Primary Mediastinal Gray Zone Lymphoma in an Immunocompetent Young Adult.

A 28 -year-old man presented to our hospital with a rapidly growing nodule in the left cervical and bilateral axilla with a history of loss of weight. He has been experiencing a nodule in her right cervical since two years ago and had done FNAC and diagnosed extrapulmonary tuberculosis (EPTB), on Examination at left cervical colli; mass size 9cm x 7 cm, mobile, Lymphadenopathy at pre auricular size 3cm x 3cm, lymphadenopathy supraclavicular size 1cm x 0,5 cm. bilateral lymphadenopathy Axila size 4cmx 4cmx 2xcm mobile. The other physical exam was normal. Laboratory test Hb 10,4 d/dL, WBC 14.250/ mm3, LED 78 mm/hours, D-dimer 1,81 ug/mL, Fibrinogen 452 mg/dL. HIV test non-reactive. HbsAg and HCV test negative. CT-Scan Thorax: Enlarged Anterior mediastinal Lymph node with a diameter 0f 2.9 cm, right paratracheal with a diameter of 1,2cm and 1,1 cm, and right perihilar with a diameter of 1,3 cm. and the left perihilar diameter 0,9. And hypodense lesion of the spleen measuring 2,3cm x 1,6 cm. The patient underwent a biopsy with pathology biopsy and immunohistochemistry (IHC), CD 20+. CD 3-, CD 30+ CD79a +, MUM1 +, Ki67 80-90% +, CD15-, BCL6+ and BCL 2+. For this patient, we started an R-CHOP regimen (Rituximab 375 mg/m2 (d1), Cyclophopamid 750 mg/m2 (d1), Doxorubicin 50 mg/m2 (d1), Vincristine1,2 mg/m2 (d1) and 1 Prednisone 100 mg (d1-d5). We presented the patient with PMGZL has achieved a complete response, especially with chemotherapy R-CHOP regimens.

NFATc1 releases BCL6-dependent repression of CCR2 agonist expression in peritoneal macrophages from Saccharomyces cerevisiae infected mice.

The link between the extensive usage of calcineurin (CN) inhibitors cyclosporin A and tacrolimus (FK506) in transplantation medicine and the increasing rate of opportunistic infections within this segment of patients is alarming. Currently, how peritoneal infections are favored by these drugs, which impair the activity of several signaling pathways including the Ca(++) /CN/NFAT, Ca(++) /CN/cofilin, Ca(++) /CN/BAD, and NF-κB networks, is unknown. Here, we show that Saccharomyces cerevisiae infection of peritoneal resident macrophages triggers the transient nuclear translocation of NFATc1ß isoforms, resulting in a coordinated, CN-dependent induction of the Ccl2, Ccl7, and Ccl12 genes, all encoding CCR2 agonists. CN inhibitors block the CCR2-dependent recruitment of inflammatory monocytes (IM) to the peritoneal cavities of S. cerevisiae infected mice. In myeloid cells, NFATc1/ß proteins represent the most prominent NFATc1 isoforms. NFATc1/ß ablation leads to a decrease of CCR2 chemokines, impaired mobilization of IMs, and delayed clearance of infection. We show that, upon binding to a composite NFAT/BCL6 regulatory element within the Ccl2 promoter, NFATc1/ß proteins release the BCL6-dependent repression of Ccl2 gene in macrophages. These findings suggest a novel CN-dependent cross-talk between NFAT and BCL6 transcription factors, which may affect the outcome of opportunistic fungal infections in immunocompromised patients.

NF-κB factors control the induction of NFATc1 in B lymphocytes.

