Tissue Pathology Research Articles

The impact of tertiary lymphoid structures on tumor prognosis and the immune microenvironment in non-small cell lung cancer

Non-small cell lung cancer (NSCLC) is a common malignancy whose prognosis and treatment outcome are influenced by many factors. Some studies have found that tertiary lymphoid structures (TLSs) in cancer may contribute to prognosis and the prediction of immunotherapy efficacy However, the combined role of TLSs in NSCLC remains unclear. We accessed The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases to obtain mRNA sequencing data and clinical information as the TCGA cohort, and used our own sample of 53 advanced NSCLC as a study cohort. The samples were divided into TLS+ and TLS- groups by pathological tissue sections. Patients of the TLS+ group had a better OS (p = 0.022), PFS (p = 0.042), and DSS (p = 0.004) in the TCGA cohort, and the results were confirmed by the study cohort (PFS, p = 0.012). Furthermore, our result showed that the count and size of TLSs are closely associated with the efficacy of immunotherapy. In addition, the TLS+ group was associated with better immune status and lower tumor mutation load. In the tumor microenvironment (TME), the expression levels of CD4+ T cells and CD8+ T cells of different phenotypes were associated with TLSs. Overall, TLSs are a strong predictor of survival and immunotherapeutic efficacy in advanced NSCLC, and T cell-rich TLSs suggest a more ordered and active immune response site, which aids in the decision-making and application of immunotherapy in the clinic.

Weissella paramesenteroides NRIC1542 inhibits dextran sodium sulfate-induced colitis in mice through regulating gut microbiota and SIRT1/NF-κB signaling pathway.

Inflammatory bowel disease (IBD) is a kind of recurrent inflammatory disorder of the intestinal tract. The purpose of this study was to investigate the effects of Weissella paramesenteroides NRIC1542 on colitis in mice. A colitis model was induced by adding 1.5% DSS to sterile distilled water for seven consecutive days. During this process, mice were administered different concentrations of W. paramesenteroides NRIC1542. Colitis was assessed by DAI, colon length and hematoxylin-eosin staining of colon sections. The expressions of NF-κB signaling proteins and the tight junction proteins ZO-1 and occludin were detected by western blotting, and the gut microbiota was analyzed by 16S rDNA. The results showed that W. paramesenteroides NRIC1542 significantly reduced the degree of pathological tissue damage and the levels of TNF-α and IL-1β in colonic tissue, inhibiting the NF-κB signaling pathway and increasing the expression of SIRT1, ZO-1 and occludin. In addition, W. paramesenteroides NRIC1542 can modulate the structure of the gut microbiota, characterized by increased relative abundance of Muribaculaceae_unclassified, Paraprevotella, Prevotellaceae_UCG_001 and Roseburia, and decrease the relative abundance of Akkermansia and Alloprevotella induced by DSS. The above results suggested that W. paramesenteroides NRIC1542 can protect against DSS-induced colitis in mice through anti-inflammatory, intestinal barrier maintenance and flora modulation.

Self-supervised learning for characterising histomorphological diversity and spatial RNA expression prediction across 23 human tissue types

As vast histological archives are digitised, there is a pressing need to be able to associate specific tissue substructures and incident pathology to disease outcomes without arduous annotation. Here, we learn self-supervised representations using a Vision Transformer, trained on 1.7 M histology images across 23 healthy tissues in 838 donors from the Genotype Tissue Expression consortium (GTEx). Using these representations, we can automatically segment tissues into their constituent tissue substructures and pathology proportions across thousands of whole slide images, outperforming other self-supervised methods (43% increase in silhouette score). Additionally, we can detect and quantify histological pathologies present, such as arterial calcification (AUROC = 0.93) and identify missing calcification diagnoses. Finally, to link gene expression to tissue morphology, we introduce RNAPath, a set of models trained on 23 tissue types that can predict and spatially localise individual RNA expression levels directly from H&E histology (mean genes significantly regressed = 5156, FDR 1%). We validate RNAPath spatial predictions with matched ground truth immunohistochemistry for several well characterised control genes, recapitulating their known spatial specificity. Together, these results demonstrate how self-supervised machine learning when applied to vast histological archives allows researchers to answer questions about tissue pathology, its spatial organisation and the interplay between morphological tissue variability and gene expression.

Clinical and diagnostic implications of Alzheimer's disease copathology in Lewy body disease.

