Immune mechanisms have evolved to cope with local entry of microbes acting in a confined fashion but eventually inducing systemic immune memory. Indeed, in situ delivery of a number of agents into ...tumors can mimic in the malignant tissue the phenomena that control intracellular infection leading to the killing of infected cells. Vascular endothelium activation and lymphocyte attraction, together with dendritic cell-mediated cross-priming, are the key elements. Intratumoral therapy with pathogen-associated molecular patterns or recombinant viruses is being tested in the clinic. Cell therapies can be also delivered intratumorally, including infusion of autologous dendritic cells and even tumor-reactive T lymphocytes. Intralesional virotherapy with an HSV vector expressing GM-CSF has been recently approved by the Food and Drug Administration for the treatment of unresectable melanoma. Immunomodulatory monoclonal Abs have also been successfully applied intratumorally in animal models. Local delivery means less systemic toxicity while focusing the immune response on the malignancy and the affected draining lymph nodes.
COVID-19 Pathogenesis and Clinical Manifestations Hernandez Acosta, R Alfonso; Esquer Garrigos, Zerelda; Marcelin, Jasmine R ...
Infectious disease clinics of North America,
06/2022, Letnik:
36, Številka:
2
Journal Article
Recenzirano
Odprti dostop
In this review, we summarize the current knowledge about the virology, the host-pathogen interactions and pathogenesis of coronavirus disease 2019 in humans. We also describe the various clinical ...presentations of the disease including respiratory system and extrapulmonary manifestations.
Weak and ineffective antitumor cytotoxic T lymphocyte (CTL) responses can be rescued by immunomodulatory mAbs targeting PD-1 or CD137. Using Batf3(-/-) mice, which are defective for ...cross-presentation of cell-associated antigens, we show that BATF3-dependent dendritic cells (DC) are essential for the response to therapy with anti-CD137 or anti-PD-1 mAbs. Batf3(-/-) mice failed to prime an endogenous CTL-mediated immune response toward tumor-associated antigens, including neoantigens. As a result, the immunomodulatory mAbs could not amplify any therapeutically functional immune response in these mice. Moreover, administration of systemic sFLT3L and local poly-ICLC enhanced DC-mediated cross-priming and synergized with anti-CD137- and anti-PD-1-mediated immunostimulation in tumor therapy against B16-ovalbumin-derived melanomas, whereas this function was lost in Batf3(-/-) mice. These experiments show that cross-priming of tumor antigens by FLT3L- and BATF3-dependent DCs is crucial to the efficacy of immunostimulatory mAbs and represents a very attractive point of intervention to enhance their clinical antitumor effects.
Immunotherapy with immunostimulatory mAbs is currently achieving durable clinical responses in different types of cancer. We show that cross-priming of tumor antigens by BATF3-dependent DCs is a key limiting factor that can be exploited to enhance the antitumor efficacy of anti-PD-1 and anti-CD137 immunostimulatory mAbs.
A
bstract
In this work, we consider an extension to the Standard Model composed by a Massive Vector Doublet under SU(2)
L
and a Left-handed Heavy Neutral Lepton. We study the production of these ...exotic leptons with the Same Flavor Opposite Sign standard lepton pair, and jets, considering Drell-Yan and Vector Boson Fusion as independent cases. We find that for the latter, the dilepton angular distribution is different enough from the background to use it as a smoking-gun for our model. Based on this fact, we establish limits on the parameter space considering previous experimental searches in this final state.
STUDY QUESTION
What is the prevalence of chronic endometritis (CE) in women with repeated unexplained implantation failure (RIF) at IVF, and how does antibiotic treatment affect the reproductive ...outcome?
SUMMARY ANSWER
Chronic endometritis, associated with infection with common bacteria or mycoplasma, is common in women complaining of RIF and antibiotic treatment significantly improves the reproductive outcome at a subsequent IVF cycle.
WHAT IS KNOWN ALREADY
We have reported that CE is a frequent finding in women with repeated pregnancy loss and a significantly higher rate of successful pregnancies was achieved after adequate antibiotic treatment. Moreover, CE was identified in 30.3% of patients with repeated implantation failure at IVF and women diagnosed with CE had lower implantation rates (11.5%) after IVF cycles. In contrast, other authors reported that the clinical implication of CE should be considered minimal and that the reproductive outcome at IVF/ICSI cycles was not negatively affected by CE.
