Establishment of a swine model of delayed bleeding after endoscopic procedure.

Objectives: Although delayed bleeding after endoscopic procedures has become a problem, currently, there are no appropriate animal models to validate methods for preventing it. This study aimed to establish an animal model of delayed bleeding after endoscopic procedures of the gastrointestinal tract. Methods: Activated coagulation time (ACT) was measured using blood samples drawn from a catheter inserted into the external jugular vein of swine (n = 7; age, 6 months; mean weight, 13.8 kg) under general anesthesia using the cut-down method. An upper gastrointestinal endoscope was inserted orally, and 12 mucosal defects were created in the stomach by endoscopic mucosal resection using a ligating device. Hemostasis was confirmed at this time point. The heparin group (n = 4) received 50 units/kg of unfractionated heparin via a catheter; after confirming that the ACT was ≥200 s 10 min later, continuous heparin administration (50 units/kg/h) was started. After 24 h, an endoscope was inserted under general anesthesia to evaluate the blood volume in the stomach and the degree of blood adherence at the site of the mucosal defect. Results: Delayed bleeding was observed in three swine (75%) in the heparin-treated group, who had a maximum ACT of >220 s before the start of continuous heparin administration. In the non-treated group (n = 3), no prolonged ACT or delayed bleeding was observed at 24 h. Conclusion: An animal model of delayed bleeding after an endoscopic procedure in the gastrointestinal tract was established using a single dose of heparin and continuous heparin administration after confirming an ACT of 220 s.

Comparative Transcriptome Analysis of Human and Mouse Canalicular Lungs in Fetal Diaphragmatic Hernia.

BACKGROUND: The nitrofen model of congenital diaphragmatic hernia (CDH) is widely used in translational research. However, the molecular pathways associated with pulmonary hypoplasia in this model compared to the human CDH phenotype have not been well described. The aim of this study was to investigate differentially expressed genes (DEG) and signaling pathways in early stage fetal lungs in mouse and human CDH. METHODS: CDH lung tissue was obtained from human fetuses (21-23 weeks gestation) and nitrofen mouse pups (E15.5). NovaSeq Flowcell RNA-seq was performed to evaluate differentially expressed transcriptional and molecular pathways (DEGs) in fetal mice with CDH, compared with age-matched normal mouse lungs and human CDH samples. RESULTS: There were thirteen overlapping DEGs in human and mouse CDH lung samples compared to controls. These genes were involved in extracellular matrix, myogenesis, cilia, and immune modulation pathways. Human CDH was associated with an upregulation of collagen formation and extracellular matrix reorganization whereas mouse CDH was associated with an increase in muscular contraction. The most common cell types upregulated in human and mouse CDH samples were ciliated airway cells. CONCLUSIONS: This study highlights the unique gene transcriptional patterns in early fetal mouse and human lungs with CDH. These data have implications when determining the translational potential of novel therapies in CDH using nitrofen-based animal models. LEVEL OF EVIDENCE: Level IV. STUDY TYPE: Basic science/case series.

Pre- and Post-Synaptic protein in the major depressive Disorder: From neurobiology to therapeutic targets.

Major depressive disorder (MDD) has demonstrated its negative impact on various aspects of the lives of those affected. Although several therapies have been developed over the years, it remains a challenge for mental health professionals. Thus, understanding the pathophysiology of MDD is necessary to improve existing treatment options or seek new therapeutic alternatives. Clinical and preclinical studies in animal models of depression have shown the involvement of synaptic plasticity in both the development of MDD and the response to available drugs. However, synaptic plasticity involves a cascade of events, including the action of presynaptic proteins such as synaptophysin and synapsins and postsynaptic proteins such as postsynaptic density-95 (PSD-95). Additionally, several factors can negatively impact the process of spinogenesis/neurogenesis, which are related to many outcomes, including MDD. Thus, this narrative review aims to deepen the understanding of the involvement of synaptic formations and their components in the pathophysiology and treatment of MDD.

Solitary Functioning Kidneys Attenuate Renal Hemodynamics Responses to Angiotensin II in Male But Not in Female Rats.

