Serum Markers Research Articles

NaHS protects brain, heart, and lungs as remote organs from renal ischemia/reperfusion-induced oxidative stress in male and female rats

Acute Kidney Injury (AKI) is frequently observed in hospitalized patients in intensive care units, often caused by renal ischemia-reperfusion injury (IRI). IRI disrupts the function of various ‘remote organs’ such as the lungs, pancreas, intestine, liver, heart, and brain through inflammation, oxidative stress, apoptosis, leukocyte infiltration, and increased urea and creatinine levels. Gender differences in renal IRI-induced injury are noted. H2S, an endogenous gaseous modulator, shows potential in vasodilation, bronchodilation, and hypotension and can regulate apoptosis, inflammation, angiogenesis, metabolism, and oxidative stress. This study aims to investigate the protective effects of NaHS on brain, heart, and lung injuries following renal IR and to assess the oxidative system status as a potential mechanism in male and female rats.Forty-eight Wistar rats were randomly divided into eight groups (n = 6): Control/Saline, Sham/Saline, IR/Saline, and IR/NaHS in both sexes. Forty-five minutes of bilateral renal ischemia followed by 24-hour reperfusion was induced in the IR groups. NaHS (100µM/Kg, IP) was administered 10 min before clamp release in treated groups. BUN, SCr, BUN/SCr, albuminuria, histopathology, and oxidative stress biomarkers of the brain, heart, and lung were assessed as remote organs. IR increased serum markers of renal function, albuminuria, malondialdehyde levels, and tissue injury scores while reducing nitrite levels and superoxide dismutase and glutathione peroxidase activities. NaHS treatment reversed the adverse effects of IR in remote organs in both sexes, although it showed limited improvement in renal function. Our findings demonstrate that NaHS has a beneficial effect on remote organ injury following renal IR by mitigating oxidative stress, with noted tissue-specific and gender-specific differences in response. These findings suggest NaHS as a potential therapeutic agent for mitigating multi-organ injury after renal IR, with effects varying by tissue and gender.

ANGIOGENIC FACTORS AS PREDICTORS OF SURVIVAL IN PATIENTS WITH BONE SARCOMAS

Introduction. Primary bone sarcomas are relatively rare neoplasms. They occur predominantly in adolescents and young adults, are characterized by an aggressive clinical course and a high metastatic potential, have a poor prognosis. In this regard, the problem of stratifying the risk of metastasis and death in order to select the optimal treatment tactics always remains relevant. The study of such markers as endostatin, vascular endothelial growth factor (VEGF), insulin-like growth factors IGF-1, IGF-2 as potentially informative predictors of survival in patients with bone sarcomas is pathogenetically determined by their involvement in the processes of tumor growth and metastasis. Aim – to analyze the relationship between pre-treatment serum levels of endostatin, VEGF, IGF-1 and IGF-2 with overall survival rates in patients with bone sarcomas. Material and methods. An analysis of overall survival rates was carried out in 134 patients with malignant bone tumors aged from 1 to 73 years (Me=27.0 years; Q1–Q3: 18.0 – 43.0 years), among them 87 men (64.9%) and 47 women (35.1%). All patients comprised 4 groups: osteosarcoma (n=58), undifferentiated pleomorphic sarcoma (n=5), Ewing sarcoma (n=29), chondrosarcoma (n=42). In all of them, before the start of specific antitumor treatment, the levels of endostatin, VEGF, IGF-1, and IGF-2 in the blood serum were determined using enzyme immunoassay. The follow-up period ranged from 1 to 229 months (Me=23.0 months; Q1–Q3: 10.0–121.0 months). To analyze overall survival, life tables and Kaplan–Meier curves were constructed. The effect of the studied serum markers on survival rates was assessed using the logrank test and Cox proportional hazards regression model. Results. During observation, death occurred in 51 patients (38.1%). In the group of deceased patients, serum levels of endostatin and IGF-2 were statistically significantly increased compared to the group of surviving patients (p 0.001 and p=0.011, respectively). Kaplan-Meier survival analysis using the logrank test revealed statistically significant differences in overall survival between the four groups of patients with different serum levels of endostatin, IGF-1 and IGF-2. The Cox regression method established the prognostic significance of endostatin as a predictor of overall survival (HR=1.012; p=0.013). Conclusion. Endostatin, IGF-1, IGF-2 can serve as predictors of overall survival of patients with bone sarcomas.

Enhancing Blood-Brain Barrier Integrity in Patients With Acute Ischemic Stroke Via Normobaric Hyperoxia.

