bluuebunny/crossref_metadata_2025 huggingface dataset:
Early urinary continence recovery after robot‐assisted radical prostatectomy in older Australian men
Authors: Basto Marnique Y. , Vidyasagar Chinni , te Marvelde Luc , Freeborn Helen , Birch Emma , Landau Adam , Murphy Declan G. , Moon Daniel
Published: May 2014

Objective

To compare the recovery of urinary continence (UC) after robot‐assisted radical prostatectomy (RARP) in men aged ≥70 and <70 years at 1‐year follow‐up and to assess for preoperative predictors ofUCrecovery, as older, healthy men with localised prostate cancer are often denied curative surgical treatment on the grounds of worseUCrecovery.

Patients and methods

In all, 262 patients with prostate cancer having undergoneRARPbetweenMay 2008 andSeptember 2012, under the care of two consultant urological surgeons at three Melbourne hospitals, were identified. Patients were categorised based on their age ≥70 and <70 years and compared with regards to two endpoints; percentage fully continent and mean pads/day at 4–6 weeks, and 3, 6, 9 and 12 months afterRARP.

Results

Of the 262 men, 9% (24) were aged ≥70 years. Older men had higherPSAlevels (P= 0.007) and clinical stages (P< 0.001) compared with the younger cohort. There were more non‐nerve sparing procedures in the older group (P= 0.009) and a shorter mean operative time (P= 0.004). At 4–6 weeks afterRARP, the number of pads used per day was greater in older men (P= 0.03) and there was a trend towards fewer older men being fully continent (P= 0.08) than their younger counterparts; however, by 3 months and all time‐points thereafter there was no difference. The 12‐monthUCrates were 89% and 92% for men aged <70 and ≥70 years, respectively. Neither age, body mass index, D'Amico risk group, nerve sparing nor use of Rocco suture were predictors of time toUCrecovery.

Conclusion

UCrecovery afterRARPin men aged ≥70 years appears comparable to younger men and therefore not a reason to deny older men with a reasonable life‐expectancy curative surgical treatment of localised prostate cancer.
The role of adjuvant chemotherapy for lymph node‐positive upper tract urothelial carcinoma following radical nephroureterectomy: a retrospective study
Authors: Lucca Ilaria , Kassouf Wassim , Kapoor Anil , Fairey Adrian , Rendon Ricardo A. , Izawa Jonathan I. , Black Peter C. , Fajkovic Harun , Seitz Christian , Remzi Mesut , Nyirády Peter , Rouprêt Morgan , Margulis Vitaly , Lotan Yair , de Martino Michela , Hofbauer Sebastian L. , Karakiewicz Pierre I. , Briganti Alberto , Novara Giacomo , Shariat Shahrokh F. , Klatte Tobias
Published: May 2014

Objective

To evaluate the effect of adjuvant chemotherapy (AC) on mortality after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) with positive lymph nodes (LNs) and to identify patient subgroups that are most likely to benefit from AC.

Patients and methods

We retrospectively analysed data of 263 patients with LN‐positive UTUC, who underwent full surgical resection. In all, 107 patients (41%) received three to six cycles of AC, while 156 (59.3%) were treated with RNU alone. UTUC‐related mortality was evaluated using competing‐risks regression models.

Results

In all patients (Tall N+), administration of AC had no significant impact on UTUC‐related mortality on univariable (P = 0.49) and multivariable (P = 0.11) analysis. Further stratified analyses showed that only N+ patients with pT3–4 disease benefited from AC. In this subgroup, AC reduced UTUC‐related mortality by 34% (P = 0.019). The absolute difference in mortality was 10% after the first year and increased to 23% after 5 years. On multivariable analysis, administration of AC was associated with significantly reduced UTUC‐related mortality (subhazard ratio 0.67, P = 0.022). Limitations of this study are the retrospective non‐randomised design, selection bias, absence of a central pathological review and different AC protocols.

Conclusions

AC seems to reduce mortality in patients with pT3–4 LN‐positive UTUC after RNU. This subgroup of LN‐positive patients could serve as target population for an AC prospective randomised trial.
The ‘double‐bind of dependency’: early relationships in men with learning disabilities in secure settings
Authors: Rayner Kelly , Wood Harry , Beail Nigel
Published: May 2014

Accessible Summary

This research project is about social lives.

Ten men with learning disabilities who had broken the law and who lived in hospital talked about their social lives.

We asked the 10 men about the people who had been in their lives before they broke the law.

This research project matters to people with learning disabilities because it tries to find out how different experiences affected the 10 men who were interviewed.

This could help us understand all people with learning disabilities better and could make services better for everyone.

Although the development of secure attachments has been shown to be more problematic for people with learning disabilities, there is a shortage of research into the attachment experience of people with learning disabilities who have broken the law. The present study used thematic analysis to explore the attachment experiences of 10 men with learning disabilities in secure settings. Attention was paid to formative relationship experiences in early life, along with an exploration of current relationships, with the content and direction of interviews being guided by participants. Two superordinate themes emerged from the analysis: ‘disempowerment’ and ‘ineffective care’. Results suggest that participants experienced a ‘double‐bind of dependency’ in which they felt a strong need for others, but had experienced unhelpful or harmful relationships. The clinical and practical implications for this are discussed.
Incidence of multiple primary cancers and interval between first and second primary cancers
Authors: Utada Mai , Ohno Yuko , Hori Megumi , Soda Midori
Published: May 2014

