Changes In Tissue Levels Research Articles

Role of inter- and extra-lesion tissue, transfer learning, and fine-tuning in the robust classification of breast lesions

Accurate and unbiased classification of breast lesions is pivotal for early diagnosis and treatment, and a deep learning approach can effectively represent and utilize the digital content of images for more precise medical image analysis. Breast ultrasound imaging is useful for detecting and distinguishing benign masses from malignant masses. Based on the different ways in which benign and malignant tumors affect neighboring tissues, i.e., the pattern of growth and border irregularities, the penetration degree of the adjacent tissue, and tissue-level changes, we investigated the relationship between breast cancer imaging features and the roles of inter- and extra-lesional tissues and their impact on refining the performance of deep learning classification. The novelty of the proposed approach lies in considering the features extracted from the tissue inside the tumor (by performing an erosion operation) and from the lesion and surrounding tissue (by performing a dilation operation) for classification. This study uses these new features and three pre-trained deep neuronal networks to address the challenge of breast lesion classification in ultrasound images. To improve the classification accuracy and interpretability of the model, the proposed model leverages transfer learning to accelerate the training process. Three modern pre-trained CNN architectures (MobileNetV2, VGG16, and EfficientNetB7) are used for transfer learning and fine-tuning for optimization. There are concerns related to the neuronal networks producing erroneous outputs in the presence of noisy images, variations in input data, or adversarial attacks; thus, the proposed system uses the BUS-BRA database (two classes/benign and malignant) for training and testing and the unseen BUSI database (two classes/benign and malignant) for testing. Extensive experiments have recorded accuracy and AUC as performance parameters. The results indicate that the proposed system outperforms the existing breast cancer detection algorithms reported in the literature. AUC values of 1.00 are calculated for VGG16 and EfficientNet-B7 in the dilation cases. The proposed approach will facilitate this challenging and time-consuming classification task.

Early Radiation-Induced Changes in Lung Tissue and Intercellular Junctions: Implications for Tissue Repair and Fibrosis.

Early changes in lung tissue following ionizing radiation (IR) initiate processes that may lead to either regeneration or fibrosis. Intercellular junction proteins play a crucial role in the organization and function of epithelial tissues, both under normal conditions and after injuries. Alterations in the expression and localization of these proteins can influence the fate of epithelial cells. This study aims to investigate the effects of IR on lung tissue structure, as well as on the levels and distribution of intercellular junction proteins. Wistar rats were subjected to total X-ray irradiation at doses of 2 and 10 Gy. Lung tissue samples were collected for Western blot and histological analysis 72 h post-IR. IR at doses of 2 and 10 Gy led to structural changes in lung tissue and elevated levels of E-cadherin. The 10 Gy IR resulted in increased claudin-4 and occludin in lung parenchyma, decreased claudin-8 and claudin-12 in bronchial epithelium and endothelium, and suppression of apoptosis. Data evaluation indicated that alterations in the protein composition of intercellular junctions are essential processes in lung tissue at early stages after IR, and at least some of these alterations are associated with adaptation.

Automated multi-scale computational pathotyping (AMSCP) of inflamed synovial tissue

Rheumatoid arthritis (RA) is a complex immune-mediated inflammatory disorder in which patients suffer from inflammatory-erosive arthritis. Recent advances on histopathology heterogeneity of RA synovial tissue revealed three distinct phenotypes based on cellular composition (pauci-immune, diffuse and lymphoid), suggesting that distinct etiologies warrant specific targeted therapy which motivates a need for cost effective phenotyping tools in preclinical and clinical settings. To this end, we developed an automated multi-scale computational pathotyping (AMSCP) pipeline for both human and mouse synovial tissue with two distinct components that can be leveraged together or independently: (1) segmentation of different tissue types to characterize tissue-level changes, and (2) cell type classification within each tissue compartment that assesses change across disease states. Here, we demonstrate the efficacy, efficiency, and robustness of the AMSCP pipeline as well as the ability to discover novel phenotypes. Taken together, we find AMSCP to be a valuable cost-effective method for both pre-clinical and clinical research.

Bone density in postmenopausal women with scoliosis is associated with markers of degenerative joint disease.

