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1.  A small molecule inhibitor of ITK and RLK impairs TH1 differentiation and prevents colitis disease progression 
In T cells, the Tec kinases ITK and RLK are activated by TCR stimulation, and are required for optimal downstream signaling. Studies of CD4+ T cells from Itk−/− and Itk−/− Rlk−/− mice have indicated differential roles of ITK and RLK in TH1, TH2, and TH17 differentiation and cytokine production. However, these findings are confounded by the complex T cell developmental defects in these mice. Here, we examine the consequences of ITK and RLK inhibition using a highly selective and potent small molecule covalent inhibitor PRN694. In vitro TH polarization experiments indicate that PRN694 is a potent inhibitor of TH1 and TH17 differentiation and cytokine production. Using a T cell adoptive transfer model of colitis, we find that in vivo administration of PRN694 markedly reduces disease progression, T cell infiltration into the intestinal lamina propria, and IFN-γ production by colitogenic CD4+ T cells. Consistent with these findings, TH1 and TH17 cells differentiated in the presence of PRN694 show reduced P-selectin binding and impaired migration to CXCL11 and CCL20, respectively. Together, these data indicate that ITK plus RLK inhibition may have therapeutic potential in TH1-mediated inflammatory diseases.
doi:10.4049/jimmunol.1501828
PMCID: PMC4635571  PMID: 26466958
2.  Prolonged and tunable residence time using reversible covalent kinase inhibitors 
Nature chemical biology  2015;11(7):525-531.
Drugs with prolonged, on-target residence time often show superior efficacy, yet general strategies for optimizing drug-target residence time are lacking. Here, we demonstrate progress toward this elusive goal by targeting a noncatalytic cysteine in Bruton's tyrosine kinase (BTK) with reversible covalent inhibitors. Utilizing an inverted orientation of the cysteine-reactive cyanoacrylamide electrophile, we identified potent and selective BTK inhibitors that demonstrate biochemical residence times spanning from minutes to 7 days. An inverted cyanoacrylamide with prolonged residence time in vivo remained bound to BTK more than 18 hours after clearance from the circulation. The inverted cyanoacrylamide strategy was further utilized to discover fibroblast growth factor receptor (FGFR) kinase inhibitors with residence times of several days, demonstrating generalizability of the approach. Targeting noncatalytic cysteines with inverted cyanoacrylamides may serve as a broadly applicable platform that facilitates “residence time by design”, the ability to modulate and improve the duration of target engagement in vivo.
doi:10.1038/nchembio.1817
PMCID: PMC4472506  PMID: 26006010
3.  Rates of glaucomatous visual field change before and after transscleral cyclophotocoagulation: a retrospective case series 
BMC Ophthalmology  2015;15:179.
Background
The primary goal of glaucoma treatment is to lower and control intraocular pressure (IOP) and thereby prevent functional deterioration. For glaucomas that are refractory to medical and incisional surgical therapies, transscleral diode cyclophotocoagulation (TCP) is a well-established procedure to effectively decrease IOP. This study investigated rates of visual field (VF) change in patients with glaucoma before and after TCP.
Methods
This retrospective case series investigated rates of VF changes in glaucoma patients before and after they underwent TCP. At least four VF examinations were required, two before and two after surgery. VF examinations were performed using standard automated perimetry and rates of change were calculated by linear regression analysis of mean deviation (MD) values measured over time.
Results
A total of 46 eyes of 43 patients were included and followed on average 3.6 years before and 2.1 years after TCP. 67 % of the eyes showed further progression of glaucoma following surgery. Mean preoperative MD change was −0.21 dB/year (SE = 0.08, 95 % CI [−0.06, −0.37]). Postoperatively the mean change was −0.26 dB/year (SE = 0.22 95 % CI [0.38, −0.48]) which results in a difference between pre- and postoperative MD rate of 0.05 dB/year (p = 0.824). The mean MD value was worse after surgery and dropped by 1.73 dB (SE = 0.58, 95 % CI [−0.59, −2.87], p = 0.003). Intraocular pressure (IOP) decreased from 23.2 mmHg (SD = 4.67) before TCP to 14.3 mmHg (SD = 3.17) after TCP (p < 0.001). For each 1 mmHg of IOP reduction after surgery, postoperative rate of VF loss decreased by 0.15 dB/year.