In peripheral lymphocytes, the transcription factors (TFs) NF-κB, NFAT, and AP-1 are the prime targets of signals that emerge from immune receptors. Upon activation, these TFs induce gene networks that orchestrate the growth, expansion, and effector function of peripheral lymphocytes. NFAT and NF-κB factors share several properties, such as a similar mode of induction and architecture in their DNA-binding domain, and there is a subgroup of κB-like DNA promoter motifs that are bound by both types of TFs. However, unlike NFAT and AP-1 factors that interact and collaborate in binding to DNA, NFAT, and NF-κB seem neither to interact nor to collaborate. We show here that NF-κB1/p50 and c-Rel, the most prominent NF-κB proteins in BCR-induced splenic B cells, control the induction of NFATc1/αA, a prominent short NFATc1 isoform. In part, this is mediated through two composite κB/NFAT-binding sites in the inducible Nfatc1 P1 promoter that directs the induction of NFATc1/αA by BCR signals. In concert with coreceptor signals that induce NF-κB factors, BCR signaling induces a persistent generation of NFATc1/αA. These data suggest a tight connection between NFATc1 and NF-κB induction in B lymphocytes contributing to the effector function of peripheral B cells.

Characterization of the prostate cancer susceptibility gene KLF6 in human and mouse prostate cancers.

BACKGROUND: Krüppel-like factor (KLF) 6 is a candidate tumor suppressor gene in prostate cancer, but the mechanisms contributing to its loss of expression are poorly understood. We characterized KLF6 expression and DNA methylation status during prostate tumorigenesis in humans and mice. METHODS: KLF6 expression was assessed in matched human non-malignant (NM) and tumor prostate tissues (n = 22) by quantitative real-time PCR (qPCR) and in three independent human prostate cancer cohorts bioinformatically. QPCR for KLF6 expression and methylation-sensitive PCR (MSP) were performed in human prostate LNCaP cancer cells after 5-aza-2'-deoxycytidine treatment. Klf6 protein levels and DNA promoter methylation were assessed in TRansgenic Adenocarcinoma of Mouse Prostate (TRAMP) tumors by immunohistochemistry and MSP, respectively. RESULTS: KLF6 splice variants expression was increased (P = 0.0015) in human prostate tumors compared to NM tissues. Overall, KLF6 was decreased in metastatic compared to primary prostate cancers and reduced expression in primary tumors was associated with a shorter time to relapse (P = 0.0028). Treatment with the demethylating agent 5-aza-2'-deoxycytidine resulted in up-regulation of KLF6 expression (two-fold; P = 0.002) and a decrease in DNA methylation of the KLF6 promoter in LNCaP cells. Klf6 protein levels significantly decreased with progression in the TRAMP model of prostate cancer (P < 0.05), but there was no difference in Klf6 promoter methylation. CONCLUSION: KLF6 expression was decreased in both clinical prostate cancer and the TRAMP model with disease progression, but this could not be explained by DNA methylation of the KLF6 promoter.

The role of gut microbiota on cognitive development in rodents: a meta-analysis.

Cognitive function includes learning, remembering and using acquired information. Emerging studies indicate the correlation between microbiota and cognitive function. Higher abundance of a specific gut microbiota, such as Bacteroidetes may improve cognitive abilities. However, another study reported different result. These results suggest that further systematic analysis is required to determine the effect of the gut microbiota abundance on cognitive development. The aim of this study is to summarize the abundance of the specific gut microbiota and cognitive development using meta-analysis. PubMed, ScienceDirect, and Clinical-Key were used as data bases to perform the literature search. Phylum Bacteroidetes, and family Lactobacillaceae were more abundant in cognitive-behavioral enhancement (CBE), whereas Firmicutes, Proteobacteria, Actinobacteria, and family Ruminococcaceae were less abundant in CBE. Differences in gut microbiota abundance are influenced by differences in stage of cognitive dysfunction, intervention, and strain of gut microbiota.

Association of vitamin D with deoxyribonucleic acid (dna) damage: A systematic review of animal and human studies.

Vitamin D has anti-proliferative, anti-inflammatory, and apoptotic abilities. Vitamin D deficiency can induce deoxyribonucleic acid (DNA) damage. The aim of the study was to create a systematic review to analyze the relationship between vitamin D and DNA damage in various populations. PubMed, Scopus, EbscoHost, Google Scholar, and Epistemonikos were used to identify literature regarding the relationship between vitamin D and DNA damage. Assessment of study quality was carried out by three independent reviewers individually. A total of 25 studies were assessed as eligible and included in our study. Twelve studies were conducted in humans consisting of two studies with experimental design and ten studies with observational pattern. Meanwhile, thirteen studies were conducted in animals (in vivo). It is found that the majority of studies demonstrated that vitamin D prevents DNA damage and minimizes the impact of DNA damage that has occurred (p<0.05). However, two studies (8%) did not find such an association and one research only found a specific association in the cord blood, not in maternal blood. Vitamin D has a protective effect against DNA damage. A diet rich in vitamin D and vitamin D supplementation is recommended to prevent DNA damage.

