Study of the Effects of Remote Heavy Group Vibrations on the Temperature Dependence of Hydride Kinetic Isotope Effects of the NADH/NAD+ Model Reactions.

It has recently been observed that the temperature(T)-dependence of KIEs in H-tunneling reactions, characterized by isotopic activation energy difference (ΔEa = EaD - EaH), is correlated to the rigidity of the tunneling ready states (TRSs) in enzymes. A more rigid system with narrowly distributed H-donor-acceptor distances (DADs) at the TRSs gives rise to a weaker T-dependence of KIEs (i.e., a smaller ΔEa). Theoreticians have attempted to develop new H-tunneling models to explain this, but none has been universally accepted. In order to further understand the observations in enzymes and provide useful data to build new theoretical models, we have studied the electronic and solvent effects on ΔEa's for the hydride-tunneling reactions of NADH/NAD+ analogues. We found that a tighter charge-transfer (CT) complex system gives rises to a smaller ΔEa, consistent with the enzyme observations. In this paper, we use the remote heavy group (R) vibrational effects to mediate the system rigidity to study the rigidity-ΔEa relationship. The specific hypothesis is that slower vibrations of a heavier remote group would broaden the DAD distributions and increase the ΔEa value. Four NADH/NAD+ systems were studied in acetonitrile but most of such heavy group vibrations do not appear to significantly increase the ΔEa. The remote heavy group vibrations in these systems may have not affected the CT complexation rigidity to a degree that can significantly increase the DADs, and further, the ΔEa values.

Structural Effects on the Temperature Dependence of Hydride Kinetic Isotope Effects of the NADH/NAD+ Model Reactions in Acetonitrile: Charge-Transfer Complex Tightness Is a Key.

It has recently frequently been found that the kinetic isotope effect (KIE) is independent of temperature (T) in H-tunneling reactions in enzymes but becomes dependent on T in their mutants. Many enzymologists found that the trend is related to different donor-acceptor distances (DADs) at tunneling-ready states (TRSs), which could be sampled by protein dynamics. That is, a more rigid system of densely populated short DADs gives rise to a weaker T dependence of KIEs. Theoreticians have attempted to develop H-tunneling theories to explain the observations, but none have been universally accepted. It is reasonable to assume that the DAD sampling concept, if it exists, applies to the H-transfer reactions in solution, as well. In this work, we designed NADH/NAD+ model reactions to investigate their structural effects on the T dependence of hydride KIEs in acetonitrile. Hammett correlations together with N-CH3/CD3 secondary KIEs were used to provide the electronic structure of the TRSs and thus the rigidity of their charge-transfer complexation vibrations. In all three pairs of reactions, a weaker T dependence of KIEs always corresponds to a steeper Hammett slope on the substituted hydride acceptors. It was found that a tighter/rigid charge-transfer complexation system corresponds with a weaker T dependence of KIEs, consistent with the observations in enzymes.

Deep Inspiratory Breath-Hold Radiation for Left-Sided Breast Cancer using Novel Frame-based Tactile Feedback.

A frame providing tactile feedback for the reproducibility of deep inspiratory breath-hold (DIBH) is described. The frame, fitted across the patient, comprises a horizontal bar, parallel to the patient's long axis, and holds a graduated pointer perpendicular to it. The pointer provides individualized tactile feedback for reproducibility of DIBH. Within the pointer is a movable pencil, bearing a 5 mm coloured strip which becomes visible only during DIBH, and acts as a visual cue to the therapist. The average variation in separation in the planning and pretreatment cone-beam computed tomography of 10 patients was 2 mm (confidence interval 1.95-2.05). Frame-based tactile feedback is a novel, reproducible technique for DIBH.

The Hippocampus: A New Organ at Risk for Postoperative Radiation Therapy for Bucco-alveolar Cancer? A Dosimetric and Biological Analysis.

PURPOSE: A significant proportion of patients with bucco-alveolar cancer are long-term survivors, warranting attention to survivorship issues. Decline in neurocognitive function after cranial irradiation for brain tumors correlates with a hippocampal maximum dose (Dmax) of more than 16 Gy, minimum dose (Dmin) of more than 9 Gy, and dose to 40% of the hippocampal volume (D40%) exceeding 7.3 Gy in 2-Gy equivalent dose (EQD2), respectively. We analyzed the utility of sparing the hippocampus in postoperative radiation therapy (PORT) for patients with bucco-alveolar cancer, given the proximity of target volumes to the hippocampus, by virtue of inclusion of the infratemporal fossa. METHODS AND MATERIALS: We instituted hippocampal sparing for patients with bucco-alveolar cancer receiving PORT in March 2018. Ten prior and 10 subsequent consecutive patients with pathologically staged I-IVA cancers of the buccal mucosa, alveolus, and retromolar trigone formed the control group (no hippocampal sparing) and the study group (hippocampal sparing), respectively. The brain and temporal lobes were prescribed dose constraints in both groups. Patients received doses of 60 to 66 Gy at 2 Gy per fraction using the image-guided intensity modulated radiation therapy / volumetric modulated arc therapy technique. Treatment plans were evaluated for (1) hippocampal dosimetric parameters, (2) planning target volume dosimetry and plan-quality indices, and (3) biological indices of equivalent uniform dose (EUD) and normal-tissue complication probability (NTCP) for impaired neurocognitive function. RESULTS: Hippocampal sparing significantly reduced the hippocampal DmaxEQD2, DmeanEQD2, and D40%EQD2 from 27 Gy to 10.9 Gy (P = .002), 14.3 Gy to 6.4 Gy (P = .002), and 15.5 Gy to 6.6 Gy (P = .005), respectively, with comparable plan-quality indices. The radiobiologically robust endpoints of ipsilateral hippocampal EUD (P = .005) and NTCP (P = .01) were statistically significantly improved. CONCLUSIONS: Meaningful dosimetric benefit, corroborated with radiobiological indices, was observed with hippocampal sparing. The feasibility and benefit of hippocampal sparing supports our view that the hippocampus should be incorporated as an organ at risk and attention should be given to neurocognitive function in patients with bucco-alveolar cancer who are receiving PORT.