Multipotent, dedifferentiated cancer stem-like cells from brain gliomas

In modern cancer biology, external factors and niches can act on differentiated tissue cells to cause cancer by inducing dedifferentiation of mature adult cells. Recently, we discovered that dedifferentiation of glioma cancer cells alters the expression of mature and neural stem cell (NSC)-related genes, in that cancer cells adjust to the serum-deprived environment and cell-to-cell interaction by down-regulating genes associated with neural mature markers and up-regulating genes that are primitive NSC markers. Neurogenesis of dedifferentiated glioma cancer cells also showed a highly increased neuronal marker associated with highly decreased glial and oligodendrocyte cell markers. After treatment with chemotherapeutic drugs, dedifferentiated cancer cells showed strong drug resistance and continued active cell growth. After grafting to severe combined immunodeficient (SCID) mouse brains, dedifferentiated cancer stem cells migrated and continued active proliferation for more than 4 weeks. We also performed microarray analysis and characterized the gene expression patterns in control cancer cells with dedifferentiated cancer stem-like cells. We delineated specific numbers of important proliferation signaling proteins, primitive neural lineage-related proteins, cancer genes, and transporter genes. In this report, we propose that the dedifferentiation process of brain tumor and normal tissue may contribute to the malignancy and aggressiveness of the brain cancer.     

Inaudible temporomandibular joint vibrations

The aim was to test the hypothesis that inaudible vibrations with significant amounts of energy increasing during jaw movements can be recorded in the temporomandibular joint (TMJ) area. Twenty one subjects, who could perform wide opening movements without feeling discomfort, 12 with and 9 without TMJ sounds audible at conventional auscultation with a stethoscope, were included. Recordings were made during opening-closing, 2/s without tooth contact, and during mandibular rest, using accelerometers with a flat frequency response between the filter cutoff frequencies 0.1 Hz and 1000 Hz. The signals were digitized using a 24 bits card and sampled with the rate 96000 Hz. Power spectral analyses, and independent and paired samples t-tests were used in the analysis of the vibration power observed in frequency bands corresponding to audible and inaudible frequencies. An alpha-level of 5% was chosen for accepting a difference as being significant. In the group with audible sounds, about 47% of the total vibration energy was in the inaudible area below 20 Hz during opening-closing and about 76% during mandibular rest. In the group without audible sounds, the corresponding proportions were significantly different, 85% vs. 69%. The energy content of the vibrations, both those below and those above 20 Hz, increased significantly during jaw movement in both groups. Furthermore, percentage of signal energy above 20 Hz showed a noticeable increase in the group of subjects with audible sounds. This can physically be explained by decreased damping properties of damaged tissues surrounding the TMJ. Vibrations in the TMJ area can be observed with significant portions in the inaudible area below 20 Hz both during mandibular rest and during jaw movements whether or not the subjects have audible joint sounds. Further studies are needed to identify sources and evaluate possible diagnostic value.     

Cyclooxygenase-2 polymorphisms and risk of systemic lupus erythematosus in Koreans

Cyclooxygenase-2 (COX-2) is a key regulatory enzyme in the synthesis of prostanoids associated with trauma and inflammation. Upregulation of COX-2 in human lupus T cells resists anergy and apotosis. We investigated the COX-2 gene for functional variants that may influence susceptibility, clinical outcomes and severity of systemic lupus erythematosus (SLE) in a Korean population. The study included 345 patients with SLE and 400 unrelated healthy controls. Genotyping for the −765G → C polymorphism of COX-2 was performed by PCR–RFLP analysis. No difference in the distribution of the genotype frequencies between patients and controls was found. COX-2 genotypes were not associated with clinical features except hematologic abnormalities and anti-RNP antibody. We did not detect any association between COX-2 genotype and disease severity in SLE patients. These results suggest that the −765G → C polymorphism of COX-2 does not play a significant role in the development of SLE in a Korean population. A possible protective effect of the low activity C allele against the production of anti-RNP antibodies merits further investigation.     

Effects of isolated compounds from Catalpa ovata on the T cell-mediated immune responses and proliferation of leukemic cells

Three compounds were isolated from the ethyl acetate soluble fraction of the methanolic extract of the leaves of Catalpa ovata (Bignoniaceae) through repeated column chromatography. We investigated the effects of these compounds on T cell-mediated responses for tumor surveillance and proliferation in U937, HL60, and Molt-4 leukemia cells. Compounds 1–3 inhibited proliferation of those cells in a dose-dependent manner. Compound 3 showed mild effect in Molt-4 cell cytotoxicity. Compound 3 enhanced gene expressions of p53 and IL-4, but decreased IL-2 and IFN-Γ genes in Molt-4 cell. Our findings indicate that compound 3 may enhance T cell-mediated immune responses and anticancer properties.     

Association of stress with symptoms of atopic dermatitis

Psychological stress and atopic dermatitis (AD) symptoms appear to form a vicious cycle. This study compared the degree of stress and impairment of dermatology life quality between patients with AD and healthy controls, and examined for neuropeptides and neurotrophins associated with stress in AD. Questionnaires, comprising five tests evaluating depression, anxiety, interaction anxiousness, private body consciousness, and dermatology life quality, were examined in age- and sex-matched patients with AD (n?=?28) and healthy controls (n?=?28). Immunohistochemical staining of nerve growth factor, substance P, corticotrophin-releasing factor receptor and neuropeptide Y was performed in the AD-involved and normal skin. Patients with AD showed high scores on all of the questionnaires, including Beck Depression Inventory, state anxiety, trait anxiety, Interaction Anxiousness Scale, Private Body Consciousness subscale, and Dermatology Life Quality Index. All of the parameters, except for Beck Depression Inventory, showed higher values in AD than healthy controls (p?相似文献   

