bluuebunny/crossref_metadata_2025 huggingface dataset:
Sirtuin 6 inhibits myofibroblast differentiation via inactivating transforming growth factor‐β1/Smad2 and nuclear factor‐κB signaling pathways in human fetal lung fibroblasts
Authors: Zhang Qian , Tu Wei , Tian Kunming , Han Lianyong , Wang Qin , Chen Panpan , Zhou Xue
Published: September 2018

Fibroblast‐to‐myofibroblast differentiation, which is characterized by increased expression of α‐smooth muscle actin, is known to be involved in the pathogenesis of idiopathic pulmonary fibrosis. Sirtuin 6 (SIRT6), a member of the sirtuin family, has been proved to inhibit epithelial‐to‐mesenchymal transition during idiopathic pulmonary fibrosis. However, the function of SIRT6 in lung myofibroblast differentiation is still obscure. Transforming growth factor‐β1 (TGF‐β1) is one of the main factors that can powerfully promote myofibroblast differentiation. In the current study, we aimed to explore the role of SIRT6 in the cellular model of fibroblast‐to‐myofibroblast differentiation induced by TGF‐β1 using human fetal lung fibroblasts (HFL1). We demonstrated that the SIRT6 protein level is upregulated by TGF‐β1 in HFL1 cells. Overexpression of SIRT6 significantly suppresses TGF‐β1‐induced myofibroblast differentiation in HFL1 cells. Mechanistically, SIRT6 decreases phosphorylation and nuclear translocation of Smad2 under TGF‐β1 stimulation. Nevertheless, mutant SIRT6 (H133Y) without histone deacetylase activity fails to inhibit phosphorylation and nuclear translocation of Smad2. Meanwhile, SIRT6 interacts with the nuclear factor‐κB (NF‐κB) subunit p65 and represses TGF‐β1‐induced NF‐κB‐dependent transcriptional activity, which is also dependent on its deacetylase activity. Overexpression of wild‐type SIRT6 but not the H133Y mutant inhibits the expression of NF‐κB‐dependent genes including interleukin (IL)‐1β, IL‐6 and matrix metalloproteinase‐9 (MMP‐9) induced by TGF‐β1, all of which have been demonstrated to promote myofibroblast differentiation. Collectively, our study reveals that SIRT6 prevents TGF‐β1‐induced lung myofibroblast differentiation through inhibiting TGF‐β1/Smad2 and NF‐κB signaling pathways.
MED12 somatic mutations encompassing exon 2 associated with benign breast fibroadenomas and not breast carcinoma in Indian women
Authors: Darooei Mina , Khan Fazal , Rehan Mohd , Zubeda Syeda , Jeyashanker Erukambattu , Annapurna Srirambhatla , Shah Ashwin , Maddali Srinivas , Hasan Qurratulain
Published: September 2018

Fibroadenoma is the most common type of benign breast tumor, accounting for 90% of benign lesions in India. Somatic mutations in the mediator complex subunit 12 (MED12) gene play a critical role in fibroepithelial tumorigenesis. The current study evaluated the hotspot region encompassing exon 2 of the
MED12 gene, in benign and malignant breast tumor tissue from women who presented for breast lump evaluation. A total of 100 (80 fibroadenoma and 20 breast cancer) samples were analyzed by polymerase chain reaction‐Sanger sequencing. Sequence variant analysis showed that 68.75% of nucleotide changes were found in exon 2 and the remaining in the adjacent intron 1. Codon 44 was implicated as a hotspot mutation in benign tumors, and 86.36% of the identified mutations involved this codon. An in silico functional analysis of missense mutations using consensus scoring sorting intolerant from tolerant (SIFT), SIFT seq, Polyphen2, Mutation Assessor, SIFT transFIC, Polyphen2 transFIC, Mutation Assesor transFIC, I‐Mutant, DUET, PON‐PS, SNAP2, and protein variation effect analyzer] revealed that apart from variants involving codon 44 (G44S; G44H), others like V41A and E55D were also predicted to be deleterious. Most of the missense mutations appeared in the loop region of the MED12 protein, which is expected to affect its functional interaction with cyclin C–CDK8/CDK19, causing loss of mediator‐associated cyclin depended kinase (CDK) activity. These results suggest a key role of
MED12 somatic variations in the pathogenesis of fibroadenoma. For the first time, it was demonstrated that
MED12 sequence variations are present in benign breast tumors in the south Indian population.
Identification specific miRNA in t(4;14) multiple myeloma based on miRNA‐mRNA expressing profile correlation analysis
Authors: Liu Huimin , Wang Guihua , Huang Ying , Zhao Chunmei , Chen Jing , Wang Xudong
Published: September 2018

Background

Multiple myeloma (MM) is a common malignancy belonging to the hematological system. The translocation t(4;14)(p16.3;q32.3) is a critical cytogenetic change of MM, which is presenting a poor prognosis. The specific microRNAs (miRNAs) that are involved in t(4;14) myeloma are still unknown. Thus, the main purpose of this research was to identify specific miRNAs in t(4;14) positive myeloma.

Methods

The expression profiles of miRNA and messenger RNA (mRNA) in t(4; 14) positive and negative samples were obtained from the gene expression omnibus data series. The miRNA‐mRNA regulatory network was constructed based on two self‐defined regulation models. Subsequently, we performed the topology analysis for mining the hub genes, and Pearson’s correlation coefficient analysis was used to calculate the relevance of the hub genes and specific miRNAs.

Results

Thirteen differentially expressed miRNAs and 206 differential mRNAs were extracted between t(4;14) positive group and negative group. The network consisted of 8 miRNAs and 154 mRNAs in 2 reverse regulated models, which showed a total of 485 interactions, including 376 cis‐regulated and 109
trans‐regulated relationships. The miR‐125a‐3p, miR‐125a‐5p, miR‐99b‐5p, and let‐7e were powerful miRNAs correlating with the FGFR3, MAP1B, MYRIP, and CDC42BPA under the relevance analysis in the subnetwork.

