Hedgehog Signaling Antagonist Promotes Regression of Both Liver Fibrosis and Hepatocellular Carcinoma in a Murine Model of Primary Liver Cancer

Chronic fibrosing liver injury is a major risk factor for hepatocarcinogenesis in humans. Mice with targeted deletion of Mdr2 (the murine ortholog of MDR3) develop chronic fibrosing liver injury. Hepatocellular carcinoma (HCC) emerges spontaneously in such mice by 50–60 weeks of age, providing a model of fibrosis-associated hepatocarcinogenesis. We used Mdr2−/− mice to investigate the hypothesis that activation of the hedgehog (Hh) signaling pathway promotes development of both liver fibrosis and HCC

Does Saline Irrigation at Different Temperatures Affect Pain, Edema, and Trismus After Impacted Third Molar Surgery: A Clinical Trial

Purpose: Lower impacted third molar surgery is a very common oral-maxillofacial surgical procedure, which has complications such as facial swelling, pain, and trismus. This clinical trial aimed to compare the intensity of postoperative morbidity (pain, facial swelling, and trismus) following the third molar surgery performed using saline irrigation at different temperatures (4 degrees C, 10 degrees C, or 25 degrees C).Materials and Methods: This double-blind, single-center, split-mouth, randomized prospective clinical trial was conducted among 48 systemically and periodontally healthy patients who had bilaterally asymp-tomatic mandibular third molars. Patients were randomly allocated into 2 groups (n = 24) according to the temperature of the saline used. In each patient, one impacted third molar was determined as the test group (4 degrees C or 10 degrees C saline irrigation) and the other impacted third molar as the control group (25 degrees C saline irri-gation). Trismus and swelling were evaluated on the 1st, 3rd, and 7th days postoperatively. Pain perception by visual analog scale (VAS) and the total number of analgesics taken during the 7 postoperative days were recorded. Data were analyzed using the Shapiro-Wilk test, the chi-square test, one-way analysis of variance, Duncan test, the Kruskal-Wallis test, the Dunn test, and the Friedman test (P < .05).Results: Forty-eight patients (28 females, 20 males) with a mean age of 24.6 +/- 3.8 years were included in the study. The duration of operations was similar. VAS values of test groups [test group 1 (4 degrees C): 4.0, test group 1 (10 degrees C): 8.0] and the number of analgesics taken [test group 1 (4 degrees C): 0, test group 1 (10 degrees) C): 3] were significantly lower (P < .001) than control groups (VAS, control group 1: 13.0, control group 2: 15.5, number of analgesic taken, control group 1: 5.5, control group 2: 4.0). Significant differences were found between the test groups in VAS values and the number of analgesics taken (P < .001). Also, the lowest trismus and facial swelling values were detected in the 4 degrees C test group at all time points (P < .001). Conclusion: In the impacted third molar surgery, the use of cooled saline irrigation during bone removal may be a simple, inexpensive, and effective method for reducing early postoperative complaints. (c) 2022 American Association of Oral and Maxillofacial Surgeon

Pazopanib for metastatic soft-tissue sarcoma: A multicenter retrospective study

Purpose: Soft tissue sarcomas are associated with a poor prognosis and low chemotherapeutic efficiency. Pazopanib is an orally available multi-tyrosine kinase inhibitor that was explored in patients with non-adipocytic advanced soft tissue sarcomas. The aim of this retrospective study was to evaluate the real life data of single-agent pazopanib efficacy and safety for soft tissue sarcomas in the Turkish population. Materials and methods: We evaluated a total of 103 patients (41 males, 62 females) who received pazopanib for advanced non-adipocytic soft tissue sarcomas diagnosis in eight centers of Turkey, retrospectively. The pazopanib dose was 800 mg once daily. Progression-free survival, overall survival, and adverse events were analyzed. Results: The median age was 50 years (range, 38–58). Majority of the patients had leimyosarcoma (41%). Median progression-free survival was 4.3 months, and the median overall survival was 10.1 months. The main common toxicities were fatigue, anorexia, weight loss, nausea, hypertension, and grade ≥3 toxicities were fatigue, anorexia, weight loss, and liver disorder. Conclusion: Pazopanib is an efficient and tolerable agent and is well tolerated in good performance status patients with relapsed, advanced non-adipocytic soft tissue sarcomas. © The Author(s) 2020

Tracing preferential saline seepage and assessing its flow velocities using temperature measurements

