bluuebunny/crossref_metadata_2025 huggingface dataset:
A cellular perspective of adipogenesis transcriptional regulation
Authors: Kuri‐Harcuch Walid , Velez‐delValle Cristina , Vazquez‐Sandoval Alfredo , Hernández‐Mosqueira Claudia , Fernandez‐Sanchez Veronica
Published: August 2018

Adipose cells store lipids in the cytoplasm and signal systemically through secretion of adipokines and other molecules that regulate body energy metabolism. Differentiation of fat cells and its regulation has been the focus of extensive research since the early 1970s. In this review, we had attempted to examine the research bearing on the control of adipose cell differentiation, some of it dating back to the early days when Howard Green and his group described the preadipocyte cell lines 3T3‐L1 and 3T3‐F442A during 1974–1975. We also concentrated our attention on research published during the last few years, emphasizing data described on transcription factors that regulate adipose differentiation, outside of those that were reported earlier as part of the canonical adipogenic transcriptional cascade, which has been the subject of ample reviews by several groups of researchers. We focused on the studies carried out with the two preadipocyte cell culture models, the 3T3‐L1 and 3T3‐F442A cells that have provided essential data on adipose biology.
Retracted: Inhibitory role of large intergenic noncoding RNA‐ROR on tamoxifen resistance in the endocrine therapy of breast cancer by regulating the PI3K/Akt/mTOR signaling pathway
Authors: Lu Peng‐Wei , Li Lin , Wang Fang , Gu Yuan‐Ting
Published: August 2018

Breast cancer (BC) is the second‐leading cause of central nervous system metastases among severe malignancies. This study aimed at investigating the underlying mechanism by which large intergenic noncoding RNA‐regulator of reprogramming (lincRNA‐ROR) affects the tamoxifen (TAM) resistance of BC cells by regulating the PI3K/Akt/mTOR signaling pathway. Immortalized human mammary epithelial cell line (MCF10A) and BC cell lines (MCF‐7, MDA‐MB‐231, T47D, BCAP‐37, and ZK‐75‐1) were cultured, and BC tissues and adjacent normal breast tissues were collected from 152 BC patients. LincRNA‐ROR expression in tissues and cells were detected using reverse transcription quantitative polymerase chain reaction. RNA interference was used to silence lincRNA‐ROR in MDA‐MB‐231 cells, and then the cell proliferation and apoptosis were detected by 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assay and annexin‐V and propidium iodide (PI) double staining respectively. The expression of apoptosis‐related proteins and PI3K/Akt/mTOR signaling pathway–related proteins was measured by performing western blot assay. The BC tissues and cells presented a higher expression of lincRNA‐ROR. MAD‐MB‐231 cells exhibited the highest lincRNA‐ROR expression. After lincRNA‐ROR silencing, MAD‐MB‐231 cells showed decreased proliferation, and increased sensitivity to TAM. Besides, the apoptosis‐promoting effect of TAM on MAN‐MB‐231 cells significantly increased. The expression of PI3K/Akt/mTOR signaling pathway–related proteins and the PI3K/Akt/mTOR signaling pathway were repressed by TAM after silencing lincRNA‐ROR. Our study demonstrated that silencing lincRNA‐ROR could increase the sensitivity of BC MAD‐MB‐231 cells to TAM by suppressing the activation of P13K/Akt/mTOR signaling pathway.
The landscape of DNA methylation in hepatocellular carcinoma
Authors: Zheng Yong‐Fa , Lu Xiaojie , Zhang Xiao‐Yu , Guan Bu‐Gao
Published: August 2018

Better understanding of the relationship between changes in the overall methylation status of hepatocellular carcinoma (HCC) and disease progression will help us find good strategies for the early detection and treatment of HCC patients. The purpose of the study was to study the relations between the methylation status changes in HCC patients and progression of the disease to enable early detection and treatment of HCC patients. First, the DNA methylation data of 50 HCC samples and the surrounding normal samples were extracted and the change pattern of methylation status in the DNA promoter region of HCC samples against that of normal samples was studied. Then, some DNA methylation genes that could accurately identify cancer and cancer‐adjacent tissues were identified using the k‐top scoring pair method. Also, a prognostic signature that could predict the survival of HCC patients was constructed based on the overall survival time and death information of the early HCC patients. Finally, the obtained prognostic signature was verified. In conclusion, this study described the changes in the methylation spectrum during the development of HCC and identified genes associated with HCC progression and prognosis, which may offer new opportunities for the diagnosis and treatment of HCC.
Chondrocyte mTORC1 activation stimulates miR‐483‐5p via HDAC4 in osteoarthritis progression
Authors: Wang Hua , Zhang Haiyan , Sun Qiuyi , Yang Jian , Zeng Chun , Ding Changhai , Cai Daozhang , Liu Anling , Bai Xiaochun
Published: August 2018

The hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1) in chondrocytes has been shown to accelerate the severity of destabilization of the medial meniscus‐induced and age‐related osteoarthritis (OA) phenotypes with aberrant chondrocyte hypertrophy and angiogenesis. Meanwhile, we previously reported that miR‐483‐5p is essential for the initiation and development of OA by stimulating chondrocyte hypertrophy and angiogenesis. The connection between mTORC1 and miR‐483‐5p activation in OA progression, however, remains unclear. In this study, we elucidated their relationship and identified the underlying mechanisms. The expression of miR‐483‐5p in the articular cartilage of cartilage‐specific TSC1 knockout mice was assessed compared with control mice using the Agilent Mouse miRNA (8*60K) V19.0 array and real‐time polymerase chain reaction (RT‐PCR). The functional effects of the stimulation of miR‐483‐5p via histone deacetylase 4 (HDAC4) by mTORC1 in OA development, subsequently modulating its downstream targets matrilin 3 and tissue inhibitor of metalloproteinase 2, were examined by immunostaining, western blotting, and real‐time PCR. This study revealed that miR‐483‐5p was responsible for mTORC1 activation‐stimulated OA. Mechanistically, mTORC1 controls the HDAC4‐dependent expression of miR‐483‐5p to stimulate chondrocyte hypertrophy, extracellular matrix degradation, and subchondral bone angiogenesis, and it consequently initiates and accelerates the development of OA. Our findings revealed a novel mTORC1‐HDAC4‐miR‐483‐5p pathway that is critical for OA development.
Quercetin relieved diabetic neuropathic pain by inhibiting upregulated P2X4 receptor in dorsal root ganglia
Authors: Yang Runan , Li Lin , Yuan Huilong , Liu Hui , Gong Yingxin , Zou Lifang , Li Shunhua , Wang Zilin , Shi Liran , Jia Tianyu , Zhao Shanhong , Wu Bing , Yi Zhihua , Gao Yun , Li Guilin , Xu Hong , Liu Shuangmei , Zhang Chunping , Li Guodong , Liang Shangdong
Published: August 2018

The upregulation of nociceptive ion channels expressed in dorsal root ganglia (DRG) contributes to the development and retaining of diabetic pain symptoms. The flavonoid quercetin (3,3′,4′,5,7‐pentahydroxyflavone) is a component extracted from various fruits and vegetables and exerts anti‐inflammatory, analgesic, anticarcinogenic, antiulcer, and antihypertensive effects. However, the exact mechanism underlying quercetin's analgesic action remains poorly understood. The aim of this study was to investigate the effects of quercetin on diabetic neuropathic pain related to the P2X4 receptor in the DRG of type 2 diabetic rat model. Our data showed that both mechanical withdrawal threshold and thermal withdrawal latency in diabetic rats treated with quercetin were higher compared with those in untreated diabetic rats. The expression levels of P2X4 messenger RNA and protein in the DRG of diabetic rats were increased compared with the control rats, while quercetin treatment significantly inhibited such enhanced P2X4 expression in diabetic rats. The satellite glial cells (SGCs) enwrap the neuronal soma in the DRG. Quercetin treatment also lowered the elevated coexpression of P2X4 and glial fibrillary acidic protein (a marker of SGCs) and decreased the upregulation of phosphorylated p38 mitogen‐activated protein kinase (p38MAPK) in the DRG of diabetic rats. Quercetin significantly reduced the P2X4 agonist adenosine triphosphate‐activated currents in HEK293 cells transfected with P2X4 receptors. Thus, our data demonstrate that quercetin may decrease the upregulation of the P2X4 receptor in DRG SGCs, and consequently inhibit P2X4 receptor‐mediated p38MAPK activation to relieve the mechanical and thermal hyperalgesia in diabetic rats.
Loss of exosomal miR‐148b from cancer‐associated fibroblasts promotes endometrial cancer cell invasion and cancer metastasis
Authors: Li Bi‐Lan , Lu Wen , Qu Jun‐Jie , Ye Lei , Du Gui‐Qiang , Wan Xiao‐Ping
Published: August 2018

Cancer‐associated fibroblasts (CAFs) play crucial roles in tumor progression, given the dependence of cancer cells on stromal support. Therefore, understanding how CAFs communicate with endometrial cancer cell in tumor environment is important for endometrial cancer therapy. Exosomes, which contain proteins and noncoding RNA, are identified as an important mediator of cell–cell communication. However, the function of exosomes in endometrial cancer metastasis remains poorly understood. In the current study we found that CAF‐derived exosomes significantly promoted endometrial cancer cell invasion comparing to those from normal fibroblasts (NFs). We identified a significant decrease of miR‐148b in CAFs and CAFs‐derived exosomes. By exogenously transfect microRNAs, we demonstrated that miR‐148b could be transferred from CAFs to endometrial cancer cell through exosomes. In vitro and in vivo studies further revealed that miR‐148b functioned as a tumor suppressor by directly binding to its downstream target gene, DNMT1 to suppress endometrial cancer metastasis. In endometrial cancer DNMT1 presented a potential role in enhancing cancer cell metastasis by inducing epithelial–mesenchymal transition (EMT). Therefore, downregulated miR‐148b induced EMT of endometrial cancer cell as a result of relieving the suppression of DNMT1. Taken together, these results suggest that CAFs‐mediated endometrial cancer progression is partially related to the loss of miR‐148b in the exosomes of CAFs and promoting the transfer of stromal cell‐derived miR‐148b might be a potential treatment to prevent endometrial cancer progression.
Long noncoding RNA MALAT1 mediates cardiac fibrosis in experimental postinfarct myocardium mice model
Authors: Huang Songqun , Zhang Liang , Song Jingwen , Wang Zhongkai , Huang Xinmiao , Guo Zhifu , Chen Feng , Zhao Xianxian
Published: August 2018

