bluuebunny/crossref_metadata_2025 huggingface dataset:
A trajectory analysis of childhood motor development following stress in pregnancy: The QF2011 flood study
Authors: Simcock Gabrielle , Laplante David P. , Elgbeili Guillaume , Kildea Sue , King Suzanne
Published: August 2018

This prospective, longitudinal cohort study examined the effects of flood‐related stress in pregnancy on the trajectory of children's motor development; and the moderating effects of gestational timing of the flood or sex of the child. Women who were pregnant during a severe flood reported on their objective flood‐related experiences, emotional reactions, and cognitive appraisal of the disaster. At 2‐, 6‐, 16‐months, 2½‐ and 4‐years postpartum, mothers’ assessed their children's fine and gross motor development using the Ages and Stages‐3 Questionnaire. High objective flood‐exposure, or a negative appraisal, especially in later pregnancy, predicted poorer gross motor skills which rapidly improved across early childhood. Children's fine motor skill was influenced by the sex of the child with improvements in girls’ fine motor skills over time, but not boys’. This demonstrates that stress in pregnancy has enduring influences on gross, but not fine, motor skills. Results are discussed in relation to fetal programming and stress appraisal theory.
Flawed mothering or infant signaling? The effects of deficient acoustic cues on ovine maternal response
Authors: Morton Christine L. , Hinch Geoff , Small Alison , McDonald Paul G.
Published: August 2018

The neonate distress cry, which displays a similar acoustic structure across a range of mammalian species, is highly effective in attracting, even compelling, parental care. However, if this cry is defective, as found in human and rodent neonates with poor neurobehavioral function, is the signal less enticing? Using playback recordings of a ewe's own co‐twins as stimuli in a two choice test, we compared the preference of each sheep dam for acoustic features of lamb distress calls to assess the impact of signal quality on maternal response. The results of this study indicate that lamb vocalizations with acoustic parameters reflecting poor vocal fold engagement and arousal were less likely to be preferred by their dam. Additionally, these calls were associated with delayed vocal initiation and poor infant survival behavior suggestive of subtle cognitive deficit; and support the possibility that, as in deer and rodents, ovine vocalizations within a specific fundamental frequency range may well be a trigger for optimal maternal behavior. This research has important implications for understanding failed maternal–young interactions in ungulate and other species, and for verifying standardization of infant stimuli used in maternal behavior studies.
Gene expression profiles of rat MMECs with different glucose levels and fgl2 gene silencing
Authors: Zheng Zhenzhong , Zhang Fan , Gao Dengpeng , Wu Yujing , Wu Hao
Published: August 2018

Background

Cardiac microvascular endothelial cells (MMECs) is one of the key factors in the process of diabetic cardiomyopathy, a common chronic complication of diabetes. Fibrinogen‐like protein 2 (FGL2) is linked to apoptosis, angiogenesis, and inflammatory response, all of which also occur in diabetes. Thus, we investigate the role of FGL 2 and other genes in the pathology of diabetic cardiomyopathy.

Methods

In the present study, we used high‐throughput microarray to profile gene expression in rat myocardial MMECs with or without silencing the fgl2 gene and in different glucose environments. We use volcanic maps to isolate genes with significantly different expression levels between conditions, using the standard statistical criteria of fold changes ≥1.5 and P‐values ≤0.05. From this list, we identified genes with the most signicant changes in RNA levels and confirmed their protein‐level changes with Western blot. Furthermore, bioinformatic analysis predicts possible pathophysiology and clinical relevance of these proteins in diabetic cardiomyopathy.

Results

We identified 17 upregulated and 15 downregulated genes caused by silencing fgl2 gene. Most of them are involved in metabolism, ion transport, cell membrane surface recognition signal modification, inflammatory response, and immune response. Using Western blot, we were able to confirm protein‐level expression changes of three genes. Specifically, in both normal and high glucose conditions, silencing fgl2 significantly decreased the expression levels of CCL3 and PLAGL1 while increasing the expression level of CTSC. Significantly, bioinformatic analyses show that CCL3 is related to type 1 diabetes, PLAGL1 to cardiomyocytes, and CTSC to albuminuria in type 2 diabetes.

Conclusions

Our study provides clues for further studies on the mechanism of diabetic cardiomyopathy as well as function of FGL2 in this process, potentially offering new therapeutic strategies for treating diabetic cardiomyopathy.
Melatonin improves hyperglycemia induced damages in rat brain
Authors: Gurel‐Gokmen Begum , Ipekci Hazal , Oktay Sehkar , Alev Burcın , Ustundag Unsal Velı , Ak Esın , Akakın Dılek , Sener Goksel , Emekli‐Alturfan Ebru , Yarat Aysen , Tunali‐Akbay Tugba
Published: August 2018

Background

Diabetes mellitus is an endocrine disorder which is characterized by the development of resistance to the cellular activity of insulin or inadequate insulin production. It leads to hyperglycemia, prolonged inflammation, and oxidative stress. Oxidative stress is assumed to play an important role in the development of diabetic complications. Melatonin is the hormone that interacts with insulin in diabetes. Therefore, in this study, the effects of melatonin treatment with or without insulin were examined in diabetic rat brain.

Methods

Rats were divided into five groups as control, diabetes, diabetes + insulin, diabetes + melatonin, and diabetes + melatonin + insulin. Experimental diabetes was induced by streptozotocin (60 mg/kg, i.p.). Twelve weeks after diabetes induction, rats were decapitated. Malondialdehyde, glutathione, sialic acid and nitric oxide levels, superoxide dismutase, catalase, glutathione‐S‐transferase, myeloperoxidase, and tissue factor activities were determined in brain tissue.

