bluuebunny/crossref_metadata_2025 huggingface dataset:
Altered neural signatures of interoception in multiple sclerosis
Authors: Salamone Paula C. , Esteves Sol , Sinay Vladimiro J. , García‐Cordero Indira , Abrevaya Sofía , Couto Blas , Adolfi Federico , Martorell Miguel , Petroni Agustín , Yoris Adrián , Torquati Kathya , Alifano Florencia , Legaz Agustina , Cassará Fátima P. , Bruno Diana , Kemp Andrew H. , Herrera Eduar , García Adolfo M. , Ibáñez Agustín , Sedeño Lucas
Published: August 2018

Multiple sclerosis (MS) patients present several alterations related to sensing of bodily signals. However, no specific neurocognitive impairment has yet been proposed as a core deficit underlying such symptoms. We aimed to determine whether MS patients present changes in interoception—that is, the monitoring of autonomic bodily information—a process that might be related to various bodily dysfunctions. We performed two studies in 34 relapsing–remitting, early‐stage MS patients and 46 controls matched for gender, age, and education. In Study 1, we evaluated the heartbeat‐evoked potential (HEP), a cortical signature of interoception, via a 128‐channel EEG system during a heartbeat detection task including an exteroceptive and an interoceptive condition. Then, we obtained whole‐brain MRI recordings. In Study 2, participants underwent fMRI recordings during two resting‐state conditions: mind wandering and interoception. In Study 1, controls exhibited greater HEP modulation during the interoceptive condition than the exteroceptive one, but no systematic differences between conditions emerged in MS patients. Patients presented atrophy in the left insula, the posterior part of the right insula, and the right anterior cingulate cortex, with abnormal associations between neurophysiological and neuroanatomical patterns. In Study 2, controls showed higher functional connectivity and degree for the interoceptive state compared with mind wandering; however, this pattern was absent in patients, who nonetheless presented greater connectivity and degree than controls during mind wandering. MS patients were characterized by atypical multimodal brain signatures of interoception. This finding opens a new agenda to examine the role of inner‐signal monitoring in the body symptomatology of MS.
Terlipressin Is Superior to Noradrenaline in the Management of Acute Kidney Injury in Acute on Chronic Liver Failure
Authors: Arora Vinod , Maiwall Rakhi , Rajan Vijayaraghavan , Jindal Ankur , Muralikrishna Shasthry Saggere , Kumar Guresh , Jain Priyanka , Sarin Shiv Kumar
Published: August 2018

Hepatorenal syndrome (HRS) carries a high short‐term mortality in patients with cirrhosis and acute on chronic liver failure (ACLF). Terlipressin and noradrenaline are routinely used in cirrhosis with HRS and have been found to be equally effective. There are no data comparing the efficacy of terlipressin with noradrenaline in ACLF patients with HRS. In an open‐label, randomized controlled trial (RCT), consecutive patients with ACLF diagnosed with HRS acute kidney injury (AKI) were randomized to albumin with infusion of terlipressin (2‐12 mg/day; n = 60) or noradrenaline (0.5‐3.0 mg/h; n = 60). Response to treatment, course of AKI, and outcome were studied. Baseline characteristics, including AKI stage and sepsis‐related HRS‐AKI, were comparable between groups. Compared to noradrenaline, terlipressin achieved greater day 4 (26.1% vs. 11.7%; P = 0.03) and day 7 (41.7% vs. 20%; P = 0.01) response. Reversal of HRS was also better with terlipressin (40% vs. 16.7%; P = 0.004), with a significant reduction in the requirement of renal replacement therapy (RRT; 56.6% vs. 80%; P = 0.006) and improved 28‐day survival (48.3% vs. 20%; P = 0.001). Adverse events limiting use of drugs were higher with terlipressin than noradrenaline (23.3% vs. 8.3%; P = 0.02), but were reversible. On multivariate analysis, high Model for End‐Stage Liver Disease (MELD; odds ratio [OR], 1.10; confidence interval [CI] = 1.009‐1.20; P = 0.03) and noradrenaline compared to terlipressin (OR, 3.05; CI = 1.27‐7.33; P = 0.01) predicted nonresponse to therapy. Use of noradrenaline compared to terlipressin was also predictive of higher mortality (hazard ratio [HR], 2.08; CI = 1.32‐3.30; P = 0.002). Conclusion: AKI in ACLF carries a high mortality. Infusion of terlipressin gives earlier and higher response than noradrenaline, with improved survival in ACLF patients with HRS‐AKI.
Siltuximab in relapsed/refractory multicentric Castleman disease: Experience of the Italian NPP program
Authors: Tonialini Lorenzo , Bonfichi Maurizio , Ferrero Simone , Malipiero Giacomo , Nozza Andrea , Argnani Lisa , Zinzani Pier Luigi
Published: August 2018

