Biomarkers and imaging: physics and chemistry for noninvasive analyses

The era of 'modern medicine' has changed its name to 'molecular medicine', and reflects a new age based on personalized medicine utilizing molecular biomarkers in the diagnosis, staging and monitoring of therapy. Alzheimer's disease has a classical biomarker determined at autopsy with the histologic staining of amyloid accumulation in the brain. Today we can diagnose Alzheimer's disease using the same classical pathologic biomarker, but now using a noninvasive imaging probe to image the amyloid deposition in a patient and potentially provide treatment strategies and measure their effectiveness. Molecular medicine is the exploitation of biomarkers to detect disease before overt expression of pathology. Physicians can now find, fight and follow disease using imaging, and the need for other disease biomarkers is in high demand. This review will discuss the innovative physical and molecular biomarker probes now being developed for imaging systems and we will introduce the concepts needed for validation and regulatory acceptance of surrogate biomarkers in the detection and treatment of disease.     

Theranostic Nanoparticles for Cancer and Cardiovascular Applications

Theranostics have received enormous attentions for individualized diagnosis and treatment in the past few years. Especially, the availability of various nanoplatforms provides great potentials for designing of sophisticated theranostic agents including imaging, targeting and therapeutic functions. Numerous reports have been published on how to construct multifunctional nanoparticles for the targeted diagnosis and therapy simultaneously since the concept of “theranostics”. This review presents recent advances of molecular imaging and nanoplatform technology, and their applications in drug discovery and development. Applications of nanoplatform-based theranostics in cancer and cardiovascular diseases will also be covered including diagnosis, assessment of drug biodistribution, and visualization of drug release from nanoparticles, as well as monitoring of therapeutic effects.     

Alternative spliced variants as biomarkers of colorectal cancer

Surgical resection and adjuvant therapy, which mainly involves 5-fluorouracil (5-FU), irinotecan (CPT-11), oxaliplatin (LOHP) chemotherapy and recently targeted therapy, are the most common treatments of colorectal cancer (CRC). As to improve the therapeutic efficacy and assist with therapeutic decisions, there is an urgent need for prognostic and predictive molecular biomarkers. Recent evidence demonstrates that aberrations in alternative splicing process of cancer will provide candidate biomarkers for cancers to meet this need. In this review, we outline the fundamental mechanism of alternative splicing that plays a major role in protein diversity, and summarize the relationship between imbalance alternative splicing with cancer. Moreover, several alternative spliced variants and cancer-specific splicing events at the mRNA level in CRC, which may serve as diagnostic, predictive, prognostic markers of CRC, are also discussed. These specific splice variants or the RNA splicing machinery will be new, potential targets for the treatment of CRC that offers a specific site of anti-cancer chemotherapy.     

Role of X-linked inhibitor of apoptosis protein in chemoresistance in ovarian cancer: possible involvement of the phosphoinositide-3 kinase/Akt pathway.

Although cisplatin derivatives are first-line chemotherapeutic agents for the treatment of epithelial ovarian cancer, chemoresistance remains a major hurdle to successful therapy and the molecular mechanisms involved are poorly understood. Apoptosis is the cellular underpinning of cisplatin-induced cell death, which is associated with expression of specific "death" genes and down-regulation of "survival" counterparts. The X-linked inhibitor of apoptosis proteins (Xiap), an intracellular anti-apoptotic protein, plays a key role in cell survival by modulating death signaling pathways and is a determinant of cisplatin resistance in ovarian cancer cells in vitro. This review focuses on the role of Xiap and its interactions with the phosphoinositide-3 kinase (PI3K)/Akt cell survival pathway in conferring resistance of ovarian cancer cells to chemotherapeutic agents and discusses potential therapeutic strategies in overcoming chemoresistant ovarian cancer.     