Conclusion

In our study, a distinctive correlation analysis of miRNA‐mRNA was established to excavate specific miRNAs and hub target mRNAs in patients with t(4;14), but it was only a matter of theoretical principles. The further experimental explorations are needed to confirm valuable diagnostic and therapeutic symbols specific associated with t(4;14) in the future.
Physical exercise prevents alterations in purinergic system and oxidative status in lipopolysaccharide‐induced sepsis in rats
Authors: Miron Vanessa Valéria , Bottari Nathieli Bianchin , Assmann Charles Elias , Stefanello Naiara , da Costa Pauline , Pelinson Luana Paula , Reichert Karine Paula , da Silva Anielen Dutra , Lopes Thauan Faccin , da Cruz Ivana Beatrice Mânica , Sévigny Jean , Morsch Vera Maria , Schetinger Maria Rosa Chitolina , Cardoso Andréia Machado
Published: September 2018

Sepsis is a generalized infection that involves alterations in inflammatory parameters, oxidant status, and purinergic signaling in many tissues. Physical exercise has emerged as a tool to prevent this disease because of its anti‐inflammatory and antioxidant properties. Thus, in this study, we investigated the effects of physical exercise on preventing alterations in purinergic system components, oxidative stress, and inflammatory parameters in lipopolysaccharide (LPS)‐induced sepsis in rats. Male Wistar rats were divided into four groups: control, exercise (EX), LPS, and EX+LPS. The resisted physical exercise was performed for 12 weeks on a ladder with 1 m height. After 72 hours of the last exercise session, the animals received 2.5 mg/kg of LPS for induction of sepsis, and after 24 hours, lungs and blood samples were collected for analysis. The results showed that the exercise protocol used was able to prevent, in septic animals: (1) the increase in body temperature; (2) the increase of lipid peroxidation and reactive species levels in the lung, (3) the increase in adenosine triphosphate levels in serum; (4) the change in the activity of the enzymes ectonucleotidases in lymphocytes, partially; (5) the change in the density of purinergic enzymes and receptors in the lung, and (6) the increase of IL‐6 and IL‐1β gene expression. Our results revealed the involvement of purinergic signaling and oxidative damage in the mechanisms by which exercise prevents sepsis aggravations. Therefore, the regular practice of physical exercise is encouraged as a better way to prepare the body against sepsis complications.
Long noncoding RNA HEIH promotes the proliferation and metastasis of non–small cell lung cancer
Authors: Jia Kegang , Chen Fan , Xu Lian
Published: September 2018

Objectives

This study is aimed to explore the functions of long noncoding RNA (lncRNA) HEIH on the proliferation as well as metastasis of non–small cell lung cancer (NSCLC).

Methods

HEIH was shown to be increased in NSCLC by a microarray study on lncRNA profiling. We detected the expression of HEIH in different human NSCLC lines and tissues by quantitative real‐time PCR. After gain‐ and loss‐of‐function approaches in A549 and Calu‐1 cells, 3‐(4,5‐dimethyl‐2‐thiazolyl)‐2,5‐diphenyl‐2‐H‐tetrazolium bromide, thiazolyl blue tetrazolium bromide (MTT) assays and a colony formation assay were applied to test the proliferative activity of cells, and the apoptosis of cells was measured by flow cytometry. Western blot analysis was used to evaluate the protein expression, and the effects of lncRNA HEIH on cell migratory and invasive abilities of A549 and Calu‐1 cells were evaluated using wound healing and transwell assays.

Results

In our study, we confirmed the elevated expression of HEIH in NSCLC tissues and cell lines compared with the normal ones. After constructing A549 and Calu‐1 cells with altered HEIH expression by transient transfection, cell viability was found to be positively regulated by the HEIH level. Moreover, overexpression of HEIH accelerated the cell migrating rate and increased the invasive cell number according to the results of a wound healing assay and transwell assay.

Conclusions

HEIH could accelerate the proliferation and metastasis of NSCLC, providing a novel therapeutic target for clinical treatment.
Oridonin‐induced mitochondria‐dependent apoptosis in esophageal cancer cells by inhibiting PI3K/AKT/mTOR and Ras/Raf pathways
Authors: Jiang Jin‐Huan , Pi Jiang , Jin Hua , Cai Ji‐Ye
Published: September 2018

Oridonin, an active diterpenoid isolated from Rabdosia rubescens, has been reported for its antitumor activity on several cancers. However, its effect on human esophageal cancer remains unclear. In this study, we demonstrated that oridonin could inhibit the growth of human esophageal cancer cells both in vitro and in vivo. Oridonin not only suppressed the proliferation, but also induced cell cycle arrest and mitochondrial‐mediated apoptosis in KYSE‐30, KYSE‐150, and EC9706 cells with dose‐dependent manner. Further mechanism studies revealed that oridonin led cell cycle arrest in esophageal cancer cells via downregulating cell cycle‐related proteins, such as cyclin B1 and CDK2, while upregulating p53 and p21. Oridonin also increased proapoptotic protein Bax and reduced antiapoptotic protein Bcl‐2, as well as the increased expression of cleaved caspase‐3, ‐8, and ‐9. In addition, oridonin treatment could significantly inhibit the PI3K/Akt/mTOR and Ras/Raf signaling pathway. In vivo results further demonstrated that oridonin treatment markedly inhibited tumor growth in the esophageal cancer xenograft mice model. Taken together, these results suggest that oridonin may be a potential anticancer agent for the treatment of esophageal cancer.
Social and community program approaches to participants: Exploring best practices
Authors: Minas Maria , Ribeiro Maria Teresa , Anglin James P.
Published: September 2018