Because of the rarity of the disease, randomized clinical trials for multicentric Castleman disease (MCD) remain a challenge and, as a consequence, there is no established standard of care. Siltuximab is a chimeric immunoglobulin G1κ monoclonal antibody against human IL‐6 which was recently approved by FDA. Eligible patients in Italy were granted early access through a Named Patient Program (NPP). The aim of this observational multicenter retrospective study was to analyze outcomes and toxicity data of relapsed or refractory MCD patients treated with siltuximab in a real life context. All the 9 patients who received siltuximab in Italy under the NPP were enrolled. Median duration of treatment was 285 days (range, 104‐1113 days). The global overall response rate was 33.3%. At the time of this analysis, none of the 3 responder patients had subsequently disease relapse: response duration was 20, 23, and 37 months, respectively. Grade 1 to 2 fatigue and pruritus were observed in 2 (22.2%) patients, and weight gain was reported in only 1 patient (grade 1); local edema was reported in 2 patients with a grade 2 presentation. The most common side effect was upper respiratory tract infection reported in 3 (33.3%) patients but in these cases was grades 1 to 2. No patient developed an infusion‐related reaction. Our NPP data support siltuximab as single agent in the real‐life experience of the treatment of relapse/refractory MCD patients in effectiveness, safety profile, and sustained disease control.
Precision immunotherapy, mutational landscape, and emerging tools to optimize clinical outcomes in patients with classical myeloproliferative neoplasms
Authors: Mughal Tariq I. , Lion Thomas , Abdel‐Wahab Omar , Mesa Ruben , Scherber Robyn M. , Perrotti Danilo , Mauro Michael , Verstovsek Srdan , Saglio Giuseppe , Van Etten Richard A. , Kralovics Robert
Published: August 2018

Following the 47th American Society of Hematology Meeting in 2005, the late John Goldman and Tariq Mughal commenced a conference, the 1st Post‐ASH Workshop, which brought together clinicians and scientists, to accelerate the adoption of new therapies for patients with myeloproliferative neoplasms (MPNs). The concept began with recognition of the CML success story following imatinib therapy, the discovery of JAK2V617F, and the demonstration that BCR‐ABL1‐negative MPNs are driven by abnormal JAK2 activation. This review is based on the presentations and deliberations at the XIIth Post‐ASH Workshop on BCR‐ABL1 positive and negative MPNs that took place on December 12 to 13, 2017, in Atlanta, Georgia, immediately following the 59th American Society of Hematology Meeting. We have selected some of the translational research and clinical topics, rather than an account of the proceedings. We discuss the role of immunotherapy in MPNs and the impact of the mutational landscape on TKI treatment in CML. We also consider how we might reduce TKI cardiovascular side effects, the potential role of nutrition as adjunctive nonpharmacologic intervention to reduce chronic inflammation in MPNs, and novel investigational therapies for MPNs.
Change from health center to family physician period in the Turkish health system: A qualitative study
Authors: Cevik Celalettin , Kilic Bulent
Published: August 2018

Introduction

Health care reforms in Turkey have been implemented resolutely in the last 12 years. The shift from health center (HC) to a family physician (FP) approach is 1 of the basic interventions of these reforms. The goal of the current study is to evaluate opinions of patients, health care workers, and managers, using qualitative methods.

Methods

In‐depth interviews were conducted with patients who received health care services in both the FP and the HC periods, and with health care workers and managers in health care facilities that served in both periods. The interviews were recorded after obtaining permission, and then transcribed. Both health care staff that worked in the 2 periods and the patients that received health care services in the 2 periods reported that FP system was superior to HC system in attention showed by the family physicians, being followed by the same physician, and having confidence in physicians.

Results

The current FP period is superior to HC in facilities such as patient records, computer, internet, and phone. The strengths of HC period include home visits, environmental health studies, and family planning services. According to health care workers who worked in the 2 periods, HC was superior to FP in team spirit, public service delivery, and surveillance of communicable diseases.

Conclusion

Public service delivery and environmental health studies and primary care practice in rural areas must be scrutinized in the context of the FP approach.
Choosing cooperation over competition; hospital strategies in response to selective contracting
Authors: van Ineveld Martin , van Wijngaarden Jeroen , Scholten Gerard
Published: August 2018

With the introduction of market competition in health care, the Dutch government enabled health insurers to contract hospital care selectively. The assumption is that “selective contracting” will stimulate efficiency, effectiveness, and innovation and will diminish overcapacity. In 2010, the first Dutch health insurers started experimenting with “selective contracting” by setting a minimum treatment volume per year for complex treatments. In an explorative, multiple case study among 15 hospitals in five regions, we found that instead of competing, hospitals started to cooperate and strengthen their networks. The government intended to remove redundant hospital capacity and improve quality by stimulating specialization and concentration. Our study showed that specialization was indeed stimulated, which may have increased quality of care. However, facilitated by the absence of a countervailing power (government or insurer), hospitals in our cases negotiated to the effect of preserving hospital capacity. Within the current political debate between supporters of competition and advocates of a national health service, the importance and role of the (medical) networks should be taken into account. Otherwise, the outcomes of health care governance will be different than intended by either party.
Operation of two major reservoirs of Iran under IPCC scenarios during the XXI century
Authors: Akbari‐Alashti Habib , Soncini Andrea , Dinpashoh Yagob , Fakheri‐Fard Ahmad , Talatahari Siamak , Bocchiola Daniele
Published: August 2018

