Molecular Design and Photophysical Characterization of Synthetic Bacteriochlorins for Solar Energy Conversion and Photodynamic Therapy

The design, photophysical characteristics and some potential applications of synthetic bacteriochlorins are discussed. Bacteriochlorins: e.g., bacteriochlorophylls) are tetrapyrrole macrocycles with two reduced pyrrole rings, whereas chlorins: e.g., chlorophylls) and porphyrins: e.g., hemes) have one and zero reduced pyrrole rings. Molecular design characteristics are revealed by understanding the effects of substituent types and patterns and the central metal ion on the photophysical properties and electronic structure. These effects are elucidated via studies of the optical absorption and emission spectra and excited-state decay pathways, and analysis of the molecular-orbital characteristics within the four-orbital model. The studies also encompass analysis of the properties of bacteriochlorins as photosensitizers for photodynamic therapy: PDT). The factors studied and correlated include photostability, redox potentials, photophysical properties, electrochemical and molecular-orbital characteristics, reactive-oxygen-species production, photosensitizer cellular uptake and distribution. Collectively, the studies address the design of synthetic bacteriochlorins for solar-energy conversion and photomedicine

Risks of complicated acute appendicitis in patients with psychiatric disorders

Background Acute appendicitis often presents with vague abdominal pain, which fosters diagnostic challenges to clinicians regarding early detection and proper intervention. This is even more problematic with individuals with severe psychiatric disorders who have reduced sensitivity to pain due to long-term or excessive medication use or disturbed bodily sensation perceptions. This study aimed to determine whether psychiatric disorder, psychotropic prescription, and treatment compliance increase the risks of complicated acute appendicitis. Methods The diagnosis records of acute appendicitis from four university hospitals in Korea were investigated from 2002 to 2020. A total of 47,500 acute appendicitis-affected participants were divided into groups with complicated and uncomplicated appendicitis to determine whether any of the groups had more cases of psychiatric disorder diagnoses. Further, the ratio of complicated compared to uncomplicated appendicitis in the mentally ill group was calculated regarding psychotropic dose, prescription duration, and treatment compliance. Results After adjusting for age and sex, presence of psychotic disorder (odds ratio [OR]: 1.951; 95% confidence interval [CI]: 1.218–3.125), and bipolar disorder (OR: 2.323; 95% CI: 1.194–4.520) was associated with a higher risk of having complicated appendicitis compared with absence of psychiatric disorders. Patients who are taking high-daily-dose antipsychotics, regardless of prescription duration, show high complicated appendicitis risks; High-dose antipsychotics for < 1 year (OR: 1.896, 95% CI: 1.077–3.338), high-dose antipsychotics for 1–5 years (OR: 1.930, 95% CI: 1.144–3.256). Poor psychiatric outpatient compliance was associated with a high risk of complicated appendicitis (OR: 1.664, 95% CI: 1.014–2.732). Conclusions This study revealed a close relationship in the possibility of complicated appendicitis in patients with severe psychiatric disorders, including psychotic and bipolar disorders. The effect on complicated appendicitis was more remarkable by the psychiatric disease entity itself than by psychotropic prescription patterns. Good treatment compliance and regular visit may reduce the morbidity of complicated appendicitis in patients with psychiatric disorders.This work was supported by the Technology Innovation Program (or Industrial Strategic Technology Development Program) (20004927, Upgrade of CDM based Distributed Biohealth Data Platform and Development of Verification Technology) funded by the Ministry of Trade, Industry & Energy (MOTIE, Korea), and the Bio Industrial Strategic Technology Development Program (20003883) funded by the Ministry of Trade, Industry & Energy (MOTIE, Korea), Bio & Medical Technology Development Program of the National Research Foundation of Korea funded by the Ministry of Health and Welfare, Ministry of Science and ICT, Ministry of Trade Industry and Energy (MOTIE, Korea) Disease Control and Prevention Agency (The National Project of Bio Big Data) (NRF‑2020M3E5D7085175), and Bio & Medical Technology Development Program of the National Research Foundation funded by the Ministry of Science & ICT (No. 2021M3A9E408078412)

Abstract 2328: Metabolomics pathways and biomarkers in predicting breast cancer prognosis

