bluuebunny/crossref_metadata_2025 huggingface dataset:
Joint problems arising from lack of repair mechanisms: can cannabinoids help?
Authors: Malek Natalia , Starowicz Katarzyna
Published: March 2018

Osteoarthritis (OA) is the most common disease of joints, which are complex organs where cartilage, bone and synovium cooperate to allow a range of movements. During progression of the disease, the function of all three main components is jeopardized. Nevertheless, the involvement of each tissue in OA development is still not established and is the topic of the present review. The OA therapies available are symptomatic, largely targeting pain management rather than disease progression. The strong need to develop a treatment for cartilage degeneration, bone deformation and synovial inflammation has led to research on the involvement of the endocannabinoid system in the development of OA. The current review discusses the research on this topic to date and notes the advantages of exploiting endocannabinoid system modulation for cartilage, bone and synovium homeostasis, which could prevent the further progression of OA.

Linked Articles

This article is part of a themed section on 8th European Workshop on Cannabinoid Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.10/issuetoc
Targeting glial cannabinoid CB2 receptors to delay the progression of the pathological phenotype in TDP‐43 (A315T) transgenic mice, a model of amyotrophic lateral sclerosis
Authors: Espejo‐Porras Francisco , García‐Toscano Laura , Rodríguez‐Cueto Carmen , Santos‐García Irene , de Lago Eva , Fernandez‐Ruiz Javier
Published: March 2018

Background and Purpose

Cannabinoid CB2 receptors are up‐regulated in reactive microglia in the spinal cord of TDP‐43 (A315T) transgenic mice, an experimental model of amyotrophic lateral sclerosis. To determine whether this up‐regulation can be exploited pharmacologically, we investigated the effects of different treatments that affect CB2 receptor function.

Experimental Approach

We treated TDP‐43 (A315T) transgenic mice with the non‐selective agonist WIN55,212‐2, alone or combined with selective CB1 or CB2 antagonists, as well as with the selective CB2 agonist HU‐308, and evaluated their effects on the pathological phenotype.

Key Results

WIN55,212‐2 had modest beneficial effects in the rotarod test, Nissl staining of motor neurons, and GFAP and Iba‐1 immunostainings in the spinal cord, which were mediated in part by CB2 receptor activation. HU‐308 significantly improved the rotarod performance of the transgenic mice, with complete preservation of Nissl‐stained motor neurons in the ventral horn. Reactive astrogliosis labelled with GFAP was also attenuated by HU‐308 in the dorsal and ventral horns, in which CB2 receptors colocalize with this astroglial marker. Furthermore, HU‐308 reduced the elevated Iba‐1 immunostaining in the ventral horn of TDP‐43 transgenic mice, but did not affect this immunoreactivity in white matter, in which CB2 receptors also colocalize with this microglial marker.

Conclusions and Implications

Our study shows an important role for glial CB2 receptors in limiting the progression of the pathological phenotype in TDP‐43 (A315T) transgenic mice. Such benefits appear to derive from the activation of CB2 receptors concentrated in astrocytes and reactive microglia located in spinal dorsal and ventral horns.

Linked Articles

This article is part of a themed section on 8th European Workshop on Cannabinoid Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.10/issuetoc
P2Y12 receptor modulation of ADP‐evoked intracellular Ca2+ signalling in THP‐1 human monocytic cells
Authors: Micklewright J J , Layhadi J A , Fountain S J
Published: March 2018

Background and Purpose

The Gi‐coupled, ADP‐activated P2Y12 receptor is well characterized as playing a key role in platelet activation via crosstalk with the P2Y1 receptor in ADP‐evoked intracellular Ca2+ responses. However, there is limited knowledge on the role of P2Y12 receptors in ADP‐evoked Ca2+ responses in other blood cells. Here, we investigated the role of P2Y12 receptor activation in the modulation of ADP‐evoked Ca2+ responses in human THP‐1 monocytic cells.

Experimental Approach

A combination of intracellular Ca2+ measurements, RT‐PCR, immunocytochemistry, leukocyte isolation and siRNA‐mediated gene knockdown were used to identify the role of P2Y12 receptor activation.

Key Results

ADP‐evoked intracellular Ca2+ responses (EC50 2.7 μM) in THP‐1 cells were abolished by inhibition of PLC (U73122) or sarco/endoplasmic reticulum Ca2+‐ATPase (thapsigargin). Loss of ADP‐evoked Ca2+ responses following treatment with MRS2578 (IC50 200 nM) revealed a major role for P2Y6 receptors in mediating ADP‐evoked Ca2+ responses. ADP‐evoked responses were attenuated either with pertussis toxin treatment, or P2Y12 receptor inhibition with two chemically distinct antagonists (ticagrelor, IC50 5.3 μM; PSB‐0739, IC50 5.6 μM). ADP‐evoked responses were suppressed following siRNA‐mediated P2Y12 gene knockdown. The inhibitory effects of P2Y12 antagonists were fully reversed following adenylate cyclase inhibition (SQ22536). P2Y12 receptor expression was confirmed in freshly isolated human CD14+ monocytes.

