Evidence of slow and variable choice-stepping reaction time in cancer survivors with chemotherapy-induced peripheral neuropathy.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is reported to affect up to 70 % of cancer survivors. Despite evidence that CIPN-related impairments often translate into balance and mobility deficits, the effects on stepping and quality of gait, well-documented risk factors for falls, are unclear. AIMS: (i) Establish choice-stepping reaction time (CSRT) performance in survivors with CIPN compared to young and older healthy controls and people with Parkinson's disease; (ii) document walking stability; (iii) investigate relationships between stepping and gait data to objective and patient-reported outcomes. METHODS: 41 cancer survivors with CIPN (mean (SD) age: 60.8 (9.7) years) who were ≥3months post chemotherapy, performed tests of simple and inhibitory CSRT. Walking stability measures were derived from 3-D accelerometry data during the 6-minute walk test. CIPN was assessed using neurological grading and patient-reported outcome measures (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire in CIPN Questionnaire scale EORTC CIPN20). RESULTS: In both stepping tests, CIPN participants performed at the level of adults aged 10 years older and people with mild to moderate Parkinson's disease. Mean (SD) total stepping response times in both CSRT (1160 (190) milliseconds) and inhibitory CSRT (1191 (164) milliseconds) tests were not associated with objective neurological grading but were correlated with increased difficulty feeling the ground. Participants with lower-limb vibration sensation deficit had slower and more variable CSRT times. There were no associations between walking stability and objective measures of CIPN, and limited correlations with the EORTC-CIPN20. CONCLUSIONS: Cancer survivors with CIPN showed deficits in voluntary stepping responses and seemed to compensate for their sensory and motor deficits by walking slower to maintain stability. Objective and patient-reported outcomes of CIPN were correlated with slower and more variable stepping response times. Future studies should aim to identify the causes of the apparent premature decline in cognitive-motor function and develop remediating interventions.

Changes in long term peripheral nerve biophysical properties in childhood cancer survivors following neurotoxic chemotherapy.

OBJECTIVE: In the context of increasing numbers of childhood cancer survivors (CCS), this study aimed to enhance understanding of the biophysical basis for long term chemotherapy induced peripheral neuropathy from different chemotherapy agents in CCS. METHODS: Detailed cross-sectional neurophysiological examination, using median nerve axonal excitability studies, alongside clinical assessments, in 103 long term CCS (10.5 ± 0.6 years post-treatment). RESULTS: Cisplatin treated CCS (n = 16) demonstrated multiple sensory axonal excitability changes including increased threshold (P < 0.05), alterations in depolarising and hyperpolarising threshold electrotonus (P < 0.05) and reduction in resting and minimum IV slope (P < 0.01). Vincristine treated CCS (n = 73) were comparable to controls, except for prolonged distal motor latency (P = 0.001). No differences were seen in the non-neurotoxic chemotherapy group (n = 14). Abnormalities were more evident in the cisplatin subgroup with greater clinical neuropathy manifestations. CONCLUSION: Persistent long term changes in axonal biophysical properties vary with different chemotherapy agents, most evident after cisplatin exposure. Longitudinal studies of nerve function during chemotherapy treatment are required to further evaluate these differences and their mechanistic basis. SIGNIFICANCE: This study provides a unique biophysical perspective for persistent cisplatin related neurotoxicity in children, previously under recognised.

Comparison of the diagnostic performance of the 2017 and 2018 versions of LI-RADS for hepatocellular carcinoma on gadoxetic acid enhanced MRI.

