Saline Control Research Articles

Abstract 6753: Exploring new approaches to widening of the therapeutic index of ADCs with dual-payload design and combination with a novel HMA

Abstract Antibody-drug conjugates (ADCs) have revolutionized targeted cancer therapy by delivering potent cytotoxic agents directly to tumor cells. Recent approvals of ADCs such as trastuzumab deruxtecan, sacituzumab govitecan have significantly improved patient treatment options, underscoring the clinical potential of this therapeutic class. However, single-payload ADCs often face limitations in efficacy. Tumor heterogeneity poses a significant challenge, as targeting cancer cells with a single cytotoxic mechanism may not sufficiently overcome resistance or achieve optimal therapeutic outcomes. These limitations call for the development of novel strategies that widen the therapeutic index by increasing the Maximum Tolerated Dose (MTD) and lowering the Minimum Effective Dose (MED). We have designed and synthesized a novel dual-payload ADC combining two distinct cytotoxic agents: a potent topoisomerase I inhibitor (Top1i) and a microtubule-disrupting agent. This innovative approach allows for a synergistic therapeutic effect, leveraging the complementary mechanisms of action of both payloads within a single ADC. In vitro cell viability was determined using the CellTiter-Glo assay against the NCI-N87 and MDA-MB-468 cell lines. These studies demonstrated robust potency of the dual-payload ADC across multiple cancer cell lines. In vivo efficacy studies were conducted in HER2-expressing NCI-N87 gastric cancer xenograft model. The tumor-bearing mice were treated with various doses of dual-payload ADC, single-payload ADC, or saline control. Notably, dual-payload ADC displayed superior efficacy compared to single-payload ADC, achieving a tumor growth inhibition (TGI) of 103% (p < 0.05). This demonstrates superior tumor growth inhibition of the dual-payload ADC compared to a Top1i-based single-payload ADC and a more favorable safety profile compared to a microtubule inhibitor-based single-payload ADC. Pharmacokinetic (PK) profiling and non-GLP toxicity studies are currently underway to further characterize its suitability for clinical development. Moreover, we have explored combination strategies to further augment the therapeutic index. One promising approach involves the combination of the ADC with NTX-301, a novel 4′-thio-modified analog of decitabine (DAC). NTX-301 enhances p53 stabilization more effectively than DAC, potentially improving the ADC’s efficacy through synthetic lethality with BCL2 inhibition. Preliminary data suggest that the ADC+NTX-301 combination produces greater synergy and a more favorable therapeutic index than ADC combinations with traditional hypomethylating agents (HMAs). In this study, we present novel strategies to enhance the therapeutic index of ADCs through a dual-payload design and combination with NTX-301. These results highlight the potential of both approaches for further development in cancer treatment. Citation Format: Younghwa Chun, Areum Go, Byeong Sung Lee, Seunggun Shin, Sohui Kweon, Hyemin Han, JaeHyeon Lee, Suhyun Park, Ha Young Lee, Min Young Lee, Hyun Yong Cho, Doo Young Jung. Exploring new approaches to widening of the therapeutic index of ADCs with dual-payload design and combination with a novel HMA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6753.

Abstract 1684: Combination of L-NMMA and sacituzumab govitecan as a novel targeted therapy for inflammatory breast cancer

