HLA Diversity in Transylvanian Ethnic Groups: Consequences for Hematopoietic Cell Transplantation.

The HLA profile is essential in cell and tissue transplantation, particularly in patients with autoimmune conditions and infections. Due to the extreme polymorphism in certain HLA loci, it also serves as a key tool for population genetic analysis. This study aimed to identify the allele and haplotype distributions of HLA class I (A, B, and C) and class II (DRB1) genotypes in unrelated hematopoietic stem cell donors. A retrospective analysis was conducted between 2016 and 2020 on 9832 Transylvanian volunteers, divided into Romanian and Hungarian groups based on self-reported ethnicity. Using PCR-SSO for HLA typing, significant differences were found in allele frequencies between ethnic groups. A total of 19 HLA-A, 31 HLA-B, 14 HLA-C, and 13 HLA-DRB1 distinct allele groups were identified between ethnic groups. Notably, B*18, B*51, and C*12 were more frequent in Romanians, while B*44, B*40, and C*07 were more common in Hungarians. Differences in haplotype distributions were also observed, with HLA-A*02~B*18~C*07~DRB1*11 being significantly more frequent in Romanians. Understanding these population-specific HLA profiles can improve donor matching for hematologic diseases, enhancing patient outcomes and access to life-saving hematopoietic stem cell transplantation.

Chitotriosidase and Neopterin as Two Novel Potential Biomarkers for Advanced Stage and Survival Prediction in Gastric Cancer-A Pilot Study.

Gastric cancer is the fifth type of neoplasia most frequently diagnosed and the fourth cause of death among other cancers. Prevalence is around two times higher for males than females. Chitotriosidase and neopterin are two molecular biomarkers with potential diagnostic and prognostic use in malignant pathology. We conducted a longitudinal prospective cohort study on thirty-nine patients with gastric adenocarcinoma, with a male-to-female ratio of 1.78 and an average age of 64.3 ± 9.97 years. No statistically significant differences in biomarker levels at presentation were observed between curative-intent surgery (28 patients) and advanced cases, suited only for palliative procedures (11 patients). Biomarker values were not significantly different for the advanced T stage and the presence of metastasis (p > 0.05-Mann Whitney test). The patients that died in the first 30 days after surgery did not present significantly different values at baseline, in comparison with those that had longer survival times, though a significant cut-off value was observed for chitotriosidase activity at 310 nmol/mL/h [AUC (area under the curve) = 0.78; 95% CI (0.61-0.92)]. The cut-off values corresponding to death after the first year, tumor invasion, and metastasis were not statistically significant. In the COX multivariate model, neopterin did not validate itself as a prognostic biomarker, however, chitotriosidase activity before surgery was significantly associated with overall survival (HR = 1.0038, p = 0.03). We conclude that chitotriosidase may have the potential to improve the prognostic model for gastric adenocarcinoma.

Exploratory Evaluation of Neopterin and Chitotriosidase as Potential Circulating Biomarkers for Colorectal Cancer.

Chronic inflammation is demonstrated to play a direct role in carcinogenesis. Our exploratory study aimed to assess the potential added value of two inflammation biomarkers, chitotriosidase and neopterin, in follow-up evaluation of patients with colorectal cancer (CRC). An observational exploratory study was conducted. Patients with CRC and matched controls (1:1, age, sex, and living environment) were evaluated. The patients with CRC (CRC group) and controls were assessed at baseline (before surgical intervention for patients with CRC). Patients with CRC were also evaluated at 1-year follow-up. Significantly more patients with blood group A (54.5% vs. 25.0%) and smokers (50.0% vs. 22.7%) were in the CRC group. The serum values of chitotriosidase and neopterin were higher in CRC patients than in controls, but only neopterin reached the conventional level of statistical significance (p-value = 0.015). The circulating chitotriosidase and neopterin values decreased significantly at 1-year follow-up (p-value < 0.0001). Patients with higher N- and M-stage showed statistically significant higher levels of chitotriosidase and neopterin at baseline and 1-year follow-up (p-values < 0.03). Circulating chitotriosidase levels also showed statistically significant differences regarding baseline and 1-year follow-up on patients with CRC and different differentiation grades (p-values < 0.02). The circulating levels of neopterin significantly decreased at 1-year follow-up, indicating its potential as a prognostic marker. The circulating values of chitotriosidase and neopterin exhibit significant differences in patients with than without recurrences. Our results support further evaluation of chitotriosidase and neopterin as prognostic markers in patients with CRC.

