The role of mesenchymal stem cells in the treatment and pathogenesis of psoriasis.

Psoriasis, a prevalent inflammatory skin condition impacting millions globally, continues to pose treatment challenges, despite the availability of multiple therapies. This underscores the demand for innovative treatments. Mesenchymal stem cells (MSCs) have emerged as a promising therapeutic option due to their capacity to modulate the immune system and facilitate tissue healing. Recent research indicates that MSCs don't just work through direct cell-to-cell interactions but also release extracellular vesicles (EVs), containing various bioactive substances like proteins, lipids, and nucleic acids. This article explores our current knowledge of psoriasis's origins and the potential utilization of MSCs and their EVs, particularly exosomes, in managing the condition. Additionally, we delve into how MSCs and EVs function in therapy, including their roles in regulating immune responses and promoting tissue repair. Lastly, we discuss the obstacles and opportunities associated with translating MSC-based treatments for psoriasis into clinical practice.

Phosphate adsorption on dried alum sludge: Modeling and application to treatment of dairy effluents.

This study evaluates Alum sludge from drinking water treatment plants for the efficient and cost-effective removal of phosphates from aqueous solutions. Extensive characterization and batch experiments have established that optimal phosphate removal was achieved with a sludge dosage of 20 g L-1 (at an initial phosphate concentration of 100 mg L-1), a pH of 5, a temperature of 23 °C, and a stirring speed of 200 rpm. These conditions significantly reduced phosphate levels, ensuring compliance with legal discharge limits. The Langmuir isotherm, pseudo-second-order kinetic and intraparticle diffusion models best described the adsorption process, highlighting the spontaneous and endothermic nature of the phenomenon. The sludge effectively reduced phosphate concentrations to acceptable levels when applied to dairy effluents. This study underscores the potential of Alum sludge as a viable solution for phosphate management in environmental cleanup efforts.

Therapeutic significance of long noncoding RNAs in estrogen receptor-positive breast cancer.

About 70% of cases of breast cancer are compromised by Estrogen-positive breast cancer. Through its regulation of several processes, including cell proliferation, cell cycle progression, and apoptosis, Estrogen signaling plays a pivotal role in the genesis and progression of this particular kind of breast cancer. One of the best treatment strategies for treating Estrogen-positive breast cancer is blocking Estrogen signaling. However, patients' treatment failure is mainly caused by the emergence of resistance and metastases, necessitating the development of novel therapeutic targets. Numerous studies have shown long noncoding RNAs (lncRNAs) to play a role in Estrogen-mediated carcinogenesis. These lncRNAs interact with co-regulators and the Estrogen signaling cascade components, primarily due to Estrogen activation. Vimentin and E-cadherin are examples of epithelial-to-mesenchymal transition markers, and they regulate genes involved in cell cycle progression, such as Cyclins, to affect the growth, proliferation, and metastasis of Estrogen-positive breast cancer. Furthermore, a few of these lncRNAs contribute to developing resistance to chemotherapy, making them more desirable targets for enhancing results. Thus, to shed light on the creation of fresh approaches for treating this cancer, this review attempts to compile recently conducted studies on the relationship between lncRNAs and the advancement of Estrogen-positive breast cancer.

Effective extracellular vesicles in glioma: Focusing on effective ncRNA exosomes and immunotherapy methods for treatment.

This comprehensive article explores the complex field of glioma treatment, with a focus on the important roles of non-coding RNAsRNAs (ncRNAs) and exosomes, as well as the potential synergies of immunotherapy. The investigation begins by examining the various functions of ncRNAs and their involvement in glioma pathogenesis, progression, and as potential diagnostic biomarkers. Special attention is given to exosomes as carriers of ncRNAs and their intricate dynamics within the tumor microenvironment. The exploration extends to immunotherapy methods, analyzing their mechanisms and clinical implications in the treatment of glioma. By synthesizing these components, the article aims to provide a comprehensive understanding of how ncRNAs, exosomes, and immunotherapy interact, offering valuable insights into the evolving landscape of glioma research and therapeutic strategies.

Effect of walnut consumption on markers of endothelial function in adults: A systematic review and meta-analysis of randomized controlled trials.

