We investigated the action of a protein-bound polysaccharide, PSK, on transforming <em>growth</em> <em>factor</em>-beta (TGF-beta). (1) In in vitro-mixed culture of peripheral blood mononuclear cells (PBMC) from healthy human and mitomycin C-treated human colon cancer cells, PSK or polyclonal antibody to TGF-beta significantly enhanced incorporation of 3H-thymidine into PBMC, and apparently decreased TGF-beta1 levels of acid-treated culture supernatant. (2) PSK or the antibody interfered with the quantitation by enzyme immunoassay of TGF-beta1 in acid-treated supernatant of the mixed culture. (3) PSK was suggested to form a complex with 125I-human recombinant TGF-beta1 standard, when changes in molecular weight of radioactivities were assessed by gel filtration. Recombinant human TGF-beta1 inhibited <em>growth</em> of mink lung epithelial cell line Mv1Lu and promoted collagen synthesis in rat kidney <em>fibroblast</em> cell line NRK49F, but the complex did not have such activities. (4) In addition to TGF-beta1, PSK bound with TGF-beta2 and platelet-derived <em>growth</em> <em>factor</em>; however, PSK did not bind with <em>22</em> other species of cytokines and <em>growth</em> <em>factors</em>. (5) Protein moiety of PSK is suggested to play an important role in the expression of the activity. These results suggest that PSK modulates the biological activity of TGF-beta1 by binding to its active form.

<em>Fibroblast</em> <em>growth</em> <em>factors</em> (FGFs) and FGF receptors (FGFRs) are known for their potent effects on cell proliferation/differentiation and cortical patterning in the developing brain. However, little is known regarding the roles of FGFs/FGFRs in cortical circuit formation. Here we show that Fgfr1/2/3 and Fgf7/9/10/<em>22</em> mRNAs are expressed in the developing primary somatosensory (S1) barrel cortex. Barrel cortex layer IV spiny stellate cells (bSCs) are the primary recipients of ascending sensory information via thalamocortical axons (TCAs). Detail quantification revealed distinctive phases for bSC dendritogenesis: orienting dendrites toward TCAs, adding de novo dendritic segments, and elongating dendritic length, while maintaining dendritic patterns. Deleting Fgfr1/2/3 in bSCs had minimal impact on dendritic polarity but transiently increased the number of dendritic segments. However, 6 d later, FGFR1/2/3 loss of function reduced dendritic branch numbers. These data suggest that FGFs/FGFRs have a role in stabilizing dendritic patterning. Depolarization of cultured mouse cortical neurons upregulated the levels of several Fgf/Fgfr mRNAs within 2 h. In vivo, within 6 h of systemic kainic acid administration at postnatal day 6, mRNA levels of Fgf9, Fgf10, Fgfr2c, and Fgfr3b in S1 cortices were enhanced, and this was accompanied by exuberant dendritogenesis of bSCs by 24 h. Deleting Fgfr1/2/3 abolished kainic acid-induced bSC dendritic over<em>growth</em>. Finally, FGF9/10 gain of function also resulted in extensive dendritogenesis. Together, our data suggest that FGFs/FGFRs can be regulated by glutamate transmission to modulate/stabilize bSC dendritic complexity. Both male and female mice were used for our study.SIGNIFICANCE STATEMENT Glutamatergic transmission plays critical roles in cortical circuit formation. Its dysregulation has been proposed as a core <em>factor</em> in the etiology of many neurological diseases. We found that excessive glutamate transmission upregulated mRNA expression of Fgfrs and their ligands Fgfs Deleting Fgfr1/2/3 not only impaired bSC dendritogenesis but also abolished glutamate transmission-induced dendritic over<em>growth</em>. Overexpressing FGF9 or FGF10 in cortical glutamatergic neurons results in excessive dendritic out<em>growth</em> within 24 h, resembling the changes induced by excessive glutamate transmission. Our findings provide strong evidence for the physiological role of <em>fibroblast</em> <em>growth</em> <em>factors</em> (FGFs) and FGF receptors (FGFRs) in establishing and maintaining cortical circuits. Perturbing the expression levels of FGFs/FGFRs by excessive glutamatergic neurotransmission could lead to abnormal neuronal circuits, which may contribute to neurological and psychiatric disease.

The inhibitory effects of isoliensinine (IL), a bisbenzylisoquinoline alkaloid extracted from the seed embryo of the traditional chinese medicinal herb Nelumbo nucifera Gaertn, on the proliferation of porcine coronary arterial smooth muscle cells (CASMCs) induced by angiotensin II(Ang II) and its mechanisms of action were investigated. Counting cultured cell number, MTT assay, immunohistochemical method and Western blot were adopted. Ang II 0.1 micromol l (-1) significantly evoked CASMC proliferation by 42%, which could be dose-dependently inhibited by IL 0.01-3 micromol l (-1) and the percentage of inhibition of IL 0.1 micromol l (-1) was 25%. Irbesartan (Irb) 0.1 micromol l (-1) inhibited CASMC proliferation by <em>22</em>%. IL or Irb 0.1 micromol l (-1) decreased Ang II-induced overexpression of Platelet-derived <em>growth</em> <em>factor</em> (PDGF)-beta and basic <em>fibroblast</em> <em>growth</em> <em>factor</em> (bFGF), respectively. Both of them also declined c-fos, c-myc and hsp70 overexpression, respectively. At the same concentration, the inhibitory effects of IL on PDGF-beta were even stronger than those of Irb (P < 0.05). In summary, the data showed that IL possesses an anti-proliferative effect, which is related to the decrease of the overexpression of <em>growth</em> <em>factors</em> PDGF-beta, bFGF, proto-oncogene c-fos, c-myc and hsp70.

