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Purpose:The programmed death-1ligand/programmed death-1 (PD-L/PD-1) pathway has been recently suggested to play a pivotal role in the immune evasion of tumors from host immune system. In this study, we tried to reveal the clinical importance and therapeutic potential of the PD-L/ PD-1pathway in pancreatic cancer, which is one of the most aggressive and intractable malignant tumors. Experimental Design: We used immunohistochemistry to investigate PD-L expression in 51 patients with pancreatic cancer who underwent surgery and explored the therapeutic efficacy of blocking the PD-L1/PD-1pathway in murine pancreatic cancer in vivo. Results: PD-L1^positive patients had a significantly poorer prognosis than the PD-L1^negative patients, whereas there was no significant correlation of tumor PD-L2 expression with patient survival. PD-L1 expression was inversely correlated with tumor-infiltrating T lymphocytes, particularly CD8 + T cells. These clinical data have suggested that the PD-L1/PD-1 pathway may be a critical regulator in human pancreatic cancer. Monoclonal antibodies against PD-L1 or PD-1 induced a substantial antitumor effect on murine pancreatic cancer in vivo. PD-L1 blockade promoted CD8 + T-cell infiltration into the tumor and induced local immune activation. Furthermore, the combination of anti^PD-L1 monoclonal antibody and gemcitabine exhibited a significant synergistic effect on murine pancreatic cancer and resulted in complete response without overt toxicity. Conclusion: Our data suggest for the first time that PD-L1 status may be a new predictor of prognosis for patients with pancreatic cancer and provide the rationale for developing a novel therapy of targeting the PD-L/PD-1pathway against this fatal disease.

Two recently proposed 13 C-13 C recoupling methods under magic angle spinning ͑MAS͒, resonant interference recoupling ͑RIR͒, and 13 C-1 H dipolar-assisted rotational resonance ͑DARR͒, are examined on a common theoretical foundation using the average Hamiltonian theory. In both methods, a rf field is applied on not 13 C but 1 H to recouple the 13 C-1 H dipolar interactions, and spectral overlap necessary to conserve energy for 13 C-13 C polarization transfer is achieved by the 13 C-1 H dipolar line broadening. While DARR employs time-independent 13 C-1 H interactions recoupled by suitable rf irradiation to 1 H spins, RIR uses time-dependent 13 C-1 H interactions modulated appropriately by 1 H rf irradiation. There are two distinct cases where 13 C-1 H line broadening realizes 13 C-13 C spectral overlap. For a pair of a carbonyl or aromatic carbon and an aliphatic carbon, spectral overlap can be achieved between one of the spinning sidebands of the former 13 C resonance and the 13 C-1 H dipolar powder pattern of the latter. On the other hand for a pair of spins with a small chemical shift difference, the two center bands are overlapped with each other due to 13 C-1 H dipolar broadening. For the former, we show that both RIR and DARR occur in the first order, while for the latter, DARR recoupling is appreciable for time-independent 13 C-1 H interactions. We refer to the former DARR as the first-order DARR recoupling and the latter as the second-order DARR. Experimentally, we examined the following 13 C-1 H recoupling methods for DARR: 1 H CW irradiation fulfilling a rotary-resonance condition or a modulatory-resonance condition, and 1 H pulses applied synchronously to MAS. For RIR, the FSLG-m2mm sequence is applied to 1 H. Several one-dimensional DARR and RIR experiments were done for N-acetyl͓1,2-13 C, 15 N͔ DL-valine, and ͓2,3-13 C͔ L-alanine. It was found that the polarization transfer rate for RIR is larger than that for DARR except for fast spinning, while the rate for DARR is less sensitive to the spinning speed. Further, we showed that the efficiency of the second-order DARR recoupling is not significantly less than that of the first-order DARR. Among the 13 C-1 H recoupling methods examined, CW irradiation at the nϭ1 rotary-resonance condition is superior for DARR because it gives a larger 13 C-1 H dipolar broadening, leading to broadband recoupling. We showed that a broadband-recoupling experiment with the first and the second-order DARR by CW irradiation at the nϭ1 rotary-resonance condition is applicable to signal assignment as well as structural determination of a multiply/uniformly 13 C labeled molecule as demonstrated by two-dimensional 13 C-13 C DARR polarization-transfer experiments of uniformly 13 C, 15 N-labeled glycylisoleucine.

We performed a prospective study to determine the effects of introducing low-load muscular training with moderate restriction of blood flow during the first 16 weeks after reconstruction of the anterior cruciate ligament. 44 subjects (average age 29 (18-52) years) were randomized into a group that trained restriction of blood flow (group R, n = 22) and a group that trained without restriction (group N, n = 22). Both groups followed the same training schedule. Evaluations of knee extensor and flexor torques before surgery and 16 weeks after it showed a significant increase in muscular strength in group R as compared to group N. The preoperative/16-week postoperative ratio of the crosssectional area of the knee extensor muscles showed a statistically significant enlargement in group R as compared to group N. 16 weeks after surgery, the short diameters of type 1 and type 2 fibers of M. vastus lateralis tended to be larger in group R (n = 8) than in group N (n = 8), although the differences were not significant. These findings show that low-load resistance muscular training during moderate restriction of blood flow is an effective exercise for early muscular training after reconstruction of the anterior cruciate ligament.  Recently, many studies have reported stable postoperative results of ligament reconstruction by autologous tendon grafting of the anterior cruciate ligament (ACL), a procedure which permits early rehabilitation according activities of daily living and sports. However, an important issue is how early the patients can return to athletic activities. Currently, several techniques of ACL reconstruc

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is known to have pivotal roles in various inflammatory processes. The TWEAK receptor, fibroblast growth factor-inducible 14 (Fn14), has various unique functions under physiological and pathological conditions; however, the therapeutic potential of its direct targeting remains unknown. Here, we found that Fn14 expression was highly upregulated in ischemic renal tissues and tubular epithelial cells of patient biopsies and experimental animal models of renal injury. To clarify the function of Fn14 in ischemia reperfusion injury, we coincubated renal tubular cells with ITEM-2, an anti-Fn14 blocking monoclonal antibody, and found that it inhibited the production of proinflammatory cytokines and chemokines after injury. Furthermore, Fn14 blockade downregulated the local expression of several proinflammatory mediators, reduced accumulation of neutrophils and macrophages in ischemic tissues, and inhibited tubular cell apoptosis. Importantly, Fn14 blockade attenuated the development of chronic fibrosis after ischemia reperfusion injury and significantly prolonged the survival of lethally injured mice. Thus, we conclude that Fn14 is a critical mediator in the pathogenesis of ischemia reperfusion injury.