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Introduction: Ovarian and other peritoneal cancers have a strong tendency to metastasize into the surrounding adipose tissue. This study describes an effect of the adipose microenvironment on upregulation of sialic acid-containing glycans in ovarian cancer (OC). Heterogeneous populations of glycosylated OC tumors converged to a highly sialylated cell state that regulates tumorigenesis in an immune-dependent manner. Methods: We modeled the adipose microenvironment by conditioning growth media with human patient-derived adipose tissue. OC cell lines grown in the presence vs. absence of adipose conditioned media (ACM) were characterized by transcriptomics, western blotting, and chemical biology glycan labeling methods. Fluorescence-activated cell sorting was used to separate adipose-driven upregulation of hypersialylated ("SNA-high") vs. hyposialylated ("SNA-low") OC subpopulations. The two subpopulations were characterized by further transcriptomic and quantitative polymerase chain reaction analyses, then injected into a syngeneic mouse model. Immune system involvement was implicated using wild type and athymic nude mice with a primary endpoint of overall survival. Results: Adipose conditioning resulted in upregulation of sialyltransferases ST3GAL1, ST6GAL1, ST6GALNAC3, and ST8Sia1. In culture, OC cells displayed two distinct sialylated subpopulations that were stable for up to 9 passages, suggesting inherent heterogeneity in sialylation that is maintained throughout cell division and media changes. OC tumors that implanted in the omental adipose tissue exclusively reprogrammed to the highly sialylated subpopulation. In wild type C57BL/6 mice, only the hypersialylated SNA-high subpopulation implanted in the adipose, whereas the hyposialylated SNA-low subpopulation failed to be tumorigenic (p=0.023, n=5). In the single case where SNA-low established a tumor, post-mortem analysis revealed reprogramming of the tumor to the SNA-high state in vivo. In athymic nude mice, both subpopulations rapidly formed tumors, implicating a role of the adaptive immune system. Conclusions: These findings suggest a model of glycan-dependent tumor evolution wherein the adipose microenvironment reprograms OC to a tumorigenic state that resists the adaptive immune system. Mechanistically, adipose factors upregulate sialyltransferases. To our knowledge, this is the first demonstration of the effect of adipose microenvironment on OC tumor sialylation. Our results set the stage for translational applications targeting sialic acid pathways in OC and other peritoneal cancer tumorigenesis and metastasis. [ABSTRACT FROM AUTHOR]

In 1957, Hadwiger conjectured that every convex body in |${\mathbb{R}}^{d}$| can be covered by |$2^{d}$| translates of its interior. For over 60 years, the best known bound was of the form |$O(4^{d} \sqrt{d} \log d)$|⁠ , but this was recently improved by a factor of |$e^{\Omega (\sqrt{d})}$| by Huang, Slomka, Tkocz, and Vritsiou. In this note, we take another step towards Hadwiger's conjecture by deducing an almost-exponential improvement from the recent breakthrough work of Chen, Klartag, and Lehec on Bourgain's slicing problem. More precisely, we prove that, for any convex body |$K \subset{\mathbb{R}}^{d}$|⁠ , $$\begin{align*} &\exp\bigg(- \Omega\bigg(\frac{d}{\log d} \bigg) \bigg) \cdot 4^d \end{align*}$$ translates of |$\operatorname{int}(K)$| suffice to cover |$K$|⁠. We also show that a positive answer to Bourgain's slicing problem would imply an exponential improvement for Hadwiger's conjecture. [ABSTRACT FROM AUTHOR]

The method of hypergraph containers, which was introduced several years ago by Balogh, Morris, and Samotij, and independently by Saxton and Thomason, has proved to be an extremely useful tool in the study of various monotone graph properties. In particular, a fairly straightforward application of this technique allows one to locate, for each non-bipartite graph H, the threshold at which the distribution of edges in a typical H-free graph with a given number of edges undergoes a transition from 'random-like' to 'structured'. On the other hand, for nonmonotone hereditary graph properties, the standard version of this method does not allow one to establish even the existence of such a threshold. In this paper we introduce a refinement of the container method that takes into account the asymmetry between edges and non-edges in a sparse member of a hereditary graph property. As an application, we determine the approximate structure of a typical graph with n vertices, m edges, and no induced copy of the 4-cycle, for each function m D m.n/ satisfying n4=3.log n/4 6 m n2. We show that almost all such graphs G have the following property: the vertex set of G can be partitioned into an 'almost independent' set (a set with o.m/ edges) and an 'almost-clique' (a set inducing a subgraph with density 1-a The lower bound on m is optimal up to a polylogarithmic factor, as standard arguments show that if n then almost all such graphs are 'random-like'. As a further consequence, we deduce that the random graph G.n; p/ conditioned to contain no induced 4-cycles undergoes phase transitions at p=n -2/3+o(1) p=n -2/3+o(1). [ABSTRACT FROM AUTHOR]