Concomitant Alzheimer's disease (AD) pathology is a frequent event in the context of Lewy body disease (LBD), occurring in approximately half of all cases. Evidence shows that LBD patients with AD copathology show an accelerated disease course, a greater risk of cognitive decline and an overall poorer prognosis. However, LBD-AD cases may show heterogeneous motor and non-motor phenotypes with a higher risk of dementia and, consequently, be not rarely misdiagnosed. In this review, we summarize the current understanding of LBD-AD by discussing the synergistic effects of AD neuropathological changes and Lewy pathology and their clinical relevance. Furthermore, we provide an extensive overview of neuroimaging and fluid biomarkers under assessment for use in LBD-AD and their possible diagnostic and prognostic values. AD pathology can be predicted in vivo by means of CSF, MRI and PET markers, whereas the most promising technique to date for identifying Lewy pathology in different biological tissues is the α-synuclein seed amplification assay. Pathological imaging and CSF AD biomarkers are associated with a higher likelihood of cognitive decline in LBD but do not always mirror the neuropathological severity as in pure AD. Implementing the use of blood-based AD biomarkers might allow faster screening of LBD patients for AD copathology, thus improving the overall diagnostic sensitivity for LBD-AD. Finally, we discuss the literature on novel candidate biomarkers being exploited in LBD-AD to investigate other aspects of neurodegeneration, such as neuroaxonal injury, glial activation and synaptic dysfunction. The thorough characterization of AD copathology in LBD should be taken into account when considering differential diagnoses of dementia syndromes, to allow prognostic evaluation on an individual level, and to guide symptomatic and disease-modifying therapies.

Investigating the involvement of the NLRP3/ASC/caspase-1 and NF-κb/MAPK pathways in the pathogenesis of gouty arthritis: Insights from irradiated and non-irradiated Trifolium alexandrium L. extracts and some metabolites

Ethnopharmacological relevanceTrifolium alexandrinum L. (TA), has traditionally been used in folk medicine for its anti-inflammatory properties against hyperuricemia and gout. However, the specific mechanisms of action of TA have not been thoroughly studied. Aim of the workThis study aimed to evaluate the protective effects of irradiated (TR25) and non-irradiated (TR0) Trifolium alexandrinum L. aqueous extract (TAAE), along with two isolated compounds, caffeine (CAF) and saponin (SAP), in a rat model of acute gouty arthritis (GA). Materials and methodsThe GA model was established by injecting a monosodium urate (MSU) suspension into the knee joint. Synovial tissue pathology was assessed, and levels of TNF-α, IL-6, IL-1β, NF-κB, mTOR, AKT1, PI3K, NLRP3, and ASC were measured by ELISA. mRNA expression of ERK1, JNK, and p-38 MAPK was detected using qRT-PCR, and Caspase-1 protein expression was assessed by immunohistochemical analysis. Knee swelling, uric acid levels, liver and kidney function, and oxidative stress markers were also evaluated. ResultsTAAE analysis identified 170 compounds, with 73 successfully identified using LC-HR-MS/MS, including caffeine citrate and theasapogenol B glycoside as the main constituents. The studied materials demonstrated significant protective effects against GA. TR25 administration significantly mitigated knee joint circumference compared to other treatments. It demonstrated potential in alleviating hyperuricemia, renal and hepatic impairments induced by MSU crystals. TR25 also alleviated oxidative stress and reduced levels of IL1β, IL-6, TNF-α, and NF-κB. Weak Caspase-1 immune-positive staining was observed in the TR25 group. TR25 decreased NLRP3 and ASC expression, reducing inflammatory cytokine levels in GA. It effectively inhibited the PI3K, AKT, and mTOR signaling pathways, promoting autophagy. Additionally, TR25 suppressed ERK1, JNK, and p-38 MAPK gene expression in synovial tissue. These effects were attributed to various components in TAAE, such as flavonoids, phenolic acids, tannins, alkaloids, and triterpenes. ConclusionImportantly, irradiation (25 KGy) enhanced the antioxidant effects and phtchemical contents of TAAE. Additionally, TR0, TR25, CAF, and SAP exhibited promising protective effects against GA, suggesting their therapeutic potential for managing this condition. These effects were likely mediated through modulation of the NLRP3/ASC/Caspase-1 and ERK/JNK/p-38 MAPK signaling pathways, as well as regulation of the PI3K/AKT/mTOR pathway. Further research is warranted to fully elucidate the underlying mechanisms and optimize their clinical applications.

Specific depletion of myeloid-derived suppressor cells by the chemotherapeutic agent 5-Fluorouracil enhances protective immune response in Paracoccidioidomycosis.

Paracoccidioidomycosis (PCM), a systemic mycosis in Latin America, is regulated by suppressive mechanisms mediated by tolerogenic plasmacytoid-dendritic-cells and regulatory T-cells. Our recent studies revealed that myeloid-derived suppressor cells (MDSCs), are important mediators in PCM. Their suppressive activity on Th1/Th17 immunity was shown to be mediated by inhibitory effect of IL-10, IDO-1 and PD-L1. Studies revealed the chemotherapeutic drug 5-Fluorouracil (5-FU) as a selective MDSC apoptosis-inducing agent, but its in vivo effect on infectious processes remains poorly investigated. MDSCs and other leukocytes were evaluated in the lungs of 5-FU-treated mice after four, six, and eight weeks of P. brasiliensis infection. Disease severity and immunological response were evaluated in MDSCs-depleted. 5-FU treatment caused a significant reduction of pulmonary MDSCs and fungal loads. The specific depletion of MDSCs by 5-FU reduced all pulmonary CD4+ T-cell populations (Th1, Th2, Th17, and Treg) resulting in improved tissue pathology and increased survival rates. Importantly, this reduction was concomitant with increased frequencies of Th1/Th17 cells and the increased levels of Th1/Th2/Th17 cytokines in the lungs and liver of treated mice suggesting an early and efficient protective effect of these cells. Furthermore, the immuneprotection conferred by the specific depletion of MDSCs by 5FU treatment could be reversed by the adoptive transfer of MDSCs. 5-FU treatment depletes lung-MDSCs of P. brasiliensis-infected mice resulting in enhanced immunity. The protective effect of 5-FU treatment in pulmonary PCM suggests that the specific depletion of MDSCs can be viewed as a potential immunotherapeutic tool for PCM.