Abstract Background: Inflammatory breast cancer (IBC) is a rare and aggressive form of breast cancer characterized by rapid progression, early metastatic potential, and distinct clinical and pathological features. The main treatment includes systemic cytotoxic therapy, surgery, and radiation. There is a need for novel targeted therapies to improve patients’outcomes. Inducible nitric oxide synthase (iNOS) is a mediator of various cancers including breast cancer. The pan-NOS inhibitor L-NMMA has been studied in preclinical and clinical settings, primarily focusing on cancers with high iNOS expression. Our preclinical studies provided the rationale for a recently completed phase I/II clinical trial of L-NMMA plus taxane for treating patients with triple-negative breast cancer (TNBC), with favorable toxicity and robust responses. Exploring the interaction between iNOS and IBC could identify novel therapeutic strategies, improving management approaches for this aggressive and highly lethal breast cancer subtype. Hypothesis: we hypothesize that, in combination with sacituzumab govitecan, the inhibition of iNOS by L-NMMA will significantly reduce tumor progression and survival in preclinical models of IBC. Sacituzumab govitecan is an antibody-drug conjugate where SN-38, a topoisomerase I inhibitor, is coupled to an anti-trophoblast cell-surface antigen 2 (Trop-2) monoclonal antibody, currently used in the treatment of TNBC. Experimental Procedures: The IBC xenograft SUM149 was orthotopically established in the mammary fat pad of female NSG mice by injection of 2x106 cells/mouse. Once tumors reached 200 mm3 in size, mice were randomly assigned into the following groups (n=7 mice per group): 1) Control (Saline, administered via i.p. injection); 2) Sacituzumab (administered at 5 mg/kg via i.v. injection weekly); 3) L-NMMA plus the calcium channel blocker amlodipine (LNMMA administered at 400 mg/kg on day 1 followed by 200 mg/kg per subsequent day by daily oral gavage; amlodipine administered at 10 mg/kg via i.p. injection daily); 4) Combination of Sacituzumab, L-NMMA, and amlodipine (Combo). Animals were treated as indicated for 21 days. Tumor size was monitored twice per week using caliper measurements. Results: The Combo treatment was more effective at reducing tumor volume than each individual drug (adj p value = 0.0010 by one-way ANOVA). Conclusions: Treatment with the Combo significantly reduced tumor growth compared to single drugs and control group. There was no statistically significant difference between the L-NMMA group and sacituzumab govitecan-treated mice. Overall, our findings demonstrate the synergism between L-NMMA and sacituzumab govitecan, highlighting the potential use of these drugs in future clinical trials. Citation Format: Karina A. Ortega Martinez, Maria F. Chervo, Wei Qian, Jianying Zhou, Liliana Guzman-Rojas, Ivonne D. Uzair, Gianmarco Melone, Mailin Li, Christoforos Thomas, Jenny C. Chang. Combination of L-NMMA and sacituzumab govitecan as a novel targeted therapy for inflammatory breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1684.

The effects of chronic sleep restriction on the hypothalamic-pituitary-adrenal axis and its interaction with abstinence from opioid use.

The hypothalamic-pituitary-adrenal (HPA) axis is critical in regulating responses to physiological and psychological disturbances. Chronic sleep restriction (SR) interacts with the HPA axis in ways that are poorly delineated. The present study evaluated how chronic SR alters pituitary and adrenal function. Chronic SR was studied both alone and in a model of opioid use disorder as a potential cause of HPA axis abnormalities during abstinence. After established self-administration of oxycodone or a saline control, male and female rats were either chronically sleep restricted or allowed to sleep ad libitum for five weeks to permit changes in phenotype to manifest. Tests of pituitary and adrenal function were then carried out using acute CRH and dexamethasone-ACTH stimulation testing. Sexual dimorphisms were prominent in the effects of chronic SR on the HPA axis which did not vary by prior opioid exposure. There were essentially no abnormalities in the HPA axis that were due to prior opioid exposure alone. In male SR rats, basal corticosterone concentrations decreased, ACTH responses to stimulation were enhanced, and ACTH suppression by dexamethasone was reduced. In female SR rats, the corticosterone response to CRH-stimulated ACTH release peaked early. Both male and female SR rats consumed more food relative to body weight than comparison rats, indicating homeostatic disruption that is known to require HPA axis mediation. Chronic SR interferes with HPA axis dynamics in sexually dimorphic ways that are expected to differentially affect SR-induced pathophysiology and disease risks. Chronic SR caused the HPA axis abnormalities observed during abstinence, providing biological linkage between two hypothesized risk factors in vulnerability to drug taking and relapse that demonstrate sexual dimorphisms.

