Atherosclerosis is the primary pathological basis of cardiovascular diseases, with macrophage dysfunction, lipid accumulation, and oxidative stress driving plaque formation and progression. Ferroptosis, an iron-dependent form of regulated cell death characterized by lipid peroxidation, has recently emerged as a pivotal mechanism influencing atherosclerosis. Heme oxygenase-1 (HO-1), a key regulator of heme catabolism and iron homeostasis, exerts dual roles in this process: moderate HO-1 activity confers cytoprotection through antioxidant effects, whereas excessive HO-1 expression promotes intracellular iron accumulation, oxidative stress, and ferroptotic cell death. In macrophages, HO-1 mediates both classical ferroptosis pathways via glutathione peroxidase 4 (GPX4) regulation and non-classical, erythrophagocytosis-induced ferroptosis, contributing to plaque instability. This review systematically examines the molecular mechanisms underlying HO-1-induced ferroptosis in atherosclerosis, emphasizing its interplay with iron metabolism, oxidative stress, and macrophage function. Understanding the context-dependent effects of HO-1 provides novel insights into the regulation of vascular cell fate and plaque stability, highlighting potential therapeutic targets for the prevention and treatment of atherosclerotic cardiovascular diseases.
ABSTRACT It is conventionally held that most DNA viruses package their genomes by one of two fundamental mechanisms: described by the sequential or concurrent models of assembly and packaging. Sequential packaging involves the translocation of a viral genome into a pre-formed capsid, often referred to as the pro-capsid. In contrast, concurrent packaging does not require the assembly of a pro-capsid. Instead, the genome is condensed, and the capsid shell is formed around the genome. The accumulation of empty particles in adenovirus infected cells has led to the assumption that adenovirus packaging may be best described by the sequential model. However, existing models fail to adequately explain all experimental observations, leaving many mysteries of adenovirus genome packaging unresolved. In this review, we describe key findings in adenovirus assembly and packaging, and we discuss them in the context of the competing models of sequential versus concurrent packaging. We discuss recent findings that have redefined our understanding of adenovirus packaging, including the role of viral biomolecular condensates and visualization of viral assembly and packaging in situ . These advances have renewed interest in the concurrent model of packaging. We anticipate that lessons learned from adenovirus packaging will be highly valuable for the advancement of viral vectors and gene-delivery technologies. In reviewing this topic, we hope to stimulate discussion and facilitate future investigation that will ultimately resolve gaps in knowledge and expand our understanding of DNA virus genome packaging.
Zahra Valizadeh, Farideh Jafari-Raddani, Safoura Shakoei
et al.
Abstract Introduction Para-Kala-Azar Dermal Leishmaniasis (para-KDL) is a rare manifestation of leishmaniasis that occurs concurrently with active Visceral Leishmaniasis (VL). It is characterized by a combination of cutaneous and systemic symptoms, posing diagnostic and therapeutic challenges. This condition is even more complex in immunocompromised patients, such as those with HIV. Case presentation We report a case of a 52-year-old male from south of Iran, who presented with prolonged fever, severe weight loss, pancytopenia, and massive splenomegaly. The patient was diagnosed with HIV and had been receiving antiretroviral therapy (ART). He underwent a splenectomy 1 month later and developed progressive generalized lymphadenopathy and hepatomegaly 5 months after that. Histopathological analysis of lymph node biopsies confirmed leishmaniosis, and the patient was started on Meglumine antimoniate. Shortly after, he developed widespread maculopapular skin lesions. Subsequent diagnostic evaluations, including skin biopsy, confirmed the presence of Leishman bodies. The patient was successfully treated with liposomal amphotericin B, leading to significant clinical improvement. Conclusion The co-existence of active VL and PKDL can make diagnosis difficult, potentially leading to misdiagnosis and treatment, particularly in immunocompromised patients. The simultaneous occurrence of VL and PKDL-like skin lesions requires heightened clinical suspicion, especially in endemic regions. Delayed or misdiagnosed cases may lead to significant morbidity. Further research is needed to understand the pathophysiology, immune response, and optimal treatment strategies for para-KDL in HIV-infected individuals.