Paeoniae Decoction restores intestinal barrier dysfunction by promoting the interaction between ILC3 and gut flora

BackgroundIntestinal barrier dysfunction is a significant contributor to the recurrence and refractory of ulcerative colitis (UC). Promoting the interaction between group 3 innate lymphoid cells (ILC3s) and gut flora is a valuable strategy for mucosal repair. Paeoniae decoction (PD) is a compound commonly used in clinical treatment of UC, but its exact mechanism remains unclear. PurposeWe aimed to investigate the protective effect of PD on intestinal mucosal injury induced by dextran sulfate sodium (DSS) in chronic colitis, as well as to elucidate its potential mechanism. MethodsC57BL/6 mice were induced with chronic colitis by 2 % DSS and divided into four groups: control group, model group, PD low dose (4 g/kg), and high dose (8 g/kg) group. The effectiveness of PD in treating chronic colitis mice was evaluated based on changes in body weight, colon length, colon pathological tissue scores, and the mRNA levels of inflammatory factors IL-6 and IL-1β. The expressions of intestinal epithelial tight junction proteins (ZO-1 and Occludin), IL-22, and MUC2 were observed using immunofluorescence and RT-PCR. Additionally, the proportion of ILC3 and natural cytotoxicity receptor (NCR)+ ILC3 in the colon were detected using flow cytometry. Furthermore, UHPLC-QE-MS was utilized to identify chemical components of PD and network pharmacology was employed to predict potential pathways for PD intervention in UC. Subsequently, MNK-3 cells (ILC3 in vitro cell line) and NCM460 cells were used to verify the network pharmacology results. Finally, the effects of PD on UC gut flora have been explored using in vitro fermentation and 16S rDNA techniques. ResultsThe results showed that PD significantly restored body weight and colon length in mice with chronic colitis, while also reducing colon inflammatory cell infiltration and the expression of IL-6 and IL-1β. Additionally, PD notably promoted the expression of MUC2, ZO-1, Occludin, and IL-22, as well as increasing the ratio of ILC3 and NCR+ILC3. UHPLC-QE-MS analysis identified 443 components of PD, and network pharmacology suggested that PD could target the aryl hydrocarbon receptor (AHR) signaling pathway, which was confirmed by MNK-3 cells and in vitro fermentation experiments. Furthermore, MNK-3-conditioned medium (CM) increased the expression of ZO-1 and Occludin in NCM460 cells. In addition, 16S rDNA results indicated that PD promoted the abundance of Lactobacillales, thus contributing to mucosal damage repair by activating the AHR signal in ILC3s. ConclusionIn summary, our study demonstrates that PD repairs intestinal mucosal damage in chronic colitis by regulating the interaction of gut flora with ILC3, and the specific mechanism is related to the activation of AHR signaling pathway.

NUSAP1 Promotes Immunity and Apoptosis by the SHCBP1/JAK2/STAT3 Phosphorylation Pathway to Induce Dendritic Cell Generation in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the most common type of liver cancer and is associated with high morbidity and mortality rates. The aims of this study were to investigate the immune-promoting action of nucleolar and spindle-associated protein 1 (NUSAP1) and identify an immunotherapy target for HCC. The Cancer Genome Atlas (TCGA) was used to analyze interaction molecules and immune correlation. The interaction between NUSAP1 and SHC binding and spindle associated 1 (SHCBP1) was examined. The role of the SHCBP1/Janus kinase 2/signal transducer and activator of transcription 3 (SHCBP1/JAK2/STAT3) pathway in this process was explored. After co-culture with HCC cell lines, the differentiation of peripheral blood mononuclear cells (PBMCs) into dendritic cells (DC) was evaluated by measuring the expression of surface factors CD1a and CD86. Pathological tissues from 50 patients with HCC were collected to validate the results of cell experiments. The expression levels of CD1a and CD86 in tissues were also determined. The results show that NUSAP1 interacted with SHCBP1 and was positively correlated with DC. In HCC cell lines, an interaction was observed between NUSAP1 and SHCBP1. It was verified that NUSAP1 inhibited the JAK2/STAT3 phosphorylation pathway by blocking SHCBP1. After co-culture, the levels of CD1a and CD86 in PBMC were elevated. In the clinical specimens, CD1a and CD86 expression levels were significantly higher in the high-NUSAP1 group versus the low-NUSAP1 group. In Summary, NUSAP1 enhanced immunity by inhibiting the SHCBP1/JAK2/STAT3 phosphorylation pathway and promoted DC generation and HCC apoptosis. NUSAP1 may be a target of immunotherapy for HCC.

