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Search Results (1,180)

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14 pages, 1253 KB  
Article
Statistical Modelling of Waning Immunity After Shanchol™ Vaccination: A Prospective Cohort Study
by Samuel Bosomprah, Fraser Liswaniso, Bernard Phiri, Mwelwa Chibuye, Charlie C. Luchen, Harriet Ng’ombe, Kennedy Chibesa, Dennis Ngosa, Mutinta Muchimba, Amanda K. Debes, Roma Chilengi, David A. Sack and Caroline C. Chisenga
Vaccines 2026, 14(2), 147; https://doi.org/10.3390/vaccines14020147 - 30 Jan 2026
Abstract
Introduction: Cholera remains a major public health threat in endemic settings, and oral cholera vaccine (Shanchol™) campaigns are increasingly used amid constrained global supply. However, practical decisions on revaccination require clearer, setting-specific estimates of how rapidly vaccine-induced vibriocidal antibodies peak and wane. [...] Read more.
Introduction: Cholera remains a major public health threat in endemic settings, and oral cholera vaccine (Shanchol™) campaigns are increasingly used amid constrained global supply. However, practical decisions on revaccination require clearer, setting-specific estimates of how rapidly vaccine-induced vibriocidal antibodies peak and wane. Methods: We conducted a prospective cohort kinetics analysis in Lukanga Swamps (Central Province, Zambia), enrolling adults (18–65 years) stratified by prior Shanchol™ exposure (0, 1, or 2 previous doses). All participants received two Shanchol™ doses 14 days apart, with serum collected at baseline and days 14, 28, 60, and 90 (end of follow-up). Ogawa and Inaba vibriocidal titres were measured using a complement-based assay and analysed on the log10 scale. Serotype-specific mixed-effects models with natural cubic splines for time (knots: 14, 28, 60 days) assessed trajectories by prior-dose strata, adjusting for age, sex, and HIV status. Peak timing and post-peak half-life were derived from model-based predictions with participant-level bootstrap CIs (1000 replications). Results: The analysis included 225 participants: 68 (30.2%) with zero prior doses, 89 (39.6%) with one, and 68 (30.2%) with two; median age was 33 years (IQR 25–49), 56.4% were female, and 19.2% were HIV-positive. Modelled titres for both serotypes rose steeply after vaccination, peaking around day 36–37 across prior-dose strata. Ogawa titres reached half of peak by about day 73–78, corresponding to post-peak half-lives of 37–41 days; Inaba declined more slowly with half-lives of 42–46 days. Confidence intervals overlapped across prior-dose strata, indicating minimal differences by vaccination history. Conclusions: In this cholera-endemic adult population, Shanchol™ induced vibriocidal responses that peaked at ~5 weeks and waned over the following 5–7 weeks, with broadly similar kinetics regardless of prior vaccination and slightly slower decay for Inaba than Ogawa. These parameters can inform booster timing in hotspot settings. Full article
(This article belongs to the Section Vaccines, Clinical Advancement, and Associated Immunology)
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19 pages, 1860 KB  
Article
Assessment of the Pathogenicity of Candidatus Rickettsia Colombiensis in a Syrian Hamster Model and Serological Cross-Reactivity Between Spotted Fever Rickettsia Species
by Jorge Miranda, Alejandra García, Cristina Cervera-Acevedo, Sonia Santibañez, Aránzazu Portillo, José Oteo and Salim Mattar
Pathogens 2026, 15(2), 146; https://doi.org/10.3390/pathogens15020146 - 29 Jan 2026
Viewed by 54
Abstract
Candidatus Rickettsia colombiensis is a new candidate species of Rickettsiae spotted fever group that have been isolated only from ticks. The pathogenicity of Ca. R. colombiensis to human and animals is unknown. This study evaluated the pathogenic potential of Ca. R. [...] Read more.
Candidatus Rickettsia colombiensis is a new candidate species of Rickettsiae spotted fever group that have been isolated only from ticks. The pathogenicity of Ca. R. colombiensis to human and animals is unknown. This study evaluated the pathogenic potential of Ca. R. colombiensis in Syrian hamsters and assessed the cross-reactivity between Ca. R. colombiensis and other Rickettsia in human and hamster sera. Shell vial technique was employed to isolate Ca. R. colombiensis. Subsequently, five male Syrian hamsters were inoculated intraperitoneally (IP) and five intradermally (ID) with 1 × 106 Vero cells infected with Ca. R. colombiensis. One control hamster was used in each group. The health status was assessed daily, and necropsies were performed. Serum samples were tested by indirect immunofluorescence and tissues were processed by qPCR and histological stains. All Syrian hamsters remained healthy during the trial. No histopathological damages associated with rickettsial infection were observed. No Rickettsial DNA was detected in tissues. Syrian hamsters showed IgG antibody titers ranging from 1:64 to 1:1024. Control hamsters were negative. Regarding human sera, 56% (84/150) had IgG cross-reactivity antibodies against Ca. R. colombiensis. Subsequently, in a selected subset of 30 sera with moderate to high titers, all samples reacted with Ca. R. colombiensis antigen. Under specific conditions of this study, Ca. R. colombiensis did not behave as a highly virulent pathogen in the hamster model, although all infected Syrian hamsters developed IgG antibodies responses. Regarding cross-reactivity, it is possible to serologically diagnose rickettsial infection using Ca. R. colombiensis as an antigen. Full article
(This article belongs to the Special Issue New Insights into Rickettsia and Related Organisms)
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25 pages, 3229 KB  
Systematic Review
Major Advances in Gynecologic Oncology in 2025: Systematic Review and Synthesis of Conference and Published Evidence
by Nabil Ismaili
Biomedicines 2026, 14(2), 295; https://doi.org/10.3390/biomedicines14020295 - 28 Jan 2026
Viewed by 176
Abstract
Background: The year 2025 witnessed paradigm-shifting advances in gynecologic oncology, with pivotal clinical trial results redefining therapeutic standards across cervical, ovarian, endometrial, and vulvar cancers. Objectives: This systematic review aimed to comprehensively identify, synthesize, and critically evaluate pivotal phase II and [...] Read more.
