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author:("Hayashi, yki")
1.  Changes in metamorphopsia in daily life after successful epiretinal membrane surgery and correlation with M-CHARTS score 
To determine the correlation between the changes in metamorphopsia in daily life environment and the M-CHARTS scores after epiretinal membrane (ERM) removal, and to determine the criterion for determining whether clinically significant changes in the metamorphopsia score have occurred in M-CHARTS.
We studied 65 eyes undergoing vitrectomy for unilateral ERM. Self-administered questionnaires were used to examine the metamorphopsia in their daily life. The degree of metamorphopsia was determined by M-CHARTS. The receiver operating characteristic curve was used to determine the best predictor of the changes in metamorphopsia in daily life. To determine the reproducibility of the M-CHARTS score, another set of 56 eyes with ERM was tested twice on two different days.
The postoperative changes in the logarithm of the M-CHARTS score was defined as M2-value. The area under the receiver operating characteristic curve for the M2-value as a predictor of the changes in metamorphopsia in daily life was larger than area under the receiver operating characteristic curve obtained for any other parameter. The optimal cutoff value was −0.4. The 95% limits of agreement between test and retest measurements had a reproducibility of ±0.3 logarithm of the M-CHARTS score. Taking into account not only the reproducibility but also the consistency with the subjective changes, we determined the criterion for clinically significant changes in the M-CHARTS scores as a change of the M2-value by ≥0.4.
Evaluating the changes in the M-CHARTS scores in logarithmic form is favorable not only theoretically but also from the perspective of consistency with the subjective changes.
PMCID: PMC4322879
metamorphopsia score; ERM; criterion; vitrectomy
2.  Factors affecting discontinuation of initial treatment with paroxetine in panic disorder and major depressive disorder 
The aims of the present study were to analyze the association between discontinuation of paroxetine (PAX) and the genetic variants of the polymorphism in the serotonin transporter gene-linked polymorphic region (5-HTTLPR) in Japanese patients with panic disorder (PD) and major depressive disorder (MDD).
The 5-HTTLPR genotype was determined by polymerase chain reaction method. PAX plasma concentration was measured by high-performance liquid chromatography to confirm adherence.
When comparing between the PD and MDD patients with the chi-square test and Fisher’s exact test, the PD patients had a significant and higher discontinuation rate due to non-adherence than did the MDD patients (13.5% [7/52] versus 0% [0/88], respectively; P<0.001). MDD patients had a significant and higher discontinuation rate due to untraceability than PD patients (12.5% [11/88] versus 1.9% [1/52]; P=0.032). Multilogistic regression revealed a tendency for the long/short and short/short genotypes to affect discontinuation due to adverse effects in PD patients (25.0% versus 6.3%, respectively; P=0.054).
The results indicate that the 5-HTTLPR genotype might contribute to the discontinuation of initial PAX treatment due to adverse effects in PD patients.
PMCID: PMC4174019  PMID: 25258536
paroxetine; discontinuation; panic disorder; major depressive disorder
3.  Swept-Source Optical Coherence Tomographic Findings of Choroidal Osteoma 
Case Reports in Ophthalmology  2014;5(2):195-202.
To report the morphologic features of a choroidal osteoma using swept-source optical coherence tomography (SS-OCT) and fundus autofluorescence (FAF).
Two eyes of two cases with a choroidal osteoma were studied using SS-OCT and FAF.
The location of the tumor was circumpapillary without macular involvement in case 1 and juxtapapillary with macular involvement in case 2. Both cases had a mixture of calcified and decalcified areas, and a concomitant choroidal neovascularization was found in case 2. The FAF images showed decreased autofluorescence in the central decalcified regions and relatively preserved fluorescence in marginal calcified regions in both cases. SS-OCT revealed a normal inner retina and an abnormal outer retina in both cases, and subretinal fluid in case 2. The calcified regions appeared sponge-like and were multilayered in case 2. A lamellar reflective pattern was observed in the decalcified regions in case 1, and hyperreflective mound-like areas were observed in both cases. SS-OCT demonstrated hyperreflective areas above Bruch's membrane accompanied by disruption of Bruch's membrane in case 1. The chorioscleral border was visible in both cases.