This article presents the results of a deepened study of the best practices and outcomes of 15 programs (across 9 countries) that work with socioeconomically disadvantagedd communities. Using thematic analysis, we identified best practices that participants, community leaders, and professionals recognized as key. Data collection involved in loco observation and semistructured interviews with participants and professionals, and focus groups with professionals. Associated with best practices, programs adopted two central perspectives on approaching participants: approaching participants as users and approaching participants as contributors. Such approaches were crossed with best practices and outcomes identified througout the analysis. For programs that approached participants as users, the best practices were valuing, facilitating the access to resources, showing availability, and promoting competencies and openness, and the main outcome was participants’ improved self‐confidence. For programs that approached participants as contributors, the best practices were contributing, encouraging participation, valuing participants, becoming masters, and reciprocity, and the main outcome was participants having an impact.
A critical role of the transient receptor potential melastatin 2 channel in a positive feedback mechanism for reactive oxygen species‐induced delayed cell death
Authors: Li Xin , Jiang Lin‐Hua
Published: September 2018

Transient receptor potential melastatin 2 (TRPM2) channel activation by reactive oxygen species (ROS) plays a critical role in delayed neuronal cell death, responsible for postischemia brain damage via altering intracellular Zn2+ homeostasis, but a mechanistic understanding is still lacking. Here, we showed that H2O2 induced neuroblastoma SH‐SY5Y cell death with a significant delay, dependently of the TRPM2 channel and increased [Zn2+]i, and therefore used this cell model to investigate the mechanisms underlying ROS‐induced TRPM2‐mediated delayed cell death. H2O2 increased concentration‐dependently the [Zn2+]i and caused lysosomal dysfunction and Zn2+ loss and, furthermore, mitochondrial Zn2+ accumulation, fragmentation, and ROS generation. Such effects were suppressed by preventing poly(adenosine diphosphate ribose, ADPR) polymerase‐1‐dependent TRPM2 channel activation with PJ34 and 3,3′,5,5′‐tetra‐tert‐butyldiphenoquinone, inhibiting the TRPM2 channel with 2‐aminoethoxydiphenyl borate (2‐APB) and N‐(p‐amylcinnamoyl)anthranilic acid, or chelating Zn2+ with N,N,N,N‐tetrakis(2‐pyridylmethyl)‐ethylenediamine (TPEN). Bafilomycin‐induced lysosomal dysfunction also resulted in mitochondrial Zn2+ accumulation, fragmentation, and ROS generation that were inhibited by PJ34 or 2‐APB, suggesting that these mitochondrial events are TRPM2 dependent and sequela of lysosomal dysfunction. Mitochondrial TRPM2 expression was detected and exposure to ADPR‐induced Zn2+ uptake in isolated mitochondria, which was prevented by TPEN. H2O2‐induced delayed cell death was inhibited by apocynin and diphenyleneiodonium, nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) oxidase (NOX) inhibitors, GKT137831, an NOX1/4‐specific inhibitor, or Gö6983, a protein kinase C (PKC) inhibitor. Moreover, inhibition of PKC/NOX prevented H2O2‐induced ROS generation, lysosomal dysfunction and Zn2+ release, and mitochondrial Zn2+ accumulation, fragmentation and ROS generation. Collectively, these results support a critical role for the TRPM2 channel in coupling PKC/NOX‐mediated ROS generation, lysosomal Zn2+ release, and mitochondrial Zn2+ accumulation, and ROS generation to form a vicious positive feedback signaling mechanism for ROS‐induced delayed cell death.
Association of the genetic polymorphisms in immunoinflammatory microRNAs with risk of ischemic stroke and subtypes in an Iranian population
Authors: Darabi Hassan , Salmaninejad Arash , Jaripour Mohamad Ehsan , Azarpazhooh Mahmoud reza , Mojarrad Majid , Sadr‐Nabavi Ariane
Published: September 2018

Stroke is one of the most common type of cerebrovascular disease threatening human health and life with high mortality, disability, and morbidity. Ischemic stroke (IS) is determined to be a complex disease containing a group of heterogeneous disorders with various environmental and genetic risk factors. This study evaluated the polymorphisms of microRNAs involved in inflammatory routes leading to stroke in an Iranian population. This study evaluated the associations of hsa‐mir‐608 C/G rs4919510, hsa‐mir‐499 A/G rs3746444, and hsa‐mir‐145 C/T rs190323149 polymorphisms in precursor miRNAs with the risk of IS. These microRNA polymorphisms were analyzed in 470 patients with IS and 489 control subjects. The TOAST criteria was applied for IS subtypes classification. The frequency of the allele G of hsa‐mir‐499/rs3746444 A/G revealed significant association with IS in comparison with controls (
p < 0.0001, OR = 1.838, 95% CI = 1.406–2.401). Increased IS risks were associated with hsa‐mir‐499/ rs3746444 A/G genotypes in diverse genetic model (homozygote comparison:
p = 0.004, OR = 2.136, 95% CI = 1.269–3.597; heterozygote comparison:
p = 0.029, OR = 1.373, 95% CI = 1.033–1.825). Statistical analysis in IS subtypes showed that cardio‐embolic patients compared with other subtypes (large artery atherosclerosis and lacunar) had higher frequency of G allele (LAA vs. CEI,
p = 0.017; LAC vs. CEI,
p = 0.009), AG genotype (LAA vs. CEI,
p = 0.016; LAC vs. CEI,
p = 0.013). Nevertheless, this study did not find any association between the alleles and genotypes of mir‐608 C/G rs4919510 SNP and IS, respectively (
p > 0.05). The current investigation provided verification that hsa‐mir‐499 rs3746444 A/G polymorphism may be associated with a significantly increased risk of IS in an Iranian population.
Pyruvate dehydrogenase kinase 1 contributes to cisplatin resistance of ovarian cancer through EGFR activation
Authors: Zhang Meng , Cong Qing , Zhang Xiao‐Yan , Zhang Ming‐Xing , Lu Ying‐Ying , Xu Cong‐Jian
Published: September 2018