Conclusions and Implications

Taken together, these data suggest that P2Y12 receptor activation positively regulates P2Y6 receptor‐mediated intracellular Ca2+ signalling through suppression of adenylate cyclase activity in human monocytic cells.
No effects without causes: the Iron Dysregulation and Dormant Microbes hypothesis for chronic, inflammatory diseases
Authors: Kell Douglas B. , Pretorius Etheresia
Published: March 2018

Since the successful conquest of many acute, communicable (infectious) diseases through the use of vaccines and antibiotics, the currently most prevalent diseases are chronic and progressive in nature, and are all accompanied by inflammation. These diseases include neurodegenerative (e.g. Alzheimer's, Parkinson's), vascular (e.g. atherosclerosis, pre‐eclampsia, type 2 diabetes) and autoimmune (e.g. rheumatoid arthritis and multiple sclerosis) diseases that may appear to have little in common. In fact they all share significant features, in particular chronic inflammation and its attendant inflammatory cytokines. Such effects do not happen without underlying and initially ‘external’ causes, and it is of interest to seek these causes. Taking a systems approach, we argue that these causes include (i) stress‐induced iron dysregulation, and (ii) its ability to awaken dormant, non‐replicating microbes with which the host has become infected. Other external causes may be dietary. Such microbes are capable of shedding small, but functionally significant amounts of highly inflammagenic molecules such as lipopolysaccharide and lipoteichoic acid. Sequelae include significant coagulopathies, not least the recently discovered amyloidogenic clotting of blood, leading to cell death and the release of further inflammagens. The extensive evidence discussed here implies, as was found with ulcers, that almost all chronic, infectious diseases do in fact harbour a microbial component. What differs is simply the microbes and the anatomical location from and at which they exert damage. This analysis offers novel avenues for diagnosis and treatment.
The anatomical components of the cardiac outflow tract of chondrichthyans and actinopterygians
Authors: Lorenzale Miguel , López‐Unzu Miguel A. , Rodríguez Cristina , Fernández Borja , Durán Ana C. , Sans‐Coma Valentín
Published: March 2018

The outflow tract of the fish heart is the segment interposed between the ventricle and the ventral aorta. It holds the valves that prevent blood backflow from the gill vasculature to the ventricle. The anatomical composition, histological structure and evolutionary changes in the fish cardiac outflow tract have been under discussion for nearly two centuries and are still subject to debate. This paper offers a brief historical review of the main conceptions about the cardiac outflow tract components of chondrichthyans (cartilaginous fish) and actinopterygians (ray‐finned fish) which have been put forward since the beginning of the nineteenth century up to the current day. We focus on the evolutionary origin of the outflow tract components and the changes to which they have been subject in the major extant groups of chondrichthyans and actinopterygians. In addition, an attempt is made to infer the primitive anatomical design of the heart of the gnathostomes (jawed vertebrates). Finally, several areas of further investigation are suggested. Recent work on fish heart morphology has shown that the cardiac outflow tract of chondrichthyans does not consist exclusively of the myocardial conus arteriosus as classically thought. A conus arteriosus and a bulbus arteriosus, devoid of myocardium and mainly composed of elastin and smooth muscle, are usually present in cartilaginous and ray‐finned fish. This is consistent with the suggestion that both components coexisted from the onset of the gnathostome radiation. There is evidence that the conus arteriosus appeared in the agnathans. By contrast, the evolutionary origin of the bulbus is still unclear. It is almost certain that in all fish, both the conus and bulbus develop from the embryonic second heart field. We suggest herein that the primitive anatomical heart of the jawed vertebrates consisted of a sinus venosus containing the pacemaker tissue, an atrium possessing trabeculated myocardium, an atrioventricular region with compact myocardium which supported the atrioventricular valves, a ventricle composed of mixed myocardium, and an outflow tract consisting of a conus arteriosus, with compact myocardium in its wall and valves at its luminal side, and a non‐myocardial bulbus arteriosus that connected the conus with the ventral aorta. Chondrichthyans have retained this basic anatomical design of the heart. In actinopterygians, the heart has been subject to notable changes during evolution. Among them, the following two should be highlighted: (i) a decrease in size of the conus in combination with a remarkable development of the bulbus, especially in teleosts; and (ii) loss of the myocardial compact layer of the ventricle in many teleost species.
The evolution of individuality revisited
Authors: Radzvilavicius Arunas L. , Blackstone Neil W.
Published: March 2018

Evolutionary theory is formulated in terms of individuals that carry heritable information and are subject to selective pressures. However, individuality itself is a trait that had to evolve – an individual is not an indivisible entity, but a result of evolutionary processes that necessarily begin at the lower level of hierarchical organisation. Traditional approaches to biological individuality focus on cooperation and relatedness within a group, division of labour, policing mechanisms and strong selection at the higher level. Nevertheless, despite considerable theoretical progress in these areas, a full dynamical first‐principles account of how new types of individuals arise is missing. To the extent that individuality is an emergent trait, the problem can be approached by recognising the importance of individuating mechanisms that are present from the very beginning of the transition, when only lower‐level selection is acting. Here we review some of the most influential theoretical work on the role of individuating mechanisms in these transitions, and demonstrate how a lower‐level, bottom‐up evolutionary framework can be used to understand biological complexity involved in the origin of cellular life, early eukaryotic evolution, sexual life cycles and multicellular development. Some of these mechanisms inevitably stem from environmental constraints, population structure and ancestral life cycles. Others are unique to specific transitions – features of the natural history and biochemistry that are co‐opted into conflict mediation. Identifying mechanisms of individuation that provide a coarse‐grained description of the system's evolutionary dynamics is an important step towards understanding how biological complexity and hierarchical organisation evolves. In this way, individuality can be reconceptualised as an approximate model that with varying degrees of precision applies to a wide range of biological systems.
Casting for service innovation: The roles of frontline employees
Authors: Engen Marit , Magnusson Peter
Published: March 2018