The FAF pattern in the calcified and decalcified areas of the choroidal osteoma may correspond to the different stage of tumor evolution. The SS-OCT findings indicate that choroidal osteomas can have characteristic reflective patterns and alterations of the overlying retina.
PMCID: PMC4127548  PMID: 25120475
Choroidal osteoma; Fundus autofluorescence; Swept-source optical coherence tomography
4.  Ineffectiveness of intrastromal voriconazole for filamentous fungal keratitis 
The purpose of this study is to describe the ineffectiveness of intrastromal voriconazole injection for filamentous fungal keratitis by contrasting the effectiveness for yeast keratitis.
We examined seven fungal keratitis patients prospectively. All yeast was identified by molecular phylogenetic analyses of the chromosomal regions coding for the D1/D2 domain of the large-subunit 26S ribosomal RNA gene. All filamentous fungi were identified by the sequencing of internal transcribed spacers of the ribosomal DNA gene regions. Approximately 0.1 mL of voriconazole diluted with saline to 1.0% was injected with a 30-gauge needle inserted obliquely into the three to five clear cornea sites around the abscess. All subjects were administered natamycin ointment and oral itraconazole. When needed, intravenous micafungin, voriconazole, and/or intracameral voriconazole were added. Clinical courses were observed by the slit lamp microscope. Histopathology was examined when the corneas were removed.
All cases that were caused by yeast healed quickly after injections. Two cases of keratitis caused by Fusarium, and one case caused by Aspergillus, did not heal completely. In the Fusarium cases, additional antifungal medications (3.0% topical voriconazole and intravenous injection of micafungin) were needed. After optical penetrating keratoplasty in one of the cases, fungi were found in the deep stroma of the removed cornea. In the case of Aspergillus keratitis, pathological findings also showed fungi deep in the stroma of the removed cornea and the keratitis recurred after therapeutic penetrating keratoplasty.
Intrastromal voriconazole injection is successful in treating yeast keratitis. However this is not the case for filamentous fungal keratitis.
PMCID: PMC4051793  PMID: 24940044
voriconazole; intrastromal injection; filamentous fungal keratitis
5.  Downregulation of rRNA Transcription Triggers Cell Differentiation 
PLoS ONE  2014;9(5):e98586.
Responding to various stimuli is indispensable for the maintenance of homeostasis. The downregulation of ribosomal RNA (rRNA) transcription is one of the mechanisms involved in the response to stimuli by various cellular processes, such as cell cycle arrest and apoptosis. Cell differentiation is caused by intra- and extracellular stimuli and is associated with the downregulation of rRNA transcription as well as reduced cell growth. The downregulation of rRNA transcription during differentiation is considered to contribute to reduced cell growth. However, the downregulation of rRNA transcription can induce various cellular processes; therefore, it may positively regulate cell differentiation. To test this possibility, we specifically downregulated rRNA transcription using actinomycin D or a siRNA for Pol I-specific transcription factor IA (TIF-IA) in HL-60 and THP-1 cells, both of which have differentiation potential. The inhibition of rRNA transcription induced cell differentiation in both cell lines, which was demonstrated by the expression of the common differentiation marker CD11b. Furthermore, TIF-IA knockdown in an ex vivo culture of mouse hematopoietic stem cells increased the percentage of myeloid cells and reduced the percentage of immature cells. We also evaluated whether differentiation was induced via the inhibition of cell cycle progression because rRNA transcription is tightly coupled to cell growth. We found that cell cycle arrest without affecting rRNA transcription did not induce differentiation. To the best of our knowledge, our results demonstrate the first time that the downregulation of rRNA levels could be a trigger for the induction of differentiation in mammalian cells. Furthermore, this phenomenon was not simply a reflection of cell cycle arrest. Our results provide a novel insight into the relationship between rRNA transcription and cell differentiation.