Insulin-like growth factor-binding protein 7 (IGFBP7): A microenvironment-dependent regulator of angiogenesis and vascular remodeling.

Insulin-like Growth Factor-Binding Protein 7 (IGFBP7) is an extracellular matrix (ECM) glycoprotein, highly enriched in activated vasculature during development, physiological and pathological tissue remodeling. Despite decades of research, its role in tissue (re-)vascularization is highly ambiguous, exhibiting pro- and anti-angiogenic properties in different tissue remodeling states. IGFBP7 has multiple binding partners, including structural ECM components, cytokines, chemokines, as well as several receptors. Based on current evidence, it is suggested that IGFBP7's bioactivity is strongly dependent on the microenvironment it is embedded in. Current studies indicate that during physiological angiogenesis, IGFBP7 promotes endothelial cell attachment, luminogenesis, vessel stabilization and maturation. Its effects on other stages of angiogenesis and vessel function remain to be determined. IGFBP7 also modulates the pro-angiogenic properties of other signaling factors, such as VEGF-A and IGF, and potentially acts as a growth factor reservoir, while its actual effects on the factors' signaling may depend on the environment IGFBP7 is embedded in. Besides (re-)vascularization, IGFBP7 clearly promotes progenitor and stem cell commitment and may exhibit anti-inflammatory and anti-fibrotic properties. Nonetheless, its role in inflammation, immunomodulation, fibrosis and cellular senescence is again likely to be context-dependent. Future studies are required to shed more light on the intricate functioning of IGFBP7.

Fraxin alleviates oral lichen planus by suppressing OCT3-mediated activation of FGF2/NF-κB pathway.

Oral lichen planus (OLP) is a carcinogenic chronic inflammatory oral disease, which lacks effective treatments. Fraxin is an active ingredient of the traditional Chinese medicine Qin Pi, which has an anti-inflammatory effect, but its effect on OLP is unclear. The aim of this study was to investigate the therapeutic effect of fraxin on OLP and the underlying mechanism. Human immortalized keratinocytes (HaCat) were incubated with fraxin (10, 20, or 40µM) for 48h and then treated with 10µg/mL LPS for 24h. Cell viability and apoptosis were detected. Next, the interaction between OCT3 and FGF2 was predicted by online database and verified by Co-IP analysis. Fraxin, Ad-OCT3, sh-OCT3, and sh-FGF2 were, respectively, applied to treat LPS-incubated HaCat cells, and cell viability, apoptosis, and secretion of inflammatory factors were detected with MTT, flow cytometry, and ELISA assays. Then, the involvement of OCT3 and FGF2 in the prevention of fraxin on HaCat cells from LPS-induced cell apoptosis and inflammation was investigated through multiple rescue experiments. In addition, OLP models were constructed in VDR-/- mice and NOD/SCID mice by injecting with human OLP pathological tissue homogenates to verify the therapeutic effect of fraxin on OLP. Fraxin treatment increased cell viability and reduced cell apoptosis and the secretion of IL-6 and TNF-α in a dose-dependent manner. OCT3 was significantly upregulated in oral mucosa tissues of OLP mice. OCT3 silencing inhibited LPS-induced cell apoptosis and secretion of inflammatory factors. Fraxin incubation reduced the expression of OCT3, and OCT3 interacted with FGF2 to upregulate FGF2 protein. FGF2 silencing reduced the expression of p-p65/NF-κB protein and improved LPS-induced cell apoptosis and secretion of inflammatory factors. OCT3 overexpression increased the expression of FGF2 and p-p65/NF-κB proteins, rh-FGF2 aggravated this effect, while FGF2-Neu-Ab reversed this effect. The results of in vivo experiments showed that fraxin alleviated cell apoptosis and inflammation in oral buccal mucosa tissues of OLP mice. Fraxin inhibited cell apoptosis and inflammation by suppressing OCT3-mediated activation of the FGF2/NF-κB pathway, alleviating the progression of OLP.

Hong Guo Ginseng Guo (HGGG) protects against kidney injury in diabetic nephropathy by inhibiting NLRP3 inflammasome and regulating intestinal flora

