An R132H Mutation in Isocitrate Dehydrogenase 1 Enhances p21 Expression and Inhibits Phosphorylation of Retinoblastoma Protein in Glioma Cells

Cytosolic isocitrate dehydrogenase 1 (IDH1) with an R132H mutation in brain tumors loses its enzymatic activity for catalyzing isocitrate to α-ketoglutarate (α-KG) and acquires new activity whereby it converts α-KG to 2-hydroxyglutarate. The IDH1 mutation induces down-regulation of tricarboxylic acid cycle intermediates and up-regulation of lipid metabolism. Sterol regulatory element-binding proteins (SREBPs) regulate not only the synthesis of cholesterol and fatty acids but also acyclin-dependent kinase inhibitor p21 that halts the cell cycle at G1. Here we show that SREBPs were up-regulated in U87 human glioblastoma cells transfected with an IDH1^R132H-expression plasmid. Small interfering ribonucleic acid (siRNA) for SREBP1 specifically decreased p21 messenger RNA (mRNA) levels independent of the p53 pathway. In IDH1^R132H-expressing U87 cells, phosphorylation of Retinoblastoma (Rb) protein also decreased. We propose that metabolic changes induced by the IDH1 mutation enhance p21 expression via SREBP1 and inhibit phosphorylation of Rb, which slows progressionof the cell cycle and may be associated with non-aggressive features of gliomas with an IDH1 mutation.     

Perineural Invasion in Extrahepatic Cholangiocarcinoma: Prognostic Impact and Treatment Strategies

Background

The significance of perineural invasion in extrahepatic cholangiocarcinoma has not been fully elucidated. This study aims to determine the prognostic impact of and optimal treatment strategy for perineural invasion in patients with extrahepatic cholangiocarcinoma.

Methods

Medical records of 133 patients with extrahepatic cholangiocarcinoma who underwent curative resection were reviewed retrospectively. Ninety-eight patients had perineural invasion and 35 patients did not. Univariate and multivariate survival analyses were performed to clarify the prognostic impact of and optimal treatment strategy for perineural invasion.

Results

Only tumor differentiation (P?=?0.024) was independently associated with perineural invasion in the multivariate logistic regression model. Multivariate survival analysis revealed that perineural invasion (P?=?0.002), resection margin status (P?=?0.016), and International Union Against Cancer (UICC) pT factor (P?=?0.015) were independent prognostic factors of overall survival. Overall 5-year survival rates for patients with and without perineural invasion were 28 and 74 %, respectively. Among 98 patients with perineural invasion, the use of adjuvant chemotherapy (P?=?0.003), lymph node status (P?=?0.015), resection margin status (P?=?0.008), and UICC pT factor (P?=?0.016) were independently associated with overall survival by multivariate analysis. Overall 5-year survival rates for patients with perineural invasion who did and did not receive adjuvant chemotherapy were 33 and 21 %, respectively (P?=?0.023).

Conclusions

Perineural invasion is a potent prognostic factor in extrahepatic cholangiocarcinoma. Adjuvant chemotherapy may improve the overall survival of patients with perineural invasion.     

Tibial tubercle malposition in patellar joint instability: A computed tomography study in full extension and at 30° flexion

We evaluated the tibial tubercle position in knees with patellar instability. CT in full extension and at 30° flexion was used in 18 knees with instability and 18 control knees. Scans were taken at the level of the femoral epicondyles, tibial tubercle and distal tibia. We found that in full extension, the tibial tubercle was in a more lateral position in the unstable than in the control knees. At 30° flexion, the tibial tubercle in the unstable knees rotated internally, but it was never within the normal range. CT scans taken in full extension and at 30° flexion seem to be of value for ascertaining the degree of tibial tubercle malposition during knee flexion in patellar instability.     

Alendronate does not prevent long bone fragility in an inactive rat model

The lack of estrogen and inactivity are both important in the pathogenesis of osteoporosis in elderly women, and there have been no appropriate rodent studies to examine the effects of common bisphosphonates on these two components separately. We compared the efficacy of alendronate (ALN) on the long bones of aged female rats, which were sedentary, estrogen deficient, or both. The rats were either forced to remain in a sitting position or allowed to walk in standard cages with or without ALN administration. The 8-week experimental period began 5 weeks after ovariectomy or sham surgery. Parameters of the hindlimb bones were determined by a three-point bending test, peripheral quantitative computed tomography, microfocus computed tomography, confocal laser Raman microspectroscopy, and dynamic histomorphometry. Regardless of ovariectomy, ALN was ineffective against the deterioration of breaking stress caused by sitting even though the trabecular bone mineral density was significantly higher in the sitting–ALN groups. Toughness was significantly deficient in the ovariectomy sitting–ALN group. This was in agreement with the bone geometry with a greater marrow space. Sitting also increased the mineral-to-matrix ratio and the carbonate-to-phosphate ratio, both indicative of aged bone. A greater loss of proteinaceous amide intensity compared with mineral intensity resulted in an increased mineral-to-matrix ratio in the presence of ALN. Sitting resulted in deficits in the quality and the geometry of cortical bone, resulting in fragility. The use of bisphosphonates, such as ALN, may provide a therapy best suited for osteoporotic individuals whose daily activity is not limited.     

