Faculty Bibliography

Signal transduction pathways regulate the proliferation and viability of acute myeloid leukemia (AML) blasts. The regulation in the expression of cytokine receptors in AML is not well understood. In this study, we investigated how the CBFbeta-SMMHC fusion protein regulates expression of cytokine receptors in inv(16) AML, with focus on the co-receptor Neuropilin-1 (NRP1). Knock-down of CBFbeta-SMMHC expression, utilizing shRNA transduction, induced G1 phase of cell cycle arrest and reduced the viability of inv(16) ME-1 cells in culture. Expression profile analysis of CBFbeta-SMMHC knock-down cells revealed a significant repression of genes associated with transmembrane receptor protein kinase pathways, including NRP1 (-5 fold), FGFR1 (-4.2 fold), FLT3 (-2 fold) and TGFBR2 (-1.2 fold). The expression of NRP1 was significantly upregulated in inv(16) AML cases when compared to other AML sub-types and to hematopoietic stem and progenitor cells. Functionally, NRP1 knock-down reduced the viability of ME-1 cells with a similar dynamics as when using CBFbeta-SMMHC shRNAs. In addition, the proliferation of inv(16) AML cells was reduced 4.1-fold when treated with a function-blocking antibody for the FV/VIII extracellular NRP1 domain, while having no effect in non-inv(16) AML cells or when using blocking antibody for the CUB extracellular domain. Furthermore, deletion of Nrp1 by gene editing reduced the colony-forming unit capacity of primary mouse Cbfb ^+/MYH11 leukemic cells and extended the median leukemia latency in vivo. To identify the genes regulated by NRP1 in inv(16) AML, we analysed the transcription profile of NRP1 knock-down in ME-1 cells. Gene Set Enrichment and Pathway Analysis revealed a repression in STAT5 pathway, and in signalling receptor activity, including FLT3 (-1.8 fold) and TGFBR2 (-1.8 fold) expression, indicating that NRP1 mediates transcriptional regulation of FLT3 and TGFBR2 expression in inv(16) AML. Furthermore, the regulation of FLT3 and TGFB2 expression by CBFbeta-SMMHC and by NRP1 was validated by gene editing in inv(16) AML blasts. Accordingly, NRP1 knock-down in AML cells reduced SMAD2/3 phosphorylation. The repression of RUNX1/CBFbeta function, using small molecule inhibitors, in inv(16) AML cells with CBFbeta-SMMHC knockdown restored NRP1 expression, suggesting that RUNX1 may repress NRP1 expression in AML cells. To evaluate if RUNX1 directly regulates NRP1 expression, we tested RUNX1 binding in the NRP1 locus of AML cells with CBFbeta-SMMHC knockdown. RUNX1 binding at one of six sites with RUNX1 occupancy identified by chromatin immunoprecipitation followed by sequencing (RE5, regulatory element 5) was increased in the CBFbeta-SMMHC knock-down cells. The RE5 is located 178kb upstream of the NRP1 transcription start site and it is evolutionarily conserved in vertebrates. The deletion of RE5 by gene editing (~50% editing efficiency) increased NRP1 expression 1.8-fold, suggesting that RUNX1 may repress NRP1 expression at by binding to the RE5 enhancer. Taken together, these studies demonstrate that CBFbeta-SMMHC regulates expression of cytokine receptors in inv(16) AML. Specifically, it directly regulates expression of the co-receptor NRP1, which is essential for AML survival, acting (at least in part) by regulating FLT3 and TGFB pathways. Disclosures: Guzman: SeqRx: Consultancy; BridgeMedicines: Consultancy; Cellectis: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees.
