IRT5 Probiotics Changes Immune Modulatory Protein Expression in the Extraorbital Lacrimal Glands of an Autoimmune Dry Eye Mouse Model

PURPOSE. While the association between the gut microbiome and the immune system has been studied in autoimmune disorders, little is known about ocular disease. Previously we reported that IRT5, a mixture of five probiotic strains, could suppress autoimmune dry eye. In this study, we investigated the mechanism by which IRT5 performs its immunomodulatory function in a mouse model of autoimmune dry eye. METHODS. NOD.B10.H2b mice were used as an autoimmune dry eye model. Either IRT5 or PBS was gavaged orally for 3 weeks, with or without 5 days of antibiotic pretreatment. The effects on clinical features, extraorbital lacrimal gland and spleen proteins, and fecal microbiota were analyzed. RESULTS. The ocular staining score was lower, and tear secretion was higher, in the IRT5-treated groups than in the PBS-treated groups. After IRT5 treatment, the downregulated lacrimal gland proteins were enriched in the biological processes of defense response and immune system process. The relative abundances of 33 operational taxonomic units were higher, and 53 were lower, in the feces of the IRT5-treated groups than in those of the PBS-treated groups. IRT5 administration without antibiotic pretreatment also showed immunomodulatory functions with increases in the Lactobacillus helveticus group and Lactobacillus hamsteri. Additional proteomic assays revealed a decrease of proteins related to antigen-presenting processes in the CD11b(+) and CD11c(+) cells of spleen in the IRT5-treated groups. CONCLUSIONS. Changes in the gut microbiome after IRT5 treatment improved clinical manifestations in the autoimmune dry eye model via the downregulation of antigen-presenting processes in immune networks.11Ysciescopu

Reductively degradable polyester-based block copolymers prepared by facile polycondensation and ATRP: synthesis, degradation, and aqueous micellization

Well-defined reductively degradable amphiphilic block copolymers having disulfide linkages positioned repeatedly on hydrophobic chains, thus exhibiting fast degradation, were prepared by a combination of polycondensation and ATRP. The new method consists of three synthetic steps including, (1) polycondensation of commercially available diols and diacids through carbodiimide coupling or high temperature processes to synthesize degradable polyesters with disulfides labeled on the main chain at regular intervals (ssPES–OH), (2) bromination of ssPES–OH to ssPES–Br, and (3) ATRP for chain extension of ssPES–Br with water-soluble polymethacrylate, yielding ssPES-b-polymethacrylate block copolymers (ssABPs). The reductive cleavage of disulfide linkages in reducing conditions resulted in the degradation of ssPES homopolymers; their degradation rate was significantly enhanced with the increasing amounts of disulfide linkages in ssPES–OH and reducing agents. For ATRP, gel permeation chromatography and 1H-NMR results confirmed the synthesis of well-defined ssABPs and revealed that polymerizations were well controlled. Because of their amphiphilic nature, ssABPs self-assembled in water toward the formation of core/shell micelles consisting of a hydrophobic ssPES core surrounded with polymethacrylate coronas. The effects of the corona's chain length on thermal properties and micellization in water of well-defined ssABPs were examined. Moreover, reductive (or thiol-responsive) degradation of ssABP-based micelles enabled fast release of encapsulated model drugs. Cell culture experiments confirmed nontoxicity and biocompatibility of well-defined ssABPs as effect candidates for targeted delivery applications

Novel Pyrrolopyrimidine-Based α-Helix Mimetics: Cell- Permeable Inhibitors of Protein-Protein Interactions

This document is the Accepted Manuscript version of a Published Work that appeared in final form in the Journal of the American Chemical Society, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://doi.org/10.1021/ja108230s.There is considerable interest in developing nonpeptidic, small molecule α-helix mimetics to disrupt α-helix-mediated protein-protein interactions. Herein, we report the design of a novel pyrrolopyrimidine-based scaffold for such α-helix mimetics with increased conformational rigidity. We also developed a facile solid phase synthetic route, which is amenable to divergent synthesis of a large library. Using a fluorescence polarization-based assay, we identified cell permeable, dual MDMX/MDM2 inhibitors, demonstrating that the designed molecules can act as α-helix mimetics

