Caspase Cleavage of Receptor Tyrosine Kinases in the Dependence Receptor Family

Dependence receptors are a group of receptor proteins with shared characteristics of transducing two different signals within cells.They can transduce a positive signal of survival and differentiation in the presence of ligands. On the other hand, dependence receptors can transduce an apoptosis signal in the absence of ligands. The function of these receptors depends on the availability of their ligands. Several receptor tyrosine kinases (RTKs) have been reported as dependence receptors. When cells undergo apoptosis by dependence receptors, the intracellular domain of some RTKs is cleaved by the caspases. Among the RTKs that belong to dependence receptors, we focused on eight RTKs (RET, HER2, MET, ALK, TrkC, EphA4, EphB3, and c-KIT) that are cleaved by caspases. In this review, we describe the features of the receptors, their cleavage sites, and the fate of the cleaved products, as well as recent implications on them being used as potential therapeutics for cancer treatment.

Characterization of KRC-108 as a TrkA Kinase Inhibitor with Anti-Tumor Effects

Tropomyosin receptor kinase A (TrkA) protein is a receptor tyrosine kinase encoded by the NTRK1 gene. TrkA signaling mediates the proliferation, differentiation, and survival of neurons and other cells following stimulation by its ligand, the nerve growth factor.Chromosomal rearrangements of the NTRK1 gene result in the generation of TrkA fusion protein, which is known to cause deregulation of TrkA signaling. Targeting TrkA activity represents a promising strategy for the treatment of cancers that harbor the TrkA fusion protein. In this study, we evaluated the TrkA-inhibitory activity of the benzoxazole compound KRC-108. KRC-108 inhibited TrkA activity in an in vitro kinase assay, and suppressed the growth of KM12C colon cancer cells harboring an NTRK1 gene fusion.KRC-108 treatment induced cell cycle arrest, apoptotic cell death, and autophagy. KRC-108 suppressed the phosphorylation of downstream signaling molecules of TrkA, including Akt, phospholipase Cγ, and ERK1/2. Furthermore, KRC-108 exhibited antitumor activity in vivo in a KM12C cell xenograft model. These results indicate that KRC-108 may be a promising therapeutic agent for Trk fusion-positive cancers.

Possibility of a Standardized System for Task-Related Hierarchal Positions of Dental Hygienists / 치위생과학회지

Background@#Despite the demand for greater competence of dental hygienists in recent times, and the consequent standardization of systems in the organizations, there is a lack of a proper system for hierarchal positions of dental hygienists.The aim of this study was to identify the tasks performed by Korean dental hygienists in various work settings and hierarchal positions to suggest a standardized system for task-related hierarchal positions. @*Methods@#A survey was conducted by sending questionnaires to 966 dental hygienists, and responses from 757 participants were included in the final analysis. The survey comprised questions regarding participants’ general characteristics, tasks, current positions, and the internal policies or standards of the respective organizations to define these positions. The participants’ positions were analyzed as frequency and cross-sectional analysis with respect to their general characteristics, their place in the organizational charts, the size of their workplaces, and differences in the tasks performed. @*Results@#Data showed that 82.6% of the hospitals and clinics in Korea have organizational systems to determine the positions, and there was a significant difference in the systems according to the size of the health facility (p＜0.05). The standards or policies used to define positions within general or university hospitals were determined by internal regulations or bylaws, whereas work experience was the major determinant of positions in smaller dental hospitals or clinics. The main tasks performed by dental hygienists in Korea were dental assistance (81.2%), routine dental hygiene tasks (53.4%), and administrative tasks, such as reception and billing (46.1%). @*Conclusion@#Most dental hygienists in Korea are actively involved in dental assistance. Therefore, their specific tasks and responsibilities should be standardized more effectively. The data obtained from this study can be used to establish a standardized position system.

Discovery of an Indirubin Derivative as a Novel c-Met Kinase Inhibitor with In Vitro Anti-Tumor Effects

