Search Results (3,282)

Antiretroviral therapy (ART) has significantly improved outcomes in individuals with human immunodeficiency virus (HIV), yet its long-term cardiovascular effects, especially on hypertension risk, remain debated. This pilot study investigated hypertension risk factors in HIV-positive patients undergoing ART and aimed at hypothesis generation rather than drawing definitive causal conclusions. Seventy HIV-infected adults without baseline hypertension were enrolled and followed. Hypertension was defined using the 2017 ACC/AHA guidelines by the South African Hypertension Society. Data on demographic, anthropometric, metabolic, inflammatory, coagulation, and HIV-related variables were collected. Cox regression analysis identified independent predictors of hypertension. Participants had a median age of 37 years (IOR = 10.96), with 84.3% being female. After a median ART exposure of 61.01 months (range: 2–164), 27 individuals (38.6%) developed high blood pressure. In multivariable Cox models adjusting for metabolic syndrome and BMI, age ≥ 35 years was associated with a 2.2-fold higher hypertension risk (Hazard Ratio [HR]: 2.2; 95% Confidence Interval [CI]: 1.04–4.55; p = 0.04). Elevated triglycerides significantly increased risk, with a 7.9-fold higher likelihood of hypertension (HR: 7.9; 95% CI: 1.04–59.5; p = 0.046). ART regimen type, whether initial or current, did not independently predict hypertension. In conclusion, hypertension is prevalent during ART. We hypothesized that traditional cardiovascular risk factors, notably age ≥35 years and hypertriglyceridemia, were key independent predictors, emphasizing the need for routine cardiovascular risk assessment in HIV management. Full article

Immune dysregulation is being increasingly recognized as a leading sign of a wide spectrum of inborn errors of immunity (IEIs). Therefore, patients with IEIs are frequently managed in non-immunological settings, including hematology and oncology units, during the diagnostic process or follow-up. The most relevant hematological signs associated with IEIs comprise autoimmune cytopenia (AIC), lymphoproliferative diseases (LPD), malignancies, hemophagocytic lymphohystiocitosis (HLH), bone marrow failure (BMF), myelodysplastic syndromes (MDS), and peripheral or tissue eosinophilia. The prognosis of patients with IEIs can significantly improve when a molecular diagnosis is established, as it can allow the use of targeted treatments, guide appropriate follow-up strategies and, in some cases, support the rationale for hematopoietic stem cell transplantation or gene therapy. Therefore, there is an urgent need to recognize the warning signs suggestive for an underlying IEI among patients presenting with common hematological features and to ensure an appropriate diagnostic approach. As a general rule, clinicians should always provide a clinical alert in the presence of two or more IEI-associated hematological signs, as well as a positive familial history for IEI or hematologic immune dysregulation, a personal history of severe infections, and other signs of immune dysregulation. Concerning AIC, an increased likelihood of IEI is characteristic of patients with treatment refractoriness, autoimmune hemolytic anemia, or multilineage cytopenia. In the case of LPD, the main elements of suspicion are represented by the chronic or recurrent disease course, the persistence of Epstein–Barr Virus (EBV) infection, and the development of lymphoproliferation in atypical localizations. Among patients with malignancy, clinicians should investigate for IEI those with rare neoplasia, virus-associated tumors, and an association with syndromic features, while patients with HLH should always receive an immunological assessment when a clear rheumatologic trigger, underlying malignancy, or well-recognized cause is not evident. The case of MDS and BMF is complex, as new monogenic entities are continuously being described. However, it is pivotal to consider the presence of monocytopenia, warts, vasculitis, and neurological disease, as well as specific cytogenetic abnormalities, such as chromosome 7 monosomy, as warning sings for IEIs. Finally, the main red flags for IEIs in patients with eosinophilia are skeletal/facial abnormalities, recurrent abscesses, refractory eczema, organomegaly, or thrombocytopenia. Full article