Background: The year 2025 witnessed paradigm-shifting advances in gynecologic oncology, with pivotal clinical trial results redefining therapeutic standards across cervical, ovarian, endometrial, and vulvar cancers. Objectives: This systematic review aimed to comprehensively identify, synthesize, and critically evaluate pivotal phase II and III randomized controlled trials and major studies presented at the major annual meetings, alongside significant peer-reviewed publications from 2025 that introduce innovative therapeutic strategies across gynecologic malignancies. Methods: Conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines, this review involved exhaustive searches of electronic databases (PubMed/MEDLINE, Embase), conference proceedings (ASCO 2025, ESMO 2025), and major oncology journals for records from January to December 2025. Inclusion criteria encompassed: (1) Phase II or III randomized controlled trials (RCTs) and (2) Non-randomized studies (including phase I and II trials), reporting on novel therapeutic approaches in gynecologic oncology. All studies were required to report primary survival endpoints (overall survival or progression-free survival) or key efficacy outcomes. Study selection, data extraction, and methodological quality assessment were performed independently by two reviewers, with disagreements resolved through consensus or third-party adjudication. Results: From 1842 records, 23 studies met inclusion criteria (17 phase-III RCTs and 6 non-phase III RCTs/early-phase studies), distributed as follows: cervical cancer (9 studies, 39%), ovarian cancer (9 studies, 39%), endometrial cancer (4 studies, 17.5%), and vulvar cancer (1 study, 4.5%). The major advances identified include: (1) In cervical cancer, the KEYNOTE-A18 trial established pembrolizumab combined with chemoradiotherapy as a new standard for high-risk locally advanced disease, while the PHENIX trial validated sentinel lymph node biopsy as a safe surgical de-escalation strategy. (2) In ovarian cancer, the ENGOT-ov65/KEYNOTE-B96 trial demonstrated the first statistically significant overall survival improvement with an immune checkpoint inhibitor in platinum-resistant recurrent disease, establishing pembrolizumab plus weekly paclitaxel as a new standard of care. Novel therapeutic mechanisms, including glucocorticoid receptor modulation (ROSELLA trial) and cadherin-6-targeted antibody-drug conjugates (REJOICE-Ovarian01), showed remarkable efficacy. (3) In endometrial cancer, updated analyses from NRG GY018 and RUBY trials solidified the role of first-line immuno-chemotherapy, with differential benefits according to mismatch repair status. (4) In vulvar cancer, a pivotal phase II study demonstrated meaningful clinical activity of anti-PD-1 therapy in advanced disease. (5) The extensive circulating tumor DNA analysis from the CALLA trial provided crucial insights into biomarker dynamics in cervical cancer. Conclusions: The convergence of high-impact data from 2025 established multiple new standards of care, emphasizing biomarker-driven approaches, immunotherapy integration across disease stages, and novel mechanisms to overcome resistance, while highlighting challenges in treatment sequencing and global access. Full article
(This article belongs to the Special Issue Women’s Special Issue Series: Biomedicines (2nd Edition))
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23 pages, 1668 KB  
Article
Impact of Selenium and Vitamin E Deficiency on Zika Virus Pathogenesis and Immune Response in Mice
by Olukunle O. Oluwasemowo, Monica E. Graham, James B. Thissen, Aram Avila-Herrera, Jeffrey A. Kimbrel, Deepa K. Murugesh, Dina R. Weilhammer, Tanya Tanner, Nicole M. Collette and Monica K. Borucki
Viruses 2026, 18(2), 177; https://doi.org/10.3390/v18020177 - 28 Jan 2026
Viewed by 172
Abstract
Micronutrient status is recognized to influence host susceptibility to viral infections, yet its impact on Zika virus (ZIKV) pathogenesis remains incompletely understood. We investigated the effects of dietary selenium and combined selenium plus vitamin E deficiency on ZIKV infection outcomes in a type [...] Read more.
