Biomedicines, Volume 12, Issue 5 (May 2024) – 155 articles

Using an Inductively Coupled Plasma Mass Spectrometer we measured the concentration of selenium and arsenic in serum and blood samples from 336 unselected psoriatic patients and 336 matched healthy controls to evaluate any associations with the clinical course of the disease. We genotyped 336 patients and 903 matched controls to evaluate the prevalence of SOD2 (rs4880), CAT (rs1001179), GPX1 (rs1050450), and DMGDH (rs921943) polymorphisms using Taqman assays. The mean selenium (Se) level in serum was 74 µg/L in patients and 86 µg/L in controls (p < 0.001). The mean Se level in blood was 95 µg/L in patients and 111 µg/L in controls (p < 0.001). Psoriasis risk was greatest among participants with the lowest serum (<68.75 µg/L, OR: 8.30; p < 0.001) and lowest blood concentrations of Se (<88.04 µg/L, OR: 10.3; p < 0.001). Similar results were observed in subgroups of males and females. We found an inverse correlation of selenium levels with PASI, NAPSI, and BSA scores. There was no significant difference in the distribution of the CAT, GPX1, DMGDH, and SOD2 polymorphisms. Among carriers of rs4880, rs1001179, and rs921943 polymorphisms, blood selenium levels were significantly lower. The mean arsenic level in serum was 0.79 µg/L in patients and 0.7 µg/L in controls (p = 0.2). The mean concentration in blood was 1.1 µg/L in patients and 1.3 µg/L in controls (p < 0.001). In conclusion, we found that lower selenium levels, in blood and serum, are associated with psoriasis risk and its more severe course. Future prospective studies should focus on the optimalisation of the concentration of this trace element not only for prophylactic guidance but also to support the treatment of this disease. Full article

Acute hypoxemic respiratory failure (AHRF) is defined as acute and progressive, and patients are at a greater risk of developing acute respiratory distress syndrome (ARDS). Until now, most studies have focused on prognostic and diagnostic biomarkers in ARDS. Since there is evidence supporting a connection between dysregulated coagulant and fibrinolytic pathways in ARDS progression, it is plausible that this dysregulation also exists in AHRF. The aim of this study was to explore whether levels of soluble endothelial protein C receptor (sEPCR) and plasminogen differentiate patients admitted to the emergency department (ED) with AHRF. sEPCR and plasminogen levels were measured in 130 AHRF patients upon ED presentation by ELISA. Our results demonstrated that patients presenting to the ED with AHRF had elevated levels of sEPCR and plasminogen. It seems that dysregulation of coagulation and fibrinolysis occur in the early stages of respiratory failure requiring hospitalisation. Further research is needed to fully comprehend the contribution of sEPCR and plasminogen in AHRF. Full article

Human dihydrofolate reductase (hDHFR) is an essential cellular enzyme, and inhibiting its activity is a promising strategy for cancer therapy. We have chosen the trimethoprim molecule (TMP) as a model compound in our search for a new class of hDHFR inhibitors. We incorporated an amide bond, a structural element typical of netropsin, a ligand that binds selectively in the minor groove of DNA, into the molecules of TMP analogs. In this work, we present previously obtained and evaluated eleven benzamides (JW1–JW8; MB1, MB3-MB4). Recently, these compounds were specifically projected as potential inhibitors of the enzymes acetylcholinesterase (AChE) and β-secretase (BACE1). JW8 was most active against AChE, with an inhibitory concentration of AChE IC₅₀ = 0.056 µM, while the IC₅₀ for donepezil was 0.046 µM. This compound was also the most active against the BACE1 enzyme. The IC₅₀ value was 9.01 µM compared to that for quercetin, with IC₅₀ = 4.89 µM. All the benzamides were active against hDHFR, with IC₅₀ values ranging from 4.72 to 20.17 µM, and showed activity greater than TMP (55.26 µM). Quantitative results identified the derivatives JW2 and JW8 as the most promising. A molecular modeling study demonstrates that JW2 interacts strongly with the key residue Gly-117, while JW8 interacts strongly with Asn-64 and Arg-70. Furthermore, JW2 and JW8 demonstrate the ability to stabilize the hDHFR enzyme, despite forming fewer hydrogen bonds with the protein compared to reference ligands. It can be concluded that this class of compounds certainly holds great promise for good active leads in medicinal chemistry. Full article

