Anoush Shahidzadeh

Quantifying Microvascular Density and Morphology in Diabetic Retinopathy Using Spectral-Domain Optical Coherence Tomography Angiography.

Purpose To quantify changes in retinal microvasculature in diabetic retinopathy (DR) by using spectral-domain optical coherence tomography angiography (SD-OCTA). Methods Retrospective, cross-sectional, observational study of healthy and diabetic adult subjects with and without DR. Retinal microvascular changes were assessed by using SD-OCTA images and an intensity-based optical microangiography algorithm. A semiautomated program was used to calculate indices of microvascular density and morphology in nonsegmented and segmented SD-OCTA images. Microvascular density was quantified by using skeleton density (SD) and vessel density (VD), while vessel morphology was quantified as fractal dimension (FD) and vessel diameter index (VDI). Statistical analyses were performed by using the Students t-test or analysis of variance with post hoc Tukey honest significant difference tests for multiple comparisons. Results Eighty-four eyes with DR and 14 healthy eyes were studied. Spearmans rank test demonstrated a negative correlation between DR severity and SD, VD, and FD, and a positive correlation with VDI (ρ = −0.767, −0.7166, −0.768, and +0.5051, respectively; P < 0.0001). All parameters showed high reproducibility between graders (ICC = 0.971, 0.962, 0.937, and 0.994 for SD, VD, FD, and VDI, respectively). Repeatability (κ) was greater than 0.99 for SD, VD, FD, and VDI. Conclusions Vascular changes in DR can be objectively and reliably characterized with SD, VD, FD, and VDI. In general, decreasing capillary density (SD and VD), branching complexity (FD), and increasing average vascular caliber (VDI) were associated with worsening DR. Changes in capillary density and morphology were significantly correlated with diabetic macular edema.

Nanoscale liposomal formulation of a SYK P-site inhibitor against B-precursor leukemia

We report preclinical proof of principle for effective treatment of B-precursor acute lymphoblastic leukemia (ALL) by targeting the spleen tyrosine kinase (SYK)-dependent antiapoptotic blast cell survival machinery with a unique nanoscale pharmaceutical composition. This nanoscale liposomal formulation (NLF) contains the pentapeptide mimic 1,4-Bis (9-O dihydroquinidinyl) phthalazine/hydroquinidine 1,4-phathalazinediyl diether (C61) as the first and only selective inhibitor of the substrate binding P-site of SYK. The C61 NLF exhibited a very favorable pharmacokinetic and safety profile in mice, induced apoptosis in primary B-precursor ALL blast cells taken directly from patients as well as in vivo clonogenic ALL xenograft cells, destroyed the in vivo clonogenic fraction of ALL blast cells, and, at nontoxic dose levels, exhibited potent in vivo antileukemic activity against patient-derived ALL cells in xenograft models of aggressive B-precursor ALL. Our findings establish SYK as an attractive molecular target for therapy of B-precursor ALL. Further development of the C61 NLF may provide the foundation for therapeutic innovation against therapy-refractory B-precursor ALL.

CD19-antigen specific nanoscale liposomal formulation of a SYK P-site inhibitor causes apoptotic destruction of human B-precursor leukemia cells

We report the anti-leukemic potency of a unique biotargeted nanoscale liposomal nanoparticle (LNP) formulation of the spleen tyrosine kinase (SYK) P-site inhibitor C61. C61-loaded LNP were decorated with a murine CD19-specific monoclonal antibody directed against radiation-resistant CD19-receptor positive aggressive B-precursor acute lymphoblastic leukemia (ALL) cells. The biotargeted C61-LNP were more potent than untargeted C61-LNP and consistently caused apoptosis in B-precursor ALL cells. The CD19-directed C61-LNP also destroyed B-precursor ALL xenograft cells and their leukemia-initiating in vivo clonogenic fraction. This unique nanostructural therapeutic modality targeting the SYK-dependent anti-apoptotic blast cell survival machinery shows promise for overcoming the clinical radiochemotherapy resistance of B-precursor ALL cells.

