Late Disease Research Articles

The Immunomodulatory Effects and Mechanism of Wogonin for the Treatment of Multiple Sclerosis in a Murine Experimental Autoimmune Encephalomyelitis Model

Abstract Multiple sclerosis (MS) stands out as the most prevalent inflammatory autoimmune disease affecting the central nervous system (CNS). The primary driver of MS involves myelin-specific autoreactive T cells that infiltrate the CNS, initiating attacks on myelinated axons and triggering neuroinflammatory responses. Wogonin, a flavonoid, exhibits pharmacologic properties, including neuroprotective, anticancer, antiviral, anti-inflammatory, and anti-oxyradical effects. Our study demonstrates that wogonin significantly suppresses TLR-dependent DC activation, migration, and the expression of adhesion molecules in LPS-stimulated bone marrow-derived dendritic cells (BMDCs). In the experimental autoimmune encephalomyelitis (EAE) model, preventive treatment with wogonin led to reduced lymphocyte infiltration, prevented demyelination in the CNS, and consequently mitigated disease symptoms. Moreover, wogonin suppressed the release of neuroinflammatory cytokines by activated microglial cells, Th1 cells, Th2 cells, and Th17 cells in vitro and exerted therapeutic effects on attenuating the disease severity in the early disease onset stage and late disease progression stage. Our study suggests that wogonin treatment may not only prevent the onset of MS by inhibiting DC activation and migration but also potentially ameliorate the progression of MS by reducing neuroinflammation. This opens avenues for the development of new approaches in the therapy of autoimmune diseases.

P147 M2 macrophage associated fibrosis in early stage systemic sclerosis: an update on plasma biomarkers

Abstract Background/Aims Systemic sclerosis is an autoimmune connective tissue disease characterised by vasculopathy and fibrosis. The CCN family of matricellular proteins have a regulatory role in inflammation and fibrosis. CD206, an M2 macrophage surface marker, is cleaved by metalloproteases to release soluble form of CD206; this acts as an active disease marker in systemic sclerosis. We investigated the profile of CCN2 and CCN3 in the presence of soluble CD206 (sCD206) in patients with early and late stage diffuse systemic sclerosis (dcSSc). Methods Patients with a diagnosis of dcSSc at the UCL Centre for Rheumatology and Connective Tissue Diseases were recruited. Informed consent was obtained from patients and healthy controls (HC). Blood samples were taken from which plasma was isolated and stored at -80 °C prior to assay. Expression of CCN2, CCN3, and sCD206 was measured in these plasma samples by ELISA. Study participants were categorised into healthy controls (n = 20), early stage dcSSc (n = 20) and late dcSSc (n = 20), with early stage defined as the blood sample taken within two years since diagnosis, and late stage defined as over five years since diagnosis. Results Plasma CCN2, CCN3 and sCD206 levels were significantly higher in early dcSSc patients, when compared to HC. CCN2 was raised in early dcSSc patients (early dcSSc mean 20,221pg/ml, SD 16,503, p < 0.05) with concentration in late disease matching that of HC (late dcSSc 12,893pg/ml, HC 11,289pg/ml). CCN3 was significantly higher in early and late disease when compared to HC (early mean 16,526pg/ml, late 12,838pg/ml, HC 4,201pg/ml, p < 0.05). sCD206 levels were higher in early dcSSc (mean 5356pg/ml, SD 3154, p < 0.05), with there being no significance between levels in late dcSSc (mean 4184pg/ml, SD 3900, p > 0.05) and HC (mean 3319pg/ml, SD 1925). CCN2 expression was higher compared to that of CCN3 in early disease, with CCN2:CCN3 ratio elevated in early dcSSc (mean 3.17, SD 8.26) compared to late dcSSc (mean 1.26, SD 0.99) and HC. Conclusion This investigation demonstrates that upregulation of CCN2 and CCN3 expression has a regulatory role in fibrosis in early stage dcSSc. These biomarkers of M2 macrophage associated fibrosis are to be correlated with their clinical phenotype and have potential for a role in targeted treatment of systemic sclerosis. Disclosure L.A. Leeves: None. Z. Kannan: None. Y. Ali: None. L. Pan: None. T. Malley: None. D. Abraham: None. A. Leask: None. B. Riser: None. B. Ahmed Abdi: None. R.J. Stratton: None.