PMCID: PMC4039485  PMID: 24879416
6.  Isolation of a Stable Subpopulation of Mobilized Dental Pulp Stem Cells (MDPSCs) with High Proliferation, Migration, and Regeneration Potential Is Independent of Age 
PLoS ONE  2014;9(5):e98553.
Insights into the understanding of the influence of the age of MSCs on their cellular responses and regenerative potential are critical for stem cell therapy in the clinic. We have isolated dental pulp stem cells (DPSCs) subsets based on their migratory response to granulocyte-colony stimulating factor (G-CSF) (MDPSCs) from young and aged donors. The aged MDPSCs were efficiently enriched in stem cells, expressing high levels of trophic factors with high proliferation, migration and anti-apoptotic effects compared to young MDPSCs. In contrast, significant differences in those properties were detected between aged and young colony-derived DPSCs. Unlike DPSCs, MDPSCs showed a small age-dependent increase in senescence-associated β-galactosidase (SA-β-gal) production and senescence markers including p16, p21, Interleukin (IL)-1β, -6, -8, and Groα in long-term culture. There was no difference between aged and young MDPSCs in telomerase activity. The regenerative potential of aged MDPSCs was similar to that of young MDPSCs in an ischemic hindlimb model and an ectopic tooth root model. These results demonstrated that the stem cell properties and the high regenerative potential of MDPSCs are independent of age, demonstrating an immense utility for clinical applications by autologous cell transplantation in dental pulp regeneration and ischemic diseases.
PMCID: PMC4037225  PMID: 24870376
7.  Spectral-domain optical coherence tomographic and fundus autofluorescence findings in eyes with primary intraocular lymphoma 
The purpose of this study was to evaluate the findings on spectral-domain optical coherence tomography (SD-OCT) and fundus autofluorescence (FAF) in three eyes with primary intraocular lymphoma (PIOL).
The medical records of three eyes from three patients with biopsy-proven PIOL and retinal infiltrations were reviewed. The SD-OCT and fluorescein angiographic findings were evaluated in the three eyes and FAF images in two eyes.
The PIOL in the three patients was monocular. Vitreous opacities and retinal infiltrations were observed in the three eyes, and iritis was present in two eyes. The cytologic diagnosis was class V in two eyes and class III in one eye. The interleukin-10/interleukin-6 ratio was >1.0 in the vitreous and aqueous humor of the three eyes. The FAF images for two eyes showed abnormal granular hyperautofluorescence and hypoautofluorescence which were the reverse of the pattern in the fluorescein angiographic images. In all three eyes, SD-OCT showed hyper-reflective infiltrations at the level of the retinal pigment epithelium (RPE), a separation of the Bruch membrane from the RPE, damage to the RPE, disruption of the photoreceptor inner segment/outer segment junction, and multiple hyper-reflective signals in the inner retina.
Because of the characteristic FAF and SD-OCT findings in these eyes with PIOL, we suggest that these noninvasive methods may be used for a rapid diagnosis of PIOL and also for understanding the pathology of PIOL.
PMCID: PMC3917953  PMID: 24520190
spectral-domain optical coherence tomography; fundus autofluorescence; primary intraocular lymphoma
8.  Changes of fundus autofluorescence and spectral-domain optical coherence tomographic findings after treatment of primary intraocular lymphoma 
We report the fundus autofluorescence (FAF), spectral-domain optical coherence tomographic (SD-OCT), microperimetric, and multifocal electroretinographic (mfERG) findings before, during, and after successful treatment of a primary intraocular lymphoma (PIOL).
