Boesenbergia stenophylla-Derived Stenophyllol B Exerts Antiproliferative and Oxidative Stress Responses in Triple-Negative Breast Cancer Cells with Few Side Effects in Normal Cells.

Triple-negative breast cancer (TNBC) is insensitive to target therapy for non-TNBC and needs novel drug discovery. Extracts of the traditional herb Boesenbergia plant in Southern Asia exhibit anticancer effects and contain novel bioactive compounds but merely show cytotoxicity. We recently isolated a new compound from B. stenophylla, stenophyllol B (StenB), but the impact and mechanism of its proliferation-modulating function on TNBC cells remain uninvestigated. This study aimed to assess the antiproliferative responses of StenB in TNBC cells and examine the drug safety in normal cells. StenB effectively suppressed the proliferation of TNBC cells rather than normal cells in terms of an ATP assay. This preferential antiproliferative function was alleviated by pretreating inhibitors for oxidative stress (N-acetylcysteine (NAC)) and apoptosis (Z-VAD-FMK). Accordingly, the oxidative-stress-related mechanisms were further assessed. StenB caused subG1 and G2/M accumulation but reduced the G1 phase in TNBC cells, while normal cells remained unchanged between the control and StenB treatments. The apoptosis behavior of TNBC cells was suppressed by StenB, whereas that of normal cells was not suppressed according to an annexin V assay. StenB-modulated apoptosis signaling, such as for caspases 3, 8, and 9, was more significantly activated in TNBC than in normal cells. StenB also caused oxidative stress in TNBC cells but not in normal cells according to a flow cytometry assay monitoring reactive oxygen species, mitochondrial superoxide, and their membrane potential. StenB induced greater DNA damage responses (γH2AX and 8-hydroxy-2-deoxyguanosine) in TNBC than in normal cells. All these StenB responses were alleviated by NAC pretreatment. Collectively, StenB modulated oxidative stress responses, leading to the antiproliferation of TNBC cells with little cytotoxicity in normal cells.

HSPA5 Promotes the Proliferation, Metastasis and Regulates Ferroptosis of Bladder Cancer.

Heat shock protein family A (HSP70) member 5 (HSPA5) is aberrantly expressed in various tumors and closely associated with the progression and prognosis of cancer. Nevertheless, its role in bladder cancer (BCa) remains elusive. The results of our study demonstrated that HSPA5 was upregulated in BCa and correlated with patient prognosis. Cell lines with low expression level of HSPA5 were constructed to explore the role of this protein in BCa. HSPA5 knockdown promoted apoptosis and retarded the proliferation, migration and invasion of BCa cells by regulating the VEGFA/VEGFR2 signaling pathway. In addition, overexpression of VEGFA alleviated the negative effect of HSPA5 downregulation. Moreover, we found that HSPA5 could inhibit the process of ferroptosis through the P53/SLC7A11/GPX4 pathway. Hence, HSPA5 can facilitate the progression of BCa and may be used as a novel biomarker and latent therapeutic target in the clinic.

Zinc aspartate induces proliferation of resting and antigen-stimulated human PBMC under high-density cell culture condition.

