Deterministic evolution and stringent selection during preneoplasia.

The earliest events during human tumour initiation, although poorly characterized, may hold clues to malignancy detection and prevention1. Here we model occult preneoplasia by biallelic inactivation of TP53, a common early event in gastric cancer, in human gastric organoids. Causal relationships between this initiating genetic lesion and resulting phenotypes were established using experimental evolution in multiple clonally derived cultures over 2 years. TP53 loss elicited progressive aneuploidy, including copy number alterations and structural variants prevalent in gastric cancers, with evident preferred orders. Longitudinal single-cell sequencing of TP53-deficient gastric organoids similarly indicates progression towards malignant transcriptional programmes. Moreover, high-throughput lineage tracing with expressed cellular barcodes demonstrates reproducible dynamics whereby initially rare subclones with shared transcriptional programmes repeatedly attain clonal dominance. This powerful platform for experimental evolution exposes stringent selection, clonal interference and a marked degree of phenotypic convergence in premalignant epithelial organoids. These data imply predictability in the earliest stages of tumorigenesis and show evolutionary constraints and barriers to malignant transformation, with implications for earlier detection and interception of aggressive, genome-instable tumours.

Modeling and digital calibration for the mirror normal pointing error of the 2D scanning reflector.

The 2D scanning reflector (2DSR) has been widely used in various important opto-mechanical systems. The pointing error of the mirror normal of the 2DSR will greatly affect the optical axis pointing accuracy. In this work, a digital calibration method for the pointing error of the mirror normal of the 2DSR is researched and verified. At first, the error calibration method is proposed based on the datum, which consists of a high-precision two-axis turntable and the photoelectric autocollimator. All the error sources, including the assembly errors and the datum errors in the calibration are analyzed comprehensively. Then the pointing models of the mirror normal are derived from the 2DSR path and the datum path by using the quaternion mathematical method. Additionally, the pointing models are linearized by the Taylor series first-order approximation of the error parameter trigonometric function items. The solution model of the error parameters is further established by using the least square fitting method. In addition, the procedure of the datum establishment is introduced in detail to strictly control the datum error to be small enough, and the calibration experiment is carried out subsequently. At last, the errors of the 2DSR are calibrated and discussed. The results show that the pointing error of the mirror normal of the 2DSR decreases from 365.68 to 6.46 arc seconds after the error compensation. The consistency of the error parameters of the 2DSR calibrated by digital calibration and physical calibration verifies the effectiveness of the digital calibration method proposed in this paper.

Which is the appropriate surgical procedure for appendiceal adenocarcinoma: appendectomy, partial colectomy or right hemicolectomy?

OBJECTIVE: The purpose of this study was to explore the appropriate surgical procedure and clinical decision for appendiceal adenocarcinoma. METHODS: A total of 1,984 appendiceal adenocarcinoma patients from 2004 to 2015 were retrospectively identified from the Surveillance, Epidemiology, and End Results (SEER) database. All patients were divided into three groups based on the extent of surgical resection: appendectomy (N = 335), partial colectomy (N = 390) and right hemicolectomy (N = 1,259). The clinicopathological features and survival outcomes of three groups were compared, and independent prognostic factors were assessed. RESULTS: The 5-year OS rates of patients who underwent appendectomy, partial colectomy and right hemicolectomy were 58.3%, 65.5% and 69.1%, respectively (right hemicolectomy vs appendectomy, P < 0.001; right hemicolectomy vs partial colectomy, P = 0.285; partial colectomy vs appendectomy, P = 0.045). The 5-year CSS rates of patients who underwent appendectomy, partial colectomy and right hemicolectomy were 73.2%, 77.0% and 78.7%, respectively (right hemicolectomy vs appendectomy, P = 0.046; right hemicolectomy vs partial colectomy, P = 0.545; partial colectomy vs appendectomy, P = 0.246). The subgroup analysis based on the pathological TNM stage indicated that there was no survival difference amongst three surgical procedures for stage I patients (5-year CSS rate: 90.8%, 93.9% and 98.1%, respectively). The prognosis of patients who underwent an appendectomy was poorer than that of those who underwent partial colectomy (5-year OS rate: 53.5% vs 67.1%, P = 0.005; 5-year CSS rate: 65.2% vs 78.7%, P = 0.003) or right hemicolectomy (5-year OS rate: 74.2% vs 53.23%, P < 0.001; 5-year CSS rate: 65.2% vs 82.5%, P < 0.001) for stage II disease. Right hemicolectomy did not show a survival advantage over partial colectomy for stage II (5-year CSS, P = 0.255) and stage III (5-year CSS, P = 0.846) appendiceal adenocarcinoma. CONCLUSIONS: Right hemicolectomy may not always be necessary for appendiceal adenocarcinoma patients. An appendectomy could be sufficient for therapeutic effect of stage I patients, but limited for stage II patients. Right hemicolectomy was not superior to partial colectomy for advanced stage patients, suggesting omission of standard hemicolectomy might be feasible. However, adequate lymphadenectomy should be strongly recommended.

