Hypoxia stabilizes SETDB1 to maintain genome stability.

Von Hippel-Lindau (VHL) is a tumor suppressor that functions as the substrate recognition subunit of the CRL2VHL E3 complex. While substrates of VHL have been identified, its tumor suppressive role remains to be fully understood. For further determination of VHL substrates, we analyzed the physical interactome of VHL and identified the histone H3K9 methyltransferase SETBD1 as a novel target. SETDB1 undergoes oxygen-dependent hydroxylation by prolyl hydroxylase domain proteins and the CRL2VHL complex recognizes hydroxylated SETDB1 for ubiquitin-mediated degradation. Under hypoxic conditions, SETDB1 accumulates by escaping CRL2VHL activity. Loss of SETDB1 in hypoxia compared with that in normoxia escalates the production of transposable element-derived double-stranded RNAs, thereby hyperactivating the immune-inflammatory response. In addition, strong derepression of TEs in hypoxic cells lacking SETDB1 triggers DNA damage-induced death. Our collective results support a molecular mechanism of oxygen-dependent SETDB1 degradation by the CRL2VHL E3 complex and reveal a role of SETDB1 in genome stability under hypoxia.

Pre-operative dual-time-point [18F]FET PET differentiates CDKN2A/B loss and PIK3CA mutation status in adult-type diffuse glioma: a single-center prospective study.

PURPOSE: While [18F]FET PET plays a complementary role in glioma imaging, it needs to be more comprehensively understood for improved characterization of glioma prior to surgery given the evolving landscape of molecular neuropathology. Thus, we investigated the utility of pre-operative dual-time-point [18F]FET PET in correlation with next-generation sequencing (NGS) data in patients with adult-type diffuse glioma (ADG). METHODS: Adult patients who were suspected to have primary glioma were prospectively recruited between June 2021 and January 2024. They underwent pre-operative dual-time-point static PET/CT at 20 min (early) and 80 min (delay) after [18F]FET injection. Semi-quantitative parameters of the hottest lesion (SUVmax) of tumour and the hottest lesion-to-normal brain ratio (TBRmax) were assessed from each summed image. Furthermore, the percentage changes (△) of SUVmax and TBRmax between two images were calculated. Histopathology of glioma was determined according to the 2021 WHO classification and NGS data. RESULTS: This study investigated a dozen genes in 76 patients, of whom 51 had isocitrate dehydrogenase (IDH)-wild-type glioblastoma, 13 had IDH-mutant astrocytoma, and 12 had IDH-mutant oligodendroglioma. Every tumour was [18F]FET-avid having TBRmax more than 1.6. Patients with CDKN2A/B loss had significantly higher values of SUVmax (5.7 ± 1.6 vs. 4.7 ± 1.3, p = 0.004; 5.0 ± 1.4 vs. 4.4 ± 1.2, p = 0.026) and TBRmax (6.5 ± 1.8 vs. 5.1 ± 1.7, p = 0.001; 5.3 ± 1.5 vs. 4.3 ± 1.3, p = 0.004) in both scans than patients without CDKN2A/B loss, even after adjustment for age, MRI enhancement, tumor grade and type of pathology. Furthermore, patients with PIK3CA mutation (16.2 ± 11.8 vs. 6.7 ± 11.6, p = 0.007) had significantly higher △SUVmax than patients without PIK3CA mutation, even after adjustment for age, MRI enhancement, tumor grade, and type of pathology. CONCLUSION: Among the dozen genes investigated in this prospective study in patients with ADG, we found out that CDKN2A/B loss and PIK3CA mutation status could be differentiated by pre-operative dual-time-point [18F]FET PET/CT.

Prospective longitudinal analysis of imaging-based spatiotemporal tumor habitats in glioblastoma, IDH-wild type: implication in patient outcome using multiparametric physiologic MRI.

