Lower Levels In Patients Research Articles

Metabolic Dysfunction-Associated Steatotic Liver Disease: The Associations between Inflammatory Markers, TLR4, and Cytokines IL-17A/F, and Their Connections to the Degree of Steatosis and the Risk of Fibrosis.

Background: The pathogenesis of MASLD (metabolic dysfunction-associated steatotic liver disease) is driven by environmental, genetic, metabolic, immune, and inflammatory factors. IL-17 and TLR4 determine hepatic steatosis, inflammation, and finally fibrosis. Objectives: To explore the associations between the plasma levels of inflammatory markers, TLR4, and the cytokines IL17A/F, as well as their connections with the degree of hepatic steatosis and the risk of hepatic fibrosis (defined by the FIB-4 score) in MASLD patients. Methods: The study cohort included 80 patients diagnosed with MASLD. The IL-17A/F and TLR4 serum concentrations were determined using the ELISA method. Results: We found a significant difference in the CAR levels (C-reactive protein to albumin ratio) when comparing MASLD patients with severe steatosis to those with mild/moderate steatosis (Student's t test, t (71) = 2.32, p = 0.023). The PIV (pan-immune inflammatory value) was positively correlated with the SII (systemic immune inflammation index), (r = 0.86, p < 0.0001) and the CAR (r = 0.41, p = 0.033) in MASLD patients with severe steatosis. In contrast, increased values of the LMR (lymphocyte to monocyte ratio) were significantly associated, with decreased levels of the SII (ρ = -0.38, p = 0.045). We also found a positive correlation between the CAR and the SII (r = 0.41, p = 0.028). In patients with mild/moderate steatosis, a significant positive correlation was observed between the SII and IL17A (r = 0.36, p = 0.010), the PIV and the CAR (r = 0.29, p = 0.011), the PIV and the SII (r = 0.87, p < 0.0001) and the PIV and IL17A (r = 0.3, p = 0.036). A negative correlation was observed between the LMR and the SII (r = -0.55, p < 0.0001) and the CAR and IL17F (r = -0.37, p = 0.011). Regarding the inflammatory markers, the PIV (336.4 vs. 228.63, p = 0.0107), and the SII (438.47 vs. 585.39, p = 0.0238) had significantly lower levels in patients with an intermediate-high risk of hepatic fibrosis as compared with the patients with a low risk of hepatic fibrosis. The PNI (prognostic nutritional index) (47.16 vs. 42.41, p = 0.0392) had significantly different levels in patients with the likelihood of hepatic fibrosis than those with a low risk of hepatic fibrosis. Conclusions: Regarding the inflammatory markers, the PIV and the SII hold promise as biomarkers for discriminating between MASLD patients with an intermediate-high risk and those with a low risk of hepatic fibrosis. Our findings underscore the role of IL-17A and its potential relationship with inflammatory markers in MASLD pathogenesis and the progression to hepatic fibrosis.

Serum insulin-like growth factor-1 as a potential prognostic biomarker for heart failure with reduced ejection fraction: a meta-analysis.

Most studies have indicated that peripheral insulin-like growth levels factor-1 (IGF-1) is valuable in diagnosing heart failure, although the results have been inconsistent. To help solve the debate, we performed a meta-analysis to explore the relationship between IGF-1 and heart failure (HF). We conducted an extensive search across various databases such as Embase, Cochrane Library, Pubmed, Medline, and Web of Science on May 30, 2023. From the extensive pool of studies, we selected 16 relevant articles, encompassing a total of 1,380 cases and 1,153 controls, to conduct a rigorous meta-analysis. The total results indicated that there is an association between lower IGF-1 level and HF. The random-effects model yielded a pooled standardized mean difference (SMD) of -0.598 (95% CI: -1.081 to -0.116, P = 0.015). Further subgroup analysis also showed that IGF-1 levels were associated with HF in the age difference ≥5 years subgroup and body mass index difference >1 subgroup. Additionally, significant association between IGF-1 levels and HF were detected in the "serum" samples and "Europe" subgroups. Importantly, we observed IGF-1 showed significant lower levels in patients with reduced ejection fraction (HFrEF) compared to the controls, not in patients with preserved ejection fraction (HFpEF). The Begg's and Egger's tests revealed no indication of publication bias. Our meta-analysis has provided evidence suggesting a substantial correlation between reduced levels of IGF-1 and the occurrence of HF. Further prospective studies are necessary to ascertain the use of IGF-1 as a reliable biomarker for diagnosing HF, especially for HFrEF. But the diagnosis of HFpEF should be cautious.

Serum zinc, selenium, and vitamin D levels in patients with acne vulgaris: A case-control study.

