Differential impact of TIM-3 ligands on NK cell function.

Background: The transmembrane protein T-cell immunoglobulin and mucin-domain containing molecule 3 (TIM-3) is an immune checkpoint receptor that is expressed by a variety of leukocyte subsets, particularly in the tumor microenvironment. An effective TIM-3-targeting therapy should account for multiple biological factors, including the disease setting, the specific cell types involved and their varying sensitivities to the four putative TIM-3 ligands (galectin-9, phosphatidylserine, high mobility group protein B1 and carcinoembryonic antigen cell adhesion molecule 1), each of which engages a unique binding site on the receptor's variable immunoglobulin domain. The primary objectives of this study were to assess the prevalence and function of TIM-3 natural killer (NK) cells in patients with head and neck squamous cell carcinoma (HNSCC), determine whether the four TIM-3 ligands differentially affect TIM-3 NK cell functions, identify the most immunosuppressive ligand, and evaluate whether targeting ligand-mediated TIM-3 signaling enhances NK cell effector functions.

Understanding the Clinical Relationship Between Diabetic Retinopathy, Nephropathy, and Neuropathy: A Comprehensive Review.

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.

Fulminant Eye Infection in a Patient With Nephrotic Syndrome: A Case Report.

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.

A Genome Wide CRISPR Proling Approach Identies Mechanisms of Cisplatin Resistance in Head and Neck Squamous Cell Carcinoma.

Background: Head and neck squamous cell carcinoma (HNSCC) is a lethal disease with poor survival rates, especially for cancers arising in the oral cavity or larynx. Cisplatin is a key chemotherapeutic for HNSCC; however poor survival rates may be partially due to cisplatin resistance observed in some HNSCCs. Here, we examined the utility of genome-wide CRISPR knockout profiling for nominating pivotal mechanisms of cisplatin resistance in HNSCC models.

Streamlined Adeno-Associated Virus Production Using Suspension HEK293T Cells.

Recombinant adeno-associated viruses (rAAVs) are valuable viral vectors for in vivo gene transfer, also having significant ex vivo therapeutic potential. Continued efforts have focused on various gene therapy applications, capsid engineering, and scalable manufacturing processes. Adherent cells are commonly used for virus production in most basic science laboratories because of their efficiency and cost.

Genomic and transcriptomic analysis of cutaneous squamous cell carcinoma arising in immunocompetent and immunosuppressed patients.

Background: Cutaneous squamous cell carcinoma (cSCC) is the most common skin malignancy arising in immunocompromised patients such as solid organ transplant recipients. In addition to an abundance in number, the morbidity and mortality of these tumors in this patient population exceeds that of immune competent individuals. Here, we used whole exome and bulk RNA sequencing to analyze mutation profiles between tumors arising in immunocompetent and immunosuppressed patients.

Urinary phenotyping of SARS-CoV-2 infection connects clinical diagnostics with metabolomics and uncovers impaired NAD pathway and SIRT1 activation.

Objectives: The stratification of individuals suffering from acute and post-acute SARS-CoV-2 infection remains a critical challenge. Notably, biomarkers able to specifically monitor viral progression, providing details about patient clinical status, are still not available. Herein, quantitative metabolomics is progressively recognized as a useful tool to describe the consequences of virus-host interactions considering also clinical metadata.

Current Status of Omics Studies Elucidating the Features of Reproductive Biology in Blood-Feeding Insects.

Female insects belonging to the genera and account for the majority of global vector-borne disease mortality. In response to mating, these female insects undergo several molecular, physiological, and behavioral changes. Studying the dynamic post-mating molecular responses in these insects that transmit human diseases can lead to the identification of potential targets for the development of novel vector control methods.

Multi-kinase compensation rescues EGFR knockout in a cell line model of head and neck squamous cell carcinoma.

Background: Head and neck squamous cell carcinoma (HNSCC) is a debilitating disease with poor survival rates. While the epidermal growth factor receptor (EGFR)-targeting antibody Cetuximab is approved for treatment, responses are limited and the molecular mechanisms driving resistance remain incompletely understood.

Methods: To better understand how cells survive without EGFR activity, we developed an EGFR knockout derivative of the UM-SCC-92 cell line using CRISPR/Cas9 technology.

