Research Agreement Research Articles

0013 Psychomotor Vigilance Test Performance Declines Related to Illness Severity, not Sleep

Abstract Introduction While the Psychomotor Vigilance Test (PVT) has been used extensively to track vigilance degradation following sleep loss, there is evidence that it may also track vigilance degradation related to illness. However, it is unclear how much performance decline is driven by sleep loss related to an illness or the illness itself independent of sleep loss. Here we assessed how sleep and acute infectious diarrhea impact vigilance performance in a controlled human infection model (CHIM) with enterotoxigenic Escherichia coli (ETEC). Methods During a CHIM assessing the efficacy of an immunoprophylactic targeting ETEC, we measured sleep via actigraphy over an 8-day inpatient period. A 10-minute PVT was also administered up to three times each day in the morning, afternoon, and evening. Participants ingested an oral immunoprophylaxis 3 times/day on days -2 and -1, and ingested ETEC on day 0. Participants were categorized as to whether or not they experienced the primary endpoint of moderate-severe diarrhea (MSD). Results Among 56 participants (aged 34.7±8.5 years, 64% male), 54% reached the primary endpoint of moderate-severe diarrhea following ETEC infection. Total sleep times across the study did not differ between those with and without MSD. While PVT minor lapses (i.e., not responding within 500 milliseconds) did increase following ETEC infection for all subjects as revealed by a mixed linear model [effect of day: f(7,657)=3.35, p=0.002], there was also a significant main effect of group [f(1,657)=5.85, p=0.016], where those participants who experienced MSD following ETEC infection had more minor lapses across the study than those who did not experience MSD (6.28±0.43 vs 4.88±0.38). Conclusion While the negative impact of sleep loss on performance has been well demonstrated, these are the first data to suggest that illness severity[KT1] , independent of sleep loss, also negatively impacts performance. In operational populations such as the military, special care should be taken to prevent illness and remove ill operators from the field, just as this care should be taken to prevent sleep loss and remove sleepy operators. By preventing and monitoring sleep loss and illness, these operations can avoid potentially costly performance errors. Support (If Any) The clinical trial from which these data were obtained was funded by the Congressionally Directed Medical Research Program through the Joint Warfighter Medical Research Program under Award No. W81XWH-15-C-0083 to the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. The U.S. Army Medical Research Acquisition Activity was the awarding and administering acquisition office. The study was also funded by a Collaborative Research and Development Agreement with PATH Enteric Vaccine Solutions (NCRADA-NMRC-15-9589), as well as by the Military Operational Medicine Research Program (MOMRP).

Ultrasound-facilitated, catheter-directed thrombolysis vs anticoagulation alone for acute intermediate-high-risk pulmonary embolism: Rationale and design of the HI-PEITHO study

BackgroundDue to the bleeding risk of full-dose systemic thrombolysis and the lack of major trials focusing on the clinical benefits of catheter-directed treatment, heparin antiocoagulation remains the standard of care for patients with intermediate-high-risk pulmonary embolism (PE). Methods and resultsThe Higher-Risk Pulmonary Embolism Thrombolysis (HI-PEITHO) study (ClinicalTrials.gov Identifier: NCT04790370) is a multinational multicenter randomized controlled parallel-group comparison trial. Patients with: (1) confirmed acute PE; (2) evidence of right ventricular (RV) dysfunction on imaging; (3) a positive cardiac troponin test; and (4) clinical criteria indicating an elevated risk of early death or imminent hemodynamic collapse, will be randomized 1:1 to treatment with a standardized protocol of ultrasound-facilitated catheter-directed thrombolysis plus anticoagulation, vs anticoagulation alone. The primary outcome is a composite of PE-related mortality, cardiorespiratory decompensation or collapse, or non-fatal symptomatic and objectively confirmed PE recurrence, within 7 days of randomization. Further assessments cover, apart from bleeding complications, a broad spectrum of functional and patient-reported outcomes including quality of life indicators, functional status and the utilization of health care resources over a 12-month follow-up period. The trial plans to include 406 patients, but the adaptive design permits a sample size increase depending on the results of the predefined interim analysis. As of May 11, 2022, 27 subjects have been enrolled. The trial is funded by Boston Scientific Corporation and through collaborative research agreements with University of Mainz and The PERT Consortium. ConclusionsRegardless of the outcome, HI-PEITHO will establish the first-line treatment in intermediate-high risk PE patients with imminent hemodynamic collapse. The trial is expected to inform international guidelines and set the standard for evaluation of catheter-directed reperfusion options in the future.

Androgen deprivation therapy allows for effective anti-TIGIT immunotherapy in murine model of castration resistant prostate cancer.

