Role of autophagy in acute myeloid leukemia therapy

Despite its dual role in determining cell fate in a wide array of solid cancer cell lines, autophagy has been robustly shown to suppress or kill acute myeloid leukemia cells via degradation of the oncogenic fusion protein that drives leukemogenesis. However, autophagy also induces the demise of acute leukemia cells that do not express the known fusion protein, though the molecular mechanism remains elusive. Nevertheless, since it can induce cooperation with apoptosis and differentiation in response to autophagic signals, autophagy can be manipulated for a better therapy on acute myeloid leukemia.

乳腺癌患者循环肿瘤细胞的检测及其临床应用(英文)

肿瘤转移是乳腺癌治疗失败的主要原因之一。肿瘤细胞进人外周血是发生远处转移的前提,早在1896年,Ashworth在1例因癌症死亡的患者外周血中发现了类似肿瘤的细胞,并首次提出了循环肿瘤细胞(circulating tumor cell.CTC)的概念。进人循环未被清除的肿瘤细胞可相互聚集形成微小癌栓,并在一定条件下发展为转移灶。越来越多的学者开始关注循环肿瘤细胞方面的研究,近年来,有关乳腺癌患者CTC检测及其临床应用的研究已取得了长足的进展。

Combination of Rapamycin and Imatinib in Treating Refractory Chronic Myeloid Leukemia Myeloid Blast Crisis:a Case Report

CHRONIC myeloid leukemia (CML) is characterized by the presence of the BCR/ABL fusion gene,which is the result of a reciprocal translocation between chromosomes 9 and 22,called Philadelphia (Ph) chromosome.Imatinib mesylate (imatinib),

MicroRNA Let-7g and Atherosclerosis Plaque Stabilization

Vascular atherosclerotic vulnerable plaque rupture is the primary cause of acute myocardial infarctions and strokes. Thus, stabilization of vulnerable plaques is of important clinical endeavor to decrease the fatal risk of atherosclerosis. Inflammatory infiltration, apoptosis of endothelial cells (ECs) and vascular smooth muscle cells (VSMCs), destruction of extracellular matrix (ECM) or collagen, and neovascularization all contribute to the formation and stability of plaque. Let-7g, one miRNA of let-7 family, is related to retardation of the progress of vulnerable atherosclerosis plaque. First of all, let-7g induced preservation on vascular diseases through regulating on the intracellular Ca2+- activated protein kinase C-oxLDL-LOX-1 pathway, which resulted in reduced leukocyte adhesion to and migration across endothelium. Over expression of let-7g negatively regulated apoptosis in the ECs by targeting lectin-like oxidized LDL receptor-1(LOX-1)/CASP3 expression, therefore made the fibrous cap of plaque integrated and thick, increased the density of vascular atherosclerotic plaque. In addition, let-7g might stabilize the atherosclerotic plaque through other aspects. In this review, we focus on current and potential importance of let-7g on the stabilization of atherosclerosis plaque which might lead to the future development of an alternative strategy of CAD.

Ribosome biogenesis in disease:new players and therapeutic targets

The ribosome is a multi-unit complex that translates mRNA into protein.Ribosome biogenesis is the process that generates ribosomes and plays an essential role in cell proliferation,differentiation,apoptosis,development,and transformation.The mTORC1,Myc,and noncoding RNA signaling pathways are the primary mediators that work jointly with RNA polymerases and ribosome proteins to control ribosome biogenesis and protein synthesis.Activation of mTORC1 is required for normal fetal growth and development and tissue regeneration after birth.Myc is implicated in cancer development by enhancing RNA Pol II activity,leading to uncontrolled cancer cell growth.The deregulation of noncoding RNAs such as microRNAs,long noncoding RNAs,and circular RNAs is involved in developing blood,neurodegenerative diseases,and atherosclerosis.We review the similarities and differences between eukaryotic and bacterial ribosomes and the molecular mechanism of ribosome-targeting antibiotics and bacterial resistance.We also review the most recent findings of ribosome dysfunction in COVID-19 and other conditions and discuss the consequences of ribosome frameshifting,ribosome-stalling,and ribosome-collision.We summarize the role of ribosome biogenesis in the development of various diseases.Furthermore,we review the current clinical trials,prospective vaccines for COVID-19,and therapies targeting ribosome biogenesis in cancer,cardiovascular disease,aging,and neurodegenerative disease.