In this retrospective study, we aimed to clarify the risk of developing a second primary cancer and to determine the periods of high risk of second primary cancers. Subjects were all patients who had been diagnosed with a first primary cancer and registered with the Nagasaki Prefecture Cancer Registry between 1985 and 2007. We calculated the standardized incidence ratio (SIR) of second primary cancer according to site and years after diagnosis of the first primary cancer. A second primary cancer developed in 14 167 of 174 477 subjects (8.1%) during a median follow‐up of 1.8 years. The SIR of all cancer was 1.10 (95% confidence interval, 1.08–1.11). Some specific relationships were observed between sites with risk factors in common, such as smoking, drinking, and hormone status. The SIRs were relatively high after approximately 10 years for all sites, and trends differ among cancer sites. We showed that cancer patients are at higher risk of a second primary cancer than the general population. In respect of the risk of a second primary cancer, physicians should be alert for cancers that have risk factors in common with the first primary cancer.
Immunophenotypic features of metastatic lymph node tumors to predict recurrence in N2 lung squamous cell carcinoma
Authors: Matsuwaki Rie , Ishii Genichiro , Zenke Yoshitaka , Neri Shinya , Aokage Keiju , Hishida Tomoyuki , Yoshida Junji , Fujii Satoshi , Kondo Haruhiko , Goya Tomoyuki , Nagai Kanji , Ochiai Atsushi
Published: May 2014

Patients with mediastinal lymph node metastasis (N2) in squamous cell carcinoma (SqCC) of the lung have poor prognosis after surgical resection of the primary tumor. The aim of this study was to clarify predictive factors of the recurrence of pathological lung SqCC with N2 focusing on the biological characteristics of both cancer cells and cancer‐associated fibroblasts (CAFs) in primary and metastatic lymph node tumors. We selected 64 patients with pathological primary lung N2 SqCC who underwent surgical complete resection and investigated the expressions of four epithelial–mesenchymal transition‐related markers (caveolin, clusterin, E‐cadherin, ZEB2), three cancer stem cell‐related markers (ALDH‐1, CD44 variant6, podoplanin) of cancer cells, and four markers of CAFs (caveolin, CD90, clusterin, podoplanin) in both primary and matched metastatic lymph node tumors in the N2 area. In the primary tumors, the expressions of all the examined molecules were not related to recurrence. However, in the metastatic lymph node tumors, high clusterin and ZEB2 expressions in the cancer cells and high podoplanin expression in the CAFs were significantly correlated with recurrence (P = 0.03, 0.04, and 0.007, respectively). In a multivariate analysis, only podoplanin expression in the CAFs in metastatic lymph node tumors was identified as a significantly independent predictive factor of recurrence (P = 0.03). Our study indicated that the immunophenotypes of both cancer cells and CAFs in metastatic lymph node tumors, but not primary tumors, provide useful information for predicting the recurrence of pathological N2 lung SqCC.
Phase I / II study of brentuximab vedotin in Japanese patients with relapsed or refractory CD30‐positive Hodgkin's lymphoma or systemic anaplastic large‐cell lymphoma
Authors: Ogura Michinori , Tobinai Kensei , Hatake Kiyohiko , Ishizawa Kenichi , Uike Naokuni , Uchida Toshiki , Suzuki Tatsuya , Aoki Tomohiro , Watanabe Takashi , Maruyama Dai , Yokoyama Masahiro , Takubo Takatoshi , Kagehara Hideaki , Matsushima Takafumi
Published: May 2014

Brentuximab vedotin is an antibody–drug conjugate that selectively delivers the antimicrotubule agent monomethyl auristatin E into CD30‐expressing cells. To assess its safety, pharmacokinetics, and efficacy in Japanese patients with refractory or relapsed CD30‐positive Hodgkin's lymphoma or systemic anaplastic large‐cell lymphoma, we carried out a phase I/II study. Brentuximab vedotin was given i.v. on day 1 of each 21‐day cycle up to 16 cycles. In the phase I part of a dose‐escalation design, three patients per cohort were treated at doses of 1.2 and 1.8 mg/kg. In the phase II part, a dose of 1.8 mg/kg was given to 14 patients (nine with Hodgkin's lymphoma and five with systemic anaplastic large‐cell lymphoma). The median number of treatment cycles was 16 (range, 4–16). In the phase I part, no dose‐limiting toxicity event was observed. In the total population, common adverse events included lymphopenia (80%), neutropenia (65%), leukopenia (65%), and peripheral sensory neuropathy (60%). Grade 3/4 adverse events in more than two patients were lymphopenia (50%) and neutropenia (15%). The pharmacokinetic profile was similar to that observed in the previous studies in the USA. In the phase II part, six patients (67%) with Hodgkin's lymphoma achieved an objective response with 56% of complete response rate, and five patients (100%) with systemic anaplastic large‐cell lymphoma achieved an objective response with 80% of complete response rate. These results show that brentuximab vedotin has an acceptable safety profile and promising antitumor activity in the Japanese population. This trial was registered in JAPIC Clinical Trials Information (JapicCTI‐111650).
Busulfan inhibits growth of human osteosarcoma through miR‐200 family microRNAs in vitro and in vivo
Authors: Mei Qiang , Li Fang , Quan Hongyu , Liu Yunlai , Xu Haidong
Published: May 2014

