bluuebunny/crossref_metadata_2025 huggingface dataset:
Load Balancing with Job-Size Testing: Performance Improvement or Degradation?
Authors: Anselmi Jonatha , Doncel Josu
Published: March 2024

In the context of decision making under explorable uncertainty, scheduling with testing is a powerful technique used in the management of computer systems to improve performance via better job-dispatching decisions. Upon job arrival, a scheduler may run some
testing algorithm
against the job to extract some information about its structure, e.g., its size, and properly classify it. The acquisition of such knowledge comes with a cost because the testing algorithm delays the dispatching decisions, though this is under control. In this article, we analyze the impact of such extra cost in a load balancing setting by investigating the following questions: does it really pay off to test jobs? If so, under which conditions? Under mild assumptions connecting the information extracted by the testing algorithm in relationship with its running time, we show that whether scheduling with testing brings a performance degradation or improvement strongly depends on the traffic conditions, system size and the coefficient of variation of job sizes. Thus, the general answer to the above questions is non-trivial and some care should be considered when deploying a testing policy. Our results are achieved by proposing a load balancing model for scheduling with testing that we analyze in two limiting regimes. When the number of servers grows to infinity in proportion to the network demand, we show that job-size testing actually degrades performance unless short jobs can be predicted reliably almost instantaneously
and
the network load is sufficiently high. When the coefficient of variation of job sizes grows to infinity, we construct testing policies inducing an arbitrarily large performance gain with respect to running jobs untested.
CFLOBDDs: Context-Free-Language Ordered Binary Decision Diagrams
Authors: Sistla Meghana Aparna , Chaudhuri Swarat , Reps Thomas
Published: March 2024

This article presents a new compressed representation of Boolean functions, called
CFLOBDDs
(for Context-Free-Language Ordered Binary Decision Diagrams). They are essentially a plug-compatible alternative to BDDs (Binary Decision Diagrams), and hence are useful for representing certain classes of functions, matrices, graphs, relations, and so forth in a highly compressed fashion. CFLOBDDs share many of the good properties of BDDs, but—in the best case—the CFLOBDD for a Boolean function can be
exponentially smaller than any BDD for that function
. Compared with the size of the decision tree for a function, a CFLOBDD—again, in the best case—can give a
double-exponential reduction in size
. They have the potential to permit applications to (i) execute much faster and (ii) handle much larger problem instances than has been possible heretofore.

We applied CFLOBDDs in quantum-circuit simulation and found that for several standard problems, the improvement in scalability, compared to BDDs, is quite dramatic. With a 15-minute timeout, the number of qubits that CFLOBDDs can handle are 65,536 for Greenberger-Horne-Zellinger, 524,288 for Bernstein-Vazirani, 4,194,304 for Deutsch-Jozsa, and 4,096 for Grover’s algorithm, besting BDDs by factors of 128×, 1,024×, 8,192×, and 128×, respectively.
Li2B5O8Cl: A New Borate Chloride with Interpenetrating 3D B–O Frameworks Enriching Structural Chemistry of Borate
Authors: Deng Lihan , Bai Chunyan , Li Jin , Zhang Nana
Published: March 2024

A new borate chloride, Li2B5O8Cl, has been obtained. It exhibits complicated interpenetrating 3D B–O frameworks composed of the functional building block (FBB) [B5O10], enriching the structural diversity of B–O configurations. The theoretical study indicates that the birefringence is estimated to be 0.026 at 1064 nm. Meanwhile, the structure-property relationships were analyzed through the first-principles calculation with a bandgap of 5.737 eV for GGA and 6.880 eV for HSE06, and the electronic properties of each group are analyzed by the density of states (DOS).
Two- and Three-Dimensional Recrystallization of Discrete Amorphous in C3H5-Molecular-Ion-Implanted Silicon Surface Analyzed by TCAD Simulation
Authors: Kobayashi Koji , Okuyama Ryosuke , Kadono Takeshi , Onaka-Masada Ayumi , Hirose Ryo , Suzuki Akihiro , Koga Yoshihiro , Sueoka Koji , Kurita Kazunari
Published: March 2024

Technology computer-aided design (TCAD) kinetic Monte Carlo simulations revealed the unique recrystallization processes of discrete amorphous regions connected to a buried amorphous layer in a C3H5-molecular-ion-implanted silicon (Si) substrate. The faithful simulation models show that the discrete amorphous regions are first recrystallized two-dimensionally in the lateral direction from both sides and separated from the buried amorphous layer. Then, the separated discrete amorphous regions are recrystallized three-dimensionally in the lateral and vertical directions from both sides and the bottom. We found that the first two-dimensional recrystallization of discrete amorphous regions is caused by the retardation of solid-phase epitaxial growth at the Si substrate surface and near the buried amorphous layer. We also found that the large (small) discrete amorphous regions require a long (short) two-dimensional recrystallization before separating from the buried amorphous layer. The transition point in the recrystallization dimension can be determined from the lateral recrystallization length and the equivalent radius of discrete amorphous regions.
First-Principles Analysis on the Optoelectronic, Structural, Elastic and Transport Characteristics of Novel Fluoroperovskites Cs2TlAgF6 for Green Technology
Authors: Murtaza Hudabia , Ain Quratul , Munir Junaid , Ghaithan Hamid M. , Ahmed Abdullah Ahmed Ali , Qaid Saif M. H.
Published: March 2024