Bone mineral density (BMD) measured with dual x-ray absorptiometry (DXA) is the clinical standard for the diagnosis of osteoporosis and prediction of bone fracture risk. In the aging skeleton, osteoporosis is often concomitantly present with degenerative joint disease (DJD). In this study, we evaluated tissue-level changes in the differentially loaded concave (CC) and convex (CV) sides of the lumbar spine in a sample of postmenopausal women with scoliosis. We used a cumulative degeneration score to assess osteophyte formation, the severity of sclerotic morphology, and marrow changes as markers of DJD in the lumbar spine and examined the correlation between markers of DJD and BMD. More severe osteophyte growth and sclerosis were present on the CC side of the spine. The degenerative score (DS) was higher on the CC side of the lumbar spine compared with the CV side. While CC BMD was positively correlated with CC DS and marrow, CV DS was not correlated with CV BMD. Marrow changes were correlated with DS on the CC lumbar spine. These results highlight the importance of mechanoadaptive as well as broader inflammatory processes in the manifestation of degenerative changes and local mineral deposition at the lumbar spine. DXA-based BMD measurement of osteoporosis need to be contextualized within the biomechanical and degenerative conditions of a joint rather than using a strict threshold cutoff.

The Effects of Intermittent Fasting on the Size and Number of Subcutaneus Adipocytes in Obese Mouse Models

Highlights:1. This study helps bridge the gap between systemic effects and tissue-level changes, providing a deeper understanding of how histological analysis can be used to explore the effects of intermittent fasting on adipocytes and body weight regulation.2. This study contributes to obesity management through lifestyle modification, specifically intermittent fasting, by focusing on histological changes in adipose tissue. Abstract The accumulation of adipose tissue can have deleterious effects and lead to obesity. Intermittent fasting (IF), an approach that involves time-restricted eating, has gained popularity as an obesity treatment option because it enhances insulin sensitivity and promotes beneficial changes in glucose metabolism. This study used a time-restricted meal intake (TRM) approach to assess the effects of IF on the histological features of obese mouse models' subcutaneous inguinal adipose tissue. The investigation employed an in vivo experimental posttest-only control group design. Twenty male mice were divided into four groups: a normal control group, an obese control group, a TRM group with a high-fat diet (TRM-HF), and a TRM group with a standard diet (TRM-S). The TRM treatment was administered for fourteen days, with a fasting window from 4 p.m. to 8 a.m. The pre- and post-treatment weight analyses were conducted using the paired t-test for normally distributed data and the Wilcoxon test for non-normally distributed data (p<0.05). One-way analysis of variance (ANOVA) was employed for unpaired data on the post-treatment weight. Per field of view, there were an average of 120,500 cells (49,700–136,200) in the normal control group, 68,380±9,194 cells in the obese control group, 70,860±11,029 cells in the TRM-HF group, and 79,360±5,112 cells in the TRM-S group. The average cell sizes (μm3) were 56,730.142±19,273.257 in the normal control group, 138,934.331±27,670.558 in the obese control group, 106,827.767±20,580.501 in the TRM-HF group, and 68,689.114±8,219.727 in the TRM-S group. The number of cells in each group did not differ significantly, but there were significant variations in cell size. The mice receiving TRM treatment did not exhibit substantial body weight changes, whereas the obese control group showed a significant body weight increase. In conclusion, TRM has an effect on cell size but does not affect the quantity of adipocytes in subcutaneous inguinal fat tissue.

Abstract PO3-07-01: Multiscale Computational Analysis of Patient-Matched Multi-Modal Imaging of Breast Tissue Microenvironment

