Exploring the Connection Between HLA Class I and Class II Genotypes and Diabetic Retinopathy: A Comprehensive Review of Experimental Evidence.

Diabetic retinopathy (DR) is a microvascular complication associated with diabetes mellitus (DM). During the course of the disease, high blood glucose levels induce damage to the vasculature of the retina and promote neovascularization. Although numerous environmental risk factors have been associated with the emergence of DR, the role of genetics should not be underestimated. The human leukocyte antigen (HLA) plays a significant role in the regulation of the immune system. DR exhibits significant heterogeneity among patients, with differences in how the disease presents and progresses over time. The HLA gene, characterized by its extensive genetic variation, largely contributes to this diverse spectrum. Differences in HLA allele frequencies among healthy people, diabetic patients without retinopathy, and diabetic patients with different stages of retinopathy highlight the need for proper management of the disease. This comprehensive review outlines the current understanding of the relationship between HLA class I and class II variants and DR, shedding light on their potential significance as early onset indicators, prognostic indicators, and important risk factors for the development of this retinal condition.

Improved physiological defense responses by application of sodium nitroprusside in Isatis cappadocica Desv. under cadmium stress.

Isatis cappadocica is a well-known arsenic-hyperaccumulator, but there are no reports of its responses to cadmium (Cd). Nitric oxide (NO) is a signaling molecule, which induces cross-stress tolerance and mediates several physio-biochemical processes related to heavy metal toxicity. In this study, the effects of Cd and sodium nitroprusside (SNP as NO donor) on the growth, defense responses and Cd accumulation in I. cappadocica were investigated. When I. cappadocica was treated with 100 and 200 µM Cd, there was an insignificant inhibition of shoot growth. However, Cd stress at Cd400 treatment decreased significantly the dry weight of root and shoot by 73 and 38%, respectively, as compared to control. The application of SNP significantly improved the growth parameters and mitigated Cd toxicity. In addition, SNP decreased reactive oxygen species (ROS) production induced by Cd. The increased total thiol and glutathione (GSH) concentrations after SNP application may play a decisive role in maintaining cellular redox homeostasis, thereby protecting plants against oxidative damage under Cd stress. Bovine hemoglobin (Hb as NO scavenger) reduced the protective role of SNP, suggesting a major role of NO in the defensive effect of SNP. Furthermore, the reduction in shoot growth and the increase of oxidative damage were more severe after the addition of Hb, which confirms the protective role of NO against Cd-induced oxidative stress. The protective role of SNP in decreasing Cd-induced oxidative stress may be related to NO production, which can lead to stimulation of the thiols synthesis and improve defense system.

The effect of NADPH oxidase inhibitor diphenyleneiodonium (DPI) and glutathione (GSH) on Isatis cappadocica, under Arsenic (As) toxicity.

The present work was conducted to assess the effects of arsenic (As, 1000 µM), diphenyleneiodonium (DPI, 10 µM) and reduced glutathione (GSH, 500 µM) on Isatis cappadocica. As treatment decreased plant growth and fresh and dry weight of shoot and root and also enhanced the accumulation of As. As stress also enhanced the oxidative stress biomarkers, hydrogen peroxide (H2O2) and malondialdehyde (MDA) content. However, the application of GSH decreased the content of H2O2 and MDA by 43% and 55%, respectively, as compared to As treatment. The antioxidants like superoxide dismutase (SOD), catalase (CAT), peroxidase (POD), ascorbate peroxidase (APX), glutathione reductase (GR) and glutathione S-transferase (GST) also enhanced with As stress. NADPH oxidase inhibitor, the DPI, enhances the effect of As toxicity by increasing the accumulation of As, H2O2, MDA. DPI also enhances the activity of antioxidant enzymes except GR and GST, However, the application GSH increased the plant growth and biomass yield, decreases accumulation of As, H2O2 and MDA content in As as well as As + DPI treated plants. The thiols content [total thiol (TT), non-protein thiol (NPT) protein thiols (PT), and glutathione (GSH)] were decreased in the As + DPI treatment but supplementation of GSH enhanced them. Novelty statement: The study reveals the beneficial role of GSH in mitigating the deleterious effects of Arsenic toxicity through its active involvement in the antioxidant metabolism, thiol synthesis and osmolyte accumulation. Apart from As, We provided the plants NADPH oxidase inhibitor, the diphenyleneiodonium (DPI), which boosts the As toxicity. At present, there is dearth of information pertaining to the effects of DPI on plants growth and their responses under heavy metal stress.GSH application reversed the effect of diphenyleneiodonium (DPI) under As stress preventing the oxidative damage to biomolecules through the modulation of different antioxidant enzymes. The application of GSH for As stressed soil could be a sustainable approach for crop production.