Cardiac fibrosis is a pathological remodeling response to myocardial infarction (MI) and impairs cardiac contractility. Long noncoding RNA (lncRNA) metastasis‐associated lung adenocarcinoma transcript 1 (MALAT1) is increased in patients with MI. However, the functions of MALAT1 in cardiac fibrosis have not been elucidated. This study elucidates the roles of MALAT1 in MI and the underlying mechanisms. The MI model was established by artificial coronary artery occlusion in mice. Western blot analysis and quantitative reverse transcription‐polymerase chain reaction were performed to analyze protein expression and RNA expression, respectively. Cardiac function was measured by echocardiography. Masson’s trichrome staining was used to exhibit the fibrotic area in MI hearts. Cardiac fibroblasts were isolated from newborn pups, and cell proliferation was determined by 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assay. Upregulation of MALAT1 and downregulation of microRNA‐145 (miR‐145) were induced in MI heart and angiotensin II (AngII)‐treated cardiac fibroblasts, and the inhibition of miR‐145 expression was reversed by MALAT1 depletion. Knockdown MALAT1 ameliorated MI‐impaired cardiac function and prevented AngII‐induced fibroblast proliferation, collagen production, and α‐SMA expression in cardiac fibroblasts. MALAT1 stability and transforming growth factor‐β1 (TGF‐β1) activity were regulated by miR‐145. AngII‐induced TGF‐β1 activity in cardiac fibroblasts was blocked by MALAT1 knockdown. Based on these results, we concluded that lncRNA MALAT1 promotes cardiac fibrosis and deteriorates cardiac function post‐MI by regulating TGF‐β1 activity via miR‐145.
Antrodia salmonea‐induced oxidative stress abrogates HER‐2 signaling cascade and enhanced apoptosis in ovarian carcinoma cells
Authors: Yang Hsin‐Ling , Lin Ruei‐Wan , Rajendran Peramaiyan , Mathew Dony Chacko , Thigarajan Varadharajan , Lee Chuan‐Chen , Hsu Chih‐Jung , Hseu You‐Cheng
Published: August 2018

Antrodia salmonea is well known in Taiwan as a traditional Chinese medicinal fungus and has demonstrated antioxidant, anti‐inflammatory, and anticancer effects. However, the anticancer activity of A. salmonea against human ovarian cancer is still elusive. Therefore, we investigated the antiovarian tumor activity of a fermented culture broth of A. salmonea and exhibits its underlying molecular mechanism. A. salmonea shows a significant effect on cell viability in human ovarian carcinoma (SKOV‐3 or A2780) cell lines with an 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assay. Increased terminal deoxynucleotidyl transferase dUTP nick‐end labeling‐positive cells and annexin V–propidium iodide stained cells indicate that A. salmonea induces late apoptosis in SKOV‐3 cells. Notably, treatment with A. salmonea induced the following events: Apoptosis; caspase‐3, ‐8, ‐9 and poly(ADP‐ribose) polymerase activation; first apoptosis signal (Fas) and Fas ligand activation; Bid cleavage; and Bax2–B‐cell lymphoma 2 dysregulation. The results show that A. salmonea‐induced apoptosis was mediated by both mitochondrial and death receptor pathways. An increase in intracellular reactive oxygen species (ROS) was also observed in A. salmonea‐treated cells, whereas the antioxidant N‐acetylcysteine (NAC) prevented A. salmonea‐induced cell death and DNA fragmentation, indicating that A. salmonea‐induced apoptosis was mediated by ROS generation. Interestingly, A. salmonea‐induced apoptosis is associated with the suppression of human epidermal growth factor receptor‐2 (HER‐2/neu) and phosphoinositide 3‐kinase (PI3K)–protein kinase B (AKT) expression in HER‐2/neu overexpressing SKOV‐3 cells. NAC significantly prevented A. salmonea‐induced HER‐2/neu depletion and PI3K/AKT inactivation, indicating that A. salmonea‐triggered apoptosis is mediated by ROS‐inhibited HER‐2/neu signaling cascades. To our knowledge, this is the first report describing the anticancer activity of this potentially beneficial mushroom against human ovarian carcinoma.
Emerging role of circulating microRNA in the diagnosis of human infectious diseases
Authors: Ojha Rupal , Nandani Raj , Pandey Rajan Kumar , Mishra Amit , Prajapati Vijay Kumar
Published: August 2018

The endogenic microRNAs (miRNA) are evolutionary, conserved, and belong to a group of small noncoding RNAs with a stretch of 19–24 nucleotides. The miRNAs play an indispensable role in gene modulation at the posttranscriptional level, inclusive of stem‐cell differentiation, embryogenesis, hematopoiesis, metabolism, immune responses, or infections. The miRNAs secreted from the cells and their presence in the biological fluids signifies the regulatory role of circulating miRNAs in the pathogenesis. The phenomenal expression levels of circulating miRNAs in serum or plasma during infection makes them the potential therapeutic biomarkers for the diagnosis of assorted human infectious diseases. In this article, we have accentuated the methods for the profiling of circulating miRNA as well as the importance of miRNA as biomarkers for the diagnosis of human infectious diseases. To date, numerous biomarkers have been identified for the diagnostic or prognostic purpose; for instance, miR‐182, miR‐486, and miR15a in sepsis; miR‐320 and miR505 in inflammatory bowel disease; miR‐155 and miR‐1260 in influenza; miR‐12, miRVP‐3p, and miR‐184 in arboviruses; and miR‐29b and miR‐125 in hepatitis infection. Nevertheless, the noninvasive diagnostic approach, with the aid of biomarkers, currently plays a decisive role in the untimely diagnosis of human infections. So, in the near future, the exploitation of circulating miRNAs as therapeutic biomarkers for the diagnosis of human infections will help us to cure the associated diseases promptly and effectively.
hiPSC‐derived hepatocytes closely mimic the lipid profile of primary hepatocytes: A future personalised cell model for studying the lipid metabolism of the liver
Authors: Kiamehr Mostafa , Alexanova Anna , Viiri Leena E. , Heiskanen Laura , Vihervaara Terhi , Kauhanen Dimple , Ekroos Kim , Laaksonen Reijo , Käkelä Reijo , Aalto‐Setälä Katriina
Published: August 2018

