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Head and neck squamous cell carcinoma (HNSCC) is characterized by complex relations between stromal, epithelial, and immune cells within the tumor microenvironment (TME). To enable the development of more efficacious therapies, we aim to study the heterogeneity, signatures of unique cell populations, and cell-cell interactions of non-immune and immune cell populations in 6 human papillomavirus (HPV) + and 12 HPV – HNSCC patient tumor and matched peripheral blood specimens using single-cell RNA sequencing. Using this dataset of 134,606 cells, we show cell type-specific signatures associated with inflammation and HPV status, describe the negative prognostic value of fibroblasts with elastic differentiation specifically in the HPV + TME, predict therapeutically targetable checkpoint receptor-ligand interactions, and show that tumor-associated macrophages are dominant contributors of PD-L1 and other immune checkpoint ligands in the TME. We present a comprehensive single-cell view of cell-intrinsic mechanisms and cell-cell communication shaping the HNSCC microenvironment. The tumor microenvironment (TME) has an important role in Head and Neck Squamous Cell Carcinoma (HNSCC) progression. Here, using single-cell RNA sequencing and multiplexed imaging, the authors report the cellular complexity of the TME in patients with HNSCC, exploring inflammatory status, stromal heterogeneity and immune checkpoint receptor-ligand interactions.

Diabetic retinopathy, nephropathy, and neuropathy are significant microvascular complications of diabetes mellitus, contributing to substantial morbidity and mortality worldwide. This comprehensive review examines the clinical relationship between these complications, focusing on shared pathophysiological mechanisms, bidirectional relationships, and implications for patient management. The review highlights the importance of understanding the interconnected nature of diabetic complications and adopting a holistic approach to diabetes care. Insights gleaned from this review underscore the necessity for early detection, timely intervention, and integrated care models involving collaboration among healthcare professionals. Furthermore, the review emphasizes the need for continued research to elucidate underlying mechanisms, identify novel therapeutic targets, and assess the efficacy of integrated care strategies in improving patient outcomes. By fostering interdisciplinary collaboration and knowledge exchange, future research endeavors hold the potential to advance our understanding and management of diabetic complications, ultimately enhancing patient care and quality of life.

Immune responses require delicate controls to maintain homeostasis while executing effective defense. Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor. The Krüppel-like factor 10 (KLF10) is a C2H2 zinc-finger containing transcription factor. The functions of mosquito AhR and KLF10 have not been characterized. Here we show that AhR and KLF10 constitute a transcriptional axis to modulate immune responses in mosquito Anopheles gambiae . The manipulation of AhR activities via agonists or antagonists repressed or enhanced the mosquito antibacterial immunity, respectively. KLF10 was recognized as one of the AhR target genes in the context. Phenotypically, silencing KLF10 reversed the immune suppression caused by the AhR agonist. The transcriptome comparison revealed that silencing AhR and KLF10 plus challenge altered the expression of 2245 genes in the same way. The results suggest that KLF10 is downstream of AhR in a transcriptional network responsible for immunomodulation. This AhR–KLF10 axis regulates a set of genes involved in metabolism and circadian rhythms in the context. The axis was required to suppress the adverse effect caused by the overactivation of the immune pathway IMD via the inhibitor gene  Caspar silencing without a bacterial challenge . These results demonstrate that the AhR–KLF10 axis mediates an immunoregulatory transcriptional network as a negative loop to maintain immune homeostasis.

Persistent HPV16 infection is a major cause of the global cancer burden. The viral life cycle is dependent on the differentiation program of stratified squamous epithelium, but the landscape of keratinocyte subpopulations which support distinct phases of the viral life cycle has yet to be elucidated. Here, single cell RNA sequencing of HPV16 infected compared to uninfected organoids identifies twelve distinct keratinocyte populations, with a subset mapped to reconstruct their respective 3D geography in stratified squamous epithelium. Instead of conventional terminally differentiated cells, an HPV-reprogrammed keratinocyte subpopulation (HIDDEN cells) forms the surface compartment and requires overexpression of the ELF3/ESE-1 transcription factor. HIDDEN cells are detected throughout stages of human carcinogenesis including primary human cervical intraepithelial neoplasias and HPV positive head and neck cancers, and a possible role in promoting viral carcinogenesis is supported by TCGA analyses. Single cell transcriptome information on HPV-infected versus uninfected epithelium will enable broader studies of the role of individual keratinocyte subpopulations in tumor virus infection and cancer evolution. The role of keratinocyte subpopulations in the different phases of the viral cycle during HPV16 infection remains to be characterised. Here, single cell RNA sequencing of HPV16 infected and uninfected organoids identifies 12 distinct keratinocyte populations including an HPV-reprogrammed keratinocyte subpopulation that is linked to cancer.