Lanthanide Exposure In Vitro Differentially Diminishes MTT Cell Viability in Axenic Neuronal or Glial Cell Model Systems

Applications of lanthanide chemistry have been successful in metallics and the petroleum industry. In the medical realm, lanthanides have shown utility in radiotherapy agents, photodynamic therapy agents, and magnetic resonance imaging (MRI) contrast agents. The lanthanide group elements have a few known biological roles, notably among some bacteria and the yeast Saccharomyces cerevisiae, which have been used as models for changes in gene expression. However, the systematic effects of lanthanide nitrates on eukaryotic cell model systems have not yet been reported. This study presents the first documented effects on cell viability, after acute incubations of various lanthanide nitrate salts, using axenic C6 glial or PC12 neuronal cells in vitro. Cultures were exposed to a 1 mM concentration of lanthanide nitrate salts for 24 h. In comparison to the saline control, several cultures demonstrated significantly lower cell viability, as measured by the MTT viability assay. Data were analyzed as an average absorbance of n = 4 replicate samples, corrected for the average absorbance of cell-free blanks. The reported results were normalized to the average of the saline control cells. Among the 13 lanthanides tested, Praseodymium, Holmium, Erbium, Thulium, and Ytterbium nitrates exhibited the most pronounced inhibitory effects, resulting in over 40% reduction in cell viability at 1 mM for either or both cell types. Recovery after lanthanide exposure also was cell-type-dependent as well as lanthanide-type-dependent, with Lutetium having the greatest effect on both cell types. PC12 cells displayed greater sensitivity for inhibition than the C6 cells with some of the lanthanides but not all. Furthermore, the controls of sodium nitrate and calcium nitrate showed only modest discernible impacts on cell viability for PC12 and C6 cells, highlighting the role of the lanthanides in influencing cell viability.

Evaluation of the Effects of Detomidine on Equine Myoelectrical Activity Using Electrointestinography.

To evaluate the effects of detomidine on equine intestinal slow-wave activity and frequency distribution measured by electrointestinography (EIG). Prospective, experimental study. University teaching hospital. A convenience sample of twelve 7- to 21-year-old clinically normal horses. Horses were randomly assigned to saline control (four horses) or detomidine treatment (eight). After obtaining a 30-min baseline EIG, a saline or detomidine bolus was administered, followed by a constant rate infusion, and another EIG was recorded. Ultrasonographic examinations monitored cecal and left ventral colon contractions. Spectral analysis was performed to evaluate changes in dominant frequency, dominant power, total power, percent frequency distribution, and changes in slow-wave rhythmic activity. Median (interquartile range [IQR]) dominant frequency in cycles per minute (cpm) was similar for the cecum (2.4cpm; IQR: 0.51cpm) and left ventral colon (2.13cpm; IQR: 0.16cpm) and unchanged by either treatment (P>0.074). Compared with saline, which was unchanged, detomidine reduced dominant power ratios for both cecum (0.45; IQR: 0.18) and left ventral colon (0.63; IQR: 0.35; P=0.002). Detomidine decreased total power for the cecum in the 2-4 cpm frequency range from 55.0% (IQR: 4.4%) to 43.1% (IQR: 6.7%) and for the left ventral colon from 54.4% (IQR: 5.5%) to 27.3% (IQR: 9.3%; P<0.087). Total power for the cecum was increased in the 8-12 cpm frequency range from 9.6% (IQR: 1.9%) to 18.5% (IQR: 6.6%; P=0.0044) with detomidine. No change in frequency distribution was noted in controls (P>0.08). Dominant power correlated with the rate of contractions measured ultrasonographically (P<0.001). Detomidine decreased dominant power ratios for both the cecum and left ventral colon and produced tachyarrhythmias in cecal slow-wave activity. The correlation of dominant power with intestinal contractions supports the clinical development of EIG to diagnose equine motility disorders.