Hepatocyte‐like cells (HLCs) differentiated from human‐induced pluripotent stem cells offer an alternative platform to primary human hepatocytes (PHHs) for studying the lipid metabolism of the liver. However, despite their great potential, the lipid profile of HLCs has not yet been characterized. Here, we comprehensively studied the lipid profile and fatty acid (FA) metabolism of HLCs and compared them with the current standard hepatocyte models: HepG2 cells and PHHs. We differentiated HLCs by five commonly used methods from three cell lines and thoroughly characterized them by gene and protein expression. HLCs generated by each method were assessed for their functionality and the ability to synthesize, elongate, and desaturate FAs. In addition, lipid and FA profiles of HLCs were investigated by both mass spectrometry and gas chromatography and then compared with the profiles of PHHs and HepG2 cells. HLCs resembled PHHs by expressing hepatic markers: secreting albumin, lipoprotein particles, and urea, and demonstrating similarities in their lipid and FA profile. Unlike HepG2 cells, HLCs contained low levels of lysophospholipids similar to the content of PHHs. Furthermore, HLCs were able to efficiently use the exogenous FAs available in their medium and simultaneously modify simple lipids into more complex ones to fulfill their needs. In addition, we propose that increasing the polyunsaturated FA supply of the culture medium may positively affect the lipid profile and functionality of HLCs. In conclusion, our data showed that HLCs provide a functional and relevant model to investigate human lipid homeostasis at both molecular and cellular levels.
Nanos2 promotes differentiation of male germ cells basing on the negative regulation of Foxd3 and the treatment of 5‐Azadc and TSA
Authors: Zhang Wenhui , Bi Yulin , Wang Yingjie , Wang Man , Li Dong , Cheng Shaoze , Jin Jing , Li Tingting , Li Bichun , Zhang Yani
Published: August 2018

The transcription factor positioning in promoter regions relate to gene regulation, and the level of DNA methylation and histone acetylation also impact the promoter activity. In this study, we tested and verified the core promoter region and key transcription factor of Nanos2 which is a male‐critical gene in the differentiation of embryonic stem cells to male germ cells, meanwhile, epigenetic effects by mean of 5‐Aza‐2′‐deoxycytidine (5‐Azadc) and Trichostin A (TSA) on the activity of Nanos2 promoter were detected. The results reveal that key transcription factor Foxd3 is a negative regulator of Nanos2, which suggests that loss‐of‐function of Foxd3 causes strong expression of Nanos2 responsive to large amounts of primordial germ cells and spermatogonial stem cells,whereas its overexpression causes the opposite effect. Furthermore, both 5‐Azadc and TSA can provoke responses of Nanos2, but the combination effect of the two is better.
The viral approach to breast cancer immunotherapy
Authors: Arab Atefeh , Behravan Nima , Razazn Atefeh , Barati Nastaran , Mosaffa Fatemeh , Nicastro Jessica , Slavcev Roderick , Behravan Javad
Published: August 2018

Despite years of intensive research, breast cancer remains the leading cause of death in women worldwide. New technologies including oncolytic virus therapies, virus, and phage display are among the most powerful and advanced methods that have emerged in recent years with potential applications in cancer prevention and treatment. Oncolytic virus therapy is an interesting strategy for cancer treatment. Presently, a number of viruses from different virus families are under laboratory and clinical investigation as oncolytic therapeutics. Oncolytic viruses (OVs) have been shown to be able to induce and initiate a systemic antitumor immune response. The possibility of application of a multimodal therapy using a combination of the OV therapy with immune checkpoint inhibitors and cancer antigen vaccination holds a great promise in the future of cancer immunotherapy. Display of immunologic peptides on bacterial viruses (bacteriophages) is also increasingly being considered as a new and strong cancer vaccine delivery strategy. In phage display immunotherapy, a peptide or protein antigen is presented by genetic fusions to the phage coat proteins, and the phage construct formulation acts as a protective or preventive vaccine against cancer. In our laboratory, we have recently tested a few peptides (E75, AE37, and GP2) derived from HER2/neu proto‐oncogene as vaccine delivery modalities for the treatment of TUBO breast cancer xenograft tumors of BALB/c mice. Here, in this paper, we discuss the latest advancements in the applications of OVs and bacterial viruses display systems as new and advanced modalities in cancer immune therapeutics.
Modulation of the immune response by Middle East respiratory syndrome coronavirus
Authors: Shokri Somayeh , Mahmoudvand Shahab , Taherkhani Reza , Farshadpour Fatemeh
Published: August 2018