BackgroundDiabetic nephropathy (DN) is one of the most serious complications of diabetes which leads to end-stage renal failure and approximately one-third of patients need dialysis. There is still a lack of effective and specific treatment for DN. Searching new drugs from natural foods is an alternative approach to treat diabetes and its complications. Hong Guo Ginseng Guo (HGGG), a berry with palatability and nutritional benefits, has exhibited medicinal properties to mitigate the progression of DN. PurposeThis study investigates the effects of HGGG on streptozotocin (STZ)-induced diabetic nephropathy (DN) in rats and elucidates the mechanisms underlying its reno-protective and diabetes management benefits. MethodsThe LC-MS spectra method identified the primary ingredients in HGGG. To induce DN, male Sprague-Dawley (SD) rats received a single intraperitoneal injection of 75 mg/kg STZ. Over an eight-week treatment period, we assessed biochemical parameters including blood glucose, urine albumin-to-creatinine ratio (UACR), blood urea nitrogen (BUN), and urine N-acetyl-beta-d-glucosaminidase (NAG). Tissue pathology was examined using Masson's trichrome, Periodic Acid-Schiff (PAS), and Hematoxylin-Eosin (H&E) stains. We analyzed pro-inflammatory mediators and tissue fibrosis extent using Western blotting and immunohistochemistry. Gut microbiota composition was characterized via 16S rDNA sequencing. ResultsSeventeen chemical compounds were identified, with lobetyolin, luteolin, and rutin highlighted as the primary active elements. HGGG extract appeared to confer renal protection, demonstrated by improvements in UACR, BUN, and urine NAG levels. The reno protective effects in HGGG-treated DN rats were linked to reduced renal fibrosis and inhibition of the NLRP3 inflammasome. Additionally, HGGG administration improved gut barrier integrity and altered the gut microbiota in DN rats, increasing the relative abundance of beneficial bacteria known for regulating polyamines and producing short-chain fatty acids (SCFAs), including Ruminococcus, Barnesiella_sp, Anaerovoracaceae, and Prevotellaceae_NK3B31. Meanwhile, treatment with HGGG decreasing the presence of Oscillospira, potential pathogens responsible for producing lipopolysaccharide (LPS). ConclusionHGGG has potential as a beneficial fruit for managing diabetes and its associated complications through modulation of the gut microbiota.

Evidence for enduring cardiac and multiorgan toxicity after repeated exposure to the synthetic cannabinoid JWH-018 in male rats

The use of synthetic cannabinoid receptor agonists (SCRAs) represents a public health concern. Besides abuse liability and cognitive impairments, SCRAs consumption is associated with serious medical consequences in humans, including cardiotoxicity. The precise mechanisms underlying cardiac or other toxicities induced by SCRAs are not well understood. Here, we used in silico, in vivo, and ex vivo approaches to investigate the toxicological consequences induced by exposure to the SCRA JWH-018. Along with in silico predictive toxicological screening of 36 SCRAs by MC4PC software, adult male Sprague-Dawley rats were repeatedly exposed to JWH-018 (0.25 mg/kg ip) for 14 consecutive days, with body temperature and cardiovascular parameters measured over the course of treatment. At 1 and 7 days after JWH-018 discontinuation, multiorgan tissue pathologies and heart mitochondria bioenergetics were assessed. The in silico findings predicted risk of cardiac adverse effects specifically for JWH-018 and other aminoalkylindole SCRAs (i.e., electrocardiogram abnormality and QT prolongation). The results from rats revealed that repeated, but not single, JWH-018 exposure induced hypothermia and cardiovascular stimulation (e.g., increased blood pressure and heart rate) which persisted throughout treatment. Post-mortem findings demonstrated cardiac lesions (i.e., vacuolization, waving, edema) 1 day after JWH-018 discontinuation, which may contribute to lung, kidney, and liver tissue degeneration observed 7 days later. Importantly, repeated JWH-018 exposure induced mitochondrial dysfunction in cardiomyocytes, i.e., defective lipid OXPHOS, which may represent one mechanism of JWH-018-induced toxicity. Our results demonstrate that repeated administration of even a relatively low dose of JWH-018 is sufficient to affect cardiovascular function and induce enduring toxicological consequences, pointing to risks associated with SCRA consumption.

M2-type tumor-associated macrophages upregulated PD-L1 expression in cervical cancer via the PI3K/AKT pathway

Background and purposePD-1/PD-L1 inhibitors have become a promising therapy. However, the response rate is lower than 30% in patients with cervical cancer (CC), which is related to immunosuppressive components in tumor microenvironment (TME). Tumor-associated macrophages (TAMs), as one of the most important immune cells, are involved in the formation of tumor suppressive microenvironment. Therefore, it will provide a theoretical basis for curative effect improvement about the regulatory mechanism of TAMs on PD-L1 expression.MethodsThe clinical data and pathological tissues of CC patients were collected, and the expressions of PD-L1, CD68 and CD163 were detected by immunohistochemistry. Bioinformatics was used to analyze the macrophage subtypes involved in PD-L1 regulation. A co-culture model was established to observe the effects of TAMs on the morphology, migration and invasion function of CC cells, and the regulatory mechanism of TAMs on PD-L1.ResultsPD-L1 expression on tumor cells could predict the poor prognosis of patients. And there was a strong correlation between PD-L1 expression with CD163+TAMs infiltration. Similarly, PD-L1 expression was associated with M1/M2-type TAMs infiltration in bioinformatics analysis. The results of cell co-culture showed that M1/M2-type TAMs could upregulate PD-L1 expression, especially M2-type TAMs may elevate the PD-L1 expression via PI3K/AKT pathway. Meanwhile, M1/M2-type TAMs can affect the morphological changes, and enhance migration and invasion abilities of CC cells.ConclusionsPD-L1 expression in tumor cells can be used as a prognostic factor and is closely related to CD163+TAMs infiltration. In addition, M2-type TAMs can upregulate PD-L1 expression in CC cells through PI3K/AKT pathway, enhance the migration and invasion capabilities, and affect the tumor progression.

