A major goal in cancer research is to develop carriers that can deliver drugs effectively and without side effects. Liposomal and particulate carriers with diameters of ∼100 nm have been widely used ...to improve the distribution and tumour accumulation of cancer drugs, but so far they have only been effective for treating highly permeable tumours. Here, we compare the accumulation and effectiveness of different sizes of long-circulating, drug-loaded polymeric micelles (with diameters of 30, 50, 70 and 100 nm) in both highly and poorly permeable tumours. All the polymer micelles penetrated highly permeable tumours in mice, but only the 30 nm micelles could penetrate poorly permeable pancreatic tumours to achieve an antitumour effect. We also showed that the penetration and efficacy of the larger micelles could be enhanced by using a transforming growth factor-β inhibitor to increase the permeability of the tumours.
Objectives
To validate the SARC-F questionnaire for sarcopenia screening in musculoskeletal disease setting, and to assess improvements in diagnostic accuracy by adding “EBM” (elderly and body mass ...index information) to the SARC-F.
Design
Diagnostic accuracy study.
Setting and Participants
The center involved in this study was located in an urban area of Kobe City, Japan. People with musculoskeletal disease in the knee, hip, or spine who were scheduled for surgical treatment were included.
Measurements
Sarcopenia was evaluated using the Asian Working Group for Sarcopenia (AWGS) and the European Working Group on Sarcopenia in Older People (EWGSOP2), which included bioimpedance, handgrip strength, and gait speed. Patients answered the SARC-F questionnaire and their body mass index was measured. SARC-F and “EBM” information were combined into an original score. The sensitivities, specificities, and areas under the receiver operating characteristic curve (AUC) were estimated and compared to identify sarcopenia.
Results
A total of 959 patients were included. Sarcopenia by AWGS criteria was identified in 36 (3.8%) patients. SARC-F had a sensitivity of 41.7% and specificity of 68.5%. SARC-F+EBM had a sensitivity of 77.8% and specificity of 69.6%, with substantial improvement in sensitivity (P<0.001). The AUCs for SARC-F and SARC-F+EBM were 0.557 (95% confidence interval CI 0.452–0.662) and 0.824 (95% CI 0.762–0.886), respectively (P<0.001). Similar results were obtained when EWGSOP2 criteria were used as the reference standard.
Conclusion
The SARC-F alone is not adequate for finding cases in musculoskeletal disease settings. SARC-F+EBM significantly improved the sensitivity and overall diagnostic accuracy of the SARC-F for screening sarcopenia. SARC-F+EBM is potentially useful for screening sarcopenia in different ethnic and disease settings.
Cellulose synthesis in plants is believed to be carried out by the plasma membrane-associated rosette structure which can be observed by electron microscopy. Despite decade-long speculation, it had ...not been demonstrated whether the rosette is the site of catalytic activity of cellulose synthesis. To determine the relationship between this structure and cellulose synthesis, we successfully isolated detergent-insoluble rosettes from the plasma membrane of bean epicotyls. However, the purified rosettes did not possess cellulose synthesis activity in vitro. Conversely, detergent-soluble granular particles of about 9.5 - 10 nm diameter were also isolated and exhibited UDP-glucose binding activity and possessed beta-1,4-glucan (cellulose ) synthesis activity in vitro. The particle, referred to as the catalytic unit of cellulose synthesis, was enriched with a 78 kDa polypeptide which was verified as sucrose synthase like by mass spectrometry and immunoblotting. The catalytic units were able to bind to the rosettes and retained the cellulose synthesis activity in the presence of UDP-glucose or sucrose plus UDP when supplemented with magnesium. The incorporation of the catalytic unit into the rosette structure was confirmed by immunogold labeling with anti-sucrose synthase antibodies under an electron microscope. Our results suggest that the plasma membrane-associated rosette anchors the catalytic unit of cellulose synthesis to form the functional cellulose synthesis machinery.
Background
Histopathology of muscularis externa in primary esophageal motility disorders has been characterized previously. We aimed to correlate the results of high‐resolution manometry with those ...of histopathology.
Methods
During peroral endoscopic myotomy, peroral esophageal muscle biopsy was performed in patients with primary esophageal motility disorders. Immunohistochemical staining for c‐kit was performed to assess the interstitial cells of Cajal (ICCs). Hematoxylin Eosin and Azan‐Mallory staining were used to detect muscle atrophy, inflammation, and fibrosis, respectively.