Backgrounds: People with solitary functioning kidneys (SFK) are prone to renal failure with time. Accordingly, local renin angiotensin system (RAS) and renal functions in subjects with SFK may act differently compared to normal condition. This study was designed to determine the renal hemodynamics responses to angiotensin II (Ang. II) in SFK male and female rats. Methods: Fifty to sixty-day-old male and female Wistar rats were subjected to unilateral renal artery obstruction, and 28 days later basal renal hemodynamic responses to Ang. II were examined in SFK groups compared to sham groups. Results: The findings indicated lower renal vascular resistance (RVR) and renal blood flow (RBF) responses to Ang. II in male SFK compared to sham group. Such observation was not seen in female animals. Conclusions: An increase in renal metabolism due to hyperfunction, especially in SFK male rats, may cause a decrease in RVR. Moreover, the lower RBF response to Ang. II may be related to alteration to Ang. II receptors in the remnant kidneys in SFK rats.

Short-term therapy with R568 ameliorated secondary hyperparathyroidism but does not prevent aortic valve calcification in uremic rats.

Introduction: Renal failure associated aortic valve calcification (AVC) is the result of hyperphosphatemia and hyperparathyroidism. Calcimimetics is an effective tool for management of secondary hyperparathyroidism. Our goal was to evaluate the effect of the medical intervention with calcimimetic R568 on the AVC process. Methods and results: The experimental design consisted of administering a uremia-inducing phosphate-enriched diet to rats for six weeks. Rats received a daily R568 injection at different times. Biochemical analysis demonstrated increased urea (34.72 ± 3.57 vs. 5.18 ± 0.15 mmol/L, p<0.05) and creatinine (293.93 ± 79.6 vs. 12.82 ± 1.56 µmol/L, p<0.05). R568 treatment markedly reduced parathyroid hormone (PTH) levels in both treated groups (192.63 ± 26.85, 301.23 ± 101.79 vs. 3570 ± 986.63 pg/mL, p<0.05), with no impact on serum calcium and phosphate. von Kossa staining showed increase in AVC in uremic rats compared to control (1409 ± 159.5 vs. 27.33 ± 25.83, p<0.05). AVC was not affected by R568 in both groups (3343 ± 2462, 1593 ± 792 vs. 1409 ± 159.5, NS). Similarly, the inflammatory marker CD68 was elevated in uremic rats (15592 ± 3792 vs. 181.8 ± 15.29, p<0.01), and was not influenced by R568 treatment (8453 ± 818.5, 9318 ± 2232 vs. 15592 ± 3792, NS). Runt-related transcription factor 2 (Runx2), the regulator of osteoblast differentiation, was upregulated in uremic rats (23186 ± 9226 vs. 3184 ± 2495), that accompanied by elevated levels of Osteopontin (158395 ± 45911 vs. 237.7 ± 81.5, p<0.05) and Osteocalcin (22203 ± 8525 vs. 489.7 ± 200.6, p<0.05). R568 had no impact on osteoblastic markers (Runx2: 21743 ± 3193, 23004 ± 10871 vs. 23186 ± 9226, NS; osteopontin: 57680 ± 19522, 137116 ± 60103 vs. 158395 ± 45911, NS; osteocalcin: 10496 ± 5429, 8522 ± 5031 vs. 22203 ± 8525, NS). Conclusion: In an adenine-induced uremic rat model, we showed that short-term R568 therapy had no effect on AVC. Treatment with R568 decreased PTH levels but had no effect on high phosphate levels. Regression of AVC necessitates not only a decrease in PTH levels, but also a decline in phosphate levels. To achieve improved outcomes, it is advisable to consider administering a combination of R568 with other medications, such as calcium supplements or phosphate binders. Additional studies are required for further evaluation of the potential treatment of chronic kidney disease (CKD)-associated AVC.

Progress in the field of animal models of antiphospholipid syndrome.

Antiphospholipid syndrome (APS) is an autoimmune disease characterized by recurrent arteriovenous thrombosis and pathological pregnancy, accompanied by persistent antiphospholipid antibodies, (aPL). The incidence of APS is increasing year by year, clinicians lack of understanding of this type of disease, easy to misdiagnose and miss the diagnosis. Therefore, it is extremely important to establish a suitable animal model to reduce the process of disease development as much as possible and improve clinicians' understanding and understanding. This review will summarize the animal models of APS from the aspects of modeling methods, modeling mechanism, evaluation indicators and advantages and disadvantages of methods, providing a reference for finding an animal model highly similar to human APS, helping researchers to further clarify the pathogenesis of APS and find potential therapeutic targets, so as to achieve early diagnosis, early intervention, and ultimately improve the prognosis of patients.

