Self-Recording of Eye Movements in Amyotrophic Lateral Sclerosis Patients Using a Smartphone Eye-Tracking App.

Introduction: Amyotrophic lateral sclerosis (ALS) can affect various eye movements, making eye tracking a potential means for disease monitoring. In this study, we evaluated the feasibility of ALS patients self-recording their eye movements using the "EyePhone," a smartphone eye-tracking application. Methods: We prospectively enrolled ten participants and provided them with an iPhone equipped with the EyePhone app and a PowerPoint presentation with step-by-step recording instructions. The goal was for the participants to record their eye movements (saccades and smooth pursuit) without the help of the study team. Afterward, a trained physician administered the same tests using video-oculography (VOG) goggles and asked the participants to complete a questionnaire regarding their self-recording experience. Results: All participants successfully completed the self-recording process without assistance from the study team. Questionnaire data indicated that participants viewed self-recording with EyePhone favorably, considering it easy and comfortable. Moreover, 70% indicated that they prefer self-recording to being recorded by VOG goggles. Conclusion: With proper instruction, ALS patients can effectively use the EyePhone to record their eye movements, potentially even in a home environment. These results demonstrate the potential for smartphone eye-tracking technology as a viable and self-administered tool for monitoring disease progression in ALS, reducing the need for frequent clinic visits.

Quantifying Induced Nystagmus Using a Smartphone Eye Tracking Application (EyePhone).

BACKGROUND: There are ≈5 million annual dizziness visits to US emergency departments, of which vestibular strokes account for over 250 000. The head impulse, nystagmus, and test of skew eye examination can accurately distinguish vestibular strokes from peripheral dizziness. However, the eye-movement signs are subtle, and lack of familiarity and difficulty with recognition of abnormal eye movements are significant barriers to widespread emergency department use. To break this barrier, we sought to assess the accuracy of EyePhone, our smartphone eye-tracking application, for quantifying nystagmus. METHODS AND RESULTS: We prospectively enrolled healthy volunteers and recorded the velocity of induced nystagmus using a smartphone eye-tracking application (EyePhone) and then compared the results with video oculography (VOG). Following a calibration protocol, the participants viewed optokinetic stimuli with incremental velocities (2-12 degrees/s) in 4 directions. We extracted slow phase velocities from EyePhone data in each direction and compared them with the corresponding slow phase velocities obtained by the VOG. Furthermore, we calculated the area under the receiver operating characteristic curve for nystagmus detection by EyePhone. We enrolled 10 volunteers (90% men) with an average age of 30.2±6 years. EyePhone-recorded slow phase velocities highly correlated with the VOG recordings (r=0.98 for horizontal and r=0.94 for vertical). The calibration significantly increased the slope of linear regression for horizontal and vertical slow phase velocities. Evaluating the EyePhone's performance using VOG data with a 2 degrees/s threshold showed an area under the receiver operating characteristic curve of 0.87 for horizontal and vertical nystagmus detection. CONCLUSIONS: We demonstrated that EyePhone could accurately detect and quantify optokinetic nystagmus, similar to the VOG goggles.

Lessons from (S)-6-(1-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline (PF-04254644), an inhibitor of receptor tyrosine kinase c-Met with high protein kinase selectivity but broad phosphodiesterase family inhibition leading to myocardial degeneration in rats.

The hepatocyte growth factor (HGF)/c-Met signaling axis is deregulated in many cancers and plays important roles in tumor invasive growth and metastasis. An exclusively selective c-Met inhibitor (S)-6-(1-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline (8) was discovered from a highly selective high-throughput screening hit via structure-based drug design and medicinal chemistry lead optimization. Compound 8 had many attractive properties meriting preclinical evaluation. Broad off-target screens identified 8 as a pan-phosphodiesterase (PDE) family inhibitor, which was implicated in a sustained increase in heart rate, increased cardiac output, and decreased contractility indices, as well as myocardial degeneration in in vivo safety evaluations in rats. Compound 8 was terminated as a preclinical candidate because of a narrow therapeutic window in cardio-related safety. The learning from multiparameter lead optimization and strategies to avoid the toxicity attrition at the late stage of drug discovery are discussed.

Discovery of a novel class of exquisitely selective mesenchymal-epithelial transition factor (c-MET) protein kinase inhibitors and identification of the clinical candidate 2-(4-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)-1H-pyrazol-1-yl)ethanol (PF-04217903) for the treatment of cancer.

The c-MET receptor tyrosine kinase is an attractive oncology target because of its critical role in human oncogenesis and tumor progression. An oxindole hydrazide hit 6 was identified during a c-MET HTS campaign and subsequently demonstrated to have an unusual degree of selectivity against a broad array of other kinases. The cocrystal structure of the related oxindole hydrazide c-MET inhibitor 10 with a nonphosphorylated c-MET kinase domain revealed a unique binding mode associated with the exquisite selectivity profile. The chemically labile oxindole hydrazide scaffold was replaced with a chemically and metabolically stable triazolopyrazine scaffold using structure based drug design. Medicinal chemistry lead optimization produced 2-(4-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)-1H-pyrazol-1-yl)ethanol (2, PF-04217903), an extremely potent and exquisitely selective c-MET inhibitor. 2 demonstrated effective tumor growth inhibition in c-MET dependent tumor models with good oral PK properties and an acceptable safety profile in preclinical studies. 2 progressed to clinical evaluation in a Phase I oncology setting.

Sensitivity of selected human tumor models to PF-04217903, a novel selective c-Met kinase inhibitor.

The c-Met pathway has been implicated in a variety of human cancers for its critical role in tumor growth, invasion, and metastasis. PF-04217903 is a novel ATP-competitive small-molecule inhibitor of c-Met kinase. PF-04217903 showed more than 1,000-fold selectivity for c-Met compared with more than 150 kinases, making it one of the most selective c-Met inhibitors described to date. PF-04217903 inhibited tumor cell proliferation, survival, migration/invasion in MET-amplified cell lines in vitro, and showed marked antitumor activity in tumor models harboring either MET gene amplification or a hepatocyte growth factor (HGF)/c-Met autocrine loop at well-tolerated dose levels in vivo. Antitumor efficacy of PF-04217903 was dose-dependent and showed a strong correlation with inhibition of c-Met phosphorylation, downstream signaling, and tumor cell proliferation/survival. In human xenograft models that express relatively high levels of c-Met, complete inhibition of c-Met activity by PF-04217903 only led to partial tumor growth inhibition (38%-46%) in vivo. The combination of PF-04217903 with Recepteur d'origine nantais (RON) short hairpin RNA (shRNA) knockdown in the HT29 model that also expresses activated RON kinase-induced tumor cell apoptosis and resulted in enhanced antitumor efficacy (77%) compared with either PF-04217903 (38%) or RON shRNA alone (56%). PF-04217903 also showed potent antiangiogenic properties in vitro and in vivo. Furthermore, PF-04217903 strongly induced phospho-PDGFRß (platelet-derived growth factor receptor) levels in U87MG xenograft tumors, indicating a possible oncogene switching mechanism in tumor cell signaling as a potential resistance mechanism that might compromise tumor responses to c-Met inhibitors. Collectively, these results show the use of highly selective inhibition of c-Met and provide insight toward targeting tumors exhibiting different mechanisms of c-Met dysregulation.