Susan L. Moore, Susan L. Moore, Glen J. Peterson
et al.
IntroductionFebrile neutropenia, neurotoxicity, and cytokine release syndrome are dangerous and damaging side effects seen in more than half of patients with cancer who receive critical chemotherapies or immunotherapies respectively. Early intervention and care can reduce complications, but timely treatment in the outpatient setting is often delayed due to dependency on interval-based, patient-driven self-assessments. Using digital health technologies (DHT) to monitor patients remotely can improve time-to-intervention and health outcomes. Providing follow-up treatment and essential support to patients at home can further reduce patients’ and caregivers’ burden and improve patient satisfaction.MethodsThis pilot feasibility study examined the results of a patient-centered program for technology-assisted remote patient monitoring and symptom reporting for patients undergoing autologous or allogeneic stem cell transplant (SCT) or CAR T-cell therapy. Technical and operational feasibility and user experience were assessed for patients, caregivers, and providers. Ten patients between 30 and 80 years old participated in the study for up to 30 days after CAR T-cell therapy or autologous SCT or up to 90 days after allogeneic SCT. Patients wore biometric sensors around the clock to monitor vital signs and engaged with a chatbot through bidirectional SMS text messages for symptom reporting and regular health check-ins. Virtual care center personnel monitored patient status and followed up with patients or their care providers as needed. Patients, caregivers, and providers completed surveys about their program experience; patients also completed brief interviews.ResultsNine of 10 patients engaged with DHT based monitoring as intended. A total of 219 alerts were generated, 171 from wearables and 48 from the chatbot and check-ins. Fifty-seven alerts required follow-up with patients, 26 required care team follow-up, and 10 required patients to be seen in a clinical setting. Users found the program acceptable overall, with patients and caregivers reporting perceptions of being more cared for and providers feeling that it improved quality of care. Suggestions received included a desire for more information and improved communication and alerting processes.DiscussionOverall, DHT-based remote patient monitoring was feasible for use with patients receiving SCT and CAR T-cell therapy. Effective practice integration requires adaptation to clinical workflows. Further evaluation of patient acceptance over time and effectiveness at improving health outcomes is recommended.
BackgroundConcomitant administration of COVID-19, influenza, and pneumococcal vaccines could reduce the burden on healthcare systems. However, the immunogenicity and safety of various combinations of a third booster dose of SARS-CoV-2 inactivated vaccine (CoronaVac), inactivated quadrivalent influenza vaccine (IIV4), and 23-valent pneumococcal polysaccharide vaccine (PPV23), particularly in different age groups, is still unknown.MethodsA phase 4, randomized, open-label, controlled trial was conducted in Beijing, China. 636 healthy adults were divided into two age groups (18-59 and ≥60 years) and randomized equally into three groups: CoronaVac and IIV4 followed by PPV23; CoronaVac and PPV23 followed by IIV4; or CoronaVac followed by IIV4 and PPV23, with a 28-day interval between vaccinations. Immunogenicity was evaluated by measuring antibody titers, and safety was monitored. ClinicalTrials.gov Identifier: NCT05298800.ResultsCo-administration of a third dose of CoronaVac, IIV4, and PPV23 in any combination was safe. Among adults aged 18-59, co-administration with PPV23 maintained non-inferiority of antibody levels for CoronaVac and IIV4, despite a slight reduction in antibody responses. This reduction was not observed in participants ≥60 years. Furthermore, co-administration of IIV4 and PPV23 affected seroconversion rates for both vaccines.ConclusionsCo-administration of the third dose of SARS-CoV-2 inactivated vaccine with the influenza vaccine, followed by PPV23, may be optimal for adults aged 18-59. In adults ≥60, all vaccine combinations were immunogenic, suggesting a flexible vaccination approach. Since antibody measurements were taken 28 days post-vaccination, ongoing surveillance is essential to assess the longevity of the immune responses.