Multiple biological functions and pharmacological effects of lycorine

Lycorine is the major active component from the amaryllidaceae family plant Lycoris radiate,a represent traditional Chinese medicinal herb,and is one of the typical alkaloids with pyrrolophenanthridine nucleus core.Lycorine has drawn great interest in medicinal field due to its divergent chemical structures and multiple biological functions,as well as pharmacological effects on various diseases.Accumulated evidence shows that lycorine not only possesses strong pharmacological effects on many diseases,including anti-leukemia,anti-tumor,anti-angiogenesis,anti-virus,anti-bacteria,anti-inflammation,and anti-malaria,but also exerts many other biological functions,such as inhibition of acetylcholinesterase and topoisomerase,suppression of ascorbic acid biosynthesis,and control of circadian period length.Notably,lycorine exhibits its numerous pharmacological effects on various diseases with very low toxicity and mild side effects.The divergent chemical structures,multiple biological functions,and very low toxicity of lycorine imply that the agent is a potential drug candidate that warrants for further preclinical and clinic investigation.

Phase 1 clinical trial demonstrated that MUC1 positive metastatic seminal vesicle cancer can be effectively eradicated by modified Anti-MUC1 chimeric antigen receptor transduced T cells

Recent progress in chimeric antigen receptor-modified T-cell(CAR-T cell) technology in cancer therapy is extremely promising, especially in the treatment of patients with B-cell acute lymphoblastic leukemia. In contrast, due to the hostile immunosuppressive microenvironment of a solid tumor, CAR T-cell accessibility and survival continue to pose a considerable challenge, which leads to their limited therapeutic efficacy. In this study, we constructed two anti-MUC1 CAR-T cell lines. One set of CAR-T cells contained SM3 single chain variable fragment(sc Fv) sequence specifically targeting the MUC1 antigen and co-expressing interleukin(IL) 12(named SM3-CAR). The other CAR-T cell line carried the SM3 sc Fv sequence modified to improve its binding to MUC1 antigen(named p SM3-CAR) but did not co-express IL-12. When those two types of CAR-T cells were injected intratumorally into two independent metastatic lesions of the same MUC1+ seminal vesicle cancer patient as part of an interventional treatment strategy, the initial results indicated no side-effects of the MUC1 targeting CAR-T cell approach, and patient serum cytokines responses were positive. Further evaluation showed that p SM3-CAR effectively caused tumor necrosis, providing new options for improved CAR-T therapy in solid tumors.

Progress in tumor vascular normalization for anticancer therapy:challenges and perspectives

Antitumor angiogenic therapy has been shown promising in the treatment of several advanced cancers since the approval of the first antiangiogenic drug Avastin in 2004.Although the current antiangiogenic drugs reduce the density of tumor blood vessels and result in tumor shrinkage at the early stage of treatment,recent studies have shown that antiangiogenic therapy has transient and insufficient efficacy,resulting in tumor recurrence in patients after several months of treatment.Blockage of blood and oxygen supplies creates a hypoxic and acidic microenvironment in the tumor tissues,which fosters tumor cells to become more aggressive and metastatic.In 2001,Jain proposed tumor vascular normalization as an alternative approach to treating cancers based on the pioneering work on tumor blood vessels by several other researchers.At present,normalizing the disorganized tumor vasculature,rather than disrupting or blocking them,has emerged as a new option for anticancer therapy.Preclinical and clinical data have shown that tumor vascular normalization using monoclonal antibodies,proteins,peptides,small molecules,and pericytes resulted in decreased tumor size and reduced metastasis.However,current tumor vascular normalizing drugs display moderate anticancer efficacy.Accumulated data have shown that a variety of vasculogenic/angiogenic tumor cells and genes play important roles in tumor neovascularization,growth,and metastasis.Therefore,multiple-targeting of vasculogenic tumor cells and genes may improve the efficacy of tumor vascular normalization.To this end,the combination of antiangiogenic drugs with tumor vascular normalizing therapeutics,as well as the integration ofWestern medicine with traditional Chinese medicine,may provide a good opportunity for discovering novel tumor vascular normalizing drugs for an effective anticancer therapy.