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Purpose : Intraocular pressure (IOP) is currently the only modifiable risk factor for glaucoma, yet glaucoma can continue to progress despite controlled IOP. Thus, development of glaucoma neurotherapeutics remains an unmet need. Scutellarin is a flavonoid that exhibits a number of neuroprotective effects on the brain and the eye. Here, we investigated the neurobehavioral effects of oral scutellarin treatment in a novel experimental model of chronic glaucoma. Methods : Ten adult C57BL/6J mice (Group 1) were unilaterally injected with an optically clear hydrogel into the anterior chamber to obstruct aqueous outflow and induce chronic IOP elevation. Eight other mice (Group 2) received a unilateral intracameral injection of phosphate-buffered saline only. Another eight mice (Group 3) with hydrogel-induced unilateral chronic IOP elevation also received daily oral gavage of 300 mg/kg scutellarin from 1 week before to 2 weeks after hydrogel injection. Tonometry, optical coherence tomography, and optokinetic visuobehavioral testing were performed longitudinally to monitor the IOP, total retinal thickness, visual acuity, and contrast threshold of bilateral eyes in all three groups. Results : Intracameral hydrogel injection resulted in unilateral chronic IOP elevation with no significant IOP difference between scutellarin treatment and untreated groups (Figure site uses cookies. By continuing to use our website, you are agreeing to 1). With scutellarin treatment, the hydrogel-injected eyes showed less retinal thinning and reduced visual behavioral deficits when compared to the untreated, hydrogel-injected eyes (Figure 2). No significant difference in retinal thickness or optokinetic measures was found in the non-injected eyes over time or between all groups. Conclusions : Oral scutellarin treatment appeared to preserve retinal structure and visual function in experimental glaucoma induced by chronic IOP elevation. Scutellarin may be a possible candidate as a novel neurotherapeutic agent for glaucoma treatment

With the development of human society, haze has become an important form of air pollution. Haze is a mixture of fog and haze, and the main component of haze is fine particulate matter (PM2.5), which is the most important indicator of composite air pollution. Epidemiological studies proved that PM2.5 can break through the respiratory mucosal barrier and enter the human body, causing pathological effects on multiple systems of the body. In the past, people put more attention to PM2.5 in the respiratory system, cardiovascular system, nervous system, etc, and relatively paid less attention to the reproductive system. Recent studies have shown that PM2.5 will accumulate in the reproductive organs through blood-testis barrier, placental barrier, epithelial barrier and other barriers protecting reproductive tissues. In addition, PM2.5 can disrupt hormone levels, ultimately affecting fertility. Prior studies have shown that oxidative stress, inflammation, apoptosis, and the breakdown of barrier structures are now considered to contribute to reproductive toxicity and may cause damage at the molecular and genetic levels. However, the exact mechanism remains to be elucidated. Our review aims to provide an understanding of the pathological effects of PM2.5 on reproductive system and the existing injury mechanism.
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Purpose : Development and pre-clinical testing of glaucoma neurotherapeutics have been obfuscated by limited experimental models that provide chronic elevation of intraocular pressure (IOP) while preserving optical media clarity for structural and functional assessments over time. In this study, we developed an in vivo model system involving the use of non-invasive tonometry, optical coherence tomography (OCT) and optokinetics to characterize retinal integrity and visual behavior in a novel hydrogel-induced chronic IOP elevation model. Methods : Six adult C57BL/6J mice underwent unilateral intracameral injection of an optically clear, chemically cross-linked hydrogel composed of hyaluronic acid functionalized with vinyl sulfone and thiol groups. IOP was measured with a rebound tonometer at baseline and 1, 3, 7, 10 and 14 days after hydrogel injection. The optic nerve head (ONH) region was scanned for each eye using OCT at baseline and 2 weeks after injection, and total retinal thickness (TRT) was measured within a 0.26-0.36 mm radius ring centered on the ONH using custom-written software (Fig 1). Visual acuity (VA) was measured for each eye using an optokinetic virtual-reality system at baseline and 2 weeks after injection. Data are presented as mean+/-SEM. Results : Intracameral hydrogel injection resulted in mild-to-moderate IOP elevation throughout the 2-week experimental period (Fig 2a). TRT in the hydrogel-injected eye was 10.06+/-3.61% thinner at 2 weeks post-injection compared to baseline (p<0.01) (Fig 2b). IOP elevation also led to a decline in VA by 58.12+/-7.22% at 2 weeks post-injection compared to baseline (p<0.001) (Fig 2c). Interestingly, among the hydrogel-injected eyes, cumulative IOP measured from 0 to 14 days post-injection did not correlate with TRT or VA (p>0.05) (Fig 2d-e), whereas TRT was positively associated with VA at 2 weeks post-injection (r=0.824, p<0.05) (Fig 2f). No significant change in IOP, TRT or VA was found in the non-injected eye. Conclusions : An in vivo glaucoma model system was developed that showed a positive correlation between retinal thinning and visual behavioral deficits after chronic IOP elevation. The weak association between cumulative IOP and TRT or VA suggests additional factors apart from IOP level in contributing to glaucomatous damage after chronic IOP elevation

Background: We report results of a phase 1/2 open-label, multicenter study of TAK-788 (NCT02716116), an oral investigational EGFR/HER2 inhibitor.
Method(s): Patients with advanced, previously treated NSCLC received daily TAK-788 in dose escalation and expansion cohorts based on tumor genotype. Antitumor activity was determined for patients with EGFR exon 20 insertions who received TAK-788 160 mg QD. Safety is reported for all patients across all doses and at 160 mg. To improve gastrointestinal tolerability, food intake instructions in this ongoing study were amended to allow for administration with or without a low-fat meal based on emerging clinical pharmacokinetic data in a healthy volunteer study (data on file).
