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Chimeric antigen receptors (CARs) are receptors for antigen that direct potent immune responses. Tumor escape associated with low target antigen expression is emerging as one potential limitation of their efficacy. Here we edit the TRAC locus in human peripheral blood T cells to engage cell-surface targets through their T cell receptor–CD3 complex reconfigured to utilize the same immunoglobulin heavy and light chains as a matched CAR. We demonstrate that these HLA-independent T cell receptors (HIT receptors) consistently afford high antigen sensitivity and mediate tumor recognition beyond what CD28-based CARs, the most sensitive design to date, can provide. We demonstrate that the functional persistence of HIT T cells can be augmented by constitutive coexpression of CD80 and 4-1BBL. Finally, we validate the increased antigen sensitivity afforded by HIT receptors in xenograft mouse models of B cell leukemia and acute myeloid leukemia, targeting CD19 and CD70, respectively. Overall, HIT receptors are well suited for targeting cell surface antigens of low abundance. HLA-independent T cell receptors, in which the heavy and light chains of a chimeric antigen receptor are incorporated into the endogenous T cell receptor locus, are more effective than CD28-based chimeric antigen receptors at targeting tumors with low antigen expression.

Purpose: To report the clinical profile and visual impairment in various stages of neovascular glaucoma (NVG) at a tertiary eye center in East India. Methods: The electronic medical records of the hospital database of patients with neovascular glaucoma seen between 2013 and 2020 were reviewed. Gonioscopic details were used to stratify patients into nonspecified NVG (Group 1), open-angle NVG (Group 2), and closed-angle NVG (Group 3). The clinical profile, angle features, cause of NVG, systemic associations, visual impairment, and blindness (defined as logarithm of the minimum angle of resolution, LogMar >1.3 at baseline and at final follow-up), and outcomes of medical/surgical interventions were compared between the three groups. Results: Of 846 eyes of 810 patients with NVG (Group 1, n = 564 eyes, Group 2, n = 61 eyes, and Group 3, n = 220 eyes), at baseline, the blindness rates in Groups 3 and 2 were 90 and 75%, respectively. The time from a previous intervention to the onset of NVG ranged from 3 to 5 months, while the median duration of NVG was about 4-4.5 months (0.03-120 months). Multivariate regression identified a longer duration of NVG as the only variable associated with poor final visual acuity. Conclusion: Visual morbidity by NVG remains as high as 75-90% in developing countries, even with the availability of anti-VEGFs and after improved management/investigative at all stages.

Understanding the heterogeneity of Rheumatoid Arthritis (RA) and identifying therapeutic targets remain challenging using traditional bulk transcriptomics alone, as it lacks the spatial and protein-level resolution needed to fully capture disease and tissue complexities. In this study, we applied Laser Capture Microdissection (LCM) coupled with mass spectrometry-based proteomics to analyze histopathological niches of the RA synovium, enabling the identification of protein expression profiles of the diseased synovial lining and sublining microenvironments compared to their healthy counterparts. In this respect, key pathogenetic RA proteins like membrane proteins (TYROBP, AOC3, SLC16A3, TCIRG1, and NCEH1), and extracellular matrix (ECM) proteins (PLOD2, OGN, and LUM) showed different expression patterns in diseased synovium compartments. To enhance our understanding of cellular dynamics within the dissected regions, we further integrated the proteomic dataset with single-cell RNA sequencing (scRNA-seq), and deduced cell type enrichment, including T cells, fibroblasts, NK cells, myeloid cells, B cells, and synovial endothelial cells. By combining high-resolution spatial proteomics and transcriptomic analyses, we provide novel insights into the molecular mechanisms driving RA, and highlight potential protein targets for therapeutic intervention. This integrative approach offers a more comprehensive view of RA synovial pathology, and mitigates the limitations of traditional bulk transcriptomics in target discovery.

