Abstract Ischemic retinopathies including diabetic retinopathy are major causes of vision loss. Inner blood-retinal barrier (BRB) breakdown with retinal vascular hyperpermeability results in macular edema. Although dysfunction the neurovascular unit neurons, glia, and cells is now understood to underlie this process, there a need for fuller elucidation underlying events BRB ischemic disease, systematic analysis myeloid exploration cellular cross-talk. We used an approach microglia depletion...

Beyond the clinically apparent damage to retinal vasculature, diabetes affects neuroretina and choroid. Nonhuman primates (NHPs) serve as valuable models for human diseases, including diabetic retinopathy. This study aimed investigate changes in thickness of retina, RPE, choriocapillaris spontaneously cynomolgus macaques. Optical coherence tomography (OCT) images were obtained from 25 macaques 26 age-matched nondiabetic The individual layers macula, along with RPE choriocapillaris, was...

Abstract Constitutively active mutant EGFR is one of the major oncogenic drivers in non–small cell lung cancer (NSCLC). Targeted therapy using tyrosine kinase inhibitor (TKI) a first-line option patients that have metastatic or recurring disease. However, despite high response rate to TKI, most partial response, and disease eventually progresses 10 19 months. It believed drug-tolerant cells survive TKI exposure during progression-free period facilitate emergence acquired resistance. Thus,...

Abstract Mutant epidermal growth factor receptor (EGFR), a major oncogenic driver in non-small cell lung cancer (NSCLC), is found the tumors of 15% (western countries) to 50% (Asian patients. EGFR-targeted therapy using tyrosine kinase inhibitors (TKIs) standard care for those patients who developed metastatic or recurrent diseases. However, despite having an 80% initial response rate, most had partial tumor regression and their disease would progress when acquired resistance emerges. Thus,...

<p>Characteristics of HDGF binding by humanized anti-HDGF antibody H3. <b>A,</b> Binding native Recombinant H3 was immobilized on protein G agarose beads and used to capture in HEK293 lysate. Lane 1, loaded-beads; lane 2, H3-beads plus HEK292 lysate; 3, captured probed with rabbit anti–HDGF T221; 4, the same blot striped goat anti–human IgG antibody. migrates at 37–42 kDa, larger than calculated molecular weight 26.7 kDa. <b>B,</b> Specificity recognition....

<p>Characteristics of HDGF binding by humanized anti-HDGF antibody H3. <b>A,</b> Binding native Recombinant H3 was immobilized on protein G agarose beads and used to capture in HEK293 lysate. Lane 1, loaded-beads; lane 2, H3-beads plus HEK292 lysate; 3, captured probed with rabbit anti–HDGF T221; 4, the same blot striped goat anti–human IgG antibody. migrates at 37–42 kDa, larger than calculated molecular weight 26.7 kDa. <b>B,</b> Specificity recognition....

<p>Supplement Figure 1 shows the incomplete response of Hcc827 tumor to erlotinib treatment.</p>

<p>Anti-HDGF antibody enhances the efficacy of EGFR-targeted therapy. Mice with established PDXs NSCLC tumors were randomized into two arms (<i>n</i> = 6 each) to receive osimertinib or plus anti-HDGF antibody. <b>A</b> and <b>B,</b> Spider plot tumor volume changes in mice treated <b>C</b> <b>D,</b> Waterfall best percent change from baseline each treatment arms. <b>E</b> <b>F,</b> Mean Asterisks mark...

<p>Anti-HDGF antibody enhances the efficacy of EGFR-targeted therapy. Mice with established PDXs NSCLC tumors were randomized into two arms (<i>n</i> = 6 each) to receive osimertinib or plus anti-HDGF antibody. <b>A</b> and <b>B,</b> Spider plot tumor volume changes in mice treated <b>C</b> <b>D,</b> Waterfall best percent change from baseline each treatment arms. <b>E</b> <b>F,</b> Mean Asterisks mark...

<p>HDGF expression in naïve and osimertinib-treated PDX tumors. Formalin-fixed, paraffin-embedded sections of TM00219 tumors were stained with mouse anti–HDGF antibody T221. Representative fields (10×) staining naïve, osimertinib-treated, or osimertinib plus anti-HDGF H3–treated arms (<b>A</b>). slides from (<b>B</b>) (<b>C</b>) tumor viewed under different power: left to right are low power (1.5×) wide field views, medium (10×), high (40×) view....