程序性坏死在癌症中的复杂作用（英文）

细胞程序性坏死是一种受到严格调控的细胞坏死形式,其发生依赖于受体相互作用蛋白(RIP)激酶RIPK1和RIPK3以及RIPK3底物混合谱系激酶域样蛋白(MLKL)的活化。由于细胞膜破裂,发生程序性坏死的细胞会释放损伤相关分子模式(DAMPs)分子,进而引发炎症反应。越来越多的研究表明细胞程序性坏死参与调控癌症的发生、发展和转移。肿瘤细胞程序性坏死被认为是一种具有激活抗肿瘤免疫功能的免疫原性细胞死亡,从而抑制肿瘤生长。细胞程序性坏死也被发现能增强髓系细胞诱导的适应性免疫抑制,进而促进肿瘤发生。此外,内皮细胞和肿瘤细胞的程序性坏死会促进肿瘤细胞的转移。在这篇综述中,我们总结了细胞程序性坏死信号通路及其在癌症中的复杂作用机制,并讨论了靶向程序性坏死调控蛋白在癌症治疗中的作用。

GSDME as an executioner of chemotherapy-induced cell death

Cell death is a crucial process required for development,tissue homeostasis,and pathological cell loss in multicellular organisms.Cell death mainly occurs in two alternative modes:apoptosis or necrosis.Apoptosis is a form of programmed cell death with typical morphological features,including cell shrinkage,chromatin condensation,and DNA fragmentation(Degterev and Yuan,2008).The dying cell is eventually fragmented into membrane-bound

Comparison of cellular responses across multiple passage numbers in Ba/F3-BCR-ABL cells induced by silver nanoparticles

With the rapid development of nanotechnology and increasingly broad bio-application of engineered nanomaterials, their biohazards have become a serious public concern. It is believed that the chemical nature, particle size, morphology, and surface chemistry of nanomaterials are key parameters that influence their toxicity. Although cultured cells have been widely used to evaluate nanomaterial toxicity, it remains unclear whether the passage of these cells affects the evaluation results. In the present study, Ba/F3 cells transfected with the BCR-ABL gene were subcultured to study the effect of passage number on cell stability and their cellular responses upon exposure to nanomaterials. The results demonstrated that proliferation, cellular senescence, BCR-ABL gene expression, cell cycle and apoptosis were stable across multiple passages. Senescence and BCR-ABL gene expression of cells from different passage cells were unchanged when treated with silver nanoparticles (AgNPs). In addition, the cells at multiple passage numbers were all arrested in the G 2 /M phase and apoptosis was induced by the AgNPs. These nanoparticles could enter cells via endocytosis and localize in the endosomes, which were also not influenced by passage number. These data suggest that short-term passage would not affect cultured cell stability and toxicity assessment using these cells would be consistent when maintained appropriately.

Inflammasomes as therapeutic targets in human diseases

Inflammasomes are protein complexes of the innate immune system that initiate inflammation in response to either exogenous pathogens or endogenous danger signals.Inflammasome multiprotein complexes are composed of three parts:a sensor protein,an adaptor,and pro-caspase-1.Activation of the inflammasome leads to the activation of caspase-1,which cleaves pro-inflammatory cytokines such as IL-ip and IL-18,leading to pyroptosis.Effectors of the inflammasome not only provide protection against infectious pathogens,but also mediate control over sterile insults.Aberrant inflammasome signaling has been implicated in the development of cardiovascular and metabolic diseases,cancer,and neurodegenerative disorders.Here,we review the role of the inflammasome as a double-edged sword in various diseases,and the outcomes can be either good or bad depending on the disease,as well as the genetic background.We highlight inflammasome memory and the two-shot activation process.We also propose the M-and N-type inflammation model,and discuss how the inflammasome pathway may be targeted for the development of novel therapy.