AIM: To compare the diagnostic performance of the 2017 (v2017) and 2018 versions (v2018) of the Liver Imaging-Reporting and Data System (LI-RADS) for hepatocellular carcinoma (HCC) using gadoxetic acid-enhanced magnetic resonance imaging (Gd-EOB-MRI) and to evaluate the effect in v2018. MATERIALS AND METHODS: Treatment-naive patients at high-risk for HCC who underwent Gd-EOB-MRI were included. The LI-RADS categories were assigned according to v2017 and v2018. The diagnostic performances were compared between v2017 and v2018 according to the size and combination of imaging features. RESULTS: A total of 117 patients with 137 observations were identified, including 89 HCCs; 76.2% (64/84) of observations with threshold growth were re-classified as subthreshold growth when using v2018 instead of v2017. The final categories changed in nine (14%) cases. For the combination of LR-5/LR-5V, there were no significant differences in sensitivity and specificity between the two versions (sensitivity, 64% versus 58.4%; specificity, 87.5% versus 85.4%; all p>0.05). For the combination of LR-4 and LR-5/5V, the diagnostic performance of v2018 was inferior to that of v2017 when considering only major features (accuracy, 86.1% versus 80.3%, respectively; p=0.013), particularly in observations measuring 10-20 mm, but was comparable after adding the ancillary features (accuracy, 86.9% versus 86.1%, respectively; p=1.00). CONCLUSION: In LI-RADS v2018, although a considerable number of observations re-classified subthreshold growth, changes in the assigned categories were insignificant; overall diagnostic performance was comparable to that of v2017, but v2018 might emphasise the value of ancillary features in combination with major features for determining the probability of HCC.

Deficiency in proliferative, angiogenic, and LH receptors in the follicle wall: implications of season toward the anovulatory condition.

This study aimed to gain insight on the effect of different seasons of the year on the expression pattern of growth factor and hormone receptors involved in follicle development. A novel follicle wall biopsy technique was used to collect in vivo follicle wall layers (ie, granulosa, theca interna, and theca externa) and follicular fluid samples from growing dominant follicles, simultaneously and repeatedly, using the same mares during the spring anovulatory (SAN), spring ovulatory (SOV), summer (SU), and fall ovulatory (FOV) seasons. The immunofluorescent expression patterns of epidermal growth factor receptor (EGFR), Ki-67, vascular endothelial growth factor receptor (VEGFR), and LH receptor (LHR) were evaluated in each follicle wall layer, in addition to intrafollicular estradiol and nitric oxide (NO). Proliferative proteins (EGFR and Ki-67) were highly (P < 0.05-P < 0.001) expressed during the SOV season compared with the SAN and FOV seasons. Lower (P < 0.05-P < 0.001) expression of both proteins was observed during SU compared with the SOV season. The expression of VEGFR was greater (P < 0.05-P < 0.01) in the theca interna of dominant follicles during the SOV season compared with the SAN and SU seasons. Similarly, in the overall quantification, the VEGFR expression was greater (P < 0.001) during the SOV season compared with the SU and FOV seasons. A higher (P < 0.05) LHR expression was detected in the theca interna during the SOV season than the SAN season. Furthermore, a higher (P < 0.05-P < 0.001) expression of LHR was observed in the granulosa, theca interna, and in the overall quantification during the SOV season compared with the SU and FOV seasons. Intrafollicular NO concentration did not differ (P > 0.05) among different seasons of the year. The intrafollicular estradiol concentration was higher (P < 0.05) during the SU compared with the SAN season and higher (P < 0.05) during the FOV season compared with the SAN and SOV seasons. In conclusion, the synergistic effect of lower expression of proliferative protein, angiogenic, and LH receptors in at least some of the layers of the follicle wall seems to trigger dominant follicles toward the anovulation process during the spring and fall transitional seasons.

Clinical Outcomes of Kidney Transplantation in Patients With Biopsy-Proven Glomerulonephritis.

BACKGROUND: The clinical outcomes after kidney transplantation (KT) according to the types of glomerulonephritis (GN) as the cause of end-stage renal disease (ESRD) are various, but there are not many studies on this. METHODS: Among 1,253 patients who had KT between November 1982 and January 2017, 183 recipients with biopsy-proven GN as the primary cause of ESRD were enrolled. We analyzed the incidence of recurrent GN and the factors associated with recurrence and graft and patient survivals. RESULTS: The types of GN were 95 IgA nephropathy, 47 focal segmental glomerulosclerosis, 14 membranous proliferative GN, 9 membranous GN, 8 lupus nephritis, 6 rapid progressive GN, and 4 Alport syndrome. The mean follow-up duration was 103 ± 81.7 months. Recurrence was reported in 36 patients, of which 20 grafts failed due to recurrence. The age of patients with GN recurrence was significantly younger than that of patients without GN recurrence (P = .030). The graft failure rate of KT recipients with recurrent GN was significantly higher than that of the recipients without recurrent GN (55.6% vs 18.4%, P < .001). In multivariate analysis, recurrence of primary GN, the number of HLA mismatches at AB, delayed graft function, and acute rejection were independent risk factors for graft failure. CONCLUSION: Recurrent GN remains a significant cause of graft loss in KT recipients. Surveillance of GN recurrence in the KT recipients with biopsy-proven GN can reduce allograft dysfunction.