Stem cell factor‐activated bone marrow ameliorates amyotrophic lateral sclerosis by promoting protective microglial migration

Amyotrophic lateral sclerosis (ALS) is a progressive disease associated with motor neuron death. Several experimental treatments, including cell therapy using hematopoietic or neuronal stem cells, have been tested in ALS animal models, but therapeutic benefits have been modest. Here we used a new therapeutic strategy, bone marrow transplantation (BMT) with stem cell factor (SCF)‐ or FMS‐like tyrosine kinase 3 (flt3)‐activated bone marrow (BM) cells for the treatment of hSOD1(G93A) transgenic mice. Motor function and survival showed greater improvement in the SCF group than in the group receiving BM cells that had not been activated (BMT alone group), although no improvement was shown in the flt3 group. In addition, larger numbers of BM‐derived cells that expressed the microglia marker Iba1 migrated to the spinal cords of recipient mice compared with the BMT‐alone group. Moreover, after SCF activation, but not flt3 activation or no activation, the migrating microglia expressed glutamate transporter‐1 (GLT‐1). In spinal cords in the SCF group, inflammatory cytokines tumor necrosis factor‐α and interleukin‐1β were suppressed and the neuroprotective molecule insulin‐like growth factor‐1 increased relative to nontreatment hSOD1(G93A) transgenic mice. Therefore, SCF activation changed the character of the migrating donor BM cells, which resulted in neuroprotective effects. These studies have identified SCF‐activated BM cells as a potential new therapeutic agent for the treatment of ALS. © 2014 Wiley Periodicals, Inc.     

Association of crossing capillaries in the finger nailfold with diabetic retinopathy in type 2 diabetes mellitus

Aims/IntroductionCrossing capillaries in the finger nailfold might potentially be a novel diabetic retinopathy (DR) biomarker that could be assessed non‐invasively in the clinical setting. However, the association between crossing capillaries and DR is controversial. This study aimed to investigate the association between the percentage of crossing capillaries in the finger nailfold and DR in patients with type 2 diabetes mellitus.Materials and MethodsThis cross‐sectional study enrolled 108 type 2 diabetes mellitus patients (aged 40–75 years) who visited the outpatient diabetic clinic at Osaka University Hospital, Osaka, Japan, between May and October 2019. Capillary morphology was assessed using nailfold capillaroscopy based on the simple capillaroscopic definitions of the European League Against Rheumatism Study Group. Details of DR and other laboratory data were obtained from medical records. The association between the tertile of the percentage of the crossing capillary and DR was analyzed using multivariable logistic regression.ResultsAfter adjusting for age, sex, diabetes duration, glycated hemoglobin, systolic blood pressure, body mass index, and use of renin–angiotensin system inhibitor and antihyperlipidemic medication, the percentage of crossing capillaries was significantly associated with DR (multivariable‐adjusted odds ratios for increasing tertiles of the percentage of crossing capillary: 1 [reference], 2.05 [95% confidence interval 0.53–7.94], and 4.33 [95% confidence interval 1.16–16.21]; P‐trend = 0.028).ConclusionsA higher percentage of crossing capillaries in the nailfold was associated with a higher risk of DR, independent of traditional risk and inhibiting factors, in patients with type 2 diabetes mellitus.     

Elevated levels of soluble fibrin in patients with venous thromboembolism

The fibrin-related markers (FRMs), including soluble fibrin (SF), d-dimer and fibrin and fibrinogen degradation products (FDP) are considered to be useful for the diagnosis of thrombosis; however, evidence for the diagnosis of thrombosis by SF is still not well established. The present study was designed to evaluate the usefulness of SF in the diagnosis of venous thromboembolism (VTE). The plasma concentrations of FRMs were measured in 551 in-patients suspected to have a VTE. The plasma levels of SF, d-dimer and FDP were significantly higher in patients with VTE than patients without VTE and those were significantly higher in patients without VTE than in healthy volunteers. In a receiver operating characteristic analysis for the diagnosis of VTE, the area under the curve was 0.950 for SF, 0.933 for FDP and 0.805 for d-dimer. The appropriate cut-off values for the diagnosis were as follows SF 5.9 μg/ml, FDP 2.1 μg/ml and d-dimer 4.8 μg/ml. To obtain a 100% negative predictive value for the diagnosis of VTE, the SF was less than 5.2 μg/ml, FDP was less than 1.3 μg/ml, and d-dimer was less than 0.5 μg/ml. Our findings suggest that the SF assay is useful for the diagnosis and exclusion of VTE.