Evaluation of early chemotherapy response by combining static- and dynamic [18F]FDG-PET with diffusion-weighted MRI in subcutaneous patient-derived endometrial cancer mouse models

BackgroundThe combination of carboplatin and paclitaxel is the standard chemotherapy for treatment of high-risk and recurrent endometrial cancer. Evaluation of treatment response by diagnostic imaging is routinely carried out months after start of treatment, and is based on changes in tumor size or appearance of new metastases. The aim of this study was to evaluate early chemotherapeutic response in two subcutaneous endometrial cancer mouse models generated from patient-derived organoids using static- and dynamic [18F]fluorodeoxyglucose ([18F]FDG) positron emission tomography (PET) and diffusion-weighted (DW) magnetic resonance imaging (MRI). Mice were injected bilaterally with endometrioid endometrial cancer grade 3 (EEC G3), International Federation of Gynaecology and Obstetrics (FIGO) stage 3C1 (Model A) or stage 1B (Model B) organoids (n = 15 mice). The mice were randomized into treatment (combined carboplatin and paclitaxel, nA=8 / nB=6 tumors) or control (saline, nA=8 / nB=8 tumors) groups. During tumor progression, the mice underwent T2-weighted (T2w) MRI, DW-MRI and dynamic [18F]FDG-PET at baseline/Day 0 (start of treatment), Day 3 (early) and Day 10 (endpoint) using a sequential PET-MRI small-animal scanner.ResultsAt endpoint, tumor volumes at T2w-MRI (vMRI) were lower in the treatment groups in both models (p ≤ 0.029). The tumor metabolic rate (MRFDG) from dynamic PET, was significantly lower in the treatment group at the early timepoint (Day 3) and at the endpoint in Model A (p ≤ 0.042). In Model B, MRFDG was similar for both groups at Day 3 and at endpoint (p≥0.217). The 10 tumor voxels with the highest standardised uptake value (SUV10) from static [18F]-FDG-PET was significantly lower at endpoint in the treatment groups in both models (p ≤ 0.041), but not at the early timepoint (p≥0.083). Similarly, the tumor apparent diffusion coefficient (ADCmean) was significantly higher indicating treatment response at endpoint for treatment groups in both models (p ≤ 0.036).ConclusionsMultimodal imaging is feasible for evaluation of early signs of treatment response in preclinical subcutaneous endometrial cancer models. The novel MRFDG dynamic PET imaging parameter seems most promising for detecting very early treatment response following chemotherapy.

In Vivo Effectiveness of Poly-L-Lactic Acid Microsphere Dermal Fillers in Stimulating Collagen Synthesis.

Intradermal injections of fillers such as poly-L-lactic acid (PLLA) microspheres and hyaluronic acid (HA) offer the possibility of skin rejuvenation. However, the biological effects of these fillers and the mechanisms underlying collagen synthesis have not been fully elucidated. We investigated the histological effects of PLLA microsphere fillers on the rat dermis. PLLA microspheres were used as the experimental group, while HA and saline served as the positive and negative controls, respectively. Equal doses of cross-linked HA, saline, and PLLA microspheres were intradermally injected into the backs of male Sprague-Dawley rats. Biopsy specimens were collected and histologically analyzed using hematoxylin and eosin, Ki-67, alpha-smooth muscle actin, Herovici, and Sirius scarlet staining. Immunofluorescence staining for types I and III collagen, CD68, and CD90 was also performed. Quantitative data were statistically analyzed using a two-way analysis of variance. PLLA microspheres increased collagen type I and III levels and maintained tissue homeostasis in rat dermis. The PLLA microspheres primarily stimulated type III collagen in the early stage, whereas type I collagen was predominantly stimulated in the later stages. After the PLLA microspheres were injected into the dermal tissue, early fibroblasts and macrophages surrounded the microspheres, followed by the transformation of fibroblasts into myofibroblasts, which positively affected the production of type I collagen. Notably, HA demonstrated a significant stimulatory effect on type I collagen synthesis (P<0.05) but showed no statistically significant impact on type III collagen production. In contrast, the saline control group failed to show any measurable increase in either collagen subtype throughout the experimental period. HA and PLLA microspheres effectively increased type I collagen levels and maintained dermal tissue homeostasis. PLLA microspheres can be used as the main ingredient in intradermal collagen regenerative fillers due to their long degradation time and lasting effects. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Aspects clinical and pathological associated with the eletrophoretic profile of turkeys (Meleagris gallopavo) inoculated with Salmonella enteritidis