Upward seepage of saline groundwater leads to surface water salinization in deep polders in The Netherlands. As preferential saline seepage via boils is the dominant salinization process in the Dutch deep polders, we started a detailed monitoring program around three boils. Temperature measurements with a fiber optic cable were used to trace the preferential seepage flow paths. Temperature depth profiles around the boils were measured to evaluate flow velocities

Osteopontin is induced by hedgehog pathway activation and promotes fibrosis progression in nonalcoholic steatohepatitis

BACKGROUND: Nonalcoholic steatohepatitis (NASH) is a leading cause of cirrhosis. Recently, we showed that NASH-related cirrhosis is associated with Hedgehog (Hh) pathway activation. The gene encoding Osteopontin (OPN), a pro-fibrogenic extracellular matrix protein and cytokine, is a direct transcriptional target of the Hh pathway. Thus, we hypothesized that Hh signaling induces OPN to promote liver fibrosis in NASH. METHODS: Hepatic OPN expression and liver fibrosis were analyzed in wild-type (WT) mice, Patched-deficient (Ptc+/−) (overly-active Hh signaling) mice, and OPN-deficient mice before and after feeding methionine-choline deficient (MCD) diets to induce NASH-related fibrosis. Hepatic OPN was also quantified in human NASH and non-diseased livers. Hh signaling was manipulated in cultured liver cells to assess direct effects on OPN expression, and hepatic stellate cells (HSC) were cultured in medium with different OPN activities to determine effects on HSC phenotype. RESULTS: When fed MCD diets, Ptc+/− mice expressed more OPN and developed worse liver fibrosis (p<0.05) than WT mice, while OPN-deficient mice exhibited reduced fibrosis (p<0.05). In NASH patients, OPN was significantly up-regulated and correlated with Hh pathway activity and fibrosis stage. During NASH, ductular cells strongly expressed OPN. In cultured HSC, SAG (a Hh agonist) upregulated, while Cyclopamine (a Hh-antagonist) repressed, OPN expression (p<0.005). Cholangiocyte-derived OPN and recombinant OPN promoted fibrogenic responses in HSC (p<0.05); neutralizing OPN with RNA-aptamers attenuated this (p<0.05). CONCLUSIONS: OPN is Hh-regulated and directly promotes pro-fibrogenic responses. OPN induction correlates with Hh pathway activity and fibrosis-stage Therefore, OPN inhibition may be beneficial in NASH

Leptin Promotes the Myofibroblastic Phenotype in Hepatic Stellate Cells by Activating the Hedgehog Pathway

Trans-differentiation of quiescent hepatic stellate cells (Q-HSCs), which exhibit epithelial and adipocytic features, into myofibroblastic-HSC (MF-HSCs) is a key event in liver fibrosis. Culture models demonstrated that Hedgehog (Hh) pathway activation is required for transition of epithelioid/adipocytic Q-HSCs into MF-HSCs. Hh signaling inhibits adiposity and promotes epithelial-to-mesenchymal transitions (EMTs). Leptin (anti-adipogenic, pro-EMT factor) promotes HSC trans-differentiation and liver fibrosis, suggesting that the pathways may interact to modulate cell fate. This study aimed to determine whether leptin activates Hh signaling and whether this is required for the fibrogenic effects of leptin. Cultures of primary HSCs from lean and fa/fa rats with an inherited ObRb defect were examined. Inhibitors of PI3K/Akt, JAK/STAT, and Hh signaling were used to delineate how ObRb activation influenced Hh signaling and HSC trans-differentiation. Fibrogenesis was compared in wild type and db/db mice (impaired ObRb function) to assess the profibrotic role of leptin. The results demonstrate that leptin-ObR interactions activate Hh signaling with the latter necessary to promote trans-differentiation. Leptin-related increases in Hh signaling required ObR induction of PI3K/Akt, which was sufficient for leptin to repress the epithelioid/adipocytic program. Leptin-mediated induction of JAK/STAT was required for mesenchymal gene expression. Leptin-ObRb interactions were not necessary for HSC trans-differentiation to occur in vitro or in vivo but are important because liver fibrogenesis was attenuated in db/db mice. These findings reveal that leptin activates Hh signaling to alter gene expression programs that control cell fate and have important implications for liver fibrosis and other leptin-regulated processes involving EMTs, including development, obesity, and cancer metastasis