Non-Coding RNAs: Prevention, Diagnosis, and Treatment in Myocardial Ischemia-Reperfusion Injury.

Recent knowledge concerning the role of non-coding RNAs (ncRNAs) in myocardial ischemia/reperfusion (I/R) injury provides new insight into their possible roles as specific biomarkers for early diagnosis, prognosis, and treatment. MicroRNAs (miRNAs) have fewer than 200 nucleotides, while long ncRNAs (lncRNAs) have more than 200 nucleotides. The three types of ncRNAs (miRNAs, lncRNAs, and circRNAs) act as signaling molecules strongly involved in cardiovascular disorders (CVD). I/R injury of the heart is the main CVD correlated with acute myocardial infarction (AMI), cardiac surgery, and transplantation. The expression levels of many ncRNAs and miRNAs are highly modified in the plasma of MI patients, and thus they have the potential to diagnose and treat MI. Cardiomyocyte and endothelial cell death is the major trigger for myocardial ischemia-reperfusion syndrome (MIRS). The cardioprotective effect of inflammasome activation in MIRS and the therapeutics targeting the reparative response could prevent progressive post-infarction heart failure. Moreover, the pharmacological and genetic modulation of these ncRNAs has the therapeutic potential to improve clinical outcomes in AMI patients.

Evaluation of Chitotriosidase and Neopterin as Biomarkers of Microvascular Complications in Patients with Type 1 Diabetes Mellitus.

The chronic complications of diabetes mellitus (DM) are accompanied by inflammatory manifestations. Our study aimed to evaluate a possible association between the inflammatory status (reflected by serum chitotriosidase and neopterin) and the timely evolution and occurrence of chronic microvascular complications in patients with type 1 DM. This observational, cross-sectional study included 82 type 1 DM patients from the Centre for Diabetes, Nutrition and Metabolic Diseases, Cluj-Napoca, Romania. Our results demonstrated a link between the extent of inflammation, evaluated by the enzymatic activity of circulating chitotriosidase, and the onset of microvascular complications, especially diabetic neuropathy and retinopathy. Chitotriosidase enzymatic activity showed an ascending evolution over time. In non-smoking patients, the increase in chitotriosidase activity was correlated with the extent of microalbuminuria and the decline of glomerular filtration rate, while in smokers, only the presence of a positive correlation between chitotriosidase activity and disease progression was noticed. According to our results, the time span between the moment of diagnosis and the onset of microvascular complications was longer in non-smokers than in smokers. These results also imply that increased chitotriosidase activity may be a predictor of endothelial dysfunction in type 1 DM.

Implications of Long Non-Coding RNAs in Age-Altered Proteostasis.

This review aims to summarize the current knowledge on how lncRNAs are influencing aging and cancer metabolism. Recent research has shown that senescent cells re-enter cell-cycle depending on intrinsic or extrinsic factors, thus restoring tissue homeostasis in response to age-related diseases (ARDs). Furthermore, maintaining proteostasis or cellular protein homeostasis requires a correct quality control (QC) of protein synthesis, folding, conformational stability, and degradation. Long non-coding RNAs (lncRNAs), transcripts longer than 200 nucleotides, regulate gene expression through RNA-binding protein (RBP) interaction. Their association is linked to aging, an event of proteostasis collapse. The current review examines approaches that lead to recognition of senescence-associated lncRNAs, current methodologies, potential challenges that arise from studying these molecules, and their crucial implications in clinical practice.

Association between cardiovascular risk factors and coronary artery disease assessed using CAD-RADS classification: a cross-sectional study in Romanian population.

OBJECTIVES: This study aimed to evaluate the association between cardiovascular risk factors and Coronary Artery Disease-Reporting and Data System (CAD-RADS) score in the Romanian population. CAD-RADS is a new, standardised method to assess coronary artery disease (CAD) using coronary CT angiography (CCTA). DESIGN: A cross-sectional observational, patient-based study. SETTING: Referred imaging centre for CAD in Transylvania, Romania. PARTICIPANTS: We retrospectively reviewed 674 patients who underwent CCTA between January 2017 and August 2018. The exclusion criteria included: previously known CAD, defined as prior myocardial infarction, percutaneous coronary intervention or coronary artery bypass graft surgery (n=91), cardiac CT for other than evaluation of possible CAD (n=85), significant arrhythmias compromising imaging quality (n=23). Finally, 475 patients fulfilled the inclusion criteria. METHODS: Demographical, clinical and CCTA characteristics of the patients were obtained. CAD was evaluated using CAD-RADS score. Obstructive CAD was defined as ≥50% stenosis of ≥1 coronary segment on CCTA. RESULTS: We evaluated the association between risk factors and CAD-RADS score in univariate and multivariable analysis. We divided the patients into two groups according to the CAD-RADS system: group 1: CAD-RADS score between 0 and 2 (stenosis <50%) and group 2: CAD-RADS score ≥3 (stenosis ≥50%). On univariate analysis, male gender, age, hypertension, dyslipidaemia, smoking and diabetes mellitus were positively associated with a CAD-RADS score ≥3. The multivariate analysis showed that male sex, age, dyslipidaemia, hypertension and smoking were independently associated with obstructive CAD. CONCLUSION: This study demonstrated a significant association between multiple cardiovascular risk factors and a higher coronary atherosclerotic burden assessed using CAD-RADS system in the Romanian population.

