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The TGF-β superfamily comprises pleiotropic cytokines that regulate SMAD and non-SMAD signaling. TGF-β-SMAD signal transduction is known to be involved in tissue fibrosis, including renal fibrosis. Here, we found that 1,25-dihydroxyvitamin D3-bound [1,25(OH)2D3-bound] vitamin D receptor (VDR) specifically inhibits TGF-β-SMAD signal transduction through direct interaction with SMAD3. In mouse models of tissue fibrosis, 1,25(OH)2D3 treatment prevented renal fibrosis through the suppression of TGF-β-SMAD signal transduction. Based on the structure of the VDR-ligand complex, we generated 2 synthetic ligands. These ligands selectively inhibited TGF-β-SMAD signal transduction without activating VDR-mediated transcription and significantly attenuated renal fibrosis in mice. These results indicate that 1,25(OH)2D3-dependent suppression of TGF-β-SMAD signal transduction is independent of VDR-mediated transcriptional activity. In addition, these ligands did not cause hypercalcemia resulting from stimulation of the transcriptional activity of the VDR. Thus, our study provides a new strategy for generating chemical compounds that specifically inhibit TGF-β-SMAD signal transduction. Since TGF-β-SMAD signal transduction is reportedly involved in several disorders, our results will aid in the development of new drugs that do not cause detectable adverse effects, such as hypercalcemia.

MRI plays an essential role in patients before treatment for uterine mesenchymal malignancies. Although MRI includes methods such as diffusion-weighted imaging and dynamic contrast-enhanced MRI, the differentiation between uterine myoma and sarcoma always becomes problematic. The present paper discusses important findings to ensure that sarcomas are not overlooked in magnetic resonance (MR) images, and we describe the update in the differentiation between uterine leiomyoma and sarcoma with recent reports.

Ovarian teratoid carcinosarcoma involves an epithelial tumor of the Müllerian duct and an immature neuroepithelium, which is a characteristic of immature teratomas. Here, we describe the case of a 60-year-old woman who underwent surgery for a stage IC3 ovarian malignancy. The tumor showed a variety of histological features, including clear cell carcinoma, immature teratoma, and rhabdomyosarcoma, and a PIK3CA mutation was detected at the same locus in each. Two months after surgery and before the start of chemotherapy, multiple bone and liver metastases were found. Four courses of combination therapy with vincristine, actinomycin D and cyclophosphamide, the standard chemotherapy regimen for pediatric rhabdomyosarcoma, were administered, and a complete response was achieved. After a 2-month rest period, the patient developed recurrent peritoneal dissemination and underwent 6 courses of paclitaxel, carboplatin, and bevacizumab chemotherapy, resulting in a partial response. This is the eighth reported case of ovarian teratoid carcinosarcoma. This tumor has a very aggressive course, but initially responds to chemotherapy. However, survival over 5 years has not been reported, and elucidation of the pathogenesis and development of new treatment methods are needed.

Leukocyte telomere length and serum levels of high-molecular-weight adiponectin and dehydroepiandrosterone-sulfate (DHEA-S) were assessed in association with nutrition and performance status (PS) in Japanese centenarians. Twenty-three centenarians (five men, 18 women) were classified according to their PS 1 (nearly fully ambulatory, n = 2), 2 (in bed less than 50% of daytime, n = 10), 3 (in bed greater than 50%, n = 6), and 4 (completely bedridden, n = 5). Leukocyte telomere length was determined by the hybridization protection assay, and the adiponectin and DHEA-S levels were measured by chemiluminescent enzyme immunoassay. Among variables of PS, body mass index (BMI), albumin, adiponectin, DHEA-S, and telomere length, there were significant correlations between PS and albumin (r = −.694, p < .01), between telomere length and BMI (r = .522, p < .05), between adiponectin and BMI (r = −.574, p < .01), and between DHEA-S and albumin (r = .530, p < .01). When excluding two cancer-bearing centenarians with short telomere, telomere length significantly correlated with PS (r = −.632, p < .01). It was indicated that the short leukocyte telomere was associated with poor PS and cancer development and that the adiponectin or DHEA-S was associated with adiposity or nutritional status. Despite a small number of subjects, these biomarkers seemed to reflect distinct aspects of longevity in Japanese centenarians.

Background: Because reports on the management of recurrent granulosa cell tumor have been sparse, a consensus as to which patients should undergo surgical resection and which patients should be considered for chemotherapy has not been established. Methods: A total of 21 tumor recurrences in eight patients with granulosa cell tumor were reviewed. Results: Surgery was performed as the main treatment for 13 recurrences, while chemotherapy was chosen as the main treatment for eight recurrences. Complete tumor resection could be accomplished in 13 of 16 surgeries (81.3%), which include all the ten recurrences without involvement of liver or diaphragm and without ascites. The number of recurrent masses was significantly higher in the early recurrence group (progression free survival < 2 years) than in the late recurrence (progression free survival > 2 years). All cases with a solitary recurrent tumor at an extra-peritoneal site presented a significantly longer progression free survival. Conclusions: For patients with recurrent granulosa cell tumor, surgery may provide the best disease control. In cases with complete resection, the number of recurrent masses was the predictive factor for the next recurrence, and adjuvant chemotherapy might be considered in such cases.