Micronutrient status is recognized to influence host susceptibility to viral infections, yet its impact on Zika virus (ZIKV) pathogenesis remains incompletely understood. We investigated the effects of dietary selenium and combined selenium plus vitamin E deficiency on ZIKV infection outcomes in a type I interferon α/β receptor knockout (Ifnar1−/−) murine model. Mice maintained on deficient diets exhibited significantly lower neutralizing antibody titers and reduced levels of key antiviral cytokines (IFN-γ, TNF-α, IFN-α, IFN-β, IL-12p70, CCL5) compared to controls. Correspondingly, higher viral RNA loads were detected in the brains of double-deficient mice, which also experienced greater weight loss and increased mortality. Deep sequencing revealed no major differences in overall viral genome diversity across diet groups; however, specific mutations, including V330L and D67E in the E gene, and V360I in the NS3 gene, were enriched or detected in nutritionally deficient animals. These findings suggest that antioxidant micronutrient deficiency impairs both humoral and cellular immune responses to ZIKV, potentially facilitating enhanced neuroinvasion. While the functional consequences of the identified mutations warrant further investigation, our results underscore the importance of adequate micronutrient intake for optimal antiviral defense. Further studies are needed to clarify the epidemiological significance of these observations. Full article
(This article belongs to the Section Human Virology and Viral Diseases)
11 pages, 876 KB  
Article
Robust Adaptive Immunity to MPXV in Older People Who Received Childhood Vaccinia Vaccination
by Chris Davis, Jianmin Zuo, Rachel Bruton, Marie Hodges, Tom Roberts, Maria Manali, Paula Olmo, Brian Willett, Paul Moss and Helen Parry
Biology 2026, 15(3), 234; https://doi.org/10.3390/biology15030234 - 26 Jan 2026
Viewed by 238
Abstract
Monkeypox virus (MPXV) is a zoonotic Orthopoxvirus responsible for Monkeypox (Mpox), historically associated with sporadic zoonotic transmission but increasingly characterised by sustained human-to-human spread. While vaccinia-based vaccination is known to confer cross-protection against MPXV, the durability of such immunity over a human lifetime [...] Read more.
Monkeypox virus (MPXV) is a zoonotic Orthopoxvirus responsible for Monkeypox (Mpox), historically associated with sporadic zoonotic transmission but increasingly characterised by sustained human-to-human spread. While vaccinia-based vaccination is known to confer cross-protection against MPXV, the durability of such immunity over a human lifetime remains incompletely characterised. Here, we assessed humoral and cellular immune responses to MPXV in octogenarians and nonagenarians vaccinated against smallpox during childhood. Twenty-three adults aged 79–94 years (median 83), who self-reported childhood vaccinia vaccination between 1925 and 1940, were recruited. MPXV-specific antibody responses were evaluated using ELISA, targeting homologous vaccinia and MPXV proteins, and live-virus neutralisation assays. Cellular immunity was assessed by IFN-γ ELISpot following stimulation with peptide pools derived from highly conserved vaccinia antigens. Responses were also obtained from younger, recently MVA–BN-vaccinated and unvaccinated control donors. All historically vaccinated participants exhibited MPXV-reactive IgG responses, with antibody binding and neutralisation levels comparable to recently vaccinated individuals. Functional neutralising activity against MPXV was detected in all donors, with ≥50% neutralisation observed in 78% of participants. Antibody concentrations correlated strongly with neutralisation capacity. T-cell responses were detectable in all historically vaccinated donors, most prominently against the major core protein A10L, although reduced magnitudes were observed in participants over 90 years of age. No MPXV-specific humoral or cellular responses were detected in unvaccinated controls. These findings demonstrate that childhood vaccinia vaccination induces durable humoral and cellular immunity against MPXV persisting for over seven decades. Historical smallpox vaccination status may therefore remain a relevant determinant of protection against Mpox. Full article
(This article belongs to the Section Infection Biology)
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20 pages, 1694 KB  
Article
Antibodies to Burkholderia pseudomallei Outer Membrane Proteins Coupled to Nanovaccines Exhibit Cross-Reactivity to B. cepacia Complex and Pseudomonas aeruginosa Homologues
by Alexander J. Badten, Susana Oaxaca-Torres and Alfredo G. Torres
Microorganisms 2026, 14(1), 221; https://doi.org/10.3390/microorganisms14010221 - 17 Jan 2026
Viewed by 355
Abstract
Burkholderia pseudomallei complex and B. cepacia complex are two evolutionary distinct clades of pathogens causing human disease. Most vaccine efforts have focused on the former group largely due to their biothreat status and global disease burden. It has been proposed that a vaccine [...] Read more.
