AIMS: This study aimed to examine changes in the repertoire of functional T-cells specific for six leukemia-associated antigens (LAA), including WT1, PRAME, MUC1, CCNA1, NPM1, and NPM1c, during immune reconstitution following allogeneic transplantation of hematopoietic stem cells (HSCT) in patients with acute myeloid leukemia. PATIENTS & METHODS: LAA-specific T cell response was measured by ELISPOT- IFNγ and intracellular cytokine staining in 47 patients before starting conditioning therapy (baseline) and 7 months after HSCT. RESULTS: The positive cumulative LAA-specific T cell response before HSCT was associated with a decreased risk of relapse after HSCT. The prevalent genetic aberration - an internal tandem duplication of Fms 3 - related receptor tyrosine kinase, which has been previously implicated in immune escape mechanisms, is presented here for the first time as a factor associated with the absence of an adaptive T cell response against multiple LAAs. T-cell specific responses against wild-type and mutated NPM1 antigens were less frequent in the study cohort and did not correlate with mutations in the NPM1 gene. CONCLUSIONS: Our results showed that the T-cell response to LAA can be reconstituted after HSCT. Measurement of functional pre-transplant T-cell responses against multiple LAAs could help to find patients with an increased risk of relapse.

• MeSH
• akutní myeloidní leukemie * terapie   imunologie   genetika   MeSH
• antigeny nádorové imunologie   MeSH
• dospělí MeSH
• homologní transplantace MeSH
• jaderné proteiny genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mucin 1 genetika   imunologie   MeSH
• mutace * MeSH
• nukleofosmin * MeSH
• proteiny WT1 imunologie   genetika   MeSH
• recidiva MeSH
• senioři MeSH
• T-lymfocyty * imunologie   MeSH
• transplantace hematopoetických kmenových buněk * MeSH
• tyrosinkinasa 3 podobná fms * genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Spontaneous tumor regression is a recognized phenomenon across various cancer types. Recent research emphasizes the alterations in autoantibodies against carbonic anhydrase I (CA I) (anti-CA I) levels as potential prognostic markers for various malignancies. Particularly, autoantibodies targeting CA I and II appear to induce cellular damage by inhibiting their respective protein's catalytic functions. Our study illuminates the profound impact of anti-CA I autoantibodies from patient serum on the esterase activity of human CA I, exhibiting inhibitory effects akin to the acetazolamide inhibitor. Concurrently, our newly synthesized mouse monoclonal IgG antibody, mAb 2B8, against human CA I showcased a potent inhibitory action. An in-depth exploration into mAb 2B8's binding dynamics with its target enzyme was undertaken. Leveraging epitope extraction and phage display library techniques, we identified the amino acid sequence DFWTYP (positions 191-196 of CA I) as crucial for mAb 2B8's interaction. In 3-D structural analysis, this sequence is spatially adjacent to a previously identified epitope (DFWTYP) that interacts with patient-derived autoantibodies. Critically, mAb 2B8 demonstrated an ability to infiltrate eukaryotic cells, engaging specifically with its intracytoplasmic target. This positions mAb 2B8 as a promising model for future studies aimed at tumor cell eradication.

• MeSH
• autoprotilátky * imunologie   metabolismus   MeSH
• epitopy imunologie   chemie   MeSH
• karboanhydrasa I * metabolismus   antagonisté a inhibitory   MeSH
• lidé MeSH
• monoklonální protilátky * imunologie   MeSH
• myši MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: MUC1 and UMOD pathogenic variants cause autosomal dominant tubulointerstitial kidney disease (ADTKD). MUC1 is expressed in kidney, nasal mucosa and respiratory tract, while UMOD is expressed only in kidney. Due to haplo-insufficiency ADTKD-MUC1 patients produce approximately 50% of normal mucin-1. METHODS: To determine whether decreased mucin-1 production was associated with an increased COVID-19 risk, we sent a survey to members of an ADTKD registry in September 2021, after the initial, severe wave of COVID-19. We linked results to previously obtained ADTKD genotype and plasma CA15-3 (mucin-1) levels and created a longitudinal registry of COVID-19 related deaths. RESULTS: Surveys were emailed to 637 individuals, with responses from 89 ADTKD-MUC1 and 132 ADTKD-UMOD individuals. 19/83 (23%) ADTKD-MUC1 survey respondents reported a prior COVID-19 infection vs. 14/125 (11%) ADTKD-UMOD respondents (odds ratio (OR) 2.35 (95%CI 1.60-3.11, P = 0.0260). Including additional familial cases reported from survey respondents, 10/41 (24%) ADTKD-MUC1 individuals died of COVID-19 vs. 1/30 (3%) with ADTKD-UMOD, with OR 9.21 (95%CI 1.22-69.32), P = 0.03. The mean plasma mucin-1 level prior to infection in 14 infected and 27 uninfected ADTKD-MUC1 individuals was 7.06 ± 4.12 vs. 10.21 ± 4.02 U/mL (P = 0.035). Over three years duration, our longitudinal registry identified 19 COVID-19 deaths in 360 ADTKD-MUC1 individuals (5%) vs. 3 deaths in 478 ADTKD-UMOD individuals (0.6%) (P = 0.0007). Multivariate logistic regression revealed the following odds ratios (95% confidence interval) for COVID-19 deaths: ADTKD-MUC1 8.4 (2.9-29.5), kidney transplant 5.5 (1.6-9.1), body mass index (kg/m2) 1.1 (1.0-1.2), age (y) 1.04 (1.0-1.1). CONCLUSIONS: Individuals with ADTKD-MUC1 are at an eight-fold increased risk of COVID-19 mortality vs. ADTKD-UMOD individuals. Haplo-insufficient production of mucin-1 may be responsible.