Recent advancements in animal studies have demonstrated the potential of normobaric hyperoxia (NBO) as a promising intervention for preserving the integrity of the blood-brain barrier (BBB). However, there is still limited understanding of the effects of NBO on BBB function in patients with clinical stroke. Therefore, the objective of this study was to investigate the efficacy of NBO therapy in attenuating BBB damage and reducing brain injury in individuals undergoing endovascular treatment (EVT) for acute stroke. This study enrolled patients from the OPENS-1 (Normobaric Hyperoxia Combined With Reperfusion for Acute Ischemic Stroke) study, with 43 patients receiving NBO combined with EVT and 43 patients receiving EVT alone. The main outcome measures included serum levels of occludin, MMP-9 (matrix metalloproteinase-9), NSE (neuron-specific enolase), and S100b at 24 hours and 7 days, as well as the intracranial extravasation rate at 24 hours. Serum markers were assessed using ELISA, and intracranial contrast extravasation was visualized using dual-energy computed tomography scan. We analyzed a total of 86 patients and found that the 24-hour serum markers levels of BBB damage and brain injury were significantly lower in the group receiving NBO therapy combined with EVT compared with the group receiving EVT alone. Similarly, at 7 days, the levels of occludin, MMP-9, and NSE were lower in the NBO+EVT group. We also found that the 24-hour serum levels of occludin and MMP-9 were correlated with intracranial contrast extravasation. Additionally, the incidence of intracranial contrast extravasation was lower in the NBO+EVT group compared with the EVT group (35.9% versus 60.5%, P=0.031). This study offers valuable insights into the positive impact of NBO on maintaining BBB integrity and reducing brain injury in patients with acute stroke undergoing EVT.

Clinical features and predictive nomogram for fatigue sequelae in non-severe patients infected with SARS-CoV-2 Omicron variant in Shanghai, China

BackgroundPatients with coronavirus disease 2019(COVID-2019) infections may still experience long-term effects, with fatigue being one of the most frequent ones. Clinical research on the long COVID in the Chinese population after infection is comparatively lacking. ObjectiveTo collect and analyze the long-term effects of non-severe COVID-19 infection patients and to develop a model for the prediction of fatigue symptoms. Methods223 non-severe COVID-19 patients admitted to one designated hospital were enrolled after finish all the self-designed clinical information registration form and nine-month follow-up. We explored the frequency and symptom types of long COVID. Correlation analysis was done on the neuropsychological scale results. After cluster analysis, lasoo regression and logistic regressions, a nomogram prediction model was produced as a result of investigating the risk factors for fatigue. ResultsA total of 108 (48.4%) of the 223 non-severe COVID-19 patients reported sequelae for more than 4 weeks, and of these, 35 (15.7%) had fatigue sequelae that were scale-confirmed. Other sequelae of more than 10% were brain fog (n = 37,16.6%), cough (n = 26,11.7%) and insomnia (n = 23,10.3%). A correlation between depression and fatigue was discovered following the completion of neuropsychological scale. The duration of hospitalization, the non-use of antiviral medications in treatment, IL-6 and CD16+CD56+ cell levels in blood are the main independent risk factors and predictors of fatigue sequelae in long COVID. Additionally, the neurology diseases and vaccination status may also influence the fatigue sequelae. ConclusionNearly half of the patients infected with COVID-19 Omicron variant complained of sequelae, and fatigue was the most common symptom, which was correlated with depression. Significant predictors of fatigue sequelae included length of hospitalization, non-use of antiviral drug, and immune-related serum markers of IL-6 and CD16+CD56+ NK cell levels. The presence of neurology diseases and a lack of vaccination could also predict the occurrence of fatigue sequelae.

Quercetin alleviates liver fibrosis via regulating glycolysis of liver sinusoidal endothelial cells and neutrophil infiltration.

Liver fibrosis, a common characteristic in various chronic liver diseases, is largely influenced by glycolysis. Quercetin (QE), a natural flavonoid known to regulate glycolysis, was studied for its effects on liver fibrosis and its underlying mechanism. In a model of liver fibrosis induced by carbon tetrachloride (CCl4), we aimed to assess pathological features, serum marker levels, and analyze the expression of glycolysis-related enzymes at both mRNA and protein levels, with a focus on changes in liver sinusoidal endothelial cells (LSECs). Our results showed that QE effectively improved liver injury and fibrosis evident by improved pathological features and lowered levels of serum markers, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), γ-glutamyl transferase (GGT), total bile acid (TBA), total bilirubin (TBIL), direct bilirubin (DBIL), hyaluronic acid (HA), laminin (LN), and procollagen type III (PCIII). QE also decreased lactate production and downregulated the expression of glycolysis-related enzymes-pyruvate kinase M2 (PKM2), phosphofructokinase platelet (PFKP), and hexokinase II (HK2)-at both the mRNA and protein levels. QE reduced the expression and activity of these enzymes, resulting in reduced glucose consumption, adenosine triphosphate (ATP) production, and lactate generation. Further analysis revealed that QE inhibited the production of chemokine (C-X-C motif) ligand 1 (CXCL1) and suppressed neutrophil recruitment. Overall, QE showed promising therapeutic potential for liver fibrosis by targeting LSEC glycolysis and reducing neutrophil infiltration.

Silybin Meglumine Mitigates CCl4-Induced Liver Fibrosis and Bile Acid Metabolism Alterations.