Influences of plasma treatment parameters on the hydrophobicity of cathode and anode materials from spent lithium-ion batteries.

The recycling of spent lithium-ion batteries (LIBs) can not only reduce the potential harm caused by solid waste piles to the local environment but also provide raw materials for manufacturing new batteries. Flotation is an alternative approach to achieve the selective separation of cathode and anode active materials from spent LIBs. However, the presence of organic binder on the surface of hydrophilic lithium transition-metal oxides results in losses of cathode materials in the froth phase. In this study, plasma treatment was utilized to remove organic layers from cathode and anode active materials. Firstly, the correlations between plasma treatment parameters (e.g., input power, air flowrate, and treatment time) were explored and the contact angles of cathode and anode active materials were investigated by the response surface methodology. Secondly, differences in the flotation recoveries of cathode and anode active materials were enhanced with plasma modification prior to flotation, which is consistent with the contact angle measurement. Finally, the plasma-modification mechanisms of hydrophobicity of cathode and anode active materials were discussed according to Fourier Transform infrared spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS) analyses. The proposed method could be a promising tool to enhance the flotation separation efficiency of cathode and anode active materials for the recycling of spent LIBs.

Systematic evaluation of bladder cancer risk-associated single-nucleotide polymorphisms in a Chinese population.

Recently, genome-wide association studies (GWAS) have identified over 12 single-nucleotide polymorphisms (SNPs) associated with bladder cancer risk in populations of European descent. However, effects of these SNPs in bladder cancer have not been systemically evaluated in the Chinese population. We conducted association studies of 12 SNPs in a Chinese population of 184 cases and 962 controls. These SNPs were previously identified in European GWAS and a fine mapping study. The reported risk alleles of rs798766 on TACC3 at 4p16 and rs9624880 on MYC at 8q24 were significantly associated with increased bladder cancer risk with P-values of 0.003 and 0.03, respectively. Next, we performed a meta-analysis, by combining our study with previous association studies performed in Chinese. In the meta-analysis, the reported risk allele for four SNPs were significantly associated with increased bladder cancer risk, including rs798766 on TACC3 at 4p16, rs9624880 on MYC at 8q24, rs2294008 on PSCA at 8q24, and rs2736100 on TERT at 5p15. The meta-analysis P-values for the four SNPs ranged from 0.017 to 5.52E-05. The results from our study suggest that a sub-set of bladder cancer risk-associated SNPs identified from the European population are also associated with bladder cancer risk in the Chinese population. Additional studies with larger sample sizes are needed to further confirm our results.

DCSAU-Net: A deeper and more compact split-attention U-Net for medical image segmentation.

