Selenocompounds in leukemia treatment : advantages and pitfalls

In 2018, cancer was reported to be the second top cause of morbidity and mortality globally with over 9 million deaths. Hematological malignancies including leukemia constitute about 7% of the total cancer cases. Substantial developments in treatment modalities and strategies have increased the 5-year survival rate in leukemia to around 60% in developed countries. However, complete remission and long-term disease control are not yet achieved. Oxidative stress is imprinted in many types of cancer including leukemia and represents a valuable trait for achieving leukemiaselective cytotoxicity. The present thesis represents a systematic study of the role of redox-active selenocompounds (SeCs) in leukemia treatment. Six diverse selenocompounds representing different compound classes were studied. Among them, p-xyelenselenocyanate (p-XSC) was shown to have the most potent cytotoxic activity against several leukemia cell lines carrying distinct oncogenes. p-XSC exerted its cytotoxicity in a concentration- and time-dependent manner. Mechanistic studies revealed that the cytotoxicity of p-XSC was mediated by upregulation of oxidative stress and accompanied with massive mitochondria damages. Importantly, the cytotoxicity of SeCs was antagonized by albumin which is ubiquitously present in biological conditions. By the combination of two distinct, but complementary selenium speciation methods including liquid chromatographymass spectrometry and X-ray absorption spectroscopy, we showed that cytotoxic SeCs were capable of transforming into selenol intermediates that subsequently bound to albumin via selenium-sulfur bond. Furthermore, we found that the macromolecular selenocompound-albumin conjugate was also internalized and able to kill leukemia cells. In addition to interfering with cytotoxicity, binding of SeCs to albumin also hindered the quantification of these compounds in biological matrix e.g. plasma. To elucidate the pharmacokinetics properties of SeCs for in vivo applications, we developed a novel REductive Cleavage and Instant Derivatization (RECID) method, by which we were able to measure both free and albumin-bound SeCs. In the leukemia mouse model, intravenous administration of p-XSC was shown to reduce the disease burden in whole body as well as in bone marrow. In conclusion, the results obtained in the present thesis provide substantial experimental evidences that redox-active SeCs, in particular p-XSC, possess high therapeutic potential as treatment for leukemia. Further investigations to optimize treatment regimen and to design an appropriate drug carrier are needed to achieve successful clinical trials

MetaMask: Revisiting Dimensional Confounder for Self-Supervised Learning

As a successful approach to self-supervised learning, contrastive learning aims to learn invariant information shared among distortions of the input sample. While contrastive learning has yielded continuous advancements in sampling strategy and architecture design, it still remains two persistent defects: the interference of task-irrelevant information and sample inefficiency, which are related to the recurring existence of trivial constant solutions. From the perspective of dimensional analysis, we find out that the dimensional redundancy and dimensional confounder are the intrinsic issues behind the phenomena, and provide experimental evidence to support our viewpoint. We further propose a simple yet effective approach MetaMask, short for the dimensional Mask learned by Meta-learning, to learn representations against dimensional redundancy and confounder. MetaMask adopts the redundancy-reduction technique to tackle the dimensional redundancy issue and innovatively introduces a dimensional mask to reduce the gradient effects of specific dimensions containing the confounder, which is trained by employing a meta-learning paradigm with the objective of improving the performance of masked representations on a typical self-supervised task. We provide solid theoretical analyses to prove MetaMask can obtain tighter risk bounds for downstream classification compared to typical contrastive methods. Empirically, our method achieves state-of-the-art performance on various benchmarks.Comment: Accepted by NeurIPS 202

A general covalent binding model between cytotoxic selenocompounds and albumin revealed by mass spectrometry and X-ray absorption spectroscopy

Selenocompounds (SeCs) are promising therapeutic agents for a wide range of diseases including cancer. The treatment results are heterogeneous and dependent on both the chemical species and the concentration of SeCs. Moreover, the mechanisms of action are poorly revealed, which most probably is due to the detection methods where the quantification is based on the total selenium as an element. To understand the mechanisms underlying the heterogeneous cytotoxicity of SeCs and to determine their pharmacokinetics, we investigated selenium speciation of six SeCs representing different categories using liquid chromatography-mass spectrometry (LC-MS) and X-ray absorption spectroscopy (XAS) and the cytotoxicity using leukemic cells. SeCs cytotoxicity was correlated with albumin binding degree as revealed by LC-MS and XAS. Further analysis corroborated the covalent binding between selenol intermediates of SeCs and albumin thiols. On basis of the Se-S model, pharmacokinetic properties of four SeCs were for the first time profiled. In summary, we have shown that cytotoxic SeCs could spontaneously transform into selenol intermediates that immediately react with albumin thiols through Se-S bond. The heterogeneous albumin binding degree may predict the variability in cytotoxicity. The present knowledge will also guide further kinetic and mechanistic investigations in both experimental and clinical settings