Nonionizing diagnostic imaging modalities for visualizing health and pathology of periodontal and peri-implant tissues.

Radiographic examination has been an essential part of the diagnostic workflow in periodontology and implant dentistry. However, radiographic examination unavoidably involves ionizing radiation and its associated risks. Clinicians and researchers have invested considerable efforts in assessing the feasibility and capability of utilizing nonionizing imaging modalities to replace traditional radiographic imaging. Two such modalities have been extensively evaluated in clinical settings, namely, ultrasonography (USG) and magnetic resonance imaging (MRI). Another modality, optical coherence tomography (OCT), has been under investigation more recently. This review aims to provide an overview of the literature and summarize the usage of USG, MRI, and OCT in evaluating health and pathology of periodontal and peri-implant tissues. Clinical studies have shown that USG could accurately measure gingival height and crestal bone level, and classify furcation involvement. Due to physical constraints, USG may be more applicable to the buccal surfaces of the dentition even with an intra-oral probe. Clinical studies have also shown that MRI could visualize the degree of soft-tissue inflammation and osseous edema, the extent of bone loss at furcation involvement sites, and periodontal bone level. However, there was a lack of clinical studies on the evaluation of peri-implant tissues by MRI. Moreover, an MRI machine is very expensive, occupies much space, and requires more time than cone-beam computed tomography (CBCT) or intraoral radiographs to complete a scan. The feasibility of OCT to evaluate periodontal and peri-implant tissues remains to be elucidated, as there are only preclinical studies at the moment. A major shortcoming of OCT is that it may not reach the bottom of the periodontal pocket, particularly for inflammatory conditions, due to the absorption of near-infrared light by hemoglobin. Until future technological breakthroughs finally overcome the limitations of USG, MRI and OCT, the practical imaging modalities for routine diagnostics of periodontal and peri-implant tissues remain to be plain radiographs and CBCTs.

Lymphatic Vessels in the Inner Ear of Patients With Meniere Disease: A Novel Pathological Finding.

Meniere disease, characterized by intermittent episodes of vertigo, fluctuating sensorineural hearing loss, tinnitus, and aural pressure, is a common cause of vertigo in humans. The pathogenesis of Meniere disease remains unknown. The current study aimed to describe a novel pathological change discovered in the inner ears of patients with Meniere disease who underwent labyrinthectomy. This retrospective case-control study was conducted with 21 patients with MD who underwent labyrinthectomy. A total of 15 patients diagnosed with acoustic neuroma or glomus jugular tumor were review over the same period of time as control. The clinical information of the patients and the pathological features of the membrane are described. The new pathological tissue was a morbid membrane structure sealing the round window, characterized by the formation of lymphatic capillaries. Histochemical and immunofluorescent staining was positive for D2-40, LYVE-1, podoplanin, and PROX1, which are the classical markers of the lymphatic vessels. Transmission electron microscopy revealed that the lymph capillaries lacked a typical basement membrane and that their ends were blind, composed of a single layer of endothelial cells with valval connection structures between adjacent capillary epithelial cells. This is the first report of lymphatic vessels in the human inner ear, and this pathological structure is a completely new discovery. The lymphatic vessels may develop due to inflammation or decompensation of pressure in the inner ear, suggesting that the inner ear can reactively form lymphatic vessels in some inflammation and fluid flow-dependent pathological conditions. The current findings help in improving our understanding of the pathogenesis of Meniere disease.

A Retrospective Hospital-Based Study to Evaluate the Results of Extensor Tendon Injuries of the Hand, Wrist, and Forearm Treated Surgically in a Tertiary Care Hospital.

Introduction The important factors determining the treatment of extensor tendon injuries include the anatomical zone, type of injury, mode of injury, chronicity, and pathology of the adjacent tissues (principally the skin, bone, and joints). Very few studies have collectively studied the outcomes of all the wrist, forearm, and hand extensors.Hence, the major aim of this study was to evaluate the resultsof extensor tendon injuries of the hand, wrist, and forearm that were treated surgically. Methodology This was a hospital-based retrospective study done in a tertiary teaching hospital in South India. A total of 30 patients (23 males, seven females) were included in the study.All the cases of extended tendon injuries of the wrist, hand, and forearm were treated surgically, and those willing to participate were included in the study afterobtaining institutional ethics committee approval. Results The study included 30 patients, predominantly males (76.66%). The majority were aged 31-40 years (33.33%). Occupational injuries were the most common cause (36.66%), followed by road traffic accidents (RTAs) and glass cuts (26.66%). Right-sided injuries were more frequent (56.66%), with zone VI being the most affected (43.33%). Extensor digitorum communis was the most injured tendon (40%). Various suture techniques were used, including horizontal mattress and modified Kessler's. Complications occurred in four patients, including hematoma and surgical site infections. Functional outcomes, assessed by Miller's Criteria, indicated extension lag and flexion loss as key recovery measures. Conclusion Hand function is essential for daily life activities, and optimal repair and reconstruction of extensor tendon injuries are crucial to avoid functional disability. While the present study demonstrated positive outcomes, further research with larger sample sizes and more rigorous designs is needed to validate these findings and improve treatment strategies for hand injuries.

