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Background: BMF-219 is a selective covalent inhibitor of menin, a transcriptional regulator of oncogenic signaling pathways in multiple cancers, that inhibits the menin/MYC interaction and downregulates the expression of MYC and MYC target genes, including KRAS. Mechanism of Action (hypothesis): In addition to MYC disruption, inhibition of the Menin-MLL complex by BMF-219 alters JunD genomic function, a crucial factor for KRAS-driven tumorigenesis. Inhibition of the Menin-MLL complex suppresses expression of Rasgrf1, which is essential for generation of the active RAS-GTP conformation of KRAS, activation of downstream pathways, and tumorigenesis. Preclinically, BMF-219 shows sustained potent abrogation of menin-dependent oncogenic signaling. BMF-219 exerts pan-mutant KRAS anticancer activity that is independent of the specific KRAS-activating mutation. Methods: COVALENT-102 (NCT05631574) is a prospective, open-label, multicenter, dose finding study evaluating the safety, tolerability, and clinical activity of escalating doses of BMF-219 administered daily in patients with unresectable, locally advanced, or metastatic NSCLC (Cohort 1), PDAC (Cohort 2) & CRC (Cohort 3) with activating KRAS mutations who have received standard therapy. All indications as a group will follow a 3+3 dose escalation design. BMF-219 will be administered orally daily as continuous therapy as 28-days treatment cycle until progression or intolerability/unacceptable toxicity. Following conclusion of the dose-escalation, each indication will enroll patients in expansion cohorts independently to obtain further safety and efficacy data. Eligible patients include those with any KRAS mutation & (Cohort 1) stage IIIB/IV NSCLC with 2-4 prior lines of therapy including immune checkpoint inhibitors (ICI) &/or platinum-based chemo ± bevacizumab with ECOG PS 0-2; (Cohort 2) stage III/IV PDAC with ≥ 1 prior line of therapy including either FOLFIRINOX or gemcitabine/nab-paclitaxel, ECOG PS 0-1; or (Cohort 3) stage III/IV CRC with ≥ 1 prior line of therapy including FOLFOX or FOLFIRI ± bevacizumab (prior ICI if MSI-H/dMMR), ECOG PS 0-2. Patients must have documented progression & measurable disease as defined by RECIST 1.1. Patients with prior KRAS inhibitor exposure are eligible. Key exclusion criteria include symptomatic &/untreated CNS metastasis, prior menin inhibitor therapy, and clinically significant cardiovascular disease. The primary objective is to determine the optimal biological dose (OBD)/recommended Phase 2 dose (RP2D) of BMF-219 monotherapy. Secondary objectives include further evaluation of safety & tolerability, characterization of the pharmacodynamics and pharmacokinetics of BMF-219, and efficacy based on duration of response (DOR) & disease control rate (DCR). Assessment of progression-free survival (PFS), overall survival (OS) & time to response (TTR) are part of the exploratory endpoints. The first patient in the study is anticipated to be dosed in Q4 of 2022. Citation Format: Stacey A. Cohen, Christos Fountzilas, David Sommerhalder, Sandip Patel, Ai Benson, Kai He, Apar Ganti, Alex Spira, Bhagyashree (Kelshikar) Yadav, Alex Cacovean, Steve Morris, Tom Butler, David Hong. COVALENT-102: A phase 1/1b dose finding study of BMF-219, an oral covalent menin inhibitor, in patients with metastatic non-small cell lung cancer (NSCLC), pancreatic cancer (PDAC), and colorectal cancer (CRC) with activating KRAS mutations [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr A003.