Osteosarcoma typically arises in tissues of mesenchymal origin, and is the most malignant bone tumor characterized by high local aggressiveness, with poor therapeutic outcome. Busulfan has been widely used to treat CML. So far, there are no reports on the therapeutic effect of busulfan on osteosarcoma. Here, we showed that busulfan dose‐dependently reduced the cell viability and proliferation, and induced cell apoptosis, senescence, and reactive oxygen species levels in two osteosarcoma cell lines. Moreover, a series of loss‐of‐function and gain‐of‐function experiments further indicated that busulfan may have its anti‐osteosarcoma effect by upregulating the microRNA‐200 (miR‐200) family which subsequently downregulated its target genes ZEB1 and ZEB2. Furthermore, treatment with busulfan potentially inhibited the growth of implanted osteosarcoma in nude mice. Taken together, our data suggest that busulfan may have an anti‐osteosarcoma effect through downregulating ZEB1 and ZEB2 through activating the miR‐200 family, highlighting a possibility of using busulfan as a novel therapy for osteosarcoma.
Size‐ and shape‐dependent pleural translocation, deposition, fibrogenesis, and mesothelial proliferation by multiwalled carbon nanotubes
Authors: Xu Jiegou , Alexander David B. , Futakuchi Mitsuru , Numano Takamasa , Fukamachi Katsumi , Suzui Masumi , Omori Toyonori , Kanno Jun , Hirose Akihiko , Tsuda Hiroyuki
Published: May 2014

Multiwalled carbon nanotubes (MWCNT) have a fibrous structure similar to asbestos, raising concern that MWCNT exposure may lead to asbestos‐like diseases. Previously we showed that MWCNT translocated from the lung alveoli into the pleural cavity and caused mesothelial proliferation and fibrosis in the visceral pleura. Multiwalled carbon nanotubes were not found in the parietal pleura, the initial site of development of asbestos‐caused pleural diseases in humans, probably due to the short exposure period of the study. In the present study, we extended the exposure period to 24 weeks to determine whether the size and shape of MWCNT impact on deposition and lesion development in the pleura and lung. Two different MWCNTs were chosen for this study: a larger sized needle‐like MWCNT (MWCNT‐L; l = 8 μm, d = 150 nm), and a smaller sized MWCNT (MWCNT‐S; l = 3 μm, d = 15 nm), which forms cotton candy‐like aggregates. Both MWCNT‐L and MWCNT‐S suspensions were administered to the rat lung once every 2 weeks for 24 weeks by transtracheal intrapulmonary spraying. It was found that MWCNT‐L, but not MWCNT‐S, translocated into the pleural cavity, deposited in the parietal pleura, and induced fibrosis and patchy parietal mesothelial proliferation lesions. In addition, MWCNT‐L induced stronger inflammatory reactions including increased inflammatory cell number and cytokine/chemokine levels in the pleural cavity lavage than MWCNT‐S. In contrast, MWCNT‐S induced stronger inflammation and higher 8‐hydroxydeoxyguanosine level in the lung tissue than MWCNT‐L. These results suggest that MWCNT‐L has higher risk of causing asbestos‐like pleural lesions relevant to mesothelioma development.
Novel regulatory program for norepinephrine‐induced epithelial–mesenchymal transition in gastric adenocarcinoma cell lines
Authors: Shan Tao , Cui Xijuan , Li Wei , Lin Wanrun , Li Yiming , Chen Xi , Wu Tao
Published: May 2014

Norepinephrine and epinephrine, catecholamine hormones that are major mediators for chronic stress‐induced cancers, are implicated in the progression of a number of cancer cells, including gastric adenocarcinoma. However, the underlying mechanisms of these hormones have not been well elucidated. Epithelial–mesenchymal transition (EMT) is a crucial event responsible for cancer cell invasion and metastasis. The hypothesis regarding whether the promotive effects of norepinephrine (NE) on cancer are in part due to its ability to induce an EMT program has not been proven. In this study, we show that NE does not only obviously induce EMT alterations in the morphological characteristics of gastric adenocarcinoma cells, but also increases the markers of EMT, including vimentin expression, and decreases E‐cadherin expression, further resulting in cell motility and invasiveness. We also reveal that these actions are mainly mediated through the activation of β2‐AR–HIF‐1α–Snail signaling pathways. In summary, this study implies that NE induces EMT in gastric adenocarcinoma through the regulation of β2‐AR–HIF‐1α–Snail activity. The data provide a new perspective on chronic stress in a negative social and psychological state, which may be a risk factor for cancer development and progression.
Clinicopathological analysis of 17 primary cutaneous T‐cell lymphoma of the γδ phenotype from Japan
Authors: Takahashi Yuka , Takata Katsuyoshi , Kato Seiichi , Sato Yasuharu , Asano Naoko , Ogino Tetsuro , Hashimoto Kimio , Tashiro Yukie , Takeuchi Shogo , Masunari Taro , Hiramatsu Yasushi , Maeda Yoshinobu , Tanimoto Mitsune , Yoshino Tadashi
Published: May 2014

Primary cutaneous γδ T‐cell lymphoma (PCGD‐TCL) is an aggressive lymphoma consisting of clonal proliferation of mature activated γδ T‐cells of a cytotoxic phenotype. Because primary cutaneous γδ T‐cell lymphoma is a rare disease, there are few clinicopathological studies. In addition, T‐cell receptor (TCR) γδ cells are typically immunostained in frozen sections or determined by TCRβ negativity. We retrospectively analyzed 17 primary cutaneous T‐cell lymphomas of the γδ phenotype (CTCL‐γδ) in a clinicopathological and molecular study using paraffin‐embedded sections. Among 17 patients, 11 had CTCL‐γδ without subcutaneous panniculitis‐like T‐cell lymphoma (SPTCL) features and six had CTCL‐γδ with SPTCL features. Immunophenotypically, some significant differences were found in CD8 and CD56 positivity between our patient series of CTCL‐γδ patients with SPTCL features and SPTCL‐γδ patients described in the previous literature. A univariate analysis of 17 CTCL‐γδ patients showed that being more than 60 years old, presence of visceral organ involvement, and small‐to‐medium cell size were poor prognostic factors. In addition, the 5‐year overall survival rate was 42.4% for the CTCL‐γδ patients without SPTCL features and 80.0% for those with SPTCL features. Consequently, there was a strikingly significant difference in overall survival among SPTCL, CTCL‐γδ with SPTCL features and CTCL‐γδ without SPTCL features (P = 0.0005). Our data suggests that an indolent subgroup may exist in CTCL‐γδ. Studies on more cases, including those from other countries, are warranted to delineate the clinicopathological features and the significance in these rare lymphomas.
Endoscopic findings using narrow‐band imaging to distinguish between basal cell hyperplasia and carcinoma of the pharynx
Authors: Yagishita Atsushi , Fujii Satoshi , Yano Tomonori , Kaneko Kazuhiro
Published: May 2014