Results

Melatonin alone showed its antioxidant effect by increasing brain glutathione level, superoxide dismutase, catalase, and glutathione‐S‐transferase activities and decreasing malondialdehyde level in experimental diabetes. Although insulin did not have a significant effect on glutathione and glutathione‐S‐transferase, its effects on lipid peroxidation, superoxide dismutase, and catalase were similar to melatonin; insulin also decreased myolopeoxidase activity and increased tissue factor activity. Combined melatonin and insulin treatment mimicked the effects of insulin.

Conclusion

Addition of melatonin to the insulin treatment did not change the effects of insulin, but the detailed role of melatonin alone in the treatment of diabetes merits further experimental and clinical investigation.
Behavioural and neural responses to aversive visceral stimuli in women with primary dysmenorrhoea
Authors: Böttcher Bettina , Gizewski Elke R. , Siedentopf Christian , Steiger Ruth , Verius Michael , Riedl David , Ischebeck Anja , Schmid Julia , Wildt Ludwig , Elsenbruch Sigrid
Published: August 2018

Background

Chronic pelvic pain, in particular dysmenorrhoea, is a significant yet unresolved healthcare problem in gynaecology. As interoceptive sensitivity and underlying neural mechanisms remain incompletely understood, this functional magnetic resonance imaging (fMRI) study assessed behavioural and neural responses to visceral stimuli in primary dysmenorrhoea (PMD).

Methods

Women with PMD (N = 19) without psychological comorbidity and healthy women (N = 20) were compared with respect to visceral sensory and pain thresholds, and to neural responses to individually calibrated mildly painful and painful rectal distensions implemented during scanning. Trial‐by‐trial ratings of perceived intensity were accomplished with visual analogue scales (VAS).

Results

Although women with dysmenorrhoea reported significantly higher chronic pain intensity and pain interference with daily life activities (p < 0.01, assessed with the West Haven‐Yale Multidimensional Pain Inventory), there were no differences between groups in visceral sensitivity and mean trial‐by‐trial VAS ratings were virtually identical. Analysis of neural responses revealed activation in brain regions previously shown to be involved in the processing of visceral stimuli with differences between painful and mildly painful stimulation, but no group differences were found even when using a liberal statistical threshold.

Conclusions

Dysmenorrhoea patients show unaltered perceptual and neural responses to experimental interoceptive stimuli. Despite limited sample size, these negative results argue against a generalized sensitization towards interoceptive stimuli in patients without psychological comorbidities. Future studies should clarify the role of psychosocial factors in central sensitization using more pain region‐specific models in larger and clinically more heterogeneous samples.

Significance

Despite higher chronic pain and pain interference with daily life activities, women with primary dysmenorrhoea do not differ from healthy women with respect to visceral sensitivity or neural processing of aversive interoceptive stimuli induced by rectal distensions. Generalized sensitization may be present only in subgroups with pronounced psychosocial or psychiatric disturbances.
Inflammatory and neuropathic pain conditions do not primarily evoke anxiety‐like behaviours in C57BL/6 mice
Authors: Pitzer Claudia , La Porta Carmen , Treede Rolf‐Detlef , Tappe‐Theodor Anke
Published: August 2018

Background

Chronic pain is often accompanied by comorbidities like anxiety and depression. The temporal correlations, as well as the underlying mechanisms of these reciprocal correlations, are unclear. Moreover, preclinical studies examining emotional behaviour are very controversial, and a chronological analysis of anxiety‐like behaviour in mouse pain models considering both genders has not been performed so far.

Methods

We used several behavioural tests to assess and validate anxiety‐like behaviour in complete Freund's adjuvant (CFA) and spared nerve injury (SNI) pain models in C57BL/6 mice. Among these were the elevated plus maze test, open field test, hole‐board test and light‐dark test. Additionally, we included a late stage analysis of depression‐like behaviour using the forced swim test. All tests were applied once for each cohort of mice. Importantly, we used C57BL/6N mice of both genders; we investigated the effect of social isolation, the impact of pain induction to either the right or left hind limb and also investigated C57BL/6J mice.

Results

The validity of test conditions was confirmed using the anxiogenic drugs Yohimbine and Pentylenetetrazol. Anxiety‐like behaviour was analysed throughout the time period when mice exhibited hypersensitivity to mechanical stimuli. We did not observe any consistent alteration in anxiety‐like behaviour at any of the investigated time points between 1 and 14 days following CFA‐induced inflammation or 3 and 84 days following SNI surgery using different behavioural tests.

Conclusions

Inflammatory and neuropathic pain conditions do not primarily evoke anxiety‐ and depression‐like behavioural alterations within the herein investigated time period.

Significance

Anxiety‐like behaviour is not primarily altered following CFA and SNI in C57BL6 mice, irrespective of the gender, mouse sub‐strain, housing conditions or affected body side within the herein investigated time period.
The Adjective Rating Scale for Withdrawal: Validation of its ability to assess severity of prescription opioid misuse
Authors: Coloma‐Carmona Ainhoa , Carballo José Luis , Rodríguez‐Marín Jesús , van‐der Hofstadt Carlos Javier
Published: August 2018

Background

Withdrawal symptoms have been widely shown to be a useful indicator of the severity of opioid dependence. One of the most used instruments to assess them is the Adjective Rating Scale for Withdrawal (ARSW). However, there is a lack of adaptations and validations for its use with prescription opioids, even less for chronic pain patients under treatment with these analgesics. Thus, the aims of this study were to analyse the psychometric properties and invariance across gender of the ARSW in a sample of chronic noncancer pain patients.

