Personal risk or societal benefit? Investigating adults' support for COVID-19 childhood vaccination.

Parental hesitancy poses a serious threat to the success of the COVID-19 childhood vaccination campaign. We investigate whether adults' opinions on childhood vaccination can be influenced via two survey experiments in Italy (n = 3,633 participants) and the UK (n = 3,314 participants). Respondents were randomly assigned to: a "risk treatment" that highlighted the potential risks of COVID-19 to a child, a "herd immunity treatment" that emphasized the community benefits of pediatric vaccination, or a control message. Participants' probability of supporting COVID-19 childhood vaccination was then assessed on a 0-100 scale. We find that the "risk treatment" reduced the proportion of Italian parents strongly against vaccination by up to 29.6 %, while increasing the proportion of neutral parents by up to 45.0 %. The "herd immunity treatment", instead, was only effective among non-parents, resulting in a lower proportion of individuals against pediatric vaccination and a higher proportion of individuals in favor (both shifted by around 20 %).

Deep denoising for multi-dimensional synchrotron X-ray tomography without high-quality reference data.

Synchrotron X-ray tomography enables the examination of the internal structure of materials at submicron spatial resolution and subsecond temporal resolution. Unavoidable experimental constraints can impose dose and time limits on the measurements, introducing noise in the reconstructed images. Convolutional neural networks (CNNs) have emerged as a powerful tool to remove noise from reconstructed images. However, their training typically requires collecting a dataset of paired noisy and high-quality measurements, which is a major obstacle to their use in practice. To circumvent this problem, methods for CNN-based denoising have recently been proposed that require no separate training data beyond the already available noisy reconstructions. Among these, the Noise2Inverse method is specifically designed for tomography and related inverse problems. To date, applications of Noise2Inverse have only taken into account 2D spatial information. In this paper, we expand the application of Noise2Inverse in space, time, and spectrum-like domains. This development enhances applications to static and dynamic micro-tomography as well as X-ray diffraction tomography. Results on real-world datasets establish that Noise2Inverse is capable of accurate denoising and enables a substantial reduction in acquisition time while maintaining image quality.

Molecular Detection of EMT Markers in Circulating Tumor Cells from Metastatic Non-Small Cell Lung Cancer Patients: Potential Role in Clinical Practice.

BACKGROUND: Non-small cell lung cancer (NSCLC) is the most common cause of cancer-related mortality; nevertheless, there are few data regarding detection of circulating tumor cells (CTCs) in NSCLC, compared to other kinds of cancers in which their prognostic roles have already been defined. This difference is likely due to detection methods based on the epithelial marker expression which ignore CTCs undergoing epithelial-mesenchymal transition (CTCsEMT). METHODS: After optimization of the test with spiking experiments of A549 cells undergoing TGF-ß1-induced EMT (A549EMT), the CTCsEMT were enriched by immunomagnetic depletion of leukocytes and then characterized by a RT-PCR assay based on the retrieval of epithelial and EMT-related genes. Blood samples from ten metastatic NSCLC patients before starting treatment and during chemotherapy were used to test this approach by longitudinal monitoring. Ten age- and sex-matched healthy subjects were also enrolled as controls. RESULTS: Recovery experiments of spiked A549EMT cells showed that the RT-PCR assay is a reliable method for detection of CTCsEMT. CTCsEMT were detected in three patients at baseline and in six patients after four cycles of cysplatin-based chemotherapy. Longitudinal monitoring of three patients showed that the CTCsEMT detection is related to poor therapeutic response. CONCLUSIONS: The RT-PCR-based approach for the evaluation of CTCsEMT phenotype could be a promising and inexpensive tool to predict the prognosis and the therapeutic response in NSCLC patients.

Extracorporeal Shock Wave Treatment (ESWT) enhances the in vitro-induced differentiation of human tendon-derived stem/progenitor cells (hTSPCs).

Extracorporeal shock wave therapy (ESWT) is a non-invasive and innovative technology for the management of specific tendinopathies. In order to elucidate the ESWT-mediated clinical benefits, human Tendon-derived Stem/Progenitor cells (hTSPCs) explanted from 5 healthy semitendinosus (ST) and 5 ruptured Achilles (AT) tendons were established. While hTSPCs from the two groups showed similar proliferation rates and stem cell surface marker profiles, we found that the clonogenic potential was maintained only in cells derived from healthy donors. Interestingly, ESWT significantly accelerated hTSPCs differentiation, suggesting that the clinical benefits of ESWT may be ascribed to increased efficiency of tendon repair after injury.

