Long-term treatment success and safety of combined phacoemulsification plus excimer laser trabeculostomy: an 8-year follow-up study.

PURPOSE: Combined phacoemulsification plus excimer laser trabeculostomy (phaco-ELT) is a minimally invasive surgery that effectively reduces intraocular pressure (IOP) in patients with glaucoma and a concomitant diagnosis of cataract. The aim of this study was to evaluate the long-term treatment success as well as safety of phaco-ELT over an 8-year follow-up period. METHODS: Patients with a diagnosis of primary or secondary glaucoma or ocular hypertension and a visually significant cataract who underwent a combined phaco-ELT between January 1, 2008, and December 31, 2010, were included. Data for IOP, the number of IOP-lowering medications (meds), best-corrected visual acuity, complications, and subsequent surgeries to lower IOP were collected preoperatively (baseline) and intraoperatively as well as at 1 day, 1 week, 1 month, 3 months, 6 months, 9 months, 1 year, and every 6 months thereafter to 8 years postoperatively. RESULTS: One hundred sixty-one eyes of 128 patients were included. After 8 years of follow-up, the long-term treatment success rate with IOP ≤ 21 mmHg was 50.2%. No serious intra- or postoperative complications occurred. The mean IOP decreased significantly from 19.3 (±4.8) mmHg at baseline to 15.4 (±3.2, p =0.0040) mmHg at 8 years. Additionally, meds remained below baseline after 8 years of follow-up and were reduced significantly for up to 4 years. Only 25.5% of the eyes required a subsequent surgery to lower IOP during the follow-up period. CONCLUSION: Combined phaco-ELT is a safe procedure without serious intra- or postoperative complications, which has a positive long-term effect regarding IOP and meds. Remarkably, the mean IOP-lowering effect remained stable and was reduced ≥ 20% from baseline after 3 months for the remainder of the follow-up duration, whereas the number of meds was reduced significantly for up to 4 years. Furthermore, only 25.5% of the eyes required a subsequent surgery to control IOP throughout the whole follow-up of 8 years.

Correction to: Incidence of dyschromatopsy in glaucoma.

In the original publication, the family and given name of authors were swapped incorrectly in the author group.

Incidence of dyschromatopsy in glaucoma.

PURPOSE: As proven in studies dating back to the eighteenth century, color vision changes may occur early in the course of glaucoma. Our aim was to reevaluate the incidence of acquired color vision deficiency in glaucoma patients of the University hospital Zürich by using the Panel D-15 test. METHODS: Inclusion criteria of the study involved a diagnosis of glaucoma, age equal or greater than 18 years with no upper limit and a best-corrected visual acuity (BCVA) smaller than ≤ 0.7 logMAR. All volunteers were tested twice monocularly for color vision with (1) the Ishihara color plate test and (2) the Farnsworth and Lanthony Panel D-15 test by one examiner (L.B.). Using the Moment of Inertia Method of Vingrys and King-Smith (Investig Ophthalmol Vis Sci 29(1):50-63, 1988), we measured the color defect type (blue-yellow, red-green or non-selective). RESULTS: One hundred and fifty-one eyes of 87 glaucoma patients were included in this study. Nine eyes showed a deficient result in the Ishihara test, which proves a congenital red-green weakness. Fifty-one (33.8%) eyes showed color vision anomalies in the desaturated test and 24 (15.9%) eyes in the saturated Panel D-15 test. A total of 25.2% and 8.6% of eyes in the desaturated and saturated test were diffuse dyschromatopsia, respectively. The second most prevalent deficiencies were blue-yellow defects with 4.0% and 4.6% of saturated and desaturated results. Just the covariate visual acuity had a significant influence on the Panel D-15 result, whereas other variables like age, sex or intraocular pressure did not show any impact. CONCLUSION: This study ascertains that the long-known theory of color vision defects in patients with glaucoma is also relevant in our sample of 151 eyes, providing continuity to claims firstly reported many years ago. Despite our results highlighting more diffuse dyschromatopsia than other similar experiments, we have also proven that the tritanomalous defects occur more frequently than other color defects.