Constitutive Function of the Ikaros Transcription Factor in Primary Leukemia Cells from Pediatric Newly Diagnosed High-Risk and Relapsed B-precursor ALL Patients

We examined the constitutive function of the Ikaros (IK) transcription factor in blast cells from pediatric B-precursor acute lymphoblastic leukemia (BPL) patients using multiple assay platforms and bioinformatics tools. We found no evidence of diminished IK expression or function for primary cells from high-risk BPL patients including a Philadelphia chromosome (Ph)+ subset. Relapse clones as well as very aggressive in vivo clonogenic leukemic B-cell precursors isolated from spleens of xenografted NOD/SCID mice that developed overt leukemia after inoculation with primary leukemic cells of patients with BPL invariably and abundantly expressed intact IK protein. These results demonstrate that a lost or diminished IK function is not a characteristic feature of leukemic cells in Ph+ or Ph- high-risk BPL.

Quantitative microvascular analysis of retinal venous occlusions by spectral domain optical coherence tomography angiography

Purpose To quantitatively evaluate the retinal microvasculature in human subjects with retinal venous occlusions (RVO) using optical coherence tomography angiography (OCTA). Design Retrospective, cross-sectional, observational case series. Participants Sixty subjects (84 eyes) were included (20 BRVO, 14 CRVO, 24 unaffected fellow eyes, and 26 controls). Methods OCTA was performed on a prototype, spectral domain-OCTA system in the 3x3mm central macular region. Custom software was used to quantify morphology and density of retinal capillaries using four quantitative parameters. The vasculature of the segmented retinal layers and nonsegmented whole retina were analyzed. Main outcome measures Fractal dimension (FD), vessel density (VD), skeletal density (SD), and vessel diameter index (VDI) within the segmented retinal layers and nonsegmented whole retina vasculature. Results Nonsegmented analysis of RVO eyes demonstrated significantly lower FD (1.64±0.01 vs 1.715±0.002; p<0.001), VD (0.32±0.01 vs 0.432±0.002; p<0.001), and SD (0.073±0.004 vs 0.099±0.001; p<0.001) compared to controls. Compared to the fellow eye, FD, VD and SD were lower (p<0.001), and VDI was higher (p<0.001). FD, VD, and SD progressively decreased as the extent (or type) of RVO increased (control vs BRVO vs CRVO; p<0.001). In the unaffected fellow eye FD, VD and SD showed significant differences when compared to control eyes or affected RVO eyes (p<0.001). Conclusions Quantitative OCTA of the central 3x3mm macular region demonstrates significant differences in capillary density and morphology among subjects with BRVO and CRVO compared to controls or unaffected fellow eyes in all vascular layers. The unaffected fellow eyes also demonstrate significant differences when compared to controls. OCTA allows for noninvasive, layer-specific, quantitative evaluation of RVO-associated microvascular changes.

Utility of optical coherence tomography angiography in detecting glaucomatous damage in a uveitic patient with disc congestion: A case report

Purpose To report a case of uveitic glaucoma with a congested optic disc where optical coherence tomography angiography (OCT-A) provided diagnostic utility in assessing glaucomatous damage but optical coherence tomography (OCT) alone had limited utility. Observations We report a case of a 33-year-old Caucasian female referred to the USC Roski Eye Institute for uncontrolled intraocular pressure (IOP) in the left eye. She was managed by an outside provider for 6 months, where her IOP ranged from 28 to 42 mm Hg in the left eye on maximally tolerated medical therapy. Her clinical exam was consistent with Herpes family trabeculitis, optic nerve congestion, and possible glaucomatous damage. Initial evaluation of the optic nerve by standard modalities (fundus exam and OCT) was limited by optic nerve congestion; however, OCT-A showed peripapillary hypoperfusion, as commonly observed in glaucomatous eyes. She underwent aqueous shunt implantation for elevated IOPs poorly controlled by medications. Conclusions and importance OCT-A can be a useful tool in the evaluation of glaucoma in instances where disc congestion masks both nerve excavation and retinal nerve fiber thinning normally seen on exam and on standard OCT of the optic nerve.

Widefield OCT Findings of a Patient With Stellate Nonhereditary Idiopathic Foveomacular Retinoschisis

The authors report extensive peripheral retinoschisis in a patient with stellate nonhereditary idiopathic foveomacular retinoschisis (SNIFR) detected by widefield optical coherence tomography (OCT). A 64-year-old woman diagnosed with foveomacular retinoschisis 3 years prior presented for evaluation after being seen by multiple other retina specialists. Standard macular spectral-domain OCT (6 mm) revealed typical foveomacular schisis involving only the outer retina. However, widefield OCT (12 mm) revealed diffuse bilateral retinoschisis involving both inner and outer retinal layers in the macula and midperiphery. Widefield imaging is important to evaluate and monitor complex peripheral retinoschisis that may be otherwise undetectable using conventional techniques. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:774-777.].