The purpose of this paper is to explore the roles of frontline employees (FLEs) in service innovation processes and how they contribute to these roles. In the literature, FLEs are argued to play an important role in service innovation; however, neither the potential types of roles nor what taking on these potential roles means to FLEs, have previously been studied. This study investigates FLEs' actions in different types of service innovation processes. Based on analyses of eight different service business units, FLEs are identified as having either of two sets of roles: (1) leading roles as idea creators, developers and implementers, or (2) supporting roles as problem reporters, advisors and executors. The analysis provides managers with guidelines which can help them to better utilize FLEs as contributors to service innovation, either as leading or supporting actors. These imply different management challenges, which are discussed. Advice on how to tackle these challenges is given on the basis of the findings.
Cluster‐randomised controlled trial of an occupational therapy intervention for children aged 11–13 years, designed to increase participation to prevent symptoms of mental illness
Authors: Tokolahi Ema , Vandal Alain C. , Kersten Paula , Pearson Janet , Hocking Clare
Published: March 2018

Background

The impact of occupational therapy on mental health outcomes for children is largely unexplored. The aim of this study was to investigate an evidence‐based occupational therapy intervention designed to increase participation in daily occupations to prevent symptoms of mental illness for children and run in schools.

Methods

The study used a pragmatic, cluster‐randomised controlled trial design with two arms. Fourteen clusters (schools), equating to 151 child participants, were stratified by school decile‐rank category and block randomised. Blinding of participants post‐randomisation was not feasible; however, outcomes assessors were blinded. Outcomes were measured at baseline, after the parallel and crossover phases, and at follow‐up; and were anxiety symptoms (primary), depression symptoms, self‐esteem, participation and wellbeing. Intention‐to‐treat analysis was applied and mixed linear modelling was used to account for clusters and repeated measures, and to adjust for covariates identified.

Results

This trial found significant positive effects of the intervention on child‐rated satisfaction with their occupational performance and teacher‐rated child anxiety. No evidence was found to support the effect of the intervention on anxiety and depression symptoms, self‐esteem and wellbeing.

Conclusions

This was the first known cluster‐randomised controlled trial to investigate an occupational therapy intervention promoting emotional wellbeing in a non‐clinical sample of children. No compelling evidence was found to support the use of the intervention in schools in its current format, however, results were promising that the focus on occupations influenced participation. Recommendations are made to redesign the intervention as an embedded intervention in the classroom, cotaught by teachers and including parental involvement.
Metabolome analysis for pancreatic cancer risk in nested case‐control study: Japan Public Health Center‐based prospective Study
Authors: Nakagawa Takashi , Kobayashi Takashi , Nishiumi Shin , Hidaka Akihisa , Yamaji Taiki , Sawada Norie , Hirata Yuichi , Yamanaka Kodai , Azuma Takeshi , Goto Atsushi , Shimazu Taichi , Inoue Manami , Iwasaki Motoki , Yoshida Masaru , Tsugane Shoichiro
Published: March 2018

Discovery of a high‐risk group for pancreatic cancer is important for prevention of pancreatic cancer. The present study was conducted as a nested case‐control study including 170 pancreatic cancer cases and 340 matched controls of our population‐based cohort study involving 30 239 subjects who answered a baseline questionnaire and supplied blood samples. Twelve targeted metabolites were quantitatively analyzed by gas chromatography/tandem mass spectrometry. Odds ratios (OR) and their corresponding 95% confidence intervals (CI) were calculated using conditional logistic regression models. Statistically significant P‐value was defined as P < .05. Increasing 1,5‐anhydro‐d‐glucitol (1,5‐AG) levels were associated with a decreasing trend in pancreatic cancer risk (OR of quartile 4 [Q4], 0.50; 95% CI, 0.27‐0.93; P = .02). Increasing methionine levels were also associated with an increasing trend of pancreatic cancer risk (OR of Q4, 1.79; 95% CI, 0.94‐3.40: P = .03). Additional adjustment for potential confounders attenuated the observed associations of 1,5‐AG and methionine (P for trend = .06 and .07, respectively). Comparing subjects diagnosed in the first 0‐6 years, higher levels of 1,5‐AG, asparagine, tyrosine and uric acid showed a decreasing trend for pancreatic cancer risk (P for trend = .04, .04, .04 and .02, respectively), even after adjustment for potential confounders. We found that the 12 target metabolites were not associated with pancreatic cancer risk. However, metabolic changes in the subjects diagnosed in the first 0‐6 years showed a similar tendency to our previous reports. These results might suggest that these metabolites are useful for early detection but not for prediction of pancreatic cancer.
Ribosome display and selection of single‐chain variable fragments effectively inhibit growth and progression of microspheres in vitro and in vivo
Authors: Huang Shangke , Feng Lu , An Gaili , Zhang Xiaojin , Zhao Zixuan , Han Rui , Lei Fuxi , Zhang Yujiao , Luo Anqi , Jing Xin , Zhao Lin , Gu Shanzhi , Zhao Xinhan , Zhang Lingxiao
Published: March 2018

Distinguishing the surface markers of cancer stem cells (CSCs) is a useful method for early diagnosis and treatment of tumors, as CSCs may participate in tumorigenesis and metastasis by migrating into the circulatory system. However, the potential targets of CSCs are expressed at low levels in the natural state and are always changing. Thus, dynamic screening has been reported to be an effective measure for exploring CSC markers. In recent years, diverse single‐chain variable fragments (scFvs) have been widely used in immunotherapy. In this study, we determined that the scFvs, screened using RD, had a high affinity to microspheres and could inhibit their progression. We also observed that the selected scFvs underwent evolution in vitro, and antitumor‐associated proteins were successfully expressed. Combined with chemotherapy, the scFvs had a synergistic effect on the inhibition of the microspheres’ progression in vitro and in vivo, which could be ascribed to their high affinity for stem‐like cells and the inhibition of the microspheres’ collective behaviors. In addition, proteins inhibiting CD44+/CD24+ and MAPK were involved. Our data indicated that dynamic screening of the scFvs in a natural state was of great significance in the inhibition of the microspheres in vitro and in vivo.
Retracted: Hispidulin suppresses cell growth and metastasis by targeting PIM1 through JAK2/STAT3 signaling in colorectal cancer
Authors: Liu Kaili , Gao Hui , Wang Qiaoyun , Wang Longyuan , Zhang Bin , Han Zhiwu , Chen Xuehong , Han Mei , Gao Mingquan
Published: March 2018

