Background Oral cavity squamous cell carcinoma (OCSCC) is the most frequent head and neck cancer. Surgery is the mainstay treatment for patients with OCSCC. In case of bone involvement, the affected bone needs to be resected. Cancer-free bone resection margins (BRMs) are of crucial importance: patients with cancer-free BRMs have a 2 times higher chance of survival. Currently, there is no standard method for intraoperative assessment of BRMs. Bone margin status is only known after tissue decalcification, which takes 1 to 2 weeks. After that time reoperations are highly undesirable, because the surgical defect has healed. Therefore, it is crucial to achieve tumor-free resection surfaces, which requires the possibility of intraoperative assessment of BRMs. Objective The aim of this study was to investigate the potential of Raman spectroscopy (RS) for detection of OCSCC in bone resection surfaces during mandibulectomy. RS is a nondestructive objective optical technique that provides information about the molecular composition of tissues. Methods Raman mapping experiments were performed on fresh mandible resection specimens from patients treated with mandibulectomy for OCSCC. A tumor detection algorithm was created based on water concentration and the high-wavenumber range (2800 cm−1-3050 cm−1) of the Raman spectra. Results Results show that RS can detect OCSCC in bone resection surfaces with a high sensitivity (96%) and specificity (83%; 26 mapping experiments, 22 patients). Conclusions These results form the basis for further development of an RS tool as an objective method for intraoperative assessment of BRMs.

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.

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 clinical and immunologic implications of the SARS-CoV-2 pandemic for patients with cancer receiving systemic anticancer therapy have introduced a multitude of clinical challenges and academic controversies. This review summarizes the current evidence, discussion points, and recommendations regarding the use of immune checkpoint inhibitors (ICIs) in patients with cancer during the SARS-CoV-2 pandemic, with a focus on patients with melanoma and renal cell carcinoma (RCC). More specifically, we summarize the theoretical concepts and available objective data regarding the relationships between ICIs and the antiviral immune response, along with recommended clinical approaches to the management of melanoma and RCC patient cohorts receiving ICIs throughout the course of the COVID-19 pandemic. Additional insights regarding the use of ICIs in the setting of current and upcoming COVID-19 vaccines and broader implications toward future pandemics are also discussed.

Introduction Immune checkpoint inhibitors (CPIs) have changed the treatment landscape for many cancers, but also cause severe inflammatory side effects including enterocolitis. CPI-induced enterocolitis is treated empirically with corticosteroids, and infliximab (IFX) is used in corticosteroid-refractory cases. However, robust outcome data for these patients are scarce. Methods We conducted a multicenter (six cancer centers), cohort study of outcomes in patients treated with IFX for corticosteroid-refractory CPI-induced enterocolitis between 2007 and 2020. The primary outcome was corticosteroid-free clinical remission (CFCR) with Common Terminology Criteria for Adverse Events (CTCAE) grade 0 for diarrhea at 12 weeks after IFX initiation. We also assessed cancer outcomes at 1 year using RECIST V1.1 criteria. Results 127 patients (73 male; median age 59 years) were treated with IFX for corticosteroid-refractory CPI-induced enterocolitis. Ninety-six (75.6%) patients had diarrhea CTCAE grade >2 and 115 (90.6%) required hospitalization for colitis. CFCR was 41.2% at 12 weeks and 50.9% at 26 weeks. In multivariable logistic regression, IFX-resistant enterocolitis was associated with rectal bleeding (OR 0.19; 95% CI 0.04 to 0.80; p=0.03) and absence of colonic crypt abscesses (OR 2.16; 95% CI 1.13 to 8.05; p=0.03). Cancer non-progression was significantly more common in patients with IFX-resistant enterocolitis (64.4%) as compared with patients with IFX-responsive enterocolitis (37.5%; p=0.013). Conclusion This is the largest study to date reporting outcomes of IFX therapy in patients with corticosteroid-refractory CPI-induced enterocolitis. Using predefined robust endpoints, we have demonstrated that fewer than half of patients achieved CFCR. Our data also indicate that cancer outcomes may be better in patients developing prolonged and severe inflammatory side effects of CPI therapy.