Relation between serum cotinine levels and trophic lesions in patients with critical limb ischemia: a pilot study.

Aim: To evaluate if smoking, quantified by the serum cotinine levels, is related to the evolution of patients with critical limb ischemia (CLI).Method: A pilot study was conducted on CLI patients who addressed at the Second Surgery Clinic of the Emergency County Hospital, Cluj-Napoca, Romania between November 2015 and December 2016. The sample of patients was split into two groups using the threshold of 15 ng/mL for the serum level of cotinine (low cotinine level - LCL vs. high cotinine level - HCL). Furthermore, the ROC analysis was conducted to identify the threshold of cotinine level able to discriminate between CLI patients with and without trophic lesions.Results: The mean age of patients was 60.7 ± 10.5 years with a significantly higher percentage of male patients (84%). A significant association was identified between urban origin and serum cotinine level, which is related to the increased number of cigarettes smoked per day among urban participants. Excepting necrectomy and toe disarticulation, no differences were found between LCL and HCL group regarding symptoms, signs or comorbidities. In smokers with CLI (38/43), a serum cotinine cut-off of 9.765 ng/mL was observed on eight out of 10 CLI patients with necrectomy and five out of 28 patients without necrectomy.Conclusion: Our study showed higher serum cotinine levels associated with a higher number of smoked cigarettes and necrectomy in patients with CLI. The serum cotinine could be a fair screening test for necrectomy in smokers CLI patients.

SIRT1 in the Development and Treatment of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death worldwide. Current treatment options for inoperable HCCs have decreased therapeutic efficacy and are associated with systemic toxicity and chemoresistance. Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide-dependent enzyme that is frequently overexpressed in HCC, where it promotes tumorigenicity, metastasis, and chemoresistance. SIRT1 also maintains the tumorigenic and self-renewal proprieties of liver cancer stem cells. Multiple tumor-suppressive microRNAs (miRNAs) are downregulated in HCC and, as a consequence, permit SIRT1-induced tumorigenicity. However, either directly targeting SIRT1, combining conventional chemotherapy with SIRT1 inhibitors, or upregulating tumor-suppressive miRNAs may improve therapeutic efficacy and patient outcomes. Here, we present the interaction between SIRT1, miRNAs, and liver cancer stem cells and discuss the consequences of their interplay for the development and treatment of HCC.

Natural products with anti-aging potential: Affected targets and molecular mechanisms.

In recent years, there has been a great deal of attention toward the molecular machinery relevant to age-related progression controlled through the external intervention of polyphenols- an epigenetic-modulating diet. Natural products modulate cellular longevity through histone post-translational modification and can also induce the upregulation of autophagy, thus reducing the level of acetyl coenzyme A (AcCoA). In addition, the effect of caloric restriction (CR) on cancer-related chronic inflammation is of great significance in aging. In line with this, SIRT1 protein levels are expanded in response to calorie restriction mimetics (CRM), in this way acting as autophagy inducers relevant to cancer prevention.

Evaluation of Chitotriosidase as a Marker of Inflammatory Status in Critical Limb Ischemia.