A wide range of therapeutic options exists for the treatment of keloids, all of which have their own strengths; however, a high risk of side‑effects and frequent recurrence remains. Therefore, the present study aimed to identify improved therapeutic approaches or drugs for the treatment of keloids. Ginsenoside Rg3 (Rg3) has been reported to exert numerous antitumor effects, thus indicating that Rg3 may be a potential therapeutic agent that targets keloids. The present study determined the effects of Rg3 on human keloid <em>fibroblasts</em> (KFs) in vitro, and further explored the associated molecular and cellular mechanisms. Keloid scar specimens were obtained from patients, aged between <em>22</em> and 35 years, without systemic diseases and primary cells were isolated from keloid tissues. In each assay, KFs were divided into three groups and were cultured in medium with or without various concentrations of Rg3 (50 or 100 µg/ml). Cell viability assay, flow cytometry, quantitative polymerase chain reaction, cell migration assay, immunofluorescence staining, western blot analysis, Transwell cell invasion assay and immunohistochemical analysis were used to analyze the KFs and keloid explant cultures. The results of the present study demonstrated that Rg3 was able to exert an inhibitory effect on the transforming <em>growth</em> <em>factor</em>‑β/Smad and extracellular signal‑regulated kinase signaling pathways in KFs. The proliferation, migration, invasion, angiogenesis and collagen synthesis of KFs were markedly suppressed following treatment with Rg3. Furthermore, the results of an ex vivo assay indicated that Rg3 inhibited angiogenesis and reduced collagen accumulation in keloids. Significant statistical differences existed between the control and Rg3‑treated groups (P<0.05). All of these experimental results suggested that Rg3 may serve as a reliable drug for the treatment of patients with keloids.

BACKGROUND

In this study we compared levels of selected adipokines between patients with type 2 diabetes (T2D) and healthy individuals and we determined their relationship with early vascular damage markers.

METHODS

Seventy-seven subjects: 56 patients with T2D (34 men and <em>22</em> women) and 21 healthy controls (8 men and 13 women) were examined in this cross-sectional study. Selected adipokines [adiponectin, adipocyte fatty acid-binding protein (A-FABP), <em>fibroblast</em> <em>growth</em> <em>factor</em> 21 (FGF-21), C1q/TNF-related protein 9 (CTRP-9), and allograft inflammatory <em>factor</em>-1 (AIF-1)] with possible cardiovascular impact were measured in all participants. To identify markers of vascular damage von Willebrand <em>factor</em> (vWF), plasminogen activator inhibitor-1 (PAI-1) and arterial stiffness parameters were examined in all the subjects.

RESULTS

When compared with healthy controls, T2D had significantly higher levels of A-FABP [50.0 (38.1-68.6) vs. 28.6 (23.6-32.9) ng/mL, P < 0.0001] and lower levels of adiponectin [5.9 (4.3-9.0) vs. 11.3 (8.7-14.8) μg/mL, P < 0.0001]. Differences in other adipokines were not statistically significant. Adiponectin level correlated negatively with vWF levels (ρ = -0.29, P < 0.05) and PAI-1 (ρ = -0.36, P < 0.05) and A-FABP positively with vWF (ρ = 0.61, P < 0.05) and PAI-1 (ρ = 0.47, P < 0.05) and augmentation index (ρ = 0.26, P < 0.05). Multivariate regression analysis showed independent association between A-FABP and vWF (b = 0.24, P < 0.05).

CONCLUSIONS

Patients with T2D have significantly higher levels of A-FABP and lower levels of adiponectin. These adipokines correlate with indicators of vascular damage and could contribute to cardiovascular risk in patients with T2D. A-FABP may participate in direct endothelium damage.

<em>Fibroblast</em> <em>growth</em> <em>factor</em> 2 (FGF2) is involved in many physiological and pathological processes. Fgf2 deregulation contributes to the acquisition of malignant features of melanoma and other cancers. FGF2 is an alternative translation product expressed as five isoforms, a low-molecular-weight (18 KDa) and four high-molecular-weight (<em>22</em>, <em>22</em>.5, 24, 34 KDa) isoforms, with different subcellular distributions. An internal ribosomal entry site (IRES) in its mRNA controls the translation of all the isoforms with the exception for the cap-dependent 34 KDa. The 18-KDa isoform has been extensively studied, while very few is known about the roles of high molecular weight isoforms. FGF2 is known to promote melanoma development and progression. To disclose the differential contribution of FGF2 isoforms in melanoma, we forced the expression of IRES-dependent low-molecular-weight (LMW, 18 KDa) and high-molecular-weight (HMW, <em>22</em>, <em>22</em>.5, 24 KDa) isoforms in a human metastatic melanoma cell line. This comparative study highlights that, while LMW isoform confers stem-like features to melanoma cells and promotes angiogenesis, HMW isoforms induce higher migratory ability and contribute to tumor perfusion by promoting vasculogenic mimicry (VM) when endothelial cell-driven angiogenesis is lacking. To conclude, FGF2 isoforms mainly behave in specific, antithetical manners, but can cooperate in different steps of tumor progression, providing melanoma cells with major malignant features.

FGF2 is an alternative translation product expressed as different isoforms termed LMW and HMW. FGF2 is involved in melanoma development and progression. HMW FGF2 isoforms enhance in vitro motility of melanoma cells. LMW FGF2 confers stem-like features and increases in vivo metastasization. LMW FGF2 promotes angiogenesis while HMW FGF2 induces vasculogenic mimicry.