Objectives: In this study, we investigated the antitumor immunomodulatory effects of rapamycin in oral cancer. Study Design: We examined the proliferation, apoptosis, and migration of cancer cells and investigated the cell surface expression levels of immune accessory molecules and T cell immune responses in vitro. We investigated the effect of in vivo administration of rapamycin on immune cell distribution and T cell immune responses in oral tumor-bearing mice. Results: Rapamycin treatment significantly inhibited OSCC cell proliferation and migration, increased apoptotic cell death, and upregulated cell surface expression of several immune accessory and adhesion molecules, including CD40, CD83, PD-L1, PD-L2, MHC class I, P-selectin, and VCAM-1. These cancer cells augmented T cell proliferation. In vivo rapamycin administration significantly attenuated mouse tumor growth with an increased proportion of immune cells, including CD4⁺ T cells, CD8⁺ T cells, and dendritic cells (DCs); decreased the proportion of immune suppressive cells, such as myeloid-derived suppressor cells and regulatory T cells; enhanced DC maturation and upregulated the surface expression of CD40, CD86, and ICAM-1. Conclusions: Our results suggest that the therapeutic effect of mTOR inhibition in oral cancer can cause direct antitumor and immunomodulatory effects. Full article

Acute myocardial infarction (AMI) is one of the leading causes of death worldwide. Cell apoptosis in the myocardium plays an important role in ischemia and reperfusion (I/R) injury, leading to cardiac damage and dysfunction. Platelets are major players in hemostasis and play a crucial role in vessel occlusion, inflammation, and cardiac remodeling after I/R. Here, we studied the impact of platelets on cell apoptosis in the myocardium using a close-chest mouse model of AMI. We found caspase-3-positive resident cardiac cells, while leukocytes were negative for caspase-3. Using two different mouse models of thrombocytopenia, we detected a significant reduction in caspase-3 positive cells in the infarct border zone after I/R injury. Further, we identified platelet FasL to induce cell apoptosis via the extrinsic pathway of Fas receptor activation of target cells. Mechanistically, hypoxia triggers platelet adhesion to FasR, suggesting that platelet-induced apoptosis is elevated after I/R. Platelet-specific FasL knock-out mice showed reduced Bax and Bcl2 expression, suggesting that platelets modulate the intrinsic and extrinsic pathways of apoptosis, leading to reduced infarct size after myocardial I/R injury. Thus, a new mechanism for how platelets contribute to tissue homeostasis after AMI was identified that should be validated in patients soon. Full article

TAFRO syndrome is a rare and aggressive inflammatory entity characterized by thrombocytopenia, anasarca, fever, renal failure, reticulin fibrosis, and organomegaly. This entity supposes a diagnostic and therapeutic challenge due to its significant overlap with Castleman’s disease. However, distinct clinical and histological features warrant its classification as a separate subtype of idiopathic multicentric Castleman’s disease (iMCD). While recent modifications have been made to the diagnostic criteria for iMCD, these criteria lack specificity for this particular condition, further complicating diagnosis. Due to its inflammatory nature, several complex molecular signaling pathways are involved, including the JAK-STAT pathway, NF-kB, and signal amplifiers such as IL-6 and VEGF. Understanding the involvement of immune dysfunction, some infectious agents, genetic mutations, and specific molecular and signaling pathways could improve the knowledge and management of the condition, leading to effective treatment strategies. The current therapeutic approaches include corticosteroids, anti-IL6 drugs, rituximab, and chemotherapy, among others, but response rates vary, highlighting the need for personalized strategies. The prognosis is uncertain due to diagnostic difficulties, emphasizing the importance of early intervention and appropriate targeted treatment. This comprehensive review examines the evolving landscape of TAFRO syndrome, including the pathophysiology, diagnostic criteria, treatment strategies, prognosis, and future perspectives. Full article