Clinical and genetic predictors of paclitaxel neurotoxicity based on patient- versus clinician-reported incidence and severity of neurotoxicity in the ICON7 trial.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting toxicity of paclitaxel, with no reliable method to identify at-risk patients. We investigated the incidence and risk factors including genetic polymorphisms associated with the development of CIPN based on clinician and patient reporting of neuropathic symptoms. PATIENTS AND METHODS: Risk factors for the development of CIPN were examined in 454 patients treated with paclitaxel/carboplatin from the International Collaboration on Ovarian Neoplasms 7 (ICON7) trial. Neuropathy was graded by clinicians by standard adverse event reporting and by patients utilising OV28 questionnaire. Genetic risk factors were examined by selecting six single nucleotide polymorphisms in genes associated with microtubule function. Risk factors were assessed via dose-to-event cox regression models. RESULTS: Grade >2 neuropathy was reported by clinicians in 28% of patients, while 67% of patients reported 'quite a bit' or 'very much' tingling or numbness. Agreement between clinicians and patients was poor (κ = 0.236, 95% confidence interval, 0.177-0.296, P < 0.001). Older age, bevacizumab treatment and bowel resection were associated with clinician reported CIPN, while older age and volume of residual disease were associated with patient-reported neuropathy. There were no significant associations between clinician-reported neuropathy or patient-reported neuropathy and TUBB2, CEP72 or individual MAPT or GSK3B SNPs, however MAPT additive polymorphisms were associated with patient-reported neuropathy and GSK3B additive polymorphisms were associated with clinician reported CIPN. CONCLUSIONS: There was significant discordance between patient- and clinician-reported neurotoxicity. The lack of consensus regarding optimal outcome measures and whose opinion with regard to CIPN takes precedence is a limitation in the investigation of risk factors for CIPN. Care must be taken to select and include patient-reported outcome measures in CIPN assessment to enable accurate identification of genetic and other risk factors for neuropathy.

Kidney Transplantation in Korean Patients With End-Stage Renal Disease Aged 65 and Older: A Single-Center Experience.

BACKGROUND: The mean age of patients starting dialysis in Korea has increased to older than 60 years and the proportion of patients aged 65 and older exceeded 40% in 2014. Although the number of elderly dialysis patients is increasing rapidly, percentages of elderly patients undergoing kidney transplantation (KT) are very low. METHODS: We retrospectively reviewed the medical records of patients who underwent KT at Keimyung University Dongsan Medical Center between 1982 and 2016. Elderly patients (≥65 years old) were compared with the control group of patients in their early sixties (60-64 years old). RESULTS: Among a total of 1209 KT patients, those in their early sixties totaled 34 (2.8%) and the elderly totaled only 18 (1.5%). Patient and allograft survival rate showed no significant differences between the elderly and those in their early sixties. Death with a functioning graft accounted for 50% in both groups. However, occurrences of bacterial infection and tuberculosis were higher in the elderly (P = .011 and .047, respectively). In a multivariate analysis, longer duration of renal replacement therapy before KT and the occurrence of malignancy were independent risk factors for patient death (hazard ratio [HR], 1.027; P = .014; HR, 31.934; P = .016, respectively). Also, albuminuria at 6 months after KT was an independent risk factor for allograft loss (HR, 51.155; P = .016). CONCLUSION: The overall survival rate of the elderly was not significantly lower than those in their early sixties. Even in the elderly, KT should not be delayed. In addition, careful surveillance for malignancy and measures to decrease the risk of infection are necessary.

Long-term Clinical Outcomes of First and Second Kidney Transplantation in Patients With Biopsy-Proven IgA Nephropathy.

