FGFR2 fusions, amplifications, and mutations are oncogenic drivers that occur across multiple tumor types. Clinical efficacy observed with pan-FGFR inhibitors has validated the driver status of FGFR2 in FGFR2 fusion-positive intrahepatic cholangiocarcinoma (ICC), however, FGFR1-mediated toxicities (hyperphosphatemia, tissue mineralization) and the emergence of on-target FGFR2 resistance mutations limit the efficacy of pan-FGFR inhibitors. To overcome these limitations, we designed RLY-4008, a potent and highly selective, FGFR2 inhibitor. Despite significant investment in traditional structure-based drug design, selective targeting of FGFR2 has not been achieved. We leveraged differences in conformational dynamics between FGFR2 and other FGFR isoforms observed through molecular dynamics simulations to enable the design of RLY-4008. RLY-4008 inhibits FGFR2 with low nanomolar potency and demonstrates > 200-fold selectivity over FGFR1, and > 80- and > 5000-fold selectivity over FGFR3 and FGFR4, respectively, in biochemical assays. Additionally, RLY-4008 demonstrates high kinome selectivity for FGFR2 against a panel of > 400 human kinases. RLY-4008 has strong activity against primary and acquired FGFR2 resistance mutations in cellular assays, and potent antiproliferative effects on FGFR2-altered human tumor cell lines. In vivo, RLY-4008 demonstrates dose-dependent FGFR2 inhibition and induces regression in multiple human xenograft tumor models, including FGFR2 fusion-positive ICC, gastric, and lung cancers, FGFR2-amplified gastric cancer, and FGFR2-mutant endometrial cancer. Strikingly, RLY-4008 induces regression in an FGFR2 fusion-positive ICC model harboring the FGFR2V564F gatekeeper mutation and an endometrial cancer model harboring the FGFR2N549K mutation, two mutations that drive clinical progression on current pan-FGFR inhibitors. In the FGFR2V564F model, pan-FGFR inhibitors are ineffective, even at maximally tolerated doses. Notably, treatment of these tumors with RLY-4008 induces rapid regression and restores body weight. In rat and dog toxicology studies, RLY-4008 is well tolerated and is not associated with hyperphosphatemia or tissue mineralization at exposures significantly above those required to induce regression in all models. In contrast to pan-FGFR inhibitors, RLY-4008 is highly selective for FGFR2 and demonstrates strong activity against FGFR2 resistance mutations, suggesting that RLY-4008 may have broader therapeutic potential via preventing and overcoming therapeutic resistance. Together, these data and the favorable pharmaceutical properties of RLY-4008 strongly support its clinical development in FGFR2-altered tumors. Citation Format: Jessica Casaletto, Dejan Maglic, B. Barry Toure, Alex Taylor, Heike Schoenherr, Brandi Hudson, Kamil Bruderek, Songping Zhao, Patrick O9Hearn, Nastaran Gerami-Moayed, Demetri Moustakas, Roberto Valverde, Lindsey Foster, Hakan Gunaydin, Pelin Ayaz, Dina Sharon, Donald Bergstrom, James Watters. RLY-4008, a novel precision therapy for FGFR2-driven cancers designed to potently and selectively inhibit FGFR2 and FGFR2 resistance mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1455.

The emerging mycotoxin fusaproliferin is produced by Fusarium proliferatum and other related Fusarium species. Several fungi from other taxonomic groups were also reported to produce fusaproliferin or the deacetylated derivative, known as siccanol or terpestacin. Here, we describe the identification and functional characterization of the Fusarium proliferatum genes encoding the fusaproliferin biosynthetic enzymes: a terpenoid synthase, two cytochrome P450s, a FAD-oxidase and an acetyltransferase. With the exception of one gene encoding a CYP450 (FUP2, FPRN_05484), knock-out mutants of the candidate genes could be generated, and the production of fusaproliferin and intermediates was tested by LC-MS/MS. Inactivation of the FUP1 (FPRN_05485) terpenoid synthase gene led to complete loss of fusaproliferin production. Disruption of a putative FAD-oxidase (FUP4, FPRN_05486) did not only affect oxidation of preterpestacin III to terpestacin, but also of new side products (11-oxo-preterpstacin and terpestacin aldehyde). In the knock-out strains lacking the predicted acetyltransferase (FUP5, FPRN_05487) fusaproliferin was no longer formed, but terpestacin was found at elevated levels. A model for the biosynthesis of fusaproliferin and of novel derivatives found in mutants is presented.

