Tissue Levels Research Articles

Determination of PCB and PAH tissue levels in bottlenose dolphins that stranded in the Mississippi sound before and after the unusual mortality event in 2019

Cetaceans are regarded as a sentinel species because their health and population changes can serve as indicators of effects on marine ecosystems. We characterized levels of 24 polycyclic aromatic hydrocarbons (PAHs) and 7 polychlorinated biphenyls (PCBs) in blubber, kidney, liver, and muscle of 138 bottlenose dolphins (Tursiops truncatus) that stranded in the Mississippi Sound (MSS) between 2010 and 2021. The samples were divided into four time periods: 2010–2018, 2019, 2020, and 2021, to assess whether there was a significant association between chemical levels in dolphin tissues and the 2019 unusual mortality event (UME) in the MSS resulting from the unprecedented freshwater incursion from 2 openings of the Bonnet Carré Spillway (BCS). We found 7 PCBs were readily detected in all tissues across time, and the major PAH was naphthalene, with detection of biphenyl and acenaphthene at lower levels and frequency. There was little change in tissue PCB levels over time; only naphthalene in the blubber was higher in tissues from dolphins that stranded before 2019. However, there were not significant changes in chemical levels in tissues from stranded bottlenose dolphins in the MSS before or after the UME in 2019.

Effect of Endurance Exercise Training on Gut Microbiota and ER Stress

Regular exercise as part of one’s lifestyle is well-recognized for its beneficial effect on several diseases such as cardiovascular disease and obesity; however, many questions remain unanswered regarding the effects of exercise on the gut environment. This study aimed to investigate the impact of long-term endurance exercise on modulating inflammation and endoplasmic reticulum (ER) stress. Fifteen-week-old male Sprague-Dawley (SD) rats were subjected to six months of endurance treadmill training, while age-matched controls remained sedentary. Results showed that IL-6 mRNA levels in colon tissues were significantly higher in the exercise group compared to the sedentary group. Exercise activated a significant ER stress-induced survival pathway by increasing BiP and phosphorylation of eIF2α (p-eIF2α) expressions in the liver and colon, while decreasing CHOP in the liver. Gene expressions of MUC2, Occludin, and Claudin-2 were increased in the colon of the exercise group, indicating enhanced intestinal integrity. Furthermore, the data showed a positive correlation between microbiota α-diversity and BiP (r = 0.464~0.677, p < 0.05). Populations of Desulfovibrio C21 c20 were significantly greater in the exercise group than the sedentary group. Additionally, predicted functions of the gut microbial community in terms of enzymes and pathways supported the enhancement of fatty-acid-related processes by exercise. These findings suggest that prolonged endurance exercise can affect the colon environment, which is likely related to changes in inflammation, ER stress, mucin layers and tight junctions, associated with modifications in the gut microbiome.

Deciphering MOSPD1's impact on breast cancer progression and therapeutic response.

Motile Sperm Domain-Containing Protein 1 (MOSPD1) has been implicated in breast cancer (BC) pathophysiology, but its exact role remains unclear. This study aimed to assess MOSPD1 expression levels in BC versus normal tissues and investigate its diagnostic potential. MOSPD1 expression was analyzed in BC and normal tissues, with Receiver Operating Characteristic analysis for diagnostic evaluation. Validation was performed using immunohistochemistry. Functional studies included tumor growth assays, MOSPD1 suppression and overexpression experiments, and testing BC cell responses to anti-PD-L1 therapy. MOSPD1 expression was significantly higher in BC samples than normal tissues, correlating with poor clinical outcomes in BC patients. MOSPD1 suppression inhibited tumor growth, while overexpression accelerated it. Silencing MOSPD1 enhanced BC cell sensitivity to anti-PD-L1 therapy and decreased Th2 cell activity. In vivo experiments supported these findings, showing the impact of MOSPD1 on tumor growth and response to therapy. Elevated MOSPD1 levels in BC suggest its potential as a biomarker for adverse outcomes. Targeting MOSPD1, particularly with anti-PD-L1 therapy, may effectively inhibit BC tumor growth and modulate immune responses. This study emphasizes the significance of MOSPD1 in BC pathophysiology and highlights its promise as a therapeutic target.

