Combination phacoemulsification and pars plana vitrectomy for retinal reattachment surgery in the Siberian Husky breed.

OBJECTIVE: To report the success rate and complications of combined phacoemulsification and pars plana vitrectomy (PPV) for treatment of cataracts and retinal detachment in the Siberian Husky breed. ANIMALS STUDIED: Client-owned Siberian Husky dogs that underwent combined phacoemulsification and PPV at two veterinary referral centers. PROCEDURE: Retrospective study of 16 Siberian Husky dogs that underwent combined phacoemulsification and PPV with a minimum 3-month postoperative follow-up. Signalment and preoperative ophthalmic examination findings, intraoperative findings, and postoperative visual status and complications were recorded. Functional success was defined as the maintenance or restoration of vision. RESULTS: Seventeen eyes of 16 dogs were evaluated. Immediate postoperative anatomic success was achieved in all 17 eyes (100%), with functional success through the last known follow-up examination achieved in 88.2% of operated eyes (15/17). The most common postoperative complication was silicone oil migration into the anterior chamber (AC-SiO migration), occurring in 47.1% of eyes (8/17), followed by corneal endothelial decompensation and glaucoma each occurring in 17.6% of eyes (3/17). CONCLUSIONS: Combined phacoemulsification and PPV is a viable option in Siberian Husky dogs with cataracts and preoperative retinal detachment. Visual success was achieved in 88.2% of eyes, with the most common postoperative complication being AC-SiO migration.

Lamellar Keratoplasty Using Acellular Bioengineering Cornea (BioCorneaVetTM) for the Treatment of Feline Corneal Sequestrum: A Retrospective Study of 62 Eyes (2018-2021).

To retrospectively evaluate the effectiveness and outcome of lamellar keratoplasty using acellular bioengineering cornea (BioCorneaVetTM) for the treatment of feline corneal sequestrum (FCS). The medical records of cats diagnosed with FCS that underwent lamellar keratoplasty with BioCorneaVetTM between 2018 and 2021 with a minimum of 3 months of follow-up were reviewed. Follow-up examinations were performed weekly for 3 months, and then optical coherence tomography (OCT) examination was performed on select patients at 0, 3, 6, and 12 months post-operatively. A total of 61 cats (30 left eyes and 32 right eyes) were included. The Persian breed was overrepresented, 48/61 (78.69%). Four different thicknesses of acellular bioengineering cornea were used (200, 300, 400, or 450 microns), and the mean graft size was 8.23 mm (range, 5.00-12.00 mm). Minor complications were composed of partial dehiscence, and protrusion of the graft occurred in 7/62 eyes (11.29%). The median postoperative follow-up was 12.00 months (range, 3-41 months). A good visual outcome was achieved in 60/62 eyes (96.77%), and a mild to moderate corneal opacification occurred in 2/62 (3.23%). No recurrence of corneal sequestrum was observed. From the results, lamellar keratoplasty using acellular bioengineering cornea (BioCorneaVetTM) is an effective treatment for FCS, providing a good tectonic support and natural collagen framework, and resulting in satisfactory visual and cosmetic effects.

Discovery of the Selective Protein Kinase C-θ Kinase Inhibitor, CC-90005.

The PKC-θ isoform of protein kinase C is selectively expressed in T lymphocytes and plays an important role in the T cell antigen receptor (TCR)-triggered activation of mature T cells, T cell proliferation, and the subsequent release of cytokines such as interleukin-2 (IL-2). Herein, we report the synthesis and structure-activity relationship (SAR) of a novel series of PKC-θ inhibitors. Through a combination of structure-guided design and exploratory SAR, suitable replacements for the basic C4 amine of the original lead (3) were identified. Property-guided design enabled the identification of appropriately substituted C2 groups to afford potent analogs with metabolic stability and permeability to support in vivo testing. With exquisite general kinase selectivity, cellular inhibition of T cell activation as assessed by IL-2 expression, a favorable safety profile, and demonstrated in vivo efficacy in models of acute and chronic T cell activation with oral dosing, CC-90005 (57) was selected for clinical development.

Long-term results (>1 year) in 19 dogs treated with MicroPulse transscleral diode cyclophotocoagulation for refractory glaucoma.