The phenomenon of bone metastases presents a significant challenge within the context of advanced cancer treatments, particularly pertaining to breast, prostate, and lung cancers. These metastatic occurrences stem from the dissemination of cancerous cells into the bone, thereby interrupting the equilibrium between osteoblasts and osteoclasts. Such disruption results in skeletal complications, adversely affecting patient morbidity and quality of life. This review discusses the intricate interplay between cancer cells and the bone microenvironment, positing the bone not merely as a passive recipient of metastatic cells but as an active contributor to cancer progression through its distinctive biochemical and cellular makeup. A thorough examination of bone structure and the dynamics of bone remodeling is undertaken, elucidating how metastatic cancer cells exploit these processes. This review explores the genetic and molecular pathways that underpin the onset and development of bone metastases. Particular emphasis is placed on the roles of cytokines and growth factors in facilitating osteoclastogenesis and influencing osteoblast activity. Additionally, this paper offers a meticulous critique of current diagnostic methodologies, ranging from conventional radiography to advanced molecular imaging techniques, and discusses the implications of a nuanced understanding of bone metastasis biology for therapeutic intervention. This includes the development of targeted therapies and strategies for managing bone pain and other skeletal-related events. Moreover, this review underscores the imperative of ongoing research efforts aimed at identifying novel therapeutic targets and refining management approaches for bone metastases. It advocates for a multidisciplinary strategy that integrates advancements in medical oncology and radiology with insights derived from molecular biology and genetics, to enhance prognostic outcomes and the quality of life for patients afflicted by this debilitating condition. In summary, bone metastases constitute a complex issue that demands a comprehensive and informed approach to treatment. This article contributes to the ongoing discourse by consolidating existing knowledge and identifying avenues for future investigation, with the overarching objective of ameliorating patient care in the domain of oncology. Full article

Parkinson’s disease (PD), a progressive neurodegenerative disease, has no cure, and current therapies are not effective at halting disease progression. The disease affects mid-brain dopaminergic neurons and, subsequently, the spinal cord, contributing to many debilitating symptoms associated with PD. The GTP-binding protein, Rho, plays a significant role in the cellular pathology of PD. The downstream effector of Rho, Rho-associated kinase (ROCK), plays multiple functions, including microglial activation and induction of inflammatory responses. Activated microglia have been implicated in the pathology of many neurodegenerative diseases, including PD, that initiate inflammatory responses, leading to neuron death. Calpain expression and activity is increased following glial activation, which triggers the Rho-ROCK pathway and induces inflammatory T cell activation and migration as well as mediates toxic α-synuclein (α-syn) aggregation and neuron death, indicating a pivotal role for calpain in the inflammatory and degenerative processes in PD. Increased calpain activity and Rho-ROCK activation may represent a new mechanism for increased oxidative damage in aging. This review will summarize calpain activation and the role of the Rho-ROCK pathway in oxidative stress and α-syn aggregation, their influence on the neurodegenerative process in PD and aging, and possible strategies and research directions for therapeutic intervention. Full article

Ubiquitin-specific protease 18 (USP18) is a protein recognized for its dual enzymatic and non-enzymatic nature. It is involved in many physiological processes like the cell cycle and cell signaling. It also suppresses heart muscle remodeling upon an increase in the afterload. The role of USP18 in kidney pathology remains unknown. The objective of the study was to assess the relationship between serum and urine USP18 levels, the factors contributing to cardiovascular risk, and the markers of kidney disease activity at different stages of chronic kidney disease (CKD). One hundred participants, aged between 24 and 85 years (mean 53.1 ± 17.1 years), were included. Five groups (n = 20 each) were recruited according to their renal status (healthy individuals, patients with proteinuric glomerulonephritis, patients with non-proteinuric CKD, patients who were treated with hemodialysis, and kidney transplant recipients). The measurements of serum and urine USP18 levels were performed using ELISA. The median serum USP18 level was the highest in healthy participants (1143.0 pg/mL) and kidney transplant recipients (856.6 pg/mL), whereas, in individuals with different forms of CKD, it fitted within the range of 402.1–471.9 pg/mL. Urinary USP18 reached the highest level in the group of CKD patients not yet on dialysis (303.3 pg/mL). Only in this group did it correlate with serum creatinine and urea concentrations. Our results suggest the inhibition of cardioprotective USP18 signaling when kidney function is impaired. Moreover, an increased level of urinary USP18 may indicate chronic tubular damage. Full article

Nitric oxide (NO) is a key diffusible messenger in the mammalian brain. It has been proposed that NO may diffuse in retrograde into presynaptic terminals, contributing to the induction of hippocampal long-term potentiation (LTP). Here, we present novel evidence that NO is selectively required for the synaptic potentiation of the interhemispheric projection in the anterior cingulate cortex (ACC). Unilateral low-frequency stimulation (LFS) induced a short-term synaptic potentiation on the contralateral ACC through the corpus callosum (CC). The use of the antagonists of the NMDA receptor (NMDAR), or the inhibitor of the L-type voltage-dependent Ca²⁺ channels (L-VDCCs), blocked the induction of this ACC-ACC potentiation. In addition, the inhibitor of NO synthase, or inhibitors for its downstream signaling pathway, also blocked this ACC-ACC potentiation. However, the application of the NOS inhibitor blocked neither the local electric stimulation-induced LTP nor the stimulation-induced recruitment of silent responses. Our results present strong evidence for the pathway-selective roles of NO in the LTP of the ACC. Full article