Background: The objective of this study was to evaluate the efficacy of modified clinoptilolite (Minazel Plus®, MZ) as a mycotoxin adsorbent for preventing the negative the effects of ochratoxin A (OTA) on performance, pathohistological changes, and OTA residue in the eggs of laying hens. Methods: Forty eight (n = 48) laying hens (27 weeks old) were equally divided into six groups and depending on the type of addition were allocated to the following experimental treatments for 7 weeks: E-I group-1 mg/kg OTA; E-II group 0.25 mg/kg OTA; E-III group 1 mg/kg OTA + 0.2% of MZ; E-IV group 0.25 mg/kg OTA + 0.2% of MZ; MZ group supplemented with 0.2% of the adsorbent; and control (K, without feed additive). Results: Overall, the addition of 0.2% MZ to laying hen feed mitigated the harmful effects of OTA on target organs and reduced the presence of OTA residue in eggs. The groups that received 0.2% of MZ achieved better production results in terms of body weight, number of eggs, and feed consumption, compared to the other treatments. Conclusions: The current findings confirm the efficacy of MZ in preventing performance losses in laying hens exposed to OTA, as well as for improving the welfare and health of food producing animals.

ABSTRACT Introduction The need to individualize a drug dosage and adjust it to a patient’s physiological and/or pathophysiological status is rarely satisfied in routine clinical practice, primarily because of complexity of the adjustment task. Areas covered The aim of this article is to shed light to basic principles of drug dosage individualization in the most frequent clinical states that affect pharmacokinetics of drugs. The principles are derived from published clinical studies conducted on diverse patient populations, using non-compartmental pharmacokinetic model. Expert opinion Simple, but sufficiently exact, way to calculate appropriate drug dose for a patient is the one based on target average steady-state concentration and non-compartmental pharmacokinetic model. If target steady-state drug concentration and dosage interval are considered fixed, maintenance dose could be adjusted on the basis of expected changes of total drug clearance and bioavailability, while loading dose should be related to changes of volume of distribution and bioavailability. Relative increase or decrease of these pharmacokinetic parameters in regard to normal values in healthy persons is translated to relative (percentual) increase or decrease of maintenance and loading doses recommended in the drug monograph.