Correction to: Success of combined cataract extraction plus excimer laser trabeculotomy exceeds that of combined ab interno trabeculectomy with the trabectome or cataract extraction alone.

In the original publication, the corresponding author name was spelt incorrectly.

Success of combined cataract extraction plus excimer laser trabeculotomy exceeds that of combined ab interno trabeculectomy with the trabectome or cataract extraction alone.

PURPOSE: To determine the efficacy of cataract surgery alone and combined with two minimally invasive glaucoma surgery (MIGS) procedures (phaco-ELT and phaco-aiT). METHODS: Data was collected from 12/2007 to 02/2012 in this retrospective, non-randomized, comparative single surgery center study. Reduction in IOP and hypotensive medication (AGD), change in visual acuity, success rates, and complications were computed by comparing preoperative data with data at 1 year postoperatively. RESULTS: A total of 245 eyes of 245 subjects were included. Study eyes underwent phaco alone (38 eye) or combined phaco-ELT (105 eye) and phaco-aiT (102 eye). Phaco alone, combined phaco-ELT, and combined phaco-aiT lowered IOP by 1.5 ± 4.0 mmHg, 4.3 ± 5.6, and 5.3 ± 4.5 mmHg, respectively (P < 0.01). Survival time of phaco-ELT outreached survival time of phaco alone and combined phaco-aiT (20.6 ± 1.0 vs. 13.2 ± 0.4 and 12.9 ± 0.6 month, respectively). No serious complications or adverse events occurred. None of the cases required a subsequent procedure within the first year to lower IOP further. CONCLUSIONS: All three surgical procedures lowered IOP and reduced medication. However, the IOP-lowering efficacy of the two combined MIGS procedures exceeded the effect of phaco alone. A combined phaco and MIGS procedures seem reasonable to consider whenever a cataract surgery in an eye with glaucoma or ocular hypertension is considered. In addition, the combined MIGS procedure effectively lowers IOP whenever a target IOP in the mid-teens is sufficient. In this study, the nonthermal phaco-ELT procedure showed superior efficacy at 1 year over phaco alone and phaco-aiT in the Kaplan-Meier statistics.

[Cyclodestructive Procedures to Lower Intraocular Pressure - A Review]. / Zyklodestruktive Verfahren zur Senkung des Augeninnendrucks ­ eine Übersicht.

The only therapy for glaucoma, for which there is sufficient evidence, is the lowering of intraocular pressure. Intraocular pressure reduction can be achieved by an improvement in outflow or a reduction of aqueous humor production. Surgically, a reduction of aqueous humor production can be achieved by cyclodestructive procedures. This article provides a brief summary of the different cyclodestructive procedures. The efficacy of cyclophotocoagulation is well documented. The risk profile has been reduced by changes in the laser protocols. Serious complications described in early studies (e.g., visual loss) rarely occur nowadays. The indication spectrum of cyclophotocoagulation has expanded from end-stage glaucoma to glaucoma with good visual acuity. Even the use of cyclodestructive procedures in pediatric glaucoma has gained acceptance. A promising next generation of micropulsed diode lasers could further reduce the risk profile with the same effectiveness. The non-inferiority of micropulse cyclophotocoagulation versus the established procedures has been proven in early studies. However, studies with long-term follow-up and on side-effects are still lacking. Furthermore, a standardized laser protocol must be established.

Prolonged and tunable residence time using reversible covalent kinase inhibitors.

