Exposure-response modeling improves selection of radiation and radiosensitizer combinations

A central question in drug discovery is how to select drug candidates from a large number of available compounds. This analysis presents a model-based approach for comparing and ranking combinations of radiation and radiosensitizers. The approach is quantitative and based on the previously-derived Tumor Static Exposure (TSE) concept. Combinations of radiation and radiosensitizers are evaluated based on their ability to induce tumor regression relative to toxicity and other potential costs. The approach is presented in the form of a case study where the objective is to find the most promising candidate out of three radiosensitizing agents. Data from a xenograft study is described using a nonlinear mixed-effects modeling approach and a previously-published tumor model for radiation and radiosensitizing agents. First, the most promising candidate is chosen under the assumption that all compounds are equally toxic. The impact of toxicity in compound selection is then illustrated by assuming that one compound is more toxic than the others, leading to a different choice of candidate

selection of the recommended phase 2 dose for bintrafusp alfa a bifunctional fusion protein targeting tgf β and pd l1

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First-in-Man Phase I Trial of the Selective MET Inhibitor Tepotinib in Patients with Advanced Solid Tumors.

PurposeTepotinib is an oral, potent, highly selective MET inhibitor. This first-in-man phase I trial investigated the MTD of tepotinib to determine the recommended phase II dose (RP2D).Patients and methodsPatients received tepotinib orally according to one of three dose escalation regimens (R) on a 21-day cycle: R1, 30-400 mg once daily for 14 days; R2, 30-315 mg once daily 3 times/week; or R3, 300-1,400 mg once daily. After two cycles, treatment could continue in patients with stable disease until disease progression or unacceptable toxicity. The primary endpoint was incidence of dose-limiting toxicity (DLT) and treatment-emergent adverse events (TEAE). Secondary endpoints included safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor effects.ResultsOne hundred and forty-nine patients received tepotinib (R1: n = 42; R2: n = 45; R3: n = 62). Although six patients reported DLTs [one patient in R1 (115 mg), three patients in R2 (60, 100, 130 mg), two patients in R3 (1,000, 1,400 mg)], the MTD was not reached at the highest tested dose of 1,400 mg daily. The RP2D of tepotinib was established as 500 mg once daily, supported by translational modeling data as sufficient to achieve ≥95% MET inhibition in ≥90% of patients. Treatment-related TEAEs were mostly grade 1 or 2 fatigue, peripheral edema, decreased appetite, nausea, vomiting, and lipase increase. The best overall response in R3 was partial response in two patients, both with MET overexpression.ConclusionsTepotinib was well tolerated with clinical activity in MET-dysregulated tumors. The RP2D of tepotinib was established as 500 mg once daily. MET abnormalities can drive tumorigenesis. This first-in-man trial demonstrated that the potent, highly selective MET inhibitor tepotinib can reduce or stabilize tumor burden and is well tolerated at doses up to 1,400 mg once daily. An RP2D of 500 mg once daily, as determined from translational modeling and simulation integrating human population pharmacokinetic and pharmacodynamic data in tumor biopsies, is being used in ongoing clinical trials