PurposeThe main reason for writing this paper was the systematic determination of the state of internationalization of public higher education for the first time in Bosnia and Herzegovina (B&H). This paper aims to compare the state of internationalization with the results of comparative European and world research in higher education in order to determine the direction of public universities in B&H following globalization and connection with the European Higher Education Area (EHEA), as well as to determine future steps for mandatory inclusion into global higher education flows. Furthermore, the aim was to determine the treatment of mobility and student exchange programs and the ways of recognizing acquired qualifications abroad.Design/methodology/approachThe paper opted for a research study by conducting questionnaires that were divided into questions of elimination, questions of qualification and questions of the main survey. A total of 2,822 final year students were surveyed, as well as 386 representatives of the management of public universities. Within the paper, 25 different SWOT analyses of internationalization were performed by public universities, ministries and state/regional agencies, which was the basis for the SWOT analysis of the internationalization of B&H public higher education. The data were supplemented with a qualitative analysis of the obtained results compared with the International Association of Universities (IAU) and European Association for International Education (EAIE) research, as well as an overview of the most significant achievements in the field of internationalization of higher education.FindingsThe paper provides empirical results on the barriers of students to study abroad, the existence of strategies and indicators for internationalization, the benefits of internationalization, internal and external drivers of internationalization and the potential risks of internationalization. These empirical results for B&H were compared with complementary IAUs and EAIE research and provided the basis for SWOT analysis of internationalization, development of institutional internationalization strategies and indicators, B&H recognition model, new criteria for accreditation with emphasis on internationalization and criteria for assessing internationalization. The paper suggests that virtual mobility and internationalization at home are future logical trends of development internationalization in B&H.Research limitations/implicationsSuggestions for future research related to the examination of identified potential risks to the management of the internationalization of individual institutions, as well as to future comparisons of the new state of internationalization of higher education in B&H with current similar research in Europe and the world. Regarding the limitations in the research, it was possible that a larger number of participants participated in the survey with questionnaires, although the target set at the beginning of the survey was achieved.Practical implicationsMost of the research results are the basis for improving the practical situation in the internationalization of public higher education in B&H. The paper presents a special chapter (undertaken improvement activities) dedicated to the practical implications based on the conducted research and comparison of results. Considering that this is a preliminary work related to the internationalization of higher education, based on the researched results, the context of the internationalization of public higher education in B&H was changed by the activities described in the mentioned chapter. The contribution to these activities was given by the approved project of the European Commission (EC) “strengthening of internationalization in B&H higher education” - STINT. Also, the research results of this paper offered a comparison with the research results of research conducted by IAUs and EAIE.Social implicationsDifferent research groups participated in this research study: students, teachers, administration, representatives of ministries and state/regional agencies. All target groups supported the implementation of the questionnaire, the development of SWOT analyses and various reports, as well as the undertaking of various practical activities. In accordance with the research results, all these target groups were subsequently educated on issues of internationalization and recognition of qualifications. Stronger and better internationalization certainly increases the social impact on future students, higher education funders, as well as other interested stakeholders.Originality/valueThis is a preliminary study whose main goal was to review the state of internationalization and to identify the most important undertaken activities in B&H. For the higher education area in B&H, the research study is new and has undertaken internationalization activities, but on the other side, in other developed European countries, similar studies and activities are not new. For the field of higher education in B&H, this work and research results are important because they will be the basis for future internationalization activities and will also serve as a basis for future activities to be undertaken in this field. The value of this paper is significant for both internal and external stakeholders of higher education.

Introduction: Graph theory has been applied to study the pathophysiology of multiple sclerosis (MS) since it provides global and focal measures of brain network properties that are affected by MS. Typically, the connection strength and, consequently, the network properties are computed by counting the number of streamlines (NOS) connecting couples of gray matter regions. However, recent studies have shown that this method is not quantitative. Methods: We evaluated diffusion-based microstructural measures extracted from three different models to assess the network properties in a group of 66 MS patients and 64 healthy subjects. Besides, we assessed their correlation with patients' disability and with a biological measure of neuroaxonal damage. Results: Graph metrics extracted from connectomes weighted by intra-axonal microstructural components were the most sensitive to MS pathology and the most related to clinical disability. In contrast, measures of network segregation extracted from the connectomes weighted by maps describing extracellular diffusivity were the most related to serum concentration of neurofilament light chain. Network properties assessed with NOS were neither sensitive to MS pathology nor correlated with clinical and pathological measures of disease impact in MS patients. Conclusion: Using tractometry-derived graph measures in MS patients, we identified a set of metrics based on microstructural components that are highly sensitive to the disease and that provide sensitive correlates of clinical and biological deterioration in MS patients. Impact statement Graph theory has been widely used to study the alterations in the structural connectivity of multiple sclerosis (MS) patients. Usually, brain graphs used for the extraction of network metrics are created by counting the number of streamlines connecting gray matter regions, however, this method is not quantitative. In this study, we used tractometry to average the values of diffusion-based microstructural maps along the reconstructed streamlines. Our results show that network metrics extracted from the connectomes weighted on microstructural maps provide sensitive information to MS pathology, which correlate with clinical and biological measures of disease impact.

