Citations

Abstract H3K27M-mutant diffuse midline glioma (DMG) patients have no proven effective therapies beyond radiation. ONC201, a mitochondrial protease ClpP agonist, has recently demonstrated efficacy in these patients, but the mechanism behind this remains unknown. We assessed clinical outcomes, tumor sequencing, and tissue samples from patients treated in two completed multi-site clinical studies (n=71). Patients treated with ONC201 monotherapy following initial radiation but prior to recurrence (n=35) demonstrated a median overall survival of 21.7 months and a median progression-free survival of 12.2 months. Radiographic response was associated with increased expression of key tricarboxylic acid cycle-related genes in baseline tumor sequencing. Similar survival benefits were observed using in utero electroporation and orthotopic mouse models of H3K27M-DMG (median 107 versus 77 days [p=0.02] and median 97 versus 141 days [p=0.004], respectively). Integrated transcriptomic and metabolomic analysis of ONC201-treated H3K27M-DMG cells revealed downregulation of TCA cycle, glycolysis, and pyruvate metabolism genes, most notably oxoglutarate dehydrogenase (OGDH), and concomitant changes in levels of associated metabolites including ɑ-ketoglutarate (ɑ-KG). Interestingly, L-2-hydroxyglutarate (L-2HG), a known inhibitor of the Jumonji C domain family of histone lysine demethylases, was also increased. This corresponded with increases in repressive H3K27me3 in vitro and in human tumors accompanied by epigenetic downregulation of cell cycle regulation and neuro-glial differentiation genes. Genetic knockdown of OGDH recapitulated ONC201-mediated increases in H3K27me3. In contrast, genetic knockdown of ClpP or lactate dehydrogenase A or overexpression of L-2-hydroxyglutarate dehydrogenase (L-2HGDH), but not D-2HGDH, abrogated ONC201-mediated increases in H3K27me3, demonstrating that ONC201 induces the production of L-2HG in H3K27M-DMG cells leading to increased H3K27me3. Overall, our data demonstrates the efficacy of ONC201 in H3K27M-mutant DMG and supports ONC201 as the first monotherapy to improve outcomes in patients with H3K27M-mutant DMG for whom few therapeutic options currently exist. Mechanistically, ONC201 disrupts integrated metabolic and epigenetic pathways and reverses pathognomonic H3K27me3 reduction.

Abstract Patients with H3K27M-mutant diffuse midline glioma (DMG) have no proven effective therapies. ONC201 has recently demonstrated efficacy in these patients, but the mechanism behind this finding remains unknown. We assessed clinical outcomes, tumor sequencing, and tissue/cerebrospinal fluid (CSF) correlate samples from patients treated in two completed multisite clinical studies. Patients treated with ONC201 following initial radiation but prior to recurrence demonstrated a median overall survival of 21.7 months, whereas those treated after recurrence had a median overall survival of 9.3 months. Radiographic response was associated with increased expression of key tricarboxylic acid cycle–related genes in baseline tumor sequencing. ONC201 treatment increased 2-hydroxyglutarate levels in cultured H3K27M-DMG cells and patient CSF samples. This corresponded with increases in repressive H3K27me3 in vitro and in human tumors accompanied by epigenetic downregulation of cell cycle regulation and neuroglial differentiation genes. Overall, ONC201 demonstrates efficacy in H3K27M-DMG by disrupting integrated metabolic and epigenetic pathways and reversing pathognomonic H3K27me3 reduction. Significance: The clinical, radiographic, and molecular analyses included in this study demonstrate the efficacy of ONC201 in H3K27M-mutant DMG and support ONC201 as the first monotherapy to improve outcomes in H3K27M-mutant DMG beyond radiation. Mechanistically, ONC201 disrupts integrated metabolic and epigenetic pathways and reverses pathognomonic H3K27me3 reduction. This article is featured in Selected Articles from This Issue, p. 2293

Background Besides Crohn's disease (CD), there are a variety of other causes that can also lead to ulcerations in the terminal ileum. The purpose of this study was to identify useful diagnostic features for CD when evaluating terminal ileum biopsies in patients with endoscopic finding of ulcers. Methods Five hundred and seventy-one patients with endoscopic finding of ulcers were included in this retrospective study. Five main histological features were analysed, which were crypt irregularity, mucosal thickening, villous stromal widening (including villous atrophy), granulomas, and pseudopyloric gland metaplasia. Clinical and pathological features were determined by uni- and multivariable logistic regression. Then another independent cohort of 99 patients was established for verifying this nomogram. Results The crypt irregularity, mucosal thickening, and villous stromal widening were combined to be considered as one new variable named mucosal architectural change which was an independent variable in diagnosing CD. We found that mucosal architectural change, age <40 years, the presence of granulomas, and the presence of pseudopyloric gland metaplasia were independent factors for the pathological diagnosis of CD. Then nomogram was developed, with receiver operating characteristic (ROC) curve (area under the ROC curve [AUC] = 0.927) in training sets, and ROC curve (AUC = 0.913) in validation sets. Conclusions We found mucosal architectural change is very helpful in distinguishing CD from non-CD patients. In the context of small biopsy which may lack full scope of changes, the model developed by combining these key features is valuable in predicting a diagnosis of CD, especially in younger patients (age <40 years).