Calcineurin-independent NFATc1 signaling is essential for survival of Burkitt lymphoma cells.

In Burkitt lymphoma (BL), a tumor of germinal center B cells, the pro-apoptotic properties of MYC are controlled by tonic B cell receptor (BCR) signals. Since BL cells do not exhibit constitutive NF-κB activity, we hypothesized that anti-apoptotic NFATc1 proteins provide a major transcriptional survival signal in BL. Here we show that post-transcriptional mechanisms are responsible for the calcineurin (CN) independent constitutive nuclear over-expression of NFATc1 in BL and Eµ-MYC - induced B cell lymphomas (BCL). Conditional inactivation of the Nfatc1 gene in B cells of Eµ-MYC mice leads to apoptosis of BCL cells in vivo and ex vivo. Inhibition of BCR/SYK/BTK/PI3K signals in BL cells results in cytosolic re-location of NFATc1 and apoptosis. Therefore, NFATc1 activity is an integrated part of tonic BCR signaling and an alternative target for therapeutic intervention in BL.

Waste anesthetic gases have a significant association with deoxyribonucleic acid (DNA) damage: A systematic review and meta-analysis of 2,732 participants.

Introduction: Operating room workers are at risk of experiencing adverse effects due to occupational exposure to waste anesthetic gases (WAGs). One of the consequences of long-term WAGs exposure is the probability of developing deoxyribonucleic acid (DNA) damage. This systematic review investigated the link between WAGs and DNA damage in operating room workers. Methods: PubMed, Science Direct, ProQuest, Scopus, and EbscoHost, as well as hand-searching, were used to find literature on the relationship between WAGs and DNA damage. Three independent reviewers independently assessed the study's quality. Meta-analysis was conducted for several DNA damage indicators, such as comet assay (DNA damage score, tail's length, tail's DNA percentage), micronuclei formation, and total chromosomal aberration. Results: This systematic review included 29 eligible studies (2732 participants). The majority of the studies used a cross-sectional design. From our meta-analysis, which compared the extent of DNA damage in operating room workers to the unexposed group, operating room workers exposed to WAGs had a significantly higher DNA damage indicator, including DNA damage score, comet tail's length, comet tail's DNA percentage, micronuclei formation, and total chromosomal aberration (p < 0.05) than non-exposed group. Conclusion: Waste anesthetic gases have been found to significantly impact DNA damage indicators in operating room personnel, including comet assay, micronuclei development, and chromosomal aberration. To reduce the impact of exposure, hospital and operating room personnel should take preventive measures, such as by adapting scavenger method.

Discovery of circulating microRNAs associated with human prostate cancer using a mouse model of disease.

Circulating microRNAs (miRNAs) are emerging as useful non-invasive markers of disease. The objective of this study was to use a mouse model of prostate cancer as a tool to discover serum miRNAs that could be assessed in a clinical setting. Global miRNA profiling identified 46 miRNAs at significantly altered levels (p ≤ 0.05) in the serum of TRansgenic Adenocarcinoma of Mouse Prostate (TRAMP) mice with advanced prostate cancer compared to healthy controls. A subset of these miRNAs with known human homologues were validated in an independent cohort of mice and then measured in serum from men with metastatic castration-resistant prostate cancer (mCRPC; n = 25) or healthy men (n = 25). Four miRNAs altered in mice, mmu-miR-141, mmu-miR-298, mmu-miR-346 and mmu-miR-375, were also found to be at differential levels in the serum of men with mCRPC. Three of these (hsa-miR-141, hsa-miR-298 and hsa-miR-375) were upregulated in prostate tumors compared with normal prostate tissue, suggesting that they are released into the blood as disease progresses. Moreover, the intra-tumoral expression of hsa-miR-141 and hsa-miR-375 were predictors of biochemical relapse after surgery. This study is the first to demonstrate that specific serum miRNAs are common between human prostate cancer and a mouse model of the disease, highlighting the potential of such models for the discovery of novel biomarkers.