Acne vulgaris is a very common inflammatory skin disease that significantly impacts the quality of life of affected individuals. Previous studies have indicated that individuals with acne vulgaris often have low levels of zinc, selenium, and vitamin D. However, these three nutrients have rarely been collectively examined in a single study. The objective of this study was to compare serum levels of zinc, selenium, and vitamin D in patients with acne vulgaris in comparison to a control group. This case-control study included 100 adult patients with acne vulgaris attending a dermatology clinic, in 2020. A group of 100 patients without acne vulgaris attending the same clinics were evaluated as controls. Participants' sociodemographic characteristics, including age, sex, occupation, alcohol consumption, and tobacco smoking were recorded. In addition, anthropometric indices, such as weight and height, were measured and the body mass index (BMI) was calculated accordingly. Acne severity was determined using Tutakne and Chari's grading system. Serum zinc, selenium, and vitamin D levels were evaluated in peripheral blood samples of all the participants. Acne patients and controls were comparable regarding age, sex, weight, height, BMI, occupation, alcohol consumption, and tobacco smoking (p > 0.05). Serum zinc, selenium, and vitamin D levels were all significantly lower in acne patients than in controls (p < 0.001). Furthermore, the frequency of abnormal zinc and vitamin D levels was significantly higher in acne patients (p = 0.002 and p = 0.001, respectively), but there was no significant difference between the two groups regarding abnormal serum selenium levels (p = 0.228). Also, serum zinc, selenium, and vitamin D levels lower levels in patients with grade 4 acne compared to other disease severity grades (p < 0.001). Patients with acne vulgaris have lower levels of serum zinc, selenium, and vitamin D compared to the control group. Additionally, there is a correlation between the severity of the disease and lower levels of these nutrients.

Discovery of core genes and intercellular communication role in osteosarcoma.

Osteosarcoma is a primary malignant bone tumor that affects children and young adults. Understanding the molecular mechanisms underlying osteosarcoma is critical to develop effective treatments. This study aimed to identify core genes and explore the role of intercellular communication in osteosarcoma. We used GSE87437 and GSE152048 dataset to conduct a weighted correlation network analysis (WGCNA) and identify co-expression modules. The enriched biological processes and cellular components of the genes in the steelblue module were analyzed. Next, we explored the expression, diagnostic value, correlation, and association with immune infiltrate of CCSER1 and LOC101929154. Finally, we utilized CIBERSORT algorithm to predict the infiltrated immune cells in osteosarcoma tissues. Our results identified 44 co-expression modules, and the steelblue module was mainly associated with axon development, axonogenesis, and innervation. CCSER1 and LOC101929154 were significantly upregulated in osteosarcoma tissues with poor response to preoperative chemotherapy. Moreover, the expressions of CCSER1 and LOC101929154 were positively correlated. The area under the receiver operating characteristic curve of CCSER1 and LOC101929154 was 0.800 and 0.773, respectively. The expression of CCSER1 was negatively correlated with follicular helper T cells and positively correlated with M0 macrophages, while LOC101929154 was negatively correlated with activated mast cells. Besides, CD4 memory-activated T cells were observed at lower levels in patients who responded well to chemotherapy. Our study identified core genes CCSER1 and LOC101929154 and provided insight into the intercellular communication profile in osteosarcoma. Our results suggested that targeting CCSER1, LOC101929154, and CD4 memory-activated T cells may be a promising strategy for the treatment of osteosarcoma.

The role of the osteoprotegerin/RANKL/RANK axis and osteopontin in acute coronary syndrome.

The primary objective of this study is to ascertain the levels of osteoprotegerin (OPG) and osteopontin (OPN), alongside osteoprotegerin/RANKL ratio (ORR), and assess their association with the SYNTAX score and ascertain the potential of these molecules as predictive markers for risk, aiding in risk stratification. Eventually, they could potentially be employed even before angiography to gauge the severity of coronary lesions. Prospective study with 147 participants, 101 (69%) were men, with an average age of 60. We included three groups - (1) patients with acute coronary syndrome undergoing percutaneous coronary intervention (ACS-PCI), (2) patients without ACS who underwent coronary angiography for an indication other than ischemia and did not undergo PCI (non-ACS without), and (3) one asymptomatic subject. OPG and OPN were measured. ORR and SYNTAX scores were calculated. The association between OPG and OPN levels and important clinical variables was investigated. OPG levels in Group 1 were lower compared to Groups 2 and 3 (controls), Group 1 (490 pg/mL) versus Group 2 (829 pg/mL) versus Group 3 (845 pg/mL) (p = 0.001). OPG had lower levels in patients with coronary artery stenosis versus without stenosis. A decrease in ORR was shown in all groups and no association with the SYNTAX score. OPG and OPN (and ORR) levels are decreased in patients with ACS and show no correlation with the SYNTAX score. As an exploratory study, our work suggest that increased OPG and OPN levels in non-ACS patients may have, in fact, a protective effect. This study is one of the few with an appropriate control in ACS and reproducibility is necessary mainly with multicenter studies.

Gadd45g insufficiency drives the pathogenesis of myeloproliferative neoplasms

Despite the identification of driver mutations leading to the initiation of myeloproliferative neoplasms (MPNs), the molecular pathogenesis of MPNs remains incompletely understood. Here, we demonstrate that growth arrest and DNA damage inducible gamma (GADD45g) is expressed at significantly lower levels in patients with MPNs, and JAK2V617F mutation and histone deacetylation contribute to its reduced expression. Downregulation of GADD45g plays a tumor-promoting role in human MPN cells. Gadd45g insufficiency in the murine hematopoietic system alone leads to significantly enhanced growth and self-renewal capacity of myeloid-biased hematopoietic stem cells, and the development of phenotypes resembling MPNs. Mechanistically, the pathogenic role of GADD45g insufficiency is mediated through a cascade of activations of RAC2, PAK1 and PI3K-AKT signaling pathways. These data characterize GADD45g deficiency as a novel pathogenic factor in MPNs.