Mechanisms of crosstalk between TNF-induced NF-kappaB and JNK activation in hepatocytes

Hepatocyte cell death is a universal feature of inflammatory liver diseases. The observation that mice deficient in the activation of nuclear factor-kappaB (NF-kappaB) are not viable because of excessive hepatocyte apoptosis induced by tumor necrosis factor (TNF) made it crystal-clear that NF-kappaB plays a central role in protecting hepatocytes against TNF-induced cell death. Also during TNF-mediated liver injury, NF-kappaB was shown to have an essential anti-apoptotic effect, underscoring the therapeutic importance of understanding its underlying molecular mechanisms. For a long time, the ability of NF-kappaB to induce the expression of a variety of anti-apoptotic proteins was thought to be solely responsible for its cytoprotective effects. However, during the past few years it has become clear that NF-kappaB-mediated inhibition of cell death also involves attenuating TNF-induced activation of c-Jun activating kinase (JNK). Whereas transient activation of JNK upon TNF treatment is associated with cellular survival, prolonged JNK activation contributes to cell death. Several studies have shown that NF-kappaB activation inhibits the sustained phase of TNF-induced JNK activation and thus protects cells against TNF cytotoxicity. In this review, we will discuss the various mechanisms by which NF-kappaB activation blunts TNF-induced JNK activation, including the induction of JNK inhibitory proteins and controlling the levels of reactive oxygen species (ROS). Moreover, because the cytoprotective effects of NF-kappaB activation are particularly important in liver physiology, we will put each of these JNK-inhibitory mechanisms into a 'hepatic perspective' by discussing their role in various mouse models of TNF-mediated liver injury.     

Advances in imaging gene-directed enzyme prodrug therapy

Gene-directed enzyme prodrug therapy (GDEPT) is one of the promising alternatives to conventional chemotherapy. Suicide gene therapy based anticancer strategy involves selective introduction of a foreign gene into tumor cells to produce a foreign enzyme that can activate an inert prodrug to its cytotoxic form and cause tumor cell death. In this review, we present three most promising suicide gene/prodrug combinations (1) herpes simplex virus thymidine kinase (HSV-TK) with ganciclovir (GCV), (2) cytosine deaminase (CD) from bacteria or yeast with 5-fluorocytodine (5-FC) and (3) bacterial nitroreductase (NTR) with 5-(azaridin-1-yl)-2,4-dinitrobenzamide (CB1954) and discuss how molecular imaging may improve therapy strategies. Current advances in noninvasive imaging technologies can measure vector dose, tumor selectivity, transgene expression and biodistribution of therapeutic gene with the aid of reporter genes and imageable probes from live animal. In this review we will discuss various imaging modalities - Optical, Magnetic Resonance Imaging (MRI), Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT), and highlight some of the approaches that can advance prodrug cancer therapy from bench to clinic.     

Imaging cellular receptors in breast cancers: an overview

Breast cancer, a leading cause of cancer death in women, is strongly correlated with the up- and down-regulation of hormone and growth factor receptors. Therefore, improving our understanding of such receptor status in different stages of breast cancer will help in the development of novel diagnostic and therapeutic solutions. In particular, molecular imaging technology in association with advanced molecular and cell biology techniques could reveal in detail dynamic molecular events in cells, allowing the study of crucial molecular pathological changes occurring in cancer and other diseases. Molecular imaging techniques such as PET, SPECT, MRI, and the combinatorial techniques have made tremendous strides in elucidating the role of cellular receptors, helping to monitor the course of breast cancer development and the therapeutic efficacy of novel drugs. Optical imaging of cellular receptors is emerging as a powerful tool given the advancement of fluorescent and bioluminescent proteins. Estrogen receptor, progesterone receptor, and HER2/neu have been adopted clinically to detect different types of breast cancer and to test novel treatment strategies; however, other cellular receptors may also be involved in breast cancer subtyping and could emerge as treatment prospects. This review will focus on the recent developments of imaging various cellular receptors pertaining to the growth and development of breast cancer.     