Establishment and evaluation of a premenstrual syndrome rat model induced by progesterone-withdrawal and emotional-stimulation

Premenstrual syndrome(PMS) lacks a highly consistent and feasible animal model that aligns with diagnostic and therapeutic standards in both traditional Chinese medicine(TCM) and western medicine, resulting in a lack of reliable experimental carriers for studying its pathogenesis and pharmacological effects. This study aims to systematically analyze the biological implications of PMS from the perspective of the "disease-syndrome-symptom" correlation and establish preparation and evaluation methods for an improved animal model of this disease. Firstly, clinical symptom gene sets related to the Qi stagnation syndromes due to liver depression and blood stasis in PMS in both modern medicine and TCM diagnostic standards were collected through GeneCards, DisGeNET, Mala-Cards, and the System of Foundational Diagnostic Association(SoFDA) database, as well as published literature. Based on the interaction information between genes, a "disease-syndrome-symptom" correlation network of PMS was established. Based on data mining results, an improved rat model of PMS was prepared by combining chronic restraint stress with the classical progesterone-withdrawal mo-del to simulate emotional depression caused by external environmental stimuli during the clinical onset process, inducing pathological damage from both physiological and emotional dimensions. The evaluation of the improved model before and after modification included open field experiment scores, organ indices, ovarian pathological changes, serum levels of estradiol(E_2), follicle-stimulating hormone/luteinizing hormone(FSH/LH), 5-hydroxytryptamine(5-HT), dopamine(DA), norepinephrine(NE), as well as coagulation parameters and hemorheology indexes. By calculating the degree, betweenness, and closeness centrality of nodes in the "disease-syndrome-symptom" correlation network, 163 core genes with topological importance were identified. Further biological function mining results indicated that core genes in PMS mainly participated in the regulation of the "nervous-endocrine-immune" system and pathways related to circulatory disorders. Mapping analysis of clinical phenotype symptom gene sets suggested significant correlations between core genes in PMS and depressive symptoms and pain symptoms caused by blood stasis. Compared with the simple progesterone withdrawal model, rats subjected to combined injections and restraint stress showed more significant abnormalities in open field experiment scores, ovarian tissue pathology, serum neurotransmitter levels of 5-HT and DA, as well as serum hormone levels of E_2 and FSH/LH. The modified modeling conditions exacerbated the pathological changes in blood rheology, coagulation function, and red blood cell morphology in model rats, confirming that the improved rat model could characterize the "nervous-endocrine-immune" system disorder and circulatory system disorders in the occurrence and progression of PMS, consistent with the clinical diagnostic and therapeutic standards of both TCM and western medicine. The establishment of the improved rat model of PMS can provide a reliable experimental carrier for elucidating the pathogenesis of PMS and discovering and evaluating therapeutic drugs. It also provides references for objectively reflecting the clinical characteristics of PMS in TCM and western medicine and precision treatment.

Poster 225: Assessing Hip-RSI in Patients that Undergo Hip Arthroscopy for Femoroacetabular Impingement

