Long-term care facility (LTCF) older residents display physiological alterations of cellular and humoral immunity that affect vaccine responses. Preliminary reports suggested a low early ...postvaccination antibody response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The aim of this study was to focus on the specific T-cell response. We quantified S1-specific IgG, neutralizing antibody titers, total specific IFNγ-secreting T cells by ELISpot, and functionality of CD4
- and CD8
-specific T cells by flow cytometry, after two doses of the BNT162b2 vaccine in younger and older people, with and without previous COVID-19 infection (hereafter referred to as COVID-19-recovered and COVID-19-naive subjects, respectively). Frailty, nutritional, and immunosenescence parameters were collected at baseline in COVID-19-naive older people. We analyzed the immune response in 129 young adults (median age 44.0 years) and 105 older residents living in a LCTF (median age 86.5 years), 3 months after the first injection. Humoral and cellular memory responses were dramatically impaired in the COVID-19-naive older (
= 54) compared with the COVID-19-naive younger adults (
= 121). Notably, older participants' neutralizing antibodies were 10 times lower than the younger's antibody titers (
< 0.0001) and LCTF residents also had an impaired functional T-cell response: the frequencies of IFNγ
and IFNγ
IL-2
TNFα
cells among specific CD4
T cells, and the frequency of specific CD8
T cells were lower in COVID-19-naive older participants than in COVID-19-naive young adults (
< 0.0001 and
= 0.0018, respectively). However, COVID-19-recovered older participants (
= 51) had greater antibody and T-cell responses, including IFNγ
and IFNγ
IL-2
TNFα
-specific CD4
T cells (
< 0.0001), as well as TNFα
-specific CD8
T cells (
< 0.001), than COVID-19-naive older adults. We also observed that "inflammageing" and particularly high plasma levels of TNFα was associated to poor antibody response in the older participants. In conclusion, our results show that the COVID-19-naive older people had low counts and impaired specific CD4
and CD8
T cells, in addition to impaired antibody response, and that specific studies are warranted to assess the efficiency of SARS-CoV-2 mRNA-based vaccines, as in other immunocompromised subjects. Our study also shows that, despite their physiological alterations of immunity, vaccination is highly efficient in boosting the prior natural memory response in COVID-19-recovered older people.
Iron-catalyzed coupling of three reactants Lefèvre, Guillaume
Science (American Association for the Advancement of Science),
2021-Oct-22, Letnik:
374, Številka:
6566
Journal Article
Recenzirano
Odprti dostop
Vinyl boronates couple under mild conditions to two partners through carbon-carbon bonds.
The mechanism of the reactions of aryl/heteroaryl halides with aryl Grignard reagents catalyzed by FeIII(acac)3 (acac=acetylacetonate) has been investigated. It is shown that in the presence of ...excess PhMgBr, FeIII(acac)3 affords two reduced complexes: PhFeII(acac)(thf)n (n=1 or 2) (characterized by 1H NMR and cyclic voltammetry) and PhFeI(acac)(thf)− (characterized by cyclic voltammetry, 1H NMR, EPR and DFT). Whereas PhFeII(acac)(thf)n does not react with any of the investigated aryl or heteroaryl halides, the FeI complex PhFeI(acac)(thf)− reacts with ArX (Ar=Ph, 4‐tolyl; X=I, Br) through an inner‐sphere monoelectronic reduction (promoted by halogen bonding) to afford the corresponding arene ArH together with the Grignard homocoupling product PhPh. In contrast, PhFeI(acac)(thf)− reacts with a heteroaryl chloride (2‐chloropyridine) to afford the cross‐coupling product (2‐phenylpyridine) through an oxidative addition/reductive elimination sequence. The mechanism of the reaction of PhFeI(acac)(thf)− with the aryl and heteroaryl halides has been explored on the basis of DFT calculations.
Iron(I) does the job: The reduction of FeIII(acac)3 by PhMgBr gives PhFeI(acac)(thf)−, which reacts with ArX (Ar=Ph, 4‐tol; X=I, Br) through an inner‐sphere monoelectronic reduction promoted by halogen bonding to afford ArH and PhPh (see scheme; acac=acetylacetonate). In contrast, PhFeI(acac)(thf)− reacts with 2‐chloropyridine to give the cross‐coupling product (2‐phenylpyridine) through a classical oxidative addition/reductive elimination sequence.