Methods

Data were collected from 208 consumers of opioid medication, chronic noncancer pain patients. Participants completed sociodemographic, ARSW, prescription opioid dependence (DSM‐IV‐TR) and prescription opioid‐use disorder (DSM‐5) measurements. Gender invariance was assessed through multigroup confirmatory factor analysis (CFA).

Results

The ARSW showed a unidimensional factor structure and high internal consistency (Cronbach's alpha = 0.85). Multigroup CFA showed configural, metric, scalar and strict invariances of ARSW across gender. Predictive validity analyses indicated that ARSW has good capacity for identifying the severity of prescription opioid‐use disorder, using both DSM‐IV‐TR and DSM‐5 criteria.

Conclusions

These findings show that the ARSW is a valid and reliable tool for use in the assessment of the withdrawal of prescription opioids in chronic pain patients under treatment with these analgesics, regardless of their gender.

Significance

Findings supported the reliability and validity of the ARSW to assess withdrawal of prescription opioids in individuals with chronic noncancer pain. The instrument can be applied indistinctly in men and women. An increase in the ARSW scores could be used as an indicator of potential risk of prescription opioid‐use disorder during long‐term treatments.
Prevalence of self‐reported chronic pain among adolescents: Evidence from 42 countries and regions
Authors: Gobina Inese , Villberg Jari , Välimaa Raili , Tynjälä Jorma , Whitehead Ross , Cosma Alina , Brooks Fiona , Cavallo Franco , Ng Kwok , de Matos Margarida Gaspar , Villerusa Anita
Published: August 2018

Background

Reports of the overall chronic pain prevalence and its associated demographic characteristics among adolescents vary greatly across existing studies. Using internationally comparable data, this study investigates age, sex and country‐level effects in the prevalence of chronic single‐site and multi‐site pain among adolescents during the last six months preceding the survey.

Methods

Data (n = 214,283) from the 2013/2014 Health Behaviour in School‐aged Children (HBSC) study were used including nationally representative samples of 11‐, 13‐ and 15‐year‐olds from general schools in 42 participating countries. Multilevel logistic regression analyses were used.

Results

The overall proportion of adolescents reporting chronic weekly pain during the last six months was high (44.2%). On average, in comparison with different specific localized types of single‐site pain, the prevalence of multi‐site pain was more common varying from 13.2% in Armenia to 33.8% in Israel. Adolescent age and sex were strong predictors for reporting pain, but significantly different demographic patterns were found in the cross‐country analyses. The most consistent findings indicate that multi‐site pain was more prevalent among girls across all countries and that the prevalence increased with age.

Conclusions

Internationally comparable data suggest that self‐reported chronic pain among adolescents is highly prevalent, but different age and sex patterns across countries exist. Adolescents with chronic pain are not a homogenous group. Chronic pain co‐occurrence and differences in chronic pain characteristics should be addressed in both clinical and public health practice for effective adolescent chronic pain management and prevention.

Significance

Chronic pain co‐occurrence is common during adolescence across countries, the prevalence being among girls and in older age groups. Significant cross‐country variations in the chronic pain prevalence and chronic pain patterns among adolescents exist. Significant country differences emerge for specific chronic pain patterns in association with adolescent demographics.
Flexible Lead‐Free Piezoelectric Composite Materials for Energy Harvesting Applications
Authors: Stuber Vincent L. , Deutz Daniella B. , Bennett James , Cannel David , de Leeuw Dago M. , van der Zwaag Sybrand , Groen Pim
Published: August 2018

Vibrational piezoelectric energy harvesters are being investigated to replace batteries in embedded sensor systems. The energy density that can be harvested depends on the figure of merit, d33g33, where d33 and g33 are the piezoelectric charge and voltage coefficient. Commonly used piezoelectric materials are based on inorganic ceramics, such as lead zirconium titanate (PZT), as they exhibit high piezoelectric coefficients. However, ceramics are brittle, leading to mechanical failure under large cyclic strains and, furthermore, PZT is classified as a Substance of Very High Concern (SVHC). To circumvent these drawbacks, we fabricated quasi 1–3 potassium sodium lithium niobate (KNLN) ceramic fibers in a flexible polydimethylsiloxane (PDMS) matrix. The fibers were aligned by dielectrophoresis. We demonstrate for the structured composites values of d33g33 approaching 18 pm3 J−1, comparable to that of state‐of‐the‐art ceramic PZT. This relatively high value is due to the reduced inter‐particle distance in the direction of the electric field. As a confirmation, the stored electrical energy for both material systems was measured under identical mechanical loading conditions. The similar values for KNLN/PDMS and PZT demonstrate that environmentally friendly, lead‐free, mechanically compliant materials can replace state‐of‐the‐art environmentally‐less‐desirable ceramic materials in piezoelectric vibrational energy harvesters.
Metallothionein‐I/II expression associates with the astrocyte DNA damage response and not Alzheimer‐type pathology in the aging brain
Authors: Waller Rachel , Murphy Mark , Garwood Claire J , Jennings Luke , Heath Paul R , Chambers Annabelle , Matthews Fiona E , Brayne Carol , Ince Paul G , Wharton Stephen B , Simpson Julie E ,   on behalf of the Cognitive Function and Ageing Neuropathology Study Group
Published: August 2018