Abstract Prostate cancer is the second leading cause of cancer associated mortality in men, and for reasons that remain unclear, immunotherapy treatments have largely failed in patients with advanced prostate cancer. Standard of care therapy for these patients relies on androgen deprivation therapies (ADT) to block testosterone production combined with small molecules that inhibit androgen synthesis and/or the function of the androgen receptor (AR). Importantly, androgens are reported to be immunosuppressive; therefore, we postulated that androgen axis blockade might promote response to immunotherapy. In the recent years, the co-inhibitory receptor TIGIT has emerged as a promising immunotherapy target, and we observed that TIGIT is highly expressed on tumor infiltrating T cells and NK cells in metastatic castration resistant prostate cancer (CRPC) patients treated with the AR antagonist enzalutamide. Likewise, in a mouse model of CRPC, we show that tumor infiltrating T cells express TIGIT and that treatment with enzalutamide increases its expression. In this model, neither treatment with anti-TIGIT alone nor with chemical castration and enzalutamide affects tumor growth. Remarkably, the combination of anti-TIGIT with chemical castration and enzalutamide leads to delayed tumor growth and long-term cures in about 60% of the animals. Taken together, our data suggest that androgen receptor blockade sensitizes immune cells in the tumor to respond to anti-TIGIT immunotherapy. This work was largely supported by an OHSU Foundation grant and a sponsored research agreement with AstraZeneca to A.E.M. Additional funding was provided by Collins Medical Trust and Prostate Cancer Foundation.

VEDOLIZUMAB REDUCES DENDRITIC CELLS AND NAÏVE LYMPHOCYTES IN THE COLON MUCOSA

Abstract Vedolizumab blocks integrin alpha4/beta7 interaction with MAdCAM-1 on intestinal vascular endothelial cells. It is believed to treat inflammatory bowel disease (IBD) by preventing alpha4/beta7+ cells in blood from entering the intestinal mucosa. By CyTOF and flow cytometry, we found high expression of alph4/beta7 on nearly all myeloid dendritic cells in the blood. Flow cytometry was also performed on colon biopsies from 71 IBD patients on vedolizumab matched 1:1 with similar biopsies from 71 matched IBD patients not on vedolizumab. In the colon, vedolizumab use was associated with significantly fewer intramucosal myeloid dendritic cells (CD1c+, CD14−, CD11c+, HLA-DR+, Wilcoxon p=0.000001) in patients responsive to vedolizumab, but not in non-responders, relative to their respective controls. Fewer intramucosal naïve B (IgD+, Wilcoxon p=0.0001) and CD4 T cells (CD45RA+, Wilcoxon p=0.001) were also observed, regardless of treatment efficacy. No differences were observed in the frequency of other T or B cell subsets, including CD8 T cells, effector T cells, plasma cells and memory B cells expressing different immunoglobin isotypes, suggesting that they have an alternative means of recruitment not present among naïve lymphocytes, such as integrin alpha4/beta1, which binds VCAM-1. Thus we find no evidence that that vedolizumab functions by preventing effector lymphocytes from entering the intestinal mucosa. We instead associated vedolizumab use with fewer colonic naïve lymphocyte and myeloid dendritic cells. The latter is of particular interest, as it alone correlates with clinical response to this therapy. Supported by a collaborative research agreement with Takeda Pharmaceuticals

The effects of interfirm cooperation purpose on export performance: Choosing between local and overseas partners

While recent research finds that cooperating with local partners increases export performance, other studies show that home ties negatively affect exports. This article contributes to the discussion on the inconclusive effects of local and overseas innovation cooperation arrangements on export performance by examining the specific purpose of the innovation collaboration agreement. In analyzing StatsNZ Business Operations Survey data, we unexpectedly find that most local cooperation agreements negatively affect export performance. In contrast, research and development agreements with local partners positively influence export performance. Our results show that although collaborating with an overseas partner on marketing and prototyping positively affects export performance, counterintuitively, interfirm cooperation with an international partner with the purpose of research and development exhibits no effect on the probability of becoming an exporter. Implications for managers and policymakers are discussed.