Burkholderia pseudomallei complex and B. cepacia complex are two evolutionary distinct clades of pathogens causing human disease. Most vaccine efforts have focused on the former group largely due to their biothreat status and global disease burden. It has been proposed that a vaccine could be developed that simultaneously protects against both groups of Burkholderia by specifically targeting conserved antigens. Only a few studies have set out to identify which antigens may be optimal targets for such a vaccine. We have previously assessed the ability of three highly conserved B. pseudomallei antigens, namely OmpA1, OmpA2, and Pal, coupled to gold nanoparticle vaccines, to protect mice against a homotypic B. pseudomallei challenge. Here, we have expanded our study by demonstrating that antibodies to each of these proteins show varying levels of reactivity to homologues in B. cepacia complex, with OmpA2 antibodies exhibiting the highest cross-reactivity. Remarkably, some nanovaccine immunized mice, particularly those that received OmpA2, produced antibodies that bind Pseudomonas aeruginosa, which harbors distantly related homologous proteins. T cells elicited to Pal and OmpA2 responded to stimulation with B. cepacia complex-derived homologues. Our study supports incorporation of these antigens, particularly OmpA2, for the development of a pan-Burkholderia vaccine. Full article
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19 pages, 914 KB  
Review
FDA-Approved Passive Immunization Treatments Against Aβ in Alzheimer’s Disease: Where Are We Now?
by Martin Higgins, Veronica Wasef and Andrea Kwakowsky
Int. J. Mol. Sci. 2026, 27(2), 883; https://doi.org/10.3390/ijms27020883 - 15 Jan 2026
Viewed by 911
Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by decreased amyloid-beta (Aβ) clearance, enhanced Aβ aggregation, an increased risk of amyloid-related imaging abnormalities (ARIA), and blood–brain barrier (BBB) dysfunction. The APOE4 allele, being the leading genetic risk factor for AD, contributes strongly [...] Read more.
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by decreased amyloid-beta (Aβ) clearance, enhanced Aβ aggregation, an increased risk of amyloid-related imaging abnormalities (ARIA), and blood–brain barrier (BBB) dysfunction. The APOE4 allele, being the leading genetic risk factor for AD, contributes strongly to these symptoms. This review covers the relationship between APOE4 status and the efficacy of FDA-approved monoclonal antibody (mAb) therapies, namely aducanumab, lecanemab, and donanemab. Across several clinical trials, APOE4 carriers exhibited higher rates of ARIA-E and ARIA-H compared to non-carriers. While the therapies did often meet biomarker endpoints (i.e., reduced amyloid), benefits were only observed in early and mild AD, and cognitive benefits were often marginal. Going forward, experimental apoE4-targeted immunotherapies may ease the burden of APOE4-related pathology. The field is shifting towards a more integrated approach, focusing on earlier interventions, biomarker-driven precision treatment, and improved drug delivery systems, such as subcutaneous injections, receptor-mediated transport, and antibodies with enhanced BBB penetration. As it stands, high treatment costs, limited accessibility, and strict eligibility criteria all stand as barriers to treatment. By integrating the APOE4 genotype into treatment planning and focusing on disease-stage-specific approaches, a safer and more effective means of treating AD could be achieved. Full article
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22 pages, 3507 KB  
Article
Extending ImmunoSpot® Assays’ Sensitivity for Detecting Rare Antigen-Specific B Cells to One in a Million—And Possibly Lower
by Greg A. Kirchenbaum, Noémi Becza, Lingling Yao, Alexey Y. Karulin and Paul V. Lehmann
Vaccines 2026, 14(1), 88; https://doi.org/10.3390/vaccines14010088 - 15 Jan 2026
Viewed by 482
Abstract
Background/Objectives: Despite clonal expansion during a primary immune response, or after subsequent antigen encounters, the frequency of memory B cells (Bmem) specific for an antigen remains low, making their detection difficult. However, unlike serum antibodies, which have a short half-life [...] Read more.
Background/Objectives: Despite clonal expansion during a primary immune response, or after subsequent antigen encounters, the frequency of memory B cells (Bmem) specific for an antigen remains low, making their detection difficult. However, unlike serum antibodies, which have a short half-life in vivo and thus require continuous replenishment to maintain stable titers, circulating Bmem are long-lived; they preserve immunological preparedness through their ability to rapidly engage in recall responses and differentiate into antibody-secreting cells (ASCs) upon antigen encounter. To this end, development of assays suited for the reliable detection of rare antigen-specific Bmem is critical and can provide insights into an individual’s antigen exposure history and immune status beyond that offered by traditional serum antibody measurements alone. Methods: ImmunoSpot® has emerged as a suitable technique for the detection of individual antigen-specific B cells through visualizing their antibody-derived secretory footprints. Here, we report the theoretical and practical foundations for detecting rare antigen-specific Bmem in human peripheral blood mononuclear cells (PBMC). Leveraging the unique availability of verifiably naïve vs. antigen-experienced human samples, we used SARS-CoV-2 Spike (S-) and Nucleocapsid (NCAP) antigens to interrogate the presence of Bmem with these respective specificities. Results: While 100% diagnostic accuracy was achieved for both antigens, detection of NCAP-specific Bmem required reducing the lower detection limit of the standard assay. Specifically, this was achieved by testing a total of 2 million PBMC across multiple replicate assay wells and assessing the cumulative number of secretory footprints detected. Conclusion: The protocols described here should facilitate the reliable detection of ASCs present at varying precursor frequencies and serve as guidance for routine immune monitoring of rare Bmem with specificity for any antigen. Full article
(This article belongs to the Special Issue Human Immune Responses to Infection and Vaccination)
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23 pages, 327 KB  
Review
Advances in Screening, Immunotherapy, Targeted Agents, and Precision Surgery in Cervical Cancer: A Comprehensive Clinical Review (2018–2025)
by Priyanka Nagdev and Mythri Chittilla
Curr. Oncol. 2026, 33(1), 48; https://doi.org/10.3390/curroncol33010048 - 15 Jan 2026
Viewed by 380
Abstract
Cervical cancer remains a significant global health burden, disproportionately affecting women in low- and middle-income countries despite being preventable. Since 2018, rapid advances in molecular profiling, immunotherapy, refinement of minimally invasive surgery, and targeted therapeutics have transformed diagnostic and therapeutic paradigms. This narrative [...] Read more.
