A new method for the high-precision assessment of tumor changes in response to treatment.

Motivation: Imaging demonstrates that preclinical and human tumors are heterogeneous, i.e. a single tumor can exhibit multiple regions that behave differently during both development and also in response to treatment. The large variations observed in control group, tumors can obscure detection of significant therapeutic effects due to the ambiguity in attributing causes of change. This can hinder development of effective therapies due to limitations in experimental design rather than due to therapeutic failure. An improved method to model biological variation and heterogeneity in imaging signals is described. Specifically, linear Poisson modeling (LPM) evaluates changes in apparent diffusion co-efficient between baseline and 72 h after radiotherapy, in two xenograft models of colorectal cancer. The statistical significance of measured changes is compared to those attainable using a conventional t-test analysis on basic apparent diffusion co-efficient distribution parameters. Results: When LPMs were applied to treated tumors, the LPMs detected highly significant changes. The analyses were significant for all tumors, equating to a gain in power of 4-fold (i.e. equivalent to having a sample size 16 times larger), compared with the conventional approach. In contrast, highly significant changes are only detected at a cohort level using t-tests, restricting their potential use within personalized medicine and increasing the number of animals required during testing. Furthermore, LPM enabled the relative volumes of responding and non-responding tissue to be estimated for each xenograft model. Leave-one-out analysis of the treated xenografts provided quality control and identified potential outliers, raising confidence in LPM data at clinically relevant sample sizes. Availability and implementation: TINA Vision open source software is available from www.tina-vision.net. Supplementary information: Supplementary data are available at Bioinformatics online.

NFκB1 is a suppressor of neutrophil-driven hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) develops on the background of chronic hepatitis. Leukocytes found within the HCC microenvironment are implicated as regulators of tumour growth. We show that diethylnitrosamine (DEN)-induced murine HCC is attenuated by antibody-mediated depletion of hepatic neutrophils, the latter stimulating hepatocellular ROS and telomere DNA damage. We additionally report a previously unappreciated tumour suppressor function for hepatocellular nfkb1 operating via p50:p50 dimers and the co-repressor HDAC1. These anti-inflammatory proteins combine to transcriptionally repress hepatic expression of a S100A8/9, CXCL1 and CXCL2 neutrophil chemokine network. Loss of nfkb1 promotes ageing-associated chronic liver disease (CLD), characterized by steatosis, neutrophillia, fibrosis, hepatocyte telomere damage and HCC. Nfkb1(S340A/S340A)mice carrying a mutation designed to selectively disrupt p50:p50:HDAC1 complexes are more susceptible to HCC; by contrast, mice lacking S100A9 express reduced neutrophil chemokines and are protected from HCC. Inhibiting neutrophil accumulation in CLD or targeting their tumour-promoting activities may offer therapeutic opportunities in HCC.

Attempted endogenous tissue repair following experimental spinal cord injury in the rat: involvement of cell adhesion molecules L1 and NCAM?

It is widely accepted that the devastating consequences of spinal cord injury are due to the failure of lesioned CNS axons to regenerate. The current study of the spontaneous tissue repair processes following dorsal hemisection of the adult rat spinal cord demonstrates a phase of rapid and substantial nerve fibre in-growth into the lesion that was derived largely from both rostral and caudal spinal tissues. The response was characterized by increasing numbers of axons traversing the clearly defined interface between the lesion and the adjacent intact spinal cord, beginning by 5 days post operation (p.o.). Having penetrated the lesion, axons became associated with a framework of NGFr-positive non-neuronal cells (Schwann cells and leptomeningeal cells). Surprisingly few of these axons were derived from CGRP- or SP-immunoreactive dorsal root ganglion neurons. At the longest survival time (56 days p.o.), there was a marked shift in the overall orientation of fibres from a largely rostro-caudal to a dorso-ventral axis. Attempts to identify which recognition molecules may be important for these re-organizational processes during attempted tissue repair demonstrated the widespread and intense expression of the cell adhesion molecules (CAM) L1 and N-CAM. Double immunofluorescence suggested that both Schwann cells and leptomeningeal cells contributed to the pattern of CAM expression associated with the cellular framework within the lesion.

Differential distribution of immunoreactivity in the developing rat spinal cord revealed by the monoclonal antibody Py.

Monoclonal antibody Py was developed as a useful tool for the identification of large diameter neurons of the adult rat central nervous system [Woodhams et al., J. Neurosci., 9 (1989) 2170-2181]. Here, we present a detailed light-microscopic study of the distribution of Py-immunoreactivity in the developing rat spinal cord. The first cells which demonstrated Py-immunoreactivity were the motoneurons in layer IX of the gray matter at embryonic day 15. These cells, including their axons and dendrites, remained Py-immunoreactive throughout subsequent developmental stages into adulthood and were the most intensely stained cells in the adult rat spinal cord. Other cell populations which became Py-immunoreactive during development were neurons in layers III-VIII, and large-to-medium diameter neurons of the dorsal root ganglion (DRG). Transient Py-immunoreactivity was observed in the distal portions of DRG axons as well as in the ascending fibers in the dorsal funiculus. Py-immunoreactive fibers could be detected in the ventral most part of the dorsal funiculus (corticospinal tract area), even at embryonic ages prior to the arrival of corticospinal fibers. The localization and transient expression of the antigen recognized by the Py-antibody in developing rat spinal cord strongly suggests an important role of this molecule in stabilization and/or plasticity of the neuronal cytoskeleton. The results presented here form the foundation for the use of Py-immunocytochemistry to study well-defined cell populations under a range of experimental and pathological conditions.