Narrow‐band imaging (NBI) has been reported to be useful for detecting superficial‐type esophageal or head and neck squamous cell carcinoma (SCC), and in the present study we have used NBI to detect non‐carcinomatous lesions, such as basal cell hyperplasia (BCH) accompanied by microvascular irregularities; these non‐carcinomatous lesions were pathologically discriminated from squamous cell carcinoma of the pharynx. The aim of the present study was to clarify the endoscopic characteristics of BCH that contribute to the discrimination of superficial‐type head and neck SCC (HNSCC). We examined the key endoscopic findings capable of distinguishing BCH from SCC using 26 BCH and 37 superficial‐type SCC of the pharynx that had been pathologically diagnosed at our institution between January 2008 and July 2012. The clinicopathological factors were also compared. The size of the BCH lesions was significantly smaller (P < 0.001), and their intervascular transparency was more clearly observed (P < 0.001). Intra‐epithelial papillary capillary loop (IPCL) shapes were less variable and monotonous (P < 0.001), and the distribution of the IPCL was more regular with an interval comparable to that of SCC (P < 0.001), although no significant differences in the sharpness of the lesion border, dilatation of IPCL and tortuosity of the IPCL were seen between the BCH and SCC lesions. This study revealed that BCH was an independent entity in terms of not only pathological findings, but also endoscopic findings observed using NBI, such as the regular distribution of IPCL and the preserved intervascular transparency.
Tumor‐suppressive microRNA‐218 inhibits cancer cell migration and invasion via targeting of LASP1 in prostate cancer
Authors: Nishikawa Rika , Goto Yusuke , Sakamoto Shinichi , Chiyomaru Takeshi , Enokida Hideki , Kojima Satoko , Kinoshita Takashi , Yamamoto Noriko , Nakagawa Masayuki , Naya Yukio , Ichikawa Tomohiko , Seki Naohiko
Published: May 2014

Our recent studies of the microRNA (miRNA) expression signature in prostate cancer (PCa) indicated that miRNA‐218 (miR‐218) was significantly downregulated in clinical specimens, suggesting that miR‐218 might act as a tumor‐suppressive miRNA in PCa. The aim of the present study was to investigate the functional significance of miR‐218 in PCa and to identify novel miR‐218‐regulated cancer pathways and target genes involved in PCa oncogenesis and metastasis. Restoration of miR‐218 in PCa cell lines (PC3 and DU145) revealed that this miRNA significantly inhibited cancer cell migration and invasion. Gene expression data and in silico analysis demonstrated that LIM and SH3 protein 1 (LASP1) is a potential target of miR‐218 regulation. LASP1 is a cytoskeletal scaffold protein that plays critical roles in cytoskeletal organization and cell migration. Luciferase reporter assays showed that miR‐218 directly regulated expression of LASP1. Moreover, downregulating the LASP1 gene significantly inhibited cell migration and invasion in cancer cells, and the expression of LASP1 was upregulated in cancer tissues. We conclude that loss of tumor‐suppressive miR‐218 enhanced cancer cell migration and invasion in PCa through direct regulation of LASP1. Our data on pathways regulated by tumor‐suppressive miR‐218 provide new insight into the potential mechanisms of PCa oncogenesis and metastasis.
Clonal heterogeneity of lymphoid malignancies correlates with poor prognosis
Authors: Suguro Miyuki , Yoshida Noriaki , Umino Akira , Kato Harumi , Tagawa Hiroyuki , Nakagawa Masao , Fukuhara Noriko , Karnan Sivasundaram , Takeuchi Ichiro , Hocking Toby D. , Arita Kotaro , Karube Kennosuke , Tsuzuki Shinobu , Nakamura Shigeo , Kinoshita Tomohiro , Seto Masao
Published: May 2014

Clonal heterogeneity in lymphoid malignancies has been recently reported in adult T‐cell lymphoma/leukemia, peripheral T‐cell lymphoma, not otherwise specified, and mantle cell lymphoma. Our analysis was extended to other types of lymphoma including marginal zone lymphoma, follicular lymphoma and diffuse large B‐cell lymphoma. To determine the presence of clonal heterogeneity, 332 cases were examined using array comparative genomic hybridization analysis. Results showed that incidence of clonal heterogeneity varied from 25% to 69% among different types of lymphoma. Survival analysis revealed that mantle cell lymphoma and diffuse large B‐cell lymphoma with clonal heterogeneity showed significantly poorer prognosis, and that clonal heterogeneity was confirmed as an independent predictor of poor prognosis for both types of lymphoma. Interestingly, 8q24.1 (MYC) gain, 9p21.3 (CDKN2A/2B) loss and 17p13 (TP53, ATP1B2, SAT2, SHBG) loss were recurrent genomic lesions among various types of lymphoma with clonal heterogeneity, suggesting at least in part that alterations of these genes may play a role in clonal heterogeneity.
Phase I study of olaratumab in Japanese patients with advanced solid tumors
Authors: Doi Toshihiko , Ma Yan , Dontabhaktuni Aruna , Nippgen Cornelia , Nippgen Johannes , Ohtsu Atsushi
Published: May 2014

