Pancreatic stellate cells (PSC), which are implicated in desmoplasia in pancreatic cancer, enhance the malignancy of cancer cells and confer resistance to established treatments. We investigated ...whether the antifibrotic agent pirfenidone can suppress desmoplasia and exert antitumor effects against pancreatic cancer. Primary PSCs were established from pancreatic cancer tissue obtained during surgery. In vitro, pirfenidone inhibited the proliferation, invasiveness, and migration of PSCs in a dose-dependent manner. Although supernatants of untreated PSCs increased the proliferation, invasiveness, and migration of pancreatic cancer cells (PCC), supernatants of pirfenidone-treated PSCs decreased these effects. Exposure to PCC supernatant increased the production of platelet-derived growth factor-A, hepatic growth factor, collagen type I, fibronectin, and periostin in PSCs, which was significantly reduced by pirfenidone. Mice were subcutaneously implanted with PCCs (SUIT-2 cells) and PSCs into the right flank and PCCs alone into the left flank. Oral administration of pirfenidone to these mice significantly reduced tumor growth of co-implanted PCCs and PSCs, but not of PCCs alone. Pirfenidone also decreased the proliferation of PSCs and the deposition of collagen type I and periostin in tumors. In mice with orthotopic tumors consisting of PCCs co-implanted with PSCs, pirfenidone suppressed tumor growth, reduced the number of peritoneal disseminated nodules, and reduced the incidence of liver metastasis. Pirfenidone in combination with gemcitabine more effectively suppressed orthotopic tumor growth compared with pirfenidone or gemcitabine alone. In conclusion, our findings indicate that pirfenidone is a promising antitumor agent for pancreatic cancer, owing to its suppression of desmoplasia through regulating PSCs.
•Forward dynamics simulation of elderly gait was conducted.•Effects of gait adaptation to muscle weakness were evaluated.•Stable walking was formed against muscle weakness due to gait adaptation.•Two ...criteria were assumed as motion criteria in elderly gait.•Gait characteristics differed depending on motion criteria.
Age-related changes of human gait characteristics associated with muscle weakness have been reported in previous studies. Human gait is considered as a cyclic motion adapted to individual body-characteristics and the surrounding-environment based on motion criteria. Based on this hypothesis, elderly gait characteristics may be caused by an adaptation to muscle weakness.
What role does gait adaptation to muscle weakness play in the development of elderly gait, and what criteria are used in elderly gait adaptation?
We examined the effects of gait adaptation to muscle weakness on steady gait characteristics using computational forward dynamics simulation with a two-dimensional neuro-musculo-skeletal model. For gait adaptation, we tested two motion criteria: (i) energy cost minimization, which is a widely used criterion for healthy adults; and (ii) energy rate minimization, based on existing measurements of elderly gait characteristics.
Progression of muscle weakness enhanced the reduction of joint angle motion and minimum toe clearance, and finally resulted in falling. Gait adaptation to muscle weakness successfully formed stable walking patterns regardless of motion criteria, even at muscle weakness of 30 %, which represents a moderate degree of elderly muscle weakness. When criterion (i) was used, the time courses of joint motion were similar to those of healthy adults and a relatively high level of muscle activation was found in the whole gait cycle to compensate for muscle weakness. When criterion (ii) was used, the muscle activity level was lower than that of criterion (i) to minimize the energy rate, and the constructed gait successfully captured the characteristics of elderly gait reported in previous studies.
These findings suggest that gait adaptation to muscle weakness plays an essential role in the development of stable gait characteristics, whereas elderly people might use a different motion criterion compared with healthy adults in gait adaptation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
IgG4-related disease (IgG4-RD) is a novel clinical entity proposed in Japan in the 21th century and is attracting strong attention over the world. The characteristic manifestations of IgG4-RD are ...increased serum IgG4 concentration and tumefaction by IgG4(+) plasma cells. Although the clinical manifestations in various organs have been established, the pathogenesis of IgG4-RD is still unknown. Recently, many reports of aberrant acquired immunity such as Th2-diminated immune responses have been published. However, many questions still remain, including questions about the pathogenesis of IgG4-RD and the roles of IgG4. In this review, we discuss the pathogenesis of IgG4-RD by focusing on the cross-talk between innate and acquired immunity.