The S 1P, receptor-selective agonist CYM-5442 reduces the severity of acute GVHD byinhibiting macrophage recruitment

FTY720, an agonist for four of the five known sphingosine- 1-phosphate （SIP） receptors, has been reported to inhibit acute graft-versus-host disease （aGVHD）. Because FTY720 functions through multiple SIP receptors, the mechanism of action through one or more of these receptors may account for its side effects. Thus, more selective SIP receptor modulators are needed to evaluate the roles of different S1P receptors and their therapeutic efficacies. In this study, we investigated the effect of an SIPl-selective agonist, CYM-5442, on the progression of aGVHD. We showed that CYM-5442 significantly inhibited but did not prevent aGVHD. CYM-5442 did not affect the infiltration of the donor T cells into the target organs, while the number of macrophages in GVHD organs was significantly reduced by CYM-5442 treatment. In vivo proliferation assays showed that the proliferation of macrophages was not suppressed by CYM-5442. Further studies using human endothelial cells demonstrated that CYM-5442 treatment downregulated CCL2 and CCL7 expression in endothelial cells, therefore reducing the migration of monocytes, from which tissue macrophages originate. Our data demonstrate the therapeutic efficacy of an SIPl-selective agonist in aGVHD and its possible mechanism of action. The results suggest that further investigations are needed regarding CYM-5442 as a potential therapeutic regimen for aGVHD.

High stearic acid diet modulates gut microbiota and aggravates acute graft-versus-host disease

Dear Editor,Acute graft-versus-host disease(aGVHD)is the leading cause of transplantation-related mortality,and limits therapeutic benefits of allogeneic bone marrow transplantation(allo-BMT).New insight is needed into the development of aGVHD.Most nutritional metabolites contribute to host health and immune homeostasis.

Roles of integrin β3 cytoplasmic tail in bidirectional signal transduction in a trans-dominant inhibition model

We evaluated the roles of calpain cleavage-related mutations of the integrin β3 cytoplasmic tail in integrin αIIbβ3 bidirectional signaling using a trans-dominant inhibition model. Chimeric Tac-β3 proteins （i.e., Tac-β3, Tac-β3△741, Tac-β3△747, Tac-β3△754, Tac-β3△759, and Tac-β3ANITY） consisting of the extracellular and transmembrane domains of human IL-2 receptor （Tac） and the human integrin β3 cytoplasmic domain were stably expressed in the 123 CHO cells harboring human glycoprotein Ib-IX and wild-type integrin uIIbβ3. The different cells were assayed for stable adhesion and spreading on immobilized fibrinogen, and for binding soluble fibrinogen representing outside-in and inside-out signaling events, respectively. The chimeric protein Tac-β3 inhibited, and Tac-β3△NITY partially attenuated stable adhesion and spreading. Tac-β3, Tac-β3△759, Tac-β3ANITY, and Tac-β3△754, but not Tac-β3△747 or Tac-β3△741, impaired the soluble fibrinogen binding. Results indicated that the bidirectional signaling was significantly inhibited by Tac-β3△ and Tac-β3ANITY, albeit to a much lesser extent. Moreover, only inside-out signaling was impaired in the 123/Tac-β3△759 and 123/Tac-β3△754 cells in contrast to an intact bidirectional signaling in the 123/Tac-β3△747 and 123/Tac-β3△741 cells. In conclusion, the calpain cleavage of integrin β3 resulted in the regulatory effects on signaling by interrupting its interaction with cytoplasmic proteins rather than altering its conformation, and may thus regulate platelet function.