Coronavirus (CoV) infections are commonly associated with respiratory and enteric disease in humans and animals. In 2012, a new human disease called Middle East respiratory syndrome (MERS) emerged in the Middle East. MERS was caused by a virus that was originally called human coronavirus‐Erasmus Medical Center/2012 but was later renamed as Middle East respiratory syndrome coronavirus (MERS‐CoV). MERS‐CoV causes high fever, cough, acute respiratory tract infection, and multiorgan dysfunction that may eventually lead to the death of the infected individuals. The exact origin of MERS‐CoV remains unknown, but the transmission pattern and evidence from virological studies suggest that dromedary camels are the major reservoir host, from which human infections may sporadically occur through the zoonotic transmission. Human to human transmission also occurs in healthcare facilities and communities. Recent studies on Middle Eastern respiratory continue to highlight the need for further understanding the virus‐host interactions that govern disease severity and infection outcome. In this review, we have highlighted the major mechanisms of immune evasion strategies of MERS‐CoV. We have demonstrated that M, 4a, 4b proteins and Plppro of MERS‐CoV inhibit the type I interferon (IFN) and nuclear factor‐κB signaling pathways and therefore facilitate innate immune evasion. In addition, nonstructural protein 4a (NSP4a), NSP4b, and NSP15 inhibit double‐stranded RNA sensors. Therefore, the mentioned proteins limit early induction of IFN and cause rapid apoptosis of macrophages. MERS‐CoV strongly inhibits the activation of T cells with downregulation of antigen presentation. In addition, uncontrolled secretion of interferon ɣ‐induced protein 10 and monocyte chemoattractant protein‐1 can suppress proliferation of human myeloid progenitor cells.
Therapeutic potential of A2 adenosine receptor pharmacological regulators in the treatment of cardiovascular diseases, recent progress, and prospective
Authors: Bahreyni Amirhossein , Avan Amir , Shabani Mohammad , Ryzhikov Mikhail , Fiuji Hamid , Soleimanpour Saman , Khazaei Majid , Hassanian Seyed Mahdi
Published: August 2018

Adenosine and its analogs are of particular interest as potential therapeutic agents for treatment of cardiovascular diseases (CVDs). A2 adenosine receptor subtypes (A2a and A2b) are extensively expressed in cardiovascular system, and modulation of these receptors using A2 adenosine receptor agonists or antagonists regulates heart rate, blood pressure, heart rate variability, and cardiovascular toxicity during both normoxia and hypoxia conditions. Regulation of A2 adenosine receptor signaling via specific and novel pharmacological regulators is a potentially novel therapeutic approach for a better understanding and hence a better management of CVDs. This review summarizes the role of pharmacological A2 adenosine receptor regulators in the pathogenesis of CVDs.
Stem cell‐based therapy for Parkinson’s disease with a focus on human endometrium‐derived mesenchymal stem cells
Authors: Bagheri‐Mohammadi Saeid , Karimian Mohammad , Alani Behrang , Verdi Javad , Tehrani Rana Moradian , Noureddini Mahdi
Published: August 2018

Parkinson’s disease (PD) as an increasing clinical syndrome is a multifunctional impairment with systemic involvement. At present, therapeutic approaches such as l‐3,4‐dihydroxy‐phenylalanine replacement therapy, dopaminergic agonist administration, and neurosurgical treatment intend to relieve PD symptoms which are palliative and incompetent in counteracting PD progression. These mentioned therapies have not been able to replace the lost cells and they could not effectively slow down the relentless neurodegenerative process. Till now, there is a lack of eligible treatment for PD, and stem cells therapy recently has been considered for PD treatment. In this review, we demonstrate how human stem cell technology especially human endometrium‐derived stem cells have made advancement as a therapeutic source for PD compared with other treatments.
5′‐Adenosine monophosphate‐activated protein kinase: A potential target for disease prevention by curcumin
Authors: Soltani Arash , Salmaninejad Arash , Jalili‐Nik Mohammad , Soleimani Anvar , Javid Hossein , Hashemy Seyed Isaac , Sahebkar Amirhossein
Published: August 2018

Curcumin (diferuloylmethane), a yellowish agent extracted from turmeric, is a bioactive compound known for its anti‐inflammatory, antiproliferative, antidiabetic, and anticancer activities. Multiple lines of evidence have indicated that curcumin regulates several regulatory proteins in the cellular signal transduction pathway. AMP‐activated protein kinase (AMPK) is one of the central regulators of cellular metabolism and energy homeostasis, which is activated in response to increasing cellular adenosine monophosphate/adenosine triphosphate ratio. AMPK plays a critical role in regulating growth and reprogramming metabolism and is linked to several cellular processes including apoptosis and inflammation. Recently, it has been demonstrated that AMPK is a new molecular target affected by curcumin and its derivatives. In this review, we discuss recent findings on the targeting of AMPK signaling by curcumin and the resulting impact on the pathogenesis of proinflammatory diseases. We also highlight the therapeutic value of targeting AMPK by curcumin in the prevention and treatment of proinflammatory diseases, including cancers, atherosclerosis, and diabetes.
Subacute treatment of carprofen facilitate splenocardiac resolution deficit in cardiac injury
Authors: Halade Ganesh V , Kain Vasundhara , Wright Griffin M , Jadapalli Jeevan Kumar
Published: August 2018