A 57-year-old man had biopsy-proven PIOL in his left eye, and he was treated with intravitreal methotrexate injections for 8 months. Before treatment, fundus examination disclosed many small, yellow lesions with distinct boundaries in the posterior fundus which became atrophic 9 months after the initial treatment. FAF showed a pattern of granular hypoautofluorescence and hyperautofluorescence before the treatments and patchy hypoautofluorescence corresponding to retinal pigment epithelial (RPE) atrophy after the treatments. SD-OCT showed increased nodularity at the level of and above the RPE, a separation of Bruch membrane from the RPE, partial damage of the RPE, disruption of the photoreceptor inner segment/outer segment (IS/OS) junction, multiple hyperreflective signals in the inner retina, foveal thinning, and parafoveal thickening. After treatment, the hyperreflective infiltrations in the inner retina were markedly decreased, and the RPE and IS/OS junction were restored. The foveal thinning and parafoveal thickening resolved, and the central choroidal thickness decreased. During the follow-up, the mfERGs remained decreased. In contrast, microperimetry showed a partial improvement of the retinal sensitivity.
FAF and SD-OCT are useful noninvasive methods to evaluate the retinal and choroidal changes before and after treatment of PIOL. Our results suggest that visual recovery after successful treatment may be limited once macula is infiltrated.
PMCID: PMC3944943  PMID: 24559259
Electroretinograms; Fundus autofluorescence; Humphrey visual field test; Microperimetry; Multifocal electroretinograms; Primary intraocular lymphoma; Spectral-domain optical coherence tomography
9.  A Nomogram associated with high probability of malignant nodes in the surgical specimen after trimodality therapy of patients with oesophageal cancer 
European journal of cancer (Oxford, England : 1990)  2012;48(18):10.1016/j.ejca.2012.06.020.
The presence of malignant lymph nodes in the surgical specimen (+ypNodes) after preoperative chemoradiation (trimodality) in patients with esophageal cancer (EC) portends a poor prognosis for overall survival (OS) and disease-free survival (DFS). There is not one clinical parameter that is correlated with +ypNodes. We hypothesized that a combination of clinical parameters might provide a model that would associate with the high likelihood of +ypNodes in trimodality EC patients.
We report on 293 consecutive EC patients who received trimodality therapy. A multivariate logistic regression analysis that included pretreatment and post-chmoradiation parameters was performed to identify independent variables that were used to construct a nomogram for +ypNodes in trimodality EC patients.
Of 293 patients, 91 (31.1%) had +ypNodes. In multivariable analysis, the significant factors associated with +ypNodes were: baseline T stage (odds ratio [OR], 7.145; 95% confidence interval [CI], 1.381-36.969; p=0.019), baseline N stage (OR, 2.246; 95% CI, 1.024-4.926; p=0.044), tumor length (OR, 1.178; 95% CI, 1.024-1.357; p=0.022), induction chemotherapy (OR, 0.471; 95% CI, 0.242-0.915; p=0.026), lymph metastasis by post-chemoradiation PET (OR, 2.923; 95% CI, 1.007-8.485; p=0.049) and enlarged lymph node metastasis by post-chemoradiation CT (OR, 3.465; 95% CI, 1.549-7.753; p=0.002). The nomogram after internal validation using the bootstrap method yielded a high concordance index of 0.756 (95% CI, xx-xx).
Our results suggest that the constructed nomogram highly correlates with the presence of +ypNodes and upon validation; it could prove useful in individualizing therapy for trimodality patients with EC.
PMCID: PMC3869451  PMID: 22853875
10.  Celiac Node Failure Patterns After Definitive Chemoradiation for Esophageal Cancer in the Modern Era 
The celiac lymph node axis acts as a gateway for metastatic systemic spread. The need for prophylactic celiac nodal coverage in chemoradiation therapy for esophageal cancer is controversial. Given the improved ability to evaluate lymph node status before treatment via positron emission tomography (PET) and endoscopic ultrasound, we hypothesized that prophylactic celiac node irradiation may not be needed for patients with localized esophageal carcinoma.
Methods and Materials
We reviewed the radiation treatment volumes for 131 patients who underwent definitive chemoradiation for esophageal cancer. Patients with celiac lymph node involvement at baseline were excluded. Median radiation dose was 50.4 Gy. The location of all celiac node failures was compared with the radiation treatment plan to determine whether the failures occurred within or outside the radiation treatment field.
