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The SpongeScapes project aims to accelerate understanding Nature-based Solutions (NBS) that enhance the sponge functioning of soil, groundwater, and surface water ecosystems, improving landscape resilience against hydrometeorological extremes across diverse climates. One NBS being explored within SpongeScapes is the adoption of Regenerative Agricultural Practices (RAPs) such as reduced tillage and cover cropping. These practices can improve soil health and potentially increase water retention capacity, compared to conventional agriculture practices that degrade soil structure and porosity. However, quantifying RAP benefits is challenging due to the delayed soil response to management changes. This report discusses an exploratory approach of back-analysing long-term soil moisture datasets to assess the impacts of RAPs on soil water retention capacity. By inferring changes in saturated water content (proxy for porosity), findings from trend analyses on UK case studies provide insights into the potential of RAPs as an NBS for enhancing landscape water resilience through improved soil sponge functioning.

We report the stabilization of ferrofluid in oleic acid synthesized by ultrasonication of nanosized Fe3O4particle and grafts of poly-dimethylsiloxane (PDMS) with acrylic acid and methacrylic acid. The nanosized polymers were prepared by microwave-assisted copolymerizaion of PDMS chain with 0.029 mol of acrylic acid and 0.023 mol of methacrylic acid. The stability of the prepared materials was characterized by Fourier Transform Infrared (FTIR) spectroscopy, thermal analysis (TG-DTA-DTA),1H NMR and transmission electron microscope (TEM). The result indicate that the ferrofluid have nanometric size with high thermal stability. A comparison of both the nanomagnetic fluids has been discussed. The structure of the fluids has been proposed on the basis of the experimental results. [ABSTRACT FROM PUBLISHER]

The purpose of this study was to compare the total epidural dose of 3 commonly used labor epidural modalities. After local institutional review board approval, 195 laboring parturients received an epidural catheter for labor analgesia. All patients received an initial bolus of 0.1% ropivacaine (10 mL) and fentanyl (100 mug). Maintenance of labor analgesia consisted of ropivacaine 0.1% with fentanyl 2 mug/mL. Patients were then randomly assigned into 3 groups: Group 1 (continuous epidural infusion [CEI]), continuous infusion at 10 mL/h; group 2 (CEI + patient-controlled epidural analgesia [PCEA]), CEI at 5 mL/h with a demand dose of 5 mL allowed every 20 minutes with a 20 mL/h maximum dose; group 3 (PCEA), demand doses only of 5 mL every 15 minutes with a 20 mL/h maximum dose. Measured variables included total epidural dose, total bolus requests and boluses delivered, number of staff interventions, pain Visual Analog Scale (VAS; 0-100), modified Bromage scores, stage I and II labor duration, delivery outcome, and maternal satisfaction after delivery. No differences were noted with respect to pain VAS, modified Bromage scores, stage I and II labor duration, number of staff interventions, delivery outcome, and maternal satisfaction score. Total infusion dose was lower in demand dose only PCEA compared with CEI and CEI + PCEA groups (P = < .01). Demand dose-only PCEA results in less total epidural dose compared with CEI and CEI + PCEA without affecting labor duration, motor block, pain VAS, maternal and neonatal outcomes, and maternal satisfaction. PERSPECTIVE: This article compares 3 commonly used labor epidural delivery modalities (traditional continuous epidural infusion, patient-controlled epidural analgesia with a background infusion, and demand dose-only patient-controlled epidural analgesia). Benefits in epidural dose reduction with demand dose only PCEA does not translate into improved maternal and neonatal outcome. [ABSTRACT FROM AUTHOR]

Lung cancer is a leading global cause of mortality, with non-small cell lung cancer (NSCLC) accounting for a significant portion of cases. Immune checkpoint inhibitors (ICIs) have transformed NSCLC treatment; however, many patients remain unresponsive. ICI resistance in NSCLC and its association with cellular plasticity, epithelial-mesenchymal transition (EMT), enhanced adaptability, invasiveness, and resistance is largely influenced by epigenetic changes, signaling pathways, tumor microenvironment, and associated immune cells, fibroblasts, and cytokines. Immunosuppressive cells, including M2 tumor-associated macrophages, myeloid-derived suppressor cells, and regulatory T cells, contribute to resistance by suppressing the immune response. This cellular plasticity is influenced when B cells, natural killer cells, and T cells are exhausted or inhibited by components of the tumor microenvironment. Conversely, diverse T cell, NK cell, and B cell subsets hold potential as predictive response markers particularly cytotoxic CD8 + T cells, effector memory T cells, activated T cells, tumor infiltrated NK cells, tertiary lymphoid structures, etc. influence treatment response. Identifying specific gene expressions and