Cervical cancer remains a significant global health burden, disproportionately affecting women in low- and middle-income countries despite being preventable. Since 2018, rapid advances in molecular profiling, immunotherapy, refinement of minimally invasive surgery, and targeted therapeutics have transformed diagnostic and therapeutic paradigms. This narrative review synthesizes clinical and translational progress across the continuum of care from 2018 to 2025. We summarize the evolving landscape of precision screening—including HPV genotyping, DNA methylation assays, liquid biopsy, and AI-assisted cytology—and discuss their implications for global elimination goals. Surgical management has shifted toward evidence-based de-escalation with data from SHAPE, ConCerv, and ongoing RACC informing fertility preservation and minimally invasive approaches. For locally advanced disease, KEYNOTE-A18 establishes pembrolizumab plus chemoradiation as a new curative standard, while INTERLACE underscores the benefit of induction chemotherapy. In the metastatic setting, survival outcomes have improved with the integration of checkpoint inhibitors (KEYNOTE-826, BEATcc, EMPOWER-Cervical 1), vascular-targeted therapies, and antibody–drug conjugates, including tisotumab vedotin and emerging HER2 and TROP-2–directed agents. We further highlight emerging biomarkers—PD-L1, TMB, MSI status, HPV integration patterns, APOBEC signatures, methylation classifiers, ctHPV-DNA—and their evolving role in treatment selection and surveillance. Future directions include neoadjuvant checkpoint inhibition, PARP-IO combinations, HER3-directed ADCs, DDR-targeted radiosensitizers, HPV-specific cellular therapies, and AI-integrated precision medicine. Collectively, these advances are reshaping cervical cancer care toward biologically individualized, globally implementable strategies capable of accelerating WHO elimination targets. Full article
(This article belongs to the Special Issue Clinical Management of Cervical Cancer)
19 pages, 2879 KB  
Article
Prevalence and Outcomes of HER2-Low Versus HER2-0 Status in Patients with Metastatic Breast Cancer
by Akshara Singareeka Raghavendra, Diane D. Liu, Senthil Damodaran, Sarah Pasyar, Yu Shen, Jason A. Mouabbi, Carlos H. Barcenas, Kelly K. Hunt and Debu Tripathy
Cancers 2026, 18(2), 253; https://doi.org/10.3390/cancers18020253 - 14 Jan 2026
Viewed by 238
Abstract
Background: HER2-low breast cancer (HER2 immunohistochemical [IHC] score 1+, or IHC 2+ without HER2 gene amplification) is distinct from HER2-positive and HER2-0 breast cancer (IHC 0), with a differing prognosis and specific therapeutic options. The DESTINY-Breast04 trial demonstrated notable efficacy of the HER2 [...] Read more.
