This study evaluated the effects of the chronic consumption of different concentrations of alcohol on the experimental periodontitis (EP). 160 rats were divided into 4 groups: (EP-NT) rats with EP ...and no alcohol exposure; (EP-A14) rats with EP exposed to 14% alcohol; (EP-A25) rats with EP exposed to 25% alcohol; (EP-A36) rats with EP exposed to 36% alcohol. The animals from the EP-A14, EP-A25 and EP-A36 groups were subjected to different concentrations of alcohol 30 days before EP induction. The histological characteristics, percentage of bone in the furcation (PBF) and bone metabolism in the furcation region were evaluated. The PBF and tartrate-resistant acid phosphatase (TRAP) data were subjected to statistical analysis. The EP-A14, EP-A25 and EP-A36 groups had lower PBFs compared with the EP-NT group. A more severe inflammatory process and a greater number of TRAP+ cells were also observed. In the EP-A14, EP-A25 and EP-A36 groups, the inflammatory process became more severe as the ingested alcoholic concentration increased. An increase in RANKL immunolabeling and a significantly higher number of TRAP+ cells were also observed. We conclude that chronic alcohol consumption increases the severity of experimental periodontitis in a dose-dependent manner by increasing the magnitude of local inflammatory responses and stimulating alveolar bone resorption.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The identity of the transporter responsible for fructose absorption in the intestine in vivo and its potential role in fructose-induced hypertension remain speculative. Here we demonstrate that Glut5 ...(Slc2a5) deletion reduced fructose absorption by ∼75% in the jejunum and decreased the concentration of serum fructose by ∼90% relative to wild-type mice on increased dietary fructose. When fed a control (60% starch) diet, Glut5-/- mice had normal blood pressure and displayed normal weight gain. However, whereas Glut5+/+ mice showed enhanced salt absorption in their jejuna in response to luminal fructose and developed systemic hypertension when fed a high fructose (60% fructose) diet for 14 weeks, Glut5-/- mice did not display fructose-stimulated salt absorption in their jejuna, and they experienced a significant impairment of nutrient absorption in their intestine with accompanying hypotension as early as 3–5 days after the start of a high fructose diet. Examination of the intestinal tract of Glut5-/- mice fed a high fructose diet revealed massive dilatation of the caecum and colon, consistent with severe malabsorption, along with a unique adaptive up-regulation of ion transporters. In contrast to the malabsorption of fructose, Glut5-/- mice did not exhibit an absorption defect when fed a high glucose (60% glucose) diet. We conclude that Glut5 is essential for the absorption of fructose in the intestine and plays a fundamental role in the generation of fructose-induced hypertension. Deletion of Glut5 results in a serious nutrient-absorptive defect and volume depletion only when the animals are fed a high fructose diet and is associated with compensatory adaptive up-regulation of ion-absorbing transporters in the colon.
Alternatively spliced tissue factor (asTF) promotes neovascularization and monocyte recruitment via integrin ligation. While asTF mRNA has been detected in some pancreatic ductal adenocarcinoma ...(PDAC) cell lines and increased asTF expression can promote PDAC growth in a subcutaneous model, the expression of asTF protein in bona fide PDAC lesions and/or its role in metastatic spread are yet to be ascertained. We here report that asTF protein is abundant in lesional and stromal compartments of the five studied types of carcinoma including PDAC. Analysis of 29 specimens of PDAC revealed detectable asTF in >90% of the lesions with a range of staining intensities. asTF levels in PDAC lesions positively correlated with the degree of monocyte infiltration. In an orthotopic model, asTF‐overexpressing high‐grade PDAC cell line Pt45P1/asTF+ produced metastases to distal lymph nodes, which stained positive for asTF. PDAC cells stimulated with and/or overexpressing asTF exhibited upregulation of genes implicated in PDAC progression and metastatic spread. Pt45P1/asTF+ cells displayed higher coagulant activity compared to Pt45P1 cells; the same effect was observed for cell‐derived microparticles (MPs). Our findings demonstrate that asTF is expressed in PDAC and lymph node metastases and potentiates PDAC spread in vivo. asTF elicits global changes in gene expression likely involved in tumor progression and metastatic dissemination, and it also enhances the procoagulant potential of PDAC cells and cell‐derived MPs. Thus, asTF may comprise a novel therapeutic target to treat PDAC and, possibly, its thrombotic complications.
What's new?
Alternatively spliced tissue factor (asTF) triggers the growth of new blood vessels and is present at elevated levels in certain cancers, indicating that it could play an important role in tumor growth and metastasis. Here, asTF was found to be abundant in human pancreatic ductal adenocarcinoma (PDAC) lesions and stromal monocytes, and its overexpression potentiated PDAC metastasis in vivo. Furthermore, asTF augmented EGFR‐linked signaling pathways in PDAC cells and contributed to the coagulant activity of PDAC cells and cell‐derived microparticles. The findings suggest that asTF may be a key target for stemming metastatic spread and complications in PDAC.