We assess the effects of prospective climate change until 2100 on water management of two major reservoirs of Iran, namely, Dez (3.34 × 109 m3) and Alavian (6 × 107 m3). We tune the Poly‐Hydro model suited for simulation of hydrological cycle in high altitude snow‐fed catchments. We assess optimal operation rules (ORs) for the reservoirs using three algorithms under dynamic and static operation and linear and non‐linear decision rules during control run (1990–2010 for Dez and 2000–2010 for Alavian). We use projected climate scenarios (plus statistical downscaling) from three general circulation models, EC‐Earth, CCSM4, and ECHAM6, and three emission scenarios, or representative concentration pathways (RCPs), RCP2.6, RCP4.5, and RCP8.5, for a grand total of nine scenarios, to mimic evolution of the hydrological cycle under future climate until 2100. We subsequently test the ORs under the future hydrological scenarios (at half century and end of century) and the need for reoptimization. Poly‐Hydro model when benchmarked against historical data well mimics the hydrological budget of both catchments, including the main processes of evapotranspiration and streamflows. Teaching–learning‐based optimization delivers the best performance in both reservoirs according to objective scores and is used for future operation. Our projections in Dez catchment depict decreased precipitation along the XXI century, with −1% on average (of the nine scenarios) at half century and −6% at the end of century, with changes in streamflows on average −7% yearly and −13% yearly, respectively. In Alavian, precipitation would decrease by −10% on average at half century and −13% at the end of century, with streamflows −14% yearly and −18% yearly, respectively. Under the projected future hydrology, reservoirs' operation would provide lower performance (i.e., larger lack of water) than now, especially for Alavian dam. Our results provide evidence of potentially decreasing water availability and less effective water management in water stressed areas like Northern Iran here during this century.
Changes in river networks and their storage and regulation capacities in the Rapidly Urbanized Taihu Basin, China
Authors: Xu Yu , Xu Youpeng , Wu Lei
Published: August 2018

Owing to the crucial environmental and hydrological functions of river systems and intensive human disturbance, further investigations of their change patterns and flood control functions are urgently needed. The Rapidly Urbanized Taihu Basin (RUTB) was selected as the study region to investigate changes in the river networks, the relationship between changes in river systems and urbanization, and the changes in the static drainage storage capacity (SC) and regulation capacity (RC) from the 1980s to the 2010s. The results indicated that the total drainage density in RUTB decreased by 10.17%. For the first‐, second‐, and third‐order rivers, the changes are +7.61%, −14.35%, and −17.84%, respectively. Spatially, the change pattern of the third‐order river drainage density displayed significant spatial clustering. The ratio of main to tributary river length (Rmt) was increased from 0.31 in the 1980s to 0.39 in the 2010s. Spatially, the drastic increases were found in the south‐east of Wu–Cheng–Xi–Yu, the east of Yang–Cheng–Dian–Mao, and the central southern part of Hang–Jia–Hu. Results moreover show that urbanization has the greatest influence on the third‐order drainage density, especially around the secondary and rapidly developing cities. The demand for flood control has led to a slight increase in the density of main rivers. The values of SC and RC decreased by 0.69% and 40.61% in RUTB, respectively. These changes were mainly concentrated around the major cities and urban corridors. The decrease in SC was caused by the decay of the river system, and the reduction in RC was caused by a combination of river system degradation and increase in ordinary water levels.
Clinical significance of circulating tumor cells in predicting disease progression and chemotherapy resistance in patients with gestational choriocarcinoma
Authors: He Weiling , Hou Minzhi , Zhang Hui , Zeng Chao , He Shanyang , Chen Xinlin , Xu Manman , Sun Cong , Jiang Wenting , Wang Han , Shen Hongwei , Zhang Yang , Liu Jing , Sun Shijun , Jiang Neng , Cui Yongmei , Sun Yu , Chen Yangshan , Cao Jessica , Wang Chunlin , Li Mengzhen , Zhang Yi , Wang Liantang , Wang Jianhong , Lin Millicent , Ke Zunfu
Published: August 2018

Gestational choriocarcinoma (GC) is a highly aggressive tumor. In our study, we systematically investigated EpCAM/CD147 expression characteristics in patients with GC and assessed the role of circulating tumor cells (CTCs) in predicting chemotherapy response and disease progression. GC tissues were positive for either epithelial cellular adhesion molecule (EpCAM) or CD147, and all samples exhibited strong human chorionic gonadotropin (HCG) expression. Among all the recruited patients (n = 115), 103 had at least 1 CTC in a 7.5‐mL peripheral blood sample, and the percentage of patients with ≥4 CTCs in a particular FIGO stage group increased with a higher FIGO stage (p < 0.001). Furthermore, the pretreatment CTC count was related to tumor size (r = 0.225, p = 0.015) and the number of metastases (r = 0.603, p < 0.001). A progression analysis showed that among the 115 included patients who qualified for further examination, 52 of the 64 patients defined as progressive had ≥4 pretreatment CTCs, while only 7 of the 51 non‐progressive patients had ≥4 pretreatment CTCs (p < 0.001). In multivariate analysis, CTCs (≥4) remained the strongest predictor of PFS when other prognostic markers, FIGO score and FIGO stage were included. Moreover, based on the chemotherapy response, patients with ≥4 CTCs were more likely to be resistant to chemotherapy than those with <4 CTCs (P < 0.001). These findings demonstrates the feasibility of CTC detection in cases of GC by adopting EpCAM/CD147 antibodies together as capturing antibodies. The CTC count is a promising indicator in the evaluation of biological activities and the chemotherapy response in GC patients.
Advanced Functional Materials Constructed from Pillar[n]arenes
Authors: Xiao Tangxin , Xu Lixiang , Zhong Weiwei , Zhou Ling , Sun Xiao‐Qiang , Hu Xiao‐Yu , Wang Leyong
Published: August 2018

Pillar[n]arenes are new generation of supramolecular macrocyclic host, which exhibit excellent host−guest recognition properties. In the last decade, functional materials constructed from pillar[n]arenes have been attracted more and more attention and displayed outstanding characteristics, such as stimuli‐responsiveness, self‐healing and adaptability. In this mini‐review, we provide a survey of the pillar[n]arene‐based literatures covering light‐harvesting systems, functional hydrogels, and solid materials. It is anticipated that more and more pillar[n]arenes‐based advanced materials with multi‐functional properties will appear in the near future.
Nonperforming loans in the euro area: Are core–periphery banking markets fragmented?
Authors: Anastasiou Dimitrios , Louri Helen , Tsionas Mike
Published: August 2018