Idiopathic aseptic necrosis of the femoral head in children who are professionally engaged in gymnastics: A literature review

BACKGROUND: Aseptic necrosis of the femoral head in school-age children is a severe, rapidly progressive degenerative and dystrophic disease. A significant proportion of girls aged 10 years with osteonecrosis of the femoral head have been professionally engaged in rhythmic gymnastics. The relationship between professional sports, in particular rhythmic gymnastics, and the development of this pathology and the mechanism of impaired blood flow in the femoral head in such cases remains unclear. The severity of the course and serious consequences of this disease in the form of multidimensional deformities of the femoral head, early arthrosis of the hip joint, and persistent disability, require close attention.
 AIM: To analyze modern world literature data on the etiology, pathomechanics, and features of the course and treatment of idiopathic aseptic necrosis of the femoral head in children professionally engaged in rhythmic gymnastics.
 MATERIALS AND METHODS: A literature search on the problem of idiopathic aseptic necrosis of the femoral head in children professionally engaged in rhythmic gymnastics in the open information databases was conducted in PubMed, Science Direct, and Library with an analysis depth of 20 years.
 RESULTS: The analysis of publications on the osteonecrosis of the femoral head allowed us to talk about the etiological connection of this condition with professional rhythmic gymnastics, namely, high-intensity repetitive loads on the hip joint of a child. Studies using in vivo laser Doppler flowmetry and 3D computer modeling prove the occlusion of blood vessel branches encircling the femur under excessive mechanical stress on the femoral head and potentially unfavorable positions in the hip joint – overextension (hyperextension), external rotation, and abduction.
 CONCLUSIONS: Professional gymnastics can be a risk factor for the development of osteonecrosis of the femoral head. Frequent late disease diagnoses with the development of severe deformity of the femoral head and end-stage coxarthrosis requiring total hip replacement in adolescents determine the need for early identification of the causes of hip pain in children engaged in gymnastics. The findings will help improve treatment results and reduce the number of organ replacement interventions.

Longitudinal markers of cerebral amyloid angiopathy and related inflammation in rTg-DI rats

Cerebral amyloid angiopathy (CAA) is a prevalent vascular dementia and common comorbidity of Alzheimer’s disease (AD). While it is known that vascular fibrillar amyloid β (Aβ) deposits leads to vascular deterioration and can drive parenchymal CAA related inflammation (CAA-ri), underlying mechanisms of CAA pathology remain poorly understood. Here, we conducted brain regional proteomic analysis of early and late disease stages in the rTg-DI CAA rat model to gain molecular insight to mechanisms of CAA/CAA-ri progression and identify potential brain protein markers of CAA/CAA-ri. Longitudinal brain regional proteomic analysis revealed increased differentially expressed proteins (DEP) including ANXA3, HTRA1, APOE, CST3, and CLU, shared between the cortex, hippocampus, and thalamus, at both stages of disease in rTg-DI rats. Subsequent pathway analysis indicated pathway enrichment and predicted activation of TGF-β1, which was confirmed by immunolabeling and ELISA. Further, we identified numerous CAA related DEPs associate with astrocytes (HSPB1 and MLC1) and microglia (ANXA3, SPARC, TGF-β1) not previously associated with astrocytes or microglia in other AD models, possibly indicating that they are specific to CAA-ri. Thus, the data presented here identify several potential brain protein biomarkers of CAA/CAA-ri while providing novel molecular and mechanistic insight to mechanisms of CAA and CAA-ri pathological progression and glial cell mediated responses.

Targeting PCSK9 to upregulate MHC-II on the surface of tumor cells in tumor immunotherapy.