Patients with ovarian cancer frequently develop acquired drug resistance after the long‐term chemotherapy, leading to disease progression. Enhanced epithelial–mesenchymal transition (EMT) has been implicated in chemoresistance of ovarian cancer cells; however, the molecular mechanisms involved are largely undefined. Pyruvate dehydrogenase kinase 1 (PDK1), a key regulatory enzyme in glucose metabolism, has been recognized as a gatekeeper of the Warburg effect, a hallmark of cancer. In this study, the function of PDK1 in cisplatin resistance of ovarian cancer in terms of growth and EMT was investigated. PDK1 was upregulated in cisplatin‐resistant ovarian cancer cells. PDK1 knockdown in resistant cells led to increased sensitivity to cisplatin‐induced cell death and apoptosis. PDK1 downregulation also reversed the EMT and cell motility in cisplatin‐resistant cells. In a mouse xenograft model, tumors derived from PDK1‐silenced ovarian cancer cells exhibited decreased tumor growth and EMT compared with control after the cisplatin treatment. Mechanistically, PDK1 overexpression led to increased phosphorylation of EGFR, and blocking EGFR kinase activity by erlotinib reversed cisplatin resistance induced by PDK1 overexpression. Furthermore, in patients with ovarian cancer, higher PDK1 and p‐EGFR levels were associated with chemoresistance. These results supported that PDK1 contributes to chemoresistance of ovarian cancer by activating EGFR. Therefore, PDK1 may serve as a promising target to combat chemoresistance of ovarian cancer.
Melatonin and pancreatic cancer: Current knowledge and future perspectives
Authors: Tamtaji Omid Reza , Mirhosseini Naghmeh , Reiter Russel J. , Behnamfar Morteza , Asemi Zatollah
Published: September 2018

Pancreatic cancer has a high mortality rate due to the absence of early symptoms and subsequent late diagnosis; additionally, pancreatic cancer has a high resistance to radio‐ and chemotherapy. Multiple inflammatory pathways are involved in the pathophysiology of pancreatic cancer. Melatonin an indoleamine produced in the pineal gland mediated and receptor‐independent action is the pancreas and other where has both receptors. Melatonin is a potent antioxidant and tissue protector against inflammation and oxidative stress. In vivo and in vitro studies have shown that melatonin supplementation is an appropriate therapeutic approach for pancreatic cancer. Melatonin may be an effective apoptosis inducer in cancer cells through regulation of a large number of molecular pathways including oxidative stress, heat shock proteins, and vascular endothelial growth factor. Limited clinical studies, however, have evaluated the role of melatonin in pancreatic cancer. This review summarizes what is known regarding the effects of melatonin on pancreatic cancer and the mechanisms involved.
Retracted: LncRNA CRNDE promotes hepatocellular carcinoma cell proliferation, invasion, and migration through regulating miR‐203/BCAT1 axis
Authors: Ji Degang , Jiang Chengwei , Zhang Lirong , Liang Na , Jiang Tiechao , Yang Bin , Liang Haiying
Published: September 2018

Objective

To investigate the impact of long noncodingRNA (lncRNA) colorectal neoplasia differentially expressed (CRNDE) on hepatocellular cancer (HCC) cell propagation, invasion, and migration by mediating miR‐203/
BCAT1 axis.

Methods

Microarray analysis was based on 25 pairs of HCC cancerous tissues and adjacent tissues. The expression levels of CRNDE, miR‐203, and BCAT1 in HCC tissues were analyzed by quantitative real‐time polymerase chain reaction (qRT‐PCR). The liver cell line L‐02 and HCC cell lines HepG2 and Huh‐7 were utilized to assess the regulatory eﬀects of CRNDE and miR‐203 on HCC progression in vitro. Western blot was used to qualify BCAT1 protein expression level. Cell proliferation and apoptosis were evaluated using CCK‐8 and flow cytometry analysis, whereas cell invasion and migration assay were performed by the Transwell assay. The relationship among CRNDE, miR‐203, and
BCAT1 was validated by dual luciferase assay. Tumor Xenograft study was established to verify the pathological effect of CRNDE on HCC development in vivo.

Results

The expression levels of the CRNDE and BCAT1 were upregulated in HCC tissues and cells, whereas miR‐203 was downregulated in HCC. Knockdown of CRNDE or miR‐203 overexpression would inhibit HCC cell propagation and metastasis, and induced cell apoptosis. Moreover, miR‐203 was negatively correlated with CRNDE, the same as miR‐203 with
BCAT1. Dual luciferase assay showed that miR‐203 was an inhibitory target of CRNDE, and
BCAT1 was directly targeted by miR‐203 as well.