CIP2A facilitates apoptotic resistance of fibroblast-like synoviocytes in rheumatoid arthritis independent of c-Myc expression

The aim of this study is to investigate the effects of CIP2A (Cancerous inhibitor of protein phosphatase 2A) on the apoptosis of RA FLS. Proliferation and apoptotic activity of RA FLS following treatment with CIP2A siRNA or control siRNA were analyzed using MTT assays and Cell Death Detection kit. RA FLS was treated with CIP2A siRNA or control siRNA in 3-, 6-, and 9-day intervals for a Western blot analysis to determine C-Myc expression. To evaluate the signal transduction pathways engaged in apoptosis, caspase-3 activity, caspase-9 activity, PARP, and phosphorylation of the Akt kinase were analyzed by Western blot. Cell viability of RA FLS was significantly lower in the CIP2A siRNA-treated group compared with the control after 7 days (p = 0.022). Apoptosis of RA FLS was significantly higher in the CIP2A siRNA-treated group compared with the control when incubated for 3, 6, and 9 days (p = 0.029, p = 0.021, p = 0.043, respectively). C-Myc expression did not change with the different incubation periods. CIP2A siRNA-treated FLS expressed higher level of activated caspase-3, caspase-9, and PARP (p = 0.014, p = 0.020, p = 0.021, respectively) and lower level of phosphorylated Akt (p = 0.001) compared with those treated with the control siRNA. Our data show that CIP2A expression in RA FLS is an important mediator of dysfunctional apoptosis independent of c-Myc stabilization. Expression of CIP2A may contribute to apoptotic resistance of RA FLS through the activation of Akt and deactivation of caspase-3, caspase-9, and PARP. Inhibition of CIP2A may therefore constitute a novel, promising therapeutic target in RA.     

Severe intestinal toxicity after stereotactic ablative radiotherapy for abdominopelvic malignancies

Purpose

The purpose of this study is to identify the predictors for severe intestinal toxicity (IT) in patients with abdominopelvic malignancies treated with three fractions of stereotactic ablative radiotherapy (SABR).

Methods

From 2001 to 2011, 202 patients with abdominopelvic malignancies were treated with curative-intent SABR. Among these, we retrospectively reviewed the clinical records of 55 patients with the presence of the intestine that received a dose ≥20 % of the prescribed dose. The total dose ranged from 33 to 60 Gy in three fractionations (median dose, 45 Gy). We analyzed the clinical and dosimetric parameters for severe IT?≥?grade 3 according to the National Cancer Institute Common Toxicity Criteria v4.0: V _20–35 (volume of the intestine that received xGy) and D _max (maximum point dose).

Results

Severe IT was found in six patients (the median time, 3 months). V ₂₅ was the best dosimetric predictor for severe IT (P?=?0.004). With V ₂₅?≤?20 ml, severe IT decreased from 50 to 4 %. SABR duration was the best clinical predictor. Severe IT decreased in patients who received SABR at 4–8 days than on three consecutive days (0 vs. 18 %, P?=?0.037).

Conclusions

Following three fractions of SABR, V ₂₅ is a valuable predictor of severe IT. And SABR would be conducted with a treatment interval of at least 48 h if possible.     

Shear stress-induced pH increase in plasma is mediated by a decrease in PCO2: The increase in pH enhances shear stress-induced P-selectin expression in platelets

To investigate shear stress-induced platelet activation, the cone-plate viscometer or the Couette rotational viscometer has been widely used. In a previous report, it was shown that shearing platelet-rich plasma using a Couette rotational viscometer could lead to an increase in pH by CO₂ release. However, any clear mechanism has not been provided. In this study, we examined whether shearing cell free plasma only using a cone-plate viscometer can also induce pH increase and studied the underlying mechanism of shear-induced pH increase by directly measuring total CO₂ (T_CO2) and CO₂ tension (P_CO2). When human plasma was sheared using a cone-plate viscometer, the pH of the human plasma increased time- and shear rate-dependently. Although T_CO2 of human plasma was not affected, P_CO2 was decreased by shearing, indicating that the decreased P_CO2 is associated with a pH increase of plasma. In addition, the pH of bicarbonate-containing suspension buffer was also shown to be increased by shearing; suggesting that the platelet studies using suspension buffers containing bicarbonate could be affected similarly. The effects of pH changes on shear stress-induced platelet activation were also investigated in the same in vitro systems. While shear stress-induced platelet aggregation was not affected by the pH changes, P-selectin expression was significantly increased in accordance with the pH increase. In conclusion, shear stress using a cone-plate viscometer induces pH increase in plasma or bicarbonate-containing suspension buffer through a P_CO2 decrease and the pH changes alone can contribute to platelet activation by enhancing shear stress-induced P-selectin expression.     

Crossed-withdrawal reflex in a rat model of neuropathic pain: implications in neural plasticity

Recently we developed a neuropathic rat model employing a distal sciatic nerve branch injury, in which rats show vigorous behavioral signs of neuropathic pain. This study was performed to evaluate the crossed-withdrawal reflex in which any stimuli applied to the uninjured side produces allodynic signs on the injured side in our neuropathic pain model. Rats that received neuropathic surgery developed behavioral signs of neuropathic pain. In addition, these rats developed pain responses of the injured paw to stimuli applied to the contralateral uninjured paw, therefore, demonstrating 'the crossed-withdrawal reflex.' Moreover, electrical stimulation of the uninjured paw developed evoked potentials in the ventral root on the injured side. These results suggest that information processing from input on the uninjured side to output on the injured side, can be facilitated in rats with a nerve injury and that neuroplasticity may contribute to the crossed-withdrawal reflex.