immunophenotypes within T cells may offer insights into early clinical responses to immunotherapy. ICI resistance in NSCLC is a multifaceted process shaped by tumor plasticity, the complex tumor microenvironment, and dynamic immune cell changes. Comprehensive analysis of these factors may lead to the identification of novel biomarkers and combination therapies to enhance ICI efficacy in NSCLC treatment., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The creatine (Cr) biosynthesis pathway buffers ATP in metabolically active tissues. We investigated whether sex of fetus and day of gestation influence Cr in endometrial and conceptus tissues from gilts on Days 60 and Day 90 (n = 6 gilts/day) of gestation. Uterine and conceptus tissues associated with one male and one female fetus from each gilt were analyzed for creatine, mRNAs, and proteins for Cr biosynthesis. Total Cr decreased in amniotic fluid but increased in allantoic fluid between Days 60 and 90 of gestation for male (P < 0.05), but not for female fetuses (P > 0.05). Endometrial expression of CKM, CKMT1, and SLC6A8 mRNAs increased (P < 0.05) between Days 60 and 90 only for female fetuses. On Day 60, expression of CKB and CKMT1 mRNAs was greater (P < 0.05) for placentae of female than male fetuses. Livers of male fetuses had greater expression of AGAT and CKB than for females on Day 60, while kidneys of female fetuses had greater expression of GAMT than male fetuses on Day 90 (P < 0.05). Localization of GAMT, CKB, CKMT1 and SLC6A8 proteins to uterine and chorionic epithelium was not influenced by gestational age or fetal sex. AGAT localized to fetal kidneys and appeared greater on Day 90 than Day 60 in both sexes. Thus, expression of the creatine-creatine kinase-phosphocreatine (Cr-CK-PCr) system at the uterine-conceptus interface is affected by gestational age and fetal sex to influence energy homeostasis in pigs., (© The Author(s) 2025. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Spinocerebellar ataxias (SCA) are a diverse group of neurodegenerative disorders with autosomal dominant inheritance, primarily affecting the cerebellum and its connections. Diagnosis typically involves genetic testing, but in resource-limited settings, clinical and neuroimaging assessments become critical. This case report highlights the role of nongenetic methods in diagnosing SCA and outlines management strategies in such settings., Case Presentation: A 41-year-old male presented with a 2-year history of progressive gait imbalance, headache, and abnormal speech. He had a family history of similar symptoms in two siblings, but no significant past medical history. Clinical examination revealed scanning speech, dysmetria, and a broad-based gait. Clinical and neuroimaging findings, including cerebellar atrophy, led to a diagnosis of SCA in the absence of genetic testing. Patient management with speech, occupational, and physical therapies, showed gradual improvement., Discussion: SCA, characterized by cerebellar atrophy and a range of clinical symptoms, is typically diagnosed through genetic testing, but clinical and imaging assessments are crucial when genetic resources are limited. This case illustrates that a comprehensive clinical evaluation, including neuroimaging, can support the diagnosis of SCA even without genetic testing. Strategic management emphasizing symptomatic relief and functional improvement through a multidisciplinary approach, including regular follow-up and personalized therapy, are crucial, as evidenced by the timely improvement observed in our case., Conclusion: In resource-limited settings, a comprehensive clinical and neuroimaging assessment is essential for diagnosing spinocerebellar ataxia when genetic testing is not feasible. Effective management through multidisciplinary therapies can improve patient outcomes, underscoring the need for innovative strategies to enhance diagnostic and treatment capabilities in such environments., Competing Interests: The authors declare no conflict of interest.Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

In pigs, the majority of embryonic mortality occurs when free-floating conceptuses (embryos/fetuses and associated placental membranes) elongate, and the uterine-placental interface undergoes folding and develops areolae. Both periods involve proliferation, migration, and changes in morphology of cells that require adenosine triphosphate (ATP). We hypothesize that insufficient ATP in conceptus and uterine tissues contributes to conceptus loss in pigs. Creatine is stored in cells as phosphocreatine for ATP regeneration through the creatine-creatine kinase- phosphocreatine pathway. However, the expression of components of this pathway in pigs has not been examined throughout gestation. Results of qPCR analyses indicated increases in AGAT, GAMT, CKM, CKB, and SLC6A8 mRNAs in elongating porcine conceptuses, and immunofluorescence microscopy localized guanidinoacetate N-methyltransferase, creatine kinase M, and creatine kinase B proteins to the trophectoderm of elongating conceptuses, to the columnar chorionic epithelial cells at the bottom of chorioallantoic troughs, and to endometrial luminal