Abstract Introduction: Mammographic breast density is a strong quantitative cancer risk factor, but its link to underlying tissue and cellular level changes are weakly understood. Understanding the complex restructuring changes in the breast tumor microenvironment and its impact on breast density is integral to improving risk assessment and treatment strategies. A novel approach was developed to stratify mammographic dense breast tissue into areas of active dense tissue and passive dense tissue. Active dense tissue is structurally reorganizing and links to cancer dynamics, whereas passive dense mammographic tissue remains organized.1,2 A complementary wavelet-based analysis technique to measure the multiscale anisotropy of collagen fibers from Second-Harmonic Generation (SHG) imaging demonstrated clinical cancer diagnostic potential in mouse carcinoma and human pancreatic cancer.3,4 This tool is now leveraged for a multi-modal study in which patient-matched H&E tissue biopsies are imaged using both bright-field microscopy and SHG imaging to compare with the patient’s corresponding mammograms. Stratifying the mammographic density into active and passive dense areas, a correlation between biopsy tissue anisotropy and mammographic density subtypes can be calculated to help understand how tumor microenvironment changes affect a patient’s mammographic breast tissue composition. Methods: SHG and brightfield-imaged biopsy slides from 10 patients (five malignant, five benign) collected from Maine Medical Center (Maine, US) were analyzed using the 2D Wavelet Transform Modulus Maxima (WTMM) Anisotropy Method generating a large-scale and a small-scale anisotropy factor as well as a scale-combined anisotropy calculated from their large- and small-scale anisotropy separation. A multi-modal anisotropy score was calculated by adding the imaged area’s H&E combined anisotropy score with its respective SHG combined anisotropy score. This analysis was done on eight randomly selected ductal areas for each imaging modality on a slide and correlated with the measured areas of density subtypes from the whole mammographic view. Linear regression was used for determining correlation between H&E and SHG anisotropy factors as well as with active and passive mammographic density subtype measurements. Results: The malignant patients’ small-scale H&E anisotropy factor positively correlated with their small scale SHG anisotropy factor (R2=0.571). No correlation was found for the benign patients (R2=0.011). The strongest correlations were found between benign patients’ mammographic passive (positive correlation) and active (negative correlation) dense tissues vs the H&E anisotropy scale-combined factor (R2=0.858 and R2=0.961, respectively). The largest malignant patient correlation was a negative relationship between SHG anisotropy scale-combined factor and overall mammographic density (inclusive of both active and passive dense tissue) (R2=0.891). The multi-modal anisotropy score correlated with overall mammographic density for both benign (positive correlation, R2=0.698) and malignant patients (negative correlation, R2=0.773). Combining the multi-modal anisotropy factor from SHG and H&E with the active dense tissue measurement using K-Means clustering, 5/5 malignant and 4/5 benign patients were correctly classified. Conclusion: Density in mammograms correlates with underlying quantitative changes in a patient’s tissue and collagen anisotropy. Combining both H&E and SHG analysis on tissue biopsy with active and passive density metrics from computational mammography leads to the best predictive potential than any one method on their own.

The biological effects of Piezocision™ on bone for accelerated tooth movement: A systematic review of animal studies

Objectives: This systematic review aimed to assess the biological response at tissue, cellular, and molecular levels following Piezocision™ surgery, and its efficacy in accelerating orthodontic tooth movement.Material and methods: A systematic review of the literature was conducted across 4 databases following the PRISMA guidelines up to May 2022. Prospective controlled animal studies involving healthy animals under active orthodontic treatment assisted by corticotomy performed with a piezotome (Piezocision™) published in the English language without time restrictions were included. The article selection, data extraction and risk of bias assessment (SYRCLE tool) were performed by two independent blinded review authors.Results: Out of 738 articles screened, 10 studies were included with various level of bias. Biological responses were categorized into tissue, cellular, and molecular levels. Tissue-level changes included a global decrease in bone mineral content post-Piezocision™. At the cellular level, increased bone turnover activity was noted. Molecularly, elevated RANKL and OPG expression, along with increased TRAP+ and cytokines, were observed after Piezocision™. Studies confirmed Piezocision's efficacy, reporting 1.35 to 3.26 times faster tooth movements, peaking between the 3rd and 50th day post-surgery. Biological responses were transient, reversible, and proportional to surgical insult, with reactivation possible through a second Piezocision™.Conclusions: After Piezocision™ surgery, a transient and reversible biological response was described at the tissue, cellular and molecular levels, which induced faster orthodontic tooth movements. This biological response could be re-activated by an additional Piezocision™ and is proportional to the surgical injury. Systematic review registration: Prospero CRD42022303237.

Hard and soft tissue alterations using dual-zone concept versus connective tissue graft at maxillary immediate implant placement: A 1-year randomized clinical and volumetric trial.