Colorectal cancer (CRC) accounts for over 600 000 deaths annually worldwide. The current study aims to evaluate the value of proto‐oncogene PIM1 as a therapeutic target in CRC and investigate the anticancer activity of hispidulin, a naturally occurring phenolic flavonoid compound, against CRC. Immunohistochemistry analysis showed that PIM1 was upregulated in CRC tissue. The role of PIM1 as an oncogene was evidenced by the fact that PIM1 knockdown inhibits cell growth, induces apoptosis, and suppresses invasion. Our results showed that hispidulin exerts antitumor activity in CRC through inhibiting the expression of PIM1. Moreover, our findings revealed that hispidulin downregulated the expression of PIM1 by inhibiting JAK2/STAT3 signaling by generating reactive oxygen species. Furthermore, our in vivo studies showed that hispidulin can significantly inhibit tumor growth and metastasis in CRC. Collectively, our results provide an experimental basis for trialing hispidulin in CRC treatment. PIM1 can be considered a potential therapeutic target in CRC.
Development of a vaccine based on bacteria‐mimicking tumor cells coated with novel engineered toll‐like receptor 2 ligands
Authors: Akazawa Takashi , Ohashi Toshimitsu , Wijewardana Viskam , Sugiura Kikuya , Inoue Norimitsu
Published: March 2018

For a successful tumor vaccine, it is necessary to develop effective immuno‐adjuvants and identify specific tumor antigens. Tumor cells obtained from surgical or biopsy tissues are a good source of tumor antigens but, unlike bacteria, they do not induce strong immune responses. Here, we designed 2 novel lipopeptides that coat tumor cell surfaces and mimic bacterial components. Tumor cells coated with these lipopeptides (called bacteria‐mimicking tumor cells [BMTC]) were prepared and their efficacy as a tumor vaccine examined. Natural bacterial lipopeptides act as ligands for toll‐like receptor 2 (TLR2) and activate dendritic cells (DC). To increase the affinity of the developed lipopeptides for the negatively charged plasma membrane, a cationic polypeptide was connected to Pam2Cys (P2C), which is the basic structure of the TLR2 ligand. This increased the non‐specific binding affinity of the peptides for the cell surface. Two such lipopeptides, P2CSK11 (containing 1 serine and 11 lysine residues) and P2CSR11 (containing 1 serine and 11 arginine residues) bound to irradiated tumor cells via the long cationic polypeptides more efficiently than the natural lipopeptide MALP2 (P2C‐GNNDESNISFKEK) or a synthetic lipopeptide P2CSK4 (a short cationic polypeptide containing 1 serine and 4 lysines). BMTC coated with P2CSR11 or P2CSK11 were efficiently phagocytosed by DC and induced antigen cross‐presentation in vitro. They also induced effective tumor‐specific cytotoxic T cell responses and inhibited tumor growth in in vivo mouse models. P2CSR11 activated DC but induced less inflammation‐inducing cytokines/interferons than other lipopeptides. Thus, P2CSR11 is a strong candidate antigen‐specific immuno‐adjuvant, with few adverse effects.
Phase II study of adjuvant chemotherapy with paclitaxel and nedaplatin for uterine cervical cancer with lymph node metastasis
Authors: Takekuma Munetaka , Shimokawa Mototsugu , Nishio Shin , Omi Hideo , Tabata Tsutomu , Takei Yuji , Nasu Kaei , Takahashi Yoshiyuki , Toyota Shinji , Ichikawa Yoshikazu , Arakawa Atsushi , Ito Fuminori , Tsubamoto Hiroshi , Mori Taisuke , Hirashima Yasuyuki , Ito Kimihiko
Published: March 2018

The purpose of this phase II trial was to assess the efficacy and toxicity of paclitaxel and nedaplatin (TN) as the initial postoperative adjuvant chemotherapy for uterine cervical cancer with lymph node metastases (LNM). Patients with FIGO stage IB1‐IIA2 squamous cell carcinoma of the uterine cervix were enrolled. Histological confirmation of LNM was mandatory. Intravenous paclitaxel at 175 mg/m2 and nedaplatin at 80 mg/m2 were administered every 28‐day cycle, of which there were 5 cycles after radical hysterectomy. Sixty‐two patients were enrolled in the study from November 2011 to July 2015. Their median age was 48.5 years (range 28‐64). The median tumor diameter was 37 mm (5‐64). Overall, 30 patients (48.4%) had 1 metastatic lymph node, 11 (17.7%) had 2, 3 (4.8%) had 3, 5 (8.1%) had 4, and 13 (21.0%) had 5 or more. With a median follow‐up of 45.7 months (range 23.4‐69.5), the 2‐year relapse‐free survival and 2‐year overall survival rates were 79.0% (90% CI, 69.0%‐86.2%) and 93.5% (95% CI, 83.7%‐97.5%), respectively. Almost all adverse events were relatively mild. Grade 3‐4 adverse events (NCI‐CTC ver. 4.0) that occurred in 5% or more of patients were neutropenia (60.7%) and infection (6.6%). The proportion of patients who completed 5 cycles of treatment was 90.3%. Postoperative adjuvant chemotherapy with TN for cervical cancer with LNM was demonstrated to be an effective and feasible treatment. A phase III trial is warranted to compare this with concurrent chemoradiotherapy.
Spontaneous development of intratumoral heterogeneity in a transposon‐induced mouse model of glioma
Authors: Sumiyoshi Keisuke , Koso Hideto , Watanabe Sumiko
Published: March 2018