BACKGROUND: Physiologic MRI-based tumor habitat analysis has the potential to predict patient outcomes by identifying the spatiotemporal habitats of glioblastoma. This study aims to prospectively validate the cut-off for tumor progression obtained from tumor habitat analysis based on physiologic MRI in ascertaining time-to-progression (TTP) and the site of progression in glioblastoma patients following concurrent chemoradiotherapy (CCRT). METHODS: In this prospective study (ClinicalTrials.gov ID: NCT02613988), we will recruit patients with IDH-wild type glioblastoma who underwent CCRT and obtained immediate post-operative and three serial post-CCRT MRI scans within a three-month interval, conducted using diffusion-weighted imaging and dynamic susceptibility contrast imaging. Voxels from cerebral blood volume and apparent diffusion coefficient maps will be grouped using k-means clustering into three spatial habitats (hypervascular cellular, hypovascular cellular, and nonviable tissue). The spatiotemporal habitats of the tumor will be evaluated by comparing changes in each habitat between the serial MRI scans (post-operative and post-CCRT #1, #2, and #3). Associations between spatiotemporal habitats and TTP will be analyzed using cox proportional hazard modeling. The site of progression will be matched with spatiotemporal habitats. DISCUSSION: The perfusion- and diffusion-derived tumor habitat in glioblastoma is expected to stratify TTP and may serve as an early predictor for tumor progression in patients with IDH wild-type glioblastoma. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT02613988.

Endoscopic Ultrasound-guided Transmural Biliary Drainage With 6 mm and 8 mm Cautery-enhanced Lumen-apposing Metal Stents: A Multicenter Collaborative Study.

OBJECTIVE: Endoscopic retrograde cholangiopancreatography (ERCP) may be unsuccessful in patients with duodenal stenosis or malignant ampullary infiltration. Endoscopic ultrasound-guided biliary drainage (EUS-BD) has been proposed as an alternative. We aimed to assess the efficacy and safety of EUS-BD for malignant distal bile duct obstruction using the newly introduced smaller caliber 6 or 8 mm cautery-enhanced lumen-apposing metal stent. METHODS: A multicenter retrospective study was performed on patients with unresectable malignant distal bile duct obstruction who underwent EUS-BD between 2021 and 2022 after unsuccessful ERCP. RESULTS: Thirty-two patients were included [7 (53.13%) males], with a mean age of 72.2 ± 12.5 years. The technical success rate was 100%. Altered anatomy was present in 2 (6.25%). The indication for drainage was biliary obstruction from pancreatic cancer in 26 patients (84.5%), cholangiocarcinoma in 3 (9.4%), and ampullary mass in 3 (9.4%). The procedure was performed mostly in an outpatient setting (n = 19, 59.38%). The clinical success rate was 92.3% [bilirubin: 14.1 (SD: 8.9) preprocedure vs 4.9 (SD: 1.1) postprocedure; P = 0.0001]. There was one early adverse event of a perforation, which was closed endoscopically and drained percutaneously. Delayed adverse events included food impaction of the stent (n = 1), which was resolved with a repeat procedure and insertion of a double pigtail stent. CONCLUSION: This study demonstrates the feasibility of EUS-BD drainage using smaller caliber 6 or 8 mm lumen-apposing metal stent to relieve malignant distal bile duct obstruction in patients who fail conventional ERCP.

Interspecific Variations in the Internal Mercury Isotope Dynamics of Antarctic Penguins: Implications for Biomonitoring.

Mercury (Hg) biomonitoring requires a precise understanding of the internal processes contributing to disparities between the Hg sources in the environment and the Hg measured in the biota. In this study, we investigated the use of Hg stable isotopes to trace Hg accumulation in Adélie and emperor penguin chicks from four breeding colonies in Antarctica. Interspecific variation of Δ199Hg in penguin chicks reflects the distinct foraging habitats and Hg exposures in adults. Chicks at breeding sites where adult penguins predominantly consumed mesopelagic prey showed relatively lower Δ199Hg values than chicks that were primarily fed epipelagic krill. Substantial δ202Hg variations in chick tissues were observed in both species (Adélie: -0.11 to 1.13‰, emperor: -0.27 to 1.15‰), whereas only emperor penguins exhibited the lowest δ202Hg in the liver and the highest in the feathers. Our results indicate that tissue-specific δ202Hg variations and their positive correlations with % MeHg resulted from MeHg demethylation in the liver and kidneys of emperor penguin chicks, whereas Adélie penguin chicks showed different internal responses depending on their exposure to dietary MeHg. This study highlights the importance of considering intra- and interspecific variations in adult foraging ecology and MeHg demethylation when selecting penguin chicks for Hg biomonitoring.