Klebsiella pneumoniae Is Able to Trigger Epithelial-Mesenchymal Transition Process in Cultured Airway Epithelial Cells.

The ability of some bacterial pathogens to activate Epithelial-Mesenchymal Transition normally is a consequence of the persistence of a local chronic inflammatory response or depends on a direct interaction of the pathogens with the host epithelial cells. In this study we monitored the abilities of the K. pneumoniae to activate the expression of genes related to EMT-like processes and the occurrence of phenotypic changes in airway epithelial cells during the early steps of cell infection. We describe changes in the production of intracellular reactive oxygen species and increased HIF-1α mRNA expression in cells exposed to K. pneumoniae infection. We also describe the upregulation of a set of transcription factors implicated in the EMT processes, such as Twist, Snail and ZEB, indicating that the morphological changes of epithelial cells already appreciable after few hours from the K. pneumoniae infection are tightly regulated by the activation of transcriptional pathways, driving epithelial cells to EMT. These effects appear to be effectively counteracted by resveratrol, an antioxidant that is able to exert a sustained scavenging of the intracellular ROS. This is the first report indicating that strains of K. pneumoniae may promote EMT-like programs through direct interaction with epithelial cells without the involvement of inflammatory cells.

Carbapenem resistance confers to Klebsiella pneumoniae strains an enhanced ability to induce infection and cell death in epithelial tissue-specific in vitro models.

BACKGROUND: Carbapenem-resistant Klebsiella pneumoniae strains (KPC-Kp) are emerging worldwide causing different nosocomial infections including those of the urinary tract, lung or skin wounds. For these strains, the antibiotic treatment is limited to only few choices including colistin, whose continuous use led to the emergence of carbapenem-resistant KPC-Kp strains resistant also to this treatment (KPC-Kp Col-R). AIM: Very little is known about the capacity of the different strains of KPC-Kp to invade the epithelial cells in vitro. To verify if the acquisition of carbapenem-resistant and the colistin-resistant phenotypes are correlated with a different ability to infect a series of epithelial cell lines of various tissutal origin and with a different capacity to induce cellular death. MATERIALS & METHODS: We used Klebsiella pneumoniae (KP), KPC-Kp and KPC-Kp Col-R strains, isolated from different patients carrying various tissue-specific infections, to infect a series of epithelial cell lines of different tissutal origin. The invasive capacity of the strains and the extent and characteristics of the cell damage and death induced by the bacteria were evaluated and compared. CONCLUSION: Our results show that both KPC-Kp and KPC-Kp Col-R display a greater ability to infect the epithelial cells, with respect to KP, and that the bacterial cell invasion results in a nonprogrammed cell death.

Circulating tumor cells count predicts survival in colorectal cancer patients.

BACKGROUND AND AIMS: Data on the potential of circulating tumor cells (CTC) count in predicting overall survival (OS) in patients with colorectal cancer are timely and worthy of interest. This study aimed to evaluate the prognostic role of CTC count in both localized and metastatic colorectal cancer patients. METHODS: Consecutive patients with histological diagnosis of colorectal cancer were enrolled. CTC count was performed, by using a quantitative immunofluorescence method, at baseline (T0) and 1 month following start of chemotherapy (T1). A CTC count <2 was considered negative, whilst a CTC level >/= 2 was positive. Overall survival was calculated accordingly. RESULTS: A total of 75 colorectal cancer patients were enrolled, including 54 stages I-III and 21 stage IV patients. Overall, 21 (28%) patients had a positive CTC count at baseline, and it was significantly associated with a worse prognosis as compared to a negative status (OS: 36.2 vs. 61.6 months; P = 0.002). CTC count remained positive after chemotherapy in 22.4% of the patients and it was an independent prognostic factor of OS (P = 0.03; Hazard Ratio: 3.55; 95% CI: 1.1-11.5). CONCLUSIONS: This study found that the presence of CTCs is associated with a reduced survival in colorectal cancer patients. Further studies aimed at testing such a predictive value in early stage colorectal cancer are awaited.

Cell wall composition of Bacillus subtilis changes as a function of pH and Zn²âº exposure: insights from cryo-XPS measurements.