Glioma is the most common form of malignant brain cancer in adults. The Sleeping Beauty (SB) transposon‐based glioma mouse model allows for effective in vivo analysis of candidate genes. In the present study, we developed a transposon vector that encodes the triple combination of platelet‐derived growth factor subunit A (PDGFA), and shRNAs against Nf1 and Trp53 (shNf1/shp53). Initiation and progression of glioma in the brain were monitored by expression of a fluorescent protein. Transduction of the vector into neural progenitor and stem cells (NPC) in the subventricular zone (SVZ) of the neonatal brain induced proliferation of oligodendrocyte precursor cells, and promoted formation of highly penetrant malignant gliomas within 2‐4 months. Cells isolated from the tumors were capable of forming secondary tumors. Two transposon vectors, encoding either PDGFA or shNf1/shp53 were co‐electroporated into NPC. Cells expressing PDGFA or shNf1/shp53 were labeled with unique fluorescent proteins allowing visualization of the spatial distribution of cells with different genetic alterations within the same tumor. Tumor cells located at the center of tumors expressed PDGFA at higher levels than those located at the periphery, indicating that intratumoral heterogeneity in PDGFA expression levels spontaneously developed within the same tumor. Tumor cells comprising the palisading necrosis strongly expressed PDGFA, suggesting that PDGFA signaling is involved in hypoxic responses in glioma. The transposon vectors developed are compatible with any genetically engineered mouse model, providing a useful tool for the functional analysis of candidate genes in glioma.
Podoplanin: An emerging cancer biomarker and therapeutic target
Authors: Krishnan Harini , Rayes Julie , Miyashita Tomoyuki , Ishii Genichiro , Retzbach Edward P. , Sheehan Stephanie A. , Takemoto Ai , Chang Yao‐Wen , Yoneda Kazue , Asai Jun , Jensen Lasse , Chalise Lushun , Natsume Atsushi , Goldberg Gary S.
Published: March 2018

Podoplanin (PDPN) is a transmembrane receptor glycoprotein that is upregulated on transformed cells, cancer associated fibroblasts and inflammatory macrophages that contribute to cancer progression. In particular, PDPN increases tumor cell clonal capacity, epithelial mesenchymal transition, migration, invasion, metastasis and inflammation. Antibodies, CAR‐T cells, biologics and synthetic compounds that target PDPN can inhibit cancer progression and septic inflammation in preclinical models. This review describes recent advances in how PDPN may be used as a biomarker and therapeutic target for many types of cancer, including glioma, squamous cell carcinoma, mesothelioma and melanoma.
Tumor necrosis factor‐α induces prostate cancer cell migration in lymphatic metastasis through CCR7 upregulation
Authors: Maolake Aerken , Izumi Kouji , Natsagdorj Ariunbold , Iwamoto Hiroaki , Kadomoto Suguru , Makino Tomoyuki , Naito Renato , Shigehara Kazuyoshi , Kadono Yoshifumi , Hiratsuka Kaoru , Wufuer Guzailinuer , Nastiuk Kent L. , Mizokami Atsushi
Published: March 2018

Understanding the mechanism of lymph node metastasis, a poor prognostic sign for prostate cancer, and the further dissemination of the disease is important to develop novel treatment strategies. Recent studies have reported that C‐C chemokine receptor 7 (CCR7), whose ligand is CCL21, is abundantly expressed in lymph node metastasis and promotes cancer progression. Tumor necrosis factor‐α (TNF‐α) is chronically produced at low levels within the tumor microenvironment. The aim of this study was to determine whether TNF‐α promotes prostate cancer dissemination from metastatic lymph nodes through activation of the CCL21/CCR7 axis. First, human prostate cancer cells were determined to express both TNF‐α and CCR7. Second, low concentrations of TNF‐α were confirmed to induce CCR7 in prostate cancer cells through phosphorylation of ERK. Finally, CCL21 was found to promote the migration of prostate cancer cells through phosphorylation of the protein kinase p38. Our results suggest that TNF‐α leads to the induction of CCR7 expression and that the CCL21/CCR7 axis might increase the metastatic potential of prostate cancer cells in lymph node metastasis.
Long non‐coding RNA metastasis‐associated lung adenocarcinoma transcript 1 promotes lung adenocarcinoma by directly interacting with specificity protein 1
Authors: Li Shufeng , Ma Fang , Jiang Kunpeng , Shan Haitao , Shi Minke , Chen Baojun
Published: March 2018