Proprotein convertase subtilisin/kexin type 9 (PCSK9), the last member of the proprotein convertase family, functions as a classic regulator of low-density lipoprotein (LDL) by interacting with low-density lipoprotein receptor (LDLR). Recent studies have shown that PCSK9 can affect the occurrence and development of tumors and can be used as a novel therapeutic target. However, a comprehensive pan-cancer analysis of PCSK9 has yet to be conducted. The potential oncogenic effects of PCSK9 in 33 types of tumors were explored based on the datasets of The Cancer Genome Atlas (TCGA) dataset. In addition, the immune regulatory role of PCSK9 inhibition was evaluated via in vitro cell coculture and the tumor-bearing mouse model. Finally, the antitumor efficacy of targeted PCSK9 combined with OVA-II vaccines was verified. Our results indicated that PCSK9 was highly expressed in most tumor types and was significantly correlated with late disease stage and poor prognosis. Additionally, PCSK9 may regulate the tumor immune matrix score, immune cell infiltration, immune checkpoint expression, and major histocompatibility complex expression. Notably, we first found that dendritic cell (DC) infiltration and major histocompatibility complex-II (MHC-II) expression could be upregulated by PCSK9 inhibition and improve CD8+ T cell activation in the tumor immune microenvironment, thereby achieving potent tumor control. Combining PCSK9 inhibitors could enhance the efficacies of OVA-II tumor vaccine monotherapy. Conclusively, our pan-cancer analysis provided a more comprehensive understanding of the oncogenic and immunoregulatory roles of PCSK9 and demonstrated that targeting PCSK9 could increase the efficacy of long peptide vaccines by upregulating DC infiltration and MHC-II expression on the surface of tumor cells. This study reveals the critical oncogenic and immunoregulatory roles of PCSK9 in various tumors and shows the promise of PCSK9 as a potent immunotherapy target.

Late cytomegalovirus disease after hematopoietic cell transplantation: significance of novel transplantation techniques

AbstractPreemptive therapy (PET) and letermovir prophylaxis are effective in preventing cytomegalovirus (CMV) disease within the first 100 days after allogeneic hematopoietic cell transplantation (HCT) but are associated with late-onset CMV disease. We retrospectively examined the clinical manifestations, risk factors, prevention algorithm, and outcome of late CMV disease in CMV seropositive day 100 survivors transplanted between 2001-2017 (PET cohort) and 2018-2021 (letermovir cohort). There were 203 episodes of late CMV disease among 2469 day 100 survivors, and the estimated cumulative incidence of first late CMV disease was 7.2% (95% confidence interval [CI], 6.2-8.3) with no difference between the PET (7.4%; 95% CI, 6.4-8.6) and the letermovir group (5.4%; 95% CI, 3.2-8.3). Thirty-seven patients (1.5%) had a second episode of CMV disease. In multivariable Cox regression models, posttransplant cyclophosphamide was associated with an increased risk of gastrointestinal CMV disease. CMV viremia or disease detected before day 100, corticosteroid treatment after day 100 at dose ≥1 mg/kg, acute and chronic graft-versus-host disease, lymphopenia, HLA-mismatched related donor status, were also associated with late CMV disease. HLA-mismatched donor status and late use of corticosteroids (≥1 mg/kg) were risk factors for late CMV disease recurrence. Late CMV disease occurred most frequently in a setting of prolonged low-level untreated viremia and was independently associated with death by 2 years after HCT. In summary, late CMV disease continues to occur in the present era. Improved prevention strategies for late CMV disease are needed.

Clinico-epidemiological characteristics of early- versus late-onset cytomegalovirus disease among renal transplant recipients: A two-decade experience

BackgroundReactivation of cytomegalovirus (CMV) infection in transplant patients is high because of immunosuppression. We have evaluated the clinical and epidemiological characteristics of early versus late onset of CMV infection among renal transplant recipients. MethodsA single center retrospective observational study was conducted among renal transplant recipients who underwent kidney transplant between January 2002 and December 2021. CMV disease was classified as early or late depending on its detection prior to or after 90 days post-transplantation. Herein, we reported the differences between early and late onset of CMV disease with respect to clinical symptoms, the use of immunosuppression and the impact on graft outcomes. ResultsOut of total 2164 renal transplant recipients, 156 patients (7.2%) were diagnosed with CMV disease. Among these 156 patients, 25 patients (16%) had early CMV while 131 patients (84%) had late CMV. Overall, the two groups did not differ with respect to the induction or maintenance of immunosuppressive agents. However, the proportion of CMV syndrome was greater among early (56.0%) than late (26.7%) CMV groups (p = 0.01). In contrast, tissue invasive disease was more frequent among late (73.3%) in comparison to early (44.0%) CMV groups (p = 0.01). Among clinical symptoms, diarrhea was more frequent in late (63.4%) vs. early (36%) CMV-affected patients (p = 0.01). Graft loss occurred in 4.0% of early CMV group vs. 25.2% of late CMV group (p = 0.03). Neither of the clinical groups differed with respect to occurrence of biopsy-proven allograft rejection post-infection. ConclusionsEarly CMV disease presents more frequently as CMV syndrome while late CMV disease usually manifests itself as tissue invasive disease. Graft loss is more common in patients with late onset of CMV disease.