Bacteria play an important role in the biogeochemical cycling of metals in the environment. Consequently, there is an interest to understand how the bacterial surfaces interact with metals in solution and how this affects the bacterial surface. In this work we have used a surface-sensitive analysis technique, cryogenic X-ray photoelectron spectroscopy (cryo-XPS), to monitor the surface of Bacillus subtilis cells as a function of pH and Zn(2+) content in saline solution. The objective of the study was twofold: (1) to investigate the agreement between two data treatment methods for XPS, as well as investigate to what extent sample pretreatment may influence XPS data of bacterial samples, and (2) to characterize how the surface chemistry of bacterial cells is influenced by different external conditions. (1) It was found that the two data treatment methods gave rise to comparable results. However, identical samples analyzed fast-frozen or dry exhibited larger differences in surface chemistry, indicating that sample pretreatment can to large extents influence the obtained surface composition of bacterial samples. (2) The bacterial cell wall (in fast-frozen samples) undergoes dramatic compositional changes with pH and with Zn(2+) exposure. The compositional changes are interpreted as an adaptive metal resistance response changing the biochemical composition of the bacterial cell wall. These results have implications for how adsorption processes at the surface of bacterial cells are analyzed, understood, modeled, and predicted.

Decreased expression of autophagic beclin 1 protein in idiopathic pulmonary fibrosis fibroblasts.

Autophagy is the main cellular pathway for degradation of long-lived proteins and organelles and regulates cell fate in response to stress. Beclin 1 is a key regulator of this process. In some settings autophagy and apoptosis seem to be interconnected. Recent reports indicate that fibroblasts in idiopathic pulmonary fibrosis (IPF) acquire resistance to apoptosis. Here, we examined the expression of beclin 1, and of the anti apoptotic protein Bcl-2 in human IPF fibroblasts using immunohistochemistry and molecular biology in bioptic sections, in primary cultures of fibroblasts taken from patients with IPF and in fibroblast cell lines. Expression of beclin 1 in fibroblasts from IPF was down-regulated in comparison with fibroblasts from normal lungs while the anti-apoptotic protein Bcl-2 expression was over-expressed. Treatment of fibroblast cell cultures with cisplatin induced a significant increase in beclin 1 and caspase 3 protein levels but a reduction in Bcl-2 expression. These observations were confirmed by the analysis of acid compartments and transmission electron microscopy. Our results demonstrate a modified expression of the apoptotic beclin 1 Bcl-2 proteins in human IPF fibroblasts suggesting the existence of an autophagy/apoptosis system dysfunction.

Extracorporeal Shock Wave Treatment (ESWT) improves in vitro functional activities of ruptured human tendon-derived tenocytes.

In vitro models of human tenocytes derived from healthy as well as from ruptured tendons were established, characterized and used at very early passage (P1) to evaluate the effects of Extracorporeal Shock Wave Treatment (ESWT). The molecular analysis of traditional tenocytic markers, including Scleraxis (Scx), Tenomodulin (Tnm), Tenascin-C (Tn-C) and Type I and III Collagens (Col I and Col III), permitted us to detect in our samples the simultaneous expression of all these genes and allowed us to compare their levels of expression in relationship to the source of the cells and treatments. In untreated conditions, higher molecular levels of Scx and Col I in tenocytes from pathological compared to healthy samples have been detected, suggesting--in the cells from injured tendon--the natural trigger of an early differentiation and repairing program, which depends by Scx and requires an increase in collagen expression. When ESWT (at the dose of 0.14 mJ/mm(2)) was applied to cultured tenocytes explanted from injured source, Scx and Col I were significantly diminished compared to healthy counterpart, indicating that such natural trigger maybe delayed by the treatment, in order to promote cellular repair. Herein, we show for the first time that ESWT enhances in vitro functional activities of ruptured tendon-derived tenocytes, such as proliferation and migration, which could probably contributes to tendon healing in vivo.

Characterization of primary cultures of cholesteatoma-associated fibroblasts.

OBJECTIVES: The aim of this study was to characterize primary cultured fibroblasts derived from cholesteatoma (CHO) tissue to get evidence of their possible role for determining the different biological behavior of this aural pathology. MATERIALS AND METHODS: Primary cultures of human fibroblasts were obtained from middle ear CHO specimens and from controls of normal human skin collected during surgical procedures. Cells were incubated with anti-vimentin monoclonal antibody, anti-cytokeratins monoclonal antibody and anti-α-smooth muscle actin monoclonal antibody. For reactive oxygen species detection, fibroblasts were incubated with 2',7'-dichlorofluorescein diacetate. Immunofluorescence, flow cytometry, confocal, and transmission electron microscopy were carried out. RESULTS: Cholesteatoma-associated fibroblasts (CHO-AFs) were characterized by a higher degree of cytoplasmic complexity, by the expression of α-smooth muscle actin and by a greater basal production of reactive oxygen species in comparison with controls, reflecting a more differentiated phenotype consistent with myofibroblasts. CONCLUSION: It is possible to suggest that the differentiated phenotype of CHO-AFs might be coupled with a more or less aggressive clinical behavior, and hence, these cultures might represent powerful tools for investigating biology and clinical evolution of this disease.

