Abstract[Fe(TPA)(N3)2](ClO4) and [Fe(TPA)Br2](ClO4), where TPA is tris-(2-pyridylmethyl)amine, crystallize in the monoclinic space group P21/c with a = 8.7029(5) Å, b = 19.168(1) Å, c = 13.5728(7) Å, β = 101.472(3)°, and a = 8.944(3) Å, b = 16.578(6) Å, c = 15.108(6) Å, β = 103.18(2)°, respectively. The structures were determined at 150 K from 3397 reflections (1426 observed) with R = 0.063 (Rw = 0.097), and at 115 K from 5617 reflections (2261 observed) with R = 0.057 (Rw = 0.065), respectively. In both cases, the iron is pseudo-octahedral with the two halide/pseudohalide ions cis. The Fe–X bond trans to the tertiary amine is shorter. The structures of [{Fe(TPA)X}2O](ClO4)2 where X = N3, Br, NCO, and two polymorphic forms of NCS, are also reported. The azide derivative [CH3CN solvate, monoclinic P21/n, a = 11.8038(11) Å, b = 22.547(2) Å, c = 17.344(2) Å, β = 106.972(4)°, determined at 100 K from 8972 reflections (4404 observed) with R = 0.087 (Rw = 0.145)] has two distinct Fe environments—the tertiary amine is cis to the oxido bridge at one site and is trans to the oxido bridge at the other site; the trans Fe–N3° distance is longer. Both the Br and NCO derivatives are monoclinic, C2/c [with a = 16.1480(17), b = 17.2036(13), c = 16.8521(12), β = 111.204(10), data collected at 293 K, 3753 reflections (2404 observed), R = 0.069 (Rw = 0.151), and a = 15.7470(9), b = 18.2270(11), c = 16.8950(8), β = 110.666(3), data collected at 90 K, 5392 reflections (3028 observed), R = 0.064 (Rw = 0.091), respectively]. Both polymorphs of the NCS derivative are monoclinic—one is P21/c and the other P21/n [a = 11.075(2), b = 15.436(2), c = 12.351(2), β = 95.528(7), data collected at 90 K, 5378 reflections (4345 observed), R = 0.068 (Rw = 0.198), and a = 12.396(2), b = 15.428(3), c = 44.505(8), β = 95.211(7), data collected at 110 K, 16,527 reflections (6540 observed), R = 0.069 (Rw = 0.105), respectively]. For the Br, NCO and NCS dimers, each iron of the [{Fe(TPA)X}2O]2+ unit is pseudo-octahedral with the halide/pseudohalide and oxide ions cis. The oxide bridge is linear, and the two halides/pseudohalides are anti. The ranking of trans influence of the ligands is O2− ≫ Br− > Cl− > N3− > NCO− ≥ NCS− > pyridyl > tertiary amine and the ranking of cis influence of the ligands is O2− ≫ N3− > NCO− > Cl− ≥ Br− > NCS−. Graphical Abstract The X-ray structures of two monomeric [Fe(TPA)(X)2](ClO4), where TPA is tris-(2-pyridylmethyl)amine and X = N3, and Br, and four dimeric [{Fe(TPA)Y}2O](ClO4)2, where Y =N3, Br, NCO, and NCS are presented and discussed.

Background: Smoking is the most common etiology for lung cancer and smoking cessation does not eliminate the risk. An emerging area of interest for risk reduction is immunoprevention. MUC1 glycoprotein is aberrantly expressed in adenocarcinomas, including lung cancer and their premalignant lesions. MUC1 vaccine in the premalignant or high-risk setting may be effective in halting neoplastic development and progression. Trial design: Through the NCI-funded Cancer Prevention Network (CPN), we conducted a two-center pilot trial to evaluate immunogenicity of the MUC1 vaccine (assessed at 12 weeks), and safety (assessed at up to 24 weeks) in current and former heavy smokers. 87 participants were screened in order to have at least 40 evaluable for baseline and 12-week immunogenicity assessments. Smoking history of ≥30 pack-years and either current (still smoking or quit < 1 year prior to pre-registration) or former smoker (quit 1-15 years prior to pre-registration); ages 55-80 years; ECOG performance status ≤1; CT scan of the chest done ≤ 6 months prior to pre-registration showing either negative findings (no nodules) or solid or part-solid nodules < 6 mm in size (consistent with < 1% probability of malignancy, Lung-RADs Version 1.0). Exclusion criteria were standard for lung cancer screening. Methods: MUC1 peptide plus polyICLC adjuvant (Hiltonol) vaccine was given at week 0, 2 and 10. Blood was collected for safety tests and immune assays pre and 2 weeks post each vaccine, and at week 24. Anti-MUC1 IgG titer was evaluated by ELISA. Based on previous studies of this vaccine, 40 evaluable participants would provide 96% power to detect immune response rate of 15% versus 40%, using a 2-sided test of proportions with type I error rate of 0.05. PBMC were assayed for the presence of regulatory T cells (Treg) and myeloid derived suppressor cells (MDSC) (secondary endpoint). Circulating levels of inflammatory cytokines and hsCRP were evaluated using commercially available tests (exploratory endpoint). AEs and toxicities were monitored for up to 24 weeks from the first vaccine. Results: 87 individuals were screened and 50 registered. 45 completed the study, 26 current and 19 former smokers (time since last smoked: average 7.8 years; 11 months -13 years). The vaccine was well-tolerated with injection site reactions being the most common AE. Immune response to the vaccine was lower than expected, with 2 current and 2 former smokers developing anti-MUC1 IgG titers ≥2 fold higher at week 12 over baseline (10%). We found high circulating levels of MDSCs in PBMC of both current and former smokers and very low or no serum cytokines. Conclusions: A preventative vaccine trial was feasible in individuals at high risk for lung cancer. However, we discovered a high level of immune suppression, previously documented only in advanced lung cancer. Mitigating the development of lung cancer in heavy smokers through vaccine administration may be limited by related immunosuppression. Citation Format: Olivera J. Finn, Julie Ward, Tami Krpata, Samantha Fatis, John McKolanis, Jia Xue, Pamela Beatty, Camille Jacqueline, Sharon Kaufman, Colleen Akerley, April Felt, Karrie Fursa, Anne Holland, Liz S. Ambulay, Nathan Foster, Ryan McMurray, Carrie Strand, Andres M. Salazar, Lisa Bengtson, Eva Szabo, Paul Limburg, Malgorzata Wojtowicz, David E. Midthun, Arjun Pennathur. A pilot study of a MUC1 vaccine in current and former smokers at high risk for lung cancer. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr PR002.