Oxidative stress and oxidative DNA damage are early features of mild cognitive impairment and Alzheimer's disease (AD), occurring before the formation of classical AD neuropathology, and resulting from an imbalance between pro‐ and anti‐oxidants. Astrocytes play a major neuroprotective role, producing high levels of anti‐oxidants including metallothionein‐I and ‐II (MT‐I/II). In the present study we characterized the immunoreactive profile of MT‐I/II in the temporal cortex of the Cognitive Function and Ageing Study (CFAS) aging population‐representative neuropathology cohort, and examined H2O2‐modulation of MT transcription by human astrocytes. MT‐I/II is primarily expressed by astrocytes in the aging brain, but is also associated with pyramidal neurons in a small proportion of cases. Astrocyte expression of MT‐I/II does not correlate with Alzheimer‐type pathology (Aβ plaques and neurofibrillary tangles) but does relate to astrocyte oxidative DNA damage (rs = .312, p = .006) and the astrocyte response to oxidative DNA damage in vivo (rs = .238, p = .04), and MT gene expression is significantly induced in human astrocytes response to oxidative stress in vitro (p = .01). In contrast, neuronal MT‐I/II does not relate to oxidative DNA damage or the neuronal DNA damage response, but is significantly higher in cases with high levels of local tangle pathology (p = .007). As MT‐I/II is neuroprotective against oxidative stress, modulation of MT‐I/II expression is a potential therapeutic target to treat the onset and progression of cognitive impairment.
The association between birth order and childhood leukemia may be modified by paternal age and birth weight. Pooled results from the International Childhood Cancer Cohort Consortium (I4C)
Authors: Paltiel Ora , Lemeshow Stanley , Phillips Gary S. , Tikellis Gabriella , Linet Martha S. , Ponsonby Anne‐Louise , Magnus Per , Håberg Siri E. , Olsen Sjurdur F. , Granström Charlotta , Klebanoff Mark , Golding Jean , Herceg Zdenko , Ghantous Akram , Hirst Jane Elizabeth , Borkhardt Arndt , Ward Mary H. , Holst Søegaard Signe , Dwyer Terence
Published: August 2018

The “delayed infection hypothesis” states that a paucity of infections in early childhood may lead to higher risks of childhood leukemia (CL), especially acute lymphoblastic leukemia (ALL). Using prospectively collected data from six population‐based birth cohorts we studied the association between birth order (a proxy for pathogen exposure) and CL. We explored whether other birth or parental characteristics modify this association. With 2.2 × 106 person‐years of follow‐up, 185 CL and 136 ALL cases were ascertained. In Cox proportional hazards models, increasing birth order (continuous) was inversely associated with CL and ALL; hazard ratios (HR) = 0.88, 95% confidence interval (CI): (0.77–0.99) and 0.85: (0.73–0.99), respectively. Being later‐born was associated with similarly reduced hazards of CL and ALL compared to being first‐born; HRs = 0.78: 95% CI: 0.58–1.05 and 0.73: 0.52–1.03, respectively. Successive birth orders were associated with decreased CL and ALL risks (P for trend 0.047 and 0.055, respectively). Multivariable adjustment somewhat attenuated the associations. We found statistically significant and borderline interactions between birth weight (p = 0.024) and paternal age (p = 0.067), respectively, in associations between being later‐born and CL, with the lowest risk observed for children born at <3 kg with fathers aged 35+ (HR = 0.18, 95% CI: 0.06–0.50). Our study strengthens the theory that increasing birth order confers protection against CL and ALL risks, but suggests that this association may be modified among subsets of children with different characteristics, notably advanced paternal age and lower birth weight. It is unclear whether these findings can be explained solely by infectious exposures.
A novel fusion gene PLEKHA6‐NTRK3 in langerhans cell histiocytosis
Authors: Cai Jiaoyang , Huang Xia , Yin Minzhi , Pan Ci , Song Lili , Zhan Zhiyan , Chen Jing , Gao Yijin , Tang Jingyan , Li Yanxin , Shen Shuhong
Published: August 2018

Langerhans cell histiocytosis (LCH) is the most common histiocytosis with constitutive activation of the RAS–RAF–MEK–ERK (MAPKinase) cell signaling pathway. We analyzed 89 cases of BRAF and MAP2K1 mutations by Sanger sequencing, of which 18 cases showed that these two gene mutations are negative. Whole genome sequencing of suitable specimens in these negative cases revealed a translocation from the 3 intron of PLEKHA6 to the 13 intron of NTRK3 in one case. We identified that this translocation could cause a novel fusion mutation, PLEKHA6‐NTRK3. Overexpression of the PLEKHA6‐NTRK3 mutant in NIH 3T3 cells enhanced MAPKinase pathway activation, promote cell growth. Our result suggested that a new mutation need be included in LCH molecular screening panel to better define its prevalence in LCH.
Mechanistic insights of epithelial protein lost in neoplasm in prostate cancer metastasis
Authors: Collins Ross J. , Morgan Liam D. , Owen Sioned , Ruge Fiona , Jiang Wen G. , Sanders Andrew J.
Published: August 2018