BACKGROUND: Zinc, one of the most important essential trace elements in the human body, regulates a wide range of cellular functions of immune cells, such as proliferation, differentiation and survival. Zinc deficiency affects both the innate and adaptive immune system. Zinc supplementation was discussed as possible therapy for infectious diseases and T cell-mediated autoimmune diseases. However, the influence of commercial zinc preparations on proliferation and cytokine production of resting and antigen-stimulated peripheral blood mononuclear cells (PBMC) has not yet been completely investigated. METHODS: Here, we examined whether zinc aspartate (Unizink®), an approved drug to treat zinc deficiency in patients, induces proliferation, cytokine production, and induction of apoptosis/caspase 3/7 activity of resting PBMC under high-density cell culture condition. In addition, we performed antigen-specific proliferation experiments, where PBMCs of healthy donors vaccinated against Influenza A (H1N1) and/or SARS-CoV-2 were stimulated with Influenza A (H1N1) peptides or SARS-CoV-2 peptides as well as the Mixed Lymphocyte Culture (MLC) in the presence of increasing concentrations of zinc aspartate. RESULTS: We observed a dose-dependent enhancement of proliferation and induction of cytokine production (IFN-γ, IL-5, GM-CSF and CXCL10) of resting PBMC in presence of zinc aspartate. The number of cells with active caspase 3/7 and, consecutively, the amount of cells undergoing apoptosis steadily decreased in presence of zinc aspartate. Moreover, zinc aspartate was capable of stimulating antigen-specific PBMC proliferation using MLC or influenza A (H1N1) and SARS-CoV-2 peptides in both a dose-dependent and a donor-specific manner. In the absence of zinc aspartate, we clearly could discriminate two groups of responders: low and high responders to antigenic stimulation. The addition of increasing concentration of zinc aspartate significantly stimulated the proliferation of PBMC from low responders, but not from high responders. CONCLUSION: Taken together, our results suggest that zinc aspartate induces the proliferation of resting and antigen-stimulated PBMCs under high-density cell culture conditions. Thus, zinc might represent a supportive treatment in patients suffering from infectious diseases.

The Phytochemical α-Mangostin Inhibits Cervical Cancer Cell Proliferation and Tumor Growth by Downregulating E6/E7-HPV Oncogenes and KCNH1 Gene Expression.

Cervical cancer is the fourth most common cancer among women worldwide. The main factor associated with the onset and progression of this neoplasia is the human papillomavirus (HPV) infection. The HPV-oncogenes E6 and E7 are critical drivers of cellular transformation, promoting the expression of oncogenes such as KCNH1. The phytochemical α-mangostin (AM) is a potent antineoplastic and antiviral compound. However, its effects on HPV oncogenes and KCNH1 gene expression remain unknown. This study evaluated the effects of AM on cell proliferation, cell cycle distribution and gene expression, including its effects on tumor growth in xenografted mice. AM inhibited cell proliferation in a concentration-dependent manner, being the most sensitive cell lines those with the highest number of HPV16 copies. In addition, AM promoted G1-cell cycle arrest in CaSki cells, while led to cell death in SiHa and HeLa cells. Of interest was the finding of an AM-dependent decreased gene expression of E6, E7 and KCNH1 both in vitro and in vivo, as well as the modulation of cytokine expression, Ki-67, and tumor growth inhibition. On these bases, we suggest that AM represents a good option as an adjuvant for the treatment and prevention of cervical cancer.

Downregulation of MALAT1 is a hallmark of tissue and peripheral proliferative T cells in COVID-19.

T cells play key protective but also pathogenic roles in COVID-19. We studied the expression of long non-coding RNAs (lncRNAs) in COVID-19 T-cell transcriptomes by integrating previously published single-cell RNA sequencing datasets. The long intergenic non-coding RNA MALAT1 was the most highly transcribed lncRNA in T cells, with Th1 cells demonstrating the lowest and CD8+ resident memory cells the highest MALAT1 expression, amongst CD4+ and CD8+ T-cells populations, respectively. We then identified gene signatures that covaried with MALAT1 in single T cells. A significantly higher number of transcripts correlated negatively with MALAT1 than those that correlated. Enriched functional annotations of the MALAT1- anti-correlating gene signature included processes associated with T-cell activation such as cell division, oxidative phosphorylation, and response to cytokine. The MALAT1 anti-correlating gene signature shared by both CD4+ and CD8+ T-cells marked dividing T cells in both the lung and blood of COVID-19 patients. Focussing on the tissue, we used an independent patient cohort of post-mortem COVID-19 lung samples and demonstrated that MALAT1 suppression was indeed a marker of MKI67+ proliferating CD8+ T cells. Our results reveal MALAT1 suppression and its associated gene signature are a hallmark of human proliferating T cells.

Hypercapnia alters stroma-derived Wnt production to limit ß-catenin signaling and proliferation in AT2 cells.