STUDY DESIGN, SIZE, DURATION
A retrospective study was performed from January 2009 through June 2012 on 106 women with unexplained infertility and a history of RIF.
PARTICIPANTS/MATERIALS, SETTING, METHODS
All patients underwent hysteroscopy and endometrial sampling for histology and microbiological investigations. Women diagnosed with CE underwent antibiotic treatment and the effect of treatment was confirmed by hysteroscopy with biopsy. Within 6 months after treatment all women had a further IVF attempt. The IVF outcomes were compared in women without signs of CE (Group 1) and persistent CE (Group 2) after antibiotic treatment. Clinical pregnancy rate (PR), and live birth rate (LBR) were compared at post-treatment IVF attempt.
MAIN RESULTS AND THE ROLE OF CHANCE
Seventy (66.0%) women were diagnosed with CE at hysteroscopy. In 61 (57.5%) CE was confirmed by histology and 48 (45.0%) by cultures. Common bacteria and mycoplasma were the most prevalent agents. In 46 (75.4%) out of 61 women, with diagnosis of CE at hysteroscopy and histology, examinations were normal after appropriate antibiotic treatment control (Group 1) while in 15 (24.6%) cases signs of CE were still present (Group 2). At IVF attempt after treatment, a significantly higher PR and LBR was reported in women from Group 1 compared with women from Group 2 (65.2 versus 33.0% P = 0.039; 60.8 versus 13.3%, P = 0.02, respectively).
LIMITATIONS, REASONS FOR CAUTION
Possible biases related to retrospective studies and to preferential referral of patients with CE, and limited number of cases.
WIDER IMPLICATIONS OF THE FINDINGS
A prospective randomized clinical trial is needed to confirm our findings but in women with RIF a hysteroscopic evaluation of the uterine cavity to exclude CE should be considered and appropriate antibiotic treatment should be given before submitting the patient to a further IVF attempt.
STUDY FUNDING/COMPETING INTEREST(S)
This research was funded by the University personal research grants of Ettore Cicinelli. The authors have no competing interests to declare.
This article presents a case that former President of the United States Donald Trump was a tyrant-like leader in the mold of the tyrant in Plato’s Republic. While he does not perfectly embody the ...tyrant as presented in the Republic, he captures its core feature. Like the tyrant, Trump is driven by unregulated desires that reflect what Plato describes as an extreme freedom that underlies and threatens democratic regimes. Extreme freedom is manifested in Trump’s disregard for social and legal norms, which mirrors the lawlessness of the tyrant. The people, in turn, interpret that posture as a mark of authenticity. Understanding Trump’s appeal in the United States helps alert friends of democracy to the possible rise of tyrant-like figures. In closing, and as a way of remedying the harm done by the tyrannical soul, the article recommends that society help temper tyrant-like passions in the people through a rededication to civic equality.
In this work we present a simple extension of the Standard Model that contains, as the only new physics component, a massive spin-one matter field in the adjoint representation of SU(2)L. In order to ...be consistent with perturbative unitarity, the vector field must be odd under a Z2 symmetry. Radiative corrections make the neutral component of the triplet (V0) slightly lighter than the charged ones. We show that V0 can be the dark matter particle while satisfying all current bounds if it has a mass between 2.8 and 3.8 TeV. We present the current limit on the model parameter space from highly complementary experimental constraints, including dark matter relic density measurement, dark matter direct and indirect detection searches, LHC data on Higgs couplings to photons and LHC data on disappearing track searches. We also show that the two-dimensional parameter space can be fully covered by disappearing track searches at a future 100 TeV hadron collider, which will probe, in particular, the whole mass range relevant for dark matter, thus giving an opportunity to discover or exclude the model.