The essential innate immunity effector cells, natural killer and dendritic cells, express multiple plasma membrane-associated tumor necrosis factor (TNF) superfamily (TNFSF) ligands that, through simultaneous and synergistic engagement, mediate anti-cancer cytotoxicity. Here, we report that circulating B cells, mediators of adaptive humoral immunity, also mediate this innate anti-cancer immune mechanism. We show that resting human B cells isolated from peripheral blood induce apoptosis of, and efficiently kill a large variety of leukemia and solid tumor cell types. Single-cell RNA sequencing analyses indicate, and flow cytometry data confirm that B cells from circulation express transmembrane TNF, Fas ligand (FasL), lymphotoxin (LT) α1β2 and TNF-related apoptosis-inducing ligand (TRAIL). The cytotoxic activity can be inhibited by individual and, especially, combined blockade of the four transmembrane TNFSF ligands. B cells from tumor-bearing head and neck squamous cell carcinoma patients express lower levels of TNFSF ligands and are less cytotoxic than those isolated from healthy individuals. In conclusion, we demonstrate that B cells have the innate capacity to mediate anti-cancer cytotoxicity through concurrent activity of multiple plasma membrane-associated TNFSF ligands, that this mechanism is deficient in cancer patients and that it may be part of a general cancer immunosurveillance mechanism.

Aedes aegypti mosquitoes are vectors of a variety of emerging viral pathogens, including yellow fever, dengue, chikungunya, and Zika virus. This species has established endemic populations in all cities across southern New Mexico sampled to date. Presently, control of Aedes-borne viruses relies on deployment of insecticides to suppress mosquito populations, but the evolution of insecticide resistance threatens the success of vector control programs. While insecticide resistance is quite common in Ae. aegypti field populations across much of the U.S., the resistance status of this species in populations from New Mexico has not previously been assessed. First, we collected information on pesticide use in cities in southern New Mexico and found that the most commonly used active ingredients were pyrethroids. The use of insecticides with the same mode-of-action over multiple years is likely to promote the evolution of resistance. To determine if there was evidence of resistance in some cities in southern New Mexico, we collected Ae. aegypti from the same cities and established laboratory strains to assess resistance to pyrethroid insecticides and, for a subset of populations, to organophosphate insecticides. F2 or F4 generation mosquitoes were assessed for insecticide resistance using bottle test bioassays. The majority of the populations from New Mexico that we analyzed were resistant to the pyrethroids permethrin and deltamethrin. A notable exception to this trend were mosquitoes from Alamogordo, a city that did not report using pyrethroid insecticides for vector control. We screened individuals from each population for known knock down resistance (kdr) mutations via PCR and found a strong association between the presences of the F1534C kdr mutation in the para gene of Ae. aegypti (homologue to F1534C in Musca domestica L.) and pyrethroid resistance. High-level pyrethroid resistance is common in Ae. aegypti from New Mexico and geographic variation in such resistance is likely associated with variation in usage of pyrethroids for vector control. Resistance monitoring and management is recommended in light of the potential for arbovirus outbreaks in this state. Also, alternative approaches to mosquito control that do not involve insecticides should be explored.

Chronically Trypanosoma cruzi -infected mice show signs of behavioral and cognitive changes, resembling aspects of Chagas disease patients. Inflammatory mediators, such as cytokines and nitric oxide (NO) have been linked to mental disorders. Preclinical studies showed the partial effects of the trypanossomicidal drug benznidazole (Bz) on mnemonic alterations. Here, we investigated the participation of the parasite and systemic inflammatory profile in behavioral and cognitive changes, using Bz combined with the immunoregulator pentoxifylline (PTX). Chronically T. cruzi -infected C57BL/6 mice were treated with Bz (25 mg/Kg/day) and PTX (20 mg/Kg/day) as mono or combined therapies, submitted to behavioral tests, and canonical biological stressors were analyzed. Bz therapy had no effects on anxiety, but partially ameliorated innate compulsive behavior, depression, and memory loss, while PTX and, mainly, Bz + PTX had a broader beneficial effect on these changes. Bz and Bz + PTX reduced parasitemia. The three therapies decreased the parasite burden in the brain. Bz and Bz + PTX therapies reduced oxidative stress in the brain tissue, while PTX and Bz + PTX therapies efficiently controlled the elevated concentrations of GABA/glutamate in the cerebral cortex. Even after parasite control, serum concentrations of NO and tumor necrosis factor (TNF) enhanced as the disease progressed. Bz and, mainly, Bz + PTX treatments reduced NO levels. The three therapeutic schemes hamper the progressive increase of TNF levels. Reanalysis of available data on the systemic miRNA transcriptome supports the beneficial role of Bz + PTX therapy on pivotal hubs involved in inflammation of the central nervous system and neurodegenerative disorders. Moreover, principal components analysis (PCA-2D and 3D projections) underlined the distinction between the noninfected and vehicle-treated infected groups, while Bz + PTX-treated infected mice were closer to noninfected controls. The combined Bz + PTX therapy reduced parasite load and regulated pivotal neurochemical changes in the brain and the systemic inflammatory profile, improving behavioral and cognitive changes in a model of Chagas disease.