Hypertension (HT) is a disease that poses a serious threat to human health, mediating organ damage such as the cardiovascular (CV) system, kidneys, central nervous system (CNS), and retinae, ultimately increasing the risk of death due to damage to the entire vascular system. Thus, the widespread prevalence of hypertension brings enormous health problems and socioeconomic burdens worldwide. The goal of hypertension management is to prevent the risk of hypertension-mediated organ damage and excess mortality of cardiovascular diseases. To achieve this goal, hypertension guidelines recommend accurate monitoring of blood pressure and assessment of associated target organ damage. Early identification of organ damage mediated by hypertension is therefore crucial. Plasma biomarkers as a non-invasive test can help identify patients with organ damage mediated by hypertension who will benefit from antihypertensive treatment optimization and improved prognosis. In this review, we provide an overview of some currently available, under-researched, potential plasma biomarkers of organ damage mediated by hypertension, looking for biomarkers that can be detected by simple testing to identify hypertensive patients with organ damage, which is of great significance in clinical work. Natriuretic peptides (NPs) can be utilized as a traditional biomarker to detect hypertension-mediated organ damage, especially for heart failure. Nevertheless, we additionally may need to combine two or more plasma biomarkers to monitor organ damage in the early stages of hypertension. Full article

TAFRO syndrome is an acute systemic inflammatory disorder characterized by thrombocytopenia, anasarca, fever, reticulin myelofibrosis, renal dysfunction, and organomegaly. While its lymph node pathology is similar to that of idiopathic multicentric Castleman disease (iMCD), the clinical features of TAFRO syndrome differ from those of typical iMCD, as they include a more aggressive clinical course and high mortality. However, an optimal treatment strategy for TAFRO syndrome has not yet been established, owing to a poor understanding of its pathogenesis. The limited cases we encountered suggest that tacrolimus treatment in combination with glucocorticoids may potentially be effective and well tolerated as an initial treatment, and hold promise as a glucocorticoid-sparing agent. Herein, we report an additional case and review the sparse literature available regarding TAFRO syndrome treated via tacrolimus. Full article

Background: In previous studies, denosumab, a RANKL human monoclonal antibody used in osteoporosis treatment, has shown efficacy in tendon healing after rotator cuff repair. This prospective study investigated the effects of denosumab on tendon healing, re-tear rates, and clinical outcomes post rotator cuff repair in women with osteoporosis. Method: This was a prospective, observational study, employing propensity score matching for the control group. From March 2018 to March 2023, female patients over the age of 60 with normal bone density undergoing arthroscopic rotator cuff repair were selected as controls through propensity score matching (PSM) and compared with female patients of the same age group with osteoporosis who were receiving denosumab treatment. The control group was matched using 1-to-2 propensity score matching. Radiological examinations and functional outcomes were assessed preoperatively and at 6 months postoperatively. Results: In the final analysis, the study comprised 34 patients in the denosumab treatment group (Group 1) and 68 patients in the control group (Group 2). The functional scores showed significant improvement at 6 months post-surgery in both groups. No significant difference in the functional scores was observed among the groups. The re-tear rate, defined according to Sugaya’s classification (types IV and V) as re-tear, was slightly higher in Group 1 at 16.7% (6 of 34) compared to Group 2 at 11.7% (8 of 68), but the difference was not statistically significant (p = 0.469). The re-tear patterns, classified according to Rhee’s classification, also showed no significant difference among the groups (Group 1: 2/4 of 6; Group 2: 4/4 of 8; p = 0.571). The occurrence of type I re-tear exhibited no significant difference between the two groups (5.9% vs. 5.9%; p = 1.000). Conclusions: The administration of denosumab following arthroscopic rotator cuff repair in women aged 60 and over with osteoporosis resulted in a re-tear rate that was similar to that observed in patients without osteoporosis. This result suggests that denosumab administration might be beneficial for rotator cuff healing, particularly in the context of osteoporosis, a known risk factor for increased retear rates. Therefore, comprehensive osteoporosis screening and treatment should be considered in conjunction with rotator cuff repair surgery in middle-aged women. Full article