OBJECTIVE: To report the long-term (>1 year) outcome of MicroPulse transscleral diode cyclophotocoagulation (MP-TSCP) in dogs. ANIMALS STUDIED: Client owned dogs that underwent MP-TSCP at a veterinary referral center. PROCEDURE: Retrospective study of 19 dogs treated with MP-TSCP. Dogs were evaluated at a median follow-up time of 30.5 months postoperatively. Reported outcomes were intraocular pressure (IOP), retention or loss of vision, number of medications, and additional procedures performed. Variables associated with time to treatment failure were evaluated. RESULTS: Data from 19 dogs (24 eyes) was available. Median laser settings employed were 140 s and 2200 mW at 31.3% duty cycle. Long-term postoperative IOP was lower than preoperative IOP values (14 mmHg (IQR = 22 mmHg, range: 4-52 mmHg) versus 30 mmHg (IQR = 31 mmHg, range: 8-62 mmHg), respectively). Laser settings >2000 mW were associated with a significantly longer time to reported failure. MP-TSCP was the sole therapy performed in 16/24 eyes resulting in long-term IOP control in 13/24 eyes and retention of vision in 6 of the 14 sighted eyes. Repeat MP-TSCP was performed in 10/24 eyes. Eight of 24 eyes required additional procedures with long-term IOP control in 4/8 eyes. CONCLUSIONS: MicroPulse transscleral diode cyclophotocoagulation can be an effective treatment for refractory glaucoma in select cases. Higher laser settings increased time to reported failure, whereas age, glaucoma type, and preoperative IOP did not affect survival. MP-TSCP as sole therapy or coupled with additional glaucoma procedures controlled the IOP in 70% of cases.

Presumed neuroprotective therapies prescribed by veterinary ophthalmologists for canine degenerative retinal and optic nerve diseases.

OBJECTIVE: To investigate veterinary ophthalmologists' use of presumed neuroprotective therapies for degenerative retinal and optic nerve diseases in dogs. PROCEDURES: An online survey was sent to 663 board-certified veterinary ophthalmologists who were Diplomates of the American College of Veterinary Ophthalmologists (ACVO), Asian College of Veterinary Ophthalmologists (AiCVO), Latin American College of Veterinary Ophthalmologists (Colegio Latinoamericano de Oftalmólogos Veterinarios, CLOVE), or European College of Veterinary Ophthalmologists (ECVO). The survey was created using Qualtrics® software and focused on the prescription of presumed neuroprotective treatments for canine glaucoma, sudden acquired retinal degeneration syndrome (SARDS), progressive retinal atrophy (PRA), and retinal detachment (RD). RESULTS: A total of 165 completed surveys were received, representing an overall response rate of 25%, which was comparable across the four specialty colleges. Of all respondents, 140/165 (85%) prescribed some form of presumed neuroprotective therapies at least once in the last five years: 114/165 (69%) for glaucoma, 51/165 (31%) for SARDS, 116/165 (70%) for PRA, and 50/165 (30%) for RD. The three most recommended neuroprotective reagents were the commercial Ocu-GLO™ Vision Supplement for animals, amlodipine, and human eye supplements. CONCLUSIONS: Despite lack of published clinical efficacy data, the majority of surveyed board-certified veterinary ophthalmologists previously prescribed a presumed neuroprotective therapy at least once in the last five years in dogs with degenerative retinal and optic nerve diseases.

CC-90009: A Cereblon E3 Ligase Modulating Drug That Promotes Selective Degradation of GSPT1 for the Treatment of Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is marked by significant unmet clinical need due to both poor survival and high relapse rates where long-term disease control for most patients with relapsed or refractory AML remain dismal. Inspired to bring novel therapeutic options to these patients, we envisioned protein degradation as a potential therapeutic approach for the treatment of AML. Following this course, we discovered and pioneered a novel mechanism of action which culminated in the discovery of CC-90009. CC-90009 represents a novel protein degrader and the first cereblon E3 ligase modulating drug to enter clinical development that specifically targets GSPT1 (G1 to S phase transition 1) for proteasomal degradation. This manuscript briefly summarizes the mechanism of action, scientific rationale, medicinal chemistry, pharmacokinetic properties, and efficacy data for CC-90009, which is currently in phase 1 clinical development.