Validation of Groundnut (Arachis hypogaea L.) Mini-core Genotypes for Phenotypic Extremities along with LLS Resistance Through Genetic and Molecular Intervention

Background: The present investigation was conducted at Agricultural College and Research Institute, Killikulam, Tamil Nadu during the year 2022-2023 involving 220 groundnut genotypes along with a resistant and susceptible check towards validation of phenotypic extremities on yield and its contributing traits besides screening against late leaf spot resistance. Methods: The data collected from two hundred and twenty germplasm along with check varieties for thirteen quantitative traits. The collected data were subjected to statistical analysis (Mahalanobis, 1936) besides interpreted by various genetic tools such as PCV, GCV, heritability and GAM. Further, ten plants were selected at random from each genotype and observation on late leaf spot disease was recorded based on modified 9 point scale. Result: Molecular analysis for LLS resistance among the groundnut germplasm had shown the concurrent superiority in terms of yield and resistance to late leaf spot disease among the genotypesICG 15233, ICG 8760, ICG 76, ICG 111, ICG 297, ICG 405, ICG 238, ICG 4598, ICG 5051, ICG 6057, ICG 8253, ICG 8285, ICG 10701 and ICG 15234. Hence, these genotypes can be exploited to develop a disease resistance and high yielding groundnut culture.

Alterations in Cerebrospinal Fluid Urea Occur in Late Manifest Huntington's Disease.

Huntington's disease (HD) is a neurodegenerative disorder caused by expanded cytosine-adenine-guanine (CAG) repeats in the Huntingtin gene, resulting in the production of mutant huntingtin proteins (mHTT). Previous research has identified urea as a key metabolite elevated in HD animal models and postmortem tissues of HD patients. However, the relationship between disease course and urea elevations, along with the molecular mechanisms responsible for these disturbances remain unknown. To better understand the molecular disturbances and timing of urea cycle metabolism across different stages in HD. We completed a global metabolomic profile of cerebrospinal fluid (CSF) from individuals who were at several stages of disease: pre-manifest (PRE), manifest (MAN), and late manifest (LATE) HD participants, and compared to controls. Approximately 500 metabolites were significantly altered in PRE participants compared to controls, although no significant differences in CSF urea or urea metabolites were observed. CSF urea was significantly elevated in LATE participants only. There were no changes in the urea metabolites citrulline, ornithine, and arginine. Overall, our study confirms that CSF elevations occur late in the HD course, and these changes may reflect accumulating deficits in cellular energy metabolism.

Metastasis of serous ovarian carcinoma to the breast: a case report and review of the literature

BackgroundBreast metastasis from primary ovarian cancer is rare, with an estimated frequency of 0.07%. More than 110 cases are reported in the literature of metastatic spread of ovarian cancer to the breast and axilla. This entity usually represents aggressive late disease characterized by multi-drug chemoresistance and a poor prognosis with a median survival time of 16 months. Currently no standardized treatment protocol exists for this condition.Case presentationWe present a case of a 59-year-old Caucasian female with recurrent high-grade serous ovarian cancer who was diagnosed with symptomatic unilateral breast metastasis while on fourth line chemotherapy with weekly paclitaxel. She was treated with local radiation with 2300 cGy to the right breast with a complete response. She then had a subsequent recurrence in the ipsilateral breast 8 months after completion of post treatment imaging. She remains alive to date approximately 2 years after her initial diagnosis of breast metastasis on seventh line treatment.ConclusionsBreast metastasis from primary ovarian cancer is rare and represents advanced disease characterized by multi-drug chemoresistance and a poor prognosis. This case describes radiation therapy as a safe, effective treatment option to improve local control and quality of life in these patients, but with limited durability of response.