Cs-based perovskites hold immense significance in the field of green technology due to their unique properties, offering promising avenues for efficient, low-cost devices. In this theoretical work, DFT has been employed to extensively scrutinize the physical properties of double fluoroperovskites Cs2TlAgF6. The modified Becke Johnson functional was used to take exchange-correlation effects into consideration accurately. From the calculated value of formation energy, volume optimization curve, Goldsmith tolerance factor and octahedral tilting, the structural stability is demonstrated. The band structure of Cs2TlAgF6 depicts a direct bandgap of 2.21 eV, proving its semiconducting nature. This study also assessed the mechanical properties in detail, showing the ductile character of Cs2TlAgF6. A thorough examination of optical characteristics reveals the potential application in a variety of photovoltaic devices due to its strong absorption in visible region. The transport attributes are accessed through large ZT value and other thermal parameters. With its exceptional heat-to-electricity conversion properties, this material shows promise for applications in thermoelectric devices, offering a sustainable way to generate electricity from waste heat. The larger value 0.788 of ZT depicts that material exhibit sufficient potential for generating energy from waste heat.
Obesity-associated inflammatory macrophage polarization is inhibited by capsaicin and phytolignans
Authors: Poynter Matthew E. , Mank Madeleine M. , Ather Jennifer L.
Published: March 2024

The utility of food-based products to prevent or alleviate chronic conditions such as obesity and its associated comorbidities is an attractive approach. Capsaicin, schisandrin A, enterodiol, and enterolactone, phytochemicals present in traditional medicinal food, decreased proinflammatory cytokine production from macrophages that, in turn, reduced obesity-associated adipocyte dysfunction. These results implicate the contribution of plant-derived dietary components to the modulation of macrophages and adipocytes in obesity.
Mutational Profile and Retinal Phenotypes of PCARE-Related Cone-Rod Dystrophies in a Mexican Cohort
Authors: López-Rodríguez Víctor R. , Arce-González Rocío , Martínez-Aguilar Alan , Rodríguez-López Carlos E. , Groman-Lupa Sergio , Neria-González M. Isabel , Rodríguez-Uribe Genaro , Zenteno Juan C.
Published: March 2024

Purpose. The aim of the study is to describe the genotype and phenotype of a Mexican cohort with PCARE-related retinal disease. Methods. The study included 14 patients from 11 unrelated pedigrees with retinal dystrophies who were demonstrated to carry biallelic pathogenic variants in PCARE. Visual assessment methods included best corrected visual acuity, color fundus photography, Goldmann visual field test, kinetic perimetry, dark/light adapted chromatic perimetry, full-field electroretinography, autofluorescence imaging, and spectral domain-optical coherence tomography imaging. Genetic screening was performed either by gene panel sequencing or by exome sequencing. Results. According to the results of multimodal imaging and functional tests, all 14 patients were diagnosed with cone-rod dystrophy. Six different PCARE pathogenic alleles were identified in our cohort, including three novel mutations: c.3048_3049del (p.Tyr1016∗), c.3314_3315del (p.Ser1105∗), and c.551A > G (p.His184Arg). Notably, alleles p.His184Arg, p.Arg613∗, and p.Arg984∗ were present in 18 of the 22 (82%) PCARE alleles from probands in our cohort. Conclusion. Our work expands the PCARE mutational profile by identifying three novel pathogenic variants causing retinal dystrophy. While phenotypic variations occurred among patients, a cone-rod dystrophy pattern was observed in all affected individuals.
Fractional Mixed Weighted Convolution and Its Application in Convolution Integral Equations
Authors: Wang Rongbo , Feng Qiang
Published: March 2024

The convolution integral equations are very important in optics and signal processing domain. In this paper, fractional mixed-weighted convolution is defined based on the fractional cosine transform; the corresponding convolution theorem is achieved. The properties of fractional mixed-weighted convolution and Young’s type theorem are also explored. Based on the fractional mixed-weighted convolution and fractional cosine transform, two kinds of convolution integral equations are considered, the explicit solutions of fractional convolution integral equations are obtained, and the computational complexity of solutions are also analyzed.
Comparative Study on Fatty Acids Composition of Lemna minor (Duckweed) Cultured in Indoor Plastic Tanks and Outdoor Earthen Ponds
Authors: Achoki Judith , Orina Paul , Kaingu Catherine , Oduma Jemima , Olale Kennedy , Chepkirui Mercy , Getabu Albert
Published: March 2024

Global interest in using duckweed (Lemna minor) as a substitute for fish, livestock, and human diets has spurred research on the mass culture of the species. There is a scarcity of information on the L. minor fatty acid composition in different aquaculture settings. A comparative study was carried out to investigate the fatty acid composition of L. minor cultured in indoor plastic tanks and outdoor earthen ponds for 30 days. During the culture period, culture facilities were fertilized using livestock manure. Fatty acid characterization was done using gas chromatography method. Fifteen fatty acids: five saturated (SAFAs), five monounsaturated (MUFAS), and five polyunsaturated (PUFAs) were identified. Fatty acid compositions varied between indoor and outdoor settings. Percentage composition of L. minor PUFAs cultured outdoor (37.13) was higher than that of indoor (21.96) settings. L. minor SAFAs percentage composition was higher in the indoor culture at 41.63% while that of outdoor was 33.75%. The composition of L. minor MUFAs in indoor tanks was higher (36.32%) than in outdoor earthen ponds (29.10%). This study indicated the presence of docosahexaenoic, eicosapentaenoic, linoelaidic, and eicosanoic acids in L. minor seldom reported in past studies. Paired Students’ t‐test indicated that the means of the fatty acid composition were significantly different (p < 0.05) in both settings, with docosahexaenoic showing the highest paired mean difference.
Stressing Out Cancer: Chronic Stress Induces Dysbiosis and Enhances Colon Cancer Growth
Authors: McCollum Shannon E. , Shah Yatrik M.
Published: March 2024

