Transforming growth factor-beta signaling promotes hepatocarcinogenesis induced by p53 loss

Hepatocellular carcinoma (HCC) results from the accumulation of deregulated tumor suppressor genes and/or oncogenes in hepatocytes. Inactivation of TP53 and inhibition of transforming growth factor-beta (TGF-β) signaling are among the most common molecular events in human liver cancers. Thus, we assessed whether inactivation of TGF-β signaling, by deletion of the TGF-β receptor, type II (Tgfbr2), cooperates with Trp53 loss to drive HCC formation. Albumin-cre transgenic mice were crossed with floxed Trp53 and/or floxed Tgfbr2 mice to generate mice lacking p53 and/or Tgfbr2 in the liver. Deletion of Trp53 alone (Trp53(KO) ) resulted in liver tumors in approximately 41% of mice by 10 months of age, whereas inactivation of Tgfbr2 alone (Tgfbr2(KO) ) did not induce liver tumors. Surprisingly, deletion of Tgfbr2 in the setting of p53 loss (Trp53(KO) ;Tgfbr2(KO) ) decreased the frequency of mice with liver tumors to around 17% and delayed the age of tumor onset. Interestingly, Trp53(KO) and Trp53(KO) ;Tgfbr2(KO) mice develop both HCC and cholangiocarcinomas, suggesting that loss of p53, independent of TGF-β, may affect liver tumor formation through effects on a common liver stem cell population. Assessment of potential mechanisms through which TGF-β signaling may promote liver tumor formation in the setting of p53 loss revealed a subset of Trp53(KO) tumors that express increased levels of alpha-fetoprotein. Furthermore, tumors from Trp53(KO) mice express increased TGF-β1 levels compared with tumors from Trp53(KO) ;Tgfbr2(KO) mice. Increased phosphorylated Smad3 and ERK1/2 expression was also detected in the tumors from Trp53(KO) mice and correlated with increased expression of the TGF-β responsive genes, Pai1 and Ctgf. CONCLUSION: TGF-β signaling paradoxically promotes the formation of liver tumors that arise in the setting of p53 inactivation.     

Co-development of autoimmune hepatitis and Sj?gren's syndrome triggered by the administration of herbal medicines

Autoimmune hepatitis (AIH) has been reported in association with Sjögren''s syndrome (SS). Drug-induced AIH has been rarely reported. A rare case of the co-development of AIH and SS in a 53-year-old woman after the consumption of herbal medicines is described. After admission, the patient complained of dryness in her mouth, and she was subsequently diagnosed with SS, which had not been detected previously. The patient''s bilirubin and aminotransferase levels initially decreased following conservative management; however, they later began to progressively increase. A diagnosis of AIH was made based on the scoring system proposed by the International Autoimmune Hepatitis Group. The patient was administered a combination of prednisolone and azathioprine, and the results of follow-up liver-function tests were found to be within the normal range. This is an unusual case of AIH and SS triggered simultaneously by the administration of herbal medicines.     

Morphometric evaluation of changes in the alveolar bone and roots of the maxillary anterior teeth before and after en masse retraction using cone-beam computed tomography

