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Spatial transcriptomics technologies developed in recent years can provide various information including tissue heterogeneity, which is fundamental in biological and medical research, and have been making significant breakthroughs. Single-cell RNA sequencing (scRNA-seq) cannot provide spatial information, while spatial transcriptomics technologies allow gene expression information to be obtained from intact tissue sections in the original physiological context at a spatial resolution. Various biological insights can be generated into tissue architecture and further the elucidation of the interaction between cells and the microenvironment. Thus, we can gain a general understanding of histogenesis processes and disease pathogenesis, etc. Furthermore, in silico methods involving the widely distributed R and Python packages for data analysis play essential roles in deriving indispensable bioinformation and eliminating technological limitations. In this review, we summarize available technologies of spatial transcriptomics, probe into several applications, discuss the computational strategies and raise future perspectives, highlighting the developmental potential.

Of nine ependymoma molecular groups detected by DNA methylation profiling, the posterior fossa type A (PFA) is most prevalent. We used DNA methylation profiling to look for further molecular heterogeneity among 675 PFA ependymomas. Two major subgroups, PFA-1 and PFA-2, and nine minor subtypes were discovered. Transcriptome profiling suggested a distinct histogenesis for PFA-1 and PFA-2, but their clinical parameters were similar. In contrast, PFA subtypes differed with respect to age at diagnosis, gender ratio, outcome, and frequencies of genetic alterations. One subtype, PFA-1c, was enriched for 1q gain and had a relatively poor outcome, while patients with PFA-2c ependymomas showed an overall survival at 5 years of > 90%. Unlike other ependymomas, PFA-2c tumors express high levels of OTX2, a potential biomarker for this ependymoma subtype with a good prognosis. We also discovered recurrent mutations among PFA ependymomas. H3 K27M mutations were present in 4.2%, occurring only in PFA-1 tumors, and missense mutations in an uncharacterized gene, CXorf67 , were found in 9.4% of PFA ependymomas, but not in other groups. We detected high levels of wildtype or mutant CXorf67 expression in all PFA subtypes except PFA-1f, which is enriched for H3 K27M mutations. PFA ependymomas are characterized by lack of H3 K27 trimethylation (H3 K27-me3), and we tested the hypothesis that CXorf67 binds to PRC2 and can modulate levels of H3 K27-me3. Immunoprecipitation/mass spectrometry detected EZH2, SUZ12, and EED, core components of the PRC2 complex, bound to CXorf67 in the Daoy cell line, which shows high levels of CXorf67 and no expression of H3 K27-me3. Enforced reduction of CXorf67 in Daoy cells restored H3 K27-me3 levels, while enforced expression of CXorf67 in HEK293T and neural stem cells reduced H3 K27-me3 levels. Our data suggest that heterogeneity among PFA ependymomas could have clinicopathologic utility and that CXorf67 may have a functional role in these tumors.

Claudin-low breast cancers are aggressive tumors defined by the low expression of key components of cellular junctions, associated with mesenchymal and stemness features. Although they are generally considered as the most primitive breast malignancies, their histogenesis remains elusive. Here we show that this molecular subtype of breast cancers exhibits a significant diversity, comprising three main subgroups that emerge from unique evolutionary processes. Genetic, gene methylation and gene expression analyses reveal that two of the subgroups relate, respectively, to luminal breast cancers and basal-like breast cancers through the activation of an EMT process over the course of tumor progression. The third subgroup is closely related to normal human mammary stem cells. This unique subgroup of breast cancers shows a paucity of genomic aberrations and a low frequency of TP53 mutations, supporting the emerging notion that the intrinsic properties of the cell-of-origin constitute a major determinant of the genetic history of tumorigenesis. Claudin-low tumors are a rare aggressive subtype of breast cancers. In this study, the authors use a multiomics approach to demonstrate that these tumors are heterogeneous and comprise three main subgroups that emerge from different evolutionary processes.