Drugs with prolonged on-target residence times often show superior efficacy, yet general strategies for optimizing drug-target residence time are lacking. Here we made progress toward this elusive goal by targeting a noncatalytic cysteine in Bruton's tyrosine kinase (BTK) with reversible covalent inhibitors. Using an inverted orientation of the cysteine-reactive cyanoacrylamide electrophile, we identified potent and selective BTK inhibitors that demonstrated biochemical residence times spanning from minutes to 7 d. An inverted cyanoacrylamide with prolonged residence time in vivo remained bound to BTK for more than 18 h after clearance from the circulation. The inverted cyanoacrylamide strategy was further used to discover fibroblast growth factor receptor (FGFR) kinase inhibitors with residence times of several days, demonstrating the generalizability of the approach. Targeting of 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.

A phase I trial of PRN1008, a novel reversible covalent inhibitor of Bruton's tyrosine kinase, in healthy volunteers.

AIM: To evaluate the safety, tolerability, and pharmacokinetics/pharmacodynamics of PRN1008, a novel Bruton's tyrosine kinase (BTK) inhibitor, in healthy volunteers, and thus determine the dose range for future clinical studies. METHODS: This was a two-part randomized, placebo controlled study in healthy volunteers using a liquid formulation. Part I was a single ascending dose design with dose levels of 50-1200 mg (n = 6 active, two placebos per cohort); Part II was a multiple ascending dose design, with dose regimens ranging from 300 to 900 mg daily, either four times or twice daily for 10 days. Plasma pharmacokinetics, adverse events, vital signs, electrocardiograms and laboratory parameters were assessed. BTK occupancy in peripheral blood mononuclear cells was evaluated as a marker of target engagement. RESULTS: PRN1008 was rapidly absorbed following oral administration, and was safe and well tolerated in all dose regimens evaluated in both single and multiple doses. PRN1008 demonstrated a large volume of distribution, and a half-life of approximately 3-4 h. BTK occupancy of >90% was observed within 4 h after dosing in both single and multiple dose regimens, and was closely linked to maximum plasma concentration. BTK occupancy decay was slow (-1.6% h-1 ), and occupancy was sustained despite drug concentrations being undetectable. No severe or serious adverse events occurred, and the most common adverse events were gastrointestinal in nature. CONCLUSIONS: PRN1008 was safe and well-tolerated following oral administration, and achieved high, sustained levels of BTK occupancy in peripheral blood mononuclear cells.

A Small Molecule Inhibitor of ITK and RLK Impairs Th1 Differentiation and Prevents Colitis Disease Progression.

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.

Targeting interleukin-2-inducible T-cell kinase (ITK) and resting lymphocyte kinase (RLK) using a novel covalent inhibitor PRN694.

Interleukin-2-inducible T-cell kinase (ITK) and resting lymphocyte kinase (RLK or TXK) are essential mediators of intracellular signaling in both normal and neoplastic T-cells and natural killer (NK) cells. Thus, ITK and RLK inhibitors have therapeutic potential in a number of human autoimmune, inflammatory, and malignant diseases. Here we describe a novel ITK/RLK inhibitor, PRN694, which covalently binds to cysteine residues 442 of ITK and 350 of RLK and blocks kinase activity. Molecular modeling was utilized to design molecules that interact with cysteine while binding to the ATP binding site in the kinase domain. PRN694 exhibits extended target residence time on ITK and RLK and is highly selective for a subset of the TEC kinase family. In vitro cellular assays confirm that PRN694 prevents T-cell receptor- and Fc receptor-induced cellular and molecular activation, inhibits T-cell receptor-induced T-cell proliferation, and blocks proinflammatory cytokine release as well as activation of Th17 cells. Ex vivo assays demonstrate inhibitory activity against T-cell prolymphocytic leukemia cells, and in vivo assays demonstrate durable pharmacodynamic effects on ITK, which reduces an oxazolone-induced delayed type hypersensitivity reaction. These data indicate that PRN694 is a highly selective and potent covalent inhibitor of ITK and RLK, and its extended target residence time enables durable attenuation of effector cells in vitro and in vivo. The results from this study highlight potential applications of this dual inhibitor for the treatment of T-cell- or NK cell-mediated inflammatory, autoimmune, and malignant diseases.

Rates of glaucomatous visual field change before and after transscleral cyclophotocoagulation: a retrospective case series.