Abstract 3974: Macronutrient composition dictates MASH-associated HCC immunosurveillance through microbiota alteration and metabolic adaptation

Abstract Hepatocellular carcinoma (HCC) is the most common form of liver cancer, with an estimated incidence of over one million cases by 2025. The advances in vaccines against HBV and HCV have led to a decrease in the number of virus-related cases; however, the obesity epidemic has contributed to a drastic increase in metabolic dysfunction-associated steatohepatitis (MASH) related HCC cases (e.g., obesity and type 2 diabetes induced HCC). Considering this trend, we aim to understand how lifestyle choices, like food composition, in combination with alcohol consumption at a “social drinking level” impacts host metabolism, and subsequently the development of MASH-induced HCC. We hypothesize that the impact of dietary composition on dysbiosis and immune cells, particularly adaptive immune cell metabolic status, will drive the phenotype. We have developed a MASH-induced HCC murine model, with long-term dietary intervention including seven different customized diets: normal chow (NC), ketogenic, solid high fat diet (sHFD), or isocaloric liquid Lieber DeCarli Diets (LDC): high fat/low carb (HF), high fat/low carb with ethanol (HF-EtOH), low fat/high carb (LF), and low fat/high carb with ethanol (LF-EtOH). Mice began special diet in late adolescences and disease progression was monitored over the course of a year, where mice developed HCC. Our model allowed for a comprehensive understanding of MASH-induced HCC where disease initiation could be studied beyond known contributors like obesity or body mass index (BMI). The animal model was analyzed comprehensively with high-parameter flow cytometry (FC), 16S sequencing, bulk RNA-seq, scRNA/ATAC-seq, and WGS. Long-term diet intervention led to macronutrient specific microbiota dysregulation, alterations in systemic metabolism and suppression of adaptive immune response, consequently impacting the progression of HCC. Customized dietary interventions showed a specific phenotype regarding HCC development and progression with distinct mutational genotype and particular response to immunotherapy. T and B cell subpopulation deficiency had a significant impact on MASH-induced HCC development in a macronutrient composition dependent manner. In summary, each dietary intervention showed a distinct pattern and effect on dysbiosis, systemic metabolic reprograming, cellular transcriptomic and epigenetic alteration, and particularly immune cell effector function. Additionally, some compositions supported the immuno-escape mechanism of malignant cells through regulation of their MHC machinery. Collectively, these accumulated data construct an atlas for understanding the underlying molecular mechanisms contributing to lifestyle-induced HCC providing the knowledge needed to advance effective strategies for treatment and prevention. Citation Format: Nicolas T. Ryujin, Jian Huang, Albert Nguyen, Jared Edwards, Yuhe Cheng, Jessica Wen, Ashish Damania, Nadim Ajami, Spencer Rosario, Mark Long, Ludmil Alexandrov, Shabnam Shalapour. Macronutrient composition dictates MASH-associated HCC immunosurveillance through microbiota alteration and metabolic adaptation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3974.

Abstract 1609: Inferring the T cell repertoire dynamics in non-small cell lung cancer metastases

Abstract Non-small cell lung cancer (NSCLC) is a highly complex disease, characterized by extensive genomic heterogeneity and dynamic evolution under therapeutic pressure. This evolution can lead to alterations in the antigens expressed by cancer cells, thereby influencing the T cell repertoire (TCR) as T cells expand in response to foreign antigens. Despite the central role of TCR in cancer progression and treatment response, only few studies have investigated the temporal and spatial changes in the TCR repertoire. In this study, we delve into the role of the TCR repertoire in metastatic progression in NSCLC. We conducted TCR sequencing of multiregion primary tumors, normal-adjacent tissues, and post-mortem metastases sampled from a cohort of 22 patients enrolled in the TRACERx and PEACE studies. Our findings reveal that primary tumor regions and normal-adjacent tissues exhibit similar fractions of expanded clonotypes. However, a higher proportion of expanded intratumoral TCRs were privately expanded in the tumor samples, suggesting a unique TCR landscape within the tumor microenvironment. The TCR repertoire across multiregion primary tumor samples was largely homogenous, with most expanded clonotypes shared across at least two regions. However, only a small fraction of these clonotypes were tracked in metastases, indicating a significant shift in the TCR repertoire during metastatic progression. Notably, the expanded clonotypes that persisted over time from early to late stage disease were significantly enriched for clonotypes ubiquitously expanded in the primary tumor across all regions. This was not shown to be associated with an increased likelihood of generation via VDJ recombination, suggesting a tumor-specific immune response. The expanded TCR repertoire in the postmortem metastases clustered mainly by anatomical site, suggesting an immune response driven by tissue-resident T cells. Moreover, we found a significant positive correlation between repertoire dissimilarity and genomic distance, suggesting that T cell clones track with tumor clones across spatial sites within patients. Our study demonstrates the significant spatiotemporal dynamics of the TCR repertoire during the metastatic progression of NSCLC, orchestrated by both tissue-resident T cells and the genomic evolutionary trajectory of tumors. Such an exploration could provide valuable insights to inform future strategies for immunotherapy treatments and enhance clinical monitoring of patients. Citation Format: Corentin Richard, Sonya Hessey, Cristina Naceur-Lombardelli, Selvaraju Veeriah, Gayathri Nageswaran, Crispin Hiley, Sergio Quezada, Benny Chain, TRACERx and PEACE Consortia, Charles Swanton, Mariam Jamal-Hanjani. Inferring the T cell repertoire dynamics in non-small cell lung cancer metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1609.