Conclusion
Rates of glaucomatous visual field loss did not significantly change after TCP and the majority of the eyes showed further progression of glaucoma after surgery. Mean MD value was considerably lower after TCP.
doi:10.1186/s12886-015-0166-0
PMCID: PMC4678611  PMID: 26667206
Glaucoma; progression; rate of progression; visual field; transscleral cyclophotocoagulation
4.  A Small Molecule Inhibitor of ITK and RLK Impairs Th1 Differentiation and Prevents Colitis Disease Progression 
The Journal of Immunology Author Choice  2015;195(10):4822-4831.
In T cells, the Tec kinases IL-2–inducible T cell kinase (ITK) and resting lymphocyte kinase (RLK) are activated by TCR stimulation and are required for optimal downstream signaling. Studies of CD4+ T cells from Itk−/− and Itk−/−Rlk−/− mice have indicated differential roles of ITK and RLK in Th1, Th2, and Th17 differentiation and cytokine production. However, these findings are confounded by the complex T cell developmental defects in these mice. In this study, we examine the consequences of ITK and RLK inhibition using a highly selective and potent small molecule covalent inhibitor PRN694. In vitro Th polarization experiments indicate that PRN694 is a potent inhibitor of Th1 and Th17 differentiation and cytokine production. Using a T cell adoptive transfer model of colitis, we find that in vivo administration of PRN694 markedly reduces disease progression, T cell infiltration into the intestinal lamina propria, and IFN-γ production by colitogenic CD4+ T cells. Consistent with these findings, Th1 and Th17 cells differentiated in the presence of PRN694 show reduced P-selectin binding and impaired migration to CXCL11 and CCL20, respectively. Taken together, these data indicate that ITK plus RLK inhibition may have therapeutic potential in Th1-mediated inflammatory diseases.
doi:10.4049/jimmunol.1501828
PMCID: PMC4635571  PMID: 26466958
5.  Repeatability of intraocular pressure measurements with Icare PRO rebound, Tono-Pen AVIA, and Goldmann tonometers in sitting and reclining positions 
BMC Ophthalmology  2013;13:44.
Background
Icare PRO (ICP) is a new Rebound tonometer that is able to measure intraocular pressure (IOP) in both sitting and reclining positions. In this study, the gold standard Goldmann tonometer (GAT) was compared to ICP and Tono-Pen AVIA (TPA). Hypothesis was that repeatability of GAT is superior to ICP and TPA.
Methods
36 eyes of 36 healthy caucasian individuals, 13 male and 26 females, 17 right and 19 left eyes have been included in this prospective, randomized, cross-sectional study. The study was conducted at a single site (Dept. of Ophthalmology, UniversityHospital Zurich, Switzerland). Primary outcome measures were Intraclass correlation coefficients (ICC) and coefficients of variation (COV) and test-retest repeatability as visualized by Bland-Altman analysis. Secondary outcome measures were IOP in sitting (GAT, ICP and TPA) and in reclining (ICP and TPA) position.
Results
Mean IOP measured by GAT was 14.9±3.5 mmHg. Mean IOP measured by ICP was 15.6±3.1 mmHg (with TPA 14.8±2.7 mmHg) in sitting and 16.5±3.5 mmHg (with TPA 17.0±3.0 mmHg) in reclining positions. COVs ranged from 2.9% (GAT) to 6.9% (ICP reclining) and ICCs from 0.819 (ICP reclining) to 0.972 (GAT).
