Pin1 is a peptidyl-prolyl isomerase consisting of a WW domain and a catalytic isomerase (PPIase) domain connected by a flexible linker. Pin1 recognizes phospho-Ser/Thr-Pro motifs in cell-signaling proteins, and is both a cancer and an Alzheimer's disease target. Here, we provide novel insight into the functional motions underlying Pin1 substrate interaction using nuclear magnetic resonance deuterium ((2)D) and carbon ((13)C) spin relaxation. Specifically, we compare Pin1 side-chain motions in the presence and absence of a known phosphopeptide substrate derived from the mitotic phosphatase Cdc25. Substrate interaction alters Pin1 side-chain motions on both the microsecond-millisecond (mus-ms) and picosecond-nanosecond (ps-ns) timescales. Alterations include loss of ps-ns flexibility along an internal conduit of hydrophobic residues connecting the catalytic site with the interdomain interface. These residues are conserved among Pin1 homologs; hence, their dynamics are likely important for the Pin1 mechanism.

To evaluate the association of normalized and absolute ADC metrics with progression free survival (PFS) and overall survival (OS) in patients treated for glioblastoma multiforme (GBM). Fifty-two patients with preradiotherapy diffusion weighted imaging treated with post-operative chemoradiation for GBM were evaluated. Region of interest analysis for ADC metrics including mean and minimum ADC value (ADCmean) and (ADCmin) was performed within the T2/FLAIR volume. Normalized (N)ADC values were generated relative to contralateral white matter. PFS and OS were analyzed relative to ADC parameters using a regression model. Kaplan-Meier and Cox proportional hazards analysis with respect to (N)ADCmean, and (N)ADCmin was performed. A (N)ADC threshold <1.3 within the T2/FLAIR volume was analyzed with respect to PFS and OS. Regression analysis indicated that normalized ADC values provide the strongest association with PFS and OS. Kaplan-Meier analysis revealed a non-significant trend toward inferior PFS and OS associated with (N)ADCmean <1.7, and a significant decrement to PFS and OS associated with (N)ADCmin <0.3. (N)ADCmin was a significant prognostic factor when taking into account age, performance status, and extent of resection. ADC thresholding analysis revealed that a retained volume of >0.45 cc per mL FLAIR volume was associated with a trend toward inferior PFS and OS. In the post-operative, pre-radiotherapy setting, the (N)ADCmin is the strongest predictor of outcomes in patients treated for GBM. ADC thresholding analysis indicates that a large volume of normalized ADC value <1.3 may be associated with adverse outcomes.

The presence of an ADC hypointensity on pre-radiotherapy diffusion-weighted imaging is associated with the location of tumor recurrence as demonstrated by frequent overlap in this series, and is associated with a trend toward inferior outcomes. This abnormality may reflect a high risk region of hypercellularity and warrants consideration with respect to radiotherapy planning.

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Background: Both fractionated external beam radiotherapy and single fraction radiosurgery for pituitary adenomas are associated with the risk of hypothalamic–pituitary (HP) axis dysfunction.Objective: To analyze the effect of treatment modality (Linac, TomoTherapy, or gamma knife) on hypothalamic dose and correlate these with HP-axis deficits after radiotherapy.Methods: Radiation plans of patients treated post-operatively for pituitary adenomas using Linac-based 3D-conformal radiotherapy (CRT) (n = 11), TomoTherapy-based intensity modulated radiation therapy (IMRT) (n = 10), or gamma knife stereotactic radiosurgery (n = 12) were retrospectively reviewed. Dose to the hypothalamus was analyzed and post-radiotherapy hormone function including growth hormone, thyroid stimulating hormone, adrenocorticotropic hormone, prolactin, and gonadotropins (follicle stimulating hormone/luteinizing hormone) were assessed.Results: Post-radiation, 13 of 27 (48%) patients eligible for analysis developed at least one new hormone deficit, of which 8 of 11 (72%) occurred in the Linac group, 4 of 8 (50%) occurred in the TomoTherapy group, and 1 of 8 (12.5%) occurred in the gamma knife group. Compared with fractionated techniques, gamma knife showed improved hypothalamic sparing for DMax Hypo and V12Gy. For fractionated modalities, TomoTherapy showed improved dosimetric characteristics over Linac-based treatment with hypothalamic DMean (44.8 vs. 26.8 Gy p = 0.02), DMax (49.8 vs. 39.1 Gy p = 0.04), and V12Gy (100 vs. 76% p = 0.004).Conclusion: Maximal dosimetric avoidance of the hypothalamus was achieved using gamma knife-based radiosurgery followed by TomoTherapy-based IMRT, and Linac-based 3D conformal radiation therapy, respectively.