Effectiveness of an Instructional Program for Teachers about Students' School Phobia at Primary Schools

Objectives: Evaluate the effectiveness of the instructional program for teacher's knowledge's about student's school phobia at primary school. Study design: A quasi-experimental design was implemented in the research to achieve the study goals by using pre- and post-tests for one group of teachers in primary school. in Al- Amara Region. The study has been carried out during the period extended from the 23th december 2021 to 20th July 2022. Data collection: The permission was presented to the Ministry of education- office of Misan provenance/ deparment of oversight specialist to ensure the research agreement and cooperation and to provide access the these school facilities. In order to attain precise data and illustrative sample , non-probability (purposive) sample is carefully chosen which consists of (25) teachers Conclusion: Illustrated from this study, the teachers have poor knowledge regarding primary students school phobia at pretest in study group. Association between teachers' knowledge and their (gender, level of education, years of experience and main source of information. Keywords: teachers, students' school phobia, primary schools

Research contract relationship between a large industry partner and South African universities

We propose and evaluate a contractual structuring instrument (in the form of a Framework Research Agreement) in support of research collaboration partnerships between universities and large industry, specifically for the case of large industry in the South African context. This study includes one large South African originated industry (as the pioneer of concluding Framework Research Agreements with several universities) and multiple South African universities, and stretches over several decades. This study was done within the broader context of the challenges and benefits experienced by both industry and university in the academic engagement sphere of industry–university collaboration. By providing insight from both industry and university perspectives, factors impacting on academic engagement (with specific emphasis on the legislative framework, contractual aspects, institutional research contract practices and institutional risks), are considered and discussed. Recommendations are made for improved industry–university collaboration by sharing experiences from the industry and universities on challenges faced, managing the expectations and proposing mechanisms to support constructive research collaboration through a mutually beneficial contractual framework instrument. Significance: A novel Framework Research Agreement as a contractual instrument was developed and pioneered by the industry partner with several South African universities, to create a transparent framework based on fair contracting and determinable remuneration principles. This study specifically highlights the need for a contractual instrument, in which the intention is to build a long-term contractual relationship to support industry–university collaboration and academic engagement within the existing South African legislative framework. It further draws attention to research contract management practices and contractual aspects, which until now have been largely ignored in industry–university collaboration and academic engagement frameworks of this kind.

Protocol for a systematic review of the in vivo studies on radiofrequency (100\u2009kHz\u2013300\u2009GHz) electromagnetic field exposure and cancer

BackgroundAn Italian project aims to review the scientific literature on the possible carcinogenicity of radiofrequency (100 kHz–300 GHz) electromagnetic field (RF-EMF) exposure. The ENEA team has to carry out a systematic review of the in vivo studies on this topic.ObjectivesDevelopment of a protocol for a systematic review (meta-analysis included) to investigate the potential carcinogenic risk following RF-EMF in vivo exposure to doses above or within legal limits. The aims of this review are (1) to provide a descriptive and, if possible, a quantitative summary of the results of the examined RF-EMF in vivo studies, together with an assessment of the consistency of observations and of the causes of heterogeneity, and (2) to assess the weight of evidence to support or refute the hypothesis of carcinogenic effects caused by RF-EMF exposure and to draw conclusions about the potential for carcinogenicity of RF-EMF exposure.MethodsWe will search for relevant studies in electronic academic databases and in the reference list of selected papers and reviews on the topic, including the descriptive reviews on RF-EMF carcinogenic effect carried out by international panels of experts since 2011. The following elements of the PECO question were defined: experimental studies on rodents of both sexes, all ages and species, all genetic backgrounds (Population) exposed to RF-EMF alone, or in combination with other physical or chemical agents (Exposure); only studies reporting outcome data in exposed and sham control groups (Comparison); and all types of cancer with all tumor-related outcome measures (Outcome) will be included.Only peer-reviewed articles written in English will be considered without limit in the publication date.Eligibility criteria were defined for papers to be included. A risk of bias assessment will be performed using a tool specifically developed for animal studies. A meta-analysis will be performed, if feasible, for all outcome measures; for subgroup analysis, a minimum of 3 studies per subgroup will be required. If meta-analysis will not be possible, a narrative synthesis of the results will be reported.Systematic review registrationPROSPERO CRD42020191105HighlightsAn Italian collaborative research agreement aims to review the scientific literature on the possible carcinogenicity of RF-EMF (100 kHz – 300 GHz).The ENEA team will systematically review and, if possible, meta-analyse estimates the effects of in vivo exposure to RF-EMF exposure on cancer.The ENEA group is a multidisciplinary team of researchers with a consolidated experience both in carcinogenicity experiments and radiofrequency dosimetric assessment.The proposed protocol uses the NTP OHAT Approach for Systematic Review as an organizing framework.The proposed protocol aims to lead to the first systematic review providing a strength of evidence assessment on this topic.

