Secondary hemophagocytic syndrome in an acquired immunodeficiency syndrome and Alpha-thalassemia patient infected with Talaromyces marneffei: A case report and literature review.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease characterized by a hyperinflammatory syndrome and impairment of multiple organ systems. Talaromycosis marneffei (TSM) is an opportunistic infection mostly found in immunosuppressed populations, such as those with acquired immunodeficiency syndrome (AIDS), and is prevalent in southern China. However, HLH secondary to TSM is extremely rare and has only been reported in isolated cases. A 30-year-old patient with recurrent high fever and progressive cytopenia was diagnosed with HLH secondary to disseminated TSM with AIDS and Alpha-thalassemia. The patient remained in sustained remission without recurrence after effective treatment with antifungals and glucocorticoids.

Discovery of a Novel Orally Bioavailable FLT3-PROTAC Degrader for Efficient Treatment of Acute Myeloid Leukemia and Overcoming Resistance of FLT3 Inhibitors.

Fms-like tyrosine receptor kinase 3 (FLT3) proteolysis-targeting chimeras (PROTACs) represent a promising approach to eliminate the resistance of FLT3 inhibitors. However, due to the poor druggability of PROTACs, the development of orally bioavailable FLT3-PROTACs faces great challenges. Herein, a novel orally bioavailable FLT3-ITD degrader A20 with excellent pharmacokinetic properties was discovered through reasonable design. A20 selectively inhibited the proliferation of FLT3-ITD mutant acute myeloid leukemia (AML) cells and potently induced FLT3-ITD degradation through the ubiquitin-proteasome system. Notably, oral administration of A20 resulted in complete tumor regression on subcutaneous AML xenograft models. Furthermore, on systemic AML xenograft models, A20 could completely eliminate the CD45+CD33+ human leukemic cells in murine and significantly prolonged the survival time of mice. Most importantly, A20 exerted significantly improved antiproliferative activity against drug-resistant AML cells compared to existing FLT3 inhibitors. These findings suggested that A20 could serve as a promising drug candidate for relapsed or refractory AML.

Triptolide Shows High Sensitivity and Low Toxicity Against Acute Myeloid Leukemia Cell Lines Through Inhibiting WSTF-RNAPII Complex.

Triptolide exhibits superior and broad-spectrum antitumor activity. However, the narrow safety window caused by the toxicity of triptolide limits its clinical applications. Although several characterized targets for triptolide are reported, the association between triptolide and its targets in cancer therapy is not fully understood. Here, we show that acute myeloid leukemia (AML) cell lines are sensitive to triptolide by constructing an in vitro cell and in vivo xenograft models. Meanwhile, the triptolide-induced hepatotoxicity increases with increasing dosages within the xenograft models. Additionally, the expression levels of WSTF-RPB1 are strongly associated with the sensitivity to triptolide in hematological cancer cells and can be downregulated in a dose and time-dependent manner. Finally, we show that optimizing dosing regimens can achieve the same pharmaceutical effect and reduce toxicity. In summary, this study aims to search for triptolide-sensitive cell lines as well as the underlying molecular mechanisms in order to broaden the safety window of triptolide; thus, increasing its clinical utility.

Roles of NOD1/Rip2 signal pathway in carotid artery remodelling in spontaneous hypertensive rats.

Nucleotide-binding and oligomerization domain (NOD) receptor is a member of inherent immunity recognition receptor family. We investigated the NOD1/Rip2 signalling pathway on carotid arterial remodelling in spontaneously hypertensive rats (SHRs). SHRs were treated with NOD1 agonist (iE-DAP), inhibitor (ML130), or normal saline. We determined the NOD1 and Rip2 expression in carotid artery tissues, serum tumour necrosis factor-α (TNF-α) and monocyte chemotactic protein-1 (MCP-1). The carotid artery remodelling in 16-week SHRs was higher than that of 8-week SHRs and 16-week Wistar-Kyoto (WKY) rats. Expression of NOD1, Rip2, MCP-1 and TNF-α in 16-week SHRs was higher than that of 8-week SHRs and 16-week WKY rats. Blood pressure in iE-DAP-treated SHRs was higher than SHR-C group (no treatment), together with MCP-1, TNF-α, NOD1 and Rip2 expression, as well as carotid artery remodelling. In ML130-treated group, these aspects were completely the opposite. Taken together, inhibition of NOD1/Rip2 signalling pathway could delay the vascular remodelling process.

The Role of the NOD1/Rip2 Signaling Pathway in Myocardial Remodeling in Spontaneously Hypertensive Rats.

BACKGROUND Chronic hypertension changes the function and structure of the heart and blood vessels. This study aimed to explore the role of the NOD1/Rip2 (nucleotide-binding oligomerization domain 1/receptor-interacting protein 2) signaling pathway in myocardial remodeling in spontaneously hypertensive rats (SHRs). MATERIAL AND METHODS Blood pressure was measured using a tail cuff. The cardiac structure was observed using echocardiography. Slices of the myocardium were stained with hematoxylin and eosin. The expression of NOD1 and Rip2 was detected using real-time polymerase chain reaction, western blot, and immunohistochemistry. The content and distribution of collagen in the myocardium were observed using Van Gieson staining. Enzyme-linked immunosorbent assay was used to detect the interleukin-1 (IL-1) concentrations. SHRs were treated with the NOD1 agonist iE-DAP and NOD1 inhibitor ML130. RESULTS The NOD1 agonist increased blood pressure in SHRs, and the NOD1 inhibitor decreased blood pressure; the interventricular septum thickness (IVST) and left ventricular posterior wall thickness (LVPWT) of the agonist-treated group were thicker than those of the control group, and the antagonist exerted the opposite effects. The levels of the NOD1 and Rip2 mRNAs and proteins, serum IL-1 concentration, and myocardial collagen volume fraction (CVF%) increased in SHRs in the NOD1 agonist group, but the levels of NOD1 and Rip2, serum IL-1 concentration, and myocardial collagen volume fraction (CVF%) decreased in SHRs in the NOD1 inhibitor group. CONCLUSIONS NOD1/Rip2 expression increased during the progression of myocardial remodeling in SHRs. The NOD1 agonist increased NOD1 expression and promoted myocardial remodeling, while the NOD1 antagonist reduced NOD1/Rip2 expression and protected against myocardial remodeling.