The objectives of this study are, first, to examine the causes of nonperforming loans (NPLs) in the euro area for the period 2003Q1 to 2016Q1 and, second, to investigate if there is fragmentation between core and periphery banking markets. By employing both fully modified ordinary least squares (FMOLS) and Bayesian panel‐cointegration vector autoregression techniques, we estimate the long‐run effects of both bank‐specific and macroeconomic factors on NPLs. We find that NPLs in the euro area have performed an upward (much higher in the periphery) shift after 2008 and are mostly related to worsening macroeconomic conditions. A chi‐square test comparing the estimated coefficients for the core and periphery NPLs rejects the hypothesis of equality revealing another aspect of financial fragmentation in the euro area that leaves the periphery more vulnerable. Such findings can be helpful when designing macroprudential as well as NPL resolution policies.
PREGNANT WOMEN'S RECOLLECTIONS OF EARLY MATERNAL BONDING: ASSOCIATIONS WITH MATERNAL–FETAL ATTACHMENT AND BIRTH CHOICES
Authors: Handelzalts Jonathan E. , Preis Heidi , Rosenbaum Maya , Gozlan Miri , Benyamini Yael
Published: August 2018

Recollections of own maternal care measured by parental bonding were found to be important in the pregnant woman's construction of herself as a mother. Although these recollections were studied with regard to various variables, there is a dearth of studies associated with pregnancy and childbirth. In this cross‐sectional study, 341 pregnant women were recruited. Measures included a Sociodemographics–Obstetric History Questionnaire; the Childbirth Choices Questionnaire (H. Preis, M. Gozlan, U. Dan, & Y. Benyamini, 2018); the Parental Bonding Instrument (G. Parker, H. Tupling, & L.B. Brown, 1979); a question regarding the planned presence of the woman's mother at delivery; and the Maternal‐Fetal Attachment Scale (M.S. Cranley, 1981). Parental recollections of Care were associated with fewer natural birth choices (hence, a more “medicalized” delivery), lower maternal–fetal attachment, and a wish for the mother's mother to be present at the birth. Parental recollections of Encouragement of Behavioral Freedom in childhood were associated with more natural choices regarding childbirth. In addition, women with higher scores on the parental bonding Denial of Autonomy factor reported stronger maternal–fetal attachment. Thus, early recollections of experiences with caregivers as manifested in parental bonding may be a possible influence on the transition to motherhood, and working through possible difficulties associated with these recollections may improve adjustment to motherhood.
Governance lessons from an interorganizational health information system implementation in Ethiopia
Authors: Gebre‐Mariam Mikael
Published: August 2018

The paper investigates interorganizational health information system implementation in a developing country health sector and the influence of the sociopolitical context that constitutes the institutions of the global health system. It argues that a comprehensive understanding of interorganizational system (IOS) implementation should include the study of the institutional context and its stakeholders who exhibit complex social and political attributes that influences its implementation and trajectory. This paper charts this course by examining the key governance dimensions of coordination and alignment. Building on this, the study challenges the viability of the unstructured institutional arrangements and the ensuing development modalities for health information system implementation, which are largely facilitated by international nongovernmental organizations and leverage on information and communication technology. The paper concludes by discussing the implications of the study. These include (1) the influence of unstructured interorganizational relations, at both the organizational and sector levels, on IOS adoption, (2) how the social and political behaviors of opportunistic interorganizational participants are implicated in the IOS adoption process, and (3) the role of strategic alignment, largely driven by the informal interorganizational relationship and social dimensions, on the prioritization and fit between IOS technological and organizational components.
In vitro cytotoxicity evaluation of cadmium by label‐free holographic microscopy
Authors: Mugnano Martina , Memmolo Pasquale , Miccio Lisa , Grilli Simonetta , Merola Francesco , Calabuig Alejandro , Bramanti Alessia , Mazzon Emanuela , Ferraro Pietro
Published: August 2018

Among all environmental pollutants, the toxic heavy metal cadmium is considered as a human carcinogen. Cadmium may induce cell death by apoptosis in various cell types, although the underlying mechanisms are still unclear. In this paper we show how a label‐free digital holography (DH)‐based technique is able to quantify the evolution of key biophysical parameters of cells during the exposure to cadmium for the first time. Murine embryonic fibroblasts NIH 3T3 are chosen here as cellular model for studying the cadmium effects. The results demonstrate that DH is able to retrieve the temporal evolution of different key parameters such as cell volume, projected area, cell thickness and dry mass, thus providing a full quantitative characterization of the cell physical behaviour during cadmium exposure. Our results show that the label‐free character of the technique would allow biologists to perform systematic and reliable studies on cell death process induced by cadmium and we believe that more in general this can be easily extended to others heavy metals, thus avoiding the time‐consuming, expensive and invasive label‐based procedures used nowadays in the field. In fact, pollution by heavy metals is severe issue that needs rapid and reliable methods to be settled.
Improved oxidation and wear resistance of ultrahigh molecular weight polyethylene using cross‐linked powder reinforcement
Authors: Xu Jia‐Zhuang , Muratoglu Orhun K. , Oral Ebru
Published: August 2018