Persistent symptoms and radiographic abnormalities suggestive of failed lung repair are among the most common symptoms in patients with COVID-19 after hospital discharge. In mechanically ventilated patients with acute respiratory distress syndrome (ARDS) secondary to SARS-CoV-2 pneumonia, low tidal volumes to reduce ventilator-induced lung injury necessarily elevate blood CO2 levels, often leading to hypercapnia. The role of hypercapnia on lung repair after injury is not completely understood. Here - using a mouse model of hypercapnia exposure, cell lineage tracing, spatial transcriptomics, and 3D cultures - we show that hypercapnia limits ß-catenin signaling in alveolar type II (AT2) cells, leading to their reduced proliferative capacity. Hypercapnia alters expression of major Wnts in PDGFRα+ fibroblasts from those maintaining AT2 progenitor activity toward those that antagonize ß-catenin signaling, thereby limiting progenitor function. Constitutive activation of ß-catenin signaling in AT2 cells or treatment of organoid cultures with recombinant WNT3A protein bypasses the inhibitory effects of hypercapnia. Inhibition of AT2 proliferation in patients with hypercapnia may contribute to impaired lung repair after injury, preventing sealing of the epithelial barrier and increasing lung flooding, ventilator dependency, and mortality.

Hypoxia induces dichotomous and reversible attenuation of T cell responses through reactive oxygen species-dependent phenotype redistribution and delay in lymphoblast proliferation.

As T cells transit between blood, lymphoid organs, and peripheral tissues, they experience varied levels of oxygen/hypoxia in inflamed tissues, skin, intestinal lining, and secondary lymphoid organs. Critical illness among COVID-19 patients is also associated with transient hypoxia and attenuation of T cell responses. Hypoxia is the fulcrum of altered metabolism, impaired functions, and cessation of growth of a subset of T cells. However, the restoration of normal T cell functions following transient hypoxia and kinetics of their phenotype-redistribution is not completely understood. Here, we sought to understand kinetics and reversibility of dichotomous T cell responses under sustained and transient hypoxia. We found that a subset of activated T cells accumulated as lymphoblasts under hypoxia. Further, T cells showed the normal expression of activation markers CD25 and CD69 and inflammatory cytokine secretion but a subset exhibited delayed cell proliferation under hypoxia. Increased levels of reactive oxygen species (ROS) in cytosol and mitochondria were seen during dichotomous and reversible attenuation of T cell response under hypoxia. Cell cycle analysis revealed maximum levels of cytosolic and mitochondrial ROS in dividing T cells (in S, G2, or M phase). Hypoxic T cells also showed specific attenuation of activation induced memory phenotype conversion without affecting naïve and activated T cells. Hypoxia-related attenuation of T cell proliferation was also found to be reversible in an allogeneic leukocyte specific mixed lymphocyte reaction assay. In summary, our results show that hypoxia induces a reversible delay in proliferation of a subset of T cells which is associated with obliteration of memory phenotype and specific increase in cytosolic/mitochondrial ROS levels in actively dividing subpopulation. Thus, the transient reoxygenation of hypoxic patients may restore normal T cell responses.

A Three-Dimensional Xeno-Free Culture Condition for Wharton's Jelly-Mesenchymal Stem Cells: The Pros and Cons.