Structural variations on the surface of metallic products at laser marking

Laser marking of products and details is used more and more wide in different production areas, because it has undisputable advantages in comparison with other marking methods. Action of laser beam on the surface of marking product is the principal feature of laser marking. It is accompanied with local heating of this surface and its partial melting together with material evaporation from the surface contact point. Influence of laser impulse action on efficiency of marking on the surface of machine-building details is examined in this work. The samples of 08Kh18N10 steel were used as material. Marking was conducted by the system “MiniMarker 2-20A4”, QR code was used as a marker. The marking parameters were optimized via the method of experimental design. The optimal marking procedure for getting maximal contrast of QR code was calculated and experimentally confirmed. Steel surface roughness was analyzed using profilograms. Contrasting effect and roughness of code were determined and relationship between these parameters was revealed. Contrast effect of marking increases with elevation of roughness. However, roughness has less input in increase of contrast effect comparing with colour hue of the surface of an information block and substrate. The link between surface roughness and contrast effect of marking is shown. Possibility of contrast effect assessment of QR code using profilometer is suggested. The reported study was financially supported by the Ministry of Science and Higher Education of the Russian Federation, research agreement No. 075-11-2019-066 of 22.11.2019, project title “Development of high-tech production of equipment and technologies for laser coding of transported goods and their optical identification for the implementation in modern material flow management systems” (within the framework of decree of the Government of the Russian Federation, No. 218 of 09.04.2010).

Managing Human Subjects Research During a Global Pandemic at an Academic Center: Lessons Learned From COVID-19.

By March 2020, New York City became the early epicenter of the COVID-19 pandemic in the United States. Consequently, Columbia University, with its large portfolio of human subjects research, had to address the challenges of protecting thousands of research participants and research staff from potential exposure to COVID-19 while facilitating essential biomedical research, especially pandemic-related studies. The authors describe, from the perspective of Columbia’s research administration leadership, how the University and its primary teaching hospital ramped down—and later ramped up—human subjects research and reflect on lessons learned.As the pandemic unfolded, only studies offering the prospect of direct benefit to subjects were permitted to continue with in-person contact. New in-person participant enrollment ceased, except for COVID-19 prevention or treatment studies. Centralized, frequently updated communication about policies and procedures was disseminated to the Columbia research community. Procedural efficiencies were rapidly developed and implemented for review and oversight of human subjects research and contractual agreements for clinical trials. More frequent institutional review board meetings and 24-hour support markedly reduced turnaround time for COVID-19 studies, without delaying approvals of non–COVID-19 research. Research administration worked closely with relevant principal federal agencies, whose regulatory flexibility facilitated the efficient implementation of COVID-19–related research.Overall, the ramp-down and ramp-up of the majority of human subjects research, with specified priorities and accelerated processes, worked well. Adjustments were made to handle the increase in administrative tasks, the need to respond rapidly to added oversight responsibilities, and the management of the many new COVID-19–related research protocols. Timely, centralized communication, support for staff needs, prioritization, and collaboration were critical to successful research oversight at a large-scale academic setting in the midst of a pandemic. These perspectives may be useful to academic research centers addressing the current and future pandemics.

Abstract LBA016: Androgen Receptor (AR) N-Terminus-Domain-Binding Small Molecule Degraders for the Treatment of AR Splice Variant-Positive Castration-Resistant Prostate Cancer

Abstract Prostate cancer is the second leading cause of cancer-related deaths in men in the United States. Over 30,000 men die of prostate cancer each year in the U.S. and the deaths predominantly occur due to late-stage castration-resistant prostate cancer (CRPC). Androgen receptor (AR) is the primary therapeutic target in castration-sensitive prostate cancer and CRPC, with over 85% of the cases expressing AR. About 30% of CRPC fail to respond to ligand-binding domain (LBD)-binding AR-signaling inhibitors, while the remaining develop resistance after an initial period of response of 12-24 months. Expression of AR splice variants (AR-SVs) that lack LBD has been identified as one of the primary causes for resistance development to AR-signaling inhibitors. AR-SVs also promote aggressive CRPC growth, resulting in shorter overall survival. We discovered novel AR N-terminus domain (NTD)-binding small molecule, GTx-534 that induce degradation of AR and AR-SV proteins, resulting in loss of AR signaling. Surface Plasmon Resonance (SPR), intrinsic fluorescence biophysical studies and thermal stability analysis with purified AR activation function-1 (AF-1) domain in the NTD showed GTX-534 binding. Notably, GTx-534 significantly inhibited AR and AR-V7-positive 22RV1 cell line xenograft in castrated immune compromised rodents with a tumor growth inhibition (TGI) of over 50% (p<0.005), while enzalutamide failed to inhibit the 22RV1 tumor growth. Serum PSA concentrations of 22RV1-bearing animals were reduced to background levels by GTx-534 (p<0.01), but not by enzalutamide. Genome-wide expression studies demonstrated a distinct mechanism of action for GTx-534 in AR-SV-positive tumors. The results from 22RV1 xenograft studies were validated in LuCaP 86.2 patient-derived xenograft (PDX) that express AR v567es, another AR variant that lacks the LBD widely expressed in CRPC. GTx-534 completely inhibited LuCaP 86.2 tumor growth with a TGI of greater than 90%, while enzalutamide failed to alter the tumor growth. These results provide preclinical proof-of-concept for the efficacy of GTx-534 in AR and AR-SV-positive CRPC. Disclosure. The work presented in here was funded by a Sponsored Research Agreement from Oncternal Therapeutics, Inc. to RN and DDM and by National Cancer Institute grant R01CA229164 to RN. RN is a consultant to Oncternal Therapeutics Inc. GFK and JBB are employees of Oncternal Therapeutics Inc. Citation Format: Ramesh Narayanan. Androgen Receptor (AR) N-Terminus-Domain-Binding Small Molecule Degraders for the Treatment of AR Splice Variant-Positive Castration-Resistant Prostate Cancer [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 LBA016.