The c-Met protein is a receptor tyrosine kinase involved in cell growth, proliferation, survival, and angiogenesis of several human tumors. Overexpression of c-Met has been found in gastric cancers and correlated with a poor prognosis. Indirubin is the active component of Danggui Longhui Wan, which is a traditional Chinese antileukemic recipe. In the present study, we tested the anti-cancer effects of an indirubin derivative, LDD-1937, on human gastric cancer cells SNU-638. When we performed the in vitro kinase assay against the c-Met activity, LDD-1937 inhibited the activity of c-Met. This result was confirmed by immunoblot and immunofluorescence of phosphorylated c-Met. Immunoblot analysis showed that LDD-1937 decreased the expression of the Erk1/2, STAT3, STAT5, and Akt, downstream proteins of c-Met. In addition, LDD-1937 reduced the cell viability and suppressed colony formation and migration of SNU-638 cells. Furthermore, LDD-1937 induced G2/M phase arrest in the SNU-638 cells by decreasing the expression levels of cyclin B1 and CDC2. Cleaved-PARP, an apoptosis-related protein, was up-regulated in cells treated with LDD-1937. Overall, this study suggests that LDD-1937 may be a novel small-molecule with therapeutic potential for selectively inhibiting c-Met and c-Met downstream pathways in human gastric cancers overexpressing c-Met.

Characterization of the Indirubin Derivative LDD970 as a Small Molecule Aurora Kinase A Inhibitor in Human Colorectal Cancer Cells

Aurora kinase A plays an essential role in mitosis including chromosome separation and cytokinesis. Aberrant expression and activity of Aurora kinase A is associated with numerous malignancies including colorectal cancer followed by poor prognosis. The aim of this study is to determine the inhibitory effects of LDD970, an indirubin derivative, on Aurora kinase A in HT29 colorectal cancer cells. In vitro kinase assay revealed that, LDD970 inhibited levels of activated Aurora kinase A (IC₅₀=0.37 mM). The inhibitory effects of LDD970 on Aurora kinase A, autophosphorylation and phosphorylation of histone H3 (Ser10), were confirmed by immunoblot analysis. Moreover, LDD970 inhibited migration of HT29 cells and upregulated apoptosis-related protein cleaved PARP. In cell viability assay, LDD970 was observed to suppress HT29 cell growth (GI₅₀=4.22 µM). Although further studies are required, results of the present study suggest that LDD970 provide a valuable insight into small molecule indirubin derivative for therapeutic potential in human colorectal cancer.

Induction of Nuclear Enlargement and Senescence by Sirtuin Inhibitors in Glioblastoma Cells

Sirtuin family members with lysine deacetylase activity are known to play an important role in anti-aging and longevity. Cellular senescence is one of the hallmarks of aging, and downregulation of sirtuin is reported to induce premature senescence. In this study, we investigated the effects of small-molecule sirtuin inhibitors on cellular senescence. Various small molecules such as tenovin-1 and EX527 were employed for direct sirtuin activity inhibition. U251, SNB-75, and U87MG glioblastoma cells treated with sirtuin inhibitors exhibited phenotypes with nuclear enlargement. Furthermore, treatment of rat primary astrocytes with tenovin-1 also increased the size of the nucleus. The activity of senescence-associated β-galactosidase, a marker of cellular senescence, was induced by tenovin-1 and EX527 treatment in U87MG glioblastoma cells. Consistent with the senescent phenotype, treatment with tenovin-1 increased p53 expression in U87MG cells. This study demonstrated the senescence-inducing effect of sirtuin inhibitors, which are potentially useful tools for senescence research.

Efficacy of dentifrices containing policresulen in controlling dental plaque and gingivitis formation / 대한구강보건학회지

OBJECTIVES: This clinical study aimed to investigate if dentifrices containing policresulen would help to control dental plaque and gingivitis. METHODS: Seventy-eight eligible adults participated in this double-blind and randomized clinical study after an initial oral examination, calculus removal, and tooth prophylaxis. Two weeks after the procedure, the participants were assigned to three groups using the following dentifrices: (1) a dentifrice containing 0.22% NaF (control group); (2) a dentifrice containing 0.22% NaF and 100 ppm policresulen (policresulen group); and (3) a dentifrice containing 0.22% NaF, 100 ppm policresulen, and 1.00% bamboo salt (policresulen/bamboo group). The participants used only the provided dentifrice (for 1 min, twice a day, over 8 weeks) when brushing their teeth and followed their normal brushing habits. Dental plaque accumulation and gingivitis measurements were conducted using the Turesky modification of the Quigley-Hein plaque index (PI), the Loe and Silness gingival index (GI), and the percent bleeding on probing (%BOP) to obtain baseline data and 4- and 8-week data after grouping. RESULTS: A total of 73 participants aged 35.92+/-11.46 years (mean+/-SD) completed the study. The results after 8 weeks demonstrated statistically significant group-by-time interactions for PI, GI, and %BOP (P<0.001). The PI observed in the control groups increased over time up to 6%, while that observed in the dentifrice groups containing policresulen decreased by 5% (P<0.001). For GI and %BOP, the control group exhibited significantly higher values after 8 weeks, while the policresulen and the policresulen/bamboo groups revealed similar index values as the baseline after 4 and 8 weeks. The changes in all indices were significantly different between the control and the two experimental groups. There were no significant differences in the results obtained from the policresulen/bamboo group and the results obtained from the policresulen group. CONCLUSIONS: Use of dentifrices containing policresulen over 8 weeks demonstrated anti-plaque and anti-gingivitis efficacy compared to a control dentifrice.