To evaluate the esthetic outcome, as well as clinical, radiographic, and volumetric tissue alterations 1 year after immediate implant placement (IIP) with connective tissue grafting (CTG) versus dual-zone concept (DZ) at sites with thin labial bone in the esthetic zone. This randomized clinical trial included 30 patients treated with IIP simultaneous with either CTG or DZ (n = 15 each). Pink esthetic score (PES) was assessed 6 months after crown placement as the primary outcome. Amount of bone labial to the implant, labio-palatal ridge reduction, and crestal bone changes were measured via CBCT after 1 year. Volumetric analysis of linear labial soft tissue contour, interdental, and mid-facial soft tissue level changes, and total volume loss (mm3) were measured after 1 year. Similar PES was observed in the CTG (12.53 ± 1.13) and DZ (12.13 ± 1.55) groups, with no significant difference (p = 0.42). Likewise, there were no statistically significant differences found between the two groups in labio-palatal bone reduction (mm&%), interdental papillae, and mid-facial gingival levels (p > 0.05). However, the mean vertical crestal bone changes in the CTG and DZ groups were -1.1 ± 0.6 mm and 0.2 ± 1.0 mm, respectively, with a statistically significant difference (p = 0.0002). Moreover, CTG revealed less linear and total volume (mm3) loss in the labial soft tissue which was statistically significant compared to DZ (p = 0.007). Both groups demonstrated the same PES, nevertheless, volumetric analysis revealed twice total labial volume loss in DZ compared to CTG. It might be concluded that the use of CTG with IIP caused less horizontal reduction in the supra-implant complex compared to the DZ.

A comparison of bone microarchitectural and transcriptomic changes in murine long bones in response to hindlimb unloading and aging

Age- and disuse-related bone loss both result in decreases in bone mineral density, cortical thickness, and trabecular thickness and connectivity. Disuse induces changes in the balance of bone formation and bone resorption like those seen with aging. There is a need to experimentally compare these two mechanisms at a structural and transcriptomic level to better understand how they may be similar or different.Bone microarchitecture and biomechanical properties were compared between 6- and 22-month-old C57BL/6 J male control mice and 6-month-old mice that were hindlimb unloaded (HLU) for 3 weeks. Epiphyseal trabecular bone was the compartment most affected by HLU and demonstrated an intermediate bone phenotype between age-matched controls and aged controls.RNA extracted from whole-bone marrow-flushed tibiae was sequenced and analyzed. Differential gene expression analysis additionally included 4-month-old male mice unloaded for 3 weeks compared to age-matched controls. Gene ontology analysis demonstrated that there were age-dependent differences in differentially expressed genes in young adult mice. Genes related to downregulation of cellular processes were most affected in 4-month-old mice after disuse whereas those related to mitochondrial function were most affected in 6-month-old mice. Cell-cycle transition was downregulated with aging.A publicly available dataset (GSE169292) from 3-month female C57BL/6 N mice unloaded for 7 days was included in ingenuity pathway analysis (IPA) with the other datasets. IPA was used to identify the leading canonical pathways and upstream regulators in each HLU age group. IPA identified “Senescence Pathway” as the second leading canonical pathway enriched in mice exposed to HLU. HLU induced activation of the senescence pathway in 3-month and 4-month-old mice but inhibited it in 6-month-old mice.In conclusion, we demonstrate that hindlimb unloading and aging initiate similar changes in bone microarchitecture and gene expression. However, aging is responsible for more significant transcriptome and tissue-level changes compared to hindlimb unloading.

Soft Tissue Manipulation Alters RANTES/CCL5 and IL-4 Cytokine Levels in a Rat Model of Chronic Low Back Pain.

Low back pain (LBP) is a common musculoskeletal complaint that can impede physical function and mobility. Current management often involves pain medication, but there is a need for non-pharmacological and non-invasive interventions. Soft tissue manipulation (STM), such as massage, has been shown to be effective in human subjects, but the molecular mechanisms underlying these findings are not well understood. In this paper, we evaluated potential changes in the soft tissue levels of more than thirty pro- or anti-inflammatory cytokines following instrument-assisted STM (IASTM) in rats with chronic, induced LBP using Complete Freund's Adjuvant. Our results indicate that IASTM is associated with reduced soft tissue levels of Regulated on Activation, Normal T cell Expressed and Secreted (RANTES)/Chemokine (C-C motif) ligand 5 (CCL5) and increased soft tissue levels of Interleukin (IL)-4, which are pro-inflammatory and anti-inflammatory factors, respectively, by 120 min post-treatment. IASTM was not associated with tissue-level changes in C-X-C Motif Chemokine Ligand (CXCL)-5/Lipopolysaccharide-Induced CXC Chemokine (LIX)-which is the murine homologue of IL-8, CXCL-7, Granulocyte-Macrophage-Colony Simulating Factor (GM-CSF), Intercellular Adhesion Molecule (ICAM)-1, IL1-Receptor Antagonist (IL-1ra), IL-6, Interferon-Inducible Protein (IP)-10/CXCL-10, L-selectin, Tumor Necrosis Factor (TNF)-α, or Vascular Endothelial Growth Factor (VEGF) at either 30 or 120 min post-treatment. Combined, our findings raise the possibility that IASTM may exert tissue-level effects associated with improved clinical outcomes and potentially beneficial changes in pro-/anti-inflammatory cytokines in circulation and at the tissue level.

