Dallfyhn2977
Euglycemic lean adolescents with IR display TRL dyslipoproteinemia with increased inhibition of LPL as highlighted by higher concentrations of ANGPTL-3, ApoC-III and fasting chylomicron remnants (ApoB-48).Pediatric cancers often mimic fetal tissues and express proteins normally silenced postnatally that could serve as immune targets. We developed T cells expressing chimeric antigen receptors (CARs) targeting glypican-2 (GPC2), a fetal antigen expressed on neuroblastoma (NB) and several other solid tumors. CARs engineered using standard designs control NBs with transgenic GPC2 overexpression, but not those expressing clinically relevant GPC2 site density (∼5,000 molecules/cell, range 1-6 × 103). Iterative engineering of transmembrane (TM) and co-stimulatory domains plus overexpression of c-Jun lowered the GPC2-CAR antigen density threshold, enabling potent and durable eradication of NBs expressing clinically relevant GPC2 antigen density, without toxicity. These studies highlight the critical interplay between CAR design and antigen density threshold, demonstrate potent efficacy and safety of a lead GPC2-CAR candidate suitable for clinical testing, and credential oncofetal antigens as a promising class of targets for CAR T cell therapy of solid tumors.We performed proteogenomic characterization of intrahepatic cholangiocarcinoma (iCCA) using paired tumor and adjacent liver tissues from 262 patients. Integrated proteogenomic analyses prioritized genetic aberrations and revealed hallmarks of iCCA pathogenesis. Aflatoxin signature was associated with tumor initiation, proliferation, and immune suppression. Mutation-associated signaling profiles revealed that TP53 and KRAS co-mutations may contribute to iCCA metastasis via the integrin-FAK-SRC pathway. FGFR2 fusions activated the Rho GTPase pathway and could be a potential source of neoantigens. Proteomic profiling identified four patient subgroups (S1-S4) with subgroup-specific biomarkers. These proteomic subgroups had distinct features in prognosis, genetic alterations, microenvironment dysregulation, tumor microbiota composition, and potential therapeutics. SLC16A3 and HKDC1 were further identified as potential prognostic biomarkers associated with metabolic reprogramming of iCCA cells. This study provides a valuable resource for researchers and clinicians to further identify molecular pathogenesis and therapeutic opportunities in iCCA.In a recent publication in Nature, Zhang et al. report that foreign antigen stimulation elicits bountiful changes in lymphatic metabolite production-changes that include B cells secreting GABA, which reprograms macrophages and limits T cell cytotoxicity. This signifies a new mechanism by which B cells regulate immune suppression and facilitate tumor progression.
The protective effect of immunization using Iranian Lizard Leishmania (ILL) mixed with CpG oligodeoxynucleotides (CpG-ODN) was demonstrated in a previous study. Here, we report the effect of leishmanization using ILL mixed with chitin microparticles (CMPs) as an adjuvant against L. major infection in BALB/c mice.
Briefly, 2×10
live ILL were mixed with 10µg CMPs (<40μm in size) (ILL+CMP) and were injected subcutaneously into the right footpad of BALB/c mice. Three control groups were included in the study and received ILL, chitin, and PBS respectively. FM19G11 cell line Three weeks later, mice were challenged with 2×10
live L. major
promastigotes, which were inoculated into the left footpad. The infection course was monitored using footpad swelling measurement and in vivo imaging. Eleven weeks after the challenge, all mice were sacrificed and parasite burden was measured in the spleen and the draining lymph node using three different methods including real-time PCR, flow cytometry, and direct fluorescent microscopy microparticles is an effective vaccine against leishmaniasis in BALB/c mice. This vaccine is able to induce an adequate immune response to decrease the parasite burden and prevent lesion formation. Further studies are needed to evaluate long-lasting immunity, especially in experimental outbreed models.Directed neuronal differentiation of human pluripotent stem cells (hPSCs), neural progenitors, or fibroblasts using transcription factors has allowed for the rapid and highly reproducible differentiation of mature and functional neurons. Exogenous expression of the transcription factor Neurogenin-2 (NGN2) has been widely used to generate different populations of neurons, which have been used in neurodevelopment studies, disease modeling, drug screening, and neuronal replacement therapies. Could NGN2 be a "one-glove-fits-all" approach for neuronal differentiations? This review summarizes the cellular roles of NGN2 and describes the applications and limitations of using NGN2 for the rapid and directed differentiation of neurons.Transplantation in Parkinson's disease using human embryonic stem cell (hESC)-derived dopaminergic (DA) neurons is a promising future treatment option. However, many of the mechanisms that govern their differentiation, maturation, and integration into the host circuitry remain elusive. Here, we engrafted hESCs differentiated toward a ventral midbrain DA phenotype into the midbrain of a preclinical rodent model of Parkinson's disease. We then injected a novel DA-neurotropic retrograde MNM008 adeno-associated virus vector capsid, into specific DA target regions to generate starter cells based on their axonal projections. Using monosynaptic rabies-based tracing, we demonstrated for the first time that grafted hESC-derived DA neurons receive distinctly different afferent inputs depending on their projections. The similarities to the host DA system suggest a previously unknown directed circuit integration. By evaluating the differential host-to-graft