Multi-omics analysis of adamantinomatous craniopharyngiomas reveals distinct molecular subgroups with prognostic and treatment response significance.

BACKGROUND: Adamantinomatous craniopharyngioma (ACP) is the commonest pediatric sellar tumor. No effective drug is available and interpatient heterogeneity is prominent. This study aimed to identify distinct molecular subgroups of ACP based on the multi-omics profiles, imaging findings, and histological features, in order to predict the response to anti-inflammatory treatment and immunotherapies. METHODS: Totally 142 Chinese cases diagnosed with craniopharyngiomas were profiled, including 119 ACPs and 23 papillary craniopharyngiomas. Whole-exome sequencing (151 tumors, including recurrent ones), RNA sequencing (84 tumors), and DNA methylome profiling (95 tumors) were performed. Consensus clustering and non-negative matrix factorization were used for subgrouping, and Cox regression were utilized for prognostic evaluation, respectively. RESULTS: Three distinct molecular subgroups were identified: WNT, ImA, and ImB. The WNT subgroup showed higher Wnt/ß-catenin pathway activity, with a greater number of epithelial cells and more predominantly solid tumors. The ImA and ImB subgroups had activated inflammatory and interferon response pathways, with enhanced immune cell infiltration and more predominantly cystic tumors. Mitogen-activated protein kinases (MEK/MAPK) signaling was activated only in ImA samples, while IL-6 and epithelial-mesenchymal transition biomarkers were highly expressed in the ImB group, mostly consisting of children. The degree of astrogliosis was significantly elevated in the ImA group, with severe finger-like protrusions at the invasive front of the tumor. The molecular subgrouping was an independent prognostic factor, with the WNT group having longer event-free survival than ImB (Cox, P = 0.04). ImA/ImB cases were more likely to respond to immune checkpoint blockade (ICB) therapy than the WNT group ( P <0.01). In the preliminary screening of subtyping markers, CD38 was significantly downregulated in WNT compared with ImA and ImB ( P = 0.01). CONCLUSIONS: ACP comprises three molecular subtypes with distinct imaging and histological features. The prognosis of the WNT type is better than that of the ImB group, which is more likely to benefit from the ICB treatment.

Hierarchical classification-based pan-cancer methylation analysis to classify primary cancer.

Hierarchical classification offers a more specific categorization of data and breaks down large classification problems into subproblems, providing improved prediction accuracy and predictive power for undefined categories, while also mitigating the impact of poor-quality data. Despite these advantages, its application in predicting primary cancer is rare. To leverage the similarity of cancers and the specificity of methylation patterns among them, we developed the Cancer Hierarchy Classification Tool (CHCT) using the idea of hierarchical classification, with methylation data from 30 cancer types and 8239 methylome samples downloaded from publicly available databases (The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO)). We used unsupervised clustering to divide the classification subproblems and screened differentially methylated sites using Analysis of variance (ANOVA) test, Tukey-kramer test, and Boruta algorithms to construct models for each classifier module. After validation, CHCT accurately classified 1568 out of 1660 cases in the test set, with an average accuracy of 94.46%. We further curated an independent validation cohort of 677 cancer samples from GEO and assigned a diagnosis using CHCT, which showed high diagnostic potential with generally high accuracies (an average accuracy of 91.40%). Moreover, CHCT demonstrates predictive capability for additional cancer types beyond its original classifier scope as demonstrated in the medulloblastoma and pituitary tumor datasets. In summary, CHCT can hierarchically classify primary cancer by methylation profile, by splitting a large-scale classification of 30 cancer types into ten smaller classification problems. These results indicate that cancer hierarchical classification has the potential to be an accurate and robust cancer classification method.

Does Lumbar Interbody Fusion Modality Affect the Occurrence of Complications in an Osteoporotic Spine Under Whole-Body Vibration? A Finite Element Study.

OBJECTIVE: To evaluate the effects of 3 lumbar interbody fusion techniques on the occurrence of complications in an osteoporotic spine under whole-body vibration. METHODS: A previously developed and validated nonlinear finite element model of L1-S1was modified to develop anterior lumbar interbody fusion (ALIF), posterior lumbar interbody fusion (PLIF), and transforaminal lumbar interbody fusion (TLIF) models with osteoporosis. In each model, the lower surface of the sacrum was absolutely fixed, a follower load of 400N was applied through the axis of the lumbar spine, and an axial sinusoidal vertical load of ±40N (5 Hz) was imposed on the superior surface of L1, to perform a transient dynamic analysis. The maximal values of intradiscal pressure, shear stress on annulus substance, disc bulge, facet joint stress, and screw and rod stress, along with their dynamic response curves, were collected. RESULTS: Among these 3 models, the TLIF model generated the greatest screw and rod stress, and the PLIF model generated the greatest cage-bone interface stress. At the L3-L4 level, compared with the other 2 models, the maximal values and dynamic response curves of intradiscal pressure, shear stress of annulus ground substance, and disc bulge were all lower in the ALIF model. However, the facet contact stress at the adjacent segment in the ALIF model was higher than that in the other 2 models. CONCLUSIONS: In an osteoporotic spine under whole-body vibration, TLIF has the highest risk of screw and rod breakage, PLIF has the highest risk of cage subsidence, and ALIF has the lowest risk of upper adjacent disc degeneration, but the highest risk of adjacent facet joint degeneration.