• MeSH
• COVID-19 * mortalita   genetika   MeSH
• dospělí MeSH
• intersticiální nefritida genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mucin 1 * krev   MeSH
• mutace * MeSH
• registrace MeSH
• SARS-CoV-2 genetika   MeSH
• senioři MeSH
• uromodulin MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• pozorovací studie MeSH

Analysis of cell-free DNA methylation (cfDNAme), alone or combined with CA125, could help to detect ovarian cancers earlier and may reduce mortality. We assessed cfDNAme in regions of ZNF154, C2CD4D and WNT6 via targeted bisulfite sequencing in diagnostic and early detection (preceding diagnosis) settings. Diagnostic samples were obtained via prospective blood collection in cell-free DNA tubes in a convenience series of patients with a pelvic mass. Early detection samples were matched case-control samples derived from the UK Familial Ovarian Cancer Screening Study (UKFOCSS). In the diagnostic set (ncases = 27, ncontrols = 41), the specificity of cfDNAme was 97.6% (95% CI: 87.1%-99.9%). High-risk cancers were detected with a sensitivity of 80% (56.3%-94.3%). Combination of cfDNAme and CA125 resulted in a sensitivity of 94.4% (72.7%-99.9%) for high-risk cancers. Despite technical issues in the early detection set (ncases = 29, ncontrols = 29), the specificity of cfDNAme was 100% (88.1%-100.0%). We detected 27.3% (6.0%-61.0%) of high-risk cases with relatively lower genomic DNA (gDNA) contamination. The sensitivity rose to 33.3% (7.5%-70.1%) in samples taken <1 year before diagnosis. We detected ovarian cancer in several patients up to 1 year before diagnosis despite technical limitations associated with archival samples (UKFOCSS). Combined cfDNAme and CA125 assessment may improve ovarian cancer screening in high-risk populations, but future large-scale prospective studies will be required to validate current findings.

• MeSH
• antigen CA-125 MeSH
• časná detekce nádoru metody   MeSH
• lidé MeSH
• metylace DNA * MeSH
• nádorové biomarkery genetika   MeSH
• nádory vaječníků * diagnóza   genetika   MeSH
• prospektivní studie MeSH
• studie případů a kontrol MeSH
• transkripční faktory Krüppel-like genetika   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

• MeSH
• farmakoterapie metody   MeSH
• hapteny imunologie   metabolismus   MeSH
• léková alergie diagnóza   imunologie   metabolismus   MeSH
• lékový hypersenzitivní syndrom * diagnóza   farmakoterapie   klasifikace   patofyziologie   MeSH
• nežádoucí účinky léčiv klasifikace   MeSH
• rizikové faktory MeSH
• Publikační typ
• přehledy MeSH