Psychologic stress significantly impacts colorectal cancer, and chronic stress is known to decrease treatment efficacy and survival rates in patients with colorectal cancer. Previous studies have linked psychologic stress to changes in the gut microbiota, and the role of the microbiota in colorectal cancer progression is well characterized. Despite this, the mechanistic link between chronic stress and colorectal cancer remains unclear. In this issue of Cancer Research, Cao and colleagues reveal that chronic stress exacerbates colorectal cancer progression by reducing the presence of Lactobacillus johnsonii (L. johnsonii) and its metabolite protocatechuic acid (PCA). The authors demonstrate an increase in β-catenin expression as the major mechanism by which chronic stress potentiates cancer stemness and pathogenesis. Administration of L. johnsonii or PCA to stressed mice decreased β-catenin activity and colorectal cancer progression. This study defines a precise mechanism underlying chronic stress and colorectal cancer progression, emphasizing the relevance of psychologic well-being in colorectal cancer outcome. In addition, the study demonstrates the potential efficacy of L. johnsonii or PCA supplementation as promising therapeutics for colorectal cancer treatment.

See related article by Cao et al., p. 771
Trastuzumab and Pertuzumab in Patients with Non-Breast/Gastroesophageal HER2-Amplified Tumors: Results from the NCI–MATCH ECOG–ACRIN Trial (EAY131) Subprotocol J
Authors: Connolly Roisin M. , Wang Victoria , Hyman David M. , Grivas Petros , Mitchell Edith P. , Wright John J. , Sharon Elad , Gray Robert J. , McShane Lisa M. , Rubinstein Larry V. , Patton David R. , Williams P. Mickey , Hamilton Stanley R. , Wang Jue , Wisinski Kari B. , Tricoli James V. , Conley Barbara A. , Harris Lyndsay N. , Arteaga Carlos L. , O'Dwyer Peter J. , Chen Alice P. , Flaherty Keith T.
Published: March 2024

Purpose:

NCI–MATCH assigned patients with advanced cancer and progression on prior treatment, based on genomic alterations in pretreatment tumor tissue. Arm J (EAY131-J) evaluated the combination of trastuzumab/pertuzumab (HP) across HER2-amplified tumors.

Patients and Methods:

Eligible patients had high levels of HER2 amplification [copy number (CN) ≥7] detected by central next-generation sequencing (NGS) or through NCI-designated laboratories. Patients with breast/gastroesophageal adenocarcinoma and those who received prior HER2-directed therapy were excluded. Enrollment of patients with colorectal cancer was capped at 4 based on emerging data. Patients received HP IV Q3 weeks until progression or unacceptable toxicity. Primary endpoint was objective response rate (ORR); secondary endpoints included progression-free survival (PFS) and overall survival (OS).

Results:

Thirty-five patients were enrolled, with 25 included in the primary efficacy analysis (CN ≥7 confirmed by a central lab, median CN = 28). Median age was 66 (range, 31–80), and half of all patients had ≥3 prior therapies (range, 1–11). The confirmed ORR was 12% [3/25 partial responses (colorectal, cholangiocarcinoma, urothelial cancers), 90% confidence interval (CI) 3.4%–28.2%]. There was one additional partial response (urothelial cancer) in a patient with an unconfirmed ERBB2 copy number. Median PFS was 3.3 months (90% CI 2.0–4.1), and median OS 9.4 months (90% CI 5.0–18.9). Treatment-emergent adverse events were consistent with prior studies. There was no association between HER2 CN and response.

Conclusions:

HP was active in a selection of HER2-amplified tumors (non-breast/gastroesophageal) but did not meet the predefined efficacy benchmark. Additional strategies targeting HER2 and potential resistance pathways are warranted, especially in rare tumors.
Data from Radiation Synergizes with IL2/IL15 Stimulation to Enhance Innate Immune Activation and Antitumor Immunity
Authors: Li Xuefeng , Huntoon Kristin , Wang Yifan , Lee DaeYong , Dong Shiyan , Antony Abin , Walkey Carl , Kim Betty Y.S. , Jiang Wen
Published: March 2024

Abstract
Ionizing radiation is known to possess immune modulatory properties. However, how radiotherapy (RT) may complement with different types of immunotherapies to boost antitumor responses is unclear. In mice implanted with EO771 syngeneic tumors, NL-201 a stable, highly potent CD25-independent agonist to IL2 and IL15 receptors with enhanced affinity for IL2Rβγ was given with or without RT. Flow analysis and Western blot analysis was performed to determine the mechanisms involved. STING (−/−) and CD11c+ knockout mice were implanted with EO771 tumors to confirm the essential signaling and cell types required to mediate the effects seen. Combination of RT and NL-201 to enhance systemic immunotherapy with an anti-PD-1 checkpoint inhibitor was utilized to determine tumor growth inhibition and survival, along characterization of tumor microenvironment as compared with all other treatment groups. Here, we showed that RT, synergizing with NL-201 produced enhanced antitumor immune responses in murine breast cancer models. When given together, RT and NL-201 enhanced activation of the cytosolic DNA sensor cyclic GMP-AMP synthase-stimulator of IFN genes (cGAS-STING) pathway, resulting in increased type I IFN production in dendritic cells (DC), and consequently greater tumor infiltration and more efficient priming of antigen-specific T cells. The immune stimulatory mechanisms triggered by NL-201 and RT resulted in superior tumor growth inhibition and survival benefit in both localized and metastatic cancers. Our results support further preclinical and clinical investigation of this novel synergism regimen in locally advanced and metastatic settings.
Abstract A028: Subclonal lineage recording in glioblastoma using CRISPR base editing
Authors: Marshall Abigail C. , McKenna Aaron
Published: March 2024