Abstract Breast cancer is the most frequently diagnosed cancer in women and the second leading cause of cancer death in Americans. With more than 3 million breast cancer survivors in the US, a number that is projected to increase, it is important to identify targets for precision intervention to improve breast cancer prognosis. With the rapid advancement of technology for metabolomics, the results from several recent studies have shown that metabolomics may have applications in breast cancer diagnosis and subtype analysis, characterization of heterogeneity of breast cancer, and prognosis. In the current study, we performed a global urinary metabolomic analysis of 120 breast cancer patients: 60 progression-free (PF) cases as the reference group and 60 with progressive disease (PD: recurrence, second primary, metastasis, or death). The urine samples were collected immediately after radiotherapy. Using UPLC-MS/MS and GC-MS, Metabolon Inc. identified a robust set of 1,742 biochemicals (1,258 known and 484 unknown structure). The most notable differences between PF and PD patients involved multiple pathways and metabolites include: carbohydrate metabolism (e.g., glucose, sedoheptulose, and N6-carboxymethyllysine), branch-chain amino acid metabolism (e.g., alpha-hydroxyisocaproate and beta-hydroxyisovalerylglycine), phosphatidylcholine metabolism (e.g., 1-palmitoyl-2-oleoyl-GPC (16:0/18:1) and 1-palmitoyl-2-linoleoyl-GPC (16:0/18:2)), arginine metabolism (e.g., dimethylarginine, N-acetylcitrulline, and homocitrulline), oxidative stress-related metabolites (e.g., cysteine-glutathione disulfide, gamma-glutamylisoleucine, and gamma-glutamylthreonine), androgenic steroids (Dehydroepiandrosterone sulfate (DHEA-S) and 16a-hydroxy DHEA 3-sulfate), and nucleotide metabolism. Some of these identified metabolomic differences may serve as potential predictive biomarkers of breast cancer prognosis. In summary, with increasing interest in targeting tumor metabolism in precision medicine and our pilot data suggesting multiple metabolic pathways in predicting breast cancer prognosis, future research is warranted to validate our findings and identify metabolomic targets for precision interventions. Citation Format: Jennifer J. Hu, Cristiane Takita, Isildinha M. Reis, George Yang, Wei Zhao, Eunkyung Lee. Metabolomics pathways and biomarkers in predicting breast cancer prognosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2328

Analysis of microstructure in mouse femur and decalcification effect on microstructure by electron microscopy

Microstructure and decalcification effect by ethylenediaminetetraacetic acid (EDTA) on microstructure were studied for the compact bone of mouse femur by optical and electron microscopy. Especially the (002) reflection plane on the selected area electron diffraction (SAED) of hydroxyapatite (HA) was analyzed in detail. Two types of HA crystals were observed by transmission electron microscopy (TEM). One was needle-like crystals known as general HA crystals, and the other was flake-like crystals. Major constituents of two types of crystals were calcium, phosphorus, and oxygen. The Ca/P ratios of two types of crystals were close to the ideal value of HA within experimental error. Intensity data obtained from each crystals were also very similar. These results indicated that two types of crystals were actually same HA crystals. It was noticed that the (002) reflection plane on SAED displayed ring, spot, or arc patterns in accordance with orientations of HA crystals. Decalcification by EDTA process obsecured outline of osteons and havarsian canals, and changed morphology of the bone section. As the results of decalcification it was observed by TEM-EDS (Energy Dispersive Spectroscopy) that all peaks of calcium and phosphorus disappeared, and intensity of oxygen peak was substantially reduced. Moreover, collagen appeared to be disaggreated

Abstract 897: Association between transforming growth factor beta 1 and progression-free survival in breast cancer

