Although cyclophosphamide (CTX) has been used for recurrent or metastatic head and neck cancers, resistance is usually expected. Thus, we conducted this study to examine the effect of adding all-trans retinoic acid (ATRA) to CTX, to increase efficacy of CTX and reduce the risk of resistance developed. In this study, we investigated the combined effect of ATRA and CTX on the expression of apoptotic and angiogenesis markers in oropharyngeal carcinoma cell line (NO3), and the possible involved mechanisms. ATRA and CTX in combination significantly inhibited the proliferation of NO3 cells. Lower dose of CTX in combination with ATRA exhibited significant cytotoxicity than that of CTX when used alone, implying lower expected toxicity. Results showed that ATRA and CTX modulated oxidative stress; increased NOx and MDA, reduced GSH, and mRNA expression of Cox-2, SIRT1 and AMPK. Apoptosis was induced through elevating mRNA expressions of Bax and PAR-4 and suppressing that of Bcl-xl and Bcl-2, parallel with increased caspases 3 and 9 and decreased VEGF, endothelin-1 and CTGF levels. The primal action of the combined regimen on inflammatory signaling highlights its impact on cell death in NO3 cell line which was mediated by oxidative stress associated with apoptosis and suppression of angiogenesis.

Although cyclophosphamide (CTX) has been used for recurrent or metastatic head and neck cancers, resistance is usually expected. Thus, we conducted this study to examine the effect of adding all-trans retinoic acid (ATRA) to CTX, to increase efficacy of CTX and reduce the risk of resistance developed. In this study, we investigated the combined effect of ATRA and CTX on the expression of apoptotic and angiogenesis markers in oropharyngeal carcinoma cell line (NO3), and the possible involved mechanisms. ATRA and CTX in combination significantly inhibited the proliferation of NO3 cells. Lower dose of CTX in combination with ATRA exhibited significant cytotoxicity than that of CTX when used alone, implying lower expected toxicity. Results showed that ATRA and CTX modulated oxidative stress; increased NOx and MDA, reduced GSH, and mRNA expression of Cox-2, SIRT1 and AMPK. Apoptosis was induced through elevating mRNA expressions of Bax and PAR-4 and suppressing that of Bcl-xl and Bcl-2, parallel with increased caspases 3 and 9 and decreased VEGF, endothelin-1 and CTGF levels. The primal action of the combined regimen on inflammatory signaling highlights its impact on cell death in NO3 cell line which was mediated by oxidative stress associated with apoptosis and suppression of angiogenesis.

RNA Velocity allows the inference of cellular differentiation trajectories from single-cell RNA sequencing (scRNA-seq) data. It would be highly interesting to study these differentiation dynamics in the spatial context of tissues. Estimating spatial RNA velocities is, however, limited by the inability to spatially capture spliced and unspliced mRNA molecules in high-resolution spatial transcriptomics. We present SIRV, a method to spatially infer RNA velocities at the single-cell resolution by enriching spatial transcriptomics data with the expression of spliced and unspliced mRNA from reference scRNA-seq data. We used SIRV to infer spatial differentiation trajectories in the developing mouse brain, including the differentiation of midbrain-hindbrain boundary cells and marking the forebrain origin of the cortical hem and diencephalon cells. Our results show that SIRV reveals spatial differentiation patterns not identifiable with scRNA-seq data alone. Additionally, we applied SIRV to mouse organogenesis data and obtained robust spatial differentiation trajectories. Finally, we verified the spatial RNA velocities obtained by SIRV using 10x Visium data of the developing chicken heart and MERFISH data from human osteosarcoma cells. Altogether, SIRV allows the inference of spatial RNA velocities at the single-cell resolution to facilitate studying tissue development.

Sjögren's disease (SjD) is a systemic autoimmune exocrinopathy with key features of dryness, pain, and fatigue. SjD can affect any organ system with a variety of presentations across individuals. This heterogeneity is one of the major barriers for developing effective disease modifying treatments. Defining core disease domains comprising both specific clinical features and incorporating the patient experience is a critical first step to define this complex disease. The OMERACT SjD Working Group held its first international collaborative hybrid meeting in 2023, applying the OMERACT 2.2 filter toward identification of core domains. We accomplished our first goal, a scoping literature review that was presented at the Special Interest Group held in May 2023. Building on the domains identified in the scoping review, we uniquely deployed multidisciplinary experts as part of our collaborative team to generate a provisional domain list that captures SjD heterogeneity.

BACKGROUND: Feed additives are products used in poultry nutrition to improve the quality of feed and the safety of food byproducts from animal origin. They are promising antibiotic alternatives for the production of broilers.

AIM: This study aimed to investigate the effect of sodium butyrate (SB) and RL on growth performance, biochemical profile, immunity, and carcass traits of broilers.

METHODS: Five hundred-one-day-old chicks of the Hubbard breed were reared on floor pens in a privet farm, Giza. The chicks were weighed on arrival (each chick weighted 43-45 gm) and randomly assigned into five equal groups, with four replicates each (25 chicks/replicate). Group 1 was fed on a broiler diet without any additions (control). The diets of groups 2 and 3 were supplemented with 500 g/ton SB and 4 kg/ton RL, respectively. In group 4, the diet was enriched with 250 g/ton SB plus 2 kg/ton RL. Chicks in group 5 were fed on a diet fortified with 500 g/ton SB plus 4 kg/ton RL.

RESULTS: Supplementation of broiler diet with 500 g/ton SB plus 4 kg /ton RL increased body weight gain (BWG) and feed efficiency ratio (FER) of birds. It decreased serum levels of aspartate aminotransferase, alanine aminotransferase, total cholesterol triglycerides, and malondialdehyde, but increased superoxide dismutase, catalase, and immunoglobulins, phagocytic activity, lysozyme activity, and nitric oxide concentrations. Antibody titers against the Newcastle disease virus were also elevated.

CONCLUSION: Supplementation of broiler diet with 500 g/ton SB plus 4 kg/ton RL gives the best result regarding productive efficiency and immunity of broiler chickens.

Leptomeningeal disease (LMD) remains a rapidly lethal complication for late-stage melanoma patients. Here, we characterize the tumor microenvironment of LMD and patient-matched extra-cranial metastases using spatial transcriptomics in a small number of clinical specimens (nine tissues from two patients) with extensive in vitro and in vivo validation. The spatial landscape of melanoma LMD is characterized by a lack of immune infiltration and instead exhibits a higher level of stromal involvement. The tumor-stroma interactions at the leptomeninges activate tumor-promoting signaling, mediated through upregulation of SERPINA3. The meningeal stroma is required for melanoma cells to survive in the cerebrospinal fluid (CSF) and promotes MAPK inhibitor resistance. Knocking down SERPINA3 or inhibiting the downstream IGR1R/PI3K/AKT axis results in tumor cell death and re-sensitization to MAPK-targeting therapy. Our data provide a spatial atlas of melanoma LMD, identify the tumor-promoting role of meningeal stroma, and demonstrate a mechanism for overcoming microenvironment-mediated drug resistance in LMD.