This case report presents the clinical course of a 53-year-old male farmer with nephrotic syndrome, specifically focal segmental glomerulosclerosis, who developed a fulminant eye infection. While receiving maintenance hemodialysis and immunosuppressive therapy, the patient presented with sudden onset redness, discharge, and decreased vision in his right eye. Initial management with topical antibiotics and steroids failed to halt the progression of the infection, leading to corneal perforation and iris prolapse within a few days. Despite the discontinuation of immunosuppressive medications and initiation of broad-spectrum antimicrobial therapy, the patient's compromised renal function and anaemia precluded surgical intervention. This case underscores the challenges in managing severe ocular infections in immunocompromised patients. It highlights the importance of early recognition, aggressive antimicrobial therapy, and close ophthalmologic monitoring in preventing sight-threatening complications. Despite intensive management, the prognosis for visual recovery in such cases may be poor, emphasizing the need for preventive strategies and careful surveillance in high-risk patient populations.

Background The poor prognosis of ovarian cancer patients is strongly related to peritoneal metastasis with the production of malignant ascites. However, it remains largely unclear how ascites in the peritoneal cavity influences tumor metabolism and recurrence. This study is an explorative approach aimed at for a deeper molecular and physical–chemical characterization of malignant ascites and to investigate their effect on in vitro ovarian cancer cell proliferation. Methods This study included 10 malignant ascites specimens from patients undergoing ovarian cancer resection. Ascites samples were deeply phenotyped by 1 H-NMR based metabolomics, blood-gas analyzer based gas flow analysis and flow cytomertry based a 13-plex cytokine panel. Characteristics of tumor cells were investigated in a 3D spheroid model by SEM and metabolic activity, adhesion, anti-apoptosis, migratory ability evaluated by MTT assay, adhesion assay, flowcytometry and scratch assay. The effect of different pH values was assessed by adding 10% malignant ascites to the test samples. Results  The overall extracellular (peritoneal) environment was alkaline, with pH of ascites at stage II-III = 7.51 ± 0.16, and stage IV = 7.78 ± 0.16. Ovarian cancer spheroids grew rapidly in a slightly alkaline environment. Decreasing pH of the cell culture medium suppressed tumor features, metabolic activity, adhesion, anti-apoptosis, and migratory ability. However, 10% ascites could prevent tumor cells from being affected by acidic pH. Metabolomics analysis identified stage IV patients had significantly higher concentrations of alanine, isoleucine, phenylalanine, and glutamine than stage II-III patients, while stage II-III patients had significantly higher concentrations of 3-hydroxybutyrate. pH was positively correlated with acetate, and acetate positively correlated with lipid compounds. IL-8 was positively correlated with lipid metabolites and acetate. Glutathione and carnitine were negatively correlated with cytokines IL-6 and chemokines (IL-8 & MCP-1). Conclusion Alkaline malignant ascites facilitated ovarian cancer progression. Additionally, deep ascites phenotyping by metabolomics and cytokine investigations allows for a refined stratification of ovarian cancer patients. These findings contribute to the understanding of ascites pathology in ovarian cancer.

Cells within a tumor microenvironment (TME) dynamically communicate and influence each other’s cellular states through an intercellular communication network (ICN). In cancers, intercellular communications underlie immune evasion mechanisms of individual tumors. We developed an individualized causal analysis framework for discovering tumor specific ICNs. Using head and neck squamous cell carcinoma (HNSCC) tumors as a testbed, we first mined single-cell RNA-sequencing data to discover gene expression modules (GEMs) that reflect the states of transcriptomic processes within tumor and stromal single cells. By deconvoluting bulk transcriptomes of HNSCC tumors profiled by The Cancer Genome Atlas (TCGA), we estimated the activation states of these transcriptomic processes in individual tumors. Finally, we applied individualized causal network learning to discover an ICN within each tumor. Our results show that cellular states of cells in TMEs are coordinated through ICNs that enable multi-way communications among epithelial, fibroblast, endothelial, and immune cells. Further analyses of individual ICNs revealed structural patterns that were shared across subsets of tumors, leading to the discovery of 4 different subtypes of networks that underlie disparate TMEs of HNSCC. Patients with distinct TMEs exhibited significantly different clinical outcomes. Our results show that the capability of estimating individual ICNs reveals heterogeneity of ICNs and sheds light on the importance of intercellular communication in impacting disease development and progression.