Elucidating the physiological mechanisms underlying enhanced arsenic hyperaccumulation by glutathione modified superparamagnetic iron oxide nanoparticles in Isatis cappadocica.

Widespread arsenic (As) contamination is a severe environmental and public health concern. Isatis cappadocica, an arsenic hyperaccumulator, holds great potential to clean up As-contaminated soil and groundwater. Iron oxide is one of the most common metal oxides in the natural environment and its nanoparticulate form has been previously utilized for the removal of heavy metals/metalloids from wastewater. However, there is a paucity of information on the impact of iron oxide nanoparticles on the growth and physiological properties of I. cappadocica and its effectiveness on As removal. Current study reports for the first time the impact of superparamagnetic iron oxide nanoparticles and glutathione (GSH) modified superparamagnetic iron oxide nanoparticles (nFe3O4 and nFe3O4@GSH) on the physiological characteristic of I. cappadocica and its accumulation of As under hydroponic condition. nFe3O4@GSH alleviated the harmful impact of As and significantly increased the shoot biomass of I. cappadocica by enhancing the plant defense mechanisms. The application of GSH, nFe3O4 and nFe3O4@GSH all lowered the As concentration in plant shoots as a protective mechanism. However, the substantial shoot biomass increase due to nFe3O4@GSH resulted in a 56% higher As accumulation in plant shoots than in plants exposed to As alone, indicating the strong effectiveness of nFe3O4@GSH as a novel enhancer of the As phytoremediation by I. cappadocica. Our data further showed that the beneficial effect of nFe3O4@GSH on As phytoremediation is due to the enhancement of activities of several enzymatic and nonenzymatic antioxidants.

Immune Checkpoints and Graves' Disease, Thyroid Eye Disease, and Orbital Myopathy: A Comprehensive Review.

Immune checkpoints (ICPs) are essential regulators of the immune system, ensuring a delicate balance between self-tolerance and autoimmune responses. ICP therapy is a rapidly growing cancer treatment strategy that inhibits the interaction between ICPs and their ligands. This biological interaction increases the ability of the immune system in combating cancer. However, in some cases, the use of these agents may lead to immune hyperactivity and, subsequently, autoimmune diseases. Graves' disease (GD), thyroid eye disease (TED), and orbital myopathy are complex autoimmune disorders characterized by the production of autoantibodies. The emergence of these treatment-related adverse events underscore the critical need for a deeper understanding of the immune-checkpoint axis in autoimmune diseases. In this review article, we provide a comprehensive survey of the biological mechanisms of ICPs that are most frequently targeted in cancer therapy, including CTLA-4, PD-1, PDL-1, and LAG3. Furthermore, we investigate the latest scientific findings on the adverse events associated with the inhibition of these ICPs. This paper will particularly focus on the potential risks these complications pose to ocular and orbital tissues, which are a concern in the context of cancer treatment.

Coincidence of Ascariasis with Appendicitis in a Pediatric Patient with abdominal Pain; a Case Report.