The set‐coloring Ramsey number Rr,s(k)$$ {R}_{r,s}(k) $$ is defined to be the minimum n$$ n $$ such that if each edge of the complete graph Kn$$ {K}_n $$ is assigned a set of s$$ s $$ colors from {1,...,r}$$ \left\{1,\dots, r\right\} $$, then one of the colors contains a monochromatic clique of size k$$ k $$. The case s=1$$ s=1 $$ is the usual r$$ r $$‐color Ramsey number, and the case s=r−1$$ s=r-1 $$ was studied by Erdős, Hajnal and Rado in 1965, and by Erdős and Szemerédi in 1972. The first significant results for general s$$ s $$ were obtained only recently, by Conlon, Fox, He, Mubayi, Suk and Verstraëte, who showed that Rr,s(k)=2Θ(kr)$$ {R}_{r,s}(k)={2}^{\Theta (kr)} $$ if s/r$$ s/r $$ is bounded away from 0 and 1. In the range s=r−o(r)$$ s=r-o(r) $$, however, their upper and lower bounds diverge significantly. In this note we introduce a new (random) coloring, and use it to determine Rr,s(k)$$ {R}_{r,s}(k) $$ up to polylogarithmic factors in the exponent for essentially all r$$ r $$, s$$ s $$, and k$$ k $$. [ABSTRACT FROM AUTHOR]

We study monotone cellular automata (also known as U-bootstrap percolation) in Zd with random initial configurations. Confirming a conjecture of Balister, Bollobás, Przykucki and Smith, who proved the corresponding result in two dimensions, we show that the critical probability is non-zero for all subcritical models. [ABSTRACT FROM AUTHOR]

Introduced by Erdős in 1950, a covering system of the integers is a finite collection of arithmetic progressions whose union is the set Z. Many beautiful questions and conjectures about covering systems have been posed over the past several decades, but until recently little was known about their properties. Most famously, the so-called minimum modulus problem of Erdős was resolved in 2015 by Hough, who proved that in every covering system with distinct moduli, the minimum modulus is at most 1016 . In this paper we answer another question of Erdős, asked in 1952, on the number of minimal covering systems. More precisely, we show that the number of minimal covering systems with exactly n elements is exp ((4√τ/3+o(1)n3/2/(logn)1/2) as n→∞, where τ=∑∞ t=1(logt+1/t)².En route to this counting result, we obtain a structural description of all covering systems that are close to optimal in an appropriate sense. [ABSTRACT FROM AUTHOR]

Objective: To assess the influence of geographies and race on the survival outcomes in patients diagnosed with cervical squamous cell carcinoma (CSCC) across three continents., Methods: This multicontinental retrospective study was conducted in 8 hospitals across Asia, Europe, and North America (NA). Clinicopathologic data of 595 patients with presumed early stages of CSCC, treated surgically, with curative intent was collected. Descriptive analysis and Cox regression models were produced., Results: A total of 595 patients, consisting of 445 (74.8 %) white, 75 (12.6 %) Blacks, and 75 (12.6 %) Asian patients were included. Geographical distribution comprised 69 % of patients from NA, 22 % from Europe, and 9 % from Asia. The median age at diagnosis was 46 years. The median overall survival (OS) and relapse-free survival (RFS) were 22.09 years and 21.19 years, respectively. Patient characteristics varied significantly across geographical regions, except for consensus tumor grade. Patients in Europe from middle-income countries with limited CC screening had a substantially higher risk of death than those in NA (HR, 1.79; 95 % CI, 1.13 to 2.79; p = 0.015). Patients from single center in Japan had higher risk of relapse than those from the four heterogeneous NA centers (sub-distribution hazard ratio, 2.19; 95 % CI, 1.22 to 3.95; p = 0.009), although OS did not differ significantly. Race remained statistically insignificant for survival outcomes across the three continents but seemed to influence survival outcomes in NA centers., Conclusion: Our study highlights impact of geographies and races on CSCC survival outcomes, emphasizing the need of considering these factors when developing targeted interventions against CSCC., Competing Interests: Declaration of competing interest The authors whose names are listed immediately below certify that they have NO affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers' bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript., (Copyright © 2024. Published by Elsevier Inc.)