To understand how malignant tumors develop, we tracked cell membrane, nuclear membrane, spindle, and cell cycle dynamics in polyploid giant cancer cells (PGCCs) during the formation of high-grade serous carcinoma organoids using long-term time-lapse imaging. Single cells underwent traditional mitosis to generate tissue with uniform nuclear size, while others formed PGCCs via asymmetric mitosis, endoreplication, multipolar endomitosis, nuclear fusion, and karyokinesis without cytokinesis. PGCCs underwent restitution multipolar endomitosis, nuclear fragmentation, and micronuclei formation to increase nuclear contents and heterogeneity. At the cellular level, the development of PGCCs was associated with forming transient intracellular cells, termed fecundity cells. The fecundity cells can be decellularized to facilitate nuclear fusion and synchronized with other nuclei for subsequent nuclear replication. PGCCs can undergo several rounds of entosis to form complex tissue structures, termed fecundity structures. The formation of PGCCs via multiple modes of nuclear replication in the absence of cytokinesis leads to an increase in the nuclear-to-cytoplasmic (N/C) ratio and intracellular cell reproduction, which is remarkably similar to the mode of nuclear division during pre-embryogenesis. Our data support that PGCCs may represent a central regulator in malignant histogenesis, intratumoral heterogeneity, immune escape, and macroevolution via the de-repression of suppressed pre-embryogenic program in somatic cells.

Infected nonunion of tibia and femur are common in clinical practice, however, the treatment of these diseases has still been a challenge for orthopaedic surgeons. Ilizarov methods can eradicate infection, compensate bone defects and promote the bone union through progressive bone histogenesis. The objective of this systematic review was to review current available studies reporting on Ilizarov methods in the treatment of infected nonunion of tibia and femur, and to perform meta-analysis of bone and functional results and complications to evaluate the efficacy of Ilizarov methods. A comprehensive literature search was performed from the SCI, PubMed, Cochrane Library; and Embase between January 1995 and August 2015. Some major data were statistically analyzed using weighted means based on the sample size in each study by SPSS 13.0, including number of patients, mean age, mean previous surgical procedures, mean bone defects, mean length of follow-up, bone union, complications per patient, external fixation time, and external fixation index(EFI). Bone results (excellent, good, fair and poor rate), functional results (excellent, good, fair and poor rate) and complications were analyzed by Stata 9.0. A total of 590 patients from 24 studies were included in this systematic review. The average of bone union rate was 97.26% in all included studies. The poor rate in bone results and functional results was 8% (95%CI, 0.04-0.12; I2 = 44.1%, P = 0.065) and 10% (95%CI, 0.05-0.14; I2 = 34.7%, P = 0.121) in patients with infected nonunion of tibia and femur treated by Ilizarov methods. The rate of refracture, malunion, infectious recurrence, knee stiffness, amputation, limb edema and peroneal nerve palsy was respectively 4%, 7%, 5%, 12%, 4%, 13% and 13%. Our systematic review showed that the patients with infected nonunion of tibia and femur treated by Ilizarov methods had a low rate of poor bone and functional results. Therefore, Ilizarov methods may be a good choice for the treatment of infected nonunion of tibia and femur.

Sonic hedgehog signaling regulates processes of embryonic development across multiple tissues, yet factors regulating context-specific Shh signaling remain poorly understood. Exome sequencing of families with polymicrogyria (disordered cortical folding) revealed multiple individuals with biallelic deleterious variants in TMEM161B, which encodes a multi-pass transmembrane protein of unknown function. Tmem161b null mice demonstrated holoprosencephaly, craniofacial midline defects, eye defects, and spinal cord patterning changes consistent with impaired Shh signaling, but were without limb defects, suggesting a CNS-specific role of Tmem161b. Tmem161b depletion impaired the response to Smoothened activation in vitro and disrupted cortical histogenesis in vivo in both mouse and ferret models, including leading to abnormal gyration in the ferret model. Tmem161b localizes non-exclusively to the primary cilium, and scanning electron microscopy revealed shortened, dysmorphic, and ballooned ventricular zone cilia in the Tmem161b null mouse, suggesting that the Shh-related phenotypes may reflect ciliary dysfunction. Our data identify TMEM161B as a regulator of cerebral cortical gyration, as involved in primary ciliary structure, as a regulator of Shh signaling, and further implicate Shh signaling in human gyral development.