Inflammation-limiting nonsteroidal pain relievers magnify myocardial infarction (MI) incidences and increase re-admission events in heart failure (HF) patients. However, the molecular and cellular mechanism of this provocative adverse effect is unclear. Our goal was to determine whether carprofen (CAP) impedes splenic leukocyte-directed acute inflammation-resolving response in cardiac injury. After subacute CAP treatment, mice were subjected to permanent coronary ligation maintaining MI- and naïve-controls. Spleen and left ventricle (LV) leukocytes were quantitated using flow cytometry pre- and 24 h post-MI. The inflammation resolution mediators were quantified using mass spectrometry while splenocardiac apoptosis and leukocyte phagocytosis were measured by immunofluorescence and ImageStream, respectively. Subacute CAP treatment promoted strain and cardiac dysfunction before MI and coronary occlusion showed signs of acute HF in CAP and MI-controls. Subacute CAP-injected mice had pre-activated splenic neutrophils, an over activated “don't eat me” signal (CD47) with reduced total Mϕs (F4/80+) and reparative Mϕs (F4/80/Ly6Clo/CD206) compared with control in LV and spleen. Post-MI, CAP pre-activated neutrophils (Ly6G+) were intensified and reduced reparative neutrophils (Ly6G+/CD206+) and Mϕs (F4/80/Ly6Clo) in LV was indicative of non-resolving inflammation compared with MI-control. Subacute CAP treatment deferred neutrophil phagocytosis functions in the spleen and LV and was more evident post-MI compared with MI-control. CAP pre-activated splenic neutrophils that tailored the Mϕ phagocytosis thereby increased splenocardiac leukocyte death. CAP over amplified COX-1 and COX-2 compared with MI-control and failed to limit prostaglandins and thromboxane in post-MI setting. Further, CAP reduced cardiac-protective epoxyeicosatrienoic acids and over amplified pyrogenic inflammatory cytokines and reduced reparative cytokines, thereby non-resolving inflammation.

Inflammation-limiting pain relievers magnify myocardial infarction incidences, and therefore redefined the mechanism that subacute carprofen treatment in mice pre-activates splenic neutrophils with signs of nonresolving inflammation.
Integrated population model to improve knowledge and management of Idaho wolves
Authors: Horne Jon S. , Ausband David E. , Hurley Mark A. , Struthers Jennifer , Berg Jodi E. , Groth Kayte
Published: August 2018

Recently, several states in the western United States have assumed management authority of gray wolves (Canis lupus). Wolves pose a challenge for management agencies who must reconcile interests related to conservation of an ecologically important carnivore with management of a dominant predator of ungulates that are highly valued by the hunting public. Thus, managers seek reliable information on the status of wolf populations, the implications of management actions, and the effects of wolf predation on ungulates. We developed an integrated population model (IPM) for wolves in Idaho to assess their status and evaluate the effects of harvest on wolf demographics. We combined pack counts with known‐fate data from global positioning system (GPS)‐collared wolves to obtain estimates of pack size, harvest, non‐harvest mortality, dispersal, and recruitment. Our application emphasizes some of the key benefits of an IPM approach including estimation of parameters for which no direct data are available, the ability to reconstruct pack sizes during periods when count data were missing, and an evaluation of harvest effects on wolf population dynamics. Mean size of wolf packs averaged 5.5 from 2005–2016. There was a general decline in pack size from 2006–2012 with the smallest occurring in 2012, just after the 2011–2012 harvest season. Since 2012, mean pack size has increased, coinciding with a declining trend in the probability of harvest. We found no difference in mid‐year recruitment of wolves into packs during periods with versus without harvest and concluded that harvest mortality is additive to non‐harvest mortality. Thus, harvest may be an effective tool for agencies to manage wolf populations. Although our IPM was informative for wolf management, future monitoring will likely benefit from seeking less costly data sources within an IPM framework. © 2018 The Wildlife Society.
Effects of distribution, behavior, and climate on mule deer survival
Authors: Schuyler Elizabeth M. , Dugger Katie M. , Jackson Dewaine H.
Published: August 2018

Mule deer (Odocoileus hemionus hemionus) populations in North America are a valuable economic wildlife resource, with the managed harvest of this species reflecting societal values and recreational opportunities in many parts of the western United States. Managing mule deer populations while allowing for harvest requires an understanding of the species’ population dynamics, including the specific factors associated with population change. We conducted a 7‐year (2005–2012) study designed to investigate habitat use and survival of mule deer in eastern Oregon, USA. We used known‐fate data for 408 adult female radio‐collared mule deer to estimate monthly survival rates and to investigate factors that might affect these rates, including seasonal distribution, temporal effects (seasonal, annual, and trends across season and year), movement behavior, and local weather and regional climatic covariates. Variation in survival rates of female mule deer was best explained by an additive effect of migration behavior, differences in survival during the fall migration period compared to the rest of the annual cycle, and precipitation levels on winter ranges of individual deer. Estimates of annual survival were higher for migrants (0.81–0.82), compared to residents (0.76–0.77). Survival was lower for migrants and residents during fall migration (Oct–Nov) and higher amounts of winter precipitation increased survival of both groups. The results of our study suggest that migrating to potentially higher quality summer foraging areas outweighed the cost of traveling through unfamiliar habitats and energy expenditure associated with migration. © 2018 The Wildlife Society.
Mobile app technology is associated with improved otolaryngology resident in‐service performance
Authors: Kuperstock Jacob E. , Horný Michal , Platt Michael P.
Published: August 2018

Objective

Otolaryngology residents face time‐management challenges between clinical duties and self‐directed learning. Mobile devices provide a new medium for education that could aid with educational efficiency. The objective of this study was to investigate whether spaced repetition mobile app use of an otolaryngology question bank was associated with improving factual knowledge as measured by in‐service exam performance.