connectivity based on projection patterns, this novel approach offers a tool to answer outstanding questions regarding the integration of grafted hESC-derived DA neurons.Research in low Earth orbit (LEO) has become more accessible. The 2020 Biomanufacturing in Space Symposium reviewed space-based regenerative medicine research and discussed leveraging LEO to advance biomanufacturing for regenerative medicine applications. The symposium identified areas where financial investments could stimulate advancements overcoming technical barriers. Opportunities in disease modeling, stem-cell-derived products, and biofabrication were highlighted. The symposium will initiate a roadmap to a sustainable market for regenerative medicine biomanufacturing in space. This perspective summarizes the 2020 Biomanufacturing in Space Symposium, highlights key biomanufacturing opportunities in LEO, and lays the framework for a roadmap to regenerative medicine biomanufacturing in space.Primordial germ cells (PGCs) arise from cells of the post-implantation epiblast in response to cytokine signaling. PGC development can be recapitulated in vitro by differentiating epiblast-like cells (EpiLCs) into PGC-like cells (PGCLCs) through cytokine exposure. Interestingly, the cytokine requirement for PGCLC induction can be bypassed by enforced expression of the transcription factor (TF) NANOG. However, the underlying mechanisms are not fully elucidated. Here, we show that NANOG mediates Otx2 downregulation in the absence of cytokines and that this is essential for PGCLC induction by NANOG. Moreover, the direct NANOG target gene Esrrb, which can substitute for several NANOG functions, does not downregulate Otx2 when overexpressed in EpiLCs and cannot promote PGCLC specification. However, expression of ESRRB in Otx2+/- EpiLCs rescues emergence of PGCLCs. This study illuminates the interplay of TFs occurring at the earliest stages of PGC specification.Human health and disease have increasingly been shown to be impacted by the gut microbiota, and mouse models are essential for investigating these effects. However, the compositions of human and mouse gut microbiotas are distinct, limiting translation of microbiota research between these hosts. To address this, we constructed the Mouse Gastrointestinal Bacteria Catalogue (MGBC), a repository of 26,640 high-quality mouse microbiota-derived bacterial genomes. This catalog enables species-level analyses for mapping functions of interest and identifying functionally equivalent taxa between the microbiotas of humans and mice. We have complemented this with a publicly deposited collection of 223 bacterial isolates, including 62 previously uncultured species, to facilitate experimental investigation of individual commensal bacteria functions in vitro and in vivo. Together, these resources provide the ability to identify and test functionally equivalent members of the host-specific gut microbiotas of humans and mice and support the informed use of mouse models in human microbiota research.
Understanding maternal morbidity and its determinants can help identify opportunities to prevent obstetric complications and improvements for maternal health. This study was conducted to determine the prevalence of severe maternal morbidity (SMM) and the associated factors.
A hospital-based cross-sectional study was conducted at Koshi Hospital, Nepal, from January to March 2020. All women who met the inclusion criteria of age ≥18 years of age, Morang residents of Nepalese nationality, had received routine antenatal care, and given birth at Koshi Hospital were recruited consecutively. The World Health Organization criteria were used to identify the women with SMM. A multiple logistic regression analysis was performed. Overall, 346 women were recruited.
The prevalence of SMM was 6.6%. Among the SMM cases, the most frequently occurring SMM conditions were hypertensive disorders (12, 56.5%), hemorrhagic disorders (6, 26.1%), and severe management indicators (8, 34.8%). Women with no or primary education (adjusted odds ratio 0.10, 95% confidence interval 0.01, 0.76) decreased the odds of SMM compared to secondary education.
The approximately 7% prevalence of SMM correlated with global studies. Maternal education was significantly associated with SMM. If referral hospitals were aware of the expected prevalence of potentially life-threatening maternal conditions, they could plan to avert future reproductive complications.
The approximately 7% prevalence of SMM correlated with global studies. Maternal education was significantly associated with SMM. If referral hospitals were aware of the expected prevalence of potentially life-threatening maternal conditions, they could plan to avert future reproductive complications.
To explore the feasibility of using random forest (RF) machine learning algorithm in assessing normal and malignant peripheral pulmonary nodules based on in vivo endobronchial optical coherence tomography (EB-OCT).
A total of 31 patients with pulmonary nodules were admitted to Department of Respiratory Medicine, Zhongda Hospital, Southeast University, and underwent chest CT, EB-OCT and biopsy. Attenuation coefficient and up to 56 different image features were extracted from A-line and B-scan of 1703 EB-OCT images. Attenuation coefficient and 29 image features with significant p-values were used to analyze the differences between normal and malignant samples. A RF classifier was trained using 70% images as training set, while 30% images were included in the testing set. The accuracy of the automated classification was validated by clinically proven pathological results.
Attenuation coefficient and 29 image features were found to present different properties with significant p-values between normal and malignant EB-OCT images.