A systematic review on neutrophil extracellular traps and its prognostication role in COVID-19 patients.

Neutrophil extracellular traps (NETs) are extracellular webs composed of neutrophil granular and nuclear elements. Because of the potentially dangerous amplification circuit between inflammation and tissue damage, NETs are becoming one of the investigated components in the current Coronavirus Disease 2019 (COVID-19) pandemic. The purpose of this systematic review is to summarize studies on the role of NETs in determining the prognosis of COVID-19 patients. The study used six databases: PubMed, Science Direct, EBSCOHost, Europe PMC, ProQuest, and Scopus. This literature search was implemented until October 31, 2021. The search terms were determined specifically for each databases, generally included the Neutrophil Extracellular Traps, COVID-19, and prognosis. The Newcastle Ottawa Scale (NOS) was then used to assess the risk of bias. Ten studies with a total of 810 participants were chosen based on the attainment of the prerequisite. Two were of high quality, seven were of moderate quality, and the rest were of low quality. The majority of studies compared COVID-19 to healthy control. Thrombosis was observed in three studies, while four studies recorded the need for mechanical ventilation. In COVID-19 patients, the early NETs concentration or the evolving NETs degradations can predict patient mortality. Based on their interactions with inflammatory and organ dysfunction markers, it is concluded that NETs play a significant role in navigating the severity of COVID-19 patients and thus impacting their prognosis.

The effect of ketogenic diets on neurogenesis and apoptosis in the dentate gyrus of the male rat hippocampus.

Ketogenic diets (KD) have become popular diet to lose weight. However, the effect of such diets on brain function has not yet been clarified. Thus, we aimed to study the effects of KD on the neurogenesis and apoptosis in the dentate gyrus by assessing the expression of Ki-67 and Caspase-3. Rats (n = 24) were divided into four groups: control (normal diet), ketogenic diet (KD), time-restricted diet (TRD), and the combination of high-fat and time-restricted diet (CD) groups. The expression of Ki-67 in the TRD and CD groups was higher compared to others (P < 0.05), whereas no such difference was observed in the KD group. The number of Capase-3-positive cells decreased significantly in the TRD group (P < 0.05), but such decrease was not observed in the CD group. These results indicate that, although KD could be effective in reducing the body weight, possible adverse effect in the brain cannot be ignored.

NFATc1 is Suppressed in Tumor Microenvironment of Hodgkin Lymphoma.

OBJECTIVE: The aims of this research are to evaluate the expression and distribution of NFATc1 in tumor microenvironment of Hodgkin lymphoma. METHODS: Twenty-eight cases of Hodgkin lymphoma were selected. Clinicopathological data of age, gender, location and subtypes were obtained. Immunohistochemistry was performed to the all cases by using anti-CD163, anti-NFATc1 and anti-PD-L1 antibodies. All protein expression was calculated by using Image J software. RESULTS: Nuclear expression of NFATc1 was not observed in Hodgkin cells neither in TAM nor in small lymphocytes surrounding Hodgkin cells in all the samples, this meant that NFATc1 showed negative nuclear expression in almost all these cells. Cytoplasmic expression of NFATc1 was observed in small lymphocytes surrounding tumor cells. While there were only few small lymphocytes which were located far from tumor cells showed nuclear expression of NFATc1. Meanwhile, 57.14% samples showed high density of TAMs CD163+, and 50% tumor cells as well as 50% TAMs exhibited positive PD-L1 expression. In addition, all macrophages did not have NFATc1 expression both in their nuclei and in their cytoplasm. CONCLUSION: NFATc1 was suppressed both in Hodgkin cells and inflammatory cells surrounding the tumor cells. This condition may contribute to progressivity and aggressiveness of the diseases. Therefore, certain mechanisms to reactivate functional NFATc1 in HL tumor microenvironment may be necessary; hence, the tumor cells are able to be eradicated by patient's immune mechanisms.