Danielle C. Ompad, Timir K. Padhan, Anne Kessler
et al.
AbstractDurgama Anchalare Malaria Nirakaran (DAMaN) is a multi-component malaria intervention for hard-to-reach villages in Odisha, India. The main component, malaria camps (MCs), consists of mass screening, treatment, education, and intensified vector control. We evaluated MC effectiveness using a quasi-experimental cluster-assigned stepped-wedge study with a pretest–posttest control group in 15 villages: six immediate (Arm A), six delayed (Arm B), and three previous interventions (Arm C). The primary outcome was PCR + Plasmodium infection prevalence. The time (i.e., baseline vs. follow-up 3) x study arm interaction term shows that there were statistically significant lower odds of PCR + Plasmodium infection in Arm A (AOR = 0.36, 95% CI = 0.17, 0.74) but not Arm C as compared to Arm B at the third follow-up. The cost per person ranged between US$3–8, the cost per tested US$4–9, and the cost per treated US$82–1,614, per camp round. These results suggest that the DAMaN intervention is a promising and financially feasible approach for malaria control.
M. Alejandra Mandel, Sinem Beyhan, Mark Voorhies
et al.
Coccidioides spp. are mammalian fungal pathogens endemic to the Southwestern US and other desert regions of Mexico, Central and South America, with the bulk of US infections occurring in California and Arizona. In the soil, Coccidioides grows in a hyphal form that differentiates into 3–5 micron asexual spores (arthroconidia). When arthroconidia are inhaled by mammals they undergo a unique developmental transition from polar hyphal growth to isotropic expansion with multiple rounds of nuclear division, prior to segmentation, forming large spherules filled with endospores. Very little is understood about the molecular basis of spherule formation. Here we characterize the role of the conserved transcription factor Ryp1 in Coccidioides development. We show that Coccidioides Δ ryp1 mutants have altered colony morphology under hypha-promoting conditions and are unable to form mature spherules under spherule-promoting conditions. We analyze the transcriptional profile of wild-type and Δ ryp1 mutant cells under hypha- and spherule-promoting conditions, thereby defining a set of hypha- or spherule-enriched transcripts (“morphology-regulated” genes) that are dependent on Ryp1 for their expression. Forty percent of morphology-regulated expression is Ryp1-dependent, indicating that Ryp1 plays a dual role in both hyphal and spherule development. Ryp1-dependent transcripts include key virulence factors such as SOWgp, which encodes the spherule outer wall glycoprotein. Concordant with its role in spherule development, we find that the Δ ryp1 mutant is completely avirulent in the mouse model of coccidioidomycosis, indicating that Ryp1-dependent pathways are essential for the ability of Coccidioides to cause disease. Vaccination of C57BL/6 mice with live Δ ryp1 spores does not provide any protection from lethal C . posadasii intranasal infection, consistent with our findings that the Δ ryp1 mutant fails to make mature spherules and likely does not express key antigens required for effective vaccination. Taken together, this work identifies the first transcription factor that drives mature spherulation and virulence in Coccidioides .
Chuan-Chin Huang, Qi Tan, Mercedes C. Becerra
et al.
Abstract Rationale Although World Health Organization guidelines emphasize contact investigation for tuberculosis (TB)-exposed children, data that support chest radiography as a useful tool are lacking. Objectives We evaluated the diagnostic and prognostic information of chest radiography in children exposed to TB and measured the efficacy of isoniazid preventive therapy (IPT) in those with relevant radiographic abnormalities. Methods Between September 2009 and August 2012, we enrolled 4,468 TB-exposed children who were screened by tuberculin skin testing, symptom assessment, and chest radiography. Those negative for TB disease were followed for 1 year for the occurrence of new TB diagnoses. We assessed the protective efficacy of IPT in children with and without abnormal chest radiographs. Measurements and Main Results Compared with asymptomatic children with normal chest films, asymptomatic children with abnormal radiographs were 25.1-fold more likely to have coprevalent TB (95% confidence interval [CI], 1.02–613.76) and 26.7-fold more likely to be diagnosed with incident TB disease during follow-up (95% CI, 10.44–68.30). Among the 29 symptom-negative and CXR-abnormal child contacts, 20% (3/15) of the isoniazid recipients developed incident TB, compared with 57% (8/14) of those who did not receive IPT (82% IPT efficacy). Conclusions Our results strongly support the use of chest radiography as a routine screening tool for the evaluation of child TB contacts, which is readily available. Radiographic abnormalities not usually considered suggestive of TB may indicate incipient or subclinical disease, although TB preventive treatment is adequate in most cases.