Steroid therapy appeared to be a standard treatment for autoimmune pancreatitis (AIP), although some AIP patients improve spontaneously. The indications for steroid therapy in AIP patients are ...symptoms such as obstructive jaundice, abdominal pain, and back pain, and the presence of symptomatic extrapancreatic lesions. Before steroid therapy, jaundice should be managed by biliary drainage in patients with obstructive jaundice, and blood glucose levels should be controlled in patients with diabetes mellitus. For the initial oral prednisolone dose for induction of remission, 0.6 mg/kg/day is recommended. The initial dose is administered for 2-4 weeks, and the dose is tapered by 5 mg every 1-2 weeks, based on changes in the clinical manifestations, biochemical blood tests (such as liver enzymes and IgG or IgG4 levels), and repeated imaging findings (US, CT, MRCP, ERCP, etc.). The dose is tapered to a maintenance dose (2.5-5 mg/day) over a period of 2-3 months. Steroid therapy should be stopped based on the disease activity in each case. Stopping of maintenance therapy should be planned within at least 3 years in cases with radiological and serological improvement. Re-administration or dose-up of steroid is effective for treating AIP relapses. The prognosis of AIP appears to be good over the short-term with steroid therapy. It is unclear whether the long-term outcome is good because there are many unknown factors, such as relapse, pancreatic exocrine or endocrine dysfunction, and associated malignancy.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background There have been few epidemiological studies on gastroenteropancreatic neuroendocrine tumors (GEP-NETs) in Japan. Methods We examined the epidemiology of GEP-NETs pancreatic endocrine ...tumors (PETs) and gastrointestinal neuroendocrine tumors (GI-NETs) in Japan in 2005 using a nationwide stratified random sampling method. Results A total of 2,845 individuals received treatment for PETs. Prevalence was estimated as 2.23/100,000 with an annual onset incidence of 1.01/100,000. Non-functioning tumor (NF)-PET constituted 47.4%, followed by insulinoma (38.2%) and gastrinoma (7.9%). Distant metastases were reported in 21% patients with NF-PETs and occurred more frequently as tumor size increased (>2 cm). Multiple endocrine neoplasia type 1 (MEN-1) was detected in 10% of PETs but only in 6.1% of NF-PETs. NF-PETs were detected incidentally by physical examination in 24% patients. In 2005, an estimated 4,406 patients received treatment for GI-NETs. Prevalence was estimated as 3.45/100,000, with an annual onset incidence of 2.10/100,000. The locations of GI-NETs varied: foregut, 30.4%; midgut, 9.6%; and hindgut, 60.0%. Distant metastases were observed in 6%. Lymph node metastases occurred more frequently as tumor size increased (>1 cm). The frequency of MEN-1 complications was 1%. Physical examination revealed GI-NETs in 44% patients. The frequency of symptomatic GI-NETs was 3.4%. Interestingly, 77.1% of patients with foregut GI-NETs had type A gastritis. Conclusion Our results show there are large differences in GEP-NETs between Japan and Western nations, primarily due to differences in the presence of MEN-1 in NF-PETs and the location, symptomatic status, and prevalence of malignancy in GI-NETs.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The purpose of this study is to clarify the contribution of the Hedgehog signaling pathway (Hh pathway) to the progression from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC). A ...total of 149 surgically resected mammary disease specimens and 12 sentinel lymph nodes with micro‐metastasis (Ly‐met) were studied. The degree of Hh pathway activation was estimated from the Gli1 nuclear staining ratio (%Gli1 nuclear translocation) in cancer cells. The invasiveness of breast cancer cells was determined using Matrigel assays. A serial increase of %Gli1 nuclear translocation to IDC from non‐neoplastic diseases was confirmed. In tumor specimens, %Gli1 nuclear translocation correlated with the invasiveness of each type of mammary disease and also correlated with invasion‐related histopathological parameters. The %Gli1 nuclear translocation in lymph nodes with micro‐metastasis was similar to that in primary sites and higher than that in DCIS with microinvasion and DCIS. Blockade of the Hh pathway decreased the invasiveness of breast cancer cells. In IDC, %Gli1 nuclear translocation correlated with the expression of estrogen receptor‐α. Estrogen increased %Gli1 nuclear translocation and the invasiveness of estrogen receptor‐α‐positive cells. The Hh pathway mediates progression from a non‐invasive phenotype to an invasive phenotype and %Gli1 nuclear translocation may be useful as a predictive marker for evaluating the ability of invasiveness. (Cancer Sci 2011; 102: 373–381)
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Recently, the microRNA-200 family was reported to affect cancer biology by regulating epithelial to mesenchymal transition (EMT). Especially, the expression of miR-200c has been shown to be ...associated with upregulating the expression of E-cadherin, a gene known to be involved in pancreatic cancer behavior. However, the significance of miR-200c in pancreatic cancer is unknown.