epithelium at the tops of the endometrial ridges of uterine-placental folds on Days 40, 60, and 90 of gestation. Guanidinoacetate N-methyltransferase protein is expressed in endometrial luminal epithelium at the uterine-placental interface, but immunostaining is more intense in luminal epithelium at the bottoms of the endometrial ridges. Results of this study indicate that key elements of the pathway for creatine metabolism are expressed in cells of the conceptus, placenta, and uterus for potential production of ATP during two timepoints in pregnancy with a high demand for energy; elongation of the conceptus for implantation and development of uterine-placental folding during placentation., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Totally extraperitoneal (TEP) and transabdominal preperitoneal (TAPP) repair are the principal techniques in laparoscopic hernia repair. Seroma formation and pain are frequent complications of moderate-large size laparoscopic direct inguinal hernia mesh repair. This study was conducted to evaluate the feasibility of defect closure in moderate-large direct inguinal hernias and its effect on various outcomes., Method: This is a prospective cohort study from September 2020 to August 2021, where a total of 88 patients with uncomplicated direct inguinal hernia (M3 or more) were enrolled in the study and divided into two equal groups of TEP defect closure and non-closure, and various outcome measures were noted., Results: The majority of patients were male (94.31%), with a mean age range of 18-85 years, and had right-sided inguinal hernia (46.5%). Seroma formation at 10th POD in the defect closure and non-closure were 24% and 33% ( p value: 0.225), which reduced to 11% and 18%, respectively, at 1 month ( p value: 1.000). All seromas resolved within 6 months. Pain in VAS at 10th POD in the defect closure and non-closure were 1.55±0.571 and 1.38±0.527, respectively ( p value: 0.121), which gradually decreased to 1.20±0.524 and 1.16±0.420 at a 6-month interval ( p value: 0.689). The mean operative time in the bilateral and unilateral defect closure groups was 72.3±4.1 and 56.5±4.3 min, respectively, whereas that in the bilateral and unilateral defect non-closure groups was 62.3±3.7 and 45.7±3.6 min, respectively., Conclusion: The defect closure was found to have higher pain and less seroma formation at various intervals of time following TEP for moderate-large direct inguinal hernia. Although these findings were statistically insignificant, they may be clinically significant, and further studies with a larger sample size are suggested., Competing Interests: The authors declare no conflicts of interest.Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Cytotrophoblast (CTB) of the early gestation human placenta are bipotent progenitor epithelial cells, which can differentiate into invasive extravillous trophoblast (EVT) and multinucleated syncytiotrophoblast (STB). Trophoblast stem cells (TSC), derived from early first trimester placentae, have also been shown to be bipotential. In this study, we set out to probe the transcriptional diversity of first trimester CTB and compare TSC to various subgroups of CTB. We performed single-cell RNA sequencing on six normal placentae, four from early (6-8 weeks) and two from late (12-14 weeks) first trimester, of which two of the early first trimester cases were separated into basal (maternal) and chorionic (fetal) fractions prior to sequencing. We also sequenced three TSC lines, derived from 6-8 week placentae, to evaluate similarities and differences between primary CTB and TSC. CTB clusters displayed notable distinctions based on gestational age, with early first trimester placentae showing enrichment for specific CTB subtypes, further influenced by origin from the basal or chorionic plate. Differential expression analysis of CTB from basal versus chorionic plate highlighted pathways associated with proliferation, unfolded protein response, and oxidative phosphorylation. We identified trophoblast states representing initial progenitor CTB, precursor STB, precursor and mature EVT, and multiple CTB subtypes. CTB progenitors were enriched in early first trimester placentae, with basal plate cells biased toward EVT, and chorionic plate cells toward STB, precursors. Clustering and trajectory inference analysis indicated that TSC were most like EVT precursor cells, with only a small percentage of TSC on the pre-STB differentiation trajectory. This was confirmed by flow cytometric analysis of 6 different TSC lines, which showed uniform expression of proximal column markers ITGA2 and ITGA5. Additionally, we found that ITGA5 + CTB could be plated in 2D, forming only EVT upon spontaneous differentiation, but failed to form self-renewing organoids; conversely, ITGA5-CTB could not be plated in 2D, but readily formed organoids. Our findings suggest that distinct CTB states exist in different regions of the placenta as early as six weeks gestation and that current TSC lines most closely resemble ITGA5 + CTB, biased toward the EVT lineage., Competing Interests: Declaration of interests Authors declare that they have no competing interests.

