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PDF file - 85K, Lung tumor cells and CAFs induce a of CAF-like phenotype in NFs

PDF file - 462KB, Forest plots summarizing the overexpression of the 11 genes from discovery meta-analysis (S1). Forest plots summarizing the overexpression of the 11 genes from validation meta-analysis (S2). Six genes of the original 11 gene ADC signature are also overexpressed in ADC relative to other NSCLC histological subtypes (S3). Expression of PTK7 in an ADC tissue microarray and in a mouse model of lung adenocarcinoma (S4). Correlation of sensitivity to PTK7 knock-down with mutations and expression (S5). MKK7-JNK pathway dysregulation upon PTK7 knock-down (S6).

XLS file - 27K, Onto-Express Analysis for Functional Pathways

PDF file - 20K, Survival prognosis of a mouse CAF-secretory gene signature in human NSCLC

PDF file - 40K, Lung CAFs stimulate lung cancer growth in vivo

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XLS file - 329K, Microarray Analysis using LIMMA

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XLS file - 21K, Ingenuity Pathway Analysis for Functional Networks

XLS file - 27K, Meta-Analysis of 5 human data sets incorporating array expression data

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PDF file - 56K, A secretory and inflammatory gene signature specific to CAFs

XLSX file - 40KB, Data sets used in discovery meta-analysis (S1). Data sets used in validation meta-analysis (S2). Gene-level results in validation meta-analysis (S3). Data sets used in NSCLC histological subtype meta-analysis (S4). Gene-level results in NSCLC histological subtype (ADC vs SCC) meta-analysis (S5). Tissue microarray specimen annotations and PTK7 staining results (S6). Cell line annotations (S7).

XLS file - 68K, Onto-Express Analysis for Cellular Components

XLS file - 53K, Ingenuity Pathway Analysis for human-mouse orthologues

Lung cancer remains the most common cause of cancer-related death worldwide and it continues to lack effective treatment. The increasingly large and diverse public databases of lung cancer gene expression constitute a rich source of candidate oncogenic drivers and therapeutic targets. To define novel targets for lung adenocarcinoma, we conducted a large-scale meta-analysis of genes specifically overexpressed in adenocarcinoma. We identified an 11-gene signature that was overexpressed consistently in adenocarcinoma specimens relative to normal lung tissue. Six genes in this signature were specifically overexpressed in adenocarcinoma relative to other subtypes of non–small cell lung cancer (NSCLC). Among these genes was the little studied protein tyrosine kinase PTK7. Immunohistochemical analysis confirmed that PTK7 is highly expressed in primary adenocarcinoma patient samples. RNA interference–mediated attenuation of PTK7 decreased cell viability and increased apoptosis in a subset of adenocarcinoma cell lines. Further, loss of PTK7 activated the MKK7–JNK stress response pathway and impaired tumor growth in xenotransplantation assays. Our work defines PTK7 as a highly and specifically expressed gene in adenocarcinoma and a potential therapeutic target in this subset of NSCLC. Cancer Res; 74(10); 2892–902. ©2014 AACR.

PDF file - 19K, Decrease response to CAF-derived clcf1 in cntfr-depleted tumor cells