NFAT5 Controls the Integrity of Epidermis.

The skin protects the human body against dehydration and harmful challenges. Keratinocytes (KCs) are the most abundant epidermal cells, and it is anticipated that KC-mediated transport of Na+ ions creates a physiological barrier of high osmolality against the external environment. Here, we studied the role of NFAT5, a transcription factor whose activity is controlled by osmotic stress in KCs. Cultured KCs from adult mice were found to secrete more than 300 proteins, and upon NFAT5 ablation, the secretion of several matrix proteinases, including metalloproteinase-3 (Mmp3) and kallikrein-related peptidase 7 (Klk7), was markedly enhanced. An increase in Mmp3 and Klk7 RNA levels was also detected in transcriptomes of Nfat5-/- KCs, along with increases of numerous members of the 'Epidermal Differentiation Complex' (EDC), such as small proline-rich (Sprr) and S100 proteins. NFAT5 and Mmp3 as well as NFAT5 and Klk7 are co-expressed in the basal KCs of fetal and adult epidermis but not in basal KCs of newborn (NB) mice. The poor NFAT5 expression in NB KCs is correlated with a strong increase in Mmp3 and Klk7 expression in KCs of NB mice. These data suggests that, along with the fragile epidermis of adult Nfat5-/- mice, NFAT5 keeps in check the expression of matrix proteases in epidermis. The NFAT5-mediated control of matrix proteases in epidermis contributes to the manifold changes in skin development in embryos before and during birth, and to the integrity of epidermis in adults.

T Cells Control Chemokine Secretion by Keratinocytes.

The massive infiltration of lymphocytes into the skin is a hallmark of numerous human skin disorders. By co-culturing murine keratinocytes with splenic T cells we demonstrate here that T cells affect and control the synthesis and secretion of chemokines by keratinocytes. While pre-activated CD8+T cells induce the synthesis of CXCL9 and CXCL10 in keratinocytes and keep in check the synthesis of CXCL1, CXCL5, and CCL20, keratinocytes dampen the synthesis of CCL3 and CCL4 in pre-activated CD8+T cells. One key molecule is IFN-γ that is synthesized by CD8+T cells under the control of NFATc1 and NFATc2. CD8+T cells deficient for both NFAT factors are unable to induce CXCL9 and CXCL10 expression. In addition, CD8+T cells induced numerous type I IFN-inducible "defense genes" in keratinocytes encoding the PD1 and CD40 ligands, TNF-α and caspase-1. The enhanced expression of type I IFN-inducible genes resembles the gene expression pattern at the dermal/epidermal interface in lichen planus, an inflammatory T lymphocyte-driven skin disease, in which we detected the expression of CXCL10 in keratinocytes in close vicinity to the infiltration front of T cells. These data reflect the multifaceted interplay of lymphocytes with keratinocytes at the molecular level.

The Transcription Factor NFATc1 Supports the Rejection of Heterotopic Heart Allografts.

The immune suppressants cyclosporin A (CsA) and tacrolimus (FK506) are used worldwide in transplantation medicine to suppress graft rejection. Both CsA and FK506 inhibit the phosphatase calcineurin (CN) whose activity controls the immune receptor-mediated activation of lymphocytes. Downstream targets of CN in lymphocytes are the nuclear factors of activated T cells (NFATs). We show here that the activity of NFATc1, the most prominent NFAT factor in activated lymphocytes supports the acute rejection of heterotopic heart allografts. While ablation of NFATc1 in T cells prevented graft rejection, ectopic expression of inducible NFATc1/αA isoform led to rejection of heart allografts in recipient mice. Acceptance of transplanted hearts in mice bearing NFATc1-deficient T cells was accompanied by a reduction in number and cytotoxicity of graft infiltrating cells. In CD8+ T cells, NFATc1 controls numerous intracellular signaling pathways that lead to the metabolic switch to aerobic glycolysis and the expression of numerous lymphokines, chemokines, and their receptors, including Cxcr3 that supports the rejection of allogeneic heart transplants. These findings favors NFATc1 as a molecular target for the development of new strategies to control the cytotoxicity of T cells upon organ transplantation.