Methods

For approximately 6 months prior to the 2016 in‐service examination, 12 otolaryngology residents at a single institution were provided access to a spaced‐repetition app with a preloaded licensed otolaryngology review question bank. The number of questions answered, as well as the time spent on the app, were electronically tracked. The associations of app usage on in‐service results were analyzed using an autoregressive model adjusted for prior historical Otolaryngology Trainee Examination performance and postgraduate year.

Results

Eleven residents used the mobile app and were included in the analysis for an average of 304 minutes (range: 3 to 1,020) and reviewed on average 679 questions (range: 6 to 1,934). Controlling for residency year and prior performance, app usage was associated with an improvement by 2.92 percentage points (pp) (95% confidence interval [CI]: 0.14, 5.70) on overall in‐service score. Allergy and pediatric subsection scores improved by 11.3 pp (95% CI: 3.8, 18.8) and 15.2 pp. (95% CI: 8.9, 21.5), respectively. Increased app use was associated with a score improvement by 0.008 pp per minute of use (95% CI: 0.004, 0.012).

Conclusion

Use of mobile spaced‐repetition technology can aid resident factual knowledge retention measured by improved in‐service exam performance.

Level of Evidence

4 Laryngoscope, 129:E15–E20, 2019
Compensation of Otolaryngologists in the Veterans Health Administration: Is There a Gender Gap?
Authors: Dermody Sarah M. , Litvack Jamie R. , Randall James A. , Malekzadeh Sonya , Maxwell Jessica H.
Published: August 2018

Objectives/Hypothesis

To determine if gender pay disparity exists amongst otolaryngologists employed by the Veterans Health Administration (VHA).

Study Design

cross‐sectional analysis.

Methods

Board‐certified otolaryngologists employed at all complex Veterans Affairs Medical Centers (VAMCs) in 2016 were identified. Salaries were collated using the Enterprise Human Resources Integration–Statistical Data Mart dataset. Additional variables, including gender, years since medical school graduation, professorship status, h‐index, and geographic location were collected. A multivariate linear regression analysis was performed where salary was the primary outcome of interest and gender was accounted for as an independent predictor while controlling for professional characteristics, geographic location, and seniority.

Results

Sixty‐nine VHA surgical programs with an operative designation of “complex” were identified. Two hundred sixty board‐certified otolaryngologists, including 197 (75.8%) men and 63 (24.2%) women, were identified. Salary data were available on 210 of these otolaryngologists. In 2016, the mean salary for male and female otolaryngologists was not significantly different ($266,707 ± $31,624 vs. $264,674 ± $27,027, P = .918) nor were salaries in early career ($243,979 ± $31,749 vs. $254,625 ± $24,558, respectively; P = .416). On multivariate linear regression analysis, number of years since graduation (P = .009) and h‐index (P = .049) were independent predictors of salary, but gender, geographic location, and faculty rank were not.

Conclusions

Although the gender pay gap persists in many areas of medicine and surgery, otolaryngologists employed at complex VAMCs do not experience gender pay disparity. The use of specific and objective criteria to establish and adjust salaries can reduce and potentially eliminate gender pay disparity. These findings may help to guide institutional policies in other practice environments.

Level of Evidence

2b. Laryngoscope, 129:113–118, 2019
Management and Follow‐up Results of Salivary Fistulas Treated With Botulinum Toxin
Authors: Send Thorsten , Bertlich Mattis , Eichhorn Klaus W. , Bootz Friedrich , Jakob Mark
Published: August 2018

Objectives/Hypothesis

Salivary fistulas are a common minor complication of parotid surgery. botulinum toxin has repeatedly been reported to be an adequate treatment of this entity. To date, there is little scientific evidence for clinical decision making after appearance of a salivary fistula.

Study Design

Retrospective chart analysis of 16 patients who had been treated with botulinum toxin for salivary fistula.

Methods

All patients who had been treated for salivary fistula at a tertiary referral hospital from 2010 to 2016 were included. Patient files were used to obtain characteristics of patients, treatment, and follow‐up.

Results

Sixteen patients with salivary fistula received 27 injections of botulinum toxin. Nine patients required one injection for the fistula to heal, five patients needed two injections, and one patient needed three and four injections, respectively. No patient underwent additional surgery or radiotherapy. We observed no adverse effects in any patient treated with botulinum toxin.

Conclusions

In most cases of salivary fistula, injections of botulinum toxin are a valid treatment. If the initial injection is not successful, injections may be repeated once. Otherwise, revision surgery should be considered. In general, treatment with botulinum toxin should be commenced in an earlier stage and with higher dosages.

Level of Evidence

4 Laryngoscope, 129:403–408, 2019
Regionalization of head and neck cancer surgery may fragment care and impact overall survival
Authors: Chen Michelle M. , Megwalu Uchechukwu C. , Liew Jazmine , Sirjani Davud , Rosenthal Eben L. , Divi Vasu
Published: August 2018

Objective

While surgical treatment concentrates in tertiary care centers, an increasing number of patients request postoperative radiation therapy (PORT) at a separate center closer to home. Our goal was to determine whether fragmentation of surgery and PORT were associated with poorer oncologic outcomes.

Methods

We conducted a retrospective cohort study of 32,813 head and neck cancer patients treated with surgery and PORT in the National Cancer Data Base. Our main outcome was overall survival (OS). Statistical analysis included χ2, t tests, Kaplan‐Meier, and Cox regression analysis.