IntroductionOlaparib is an oral poly (ADP-ribose) polymerase inhibitor that has shown antitumor activity in patients with advance or recurrent ovarian cancer. It is associated with adverse side effects, including fatigue, malaise, anorexia and anemia, which may force its discontinuation. Ninjin’yoeitou (NYT) is a herbal medicine that can effectively treat these adverse events. However, the efficacy of NYT in reducing these side effects with Olaparib is not clear.MethodsThe present study included 45 patients who received Olaparib for newly diagnosed advanced or platinum sensitive recurrent ovarian cancer at eight Kansai Clinical Oncology Group (KCOG)-related institutions. Treatment-related adverse events were graded with use of the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. Quality of life was assessed with the Functional Assessment of Cancer Therapy-Ovarian Cancer (FACT-O) questionnaire (completed at baseline and every month until 6 months had passed or disease progression), the FACT/NCCN Ovarian Symptom Index (FOSI), and the Trial Outcome Index (TOI).ResultsGrade 3 or higher anemia occurred in 13 of 45 patients (29%), Grade 2 or higher fatigue in 6 (13%), and anorexia in 2 (4%). The incidence of discontinuation due to side effects was 15% (7/45). Moreover, NYT could maintain quality of life under all measures: FACT-O, TOI, and FOCI. NYT also significantly improved fatigue after the start of Olaparib administration (p=0.017).Conclusion/ImplicationsNYT could maintain quality of life by suppressing Olaparib-induced fatigue and help the long-term maintenance therapy of Olaparib in patients with ovarian cancer by reducing these adverse events.

Study design A case report and a biomechanical study using a finite element method. Objectives To report a case with the cervical spondylolysis and to understand the biomechanics of the cervical spine with spondylolysis at C6. Summary of background data Cervical spondylolysis, although not a common spinal disorder, can occur in athletes. Presently, the exact pathology, natural history and biomechanics are not known. Thus, treatment strategies for this disorder in athletes are in controversy. To treat and/or advise patients with cervical spondylolysis, the cervical spine biomechanics regarding this disorder should be understood. Methods A case of a 12-year-old male judo player is presented. The patient presented with occipital and upper neck pain. Plain radiographs, reconstructed CT scan and MRIs of this patient were reviewed. Biomechanically, stress distributions were analyzed in response to 73.6 N axial compression and 1.5-Nm moment in flexion, extension, lateral bending, and axial rotation using a FE model of the intact ligamentous C3 to C7 segment. Bilateral spondylolysis was created in the model at C6. The stress results from the bilateral defect model were compared to the intact model predictions. Results Plain radiographs showed bilateral C6 spondylolysis, and grade I spondylolisthesis. MRI showed mild disc degeneration at C6/7. With conservative treatment, the symptoms disappeared. In the spondylolysis model, the maximum Von Mises Stresses at C6/7 increased in all cervical spine motions, as compared to the intact case. Specifically, in axial rotation, the stress increase was 3.7-fold as compared to the intact model. The range of motion at C6/7 increased in the spondylolysis model as well. Again, during axial rotation, the increase in motion was 2.3-fold when compared to the intact model. Conclusions Cervical spondylolysis can cause biomechanical alterations, especially in axial rotation, leading to increased disc stresses and range of motion. The increased stresses in the disc and the hypermobility would be a dangerous condition for athletes participating in contact sports such as judo. Thus, we recommended that judo players with cervical spondylolysis should change to non-contact sports, such as jogging.

The effect of the adsorption of catalytic metal atoms on tensile strength and structural deformation of graphene is examined using the density functional theory. In the case when a line of Ni atoms is adsorbed at hollow sites aligned along zigzag direction of the honeycomb structure, the tensile strength against the uniaxial strain in armchair direction is calculated to be 82.64 GPa, which is 21% smaller than that of the pristine graphene. The reduction of the tensile strength monotonically depends on the line density of Ni. It is predicted that if the stress reaches the tensile strength, the system will undergo a stress-induced structural transformation that involves the breaking of C-C bond adjacent to Ni atoms, the formation of Ni-C bonds and a resultant jump in the strain.

The author is an Assistant Professor in the Department of Economics at Simmons College, Boston. He thanks Donald L. Basch, Theodore A. Burczak, James R. Crotty, and anonymous reviewers of the Journal of Economic Issues for their helpful comments on a draft of this paper.

The relationship between vascular endothelial growth factor (VEGF) and induction of angiogenesis in high-metastatic RCT(+) or low-metastatic RCT(–) clones of the poorly differentiated murine RCT sarcoma was investigated. The association with E-selectin in VEGF-induced angiogenesis was also evaluated. RCT(+) cells produced significantly larger amounts of VEGF than RCT(–) cells. In a tube formation assay with murine lung microvascular endothelial (MLE) cells, conditioned medium from RCT(+) cells showed a significantly greater effect on tube formation than that from RCT(–) cells. Induction of tube formation was suppressed by anti-mouse VEGF monoclonal antibody. Furthermore, anti-mouse E-selectin monoclonal antibody suppressed the tube formation induced by recombinant mouse VEGF. In a flow-cytometric analysis, the expression of E-selectin on MLE cells was upregulated after pretreatment with conditioned medium from RCT(+) and RCT(–) cells. Conditioned medium from RCT(+) cells induced a higher expression of E-selectin compared to medium from RCT(–) cells. Anti-VEGF monoclonal antibody prevented the upregulation of E-selectin by the RCT cell-conditioned medium. These findings suggest that E-selectin plays an important role in the angiogenesis induced by VEGF. VEGF derived from tumor cells may enhance angiogenesis by upregulating the expression of E-selectin on vascular endothelial cells.