Objective:To evaluate the morphometric changes in the alveolar bone and roots of the maxillary anterior teeth (MXAT) after en masse retraction with maximum anchorage (EMR-MA).Materials and Methods:The samples consisted of 37 female adult patients who had Class I dentoalveolar protrusion (CI-DAP) and were treated by extraction of the first premolars and EMR-MA. Using three-dimensional cone-beam computed tomography taken before treatment and after space closure, the maxillary central incisors (MXCI, N  =  66), lateral incisors (MXLI, N  =  69), and canines (MXC, N  =  69) were superimposed using individual reference planes. After alveolar bone area (ABA), vertical bone level (VBL), root length (RL), root area (RA), and prevalence of dehiscence (PD) were measured at the cervical, middle, and apical levels, statistical analyses were performed.Results:On the palatal side, ABA significantly decreased in all levels of MXAT (P < .001; middle of MXC, P < .01). MXCI and MXLI exhibited a greater decrease in the ratio of change in palatal ABA than did MXC (cervical, P < .01; middle and apical, P < .05; total, P < .001). Palatal/labial ABA ratios decreased in MXCI (cervical, middle, total, P < .001; apical, P < .05) and MXLI (cervical, P < .001; apical, P < .05). They showed greater amounts and ratios of change in VBL on the palatal side compared to the labial side (all P < .001). The palatal side showed more PD in the cervical area than did the labial side (MXCI and MXLI, P < .001; MXC, P < .01). Significant root resorption occurred in MXAT (RL and RA, all P < .001).Conclusions:During EMR-MA in cases with CI-DAP, ABA and VBL on the palatal side and RL and RA of MXCI and MXLI were significantly decreased.     

Finite Element Modeling of Stress Distribution in Intervertebral Spacers of Different Surface Geometries

Intervertebral disc spacers using bioactive ceramics have been used to treat degenerative spinal disease. Tooth‐shaped spacers are commonly used to prevent migration, but there is a possibility of fracture when inserted or after insertion. Intervertebral disc spacers with either an isosceles triangle‐shaped tooth (T1) or a right triangle‐shaped tooth (T2) were used as a control group. The design factors for the experimental group were modified to prevent fractures induced by stress concentration, and the surfaces of the spacers were designed as either an isosceles triangle‐shaped valley (V1) or a right triangle‐shaped valley (V2). Linear analysis using finite element model (FEM) was performed, and Von Mises stress distribution was calculated by applying 1000 N of uniformly distributed load. Samples of the V2 design were made with bioactive glass‐ceramics (BGS‐7) and evaluated for compressive strength, fatigue degree, and impact strength. Von Mises stress was highest at the first tooth from the posterior side for the control group and at the center for the experimental group. Compared with the control group, the experimental group showed 18.4% and 82.5% reduction (V1 vs. T1 and V2 vs. T2, respectively) in the maximum stress at the bottom of the valleys. The FEM analysis revealed that the V2 design had the most even load distribution. The V2 samples with bioactive glass‐ceramics were evaluated for compressive strength, and all six samples were not fractured up to 24 000 N. However, the average impact strength was 19.42 kN, suggesting that momentary force caused damage at a lower load than compression with a steady speed. The BGS‐7 intervertebral disc spacer with V2 design was not fractured during the fatigue test at maximum pressure of 8000 N, R ≥10, 5 Hz, and 5 million cycles. These data confirm that the BGS‐7 spacer with the V2 design may be clinically applicable. Collectively, the modified surface geometry of the experimental group significantly lowered Von Mises stress values at the bottom of the valleys, and thus the possibility of fracture by compressive load was greatly reduced. Also, impact during insertion was confirmed to cause fracture more easily, as the impact strength was lower than the compressive strength in the experimental group.     

Mechanical properties of composite resins light-cured using a blue DPSS laser

Lasers have many favorable features as a light source owing to their monochromaticity and coherence. This study examined the mechanical properties of composite resins that were light-cured using a diode-pumped solid state (DPSS) laser. Eight composite resins were light-cured using four different light sources (one quartz–tungsten–halogen (QTH), two light-emitting diodes (LEDs), and one DPSS laser with a wavelength of 473 nm). The light intensity of the DPSS laser and remaining light-curing units were approximately 500 and 900 mW/cm², respectively. The microhardness, flexural properties, and compressive properties were evaluated using the Vickers hardness test, three-point bending test, and compression test, respectively. In most cases, the microhardness, flexural properties, and compressive properties of the specimens light-cured using the DPSS laser were similar to those obtained using the other light-curing units. Within the limits of the study, the microhardness, flexural modulus, and compressive strength were linearly correlated with the filler content (in weight percent). The flexural modulus and compressive modulus were also linearly correlated with the microhardness. Even with a much lower light intensity, the DPSS laser with a wavelength of 473 nm can polymerize composite resins and give comparable mechanical properties to those obtained using the other light-curing units.     