MYCN amplification without concurrent RB1 mutations characterizes a rare yet highly aggressive subtype of retinoblastoma; however, its precise developmental origins and therapeutic vulnerabilities remain incompletely understood. Here, we modeled this subtype by lentiviral-mediated MYCN overexpression in human pluripotent stem cell-derived retinal organoids, revealing a discrete developmental window (days 70–120) during which retinal progenitors showed heightened susceptibility to transformation. Tumors arising in this period exhibited robust proliferation, expressed SOX2, and lacked CRX, consistent with origin from primitive retinal progenitors. MYCN-overexpressing organoids generated stable cell lines that reproducibly gave rise to MYCN-driven tumors when xenografted into immunodeficient mice. Transcriptomic profiling demonstrated that MYCN-overexpressing organoids closely recapitulated molecular features of patient-derived MYCN-amplified retinoblastomas, particularly through activation of MYC/E2F and mTORC1 signaling pathways. Pharmacological screening further identified distinct therapeutic vulnerabilities, demonstrating distinct subtype-specific sensitivity of MYCN-driven cells to transcriptional inhibitors (THZ1, Flavopiridol) and the cell-cycle inhibitor Volasertib, indicative of a unique oncogene-addicted state compared to RB1-deficient retinoblastoma cells. Collectively, our study elucidates the developmental and molecular mechanisms underpinning MYCN-driven retinoblastoma, establishes a robust and clinically relevant human retinal organoid platform, and highlights targeted transcriptional inhibition as a promising therapeutic approach for this aggressive pediatric cancer subtype. Full article

Chalcones are flavonoid compounds containing an α,β-unsaturated ketone core that are often found in plants and have diverse biological activities including antiviral activity. For example, chalcone 8o was previously shown to have antiviral activity against human cytomegalovirus (HCMV) and human immunodeficiency virus (HIV); two viruses that use a nuclear phase to complete their growth cycle. Here, we synthesized ten new derivatives of 8o and tested them for antiviral activity against four RNA viruses that replicate exclusively in the cytoplasm, including prototype members of the paramyxovirus, flavivirus, bunyavirus, and coronavirus families. For example, chalcones 8o and 8p showed potent inhibition of PIV5 replication with minimal cytotoxicity in human fibroblast cultures. Time-of-addition studies showed that these chalcones inhibit an early stage of viral replication and prevent viral spread through cell cultures. Most importantly, our top performing chalcones showed potent in vitro antiviral activity against Zika virus, La Crosse Virus, and the coronavirus OC43. These studies offer mechanistic insight into chalcone-mediated inhibition of viral replication, demonstrate the influence of functional group changes of chalcone scaffolds on their efficacy as antivirals, and support the development of chalcones as broad-spectrum antiviral compounds. Full article

Background: Sexually transmitted infections (STIs) are common globally, posing significant public health challenges and financial strain, especially in low- and middle-income countries. Sub-Saharan Africa (SSA) accounts for 40% of global STI prevalence, with South Africa having the highest rates of curable STIs and human immunodeficiency virus (HIV), both of which are closely linked to increasing HIV transmission risk and other STIs. Genital ulcer disease (GUD), primarily caused by HSV-1, HSV-2, and Treponema pallidum, and less frequently by Haemophilus ducreyi, Klebsiella granulomatis, and Chlamydia trachomatis, exemplifies the complex interplay of STIs. Methods: This study analyzed GUD and co-infection with HIV, testing patterns, and co-occurrence trends among public clinic attendees in Mthatha, South Africa, to identify demographic, behavioral, and occupational disparities. Results: Sex-specific analysis revealed higher HIV prevalence among female attendees (47.00%) compared to male attendees (22.00%), alongside notable testing gaps and disparities in diseases such as syphilis, genital herpes, and lymphogranuloma venereum (LGV). Age-specific trends indicated the highest HIV prevalence in individuals aged 30–49, with peaks at 66.67% (30–39) and 76.47% (40–49). Treponema pallidum and HSV-2 prevalence were most pronounced in younger age groups (<20 and 20–29), while older demographics (50+) exhibited significant diagnostic gaps. Occupation-based analysis highlighted elevated HIV (65.91%) and HSV-2 (19.61%) prevalence among unemployed individuals, reflecting socioeconomic vulnerabilities. Co-occurrence analysis revealed notable overlaps, such as HIV and HSV-2 (6.67%) and Chlamydia trachomatis with HSV-1 (5.71%) and HSV-2 (4.76%), driven by shared risk factors. Correlation analysis identified strong links between HSV-1 and Haemophilus ducreyi (0.64) and between Chlamydia trachomatis and HSV-1 (0.56), underscoring the potential for integrated diagnostic strategies. Conclusion: These findings emphasize the need for targeted public health interventions addressing sex, age, and occupational disparities while improving diagnostic coverage and prevention efforts for co-occurring infections. Full article