Evaluation of inhibitory potential of the flavonoid-rich fraction of Myrica esculenta Buch.-Ham. ex D. Don against DSS-induced colonic inflammation in mice

ObjectiveMyrica esculenta (family Myricaceae), a valuable plant species in China and India, has been traditionally used by many tribes and local communities to manage gut disorders. Scientific validation of its anti-ulcerative colitis activity was aimed. MethodsThe ethyl acetate fraction of Myrica esculenta (MeEa) was prepared and evaluated for its potency against DSS-induced ulcerative colitis (UC) in mice at 200 and 400 mg/kg BW oral dose. The effective dose of MeEa was determined through its effect on DSS-induced UC and was further analyzed through its effects on disease activity index (DAI), colon length, colon weight/length ratio, spleen weight, serum and colon tissue cytokine level, cell count and hemoglobin content. Further, the effect was determined through histopathology and FITC-dextran-induced membrane permeability assay. ResultsBetween the two doses, MeEa at 400 mg/kg BW was found to be the most effective dose in terms of reduced DAI scores, protected colon length from shortening, decreased colon weight/length ratio, reduced spleen weight, decreased pro-inflammatory cytokine level and stabilized the anti-inflammatory cytokine level in serum and colon tissue. MeEa 400 reduced cell counts and increased hemoglobin content and platelet count. MeEa 400 also prevented the colon by protecting epithelial cells and crypts. MeEa 400 provided significant protection from intestinal leakage and reduced FITC dextran level in serum. DiscussionMeEa 400 possesses significant anti-inflammatory potential and acts via attenuation of DSS-induced UC and inhibition of DAI scores. It reduces pro-inflammatory cytokines and stabilizes anti-inflammatory cytokine levels, reduces cell count, and protects epithelial tissue and crypts in the colon, as well as intestinal membrane leakage that occurred due to FITC-dextran administration in mice.

Acetyl-11-keto-beta-boswellic Acid (AKBA) Ameliorates Histopathological and Oxidative Stress Brain Disorders in the Experimental Model of Cuprizone-induced Demyelination

Background: Multiple sclerosis is an inflammatory autoimmune disease that destroys the myelin sheath (demyelination) and neurons of the central nervous system (CNS), with several factors contributing to its development. Objectives: This study investigated the impact of administering acetyl 11-keto-beta boswellic acid (AKBA) in an animal model of cuprizone-induced demyelination. Methods: Thirty-two C57BL/6 female mice (WT; 20 - 25 g, 8 - 10 weeks old) were randomly divided into four groups: (1) Control (CO), (2) Cuprizone-treated (CPZ, 0.3%), (3) AKBA + CPZ (50 mg/kg, pre-treatment), and (4) CPZ + AKBA (50 mg/kg, post-treatment). At the end of the study, the weight and movement balance of the animals were assessed using the rotarod test. After sampling the brain, the extent of the demyelination area in the corpus callosum was measured with Luxol Fast Blue staining, the number of oligodendrocyte cells was determined by immunohistochemistry, and the levels of malondialdehyde (MDA) and total antioxidant capacity (TAC) as oxidative stress factors in the brain tissue were measured. Results: The use of acetyl-11-keto-beta boswellic acid in the cuprizone-induced demyelination model prevented weight loss, increased animal resistance in the rotarod test, and reduced the demyelination rate in the corpus callosum. Additionally, AKBA elevated the number of oligodendrocytes and total antioxidant capacity levels while reducing malondialdehyde levels in brain tissue. Pretreatment with AKBA exhibited a more significant effect. Conclusions: This study showed that acetyl-11-keto-beta boswellic acid, an important active substance of the frankincense plant, likely protects the nervous system and neurons in the cuprizone-induced demyelination model by preventing the decrease in the number of oligodendrocytes, reducing oxidative stress, and preventing the destruction of myelin.

8041 Eneboparatide, A Potent Stimulator Of Urinary Calcium Reabsorption, Induces Prolonged Renal Cortex Retention And PTH1 Receptor Signaling

