Intra-tumor heterogeneity is now arguably one of the most-studied topics in tumor biology, as it represents a major obstacle to effective cancer treatment. Since tumor cells are highly diverse at genetic, epigenetic, and phenotypic levels, intra-tumor heterogeneity can be assumed as an important contributing factor to the nullification of chemotherapeutic effects, and recurrence of the tumor. Based on the role of heterogeneous subpopulations of cancer cells with varying cell-cycle dynamics and behavior during cancer progression and treatment; herein, we aim to establish a comprehensive definition for adaptation of neoplastic cells against therapy. We discuss two parallel and yet distinct subpopulations of tumor cells that play pivotal roles in reducing the effects of chemotherapy: "resistant" and "tolerant" populations. Furthermore, this review also highlights the impact of the quiescent phase of the cell cycle as a survival mechanism for cancer cells. Beyond understanding the mechanisms underlying the quiescence, it provides an insightful perspective on cancer stem cells (CSCs) and their dual and intertwined functions based on their cell cycle state in response to treatment. Moreover, CSCs, epithelialemesenchymal transformed cells, circulating tumor cells (CTCs), and disseminated tumor cells (DTCs), which are mostly in a quiescent state of the cell cycle are proved to have multiple biological links and can be implicated in our viewpoint of cell cycle heterogeneity in tumors. Overall, increasing our knowledge of cell cycle heterogeneity is a key to identifying new therapeutic solutions, and this emerging concept may provide us with new opportunities to prevent the dreadful cancer recurrence.

Diffuse large B cell lymphoma (DLBCL) is one of the most prevalent lymphoid malignancies. The current standard of care can cure about two-thirds of DLBCL patients. Primary testicular diffuse large B-cell lymphoma (PT-DLBCL) is a rare but highly aggressive form of mature B-cell lymphoma that accounts for approximately 1%-9% of testicular malignancies. Different from nodal DLBCL, PT-DLBCL has a markedly worse prognosis because of inferior response to the current treatment regimens and significant extranodal tropism. Three main questions remained unresolved in the field of PT-DLBCL research. Previously, two prognostically important categories of DLBCL have been defined: activated B cell-like (ABC) DLBCL and germinal center B cell-like (GCB) DLBCL. Most PT-DLBCLs were classified as ABC-DLBCL. However, the exact cells of origin (COO) of PT-DLBCL were still under debate. Secondly, the lack of transcriptomics profiling of PT-DLBCL at the single-cell level hindered the discovery of intra-tumor heterogeneity. Finally, the role of the testis microenvironment in PT-DLBCL was unclear. Herein, we performed single-cell RNA sequencing (scRNASeq) and bulk whole exome sequencing (WES) to reveal the molecular landscape of PT-DLBCL. We defined predictive signatures based on gene profiles of the pivotal clusters. Our study could be a benefit for the clinical classification of PTDLBCL and provide valuable therapeutic targets.

Fractures have an extraordinarily negative impact on individuals’ quality of life and functional status. Nonunion or disability of fracture is a major health issue with important clinical, social, and economic implications. Mesenchymal stem cells (MSCs) play an indispensable role in the initiation of the fracture repair process including the formation of a callus which is replaced by new bone. The use of MSCs in the treatment of fractures is very attractive as they can reduce the time of healing and occurrence of nonunion. However, the effects of MSCs are often hindered by the harsh ischemic micro-environment at the fracture sites, such as low cell survival rate and differentiation in vivo. Histone modifications are one of the most important epigenetic regulations with the ability to control the fate of stem cells. Lysine demethylase 5C (Kdm5c) is frequently mutated in patients with X-linked intellectual disabilities, many of whom exhibit physical and behavioral abnormalities, including epilepsy, short stature, etc. In our previous study, we investigated the de-differentiated MSCs with enhanced osteogenic differentiation capacity and found that Kdm5c might be involved in regulating the properties of dedifferentiated osteogenic MSCs by PCR array. However, it is still unclear whether Kdm5c plays a role in osteogenesis, bone formation, and fracture repair.