What happens in the early, still undetectable human malignancy is unknown because direct observations are impractical. Here we present and validate a “Big Bang” model, whereby tumors grow predominantly as a single expansion producing numerous intermixed sub-clones that are not subject to stringent selection, and where both public (clonal) and most detectable private (subclonal) alterations arise early during growth. Genomic profiling of 349 individual glands from 15 colorectal tumors revealed the absence of selective sweeps, uniformly high intra-tumor heterogeneity (ITH), and sub-clone mixing in distant regions, as postulated by our model. We also verified the prediction that most detectable ITH originates from early private alterations, and not from later clonal expansions, thus exposing the profile of the primordial tumor. Moreover, some tumors appear born-to-be-bad, with sub-clone mixing indicative of early malignant potential. This new model provides a quantitative framework to interpret tumor growth dynamics and the origins of ITH with significant clinical implications.

Degenerative disorders of the intervertebral discs (IVDs) are generally characterized by enhanced matrix degradation, angiogenesis, innervation, and increased expression of catabolic cytokines. In this study, we investigated the effects of inflammatory cytokines, IL-1␤, and TNF-␣, on the expression of an angiogenic factor, vascular endothelial growth factor (VEGF), and neurotrophic factors, nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), in human IVD degeneration. IL-1␤ and TNF-␣ stimulated the gene expression of VEGF, NGF, and BDNF in nucleus pulposus (NP) cells isolated from patient tissues. Immunohistochemical results demonstrated a positive correlation between IL-1␤ and VEGF/NGF/BDNF expression in human IVD tissues. RNA expression analysis of patient tissues also identified positive correlations between VEGF and platelet endothelial cell adhesion molecule-1 (PECAM-1) and between NGF/BDNF and protein gene product 9.5 (PGP9.5). Our findings suggest that IL-1␤ is generated during IVD degeneration, which stimulates the expression of VEGF, NGF, and BDNF, resulting in angiogenesis and innervation. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J. Orthop. Res. 29: 265-269, 2011 Keywords: interleukin-1␤; vascular endothelial growth factor (VEGF); angiogenesis; innervation; intervertebral disc (IVD) Degenerative changes in intervertebral discs (IVDs) include increased expression of catabolic cytokines, decreased synthesis of normal IVD matrix and enhanced matrix degradation, and disc cell senescence and apoptosis.1-5 IVD degeneration results in the loss of hydrophilic matrix molecules leading to spinal instability and is the main cause of disc-related diseases, such as disc herniation and spinal stenosis. Normal lumbar IVD is avascular and aneural except for the outer third of the annulus fibrosus (AF). However, previous studies have described the ingrowth of nerves into the AF and nucleus pulposus (NP) of degenerated IVD 6,7 and these nerves were usually accompanied by microvascular blood vessels.8 Though, the mechanisms underlying nerve ingrowth and neovascularization are largely unknown.Neurotrophins play a role in the survival, growth, differentiation, and function of neurons.9 The neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) have been detected in human IVD degeneration and have been implicated in the promotion of nerve ingrowth and generation of discogenic pain. 8,10,11 A histologic study examining degenerative IVD tissues from rats demonstrated that the major population of disc-innervating dorsal root ganglion neurons was the NGF-dependent neurons.

Immune checkpoint blockade is promising for treating non-small-cell lung cancer (NSCLC). We used multipanel markers to predict the response to immune checkpoint inhibitors (ICIs) by characterizing gene expression signatures or individual genes in patients who showed durable clinical benefit to ICIs. Twenty-one patients with NSCLC treated with single-agent anti-programmed cell death protein (PD)-1 antibody were analyzed and their clinicopathological characteristics and response to ICIs were characterized. Nine (43%) showed a durable clinical benefit (DCB), while the remaining 12 (57%) patients showed non-durable benefit (NDB). The M1 and peripheral T cell signatures showed the best performance for discriminating DCB from NDB (sensitivity, specificity, accuracy = 0.89, 1.0, 0.95, respectively). Progression-free survival (PFS) was significantly longer in patients with high M1 signature or high peripheral T cell signature scores. CD137 and PSMB9 mRNA expression was higher in the DCB group than in the NDB group. Patients with high PSMB9 expression showed longer PFS. M1 signature, peripheral T cell signature and high mRNA expression level of CD137 and PSMB9 showed better predictive performance than known biomarkers, such as PD-L1 immunohistochemistry, tumor mutation burden, or tumor-infiltrating lymphocytes.