Altered patterns of bile acids (BAs) are frequently present in liver fibrosis, and BAs function as signaling molecules to initiate inflammatory responses. Silybin meglumine (SLB-M) is widely used in treating various liver diseases including liver fibrosis. However, research on its effects on bile acid (BA) metabolism is limited. This study investigated the therapeutic effects of SLB-M on liver fibrosis and BA metabolism in a CCl4-induced murine model. A murine liver fibrosis model was induced by CCl4. Fibrosis was evaluated using HE, picrosirius red, and Masson's trichrome staining. Liver function was assessed by serum and hepatic biochemical markers. Bile acid (BA) metabolism was analyzed using LC-MS/MS. Bioinformatics analyses, including PPI network, GO, and KEGG pathway analyses, were employed to explore molecular mechanisms. Gene expression alterations in liver tissue were examined via qRT-PCR. SLB-M treatment resulted in significant histological improvements in liver tissue, reducing collagen deposition and restoring liver architecture. Biochemically, SLB-M not only normalized serum liver enzyme levels (ALT, AST, TBA, and GGT) but also mitigated disruptions in both systemic and hepatic BA metabolism by increased unconjugated BAs like cholic acid and chenodeoxycholic acid but decreased conjugated BAs including taurocholic acid and taurodeoxycholic acid, compared to that in CCl4-induced murine model. Notably, SLB-M efficiently improved the imbalance of BA homeostasis in liver caused by CCl4 via activating Farnesoid X receptor. These findings underscore SLB-M decreased inflammatory response, reconstructed BA homeostasis possibly by regulating key pathways, and gene expressions in BA metabolism.

Effect of intravenous versus inhaled anesthetics on blood-brain barrier dysfunction and neuroinflammation in elderly patients undergoing major surgery: study protocol of a randomized controlled trial

BackgroundPostoperative cognitive dysfunction (POCD) is one of the major complications after surgery, with devastating clinical outcomes. Although POCD is a condition with a multifactorial pathophysiology, blood-brain barrier (BBB) dysfunction and neuronal injury have been shown to play a critical role, especially in the elderly. Previous studies have demonstrated that the choice of anesthetics affect BBB permeability and neuroinflammation. However, most studies are carried out on animals, with limited research undertaken on humans. Therefore, we will compare the effect of intravenous anesthetics and inhaled anesthetics on BBB dysfunction and the change of inflammatory markers after surgery.MethodsOne hundred and fifty-four patients who are 60 years of age or older undergoing major surgery for more than 2 h will be randomly allocated to two anesthetics groups (intravenous, inhaled) in a 1:1 ratio. In the intravenous anesthetics group (group P), propofol will be infused with a target-controlled infusion (TCI) system throughout the entire surgery. In the inhaled anesthetics group (group G), bolus injection of propofol will be administered for loss of consciousness, and simultaneously sevoflurane will be initiated for the maintenance of anesthesia. The primary outcome is the change in serum S100 calcium binding protein β (S100β) at four time points: before induction of anesthesia, at the end of surgery, 4 h after surgery, postoperative day 1. Secondary outcomes include changes in the inflammatory markers, serum interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-α, and C-reactive protein; the incidence of delirium; and the change in the cognitive function between groups. In patients pre-scheduled for postoperative intensive care unit admission, the cerebrospinal fluid/serum albumin quotient (Qalb) between the two groups will be compared before and after surgery, and change in inflammatory markers in serum and CSF will be analyzed in relation to the Qalb.DiscussionThe current study will compare the effect of intravenous versus inhaled anesthetics on blood-brain barrier permeability and, as a result, the difference in neuroinflammation in elderly patients. Also, the study results will provide additional information to develop intraoperative anesthetic strategies to reduce POCD.Trial registrationThe trial was prospectively registered at Clinical Trials protocol registration with identifier 2310-117-126 on April 9, 2024.

Challenging antibiotic stewardship: antibiotic use in the management of acute pancreatitis without waiting for a CT scan or CRP marker.

Madam, Acute pancreatitis is an acute inflammation of the pancreas presenting as severe abdominal pain and elevated pancreatic enzymes. The global burden of Acute pancreatitis has increased by 3.07% per year, for the last 56 years.1 Gallstones, chronic alcohol, and hypertriglyceridemia are the main risk factors involved in the pathogenesis of Acute pancreatitis worldwide.2 However, in Pakistan gall stones impacting the common bile duct and hypertriglyceridemia are the main culprits. There has been an extensive debate regarding the use of prophylactic antibiotics and the outcome of acute pancreatitis. The cumulative evidence suggests that the prompt use of antibiotics, before obtaining serum markers, is not associated with a significant decrease in secondary pancreatic infection.3 Multiple studies have shown that the use of antibiotics, deviating from the recent guidelines, boosts antibiotic resistance and the risk of invasive fungal infections. A 2020 study conducted by Soulountsi has also rendered this practice unjustified.4 In studies supporting the use of prophylactic antibiotics in improving outcomes, the quality of evidence is low suggesting that the approach should be more tailored to individual patient conditions while adhering to the guidelines. Despite the sterile nature of the early stages of acute pancreatitis, some clinicians continue to opt for prophylactic use, however, it is strictly against the international consensus. Unfortunately, in Pakistan, there is a common practice of using antibiotics in acute pancreatitis within 72hrs, without waiting for the CT scan results and inflammatory markers screening. Antimicrobial resistance is an anticipated outcome of such practice. The prevalence of antimicrobial resistance to commonly prescribed antibiotics is already very high.5 Not weighing the risk-benefit ratio will not only contribute to increasing resistance but also predispose to avoidable and potentially fatal fungal infections. The appropriate approach to management of Acute pancreatitis should be based on a thorough knowledge of recent guidelines, carrying out proper investigations, and making an individualized plan for the patient based on clinical findings. This will not only minimize the burden of complications but also provide more room for improvements in the management of acute pancreatitis.

