Progressively transformed germinal centers is a benign condition of unknown pathogenesis characterized by a distinctive variant form of reactive follicular hyperplasia in lymph nodes. We recently reported Ig G4-related disease in progressively transformed germinal centers. However, no large case series has been reported and clinicopathologic findings remain unclear. Here, we report 40 Japanese patients (28 men, 12 women; median age, 56 years) with progressively transformed germinal centers of the lymph nodes who fulfilled the histological diagnostic criteria for IgG4-related disease (IgG4 þ progressively transformed germinal centers), with asymptomatic localized lymphadenopathy involving the submandibular nodes in 24, submandibular and cervical nodes in 14, cervical nodes only in 1, and cervical and supraclavicular nodes in 1. In all, 16 (52%) of 31 examined patients had allergic disease. Histologically, the lymph nodes demonstrated uniform histological findings, namely marked follicular hyperplasia with progressively transformed germinal centers, and localization of the majority of IgG4 þ plasma cells in the germinal centers. Serum IgG4, serum IgE and peripheral blood eosinophils were elevated in 87%, 92% and 53% of examined patients, respectively. Eighteen patients subsequently developed extranodal lesions (including five who developed systemic disease), which on histological examination were consistent with IgG4-related disease. IgG4 þ progressively transformed germinal centers presents with uniform clinicopathological features of asymptomatic localized submandibular lymphadenopathy, which persists and/or relapses, and sometimes progresses to extranodal lesions or systemic disease. Nine patients were administered steroid therapy when the lesions progressed, to which all

Fibrosis is characterized by extracellular matrix (ECM) remodeling and stiffening. However, the functional contribution of tissue stiffening to noncancer pathogenesis remains largely unknown. Fibronectin (Fn) is an ECM glycoprotein substantially expressed during tissue repair. Here we show in advanced chronic liver fibrogenesis using a mouse model lacking Fn that, unexpectedly, Fn-null livers lead to more extensive liver cirrhosis, which is accompanied by increased liver matrix stiffness and deteriorated hepatic functions. Furthermore, Fnnull livers exhibit more myofibroblast phenotypes and accumulate highly disorganized/diffuse collagenous ECM networks composed of thinner and significantly increased number of collagen fibrils during advanced chronic liver damage. Mechanistically, mutant livers show elevated local TGF-␤ activity and lysyl oxidase expressions. A significant amount of active lysyl oxidase is released in Fn-null hepatic stellate cells in response to TGF-␤1 through canonical and noncanonical Smad such as PI3 kinase-mediated pathways. TGF-␤1-induced collagen fibril stiffness in Fn-null hepatic stellate cells is significantly higher compared with wild-type cells. Inhibition of lysyl oxidase significantly reduces collagen fibril stiffness, and treatment of Fn recovers collagen fibril stiffness to wild-type levels. Thus, our findings indicate an indispensable role for Fn in chronic liver fibrosis/cirrhosis in negatively regulating TGF-␤ bioavailability, which in turn modulates ECM remodeling and stiffening and consequently preserves adult organ functions. Furthermore, this regulatory mechanism by Fn could be translated for a potential therapeutic target in a broader variety of chronic fibrotic diseases.

Current evidence has suggested the possible involvement of ROS as signaling messengers in IL-1␤-or LPS-induced gene expression. We previously reported that both IL-1␤ and LPS induce uPA in RC-K8 human lymphoma cells. Here, we provide evidence that ROS-generating anthracycline antibiotics, including doxorubicin and aclarubicin, upregulate uPA expression in 2 human malignant cell lines, RC-K8 and H69 small-cell lung-carcinoma cells. Both doxorubicin and aclarubicin markedly increased uPA accumulation in RC-K8-and H69-conditioned medium in a dose-dependent manner. In each case, maximal induction was observed at a sublethal concentration, i.e., at a concentration where cell growth was slightly inhibited. Both doxorubicin and aclarubicin increased uPA mRNA levels, and induction in each case reached the maximal level 9 hr after stimulation. Doxorubicin barely changed the half-life of uPA mRNA and activated uPA gene transcription. Antioxidants such as NAC and PDTC inhibited doxorubicin-induced uPA mRNA accumulation. Microarray analysis, using Human Cancer CHIP version 2 (Takara Shuzo, Kyoto, Japan), in which 425 human cancer-related genes were spotted on glass plates, revealed that uPA is 1 of 3 genes that were clearly upregulated in H69 cells by doxorubicin stimulation. These findings suggest that the anthracycline induces uPA in human malignant cells by activating gene transcription in which ROS may be involved. Therefore, by upregulating uPA expression, the anthracycline may influence many biologic cell functions mediated by the uPA/plasmin system.

Several chemokines/chemokine receptors such as CXCL12, CCL3, CXCR4 and CCR1 attract multiple myelomas to specific microenvironments. In the present study, we investigated whether the CX3CL1/CX3CR1 axis is involved in the interaction of the multiple myeloma cells with their microenvironment. The expression of CX3CR1 (also known as fractalkine) was detected in three of the seven human myeloma cell lines. CX3CL1-induced phosphorylation of Akt and ERK1/2 was detected in the CX3CR1-positive cell lines, but not in the CX3CR1-negative cell lines. In addition, CX3CL1-induced cell adhesion to fibronectin and vascular cell adhesion molecule-1 (VCAM-1) in the human myeloma RPMI-8226 cell line. We also investigated whether a relationship existed between myeloma cells and osteoclasts that may function via the CX3CL1/CX3CR1 axis. Conditioned medium from CX3CL1-stimulated RPMI-8226 cells drastically increased the osteoclast differentiation. Collectively, the results from the present study support the concept of the CX3CL1-mediated activation of the progression of the multiple myeloma via CX3CR1. Thus, CX3CR1 may represent a potential therapeutic target for the treatment of multiple myeloma in a bone microenvironment.

A patient with acute myeloid leukemia had a relapse with a myeloid sarcoma of the stomach 32 months after allogeneic bone marrow transplantation. The patient was treated with the first donor lymphocyte infusion (DLI) and one course of induction chemotherapy. Due to severe infectious complication after chemotherapy, the patient could not continue chemotherapy. Subsequently, the patient was treated with a total of 13 cycles of DLI at 1-2 month intervals. Complete remission was achieved and neither relapse nor graft versus host disease has occurred during a follow-up of more than 10 years.