Significant Extension Research Articles

First records of two siluriform fishes: Bagrichthys micranodus (Actinopterygii: Siluriformes: Bagridae) and Pangasianodon hypophthalmus (Pangasiidae) from Sumatra, Indonesia

A bagrid catfish, Bagrichthys micranodus Roberts, 1989, has been reliably reported only from Borneo Island, whereas a pangasiid catfish, Pangasianodon hypophthalmus (Sauvage, 1878), originally from the Mekong and Chao Phraya rivers, has been widely introduced for aquaculture throughout southeast Asia. However, an ichthyofaunal survey of Cala Lake, South Sumatra, disclosed significant distribution extensions for both species, that of B. micranodus being the first from a land mass other than Borneo Island. Additionally, P. hypophthalmus was recorded from a natural freshwater habitat, outside the controlled environments of aquaculture facilities. The specimens are described in detail and comparisons are made with closely related species.

The influence of pelvic tilt on sacral insufficiency fracture occurrence: Insights into the prevalence of high pelvic tilt among patients affected

IntroductionFragility fractures without significant trauma of the pelvic ring in older patients have an increasing incidence due to demographic change. Influencing factors other than osteoporotic bone quality that lead to an insufficiency fracture are not yet known. However, it is suspected that the pelvic tilt (PT) has an effect on the development of such an insufficiency fracture. This study explores the influence of the PTs in patients with insufficiency fractures of the posterior pelvic ring. Materials and MethodsA total of 49 geriatric patients with fragility fractures of the pelvic ring were treated at a university hospital level-1 trauma center during a period between February and December 2023, and their fractures were classified according to the FFP classification of Rommens and Hofmann. Complete sets of computer tomography (CT) and radiological images were available to determine the PT angle of the patients. Results34 FFP type 2 and 15 FFP type 3 classified patients were included in the study. Significant difference was seen in the pelvic tilt (PT) angle between the patient group with insufficiency fractures (n= 49; mean age: 78.02 ± 11.80) and the control group with lumbago patients (n= 53; mean age: 69.23 ± 11.23). The PT was significantly higher in the patients with insufficiency fractures (25.74° ± 4.76; p⁎⁎⁎⁎ ≤ 0.0001). ConclusionsThe study demonstrates a significant extension of the PT angle of individuals with insufficiency fractures when compared to those with lumbago. The result suggests a potential association between pelvic tilt and fracture susceptibility. Trial registrationA retrospective study about the influence of sagittal balance of the spine on insufficiency fractures of the posterior pelvic ring measured by the "pelvic tilt angle", DRKS00032120. Registered 20th June 2023 - Prospectively registered. Trial registration number DRKS00032120.

Impact of Three Thiazolidinone Compounds with Piperine Skeletons on Trehalase Activity and Development of Spodoptera frugiperda Larvae.

Trehalases (TREs) are pivotal enzymes involved in insect development and reproduction, making them prime targets for pest control. We investigated the inhibitory effect of three thiazolidinones with piperine skeletons (6a, 7b, and 7e) on TRE activity and assessed their impact on the growth and development of the fall armyworm (FAW), Spodoptera frugiperda. The compounds were injected into FAW larvae, while the control group was treated with 2% DMSO solvent. All three compounds effectively inhibited TRE activity, resulting in a significant extension of the pupal development stage. Moreover, the treated larvae exhibited significantly decreased survival rates and a higher incidence of abnormal phenotypes related to growth and development compared to the control group. These results suggest that these TRE inhibitors affect the molting of larvae by regulating the chitin metabolism pathway, ultimately reducing their survival rates. Consequently, these compounds hold potential as environmentally friendly insecticides.

Searching for large dark matter clumps using the Galileo Constellation clock variations

This study presents bounds on transient variations of fundamental constants, with typical timescales ranging from minutes to months, using clocks in space. The underlying phenomenology describing such transient variations relies on models for Dark Matter (DM) which suggest possible encounters of macroscopic compact objects with the Earth, due to the motion of the solar system in the galactic halo. If such compact objects possess an effective feeble interaction with the ordinary matter beyond the gravitational one, it may result in effective transient variations of fundamental constants. Such variations leave signatures on clocks onboard GNSS satellites. In this paper, we introduce a phenomenological study dedicated to the search for such DM transient objects using the network of passive hydrogen masers (H-Masers) onboard Galileo satellites. We first model the signature of transient variations of fundamental constants as a frequency modulation in the difference between two satellite clocks, considering the satellite trajectories relative to the transient event. Then, we present first results based on a fast analysis method, the maximum reach analysis. The main result is a significant extension of the discovery range for DM transients, with a sensitivity never achieved before. We investigate indeed the range of transient sizes from 105 to 109 kilometres, which, apart from indirect and model-dependent non-transient effects, has never been explored previously.