At a median follow-up time of 52.6 months (95% CI 46.1–56.7 months), 6 of 60 patients (10%) without celiac node coverage had celiac nodal failure; in 5 of these patients, these failures represented the first site of recurrence. Of the 71 patients who had celiac coverage, only 5 patients (7%) had celiac region relapse. In multivariate analyses, having a pretreatment-to-posttreatment change in standardized uptake value on PET >52% (odds ratio [OR] 0.198, p=0.0327) and having failure in the clinical target volume (OR 10.72, p=0.001) were associated with risk of celiac region relapse. Of those without celiac coverage, the 6 patients that later developed celiac failure had a worse median overall survival time compared to the other 54 patients who did not fail (median OS time: 16.5 months vs. 31.5 months, p=0.041). Acute and late toxicities were similar in both groups.
While celiac lymph node failures occur in approximately 1 of 10 patients, the lack of effective salvage treatments and subsequent low morbidity may justify prophylactic treatment in distal esophageal cancer patients.
PMCID: PMC3795392  PMID: 22436793
Esophageal cancer; celiac lymph node; failure patterns
11.  Failure Patterns in Patients with Esophageal Cancer Treated with Definitive Chemoradiation 
Cancer  2011;118(10):2632-2640.
Local failure after definitive chemoradiation therapy for unresectable esophageal cancer remains problematic. Little is known about the failure pattern based on modern day radiation treatment volumes. We hypothesized that most local failures would be within the gross tumor volume (GTV), where the bulk of the tumor burden resides.
Methods and Materials
We reviewed treatment volumes for 239 patients who underwent definitive chemoradiation therapy and compared this information with failure patterns on follow-up positron emission (PET). Failures were categorized as within the GTV, the larger clinical target volume (CTV, which encompasses microscopic disease), or the still larger planning target volume (PTV, which encompasses setup variability) or outside the radiation field.
At a median follow-up time of 52.6 months (95% CI: 46.1 – 56.7 months), 119 patients (50%) had experienced local failure, 114 (48%) had distant failure, and 74 (31%) had no evidence of failure. Of all local failures, 107 (90%) were in the GTV, 27 (23%) in the CTV; and 14 (12%) in the PTV. In multivariate analysis, GTV failure was associated with tumor status (T3/T4 vs. T1/T2: OR=6.35, p value =0.002), change in standardized uptake value on PET before and after treatment (decrease >52%: OR=0.368, p value = 0.003) and tumor length (>8 cm: 4.08, p value = 0.009).
Most local failures after definitive chemoradiation for unresectable esophageal cancer occur in the GTV. Future therapeutic strategies should focus on enhancing local control.
PMCID: PMC3747650  PMID: 22565611
Esophageal cancer; dose escalation; failure patterns
12.  Identification of Substituted Pyrimido[5,4-b]indoles as Selective Toll-Like Receptor 4 Ligands 
Journal of Medicinal Chemistry  2013;56(11):4206-4223.
A cell-based high-throughput screen to identify small molecular weight stimulators of the innate immune system revealed substituted pyrimido[5,4-b]indoles as potent NFκB activators. The most potent hit compound selectively stimulated Toll-like receptor 4 (TLR4) in human and mouse cells. Synthetic modifications of the pyrimido[5,4-b]indole scaffold at the carboxamide, N-3, and N-5 positions revealed differential TLR4 dependent production of NFκB and type I interferon associated cytokines, IL-6 and interferon γ-induced protein 10 (IP-10) respectively. Specifically, a subset of compounds bearing phenyl and substituted phenyl carboxamides induced lower IL-6 release while maintaining higher IP-10 production, skewing toward the type I interferon pathway. Substitution at N-5 with short alkyl substituents reduced the cytotoxicity of the leading hit compound. Computational studies supported that active compounds appeared to bind primarily to MD-2 in the TLR4/MD-2 complex. These small molecules, which stimulate innate immune cells with minimal toxicity, could potentially be used as adjuvants or immune modulators.