The simultaneous occurrence of intestinal ascariasis and appendicitis presents a challenge in diagnosing pediatric abdominal emergencies due to overlapping symptoms. We present the case of an 8-year-old boy who experienced acute abdominal pain, characterized by a severe cramp in the mid and lower right abdomen, with pain rated 7 out of 10, a mild fever, and continuous nausea. The initial evaluation suggested appendicitis, supported by an Alvarado score of 9. However, ultrasonography did not conclusively confirm appendicitis but revealed an Ascaris worm in the ileum. This finding highlights the importance of careful diagnostic processes that combine clinical assessment with imaging techniques, while being mindful of their limitations. Surgical exploration confirmed retrocecal appendicitis coexisting with an Ascaris lumbricoides infection. The treatment involved surgical removal of the affected appendix and pharmacological expulsion of the parasitic worm using albendazole, which proved effective. This report emphasizes the consideration of ascariasis in diagnosing appendicitis, particularly in areas where intestinal parasites are common. It also demonstrated the improved diagnostic accuracy achieved through clinical scoring and imaging, thus reducing the risk of missing dual pathologies in young patients with acute abdominal pain.

Fabrication of ɛ-Polylysine-Loaded Electrospun Nanofiber Mats from Persian Gum-Poly (Ethylene Oxide) and Evaluation of Their Physicochemical and Antimicrobial Properties.

In the present study, electrospun nanofiber mats were fabricated by mixing different ratios (96:4, 95:5, 94:6, 93:7, and 92:8) of Persian gum (PG) and poly (ethylene oxide) (PEO). The SEM micrographs revealed that the nanofibers obtained from 93% PG and 7% PEO were bead-free and uniform. Therefore, it was selected as the optimized ratio of PG:PEO for the development of antimicrobial nanofibers loaded with ɛ-Polylysine (ɛ-PL). All of the spinning solutions showed pseudoplastic behavior and the viscosity decreased by increasing the shear rate. Additionally, the apparent viscosity, G', and G″ of the spinning solutions increased as a function of PEO concentration, and the incorporation of ɛ-PL did not affect these parameters. The electrical conductivity of the solutions decreased when increasing the PEO ratio and with the incorporation of ɛ-PL. The X-ray diffraction (XRD) and Fourier-transform infrared (FTIR) spectra showed the compatibility of polymers. The antimicrobial activity of nanofibers against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) was investigated, and the samples loaded with ɛ-PL demonstrated stronger antimicrobial activity against S. aureus.

Exogenous supplementation of Sulfur (S) and Reduced Glutathione (GSH) Alleviates Arsenic Toxicity in Shoots of Isatis cappadocica Desv and Erysimum allionii L.

The current study was conducted to investigate the role of sulfur (S) and reduced glutathione (GSH) in mitigating arsenic (As) toxicity in Isatis cappadocica and Erysimum allionii. These plants were exposed for 3 weeks to different concentrations (0, 400 and 800 µM) of As to measure fresh weight, total chlorophyll, proline and hydrogen peroxide (H2O2) content, As and S accumulation, and guaiacol peroxidase (POD) and glutathione S-transferase (GST) along with the supplementation of 20 mg L-1 of S and 500 µM of GSH. Results revealed the significant reduction of fresh weight (especially in E. allionii), activities of POD and GST enzymes and proline content as compare to control. However, the application of S and GSH enhanced the fresh weight. Inhibition in H2O2 accumulation and improvement in antioxidant responses were measured with the application of S and GSH. Hence, the supplementation of S and GSH enhanced fresh weight and total chlorophyll in both I. cappadocica and E. allionii by alleviating the adverse effects of As stress via decreased H2O2 content and restricted As uptake.

A green protocol for the electrochemical synthesis of a fluorescent dye with antibacterial activity from imipramine oxidation.

Electrochemical oxidation of imipramine (IMP) has been studied in aqueous solutions by cyclic voltammetry and controlled-potential coulometry techniques. Our voltammetric results show a complex behavior for oxidation of IMP at different pH values. In this study, we focused our attention on the electrochemical oxidation of IMP at a pH of about 5. Under these conditions, our results show that the oxidation of IMP leads to the formation of a unique dimer of IMP (DIMP). The structure of synthesized dimer is fully characterized by UV-visible, FTIR, 1H NMR, 13C NMR and mass spectrometry techniques. It seems that the first step in the oxidation of IMP is the cleavage of the alkyl group (formation of IMPH). After this, a domino oxidation-hydroxylation-dimerization-oxidation reaction, converts IMPH to (E)-10,10',11,11'-tetrahydro-[2,2'-bidibenzo[b,f]azepinylidene]-1,1'(5H,5'H)-dione (DIMP). The synthesis of DIMP is performed in an aqueous solution under mild conditions, without the need for any catalyst or oxidant. Based on our electrochemical findings as well as the identification of the final product, a possible reaction mechanism for IMP oxidation has been proposed. Conjugated double bonds in the DIMP structure cause the compound to become colored with sufficient fluorescence activity (excitation wave-length 535 nm and emission wave-length 625 nm). Moreover, DIMP has been evaluated for in vitro antibacterial. The antibacterial tests indicated that DIMP showed good antibacterial performance against all examined gram-positive and gram-negative bacteria (Staphylococcus aureus, Bacillus cereus, Escherichia coli and Shigella sonnei).

