Metaplasia arises from differentiated cell types in response to injury and is considered a precursor in many cancers. Heterogeneous cell lineages are present in the reparative metaplastic mucosa with ...response to injury, including foveolar cells, proliferating cells and spasmolytic polypeptide-expressing metaplasia (SPEM) cells, a key metaplastic cell population. Zymogen-secreting chief cells are long-lived cells in the stomach mucosa and have been considered the origin of SPEM cells; however, a conflicting paradigm has proposed isthmal progenitor cells as an origin for SPEM.
Gastric intrinsic factor (GIF) is a stomach tissue-specific gene and exhibits protein expression unique to mature mouse chief cells. We generated a novel chief cell-specific driver mouse allele, GIF-rtTA. GIF-GFP reporter mice were used to validate specificity of GIF-rtTA driver in chief cells. GIF-Cre-RnTnG mice were used to perform lineage tracing during homoeostasis and acute metaplasia development. L635 treatment was used to induce acute mucosal injury and coimmunofluorescence staining was performed for various gastric lineage markers.
We demonstrated that mature chief cells, rather than isthmal progenitor cells, serve as the predominant origin of SPEM cells during the metaplastic process after acute mucosal injury. Furthermore, we observed long-term label-retaining chief cells at 1 year after the GFP labelling in chief cells. However, only a very small subset of the long-term label-retaining chief cells displayed the reprogramming ability in homoeostasis. In contrast, we identified chief cell-originating SPEM cells as contributing to lineages within foveolar cell hyperplasia in response to the acute mucosal injury.
Our study provides pivotal evidence for cell plasticity and lineage contributions from differentiated gastric chief cells during acute metaplasia development.
Kiruna-type apatite-iron-oxide ores are key iron sources for modern industry, yet their origin remains controversial. Diverse ore-forming processes have been discussed, comprising low-temperature ...hydrothermal processes versus a high-temperature origin from magma or magmatic fluids. We present an extensive set of new and combined iron and oxygen isotope data from magnetite of Kiruna-type ores from Sweden, Chile and Iran, and compare them with new global reference data from layered intrusions, active volcanic provinces, and established low-temperature and hydrothermal iron ores. We show that approximately 80% of the magnetite from the investigated Kiruna-type ores exhibit δ
Fe and δ
O ratios that overlap with the volcanic and plutonic reference materials (> 800 °C), whereas ~20%, mainly vein-hosted and disseminated magnetite, match the low-temperature reference samples (≤400 °C). Thus, Kiruna-type ores are dominantly magmatic in origin, but may contain late-stage hydrothermal magnetite populations that can locally overprint primary high-temperature magmatic signatures.
Severe injury to the lining of the stomach leads to changes in the epithelium (reprogramming) that protect and promote repair of the tissue, including development of spasmolytic ...polypeptide-expressing metaplasia (SPEM) and tuft and foveolar cell hyperplasia. Acute gastric damage elicits a type-2 inflammatory response that includes production of type-2 cytokines and infiltration by eosinophils and alternatively activated macrophages. Stomachs of mice that lack interleukin 33 (IL33) or interleukin 13 (IL13) did not undergo epithelial reprogramming after drug-induced injury. We investigated the role of group 2 innate lymphoid cells (ILC2s) in gastric epithelial repair.
Acute gastric injury was induced in C57BL/6J mice (wild-type and RAG1 knockout) by administration of L635. We isolated ILC2s by flow cytometry from stomachs of mice that were and were not given L635 and performed single-cell RNA sequencing. ILC2s were depleted from wild-type and RAG1-knockout mice by administration of anti-CD90.2. We assessed gastric cell lineages, markers of metaplasia, inflammation, and proliferation. Gastric tissue microarrays from patients with gastric adenocarcinoma were analyzed by immunostaining.
There was a significant increase in the number of GATA3-positive ILC2s in stomach tissues from wild-type mice after L635-induced damage, but not in stomach tissues from IL33-knockout mice. We characterized a marker signature of gastric mucosal ILC2s and identified a transcription profile of metaplasia-associated ILC2s, which included changes in expression of Il5, Il13, Csf2, Pd1, and Ramp3; these changes were validated by quantitative polymerase chain reaction and immunocytochemistry. Depletion of ILC2s from mice blocked development of metaplasia after L635-induced injury in wild-type and RAG1-knockout mice and prevented foveolar and tuft cell hyperplasia and infiltration or activation of macrophages after injury. Numbers of ILC2s were increased in stomach tissues from patients with SPEM compared with patients with normal corpus mucosa.
In analyses of stomach tissues from mice with gastric tissue damage and patients with SPEM, we found evidence of type 2 inflammation and increased numbers of ILC2s. Our results suggest that ILC2s coordinate the metaplastic response to severe gastric injury.
