Refining colorectal cancer classification and clinical stratification through a single-cell atlas

Background Colorectal cancer (CRC) consensus molecular subtypes (CMS) have different immunological, stromal cell, and clinicopathological characteristics. Single-cell characterization of CMS subtype tumor microenvironments is required to elucidate mechanisms of tumor and stroma cell contributions to pathogenesis which may advance subtype-specific therapeutic development. We interrogate racially diverse human CRC samples and analyze multiple independent external cohorts for a total of 487,829 single cells enabling high-resolution depiction of the cellular diversity and heterogeneity within the tumor and microenvironmental cells. Results Tumor cells recapitulate individual CMS subgroups yet exhibit significant intratumoral CMS heterogeneity. Both CMS1 microsatellite instability (MSI-H) CRCs and microsatellite stable (MSS) CRC demonstrate similar pathway activations at the tumor epithelial level. However, CD8+ cytotoxic T cell phenotype infiltration in MSI-H CRCs may explain why these tumors respond to immune checkpoint inhibitors. Cellular transcriptomic profiles in CRC exist in a tumor immune stromal continuum in contrast to discrete subtypes proposed by studies utilizing bulk transcriptomics. We note a dichotomy in tumor microenvironments across CMS subgroups exists by which patients with high cancer-associated fibroblasts (CAFs) and C1Q+TAM content exhibit poor outcomes, providing a higher level of personalization and precision than would distinct subtypes. Additionally, we discover CAF subtypes known to be associated with immunotherapy resistance. Conclusions Distinct CAFs and C1Q+ TAMs are sufficient to explain CMS predictive ability and a simpler signature based on these cellular phenotypes could stratify CRC patient prognosis with greater precision. Therapeutically targeting specific CAF subtypes and C1Q + TAMs may promote immunotherapy responses in CRC patient

Redefining tumor classification and clinical stratification through a colorectal cancer single-cell atlas

Colorectal cancer (CRC), a disease of high incidence and mortality, exhibits a large degree of inter- and intra-tumoral heterogeneity. The cellular etiology of this heterogeneity is poorly understood. Here, we generated and analyzed a single-cell transcriptome atlas of 49,859 CRC cells from 16 patients, validated with an additional 31,383 cells from an independent CRC patient cohort. We describe subclonal transcriptomic heterogeneity of CRC tumor epithelial cells, as well as discrete stromal populations of cancer-associated fibroblasts (CAFs). Within CRC CAFs, we identify the transcriptional signature of specific subtypes that significantly stratifies overall survival in more than 1,500 CRC patients with bulk transcriptomic data. We demonstrate that scRNA analysis of malignant, stromal, and immune cells exhibit a more complex picture than portrayed by bulk transcriptomic-based Consensus Molecular Subtypes (CMS) classification. By demonstrating an abundant degree of heterogeneity amongst these cell types, our work shows that CRC is best represented in a transcriptomic continuum crossing traditional classification systems boundaries. Overall, this CRC cell map provides a framework to re-evaluate CRC tumor biology with implications for clinical trial design and therapeutic development. Competing Interest Statement: The authors have declared no competing interest

Caesarean scar pregnancy: time to explore indications of the caesarean sections?

A retrospective study was conducted in women with history of a caesarean scar pregnancy (CSP) to explore the possible causative mechanisms. Over a period of 40 months, a total of 16,926 deliveries and 3554 caesarean sections (CS) occurred in our hospital. Nine cases of CSP were identified at an incidence of 1:1880 births and 0.25% of all CS. Analysis of the indications of the previous CS revealed that 88.8% of women with known indication had undergone CS without labour. Out of them, 75% underwent CS at preterm gestation and 25% had term elective procedure for breech presentation. Of the patients, 77.7% had multiple CS. Conservation of the uterus was possible in 77.7% of patients utilising non-radical forms of treatment. As most of the women underwent CS with a non-contractile uterus without labour, we believe that the risk of CSP may be related to the indications of the previous CS as the number of CS alone could not explain the occurrence of CSP. It is time to explore this area so that screening strategies can be developed to detect CSP at the earliest possible gestation and to prevent life-threatening complications such as uterine rupture and severe hemorrhage.Impact statement What is already known on this subject? A caesarean scar pregnancy (CSP) is a life-threatening condition that can result in uterine rupture and in severe haemorrhage. Although the diagnostic criteria for the CSP have been established, the risk factors that favour the condition are not well understood. We know that the incomplete healing of the lower uterine segment (LUS) from poor vascularisation can create a microscopic dehiscent tract through which the blastocyst enters the myometrium. Some have postulated that the healing processes following the elective procedures, such as for breech deliveries performed in a non-developed LUS, might facilitate this process. What do the results of this study add? In this study, analysis of the indications of the previous CS revealed that majority of women with a known indication had undergone CS without labour, either at preterm gestation or term elective procedure for breech presentation. We have postulated the possible causative mechanisms in relation to the physiology of LUS development. To the best of our knowledge, this is the first study that has looked specifically at the relationship between the indications of previous CS and CSP. What are the implications of these findings for clinical practice and/or further research? Further studies exploring the indications of the previous CS are recommended so that early first-trimester screening strategies can be generated towards this subgroup of patients to detect CSP at the earliest possible gestation

Novel Techniques For the Preparation of Different Epoxy/Thermoplastic Blends

© Springer International Publishing AG 2017. All rights reserved. Epoxy/thermoplastic blends have received a high degree of attention owing to the fracture toughness improving without significantly compromising the thermal and mechanical properties. These materials are mostly prepared by mixing thermoplastic with epoxy monomers and curatives, and then undergoing a reaction-induced phase separation mechanism to form the final products. The mixing processes are very critical for forming the blends with the optimal properties and processabilities. A poor mixing can lead to localized property variation and deteriorate the morphological and mechanical properties of the final cured blends. Due to the importance of the mixing process, methods used for fabrication of epoxy/thermoplastic blends are described in detail in this chapter. Some novel techniques suitable for specific epoxy/thermoplastic blends are also discussed