scholarly journals Rheumatoid Factor: A Novel Determiner in Cancer History

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 591
Author(s):  
Alessio Ugolini ◽  
Marianna Nuti
Keyword(s):  
Rheumatoid Factors ◽  
Chronic Infections ◽  
Cancer History ◽  
Transient Event ◽  
Effector Functions ◽  
Physiological Conditions ◽  
Diagnosis And Prognosis ◽  
Anti Cancer

The possible interplay between autoimmunity and cancer is a topic that still needs to be deeply explored. Rheumatoid factors are autoantibodies that are able to bind the constant regions (Fc) of immunoglobulins class G (IgGs). In physiological conditions, their production is a transient event aimed at contributing to the elimination of pathogens as well as limiting a redundant immune response by facilitating the clearance of antibodies and immune complexes. Their production can become persistent in case of different chronic infections or diseases, being for instance a fundamental marker for the diagnosis and prognosis of rheumatoid arthritis. Their presence is also associated with aging. Some studies highlighted how elevated levels of rheumatoid factors (RFs) in the blood of patients are correlated with an increased cancer risk, tumor recurrence, and load and with a reduced response to anti-tumor immunotherapies. In line with their physiological roles, RFs showed in different works the ability to impair in vitro anti-cancer immune responses and effector functions, suggesting their potential immunosuppressive activity in the context of tumor immunity. Thus, the aim of this review is to investigate the emerging role of RFs as determiners of cancer faith.

scholarly journals Impaired FcϵRI stability, signaling, and effector functions in murine mast cells lacking glycosylphosphatidylinositol-anchored proteins

Blood ◽  
2011 ◽  
Vol 118 (16) ◽  
pp. 4377-4383 ◽  
Author(s):  
Wouter L. W. Hazenbos ◽  
Ping Wu ◽  
Jeffrey Eastham-Anderson ◽  
Taroh Kinoshita ◽  
Eric J. Brown
Keyword(s):  
Mast Cells ◽  
Targeted Disruption ◽  
Potential Therapeutic Target ◽  
Effector Functions ◽  
Ige Mediated ◽  
Interchain Interactions ◽  
Β Chain ◽  
Stimulation Of

Abstract A key event and potential therapeutic target in allergic and asthmatic diseases is signaling by the IgE receptor FcϵRI, which depends on its interactions with Src family kinases (SFK). Here we tested the hypothesis that glycosylphosphatidylinositiol-anchored proteins (GPI-AP) are involved in FcϵRI signaling, based on previous observations that GPI-AP colocalize with and mediate activation of SFK. We generated mice with a hematopoietic cell-specific GPI-AP deficiency by targeted disruption of the GPI biosynthesis gene PigA. In these mice, IgE-mediated passive cutaneous anaphylaxis was largely abolished. PigA-deficient mast cells cultured from these mice showed impaired degranulation in response to stimulation with IgE and antigen in vitro, despite normal IgE binding and antigen-induced FcϵRI aggregation. On stimulation of these cells with IgE and antigen, coprecipitation of the FcϵRI α-chain with the γ-chain and β-chain was markedly reduced. As a result, IgE/antigen–induced FcϵRI-Lyn association and γ-chain tyrosine phosphorylation were both impaired in PigA-deficient cells. These data provide genetic evidence for an unanticipated key role of GPI-AP in FcϵRI interchain interactions and early FcϵRI signaling events, necessary for antigen-induced mast cell degranulation.

scholarly journals Peripheral self-reactivity regulates antigen-specific CD8 T-cell responses and cell division under physiological conditions

Open Biology ◽  
2016 ◽  
Vol 6 (11) ◽  
pp. 160293 ◽  
Author(s):  
Lee Kim Swee ◽  
Zhen Wei Tan ◽  
Anna Sanecka ◽  
Nagisa Yoshida ◽  
Harshil Patel ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Toxoplasma Gondii ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Effector Function ◽  
Effector Functions ◽  
Physiological Conditions ◽  
Cell Clones