Conclusion

LncRNA CRNDE could enhance HCC tumorgenesis by sponging miR‐203 and mediating BCAT1. LncRNA CRNDE might facilitate HCC cell propagation, invasiveness, and migration through regulating miR‐203/
BCAT1 axis.
Chloride channel‐3 mediates multidrug resistance of cancer by upregulating P‐glycoprotein expression
Authors: Chen Qi , Liu Xueqiang , Luo Zhesi , Wang Shisi , Lin Jialin , Xie Zheng , Li Mengge , Li Chunmei , Cao Hua , Huang Qingsong , Mao Jianwen , Xu Bin
Published: September 2018

Chloride channel‐3 (ClC‐3), a member of the ClC family of voltage‐gated Cl− channels, is involved in the resistance of tumor cells to chemotherapeutic drugs. Here, we report a new mechanism for ClC‐3 in mediating multidrug resistance (MDR). ClC‐3 was highly expressed in the P‐glycoprotein (P‐gp)‐dependent human lung adenocarcinoma cell line (A549)/paclitaxel (PTX) and the human breast carcinoma cell line (MCF‐7)/doxorubicin (DOX) resistant cells. Changes in the ClC‐3 expression resulted in the development of drug resistance in formerly drug‐sensitive A549 or MCF‐7 cells, and drug sensitivity in formerly drug‐resistant A549/Taxol and MCF‐7/DOX cells. Double transgenic MMTV‐PyMT/CLCN3 mice with spontaneous mammary cancer and ClC‐3 overexpression demonstrated drug resistance to PTX and DOX. ClC‐3 expression upregulated the expression of MDR1 messenger RNA and P‐gp by activating the nuclear factor‐κB (NF‐κB)‐signaling pathway. These data suggest that ClC‐3 expression in cancer cells induces MDR by upregulating NF‐κB‐signaling‐dependent P‐gp expression involving another new mechanism for ClC‐3 in the development of drug resistance of cancers.
Short‐term effects of levosimendan on strain/strain rate markers in patients with nonischemic dilated cardiomyopathy
Authors: Kırış Tuncay , Avcı Eyüp
Published: September 2018

Objective

To investigate whether repetitive measurements of speckle tracking echocardiography (STE)‐derived strain (S) and strain rate (SR) could reveal changes in left ventricular function in patients with nonischemic dilated cardiomyopathy treated with levosimendan.

Methods

We included 22 consecutive patients (age 53 ±12 years) with an ejection fraction (EF) below 35% and New York Heart Association (NYHA) class III‐IV symptoms that required intravenous inotropic support despite optimal medical therapy. The absence of any occlusive coronary artery disease was identified via previous coronary angiography in all patients. Echocardiographic variables, including strain/strain rate, and NYHA functional class, were evaluated before and after levosimendan infusion at the 72nd hour and one month.

Results

The strain and strain rate values for both left and right ventricles were observed to be increased NYHA functional class and left ventricular EF (P <.05).

Conclusion

STE can successfully completed conventional echocardiography in the evaluation of patients with decompensated heart failure who were treated with levosimendan.
Modification of a modulated arc total body irradiation technique: Implementation and first clinical experience for paediatric patients
Authors: Pemberton Melanie , Brady Carole , Taylor Beth , Tyrrell Danielle , Sim Lucy , Zawlodzka‐Bednarz Sylwia , Biggs Jennifer , Peters Mitchell , Baines John , Hargrave Catriona
Published: September 2018

Introduction

To implement the modulated arc total body irradiation (MATBI) technique within the existing infrastructure of a radiation oncology department. The technique needed to treat paediatric patients of all ages, some of whom would require general anaesthesia (GA).

Methods

The MATBI technique required minor modifications to be incorporated within existing departmental infrastructure. Ancillary equipment essential to the technique were identified and in some cases custom designed to meet health and safety criteria. GA equipment was also considered. To evaluate the effectiveness of the implemented technique, an audit of the cases clinically treated was conducted.

Results

A motorised treatment couch was designed to allow the patient to be positioned in stabilisation equipment at a height, then lowered to the floor to accommodate source‐to‐skin‐distances from 180 cm to 198 cm to treat the fixed 40 cm × 40 cm field size. Treatment couch design also facilitated positioning of the bespoke two‐part spoiler. While organ at risk dose is limited using a beam weight optimisation technique, the dose is further reduced using compensators placed close to the patient's skin on a 3D printed custom‐made support bridge. A digital radiography system is used to verify compensator position. Fifteen patients have been treated to date for various diseases using a variety of dose fractionations ranging from 2 Gy in a single fraction to 12 Gy in 6 fractions. Five patients have required GA due to age or behavioural issues.

Conclusion

The modified MATBI technique and the equipment required for treatment delivery has been found to be well tolerated by all patients.
Prevalence of thyroid stimulating hormone dysfunction among sofosbuvir‐treated HCV‐infected patients: A real‐world clinical experience
Authors: Wahid Braira , Waqar Muhammad , Rasool Nouman , Wasim Muhammad , Khalid Ifrah , Idrees Muhammad
Published: September 2018

Thyroid dysfunctions occur frequently among hepatitis C virus (HCV)‐infected patients. Accumulating evidence has shown the higher incidence of thyroid dysfunctions in interferon‐treated patients that was previously the standard of care therapy. However, the prevalence of thyroid disorders has not been studied in the recently developed interferon‐free regimens or direct‐acting antiviral (DAA) drugs‐treated patients. We recruited 37 patients who had just completed 6 months long sofosbuvir‐based treatment, and 26 interferon‐treated patients were also included in the study. Serum thyrotropin level of all participants was measured using VIDAS. We observed thyroid dysfunctions in both pegylated interferon–experienced and DAA drug–experienced patients but the prevalence of hyperthyroidism was found significantly higher in patients treated with interferon‐based regimen as compared with interferon‐free regimens. This high prevalence of hypothyroidism in patients with HCV posttreatment highlights the need for regular periodic screening of patients during the treatment.
The Experience of Insight Facilitates Long‐Term Semantic Priming in the Right Hemisphere
Authors: Kraus Brian , Holtgraves Thomas
Published: September 2018