Functional synapse formation requires tight coordination between pre- and post-synaptic termini. Previous studies have shown that postsynaptic expression of heparan sulfate proteoglycan syndecan-2 (SDC2) induces dendritic spinogenesis. Those SDC2-induced dendritic spines are frequently associated with presynaptic termini. However, how postsynaptic SDC2 accelerates maturation of corresponding presynaptic termini is unknown. Because <em>fibroblast</em> <em>growth</em> <em>factor</em> <em>22</em> (FGF<em>22</em>), a heparan sulfate binding <em>growth</em> <em>factor</em>, has been shown to act as a presynaptic organizer released from the postsynaptic site, it seems possible that postsynaptic SDC2 presents FGF<em>22</em> to the presynaptic FGF receptor to promote presynaptic differentiation. Here, we show that postsynaptic SDC2 uses its ectodomain to interact with and facilitate dendritic filopodial targeting of FGF<em>22</em>, triggering presynaptic maturation. Since SDC2 also enhances filopodial targeting of NMDAR via interaction with the CASK-mLIN7-MINT1 adaptor complex, presynaptic maturation promoted by FGF<em>22</em> further feeds back to activate NMDAR at corresponding postsynaptic sites through increased neurotransmitter release and, consequently, promotes the dendritic filopodia-spines (F-S) transition. Meanwhile, via regulation of the KIF17 motor, CaMKII (activated by the NMDAR pathway) may further facilitate FGF<em>22</em> targeting to dendritic filopodia that receive presynaptic stimulation. Our study suggests a positive feedback that promotes the coordination of postsynaptic and presynaptic differentiation.

<AbstractText>Endothelial Progenitor Cells (EPCs) are important players in neovascularization, mobilized through signalling by Angiogenic <em>Growth</em> <em>Factors</em> (AGFs) such as Vascular Endothelial <em>Growth</em> <em>Factor</em> (VEGF) and <em>fibroblast</em> <em>growth</em> <em>factor</em> (FGF). In vitro, inflammatory parameters impair the function and influence of EPCs on AGFs. However, this connection is not clear in vivo. To understand the mechanisms of augmented arteriogenesis and angiogenesis in acute ischemic stroke (AIS) patients, we investigated whether circulating stem cells (CD133+), early endothelial progenitor cells (CD133+/VEGFR2+), and endothelial cells (ECs; CD34¯/CD133¯/VEGFR2+) were increasingly mobilized during AIS, and whether there were correlations between EPC levels, <em>growth</em> <em>factor</em> levels and inflammatory parameters.</AbstractText><AbstractText>Data on demographics, classical vascular risk <em>factors</em>, neurological deficit information (assessed using the National Institutes of Health Stroke Scale), and treatment were collected from 43 consecutive AIS patients (group I). Risk <em>factor</em> control patients (group II) included <em>22</em> nonstroke subjects matched by age, gender, and traditional vascular risk <em>factors</em>. EPCs were measured by flow cytometry and the populations of circulating stem cells (CD133+), early EPCs (CD133+/VEGFR2+), and ECs (CD34¯/CD133¯/VEGFR2+) were analysed. Correlations between EPC levels and VEGF and FGF vascular <em>growth</em> <em>factor</em> levels as well as the influence of inflammatory parameters on EPCs and AGFs were assessed.</AbstractText><AbstractText>Patient ages ranged from 54 to 92 years (mean age 75.2 ± 11.3 years). The number of circulating CD34¯/CD133¯/VEGF-R2+ cells was significantly higher in AIS patients than in control patients (p < 0.05). VEGF plasma levels were also significantly higher in AIS patients compared to control patients on day 7 (p < 0.05). FGF plasma levels in patients with AIS were significantly higher than those in the control group on day 3 (p < 0.05). There were no correlations between increased VEGF and FGF levels and the number of CD133+, CD133+/VEGFR2+, or CD34¯/CD133¯/VEGFR2+ cells. Leukocyte levels, FGF plasma levels, and the number of early EPCs were negatively correlated on day 3. High sensitivity C-reactive protein levels and the number of CD133+ and CD133+/VEGFR2+ cells were negatively correlated on day 7. In addition, there was a negative correlation between fibrinogen levels and FGF plasma levels as well as the number of early EPCs (CD133+/VEGFR2+).</AbstractText><AbstractText>AIS patients exhibited increased numbers of early EPCs (CD133+/VEGFR2+) and AGF (VEGF and FGF) levels. A negative correlation between inflammatory parameters and AGFs and EPCs indicated the unfavourable influence of inflammatory <em>factors</em> on EPC differentiation and survival. Moreover, these correlations represented an important mechanism linking inflammation to vascular disease.</AbstractText>

G-CSF is a myeloid <em>growth</em> <em>factor</em> produced by monocytes, macrophages, <em>fibroblasts</em>, and endothelial cells. Clinical uses of G-CSF includes mobilization of peripheral blood progenitor cells from healthy donors before hematopoietic stem cell transplantation, acceleration of neutrophil recovery following chemotherapy, and in the management of neutropenia due to other causes including AIDS and genetic disorders of granulocyte production. G-CSF is well tolerated and reports to be safe in healthy donors, although follow-up studies are limited in duration (D'Souza et al. in Transfus Med Rev <em>22</em>(4):280-290, 2008).Isolated abdominal aortitis (IAA) is a rare disorder most commonly caused by the large-vessel vasculitides giant cell arteritis (GCA) and Takayasu arteritis, although it may also be associated with several other rheumatologic diseases and infections (Gornik and Creager in Circulation 117:3039-3051, 2008). To our knowledge, there only two cases have been published of IAA occurring in patients who had received G-CSF therapy (Dariea et al. in Rev Med Interne 25(3):<em>22</em>5-<em>22</em>9, 2004; Adiga et al. in Clin Drug Investig 29:821-825, 2009).We describe a case of a 55-year-old male, with peripheral vascular disease who after receiving Neupogen (G-CSF) developed a latent case of IAA. After further investigation and exclusion of other possible causative <em>factors</em>, we conclude that the most probable etiology is induction by G-CSF.