Novel lineage tracing approaches are needed to undercover lineage relationships between diverse cells in complex tumors such as glioblastoma (GBM). Intratumoral heterogeneity in GBM drives treatment resistance and recurrence. This intratumoral heterogeneity is reflected by multiple cellular states seen within tumors and across patients. Unfortunately, little is known about their lineage relationships and shared origins. Here we’ve developed a novel lineage tracing technology to track the clonal and subclonal evolution in patient-derived GBM models. Our adenine base editor lineage tracing (ABELT) system uses a Cas9 adenine base editor (ABE) to induce heritable single-nucleotide changes in the 3’ untranslated region of endogenous transcripts. These heritable marks distinguish individual clonal populations and can be used to trace the relationship between progeny within each clone. We demonstrate our system's in vitro lineage tracing capacity and show that the ABELT system faithfully records lineage, which is recoverable with unmodified single-cell RNA sequencing approaches. We then track the relationships between evolving cellular states across multiple divisions in an evolving GBM model. Our ABELT technology enables the rapid engineering and lineage tracing of cancer models incompatible with previous approaches. This novel approach will enable our group and others to explore GBM intratumoral heterogeneity with subclonal resolution to determine transcriptional plasticity that ultimately leads to treatment resistance.

Citation Format: Abigail C. Marshall, Aaron McKenna. Subclonal lineage recording in glioblastoma using CRISPR base editing [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 A028.
Abstract A043: Pericytes orchestrate a tumor-suppressive microenvironment by impinging on the crosstalk between macrophages and tumor-initiating cells in glioblastoma multiforme
Authors: Braun Sebastian , Oudenaarden Clara , Bolivar Paulina , Sjölund Jonas , Cordero Eugenia , Roslund Rebecca , Johansson Elinn , Pietras Alexander , Pietras Kristian
Published: March 2024

Glioblastoma multiforme (GBM) is characterized by fast progression, infiltrative growth pattern and a high rate of relapse. A defining feature of GBM is the existence of spatially and functionally distinct cellular niches, i.e. a hypoxic niche, a leading-edge niche, and a peri-vascular niche, in which malignant cells engage in paracrine crosstalk with cell types comprising the tumor microenvironment, including immune cells, astrocytes, and vascular cells. Here, by analysis of single-cell transcriptomic data of human GBM and transgenic mouse models of GBM, we unexpectedly identified pericytes intimately associated with the endothelium as the most active paracrine signaling hub within the tumor parenchyma. Exclusive signaling axes emanating from pericytes were received by endothelial cells, malignant cells, astrocytes, and immune cells. Depletion of pericytes through genetic engineering in several different transgenic and orthotopic mouse models of GBM demonstrated accelerated tumor progression, a disrupted blood-brain-barrier, and premature death of pericyte-poor mice. Mechanistic studies revealed that pericyte deficiency altered the cellular composition of GBM, remodeled the endothelium, and impacted on the immune cell landscape. Specifically, endothelial cells deprived of pericyte association upregulated Colony Stimulating Factor (CSF)-1, which in turn attracted peri-vascular tumor-associated macrophages polarized towards an immune-suppressive phenotype. In the absence of pericytes, the recruited macrophages expressed Hepatocyte Growth Factor (HGF), which reinforced activation of its receptor tyrosine kinase c-Met on a subset of GBM cells harboring an extreme mesenchymal-like state. Indeed, orthotopic implantation of isolated c-Met-expressing GBM cells corroborated their superior tumor-initiating capability and invasive phenotype, compared to cells negative for c-Met. Taken together, we infer that the pericyte represents a critical modulator of GBM development by orchestrating a tumor-suppressive microenvironment; our findings thus highlight the importance of pericyte preservation in the face of current and future GBM therapies.

Citation Format: Sebastian Braun, Clara Oudenaarden, Paulina Bolivar, Jonas Sjölund, Eugenia Cordero, Rebecca Roslund, Elinn Johansson, Alexander Pietras, Kristian Pietras. Pericytes orchestrate a tumor-suppressive microenvironment by impinging on the crosstalk between macrophages and tumor-initiating cells in glioblastoma multiforme [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 A043.
Abstract B035: A compendium of syngeneic, transplantable pediatric high-grade glioma models reveals subtype-specific therapeutic vulnerabilities
Authors: McNicholas Michael , De Cola Antonella , Bashardanesh Zahedeh , Foss Amelia , Lloyd Cameron , Hebert Steven , Faury Damien , Andrade Augusto Faria , Jabado Nada , Kleinman Claudia , Pathania Manav
Published: March 2024

Pediatric high-grade gliomas (pHGGs) are lethal, incurable brain tumors frequently driven by clonal mutations in histone genes. They often harbor a range of additional genetic alterations that correlate with different ages, anatomical locations, and tumor subtypes. We developed models representing 16 pHGG subtypes driven by different combinations of alterations targeted to specific brain regions. Tumors developed with varying latencies and cell lines derived from these models engrafted in syngeneic, immunocompetent mice with high penetrance. Targeted drug screening revealed unexpected selective vulnerabilities. Moreover, H3.3K27M tumors with PIK3CA, NF1 and FGFR1 mutations were more invasive and harbored distinct additional phenotypes, such as exophytic spread, cranial nerve invasion and spinal dissemination. Collectively, these models reveal that different partner alterations produce distinct effects on pHGG cellular composition, latency, invasiveness, and treatment sensitivity.

