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Hypothesis: As a fluid approaches three phase coexistence, adsorption may take place by the successive formation of two intervening wetting films. The equilibrium thickness of these wetting layers is the result of a delicate balance of intermolecular forces, as dictated by an underlying interface potential. The van der Waals forces for the two variable adsorption layers may be formulated exactly from Dzyaloshinskii-Lifshitz-Pitaevskii theory, and analytical approximations may be derived that extent well beyond the validity of conventional Hamaker theory. Calculations: We consider the adsorption equilibrium of water vapor on Silver Iodide where both ice and a water layers can form simultaneously and compete for the vapor as the triple point is approached. We perform numerical calculations of Lifshitz theory for this complex system and work out analytical approximations which provide quantitative agreement with the numerical results. Findings: At the three phase contact line between AgI/water/air, surface forces promote growth of ice both on the AgI/air and the water/vapor interfaces, lending support to a contact nucleation mode of AgI in the atmosphere. Our approach provides a framework for the description of adsorption at three phase coexistence, and allows for the study of ice nucleation efficiency on atmospheric aerosols., Accepted Manuscript

Using Lifshitz theory we assess the role of van der Waals forces at interfaces of ice and water. The results are combined with measured structural forces from computer simulations to develop a quantitative model of the surface free energy of premelting films. This input is employed within the framework of wetting theory and allows us to predict qualitatively the behavior of quasi-liquid layer thickness as a function of ambient conditions. Our results emphasizes the significance of vapor pressure. The ice vapor interface is shown to exhibit only incomplete premelting, but the situation can shift to a state of complete surface melting above water saturation. The results obtained serve also to assess the role of subsurface freezing at the water-vapor interface, and we show that intermolecular forces favor subsurface ice nucleation only in conditions of water undersaturation. We show ice regelation at ambient pressure may be explained as a process of capillary freezing, without the need to invoke the action of bulk pressure melting. Our results for van der Waals forces are exploited in order to gauge dispersion interactions in empirical point charge models of water., 27 pages, 15 figures, 7 tables (including supplementary material)

The van der Waals force established between two surfaces plays a central role in many phenomena, such as adhesion or friction. However, the dependence of this forces on the distance of separation between plates is very complex. Two widely different non-retarded and retarded regimes are well known, but these have been traditionally studied separately. Much less is known about the important experimentally accesible cross-over regime. In this study, we provide analytical approximations for the van der Waals forces between two plates that interpolates exactly between the short distance and long distance behavior, and provides new insight into the crossover from London to Casimir forces at finite temperature. At short distance, where the behavior is dominated by non-retarded interactions, we work out a very accurate simplified approximation for the Hamaker constant which adopts analytical form for both the Drude and Lorentz models of dielectric response. We apply our analytical expressions for the study of forces between metallic plates, and observe very good agreement with exact results from numerical calculations. Our results show that contributions of interband transitions remain important in the experimentally accessible regime of decades nm for several metals, including gold., 10 pages, 3 figures, supplementary materials

Protein arginine methyltransferase 5 (PRMT5) is known to symmetrically dimethylate numerous cytosolic and nuclear proteins that are involved in a variety of cellular processes. Recent findings have revealed its potential as a cancer therapeutic target. PRMT5 possesses a cysteine (C449) in the active site, unique to PRMT5. Therefore, covalent PRMT5 inhibition is an attractive chemical approach. Herein, we report an exciting discovery of a series of novel hemiaminals that under physiological conditions can be converted to aldehydes and react with C449 to form covalent adducts, which presumably undergo an unprecedented elimination to form the thiol-vinyl ethers, as indicated by electron density in the co-crystal structure of the PRMT5/MEP50 complex.

