Comprehensive characterization of the prostate tumor microenvironment identifies CXCR4/CXCL12 crosstalk as a novel antiangiogenic therapeutic target in prostate cancer

Background: Crosstalk between neoplastic and stromal cells fosters prostate cancer (PCa) progression and dissemination. Insight in cell-to-cell communication networks provides new therapeutic avenues to mold processes that contribute to PCa tumor microenvironment (TME) alterations. Here we performed a detailed characterization of PCa tumor endothelial cells (TEC) to delineate intercellular crosstalk between TEC and the PCa TME. Methods: TEC isolated from 67 fresh radical prostatectomy (RP) specimens underwent multi-omic ex vivo characterization as well as orthogonal validation of both TEC functions and key markers by immunohistochemistry (IHC) and immunofluorescence (IF). To identify cell-cell interaction targets in TEC, we performed single-cell RNA sequencing (scRNA-seq) in four PCa patients who underwent a RP to catalogue cellular TME composition. Targets were cross-validated using IHC, publicly available datasets, cell culture expriments as well as a PCa xenograft mouse model. Results: Compared to adjacent normal endothelial cells (NEC) bulk RNA-seq analysis revealed upregulation of genes associated with tumor vasculature, collagen modification and extracellular matrix remodeling in TEC. PTGIR, PLAC9, CXCL12 and VDR were identified as TEC markers and confirmed by IF and IHC in an independent patient cohort. By scRNA-seq we identified 27 cell (sub)types, including endothelial cells (EC) with arterial, venous and immature signatures, as well as angiogenic tip EC. A focused molecular analysis revealed that arterial TEC displayed highest CXCL12 mRNA expression levels when compared to all other TME cell (sub)populations and showed a negative prognostic role. Receptor-ligand interaction analysis predicted interactions between arterial TEC derived CXCL12 and its cognate receptor CXCR4 on angiogenic tip EC. CXCL12 was in vitro and in vivo validated as actionable TEC target by highlighting the vessel number- and density- reducing activity of the CXCR4-inhibitor AMD3100 in murine PCa as well as by inhibition of TEC proliferation and migration in vitro. Conclusions: Overall, our comprehensive analysis identified novel PCa TEC targets and highlights CXCR4/CXCL12 interaction as a potential novel target to interfere with tumor angiogenesis in PCa

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Modeling the Epidermal Barrier in Atopic Dermatitis with 3D Human Skin Organoids

The epidermal barrier is essential for maintaining skin homeostasis, yet the cellular signaling mechanisms that lead to its formation and function are relatively unknown. Perturbations in the epidermal barrier cause many different skin diseases, including atopic dermatitis. Our investigations will help define signaling mechanisms impacting the barrier in atopic dermatitis using a 3D human skin organoid model made from primary skin cells. To probe these mechanisms, we will determine expression levels of transcripts (mRNA) by quantitative polymerase chain reaction (qPCR). First, we had to ensure that known atopic dermatitis mRNA expression patterns were the same in our model. For example, the barrier protein filaggrin is downregulated in the skin of patients with atopic dermatitis. According to our qPCR data, our results align with patient data. We observed the same loss of filaggrin transcripts in our atopic dermatitis 3D organoid model. These results establish the validity of the model. The long-term goal of our studies is to investigate the potential of re-establishing the balance of signaling mechanisms as possible means of restoring the epidermal barrier and treating atopic dermatitis

Peptic Ulcer

https://digitalcommons.imsa.edu/hd_graphic_novels/1059/thumbnail.jp

Asthma

https://digitalcommons.imsa.edu/hd_graphic_novels/1057/thumbnail.jp

doi: 10.3389/fpsyg.2012.00095 The role of words in cognitive tasks: what, when, and how?

The current review focuses on how exposure to linguistic input, and count nouns in particular, affect performance on various cognitive tasks, including individuation, categorization and category learning, and inductive inference. We review two theoretical accounts of effects of words. Proponents of one account argue that words have top-down effects on cognitive tasks, and, as such, function as supervisory signals. Proponents of the other account suggest that early in development, words, just like any other perceptual feature, are first and foremost part of the stimulus input and influence cognitive tasks in a bottom-up, non-supervisory fashion. We then review evidence supporting each account. We conclude that, although much research is needed, there is a large body of evidence indicating that words start out like other perceptual features and become supervisory signals in the course of development

Treatment of right hepatic artery stump bleeding after pylorus-preserving pancreaticoduodenectomy by covered stent endoprosthesis placement

Serious complications after pancreaticoduodenectomy include rupture of pseudoaneurysms arising from pancreatic fistula and pancreatojejunostomy leakage. We report a case of successful endovascular minimally invasive treatment using a covered stent endoprosthesis of a right hepatic artery stump bleeding following pylorus-preserving pancreaticoduodenectomy that was not suitable for coil or glue embolization due to an insufficiently short neck

Th17-inducing dendritic cell vaccines stimulate effective CD4 T cell-dependent antitumor immunity in ovarian cancer that overcomes resistance to immune checkpoint blockade