Mycobacterial spindle cell pseudotumors (MSCPs) are rare lesions characterized by the proliferation of spindle-shaped histiocytes caused by mycobacterial infections. MSCPs have been reported in the lung, lymphatic system, and skin of immunodeficient patients. We present the case of a spindle cell pseudotumor of the pancreas in a 30-year-old male with advanced human immunodeficiency virus (HIV) infection, which led to biliary stricture, splenomegaly, chronic pancreatitis, portal hypertension, compression of the hepatic artery and portal vein, and ascites. This was the patient’s third mycobacterial infection diagnosis. The MSCP was diagnosed via endoscopic biopsy after two prior non-diagnostic biopsies of the pancreatic lesion. Following 18 months of tailored antimycobacterial therapy, the pancreatic mass resolved radiographically with normalization of liver tests and sustained clinical improvement, and there has been no relapse more than 8 months after treatment completion. This case highlights the presentation of an MSCP in a unique anatomic location not previously documented and the challenges encountered with diagnosis and management. Full article

Background: T-cell receptor excision circles (TRECs) are measured in newborn screening programs in the United States to identify severe combined immunodeficiency (SCID). We hypothesized that relatively low TREC levels at birth, even within the normal range, could indicate compromised immunity and higher susceptibility to childhood cancers. Methods: We conducted a case–control study using linked data from the newborn screening programs and cancer registries in California and Texas to examine the association between TREC levels and risk of childhood cancer. The study included 2196 cancer cases and 10,980 controls from California and 1186 cancer cases and 5890 controls from Texas. Results: In California, acute myeloid leukemia cases had significantly lower TREC levels compared with their matched controls (p = 0.0051), while in Texas, acute lymphocytic leukemia cases had significantly higher TREC levels compared with their matched controls (p = 0.0034). However, each association was not replicated in the other state, and other cancer types did not show significant differences in TREC levels between cases and controls. Conclusions: We did not observe consistent associations between TREC levels at birth and childhood cancer risk. A possible explanation for the lack of more clear-cut differences in TREC levels between cases and matched controls might be the complex etiology of childhood cancers. The results underscore the need for longitudinal studies that incorporate additional immune biomarkers to understand the immunologic basis of childhood cancer development. Full article