The <em>fibroblast</em> <em>growth</em> <em>factor</em> receptor 3 (FGFR3) is a tyrosine kinase receptor frequently activated by point mutations in bladder cancer (BC). These mutations are associated with genetically stable, Ta and low-grade BC, representing the favourable BC pathway. Conversely, FGFR3 over-expression was recently found in 40 % of muscle invasive BC. We examined FGFR3 mutation status and protein expression in patients originally diagnosed as T1. We also investigated copy-number variations in FGFR3 as a possible alternative mechanism to activate FGFR3. We included 84 patients with T1 BC as their initial diagnosis. A uropathologist reviewed the slides for grade and (sub)stage. The FGFR3 mutation status was examined by PCR-SNaPshot and FGFR3 protein expression by standard immuno-histochemistry (FGFR3-B9). Copy-number status was determined in 69/84 cases with nine probes covering nine exons of the FGFR3 gene (MLPA). Of 27 BC with FGFR3 mutations, 26 (96 %) showed FGFR3 over-expression. Of the 57 wild-type BC, 27 (47 %) BC showed over-expression. Pathological parameters significantly differed (p < 0.01) between mutant and wild-type tumours with the FGFR3 mutation pointing to more favourable BC. However, if the BC exhibited wild-type FGFR3, FGFR3 protein status had no influence on grade and (sub)stage. We found six tumours with more than or equal to three copies of FGFR3. Only 1 of <em>22</em> wild-type tumours with over-expression of FGFR3 had more than or equal to three gene copies. In initially diagnosed T1 BC, only the FGFR3 mutation was significantly associated with favourable BC disease characteristics. In addition to almost all FGFR3 mutant BC, 47 % of wild-type BC displayed FGFR3 over-expression, suggesting an alternative mechanism to activate FGFR3. Increased FGFR3 copy number was a rare event and did not account for this mechanism. Nevertheless, FGFR3 wild-type tumours with over-expression of the protein may still represent a subset that might potentially benefit from FGFR3-targeted therapy.

<em>Fibroblast</em> <em>growth</em> <em>factor</em> 2 (FGF-2) and its receptors (FGFRs) are important regulators of bone cell function. Although FGF-2 is a major modulator of bone cell function, its expression and regulation in human osteoblasts have not been investigated. We examined FGF-2 messenger RNA (mRNA) expression and regulation in the human osteosarcoma MG-63 cells. Northern analysis revealed that MG-63 cells expressed FGF-2 mRNA transcripts of 7, 4, 2.2, and 1.3 kilobases (kb). In the absence of serum, treatment with transforming <em>growth</em> <em>factor</em> beta (TGF-beta; 0.1-10 ng/ml) increased all FGF-2 mRNA transcripts. Maximal increase was seen with 1 ng/ml of TGF-beta. TGF-beta increased FGF-2 mRNA expression within 2 h and this was sustained for 24 h. Phorbal myristate acetate (PMA; 1 microM) also increased FGF-2 mRNA at 6 h. Time course studies showed that TGF-beta did not significantly alter FGFR1 or FGFR2 mRNA expression in MG-63 cells. Western blotting with anti-human FGF-2 revealed that MG-63 cells synthesize three isoforms of FGF-2 protein of approximately 18, <em>22</em>/23, and 24 kDa, which were increased after either 6 h or 24 h of treatment with TGF-beta. Increased FGF-2 mRNA and protein expression in response to TGF-beta was markedly reduced by the protein kinase A (PKA) inhibitor H-89. Immunogold labeling of MG-63 cells treated with TGF-beta showed increased labeling for FGF-2 and FGFR2 in the nuclei. In contrast, TGF-beta treatment significantly decreased FGFR1 labeling in the nuclei. These data show that TGF-beta regulates FGF-2 gene expression in human osteosarcoma cells. Furthermore, TGF-beta modulates the cellular localization of FGF-2 and its receptors.

Inactivating mutations in phosphate-regulating gene with homologies to endopeptidase on the X chromosome (PHEX) have been identified as a cause of X-linked hypophosphatemic rickets (XLH; OMIM 307800). In the present study, we enrolled 43 patients from 18 unrelated families clinically diagnosed with hypophosphatemic rickets and 250 healthy controls. For each available individual, all <em>22</em> exons with their exon-intron boundaries of the PHEX gene were directly sequenced. The levels of serum <em>fibroblast</em> <em>growth</em> <em>factor</em> 23 (FGF23) were measured as well. Sequencing analysis detected 17 different PHEX gene mutations, and 7 of these were identified as novel: 3 missense mutations, including c.304G>A (p.Gly102Arg) in exon 3, c.<em>22</em>9T>C (p.Cys77Arg) in exon 3 and c.824T>C (p.Leu275Pro) in exon 7; 2 deletion mutations, including c.528delT (p.Glu177LysfsX44) in exon 5 and c.1234delA (p.Ser412ValfsX12) in exon 11; and 2 alternative splicing mutations, including c.436_436+1delAG in intron 4 at splicing donor sites and c.1483-1G>C in intron 13 at splicing acceptor sites. Moreover, 6 mutations were proven to be de novo in 6 sporadic cases and the probands were all females. No mutations were found in the 250 healthy controls. The serum levels of FGF23 varied widely among the patients with XLH, and no significant difference was found when compared with those of the healthy controls. On the whole, the findings of this study provide new insight into the spectrum of PHEX mutations and provide potential evidence of a critical domain in PHEX protein. In addition, the finding of an overlap of the serum FGF23 levels between the patients with XLH and the healthy controls indicates its limited diagnostic value in XLH.

