Relevance network between chemosensitivity and transcriptome in human hepatoma cells

Generally, hepatoma is not a chemosensitive tumor, and the mechanism of resistance to anticancer drugs is not fully elucidated. We aimed to comprehensively evaluate the relationship between chemosensitivity and gene expression profile in human hepatoma cells, by using microarray analysis, and analyze the data by constructing relevance networks. In eight hepatoma cell lines (HLE, HLF, Huh7, Hep3B, PLC/PRF/5, SK-Hep1, Huh6, and HepG2), the baseline expression levels of 2300 genes were measured by cDNA microarray. The concentrations of eight anticancer drugs (nimustine, mitomycin C, cisplatin, carboplatin, doxorubicin, epirubicin, mitoxantrone, and 5-fluorouracil) needed for 50% growth inhibition were examined and used as a measure of chemosensitivity. These data were combined and comprehensive pair-wise correlations between gene expression levels and the 50% growth inhibition values were calculated. Significant correlations with significance were used to construct networks of similarity. Fifty-two relations, including 42 genes, were selected. Among them, nearly 20% were various types of transporters, and most of them negatively correlated with chemosensitivity. Transporter associated with antigen processing 1 was associated with resistance to mitoxantrone, consistent with previous reports. Other transporters were not reported previously to associate with chemosensitivity. Resistance to doxorubicin and its analogue, epirubicin, were positively correlated with topoisomerase II beta expression, whereas it negatively correlated with expression of carboxypeptidases A3 and Z. Response to nimustine was associated with expression of superoxide dismutase 2. Relevance networks identified several negative correlations between gene expression and resistance, which were missed by hierarchical clustering. Our results suggested the necessity of systematically evaluating the transporting systems that may play a major role in resistance in hepatoma. This may provide useful information to modify anticancer drug action in hepatoma.     

Relationship between sick building syndrome and indoor environmental factors in newly built Japanese dwellings

Objectives  Indoor air contaminants and dampness in dwellings have become important environmental health issues. The aim of this study is to clarify which factors are related to sick building syndrome (SBS) in newly built dwellings at Hokkaido, Japan, through a comprehensive evaluation of the indoor environment and validated sick building symptom questionnaires. Methods  The symptoms of 343 residents in 104 detached houses were surveyed by standardized questionnaires, and the concentrations of formaldehyde, acetaldehyde, volatile organic compounds (VOCs), airborne fungi, and dust mite allergen in their living rooms were measured. By summing the presence or absence of the five dampness indicators (condensations, mold growth, moldy odor, high air humidity of the bathroom, water leakage), a dampness index was calculated. Results  SBS symptoms were found in 21.6% of surveyed individuals. In a fully adjusted multivariate logistic regression analysis, the dampness index [odds ratio (OR) = 1.50; 95% confidence interval (CI): 1.06–1.11], log formaldehyde (OR = 23.79, 95% CI: 2.49–277.65), and log alpha-pinene (OR = 2.87, 95% CI: 1.36–6.03) had significantly higher ORs for SBS symptoms. However, other VOCs, airborne fungi, and dust mite allergen did not have significantly higher ORs. Conclusion  Dampness, formaldehyde, and alpha-pinene were significantly related to SBS symptoms in newly built dwellings. We should, therefore, take measures to reduce the chemicals and dampness in dwellings.     

Post-treatment cell-free DNA as a predictive biomarker in molecular-targeted therapy of hepatocellular carcinoma

Journal of Gastroenterology - Liquid biopsies, particularly those involving circulating tumor DNA (ctDNA), are rapidly emerging as a non-invasive alternative to tumor biopsies. However, clinical...     

Is the eCura system useful for selecting patients who require radical surgery after noncurative endoscopic submucosal dissection for early gastric cancer? A comparative study

Background

We have established a risk-scoring system, termed the “eCura system,” for the risk stratification of lymph node metastasis in patients who have received noncurative endoscopic submucosal dissection (ESD) for early gastric cancer (EGC). We aimed to clarify whether this system contributes to the selection of patients requiring radical surgery after ESD.