Factors Affecting Willingness to Undergo Carpal Tunnel Release

Background: Factors regarding patient willingness to undergo or avoid joint replacement have been studied; however, these factors have not been studied in patients with carpal tunnel syndrome. To further understand the aspects that are important for a patient with carpal tunnel syndrome in deciding whether to have surgery, we identified factors that affect this decision in women and that are not related to Workers` Compensation status. Methods: We retrospectively reviewed 282 female patients with electrophysiologically confirmed carpal tunnel syndrome without a known cause who were recommended for carpal tunnel release by a single hand surgeon in a tertiary medical setting. Of those, thirty-six female patients who were not entitled to Workers` Compensation canceled the operation during the waiting period, which averaged four weeks. Thirty-three of them were surveyed with a questionnaire sent by mail, and eighteen completed surveys were reviewed at a mean follow-up of thirty-two months. Furthermore, seventy female patients who underwent carpal tunnel release were randomly sampled, and thirty-eight patients completed the survey. The operation and cancellation groups were compared with regard to the reasons for choosing or canceling surgery. Results: The groups were similar with regard to age, sociodemographic variables, follow-up length, initial electro-physiological findings, and functional status. The highest-ranked reason for choosing surgery was symptom severity rather than fear of progression or a positive electrodiagnostic result. Those who canceled the operation rated symptom improvement during the waiting period as the leading reason for doing so, but they were also concerned about transient weakness, the financial burden, and a scar or pillar pain. Disease persistence or recurrence was the issue of most concern in both groups. At the time of the final review, the functional status was significantly improved in both groups and no significant difference between the groups was detected. Conclusions: Women with carpal tunnel syndrome report that subjective symptom severity is the most important reason for undergoing surgery. Understanding this and other patient concerns may help physicians during patient-oriented consultation and decision-making. In particular, recommendations for carpal tunnel release on the basis of symptoms are reasonable from the perspective of the patient who has carpal tunnel syndrome without a known cause.Lee JY, 2008, J SHOULDER ELB SURG, V17, P570, DOI 10.1016/j.jse.2007.12.005Hudak PL, 2008, J BONE JOINT SURG AM, V90A, P1427, DOI 10.2106/JBJS.G.01077Park KK, 2007, CLIN ORTHOP RELAT R, P143, DOI 10.1097/BLO.0b013e31804ea0bcTaylor-Gjevre RM, 2007, CAN FAM PHYSICIAN, V53, P1186Rigler I, 2007, EUR J NEUROL, V14, P783, DOI 10.1111/j.1468-1331.2007.01855.xBallantyne PJ, 2007, ARTHRIT RHEUM-ARTHR, V57, P27, DOI 10.1002/art.22472*AAOS CARP TUNN SY, 2007, AM AC ORTH SURG GUIDSCHOLTEN RJ, 2007, COCHRANE DB SYST REV, V17, P3905Hawker GA, 2006, CURR OPIN RHEUMATOL, V18, P526Mazur DJ, 2005, HEALTH EXPECT, V8, P97FIGARO MK, 2005, J AMBUL CARE MANAGE, V28, P41Hawker GA, 2004, ARTHRIT RHEUM-ARTHR, V51, P635, DOI 10.1002/art.20524Figaro MK, 2004, HEALTH PSYCHOL, V23, P324, DOI 10.1037/0278-6133.23.3.324Chang HJ, 2004, ARTHRIT RHEUM-ARTHR, V51, P117, DOI 10.1002/art.20073AKELMAN E, 2004, HAND SURG, P867Moran M, 2003, J ARTHROPLASTY, V18, P442, DOI 10.1016/S0883-5403(03)00061-5RESENDE LA, 2003, ELECTROMYOGR CLIN NE, V43, P301Ang DC, 2002, MED CARE, V40, P471Hawker GA, 2001, MED CARE, V39, P206Bland JDP, 2000, MUSCLE NERVE, V23, P1280Trousdale RT, 1999, MAYO CLIN PROC, V74, P978Atroshi I, 1999, JAMA-J AM MED ASSOC, V282, P153Homan MM, 1999, SCAND J WORK ENV HEA, V25, P115Padua L, 1998, ITAL J NEUROL SCI, V19, P357Aulisa L, 1998, J HAND SURG-AM, V23A, P687Nathan PA, 1998, MUSCLE NERVE, V21, P711Concannon MJ, 1997, PLAST RECONSTR SURG, V100, P1452Asch DA, 1997, J CLIN EPIDEMIOL, V50, P1129Hudak PL, 1996, AM J IND MED, V30, P372Deber RB, 1996, ARCH INTERN MED, V156, P1414Hudak PL, 1996, AM J IND MED, V29, P602WRIGHT JG, 1994, J BONE JOINT SURG BR, V76B, P229LEVINE DW, 1993, J BONE JOINT SURG AM, V75A, P1585SIMINOFF LA, 1991, SOC SCI MED, V32, P813GRUNDBERG AB, 1983, J HAND SURG-AM, V8, P348