DBC1 is a key positive regulator of enhancer epigenomic writers KMT2D and p300.

Histone modification is a key epigenetic mechanism for regulation of chromatin dynamics and gene expression. Deleted in breast cancer 1 (DBC1) has been shown to act as a negative regulator of epigenetic modifiers and as a co-activator for nuclear receptors and other transcription factors. However, little is known about the role of DBC1 in the regulation of histone modifications and chromatin landscapes. Here, we analyzed genome-wide profiles of active enhancer and promoter marks in colorectal cancer cells and report DBC1 as a critical positive regulator of histone epigenetic writers KMT2D (H3K4 methyltransferase) and p300 (histone acetyltransferase). DBC1 is required for establishing the landscape of active enhancers, for genome-wide chromatin binding and enhancer recruitment of KMT2D and p300, and for gene activation involved in colorectal cancer progression. DBC1 interacts directly with KMT2D and p300, and enhances KMT2D-mediated histone H3K4 methylation (H3K4me1/2/3) and p300-mediated H3 acetylation. Importantly, DBC1 contributes to super-enhancer formation and function by facilitating the recruitment of KMT2D and p300 and by enhancing their functional interaction and cooperative cross-talk. Our results highlight the critical role of DBC1 as a key positive regulator of KMT2D and p300, and provide insights into regulatory mechanisms underlying the interplay between the enhancer epigenomic writers in enhancer activation.

Proteomic analysis predicts anti-angiogenic resistance in recurred glioblastoma.

BACKGROUND: Recurrence is common in glioblastoma multiforme (GBM) because of the infiltrative, residual cells in the tumor margin. Standard therapy for GBM consists of surgical resection followed by chemotherapy and radiotherapy, but the median survival of GBM patients remains poor (~ 1.5 years). For recurrent GBM, anti-angiogenic treatment is one of the common treatment approaches. However, current anti-angiogenic treatment modalities are not satisfactory because of the resistance to anti-angiogenic agents in some patients. Therefore, we sought to identify novel prognostic biomarkers that can predict the therapeutic response to anti-angiogenic agents in patients with recurrent glioblastoma. METHODS: We selected patients with recurrent GBM who were treated with anti-angiogenic agents and classified them into responders and non-responders to anti-angiogenic therapy. Then, we performed proteomic analysis using liquid-chromatography mass spectrometry (LC-MS) with formalin-fixed paraffin-embedded (FFPE) tissues obtained from surgical specimens. We conducted a gene-ontology (GO) analysis based on protein abundance in the responder and non-responder groups. Based on the LC-MS and GO analysis results, we identified potential predictive biomarkers for anti-angiogenic therapy and validated them in recurrent glioblastoma patients. RESULTS: In the mass spectrometry-based approach, 4957 unique proteins were quantified with high confidence across clinical parameters. Unsupervised clustering analysis highlighted distinct proteomic patterns (n = 269 proteins) between responders and non-responders. The GO term enrichment analysis revealed a cluster of genes related to immune cell-related pathways (e.g., TMEM173, FADD, CD99) in the responder group, whereas the non-responder group had a high expression of genes related to nuclear replisome (POLD) and damaged DNA binding (ERCC2). Immunohistochemistry of these biomarkers showed that the expression levels of TMEM173 and FADD were significantly associated with the overall survival and progression-free survival of patients with recurrent GBM. CONCLUSIONS: The candidate biomarkers identified in our protein analysis may be useful for predicting the clinical response to anti-angiogenic agents in patients with recurred GBM.

Prediction of pseudoprogression in post-treatment glioblastoma using dynamic susceptibility contrast-derived oxygenation and microvascular transit time heterogeneity measures.