BackgroundDespite the likely association between coronavirus 2019 (COVID-19) mRNA vaccines and cases of myocarditis/pericarditis, the benefit–risk assessment by the Centers for Disease Control (CDC) still showed a favorable balance for the primary series of COVID-19 mRNA vaccinations. Since August 2021, a full-scale booster vaccination in certain recipients has been recommended. Great concerns about whether the COVID-19 mRNA booster vaccination could increase the risks of myocarditis/pericarditis have been raised since then. The present study aimed to compare the incidence rates and risks of myocarditis/pericarditis between booster and primary vaccination programs.MethodsThe CDC COVID Data Tracker and the Vaccines Adverse Event Reporting System (VAERS) were queried between December 11, 2020 and March 15, 2022. Incidence rates were calculated by cases of myocarditis/pericarditis divided by the number of vaccinated people or the total doses of COVID-19 mRNA vaccines. Disproportionality patterns for myocarditis/pericarditis of different COVID-19 mRNA vaccinations were accessed based on the reporting odds and proportional reporting ratios (ROR and PRR, respectively).ResultsA total of 2,588 reports of myocarditis/pericarditis were identified after administration of primary-series COVID-19 mRNA vaccination and 269 after the booster dose program during the study period. The incidence of myocarditis/pericarditis following booster COVID-19 mRNA vaccination was lower than that of primary series. The results showed significantly high reporting of myocarditis/pericarditis following the administration of primary COVID-19 mRNA vaccination, whereas the disproportional level was lower in the booster-dose vaccination.ConclusionThis study found that the booster dose of COVID-19 mRNA vaccination when compared with primary series course did not lead to an increase in the risks of myocarditis/pericarditis.
Robyn D. Gartrell, Thomas Enzler, Pan S. Kim
et al.
Patients with pancreatic ductal adenocarcinoma (PDAC) have a grim prognosis despite complete surgical resection and intense systemic therapies. While immunotherapies have been beneficial with many different types of solid tumors, they have almost uniformly failed in the treatment of PDAC. Understanding how therapies affect the tumor immune microenvironment (TIME) can provide insights for the development of strategies to treat PDAC. We used quantitative multiplexed immunofluorescence (qmIF) quantitative spatial analysis (qSA), and immunogenomic (IG) analysis to analyze formalin-fixed paraffin embedded (FFPE) primary tumor specimens from 44 patients with PDAC including 18 treated with neoadjuvant chemoradiation (CRT) and 26 patients receiving no treatment (NT) and compared them with tissues from 40 treatment-naïve melanoma patients. We find that relative to NT tumors, CD3+ T cell infiltration was increased in CRT treated tumors (p = .0006), including increases in CD3+CD8+ cytotoxic T cells (CTLs, p = .0079), CD3+CD4+FOXP3− T helper cells (Th, p = .0010), and CD3+CD4+FOXP3+ regulatory T cells (Tregs, p = .0089) with no difference in CD68+ macrophages. IG analysis from micro-dissected tissues indicated overexpression of genes involved in antigen presentation, T cell activation, and inflammation in CRT treated tumors. Among treated patients, a higher ratio of Tregs to total T cells was associated with shorter survival time (p = .0121). Despite comparable levels of infiltrating T cells in CRT PDACs to melanoma, PDACs displayed distinct spatial profiles with less T cell clustering as defined by nearest neighbor analysis (p < .001). These findings demonstrate that, while CRT can achieve high T cell densities in PDAC compared to melanoma, phenotype and spatial organization of T cells may limit benefit of T cell infiltration in this immunotherapy-resistant tumor.
