Multiple myeloma is an incurable hematological malignancy that impacts tens of thousands of people every year in the United States. Treatment for eligible patients involves induction, consolidation with stem cell rescue, and maintenance. High-dose therapy with a DNA alkylating agent, melphalan, remains the primary drug for consolidation therapy in conjunction with autologous stem-cell transplantation; as such, melphalan resistance remains a relevant clinical challenge. Here, we describe a proteometabolomic approach to examine mechanisms of acquired melphalan resistance in two cell line models. Drug metabolism, steady-state metabolomics, activity-based protein profiling (ABPP, data available at PRIDE: PXD019725), acutetreatment metabolomics, and western blot analyses have allowed us to further elucidate metabolic processes associated with melphalan resistance. Proteometabolomic data indicate that drug-resistant cells have higher levels of pentose phosphate pathway metabolites. Purine, pyrimidine, and glutathione metabolisms were commonly altered, and cell-line-specific changes in metabolite levels were observed, which could be linked to the differences in steady-state metabolism of nai ̈ve cells. Inhibition of selected enzymes in purine synthesis and pentose phosphate pathways was evaluated to determine their potential to improve melphalan's efficacy. The clinical relevance of these proteometabolomic leads was confirmed by comparison of tumor cell transcriptomes from newly diagnosed MM patients and patients with relapsed disease after treatment with high-dose melphalan and autologous stem-cell transplantation. The observation of common and cell-line-specific changes in metabolite levels suggests that omic approaches will be needed to fully examine melphalan resistance in patient specimens and define personalized strategies to optimize the use of high-dose melphalan.

Platinum (Pt) drugs (e.g., oxaliplatin, cisplatin) are applied in the clinic worldwide for the treatment of various cancers. However, platinum-induced peripheral neuropathy (PIPN) caused by the accumulation of Pt in the peripheral nervous system limits the clinical application, whose prevention and treatment are still a huge challenge. To date, Pt-induced reactive oxygen species (ROS) generation has been studied as one of the primary mechanisms of PIPN, whose downregulation would be feasible to relieve PIPN. This review will discuss ROS-related PIPN mechanisms including Pt accumulation in the dorsal root ganglia (DRG), ROS generation, and cellular regulation. Based on them, some antioxidant therapeutic drugs will be summarized in detail to alleviate the Pt-induced ROS overproduction. More importantly, we focus on the cutting-edge nanotechnology in view of ROS-related PIPN mechanisms and will discuss the rational fabrication of tailor-made nanosystems for efficiently preventing and treating PIPN. Last, the future prospects and potential breakthroughs of these anti-ROS agents and nanosystems will be briefly discussed.

Parvovirus B19 (B19V) as a human pathogenic virus, would cause a wide range of clinical manifestations. Besides the supportive and symptomatic treatments, the only FDA-approved antiviral drug for the treatment of B19V is intravenous immunoglobulins, which however, have limited efficacy and high cost. By far, there are still no virus-specific therapeutics clinically available to treat B19V infection. Therefore, exploiting the potential targets with a deep understanding of the life cycle of B19V, are pivotal to the development of B19V-tailored effective antiviral approaches. This review will introduce antiviral agents via blocking viral invasion, inhibiting the enzymes or regulatory proteins involved in DNA synthesis, and so on. Moreover, nanotechnology-enabled approaches against B19V will also be outlined and discussed through a multidisciplinary perspective involving virology, nanotechnology, medicine, pharmaceutics, chemistry, materials science, and other fields. Lastly, the prospects of the antiviral agents and nanosystems in terms of fabrication, clinical translation and potential breakthroughs will be briefly discussed.

The plasma cell malignancy multiple myeloma (MM) evolves from a pre-malignant state and remains all but incurable due to emergence of therapy resistance. Despite intensive analyses, mechanisms driving MM progression and refractory disease are poorly understood. Integrating topologic, expression and epigenetic analyses of 1,016 patient specimens, we report super-enhancer core regulatory circuits (SECRCs) that drive and sustain MM epigenetic states. Reprogramming of cell identity and tumor microenvironment genes drive malignant conversion, while alterations in cell cycle and metabolic control genes cause refractory disease. Thus, select epigenetic states drive progression and therapy resistance, providing strategies to prevent and effectively treat MM.

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