Multiple effects of silicon on alleviation of arsenic and cadmium toxicity in hyperaccumulator Isatis cappadocica Desv.

Arsenic (As) and cadmium (Cd) belong to the group of major pollutants extremely toxic to plants. Metal hyperaccumulating plants play an important role in phytoextraction of heavy metals. Silicon (Si) plays an important role in the amelioration of heavy metal stress through physio-biochemical mechanisms, which remain poorly understood in hyperaccumulators. The main purpose of this study was to determine the impact of Si on growth and performance of As hyperaccumulator Isatis cappadocica Desv., exposed to As and Cd. Results showed that Si (especially at 1 mM level) alleviated the harmful impact of As/Cd and significantly increased the root and shoot biomass, root and shoot length and chlorophyll contents of I. cappadocica by enhancing the plant defense mechanisms. Between the two investigated harmful elements, As was accumulated in plant parts significantly more than Cd, however with considerably lower toxic growth effects. The As/Cd concentration, bioaccumulation and translocation factor and total As content both in roots and shoots of Si-supplied plant were significantly reduced as a protective mechanism, especially in Cd exposed plant. In comparison with single As/Cd treatment, Si supply reduced H2O2 content, increased total soluble protein content and enhanced glutathione S-transferase activity in shoots. The results of this study clearly showed that Si minimized As/Cd uptake and root to shoot translocation, and therefore Si cannot enhance the phytoextraction potential of this plant species. Additionally, Si-improved growth and reduced oxidative damages caused by excess of As and Cd suggested that the similar mechanisms of metal(loid) alleviation are adopted in hyperaccumulators as well as non-hyperaccumulating plants.

Positive Predictive Value of Panoramic Radiography for Assessment of the Relationship of Impacted Mandibular Third Molars with the Mandibular Canal Based on Cone-Beam Computed Tomography: A Cross-Sectional Study.

The aim of the present study was to assess the positive predictive value (PPV) of panoramic radiographic signs in the assessment of the relationship between impacted mandibular third molars (IMTMs) and the mandibular canal (MC). This cross-sectional study was conducted by reviewing 102 cone-beam computed tomography (CBCT) and panoramic radiographs of patients with IMTMs and radiographic signs of the contact of the IMTMs with the MC on panoramic radiographs (i.e., root apex darkening and interference with the white line). A positive relationship of the IMTM roots with the MC based on CBCT findings was recorded as the gold standard. The PPV of panoramic radiographic signs was calculated for the detection of the relationship of the IMTM root with the MC. The IMTMs were in contact with the MC on CBCT scans in 90.1% of the cases. The PPV of root apex darkening and the interference with the white line was found to be 89.09% (95% CI: (77.75, 95.88)) and 91.48% (95% CI: (79.62, 97.63)), respectively. The MC had a buccal position in 63.7%, and a lingual position in 35.2%, of the cases. The contact of IMTMs with the MC was more commonly seen in patients with a lingual position (100% of the samples). The IMTM root apex darkening and interference with the white line of the MC on panoramic radiographs had a high PPV for determination of the contact of IMTMs with the MC. Thus, presence of the above-mentioned risk factors indicates the need for subsequent 3D radiographic assessments.

MiRNAs Correlate with HLA Expression in Uveal Melanoma: Both Up- and Downregulation Are Related to Monosomy 3.