INTRODUCTION: The recurrence of IgA nephropathy (IgAN) after kidney transplantation (KT) has an effect on graft survival, but there are few reports about long-term clinical outcomes of KT with recurrent IgAN. This study shows the long-term clinical outcomes of KT in patients with IgAN. METHODS: All recipients who had biopsy-proven IgAN were followed from February 1990 to February 2016. We analyzed overall graft and patient survival rates, incidence of recurrent IgAN, factors affecting graft survival, and IgAN recurrence. RESULTS: There were 88 patients with first KT. The mean follow-up duration was 82.5 months. Twenty patients went through graft loss and 1 patient died due to sepsis. IgAN recurred in 15 patients, and 11 patients experienced graft failure. Among the patients who had failed graft after first KT, 7 patients underwent retransplantation. The graft survival period, presence of rejection, and proteinuria were the relevant risk factors for recurrence of IgAN. In the first KT patients, presence of rejection and 1-year serum creatinine were the significant risk factors for graft loss. But recurrence of IgAN was not a relevant risk factor. Overall graft survival rates at 5 and 10 years were 93.8% and 73.1% in the first transplantation group and 100% and 100% in the retransplantation group, respectively. CONCLUSION: Although IgAN recurrence was a significant risk factor for graft failure, the patient who underwent retransplantation showed favorable results. Retransplantation should be considered in patients who lost their first graft after recurrence of IgAN.

Long-term Clinical Outcomes of Kidney Re-transplantation.

BACKGROUND: Kidney re-transplantation is commonly considered to have a higher immunological risk than first kidney transplantation. Because of the organ shortage and increasing waiting lists, long-term outcomes of kidney re-transplantation are being studied. However, reports of re-transplantation outcomes are not common. We have reported our 30 years of experience with second kidney transplantations. METHODS: Of 1210 kidney transplantations between November 1982 and August 2016 performed in our hospital, 105 were second kidney transplantations (2nd KT). Living donor KT was 44; deceased donor KT was 61. RESULTS: Patient survival rates at 1, 5, and 10 years were 100%, 97.2%, and 90.7%, and graft survival rates were 97.0%, 94.6%, and 71.5%, respectively. The leading cause of graft failure in the 2nd KT was chronic rejection (60%). In addition, induction immunosuppressant, maintenance immunosuppressant, delayed graft function, and graft survival time at the 1st KT had a significant impact on graft survival time at the 2nd KT. CONCLUSIONS: Reasonable results in both patient survival and graft survival rates were found in the 2nd KT. Careful monitoring of immunologic risk is needed.

Effects of stock density on the laying performance, blood parameter, corticosterone, litter quality, gas emission and bone mineral density of laying hens in floor pens.

The effects of stocking density on the performance, egg quality, leukocyte concentration, blood biochemistry, corticosterone levels, bone mineral density, and noxious gas emission of laying hens were investigated. Eight hundred 34-week-old Hy-Line Brown laying hens (Gallus gallus domesticus) were randomly assigned to one of 4 treatments, each of which was replicated 4 times. Four stocking densities, including 5, 6, 7, and 10 birds/m2, were compared. A commercial-type basal diet was formulated to meet or exceed nutrient recommendations for laying hens from the National Research Council. The diet was fed to the hens ad libitum for 8 wk. Results indicated that hen-day egg production, egg mass, and feed intake were less for (P < 0.01) 10 birds/m2 stock density than other stock densities. Production rate of floor and broken eggs and eggshell strength were greater (P < 0.01) for 10 birds/m2 stock density than other stock densities. There were no significant differences in the level of leukocytes among densities. However, heterophils and the H/L ratio were greater (P < 0.01) for 10 birds/m2 than in stock density of 6 or 7 birds/m2 Serum corticosterone was greater (P < 0.01) 10 birds/m2 than stock density than other stock densities. Litter moisture and gas emission (CO2 and NH3) were greater (P < 0.01) for 10 birds/m2 than stock density than 6 and 7 birds/m2 stock density. Bone mineral content was not influenced by increasing stock density. However, bone mineral density was less (P < 0.05) for 10 m2 stock density than other stock densities. These results indicate that increasing the density beyond 5 birds/m2 elicits some negative effects on laying performance of Hy-Line brown laying hens.

Effect of setback Le Fort I osteotomy on midfacial soft-tissue changes as evaluated by cone-beam computed tomography superimposition for cases of skeletal Class III malocclusion.