Prophylactic anti-glaucoma therapy in dogs with primary glaucoma: A practitioner survey of current medical protocols.

AIM: To examine the use of prophylactic anti-glaucoma medications in the normotensive fellow eye in dogs with unilateral overt primary glaucoma by veterinary ophthalmology clinicians. METHODS: A survey of veterinary ophthalmology clinicians was distributed over two international list serves servicing veterinary ophthalmologists, trainees, and individuals whose practice consisted primarily of ophthalmic patients. The survey was developed following analysis of historical and currently available medical options for control of intraocular pressure and for neuroprotection. RESULTS: Responses from 199 veterinary ophthalmology clinicians were evaluated. While a large variety of topical anti-hypertensive drugs and protocols were used, the most commonly used medications were aqueous humor production suppressors such as dorzolamide 2.0% ophthalmic solution, timolol 0.5% ophthalmic solution, and a combination product containing both drugs. Latanoprost 0.005% ophthalmic solution was used infrequently for prophylaxis by comparison. The majority of respondents do not use concurrent anti-inflammatory medications (61.22%), although a sizeable minority used prednisolone acetate, dexamethasone, or ketorolac as prophylactic treatment. Systemically administered ocular anti-hypertensive agents were rarely used. Only 40% of respondents used neuroprotectant agents; the most commonly prescribed were the calcium channel blocker amlodipine and the nutraceutical Ocu-Glo™. Recommended intervals between re-examination by the clinician ranged from one month to one year, with most re-evaluations occurring every 3 to 6 months. The majority of respondents recommended more frequent assessments of IOP at intervals between once monthly and once every 3 months. CONCLUSIONS: Data analysis of medical therapy for the normotensive fellow eye of dogs previously diagnosed with primary glaucoma suggests that there is a great need for well-designed, prospective, controlled, multi-center studies to determine which protocols have the greatest efficacy in delaying an overt attack in the previously normotensive eye in dogs with a genetic predisposition to glaucoma. Prospective studies utilizing a carbonic anhydrase inhibitor such as dorzolamide and a prostaglandin analogue such as latanoprost would be reasonable as these two drugs are widely used in the treatment of overt glaucoma and would allow for an exploration of the impact of different mechanisms of action of lowering IOP on the pathophysiology of primary glaucoma.

Preliminary report of postoperative complications of phacoemulsification in Pugs: A multicenter retrospective study of 32 cases.

OBJECTIVE: To compare complication rates and visual outcomes following phacoemulsification in Pugs versus dogs of other breeds. ANIMALS STUDIED: Thirty-two pure-bred Pugs (55 eyes) and 32 dogs of other breeds (56 eyes) undergoing phacoemulsification. PROCEDURES: Multi-institutional retrospective medical record review of perioperative factors, postoperative complications, and visual outcomes. The reference population of dogs of varying breeds included surgical cases following each Pug case at the same institutions. Perioperative risk factors and postoperative complication rates were compared between the two populations. RESULTS: Pigmentary keratitis and diabetes mellitus were the most common preoperative comorbidities, found in 75% (P < .001) and 72% (P = .12) of Pugs, respectively. No perioperative factors were significantly associated with postoperative complications in Pugs. Postoperative complication rates were similar between groups; however, the most common complication in Pugs was corneal ulceration (15% of operated eyes), whereas glaucoma was most common in the reference population (13% of operated eyes). Three months postoperatively, vision was preserved in 91% of eyes of Pugs (50/55) and 95% of the reference population (53/56). One year postoperatively, 80% (32/40) of Pug eyes and 82% (28/34) of eyes in the reference population remained sighted. CONCLUSIONS: Comorbidities and complications of cataract surgery in Pugs of this study demonstrate a predisposition for corneal disease. This highlights the importance of preoperative evaluation of factors associated with PK and corneal clarity, and postoperative monitoring for corneal ulceration in this breed.

Corneal hypoesthesia, aqueous tear deficiency, and neurotrophic keratopathy following micropulse transscleral cyclophotocoagulation in dogs.