The role of methionine in tuberculosis and its potential clinical significance

Tuberculosis (TB) remains a significant global health challenge. Multidrug-resistant tuberculosis (MDR-TB) holds a substantial health risk, and only a limited number of patients receive treatment for drug-resistant tuberculosis. Various studies have been conducted to address this condition, including through metabolic approaches to further understand the mechanisms of tuberculosis infection, one of which is methionine. There are various enzymes in the Mycobacterium tuberculosis (MTB) methionine biosynthesis pathway, the key enzymes such as MetX, MetC, MetE/MetH, MetK, MTHFR, and BCAT are essential in the biosynthesis of methionine, and hindering these enzyme activities may hold potential for new antitubercular drug development. Deletion of the metA gene weakens MTB, making it more prone to host immune responses. There is also the role of cobalamin, where cobalamin availability regulates the choice between metE and metH in methionine biosynthesis. Methionine plays a crucial role in bacterial protein translation and antioxidant activities. In bacteria including MTB, the initial methionine is formulated; this process involves several enzymes such as FMT, MetRS, PDF, and MetAP. Some compounds targeting MetAP have been identified to have significant inhibitory action against MTB, such as transitmycin and bengamides, and this also includes the drug resistant strain. Methionine supplementation alongside vitamin B-complex have shown to improve drug-induced toxicity in tuberculosis patients, this due to methionine serves as precursor to antioxidant glutathione. Metabolomics studies have shown that altered methionine levels in tuberculosis infection, with samples taken from human blood or urine show significantly lower levels in patients with active TB or failed treatment groups. This review aims to discuss the role of methionine in Mycobacterium tuberculosis and the progress of research targeting methionine metabolism and function.

Correlating the Depth of Sedation Between the Ramsay Sedation Scale and Bispectral Index Using Either Intravenous Midazolam or Intravenous Propofol in Elderly Patients Under Spinal Anaesthesia.

Supplementation of spinal anaesthesia with sedatives or anxiolytics has emerged as a standard protocol to alleviate patients' anxiety and to produce amnesia during the surgical procedure. Thus, judicious use of sedation can make surgeries under spinal anaesthesia more comfortable and acceptable for the elderly patient, the surgeon, and the anaesthesiologist. However, over-sedation may jeopardise the safety of the patient. Appropriate sedation helps reduce physiological stress, which leads to a better result. Therefore, monitoring the depth of sedation becomes essential. The Ramsay sedation scale (RSS) and bispectral index (BIS) both are used widely to assess the depth of sedation. The primary objective of the study was to assess and correlate the depth of sedation between the BIS and RSS in elderly patients using midazolam and propofol under spinal anaesthesia. The secondary objectives were to observe any difference in the commencement of sedation between the two groups and to observe haemodynamic changes between the two groups. A total of 60 elderly patients undergoing urological procedures under spinal anaesthesia were randomly assigned to receive either midazolam (Group A, n=30) or propofol (Group B, n=30) for sedation. In Group A, patients were given an initial bolus of midazolam 0.03 mg/kg and a maintenance incremental bolus of 0.01 mg/kg up to a maximum of 2.5 mg in 10-minute intervals. Group B used propofol with an initial bolus dose of 0.5 mg/kg over two minutes and a maintenance bolus of 10-20 mg as required for the maintenance of sedation depth. Sedation was titrated to achieve a BIS score of 70-80 and an RSS score of 3-4. Heart rate, non-invasive systolic, diastolic, mean arterial blood pressure, oxygen saturation (SPO2), and the correlation coefficient between the BIS and RSS were measured at 0 (baseline), 5, 10, 20, 30, 40, 50, and 60 minutes of interval. The correlation coefficient between the BIS and RSS scores in Group A at various time intervals indicate a strong correlation coefficient of -0.76 at five minutes, -0.64 at 20 minutes, -0.78 at 30 minutes, -0.56 at 40 minutes, and -0.39 at 50 minutes. In Group B, the correlation coefficient between the BIS and RSS scores at various time intervals indicate a strong correlation coefficient of -0.75 at five minutes, -0.76 at 20 minutes,-0.64 at 30 minutes, -0.89 at 40 minutes, and -0.46 at 50 minutes of interval. We also observed that the BIS drops to a lower level in patients receiving propofol (Group B) with a significant difference depicting early onset of sedation with propofol. In Group B, HR and MAP were significantly less than those of Group A. There was no significant difference in terms of mean age, sex, and body weight in the patients of both groups. The BIS and RSS scores indicate a strong correlation with a magnitude of 70%-80%, but more in Group B (propofol) than Group A (midazolam). Therefore, the characteristics of each sedative drug can influence the level of sedation during spinal anaesthesia. Clinicians should use a combination of BIS values and other objective sedative methods to determine the degree of sedation, rather than relying exclusively on BIS values.

Serum Metabolites Are Associated With HFpEF in Biopsy-Proven Nonalcoholic Fatty Liver Disease.