A Pilot Clinical Study of Ocular Prosthesis Fabricated by Three-dimensional Printing and Sublimation Technique

PurposeWe sought to evaluate the safety and effectiveness of patient-specific ocular prostheses produced by three-dimensional (3D) printing and the sublimation technique. A comparison with prostheses produced using manual manufacturing methods was then performed.MethodsTo confirm the biological and physiochemical safety, cytotoxicity, systemic acute toxicity, intradermal reaction, and skin sensitization tests were conducted according to the International Organization for Standardization guidelines. The compressive strength of the prostheses was also tested. Further, a case series of three patients who wore the 3D printed prostheses for more than eight hours daily for 4 weeks was executed. Self-assessments by these individuals using a questionnaire and safety evaluations focusing on the occurrence of conjunctival inflammation or allergic reactions according to the Cornea and Contact Lens Research Unit criteria by slit-lamp examination and similarity assessment were completed.ResultsThe 3D printed ocular prostheses met the necessary qualifications per the biological and physiochemical safety tests, showing the absence of cytotoxicity, acute systemic toxicity, intradermal reactivity, and skin-sensitizing potency. Also, there was no difference in strength test results between previous ocular prostheses and the 3D printed ones. Self-assessment by the patients yielded satisfactory results, with no significant difference in the level of satisfaction reported for the 3D printed and previous handmade ocular prostheses. The 3D printed prosthesis did not trigger any side effects in the conjunctival sac and showed similar objective findings with respect to the color of the iris, sclera, and vessel patterns.ConclusionsOur study confirms the biologic and physiochemical safety of 3D-printed ocular prostheses created using computer-aided design technology and a sublimation technique. The patients’ questionnaires and the judgment of the ophthalmologists/ocularists showed that the 3D printed ocular prosthesis was acceptable in function and appearance through a case series report.     

Treatment outcomes according to neuropathic bladder sphincter dysfunction type after treatment of oxybutynin chloride in children with myelodysplasia

Purpose

We investigated the treatment outcomes according to neuropathic bladder sphincter dysfunction (NBSD) type after oral oxybutynin (OBT) treatment in children with NBSD caused by myelodysplasia.

Methods

Among 334 pediatric patients who were diagnosed with NBSD caused by myelodysplasia, only children treated with oral OBT for more than 1 year with pre- and post-treatment urodynamic studies and dimercaptosuccinic acid (DMSA) were retrospectively reviewed. We compared pre- and post-treatment urodynamic parameters including maximum cystometric capacity (MCC), MCC/estimated bladder capacity (EBC), and compliance by NBSD type in children. We also compared renal scarring on pre- and post-treatment DMSA by NBSD type in children.

Results

Our study population was comprised of 81 children (45 boys and 36 girls), with a mean age of 4.2 ± 3.4 years. The mean follow-up duration was 4.5 (range 1.0–15.1) years. After OBT treatment, MCC was increased significantly in all types of NBSD from 110.3 ± 62.2 to 202.3 ± 103.9 ml (p < 0.05), compliance was significantly improved from 6.4 ± 6.1 to 11.1 ± 9.6 ml/cmH₂O (p < 0.05), but MCC/EBC was slightly decreased from 75.2 ± 46.9 to 69.8 ± 33.3 % (p = 0.40). Sub-analyzed by NBSD type, the pre-treatment compliance of children with acontractile detrusor with spastic sphincter (n = 16) was markedly decreased compared with other types of NBSD. Acontractile detrusor with spastic sphincter demonstrated the worst renal deterioration on DMSA.

Conclusions

Although increases in MCC/EBC were limited, oral OBT treatment markedly improved MCC and compliance in all NBSD types. Children who had acontractile detrusor with spastic sphincter had a relatively high probability of renal deterioration and required specific attention.