Findings on the effect of walnut consumption on endothelial function are conflicting. Therefore, the present systematic review and meta-analysis summarized available trials in this regard. A systematic search was performed in online databases including PubMed-Medline, Scopus, and ISI Web of Science up to October 2023. Articles that reported the effect of walnut intake on flow-mediated dilation (FMD), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and stimulus-adjusted response measure (SARM) were included. Random effects models for a weighted mean difference (WMD) or standardized mean difference (SMD) were used to test for the overall effect. Six eligible trials were analyzed (250 participants). Walnut intake significantly increased FMD (WMD: 0.94%, 95% CI: 0.12 to 1.75; p = 0.02). However, meta-analysis could not show any beneficial effect of walnut intake on ICAM-1 (SMD: -0.23, 95% CI: -0.68 to 0.22; p = 0.31), VCAM-1 (SMD: -0.02, 95% CI: -1.38 to 1.34; p = 0.97), and SARM (WMD: 0.01%, 95% CI: -0.01 to 0.04; p = 0.28). In conclusion, the present meta-analysis suggests that walnuts may reduce cardiovascular disease risk by improving FMD. However, further studies should be performed on adults to determine the effect of walnut intake on endothelial function.

Central obesity accelerates leukocyte telomere length (LTL) shortening in apparently healthy adults: A systematic review and meta-analysis.

Shorter telomere length is associated with numerous comorbidities; central obesity might trigger leukocyte telomere shortening; in the current meta-analysis we evaluated the association of central obesity with leukocyte telomere length among adults. A systematic search from Scopus, PubMed, Embase and Proquest electronic databases up to May 2021 was done. The final screening, provided five articles to be included in final meta-analysis. Those in the highest category of telomere length had 3.72 cm lower waist circumference (WC) compared with those in the lowest category (WMD=-3.718; CI=-7.180, -0.257 P = 0.035; I2 = 95.4%). Also, those in the highest LTL category had 0.02 lower waist to hip ratio (WHR) compared with those in the lowest category, although this association was not significant (WMD: -0.02; CI=-0.04, 0.01; P = 0.19; I2= 90.7%). In quality assessment of included studies, all of the studies had moderate or high quality score and there was no study with poor quality. Higher leukocyte telomere length was accompanied with lower WC among adults. This association was not significant for difference in WHR. Because of the high heterogeneity values and also because of the observational design of included studies, the inference of causality of these associations needs further investigations.Supplemental data for this article is available online at https://doi.org/10.1080/10408398.2021.1971155 .

Potential of chimeric antigen receptor (CAR)-redirected immune cells in breast cancer therapies: Recent advances.

Despite substantial developments in conventional treatments such as surgery, chemotherapy, radiotherapy, endocrine therapy, and molecular-targeted therapy, breast cancer remains the leading cause of cancer mortality in women. Currently, chimeric antigen receptor (CAR)-redirected immune cell therapy has emerged as an innovative immunotherapeutic approach to ameliorate survival rates of breast cancer patients by eliciting cytotoxic activity against cognate tumour-associated antigens expressing tumour cells. As a crucial component of adaptive immunity, T cells and NK cells, as the central innate immune cells, are two types of pivotal candidates for CAR engineering in treating solid malignancies. However, the biological distinctions between NK cells- and T cells lead to differences in cancer immunotherapy outcomes. Likewise, optimal breast cancer removal via CAR-redirected immune cells requires detecting safe target antigens, improving CAR structure for ideal immune cell functions, promoting CAR-redirected immune cells filtration to the tumour microenvironment (TME), and increasing the ability of these engineered cells to persist and retain within the immunosuppressive TME. This review provides a concise overview of breast cancer pathogenesis and its hostile TME. We focus on the CAR-T and CAR-NK cells and discuss their significant differences. Finally, we deliver a summary based on recent advancements in the therapeutic capability of CAR-T and CAR-NK cells in treating breast cancer.

A comprehensive review of IL-26 to pave a new way for a profound understanding of the pathobiology of cancer, inflammatory diseases and infections.

