Homeostasis of hematopoietic stem cells regulated by the myeloproliferative disease associated-gene product Lnk/Sh2b3 via Bcl-xL

Hematopoietic stem cells (HSCs) are maintained at a very low frequency in adult bone marrow under steady-state conditions. However, it is not fully understood how homeostasis of bone marrow HSCs is maintained. We attempted to identify a key molecule involved in the regulation of HSC numbers, a factor that, in the absence of Lnk, leads to HSC expansion. Here, we demonstrate that upon stimulation with thrombopoietin, expression of Bcl-xL, an antiapoptotic protein, was highly enhanced in Lnk-deficient HSCs compared to normal HSCs. As a result, Lnk-deficient HSCs underwent reduced apoptosis following exposure to lethal radiation. Downregulation of Bcl-xL expression in Lnk-deficient HSCs by short-hairpin RNA resulted in a great reduction of their capacity for reconstitution. These findings suggest that Lnk/Sh2b3 constrains the expression of Bcl-xL and that the loss of Lnk/Sh2b3 function enhances survival of HSCs by inhibiting apoptosis. Furthermore, our observations indicate that HSCs in patients with an Lnk/Sh2b3 mutation might become resistant to apoptosis due to thrombopoietin-mediated enhanced expression of Bcl-xL. Consequently, reduced apoptosis could facilitate accumulation of HSCs with oncogenic mutations leading to development of myeloproliferative disorders.     

Wernicke's encephalopathy after chemoradiotherapy for tongue cancer: Report of a case

A case of acute Wernicke's encephalopathy induced by thiamine deficiency due to malnutrition subsequent to chemoradiotherapy for tongue cancer is presented. A 63-year-old male patient had severe oral mucositis and mental stress in a long-term hospitalization for chemoradiotherapy of tongue cancer. After discharge from hospital, he had alcoholism and malnutrition. Three months later, disturbance of consciousness and ataxia followed by memory disturbance appeared. Laboratory examination revealed low serum level of thiamine. The symptoms, laboratory data, and magnetic resonance imaging suggested acute Wernicke's encephalopathy. The patient was intravenously administered thiamine and received nutritional control, thereby the symptoms were improved.     

Combined measurements of serum bile acid level and splenic volume may be useful to noninvasively assess portal venous pressure

Background

We aimed to identify a noninvasive predictor of portal venous pressure (PVP).

Methods

We directly measured the PVP in 40 consecutive patients who underwent direct percutaneous transhepatic portal vein puncture as part of the therapeutic management for liver diseases, and we evaluated the association of the PVP with noninvasive clinical parameters. The backgrounds of the liver were normal in 13 patients, chronic hepatitis in 17, and liver cirrhosis in ten.

Results

The mean PVP was 202 ± 114 mmH₂O. In a multivariate linear regression analysis, the serum bile acid level and splenic volume showed independent positive correlations with the PVP (P < 0.001 and 0.002, respectively). The formula for estimating PVP was identified as follows: PVP (mmH₂O) = serum bile acid (??mol/L) × 2.593 + splenic volume (cm³) × 0.416 + 65.929 (R ² = 0.698). In a receiver operating characteristic (ROC) analysis, the AUC values of serum bile acid and splenic volume at a PVP of 200 mmH₂O were 0.909 and 0.758, respectively. However, the AUC values of serum bile acid and splenic volume at a PVP of 250 mmH₂O were 0.792 and 0.926, respectively, suggesting that the serum bile acid level and splenic volume are sensitive predictors of early and advanced portal hypertension, respectively.

Conclusions

Combined measurements of the serum bile acid level and splenic volume may be useful to noninvasively assess the PVP prior to further invasive procedures.     

Combination of hepatitis B viral antigens and DNA for prediction of relapse after discontinuation of nucleos(t)ide analogs in patients with chronic hepatitis B

Aim: The factors associated with hepatitis recurrence after discontinuation of nucleos(t)ide analogs (NAs) in patients with chronic hepatitis B were analyzed to predict the risk of relapse more accurately. Methods: A total of 126 patients who discontinued NA therapy were recruited retrospectively. The clinical conditions of a successful discontinuation were set as alanine aminotransferase (ALT) below 30 IU/L and serum hepatitis B virus (HBV) DNA below 4.0 log copies/mL. Results: Relapse of hepatitis B were judged to occur when maximal serum ALT became higher than 79 IU/L or when maximal serum HBV DNA surpassed 5.7 log copies/mL following NA discontinuation since these values corresponded with mean values of ALT (30 IU/L) and HBV DNA (4.0 log copies/mL), respectively. At least 90% of patients with either detectable hepatitis B e antigen or serum HBV DNA higher than 3.0 log copies/mL at the time of NA discontinuation relapsed within one year. In the remaining patients, higher levels of both hepatitis B surface and core‐related antigens at the time of discontinuation, as well as a shorter course of NA treatment, were significantly associated with relapse by multivariate analysis. Conclusions: It appears that negative results for hepatitis B e antigen and serum HBV DNA lower than 3.0 log copies/mL are essential for successful NA discontinuation, which may be attained by a longer treatment period. Levels of hepatitis B surface and core‐related antigens are also significant factors independently associated with relapse of hepatitis.     

