[Venous thromboembolism and risk factors for deep vein thrombosis in patients with pancreatic cancer undergoing chemotherapy].

Among various types of cancers, pancreatic cancer is known to be prone to venous thromboembolism (VTE). We investigated the complication rate of VTE and risk factors for deep vein thrombosis (DVT) in patients with pancreatic cancer undergoing chemotherapy. We retrospectively analyzed the data of 51 patients with pancreatic cancer who had undergone chemotherapy at our hospital from January 2016 to March 2021, had their D-dimer levels measured at the initial visit, and had undergone venous ultrasonography if D-dimer levels were elevated. At the initial visit, the complication rate of VTE was 35.3% (18/51 patients). Multivariate analysis revealed that the risk factors for DVT were primary tumors in the pancreas's body and tail and elevated D-dimer levels. Patients with DVT tended to have shorter overall survival than those without (218 vs 523 days). Patients with pancreatic cancer frequently develop VTE and should be aggressively screened for thrombosis, particularly in those with primary tumors in the pancreas's body and tail and elevated D-dimer levels.

Gastrointestinal stromal tumors in the duodenum show increased contrast enhancement compared with those in the stomach on computed tomography.

Duodenal gastrointestinal stromal tumors (D-GISTs) are a rare and relatively small subset of GISTs whose imaging features are not well known. The present study aimed to evaluate the enhancement pattern of D-GISTs compared with that of gastric GISTs (G-GISTs) using dynamic computed tomography. This single-center, retrospective, clinicopathological analysis was conducted on 10 patients with D-GISTs who underwent surgery between June 2006 and October 2018. In the same period, 25 patients with G-GISTs underwent surgery and were enrolled. The contrast ratio was defined as the ratio between Hounsfield units in contrast enhanced and unenhanced images in different phases, and these ratios were compared between the D-GIST and G-GIST groups. Furthermore, microvessel density, analyzed by immunohistochemical staining for CD31, was compared between the D-GIST and G-GIST groups. The contrast ratio of D-GIST was significantly higher than that of G-GIST in the arterial, portal and delayed phases (P<0.01, P<0.01 and P=0.02, respectively). The microvessel density of the D-GISTs was significantly higher than that of the G-GISTs (P<0.0001). D-GISTs were more hypervascular than G-GISTs on both imaging and pathological analyses.

Fluvastatin promotes chondrogenic differentiation of adipose-derived mesenchymal stem cells by inducing bone morphogenetic protein 2.

BACKGROUND: Adipose-derived mesenchymal stem cells (ADMSCs) are a promising source of material source for medical regeneration of cartilage. Growth factors, including transforming growth factor-ß (TGFß) subfamily members and bone morphogenetic proteins (BMPs), play important roles in inducing and promoting chondrogenic differentiation of MSCs. However, these exogenous growth factors have some drawbacks related to their cost, biological half-life, and safety for clinical application. Several studies have reported that statins, the competitive inhibitors of 3-hydroxy-2-methylglutaryl coenzyme A (HMG-CoA) reductase, induce the expression of BMP2 in multiple cell types as the pleotropic effects. The objective of this study was to investigate the effects of fluvastatin during chondrogenic differentiation of human ADMSCs (hADMSCs). METHODS: The effects of fluvastatin were analyzed during chondrogenic differentiation of hADMSCs in the pellet culture without exogenous growth factors by qRT-PCR and histology. For functional studies, Noggin, an antagonist of BMPs, mevalonic acid (MVA) and geranylgeranyl pyrophosphate (GGPP), metabolites of the mevalonate pathway, ROCK inhibitor (Y27632), or RAC1 inhibitor (NSC23766) were applied to cells during chondrogenic differentiation. Furthermore, RhoA activity was measured by RhoA pulldown assay during chondrogenic differentiation with or without fluvastatin. Statistically significant differences between groups were determined by Student's t-test or the Tukey-Kramer test. RESULTS: Fluvastatin-treated cells expressed higher levels of BMP2, SOX9, ACAN, and COL2A1 than control cells, and accumulated higher levels of glycosaminoglycans (GAGs). Noggin significantly inhibited the fluvastatin-mediated upregulation of ACAN and COL2A1. Both MVA and GGPP suppressed the effects of fluvastatin on the expressions of BMP2, SOX9, ACAN, and COL2A1. Furthermore, fluvastatin suppressed the RhoA activity, and inhibition of RhoA-ROCK signaling by Y27632 increased the expressions of BMP2, SOX9, ACAN, and COL2A1, as well as fluvastatin. CONCLUSIONS: Our results suggest that fluvastatin promotes chondrogenic differentiation of hADMSCs by inducing endogenous BMP2, and that one of the mechanisms underlying the effects is inhibition of RhoA-ROCK signaling via suppression of GGPP. Fluvastatin is a safe and low-cost compound that holds promise for use in transplantation of hADMSCs for cartilage regeneration.

