Hasil untuk "Immunologic diseases. Allergy"

Li Ma, Junbo Wu, Yunyi Du et al.

Immune checkpoint inhibitors (ICIs) may cause immune-related adverse events (irAEs), ranging from mild to life-threatening. High-risk irAEs can lead to treatment discontinuation and higher mortality, though ICI-treated patients’ death rate is under 5%. Currently, no reliable biomarkers predict irAEs’ occurrence or severity. This study investigates the link between accessible biomarkers and high-risk irAEs in gastric cancer patients on ICIs, as well as to develop and assess a predictive model for such events. Data were collected from patients with gastric cancer who received ICIs therapy between May 2020 and March 2025. The incidence and risk factors associated with irAEs were analyzed using the chi-square test or the Mann–Whitney U test. Univariate and multivariate logistic regression analyses were conducted to develop a predictive model. This model was validated through 10-fold cross-validation and assessed using the area under the receiver operating characteristic curve (AUC), sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), calibration curves, and decision curve analysis. A total of 184 gastric cancer patients receiving ICIs therapy were enrolled in this study. The incidence of irAEs of any grade was 21.2%, while the incidence of grade ≥3 irAEs was 12.5%. Multivariate logistic regression analysis identified NLR-1 (p < .001), NLR2-1 (p < .001), PLR-1 (p = .001), tumor thickness (p = .018), CV (p = .001), and intratumoral necrosis (p = .028) as independent predictors of grade ≥3 irAEs. The AUC of the developed model was 0.878, with a sensitivity of 78.26%, specificity of 80.12%, PPV of approximately 80.95%, and NPV of approximately 75.52%. The corrected C-index, derived from bootstrap resampling, was 0.849, and both calibration curves and decision curve analysis confirmed good calibration and clinical utility. These predictors may aid risk stratification and optimized patient management.

Lorenzo Briganti, Arun S. Annamalai, Stephanie M. Bester et al.

ABSTRACT Lenacapavir (LEN) is the first-in-class viral capsid protein (CA) targeting antiretroviral for treating multi-drug-resistant HIV-1 infection. Clinical trials and cell culture experiments have identified resistance-associated mutations (RAMs) in the vicinity of the hydrophobic CA pocket targeted by LEN. The M66I substitution conferred by far the highest level of resistance to the inhibitor compared to other RAMs. Here we investigated structural and mechanistic bases for how the M66I change affects LEN binding to CA and viral replication. The high-resolution X-ray structure of the CA(M66I) hexamer revealed that the β-branched side chain of Ile66 induces steric hindrance specifically to LEN, thereby markedly reducing the inhibitor binding affinity. By contrast, the M66I substitution did not affect the binding of Phe-Gly (FG)-motif-containing cellular cofactors CPSF6, NUP153, or SEC24C, which engage the same hydrophobic pocket of CA. In cell culture, the M66I variant did not acquire compensatory mutations. Analysis of viral replication intermediates revealed that HIV-1 (M66I CA) predominantly formed correctly matured viral cores, which were more stable than their wild-type counterparts. The mutant cores stably bound to the nuclear envelope but failed to penetrate inside the nucleus. Furthermore, the M66I substitution markedly altered HIV-1 integration targeting. Taken together, our findings elucidate mechanistic insights into how the M66I change confers remarkable resistance to LEN and affects HIV-1 replication. Moreover, our structural findings provide a powerful means for future medicinal chemistry efforts to rationally develop second-generation inhibitors with a higher barrier to resistance. IMPORTANCE Lenacapavir (LEN) is a highly potent and long-acting antiretroviral that works by a unique mechanism of targeting the viral capsid protein. The inhibitor is used in combination with other antiretrovirals to treat multi-drug-resistant HIV-1 infection in heavily treatment-experienced adults. Furthermore, LEN is in clinical trials for preexposure prophylaxis (PrEP) with interim results indicating 100% efficacy to prevent HIV-1 infections. However, one notable shortcoming is a relatively low barrier of viral resistance to LEN. Clinical trials and cell culture experiments identified emergent resistance mutations near the inhibitor binding site on capsid. The M66I variant was the most prevalent capsid substitution identified in patients receiving LEN to treat multi-drug-resistant HIV-1 infections. The studies described here elucidate the underlying mechanism by which the M66I substitution confers a marked resistance to the inhibitor. Furthermore, our structural findings will aid future efforts to develop the next generation of capsid inhibitors with enhanced barriers to resistance.