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Mesenchymal stem cells (MSC) have a therapeutic potential in patients with fractures to reduce the time of healing and treat nonunions. The use of MSC to treat fractures is attractive for several ...reasons. First, MSCs would be implementing conventional reparative process that seems to be defective or protracted. Secondly, the effects of MSCs treatment would be needed only for relatively brief duration of reparation. However, an integrated approach to define the multiple regenerative contributions of MSC to the fracture repair process is necessary before clinical trials are initiated. In this study, using a stabilized tibia fracture mouse model, we determined the dynamic migration of transplanted MSC to the fracture site, their contributions to the repair process initiation, and their role in modulating the injury‐related inflammatory responses. Using MSC expressing luciferase, we determined by bioluminescence imaging that the MSC migration at the fracture site is time‐ and dose‐dependent and, it is exclusively CXCR4‐dependent. MSC improved the fracture healing affecting the callus biomechanical properties and such improvement correlated with an increase in cartilage and bone content, and changes in callus morphology as determined by micro‐computed tomography and histological studies. Transplanting CMV‐Cre‐R26R‐Lac Z‐MSC, we found that MSCs engrafted within the callus endosteal niche. Using MSCs from BMP‐2‐Lac Z mice genetically modified using a bacterial artificial chromosome system to be β‐gal reporters for bone morphogenic protein 2 (BMP‐2) expression, we found that MSCs contributed to the callus initiation by expressing BMP‐2. The knowledge of the multiple MSC regenerative abilities in fracture healing will allow design of novel MSC‐based therapies to treat fractures. STEM CELLS 2009;27:1887–1898
Summary Objective To determine if type III collagen is concentrated in the chymotrypsin-extractable collagen pool from osteoarthritic articular cartilage to assess its potential as a biomarker of ...Osteoarthritis (OA) pathogenic mechanisms. Methods Full thickness articular cartilage from grossly normal surfaces was analyzed from femoral heads, obtained at hip replacement surgery, from OA ( n = 10) and fracture ( n = 10) patients. Collagen, extracted by α-chymotrypsin, was characterized by SDS-PAGE/Western blot analysis, ELISA and immunohistochemistry using monoclonal antibodies specific to collagens types II and III. Results α-Chymotrypsin extracted more collagen from OA than control cartilage. The extractable pool included collagen types II and III from both OA and control hips. Importantly, OA cartilage contained 6-fold more collagen type III than control cartilage, based on ELISA. The estimated total tissue ratio of collagen III/II was in the 1–10% range for individual OA cartilage samples, based on pepsin-solubilized collagen using SDS-PAGE densitometry. Collagen type III N-propeptide trimers were the main molecular fragments seen on Western blot analysis of OA and control extracts. The chymotrypsin-extracted type II collagen gave primarily full-length α1(II) chains and chain fragments of α1(II) on Western blot analysis from both OA and control tissues. Immunohistochemistry showed that type III collagen was more concentrated in the upper half of OA cartilage and in the territorial matrix around individual chondrocytes and chondrocyte clusters. Conclusions The findings confirm that collagen type III deposition occurs in adult articular cartilage but significantly more pronounced in osteoarthritic joints, presenting a potential marker of matrix repair or pathobiology.
Although there are considerable data on the use of mathematical modeling to describe tumor growth and response to therapy, previous approaches are often not of the form that can be easily applied to ...clinical data to generate testable predictions in individual patients. Thus, there is a clear need to develop and apply clinically relevant oncologic models that are amenable to available patient data and yet retain the most salient features of response prediction. In this study we show how a biomechanical model of tumor growth can be initialized and constrained by serial patient-specific magnetic resonance imaging data, obtained at two time points early in the course of therapy (before initiation and following one cycle of therapy), to predict the response for individual patients with breast cancer undergoing neoadjuvant therapy. Using our mechanics coupled modeling approach, we are able to predict, after the first cycle of therapy, breast cancer patients that would eventually achieve a complete pathologic response and those who would not, with receiver operating characteristic area under the curve (AUC) of 0.87, sensitivity of 92%, and specificity of 84%. Our approach significantly outperformed the AUCs achieved by standard (i.e., not mechanically coupled) reaction-diffusion predictive modeling (0.75), simple analysis of the tumor cellularity estimated from imaging data (0.73), and the Response Evaluation Criteria in Solid Tumors (0.71). Thus, we show the potential for mathematical model prediction for use as a prognostic indicator of response to therapy. The work indicates the considerable promise of image-driven biophysical modeling for predictive frameworks within therapeutic applications.
Purpose
Fatty acid-binding protein 5 (FABP5), a transport protein for lipophilic molecules, has been proposed as protein marker in prostate cancer (PCa). The role of
FABP5
gene expression is merely ...unknown.