Metastasis‐associated lung adenocarcinoma transcript 1 (malat1) is an oncogenic long non‐coding RNA (lncRNA) which has been proven to be associated with various types of tumors. Transcription factor specificity protein 1 (SP1) is overexpressed in many types of cancers. Previously, we observed that malat1 expression level is regulated by SP1 in lung cancer. In the present study, we found that transfection of expression construct of malat1 5′ end fragment M5 enhances stability and transcriptional activity of SP1. Various SP1 target genes are also upregulated following overexpression of malat1 M5 in lung adenocarcinoma cells. We also showed that malat1 M5 interacts with the C‐terminal domain of SP1 by RNA immunoprecipitation (RIP) assay coupled with UV cross‐linking. Malat1‐SP1 association results in increase of SP1 stability. In turn, SP1 promotes malat1 transcription, thus forming a positive feedback loop. In conclusion, our data show that in lung adenocarcinoma cells, malat1 interacts with SP1 protein and promotes SP1‐mediated transcriptional regulation of SP1 target genes.
MicroRNA‐708‐3p mediates metastasis and chemoresistance through inhibition of epithelial‐to‐mesenchymal transition in breast cancer
Authors: Lee Jin‐Won , Guan Wei , Han Sanghak , Hong Deok‐Ki , Kim Lee‐Su , Kim Haesung
Published: March 2018

Metastasis and chemoresistance remain major challenges in the clinical treatment of breast cancer. Recent studies show that dysregulated microRNAs (miRNAs) play an important role in metastasis and chemoresistance development in breast cancer. Herein, we identified downregulated expression of miR‐708‐3p in breast cancers. In particular, miR‐708‐3p expression was significantly decreased in specimens from breast cancer patients with metastasis compared to that in specimens from patients with no metastasis. Consistent with clinical data, our in vitro data show that miR‐708‐3p was more significantly decreased in invasive breast cancer cell lines. In addition, our data show that inhibition of miR‐708‐3p significantly stimulated breast cancer cell metastasis and induced chemoresistance both in vitro and in vivo. In contrast, overexpression of miR‐708‐3p dramatically inhibited breast cancer cell metastasis and enhanced the sensitivity of breast cancer cells to chemotherapy both in vitro and in vivo. Furthermore, we identified that miR‐708‐3p inhibits breast cancer cell epithelial‐to‐mesenchymal transition (EMT) by directly targeting EMT activators, including ZEB1, CDH2 and vimentin. Taken together, our findings suggest that miR‐708‐3p acts as a cancer suppressor miRNA and carries out its anticancer function by inhibiting EMT in breast cancer. In addition, our findings suggest that restoration of miR‐708‐3p may be a novel strategy for inhibiting breast cancer metastasis and overcoming the chemoresistance of breast cancer cells.
Anti‐epidermal growth factor receptor therapy concurrently with induction chemotherapy in locoregionally advanced nasopharyngeal carcinoma
Authors: Peng Hao , Tang Ling‐Long , Liu Xu , Chen Lei , Li Wen‐Fei , Mao Yan‐Ping , Zhang Yuan , Liu Li‐Zhi , Tian Li , Guo Ying , Sun Ying , Ma Jun
Published: March 2018

Little is known about the efficacy and toxicity of anti‐epidermal growth factor receptor therapy concurrently with induction chemotherapy (IC) in locoregionally advanced nasopharyngeal carcinoma (LA‐NPC). The present study aimed to address this question. We identified 2848 patients with newly diagnosed LA‐NPC receiving IC between January 2012 and May 2015. The propensity score matching (PSM) method was used to balance various factors and to match patients. Survival outcomes and toxicities between different groups were compared. In total, 596 patients were selected at a 1:3 ratio, with 149 in the IC + CTX/NTZ group and 447 in the IC alone group. The 3‐year disease‐free survival, overall survival, distant metastasis‐free survival and locoregional relapse‐free survival rates for IC + CTX/NTZ vs IC alone were 84.3% vs 75.2% (P = .059), 94.0% vs 87.9% (P = .053), 88.0% vs 84.9% (P = .412) and 93.3% vs 88.2% (P = .242). Multivariate analysis established a treatment group (IC vs IC + CTX/NTZ) as a prognostic predictor for DFS (hazard ratio [HR], 1.497; 95% confidence interval [CI], 1.016‐2.206; P = .041) and OS (HR, 1.984; 95%, CI, 1.023‐3.848; P = .043). Grade 3‐4 skin reaction (15.4% vs 0.4%, P < .001) and mucositis (10.1% vs 2.7%, P < .001) were more common in the IC + CTX/NTZ group than that in the IC alone group. Our findings suggested that CTX/NTZ in combination with IC may be a more effective and promising strategy for patients with LA‐NPC treated with intensity‐modulated radiotherapy.
Synthesis and effect of a new Terbium gibberellic complex on the histopathological alteration induced by Gibberellic acid on liver and kidney of mice Mus musculus
Authors: Seleem Amin A. , Hussein Belal H. M.
Published: March 2018

The objective of this study was to synthesize Gibberellic lanthanide complex and evaluate its biological activity to reduce the Gibberellic acid toxicity on liver and kidney. The new bis(Gibberellic)‐nitro‐terbium(III) complex was characterized by different analytical methods: elemental analyses, UV–Vis, molar ratio, fluorescence, FT‐IR, and TGA‐DTA measurements. Thirty newborns were classified into three groups control, Gibberellic acid, and Terbium gibberellic acid complex. Livers and kidneys of studied groups proceed for general histology and immunohistochemical staining of Cyr61, cytochrome C, and TNFR2. From the absorption titration measurements, the binding constants of DNA with Tb(III)‐(GA)2 complex and free ligand were found to be 3.9 × 104 and 2.1 × 103 m−1, respectively, with the stoichiometry of 1:1. Hypochromism was observed from the absorption titration experiment which indicates the intercalation of Tb(III)‐(GA)2 complex between the base pairs of DNA. Gibberellic acid‐treated group showed alteration in the histological picture of livers and kidneys that accompanied with the reduction in the expression of Cyr61, cyt C, and TNFR2. The amelioration was observed in Gibberellic acid complex with Terbium group. The study concluded that Terbium gibberellic complex is less dangerous effects than Gibberellic acid alone.
Discovery of novel pyrrolopyrimidine/pyrazolopyrimidine derivatives bearing 1,2,3‐triazole moiety as c‐Met kinase inhibitors
Authors: Wang Linxiao , Liu Xiaobo , Duan Yongli , Li Xiaojing , Zhao Bingbing , Wang Caolin , Xiao Zhen , Zheng Pengwu , Tang Qidong , Zhu Wufu
Published: March 2018

