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Background and objectives: Inhibition of tumor angiogenesis is a promising strategy employed in the treatment of various cancer types. Its clinical effectiveness is however constrained due to the adverse side effects of antiangiogenic drugs. There is growing interest in the use of medicinal plants for the development of novel drugs with enhanced efficacy. In the present study, we have evaluated three evergreen plants namely, Alstonia scholaris, Polyalthia longifolia, and Terminalia catappa for antiangiogenic properties. Methods: The leaf extracts of the selected plants were investigated for antiproliferative effects on cervical cancer (SiHa) and Human endothelial (HUVEC) cell lines. The anti-angiogenic properties were evaluated in vitro using HUVEC tube formation and cell migration assays, and in vivo using chick chorioallantoic membrane (CAM) assay. They were further assessed for the expression of key angiogenesis-promoting genes HIF1 α, COX-2, VEGFA, and VEGFR2 using quantitative real-time PCR. Results: The three samples showed significant inhibition of the growth and differentiation of HUVEC cells, as well as the vascularization of CAM layer. Additionally, the extracts displayed a notable down-regulatory effect on the expression of angiogenesis promoter genes. Terminalia catappa demonstrated the highest efficacy in downregulating all genes. Polyalthia longifolia and Alstonia scholaris exhibited selective inhibition of HIF1 α and VEGFA genes, indicating variations in their anti-angiogenesis potential. Conclusion: The study highlighted the remarkable efficacy of Terminalia catappa in inhibiting angiogenesis and its associated genes across multiple pathways. Overall, the study, for the first time, identified the promising potential of three natural candidates for arresting angiogenesis.

Sang-Soo Kim,1,2 Manish Moghe,1 Antonina Rait,1 Kathryn Donaldson,1 Joe B Harford,2 Esther H Chang1 1Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA; 2SynerGene Therapeutics, Inc, Potomac, MD, USACorrespondence: Esther H Chang, Lombardi Comprehensive Cancer Center, Georgetown University, 3970 Reservoir Road N.W., Research Building E420, Washington, DC, 20057, USA, Email change@georgetown.eduPurpose: Atypical teratoid rhabdoid tumor (ATRT) is a deadly, fast-growing form of pediatric brain cancer with poor prognosis. Most ATRTs are associated with inactivation of SMARCB1, a subunit of the chromatin remodeling complex, which is involved in developmental processes. The recent identification of SMARCB1 as a tumor suppressor gene suggests that restoration of SMARCB1 could be an effective therapeutic approach.Methods: We tested SMARCB1 gene therapy in SMARCB1-deficient rhabdoid tumor cells using a novel tumor-targeted nanomedicine (termed scL-SMARCB1) to deliver wild-type SMARCB1. Our nanomedicine is a systemically administered immuno-lipid nanoparticle that can actively cross the blood-brain barrier via transferrin receptor-mediated transcytosis and selectively target tumor cells via transferrin receptor-mediated endocytosis. We studied the antitumor activity of the scL-SMARCB1 nanocomplex either as a single agent or in combination with traditional treatment modalities in preclinical models of SMARCB1-deficient ATRT.Results: Restoration of SMARCB1 expression by the scL-SMARCB1 nanocomplex blocked proliferation, and induced senescence and apoptosis in ATRT cells. Systemic administration of the scL-SMARCB1 nanocomplex demonstrated antitumor efficacy as monotherapy in mice bearing ATRT xenografts, where the expression of exogenous SMARCB1 modulates MYC-target genes. scL-SMARCB1 demonstrated even greater antitumor efficacy when combined with either cisplatin-based chemotherapy or radiation therapy, resulting in significantly improved survival of ATRT-bearing mice.Conclusion: Collectively, our data suggest that restoring SMARCB1 function via the scL-SMARCB1 nanocomplex may lead to therapeutic benefits in ATRT patients when combined with traditional chemoradiation therapies. Keywords: lipid nanoparticle, nanodelivery, SMARCB1, gene therapy, atypical teratoid rhabdoid tumor

Plant responses to environmental change are mediated via changes in cellular metabolomes. However,