The study evaluated clinical, anatomopathological, immunological aspects, and the electrophoretic profile of serum proteins in turkeys experimentally inoculated with Salmonella enteritidis at different concentrations. A total of 160 one-day-old turkeys were used, distributed into four groups: control (saline solution) and three treatment groups with inocula of 6.0×10², 7.0×10⁵, and 8.0×10⁹ CFU/mL. Blood was collected at specific post-inoculation time points (1 to 24 hours, and on days 3, 4, 38, and 49) for protein analysis. After euthanasia, liver, spleen, and bursa of Fabricius fragments were collected for bacteriological and histopathological examinations. The results showed significant differences in total serum proteins from 6 hours post-inoculation, with higher values observed in the group that received the highest concentration of Salmonella enteritidis. Bacterial isolation from the liver was detected from 6 hours up to four days post-inoculation. Hepatic alterations, such as vacuolar degeneration and inflammatory infiltrates, were observed up to 49 days. In the spleen and bursa, lymphocytic depletion and heterophilic infiltrates were noted. Clinically, the turkeys exhibited drowsiness, apathy, and dirty cloaca, with some birds dying without symptoms while others recovered between the third and fourth weeks. Mortality was high in the first week, decreasing in the following weeks. It is concluded that Salmonella enteritidis induces significant protein and histopathological alterations, with more pronounced effects at high doses and in the early days following infection.

Sodium propionate protects against bronchopulmonary dysplasia by inhibiting IL-17-mediated apoptosis of alveolar epithelial cells

Sodium propionate (SP) has been shown to enhance alveolar growth retardation in Bronchopulmonary Dysplasia (BPD), but the mechanism remains unclear. The aim of this study is to explore the potential mechanism of SP in the treatment of BPD by utilizing animal and cell models along with bioinformation analysis. Neonatal mice were exposed to either air (21% O2) or hyperoxia (85% O2) from the first day after birth to establish the BPD model. The neonatal mice were intraperitoneally injected with normal saline (control group) or SP (500 mg/kg, SP group) from day 8 to day 14. SP significantly reduced the inflammatory condition of alveolar septal thickening, and decreased the alveolar fusion and mitigated weight loss in BPD mice. ELISA results demonstrated that SP significantly inhibited the secretion of IL-17, IL-6 and TNFα. Transcriptome analysis confirmed that IL-17 signaling pathway is closely related to the therapeutic effects of SP on BPD. In addition, MX2, MMP10, IL-11, ZMAT4 and SEC1 genes were identified as key and potential targets involved in the mechanism of SP treating BPD. Meanwhile, in mouse alveolar epithelial cells, apoptosis was induced by hyperoxia, but it was reduced following SP intervention. The expression of IL-17 pathway related genes: IL-17A, IL-6, TNFα and cox2 was decreased in hyperoxia treated cells after SP intervention. In conclusion, through transcriptome analysis, animal and cell experiments, we explored the role of sodium propionate in attenuating apoptosis in a BPD model through IL-17 pathway.

Revisiting the classical biodiversity-ecosystem functioning and stability relationships in microbial microcosms

Abstract The question of how biodiversity influences ecosystem functioning and stability has been a central focus in ecological research. Yet, this question remains unresolved, primarily because of the widely divergent definitions of functioning, stability, and diversity. Consequently, forecasts of ecosystem services will remain speculative until we can establish more precise and comprehensive definitions for these concepts than previously. Here, we investigated how the maximum specific growth rate, productivity, mortality rate, and species interaction in microbial communities vary with a diversity gradient ranging from 1 to 16 species under control conditions, starvation, or saline stress. We found that diversity played a critical role in maintaining community growth and stability under control conditions, with higher diversity associated with increased maximum specific growth rate and decreased mortality rate. However, higher diversity was associated with an increased mortality rate under starvation, while diversity did not affect the mortality rate under saline stress. Diversity stabilized microbial productivity only under control conditions, defying the “diversity begets stability” hypothesis under stress. Beneficial interactions among species were prevalent in most samples, but species interaction increased mortality rates under starvation. Our findings suggest that while biodiversity is crucial for preserving ecosystem functioning and stability, the presence of multiple definitions and contextual dependence on environmental conditions argue against any general relationship between diversity and ecosystem functioning/stability. Furthermore, we provide new insights into the longstanding debate surrounding the “diversity begets stability” hypothesis and the “diversity destabilizes ecosystem” hypothesis in that diversity begets stability under control conditions but destabilizes ecosystems under severe stress.