This study employed the cone-beam computed tomography (CBCT) superimposition method to evaluate postoperative midfacial soft-tissue changes in cases of skeletal Class III malocclusion after double-jaw surgery with setback and vertical reduction Le Fort I osteotomy. A retrospective study was carried out on 15 patients who had undergone maxillary setback Le Fort I osteotomy and mandibular setback sagittal split ramus osteotomy with alar cinch suturing and V-Y soft-tissue closure. Three dimensional CBCT volume scans were recorded preoperatively (T0) and 6 months postoperatively (T1) to measure soft-tissue changes of the upper lip and midface. Post-surgery, soft-tissue landmarks in the cheek and paranasal areas had moved forward; the soft-tissue thickness at the A-point had markedly increased (P<0.05); there was no significant change in the subnasale, and the midline of the soft-tissue of the upper-lip area had moved backward. The extent of the mean soft-tissue change at the labrale superius was greater than that at the other soft-tissue landmarks of the upper lip. The results suggest that maxillary setback movement of the maxilla by alar cinch suturing has a beneficial effect on paranasal soft-tissue and lip contours for patients with protrusive lip and acute nasolabial angle.

SU-E-J-113: A New Quantification Measure of the Difference Between Two Organ Contours.

PURPOSE: To develop a measuring method between two contours, which can be used for validating a PTV during IGRT, organ motion and/or deformation studies. METHODS: Quantifying the geometric difference between two organ/target surfaces is essential for Radiation therapy planning and delivery. Point-to-surface distance measures have been utilized to evaluate and visualize the local surface differences. However, previously well-known distance measures have critical shortfalls. Normal distance (ND) measure suffers when the reference surface is strongly curved. Minimum distance (MD) measure (a.k.a. Hausdorff distance) suffers when the test surface is strongly curved. Our new distance measure named Error-Proof Distance (EPD) can deal with both difficult cases.EPD measure calculates the maximum value between the Forward Minimum Distance (FMinD) and the Backward Maximum Distance (BMaxD) at each point. The FMinD denotes the minimum distance to the test surface from a point on the reference surface. The BMaxD means the maximum value among the minimum distances from all points of the test surface to the point on the reference surface. We tested EPD using three 2-D contour examples including a 20mm shifted contour, and two 3-D clinical cases. RESULTS: In case of 2-D contour examples, ND and MD measure failed in strongly curved areas, but EPD measure outperformed the others. The maximum distance measured between a reference and a 20mm shifted test contour should be equal to 20mm, but ND erroneously measured 24mm. Furthermore, ND reported erroneous distances where the reference surface is strongly curved in 3-D clinical cases. CONCLUSIONS: We succeeded to prove that a new EPD is arobust and accurate distance measure to compare two 2D or 3D surfaces. EPD measure can be used to evaluate and visualize the surface difference of organ contours. It is also helpful for proving PTV margin during IGRT, and organ motion and/or deformation studies. This project is partially supported by the Agency for Healthcare Research and Quality (AHRQ) grant 1R18HS017424-01A2.

SOX2 has a crucial role in the lineage determination and proliferation of mesenchymal stem cells through Dickkopf-1 and c-MYC.

SOX2 is a well-known core transcription factor in embryonic stem cells (ESCs) and has an important role in the maintenance of pluripotency. Recently, SOX2 expression has also been reported in adult stem cells (ASCs), but the role of SOX2 in ASCs remains unknown. In this study, we examined the molecular mechanisms of SOX2 in human mesenchymal stem cells (hMSCs), a type of ASCs, by performing inhibition studies. SOX2 inhibition resulted in altered cell growth and differentiation capabilities. These changes coincided with a decrease in Dickkopf-1 (DKK1), a soluble inhibitor of WNT signaling. Chromatin immunoprecipitation and luciferase assays showed that SOX2 binds to DKK1 and has a positive regulatory role in transcription. The enforced expression of DKK1 in SOX2-inhibited hMSCs reversed the differentiation deformities, but could not abrogate the cell proliferation defect. Proliferation was regulated by c-MYC, whose expression can also be controlled by SOX2. Our study shows that SOX2 directly regulates DKK1 expression and, as a consequence, determines the differentiation lineage of hMSCs. Moreover, SOX2 also regulates proliferation by affecting c-MYC. Therefore, these results suggest that SOX2 might have a specific function by regulating DKK1 and c-MYC in the differentiation and growth of ASCs, which is separate from its roles in ESCs.

Cone-beam computed tomography evaluation of short- and long-term airway change and stability after orthognathic surgery in patients with Class III skeletal deformities: bimaxillary surgery and mandibular setback surgery.