Key Results
Slides from 30 patients with the following motility disorders were analyzed: achalasia (type I: 14, type II: 5, type III: 3), one diffuse esophageal spasm (DES), two outflow obstruction (OO), four jackhammer esophagus (JE), and one nutcracker esophagus (NE). ICCs were preserved in high numbers in type III achalasia (n=9.4±1.2 cells/high power field HPF), compared to types I (n=3.7±0.3 cells/HPF) and II (n=3.5±1.0 cells/HPF). Moreover, severe fibrosis was only observed in type I achalasia and not in other types of achalasia, OO, or DES. Four of five patients with JE and NE had severe inflammation with eosinophilic infiltration of the esophageal muscle layer (73.8±50.3 eosinophils/HPF) with no epithelial eosinophils. One patient with JE showed a visceral myopathy pattern.
Conclusions & Inferences
Compared to types I and II, type III achalasia showed preserved ICCs, with variable data regarding DES and OO. In disorders considered as primary esophageal motility disorders, a disease category exists, which shows eosinophilic infiltration in the esophageal muscle layer with no eosinophils in the epithelium.
We aimed to analyze the relation between high‐resolution manometry (HRM) findings and histopathology of muscularis externa in esophageal motility disorders. ICCs were preserved in high numbers in type III achalasia compared to other achalasia types. In some patients with JE and NE, eosinophilic infiltration of the esophageal muscle layer was shown, possibly related to the hypercontraction on HRM. Histopathological examination of the muscle layer in esophageal motility disorders may elucidate the pathology.
Summary
The effect of endoscopic submucosal dissection (ESD) on esophageal motility remains unknown. Therefore, the aim of this study is to elucidate changes in esophageal motility after ESD along ...with the cause of dysphagia using high-resolution manometry (HRM). This is a before-and-after trial of the effect of ESD on the esophageal motility. Twenty patients who underwent ESD for superficial esophageal carcinoma were enrolled in this study. Patients filled out a questionnaire about dysphagia and underwent HRM before and after ESD. Results before and after ESD were compared. Data were obtained from 19 patients. The number of patients who complained of dysphagia before and after ESD was 1/19 (5.3%) and 6/19 (31.6%), respectively (P = 0.131). Scores from the five-point Likert scale before and after ESD were 0.1 ± 0.5 and 1.0 ± 1.6, respectively (P = 0.043). The distal contractile integral (DCI) before and after ESD and the number of failed, weak, or fragmented contractions were not significantly different. However, in five patients with circumferential ESD, DCI was remarkably decreased and the frequency of fail, weak, or fragmented contractions increased. Univariate regression analysis showed a relatively strong inverse correlation of ΔDCI with the circumferential mucosal defect ratio {P < 0.01, standardized regression coefficient (r) = −0.65}, the number of stricture preventions (P < 0.01, r = −0.601), and the number of stricture resolutions (P < 0.01, r = −0.77). This HRM study showed that impairment of esophageal motility could be caused by ESD. The impairment of esophageal motility was conspicuous, especially in patients with circumferential ESD and subsequent procedures such as endoscopic triamcinolone injection and endoscopic balloon dilatation. Impaired esophageal motility after ESD might explain dysphagia.
High-temperature superconducting (HTS) tapes have been the subject of intensive research for various applications. In addition to their use at high temperatures in liquid nitrogen cooling, they are ...expected to be utilized in ultra-high field magnets at 30 T or higher at low temperatures, as well as in compact fusion reactors and rotating machines in intermediate temperature ranges. Each company has made significant strides in improving the critical current of HTS tapes, necessitating the development of test facilities with variable temperatures and high currents, such as those of the 2000 A and 20 T class. Typically, a steady current is employed for critical current measurements. In this study, we focus on pulsed current measurements to perform critical current measurements at high currents in limited spaces with high magnetic fields. A probe with a low inductance was fabricated, and a trapezoidal pulse current of 2-10 ms was applied to the sample using a 500 A-class pulse power supply. The current and voltage of the sample were recorded using a high-resolution isolated oscilloscope. By integrating this system with a 20 T cryogen-free superconducting magnet and a He-flow cryostat, critical currents in commercially available HTS tapes with 4 mm width were measured at temperatures ranging from 4 K to 77 K and magnetic fields up to 19 T. The Lorentz force caused the probe to oscillate and the voltage leads to swing, resulting in substantial voltage noise. Noise reduction down to 0.6 μV was achieved under 19 T, 500 A conditions, by fixing the voltage leads and changing the direction of Lorentz forces on the probe. The field dependences of the critical currents in a HTS REBCO tape characterized with pulsed and steady-state currents were compared and determined to be equivalent.