Brain wiring is a highly intricate process in which trillions of neuronal connections are established. Its initial phase is particularly crucial in establishing the general framework of neuronal circuits. During this early step, differentiating neurons extend axons, which reach their target by navigating through a complex environment with extreme precision. Research in the past 20 years has unraveled a vast and complex array of chemotropic cues that guide the leading tip of axons, the growth cone, throughout its journey. Tight regulation of these cues, and of their receptors and signaling pathways, is necessary for the high degree of accuracy required during circuit formation. However, little is known about the nature of regulatory molecules or mechanisms fine-tuning axonal cue response. Here we review recent, and somewhat fragmented, research on the possibility that microRNAs (miRNAs) could be key fine-tuning regulatory molecules in axon guidance. miRNAs appear to shape long-range axon guidance, fasciculation and targeting. We also present several lines of evidence suggesting that miRNAs could have a compartmentalized and differential action at the cell soma, and within axons and growth cones.

This review documents the sporadic reporting of poultry Salmonella serovars in South Africa, Egypt, Indonesia, India, and Romania, five countries selected based on the importance of their distribution in different regions of the world and their cumulative significant population size of 1.6 billion. South Africa reported contamination of its poultry carcasses by S. Hadar, S. Blockley, S. Irumu, and S. Anatum. Results from Egypt showed that S. Enteritidis and S. Typhimurium were predominant in poultry along with other non-typhoid strains, namely S. Infantis, S. Kentucky, S. Tsevie, S. Chiredzi, and S. Heidelberg. In Indonesia, the isolation of Salmonella Typhi was the main focus, while other serovars included S. Kentucky, S. Typhimurium, and S. Paratyhi C. In India, S. Bareilly was predominant compared to S. Enteritidis, S. Typhimurium, S. Paratyphi B, S. Cerro, S. Mbandaka, S. Molade, S. Kottbus, and S. Gallinarum. Romania reported two Salmonella serovars in poultry that affect humans, namely S. Enteritidis and S. Typhimurium, and other non-typhoid strains including S. Infantis, S. Derby, S. Colindale, S. Rissen, S. Ruzizi, S. Virchow, S. Brandenburg, S. Bredeney, S. Muenchen, S. Kortrijk, and S. Calabar. The results showed the spread of different serovars of Salmonella in those five developing countries, which is alarming and emphasizes the urgent need for the World Health Organization Global Foodborne Infections Network (WHO-GFN) to expand its activities to include more strategic participation and partnership with most developing countries in order to protect poultry and humans from the serious health impact of salmonellosis.

To understand drug combination effect, it is necessary to decipher the interactions between drug targets-many of which are signaling molecules. Previously, such signaling pathway models are largely based on the compilation of literature data from heterogeneous cellular contexts. Indeed, de novo reconstruction of signaling interactions from large-scale molecular profiling is still lagging, compared to similar efforts in transcriptional and protein-protein interaction networks. To address this challenge, we introduce a novel algorithm for the systematic inference of protein kinase pathways, and applied it to published mass spectrometry-based phosphotyrosine profile data from 250 lung adenocarcinoma (LUAD) samples. The resulting network includes 43 TKs and 415 inferred, LUAD-specific substrates, which were validated at >60% accuracy by SILAC assays, including \"novel' substrates of the EGFR and c-MET TKs, which play a critical oncogenic role in lung cancer. This systematic, data-driven model supported drug response prediction on an individual sample basis, including accurate prediction and validation of synergistic EGFR and c-MET inhibitor activity in cells lacking mutations in either gene, thus contributing to current precision oncology efforts.

Further advances in cell engineering are needed to increase the efficacy of chimeric antigen receptor (CAR) and other T cell-based therapies 1 – 5 . As T cell differentiation and functional states are associated with distinct epigenetic profiles 6 , 7 , we hypothesized that epigenetic programming may provide a means to improve CAR T cell performance. Targeting the gene that encodes the epigenetic regulator ten–eleven translocation 2 ( TET2 ) 8 presents an interesting opportunity as its loss may enhance T cell memory 9 , 10 , albeit not cause malignancy 9 , 11 , 12 . Here we show that disruption of TET2 enhances T cell-mediated tumour rejection in leukaemia and prostate cancer models. However, loss of TET2 also enables antigen-independent CAR T cell clonal expansions that may eventually result in prominent systemic tissue infiltration. These clonal proliferations require biallelic TET2 disruption and sustained expression of the AP-1 factor BATF3 to drive a MYC-dependent proliferative program. This proliferative state is associated with reduced effector function that differs from both canonical T cell memory 13 , 14 and exhaustion 15 , 16 states, and is prone to the acquisition of secondary somatic mutations, establishing TET2 as a guardian against BATF3-induced CAR T cell proliferation and ensuing genomic instability. Our findings illustrate the potential of epigenetic programming to enhance T cell immunity but highlight the risk of unleashing unchecked proliferative responses. Disruption of TET2 increases the antitumour efficacy of CAR T cells, but establishes an epigenetic state that is prone to hyperproliferation and accumulation of secondary mutations.