Background Ovarian cancer (OC), a highly lethal cancer in women, has a 48% 5-year overall survival rate. Prior studies link the presence of IL-17 and Th17 T cells in the tumor microenvironment to improved survival in OC patients. To determine if Th17-inducing vaccines are therapeutically effective in OC, we created a murine model of Th17-inducing dendritic cell (DC) (Th17-DC) vaccination generated by stimulating IL-15 while blocking p38 MAPK in bone marrow-derived DCs, followed by antigen pulsing.Methods ID8 tumor cells were injected intraperitoneally into mice. Mice were treated with Th17-DC or conventional DC (cDC) vaccine alone or with immune checkpoint blockade (ICB). Systemic immunity, tumor associated immunity, tumor size and survival were examined using a variety of experimental strategies.Results Th17-DC vaccines increased Th17 T cells in the tumor microenvironment, reshaped the myeloid microenvironment, and improved mouse survival compared with cDC vaccines. ICB had limited efficacy in OC, but Th17-inducing DC vaccination sensitized it to anti-PD-1 ICB, resulting in durable progression-free survival by overcoming IL-10-mediated resistance. Th17-DC vaccine efficacy, alone or with ICB, was mediated by CD4 T cells, but not CD8 T cells.Conclusions These findings emphasize using biologically relevant immune modifiers, like Th17-DC vaccines, in OC treatment to reshape the tumor microenvironment and enhance clinical responses to ICB therapy

Impact of CLEC3B mRNA expression on genetic landscape and immune tumor-microenvironment in NSCLC

e20517 Background: Downregulation of C-type lectin domain family 3 member B (CLEC3B) is observed in non-small cell lung cancer (NSCLC), but its role remains largely unclear. Thus, we conducted this large scale genomic and transcriptomic analysis to gain novel insights into molecular and immunological functions of CLEC3B mRNA expression in NSCLC. Methods: Five publicly available WTS/WES NSCLC datasets (TCGA LUAD/LUSC, GSE41271, GSE66863, GSE81089, BATTLE) and the lung cancer single-cell atlas (Salcher, Cancer Cell 2022) were re-analyzed to decipher various molecular and biological aspects of CLEC3B in NSCLC. Findings were validated in a cohort of 19,982 NSCLC samples, which were centrally profiled (Caris Life Sciences, Phoenix, AZ) using WES/WTS. The cohort was stratified in quartiles according to CLEC3B mRNA expression status, with CLEC3B high ( CLEC3B H ) and CLEC3B low ( CLEC3B L ) expression defined as top and bottom quartile of transcripts per million (TPM) for further comparison. Immune cell fractions were calculated using QuantiSeq. Real-world overall survival (OS) was calculated using data from insurance claims. Results: CLEC3B mRNA expression was diminished in NSCLC compared to matched normal tissue (p < 0.001). Adenomatous histology was associated with higher CLEC3B expression compared to squamous/large-cell carcinomas (p < 0.005). In CLEC3B H tumors we observed lower rates of somatic mutations in TP53 (44.1 vs 81.7%), TTN (54.1 vs 79%), CDKN2A (5.2 vs 15%), but higher rates in KRAS (24 vs 7.8%) and STK11 (15.8 vs 2.69%) (all, q < 0.01), which we corroborated in our validation cohort (TP53 (52.4 vs 74.7%), CDKN2A (8.3 vs 13%), RB1 (9.2 vs 13.5%), KMT2D (3.8 vs 7.3%), KRAS (31.8 vs 25.6%), EGFR (17.2 vs 8.1%) and STK11 (15.9 vs 11.3%, all q < 0.05)). Further, CLEC3B H tumors were characterized by an immunosuppressive phenotype reflected by lower TMB and lower rates of MSI-H/dMMR, lower PD-L1 IHC expression and abundance of M2 macrophages and regulatory T-cells. Analysis of bulk and single cell transcriptomic datasets revealed that CLEC3B H was linked to endothelium-specific signaling and higher expression levels in endothelial cells. Finally, increased CLEC3B expression was associated with improved OS in the exploratory and validation cohorts. Conclusions: We herein described the molecular landscape of NSCLCs according to CLEC3B mRNA expression. We speculate that CLEC3B is mainly expressed by endothelial cells, and observed that CLEC3B H was associated with a distinct genetic profile and an immunosuppressive tumor-microenvironment. Thus, CLEC3B expression warrants further investigation as a stratification marker for NSCLC patients undergoing immune checkpoint therapy

Isolation of potential plant growth-promoting bacteria from nodules of legumes grown in arid Botswana soil

As the world population increases, improvements in crop growth and yield will be needed to meet rising food demands, especially in countries that have not developed agricultural practices optimized for their own soils and crops. In many African countries, farmers improve agricultural productivity by applying synthetic fertilizers and pesticides to crops, but their continued use over the years has had serious environmental consequences including air and water pollution as well as loss of soil fertility. To reduce the overuse of synthetic amendments, we are developing inocula for crops that are based on indigenous soil microbes, especially those that enhance plant growth and improve agricultural productivity in a sustainable manner. We first isolated environmental DNA from soil samples collected from an agricultural region to study the composition of the soil microbiomes and then used Vigna unguiculata (cowpea), an important legume crop in Botswana and other legumes as “trap” plants using the collected soil to induce nitrogen-fixing nodule formation. We have identified drought-tolerant bacteria from Botswana soils that stimulate plant growth; many are species of Bacillus and Paenibacillus . In contrast, the cowpea nodule microbiomes from plants grown in these soils house mainly rhizobia particularly Bradyrhizobium , but also Methylobacterium spp. Hence, the nodule microbiome is much more limited in non-rhizobial diversity compared to the soil microbiome, but also contains a number of potential pathogenic bacteria