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Peter Anthony D'Amato, the inimitable pioneer of carnivorous plants, founder of California Carnivores, and author of The Savage Garden, passed away from cancer on the afternoon of 26 June 2024. He leaves behind his brother, Dino D'Amato, his niece Tara Page, his nephew Anthony D'Amato, and of course his California Carnivores tribe that loved him and called him family.

Abstract KRLS-017 is a potent, selective, and reversible inhibitor of Cyclin Dependent Kinase 7 (CDK7). Its molecular formula is C24H35N5O2Si and its molecular weight is 453.65 Daltons. KRLS-017 is being developed for the treatment of patients with advanced solid tumor malignancies. To differentiate KRLS-017 from other CDK7 inhibitors, we created a reversible inhibitor to allow for treatment schedule optimization and maximization of therapeutic index in clinic. High selectivity of KRLS-017 for CDK7 was confirmed using a panel of 313 recombinant human kinases. The IC50 of KRLS-017 against recombinant human CDK7 was determined to be 16 nM, and no other kinases in the panel showed IC50 values less than 300 nM. Antiproliferative activity of KRLS-017 was investigated in vitro using a broad panel of human tumor cell lines. KRLS-017 showed potent antiproliferative effect across a wide variety of both solid and hematologic tumor types, producing GI50 values <200 nM in 258/302 human tumorcell lines tested. Antitumor activity of KRLS-017 was investigated in vivo using multiple mouse xenograft tumormodels at dose levels ranging from 25 mg/kg to 200 mg/kg using both continuous (daily) andintermittent dosing schedules. Statistically significant tumor growth inhibition was seen at doselevels of 50 mg/kg and higher, with tumor regression observed at 100 mg/kg and 200 mg/kg. Better in vivo tolerability at efficacious doses was observed using intermittent dosing schedules in mouse xenograft models, which led to adoption of an intermittent schedule in the proposed first-in-human phase 1 trial. KRLS-017 is orally bioavailable in mice, rats, and dogs and plasma drug exposure increased in a proportional manner with dose. Comparing first dose and 28th dose in the dog, minimal plasma accumulation was observed, suggesting once daily dosing in humans would be initially tested. Repeat dose 28 day GLP toxicology studies in rat and dog showed adverse effects in highly proliferative bone marrow and gastrointestinal tissues which is consistent with the known mechanism of action for CDK7 and is considered to be monitorable and manageable in the setting of oncology. The clinical development plan for KRLS-017 includes an initial Phase 1 dose escalation study (KRLS-017-101) in patients with refractory solid tumor malignancies to assess pharmacokinetics/pharmacodynamics and to determine an optimal dose level and treatment schedule to test in expansion cohorts. Given the potential of CDK7 inhibitors in the treatment of hormone receptor positive breast cancer, combination work with other agents (such as selective estrogen receptor degraders) is on-going. Citation Format: Alison L. Hannah, Steve Ritland, Thomas Steele, Steven Smith, Ashwin Ram, BT Slingsby, Kapil Dhingra, James Chrisman, Rajesh Dua, Yasunori Tokunaga, Shigeyuki Kono, Yasuhiro Aga. Preclinical evaluation of KRLS-017, a potent, highly selective and reversible CDK7 inhibitor with broad antitumor effect in preclinical models, in preparation for a Phase 1 clinical trial in advanced solid tumor malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5707.

Most modern communication systems can be roughly divided into two general classifications: constant envelope and quadrature amplitude modulated. Constant envelope systems typically employ FM modulation or phase modulation. As such, these systems are quite immune to noise and distortion in the form of gain compression. Modern vector network analyzers consist multiple, synchronized down-converters with fully digital IF processing and as such can be reconfigured to be used as different instrument types including tuned receivers, noise figure receivers, and spectrum analyzers. The distortion measurement of two-tone intermodulation distortion (IMD) provides a means to characterize the linearity of an amplifier or mixer, but the response to complex signals may be difficult to predict from the two-tone IMD, and further the distortion caused by the in-channel part of the signal may produce products outside the signal band interfering with the operation of adjacent channel services.

A clear understanding of the underlying architecture of a vector network analyzer (VNA) is necessary to understand the full capabilities and limitations of the modern VNA. This chapter deconstructs the VNA to discuss the individual block diagram elements, their attributes and deficiencies, and how they operate together to provide the capability and applications. It describes the wide range of measurements and characteristics that can be derived from the basic measurements. The chapter also describes the basic functionality for making measurements along with real-world issues and errors that affect these measurements. It discusses the fundamentals of making microwave measurements for a variety of parameters, along with the consequences of the practical limitations of the radio frequency hardware. S-parameter measurements provide substantial information about the qualities of a device-under-test (DUT). In many cases, the transformation and formatting of these parameters is necessary to more readily understand the intrinsic attributes of the DUT.

SymbolDefinition Value c Speed of light in free space 2.997 9 × 10 8 m s -1 ≈ 300 × 10 6 m s -1 0 Permittivity of free space 8.854Noise power at 290 K in a given bandwidth 4 × 10 -21 W Hz -1 ≈ -173.98 dBm in 1 Hz BW

2562 Background: BAL101553 is a prodrug of the small molecule BAL27862, a novel microtubule-targeting agent (MTA) with potent activity in tumor models refractory to conventional MTAs. Its anti-canc...