Cholesteatoma-associated fibroblasts modulate epithelial growth and differentiation through KGF/FGF7 secretion.

The keratinocyte growth factor (KGF/FGF7), produced by stromal cells, is a key paracrine mediator of epithelial proliferation, differentiation and migration. Expression of the growth factor is increased in wound healing and in hyperproliferative epithelial diseases, as a consequence of the activation of dermal fibroblasts by the inflammatory microenvironment. The middle ear cholesteatoma, an aural epidermal pathology characterized by keratinocyte hyperproliferation and chronic inflammation, may represent a model condition to study the epithelial-mesenchymal interactions. To develop an in vitro model for this disease, we isolated and characterized human primary cultures of fibroblasts associated with the cholesteatoma lesion, analyzing their secretory behaviour and degree of differentiation or activation. Compared to the perilesional or control normal fibroblasts, all cultures derived from cholesteatoma tissues were less proliferating and more differentiated and their highly variable activated phenotype correlated with the secretion of KGF as well as of metalloproteases 2 and 9. Culture supernatants collected from the cholesteatoma-associated fibroblasts were able to increase the proliferation and differentiation of human keratinocytes assessed by the expression of Ki67 and keratin-1 markers. The single crucial contribution of the KGF released by fibroblasts on the keratinocyte biological response was shown by the specific, although partial, block induced by inhibiting the KGF receptor or by immunoneutralizing the growth factor. Altogether, these results suggest that the activation of the stromal fibroblasts present in the pathological tissue, and the consequent increased secretion of KGF, play a crucial role in the deregulation of the epidermal proliferation and differentiation.

Adsorption of hydrogen gas and redox processes in clays.

In order to assess the adsorption properties of hydrogen gas and reactivity of adsorbed hydrogen, we measured H(2)(g) adsorption on Na synthetic montmorillonite-type clays and Callovo-Oxfordian (COx) clayrock using gas chromatography. Synthetic montmorillonites with increasing structural Fe(III) substitution (0 wt %, 3.2 wt %, and 6.4 wt % Fe) were used. Fe in the synthetic montmorillonites is principally present as structural Fe(III) ions. We studied the concomitant reduction of structural Fe(III) in the clays using (57)Fe Mössbauer spectrometry. The COx, which mainly contains smectite/illite and calcite minerals, is also studied together with the pure clay fraction of this clayrock. Experiments were performed with dry clay samples which were reacted with hydrogen gas at 90 and 120 °C for 30 to 45 days at a hydrogen partial pressure close to 0.45 bar. Results indicate that up to 0.11 wt % of hydrogen is adsorbed on the clays at 90 °C under 0.45 bar of relative pressure. (57)Fe Mössbauer spectrometry shows that up to 6% of the total structural Fe(III) initially present in these synthetic clays is reduced upon adsorption of hydrogen gas. No reduction is observed with the COx sample in the present experimental conditions.

Preliminary evidences on mitochondrial injury and impaired oxidative metabolism in breast cancer.

Mitochondriopathy is emerging as a new cancer theory; however, the relevance of mitochondrial pathobiology in breast cancer has not yet been completely explored. Herein we report on altered expression levels of the oxidative phosphorylation system (OXPHOS) subunits, mitochondrial structural injury and impaired ATP content from a breast-infiltrating ductal carcinoma (IDC). With this purpose, a human mammary carcinoma (HMC-1) cell, referred to a human mammary epithelial cell (HMEC) line, was assayed for: a) OXPHOS levels by quantitative cryo-immunoelectron microscopy (CIEM) labeling; b) morphological characterization by a newly introduced damage grading (scale Mt-g1-3), calculated on the % of intact cristae carrying mitochondria; c) bioenergetic impairment by luminometric determinations of cellular ATP content and cytochemical visualization of COX activity. Drastic OXPHOS reduction was observed in HMC-1 cells for the succinate-dehydrogenase complex II SDH-B protein, while decreasing was reported for the NADH-ubiquinone oxidoreductase complex I NDUFS3 and the ubiquinol cytochrome c reductase complex III UQCRC2 subunits. A significant dropping was detected for the ATP-synthase complex V F1ß protein. For the COX complex near-depletion of the mitochondrial-encoded COXI and no apparent variation of the COXIV subunits were observed. Injury grading was categorized assigning three levels of morphological damage in HMC-1 mitochondria: i) severe (4.6%), ii) moderate (23.1%), iii) slight (44.6%), corresponding to 0%, 1-50% and 51-75% of area occupied by intact cristae. ATP generation and COX activity appeared significantly reduced in HMC-1 cells. The structural damage grading here described could provide new insight on IDC mitochondrial impairment and represent hallmark in the breast cancer mitochondriopathy.