Citation Format: Michael McNicholas, Antonella De Cola, Zahedeh Bashardanesh, Amelia Foss, Cameron Lloyd, Steven Hebert, Damien Faury, Augusto Faria Andrade, Nada Jabado, Claudia Kleinman, Manav Pathania. A compendium of syngeneic, transplantable pediatric high-grade glioma models reveals subtype-specific therapeutic vulnerabilities [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 B035.
Abstract PR-010: Asc1lb progenitor-specific RB conditional inactivation in zebrafish models rare CNS primitive neuroectodermal tumors
Authors: McGrail Maura , Liu Fang , Kambakam Sekhar , Ming Zhitao
Published: March 2024

We generated a new zebrafish model of human brain cancer by Cre/lox regulated conditional inactivation of the tumor suppressor RB in embryonic neural progenitors. An ascl1b progenitor Cre driver was used to inactivate RB by Cre recombination of an intronic floxed mRFP gene trap cassette, leading to mRFP expression and lineage labeling of RB mutated cells. Beginning at 6 months of age adult fish developed poorly differentiated brain tumors, similar to our previous zebrafish brain tumor model generated by CRISPR targeting of RB in embryos. Tumor transcriptome analysis revealed a proneural transcription factor molecular signature of the olig2+/sox10+ human CNS primitive neuroectodermal tumor subtype. Overexpression of chromatin remodelers suggest epigenetic mechanisms may contribute to tumorigenesis. Our model will allow sorting of RB mutant cells from the earliest stage of mutagenesis in the embryo to induction of cellular transformation in juveniles. With this approach we can profile the epigenetic time course of cellular transformation and reveal new insight into the molecular mechanisms driving PNET oncogenesis. Our approach to model cancer in fish with Cre/lox conditional inactivation can be applied to other cell lineages and brain tumor types.

Citation Format: Maura McGrail, Fang Liu, Sekhar Kambakam, Zhitao Ming. Asc1lb progenitor-specific RB conditional inactivation in zebrafish models rare CNS primitive neuroectodermal tumors [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 PR-010.
Abstract A036: Nanoparticle targeting in platinum-resistant ovarian cancer reveals dual axis of therapeutic vulnerability involving cholesterol uptake and cell redox balance
Authors: Wang Yinu , Calvert Andrea , Horacio Cardenas , Chen Fukai , Keathley Russell , Chen Ji-Xin , Thaxton Shad , Matei Daniela
Published: March 2024

Platinum (Pt) is the main therapy for ovarian cancer (OC); however, most patients develop Pt resistance (Pt-R). We show that Pt-R OC cells increase intracellular cholesterol through uptake via the HDL receptor, scavenger receptor type B-1 (SR-B1). SR-B1 blockade using synthetic cholesterol-poor HDL-like nanoparticles (HDL NPs) diminished cholesterol uptake leading to cell death and suppressed tumor growth. Reduced cholesterol accumulation induced lipid oxidative stress through reduction of glutathione peroxidase 4 (GPx4) leading to ferroptosis. In turn, GPx4 depletion is associated with reduced cholesterol uptake and re-sensitized OC cells to Pt. Mechanistically, GPx4 knockdown induced decreased expression of EP300, leading to reduced H3K27Ac on the SREBP2 promoter. Suppressed SREBP2 caused the downregulation of SR-B1. Thus, chemoresistance and cancer cell survival under a high ROS burden obligate high GPx4 and SR-B1 expression through SREBP2. Targeting SR-B1 to modulate cholesterol uptake inhibits this axis and causes ferroptosis in vitro and in vivo in Pt-R OC.

Citation Format: Yinu Wang, Andrea Calvert, Cardenas Horacio, Fukai Chen, Russell Keathley, Ji-Xin Chen, Shad Thaxton, Daniela Matei. Nanoparticle targeting in platinum-resistant ovarian cancer reveals dual axis of therapeutic vulnerability involving cholesterol uptake and cell redox balance [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A036.
Abstract A098: Microenvironment-regulated matrix Gla protein drives ovarian cancer stemness
Authors: Nieddu Valentina , Melocchi Valentina , Battistini Chiara , Franciosa Giulia , Lupia Michela , Olsen Jesper , Colombo Nicoletta , Bianchi Fabrizio , Cavallaro Ugo
Published: March 2024