Lactate, an abundant molecule in fetal fluids and blood of mammalian species, is often overlooked as a metabolic waste product generated during pregnancy. Most of the glucose and fructose consumed by ovine conceptuses is converted to lactate, but proteins involved in lactate metabolism and transport have not been investigated. This study characterized total lactate produced by ovine conceptuses throughout gestation, as well as expression of mRNAs and proteins involved in lactate metabolism. Lactate increased in abundance in the uterine lumen during the preimplantation period and was more abundant than pyruvate. The abundance of lactate in allantoic and amniotic fluids increased with advancing days of gestation and most abundant on Day 125 of pregnancy (P < 0.05). Lactate dehydrogenase subunits A (converts pyruvate to lactate) and B (converts lactate to pyruvate) were expressed by conceptuses throughout gestation. Lactate is transported via monocarboxylic acid transporters SLC16A1 and SLC16A3, both of which were expressed by the conceptus throughout gestation. Additionally, the interplacentomal chorioallantois from Day 126 expressed SLC16A1 and SLC16A3 and transported lactate across the tissue. Hydrocarboxylic acid receptor 1 (HCAR1), a receptor for lactate, was localized to the uterine luminal and superficial glandular epithelia of pregnant ewes throughout gestation and conceptus trophectoderm during the peri-implantation period of gestation. These results provide novel insights into the spatiotemporal profiles of enzymes, transporters, and receptor for lactate by ovine conceptuses throughout pregnancy., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Fructose, the most abundant hexose sugar in fetal fluids and the blood of sheep and other ungulates and cetaceans, is synthesized from glucose via the polyol pathway in trophectoderm and chorion. However, the cell-specific and temporal expression of enzymes for the synthesis and metabolism of fructose in sheep conceptuses (embryo and placental membranes) and placentomes has not been characterized. This study characterized key enzymes involved in fructose synthesis and metabolism by ovine conceptuses throughout pregnancy. Day 17 conceptuses expressed mRNAs for the polyol pathway (SORD and AKR1B1) and glucose and fructose metabolism (HK1, HK2, G6PD, OGT, and FBP), but not those required for gluconeogenesis (G6Pase or PCK). Ovine placentomes also expressed mRNAs for SORD, AKR1B1, HK1, and OGT. Fructose can be metabolized via the ketohexokinase (KHK) pathway, and isoforms, KHK-A and KHK-C, were expressed in ovine conceptuses from Day 16 of pregnancy and placentomes during pregnancy in a cell-specific manner. The KHK-A protein was more abundant in the trophectoderm and cotyledons of placentomes, while KHK-C protein was more abundant in the endoderm of Day 16 conceptuses and the chorionic epithelium in placentomes. Expression of KHK mRNAs in placentomes was greatest at Day 30 of pregnancy (P < 0.05), but not different among days later in gestation. These results provide novel insights into the synthesis and metabolism of fructose via the uninhibited KHK pathway in ovine conceptuses to generate ATP via the tricarboxylic cycle, as well as substrates for the pentose cycle, hexosamine biosynthesis pathway, and one-carbon metabolism required for conceptus development throughout pregnancy., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Chemoresistance contributes to the majority of deaths in women with ovarian cancer (OC). Altered DNA repair and metabolic signaling is implicated in mediating therapeutic resistance. DNA damage checkpoint kinase 1 (CHK1) integrates cell cycle and DNA repair in replicating cells, and its inhibition causes replication stress, repair deficiency and cell cycle dysregulation. We observed elevated Poly-ADP-ribosylation (PAR) of proteins (PARylation) and subsequent decrease in cellular NAD + levels in OC cells treated with the CHK1 inhibitor prexasertib, indicating activation of NAD + dependent DNA repair enzymes poly-ADP-ribose polymerases (PARP1/2). While multiple PARP inhibitors are in clinical use in treating OC, tumor resistance to these drugs is highly imminent. We reasoned that inhibition of dePARylation by targeting Poly (ADP-ribose) glycohydrolase (PARG) would disrupt metabolic and DNA repair crosstalk to overcome chemoresistance. Although PARG inhibition (PARGi) trapped PARylation of the proteins and activated CHK1, it did not cause any significant OC cell death. However, OC cells deficient in CHK1 were hypersensitive to PARGi, suggesting a role for metabolic and DNA repair crosstalk in protection of OC cells. Correspondingly, OC cells treated with a combination of CHK1 and PARG inhibitors exhibited excessive replication stress-mediated DNA lesions, cell cycle dysregulation, and mitotic catastrophe compared to individual drugs. Interestingly, increased PARylation observed in combination treatment resulted in depletion of NAD + levels. These decreased NAD + levels were also paralleled with reduced aldehyde dehydrogenase (ALDH) activity, which requires NAD + to maintain cancer stem cells. Furthermore, prexasertib and PARGi combinations exhibited synergistic cell death in OC cells, including an isogenic chemoresistant cell line and 3D organoid models of primary patient-derived OC cell lines. Collectively, our data highlight a novel crosstalk between metabolism and DNA repair involving replication stress and NAD + -dependent PARylation, and suggest a novel combination therapy of CHK1 and PARG inhibitors to overcome chemoresistance in OC., (© 2024. The Author(s).)