Result(s): As of 14 Sep 2018, 101 patients (median age, 61 y; female, 70%; >=2 prior anticancer therapies, 76%; brain metastases, 53%) were treated with TAK-788 at 5-180 mg QD. RP2D was determined to be 160 mg QD. 28 patients with EGFR exon 20 insertions were treated with 160 mg QD during dose escalation or in expansion cohort 1 (3.6 months on treatment; 3.8 treatment cycles [medians]); 24 patients remain on treatment. At data cutoff, best response (RECIST v1.1) among 26 patients with >=1 disease assessment was PR, n=14; SD, n=9; and PD, n=1 (objective response rate, 54%; 95% CI: 33.4%-73.4%); 2 patients were unevaluable. 7/14 objective responses (all PR) were confirmed (6 awaiting confirmation; 1 unconfirmed PR at 160 mg QD); median time to response in these 14 patients was 56 days. 23/26 patients (89%; 95% CI: 69.9%-97.6%) achieved disease control. 23/24 evaluable patients with EGFR exon 20 insertions treated at 160 mg QD had decreased target lesion measurements (median best percent change, -32.6% [-79.1%-3.8%]). Most common TEAEs (>=20%) in patients treated with 160 mg QD: diarrhea (85%), rash (43%), nausea (41%), vomiting (30%), decreased appetite (28%), stomatitis (22%); grade >=3 TEAEs (>=5%): diarrhea (26%); hypokalemia, nausea, stomatitis (7% each). Among patients treated with 160 mg QD, median dose intensity was 93%, rate of dose reduction due to AEs was 21.7%, and rate of treatment discontinuation due to AEs was 10.9%. There was no clear trend that response to TAK-788 was enriched in any single EGFR exon 20 insertion variant.
Conclusion(s): In NSCLC patients with EGFR exon 20 insertions, TAK-788 demonstrated antitumor activity and a safety profile consistent with other EGFR TKIs. Keywords: EGFR tyrosine kinase inhibitor, EGFR exon 20 mutation
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Background:We report results of a phase 1/2 open-label, multicenter study of TAK- 788 (NCT02716116), an oral investigational EGFR/HER2 inhibitor.
Method(s): Pts with advanced, previously treated NSCLC received daily TAK-788 in dose escalation and expansion cohorts based on tumor genotype. Antitumor activity was determined for pts with EGFR exon 20 insertions who received TAK-788 at the RP2D. Safety is reported for all pts across all doses and at 160 mg.
Result(s): As of 14 Sep 2018, 101 pts (median age, 61 y; female, 70%; >=2 prior anticancer therapies, 76%; brain metastases, 53%) were treated with TAK-788 at 5-180 mg qd. RP2D was determined to be 160 mg. 28 pts with EGFR exon 20 insertions were treated with 160 mg qd during dose escalation or in expansion cohort 1 (3.6 mo on treatment; 3.8 treatment cycles [medians]); 24 pts remain on treatment. At data cutoff, best response (by RECIST v1.1) among 26 pts with >=1 disease assessment was PR, n=14; SD, n=9; and PD, n=1; 2 pts were not evaluable. 7/14 objective responses (all PR) were confirmed, with 6 awaiting confirmation and 1 unconfirmed PR at 160 mg qd; median time to response in these 14 pts was 56 days. 23/26 pts achieved disease control. 23/24 evaluable pts with EGFR exon 20 insertions treated at 160 mg qd had decreased target lesion measurements (median best percent change, -32.6% [-79.1%, 3.8%]). Most common TEAEs (>=20%) in pts treated with 160 mg qd: diarrhea (85%), rash (43%), nausea (41%), vomiting (30%), decreased appetite (28%), and stomatitis (22%); gr>=3 TEAEs (>=5%): diarrhea (26%); hypokalemia, nausea, and stomatitis (7% each). Among pts treated with 160 mg qd, median dose intensity was 93%, and the rate of treatment discontinuation due to AEs was 10.7%. There is no clear trend that response to TAK-788 is enriched in any single EGFR exon 20 insertion variant.
Conclusion(s): In NSCLC pts with EGFR exon 20 insertions, TAK-788 demonstrated antitumor activity and an AE profile consistent with other EGFR TKIs

Background: Peer comparisons, providing feedback on clinician performance relative to peers, have been tested successfully in narrow settings such as increasing guideline-based antibiotic and opioid prescribing. However, there are no studies evaluating the effectiveness of peer comparisons on broader quality measures in the setting of alternative payment models.