The clinical evolution of ovarian cancer (OC), with peritoneal dissemination, tumor relapse and chemoresistance, seems to be accounted for by a small population of ovarian cancer stem cells (OCSC), thus making them an attractive target for more efficacious treatments. However, this could only be achieved through the detailed characterization of the molecular and functional traits of this elusive cell subpopulation. Therefore, the identification of novel OCSC-associated targets and therapeutic approaches may offer alternative treatment options. We established a new platform of patient-derived organotypic models of OC and found that Matrix Gla Protein (MGP) was upregulated in cancer cells upon contact with the peritoneal tumor microenvironment. MGP is classically known as a vitamin K-dependent calcium chelator, mainly associated with the inhibition of tissue calcification and cardiovascular disease. In addition, MGP is also aberrantly expressed in different cancer types, but the biological mechanisms that regulate its functional contribution to cancer progression is still unknown. Our transcriptomic profiling of primary OCSC versus their non-stem counterpart pointed to MGP as a potential driver of cancer stemness. Indeed, we obtained evidence that MGP promotes, and is required for, stemness-associated biological features in vitro and in animal models, including sphere formation and tumor initiation. MGP was also implicated in the regulation of the expression of several key genes involved in stemness and/or EMT. Finally, MGP was upregulated in OC patients following chemotherapy, suggesting that the protein may be involved in OCSC-driven chemoresistance. The molecular mechanisms underlying MGP-regulated OCSC pathophysiology were investigated by RNA sequencing experiments on MGP-manipulated OC cells, which unveiled genetic networks and pathways that are orchestrated by MGP to promote OCSC function. The biological role of MGP in OC provides novel insight into the biology of OCSC, thus defining new pathways involved in OC stemness and paving the way to innovative therapeutic strategies for OC eradication.

Citation Format: Valentina Nieddu, Valentina Melocchi, Chiara Battistini, Giulia Franciosa, Michela Lupia, Jesper Olsen, Nicoletta Colombo, Fabrizio Bianchi, Ugo Cavallaro. Microenvironment-regulated matrix Gla protein drives ovarian cancer stemness [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A098.
Abstract B018: Enhanced transfection efficiency with folic acid conjugated synthetic polymer nanoparticles for high grade serous ovarian cancer
Authors: Lee Chaebin , Elias Kevin
Published: March 2024

Objective High grade serous ovarian cancer (HGSOC) represents the predominant subtype of epithelial ovarian cancer. Developing targeted therapies for HGSOC presents challenges due to its distinctive characteristic of copy number variation rather than recurrent somatic mutation. In our recent study, we proposed a novel approach for treating ovarian cancer by combining a gene editing system and nanotechnology, utilizing a cationic synthetic biopolymer, poly (γ-propargyl L-glutamine) (PPLQ). While our findings demonstrated promising results, we identified the presence of a negatively charged polymer layer, required for systematic delivery in vivo, significantly reduced both transfection efficiency and therapeutic efficacy. Therefore, an innovative approach to enhance transfection efficiency is desired to achieve improved treatment outcomes. Folate receptor alpha (FRα) is highly overexpressed in various epithelial cancers, including breast, lung, and ovarian cancer. Previous studies have revealed that FRα exhibits high tumor specificity, with epithelial ovarian cancers demonstrating 10 to 100-fold higher FRα expression levels compared to kidney, lung, and breast epithelial cells. Therefore, FRα is an attractive candidate for targeted therapy for ovarian cancer. Method In this study, we conjugated folic acid (FA), which has high affinity for FRα, to PPLQ to enhance gene delivery efficiency. Polyplexes were synthesized using FA conjugated PPLQ (FA-PPLQ) with pGL3 luciferase reporter vector. The particle size and the zeta potential were analyzed by Zetasizer, and transfection efficiency was evaluated by a luminescence assay. Result Compared to the positively charged PPLQ polyplexes, +55.5 mV, the FA-PPLQ polyplexes showed highly negative surface charges of -43.8 mV. The particle size was slightly increased from 35.07 ± 0.5422 for the PPLQ polyplexes to 48.63 ± 0.4239 for the FA-PPLQ polyplexes. The luminescence assay using a pGL3 luciferase reporter vector demonstrated a 74.4% improvement in transfection efficiency with FA conjugation compared to the negatively charged polymer layer. Conclusion Through the conjugation of folic acid to a cationic biopolymer, we successfully achieved enhanced transfection efficiency compared to a negatively charged polymer layer. Notably, the FA-PPLQ polyplexes exhibited a negative surface charge, which is advantageous for in vivo delivery. The results suggest that folic acid conjugation on the surface of polyplexes has a great promise as an effective approach for targeted gene therapy in HGSOC.

Citation Format: Chaebin Lee, Kevin Elias. Enhanced transfection efficiency with folic acid conjugated synthetic polymer nanoparticles for high grade serous ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B018.
Abstract P28: Immunoproteasome inhibitors for the treatment of ALL
Authors: Kisselev Alexei F
Published: March 2024

The t(4;11)(q21;q23) chromosomal translocation that creates the MLL-AF4 fusion protein, confers a poor prognosis in infant acute lymphoblastic leukemia (ALL). This translocation also sensitizes cells to proteasome inhibitors bortezomib and carfilzomib, which are approved by the FDA for the treatment of multiple myeloma. Clinical activity of bortezomib in combination with standard chemotherapy has been documented in several clinical trials of ALL patients, and a case of a single-agent activity against relapsed leukemia driven by the MLL-AF4 translocation has been described. However, toxicities of bortezomib and carfilzomib linmit their use to treat to pediatric patients. We found that the overwhelming majority of proteasomes in this subtype of ALL are lymphoid tissue specific immunoproteasomes. Cells with MLL-AF4 translocations were sensitive to pharmacologically relevant concentrations of specific immunoproteasome inhibitors ONX-0914 and M3258. Furthermore, both compounds dramatically delayed growth of orthotopic xenograft tumors in mice, and improved responce to induction chemotherapy. Thus, immunoproteasomes are therapeutic targets in ALL and replacing bortezomib and carfilzomib with immunoproteasome inhibitors in ALL should reduce toxicities associated with inhibition of the proteasomes in non-lymphoid tissues.

