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T cells expressing CD19-targeting chimeric antigen receptors (CARs) reveal high efficacy in the treatment of B cell malignancies. Here, we report that T cell receptor fusion constructs (TRuCs) comprising an antibody-based binding domain fused to T cell receptor (TCR) subunits can effectively reprogram an intact TCR complex to recognize tumor surface antigens. Unlike CARs, TRuCs become a functional component of the TCR complex. TRuC-T cells kill tumor cells as potently as second-generation CAR-T cells, but at significant lower cytokine release and despite the absence of an extra co-stimulatory domain. TRuC-T cells demonstrate potent anti-tumor activity in both liquid and solid tumor xenograft models. In several models, TRuC-T cells are more efficacious than respective CAR-T cells. TRuC-T cells are shown to engage the signaling capacity of the entire TCR complex in an HLA-independent manner. Supraphysiological T cell activation by chimeric antigen receptor (CAR) contributes to T cell exhaustion and adverse events in CAR T cell therapies. Here the authors engineer a synthetic antigen receptor that integrates into the endogenous TCR complex, preserving natural regulatory circuits and achieving improved performance in mouse tumor models.

The first lineage allocation in mouse and human embryos separates the inner cell mass (ICM) from the outer trophectoderm (TE). This symmetry-breaking event is executed through polarization of cells at the 8 cell stage and subsequent asymmetric divisions, generating polar (TE) and apolar (ICM) cells. Here, we show that mouse embryo polarization is unexpectedly asynchronous. Cells polarizing at the early and late 8 cell stage have distinct molecular and morphological properties that direct their following lineage specification, with early polarizing cells being biased towards producing the TE lineage. More recent studies have also implicated heterogeneities between cells prior to the 8 cell stage in the first lineage allocation: cells exhibiting reduced methyltransferase CARM1 activity at the 4 cell stage are predisposed towards the TE fate. Here, we demonstrate that reduced CARM1 activity and upregulation of its substrate BAF155 promote early polarization and TE specification. These findings provide a link between asymmetries at the 4 cell stage and polarization at the 8 cell stage, mechanisms of the first lineage allocation that had been considered separate.

ObjectiveTo assess the effects of earlier vs. later re-initiation of enteral feeds after necrotizing enterocolitis (NEC).Study designWe reviewed the literature to assess timing of enteral feeding after NEC using fixed effects models.ResultsThree studies met inclusion criteria; no randomized trials. After removal of Bell’s Stage I infants, the earlier refeeding group (<5–7 or median 4 days) included 79 infants and later refeeding group (≥5–7 or median 10 days) included 119 infants. Pooled analysis revealed earlier re-initiation reduced the incidence in the composite outcome of recurrent NEC and/or post-NEC stricture (OR = 0.27; 95% Cl = 0.10–0.75; p = 0.012). Individually, NEC recurrence (pooled OR = 0.34; 95% Cl = 0.09–1.29; p = 0.112) or stricture (OR = 0.34; 95% Cl = 0.09–1.26; p = 1.06) did not differ between groups.ConclusionsThere was no increase in negative outcomes with earlier refeeding after NEC. Earlier initiation of enteral feeds resulted in a significantly lower risk for the combined outcome of recurrent NEC and/or post-NEC stricture.

Sugarcane ( Saccharum spp.)is an economically useful crop grown globally for sugar, ethanol and biofuel production. The crop is vulnerable to fungus Colletotrichum falcatum known to cause red rot disease. The pathogen hydrolyses stalk parenchyma cells where sucrose is accumulated resulting in upto 75% losses in sugar recovery. In this study, transgenic sugarcane having resistance against red rot was developed by introducing Trichoderma spp. endochitinase following Agrobacterium mediated transformation. The transgene introduction and expression in genetically modified plants were verified through qRT-PCR revealing upto 6-fold enhancement in endochitinase expression than non-transgenic plants. Hyperspectral Imaging of transgenic plants displayed altered leaf reflectance spectra and vegetative indices that were positively correlated with ransgene expression. The bioassay with virulent pathotypes of C . falcatum CF08 and CF13 known for epiphytotic occurrence resulted in identification of resistant plant Chit 3-13.The plants with higher reflectance also displayed improved disease resistance, implying their early classification into resistant/susceptible. The losses in sucrose content were minimized (up to 4-fold) in inoculated resistant plant Chit 3–13 as compared to susceptible non-transgenic plant, and a fewer pathogen hyphae were detected in vascular cells of the former through optical microscopy. The electron micrographs confirmed sucrose-filled stalk parenchyma cells in Chit 3–13; in contrast, cells of non-transgenic inoculated plant were depleted of sucrose. The active sites involved in cleaving 1–4 β-glycoside bonds of N-acetyl-d-glucosaminein the pathogen hyphal walls were detected through endochitinase protein structural modelling. The transgenic sugarcane is an important source for in trogressingred rot resistance in plant breeding programs.

