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Soft tissue sarcoma (STS) is a locally aggressive and infiltrative tumor in dogs. Surgical resection is the treatment of choice for local tumor control. Currently, post-operative pathology is performed for surgical margin assessment. Spectral-domain optical coherence tomography (OCT) has recently been evaluated for its value for surgical margin assessment in some tumor types in dogs. The purpose of this study was to develop an automatic diagnosis system that can assist clinicians in real-time for OCT image interpretation of tissues at surgical margins. We utilized a ResNet-50 network to classify healthy and cancerous tissues. A patch-based approach was adopted to achieve accurate classification with limited training data (80 cancer images, 80 normal images) and the validation set (20 cancer images, 20 normal images). The proposed method achieved an average accuracy of 97.1% with an excellent sensitivity of 94.3% on the validation set; the quadratic weighted κ was 0.94 for the STS diagnosis. In an independent test data set of 20 OCT images (10 cancer images, 10 normal images), the proposed method correctly differentiated all the STS images. Furthermore, we proposed a diagnostic curve, which could be evaluated in real-time to assist clinicians in detecting the specific location of a lesion. In short, the proposed method is accurate, operates in real-time, and is non-invasive, which could be helpful for future surgical guidance. This article is protected by copyright. All rights reserved.

Genetic alphabet expansion of DNA by introducing unnatural bases (UBs), as a fifth letter, dramatically augments the affinities of DNA aptamers that bind to target proteins. To determine whether UB-containing DNA (UB-DNA) aptamers obtained by affinity selection could spontaneously achieve high specificity, we have generated a series of UB-DNA aptamers (KD: 27−182 pM) targeting each of four dengue non-structural protein 1 (DEN-NS1) serotypes. The specificity of each aptamer is remarkably high, and the aptamers can recognize the subtle variants of DEN-NS1 with at least 96.9% amino acid sequence identity, beyond the capability of serotype identification (69−80% sequence identities). Our UB-DNA aptamers specifically identified two major variants of dengue serotype 1 with 10-amino acid differences in the DEN-NS1 protein (352 aa) in Singaporeans’ clinical samples. These results suggest that the high-affinity UB-DNA aptamers generated by affinity selection also acquire high target specificity. Intriguingly, one of the aptamers contained two different UBs as fifth and sixth letters, which are essential for the tight binding to the target. These two types of unnatural bases with distinct physicochemical properties profoundly expand the potential of DNA aptamers. Detection methods incorporating the UB-DNA aptamers will facilitate precise diagnoses of viral infections and other diseases.

Introduction: PRT1419, a selective inhibitor of MCL-1, has demonstrated preclinical activity in solid tumors and hematologic malignancies. We report the results of a phase 1, open-label, multicenter, dose-escalation study of PRT1419 in pts with advanced/metastatic solid tumors (NCT04837677). Methods: Adults with select advanced/metastatic solid tumors were enrolled. Key inclusion criteria were absolute neutrophil count >1.0, platelets >75, hemoglobin >9, and left ventricular ejection fraction ≥50%. Key exclusion criteria were active central nervous system malignancy, significant cardiac disease, and concurrent strong CYP2C8 inhibitors. The study employed a 3+3 dose escalation design. PRT1419 was administered as a once-weekly (QW) infusion. Primary outcome measures were to evaluate dose-limiting toxicities (DLT) and establish the maximum tolerated dose and recommended phase 2 dose (RP2D). Secondary outcome measures included safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity. Results: Pts with melanoma (n=8), sarcoma (n=5), esophageal (n=4), cervical (n=3), head and neck (n=3), non-small cell lung, small cell lung, and triple-negative breast cancer (all n=1) were enrolled. Median age was 59.5 (range, 32-78) years, 61.5% pts were female, and median prior lines of systemic therapy was 3 (range, 1-8). Overall, 26 pts received ≥1 dose of PRT1419 (20 mg/m2 [n=4], 40 mg/m2 [n=4], 80 mg/m2 [n=15], and 120 mg/m2 [n=3]). Most pts (84.6%) discontinued treatment (primary reason: progressive disease, 72.7%). No DLTs, adverse events (AEs) of increased troponin or heart failure, or grade 5 (fatal) AEs were observed. Any grade treatment-related AEs (TRAE) occurred in 80.8% pts; the most common were nausea (50.0%), diarrhea (46.2%), and vomiting (46.2%). Grade 3/4 TRAEs occurred in 11.5% pts; the most common was neutropenia (11.5%), which was dose related. Due to neutropenia observed at doses >80 mg/m2, further dose escalation was not investigated. BAX and caspase 3 activation in peripheral blood monocytes was observed at 80 mg/m2 and 120 mg/m2. Stable disease was the best response observed. Tumor shrinkage was seen in 1 pt with melanoma (10% reduction) and 1 pt with lung cancer (4% reduction) but did not meet the criteria for partial response. At Week 3, mean clearance was 12.6 L/hr and mean half-life was 2.5 hrs; no PRT1419 accumulation was seen with QW dosing. Conclusions: PRT1419 demonstrated acceptable safety and tolerability in pts with advanced/metastatic solid tumors, with primary TRAEs of neutropenia, nausea, diarrhea, and vomiting. No cardiac toxicity was observed. BAX and caspase 3 activation was observed, suggesting potentially successful MCL-1 inhibition. Investigation of PRT1419 in pts with hematologic malignancy in a separate study is ongoing (NCT05107856). Citation Format: Gerald Falchook, Manish Patel, Meredith McKean, Alexander Philipovskiy, Rachel Chiaverelli, William Sun, Michael Fossler, William Novotny, Michael Kurman, Sarah Rowe, Deborah Hunter, Mohammed Milhem. A phase 1, open-label, dose-escalation study of PRT1419, a selective induced myeloid leukemia cell differentiation protein (MCL-1) inhibitor, in patients (pts) with advanced/metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT172.

Serologic tests to detect specific IgGs to antigens related to viral infections are urgently needed for diagnostics and therapeutics. We present a diagnostic method for serotype-specific IgG identification of dengue infection by a competitive enzyme-linked immunosorbent assay (ELISA), using high-affinity unnatural-base-containing DNA (UB-DNA) aptamers that recognize the four categorized serotypes. Using UB-DNA aptamers specific to each serotype of dengue NS1 proteins (DEN-NS1), we developed our aptamer-antibody sandwich ELISA for dengue diagnostics. Furthermore, IgGs highly specific to DEN-NS1 inhibited the serotype-specific NS1 detection, inspiring us to develop the competitive ELISA format for dengue serotype-specific IgG detection. Blood samples from Singaporean patients with primary or secondary dengue infections confirmed the highly specific IgG detection of this format, and the IgG production initially reflected the serotype of the past infection, rather than the recent infection. Using this dengue competitive ELISA format, cross-reactivity tests of 21 plasma samples from Singaporean Zika virus-infected patients revealed two distinct patterns: 8 lacked cross-reactivity, and 13 were positive with unique dengue serotype specificities, indicating previous dengue infection. This antigen-detection ELISA and antibody-detection competitive ELISA combination using the UB-DNA aptamers identifies both past and current viral infections and will facilitate specific medical care and vaccine development for infectious diseases. Agency for Science, Technology and Research (A*STAR) National Research Foundation (NRF) Published version This work was supported by the Institute of Bioengineering and Bioengineering (Biomedical Research Council, Agency for Science, Technology and Research, Singapore) and the National Research Foundation of Singapore (NRF-CRP17-2017-07).

We aimed to bioengineer a scaffold that can facilitate the transplantation of corneal endothelial cells (CEC), given the global shortage of cadaveric donor tissues. Although agarose (A) has outstanding biocompatibility and mechanical properties, it natively does not permit cell adhesion. In this study, agarose was modified with different attachment signals: GRGD (giving AR as product), lysine (AK), poly lysine (AP), and fish-derived gelatin (AG). Samples with varying conjugation ratios were prepared. All products formed bulk hydrogels, which were then collapsed into ultrathin membranes in a controlled environment. Membranes were evaluated for their ability to support attachment of various cell types. Cells, however, preferred the AG series of membrane. Notably, primary rabbit CEC remained attached and viable for ⩾4 weeks. The cells also stained positive for CD166, ZO-1 and Na+/K+ ATPase, indicative of function. The hydrated AG membranes allowed >96% transmittance of visible light. The membranes were typically ∼15 μm thick and did not swell significantly after immersion in PBS. Tensile strength was 49-60 MPa, while young's modulus was 525-596 MPa. This membrane thus offers great promise as a scaffold for CEC during endothelial keratoplasty.