Introduction: Magnesium is a vital intracellular cation crucial for over 320 enzymatic reactions related to energy metabolism, musculoskeletal function, and nucleic acid synthesis and plays a pivotal role in human physiology. This study aimed to explore the prevalence of dysmagnesemia in patients with diabetes mellitus and evaluate its correlations with glycemic control, medication use, and diabetic complications. Methods: A cross-sectional study was conducted at Sultan Qaboos University Hospital, including 316 patients aged 18 years or older with diabetes mellitus. Data included demographics, medical history, medications, and biochemical parameters. Serum total magnesium concentrations were measured, and dysmagnesemia was defined as magnesium ≤ 0.69 mmol/L for hypomagnesemia and ≥1.01 mmol/L for hypermagnesemia. Results: The prevalence of hypomagnesemia in patients with diabetes was 17.1% (95% CI: 13.3–21.7%), and hypermagnesemia was 4.1% (95% CI: 2.4–7.0%). Females were significantly overrepresented in the hypomagnesemia group, while the hypermagnesemia group showed a higher prevalence of hypertension, retinopathy, an increased albumin/creatinine ratio, chronic kidney disease (CKD), elevated creatinine levels, and a lower adjusted calcium concentration. The multinominal logistic regression exhibited that the female sex and higher serum-adjusted calcium were independent risk factors of hypomagnesemia. In contrast, the presence of hypertension, higher levels of albumin/creatinine ratio, and stage 5 CKD were independent risk factors of hypermagnesemia. Conclusions: Hypomagnesemia was common among patients with diabetes mellitus; however, hypermagnesemia was associated with microvascular complications. Full article

In our study, we investigated the prognostic significance of hematological markers—NLR (Neutrophil-to-Lymphocyte Ratio), PLR (Platelet-to-Lymphocyte Ratio), and RDW-CV (Red Blood Cell Distribution Width—Coefficient of Variation)—in 117 glioblastoma patients. The data collected from January 2016 to December 2018 included demographics, clinical scores, and treatment regimens. Unlike previous research, which often examined these markers solely before surgery, our unique approach analyzed them at multiple stages: preoperative, postoperative, and before adjuvant therapies. We correlated these markers with the overall survival (OS) and progression-free survival (PFS) using statistical tools, including ANOVA, Cox regression, and Kaplan–Meier survival analyses, employing SPSS version 29.0. Our findings revealed notable variations in the NLR, PLR, and RDW-CV across different treatment stages. The NLR and PLR decreased after surgery, with some stabilization post-STUPP phase (NLR: p = 0.007, η²p = 0.06; PLR: p = 0.001, η²p = 0.23), while the RDW-CV increased post-surgery and during subsequent treatments (RDW-CV: p < 0.001, η²p = 0.67). Importantly, we observed significant differences between the preoperative phase and other treatment phases. Additionally, a higher NLR and RDW-CV at the second-line treatment and disease progression were associated with an increased risk of death (NLR at 2nd line: HR = 1.03, p = 0.029; RDW-CV at progression: HR = 1.14, p = 0.004). We proposed specific marker cut-offs that demonstrated significant associations with survival outcomes when applied to Kaplan–Meier survival curves (NLR at 2nd line < 5: p < 0.017; RDW-CV at progression < 15: p = 0.007). An elevated NLR and RDW-CV at later treatment stages correlated with poorer OS and PFS. No significant preoperative differences were detected. These biomarkers may serve as non-invasive tools for glioblastoma management. Full article

The associations of cardiovascular disease (CVD) with comorbidities and biochemical and body composition measurements are repeatedly described but have not been studied simultaneously. In the present cross-sectional study, information on CVD and comorbidities [type 2 diabetes mellitus (T2DM), hypertension (HTN), and hyperlipidemia (HDL)], body composition, levels of soluble markers, and other measures were collected from 1079 individuals. When we examined the association of each comorbidity and CVD, controlling for other comorbidities, we observed a clear pattern of the comorbidity-related specific associations with tested covariates. For example, T2DM was significantly associated with GDF-15 levels and the leptin/adiponectin (L/A) ratio independently of two other comorbidities; HTN, similarly, was independently associated with extracellular water (ECW) levels, L/A ratio, and age; and HDL was independently related to age only. CVD showed very strong independent associations with each of the comorbidities, being associated most strongly with HTN (OR = 10.89, 6.46–18.38) but also with HDL (2.49, 1.43–4.33) and T2DM (1.93, 1.12–3.33). An additive Bayesian network analysis suggests that all three comorbidities, particularly HTN, GDF-15 levels, and ECW content, likely have a main role in the risk of CVD development. Other factors, L/A ratio, lymphocyte count, and the systemic inflammation response index, are likely indirectly related to CVD, acting through the comorbidities and ECW. Full article