Abstract 6707: IgG based B7-H3xCD3 bispecific antibody for treatment of gynecological tumors

Abstract Ovarian cancer is characterized by late stage disease and a poor prognosis. Endometrial cancer is a heterogeneous disease with different prognoses depending on the molecular subtype. Novel treatment strategies are needed to improve patient survival in both entities. T cell-based immunotherapy has significantly improved the treatment options for many malignancies. B7-H3 (CD276) is an interesting target for immunotherapeutic approaches because it is overexpressed on a wide range of tumor entities and has characteristics of immune checkpoint molecules. Its expression not only on tumor cells but also on the tumor vasculature allows improved infiltration of immune effector cells into the tumor to overcome the major limitation of T cell-based therapy of solid tumors, which is the access of immune cells to the tumor site. A novel bispecific antibody in an IgG-based format called CC-3 with B7-H3xCD3 specificity has already been shown to efficiently induce T cell responses against gastrointestinal malignancies. Here we show that B7-H3 is highly expressed on endometrial and ovarian cancer cell lines. Treatment with CC-3 induced T cell activation and degranulation as well as secretion of IL-2, IFNy and perforin. These results demonstrate CC-3 induced T cell reactivity against ovarian and endometrial cancer cells. In addition, CC-3 induced efficient T cell proliferation and formation of T cell memory subsets. This resulted in potent target cell lysis. Taken together, our results underscore the potential of CC-3, which is currently in GMP manufacturing, to enable clinical evaluation for the treatment of gynecologic malignancies. Citation Format: Sarah Maria Greiner, Jonas Mauermann, Martina Lutz, Ilona Hagelstein, Engler Tobias, André Koch, Hartkopf Andreas, Brucker Sara, Latifa Zekri, Melanie Märklin. IgG based B7-H3xCD3 bispecific antibody for treatment of gynecological tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6707.

Pityriasis Rubra Pilaris refractory to ustekinumab successfully treated with guselkumab

AbstractPityriasis Rubra Pilaris (PRP) is a rare papulosquamous inflammatory dermatosis with variable clinical presentation and poorly understood pathogenesis that often poses diagnostic and therapeutic challenges. Data on currently available treatment options are limited, particularly when facing refractory cases. Both ustekinumab, an interleukin‐12 (IL‐12) and IL‐23 inhibitor, and guselkumab, an IL‐23p19 inhibitor, target the Th‐17 axis and are well established treatment options in moderate to severe psoriasis. However, increasing evidence, mostly derived from case reports and supported by recent understanding of the role of Th‐17 axis in PRP, also favours the use of IL‐17/IL‐23 pathway inhibitors in this disease. We present an adult female patient with long history of recalcitrant PRP refractory to multiple treatment options. Although initial improvement with ustekinumab was achieved, late disease progression ensued, leading to transition to guselkumab with remarkable clinical response.

Ebola virus disease sequelae and viral persistence in animal models: Implications for the future.

Ebola virus disease (EVD), caused by infection with Ebola virus, results in severe, acute illness with a high mortality rate. As the incidence of outbreaks of EVD increases and with the development and approval of medical countermeasures (MCMs) against the acute disease, late phases of EVD, including sequelae, recrudescence, and viral persistence, are occuring more frequently and are now a focus of ongoing research. Existing animal disease models recapitulate acute EVD but are not suitable to investigate the mechanisms of these late disease phenomena. Although there are challenges in establishing such a late disease model, the filovirus research community has begun to call for the development of an EBOV persistence model to address late disease concerns. Ultimately, this will aid the development of MCMs against late disease and benefit survivors of future EVD and filovirus outbreaks.

HER2 and PD-L1 Expression in Gastric and Gastroesophageal Junction Cancer: Insights for Combinatorial Targeting Approaches.