Fulfilling consumer expectations of corporate social responsibility (CSR) can bring strategic advantage to firms. However, research on the topic is fragmented across disparate disciplines, and a comprehensive framework to connect CSR supply and demand is missing. As a result, firms often supply CSR that does not attract demand, as signified by pessimism about ethical consumerism in recent years and the inconclusive link between corporate financial and social performance. In this study, we propose a framework of strategic CSR management to define how a company’s supply of CSR could meet consumer demand for ethical products by aligning managerial and consumer perspectives. We then investigate empirically whether such a strategic approach, which integrates potential demand in CSR management, would influence consumer choice of products with CSR components. Our hybrid choice modeling allows the inclusion of psychological biases caused by social desirability and cynicism to increase result validity. The findings support the explanatory power of the framework and reveal that consumers prefer some CSR elements while others adversely affect choices. This study advances the understanding of strategic CSR management and its impact on consumer choice and helps managers include the right mix of CSR characteristics in their products to satisfy ethical consumers.

Background: 1-α-D-(5-Deoxy-5-[18F]fluoroarabinofuranosyl)-2-nitroimidazole ([18F]FAZA) is manufactured by nucleophilic radiofluorination of 1-α-D-(2’,3’-di-O-acetyl-5’-O-toluenesulfonylarabinofuranosyl)- 2-nitroimidazole (DiAcTosAZA) and alkaline deprotection to afford [18F]FAZA. High yields (>60%) under optimized conditions frequently revert to low yields ( Objective: To develop alternative precursors for facile routine clinical manufacture of [18F]FAZA that are compatible with current equipment and automated procedures. Methods: Two new precursors, 1-α-D-(2’,3’-di-O-acetyl-5’-O-(4-nitrobenzene)sulfonyl-arabinofuranosyl)-2- nitroimidazole (DiAcNosAZA) and 1-α-D-(2’,3’-di-O-acetyl-5’-iodo-arabinofuranosyl)-2-nitroimidazole (DiAcIAZA), were synthesized from commercially-available 1-α-D-arabinofuranosyl-2-nitroimidazole (AZA). A commercial automated synthesis unit (ASU) was used to condition F-18 for anhydrous radiofluorination, and to radiofluorinate DiAcNosAZA and DiAcIAZA using the local standardized protocol to manufacture [18F]FAZA from AcTosAZA. Results: DiAcNosAZA was synthesized via two pathways, in recovered yields of 29% and 40%, respectively. The nosylation of 1-α-D-(2’,3’-di-O-acetyl-arabinofuranosyl)-2-nitroimidazole (DiAcAZA) featured a strong competing reaction that afforded 1-α-D-(2’,3’-di-O-acetyl-5’-chloro-arabinofuranosyl)-2- nitroimidazole (DiAcClAZA) in 55% yield. Radiofluorination yields were better from DiAcNosAZA and DiAcIAZA than from DiAcTosAZA, and the presence of fewer side products afforded higher purity [18F]FAZA preparations. Several radioactive and non-radioactive by products of radiofluorination were assigned tentative chemical structures based on co-chromatography with authentic reference compounds. Conclusion: DiAcClAZA, a major side-product in the preparation of DiAcNosAZA, and its deprotected analogue (ClAZA), are unproven hypoxic tissue radiosensitizers. DiAcNosAZA and DiAcIAZA provided good radiofluorination yields in comparison to AcTosAZA and could become preferred [18F]FAZA precursors if the cleaner reactions can be exploited to bypass HPLC purification.

Dengue virus (DENV) and Zika virus (ZIKV) belong to the Flaviviridae family of viruses spread by Aedes aegypti mosquitoes in tropical and subtropical areas. Accurate diagnostic tests to differentiate the 2 infections are necessary for patient management and disease control. Using characterized ZIKV and DENV patient plasma in a blind manner, we validated an ELISA and a rapid immunochromatographic test for ZIKV detection. We engineered the ZIKV nonstructural protein 1 (NS1) for sensitive serologic detection with low cross reactivity against dengue and developed monoclonal antibodies specific for the ZIKV NS1 antigen. As expected, the serologic assays performed better with convalescent than acute plasma samples; the sensitivity ranged from 71% to 88%, depending on the performance of individual tests (IgM/IgG/NS1). Although serologic tests were generally less sensitive with acute samples, our ZIKV NS1 antibodies were able to complement the serologic tests to achieve greater sensitivity for detecting early infections.

PurposePrevious studies support the notion that corporate social responsibility (CSR) initiatives can have a positive effect on customers in the hospitality and tourism industry. However, most of these studies have ignored response biases and none have incorporated them into their analyses numerically. This study aims at closing this research gap.Design/methodology/approachThe authors utilized a hybrid choice model to test for the hypothesized effects of social desirability (SD) and cynicism biases on reported purchase intention. The authors further compared the results with those of analyses that ignore these biases to demonstrate their distorting influence.FindingsThe results indicate that SD and cynicism biases have a moderating effect on reported purchase intention. Older generations and frequent travelers seem particularly prone to bias, and the biases have a distorting effect on the overall survey results.Research limitations/implicationsTraditional analyses that exclude biases, incorrectly, suggest several aspects of CSR that are significant (or insignificant) to purchase intention, provide unreliable results. The authors did not generalize bias-prone respondent segments but urge future research to investigate this.Practical implicationsHotel managers aspiring to gain competitive advantage through CSR investment must consider biases in their market research. Otherwise, they risk developing CSR initiatives that do not instigate positive customer behaviors, leading to the failure of the investment.Originality/valueThe authors quantified SD and cynicism as significant causes of response bias, which distorts survey results. Previous studies have conceptualized SD without quantifying its impact, while cynicism has been identified as a novel source of bias in the industry. This study further introduces hybrid choice modeling as a novel approach to address response bias that could extend itself beyond the industry studied here.

A group of students in 7-9 grades are inventing combinatorial impartial games. The games are played on graphs, piles, and grids. We found winning positions, optimal strategies, and other interesting facts about the games., Comment: 12 pages, 1 figure

Abstract While the concept of integrity has long been explored by great philosophers and thinkers, its application in modern and postmodern business and economic contexts has been underdeveloped. Little have been done to address the vagueness and paradoxicality of integrity and its shadow reality of counterfeits. The thematic collection, which this paper complements, entitled ‘Integrity and Its Counterfeits: Implications for Economy, Business and Management’, makes a contribution towards filling the gap between the abstract concept of integrity and its application into business and economy, with a particular attention on the ambiguous, equivocal and diverse meanings of the concept, the complex and dynamic practicality of integrity, and the grey and dark areas of business out of integrity. This article introduces the background of the research theme and provides exemplary debates and emerging avenues of discussion on this topic.

Background: PRMT5 catalyzes symmetric arginine dimethylation of protein substrates with important roles in cancer cell growth/survival, including glioblastoma (GBM) cells. PRT811 is a brain penetrant, potent, selective, oral PRMT5 inhibitor with preclinical efficacy in a GBM orthotopic model (Zhang AACR 2020). An open-label Phase I study of PRT811 in patients (pts) with advanced solid tumors and recurrent high-grade glioma (NCT04089449) is ongoing. Dose escalation results are presented herein. Materials and Methods: This study assesses the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary anti-tumor activity (RECIST v1.1, Lugano, & RANO) of PRT811 administered at varying doses/schedules (15-600 mg daily [QD]; 300 mg twice daily [BID]). Serum symmetric dimethylarginine (sDMA) and intron retention, a marker of PRMT5-mediated mRNA splicing fidelity, were assessed as measures of PRMT5 target engagement and function, respectively. Results: As of 18 June 2021, 38 unselected pts with recurrent or refractory disease had enrolled (22 solid tumor, 16 GBM). Median number of prior lines of systemic therapies was 2. No dose-limiting toxicities have been identified. Most frequent treatment-related adverse events (TRAEs), any grade, were nausea (n=10, 26%), vomiting (n=7, 18%), diarrhea (n=4, 11%), fatigue (n=4, 11%), constipation (n=3, 8%), and pruritis (n=3, 8%). Decreased lymphocyte count (n=1, 3%) and vomiting (n=1, 3%) were the only Grade ≥3 TRAEs. 28 pts discontinued treatment, mainly due to disease progression. No pts discontinued due to treatment-emergent AEs (TEAEs). PRT811 exhibited linear PK characteristics. At the highest evaluated dose (600 mg QD), Cmax,of 3777 nM, AUC of 12,487 nM.hr, and T½ of 5.8 hrs were observed. Comparison of PK parameters of 300 mg administered either QD or BID demonstrated similar PK with no accumulation with the BID schedule. Serum sDMA levels decreased by 80% with 600 mg QD. PRMT5-mediated mRNA splicing fidelity in peripheral blood mononuclear cells showed increased intron retention in specific transcripts at the higher PRT811 doses, indicating PRMT5 functional activity was decreased. A partial response was observed in 1 pt with GBM (>9 months duration) who remains on study. In addition, a pt with uveal melanoma (spliceosome SF3B1 mutation) achieved a 25% decrease in tumor burden per RECIST v1.1. An additional 3 pts with solid tumors had stable disease ≥6 mo. Conclusions: PRT811 was well tolerated with a favorable safety profile when administered at either QD or BID schedules. Target engagement and inhibition of PRMT5 functional activity were observed across multiple dose levels. Preliminary evidence of antitumor activity was observed in GBM and uveal melanoma. The expansion phase of the study will be initiated in select tumor types upon establishing the recommended expansion dose. Citation Format: Gerald S. Falchook, Jon Glass, Varun Monga, Pierre Giglio, David Mauro, John Viscusi, Peggy Scherle, Neha Bhagwat, William Sun, Rachel Chiaverelli, Eric Mintah, Lydia Clements, Tanner M. Johanns, Meredith McKean. A phase 1 dose escalation study of protein arginine methyltransferase 5 (PRMT5) brain penetrant inhibitor PRT811 in patients with advanced solid tumors, including recurrent high-grade gliomas [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P044.