Six-transmembrane epithelial antigen of prostate4 (STEAP4) is a tumor necrosis factor alpha-induced protein that regulates IL-6, IL-8, and cell proliferation in synovium from patients with rheumatoid arthritis

Human six-transmembrane epithelial antigen of prostate4 (STEAP4), an ortholog of mouse tumor necrosis factor-α-induced adipose-related protein (TIARP), plays a role in tumor necrosis factor (TNF)-dependent arthritis models. However, its role in rheumatoid arthritis (RA) is still obscure. This study explored such a role for STEAP4. The expressions of STEAP4, TNFα, and IL-6 were compared in synovia of RA and osteoarthritis patients. STEAP4 induction was examined in TNFα-stimulated fibroblast-like synoviocytes (FLS) in vitro. FLS (with/without TNFα stimulation) were also analyzed for IL-6 expression after STEAP4 knockdown, using siRNA or transfection with STEAP4-plasmid DNA. IL-8, cell proliferation, and apoptosis were also evaluated in STEAP4-overexpressing FLS. The expression of STEAP4 in joints correlated with TNFα expression, specifically in RA synovium. In the cultured FLS, STEAP4 protein expression was augmented by TNFα activation, and localized in endosomal/lysosomal compartments. STEAP4 downregulation by siRNA enhanced the expression of IL-6 mRNA, while STEAP4 overexpression suppressed IL-6 and IL-8 expression, inhibited cell proliferation, and induced apoptosis via caspase-3. The results indicated that human STEAP4 is regulated by TNFα in synovium, where it controls IL-6 secretion and proliferation of FLS, suggesting that STEAP4 might potentially suppress the pathogenesis of TNFα-induced arthritis such as RA.     

Structure and glass transition of amorphous materials composed of titanium-oxo oligomers chemically modified with benzoylacetone

Titanium-n-butoxide was hydrolyzed in the presence of benzoylacetone, and the resulting solution was concentrated and dried at 120 or 140 °C to obtain transparent amorphous materials. High-energy X-ray diffraction measurement was conducted at the SPring-8 facility, and the reduced pair distribution function, G(r) was calculated by Fourier transform of the total structure factor, S(Q). The G(r) value suggested that the materials are composed of TiO₆ octahedra linked by corner- and edge-sharing. Low temperature thermomechanical analysis (TMA) and differential scanning calorimetry (DSC) were conduced on the materials, where a deflection was detected both in the TMA and DSC curves, revealing the glass transition of the materials. Combined with the previous work based on infrared absorption spectroscopy and gel permeation chromatography, the materials are demonstrated to be a new class of glassy materials composed of linked metal-oxygen polyhedra chelated with organic molecules. The materials are innovative due to the high refractive indices that originate in the metal-oxo oligomers and to the shapability given by their thermoplastic properties.

Titanium-n-butoxide was hydrolyzed in the presence of benzoylacetone, and the resulting solution was concentrated and dried at 120 or 140 °C to obtain transparent amorphous materials.     

Clinical outcome of up-front surgery in patients with asymptomatic, incurable synchronous peritoneal carcinomatosis

Purposes

The purpose of this study was to show the clinical features of up-front surgery of the primary tumor in asymptomatic patients with incurable colorectal PC.

Methods

Forty-six patients that were diagnosed between 1998 and 2007 with asymptomatic colorectal PC who could not be successfully cured by surgery were assessed retrospectively.

Results

A univariate analysis revealed the presence of liver metastases, without the use of oxaliplatin (OX)/irinotecan (IRI) and without a primary tumor resection to be poor prognostic factors for survival (p = 0.044, p = 0.030, p < 0.001, respectively). According to a multivariate analysis, no use of OX/IRI and no primary tumor resection, were found to be independent poor prognostic factors for survival (HR 2.57; p = 0.047, HR 6.62; p = 0.003, respectively). The median survival time of patients treated with and without OX/IRI was 18 and 7 months, respectively. The median survival time of patients with and without primary tumor resection was 10 and 2 months, respectively. The number of patients needing surgical intervention for intestinal obstruction after surgery significantly increased in patients treated with OX/IRI (p = 0.001).

Conclusion

Improvement of survival may be related to widespread use of modern systemic chemotherapy and primary tumor resection. However, an increased number of patients that needed surgery for an intestinal obstruction were observed, even after up-front surgery, when patients were treated with modern systemic chemotherapy.