High heterogeneity of bone and soft tissue sarcomas limits the development of molecular-targeted therapy but in turn provides an important clue to inner genomic and regulomic diversityof driver pathways that define molecular subtypes associated with patient outcome. The importance of malignant biological behaviorshave been re-emphasized, since tumor arises from the collaborative interplay of oncogenic events acquired the tissue-specifying gene expression programs to survive cancer cells and benefit multi-step tumorigenesis and neoplastic progression. Differ from most epithelial carcinomas that harbor clinically operative mutation sites, sarcomas are characterizedpredominantly by chromosomal alterations and copy-number changes, with low mutation loads. Sarcoma-specific fusion proteins produced by chromosomal translocations are common significant transcription factors, driving tumor cells exhibit an absolute dependence on "transcription addiction". It has been confirmed that cyclin-dependent kinase-7 (CDK7) plays a key role in transcriptional regulation such as cell growth and proliferation, invasion and metastasis. The dysregulated transcriptional regulation acquired during tumor development strictly depends on the essential regulation of CDK7. Targeted inhibition of CDK7 is an effective strategy to suppress tumors, especially those with specific genomic backgrounds (oncogene or fusion-gene driven) which are highly sensitive to CDK7 intervention. Emerging studies have shown that CDK7 is closely related to the malignant behaviors of bone and soft tissue sarcomas, and is expected to become a potential target for the treatment of sarcoma.

TSCI have dyskinesia and sensory disturbance that can cause various life-threaten complications. The patients with traumatic spinal cord injury (TSCI), seriously affecting the quality of life of patients. Based on the epidemiology of TSCI and domestic and foreign literatures as well as expert investigations, this expert consensus reviews the definition, injury classification, rehabilitation assessment, rehabilitation strategies and rehabilitation measures of TSCI so as to provide early standardized rehabilitation treatment methods for TSCI.

Metastasis accounts for 90% of breast cancer deaths, where the lethality could be attributed to the poor drug accumulation at the metastatic loci. The tolerance to chemotherapy induced by breast cancer stem cells (BCSCs) and their particular redox microenvironment further aggravate the therapeutic dilemma. To be specific, therapy-resistant BCSCs can differentiate into heterogeneous tumor cells constantly, and simultaneously dynamic maintenance of redox homeostasis promote tumor cells to retro-differentiate into stem-like state in response to cytotoxic chemotherapy. Herein, we develop a specifically-designed biomimic platform employing neutrophil membrane as shell to inherit a neutrophil-like tumor-targeting capability, and anchored chemotherapeutic and BCSCs-differentiating reagents with nitroimidazole (NI) to yield two hypoxia-responsive prodrugs, which could be encapsulated into a polymeric nitroimidazole core. The platform can actively target the lung metastasis sites of triple negative breast cancer (TNBC), and release the escorted drugs upon being triggered by the hypoxia microenvironment. During the responsiveness, the differentiating agent could promote transferring BCSCs into non-BCSCs, and simultaneously the nitroimidazole moieties conjugated on the polymer and prodrugs could modulate the tumor microenvironment by depleting nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) and amplifying intracellular oxidative stress to prevent tumor cells retro-differentiation into BCSCs. In combination, the BCSCs differentiation and tumor microenvironment modulation synergistically could enhance the chemotherapeutic cytotoxicity, and remarkably suppress tumor growth and lung metastasis. Hopefully, this work can provide a new insight in to comprehensively treat TNBC and lung metastasis using a versatile platform.

BACKGROUND: Bladder cancer, characterized by a high potential of tumor recurrence, has high lifelong monitoring and treatment costs. To date, tumor cells with intrinsic softness have been identified to function as cancer stem cells in several cancer types. Nonetheless, the existence of soft tumor cells in bladder tumors remains elusive. Thus, our study aimed to develop a micro-barrier microfluidic chip to efficiently isolate deformable tumor cells from distinct types of bladder cancer cells. METHODS: The stiffness of bladder cancer cells was determined by atomic force microscopy (AFM). The modified microfluidic chip was utilized to separate soft cells, and the 3D Matrigel culture system was to maintain the softness of tumor cells. Expression patterns of integrin β8 (ITGB8), protein kinase B (AKT), and mammalian target of rapamycin (mTOR) were determined by Western blotting. Double immunostaining was conducted to examine the interaction between F-actin and tripartite motif containing 59 (TRIM59). The stem-cell-like characteristics of soft cells were explored by colony formation assay and in vivo studies upon xenografted tumor models. RESULTS: Using our newly designed microfluidic approach, we identified a small fraction of soft tumor cells in bladder cancer cells. More importantly, the existence of soft tumor cells was confirmed in clinical human bladder cancer specimens, in which the number of soft tumor cells was associated with tumor relapse. Furthermore, we demonstrated that the biomechanical stimuli arising from 3D Matrigel activated the F-actin/ITGB8/TRIM59/AKT/mTOR/glycolysis pathways to enhance the softness and tumorigenic capacity of tumor cells. Simultaneously, we detected a remarkable up-regulation in ITGB8, TRIM59, and phospho-AKT in clinical bladder recurrent tumors compared with their non-recurrent counterparts. CONCLUSIONS The ITGB8/TRIM59/AKT/mTOR/glycolysis axis plays a crucial role in modulating tumor softness and stemness. Meanwhile, the soft tumor cells become more sensitive to chemotherapy after stiffening, that offers new insights for hampering tumor progression and recurrence.
Animals ; Mice ; Humans ; Proto-Oncogene Proteins c-akt/metabolism* ; Actins/metabolism* ; Neoplasm Recurrence, Local ; TOR Serine-Threonine Kinases/metabolism* ; Urinary Bladder Neoplasms ; Glycolysis ; Cell Line, Tumor ; Cell Proliferation ; Mammals/metabolism* ; Tripartite Motif Proteins/metabolism* ; Intracellular Signaling Peptides and Proteins/metabolism* ; Integrin beta Chains