OBJECTIVES: To evaluate the added value of MR dynamic susceptibility contrast (DSC)-perfusion-weighted imaging (PWI)-derived tumour microvascular and oxygenation information with cerebral blood volume (CBV) to distinguish pseudoprogression from true progression (TP) in post-treatment glioblastoma. METHODS: This retrospective single-institution study included patients with isocitrate dehydrogenase (IDH) wild-type glioblastoma and a newly developed or enlarging measurable contrast-enhancing mass within 12 weeks after concurrent chemoradiotherapy. CBV, capillary transit time heterogeneity (CTH), oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen (CMRO2) were obtained from DSC-PWI. Predictors were selected using univariable logistic regression, and performance was measured with adjusted diagnostic odds with tumour volume and area under the curve (AUC) of receiver operating characteristics analysis. RESULTS: A total of 103 patients were included (mean age, 59.6 years; 59 women), with 67 cases of TP and 36 cases of pseudoprogression. Pseudoprogression exhibited higher CTH (4.0 vs. 3.4, p = .019) and higher OEF (12.7 vs. 10.7, p = .014) than TP, but a similar CBV (1.48 vs. 1.53, p = .13) and CMRO2 (7.7 vs. 7.3s, p = .598). Independent of tumour volume, both high CTH (adjusted odds ratio [OR] 1.52; 95% confidence interval [CI]: 1.11-2.09, p = .009) and high OEF (adjusted OR 1.17; 95% CI:1.03-1.33, p = .016) were predictors of pseudoprogression. The combination of CTH, OEF, and CBV yielded higher diagnostic performance (AUC 0.71) than CBV alone (AUC 0.65). CONCLUSION: High intratumoural capillary transit heterogeneity and high oxygen extraction fraction derived from DSC-PWI have enhanced the diagnostic value of CBV in pseudoprogression of post-treatment IDH-wild type glioblastoma. CLINICAL RELEVANCE STATEMENT: In the early post-treatment stage of glioblastoma, pseudoprogression exhibited both high oxygen extraction fraction and high capillary transit heterogeneity and these dynamic susceptibility contrast-perfusion weighted imaging derived parameters have added value in cerebral blood volume-based noninvasive differentiation of pseudoprogression from true progression. KEY POINTS: • Capillary transit time heterogeneity and oxygen extraction fraction can be measured noninvasively through processing of dynamic susceptibility contrast imaging. • Pseudoprogression exhibited higher capillary transit time heterogeneity and higher oxygen extraction fraction than true progression. • A combination of cerebral blood volume, capillary transit time heterogeneity, and oxygen extraction fraction yielded the highest diagnostic performance (area under the curve 0.71).

Vessel size and perfusion-derived vascular habitat refines prediction of treatment failure to bevacizumab in recurrent glioblastomas: validation in a prospective cohort.

OBJECTIVES: Anti-angiogenic therapy may not benefit all patients with recurrent glioblastomas, and imaging biomarker predicting treatment response to anti-angiogenic therapy is currently limited. We aimed to develop and validate vascular habitats based on perfusion and vessel size to predict time to progression (TTP) in patients with recurrent glioblastomas treated with bevacizumab. METHODS: Sixty-nine patients with recurrent glioblastomas treated with bevacizumab who underwent pretreatment MRI with dynamic susceptibility contrast imaging and vessel architectural imaging were enrolled. Vascular habitats were constructed using vessel size index (VSI) and relative cerebral blood volume (rCBV). Associations with vascular habitats and TTP were analyzed using Cox proportional hazard regression analysis. In a prospectively enrolled validation cohort consisting of 15 patients ( ClinicalTrials.gov identifier; NCT04143425), stratification of TTP was demonstrated by the Kaplan-Meier method (log-rank test) using vascular habitats. RESULTS: Three vascular habitats consisting of high, intermediate, and low angiogenic habitats were identified with rCBV and VSI. Both high angiogenic and intermediate angiogenic habitats were significantly associated with a shorter TTP (hazard ratio [HR], 2.78 and 1.82, respectively; largest p = .003) and so was rCBV (HR, 2.15; p = .02). Concordance probability index of vascular habitat combining high and intermediate angiogenic habitats was 0.74. Vascular habitats stratified patients as good or poor responder in a prospective cohort (p = .059). CONCLUSIONS: Perfusion- and vessel size-derived vascular habitats predicted TTP in recurrent glioblastomas treated with anti-angiogenic therapy and aided patient stratification in a prospective validation cohort. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04143425 KEY POINTS: • High and intermediate angiogenic habitats predicted TTP in recurrent glioblastomas treated with anti-angiogenic therapy. • Vascular habitats combining high and intermediate angiogenic habitats aided patient stratification for anti-angiogenic therapy in recurrent glioblastomas.

