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Highly multiplexed, single-cell imaging has revolutionized our understanding of spatial cellular interactions associated with health and disease. With ever-increasing numbers of antigens, region sizes, and sample sizes, multiplexed fluorescence imaging experiments routinely produce terabytes of data. Fast and accurate processing of these large-scale, high-dimensional imaging data is essential to ensure reliable segmentation and identification of cell types and for characterization of cellular neighborhoods and inference of mechanistic insights. Here, we describe RAPID, a Real-time, GPU-Accelerated Parallelized Image processing software for large-scale multiplexed fluorescence microscopy Data. RAPID deconvolves large-scale, high-dimensional fluorescence imaging data, stitches and registers images with axial and lateral drift correction, and minimizes tissue autofluorescence such as that introduced by erythrocytes. Incorporation of an open source CUDA-driven, GPU-assisted deconvolution produced results similar to fee-based commercial software. RAPID reduces data processing time and artifacts and improves image contrast and signal-to-noise compared to our previous image processing pipeline, thus providing a useful tool for accurate and robust analysis of large-scale, multiplexed, fluorescence imaging data.

Erb‐b2 receptor tyrosine kinase 2 (ERBB2; also known as HER2) expression is observed in 25–40% of head and neck squamous cell carcinomas (HNSCC), yet there are no anti‐HER2 therapies under evaluation for HNSCC, as conventional cytostatic anti‐HER2 antibodies have had limited effectiveness and levels of HER2 overexpression are lower in HNSCC tumors compared to breast cancer. Trastuzumab‐deruxtecan (T‐DXd; Enhertu) is a HER2‐targeting antibody‐drug conjugate (ADC) comprising an anti‐HER2 monoclonal antibody, a cleavable linker, and a potent topoisomerase I inhibitor payload, and has shown promising results in very low HER2‐expressing tumors. We compare the efficacy of T‐DXd, trastuzumab‐emtansine (ADC comprising an anti‐HER2 antibody and microtubule inhibitor, T‐DM1; Kadcyla) and trastuzumab (Herceptin) therapy in HNSCC with low and absent HER2 expression in vitro and in vivo. In vitro treatment of a low HER2‐expressing human HNSCC cell line (FaDu) with T‐DXd resulted in dose‐dependent cell death (IC50 values of 9856 ng·mL−1). T‐DXd treatment of FaDu and UMSCC‐47 (low HER2‐expressing cell line) mouse xenografts displayed antitumor activity (P = 0.0001 and 0.015 respectively). When comparing T‐DXd to other approved anti‐HER2 therapies, only FaDu mice treated with T‐DXd showed a reduction in tumor growth (P = 0.0012). In UMSCC‐1 cells (absent HER2 expression), the drug failed to accumulate in tumors and showed no measurable antitumor effect, in contrast to FaDu xenografts, where drug accumulation in the tumor correlated with a therapeutic response. T‐DXd treatment yielded antitumor activity in FaDu and UMSCC‐47 tumors, highlighting the potential for T‐DXd efficacy in low HER2‐expressing tumors. Trastuzumab‐deruxtecan, a HER2‐targeting antibody‐drug conjugate, shows promising antitumor activity in head and neck squamous cell carcinoma with low HER2 expression. In vitro and in vivo studies demonstrated dose‐dependent cell death and tumor growth reduction in low HER2‐expressing cell lines, which correlated with drug accumulation measured using a fluorescent antibody‐drug conjugate.