Measuring the effectiveness of homeopathic care through objective and shared indicators.

OBJECTIVE: To test a methodology to evaluate, at population level, the effectiveness of homeopathic treatment through standard objective public health indicators. METHODS AND SETTINGS: Indicators of hospitalization and drug use were obtained from the Health Statistical Documentation System of Tuscany for two homeopathic centers in the Local Health Authority of Pisa, Italy. We compared homeopathic users with the general population in the same area and by comparing patients before and after homeopathic treatment. RESULTS: The homeopathic patients used less drugs than the reference population, this effect was more evident for patients with repeated homeopathic consultations. A significant decrease in drug use was found on comparing the same patients before and after homeopathic treatment. Hospitalization indicators tended to favour patients who had received homeopathic treatment but were not always statistically significant. CONCLUSIONS: This paper demonstrates a new methodological approach to assess the effectiveness of a therapeutic modality, without ad-hoc clinical trials. This methodology can be used by public health institutions in which non-conventional medicines are integrated into the public health care system.

Expression and signaling of the tyrosine kinase FGFR2b/KGFR regulates phagocytosis and melanosome uptake in human keratinocytes.

Membrane and actin cytoskeleton dynamics during phagocytosis can be triggered and amplified by the signal transduction of receptor tyrosine kinases. The epidermal keratinocytes appear to use the phagocytic mechanism of uptake to ingest melanosomes released by the melanocytes and play a pivotal role in the transfer process. We have previously demonstrated that the keratinocyte growth factor KGF/FGF7 promotes the melanosome uptake through activation of its receptor tyrosine kinase FGFR2b/KGFR. The aim of the present study was to investigate the contribution of KGFR expression, activation, and signaling in regulating the phagocytic process and the melanosome transfer. Phagocytosis was analyzed in vitro using fluorescent latex beads on human keratinocytes induced to differentiate. Melanosome transfer was investigated in keratinocyte-melanocyte cocultures. KGFR depletion by small interfering RNA microinjection and overexpression by transfection of wild type or defective mutant KGFR were performed to demonstrate the direct effect of the receptor on phagocytosis and melanosome transfer. Colocalization of the phagocytosed beads with the internalized receptors in phagolysosomes was analyzed by optical sectioning and 3-dimensional reconstruction. KGFR ligands triggered phagocytosis and melanosome transfer in differentiated keratinocytes, and receptor kinase activity and signaling were required for these effects, suggesting that FGFR2b/KGFR expression/activity and PLCγ signaling pathway play crucial roles in phagocytosis.

The running waters macroinvertebrates community: sampling techniques.

The community of running water macroinvertebrates has proved to be one of key subjects for fluvial ecology and bioindication studies, thanks both to the different trophic roles within the range of taxa and to the ease with which they may be collected and identified. However, the complex nature of this community creates problems concerning the complete identification of the full range of taxa, even when restricting the taxonomic classification to families and genera. Even so, the need to use the community for the implementation of indexes of Ecological Status of freshwaters and for the detection of reference conditions, necessarily means a deeper knowledge of this structure. Hence, a standard methodology of the capture effort is required to identify not only the ecological quality but also a reference community for each selected fluvial typology and for each section examined. Starting from the processing of data collected during intercalibration exercises of the IBE method, the authors analyse the results underlining the share given by the size of the sample collected (catchment effort), and by the distribution models of different taxa within the community, in order to give a contribution to the evaluation of the reliability level of standard samples. The results confirm the models already described in previous publications and lead us to accept the presence of marginal degrees of uncertainty in standard samples.

Hrs regulates the endocytic sorting of the fibroblast growth factor receptor 2b.