Effects of jujube (Ziziphus jujuba mill.) fruit extracts on oxidative stress: A systematic review and meta-analysis of rodent studies.

This study aimed to evaluate the effects of jujube (Ziziphus jujuba Mill.) fruit extracts on oxidative stress levels in rodent models. Animal studies meeting the inclusion criteria were retrieved from PubMed, Web of Science, Embase, China National Knowledge Infrastructure (CNKI), Wanfang Data Knowledge Service Platform, and VIP Periodical Service Platform. The Systematic Review Center for Laboratory Animal Experimentation (SYRCLE) risk-of-bias tool was used to evaluate the risk of bias in the included studies. A meta-analysis was performed based on the guidelines provided in the Cochrane Handbook for Systematic Reviews of Interventions (CHSRI) by using Stata 17.0 software. Nineteen studies were included in the meta-analysis. Jujube fruit extracts significantly decreased the level of malonaldehyde (MDA) and increased the levels of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). Meanwhile, there was no significant improvement in the catalase (CAT) levels. In addition, there was considerable heterogeneity in the results of the meta-analysis. The results of the subgroup analysis indicated that the animal model, type of extracts, and source of target parameters may have contributed to the heterogeneity. Jujube fruit extracts are healthy and effective antioxidant dietary supplements that may be an effective adjunctive therapy for diseases in which oxidative stress is a major pathological factor. However, the overall methodological quality of the included studies was low, and additional research is warranted.

A lmod1a mutation causes megacystis microcolon intestinal hypoperistalsis in a CRISPR/Cas9-modified zebrafish model.

PURPOSE: Megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) is defined as a congenital visceral myopathy with genetic mutations. However, the etiology and pathophysiology are not fully understood. We aimed to generate a gene leiomodin-1a (lmod1a) modification technique to establish a zebrafish model of MMIHS. METHODS: We targeted lmod1a in zebrafish using CRISPR/Cas9. After confirming the genotype, we measured the expression levels of the target gene and protein associated with MMIHS. A gut transit assay and spatiotemporal mapping were conducted to analyze the intestinal function. RESULTS: Genetic confirmation showed a 5-base-pair deletion in exon 1 of lmod1a, which caused a premature stop codon. We observed significant mRNA downregulation of lmod1a, myh11, myod1, and acta2 and the protein expression of Lmod1 and Acta2 in the mutant group. A functional analysis of the lmod1a mutant zebrafish showed that its intestinal peristalsis was fewer, slower, and shorter in comparison to the wild type. CONCLUSION: This study showed that targeted deletion of lmod1a in zebrafish resulted in depletion of MMIHS-related genes and proteins, resulting in intestinal hypoperistalsis. This model may have the potential to be utilized in future therapeutic approaches, such as drug discovery screening and gene repair therapy for MMIHS.

Collagen Membrane as artificial Dura Substitute: A Comprehensive in vivo study of efficiency and substitution compared to Durepair.

BACKGROUND AND OBJECTIVES: The dura mater is a barrier between the brain and the surrounding environment. Injuries to the dura can lead to serious complications, therefore, ensuring a hermetic closure of the dura is a primary task for a neurosurgeon. The aim of the study is to compare the effectiveness of applying the newly developed Viscoll®DURA collagen membrane (VDCM), with the commercially available Durepair (xenogeneic collagen) in animal model. METHODS: A dural tear model was utilized in rats with membrane implantation using an application method. The sample size consisted of 24 rats. Group I underwent VDCM implantation, while Group II underwent Durepair implantation. Results were evaluated at 30, 60, and 90 days. The study was assessed using MRI, histology, electron scanning microscopy, and immunohistochemistry. The obtained results underwent statistical analysis. RESULTS: In the clinical presentation there were no difference between groups. Histologically, Group 1 showed comparable results to Group 2. The integration process of the membrane statistically differed between the groups. In Group 1, neovascularization and tissue replacement showed better results than in Group 2. MRI differences were observed at later stages, with group 2 showing adhesion and brain deformation in the implantation area. CONCLUSION: Both membranes showed safety and compatibility. The collagen membrane produced under sterile conditions demonstrated better regeneration with minimal inflammatory reaction. The study suggests that VDCM exhibits biocompatibility comparable to Durepair, providing prospects for potential applications in neurosurgery.