Functional inactivation of tumor suppressor genes drives cancer initiation, progression, and treatment responses. Most tumor suppressor genes are inactivated through 1 of 2 well-characterized mechanisms: DNA-level mutations, such as point mutations or deletions, and promoter DNA hypermethylation. Here, we report a distinct third mechanism of tumor suppressor inactivation based on alterations to the histone rather than DNA code. We demonstrated that PAX2 is an endometrial tumor suppressor recurrently inactivated by a distinct epigenetic reprogramming event in more than 80% of human endometrial cancers. Integrative transcriptomic, epigenomic, 3D genomic, and machine learning analyses showed that PAX2 transcriptional downregulation is associated with replacement of open/active chromatin features (H3K27ac/H3K4me3) with inaccessible/repressive chromatin features (H3K27me3) in a framework dictated by 3D genome organization. The spread of the repressive H3K27me3 signal resembled a pearl necklace, with its length modulated by cohesin loops, thereby preventing transcriptional dysregulation of neighboring genes. This mechanism, involving the loss of a promoter-proximal superenhancer, was shown to underlie transcriptional silencing of PAX2 in human endometrial cancers. Mouse and human preclinical models established PAX2 as a potent endometrial tumor suppressor. Functionally, PAX2 loss promoted endometrial carcinogenesis by rewiring the transcriptional landscape via global enhancer reprogramming. The discovery that most endometrial cancers originate from a recurring epigenetic alteration carries profound implications for their diagnosis and treatment.

Kaposi's sarcoma (KS) herpesvirus (KSHV) causes KS, an angiogenic AIDS-associated spindle-cell neoplasm, by activating host oncogenic signaling cascades through autocrine and paracrine mechanisms. Tyrosine kinase receptor (RTK) proteomic arrays, identified PDGF receptor-alpha (PDGFRA) as the predominantly-activated RTK in KSHV-induced mouse KS-tumors. We show that: 1) KSHV lytic replication and the vGPCR can activate PDGFRA through upregulation of its ligands PDGFA/B, which increase c-myc, VEGF and KSHV gene expression in infected cells 2) KSHV infected spindle cells of most AIDS-KS lesions display robust phospho-PDGFRA staining 3) blocking PDGFRA-signaling with N-acetyl-cysteine, RTK-inhibitors Imatinib and Sunitinib, or dominant-negative PDGFRA inhibits tumorigenesis 4) PDGFRA D842V activating-mutation confers resistance to Imatinib in mouse-KS tumorigenesis. Our data show that KSHV usurps sarcomagenic PDGFRA signaling to drive KS. This and the fact that PDGFRA drives non-viral sarcomas highlights the importance for KSHV-induced ligand-mediated activation of PDGFRA in KS sarcomagenesis and shows that this oncogenic axis could be successfully blocked to impede KS tumor growth.

Eye injuries due to corneal abrasions, chemical spills, penetrating wounds, and microbial infections cause corneal scarring and opacification that result in impaired vision or blindness. However, presently available eye drop formulations of anti-inflammatory and antibiotic drugs are not effective due to their rapid clearance from the ocular surface or due to drug-related side effects such as cataract formation or increased intraocular pressure. In this article, we presented the development of a dextran sulfate-based polymer wafer (DS-wafer) for the effective modulation of inflammation and fibrosis and demonstrated its efficacy in two corneal injury models: corneal abrasion mouse model and alkali induced ocular burn mouse model. The DS-wafers were fabricated by the electrospinning method. We assessed the efficacy of the DS-wafer by light microscopy, qPCR, confocal fluorescence imaging, and histopathological analysis. These studies demonstrated that the DS-wafer treatment is significantly effective in modulating corneal inflammation and fibrosis and inhibited corneal scarring and opacification compared to the unsulfated dextran-wafer treated and untreated corneas. Furthermore, these studies have demonstrated the efficacy of dextran sulfate as an anti-inflammatory and antifibrotic polymer therapeutic.