The long-term follow-up findings of the phase I trial evaluating the efficacy of oncolytic adenovirus-mediated cytotoxic and interleukin-12 gene therapy in metastatic pancreatic cancer (mPC) seem very promising. The study employed a replication-competent Adenovector in combination with chemotherapy in a dose-escalation format. The trial demonstrated a clinically meaningful median overall survival (OS) benefit, with patients in the highest dose cohort exhibiting an impressive median OS of 18.4 months. This contrasts starkly with patients receiving lower doses who experienced a median OS of 4.8 and 3.5 months, respectively. Remarkably, subject number 10, who received the highest dose, demonstrated an extraordinary survival of 59.1 months, presenting a compelling case for further exploration. Additionally, this patient displayed complete responses in lung and liver metastases, a rare occurrence in mPC treatment. Statistical analyses supported the observed survival benefit. The unprecedented OS results emphasize the potential of this treatment strategy and pave the way for future investigations into this promising gene therapy approach. Full article

Cell-based therapies hold promise for novel therapeutic strategies in regenerative medicine. We previously characterized in vitro human umbilical di-chimeric cells (HUDCs) created via the ex vivo fusion of human umbilical cord blood (UCB) cells derived from two unrelated donors. In this in vivo study, we assessed HUDC safety and biodistribution in the NOD SCID mouse model at 90 days following the systemic intraosseous administration of HUDCs. Twelve NOD SCID mice (n = 6/group) received intraosseous injection of donor UCB cells (3.0 × 10⁶) in Group 1, or HUDCs (3.0 × 10⁶) in Group 2, without immunosuppression. Flow cytometry assessed hematopoietic cell surface markers in peripheral blood and the presence of HLA-ABC class I antigens in lymphoid and non-lymphoid organs. HUDC safety was assessed by weekly evaluations, magnetic resonance imaging (MRI), and at autopsy for tumorigenicity. At 90 days after intraosseous cell administration, the comparable expression of HLA-ABC class I antigens in selected organs was found in UCB control and HUDC therapy groups. MRI and autopsy confirmed safety by no signs of tumor growth. This study confirmed HUDC biodistribution to selected lymphoid organs following intraosseous administration, without immunosuppression. These data introduce HUDCs as a novel promising approach for immunomodulation in transplantation. Full article

Pathological cleavage of type II collagen (Col2) and generation of Col2 neoepitopes can serve as useful molecular markers of the progression of osteoarthritis (OA). One of such potential biomarkers is type II collagen neoepitope C2C. The aim of this study was to correlate the degree of articular cartilage damage in OA patients with C2C expression in histological samples of tissues removed during total knee replacement. Cartilage samples were obtained from 27 patients ranging in age from 55 to 66 years. In each patient, medial and lateral tibia plateau samples were analyzed according to the OARSI histopathology grading system. The C2C expression was evaluated on histological slides by semi-quantitative analysis using ImageJ Fiji 2.14.0 software. Spearman’s rank correlation analysis revealed a positive weak correlation (rho = 0.289, p = 0.0356) between the histological grade of tissue damage and the percentage of C2C staining. In addition, a highly significant positive correlation (rho = 0.388, p = 0.0041) was discovered between the osteoarthritis score (combining the histological grade of damage with the OA macroscopic stage) and the percentage of C2C staining in the samples. The C2C expression was detected in all the regions of the articular cartilage (i.e., the superficial zone, mid zone, deep zone and tidemark area, and the zone of calcified cartilage). Our findings imply that local expression of C2C correlates with the articular cartilage damage in OA-affected knees. This confirms that C2C can be used as a prospective marker for assessing pathological changes in the OA course and OA clinical trials. Full article

