A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal cord injury

LncRNA RP11-361F15.2 promotes osteosarcoma tumorigenesis by inhibiting M2-Like polarization of tumor-associated macrophages of CPEB4.

Pancreatic neuroendocrine tumors (pNETs) are unique, slow-growing malignancies whose molecular pathogenesis is incompletely understood. With rising incidence of pNETs over the last four decades, larger and more comprehensive ‘omic’ analyses of patient tumors have led to a clearer picture of the pNET genomic landscape and transcriptional profiles for both primary and metastatic lesions. In pNET patients with advanced disease, those insights have guided the use of targeted therapies that inhibit activated mTOR and receptor tyrosine kinase (RTK) pathways or stimulate somatostatin receptor signaling. Such treatments have significantly benefited patients, but intrinsic or acquired drug resistance in the tumors remains a major problem that leaves few to no effective treatment options for advanced cases. This demands a better understanding of essential molecular and biological events underlying pNET growth, metastasis, and drug resistance. This review examines the known molecular alterations associated with pNET pathogenesis, identifying which changes may be drivers of the disease and, as such, relevant therapeutic targets. We also highlight areas that warrant further investigation at the biological level and discuss available model systems for pNET research. The paucity of pNET models has hampered research efforts over the years, although recently developed cell line, animal, patient-derived xenograft, and patient-derived organoid models have significantly expanded the available platforms for pNET investigations. Advancements in pNET research and understanding are expected to guide improved patient treatments.

Pancreatic Neuroendocrine Tumors: Molecular Mechanisms and Therapeutic Targets.

Purpose: Malignant peripheral nerve sheath tumors (MPNST) are deadly sarcomas that lack effective therapies. In most MPNSTs, the retinoblastoma (RB1) tumor suppressor is disabled by hyperactivation of cyclin-dependent kinases (CDK), commonly through loss of CDK-inhibitory proteins such as p27(Kip1). RABL6A is an inhibitor of RB1 whose role in MPNSTs is unknown. To gain insight into MPNST development and establish new treatment options, we investigated RABL6A-RB1 signaling and CDK inhibitor–based therapy in MPNSTs. Experimental Design: We examined patient-matched MPNSTs and precursor lesions by RNA sequencing (RNA-Seq) and IHC. Molecular and biological effects of silencing RABL6A and/or p27 in MPNST lines and normal human Schwann cells were determined. Tumor-suppressive effects of CDK inhibitors were measured in MPNST cells and orthotopic tumors. Results: RABL6A was dramatically upregulated in human MPNSTs compared with precursor lesions, which correlated inversely with p27 levels. Silencing RABL6A caused MPNST cell death and G1 arrest that coincided with p27 upregulation, CDK downregulation, and RB1 activation. The growth-suppressive effects of RABL6A loss, and its regulation of RB1, were largely rescued by p27 depletion. Importantly, reactivation of RB1 using a CDK4/6 inhibitor (palbociclib) killed MPNST cells in vitro in an RABL6A-dependent manner and suppressed MPNST growth in vivo. Low-dose combination of drugs targeting multiple RB1 kinases (CDK4/6, CDK2) had enhanced antitumorigenic activity associated with potential MPNST cell redifferentiation. Conclusions: RABL6A is a new driver of MPNST pathogenesis that acts in part through p27-RB1 inactivation. Our results suggest RB1 targeted therapy with multiple pathway drugs may effectively treat MPNSTs.

https://clincancerres.aacrjournals.org/content/clincanres/26/12/2997.full.pdf

RABL6A is an essential driver of mpnsts that negatively regulates the rb1 pathway and sensitizes tumor cells to CDK4/6 inhibitors

Spinal cord injury (SCI) is the main cause of severe damage to the central nervous system and leads to irreversible tissue loss and neurological dysfunction. Ferroptosis is a cell death pattern, newly discovered in recent years. Ferroptosis is an oxidizing cell death induced by small molecules, and is an iron-dependent process caused by the imbalance between the generation and degradation of lipid reactive oxygen species (ROS) in cells. As an antioxidant, trehalose can effectively prevent lipid peroxidation. Studies have reported that trehalose can improve the prognosis of SCI. However, it is unclear whether these benefits are related to ferroptosis. In this study, we demonstrated for the first time that trehalose reduces the degeneration and iron accumulation of neurons by inhibiting the production of ROS and ferroptosis caused by lipid peroxides after SCI, thus promoting the survival of neurons and improving the recovery of motor function. More specifically, we found that trehalose inhibited the expansion of cavities in the nerve tissue of mice with SCI, inhibited neuron loss, and improved functional recovery. In terms of mechanism, our results indicate that the neuroprotective effect of trehalose is due to the activation of the NRF2/HO-1 pathway, which in turn inhibits ferroptosis and ferroptosis-related inflammation. Our findings provide important insights into the previously unknown role of trehalose in SCI, as well as new evidence supporting the hypothesis that suppression of ferroptosis plays a key neuroprotective role in SCI.