OBJECTIVE: To describe ocular surface complications following micropulse transscleral cyclophotocoagulation (MP-TSCPC) in dogs. ANIMALS STUDIED: Eighteen dogs treated with MP-TSCPC at two institutions for glaucoma management. PROCEDURES: MP-TSCPC was applied to each eye (avoiding 3 and 9 o'clock positions) with 31.3% duty cycle, 2000-3000 mW energy, and 90-180 seconds duration per hemisphere. Central corneal tactile sensation (CTS) and Schirmer tear test-1 (STT-1) were measured at baseline and ≥2 post-operative visits in each dog. RESULTS: Corneal sensitivity decreased in 16/18 dogs (89%) by an average of 10%-42% (up to 100% in 4 dogs). CTS decline was rapid (≤1 week) and only fully recovered in 50% of dogs within 8-180 days. Patients' age, glaucoma duration, laser energy, and total energy delivered did not affect CTS at any visit. However, brachycephalic dogs had significantly lower CTS and likelihood to recover full sensation compared with nonbrachycephalic dogs. Aqueous tear deficiency (STT-1 < 15 mm/min) occurred in 8/18 dogs (44%) within 7-270 days, and concurrent signs of keratoconjunctivitis sicca were noted in 2/18 dogs (11%). Neurotrophic corneal ulcers developed in 6/18 dogs (33.3%) and required 16-53 days to heal. CONCLUSIONS: Corneal hypoesthesia is a common complication of MP-TSCPC in dogs, and can lead to serious adverse effects such as aqueous tear deficiency and neurotrophic corneal ulcers. Brachycephalic dogs represent a population at higher risk. Close monitoring of ocular surface health is recommended for months following MP-TSCPC in dogs.

The future of canine glaucoma therapy.

Canine glaucoma is a group of disorders that are generally associated with increased intraocular pressure (IOP) resulting in a characteristic optic neuropathy. Glaucoma is a leading cause of irreversible vision loss in dogs and may be either primary or secondary. Despite the growing spectrum of medical and surgical therapies, there is no cure, and many affected dogs go blind. Often eyes are enucleated because of painfully high, uncontrollable IOP. While progressive vision loss due to primary glaucoma is considered preventable in some humans, this is mostly not true for dogs. There is an urgent need for more effective, affordable treatment options. Because newly developed glaucoma medications are emerging at a very slow rate and may not be effective in dogs, work toward improving surgical options may be the most rewarding approach in the near term. This Viewpoint Article summarizes the discussions and recommended research strategies of both a Think Tank and a Consortium focused on the development of more effective therapies for canine glaucoma; both were organized and funded by the American College of Veterinary Ophthalmologists Vision for Animals Foundation (ACVO-VAF). The recommendations consist of (a) better understanding of disease mechanisms, (b) early glaucoma diagnosis and disease staging, (c) optimization of IOP-lowering medical treatment, (d) new surgical therapies to control IOP, and (e) novel treatment strategies, such as gene and stem cell therapies, neuroprotection, and neuroregeneration. In order to address these needs, increases in research funding specifically focused on canine glaucoma are necessary.

Bilateral phacoemulsification and intraocular lens implantation in a young African lion (Panthera leo).

An 18-month-old intact female lioness (Panthera leo) was referred to the Clinica Veterinaria Roma Sud for evaluation of bilateral cataracts. Phacoemulsification and implantation of +30 diopter intraocular lens (IOL) were performed bilaterally. Seven years after surgery, the IOL remained centrally positioned and the patient had normal activity.

Phaco-émulsification bilatérale et implantation d'une lentille intra-oculaire chez une jeune lionne africaine (Panthera leo) . Une lionne entière âgée de 18 mois (Panthera leo) a été dirigée à la Clinica Veterinaria Roma Sud pour l'évaluation de cataractes bilatérales. La phaco-émulsification et l'implantation de lentilles intraoculaires dioptriques +30 (LID) ont été réalisées bilatéralement. Sept années après la chirurgie, les LID sont demeurées en position centrale et la patiente s'adonnait à des activités normales.(Traduit par Isabelle Vallières).

Preliminary findings in 30 dogs treated with micropulse transscleral cyclophotocoagulation for refractory glaucoma.