Biomechanical Effect of Osteoporosis on Adjacent Segments After Anterior Cervical Corpectomy and Fusion.

BACKGROUND: Adjacent segmental degeneration (ASD) is one common long-term complication of anterior cervical corpectomy and fusion (ACCF), and osteoporosis is one basic disease in the elderly. After ACCF, patients may experience osteoporosis with age. However, the influence of osteoporosis on ASD remains unclear. The purpose of this study was to determine whether osteoporosis could affect the development of ASD following ACCF. METHODS: Three finite element models of the cervical spine, including 1 normal model, 1 ACCF model, and 1 ACCF with osteoporosis model, were constructed. ACCF was simulated at the C4-C6 level. A 73.6 N follower load and a 1 Nm moment were imposed on the normal model, and the same follower load together with an adjusted moment was applied to the ACCF model and the ACCF with osteoporosis model, to simulate movement in each direction. The range of motion, intradiscal pressure, shear stress on anulus fibrosus, and facet joint stress at C3-C4 and C6-C7 levels of the models were calculated. RESULTS: In this study, the normal model was well validated. In flexion, extension, right lateral bending, and right axial rotation, the overall range of motion was 8.92°, 19.7°, 15.37°, and 45.27° in the normal model, and the adjusted moment was 1.4 Nm, 2.7 Nm, 1.1 Nm, and 2.6 Nm in the ACCF model, and 1.3 Nm, 2.5 Nm, 1.1 Nm, and 2.4 Nm in the ACCF with osteoporosis model. Despite of a few exceptions, the maximum values of the outcome measurements were mostly found in the ACCF model, and the minimum values in the normal model. Compared with the ACCF model, most of the outcome measurements were decreased in the ACCF with osteoporosis model. CONCLUSIONS: Osteoporosis can retard the adverse influence of ACCF on adjacent segments.

Effect of Pedicle Screw Fixation on Adjacent Segments in Osteoporotic Spine Following Transforaminal Lumbar Interbody Fusion Under Whole Body Vibration.

BACKGROUND: Adjacent segmental degeneration (ASD) is the long-term complication of transforaminal lumbar interbody fusion (TLIF) combined with pedicle screw fixation. Both osteoporosis and whole-body vibration (WBV) can alter the biomechanics of adjacent segments. However, the effect of pedicle screw fixation on ASD in an osteoporotic spine after TLIF under WBV was unknown. METHODS: According to a previously validated model of L1-S1, 2 osteoporotic TLIF models with and without pedicle screw fixation were developed. In each model, a 400 N preload was applied and a 5-Hz, 40 N sinusoidal vertical load with a 40-kg mass point was imposed on the superior surface of L1. The parameters of intradiskal pressure, shear stress of annulus fibrosus, disk bulge, superior and inferior end plate stress, and facet joint contact pressure at L3-L4 and L5-S1 levels were evaluated. RESULTS: At L3-L4, the dynamic responses in intradiskal pressure, shear stress, facet joint contact pressure, superior end plate stress, and inferior end plate stress generated an increase after pedicle screw fixation, and their maximum values increased by 15.1%, 9.5%, 18.6%, 10.6%, and 9.3%, respectively. However, the parameter of disk bulge demonstrated an opposite trend. At L5-S1, the differences in maximum values of the parameters were slight and the corresponding dynamic response curves were close, overlapping, or intersecting. CONCLUSIONS: In an osteoporotic spine after TLIF, removal of pedicle screw fixation can mitigate ASD in the upper adjacent segment but has no apparent influence on the lower adjacent segment under WBV.

Multi-time scale transcriptomic analysis on the dynamic process of tamoxifen resistance development in breast cancer cell lines.