PMCID: PMC3722616  PMID: 23656327
13.  MYBBP1A suppresses breast cancer tumorigenesis by enhancing the p53 dependent anoikis 
BMC Cancer  2013;13:65.
Tumor suppressor p53 is mutated in a wide variety of human cancers and plays a critical role in anoikis, which is essential for preventing tumorigenesis. Recently, we found that a nucleolar protein, Myb-binding protein 1a (MYBBP1A), was involved in p53 activation. However, the function of MYBBP1A in cancer prevention has not been elucidated.
Relationships between MYBBP1A expression levels and breast cancer progression were examined using patient microarray databases and tissue microarrays. Colony formation, xenograft, and anoikis assays were conducted using cells in which MYBBP1A was either knocked down or overexpressed. p53 activation and interactions between p53 and MYBBP1A were assessed by immunoprecipitation and western blot.
MYBBP1A expression was negatively correlated with breast cancer tumorigenesis. In vivo and in vitro experiments using the breast cancer cell lines MCF-7 and ZR-75-1, which expresses wild type p53, showed that tumorigenesis, colony formation, and anoikis resistance were significantly enhanced by MYBBP1A knockdown. We also found that MYBBP1A binds to p53 and enhances p53 target gene transcription under anoikis conditions.
These results suggest that MYBBP1A is required for p53 activation during anoikis; therefore, it is involved in suppressing colony formation and the tumorigenesis of breast cancer cells. Collectively, our results suggest that MYBBP1A plays a role in tumor prevention in the context of p53 activation.
PMCID: PMC3575238  PMID: 23388179
Breast cancer; Tumorigenesis; Anoikis; p53; MYBBP1A
14.  Prognostic Significance of Baseline Positron Emission Tomography And Importance of Clinical Complete Response In Patients With Esophageal or Gastroesophageal Junction Cancer Treated With Definitive Chemoradiotherapy 
Cancer  2011;117(21):4823-4833.
Metabolic imaging is of interest in esophageal cancer, however, the usefulness of initial standardized uptake value (iSUV) of positron emission tomography (PET) is unknown in patients with esophageal or gastroesophageal carcinoma (E-GEC) treated with definitive chemoradiotherapy. We hypothesized that iSUV would correlate with patient outcome.
We retrospectively analyzed E-GEC patients who had a baseline PET and endoscopic ultrasonography (EUS) in addition to other routine staging. All patients received definitive chemoradiotherapy. Multiple statistical methods were employed.
We analyzed 209 consecutive E-GEC patients treated with definitive chemoradiation for outcome; of these 179 had baseline PET for additional analyses. The median overall survival (OS) for all patients was 20.7 months (95% confidence interval; 18.8, 26.3 months). Patients with clinical complete response (cCR) lived longer than those with
Our data indicate that a higher iSUV is associated with poorer OS in patients with E-GEC receiving definitive chemoradiation. Upon validation, baseline PET may become a useful stratification factor in randomized trials and for individualizing therapy.
PMCID: PMC3144261  PMID: 21456015
Case Reports in Ophthalmology  2012;3(3):291-297.
To report a case of delayed-onset endophthalmitis after implantation of a preloaded intraocular lens (IOL) and examine the surgically removed IOL by scanning electron microscopy (SEM).
A 77-year-old female underwent uneventful phacoemulsification and aspiration with preloaded silicone IOL implantation. Since intraocular inflammation unexpectedly worsened 1 month after the surgery, she was referred to our hospital. Her visual acuity was hand motion in the left eye. Hypopyon and fibrin formation were observed in the anterior chamber. A diagnosis of postoperative delayed-onset endophthalmitis was made, and vitrectomy with anterior chamber wash-out was performed. As intraocular inflammation remained unchanged postoperatively, an additional surgery with IOL removal was performed. We cultivated the surgically removed samples of aqueous humor and vitreous fluid under both aerobic and anaerobic conditions, performed 16S rDNA clone library analysis of these clinical samples, and examined the removed IOL by SEM.