Assessment of tissue levels of miR-146a and proinflammatory cytokines in experimental cerebral toxoplasmosis following atovaquone and clindamycin treatment: An in vivo study

BackgroundDespite recent advances for treating cerebral toxoplasmosis (CT), monitoring the parasite burden and treatment response is still challenging. miRNAs are small non-coding RNAs with regulatory functions that can be used in diagnosis and treatment monitoring. We investigated the changes in miR-146a, BAG-1 gene, IL-6, and IL-10 tissue levels in the brain of BALB/c mice with chronic CT caused by the PRU strain of T. gondii following anti-parasitic and antibiotic treatment. MethodFifty-three 6-to 8-week-old BALB/c mice were infected using intraperitoneal inoculation of cerebral cysts of T. gondii PRU strain and then divided into five groups as follows: group 1 included mice treated with 100 mg/kg/d Atovaquone (AT), group 2 included mice treated with 400 mg/kg/d clindamycin (CL), group 3 included mice treated with combination therapy (AT + CL), group 4 included infected untreated mice as a positive control (PC), and; group 5 included uninfected untreated mice as negative control (NC). After the completion of the treatment course, tissue level of mir-146a, miR-155, BAG-1 gene, IL-6, and IL-10 was investigated with real-time polymerase chain reaction. The IL-6/IL-10 ratio was calculated as an indicator of immune response. Moreover, brain cyst numbers were counted on autopsy samples. ResultsmiR-146a, IL-6, IL-10, and BAG-1 genes were expressed in PC, but not in the NC group; miR-146a, IL-6, IL-10, and BAG-1 gene expression were significantly lower in AT, CL, and AT + CL compared with PC. MiR-146a and BAG-1 levels in AT and CL were not different statistically, however, they both had lower levels compared to AT + CL (P < 0.01). There was no difference in the expression of IL-6 and IL-10 between treatment groups. BAG-1 expression was significantly lower in AT, than in CL and AT + CL (P < 0.0089 and < 0.002, respectively). The PC group showed a higher ratio of IL-6/IL-10, although this increase was not statistically significant. It is noteworthy that the treatment with AT reduced this ratio; in the inter-group comparison, this ratio showed a decrease in the AT and AT + CL compared to the PC. The number of brain tissue cysts was significantly lower in AT, CL, and AT + CL, than in PC (p < 0.0001). AT had significantly lower brain cysts than CL and AT + CL (P < 0.0001). ConclusionIt seems that the factors studied in the current research (microRNA and cytokines) are a suitable index for evaluating the response to antiparasitic and antibiotic treatment. However, more studies should be conducted in the future to confirm our findings.

Stocking density affects immune and stress-related gene expression of Butter catfish (Ompok bimaculatus) fry in biofloc landscapes

Scientific research into fish wellness is critical, and the concerns about crowding-related stress due to increased stocking density are inevitable. Taking this into consideration, the study defines the physiological signature of Ompok bimaculatus (Butter catfish) in a biofloc system when subjected to varying levels of stocking density. Fish (mean weight = 1.21 g ± 0.08, n = 600) were randomly stocked in 40-L glass aquaria at stocking densities of 0.5 g/L (T1), 1 g/L (T2), 1.5 g/L (T3), and 2 g/L (T4) and fed a 35% protein diet. After the 90-day trial, the physio-biochemical, molecular, and tissue-level changes were assessed. An integrated biomarker response (IBR) analysis for the key stress indicators aided us in better understanding them. There was a significant difference in blood count between T1 and T4 (total erythrocyte count, hemoglobin, and packed cell volume). T1 had higher levels of globulin and total plasma protein, but T2 had higher levels of albumin. Only in T1 did the respiratory burst and lysozyme activity appear to be higher (p < 0.05). Increased stocking densities had a significant impact on the liver function enzymes, GOT and GPT (p < 0.05). In comparison to lower densities (T1 & T2), higher stocking density (T3 & T4) was found to raise glucose and cortisol levels (p < 0.05). Antioxidant enzymes such as catalase, glutathione-S-transferase, and malondialdehyde were found to be more pronounced in lower density tissues (T1). Furthermore, the IBR plots show that lower densities have better health than higher densities. At higher stocking densities, mRNA expression of HSP70, IL-1, and IL-20 increased (p < 0.05) in kidney and liver tissues. The Nrf-2 and Tlr-9 genes were also upregulated. Also, when stocking density was increased, tissue-level histo-architectural changes were more pronounced than when stocking density was kept low. The findings of this study show that the welfare of Butter catfish cultured at high density in biofloc systems suffers from severe stress, and therefore draw more attention to the development of a species-specific standard rearing methodology in the pursuit of a profitable aqua-farming enterprise.