Conclusions
Repeatability is good with all three devices. GAT has higher repeatability compared to the two tested hand-held devices with lowest COVs and highest ICCs. IOP was higher in the reclining compared to the sitting position.
Trial registration
The study was registered to the Clinical Trials Register of the US National Institute of Health, NCT01325324.
doi:10.1186/1471-2415-13-44
PMCID: PMC3844420  PMID: 24006952
6.  Cataract Surgery combined with excimer laser trabeculotomy to lower intraocular pressure: effectiveness dependent on preoperative IOP 
BMC Ophthalmology  2013;13:24.
Background
Cataract surgery combined with excimer laser trabeculotomy (phaco-ELT) can reduce intraocular pressure (IOP). The aim of this study was to evaluate the effect of phaco-ELT on IOP in patients as a function of preoperative IOP.
Methods
Patients with open-angle glacuoma or ocular hypertension who received phaco-ELT between 01/2008 and 10/2009 were included. Patients were assigned based on preoperative IOP either to the study group (≤21 mmHg) or control group (>21 mmHg) in this IRB-approved, prospective, consecutive case series. Visual Acuity, IOP, and number of anti-glaucoma drugs (AGD) were recorded at baseline and 12 months after phaco-ELT. Any postoperative complications were also recorded.
Results
64 eyes of 64 patients (76.5 ± 9.4 years) were included. Baseline IOP was 19.8 ± 5.3 mmHg (AGD 2.4 ± 1.1) for all eyes, 16.5 ± 2.9 mmHg (AGD 2.5 ± 1.0) for the study group, and 25.8 ± 2.9 mmHg (AGD 2.2 ± 1.4) for the control group. Across the two groups, IOP was reduced by 4.5 ± 5.9 mmHg (-23.0%, p < 0.001) and AGD by 0.9 ± 1.5 (-38.9%, p < 0.001). For the study group IOP was reduced by 1.9 ± 4.4 mmHg (-11. 5 %, p = 0.012) and AGD by 1.1 ± 1.4 (-42.9%, p < 0.001), and for the control group by 9.5 ± 5.4 mmHg (-36.6%, p < 0.001) and AGD by 0.7 ± 1.6 (-29.5%, p = 0.085). There were no serious postoperative complications such as endophthalmitis, significant hyphema, or a severe fibrinous reaction of the anterior chamber.
Conclusions
IOP remained significantly reduced from baseline 12 months after phaco-ELT regardless of preoperative IOP levels, with no major complications. The IOP reduction remained constant over the entire follow-up. Hence, phaco-ELT can be considered in glaucoma and ocular hypertensive patients whenever cataract surgery is performed, in order to further reduce IOP or to reduce the requirement for IOP-reducing medications.
doi:10.1186/1471-2415-13-24
PMCID: PMC3724507  PMID: 23799932
Cataract; Cataract surgery; Extracapsular cataract extraction; Phacoemulsification; Glaucoma; Glaucoma surgery; Excimer laser trabeculotomy; Excimer laser trabeculostomy; Trabecular meshwork; Primary open angle glaucoma; Ocular hypertension
7.  Evaluation of filtering blebs using the ‘Wuerzburg bleb classification score’ compared to clinical findings 
BMC Ophthalmology  2012;12:24.
Background
To determine the agreement between intraocular pressure and the ‘Wuerzburg bleb classification score’, as well as between single items of the score and intraocular pressure. Interobserver variability was analyzed.
Methods
57 post-trabeculectomy eyes were included. Colour photographs were used to score the filtering bleb in accordance to the Wuerzburg bleb classification score by two different examiners. At the same visit, clinical data such as intraocular pressure, best corrected visual acuity, slit lamp biomicroscopy and medical history were obtained by another examiner.