Observed Synostoses in an Avian and Murine Crania following in utero Thyroxine Exposure

Hyperthyroidism is a condition that leads to increased concentration of thyroid hormones (THs), such as triiodothyronine (T3) and thyroxine (T4). An increase in these circulating THs, or thyrotoxicosis, in utero can lead to developmental conditions such as craniosynostosis. Craniosynostosis is the premature fusion of cranial sutures during development. This study focused on the development of sagittal and coronal sutures within crania of both juvenile mice and embryonic chickens following in utero thyroxine exposure. In previous studies, the murine model of induced thyrotoxicosis has shown a widening of the sagittal suture and a narrowing of the coronal suture. We hypothesized that we would see a similar morphology in the murine and avian crania following our model for induced thyrotoxicosis. For the (1) murine model, pregnant dams were given levothyroxine (synthetic thyroxine; 667 ng per day) or a vehicle dose (no treatment) daily to their drinking water. At 3 weeks post-natal, skulls from pups were then harvested. In the (2) avian model, 25 ng thyroxine or saline (control) was injected into the air cell of fertilized chicken eggs on days 11 and 15 post-fertilization. At 19 days post-fertilization, skulls from chicken embryos were then harvested. All crania were whole-mount stained with Alizarin red and Alcian blue, photographed, and measured from both treatment and control groups. This data was then analyzed in R-Studio using unpaired t-tests to determine significance. This morphological study supports our previous findings demonstrating that the coronal and sagittal sutures undergo differential development with increased thyroxine exposure.

Efficacy of RADA16-Based Self-Assembling Peptides on Wound Healing: A Meta-Analysis of Preclinical Animal Studies

Objectives: This analysis aims to provide evidence supporting the feasibility of clinical application of self-assembling peptides for skin wound healing. Methods: This review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed, Web of Science, and Cochrane Library were searched (up to June 17, 2024). The primary outcome, wound closure rate at 7 and 14 days post-injury, was pooled using a random-effects meta-analysis. The risk of bias (ROB) assessment and meta-analysis were performed using the Systematic Review Centre for Laboratory animal Experimentation (SYRCLE)’s ROB tool for animal studies and RevMan software. Results: A total of 502 unique records were identified from our search, with 12 experimental animal studies meeting the prespecified inclusion criteria (n = 272 animals). The RADA16 interventions promoted wound closure rate compared to controls (saline or no treatment group) in both diabetic and non-diabetic animal models (Mean Difference (MD) = 11.25, 95% Confidence Interval (CI): 5.73 to 16.78, p &lt; 0.0001; MD = 9.48, 95% CI: 4.75 to 14.22, p &lt; 0.0001 at 7 and 14 days post-injury, respectively). Healing was further enhanced using RADA16-based functional self-assembling peptides compared to RADA16 group in both diabetic and non-diabetic animal models (MD = 27.25, 95% CI: 22.68 to 31.83, p &lt; 0.00001; MD = 29.11, 95% CI: 24.30 to 33.91, p &lt; 0.00001 at 7 and 14 days after injury, respectively). The ROB was uncertain for most studies due to insufficient reporting. Conclusions: RADA16-based self-assembling peptides, particularly those modified with functional peptide motifs, represent a promising treatment for non-diabetic and diabetic wounds in pre-clinical studies, and translation to the clinical domain appears warranted.