The purpose of this study was to evaluate the volumetric change of the upper airway space in 36 Class III patients who had undergone bimaxillary surgery or isolated mandibular setback, and, further, to analyse the relation between post-surgical stability and airway change using cone-beam computed tomography (CBCT). A three-dimensional (3D) CBCT examination was performed at three stages: T0 (before surgery), T1 (an average of 4.6 months after surgery), and T2 (an average of 1.4 years after surgery). The results showed that the volumes of the oropharyngeal and hypopharyngeal airways decreased significantly 4.6 months post-surgery in the mandibular setback group (p<0.05), and these diminished airways had not recovered 1.4 years post-surgery. In the bimaxillary surgery group, the volume of the oropharyngeal airway also decreased. A Spearman correlation analysis showed that the anteroposterior length of the hypopharyngeal area had a correlation with post-surgical stability in the isolated mandibular surgery group, and that the cross-sectional area of the nasopharynx was correlated with maxillary relapse only in the bimaxillary surgery group (p<0.05).

Adenoma malignum of the uterine cervix: ultrasonographic findings in 11 patients.

OBJECTIVE: To evaluate the ultrasonographic features of adenoma malignum, a minimal deviation adenocarcinoma of the uterine cervix. METHODS: Eighteen consecutive patients with pathologically confirmed adenoma malignum were enrolled in this study at two institutions. Preoperative ultrasound examination was performed and the results were available in 11 patients. We analyzed retrospectively the gray-scale ultrasound findings for the following morphologic characteristics: cervical enlargement, as well as size, location and ultrasonographic characteristics of lesions. In five patients we also evaluated Doppler features with regard to intralesional vascularity. RESULTS: The cervix was enlarged in 73% (8/11) of cases. The mean greatest tumor diameter was 4.2 (range, 2.5-6.8) cm. In five (45%) cases, the cervix was completely infiltrated by the tumor. At gray-scale ultrasound examination, three (27%) tumors were multilocular lesions, four (36%) were multilocular lesions with solid components and four (36%) were solid lesions. In the multilocular lesions with or without a solid component, locules tended to be 1 cm or less in average diameter (86%, 6/7 cases) and there tended to be 11-20 in number (57%, 4/7 cases). In most (57%, 4/7) cases the locular fluid was homogeneously hypoechoic. Most (75%, 3/4) solid lesions manifested heterogeneous echogenicity. The five (100%) tumors examined with Doppler manifested moderate or abundant color content on color or power Doppler. CONCLUSIONS: Adenoma malignum can appear sonographically as solid, multilocular and multilocular solid cervical lesions. Awareness of its clinical and ultrasonographic features might improve diagnosis before surgery.

The assessment of the short- and long-term changes in the condylar position following sagittal split ramus osteotomy (SSRO) with rigid fixation.

The purpose of this study was to compare the short- and long-term changes in condylar position related to the glenoid fossa, and skeletal and occlusal stability after orthognathic surgery. All of the study patients were assessed by cone-beam computed tomography images for condylar rotational changes and anteroposterior position in the pre-surgery, post-surgery and post-retention period. The condylar positions were evaluated on three planes: axial, coronal and sagittal. In the skeletal and occlusal measurements, there was no significant difference between the post-surgery group and the post-retention group. After sagittal split ramus osteotomy (SSRO), the condyle on the axial plane rotated inward (P < 0.05) and maintained during the post-retention period. In the anteroposterior condylar position related to the glenoid fossa, the condyles had changed from the anterior position in the pre-surgery group to a concentric position in the post-surgery group and then returned to the anterior position in the post-retention groups. These results suggested that the changed anteroposterior condylar position in the glenoid fossa after SSRO with rigid fixation had moved from a concentric to anterior position for post-retention period.

Histone deacetylase inhibitors decrease proliferation potential and multilineage differentiation capability of human mesenchymal stem cells.