A Scoping Review of Animal Models for Development of Abdominal Adhesion Prevention Strategies.

INTRODUCTION: Abdominal adhesions represent a chronic postsurgical disease without reliable prophylaxis. Animal modeling has been a cornerstone of novel therapeutic development but has not produced reliable clinical therapies for prevention of adhesive small bowel obstruction. The purpose of this scoping review is to analyze animal models for abdominal adhesion generation by key considerations of external validity (i.e., fidelity, homology, and discrimination). METHODS: A literature review was performed in accordance with the Preferred Reporting Items for Systematic Reviews Extension for Scoping Reviews guidelines. Peer-reviewed publications were included that described the development or quality assessment of experimental animal models for abdominal adhesions with inclusion of a scoring system. Studies that focused on treatment evaluation, implantation of surgical devices, models of nonsurgical etiologies for abdominal adhesions, non-in vivo modeling, and investigations involving human subjects were excluded. RESULTS: Four hundred and fifteen (n = 415) articles were identified by prespecified search criteria. Of these, 13 studies were included for review. CONCLUSIONS: Translation of investigational therapeutics for abdominal adhesion prevention is dependent upon high-quality experimental animal models that reproduce the clinical adhesions seen in the operating room as a disease of the entire abdomen.

Vertical Alveolar Ridge Regeneration by Means of Periosteal Activation-A Proof-of-Principle Study.

AIM: To assess the possibility of vertical alveolar ridge augmentation by means of activation of the periosteum. MATERIALS AND METHODS: Six adult male Beagle dogs were used for the study. All premolars and first molars were extracted, and one vertical saucer-shaped bony defect was created on each side of the mandible. After 3 months of healing, full-thickness muco-periosteal flaps were elevated, and one distraction device was placed on each side of the mandible. The distraction plate was left submerged, and the activation mechanism connected to the distraction rod was exposed intra-orally. The protocol of periosteal activation (PP: periosteal 'pumping') was initiated after a latency of 7 days. The alternation of activation and relaxation at the rate of 0.35 mm/12 h during 5 days was followed by the sole activation of 0.35 mm/12 h for 5 days (PP group). Devices were left inactivated on the contralateral control side of the mandible (C group). All animals were euthanized after 8 weeks of consolidation. Samples were analysed histologically and by means of micro-CT. RESULTS: New mature lamellar bone was formed over the pristine bone in all groups. More intensive signs of bone modelling and remodelling were observed in the PP group compared to the C group. Mean new bone, bone marrow, connective tissue and total volumetric densities were greater in the PP group (p < 0.001, p = 0.001, p = 0.003 and p < 0.001, respectively). No differences were observed in the relative area parameters. Total tissue volume and bone volume were higher in the PP group (p = 0.031 and p = 0.076, respectively), while the bone mineral densities were higher in the C group (p = 0.041 and p = 0.003, respectively). Trabecular number, trabecular thickness and trabecular separation values were similar between the two groups. CONCLUSIONS: Regeneration of vertical alveolar bone ridge defects may be enhanced by activation of the periosteum, without the application of bone grafting materials.

An update on nonhuman primate usage for drug and vaccine evaluation against filoviruses.

INTRODUCTION: Due to their faithful recapitulation of human disease, nonhuman primates (NHPs) are considered the gold standard for evaluating drugs against Ebolavirus and other filoviruses. The long-term goal is to reduce the reliance on NHPs with more ethical alternatives. In silico simulations and organoid models have the potential to revolutionize drug testing by providing accurate, human-based systems that mimic disease processes and drug responses without the ethical concerns associated with animal testing. However, as these emerging technologies are still in their developmental infancy, NHP models are presently needed for late-stage evaluation of filovirus vaccines and drugs, as they provide critical insights into the efficacy and safety of new medical countermeasures. AREAS COVERED: In this review, the authors introduce available NHP models and examine the existing literature on drug discovery for all medically significant filoviruses in corresponding models. EXPERT OPINION: A deliberate shift toward animal-free models is desired to align with the 3Rs of animal research. In the short term, the use of NHP models can be refined and reduced by enhancing replicability and publishing negative data. Replacement involves a gradual transition, beginning with the selection and optimization of better small animal models; advancing organoid systems, and using in silico models to accurately predict immunological outcomes.