Methods

Between 2000 and 2011, 1,969 patients with noncurative ESD for EGC were included in this multicenter study. Depending on the treatment strategy after ESD, we had patients with no additional treatment (n = 905) and those with radical surgery after ESD (n = 1,064). After the application of the eCura system to these patients, cancer recurrence and cancer-specific mortality in each risk category of the system were compared between the two patient groups.

Results

Multivariate Cox analysis revealed that in the high-risk category, cancer recurrence was significantly higher (hazard ratio = 3.13, p = 0.024) and cancer-specific mortality tended to be higher (hazard ratio = 2.66, p = 0.063) in patients with no additional treatment than in those with radical surgery after ESD, whereas no significant differences were observed in the intermediate-risk and low-risk categories. In addition, cancer-specific survival in the low-risk category was high in both patient groups (99.6 and 99.7%). A limitation of this study is that it included a small number of cases with undifferentiated-type EGC (292 cases).

Conclusions

The eCura system is a useful aid for selecting the appropriate treatment strategy after noncurative ESD for EGC. However, caution is needed when applying this system to patients with undifferentiated-type EGC.

     

The Teramoto distal tibial oblique osteotomy (DTOO): surgical technique and applicability for ankle osteoarthritis with varus deformity

We have devised a medial peri-articular osteotomy, the distal tibial oblique osteotomy (DTOO), and have used this technique since 1994 for ankle osteoarthritis of advanced and late stages associated with varus inclination. This report describes the surgical technique and its applicability. DTOO can be used for cases of varus ankle osteoarthritis with a range of the ankle joint movement of at least 10° or more. The osteotomy is obliquely directed cut across the distal tibia from proximal-medial to distal lateral and is of an opening-wedge type with the centre of rotation coincident with the centre of the tibiofibular joint. A laminar spreader instrument is inserted in the osteotomy to open the wedge until the lateral surface of the talar body is seen on X-ray to be in contact and congruent with medial articular surface of the lateral malleolus. Common obstacles which may prevent this contact and congruency are bony spurs present on the anterior side of fibula or on the lateral side of the tibia; these require removal. The opening-wedge osteotomy is held in position by an Ilizarov external fixator or internally fixed with a plate. Bone graft is taken from the iliac crest and inserted into the open wedge. If, after completion of the osteotomy, the dorsiflexion angle of the ankle joint does not exceed 0°, a Z-lengthening is performed of the Achilles tendon. In the DTOO for ankle osteoarthritis, the contact area of the ankle joint increases and decreases the load pressure per unit area. Furthermore, as the width of the ankle mortice is restored through the realignment of the body of the talus, instability at the ankle joint decreases. There is additional improvement with restoration of the inclination of the distal tibial articular surface as this directs the hindfoot valgus and corrects the alignment of the foot, with consequent improvement of ankle pain.     

The N-terminal domain of thrombomodulin sequesters high-mobility group-B1 protein, a novel antiinflammatory mechanism

Thrombomodulin (TM) is an endothelial anticoagulant cofactor that promotes thrombin-mediated formation of activated protein C (APC). We have found that the N-terminal lectin-like domain (D1) of TM has unique antiinflammatory properties. TM, via D1, binds high-mobility group-B1 DNA-binding protein (HMGB1), a factor closely associated with necrotic cell damage following its release from the nucleus, thereby preventing in vitro leukocyte activation, in vivo UV irradiation-induced cutaneous inflammation, and in vivo lipopolysaccharide-induced lethality. Our data also demonstrate antiinflammatory properties of a peptide spanning D1 of TM and suggest its therapeutic potential. These findings highlight a novel mechanism, i.e., sequestration of mediators, through which an endothelial cofactor, TM, suppresses inflammation quite distinctly from its anticoagulant cofactor activity, thereby preventing the interaction of these mediators with cell surface receptors on effector cells in the vasculature.