Effect of subcutaneous application of chlorhexidine nanocapsules on local microvascularization in rats

Objective: To evaluate the effects of subcutaneous application of chlorhexidine-containing nanocapsules (N_CLX) on local microvascularization and inflammatory response in rats. Methods: Thirty Wistar rats were divided into five groups (n=6): saline solution (control), pure chlorhexidine (CLX), nanocapsules without chlorhexidine (Nano 0), nanocapsules with chlorhexidine (Nano CLX), and formalin 1% (positive control). Each received 0.1 mL subcutaneous injections. Laser-Doppler flowmetry measured microvascular blood flow, erythrocyte concentration, and skin temperature at baseline, 3, 6, and 24 hours. Histological analysis assessed collagen fibers, fibroblast proliferation, and inflammation. Results: N_CLX and CLX groups showed no significant alterations in blood flow, erythrocyte concentration, or skin temperature compared to control (p&gt;0.05), while formalin increased all parameters (p&lt;0.05). Histological analysis revealed slight fibroblast proliferation and collagen deposition in N_CLX, indicating moderate inflammation and tissue repair. Fibroblast density and collagen differed significantly between N_CLX and formalin groups (p&lt;0.05). Conclusion: N_CLX induced a mild inflammatory response without affecting microcirculation, confirming its biocompatibility. These findings support its potential for controlled drug delivery in localized therapies.

Vagus nerve stimulation rescues impaired fear extinction and social interaction in a rat model of autism spectrum disorder.

Vagus nerve stimulation rescues impaired fear extinction and social interaction in a rat model of autism spectrum disorder.

Establishing the Median and 95% Effective Doses of Oliceridine for Immediate Post-Surgical Analgesia Following Laparoscopic Cholecystectomy: A Double-Blind, Sequential Dose-Finding Study.

This investigation aimed to establish the optimal dosing parameters of oliceridine for postoperative pain control in laparoscopic cholecystectomy (LC) procedures. Using Dixon and Massey's up-and-down sequential allocation method, the median effective dose (ED50) and the dose required for 95% effective dose (ED95) were determined, alongside an evaluation of the agent's safety profile. In this prospective trial, 82 participants scheduled for LC were enrolled and randomly assigned to receive either oliceridine or saline (control). Prior to surgical incision, the intervention group received varying doses of intravenous oliceridine, while control subjects received equivalent volumes of saline solution. Post-surgical pain management involved standardized multimodal analgesic protocols for both cohorts. Baseline demographic data was documented for all participants. Pain evaluations using the 11-point verbal numeric rating scale (NRS) at 15 min, 30 min, and 2h post-extubation. Using Dixon's up-and-down methodology, the ED50 and ED95 were determined. Hemodynamic variables were tracked and pain levels quantified throughout the procedure. The study protocol included monitoring post-anesthetic recovery characteristics and documenting adverse effects. Probability unit regression analysis indicated that the ED50 of oliceridine for the prevention of early postoperative pain was calculated to be 18.45µg/kg (95% CI: 16.85-19.82µg/kg), while the ED95 was determined to be 22.39µg/kg (95% CI: 20.75-26.98µg/kg). Statistical analysis showed comparable rates of adverse events between study groups (p > 0.05). Additional analyses demonstrated similar outcomes between oliceridine and control cohorts regarding hemodynamic stability, and adverse effect profiles. Pain management satisfaction assessment at 24hours post-LC revealed high approval rates in the oliceridine group, with 90% of patients (36/40, p=0.31) and 97.5% of surgeons (39/40, p=0.03) expressing satisfaction, regardless of administered dose. Our findings establish that for early postoperative pain management, oliceridine demonstrates optimal therapeutic efficacy at an ED50 of 18.45 ug/kg, with the ED95 determined to be 22.39 ug/kg.

Modulating mitochondrial dynamics preserves cognitive performance via ameliorating iron-mediated brain toxicity in iron-overload rats.

Modulating mitochondrial dynamics preserves cognitive performance via ameliorating iron-mediated brain toxicity in iron-overload rats.

Intraamniotic vitamin D preserves lung development and prevents pulmonary hypertension in experimental bronchopulmonary dysplasia due to intraamniotic sFlt-1.