Abstract Transforming growth factor-beta 1 (TGF-β1) has a dual role in cancer progression, with inhibitory functions in early tumor stages and tumor promotion in advanced stages. However, most prior studies have studied survival in either all tumor stages together or a subset of stages. Therefore, this study examined the effect of TGF-β1 before and after radiotherapy (RT) on progression-free survival (PFS) in a racially/ethnically diverse breast cancer patient population and stratified by cancer stage (n=488). Plasma samples were collected on the first (pre-RT) and last day of RT (post-RT), and patients were followed for up to 10 years through electronic medical records. TGF-β1 was assayed with the ELISA kit (R&D Systems, Inc, Minneapolis, MN). PFS was calculated as the time between the date of diagnosis to the first event (death, recurrence, or metastasis) or last follow-up if no event occurred. TGF-β1 was treated as a continuous variable (per 1,000 pg/mL increase). Univariable and multivariable Cox proportional hazards regression models were used to evaluate the association between TGF-β1 and PFS, adjusted for age at diagnosis, clinical tumor stage, and triple-negative breast cancer status in total, stage 0-II, or stage III-IV patients. The study population was comprised of 306 Hispanic white (63%), 102 Black/African American (21%), 64 non-Hispanic white (13%), and 16 other patients (3%). In univariable analyses, stage 0-II patients had 12% and 11% higher risk for event for every 1,000 pg/mL increase in pre-RT (HR=1.12, 95%CI=1.05-1.19, p<0.001) and post-RT (HR=1.11, 95%CI=1.01-1.23, p=0.034) TGF-β1, respectively. In multivariable models, increases in pre-RT (HR=1.11, 95%CI=1.04-1.19, p<0.001) and post-RT TGF-β1 (HR=1.12, 95%CI=1.01-1.24, p=0.031) remained significantly associated with worse PFS in stage 0-II patients, and post-RT TGF-β1 became significantly associated with worse PFS in all patients (HR=1.10, 95%CI=1.00-1.20, p=0.048). In a subset of 107 patients, there was a significant drop of TGF-β1 levels from baseline before any treatment to pre-RT (mean±SD: 6269±3296 to 3787±2810, p<0.001). The implication is that other treatment(s) before RT reduced the tumor burden that may contribute to decreasing circulating TGF-β1 levels. However, TGF-β1 levels were not different between pre- and post-RT. In summary, our current data suggest that higher pre- and post-RT TGF-β1 levels were associated with worse PFS in early-stage patients. Although plasma TGF-β1 levels may not represent the amount of TGF-β1 in tumor, it may still serve as a surrogate prognostic marker and a potential target in cancer therapy. Future larger studies are warranted to validate our findings that circulating TGF-β1 may predict progression-free survival of breast cancer, especially in patients with early stage tumors. Citation Format: George Ruochen Yang, Cristiane Takita, Jean L. Wright, Isildinha M. Reis, Eunkyung Lee, Jennifer J. Hu. Association between transforming growth factor beta 1 and progression-free survival in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 897

Electrospun Silk Fibroin Nanofibrous Scaffolds with Two-Stage Hydroxyapatite Functionalization for Enhancing the Osteogenic Differentiation of Human Adipose-Derived Mesenchymal Stem Cells

The development of functional scaffolds with improved osteogenic potential is important for successful bone formation and mineralization in bone tissue engineering. In this study, we developed a functional electrospun silk fibroin (SF) nanofibrous scaffold functionalized with two-stage hydroxyapatite (HAp) particles, using mussel adhesive-inspired polydopamine (PDA) chemistry. HAp particles were first incorporated into SF scaffolds during the electrospinning process, and then immobilized onto the electrospun SF nanofibrous scaffolds containing HAp via PDA-mediated adhesive chemistry. We obtained two-stage HAp-functionalized SF nanofibrous scaffolds with improved mechanical properties and capable of providing a bone-specific physiological microenvironment. The developed scaffolds were tested for their ability to enhance the osteogenic differentiation of human adipose-derived mesenchymal stem cells (hADMSCs) in vitro and repair bone defect in vivo. To boost their ability for bone repair, we genetically modified hADMSCs with the transcriptional coactivator with PDZbinding motif (TAZ) via polymer nanoparticle-mediated gene delivery. TAZ is a well-known transcriptional modulator that activates the osteogenic differentiation of mesenchymal stem cells (MSCs). Two-stage HAp-functionalized SF scaffolds significantly promoted the osteogenic differentiation of TAZ-transfected hADMSCs in vitro and enhanced mineralized bone formation in a critical-sized calvarial bone defect model. Our study shows the potential utility of SF scaffolds with nanofibrous structures and enriched inorganic components in bone tissue engineering.© 2017 American Chemical Societ

An indirect method for in vivo T-2 mapping of [1-C-13] pyruvate using hyperpolarized C-13 CSI

An indirect method for in vivo T-2 mapping of C-13-labeled metabolites using T-2 and T-2* information of water protons obtained a priori is proposed. The T-2 values of C-13 metabolites are inferred using the relationship to T-2 of coexisting H-1 and the T-2* of C-13 metabolites, which is measured using routine hyperpolarized C-13 CSI data. The concept is verified with phantom studies. Simulations were performed to evaluate the extent of T-2 estimation accuracy due to errors in the other measurements. Also, bias in the C-13 T-2* estimation from the C-13 CSI data was studied. In vivo experiments were performed from the brains of normal rats and a rat with C6 glioma. Simulation results indicate that the proposed method provides accurate and unbiased C-13 T-2 values within typical experimental settings. The in vivo studies found that the estimated T-2 of [1-C-13] pyruvate using the indirect method was longer in tumor than in normal tissues and gave values similar to previous reports. This method can estimate localized T-2 relaxation times from multiple voxels using conventional hyperpolarized C-13 CSI and can potentially be used with time resolved fast CSI. Copyright © 2017 John Wiley & Sons, Ltd.1