Inflammation subsided after the re-operation. Although cultures of aqueous and vitreous samples were negative, DNA of Propionibacterium acnes was detected in the aqueous humor. The SEM images showed that the rod bacteria and biofilm-like material formed on the tip of the IOL haptic.
Delayed-onset endophthalmitis may occur after uneventful implantation of a preloaded IOL. The SEM findings suggested that the tip of the preloaded IOL haptic might scratch bacteria which adhered to the tip of the injector nozzle when the IOL was inserted into the anterior chamber. In some cases with delayed-onset endophthalmitis, IOL removal is needed to eliminate the bacteria which adhere to the tip of the IOL haptic.
PMCID: PMC3530151  PMID: 23275791
Endophthalmitis; Preloaded intraocular lens; Propionibacterium acnes; Scanning electron microscopy
Bioconjugate chemistry  2011;22(3):445-454.
Toll like receptor 7 (TLR7) is located in the endosomal compartment of immune cells. Signaling through TLR7, mediated by the adaptor protein MyD88, stimulates the innate immune system and shapes adaptive immune responses. Previously, we characterized TLR7 ligands conjugated to protein, lipid or polyethylene glycol (PEG). Among the TLR7 ligand conjugates, the addition of PEG chains reduced the agonistic potency. PEGs are safe in humans and widely used for improvement of pharmacokinetics in existing biologics and some low molecular weight compounds. PEGylation could be a feasible method to alter the pharmacokinetics and pharmacodynamics of TLR7 ligands. In this study, we systematically studied the influence of PEG chain length on the in vitro and in vivo properties of potent TLR7 ligands. PEGylation increased solubility of the TLR7 ligands and modulated protein binding. Adding a 6–10 length PEG to the TLR7 ligand reduced its potency toward induction of interleukin (IL)-6 by murine macrophages in vitro and IL-6 and tumor necrosis factor (TNF) in vivo. However, PEGylation with 18 or longer chain restored, and even enhanced, the agonistic activity of the drug. In human peripheral blood mononuclear cells, similar effects of PEGylation were observed for secretion of proinflammatory cytokines, IL-6, IL-12, TNF-α, IL-1β and type 1 interferon, as well for B cell proliferation. In summary, these studies demonstrate that conjugation of PEG chains to a synthetic TLR ligand can impact its potency for cytokine induction depending on the size of the PEG moiety. Thus, PEGylation may be a feasible approach to regulate the pharmacological properties of TLR7 ligands.
PMCID: PMC3063487  PMID: 21338093
polyethylene glycol; PEG; Toll like receptor 7
PLoS ONE  2011;6(10):e25871.
Protein ubiquitination is a post-translational protein modification that regulates many biological conditions [1], [2], [3], [4]. Trip12 is a HECT-type E3 ubiquitin ligase that ubiquitinates ARF and APP-BP1 [5], [6]. However, the significance of Trip12 in vivo is largely unknown. Here we show that the ubiquitin ligase activity of Trip12 is indispensable for mouse embryogenesis. A homozygous mutation in Trip12 (Trip12mt/mt) that disrupts the ubiquitin ligase activity resulted in embryonic lethality in the middle stage of development. Trip12mt/mt embryos exhibited growth arrest and increased expression of the negative cell cycle regulator p16 [7], [8], [9], [10]. In contrast, Trip12mt/mt ES cells were viable. They had decreased proliferation, but maintained both the undifferentiated state and the ability to differentiate. Trip12mt/mt ES cells had increased levels of the BAF57 protein (a component of the SWI/SNF chromatin remodeling complex) and altered gene expression patterns. These data suggest that Trip12 is involved in global gene expression and plays an important role in mouse development.
PMCID: PMC3196520  PMID: 22028794
Obesity, which is one of the most serious health problems in United States, is considered a risk factor for lower esophageal and gastric cardia adenocarcinoma. However, the influence of obesity on esophageal cancer survival has not been determined. The aim of this study is to examine the impact of obesity on the long-term mortality outcomes for patients with esophageal cancer after surgery.