Myeloablative Fractionated Busulfan Conditioning Regimen with Sorafenib in Patients with AML: Results of Phase I Clinical Trial

Myeloablative Fractionated Busulfan Conditioning Regimen with Sorafenib in Patients with AML: Results of Phase I Clinical Trial

Optimizing Myeloablative Fractionated Busulfan, Fludarabine and Thiotepa Regimen: Results of Two Parallel Cohorts in a Phase 2 Prospective Clinical Trial

Background: Myeloablative conditioning can be given safely to older patients by simply administering busulfan (Bu) over a longer period (fractionated (f)-Bu) with fludarabine (Flu) than the standard four-day regimen. (Popat et al Lancet Haematology 2018). We added thiotepa (Thio) to this f-Bu/Flu regimen in patients with haploidentical (haplo) donors to promote engraftment and to reduce relapse. With encouraging results, Thio was then added in matched unrelated (MUD) and sibling (MSD) donor recipients also. However, the optimal doses of Thio and Bu were undefined. To further optimize the regimen, we tested two different f-Bu/Flu/Thio regimens in parallel prospective cohorts: (a) higher dose Bu with lower dose Thio, and (b) lower dose Bu with a higher dose Thio. Patients were enrolled on these cohorts based on age and co-morbidity index (HCT-CI). Herein, we report on the safety and preliminary efficacy of these regimens (NCT02861417).Methods: Patients <60 years with HCT-CI <3, or >60 years with HCT-CI <2 received IV f-Bu to target an area under the concentration vs time curve (AUC) of 20,000 ± 12% μmol.min with Thio 2.5 mg/kg (Bu20K/Thio2.5; Cohort 1). Patients <60 years with an HCT-CI >3, or >60 years with HCT-CI >2, or >70 years irrespective of HCT-CI received f-BU to target AUC of 16,000 with Thio 5mg/kg (Bu16K/Thio5; Cohort 2). In both cohorts, the first two doses of Bu (80 mg/m2 IV each) were given as outpatient on days -20 and -13. The last four Bu doses were given as inpatient following each dose of Flu 40 mg/m2 on days -6 through -3. Thio was given on day -7. GVHD prophylaxis was post-transplant cyclophosphamide (PTCy) 50mg/kg on days 3 and 4, tacrolimus and MMF.Results: 66 patients were enrolled - 25 in cohort 1 and 41 in cohort 2, with a median age 60 years (range, 22-69) vs 62 years (range, 30-74), respectively (P=0.14). Diagnoses were AML/MDS (64% vs 54%), CML/MPD (24% vs 22%), ALL (12% vs 22%) and 1 myeloma; P=0.24. Most had intermediate disease risk index (80% vs 73%, P=0.57); median HCT-CI was 1 (range, 0-6) vs 3 (range, 0-9); P<0.0001. Donor was haplo (60% vs 19%), MUD (24% vs 54%) or MSD (16% vs 27%); P=0.002; BM graft was used in 56% vs 27%; p=0.02, respectively, in cohorts 1 and 2. The median follow-up among survivors was 18.7 months.Primary graft failure occurred in 1 patient in cohort 1 and none in cohort 2. The median time to neutrophil engraftment was 17.5 days (range, 14-26) vs 18 days (range, 12-26); P=0.12, respectively; platelet engraftment > 20K was 30 days in both groups; P=0.75. Median donor chimerism at day 30 was 100% in both groups. The incidence of acute GVHD grade III-IV was 4% vs 5%; P=0.88 at day 100; extensive chronic GVHD at 1 year was 13% vs 10%; P=0.83. At 1-year overall survival was 72% vs 78%; P=0.95; relapse was 12% each; non-relapse mortality was 20% vs 17%; P=0.97 [Table 1, Fig 1]. Common grade >3 toxicities were neutropenic fever (64% vs 42%; P=0.13), bacterial infection (44% vs 34%; P=0.45), nausea (12% vs 2%; P=0.15), mucositis (8% vs 5%; P=0.63), pneumonitis (12% vs 7%; P=0.67), hemorrhagic cystitis (8% vs 5%) and sinusoidal obstructive syndrome (8% vs 2.4%).Conclusion: In this population of older patients and/or high co-morbidities, both myeloablative regimens with f-Bu/Flu with thiotepa and PTCy were well tolerated and led to low NRM, low risk of relapse and encouraging survival. Although both regimens led to similar outcomes, the f-Bu/Flu/Thio regimen with Bu16K and thiotepa 5 mg/kg dose may be preferred as this was used in patients who were older and/or had high co-morbidities. [Display omitted] DisclosuresPopat: Bayer: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Incyte: Research Funding. Mehta: CSLBehring: Research Funding; Kadmon: Research Funding; Syndax: Research Funding; Incyte: Research Funding. Hosing: Nkarta Therapeutics: Membership on an entity's Board of Directors or advisory committees. Rezvani: Caribou: Other: Scientific Advisory Board; Virogin: Other: Scientific Advisory Board ; AvengeBio: Other: Scientific Advisory Board ; GSK: Other: Scientific Advisory Board ; Bayer: Other: Scientific Advisory Board ; Navan Technologies: Other: Scientific Advisory Board; GemoAb: Other: Scientific Advisory Board ; Takeda: Other: License agreement and research agreement, Patents & Royalties; Pharmacyclics: Other: Educational grant, Research Funding; Affimed: Other: License agreement and research agreement; education grant, Patents & Royalties, Research Funding. Qazilbash: Oncopeptides: Other: Advisory Board; Janssen: Research Funding; Bristol-Myers Squibb: Other: Advisory Board; NexImmune: Research Funding; Amgen: Research Funding; Angiocrine: Research Funding; Biolline: Research Funding. Shpall: Affimed: Patents & Royalties; Adaptimmune: Consultancy; Novartis: Consultancy; Magenta: Consultancy; Magenta: Honoraria; Axio: Consultancy; Takeda: Patents & Royalties; Navan: Consultancy; Novartis: Honoraria; Bayer HealthCare Pharmaceuticals: Honoraria.