Background Nonalcoholic fatty liver disease (NAFLD) and heart failure with preserved ejection fraction (HFpEF) share common risk factors, including obesity and diabetes. They are also thought to be mechanistically linked. The aim of this study was to define serum metabolites associated with HFpEF in a cohort of patients with biopsy-proven NAFLD to identify common mechanisms. Methods and Results We performed a retrospective, single-center study of 89 adult patients with biopsy-proven NAFLD who had transthoracic echocardiography performed for any indication. Metabolomic analysis was performed on serum using ultrahigh performance liquid and gas chromatography/tandem mass spectrometry. HFpEF was defined as ejection fraction >50% plus at least 1 echocardiographic feature of HFpEF (diastolic dysfunction, abnormal left atrial size) and at least 1 heart failure sign or symptom. We performed generalized linear models to evaluate associations between individual metabolites, NAFLD, and HFpEF. Thirty-seven out of 89 (41.6%) patients met criteria for HFpEF. A total of 1151 metabolites were detected; 656 were analyzed after exclusion of unnamed metabolites and those with >30% missing values. Fifty-three metabolites were associated with the presence of HFpEF with unadjusted P value <0.05; none met statistical significance after adjustment for multiple comparisons. The majority (39/53, 73.6%) were lipid metabolites, and levels were generally increased. Two cysteine metabolites (cysteine s-sulfate and s-methylcysteine) were present at significantly lower levels in patients with HFpEF. Conclusions We identified serum metabolites associated with HFpEF in patients with biopsy-proven NAFLD, with increased levels of multiple lipid metabolites. Lipid metabolism could be an important pathway linking HFpEF to NAFLD.

Could endothelial progenitor cells complement the diagnosis of inflammatory arthritis? A systematic review and meta-analysis.

The objective of this meta-analysis was to systematically review existing evidence and evaluate variations in levels of circulating endothelial progenitor cells (EPCs) among individuals with psoriatic arthritis (PsA), juvenile idiopathic arthritis (JIA), and rheumatoid arthritis (RA). Relevant studies were identified through database searches, and 20 records were enrolled. We used the fixed-effect model or random-effect model to estimate the pooled standardized mean difference (SMD) with 95% confidence intervals (CIs) in circulating EPC levels between inflammatory arthritis patients and controls. The results showed that circulating EPC levels differed among subtypes of inflammatory arthritis, with significantly lower levels in patients with RA (SMD = -0.848, 95% CI = -1.474 to -0.221, p = 0.008) and PsA (SMD = -0.791, 95% CI = -1.136 to -0.446, p < 0.001). However, no statistically significant difference was found in circulating EPC levels between patients with JIA and controls (SMD = -1.160, 95% CI = -2.578 to 0.259, p = 0.109). Subgroup analyses suggested that in patients with RA, circulating EPC levels were influenced by age, disease activity, and duration. Although many studies have investigated circulating EPC levels in patients with inflammatory arthritis, the results have been inconsistent. This meta-analysis offers a comprehensive overview of the existing evidence and emphasizes the association between levels of circulating EPCs and various types of arthritis. However, further research is needed to determine the specific mechanisms underlying the observed differences in EPC levels in different types of arthritis and to establish the clinical utility of this biomarker.

MicroRNA‑153 may act as a potential biomarker and prognostic indicator of patients with gastric cancer.

MicroRNA (miR/miRNA)-153, as a novel tumor-related miRNA, has been found to be aberrantly expressed in different types of cancer; however, to the best of our knowledge, the role of miR-153 in gastric cancer (GC) remains unclear. The present study demonstrated that miR-153 expression was markedly decreased in GC, including GC cell lines and culture medium, GC tissues, and serum samples, based on reverse transcription-quantitative PCR, and this was further confirmed by fluorescence in situ hybridization. Transfection with miR-153 mimics inhibited proliferation and migration, and promoted apoptosis in GC cells. The serum expression levels of miR-153 were decreased in 59 patients with GC compared with those of 9 healthy controls, and more decreased in advanced GC compared with early-stage GC, suggesting that miR-153 was associated with tumor progression. Furthermore, serum miR-153 was expressed at significantly lower levels in patients with GC with larger tumor size (≥4 cm; P=0.013), poor differentiation and signet histology (P=0.013), lymph node metastasis (P=0.025) and advanced tumor stage (TNM stage III and IV; P=0.048) compared with patients with a smaller tumor size (<4 cm), well and moderate differentiation, no lymph node metastasis, and TNM stage I and II, respectively. In conclusion, the present study revealed that low miR-153 expression was associated with poor prognosis in GC and miR-153 may potentially act as a tumor biomarker and therapeutic target in GC.

Myostatin is associated with the presence and development of acute-on-chronic liver failure

Acute-on-chronic liver failure (ACLF) has been linked to different pathophysiological mechanisms, including systemic inflammation and mitochondrial dysfunction. Sarcopenia has also been proposed as a potential mechanism; myostatin is a key factor inducing sarcopenia. Therefore, this study aimed to evaluate the association of myostatin levels with the development of ACLF and mortality in patients with cirrhosis. We performed a prospective cohort study, including both outpatient and hospitalized patients with cirrhosis. Clinical, biochemical, and nutritional parameters were evaluated, and the development of acute decompensation (AD) or ACLF during follow-up was recorded. ACLF was defined according to the EASL-CLIF criteria. Receiver-operating characteristic, Kaplan-Meier and Cox regression analyses were performed. A total of 186 patients with the whole spectrum of cirrhosis were included; mean age was 53.4 ± 14 years, mean Child-Pugh score was 8 ± 2.5 and mean MELD score was 15 ± 8. There was a stepwise decrease in myostatin levels from a compensated stage to AD and ACLF. Myostatin correlated positively with nutritional markers and negatively with severity scores. The prevalence of sarcopenia was 73.6%. During follow-up, 27.9% of patients developed AD and 25.8% developed ACLF. Most episodes were grade 2-3, mainly (62.5%) precipitated by infections. The most common organ failures observed were in the liver (63.3%) and the kidney (64.6%). Receiver-operating characteristic analysis yielded <1,280pg/ml as the best serum myostatin cut-off for the prediction of ACLF. In Kaplan-Meier curves and multivariate analysis, myostatin levels remained independently associated with the incidence of ACLF and survival. There is a progressive decrease in myostatin levels as cirrhosis progresses, demonstrating an association of sarcopenia with the development of ACLF and increased mortality. Myostatin is a muscle hormone, it is decreased in patients with muscle loss and is a marker of impaired muscle function. In this study we show that myostatin levels are decreased in patients with cirrhosis, with lower levels in patients with acute decompensation and acute-on chronic liver failure (ACLF). Low myostatin levels in cirrhosis predict the development of ACLF and mortality independently of liver disease severity and sex.