Jannatul Ruhan Raha, Ki-Hye Kim, Chau Thuy Tien Le et al.

Brook Jeang, Daibin Zhong, Ming-Chieh Lee et al.

Abstract Background Timely molecular surveillance of Plasmodium falciparum kelch 13 (k13) gene mutations is essential for monitoring the emergence and stemming the spread of artemisinin resistance. Widespread artemisinin resistance, as observed in Southeast Asia, would reverse significant gains that have been made against the malaria burden in Africa. The purpose of this study was to assess the prevalence of k13 polymorphisms in western Kenya and Ethiopia at sites representing varying transmission intensities between 2018 and 2022. Methods Dried blood spot samples collected through ongoing passive surveillance and malaria epidemiological studies, respectively, were investigated. The k13 gene was genotyped in P. falciparum isolates with high parasitaemia: 775 isolates from four sites in western Kenya (Homa Bay, Kakamega, Kisii, and Kombewa) and 319 isolates from five sites across Ethiopia (Arjo, Awash, Gambella, Dire Dawa, and Semera). DNA sequence variation and neutrality were analysed within each study site where mutant alleles were detected. Results Sixteen Kelch13 haplotypes were detected in this study. Prevalence of nonsynonymous k13 mutations was low in both western Kenya (25/783, 3.19%) and Ethiopia (5/319, 1.57%) across the study period. Two WHO-validated mutations were detected: A675V in three isolates from Kenya and R622I in four isolates from Ethiopia. Seventeen samples from Kenya carried synonymous mutations (2.17%). No synonymous mutations were detected in Ethiopia. Genetic variation analyses and tests of neutrality further suggest an excess of low frequency polymorphisms in each study site. Fu and Li’s F test statistic in Semera was 0.48 (P > 0.05), suggesting potential population selection of R622I, which appeared at a relatively high frequency (3/22, 13.04%). Conclusions This study presents an updated report on the low frequency of k13 mutations in western Kenya and Ethiopia. The WHO-validated R622I mutation, which has previously only been reported along the north-west border of Ethiopia, appeared in four isolates collected from eastern Ethiopia. The rapid expansion of R622I across Ethiopia signals the need for enhanced monitoring of the spread of drug-resistant P. falciparum parasites in East Africa. Although ACT remains currently efficacious in the study areas, continued surveillance is necessary to detect early indicators of artemisinin partial resistance.

Austin T. Hertel, Cynthia M. McMillen, Ryan M. Hoehl et al.

Abstract Rift Valley fever virus (RVFV) causes high rates of spontaneous abortions and neonatal mortality in ruminants resulting in severe socioeconomic and public health consequences. Maternal vaccination may protect pregnant animals, fetuses, and neonates via transfer of maternal antibodies; however, currently available live-attenuated RVFV vaccines are generally unsafe for use during pregnancy. RVFV-delNSs/NSm is a live attenuated strain that has demonstrated favorable safety and efficacy in pregnant livestock, yet studies investigating maternal vaccination as a strategy to protect neonates from RVF are limited. Using pregnant Sprague-Dawley rats, we show that maternal vaccination with RVFV-delNSs/NSm leads to efficient transfer of anti-RVFV antibodies to offspring. These offspring were completely protected from lethal RVFV challenge. Although further investigation is required in susceptible ruminant species, our findings indicate that maternal anti-RVFV immunity is sufficient to protect offspring, highlighting maternal vaccination as a potential strategy to reduce RVF disease burden in endemic regions.

Jessica Sherry, Komal Ishwar Pawar, Lee Dolat et al.

Elena Morrocchi, Simon van Haren, Paolo Palma et al.

Yuya Fujita, Haruki Matsumoto, Kenji Inada et al.