High-pressure and high-temperature modulation of one-dimensional infinite chain in SeO2

The structural evolution of lone-pair compounds under high-pressure and high-temperature conditions has been a subject of fundamental interest in revealing modulated polymorphs. As one of the archetypal lone-pair compounds, selenium dioxide (SeO2) has attracted much attention due to the pressure modulation of its one-dimensional infinite W-shaped chain arrangement. Here, through swarm intelligence algorithm in conjunction with the first-principles simulation, we propose the existence of an orthorhombic Pnma-SeO2 structure, characterized by V-shaped chains interconnected via vertex-sharing SeO3 pyramids. These V-shaped chains demonstrate reduced compressibility along their chain direction compared to the W-shaped chains. Calculations indicate that Pnma-SeO2 is a semiconductor with a large indirect bandgap of 2.39 eV. Remarkably, we synthesized the predicted Pnma-SeO2 in a laser-heated diamond anvil cell at a pressure of 48.5 or 87 GPa as identified by in situ synchrotron x-ray diffraction data. Our findings lead to a significant extension of the phase diagram and transition path of SeO2 and provide key insights into understanding the pressure modulation in lone-pair compounds.

Biogenic crocetin-crosslinked chitosan nanoparticles with high stability and drug loading for efficient radioprotection

The risk of radiation exposure increases with the development of nuclear energy and technology, and radiation protection receives more and more attention from public health and safety. However, the numerous adverse effects and low drug utilization limit the practical applications of radioprotective agents. In this study, we developed a biogenic crocetin-crosslinked chitosan nanoparticle with high stability and drug loading for efficient radioprotection. In detail, the nanoparticles were prepared using the natural antioxidant crocetin as a cross-linking reagent in amidation reactions of chitosan and mPEG-COOH. The nanoparticles exhibit a quick scavenging ability for common reactive oxygen species and reactive nitrogen in vitro. Meanwhile, cellular experiments demonstrate the good biocompatibility of the nanoparticles and the alleviation of radiation damage by scavenging reactive oxygen species, reducing apoptosis, and inhibiting DNA damage, etc. Importantly, the nanoparticles are effective in mitigating oxidative damage in major organs and maintaining peripheral blood cell content. In addition, they perform better radioprotective properties than free drug due to the significant extension of the blood half-life of crocetin in vivo from 10 min to 5 h. This work proposes a drug-crosslinking strategy for the design of a highly efficient radioprotective agent, which exhibits a promising prospect in the fields of nuclear emergency and public health.

270 Inducing Neural Maturation and Increasing Survival in SHH Medulloblastoma Using EZH2 Inhibition in a Mouse Model

INTRODUCTION: Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Genetically, MB can be divided into four subgroups of which the SHH subtype histologically shows nodular architecture. Within this nodular architecture, there are islands of mature cells, with more abundant neuropil and a low proliferation rate, scattered among sheets of primitive cells. METHODS: We performed laser capture microdissection followed by whole transcriptome analysis, spatial transcriptomics using Digital Spatial Profiling, whole genome DNA methylation and ChIP-Seq analysis of mature and primitive areas from 8 medulloblastomas. We developed a genetically-engineered mouse model of SHH MB showing spontaneous maturation and lack of maturation with a conditional EZH2 genetic ablation or EZH2 overactivation respectively. Finally, we developed a fucoidan-based nanoparticle drug delivery across the blood brain barrier (BBB) for targeted molecular inhibition. RESULTS: Using whole transcriptome and DNA methylation analysis, we identified ∼120 differentially expressed genes between primitive and mature regions with enrichment for genes regulated by H3K4me3 and H3K27me3. ChIP-Seq analysis showed striking differences in H3K27me3 enrichment between primitive and mature medulloblastoma cells including at the EZH2 locus. Medulloblastoma specific EZH2 genetic ablation resulted in diffuse tumor cell differentiation and prolonged survival in mice (n = 10 per group, log-rank p = 0.01). Conversely, conditional EZH2 (Y641F) activation prevented medulloblastoma differentiation. A fucoidan-based nanoparticle successfully delivered the EZH2 inhibitor (EPZ-6438) across the murine BBB to achieve significant extension of mouse survival (median 70 days compared to 21 days in control mice; *p = 0.01, Mantel-Cox). CONCLUSIONS: Spontaneous maturation of medulloblastoma cells can be induced by inhibition of EZH2. Fucoidan-based nanoparticle delivery systems allows tumor specific targeted delivery across the BBB extending survival in mice.