The keratinocyte growth factor receptor or fibroblast growth factor receptor 2b (KGFR/FGFR2b) is activated by the specific interaction with the keratinocyte growth factor (KGF/FGF7), which targets the receptor to the degradative pathway, and the fibroblast growth factor 10 (FGF10/KGF2), which drives the receptor to the juxtanuclear recycling route. Hrs plays a key role in the regulation of the endocytic degradative transport of ubiquitinated receptor tyrosine kinases, but the direct involvement of this protein in the regulation of FGFR endocytosis has not been investigated yet. We investigated here the possible role of Hrs in the alternative endocytic pathways of KGFR. Quantitative immunofluorescence microscopy and biochemical analysis showed that both overexpression and siRNA interference of Hrs inhibit the KGF-triggered KGFR degradation, blocking receptor transport to lysosomes and causing its rapid reappearance at the plasma membrane. In contrast, the FGF10-induced KGFR targeting to the recycling compartment is not affected by Hrs overexpression or depletion. Coimmunoprecipitation approaches indicated that Hrs is recruited to KGFR only after KGF treatment, although it is not tyrosine phosphorylated by the ligand. In conclusion, Hrs regulates the KGFR degradative pathway, but not its juxtanuclear recycling transport. In addition, the results suggest that Hrs recruitment to the receptor, but not its ligand-induced phosphorylation, could be required for its function.

Characterization of PiB binding to white matter in Alzheimer disease and other dementias.

UNLABELLED: 11C-Pittsburgh Compound B (11C-PiB) PET has demonstrated significantly higher PiB retention in the gray matter of Alzheimer disease (AD) patients than in healthy controls (HCs). PiB is similarly retained within the white matter of HC and AD brains. Although the specificity of PiB for Abeta plaques in gray matter has been well described, the nature of PiB binding to white matter remains unclear. In this study, we characterized the binding of PiB to human white matter homogenates. METHODS: In vitro binding studies were conducted using 3H-PiB (0.1-500 nM) and white matter brain homogenates (100 microg) from 3 AD patients and 3 HCs. Nonspecific binding was determined using PiB (1 microM). White matter from the same patients was also analyzed by immunofluorescence/immunohistochemistry (IF/IHC) microscopy and Western blotting for Abeta expression. White matter kinetics were also characterized in vivo through 11C-PiB PET studies in 27 HCs and 34 patients with dementia. IF/IHC experiments were conducted on 1 postmortem patient with dementia, to compare with the 11C-PiB distribution volume ratio data acquired 23 mo earlier. RESULTS: In vitro saturation studies indicated that 3H-PiB binds nonspecifically to white matter brain homogenates. PiB fluorescence staining of AD and HC brain sections was consistent with absence of Abeta in IHC staining. Higher gray matter-to-white matter ratios were observed in IHC images than in 11C-PiB PET images. CONCLUSION: These studies suggest that PiB binding to white matter is mainly nonsaturable and nonspecific and that PiB retention in the 11C-PiB PET studies is largely attributable to slower PiB white matter kinetics.

Keratinocyte growth factor receptor ligands target the receptor to different intracellular pathways.

The keratinocyte growth factor receptor (KGFR)/fibroblast growth factor receptor 2b is activated by high-affinity-specific interaction with two different ligands, keratinocyte growth factor (KGF)/fibroblast growth factor (FGF)7 and FGF10/KGF2, which are characterized by an opposite requirement of heparan sulfate proteoglycans and heparin for binding to the receptor. We investigated here the possible different endocytic trafficking of KGFR, induced by the two ligands. Immunofluorescence and immunoelectron microscopy analysis showed that KGFR internalization triggered by either KGF or FGF10 occurs through clathrin-coated pits. Immunofluorescence confocal microscopy using endocytic markers as well as tumor susceptibility gene 101 (TSG101) silencing demonstrated that KGF drives KGFR to the degradative pathway, while FGF10 targets the receptor to the recycling endosomes. Biochemical analysis showed that KGFR is ubiquitinated and degraded after KGF treatment but not after FGF10 treatment, and that the alternative fate of KGFR might depend on the different ability of the receptor to phosphorylate the fibroblast growth factor receptor substrate 2 (FRS2) substrate and to recruit the ubiquitin ligase c-Cbl. The recycling endocytic pathway followed by KGFR upon FGF10 stimulation correlates with the higher mitogenic activity exerted by this ligand on epithelial cells compared with KGF, suggesting that the two ligands may play different functional roles through the regulation of the receptor endocytic transport.