Abstract1q gain (+1q) is the most common high‐risk cytogenetic abnormality (HRCA) in patients with multiple myeloma (MM). However, its prognostic value remains unclear in the era of novel agents. Here, we retrospectively analyzed the impact of +1q on the outcomes of 934 patients newly diagnosed with MM. +1q was identified in 53.1% of patients and verified as an independent variate for inferior overall survival (OS) (hazard ratio, 1.400; 95% confidence interval, 1.097–1.787; p = .007). Concurrence of other HRCAs (particularly t(14;16) and del(17p)) further exacerbated the outcomes of patients with +1q, suggesting prognostic heterogeneity. Thus, a risk‐scoring algorithm based on four risk variates (t(14;16), hypercalcemia, ISS III, and high LDH) was developed to estimate the outcomes of patients with +1q. Of the patients, 376 evaluable patients with +1q were re‐stratified into low (31.6%), intermediate (61.7%), and high risk (6.7%) groups, with significantly different progression‐free survival and OS (p < .0001), in association with early relapse of the disease. The prognostic value of this model was validated in the CoMMpass cohort. While attaining undetectable MRD largely circumvented the adverse impact of +1q, it scarcely ameliorated the outcome of the patients with high risk, who likely represent a subset of patients with extremely poor survival. Hence, patients with +1q are a heterogeneous group of high‐risk patients, therefore underlining the necessity for their re‐stratification. The proposed simple risk‐scoring model can estimate the outcomes of patients with +1q, which may help guide risk‐adapted treatment for such patients.

AbstractHeart regeneration occurs by dedifferentiation and proliferation of pre-existing cardiomyocytes (CMs). However, the signaling mechanisms by which injury induces CM renewal remain incompletely understood. Here, we find that cardiac injury in zebrafish induces expression of the secreted Wnt inhibitors, including Dickkopf 1 (Dkk1), Dkk3, secreted Frizzled-related protein 1 (sFrp1), and sFrp2, in cardiac tissue adjacent to injury sites. Experimental blocking of Wnt activity via Dkk1 overexpression enhances CM proliferation and heart regeneration, whereas ectopic activation of Wnt8 signaling blunts injury-induced CM dedifferentiation and proliferation. Although Wnt signaling is dampened upon injury, the cytoplasmic β-catenin is unexpectedly increased at disarrayed CM sarcomeres in myocardial wound edges. Our analyses indicated that p21-activated kinase 2 (Pak2) is induced at regenerating CMs, where it phosphorylates cytoplasmic β-catenin at Ser 675 and increases its stability at disassembled sarcomeres. Myocardial-specific induction of the phospho-mimetic β-catenin (S675E) enhances CM dedifferentiation and sarcomere disassembly in response to injury. Conversely, inactivation of Pak2 kinase activity reduces the Ser 675-phosphorylated β-catenin (pS675-β-catenin) and attenuates CM sarcomere disorganization and dedifferentiation. Taken together, these findings demonstrate that coordination of Wnt signaling inhibition and Pak2/pS675-β-catenin signaling enhances zebrafish heart regeneration by supporting CM dedifferentiation and proliferation.

AbstractDisturbed intrauterine development increases the risk of renal disease. Various studies have reported that Notch signalling plays a significant role in kidney development and kidney diseases. A disintegrin and metalloproteinase domain 10 (ADAM10), an upstream protease of the Notch pathway, is also reportedly involved in renal fibrosis. However, how ADAM10 interacts with the Notch pathway and causes renal fibrosis is not fully understood. In this study, using a prenatal chlorpyrifos (CPF) exposure mouse model, we investigated the role of the ADAM10/Notch axis in kidney development and fibrosis. We found that prenatal CPF‐exposure mice presented overexpression of Adam10, Notch1 and Notch2, and led to premature depletion of Six2+ nephron progenitors and ectopic formation of proximal tubules (PTs) in the embryonic kidney. These abnormal phenotypic changes persisted in mature kidneys due to the continuous activation of ADAM10/Notch and showed aggravated renal fibrosis in adults. Finally, both ADAM10 and NOTCH2 expression were positively correlated with the degree of renal interstitial fibrosis in IgA nephropathy patients, and increased ADAM10 expression was negatively correlated with decreased kidney function evaluated by serum creatinine, cystatin C, and estimated glomerular filtration rate. Regression analysis also indicated that ADAM10 expression was an independent risk factor for fibrosis in IgAN. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.