OBJECTIVES: To externally and prospectively validate the International Ovarian Tumor Analysis (IOTA) Simple Rules (SRs), Logistic Regression model 2 (LR2) and Assessment of Different NEoplasias in the adneXa (ADNEX) model in a Portuguese population, comparing these approaches with subjective assessment and the risk-of-malignancy index (RMI), as well as with each other. This study also aimed to retrospectively validate the IOTA two-step strategy, using modified benign simple descriptors (MBDs) followed by the ADNEX model in cases in which MBDs were not applicable. METHODS: This was a prospective multicenter diagnostic accuracy study conducted between January 2016 and December 2021 of consecutive patients with an ultrasound diagnosis of at least one adnexal tumor, who underwent surgery at one of three tertiary referral centers in Lisbon, Portugal. All ultrasound assessments were performed by Level-II or -III sonologists with IOTA certification. Patient clinical data and serum CA 125 levels were collected from hospital databases. Each adnexal mass was classified as benign or malignant using subjective assessment, RMI, IOTA SRs, LR2 and the ADNEX model (with and without CA 125). The reference standard was histopathological diagnosis. In the second phase, all adnexal tumors were classified retrospectively using the two-step strategy (MBDs + ADNEX). Sensitivity, specificity, positive and negative predictive values, positive and negative likelihood ratios and overall accuracy were determined for all methods. Receiver-operating-characteristics curves were constructed and corresponding areas under the curve (AUC) were determined for RMI, LR2, the ADNEX model and the two-step strategy. The ADNEX model calibration plots were constructed using locally estimated scatterplot smoothing (LOESS). RESULTS: Of the 571 patients included in the study, 428 had benign disease and 143 had malignant disease (prevalence of malignancy, 25.0%), of which 42 had borderline ovarian tumor, 93 had primary invasive adnexal cancer and eight had metastatic tumors in the adnexa. Subjective assessment had an overall sensitivity of 97.9% and a specificity of 83.6% for distinguishing between benign and malignant lesions. RMI showed high specificity (95.6%) but very low sensitivity (58.7%), with an AUC of 0.913. The IOTA SRs were applicable in 80.0% of patients, with a sensitivity of 94.8% and specificity of 98.6%. The IOTA LR2 had a sensitivity of 84.6%, specificity of 86.9% and an AUC of 0.939, at a malignancy risk cut-off of 10%. At the same cut-off, the sensitivity, specificity and AUC for the ADNEX model with vs without CA 125 were 95.8% vs 98.6%, 82.5% vs 79.7% and 0.962 vs 0.960, respectively. The ADNEX model gave heterogeneous results for distinguishing between benign masses and different subtypes of malignancy, with the highest AUC (0.991) for discriminating benign masses from primary invasive adnexal cancer Stages II-IV, and the lowest AUC (0.696) for discriminating primary invasive adnexal cancer Stage I from metastatic lesion in the adnexa. The calibration plot suggested underestimation of the risk by the ADNEX model compared with the observed proportion of malignancy. The MBDs were applicable in 26.3% (150/571) of cases, of which none was malignant. The two-step strategy using the ADNEX model in the second step only, with and without CA 125, had AUCs of 0.964 and 0.961, respectively, which was similar to applying the ADNEX model in all patients. CONCLUSIONS: The IOTA methods showed good-to-excellent performance in the Portuguese population, outperforming RMI. The ADNEX model was superior to other methods in terms of accuracy, but interpretation of its ability to distinguish between malignant subtypes was limited by sample size and large differences in the prevalence of tumor subtypes. The IOTA MBDs are reliable in identifying benign disease. The two-step strategy comprising application of MBDs followed by the ADNEX model if MBDs are not applicable, is suitable for daily clinical practice, circumventing the need to calculate the risk of malignancy in all patients. © 2024 International Society of Ultrasound in Obstetrics and Gynecology.

• MeSH
• antigen CA-125 krev   MeSH
• diferenciální diagnóza MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• logistické modely MeSH
• nádory vaječníků * diagnostické zobrazování   patologie   klasifikace   krev   MeSH
• nemoci děložních adnex * diagnostické zobrazování   MeSH
• prediktivní hodnota testů MeSH
• prospektivní studie MeSH
• reprodukovatelnost výsledků MeSH
• retrospektivní studie MeSH
• ROC křivka MeSH
• senioři MeSH
• senzitivita a specificita MeSH
• ultrasonografie * metody   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• validační studie MeSH
• Geografické názvy
• Portugalsko MeSH

Human immunodeficiency virus type 1 (HIV-1) vaccine immunogens capable of inducing broadly neutralizing antibodies (bNAbs) remain obscure. HIV-1 evades immune responses through enormous diversity and hides its conserved vulnerable epitopes on the envelope glycoprotein (Env) by displaying an extensive immunodominant glycan shield. In elite HIV-1 viremic controllers, glycan-dependent bNAbs targeting conserved Env epitopes have been isolated and are utilized as vaccine design templates. However, immunological tolerance mechanisms limit the development of these antibodies in the general population. The well characterized bNAbs monoclonal variants frequently exhibit extensive levels of somatic hypermutation, a long third heavy chain complementary determining region, or a short third light chain complementarity determining region, and some exhibit poly-reactivity to autoantigens. This review elaborates on the obstacles to engaging and manipulating the Env glycoprotein as an effective immunogen and describes an alternative reverse vaccinology approach to develop a novel category of bNAb-epitope-derived non-cognate immunogens for HIV-1 vaccine design.

