Alternating electric fields (TTFields) inhibit metastatic spread of solid tumors to the lungs

Tumor treating fields (TTFields) are low intensity, intermediate frequency, alternating electric fields used to treat cancerous tumors. This novel treatment modality effectively inhibits the growth of solid tumors in vivo and has shown promise in pilot clinical trials in patients with advanced stage solid tumors. TTFields were tested for their potential to inhibit metastatic spread of solid tumors to the lungs in two animal models: (1) Mice injected with malignant melanoma cells (B16F10) into the tail vein, (2) New Zealand White rabbits implanted with VX-2 tumors within the kidney capsule. Mice and rabbits were treated using two-directional TTFields at 100–200 kHz. Animals were either monitored for survival, or sacrificed for pathological and histological analysis of the lungs. The total number of lung surface metastases and the absolute weight of the lungs were both significantly lower in TTFields treated mice then in sham control mice. TTFields treated rabbits survived longer than sham control animals. This extension in survival was found to be due to an inhibition of metastatic spread, seeding or growth in the lungs of TTFields treated rabbits compared to controls. Histologically, extensive peri- and intra-tumoral immune cell infiltration was seen in TTFields treated rabbits only. These results raise the possibility that in addition to their proven inhibitory effect on the growth of solid tumors, TTFields may also have clinical benefit in the prevention of metastatic spread from primary tumors

CEDNIK syndrome results from loss-of-function mutations in SNAP29

Background  CEDNIK (cerebral dysgenesis, neuropathy, ichthyosis and keratoderma) syndrome is a rare genodermatosis which was shown 5 years ago in one family to be associated with a loss-of-function mutation in SNAP29, encoding a member of the SNARE family of proteins. Decrease in SNAP29 expression was found to result in abnormal lamellar granule maturation leading to aberrant epidermal differentiation and ichthyosis. Objectives  To delineate the molecular consequences of disease-causing mutations in SNAP29. Methods  We used direct sequencing, in vitro mutagenesis and three-dimensional organotypic cell cultures. Results  We identified a novel homozygous insertion in SNAP29 (c.486insA) in two sibs presenting with ichthyosis and dysgenesis of the corpus callosum. In vitro transfection experiments indicated that this mutation results in SNAP29 loss-of-function. Further substantiating this notion, we could replicate histological features typical for CEDNIK syndrome in three-dimensional primary human keratinocyte organotypic cell cultures downregulated for SNAP29. Conclusions  The identification of a second mutation in SNAP29 in the present study definitely establishes a causal relationship between defective function of SNAP29 and the pleiotropic manifestations of CEDNIK syndrome. Our present and previous data position SNAP29 as an essential component of the epidermal differentiation machinery