Potential pharmacological chaperones targeting cancer-associated MCL-1 and Parkinson disease-associated α-synuclein

Pharmacological chaperones are small molecules that bind to proteins and stabilize them against thermal denaturation or proteolytic degradation, as well as assist or prevent certain protein-protein assemblies. These activities are being exploited for the development of treatments for diseases caused by protein instability and/or aberrant protein-protein interactions, such as those found in certain forms of cancers and neurodegenerative diseases. However, designing or discovering pharmacological chaperones for specific targets is challenging because of the relatively featureless protein target surfaces, the lack of suitable chemical libraries, and the shortage of efficient high-throughput screening methods. In this study, we attempted to address all these challenges by synthesizing a diverse library of small molecules that mimic protein α-helical secondary structures commonly found in protein-protein interaction surfaces. This was accompanied by establishing a facile "on-bead" high-throughput screening method that allows for rapid and efficient discovery of potential pharmacological chaperones and for identifying novel chaperones/inhibitors against a cancer-associated protein, myeloid cell leukemia 1 (MCL-1), and a Parkinson disease-associated protein, α-synuclein. Our data suggest that the compounds and methods described here will be useful tools for the development of pharmaceuticals for complex-disease targets that are traditionally deemed "undruggable.

MMP-Inhibitory Effects of Flavonoid Glycosides from Edible Medicinal Halophyte Limonium tetragonum

Limonium tetragonum has been well-known for its antioxidative properties as a halophyte. This study investigated the antimetastasis effect of solvent-partitioned L. tetragonum extracts (LTEs) and isolated compounds on HT1080 mouse melanoma cell model with a focus on matrix metalloproteinase (MMP) activity and TIMP and MAPK pathways. Upregulation and stimulation of MMPs result in elevated degradation of extracellular matrix which is part of several complications such as metastasis, cirrhosis, and arthritis. The anti-MMP capacity of LTEs was confirmed by their MMP-inhibitory effects, regulation of MMP and TIMP expression, and suppression of MAPK pathway. Among all tested LTEs, 85% aq. MeOH and n-BuOH were found to be most active fractions which later yielded two known flavonoid glycosides, myricetin 3-galactoside and quercetin 3-o-beta-galactopyranoside. Anti-MMP potential of the compounds was confirmed by their ability to regulate MMP expression through inhibited MAPK pathway activation. These results suggested that L. tetragonum might serve as a potential source of bioactive substances with effective anti-MMP properties

Influence of Radiation Dose to Reconstructed Breast Following Mastectomy on Complication in Breast Cancer Patients Undergoing Two-Stage Prosthetic Breast Reconstruction