In the present study, we investigated the relationship between E-cadherin and miR-200c expression in a panel of 14 pancreatic cancer cell lines and in macro-dissected formalin-fixed paraffin-embedded (FFPE) tissue samples obtained from 99 patients who underwent pancreatectomy for pancreatic cancer. We also investigated the effects of miR-200c on the proliferation and invasion of pancreatic cancer cells.
We found that patients with high levels of miR-200c expression had significantly better survival rates than those with low levels of miR-200c expression. We also found a remarkably strong correlation between the levels of miR-200c and E-cadherin expression.
These data indicate that miR-200c may play a role in the pancreatic cancer biology and may be a novel marker for the prognosis of pancreatic cancer.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Due to the poor prognosis of pancreatic cancer, novel diagnostic modalities for early diagnosis and new therapeutic strategy
are urgently needed. Recently, microRNA-21 (miR-21) was reported to be ...strongly overexpressed in pancreatic cancer as well
as in other solid cancers. We investigated the functional roles of miR-21, which have not been fully elucidated in pancreatic
cancer. miR-21 expression was assessed in pancreatic cancer cell lines (14 cancer cell lines, primary cultures of normal pancreatic
epithelial cells and fibroblasts, and a human normal pancreatic ductal epithelial cell line) and pancreatic tissue samples
(25 cancer tissues and 25 normal tissues) by quantitative real-time reverse transcription-PCR amplification. Moreover, we
investigated the proliferation, invasion, and chemoresistance of pancreatic cancer cells transfected with miR-21 precursor
or inhibitor. miR-21 was markedly overexpressed in pancreatic cancer cells compared with nonmalignant cells, and miR-21 in
cancer tissues was much higher than in nonmalignant tissues. The cancer cells transfected with the miR-21 precursor showed
significantly increased proliferation, Matrigel invasion, and chemoresistance for gemcitabine compared with the control cells.
In contrast, inhibition of miR-21 decreased proliferation, Matrigel invasion, and chemoresistance for gemcitabine. Moreover,
miR-21 positively correlated with the mRNA expression of invasion-related genes, matrix metalloproteinase-2 and -9, and vascular
endothelial growth factor. These data suggest that miR-21 expression is increased in pancreatic cancer cells and that miR-21
contributes to the cell proliferation, invasion, and chemoresistance of pancreatic cancer.Mol Cancer Ther 2009;8(5):1067–74
The standard treatment for autoimmune pancreatitis (AIP) is steroid therapy, although some patients improve spontaneously. Indications for steroid therapy in AIP patients are symptoms such as ...obstructive jaundice, abdominal pain, back pain, and the presence of symptomatic extrapancreatic lesions. Prior to steroid therapy, obstructive jaundice should be managed by biliary drainage, and blood glucose levels should be controlled in patients with diabetes mellitus. The recommended initial oral prednisolone dose for induction of remission is 0.6 mg/kg/day, which is administered for 2–4 weeks. The dose is then tapered by 5 mg every 1–2 weeks, based on changes in clinical manifestations, biochemical blood tests (such as liver enzymes and IgG or IgG4 levels), and repeated imaging findings (US, CT, MRCP, ERCP, etc.). The dose is tapered to a maintenance dose (2.5–5 mg/day) over a period of 2–3 months. Cessation of steroid therapy should be based on the disease activity in each case. Termination of maintenance therapy should be planned within 3 years in cases with radiological and serological improvement. Re-administration or dose-up of steroid is effective for treating AIP relapse. Application of immunomodulatory drugs is considered for AIP patients who prove resistant to steroid therapy. The prognosis of AIP appears to be good over the short-term with steroid therapy. The long-term outcome is less clear, as there are many unknown factors, such as relapse, pancreatic exocrine or endocrine dysfunction, and associated malignancy.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
In Japan, we are now using the clinical diagnostic criteria for chronic pancreatitis (CP) that were revised in 2001 to add the findings of magnetic resonance cholangiopancreatography to the criteria ...compiled by the Japan Pancreas Society (JPS) in 1995. Because the current criteria are set for diagnosing advanced CP, they are unlikely to improve patients’ prognoses. In addition, they seem unsuitable for current clinical practice because exocrine pancreatic function tests, which have become obsolete in Japan, are included in the diagnostic factors. For these reasons, the Research Committee on Intractable Pancreatic Diseases supported by the Ministry of Health, Labour and Welfare of Japan, the JPS and the Japanese Society of Gastroenterology have revised the criteria. The revised criteria are unique in that they contain an introduction to the concept of early CP. It is a challenge aimed at improvement of the long-term prognosis of CP patients by early diagnosis and therapeutic intervention in this disease. We need to determine and clarify the clinico-pathological outcome of early CP by a prospective long-term follow-up of the patients in this category.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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