OBJECTIVE: The purpose of this study was to report the preliminary results of a novel micropulse transscleral diode laser cyclophotocoagulation (MP-TSCP) as primary therapy for glaucomatous dogs. ANIMAL STUDIED: Client owned dogs undergoing MP-TSCP therapy at a veterinary referral center. PROCEDURE: Retrospective study of dogs with glaucoma that were treated with MP-TSCP with a minimum of 1 month (range: 1-18 months) of follow-up. Reported outcomes were intraocular pressure (IOP), treatment parameters, reduction in medications, complications, and incidence of repeat therapy. RESULTS: Thirty dogs (35 eyes) were evaluated. The mean age was 9.0 years. Mean preoperative IOP was 34.5 mm Hg. Mean postoperative IOP at 1 month (35/35 eyes) was 22 mm Hg, 2 months (26/35 eyes) was 20.5 mm Hg, 4 months (20/35 eyes) was 19 mm Hg, 6 months (10/35 eyes) was 19 mm Hg, 12 months (8/35 eyes) was 21 mm Hg. First treatment success rate was 19/35 eyes (54.3%). Repeat laser was performed in 11 eyes with 4/11 eyes responding favorably for a total IOP control of 23/35 eyes (65.7%). Mean energy levels employed were 137.5 seconds and 2351 mW at 31.3% duty cycle. Reduction in medications was from a mean of 3.6 medications preoperatively to 3.1 medications postoperatively. Complications included corneal ulcers 5/35 eyes (14.3%), uncontrolled IOP in 12/35 eyes (34.3%) and repeat treatment in 11/35 eyes (31.4%). CONCLUSIONS: MP-TSCP was successful in controlling IOP in most patients as well as to reduce postoperative medications with minimal resultant intraocular inflammation and complications. The micropulse procedure also can be repeated. Future investigations to study effective treatment parameters are warranted in a larger series of patients over a longer period of evaluation.

Sudden acquired retinal degeneration in dogs: breed distribution of 495 canines.

PURPOSE: The purpose of this study was to describe breed, age, gender, and weight distribution of dogs affected with sudden acquired retinal degeneration (SARD) and to investigate whether SARD is more common in small breed dogs. METHODS: Medical records of dogs diagnosed with SARD confirmed by an electroretinogram were reviewed. Breed, age, gender, and weight were recorded when available. The same data were obtained for dogs with SARD described in the veterinary literature. RESULTS: Three hundred and two dogs were included from the ophthalmology practices and 193 dogs from the veterinary literature. Sixty breeds were present in the study. Mixed-breed dogs were the most common at 108 dogs (21.8%), followed by the Dachshund (68, 13.7%), Chinese Pug (44, 8.9%), Miniature Schnauzer (39, 7.9%), Maltese (23, 4.6%), Cocker Spaniel (22, 4.4%), Bichon Frise (18, 3.6%), Beagle (16, 3.2%), Brittany (15, 3.0%), and Pomeranian (10, 2.0%). Fifty other breeds were represented by 1-9 dogs each. The median age was 9 years (range = 10 months-16 years). The weight was known for 197 dogs. About 60.9% of dogs were less than 25 pounds, 31.5% were between 25 and 50 pounds, and 7.6% were greater than 50 pounds. Gender was recorded in 393 dogs: 217 female dogs and 176 male dogs. CONCLUSIONS: As previously reported, SARD is most common in middle-aged to older dogs. Smaller dogs of less than 25 pounds appear overrepresented, while large/giant breed dogs of greater than 50 pounds are infrequently diagnosed. In this study, there was no statistical significance between female and male dogs.

The combined use of surgical debulking and diode laser photocoagulation for limbal melanoma treatment: a retrospective study of 21 dogs.