To the editor—We read with interest the comments by Dr Musher about our manuscript entitled “High Frequency of Specific Polysaccharide Antibody Deficiency in Adults With Unexplained, Recurrent and/or ...Severe Infections With Encapsulated Bacteria” 1.Dr Musher notes that no etiologic diagnosis for the pneumonia was established in 23 of the 37 specific polysaccharide antibody deficiency (SPAD) patients. Indeed, patients were included when they had a history of recurrent and/or severe bacterial infections, and most were outcome patients with recurrent upper and/or lower respiratory tract infections (RTIs): bacterial identification is not easily available in such patients but must be encouraged. Dr Musher also noted that we did not confirm that Haemophilus infections were due to encapsulated organisms: once again, this is easily explained by the fact that this identification is not available in routine practice. However, the 3 patients had recurrent lower (n = 3) RTIs, upper RTIs (n = 1), and/or bronchiectasis (n = 2): documented Haemophilus infections in this context were just an additional information, and not the only reason for suspecting an antibody deficiency.Considering the extremely low frequency of meningococcal infections in healthy adults in absence of any outbreaks and in absence of any personal history of asplenia, human immunodeficiency virus (HIV) infection, active/passive smoking…, there is a broad consensus on the need to look for immune deficiencies such complement pathway deficiencies, but antibody deficiencies can also be found 2, 3.Dr Musher also adds that around 10% of healthy subjects can display low responses to pneumococcal capsular polysaccharides (PCP), implying that a poor response is not synonymous of immunodeficiency. We used the guidelines proposed by the American Academy of Allergy, Asthma and Immunology (AAAAI) and the American College of Allergy, Asthma and Immunology (ACAAI) for the use and the interpretation of anti-PCP response: these guidelines are widely accepted, despite the arbitrarily choices of the cutoff levels for anti-PCP antibodies 4–6. The most important is that we used these criteria in patients with relevant unexplained bacterial infections (and not healthy subjects). More robust arguments are needed to contest these expert recommendations.Dr Musher considers that we should have measured anti-PCP antibody concentration after pneumococcal conjugate vaccine (PCV) before suggesting immunoglobulin replacement therapy. Conjugate vaccines were given as the only treatment after SPAD diagnosis in a large part of patients with recurrent infections (10/23), when infections were not too frequent. However, a part of pneumococcal polysaccharide vaccine (PPV) non-responders (SPAD patients) are also PCV non responders suggesting that the defect of PCP recognition and/or specific antibody production is not bypassed by PCP conjugation with protein (6 and several personal unpublished observations in adult patients). We must also recall that the number of serotypes in available conjugate vaccines was limited to 13 and that some emerging non-PCV13 serotypes are responsible for most invasive infections in the general population 7: further studies are warranted to know if PCV containing 20 conjugated PCP or more, would change this practice.Dr Musher adds that “levels of antibody to pneumococcal capsular polysaccharide are relatively low in commercial preparations of IVIG”. We must reaffirm that all SPAD patients must not be treated with Ig replacement therapy. But we fully agree with some experts who consider immunoglobulin G (IgG) replacement therapy in SPAD patients who have severe or very frequent recurrent infections and/or bronchiectasis, inability to tolerate antibiotic prophylaxis (severe side effects or complications), or failure to respond to prophylactic antibiotics 8. Our study also supports this recommendation, since all patients were dramatically improved by Ig therapy: this confirms, if necessary, that the diagnosis criteria of this antibody deficiency seem appropriate in these patients, and that Ig preparations seem to contain enough anti-pneumococcal antibodies.
Breast cancer is a major health problem worldwide. In ~15% of breast cancers, the epidermal growth factor receptor HER2, a transmembrane protein, is overexpressed. This HER2 overexpression is ...associated with an aggressive form of the disease and a poor clinical prognosis. The extracellular domain (ECD) of HER2 is released into the blood by a proteolytic mechanism known as “ECD shedding”. This proteolytic shedding leaves a constitutively active truncated receptor in the membrane that is 10–100-fold more oncogenic than the full-length receptor and promotes the growth and survival of cancer cells. Shedding of the HER2 ECD is increased during metastasis: whereas 15% of primary breast cancer patients have elevated levels of serum HER2 ECD (sHER2 ECD), the levels reach 45% in patients with metastatic disease. Thus, sHER2 ECD has been proposed as a promising biomarker for cancer recurrence and for monitoring the disease status of patients overexpressing HER2. Nevertheless, in 2016, the American Society of Clinical Oncology advises clinicians not to use soluble HER2 levels to guide their choice of adjuvant therapy for patients with HER2-positive breast cancer, because the evidence was considered not strong enough. Currently, biomarkers such as carcinoembryonic antigen and cancer antigen 15-3 are widely used to monitor metastatic breast cancer disease even if the level of evidence of clinical impact of this monitoring is poor. In this article, we review the evidence that sHER2 ECD might be used in some situations as a biomarker for breast cancer. Although this serum biomarker will not replace the direct measurement of tumor HER2 status for diagnosis of early-stage tumors; it might be especially useful in metastatic disease for prognosis, as an indicator of cancer progression and of therapy response, particularly to anti-HER2 therapies. Owing to these data, sHER2 ECD should be considered as a promising biomarker to detect cancer recurrence and metastasis.
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