Deep learning architecture with convolutional neural network achieves outstanding success in the field of computer vision. Where U-Net has made a great breakthrough in biomedical image segmentation and has been widely applied in a wide range of practical scenarios. However, the equal design of every downsampling layer in the encoder part and simply stacked convolutions do not allow U-Net to extract sufficient information of features from different depths. The increasing complexity of medical images brings new challenges to the existing methods. In this paper, we propose a deeper and more compact split-attention u-shape network, which efficiently utilises low-level and high-level semantic information based on two frameworks: primary feature conservation and compact split-attention block. We evaluate the proposed model on CVC-ClinicDB, 2018 Data Science Bowl, ISIC-2018, SegPC-2021 and BraTS-2021 datasets. As a result, our proposed model displays better performance than other state-of-the-art methods in terms of the mean intersection over union and dice coefficient. More significantly, the proposed model demonstrates excellent segmentation performance on challenging images. The code for our work and more technical details can be found at https://github.com/xq141839/DCSAU-Net.

Development and validation of a prognostic nomogram for rectal cancer patients who underwent surgical resection.

Objective: The purpose of this study was to develop and validate a nomogram model for the prediction of survival outcome in rectal cancer patients who underwent surgical resection. Methods: A total of 9,919 consecutive patients were retrospectively identified using the Surveillance, Epidemiology, and End Results (SEER) database. Significant prognostic factors were determined by the univariate and multivariate Cox analysis. The nomogram model for the prediction of cancer-specific survival (CSS) in rectal cancer patients were developed based on these prognostic variables, and its predictive power was assessed by the concordance index (C-index). Calibration curves were plotted to evaluate the associations between predicted probabilities and actual observations. The internal and external cohort were used to further validate the predictive performance of the prognostic nomogram. Results: All patients from the SEER database were randomly split into a training cohort (n = 6,944) and an internal validation cohort (n = 2,975). The baseline characteristics of two cohorts was comparable. Independent prognostic factors were identified as age, pT stage, lymph node metastasis, serum CEA level, tumor size, differentiation type, perineural invasion, circumferential resection margin involvement and inadequate lymph node yield. In the training cohort, the C-index of the nomogram was 0.719 (95% CI: 0.696-0.742), which was significantly higher than that of the TNM staging system (C-index: 0.606, 95% CI: 0.583-0.629). The nomogram had a C-index of 0.726 (95% CI: 0.691-0.761) for the internal validation cohort, indicating a good predictive power. In addition, an independent cohort composed of 202 rectal cancer patients from our institution were enrolled as the external validation. Compared with the TNM staging system (C-index: 0.573, 95% CI: 0.492-0.654), the prognostic nomogram still showed a better predictive performance, with the C-index of 0.704 (95% CI: 0.626-0.782). Calibration plots showed a good consistency between predicted probability and the actual observation in the training and two validation cohorts. Conclusion: The nomogram showed an excellent predictive ability for survival outcome of rectal cancer patients, and it might provide an accurate prognostic stratification and help clinicians determine individualized treatment strategies.

Comparison of the protective efficacy between the candidate vaccine ZJ01R carrying gE/gI/TK deletion and three commercial vaccines against an emerging pseudorabies virus variant.