Method(s): We conducted a cluster randomized trial with the Blue Cross Blue Shield of Hawaii to examine the impact of providing peer comparison feedback to its primary care practitioners (PCPs) on the quality of care. This study included patients of 86 PCPs randomized to receiving peer comparisons plus individual feedback (intervention group) versus individual feedback alone (control group). Feedback was provided on quality, cost, and utilization performance. All PCPs were also simultaneously moved to a new population-based primary care payment system. The primary outcome was the probability of achieving national benchmark thresholds on thirteen primary care focused quality metrics that included preventative and chronic disease measures. We analyzed the primary outcome using a generalized linear model, adjusting for patient characteristics, PCP characteristics, baseline proportion of measures achieved by the patient, and a quality measure fixed-effect, clustering standard errors at the PCP.
Result(s): The RCT included 27,930 patients and 31 PCPs in the control group and 46,694 patients and 55 PCPs in the intervention group. Patients nor PCPs exhibited large differences across groups, with small differences in demographics and panel size, respectively. In primary analysis, the patients in the peer comparisons intervention group experienced a 2.4 percentage point (pp) increase in the probability of achieving an eligible quality measure (95% CI 0.3 pp to 4.6 pp, p=0.03). Secondary analysis of individual measures indicated that Breast Cancer Screening (3.9 pp, 95% CI 0.2 to 6.0 pp, p< 0.001), Cervical Cancer Screening (2.4 pp, 95% CI 0.01to 4.8 pp, p=0.05), Colorectal Cancer Screening (2.8 pp, 95% CI 0.3 to 5.2 pp, p=0.03), Diabetes Care-Eye Exam (5.6 pp, 95% CI 1.6 to 9.5 pp, p = 0.006), Diabetes Care-Medical Attention for Nephrop-athy (2.5 pp, 95% CI 0.4 to 4.6 pp, p=0.02) and Review of Chronic Conditions (4.9 pp, 95% CI 0.0 to 9.8 pp, p=0.05) likely accounted for the increased overall quality score. Other measures demonstrated trends toward differential improvement, but associations were not significant. Cost and utilization did not demonstrate differences between arms.
Conclusion(s): A peer comparisons intervention that displayed quality information in a real-time dashboard in the setting of a broad primary care payment system change improved quality scores by over 2 percentage points. This highlights the ability of peer comparisons to influence clinician practice in broad endpoints and is reassuring in light of new payment programs that have begun sharing comparative feedback

Background: In response to modest impact from quality programs, we worked with the Blue Cross Blue Shield of Hawaii to design and implement the Population-based Payments for Primary Care (3PC) system. This system was designed using behavioral economic insights and implemented in a staggered rollout across all Medicare, Medicaid, and commercial members starting in April 2016.
Method(s): We analyzed 2012-2016 claims and quality registry data for 77,225 HMSA members attributed to 107 primary care physicians (PCPS) and 4 organizations (POs) participating in the 1st wave of the 3PC and for 222,233 members attributed to 312 PCPS in 14 POs that continued in fee-for service in 2016 but had staggered 3PC start dates thereafter. We used a propensity-weighted, difference-in-differences design to compare risk-adjusted changes in quality, cost, and utilization among patients in the 3PC group to those in the non-3PC group-after confirming parallel pre-intervention trends. We used generalized linear models with an identity link for quality, log link and gamma distribution for cost, and log link and negative binomial distribution for utilization, with standard errors clustered by PCP.
Result(s): The groups exhibited small baseline differences in demographics, risk scores, and socioeconomic characteristics. Adjusted analysis indicated an association between the 3PC group and increases in quality in 2016 (differential change in risk-standardized quality scores of 2.3 percentage points (p.p.), 95% CI 2.1 to 2.6 p.p., p< 0.001). In secondary analyses, performance on 5 quality measures improved, 2 measures worsened, with no changes for six measures (see Figure). There were significant differential reductions in primary care cost (-3.9%, 95% CI-4.8% to-2.9%, p< 0.001), but not total cost of care (1.0%, 95% CI-1.3% to 3.4%, p=0.39). Prescription drug cost differentially increased by 20.1% (95% CI 10.2% to 32.5%, p< 0.001). Changes in utilization by category were similar in magnitude to changes in cost by category.
Conclusion(s): The 3PC was associated with improvements in quality in its first year. Reduction in primary care visits and costs indicate shifts in practice patterns away from visit-based care. This study offers early evidence on the feasibility and effectiveness of shifting to a population-based primary care payment system across commercial, Medicare, and Medicaid populations in a fragmented market, which may have generalizable implications for other markets with similar characteristics nationwide. [Figure Presented]