Expect the unexpected: fulminant myocardial cytotoxic Injury from Trabectedin

BackgroundTrabectedin (Tbt) is an alkylating agent prescribed for soft tissue sarcomas after treatment failure of first line agents. While cardiomyopathy can occur with Tbt treatment after anthracycline exposure, Tbt-induced fulminant myocardial cytotoxic injury in the setting of other systemic cytotoxicity associated with Tbt has not been reported.Case presentation51-year-old female with hypertension, hyperlipidemia, metastatic leiomyosarcoma with progression of disease despite several lines of chemotherapy including doxorubicin-based therapy was started on Trabectedin (Tbt) 5 days prior to presentation with symptoms of fever, myalgias, arthralgias, and palpitations. She was admitted for management of rhabdomyolysis, acute kidney and liver injuries which were reportedly known to be associated with Tbt treatment. A baseline electrocardiogram (ECG) revealed sinus tachycardia with non-specific T-wave changes, and a transthoracic echocardiogram (TTE) was unremarkable. However, on day 3 of hospitalization, an episode of asymptomatic sustained monomorphic ventricular tachycardia with a heart rate of 150 beats per minute was captured on telemetry. A 12-lead ECG revealed new septal T-wave inversions. Labs revealed rising hs-TnI levels (peak at 37,933ng/L) and serum markers suggested multi-organ failure. Steroids were initiated given its role in treating multi-organ Tbt-induced toxicity. A cardiac MRI to rule out myocarditis and left heart catheterization to rule out obstructive coronary artery disease were forgone due to acute renal failure. A right heart catheterization with an endomyocardial biopsy was performed revealing normal cardiac filling pressures and indices. Pathology showed cytoplasmic vacuoles indicating drug-induced myocardial cytotoxicity. Serial echocardiograms revealed preserved biventricular function. The patient’s clinical condition deteriorated with multi-organ failure despite maximal supportive care in the intensive care unit. She ultimately passed away, and an autopsy was declined.ConclusionThis is the first reported case of fulminant myocardial injury after initiation of Tbt with histologic evidence of drug-induced myocardial cytotoxicity. While it is unclear if anthracyclines potentiate Tbt cytotoxic injury as in this case, it is plausible; and that Tbt-induced cardiotoxicity ranges from subclinical to fulminant. Given increasing use of Tbt in refractory high-grade sarcomas, raising awareness of its toxicity profile will improve early detection and outcomes.

The association of glyphosate exposure with kidney stones in American adults: A nationally representative cross-sectional study

ObjectiveGlyphosate has been ubiquitously present in our living environment due to its efficient herbicidal ability, but its association with the prevalence of kidney stones remains uncertain. This study aims to explore the impact of glyphosate exposure on kidney stones and to investigate the mediating effects of some serologic indicators. Furthermore, we attempt to identify the specific populations at greater risk of exposure. MethodsThis is a cross-sectional study of the U.S. adult population examining the association between glyphosate exposure and kidney stones based on data from the 2013–2018 National Health and Nutrition Examination Survey (NHANES). We implemented multi-model-adjusted logistic regression and smoothed curve fitting to explore the connection between them. Further subgroup analyses were conducted to confirm the magnitude of exposure risk in specific populations. Mediation effects analysis served to provide insight into the underlying mechanisms of the link. ResultsA total of 4302 participants' health data were ultimately analyzed, and the prevalence of kidney stones was 10.85 %. Participants with the highest urinary glyphosate(uGLY) content(Q3) had a higher prevalence of kidney stones compared with participants with the lowest uGLY content(Q1) (OR=1.70, 95 %CI: 1.10–2.63). Smoothed curve fitting revealed a linear positive association between ln-transformed uGLY and kidney stones (OR=1.21,95 %CI:1.08–1.37, LLR=0.291), and this exposure-outcome effect was at greater risk in men (OR=1.24,95 %CI: 1.05–1.46), non-Hispanic whites (OR=1.29, 95 %CI: 1.09–1.53), and hypertensive groups (OR=1.23,95 %CI: 1.05–1.44). Serum biochemical markers HDL, ALP, and serum glucose partially mediated the correlation between glyphosate and kidney stones (2.44–4.20 %). ConclusionGlyphosate exposure is significantly associated with the prevalence of kidney stones. In men, non-Hispanic whites, and hypertensive populations, the management of glyphosate exposure should be emphasized, and appropriate protective strategies may be beneficial in reducing the burden of kidney stones. More high-quality clinical inquiries and animal toxicology experiments are still required to verify the reliability of our findings and their underlying mechanisms.

Evaluation of Biochemical Serum Markers for the Diagnosis of Polycystic Ovary Syndrome (PCOS) in Obese Women in Kazakhstan: Is Anti-Müllerian Hormone a Potential Marker?