Xeno-free three-dimensional cultures are gaining attention for mesenchymal stem cell (MSCs) expansion in clinical applications. We investigated the potential of xeno-free serum alternatives, human serum and human platelet lysate, to replace the current conventional use of foetal bovine serum for subsequent MSCs microcarrier cultures. In this study, Wharton's Jelly MSCs were cultured in nine different media combinations to identify the best xeno-free culture media for MSCs culture. Cell proliferation and viability were identified, and the cultured MSCs were characterised in accordance with the minimal criteria for defining multipotent mesenchymal stromal cells by the International Society for Cellular Therapy (ISCT). The selected culture media was then used in the microcarrier culture of MSCs to determine the potential of a three-dimensional culture system in the expansion of MSCs for future clinical applications, and to identify the immunomodulatory potential of cultured MSCs. Low Glucose DMEM (LG) + Human Platelet (HPL) lysate media appeared to be good candidates for replacing conventional MSCs culture media in our monolayer culture system. MSCs cultured in LG-HPL achieved high cell yield, with characteristics that remained as described by ISCT, although the overall mitochondrial activity of the cells was lower than the control and the subsequent effects remained unknown. MSC microcarrier culture, on the other hand, showed comparable cell characteristics with monolayer culture, yet had stagnated cell proliferation, which is potentially due to the inactivation of FAK. Nonetheless, both the MSCs monolayer culture and the microcarrier culture showed high suppressive activity on TNF-α, and only the MSC microcarrier culture has a better suppression of IL-1 secretion. In conclusion, LG-HPL was identified as a good xeno-free media for WJMSCs culture, and although further mechanistic research is needed, the results show that the xeno-free three-dimensional culture maintained MSC characteristics and improved immunomodulatory activities, suggesting the potential of translating the monolayer culture into this culture system in MSC expansion for future clinical application.

Diminished cell proliferation promotes natural killer cell adaptive-like phenotype by limiting FcεRIγ expression.

Human adaptive-like natural killer (NK) cells express low levels of FcεRIγ (FcRγ-/low) and are reported to accumulate during COVID-19 infection; however, the mechanism underlying and regulating FcRγ expression in NK cells has yet to be fully defined. We observed lower FcRγ protein expression in NK cell subsets from lung transplant patients during rapamycin treatment, suggesting a link with reduced mTOR activity. Further, FcRγ-/low NK cell subsets from healthy donors displayed reduced mTOR activity. We discovered that FcRγ upregulation is dependent on cell proliferation progression mediated by IL-2, IL-15, or IL-12, is sensitive to mTOR suppression, and is inhibited by TGFß or IFNα. Accordingly, the accumulation of adaptive-like FcRγ-/low NK cells in COVID-19 patients corresponded to increased TGFß and IFNα levels and disease severity. Our results show that an adaptive-like NK cell phenotype is induced by diminished cell proliferation and has an early prognostic value for increased TGFß and IFNα levels in COVID-19 infection associated with disease severity.

Efficient Targeted Delivery of Bifunctional Circular Aptamer-ASO Chimera to Suppress the SARS-CoV-2 Proliferation and Inflammation.

Inhibition of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and excessive inflammation is the current task in the prevention and treatment of corona vireus disease 2019 (COVID-19). Here, a dual-function circular aptamer-ASO chimera (circSApt-NASO) is designed to suppress SARS-CoV-2 replication and inflammation. The chemically unmodified circSApt-NASO exhibits high serum stability by artificial cyclization. It is also demonstrated that the SApt binding to spike protein enables the chimera to be efficiently delivered into the host cells expressing ACE2 along with the infection of SARS-CoV-2. Among them, the SApt potently inhibits spike-induced inflammation. The NASO targeting to silence N genes not only display robust anti-N-induced inflammatory activity, but also achieve efficient inhibition of SARS-CoV-2 replication. Overall, benefiting from the high stability of the cyclization, antispike aptamer-dependent, and viral infection-mediate targeted delivery, the circSApt-NASO displays robust potential against authentic SARS-CoV-2 and Omicron, providing a promising specific anti-inflammatory and antiproliferative reagent for therapeutic COVID-19.

A global analysis of One Health Networks and the proliferation of One Health collaborations.