Abstract Disclosure: G. Ravel: Employee; Self; Amolyt Pharma. R. Datta: Consulting Fee; Self; Amolyt Pharma. S. Milano: Employee; Self; Amolyt Pharma. M. Ovize: Employee; Self; Amolyt Pharma. S. Allas: Employee; Self; Amolyt Pharma. M. Aouadi: None. M.D. Culler: Employee; Self; Amolyt Pharma. Natural parathyroid hormone (PTH) replacement therapy for chronic hypoparathyroidism (cHP) is not ideal due to both short circulating half-life and brief receptor signaling, making the effect too transient. Following agonist binding to the PTH 1 receptor (PTH1R), the magnitude and duration of the receptor signal, and consequently the biological response, appears to depend on the affinity of the ligand for a specific receptor conformation termed R0, which determines the duration of ligand binding. Eneboparatide (Enebo) is a hybrid analog of PTH and PTH-related peptide designed to strongly bind to the R0 conformation while having a short circulating half-life similar to that of PTH. When tested in cHP patients, Enebo eliminated the need for calcium (Ca) (88% patients) and Vitamin D (92% patients) supplementation, while maintaining serum Ca levels over a full 24 hours. Urinary calcium (uCa) was rapidly decreased and was normalized in 92% of patients who were hypercalciuric prior to treatment. To explore the mechanism of the potent effect of Enebo on uCa, a binding assay specific for the R0 conformation of the PTH1R confirmed the high affinity of Enebo versus natural PTH1-34, with IC50 = 1.5nM and 30.9nM, respectively. Postulating that the high-affinity binding of Enebo to R0 should result in longer tissue retention in vivo, we examined the tissue levels of PTH1-34 and Enebo in male, 200-300g rats using quantitative whole-body autoradiography (QWBA) following subcutaneous injection of 3H-labeled Enebo and PTH1-34. Tissue levels of the compounds were normalized based on the concentrations observed in cardiac blood. The highest level observed for both compounds was in the renal cortex, the major site of active PTH-induced Ca reabsorption, with peak concentrations observed 30 minutes post-injection. Six hours after injection, 96.3% of PTH1-34 had disappeared from the renal cortex, as compared with only 61.4% of Enebo, despite both compounds having similar circulating half-lives. With respect to activating the PTH1R, both compounds showed a similar increase in cAMP in human embryonic kidney (HEK293) cells transfected with the PTH1R and the Green Downward cADDis cAMP biosensor, with EC50 of 0.32 and 0.48nM for Enebo and PTH1-34, respectively. To mimic the effect of rapid elimination in vivo, the ligands were added to the cells, washed-off after 15 minutes, and cAMP production followed over the next 16 hours. After washout, the cAMP signal induced by PTH1-34 rapidly returned to baseline in less than 60 minutes, whereas the cAMP signal induced by Enebo gradually decreased and was still evident after 16 hours. Collectively, these data confirm high affinity of Enebo for the R0 conformation of the PTH1R, as well as prolonged receptor signaling and retention by the renal cortex, clearly differentiating Enebo from PTH1-34 and providing strong rationale for the efficacy of Enebo in reducing uCa in cHP patients. Presentation: 6/3/2024

Aluminum phthalocyanine tetrasulfonate conjugated to surface-modified Iron oxide nanoparticles as a magnetic targeting platform for photodynamic therapy of Ehrlich tumor-bearing mice

BackgroundPhotodynamic therapy (PDT) is a targeted treatment option for cancers that are non-responding to ordinary anticancer therapies. It involves activating a photosensitizer with a light source of a specific wavelength to destroy targeted cells and their surrounding vasculature. Aluminum phthalocyanine tetra sulfonate (AlPcS4) has gained attention as a second-generation photosensitizer for its strong absorption in the red-light region. AlPcS4 can be conjugated to magnetic iron oxide nanoparticles (IONs) to provide targeted drug delivery to the tumor cells while reducing its undesired effect on healthy tissues in other body parts. MethodsMagnetic glutamine functionalized iron oxide nanocomposites loaded with AlPcS4 (IONs-NH2-AlPcS4) were synthesized via the co-precipitation method. The conjugate (IONs-NH2-AlPcS4) was characterized by TEM, Zeta potential, DLS, FTIR, and UV–VIS absorption spectroscopy. Furthermore, its photodynamic activity was investigated using albino mice with induced Ehrlich solid tumors. ResultsAlPcS4 was successfully conjugated to IONs-NH2 with a high loading efficiency of 54±2%. The synthesized conjugate exhibited a spherical shape, with 7 ± 2 nm particle size. The In vivo experiment revealed that the albino mice with induced Ehrlich solid tumor that were treated by combined PDT and magnetic targeting conjugate exhibited significant tumor regression and notably higher levels of necrotic tissue compared to the animals in other groups. ConclusionPDT mediated by magnetic targeting significantly inhibited tumor growth with minimal adverse effects, indicating its great potential as a promising strategy for solid cancer treatment.