Pseudorabies virus (PRV) is a swine alpha-herpesvirus that mainly causes reproductive disorders in sows and neurological diseases in piglets. Vaccination is the most efficient method to prevent the disease. In China, since the emergence of PRV mutant strains in late 2011, the traditional commercial vaccines have not been providing complete protection. Our previous studies have demonstrated that PRV ZJ01 is a highly virulent strain, and its derivative, ZJ01R, which carries the gE/gI/TK gene deletion, could provide protection against the variant PRV challenge. However, the difference in immune efficacy between ZJ01R and other commercial vaccines remains unclear. In this study, the immune protection efficacy between ZJ01R and three commercial PRV vaccines (Bartha-K61, HB2000, and SA215) was evaluated in piglets. The safety of ZJ01R was shown to be equivalent to that of the three commercial vaccines. The titers of the neutralizing antibodies against the PRV classical strain LA in the four vaccine groups were similar, while the anti-PRV variant neutralizing antibody titers in the ZJ01R group were significantly higher than those in the Bartha-K61, HB2000, and SA215 strain groups. After the PRV challenge, ZJ01R, HB2000, and SA215 vaccinations could provide complete protection, whereas the Bartha-K61 vaccination could only provide 60 % protection. Importantly, the rectal viral excretion and PRV DNA loads in the lung tissues in the ZJ01R group were significantly lower than those in the Bartha-K61, HB2000, and SA215 groups. Altogether, these results indicated that ZJ01R could provide higher protection efficacy against the PRV virulent ZJ01 challenge than the three commercial PRV gene-deleted live vaccines derived from the classical vaccine strains, providing the potential to develop a new PRV vaccine to control the epidemic PRV variant strains in the future.

Functional screening of amplification outlier oncogenes in organoid models of early tumorigenesis.

Somatic copy number gains are pervasive across cancer types, yet their roles in oncogenesis are insufficiently evaluated. This inadequacy is partly due to copy gains spanning large chromosomal regions, obscuring causal loci. Here, we employed organoid modeling to evaluate candidate oncogenic loci identified via integrative computational analysis of extreme copy gains overlapping with extreme expression dysregulation in The Cancer Genome Atlas. Subsets of "outlier" candidates were contextually screened as tissue-specific cDNA lentiviral libraries within cognate esophagus, oral cavity, colon, stomach, pancreas, and lung organoids bearing initial oncogenic mutations. Iterative analysis nominated the kinase DYRK2 at 12q15 as an amplified head and neck squamous carcinoma oncogene in p53-/- oral mucosal organoids. Similarly, FGF3, amplified at 11q13 in 41% of esophageal squamous carcinomas, promoted p53-/- esophageal organoid growth reversible by small molecule and soluble receptor antagonism of FGFRs. Our studies establish organoid-based contextual screening of candidate genomic drivers, enabling functional evaluation during early tumorigenesis.

Molecular signature of primary retinal pigment epithelium and stem-cell-derived RPE cells.

Age-related macular degeneration (AMD) is characterized by the loss or dysfunction of retinal pigment epithelium (RPE) and is the most common cause of vision loss among the elderly. Stem-cell-based strategies, using human embryonic stem cells (hESCs) or human-induced pluripotent stem cells (hiPSCs), may provide an abundant donor source for generating RPE cells in cell replacement therapies. Despite a significant amount of research on deriving functional RPE cells from various stem cell sources, it is still unclear whether stem-cell-derived RPE cells fully mimic primary RPE cells. In this report, we demonstrate that functional RPE cells can be derived from multiple lines of hESCs and hiPSCs with varying efficiencies. Stem-cell-derived RPE cells exhibit cobblestone-like morphology, transcripts, proteins and phagocytic function similar to human fetal RPE (fRPE) cells. In addition, we performed global gene expression profiling of stem-cell-derived RPE cells, native and cultured fRPE cells, undifferentiated hESCs and fibroblasts to determine the differentiation state of stem-cell-derived RPE cells. Our data indicate that hESC-derived RPE cells closely resemble human fRPE cells, whereas hiPSC-derived RPE cells are in a unique differentiation state. Furthermore, we identified a set of 87 signature genes that are unique to human fRPE and a majority of these signature genes are shared by stem-cell-derived RPE cells. These results establish a panel of molecular markers for evaluating the fidelity of human pluripotent stem cell to RPE conversion. This study contributes to our understanding of the utility of hESC/hiPSC-derived RPE in AMD therapy.

Repression of retrotransposal elements in mouse embryonic stem cells is primarily mediated by a DNA methylation-independent mechanism.

