miR-590-3p protects against ischaemia/reperfusion injury in an oxygen-glucose deprivation and reoxygenation cellular model by regulating HMGB1/TLR4/MyD88/NF-κB signalling

miR-590-3p has been reported to be reduced in myocardial ischaemia-reperfusion (I/R) injury, but its specific role in cerebral I/R injury is still uncertain. Thus, we explored the function and mechanism of miR590-3p in cerebral I/R injury using a cellular model. miR-590-3p, high mobility group Box 1 (HMGB1), and signalling-related factor levels were assessed using qPCR or a western blot analysis. Cell apoptosis was measured by flow cytometry. Inflammatory factors were detected by ELISA. The target of miR-590-3p was confirmed by dual-luciferase reporter assay and western blot analysis. We found that miR-590-3p was decreased and HMGB1 was increased in the OGD/R model. Upregulation of miR-590-3p reduced cell apoptosis and inflammation in the OGD/R model, and the TLR4/MyD88/NF-κB signalling pathway was suppressed. However, inhibition of miR-590-3p showed the opposite effects. Moreover, HMGB1 was verified as a target gene of miR-590-3p. HMGB1 reversed the decrease in apoptosis and inflammation caused by overexpression of miR590-3p, and the TLR4/MyD88/NF-κB signalling pathway was activated. Our results suggest that miR-590-3p regulates the TLR4/MyD88/NF-κB pathway by interacting with HMGB1 to protect against OGD/R-induced I/R injury. Thus, miR-590-3p may serve as a potential therapeutic target in cerebral I/R repair

Phase 1 study of mTORC1/2 inhibitor sapanisertib (TAK-228) in advanced solid tumours, with an expansion phase in renal, endometrial or bladder cancer

Background: This Phase 1 dose-escalation/expansion study assessed safety/tolerability of sapanisertib, an oral, highly selective inhibitor of mTORC1/mTORC2, in advanced solid tumours. Methods: Eligible patients received increasing sapanisertib doses once daily (QD; 31 patients), once weekly (QW; 30 patients), QD for 3 days on/4 days off QW (QD × 3dQW; 33 patients) or QD for 5 days on/2 days off QW (QD × 5dQW; 22 patients). In expansion cohorts, 82 patients with renal cell carcinoma (RCC), endometrial or bladder cancer received sapanisertib 5 mg QD (39 patients), 40 mg QW (26 patients) or 30 mg QW (17 patients). Results: Maximum tolerated doses of sapanisertib were 6 mg QD, 40 mg QW, 9 mg QD × 3dQW and 7 mg QD × 5dQW. Frequent dose-limiting toxicities (DLTs) included hyperglycaemia, maculo-papular rash (QD), asthenia and stomatitis (QD × 3dQW/QD × 5dQW); expansion phase doses of 5 mg QD and 30 mg QW were selected based on tolerability beyond the DLT evaluation period. One patient with RCC achieved complete response; nine experienced partial responses (RCC: seven patients; carcinoid tumour/endometrial cancer: one patient each). Sapanisertib pharmacokinetics were time-linear and supported multiple dosing. Pharmacodynamic findings demonstrated treatment-related reductions in TORC1/2 biomarkers. Conclusions: Sapanisertib demonstrated a manageable safety profile, with preliminary antitumour activity observed in RCC and endometrial cancer

A der(8)t(8;11) chromosome in the Karpas-620 myeloma cell line expresses only cyclin D1: yet both cyclin D1 and MYC are repositioned in close proximity to the 3'IGH enhancer