OBJECTIVES: Histone deacetylase (HDAC) is an important therapeutic target in cancer. Two of the main anticancer mechanisms of HDAC inhibitors are induction of terminal differentiation and inhibition of cell proliferation. To investigate the role of HDAC in maintenance of self-renewal and cell proliferation, we treated mesenchymal stem cells (MSCs) that originated from adipose tissue or umbilical cord blood with valproic acid (VPA) and sodium butyrate (NaBu). MATERIALS AND METHODS: Human MSCs were isolated from mammary fat tissue and cord blood. We performed MTT assay and flow cytometry-based cell cycle analysis to assess self-renewal of MSCs. In vitro differentiation assays into osteogenic, adipogenic, neurogenic and chondrogenic lineages were conducted to investigate MSC multipotency. Immunocytochemistry, Western blot and reverse transcription-polymerase chain reaction were used to interrogate molecular pathways. RESULTS: VPA and NaBu flattened the morphology of MSCs and inhibited their growth. VPA and NaBu activated the transcription of p21(CIP1/WAF1) by increasing the acetylation of histone H3 and H4 and eventually blocked the cell cycle at G2/M phase. The expression level of p16(INK4A), a cdk inhibitor that is closely related to cellular senescence, was not changed by HDAC inhibitor treatment. We performed controlled differentiation into bone, fat, cartilage and nervous tissue to elucidate the role of HDAC in the pluripotency of MSC to differentiate into functional tissues. VPA and NaBu decreased the efficiency of adipogenic, chondrogenic, and neurogenic differentiation as visualized by specific staining and reverse transcription-polymerase chain reaction. In contrast, osteogenic differentiation was elevated by HDAC inhibitor treatment. CONCLUSION: HDAC activity is essential for maintaining the self-renewal and pluripotency of MSCs.

Decreased expression of p12 is associated with more advanced tumor invasion in human gastric cancer tissues.

BACKGROUND/AIMS: p12(DOC-1) is a well-known growth suppressor; however, its role in gastric carcinogenesis is still unclear. We investigated the expression of p12(DOC-1) in gastric cancer tissues and its possible correlation with p53 expression, and determined its clinical significance. METHODS: Immunohistochemical staining using the tissue array method was performed on 180 human gastric carcinomas. The clinicopathological features and prognostic significance were analyzed. RESULTS: Of the 180 tissue samples, p53 expression was positive in 85 (47.2%) and p12(DOC-1) expression was negative in 140 (77.8%). The negative expression of p12(DOC-1) was significantly associated with a more advanced depth of tumor invasion and stage (p < 0.05). No apparent correlation was found between p12(DOC-1) and p53 expressions. The 5-year survival rate of the p12(DOC-1)-positive cases (53.7%) was higher than that of the p12(DOC-1)-negative cases (39.3%); however, neither p12(DOC-1) nor p53 expression status had any statistically significant prognostic value. Multivariate analysis revealed that lymph node metastasis, distant metastasis, lymphatic invasion and perineural invasion were independent prognostic factors. CONCLUSIONS: This is the first report that suggests that p12(DOC-1) may be involved in the development and progression of gastric cancer. Further studies are required to clarify its exact role in the mechanism of gastric carcinogenesis.

The clinical outcomes after complete surgical resection of intramedullary cavernous angiomas: changes in motor and sensory symptoms.

STUDY DESIGN: Evaluation of the surgical effects of patients with intramedullary spinal cord cavernous angiomas (CAs). OBJECTIVES: To assess the sensory and motor deficits in the clinical symptoms of patients with intramedullary CAs after complete surgical resection. SETTING: Seoul National University Hospital, Korea. METHODS: The authors reviewed 14 patients with intramedullary spinal cord CAs who underwent surgical resection between 1995 and 2006. The average follow-up duration was 55.0+/-45.1 months. To analyze the changes in the patients' symptoms after surgery, the ASIA (American Spinal Injury Association) and JOA (Japanese Orthopedic Association) scoring systems were used at different time points: preoperative, postoperative and during the final follow-up period. RESULTS: The patients' mean ASIA score at follow-up was increased in comparison to the preoperative score (97.2+/-5.3 vs 95.2+/-7.6, P=0.201), but this difference was not significant. The mean JOA motor score at follow-up was slightly increased in comparison to the preoperative score (7.2+/-1.3 vs 6.8+/-1.3, P=0.107). There was a significant difference between the patients' preoperative and follow-up JOA sensory score (4.3+/-1.0 vs 4.9+/-0.9, P=0.007). The rates of complete resolution of motor and sensory deficits were 45.5% (5/11 patients) and 7.1% (1/14 patients), respectively. CONCLUSION: Although complete surgical resection could improve the clinical symptoms of intramedullary CAs, the sensory deficits usually remain in the long-term period after complete resection.