Monitoring peripheral nerve degeneration in ALS by label-free stimulated Raman scattering imaging.

The study of amyotrophic lateral sclerosis (ALS) and potential interventions would be facilitated if motor axon degeneration could be more readily visualized. Here we demonstrate that stimulated Raman scattering (SRS) microscopy could be used to sensitively monitor peripheral nerve degeneration in ALS mouse models and ALS autopsy materials. Three-dimensional imaging of pre-symptomatic SOD1 mouse models and data processing by a correlation-based algorithm revealed that significant degeneration of peripheral nerves could be detected coincidentally with the earliest detectable signs of muscle denervation and preceded physiologically measurable motor function decline. We also found that peripheral degeneration was an early event in FUS as well as C9ORF72 repeat expansion models of ALS, and that serial imaging allowed long-term observation of disease progression and drug effects in living animals. Our study demonstrates that SRS imaging is a sensitive and quantitative means of measuring disease progression, greatly facilitating future studies of disease mechanisms and candidate therapeutics.

Loss-of-function mutations in the C9ORF72 mouse ortholog cause fatal autoimmune disease.

C9ORF72 mutations are found in a significant fraction of patients suffering from amyotrophic lateral sclerosis and frontotemporal dementia, yet the function of the C9ORF72 gene product remains poorly understood. We show that mice harboring loss-of-function mutations in the ortholog of C9ORF72 develop splenomegaly, neutrophilia, thrombocytopenia, increased expression of inflammatory cytokines, and severe autoimmunity, ultimately leading to a high mortality rate. Transplantation of mutant mouse bone marrow into wild-type recipients was sufficient to recapitulate the phenotypes observed in the mutant animals, including autoimmunity and premature mortality. Reciprocally, transplantation of wild-type mouse bone marrow into mutant mice improved their phenotype. We conclude that C9ORF72 serves an important function within the hematopoietic system to restrict inflammation and the development of autoimmunity.

Malignant phyllodes tumor composed almost exclusively of a fibrosarcomatous component: a case report and review of malignant phyllodes tumors with metastases.

Here we present a case of malignant phyllodes tumor which was composed almost exclusively of a fibrosarcomatous component. A 52-year-old Japanese female noted a rapid increase of her right breast tumor. On admission, multiple lung metastases were detected by imaging. Right simple mastectomy was performed. The tumor, 10 x 10 cm in the largest dimension, had somewhat of a pushing margin, and showed a flesh-like appearance with marked necrosis. Microscopically, the tumor showed proliferation of atypical ovoid- or spindle-shaped cells in a myxoid matrix. Multiple sectioning revealed that the tumor had only focal occurrence of elongated tubular structures, and the occurrence of a small component of benign phyllodes tumor, leading to the aforementioned final diagnosis. Spindle cell carcinoma was excluded on the basis of the HE findings and the lack of immunoreactivity for cytokeratin when using a broad spectrum antibody mixture. Although the patient received adjuvant chemotherapy, no responsiveness was obtained. The patient died 4 months following surgery. We reviewed 15 malignant phyllodes tumors with metastases reported in Japan. The estimated 2.2-year survival rate following detection of metastasis was 11%, thus confirming the aggressiveness of the disease.