Lung squamous cell carcinoma (SqCC) is a molecularly complex and genomically unstable disease. No targeted therapy is currently approved for lung SqCC, although potential oncogenic drivers of SqCC have been identified, including amplification of the <em>fibroblast</em> <em>growth</em> <em>factor</em> receptor 1 (FGFR1). Reports from a recently completed clinical trial indicate low response rates in patients treated with FGFR tyrosine kinase inhibitors, suggesting inadequacy of FGFR1 amplification as a biomarker of response, or the need for combination treatment. We aimed to develop accurate models of lung SqCC and determine improved targeted therapies for these tumors. We show that detection of FGFR1 mRNA by RNA in situ hybridization is a better predictor of response to FGFR inhibition than FGFR1 gene amplification using clinically relevant patient-derived xenograft (PDX) models of lung SqCC. FGFR1-overexpressing tumors were observed in all histologic subtypes of non-small cell lung cancers (NSCLC) as assessed on a tissue microarray, indicating a broader range of tumors that may respond to FGFR inhibitors. In FGFR1-overexpressing PDX tumors, we observed increased differentiation and reduced proliferation following FGFR inhibition. Combination therapy with cisplatin was able to increase tumor cell death, and dramatically prolonged animal survival compared to single-agent treatment. Our data suggest that FGFR tyrosine kinase inhibitors can benefit NSCLC patients with FGFR1-overexpressing tumors and provides a rationale for clinical trials combining cisplatin with FGFR inhibitors. Mol Cancer Ther; 16(8); 1610-<em>22</em>. ©2017 AACR.

Early pregnancy, when most embryonic losses occur, is a critical period in which vital placental vascularization is established. Vascular endothelial <em>growth</em> <em>factor</em> (VEGF) is a potent inducer of angiogenesis, and <em>factors</em> that regulate VEGF function, expression, or both may ultimately affect vascularization. Activation of the C-X-C chemokine receptor type 4 (CXCR4) by its cognate ligand, C-X-C chemokine ligand 12 (CXCL12), increases VEGF synthesis and secretion, which in turn stimulates CXCL12 and CXCR4 production and this synergistic regulation may influence placental vascularization. We hypothesized that expression of CXCL12, CXCR4, select angiogenic <em>factors</em>, and their receptors would increase in placental tissues during early pregnancy and that treatment of ovine trophectoderm cells with CXCL12 would increase production of angiogenic <em>factors</em>. To test this hypothesis, maternal caruncle (CAR) and fetal extraembryonic membrane (FM) tissues were collected on days 18, 20, <em>22</em>, 25, 26, and 30 of pregnancy and on day 10 of the estrous cycle (control, NP) to determine relative mRNA or protein expression of CXCL12 and CXCR4 and selected angiogenic <em>factors</em>. In CAR, expression of mRNA for CXCR4 increased on day 18, 20, <em>22</em>, and 25 and CXCL12 increased on day 18 and 20 compared with NP ewes. CXCL12 protein followed a similar pattern in CAR tissue, with greater levels on day 20 than in NP tissue. Greater levels of <em>fibroblast</em> <em>growth</em> <em>factor</em> 2 (FGF2) mRNA was observed in CAR on day 20 of gestation than on day 30. In FM, CXCL12, CXCR4, angiopoietin 1, VEGF, and VEGF receptor 1 were enhanced with advancing pregnancy, whereas FGF2 and kinase insert domain receptor (or VEGF receptor 2) peaked on day 25. An increase in protein levels occurred on day 25 compared with day 20 in FM for CXCL12 and CXCR4, as well as a similar tendency for FGF2 protein. Both CXCL12 and CXCR4 are specifically localized to trophoblast cells and to the uterine luminal and glandular epithelium. Treatment of ovine trophectoderm cells with CXCL12 increased mRNA expression for VEGF and FGF2. The relationship between VEGF, FGF2, and the CXCL12/CXCR4 signaling underscores the potential role for this chemokine axis in driving placentation.

Gadolinium-containing fullerenol Gd@C82(OH)<em>22</em> has demonstrated low-toxicity and highly therapeutic efficacy in inhibiting tumor <em>growth</em> and metastasis through new strategy of encaging cancer, however, little is known about the mechanisms how this nanoparticle regulates <em>fibroblast</em> cells to prison (instead of poison) cancer cells. Here, we report that Gd@C82(OH)<em>22</em> promote the binding activity of tumor necrosis <em>factor</em> (TNFα) to tumor necrosis <em>factor</em> receptors 2 (TNFR2), activate TNFR2/p38 MAPK signaling pathway to increase cellular collagen expression in fibrosarcoma cells and human primary lung cancer associated <em>fibroblasts</em> isolated from patients. We also employ molecular dynamics simulations to study the atomic-scale mechanisms that dictate how Gd@C82(OH)<em>22</em> mediates interactions between TNFα and TNFRs. Our data suggest that Gd@C82(OH)<em>22</em> might enhance the association between TNFα and TNFR2 through a "bridge-like" mode of interaction; by contrast, the fullerenol appears to inhibit TNFα-TNFR1 association by binding to two of the receptor's cysteine-rich domains. In concert, our results uncover a sequential, systemic process by which Gd@C82(OH)<em>22</em> acts to prison tumor cells, providing new insights into principles of designs of cancer therapeutics.