Methanolic stem-bark extracts of Adansonia digitata modulates haematological and antioxidant parameters in streptozotocin-induced diabetic rats

Background and AimDiabetes mellitus is associated with haematological abnormalities and oxidative stress, contributing to disease progression and complications. Adansonia digitata, is a traditional medicinal plant well known for its potential therapeutic properties. This study investigates the effects of methanolic stem-bark extracts of Adansonia digitata on haematological and antioxidant status in streptozotocin-induced diabetic rats. Experimental ProcedureFourty-two wistar rats were distributed into 6 groups of 7 each. Group 1 served as normal control, group 2 to 6 animals were made diabetic by intraperitoneal administration of single dose of 50 mg kg-1 streptozotocin. Group 2 served as the negative control and did not receive treatment, group 3 served as the positive control and received 150 mg kg-1 metformin (Glucophage) (standard drug), while group 4, 5 and 6 received oral treatment of 100 mg kg-1, 200 mg kg-1 and 300 mg kg-1 of Adansonia digitata stem-bark methanolic extract respectively for 21days, after which the animals were sacrificed, and blood and liver were collected for haematological analysis including White Blood cell (WBC), red blood cell (RBC), haemoglobin (HGB), hematocrit (H CT), platelet (PLT), mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), mean corpuscular haemoglobin concentration (MCHC), total bilirubin (TB), direct bilirubin(DB) and indirect bilirubin (IB) concentration and antioxidant parameters including antioxidant enzymes [catalase (CAT) and superoxide dismutase (SOD) activities] and oxidative stress marker [thiobarbituric acid reactive substance (TBARS)]. ResultsSTZ administration evoked a marked (p < 0.05) decline in the level of WBC, RBC, HGB, PLT, LYM and MCV in the diabetic rats when compared with the normal control. Howbeit, treatment with methanolic extracts of adansonia digitata stem-bark led to a profound (p < 0.05) increase in concentrations of these parameters close to the normal. In addition, STZ caused a non-significant (p > 0.05) decrease in MCH and MCHC. On the contrary, STZ caused an insignificant (p > 0.05) increase in the levels of TB and DB, but a significant (p > 0.05) increase IDB level in the diabetic control group when compared with the normal control group, while treatment with stem-bark extracts resulted in a marked (p > 0.05) fall in IDB level. Furthermore, there was a marked (P < 0.05) reduction in the activity of hepatic CAT and SOD and a considerable (P < 0.05) elevation in Malondialdehyde (MDA) level in the hepatic tissue of the diabetic control. Nonetheless, Adansonia digitata stem-bark extracts profoundly (P < 0.05) raised the activities of the enzymes and concomitantly counteracted MDA level. The extract elicited strong potency at 300 mg kg-1 which is comparable to metformin (Glucophage). ConclusionConsequently, this study advocates for the utility of Adansonia digitata extracts for the development of novel drugs for combating diabetes mellitus, associated hematological and oxidative stress complications and other ailments. Further research is needed to evaluate the clinical relevance of these effects in human subjects and to provide information on the sustained efficacy of the extracts in chronic models. Significant statementOxidative stress and hematological abnormalities are two of the consequences linked to diabetes mellitus. Anaemia and poor blood coagulation are two haematological changes that increase the risk of diabetes-related illness and death. Furthermore, oxidative stress is essential to the pathophysiology of diabetic complications such as nephropathy and cardiovascular disease. In addition, there are reports on hematological and biochemical alterations in diabetic subjects arising from the intake of synthetic antidiabetic medications.. Consequent to the safety, ease of use, efficacy, and lack of cytotoxic side effects of plants’ herbs, the study of Adansonia digitata's methanolic stem-bark extracts on haematological and antioxidant parameters in streptozotocin-induced diabetic rats is of paramount importance as the extracts' capacity to modify these parameters, will lead to the development of novel drugs that cures anemia, other blood abnormalities, and oxidative stress linked to diabetes as well as other ailments.

Exploring the protective role of green tea extract against cardiovascular alterations induced by chronic REM sleep deprivation via modulation of inflammation and oxidative stress

BackgroundChronic Rapid eye movement (REM) sleep deprivation has been associated with various cardiovascular alterations, including disruptions in antioxidant defense mechanisms, lipid metabolism, and inflammatory responses. This study investigates the therapeutic potential of green tea extract (GTE) in mitigating these adverse effects.MethodsA total of 24 male Wistar albino rats were used in this study and divided into the control group (n = 8), Chronic-REM Sleep Deprivation (CRSD) Group (n = 8) and Chronic-REM SD + Green Tea 200 (CRSD + GTE200) Group (n = 8). After 21 days, a comprehensive analysis of paraoxonase (PON1), arylesterase (ARE), malondialdehyde (MDA), glutathione (GSH), nitric oxide (NOx), proinflammatory cytokines, and lipid profiles in aortic tissue, heart tissue, and serum was conducted in a sleep-deprived rat model.ResultsChronic REM sleep deprivation led to a significant reduction in PON1 and ARE levels in aortic (p = 0.046, p = 0.035 respectively) and heart tissues (p = 0.020, p = 0.019 respectively), indicative of compromised antioxidant defenses. MDA levels increased, and NOx levels decreased, suggesting oxidative stress and impaired vascular function. Lipid profile alterations, including increased triglycerides and total cholesterol, were observed in serum. Elevated levels of inflammatory cytokines (IL-6 and TNF-alpha) further indicated an inflammatory response (p = 0.007, p = 0.018 respectively). GTE administration demonstrated a protective role, restoring antioxidant enzyme levels, suppressing lipid peroxidation, and improving NOx levels.ConclusionThese findings suggest the therapeutic potential of GTE in alleviating the cardiovascular impairments of chronic REM sleep deprivation, emphasizing its candidacy for further clinical exploration as a natural intervention in sleep-related disorders and associated cardiovascular risks.