Background: Polycystic Ovarian Syndrome (PCOS) is a common endocrine condition that affects 8-13% of women of reproductive age. In Kazakhstan, the prevalence of this syndrome is particularly high compared with other countries and the global average. Currently, the diagnosis of PCOS is based on internationally established Rotterdam criteria, using hyperandrogenism as a key parameter. These criteria are applied to diagnose PCOS in all female patients, although obese patients may have excess testosterone produced by adipose tissue. To avoid possible misdiagnosis, an additional criterion, especially for the diagnosis of PCOS in obese women, could be considered. The aim of this study was to identify whether anti-Müllerian hormone (AMH) or other biochemical criteria can be used for this purpose. Methods: A total of 138 women were recruited for this study and grouped into control (n = 46), obese subjects without PCOS (n = 67), and obese patients with PCOS (n = 25). The health status, anthropometric parameters, and serum indicators for glucose, glycosylated hemoglobin, and hormone levels were examined for all subjects. Statistical data were analyzed using GraphPad Prism 10 software for interpretation of the data. Results: Serum AMH, testosterone, and LH were positively correlated in obese PCOS patients, while AMH and FSH were negatively correlated. Compared with other biochemical indicators, the serum AMH and testosterone levels in obese PCOS patients were significantly higher than those in non-PCOS patients (regardless of obesity), and AMH was also positively correlated with testosterone. Conclusions: AMH appears to be a reliable criterion in addition to testosterone for the diagnosis of PCOS in obese women.

Hydrogel Grating Sensors with Boron Affinity and Molecular Imprinting Effects for Rapid and Sensitive Detection of Tumor Marker Sialic Acid.

Rapid and sensitive detection of the concentration of sialic acid (SA) in serum is crucial for early tumor screening and prognostic assessment; however, it still remains challenging. Here, we propose a novel kind of hydrogel grating sensor with boron affinity and molecular imprinting effects (B-MIP) for the rapid and sensitive detection of SA concentration in serum. The hydrogel gratings feature uniform surface relief microstructures and incorporate highly specific recognition binding sites into SA molecules provided by boron affinity and molecular imprinting. The periodic nanoridges of hydrogel gratings increase the specific surface area contacting the environmental solution; therefore, fast detection can be achieved within 2 min. Upon recognition of SA molecules, the height of hydrogel gratings changes at the nanoscale, causing a change in the diffraction efficiency of the hydrogel gratings. The B-MIP hydrogel grating sensors have highly specific binding sites to SA molecules distributed throughout the whole hydrogel and can preferentially and selectively recognize and respond to the SA molecules even in the presence of interference substances glucose and fructose with high concentrations. The B-MIP hydrogel grating sensors are effectively applicable for the rapid and sensitive detection of SA concentrations in real serum samples with satisfactory accuracy and precision. Our approach provides an excellent strategy to address the current challenges in SA detection and provides new insights into the detection of tumor markers in serum, thereby opening up new ways to accurately detect complex biological samples in analytical science.

Evaluation of the Pandemic Normalization Process in Pediatric Surgery Operations: Tertiary Center Experience

Objectives: The aim of this study was to evaluate pandemicinormalization process in pediatric surgery operations. Methods: This was a retrospective study conducted at a tertiary center. In our study, 917 individuals were included. It was defined as the period between June 2020, when normalization was announced after the first wave of the Coronavirusidisease-19 (COVID-19) pandemic in our country, and November 2020, when the second wave of measures began [Group 1 (n=393,42.7%)]. One year later was defined as the second period [Group 2 (n=525, 57.3%)], corresponding to the same time period (June 2021-November 2021). Results: The median age of Group 1 was 5 years and Group 2 was 6 years (p <0.001). Emergency surgery was more common in Group 2 (31.1% vs 35.4%). General anesthesia is the most commonly perfomed anesthesia method in both groups (98.5% vs 97.3%). Abdominal operations were the most common in both groups (48% vs 49%). While the rate of laparoscopic surgery was 62% in Group 1, it was 62.1% in Group 2. A statistically significant difference was detected in preoperative COVID-19 polymeraseichain reaction (PCR) test examination Group 2 and postoperative COVID-19 PCR test examination Group 1. Lymphocyte and C-reactive protein (CRP) serum markers were similar between groups. There was no difference between the need for intensive care unit/postanesthesia care unit and mortality rates. Conclusion: Although the number of pediatric surgical operations decreased during the normalization period, a successful process was managed in terms of the quality and results of the cases.

Diagnostic Utility of Canine C-Reactive Protein, Haptoglobin, and 25-Hydroxyvitamin-D in Dogs with Nasal Cavity Disease

In this prospective blinded study, canine C-reactive protein (c-CRP), haptoglobin (HPT), and 25-hydroxyvitamin-D (25(OH)D) were investigated for their diagnostic value in 55 dogs with nasal cavity disease (ND). After comprehensive diagnostics including a culture-dependent microbiological examination (ME) of nasal swabs, 17 dogs were excluded due to additionally detected systemic diseases or steroid pre-treatment. Included were 25 dogs with malignant ND (13 carcinomas and 12 sarcomas) and 30 dogs with benign ND (7 benign tumors, 13 idiopathic rhinitis (IR), and 10 others), as well as 10 controls. In none of the 72 dogs with ND was primary bacterial rhinitis diagnosed. Although within the reference interval, compared to the controls, c-CRP was significantly higher in dogs with ND in general and in every subgroup except for benign tumors. Serum HPT concentrations were not different among groups. Compared to the controls, 25(OH)D concentrations were significantly lower (p = 0.041) in malignant ND and sarcomas (p = 0.025). Despite pre-treatment with antibiotics (40/54; 74.1%), in 23/51 (45%) dogs, the ME was positive. Cultivated bacteria did not differ significantly between nasal diseases. The serum markers were not significantly different regarding the positivity of ME. In conclusion, the investigated serum markers were not clinically useful for the reliable detection of canine ND, as was the ME. Because of the low number of dogs with IR and positive or negative ME, further studies regarding c-CRP are needed in a larger group of IR dogs without concomitant diseases to reliably evaluate its utility in IR dogs with suspected secondary bacterial nasal infection.