In defense of deleterious retrotransposition of intracisternal A particle (IAP) elements, IAP loci are heavily methylated and silenced in mouse somatic cells. To determine whether IAP is also repressed in pluripotent stem cells by DNA methylation, we examined IAP expression in demethylated mouse embryonic stem cells (mESCs) and epiblast-derived stem cells. Surprisingly, in demethylated ESC cultures carrying mutations of DNA methyltransferase I (Dnmt1), no IAP transcripts and proteins are detectable in undifferentiated Oct4(+) ESCs. In contrast, approximately 3.6% of IAP-positive cells are detected in Oct4(-) Dnmt1(-/-) cells, suggesting that the previously observed increase in IAP transcripts in the population of Dnmt1(-/-) ESCs could be accounted for by this subset of Oct4(-) Dnmt1(-/-) ESCs undergoing spontaneous differentiation. Consistent with this possibility, a dramatic increase of IAP mRNA (>100-fold) and protein expression was observed in Dnmt1(-/-) ESC cultures upon induction of differentiation through the withdrawal of leukemia-inhibitory factor for 6 or more days. Interestingly, both mRNAs and proteins of IAP can be readily detected in demethylated Oct4(+) epiblast-derived stem cells as well as differentiated mouse embryo fibroblasts, neurons, and glia upon conditional Dnmt1 gene deletion. These data suggest that mESCs are a unique stem cell type possessing a DNA methylation-independent IAP repression mechanism. This methylation-independent mechanism does not involve Dicer-mediated action of microRNAs or RNA interference because IAP expression remains repressed in Dnmt1(-/-); Dicer(-/-) double mutant ESCs. We suggest that mESCs possess a unique DNA methylation-independent mechanism to silence retrotransposons to safeguard genome stability while undergoing rapid cell proliferation for self-renewal.

Periostin identified as a potential biomarker of prostate cancer by iTRAQ-proteomics analysis of prostate biopsy.

BACKGROUND: Proteomics may help us better understand the changes of multiple proteins involved in oncogenesis and progression of prostate cancer(PCa) and identify more diagnostic and prognostic biomarkers. The aim of this study was to screen biomarkers of PCa by the proteomics analysis using isobaric tags for relative and absolute quantification(iTRAQ). METHODS: The patients undergoing prostate biopsies were classified into 3 groups according to pathological results: benign prostate hyperplasia (BPH, n = 20), PCa(n = 20) and BPH with local prostatic intraepithelial neoplasm(PIN, n = 10). Then, all the specimens from these patients were analyzed by iTRAQ and two-dimensional liquid chromatography-tandem mass spectrometry (2DLC-MS/MS). The Gene Ontology(GO) function and the transcription regulation networks of the differentially expressed were analyzed by MetaCore software. Western blotting and Immunohistochemical staining were used to analyze the interesting proteins. RESULT: A total of 760 proteins were identified from 13787 distinct peptides, including two common proteins that enjoy clinical application: prostate specific antigen (PSA) and prostatic acid phosphatase(PAP). Proteins that expressed differentially between PCa and BPH group were further analyzed. Compared with BPH, 20 proteins were significantly differentially up-regulated (>1.5-fold) while 26 were significantly down-regulated in PCa(<0.66-fold). In term of GO database, the differentially expressed proteins were divided into 3 categories: cellular component(CC), molecular function (MF) and biological process(BP). The top 5 transcription regulation networks of the differentially expressed proteins were initiated through activation of SP1, p53, YY1, androgen receptor(AR) and c-Myc The overexpression of periostin in PCa was verified by western blotting and immunohistochemical staining. CONCLUSION: Our study indicates that the iTRAQ technology is a new strategy for global proteomics analysis of the tissues of PCa. A significant up-regulation of periostin in PCa compared to BPH may provide clues for not only a promising biomarker for the prognosis of PCa but also a potential target for therapeutical intervention.

Spatial proteomic characterization of HER2-positive breast tumors through neoadjuvant therapy predicts response.