Expression and Therapeutic Targeting of TROP-2 in Treatment-Resistant Prostate Cancer.

Men with metastatic castration-resistant prostate cancer (mCRPC) frequently develop resistance to androgen receptor signaling inhibitor (ARSI) treatment; therefore, new therapies are needed. Trophoblastic cell-surface antigen (TROP-2) is a transmembrane protein identified in prostate cancer and overexpressed in multiple malignancies. TROP-2 is a therapeutic target for antibody-drug conjugates (ADC). TROP-2 gene (TACSTD2) expression and markers of treatment resistance from prostate biopsies were analyzed using data from four previously curated cohorts of mCRPC (n = 634) and the PROMOTE study (dbGaP accession phs001141.v1.p1, n = 88). EPCAM or TROP-2-positive circulating tumor cells (CTC) were captured from peripheral blood for comparison of protein (n = 15) and gene expression signatures of treatment resistance (n = 40). We assessed the efficacy of TROP-2-targeting agents in a mouse xenograft model generated from prostate cancer cell lines. We demonstrated that TACSTD2 is expressed in mCRPC from luminal and basal tumors but at lower levels in patients with neuroendocrine prostate cancer. Patients previously treated with ARSI showed no significant difference in TACSTD2 expression, whereas patients with detectable AR-V7 expression showed increased expression. We observed that TROP-2 can serve as a cell surface target for isolating CTCs, which may serve as a predictive biomarker for ADCs. We also demonstrated that prostate cancer cell line xenografts can be targeted specifically by labeled anti-TROP-2 agents in vivo. These results support further studies on TROP-2 as a therapeutic and diagnostic target for mCRPC.

Vasostatin-2 associates with coronary collateral vessel formation in diabetic patients and promotes angiogenesis via angiotensin-converting enzyme 2.

Members of the chromogranin family play a role in angiogenesis. One such biologically active peptide, generated through the processing of chromogranin A, is vasostatin-2. This study aimed at assessing the association of serum vasostatin-2 levels with coronary collateral vessels (CCV) in diabetic patients with chronic total occlusions (CTO) and the effects of vasostatin-2 on angiogenesis in diabetic mice with hindlimb or myocardial ischemia. Serum levels of vasostatin-2 in 452 diabetic CTO patients were evaluated. The status of CCV was categorized according to the Rentrop score. Vasostatin-2 recombinant protein or phosphate-buffered saline were then injected intraperitoneally in diabetic mouse models of hindlimb or myocardial ischemia, followed by laser Doppler imaging and molecular biology examinations. The effects of vasostatin-2 were also ascertained in endothelial cells and macrophages, with mechanisms clarified using ribonucleic acid (RNA) sequencing. Serum levels of vasostatin-2 were significantly different and progressively higher across Rentrop score 0, 1, 2, and 3 groups (P < .001), with significantly lower levels in patients with poor CCV (Rentrop score 0 and 1) than in those with good CCV (Rentrop score 2 and 3) (P < .05). Vasostatin-2 significantly promoted angiogenesis in diabetic mice with hindlimb or myocardial ischemia. RNA-seq analyzes verified an angiotensin-converting enzyme 2 (ACE2)-mediated vasostatin-2-induction of angiogenesis in ischemic tissues. Lower serum levels of vasostatin-2 are associated with poor CCV in diabetic CTO patients compared with patients with good CCV. Vasostatin-2 significantly promotes angiogenesis in diabetic mice with hindlimb or myocardial ischemia. Such effects are mediated by ACE2.

Intermediate Results of the Cornell Blood Coagulation in Cancer Study (COBLOCA-Study)