A novel minimally invasive and versatile kyphoplasty balloon-based model of porcine spinal cord injury.

Introduction: Spinal cord injury (SCI) animal models often utilize an open surgical laminectomy, which results in animal morbidity and also leads to changes in spinal canal diameter, spinal cord perfusion, cerebrospinal fluid flow dynamics, and spinal stability which may confound SCI research. Moreover, the use of open surgical laminectomy for injury creation lacks realism when considering human SCI scenarios. Methods: We developed a novel, image-guided, minimally invasive, large animal model of SCI which utilizes a kyphoplasty balloon inserted into the epidural space via an interlaminar approach without the need for open surgery. Results: The model was validated in 5 Yucatán pigs with imaging, neurofunctional, histologic, and electrophysiologic findings consistent with a mild compression injury. Discussion: Few large animal models exist that have the potential to reproduce the mechanisms of spinal cord injury (SCI) commonly seen in humans, which in turn limits the relevance and applicability of SCI translational research. SCI research relies heavily on animal models, which typically involve an open surgical, dorsal laminectomy which is inherently invasive and may have untoward consequences on animal morbidity and spinal physiology that limit translational impact. We developed a minimally invasive, large animal model of spinal cord injury which utilizes a kyphoplasty balloon inserted percutaneously into the spinal epidural space. Balloon inflation results in a targeted, compressive spinal cord injury with histological and electrophysiological features directly relevant to human spinal cord injury cases without the need for invasive surgery. Balloon inflation pressure, length of time that balloon remains inflated, and speed of inflation may be modified to achieve variations in injury severity and subtype.

An arteriovenous fistula model: Carotid artery-posterior facial vein fistula in rats.

OBJECTIVE: To describe an alternative arteriovenous fistula (AVF) model involving anastomosis of the common carotid artery (CCA) with the posterior facial vein (PFV). METHODS: Twenty-two male Sprague-Dawley rats (age 6-8 weeks) were used to establish the AVF model involving end-to-side anastomosis of PFV and CCA. The peak velocity of the CCA and the diameter of the outflow vein were recorded at 7, 14, and 42 days after the operation using Doppler ultrasound. Pathological examination of the intimal lesions was performed at 14 and 42 days after operation. RESULTS: One rat died within 24 h after surgery related to anesthesia. The patency rates at days 7, 14, and 42 were 85.7%, 81%, and 81%, respectively. The diameter of the carotid artery in rats is approximately 0.8 mm. The diameter of the outflow vein was increased by 1.7-fold and 2.2-fold at 7 days (1.1 ± 0.118 mm) and 14 days (1.4 ± 0.073 mm). At 42 days (1.96 ± 0.101 mm) after operation, the diameter was 3-fold greater compared to the unoperated control rat. The peak systolic flow velocity of the carotid artery at 7 days (593 ± 17.36 mm/s) and 14 days (767 ± 13.64 mm/s) after surgery was significantly greater compared to the control rat (314 ± 15.13 mm/s). The rate of increase was fastest at 7 days and leveled off from 14 to 42 days (875 ± 26 mm/s) after surgery. At 14 days, the intima area showed a nearly 50-fold increase (230 ± 9.93 µm2 × 103) compared to control (area 5 ± 0.37 µm2 × 103). Comparing 6 weeks with 2 weeks (280 ± 10.54 µm2 × 103) after surgery, the intima area increased 1.2 times. CONCLUSION: The CCA-PFV fistula in rats is a viable alternative AVF model.

Resolvin D2-induced reparative dentin and pulp stem cells after pulpotomy in a rat model.