Cytokines are considered vital mediators of the immune system. Down- or upregulation of these mediators is linked to several inflammatory and pathologic situations. IL-26 is referred to as an identified member of the IL-10 family and IL-20 subfamily. Due to having a unique cationic structure, IL-26 exerts diverse functions in several diseases. Since IL-26 is mainly secreted from Th17, it is primarily considered a pro-inflammatory cytokine. Upon binding to its receptor complex (IL-10R1/IL-20R2), IL-26 activates multiple signalling mediators, especially STAT1/STAT3. In cancer, IL-26 induces IL-22-producing cells, which consequently decrease cytotoxic T-cell functions and promote tumour growth through activating anti-apoptotic proteins. In hypersensitivity conditions such as rheumatoid arthritis, multiple sclerosis, psoriasis and allergic disease, this cytokine functions primarily as the disease-promoting mediator and might be considered a biomarker for disease prognosis. Although IL-26 exerts antimicrobial function in infections such as hepatitis, tuberculosis and leprosy, it has also been shown that IL-26 might be involved in the pathogenesis and exacerbation of sepsis. Besides, the involvement of IL-26 has been confirmed in other conditions, including graft-versus-host disease and chronic obstructive pulmonary disease. Therefore, due to the multifarious function of this cytokine, it is proposed that the underlying mechanism regarding IL-26 function should be elucidated. Collectively, it is hoped that the examination of IL-26 in several contexts might be promising in predicting disease prognosis and might introduce novel approaches in the treatment of various diseases.

Does CCL19 act as a double-edged sword in cancer development?

Cancer is considered a life-threatening disease, and several factors are involved in its development. Chemokines are small proteins that physiologically exert pivotal roles in lymphoid and non-lymphoid tissues. The imbalance or dysregulation of chemokines has contributed to the development of several diseases, especially cancer. CCL19 is one of the homeostatic chemokines that is abundantly expressed in the thymus and lymph nodes. This chemokine, which primarily regulates immune cell trafficking, is involved in cancer development. Through the induction of anti-tumor immune responses and inhibition of angiogenesis, CCL19 exerts tumor-suppressive functions. In contrast, CCL19 also acts as a tumor-supportive factor by inducing inflammation, cell growth, and metastasis. Moreover, CCL19 dysregulation in several cancers, including colorectal, breast, pancreatic, and lung cancers, has been considered a tumor biomarker for diagnosis and prognosis. Using CCL19-based therapeutic approaches has also been proposed to overcome cancer development. This review will shed more light on the multifarious function of CCL19 in cancer and elucidate its application in diagnosis, prognosis, and even therapy. It is expected that the study of CCL19 in cancer might be promising to broaden our knowledge of cancer development and might introduce novel approaches in cancer management.

The deciphering of the immune cells and marker signature in COVID-19 pathogenesis: An update.

The precise interaction between the immune system and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical in deciphering the pathogenesis of coronavirus disease 2019 (COVID-19) and is also vital for developing novel therapeutic tools, including monoclonal antibodies, antivirals drugs, and vaccines. Viral infections need innate and adaptive immune reactions since the various immune components, such as neutrophils, macrophages, CD4+ T, CD8+ T, and B lymphocytes, play different roles in various infections. Consequently, the characterization of innate and adaptive immune reactions toward SARS-CoV-2 is crucial for defining the pathogenicity of COVID-19. In this study, we explain what is currently understood concerning the conventional immune reactions to SARS-CoV-2 infection to shed light on the protective and pathogenic role of immune response in this case. Also, in particular, we investigate the in-depth roles of other immune mediators, including neutrophil elastase, serum amyloid A, and syndecan, in the immunopathogenesis of COVID-19.

Various types of electrochemical biosensors for leukemia detection and therapeutic approaches.

Leukemia often initiates following dysfunctions in hematopoietic stem cells lineages. Various types of leukemia, including acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), acute promyelocytic leukemia (APL), and human T-cell leukemia/lymphoma virus type 1 (HTLV-1) can thus call for different diagnosis and treatment options. One of the most important subjects in leukemia is the early detection of the disease for effective therapeutic purposes. In this respect, biosensors detecting the molecules of deoxyribonucleic acid (DNA) as analytes are called genosensors or DNA biosensors. Electrochemical sensors, as the most significant approach, also involve reacting of chemical solutions with sensors to generate electrical signals proportional to analyte concentrations. Biosensors can further help detect cancer cells in the early stages of the disease. Moreover, electrochemical biosensors, developed based on various nanomaterials (NMs), can increase sensitivity to the detection of leukemia-related genes, e.g., BCR/ABL as a fusion gene and promyelocytic leukemia/retinoic acid receptor alpha (PML/RARα). Therefore, the present review reflects on previous studies recruiting different NMs for leukemia detection.