Analysis of Fibropapillomatosis in Roe Deer (Capreolus capreolus) Confirms High Content of Heavy Metals.

In recent decades, there has been an increase in European wild ungulate populations, often associated with a decline in health and spread of disease. This is true for the roe deer (Capreolus capreolus), the most common European cervid, with populations apparently affected by fibropapillomatosis, an increasingly common cancer. To date, however, there has been little research into this disease, thus many interactions remain unclear and descriptions of tumour composition are poorly validated. The main aim of the present study was to evaluate the presence and concentration of toxic heavy metals in roe deer skin tumours. Our results confirmed the presence of virtually all the metals tested for, i.e., Pb, Hg, Cd, As, Cr, Mn, Al, Co, Cu, Ni, Se, Zn, and Fe, with the highest average concentrations found for Cr (0.99 mg/kg-1 ± 2.23 SD), Cd (0.03 mg/kg-1 ± 0.03 SD), and Hg (0.02 mg/kg-1 ± 0.02 SD), exceeding FAO limits for meat from slaughtered animals. We also observed a significant positive relationship between heavy metal concentration and age, especially for Pb, As, Hg, Mn, Se, Al, Zn, and Ni. Our findings provide a strong baseline for further research on the impact of fibropapillomatosis, not only on the welfare and health status of game but also on the final consumer of venison, which in many respects is regarded as a high-quality, ecological, and renewable wild resource. While deer with this disease are not considered qualitatively or medically defective, they could represent a potential reservoir of substances toxic to humans and could affect substance levels in adjacent tissues or the animal as a whole.

Evaluation of Multiple Tissue Levels Frequently Upstages Patients With Clinically Localized Thin Primary Cutaneous Melanoma.

Breslow thickness (BT), ulceration, and microsatellitosis are critical prognostic parameters for cutaneous melanoma staging. These parameters can vary depending on the number of tissue levels examined from individual paraffin blocks. We sought to evaluate all prognostic histopathologic parameters in melanoma for their variations between levels, taken at regular intervals, in a single study. We analyzed 40 consecutive cases of primary cutaneous (nonacral) melanoma through five hematoxylin and eosin sections, taken at 100 μm intervals, for staging and prognostic parameters. Examination of additional levels resulted in (a) an increase in BT in 47.5% (19 out of 40) of cases and (b) detection of ulceration in a further 5% (2/40). This resulted in upstaging for 20% (8 out of 40) of patients (15% because of BT, 2.5% because of ulceration, and 2.5% because of BT and ulceration). The upstaging effect was incremental, with approximately 5% of patients upstaged with each additional 100 μm interval (up to 400 μm). Incipient ulceration and epidermal consumption were infrequent (10% of cases); however, when present, ulceration was subsequently observed in half of cases. We encountered no cases where microsatellitosis was detected at deeper levels. The performance of additional tissue levels is a simple and inexpensive procedure that can improve the accuracy of staging for patients with thin (pT1) primary cutaneous melanomas. It may be pertinent for pathologists to consider additional levels for thin melanomas when a BT measurement is close to a staging threshold (e.g., within 0.1-0.3 mm for pT1a vs. pT1b, or pT1b vs. pT2a), or when incipient ulceration is encountered.