Although epigenetic modifications have been intensely investigated over the last decade due to their role in crop adaptation to rapid climate change, it is unclear which epigenetic changes are heritable and therefore transmitted to their progeny. The identification of epigenetic marks that are transmitted to the next generations is of primary importance for their use in breeding and for the development of new cultivars with a broad-spectrum of tolerance/resistance to abiotic and biotic stresses. In this review, we discuss general aspects of plant responses to environmental stresses and provide an overview of recent findings on the role of transgenerational epigenetic modifications in crops. In addition, we take the opportunity to describe the aims of EPI-CATCH, an international COST action consortium composed by researchers from 28 countries. The aim of this COST action launched in 2020 is: (1) to define standardized pipelines and methods used in the study of epigenetic mechanisms in plants, (2) update, share, and exchange findings in epigenetic responses to environmental stresses in plants, (3) develop new concepts and frontiers in plant epigenetics and epigenomics, (4) enhance dissemination, communication, and transfer of knowledge in plant epigenetics and epigenomics.

Objectives: Food supplements and medicines which are not on the list of prohibited substances of the World Anti-Doping Agency are included in the group of permitted pharmacological agents for athlete’s recovery. The aim of this study was to describe qualitatively and quantitatively food supplements (FS) and over-the-counter drugs use among athletes in the last six month. Methods: This was a cross sectional study. Data on food supplements and the over-the-counter drugs, usage were collected during 2018 by self-administered, anonymous questionnaire. Results: A total of 112 athletes completed the survey. A total of 51.8% (n = 58) athletes reported the use of food supplements. The use of medical supplements was reported by 50.0% (n = 56) of athletes, 26.8% (n = 30) reported using ergogenic supplements, 1.8% (n = 2) using of sports food and 4.5% (n = 5) using other supplements. The use of over-the-counter drugs was reported by 35.7% (n = 40) of athletes. The over-the-counter analgesic drugs were used by 95% (n = 38) of over-the-counter drug users. Concomitant administration two or more over-the-counter drugs was reported by 40% (n = 16) athletes. Doctors and coaches had no advisory role in the use of food supplements or over-the-counter drugs.

This work is motivated by growing evidence that the standard Cyclic Prefix (CP) length, adopted in the Long Term Evolution (LTE) physical layer (PHY) specifications, is oversized in propagation environments ranging from indoor to typical urban. Although this ostensibly seems to be addressed by 5G New Radio (NR) numerology, its scalable CP length reduction is proportionally tracked by the OFDM symbol length, which preserves the relative CP overhead of LTE. Furthermore, some simple means to optimize fixed or introduce adaptive CP length arose from either simulations or models taking into account only the bit-oriented PHY transmission performance. On the contrary, in the novel crosslayer analytical model proposed here, the closed-form expression for the optimal CP length is derived such as to minimize the effective average codeblock length, by also considering the error recovery retransmissions through the layers above PHY—the Medium Access Control (MAC) and the Radio Link Control (RLC), in particular. It turns out that, for given protective coding, the optimal CP length is determined by the appropriate rms delay spread of the channel power delay profile part remaining outside the CP span. The optimal CP length values are found to be significantly lower than the corresponding industry-standard ones, which unveils the potential for improving the net throughput.

Metal injection molding technology is commonly used in production of small and very complex parts. Residual porosity is unavoidable characteristic of P/M parts, affecting their final properties. During injection molding phase powder-binder separation can occur, causing green density variation through cross section of the part. This behaviour is particularly pronounced as complexity of the parts increases. As a consequence, zones with different density and residual porosity can be seen after sintering. In this regard, porosity and hardness distribution of the sintered ring-shaped part is analysed and presented in the paper.