Modulating apoptosis: current applications and prospects for future drug development

Agents modulating apoptosis are of extraordinary promise for the treatment of several states of disease including cancer, AIDS, neurodegenerative and ischemic diseases. In this review a brief summary of cellular pathways relevant to programmed cell death first is given and potential therapeutic targets therein are emphasized. Current efforts in drug development are discussed from a mechanistic, biochemical point of view and pro- and anti-apoptotic strategies are related to the respective diseases. Therapeutic approaches addressed in this paper include the design and activity of novel low molecular weight agents (e.g. caspase inhibitors) as well as gene therapy (e.g. p53, adenovirus as vector in cancer treatment). In final sections, the latest findings in the field of apoptosis are highlighted and future applications are outlined.     

Recent advances in the imaging of programmed cell death

A deficiency or an excess of programmed cell death (apoptosis) is an integral component of autoimmune disorders, organ and bone marrow transplant rejection, and cancer. A technique to image programmed cell death would be useful in the development of drugs to treat these and others diseases, and to monitor the effectiveness of therapy. The most widely studied agent for the in vivo study of apoptosis is radiolabeled annexin V, an endogenous protein labeled with technectium-99m, now undergoing clinical trials in both Europe and the United States. While annexin V has been studied extensively in humans the precise mechanism(s) of uptake of this agent in vivo is unclear and needs further study. Other agents are also underdevelopment including radiolabeled forms of Z-VAD.fmk, a potent inhibitor of the enzymatic cascade intimately associated with apoptosis. MR imaging techniques and tracers also hold promise as methods to monitor apoptotic cell death. In this article we will review these and other imaging technologies for the non-invasive imaging of cell death. The mechanism(s) and latest data on the conditions in which cellular stress and early apoptosis occur will also be discussed in detail including potential new strategies for the targeting and novel therapeutic interventions of tissues and organs undergoing stress or apoptosis when cell salvage is still possible.     

Non-apoptotic cell death-based cancer therapy: Molecular mechanism,pharmacological modulators,and nanomedicine

As an emerging cancer therapeutic target, non-apoptotic cell death such as ferroptosis, necroptosis and pyroptosis, etc., has revealed significant potential in cancer treatment for bypassing apoptosis to enhance the undermined therapeutic efficacy triggered by apoptosis resistance. A variety of anticancer drugs, synthesized compounds and natural products have been proven recently to induce non-apoptotic cell death and exhibit excellent anti-tumor effects. Moreover, the convergence of nanotechnology with functional materials and biomedicine science has provided tremendous opportunities to construct non-apoptotic cell death-based nanomedicine for innovative cancer therapy. Nanocarriers are not only employed in targeted delivery of non-apoptotic inducers, but also used as therapeutic components to induce non-apoptotic cell death to achieve efficient tumor treatment. This review first introduces the main characteristics, the mechanism and various pharmacological modulators of different non-apoptotic cell death forms, including ferroptosis, necroptosis, pyroptosis, autophagy, paraptosis, lysosomal-dependent cell death, and oncosis. Second, we comprehensively review the latest progresses of nanomedicine that induces various forms of non-apoptotic cell death and focus on the nanomedicine targeting different pathways and components. Furthermore, the combination therapies of non-apoptotic cell death with photothermal therapy, photodynamic therapy, immunotherapy and other modalities are summarized. Finally, the challenges and future perspectives in this regard are also discussed.     

Liposomes and their applications in molecular imaging

Molecular imaging is a relatively new discipline with a crucial role in diagnosis and treatment tracing of diseases through characterization and quantification of biological processes at cellular and sub-cellular levels of living organisms. These molecular targeted systems can be conjugated with contrast agents or radioligands to obtain specific molecular probes for the purpose of diagnosis of diseases more accurately by different imaging modalities. Nowadays, an interesting new approach to molecular imaging is the use of stealth nanosized drug delivery systems such as liposomes having convenient properties such as biodegradability, biocompatibility and non-toxicity and they can specifically be targeted to desired disease tissues by combining with specific targeting ligands and probes. The targeted liposomes as molecular probes in molecular imaging have been evaluated in this review. Therefore, the essential point is detection of molecular target of the disease which is different from normal conditions such as increase or decrease of a receptor, transporter, hormone, enzyme etc, or formation of a novel target. Transport of the diagnostic probe specifically to targeted cellular, sub-cellular or even to molecular entities can be performed by molecular imaging probes. This may lead to produce personalized medicine for imaging and/or therapy of diseases at earlier stages.     