Concanavalin A as a promising lectin-based anti-cancer agent: the molecular mechanisms and therapeutic potential.

Concanavalin A (ConA), the most studied plant lectin, has been known as a potent anti-neoplastic agent for a long time. Since initial reports on its capacity to kill cancer cells, much attention has been devoted to unveiling the lectin's exact molecular mechanism. It has been revealed that ConA can bind to several receptors on cancerous and normal cells and modulate the related signaling cascades. The most studied host receptor for ConA is MT1-MMP, responsible for most of the lectin's modulations, ranging from activating immune cells to killing tumor cells. In this study, in addition to studying the effect of ConA on signaling and immune cell function, we will focus on the most up-to-date advancements that unraveled the molecular mechanisms by which ConA can induce autophagy and apoptosis in various cancer cell types, where it has been found that P73 and JAK/STAT3 are the leading players. Moreover, we further discuss the main signaling molecules causing liver injury as the most significant side effect of the lectin injection. Altogether, these findings may shed light on the complex signaling pathways controlling the diverse responses created via ConA treatment, thereby modulating these complex networks to create more potent lectin-based cancer therapy. Video Abstract.

Cancer combination therapies by angiogenesis inhibitors; a comprehensive review.

Abnormal vasculature is one of the most conspicuous traits of tumor tissue, largely contributing to tumor immune evasion. The deregulation mainly arises from the potentiated pro-angiogenic factors secretion and can also target immune cells' biological events, such as migration and activation. Owing to this fact, angiogenesis blockade therapy was established to fight cancer by eliminating the nutrient and oxygen supply to the malignant cells by impairing the vascular network. Given the dominant role of vascular-endothelium growth factor (VEGF) in the angiogenesis process, the well-known anti-angiogenic agents mainly depend on the targeting of its actions. However, cancer cells mainly show resistance to anti-angiogenic agents by several mechanisms, and also potentiated local invasiveness and also distant metastasis have been observed following their administration. Herein, we will focus on clinical developments of angiogenesis blockade therapy, more particular, in combination with other conventional treatments, such as immunotherapy, chemoradiotherapy, targeted therapy, and also cancer vaccines. Video abstract.

Type 2 alveolar epithelial cell-derived circulating extracellular vesicle-encapsulated surfactant protein C as a mediator of cardiac inflammation in COVID-19.

Among the countless endeavours made at elucidating the pathogenesis of COVID-19, those aimed at the histopathological alterations of type 2 alveolar epithelial cells (AT2) are of outstanding relevance to the field of lung physiology, as they are the building blocks of the pulmonary alveoli. A merit of high regenerative and proliferative capacity, exocytotic activity resulting in the release of extracellular vesicles (EVs) is particularly high in AT2 cells, especially in those infected with SARS-CoV-2. These AT2 cell-derived EVs, containing the genetic material of the virus, might enter the bloodstream and make their way into the cardiovascular system, where they may infect cardiomyocytes and bring about a series of events leading to heart failure. As surfactant protein C, a marker of AT2 cell activity and a constituent of the lung surfactant complex, occurs abundantly inside the AT2-derived EVs released during the inflammatory stage of COVID-19, it could potentially be used as a biomarker for predicting impending heart failure in those patients with a history of cardiovascular disease.

The profile of the key pro-inflammatory cytokines in the serum of patients with CD and their association with the disease severity and activity.