OBJECTIVE: To evaluate effectiveness and safety of debulking and diode laser photocoagulation (DPC) for the treatment of limbal melanoma (LM). PROCEDURE: Retrospective multi-institutional case series. Medical records of animals diagnosed with LM at the Centro Veterinario Specialistico (CVS) and at the Long Island Veterinary Specialists from 1994 to 2014 were retrieved. Signalment, location, extent of tumors, recurrence rate, and early and late complications were reported. Patient follow-up information was obtained from veterinary ophthalmologists, primary care veterinarians, and where appropriate, owners. RESULTS: Twenty-one eyes of 21 dogs (13 females and 8 males) were included in this study. The dogs' average age was 6 years (range: 7 months-11 years). The follow-up period ranged from 1-108 months (median 48 months) after the last DPC procedure. Long-term follow-up was obtained by telephone interviews in 6 of 20 cases and by clinical re-evaluations in 14 of 20 cases. The most common early complications were a moderate anterior uveitis and peripheral corneal edema (21/21 eyes). Late complications included corneal fibrosis and/or pigmentation (20/21). In one case, a severe bullous keratopathy associated with extensive corneal fibrosis was observed (1/21). One case was blind due to concurrent Sudden Acquired Retinal Degeneration (SARD). However, after surgery 2 of 20 eyes lost vision and one of these was enucleated. CONCLUSIONS: Debulking, in addition to diode laser photocoagulation, was technically straightforward to perform, minimally invasive, well tolerated, and highly successful in this case series.

RETROSPECTIVE INVESTIGATION OF CATARACT MANAGEMENT IN AVIAN SPECIES IN A ZOOLOGIC COLLECTION.

A review of avian cataracts at the Wildlife Conservation Society's Bronx Zoo between 1992 and 2011 was conducted. Ninety cataracts in 54 birds from 42 species were identified. Cataracts were found primarily during examination for ocular abnormalities (29/54, 53.7%) or opportunistically (13/54, 24.1%) and were most commonly diagnosed as mature (22/90, 24.4%). Systemic medical conditions diagnosed in these birds included West Nile virus (4/54, 7.4%), head trauma (3/54, 5.6%), plumbism and Salmonella Pullorum (1/54, 1.9%), Marek's disease (1/54, 1.9%), leukocytosis (1/54, 1.9%), and hyperglycemia (1/54, 1.9%). Cataracts were progressive in seven birds of four species. Unilateral enucleation was performed in 2/54 (3.7%) birds, and 12/54 (22.2%) underwent cataract removal (phacoemulsification in 16 eyes and standard extracapsular cataract extraction in 2 eyes). Concurrent ocular abnormalities, such as corneal scarring and lens-induced uveitis, were seen in 2/18 (11.1%) eyes preoperatively in the group undergoing cataract removal, 2/2 (100%) eyes preoperatively in the group undergoing enucleation, and 33/70 (47.1%) of eyes that did not undergo surgery. For birds undergoing cataract removal, complications included successfully treated cardiorespiratory arrest intraoperatively (1/12, 8.3%) as well as postanesthetic complications of acute respiratory distress and tracheal stricture (2/12, 16.7%). The most common postoperative ocular abnormalities included posterior capsular opacity (4/18 eyes, 22.2%) and corneal scarring (2/18 eyes, 11.1%). Lens cortical regrowth and marked posterior lens capsular opacity occurred in one eye of one bird after phacoemulsification, necessitating a second ocular surgery. A successful outcome, as determined by improved postoperative visual acuity, was seen in 10/12 (83.3%) birds undergoing cataract removal, and 5/12 (41.7%) of these birds were alive >3 yr after surgery. The results of this review will aid clinicians in identifying common stages of cataracts, determining eligibility for cataract surgery, and managing postoperative complications in avian patients.

Discovery of mammalian target of rapamycin (mTOR) kinase inhibitor CC-223.

We report here the synthesis and structure-activity relationship (SAR) of a novel series of mammalian target of rapamycin (mTOR) kinase inhibitors. A series of 4,6- or 1,7-disubstituted-3,4-dihydropyrazino[2,3-b]pyrazine-2(1H)-ones were optimized for in vivo efficacy. These efforts resulted in the identification of compounds with excellent mTOR kinase inhibitory potency, with exquisite kinase selectivity over the related lipid kinase PI3K. The improved PK properties of this series allowed for exploration of in vivo efficacy and ultimately the selection of CC-223 for clinical development.

Optimization of a Series of Triazole Containing Mammalian Target of Rapamycin (mTOR) Kinase Inhibitors and the Discovery of CC-115.

