NF-κB perturbation reveals unique immunomodulatory functions in Prx1 + Fibroblasts that Promote Development of Atopic Dermatitis

Skin is composed of diverse cell populations that cooperatively maintain homeostasis. Up-regulation of the nuclear factor кB (NF-кB) pathway may lead to the development of chronic inflammatory disorders of the skin, but its role during the early events remains unclear. Through analysis of single-cell RNA sequencing data via iterative random forest leave one out prediction, an explainable artificial intelligence method, we identified an immunoregulatory role for a unique paired related homeobox-1 (Prx1)+ fibroblast subpopulation. Disruption of Ikkb-NF-кB under homeostatic conditions in these fibroblasts paradoxically induced skin inflammation due to the overexpression of C-C motif chemokine ligand 11 (CCL11; or eotaxin-1) characterized by eosinophil infiltration and a subsequent TH2 immune response. Because the inflammatory phenotype resembled that seen in human atopic dermatitis (AD), we examined human AD skin samples and found that human AD fibroblasts also overexpressed CCL11 and that perturbation of Ikkb-NF-кB in primary human dermal fibroblasts up-regulated CCL11. Monoclonal antibody treatment against CCL11 was effective in reducing the eosinophilia and TH2 inflammation in a mouse model. Together, the murine model and human AD specimens point to dysregulated Prx1+ fibroblasts as a previously unrecognized etiologic factor that may contribute to the pathogenesis of AD and suggest that targeting CCL11 may be a way to treat AD-like skin lesions. © 2022 The Authors, some rights reserve

Where to from here? A quality improvement project investigating burns treatment and rehabilitation practices in India

Abstract Objective To describe the capacity of the Indian healthcare system in providing appropriate and effective burns treatment and rehabilitation services. Results Health professionals involved in burns treatment or rehabilitation at seven hospitals from four states in India were invited to participate in consultative meetings. Existing treatment and rehabilitation strategies, barriers and enablers to patient flow across the continuum of care and details on inpatient and outpatient rehabilitation were discussed during the meetings. Seventeen health professionals from various clinical backgrounds were involved in the consultation process. Key themes highlighted (a) a lack of awareness on burn first aid at the community level, (b) a lack of human resource to treat burn injuries in hospital settings, (c) a gap in burn care training for medical staff, (d) poor hospital infrastructure and (e) a variation in treatment practices and rehabilitation services available between hospitals. A number of opportunities exist to improve burns treatment and rehabilitation in India. Improvements would most effectively be achieved through promoting multidisciplinary care across a number of facilities and service providers. Further research is required to develop context-specific burn care models, determining how these can be integrated into the Indian healthcare system

Clinical significance of VEGF-A, -C and -D expression in esophageal malignancies

Vascular endothelial growth factors ( VEGF)- A, - C and - D are members of the proangiogenic VEGF family of glycoproteins. VEGF-A is known to be the most important angiogenic factor under physiological and pathological conditions, while VEGF-C and VEGF-D are implicated in the development and sprouting of lymphatic vessels, so called lymphangiogenesis. Local tumor progression, lymph node metastases and hematogenous tumor spread are important prognostic factors for esophageal carcinoma ( EC), one of the most lethal malignancies throughout the world. We found solid evidence in the literature that VEGF expression contributes to tumor angiogenesis, tumor progression and lymph node metastasis in esophageal squamous cell carcinoma ( SCC), and many authors could show a prognostic value for VEGF-assessment. In adenocarcinoma (AC) of the esophagus angiogenic properties are acquired in early stages, particularly in precancerous lesions like Barrett's dysplasia. However, VEGF expression fails to give prognostic information in AC of the esophagus. VEGF-C and VEGF-D were detected in SCC and dysplastic lesions, but not in normal mucosa of the esophagus. VEGF-C expression might be associated with lymphatic tumor invasion, lymph node metastases and advanced disease in esophageal SCC and AC. Therapeutic interference with VEGF signaling may prove to be a promising way of anti-angiogenic co-treatment in esophageal carcinoma. However, concrete clinical data are still pending

Naïve CD8 + T cell derived tumor-specific cytotoxic effectors as a potential remedy for overcoming TGF-β immunosuppression in the tumor microenvironment