The distribution of adipose tissue in the lungs is intricately linked to a variety of lung diseases, including asthma, chronic obstructive pulmonary disease (COPD), and lung cancer. Accurate detection and quantitative analysis of subcutaneous and visceral adipose tissue surrounding the lungs are essential for effectively diagnosing and managing these diseases. However, there remains a noticeable scarcity of studies focusing on adipose tissue within the lungs on a global scale. Thus, this paper introduces a ConvBiGRU model for localizing lung slices and a multi-module UNet-based model for segmenting subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT), contributing to the analysis of lung adipose tissue and the auxiliary diagnosis of lung diseases. In this study, we propose a bidirectional gated recurrent unit (BiGRU) structure for precise lung slice localization and a modified multi-module UNet model for accurate SAT and VAT segmentations, incorporating an additive weight penalty term for model refinement. For segmentation, we integrate attention, competition, and multi-resolution mechanisms within the UNet architecture to optimize performance and conduct a comparative analysis of its impact on SAT and VAT. The proposed model achieves satisfactory results across multiple performance metrics, including the Dice Score (92.0% for SAT and 82.7% for VAT), F1 Score (82.2% for SAT and 78.8% for VAT), Precision (96.7% for SAT and 78.9% for VAT), and Recall (75.8% for SAT and 79.1% for VAT). Overall, the proposed localization and segmentation framework exhibits high accuracy and reliability, validating its potential application in computer-aided diagnosis (CAD) for medical tasks in this domain. Full article

Darier disease (DD) is an autosomal dominant disorder due to pathogenic variants of the ATP2A2 gene that causes an isolated skin manifestation based on keratinocyte disconnection and apoptosis. Systemic manifestations of DD have not been demonstrated so far, although a high incidence of neuropsychiatric syndromes suggests an involvement of the central nervous system. We report that the pathogenic ATP2A2 gene variant c.118G>A may cause cardiac involvement in patients with DD, consisting of keratinocyte and cardiomyocyte disconnection. Their common pathologic pathway, still unreported, was documented by both skin and left ventricular endomyocardial biopsies because cardiac dilatation and dysfunction appeared several decades after skin manifestations. Keratinocyte disconnection was paralleled by cardiomyocyte separation at the lateral junction. Cardiomyocyte separation was associated with cell disarray, sarcoplasmic reticulum dilatation, and increased myocyte apoptosis. Clinically, hyperkeratotic skin papules are associated with chest pain, severe muscle exhaustion, and ventricular arrhythmias that improved following administration of aminophylline, a phosphodiesterase inhibitor enhancing SERCA2 protein phosphorylation. Cardiac pathologic changes are similar to those documented in the skin, including cardiomyocyte disconnection that promotes precordial pain and cardiac arrhythmias. Phosphodiesterase inhibitors that enhance SERCA2 protein phosphorylation may substantially attenuate the symptoms. Full article

Vitamin A, an essential micronutrient, is integral to various biological processes crucial for organismal development and maintenance. Dietary sources of vitamin A encompass preformed retinol, retinyl esters, and provitamin A carotenoids. Retinoic acid (RA), a key component, plays pivotal roles in vision, cell proliferation, apoptosis, immune function, and gene regulation. Drug repurposing, an effective strategy for identifying new therapeutic applications for existing drugs, has gained prominence in recent years. This review seeks to provide a comprehensive overview of the current research landscape surrounding retinoids and drug repurposing. The scope of this review encompasses a comprehensive examination of retinoids and their potential for repurposing in various therapeutic contexts. Despite their efficacy in treating dermatological conditions, concerns about toxicity persist, driving the search for safer and more potent retinoids. The molecular mechanisms underlying retinoid activity involve binding to retinoic acid receptors (RARs) and retinoid X receptors (RXRs), leading to transcriptional regulation of target genes. This review seeks to shed light on the possibilities for repurposing retinoids to cover a wider spectrum of therapeutic uses by exploring recent scientific progress. It also aims to offer a more comprehensive understanding of the therapeutic prospects of retinoids and the broader impact of drug repositioning in contemporary medicine. Full article

Botulism is a priority disease worldwide because it has a very severe course of evolution that can lead to death. This paper aims to describe the main epidemiological characteristics of botulism cases confirmed in Romania over 14 years (2007–2020). We performed a retrospective study using the publicly available national surveillance data and reported to the National Institute of Public Health. A total of 325 cases of foodborne botulism were reported in Romania, with no infant or wound botulism. Most of the cases (125, 38.5%) were reported among young adults (25–44 years old), over half (205, 63%) of them living in rural areas. The incriminated food item was identified in 161 cases; in most cases (145, 90%) the food item was prepared in the household. The main food category was represented by meat and meat-based products (94, 68.6%). In almost all cases the identified type was BoNT/B (230/231, 99.5%). Fifteen deaths were recorded, and the case fatality rate was 4.6%. Botulism cases were reported annually in Romania. Surveillance data are essential for implementing control measures and adapting educational campaigns according to existing needs. Full article