Preterm infants born to mothers with preeclampsia, a disease of vascular dysfunction, are at increased risk for bronchopulmonary dysplasia (BPD). Endothelial cells are critical in both maintaining proper vascular function and coordinating lung development. Understanding the mechanisms contributing to BPD in the setting of preeclampsia and how preeclampsia impacts pulmonary endothelial cells (PECs) in the newborn lung are required to decrease the burden of BPD. Vitamin D has been shown to improve lung angiogenesis and lung development in inflammatory models of BPD, but its therapeutic potential in the setting of preeclampsia is unknown. We hypothesized that intraamniotic (IA) treatment with the biologically active form of vitamin D, 1,25 dihydroxyvitamin D [1,25(OH)2D], will preserve lung growth in an experimental model of BPD induced by antenatal exposure to soluble vascular endothelial growth factor receptor-1 [sFlt-1 (soluble fms-like tyrosine kinase 1)]. Fetal rats were exposed to saline (control), sFlt-1 alone, 1,25(OH)2D alone, or simultaneous sFlt-1 + 1,25(OH)2D via IA injection during the late canalicular stage of lung development and delivered 2 days later. IA treatment with 1,25(OH)2D in sFlt-1-exposed pups improved lung alveolar and vascular growth and function at 14 days of life. PECs orchestrate alveolar development, and we demonstrate that IA sFlt-1 exposure alone decreased in vitro growth and tube formation of PECs isolated from newborn pups and that PECs from pups coexposed to IA sFlt-1 and 1,25(OH)2D demonstrated increased growth and tube formation. We conclude that IA 1,25(OH)2D treatment improves distal lung development during sFlt-1 exposure through preservation of angiogenesis in the developing lung.NEW & NOTEWORTHY This study highlights that experimental BPD induced by intraamniotic sFlt-1 is associated with impaired growth in postnatal pulmonary endothelial cells. We demonstrate that 1,25(OH)2D may be a therapeutic option to improve lung development through enhancement of VEGF signaling and preservation of early pulmonary endothelial growth in the newborn rat lung.

In Vitro and InVivo Evaluation of an Emollient-Rich Moisturizer Developed to Address Three Critical Elements of Natural Moisturization.

A new, emollient-rich moisturizing cream has been developed to support three critical elements of natural skin moisturization-hyaluronic acid, natural moisturizing factors, and lipids. The aim of this study was to evaluate invitro biomarkers associated with skin hydration and barrier support, followed by invivo clinical hydration assessment and tolerability. Using an invitro epidermal skin model, tissues were treated with the study moisturizer or control (saline) for 24 h. Genes associated with hydration and barrier support were analyzed: claudin 4 (CLD4), aquaporin 3 (AQP3), hyaluronic acid synthase 2 (HAS2), and hyaluronidase 1 (HYAL1). The clinical study evaluated twice-daily use of the study moisturizer in subjects with moderate-to-severe dry skin. Subject satisfaction and skin hydration measurementswere captured at baseline, 2, 4, and 8 weeks. Increased expression of CLD4, AQP3, and HAS2 and reduced activity of HYAL1 were demonstrated after 24 h. In subjects applying the study moisturizer, significant mean percent improvements from baseline in skin hydration occurred at Weeks 2 (41%; p < 0.0001), 4 (38%; p < 0.0001), and 8 (116%; p < 0.0001). Ninety-six percent of subjects reported their skin felt hydrated after 8 weeks. An emollient-rich moisturizing cream developed to support three critical elements of natural skin moisturization increased the expression of biomarkers associated with skin barrier support and hydration, and reduced the expression of HA-degrading enzymes. Early, significant increases in skin hydration were observed.

Histopathological and functional Characterization of a neonatal mouse model of intraventricular hemorrhage.

Histopathological and functional Characterization of a neonatal mouse model of intraventricular hemorrhage.

Neuropsin, TRPV4 and intracellular calcium mediate intrinsic photosensitivity in corneal epithelial cells.

Neuropsin, TRPV4 and intracellular calcium mediate intrinsic photosensitivity in corneal epithelial cells.