Liposomes and their applications in molecular imaging

Molecular imaging is a relatively new discipline with a crucial role in diagnosis and treatment tracing of diseases through characterization and quantification of biological processes at cellular and sub-cellular levels of living organisms. These molecular targeted systems can be conjugated with contrast agents or radioligands to obtain specific molecular probes for the purpose of diagnosis of diseases more accurately by different imaging modalities. Nowadays, an interesting new approach to molecular imaging is the use of stealth nanosized drug delivery systems such as liposomes having convenient properties such as biodegradability, biocompatibility and non-toxicity and they can specifically be targeted to desired disease tissues by combining with specific targeting ligands and probes. The targeted liposomes as molecular probes in molecular imaging have been evaluated in this review. Therefore, the essential point is detection of molecular target of the disease which is different from normal conditions such as increase or decrease of a receptor, transporter, hormone, enzyme etc, or formation of a novel target. Transport of the diagnostic probe specifically to targeted cellular, sub-cellular or even to molecular entities can be performed by molecular imaging probes. This may lead to produce personalized medicine for imaging and/or therapy of diseases at earlier stages.     

细胞死亡模式交互作用作为药理学靶点（英文）

Cell death plays an essential role in the development of organs,homeostasis,and cancer.Apoptosis and programmed necrosis are two major types of cell death,characterized by different cell morphology and pathways.Accumulating evidence shows autophagy as a new alternative target to treat tumour resistance.Besides its well-known pro-survival role,autophagy can be a physiological cell death process linking apoptosis and programmed necrosis cell death pathways,by various molecular mediators.Here,we summarize the effects of pharmacologically active compounds as modulators of different types of cancer cell death depending on the cellular context.Indeed,current findings show that both natural and synthetic compounds regulate the interplay between apoptosis,autophagy and necroptosis stimulating common molecular mediators and sharing common organelles.In response to specific stimuli,the same death signal can cause cells to switch from one cell death modality to another depending on the cellular setting.The discovery of important interconnections between the different cell death mediators and signalling pathways,regulated by pharmacologically active compounds,presents novel opportunities for the targeted treatment of cancer.The aim of this review is to highlight the potential role of these compounds for context-specific anticancer therapy.     

Superparamagnetic iron oxide nanoparticle 'theranostics' for multimodality tumor imaging, gene delivery, targeted drug and prodrug delivery

The superparamagnetic iron oxide nanoparticle (SPIO) 'theranostics', which contain imaging probes for tumor diagnosis and therapeutic compounds for therapy in a single nanoparticle, might provide significant benefits compared with exiting tumor imaging and therapeutic strategies. In this review, we summarize the progress of SPIO 'theranostics' that integrate tumor targeting, multimodality imaging, and gene delivery or targeted drug and prodrug delivery. This review describes various methods of SPIO synthesis, surface coating and characterization. Different tumor-targeting strategies, such as antibody fragments, nucleotides and receptor ligands, are discussed to improve SPIO delivery for multimodality imaging. We also examine the utility of SPIOs for gene delivery, siRNA delivery and imaging. Several methods for drug encapsulation and conjugation onto SPIOs are compared for targeted drug delivery, site-specific release and imaging-guided drug delivery. Finally, we also review the pharmacokinetics (including biodistribution) of SPIOs based on their characteristics.     

Role of pyroptosis in liver diseases

Pyroptosis is known as a novel form of pro-inflammatory cell death program, which is exceptional from other types of cell death programs. Particularly, pyroptosis is characterized by Gasdermin family-mediated pore formation and subsequently cellular lysis, also release of several pro-inflammatory intracellular cytokines. In terms of mechanism, there are two signaling pathways involved in pyroptosis, including caspase-1, and caspase-4/5/11 mediated pathways. However, pyroptosis plays important roles in immune defense mechanisms. Recent studies have demonstrated that pyroptosis plays significant roles in the development of liver diseases. In our review, we have focused on the role of pyroptosis based on the molecular and pathophysiological mechanisms in the development of liver diseases. We have also highlighted targeting of pyroptosis for the therapeutic implications in liver diseases in the near future.     