Methods
In two cohorts of PCa patients who underwent radical prostatectomy (
n
= 40 and
n
= 57) and one cohort of patients treated with palliative transurethral resection of the prostate (pTUR-P;
n
= 50)
FABP5
mRNA expression was analyzed with qRT-PCR. Expression was correlated with clinical parameters. BPH tissue samples served as control. To independently validate findings on
FABP5
expression, three microarray and sequencing datasets were reanalyzed (MSKCC 2010
n
= 216; TCGA 2015
n
= 333; mCRPC, Nature Medicine 2016
n
= 114). FABP5 expression was correlated with
ERG
-fusion status, TCGA subtypes, cancer driver mutations and the expression of druggable downstream pathway components.
Results
FABP5
was overexpressed in PCa compared to BPH in the cohorts analyzed by qRT-PCR (radical prostatectomy
p
= 0.003,
p
= 0.010; pTUR-P
p
= 0.002).
FABP5
expression was independent of T stage, Gleason Score, nodal status and PSA level.
FABP5
overexpression was associated with the absence of
TMPRSS2:ERG
fusion (
p
< 0.001 in TCGA and MSKCC). Correlation with TCGA subtypes revealed
FABP5
overexpression to be associated with
SPOP
and
FOXA1
mutations.
FABP5
was positively correlated with potential drug targets located downstream of
FABP5
in the PPAR-signaling pathway.
Conclusion
FABP5
overexpression is frequent in PCa, but seems to be restricted to
TMPRESS2:ERG
fusion-negative tumors and is associated with
SPOP
and
FOXA1
mutations.
FABP5
overexpression appears to be indicative for increased activity in PPAR signaling, which is potentially druggable.
Infrared spectra of carbon-rich objects that have evolved off the asymptotic giant branch reveal a range of dust properties, including fullerenes, polycyclic aromatic hydrocarbons (PAHs), aliphatic ...hydrocarbons, and several unidentified features, including the 21 mu m emission feature. To test for the presence of fullerenes, we used the position and width of the feature at 18.7-18.9 mu m and examined other features at 17.4 and 6-9 mu m. This method adds three new fullerene sources to the known sample, but it also calls into question three previous identifications. We confirm that the strong 11 mu m features seen in some sources arise primarily from SiC, which may exist as a coating around carbonaceous cores and result from photo-processing. Spectra showing the 21 mu m feature usually show the newly defined Class D PAH profile at 7-9 mu m. These spectra exhibit unusual PAH profiles at 11-14 mu m, with weak contributions at 12.7 mu m, which we define as Class D1, or show features shifted to ~11.4, 12.4, and 13.2 mu m, which we define as Class D2. Alkyne hydrocarbons match the 15.8 mu m feature associated with 21 mu m emission. Sources showing fullerene emission but no PAHs have blue colors in the optical, suggesting a clear line of sight to the central source. Spectra with 21 mu m features and Class D2 PAH emission also show photometric evidence for a relatively clear line of sight to the central source. The multiple associations of the 21 mu m feature with aliphatic hydrocarbons suggest that the carrier is related to this material in some way
Light (pseudo-)scalar fields are promising candidates to be the dark matter in the Universe. Under certain initial conditions in the early Universe and/or with certain types of self-interactions, ...they can form compact dark-matter objects such as axion stars or Q-balls. Direct encounters with such objects can be searched for by using a global network of atomic magnetometers. It is shown that for a range of masses and radii not ruled out by existing observations, the terrestrial encounter rate with axion stars or Q-balls can be sufficiently high (at least once per year) for a detection. Furthermore, it is shown that a global network of atomic magnetometers is sufficiently sensitive to pseudoscalar couplings to atomic spins so that a transit through an axion star or Q-ball could be detected over a broad range of unexplored parameter space.
Gene flow is generally considered a random process, that is the loci under consideration have no effect on dispersal success. Edelaar and Bolnick (Trends Ecol Evol, 27, 2012 659) recently argued that ...nonrandom gene flow could exert a significant evolutionary force. It can, for instance, ameliorate the maladaptive effects of immigration into locally adapted populations. I examined the potential strength for nonrandom gene flow for flowering time genes, a trait frequently found to be locally adapted. The idea is that plants that successfully export pollen into a locally adapted resident population will be a genetically biased subset of their natal population – they will have resident‐like flowering times. Reciprocally, recipients will be more migrant‐like than the resident population average. I quantified the potential for biased pollen exchange among three populations along a flowering time cline in Brassica rapa from southern California. A two‐generation line cross experiment demonstrated genetic variance in flowering time, both within and among populations. Calculations based on the variation in individual flowering schedules showed that resident plants with the most migrant‐like flowering times could expect to have up to 10 times more of the their flowers pollinated by immigrant pollen than the least migrant‐like. Further, the mean flowering time of the pollen exporters that have access to resident mates differs by up to 4 weeks from the mean in the exporters’ natal population. The data from these three populations suggest that the bias in gene flow for flowering time cuts the impact on the resident population by as much as half. This implies that when selection is divergent between populations, migrants with the highest mating success tend to be resident‐like in their flowering times, and so, fewer maladaptive alleles will be introduced into the locally adapting gene pool.
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