PPARγ-downregulated signaling in psoriasis. We hypothesize that the expression of IL17, STAT3, FOXP3, and RORC and FOSL1 genes in psoriatic skin is correlated with the level of PPARγ expression, and they belong to the same signaling pathway that regulates the development of psoriasis lesion.

Apatinib Mesylate in the treatment of advanced progressed lung adenocarcinoma patients with EGFR-TKI resistance -A Multicenter Randomized Trial.

Few pieces of evidence have been published on the use of Apatinib Mesylate (AM) against EGFR-TKI resistance in lung adenocarcinoma (LA) patients. Here, we investigate the clinical efficacy and safety of AM in the treatment of advanced progressed epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) resistant LA patients. We conducted a double-blind, randomized controlled trial in 68 patients admitted to 18 hospitals of Anhui province in China. The efficacy and safety of AM treatment were evaluated in terms of progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR), as well as related adverse events (AE). A literature knowledge database analysis and a pathway model reconstruction were performed to decipher the relevant mechanism may be involved. Our results showed that, compared to the control group, AM presented improved efficacy in PFS (P = 0.033), ORR (P < 0.001), and DCR (P < 0.001). No significant difference was observed between case and control group in terms of AE, and no drug-related death occurred. Pathway analysis supports that Apatinib can be repurposed for the treatment of LA. Our results suggested that AM could be a potential option for advanced progressed LA patients to combat EGFR-TKI resistance.

Empowerment of 15-Lipoxygenase Catalytic Competence in Selective Oxidation of Membrane ETE-PE to Ferroptotic Death Signals, HpETE-PE.

sn2-15-Hydroperoxy-eicasotetraenoyl-phosphatidylethanolamines ( sn2-15-HpETE-PE) generated by mammalian 15-lipoxygenase/phosphatidylethanolamine binding protein-1 (15-LO/PEBP1) complex is a death signal in a recently identified type of programmed cell demise, ferroptosis. How the enzymatic complex selects sn2-ETE-PE as the substrate among 1 of ∼100 total oxidizable membrane PUFA phospholipids is a central, yet unresolved question. To unearth the highly selective and specific mechanisms of catalytic competence, we used a combination of redox lipidomics, mutational and computational structural analysis to show they stem from (i) reactivity toward readily accessible hexagonally organized membrane sn2-ETE-PEs, (ii) relative preponderance of sn2-ETE-PE species vs other sn2-ETE-PLs, and (iii) allosteric modification of the enzyme in the complex with PEBP1. This emphasizes the role of enzymatic vs random stochastic free radical reactions in ferroptotic death signaling.

Hair follicle morphogenesis and epidermal homeostasis in we/we wal/wal mice with postnatal alopecia.

Mice with skin and hair follicle (HF) defects are common models of human skin disorders. A mutant strain with the we/we wal/wal genotype develops alopecia. We found the hair shaft structure in the pelage of mutant mice to have significant defects. Although these mice lose their hair at 21 days, a label-retaining cell population persists in HFs until at least day 54. Depilation-induced anagen was accomplished in we/we wal/wal mutants but the resulting hair shafts were short and extremely deformed. Serious abnormalities in epidermis stratification and HF morphogenesis exist in we/we wal/wal homozygous E18.5 embryos. There were significantly fewer HF primordia in this mutant compared with wild type. We discovered specific structures, identified as invalid placodes, positive for ectodysplasin A1 receptor, nuclear ß-catenin, and LEF1, which failed to invaginate, produced a double basal-like layer of epidermal cells, and lacked cylindrical keratinocytes. Specification of dermal papillae (DP) was impaired, and the papillary dermis expressed alkaline phosphatase and LEF1. We also detected DP-like groups of intensively stained cells in the absence of visible signs of folliculogenesis in the epidermis. We showed differentiation disturbances in the mutant embryonic E18.5 epidermis and HFs: The cornified layer was absent, the width of the spinous layer was reduced, and HFs lacked LEF1-positive precortex cells. In this study, we used a very interesting and useful mouse model of alopecia. The presence of symptoms of skin disorders in we/we wal/wal murine embryos correlates with the postnatal skin phenotype. This correlation may help to evaluate reasons of alopecia.