Comparison of Epithelial Differentiation and Immune Regulatory Properties of Mesenchymal Stromal Cells Derived from Human Lung and Bone Marrow

Mesenchymal stromal cells (MSCs) reside in many organs including lung, as shown by their isolation from fetal lung tissues, bronchial stromal compartment, bronchial-alveolar lavage and transplanted lung tissues. It is still controversial whether lung MSCs can undergo mesenchymal-to-epithelial-transition (MET) and possess immune regulatory properties. To this aim, we isolated, expanded and characterized MSCs from normal adult human lung (lung-hMSCs) and compared with human bone marrow-derived MSCs (BM-hMSCs). Our results show that lung-MSCs reside at the perivascular level and do not significantly differ from BM-hMSCs in terms of immunophenotype, stemness gene profile, mesodermal differentiation potential and modulation of T, B and NK cells. However, lung-hMSCs express higher basal level of the stemness-related marker nestin and show, following in vitro treatment with retinoic acid, higher epithelial cell polarization, which is anyway partial when compared to a control epithelial bronchial cell line. Although these results question the real capability of acquiring epithelial functions by MSCs and the feasibility of MSC-based therapeutic approaches to regenerate damaged lung tissues, the characterization of this lung-hMSC population may be useful to study the involvement of stromal cell compartment in lung diseases in which MET plays a role, such as in chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis

Vitamin A derivatives in the prevention and treatment of human cancer.

Vitamin A is essential for normal cellular growth and differentiation. A vast amount of laboratory data have clearly demonstrated the potent antiproliferative and differentiation-inducing effects of vitamin A and the synthetic analogues (retinoids). Recent in-vitro work has led to the exciting proposal that protein kinase-C may be centrally involved in many of retinoids' anticancer actions including the effects on ornithine decarboxylase induction, intracellular polyamine levels, and epidermal growth factor receptor number. Several intervention trials have clearly indicated that natural vitamin A at clinically tolerable doses has only limited activity against human neoplastic processes. Therefore, clinical work has focused on the synthetic derivatives with higher therapeutic indexes. In human cancer prevention, retinoids have been most effective for skin diseases, including actinic keratosis, keratoacanthoma, epidermodysplasia verruciformis, dysplastic nevus syndrome, and basal cell carcinoma. Several noncutaneous premaligancies, however, are currently receiving more attention in retinoid trials. Definite retinoid activity has been documented in oral leukoplakia, laryngeal papillomatosis, superficial bladder carcinoma, cervical dysplasia, bronchial metaplasia, and preleukemia. Significant therapeutic advances are also occurring with this class of drugs in some drug-resistant malignancies and several others that have become refractory, including advanced basal cell cancer, mycosis fungoides, melanoma, acute promyelocytic leukemia, and squamous cell carcinoma of the skin and of the head and neck. This report comprehensively presents the clinical data using retinoids as anticancer agents in human premalignant disorders and outlines the ongoing and planned studies with retinoids in combination and adjuvant therapy

Extraordinary biomass-burning episode and impact winter triggered by the younger dryas cosmic impact ∼12,800 years ago. 1. Ice cores and glaciers

The Younger Dryas boundary (YDB) cosmic-impact hypothesis is based on considerable evidence that Earth collided with fragments of a disintegrating ≥100-km-diameter comet, the remnants of which persist within the inner solar system ∼12,800 y later. Evidence suggests that the YDB cosmic impact triggered an “impact winter” and the subsequent Younger Dryas (YD) climate episode, biomass burning, late Pleistocene megafaunal extinctions, and human cultural shifts and population declines. The cosmic impact deposited anomalously high concentrations of platinum over much of the Northern Hemisphere, as recorded at 26 YDB sites at the YD onset, including the Greenland Ice Sheet Project 2 ice core, in which platinum deposition spans ∼21 y (∼12,836–12,815 cal BP). The YD onset also exhibits increased dust concentrations, synchronous with the onset of a remarkably high peak in ammonium, a biomass-burning aerosol. In four ice-core sequences from Greenland, Antarctica, and Russia, similar anomalous peaks in other combustion aerosols occur, including nitrate, oxalate, acetate, and formate, reflecting one of the largest biomass-burning episodes in more than 120,000 y. In support of widespread wildfires, the perturbations in CO2 records from Taylor Glacier, Antarctica, suggest that biomass burning at the YD onset may have consumed ∼10 million km2, or ∼9% of Earth’s terrestrial biomass. The ice record is consistent with YDB impact theory that extensive impact-related biomass burning triggered the abrupt onset of an impact winter, which led, through climatic feedbacks, to the anomalous YD climate episode