The aim of this study was to evaluate an experimental Salmonella Enteritidis (SE) bacterin and an indirect ELISA system to assess quantitatively the acquired immunity in Awassi ewes to the vaccine and/or Echinacea purpurea (EP) dried roots. Four treatments of the ewes were included in the experimental design, with 6 ewes/treatment. The first treatment (T1) had the controls that were non-vaccinated and non-treated with EP. The T2 ewes were only treated with EP. The T3 and T4 ewes were vaccinated at D1 (initiation of trial) and D10, while the T4 ewes were additionally administered the EP dried roots. Blood was collected from the jugular vein of all ewes at D1, D10, D21 and D45. The construction of the vaccine and the ELISA are detailed within the manuscript. The ELISA was able to detect quantitatively the significant acquired primary and secondary immunity to the vaccine in T3 and T4 ewes, compared to their low level of background immunities at initiation of the experiment (p<0.05). In addition, the ELISA detected the absence of seroconversion at all blood sampling times (p>0.05) in T1 control ewes, and in the T2 ewes that were given only the (EP) (p>0.05). Moreover, the ELISA was able to uncover the significant seroconversion of secondary immune response in T4 ewes at D21 compared to that at D10 (p<0.05), and the absence of significant seroconversion of secondary response in T3 ewes. This is the first work in literature that reports the need to supplement the vaccination by the experimental SE bacterin with daily oral intake of 250mg of EP-dried roots, effective the first vaccination day and up to 21 days, for obtaining a statistically significant seroconversion.

Introduction: Nosocomial infections are normally hospital acquired. Nasal carriage of Staphylococcus aureus (S. aureus) is very common and may be transmitted via a hand-to-nose route. The objective of the present study was to screen healthcare workers for the colonization of their nasal cavities with MRSA. Methodology: The study group included hospital staff such as nurses, doctors, and technicians. The control group included university students. For isolation, nasal swabs were taken from the volunteers and cultured on mannitol salt agar media selective for S. aureus. Suspected colonies were confirmed by PCR using specific primers for the coagulase and mecA gene. Typing of the coagulase-positive strains was done using restriction fragment length polymorphism (RFLP). Results: The results indicated an incidence rate of 76percent among healthcare workers. This is in comparison with students who served as control and were negative for MRSA. Using RFLP, four different types of MRSA were confirmed. Conclusions: The results of this study are alarming. Effective control measures must be formulated and implemented to avoid indiscriminate use of antimicrobials and the spread of these infectious agents in the region. © 2014 Iyer et al.

Introduction: Food-borne pathogens are the leading cause of illness and death in developing countries, killing approximately 1.8 million people annually. In developed countries, food-borne pathogens are responsible for millions of cases of infectious gastrointestinal diseases each year, costing billions of dollars. The objective of this study was to screen for two major food-borne pathogens, Escherichia coli and Salmonella spp., from meat samples obtained from different strata of the consumer market in Jeddah. Methodology: A total of 60 meat samples, 20 each from large hypermarkets, groceries and small butcher shops were used in the study. Samples were transported to the laboratory in a cooler. They were macerated in peptone water and then seeded on selective media appropriate for each organism. Colonies were identified using conventional microbiological methods and suspected colonies were confirmed as E. coli and Salmonella spp. by polymerase chain reaction (PCR) using specific primers. Results: The results indicated a high degree of contamination in samples from butcher shops as compared to those from groceries or hypermarkets (high scale supermarkets). Both pathogens E. coli and Salmonella spp. were found in higher rates in the samples from butcher shops. In small butcher shops, E. coli was found at an incidence of 65%, and Salmonella at 45%. Conclusion: The results indicate an urgent need for applying proper food hygienic practices in food outlets, especially in small ones, to reduce the incidence of food-borne diseases. Vigilance by the right agencies must be implemented in order to prevent future food-borne outbreaks.