Background: HER2-low breast cancer (HER2 immunohistochemical [IHC] score 1+, or IHC 2+ without HER2 gene amplification) is distinct from HER2-positive and HER2-0 breast cancer (IHC 0), with a differing prognosis and specific therapeutic options. The DESTINY-Breast04 trial demonstrated notable efficacy of the HER2 antibody–drug conjugate trastuzumab deruxtecan over standard chemotherapy in patients with metastatic breast cancer (MBC) defined as HER2-low. More recently, the DESTINY-Breast06 trial confirmed this benefit in hormone receptor-positive and HER2-ultralow (less than 1+, but with ≤10% of infiltrating cancer cells showing incomplete and faint/weak membrane staining) cases, prompting re-evaluation of HER2 diagnostic thresholds and treatment strategies. Methods: Eligible patients were women with HER2-low or HER2-0 MBC evaluated at MD Anderson between January 2006 and January 2019. HER2-low was defined as either (1) IHC 1+ or (2) IHC 2+ and negative on fluorescence in situ hybridization. Multivariate logistic regression was used to evaluate distinct clinicopathologic features of patients with HER2-low status. Overall survival (OS) was estimated by the Kaplan–Meier method. Multivariate Cox proportional hazards regression was applied to assess the effects of covariates of interest on OS across different HER2 groups. Results: We included 3834 women: 2637 (69%) with recurrent and 1197 (31%) with de novo MBC; HER2-low disease was present in 1575 (60%) and 712 (59%), respectively. In de novo cases, higher nuclear grade was associated with HER2-low status (grade 2 vs. 1, OR = 2.02, p = 0.007; grade 3 vs. 1, OR = 1.87, p = 0.015), while recurrent cases were associated with ER-positivity (OR = 1.96, p < 0.001) and prior adjuvant radiotherapy (OR = 0.79, p = 0.007). Median OS was 3.2 years (95% CI 3.0–3.5). In de novo disease, Black race (HR = 1.48), metaplastic (HR = 3.15) or other non-ductal/lobular histologies (HR = 2.36), and grade 3 (HR = 1.67) predicted worse OS, whereas Hispanic ethnicity (HR = 0.74) and Other races (HR = 0.57), higher ER (HR = 0.48–0.41) and PR (HR = 0.72–0.53), and HER2-low status (HR = 0.77) conferred improved outcomes. In recurrent disease, Black race predicted worse OS (HR = 1.21, 95% CI 1.05–1.39), while Other race (HR = 0.78, 95% CI 0.62–0.97), higher ER (HR = 0.69–0.44) and PR (HR = 0.73–0.73), and HER2-low (HR = 0.89) were protective. HER2 discordance between primary and metastatic sites occurred in 38.8% of recurrent and 13.1% of de novo cases. Conclusions: HER2-low status was significantly associated with longer OS compared to HER2-0 status in both recurrent and de novo MBC cases. These real-world data help establish the prevalence of HER2-low status and its distinct outcomes. The discrepancy in HER2-low status between the primary tumor and metastatic sites highlights the potential for changes in HER2 expression over time, exploring the interaction between HER2-low breast cancer and the tumor microenvironment and emphasizing the importance of monitoring and reassessing HER2 status at various stages to guide treatment decisions effectively and the need for more quantitative and reproducible HER assays. Full article
(This article belongs to the Special Issue Cancer Metastasis in 2025–2026)
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13 pages, 1957 KB  
Article
Combinatorial Analysis of CD4+Tregs, CD8+Teffs, and Inflammatory Indices Predict Response to ICI in ES-SCLC Patients
by Anastasia Xagara, Konstantinos Tsapakidis, Vassileios Papadopoulos, Alexandros Kokkalis, Evangelia Chantzara, Chryssovalantis Aidarinis, Alexandros Lazarou, George Christodoulopoulos, Matina Perifanou-Sotiri, Dimitris Verveniotis, Vasiliki Rammou, Maria Smaragdi Vlachou, Galatea Kallergi, Alexandra Markou, Ioannis Samaras, Filippos Koinis, Emmanouil Saloustros and Athanasios Kotsakis
Cancers 2026, 18(2), 192; https://doi.org/10.3390/cancers18020192 - 7 Jan 2026
Viewed by 211
Abstract
Background: Small-cell lung cancer (SCLC) is an aggressive type of lung cancer, and several factors are currently used to predict poor outcomes, including performance status (PS), extensive-stage disease, male sex, advanced age, and elevated lactate dehydrogenase (LDH) levels. In this study, we [...] Read more.
Background: Small-cell lung cancer (SCLC) is an aggressive type of lung cancer, and several factors are currently used to predict poor outcomes, including performance status (PS), extensive-stage disease, male sex, advanced age, and elevated lactate dehydrogenase (LDH) levels. In this study, we aimed to explore the role of Tegs and inflammatory indices, such as CRP and NLR, in predicting response to immunotherapy. Methods: Fifty-one therapy-naïve ES-SCLC patients and ten healthy donors were enrolled. Peripheral blood mononuclear cells (PBMCs) were isolated and stained with fluorochrome-conjugated monoclonal antibodies. Multicolor flow cytometry was performed to determine the levels of CD8+ T cells and CD4+ Tregs, as well as their correlation with inflammatory indices and clinical outcomes. Results: ES-SCLC patients harbored higher percentages of CD8+ Teffs (p = 0.005) and FOXP3+ Tregs (p < 0.0001) in circulation before therapy compared with healthy donors. In addition, high levels of CD3+CD8+ T effectors were associated with longer PFS (p = 0.018) and longer OS (p = 0.012) compared with patients bearing low levels, while Tregs were not found to be predictive. More importantly, a survival benefit was observed in ES-SCLC patients with a low Treg/Teff ratio, as longer OS was observed in those with high percentages of CD8+ Teffs and low FOXP3+CTLA-4+ Tregs (p = 0.014) compared with those bearing low CD8+ Teffs and high FOXP3+CTLA-4+ Tregs. A low Treg/Teff ratio was further associated with low eosinophil levels and a low NLR before treatment initiation. Conclusions: These findings suggest a novel, easily obtainable blood-based signature that may help predict response to ICIs in ES-SCLC patients. Full article
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17 pages, 2250 KB  
Article
Latent Toxoplasma gondii Infection Does Not Modulate Immune Aging in a Cross-Sectional Working-Age Population Study
by Peter Bröde, Maren Claus, Stephan Getzmann, Klaus Golka, Jan G. Hengstler, Jörg Reinders, Edmund Wascher, Carsten Watzl and Patrick D. Gajewski
Biomolecules 2026, 16(1), 55; https://doi.org/10.3390/biom16010055 - 30 Dec 2025
Viewed by 370
Abstract
Latent, i.e., asymptomatic Toxoplasma gondii (T. gondii) infection might accelerate or modulate the aging process of cognitive and sensory functions involving pro-inflammatory immune responses. For evaluating a potential role of latent T. gondii infection in immunological aging, we determined T. gondii [...] Read more.