While our knowledge of the evolutionary features of primary tumors has grown exponentially over the last few years our understanding of evolution of metastases is more limited and many open questions remain, regarding the timing of metastatic dissemination, the acquisition of metastatic competence and the underpinning of the variety of metastatic phenotypes observed in the clinic from latent metastases to solitary and oligo-metastases to widespread metastases. We have leveraged unique translational protocols that allow interrogation of tumor evolution from the earliest stages of diseases to death to address some of these questions. In the context of renal cell cancers we show that the mode of evolution at the primary tumor site determines the tempo and distribution of systemic metastases; that the features that distinguish metastasis-competent clones included genome instability and aneuploidy; and that metastatic competence often emerges in the centre of the primary tumor. In the context of melanoma we observe a wide spectrum of metastatic seeding that includes organ-specific metastatic clones, monophyletic and polyphyletic seeding and polyclonal mixing at metastatic sites. We observe progressive increase in aneuploidy and occurrence of whole genome doubling as melanoma metastases progress and resist treatment suggesting this as a a mechanism of immune-evasion and treatment resistance. Citation Format: Samra Turajlic. Understanding evolution of metastatic disease in renal cancer and melanoma [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 SY02-02.

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.

Chronic inflammatory lung diseases are characterized by uncontrolled immune response in the airways as their main pathophysiological manifestation. The lack of specific diagnostic and therapeutic biomarkers for many pulmonary diseases represents a major challenge for pulmonologists. The majority of the currently approved therapeutic approaches are focused on achieving disease remission, although there is no guarantee of complete recovery. It is known that angiotensin-converting enzyme 2 (ACE2), an important counter-regulatory component of the renin–angiotensin–aldosterone system (RAAS), is expressed in the airways. It has been shown that ACE2 plays a role in systemic regulation of the cardiovascular and renal systems, lungs and liver by acting on blood pressure, electrolyte balance control mechanisms and inflammation. Its protective role in the lungs has also been presented, but the exact pathophysiological mechanism of action is still elusive. The aim of this study is to review and discuss recent findings about ACE2, including its potential role in the pathophysiology of chronic inflammatory lung diseases:, i.e., chronic obstructive pulmonary disease, asthma, and pulmonary hypertension. Additionally, in the light of the coronavirus 2019 disease (COVID-19), we will discuss the role of ACE2 in the pathophysiology of this disease, mainly represented by different grades of pulmonary problems. We believe that these insights will open up new perspectives for the future use of ACE2 as a potential biomarker for early diagnosis and monitoring of chronic inflammatory lung diseases.

Abstract:This paper analyses impact of aircraft noise on community around Podgorica Airport, Montenegro. The airport is located 12 km from the city centre of the Montenegro capital, Podgorica. It served 1.3 million passengers and 7.5 thousand operations in 2019. The noise impact assessment is conducted in IMPACT web-based modelling platform using the distribution of operations by aircraft types, time of the day, and radar tracks for the busiest day (August 15) in 2019. Noise contours are assessed for Lden and Lnight indicators. They were merged with the Global Human Settlement Layer to assess the number of people exposed to different noise levels. In addition, based on the World Health Organization recommended exposure levels related to their health implications, the percentages of the population highly annoyed and highly sleep-disturbed are estimated. Furthermore, facilities of public importance (schools, hospitals, churches, etc.) are assessed against compatibility with the requirements set for the Zones with increased noise protection in national regulations. The results show that the exposure of community around Podgorica Airport to aircraft noise is still not a serious issue. The near vicinity of the airport is industrial zone and the number of people highly annoyed by noise is approximately 3.2% of the total city population. Nevertheless, it is crucial to draw attention to planners to preserve airport neighbourhood from potential inhabiting, to avoid problems that some airports in the region are facing nowadays.