AbstractThe complement component C5a contributes to the recruitment of immune cells to inflamed tissues and local inflammation. The proinflammatory cytokine interleukin (IL)-1β is also related to inflammatory disorders through inflammasome activation. However, the association between inflammasome activation and C5a is unclear. Human peripheral blood mononuclear cells (PBMCs) were stimulated with C5a and measured for IL-1β secretion by enzyme-linked immunosorbent assay (ELISA). The pro-IL-1β expression in cell lysates was also examined by Western blot analysis. Similarly, magnetic bead-isolated CD14+ monocyte-depleted and lymphocyte-depleted PBMCs were stimulated with C5a, and immunoblot analysis was performed using an anti-cleaved-IL-1β (p17) antibody. FACS was performed to detect caspase-1-activated cells. C5a-stimulated PBMCs produced IL-1β in C5a concentration-dependent manner. The protein levels of pro-IL-1β in the cell lysates were significantly increased. Furthermore, the cleaved-IL-1β (p17) was faintly detected in the same lysates. Active caspase-1 was demonstrated in C5a-simulated CD14+ monocytes by FACS. Cleaved-IL-1β (p17) was demonstrated in the supernatant of C5a-stimulated PBMCs. Lymphocyte-depleted PBMCs stimulated with C5a but monocyte-depleted PBMCs produced cleaved-IL-1β (p17). C5a induced the production of mature IL-1β in PBMCs. The IL-1β production is mediated mainly by caspase-1 activation in CD14+ monocytes. These results suggest that C5a alone potentiates mature IL-1β production mainly in monocytes.

Rosalaura Virginia Villarreal-González, Margarita Ortega-Cisneros, Diana Estefanía Cadenas-García et al.

Antecedentes: La reacción adversa a medicamentos es estímulo imprevisto, derivado de la farmacocinética del tratamiento (tipo A) o por respuesta inmunológica (tipo B), que resulta en manifestaciones indeseables para el paciente luego de la administración de algún fármaco. Las reacciones tipo B están menos definidas y se consideran una reacción de hipersensibilidad al medicamento, categorizadas como inmediatas (se manifiestan entre 1-6 horas después de la exposición) y tardías o no inmediatas (posteriores a 6 horas de la exposición). Objetivo: Revisión de la bibliografía que describe los mecanismos inmunológicos de las reacciones de hipersensibilidad tardía. Métodos: La búsqueda de la información se llevó a cabo en las principales bases de datos, en relación con las reacciones de hipersensibilidad tardía a medicamentos. la búsqueda se limitó a artículos publicados entre 2013 y 2023, en idioma inglés y español. Resultados: Se describen las reacciones de hipersensibilidad tardías a medicamentos, clasificación, manifestaciones clínicas, diagnóstico, algoritmos de tratamiento y pronóstico. Conclusión: Las reacciones adversas a medicamentos representan un desafío para el médico especialista, con una fisiopatología compleja. Se requiere establecer el diagnóstico oportuno y tratamiento enfocado en el fenotipo del fármaco y su expresión inmunológica, para de esta forma brindar el abordaje multidisciplinario correspondiente. Palabras clave: Alergia a medicamentos; Hipersensibilidad a medicamentos; Reacción adversa a medicamentos; Reacción tardía a medicamentos.

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Michał Mielnik, Martyna Podgajna-Mielnik, Aneta Szudy-Szczyrek et al.

IntroductionMultiple Myeloma (MM), a prevalent hematological malignancy, poses significant treatment challenges due to varied patient responses and toxicities to chemotherapy. This study investigates the predictive value of pretreatment serum levels of interleukin-6 (IL-6), interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), and vascular endothelial growth factor (VEGF) for chemotherapy-induced toxicities in newly diagnosed MM patients. We hypothesized that these cytokines, pivotal in the tumor microenvironment, might correlate with the incidence and severity of treatment-related adverse events.MethodsWe conducted a prospective observational study with 81 newly diagnosed MM patients, analyzing serum cytokine levels using the multiplex cytometric bead assay (CBA) flow cytometry method. The study used non-parametric and multivariate analysis to compare cytokine levels with treatment-induced toxicities, including lymphopenia, infections, polyneuropathy, and neutropenia.ResultsOur findings revealed significant associations between cytokine levels and specific toxicities. IL-8 levels were lower in patients with lymphopenia (p=0.0454) and higher in patients with infections (p=0.0009) or polyneuropathy (p=0.0333). VEGF concentrations were notably lower in patients with neutropenia (p=0.0343). IL-8 demonstrated an 81% sensitivity (AUC=0.69; p=0.0015) in identifying infection risk. IL-8 was an independent predictor of lymphopenia (Odds Ratio [OR]=0.26; 95% Confidence Interval [CI]=0.07-0.78; p=0.0167) and infection (OR=4.76; 95% CI=0.07-0.62; p=0.0049). High VEGF levels correlated with a 4-fold increased risk of anemia (OR=4.13; p=0.0414).ConclusionsPre-treatment concentrations of IL-8 and VEGF in serum can predict hematological complications, infections, and polyneuropathy in patients with newly diagnosed MM undergoing chemotherapy. They may serve as simple yet effective biomarkers for detecting infections, lymphopenia, neutropenia, and treatment-related polyneuropathy, aiding in the personalization of chemotherapy regimens and the mitigation of treatment-related risks.