Antipsychotics are associated with severe metabolic side effects including insulin resistance; however, the mechanisms underlying this side effect are not fully understood. The skeletal muscle plays a critical role in insulin-stimulated glucose uptake, and changes in skeletal muscle DNA methylation by antipsychotics may play a role in the development of insulin resistance. A double-blind, placebo-controlled trial of olanzapine was performed in healthy volunteers. Twelve healthy volunteers were randomized to receive 10 mg/day of olanzapine for 7 days. Participants underwent skeletal muscle biopsies to analyze DNA methylation changes using a candidate gene approach for the insulin signaling pathway. Ninety-seven methylation sites were statistically significant (false discovery rate < 0.05 and beta difference between the groups of ≥10%). Fifty-five sites had increased methylation in the skeletal muscle of olanzapine-treated participants while 42 were decreased. The largest methylation change occurred at a site in the Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-Alpha (PPARGC1A) gene, which had 52% lower methylation in the olanzapine group. Antipsychotic treatment in healthy volunteers causes significant changes in skeletal muscle DNA methylation in the insulin signaling pathway. Future work will need to expand on these findings with expression analyses. Full article

As biofilms mature, biomass and extracellular polysaccharide (EPS) content increases, enhancing pathogenicity. Therefore, this study aimed to evaluate the antibacterial efficacy of cold atmospheric plasma (CAP) against oral microcosm biofilms and the influence of biofilm maturity on treatment. Oral microcosm biofilms were cultured on hydroxyapatite disks for 2 and 6 days. Based on the treatment and biofilm maturity, these were subsequently allocated into six groups (N = 19 each): Groups 1 and 2 were incubated with distilled water for 1 min; Groups 3 and 4 were treated with CAP for 2 min, and Groups 5 and 6 were treated with 0.12% chlorhexidine gluconate for 1 min. Groups 1, 3, and 5 represent 2-day biofilms, and Groups 2, 4, and 6 represent 6-day biofilms. Treatments were repeated daily for 5 days. Antibacterial efficacy was analyzed by measuring oral biofilms’ red fluorescence intensity (Ratio_R/G) and quantifying EPS content and bacterial viability. The Ratio_R/G was 1.089-fold and 1.104-fold higher in Groups 4 and 6 than in Groups 3 and 5 following antibacterial treatment, respectively (p < 0.001). EPS content increased by 1.71-fold in Group 6 than in Group 5 (p < 0.001). Bacterial survival rate was the lowest in Group 3 (p = 0.005). These findings underscore the relevance of CAP treatment in maintaining antibacterial efficacy regardless of the biofilm development stage, highlighting its potential utility in oral care. Full article

Cardiovascular diseases remain the leading cause of death worldwide, with ischemic heart disease (IHD) as the most common. Ischemia-induced angiogenesis is a process in which vascular endothelial growth factor (VEGF) plays a crucial role. To conduct research in the field of VEGF’s association in cardiovascular diseases, it is vital to understand its role in the physiological and pathological processes in the heart. VEGF-based therapies have demonstrated a promising role in preclinical studies. However, their potential in human therapies is currently under discussion. Furthermore, VEGF is considered a potential biomarker for collateral circulation assessment and heart failure (HF) mortality. Additionally, as VEGF is involved in angiogenesis, there is a need to elucidate the impact of VEGF-targeted therapies in terms of cardiovascular side effects. Full article

Therapy-related myeloid neoplasms (t-MN) arise after a documented history of chemo/radiotherapy as treatment for an unrelated condition and account for 10–20% of myelodysplastic syndromes and acute myeloid leukemia. T-MN are characterized by a specific genetic signature, aggressive features and dismal prognosis. The nomenclature and the subsets of these conditions have changed frequently over time, and despite the fact that, in the last classification, they lost their autonomous entity status and became disease qualifiers, the recognition of this feature remains of major importance. Furthermore, in recent years, extensive studies focusing on clonal hematopoiesis and germline variants shed light on the mechanisms of positive pressure underpinning the rise of driver gene mutations in t-MN. In this manuscript, we aim to review the evolution of defining criteria and characteristics of t-MN from a clinical and biological perspective, the advances in mechanistic aspects of malignant progression and the challenges in prevention and management. Full article