Objectives: Femoroacetabular impingement (FAI) is a condition that affects young athletes who participate in high impact activities. Patients often experience gradually worsening hip and/or groin pain, and thus have months to years of symptoms before choosing to undergo hip arthroscopy to correct the bony and soft tissue pathology. Patients undergoing surgery usually report that they are pursuing surgery for pain relief and expect to be able to return to their previous level of activity. An athlete’s ability to return to their previous level of sport depends not only on their physical ability, but their psychological ability as well. Because patients often experience months to years of symptoms before surgery, this group is particularly vulnerable to kinesiophobia, pain catastrophizing, and other psychological factors that may influence recovery and overall return to physical activity. The Hip-Return to Sport after Injury (Hip-RSI) scale is a validated tool used to assess an athlete’s psychological readiness to return to sport and specifically looks at emotions, confidence, and risk appraisal in relation to a patient’s perception of hip function and is positively associated with return to sport (RTS). Recovery and RTS is not a linear process, as an athlete’s psychological readiness likely changes over time. However, this potential change in readiness throughout the recovery process has not yet been described. This study primarily aimed to describe the change in Hip-RSI in patients who undergo hip arthroscopy for FAI. A secondary objective was to examine the relationship between Hip- RSI and patient satisfaction with hip function, patient expectations of recovery timeline, patient expectations to return to sport, and history of anxiety/depression. Methods: A single surgeon’s prospectively collected Hip Database was used to obtain a comprehensive patient list. This study was conducted under the IRB approval of the Hip Database. Patients were included if they underwent a hip arthroscopy and completed the Hip-Return to Sport after Injury questionnaire (Hip-RSI) at minimum one of four postoperative timepoints: 3 months, 6 months, 1 year and 2 years. One hundred and fifty patients had a completed Hip-RSI score at at least one of these timepoints. Additional variables included BMI, diagnosis codes, patient satisfaction and expectations, history or presence of anxiety/depression, and other patient reported outcomes (PROs), including iHOT-12, HOS-ADL and HOS-SSS. There were four patient satisfaction and expectations questions patients answered in their questionnaire, three of which were yes/no questions, and one was a slider scale from 0-10 that pertained to hip function satisfaction. A chart review was performed to determine the BMI, diagnosis codes, and history/presence of history of anxiety/depression for patients who did not have this data in the Hip Database. A Mann Whitney U test and Pearson correlation tests were performed to determine averages and correlations between Hip-RSI and the history/presence of anxiety/depression and satisfaction and expectations. Results: The average age of this population was 30 ± 13 years, with an average BMI of 25.8 ± 5.7, and an average duration of symptoms for 24.7± 22.6 months. Hip-RSI scores were determined for each of the four timepoints, which showed that there was an increase in Hip-RSI scores from 3 months to 1 year postoperatively, and an almost a 10-point decrease at 2 years postoperatively, as shown in Table 1. There was no significant difference in Hip-RSI in patients with a history of anxiety and/or depression at any of the four timepoints. There were no significant correlations between Hip-RSI and any other variables or outcome measures at two years postoperatively. At 3 months, 6 months, and 12 months postoperatively, Hip-RSI had a strong, positive correlation with a patient’s self-reported satisfaction level of their current hip function (p<0.001). The averages of Hip-RSI and this patient satisfaction question are shown in Table 2. Two other patient expectation questions were also positively correlated with Hip-RSI at various timepoints, as shown in Figure 1. Hip-RSI had a strong correlation with three other PROs: iHOT-12, HOS-ADL, and HOS-SSS at all three timepoints (p<0.001). The only exceptions were two moderative, positive correlations between Hip-RSI and HOS-ADL, as well as between Hip-RSI and HOS-SSS, at 3 months postoperatively. Conclusions: Based on our findings, a patient’s psychological readiness for return to sport changes over time, with an increase in readiness up to 1 year postoperatively, and a decrease in readiness at two years postoperatively. While history or presence of anxiety and/or depression does not influence Hip-RSI scores, patient satisfaction and expectations after a hip arthroscopy appears to influence it, however further investigation is required.

Small AAAs: Recommendations for Rodent Model Research for the Identification of Novel Therapeutics.

Most abdominal aortic aneurysms (AAAs) are small with low rupture risk (<1%/y) when diagnosed but slowly expand to ≥55 mm and undergo surgical repair. Patients and clinicians require medications to limit AAA growth and rupture, but drugs effective in animal models have not translated to patients. Use models that simulate human AAA tissue pathology, growth patterns, and rupture; focus on the clinically relevant outcomes of growth and rupture; design studies with the rigor required of human clinical trials; monitor AAA growth using reproducible ultrasound; and perform studies in both males and females. The aortic adventitial elastase oral β-aminopropionitrile model has many strengths including simulating human AAA pathology and modeling prolonged aneurysm growth. The Ang II (angiotensin II) model performed less well as it better simulates acute aortic syndrome than AAA. The elastase plus TGFβ (transforming growth factor-β) blocking antibody model displays a high rupture rate, making prolonged monitoring of AAA growth not feasible. The elastase perfusion and calcium chloride models both display limited AAA growth.

Skin-Conformable Flexible and Stretchable Ultrasound Transducer for Wearable Imaging.

Ultrasound imaging offers a noninvasive, radiation-free method for visualizing internal tissues and organs, with deep penetration capabilities. This has established it as a crucial tool for physicians in diagnosing internal tissue pathologies and monitoring human conditions. Nonetheless, conventional ultrasound probes are often characterized by their rigidity and bulkiness. Designing a transducer that can seamlessly adapt to the contours and dynamics of soft, curved human skin presents significant technical hurdles. We present a novel flexible and stretchable ultrasound transducer (FSUT) designed for adaptability to large-curvature surfaces while preserving superior imaging quality. Central to this breakthrough is the innovative use of screen-printed silver nanowires (AgNWs) coupled with a composite elastic substrate, together ensuring robust and stable electrical and mechanical connections. Standard tensile and fatigue tests verify its durability. The mechanical, electrical, and acoustic properties of FSUTs are characterized using standard methods, with large tensile strains (≥110%), high flexibility ( R ≥ 1.4 mm), and lightweight ( ≤ 1.58 g) to meet the needs of wearable devices. Center frequency and -6-dB bandwidth are approximately 5.3 MHz and 66.47%, respectively. Images of the commercial anechoic cyst phantom yielded an axial and lateral resolution (depths of 10-70 mm) of approximately 0.31 and 0.46, and 0.34 and 0.84 mm, respectively. The complex curved surface imaging capabilities of FSUT were tested on agar-gelatin-based breast cyst phantoms under different curvatures. Finally, ultrasound images of the thyroid, brachial, and carotid arteries were also obtained from volunteer wearing FSUT.