The addition of HER2-targeted agents to neoadjuvant chemotherapy has dramatically improved pathological complete response (pCR) rates in early-stage, HER2-positive breast cancer. Nonetheless, up to 50% of patients have residual disease after treatment, while others are likely overtreated. Here, we performed multiplex spatial proteomic characterization of 122 samples from 57 HER2-positive breast tumors from the neoadjuvant TRIO-US B07 clinical trial sampled pre-treatment, after 14-21 d of HER2-targeted therapy and at surgery. We demonstrated that proteomic changes after a single cycle of HER2-targeted therapy aids the identification of tumors that ultimately undergo pCR, outperforming pre-treatment measures or transcriptomic changes. We further developed and validated a classifier that robustly predicted pCR using a single marker, CD45, measured on treatment, and showed that CD45-positive cell counts measured via conventional immunohistochemistry perform comparably. These results demonstrate robust biomarkers that can be used to enable the stratification of sensitive tumors early during neoadjuvant HER2-targeted therapy, with implications for tailoring subsequent therapy.

Multi-cancer analysis of clonality and the timing of systemic spread in paired primary tumors and metastases.

Metastasis is the primary cause of cancer-related deaths, but the natural history, clonal evolution and impact of treatment are poorly understood. We analyzed whole-exome sequencing (WES) data from 457 paired primary tumor and metastatic samples from 136 patients with breast, colorectal and lung cancer, including untreated (n = 99) and treated (n = 100) metastases. Treated metastases often harbored private 'driver' mutations, whereas untreated metastases did not, suggesting that treatment promotes clonal evolution. Polyclonal seeding was common in untreated lymph node metastases (n = 17 out of 29, 59%) and distant metastases (n = 20 out of 70, 29%), but less frequent in treated distant metastases (n = 9 out of 94, 10%). The low number of metastasis-private clonal mutations is consistent with early metastatic seeding, which we estimated occurred 2-4 years before diagnosis across these cancers. Furthermore, these data suggest that the natural course of metastasis is selectively relaxed relative to early tumorigenesis and that metastasis-private mutations are not drivers of cancer spread but instead associated with drug resistance.

Quantitative evidence for early metastatic seeding in colorectal cancer.

Both the timing and molecular determinants of metastasis are unknown, hindering treatment and prevention efforts. Here we characterize the evolutionary dynamics of this lethal process by analyzing exome-sequencing data from 118 biopsies from 23 patients with colorectal cancer with metastases to the liver or brain. The data show that the genomic divergence between the primary tumor and metastasis is low and that canonical driver genes were acquired early. Analysis within a spatial tumor growth model and statistical inference framework indicates that early disseminated cells commonly (81%, 17 out of 21 evaluable patients) seed metastases while the carcinoma is clinically undetectable (typically, less than 0.01 cm3). We validated the association between early drivers and metastasis in an independent cohort of 2,751 colorectal cancers, demonstrating their utility as biomarkers of metastasis. This conceptual and analytical framework provides quantitative in vivo evidence that systemic spread can occur early in colorectal cancer and illuminates strategies for patient stratification and therapeutic targeting of the canonical drivers of tumorigenesis.

Clonal replacement and heterogeneity in breast tumors treated with neoadjuvant HER2-targeted therapy.

Genomic changes observed across treatment may result from either clonal evolution or geographically disparate sampling of heterogeneous tumors. Here we use computational modeling based on analysis of fifteen primary breast tumors and find that apparent clonal change between two tumor samples can frequently be explained by pre-treatment heterogeneity, such that at least two regions are necessary to detect treatment-induced clonal shifts. To assess for clonal replacement, we devise a summary statistic based on whole-exome sequencing of a pre-treatment biopsy and multi-region sampling of the post-treatment surgical specimen and apply this measure to five breast tumors treated with neoadjuvant HER2-targeted therapy. Two tumors underwent clonal replacement with treatment, and mathematical modeling indicates these two tumors had resistant subclones prior to treatment and rates of resistance-related genomic changes that were substantially larger than previous estimates. Our results provide a needed framework to incorporate primary tumor heterogeneity in investigating the evolution of resistance.