There has been a renewed focus on threats to the human-animal-environment interface as a result of the COVID-19 pandemic, and investments in One Health collaborations are expected to increase. Efforts to monitor the development of One Health Networks (OHNs) are essential to avoid duplication or misalignment of investments. This Series paper shows the global distribution of existing OHNs and assesses their collective characteristics to identify potential deficits in the ways OHNs have formed and to help increase the effectiveness of investments. We searched PubMed, Google, Google Scholar, and relevant conference websites for potential OHNs and identified 184 worldwide for further analysis. We developed four case studies to show important findings from our research and exemplify best practices in One Health operationalisation. Our findings show that, although more OHNs were formed in the past 10 years than in the preceding decade, investment in OHNs has not been equitably distributed; more OHNs are formed and headquartered in Europe than in any other region, and emerging infections and novel pathogens were the priority focus area for most OHNs, with fewer OHNs focusing on other important hazards and pressing threats to health security. We found substantial deficits in the OHNs collaboration model regarding the diversity of stakeholder and sector representation, which we argue impedes effective and equitable OHN formation and contributes to other imbalances in OHN distribution and priorities. These findings are supported by previous evidence that shows the skewed investment in One Health thus far. The increased attention to One Health after the COVID-19 pandemic is an opportunity to focus efforts and resources to areas that need them most. Analyses, such as this Series paper, should be used to establish databases and repositories of OHNs worldwide. Increased attention should then be given to understanding existing resource allocation and distribution patterns, establish more egalitarian networks that encompass the breadth of One Health issues, and serve communities most affected by emerging, re-emerging, or endemic threats at the human-animal-environment interface.

Donor selection for adoptive cell therapy with CD45RA- memory T cells for patients with coronavirus disease 2019, and dexamethasone and interleukin-15 effects on the phenotype, proliferation and interferon gamma release.

BACKGROUND AIMS: We have previously demonstrated the safety and feasibility of adoptive cell therapy with CD45RA- memory T cells containing severe acute respiratory syndrome coronavirus 2-specific T cells for patients with coronavirus disease 2019 from an unvaccinated donor who was chosen based on human leukocyte antigen compatibility and cellular response. In this study, we examined the durability of cellular and humoral immunity within CD45RA- memory T cells and the effect of dexamethasone, the current standard of care treatment, and interleukin-15, a cytokine critically involved in T-cell maintenance and survival. METHODS: We performed a longitudinal analysis from previously severe acute respiratory syndrome coronavirus 2-infected and infection-naïve individuals covering 21 months from infection and 10 months after full vaccination with the BNT162b2 Pfizer/BioNTech vaccine. RESULTS: We observed that cellular responses are maintained over time. Humoral responses increased after vaccination but were gradually lost. In addition, dexamethasone did not alter cell functionality or proliferation of CD45RA- T cells, and interleukin-15 increased the memory T-cell activation state, regulatory T cell expression, and interferon gamma release. CONCLUSIONS: Our results suggest that the best donors for adoptive cell therapy would be recovered individuals and 2 months after vaccination, although further studies with larger cohorts would be needed to confirm this finding. Dexamethasone did not affect the characteristics of the memory T cells at a concentration used in the clinical practice and IL-15 showed a positive effect on SARS-CoV-2-specific CD45RA- T cells.

Multiple Death Pathways of Neutrophils Regulate Alveolar Macrophage Proliferation.

Alveolar macrophage (AM) proliferation and self-renewal play an important role in the lung tissue microenvironment. However, the impact of immune cells, especially the neutrophils, on AM homeostasis or function is not well characterized. In this study, we induced in vivo migration of neutrophils into bronchoalveolar lavage (BAL) fluid and lung using CXCL1, and then co-cultured these with AMs in vitro. Neutrophils in the BAL (BAL-neutrophils), rather than neutrophils of bone marrow (BM-neutrophils), were found to inhibit AM proliferation. Analysis of publicly available data showed high heterogeneity of lung neutrophils with distinct molecular signatures of BM- and blood-neutrophils. Unexpectedly, BAL-neutrophils from influenza virus PR8-infected mice (PR8-neutrophils) did not inhibit the proliferation of AMs. Bulk RNA sequencing further revealed that co-culture of AMs with PR8-neutrophils induced IFN-α and -γ responses and inflammatory response, and AMs co-cultured with BAL-neutrophils showed higher expression of metabolism- and ROS-associated genes; in addition, BAL-neutrophils from PR8-infected mice modulated AM polarization and phagocytosis. BAL-neutrophil-mediated suppression of AM proliferation was abrogated by a combination of inhibitors of different neutrophil death pathways. Collectively, our findings suggest that multiple cell death pathways of neutrophils regulate the proliferation of AMs. Targeting neutrophil death may represent a potential therapeutic strategy for improving AM homeostasis during respiratory diseases.