•Green tea extract (GTE) adjuvant to scaling and root planning (SRP) reduces alveolar bone loss in experimental periodontitis.•GTE adjuvant to SRP improves inflammatory markers and reduces the number ...of TRAP-positive cells.•GTE is a secure and effective adjuvant therapy to scaling and root planning for the treatment of experimental periodontitis.
This study evaluated the effects of topical green tea extract solution (GTE) as adjuvant therapy to mechanical debridement for the treatment of experimental periodontitis (EP).
We used 120 male rats (Rattus norvegicus albinus – Wistar), divided into the following four groups: NEP (sham) (n = 30): no experimental periodontitis (NEP), only simulation of EP by installation and removal of a ligature; EP (n = 30): EP induction by ligature; SRP (n = 30): EP, scaling and root planing (SRP), and irrigation with physiological saline solution; SRP/GT (n = 30): EP, SRP, and irrigation with GTE. Histologic analysis and immunohistochemistry were performed for detection of interleukin (IL)1ß, tumor necrosis factor-alpha (TNF-α), IL-10, and anti-tartrate resistant acid phosphatase (TRAP) in the furcation area. The percentage of bone in the furcation (PBF) was considered the primary variable and evaluated at 14, 22, and 37 days. The data from the histological analysis and the IL- 1B, TNF- A, and IL-10 were submitted to a Kruskal-Wallis variance test and Dunn’s posttest (p ≤ 0.05). The histometric data and TRAP were submitted to analysis of variance (ANOVA) and Tukey’s posttest (p ≤ 0.05).
The SRP/GT group showed lower inflammatory process, lower immunolabeling pattern of IL-1ß and TNF-α, and greater immunolabeling pattern of IL-10 compared with the EP and SRP groups at 22 days. Fewer TRAP-positive multinucleated osteoclasts were observed in all periods in the SRP/GT group (5.22 ± 0.65; 7.33 ± 0.80; 8.55 ± 1.15) compared with the SRP group (30.67 ± 8.55; 13.22 ± 0.77; 13.87 ± 0.77). Higher PBF was observed in all periods in the SRP/GT group (74.65 ± 7.14; 76.61 ± 5.36; 79.24 ± 3.75) compared with the SRP group (61.60 ± 9.48; 54.84 ± 9.06; 53.25 ± 9.66).
GTE adjuvant to SRP reduced inflammation, osteoclastic activity, and alveolar bone loss in EP.
Therapy related chronic myelomonocytic leukemia (t-CMML) is rare. We report a 23-year-old female who developed acute fulminant hepatic failure after drug overdose. She underwent ABO incompatible ...orthotopic liver transplant. She received cyclophosphamide along with other immunosuppressants. Seven years later, she was diagnosed with t-CMML-2 with 45XX,-7 karyotype. She received 4 cycles of azacitidine and proceeded with allogeneic bone marrow transplant. This is the first a case of t-CMML reported in a liver transplant recipient. In this article, we also summarize all reported cases of t-CMML, and we review therapy related MDS in recipients of solid organ transplant.
To assess sodium alendronate as a local adjunctive therapy for treating experimental periodontitis in male rats treated with chemotherapy.
One-hundred-eighty male rats were randomly divided into two ...groups (n = 90) based on the systemic treatments: PSS, physiological saline solution; and 5-Fluorouracil, and then, subdivided into three subgroups (n = 30): NT, no treatment; scaling and root planing; and sodium alendronate. Treatments were performed 7 days after induction of experimental periodontitis. Specimens were collected at 14, 22, and 37 days after induction. Alveolar bone level, percentage of bone in the furcation, percentage of non-vital bone in the furcation, histopathologic features, and immunolabeling pattern for tartrate-resistant acid phosphatase (TRAP) and osteocalcin (OCN) were evaluated.
The lowest amount of alveolar bone and highest amount of non-vital bone was found in group 5-Fluorouracil when no treatment was performed. In animals receiving 5-Flurouracil and subjected to periodontal treatment, adjunctive sodium alendronate resulted in higher percentage of bone in the furcation and higher alveolar bone loss, when compared with scaling and root planing alone. Better structural and cellularity patterns were found in the periodontal tissues when sodium alendronate was used, regardless of systemic treatment. Higher TRAP-expression was found when no treatment was performed. Sodium alendronate didn’t affect the immunolabeling pattern of osteocalcin in the presence of 5-Fluorouracil.
Adjunctive therapy with local sodium alendronate prevented alveolar bone loss and improved the histopathological features of the periodontal tissues following scaling and root planing in male rats with experimental periodontitis receiving anticancer chemotherapy with 5-Fluorouracil.
•5-Fluorouracil (5FU) aggravates experimental periodontitis (EP).•5-FU reduces the effectiveness of scaling and root planing (SRP).•Sodium alendronate (SA) improves tissue response after SRP in 5-FU animals.•SA reduces the alveolar bone loss in 5-FU animals.•SA is an effective adjunctive therapy to treat EP in rats under 5-FU.