Olaratumab (IMC‐3G3) is a fully human IgG1 monoclonal antibody that selectively binds the external domain of human platelet‐derived growth factor receptor‐α with high affinity and blocks ligand binding. This was a single‐center, dose‐escalation, phase I trial of olaratumab in Japanese patients with advanced/refractory solid malignancies. Three to six patients were enrolled into each of three cohorts: Patients received i.v. olaratumab: 10 mg/kg on days 1 and 8 every 3 weeks (cohort 1); 20 mg/kg every 2 weeks (cohort 2); and 15 mg/kg on days 1 and 8 every 3 weeks (cohort 3). Doses were escalated from cohort 1 through cohort 3. The primary objective was to establish the safety and pharmacokinetic profile of olaratumab. Sixteen patients were treated across three cohorts. There were no dose‐limiting toxicities, so the maximum tolerated dose was not reached. The most common olaratumab‐related treatment‐emergent adverse events (TEAEs) were proteinuria (25.0%) and elevated aspartate transaminase (12.5%). One patient (cohort 2) had two olaratumab‐related Grade 3 TEAEs (increased aspartate aminotransferase and tumor hemorrhage); otherwise, olaratumab‐related TEAEs were Grade 1/2. Seven patients (43.8%) had a best response of stable disease. Based on the pharmacokinetic concentration profile of olaratumab, the trough concentrations following single and multiple doses at 15 mg/kg on days 1 and 8 every 3 weeks (cohort 3) and multiple doses at 20 mg/kg every 2 weeks (cohort 2) were above the 155 μg/mL target. Thus, these two doses could represent an acceptable schedule for future trials in Japanese patients. Olaratumab had an acceptable safety profile and was well tolerated.
Indoleamine 2,3‐dioxygenase promotes peritoneal metastasis of ovarian cancer by inducing an immunosuppressive environment
Authors: Tanizaki Yuko , Kobayashi Aya , Toujima Saori , Shiro Michihisa , Mizoguchi Mika , Mabuchi Yasushi , Yagi Shigetaka , Minami Sawako , Takikawa Osamu , Ino Kazuhiko
Published: May 2014

Indoleamine 2,3‐dioxygenase (IDO) is a tryptophan‐catabolizing enzyme that has immunoregulatory functions. Our prior study showed that tumoral IDO overexpression is involved in disease progression and impaired patient survival in human ovarian cancer, although its mechanism remains unclear. The purpose of the present study is to clarify the role of IDO during the process of peritoneal dissemination of ovarian cancer. Indoleamine 2,3‐dioxygenase cDNA was transfected into the murine ovarian carcinoma cell line OV2944‐HM‐1, establishing stable clones of IDO‐overexpressing cells (HM‐1‐IDO). Then HM‐1‐IDO or control vector‐transfected cells (HM‐1‐mock) were i.p. transplanted into syngeneic immunocompetent mice. The HM‐1‐IDO‐transplanted mice showed significantly shortened survival compared with HM‐1‐mock‐transplanted (control) mice. On days 11 and 14 following transplantation, the tumor weight of peritoneal dissemination and ascites volume were significantly increased in HM‐1‐IDO‐transplanted mice compared with those of control mice. This tumor‐progressive effect was coincident with significantly reduced numbers of CD8+ T cells and natural killer cells within tumors as well as increased levels of transforming growth factor‐β and interleukin‐10 in ascites. Finally, treatment with the IDO inhibitor 1‐methyl‐tryptophan significantly suppressed tumor dissemination and ascites with reduced transforming growth factor‐β secretion. These findings showed that tumor‐derived IDO promotes the peritoneal dissemination of ovarian cancer through suppression of tumor‐infiltrating effector T cell and natural killer cell recruitment and reciprocal enhancement of immunosuppressive cytokines in ascites, creating an immunotolerogenic environment within the peritoneal cavity. Therefore, IDO may be a promising molecular target for the therapeutic strategy of ovarian cancer.
Distributed expertise: qualitative study of a British network of multidisciplinary teams supporting parents of children with chronic kidney disease
Authors: Swallow V. , Smith T. , Webb N. J. A. , Wirz L. , Qizalbash L. , Brennan E. , Birch A. , Sinha M. D. , Krischock L. , van der Voort J. , King D. , Lambert H. , Milford D. V. , Crowther L. , Saleem M. , Lunn A. , Williams J.
Published: May 2014

Background

Long‐term childhood conditions are often managed by hospital‐based multidisciplinary teams (MDTs) of professionals with discipline specific expertise of a condition, in partnership with parents. However, little evidence exists on professional–parent interactions in this context. An exploration of professionals' accounts of the way they individually and collectively teach parents to manage their child's clinical care at home is, therefore, important for meeting parents' needs, informing policy and educating novice professionals. Using chronic kidney disease as an exemplar this paper reports on one aspect of a study of interactions between professionals and parents in a network of 12 children's kidney units in Britain.

Methods

We conducted semi‐structured, qualitative interviews with a convenience sample of 112 professionals (clinical‐psychologists, dietitians, doctors, nurses, pharmacists, play‐workers, therapists and social workers), exploring accounts of their parent‐educative activity. We analysed data using framework and the concept of distributed expertise.

Results

Four themes emerged that related to the way expertise was distributed within and across teams: (i) recognizing each other's' expertise, (ii) sharing expertise within the MDT, (iii) language interpretation, and (iv) acting as brokers. Two different professional identifications were also seen to co‐exist within MDTs, with participants using the term ‘we’ both as the intra‐professional ‘we’ (relating to the professional identity) when describing expertise within a disciplinary group (for example: ‘As dietitians we aim to give tailored advice to optimize children's growth’), and the inter‐professional ‘we’ (a ‘team‐identification’), when discussing expertise within the team (for example: ‘We work as a team and make sure we're all happy with every aspect of their training before they go home’).