Latent, i.e., asymptomatic Toxoplasma gondii (T. gondii) infection might accelerate or modulate the aging process of cognitive and sensory functions involving pro-inflammatory immune responses. For evaluating a potential role of latent T. gondii infection in immunological aging, we determined T. gondii antibody levels and immunosenescence biomarkers in a cross-sectional sample of 584 volunteers aged 20–70 years from the Dortmund Vital Study (ClinicalTrials.gov Identifier NCT05155397) representing the regional population. One-hundred-sixty-one participants were seropositive, representing an overall 28% latent T. gondii seroprevalence, which did not significantly differ between males and females, but increased with age. Consequently, seropositive individuals were older than the seronegative participants. Latent T. gondii infection exhibited significant bivariate associations with the composite immune age index IMMAX pointing to accelerated immune aging in seropositive individuals. In addition, IMMAX increased with age and in males. However, associations of latent T. gondii infection with immunosenescence biomarkers disappeared when adjusting the analyses for sex and age. Moreover, the non-significant interaction between T. gondii status and age when predicting biomarker levels indicated that latent T. gondii infection did not modify the immunosenescence trend. Summarized, our results suggest that latent T. gondii infection is unlikely to modulate immune aging concerning cellular senescence in otherwise healthy working-age adults. Full article
(This article belongs to the Section Molecular Biomarkers)
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9 pages, 597 KB  
Brief Report
Field Evidence of Fasciola hepatica-Mediated Modulation of Antibody Responses to Foot-and-Mouth Disease Vaccination in Buffaloes
by Juan Manuel Sala, Maximiliano Wilda, María Cruz Miraglia, Mariángeles Castillo, Daniel Mariano Pérez-Filgueira, Teresa Freire and Alejandra Victoria Capozzo
Vaccines 2026, 14(1), 36; https://doi.org/10.3390/vaccines14010036 - 28 Dec 2025
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Abstract
Background: Fasciola hepatica (F. hepatica) infection reduces antibody avidity to foot-and-mouth disease virus (FMDV) vaccination in cattle despite preserved total antibody levels. However, its effect on vaccine-induced immunity in water buffaloes (Bubalus bubalis), which contribute to FMDV maintenance in endemic settings, [...] Read more.
Background: Fasciola hepatica (F. hepatica) infection reduces antibody avidity to foot-and-mouth disease virus (FMDV) vaccination in cattle despite preserved total antibody levels. However, its effect on vaccine-induced immunity in water buffaloes (Bubalus bubalis), which contribute to FMDV maintenance in endemic settings, has not been investigated. Objectives: To evaluate the effect of natural F. hepatica infection on the magnitude and functional quality of the FMDV–specific antibody response in buffaloes under field conditions. Methods: Two buffalo herds (n = 50 each) were classified by infection status using coproparasitological analysis and serology. All animals were vaccinated within the national foot-and-mouth disease control programme, with the last dose administered 264 days before sampling. Serum neutralising titres, total antibodies by liquid-phase blocking ELISA, IgG levels, and IgG avidity to the A24/Cruzeiro vaccine strain were determined. Results: F. hepatica-infected buffaloes exhibited consistent decreases across all vaccine-induced antibody parameters. Neutralising titres were reduced approximately two-fold, IgG avidity by about 38 percent, IgG levels by about 36 percent, and liquid-phase blocking ELISA titres by about 1.6-fold compared with non-infected animals. Conclusions: This study provides the first field evidence that fasciolosis is associated with changes in the magnitude and quality of vaccine-induced humoral responses following FMDV vaccination in water buffaloes, indicating that F. hepatica infection may influence the interpretation of post-vaccination serological monitoring in this species under endemic field conditions. Full article
(This article belongs to the Special Issue Animal Virus Infection, Immunity and Vaccines: 2nd Edition)
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18 pages, 818 KB  
Article
A Phase II Study of Toripalimab in Combination with Gemcitabine and 5-Fluorouracil as First-Line Therapy for Advanced or Metastatic Biliary Tract Carcinoma
by Fangyong Lei, Wenjing Deng, Ying Zhou, Lilan Fang, Xiuxin Lin, Lingyu Qin, Chunming Li, Jian Rao and Gengsheng Yu
Cancers 2026, 18(1), 88; https://doi.org/10.3390/cancers18010088 - 27 Dec 2025
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Abstract
Background/Objectives: The anti-PD-L1 antibody has been applied for use in first-line advanced biliary duct cancer patients. However, clinical evidence of toripalimab in combination with biweekly 5-fluorouracil (5-FU) is limited and predictive biomarkers of treatment benefits remain unclear. Methods: This prospective study enrolled patients [...] Read more.