Background Venous thromboembolism (VTE) and arterial thrombosis are common complications of cancer and cancer treatment. A history of VTE in cancer patients increases the mortality risk by more than 2-fold compared to patients without prior VTE. The risk of cancer-associated thrombosis depends on the type of cancer, anti-cancer treatment and patient related factors. Some cancers have a high risk of thrombosis including lung, pancreas, gastric and brain. Several cancer-related prediction scores, such as the Khorana score or the PROTECHT score are used to predict the risk of thrombosis. Many mechanisms have been proposed through which cancer-related thrombosis may occur, however it remains difficult to predict thrombotic events in individual patients. Thus, accurate prediction of thrombotic events would be useful in the clinic to identify which patient may benefit from pharmacologic thromboprophylaxis. Therefore, we aim to study whether VTE can be predicted in individual cancer patients using hematological parameters. Methods The Cornell Blood Coagulation in Cancer (COBLOCA) study is an ongoing prospective study of cancer patients seen in a large academic medical center with a follow-up duration of 2 years and a detailed documentation of thrombotic events. We aim to enroll 600 patients with cancer (500 without VTE and 100 with prior VTE). Demographics, type and stage of cancer, treatment, thrombotic events (prior and during study enrollment) and anticoagulation treatment are collected. The levels of fibrinogen, prothrombin, coagulation factor FV, FVII, FVIII, FIX, FX, FXI, FXII, and FXIII, antithrombin, protein C, protein S, von Willebrand Factor antigen and activity, and D-dimer levels were determined in the patient plasma samples. We present an intermediate analysis on the acquired data. Results A total of 76 patients with cancer have been enrolled in the study to date. The association of prior VTE and the levels of hematological variables in patients with cancer were explored in this intermediate analysis. At baseline, 24 patients (32%) had a prior VTE. Twenty-four patients were on anticoagulants at the time of enrollment, of which 54% were on apixaban, 21% on rivaroxaban, 21% on heparin, and 4% on warfarin. Seven patients used aspirin in addition to anticoagulants, and 10 patients only used aspirin. A history of VTE was most common in patients with lung or endometrial cancer. Patients with esophageal, gastric or hematologic neoplasm did not have a history of VTE at enrollment, although 1 patient with gastric cancer developed a VTE during follow-up. From the remaining patients, 67% of patients with pancreatic cancer, 50% of patients with breast, liver and renal cancer, 36% of patients with colon cancer, and 19% with prostate cancer, previously suffered from VTE (Figure 1). At the time of this intermediate analysis, 3 VTE events were reported during the ongoing follow-up period, 1 in a patient with lung cancer, 1 in a patient with gastric cancer and 1 in a patient with duodenal cancer and history of hereditary hemorrhagic telangiectasia. Pro- and anticoagulant factor levels were compared between patients with and without a prior VTE. Von Willebrand Factor (VWF) antigen (+31%) and activity (+36%) levels were significantly increased in cancer patients with a history of VTE. The plasma level of FXI was significantly decreased in cancer patients with prior VTE. Additionally, plasma levels of fibrinogen, prothrombin, FV, FVII, FVIII, FIX, FX, FXII, FXIII, antithrombin, protein C, and protein S showed a trend towards lower levels in patients with a prior VTE, although these differences did not reach statistical significance (Figure 2). Moreover, D-dimer levels were significantly higher in cancer patients with prior VTE (551 μg/mL ± 942 μg/mL) than cancer patients without a history of VTE (332 μg/mL ± 451 μg/mL). Conclusion Both VWF antigen and activity were significantly increased in cancer patients with a history of VTE, indicating that the vessel wall plays an important role in cancer-associated thrombosis. Likewise, elevated D-dimer levels, and reduced levels of available coagulation factors in cancer patients with a history of VTE indicate that these patients might be in a more pro-coagulant state, resulting in (sub-clinical) consumption of coagulation factors and ongoing low grade intra-vascular coagulation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Reduced MDM2 and MDM4 Protein, but Not mRNA, Expression Is Associated with More Severe Disease in Acute Myeloid Leukemia (AML), Myelodysplastic Syndromes (MDS), and Chronic Myelomoncytic Leukemia (CMML)