Molecular Cloning and Characterization of a Human Mitochondrial Ceramidase

We have recently purified a rat brain membrane-bound nonlysosomal ceramidase (El Bawab, S., Bielawska, A., and Y. A. Hannun (1999) J. Biol. Chem. 274, 27948-27955). Using peptide sequences obtained from the purified rat brain enzyme, we report here the cloning of the human isoform. The deduced amino acid sequence of the protein did not show any similarity with proteins of known function but was homologous to three putative proteins from Arabidospis thaliana, Mycobacterium tuberculosis, and Dictyostelium discoideum. Several blocks of amino acids were highly conserved in all of these proteins. Analysis of the protein sequence revealed the presence at the N terminus of a signal peptide followed by a putative myristoylation site and a putative mitochondrial targeting sequence. The predicted molecular mass was 84 kDa, and the isoelectric point was 6.69, in agreement with rat brain purified enzyme. Northern blot analysis of multiple human tissues showed the presence of a major band corresponding to a size of 3.5 kilobase. Analysis of this major band on the blot indicated that the enzyme is ubiquitously expressed with higher levels in kidney, skeletal muscle, and heart. The enzyme was then overexpressed in HEK 293 and MCF7 cells using the pcDNA3. 1/His-ceramidase construct, and ceramidase activity (at pH 9.5) increased by 50- and 12-fold, respectively. Next, the enzyme was characterized using lysate of overexpressing cells. The results confirmed that the enzyme catalyzes the hydrolysis of ceramide in the neutral alkaline range and is independent of cations. Finally, a green fluorescent protein-ceramidase fusion protein was constructed to investigate the localization of this enzyme. The results showed that the green fluorescent protein-ceramidase fusion protein presented a mitochondrial localization pattern and colocalized with mitochondrial specific probes. These results demonstrate that this novel ceramidase is a mitochondrial enzyme, and they suggest the existence of a topologically restricted pathways of sphingolipid metabolism

Modeling of radiation therapy and radiosensitizing agents in tumor xenografts

III-36\ua0Tim\ua0Cardilin\ua0Modeling of radiation therapy and radiosensitizing agents in tumor xenografts\ua0Tim Cardilin (1,2), Joachim Almquist (1), Mats Jirstrand (1), Astrid Zimmermann (3), Floriane Lignet (4), Samer El Bawab (4), and Johan Gabrielsson (5)(1) Fraunhofer-Chalmers Centre, Gothenburg, Sweden, (2) Department of Mathematical Sciences, Chalmers University of Technology and Gothenburg University, Gothenburg, Sweden, (3) Merck, Translational Innovation Platform Oncology, Darmstadt, Germany, (4) Merck, Global Early Development - Quantitative Pharmacology, Darmstadt, Germany, (5) Division of Pharmacology and Toxicology, Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, Uppsala, SwedenObjectives:\ua0To conceptually and mathematically describe the treatment effects of radiation and radiosensitizing agents on tumor volume in xenografts with respect to short- and long-term effects.Methods:\ua0Data were generated in FaDu xenograft mouse models, where animals were treated with radiation given either as monotherapy (2 Gy per dose) or together with an early-discovery radiosensitizing agent (25 or 100 mg/kg per dose) that interferes with the repair of the DNA damage induced by irradiation. Animals received treatment following a clinically-relevant administration schedule with doses five days a week for six weeks. Tumor diameters were measured by caliper twice a week for up to 140 days. A pharmacodynamic tumor model was adapted from a previously-published model [1,2]. The improved model captures both short- and long-term treatment effects including tumor eradication and tumor regrowth. Short-term radiation effects are described by allowing lethally irradiated cells up to one more cell division before apoptosis. Long-term radiation effects are described by an irreversible decrease in tumor growth rate. The radiosensitizing agent was assumed to stimulate both processes. The model also includes a natural death rate of cancer cells. The model was calibrated to the xenograft data using a mixed-effects approach based on the FOCE method that was implemented in Mathematica [3]. Between-subject variability was accounted for in initial tumor volume, as well as in the short- and long-term radiation effects.Results:\ua0Data across all treatment groups were well-described by the model. All model parameters were estimated with acceptable precision and biologically reasonable values. Vehicle growth was approximately exponential during the observed time period with an estimated tumor doubling time of approximately 5 days. Tumor growth following radiation therapy resulted in significant tumor regression followed by either tumor eradication (2 animals) or slow regrowth (7 animals). The short- and long-term effects incorporated into the tumor model were able to account for both of these scenarios. A simple analysis shows that if the tumor growth rate is decreased below the natural death rate, the tumor will be eradicated. Otherwise, the tumor will regrow but at a slower rate compared to pre-treatment. The model predicts that each fraction of radiation (2 Gy) results in lethal damage in 15 % of viable cells, and that a total dose above 120 Gy will eradicate the tumor. Tumor growth following combination therapy with a lower dose (25 mg/kg) resulted in more cases of tumor eradication (6 animals) and fewer cases of regrowth (3 animals), whereas combination therapy with the higher dose (100 mg/kg) resulted in tumor eradication in all 9 animals. When radiation therapy was complemented by radiosensitizing treatment (100 mg/kg per dose), each fraction of 2 Gy was estimated to kill 25 % of viable cells, and the total radiation dose required for tumor eradication was decreased by a factor four to 30 Gy.Conclusions:\ua0A tumor model has been developed to describe the treatment effects of radiation therapy, as well as combination therapies involving radiation, in tumor xenografts. The model distinguishes between short- and long-term effects of radiation treatment and can describe different tumor dynamics, including tumor eradication and tumor regrowth at different rates. The novel tumor model can be used to predict treatment outcomes for a broad range of treatments including radiation therapy and combination therapies with different radiosensitizing agents.References:\ua0[1] Cardilin T, Almquist J, Jirstrand M, Zimmermann A, El Bawab S, Gabrielsson J. Model-based evaluation of radiation and radiosensitizing agents in oncology. CPT: Pharmacometrics & Syst. Pharmacol.\ua0(2017).[2] Cardilin T, Zimmermann A, Jirstrand M, Almquist J, El Bawab S, Gabrielsson J. Extending the Tumor Static Concentration Curve to average doses – a combination therapy example using radiation therapy. PAGE 25 (2016) Abstr 5975 [www.page-meeting.org/?abstract=5975].[3] Almquist J, Leander J, Jirstrand M. Using sensitivity equations for computing gradients of the FOCE and FOCEI approximations to the population likelihood. J Pharmacokinet Pharmacodyn (2015) 42: 191-209