Background/Objectives: The anti-PD-L1 antibody has been applied for use in first-line advanced biliary duct cancer patients. However, clinical evidence of toripalimab in combination with biweekly 5-fluorouracil (5-FU) is limited and predictive biomarkers of treatment benefits remain unclear. Methods: This prospective study enrolled patients with unresectable or metastatic BTC who received toripalimab in combination with gemcitabine and biweekly 5-FU. The primary endpoints were progression-free survival (PFS) and objective response rate (ORR). Secondary endpoints included overall survival (OS) and safety. Exploratory analyses evaluated associations between programmed cell death-ligand 1 (PD-L1) expression or tumor mutational burden (TMB) and clinical outcomes. Results: A total of 30 patients were enrolled, with a median follow-up duration of 16.0 months. The ORR was 13.0%. The median PFS and OS were 5.3 months (95% CI: 3.59–7.01) and 11.7 months (95% CI: 6.07–17.33), respectively. Subgroup analyses revealed no significant association between PD-L1 status or TMB level and improved PFS. All patients experienced adverse events (AEs), while grade 3–4 AEs occurred in eight patients (26.7%), most commonly anemia (20.0%), leukocytopenia (13.3%), and nausea (6.6%). No grade 5 AEs were observed, and the safety profile was considered manageable. Conclusions: Toripalimab in combination with gemcitabine and 5-fluorouracil showed promising efficacy and was well-tolerated as a first-line therapy in advanced biliary duct cancer patients. Although PD-L1 expression and TMB did not predict treatment benefit, larger studies are needed to validate potential biomarkers and further optimize immunochemotherapy strategies for BTC. Full article
(This article belongs to the Special Issue Cancer Immunotherapy in Clinical and Translational Research)
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20 pages, 6127 KB  
Article
Potentiation of Electrochemotherapy by Anti-PD-1 Immunotherapy in Murine Tumors with Distinct Immune Profiles
by Masa Omerzel, Simona Kranjc Brezar, Ursa Lampreht Tratar, Tanja Jesenko, Barbara Lisec, Gregor Sersa and Maja Cemazar
Cancers 2026, 18(1), 90; https://doi.org/10.3390/cancers18010090 - 27 Dec 2025
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Abstract
Background: Electrochemotherapy (ECT) is a clinically validated local ablative treatment increasingly recognized for its ability to induce immunogenic cell death and stimulate antitumor immunity. Its combination with immune checkpoint inhibitors, such as anti-PD-1 antibodies, may enhance systemic immune responses and improve therapeutic [...] Read more.
Background: Electrochemotherapy (ECT) is a clinically validated local ablative treatment increasingly recognized for its ability to induce immunogenic cell death and stimulate antitumor immunity. Its combination with immune checkpoint inhibitors, such as anti-PD-1 antibodies, may enhance systemic immune responses and improve therapeutic efficacy, particularly in poorly immunogenic tumors. Methods: We evaluated the antitumor effectiveness of ECT combined with a murine analog of the anti-PD-1 antibody in four syngeneic murine tumor models with differing histology and immune status: WEHI fibrosarcoma, CT26 and MC38 colorectal carcinoma, and 4T1 mammary carcinoma. In vitro cytotoxicity assays assessed tumor cell sensitivity to ECT, while in vivo experiments evaluated complete response (CR) rates, immune cell infiltration, and long-term immune memory through secondary tumor challenge. Immunohistochemical analysis of CD4+, CD8+, and granzyme B+ effector cells. Results: In vitro, WEHI cells exhibited the highest sensitivity to ECT. In vivo, ECT monotherapy induced CRs in 100% of WEHI tumors, 60% of CT26, 17% of 4T1, and 15% of MC38. The addition of anti-PD-1 significantly enhanced outcomes in less responsive models, increasing CRs to 90% in CT26, 91% in MC38, and 53% in 4T1. Combination therapy promoted pronounced infiltration of CD4+, CD8+, and granzyme B+ T cells and the formation of tertiary lymphoid structure, particularly in MC38 tumors. Secondary challenge experiments confirmed long-term immune memory in CT26 and MC38 models and induced memory in 4T1, which was absent following monotherapy. Conclusions: ECT synergizes with PD-1 blockade to potentiate local and systemic antitumor immunity, overcoming immune resistance in poorly immunogenic tumors. These findings support further clinical development of ECT in combination with immune checkpoint inhibitors as a component of personalized cancer immunotherapy. Full article
(This article belongs to the Special Issue Advances in Electroporation-Based Technologies for Cancer Treatment)
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