EPLIN is frequently downregulated or lost in various cancers. The purpose of this study was to evaluate the importance of EPLIN in prostate cancer progression, with particular focus on the mechanistic implications to elucidate EPLIN's tumor suppressive function in cancer. EPLIN expression was evaluated in prostate cancer cell lines and tissues. PC‐3 and LNCaP EPLINα overexpression models were generated through transfection with EPLINα sequence and EPLIN knockdown was achieved using shRNA in CA‐HPV‐10 cells. Functional assays were performed to evaluate cellular characteristics and potential mechanisms were evaluated using a protein microarray, and validated using western blot analysis. EPLIN expression was reduced in clinical prostate cancer sections, including hyperplasia (p ≤ 0.001) and adenocarcinoma (p = 0.005), when compared to normal prostate tissue. EPLINα overexpression reduced cell growth, migration and invasion, and influenced transcript, protein and phosphoprotein expression of paxillin, FAK and Src. EPLIN knockdown increased the invasive and migratory nature of CA‐HPV‐10 cells and also induced changes to FAK and Src total and/or phospho expression. Functional characterization of cellular migration and invasion in addition to FAK and Src inhibition demonstrated differential effects between control and EPLINα overexpression and EPLIN knockdown cell lines. This study highlights that EPLIN expression in prostate cancer is able to influence several aspects of cancer cell characteristics, including cell growth, migration and invasion. The mechanism of the tumor suppressive action of EPLIN remains to be fully elucidated; and this study proposes a role for EPLIN's ability to regulate the aggressive characteristics of prostate cancer cells partially through regulating FAK/Src signaling.
Reliable identification of women with CIN3+ using hrHPV genotyping and methylation markers in a cytology‐screened referral population
Authors: Leeman Annemiek , del Pino Marta , Marimon Lorena , Torné Aureli , Ordi Jaume , ter Harmsel Bram , Meijer Chris J.L.M. , Jenkins David , Van Kemenade Folkert J. , Quint Wim G.V.
Published: August 2018

Cervical screening aims to identify women with high‐grade squamous intraepithelial lesion/cervical intraepithelial neoplasia 2‐3 (HSIL/CIN2‐3) or invasive cervical cancer (ICC). Identification of women with severe premalignant lesions or ICC (CIN3+) could ensure their rapid treatment and prevent overtreatment. We investigated high‐risk human papillomavirus (hrHPV) detection with genotyping and methylation of FAM19A4/miR124‐2 for detection of CIN3+ in 538 women attending colposcopy for abnormal cytology. All women had an additional cytology with hrHPV testing (GP5+/6+‐PCR‐EIA+), genotyping (HPV16/18, HPV16/18/31/45), and methylation analysis (FAM19A4/miR124‐2) and at least one biopsy. CIN3+ detection was studied overall and in women <30 (n = 171) and ≥30 years (n = 367). Positivity for both rather than just one methylation markers increased in CIN3, and all ICC was positive for both. Overall sensitivity and specificity for CIN3+ were, respectively, 90.3% (95%CI 81.3–95.2) and 31.8% (95%CI 27.7–36.1) for hrHPV, 77.8% (95%CI 66.9–85.8) and 69.3% (95%CI 65.0–73.3) for methylation biomarkers and 93.1% (95%CI 84.8–97.0) and 49.4% (95%CI 44.8–53.9) for combined HPV16/18 and/or methylation positivity. For CIN3, hrHPV was found in 90.9% (95%CI 81.6–95.8), methylation positivity in 75.8% (95%CI 64.2–84.5) and HPV16/18 and/or methylation positivity in 92.4% (95%CI 83.5–96.7). In women aged ≥30, the sensitivity of combined HPV16/18 and methylation was increased (98.2%, 95%CI 90.6–99.7) with a specificity of 46.3% (95%CI 40.8–51.9). Combination of HPV16/18 and methylation analysis was very sensitive and offered improved specificity for CIN3+, opening the possibility of rapid treatment for these women and follow‐up for women with potentially regressive, less advanced, HSIL/CIN2 lesions.
DNA primase polypeptide 1 (PRIM1) involves in estrogen‐induced breast cancer formation through activation of the G2/M cell cycle checkpoint
Authors: Lee Wei‐Hwa , Chen Li‐Ching , Lee Chia‐Jung , Huang Chi‐Cheng , Ho Yuan‐Soon , Yang Po‐Sheng , Ho Chi‐Tang , Chang Hang‐Lung , Lin I‐Hsuan , Chang Hui‐Wen , Liu Yun‐Ru , Wu Chih‐Hsiung , Tu Shih‐Hsin
Published: August 2018

The DNA primase polypeptide 1 (PRIM1) is responsible for synthesizing small RNA primers for Okazaki fragments generated during discontinuous DNA replication. PRIM1 mRNA expression levels in breast tumor samples were detected by real‐time PCR analysis. Xenografted tumor model was established to study the carcinogenic role of PRIM1 and its potential therapeutic applications. The average PRIM1 mRNA (copy number × 103/μg) expression was 4.7‐fold higher in tumors than in normal tissue (*p = 0.005, n = 254). PRIM1 was detected preferentially at a higher level (>40‐fold) in poorly differentiated tumor tissues (n = 46) compared with more highly differentiated tumors tissues (n = 10) (*p = 0.005). Poor overall survival rate was correlated to the estrogen receptor positive (ER+, n = 20) patients with higher PRIM1 expression when compare to the ER− (n = 10) patients (Chi Square test, p = 0.03). Stable expression of PRIM1‐siRNA in the ER+ BT‐474 cells‐xenograft tumors significantly reduced tumor volume in SCID mice (*p = 0.005). The anti‐tumoral effects of inotilone isolated from Phellinus linteus was tested and had significant effects on the inhibition of PRIM1 protein expression in ER+ breast cancer cells. In vivo study was performed by administering inotilone (10 mg/kg, twice a week for 6 weeks), which resulted in significantly reduced BT‐474‐xenografted tumor growth volume compared with control (n =5 per group, *p < 0.05). This study provides evidences for the prognostic effects of PRIM1 with poor overall survival rate in the ER+ patients and will be valuable to test for therapeutic purpose.
Surviving childhood cancer: a systematic review of studies on risk and determinants of adverse socioeconomic outcomes
Authors: Frederiksen Line Elmerdahl , Mader Luzius , Feychting Maria , Mogensen Hanna , Madanat‐Harjuoja Laura , Malila Nea , Tolkkinen Anniina , Hasle Henrik , Winther Jeanette Falck , Erdmann Friederike
Published: August 2018