T-cell identity is established by the expression of a clonotypic T-cell receptor (TCR), generated by somatic rearrangement of TCRα and β genes. The properties of the TCR determine both the degree of self-reactivity and the repertoire of antigens that can be recognized. For CD8 T cells, the relationship between TCR identity—hence reactivity to self—and effector function(s) remains to be fully understood and has rarely been explored outside of the H-2 b haplotype. We measured the affinity of three structurally distinct CD8 T-cell-derived TCRs that recognize the identical H-2 L d -restricted epitope, derived from the Rop7 protein of Toxoplasma gondii . We used CD8 T cells obtained from mice generated by somatic cell nuclear transfer as the closest approximation of primary T cells with physiological TCR rearrangements and TCR expression levels. First, we demonstrate the common occurrence of secondary rearrangements in endogenously rearranged loci. Furthermore, we characterized and compared the response of Rop7-specific CD8 T-cell clones upon Toxoplasma gondii infection as well as effector function and TCR signalling upon antigenic stimulation in vitro . Antigen-independent TCR cross-linking in vitro uncovered profound intrinsic differences in the effector functions between T-cell clones. Finally, by assessing the degree of self-reactivity and comparing the transcriptomes of naive Rop7 CD8 T cells, we show that lower self-reactivity correlates with lower effector capacity, whereas higher self-reactivity is associated with enhanced effector function as well as cell cycle entry under physiological conditions. Altogether, our data show that potential effector functions and basal proliferation of CD8 T cells are set by self-reactivity thresholds.

Metabolism at the pyruvate branch point in the radula retractor muscle of the whelk, Busycon contrarium

1982 ◽  
Vol 60 (11) ◽  
pp. 2973-2977 ◽  
Author(s):  
W. Ross Ellington
Keyword(s):  
Branch Point ◽  
Physiological Role ◽  
Redox Balance ◽  
Retractor Muscle ◽  
Physiological Conditions ◽  
Wet Weight ◽  
Octopine Dehydrogenase

The radula retractor muscle of the whelk Busycon contrarium contains high activities of both octopine dehydrogenase (~500 μmol∙min−1∙g wet weight−1) and strombine dehydrogenase (~150 μmol∙min−1∙g wet weight−1). Experiments were conducted with in vitro radula muscle preparations to assess under what physiological conditions these dehydrogenases function. Alanopine–strombine accumulated during anoxia, postanoxic recovery, and potassium-induced contractures in radula retractor muscles. No significant accumulation of octopine was observed. Although the accumulation of alanopine–strombine was significant, it was quantitatively small when compared with the production of succinate. Thus, it appears that alanopine–strombine formation has only an accessory role in cytoplasmic redox balance in B. contrarium radula retractor muscle. The physiological role of octopine dehydrogenase in this system remains unclear.

scholarly journals Role of long non-coding RNA TP73-AS1 in cancer

2019 ◽  
Vol 39 (10) ◽  
Author(s):  
Caizhi Chen ◽  
Long Shu ◽  
Wen Zou
Keyword(s):  
Cell Carcinoma ◽  
Signaling Pathways ◽  
Cell Renal Cell Carcinoma ◽  
Aberrant Expression ◽  
Diagnosis And Prognosis ◽  
Early Diagnosis Of Cancer ◽  
Cause Of Deaths