Background: PRMT5 catalyzes symmetric arginine dimethylation of protein substrates with important roles in cancer cell growth/survival. PRT543 is a potent, selective, oral PRMT5 inhibitor with robust preclinical efficacy (Bhagwat AACR 2020). An open-label Phase I study of PRT543 in unselected patients (pts) with advanced solid tumors and hematologic malignancies (NCT03886831) is ongoing. Dose escalation results from pts with solid tumors and lymphoma are presented herein. Materials and Methods: This study assesses safety, pharmacokinetics, pharmacodynamics, and preliminary tumor response (REClST v1.1) of PRT543 administered at varying schedules beginning with twice weekly (BIW) and increasing to once daily (QD) with doses ranging from 5-50 mg in 28-day cycles. Dose escalation followed a 3+3 design. Serum symmetric dimethylarginine (sDMA) and intron retention, a marker of PRMT5-mediated mRNA splicing fidelity, were assessed as measures of PRMT5 target engagement and function, respectively. Results: As of 18 June 2021, 49 unselected pts with measurable disease refractory to established therapies had enrolled (17 pts BIW, 11 pts 5x/week [wk], 21 pts QD). Median number of prior lines of systemic therapies was 3. Six of 21 pts dosed at 25-50 mg QD experienced dose limiting toxicity (DLT) of thrombocytopenia, and 1 pt of 6 dosed at 45 mg 5x/wk had DLT of fatigue. Most frequent treatment-related adverse events (TRAEs), any grade, in all regimens were fatigue (n=20, 41%), nausea (n=14, 29%), thrombocytopenia (n=13, 27%), and anemia (n=12, 24%). Grade ≥3 TRAEs in all regimens occurring in ≥5 pts included thrombocytopenia (n=10, 20%) and anemia (n=6, 12%). Cytopenias were reversible and managed with dose modifications. 44 pts discontinued treatment, mainly due to disease progression, with 2 due to AEs (Grade 3 thrombocytopenia and Grade 4 cholangitis). The 45 mg 5x/wk regimen was selected as the expansion dose. PRT543 demonstrated dose-dependent increases of Cmax (nM) and AUC (nM.hr). At the expansion dose, T½ was 15 hrs, and plasma drug exposures (Cmax, 2142 nM; AUC, 26,293 nM.hr) exceeded those for preclinical efficacy models. Serum sDMA decreased in a dose-dependent manner reaching 77% reduction with 50 mg QD and 69% reduction with the expansion dose. Increased intron retention was seen in peripheral blood mononuclear cells. A complete response (CR) has been maintained for >1 yr in a pt with homologous recombination deficiency-positive (HRD+) ovarian cancer who remains on study therapy. An additional 5 pts exhibited stable disease ≥6 mo. Conclusions: PRT543 was well tolerated with a favorable safety profile. Dose-dependent inhibition of target engagement and functional activity of PRMT5 were observed. PRT543 demonstrated encouraging clinical activity with a CR in HRD+ ovarian cancer and prolonged stable disease in multiple pts. An expansion phase in biomarker-selected solid tumor cohorts is ongoing. Citation Format: Meredith McKean, Manish R. Patel, Robert Wesolowski, Renata Ferrarotto, Eytan M. Stein, Alexander N. Shoushtari, David Mauro, John Viscusi, Peggy Scherle, Neha Bhagwat, William Sun, Rachel Chiaverelli, Eric Mintah, Shekeab Jauhari, Laura Finn, Neil D. Palmisiano, Robert A. Baiocchi. A phase 1 dose escalation study of protein arginine methyltransferase 5 (PRMT5) inhibitor PRT543 in patients with advanced solid tumors and lymphoma [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P039.