Substantial improvements in childhood cancer survival have resulted in a steadily increasing population of childhood cancer survivors. Whereas somatic late effects have been assessed in many studies, less is known about the impact of childhood cancer on socioeconomic outcomes in survivors. The aim of this article was to evaluate and summarise the evidence on the socioeconomic conditions of childhood cancer survivors and to identify survivors at particular risk of adverse socioeconomic outcomes. An extensive literature search of three electronic databases was conducted. Of 419 articles identified, 52 met the inclusion criteria. All the selected articles were appraised for quality, and findings were summarised in a narrative synthesis. Childhood cancer survivors were at higher risk of adverse socioeconomic outcomes with regard to educational achievement, income and social security benefits than the general population or a sibling comparison group. The risks for unemployment and a lower occupational position were significantly increased only for survivors of a central nervous system tumour. Notably, survivors of central nervous system tumours, survivors treated with cranial radiotherapy and those diagnosed at younger age independent of cancer type were determinants of particular adverse socioeconomic outcomes. Given the increasing population of childhood cancer survivors, targeted follow‐up interventions and support strategies addressing not only the somatic and psychiatric late effects but also the socioeconomic difficulties that some childhood cancer survivors face is of high importance to reduce social inequity, and ensure a high quality of life after childhood cancer.
Acidic extracellular environment affects miRNA expression in tumors in vitro and in vivo
Authors: Riemann Anne , Reime Sarah , Thews Oliver
Published: August 2018

Hypoxia can control the expression of miRNAs in tumors which play an important role for the control of the malignant behavior. The aim of the study was to analyze whether extracellular acidosis, a common feature of tumors, also has an impact on the miRNA expression in isolated cells as well as in solid tumors. MiRNA expression was analyzed in two rat tumor cell lines (AT1 prostate and Walker‐256 mammary carcinomas) by NGS and qPCR. In vivo the same cell lines were implanted subcutaneously and the tumor pH was modulated by inspiratory hypoxia and inhibition of the respiratory chain. In addition, the expression of five genes (Brip1, Ercc6l, Ikbke, Per3, Tlr5) which are potential targets of the miRNAs were analyzed on mRNA level.

Screening showed that 38 (AT1) resp. 41 (Walker‐256) miRNAs were pH‐dependent. Validation by qPCR revealed that only 4 miRNAs were consistently regulated in both cell lines: miR‐183, miR‐203a, miR‐215 and miR‐7a. The expression of miR‐7a was increased by low pH whereas all others were decreased. In the tumors in vivo all 4 miRNAs were down‐regulated. The potential targets showed pH dependency in both cell lines. In conclusion, extracellular acidosis regulates the expression of miRNAs in vitro and in vivo. The expression of targets of these miRNAs were also pH‐dependent. The pH may therefore affect the biological behavior of tumors via miRNAs.
Prodrug suicide gene therapy for cancer targeted intracellular by mesenchymal stem cell exosomes
Authors: Altanerova Ursula , Jakubechova Jana , Benejova Katarina , Priscakova Petra , Pesta Martin , Pitule Pavel , Topolcan Ondrej , Kausitz Juraj , Zduriencikova Martina , Repiska Vanda , Altaner Cestmir
Published: August 2018

The natural behavior of mesenchymal stem cells (MSCs) and their exosomes in targeting tumors is a promising approach for curative therapy. Human tumor tropic mesenchymal stem cells (MSCs) isolated from various tissues and MSCs engineered to express the yeast cytosine deaminase::uracil phosphoribosyl transferase suicide fusion gene (yCD::UPRT‐MSCs) released exosomes in conditional medium (CM). Exosomes from all tissue specific yCD::UPRT‐MSCs contained mRNA of the suicide gene in the exosome's cargo. When the CM was applied to tumor cells, the exosomes were internalized by recipient tumor cells and in the presence of the prodrug 5‐fluorocytosine (5‐FC) effectively triggered dose‐dependent tumor cell death by endocytosed exosomes via an intracellular conversion of the prodrug 5‐FC to 5‐fluorouracil. Exosomes were found to be responsible for the tumor inhibitory activity. The presence of microRNAs in exosomes produced from naive MSCs and from suicide gene transduced MSCs did not differ significantly. MicroRNAs from yCD::UPRT‐MSCs were not associated with therapeutic effect. MSC suicide gene exosomes represent a new class of tumor cell targeting drug acting intracellular with curative potential.
A risk‐based approach to identifying oligometastatic disease on imaging
Authors: deSouza Nandita M , Tempany Clare M
Published: August 2018

Recognition of <3 metastases in <2 organs, particularly in cancers with a known predisposition to oligometastatic disease (OMD) (colorectal, prostate, renal, sarcoma and lung), offers the opportunity to focally treat the lesions identified and confers a survival advantage. The reliability with which OMD is identified depends on the sensitivity of the imaging technique used for detection and may be predicted from phenotypic and genetic factors of the primary tumour, which determine metastatic risk. Whole‐body or organ‐specific imaging to identify oligometastases requires optimization to achieve maximal sensitivity. Metastatic lesions at multiple locations may require a variety of imaging modalities for best visualisation because the optimal image contrast is determined by tumour biology. Newer imaging techniques used for this purpose require validation. Additionally, rationalisation of imaging strategies is needed, particularly with regard to timing of imaging and follow‐up studies. This article reviews the current evidence for the use of imaging for recognising OMD and proposes a risk‐based roadmap for identifying patients with true OMD, or at risk of metastatic disease likely to be OM.
Spectral correction for handheld optoacoustic imaging by means of near‐infrared optical tomography in reflection mode
Authors: Ulrich Leonie , Ahnen Linda , Akarçay Hidayet Günhan , Majos Salvador Sánchez , Jaeger Michael , Held Kai Gerrit , Wolf Martin , Frenz Martin
Published: August 2018