Background: Following studies suggesting overexpression of MDM2 and MDM4 in AML, clinical trials were conducted in AML with MDM2 inhibitors, generally combined with chemotherapy, with so far relatively limited results. On the other hand , in those studies, MDM2 and 4 expressionwas mainly assessed on mRNA and the indirect estimation of protein expression using immunohistochemistry on mononuclear cells (MNCs). In addition, results were often conflicting, based in particular on different cells studied and techniques used. We analyzed MDM2 and MDM4 expressioin AML, MDS and CMML, analyzing both mRNA and protein levels, the latter by flow cytometry. Methods: Bone marrow samples from 113 (53 AML, 17 of them in complete remission (CR) after treatment, 50 MDS or 10 CMML) adult patients (classified according to WHO2016) seen at Hôpital Saint-Louis, Paris, were collected between 2018 and 2021 . Bone marrow samples collected from hip surgery of 17 elderly aged-matched donors without hematological disorder were used as controls. For the mRNA Human,CD34+ cells were purified from MNCs and total mRNA purified. RT-qPCR was performed and expression of each mRNA was analyzed in the CD34+ population. MDM2, MDM4 and p53 protein expression was determined in all samples with monoclonal antibody staining and flow cytometry analysis. In controls and in MDS and CMML patients without excess of marrow blasts (<5%), protein expression was assessed in the CD34+/CD45low population In patients with excess of marrow blasts (5% or greater,), because of the heterogeneity of CD34 expression on blast cells, protein expression was assessed on the CD45low/SSC blast population. Data were acquired using a BD FACS Canto II. Results: For protein expression, In CD34+/CD45low cells from MDS/CMML patients without excess of blasts, MFI was 795.7 for MDM2, 2555 for MDM4 and 500.6 for p53, with no significant differences with controls for p53 (p=0.3620) but lower levels in patients for MDM2 (p=0.0123) and MDM4 (p=0.0337). In the blast population of patients with excess of blasts, MDM2, MDM4 and p53 protein expression were drastically decreased in MDS (MFI: MDM2=320.8, p<0.0001; MDM4=1017, p<0.0001; p53=137.5, p<0.0001), AML (MFI: MDM2=233.2, p<0.0001; MDM4=833.8, p<0.0001; p53=111.8, p<0.0001) and CMML (MFI: MDM2=262.2, p=0.0001; MDM4=851.7, p<0.0001; p53=113.3, p=0.0007) (Fiigure A) compared with control CD34+/CD45low cells. Comparison between CD34+/CD45low bone marrow cells from patients without excess of blasts and CD45low/SSC blasts of patients with excess of blasts (AML, MDS, CMML) showed in the latter group lower expression of each protein for MDS (MFI: MDM2 p<0.0001; MDM4 p=0.0005; p53 p=0.0007), AML (MFI: MDM2 p<0.0001; MDM4 p<0.0001; p53 p<0.0001) and CMML (MFI: MDM2 p=0.005; MDM4 p=0.0165; p53 p=0.0268). We found a negative correlation for MDM2 (r=-0.3191, p=0.0018), MDM4 (r=-0.3925, p<0.0001), p53 (r =0.3195, p=0.0018) between protein expression levels and marrow blast percentage. Expression of CD34+/CD45low cells from patients in CR (MFI: MDM2= 1797; MDM4 =2993; p53=971) showed no significant differences with the control CD34+/CD45low cells (MFI:MDM2 p=0,4533; MDM4 p=0.1420; p53 p=0.2891). For MDM2 and MDM4 proteins, patients whose expression value was lower than the median had significant poorer survival than those with a higher value (MDM2 p=0.0209; MDM4 p= 0.1025; p53 p=0.0304) (Figure B). In MDS, however, protein expression had no significant impact on the probability of progression to AML (MDM2 p=0.5636; MDM4 p= 0.1488; p53p=0.7816). No significant differences in mRNA expression were found between CD34+ cells from healthy donors and patients without excess blast or patients with excess blast. We observed no correlation between the mRNA and protein expression levels Conclusions: We found in AML, MDS and CMML a discrepancy between mRNA levels and protein levels for MDM2, MDM4 and p53, and overall low MDM2 and MDM4 protein expression, which might explain the relatively low efficacy of MDM2 inhibitors observed so far in clinical trials . The relatively high MDM2 and p53 levels observed in control bone marrows possibly also explains, at least in part, the reported toxicity of these drugs on myeloid cells in clinical trials. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Hypotensive effects of drug combinations in elderly and old patients with controlled arterial hypertension

Aim. To assess the frequency of arterial hypotension, orthostatic hypotension, low blood pressure (BP) and their clinical manifestations in the group of elderly and senile patients with a controlled course of arterial hypertension (AH), taking combinations of drugs based on an angiotensin-converting enzyme inhibitor (ACE inhibitor).Materials and methods. The study included 171 male and female residents of Krasnodar Territory with drug-controlled AH (blood pressure - BP less than 140/90 mm Hg in the background of previous antihypertensive therapy containing an ACE inhibitor perindopril), and with diseases of atherosclerotic genesis. All patients were questioned, tested for balance control, assessed for the risk of falls according to the Morse scale, hypotension in orthostasis was determined, measured office BP, carried out daily monitoring of BP with the determination of the time indices of hypotension and low BP.Results. Most often patients took a combination of ACE inhibitors with calcium channel blockers (CCB) (28.1% of cases), beta-blockers (BB) (27.1%) or diuretics (29.1%). Assessing the risk of falls on the Morse scale, there was a significantly lower level in patients who took the combination of perindopril with CCB compared with those who received perindopril with BB (15 versus 25 points respectively, p=0.039). Patients receiving perindopril and CCB lost balance in the “legs together” position in 19.3% and in the “tandem” or “semi-tandem” position of the feet in 29.8% of cases, that could be compared to the group taking perindopril and a diuretic (22% and 33.9%, respectively) and significantly lower than in the groups with perindopril and BB therapy (34.5% and 50.9%, respectively, p1=0.037, p2=0.043). The time index of low systolic and diastolic BP during therapy with perindopril and CCB was significantly lower than the corresponding indicator in the groups of patients treated with perindopril and BB (22% and 17% versus 27% and 21%, respectively, p1=0,009, p2=0,024), and the time index of low systolic BP for the combination of perindopril and diuretic is lower than for the combination of perindopril and BB (23% versus 27%, respectively, p=0.023).Conclusion. The data obtained on the frequency of arterial hypotension, orthostatic hypotension and low BP in the group of elderly and senile patients indicate the advisability of further studying the risks of drug hypotension in order to better personalize the treatment of AH.

Contribution of blood-brain barrier-related blood-borne factors for Alzheimer’s disease vs. vascular dementia diagnosis: A pilot study