Rapid and noninvasive estimation of human arsenic exposure based on 4-photo-set of the hand and foot photos through artificial intelligence

Chronic exposure to arsenic is linked to the development of cancers in the skin, lungs, and bladder. Arsenic exposure manifests as variegated pigmentation and characteristic pitted keratosis on the hands and feet, which often precede the onset of internal cancers. Traditionally, human arsenic exposure is estimated through arsenic levels in biological tissues; however, these methods are invasive and time-consuming. This study aims to develop a noninvasive approach to predict arsenic exposure using artificial intelligence (AI) to analyze photographs of hands and feet. By incorporating well water consumption data and arsenic concentration levels, we developed an AI algorithm trained on 9988 hand and foot photographs from 2497 subjects. This algorithm correlates visual features of palmoplantar hyperkeratosis with arsenic exposure levels. Four pictures per patient, capturing both ventral and dorsal aspects of hands and feet, were analyzed. The AI model utilized existing arsenic exposure data, including arsenic concentration (AC) and cumulative arsenic exposure (CAE), to make binary predictions of high and low arsenic exposure. The AI model achieved an optimal area under the curve (AUC) values of 0.813 for AC and 0.779 for CAE. Recall and precision metrics were 0.729 and 0.705 for CAE, and 0.750 and 0.763 for AC, respectively. While biomarkers have traditionally been used to assess arsenic exposure, efficient noninvasive methods are lacking. To our knowledge, this is the first study to leverage deep learning for noninvasive arsenic exposure assessment. Despite challenges with binary classification due to imbalanced and sparse data, this approach demonstrates the potential for noninvasive estimation of arsenic concentration. Future studies should focus on increasing data volume and categorizing arsenic concentration statistics to enhance model accuracy. This rapid estimation method could significantly contribute to epidemiological studies and aid physicians in diagnosis.

Genetic variants of LRRC8C, OAS2, and CCL25 in the T cell exhaustion-related genes are associated with non-small cell lung cancer survival.

T cell exhaustion is a state in which T cells become dysfunctional and is associated with a decreased efficacy of immune checkpoint inhibitors. Lung cancer has the highest mortality among all cancers. However, the roles of genetic variants of the T cell exhaustion-related genes in the prognosis of non-small cell lung cancer (NSCLC) patients has not been reported. We conducted a two-stage multivariable Cox proportional hazards regression analysis with two previous genome-wide association study (GWAS) datasets to explore associations between genetic variants in the T cell exhaustion-related genes and survival of NSCLC patients. We also performed expression quantitative trait loci analysis for functional validation of the identified variants. Of all the 52,103 single nucleotide polymorphisms (SNPs) in 672 T cell exhaustion-related genes, 1,721 SNPs were found to be associated with overall survival (OS) of 1185 NSCLC patients of the discovery GWAS dataset from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, and 125 of these 1,721 SNPs remained significant after validation in an additional independent replication GWAS dataset of 984 patients from the Harvard Lung Cancer Susceptibility (HLCS) Study. In multivariable stepwise Cox model analysis, three independent SNPs (i.e., LRRC8C rs10493829 T>C, OAS2 rs2239193 A>G, and CCL25 rs3136651 T>A) remained significantly associated with OS with hazards ratios (HRs) of 0.86 (95% confidence interval (CI) = 0.77-0.96, P = 0.008), 1.48 (95% CI = 1.18-1.85, P < 0.0001) and 0.78 (95% CI = 0.66-0.91, P = 0.002), respectively. Further combined analysis for these three SNPs suggested that an unfavorable genotype score was associated with a poor OS and disease-specific survival. Expression quantitative trait loci analysis suggested that the LRRC8C rs10493829 C allele was associated with elevated LRRC8C mRNA expression levels in normal lymphoblastoid cells, lung tissue, and whole blood. Our findings suggested that these functional SNPs in the T cell exhaustion-related genes may be prognostic predictors for survival of NSCLC patients, possibly via a mechanism of modulating corresponding gene expression.

Clear aligners for patients with severe gingival recession: A case report

Fixed appliances are an excellent treatment approach for mild to severe malocclusions. Increasingly, aligner-based treatments are being provided as a treatment option. The latter may be preferable to fixed appliances in selected cases. A young adult with severe gingival recession is presented who was treated successfully with aligner-based treatment with minimal deterioration of the gingival tissue levels. However, limits should be applied to the buccal and labial movement of teeth to reduce the risk of worsening of the gingival recession. CPD/Clinical Relevance: Aligner-based treatment may be preferable for orthodontic patients with severe gingival recession.