Oncogenic mutations in the RAS family are the most frequently occurring among human cancers. The recent development of KRAS-targeted covalent inhibitors display efficacy in KRAS-mutant tumors; however, this approach is limited to KRASG12C mutant cancers. Here, we describe a novel drug discovery program to target the full-scope of mutant RAS-driven cancers through allosteric inhibition of the oncogenic KRAS-RAF1 signaling complex. To identify novel allosteric inhibitors, we developed a second harmonic generation (SHG) assay to detect conformational changes in the KRAS-RAF1 membrane-bound complex. Fully processed farnesylated and methylated KRAS4b-G12D protein (KRASG12D-FMe) was complexed with the RAF1 N-terminal RAS-binding domain (RBD) and cysteine rich domain (CRD) and immobilized on a phosphatidylserine-enriched bilayer. The RAF1RBD-CRD protein was rendered SHG-active by chemical conjugation and tethered to the bilayer by KRASG12D-FMe, thus replicating the physiological complex orientation. Ligands that disrupted or altered the orientation of the complex relative to the surface were identified from a curated diversity library of 60,000 chemical compounds based on % SHG signal change relative to baseline. Validated hit compounds were selected for SAR characterization and development wherein newly synthesized molecules were assayed by SHG and inhibition of cellular ERK phosphorylation by HTRF. Quanta (QTX) molecules were confirmed to rapidly inhibit ERK phosphorylation across multiple RAS-mutant cell lines by Western blot. Biochemical cellular target engagement studies reveal inhibition of RAF1:BRAF dimerization downstream of allosteric modulation of the KRAS:RAF1 signaling complex. Mass spectrometry with a photoactive derivative identified modified residues clustered along the KRAS:RAF1 interface, thus providing structural evidence for this unique mechanism of action. In addition to MAPK inhibition, we observe inhibition of cellular proliferation across mutant RAS cell lines. Cellular growth assays in the presence of QTX molecules combined with the SHP-2 inhibitor, RMC4550, displayed synergistic growth inhibition, providing a rationale combination therapy. Moreover, RAS-mutant cell-line derived xenograft tumors treated with QTX inhibitors elicited significant tumor growth inhibition and dose-dependent reductions in the pharmacodynamic MAPK targets, P-ERK and DUSP6, which is consistent with anti-tumor activity. This research illustrates a promising approach towards the development of mutant RAS-targeted inhibitors with a unique mechanism of action and target engagement. Citation Format: Elizabeth Donohue Vo, Juan Luengo, Hong Lin, Jerry Chen, Ben Reid, Brooke McDonough, Norman Fultang, Jillian Silva, Cameron Pitt. Discovery and characterization of oncogenic KRAS:RAF1 conformational modulators with in vitro and in vivo MAPK inhibition [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr LBA007.

Protein arginine methyltransferase 5 (PRMT5) is the major type II PRMT that catalyzes the formation of symmetrical dimethyl arginine (SDMA) on protein substrates and plays important roles in regulating RNA splicing as well as transcription and activity of critical oncogenic signaling pathways. Recent studies have revealed PRMT5 as a potential therapeutic target for various cancers including Central Nervous System (CNS) tumors such as glioblastoma (GBM), the most common and aggressive primary brain tumor in adults. Several PMRT5 inhibitors have entered into the clinic for hematological and solid tumors, but none have been reported to be brain penetrant, a potentially desirable feature of a small molecule designed for treating CNS cancers and brain metastases. PRT811 is a potent, selective, and brain penetrant PRMT5 inhibitor, and exhibits potent in vitro and in vivo activities in preclinical models of brain tumors. PRT811 inhibited the methyltransferase activity of the PRMT5/MEP50 complex with an IC50 of 3.9 nM, but showed minimal inhibition against a panel of 37 human methyltransferases at 10 µM. In a panel of brain cancer cell lines of varied histology, PRT811 reduced SDMA levels and inhibited cell proliferation with IC50 values in the range of 7-40 nM and 29-134 nM, respectively, regardless of expression levels of methylguanine methyltransferase (MGMT), the expression of which is associated with temozolomide (TMZ) resistance. Furthermore, PRT811 demonstrated broad antiproliferative activity in a panel of 87 cell lines consisting of brain, breast, lung, and skin cancers, representing primary and the most common cancer types that metastasize to the brain. Finally, PRT811 effectively inhibited cell growth in a panel of patient derived xenograft models of GBM in ex vivo 3D cultures. PRT811 is a highly permeable molecule with high brain penetrance in rodents, with an efflux ratio PRT811 is currently under evaluation in a Phase I clinical trial in patients with advanced solid tumors, gliomas, and myelofibrosis (NCT04089449). Citation Format: Yang Zhang, Hong Lin, Min Wang, Dimitrios Angelis, Michael Hawkins, Dave Rominger, Tom Emm, Juan Luengo, Bruce Ruggeri, Peggy Scherle, Kris Vaddi. Discovery of PRT811, a potent, selective, and orally bioavailable brain penetrant PRMT5 Inhibitor for the treatment of brain tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2919.