Regulating Local Atomic Environment around Vacancies for Efficient Hydrogen Evolution.

Defect engineering is essential for the development of efficient electrocatalysts at the atomic level. While most work has focused on various vacancies as effective catalytic modulators, little attention has been paid to the relation between the local atomic environment of vacancies and catalytic activities. To face this challenge, we report a facile synthetic approach to manipulate the local atomic environments of vacancies in MoS2 with tunable Mo-to-S ratios. Our studies indicate that the MoS2 with more Mo terminated vacancies exhibits better hydrogen evolution reaction (HER) performance than MoS2 with S terminated vacancies and defect-free MoS2. The improved performance originates from the adjustable orbital orientation and distribution, which is beneficial for regulating H adsorption and eventually boosting the intrinsic per-site activity. This work uncovers the underlying essence of the local atomic environment of vacancies on catalysis and provides a significant extension of defect engineering for the rational design of transition metal dichalcogenides (TMDs) catalysts and beyond.

Decoding lifespan secrets: the role of the gonad in Caenorhabditis elegans aging.

The gonad has become a central organ for understanding aging in C. elegans, as removing the proliferating stem cells in the germline results in significant lifespan extension. Similarly, when starvation in late larval stages leads to the quiescence of germline stem cells the adult nematode enters reproductive diapause, associated with an extended lifespan. This review summarizes recent advancements in identifying the mechanisms behind gonad-mediated lifespan extension, including comparisons with other nematodes and the role of lipid signaling and transcriptional changes. Given that the gonad also mediates lifespan regulation in other invertebrates and vertebrates, elucidating the underlying mechanisms may help to gain new insights into the mechanisms and evolution of aging.

Abstract 6565: Improving survival of atypical teratoid/rhabdoid tumor orthotopic xenografts through the combination of PI3K inhibitor paxalisib and nucleoside analog gemcitabine

Abstract Atypical teratoid/rhabdoid tumors (AT/RT) are an aggressive infantile brain tumor with a dismal four-year event-free survival of 37%. We have previously identified high activation of mTORC1 and mTORC2 within AT/RT and shown that the highly brain penetrant PI3K inhibitor paxalisib is capable of simultaneously inhibiting mTORC1/2 by acting upstream of both complexes. In two orthotopic xenograft models, paxalisib slowed tumor growth and significantly extended survival (CHLA-06: 40 to 54 days, p=0.001; BT-12: 21 to 35 days, p=0.02). RNAseq analysis following mTOR inhibition in AT/RT cell lines showed an upregulation of genes involved in the activation of the integrated stress response (ISR) (ATF4, CHOP, PPP1R15A t-test p<0.05). Analysis of primary pediatric brain tumors through the Children’s Brain Tumor Network showed increased levels of ATF4 mRNA and eIF2α protein and mRNA in AT/RT compared to other indolent pediatric brain tumors. Increased expression of ISR components suggests this pathway may be a dependency in AT/RT. Activation of this pathway is known to be cytoprotective, however persistent over-activation drives cell death through induction of pro-apoptotic factors. Gemcitabine is a pyrimidine analog functioning to inhibit DNA synthesis and induce DNA damage; notably, recent literature has correlated DNA damage to activation of the ISR with downstream phosphorylation of eIF2α. We hypothesize that due to high baseline activation of ISR for AT/RT, paxalisib combined with gemcitabine will result in an over-activation of the ISR leading to AT/RT cell death. Western blot analysis of combination therapy compared to DMSO control showed induction of phospho-eIF2α, ATF4, and CHOP, denoting an activation of the ISR. Combination therapy in AT/RT cells induces cell death (Western blot analysis cPARP, MUSE Annexin V assay, SynergyFinder BLISS score [viability] CHLA-06: 21.50, CHLA-266: 22.60) and synergizes to decrease cell growth (SynergyFinder BLISS score [inhibition] CHLA-06: 16.80, BT-12: 14.30, CHLA-266: 13.90, BT-37: 11.40, CHLA-05: 10.40). Paxalisib/gemcitabine combination therapy in murine orthotopic xenograft models of AT/RT has slowed tumor growth (bioluminescent imaging) and led to significant extension of survival. Mice bearing BT-37 orthotopic xenografts and treated with vehicle control had a median survival of 56 days, while all of the paxalisib/gemcitabine treated mice were alive at 100 days of treatment (p<0.0001). In CHLA-06 orthotopic tumors combination therapy extended median survival from 22 days for control to 82.5 days (p<0.0001). Based on these findings, the Pacific Pediatric Neuro-Oncology Consortium (PNOC) is planning to include paxalisib/gemcitabine combination therapy in the next international clinical trial for patients with relapsed/recurrent AT/RT. Citation Format: Tyler Findlay, Kristen Malebranche, Anupa Geethadevi, Charles Eberhart, Jeffrey Rubens, Eric Raabe. Improving survival of atypical teratoid/rhabdoid tumor orthotopic xenografts through the combination of PI3K inhibitor paxalisib and nucleoside analog gemcitabine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6565.