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.

Cataract surgery combined with excimer laser trabeculotomy to lower intraocular pressure: effectiveness dependent on preoperative IOP.

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.

Repeatability of intraocular pressure measurements with Icare PRO rebound, Tono-Pen AVIA, and Goldmann tonometers in sitting and reclining positions.

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, University Hospital 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.

Repeatability of nerve fiber layer thickness measurements in patients with glaucoma and without glaucoma using spectral-domain and time-domain OCT.

BACKGROUND: The aim of this work is to assess the repeatability of spectral-domain-OCT (SD-OCT) retinal nerve fiber layer thickness (RNFL) thickness measurements in a non-glaucoma group and patients with glaucoma and to compare these results to conventional time-domain-OCT (TD-OCT). METHODS: In a prospective, comparative, observational case-control study, 50 eyes of 25 non-glaucoma and 22 eyes of 11 patients with primary open angle glaucoma (POAG) were included. SD-OCT and TD-OCT circle scans were centered on the optic disc. In each eye, OCT scans were performed three times by two independent observers. RNFL thickness was measured in four quadrants around the optic disc. In addition, the overall mean RNFL thickness was assessed. Intraclass correlation coefficients (ICC) and coefficients of variation (COV) were calculated. Inter-observer and inter-OCT repeatability was visualized by using Bland-Altman analysis. RESULTS: Intra-observer repeatability for TD- OCT was good with an ICC(mean RNFL thickness) of 0.939 in non-glaucomas and 0.980 in glaucomatous eyes. For SD-OCT, intra-observer repeatability was higher with an ICC of 0.989 for non-glaucomas and 0.997 for glaucomatous eyes. COVs for TD-OCT ranged from 2.9-7.7% in non-glaucomas and from 6.0-13.3% in glaucoma patients. COVs for SD-OCT ranged from 0.3-1% in non-glaucomas and from 0.9-2.3% in glaucomatous eyes. COVs were influenced by various factors. In the glaucoma group, COVs were significantly higher (p < 0.001) compared to the non-glaucoma group. COVs increased by a mean of 5.1% when TD-OCT was used instead of SD-OCT (p < 0.001). CONCLUSIONS: SD-OCT RNFL thickness measurements in healthy volunteers and glaucoma patients showed good intra- and inter-observer repeatability. Especially in glaucomatous eyes, repeatability of SD-OCT was superior to TD-OCT.

Evaluation of filtering blebs using the 'Wuerzburg bleb classification score' compared to clinical findings.

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.

Dynamic contour tonometry: handheld versus slit-lamp-mounted.

PURPOSE: To compare the newly developed handheld dynamic contour tonometer (hh-DCT) with the established slit-lamp-mounted DCT (sl-DCT) in terms of agreement for intraocular pressure (IOP) and ocular pulse amplitude (OPA) measurements, intraobserver variability, and tonography effect. DESIGN: Evaluation of diagnostic technology. PARTICIPANTS: Fifty eyes of 50 healthy volunteers were examined with the hh-DCT and sl-DCT. METHODS: A paired t test was performed to analyze differences in IOP and OPA readings. Measurements were compared for bias and agreement according to the method of Bland and Altman. Intraclass correlation coefficients (ICCs) were calculated to compare intraobserver variability. A mixed model analysis was performed to assess a possible tonography effect. MAIN OUTCOME MEASURES: The differences in IOP and OPA measurements, intraobserver variability, and tonography effect between the hh-DCT and the sl-DCT were examined. RESULTS: No statistically significant differences in IOP (sl-DCT-hh-DCT: 0.1+/-1.43 mmHg, 95% confidence interval [CI], -0.31 to 0.5, P = 0.63) or OPA (sl-DCT-hh-DCT: -0.1+/-0.52 mmHg, 95% CI, -0.28 to 0.01, P = 0.08) measurements were detected. Bland-Altman analysis revealed a bias of 0.1 with the limits of agreement of IOP measurement differences ranging from -2.71 to +2.90 mmHg. With regard to IOP readings obtained by sl-DCT, hh-DCT overestimated IOPs less than 15.6 mmHg and underestimated IOPs more than 15.6 mmHg. ICCs calculated for IOP readings were 0.87 (95% CI, 0.8-0.92) for hh-DCT and 0.85 (95% CI, 0.78-0.90) for sl-DCT. ICCs for OPA readings were 0.86 (95% CI, 0.79-0.91) for hh-DCT and 0.87 (95% CI, 0.8-0.91) for sl-DCT. Comparing the ICCs revealed no statistically significant difference between the devices with regard to IOP and OPA measurements (P = 0.53 and P = 0.93, respectively). Mixed model analysis of 3 consecutive IOP measurements revealed a decrease in IOP of 0.5 mmHg after each measurement in both devices, which was not significant between the 2 methods (P = 0.68). CONCLUSIONS: IOP and OPA readings obtained by the novel hh-DCT were shown to be strongly concordant with measurements obtained by the sl-DCT device. The hh-DCT may be a valuable alternative to the sl-DCT in clinical practice.