Protein arginine methyltransferase 5 (PRMT5) is the major type II PRMT that catalyzes the formation of symmetrical dimethyl arginine (SDMA) on protein substrates and plays important roles in various cellular pathways including tumorigenesis. PRMT5 can methylate histones H3 and H4, thereby leading to repression of tumor suppressor genes at specific loci. PRMT5 also regulates gene expression on a global level by methylating and altering the function of transcription factors such as p53, E2F-1, NF-κB and others. Additionally, PRMT5 has been shown to interact with members of the spliceosome complex and regulate pre-mRNA processing of key target genes. In this study, we describe the in vitro and in vivo activity of PRT543, a novel, potent and selective inhibitor of PRMT5, in hematological and solid tumor models. In a scintillation proximity based radiometric assay, PRT543 inhibited the methyltransferase activity of the PRMT5/MEP50 complex with an IC50 of 10.8 nM. It was also highly selective against a panel of 36 other methyltransferases. PRT543 robustly inhibited cell proliferation in a panel of >50 cancer cell lines, representing both solid tumors and cancers of hematological origin, in a concentration-dependent manner with IC50 values ranging from 10 - 1000 nM. This anti-proliferative activity correlated with a reduction of symmetrically dimethylated SmD3 protein, a known PRMT5 substrate, demonstrating effective inhibition of PRMT5 enzymatic activity in cells. PRT543 demonstrated good oral bioavailability and favorable pharmacokinetic properties. Oral administration of this compound led to significant tumor growth inhibition in several subcutaneous mouse xenograft models including mantle cell lymphoma (Granta-519, Z-138), acute myeloid leukemia (MV4-11, SET2, HEL), small cell lung cancer (NCI-H1048) and bladder cancer (5637) at well-tolerated doses. This in vivo activity was accompanied by a corresponding decrease in symmetrically dimethylated SmD3 in tumor tissue collected from the treated animals. PRT543 was also tested in combination with other approved targeted therapies both in vitro and in vivo. Combining PRT543 with the BCL2 inhibitor, venetoclax, revealed a potent synergistic interaction in models of leukemia and lymphoma. Further ex vivo testing in genetically-defined primary patient tumor samples is ongoing. PRT543 is currently under evaluation in a Phase I clinical trial in patients with advanced solid tumors and hematological malignancies (NCT03886831). Citation Format: Neha Bhagwat, Yang Zhang, Hong Lin, Min Wang, Dave Rominger, Tom Emm, Divya Chugani-Mahtani, Dimitrios Angelis, Rupa Shetty, Raul Leal, William Gowen-MacDonald, Alexander Grego, Juan Luengo, Taghi Manshouri, Friederike Pastore, Ross L. Levine, Srdan Verstovsek, Bruce Ruggeri, Peggy Scherle, Kris Vaddi. Preclinical characterization of PRT543, a potent and selective inhibitor of protein arginine methyltransferase 5 (PRMT5), with broad antitumor activity in in vitro and in vivo models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2915.

Se describe la distribución anual y regional de los casos y tasas de fasciolosis en las poblaciones bovina, porcina, ovina, equina, caprina y camélida desde los años 1989 a 1995. Para la construcción de las tasas se contó con la información que disponía el Ministerio de Salud y el Instituto Nacional de Estadísticas. La distribución regional señala que este parasitismo no se encuentra en la XII Región. En los bovinos es de amplia distribución, con una tasa de 30,1% y una tendencia al aumento; en caprinos muestra una tasa de 14% y también con tendencia al aumento. En porcinos, ovinos y equinos las tasas son de 1,4%, 2,1% y 12,3% respectivamente y con tendencia la disminución With data obtained from the Minestry of Health of Chile, the geographic distribution and yearly number of cases and rates of fasciolosis in bovines, porcines, ovines, equines, caprines and camelids populations from 1989-1995 were calculated. This infection is present in all the country with the exception of the XII Region. The mean rate in bovines was 30.1%, caprines 14%; porcines 1.4%, ovines 2.1 % and equines 12.3 %. In the first two species the number of cases increased during the period and in the three last species the same variable decreased. In all the species, with exception of camelids the highest rates are observed in the VII and VIII Region of the country..

RESUMEN Con información de los años 1989 a 1995, obtenida del Ministerio de Salud de Chile, se describe la prevalencia de la trichinellosis de las poblaciones humana y porcina. La enfermedad en la población porcina se presenta desde la V a la XII Región, En la población humana no se observaron casos en la I, II y X Región. En ambas poblaciones la tendencia es al descenso. No se observó asociación entre las tasas observadas en la población humana con las determinadas en la especie porcina. Tanto entre regiones como entre años. DISTRIBUTION AND TENDENCY OF HUMAN AND SWINE THRICHINELLOSIS IN CHILE (1989-1995) With data obtained from the Ministry of Health the prevalence of trichinellosis in human and porcine populations from 1989 to 1995 was calculated. The infection is present in swine from the V to the XII Region of the country. In both populations, the rates of trichinellosis are decreasing during the studied period. There was no association between human and swine frequency of trichinellosis according to regions or years.