BACKGROUND: Approximately 30% of breast cancer patients develop endocrine resistance after tamoxifen therapy. There still lacks a comprehensive understanding on the mechanism of tamoxifen resistance. This study aims to explore the dynamic process of ER + breast cancer resistance to tamoxifen through the time course transcriptomic analysis. METHODS: The transcriptome profiles of human breast cancer cell line MCF-7 treated with tamoxifen at different time scales were collected from LINCS, SRA and GEO databases. Differentially expressed genes (DEGs) were identified in the short-term tamoxifen treatment and tamoxifen-resistant cell lines. The time course analysis was used to explore the dynamic development of tamoxifen resistance using the transcriptome profiles of tamoxifen-cultured MCF-7 for 1-12 weeks. RESULTS: After the short-term treatment of MCF-7 with tamoxifen for 6 h or 24 h, the expression level of gene PRSS23 was significantly reduced. However, its expression recovered in the resistant cell lines. The time course analysis identified 9 clusters of the DEGs based on the temporal trend of their expression levels. Gene PRSS23 belongs to cluster 2 in which the expression levels were significantly down-regulated in the first 4 weeks but gradually recovered afterwards. Functional enrichment analysis of the DEGs in cluster 2 showed that they are significantly enriched in DNA replication, mismatch repair and cell cycle pathways. Their specific role in the resistance development needs to be further explored. The protein-protein interaction network analysis indicates that gene PRSS23 participates in the drug resistance by regulating multiple tamoxifen drug targets. CONCLUSIONS: The acquired drug resistance in ER + breast cancer is a complex and dynamic biological process. PRSS23 plays an important role in the development of resistance and is a potential target for overcoming resistance.

Effect of Osteoporosis on Adjacent Segmental Degeneration After Posterior Lumbar Interbody Fusion Under Whole Body Vibration.

BACKGROUND: Adjacent segmental degeneration (ASD) is one of the common complications after posterior lumbar interbody fusion (PLIF). Both whole body vibration (WBV) and osteoporosis are important factors associated with the biomechanics of the lumbar spine. However, to the best of our knowledge, no studies have investigated the effects of osteoporosis on ASD after PLIF under WBV. METHODS: In the present study, using one normal model, one PLIF model and one PLIF with osteoporosis model of the L1-S1 segment were developed. A 5-Hz, 40-N sinusoidal vertical load was imposed on the superior surface of L1 of each model to simulate WBV, and the dynamic responses and maximal values of intradiscal pressure, shear stress on annulus fibrosus, total deformation, and disc bulge were evaluated in the L1-L2, L2-L3, L3-L4, and L5-S1 segments. RESULTS: At the L1-L2, L2-L3, and L3-L4 levels, the differences in the dynamic responses and maximal values in intradiscal pressure, shear stress, total deformation, and disc bulge between the PLIF and PLIF with osteoporosis models were slight. However, at the L5-S1 level, the dynamic response curves and maximal intradiscal pressure, shear stress, and disc bulge values in the PLIF with osteoporosis model were significantly lower than those in the PLIF model. CONCLUSIONS: Osteoporosis can mitigate the development of ASD in the lower adjacent segment but has no obvious influence on the upper adjacent segments during WBV.

A Qualitative Transcriptional Signature for the Risk Assessment of Precancerous Colorectal Lesions.

It is meaningful to assess the risk of cancer incidence among patients with precancerous colorectal lesions. Comparing the within-sample relative expression orderings (REOs) of colorectal cancer patients measured by multiple platforms with that of normal colorectal tissues, a qualitative transcriptional signature consisting of 1,840 gene pairs was identified in the training data. Within an evaluation dataset of 16 active and 18 inactive (remissive) ulcerative colitis subjects, the median incidence risk score of colorectal carcinoma was 0.6402 in active ulcerative colitis subjects, significantly higher than that in remissive subjects (0.3114). Evaluation of two other independent datasets yielded similar results. Moreover, we found that the score significantly positively correlated with the degree of dysplasia in the case of colorectal adenomas. In the merged dataset, the median incidence risk score was 0.9027 among high-grade adenoma samples, significantly higher than that among low-grade adenomas (0.8565). In summary, the developed incidence risk score could well predict the incidence risk of precancerous colorectal lesions and has value in clinical application.

A qualitative transcriptional signature for the early diagnosis of colorectal cancer.

Currently, using biopsy specimens for the early diagnosis of colorectal cancer (CRC) is not entirely reliable due to insufficient sampling amount and inaccurate sampling location. Thus, it is necessary to develop a signature that can accurately identify patients with CRC under these clinical scenarios. Based on the relative expression orderings of genes within individual samples, we developed a qualitative transcriptional signature to discriminate CRC tissues, including CRC adjacent normal tissues from non-CRC individuals. The signature was validated using multiple microarray and RNA sequencing data from different sources. In the training data, a signature consisting of 7 gene pairs was identified. It was well validated in both biopsy and surgical resection specimens from multiple datasets measured by different platforms. For biopsy specimens, 97.6% of 42 CRC tissues and 94.5% of 163 non-CRC (normal or inflammatory bowel disease) tissues were correctly classified. For surgically resected specimens, 99.5% of 854 CRC tissues and 96.3% of 81 CRC adjacent normal tissues were correctly identified as CRC. Notably, we additionally measured 33 CRC biopsy specimens by the Affymetrix platform and 13 CRC surgical resection specimens, with different proportions of tumor epithelial cells, ranging from 40% to 100%, by the RNA sequencing platform, and all these samples were correctly identified as CRC. The signature can be used for the early diagnosis of CRC, which is also suitable for minimum biopsy specimens and inaccurately sampled specimens, and thus has potential value for clinical application.