A case-control study on the combined effects of p53 and p73 polymorphisms on head and neck cancer risk in an Italian population

<p>Abstract</p> <p>Background</p> <p>The purpose of this study is to analyze the combined effects of selected <it>p</it>53 and <it>p</it>73 polymorphisms and their interaction with lifestyle habits on squamous cell carcinoma of the head and neck (SCCHN) risk and progression in an Italian population.</p> <p>Methods</p> <p>Two hundred and eighty-three cases and 295 hospital controls were genotyped for <it>p</it>53 polymorphisms on exon 4 (Arg72Pro), intron 3 and 6, and <it>p</it>73 G4C14-to-A4T14. Their association with SCCHN was estimated using a logistic regression analysis, while a multinomial logistic regression approach was applied to calculate the effect of the selected polymorphisms on SCCHN different sites (oral cavity, oropharynx, hypopharynx and larynx). We performed an haplotype analysis of the <it>p</it>53 polymorphisms, and a gene-gene interaction analysis for the combined effects of <it>p</it>73 G4C14-to-A4T14 and <it>p</it>53 polymorphisms.</p> <p>Results</p> <p>We found a significant increased risk of SCCHN among individuals with combined <it>p</it>73 exon 2 G4A and <it>p</it>53 intron 3 variant alleles (OR = 2.22, 95% CI: 1.08–4.56), and a protective effect for those carrying the <it>p</it>53 exon 4-<it>p</it>53 intron 6 diplotype combination (OR = 0.67; 95% CI: 0.47–0.92). From the gene-environment interaction analysis we found that individuals aged < 45 years carrying <it>p</it>73 exon 2 G4A variant allele have a 12.85-increased risk of SCCHN (95% CI: 2.10–78.74) compared with persons of the same age with the homozygous wild type genotype. Improved survival rate was observed among <it>p</it>53 intron 6 variant allele carriers (Hazard Ratio = 0.51 (95% CI: 0.23–1.16).</p> <p>Conclusion</p> <p>Our study provides for the first time evidence that individuals carrying <it>p</it>53 exon 4 and <it>p</it>53 intron 6 variant alleles are significantly protected against SCCHN, and also shows that an additional risk is conferred by the combination of <it>p</it>73 exon 2 G4C14-to-A4T14 and <it>p</it>53 intron 3 variant allele. Larger studies are required to confirm these findings.</p

Humoral and cellular immune response elicited by mRNA vaccination against SARS-CoV-2 in people living with HIV (PLWH) receiving antiretroviral therapy (ART) according with current CD4 T-lymphocyte count

BACKGROUND: Data on SARS-CoV-2 vaccine immunogenicity in PLWH are currently limited. Aim of the study was to investigate immunogenicity according to current CD4 T-cell count. METHODS: PLWH on ART attending a SARS-CoV-2 vaccination program, were included in a prospective immunogenicity evaluation after receiving BNT162b2 or mRNA-1273. Participants were stratified by current CD4 T-cell count (poor CD4 recovery, PCDR: 500/mm^{3}). RBD-binding IgG, SARS-CoV-2 neutralizing antibodies (nAbs) and IFN-γ release were measured. As control group, HIV-negative healthcare workers (HCWs) were used. FINDINGS: Among 166 PLWH after 1 month from the second dose, detectable RBD-binding IgG were elicited in 86.7% of PCDR, 100% of ICDR, 98.7% of HCDR, and a neutralizing titre ≥1:10 elicited in 70.0%, 88.2% and 93.1%, respectively. Compared to HCDR, all immune response parameters were significantly lower in PCDR. After adjusting for confounders, current CD4 T-cell 500 cell/mm^{3} and HIV-negative controls. A decreased RBD-binding antibody response than HCWs was also observed in PLWH with CD4 T-cell 200-500/mm^{3}, whereas immune response elicited in PLWH with a CD4 T-cell >500/mm^{}3 was comparable to HIV-negative population

Co-mutation pattern, clonal hierarchy, and clone size concur to determine disease phenotype of SRSF2 P95-mutated neoplasms