Radiation crosslinking decreases the wear of ultrahigh molecular weight polyethylene (UHMWPE) used in total joint implants and creates residual free radicals, which are the precursors of oxidative degradation. It is desirable to obtain a simultaneously wear‐ and oxidation‐resistant UHMWPE in order to prolong the longevity of implants. In this study, we hypothesized that the oxidative stability of a vitamin E‐containing, wear resistant UHMWPE can be improved by limiting the exposure of the antioxidant to radiation to maximize its activity. We blended UHMWPE powder with 0.1 wt % vitamin‐E and irradiated these powder blends (XPE). We further blended and consolidated uncrosslinked 0.1 wt % vitamin E‐blended UHMWPE with XPE and assessed the effects of radiation dose used for XPE and XPE content in the formulation on pin‐on‐disk wear resistance, static mechanical properties, and squalene‐initiated accelerated thermal aging. The wear rate decreased significantly with increasing XPE content in UHMWPE/XPE and increasing radiation dose used in the XPE preparation. The UHMWPE/XPE blends displayed improved oxidation resistance in the presence of the pro‐oxidant squalene compared to vitamin E‐blended UHMWPE irradiated to 125 kGy after consolidation. Strength and toughness of the UHMWPE/XPE blends decreased with increasing radiation dose and increasing XPE content; and these were comparable to those measured with the consolidated and irradiated vitamin E‐blended UHMWPE. Blending UHMWPE with XPE is a feasible approach to create a wear resistant UHMWPE with more active vitamin E available for long‐term oxidative protection of the polymer as the radiation exposure of the vitamin‐E in the vitamin E‐blended UHMWPE matrix is minimized. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 716–723, 2019.
MiR‐125a‐5p functions as a tumour suppressor in breast cancer by downregulating BAP1
Authors: Yan Liang , Yu Meng‐Chao , Gao Guang‐Lei , Liang Hong‐Wei , Zhou Xin‐Yan , Zhu Zhou‐Ting , Zhang Chen‐Yu , Wang Ya‐Bing , Chen Xi
Published: August 2018

MicroRNAs (miRNAs) play an important role in the regulation of human cancers, including breast cancer (BC). In the current study, we examined the expression pattern of the miRNA miR‐125a‐5p in human BC tissues, tumorigenesis of BC progression. We found that miR‐125a‐5p was significantly downregulated in human BC tissues. Overexpression of miR‐125a‐5p in a xenograft mouse model indicated that miR‐125a‐5p may function as a tumour suppressor during carcinogenesis. To explore the molecular mechanism by which miR‐125a‐5p contributes to BC progression, we predicted the target genes of miR‐125a‐5p and identified BC susceptibility gene 1–associated protein 1 (BAP1) as a direct target. Finally, we demonstrated that BAP1 had opposing effects to those of miR‐125a‐5p on BC cells, suggesting that miR‐125a‐5p may inhibit cell proliferation and promote cell apoptosis by negatively regulating BAP1. Taken together, our findings provide the first clues regarding the role of miR‐125a‐5p as a tumour suppressor in BC via the inhibition of BAP1 translation.
Analgesic and sedative agents used in the intensive care unit: A review
Authors: Panahi Yunes , Dehcheshmeh Hamid Sadeghi , Mojtahedzadeh Mojtaba , Joneidi‐Jafari Nosratollah , Johnston Thomas P. , Sahebkar Amirhossein
Published: August 2018

Pain is a common experience for most patients in the intensive care unit (ICU). In the current study, the advantages and disadvantages of analgesic and sedative drugs used in the ICU are reviewed. An ideal sedative and analgesic agent should have features such as rapid onset of action, rapid recovery after discontinuation, predictability, minimal accumulation of the agent and metabolites in the body, and lack of toxicity. None of the sedative and analgesic agents have all of these desired characteristics; nevertheless, clinicians must be familiar with these classes of drugs to optimize pharmacotherapy and ensure as few side‐effects as possible for ICU patients.
SPDEF is overexpressed in gastric cancer and triggers cell proliferation by forming a positive regulation loop with FoxM1
Authors: Wu Jing , Qin Wen , Wang Ying , Sadik Arsil , Liu Jilan , Wang Yangyang , Song Ping , Wang Xiaoyun , Sun Kaiyue , Zeng Jiping , Wang Lixiang
Published: August 2018

The SAM‐pointed domain‐containing ETS transcription factor (SPDEF) is an epithelial‐specific transcription factor of the E26 transformation‐specific (ETS) family, which binds the target gene through the high‐affinity sequence of GGAT. It is suggested that SPDEF targets the promoter activity of Forkhead Box M1 (FoxM1), which has been proven to be highly expressed in gastric cancer. We found that SPDEF was overexpressed both at the messenger RNA (mRNA) and at the protein level in human gastric cancer species. The gastric cancer cells transfected with the SPDEF expression plasmid or SPDEF small interfering RNA (siRNA) led to observations on the clone genetics assay that indicated the promotion or the inhibition of gastric cancer cell proliferation, respectively. Both mRNA and protein levels of FoxM1 were regulated by SPDEF in gastric cancer cells and FoxM1 was also overexpressed in the corresponding human gastric cancer species. The overexpression and inhibition of FoxM1 could upregulate and downregulate the mRNA and protein levels of SPDEF expression, respectively. The recovery experiments verified that the overexpression of FoxM1 could at least partially revert both the expression of SPDEF and the proliferation of the cell lines even with the siRNA inhibition of SPDEF. The result of the dual luciferase activity assay showed that SPDEF bound to the promoter of FoxM1 and activated it. FoxM1 might also bind to the promoter of SPDEF to affect its expression. The results were checked in vivo. In conclusion, SPDEF is overexpressed in gastric cancer, which can form a positive regulation loop with FoxM1 to promote gastric carcinogenesis.
DNA hydroxymethylation mediated traumatic spinal injury by influencing cell death–related gene expression
Authors: Sun Hao , Miao Zhigang , Wang Hua , Tao Yuping , Yang Jiandong , Cai Jun , Wang Jingcheng , Wang Yongxiang
Published: August 2018