Gastric and gastroesophageal junction adenocarcinomas (GA/GEJA) are associated with a poor prognosis, primarily due to late disease diagnosis. Human Epidermal Growth Factor Receptor 2 (HER2) overexpression and programmed death-ligand 1 (PD-L1) expression are important biomarkers for treatment selection in locally advanced unresectable and metastatic GA/GEJA, and there is increasing interest in their role in earlier stages of disease. In this study, we aimed to evaluate HER2 and PD-L1 expression in a curative-intent GA/GEJA cohort to describe their expression patterns and analyze the association between HER2 expression and clinicopathological features. HER2 expression was evaluated in surgical and endoscopic submucosal dissection tumor samples, and PD-L1 was evaluated in HER2-positive cases. The clinical cohort included 107 patients, with 8.4% testing positive for HER2 (seven of whom also exhibited a PD-L1 combined positive score of ≥1. HER2 status was not significantly associated with survival outcomes. A pathologist-guided, region-specific analysis revealed that PD-L1 expression rarely overlaps with HER2-positive tumor areas. While the therapeutic implications of these observations remain unknown, these findings suggest that combination strategies targeting HER2 and PD-L1 might be directed toward distinct tumor subclones. The herein disclosed region-specific biomarker expression patterns may have important therapeutic and prognostic impacts, warranting further evaluation.

Phenotypes and ontogeny of senescent hepatic stellate cells in metabolic dysfunction-associated steatohepatitis

Hepatic stellate cells (HSCs) are the key drivers of fibrosis in metabolic dysfunction-associated steatohepatitis (MASH), the fastest growing cause of hepatocellular carcinoma (HCC) worldwide. HSCs are heterogenous, and a senescent subset of HSCs is implicated in hepatic fibrosis and HCC. Administration of anti-uPAR (urokinase-type plasminogen activator receptor) CAR T cells has been shown to deplete senescent HSCs and attenuate fibrosis in murine models. However, the comprehensive features of senescent HSCs in MASH, as well as their cellular ontogeny have not been characterized; hence, we aimed to comprehensively characterize and define the origin of HSCs in human and murine MASH. To comprehensively characterize the phenotype and ontogeny of senescent HSCs in human and murine MASH, we integrated senescence-associated beta galactosidase activity with immunostaining, flow cytometry and single-nucleus RNA sequencing (snRNAseq). We integrated the immunohistochemical profile with a senescence score applied to snRNAseq data to characterize senescent HSCs and mapped the evolution of uPAR expression in MASH. Using pseudotime trajectory analysis, we establish that senescent HSCs arise from activated HSCs. While uPAR is expressed in MASH, the magnitude and cell-specificity of its expression evolve with disease stage. In early disease, uPAR is more specific to activated and senescent HSCs, while it is also expressed by myeloid-lineage cells, including Trem2+ macrophages and myeloid-derived suppressor cells, in late disease. Furthermore, we identify novel surface proteins expressed on senescent HSCs in human and murine MASH that could be exploited as therapeutic targets. These data define features of HSC senescence in human and murine MASH, establishing an important blueprint to target these cells as part of future antifibrotic therapies. Hepatic stellate cells (HSCs) are the primary drivers of scarring in chronic liver diseases. As injury develops, a subset of HSCs become senescent; these cells are non-proliferative and pro-inflammatory, thereby contributing to worsening liver injury. Here we show that senescent HSCs are expanded in MASH (metabolic dysfunction-associated steatohepatitis) in humans and mice, and we trace their cellular origin from the activated HSC subset. We further characterize expression of uPAR (urokinase plasminogen activated receptor), a protein that marks senescent HSCs, and report that uPAR is also expressed by activated HSCs in early injury, and in immune cells as liver injury advances. We have integrated high-resolution single-nucleus RNA sequencing with immunostaining and flow cytometry to identify five other novel proteins expressed by senescent HSCs, including mannose receptor CD206, which will facilitate future therapeutic development.