Background: PRMT5 is overexpressed in certain myeloid malignancies and catalyzes symmetric arginine dimethylation of protein substrates that regulate expression of genes associated with disease pathogenesis (Pastore et al. Cancer Discov. 2020). PRT543 is a potent, selective, oral PRMT5 inhibitor with preclinical antitumor activity in acute myeloid leukemia and myeloproliferative neoplasm models (Bhagwat AACR 2020). An open-label phase 1 study of PRT543 in unselected patients (pts) with advanced solid tumors and hematologic malignancies (NCT03886831) is ongoing. Dose escalation results from pts with myeloid malignancies are presented herein. Materials and Methods: This study assesses the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy per International Working Group (IWG) response criteria for myelodysplastic syndrome (MDS) and myeloproliferative neoplasm of PRT543 administered at varying schedules beginning with twice weekly (BIW) and increasing to once daily (QD) with doses ranging from 5 to 40 mg in 28-day cycles. Dose escalation followed a modified 3+3 design, allowing for accelerated titration at lower doses. Serum symmetric dimethylarginine (sDMA) and intron retention, a marker of PRMT5-mediated mRNA splicing fidelity, were assessed as measures of PRMT5 target engagement and function, respectively. Results: As of 16 July 2021, 23 unselected pts (12 with myelofibrosis [MF] and 11 with MDS) with disease refractory to established therapies had enrolled (5 pts were dosed BIW, 6 pts 3 times per week [TIW], 5 pts 5 times per week, and 7 pts QD). The median number of prior lines of systemic therapies was 2 (range, 0 to 6). Ten of 12 MF pts had prior exposure to ruxolitinib. Median platelet counts at baseline were 176,500/µL for MF pts and 52,000/µL for MDS pts. Three of 23 pts (13%) experienced dose limiting toxicity (DLT) of thrombocytopenia, with a single occurrence at each of 3 different doses/schedules (40 mg TIW, 35 mg 5 times per week, and 20 mg QD). No other DLTs were reported. The most frequent treatment-related adverse events (TRAEs), any grade, in all regimens were nausea (n=5, 22%), thrombocytopenia (n=5, 22%), anemia (n=4, 17%), diarrhea (n=4, 17%), and fatigue (n=3, 13%). Grade ≥3 TRAEs in all regimens were limited to anemia (n=4, 17%) and thrombocytopenia (n=4, 17%). Cytopenias were reversible and managed with dose modifications. Eighteen pts discontinued treatment, primarily due to disease progression or investigator decision. One pt was discontinued due to an AE (performance status decreased/weakness). PRT543 demonstrated dose-dependent increases of C max (nM) and AUC (nM.hr). At the expansion dose (35 mg 5 times per week), half-life (T ½) was 14 hrs, and plasma drug exposures (C max, 1988 nM; AUC, 19813 nM.hr) exceeded those required for preclinical efficacy. Serum sDMA decreased in a dose-dependent manner reaching 58% reduction with the expansion dose. Increased intron retention in select transcripts was observed in peripheral blood mononuclear cells at the expansion dose. Reductions in inflammatory serum markers, including C-reactive protein and serum amyloid A and cytokines interleukin (IL)-6 and IL-8 were observed. Improvement in individual symptoms such as night sweats, fever and pruritis were noted. Of the 5 MF patients with spliceosome mutations, 1 MF pt (SF3B1) with anemia and transfusion history (8 units over the 121 days prior to baseline) experienced a substantial improvement in anemia (hemoglobin increase from 6.0 to ≥11.1 g/dL). This pt has been transfusion-free for over 300 days and remains on study. Three pts with MF exhibited stable disease per IWG for at least 1 year, with 1 MF pt demonstrating improvement in bone marrow reticulin fibrosis (+2-3 to +1-2). Conclusions: PRT543 was well tolerated with a favorable safety profile. Dose-dependent inhibition of target engagement and functional activity of PRMT5 were observed. PRT543 treatment demonstrated reduction in inflammatory markers and improvement in symptoms and anemia in select patients. Prolonged stable disease per IWG was observed in several pts with refractory MF. PRT543 is currently being evaluated as monotherapy in pts with at least one spliceosome mutation (MF and MDS pts with anemia and pts with high-risk myeloid malignancies) and in combination with ruxolitinib in MF patients demonstrating a suboptimal response to ruxolitinib. Disclosures Patel: Vigeo: Research Funding; Portola Pharmaceuticals: Research Funding; Boehringer Ingelheim: Research Funding; AstraZeneca: Research Funding; TopAlliance: Research Funding; Tesaro: Research Funding; Vedanta: Research Funding; Curis: Research Funding; Ciclomed: Research Funding; Klus Pharma: Research Funding; Kymab: Research Funding; Lycera: Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Bicycle Therapeutics: Research Funding; Hutchinson MediPharma: Research Funding; Ignyta: Research Funding; Taiho: Research Funding; Loxo Oncology: Research Funding; Millennium Pharmaceuticals: Research Funding; Incyte: Research Funding; Jounce Therapeutics: Research Funding; Prelude Therapeutics: Research Funding; H3 Biomedicine: Research Funding; Revolution Medicines: Research Funding; Hengrui: Research Funding; Cyteir Therapeutics: Research Funding; Ribon Therapeutics: Research Funding; Jacobio: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Evelo Biosciences: Research Funding; Takeda: Research Funding; Forma Therapeutics: Research Funding; Artios Pharma: Research Funding; Aileron Therapeutics: Research Funding; Genentech/Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Verastem: Research Funding; Phoenix Molecular Designs: Research Funding; Macrogenics: Research Funding; Mabspace: Research Funding; Alexion, AstraZeneca Rare Disease: Other: Study investigator; Seven and Eight Biopharmaceuticals: Research Funding; Syndax: Research Funding; Synthorx: Research Funding; GlaxoSmithKline: Research Funding; Gilead: Research Funding; Eli Lilly: Research Funding; EMD Serono: Membership on an entity's Board of Directors or advisory committees, Research Funding; Agenus: Research Funding; Checkpoint Therapeutics: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; Xencor: Research Funding; Daiichi Sankyo: Research Funding; ADC Therapeutics: Research Funding; Acerta Pharma: Research Funding; Florida Cancer Specialists: Research Funding; Qilu Puget Sound Biotherapeutics: Research Funding; ORIC Pharmaceuticals: Research Funding; Stemline Therapeutics: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; BioNTech: Research Funding; ModernaTX: Research Funding; Mirati Therapeutics: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Exelixis: Membership on an entity's Board of Directors or advisory committees; LSK Biopartners: Research Funding; Placon Therapeutics: Research Funding; Calithera: Research Funding; Effector Therapeutics: Research Funding; Clovis: Research Funding. Monga: Gunderson Foundation: Other; Rising Tide Foundation: Other; Amgen: Research Funding; Orbus Therapeutics: Research Funding; Prelude Therapeutics: Research Funding; Deciphera: Research Funding; Forma Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees. McKean: Ascentage Pharma Group: Research Funding; Bicycle Therapeutics: Research Funding; Dragonfly Therapeutics: Research Funding; Epizyme: Research Funding; Exelixis: Research Funding; Genentech: Research Funding; GlaxoSmithKline: Research Funding; IDEAYA Biosciences: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ikena Oncology: Research Funding; Infinity Pharmaceuticals: Research Funding; Jacobio Pharmaceuticals: Research Funding; Moderna: Research Funding; NBE Therapeutics: Research Funding; Novartis: Research Funding; Oncorus: Research Funding; Plexxikon: Research Funding; Prelude Therapeutics: Research Funding; Regeneron: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sapience Therapeutics: Research Funding; Seattle Genetics: Research Funding; Tizona Therapeutics: Research Funding; TMUNITY Therapeutics: Research Funding; TopAlliance Biosciences: Research Funding; Astellas Pharma: Membership on an entity's Board of Directors or advisory committees; Array BioPharma: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; BicycleTX Limited: Membership on an entity's Board of Directors or advisory committees; Castle Biosciences: Membership on an entity's Board of Directors or advisory committees; MedPage Today: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Mauro: Prelude Therapeutics: Current Employment, Current equity holder in publicly-traded company. Viscusi: Prelude Therapeutics: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Scherle: Prelude Therapeutics: Current Employment, Current equity holder in publicly-traded company. Bhagwat: Prelude Therapeutics: Current Employment. Moore: Prelude Therapeutics: Current Employment, Current equity holder in publicly-traded company. Sun: Prelude Therapeutics: Current Employment, Current equity holder in publicly-traded company. Chiaverelli: Prelude Therapeutics: Current Employment, Current equity holder in publicly-traded company. Mintah: Prelude Therapeutics: Current Employment. Nath: Actinium: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Stein: PinotBio: Consultancy; Daiichi Sankyo: Consultancy; Syros Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy; Bristol Myers Squibb: Consultancy; Jazz Pharmaceuticals: Consultancy; Foghorn Therapeutics: Consultancy; Genentech: Consultancy; Janssen Pharmaceuticals: Consultancy; Syndax Pharmaceuticals: Consultancy; Astellas: Consultancy; Novartis: Consultancy; Agios Pharmaceuticals, Inc: Consultancy; Blueprint Medicines: Consultancy; Gilead Sciences, Inc.: Consultancy; Abbvie: Consultancy. Palmisiano: Genentech: Research Funding; Takeda: Consultancy; AbbVie: Consultancy, Research Funding; Foundation One: Consultancy. Verstovsek: Ital Pharma: Research Funding; Roche: Research Funding; Novartis: Consultancy, Research Funding; Genentech: Research Funding; Gilead: Research Funding; Protagonist Therapeutics: Research Funding; Promedior: Research Funding; NS Pharma: Research Funding; Incyte Corporation: Consultancy, Research Funding; CTI BioPharma: Research Funding; PharmaEssentia: Research Funding; Celgene: Consultancy, Research Funding; Blueprint Medicines Corp: Research Funding; AstraZeneca: Research Funding; Sierra Oncology: Consultancy, Research Funding; Constellation: Consultancy; Pragmatist: Consultancy.

Background: In 2 phase III studies comparing the Janus kinase (JAK) 1 and JAK2 inhibitor ruxolitinib with placebo (Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment I [COMFORT-I]) or best available therapy (COMFORT-II), ruxolitinib treatment was associated with rapid and durable reductions in spleen volume, improved myelofibrosis (MF)-related symptoms and quality of life measures, and prolonged survival. However, the key measures of efficacy used in the COMFORT studies—magnetic resonance imaging/computed tomography (MRI/CT) to measure change in spleen volume and the modified Myelofibrosis Symptom Assessment Form v2.0 to assess change in MF-related symptoms—are not commonly used in clinical practice. Therefore, we analyzed the efficacy of ruxolitinib in COMFORT-I using practical, community-based measures of clinical benefit (spleen palpation and the Patient Global Impression of Change [PGIC] questionnaire). Methods: In COMFORT-I, patients (N = 309) with primary MF, post–polycythemia vera MF or post–essential thrombocythemia MF were randomized to receive ruxolitinib (n = 155) or placebo (n = 154). For this analysis, patients were divided into groups by degree of palpable spleen reduction and symptom improvement at week 12 as follows: patients with clinically relevant reductions in palpable spleen as defined by the International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European LeukemiaNet (ELN) consensus criteria (SPL), patients with “much improved” or “very much improved” symptoms as measured by the PGIC (PGIC), or patients who did not achieve SPL or PGIC (Neither). The Neither group encompassed patients with “minimally improved” symptoms with no worsening in palpable spleen or patients who achieved 10% reduction in palpable spleen with no worsening in symptoms (Minor), and patients who did not achieve any palpable spleen reduction or PGIC-assessed symptom improvement (None). Nonevaluable patients (4/155 for ruxolitinib and 13/154 for placebo) were not included in the analysis. Additional measures of clinical benefit assessed at week 12 included changes in spleen volume and changes in white blood cell (WBC) count. Durability of all measures of clinical benefit with longer-term ruxolitinib therapy was also evaluated. Results: At week 12, the majority (91.4%) of patients randomized to ruxolitinib achieved some clinical benefit as measured by palpable spleen reduction and/or PGIC-assessed symptom improvement, vs 31.9% of those assigned to placebo (Figure 1). Benefits in palpable spleen length reduction and PGIC-assessed symptom improvement achieved at week 12 with ruxolitinib were sustained at week 24. Benefits in palpable spleen length reduction were sustained with longer-term ruxolitinib therapy (median follow-up: 149 weeks). At week 12, ruxolitinib treatment was associated with meaningful reductions in spleen volume by MRI or CT and WBC count in patients who achieved SPL and PGIC criteria, while worsening spleen volume and WBC count was observed with placebo (Figure 2); these effects were durable with longer-term therapy. Patients who achieved neither SPL nor PGIC criteria by week 12 (n = 47; 31.1%) achieved a clinically meaningful reduction in spleen volume by MRI or CT (mean change, −25.6%) and decreased WBC counts (mean change, −7.4%) at week 12 (Figure 2). Patients who did not achieve any palpable spleen reduction or PGIC-assessed symptom improvement (n = 13; 8.6%) were generally older, more likely to have high-risk MF as assessed by the International Prognostic Scoring System, and had higher WBC counts, lower platelet counts, and worse fibrosis grade at baseline compared with those achieving defined palpable spleen length reduction and/or PGIC-assessed symptom improvement with ruxolitinib. Conclusions: Nearly all patients treated with ruxolitinib achieved some clinical benefit as assessed by practical measures of assessing efficacy (ie, palpable spleen reduction or PGIC-assessed symptom improvement) within 12 weeks of treatment initiation. Meaningful reductions in spleen volume and WBC count were observed in patients receiving ruxolitinib whether or not they achieved palpable spleen reduction by IWG-MRT/ELN consensus criteria or PGIC symptom improvement (“much improved” or “very much improved”) at week 12; these reductions were durable with long-term ruxolitinib therapy. Disclosures Miller: Incyte Corporation: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Komrokji:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Mesa:CTI: Research Funding; NS Pharma: Research Funding; Gilead: Research Funding; Incyte Corporation: Research Funding; Celgene: Research Funding. Sun:Incyte Corporation: Employment. Montgomery:Incyte Corporation: Employment. Verstovsek:Incyte Corporation: Research Funding.