<p>Selected characteristics of the PDX models used in study. Data were extracted from database The Jackson Laboratory</p>

<p>Selected characteristics of the PDX models used in study. Data were extracted from database The Jackson Laboratory</p>

<div>Abstract<p>Constitutively active mutant EGFR is one of the major oncogenic drivers in non–small cell lung cancer (NSCLC). Targeted therapy using tyrosine kinase inhibitor (TKI) a first-line option patients that have metastatic or recurring disease. However, despite high response rate to TKI, most partial response, and disease eventually progresses 10 19 months. It believed drug-tolerant cells survive TKI exposure during progression-free period facilitate emergence acquired...

<p>Dynamics of EGFR signaling during the early stage osimertinib treatment. Mice bearing TM00219 tumors were treated with (10 mg/kg <i>per os</i>, every 24 hours) for up to 72 hours. Duplicate tumor samples serially collected at indicated time intervals. Each was split formalin-fixing and paraffin-embedding snap-freezing in liquid nitrogen. formalin-fixed, paraffin-embedded sections stained (<b>A</b>) P-EGFR (Y1068), (<b>B</b>) P-Erk1/2 (T202/Y204),...

<p>Supplement Figure 3 shows the Effect of anti-HDGF antibody H3 on post-progression tumor.</p>

<p>Effect of anti-HDGF antibody on EGFR signaling in osimertinib-treated TM00219 PDX tumor. Mice with established tumors were randomized into two arms (<i>n</i> = 6 each) to receive osimertinib or plus H3. After 10 days treatment, collected from euthanized animals and split for formalin-fixing paraffin-embedding Western blot analysis. <b>A–D,</b> IHC staining tumor formalin-fixed, paraffin-embedded sections using (<b>A</b>) P-Erk1/2 (T202/Y204),...

<p>HDGF expression in naïve and osimertinib-treated PDX tumors. Formalin-fixed, paraffin-embedded sections of TM00219 tumors were stained with mouse anti–HDGF antibody T221. Representative fields (10×) staining naïve, osimertinib-treated, or osimertinib plus anti-HDGF H3–treated arms (<b>A</b>). slides from (<b>B</b>) (<b>C</b>) tumor viewed under different power: left to right are low power (1.5×) wide field views, medium (10×), high (40×) view....

<p>Supplement Figure 3 shows the Effect of anti-HDGF antibody H3 on post-progression tumor.</p>

<p>Supplement Figure 4A shows the expression of MET and P-MET in naive treated tumors. Supplement 4B sequencing result EGFR exon 20 flanking C797 tumors.</p>

<p>Supplement Figure 2 shows the Effect of anti-HDGF antibody H3 on treatment naive tumor.</p>

<p>Effect of anti-HDGF antibody on EGFR signaling in osimertinib-treated TM00219 PDX tumor. Mice with established tumors were randomized into two arms (<i>n</i> = 6 each) to receive osimertinib or plus H3. After 10 days treatment, collected from euthanized animals and split for formalin-fixing paraffin-embedding Western blot analysis. <b>A–D,</b> IHC staining tumor formalin-fixed, paraffin-embedded sections using (<b>A</b>) P-Erk1/2 (T202/Y204),...

<p>Supplement Figure 2 shows the Effect of anti-HDGF antibody H3 on treatment naive tumor.</p>

<p>Dynamics of EGFR signaling during the early stage osimertinib treatment. Mice bearing TM00219 tumors were treated with (10 mg/kg <i>per os</i>, every 24 hours) for up to 72 hours. Duplicate tumor samples serially collected at indicated time intervals. Each was split formalin-fixing and paraffin-embedding snap-freezing in liquid nitrogen. formalin-fixed, paraffin-embedded sections stained (<b>A</b>) P-EGFR (Y1068), (<b>B</b>) P-Erk1/2 (T202/Y204),...

<div>Abstract<p>Constitutively active mutant EGFR is one of the major oncogenic drivers in non–small cell lung cancer (NSCLC). Targeted therapy using tyrosine kinase inhibitor (TKI) a first-line option patients that have metastatic or recurring disease. However, despite high response rate to TKI, most partial response, and disease eventually progresses 10 19 months. It believed drug-tolerant cells survive TKI exposure during progression-free period facilitate emergence acquired...

<p>Supplement Figure 1 shows the incomplete response of Hcc827 tumor to erlotinib treatment.</p>