Modeling long-term tumor growth and kill after combinations of radiation and radiosensitizing agents

Purpose: Radiation therapy, whether given alone or in combination with chemical agents, is one of the cornerstones of oncology. We develop a quantitative model that describes tumor growth during and after treatment with radiation and radiosensitizing agents. The model also describes long-term treatment effects including tumor regrowth and eradication. Methods: We challenge the model with data from a xenograft study using a clinically relevant administration schedule and use a mixed-effects approach for model-fitting. We use the calibrated model to predict exposure combinations that result in tumor eradication using Tumor Static Exposure (TSE). Results: The model is able to adequately describe data from all treatment groups, with the parameter estimates taking biologically reasonable values. Using TSE, we predict the total radiation dose necessary for tumor eradication to be 110\ua0Gy, which is reduced to 80 or 30\ua0Gy with co-administration of 25 or 100\ua0mg\ua0kg\ua0−1\ua0of a radiosensitizer. TSE is also explored via a heat map of different growth and shrinkage rates. Finally, we discuss the translational potential of the model and TSE concept to humans. Conclusions: The new model is capable of describing different tumor dynamics including tumor eradication and tumor regrowth with different rates, and can be calibrated using data from standard xenograft experiments. TSE and related concepts can be used to predict tumor shrinkage and eradication, and have the potential to guide new experiments and support translations from animals to humans

Terahertz Communications and Sensing for 6G and Beyond: A Comprehensive View

The next-generation wireless technologies, commonly referred to as the sixth generation (6G), are envisioned to support extreme communications capacity and in particular disruption in the network sensing capabilities. The terahertz (THz) band is one potential enabler for those due to the enormous unused frequency bands and the high spatial resolution enabled by both short wavelengths and bandwidths. Different from earlier surveys, this paper presents a comprehensive treatment and technology survey on THz communications and sensing in terms of the advantages, applications, propagation characterization, channel modeling, measurement campaigns, antennas, transceiver devices, beamforming, networking, the integration of communications and sensing, and experimental testbeds. Starting from the motivation and use cases, we survey the development and historical perspective of THz communications and sensing with the anticipated 6G requirements. We explore the radio propagation, channel modeling, and measurements for THz band. The transceiver requirements, architectures, technological challenges, and approaches together with means to compensate for the high propagation losses by appropriate antenna and beamforming solutions. We survey also several system technologies required by or beneficial for THz systems. The synergistic design of sensing and communications is explored with depth. Practical trials, demonstrations, and experiments are also summarized. The paper gives a holistic view of the current state of the art and highlights the issues and challenges that are open for further research towards 6G.Comment: 55 pages, 10 figures, 8 tables, submitted to IEEE Communications Surveys & Tutorial

Anxiety and depressive symptoms are associated with poor sleep health during a period of COVID-19-induced nationwide lockdown: a cross-sectional analysis of adults in Jordan.