High-resolution CMOS-based biosensor for assessing hippocampal circuit dynamics in experience-dependent plasticity

Experiential richness creates tissue-level changes and synaptic plasticity as patterns emerge from rhythmic spatiotemporal activity of large interconnected neuronal assemblies. Despite numerous experimental and computational approaches at different scales, the precise impact of experience on network-wide computational dynamics remains inaccessible due to the lack of applicable large-scale recording methodology. We here demonstrate a large-scale multi-site biohybrid brain circuity on-CMOS-based biosensor with an unprecedented spatiotemporal resolution of 4096 microelectrodes, which allows simultaneous electrophysiological assessment across the entire hippocampal-cortical subnetworks from mice living in an enriched environment (ENR) and standard-housed (SD) conditions. Our platform, empowered with various computational analyses, reveals environmental enrichment's impacts on local and global spatiotemporal neural dynamics, firing synchrony, topological network complexity, and large-scale connectome. Our results delineate the distinct role of prior experience in enhancing multiplexed dimensional coding formed by neuronal ensembles and error tolerance and resilience to random failures compared to standard conditions. The scope and depth of these effects highlight the critical role of high-density, large-scale biosensors to provide a new understanding of the computational dynamics and information processing in multimodal physiological and experience-dependent plasticity conditions and their role in higher brain functions. Knowledge of these large-scale dynamics can inspire the development of biologically plausible computational models and computational artificial intelligence networks and expand the reach of neuromorphic brain-inspired computing into new applications.

Sexual dimorphism in the response to chronic circadian misalignment on a high-fat diet.

Longitudinal studies associate shiftwork with cardiometabolic disorders but do not establish causation or elucidate mechanisms of disease. We developed a mouse model based on shiftwork schedules to study circadian misalignment in both sexes. Behavioral and transcriptional rhythmicity were preserved in female mice despite exposure to misalignment. Females were protected from the cardiometabolic impact of circadian misalignment on a high-fat diet seen in males. The liver transcriptome and proteome revealed discordant pathway perturbations between the sexes. Tissue-level changes were accompanied by gut microbiome dysbiosis only in male mice, biasing toward increased potential for diabetogenic branched chain amino acid production. Antibiotic ablation of the gut microbiota diminished the impact of misalignment. In the United Kingdom Biobank, females showed stronger circadian rhythmicity in activity and a lower incidence of metabolic syndrome than males among job-matched shiftworkers. Thus, we show that female mice are more resilient than males to chronic circadian misalignment and that these differences are conserved in humans.

LaMiNa: A Creative Synergistic Approach to Facial Rejuvenation.

Treating facial aging with CO2 lasering or microneedling are cornerstones of facial rejuvenation. Skin rejuvenation utilizing thermal and mechanical treatments have historically been considered too injurious to be combined at a single setting. Autologous nanofat has been shown to deliver wound healing properties. We investigated the safety and efficacy of co-terminus CO2 lasering and microneedling to resolve fine lines and rhytids in facial skin with addition of autologous nanofat to aid in recovery. Combination treatments may result in better results with faster recovery. We investigated the safety and efficacy of co-terminus CO2 lasering and microneedling to resolve fine lines and rhytids in facial skin with addition of autologous nanofat to aid in recovery. Twenty-three patients underwent facial treatment with CO2 lasering followed by microneedling and application of autologous nanofat (LaMiNa). One volunteer patient had tissue biopsies of treatment areas to demonstrate histologic tissue level changes. All patients verbally reported no pain (Numerical Rating System 0-10) following procedure and had rapid recovery within an average of 5 days. Pathology results demonstrated that CO2 and microneedling had persistent epidermal disruption and perineural inflammation at 4 days, while the introduction of autologous nanofat at the time of CO2 and microneedling resulted in full recovery of epidermis and resolution of perineural inflammation. Triple therapy (LaMiNa) with thermal CO2 remodeling and mechanical microneedling penetration have accelerated and pain-free recovery with the addition of autologous nanofat. Histologic analysis reveals that epidermal recovery is accelerated and perineural inflammation is reduced with the addition of autologous nanofat following skin remodeling from combined CO2 and microneedling.