Despite of the potential implications for cancer immunotherapy, conventional approaches using in vitro expanded CD8 + T cells have suboptimal outcomes, mostly due to loss of functionality from cellular exhaustion. We therefore investigated the phenotypic and functional differences among in vitro activated CD8 + T cells of three different sources, namely naïve (NT eff), memory (MT eff) and tumor-infiltrating lymphocytes (TIL eff) from human and mice, to better understand mechanisms behind potent effector functions and potential for overcoming current limitations. In line with the greater proliferation activity and longer telomere lengths of NT eff populations, cells of naïve origin exhibited significantly less amounts of T cell exhaustion markers than those of MT eff and TIL eff, and moreover, acquired distinct expression patterns of memory-promoting transcription factors, T-bet and Eomes, induced in a rapid and sustainable manner. NT eff cells appeared to have lower expression of Foxp1 and were refractory to apoptosis upon TGF-β conditioning, implying better survival potential and resistance to tumor-induced immune suppression. Of CD8 + T cell pools activated to tumor-specific CTLs, naïve cell generated effectors possessed the most potent cytotoxic activity, validating implications for use in rational design of adoptive immunotherapy11091sciescopu

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types

Mucin Secretion Induced by Titanium Dioxide Nanoparticles

Nanoparticle (NP) exposure has been closely associated with the exacerbation and pathophysiology of many respiratory diseases such as Chronic Obstructive Pulmonary Disease (COPD) and asthma. Mucus hypersecretion and accumulation in the airway are major clinical manifestations commonly found in these diseases. Among a broad spectrum of NPs, titanium dioxide (TiO2), one of the PM10 components, is widely utilized in the nanoindustry for manufacturing and processing of various commercial products. Although TiO2 NPs have been shown to induce cellular nanotoxicity and emphysema-like symptoms, whether TiO2 NPs can directly induce mucus secretion from airway cells is currently unknown. Herein, we showed that TiO2 NPs (<75 nm) can directly stimulate mucin secretion from human bronchial ChaGo-K1 epithelial cells via a Ca2+ signaling mediated pathway. The amount of mucin secreted was quantified with enzyme-linked lectin assay (ELLA). The corresponding changes in cytosolic Ca2+ concentration were monitored with Rhod-2, a fluorescent Ca2+ dye. We found that TiO2 NP-evoked mucin secretion was a function of increasing intracellular Ca2+ concentration resulting from an extracellular Ca2+ influx via membrane Ca2+ channels and cytosolic ER Ca2+ release. The calcium-induced calcium release (CICR) mechanism played a major role in further amplifying the intracellular Ca2+ signal and in sustaining a cytosolic Ca2+ increase. This study provides a potential mechanistic link between airborne NPs and the pathoetiology of pulmonary diseases involving mucus hypersecretion

Azimuthal asymmetry in the risetime of the surface detector signals of the Pierre Auger Observatory

The azimuthal asymmetry in the risetime of signals in Auger surface detector stations is a source of information on shower development. The azimuthal asymmetry is due to a combination of the longitudinal evolution of the shower and geometrical effects related to the angles of incidence of the particles into the detectors. The magnitude of the effect depends upon the zenith angle and state of development of the shower and thus provides a novel observable, $(\sec \theta)_\mathrm{max}$, sensitive to the mass composition of cosmic rays above $3 \times 10^{18}$ eV. By comparing measurements with predictions from shower simulations, we find for both of our adopted models of hadronic physics (QGSJETII-04 and EPOS-LHC) an indication that the mean cosmic-ray mass increases slowly with energy, as has been inferred from other studies. However, the mass estimates are dependent on the shower model and on the range of distance from the shower core selected. Thus the method has uncovered further deficiencies in our understanding of shower modelling that must be resolved before the mass composition can be inferred from $(\sec \theta)_\mathrm{max}$.Comment: Replaced with published version. Added journal reference and DO

THE DATA REDUCTION PIPELINE FOR THE APACHE POINT OBSERVATORY GALACTIC EVOLUTION EXPERIMENT

The Apache Point Observatory Galactic Evolution Experiment (APOGEE), part of the Sloan Digital Sky Survey III, explores the stellar populations of the Milky Way using the Sloan 2.5-m telescope linked to a high resolution (R ~ 22,500), near-infrared (1.51–1.70 µm) spectrograph with 300 optical fibers. For over 150,000 predominantly red giant branch stars that APOGEE targeted across the Galactic bulge, disks and halo, the collected high signal-to-noise ratio (>100 per half-resolution element) spectra provide accurate (~0.1 km s-1) RVs, stellar atmospheric parameters, and precise (lesssim0.1 dex) chemical abundances for about 15 chemical species. Here we describe the basic APOGEE data reduction software that reduces multiple 3D raw data cubes into calibrated, well-sampled, combined 1D spectra, as implemented for the SDSS-III/APOGEE data releases (DR10, DR11 and DR12). The processing of the near-IR spectral data of APOGEE presents some challenges for reduction, including automated sky subtraction and telluric correction over a 3°-diameter field and the combination of spectrally dithered spectra. We also discuss areas for future improvement