BackgroundCOVID-19 is associated with higher morbidity and mortality in patients with chronic liver diseases (CLDs). However, our understanding of the long-term outcomes of COVID-19 in patients with CLD is limited.MethodsWe conducted a multicenter, observational cohort study of adult patients with CLD who were diagnosed with COVID-19 before May 30, 2020, to determine long-term clinical outcomes. We used a control group of patients with CLD confirmed negative for COVID-19.ResultsWe followed 666 patients with CLD (median age 58 years, 52.8% male) for a median of 384 (interquartile range: 31-462) days. The long-term mortality was 8.1%; with 3.6% experiencing delayed COVID-19-related mortality. Compared to a propensity-matched control group of patients with CLD without COVID-19 (n=1332), patients with CLD with COVID-19 had worse long-term survival [p

Over the last 25 years, biology has entered the genomic era and is becoming a science of 'big data'. Most interpretations of genomic analyses rely on accurate functional annotations of the proteins encoded by more than 500 000 genomes sequenced to date. By different estimates, only half the predicted sequenced proteins carry an accurate functional annotation, and this percentage varies drastically between different organismal lineages. Such a large gap in knowledge hampers all aspects of biological enterprise and, thereby, is standing in the way of genomic biology reaching its full potential. A brainstorming meeting to address this issue funded by the National Science Foundation was held during 3-4 February 2022. Bringing together data scientists, biocurators, computational biologists and experimentalists within the same venue allowed for a comprehensive assessment of the current state of functional annotations of protein families. Further, major issues that were obstructing the field were identified and discussed, which ultimately allowed for the proposal of solutions on how to move forward.

Neuroinflammation is one of the hallmarks contributing to Parkinson's Disease (PD) pathology, where microglial activation occurs as one of the earliest events, triggered by extracellular alpha synuclein (aSYN) binding to the CD36 receptor. Here, CD36-binding nanoparticles (NPs) containing synthetic tartaric acid-based amphiphilic polymers (AMs) were rationally designed to inhibit this aSYN-CD36 binding. In silico docking revealed that four AMs with varying alkyl side chain lengths presented differential levels of CD36 binding affinity and that an optimal alkyl chain length would promote the strongest inhibitory activity towards aSYN-CD36 interactions. In vitro competitive binding assays indicated that the inhibitory activity of AM-based NPs plateaued at intermediate side chain lengths of 12- and 18-carbons, supporting the in silico docking predictions. These 12- and 18-carbon length AM NPs also had significantly stronger effects on reducing aSYN internalization and inhibiting the production of the proinflammatory molecules TNF-α and nitric oxide from aSYN-challenged microglia. All four NPs modulated the gene expression of aSYN-challenged microglia, downregulating the expression of the proinflammatory genes TNF, IL-6, and IL-1β, and upregulating the expression of the anti-inflammatory genes TGF-β and Arg1. Overall, this work represents a novel polymeric nanotechnology platform that can be used to modulate aSYN-induced microglial activation in PD.

Kathleen F Pirollo,1 Manish Moghe,1 Miaoyin Guan,1 Antonina S Rait,1 Aibing Wang,1 Sang-Soo Kim,1,2 Esther H Chang,1 Joe B Harford2 1Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, 20057, USA; 2SynerGene Therapeutics, Inc., Potomac, MD, 20854, USACorrespondence: Esther H Chang, Lombardi Comprehensive Cancer Center, Georgetown University, 3970 Reservoir Road N.W., Research Building E420, Washington, DC, 20057, USA, Tel +1 202 687 8418, Email change@georgetown.eduIntroduction: Organophosphates are among the deadliest of known chemicals based on their ability to inactivate acetylcholinesterase in neuromuscular junctions and synapses of the central and peripheral nervous systems. The consequent accumulation of acetylcholine can produce severe acute toxicities and death. Oxime antidotes act by reactivating acetylcholinesterase with the only such reactivator approved for use in the United States being 2-pyridine aldoxime methyl chloride (a.k.a., pralidoxime or 2-PAM). However, this compound does not cross the blood–brain barrier readily and so is limited in its ability to reactivate acetylcholinesterase in the brain.Methods: We have developed a novel formulation of 2-PAM by encapsulating it within a nanocomplex designed to cross the blood–brain barrier via transferrin receptor-mediated transcytosis. This nanocomplex (termed scL-2PAM) has been subjected to head-to-head comparisons with unencapsulated 2-PAM in mice exposed to paraoxon, an organophosphate with anticholinesterase activity.Results and Discussion: In mice exposed to a sublethal dose of paraoxon, scL-2PAM reduced the extent and duration of cholinergic symptoms more effectively than did unencapsulated 2-PAM. The scL-2PAM formulation was also more effective than unencapsulated 2-PAM in rescuing mice from death after exposure to otherwise-lethal levels of paraoxon. Improved survival rates in paraoxon-exposed mice were accompanied by a higher degree of reactivation of brain acetylcholinesterase.Conclusion: Our data indicate that scL-2PAM is superior to the currently used form of 2-PAM in terms of both mitigating paraoxon toxicity in mice and reactivating acetylcholinesterase in their brains.Keywords: lipid nanoparticle, nanodelivery, organophosphate, paraoxon, blood–brain barrier, transcytosis

