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External beam radiotherapy remains the primary treatment modality for localized prostate cancer. The radiobiology of prostate carcinoma lends itself to hypofractionation, with recent studies showing good outcomes with shorter treatment schedules. However, the ability to accurately deliver hypofractionated treatment is limited by current image-guided techniques. Magnetic resonance imaging is the main diagnostic tool for localized prostate cancer and its use in the therapeutic setting offers anatomical information to improve organ delineation. MR-guided radiotherapy, with daily re-planning, has shown early promise in the accurate delivery of radiotherapy. In this article, we discuss the shortcomings of current image-guidance strategies and the potential benefits and limitations of MR-guided treatment for prostate cancer. We also recount present experiences of MR-linac workflow and the opportunities afforded by this technology.

The inositol hexakisphosphate kinases (IP6Ks) are the principal enzymes that generate inositol pyrophosphates. There are three IP6Ks (IP6K1, 2, and 3). Functions of IP6K1 and IP6K2 have been substantially delineated, but little is known of IP6K3's role in normal physiology, especially in the brain. To elucidate functions of IP6K3, we generated mice with targeted deletion of IP6K3. We demonstrate that IP6K3 is highly concentrated in the brain in cerebellar Purkinje cells. IP6K3 physiologically binds to the cytoskeletal proteins adducin and spectrin, whose mutual interactions are perturbed in IP6K3-null mutants. Consequently, IP6K3 knock-out cerebella manifest abnormalities in Purkinje cell structure and synapse number, and the mutant mice display deficits in motor learning and coordination. Thus, IP6K3 is a major determinant of cytoskeletal disposition and function of cerebellar Purkinje cells.

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ImportanceMagnetic resonance imaging (MRI) guidance offers multiple theoretical advantages in the context of stereotactic body radiotherapy (SBRT) for prostate cancer. However, to our knowledge, these advantages have yet to be demonstrated in a randomized clinical trial.ObjectiveTo determine whether aggressive margin reduction with MRI guidance significantly reduces acute grade 2 or greater genitourinary (GU) toxic effects after prostate SBRT compared with computed tomography (CT) guidance.Design, Setting, and ParticipantsThis phase 3 randomized clinical trial (MRI-Guided Stereotactic Body Radiotherapy for Prostate Cancer [MIRAGE]) enrolled men aged 18 years or older who were receiving SBRT for clinically localized prostate adenocarcinoma at a single center between May 5, 2020, and October 1, 2021. Data were analyzed from January 15, 2021, through May 15, 2022. All patients had 3 months or more of follow-up.InterventionsPatients were randomized 1:1 to SBRT with CT guidance (control arm) or MRI guidance. Planning margins of 4 mm (CT arm) and 2 mm (MRI arm) were used to deliver 40 Gy in 5 fractions.Main Outcomes and MeasuresThe primary end point was the incidence of acute (≤90 days after SBRT) grade 2 or greater GU toxic effects (using Common Terminology Criteria for Adverse Events, version 4.03 [CTCAE v4.03]). Secondary outcomes included CTCAE v4.03–based gastrointestinal toxic effects and International Prostate Symptom Score (IPSS)–based and Expanded Prostate Cancer Index Composite-26 (EPIC-26)–based outcomes.ResultsBetween May 2020 and October 2021, 156 patients were randomized: 77 to CT (median age, 71 years [IQR, 67-77 years]) and 79 to MRI (median age, 71 years [IQR, 68-75 years]). A prespecified interim futility analysis conducted after 100 patients reached 90 or more days after SBRT was performed October 1, 2021, with the sample size reestimated to 154 patients. Thus, the trial was closed to accrual early. The incidence of acute grade 2 or greater GU toxic effects was significantly lower with MRI vs CT guidance (24.4% [95% CI, 15.4%-35.4%] vs 43.4% [95% CI, 32.1%-55.3%]; P = .01), as was the incidence of acute grade 2 or greater gastrointestinal toxic effects (0.0% [95% CI, 0.0%-4.6%] vs 10.5% [95% CI, 4.7%-19.7%]; P = .003). Magnetic resonance imaging guidance was associated with a significantly smaller percentage of patients with a 15-point or greater increase in IPSS at 1 month (6.8% [5 of 72] vs 19.4% [14 of 74]; P = .01) and a significantly reduced percentage of patients with a clinically significant (≥12-point) decrease in EPIC-26 bowel scores (25.0% [17 of 68] vs 50.0% [34 of 68]; P = .001) at 1 month.Conclusions and RelevanceIn this randomized clinical trial, compared with CT-guidance, MRI-guided SBRT significantly reduced both moderate acute physician-scored toxic effects and decrements in patient-reported quality of life. Longer-term follow-up will confirm whether these notable benefits persist.Trial RegistrationClinicalTrials.gov Identifier: NCT04384770