BACKGROUND: The epidemiology of Crohn's disease (CD) has changed over the past decades, demonstrating a trend toward increased prevalence in developing countries, while in developed countries, its incidence has stabilized. The study aimed to examine the profile of the key pro-inflammatory cytokines in the serum of patients with CD and establish their association with the severity and activity of the disease. METHODS: A total of 61 patients (29 women (47.5%), 32 men (52.5%) aged from 18 to 40 years (mean age (30.42 ± 2.51) years) with the verified diagnosis of CD in the active phase were examined. The control group consisted of 30 healthy people of corresponding age. RESULTS: CD is characterized by a reliable increase of pro-inflammatory cytokines in blood compared to healthy people: tumor necrosis factor-α (TNF-α) - by 4.45 times (137.46 ± 9.72 vs. 30.88 ± 2.08 pg/ml in healthy people, p < 0,001), interleukin-1α (IL-1α) - by 5.08 times (51.55 ± 4.36 vs. 10.14 ± 0.93 pg/ml, p < 0.001), interleukin-6 (IL-6) - by 2.16 times (20.03 ± 1.81 vs. 9.27 ± 0.52 pg/ml, p < 0.001), interleukin-8 (IL-8) - by 2.04 times (25.74 ± 2.05 vs. 12.62 ± 1.16 pg/ml, p < 0.001), and interferon-γ (IFN-γ) - by 5.30 times (208.63 ± 14.29 vs. 39.35 ± 2.40 pg/ml, p < 0.001). The authors have established direct correlations between the Crohn's disease activity index and blood content of TNF-α (r = 0.84, p < 0.013), INF-γ (r = 0.61, p < 0.028); between TNF-α and INF-γ content (r = 0.67, p < 0.023), IL-1α (r = 0.49, p < 0.042), IL-6 (r = 0.40, p < 0.045), and IL-8 (r = 0.51, p < 0.033); INF-γ and IL-1α (r = 0.53, p < 0.040), IL-6 (r = 0.37, p < 0.039), IL-8 (r = 0.44, p < 0.040). CONCLUSIONS: Patients with CD were found to have multiple cytokines (TNF-α, IL-1α, IL-6, IL-8, and IFN-γ,). The content of cytokines correlated positively with the CD activity index.

Cost-utility analysis of total knee arthroplasty alone and in comparison with post-surgical rehabilitation and conservative treatment in the Republic of Kazakhstan.

BACKGROUND: Despite ample international knowledge on cost-effectiveness of total knee arthroplasty (TKA), it has never been a subject of investigation in Kazakhstan or other post-Soviet economies. Our study aimed to carry-out the cost-utility analysis of TKA alone and in comparison with post-surgical rehabilitation and conservative treatment at health care facilities of Kazakhstan. METHODS: Two hundred and forty four patients with knee osteoarthritis (KOA) who underwent TKA in orthopedic departments of Almaty, Nur-Sultan and Semey hospitals between January 1, 2019 and September 30, 2019 were followed-up for 12 months. The health-related quality of life was measured by the EQ-5D utility and Western Ontario and McMaster Universities Osteoarthritis Index was used to measure the patients' health status. The costs were estimated from the view of health care provider. We calculated the cost per QALY, the Cost-Utility Ratio and the Incremental Cost-Effectiveness Ratio. RESULTS: At the time of 12-month follow-up patients who received TKA alone or with the course of rehabilitation showed benefit over patients from the group of conservative treatment in terms of overall health status. Mean QALY gained at 12 months constituted 1.66 for the group that received TKA with rehabilitation, 1.48 for the group that received TKA alone and 0.24 for the group that received conservative treatment. Mean cost per QALY gained was USD 30 795.75 for KOA patients under conservative treatment, USD 6 323.69 for KOA patients subjected to TKA and USD 2 670.32 for KOA patients with rehabilitation course after TKA. CONCLUSION: Both TKA and TKA with rehabilitation could be considered as highly cost-effective interventions. The data obtained could be of interest for policy makers, medical professionals and KOA patients.

Neuroprotective and Anti-inflammatory Effects of Pioglitazone on Traumatic Brain Injury.

Traumatic brain injury (TBI) is still a major cause of concern for public health, and out of all the trauma-related injuries, it makes the highest contribution to death and disability worldwide. Patients of TBI continue to suffer from brain injury through an intricate flow of primary and secondary injury events. However, when treatment is provided in a timely manner, there is a significant window of opportunity to avoid a few of the serious effects. Pioglitazone (PG), which has a neuroprotective impact and can decrease inflammation after TBI, activates peroxisome proliferator-activated receptor-gamma (PPARγ). The objective of the study is to examine the existing literature to assess the neuroprotective and anti-inflammatory impact of PG in TBI. It also discusses the part played by microglia and cytokines in TBI. According to the findings of this study, PG has the ability to enhance neurobehavior, decrease brain edema and neuronal injury following TBI. To achieve the protective impact of PG the following was required: (1) stimulating PPARγ; (2) decreasing oxidative stress; (3) decreasing nuclear factor kappa B (NF-κB), interleukin 6 (IL-6), interleukin-1ß (IL-1ß), cyclooxygenase-2 (COX-2), and C-C motif chemokine ligand 20 (CCL20) expression; (4) limiting the increase in the number of activated microglia; and (5) reducing mitochondrial dysfunction. The findings indicate that when PIG is used clinically, it may serve as a neuroprotective anti-inflammatory approach in TBI.