Background and aimsHCC remains a major unmet clinical need. Although activating catenin beta-1 (CTNNB1) mutations are observed in prominent subsets of HCC cases, these by themselves are insufficient for hepatocarcinogenesis. Coexpression of mutant CTNNB1 with clinically relevant co-occurrence has yielded HCCs. Here, we identify cooperation between β-catenin and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling in HCC.Approach and resultsPublic HCC data sets were assessed for concomitant presence of CTNNB1 mutations and either mutations in nuclear factor erythroid-2-related factor-2 (NFE2L2) or Kelch like-ECH-associated protein 1 (KEAP1), or Nrf2 activation by gene signature. HCC development in mice and similarity to human HCC subsets was assessed following coexpression of T41A-CTNNB1 with either wild-type (WT)-, G31A-, or T80K-NFE2L2. Based on mammalian target of rapamycin complex 1 activation in CTNNB1-mutated HCCs, response of preclinical HCC to mammalian target of rapamycin (mTOR) inhibitor was investigated. Overall, 9% of HCC cases showed concomitant CTNNB1 mutations and Nrf2 activation, subsets of which were attributable to mutations in NFE2L2/KEAP1. Coexpression of mutated CTNNB1 with mutant NFE2L2, but not WT-NFE2L2, led to HCC development and mortality by 12-14 weeks. These HCCs were positive for β-catenin targets, like glutamine synthetase and cyclin-D1, and Nrf2 targets, like NAD(P)H quinone dehydrogenase 1 and peroxiredoxin 1. RNA-sequencing and pathway analysis showed high concordance of preclinical HCC to human HCC subset showing activation of unique (iron homeostasis and glioblastoma multiforme signaling) and expected (glutamine metabolism) pathways. NFE2L2-CTNNB1 HCC mice were treated with mTOR inhibitor everolimus (5-mg/kg diet ad libitum), which led to >50% decrease in tumor burden.ConclusionsCoactivation of β-catenin and Nrf2 is evident in 9% of all human HCCs. Coexpression of mutant NFE2L2 and mutant CTNNB1 led to clinically relevant HCC development in mice, which responded to mTOR inhibitors. Thus, this model has both biological and therapeutic implications.

Evolutionary dynamics at the population level play a central role in creating the diversity of life on our planet. In this study, we sought to understand the origins of such population-level variation in mating systems and defensive acylsugar chemistry in Solanum habrochaites-a wild tomato species found in diverse Andean habitats in Ecuador and Peru. Using Restriction-site-Associated-DNA-Sequencing (RAD-seq) of 50 S. habrochaites accessions, we identified eight population clusters generated via isolation and hybridization dynamics of 4-6 ancestral populations. Detailed characterization of mating systems of these clusters revealed emergence of multiple self-compatible (SC) groups from progenitor self-incompatible populations in the northern part of the species range. Emergence of these SC groups was also associated with fixation of deleterious alleles inactivating acylsugar acetylation. The Amotape-Huancabamba Zone-a geographical landmark in the Andes with high endemism and isolated microhabitats-was identified as a major driver of differentiation in the northern species range, whereas large geographical distances contributed to population structure and evolution of a novel SC group in the central and southern parts of the range, where the species was also inferred to have originated. Findings presented here highlight the role of the diverse ecogeography of Peru and Ecuador in generating population differentiation, and enhance our understanding of the microevolutionary processes that create biological diversity.