UNASSIGNED

Calcidiol insufficiency may accelerate the development of secondary hyperparathyroidism (SHPT). We tested the effect of a substantial increase in calcidiol on mineral metabolism in patients with chronic kidney disease (CKD).

UNASSIGNED

Ninety-five patients with CKD Stages 3-4, parathyroid hormone (PTH) above 6.8 pmol/L and calcidiol below 75 nmol/L were randomized to receive either cholecalciferol 8000 IU/day or placebo for 12 weeks. The primary endpoint was difference in the mean change in iPTH after 12 weeks. The proportion of participants having a 30% reduction in PTH and the effect on hand grip strength, fatigue and different biochemical variables were also investigated.

UNASSIGNED

Baseline calcidiol was 57.5 ± <em>22</em> and 56.8 ± <em>22</em> nmol/L in the cholecalciferol and placebo groups, respectively. The corresponding concentrations of PTH were 10.9 ± 5 and 13.1 ± 9 pmol/L. Calcidiol increased to 162 ± 49 nmol/L in patients receiving cholecalciferol, and PTH levels remained constant at 10.5 ± 5 pmol/L. In the placebo group, calcidiol remained stable and PTH increased to 15.2 ± 11 pmol/L. The mean change in PTH differed significantly between the two groups (P < 0.01). The proportion of subjects reaching a 30% decrease in PTH did not differ. No effect on grip strength, fatigue, phosphate or <em>fibroblast</em> <em>growth</em> <em>factor</em> 23 was observed. Cholecalciferol treatment resulted in stable calcium concentrations and a substantial increase in calcitriol.

UNASSIGNED

Treatment with high daily doses of cholecalciferol in patients with CKD Stages 3-4 halts the progression of SHPT and does not cause hypercalcaemia or other side effects.

<AbstractText>Fetal exposure to gestational diabetes mellitus (GDM) increases the risk of metabolic diseases in the offspring. Leptin, adiponectin, and <em>fibroblast</em> <em>growth</em> <em>factor</em> 21 (FGF21) may play potential roles in the underlying disease mechanisms. We investigated the impact of fetal exposure to GDM on leptin, adiponectin, and FGF21 concentrations and their associations with measures of adiposity and metabolic traits during childhood/adolescence.</AbstractText><AbstractText>The follow-up study included 504 GDM and 540 control offspring aged 9-16 from the Danish National Birth Cohort. Anthropometric measurements, fasting blood samples, puberty status and fat percentages by Dual-energy x-ray absorptiometry were examined. Serum concentrations of leptin, adiponectin, and FGF21 were measured by validated immune assays.</AbstractText><AbstractText>GDM offspring had 38% (95% CI: <em>22</em>-55%) higher leptin, 0.6mg/L (95% CI -1.2, -0.04mg/L) lower adiponectin, and 32% (95% CI: -47%, -12%) lower FGF21 concentrations than control offspring (p<0.05). After adjustment for confounders including maternal pre-pregnancy BMI, GDM offspring had borderline higher leptin (p=0.06) and significantly lower FGF21 concentrations (p=0.006). When accounting for offspring BMI z-score, GDM exposure had no significant independent effect on leptin or adiponectin concentrations whereas FGF21 was still significant. In univariate analyses, leptin and adiponectin were associated with fasting insulin, HOMA-IR, and adiposity, and FGF21 with total fat percentage.</AbstractText><AbstractText>GDM offspring had higher leptin, lower adiponectin and FGF21 concentrations than control offspring. Elevated leptin and decreased adiponectin concentrations associated with adverse metabolic traits and were most likely driven by higher obesity prevalence among GDM offspring. The functional implications of decreased FGF21 concentrations among GDM offspring need to be further explored.</AbstractText>

<em>Fibroblast</em> <em>growth</em> <em>factor</em>-21 (FGF-21) appears to have an important role in glucose and lipid metabolism. FGF-21 secretion is mainly determined by nutritional status. The aim of this study was to measure basal and postprandial FGF-21 and postprandial change of FGF-21 concentration in type 1 diabetes mellitus (T1DM) patients and in healthy controls, and to investigate the differences between the groups. The cross-sectional study included 30 C-peptide negative T1DM patients, median age 37 years (20-59), disease duration <em>22</em> years (3-45), and nine healthy controls, median age 30 years (27-47). Basal and postprandial FGF-21 concentrations were measured by ELISA. The associations of FGF-21 with glucose, lipids, and insulin were analyzed. Individuals with T1DM showed significantly lower basal FGF-21 concentration (P=0.046) when compared with healthy controls (median value 28.2 vs 104 pg/mL) and had significantly different postprandial change (∆ 30'-0') of FGF-21 (P=0.006) in comparison with healthy controls (median value -1.1 vs -20.5 pg/mL). The glucose and lipid status did not correlate with FGF-21. In healthy controls, postprandial insulin level correlated with basal FGF-21 (ρ=0.7, P=0.036). Multiple regression analysis showed that they are independently associated after adjustment for confounding <em>factors</em> (β=1.824, P=0.04). We describe the pathological pattern of basal and postprandial change of FGF-21 secretion not associated with glucose, lipid levels, or insulin therapy in patients with T1DM. Since FGF-21 has numerous protective metabolic effects in the experimental model, the lower basal FGF-21 concentration in T1DM patients opens the question about the potential role of recombinant FGF-21 therapy.

