ABSTRACT
PURPOSE: Although radiation therapy is one of the most significant treatment modalities for localized prostate cancer, the prognostic factors for biochemical recurrence (BCR) regarding the treatment plan are unclear. We aimed to develop a novel dosiomics-based prediction model for BCR in patients with prostate cancer and clarify the correlations between the dosimetric factors and BCR. METHODS AND MATERIALS: This study included 489 patients with localized prostate cancer (BCR: 96; no-BCR: 393) who received intensity modulated radiation therapy. A total of 2475 dosiomic features were extracted from the dose distributions on the prostate, clinical target volume (CTV), and planning target volume. A prediction model for BCR was trained on a training cohort of 342 patients. The performance of this model was validated using the concordance index (C-index) in a validation cohort of 147 patients. Another model was constructed using clinical variables, dosimetric parameters, and radiomic features for comparisons. Kaplan-Meier curves with log-rank analysis were used to assess the univariate discrimination based on the predictive dosiomic features. RESULTS: The dosiomic feature derived from the CTV was significantly associated with BCR (hazard ratio, 0.73; 95% CI, 0.57-0.93; P = .01). Although the dosiomics model outperformed the dosimetric and radiomics models, it did not outperform the clinical model. The performance significantly improved by combining the clinical variables and dosiomic features (C-index: 0.67; 95% CI, 0.65-0.68; P < .0001). The predictive dosiomic features were used to distinguish high-risk and low-risk patients (P < .05). CONCLUSIONS: The dosiomic feature extracted from the CTV was significantly correlated with BCR in patients with prostate cancer, and the dosiomics model outperformed the model with conventional dose indices. Hence, new metrics for evaluating the quality of a treatment plan are warranted. Moreover, further research should be conducted to determine whether dosiomics can be incorporated in a clinical workflow or clinical trial.
Subject(s)
Prostatic Neoplasms , Radiotherapy, Intensity-Modulated , Humans , Male , Prostate , Prostatic Neoplasms/diagnostic imaging , Prostatic Neoplasms/radiotherapy , Radiometry , Radiotherapy, Intensity-Modulated/methodsABSTRACT
We have developed a new class of PDE10A inhibitor, a pyrazolo[1,5-a]pyrimidine derivative MT-3014 (1). A previous compound introduced was deprioritized due to concerns for E/Z-isomerization and glutathione-adduct formation at the core stilbene structure. We discovered pyrazolo [1,5-a] pyrimidine as a new lead scaffold by structure-based drug design utilizing a co-crystal structure with PDE10A. The lead compound was optimized for in vitro activity, solubility, and selectivity against human ether-á-go-go related gene cardiac channel binding. We observed that MT-3014 shows excellent efficacy in rat conditioned avoidance response test and suitable pharmacokinetic properties in rats, especially high brain penetration.
Subject(s)
Drug Discovery , Phosphodiesterase Inhibitors/pharmacology , Phosphoric Diester Hydrolases/metabolism , Pyrimidines/pharmacology , Stilbenes/pharmacology , Animals , Cattle , Crystallography, X-Ray , Dose-Response Relationship, Drug , Humans , Models, Molecular , Molecular Structure , Phosphodiesterase Inhibitors/chemical synthesis , Phosphodiesterase Inhibitors/chemistry , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Stilbenes/chemistry , Structure-Activity RelationshipABSTRACT
Zoanthenol, isolated from Zoanthus sp., possesses an extremely complex architecture including contiguous quaternary carbons. An enantioselective synthesis of the fully functionalized ABC-ring of zoanthenol has been achieved and is described herein. The key features of the synthesis are the enzymatic kinetic optical resolution and the Mizoroki-Heck/Simmons-Smith reaction strategy used to construct the congested asymmetric quaternary carbons.
Subject(s)
Heterocyclic Compounds, Bridged-Ring/chemical synthesis , Alkaloids/chemistry , Heterocyclic Compounds, Bridged-Ring/chemistry , Molecular Structure , Oxidation-Reduction , StereoisomerismABSTRACT
Zoanthamines are a family of marine alkaloids that have complex heptacyclic structures and are reported to be interleukin-6 modulators. While the structure of zoanthamines, especially the ABC-ring portion, is similar to that of steroids, the CDEFG-ring portion, composed of aminoacetal and lactone core, is a unique structural element. In this report, we designed and synthesized ABC-ring 6 and CDEFG-ring 7, which are truncated analogues of the northern and southern hemispheres of zoanthenol 5, respectively, and which incorporate all of the functionality of each hemisphere. A preliminary SAR study suggested that the hydrochloride of the CEFG-ring portion is an active pharmacophore for suppressing the growth of interleukin-6-dependent MH60 cells.
Subject(s)
Cnidaria/chemistry , Heterocyclic Compounds, Bridged-Ring/pharmacology , Alkaloids/chemical synthesis , Alkaloids/pharmacology , Animals , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Design , Heterocyclic Compounds, Bridged-Ring/chemical synthesis , Hybridomas , Interleukin-6/antagonists & inhibitors , Mice , Molecular Mimicry , Osteoporosis/drug therapy , Structure-Activity RelationshipABSTRACT
[reaction: see text]. Stereocontrolled synthesis of the ABC ring framework of zoanthenol has been achieved. Our studies show that a beta,beta-disubstituted enone can act as a good acceptor of arylpalladium intermediates in the formation of a congested benzylic quaternary carbon center through an intramoleculer Mizoroki-Heck reaction. The cis B/C ring system was stereoselectively converted to the trans-fused framework through a SmI2-promoted deoxygenation of the alpha-hydroxy ketone.