Immunologic diseases. Allergy, Neoplasms. Tumors. Oncology. Including cancer and carcinogens
ObjectiveTo analyze the expression of macrophages, AIM, TGF-β1 in the kidney of IgAN patients, and to explore the role of macrophages, AIM, TGF-β1 in the progression of renal fibrosis in IgAN patients.MethodsThe paraffin specimens of renal tissue from 40 IgAN patients were selected as the observation group. At the same time, paraffin specimens of normal renal tissue from 11 patients treated by nephrectomy were selected as the normal control group. We observed the distribution of macrophages, the expression of AIM and TGF-β1 by immunohistochemical staining and/or immunofluorescence.ResultThe number of M0, M1, M2 macrophages could be found increased in IgAN patients. M0 macrophages are mainly polarized towards M2 macrophages. The expression of AIM and TGF-β1 were significantly higher in IgAN patients than in NC. M2 macrophage, AIM and TGF-β1 were positively correlated with serum creatinine and 24-hour proteinuria, but negatively correlated with eGFR. M2 macrophages, AIM, TGF-β1 were positively correlated with fibrotic area.ConclusionM2 macrophages, AIM and TGF-β1 play important roles in the process of IgAN fibrosis, and the three influence each other.
Eva Katharina Egger, Damian J. Ralser, Kira Lindner
et al.
BackgroundVaginal adenocarcinomas (VAC) are most often reported after intrauterine exposition to diethylstilbestrol (DES). Rarely, VACs are reported as a malignant transformation of vaginal adenosis or endometriosis, in the context of chromosomal abnormalities or malformations of the uterus or the vagina. VACs without DES exposition have a poor prognosis and a significantly worse outcome compared to vaginal squamous cell carcinomas or DES-associated VACs.ObjectiveHere, we report the case of a primarily metastatic VAC, treated successfully with different lines of chemo-, antiangiogenic, antibody, and immunotherapy.CaseThe 49-year-old patient presented in 5/2018 with a primarily pulmonary metastatic VAC. Significant tumor reduction was seen after six cycles of carboplatin AUC5/paclitaxel 175 mg/m²/bevacizumab 15 mg/kg q3w. Bevacizumab maintenance therapy and later cisplatin mono 50 mg/m² q2w led to local and distant tumor progression. To identify a potential targeted therapy, new tumor biopsies were obtained. Immunohistochemistry revealed ERBB2 expression, and paclitaxel 80 mg/m² weekly plus trastuzumab 4 mg/m² respectively 2 mg/m² q3w was administered. Due to local and pulmonal tumor progression after 6 months and persistent ERBB2 positivity, the therapy was adjusted to trastuzumab emtansine (T-DM1) 3.6 mg/kg q3w; however, the patient remained locally progressive after three cycles of T-DM1 and additionally showed a new bone metastasis. The new tumor biopsies revealed a combined positive score (CPS) of 2 regarding PD-L1, and pembrolizumab 200 mg q3w was initiated. The bone metastasis was radiated and treated with denosumab 120 mg q4w. Extreme tumor regression followed by stable disease was maintained for 9 months. Due to a slow locoregional progress only with new inguinal lymph node and pararectal lymph node metastases, a new tumor biopsy was taken. Molecular profiling showed an ARID1A mutation, a mutational burden of 5.1 mutations per megabase, and no genfusions. Based on these findings, therapy with PD-L1 antibodies, PD-1 antibodies, gemcitabine, or dasatinib was suggested. Therefore, administration of pembrolizumab was continued and local radiation therapy was performed. This led to a decrease in local tumor manifestations and a stable systemic disease.ConclusionOur case demonstrates the diagnostic and therapeutic approach in a patient with primary metastatic vaginal adenocarcinoma. By tumorgenetic profiling, different lines of systemic therapy, namely, antiangiogenic therapy, monoclonal antibody therapy, immunotherapy, and local radiation therapy, were identified and successfully administered.