PurposeThe aim of the study is to explore the chain of relationships between service attributes, consumers' perceived benefits, fulfilment of personal goals, satisfaction judgements and future intentions.Design/methodology/approachThis research proposes and implements a model of consumer satisfaction in the performing arts. The model is based on means-end chain theory and incorporates consumer involvement as a moderator. The paper is a quantitative study using a questionnaire administered in Romanian theatres, the country chosen because of its post-communist profile.FindingsA partial least squares structural equation modelling analysis revealed that both core and peripheral attributes' evaluations were positively related to perceived benefits, which in turn were positively related to goal fulfilment. Acting as a mediator, goal fulfilment predicts satisfaction, which positively influences a series of intentions regarding supportive behaviours such as recommendation, donation, subscribing and repurchasing. Consumer involvement partially moderates the relationships within the proposed model.Research limitations/implicationsThe limitations of this research offer opportunities for future studies. First, as this study was conducted in Romania, the obtained results are not easily generalisable to other geographical or cultural contexts. Second, future studies could extend the proposed model to include other constructs that may be connected to satisfaction in performing arts. They could also apply the model (or an extended alternative) to adjacent fields such as opera, or live jazz, in order to explore whether the patterns of results which emerged here hold in other situations.Practical implicationsFrom a practical perspective, the research has implications for performing arts managers by offering actions to improve cultural consumption. First, the results support the idea that satisfaction is a key construct to investigate, even in the field of performing arts, as it can predict future positive intentions. Thus, arts managers should strive to maximise consumer satisfaction. From a marketing perspective, consumer satisfaction could be increased by improving core and peripheral service attributes, but especially the latter. The research provides means for audience segmentation in terms of consumer goals, benefits, and involvement. Arts managers should devote special attention to increasing consumer involvement in services provided.Social implicationsThe research provides a different view on the performing arts evaluation considering the theatregoers' perceptions. This type of evaluation is useful to understand the specificities of the audiences and to respond to their needs accordingly, contributing from a social point of view to audience development and making arts accessible to a wide range of people in a variety of ways: physically, geographically, socially and psychologically.Originality/valueThis research explores a new model of customer satisfaction in performing arts in a post-communist country, such as Romania, and the findings have implications at both theoretical and practical level. From a theoretical perspective, it contributes to a better understanding of the cognitive and emotional processes underlying the formation of satisfaction judgements in performing arts. The obtained findings are particularly useful for expanding current knowledge of how consumers think and behave with respect to performing arts. From a practical perspective, the findings have implications for arts managers deciding how to develop marketing strategies aimed at increasing satisfaction, and the consequential supportive behaviours towards performing arts.

"Fire on the Mountain. Disturbance and Regeneration in Deciduous and Conifer Forests. 20 Years of Experience. Two test and monitoring sites in SW Germany (Forchtenberg) and Leghia (NW Romania) furnish insights to the regeneration modes after fire, clearing, burning, and cultivation -slash and burn - in a deciduous forest or after wildfire in a conifer stand. Forest maps and archivalia helped to reconstruct the forest history of the last 250 years of the Forchtenberg site, which as a heritage still influences the present situation. We could document the autonomous co- evolution of vegetation and soil over two decades. It was done by transects and mapping as well as by soil analysis and micromorphology. The role of soil animals for the weathering of charcoals became evident. The evolution of vegetation and soil after a wildfire could be studied on the Leghia site and compared with the Forchtenberg results. As the Leghia site was not cleared after the fire, it enabled us to follow the stages of decay and of regeneration, where conifers do not play a role. Moreover, one could investigate the effects of grass- and pasture fire, still active in the region. It also evidenced the necessary differentiation of charred material into wood- and grass coal. The indicator values of topsoil/soil surfaces are presented as well as those of charred material for the regeneration stages. Finally, we will discuss the fire risk in deciduous forests under a changing climate. Keywords: Forest disturbance, succession types, forest history, slash and burn, wild fire, charcoal taphonomy, fire risk. "

In the first decade after the establishment of the Communist regime in Romania, the fortress of Alba Iulia was in a lamentable state of conservation, as revealed by the correspondence of the Directorate of Historical Monuments (DHM) and the National Institute of Heritage (NHI) photo library. The fortress was used by a military unit, the Wine-Alcohol Enterprise, GOSTAT, together with the regional museum and the two bishoprics, Catholic and Orthodox, but none of them possessed any legal documents in this regard. As the only ones concerned about the ensemble, the museum’s representatives sent numerous notifications to the DHM, who eventually initiated a long process that sought to clarify first and foremost the legal situation of the fortress, before assuming the research and restoration of its gates. The festivities that took place in 1968 on the occasion of the Great Union’s semicentenary gave the preservationists an opportunity to take important steps towards establishing the fortress as a protected area and suggesting new deployments of its improperly used monuments, in the framework of the 1967 Urban Planning Sketch. Unfortunately, the DHM’s lack of authority in questions of urban redevelopment, along with the growing involvement of the local bodies, who only complied with the Party’s recommendations, led to constant disrespect towards the legal provisions and the further destruction of the fortress.

Implementation of an IoT system for the detection of Covid-infected 19. A sample of 300 people participated in this experiment. They are assigned wearables that they must wear for a period of one week throughout the day. The data is retrieved in real time at an interval of 60 minutes. These wearables are equipped with temperature, heart rate and GPS sensors to determine people inside or outside virus outbreaks. The data is then retrieved and sent to Oracle Cloud. Here they are processed according to Machine Learning algorithms and sent predictions to the subjects' family doctors, but also to the national health system. If patients are suspected of being infected with the virus, then they should be contacted as soon as possible for testing.