Results
After trabeculectomy, 42 out of 57 eyes (73.7%) reached the target pressure (≤21mmHg, and intraocular pressure reduction of at least 20%, without antiglaucoma medication, and without any additional intervention). Fair agreement was found between intraocular pressure and Wuerzburg bleb classification score ≥8 points and ≥7 points (kappa 0.24 and 0.27, respectively). Analyzing the subgroups of the morphological criteria, best agreement was found between occurrence of microcysts and target intraocular pressure (к 0.22 – 0.34).
Conclusions
Evaluating filtering blebs after trabeculectomy by using the Wuerzburg bleb classification score is a good technique for predicting intraocular pressure control in eyes attaining a minimum score of seven points. The presence of microcysts on the filtering bleb predicts that the eye is likely to attain target pressure.
doi:10.1186/1471-2415-12-24
PMCID: PMC3439283  PMID: 22805056
Filtering bleb; Glaucoma; Filtration surgery; Bleb grading; Trabeculectomy
8.  Treatment of ocular hypertension and open angle glaucoma: meta-analysis of randomised controlled trials 
BMJ : British Medical Journal  2005;331(7509):134.
Objective Open angle glaucoma is one of the most common causes of blindness in industrialised nations. Treatments to lower ocular pressure are widely used in glaucoma prevention and treatment, despite conflicting evidence.
Design We performed meta-analyses to reassess the effectiveness of pressure lowering treatment to delay the development of glaucoma in ocular hypertension, as well as progression of manifest open angle glaucoma.
Data sources Medline, Embase, and the Cochrane Library.
Selection of studies Eligible studies were randomised controlled trials with a concurrent untreated control group and information on time to glaucomatous changes to visual field and optic disc. Trial reports were reviewed independently by two investigators in an unblinded standardised manner.
Results Meta-analysis of trials in ocular hypertension showed a significant preventive effect of reducing intraocular pressure on progression to glaucoma (hazard ratio 0.56, 95% confidence interval 0.39 to 0.81, P = 0.01; number needed to treat 12). Pooled data of studies in manifest glaucoma showed a significant delay of visual field deterioration (0.65, 0.49 to 0.87, P = 0.003; NNT = 7), with subgroup analysis showing a larger effect in patients with raised pressure and a reduced effect in normal tension glaucoma (subgroup comparison: not significant).
Conclusions Lowering intraocular pressure in patients with ocular hypertension or manifest glaucoma is beneficial in reducing the risk of visual field loss in the long term.
doi:10.1136/bmj.38506.594977.E0
PMCID: PMC558697  PMID: 15994659
9.  Inactivation of both the Retinoblastoma Tumor Suppressor and p21 by the Human Papillomavirus Type 16 E7 Oncoprotein Is Necessary To Inhibit Cell Cycle Arrest in Human Epithelial Cells 
Journal of Virology  2002;76(20):10559-10568.
The human papillomavirus (HPV) type 16 E7 oncoprotein must inactivate the retinoblastoma tumor suppressor (Rb) pathway to bypass G1 arrest. However, E7 C-terminal mutants that were able to inactivate Rb were unable to bypass DNA damage-induced G1 arrest and keratinocyte senescence, suggesting that the E7 C terminus may target additional G1 regulators. The E7 C-terminal mutant proteins E7 CVQ68-70AAA and E7 Δ79-83 (deletion of positions 79 through 83) were further tested in several models of cell cycle arrest associated with elevated levels of p21. C-terminal mutations rendered E7 unable to induce S phase and endoreduplication in differentiated keratinocytes and rendered it less efficient in delaying senescence of human mammary epithelial cells. Interestingly, when cell cycle arrest was induced with a peptide form of p21, the E7 C-terminal mutants were deficient in overcoming arrest, whereas a mutant defective in Rb binding was competent in inhibiting G1 arrest. These results suggest that the inactivation of both p21 and Rb by E7 contributes to subversion of cell cycle control in normal human epithelia but that neither p21 nor Rb inactivation alone is sufficient.
doi:10.1128/JVI.76.20.10559-10568.2002
PMCID: PMC136576  PMID: 12239337

Results 1-9 (9)