Spatial analyses revealed S100P + TFF1 + tumor cells in spread through air spaces samples correlated with undesirable therapy response in non-small cell lung cancer

Spread through air spaces (STAS) is a recognized aggressive pattern in lung cancer, serving as a crucial risk factor for postoperative recurrence. However, its phenotype and related spatial structure have remained elusive. To address these limitations, we conducted a comprehensive study based on spatial data, analyzing over 30,000 spots from 14 non-STAS samples and one STAS sample. We observed increased proliferation activities and angiogenesis in STAS, identifying S100P as a potential biomarker for STAS. Furthermore, our investigation into the heterogeneity of STAS tumor cells revealed a subset identified as S100P + TFF1 +, exhibiting a negative impact on patients' survival in public datasets. This subtype exhibited the highest activities in the TGFb and hypoxia, suggesting its potential pro-tumor role within the tumor microenvironment. To assess the role of S100P + TFF1 + tumor cells in therapy response, we included data from two clinical trial cohorts (BPI-7711 for EGFR-TKI therapy and ORIENT-3 for immunotherapy). The presence of S100P + TFF1 + tumor cells correlated with worse responses to both EGFR-TKI therapy and immunotherapy. Notably, TFF1 emerged as a serum marker for predicting EGFR-TKI response. Cell–cell communication analysis revealed that the TGFb signaling pathway was the most activated in S100P + TFF1 + tumor cells, with TGFB2-TGFBR2 identified as the main ligand-receptor pair. This was further validated by multiplex immunofluorescence performed on twenty NSCLC samples. In summary, our study identified S100P as the biomarker for STAS and highlighted the adverse role of S100P + TFF1 + tumor cells in survival outcomes.

Surgical Experience and Functional Outcomes after Laparoscopic and Robot-Assisted Partial Nephrectomy: Results from a Multi-Institutional Collaboration

Background: In patients treated with partial nephrectomy, prior evidence showed that peri-operative outcomes, such as complications and ischemia time, improved as a function of the surgical experience of the surgeon, but data on functional outcomes after surgery are still scarce. Methods: We retrospectively analyzed data of 4011 patients with a single, unilateral cT1a-b renal mass treated with laparoscopic or robot-assisted partial nephrectomy. The operations were performed by 119 surgeons at 22 participating institutions between 1997 and 2022. Multivariable models investigated the association between surgical experience (number of prior operations) and acute kidney injury (AKI) and recovery of at least 90% of baseline estimated glomerular filtration rate (eGFR) 1 yr after partial nephrectomy. The adjustment for case mix included age, Body Mass Index, preoperative serum creatinine, clinical T stage, PADUA score, warm ischemia time, pathologic tumor size, and year of surgery. Results: A total of 753 (19%) and 3258 (81%) patients underwent laparoscopic and robot-assisted partial nephrectomy, respectively. Overall, 37 (31%) and 55 (46%) surgeons contributed only to laparoscopic and robotic learning curves, respectively, whereas 27 (23%) contributed to the learning curves of both approaches. In the laparoscopic group, 8% and 55% of patients developed AKI and recovered at least 90% of their baseline eGFR, respectively. After adjusting for confounders, we did not find evidence of an association between surgical experience and AKI after laparoscopic partial nephrectomy (odds ratio [OR]: 0.9992; 95% confidence interval [CI]: 0.9963, 1.0022; p = 0.6). Similar results were found when 1-year renal function was the outcome of interest (OR: 0.9996; 95% CI: 0.9988, 1.0005; p = 0.5). Among patients who underwent robot-assisted partial nephrectomy, AKI occurred in 11% of patients, whereas 54% recovered at least 90% of their baseline eGFR. On multivariable analyses, the relationship between surgical experience and AKI after surgery was not statistically significant (OR: 1.0015; 95% CI: 0.9992, 1.0037; p = 0.2), with similar results when the outcome of interest was renal function one year after surgery (OR: 1.0001; 95% CI: 0.9980, 1.0022; p = 0.9). Virtually the same findings were found on sensitivity analyses. Conclusions: In patients treated with laparoscopic or robot-assisted partial nephrectomy, our data suggest that the surgical experience of the operating surgeon might not be a key determinant of functional recovery after surgery. This raises questions about the use of serum markers to assess functional recovery in patients with two kidneys and opens the discussion on what are the key steps of the procedure that allowed surgeons to achieve optimal outcomes since their initial cases.

