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

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

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

Treating glucosphingolipid disorders by chemotherapy: Use of approved drugs and over-the-counter remedies

The accumulation of a glucosphingolipid (GSL) in individuals lacking an adequate level of hydrolase activity could be minimized by chemotherapeutic measures that slow the formation of the GSL and stimulate the defective hydrolase. By achieving a balance in the rates of formation and breakdown, one should be able to alleviate the symptoms of excess storage and achieve a satisfactory accommodation. While several drugs seem to be specifically suitable for this purpose, only one of these has been approved for human use. However, less effective drugs and over-the-counter substances are available for human use and may prove satisfactory for a few years until better ones are made available. The proposed materials and the evidence behind the recommendations are presented in this paper.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/42500/1/10545_2004_Article_319707.pd