Saponins from Paris forrestii(Takht.) H. Li displays potent activity against acute myeloid leukemia by suppressing RNF6/AKT/mTOR signaling pathway

Acute myeloid leukemia(AML) is a heterogeneous disease characterized by the accu.mulation of immature myeloid progenitor cells in the bone marrow,compromising of normal hematopoi.esis and ultimately resulting in bone marrow failure.Chemotherapy is the mainstay treatment for all AML patients,however,drug resistance and clinical relapse limits its efficacy.The 5-year survival rate of AML patients is only 26.6%.Survival rates are even lower among patients ages 65 to 74 years(5.3%) and 75 years or older(1.6%).Therefore,exploring novel therapeutic agents is urgent for improving the outcome of patients with AML.Saponins are amphipathic glycosides found in traditional Chinese medicines.In the present study,we isolated a panel of saponins from Paris forrestii(Takht.) H.Li,a unique plant found in Tibet and Yunnan provinces,China.By examining their activities in suppressing acute myeloid leukemia cell proliferation,total saponins from Paris forrestii(TSPf) displayed more potent activity than individual ones.TSPf induced more than 40% AML cell apoptosis within 24 h and decreased the viability of all leukemia cell lines.TSPf-induced apoptosis was confirmed by both Annexin V staining and caspase-3 activation.TSPf downregulated pro-survival proteins Mcl-1,Bcl-xL and Bcl-2,but upreg.ulated the expression of tumor suppressor proteins p53,p27,Bax and Beclin 1.The AKT/mTOR signaling pathway is frequently over activated in various AML cells,and TSPf was found to suppress the activa.tion of both AKT and mTOR,but had no effects on their total protein expression.This was further con.firmed by the inactivation of 4 EBP-1 and p70 S6 K,two typical downstream signal molecules in the AKT/mTOR pathway.More specifically,TSPf-inactivated AKT/mTOR signaling was found to be associated with downregulated RNF6,a recently identified oncogene in AML.RNF6 activated AKT/mTOR,and consistently,knockdown of RNF6 led to inactivation of the AKT/mTOR pathway.Furthermore,TSPf suppressed the growth of AML xenografts in nude mice models.Oral administration of 100 mg · kg^(-1) body weight almost fully suppressed tumor growth within 14 d,without gross toxicity.This study thus demonstrated that TSPf displays potent anti-AML activity by suppressing the RNF6/AKT/mTOR pathway.Given its low toxicity,TSPf could be developed for the treatment of AML.

IMMUNE TOLERANCE INDUCED BY GAMMA-RAY IRRADIATION

Objective: To detect the existence of immune tolerance induced by gamma-ray irradiation. Methods: Peritoneal cells were harvested from mice subjected to 5 Gy 60Co gamma-ray total body irradiation at 3d, 7d, 15d and 30d, then their counts, morphological changes and IL-12 gene expression were investigated. Results: After irradiation, the peritoneal cells were sharply reduced, the cell morphology shifted from round-like to polymorphic and fusiform with some processes, expression of IL-12 p35 was seriously suppressed, while that of IL-12 p40 greatly enhanced. Conclusion: Our data highly suggest that the gamma-ray irradiation could potentially induce dendritic cell (DC) commitment and immune tolerance.

<i>Klebsiella pneumoniae</i>Carbapenamase (KPC) Outbreak in a Multispeciality Cancer Hospital—An Emerging Superbug

Aim: To identify, analyse and control the outbreak of Carbapenamase producing Klebsiella pneumoniae. Objectives: 1) To detect multidrug resistant K. pneumoniae at the earliest and isolate patients. 2) To find out the predisposing causes for the occurrence of this outbreak. 3) To break the chain of infection transmission. 4) To reduce the risk of Hospital acquired infections. Methods: This retrospective study along with the surveillance was conducted from January 2017 to March 2017 at HCG multispecialty cancer hospital, Bangalore, India. Results: Total 15 patients were diagnosed with KPC infection during the first month of the study period. Those affected were mostly Male patients (73%), admitted in ICU (73%) for further treatment. In our study, the incidence of KPC infection was mostly found with bloodstream infections (60%), mostly seen in those with central lines (80%) followed by patients on ventilatory support (66%). Before the outbreak of KPC infection, all the patients (100%) had already been treated with higher antibiotics including Carbapenems. In our study, only nine out of fifteen patients (60%) could be salvaged with treatment and were discharged. Conclusions: Hospital Infection Control Committee’s regular screening and the training of healthcare professionals are vital for the control of the outbreak.