Antigenicity and immunogenicity define a potent immunogen in vaccinology. Nowadays, there are simplified platforms to produce nanocarriers for small-peptide antigen delivery, derived from various infectious agents for the treatment of a variety of diseases, based on virus-like particles (VLPs). They have good cell-penetrating properties and protective action for target molecules from degradation. Human papillomavirus (HPV) causes anogenital warts and six types of cancer in infected women, men, or children, posing a challenge to global public health. The HPV capsid is composed of viral type-specific L1 and evolutionarily conserved L2 proteins. Produced in heterologous systems, the L1 protein can self-assemble into VLPs, nanoparticles sized around 50–60 nm, used as prophylactic vaccines. Devoid of the viral genome, they are safe for users, offering no risk of infection because VLPs do not replicate. The immune response induced by HPV VLPs is promoted by conformational viral epitopes, generating effective T- and B-cell responses. Produced in different cell systems, HPV16 L1 VLPs can be obtained on a large scale for use in mass immunization programs, which are well established nowadays. The expression of heterologous proteins was evaluated at various transfection times by transfecting cells with vectors encoding codon-optimized HPV16L1 and HPV16L2 genes. Immunological response induced by chimeric HPV16 L1/L2 VLP was evaluated through preclinical assays by antibody production, suggesting the potential of broad-spectrum protection against HPV as a prophylactic nanovaccine. These platforms can also offer promising therapeutic strategies, covering the various possibilities for complementary studies to develop potential preventive and therapeutic vaccines with broad-spectrum protection, using in silico new epitope selection and innovative nanotechnologies to obtain more effective immunobiologicals in combating HPV-associated cancers, influenza, hepatitis B and C, tuberculosis, human immunodeficiency virus (HIV), and many other illnesses. Full article

Background/Objectives: This study investigated susceptibility factors that may contribute to Post-Polio Syndrome (PPS) in elderly polio survivors. Methods: Serum immunoglobulin (Ig) levels, poliovirus neutralizing antibodies (PV NAb), and vitamin D status were evaluated in 80 PPS patients, 40 family members, and 89 healthy controls. Results: A significant number of PPS patients and their family members showed reduced levels of total IgG and/or IgA, and specific IgG subclasses, indicating a high prevalence of primary humoral immunodeficiencies within these groups. Despite these Ig deficits, PV NAb titers were similar across all groups, indicating high protection against poliovirus, likely due to vaccination campaigns with live virus in Italy and intense exposure to poliovirus, especially in long-term rehabilitation institutions. However, a small group of PPS subjects lacked neutralizing antibodies for specific poliovirus serotypes, suggesting more severe antibody deficiencies. Additionally, PPS subjects had a high prevalence of vitamin D deficiency, which likely increases their risk for osteoporosis/osteopenia and fractures. It is unclear if this deficiency was also present in their infancy, potentially enhancing their susceptibility to poliovirus. Conclusions: Overall, the findings indicate that genetic, immunological, or nutritional factors may increase individual susceptibility to the pathogenic effects of poliovirus. This study—limited to serum antibodies—highlights the complex relationship between immune status and long-term health in aging polio survivors. The results emphasize the need for potent poliovirus drugs and vaccines to help contain possible outbreaks but also—for poliomyelitis survivors—to avoid or mitigate the progression to PPS, the latest phase of this devastating disease. Full article

Extensive studies about the human immunodeficiency virus type 1 (HIV-1) have allowed the generation of lentiviral vectors as gene delivery vehicles with enhanced safety and efficacy features. In this review, several strategies for controlling the molecular mechanisms occurring during the lentiviral vector manufacturing process are presented. Specifically, modifications focused on LVV manufacturing components, such as plasmids or the producer cell line, that enable increased safety, integrity, and potency of the produced LVV, as well as manufacturing efficiency. Considering the stochasticity of the LVV manufacturing process from plasmid transfection until the budding of the virus from the target cell, minimal modifications might have a huge impact on the final LVV yield. Indeed, the extent of a potential impact may vary depending on the specificities of each LVV regarding the particular genetic payload or the envelope protein. Thus, the feasibility of each of the optimizations described herein requires thorough evaluation. The second part of the review examines the potential multi-purpose nature of the LVV. Growing research in the field has enabled the development of new engineered modalities of LVV, expanding their application scope beyond the traditional ex vivo DNA delivery approach. LVVs are becoming a versatile tool for the packaging or delivery of cargo in the form of DNA, RNA, or protein, allowing their use for in vivo approaches, vaccinology, or gene editing, among others. Full article