Citation Format: Alexei F Kisselev. Immunoproteasome inhibitors for the treatment of ALL [abstract]. In: Proceedings of the Blood Cancer Discovery Symposium; 2024 Mar 4-6; Boston, MA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(2_Suppl):Abstract nr P28.
Rare Benign Focal Lesions of the Liver: Report of 2 Cases and Literature Review
Authors: Cmarková Kristína , Nosáková Lenka , Pindura Miroslav , Vojtko Martin , Bánovčin Peter , Miklušica Juraj
Published: March 2024

Introduction: Benign lesions of the liver are very common findings, usually randomly discovered, especially during examinations for other indications. The frequent use of imaging modalities may be responsible for the statistical increase in the incidence of these findings. Case Presentation: In this publication, we present the cases of 2 female patients with benign liver lesions, the occurrence of which is considered rare, and only a few dozen cases have been described worldwide. In both cases, clinical symptoms, diagnostic approach, and surgical treatment are presented. Conclusion: Due to increasing availability of imaging methods, the occurrence of previously considered rare benign liver lesions increases as well. In many cases, the malignant potential of these findings remains unclear. Decision-making process should include a multidisciplinary board.
Exploring Immune-Related Adverse Events: A Case of Febrile Neutropenia in a Melanoma Patient Receiving Immunotherapy
Authors: Yerolatsite Melina , Torounidou Nanteznta , Amylidi Anna-Lea , Kapoulitsa Fani , Kampletsas Eleftherios , Zarkavelis George , Mauri Davide
Published: March 2024

Introduction: The introduction of immune checkpoint inhibitors (ICIs) has opened a new chapter in cancer treatment. Nevertheless, their use may result in immune-related adverse events (irAEs) with multifactorial determinants, complex mechanisms, and varying clinical implications. In specific cancer types, like melanoma, irAEs exhibit a complex relationship with patient outcomes. Case Presentation: We present a case of febrile neutropenia following ICI therapy in a patient with metastatic melanoma, underscoring the intricate clinical landscape associated with irAEs in the context of cancer immunotherapy. More specifically, a 68-year-old man was diagnosed with metastatic malignant melanoma and administered a combination of nivolumab and ipilimumab. However, after a single dose, the patient was hospitalized due to febrile neutropenia. The patient eventually recovered, but a diagnosis of myelosuppression related to prior immunotherapy led to treatment discontinuation. Subsequently, the patient transitioned to a second-line therapy. Conclusion: This case contributes to our comprehension of rare yet potentially severe hematological irAEs and their influence on immunotherapy outcomes. Such insights will guide future diagnostic and therapeutic strategies in the field of immunotherapy.
Prespecified Homeopathic Medicines in the Prevention of Confirmed and Suspected Cases of COVID-19: A Community-Based, Double-Blind, Randomized, Placebo-Controlled Prophylaxis Trial
Authors: Dutta Abhijit , Manna Arijit , Ghosh Shubhamoy , Mundle Malay , Saha Madhabananda , Gourav Kumar , Maiti Sukhdeb , Chattopadhyay Bhargab
Published: March 2024

Introduction: Homeopathic medicines have been used for decades in the prevention and treatment of infectious diseases. However, the preventive efficacy of specific homeopathic medicines in COVID-19 is not well characterized. This study aimed to evaluate the comparative efficacy of prespecified homeopathic medicines in preventing COVID-19. Methods: A community-based, double-blind, randomized, placebo-controlled trial was conducted on 4,034 participants residing in Ward No. 27 of the Howrah Municipal Corporation in India. Participants were randomized to receive one of three prespecified homeopathic medicines [Influenzinum 30C, Arsenicum album 30C, Anas barbariae hepatis et cordis extractum 200K (Oscillococcinum®)], or placebo. The outcomes were the incidence of laboratory-confirmed and suspected cases of COVID-19 during a follow-up period of 1 month. Results: During the follow-up period, a total of 13 new laboratory-confirmed COVID-19 cases were reported in the study population. Among these, 5 cases in Influenzinum group, 2 cases in Arsenicum album group, 1 case in Oscillococcinum® group, and 5 cases in Placebo group were reported. On the other hand, number of suspected COVID-19 cases was significantly less in all the three homeopathic medicine groups compared to placebo. The least number of suspected cases reported in the Oscillococcinum® group (aOR: 0.058; 95% confidence interval [CI]: 0.029, 0.114), followed by the Arsenicum album (aOR: 0.337; 95% CI: 0.238, 0.475) and Influenzinum (aOR: 0.539; 95% CI: 0.401, 0.726) groups. Conclusion: Prespecified homeopathic medicines, particularly Oscillococcinum® and Arsenicum album 30C, may have a role in preventing COVID-19, especially in reducing the incidence of suspected or COVID-19-like respiratory illnesses. However, the result failed to demonstrate a statistically significant difference in the occurrence of confirmed cases of COVID-19 between the study groups. Further research is needed to evaluate the efficacy of these medicines in different populations and settings.
Causal Relationship between Parkinson’s Disease with Heart and Vascular Disease: A Two-Sample Mendelian Randomization Study
Authors: Chen Lize , Zhang Qiushi , Li Shiduo , Chen Haoran , Guo Jing , Zhao Zongmao , Tong Jing
Published: March 2024