We report here the synthesis and structure-activity relationship (SAR) of a novel series of triazole containing mammalian target of rapamycin (mTOR) kinase inhibitors. SAR studies examining the potency, selectivity, and PK parameters for a series of triazole containing 4,6- or 1,7-disubstituted-3,4-dihydropyrazino[2,3-b]pyrazine-2(1H)-ones resulted in the identification of triazole containing mTOR kinase inhibitors with improved PK properties. Potent compounds from this series were found to block both mTORC1(pS6) and mTORC2(pAktS473) signaling in PC-3 cancer cells, in vitro and in vivo. When assessed in efficacy models, analogs exhibited dose-dependent efficacy in tumor xenograft models. This work resulted in the selection of CC-115 for clinical development.

Suture anchor placement technique around the insertion of the ventral rectus muscle for the replacement of the prolapsed gland of the third eyelid in dogs: 100 dogs.

OBJECTIVE: To evaluate a rapid and efficacious procedure to anchor the prolapsed gland of the third eyelid in dogs. METHODS: This is a retrospective study of 100 affected dogs (122 eyes) with third eyelid gland prolapse that were surgically anchored with a nonabsorbable suture around the insertion of the ventral rectus muscle. RESULTS: Hundred dogs (122 eyes) were included in this study. Twenty-three pure-bred and several mixed-breed dogs were represented with the right eye affected in 60 cases and the left eye in 62 cases. Thirty-four eyes (27.9%) were previously operated on at another facility prior to referral. The average age of the patients was 2.2 years (57 days to 11 years). No recurrences of gland prolapse were observed over the course of study. Minor intraoperative conjunctival perforations were observed and easily repaired at the time of the surgery in 21 cases (17.2%). Five cases demonstrated preexistent keratoconjunctivitis sicca (KCS), and all had improved Schirmer tear test following surgical correction and medical therapy. CONCLUSIONS: The suture anchor placement technique provides a cosmetic, rapid, and successful replacement of the prolapsed gland of the third eyelid in dogs. No recurrences were noted. Complications were easily addressed.

Use of core modification in the discovery of CC214-2, an orally available, selective inhibitor of mTOR kinase.

We report here the discovery of a novel series of selective mTOR kinase inhibitors and the identification of CC214-2, a compound with demonstrated anti-tumor activity upon oral dosing in a PC3 prostate cancer xenograft model. A series of 4,6-disubstituted-3,4-dihydropyrazino[2,3-b]pyrazine-2(1H)-ones were discovered through a core modification of our original compound series. Analogs from this series have excellent mTOR potency and maintain selectivity over the related PI3Kα lipid kinase. Compounds such as CC214-2 were found to block both mTORC1(pS6) and mTORC2(pAktS473) signaling in PC3 cancer cells, in vitro and in vivo.

Screening ADAMTS10 in dog populations supports Gly661Arg as the glaucoma-causing variant in beagles.

PURPOSE: Previously, we mapped the disease locus in the beagle model of autosomal recessive primary open angle glaucoma (POAG) to a 4-Mb interval on chromosome 20, and identified a Gly661Arg variant in ADAMTS10 as the candidate disease-causing variant. The purpose of this study was to test the hypothesis that the Gly661Arg variant of ADAMTS10 causes glaucoma by genotyping dogs of various breeds affected and unaffected by primary glaucoma. METHODS: Dogs of various breeds, affected or unaffected with primary glaucoma, were genotyped for the Gly661Arg variant of ADAMTS10, as well as 7 other nonsynonymous single nucleotide polymorphisms (SNPs) in other genes in the beagle POAG locus that segregate with disease. Alternate allele frequencies were calculated with 95% confidence intervals and comparisons made to expected allele frequency relative to disease prevalence or between cases and controls. RESULTS: For the nonsynonymous SNPs other than the ADAMTS10 variant, control dogs were identified that were homozygous for the alternative alleles, ruling out those variants as causative. None of the nonsynonymous SNPs were found associated with primary glaucoma in American cocker spaniels. The Gly661Arg variant of ADAMTS10 was the only variant with minor allele frequency consistent with the prevalence of primary glaucoma in the general beagle population. The only dog found homozygous for the Gly661Arg variant of ADAMTS10 was an affected beagle, unrelated to the POAG colony. CONCLUSIONS: These findings support the Gly661Arg mutation of ADAMTS10 as the likely cause of POAG in beagles.