Introduction: Vital pulp therapy (VPT) is performed to preserve dental pulp. However, the biocompatibility of the existing materials is of concern. Therefore, novel materials that can induce pulp healing without adverse effects need to be developed. Resolvin D2 (RvD2), one of specialized pro-resolving mediators, can resolve inflammation and promote the healing of periapical lesions. Therefore, RvD2 may be suitable for use in VPT. In the present study, we evaluated the efficacy of RvD2 against VPT using in vivo and in vitro models. Methods: First molars of eight-week-old male Sprague-Dawley rats were used for pulpotomy. They were then divided into three treatment groups: RvD2, phosphate-buffered saline, and calcium hydroxide groups. Treatment results were assessed using radiological, histological, and immunohistochemical (GPR18, TNF-α, Ki67, VEGF, TGF-ß, CD44, CD90, and TRPA1) analyses. Dental pulp-derived cells were treated with RvD2 in vitro and analyzed using cell-proliferation and cell-migration assays, real-time PCR (Gpr18, Tnf-α, Il-1ß, Tgf-ß, Vegf, Nanog, and Trpa1), ELISA (VEGF and TGF-ß), immunocytochemistry (TRPA1), and flow cytometry (dental pulp stem cells: DPSCs). Results: The formation of calcified tissue in the pulp was observed in the RvD2 and calcium hydroxide groups. RvD2 inhibited inflammation in dental pulp cells. RvD2 promoted cell proliferation and migration and the expression of TGF-ß and VEGF in vitro and in vivo. RvD2 increased the number of DPSCs. In addition, RvD2 suppressed TRPA1 expression as a pain receptor. Conclusion: RvD2 induced the formation of reparative dentin, anti-inflammatory effects, and decreased pain, along with the proliferation of DPSCs via the expression of VEGF and TGF-ß, on the pulp surface in pulpotomy models.

A New Methodology for the Oxygen Measurement in Lung Tissue of an Aged Ferret Model Proves Hypoxia during COVID-19.

Oxygen as a key element has a high impact on cellular processes. Infection with a pathogen such as SARS-CoV-2 and after inflammation may lead to hypoxic conditions in tissue that impact cellular responses. To develop optimized translational in vitro models for a better understanding of physiologic and pathophysiologic oxygen conditions, it is a prerequisite to determine oxygen concentrations generated in vivo. Our study objective was the establishment of an invasive method for oxygen measurements using a luminescence-based microsensor to determine the dissolved oxygen in the lung tissue of ferrets as animal models for SARS-CoV-2 research. By way of analogy to humans, aged ferrets are more likely to show clinical signs after SARS-CoV-2 infection than are young animals. To investigate oxygen concentrations during a respiratory viral infection, we intratracheally infected nine aged (3-yr-old) ferrets with SARS-CoV-2. The aged SARS-CoV-2-infected ferrets showed mild to moderate clinical signs associated with prolonged viral RNA shedding until 14 days postinfection. SARS-CoV-2-infected ferrets showed histopathologic lung lesion scores that significantly negatively correlated with oxygen concentrations in lung tissue. At 4 days postinfection, oxygen concentrations in lung tissue were significantly lower (mean percentage O2, 3.89 ≙ ≈ 27.78 mm Hg) than in the negative control group (mean percentage O2, 8.65 ≙ ≈ 61.4 mm Hg). In summary, we succeeded in determining the pathophysiologic oxygen conditions in the lung tissue of aged SARS-CoV-2-infected ferrets.

Quantitative diagnosis of early acute compartment syndrome using two-dimensional shear wave elastography in a rabbit model.

PURPOSE: This study explored the association of the elasticity modulus and shear wave velocity (SWV) of the tibialis anterior muscle, as measured by two-dimensional shear wave elastography (2D-SWE), with the intracompartmental pressure (ICP) determined using the Whitesides method in a New Zealand rabbit model of acute compartment syndrome (ACS). Additionally, it evaluated the viability of 2D-SWE as a noninvasive, quantitative tool for the early detection of ACS. METHODS: An ACS model was established through direct external compression by applying pressure bandaging to the lower legs of 15 New Zealand rabbits using neonatal blood pressure cuffs. Another five animals represented a non-modeled control group. To measure the elasticity modulus and SWV of the tibialis anterior muscles, 2D-SWE was employed. Blood oxygen saturation, serum creatine kinase (CK), and myoglobin levels were monitored. Subsequently, the anterior tibial compartment was dissected, and the tibialis anterior was removed for hematoxylin and eosin staining to assess muscle injury. RESULTS: The elasticity modulus and SWV of the tibialis anterior muscle increased with compression duration, as did serum CK and myoglobin levels. ICP was strongly positively correlated with these parameters, particularly mean velocity (r=0.942, P<0.001) and CK (r=0.942, P<0.001). Blood oxygen saturation was negatively correlated with ICP (r=-0.887, P<0.001). Histological analysis indicated progressive muscle cell swelling over time, with damage transitioning from reversible to irreversible and culminating in necrosis. CONCLUSION: In a rabbit ACS model, ICP was strongly positively correlated with muscle elasticity modulus/SWV. Consequently, 2D-SWE may represent a novel tool for assessing early-phase ACS.