While past research has demonstrated a link between the subjective “Aha” experience of insight and verbal insight problem solution activation in the right hemisphere (RH), no one has yet linked insight to long term semantic priming. We propose that through a shared process of semantic integration both of these concepts are linked and thus the experience of insight should facilitate semantic priming in the RH. Participants attempted to solve a group of compound remote associate problems and afterwards completed a lexical decision task. The results showed that the experience of insight facilitated semantic priming in the RH, but only for unsolved compound remote associate problems. It was also shown that participants who indicated that they generated more solutions through insight that were incorrect demonstrated the most semantic priming in the RH. These results indicate that long‐term semantic priming can occur as a result of insight solutions, and that this activation occurs predominantly in the RH. This study extends both the evidence for long‐lasting semantic priming as well the theory of coarse semantic coding in the RH.
Determination of nitenpyram and 6‐chloronicotinic acid in environmental samples by ion chromatography coupled with online photochemically induced fluorescence detector
Authors: Muhammad Nadeem , Zhang Yun , Li Weixia , Zhao Yong‐Gang , Ali Amjad , Subhani Qamar , Mahmud Tariq , Liu Junwei , Cui Hairong , Zhu Yan
Published: September 2018

A simple, cost‐effective, sensitive, and quick method for the determination of nitenpyram and its metabolite 6‐chloronicotinic acid in environmental samples was developed by coupling an ion chromatograph with a fluorescence detector and a post‐column photochemical reactor. This developed analytical method involved a rapid sample extraction by modified and miniaturized quick, easy, cheap, effective, rugged, and safe method followed by isocratic ion chromatographic separation of nitenpyram and 6‐chloronicotinic acid into an IonPac™ AS11‐HC column protected by IonPac™ AG11A guard column by running 30 mM NaOH + 10% acetonitrile mobile phase. A homemade post‐column photochemical reactor was also integrated with the ion chromatographic system for online transformation of both analytes into their respective highly fluorescent photoproduct in basic media without using an extra pump. The developed method was validated by following SANTE/11945/2015 guidelines on analytical quality control and validation procedures. The method showed a good linear response (r > 0.999), improved limit of detection (0.101–0.132 μg/L), minimum or no matrix effect, excellent recoveries (90.2–100.10%) and relative standard deviations were found to be ≤6.50%.
Electronic medical record–based tools aid in timely triage of disc‐shaped foreign body ingestions
Authors: Lavin Jennifer M. , Wiedermann Joshua , Sals Alexandra , Kato Kimberly , Brinson Dusty , Nytko Agata , Katsogridakis Yiannis , Krug Steven , Ida Jonathan
Published: September 2018

Objectives/Hypothesis

Children presenting to the emergency department with coin‐shaped foreign body (FB) ingestion must be evaluated urgently to rule out a button battery. As many of these ingestions are well‐appearing on presentation, delays in triage put patients at risk for further injury.

Study Design

Quality initiative.

Methods

A quality initiative, utilizing electronic medical record (EMR)‐based tools, was implemented at our academic children's hospital. A chief complaint pertaining to coin‐shaped FB ingestion was created and was linked to a best practice advisory, instructing assignment of acuity level 2 and the order of a Stat x‐ray. A link to the hospital's relevant algorithm was provided. A review was conducted comparing children who underwent FB removal preinitiative (January 1, 2016–January 28, 2017) and postinitiative (January 31, 2017–August 30, 2017). Primary outcomes were frequency of assignment of acuity level 2 and time from patient arrival to x‐ray order placement and x‐ray completion.

Results

Thirty‐six patients in the baseline group and 30 in the postintervention group underwent FB removal. The rate of appropriate acuity assignment increased from 63.8% (23/36) pre implementation to 100% (30/30) postimplementation (P = .0003). Median time from arrival to imaging ordered and completed decreased from 36.5 to 4 minutes (95% confidence interval [CI]: −44 to −17) and 59 to 41 minutes (95% CI: −39 to −1), respectively.

Conclusions

Utilization of EMR‐based tools was associated with improved timeliness in initiation of care in metallic FB ingestion patients. Further initiatives will be aimed at downstream events in the diagnosis and treatment of these patients.

Level of Evidence

NA Laryngoscope, 128:2697–2701, 2018
Fabrication and characterization of 3D‐printed elastic auricular scaffolds: A pilot study
Authors: Kim Ha Yeong , Jung Soo Yeon , Lee Sang Jin , Lee Hyun Jung , Truong Minh‐Dung , Kim Han Su
Published: September 2018

Objective

Aesthetic reconstruction of the external ear is challenging due to the complex anatomical shape of the auricle. Recently, artificial scaffolds such as Medpor (Stryker, Kalamasoo, MI, USA) have become widely used in ear reconstruction. However, the Medpor scaffold is stiffer than the natural ear, which may lead to discomfort, and moreover has uniform design for every patient. In this study, we investigated whether three‐dimensional (3D)‐printed artificial polyurethane (PU) scaffolds are suitable for auricular reconstruction.

Methods

PU scaffolds were fabricated using 3D printing according to a design derived from a digital imaging and communications in medicine (DICOM) image of the human auricle. The microstructure of the scaffolds was observed using scanning electron microscopy, and the porosity was examined. Cell proliferation on the scaffolds was assessed in vitro using tonsil‐derived mesenchymal stem cells to evaluate the biocompatibility of the scaffolds. The scaffolds were implanted in C57BL/6 mice, and histological analysis was performed.

Results

The structural study revealed that the 3D‐printed porous PU scaffolds have rectangular microstructure with regular pitch and line, as well as high porosity (56.46% ± 10.22%) with a pore diameter of 200 µm. The mechanical properties of the 3D‐printed PU scaffolds were similar to those of the human auricle cartilage. Cell proliferation on the PU scaffolds was greater than that on Medpor scaffolds. Histological evaluation demonstrated that the porous parts of the PU scaffolds became filled with collagen and vascular tissue.

Conclusion

Elastic, porous PU scaffolds can be obtained using 3D printing, have biomechanical properties similar to those of the natural ear, and are suitable for use in auricular reconstruction.