Gunnar Houen, Gunnar Houen, Nicole Hartwig Trier
et al.
Multiple sclerosis (MS) is a neurologic disease affecting myelinated nerves in the central nervous system (CNS). The disease often debuts as a clinically isolated syndrome, e.g., optic neuritis (ON), which later develops into relapsing-remitting (RR) MS, with temporal attacks or primary progressive (PP) MS. Characteristic features of MS are inflammatory foci in the CNS and intrathecal synthesis of immunoglobulins (Igs), measured as an IgG index, oligoclonal bands (OCBs), or specific antibody indexes. Major predisposing factors for MS are certain tissue types (e.g., HLA DRB1*15:01), vitamin D deficiency, smoking, obesity, and infection with Epstein-Barr virus (EBV). Many of the clinical signs of MS described above can be explained by chronic/recurrent EBV infection and current models of EBV involvement suggest that RRMS may be caused by repeated entry of EBV-transformed B cells to the CNS in connection with attacks, while PPMS may be caused by more chronic activity of EBV-transformed B cells in the CNS. In line with the model of EBV’s role in MS, new treatments based on monoclonal antibodies (MAbs) targeting B cells have shown good efficacy in clinical trials both for RRMS and PPMS, while MAbs inhibiting B cell mobilization and entry to the CNS have shown efficacy in RRMS. Thus, these agents, which are now first line therapy in many patients, may be hypothesized to function by counteracting a chronic EBV infection.
Simran Grewal, Rianne Korthouwer, Marijn Bögels
et al.
Surgical resection of the primary tumor provides the best chance of cure for patients with colorectal carcinoma (CRC). However, bacterial translocation during intestinal surgery has been correlated with poor long-term oncological outcome. Therefore, we investigated the influence of bacterial contamination during colon surgery on CRC liver metastases development. Blood and liver samples of patients undergoing resection of primary CRC or liver metastases were collected. Cell numbers, activation markers and inflammatory mediators were determined. Tumor cell adhesion and outgrowth after sham- or colectomy operations were determined in a rat model, in which tumor cells had been injected into the portal vein. White blood cells and granulocytes were increased in per- and post-operative patient blood samples. IL-6 was also increased post-operatively compared to the preoperative level. Expression of NOX-2, NOX-4 and polymorphonuclear cells (PMNs) numbers were elevated in post-operative human liver samples. In vitro stimulation of macrophages with plasma of rats after colectomy resulted in production of reactive oxygen species (ROS). Colectomy in rats increased D-lactate levels in plasma, supporting bacterial translocation. Decreased expression of tight junction molecules and increased tumor cell adhesion and outgrowth was observed. Treatment with a selective decontamination of the digestive tract (SDD) cocktail decreased tumor cell adherence after colectomy. In conclusion, postoperative bacterial translocation may activate liver macrophages and PMNs, resulting in ROS production. As we previously showed that ROS release led to liver vasculature damage, circulating tumor cells may adhere to exposed extracellular matrix and grow out into liver metastases. This knowledge is pivotal for development of therapeutic strategies to prevent surgery-induced liver metastases development.
Immunologic diseases. Allergy, Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Iván Chérrez-Ojeda, Daniel Simancas-Racines, Leonardo Greiding
et al.
We have read the original article entitled: "Quality of life in chronic urticaria and its relationship with the economic impact and control of the disease in patients treated at the University Hospital of Monterrey, Mexico", by Arias-Cruz et al. In this interesting article, the authors found that 72.2% of patients with chronic urticaria is obese and overweight. Given that Mexico is one of the countries with the highest number of inhabitants with weight problems (70% of the adult population is overweight or obese), these findings would have an implication in the management of patients with chronic urticaria. The authors even detail prevalences of 17% for hypertension (more than double that of international studies) and 30% for metabolic syndrome in patients with chronic urticaria, which could be associated with more severe and uncontrolled urticaria.