Role of Oncostatin M in Exercise-Induced Breast Cancer Prevention.

Moderate-to-vigorous-intensity physical activity decreases the risk of breast cancer. The muscle-derived cytokine (myokine), oncostatin M (OSM), has been shown to decrease breast cancer cell proliferation. We hypothesized that OSM is involved in physical activity-induced breast cancer prevention, and that OSM antibody (Anti-OSM) administration would mitigate the effect of physical activity in a rat model of mammary carcinoma. Female Sprague Dawley rats were injected with 50 mg/kg N-methyl-N-nitrosourea to induce mammary carcinogenesis. During the 20-week study, rats were exercise trained (EX) or remained sedentary (SED). Additional groups were treated with Anti-OSM antibody (SED + Anti-OSM and EX + Anti-OSM) to explore the impact of OSM blockade on tumor latency. Exercise training consisted of treadmill acclimation and progressive increases in session duration, speed, and grade, until reaching 30 min/day, 20 m/min at 15% incline. Experimentally naïve, age-matched, female rats also completed an acute exercise test (AET) with time course blood draws to evaluate OSM plasma concentrations. Relative tumor-free survival time was significantly longer in EX animals (1.36 ± 0.39) compared to SED animals (1.00 ± 0.17; p = 0.009), SED + Anti-OSM animals (0.90 ± 0.23; p = 0.019), and EX + Anti-OSM animals (0.93 ± 0.74; p = 0.004). There were no significant differences in relative tumor latency between SED, SED + Anti-OSM, or EX + Anti-OSM animals. Following the AET, OSM plasma levels trended higher compared to baseline OSM levels (p = 0.080). In conclusion, we observed that exercise-induced delay of mammary tumor development was mitigated through Anti-OSM administration. Thus, future studies of the OSM mechanism are required to lay the groundwork for developing novel chemo-prevention strategies in women who are unable or unwilling to exercise.

Mutant TP53 switches therapeutic vulnerability during gastric cancer progression within interleukin-6 family cytokines.

Although aberrant activation of the KRAS and PI3K pathway alongside TP53 mutations account for frequent aberrations in human gastric cancers, neither the sequence nor the individual contributions of these mutations have been clarified. Here, we establish an allelic series of mice to afford conditional expression in the glandular epithelium of KrasG12D;Pik3caH1047R or Trp53R172H and/or ablation of Pten or Trp53. We find that KrasG12D;Pik3caH1047R is sufficient to induce adenomas and that lesions progress to carcinoma when also harboring Pten deletions. An additional challenge with either Trp53 loss- or gain-of-function alleles further accelerated tumor progression and triggered metastatic disease. While tumor-intrinsic STAT3 signaling in response to gp130 family cytokines remained as a gatekeeper for all stages of tumor development, metastatic progression required a mutant Trp53-induced interleukin (IL)-11 to IL-6 dependency switch. Consistent with the poorer survival of patients with high IL-6 expression, we identify IL-6/STAT3 signaling as a therapeutic vulnerability for TP53-mutant gastric cancer.

Sulfuric acid-induced skin neoplasms in immunocompetent mice.

This study investigates the carcinogenic potential of chronic dermal exposure (16 weeks) to sulfuric acid (SA) in immunocompetent mice. Clinical assessments, histopathological analyses, immunohistochemical analyses and biochemical assays were conducted to evaluate skin irritation, oxidative stress biomarkers and the potential carcinogenic effect of SA. Results indicated that prolonged exposure to SA leads to various alterations in skin structure, notably inflammation, preneoplastic and neoplastic proliferation in hair follicles, as well as hyperkeratosis and acanthosis, resulting in an increased epidermal thickness of 98.50 ± 21.6 µm. Immunohistochemistry analysis further corroborates these observations, showcasing elevated nuclear expression of p53 and Ki-67, with a significant mitotic index of (57.5% ± 2.5%). Moreover, biochemical analyses demonstrate that SA induces lipid peroxidation in the skin, evidenced by a high level of Malondialdehyde and a consequential reduction in catalase activity. These findings suggest that prolonged exposure to SA can induce skin neoplasms, highlighting the need for stringent safety measures in environments where SA is frequently used. This study underscores the potential occupational health risks associated with SA exposure.