BackgroundRecent evidence demonstrates that earlier feeding may be beneficial after non-surgical necrotizing enterocolitis (NEC). We aimed to decrease time to reach full enteral feeds by 20% post-NEC by standardizing time to reinitiate feeds.MethodsWe implemented a consensus-based guideline for earlier feeding post-NEC. Outcome measures included days to initiate enteral feeds and reach full enteral feeds. Central venous line days and length of stay were also evaluated. Balancing measures were NEC recurrence and post-NEC stricture. Statistical analysis used process control methodology and standard comparison statistical testing.ResultsAverage days infants with Stage II NEC began feeding decreased from 9.4 to 5.1 days and average days to reach full feeds was decreased by 35% from 24.0 to 15.7 days. We observed no change in our balancing measures.ConclusionA multidisciplinary consensus-based NEC earlier feeding guideline decreased time to reach full enteral feeds and reduced central line days without adverse events.

Although currently available data indicate that Africa has the lowest usage of antimicrobials in animals in the world (adjusted by animal biomass), data show a high prevalence of antimicrobial resistance in foodborne pathogens isolated from animals and animal products. Apart from the lack of solid data on antimicrobial use in many countries in Africa, different hypotheses could explain this situation. Qualitative interviews of farmers show a lack of knowledge and uninformed use of antimicrobials. Considering the development of animal farming to meet an increasing demand for proteins, this deficiency represents a serious public health issue. We advocate for policies that consider the specific challenges faced by family farmers in Africa, to simultaneously improve access to veterinary drugs while strengthening the regulation of their use. We propose a global approach targeting the agri-food system, offering innovative social and technical interventions on antimicrobial usage, adapted to family farmers.

In this model, an inventory model for deteriorating products with dynamic demand is developed under time-dependent selling price. The selling price is supposed to be a time-dependent function of initial price of the products and the permissible discount rate at the time of deterioration. The object is sold with the constant rate in the absence of deterioration and is the exponential function of discount rate at the time; deterioration takes place. Here, the demand not only dependent on the selling price but also on the cumulative demand that represents the saturation and diffusion effect. First, an inventory model is formulated to characterize the profit function. The Classical optimization algorithm is used to solve the optimization problem. The objective is to maximize the total profit of the retailers with respect to the initial selling price and cycle time. Concavity of the objective function is discussed through graphs. At last, a sensitivity analysis is performed by changing inventory parameters and their impact on the decision variables i.e. (initial price, cycle time) together with the profit function.

Dendritic cells (DCs) are important innate and adaptive immune effectors, and have a key role in antigen presentation and T‐cell activation. Different lineages of DCs can be developed from hematopoietic progenitors following cytokine signaling, and the various lineages of DCs display distinct morphology, phenotype and functions. There has been limited information on differential cytokine‐mediated molecular signaling in DCs. Analyses of surface molecules by flow cytometry and quantitative RNA profiling revealed differences between DCs derived from interleukin‐4 (IL‐4) versus IL‐15 signaling, yet both lineages of DCs exhibited similar levels of surface molecules key to immune activation. Functional assays confirmed that IL‐15‐derived DCs elicited greater antigen‐specific, primary and secondary CD8 and CD4 T‐cell responses than did IL‐4‐derived DCs. Importantly, IL‐15 DCs secreted substantial amounts of proinflammatory cytokines, including IL‐6, interferon‐γ (IFN‐γ) and tumor necrosis factor‐α (TNFα), which helped polarize a strong T‐cell response. Assessment of signaling pathways revealed that IL‐15 DCs exhibited a lower levels of activated signal transducer and activator of transcription 5 (STAT5), STAT6 and extracellular signal‐regulated kinase 1/2 than IL‐4 DCs, but after lipopolysaccharide (LPS)/TNFα treatment, the STAT3 and p38 mitogen‐activated protein kinase (MAPK) activities were significantly enhanced in the IL‐15 DCs. Surprisingly, contrary to the canonical IL‐15‐mediated STAT5 signaling pathway in lymphoid cells, IL‐15 did not mediate a strong STAT5 or STAT3 activation in DCs. Further analysis using specific inhibitors to STAT3 and p38 MAPK pathways revealed that the STAT3 signaling, but not p38 MAPK signaling, contributed to IFN‐γ production in DCs. Therefore, while IL‐15 does not promote the STAT signaling in DCs, the increased STAT3 activity after LPS/TNFα treatment of the IL‐15 DCs has a key role in their high IFN‐γ effector activities.