Abstract 5779: Enhancing selectivity and overcoming tissue-specific toxicity in drug discovery: A novel BET inhibitor with targeted delivery for prostate cancer treatment

Abstract Improving selectivity and circumventing tissue-specific toxicity remain significant challenges in the realm of contemporary drug discovery. Despite the advanced development of highly selective inhibitors, their systemic distribution often stimulates off-tissue unwanted side-toxicity. To address this, we engineered a highly selective inhibitor that specifically targets and releases a small molecule drug payload to a desired cell type. As a proof of concept, we apply this method to epigenetic inhibitors of BET proteins, which are crucial regulators of gene transcription implicated in the progression and survival of cancer. We engineered a novel BET-selective chemotype conjugated to a Prostate-Cancer specific targeting component in order to overcome the off-tissue effects of state-of-the-art BET inhibitors. To achieve delivery of the compound, we modified the benzodiazepine (BzD) scaffold of the well-established BET inhibitor I-BET762, conjugating the tertiary amine with a self-immolating motif, allowing for intracellular compound release upon an enzymatic trigger. This new chemotype, RT53, maintains the biochemical properties of I-BET762, showing potent and selective binding to BET bromodomains in a range of established biophysical assays. In cells, RT53 phenocopied I-BET762 on cancer cell lines, including prostate cancer. We validated the established strong anti-proliferative effect following BET inhibition using clonogenic assays, flow cytometry, and monitored the suppression of MYC expression. Moreover, we established the transcriptional rationale for loss of cellular fitness using RNA sequencing, discovering strong down-regulation of solute carriers, depriving cells of nutrient flux and disrupting normal processes. Furthermore, RT53 exhibits antitumor activity in vivo, in localized models of prostate cancer established in male athymic nude mice. The targeted delivery of RT53 demonstrated superior efficacy in vivo ameliorating on-target, off-tissue toxicity, as low-dose treatment led to almost complete elimination of grafted tumor sites, significant extension of survival, and no signs of toxicity on non-targeted tissues. Taken together, our data establish a novel class of BET-specific inhibitors offering a handle for selective delivery in vivo, enhancing the therapeutic index while avoiding on-target off-tissue toxicity. Citation Format: Cong Tang, Rui Traquete, Elizabeth Henderson, João Conde, Sara Picaud, Panagis Filippakopoulos, Gonçalo Bernardes. Enhancing selectivity and overcoming tissue-specific toxicity in drug discovery: A novel BET inhibitor with targeted delivery for prostate cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5779.