• MeSH
• epitopy imunologie   MeSH
• genové produkty env - virus lidské imunodeficience imunologie   MeSH
• HIV infekce imunologie   MeSH
• HIV protilátky * imunologie   MeSH
• HIV-1 * imunologie   MeSH
• lidé MeSH
• ligandy MeSH
• molekulární mimikry imunologie   MeSH
• neutralizující protilátky * imunologie   MeSH
• polysacharidy imunologie   MeSH
• vakcíny proti AIDS * imunologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

BACKGROUND/AIM: Classical serum cancer biomarkers, such as carcinoembryonic antigen (CEA) and cancer antigen 19-9 (CA 19-9), remain important tools in colorectal cancer (CRC) management for disease follow up. However, their sensitivity and specificity are low for diagnostic and prognostic evaluation. The aim of this study was to evaluate the potential of biomarkers reflecting biological activity of tumors - tissue polypeptide specific antigen (TPS), cytokeratin fragment 19 (CYFRA 21-1), thymidine kinase (TK), insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 3 (IGF-BP3) - together with the CEA and CA 19-9 in CRC diagnosis and prognosis. PATIENTS AND METHODS: This is a retrospective study including 148 CRC patients and 68 age-matched healthy subjects. Serum biomarkers were measured in pre-operative serum samples using immunoanalytical methods. The end-point for the diagnostic evaluation was the area under the receiving operating characteristic curve (AUC ROC) of the biomarkers. The end-point for the prognostic evaluation was overall survival. RESULTS: Serum levels of CEA, CA 19-9, TPS, and TK were significantly increased in CRC early-stage patients compared with healthy controls. Each of the studied biomarkers had AUC between 0.6 and 0.7. Analysis of survival demonstrated that the patients with CEA, CA 19-9, cytokeratin, and TK above optimal cut offs had significantly shorter survival. A multivariate analysis performed on all the study biomarkers resulted in the selection of CYFRA 21-1 as the best performing biomarker with hazard ratio 10.413. CONCLUSION: The combination of cytokeratins and thymidine kinase with classical cancer biomarkers enables the prediction of tumor aggressiveness and long-term prognosis.

• MeSH
• antigen CA-19-9 * krev   MeSH
• antigeny nádorové krev   MeSH
• dospělí MeSH
• insulinu podobný růstový faktor I metabolismus   MeSH
• karcinoembryonální antigen * krev   MeSH
• keratin-19 krev   MeSH
• keratiny krev   MeSH
• kolorektální nádory * krev   diagnóza   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádorové biomarkery * krev   MeSH
• peptidy MeSH
• prognóza MeSH
• retrospektivní studie MeSH
• ROC křivka MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• studie případů a kontrol MeSH
• thymidinkináza * krev   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Bolivian hemorrhagic fever (BHF) caused by Machupo virus (MACV) is a New World arenavirus having a reported mortality rate of 25-35%. The BHF starts with fever, followed by headache, and nausea which rapidly progresses to severe hemorrhagic phase within 7 days of disease onset. One of the key promoters for MACV viral entry into the cell followed by viral propagation is performed by the viral glycoprotein (GPC). GPC is post-transcriptionally cleaved into GP1, GP2 and a signal peptide. These proteins all take part in the viral infection in host body. Therefore, GPC protein is an ideal target for developing therapeutics against MACV infection. In this study, GPC protein was considered to design a multi-epitope, multivalent vaccine containing antigenic and immunogenic CTL and HTL epitopes. Different structural validations and physicochemical properties were analysed to validate the vaccine. Docking and molecular dynamics simulations were conducted to understand the interactions of the vaccine with various immune receptors. Finally, the vaccine was codon optimised in silico and along with which immune simulation studies was performed in order to evaluate the vaccine's effectiveness in triggering an efficacious immune response against MACV.

• MeSH
• americká hemoragická horečka * imunologie   prevence a kontrola   MeSH
• arenaviry Nového světa imunologie   MeSH
• epitopy imunologie   chemie   MeSH
• lidé MeSH
• simulace molekulární dynamiky MeSH
• simulace molekulového dockingu MeSH
• virové vakcíny * imunologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Flaviviruses such as dengue virus (DENV), Zika virus (ZIKV), and yellow fever virus (YFV) are spread by mosquitoes and cause human disease and mortality in tropical areas. In contrast, Powassan virus (POWV), which causes severe neurologic illness, is a flavivirus transmitted by ticks in temperate regions of the Northern hemisphere. We find serologic neutralizing activity against POWV in individuals living in Mexico and Brazil. Monoclonal antibodies P002 and P003, which were derived from a resident of Mexico (where POWV is not reported), neutralize POWV lineage I by recognizing an epitope on the virus envelope domain III (EDIII) that is shared with a broad range of tick- and mosquito-borne flaviviruses. Our findings raise the possibility that POWV, or a flavivirus closely related to it, infects humans in the tropics.

• MeSH
• epitopy imunologie   MeSH
• Flavivirus imunologie   MeSH
• klíšťata virologie   imunologie   MeSH
• lidé MeSH
• monoklonální protilátky imunologie   MeSH
• neutralizující protilátky * imunologie   MeSH
• protilátky virové imunologie   MeSH
• viry klíšťové encefalitidy imunologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Brazílie MeSH
• Mexiko MeSH