Obesity is a risk factor for postmenopausal breast cancer. Adiponectin/Acrp30 is lower in obese individuals and may be negatively regulating breast cancer growth. Here we determined that five breast ...cancer cell lines, MDA-MB-231, MDA-MB-361, MCF-7, T47D, and SK-BR-3, expressed one or both of the Acrp30 receptors. In addition, we found that the addition of Acrp30 to MCF-7, T47D, and SK-BR-3 cell lines inhibited growth. Oestrogen receptor (ER) positive MCF-7 and T47D cells were inhibited at lower Acrp30 concentrations than ER-negative SK-BR-3 cells. Growth inhibition may be related to apoptosis since PARP cleavage was increased by Acrp30 in the ER-positive cell lines. To investigate the role of ER in the response of breast cancer cells to Acrp30, we established the MDA-ERalpha7 cell line by insertion of ER-alpha into ER-alpha-negative MDA-MB-231 cells. This line readily formed tumours in athymic mice and was responsive to oestradiol in vivo. In vitro, MDA-ERalpha7 cells were growth inhibited by globular Acrp30 while the parental cells were not. This inhibition appeared to be due to blockage of JNK2 signalling. These results provide information on how obesity may influence breast cancer cell proliferation and establish a new model to examine interactions between ER and Acrp30.
Summary Objectives Human bone-marrow stromal cells are believed to be multipotent even in adults. This study assessed the effectiveness of autologous bone-marrow stromal cells, which were embedded ...within a collagen scaffold, to repair a full-thickness articular cartilage defect in the medial femoral condyle of an athlete. Patient and methods A 31-year-old male judo player suffering from pain in the right knee was reviewed. A 20 × 30-mm full-thickness cartilage defect (International Cartilage Repair Society classification (ICRS) grade IV) was revealed in the weight-bearing area of the medial femoral condyle. With the informed consent of the patient, the defect was treated with autologous bone-marrow stromal cells. Bone marrow was aspirated from the iliac crest of the patient 4 weeks before surgery. After removing the erythrocytes, the remaining cells were expanded in culture. Adherent cells were collected and embedded within a collagen gel, which was transferred to the articular cartilage defect in the medial femoral condyle. The implant was covered with an autologous periosteal flap. Results Seven months after surgery, arthroscopy revealed the defect to be covered with smooth tissues. Histologically, the defect was filled with a hyaline-like type of cartilage tissue which stained positively with Safranin-O. One year after surgery, the clinical symptoms had improved significantly. The patient had reattained his previous activity level and experienced neither pain nor other complications. Conclusions Our findings indicate that the transplantation of autologous bone-marrow stromal cells can promote the repair of large focal articular cartilage defects in young, active patients.
Long‐term memory formation requires de novo protein synthesis and gene transcription. During contextual long‐term memory formation brain‐derived neurotrophic factor (BDNF) gene expression changes in ...conjunction with alterations of DNA methylation in the Bdnf gene. However, little is known about the molecular mechanisms underlying the maintenance and persistence of contextual long‐term memory. Here, we examined the transcription of specific Bdnf exons in the hippocampus for long periods after contextual fear conditioning. We found changes in transcription lasting for at least 24 h after contextual fear conditioning, with some sex‐specific effects. In addition, hypomethylation at a CpG site in CpG island 2 located at the end of Bdnf exon III sequence was detected at 0.5 h and maintained for up to 24 h after contextual fear conditioning. The identification of these long‐lasting changes in transcription and DNA methylation at the Bdnf gene suggests that BDNF might have a role for storage of contextual long‐term memory in the hippocampus.
Patients with FIGO stage IV epithelial ovarian carcinoma have a poor but non-uniform prognosis. This study aimed to compare the survival of patients with serous or endometrioid tumours (S/E) and ...clear cell or mucinous tumours (non-S/E).
Data for 223 patients who underwent surgery between 1987 and 2010 and were diagnosed by centralized pathology review and were retrospectively analysed. The patients included 169 with S/E tumours and 54 with non-S/E tumours.
The median overall survivals (OSs) of the S/E and non-S/E groups were 3.1 and 0.9 years, respectively (P<0.001). Six patients (2.7%), all with non-S/E tumours, died within 6 weeks after the initial surgery. Multivariate OS analysis revealed that performance status, residual tumor, metastatic sites, no debulking surgery, and non-S/E tumours were independent poor prognostic factors. For patients with non-S/E tumours, prognosis was more favourable for single-organ metastasis, except for liver or distant lymph nodes, no residual tumor, and resection of metastasis (median OS: 4.1, 4.6, and 2.6 years, respectively).
In stage IV ovarian carcinoma, non-S/E tumours are associated with a significantly poorer prognosis and higher rates of early mortality compared to S/E tumours. Therefore, careful management and development of new strategies are required.
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