The most common reason for sensorineural hearing loss is death of hair cells (HC) from diverse stressors. When HC degenerate they are not replaced, and therefore hearing loss is permanent. Heat shock proteins (HSPs) are molecular chaperones, participating in folding, targeting and degrading proteins in all cells. In addition, HSP expression is increased in response to various environmental stresses to protect cells from damage. One common HSP, HSP70, inhibits apoptosis caused by heat shock and other stresses. Here we test whether Adenovirus with HSP

70 (Ad.HSP70) gene transfer protects against a systemic ototoxic insult (kanamycin and furosemide combination) in the guinea pig cochlea, in vivo. In addition, we invested where HSP70 expresses in cochlea by HSP70 staining. Ad.HSP70-mCherry was injected to experimental animals and Ad.mCherry to controls, 4 days prior to the ototoxic insult. Hearing thresholds were measured by ABR before the insult and again prior to sacrificing the animals, 14 days after the insult. Epi-fluorescence immunocytochemistry showed that injection of Ad.HSP70-mCherry resulted in mCherry fluorescence in non-sensory cells of the organ of Corti. The ototoxic insult eliminated both outer HCs (OHCs) and inner HCs (IHCs) throughout most of the cochlea of control (Ad.mCherry-injected) ears and contralateral (un-injected) ears. Ad.HSP70-mCherry-injected ears exhibited a significant preservation of IHCs compared to control and contralateral ears. ABR thresholds were significantly better in Ad.HSP70-mCherry-injected ears than in control and contralateral ears. Our data showed that HSP70 expression was found to be in harmony with mCherry expression in non-sensory cells of cochlea.

Cytotoxic CD8 T lymphocytes are the major cells of the immune response to viral infection and tumor rejection. Differentiated CTLs have a large number of modified lysosomes including perforin and granzyme B.

Mammalian ste-20 like kinase Mst1 is abundantly expressed on lymphocytes and plays important roles during apoptosis, proliferation, cell polarity, and migration.

Here, we report the new role of Mst1 for cytotoxic T-cell responses and tumor reduction.

Mst1^–/– cytotoxic T cells also showed enhanced T-bet expression associated with elevated expression levels of IFNγ and granzyme B.

In addition, Mst1^–/– cytotoxic T cells suppressed tumor growth and prolonged overall survival of tumor bearing mice in vivo.

Thus, Mst1 is a potential therapeutic target for tumor immunotherapy.

Background and Aims: Epithelial cells affected by somatic mutations undergo transition from tumor-suppressive to carcinogenic Smad pathway during sporadic colorectal carcinogenesis, and the specific linker threonine phosphorylation of Smad2/3 in colon epithelial cells indicates stem-like cells. This study extends previous our observations (Cancer Res 2005; 65: 157–65, Cancer Res 2007; 67: 5090–6, Dig Dis Sci 2015; 60: 362–74) to a model of colitis-associated colorectal cancer.

Methods: After Crl:CD-1 mice received an intraperitoneal administration of azoxymethane (AOM), the mice were given dextran sodium sulfate (DSS) for seven days. AOM/DSS-treated mice (AOM/DSS mice) were killed at 10 or 20 weeks. After macroscopic observations, a histopathological analysis was conducted. Immunohistochemical staining was performed using the avidin-biotin immunoperoxidase method (pSmad3C-Ser, pSmad3L-Ser, c-Myc) and immunofluorescent methods (Ki67, β-catenin, CDK4, cyclin D1, Sox9, pSmad2/3L-Thr).

Results: Colons from AOM/DSS mice were shorter than those from control mice. The number of colon tumors at week 20 was higher than at week 10. Inflammation scores for AOM/DSS mice were greater than those for control mice. Immunostaining-positive cells {staining by Ki67, β-catenin (nuclear and cytoplasmic), cyclin D1, and Sox9} were diffusely distributed in colon tumors. The percentage of pSmad3L-Ser-positive cells in colon tumors was higher than in sites of colitis, and that in sites of colitis was higher than in control mice. pSmad2/3L-Thr-positive cells were sparsely detected around crypt bases in non-neoplastic colon epithelia and at the tops of tumors, and immunohistochemical co-localization of pSmad2/3L-Thr with Ki67 was not observed. Immunohistochemical co-localization of pSmad2/3L-Thr with β-catenin and CDK4 was observed.

Conclusions: pSmad3L-Ser signaling is an early event in colitis-associated colorectal cancer, and pSmad2/3L-Thr immunostaining-positive cells might be cancer stem cells.