Decision-makers need tailored information regarding future climate, land use, forest management and societal scenarios for sustainable watershed management. Such information can be attained by integrating the water-energy-land nexus approach with climate services. To support decision-makers from Brașov metropolitan area (Romania), we co-developed land use, forest management and societal scenarios and analysed their impact on the water-energy-land nexus under climate change. We applied the Soil and Water Assessment Tool (SWAT) to the Săcele reservoir from the Tărlung river basin in order to spot the interrelations between nexus components under different climate and societal scenarios. In particular, we applied four bias-corrected GCM & RCM model combinations for two climate scenarios RCP4.5 and RCP8.5, nine land use and forest management scenarios, and twelve societal scenarios. Modelling results were analysed between 2020 and 2099. The results for the study area indicate that the projected average annual precipitation is close to historical averages in most climate scenarios explored, while the projected average annual temperature is increasing. Furthermore, the analysed data suggest an increase in severe dry intervals from approximately 6% (for the period 1961–2013) to 12% by the end of the 21st century, indicating that precipitation variability may change considerably. The SWAT model results show no significant changes in the water flow under different forest management scenarios. In contrast, model results for scenarios that imply forests' clearcutting and their replacement with pastures or meadows indicate that water quality is affected by increased sediment flow. Regarding the number of months with water scarcity in the Săcele reservoir (i.e. water demand exceeds water supply), we found an increase from 0.4 months in 2020 to 1.5 months in 2099. The model results also revealed that climate change significantly influences the water supply in the reservoir. To conclude, the regional stakeholders highly value the model results for the co-developed scenarios, which have been already used to promote sustainable resource management.

Background: Menin, a protein involved in transcriptional regulation, impacting cell cycle control, apoptosis, and DNA damage repair plays a direct role in oncogenic signaling in multiple cancers. Inhibition of menin is a novel approach to cancer treatment. Preclinical data of BMF-219, a highly selective, orally bioavailable small-molecule irreversible inhibitor of menin, show sustained potent abrogation of menin-dependent oncogenic signaling in vitro and in vivo. BMF-219 demonstrated a strong anti-proliferative effect on various menin-dependent acute myeloid leukemia (AML) cell lines, DLBCL lines representing Double/Triple Hit Lymphoma (DHL/THL), Double Expressor Lymphoma (DEL), and MM cell lines harboring diverse mutational backgrounds. BMF-219 also exhibited high potency ex vivo in patient samples from MLL-rearranged and NPM1-mutant AML, THL and MYC-amplified DLBCL, and bone marrow mononuclear cells from treatment-naive and R/R MM. Methods: BF-MNN-101 (NCT05153330) is a prospective, open-label, multi-cohort, non-randomized, multicenter Phase I study evaluating the safety, tolerability, and clinical activity of escalating doses of oral BMF-219 administered once daily in patients with R/R AL, DLBCL and MM who have received standard therapy. Utilizing an accelerated titration design, doses of BMF-219 will be escalated in single-subject cohorts independently for each indication following a modified Fibonacci sequence until 1 subject experiences either a ≥ Grade 2 adverse event or dose limiting toxicity (DLT). At that point, the current and all subsequent dose level(s) for the specific indication/cohort will follow a classical “3 + 3” design. Each treatment cycle will be 28 days until progression or intolerability occurs. Following conclusion of the parallel dose-escalations, expansion cohorts for each indication will enroll patients to obtain further safety and efficacy data. Eligible patients include those with R/R AL, R/R DLBLC ≥ 2 but ≤ 5 therapies, and R/R MM who received ≥ 3 therapies who failed or are ineligible for any standard therapies. Patients must have ECOG ≤2, and adequate organ function with prior treatment-related toxicities resolved to ≤ Grade 2. Key exclusion criteria include known CNS disease involvement, prior menin inhibitor therapy, and clinically significant cardiovascular disease. The primary objective is to determine independently for each cohort/indication the optimal biological dose (OBD)/recommended Phase 2 dose (RP2D) of BMF-219 oral monotherapy. Key secondary objectives include further evaluation of safety and tolerability, characterization of the pharmacodynamics and pharmacokinetics of BMF-219, and assessment of its antitumor activity based on best overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), time to progression (TTP) per disease-specific response criteria as assessed by the investigator. Food-effect studies will be performed in DLBCL and MM patients at certain dose levels in the escalation phase and during the expansion cohort portion of the study. The first patient in the study is anticipated to dose in Q1 of 2022. Citation Format: Farhad Ravandi-Kashani, Ashwin Kishtagari, Hetty Carraway, Emily Curran, Gary Schiller, Alex Cacovean, Bhagyashree Yadav, Thomas Butler, Jeffrey Lancet. A phase 1 study of BMF-219, a novel oral irreversible menin inhibitor, as single-agent in patients with relapsed/refractory (R/R) acute leukemia (AL), diffuse large B-cell lymphoma (DLBCL), and multiple myeloma (MM) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT210.