Short-term efficiency of plasma exchange in combination with immunosuppressants and/or biologics in the treatment of idiopathic inflammatory myopathy with rapidly progressive interstitial lung disease: a systematic review and meta-analysis

Objective Rapidly progressive interstitial lung disease (RP-ILD) is a frequent and serious manifestation of idiopathic inflammatory myopathy (IIM) associated with poor outcomes. Plasma exchange (PE) can quickly remove pathogenic substances from the blood. Therefore, PE may be efficacious in IIM patients who have elevated levels of autoantibodies, cytokines and chemokines, fighting for time for immunosuppressive therapy. However, the value of adding PE to immunosuppressants remains unclear. The purpose of this study was to determine the short-term outcomes, including the survival rate at 6 months and change of the laboratory data, of PE in combination with immunosuppressants and/or biologics in the treatment of IIM-RP-ILD. Methods We searched PubMed, Embase and Cochrane Library to find reports of interest published from inception to March 4, 2024. STATA 15.1 was used for data analysis. A fixed or random-effects model with inverse-variance weighting was used to estimate the pooled risk ratio (RR) and 95% confidence interval (CI). Results Two hundred and thirty studies were identified. Eleven studies, including five retrospective cohort studies, four case-control studies and two case series, were included. PE was performed on 114 patients. The survival rate at 6 months was 80% (95%CI = 64%–92%), with moderate heterogeneity (I 2=63.45%, p < 0.05). Moreover, the 6-month survival rate was significantly better in the PE group than in the non-PE group (RR, 1.34; 95% CI = 1.05–1.71, I 2=30.7%; p = 0.194). ILD-related serum markers, including ferritin, KL-6 and anti-MDA-5 antibody titres, were significantly suppressed by a series of PE treatments (p < 0.05). Conclusion The application of PE therapy plus treatment with corticosteroids, immunosuppressants and/or biologics was effective for patients with IIM-RP-ILD. PE may have additional supportive effect in intractable disease.

7286 Higher Order Associations Linking Tryptophan, Kynurenine, And Tyrosine As Serum Markers Of Glucocorticoid Downstream Action In Adipose Tissue

Abstract Disclosure: K. Bennett: None. T. Garner: None. D. Chantzichristos: Speaker; Self; Sanofi, Takeda. P. Jansson: None. A. Stevens: None. G. Johannsson: Consulting Fee; Self; Novo Nordisk, Shire, AstraZeneca. Speaker; Self; Novo Nordisk, Pfizer, Inc.. Introduction: Treatment of Adrenal Insufficiency (AI) by glucocorticoid (GC) replacement therapy is mainly guided by clinical judgement, as there is no biomarker of GC action to individualise its dosage. Hypergraphs are networks modelling higher order associations (HOAs), which are interactions between more than two ‘omic elements. The aim of this study was to use hypergraphs to identify serum markers that reflect the action of GCs in adipose tissue (AT). Methods: In a randomised, cross-over trial, 10 patients with primary AI received saline i.v. (GC withdrawal), or circadian infusion of hydrocortisone (GC exposure), with &amp;gt; 2 weeks apart. After 26 hours (8AM), AT biopsy and PBMCs were collected for transcriptomic analysis, and abdominal subcutaneous microdialysis and PBMCs were collected for metabolomic profiling using LC/MS. Hypergraph models were generated to integrate serum and AT transcriptomics and metabolomics, identifying clusters of putatively causally linked metabolites which could represent serum markers of downstream GC action in AT. Hypergraph structure was assessed in AT and serum using entropy to infer associations within pre-defined metabolic pathways. Differences in entropy between the interventions was measured using Bayes Factor. Univariate ROC curve analysis was used to calculate AUCs for the serum markers. Results: In AT dialysate, 22 metabolites were identified as significantly different between GC exposure and withdrawal states. These included metabolites found in lipolysis and proteolysis pathways, such as acyl carnitines, lysophosphatidylcholines, fatty acids, and peptide derivatives. Nine metabolites were significantly different between the interventions in the serum. DEGs in AT (n=2048) were found to be enriched in metabolic pathways. Hypergraphs were used to refine clusters in the serum based on their HOAs with AT differentially expressed genes and metabolites. Tryptophan, Kynurenine, and Tyrosine clustered together, demonstrating a relationship between their expression in serum, and the metabolomic and transcriptomic profile of AT. These HOAs were shared with cortisol in the exposure intervention, but not in GC withdrawal, suggesting GC dependent regulation. All 3 metabolites had AUC-ROCs &amp;gt; 0.8, with Kynurenine performing the best at 0.86. Tissue specific differences were seen in the entropy of metabolic pathways between GC exposure and withdrawal, with similar changes seen in lipid and proteolysis pathways, but no difference seen in serum in carbohydrate and amino acid biosynthesis. Conclusions: During near physiological exposure, we identified changes to hypergraph structure and metabolite concentrations in lipid, protein, and carbohydrate pathways in AT and serum, compared to GC withdrawal. Hypergraph integration of multi-omic data identified tryptophan, kynurenine, and tyrosine as potential serum markers reflecting GC action in AT. Presentation: 6/3/2024

7426 Tamoxifen-Induced Ovarian Hyperstimulation in a Pre-Menopausal Patient with Breast Cancer History: Spontaneous Resolution with Conservative Management