ICG-angiography in evaluation the quality of the full-thickness rectal flap's formation at the surgery treatment of complex rectal fistulas

AIM: evaluation the feasibility of usage ICG-angiography for the full-thickness rectal flap's formation at the surgery treatment of complex rectal fistulas.PATIENTS AND METHODS: a prospective cohort study based on the study of intraoperative ICG-angiography and its video recordings in the surgery treatment of complex pararectal fistulas with bringing down a full-thickness rectal flap was performed. The study included 9 patients: 6(66.7%) - men and 3(33.3%) - women.RESULTS: based on intraoperative ICG-angiography 3 types rectum's angioarchitectonics were identified: with 3, 4 and 5 distal branches of the rectal arteries, respectively. Subsequent detailed chronometry were showed that the time of onset of the arterial phase did not differ significantly, regardless of the formed flap's width. However, the following changes in the venous outflow were identified: at full-thickness flap's width of 1/3 of the rectal circumference, a slight lengthening of the venous outflow was observed, expressed in an increase of the average time for onset of the maximum fluorescence phase to 61.5 sec., compared with the intact rectum (58.2 sec.); at full-thickness flap's width of 1/4 of the rectal circumference - significant (p<0.05) extension of the average time for onset of the phase of maximum fluorescence to 77.6 sec., that is, in 1.26 times compared to patients with flap's width of 1/3 of the rectal circumference.CONCLUSION: at the treatment of complex rectal fistulas with bringing down a full-thickness rectal flap, ICG-angiography makes it possible to visualize the vessels of the rectum at intraoperative condition, which contributes to the selection of the boundaries of the rectal area for the formation of a full-thickness flap, and also allows to assess of its blood supply.

Optimal Impact Portfolios with General Dependence and Marginals

Using Induced Order Statistics to Construct Optimal Impact Portfolios with General Dependence and Marginals We develop a mathematical framework for constructing optimal impact portfolios and quantifying their financial performance by characterizing the returns of impact-ranked assets using induced order statistics and copulas. Our results apply to any joint distribution of impact factors and residual returns, making them broadly applicable to a wide range of contexts. We develop significant extensions of the theory of induced order statistics, with which we are able to characterize the distribution of residual returns of individual assets ranked by the impact factor. Our framework provides a toolkit for practitioners to construct impact portfolios and quantify their performance based on real data. This allows impact investors to achieve higher risk-adjusted returns than those with impact portfolios constructed using simpler heuristics such as negative or positive screening.

5th-Order Multivariate Edgeworth Expansions for Parametric Estimates

The only cases where exact distributions of estimates are known is for samples from exponential families, and then only for special functions of the parameters. So statistical inference was traditionally based on the asymptotic normality of estimates. To improve on this we need the Edgeworth expansion for the distribution of the standardised estimate. This is an expansion in n−1/2 about the normal distribution, where n is typically the sample size. The first few terms of this expansion were originally given for the special case of a sample mean. In earlier work we derived it for any standard estimate, hugely expanding its application. We define an estimate w^ of an unknown vector w in Rp, as a standard estimate, if Ew^→w as n→∞, and for r≥1 the rth-order cumulants of w^ have magnitude n1−r and can be expanded in n−1. Here we present a significant extension. We give the expansion of the distribution of any smooth function of w^, say t(w^) in Rq, giving its distribution to n−5/2. We do this by showing that t(w^), is a standard estimate of t(w). This provides far more accurate approximations for the distribution of t(w^) than its asymptotic normality.

AAV9:PKP2 improves heart function and survival in a Pkp2-deficient mouse model of arrhythmogenic right ventricular cardiomyopathy

BackgroundArrhythmogenic right ventricular cardiomyopathy (ARVC) is a familial cardiac disease associated with ventricular arrhythmias and an increased risk of sudden cardiac death. Currently, there are no approved treatments that address the underlying genetic cause of this disease, representing a significant unmet need. Mutations in Plakophilin-2 (PKP2), encoding a desmosomal protein, account for approximately 40% of ARVC cases and result in reduced gene expression.MethodsOur goal is to examine the feasibility and the efficacy of adeno-associated virus 9 (AAV9)-mediated restoration of PKP2 expression in a cardiac specific knock-out mouse model of Pkp2.ResultsWe show that a single dose of AAV9:PKP2 gene delivery prevents disease development before the onset of cardiomyopathy and attenuates disease progression after overt cardiomyopathy. Restoration of PKP2 expression leads to a significant extension of lifespan by restoring cellular structures of desmosomes and gap junctions, preventing or halting decline in left ventricular ejection fraction, preventing or reversing dilation of the right ventricle, ameliorating ventricular arrhythmia event frequency and severity, and preventing adverse fibrotic remodeling. RNA sequencing analyses show that restoration of PKP2 expression leads to highly coordinated and durable correction of PKP2-associated transcriptional networks beyond desmosomes, revealing a broad spectrum of biological perturbances behind ARVC disease etiology.ConclusionsWe identify fundamental mechanisms of PKP2-associated ARVC beyond disruption of desmosome function. The observed PKP2 dose-function relationship indicates that cardiac-selective AAV9:PKP2 gene therapy may be a promising therapeutic approach to treat ARVC patients with PKP2 mutations.