Six series of pyrrolo[2,3‐d]pyrimidine and pyrazolo[3,4‐d]pyrimidine derivatives bearing 1,2,3‐triazole moiety were designed and synthesized, and some bio‐evaluation was also carried out. As a result, four points can be summarized: Firstly, some of compounds exhibited excellent cytotoxicity activity and selectivity with the IC50 values in single‐digit μm level. In particular, the most promising compound 16d showed equal activity to lead compound foretinib against A549, HepG2, and MCF‐7 cell lines, with the IC50 values of 4.79 ± 0.82, 2.03 ± 0.39, and 2.90 ± 0.43 μm, respectively. Secondly, the SARs and docking studies indicated that the in vitro antitumor activity of pyrrolo[2,3‐d]pyrimidine derivatives bearing 1,2,3‐triazole moiety was superior to the pyrazolo[3,4‐d]pyrimidine derivatives bearing 1,2,3‐triazole moiety. Thirdly, three selected compounds (16d, 18d, and 20d) were further evaluated for inhibitory activity against the c‐Met kinase, and the 16d could inhibit the c‐Met kinase selectively by experiments of enzyme‐based selectivity. What is more, 16d could induce apoptosis of HepG2 cells and inhibitor the cell cycle of HepG2 on G2/M phase by acridine orange staining and cell cycle experiments, respectively.
Parenting style impacts cognitive and behavioural outcomes of former preterm infants: A systematic review
Authors: Neel M. L. M. , Stark A. R. , Maitre N. L.
Published: March 2018

We sought to evaluate published evidence in aggregate regarding the impact of parenting style on the cognitive and behavioural outcomes of former preterm infants. We searched 5 databases using germane MeSH terms. Parenting style was defined as any descriptor of parenting using ≥2 dimensions on published parenting axes. We evaluated studies for quality of evidence and strength of recommendations using standardized tools and categorized summative recommendations by parenting axis and child outcome. Twenty‐seven articles met our inclusion criteria. Parental responsivity is the only parenting axis strongly associated with both improved child cognition and behaviour. Parental demandingness is associated only with improved child cognition, and parental warmth and rejection are associated only with child behaviour. Parental coercion is not associated with subsequent child outcomes. Parental responsivity may be essential in optimizing neurodevelopment in former preterm infants. More targeted studies are needed to inform this relationship and identify opportunities for intervention.
“Not such a kid thing anymore”: Young adults' perspectives on transfer from paediatric to adult cardiology care
Authors: Catena G. , Rempel G. R. , Kovacs A. H. , Rankin K. N. , Muhll I. V. , Mackie A. S.
Published: March 2018

Background

Transfer of adolescents with congenital heart disease from paediatric cardiology providers to specialized adult congenital heart disease (ACHD) care providers is becoming a standard practice. However, some paediatric cardiologists continue to provide care for their patients into adult life. Little is known about the perspectives of young adult patients who have been transferred to ACHD clinics versus those who continue to receive their cardiology care in paediatric settings.

Methods

Content and thematic analysis of structured telephone interviews with 21 young adults age 18–25 (13 transferred to ACHD clinic and 8 who had not transferred) was conducted to identify similarities and differences in patient characteristics of those in ACHD versus paediatric settings.

Results

There were no appreciable differences in gender, age, heart disease type, and independence between those transferred to ACHD care versus those not transferred. Participants in both groups were aware of differences between the paediatric and ACHD care settings and providers, with some favouring the familiarity offered by the paediatric setting and providers. Participants had varying views on parental involvement in their care; most of them had attended clinic appointments on their own. Those who had transferred to ACHD care acknowledged that it would take time to adjust to new relationships. Positive perspectives on actual or anticipated transfer to ACHD care included a growing sense of autonomy and responsibility, as well as access to reproductive information relevant to ACHD patients.

Conclusions

The absence of patient characteristics distinguishing those in ACHD care versus those still followed in paediatric care suggests that system, provider, and parent factors, rather than patient factors, may account for patients' perspectives on transfer to ACHD care.
Comparing Meta‐analysis and Individual Person Data Analysis Using Raw Data on Children's Understanding of Equivalence
Authors: Hornburg Caroline Byrd , Wang Lijuan , McNeil Nicole M.
Published: March 2018

A prevailing theory of mathematical problem solving predicts that children will be less accurate solving a + b = c + __ problems versus a + b = __ + c. However, this has never been tested directly. Because of low base rates, information combined from multiple studies can help improve estimation accuracy and precision. This study compared meta‐analysis and individual person data (IPD) analysis using raw data from 14 studies (N = 1,414; ns = 30–232; Mage reported = 8;7). Substantive results challenge the prevailing theory. Methodological results demonstrate the advantages of using meta‐analysis and IPD over single‐study analysis. Moreover, IPD can be more powerful than meta‐regression for detecting between‐study moderation effects.
Worse Health‐Related Quality of Life at long‐term follow‐up in patients with Cushing's disease than patients with cortisol producing adenoma. Data from the ERCUSYN
Authors: Valassi Elena , Feelders Richard , Maiter Dominique , Chanson Philippe , Yaneva Maria , Reincke Martin , Krsek Michal , Tóth Miklós , Webb Susan M. , Santos Alicia , Paiva Isabel , Komerdus Irina , Droste Michael , Tabarin Antoine , Strasburger Christian J , Franz Holger , Trainer Peter J , Newell‐Price John , Wass John AH , Papakokkinou Eleni , Ragnarsson Oskar ,   the ERCUSYN Study Group
Published: March 2018