Dental Care Utilization for Examination and Regional Deprivation / 예방의학회지

OBJECTIVES: Receiving proper dental care plays a significant role in maintaining good oral health. We investigated the relationship between regional deprivation and dental care utilization. METHODS: Multilevel logistic regression was used to identify the relationship between the regional deprivation level and dental care utilization purpose, adjusting for individual-level variables, in adults aged 19+ in the 2008 Korean Community Health Survey (n=220 258). RESULTS: Among Korean adults, 12.8% used dental care to undergo examination and 21.0% visited a dentist for other reasons. In the final model, regional deprivation level was associated with significant variations in dental care utilization for examination (p<0.001). However, this relationship was not shown with dental care utilization for other reasons in the final model. CONCLUSIONS: This study's findings suggest that policy interventions should be considered to reduce regional variations in rates of dental care utilization for examination.

The relationship between regional socioeconomic position and oral health behavior: A multilevel approach analysis / 대한구강보건학회지

OBJECTIVES: This study was conducted to identify discrepancies in oral health behaviors among communities in cities, counties, and districts (si , gun, and gu administrative divisions of South Korea) and to determine their correlations with socioeconomic status, examined in terms of the social deprivation index. METHODS: Data for 220,258 individuals, covering 247 communities, were extracted from a 2008 community health survey, and the frequency of brushing the teeth after lunch, flossing and interdental brushing was calculated and analyzed. Considering the characteristics of the data collected at individual and regional levels, a multilevel random-intercept logistic regression model was used for the analysis. RESULTS: A regional-level discrepancy was found in after-lunch brushing and the use of auxiliary oral hygiene items, with interclass correlations of 0.03 and 0.04, respectively. In particular, the odds ratio of using auxiliary oral hygiene items in the communities with the lowest socioeconomic status was as low as 0.49, compared to the highest level, thus demonstrating a conspicuous intercommunity difference. CONCLUSIONS: The regional-level correlation between socioeconomic status and oral health behaviors indicates the need for the establishment of oral health-related intervention policies based on community characteristics.

Aeromonas hydrophila Myonecrosis in an Immunocompetent Patient / 감염과화학요법

Aeromonas hydrophila is a facultative anaerobic Gram negative bacillus. It usually thrives in fresh and brackish water and primarily causes gastroenteritis in humans. Rarely aeromonads have been associated with extra-intestinal infections, such as skin and soft infection, meningitis, epidural abscess, endocarditis and pneumonia in immunocompromised hosts. Here we report Aeromonas hydrophila soft tissue infection occurring in a 53-year-old Korean woman without underlying disease who was successfully treated with proper antibiotics.

A Case of Pleuropulmonary Paragonimiasis with a Breast Abscess as the Ectopic Site / 대한내과학회지

Paragonimiasis is an infectious disease caused by consumption of raw or improperly cooked freshwater crab or crayfish contaminated with Paragonimus metacercariae. The incidence of the disease has markedly decreased, but it is still a lung disease that requires a differential diagnosis in endemic areas such as Korea and Japan. It is commonly found in the lung but has also been found as extrapulmonary infestations, such as cerebral, spinal, subcutaneous, abdominal, urinary, and gynecological infestations. We report a rare case of ectopic paragonimiasis involving the breast with pleural effusion that was initially misdiagnosed as tuberculous pleurisy and a breast abscess.

A Case of Citrobacter braakii Sepsis Complicated with Hepatocellular Carcinoma / 감염과화학요법

Citrobacter species is a gram-negative bacilli that can cause opportunistic infections in immunocompromised hosts. Citrobacter braakii refers to the genomospecies 6 of the Citrobacter freundii complex. There are no detailed studies on infections caused by this newly identified specific genetic species in Korea. We herein report a case of a patient with hepatocellular carcinoma who, after undergoing transcatheter arterial chemoembolization, developed biloma which later progressed to C.braakii sepsis and did not respond to treatment. To our knowledge, this is the first reported case in Korea on C. braakii infection resulting in septic shock in a patient with malignancy in Korea.