Spinal cord injury (SCI) is a serious neurological disease, often leading to segmental injury following severe limb dysfunction. Recent studies showed that epigenetic regulation is involved in the pathogenesis of SCI. In this study, we examined the change in 5‐hydroxymethylcytosine (5hmC), a mechanism of demethylation, and its role in SCI in rats. We found that global 5hmC modification significantly increased in traumatic spinal cord tissues. Ten‐eleven translocation (Tet) enzymes are the limiting‐rate enzyme to catalyze the conversion of 5‐methylcytosine to 5hmC. In our study, the data indicated that Tet2, but not Tet1 and Tet3, significantly increased in traumatic spinal cord tissues. Further, we treated rats with SC‐1, a Tet2 expression inhibitor. SC‐1 increased necrotic volume after SCI. To further demonstrate that the damage caused by SC‐1 was related to DNA 5hmC, we examined the messenger RNA (mRNA) expression of many genes that related to cell death and cell survival. Our data showed that the 5hmC levels were related to the mRNA levels of these genes. In conclusion, targeting Tet2 to cause change in 5hmC levels in cell death–related genes may be new therapeutic strategy for the treatment of SCI.
Stem cell‐ and gene‐based therapies as potential candidates in Alzheimer's therapy
Authors: Hosseini Seyede Atefe , Mohammadi Rezvan , Noruzi Somaye , Mohamadi Yousef , Azizian Mitra , Mousavy Seyed Mojta , Ghasemi Faezeh , Hesari AmirReza , Sahebkar Amirhossein , Salarinia Reza , Aghdam Arad Mobasher , Mirzaei Hamed
Published: August 2018

Alzheimer's disease (AD) is a progressive neurodegenerative disorder, which is associated with impairments of memory, thinking, language, and reasoning. Despite extensive research aiming at the treatment of AD, durable and complete remissions are rare. Hence, new therapeutic approaches are required. Among various therapeutic approaches, stem cells (ie, neural stem cells, mesenchymal stem cells, and embryonic stem cells) and delivery of protective genes such as encoding nerve growth factor, APOE, and glial cell–derived neurotrophic factor have generated promise in AD therapy. Here, we summarized a variety of effective therapeutic approaches (ie, stem cells, and genes) in AD therapy.
Novel THRB mutation analysis in congenital hypothyroidism with thyroid dysgenesis
Authors: Zhou Zhixia , Yang Chengyu , Lv Fuyan , Liu Wenmiao , Yan Shengli , Zang Hongwei , Li Miaomiao , Wang Fang , Zang Yucui , Liu Shiguo
Published: August 2018

Thyroid dysgenesis (TD) accounts for most cases of congenital hypothyroidism. Although mutations in thyroid hormone receptor β (THRB) have been identified in TD, the mutational spectrum of THRB and phenotype‐genotype correlations have not been fully elucidated. In this study, we aimed to find mutations of THRB, examine the functions of these mutations, and attempt to elucidate the relationship between THRB and TD. Thus, we screened the exons of THRB in 280 patients with TD and 200 normal subjects in samples collected from China. We performed cell morphology assays, MTT assays, flow cytometric analyses, and a quantitative reverse‐transcription polymerase chain reaction in human thyroid follicular epithelial cells (Nthy‐ori cell line) to examine the impact of THRB mutations. In two unrelated patients, two novel missense mutations, c.76G>A (p.D26N) and c.107G>A (p.C36Y), were identified in THRB. Functional studies suggested that the C36Y mutant caused changes in morphology, inhibiting cell proliferation and promoting apoptosis in a human thyroid cell line. In addition, we found that messenger RNA expressions of thyroglobulin (TG) and the Na+/I− symporter (NIS) were decreased in a time‐dependent manner in mutant THRB compared with the wild type. To our knowledge, this is the first study to document the prevalence of THRB mutations and the genotype‐phenotype spectrum of TD in a Chinese population. We characterized the function of a C36Y mutation, which reduced cell proliferation and increased cell death in thyroid epithelial cells. This study provides further evidence for genetic THRB defects and disease mechanisms in TD.
Green synthesis of novel pyrazolo‐fused benzophenazines using H3PW12O40 as efficient and recyclable catalyst under microwave irradiation
Authors: Mohebat Razieh , Dehgan Parisa , Yazdani‐Elah‐Abadi Afshin
Published: August 2018

A high‐yield, atom‐efficient, and green protocol for the synthesis of novel pyrazolo‐fused benzophenazines utilizing a multicomponent condensation reaction between 2‐hydroxynaphthalene‐1,4‐dione, o‐phenylenediamine, aromatic aldehydes, and 4‐methylbenzenesulfonohydrazide in the presence of phosphotungstic acid (H3PW12O40) under microwave irradiation (MWI) in EtOH is reported. We provide a novel series of 1H‐benzo[a]pyrazolo[3,4‐c]phenazine derivatives interesting for biological screening tests. This protocol offers several advantages satisfying many principles of green chemistry, including atom economy, energy saving, clean reactions, inexpensive reagents, reusability of H3PW12O40, the absence of any tedious work‐up or purification, and avoidance of hazardous or toxic reagents/catalysts/solvents.
STAC3 incorporation into skeletal muscle triads occurs independent of the dihydropyridine receptor
Authors: Campiglio Marta , Kaplan Mehmet M. , Flucher Bernhard E.
Published: August 2018