What drives consumers to purchase or not purchase ethical products remains something of a puzzle for consumer behavior researchers. Existing theory—particularly the widely applied theory of planned behavior (TPB)—cannot fully explain ethical purchase decisions. This article contends that not only is the original TPB limited in its applicability to ethical purchasing contexts but also subsequent modifications to it have been generally unfitting. This study advances the literature by taking a different approach to recharacterize and re-extend the original components of the TPB in order to make it more relevant and effective for explaining and predicting ethical consumer decisions. This new theoretical framework of intention formation features four determinants (attitude, subjective norm, moral identity, and perceived behavior control) and a key moderator (level of confidence), and thereby possesses better explanatory and predictive abilities to understand ethical consumer decisions.

1-α-D-(5-Deoxy-5-[18F]fluoroarabinofuranosyl)-2-nitroimidazole ([18F]FAZA) is manufactured by nucleophilic radiofluorination of 1-α-D-(2',3'-di-O-acetyl-5'-O-toluenesulfonylarabinofuranosyl)- 2-nitroimidazole (DiAcTosAZA) and alkaline deprotection to afford [18F]FAZA. High yields (60%) under optimized conditions frequently revert to low yields (20%) in large scale, automated syntheses. Competing side reactions and concomitant complex reaction mixtures contribute to substantial loss of product during HPLC clean-up.To develop alternative precursors for facile routine clinical manufacture of [18F]FAZA that are compatible with current equipment and automated procedures.Two new precursors, 1-α-D-(2',3'-di-O-acetyl-5'-O-(4-nitrobenzene)sulfonyl-arabinofuranosyl)-2- nitroimidazole (DiAcNosAZA) and 1-α-D-(2',3'-di-O-acetyl-5'-iodo-arabinofuranosyl)-2-nitroimidazole (DiAcIAZA), were synthesized from commercially-available 1-α-D-arabinofuranosyl-2-nitroimidazole (AZA). A commercial automated synthesis unit (ASU) was used to condition F-18 for anhydrous radiofluorination, and to radiofluorinate DiAcNosAZA and DiAcIAZA using the local standardized protocol to manufacture [18F]FAZA from AcTosAZA.DiAcNosAZA was synthesized via two pathways, in recovered yields of 29% and 40%, respectively. The nosylation of 1-α-D-(2',3'-di-O-acetyl-arabinofuranosyl)-2-nitroimidazole (DiAcAZA) featured a strong competing reaction that afforded 1-α-D-(2',3'-di-O-acetyl-5'-chloro-arabinofuranosyl)-2- nitroimidazole (DiAcClAZA) in 55% yield. Radiofluorination yields were better from DiAcNosAZA and DiAcIAZA than from DiAcTosAZA, and the presence of fewer side products afforded higher purity [18F]FAZA preparations. Several radioactive and non-radioactive by products of radiofluorination were assigned tentative chemical structures based on co-chromatography with authentic reference compounds.DiAcClAZA, a major side-product in the preparation of DiAcNosAZA, and its deprotected analogue (ClAZA), are unproven hypoxic tissue radiosensitizers. DiAcNosAZA and DiAcIAZA provided good radiofluorination yields in comparison to AcTosAZA and could become preferred [18F]FAZA precursors if the cleaner reactions can be exploited to bypass HPLC purification.

A short tetramer peptide, Ac-IVKC, spontaneously formed a hydrogel in water. Disulfide bonds were introduced via hydrogen peroxide (H2O2)-assisted oxidation, resulting in (Ac-IVKC)2 dimers. The extent of disulfide bond formation and gel stiffness increased with the amount of H2O2 used and 100% dimerization was achieved with 0.2% H2O2. The resultant gel achieved an elastic modulus of ∼0.9 MPa, which to our knowledge, has not been reported for peptide-based hydrogels. The enhanced mechanical property enabled the fabrication of thin and transparent membranes. The hydrogel could also be handled with forceps at mm thickness, greatly increasing its ease of physical manipulation. Excess H2O2 was removed and the membrane was then infused with cell culture media. Various cells, including primary human corneal stromal and epithelial cells, were seeded onto the hydrogel membrane and demonstrated to remain viable. Depending on the intended application, specific cell combination or membrane stacking order could be used to engineer layered biostructures. Statement of Significance A short tetramer peptide – Ac-IVKC – spontaneously formed a hydrogel in water and disulfide bonds were introduced via hydrogen peroxide (H2O2)-assisted oxidation. The extent of disulfide-bond formation and gel stiffness were modulated by the amount of H2O2. At maximum disulfide-bond formation, the hydrogel achieved an elastic modulus of ∼0.9 MPa, which to our knowledge, has not been reported for peptide-based hydrogels. The enhanced mechanical property enabled the fabrication of thin transparent membranes that can be physically manipulated at mm thickness. The gels also supported 3D cell growth, including primary human corneal stromal and epithelial cells. Depending on the intended application, specific combination of cells or individual membrane stacking order could be used to engineer layered biostructures.

In the phase III COMFORT-I study, the Janus kinase 1 (JAK1)/JAK2 inhibitor ruxolitinib provided significant improvements in splenomegaly, key symptoms, and quality-of-life measures and was associated with an overall survival benefit relative to placebo in patients with intermediate-2 or high-risk myelofibrosis. This planned analysis assessed the long-term efficacy and safety of ruxolitinib at a median follow-up of 149 weeks. At data cutoff, approximately 50% of patients originally randomized to ruxolitinib remained on treatment whereas all patients originally assigned to placebo had discontinued or crossed over to ruxolitinib. At week 144, mean spleen volume reduction was 34% with ruxolitinib. Previously observed improvements in quality-of-life measures were sustained with longer-term ruxolitinib therapy. Overall survival continued to favor ruxolitinib despite the majority of placebo patients crossing over to ruxolitinib [hazard ratio 0.69 (95% confidence interval: 0.46–1.03); P=0.067]. Exploratory analyses suggest that crossover may have contributed to an underestimation of the true survival difference between the treatment groups. Ruxolitinib continued to be generally well tolerated; there was no pattern of worsening grade ≥3 anemia or thrombocytopenia with longer-term ruxolitinib exposure. These longer-term data continue to support the efficacy and safety of ruxolitinib in patients with myelofibrosis. The study is registered at clinicaltrials.gov: NCT00952289.