Abstract Cancer incidence rate has increased so much that it is the second leading cause of deaths worldwide after cardiovascular diseases. Sensitive and specific biomarkers are needed for an early diagnosis of cancer and in-time treatment. Recent studies have found that long non-coding RNAs (lncRNAs) participate in cancer tumorigenesis. LncRNA P73 antisense RNA 1T (TP73-AS1), also known as KIAA0495 and p53-dependent apoptosis modulator (PDAM), is located in human chromosomal band 1p36.32 and plays a crucial role in many different carcinomas. This review summarizes current findings on the role of TP73-AS1 and its signaling pathways in various cancers, including glioma, esophageal squamous cell carcinoma (ESCC), hepatocellular carcinoma (HCC), colorectal cancer (CRC), osteosarcoma, gastric cancer (GC), clear cell renal cell carcinoma (ccRCC), breast cancer (BC), bladder cancer, ovarian cancer, cholangiocarcinoma (CCA), lung cancer, and pancreatic cancer. Its aberrant expression generally correlates with clinicopathological characterization of patients. Moreover, TP73-AS1 regulates proliferation, migration, invasion, apoptosis, and chemoresistance cancer mechanisms, both in vivo and in vitro, through different signaling pathways. Therefore, TP73-AS1 may be considered as a marker for diagnosis and prognosis, also as a target for cancer treatment.

scholarly journals Streptolysin-induced endoplasmic reticulum stress promotes group A streptococcal in vivo biofilm formation and necrotizing fasciitis

2017 ◽  
Author(s):  
Anuradha Vajjala ◽  
Debabrata Biswas ◽  
Kelvin Kian Long Chong ◽  
Wei Hong Tay ◽  
Emanuel Hanski ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Er Stress ◽  
Necrotizing Fasciitis ◽  
Biofilm Formation ◽  
Mammalian Cells ◽  
Chronic Infections ◽  
Group A

AbstractGroup A Streptococcus (GAS) is a human pathogen that causes infections ranging from mild to fulminant and life-threatening. Biofilms have been implicated in acute GAS soft-tissue infections such as necrotizing fasciitis (NF). However, most in vitro models used to study GAS biofilms have been designed to mimic chronic infections and insufficiently recapitulate in vivo conditions and the host-pathogen interactions that might influence biofilm formation. Here we establish and characterize an in vitro model of GAS biofilm development on mammalian cells that simulates microcolony formation observed in a murine model of human NF. We show that on mammalian cells, GAS forms dense aggregates that display hallmark biofilm characteristics including a three-dimensional architecture and enhanced tolerance to antibiotics. In contrast to abiotic-grown biofilms, host-associated biofilms require the expression of secreted GAS streptolysins O and S (SLO, SLS) resulting in the release of a host-associated biofilm promoting-factor(s). Supernatants from GAS-infected mammalian cells or from cells treated with endoplasmic reticulum (ER) stressors restore biofilm formation to an SLO and SLS null mutant that is otherwise attenuated in biofilm formation on cells, together suggesting a role for streptolysin-induced ER stress in this process. In an in vivo mouse model, the streptolysin-null mutant is attenuated in both microcolony formation and bacterial spread, but pre-treatment of softtissue with an ER-stressor restores the ability of the mutant to form wild type like microcolonies that disseminate throughout the soft tissue. Taken together, we have identified a new role of streptolysin-driven ER stress in GAS biofilm formation and NF disease progression.Significance StatementAlthough it is well-accepted that bacterial biofilms are associated with many chronic infections, little is known about the mechanisms by which group A Streptococcus (GAS) biofilms contribute to acute soft tissue-invasive diseases like necrotizing fasciitis (NF). In this study, we establish a physiologically relevant in vitro model to study GAS biofilm formation on mammalian cells and validate our findings in a mouse model that mimics human NF. This study demonstrates a novel role of GAS streptolysin-mediated ER stress in the development and spread of GAS biofilms in acute softtissue infections. We also show that biofilm formation depends on the release of a host-associated factor that promotes microcolony formation and GAS dissemination in vivo.