Excitation‐contraction (EC) coupling in skeletal muscles operates through a physical interaction between the dihydropyridine receptor (DHPR), acting as a voltage sensor, and the ryanodine receptor (RyR1), acting as a calcium release channel. Recently, the adaptor protein SH3 and cysteine‐rich containing protein 3 (STAC3) has been identified as a myopathy disease gene and as an additional essential EC coupling component. STAC3 interacts with DHPR sequences including the critical EC coupling domain and has been proposed to function in linking the DHPR and RyR1. However, we and others demonstrated that incorporation of recombinant STAC3 into skeletal muscle triads critically depends only on the DHPR but not the RyR1. On the contrary, here, we provide evidence that endogenous STAC3 incorporates into triads in the absence of the DHPR in myotubes and muscle fibers of dysgenic mice. This finding demonstrates that STAC3 interacts with additional triad proteins and is consistent with its proposed role in directly or indirectly linking the DHPR with the RyR1.
Andrographolide protects chondrocytes from oxidative stress injury by activation of the Keap1–Nrf2–Are signaling pathway
Authors: Li Bo , Jiang Tongmeng , Liu Hui , Miao Zhikang , Fang Depeng , Zheng Li , Zhao Jinmin
Published: August 2018

Recent studies have shown that andrographolide (AP) has the potential to be developed as a drug for therapy for osteoarthritis (OA). However, the role of AP in attenuating the progression of OA is still unknown. We hypothesized that its therapeutic effect may be associated with its antioxidant potential. In this study, we investigated the therapeutic effect of AP on chondrocytes injured by H2O2 and the association with the oxidation‐related signaling pathways through the detection of cell proliferation, cell viability, the expression of oxidative stress‐specific genes (Sod1, Cat, and malonaldehyde [Mda]) and proteins (superoxide dismutase [SOD], catalase [CAT]) after a culture period of 3 and 5 days, respectively. Further exploration of the expression of nuclear factor erythroid 2‐related factor 2 (Nrf2) messenger RNA and protein was also performed. The results showed that 0.625 µg/ml and 2.5 µg/ml of AP decreased oxidative stress injury of chondrocytes by increasing cell proliferation reduced by H2O2 and antioxidant enzyme activity, including SOD and CAT. Inflammation factors, such as matrix metallopeptidase 13 (Mmp13), tissue inhibitor of metalloproteinase 1 (Timp1), and interleukin‐6 (Il6), were downregulated in the H2O2 group with AP, demonstrating a decrease in the progression of OA. Pathway analyses identified that the kelch‐like ECH‐associated protein 1 (Keap1)–Nrf2–antioxidant response element (Are) pathway is an important mediator in AP therapy on H2O2‐induced OA. This study indicates that AP exerts protection effects on oxidative stress via activation of the Keap1–Nrf2–Are pathway in chondrocytes injured by H2O2, which may be promising for the therapy of OA.
High glucose stimulates proliferative capacity of liver cancer cells possibly via O‐GlcNAcylation‐dependent transcriptional regulation of GJC1
Authors: Chen Yan , Liu Rui , Chu Zhexuan , Le Bu , Zeng Hong , Zhang Xiao , Wu Qi , Zhu Guoqing , Chen Yuxin , Liu Ya , Sun Fenyong , Lu Zhicheng , Qiao Yongxia , Wang Jiayi
Published: August 2018

Although it is generally accepted that diabetes is one of the most important risk factors for liver cancer, the underlying mechanism is still not well understood. The purpose of the current study is to further investigate how high concentrations of glucose (HG), a major symptom of diabetes, stimulate the development of liver malignancy. Using data mining, gap junction protein gamma 1 (GJC1) was identified as a critical proto‐oncoprotein that is essential for the HG stimulation of proliferative capacity in liver cancer cells. Furthermore, enhanced transcriptional expression of GJC1 might occur after stimulation by HG. A transcription factor zinc finger protein 410 (APA1)–binding motif was found to be located at the –82 to −77 nt region within the GJC1 promoter. Without APA1, HG was unable to increase GJC1 expression. Interestingly, APA1, but not GJC1, can be O‐GlcNAcylated in liver cancer cells. Moreover, O‐GlcNAcylation is essential for HG‐induced APA1 binding to the GJC1 promoter. Notably, global O‐GlcNAcylation and expression of APA1 and GJC1 were highly elevated in liver cancer patients with diabetes compared to those in patients without diabetes. The HG‐stimulated proliferative capacity was abolished upon decreasing O‐GlcNAcylation, which could be reversed gradually by the simultaneous overexpression of APA1 and GJC1. Therefore, GJC1 could be a potential target for preventing liver cancer in patients with diabetes.
Histone methyltransferase SETD2 is required for meiotic maturation in mouse oocyte
Authors: Li Chunling , Diao Feiyang , Qiu Danhong , Jiang Manxi , Li Xiaoyan , Han Longsen , Li Ling , Hou Xiaojing , Ge Juan , Ou Xianghong , Liu Jiayin , Wang Qiang
Published: August 2018

SET‐domain‐containing 2 (SETD2), a member of the histone lysine methyltransferase family, has been reported to be involved in multiple biological processes. However, the function of SETD2 during oocyte maturation has not been addressed. In this study, we find that mouse oocytes are incapable of progressing through meiosis completely once SETD2 is specifically depleted. These oocytes present an abnormal spindle morphology and deficient chromosome movement, with disrupted kinetochore–microtubule attachments, consequently producing aneuploidy eggs. In line with this, the BubR1 signal is markedly elevated in metaphase kinetochores of oocytes with SETD2 depletion, indicative of the activation of spindle assembly checkpoint. In addition, we note that loss of SETD2 results in a drastic decrease in the trimethylation level of H3K36 in oocytes. Collectively, our data demonstrate that SETD2 is required for oocyte maturation and indicate a novel mechanism controlling the meiotic apparatus.
Oxidative stress and neuroinflammation in the story of Parkinson’s disease: Could targeting these pathways write a good ending?
Authors: Hassanzadeh Kambiz , Rahimmi Arman
Published: August 2018