Somatic mutations in splicing factor genes frequently occur in myeloid neoplasms. While SF3B1 mutations are associated with myelodysplastic syndromes (MDS) with ring sideroblasts, SRSF2P95 mutations are found in different disease categories, including MDS, myeloproliferative neoplasms (MPN), myelodysplastic/myeloproliferative neoplasms (MDS/MPN), and acute myeloid leukemia (AML). To identify molecular determinants of this phenotypic heterogeneity, we explored molecular and clinical features of a prospective cohort of 279 SRSF2P95-mutated cases selected from a population of 2663 patients with myeloid neoplasms. Median number of somatic mutations per subject was 3. Multivariate regression analysis showed associations between co-mutated genes and clinical phenotype, including JAK2 or MPL with myelofibrosis (OR = 26.9); TET2 with monocytosis (OR = 5.2); RAS-pathway genes with leukocytosis (OR = 5.1); and STAG2, RUNX1, or IDH1/2 with blast phenotype (MDS or AML) (OR = 3.4, 1.9, and 2.1, respectively). Within patients with SRSF2-JAK2 co-mutation, JAK2 dominance was invariably associated with clinical feature of MPN, whereas SRSF2 mutation was dominant in MDS/MPN. Within patients with SRSF2-TET2 co-mutation, clinical expressivity of monocytosis was positively associated with co-mutated clone size. This study provides evidence that co-mutation pattern, clone size, and hierarchy concur to determine clinical phenotype, tracing relevant genotype-phenotype associations across disease entities and giving insight on unaccountable clinical heterogeneity within current WHO classification categories

Autopsies Revealed Pathological Features of COVID-19 in Unvaccinated vs. Vaccinated Patients

Background: In Italy, by the end of 2021, a new pandemic wave led to increased hospitalizations and death, even in some vaccinated people. We aimed to investigate the death of COVID-19-vaccinated patients who acquired infection and developed severe disease, and to assess differences with fatal COVID-19 in unvaccinated subjects by studying the pathological events triggered by SARS-CoV-2. Methods: Detailed autoptic examination was performed on five fully vaccinated compared to five unvaccinated patients. Histopathological analysis focused on the lung and heart, the two major affected organs. Results: COVID-19 caused, or contributed to death, in all the unvaccinated cases. By contrast, in vaccinated group, pre-existing pathologies played a major role, and death was not COVID-19-related in four out of five patients. These patients did not show the histological features of SARS-CoV-2 lung damage. Diffuse inflammatory macrophages infiltration recently emerged as the main feature of COVID-19 cardiac injury. Interestingly, the most striking difference between the two groups was the absence of increased macrophage infiltration in the heart of vaccinated patients. Conclusions: Results of this study confirm the efficacy of anti-SARS-CoV-2 vaccination in protecting organs from injury and support the need to maintain an adequate immune response by booster dose administration

Patient-centredness and e-Health among the Italian Hospitals: results of a cross-sectional web-based survey

OBJECTIVES: Given the growing recognition of patient-centeredness as a healthcare quality indicator and its limited implementation in practice, our study evaluated how the Italian hospitals (ItHs), including research hospitals (IRCCSs), research teaching hospitals (THs), and independent public hospital trusts (AOs), address the dimension of online data access through their institutional Web sites to promote a patient-centered care. MATERIALS AND METHODS: To address patient-centeredness and e-health, eight specific indicators adapted from the Euro Health Consumer Index were evaluated from 169 ItHs: online booking of healthcare services; access to medical records; register of legitimate doctors; waiting times for most commonly delivered healthcare services; transport information; centralized booking; public relations office; and pain management hospital committee. Univariate and bivariate statistics and a logistic regression analysis have been performed. RESULTS: The majority of the ItHs were under public ownership, and half of them are located in Northern Italy. From the logistic regression analysis, AOs appeared to be more likely to develop a patient-centered healthcare approach (odds ratio [OR]=3.69; 95% confidence interval [CI] 1.14-11.89) compared with IRCCSs or THs. In addition, when grouped together, all public hospitals show more than threefold higher implementation of patient-centeredness strategies (OR=3.60; 95% CI 1.49-8.72) with respect to private ones. Northern hospitals are more likely to ensure wider implementation of a patient-centered approach to healthcare (OR=3.37; 95% CI 1.49-7.62). CONCLUSIONS: According to our results, most of the ItHs are under public ownership, and half of them are located in the northern regions of Italy. The higher implementation of patient-centeredness strategies observed for Northern hospitals highlights interregional disparity in healthcare that needs a coordinated effort at both the hospital and policymaker levels to ensure a widespread implementation of patient-centered care among all Italian regions