<em>Fibroblast</em> <em>growth</em> <em>factor</em> receptor 3 (FGFR3) is an actionable target in bladder cancer (BC). FGFR3 mutations are common in noninvasive BC and associated with favorable BC prognosis. Overexpression was reported in up to 40% of FGFR3 wild-type muscle-invasive BC. We analyzed FGFR3 mutations, FGFR3, and p53 protein expression and assessed their prognostic value in a cohort of 1000 chemotherapy-naive radical cystectomy specimens. FGFR3 mutations were found in 11%, FGFR3 overexpression was found in 28%, and p53 overexpression was found in 69% of tumors. Among FGFR3 mutant tumors, 73% had FGFR3 overexpression versus <em>22</em>% among FGFR3 wild-type tumors. FGFR3 mutations were significantly associated with lower pT stage, tumor grade, absence of carcinoma in situ, pN0, low-level p53, and longer disease-specific survival (DSS). FGFR3 overexpression was associated only with lower pT stage and tumor grade. Moreover, FGFR3 overexpression was not associated with DSS in patients with FGFR3 wild-type tumors. In conclusion, FGFR3 mutations identified patients with favorable BC at cystectomy. Our results suggest that FGFR3 mutations have a driver role and are functionally distinct from FGFR3 overexpression. Hence, patients with FGFR3 mutations would be more likely to benefit from anti-FGFR3 therapy. Ideally, further research is needed to test this hypothesis. PATIENT SUMMARY: Oncogenic <em>fibroblast</em> <em>growth</em> <em>factor</em> receptor 3 (FGFR3) mutations are very common in bladder cancer. In this report, we found that these FGFR3 mutations were associated with favorable features and prognosis of bladder cancer compared with patients with FGFR3 overexpressed tumors only. As a consequence, patients with FGFR3 mutant tumors would be more likely to benefit from anti-FGFR3 therapy than patients with FGFR3 protein overexpression only.

Keywords: Bladder; Cancer; Cystectomy; Expression; FGFR3; Mutation; Urothelial carcinoma.

Multi-wall carbon nanotubes (MWCNTs) are manufactured nanomaterials to which workers and the general population will be increasingly exposed in coming years. Little is known about potential human health effects of exposure to MWCNTs, but effects on the lung and the immune system have been reported in animal and mechanistic studies.

We conducted a cross-sectional study to assess the association between occupational exposure to MWCNTs and effects on lung health and the immune system.

We assessed 51 immune markers and three pneumoproteins in serum, complete blood cell counts (CBC), fractional exhaled nitric oxide (FENO), and lung function among <em>22</em> workers of a MWCNT producing facility and 39 age- and gender-matched, unexposed controls. Measurements were repeated four months later among 16 workers also included in the first phase of the study. Regression analyses were adjusted for potentially confounding parameters age, body mass index, smoking, and sex, and we explored potential confounding by other <em>factors</em> in sensitivity analyses.

We observed significant upward trends for immune markers C-C motif ligand 20 (p = .005), basic fibroblast growth factor (p = .05), and soluble IL-1 receptor II (p = .0004) with increasing exposure to MWCNT. These effects were replicated in the second phase of the study and were robust to sensitivity analyses. We also observed differences in FENO and several CBC parameters between exposed and non-exposed, but no difference in lung function or the pneumoproteins.

We observed indications of early effects of occupational exposure to MWCNTs on lung health and the immune system.

<AbstractText>Serum KL6/mucin 1 (MUC1) has been identified as a potential biomarker in idiopathic pulmonary fibrosis (IPF), but the role of MUC1 intracellular bioactivation in IPF is unknown.</AbstractText><AbstractText>To characterise MUC1 intracellular bioactivation in IPF.</AbstractText><p><div><b>METHODS AND RESULTS</b></div>The expression and phosphorylation of Thr⁴¹ and Tyr⁴⁶ on the intracellular MUC1-cytoplasmic tail (CT) was increased in patients with IPF (n=<em>22</em>) compared with healthy subjects (n=21) and localised to <em>fibroblasts</em> and hyperplastic alveolar type II cells. Transforming <em>growth</em> <em>factor</em> (TGF)-β1 phosphorylated SMAD3 and thereby increased the phosphorylation of MUC1-CT Thr⁴¹ and Tyr⁴⁶ in lung <em>fibroblasts</em> and alveolar type II cells, activating β-catenin to form a phospho-Smad3/MUC1-CT and MUC1-CT/β-catenin nuclear complex. This nuclear complex promoted alveolar epithelial type II and <em>fibroblast</em> to myo<em>fibroblast</em> transitions, as well as cell senescence and <em>fibroblast</em> proliferation. The inhibition of MUC1-CT nuclear translocation using the inhibitor, GO-201 or silencing MUC1 by siRNA, reduced myo<em>fibroblast</em> transition, senescence and proliferation in vitro. Bleomycin-induced lung fibrosis was reduced in mice treated with GO-201 and in MUC1-knockout mice. The profibrotic lectin, galectin-3, directly activated MUC1-CT and served as a bridge between the TGF-β receptor and the MUC1-C domain, indicating TGF-β1-dependent and TGF-β1-independent intracellular bioactivation of MUC1.</p><AbstractText>MUC1 intracellular bioactivation is enhanced in IPF and promotes fibrotic processes that could represent potential druggable targets for IPF.</AbstractText>