Defining subventricular zone involvement to predict the survival of patients in isocitrate dehydrogenase-wild type glioblastoma: validation in a prospective registry.

OBJECTIVES: The prognostic value of subventricular zone distance (SVD) is unclear because of different definitions and lack of evaluation of clinical survival models. The aim of this study was to define SVD and evaluate its prognostic value in a survival nomogram for glioblastoma. METHODS: This retrospective study included 158 (SVD biomarker) from historical glioblastoma patients and 187 (survival modeling) with IDH-wild type glioblastoma from a prospective registry (NCT02619890). SVD was assessed by two radiologists: definition 1, the distance between the tumor edge to subventricular zone (SVZ); definition 2, the distance between the tumor centroid to SVZ; definition 3, enhancement at the ventricular wall. The associations between SVD and overall survival (OS) were evaluated using multivariable Cox proportional hazards regression analysis. Performance of an updated SVD survival model was compared with that of the Radiation Therapy Oncology Group (RTOG) 0525 nomogram. RESULTS: SVD according to both definition 1 (hazard ratio [HR]: 0.97, 95% CI: 0.94-0.99; p = .011) and definition 2 (HR: 0.96, 0.94-0.98, p < .001) was adversely associated with OS. Definition 1 was adversely associated with PFS (HR: 0.96, 0.94-0.99, p = .008) and showed the highest reproducibility (intraclass correlation coefficient, 0.90). The SVD-updated model showed similar to better performance than the RTOG model for predicting OS of up to 3 years (AUC: 0.735-0.738 vs. 0.687-0.708), with higher time-dependent specificity for 1-year (89.9% vs. 70.6%) and 3-year OS (93.3% vs. 80.0%). CONCLUSION: SVZ distance is an independent adverse prognostic factor in patients with IDH-wild type glioblastoma. Updating the survival model with SVZ provides better time-dependent specificity and reproducibility. KEY POINTS: • Subventricular zone distance (SVD) measurement from tumor edge showed high reproducibility. • Longer SVD was independently associated with longer overall survival. • Adding SVD improved time-dependent specificity for survival model in a prospective registry.

A Closed Form Solution for Pricing Variance Swaps Under the Rescaled Double Heston Model.

As is well known, multi-factor stochastic volatility models are necessary to capture the market accurately in pricing financial derivatives. However, the multi-factor models usually require too many parameters to be calibrated efficiently and they do not lead to an analytic pricing formula. The double Heston model is one of them. The approach of this paper for this difficulty is to rescale the double Heston model to reduce the number of the model parameters and obtain a closed form analytic solution formula for variance swaps explicitly. We show that the rescaled double Heston model is as effective as the original double Heston model in terms of fitting to the VIX market data in a stable condition and yet the computing time is much less than that under the double Heston model. However, in a turbulent situation after the start of the COVID-19 pandemic in 2020, we acknowledge that even the double Heston model fails to capture the market accurately.

Disruption of amphetamine sensitization by alteration of dendritic thin spines in the nucleus accumbens core.

Repeated injections of psychomotor stimulants like amphetamine (AMPH) to rodents can induce behavioral sensitization, which represents a long-lasting craving that is usually observed in human addicts. Behavioral sensitization is characteristically maintained for a long duration, accompanied by structural plasticity in some brain areas involved in reward circuitry. For example, it increased dendritic spine densities in the nucleus accumbens (NAcc), which is considered to reflect neurophysiological changes at this site, leading to addictive behaviors. The ezrin, radixin, and moesin (ERM) proteins regulate spine maturity by modifying their phosphorylation at the C-terminal region. We previously showed that ERM phosphorylation is reduced by AMPH in the NAcc core, suggesting that ERM-mediated spine changes at this site might be associated with AMPH sensitization. To test this hypothesis, we administered AMPH to rats according to a sensitization development schedule, with lentivirus encoding a phosphomimetic pseudo-active mutant of radixin (Rdx T564D) in the NAcc core, and examined dendritic spines at this site. We found that compared to acute AMPH, AMPH sensitization increased thin spine density with a similar ratio of filopodia-like to mature thin spines. However, with Rdx T564D, the density of thin spines increased, with augmented filopodia-like thin spines, resulting in no AMPH sensitization. These results indicate that Rdx T564D forces thin spines to immaturity and thereby inhibits AMPH sensitization, for which an increase in mature thin spines is normally necessary. These findings provide significant clues to our understanding of the role of dendritic spines in mediating the development of psychomotor stimulant addiction.

