An increasing body of evidence from both academic and clinical studies shows that time-of-day exposure to antigens might significantly alter and modulate the development of adaptive immune responses. Considering the immense impact of the COVID-19 pandemic on global health and the diminished efficacy of vaccination in selected populations, such as older and immunocompromised patients, it is critical to search for the most optimal conditions for mounting immune responses against SARS-CoV-2. Hence, we conducted an observational study on 435 healthy young adults vaccinated with two doses of BNT162b2 (Pfizer-BioNTech) vaccine to determine whether time-of-day of vaccination influences either the magnitude of humoral response or number of adverse drug reactions (ADR) being reported. We found no significant differences between morning and afternoon vaccination in terms of both titers of anti-Spike antibodies and frequency of ADR in the studied population. In addition, our analysis of data on the occurrence of ADR in 1324 subjects demonstrated that the second administration of vaccine in those with previous SARS-CoV-2 infection was associated with lower incidence of ADR. In aggregate, vaccination against COVID-19 with two doses of BNT162b2 mRNA vaccine is presumed to generate an equally efficient anti-Spike humoral response.
IL6ST encodes the GP130 protein which transduces the proinflammatory signaling of the IL6 cytokine family through JAK/STAT activation. Biallelic loss-of-function IL6ST variants cause autosomal recessive hyper-IgE syndrome or a variant of Stuve-Wiedemann syndrome. Somatic gain-of-function IL6ST mutations, in particular small monoallelic in-frame deletions of which the most prevalent is IL6ST Ser187_Tyr190del, are an established cause of inflammatory hepatocellular tumors (IHCA) but so far, no disease caused by such mutations present constitutively has been described. Herein, we report a pediatric proband with a novel syndrome of neonatal onset immunodeficiency with autoinflammation and dysmorphy associated with the IL6ST Tyr186_Tyr190del variant present constitutively. Tyr186_Tyr190del was found by exome sequencing and shown to be de novo (absent in proband’s parents and siblings) and mosaic (present in approx. 15–40% of cells depending on the tissue studied—blood, urine sediment, hair bulbs, buccal swab). Functional studies were performed in EBV-immortalized patient’s B-cell lymphoblastoid cell line, which carried the variant in approximately 95% of cells. Western blot showed that the patient’s cells exhibited constitutive hyperphosphorylation of Tyr705 in STAT3 indicative of IL6 independent activation of GP130. Interestingly, the STAT3 phosphorylation could be inhibited with ruxolitinib as well as tofacitinib, which are clinically approved JAK1 and JAK3 (to lesser extent JAK2 and JAK1) inhibitors, respectively. Given our results and the recent reports of ruxolitinib and tofacitinib use for the treatment of diseases caused by direct activation of STAT3 or STAT1 we speculate that these drugs may be effective in the treatment of our patient’s condition.
DNA damage response (DDR) deficiencies result in genome instability, which is one of the hallmarks of cancer. Poly (ADP-ribose) polymerase (PARP) enzymes take part in various DDR pathways, determining cell fate in the wake of DNA damage. PARPs are readily druggable and PARP inhibitors (PARPi) against the main DDR-associated PARPs, PARP1 and PARP2, are currently approved for the treatment of a range of tumor types. Inhibition of efficient PARP1/2-dependent DDR is fatal for tumor cells with homologous recombination deficiencies (HRD), especially defects in breast cancer type 1 susceptibility protein 1 or 2 (BRCA1/2)-dependent pathway, while allowing healthy cells to survive. Moreover, PARPi indirectly influence the tumor microenvironment by increasing genomic instability, immune pathway activation and PD-L1 expression on cancer cells. For this reason, PARPi might enhance sensitivity to immune checkpoint inhibitors (ICIs), such as anti-PD-(L)1 or anti-CTLA4, providing a rationale for PARPi-ICI combination therapies. In this review, we discuss the complex background of the different roles of PARP1/2 in the cell and summarize the basics of how PARPi work from bench to bedside. Furthermore, we detail the early data of ongoing clinical trials indicating the synergistic effect of PARPi and ICIs. We also introduce the diagnostic tools for therapy development and discuss the future perspectives and limitations of this approach.
Ovarian cancer, like breast cancer, may either develop spontaneously or as a result of a family history. BRCA1 and BRCA2 mutations significantly increase the risk of both cancers at all ages. It is estimated that 3–5% of women are BRCA mutation carriers. BRCA1 mutation carriers have a 65% risk of breast cancer and 39% risk of ovarian cancer. These risks are lower among BRCA2 mutation carriers, i.e. 45% and 11% for breast and ovarian cancer, respectively. In breast and ovarian cancer with BRCA mutations, blocking the function of poly(ADP-ribose) polymerase (PARP) enzymes, including PARP1 and PARP2, causes an accumulation of DNA damage that ultimately leads to cancer cell death. Based on this mechanism, PARP inhibitors have been used in the treatment of hereditary neoplasms, in which the proper functioning of DNA damage repair systems is disturbed. In clinical trials to date, PARP inhibitors significantly extended the progression-free survival in patients with confirmed BRCA mutations. Similar results have been obtained for patients without confirmed genetic background. Currently, PARP inhibitors are increasingly approved for use in the treatment of ovarian and breast cancer. From May 2021, the Ministry of Health has reimbursed maintenance therapy with PARP inhibitors in patients with known BRCA mutation status.
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