In vivo imaging of tissue/vasculature oxygen saturation levels is of prime interest in many clinical applications. To this end, the feasibility of combining two distinct and complementary imaging modalities is investigated: optoacoustics (OA) and near‐infrared optical tomography (NIROT), both operating noninvasively in reflection mode. Experiments were conducted on two optically heterogeneous phantoms mimicking tissue before and after the occurrence of a perturbation. OA imaging was used to resolve submillimetric vessel‐like optical absorbers at depths up to 25 mm, but with a spectral distortion in the OA signals. NIROT measurements were utilized to image perturbations in the background and to estimate the light fluence inside the phantoms at the wavelength pair (760 nm, 830 nm). This enabled the spectral correction of the vessel‐like absorbers' OA signals: the error in the ratio of the absorption coefficient at 830 nm to that at 760 nm was reduced from 60%‐150% to 10%‐20%. The results suggest that oxygen saturation (SO
2) levels in arteries can be determined with <10% error and furthermore, that relative changes in vessels' SO
2 can be monitored with even better accuracy. The outcome relies on a proper identification of the OA signals emanating from the studied vessels.
Optical windows for head tissues in near‐infrared and short‐wave infrared regions: Approaching transcranial light applications
Authors: Golovynskyi Sergii , Golovynska Iuliia , Stepanova Ludmila I. , Datsenko Oleksandr I. , Liu Liwei , Qu Junle , Ohulchanskyy Tymish Y.
Published: August 2018

Optical properties of the rat head tissues (brain cortex, cranial bone and scalp skin) are assessed, aiming at transcranial light applications such as optical imaging and phototherapy. The spectral measurements are carried out over the wide spectral range of 350 to 2800 nm, involving visible, near‐infrared (NIR) and short‐wave infrared (SWIR) regions. Four tissue transparency windows are considered: ~700 to 1000 nm (NIR‐I), ~1000 to 1350 nm (NIR‐II), ~1550 to 1870 nm (NIR‐III or SWIR) and ~2100 to 2300 nm (SWIR‐II). The values of attenuation coefficient and total attenuation length are determined for all windows and tissue types. The spectra indicate transmittance peaks in NIR, NIR‐II and SWIR‐II, with maximum tissue permeability for SWIR light. The use of SWIR‐II window for the transcranial light applications is substantiated. Furthermore, absorbance of the head tissues is investigated in details, by defining and describing the characteristic absorption peaks in NIR‐SWIR.
Prophylactic infusion of calcium gluconate to prevent a symptomatic fall in plasma ionized calcium during therapeutic plasma exchange: A comparison of two methods
Authors: Zhao Yong , Linden Jeanne , Welch Linda , St. Pierre Patricia , Graves Molly , Garrity Danielle , Ducharme Paula , Bailey Jeffrey A. , Greene Mindy , Vauthrin Michelle , Weinstein Robert
Published: August 2018

We compared two methods of calcium gluconate infusion to maintain plasma ionized calcium ([Ca2+]) during therapeutic plasma exchange (TPE) performed using the Spectra Optia Apheresis System. Method A, our legacy method, consisted of adding 5 mL of 10% calcium gluconate to each 500 mL bottle of 5% albumin replacement fluid. Method B used an accessory IV infusion of calcium gluconate (2 g in 50 mL of 0.9% NaCl starting at 25 mL/h). Plasma [Ca2+] was measured at 20‐minute intervals, and symptoms of hypocalcemia were recorded during TPE. Baseline [Ca2+] was the same (P = 0.616), as was total acid citrate dextrose Formula A used (P = 0.865), with either method. TPE with method A used 2.62 ± 0.52 g of calcium gluconate vs 1.13 ± 0.27 g with method B (P < 0.001). [Ca2+] remained stable with method A (P = 0.251), but fell on average by 5% with method B (P < 0.05). Hypocalcemic symptoms were reported in 0 of 23 TPE with method A and 2 of 24 TPE with method B. We conclude that both methods A and B prevent a symptomatic fall in plasma [Ca2+] during TPE. Method B requires significantly less calcium gluconate than does method A.
The regulatory role of curcumin on platelet functions
Authors: Tabeshpour Jamshid , Hashemzaei Mahmoud , Sahebkar Amirhossein
Published: August 2018

Curcumin, the main ingredient of Curcuma longa L., has been used as a spice and as a herbal medicine with different therapeutic characteristics for centuries in Asian countries. This phytochemical has been shown to possess beneficial antiplatelet activity that has introduced it as a promising candidate for the treatment of thromboembolism, atherothrombosis, and inflammatory diseases. Platelet dysfunction under different circumstances may lead to cardiovascular disease, and curcumin has been shown to have beneficial effects on platelet dysfunction in several studies. Therefore, this narrative review is aimed to summarize available evidence on the antiplatelet activity of curcumin and related molecular mechanisms for this activity.
Solid phosphoric acid catalysts based on mesoporous silica for levoglucosenone production via cellulose fast pyrolysis
Authors: Santander José A , Alvarez Mariana , Gutierrez Victoria , Volpe María A
Published: August 2018

BACKGROUND

Biochemicals are interesting alternatives for biomass valorization owing to their much higher added value compared to biofuels and energy products. Several methods for the production of valuable chemicals such as levoglucosenone (LGO) via thermochemical processes over solid acid catalysts are being investigated due to their important advantages compared to conventional biomass acid impregnation techniques. The present work explores the synthesis of catalytic materials for the production of this platform molecule.