Myelofibrosis (MF), including primary myelofibrosis (PMF) and MF secondary to essential thrombocythemia (ET) or polycythemia vera (PV), is a chronic Philadelphia chromosome–negative myeloproliferative neoplasm associated with progressive bone marrow fibrosis.[1][1] Many patients with MF experience

Myelofibrosis (MF) is associated with a variety of burdensome symptoms and reduced survival compared with age-/sex-matched controls. This analysis evaluated the long-term survival benefit with ruxolitinib, a Janus kinase (JAK)1/JAK2 inhibitor, in patients with intermediate-2 (int-2) or high-risk MF. This was an exploratory analysis of 5-year data pooled from the phase 3 COMFORT-I and -II trials. In both trials, patients could cross over to ruxolitinib from the control group (COMFORT-I, placebo; COMFORT-II, best available therapy). All continuing patients in the control groups crossed over to ruxolitinib by the 3-year follow-up. Overall survival (OS; a secondary endpoint in both trials) was evaluated using pooled intent-to-treat data from patients randomized to ruxolitinib or the control groups. OS was also evaluated in subgroups stratified by baseline anemia and transfusion status at week 24. A total of 528 patients were included in this analysis; 301 were originally randomized to ruxolitinib (COMFORT-I, n = 155; COMFORT-II, n = 146) and 227 to control (n = 154 and n = 73, respectively). The risk of death was reduced by 30% among patients randomized to ruxolitinib compared with patients in the control group (median OS, 5.3 vs 3.8 years, respectively; hazard ratio [HR], 0.70 [95% CI, 0.54–0.91]; P = 0.0065). After correcting for crossover using a rank-preserving structural failure time (RPSFT) method, the OS advantage was more pronounced for patients who were originally randomized to ruxolitinib compared with patients who crossed over from control to ruxolitinib (median OS, 5.3 vs 2.3 years; HR [ruxolitinib vs RPSFT], 0.35 [95% CI, 0.23–0.59]). An analysis of OS censoring patients at the time of crossover also demonstrated that ruxolitinib prolonged OS compared with control (median OS, 5.3 vs 2.4 years; HR [ruxolitinib vs censored at crossover], 0.53 [95% CI, 0.36–0.78]; P = 0.0013). The survival benefit with ruxolitinib was observed irrespective of baseline anemia status or transfusion requirements at week 24. These findings support ruxolitinib treatment for patients with int-2 or high-risk MF, regardless of anemia or transfusion status. Further analyses will be important for exploring ruxolitinib earlier in the disease course to assess the effect on the natural history of MF. ClinicalTrials.gov identifiers, NCT00952289 and NCT00934544 .

The reproduction of the corporation and its legal person status has become something of a self-reinforcing tendency. The law accepts and works with the ambiguity and contradictions of a non-conscious immaterial entity that has legal person status. It does so in order to manage difference. There is, however, a difference between managing difference and preventing increasing disintegration of a system over time. The problem of disintegration creates issues regarding how one addresses specific problems of growing corporate power. Tax avoidance is one important area to address. Corporate tax avoidance is antithetical to human flourishing and also part of a system of human harm. As such, addressing tax avoidance has significance for any concept of Eudaimonia and the Morphogenic Society.

With the discovery of the CRISPR/Cas9 technology, genome editing could be performed in a rapid, precise and effective manner. Its potential applications in functional interrogation of cancer-causing genes and cancer therapy have been extensively explored. In this study, we demonstrated the use of the CRISPR/Cas9 system to directly target the oncogene HER2. Directing Cas9 to exons of the HER2 gene inhibited cell growth in breast cancer cell lines that harbor amplification of the HER2 locus. The inhibitory effect was potentiated with the addition of PARP inhibitors. Unexpectedly, CRISPR-induced mutations did not significantly affect the level of HER2 protein expression. Instead, CRISPR targeting appeared to exert its effect through a dominant negative mutation. This HER2 mutant interfered with the MAPK/ERK axis of HER2 downstream signaling. Our work provides a novel mechanism underlying the anti-cancer effects of HER2-targeting by CRISPR/Cas9, which is distinct from the clinical drug Herceptin. In addition, it opens up the possibility that incomplete CRISPR targeting of certain oncogenes could still have therapeutic value by generation of dominant negative mutants.

Purpose Many consumer-focused corporate social responsibility (CSR) studies suggest a positive link between the responsibility demonstrated by a company and consumers’ intention to favor the company in their purchases. Yet an analogous causal effect between corporate social and financial performances is not evident. This chapter conceptualizes how social desirability and cynicism contribute to the discrepancy between consumers’ attitudes and their actual purchase behavior, and analyzes why consumer choices indicated in surveys do not consistently convert into actions. Methodology/approach We develop a conceptual framework based on hybrid choice modeling to estimate the impact of two new variables, Corporate Social Desirability and Corporate Social Cynicism, on CSR research. The model presented synthesizes research findings from the fields of CSR and psychology with a discrete choice methodology that allows inclusion of psychological aspects as latent variables. Findings The goal of the framework is to bridge the gap between choices stated by consumers in CSR surveys and their actual choices by quantifying and extracting the effects of biases that otherwise threaten the validity of such survey results. As the next step, the practical value of the model must be evaluated through empirical research combining a CSR choice study with social desirability and cynicism measurement. Originality The framework proposes a novel way of controlling CSR surveys for potential biases created by social desirability and cynicism and enables quantification of this impact, with potential application to other fields where psychological aspects may distort research results. Future empirical evidence based on the framework may also offer new insights into the mechanisms by which the two biases distort findings.

Cell surface antigens are important targets for monoclonal antibodies, but they are often difficult to work with due to their association with the cell membrane. Phage display is a versatile technique that can be applied to generate binders against difficult targets. Here we used antibody phage display to isolate a binder for a rare and specialized cell, the human corneal endothelial cell. The human corneal endothelium is a medically important cell layer; defects in this layer account for about half of all corneal transplants. Despite its importance, no specific antigens have been found to mark this cell type. By panning a phage library directly on human corneal endothelial cells, we isolated an antibody that bound to these cells and not the other types of corneal cells. Subsequently, we identified the antibody’s putative target to be CD166 by immunoprecipitation and mass spectrometry. This approach can be used to isolate antibodies against other poorly-characterized cell types, such as stem cells or cancer cells, without any prior knowledge of their discriminating markers.

Background In the COMFORT (COntrolled MyeloFibrosis Study with ORal JAK Inhibitor Therapy)-I study, the Janus kinase (JAK)1/JAK2 inhibitor ruxolitinib provided significant reductions in splenomegaly, improvements in myelofibrosis (MF)-related symptoms, and a survival advantage relative to placebo in patients with intermediate-2 or high-risk MF. In this post hoc analysis, we assessed the effects of ruxolitinib treatment on measures of metabolic and nutritional status. Patients and Methods Patients were randomized to receive ruxolitinib (n = 155; 15 or 20 mg twice a day for patients with baseline platelet counts of 100-200 × 10 9 /L or > 200 × 10 9 /L, respectively) or placebo (n = 154). The primary end point was the proportion of patients with a ≥ 35% spleen volume reduction from baseline to week 24. A secondary end point was the proportion of patients with ≥ 50% improvement in Total Symptom Score (TSS) from baseline to week 24, measured using the modified Myelofibrosis Symptom Assessment Form version 2.0. Weight, cholesterol, and albumin were measured at specified time points throughout the study. Results Compared with placebo, ruxolitinib treatment was associated with increased weight (mean change: 3.9 kg vs. −1.9 kg), total cholesterol (mean percentage change: 26.4% vs. −3.3%), and albumin levels (mean percentage change: 5.8% vs. −1.7%) at week 24; sustained improvements were observed with longer-term ruxolitinib therapy. Relative to placebo, increases in mean weight, total cholesterol, and albumin levels were observed with ruxolitinib treatment regardless of the degree of spleen volume and TSS reductions at 24 weeks. Conclusion Treatment with ruxolitinib improved measures of metabolic and nutritional status of patients with intermediate-2 or high-risk MF.