BACKGROUND: Jordan, a Middle Eastern country, declared a state of national emergency due to COVID-19 and a strict nationwide lockdown on 17 March 2020, banning all travel and movement around the country, potentially impacting mental health. This study sought to investigate the association between mental health (eg, anxiety and depressive symptoms) and sleep health among a sample of Jordanians living through a state of COVID-19-induced nationwide lockdown. METHODS: Using Facebook, participants (n=1240) in Jordan in March 2020 were recruited and direct to a web-based survey measuring anxiety (items from General Anxiety Disorder 7-item (GAD-7) scale instrument), depressive symptoms (items from Center for Epidemiologic Studies Depression Scale), sleep health (items from the Pittsburgh Sleep Quality Index) and sociodemographic. A modified Poisson regression model with robust error variance. Adjusted prevalence ratios (aPRs) and 95% CIs were estimated to examine how anxiety and depressive symptoms may affect different dimensions of sleep health: (1) poor sleep quality, (2) short sleep duration, (3) encountering sleep problems. RESULTS: The majority of participants reported having experienced mild (33.8%), moderate (12.9%) or severe (6.3%) levels of anxiety during lockdown, and nearly half of respondents reported depressive symptoms during lockdown. Similarly, over 60% of participants reported having experienced at least one sleep problem in the last week, and nearly half reported having had short sleep duration. Importantly, anxiety was associated with poor sleep health outcomes. For example, corresponding to the dose-response relationship between anxiety and sleep health outcomes, those reporting severe anxiety were the most likely to experience poor sleep quality (aPR =8.95; 95% CI=6.12 to 13.08), short sleep duration (aPR =2.23; 95% CI=1.91 to 2.61) and at least one problem sleep problem (aPR=1.73; 95% CI=1.54 to 1.95). Moreover, depressive symptoms were also associated with poor sleep health outcomes. As compared with scoring in the first quartile, scoring fourth quartile was associated with poor sleep quality (aPR=11.82; 95% CI=6.64 to 21.04), short sleep duration (aPR=1.87; 95% CI=1.58 to 2.22), and experiencing at least one sleep problem (aPR=1.90; 95% CI=1.66 to 2.18). CONCLUSIONS: Increased levels of anxiety and depressive symptoms can negatively influence sleep health among a sample of Jordanian adults living in a state of COVID-19-induced nationwide lockdown

A proposed protocol for GMP-BoK implementation gap analysis - case study at AASTMT

Purpose: Maritime Education and Training (MET) plays a crucial role in maintaining the safety and sustainability of the maritime industry. However, it remains behind the industry expectations to fulfill the gap regarding the required level of maritime capacities to safely control efficient new technology and keep them sustainable and effective during the industrial revolution era. The International Association of Maritime Universities (IAMU) developed the Global Maritime Professional Body of Knowledge (GMP-BoK) to address the current gap between the maritime industry expectations and the delivered Maritime Education and Training (MET) programs. Design/methodology/approach: This paper briefly introduces the GMP-BoK and proposes a protocol for a new analogous instrument to efficiently implement the GMP-BoK via a user-friendly method developed at the Arab Academy for Science, Technology and Maritime Transport (AASTMT). The developed analogous instrument helps maritime universities and institutes to digitalize and develop an integrated curriculum framework that is based on robust evaluation and data analysis to develop strategic plans to improve seafarer capabilities. Moreover, the paper suggests a protocol for mapping and analysis of maritime programs and courses, enabling educators to reliably perform gap analysis and identify repetitions within delivered courses and programs based on the GMP-BoK recommended practices. As a case study, the proposed protocol was validated utilizing the Maritime Engineering Technology Program (METP). Findings: The findings of this study revealed that the examined METP includes 30% repetition and focuses on the cognitive and psychomotor methods of education, with little focus on the affective technique