靶向肿瘤相关成纤维细胞的肿瘤治疗研究进展

肿瘤是威胁人类生命健康的主要疾病之一。肿瘤细胞和肿瘤微环境(tumor microenvironment,TME)的相互作用在肿瘤发生、发展、转移和治疗过程中发挥关键作用。肿瘤相关成纤维细胞(cancer-associated fibroblasts,CAFs)是TME的重要组成部分,是一类具极强增殖、迁移、分泌与合成能力的激活态成纤维细胞。研究发现,CAFs可直接与肿瘤细胞相互作用,提高肿瘤细胞干性,促进肿瘤的侵袭和转移;还可分泌多种细胞因子、趋化因子和生长因子等介导与肿瘤细胞存活、免疫调节相关的信号通路,间接发挥促肿瘤作用。因此,靶向CAFs成为开发新的肿瘤治疗药物和策略的研究热点。该文概述了CAFs的来源、CAFs与TME中肿瘤细胞和基质细胞之间的相互作用、靶向CAFs的肿瘤治疗策略、CAFs作为肿瘤预后生物标志物的可能性及其存在的问题和挑战,为以CAFs为靶点的新型肿瘤治疗策略的应用提供依据。     

铁死亡在神经胶质瘤治疗中的作用

铁死亡是一种铁依赖性脂质过氧化物损伤诱导的调节性细胞死亡形式，其在分子生物学、形态学和遗传学等方面都不同于凋亡、自噬和坏死等细胞死亡形式。铁死亡在神经胶质瘤的治疗中发挥重要作用，诱导胶质瘤细胞铁死亡将成为治疗肿瘤的新策略。本文对铁死亡的相关基因xCT、Nox4、NCOA4、BECN1在神经胶质瘤治疗中的作用及中药在神经胶质瘤中对铁死亡的治疗作用进行阐述，以期为神经胶质瘤的临床治疗提供新方向和新思路。     

Superparamagnetic iron oxide nanoparticle ‘theranostics’ for multimodality tumor imaging,gene delivery,targeted drug and prodrug delivery

The superparamagnetic iron oxide nanoparticle (SPIO) ‘theranostics’, which contain imaging probes for tumor diagnosis and therapeutic compounds for therapy in a single nanoparticle, might provide significant benefits compared with exiting tumor imaging and therapeutic strategies. In this review, we summarize the progress of SPIO ‘theranostics’ that integrate tumor targeting, multimodality imaging, and gene delivery or targeted drug and prodrug delivery. This review describes various methods of SPIO synthesis, surface coating and characterization. Different tumor-targeting strategies, such as antibody fragments, nucleotides and receptor ligands, are discussed to improve SPIO delivery for multimodality imaging. We also examine the utility of SPIOs for gene delivery, siRNA delivery and imaging. Several methods for drug encapsulation and conjugation onto SPIOs are compared for targeted drug delivery, site-specific release and imaging-guided drug delivery. Finally, we also review the pharmacokinetics (including biodistribution) of SPIOs based on their characteristics.     

Chemical regulation of signaling pathways to programmed necrosis

Necroptosis is an active and well-orchestrated necrosis, distinctive from apoptosis in microscopic structure, and biochemical and molecular features. Unlike apoptosis-undergoing cells, which are removed by macrophage or neighboring cells, necrotic cell death releases danger signals and provokes inflammation, and further a severe damage to neighbor tissue. A regulated necrosis, termed as necroptosis or programmed necrosis, is emerging as a new paradigm of cell death that can be activated when apoptotic machinery is genetically or pathogenically defective. It plays biological significances in pathogenesis of a variety of inflammatory diseases as well as in a beneficial innate immune defense mechanism. This review highlights the identification of hits against necroptosis, and comprehensive approaches to discovery of small molecules that regulate necroptotic cell death. Also, the signaling molecular mechanism of necroptosis and future clinical uses of necroptosis inhibitor will be described in brief.