C10orf10/DEPP activates mitochondrial autophagy and maintains chondrocyte viability in the pathogenesis of osteoarthritis.

Osteoarthritis (OA), the most prevalent joint disease, is characterized by the progressive loss of articular cartilage. Autophagy, a lysosomal degradation pathway, maintains cellular homeostasis, and autophagic dysfunction in chondrocytes is a hallmark of OA pathogenesis. However, the cause of autophagic dysfunction in OA chondrocytes remains incompletely understood. Recent studies have reported that decidual protein induced by progesterone (C10orf10/DEPP) positively regulates autophagic functions. In this study, we found that DEPP was involved in mitochondrial autophagic functions of chondrocytes, as well as in OA pathogenesis. DEPP expression decreased in human OA chondrocytes in the absence or presence of pro-inflammatory cytokines, and was induced by starvation, hydrogen peroxide (H2 O2 ), and hypoxia (cobalt chloride). For functional studies, DEPP knockdown decreased autophagic flux induced by H2 O2 , whereas DEPP overexpression increased autophagic flux and maintained cell viability following H2 O2 treatment. DEPP was downregulated by knockdown of forkhead box class O (FOXO) transcription factors and modulated the autophagic function regulated by FOXO3. In an OA mouse model by destabilization of the medial meniscus, DEPP-knockout mice exacerbated the progression of cartilage degradation with TUNEL-positive cells, and chondrocytes isolated from knockout mice were decreased autophagic flux and increased cell death following H2 O2 treatment. Subcellular fractionation analysis revealed that mitochondria-located DEPP activated mitochondrial autophagy via BCL2 interacting protein 3. Taken together, our data demonstrate that DEPP is a major stress-inducible gene involved in the activation of mitochondrial autophagy in chondrocytes, and maintains chondrocyte viability during OA pathogenesis. DEPP represents a potential therapeutic target for enhancing autophagy in patients with OA.

G protein-coupled receptor kinase 5 deletion suppresses synovial inflammation in a murine model of collagen antibody-induced arthritis.

G protein-coupled receptor kinase 5 (GRK5) regulates inflammatory responses via the nuclear factor-kappa B (NF-κB) pathway. This study investigated the functional involvement of GRK5 in the pathogenesis of inflammatory arthritis. Immunohistochemically, rheumatoid arthritis (RA) synovium had a significantly higher proportion of GRK5-positive cells in the synovial lining layer than healthy control synovium. Gene expression and NF-κB activation in lipopolysaccharide-stimulated human SW982 synovial cells were significantly suppressed by silencing of the GRK5 gene. Similarly, GRK5 kinase activity inhibition in human primary RA synovial cells attenuated gene expressions of inflammatory factors. In a murine model of collagen antibody-induced arthritis, arthritis scores and serum IL6 production of GRK5 knockout (GRK5-/-) mice were significantly lower than those of wild-type mice. Histologically, the degree of synovitis and cartilage degeneration in GRK5-/- mice was significantly lower than in wild-type mice. In in vitro analyses using activated murine macrophages and fibroblast-like synoviocytes, gene expression of inflammatory factors and p65 nuclear translocation were significantly lower in GRK5-/- mice compared to wild-type mice. In conclusion, our results suggested that GRK5 is deeply involved in the pathogenesis of inflammatory arthritis, therefore, GRK5 inhibition could be a potential therapeutic target for types of inflammatory arthritis such as RA.

Prevention of Post-Endoscopic Retrograde Cholangiopancreatography Pancreatitis by Endoscopic Pancreatic Stenting after Insertion of Self-Expandable Metal Stent for Malignant Distal Biliary Stricture.

The insertion of a self-expandable metal stent (SEMS) for nonpancreatic cancer is a factor predicting the risk of post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP). We evaluated the efficacy of endo-scopic pancreatic stenting (EPS) to prevent PEP after SEMS insertion in patients with malignant distal biliary stricture and without main pancreatic duct (MPD) obstruction. We performed a single-center, retrospective, historically controlled investigation to assess the outcomes of 33 consecutive patients who underwent SEMS insertion. From March 2013 to June 2015, 13 patients did not undergo EPS (Non-EPS group). The other 20 patients underwent EPS (EPS group) between July 2015 and August 2018. The background data demonstrated no significant differences. Except for one patient in the Non-EPS group, all patients underwent biliary sphinc-terotomy. The EPS group's PEP incidence was significantly lower (n = 1, 5%) than that of the Non-EPS group (n = 4, 31%) (p = 0.04). The median serum amylase and lipase levels after the procedure were significantly lower in the EPS group than in the Non-EPS group (amylase: 104 vs. 262 U/L; p < 0.01, lipase: 102 vs. 666 U/L; p = 0.01). The use of EPS decreased the incidence of PEP after SEMS insertion in individuals with malignant distal biliary stricture and without MPD obstruction.