Purpose: This study investigated the association between radiation dose and complication rate in patients who underwent breast reconstruction to understand the role of radiation hypofractionated regimen, boost radiation therapy (RT), and RT techniques.Methods: We retrospectively evaluated 75 patients treated with post-mastectomy adjuvant RT for breast cancer in the setting of two-stage prosthetic breast reconstruction. Near maximum radiation dose (Dmax) in the 2 or 0.03 cc of reconstructed breast or overlying breast skin was obtained from dose-volume histograms.Results: Post-RT complications occurred in 22.7% of patients. Receiver operating characteristic analysis showed that all near Dmax parameters were able to predict complication risk, which retained statistical significance after adjusting other variables (odds ratio 1.12 per Gy, 95% confidence interval 1.02–1.23) with positive dose-response relationship. In multiple linear regression model (R2 = 0.92), conventional fractionation (β = 11.7) and 16 fractions in 2.66 Gy regimen (β = 3.9) were the major determinants of near Dmax compared with 15 fractions in 2.66 Gy regimen, followed by utilization of boost RT (β = 3.2). The effect of bolus and dose inhomogeneity seemed minor (P > 0.05). The location of hot spot was not close to the high density metal area of the expander, but close to the surrounding areas of partially deflated expander bag.Conclusions: This study is the first to demonstrate a dose-response relationship between risk of complications and near Dmax, where hypofractionated regimen or boost RT can play an important role. Rigorous RT-quality assurance program and modification of dose constraints could be considered as a critically important component for ongoing trials of hypofractionation. Based on our findings, we initiated a multi-center retrospective study (KROG 18-04) and a prospective study (NCT03523078) to validate our findings

Detection of Human Papillomavirus(HPV) DNA in Children's Genital and Respiratory Tract Papilloma and in Birth Canals of Their Mothers

In order to study the epidemiologic relationship between children's papillomaviral disease and papillomaviral infection of mothers, five anogenital warts and seven laryngeal papilloma in children were analyzed by polymerase chain reaction to detect HPV DNA HPV type 6 was found in 8 cases and HPV type 11 in 7 cases. Both types were found in 3 cases. From these results, anogenital warts and laryngeal papilloma in children are found to be pure viral diseases caused by HPV type 6 and 11. Nine cases of DNA extracted from cervical swabs from mothers of children with condyloma or laryngeal papilloma, were examined to identify possible latent infection of HPV. Among 9 cases, HPV DNA was found in two cases. These results suggest that inapparent infection of HPV type 6, 11 in the birth canal may contribute to the development of these viral diseases in their offspring aside from sexual abuse

Usefulness of fusion images of unenhanced and contrast-enhanced arterial phase cone-beam CT in the detection of viable hepatocellular carcinoma during transarterial chemoembolization

PURPOSE:We aimed to evaluate the diagnostic efficacy of fusion imaging of unenhanced and arterial phase contrast-enhanced cone-beam computed tomography (CBCT) by comparing with multidetector computed tomography (MDCT) in detection of viable hepatocellular carcinoma (HCC) in patients who have been previously treated with transarterial chemoembolization (TACE).METHODS:In this retrospective study, a total of 173 tumors in 33 known HCC patients (21 men, 12 women; mean age, 64±7.6 years; mean tumor size, 2.15±1.70 cm) who had been previously treated with TACE and underwent additional session of TACE were included. The sensitivity and positive predictive values of preprocedural MDCT and fusion CBCT for detection of viable tumor were analyzed with follow-up MDCT images performed 3-4 weeks after TACE, as reference standard.RESULTS:A total of 141 remote and 32 marginal viable tumors were included. The sensitivities for detection of remote, marginal, and total viable tumors were 80.9%, 68.8%, and 78.6% for MDCT and 96.5%, 96.9%, and 96.5% for fusion CBCT, respectively. The positive predictive values for detection of remote, marginal, and total viable tumors were 95.0%, 78.6%, and 95.8% for MDCT, and 97.1%, 88.6%, and 97.7% for fusion CBCT, respectively. Fusion CBCT showed statistically higher sensitivity and positive predictive value for detection of viable tumors (P < 0.001).CONCLUSION:The diagnostic performance of fusion imaging of unenhanced and contrast-enhanced arterial phase CBCT was superior to MDCT for detection of viable HCCs