Cytokines and <em>growth</em> <em>factors</em> are important at each stage of wound healing. This study aims to determine the changing profiles of these <em>factors</em> in intraperitoneal drainage, acute wound fluid, following colorectal surgery, and to correlate levels to wound healing and surgical outcomes. Acute wound fluid samples (n = 52 patients) were collected daily from postoperative day 1 until drain removal. Levels of cytokines (interleukins-6 and -1beta and tumor necrosis <em>factor</em>-alpha) and epidermal <em>growth</em> <em>factor</em>, platelet-derived <em>growth</em> <em>factor</em>, vascular endothelial derived <em>growth</em> <em>factor</em>, basic <em>fibroblast</em> <em>growth</em> <em>factor</em>, and transforming <em>growth</em> <em>factor</em>-beta1 were determined by enzyme-linked immunosorbent assay. A significant negative correlation emerged between the levels of interleukin-6, epidermal <em>growth</em> <em>factor</em>, platelet-derived <em>growth</em> <em>factor</em>, and basic <em>fibroblast</em> <em>growth</em> <em>factor</em> and the postoperative day, e.g., basic <em>fibroblast</em> <em>growth</em> <em>factor</em> : day 1, 695, median (29-2,806, range) pg/ml; day 2, 249 (1-1,784); day 3, 94 (0-7<em>22</em>); day 7, <em>22</em> (0-326) (p < 0.05, Spearman's correlation). Levels appeared to relate to the stage of wound healing. Several <em>factors</em>, in particular interleukin-1beta and tumor necrosis <em>factor</em>-alpha levels, correlated with surgical outcomes such as the need for a defunctioning stoma and/or postoperative complications. Cytokines and <em>growth</em> <em>factors</em> are involved in normal wound healing, and their levels in acute wound fluid may act as markers of wound healing and surgical outcome.

Basic <em>fibroblast</em> <em>growth</em> <em>factor</em> (bFGF or FGF-2) is a pleiotropic <em>growth</em> <em>factor</em> that promotes <em>growth</em> of mesenchymal and epithelial cells, stimulates angiogenesis and neuroprotection. Moreover, exogenous bFGF by stimulating angiogenesis promotes healing of gastroduodenal ulcers and cardiac and brain injury. All these actions were demonstrated in regard to 18kDa bFGF isoform that is secreted by cells via an ER/Golgi-independent pathway and activates FGF receptors. However in some transformed and stressed cells and in some tissues (e.g. brain) the single copy bFGF gene encodes multiple gene products: 18 kDa and also higher molecular weight (HMW) bFGF isoforms: ∼21 and ∼<em>22</em> kDa in rodents, and ∼<em>22</em>, ∼23 and ∼24 kDa in humans. The biologic roles of these HMW bFGF isoforms in vivo remain unknown. In this study we demonstrated that in normal, uninjured gastric mucosa, bFGF is almost exclusively expressed as 18kDa isoform translated through a classical AUG (methionine) codon. In contrast, in injured gastric mucosa of rat, bFGF gene is preferentially translated to HMW bFGF isoforms through alternative CUG (leucine) initiation codon. Gastric mucosal injury caused in rats a significant increase in bFGF mRNA at 8 and 24h vs. normal mucosa and a significant increase in bFGF protein at 24-72h, mainly due to increased expression of ∼21 and ∼<em>22</em> kDa HMW bFGF isoforms. This is first demonstration that gastric mucosal injury and repair triggers local activation of bFGF gene with preferential translation of HMW bFGF isoforms through a non-canonical CUG codon. This study uncovered CUG-initiated HMW bFGF translation as a novel regulatory mechanism operating in vivo during gastric injury repair.

OBJECTIVE

Fibrous dysplasia (FD) is a rare disorder characterized by pain, deformity, and pathological fractures. McCune-Albright syndrome (MAS) includes a combination of FD, hyperfunctional endocrinopathy, and/or café-au-lait pigmentation. Surgery is generally ineffective in treating FD. This study aims to evaluate the efficacy and safety of bisphosphonates (BPs), and to compare the efficacy of different bisphosphonates in FD patients.

METHODS

In this retrospective clinical study, laboratory and clinical findings of <em>22</em> polyostotic FD cases all associated with MAS were recorded before and after therapy with BPs.

RESULTS

Within the first year of therapy with BPs, the level of alkaline phosphatase (ALP) decreased by 30.3% of baseline in the alendronate case, and by <em>22</em>.7 ± 16.9% and 34.1 ± 26.3% in the pamidronate (PAM) (n=10) and zoledronic acid (ZA) (n=11) groups, respectively. There was no significant difference (P=0.256) between the PAM and ZA groups in the rate of change in ALP levels. Bone pain was alleviated in 64% of the cases. Number of affected bones was positively correlated with baseline serum ALP levels (r=0.533, P= 0.011), which was the only significant factor affecting efficacy of bisphosphonates. Bisphosphonate treatment was safe, and caused no obvious impairment on children's linear growth.

CONCLUSIONS

Our results suggest that bisphosphonates may suppress high bone turnover to partially control the activity of the disease, and are well tolerated in most patients. Zoledronic acid has similar effects as pamidronate in controlling disease activity.

BACKGROUND

25(OH)D = 25 hydroxyvitamin D; AFF = atypical femur fracture; ALP = alkaline phosphatase; β-CTX = C-terminal telopeptide of type I collagen; BPs = bisphosphonates; BTMs =bone turnover markers; FD = fibrous dysplasia; FGF 23 = fibroblast growth factor 23; GH = growth hormone; MAS = McCune-Albright syndrome; MFD = monostotic fibrous dysplasia; ONJ = osteonecrosis of the jaw; PAM = pamidronate; PFD = polyostotic fibrous dysplasia; PTH = parathyroid hormone; ULN = upper limit of normal range; ZA = zoledronic acid.