Background: Periodontal disease is a common chronic inflammatory disease affecting the oral cavity involving the tissues supporting teeth. It is a significant oral health concern worldwide, particularly amongst individuals living with human immunodeficiency virus (HIV). Biological aging is associated with a natural decline in the immune system, which can also affect the severity of periodontitis and other potential risk factors. In people living with HIV (PLWH), the contribution of both the HIV infection and the aging process can lead to increased susceptibility to periodontal disease. Objectives: This paper aims to review the recent literature about the relationships between HIV infection and early aging and their impact on periodontitis, and to inform interested clinicians about the current literature on the intersection between and within these topics. Methods: This review explores the recent literature on the complex relationship between HIV, aging, and periodontitis. The PubMed, ScienceDirect, and Medline databases were used to find clinical research studies within the last 10 years to identify significant correlations between HIV, aging, and periodontitis. Results: These studies identify key pathogens, molecules, or cellular pathways that contribute to a more comprehensive understanding of the pathophysiologic processes that link HIV, aging, and periodontitis. This complex relationship is multifactorial, involving immune dysfunction, microbial dysbiosis, and inflammatory pathways that still need further research. Conclusions: Overall, this exploration through molecular and cellular mechanisms underlying the relationships between aging, HIV, and periodontitis can provide therapeutic implications for dental clinicians to prevent and treat their affected patients. Full article

The global fight against HIV/AIDS has been significantly bolstered by the development and implementation of pre-exposure prophylaxis (PrEP), yet innovation in PrEP interventions, improved adherence and greater access are still needed to maximize its benefit. Nonhuman primate (NHP) infection with simian immunodeficiency virus (SIV) has served as an instrumental animal model in advancing HIV PrEP research. This review comprehensively examines the utility of NHP models in evaluating the efficacy, pharmacokinetics, and safety of diverse PrEP strategies, including oral, injectable, implantable, and topical formulations. It discusses the development of diverse challenge models that simulate human transmission routes and the advantages of NHPs in enabling controlled and mechanistically informative studies. It also highlights the successful translation of pivotal NHP studies evaluating tenofovir-based regimens as well the long-acting agents, cabotegravir and lenacapavir, into the clinical settings, emphasizing the consistently high predictive power of the NHP models for the HIV PrEP clinical efficacy. Finally, it underscores the importance of species-specific pharmacologic considerations and the value of NHP data in informing clinical trial design. As the global community strives to end the HIV epidemic as a public health threat in the absence of an efficacious prophylactic vaccine, NHP models make a critical contribution in the development of next-generation HIV prevention tools. Full article

Background: Donor lymphocyte infusion (DLI) is employed to enhance the graft-versus-leukemia (GvL) effect and improve remission rates following allogeneic hematopoietic cell transplantation (alloHCT). However, graft-versus-host disease (GvHD) remains a significant complication of both alloHCT and DLI. Regular exercise has been shown to reduce cancer risk, enhance treatment responses, and mitigate therapy-related toxicities. This study investigated the effects of voluntary wheel running on GvL and GvHD following DLI in a xenogeneic mouse model. Methods: Immunodeficient NSG-IL15 mice were challenged with a luciferase-expressing chronic myelogenous leukemia cell line (K562), and then they received DLI with peripheral blood mononuclear cells (PBMCs) from healthy volunteers (GvL model). Non-tumor bearing mice received DLI to model GvHD. Half of the mice in each group were then given free access to a running wheel. Tumor growth (bioluminescence), GvHD, and body weight were monitored biweekly for ~40 days. Results: In the GvHD model, exercise extended overall survival by 60% and reduced GvHD severity. In the GvL model, exercise significantly lowered tumor burden and extended tumor-free survival in both DLI and vehicle control groups by 44.5% and 37.5%, respectively, suggesting both immune-dependent and immune-independent mechanisms. RNA sequencing of bone marrow from saline-injected mice revealed that genes associated with mitochondrial function, protein synthesis, and metabolic processes were downregulated in tumors from exercised mice. Conclusions: In summary, voluntary wheel running improved DLI outcomes by enhancing GvL and reducing GvHD. These benefits may be mediated, in part, through exercise-induced metabolic reprogramming of leukemia cells. Full article