[Fe(TPA)Cl2](ClO4), where TPA is tris-(2-pyridylmethyl)amine, crystallizes in the orthorhombic space group P212121 with Z = 4, a = 8.6264(10) Å, b = 15.459(3) Å, and c = 16.008(3) Å. The structure was determined at 110 K from 4333 reflections (3520 observed) with R = 0.041 (Rw = 0.082). The iron is pseudo-octahedral with the two chloride ions cis. The Fe-Cl bond trans to the tertiary amine is shorter. [{Fe(TPA)Cl}2O](ClO4)2 exhibits two polymorphic monoclinic forms, and the monohydrate also crystallizes in a monoclinic form. For the P21/c polymorph, Z = 2, a = 10.839(2) Å, b = 15.956(3) Å, c = 12.416(2) Å, β = 107.024(10)°, and the structure was determined at 95 K from 6514 reflections (3974 observed) with R = 0.052 (Rw = 0.099). For the C2/c polymorph, Z = 4, a = 20.5023(17) Å, b = 15.2711(13) Å, c = 16.1069(11) Å, β = 124.465(4)°, and the structure was determined at 161 K from 6250 reflections (3130 observed) with R = 0.0632 (Rw = 0.1229). For the hydrate, P21/n, Z = 4, a = 16.201(2) Å, b = 16.980(3), c = 16.451(3), β = 112.234(5)°, and the structure was determined at 100 K from 12,745 reflections (6600 observed) with R = 0.097 (Rw = 0.190). In each of the [{Fe(TPA)Cl}2O]2+ units, each iron is pseudo-octahedral with the chloride and oxide ions cis. The oxide bridge is linear, and the two chlorides are anti. The Fe-N distance for the pyridyl ring trans to the oxide bridge is quite long due to the trans influence of the oxide. Graphic Abstract The X-ray structures of [Fe(TPA)Cl2](ClO4), where TPA is tris-(2-pyridylmethyl)amine, and three polymorphs of dimeric [{Fe(TPA)Cl}2O](ClO4)2 are presented and discussed.

MUC1 is a transmembrane glycoprotein aberrantly expressed in human adenocarcinoma as well as chronic inflammatory conditions. We previously demonstrated that the tumor form of MUC1, in association with p65, upregulates expression of pro-inflammatory cytokines, including IL-6 and TNF-alpha, by modulating their transcription in epithelial cancer cells. Using azoxymethane/dextran sulfate sodium (AOM/DSS) murine model of inflammation driven colon carcinogenesis, we explored mechanism underlying MUC1/p65-induced transcription of IL-6 and TNF-alpha and its significance for the microenvironment of colitis-associated cancer. MUC1.Tg mice showed higher tumor incidence, decreased survival, greater body weight loss and shorter colon length. Consistent with our previous in vitro data, expression of NF-kB-dependent cytokines was higher in MUC1.Tg mice compared to WT. Moreover, we discovered that MUC1/p65 complex modulates IL-6 and TNF gene expression by regulating the crosstalk of post-translational modifications on their promoters. To understand the significance of MUC1/p65-modulated cytokines in progressive colitis that gives rise to colon cancer, we analyzed infiltration of inflammatory cells into the inflamed colon tissues. ELISA assay and gene expression analyses demonstrated that the treatment with AOM/DSS in the presence of human MUC1 on the colonic epithelia resulted in a significant upregulation of M1 type macrophage-associated genes, including IL-6, TNF-alpha and iNOS, whereas expression of M2 type macrophage markers, such as Arginase 1, Ym1 and IL-10, were drastically reduced compared to WT mice. Thus our findings reveal a pro-inflammatory role for MUC1 in colitis-related carcinogenesis.