Comparing continuum and direct fiber models of soft tissues: An ocular biomechanics example reveals that continuum models may artificially disrupt the strains at both the tissue and fiber levels

Collagen fibers are the main load-bearing component of soft tissues but difficult to incorporate into models. Whilst simplified homogenization models suffice for some applications, a thorough mechanistic understanding requires accurate prediction of fiber behavior, including both detailed fiber-level strains and long-distance transmission. Our goal was to compare the performance of a continuum model of the optic nerve head (ONH) built using conventional techniques with a fiber model we recently introduced which explicitly incorporates the complex 3D organization and interaction of collagen fiber bundles [1]. To ensure a fair comparison, we constructed the continuum model with identical geometrical, structural, and boundary specifications as for the fiber model. We found that: 1) although both models accurately matched the intraocular pressure (IOP)-induced globally averaged displacement responses observed in experiments, they diverged significantly in their ability to replicate specific 3D tissue-level strain patterns. Notably, the fiber model faithfully replicated the experimentally observed depth-dependent variability of radial strain, the ring-like pattern of meridional strain, and the radial pattern of circumferential strain, whereas the continuum model failed to do so; 2) the continuum model disrupted the strain transmission along each fiber, a feature captured well by the fiber model. These results demonstrate limitations of the conventional continuum models that rely on homogenization and affine deformation assumptions, which render them incapable of capturing some complex tissue-level and fiber-level deformations. Our results show that the strengths of explicit fiber modeling help capture intricate ONH biomechanics. They potentially also help modeling other fibrous tissues. Statement of SignificanceUnderstanding the mechanics of fibrous tissues is crucial for advancing knowledge of various diseases. This study uses the ONH as a test case to compare conventional continuum models with fiber models that explicitly account for the complex fiber structure. We found that the fiber model captured better the biomechanical behaviors at both the tissue level and the fiber level. The insights gained from this study demonstrate the significant potential of fiber models to advance our understanding of not only glaucoma pathophysiology but also other conditions involving fibrous soft tissues. This can contribute to the development of therapeutic strategies across a wide range of applications.

Is FAM19A5 an adipokine? Peripheral FAM19A5 in wild-type, FAM19A5 knockout, and LacZ knockin mice

FAM19A5 is a novel secretory protein expressed primarily in the brain. However, a recent study reported that FAM19A5 is an adipocyte-derived adipokine that regulates vascular smooth muscle function through sphingosine-1-phosphate receptor 2 (S1PR2). In our study, we investigated FAM19A5 transcript and protein levels in peripheral tissues, including adipose tissues, from wild-type, FAM19A5 knockout, and FAM19A5 LacZ knockin mice. We found that the FAM19A5 transcript levels in the central nervous system were much greater than those in any of the peripheral tissues, including adipose tissues. Furthermore, the FAM19A5 protein levels in adipose and reproductive tissues were below detectable limits for Western blot analysis and ELISA. Additionally, we found that the FAM19A5 protein did not interact with S1PR2 in terms of G protein-mediated signal transduction, β-arrestin recruitment, or ligand-mediated internalization. Taken together, our findings revealed basal levels of FAM19A5 transcripts and proteins in peripheral tissues, confirming its primary expression in the central nervous system and lack of significant interaction with S1PR2.

Perioperative chemoimmunotherapy induces strong immune responses and long-term survival in patients with HLA class I-deficient non-small cell lung cancer

BackgroundLoss of human leukocyte antigen (HLA) class I expression and loss of heterozygosity (LOH) are common events implicated in the primary resistance of non-small cell lung cancer (NSCLC) to immunotherapy....

Europium-Containing Nanospheres for Treating Ovariectomy-Induced Osteoporosis: Targeted Bone Remodeling and Macrophage Polarization Modulation.

Osteoporosis, characterized by reduced bone mass and structural deterioration, poses a significant healthcare challenge. Traditional treatments, while effective in reducing fracture risks, are often limited by side effects. This study introduces a novel nanocomplex, europium (Eu) ions-doped superparamagnetic iron oxide (SPIO) nanocrystals encapsulated in poly(lactic-co-glycolic acid) (PLGA) nanospheres, abbreviated as SPIO:Eu@PLGA nanospheres, as a potential therapeutic agent for osteoporosis by modulating macrophage polarization, enhancing osteoblast differentiation and inhibiting osteoclastogenesis. SPIO and SPIO:Eu nanocrystals were synthesized through pyrolysis and encapsulated in PLGA using an emulsification method. To evaluate the impact of SPIO:Eu@PLGA nanospheres on macrophage reprogramming and reactive oxygen species (ROS) production, flow cytometry analysis was conducted. Furthermore, an ovariectomized (OVX) rat model was employed to assess the therapeutic efficacy of SPIO:Eu@PLGA nanospheres in preventing the deterioration of osteoporosis. In vitro, SPIO:Eu@PLGA nanospheres significantly attenuated M1 macrophage activation induced by lipopolysaccharides, promoting a shift towards the M2 phenotype. This action is linked to the modulation of ROS and the NF-κB pathway. Unlike free Eu ions, which do not achieve similar results when not incorporated into the SPIO nanocrystals. SPIO:Eu@PLGA nanospheres enhanced osteoblast differentiation and matrix mineralization while inhibiting RANKL-induced osteoclastogenesis. In vivo studies demonstrated that SPIO:Eu@PLGA nanospheres effectively targeted trabecular bone surfaces in OVX rats under magnetic guidance, preserving their structure and repairing trabecular bone loss by modulating macrophage polarization, thus restoring bone remodeling homeostasis. The study underscores the critical role of Eu doping in boosting the anti-osteoporotic effects of SPIO:Eu@PLGA nanospheres, evident at both cellular and tissue levels in vitro and in vivo. The inclusion of Eu into SPIO matrix suggests a novel approach for developing more effective osteoporosis treatments, particularly for conditions induced by OVX. This research provides essential insights into SPIO:Eu@PLGA nanospheres as an innovative osteoporosis treatment, addressing the limitations of conventional therapies through targeted delivery and macrophage polarization modulation.