CD137 (4‐1BB, TNF‐receptor superfamily 9) is a surface glycoprotein of the TNFR family which can be induced on a variety of leukocyte subsets. On T and NK cells, CD137 is expressed following ...activation and, if ligated by its natural ligand (CD137L), conveys polyubiquitination‐mediated signals via TNF receptor associated factor 2 that inhibit apoptosis, while enhancing proliferation and effector functions. CD137 thus behaves as a bona fide inducible costimulatory molecule. These functional properties of CD137 can be exploited in cancer immunotherapy by systemic administration of agonist monoclonal antibodies, which increase anticancer CTLs and enhance NK‐cell‐mediated antibody‐dependent cell‐mediated cytotoxicity. Reportedly, anti‐CD137 mAb and adoptive T‐cell therapy strongly synergize, since (i) CD137 expression can be used to select the T cells endowed with the best activities against the tumor, (ii) costimulation of the lymphocyte cultures to be used in adoptive T‐cell therapy can be done with CD137 agonist antibodies or CD137L, and (iii) synergistic effects upon coadministration of T cells and antibodies are readily observed in mouse models. Furthermore, the signaling cytoplasmic tail of CD137 is a key component of anti‐CD19 chimeric antigen receptors that are used to redirect T cells against leukemia and lymphoma in the clinic. Ongoing phase II clinical trials with agonist antibodies and the presence of CD137 sequence in these successful chimeric antigen receptors highlight the importance of CD137 in oncoimmunology.
Interplay of CD137 signaling and cancer immunotherapy by means of costimulating T and NK cells. The scheme highlights the potentiation of antitumor antibody‐dependent cell‐mediated cytotoxicity and adoptive T‐cell therapy by anti‐CD137 mAbs.
Density functional theory calculations were employed to investigate the (001), (210), (111), and (110) surfaces of FeS2. The surface free energies were calculated in equilibrium with a sulfur ...environment using first-principles based thermodynamics approach. Surfaces that feature metal atoms in their outermost layer are predicted to be higher in energy. Within the studied subset of (1 × 1) terminations, the stoichiometric (001) surface terminated by a layer of sulfur atoms is the most stable for sulfur-lean condition. For increasingly sulfur-rich environment, two structures were found to have notably lower surface energies compared to others. They have (210) and (111) orientation, both terminated by layers of sulfur. Interestingly, these surfaces are nonstoichiometric exhibiting an excess of sulfur atoms.
: Multiple lines of evidence indicate a critical role of antigen cross-presentation by conventional BATF3-dependent type 1 classical dendritic cells (cDC1) in CD8-mediated antitumor immunity. Flt3L ...and XCL1, respectively, constitute a key growth/differentiation factor and a potent and specific chemoattractant for cDC1. To exploit their antitumor functions in local immunotherapy, we prepared Semliki Forest Virus (SFV)-based vectors encoding XCL1 and soluble Flt3L (sFlt3L). These vectors readily conferred transgene expression to the tumor cells in culture and when engrafted as subcutaneous mouse tumor models. In syngeneic mice, intratumoral injection of SFV-XCL1-sFlt3L (SFV-XF) delayed progression of MC38- and B16-derived tumors. Therapeutic activity was observed and exerted additive effects in combination with anti-PD-1, anti-CD137, or CTLA-4 immunostimulatory mAbs. Therapeutic effects were abolished by CD8β T-cell depletion and were enhanced by CD4 T-cell depletion, but not by T regulatory cell predepletion with anti-CD25 mAb. Antitumor effects were also abolished in BATF3- and IFNAR-deficient mice. In B16-OVA tumors, SFV-XF increased the number of infiltrating CD8 T cells, including those recognizing OVA. Consistently, following the intratumoral SFV-XF treatment courses, we observed increased BATF3-dependent cDC1 among B16-OVA tumor-infiltrating leukocytes. Such an intratumoral increase was not seen in MC38-derived tumors, but both resident and migratory cDC1 were boosted in SFV-XF-treated MC38 tumor-draining lymph nodes. In conclusion, viral gene transfer of sFlt3L and XCL1 is feasible, safe, and biologically active in mice, exerting antitumor effects that can be potentiated by CD4 T-cell depletion. SIGNIFICANCE: These findings demonstrate that transgenic expression of sFLT3L and XCL1 in tumor cells mediates cross-priming of, and elicits potent antitumor activity from, CD8 T lymphocytes, particularly in combination with CD4 T-cell depletion.
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