Postnatal corticosteroids improve respiratory status and facilitate respiratory support weaning in preterm infants with bronchopulmonary dysplasia (BPD). Older literature describes characteristic cytokine profiles in tracheal aspirates (TA) of BPD patients which are altered with corticosteroids. Corticosteroids also influence peripheral blood T-cell presence. However, little is known regarding TA T-cell phenotype and cytokine production before or after exogenous corticosteroids. We hypothesized that postnatal dexamethasone alters the TA T-cell cytokine profiles of preterm infants. TA samples were collected from 14 infants born from 23 0/7 to 28 6/7 weeks who were mechanically ventilated for at least 14 days. Samples were collected up to 72 h before a ten-day dexamethasone course and again 1 to 3 calendar days after dexamethasone initiation. The primary outcome was change in T cell populations present in TA and their intracellular cytokine profile after dexamethasone treatment, ascertained via flow cytometry. Following dexamethasone treatment, there were significant decreases in respiratory severity score (RSS), percent CD4+IL-6+ cells, CD8+IL-6+ cells, CXCR3+IL-6+ cells, and CXCR3+IL-2+ cells and total intracellular IFN-γ in TA. RSS significantly correlated with TA percent CD4+IL-6+ cells. To our knowledge, this is the first study demonstrating that dexamethasone reduced T-cell IL-6 and this reduction was associated with improved RSS in pre-term infants with evolving BPD.

BackgroundAnti-CTLA-4 agents have demonstrated clinical benefit in a range of tumors; however, the safety risks limit the dose and their use in certain settings.1-4 XTX101 is a fully humanized mAb with an engineered Fc region for enhanced FcγR binding and with covalently linked peptides that mask each CTLA-4 antigen-binding region of the antibody. The masking peptides are designed to be selectively cleaved and released by proteases that are more active in the tumor microenvironment compared to healthy tissue. XTX101 is intended to have minimal peripheral CTLA-4 binding and inhibition. Upon proteolytic cleavage of the masking peptides within the tumor microenvironment, the cleaved and active form of XTX101 is intended to bind to CTLA-4, inhibit its function, and induce antibody-dependent cellular cytotoxicity (ADCC). Here we describe the first-in-human study that is currently enrolling subjects with locally advanced or metastatic disease who have failed standard therapy, or standard therapy is not curative or available.MethodsThe objectives of this study are to determine a dose or doses of XTX101 administered every 21 days that are well-tolerated, biologically active, and suitable for advancing into further studies. The initial portion of the study consists of three parts. Part 1A will evaluate ascending fixed doses of XTX101 monotherapy using an accelerated, single-subject, dose-level design for the first three dose cohorts followed by a standard 3+3 design. Part 1B will examine XTX101 monotherapy in patients with any histologically or cytologically confirmed solid tumor malignancy for which anti–PD-1 or anti–PD-L1 treatment is approved and has progressed on or after prior anti–PD-1 or anti–PD-L1 therapy. Currently approved tumor types for anti–PD-1 or anti–PD-L1 treatment include melanoma, squamous cell skin cancer, non-small cell lung cancer, head and neck carcinoma, esophageal carcinoma, renal cell cancer, urothelial carcinoma, or microsatellite instability-high/mismatch deficient colorectal cancer. Part 1B will require mandatory fresh tumor biopsies pre-dose and post-dose to fully characterize the pharmacodynamic profile of XTX101. Part1C will examine escalating doses of XTX101 in combination with pembrolizumab. Subjects may receive XTX101 for up to 24 months in the absence of disease progression, toxicity, a complete response, or termination of the study. Disease responses will be determined by iRECIST methods every third treatment cycle for the first year and then every four treatment cycles thereafter until progressive disease.Trial RegistrationNCT04896697ReferencesHamid O, Schmidt H, Nissan A, et al. A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma. J Transl Med 2011;9:204–19.Lebbé C, Meyer N, Mortier L, et al. Evaluation of two dosing regimens for nivolumab in combination with ipilimumab in patients with advanced melanoma: results from the phase IIIb/IV CheckMate 511 trial. J Clin Oncol 2019;37:867–875.Wolchok JD, Hodi FS, Weber JS, et al. Development of ipilimumab: a novel immunotherapeutic approach for the treatment of advanced melanoma. Ann N Y Acad Sci 2013; 1291:1-13.Wolchok JD, Neyns B, Linette G, et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol 2010;11:155–64.Ethics ApprovalThis study was approved by an Institutional Review Board for each participating site.