MicroRNAs are known to play a role in the regulation of inflammation. As a high HLA Class I expression is associated with a bad prognosis in UM, we set out to determine whether any miRNAs were related to a high HLA Class I expression and inflammation. We also determined whether such miRNAs were related to the UM's genetic status. The expression of 125 miRNAs was determined in 64 primary UM from Leiden. Similarly, the mRNA expression of HLA-A, HLA-B, TAP1, BAP1, and immune cell markers was obtained. Expression levels of 24 of the 125 miRNAs correlated with expression of at least three out of four HLA Class I probes. Four miRNAs showed a positive correlation with HLA expression and infiltration with leukocytes, 20 a negative pattern. In the first group, high miRNA levels correlated with chromosome 3 loss/reduced BAP1 mRNA expression, in the second group low miRNA levels. The positive associations between miRNA-22 and miRNA-155 with HLA Class I were confirmed in the TCGA study and Rotterdam cohort, and with TAP1 in the Rotterdam data set; the negative associations between miRNA-125b2 and miRNA-211 and HLA-A, TAP1, and CD4 were confirmed in the Rotterdam set. We demonstrate two patterns: miRNAs can either be related to a high or a low HLA Class I/TAP1 expression and the presence of infiltrating lymphocytes and macrophages. However, both patterns were associated with chromosome 3/BAP1 status, which suggests a role for BAP1 loss in the regulation of HLA expression and inflammation in UM through miRNAs.

Expression of HDACs 1, 3 and 8 Is Upregulated in the Presence of Infiltrating Lymphocytes in Uveal Melanoma.

In Uveal Melanoma (UM), an inflammatory phenotype is strongly associated with the development of metastases and with chromosome 3/BAP1 expression loss. As an increased expression of several Histone Deacetylases (HDACs) was associated with loss of chromosome 3, this suggested that HDAC expression might also be related to inflammation. We analyzed HDAC expression and the presence of leukocytes by mRNA expression in two sets of UM (Leiden and TCGA) and determined the T lymphocyte fraction through ddPCR. Four UM cell lines were treated with IFNγ (50IU, 200IU). Quantitative PCR (qPCR) was used for mRNA measurement of HDACs in cultured cells. In both cohorts (Leiden and TCGA), a positive correlation occurred between expression of HDACs 1, 3 and 8 and the presence of a T-cell infiltrate, while expression of HDACs 2 and 11 was negatively correlated with the presence of tumor-infiltrating macrophages. Stimulation of UM cell lines with IFNγ induced an increase in HDACs 1, 4, 5, 7 and 8 in two out of four UM cell lines. We conclude that the observed positive correlations between HDAC expression and chromosome 3/BAP1 loss may be related to the presence of infiltrating T cells.

LAG3 and Its Ligands Show Increased Expression in High-Risk Uveal Melanoma.

Uveal melanoma (UM) is a rare ocular malignancy which originates in the uveal tract, and often gives rise to metastases. Potential targets for immune checkpoint inhibition are lymphocyte-activation gene 3 (LAG3) and its ligands. We set out to analyse the distribution of these molecules in UM. The expression of mRNA was determined using an Illumina array in 64 primary UM from Leiden. The T lymphocyte fraction was determined by digital droplet PCR. In a second cohort of 15 cases from Leiden, mRNA expression was studied by Fluidigm qPCR, while a third cohort consisted of 80 UM from TCGA. In the first Leiden cohort, LAG3 expression was associated with the presence of epithelioid cells (p = 0.002), monosomy of chromosome 3 (p = 0.004), and loss of BAP1 staining (p = 0.001). In this Leiden cohort as well as in the TCGA cohort, LAG3 expression correlated positively with the expression of its ligands: LSECtin, Galectin-3, and the HLA class II molecules HLA-DR, HLA-DQ, and HLA-DP (all p < 0.001). Furthermore, ligands Galectin-3 and HLA class II were increased in monosomy 3 tumours and the expression of LAG3 correlated with the presence of an inflammatory phenotype (T cell fraction, macrophages, HLA-A and HLA-B expression: all p < 0.001). High expression levels of LAG3 (p = 0.01), Galectin-3 (p = 0.001), HLA-DRA1 (p = 0.002), HLA-DQA1 (p = 0.04), HLA-DQB2 (p = 0.03), and HLA-DPA1 (p = 0.007) were associated with bad survival. We conclude that expression of the LAG ligands Galectin-3 and HLA class II strongly correlates with LAG3 expression and all are increased in UM with Monosomy 3/BAP1 loss. The distribution suggests a potential benefit of monoclonal antibodies against LAG3 or Galectin-3 as adjuvant treatment in patients with high-risk UM.