SARS-CoV-2 Omicron Variant Neutralization after Third Dose Vaccination in PLWH

The aim was to measure neutralizing antibody levels against the SARS-CoV-2 Omicron (BA.1) variant in serum samples obtained from vaccinated PLWH and healthcare workers (HCW) and compare them with those against the Wuhan-D614G (W-D614G) strain, before and after the third dose of a mRNA vaccine. We included 106 PLWH and 28 HCWs, for a total of 134 participants. Before the third dose, the proportion of participants with undetectable nAbsT against BA.1 was 88% in the PLWH low CD4 nadir group, 80% in the high nadir group and 100% in the HCW. Before the third dose, the proportion of participants with detectable nAbsT against BA.1 was 12% in the PLWH low nadir group, 20% in the high nadir group and 0% in HCW, respectively. After 2 weeks from the third dose, 89% of the PLWH in the low nadir group, 100% in the high nadir group and 96% of HCW elicited detectable nAbsT against BA.1. After the third dose, the mean log2 nAbsT against BA.1 in the HCW and PLWH with a high nadir group was lower than that seen against W-D614G (6.1 log2 (&plusmn;1.8) vs. 7.9 (&plusmn;1.1) and 6.4 (&plusmn;1.3) vs. 8.6 (&plusmn;0.8)), respectively. We found no evidence of a different level of nAbsT neutralization by BA.1 vs. W-D614G between PLWH with a high CD4 nadir and HCW (0.40 (&minus;1.64, 2.43); p = 0.703). Interestingly, in PLWH with a low CD4 nadir, the mean log2 difference between nAbsT against BA.1 and W-D614G was smaller in those with current CD4 counts 201&ndash;500 vs. those with CD4 counts &lt; 200 cells/mm3 (&minus;0.80 (&minus;1.52, &minus;0.08); p = 0.029), suggesting that in this target population with a low CD4 nadir, current CD4 count might play a role in diversifying the level of SARS-CoV-2 neutralization

Immunogenicity to COVID-19 mRNA vaccine third dose in people living with HIV

HIV infection may affect the immune response to vaccination. Here the authors show that humoral response in persons living with HIV after the third dose of a SARS-CoV-2 vaccine is strong and higher than that achieved with the second dose, while cell-mediated immunity remains stable.In order to investigate safety and immunogenicity of SARS-CoV-2 vaccine third dose in people living with HIV (PLWH), we analyze anti-RBD, microneutralization assay and IFN-gamma production in 216 PLWH on ART with advanced disease (CD4 count &lt;200 cell/mm(3) and/or previous AIDS) receiving the third dose of a mRNA vaccine (BNT162b2 or mRNA-1273) after a median of 142 days from the second dose. Median age is 54 years, median CD4 nadir 45 cell/mm(3) (20-122), 93% HIV-RNA &lt; 50 c/mL. In 68% of PLWH at least one side-effect, generally mild, is recorded. Humoral response after the third dose was strong and higher than that achieved with the second dose (&gt;2 log(2) difference), especially when a heterologous combination with mRNA-1273 as third shot is used. In contrast, cell-mediated immunity remain stable. Our data support usefulness of third dose in PLWH currently receiving suppressive ART who presented with severe immune dysregulation

Humoral and Cellular Immune Response Elicited by mRNA Vaccination Against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in People Living With Human Immunodeficiency Virus Receiving Antiretroviral Therapy Based on Current CD4 T-Lymphocyte Count

Humoral and cell-mediated immune-response against SARS-CoV-2 were elicited in PLWH, significantly poorer in those with CD4 T-cell 500 cell/mm(3)and HIV-negative controls; immune response in PLWH with a CD4 T-cell &gt;500/mm3 was comparable to HIV-negative population.Background Data on SARS-CoV-2 vaccine immunogenicity in PLWH are currently limited. Aim of the study was to investigate immunogenicity according to current CD4 T-cell count Methods PLWH on ART attending a SARS-CoV-2 vaccination program, were included in a prospective immunogenicity evaluation after receiving BNT162b2 or mRNA-1273. Participants were stratified by current CD4 T-cell count (poor CD4 recovery, PCDR: &lt;200/mm(3); intermediate CD4 recovery, ICDR: 200-500/mm(3); high CD4 recovery, HCDR: &gt;500/mm(3)). RBD-binding IgG, SARS-CoV-2 neutralizing antibodies (nAbs) and IFN-gamma release were measured. As control group, HIV-negative healthcare workers (HCWs) were used Findings Among 166 PLWH, after 1 month from the booster dose, detectable RBD-binding IgG were elicited in 86.7% of PCDR, 100% of ICDR, 98.7% of HCDR, and a neutralizing titre &gt;= 1:10 elicited in 70.0%, 88.2%, and 93.1%, respectively. Compared to HCDR, all immune response parameters were significantly lower in PCDR. After adjusting for confounders, current CD4 T-cell &lt;200/mm3 significantly predicted a poor magnitude of anti-RDB, nAbs and IFN-gamma response. As compared with HCWs, PCDR elicited a consistently reduced immunogenicity for all parameters, ICDR only a reduced RBD-binding antibody response, whereas HCDR elicited a comparable immune response for all parameters Conclusion Humoral and cell-mediated immune response against SARS-CoV-2 were elicited in most of PLWH, albeit significantly poorer in those with CD4 T-cell 500 cell/mm(3) and HIV-negative controls. A lower RBD-binding antibody response than HCWs was also observed in PLWH with CD4 T-cell 200-500/mm(3), whereas immune response elicited in PLWH with a CD4 T-cell &gt;500/mm(3) was comparable to HIV-negative populatio