Conclusions

This study highlights the dual identifications implicit in ‘being professional’ in this context (to the team and to one's profession) as well as the unique role that each member of a team contributes to children's care. Our methodology and results have the potential to be transferred to teams managing other conditions.
Life satisfaction in the transition from care to adulthood: the contribution of readiness to leave care and social support
Authors: Dinisman Tamar
Published: May 2014

This research explores whether readiness to leave care mediates the association between social support – from peers, staff and biological parents – on the verge of leaving care and life satisfaction a year after among young people ageing out of care in Israel. The results represent two waves of a longitudinal study. Two hundred seventy‐two adolescents from residential settings in Israel completed a self‐administered questionnaire shortly before they left care, and one year later, 234 of them were interviewed to assess their life satisfaction. Readiness to leave care was found to mediate the relationship between most social support measurements and life satisfaction. At the same time, the findings also suggest that this mediating effect varies for different types of support and has a lesser amount of influence for profound emotional support than other types of support. These findings highlight the need to include both the preparation to leave care and the reinforcement of emotional support available to young people who aged out of care, before and throughout the transition from care to adulthood.
Quest for the Holy Grail—Is a Unified Approach to the Market Freedoms and European Citizenship Justified?
Authors: de Sousa Pedro Caro
Published: May 2014

The case law of the CJEU on the economic free movement of people has departed from the traditional requirement that a nexus must be established between individual free movement and cross‐border economic activity, which has led to an extension of its scope. It is submitted that concerns with the protection of fundamental rights of European citizens are driving this process, and that the CJEU has sought to protect these fundamental rights through the market freedoms in two ways: by arguing that market freedoms are fundamental right themselves, and/or that European Citizenship has changed their normative underpinnings and status. This Article criticises both lines of argument, and defends a third: that the protection of these fundamental rights must be achieved at European level, if at all, through a conception of European Citizenship able to stand on its own.
SIRT2 as a new player in epigenetic programming of keratinocyte differentiation and a candidate tumor suppressor
Authors: Wang Ming , Yue Zhicao , Paus Ralf , Ramot Yuval
Published: May 2014

Epidermal keratinocytes undergo a continuous process of terminal differentiation, which is accompanied by a dramatic change in the expression and composition of keratins. This complex and carefully orchestrated process is regulated by a large number of signal transduction events and transcriptional factors as well as by epigenetic regulatory mechanisms, namely by histone methylation/acetylation and DNA methylation. In a recent issue of Exp Dermatol, Ming et al. provide evidence that sirtuin‐2 (SIRT2), a NAD+‐dependent deacetylase, inhibits the expression of keratin 15 and keratin 19, epidermal stem cell markers, while it stimulates the expression of loricrin, a marker of terminal keratinocyte differentiation. Human skin cancer cells show downregulation of SIRT2, and its deletion increases tumor growth in mice. Overall, these findings suggest that this deacetylase is involved in the epigenetic regulation of keratinocyte differentiation and exerts intracutaneous tumor suppressor functions.
Matricryptins and matrikines: biologically active fragments of the extracellular matrix
Authors: Ricard‐Blum Sylvie , Salza Romain
Published: May 2014

Numerous extracellular proteins and glycosaminoglycans (GAGs) undergo limited enzymatic cleavage resulting in the release of fragments exerting biological activities, which are usually different from those of the full‐length molecules. In this review, we define matrikines and matricryptins, which are bioactive fragments released from the extracellular matrix proteins, proteoglycans and GAGs and report their major biological activities. These fragments regulate a number of physiopathological processes including angiogenesis, cancer, fibrosis, inflammation, neurodegenerative diseases and wound healing. The challenges to translate these fragments from molecules biologically active in vitro and in experimental models to potential drugs are discussed in the last part of the review.
Melanoma's high C>T mutation rate: is deamination playing a role?
Authors: Sanchez Margaret I. , Grichnik James M.
Published: May 2014

The majority of melanoma mutations are C>T transitions, and most bear UV signatures. However, other process may contribute to the high C>T mutation rate. Okura et al., have demonstrated immunohistochemical evidence of deaminating enzymes, activation‐induced cytidine deaminase (AID) and apolipoprotein B mRNA‐editing enzyme catalytic polypeptide‐like 3B (APOBEC3B) in melanoma. Both have been implicated in cancer. While further validation is necessary, these findings warrant consideration of a role for deamination in melanomagenesis. Deamination primarily drives C>T transitions. Compared with trunk/extremity melanomas, acral melanomas display a significantly higher percentage of ‘spontaneous’ and ‘AID’ mutation signature events suggesting deamination may be particularly important in this subgroup.
Psoriasis: to treat or to manage?
Authors: Mrowietz Ulrich , Steinz Kirsten , Gerdes Sascha
Published: May 2014

The recognition of psoriasis as a systemic disorder with characteristic skin symptoms and associated diseases has changed treatment concepts substantially. The complexity of psoriasis disease not only requires appropriate therapy but also weight‐loss and smoking cessation programmes as well as trigger factor elimination. The term ‘management’ may better reflect the aim for a holistic approach of disease control. Comorbidity and the presence of psoriatic arthritis are important denominators for drug selection. However, there is a lack of prospective data substantiating a benefit of associated diseases by antipsoriatic therapy. Securing success using treatment goals helps to establish an efficacious therapy and to control inflammation. A regular scoring of disease severity, patients’ quality of life and assessment of other clinically relevant conditions are mandatory to closely follow the disease course. There is debate whether an early treatment may modulate the future course of psoriasis. Concepts of minimal disease activity have not been implemented in psoriasis yet. There is a lack of evidence how long any treatment should be given and when and how to terminate. Finally, outcome tools should specifically be tailored for psoriasis to evaluate disease‐related items as well as the benefit of management from the patient's perspective.
Coming home at last: dermal white adipose tissue
Authors: Schneider Marlon R.
Published: May 2014