BackgroundAlzheimer’s disease (AD) and vascular dementia (VaD) are the two most common types of neurodegenerative dementia among the elderly with similar symptoms of cognitive decline and overlapping neuropsychological profiles. Biological markers to distinguish patients with VaD from AD would be very useful. We aimed to investigate the expression of blood-brain barrier (BBB)-related blood-borne factors of soluble low-density lipoprotein receptor-related protein 1 (sLRP1), cyclophilin A (CyPA), and matrix metalloproteinase 9 (MMP9) and its correlation with cognitive function between patients with AD and VaD.Materials and methodsPlasma levels of sLRP1, CyPA, and MMP9 were analyzed in 26 patients with AD, 27 patients with VaD, and 27 normal controls (NCs). Spearman’s rank correlation analysis was used to explore the relationships among biomarker levels, cognitive function, and imaging references. Receiver operating characteristic (ROC) curve analysis was used to discriminate the diagnosis of AD and VaD.ResultsAmong these BBB-related factors, plasma CyPA levels in the VaD group were significantly higher than that in the AD group (p < 0.05). Plasma sLRP1 levels presented an increasing trend in VaD while maintaining slightly low levels in patients with AD (p > 0.05). Plasma MMP9 in different diagnostic groups displayed the following trend: VaD group > AD group > NC group, but the difference was not statistically significant (p > 0.05). Furthermore, plasma sLRP1 levels were positively related to MoCA scores, and plasma CyPA levels were significantly correlated with MTA scores (p < 0.05) in the AD group. Plasma MMP9 levels were negatively correlated with MoCA scores (p < 0.05) in the VaD groups. No significant correlation was detected between the other factors and different cognitive scores (p > 0.05). ROC analysis showed a good preference of plasma CyPA [AUC = 0.725, 95% CI (0.586–0.865); p = 0.0064] in diagnosis.ConclusionThe plasma CyPA level is a reference index when distinguishing between an AD and subcortical ischemic vascular dementia (SIVD) diagnosis. Blood-derived factors associated with the BBB may provide new insights into the differential diagnosis of neurodegenerative dementia and warrant further investigation.

Correlation Between Blood Glucose Control and Levels of Carbohydrate Antigen 19-9 and Carcinoembryonic Antigen in Patients with Type-2 Diabetes Mellitus.

ObjectiveTo investigate The relationship between glycemic control and serum levels of carbohydrate antigen 19–9 (CA19-9) and carcinoembryonic antigen (CEA) in patients with type-2 diabetes mellitus (T2DM).MethodsA total of 211 patients with T2DM who were hospitalized were enrolled and divided into two groups according to the glycosylated hemoglobin AlC (HbAlC) levels: Group A (HbAlC ≥ 7.5%) and Group B (6.5% < HbAlC < 7.5%). Additionally, 68 subjects with healthy physical examination results were selected as the control group (Group C). The differences in the clinical biochemical indicators of the three groups were compared as well as the analysis of the indicators related to CA19-9 and CEA.ResultsThe levels of CA19-9 and CEA were highest in Group A and were lowest in the control group (P < 0.05). The levels of CA19-9 and CEA were significantly higher in the two T2DM groups compared with the control group (P < 0.01). The levels of FINS, FCP, and LDH in group A were higher than those in groups B and C (P < 0.05). The levels of HDL and BUN in groups A and B were lower, while the TSH and U-MA levels were higher than those in group C (P < 0.05). There was no significant difference in the levels of TC, TG, and Cr among the groups (P > 0.05). A correlation analysis revealed that both CA19-9 and CEA were positively correlated with HbAlC (P < 0.01). Multiple stepwise regression analysis showed that HbA1C and BUN were influencing factors for serum CA19-9 levels (P < 0.05), and HbA1C and U-MA were influencing factors for serum CEA levels (P < 0.05).ConclusionBoth CA19-9 and CEA might be elevated at low levels in patients with T2DM; levels were closely correlated to the degree of glycemic control.

Biomarkers in Ocular Graft-Versus-Host Disease: Implications for the Involvement of B Cells

Graft-versus-host disease (GVHD) is an immune-mediated inflammatory disease resulting from destruction of host tissue by donor immunoreactive cells and occurs in 30% to 70% of post-hematopoietic stem cell transplantation (HSCT) patients. Ocular involvement occurs in up to 60% to 90% of patients with chronic GVHD. T cells have long been recognized as a key driver of alloreactivity in chronic ocular GVHD (oGVHD). However, the role of B-cells has not been elucidated. To further explore the involvement of B-cells in the immune mechanism of chronic oGVHD and to uncover more sensitive biomarker indicators, we conducted this study on the tear cytokine analysis of chronic oGVHD. The study enrolled 18 patients (27 eyes) diagnosed with chronic oGVHD and 11 patients (22 eyes) diagnosed with dry eye disease (DED) as a control group. The microsphere-based immunoassay was used to determine 29 tear cytokines in both groups. Spearman's test was used to analyze the correlation between cytokine levels and different ophthalmic indexes (National Institutes of Health eye score, fluorescein tear film break-up time, corneal fluorescein staining, and Schirmer's test). Receiver operating characteristic curves were used to assess the predictive potential of the identified cytokines for chronic oGVHD. Twenty tear cytokine levels were elevated in patients with chronic oGVHD compared to those with DED (P < .05). Proliferation-inducing ligand (APRIL) and epidermal growth factor showed lower levels in patients with chronic oGVHD. Ultimately, IL-2, 6, and 8, ICAM-1 (CD54), E-selectin (CD62E), neuropilin-1, and B-cell activation factor (BAFF) levels had a strong correlation with ophthalmic indexes and an area under the curve (AUC) > 0.85. BAFF/APRIL exhibited superior diagnostic capabilities (AUC = 0.995; 95% confidence interval, 0.983-1.000). Our study identified IL-2, 6, 8, ICAM-1, CD62E, E-selectin, neuropilin-1, and BAFF as promising tear biomarkers that can indicate the severity of chronic oGVHD. Notably, APRIL/BAFF shows superior diagnostic capabilities, revealing that B cells may play an important role as immune substrates in chronic oGVHD. © 2023 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.