RESULTS

Aluminum‐loaded SBA‐15 mesoporous silica and the corresponding solid phosphoric acid (SPA) catalysts were prepared, characterized by TEM, FTIR, MAS NMR, NH3‐TPD, N2 adsorption, ICP‐AES and titration of ‘free H3PO4’, and tested in cellulose fast pyrolysis. Post‐synthesis Al deposition on the silica support produced an increase of bio‐oil yield and LGO amount in pyrolysis products. The presence of Al in SPA catalysts led to the formation of aluminum phosphates, decreasing the concentration of H3PO4 species in the surface and therefore the LGO levels. The SPAs presented relatively high LGO levels in the GC–MS detectable liquid products (up to 85 peak area%) which was found to be correlated with the amount of free H3PO4 in the solid catalysts.

CONCLUSION

Aluminum grafting over SBA‐15 is an effective way to increase the selectivity to the target anhydrosaccharide. In SPAs, the presence of Al reduced the easily leachable H3PO4 amount, which is desirable from the point of view of catalyst stability because deactivation is mainly caused by H3PO4 leaching, but also led to lower levels of LGO in bio‐oil. © 2018 Society of Chemical Industry
A comparison of pneumonia care quality between general physicians and pulmonologists
Authors: Kenzaka Tsuneaki , Kumabe Ayako , Mabuchi Mai , Goda Ken , Yahata Shinsuke
Published: August 2018

Background

We compared the quality of care for nursing‐ and healthcare‐associated pneumonia (NHCAP) and aspiration pneumonia provided by general physicians and pulmonologists.

Methods

Questionnaires were mailed to 2490 medical facilities across Japan. The questionnaire assessed participants’ implementation of microbiological investigations for NHCAP or aspiration pneumonia, as well as steps taken to prevent pneumonia recurrence (eg, use or discontinuation of drugs associated with swallowing and administration of pneumococcal polysaccharides). Survey results were statistically compared between the two groups using chi‐square tests.

Results

We received responses from 350 hospitals; of those, medical care for aspiration pneumonia was provided by pulmonologists at 190 hospitals and by general physicians at 79 hospitals. No significant differences were observed between the two groups of physicians for any of the items regarding proactive microbiological investigations or measures for preventing pneumonia recurrence. However, general physicians tended to be more proactive in conducting Gram's stains for sputum, sputum culture inspections, and blood culture tests. They also were more likely to implement measures for preventing pneumonia recurrence such as striving to increase patients’ consciousness levels, reducing medication doses, and discontinuing drugs that cause difficulty with swallowing (response rates of “is done in nearly all cases” were 73.4%, 88.6%, 36.7%, 35.4%, and 40.5%, respectively).

Conclusions

The quality of care provided by general physicians may be on par with pulmonologists in terms of proactive microbiological investigations and preventing pneumonia recurrence.
Mass spectrometric method for distinguishing isomers of dexamethasone via fragment mass ratio: An HRMS approach
Authors: Karatt Tajudheen K. , Nalakath Jahfar , Perwad Zubair , Albert Peter H. , Abdul Khader Karakka Kal , Syed Ali Padusha Mohamedkhan , Laya Saraswathy
Published: August 2018

The major challenge in identifying dexamethasone, betamethasone, and paramethasone from a mixture of these corticosteroids is difficulty in achieving an efficient separation. In this study, we aimed to develop an efficient technique to identify these co‐eluting isomers based on the mass spectral patterns of them and their corresponding phase II metabolites after electrospray ionization. Fragmentation pathways in tandem mass spectrometry revealed acceptable specificity within the groups of conjugates. The method was validated using individual isomers and mixtures at various compositions. The effects of concentration and collision energies on fragmentation patterns were also studied extensively. Matrix‐fortified equine urine and plasma samples were also included so that matrix effects and interferences on fragmentation ratios could be elucidated. Preliminary results using biological samples demonstrated the suitability of this analytical strategy for direct measurement from their fragmentation patterns. Possible fragmentation pathways for each isomer were proposed.
Hormetic approaches to the treatment of Parkinson's disease: Perspectives and possibilities
Authors: Calabrese Vittorio , Santoro Aurelia , Trovato Salinaro Angela , Modafferi Sergio , Scuto Maria , Albouchi Ferdaous , Monti Daniela , Giordano James , Zappia Mario , Franceschi Claudio , Calabrese Edward J
Published: August 2018

Age‐related changes in the brain reflect a dynamic interaction of genetic, epigenetic, phenotypic, and environmental factors that can be temporally restricted or more longitudinally present throughout the lifespan. Fundamental to these mechanisms is the capacity for physiological adaptation through modulation of diverse molecular and biochemical signaling occurring from the intracellular to the network‐systemic level throughout the brain. A number of agents that affect the onset and progression of Parkinson's disease (PD)‐like effects in experimental models exhibit temporal features, and mechanisms of hormetic dose responses. These findings have particular significance since the hormetic dose response describes the amplitude and range of potential therapeutic effects, thereby affecting the design and conduct of studies of interventions against PD (and other neurodegenerative diseases), and may also be important to a broader consideration of hormetic processes in resilient adaptive responses that might afford protection against the onset and/or progression of PD and related disorders.