Background: The phase 3 COMFORT trials demonstrated that the Janus kinase (JAK)1/JAK2 inhibitor RUX reduces spleen volume, prolongs overall survival (OS), and improves MF−related symptoms and measures of quality of life in patients with intermediate-2 or high-risk MF, compared with either placebo (COMFORT-I) or best available treatment (BAT; COMFORT-II). Many patients with MF are anemic or transfusion-dependent; the impact of these features on clinical outcomes is unknown. We evaluated the relationship between transfusion requirement and clinical outcomes in patients treated with RUX in the COMFORT studies. Methods: Analyses of data pooled from COMFORT-I and -II were stratified by baseline anemia status (defined as receiving ≥2 units of red blood cells [RBCs] within the 12 weeks before baseline or baseline hemoglobin [Hb] Results: Overall, 301 patients were randomized to RUX (baseline anemia, n=138 [45.8%]) and 227 to the control group (placebo or BAT; baseline anemia, n=113 [49.8%]). In the RUX group, a greater proportion of patients who were nonanemic at baseline (range, 73.4%-73.8%) achieved transfusion independence compared with those who had anemia at baseline (range, 15.5%-22.4%). Week 24 transfusion independence vs nonindependence status did not significantly affect OS in the RUX group (P=0.1322; Figure A), whereas it was significant (P=0.0004; Figure B) in the control group. Similarly, Week 24 transfusion dependence vs nondependence status did not significantly affect OS in the RUX group (P=0.4547; Figure C), whereas it was significant (P=0.0323; Figure D) in the control group. Median OS was significantly longer in the RUX vs control group for patients who were not transfusion independent (baseline anemia, 200 vs 137 weeks; nonanemic, 271 vs 166 weeks; overall P=0.002) or became transfusion dependent (baseline anemia, 210 vs 127 weeks; nonanemic, 292 vs 90 weeks; overall P=0.0323). Changes from baseline in spleen volume, body weight, and TSS at Week 24 were not affected by transfusion or anemia status in the RUX group; however, TSS worsened in the control group among patients who did not achieve transfusion independence vs those who did. Risk of transfusion dependence decreased after Week 24 in the RUX group. The probability of becoming transfusion independent after 1 year of treatment was similar in both treatment groups (approximately 0.75); median time to transfusion independence for the RUX and control groups was 16.6 and 12.0 weeks, respectively. For patients in the RUX group who became transfusion dependent, the mean monthly units of RBCs peaked at Week 20 (2.82 units), decreasing thereafter to 0.52 units at Week 240. Transfusion dependence did not affect RUX discontinuation rates or dosage. Conclusion: Transfusion requirement had little impact on clinical outcomes or treatment discontinuation within the RUX group but was associated with reduced OS and worsened TSS in the control group. The risk of becoming transfusion dependent, units of RBCs administered, and the monthly proportion of patients requiring transfusions decreased rapidly after 24 weeks of RUX treatment. Disclosures Gupta: Novartis: Consultancy, Honoraria, Research Funding; Incyte Corporation: Consultancy, Research Funding. Verstovsek:Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; CTI BioPharma Corp: Research Funding; Galena BioPharma: Research Funding; Gilead: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding; Seattle Genetics: Research Funding; Celgene: Research Funding; Geron: Research Funding; Lilly Oncology: Research Funding; AstraZeneca: Research Funding; Roche: Research Funding; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding. Paquette:Bristol-Myers Squibb: Research Funding, Speakers Bureau; Ariad: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Kiladjian:AOP Orphan: Research Funding; Novartis: Research Funding. Cervantes:AOP Orphan: Membership on an entity's Board of Directors or advisory committees; Baxalta: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Sun:Incyte Corporation: Employment, Equity Ownership. Gao:Incyte Corporation: Employment, Equity Ownership. Langmuir:Incyte Corporation: Employment, Equity Ownership. Gopalakrishna:Novartis Pharma AG: Employment, Equity Ownership. Harrison:Novartis: Consultancy, Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau; Shire: Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Baxaltra: Consultancy, Honoraria, Speakers Bureau; Incyte Corporation: Honoraria, Speakers Bureau.

Background: MF is a life-shortening complication of myeloproliferative neoplasms associated with ineffective hematopoiesis, splenomegaly, cytopenias, debilitating symptoms, and progressive BM fibrosis The 2 phase 3 COMFORT studies have shown that RUX, an oral Janus kinase (JAK) 1/JAK2 inhibitor, improves splenomegaly, constitutional symptoms, and overall survival in patients with MF. Accumulating evidence suggests that RUX may also modulate the BM microenvironment. Aims: We evaluated the effects of long-term RUX treatment on changes in BM fibrosis in patients with intermediate-2 or high-risk primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF who were enrolled in the phase 3 COMFORT-I study. Methods: BM biopsies were obtained at baseline (BL), Weeks 48 and 72, and approximately every 48 weeks thereafter for up to 5 years of RUX treatment. Biopsies were reviewed independently in a blinded fashion (blinded for patient and treatment) by 3 hematopathologists (HMK, JT, and CEB-R). The final grading was based on consensus; no disagreements were recorded. The WHO grading system was used to grade BM fibrosis density based on a scale of 0-3 (Thiele et al, Haematologica 2005;90). Other details on the patient population and study design for the COMFORT-I study have been published previously (Verstovsek et al, N Engl J Med 2012;366). Biopsies from 59 patients were included in this exploratory analysis; patients who failed screening or received only 1 BM measurement were excluded. Three subgroups were defined for the analysis: 1) originally randomized to RUX (n=36); 2) randomized to placebo with BM measurements at BL and Week 48 (n=15); and 3) crossover to RUX with BM measurements at BL and ≥1 post-BL measurement after crossover (n=21). Changes from BL in BM fibrosis grades at various time points were categorized for each patient as improvement (-1 to -3), stabilization (0), or worsening (1 to 3). Patients with a BL score of 0 for improvement and 3 for worsening were excluded from the analysis. Patients who received placebo for ≥36 weeks were included in the crossover group, with Week 48 used as the BL BM measurement. RUX and crossover groups were combined for evaluation of RUX effect. Placebo effect in the crossover group was assessed by analyzing change from BL to Week 48. Change from BL was evaluated using a signed rank test. Change from BL to last grade, and time to the first occurrence of a ≥1 grade improvement from BL was assessed for RUX and crossover groups. KM analysis was used to estimate time to improvement in BM fibrosis for a subgroup of patients who had a BM fibrosis grade of ≥1 at BL. Results: BL characteristics for age, gender, International Prognostic Scoring System risk, spleen volume, hemoglobin, and platelet counts were similar between the 3 groups. At BL, of 36 patients originally randomized to RUX, 17% (n=6) presented with WHO-defined fibrosis grade 1, 39% (n=14) with grade 2, and 36% (n=13) with grade 3 (3 patients were grade 0). Of the 15 patients randomized to placebo, 20% (n=3) presented with grade 1, 40% (n=6) with grade 2, and 27% (n=4) with grade 3 WHO-defined fibrosis at BL (2 patients were grade 0). Mean exposure to RUX in the RUX and crossover groups was 136.0 (SD, 67.4) weeks and 129.1 (SD, 67.7) weeks, respectively. The proportion of evaluable patients with an improvement in BM fibrosis from BL to Week 48 was 26% (n=27) in the RUX group and 15.4% (n=13) in the placebo group. When evaluating all patients who received RUX (including placebo crossover), a significant shift was observed from BL to the last change in BM fibrosis grade (P=0.0119; signed rank test). For all RUX-treated patients (n=57), 33% (grade -1, n=11; -2, n=7; -3, n=1) had an improvement, 49% had no change or stabilization, and 18% had a worsening in BM fibrosis from BL to the last grade (Figure). At the final grading, 82% (n=47) of patients had improvement or stabilization while on RUX. Median time to a ≥1 grade improvement in BM fibrosis grade was approximately 3.5 years (95% CI, 2.5 to 4.5; n=51). Conclusions: This analysis from the COMFORT-I study showed that treatment with RUX was associated with improvement and stabilization in WHO-defined BM fibrosis in the majority of patients with MF in this study cohort. These results support evidence from other studies, suggesting that RUX treatment may contribute to disease-modifying effects in MF. The clinical effect of improvement and stabilization in BM fibrosis requires further study. Disclosures Kvasnicka: Novartis: Consultancy, Honoraria; Incyte Corporation: Consultancy, Honoraria; AOP Pharma: Consultancy, Honoraria. Thiele:Novartis: Consultancy, Honoraria; Incyte Corporation: Consultancy, Honoraria. Sun:Incyte Corporation: Employment, Equity Ownership. Naim:Incyte Corporation: Employment, Equity Ownership. Svaraman:Incyte Corporation: Employment, Equity Ownership. Gao:Incyte Corporation: Employment, Equity Ownership. Gotlib:Incyte Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Gupta:Incyte Corporation: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Dao:Incyte Corporation: Research Funding. Talpaz:Incyte Corporation: Other: Travel expense reimbursement, Research Funding; Novartis: Research Funding; Ariad: Other: Expense reimbursement, travel accomodation expenses, Research Funding; Pfizer: Consultancy, Other: travel accomodation expenses, Research Funding. Winton:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Verstovsek:AstraZeneca: Research Funding; Roche: Research Funding; Celgene: Research Funding; Lilly Oncology: Research Funding; Galena BioPharma: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Geron: Research Funding; Gilead: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Genentech: Research Funding.