Incidence and Outcomes of Toxoplasma Reactivation in Patients with Hematologic Diseases after Allogeneic Hematopoietic Stem Cell Transplantation

Incidence and Outcomes of Toxoplasma Reactivation in Patients with Hematologic Diseases after Allogeneic Hematopoietic Stem Cell Transplantation

Myeloablative Fractionated Busulfan Conditioning Regimen with Venetoclax in Patients with AML/MDS: Prospective Phase II Clinical Trial

Background: Myeloablative conditioning can be given safely to older patients by simply administering busulfan over a longer period (fractionated busulfan regimen) than the standard four-day regimen (Popat et al Lancet Haematology 2018). This longer duration of conditioning regimen allows addition of targeted agents like Venetoclax, which may be synergistic with conditioning chemotherapy and may further improve disease control with this regimen. We therefore added Venetoclax to our ongoing prospective clinical trial with f-Bu-Flu-Cladribine conditioning (NCT02250937). After enrolling 83 patients, the study was amended and venetoclax was added for the next 33 patients. Here we report the safety and preliminary efficacy of venetoclax and fractionated busulfan regimen.Methods: Between 2/2019 and 3/2021, 33 patients with AML (n=21) or MDS (n=10) up to 70 years of age with adequate organ function and 8/8-HLA matched related or unrelated donor were enrolled on a prospective trial. The conditioning regimen was f-Bu to target an area under the concentration vs time curve (AUC) of 20,000 ± 12% μmol.min given over a period of 2-3 weeks. The first two doses of busulfan (80 mg/m2 IV each) were administered either consecutively (days -13 and -12) or with further fractionation, one week apart (days -20 and -13) on outpatient basis. Then, inpatient fludarabine 10 mg/m 2, and cladribine 10 mg/m 2 were given followed by Bu on days -6 to -3. Venetoclax 400mg daily was given from day -22 to -3. Azoles were avoided during this period. GVHD prophylaxis was PTCy 50mg/kg on days 3 and 4 and tacrolimus from day 5.Results: The median age was 59 years (range, 23-69); High or very high disease risk index was present in 21%; Comorbidity index score of >3 was present in 45%; Donor was a sibling in 39%; and peripheral blood stem cells was the graft source in 100%.The median follow up was 8 months. At 1-year, overall survival was 84% (95% confidence interval, 71-100), progression-free survival 77% (64-94), relapse 13% (1-25), and non-relapse mortality 10% (0-20) [Table 1, Figure 1]. Incidence of acute GVHD grade 2-4 was 28% (12-43) and grade 3-4 acute GVHD was 3% (0-9) at day 100. All patients engrafted. The median time to neutrophil engraftment was 15 days (13 -19) and median time to platelet engraftment was 23 days (11-85). Full donor chimerism at day 30 was noted in 76%. Common grade 3 or 4 toxicity were neutropenic fever (58%), mucositis (18%) and pulmonary toxicity in 21%.Conclusion: Venetoclax can be safely added to the fractionated busulfan regimen. Early data on efficacy appear promising. [Display omitted] DisclosuresPopat: Bayer: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Incyte: Research Funding. Mehta: CSLBehring: Research Funding; Syndax: Research Funding; Incyte: Research Funding; Kadmon: Research Funding. Hosing: Nkarta Therapeutics: Membership on an entity's Board of Directors or advisory committees. Gulbis: EUSA Pharma: Other: Advisory board participation. Rezvani: AvengeBio: Other: Scientific Advisory Board ; Pharmacyclics: Other: Educational grant, Research Funding; GemoAb: Other: Scientific Advisory Board ; Navan Technologies: Other: Scientific Advisory Board; Bayer: Other: Scientific Advisory Board ; Caribou: Other: Scientific Advisory Board; Takeda: Other: License agreement and research agreement, Patents & Royalties; Virogin: Other: Scientific Advisory Board ; GSK: Other: Scientific Advisory Board ; Affimed: Other: License agreement and research agreement; education grant, Patents & Royalties, Research Funding. Qazilbash: Bristol-Myers Squibb: Other: Advisory Board; Oncopeptides: Other: Advisory Board; Amgen: Research Funding; Angiocrine: Research Funding; NexImmune: Research Funding; Biolline: Research Funding; Janssen: Research Funding. Kadia: Cure: Speakers Bureau; Novartis: Consultancy; Dalichi Sankyo: Consultancy; Cellonkos: Other; Ascentage: Other; Genfleet: Other; Sanofi-Aventis: Consultancy; Genentech: Consultancy, Other: Grant/research support; Astellas: Other; Liberum: Consultancy; BMS: Other: Grant/research support; Amgen: Other: Grant/research support; Aglos: Consultancy; Pfizer: Consultancy, Other; AstraZeneca: Other; AbbVie: Consultancy, Other: Grant/research support; Pulmotech: Other; Jazz: Consultancy. Konopleva: Calithera: Other: grant support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; Ascentage: Other: grant support, Research Funding; Cellectis: Other: grant support; Ablynx: Other: grant support, Research Funding; Agios: Other: grant support, Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; AstraZeneca: Other: grant support, Research Funding; Stemline Therapeutics: Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; Forty Seven: Other: grant support, Research Funding; Sanofi: Other: grant support, Research Funding; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; KisoJi: Research Funding. Shpall: Axio: Consultancy; Magenta: Consultancy; Novartis: Consultancy; Bayer HealthCare Pharmaceuticals: Honoraria; Adaptimmune: Consultancy; Navan: Consultancy; Takeda: Patents & Royalties; Novartis: Honoraria; Affimed: Patents & Royalties; Magenta: Honoraria.

Post-Transplant Cyclophosphamide Versus Tacrolimus and Methotrexate to Prevent Graft-Versus-Host Disease in Recipients of Matched Donor Transplantation: Comparison of Sequential Cohorts in a Prospective Trial

Post-Transplant Cyclophosphamide Versus Tacrolimus and Methotrexate to Prevent Graft-Versus-Host Disease in Recipients of Matched Donor Transplantation: Comparison of Sequential Cohorts in a Prospective Trial

Lecciana, a New Low-Vigour Olive Cultivar Suitable for Super High Density Orchards and for Nutraceutical EVOO Production

Cultivar is the key factor for sustainability of the olive super high density planting system (SHD). ‘Lecciana’ is a new olive cultivar for oil production obtained in 1998 by a controlled cross between cv. Arbosana (♀) and cv. Leccino (♂) in a breeding program as part of an international research agreement between Agromillora Iberia S.L.U. and University of Bari. ‘Lecciana’ is the first olive cultivar of Italian descent suitable for SHD, featuring all the vegetative and productive traits required for efficient, sustainable olive growing intensification. Thanks to low vigor, early bearing (3rd year after planting), high yield efficiency (about 0.5 kg of fruits cm−2 of trunk section area) and good fruit size (3.5 g), ‘Lecciana’ could be planted with tree densities over 1,200 trees per hectare for an efficient continuous mechanical harvesting. High frost resistance, very low pistil abortion (3%), high fruit set (3%), oil content (over 19% fw) and, above all, good unsaturated fatty acids profile, polyphenols content (over 450 mg kg−1) and fruitiness median are the main distinctive characters of this new cultivar. The oils of ‘Lecciana’ fall into the category ‘nutraceutical EVOOs’ which can benefit from the specific functional health claim.