Thymoquinone and its nanoformulation attenuate colorectal and breast cancers and alleviate doxorubicin-induced cardiotoxicity

Nanomedicine ◽  
2021 ◽  
Author(s):  
Ali H El-Far ◽  
Taher A Salaheldin ◽  
Kavitha Godugu ◽  
Noureldien HE Darwish ◽  
Shaker A Mousa
Keyword(s):  
Xenograft Model ◽  
Double Emulsion ◽  
Tumor Model ◽  
Breast Cancers ◽  
Anti Cancer ◽  
Xenograft Tumor Model ◽  
Average Size ◽  
Hct116 Cells

Aim: To investigate the anti-cancer potential of thymoquinone (TQ) and TQ nanoparticles (TQ-NPs) and their protection against doxorubicin (DOX)-induced cardiotoxicity. Methods: TQ-NPs were prepared by double emulsion method and characterized. The efficacy of TQ and TQ-DOX was studied against HCT116 and MDA-MB-231-Luc cancer cell lines in vitro and in a xenograft tumor model. Results: TQ and TQ + DOX increased Bax levels in HCT116 cells and decreased Bcl2 levels in MDA-MB-231-Luc cells. In the xenograft model, the TQ-NPs, with an average size of 218 nm, in combination with DOX, significantly reduced tumor size. The combination of TQ or TQ-NPs with DOX significantly reduced DOX-induced cardiotoxicity. Conclusion: Data suggest the promising role of TQ and TQ-NPs alone and with DOX for anti-cancer and cardiac protection benefits.

The Role of PI3K and Wntsignaling Pathways and CSC Markers in Melanoma (B16F10) Therapy

2021 ◽  
Author(s):  
marjan hajimoradi javarsiani ◽  
javad sajedianfard ◽  
Shagayegh Haghjooy Javanmard ◽  
Micol Eleonora Fiori
Keyword(s):  
Cancer Progression ◽  
Therapeutic Agent ◽  
B16f10 Melanoma ◽  
Melanoma Cancer ◽  
Anti Cancer ◽  
Melanoma B16f10 ◽  
The Subject ◽  
Cell Growth And Proliferation

Abstract Background Metformin has been the subject of recent studies aimed at the treatment of melanoma cancer. In this study, the anti-cancer effects of metformin, an antidiabetic drug, was investigated in-vitrousing the B16F10 melanoma cell line. Methods Melanoma cells were treated for 24 h with various concentrations of metformin, alone or incombination withdacarbazine. The effects of these two treatment agents on cell viability were evaluated by MTT assay. In addition, stemness and the activation of specific signaling pathways were evaluated by FACS and immunoblotting. Results Metformin induced β-catenin phosphorylation and decreasedmTOR and PARP expressions. Also, a normal dose of metformin was found toreducethe phosphorylation levels of4E-BP1, AKT, and S6rp.In this study, we evaluated the potential of metformin as a therapeutic agent against CSCs in the adjuvant setting. Conclusion Our data indicate that some transcriptional regulators and proteins in the above-mentioned pathwayswere associated with cancer progression and inhibited by adjuvant chemotherapy with metformin.Metformin significantly inhibited cell growth and proliferation pathways, including Wnt and PI3K/AKT/mTOR. These findings show the potential of metformin in cancer treatment.

Glycosylation of autoantibodies: Insights into the mechanisms of immune thrombocytopenia

2013 ◽  
Vol 110 (12) ◽  
pp. 1259-1266 ◽  
Author(s):  
Tamam Bakchoul ◽  
Kathrin Walek ◽  
Annika Krautwurst ◽  
Mathias Rummel ◽  
Gregor Bein ◽  
...  
Keyword(s):  
Immune Thrombocytopenia ◽  
Laser Scanning ◽  
Human Platelets ◽  
Laser Scanning Microscopy ◽  
Effector Functions ◽  
Scid Mouse Model ◽  
Rapid Clearance