Artificial intelligence-based identification of octenidine as a Bcl-xL inhibitor.

Apoptosis plays an essential role in maintaining cellular homeostasis and preventing cancer progression. Bcl-xL, an anti-apoptotic protein, is an important modulator of the mitochondrial apoptosis pathway and is a promising target for anticancer therapy. In this study, we identified octenidine as a novel Bcl-xL inhibitor through structural feature-based deep learning and molecular docking from a library of approved drugs. The NMR experiments demonstrated that octenidine binds to the Bcl-2 homology 3 (BH3) domain-binding hydrophobic region that consists of the BH1, BH2, and BH3 domains in Bcl-xL. A structural model of the Bcl-xL/octenidine complex revealed that octenidine binds to Bcl-xL in a similar manner to that of the well-known Bcl-2 family protein antagonist ABT-737. Using the NanoBiT protein-protein interaction system, we confirmed that the interaction between Bcl-xL and Bak-BH3 domains within cells was inhibited by octenidine. Furthermore, octenidine inhibited the proliferation of MCF-7 breast and H1299 lung cancer cells by promoting apoptosis. Taken together, our results shed light on a novel mechanism in which octenidine directly targets anti-apoptotic Bcl-xL to trigger mitochondrial apoptosis in cancer cells.

Contrast enhancing pattern on pre-treatment MRI predicts response to anti-angiogenic treatment in recurrent glioblastoma: comparison of bevacizumab and temozolomide treatment.

OBJECTIVE: To evaluate the value of the contrast enhancing pattern on pre-treatment MRI for predicting the response to anti-angiogenic treatment in patients with IDH-wild type recurrent glioblastoma. METHODS: This retrospective study enrolled 65 patients with IDH wild-type recurrent glioblastoma who received standard therapy and then received either bevacizumab (46 patients) or temozolomide (19 patients) as a secondary treatment. The contrast enhancing pattern on pre-treatment MRI was visually analyzed and dichotomized into contrast enhancing lesion (CEL) dominant and non-enhancing lesion (NEL) dominant types. Quantitative volumetric analysis was used to support the dichotomization. The Kaplan-Meier method and Cox proportional hazards regression analysis were used to stratify progression free survival (PFS) according to the treatment in the entire patients, CEL dominant group, and NEL dominant group. RESULTS: In all patients, the PFS of those treated with bevacizumab was not significantly different from those treated with temozolomide (log-rank test, P = 0.96). When the contrast enhancing pattern was considered, bevacizumab was associated with longer PFS in the CEL dominant group (P = 0.031), whereas temozolomide showed longer PFS in the NEL dominant group (P = 0.022). Quantitative analysis revealed mean values for the proportion of solid-enhancing tumor of 13.7% for the CEL dominant group and 4.3% for the NEL dominant group. CONCLUSION: Patients with the CEL dominant type showed a better treatment response to bevacizumab, whereas NEL dominant types showed a better response to temozolomide. The contrast enhancing pattern on pre-treatment MRI can be used to stratify patients with IDH wild-type recurrent glioblastoma according to the effect of anti-angiogenic treatment.

Sequence variants in the proximal promoter and +5.8-kb site of ABO in Koreans with weak B phenotypes.