BACKGROUND: Chitotriosidase is an enzyme secreted by activated macrophages. This study aims to investigate the usefulness of circulating chitotriosidase activity as a marker of inflammatory status in patients with critical limb ischemia (CLI). MATERIALS AND METHODS: An observational gender-matched case-control study was conducted on patients hospitalized with the primary diagnosis of CLI, as well as a control group. The control group consisted of healthy volunteers. RESULTS: Forty-three patients were included in each group. Similar demographic characteristics (median age of 60-62 years and overweight) were observed in both groups. Chitotriosidase activity ranged from 110 nmol/ml/hr to 1530 nmol/ml/hr in the CLI group and from 30 nmol/ml/hr to 440 nmol/ml/hr in the control group; demonstrating significantly elevated values in the CLI group (p<0.001). Median plasma chitotriosidase activity was significantly elevated in smokers compared with non-smokers in both groups (p<0.05). However, this activity had higher values in CLI than in control subjects. Receiver operating characteristic (ROC) analysis was then performed in order to verify the diagnostic accuracy of chitotriosidase as an inflammatory biomarker in CLI. CONCLUSION: Circulating chitotriosidase is a test which can potentially be used for the monitoring of CLI patients without other inflammatory conditions. However, the interpretation of elevated values must take into account the inflammatory response induced by tobacco exposure.

Non-coding RNAs, the Trojan horse in two-way communication between tumor and stroma in colorectal and hepatocellular carcinoma.

In a continuous and mutual exchange of information, cancer cells are invariably exposed to microenvironment transformation. This continuous alteration of the genetic, molecular and cellular peritumoral stroma background has become as critical as the management of primary tumor progression events in cancer cells. The communication between stroma and tumor cells within the extracellular matrix is one of the triggers in colon and liver carcinogenesis. All non- codingRNAs including long non-coding RNAs, microRNAs and ultraconserved genes play a critical role in almost all cancers and are responsible for the modulation of the tumor microenvironment in several malignant processes such as initiation, progression and dissemination. This review details the involvement of non codingRNAs in the evolution of human colorectal carcinoma and hepatocellular carcinoma in relationship with the microenvironment. Recent research has shown that a considerable number of dysregulated non- codingRNAs could be valuable diagnostic and prognostic biomarkers in cancer. Therefore, more in-depth knowledge of the role non- codingRNAs play in stroma-tumor communication and of the complex regulatory mechanisms between ultraconserved genes and microRNAs supports the validation of future effective therapeutic targets in patients suffering from hepatocellular and colorectal carcinoma, two distinctive entities which share quite a lot common non-coding RNAs.

Inflamma-miRs in Aging and Breast Cancer: Are They Reliable Players?

Human aging is characterized by chronic low-grade inflammation known as "inflammaging." Persistent low-level inflammation also plays a key role in all stages of breast cancer since "inflammaging" is the potential link between cancer and aging through NF-kB pathways highly influenced by specific miRs. Micro-RNAs (miRNAs) are small non-coding RNAs that negatively regulate gene expression at a posttranscriptional level. Inflamma-miRs have been implicated in the regulation of immune and inflammatory responses. Their abnormal expression contributes to the chronic pro-inflammatory status documented in normal aging and major age-related diseases (ARDs), inflammaging being a significant mortality risk factor in both cases. Nevertheless, the correct diagnosis of inflammaging is difficult to make and its hidden contribution to negative health outcomes remains unknown. This methodological work flow was aimed at defining crucial unanswered questions about inflammaging that can be used to clarify aging-related miRNAs in serum and cell lines as well as their targets, thus confirming their role in aging and breast cancer tumorigenesis. Moreover, we aim to highlight the links between the pro-inflammatory mechanism underlying the cancer and aging processes and the precise function of certain miRNAs in cellular senescence (CS). In addition, miRNAs and cancer genes represent the basis for new therapeutic findings indicating that both cancer and ARDs genes are possible candidates involved in CS and vice versa. Our goal is to obtain a focused review that could facilitate future approaches in the investigation of the mechanisms by which miRNAs control the aging process by acting as efficient ARDs inflammatory biomarkers. An understanding of the sources and modulation of inflamma-miRs along with the identification of their specific target genes could enhance their therapeutic potential.

NCRNA combined therapy as future treatment option for cancer.

Cancer initiation and progression are governed by a complex multistep process in which successive alterations accumulate in multiple protein-coding and noncoding genes. MicroRNAs are an evolutionarily conserved class of endogenous 19- to 24-nucleotide noncoding RNAs that have been validated as key players in the balance of most cellular processes, including drug resistance. MicroRNAs change the output of protein-coding genes through posttranscriptional regulation by binding in a sequence-specific manner to the transcripts of their target genes. Resistance to therapy remains a major challenge in cancer treatment; clear solutions to this problem have yet to be found, in spite of intensive research in recent years. In this review, we explore the concept of cancer multitherapy using noncoding RNAs. We also address basic scientific questions that are related to personalized cancer treatment.