Targeting Mitochondria: Influence of Metabolites on Mitochondrial Heterogeneity.

Mitochondria are vital organelles that provide energy for the metabolic processes of cells. These include regulating cellular metabolism, autophagy, apoptosis, calcium ions, and signaling processes. Despite their varying functions, mitochondria are considered semi-independent organelles that possess their own genome, known as mtDNA, which encodes 13 proteins crucial for oxidative phosphorylation. However, their diversity reflects an organism's adaptation to physiological conditions and plays a complex function in cellular metabolism. Mitochondrial heterogeneity exists at the single-cell and tissue levels, impacting cell shape, size, membrane potential, and function. This heterogeneity can contribute to the progression of diseases such as neurodegenerative diseases, metabolic diseases, and cancer. Mitochondrial dynamics enhance the stability of cells and sufficient energy requirement, but these activities are not universal and can lead to uneven mitochondria, resulting in heterogeneity. Factors such as genetics, environmental compounds, and signaling pathways are found to affect these cellular processes and heterogeneity. Additionally, the varying roles of metabolites such as NADH and ATP affect glycolysis's speed and efficiency. An imbalance in metabolites can impair ATP production and redox potential in the mitochondria. Therefore, this review will explore the influence of metabolites in shaping mitochondrial morphology, how these changes contribute to age-related diseases and the therapeutic targets for regulating mitochondrial heterogeneity.

ERBB2 is a potential diagnostic and prognostic biomarker in renal clear cell carcinoma

Renal clear cell carcinoma (ccRCC) is a common parenchymal tumor of the kidney, and the discovery of biomarkers for early and effective diagnosis of ccRCC can improve the early diagnosis of patients and thus improve long-term survival. Erb-b2 receptor tyrosine kinase 2 (ERBB2) mediates the processes of cell proliferation, differentiation, and apoptosis inhibition. The purpose of this study was to investigate the diagnostic and prognostic role of ERBB2 in ccRCC. We analyzed the expression levels of ERBB2 in various cancers from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. RNA-seq data were analyzed using R packages to identify differentially expressed genes between the high and low ERBB2 expression groups in the TCGA-KIRC dataset. Spearman correlation analysis was performed to determine the correlation between ERBB2 expression and immune cell infiltration, immune checkpoint expression, and PTEN expression. DNA methylation changes and genetic alterations in ERBB2 were assessed using the MethSurv and cBioPortal databases. Logistic regression analysis was performed to determine the correlation between ERBB2 expression and the clinicopathological characteristics of ccRCC patients. The diagnostic and prognostic value of ERBB2 was assessed using Kaplan‒Meier (K‒M) survival curves, diagnostic ROC curves, time-dependent ROC curves, nomogram models, and Cox regression models. The expression level of ERBB2 is lower in tumor tissues of ccRCC patients than in the corresponding control tissues. Differentially expressed genes associated with ERBB2 were significantly enriched in the pathways “BMP2WNT4FOXO1 pathway in primary endometrial stromal cell differentiation” and “AMAN pathway”. In ccRCC tissues, ERBB2 expression levels were associated with immune cell infiltration, immune checkpoints, and PTEN. The DNA methylation status of 10 CpG islands in the ERBB2 gene was associated with the prognosis of ccRCC. ERBB2 expression levels in ccRCC tissues were associated with race, sex, T stage, M stage, histological grade, and pathological stage. Cox regression analysis showed that ERBB2 was a potential independent predictor of overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI) in ccRCC patients. ROC curve analysis showed that the expression level of ERBB2 could accurately distinguish between ccRCC tissue and adjacent normal renal tissue. Our study showed that ERBB2 expression in ccRCC tissues can be of clinical importance as a potential diagnostic and prognostic biomarker.