SummaryImmune thrombocytopenia (ITP) is a bleeding disorder caused by IgG autoantibodies (AAbs) directed against platelets (PLTs). IgG effector functions depend on their Fc-constant region which undergoes post-translational glycosylation. We investigated the role of Asn279-linked N-glycan of AAbs in vitro and in vivo. AAbs were purified from ITP patients (n=15) and N-glycans were enzymatically cleaved by endoglycosidase F. The effects of native AAbs and deglycosylated AAbs were compared in vitro on enhancement of phagocytosis of platelets by monocytes and complement fixation and activation applying flow cytometry, laser scanning microscopy, and a complement consumption assay. AAb-induced platelet phagocytosis was inhibited by N-glycan cleavage (median phagocytic activity: 8% vs 0.8%, p=0.004). Seven out of 15 native AAbs bound C1q and activated complement. N-glycan cleavage significantly reduced both effects. In vivo survival of human PLTs was assessed after co-transfusion with native or N-glycan cleaved AAbs in a NOD/SCID mouse model. Injection of AAbs resulted in rapid clearance of human platelets compared to control (platelet clearance after 5h (CL5h) 75% vs 30%, p<0.001). AAbs that were able to activate complement induced more pronounced platelet clearance in the presence of complement compared to the clearance in the absence of complement (CL5h 82% vs 62%, p=0.003). AAbs lost their ability to destroy platelets in vivo after deglycosylation (CL5h 42%, p<0.001). N-glycosylation of human ITP AAbs appears to be required for platelet phagocytosis and complement activation, reducing platelet survival in vivo. Posttranslational modification of AAbs may constitute an important determinant for the clinical manifestation of ITP.

scholarly journals The p110δ of PI3K plays a critical role in NK cell terminal maturation and cytokine/chemokine generation

2008 ◽  
Vol 205 (10) ◽  
pp. 2419-2435 ◽  
Author(s):  
Hailong Guo ◽  
Asanga Samarakoon ◽  
Bart Vanhaesebroeck ◽  
Subramaniam Malarkannan
Keyword(s):  
Nk Cells ◽  
Nk Cell ◽  
Critical Role ◽  
Cell Receptor ◽  
Cell Development ◽  
Effector Functions ◽  
Antiviral Responses

Phosphatidylinositol 3-kinases (PI3Ks) play a critical role in regulating B cell receptor– and T cell receptor–mediated signaling. However, their role in natural killer (NK) cell development and functions is not well understood. Using mice expressing p110δD910A, a catalytically inactive p110δ, we show that these mice had reduced NK cellularity, defective Ly49C and Ly49I NK subset maturation, and decreased CD27High NK numbers. p110δ inactivation marginally impaired NK-mediated cytotoxicity against tumor cells in vitro and in vivo. However, NKG2D, Ly49D, and NK1.1 receptor–mediated cytokine and chemokine generation by NK cells was severely affected in these mice. Further, p110δD910A/D910A NK cell–mediated antiviral responses through natural cytotoxicity receptor 1 were reduced. Analysis of signaling events demonstrates that p110δD910A/D910A NK cells had a reduced c-Jun N-terminal kinase 1/2 phosphorylation in response to NKG2D-mediated activation. These results reveal a previously unrecognized role of PI3K-p110δ in NK cell development and effector functions.

The role of the amphibian kidney and bladder in the regulation of acid–base relevant ions

1989 ◽  
Vol 67 (12) ◽  
pp. 3064-3069 ◽  
Author(s):  
Daniel P. Toews ◽  
Daniel F. Stiffler
Keyword(s):  
Animal Studies ◽  
Intact Animal ◽  
Bladder Function ◽  
Whole Body ◽  
Transport Mechanisms ◽  
Acid Base ◽  
Cellular Mechanisms ◽  
Physiological Conditions

The amphibian bladder and kidneys have proven to be excellent structures for in vitro investigations of ion-transport mechanisms and cellular mechanisms of hormone action. Very often, however, the normal physiological conditions that exist in the intact animal have not been duplicated in the particular experimental setup. On the other hand, whole-animal studies relating to kidney and bladder function are somewhat rare because it is technically very difficult to separate the relative contributions of the kidney, bladder, and skin to processes such as whole-body acid–base regulation. In this review we attempt to describe the most significant advances of in vitro studies as they relate to acid–base regulation and to integrate these experiments with the limited number of investigations performed on whole-animal preparations.

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