Publisher Correction: Clonal replacement and heterogeneity in breast tumors treated with neoadjuvant HER2-targeted therapy.

The original version of this Article omitted from the Author Contributions statement that 'R.S. and J.G.R contributed equally to this work.' This has been corrected in both the PDF and HTML versions of the Article.

[Biological characteristics and safety evaluation of endothelial progenitor cells from the umbilical cord blood].

OBJECTIVE: To investigate the biological characteristics of endothelial progenitor cells (EPCs) from the umbilical cord blood (UCB), and to evaluate their oncogenicity after long-term culture in vitro. METHODS: The mononuclear cells (MNCs) were isolated from the UCB and cultured in MCDB131 medium supplemented with 20% FBS, VEGF and other growth factors. Morphology of the EPCs was observed, and the growth curve of the EPCs was investigated. Surface antigens of the EPCs were analyzed by the flow-cytometer. The capability of intaking the acetylated low-density lipoprotein (acLDL) of the EPCs was detected using fluoresencent chemical method. The vasoformative capability and genetic stability of EPCs were cultured in matrigel, and examined by karyotype analysis. The oncogenicity of EPCs was verified by the tumorigenesis test in athymic mouse and soft agar. RESULTS: EPCs were successfully derived from the UCB, and could be passaged to at least 42(nd) generation and had strong abilities of proliferation, acLDL intake and vasoformation, but there was not oncogenicity. They expressed endothelial cell-surface antigens and maintained normal karyotype. CONCLUSION: The EPCs with proliferative potential can be isolated from the UCB. They can be passaged in long-term cultures without oncogenicity, and can maintain normal karyotype. The EPCs can be served as a new type of cells in cell and gene therapy.

The prognostic value of over-expressed TrkB in solid tumors: a systematic review and meta-analysis.

It is reported recently Tropomyosin-related receptor Kinase B (TrkB) plays key roles in the anoikis resistance during the processes of tumorigenesis and metastasis. However, its prognostic significance for clinical patients remains inconclusive. In order to establish a correct and practicable link between increased TrkB and prognostication of human solid tumors, a meta-analysis was performed in this article. A systematic literature research in the electronic databases PubMed, Embase and Web of Science was performed to identify eligible studies. A fixed-effects meta-analytical model was employed to correlate TrkB expression with OS, DFS and clinicopathological features. A total of 11 studies covering 1516 patients with various solid tumors were recruited in this meta-analysis. TrkB over-expression was associated with poorer OS and poorer DFS in multivariate analysis. Additionally, the pooled odds ratios (ORs) indicated that TrkB over-expression was associated with large tumor size, lymph node metastasis, distant metastasis and a higher clinical stage. Overall, these results indicated that TrkB over-expression in patients with solid tumors might be related to poor prognosis and serve as a potential predictive marker of poor clinicopathological prognosis factor.

Between-region genetic divergence reflects the mode and tempo of tumor evolution.

Given the implications of tumor dynamics for precision medicine, there is a need to systematically characterize the mode of evolution across diverse solid tumor types. In particular, methods to infer the role of natural selection within established human tumors are lacking. By simulating spatial tumor growth under different evolutionary modes and examining patterns of between-region subclonal genetic divergence from multiregion sequencing (MRS) data, we demonstrate that it is feasible to distinguish tumors driven by strong positive subclonal selection from those evolving neutrally or under weak selection, as the latter fail to dramatically alter subclonal composition. We developed a classifier based on measures of between-region subclonal genetic divergence and projected patient data into model space, finding different modes of evolution both within and between solid tumor types. Our findings have broad implications for how human tumors progress, how they accumulate intratumoral heterogeneity, and ultimately how they may be more effectively treated.