Wnt5a/ß-catenin axis is involved in the downregulation of AT2 lineage by PAI-1.

Failure to regenerate injured alveoli functionally and promptly causes a high incidence of fatality in coronavirus disease 2019 (COVID-19). How elevated plasminogen activator inhibitor-1 (PAI-1) regulates the lineage of alveolar type 2 (AT2) cells for re-alveolarization has not been studied. This study aimed to examine the role of PAI-1-Wnt5a-ß catenin cascades in AT2 fate. Dramatic reduction in AT2 yield was observed in Serpine1Tg mice. Elevated PAI-1 level suppressed organoid number, development efficiency, and total surface area in vitro. Anti-PAI-1 neutralizing antibody restored organoid number, proliferation and differentiation of AT2 cells, and ß-catenin level in organoids. Both Wnt family member 5A (Wnt5a) and Wnt5a-derived N-butyloxycarbonyl hexapeptide (Box5) altered the lineage of AT2 cells. This study demonstrates that elevated PAI-1 regulates AT2 proliferation and differentiation via the Wnt5a/ß catenin cascades. PAI-1 could serve as autocrine signaling for lung injury repair.

Type D lymphomatoid papulosis with pityriasis lichenoides et varioliformis acuta-like features in a child with parvovirus infection: a controversial diagnosis in the spectrum of lymphoid proliferations: case report and literature review.

BACKGROUND: Lymphomatoid papulosis (LyP) is a rare condition in pediatrics; LyP histological type D has been reported in only 7 children. The differential diagnosis of LyP in the spectrum of lymphoid proliferation remains controversial. CASE PRESENTATION: A 6-year-old boy presented to Emergency Department with a 3-week history of an erythematous papulo-vesicular itchy eruption over the submandibular regions, trunk and extremities. History, symptoms and laboratory tests were unremarkable. SARS-CoV-2 antigen was negative. The clinical suspicion of pityriasis lichenoides et varioliformis acuta (PLEVA) was posed, and topical steroids were introduced. One week after, he returned with an extensive painful scaly papulo-erythematous rash, with some ulcerated and necrotic lesions, and fever; therefore the child was hospitalized. Biochemical results were within reference limits, except for high level of C-reactive protein, aspartate aminotransferase, alanine transaminase and bilirubin. Due to a persistently high fever, systemic corticosteroid treatment was administered, with a good clinical response and an improvement of the skin lesions. Anti-PVB-19 Immunoglobulin M was detected. Elevated levels of IL-6, IL-10 and IFN-γ were also recorded. Five days post-admission, most of the lesions had cleared, and the child was discharged. Methotrexate was started, with a positive response. At skin biopsy a "PLEVA-like" pattern was apparent, with a dense, wedge shaped lymphoid infiltrate featuring epidermotropism and morphologically comprising pleomorphic and blastic cells. The pattern of infiltration was highlighted by immunohistochemical stains, which prove the process to feature a CD8+/CD30 + phenotype, the latter being intense on larger cells, with antigenic loss. Polymerase chain reaction for T-cell receptor gamma (TCRG) chain clonality assessment documented a monoclonal peak. A diagnosis of LyP type D was favored. CONCLUSION: The reported case encompasses most of the critical features of two separated entities-PLEVA and LyP-thus providing further support to the concept of them representing declinations within a sole spectrum of disease. Studying the role of infectious agents as trigger potential in lymphoproliferative cutaneous disorders and detecting novel markers of disease, such as cytokines, could have a crucial impact on pathogenic disease mechanisms and perspective therapies.

The role of AMPK-dependent pathways in cellular and molecular mechanisms of metformin: a new perspective for treatment and prevention of diseases.