Background: Skeletal muscle is a highly plastic tissue crucial for many functions associated with whole-body health across the life course. Magnetic resonance imaging (MRI) is the current gold standard for measuring skeletal muscle size. However, MRI is expensive, and access to facilities is often limited. B-mode ultrasonography (U/S) has been proposed as a potential alternative to MRI for the assessment of muscle size. However, to date, no work has explored the utility of U/S to assess disuse muscle atrophy (DMA) across muscles with different atrophy susceptibility profiles, an omission which may limit the clinical application of previous work., Methods: To address this significant knowledge gap, 10 young men (22 ±  years, 24.1 ± 2.3 kg/m 2 ) underwent 15-day unilateral leg immobilization using a knee-brace and air boot. Cross-sectional area (CSA) and muscle thickness (MT) of the tibialis anterior (TA) and medial gastrocnemius (MG) were assessed via U/S before and after immobilization, with CSA and muscle volume assessed via MRI., Results: With both muscles combined, there were good correlations between each U/S and MRI measure, both before (e.g., CSA MRI vs. MT U/S and CSA U/S : r = 0.88 and 0.94, respectively, both P < 0.0001) and after (e.g., VOL MRI vs. MT U/S and CSA U/S : r = 0.90 and 0.96, respectively, both P < 0.0001) immobilization. The relationship between the methods was notably stronger for MG than TA at each time-point (e.g., CSA MRI vs. MT U/S : MG, r = 0.70, P = 0.0006; TA, r = 0.37, P = 0.10). There was no relationship between the degree of DMA determined by the two methods in either muscle (e.g., TA pre- vs. post-immobilization, VOL MRI : 136 ± 6 vs. 133 ± 5, P = 0.08; CSA U/S : 6.05 ± 0.3 vs. 5.92 ± 0.4, P = 0.70; relationship between methods: r = 0.12, P = 0.75)., Conclusions: Both MT U/S and CSA U/S provide comparable static measures of lower leg muscle size compared with MRI, albeit with weaker agreement in TA compared to MG. Although both MT U/S and CSA U/S can discern differences in DMA susceptibility between muscles, neither can reliably assess degree of DMA. Based on the growing recognition of heterogeneous atrophy profiles between muscles, and the topical importance of less commonly studied muscles (i.e., TA for falls prevention in older adults), future research should aim to optimize accessible methods to determine muscle losses across the body., (© 2024 The Author(s). Journal of Cachexia, Sarcopenia and Muscle published by Wiley Periodicals LLC.)

In situ gelling polymeric biomaterials have proven useful as drug delivery vehicles to enable sustained release at sites of disease or injury. However, if delivered to mucosal tissues, such as the eyes, nose, gastrointestinal, and cervicovaginal tract, these gels must also possess the ability to adhere to an epithelium coated in mucus. Towards this end, we report a new rapid in situ gelling polyethylene glycol-based hydrogel. Unlike other chemistries that enable rapid gel formation which form via irreversible covalent bonds, we use a bio-reducible linker allowing the gels to be naturally degraded over several days once administered. We identified a set of 6 lead formulations, which rapidly form into disulfide-linked PEG hydrogels in 30 seconds or less. These rapidly forming PEG hydrogels were also able to conform and adhere to mucosal tissues via PEG-mucin entanglements and hydrogen bonding. Controlled release of protein-based cargoes from the PEG gels was achieved over several hours whereas 40 nm nanoparticle-based cargos were retained over 24 hours. We also found these rapid in situ forming PEG gels were well-tolerated by mammalian cells. These studies support further testing and development of rapid in situ forming PEG gels for drug delivery to improve therapeutic retention and efficacy at mucosal sites., Competing Interests: Conflict of interest T.Y. and G.A.D. have a pending patent based on the hydrogel formulation described in this manuscript.