Brian Effer, Daniel Ulloa, Camila Dappolonnio et al.

Gallbladder cancer (GBC) is a very aggressive malignant neoplasm of the biliary tract with a poor prognosis. There are no specific therapies for the treatment of GBC or early diagnosis tools; for this reason, the development of strategies and technologies that facilitate or allow an early diagnosis of GBC continues to be decisive. Phage display is a robust technique used for the production of monoclonal antibodies (mAbs) involving (1) the generation of gene libraries, (2) the screening and selection of isoforms related to an immobilized antigen, and (3) the in vitro maturation of the affinity of the antibody for the antigen. This research aimed to construct a human immune library from PBMCs of GBC patients and the isolation of <i>scFv-phage</i> clones with specificity against the larger extracellular loop belonging to claudin 18.2, which is an important biomarker overexpressed in GBC as well as gastric cancer. The immune-library-denominated GALLBLA1 was constructed from seven GBC patients and has a diversity of 6.12 × 10¹⁰ <i>pfu</i> mL⁻¹. After three rounds of panning, we were able to identify clones with specificity against claudin 18.2. GALLBLA1 can contribute to the selection, isolation, and recombinant production of new human mAbs candidates for the treatment of gastrointestinal cancers.

Mayuko Okamoto, Ryo Sasaki, Koki Ikeda et al.

Maternal immunoglobulin transfer plays a key role in conferring passive immunity to neonates. Maternal blood immunoglobulin Y (IgY) in avian species is transported to newly-hatched chicks in two steps: 1) IgY is transported from the maternal circulation to the yolk of maturing oocytes, 2) the IgY deposited in yolk is transported to the circulation of the embryo via the yolk sac membrane. An IgY-Fc receptor, FcRY, is involved in the second step, but the mechanism of the first step is still unclear. We determined whether FcRY was also the basis for maternal blood IgY transfer to the yolk in the first step during egg development. Immunohistochemistry revealed that FcRY was expressed in the capillary endothelial cells in the internal theca layer of the ovarian follicle. Substitution of the amino acid residue in Fc region of IgY substantially changed the transport efficiency of IgY into egg yolks when intravenously-injected into laying quail; the G365A mutant had a high transport efficiency, but the Y363A mutant lacked transport ability. Binding analyses of IgY mutants to FcRY indicated that the mutant with a high transport efficiency (G365A) had a strong binding activity to FcRY; the mutants with a low transport efficiency (G365D, N408A) had a weak binding activity to FcRY. One exception, the Y363A mutant had a remarkably strong binding affinity to FcRY, with a small dissociation rate. The injection of neutralizing FcRY antibodies in laying quail markedly reduced IgY uptake into egg yolks. The neutralization also showed that FcRY was engaged in prolongation of half-life of IgY in the blood; FcRY is therefore a multifunctional receptor that controls avian immunity. The pattern of the transport of the IgY mutants from the maternal blood to the egg yolk was found to be identical to that from the fertilized egg yolk to the newly-hatched chick blood circulation, via the yolk sac membrane. FcRY is therefore a critical IgY receptor that regulates the IgY uptake from the maternal blood circulation into the yolk of avian species, further indicating that the two steps of maternal–newly-hatched IgY transfer are controlled by a single receptor.

Ana T. A. Sachetto, Nigel Mackman

Amy Armstrong, Amy Armstrong, Yuting Tang et al.

Rangi Kandane-Rathnayake, Eric F Morand, Vera Golder et al.