BACKGROUND AND OBJECTIVES: Several studies on Chinese and Japanese populations have revealed that a substantial proportion of weak B subgroups are caused by variants in the major regulatory regions of ABO, the proximal promoter, CCAAT-binding factor/NF-Y binding site and +5.8-kb site. We performed molecular analyses of these regions in Koreans with weak B phenotypes. MATERIALS AND METHODS: This study included 16 samples with weak B phenotypes (4 B3 , 1 Bw , 5 A1 B3 and 6 A1 Bw ) harbouring no subgroup-causing variants in ABO exons 6 and 7. These samples were subjected to sequencing analysis of exons 1-5 and the major regulatory regions of ABO. RESULTS: Of the 16 samples, 14 were found to carry a sequence variant either in the proximal promoter (g.4991_5008del [n = 3]) or the +5.8-kb site (g.10893G>A [n = 4] and g.10925C>T [n = 7]). The remaining two samples were found to contain no subgroup-causing variants. CONCLUSION: Our study demonstrates that sequence variants in the proximal promoter and +5.8-kb site account for a substantial proportion of weak B subgroups in Koreans, suggesting that molecular analysis of these regions is essential for the accurate determination of ABO genotypes in Koreans with weak B phenotypes.

Diffuse glioma, not otherwise specified: imaging-based risk stratification achieves histomolecular-level prognostication.

OBJECTIVES: To determine whether imaging-based risk stratification enables prognostication in diffuse glioma, NOS (not otherwise specified). METHODS: Data from 220 patients classified as diffuse glioma, NOS, between January 2011 and December 2020 were retrospectively included. Two neuroradiologists analyzed pre-surgical CT and MRI to assign gliomas to the three imaging-based risk types considering well-known imaging phenotypes (e.g., T2/FLAIR mismatch). According to the 2021 World Health Organization classification, the three risk types included (1) low-risk, expecting oligodendroglioma, isocitrate dehydrogenase (IDH)-mutant, and 1p/19q-codeleted; (2) intermediate-risk, expecting astrocytoma, IDH-mutant; and (3) high-risk, expecting glioblastoma, IDH-wildtype. Progression-free survival (PFS) and overall survival (OS) were estimated for each risk type. Time-dependent receiver operating characteristic analysis using 10-fold cross-validation with 100-fold bootstrapping was used to compare the performance of an imaging-based survival model with that of a historical molecular-based survival model published in 2015, created using The Cancer Genome Archive data. RESULTS: Prognostication according to the three imaging-based risk types was achieved for both PFS and OS (log-rank test, p < 0.001). The imaging-based survival model showed high prognostic value, with areas under the curves (AUCs) of 0.772 and 0.650 for 1-year PFS and OS, respectively, similar to the historical molecular-based survival model (AUC = 0.74 for PFS and 0.87 for OS). The imaging-based survival model achieved high long-term performance in both 3-year PFS (AUC = 0.806) and 5-year OS (AUC = 0.812). CONCLUSION: Imaging-based risk stratification achieved histomolecular-level prognostication in diffuse glioma, NOS, and could aid in guiding patient referral for insufficient or unsuccessful molecular diagnosis. KEY POINTS: • Three imaging-based risk types enable distinct prognostication in diffuse glioma, NOS (not otherwise specified). • The imaging-based survival model achieved similar prognostic performance as a historical molecular-based survival model. • For long-term prognostication of 3 and 5 years, the imaging-based survival model showed high performance.

Structure-activity relationship analysis of novel GSPT1 degraders based on benzotriazinone scaffold and its antitumor effect on xenograft mouse model.

Molecular glue degraders, such as lenalidomide and pomalidomide, bind to cereblon (CRBN) E3 ligase and subsequently recruit neosubstrate proteins, Ikaros (IKZF1) and Aiolos (IKZF3), for the ubiquitination-proteasomal degradation process. In this study, we explored structure-activity relationship analysis for novel GSPT1 degraders utilizing a benzotriazinone scaffold previously discovered as a novel CRBN binder. In particular, we focused on the position of the ureido group on the benzotriazinone scaffold, substituent effect on the phenylureido group, and methyl substitution on the benzylic position of benzotriazinone. As a result, we identified 34f (TD-522), which exhibits strong anti-proliferative effects in both KG-1 (EC50 = 0.5 nM) and TMD-8 (EC50 = 5.2 nM) cell lines. Compound 34f effectively induced GSPT1 degradation with a DC50 of 0.269 nM and Dmax of >95 % at 10 nM concentration in KG-1 cells. An in vivo xenograft study showed that compound 34f effectively suppressed TMD8-driven tumor growth, suggesting a potential role in the development of novel GSPT1 degraders.

Sublingual immunotherapy may be effective in reducing house dust mite allergies in children with atopic dermatitis.