The Gambling Disorders Identification Test (GDIT): Psychometric Evaluation of a New Comprehensive Measure for Gambling Disorder and Problem Gambling.

The novel gambling disorder identification test (GDIT) was recently developed in an international Delphi and consensus process. In this first psychometric evaluation, gamblers (N = 603) were recruited from treatment- and support-seeking contexts (n = 79 and n = 185), self-help groups (n = 47), and a population sample (n = 292). Participants completed self-report measures, a GDIT retest (n = 499), as well as diagnostic semistructured interviews assessing gambling disorder (GD; n = 203). The GDIT showed excellent internal consistency reliability (α = .94) and test-retest reliability (6-16 days, intraclass correlation coefficient = 0.93). Confirmatory factor analysis yielded factor loadings supporting the three proposed GDIT domains of gambling behavior, gambling symptoms, and negative consequences. Receiver operator curves and clinical significance indicators were used to estimate GDIT cut-off scores in relation to recreational (<15) and problem gambling (15-19), any GD (≥20), mild GD (20-24), moderate GD (25-29), and severe GD (≥30). The GDIT can be considered a valid and reliable measure to identify and predict GD severity, as well as problem gambling. In addition, the GDIT improves content validity in relation to an international research agreement concerning features of gambling outcome measures, known as the Banff Consensus Agreement.

Nonsteroidal anti-inflammatory drug use and concussions in adolescent athletes: incidence, severity, and recovery.

Given concerns about the potential long-term effects of concussion in young athletes, concussion prevention has become a major focus for amateur sports leagues. Athletes have been known to frequently use anti-inflammatory medications to manage injuries, expedite return to play, and treat concussion symptoms. However, the effects of baseline nonsteroidal anti-inflammatory drug (NSAID) use on the susceptibility to head injury and concussion remain unclear. This study aims to assess the effects of preinjury NSAID use on concussion incidence, severity, and recovery in young athletes. Data from 25,815 ImPACT (Immediate Post-Concussion Assessment and Cognitive Testing) tests were obtained through a research agreement with ImPACT Applications Inc. Subjects ranged in age from 12 to 22 years old. Those who reported NSAID use at baseline were assigned to one (anti-inflammatory [AI]) cohort, whereas all others were assigned to the control (CT) cohort. Differences in head trauma and concussion incidence, severity, and recovery were assessed using chi-square tests, unpaired t-tests, and Kaplan-Meier plots. The CT cohort comprised a higher percentage (p < 0.0001) of males (66.30%) than the AI cohort (44.16%) and had a significantly greater portion of athletes who played football (p = 0.004). However, no statistically significant differences were found between the two cohorts in terms of the incidence of head trauma (CT = 0.489, AI = 0.500, p = 0.9219), concussion incidence (CT = 0.175, AI = 0.169, p = 0.7201), injury severity, or median concussion recovery time (CT = 8, AI = 8, p = 0.6416). In a multivariable analysis controlling for baseline differences between the cohorts, no association was found between NSAID use and concussion incidence or severity. In this analysis, the authors found no evidence that preinjury use of NSAIDs affects concussion risk in adolescent athletes. They also found no indication that preinjury NSAID use affects the severity of initial injury presentation or concussion recovery.

Jim Wilson launches gene-editing company

The gene therapy pioneer Jim Wilson is starting his third company in 3 years. The start-up, called iECURE, has launched with $50 million in series A financing to develop up to 13 gene-editing therapies based on research from Wilson’s team of more than 300 people at the University of Pennsylvania Gene Therapy Program. The company’s name (pronounced ee-ah-cure) is inspired by the Latin word for liver, iecur , and its initial focus will be on treating severe liver disease in newborns, Wilson says. Two of its lead programs are for ornithine transcarbamylase (OTC) deficiency and phenylketonuria (PKU) . A third program, in partnership with the gene-editing company Precision Biosciences, will focus on reducing cholesterol in familial hypercholesterolemia. Like Wilson’s previous two start-ups, Passage Bio and G2 Bio , the new company will maintain an intimate relationship with his lab. iECURE signed research and licensing agreements with Penn for Wilson’s lab