The association of BRCA1 and BRCA2 mutations with increased risk for developing epithelial ovarian cancer is well established. However, the observed clinical differences, particularly the improved therapy response and patient survival in BRCA2-mutant patients, are unexplained. Our objective is to identify molecular pathways that are differentially regulated upon the loss of BRCA1 and BRCA2 functions in ovarian cancer. Transcriptomic and pathway analyses comparing BRCA1-mutant, BRCA2-mutant, and homologous recombination wild-type ovarian tumors showed differential regulation of the Wnt/β-catenin pathway. Using Wnt3A-treated BRCA1/2 wild-type, BRCA1-null, and BRCA2-null mouse ovarian cancer cells, we observed preferential activation of canonical Wnt/β-catenin signaling in BRCA1/2 wild-type ovarian cancer cells, whereas noncanonical Wnt/β-catenin signaling was preferentially activated in the BRCA1-null ovarian cancer cells. Interestingly, BRCA2-null mouse ovarian cancer cells demonstrated a unique response to Wnt3A with the preferential upregulation of the Wnt signaling inhibitor Axin2. In addition, decreased phosphorylation and enhanced stability of β-catenin were observed in BRCA2-null mouse ovarian cancer cells, which correlated with increased inhibitory phosphorylation on GSK3β. These findings open venues for the translation of these molecular observations into modalities that can impact patient survival., Significance: We show that BRCA1 and BRCA2 mutation statuses differentially impact the regulation of the Wnt/β-catenin signaling pathway, a major effector of cancer initiation and progression. Our findings provide a better understanding of molecular mechanisms that promote the known differential clinical profile in these patient populations., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background: 2,4-dinitrophenol (DNP), an uncoupling mitochondrial agent, has been identified as a source of oxidative stress and linked to the pathogenesis of ovarian cancer. In this study, we determine the cytotoxic effect of DNP alone or in combination with chemotherapies in ovarian cancer cells., Methods: We utilized human ovarian cancer cell lines SKOV-3 and MDAH-2774 with their chemoresistant counterparts. Cancer stem cells (CSCs) were isolated from SKOV-3 utilizing magnetic-activated cell sorting technique for CD44+/CD117+ cells. Human normal primary ovarian epithelial (NOEC) and HOSEpiC cell lines were used as a control. Cells were treated with and without chemotherapy (taxotere 0.3 µM or cisplatin 50 µM), with or without increasing doses of DNP (0.125, 0.25, or 0.5 mM) for 24 hours followed by evaluation of cell viability and IC50 utilizing MTT assay. For determination of synergism, Fa-combination Index plots were created using the CompuSyn software (ComboSyn, Inc., Paramus, NJ, USA). All data were run in triplicates and analyzed by t-test., Results: DNP treatment of ovarian cancer and chemoresistant ovarian cancer cell lines as well as CSCs resulted in decreased cell viability in a dose dependent manner with no effect on normal cells. Combination of DNP with chemotherapy synergistically enhances cytotoxicity of chemotherapeutics in all ovarian cancer cells as compared to chemotherapy alone., Conclusions: Our data indicates the potential of the addition of DNP to the arsenal of drugs available to treat ovarian cancer, whether alone or in combination with chemotherapies. The synergistic effects of DNP in reducing the required amount of chemotherapy, is critical for the alleviation of harmful side effects.

Biliary tract cancers (BTCs) are a group of deadly malignancies encompassing intrahepatic and extrahepatic cholangiocarcinoma, gallbladder carcinoma, and ampullary carcinoma. Here, we present the integrative analysis of 63 BTC cell lines via multi-omics clustering and genome- scale CRISPR screens, providing a platform to illuminate BTC biology and inform therapeutic development. We identify dependencies broadly enriched in BTC compared to other cancers as well as dependencies selective to the anatomic subtypes. Notably, cholangiocarcinoma cell lines are stratified into distinct lineage subtypes based on biliary or dual biliary/hepatocyte marker signatures, associated with dependency on specific lineage survival factors. Transcriptional analysis of patient specimens demonstrates the prognostic significance of these lineage subtypes. Additionally, we delineate strategies to enhance targeted therapies or to overcome resistance in cell lines with key driver gene mutations. Furthermore, clustering based on dependencies and proteomics data elucidates unexpected functional relationships, including a BTC subgroup with partial squamous differentiation. Thus, this cell line atlas reveals potential therapeutic targets in molecularly defined BTCs, unveils biologically distinct disease subtypes, and offers a vital resource for BTC research.

Ovarian cancer is the deadliest gynecologic malignancy. The omentum plays a key role in providing a supportive microenvironment to metastatic ovarian cancer cells as well as immune modulatory signals that allow tumor tolerance. However, we have limited models that closely mimic the interaction between ovarian cancer cells and adipose-rich tissues. To further understand the cellular and molecular mechanisms by which the omentum provides a pro-tumoral microenvironment, we developed a unique 3D ex vivo model of cancer cell-omentum interaction. Using human omentum, we are able to grow ovarian cancer cells within this adipose-rich microenvironment and monitor the factors responsible for tumor growth and immune regulation. In addition to providing a platform for the study of this adipose-rich tumor microenvironment, the model provides an excellent platform for the development and evaluation of novel therapeutic approaches to target metastatic cancer cells in this niche. The proposed model is easy to generate, inexpensive, and applicable to translational investigations.

Drug repurposing is an emerging approach to reassigning existing pre-approved therapies for new indications. The FDA Adverse Event Reporting System (FAERS) is a large database of over 28 million adverse event reports submitted by medical providers, patients, and drug manufacturers and provides extensive drug safety signal data. In this review, four common drug repurposing strategies using FAERS are described, including inverse signal detection for a single disease, drug-drug interactions that mitigate a target ADE, identifying drug-ADE pairs with opposing gene perturbation signatures and identifying drug-drug pairs with congruent gene perturbation signatures. The purpose of this review is to provide an overview of these different approaches using existing successful applications in the literature. With the fast expansion of adverse drug event reports, FAERS-based drug repurposing represents a promising strategy for discovering new uses for existing therapies., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)