High-fat diet-induced obesity augments the deleterious effects of estrogen deficiency on bone: Evidence from ovariectomized mice.

Several epidemiological studies have suggested that obesity complicated with insulin resistance and type 2 diabetes exerts deleterious effects on the skeleton. While obesity coexists with estrogen deficiency in postmenopausal women, their combined effects on the skeleton are poorly studied. Thus, we investigated the impact of high-fat diet (HFD) on bone and metabolism of ovariectomized (OVX) female mice (C57BL/6J). OVX or sham operated mice were fed either HFD (60%fat) or normal diet (10%fat) for 12 weeks. HFD-OVX group exhibited pronounced increase in body weight (~86% in HFD and ~122% in HFD-OVX, p < 0.0005) and impaired glucose tolerance. Bone microCT-scanning revealed a pronounced decrease in trabecular bone volume/total volume (BV/TV) (-15.6 ± 0.48% in HFD and -37.5 ± 0.235% in HFD-OVX, p < 0.005) and expansion of bone marrow adipose tissue (BMAT; +60.7 ± 9.9% in HFD vs. +79.5 ± 5.86% in HFD-OVX, p < 0.005). Mechanistically, HFD-OVX treatment led to upregulation of genes markers of senescence, bone resorption, adipogenesis, inflammation, downregulation of gene markers of bone formation and bone development. Similarly, HFD-OVX treatment resulted in significant changes in bone tissue levels of purine/pyrimidine and Glutamate metabolisms, known to play a regulatory role in bone metabolism. Obesity and estrogen deficiency exert combined deleterious effects on bone resulting in accelerated cellular senescence, expansion of BMAT and impaired bone formation leading to decreased bone mass. Our results suggest that obesity may increase bone fragility in postmenopausal women.

Developmental Polyethylene Microplastic Fiber Exposure Entails Subtle Reproductive Impacts in Juvenile Japanese Medaka (Oryzias latipes)

Microplastic pollution has been recognized as a potential threat to environmental and human health. Recent studies have shown that microplastics reside in all ecosystems and contaminate human food/water sources. Microplastic exposure has been shown to result in adverse effects related to endocrine disruption; however, data are limited regarding how exposure to current environmental levels of microplastics during development may impact reproductive health. To determine the impact of environmentally relevant, chronic, low-dose microplastic fibers on fish reproductive health, juvenile Japanese medaka were exposed to five concentrations of polyethylene fibers for 21 days, and reproductive maturity was examined to assess the later life consequences. Fecundity, fertility, and hatching rate were evaluated to determine the organismal level impacts. Gonadal tissue integrity and stage were assessed to provide insights into potential tissue level changes. Expression of key reproductive genes in male and female gonads provided a molecular level assessment. A significant delay in hatching was observed, indicating cross-generational and organismal level impacts. A significant decrease in 11-beta-dehydrogenase isozyme 2 (HSD11 2) gene expression in male medaka indicated adverse effects at the molecular level. A decrease in male expression of HSD11 2 could have an impact on sperm quality because this enzyme is crucial for conversion of testosterone into the androgen 11-ketotestosterone. Our study is one of the first to demonstrate subtle impacts of virgin microplastic exposure during development on later life reproductive health. The results suggest a possible risk of polyethylene fiber exposure for wild fish during reproductive development, and populations should be monitored closely, specifically in spawning and nursery regions. Environ Toxicol Chem 2022;41:2848-2858. © 2022 SETAC.