Level of Evidence

NA Laryngoscope, 129:351–357, 2019
Voice Outcome Measures for Adult Patients With Unilateral Vocal Fold Paralysis: A Systematic Review
Authors: Walton Chloe , Carding Paul , Conway Erin , Flanagan Kieran , Blackshaw Helen
Published: September 2018

Objectives

Unilateral vocal fold paralysis (UVFP) typically results in marked changes in voice quality and performance and has a significant impact on quality of life. Treatment approaches generally aim to restore glottal closure for phonation and improve vocal function. There are a wide range of voice outcome measures that are available to measure the treatment effect. Careful selection of voice outcome measures is required to ensure that they are adequate for purpose and are psychometrically sound to detect the treatment effect. This article aims to critically evaluate the literature for voice outcome measures that are used for patients with UVFP.

Study Design

Systematic review.

Methods

Nine databases were searched for UVFP treatment studies published since 2003 (n = 2,484 articles). These articles and their references were screened using inclusion/exclusion criteria, including population characteristics, treatment, voice outcomes, and study findings. Data from the included articles was extracted and appraised with respect to multidimensionality, timing, selection rationale, validity, reliability, and responsiveness to change of the voice outcome measures.

Results

A total of 29 studies met the inclusion criteria for the systematic review. These studies showed considerable variability in the rationale, selection, and application of voice outcome measures for reporting the treatment effect for patients with UVFP.

Conclusion

There is currently a significant disparity in the selection and use of voice outcome measures for patients with UVFP. A set of principles around selection rationale, validity, reliability, and responsiveness to change is proposed to enhance the judicious selection of voice outcome measures for this patient group. Laryngoscope, 129:187–197, 2019
Determination of Iodine Value in Hydrogenated Oils: Comparison of Titration and Gas Chromatography with Flame‐Ionization Detection Methodologies
Authors: Kotoski Shaun P. , Srigley Cynthia T.
Published: September 2018

The United States Food and Drug Administration (FDA) recently issued its final determination that partially hydrogenated oils (PHO) are no longer generally recognized as safe (GRAS) for any use in human food. Consequently, the discrimination between PHO and fully hydrogenated oils (FHO), which is achieved by the iodine value (IV), has become an important regulatory issue. This study compared American Oil Chemists’ Society (AOCS) and International Organization for Standardization (ISO) titration and gas chromatography with flame‐ionization detection (GC‐FID) methodologies for the determination of IV in seven samples of hydrogenated oil, namely coconut, cottonseed (n = 2), palm kernel, palm stearine, and soybean (n = 2) oils. Titrations produced statistically higher IV determinations than those achieved by GC‐FID, for all samples except the FH coconut oil. The unsaponifiable matter content of the hydrogenated oils, which varied from 0.15% to 0.47% of total fat, likely contributed modest increases to the IV by titration. Both methodologies were prone to issues at low IV (~4), with titrations showing greater variability, and GC‐FID being susceptible to incomplete separation, identification, and quantification of all unsaturated fatty acids. The variability observed with titrations could be minimized by careful execution of the titration protocol. Although both approaches successfully discriminated PHO and FHO in the test materials, at low IV (~4), titration is the most accurate method for determining the IV, and the only approach that has been validated in oils with a very low IV (<1).
Multidecadal climate‐induced changes in Arctic tundra lake geochemistry and geomorphology
Authors: Drake Travis W. , Holmes Robert M. , Zhulidov Alexander V. , Gurtovaya Tatiana , Raymond Peter A. , McClelland James W. , Spencer Robert G. M.
Published: September 2018

Abstract

High‐latitude lakes are sensitive indicators of climate and important ecological components of Northern landscapes. The response of Arctic lakes to accelerated 20th century warming has largely been inferred from paleolimnological and shorter‐term observational studies (< 20 yr). Here, we present a long‐term observational dataset outlining a suite of chemical, biological, and physical changes in three Russian tundra lakes over a 43‐yr period (1953–1996). In all three lakes, epilimnetic water temperature, alkalinity, and calculated pCO2, measured during the ice‐free period in late summer, increased over time. Over the same period, the rates of primary and bacterial production increased significantly. Permafrost thaw at the base and margins of the lakes likely resulted in the observed increase in size, as measured by average depth, surface area, and total volume. The observed changes show strong correlation with temperature, suggesting an overall pronounced response to warming. Importantly, CO2 sourced from either in situ or allochthonous respiration of thawed permafrost would indicate the destabilization of a large C reservoir.
Facile Photochemical Modification of Silk Protein–Based Biomaterials
Authors: Hardy John G. , Bertin Annabelle , Torres‐Rendon Jose Guillermo , Leal‐Egaña Aldo , Humenik Martin , Bauer Felix , Walther Andreas , Cölfen Helmut , Schlaad Helmut , Scheibel Thomas R.
Published: September 2018

Silk protein–based materials show promise for application as biomaterials for tissue engineering. The simple and rapid photochemical modification of silk protein–based materials composed of either Bombyx mori silkworm silk or engineered spider silk proteins (eADF4(C16)) is reported. Radicals formed on the silk‐based materials initiate the polymerization of monomers (acrylic acid, methacrylic acid, or allylamine) which functionalize the surface of the silk materials with poly(acrylic acid) (PAA), poly(methacrylic acid) (PMAA), or poly(allylamine) (PAAm). To demonstrate potential applications of this type of modification, the polymer‐modified silks are mineralized. The PAA‐ and PMAA‐functionalized silks are mineralized with calcium carbonate, whereas the PAAm‐functionalized silks are mineralized with silica, both of which provide a coating on the materials that may be useful for bone tissue engineering, which will be the subject of future investigations.
Magnolin targeting of ERK1/2 inhibits cell proliferation and colony growth by induction of cellular senescence in ovarian cancer cells
Authors: Song Ji‐Hong , Lee Cheol‐Jung , An Hyun‐Jung , Yoo Sun‐Mi , Kang Han C. , Lee Joo Y. , Kim Kwang D. , Kim Dae J. , Lee Hye S. , Cho Yong‐Yeon
Published: September 2018