AIM: We evaluated the efficacy of sublingual immunotherapy for children aged 5-17 years with atopic dermatitis who were allergic to house dust mites. METHODS: This open-label, controlled, randomised trial from June 2015 to February 2018 comprised 60 subjects from a specialist allergy centre in South Korea. Half received sublingual immunotherapy for 12 months and the other half formed the control group. The subjects were evaluated using specialist scores and specific immunoglobulin and skin prick tests. RESULTS: Sublingual immunotherapy significantly decreased the mean Scoring Atopic Dermatitis measurements in the sublingual group from baseline (30.2 ± 10.7) to 3 months (20.7 ± 8.5) and the effects persisted at 12 months (21.5 ± 12.4). However, the control group only showed a significant difference between baseline (30.4 ± 11.9) and 12 months (24.3 ± 10.2). The levels of Dermatophagoides farina-specific immunoglobulin G4 significantly increased in the treatment group from baseline (0.6 ± 0.5) to 12 months (1.0 ± 0.7), with no significant changes in the control group. New sensitisations to two or more allergens between baseline and 12 months were significantly lower in the sublingual group (21.4%) than controls (54.2%). CONCLUSION: Sublingual immunotherapy improved disease severity and prevented new sensitisations in children with atopic dermatitis who were allergic to dust mites.

Swi/Snf dynamics on stress-responsive genes is governed by competitive bromodomain interactions.

The Swi/Snf chromatin remodeling complex functions to alter nucleosome positions by either sliding nucleosomes on DNA or the eviction of histones. The presence of histone acetylation and activator-dependent recruitment and retention of Swi/Snf is important for its efficient function. It is not understood, however, why such mechanisms are required to enhance Swi/Snf activity on nucleosomes. Snf2, the catalytic subunit of the Swi/Snf remodeling complex, has been shown to be a target of the Gcn5 acetyltransferase. Our study found that acetylation of Snf2 regulates both recruitment and release of Swi/Snf from stress-responsive genes. Also, the intramolecular interaction of the Snf2 bromodomain with the acetylated lysine residues on Snf2 negatively regulates binding and remodeling of acetylated nucleosomes by Swi/Snf. Interestingly, the presence of transcription activators mitigates the effects of the reduced affinity of acetylated Snf2 for acetylated nucleosomes. Supporting our in vitro results, we found that activator-bound genes regulating metabolic processes showed greater retention of the Swi/Snf complex even when Snf2 was acetylated. Our studies demonstrate that competing effects of (1) Swi/Snf retention by activators or high levels of histone acetylation and (2) Snf2 acetylation-mediated release regulate dynamics of Swi/Snf occupancy at target genes.

Glycogen Synthase Kinase 3ß Is a Key Regulator in the Inhibitory Effects of Accumbal Cocaine- and Amphetamine-Regulated Transcript Peptide 55-102 on Amphetamine-Induced Locomotor Activity.

Microinjection of cocaine- and amphetamine-regulated transcript (CART) peptide 55-102 into the nucleus accumbens (NAcc) core significantly attenuates psychostimulant-induced locomotor activity. However, the molecular mechanism remains poorly understood. We examined the phosphorylation levels of Akt, glycogen synthase kinase 3ß (GSK3ß), and glutamate receptor 1 (GluA1) in NAcc core tissues obtained 60 min after microinjection of CART peptide 55-102 into this site, followed by systemic injection of amphetamine (AMPH). Phosphorylation levels of Akt at Thr308 and GSK3ß at Ser9 were decreased, while those of GluA1 at Ser845 were increased, by AMPH treatment. These effects returned to basal levels following treatment with CART peptide 55-102. Furthermore, the negative regulatory effects of the CART peptide on AMPH-induced changes in phosphorylation levels and locomotor activity were all abolished by pretreatment with the S9 peptide, an artificially synthesized indirect GSK3ß activator. These results suggest that the CART peptide 55-102 in the NAcc core plays a negative regulatory role in AMPH-induced locomotor activity by normalizing the changes in phosphorylation levels of Akt-GSK3ß, and subsequently GluA1 modified by AMPH at this site. The present findings are the first to reveal GSK3ß as a key regulator of the inhibitory role of the CART peptide in psychomotor stimulant-induced locomotor activity.