Nitric oxide improves tolerance to arsenic stress in Isatis cappadocica desv. Shoots by enhancing antioxidant defenses.

Arsenic (As) is a toxic metalloid that severely hampers plant growth and also poses health risks for humans through the food chain. Although nitric oxide (NO) is known to improve plant resistance to multiple stresses including metal toxicity, little is known about its role in the As tolerance of hyperaccumulator plants. This study investigates the role of the exogenously applied NO donor, sodium nitroprusside (SNP), in improving the As tolerance of Isatis cappadocica, which has been reported to hyperaccumulate As. Exposure to toxic As concentrations significantly increases NO production and damages the cell membrane, as indicated by increased hydrogen peroxide (H2O2) and malondialdehyde (MDA) concentrations, thereby reducing plant growth. However, the addition of SNP improves growth and alleviates As-induced oxidative stress by enhancing the activity of superoxide dismutase (SOD), ascorbate peroxidase (APX), glutathione reductase (GR), glutathione S-transferase (GST), glutathione (GSH), as well as proline and thiol concentrations, thereby confirming the beneficial role played by NO in increasing As stress tolerance. Furthermore, the As-induced decrease in growth and the increase in oxidative stress were more marked in the presence of bovine hemoglobin (Hb; a NO scavenger) and N(G)-nitro-l-arginine methyl ester (l-NAME; a NO synthase inhibitor), thus demonstrating the protective role of NO against As toxicity. The reduction in NO concentrations by l-NAME suggests that NOS-like activity is involved in the generation of NO in response to As in I. cappadocica.

HDAC Inhibition Increases HLA Class I Expression in Uveal Melanoma.

The treatment of uveal melanoma (UM) metastases or adjuvant treatment may imply immunological approaches or chemotherapy. It is to date unknown how epigenetic modifiers affect the expression of immunologically relevant targets, such as the HLA Class I antigens, in UM. We investigated the expression of HDACs and the histone methyl transferase EZH2 in a set of 64 UMs, using an Illumina HT12V4 array, and determined whether a histone deacetylase (HDAC) inhibitor and EZH2 inhibitor modified the expression of HLA Class I on three UM cell lines. Several HDACs (HDAC1, HDAC3, HDAC4, and HDAC8) showed an increased expression in high-risk UM, and were correlated with an increased HLA expression. HDAC11 had the opposite expression pattern. While in vitro tests showed that Tazemetostat did not influence cell growth, Quisinostat decreased cell survival. In the three tested cell lines, Quisinostat increased HLA Class I expression at the protein and mRNA level, while Tazemetostat did not have an effect on the cell surface HLA Class I levels. Combination therapy mostly followed the Quisinostat results. Our findings indicate that epigenetic drugs (in this case an HDAC inhibitor) may influence the expression of immunologically relevant cell surface molecules in UM, demonstrating that these drugs potentially influence immunotherapy.

The role of selenium on mitigating arsenic accumulation, enhancing growth and antioxidant responses in metallicolous and non-metallicolous population of Isatis cappadocica Desv. and Brassica oleracea L.