Ras/Raf/MEKs/ERKs and PI3 K/Akt/mTOR signaling pathways have key roles in cancer development and growth processes, as well as in cancer malignance and chemoresistance. In this study, we screened the therapeutic potential of magnolin using 15 human cancer cell lines and combined magnolin sensitivity with the CCLE mutaome analysis for relevant mutation information. The results showed that magnolin efficacy on cell proliferation inhibition were lower in TOV‐112D ovarian cancer cells than that in SKOV3 cells by G1 and G2/M cell cycle phase accumulation. Notably, magnolin suppressed colony growth of TOV‐112D cells in soft agar, whereas colony growth of SKOV3 cells in soft agar was not affected by magnolin treatment. Interestingly, phospho‐protein profiles in the MAPK and PI3 K signaling pathways indicated that SKOV3 cells showed marked increase of Akt phosphorylation at Thr308 and Ser473 and very weak ERK1/2 phosphorylation levels by EGF stimulation. The phospho‐protein profiles in TOV‐112D cells were the opposite of those of SKOV3 cells. Importantly, magnolin treatment suppressed phosphorylation of RSKs in TOV‐112D, but not in SKOV3 cells. Moreover, magnolin increased SA‐β‐galactosidase‐positive cells in a dose‐dependent manner in TOV‐112D cells, but not in SKOV3 cells. Notably, oral administration of Shin‐Yi fraction 1, which contained magnolin approximately 53%, suppressed TOV‐112D cell growth in athymic nude mice by induction of p16Ink4a and p27Kip1. Taken together, targeting of ERK1 and ERK2 is suitable for the treatment of ovarian cancer cells that do not harbor the constitutive active P13 K mutation and the loss‐of‐function mutations of the p16 and/or p53 tumor suppressor proteins.
Unraveling the molecular effect of a rare missense mutation in BRIP1 associated with inherited breast cancer
Authors: Velázquez Carolina , Esteban‐Cardeñosa Eva M. , Lastra Enrique , Abella Luis E. , de la Cruz Virginia , Lobatón Carmen D. , Durán Mercedes , Infante Mar
Published: September 2018

BRIP1 is a component of the Fanconi Anemia/BRCA pathway responsible for DNA reparation via helicase activity. Some heterozygous variants in BRIP1 could contribute to Hereditary Breast Cancer through a defective DNA repair. The clinical utility of BRIP1 mutations in a familial cancer context is compromised by the conflicting interpretation of “variants of uncertain significance” (VUS). Defining the clinical significance of variants identified in genetic tests is a major challenge; therefore, studies that evaluate the biological effect of these variants are definitely necessary. To contribute to this purpose, we have characterized the variant c.550G>T of BRIP1, a missense mutation with little evidence about its pathogenicity. Since Human Splicing FinderTM predicts the creation of a new exonic splicing enhancer site we decided to perform cDNA analysis revealing that the c.550G>T mutation located in exon 6 led to an aberrant transcript causing exon 5 skipping. Our results demonstrate that the c.550G>T BRIP1 variant disrupts normal splicing, causing exon 5 skipping. Considering that the exon 5 encodes the helicase domain of BRIP1, it is expected an alteration of the function. This finding enhances the interpretation of this VUS, suggesting a potential pathogenic effect.
Innovation by design: SPARK and the Overcoming of Stanford University's Translational “Valley of Death” in Bio‐Medicine
Authors: Etzkowitz Henry , Mack Alex , Schaffer Thomas , Scopa Jim , Guo Lei , Pospelova Tatiana
Published: September 2018

Stanford University's world leadership as an entrepreneurial university induced a “paradox of success,” inhibiting further development of its organizational infrastructure for entrepreneurship support. Nevertheless, some prospective academic entrepreneurs realized that there were invisible persisting gaps in the university's innovation system. We discuss the role of the entrepreneurial university and provide a case study of SPARK, an organizational innovation, created to address Stanford's translational research gap, that was then spread to other universities. The creation of a support structure to encourage students and faculty to define entrepreneurial projects as part of their education and research revealed a novel organizational change dynamic.
Neurobiology of placebo effect in Parkinson's disease: What we have learned and where we are going
Authors: Quattrone Aldo , Barbagallo Gaetano , Cerasa Antonio , Stoessl A. Jon
Published: September 2018

The placebo effect is a phenomenon produced when an inert substance administered like a regular treatment improves the clinical outcome. Parkinson's disease (PD) is one of the main clinical disorders for which the placebo response rates are high. The first evidence of the neurobiological mechanisms underlying the placebo effect in PD stems from 2001, when de la Fuente‐Fernandez and colleagues demonstrated that a placebo injection led to the release of dopamine in the striatal nuclei of PD measured with positron emission tomography technology. Since then, several studies have been conducted to investigate the neurobiological underpinnings of placebo responses. This article presents a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta‐Analysis guidelines. Of an initial yield of 143 papers, 19 were included. The lessons learned from these studies are threefold: (i) motor improvement is dependent on the activation of the entire nigrostriatal pathway induced by dopamine release in the dorsal striatum; (ii) the magnitude of placebo‐induced effects is modulated by an expectancy of improvement, which is in turn related to the release of dopamine within the ventral striatum; (iii) the functioning of the neural pathways underlying the placebo response can be tuned by prior exposure and learning strategies. In conclusion, although the neural network underlying the placebo effect in PD has been largely confirmed and accepted, what remains to be established is how, when, and where the expectation of reward (mediated by the ventral striatum) interacts with the primary motor system (mediated by the dorsal striatum) to induce clinical improvement in motor symptoms. © 2018 International Parkinson and Movement Disorder Society