A retrospective review was performed of 243 consecutive esophageal cancer patients undergoing surgery who did not receive neoadjuvant therapy. Patients were grouped according to pretreatment body mass index, as normal/underweight (<25 kg/m2) and overweight (≥25 kg/m2). Overall and recurrence-free survivals were investigated using Kaplan-Meier method, and Cox regression model was used to determine the significant prognostic factors on univariate and multivariate analysis.
There were 67 patients (28%) who were classified as normal/underweight and 176 patients (72%) as overweight. In the overweight group, the numbers of patients who were male (P < .001), with adenocarcinoma (P < .001), and pathologic stage I (p=0.003) were significantly higher than in the normal/underweight group. There was no significant difference in postoperative morbidity rates between the two groups. Both local/regional and distant recurrence rates were significantly higher in the normal/underweight group (P = .027 and P = .039, respectively). The 5-year overall survival rates were 41% in the normal/underweight group, and 67% in the overweight group (P = .002). The 5-year disease free survival rates were 37% in the normal/underweight group, and 65% in the overweight group (P = .001). In univariate analysis, BMI ≥25 and lower esophagus tumor were factors associated with longer survival. Factors including older age, weight loss before treatment, smoking history, squamous cell carcinoma, tumor size>3 cm, pathologic stage III, and poorly differentiated carcinoma were significantly associated with shorter patient survival. In multivariate analysis, age, pathologic stage and tumor location ultimately remained as prognostic factors. Lower esophageal tumor (P = .015; HR, 0.386; 95% CI, 0.179–0.833) was related with better survival, and older age (P = .014; HR, 1.032; 95% CI, 1.006–1.057) and stage III disease (P = .015; HR, 6.162; 95% CI, 1.744–21.766) were related with poor survival.
Pretreatment BMI cannot be recognized as an independent predictor of long-term prognosis in esophageal cancer patients after surgery. However, high BMI tends to be associated with better prognosis.
This work was supported in part by grants from UT M. D. Anderson Cancer Center, Dallas, Park, Cantu, Smith, and Myers families and by the River Creek Foundation.
PMCID: PMC3056311
AGUIA is a front-end web application originally developed to manage clinical, demographic and biomolecular patient data collected during clinical trials at MD Anderson Cancer Center. The diversity of methods involved in patient screening and sample processing generates a variety of data types that require a resource-oriented architecture to capture the associations between the heterogeneous data elements. AGUIA uses a semantic web formalism, resource description framework (RDF), and a bottom-up design of knowledge bases that employ the S3DB tool as the starting point for the client's interface assembly.
The data web service, S3DB, meets the necessary requirements of generating the RDF and of explicitly distinguishing the description of the domain from its instantiation, while allowing for continuous editing of both. Furthermore, it uses an HTTP-REST protocol, has a SPARQL endpoint, and has open source availability in the public domain, which facilitates the development and dissemination of this application. However, S3DB alone does not address the issue of representing content in a form that makes sense for domain experts.
We identified an autonomous set of descriptors, the GBox, that provides user and domain specifications for the graphical user interface. This was achieved by identifying a formalism that makes use of an RDF schema to enable the automatic assembly of graphical user interfaces in a meaningful manner while using only resources native to the client web browser (JavaScript interpreter, document object model). We defined a generalized RDF model such that changes in the graphic descriptors are automatically and immediately (locally) reflected into the configuration of the client's interface application.
The design patterns identified for the GBox benefit from and reflect the specific requirements of interacting with data generated by clinical trials, and they contain clues for a general purpose solution to the challenge of having interfaces automatically assembled for multiple and volatile views of a domain. By coding AGUIA in JavaScript, for which all browsers include a native interpreter, a solution was found that assembles interfaces that are meaningful to the particular user, and which are also ubiquitous and lightweight, allowing the computational load to be carried by the client's machine.
PMCID: PMC2987967  PMID: 20977768

Results 1-19 (19)