Extraordinary biomass-burning episode and impact winter triggered by the younger dryas cosmic impact ∼12,800 years ago. 2. Lake, marine, and terrestrial sediments

Part 1 of this study investigated evidence of biomass burning in global ice records, and here we continue to test the hypothesis that an impact event at the Younger Dryas boundary (YDB) caused an anomalously intense episode of biomass burning at ∼12.8 ka on a multicontinental scale (North and South America, Europe, and Asia). Quantitative analyses of charcoal and soot records from 152 lakes, marine cores, and terrestrial sequences reveal a major peak in biomass burning at the Younger Dryas (YD) onset that appears to be the highest during the latest Quaternary. For the Cretaceous-Tertiary boundary (K-Pg) impact event, concentrations of soot were previously utilized to estimate the global amount of biomass burned, and similar measurements suggest that wildfires at the YD onset rapidly consumed ∼10 million km of Earth’s surface, or ∼9% of Earth’s biomass, considerably more than for the K-Pg impact. Bayesian analyses and age regressions demonstrate that ages for YDB peaks in charcoal and soot across four continents are synchronous with the ages of an abundance peak in platinum in the Greenland Ice Sheet Project 2 (GISP2) ice core and of the YDB impact event (12,835–12,735 cal BP). Thus, existing evidence indicates that the YDB impact event caused an anomalously large episode of biomass burning, resulting in extensive atmospheric soot/dust loading that triggered an “impact winter.” This, in turn, triggered abrupt YD cooling and other climate changes, reinforced by climatic feedback mechanisms, including Arctic sea ice expansion, rerouting of North American continental runoff, and subsequent ocean circulation changes.

Nanodiamond-rich layer across three continents consistent with major cosmic impact at 12,800 cal BP

A major cosmic-impact event has been proposed at the onset of the Younger Dryas (YD) cooling episode at ≈12,800 ± 150 years before present, forming the YD Boundary (YDB) layer, distributed over 150 million km2 on four continents. In 24 dated stratigraphic sections in 10 countries of the Northern Hemisphere, the YDB layer contains a clearly defined abundance peak in nanodiamonds (NDs), a major cosmic-impact proxy. Observed ND polytypes include cubic diamonds, lonsdaleite-like crystals, and diamond-like carbon nanoparticles, called n-diamond and i-carbon. The ND abundances in bulk YDB sediments ranged up to ≈500 ppb (mean: 200 ppb) and that in carbon spherules up to ≈3700 ppb (mean: ≈750 ppb); 138 of 205 sediment samples (67%) contained no detectable NDs. Isotopic evidence indicates that YDB NDs were produced from terrestrial carbon, as with other impact diamonds, and were not derived from the impactor itself. The YDB layer is also marked by abundance peaks in other impact-related proxies, including cosmic-impact spherules, carbon spherules (some containing NDs), iridium, osmium, platinum, charcoal, aciniform carbon (soot), and high-temperature melt-glass. This contribution reviews the debate about the presence, abundance, and origin of the concentration peak in YDB NDs.We describe an updated protocol for the extraction and concentration of NDs from sediment, carbon spherules, and ice, and we describe the basis for identification and classification of YDB ND polytypes, using nine analytical approaches. The large body of evidence now obtained about YDB NDs is strongly consistent with an origin by cosmic impact at ≈12,800 cal BP and is inconsistent with formation of YDB NDs by natural terrestrial processes, including wildfires, anthropogenesis, and/or influx of cosmic dust