Rare cancers, as a collective, account for around a quarter of all cancer diagnoses and deaths. Historically, they have been divided into two groups: cancers defined by their unusual histogenesis (cell of origin or differentiation state)—including chordomas or adult granulosa cell tumours—and histologically defined subtypes of common cancers. Most tumour types in the first group are still clinically and biologically relevant, and have been disproportionately important as sources of insight into cancer biology. By contrast, most of those in the second group have been shown to have neither defining molecular features nor clinical utility. Omics-based analyses have splintered common cancers into a myriad of molecularly, rather than histologically, defined subsets of common cancers, many of which have immediate clinical relevance. Now, almost all rare cancers are either histomolecular entities, which often have pathognomonic mutations, or molecularly defined subsets of more common cancers. The presence of specific genetic variants provides rationale for the testing of targeted drugs in rare cancers. However, in addition to molecular alterations, it is crucial to consider the contributions of both mutation and cell context in the development, biology, and behaviour of these cancers. Patients with rare cancers are disadvantaged because of the challenge of leading clinical trials in this setting due to poor accrual. However, the number of patients with rare cancers will only increase as more molecular subsets of common cancers are identified, necessitating a shift in the focus of clinical trials and research into these cancer types, which, by epidemiological definitions, will become rare tumours.

Oncogenic fusion proteins generated by chromosomal translocations play major roles in cancer. Among them, fusions between EWSR1 and transcription factors generate oncogenes with powerful chromatin regulatory activities, capable of establishing complex gene expression programs in permissive precursor cells. Here we define the epigenetic and 3D connectivity landscape of Clear Cell Sarcoma, an aggressive cancer driven by the EWSR1-ATF1 fusion gene. We find that EWSR1-ATF1 displays a distinct DNA binding pattern that requires the EWSR1 domain and promotes ATF1 retargeting to new distal sites, leading to chromatin activation and the establishment of a 3D network that controls oncogenic and differentiation signatures observed in primary CCS tumors. Conversely, EWSR1-ATF1 depletion results in a marked reconfiguration of 3D connectivity, including the emergence of regulatory circuits that promote neural crest-related developmental programs. Taken together, our study elucidates the epigenetic mechanisms utilized by EWSR1-ATF1 to establish regulatory networks in CCS, and points to precursor cells in the neural crest lineage as candidate cells of origin for these tumors. The relationship between cellular histogenesis and molecular phenotypes for the EWSR1- ATF1 fusion in clear cell sarcoma (CCS) requires further characterization. Here, the authors investigate the EWSR1-ATF1 gene regulation networks in CCS cell lines, primary tumors, and mesenchymal stem cells.

The current study focused on the histogenesis of the esophagus in quail embryos. Formation of the gut tube occurred on the 4th day of incubation. Development of the muscular layers occurred in a sequential manner; the inner circular layer on the 7th day, the outer longitudinal layer on the 8th day and the muscularis mucosae on the 9th day. Glandular development began on the 13th day of incubation. The epithelium was pseudostratified columnar that consisted of mucous cells, dendritic cells, and keratinocyte precursors. Epithelial stratification occurred on the 15th day of incubation. We used Mallory trichrome, Weigert-Van Gieson, and Gomori silver stains to visualize fibrous components. Scanned samples showed formation of endoderm and mesoderm on the 5th day of incubation. A layer of myoblasts developed on the 8th day of incubation. Formation of mucosal folds, which contained glandular openings, occurred on the 14th to 17th days of incubation. On the 5th to 8th days of incubation, CD34 and vascular endothelial growth factor (VEGF) positive-mesodermal cells, and telocytes (TCs) were detected. On the 15th day of incubation, CD34 and VEGF positive-telocytes, and fibroblasts, were identified. The current study described the correlations between functional morphology and evolutionary biology.