Background and Aim Epidemiological data suggest a greater risk of inflammatory bowel disease in first‐ and second‐generation migrants from a low to high prevalence country, with the risk of ulcerative colitis (UC) preceding Crohn's disease. This study evaluated demographic trends and outcomes of UC and acute severe ulcerative colitis (ASUC) hospitalizations in an area with an expanding multicultural population. Methods Demographic and disease characteristics of patients admitted with UC and ASUC at a tertiary metropolitan center from January 2016 to December 2024 were recorded. Trends in presentation and 12‐month outcomes in ASUC patients of European and non‐European descent were compared. Results Of 218 patient admissions with UC, 158 admissions met criteria for ASUC. A sixfold increase was seen in yearly admissions for UC (8 in 2016 to 48 in 2024) and ASUC (6 to 39, p < 0.001 for both). A total of 111 (50.9%) of patients hospitalized with UC, and 81 (51.2%) of patients with ASUC, were of European descent. Patients of non‐European descent comprised an increasing proportion of hospitalized patients with UC (32.1% from 2016 to 2019 to 47.5% from 2020 to 2024, p = 0.047) and ASUC (not statistically significant: 28.9% to 51.0%, p = 0.076). No differences in disease severity, length of stay, 12‐month readmission or colectomy rates were noted between European and non‐European descent patients. Conclusions A significant rise in hospitalizations for UC and ASUC, with an increasing proportion of patients with UC of non‐European descent. There were no significant differences in clinical outcomes in ASUC admissions in patients of non‐European descent compared to European descent.

BackgroundTularemia, a zoonotic disease caused by Francisella tularensis, can cause a broad spectrum of disease in humans including six major clinical presentations: the ulceroglandular, glandular, oculoglandular, oropharyngeal, typhoidal and pneumonic form. The epidemiology and ecology and thus transmission of tularemia are complex, depending on conditions unique to specific locations.Case series and methodsThirteen cases with different forms of the disease and one very rare case of a myocarditis are reported, discussed, and reviewed within the scope of current literature.ConclusionTularemia is a rare, but emerging disease in Central Europe with glandular and ulceroglandular disease as its predominant forms. Transmission is mainly caused by contact with lagomorphs, rodents and tick bites. However, domestic cats may play an important role in transmission too. Myocarditis is probably a worldwide, but very rare manifestation of tularemia.

Densification of thermally treated energy crops by torrefaction is required to increase the bulk density and to reduce the handling, transport, and storage cost for bioenergy applications. In this study, we investigated the densification characteristics of thermally treated energy cane and napier grass grown on marginal lands at various applied forces and binder levels. The addition of starch (0, 10, and 15%) and lignosulfonate (0, 5, and 10%) was examined to enhance the strength and durability of raw and torrefied briquettes, respectively. Although the use of starch binder relatively increased the bulk density, it did not improve the hardness and durability of untreated energy crop briquettes. The addition of 10% lignosulfonate binder increased the torrefied briquette density of up to 11% for energy cane and up to 38% for napier grass and decreased the compression energy by up to 35% for both samples. Moreover, the hardness (compressive resistance) was tripled, and the durability was relatively improved for both torrefied briquettes. The increase in applied force not only increased the bulk density but also increased the specific energy required for densification. However, there was no substantial change in hardness and durability when the compression force was increased from 15 to 20 kN for all samples. In overall, densification of thermally treated energy crops is required, and the quality of the briquettes can be improved by the use of appropriate binders for efficient handling, transport, and storage.

Anopheles gambiae is the principal vector of malaria, a disease that afflicts more than 500 million people and causes more than 1 million deaths each year. Tenfold shotgun sequence coverage was obtained from the PEST strain of A. gambiae and assembled into scaffolds that span 278 million base pairs. A total of 91% of the genome was organized in 303 scaffolds; the largest scaffold was 23.1 million base pairs. There was substantial genetic variation within this strain, and the apparent existence of two haplotypes of approximately equal frequency (“dual haplotypes”) in a substantial fraction of the genome likely reflects the outbred nature of the PEST strain. The sequence produced a conservative inference of more than 400,000 single-nucleotide polymorphisms that showed a markedly bimodal density distribution. Analysis of the genome sequence revealed strong evidence for about 14,000 protein-encoding transcripts. Prominent expansions in specific families of proteins likely involved in cell adhesion and immunity were noted. An expressed sequence tag analysis of genes regulated by blood feeding provided insights into the physiological adaptations of a hematophagous insect.