Introduction: Traumatic brain injury (TBI), ranging from minor impacts to severe cases, affects temporal and frontal brain areas, contributing to mortality and disability worldwide. The Glasgow Coma Scale (GCS) evaluates consciousness levels, aiding in prioritizing emergency care, while the Disability Rating Score (DRS) assesses overall function, particularly in severe cases, with greater sensitivity than GCS for clinical changes in TBI patients., Objectives: To correlate various factors with each other in patients presented with severe TBIs., Materials and Methods: The retrospective study analyzed data from patients with severe TBIs admitted to the hospital from February 2023 to April 2024. Patients' demographic and clinical data, including GCS and DRS scores, were collected. Statistical analysis, including logistic regression, assessed mortality predictors., Results: The study revealed significant correlations (p<0.05) between age and marital status (p=0.002) and surgery (p=0.003). Surgery also correlated significantly with the mechanism of injury (p<0.001). Furthermore, a negative correlation was found between GCS after 24 hours and change in GCS (p<0.001), while a positive correlation existed between DRS after 24 hours and DRS on the 14th day (p<0.001). These findings highlight the complex interplay between demographic factors, medical interventions, and clinical outcomes in TBI patients., Conclusion: The study found that older individuals, particularly those involved in road traffic accidents, had poorer recovery outcomes and higher rates of surgery, with a strong correlation between changes in GCS and DRS scores., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Sah et al.)

Introduction: Cosmesis is the primary concern for the patient undergoing facial surgery and there are numbers of well proven materials that are available such as adhesive tapes, subcuticular suture, skin adhesive or glue to achieve better cosmesis. The objective of our study was to assess the surgical outcome of sutureless skin closures using Octyl-2-cyanoacrylate (Dermabond™) versus Steri-Strip™., Method: The present prospective study was conducted in 20 patients. Patients were divided into two groups. After subcutaneous closure of wounds, either Dermabond™ or Steri-Strip™ was placed. The patients were assessed for wound complication (erythema, tenderness, dehiscence or any discharge), scar hypertrophy and cosmetic appearance also time consumed in surgical skin closure was evaluated. Wound assessment, scar hypertrophy and cosmetic appearance were assessed by using Chi-square test. Time closure was assessed by using Mann-whitney U test., Result: Twenty patients belonging to all age group were included in study. Ten patients undergone closure with Dermabond™ and ten with Steri-Strips™. Assessment of wound complications, cosmetic appearance and scar hypertrophy was done. There was no significant difference found between both the groups, but 2 patients had fair cosmetic outcomes at one month and 1 patient had fair scar hypertrophy at 6 month. However, excellent cosmetic outcome in terms of scar hypertrophy at 6 month was significantly more among group II., Conclusion: Octyl-2-cyanoacrylate (Dermabond™) and Steri-Strip™ provide similar outcomes in terms of wound complications. Cosmetic outcomes in terms of scar hypertrophy with steri-strip wound closure seem to be better and more economical., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 National Journal of Maxillofacial Surgery.)