The upper part of subcutaneous white adipose tissue (SWAT) is closely associated with the reticular dermis, surrounds hair follicles and is of great importance for a range of skin functions. In this issue of Experimental Dermatology, Driskell and colleagues propose a nomenclature in which the upper SWAT layer is renamed dermal WAT (DWAT), and its cells intradermal adipocytes. Some pros and cons are discussed below.
CD109, a novel TGF‐β antagonist, decreases fibrotic responses in a hypoxic wound model
Authors: Winocour Sebastian , Vorstenbosch Joshua , Trzeciak Alissa , Lessard Lucie , Philip Anie
Published: May 2014

Excessive extracellular matrix deposition that occurs in many fibrotic skin disorders such as hypertrophic scarring and scleroderma is often associated with hypoxia. CD109 is a novel TGF‐β co‐receptor and TGF‐β antagonist shown to inhibit TGF‐β‐induced extracellular matrix protein production in vitro. We examined whether CD109 is able to regulate extracellular matrix deposition under low oxygen tension in vivo using transgenic mice overexpressing CD109 in the epidermis. By creating dorsal bipedicle skin flaps with centrally located excisional wounds in these mice and their wild‐type littermates, we generated a novel murine hypoxic wound model. Mice were sacrificed on 7 or 14 days post‐wounding, and tissues were harvested for histological and biochemical analysis. Hypoxic wounds in both transgenic and wild‐type mice showed increased levels of HIF‐1α and delayed wound closure, validating this model in mice. Hypoxic wounds in CD109 transgenic mice demonstrated decreased collagen type 1 and fibronectin expression, and reduced dermal thickness on day 7 post‐wounding as compared to those in wild‐type mice and to non‐hypoxic control wounds. These results suggest that CD109 decreases extracellular matrix production and fibrotic responses during hypoxic wound healing. Manipulating CD109 levels may have potential therapeutic value for the treatment of fibrotic skin disorders associated with poor oxygen delivery.
P2Y2R activation by nucleotides promotes skin wound‐healing process
Authors: Jin Hana , Seo Jihye , Eun So Young , Joo Young Nak , Park Sang Won , Lee Jae Heun , Chang Ki Churl , Kim Hye Jung
Published: May 2014

P2Y2R has been shown to be upregulated in a variety of tissues in response to stress or injury and to mediate tissue regeneration through its ability to activate multiple signalling pathways. This study aimed to investigate the role of P2Y2R in the wound‐healing process and the mechanisms by which P2Y2R activation promotes wound healing in fibroblasts. The role of P2Y2R in skin wound healing was examined using a full‐thickness skin wound model in wildtype (WT) and P2Y2R−/− mice and an in vitro scratch wound model in control or P2Y2R siRNA‐transfected fibroblasts. WT mice showed significantly decreased wound size compared with P2Y2R−/− mice at day 14 post‐wounding, and immunohistochemical analysis showed that a proliferation marker Ki67 and extracellular matrix (ECM)‐related proteins VEGF, collagen I, fibronectin and α‐SMA were overexpressed in WT mice, which were reduced in P2Y2R−/− mice. Scratch‐wounded fibroblasts increased ATP release, which peaked at 5 min. In addition, scratch wounding increased the level of P2Y2R mRNA. Activation of P2Y2R by ATP or UTP enhanced proliferation and migration of fibroblasts in in vitro scratch wound assays and were blocked by P2Y2R siRNA. Finally, ATP or UTP also increased the levels of ECM‐related proteins through the activation of P2Y2R in fibroblasts. This study suggests that P2Y2R may be a potential therapeutic target to promote wound healing in chronic wound diseases.
Expression of decorin throughout the murine hair follicle cycle: hair cycle dependence and anagen phase prolongation
Authors: Jing Jing , Wu Xian‐jie , Li Yun‐ling , Cai Sui‐Qing , Zheng Min , Lu Zhong‐Fa
Published: May 2014

Decorin is a prototypical member of the small leucine‐rich proteoglycan (SLRP) family, which is involved in numerous biological processes. The role of decorin, as a representative SLRP, in hair follicle morphogenesis has not been elucidated. We present our initial findings on decorin expression patterns during induced murine hair follicle (HF) cycles. It was found that decorin expression is exclusively restricted to the epidermis, outer root sheath and sebaceous glands during the anagen phase, which correlates with the upregulation of decorin mRNA and protein expression in depilated murine dorsal skin. Furthermore, we used a functional approach to investigate the effects of recombinant human decorin (rhDecorin) via cutaneous injection into HFs at various murine hair cycle stages. The local injection of rhDecorin (100 μg/ml) into the hypodermis of depilated C57BL/6 mice at anagen delayed catagen progression. In contrast, rhDecorin injection during the telogen phase caused the premature onset of anagen, as demonstrated by the assessment of the following parameters: (i) hair shaft length, (ii) follicular bulbar diameter, (iii) hair follicle cycling score and (iv) follicular phase percentage. Taken together, our results suggest that decorin may modulate follicular cycling and morphogenesis. In addition, this study also provides insight into the molecular control mechanisms governing hair follicular epithelial–mesenchymal interactions.
Role ofEts‐1 in fibronectin‐derived heparin‐binding domain polypeptides alleviating melanoma cell invasiveness and chemoresistance
Authors: Tang Nanhong , Wang Xiaoqian , Huang Tao , Wu Yong , Chen Yuanzhong
Published: May 2014