TPS7064 Background: Menin, a protein involved in transcriptional regulation, impacting cell cycle control, apoptosis, and DNA damage repair, plays a direct role in oncogenic signaling in multiple cancers. Inhibition of menin is therefore a novel approach to cancer treatment. Preclinical data of BMF-219, a highly selective, orally bioavailable, small-molecule irreversible inhibitor of menin, show sustained potent abrogation of menin-dependent oncogenic signaling in vitro and in vivo. BMF-219 exhibited a strong anti-proliferative effect on various menin-dependent acute myeloid leukemia (AML) cell lines, DLBCL lines representing Double/Triple Hit Lymphoma (DHL/THL) and Double Expressor Lymphoma (DEL), and MM cell lines with diverse mutational backgrounds. BMF-219 also showed high potency ex vivo in patient samples from MLL-rearranged and NPM1-mutant AML, THL and MYC-amplified DLBCL, and bone marrow mononuclear cells from treatment-naive and R/R MM. Methods: COVALENT-101 (NCT05153330) is an open-label, multi-cohort, non-randomized, multicenter Phase I study evaluating the safety, tolerability, and clinical activity of escalating doses of once daily oral BMF-219 in patients with R/R AL, DLBCL and MM who have received standard therapy. Utilizing an accelerated titration design, doses of BMF-219 will be escalated in single-subject cohorts independently for each indication until 1 subject experiences either a ≥ Grade 2 related-adverse event or dose limiting toxicity (DLT). At that point, the cohort will switch to a classical “3 + 3” design. Treatment will continue in 28-day cycles until progression or intolerability. Expansion cohorts for each indication will enroll patients to obtain further safety and efficacy data. Patients with R/R AL, R/R DLBCL ≥ 2 but ≤ 5 therapies, and R/R MM who received ≥ 3 therapies and failed or are ineligible for any standard therapies are eligible. Patients must have ECOG PS ≤ 2, and adequate organ function. Key exclusion criteria include known CNS disease involvement, prior menin inhibitor therapy, and clinically significant cardiovascular disease. The primary objective is to determine independently for each cohort/indication the optimal biological dose (OBD)/ recommended Phase 2 dose (RP2D) of BMF-219 oral monotherapy. Key secondary objectives include further evaluation of safety and tolerability, characterization of the pharmacodynamics and pharmacokinetics of BMF-219, and assessment of its antitumor activity based on best overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and time to progression (TTP) per disease-specific response criteria as assessed by the investigator. Food-effect studies will be performed in DLBCL and MM patients at certain dose levels. The enrollment commenced in January 2022. Clinical trial information: NCT05153330.

Soils on riverine floodplains in temperate climate may be characterized by a mollic epipedon, i.e. by dark colour, enhanced content of soil organic matter (SOM), high ‘base’ saturation and developed structure in the topsoil. We studied 124 soil samples from ten central/east European countries to investigate whether SOM in mollic horizons has similar chemical features. We determined carbon contents with a thermal-gradient method to differentiate SOM with varying thermal stability, and carbonates. We characterized SOM by diffuse reflectance infrared Fourier-transform (DRIFT) spectroscopy. According to the World Reference Base for Soil Resources, 102 of the samples fulfilled all criteria of a mollic horizon. Mollic features were not restricted to the uppermost horizon but also detected in buried former surface horizons. Soil colour was mostly the criterion to exclude non-mollic samples. Mollic and adjacent non-mollic horizons contained thermostable SOM, indicating SOM stabilized by interaction with minerals or as black carbon (BC), to very similar extent, up to 20.4% of total soil organic carbon (SOC). However, the correlation between the contents of thermostable SOC and total SOC, the SOC:N ratios of the thermostable fraction, and the smaller extent of metal complexation of carboxyl groups, pointed to a larger contribution of BC to SOM of mollic samples than to SOM in non-mollic samples. Thus, like in mollic horizons in Chernozems and Phaeozems not affected by fluviatile dynamics, SOM in mollic horizons of floodplain soils seemed to consist of SOM affected by natural or anthropogenic fires, constituting a common chemical feature of SOM. Thus, BC may contribute to soil colour and SOM stability in mollic horizons of floodplain soils. However, apart from BC contribution, SOM in mollic horizons of floodplain soils may have further pathways of formation and development, as SOM may be inherited from deposited material or form/transform by degradative or constructive processes. Supplemenatry material: [http://aspace.agrif.bg.ac.rs/handle/123456789/5999]