Petroleum-based and biodegradable microplastics alter tissue structure and fecundity in the eastern mudsnail (Ilyanassa obsoleta)

Microplastics are hazardous to aquatic life. Most experiments focus on the effects of a single type of microbead, while in the environment, organisms are exposed to irregularly shaped fragments belonging to several chemical groups. The effects of biodegradable plastics are unknown. We tested the effects of mixed-source (MS) petroleum-based and biodegradable (polylactic acid, PLA) microplastics on the intertidal eastern mudsnail, Ilyanassa obsoleta (Say, 1822), a benthic grazer. MS plastics were collected from local coastal areas (polystyrene, polyethylene, polypropylene, polyvinyl chloride and polyethylene terephthalate, combined) and were tested at three exposures, including one similar to concentrations found locally (2250 particles/kg sediment). Plastics were milled to be similar in size to the biofilm–sediment mix provided to the snails as food (32.94 µm2 for sediment, 137.99 µm2 for MS, and 31.16 µm2 for PLA). Locally relevant exposures of MS microplastics disrupted digestive gland histology, while extreme exposures additionally increased the number of hemocytes and reduced fecundity. Effects of PLA were similar to those of MS microplastics, at the extreme exposure tested here. These results indicate that both petroleum-based and biodegradable microplastics disrupt the structure of the digestive gland and that environmentally relevant exposures induce “hidden” tissue-level changes that are invisible without specialized techniques.

Effects of a novel toll-like receptor 4 antagonist IAXO-102 in a murine model of chemotherapy-induced gastrointestinal toxicity

IntroductionGastrointestinal mucositis (GIM) is a side effect of high-dose irinotecan (CPT-11), causing debilitating symptoms that are often poorly managed. The role of TLR4 in the development of GIM has been clearly demonstrated. We, therefore, aimed to investigate the potential of the TLR4 antagonist, IAXO-102, to attenuate gastrointestinal inflammation as well as supress tumour activity in a colorectal-tumour-bearing mouse model of GIM induced by CPT-11.Methods24 C57BL/6 mice received a vehicle, daily i.p. IAXO-102 (3 mg/kg), i.p. CPT-11 (270 mg/kg) or a combination of CPT-11 and IAXO-102. GIM was assessed using validated toxicity markers. At 72 h, colon and tumour tissue were collected and examined for histopathological changes and RT-PCR for genes of interest; TLR4, MD-2, CD-14, MyD88, IL-6, IL-6R, CXCL2, CXCR1, and CXCR2.ResultsIAXO-102 prevented diarrhoea in mice treated with CPT-11. Tumour volume in IAXO-102-treated mice was lower compared to vehicle at 48 h (P < 0.05). There were no differences observed in colon and tumour weights between the treatment groups. Mice who received the combination treatment had improved tissue injury score (P < 0.05) in the colon but did not show any improvements in cell proliferation or apoptotic rate. Expression of all genes was similar across all treatment groups in the tumour (P > 0.05). In the colon, there was a difference in transcript expression in vehicle vs. IAXO-102 (P < 0.05) and CPT-11 vs. combination (P < 0.01) in MD-2 and IL-6R, respectively.ConclusionIAXO-102 was able to attenuate symptomatic parameters of GIM induced by CPT-11 as well as reduce tissue injury in the colon. However, there was no effect on cell proliferation and apoptosis. As such, TLR4 activation plays a partial role in GIM development but further research is required to understand the specific inflammatory signals underpinning tissue-level changes.

Sesamin Ameliorates Fine Particulate Matter (PM2.5)-Induced Lung Injury via Suppression of Apoptosis and Autophagy in Rats.

Lung damage can be caused by fine particulate matter (PM2.5). Thus, effective prevention strategies for PM2.5-induced lung injury are urgently required. Sesamin (Ses) is a natural polyphenolic compound that has attracted considerable attention of researchers because of its wide range of pharmacological activities. The present study aims to elucidate whether Ses pretreatment could alleviate PM2.5-induced lung damage and identify its possible mechanisms. Sprague-Dawley rats were orally dosed with 0.5% carboxymethylcellulose (CMC) and different concentrations of Ses once a day for 21 days. Then, the rats of the PM2.5 exposure group and Ses-treated group were exposed to PM2.5 by intratracheal instillation every 2 days for 1 week. Biomarkers associated with lung injury were detected in bronchoalveolar lavage fluid (BALF). Lung tissue was collected for histology, inflammation, oxidative stress, immunohistochemistry, and Western blot. Our results showed that PM2.5 exposure could cause pathological changes in lung tissue and increase levels of TP, AKP, and ALB in BALF. Meanwhile, exposure to PM2.5 can cause oxidative stress and inflammation in the lungs. In addition, Ses pretreatment could ameliorate histopathological injury, oxidative stress, and inflammation caused by PM2.5 exposure. It could also inhibit PM2.5-induced apoptosis and upregulation of autophagy-associated proteins. Collectively, our study indicated that Ses pretreatment could ameliorate PM2.5-induced lung damage via inhibiting apoptosis and autophagy in rats.