In this study, we observed that rhFNHN29 and rhFNHC36, two recombinant heparin‐binding domain polypeptides of fibronectin, suppressed adhesion and invasion ofB16F10 andA375 melanoma cells mediated by integrinαv andα2 in a dose‐dependent manner. Combined with low‐concentration epirubicin (EPI), rhFNHN29 or rhFNHC36 exhibited a synergistic inhibition on the viability and metastasis ofB16F10 cells. Moreover, in the presence of high‐concentration rhFNHN29 or rhFNHC36, theEts‐1 activity and the expression of p‐FAK, p‐Erk1/2 andEts‐1 were notably downregulated inB16F10 cells. Ets‐1 is one of the central regulatory links for rhFNHN29 and rhFNHC36 to suppress the adhesion and invasion of melanoma cells. Combining rhFNHN29 or rhFNHC36 withEPImay be a good way to alleviate invasiveness or chemoresistance in melanoma.
Co‐occurrence of autoantibodies in healthy blood donors
Authors: Prüßmann Jasper , Prüßmann Wiebke , Recke Andreas , Rentzsch Kristin , Juhl David , Henschler Reinhard , Müller Susen , Lamprecht Peter , Schmidt Enno , Csernok Elena , Görg Siegfried , Stöcker Winfried , Zillikens Detlef , Ibrahim Saleh M. , Ludwig Ralf J.
Published: May 2014

Autoimmune diseases are rare, but their incidence has increased over the past decades. Interestingly, the co‐occurrence of autoimmune diseases is well documented; however, data on the presence of more than one specific autoantibody in healthy individuals are not available. Here, we investigated the prevalence of several autoantibodies in a cohort of over 6000 healthy persons. While individual autoantibodies were rarely detected (i.e. ranging from 0.3% for ANCA to 4.6% for anti‐TPO), the cumulative prevalence of the tested autoantibodies was as high as 10%. Furthermore, our results demonstrate co‐occurrence of ANA with specific autoantibodies that target TPO, CCP and Dsg1/3, while ANCA and autoantibodies to PCA and BP180/BP230 were not more frequent in ANA‐positive compared to ANA‐negative samples. This indicates that shared and independent mechanisms influence loss of tolerance to distinct sets of self‐antigens.
Biological characteristics and gene expression pattern of bone marrow mesenchymal stem cells in patients with psoriasis
Authors: Hou Ruixia , Liu Ruifeng , Niu Xuping , Chang Wenjuan , Yan Xin , Wang Chunfang , Li Junqin , An Peng , Li Xinhua , Yin Guohua , Zhang Kaiming
Published: May 2014

Mesenchymal stem cells (MSCs) have immunoregulatory and proangiogenic effects and are suggested to be involved in the pathological processes of immune‐related diseases, including psoriasis. Biological characteristics of bone marrow MSCs (BMSCs) from patients with autoimmune diseases, such as systemic lupus erythematosus or rheumatoid arthritis, but not psoriasis, have been characterized. We compared the gene expression profile and biological characteristics of BMSCs from patients with psoriasis and healthy controls. Although the phenotype, differentiation potential and ability to support CD34+ cell proliferation were similar to those of normal BMSCs, psoriatic BMSCs showed aberrant proliferative activity, increased apoptosis rate and a characteristic gene expression profile. These aberrations may develop after the abnormal immune response in psoriasis and result in BMSC dysfunction. The functionally deficient BMSCs may then fail to suppress overactive immune cells, thereby contributing to the pathogenesis of psoriasis.
Interactions of disulfide‐deficient selenocysteine analogs of μ‐conotoxin BuIIIB with the α‐subunit of the voltage‐gated sodium channel subtype 1.3
Authors: Green Brad R. , Zhang Min‐Min , Chhabra Sandeep , Robinson Samuel D. , Wilson Michael J. , Redding Addison , Olivera Baldomero M. , Yoshikami Doju , Bulaj Grzegorz , Norton Raymond S.
Published: May 2014

Inhibitors of the α‐subunit of the voltage‐gated sodium channel subtype 1.3 (NaV1.3) are of interest as pharmacological tools for the study of neuropathic pain associated with spinal cord injury and have potential therapeutic applications. The recently described μ‐conotoxin BuIIIB (μ‐BuIIIB) from Conus bullatus was shown to block NaV1.3 with submicromolar potency (Kd = 0.2 μm), making it one of the most potent peptidic inhibitors of this subtype described to date. However, oxidative folding of μ‐BuIIIB results in numerous folding isoforms, making it difficult to obtain sufficient quantities of the active form of the peptide for detailed structure–activity studies. In the present study, we report the synthesis and characterization of μ‐BuIIIB analogs incorporating a disulfide‐deficient, diselenide‐containing scaffold designed to simplify synthesis and facilitate structure–activity studies directed at identifying amino acid residues involved in NaV1.3 blockade. Our results indicate that, similar to other μ‐conotoxins, the C‐terminal residues (Trp16, Arg18 and His20) are most crucial for NaV1 blockade. At the N‐terminus, replacement of Glu3 by Ala resulted in an analog with an increased potency for NaV1.3 (Kd = 0.07 μm), implicating this position as a potential site for modification for increased potency and/or selectivity. Further examination of this position showed that increased negative charge, through γ‐carboxyglutamate replacement, decreased potency (Kd = 0.33 μm), whereas replacement with positively‐charged 2,4‐diamonobutyric acid increased potency (Kd = 0.036 μm). These results provide a foundation for the design and synthesis of μ‐BuIIIB‐based analogs with increased potency against NaV1.3.