Assessment of Lumbar Lordosis Distribution with a Novel Mathematical Approach and Its Adaptation for Lumbar Intervertebral Disc Degeneration

Introduction. Low back pain and disc degeneration could be linked to global spinal geometry. Our study aimed to develop a reliable new mathematical method to assess the local distribution of total lumbar lordosis with a single numeric parameter and compare it with lumbar intervertebral disc degeneration using routine MRI scans. Methods. An online, open access, easy-to-use platform for measurements was developed based on a novel mathematical approach using MRIs of 60 patients. Our Spinalyze Software can be used online with uploaded MRIs. Several new parameters were introduced and assessed to describe variation in segmental lordosis distribution with a single numerical value. The Pfirrmann grading system was used for the classification of lumbar intervertebral disc degeneration. Relationships were investigated between the grade categories of L1-S1 lumbar discs and the MRI morphological parameters with correlation analysis. Results. Results confirm that the determination of measurement points and calculated parameters are reliable (ICCs and Pearson r values > 0.90), and these parameters were independent of gender. The digression percentage (K%), one of our new parameters, did not show a statistical relationship with the Cobb-angle. According to our results, the maximum deflection breaking-point of lumbar lordosis and its location can be different with the same Cobb-angle and the distribution of global lordosis is uneven because the shape of the lumbar lordosis is shifted downward and centered around the L4 lumbar vertebra. The interobserver reliability of the Pfirrmann grades reading was in the excellent agreement category (88.33% agreement percentage, 0.84 kappa), and digression percentage (K%) showed a significant negative correlation with all L1-S1 disc grades with increasing r correlation values. This means that the smaller the value of digression percentage (K%), the more the number of worn discs in the lower lumbar sections. Conclusions. Spinalyze Software based on a novel mathematical approach provides a free, easy-to-use, reliable, and online measurement tool using standard MRIs to approximate the curvature of lumbar lordosis. The new reliable K% (digression percentage) is one single quantitative parameter to assess the local distribution of total lumbar lordosis. The results indicate that digression percentage (K%) may possibly be associated with the development of lumbar intervertebral disc degeneration. Further evaluation is needed to assess its behavior and advantage

Divergent Access to Histone Deacetylase Inhibitory Cyclopeptides via Late- Stage Cyclopropane Ring Cleavage Strategy. Short Synthesis of Chlamydocin

We present a unified step-economical strategy to access histone deacetylase inhibitory peptides, based on late-stage installation of zinc-binding functionalities via the cleavage of the strained cyclopropane ring in the common pluripotent cyclopropanol precursor. The efficacy of the proposed diversity-oriented approch has been validated by short stereoselective synthesis of a natural product chlamydocin and a number of its analogs.<br /

Characterization of Tumor-Associated Macrophages and the Immune Microenvironment in Limited-Stage Neuroendocrine-High and -Low Small Cell Lung Cancer

This study aims to characterize tumor-infiltrating macrophages (TAMs), myeloid-derived suppressor cells (MDSC), and the related molecular milieu regulating anti-tumor immunity in limited-stage neuroendocrine (NE)-high and NE-low small cell lung cancer. Primary tumors and matched lymph node (LN) metastases of 32 resected, early-stage SCLC patients were analyzed by immunohistochemistry (IHC) with antibodies against pan-macrophage marker CD68, M2-macrophage marker CD163, and MDSC marker CD33. Area-adjusted cell counting on TMAs showed that TAMs are the most abundant cell type in the TME, and their number in tumor nests exceeds the number of CD3 + T-cells (64% vs. 38% in NE-low and 71% vs. 18% in NE-high). Furthermore, the ratio of CD163-expressing M2-polarized TAMs in tumor nests was significantly higher in NE-low vs. NE-high tumors (70% vs. 31%). TAM density shows a strong positive correlation with CD45 and CD3 in tumor nests, but not in the stroma. fGSEA analysis on a targeted RNAseq oncological panel of 2560 genes showed that NE-high tumors exhibited increased enrichment in pathways related to cell proliferation, whereas in NE-low tumors, immune response pathways were significantly upregulated. Interestingly, we identified a subset of NE-high tumors representing an immune-oasis phenotype, but with a different gene expression profile compared to NE-low tumors. In contrast, we found that a limited subgroup of NE-low tumors is immune-deserted and express distinct cellular pathways from NE-high tumors. Furthermore, we identified potential molecular targets based on our expression data in NE-low and immune-oasis tumor subsets, including CD70, ANXA1, ITGB6, TP63, IFI27, YBX3 and CXCR2