Abstract
Background: Pancreatic cancer remains extremely difficult to treat, resulting in an 80% 1-year mortality rate. Tissue Factor (TF) serves as a co-factor for serine protease factor VIIa and ...the full-length (fl)TF/VIIa complex initiates blood coagulation. Alternatively spliced isoform of TF (asTF) occurs naturally, is minimally coagulant and, in contrast to flTF, dispensable for normal hemostasis. flTF is overexpressed in many forms of cancer and contributes to malignant growth; however, targeting flTF is risky due to the possibility of bleeding complications. We previously described that asTF is highly expressed in pancreatic ductal adenocarcinoma (PDAC) which account for ~75% of pancreatic cancer cases. Through non-canonical interactions with β1 integrins, asTF promotes activation of Akt and p42/44 MAPK, thus potentiating cancer cell migration and proliferation. We recently developed asTF-specific monoclonal antibody that inhibited growth and spread of PDAC in vivo in an orthotopic setting (Unruh et al, Oncotarget, in press). At this time it is not known whether, aside from PDAC, asTF also contributes to pathobiology of other pancreatic tumors such as pancreatic neuroendocrine tumors (pNET). Although pNETs comprise a minority subset of pancreatic cancer cases, pNET incidence is rapidly increasing and new therapies are thus needed for patients who ultimately progress on second line therapies which include mTOR inhibitors.
Objective: To evaluate i) expression of asTF in pNET, and ii) potential utility of targeting intracellular pathways engaged by asTF in pNET.
Methods: A tissue microarray containing 6 human pNET specimens was immunostained for asTF. Two human pNET cell lines, QGP1 and BON (a kind gift of Dr. Courtney Townsend, UTMB), were evaluated for TF isoform expression and their responsiveness to mTOR inhibition using the dual PI3K/mTOR ATP-site competitive inhibitor BEZ235.
Results: All 6 pNET tissue specimens stained positive for asTF: 4 samples were highly positive and the remaining 2 moderately positive; normal pancreatic tissue specimens in the microarray exhibited minimal staining for asTF. qRT-PCR and western blotting analyses revealed that BON and QGP1 express flTF as well as asTF mRNA and protein, respectively. Compared to QGP1 cells, BON cells expressed ~3 fold more asTF and ~10 fold more flTF. Western blotting revealed that, compared to QGP1 cells, BON cells express significantly higher levels of β1 integrin. Treatment of QGP1 and BON cells with BEZ235 (400nM, 48 hours) markedly suppressed phosphorylation of mTOR targets including Akt, S6K1, 4E-BP1, and ULK1.
Conclusion: To our knowledge, this is the first study to report that flTF and asTF are expressed in pNET tumor tissue and cultured cells. In pNET cell lines QGP1 and BON, BEZ235 effectively reduced phosphorylation of Akt, a downstream target of the pathways activated by asTF:β1 interactions. Further studies are warranted to evaluate asTF as a potential target in pNET, specifically strategies aimed at concurrent inhibition of asTF:β1 interactions and Akt/S6K1 activity.
Citation Format: Clayton S. Lewis, Hala Elnakat Thomas, Fred V. Lucas, Vladimir Y. Bogdanov.{Authors}. Expression of alternatively spliced tissue factor in pancreatic neuroendocrine tumors. abstract. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A39.
Essentials
Tissue factor (TF) isoforms are expressed in pancreatic neuroendocrine tumors (pNET).
TF knockdown inhibits proliferation of human pNET cells in vitro.
mTOR kinase inhibitor ...sapanisertib/MLN0128 suppresses TF expression in human pNET cells.
Sapanisertib suppresses TF expression and activity and reduces the growth of pNET tumors in vivo.
Summary
Background
Full‐length tissue factor (flTF) and alternatively spliced TF (asTF) contribute to growth and spread of pancreatic ductal adenocarcinoma. It is unknown, however, if flTF and/or asTF contribute to the pathobiology of pancreatic neuroendocrine tumors (pNETs).
Objective
To assess TF expression in pNETs and the effects of mTOR complex 1/2 (mTORC1/2) inhibition on pNET growth.
Methods
Human pNET specimens were immunostained for TF. Human pNET cell lines QGP1 and BON were evaluated for TF expression and responsiveness to mTOR inhibition. shRNA were used to knock down TF in BON. TF cofactor activity was assessed using a two‐step FXa generation assay. TF promoter activity was assessed using transient transfection of human TF promoter‐driven reporter constructs into cells. Mice bearing orthotopic BON tumors were treated with the mTORC1/2 ATP site competitive inhibitor sapanisertib/MLN0128 (3 mg kg−1, oral gavage) for 34 days.
Results
Immunostaining of pNET tissue revealed flTF and asTF expression. BON and QGP1 expressed both TF isoforms, with BON exhibiting higher levels. shRNA directed against TF suppressed BON proliferation in vitro. Treatment of BON with sapanisertib inhibited mTOR signaling and suppressed TF levels. BON tumors grown in mice treated with sapanisertib had significantly less TF protein and cofactor activity, and were smaller compared with tumors grown in control mice.
Conclusions
TF isoforms are expressed in pNETs. Sapanisertib suppresses TF mRNA and protein expression as well as TF cofactor activity in vitro and in vivo. Thus, further studies are warranted to evaluate the clinical utility of TF‐suppressing mTORC1/2 inhibitor sapanisertib in pNET management.
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