Tumor cell p38 inhibition to overcome immunotherapy resistance.

Patients with tumors that do not respond to immune-checkpoint inhibition often harbor a non-T cell-inflamed tumor microenvironment, characterized by the absence of IFN-γ-associated CD8 T cell and dendritic cell activation. Understanding the molecular mechanisms underlying immune exclusion in non-responding patients may enable the development of novel combination therapies. p38 MAPK is a known regulator of dendritic and myeloid cells however a tumor-intrinsic immunomodulatory role has not been previously described.

Single cell transcriptomic analysis of HPV16-infected epithelium identifies a keratinocyte subpopulation implicated in cancer.

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.

Tumor gene signatures that correlate with release of extracellular vesicles shape the immune landscape in head and neck squamous cell carcinoma.

Head and neck squamous cell carcinomas (HNSCCs) evade immune responses through multiple resistance mechanisms. Extracellular vesicles (EVs) released by the tumor and interacting with immune cells induce immune dysfunction and contribute to tumor progression. This study evaluates the clinical relevance and impact on anti-tumor immune responses of gene signatures expressed in HNSCC and associated with EV production/release.

An individualized causal framework for learning intercellular communication networks that define microenvironments of individual tumors.

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.

Nanophotonics triggered thermally enhanced solar water disinfection bottles for slum dwellers.

Among several existing technologies, solar pasteurization is widely accepted as a reliable and cost-effective method for the removal of microbial pathogens from water. This work reports nanophotonics-triggered thermally enhanced solar water disinfection bottles (nano-SODIS) designed rationally by coating plasmonic carbon nanoparticles (CNP) on the outer surface for the targeted pathogen inactivation from water. The cost-effective CNP nanophotonic material used in this work has high efficiency in harvesting solar radiation and dissipating the heat locally.

Acidic ascites inhibits ovarian cancer cell proliferation and correlates with the metabolomic, lipidomic and inflammatory phenotype of human patients.

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.

Regulatory Roles of Noncoding RNAs in the Progression of Gastrointestinal Cancers and Health Disparities.

Annually, more than a million individuals are diagnosed with gastrointestinal (GI) cancers worldwide. With the advancements in radio- and chemotherapy and surgery, the survival rates for GI cancer patients have improved in recent years. However, the prognosis for advanced-stage GI cancers remains poor.

Proteasomal inhibition preferentially stimulates lysosome activity relative to autophagic flux in primary astrocytes.

Neurons and astrocytes face unique demands on their proteome to enable proper function and survival of the nervous system. Consequently, both cell types are critically dependent on robust quality control pathways such as macroautophagy (hereafter referred to as autophagy) and the ubiquitin-proteasome system (UPS). We previously reported that autophagy is differentially regulated in astrocytes and neurons in the context of metabolic stress, but less is understood in the context of proteotoxic stress induced by inhibition of the UPS.

Aryl hydrocarbon receptor and Krüppel like factor 10 mediate a transcriptional axis modulating immune homeostasis in mosquitoes.

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.

Human B Cells Mediate Innate Anti-Cancer Cytotoxicity Through Concurrent Engagement of Multiple TNF Superfamily Ligands.

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.

Direct and indirect gene repression by the ecdysone cascade during mosquito reproductive cycle.

SignificanceHematophagous mosquitoes spread devastating viral diseases. Upon blood feeding, a steroid hormone, 20-hydroxyecdysone (20E), initiates a reproductive program during which thousands of genes are differentially expressed. While 20E-mediated gene activation is well known, repressive action by this hormone remains poorly understood.

Investigating immune and non-immune cell interactions in head and neck tumors by single-cell RNA sequencing.

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.

Microbe-Mediated Activation of Toll-like Receptor 2 Drives PDL1 Expression in HNSCC.

As immunotherapies targeting the PDL1 checkpoint have become a mainstay of treatment for a subset of head and neck squamous cell carcinoma (HNSCC) patients, a detailed understanding of the mechanisms underlying PDL1-mediated immune evasion is needed. To elucidate factors regulating expression of PDL1 in HNSCC cells, a genome-wide CRISPR profiling approach was implemented to identify genes and pathways conferring altered PDL1 expression in an HNSCC cell line model. Our screen nominated several candidate PDL1 drivers, including Toll-like Receptor 2 (TLR2).