Objective

Hypercortisolism in Cushing's syndrome (CS) is associated with impaired health‐related quality of life (HRQoL), which may persist despite remission. We used the data entered into the European Registry on Cushing's syndrome (ERCUSYN) to evaluate if patients with CS of pituitary origin (PIT‐CS) have worse HRQoL, both before and after treatment than patients with adrenal causes (ADR‐CS).

Methods

Data from 595 patients (492 women; 83%) who completed the CushingQoL and/or EQ‐5D questionnaires at baseline and/or following treatment were analysed.

Results

At baseline, HRQoL did not differ between PIT‐CS (n = 293) and ADR‐CS (n = 120) on both EuroQoL and CushingQoL. Total CushingQoL score in PIT‐CS and ADR‐CS was 41 ± 18 and 44 ± 20, respectively (P = .7). At long‐time follow‐up (>1 year after treatment) total CushingQoL score was however lower in PIT‐CS than ADR‐CS (56 ± 20 vs 62 ± 23; P = .045). In a regression analysis, after adjustment for baseline age, gender, remission status, duration of active CS, glucocorticoid dependency and follow‐up time, no association was observed between aetiology and HRQoL. Remission was associated with better total CushingQoL score (P < .001), and older age at diagnosis with worse total score (P = .01). Depression at diagnosis was associated with worse total CushingQoL score at the last follow‐up (P < .001).

Conclusion

PIT‐CS patients had poorer HRQoL than ADR‐CS at long‐term follow‐up, despite similar baseline scoring. After adjusting for remission status, no interaetiology differences in HRQoL scoring were found. Age and presence of depression at diagnosis of CS may be potential predictors of worse HRQoL regardless of CS aetiology.
Children and young people's understanding of inherited conditions and their attitudes towards genetic testing: A systematic review
Authors: McGill B.C. , Wakefield C.E. , Vetsch J. , Barlow‐Stewart K. , Kasparian N.A. , Patenaude A.F. , Young M.‐A. , Cohn R.J. , Tucker K.M.
Published: March 2018

Children and young people are increasingly likely to receive information regarding inherited health risks relevant to their genetic relatives and themselves. We reviewed the literature to determine what children and young people (21 years and younger) understand about inherited conditions and their attitudes towards genetic testing. We screened 1815 abstracts to identify 20 studies representing the perspectives of 1811 children and young people between the ages of 6 and 21 years (1498 children or young people at general population‐level risk from 9 studies, 313 affected/at risk from 15 studies). Children and young people at general population‐level risk demonstrated a basic understanding that disease predisposition can be inherited within families. Those affected by or at risk of genetic conditions inferred their genetic status from observable, relational characteristics within their family and the results of personal genetic testing if it had occurred, but some misunderstandings of important genetic concepts were evident. Children and young people expressed interest in and a willingness to undertake personal genetic testing, but also articulated concerns about the limitations and risks of testing. Paediatric patients require developmentally‐sensitive genetic counselling and support in navigating the unique landscape of their condition.
Wiedemann‐Steiner syndrome as a major cause of syndromic intellectual disability: A study of 33 French cases
Authors: Baer S. , Afenjar A. , Smol T. , Piton A. , Gérard B. , Alembik Y. , Bienvenu T. , Boursier G. , Boute O. , Colson C. , Cordier M.‐P. , Cormier‐Daire V. , Delobel B. , Doco‐Fenzy M. , Duban‐Bedu B. , Fradin M. , Geneviève D. , Goldenberg A. , Grelet M. , Haye D. , Heron D. , Isidor B. , Keren B. , Lacombe D. , Lèbre A.‐S. , Lesca G. , Masurel A. , Mathieu‐Dramard M. , Nava C. , Pasquier L. , Petit A. , Philip N. , Piard J. , Rondeau S. , Saugier‐Veber P. , Sukno S. , Thevenon J. , Van‐Gils J. , Vincent‐Delorme C. , Willems M. , Schaefer E. , Morin G.
Published: March 2018

Wiedemann‐Steiner syndrome (WSS) is a rare syndromic condition in which intellectual disability (ID) is associated with hypertrichosis cubiti, short stature, and characteristic facies. Following the identification of the causative gene (KMT2A) in 2012, only 31 cases of WSS have been described precisely in the literature. We report on 33 French individuals with a KMT2A mutation confirmed by targeted gene sequencing, high‐throughput sequencing or exome sequencing. Patients' molecular and clinical features were recorded and compared with the literature data. On the molecular level, we found 29 novel mutations. We observed autosomal dominant transmission of WSS in 3 families and mosaicism in one family. Clinically, we observed a broad phenotypic spectrum with regard to ID (mild to severe), the facies (typical or not of WSS) and associated malformations (bone, cerebral, renal, cardiac and ophthalmological anomalies). Hypertrichosis cubiti that was supposed to be pathognomonic in the literature was found only in 61% of our cases. This is the largest series of WSS cases yet described to date. A majority of patients exhibited suggestive features, but others were less characteristic, only identified by molecular diagnosis. The prevalence of WSS was higher than expected in patients with ID, suggesting than KMT2A is a major gene in ID.