Fragmentation of 5-fluorouridine induced by low energy (< 12 eV) electrons: insights into the radiosensitization of DNA.

5-Fluorouracil is now routinely used in chemo- and radiotherapy. Incorporated within DNA, the molecule is bound to the sugar backbone, forming the 5-fluorouridine sub-unit investigated in the present work. For the clinical usage of the latter, no information exists on the mechanisms that control the radiosensitizing effect at the molecular level. As low energy (< 12 eV) electrons are abundantly produced along the radiation tracks during cancer treatment using beams of high energy particles, we study how these ballistic secondary electrons damage the sensitizing molecule. The salient result from our study shows that the N-glycosidic bonds are principally affected with a cross-section of approximately two orders of magnitude higher than the canonical thymidine, reflecting to some degree the surviving factor of radiation-treated carcinoma cells with and without 5-fluorouracil incorporation. This result may help in the comprehension of the radiosensitizing effect of the fluoro-substituted thymidine in DNA.

Fragmentation of the DNA Lesion 8-oxo-Guanine by Low-Energy Electrons.

8-oxo-Guanine is a mutagenic lesion produced by reactions involving reactive oxygen species and guanine in DNA. Its production induces mispairing between the canonical nucleobases during DNA replication such that various types of cancers are associated with the DNA lesion. Since radiation therapy is used in some cases, the interaction of low-energy electrons with 8-oxo-guanine can in turn produce other reactive species, which in principle could have either a detrimental or protective effect on the organism. Motivated by these facts, we report a comparative experimental study of electron-induced fragmentation of guanine and 8-oxo-guanine, along with a theoretical study of the π* shape resonances and bound anion states, which may trigger those dissociation reactions. The electron-induced fragmentation of 8-oxo-guanine is remarkably distinct from the native form. More complex reactions were observed for the oxidized species, which may produce several anion fragments at very low energies (∼0 eV). The dehydrogenated parent anion, which is already a minor fragment in guanine, was completely suppressed in 8-oxo-guanine. The calculated thermodynamical thresholds also suggest that NH2 elimination in guanine, at sub-excitation energies, proceeds via a complex reaction involving rearrangement steps.

Impact of autofluorescence for detection of parathyroid glands during thyroidectomy on postoperative parathyroid hormone levels: parallel multicentre randomized clinical trial.

BACKGROUND: Techniques for autofluorescence have been introduced to visualize the parathyroid glands during surgery and to reduce hypoparathyroidism after thyroidectomy. METHODS: This parallel multicentre RCT investigated the use of Fluobeam® LX to visualize the parathyroid glands by autofluorescence during total thyroidectomy compared with no use. There was no restriction on the indication for surgery. Patients were randomized 1 : 1 and were blinded to the group allocation. The hypothesis was that autofluorescence enables identification and protection of the parathyroid glands during thyroidectomy. The primary endpoint was the rate of low parathyroid hormone (PTH) levels the day after surgery. RESULTS: Some 535 patients were randomized, and 486 patients received an intervention according to the study protocol, 246 in the Fluobeam® LX group and 240 in the control group. Some 64 patients (26.0 per cent) in the Fluobeam® LX group and 77 (32.1 per cent) in the control group had low levels of PTH after thyroidectomy (P = 0.141; relative risk (RR) 0.81, 95 per cent c.i. 0.61 to 1.07). Subanalysis of 174 patients undergoing central lymph node clearance showed that 15 of 82 (18 per cent) in the Fluobeam® LX group and 31 of 92 (33 per cent) in the control group had low levels of PTH on postoperative day 1 (P = 0.021; RR 0.54, 0.31 to 0.93). More parathyroid glands were identified during operation in patients who had surgery with Fluobeam® LX, and fewer parathyroid glands in the surgical specimen on definitive histopathology. No specific harm related to the use of Fluobeam® LX was reported. CONCLUSION: The use of autofluorescence during thyroidectomy did not reduce the rate of low PTH levels on postoperative day 1 in the whole group of patients. It did, however, reduce the rate in a subgroup of patients. Registration number: NCT04509011 (http://www.clinicaltrials.gov).

Experimental and Theoretical Studies of Dissociative Electron Attachment to Metabolites Oxaloacetic and Citric Acids.

In this contribution the dissociative electron attachment to metabolites found in aerobic organisms, namely oxaloacetic and citric acids, was studied both experimentally by means of a crossed-beam setup and theoretically through density functional theory calculations. Prominent negative ion resonances from both compounds are observed peaking below 0.5 eV resulting in intense formation of fragment anions associated with a decomposition of the carboxyl groups. In addition, resonances at higher energies (3-9 eV) are observed exclusively from the decomposition of the oxaloacetic acid. These fragments are generated with considerably smaller intensities. The striking findings of our calculations indicate the different mechanism by which the near 0 eV electron is trapped by the precursor molecule to form the transitory negative ion prior to dissociation. For the oxaloacetic acid, the transitory anion arises from the capture of the electron directly into some valence states, while, for the citric acid, dipole- or multipole-bound states mediate the transition into the valence states. What is also of high importance is that both compounds while undergoing DEA reactions generate highly reactive neutral species that can lead to severe cell damage in a biological environment.

Energy-Selective Decomposition of Organometallic Compounds by Slow Electrons: The Case of Chloro(dimethyl sulfide)gold(I).

Gold-containing compounds offer many applications in nanoscale materials science, and electron-beam methods are versatile for shaping nanostructures. In this study, we report the energy-selective fragmentation of chloro(dimethyl sulfide)gold(I) (ClAuS(CH3)2) induced by slow electrons. We observe the resonant formation of four fragment anions, namely [Cl]-, [S]-, [CH2S]-, and [ClAuH···SH]-, which are generated in the energy range of 0-9 eV. The predominant fragment anion is formed below 1 eV from the cleavage of a single Au-Cl bond to produce the [Cl]- anion. The resonant states and the energetics of the fragmentation are investigated by DFT methods. These findings may contribute to future strategies in the elaboration of specific nanomaterials or for selective chemistry using electron-beam techniques.

Current overview of extrinsic and intrinsic factors in etiology and progression of inflammatory bowel diseases.

Inflammatory bowel diseases (IBD) are chronic, relapsing disorders affecting gastrointestinal (GI) tract and associated with intestinal mucosa damage and inflammation. The principal therapeutic goals in IBD include control of the intestinal inflammation and treatment of the major symptoms, mainly abdominal pain and diarrhea. Current therapeutic strategies for IBD rely on the use of non-specific anti-inflammatory agents and immunosuppressive drugs (e.g. aminosalicylates, monoclonal antibodies, and antibiotics), which cause severe side effects, and - in a significant number of patients - do not induce long-term benefits. In this review, we summarize the epidemiology and the most important risk factors of IBD, including genetic, immunological and environmental. Our main focus is to discuss pharmacological targets for current and future treatments of IBD.