Protective action of selenium-enriched black garlic extract in rats with lipopolysaccharide/D-galactosamine-induced acute liver failure

The contents of selenomethionine (SeMet) and selenomethylcysteine (SeMC) in Selenium-Enriched black garlic extract (Se-BGE), a popular functional food in Asian countries, were 2.9 ± 0.6 μg/g and 12.2 ± 2.3 μg/g by PITC pre-column derivatization UPLC-MS method. Improved histological injury, significant extension of the median survival time, and attenuated serum levels of alanine aminotransferase, total bilirubin and SOD activity were observed in the acute liver failure (ALF) rats treated with Se-BGE (1.0 g/mL). 1HNMR-based metabonomics revealed that serum levels of lactate, pyruvate, betaine, choline, taurine, and glycine were restored, and 16S rDNA sequencing analysis showed that the composition and number of the intestinal flora were regressed to healthy levels in ALF rats treated by Se-BGE. Serum choline and betaine showed significant correlations with g_Lactobacillus and g_Escherichia. Our findings demonstrated that Se-BGE protects against LPS/D-GalN-induced ALF in rats, possibly due to antioxidation, metabolism, and intestinal flora regulations of Se-BGE.

Abstract B016: Targeting the epigenome through combined Facilitates Chromatin Transcription (FACT) and Bromodomain and Extra-Terminal Domain (BET) inhibition in Diffuse Midline Glioma (DMG)

Abstract Aberrant epigenetic regulation is a hallmark of Diffuse Midline Glioma (DMG), an incurable tumor that primarily arises in the brainstem of young children. The H3K27M driver histone mutation and resulting permissive chromatin indicates epigenetic targeting as a key therapeutic strategy against this aggressive cancer. One such epigenetic target is the Facilitates Chromatin Transcription (FACT) histone chaperone. FACT is targeted by the curaxin compound CBL0137 which is currently in phase I/II clinical trial for pediatric cancer patients (NCT04870944). This study aims to decipher the mechanism of CBL0137 to find effective combination therapies for the next round of clinical implementation. To this end, we applied a multi-omics approach by integrating epigenetic profiling with transcriptomic data sets (CUT&RUN, ATAC-seq and RNA-seq) to interrogate the therapeutic mechanism of CBL0137 in DMG. We then employed in vitro cytotoxicity assays and in vivo orthotopic patient-derived xenograft (PDX) pre-clinical models to test a novel, mechanistic-anchored epigenetic combination therapy. We found FACT to be enriched at the promoters of developmental genes, coinciding with regions of open chromatin and binding motifs of the core DMG regulatory transcription factors TCF12 and OLIG2. Furthermore, FACT interacted and co-localized with the Bromodomain and Extra-Terminal Domain (BET) protein BRD4, suggesting cooperation between FACT and BRD4 in DMG. Given that BRD4 is an established therapeutic target in DMG and other cancers, we investigated the combination of the FACT-inhibitor CBL0137 with the BET-inhibitor JQ1. Combination treatment was cytotoxic against DMG in vitro, with enhanced cytotoxicity observed against H3K27M-mutant cells. We demonstrated a significant survival extension in three independent orthotopic PDX mouse models treated with CBL0137 and JQ1 in combination. Mechanistically, CBL0137 and JQ1 decreased chromatin accessibility and transcription of genes involved in RNA regulatory processes, such as RNA methylation and splicing. Consistently, combination treatment led to increased intron retention, highlighting a possible link between chromatin disruption and the splicing machinery in DMG. Future work will investigate whether treatment-induced intron retention acts as a source of neoantigens, with the potential to enhance DMG immunogenicity. In sum, this study has identified a promising new epigenetic combination therapy – FACT + BET inhibition – while uncovering intriguing new insights into DMG epigenetics and pathobiology. Citation Format: Holly Holliday, Aaminah Khan, Nisitha Jayatilleke, Chelsea Mayoh, Samuel E. Ross, Yolanda Colino Sanguino, Anjana Gopalakrishnan, Anahid Ehteda, Benjamin Rayner, Maria Tsoli, David S. Ziegler. Targeting the epigenome through combined Facilitates Chromatin Transcription (FACT) and Bromodomain and Extra-Terminal Domain (BET) inhibition in Diffuse Midline Glioma (DMG) [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr B016.