Background & aimsChronic liver disease (CLD) represents a major global health burden. We undertook this study to identify the factors associated with adverse outcomes in patients with CLD who acquire the novel coronavirus-2019 (COVID-19).MethodsWe conducted a multi-center, observational cohort study across 21 institutions in the United States (US) of adult patients with CLD and laboratory-confirmed diagnosis of COVID-19 between March 1, 2020 and May 30, 2020. We performed survival analysis to identify independent predictors of all-cause mortality and COVID-19 related mortality, and multivariate logistic regression to determine the risk of severe COVID-19 in patients with CLD.ResultsOf the 978 patients in our cohort, 867 patients (mean age 56.9 ± 14.5 years, 55% male) met inclusion criteria. The overall all-cause mortality was 14.0% (n = 121), and 61.7% (n = 535) had severe COVID-19. Patients presenting with diarrhea or nausea/vomiting were more likely to have severe COVID-19. The liver-specific factors associated with independent risk of higher overall mortality were alcohol-related liver disease (ALD) (hazard ratio [HR] 2.42, 95% confidence interval [CI] 1.29-4.55), decompensated cirrhosis (HR 2.91 [1.70-5.00]) and hepatocellular carcinoma (HCC) (HR 3.31 [1.53-7.16]). Other factors were increasing age, diabetes, hypertension, chronic obstructive pulmonary disease and current smoker. Hispanic ethnicity (odds ratio [OR] 2.33 [1.47-3.70]) and decompensated cirrhosis (OR 2.50 [1.20-5.21]) were independently associated with risk for severe COVID-19.ConclusionsThe risk factors which predict higher overall mortality among patients with CLD and COVID-19 are ALD, decompensated cirrhosis and HCC. Hispanic ethnicity and decompensated cirrhosis are associated with severe COVID-19. Our results will enable risk stratification and personalization of the management of patients with CLD and COVID-19. Clinicaltrials.gov number NCT04439084.

PurposeThe need for high-fidelity modeling of radiation detectors to perform reliable detector performance optimization using Monte Carlo simulations requires to accurately simulate the light transport in the scintillator and the light collection by the photodetector. In this work, we implement our well-validated crystal reflectance model computed from three-dimensional (3D) crystal surface measurement in a standalone open-source application to allow researchers to generate fully customized crystal reflectance look-up-tables (LUTs) to be used in optical Monte Carlo simulation.MethodsThe LUTDavisModel application can be installed in a few minutes on Windows, macOS, and Linux, using 26 MB of space. MATLAB Runtime is required and is automatically installed with the application. The core algorithm has been previously validated experimentally and implemented in GATE v8.0. The standalone is divided into five panels, each of which performing a specific task: generate LUTs from a combination of surface type, scintillator, and coupling medium available in the database (such as LSO or BGO) or custom; compute LUTs with the reflectors available and custom coupling thickness; create a mixture of coupling media to account for possible defects in the optical coupling; plot precomputed LUTs for visual comparison. Tooltips and errors/warnings facilitate the navigation. The reported computational times were obtained with an Intel Core i7 MacBook Pro.ResultsLUTs can be generated with computational time ranging from a few minutes to several hours depending on the selected surface, sampling, and computational power. A longer time is needed when using rough surfaces and thick coupling media (hundreds of μ m ) due to increased photon tracking.ConclusionsWe developed a user-friendly standalone application to generate LUTs that can be used inside GATE Monte Carlo simulations. It can be easily downloaded, installed, and used. Future optimizations will expand the database, decrease the computational time through greater parallelization, and include the generation of LUTs to study Cerenkov photons transport.

Checkpoint immunotherapy has made great strides in the treatment of solid tumors, but many patients do not respond to immune checkpoint inhibitors. Identification of tumor‐infiltrating cytotoxic T cells (CTLs) has the potential to stratify patients and monitor immunotherapy responses. In this study, the design of cluster of differentiation (CD8+) T cell‐targeted nanoprobes that emit shortwave infrared (SWIR) light in the second tissue‐transparent window for noninvasive, real‐time imaging of CTLs in murine models of breast cancer is presented. SWIR‐emitting rare‐earth nanoparticles encapsulated in human serum albumin are conjugated with anti‐CD8α to target CTLs with high specificity. CTL targeting is validated in vitro through binding of nanoprobes to primary mouse CTLs. The potential for the use of SWIR fluorescence intensity to determine CTL presence is validated in two syngeneic mammary fat pad tumor models, EMT6 and 4T1, which differ in immune infiltration. SWIR imaging using CD8‐targeted nanoprobes successfully identifies the presence of CTLs in the more immunogenic EMT6 model, while imaging confirms the lack of substantial immune infiltration in the nonimmunogenic 4T1 model. In this work, the opportunity for SWIR imaging using CD8‐targeted nanoprobes to assess CTL infiltration in tumors for the stratification and monitoring of responders to checkpoint immunotherapy is highlighted.