Evidence for 2 clusters among patients with noneosinophilic asthma

BackgroundAlthough asthma is often seen as an eosinophilic disease associated with atopy, patients with noneosinophilic asthma represent a substantial part of the population with asthma. ObjectiveTo apply an unsupervised clustering method in a cohort of 588 patients with noneosinophilic asthma (sputum eosinophils < 3%) recruited from an asthma clinic of a secondary care center. MethodsOur cluster analysis of the whole cohort identified 2 subgroups as cluster 1 (n = 417) and cluster 2 (n = 171). ResultsCluster 1 comprised a predominantly female group with late disease onset, a low proportion of atopy (24%), and a substantial smoking history (53%). In this cluster, treatment burden was low (<50% of inhaled corticosteroid users); asthma control and quality of life were poor, with median Asthma Control Test, Asthma Control Questionnaire, and Asthma Quality of Life scores of 16, 1.7, and 4.5, respectively, whereas lung function was preserved with a median postbronchodilation forced expiratory volume in 1 second of 93% predicted. Cluster 2 was a predominantly male group, almost exclusively comprising patients with atopy (99%) with early disease onset and a moderate treatment burden (median inhaled corticosteroids dose 800 µg/d equivalent beclomethasone). In cluster 2, asthma was partially controlled, with median Asthma Control Test and Asthma Control Questionnaire scores reaching 18 and 1.3, respectively, and lung function well preserved with a median postbronchodilation of 95% predicted. Although systemic and airway neutrophilic inflammation was the dominant pattern in cluster 1, cluster 2 essentially comprised paucigranulocytic asthma with moderately elevated fraction exhaled nitric oxide. ConclusionNoneosinophilic asthma splits into 2 clusters distinguishing by disease onset, atopic status, smoking history, systemic and airway inflammation, and disease control and quality of life.

Familial primary calcific band-shaped keratopathy with late onset systemic disease: a case series and review of the literature

BackgroundFamilial calcific band-shaped keratopathy (BSK) is a very rare disease, with no underlying cause. There is no underlying disease in this form of the disease. This article introduces a family with seven children, three of whom were diagnosed with familial primary calcific BSK. One of them developed a systemic disease 38 years after ocular manifestation.Case presentationIn this case report, three Iranian siblings from a family with familial calcific band-shaped keratopathy (BSK) are introduced. Systemic and ocular examinations performed on these patients indicated the occurrence of chronic kidney disease in the older child, a 41-year-old woman, 38 years after ocular manifestation. The examinations conducted on the other two siblings revealed no pathological findings. The 41-year-old sister and 37-year-old brother underwent unilateral deep anterior lamellar keratoplasty (DALK), while the 33-year-old sister underwent bilateral superficial keratectomy (SK).ConclusionConsidering the late onset of systemic disease in one of the siblings diagnosed with familial calcific band-shaped keratopathy (BSK), it is crucial to emphasize the necessity of long-term follow-up for these patients and their families.

"Peanut (Arachis hypogaea) Response to Fungicides and Herbicides Applied using Different Spray Nozzles"

Late leaf spot [caused by Nothopassalora personata (Berk. &amp; M.A. Curtis) U. Braun, C. Nakash, Videira &amp; Crous] is an economically important disease in peanut (Arachis hypogaea L.) and fungicides are used routinely to protect peanut from infection and the resulting yield loss. Herbicides are an important component of effective weed management in peanut. Concern over particle drift of pesticides exists in the farming community, especially after stewardship issues associated with synthetic auxin application in herbicide resistant crops in the United States. Spray nozzles that deliver larger droplets that are less prone to drift is a possible solution to this issue. However, fungicides may be less effective in penetrating the crop canopy and covering foliage for protection from pathogens with these nozzles compared with nozzles delivering smaller droplets. Research was conducted to compare suppression of late leaf spot disease when chlorothalonil, prothioconazole plus tebuconazole, azoxystrobin, pyraclostrobin, and chlorothalonil were applied sequentially every 14 days using hollow cone nozzles (fine droplet size), regular flat fan nozzles (medium droplet size), air induction flat fan nozzles (coarse droplet size), and turbo teejet induction nozzles (ultra-coarse droplet size). Regular flat fan and hollow cone nozzles were slightly more effective in delivering fungicides based on canopy defoliation at harvest compared with turbo teejet induction nozzles and in some cases air induction nozzles. However, suppression of pathogens by fungicides applied using all four nozzle types prevented canopy defoliation adequately to protect peanut from yield loss. In a separate experiment, peanut yield and control of common ragweed (Ambrosia artemisiifolia L.) and late leaf spot did not differ at harvest when herbicides and fungicides were applied with air induction or turbo teejet induction nozzles throughout the cropping cycle. These results indicate that farmers can apply fungicides and herbicides to peanut using nozzles that limit potential for particle drift with minimal concern over reduced pesticide efficacy and protection of yield from pests.