Objective Cognitive dysfunction in SLE is common, but clinical risk factors are poorly understood. This study aims to explore the associations of cognitive dysfunction in SLE with disease activity, organ damage, biomarkers and medications.Methods We performed cross-sectional cognitive assessment using a conventional neuropsychological test battery, with normative values derived from demographically matched healthy subjects. Endpoints included two binary definitions of cognitive dysfunction and seven individual cognitive domain scores. Clinical parameters included disease activity (SLEDAI-2K) and organ damage (Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index). We performed regression analyses to determine associations between clinical parameters and cognitive endpoints.Results 89 patients with SLE were studied, with median age of 45 and disease duration of 15 years. Organ damage was significantly associated with severe cognitive dysfunction (OR 1.49, CI 1.01–2.22) and worse cognitive test performance in three of the seven individual cognitive domains. In contrast, no significant associations were found between SLEDAI-2K at the time of cognitive assessment and any cognitive endpoints on multivariate analysis. Higher time-adjusted mean SLEDAI-2K was associated with better verbal memory scores but had no significant associations with other cognitive endpoints. The presence of anti-dsDNA antibodies and high IFN gene signature were negatively associated with severe cognitive dysfunction; there were no significant associations with the other autoantibodies studied or any medications. Substance use was significantly associated with lower psychomotor speed. Only 8% of patients who had cognitive dysfunction on testing had been recognised by clinicians on their SDI score.Conclusions In SLE, cognitive dysfunction was positively associated with organ damage, but not associated with disease activity, and serological activity and high IFN signature were negatively associated. Cognitive dysfunction was poorly captured by clinicians. These findings have implications for preventative strategies addressing cognitive dysfunction in SLE.

Jennifer L. Small-Saunders, Laura M. Hagenah, Kathryn J. Wicht et al.

Multidrug-resistant Plasmodium falciparum parasites have emerged in Cambodia and neighboring countries in Southeast Asia, compromising the efficacy of first-line antimalarial combinations. Dihydroartemisinin + piperaquine (PPQ) treatment failure rates have risen to as high as 50% in some areas in this region. For PPQ, resistance is driven primarily by a series of mutant alleles of the P. falciparum chloroquine resistance transporter (PfCRT). PPQ resistance was reported in China three decades earlier, but the molecular driver remained unknown. Herein, we identify a PPQ-resistant pfcrt allele (China C) from Yunnan Province, China, whose genotypic lineage is distinct from the PPQ-resistant pfcrt alleles currently observed in Cambodia. Combining gene editing and competitive growth assays, we report that PfCRT China C confers moderate PPQ resistance while re-sensitizing parasites to chloroquine (CQ) and incurring a fitness cost that manifests as a reduced rate of parasite growth. PPQ transport assays using purified PfCRT isoforms, combined with molecular dynamics simulations, highlight differences in drug transport kinetics and in this transporter’s central cavity conformation between China C and the current Southeast Asian PPQ-resistant isoforms. We also report a novel computational model that incorporates empirically determined fitness landscapes at varying drug concentrations, combined with antimalarial susceptibility profiles, mutation rates, and drug pharmacokinetics. Our simulations with PPQ-resistant or -sensitive parasite lines predict that a three-day regimen of PPQ combined with CQ can effectively clear infections and prevent the evolution of PfCRT variants. This work suggests that including CQ in combination therapies could be effective in suppressing the evolution of PfCRT-mediated multidrug resistance in regions where PPQ has lost efficacy.

Bruce S. Bochner, Whitney W. Stevens

Renata Medina, Christa Zerbe

Yue Zhang, Yue Zhang, Sihua Zhang et al.

ObjectiveHepatocellular carcinoma (HCC) is the sixth most commonly occurring cancer and ranks third in mortality among all malignant tumors; as a result, HCC represents a major human health issue. Although aberrant glycosylation is clearly implicated in HCC, changes in serum immunoglobulin (Ig)G and IgM glycosylation have not been comprehensively characterized. In this study, we used lectin microarrays to evaluate differences in serum IgG and IgM glycosylation among patients with HCC, hepatitis B cirrhosis (HBC), or chronic hepatitis B (CHB), and healthy normal controls (NC) and aimed to establish a model to improve the diagnostic accuracy of HCC.MethodsIn total, 207 serum samples collected in 2019–2020 were used for lectin microarray analyses, including 97 cases of HCC, 50 cases of HBC, 30 cases of CHB, and 30 cases of NC. Samples were randomly divided into training and validation groups at a 2:1 ratio. Training group data were used to investigate the diagnostic value of the relative signal intensity for the lectin probe combined with alpha-fetoprotein (AFP). The efficacy of models for HCC diagnosis were analyzed by receiver operating characteristic (ROC) curves.ResultsIn terms of IgG, a model combining three lectins and AFP had good diagnostic accuracy for HCC. The area under the ROC curve was 0.96 (P &lt; 0.05), the sensitivity was 82.54%, and the specificity was 100%. In terms of IgM, a model including one lectin combined with AFP had an area under the curve of 0.90 (P &lt; 0.05), sensitivity of 75.41%, and specificity of 100%.ConclusionEstimation of serum IgG and IgM glycosylation could act as complementary techniques to improve diagnosis and shed light on the occurrence and development of the HCC