A hydroponic experiment was conducted to explore the interactive effects of selenium (Se) supplementation (0, 5, and 10 µM) and arsenic (As) toxicity (0, 200, and 400 µM) on the growth, accumulation, and oxidative damage along with defense mechanisms of metallicolous (MP) and non-metallicolous population (NMP) of Isatis cappadocica, an As-hyperaccumulator, and Brassica oleracea as reference brassica. The results revealed that As stress significantly hampered plant growth particularly in B. oleracea. It reduced plant growth due to enhanced oxidative load of As-stressed plants. Between the two Isatis populations, metallicolous plants accumulated significantly higher As, however with considerably low growth defects. Furthermore, Se supplementation counteracted the adverse effects of stress on growth and physiological performance of all studied plants. Addition of Se, particularly at higher dose (10 µM), significantly suppressed root As uptake and slightly its accumulation in shoots of B. oleracea plants treated with 400 µM As, and thus improved growth characteristics of stressed plants. Under As stress, Se supplementation increased the activities of enzymatic (peroxidase (POD) and glutathione reductase (GR)) and non-enzymatic (anthocyanins and total flavonoids) antioxidants, thereby suggesting relieved As stress by reduced oxidative damage. Taken together, these results support the beneficial role of Se in the regulation of As stress by improving growth, physiology, and antioxidant capacity, and highlight its significance for plants grown on such metal-contaminated soils.

HLA Expression in Uveal Melanoma: An Indicator of Malignancy and a Modifiable Immunological Target.

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults, and gives rise to metastases in 50% of cases. The presence of an inflammatory phenotype is a well-known risk factor for the development of metastases. This inflammatory phenotype is characterized by the presence of high numbers of lymphocytes and macrophages, and a high expression of the HLA Class I and II antigens. An abnormal expression of HLA Class I may influence cytotoxic T lymphocyte (CTL) as well as Natural Killer (NK) cell responses. We provide a comprehensive review regarding the inflammatory phenotype in UM and the expression of locus- and allele-specific HLA Class I and of Class II antigens in primary UM and its metastases. Furthermore, we describe the known regulators and the role of genetics (especially chromosome 3 and BRCA-Associated Protein 1 (BAP1 status)), and, last but not least, the effect of putative therapeutic treatments on HLA expression.

Acquiring control: The evolution of ROS-Induced oxidative stress and redox signaling pathways in plant stress responses.

Reactive oxygen species (ROS) - the byproducts of aerobic metabolism - influence numerous aspects of the plant life cycle and environmental response mechanisms. In plants, ROS act like a double-edged sword; they play multiple beneficial roles at low concentrations, whereas at high concentrations ROS and related redox-active compounds cause cellular damage through oxidative stress. To examine the dual role of ROS as harmful oxidants and/or crucial cellular signals, this review elaborates that (i) how plants sense and respond to ROS in various subcellular organelles and (ii) the dynamics of subsequent ROS-induced signaling processes. The recent understanding of crosstalk between various cellular compartments in mediating their redox state spatially and temporally is discussed. Emphasis on the beneficial effects of ROS in maintaining cellular energy homeostasis, regulating diverse cellular functions, and activating acclimation responses in plants exposed to abiotic and biotic stresses are described. The comprehensive view of cellular ROS dynamics covering the breadth and versatility of ROS will contribute to understanding the complexity of apparently contradictory ROS roles in plant physiological responses in less than optimum environments.

Loss of BAP1 Is Associated with Upregulation of the NFkB Pathway and Increased HLA Class I Expression in Uveal Melanoma.

One of the characteristics of prognostically infaust uveal melanoma (UM) is an inflammatory phenotype, which is characterized by high numbers of infiltrating T cells and macrophages, and a high HLA Class I expression. We wondered how this inflammation is regulated, and considered that one of the most important regulators of inflammation, the NFkB pathway, might play a role. We analyzed 64 UM samples for expression of HLA Class I, its regulators, and of members of the NFkB transcription family, using an Illumina HT12V4 array. HLA Class I expression and infiltrating immune cells were also determined by immunohistochemical staining. Information was obtained regarding chromosome status by Affymetrix Nsp array. Our analysis shows that expression of NFkB1, NFkB2 and RELB positively correlates with the level of HLA Class I expression and the number of infiltrating T cells and macrophages, while SPP1 and PPARγ are negatively correlated. Increased levels of NFkB1 and NFkB2 and decreased levels of SPP1 and PPARγ are seen in Monosomy 3/BAP1-negative tumors. This is also the case in non-inflammatory UM, indicating that our observation not only involves infiltrating leukocytes but the tumor cells themselves. We report that the NFkB pathway is associated with inflammation and HLA Class I expression in UM, and is upregulated when BAP1 expression is lost.