Introduction: The aim of this study was to investigate the causal relationship between Parkinson’s disease (PD) and myocardial infarction (MI), atrial fibrillation and flutter (AF), and venous thromboembolism (VTE) by Mendelian randomization (MR) analysis. Methods: By using data from publicly available genome-wide association studies from databases, single nucleotide polymorphisms were screened as instrumental variables, and the MR analysis was finished by inverse-variance weighted (IVW), MR-egger, weighted median methods. Results: The primary IVW method showed a negative association between genetically predicted PD and risk of MI (OR = 0.9989; 95% CI: 0.9980–0.9998; p = 0.02). However, PD was not significantly associated with AF or VTE. Conclusion: This study suggests a negative association between PD with MI, which implies that PD has a protective effect on MI.
Laparoscopic Resection of Transverse Colon Cancer with an Anomaly of the Middle Colic Artery Originating from the Splenic Artery: A Case Report
Authors: Maeda Yoshiaki , Minagawa Nozomi , Kato Takuya , Okada Naoki , Suzuki Takuto , Ishizuka Chihiro , Fukuda Akihisa , Mori Yoichi
Published: March 2024

Introduction: We encountered a colon cancer case with a very rare anomaly of the middle colic artery (MCA) originating from the splenic artery (SA). Case Presentation: A woman was referred to our hospital for transverse colon cancer. Three-dimensional computed tomography (3D-CT) angiography showed an anomalous MCA originating from the SA rather than from the superior mesenteric artery (SMA) as is typical. Laparoscopic left hemicolectomy with D3 lymph node dissection was performed. The lymph nodes around the SMA were dissected from the caudal view, confirming the absence of a typical MCA. An anomalous SA-originating MCA was identified just below the pancreas, where it was clipped and ligated; subsequently, total mesenteric excision was achieved. Conclusion: As D3 lymph node dissection for transverse colon cancer is technically difficult, 3D-CT angiography is useful for identifying vascular anomalies preoperatively, thereby avoiding intraoperative injury. This is the first case report of laparoscopic colectomy associated with a SA-originating MCA anomaly.
Sex Discrepancies in the Population Incidence of Stroke and Hemorrhage Related to Atrial Fibrillation or Flutter
Authors: Khunte Mihir , Chen Huanwen , Colasurdo Marco , Chaturvedi Seemant , Malhotra Ajay , Gandhi Dheeraj
Published: March 2024

Introduction: Atrial fibrillation or flutter (AF) is a well-known risk factor for ischemic stroke. While female sex has been associated with higher stroke risk among AF patients, overall sex-specific real-world burdens of AF-related strokes and hemorrhages are unknown. Methods: The 2016–2020 National Inpatient Sample was queried for hospitalizations, morbidity, and mortality due to AF-related ischemic strokes and bleeds. Patient demographic information, vascular risk factors, comorbidities, and stroke characteristics were extracted using ICD-10 codes. Overall incidences were calculated using total population estimates provided by the US Census Bureau, and relative risk was calculated by comparing annual incidences between men and women. Results: 2,420,870 ischemic stroke hospitalizations were identified; 542,635 (22.4%) were associated with AF. Overall, women had similar risk of hospitalization due to AF-related ischemic strokes compared to men; however, women had a higher risk of morbidity and mortality (RR 1.13 and 1.17, respectively; both p < 0.001). In contrast, women had lower incidences of hospitalization, morbidity, and mortality due to AF-related bleeds (RR 0.82, 0.94, and 0.74, respectively; all p < 0.001). Among patients with AF-related ischemic strokes, women had lower rates of anticoagulation use, higher rates of large vessel occlusion, and higher stroke severity (all p < 0.001). These trends persisted among patients 80 years or older (all p < 0.001). Conclusion: Women in the USA have higher incidences of morbidity and mortality from AF-related ischemic strokes than men. Future studies should investigate strategies to reduce morbidity and mortality due to AF-related strokes in women.
Impact of a School-Based Intervention on Sugar-Sweetened Beverage Intake Substitution by Water in Mexican Scholars
Authors: Olvera Laura Gabriela Téllez , Martínez Lilia Castillo , Souza Bárbara da Silva Nalin de , Sichieri Rosely , Ruíz Arregui Liliana , Rodríguez Garcia Wendy D. , de la Torre Guadalupe Silvia García
Published: March 2024

Introduction: The prevalence of overweight and obesity in children has increased in recent years, associated with substituting plain water intake with sugar-sweetened beverages. The aim of the study was to evaluate the impact of a school-based intervention that aimed to replace sugar-sweetened beverages with water on Mexican scholars. Methods: We included 314 children aged 9–11 from three public schools of the State of Hidalgo, Mexico, randomized to intervention (two schools from the municipality of Apan; six classes with 146 participants) or control group (one school from the municipality of Emiliano Zapata; six classes with 168 participants) and followed for 6 months. The intervention consisted of placing drinking fountains at schools and classrooms with nutritional education lessons to increase water consumption and decrease sugar-sweetened beverages. Mixed models for repeated measures were used to assess the impact of the intervention. Results: At the end of the study, water consumption was higher (200 mL/day, p = 0.005), and flavored milk consumption was lower (94 mL/day, p = 0.044) in the intervention group compared with the control group. There was also a statistically significant reduction in energy (p = 0.016) and sugar intake (p = 0.007). Conclusions: The school-based intervention favorably modified the consumption pattern of sugar-sweetened beverages and water in Mexican students.