The Karpas-620 human myeloma cell line (HMCL) expresses high levels of Cyclin D1 (CCND1), but has a der(8)t(8;11) and a der(14)t(8;14), and not a conventional t(11;14). Fluorescent in situ hybridization (FISH) and array comparative genomic hybridization (aCGH) studies suggest that der(14)t(11;14) from a primary translocation underwent a secondary translocation with chromosome 8 to generate der(8)t(8;[14];11) and der(14)t(8;[11];14). Both secondary derivatives share extensive identical sequences from chromosomes 8, 11, and 14, including MYC and the 3' IgH enhancers. Der(14), with MYC located approximately 700 kb telomeric to the 3'IGH enhancer, expresses MYC. By contrast, der(8), with both CCND1 and MYC repositioned near a 3'IGH enhancer, expresses CCND1, which is telomeric of the enhancer, but not MYC, which is centromeric to the enhancer. The secondary translocation that dysregulated MYC resulted in extensive regions from both donor chromosomes being transmitted to both derivative chromosomes, suggesting a defect in DNA recombination or repair in the myeloma tumor cell

Phase 1 Study to Evaluate the Effect of the Investigational Anticancer Agent Sapanisertib on the QTc Interval in Patients With Advanced Solid Tumors

The aim of this phase 1 study was to determine the effects of sapanisertib on the heart rate–corrected QT (QTc) interval in patients with advanced solid tumors. Adult patients with advanced solid tumors were enrolled to receive a single sapanisertib 40‐mg dose. Blood samples for pharmacokinetic analysis were collected and electrocardiogram readings were recorded at baseline and up to 48 hours after dosing. Patients could continue to receive sapanisertib 30 mg once weekly in 28‐day cycles for up to 12 months. The primary objective was to characterize the effect of a single dose of sapanisertib (40 mg) on the QT interval. Secondary objectives were to evaluate safety, tolerability, and pharmacokinetics. Following a single sapanisertib 40‐mg dose in 44 patients, the maximum least squares mean (upper bound of 1‐sided 95% confidence interval) changes from time‐matched baseline were 7.1 milliseconds (11.4 milliseconds) for individual rate‐corrected QT interval at 24 hours after dosing, and 1.8 milliseconds (5.6 milliseconds) for Fridericia‐corrected QTc at 1 hour post‐dose. There was no sapanisertib plasma concentration‐dependent increase in the change from time‐matched baseline individual rate‐corrected QTc interval or Fridericia‐corrected QTc. The most common adverse events following sapanisertib 30 mg once‐weekly dosing were nausea (80%), fatigue (61%), vomiting (57%), and decreased appetite (45%). A single sapanisertib 40 mg dose did not produce clinically relevant effects on QTc interval in patients with advanced solid tumors. The safety profile of sapanisertib 30 mg once weekly was favorable, and no new safety signals were observed (NCT02197572, clinicaltrials.gov)

Clinical Response to Anti-CD47 Immunotherapy Is Associated with Rapid Reduction of Exhausted Bystander CD4+ BTLA+ T Cells in Tumor Microenvironment of Mycosis Fungoides

Cancer progression in mycosis fungoides, the most common form of cutaneous T-cell lymphoma, occurs in a predictable, sequential pattern that starts from patches and that evolves to plaques and later to tumors. Therefore, unlocking the relationship between the microarchitecture of mycosis fungoides and the clinical counterparts of that microstructure represents important steps for the design of targeted therapies. Using multispectral fluorescent imaging, we show that the progression of mycosis fungoides from plaque to tumor parallels the cutaneous expansion of the malignant CD4+ T cells that express TOX. The density of exhausted BTLA+ CD4+ T cells around malignant CD4+TOX+ cells was higher in tumors than it was in plaques, suggesting that undesired safeguards are in place within the tumor microenvironment that prevent immune activation and subsequent cancer eradication. Overriding the CD47 checkpoint with an intralesional SIRPαFc fusion decoy receptor induced the resolution of mycosis fungoides in patients that paralleled an amplified expansion of NK and CD8+ T cells in addition to a reduction of the exhausted BTLA+ CD4+ T cells that were engaged in promiscuous intercellular interactions. These therapeutic benefits of the CD47 blockade were further unleashed by adjuvant interferon-α, which stimulates cytotoxic cells, underscoring the importance of an inflamed microenvironment in facilitating the response to immunotherapy. Collectively, these findings support CD47 as a therapeutic target in treating mycosis fungoides and demonstrate a synergistic role of interferon-α in exploiting these clinical benefits