Amlitelimab (SAR445229), a fully human non-depleting, non-cytotoxic, monoclonal antibody, binds to OX40Ligand (OX40L) on antigen-presenting cells (APC) to block OX40-OX40L interactions. In a 16-week, double-blind, Phase 2a trial (NCT03754309), amlitelimab induced clinically meaningful disease activity improvement in patients with moderate-to-severe atopic dermatitis (AD). To assess the effects of amlitelimab on interleukin (IL)-13 and T-cell recall responses. In the trial, 89 patients were randomized to amlitelimab low dose (LD; 200 mg loading/100 mg maintenance every 4 weeks [Q4W]), high dose (HD; 500 mg loading/250 mg maintenance Q4W), or placebo. Serum IL-13 levels were assessed by single molecule immunoassay (259 samples). Using human peripheral blood mononuclear cells from five healthy donors, a T-cell recall assay was performed. At baseline in the trial, IL-13 levels significantly correlated with disease severity (Eczema Area and Severity Index; r = 0.4784, P < 0.0001). Week 16 IL-13 levels were significantly reduced with amlitelimab vs. baseline but not placebo (median fold change [95% confidence interval, CI] from baseline to week 16 with P-values based on two-way Analysis of Variance [ANOVA] of log10-transformed fold change for patients with a complete dataset at week 16: LD 0.345 [0.23–0.44], P < 0.0001; HD 0.390 [0.30–0.63], P = 0.0002; placebo 0.835 [0.34–1.12], P = 0.1544). In a T-cell recall assay, amlitelimab significantly reduced IL-13 protein levels at days 3 and 6 without negatively impacting T-cell expansion, based on the percentage of proliferating CD4+ T-cells vs. isotype control. Amlitelimab decreased IL-13 levels in patients with AD and in a T-cell recall assay without negative effects on T-cell expansion, thus reducing inflammation without blocking T-cell proliferation during recall responses.

The Eurasian Jackdaw is thought to be archetypically monogamous, but recent tagging research uncovered extra-pair copulations in the species. Here we examined extra-pair paternity (genetic monogamy) in Eurasian jackdaws breeding in the Judean Hills, Israel, at the global edge of the species range, using a set of highly polymorphic molecular microsatellites. We found roughly a sixth of nests sampled showed deviations from monogamy, more than previously found in DNA fingerprinting studies of jackdaws, suggesting a mixed mating strategy in this population. These findings support the trend of extra-pair paternity in avian species, even when social monogamy remains the rule, and highlight the importance of continued study of species throughout their geographical range.

Cutaneous vasculitis can be classified into two types based on the affected vessel size: small vessel vasculitis predominantly affecting dermal venules, and muscular vessel vasculitis as found in cutaneous arteritis predominantly affecting arteries located at the dermal‐subcutaneous junction. We describe two cases with a novel small vessel vasculitis disorder, which exclusively affected arterioles in the mid‐dermis, and show clinical and pathological difference distinct from cutaneous polyarteritis nodosa and cutaneous venulitis. Both patients were male, and presented with painful infiltrative plaques, involving the palms, soles, and thighs without extracutaneous involvement except for fever and arthralgia. Histopathological examination revealed vasculitis in the mid‐dermis characterized by a predominant infiltration of neutrophils with vessel wall fibrinoid necrosis and leukocytoclasia identical to the features of leukocytoclastic vasculitis, except that the affected vessels were arterioles rather than venules. Serological examinations showed normal levels of serum complements, immune complexes, and antineutrophil cytoplasmic antibodies, and vasculitis disorders associated with systemic diseases were excluded in both patients. The patients showed a good response to short‐term treatment with prednisolone up to 30 mg. This novel cutaneous arteriolitis clinicopathologically different from both cutaneous venulitis and cutaneous arteritis appears to be a skin‐limited disorder.

This work is part of our continuous research effort to reveal the underlying physics of bubble coalescence in microfluidics through the GPU-accelerated lattice Boltzmann method. We numerically explore the mechanism of damped oscillation in microbubble coalescence characterized by the Ohnesorge (Oh) number. The focus is to address when and how a damped oscillation occurs during a coalescence process. Sixteen cases with a range of Oh numbers from 0.039 to 1.543, varying in liquid viscosity from 0.002 to 0.08kg/(m · s) correspondingly, are systematically studied. First, a criterion of with or without damped oscillation has been established. It is found that a larger Oh enables faster/slower bubble coalescence with/without damped oscillation when (Oh 0.477) and the fastest coalescence falls at Oh ≈ 0.477. Second, the mechanism behind damped oscillation is explored in terms of the competition between driving and resisting forces. When Oh is small in the range of Oh