Background:The Janus kinase (JAK) 1/JAK2 inhibitor ruxolitinib has been evaluated for patients with MF in the phase 3 COMFORT studies. In both trials, ruxolitinib prolonged OS, reduced splenomegaly, and improved MF-related symptoms and quality of life compared with controls. Here, we report the results of an exploratory pooled analysis of OS in the COMFORT studies at 5 years of follow-up. Methods: The double-blind COMFORT-I trial and the open-label COMFORT-II trial were randomized phase 3 studies that evaluated the safety and efficacy of ruxolitinib in patients with intermediate-2 (int-2) or high-risk primary MF (PMF), post-polycythemia vera MF (PPV-MF), or post-essential thrombocythemia MF (PET-MF). The comparator was placebo in COMFORT-I and best available therapy (BAT) in COMFORT-II. The ruxolitinib starting dose was 15 or 20 mg twice daily based on baseline platelet counts (100-200 and >200 × 109/L, respectively); dose modifications were permitted for safety and efficacy. Patients were allowed to cross over to ruxolitinib from the control arm for progressive splenomegaly, defined as a ≥25% increase in spleen volume from baseline (COMFORT-I) or study nadir (COMFORT-II), or select protocol-defined progression events; crossover was mandatory following treatment unblinding in COMFORT-I. OS was a secondary endpoint in both studies and was evaluated in an intent-to-treat (ITT) analysis using a Cox proportional hazard model that estimated the treatment effect stratified by clinical trial and International Prognostic Scoring System (IPSS) risk. The crossover-corrected treatment effect was estimated using a rank-preserving structural failure time (RPSFT) method. Results: Overall, 528 patients were randomized: 301 to ruxolitinib (COMFORT-I, n=155; COMFORT-II, n=146) and 227 to placebo (n=154) or BAT (n=73). All ongoing patients in the control arms crossed over to ruxolitinib by the 3-year follow-up. Patient populations were similar between the two trials and their details were previously published. In the combined ruxolitinib group, 162 patients (53.8%) had high-risk MF and 139 (46.2%) had int-2 risk MF based on IPSS criteria. At the 5-year ITT analysis, 128 patients (42.5%) died in the ruxolitinib group compared with 117 (51.5%) in the control group. The risk of death was reduced by 30% with ruxolitinib compared with control (median OS: ruxolitinib, 63.5 mo; control, 45.9 mo; HR, 0.70; 95% CI, 0.54-0.91; P=0.0065; Figure A). After correcting for crossover using RPSFT, OS advantage was more pronounced for patients originally randomized to ruxolitinib (median OS: ruxolitinib, 63.5 mo; control, 27 mo; HR, 0.35; 95% CI, 0.23-0.59; Figure B). An analysis of OS censoring patients at the time of crossover also demonstrated that ruxolitinib prolonged survival compared with control (median OS: ruxolitinib, 63.5 mo; control, 28.3 mo; HR, 0.53; 95% CI, 0.36−0.78; P=0.0013; Figure C). Among all patients treated with ruxolitinib, those with lower-risk disease had longer survival compared with those with high-risk disease (median OS: int-2, not reached [estimated, 102 mo]; high-risk, 50 mo; HR, 2.86; 95% CI, 1.95-4.20; P65 or ≤65 y), sex, disease type (PMF, PPV-MF, PET-MF), risk status (int-2 or high), JAK2V617F mutation status, baseline spleen volume (>10 or ≤10 cm), anemia, white blood cell count (>25 or ≤25 × 109L), or platelet count (>200 or ≤200 × 109/L). Conclusion: Long-term treatment with ruxolitinib up to 5 years prolonged survival in patients with MF compared with BAT or placebo. Corrections for patients who crossed over to ruxolitinib suggested that the separation between ruxolitinib and control OS curves was primarily caused by a delay in ruxolitinib treatment. The results suggest that earlier treatment with ruxolitinib may provide a greater survival advantage for patients with MF. Disclosures Gupta: Incyte Corporation: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Mesa:Incyte: Research Funding; Ariad: Consultancy; Novartis: Consultancy; Celgene: Research Funding; CTI: Research Funding; Promedior: Research Funding; Galena: Consultancy; Gilead: Research Funding. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Kiladjian:AOP Orphan: Research Funding; Novartis: Research Funding. Cervantes:AOP Orphan: Membership on an entity's Board of Directors or advisory committees; Baxalta: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Sun:Incyte Corporation: Employment, Equity Ownership. Gao:Incyte Corporation: Employment, Equity Ownership. Dong:Novartis Pharmaceutical Corporation: Employment, Equity Ownership. Naim:Incyte Corporation: Employment, Equity Ownership. Gopalakrishna:Novartis Pharma AG: Employment, Equity Ownership. Harrison:Incyte Corporation: Honoraria, Speakers Bureau; Baxaltra: Consultancy, Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; CTI Biopharma: Consultancy, Honoraria, Speakers Bureau; Shire: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau.

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Background: Age, prior thrombotic events, and an elevated hematocrit are established risk factors for increased risk of thrombosis in patients with polycythemia vera (PV). Evidence also suggests that elevated white blood cell (WBC) counts ≥ 11×109/L are a significant independent risk factor for thrombosis in patients with PV (P =0.02; Barbui T, et al. Blood. 2015; 126:560-561). Therefore, this analysis was conducted to evaluate the impact of ruxolitinib (Rux) and best available therapy (BAT) treatment on WBC counts among patients with Baseline WBC counts ≥ 11×109/L in the RESPONSE trial. RESPONSE is a global, multicenter, open-label phase 3 trial investigating Rux and BAT in patients with PV who are resistant to or intolerant of hydroxyurea (HU). In the RESPONSE trial, Rux was associated with durable improvements in hematocrit control without phlebotomy compared with BAT as well as reductions in WBC counts. Methods: Changes from Baseline in WBC counts in the Rux arm (n=110), BAT arm (n=112), and HU subgroup of the BAT arm (n=66) were evaluated as part of an exploratory analysis using the RESPONSE 80-Week analysis dataset. Patient subgroups with Baseline WBC counts ≥ 11×109/L and < 11×109/L were analyzed for changes in WBC counts at Weeks 12, 32, and 80. For patients with Baseline WBC counts ≥ 11×109/L, the proportion of patients who achieved a decrease in WBC counts to ≤ 10×109/L or a ≥50% reduction at Week 12 and Week 32, respectively, was summarized; time to achieve the decrease was analyzed by Kaplan-Meier method. Results: Baseline mean WBC counts were generally similar among patients in the Rux arm, BAT arm, and HU subgroup (17.6×109/L, 19.0×109/L, and 17.4×109/L, respectively). The proportion of patients with Baseline WBC counts ≥ 11×109/L was also similar among the Rux arm, BAT arm, and HU subgroup (75%, 71%, and 70%, respectively). In patients with Baseline WBC counts ≥ 11×109/L, patients treated with Rux had greater mean reductions in WBC counts compared with the BAT arm and HU subgroups, and these reductions were maintained over time; mean changes from Baseline in WBC values at Week 12/Week 32 (×109/L) were -7.7/-7.2 for Rux, -3.2/-4.2 for BAT, and -1.2/-2.2 for HU. In patients with lower Baseline WBC counts, mean values remained stable over time. The change from Baseline to Week 12 for individual patients with Baseline WBC counts ≥ 11×109/L is shown in Figure 1. In patients with Baseline WBC counts ≥ 11×109/L, worsening WBC counts were observed in 10.8% of patients in the Rux arm vs 35.4% in the BAT arm (P =0.0002) and 47.8% in the HU subgroup (P Conclusion: Rux treatment resulted in better control of WBC counts compared to BAT in patients with PV. These changes in the Rux arm occurred early after study initiation (within a median of 8 weeks) and were durable over time. Although RESPONSE was not powered to assess the impact of Rux on thromboembolic events, the lower rate of thromboembolic events observed in the Rux arm vs the BAT arm (1.8 vs 8.2 per 100 patient-years of exposure) is consistent with the observed effects of Rux on hematocrit, WBC counts, and C-reactive protein levels, which are all associated with thromboembolic risk. Disclosures Miller: Incyte Corporation: Honoraria, Research Funding. Kiladjian:Novartis: Other: Travel grant; Research Funding paid to institution (Hôpital Saint-Louis et Université Paris Diderot); Incyte Corporation: Consultancy; Novartis: Consultancy. Naim:Incyte Corporation: Employment, Equity Ownership. Sun:Incyte Corporation: Employment, Equity Ownership. Gadbaw:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Vannucchi:Baxalta: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Shire: Speakers Bureau.

The purpose of the panel symposium is to engage a group of panelists in a formal, moderated and interactive discussion of how ethical governance can be properly built or rebuilt into private busine...