Although, current medications for Parkinson’s disease can control and relief symptoms of the disease efficiently, they are unable to either prevent progression of the disease or maintain their controlling ability as a long‐term medication. To find suitable adjuvant and/or alternative treatments, researchers have investigated antioxidative and anti‐inflammatory approaches, since emerging evidence consider oxidative stress and neuroinflammation as leading causes of the development of Parkinson’s disease. Here, how oxidative stress and neuroinflammation take part in Parkinson’s disease pathogenesis was discussed based on featured studies in this context. Then, preclinical and clinical trial studies, which evaluated antioxidative and anti‐inflammatory compounds’ ability to treat Parkinson’s disease, were reviewed.
TULA‐family proteins: Jacks of many trades and then some
Authors: Tsygankov Alexander Y.
Published: August 2018

UBASH3/STS/TULA is a novel two‐member family, which exerts several key regulatory effects in multiple cell types. UBASH3B/STS‐1/TULA‐2 is a highly active protein tyrosine phosphatase; its major target appears to be a specific regulatory site of protein tyrosine kinases of the Syk family, dephosphorylation of which inhibits Syk and Zap‐70 kinases and suppresses receptor signaling mediated by these kinases. UBASH3A/STS‐2/TULA exhibits substantial homology to UBASH3B/STS‐1/TULA‐2, but possesses only a small fraction of phosphatase activity of UBASH3B/STS‐1/TULA‐2, and thus, its regulatory effect may be based also on the phosphatase‐independent mechanisms. Critical physiologic effects of these proteins have been demonstrated in T lymphocytes, platelets, stem cells, and other important cell types. These proteins have also been shown to play a key role in such pathologic conditions as autoimmunity, cancer, and thrombosis. The review focuses on the recent studies of this important family of cellular regulators.
Restoration of miR‐152 expression suppresses cell proliferation, survival, and migration through inhibition of AKT–ERK pathway in colorectal cancer
Authors: Ghazanchaei Ardavan , Mansoori Behzad , Mohammadi Ali , Biglari Alireza , Baradaran Behzad
Published: August 2018

Background

MiR‐152 has been reported as a tumor suppressor microRNA that is downregulated in a number of cancers, including colorectal cancer (CRC). A recent study suggested that miR‐152 could be one of the key regulators of CRC. The aim of this study is to investigate the role of miR‐152 in CRC and its mechanisms.

Methods

The pCMV‐GPF‐miR‐152 vector was transfected into SW‐480 and HCT‐116 CRC cells via JetPEI transfection reagent. The stable miR‐152‐expressed cells were selected for the further experiment. To evaluate the effect of miR‐152 on cell proliferation, 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay was performed. Also, the effect of miR‐152 on the survival of CRC cells was analyzed using terminal deoxynucleotidyl transferase dUTP nick‐end labeling (TUNEL) assay. The inhibitory effect of miR‐152 on migration was assessed by wound healing scratch assay. Then, the proteins expression levels of protein kinase B (AKT), phosphorylated AKT (p‐AKT), extracellular signal–regulated kinase (ERK), and phosphorylated ERK (p‐ERK) were measured by the western blot analysis method.

Results

The result of MTT assay represented miR‐152 could inhibit cell proliferation. The TUNEL assay showed miR‐152 could induce apoptosis in CRC cells. The wound healing scratch assay showed that miR‐152 replacement repressed cell migration in CRC cell lines compared to control groups. The result of protein expression by western blot analysis demonstrated that miR‐152 could reduce AKT–p‐AKT, and ERK–p‐ERK ratio compared to control cells.

Conclusion

Our results show that miR‐152 has new anticancer and antimetastatic effect in CRC tissue. The current study showed that miR‐152 could be a novel therapeutic small molecule to suppress CRC cell proliferation, survival, and migration by suppressing AKT–ERK signaling pathways.
Epigallocatechin gallate in combination with eugenol or amarogentin shows synergistic chemotherapeutic potential in cervical cancer cell line
Authors: Pal Debolina , Sur Subhayan , Roy Rituparna , Mandal Suvra , Kumar Panda Chinmay
Published: August 2018

In this study, antitumor activity of epigallocatechin gallate (EGCG; major component of green tea polyphenol), eugenol (active component of clove), and amarogentin (active component of chirata plant) either alone or in combination were evaluated in Hela cell line. It was evident that EGCG with eugenol–amrogentin could highly inhibit the cellular proliferation and colony formation than individual treatments. Induction of apoptosis was also higher after treatment with EGCG in combination with eugenol–amrogentin than individual compound treatments. The antiproliferative effect of these compounds was due to downregulation of cyclinD1 and upregulation of cell cycle inhibitors LIMD1, RBSP3, and p16 at G1/S phase of cell cycle. Treatment of these compounds could induce promoter hypomethylation of LimD1 and P16 genes as a result of reduced expression of DNA methyltransferase 1 (DNMT1). Thus, our study indicated the better chemotherapeutic effect of EGCG in combination with eugenol–amarogentin in Hela cell line. The chemotherapeutic effect might be due to the epigenetic modification particularly DNA hypomethylation through downregulation of DNMT1.