Background and Objectives: Inborn errors of immunity are increasingly diagnosed in developing countries. Immunoglobulin replacement therapy (IGRT) remains the cornerstone of treatment in these patients, and its monitoring has gained importance for optimizing outcomes. We conducted a retrospective study to evaluate the relationship between IgG trough levels and infections in adults with inborn errors of immunity receiving IGRT. Materials and Methods: Adults diagnosed with primary immunodeficiency and receiving IGRT for at least six months were included. Serum IgG trough levels were measured, and infections during follow-up were systematically recorded. Results: A total of 31 adult patients (CVID: 29, XLA: 2) were analyzed. The mean follow-up was 13 months, with a mean serum IgG trough level of 815.8 ± 205.9 mg/dL, achieved with an average IGRT dose of 498.8 ± 93.0 mg/kg/month. Dose adjustments were made in 35.5% of patients, mostly due to weight changes and clinical indications. Overall, 74.2% of patients had at least one infection requiring antibiotics. Patients with mean IgG trough levels below 850 mg/dL had significantly higher rates of antibiotic-requiring infections (p = 0.032, Mann–Whitney U; mean difference = 0.109, 95% CI: 0.037–0.182; p = 0.005 via t-test). Multivariate regression confirmed that lower IgG trough levels were independently associated with higher antibiotic-requiring infection rates (B = −0.024, 95% CI: −0.045 to −0.002, p = 0.033), while IGRT dose and comorbidities were not significant. Conclusions: IGRT plays a key role in reducing antibiotic-requiring infections in patients with primary immunodeficiency. Regular monitoring and individualized dose adjustments may help optimize outcomes. Further prospective studies are needed to confirm these findings. Full article

Background/Objectives: Biliary tract cancers (BTCs), encompassing tumors of the bile ducts, gallbladder, or ampulla of Vater, are notoriously hard to manage, especially when surgery is off the table and standard chemotherapy provides only modest benefits. While emerging treatments such as immune checkpoint inhibitors have shown promise, mixed clinical trial results and varied study endpoints have left their true impact unclear. This concise review consolidates current evidence on combining chemotherapy with immunotherapy to clarify whether these regimens can significantly improve outcomes and steer more effective treatment strategies for BTCs. Methods: A comprehensive literature search was conducted across PubMed, Embase, Web of Science, and ClinicalTrials.gov for randomized controlled trials (RCTs) and prospective comparative studies published from January 2010 to December 2024. Fixed-effect meta-analyses (inverse-variance method) were used as the primary approach, with random-effects models (REML) performed as sensitivity analyses to confirm robustness were performed to calculate pooled hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS). Leave-one-out sensitivity analyses and Egger’s tests assessed result stability and publication bias. The review was conducted in accordance with PRISMA 2020 guidelines and registered in OSF. Results: Two RCTs (n = 1754; chemoimmunotherapy n = 874, chemotherapy n = 880) were included in the quantitative meta-analysis. Compared to chemotherapy alone, chemoimmunotherapy significantly reduced the risk of death by 20% (OS, HR = 0.80; 95% CI 0.72–0.89; I² = 0%) and the risk of disease progression or death by 19% (PFS, HR = 0.81; 95% CI 0.73–0.90; I² = 33.5%). Leave-one-out sensitivity analyses confirmed result stability. Egger’s tests showed no significant publication bias (OS p = 0.30; PFS p = 0.40). Two additional studies (IMbrave 151 and Monge 2022) lacking comparative survival data were qualitatively assessed. Conclusions: Chemoimmunotherapy significantly improves OS and PFS compared with chemotherapy alone in advanced BTC, with consistent findings across included trials. These results support the incorporation of chemoimmunotherapy as a first-line therapeutic strategy. Future research should prioritize biomarker-driven patient selection, evaluation of long-term clinical outcomes, and integration of targeted therapies with chemoimmunotherapy. Full article