[Glaucoma]. / Glaukom - Grüner Star.

Glaucoma is one of the most frequent causes of blindness in the world. Although there are several different subforms of glaucoma, their final common pathway is an atrophy of the optic disc leading to progressive visual field defects and finally total blindness. The loss of function in glaucoma is irreversible, i.e. early detection of the disease is the most important part of its therapy. Early detection, however, requires improved knowledge about the disease in the general population and the active help of all general practitioners, explaining their patients the insidious nature of the disease.

Neuronal cell cycle re-entry mediates Alzheimer disease-type changes.

Evidence showing the ectopic re-expression of cell cycle-related proteins in specific vulnerable neuronal populations in Alzheimer disease led us to formulate the hypothesis that neurodegeneration, like cancer, is a disease of inappropriate cell cycle control. To test this notion, we used adenoviral-mediated expression of c-myc and ras oncogenes to drive postmitotic primary cortical neurons into the cell cycle. Cell cycle re-entry in neurons was associated with increased DNA content, as determined using BrdU and DAPI, and the re-expression of cyclin B1, a marker for the G2/M phase of the cell cycle. Importantly, we also found that cell cycle re-entry in primary neurons leads to tau phosphorylation and conformational changes similar to that seen in Alzheimer disease. This study establishes that the cell cycle can be instigated in normally quiescent neuronal cells and results in a phenotype that shares features of degenerative neurons in Alzheimer disease. As such, our neuronal cell model may be extremely valuable for the development of novel therapeutic strategies.

ITK and RLK Inhibitor PRN694 Improves Skin Disease in Two Mouse Models of Psoriasis.

The chronic and highly prevalent skin disorder psoriasis vulgaris is characterized by a hyperproliferative epidermis and aberrant immune activity. Many studies have highlighted the role of differentiated T lymphocytes in psoriasis progression. Several biologics are currently available that target proinflammatory cytokines produced by T lymphocytes, but the need for improved therapies persists. The small molecule PRN694 covalently binds ITK and RLK, two Tec kinases activated downstream of T-lymphocyte activation, both of which are up-regulated in psoriatic skin. These Tec kinases are involved in signaling cascades mediating T-lymphocyte proliferation, differentiation, and migration and proinflammatory cytokine production. In vitro analysis showed that PRN694 effectively inhibited IL-17A production from murine T helper type 17-differentiated T lymphocytes. Additionally, PRN694 effectively reduced the psoriasis-like phenotype severity and reduced epidermal proliferation and thickness in both the Rac1V12 and imiquimod mouse models of psoriasis. PRN694 also inhibited CD3+ T-cell and γδ T-cell infiltration into skin regions. Inhibition of ITK and RLK attenuated psoriasis-associated signaling pathways, indicating that PRN694 is an effective psoriasis therapeutic.