Metformin can suppress gluconeogenesis and reduce blood sugar by activating adenosine monophosphate-activated protein kinase (AMPK) and inducing small heterodimer partner (SHP) expression in the liver cells. The main mechanism of metformin's action is related to its activation of the AMPK enzyme and regulation of the energy balance. AMPK is a heterothermic serine/threonine kinase made of a catalytic alpha subunit and two subunits of beta and a gamma regulator. This enzyme can measure the intracellular ratio of AMP/ATP. If this ratio is high, the amino acid threonine 172 available in its alpha chain would be activated by the phosphorylated liver kinase B1 (LKB1), leading to AMPK activation. Several studies have indicated that apart from its significant role in the reduction of blood glucose level, metformin activates the AMPK enzyme that in turn has various efficient impacts on the regulation of various processes, including controlling inflammatory conditions, altering the differentiation pathway of immune and non-immune cell pathways, and the amelioration of various cancers, liver diseases, inflammatory bowel disease (IBD), kidney diseases, neurological disorders, etc. Metformin's activation of AMPK enables it to control inflammatory conditions, improve oxidative status, regulate the differentiation pathways of various cells, change the pathological process in various diseases, and finally have positive therapeutic effects on them. Due to the activation of AMPK and its role in regulating several subcellular signalling pathways, metformin can be effective in altering the cells' proliferation and differentiation pathways and eventually in the prevention and treatment of certain diseases.

Upregulation of hsa_circ_0004812 promotes COVID-19 cytokine storm via hsa-miR-1287-5p/IL6R, RIG-I axis.

BACKGROUND: SARS-CoV-2 is one of the most contagious viruses in the Coronaviridae (CoV) family, which has become a pandemic. The aim of this study is to understand more about the role of hsa_circ_0004812 in the SARS-CoV-2 related cytokine storm and its associated molecular mechanisms. MATERIALS AND METHODS: cDNA synthesis was performed after total RNA was extracted from the peripheral blood mononuclear cells (PBMC) of 46 patients with symptomatic COVID-19, 46 patients with asymptomatic COVID-19, and 46 healthy controls. The expression levels of hsa_circ_0004812, hsa-miR-1287-5p, IL6R, and RIG-I were determined using qRT-PCR, and the potential interaction between these molecules was confirmed by bioinformatics tools and correlation analysis. RESULTS: hsa_circ_0004812, IL6R, and RIG-I are expressed higher in the severe symptom group compared with the negative control group. Also, the relative expression of these genes in the asymptomatic group is lower than in the severe symptom group. The expression level of hsa-miR-1287-5p was positively correlated with symptoms in patients. The results of the bioinformatics analysis predicted the sponging effect of hsa_circ_0004812 as a competing endogenous RNA on hsa-miR-1287-5p. Moreover, there was a significant positive correlation between hsa_circ_0004812, RIG-I, and IL-6R expressions, and also a negative expression correlation between hsa_circ_0004812 and hsa-miR-1287-5p and between hsa-miR-1287-5p, RIG-I, and IL-6R. CONCLUSION: The results of this in-vitro and in silico study show that hsa_circ_0004812/hsa-miR-1287-5p/IL6R, RIG-I can play an important role in the outcome of COVID-19.

Angioimmunoblastic T-Cell Lymphoma with Exuberant CD30-Positive Follicular Dendritic Cell Proliferation in a SARS-CoV-2 Patient: The Role of Mutational Analysis to Exclude an Associated Follicular Dendritic Cell Sarcoma.

Follicular dendritic cell (FDC) proliferation in angioimmunoblastic T-cell lymphoma (AITL) is still not well defined, challenging the accurate differential diagnosis between the AITL with expanded follicular dendritic cell meshwork and the combined AITL and follicular dendritic cell sarcoma (FDCS). Herein, we reported the case of a 58-year-old male with coexisting SARS-CoV-2 infection and AITL with an exuberant CD30-positive FDC proliferation, in which genetic analysis identified mutations of genes commonly involved in AITL but not in FDC sarcoma (i.e., RHOA, TET2, DNMT3A, and IDH2), thus supporting the reactive nature of the CD30-positive FDC expansion.