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Wnt signaling regulates embryo development and tissue homeostasis, and its deregulation leads to an array of diseases, including cancer. Dapper1 has been shown to be a key negative regulator of Wnt signaling. However, its function and regulation remain poorly understood. In this study, we report that 14-3-3␤ interacts with human Dapper1 (hDpr1). The interaction is dependent on protein kinase A (PKA)-mediated phosphorylation of hDpr1 at Ser-237 and Ser-827. 14-3-3␤ binding attenuates the ability of hDpr1 to promote Dishevelled (Dvl) degradation, thus enhancing Wnt signaling. We further provide evidence that PKA-mediated Dpr1 phosphorylation may contribute to growth and tumor formation of colon cancer Caco2 cells. Finally, we show that cyclooxygenase-2 expression and PKA activation are positively correlated with Dvl protein levels in colon cancer samples. Together, our findings establish a novel layer of regulation of Wnt signaling by PKA via the 14-3-3-Dpr1-Dvl axis.Both the canonical and noncanonical Wnt signaling pathways are evolutionarily conserved and play key roles in development and disease (1-4). The canonical Wnt/␤-catenin pathway is initiated by Wnt ligands binding to their receptors Frizzled and low density lipoprotein receptor-related protein 5/6 (LRP5/6), which leads to the cytosolic accumulation of ␤-catenin by disrupting the ␤-catenin destruction complex consisting of Axin, adenomatous polyposis coli (APC), 3 and glycogen synthase kinase 3␤ (GSK3␤). Accumulated ␤-catenin translocates into the nucleus and activates the transcription of Wnt target genes in collaboration with the transcription factor T cell factor/lymphoid enhancer factor (5, 6). In addition to the planar cell polarity (PCP) pathway, which regulates cell polarity and convergent extension, noncanonical Wnt signaling can also be mediated by Ca 2ϩ and other signaling molecules (7,8).Dishevelled (Dvl) is the central player in both the canonical and noncanonical Wnt signaling pathways, serving as a scaffold protein bridging . Dvl can also function in the nucleus (11), where it cooperates with c-Jun, ␤-catenin, and TCF to regulate Wnt target gene transcription (12). Therefore, like many other signaling proteins, Dvl activity is tightly regulated. It can be phosphorylated by casein kinase 2 (13). The stability of Dvl proteins is regulated by an array of proteins, including Dapper1/Dact1, Inversin, NEDL1, Prickle-1, and KLHL12 (14 -17). Our recent work also showed that Dvl protein is ubiquitinated by pVHL-containing E3 ubiquitin ligase and can be regulated by autophagy (18). In addition, altered Dvl expression has been implicated in oncogenesis. Dvl is overexpressed in prostate cancer, non-small cell lung cancer, mesothelioma, and other cancers, and its up-regulation has been indicated to be correlated with activation of Wnt/␤-catenin signaling (19 -21).Dapper1 (Dpr1), also called Dact1, as a Dvl-interacting protein, is a negative regulator of both canonical and noncanonical Wnt signaling (14,22). Three Dpr family members, Dpr1, Dpr2, and Dpr...