Abstract Disclosure: S. Gondi: None. M. Contento: None. A. Leiter: None. Background: Tamoxifen is a selective estrogen receptor modulator (SERM) that competitively binds to estrogen receptors (ER) on tumors and inhibits the effect of estrogen, which is used in the treatment and prevention of ER-positive breast cancer. Tamoxifen therapy has been reported to increase serum estrogens and cause ovarian hyperstimulation in premenopausal women, but knowledge on how to manage these conditions is limited. Clinical Case: A 36-year-old pre-menopausal female with history of malignant neoplasm of the right breast (ER positive) who completed neoadjuvant chemotherapy, lumpectomy, and radiation, on tamoxifen for seven years presented with new-onset oligomenorrhea. Laboratory testing done by the patient’s gynecologist revealed total estrogen 2,723 pg/mL (reference range [RR] 34-501), testosterone 132 ng/dL (RR 8-60), anti-Mullerian hormone 12.7 ng/mL (RR for age 0.66-8.75), ovulation-phase follicle stimulating hormone 11.5 mIU/mL (RR 4.7-21.5) and luteinizing hormone (LH) 63.3 mIU/mL (RR 14-95.6). Further workup revealed that ovarian tumor markers alpha-fetoprotein and serum human chorionic gonadotropin and other labs including dehydroepiandrosterone sulfate, progesterone 17-OH, lactate dehydrogenase, prolactin, and thyroid stimulating hormone were normal. Transvaginal ultrasound (TVUS) showed a new 2.8 x 1.9 x 2.3 cm complex left ovarian cyst, which, along with the elevated estrogen level, was concerning for ovarian hyperstimulation. Treatment with LH-releasing hormone (LHRH) agonists, surgical consultation, and discontinuation of tamoxifen were offered as potential management strategies, but the patient opted for observation and continued tamoxifen. Two months later, estradiol was 989 pg/mL (RR 85-498), and then three months later decreased to 152 pg/mL with repeat TVUS showing resolution of the left ovarian cyst. The patient’s oligomenorrhea resolved with resumption of regular menstrual cycles. Conclusion: While it is well-known that tamoxifen causes elevated serum estrogen levels and can lead to ovarian hyperstimulation, there is limited research on the management of these side effects. Treatment strategies in past cases have included oophorectomy or medical management with LHRH agonists or gonadotropin-RH agonists. However, this case demonstrates that a tamoxifen-induced ovarian cyst and high estrogen levels can resolve on its own with continued tamoxifen treatment. Conservative management with monitoring via imaging and repeat estrogen levels may be sufficient in management of pre-menopausal women with tamoxifen-induced ovarian hyperstimulation. Presentation: 6/1/2024

7494 Glycerol Phenylbutyrate Treatment of Two Patients with Monocarboxylate Transporter 8 Deficiency

Abstract Disclosure: A. Zung: None. N. Sonntag: None. U. Schweizer: None. E. Banne: None. D. Braun: None. Context: Monocarboxylate transporter 8 (MCT8) deficiency is a rare genetic disease that leads to severe global developmental delay. MCT8 facilitates thyroid hormone (TH) transport across the cell membrane, and the serum TH profile is characterized by high T3 and low T4 levels. Currently, the two thyromimetic agents 3,5-diiodothyropropionic acid (DITPA) and triiodothyroacetic acid (TRIAC) have been evaluated in the treatment of these patients, as they both partially restore intracellular TH action independent of MCT8. Recent studies have shown that the chemical chaperone sodium phenylbutyrate (NaPB) restored mutant MCT8 function and increased TH content in patient-derived induced pluripotent stem cells, making it a potential treatment for MCT8 deficiency. Objective: We aimed to assess the efficacy and safety of glycerol phenylbutyrate (GPB) in MCT8 deficiency. Methods: We treated two monozygotic twins aged 14.5 years with MCT8 deficiency due to P321L mutation with escalating doses of GPB over 13 months. We recorded TH, serum markers of peripheral hyperthyroidism, vital signs, anthropometric measurements and neurocognitive functions by several neurodevelopment validated tests. Resting metabolic rate (RMR) was measured by indirect calorimetry. Serum metabolites of GPB were monitored as a safety measure. In-vitro effects of NaPB were evaluated in MDCK1 cells stably expressing the MCT8P32[1]L mutation. Results: NaPB restored mutant MCT8 expression in MDCK1 cells and increased T3 transport into cells carrying the P321L mutation. GPB treatment yielded a dose-dependent decrease in FT3 and an increase in FT4 serum levels. The patients showed an elevation in cholesterol levels in parallel with GPB dose, but sex-hormone binding protein (SHBG), another marker of peripheral hyperthyroidism was not affected. The patients showed a significant weight gain simultaneously with a reduction in RMR. Only minor neuro-cognitive improvement was observed, mainly in hyperreflexia score, slight improvement in gross motor functions and a mild progression in cognitive functions. Serum metabolites of GPB did not exceed the toxic range but elevated liver transaminases restricted the dose intensification of GPB. Conclusions: In the first report of GPB treatment in MCT8 deficiency patients we found an improvement in TH profile and body-mass index (BMI). The reduction in T3 levels could contribute to the remarkable increase in BMI-SDS, since various aspects of peripheral hyperthyroidism in MCT8 deficiency, including poor weight gain, were attributed to elevated T3. The limited effects of GPB treatment on cognitive and motor functions can derive from the advanced age of the patients at the time of the intervention. Presentation: 6/2/2024