/pdf/trehalose-inhibits-ferroptosis-via-nrf2-ho-1-pathway-and-1ua99a5m.pdf

Trehalose inhibits ferroptosis via NRF2/HO-1 pathway and promotes functional recovery in mice with spinal cord injury

Osteosarcoma is the most common type of primary malignant tumor of the bone. However, mechanisms underlying osteosarcoma cell proliferation are poorly understood. The present study shows that RBEL1, a newly identified Rab-like GTPase, may be a key regulator of osteosarcoma cell proliferation. Knockdown of RBEL1 in osteosarcoma cells resulted in impaired colony formation and cell proliferation. Cell cycle analysis suggested that RBEL1 depletion induced G1-S arrest in osteosarcoma cells. Furthermore, it was demonstrated that retinoblastoma 1 (Rb) was upregulated and activated following RBEL1 knockdown. In addition, Rb inhibitory downstream targets, such as cyclin A2, cyclin D1, c-Myc and cyclin-dependent kinase 2, were downregulated. Rb knockdown reversed RBEL1 depletion-induced tumor suppressive effects. In conclusion, the present results suggest that RBEL1 modulates cell proliferation and G1‑S transition by inhibiting Rb in osteosarcoma. These results suggest a potential therapeutic target in osteosarcoma.

/pdf/rbel1-is-required-for-osteosarcoma-cell-proliferation-via-2ced2rs0de.pdf

RBEL1 is required for osteosarcoma cell proliferation via inhibiting retinoblastoma 1

Xueshuantong injection combined with Salvianolate lyophilized injection improves the synaptic plasticity against focal cerebral ischemia/reperfusion injury in rats through PI3K/AKT/mTOR and RhoA/ROCK pathways

Background Biosynthesis of leukotriene (LT) by arachidonic acid involves 5-lipoxygenase (5-LO) as an important precursor. Here, we evaluated the role of pseudohypericin (PHP) for its postulated 5-LO inhibitory activity along with a Cys-LT receptor antagonist zafirlukast (ZFL) against inflammatory response and tissue injury in mice. Materials and methods The spinal injury was induced by two-level laminectomy of T6 and T7 vertebrae. The inflammation was assessed by histology, inflammatory mediators by enzyme-linked immunosorbent assay, apoptosis by Annexin-V, FAS staining, terminal deoxynucleoti-dyltransferase-mediated UTP end labeling (TUNEL) assay and expression of Bax and Bcl-2 by Western blot. Effect on motor recovery of hind limbs was evaluated for 10 days postinjury. Results The spinal injury resulted in tissue damage, apoptosis, edema, infiltration of neutrophils with increased expression of tumor necrosis factor-α (TNF-α) and cyclooxygenase-2 (COX-2). The spinal tissue showed elevated levels of prostaglandin E2 (PGE2), and LTB4 and increased phosphorylation of injured extracellular signal-regulated kinase-1/2 (ERK1/2). The PHP, ZFL and combination decreased inflammation, tissue injury and infiltration of neutrophils. Treatment also decreased the levels of PGE2, phosphorylation of extracellular signal-regulated kinase-1/2 (pERK 1/2), LT, TNF-α and COX-2 with a marked reduction in apoptosis and improved the motor function. Conclusion The present study confirmed 5-LO antagonist activity of PHP and established its neuroprotective role along with ZFL.

/pdf/zafirlukast-in-combination-with-pseudohypericin-attenuates-34w136unug.pdf

Zafirlukast in combination with pseudohypericin attenuates spinal cord injury and motor function in experimental mice.

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RBEL1 is required for osteosarcoma cell proliferation via inhibiting retinoblastoma 1

Xueshuantong injection combined with Salvianolate lyophilized injection improves the synaptic plasticity against focal cerebral ischemia/reperfusion injury in rats through PI3K/AKT/mTOR and RhoA/ROCK pathways

Zafirlukast in combination with pseudohypericin attenuates spinal cord injury and motor function in experimental mice.