Effectiveness of Adjuvant Chemotherapy in Variant Histology Upper Tract Urothelial Carcinoma Following Radical Nephroureterectomy: Stabilized Inverse Probability Treatment Weighting Analysis of Single Center Experience

PurposeThe study aimed to investigate the impact of adjuvant chemotherapy on time to recurrence (TTR) and overall survival (OS) in patients with histologic variants of upper tract urothelial carcinoma (VUTUC) following radical nephroureterectomy (RNU). Materials and methodsA retrospective review of 131 VUTUC patients' medical records, from a pool of 368 non-metastatic localized or locally advanced UTUC cases, treated at a single tertiary referral center between January 2011 and January 2021. The intervention was adjuvant chemotherapy administration post-RNU. TTR and OS were evaluated using Kaplan-Meier and Cox proportional hazard regression, covariates adjusted for age, postoperative GFR, history of neoadjuvant chemotherapy, T and N stage with stabilized inverse probability of treatment weighting (sIPTW). ResultsThe application of adjuvant chemotherapy showed a significant extension in TTR (P = .01), but no substantial impact on OS (P = .19) after sIPTW adjustment for covariates. Multivariate analysis revealed adjuvant chemotherapy, tumor size, and lymphovascular invasion as significant prognostic factors for TTR. In contrast, only tumor size and perineural invasion were significant for OS. Adjuvant chemotherapy reduced the progression risk in certain VUTUC subtypes (squamous or glandular/micropapillary), but not in sarcomatoid variants. ConclusionsAdjuvant chemotherapy appears to improve TTR, albeit without a significant effect on OS, in nonmetastatic localized and locally advanced VUTUC patients post-RNU. While beneficial to some VUTUC subtypes, it did not yield significant advantages for sarcomatoid variants. Despite adjustments for known confounders, the study's findings may be subject to potential selection bias and unmeasured confounding factors.

Full power range DAB unified ZVS control strategy based on low current RMS

Inductive current RMS and soft switching are important performance indexes of dual active bridge DC-DC converter (DAB). This paper proposes a new optimal control strategy for the soft switching range based on the optimization of the effective value of the inductor current. This control strategy restricts the inductor current during switch action, ensuring a significant extension of the soft switching range across the entire power range, reducing switch losses, and achieving the accurate effective value of current, thereby further enhancing the efficiency of the DAB converter. Meanwhile, a new modulation method is proposed to achieve thermal balance between bridge arms. Finally, a simulation model is built and verified using Matlab.

Endogenous chondroitin extends the lifespan and healthspan in C. elegans.

Chondroitin, a class of glycosaminoglycan polysaccharides, is found as proteoglycans in the extracellular matrix, plays a crucial role in tissue morphogenesis during development and axonal regeneration. Ingestion of chondroitin prolongs the lifespan of C. elegans. However, the roles of endogenous chondroitin in regulating lifespan and healthspan mostly remain to be investigated. Here, we demonstrate that a gain-of-function mutation in MIG-22, the chondroitin polymerizing factor (ChPF), results in elevated chondroitin levels and a significant extension of both the lifespan and healthspan in C. elegans. Importantly, the remarkable longevity observed in mig-22(gf) mutants is dependent on SQV-5/chondroitin synthase (ChSy), highlighting the pivotal role of chondroitin in controlling both lifespan and healthspan. Additionally, the mig-22(gf) mutation effectively suppresses the reduced healthspan associated with the loss of MIG-17/ADAMTS metalloprotease, a crucial for factor in basement membrane (BM) remodeling. Our findings suggest that chondroitin functions in the control of healthspan downstream of MIG-17, while regulating lifespan through a pathway independent of MIG-17.