Rett syndrome is an X-linked neurodevelopmental disorder caused by mutation of Mecp2 gene and primarily affects females. Glial cell dysfunction has been implicated in in Rett syndrome (RTT) both in patients and in mouse models of this disorder and can affect synaptogenesis, glial metabolism and inflammation. Here we assessed whether treatment of adult (5-6 months old) symptomatic Mecp2-heterozygous female mice with N-acetyl cysteine conjugated to dendrimer (D-NAC), which is known to target glia and modulate inflammation and oxidative injury, results in improved behavioral phenotype, sleep and glial inflammatory profile. We show that unbiased global metabolomic analysis of the hippocampus and striatum in adult Mecp2-heterozygous mice demonstrates significant differences in lipid metabolism associated with neuroinflammation, providing the rationale for targeting glial inflammation in this model. Our results demonstrate that treatment with D-NAC (10 mg/kg NAC) once weekly is more efficacious than equivalently dosed free NAC in improving the gross neurobehavioral phenotype in symptomatic Mecp2-heterozygous female mice. We also show that D-NAC therapy is significantly better than saline in ameliorating several aspects of the abnormal phenotype including paw clench, mobility, fear memory, REM sleep and epileptiform activity burden. Systemic D-NAC significantly improves microglial proinflammatory cytokine production and is associated with improvements in several aspects of the phenotype including paw clench, mobility, fear memory, and REM sleep, and epileptiform activity burden in comparison to saline-treated Mecp2-hetereozygous mice. Systemic glial-targeted delivery of D-NAC after symptom onset in an older clinically relevant Rett syndrome model shows promise in improving neurobehavioral impairments along with sleep pattern and epileptiform activity burden. These findings argue for the translational value of this approach for treatment of patients with Rett Syndrome., (© 2023 International Society for Neurochemistry.)

Combination chemotherapy regimens that include fluoropyrimidine (FP) drugs, e.g., 5-fluorouracil (5-FU), are central to the treatment of colorectal cancer liver metastases (CRLMs), a major cause of cancer mortality. We tested a second-generation FP polymer, CF10, in a CC531/WAGRij syngeneic orthotopic rat model of liver metastasis to determine if CF10 improved response relative to 5-FU. CF10 displayed increased potency relative to 5-FU in CC531 rat colorectal cancer cells based on clonogenic assay results and caused increased apoptosis, as shown using a live/dead assay. The increased potency of CF10 to CC531 cells was associated with increased replication stress, as assessed by Western blot for biomarkers of ATR/Chk1 and ATM/Chk2 pathway activation. CF10 dosed to deliver equivalent FP content as an established dose of 5-FU in rats (50 mg/kg) did not cause weight loss in WAGRij rats even when combined with ethynyl uracil (EU), an inhibitor of dihydropyrimidine dehydrogenase, the enzyme primarily responsible for 5-FU degradation in the liver. In contrast, 5-FU caused significant weight loss that was exacerbated in combination with EU. Importantly, CF10 was significantly more effective than 5-FU at inhibiting tumor progression (~90% reduction) in the CC531/WAG/Rij CRLM model. Our results reveal strong potential for CF10 to be used for CRLM treatment.

Neuronal hyperexcitability and excitotoxicity lies at the core of debilitating brain disorders such as epilepsy and traumatic brain injury, culminating in neuronal death and compromised brain function. Overcoming this challenge requires a unique approach that selectively restores normal neuronal activity and rescues neurons from impending damage. However, delivering drugs selectively to hyperexcitable neurons has been a challenge, even upon local administration. Here, we demonstrate the remarkable ability of a novel, scalable, generation-two glucose-dendrimer (GD2) made primarily of glucose and ethylene glycol building blocks, to specifically target hyperexcitable neurons in primary culture, ex vivo acute brain slices, and in vivo mouse models of acute seizures. Pharmacology experiments in ex vivo brain slices suggest GD2 uptake in neurons is mediated through glucose transporters (GLUT and SGLT). Inspired by these findings, we conjugated GD2 with a potent anti-epileptic drug, valproic acid (GD2-VPA), for efficacy studies in the pilocarpine-mouse model of seizure. When delivered intranasally, GD2-VPA significantly decreased the seizure-severity. In summary, our findings demonstrate the unique selectivity of glucose dendrimers in targeting hyperexcitable neurons, even upon intranasal delivery, laying the foundation for neuron-specific therapies for the precise protection and restoration of neuronal function, for targeted neuroprotection., Competing Interests: R. M. K., S. K., A. S., N. S., and R. S. are co‐inventors on patent applications relating to the compounds discussed here., (© 2024 The Authors. Bioengineering & Translational Medicine published by Wiley Periodicals LLC on behalf of American Institute of Chemical Engineers.)