Effects of licorice root supplementation on liver enzymes, hepatic steatosis, metabolic and oxidative stress parameters in women with nonalcoholic fatty liver disease: A randomized double-blind clinical trial.

This study aimed to evaluate the effects of licorice root supplementation on liver enzymes, hepatic steatosis, metabolic and oxidative stress parameters in women with nonalcoholic fatty liver disease (NAFLD). In this randomized double-blind, placebo-controlled trial, 60 women with NAFLD were selected and randomly assigned into 2 groups to take 1,000 mg/day powder of licorice root extract or placebo for 12 weeks. In addition, all the patients were advised to follow a weight loss diet and healthy lifestyle. The plasma levels of liver enzymes, glycemic indices, lipid profile, oxidative stress parameters, as well as hepatic steatosis were measured at the beginning and end of the study. Through the 12-weeks period of supplementation, women who received powder of licorice root experienced a statistically significant improvement in alanine aminotransferase (p < .001), insulin (p = .002), insulin resistance (p = .003), malondialdehyde (p < .001) serum levels, and ultrasonographic findings of liver steatosis (p < .001), compared to the placebo group. In conclusion, licorice root supplementation in addition to gradual weight loss and lifestyle modification is superior to lifestyle modification alone for the treatment of NAFLD.

Resveratrol supplementation efficiently improves endothelial health: A systematic review and meta-analysis of randomized controlled trials.

We perform a systematic review and meta-analysis of randomized controlled trials (RCTs) to quantify the effect of resveratrol supplementation on endothelial function. A comprehensive search was performed in electronic databases including PubMed, Scopus, Web of Science, and Cochrane Library up to February 2021 with no limitation in time and language. A meta-analysis of eligible studies was performed using a random-effects model to estimate the pooled effect size of flow-mediated dilation (FMD), intracellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), fibrinogen, and plasminogen activator inhibitor-1 (PAI-1). In total, 21 arms from 17 studies were included. The meta-analysis results showed that resveratrol significantly change the concentrations of FMD (WMD: 1.43%; 95% CI: 0.98 to 1.88, p < .001) and ICAM-1 (WMD: -7.09 ng/ml, 95% CI: -7.45 to -6.73, p < .001). However, VCAM-1, fibrinogen, and PAI-1 did not change significantly after resveratrol supplementation. In conclusion, the results of this study suggest that resveratrol supplementation can improve endothelial function which could be important, especially in patients with cardiovascular diseases.

The effect of flaxseed oil consumtion on blood pressure among patients with metabolic syndrome and related disorders: A systematic review and meta-analysis of randomized clinical trials.

We systematically reviewed randomized clinical trials (RCTs) to elucidate the overall effects of flaxseed oil consumption on blood pressure (BP) in patients with metabolic syndrome and related disorders. PubMed, Scopus, Cochrane Library, and ISI Web of Science databases were systematically searched until March 31, 2020, to find RCTs that examined the effect of flaxseed oil consumption on BP. Weighed mean difference (WMD) was pooled using a random-effects model. Standard methods were used for the assessment of heterogeneity, sensitivity analysis, and publication bias. Meta-analysis of five trials (6 arms) showed significant reductions in systolic (WMD: -3.86 mmHg, 95% CI: -7.59 to -0.13, p = .04) BP (SBP) after flaxseed oil consumption. However, the overall effect illustrated no significant change in diastolic (WMD: -1.71 mmHg, 95% CI: -3.67 to 0.26, p = .09) BP (DBP) in the intervention group compared with the control group. Our findings revealed that flaxseed oil consumption has favorable effects on SBP in patients with metabolic syndrome and related disorders. However, further investigations are needed to provide more reliable evidence.