Results

Fragmented care was independently associated with increased risk of mortality (hazard ratio [HR], 1.08; 95% confidence interval [CI], 1.03–1.13), whereas distance to surgical center > 30 miles (HR, 0.92; 95% CI, 0.87–0.97) was associated with improved OS. On subgroup analysis, fragmented care was associated with decreased OS only among patients who had surgery at an academic center (HR, 1.10; 95% CI, 1.04–1.17). Within academic centers, greater distance from the surgical center was associated with improved survival only in patients who received PORT at the same facility (HR, 0.85; 95% CI, 0.78–0.93), but this effect was negated among patients who had fragmented care (HR, 0.97; 95% CI, 0.85–1.11).

Conclusion

When cancer care is fragmented, there is no longer a survival benefit for patients to travel for surgical care at academic medical centers. Fragmented care is independently associated with worse survival, and further research is needed to evaluate the causes of this difference in survival to determine if improving care coordination can mitigate this survival difference.

Level of Evidence

NA

Laryngoscope, 129:1413–1419, 2019
Free Flap Transfer for Pediatric Head and Neck Reconstruction: What Factors Influence Flap Survival?
Authors: Liu Shuo , Zhang Wen‐bo , Yu Yao , Wang Yang , Mao Chi , Guo Chuan‐bin , Yu Guang‐yan , Peng Xin
Published: August 2018

Objectives

The objective of this study was to identify the factors that influence free flap survival after head and neck reconstructive surgery in pediatric patients.

Methods

One hundred thirty consecutive cases of head and neck reconstruction with free flaps in pediatric patients at the Department of Oral and Maxillofacial Surgery at Peking University School and Hospital of Stomatology, Beijing, People's Republic of China, between 1999 and 2017 were reviewed. A single head and neck surgical team performed all the included surgeries. Demographic and surgical patient data with possible associations with free flap survival were recorded. Relevant influencing factors were determined using the χ2 test and logistic regression analysis.

Results

There were 135 free flap transfers performed in the patients, with an overall success rate of 95.6%. Free flap failure occurred in six flaps (4.4%). Arterial crisis was the main cause of flap failure. The overall complication rate was 7.0%. Patient age (5–9 years old; odds ratio, 13.397; 95% confidence interval, 1.167–153.838; P = 0.037) was a statistically significant risk factor influencing free flap survival. Donor site, defect region, recipient vessel, and surgery time were not associated with free flap outcome.

Conclusion

Free flap transfer for head and neck reconstruction in pediatric patients is safe and reliable. However, special attention should be paid to pediatric patients under 9 years of age when performing head and neck reconstruction.

Level of Evidence

4

Laryngoscope, 129:1915–1921, 2019
Outcome measures for pediatric laryngotracheal reconstruction: International consensus statement
Authors: Balakrishnan Karthik , Sidell Douglas R. , Bauman Nancy M. , Bellia‐Munzon Gaston F. , Boesch R. Paul , Bromwich Matthew , Cofer Shelagh A. , Daines Cori , de Alarcon Alessandro , Garabedian Nöel , Hart Catherine K. , Ida Jonathan B. , Leboulanger Nicolas , Manning Peter B. , Mehta Deepak K. , Monnier Philippe , Myer Charles M. , Prager Jeremy D. , Preciado Diego , Propst Evan J. , Rahbar Reza , Russell John , Rutter Michael J. , Thierry Briac , Thompson Dana M. , Torre Michele , Varela Patricio , Vijayasekaran Shyan , White David R. , Wineland Andre M. , Wood Robert E. , Wootten Christopher T. , Zur Karen , Cotton Robin T.
Published: August 2018

Objectives

Develop multidisciplinary and international consensus on patient, disease, procedural, and perioperative factors, as well as key outcome measures and complications, to be reported for pediatric airway reconstruction studies.

Methods

Standard Delphi methods were applied. Participants proposed items in three categories: 1) patient/disease characteristics, 2) procedural/intraoperative/perioperative factors, and 3) outcome measures and complications. Both general and anatomic site‐specific measures were elicited. Participants also suggested specific operations to be encompassed by this project. We then used iterative ranking and review to develop consensus lists via a priori Delphi consensus criteria.

Results

Thirty‐three pediatric airway experts from eight countries in North and South America, Europe, and Australia participated, representing otolaryngology (including International Pediatric Otolaryngology Group members), pulmonology, general surgery, and cardiothoracic surgery. Consensus led to inclusion of 19 operations comprising open expansion, resection, and slide procedures of the larynx, trachea, and bronchi as well as three endoscopic procedures. Consensus was achieved on multiple patient/comorbidity (10), disease/stenosis (7), perioperative‐/intraoperative‐/procedure‐related (16) factors. Consensus was reached on multiple outcome and complication measures, both general and site‐specific (8 general, 13 supraglottic, 15 glottic, 17 subglottic, 8 cervical tracheal, 12 thoracic tracheal). The group was able to clarify how each outcome should be measured, with specific instruments defined where applicable.

Conclusion

This consensus statement provides a framework to communicate results consistently and reproducibly, facilitating meta‐analyses, quality improvement, transfer of information, and surgeon self‐assessment. It also clarifies expert opinion on which patient, disease, procedural, and outcome measures may be important to consider in any pediatric airway reconstruction patient.

Level of Evidence

5 Laryngoscope, 129:244–255, 2019
Objectively Measuring Observer Attention in Severe Thyroid‐Associated Orbitopathy: A 3D Study
Authors: Liao David , Ishii Masaru , Darrach Halley M. , Bater Kristin L. , Smith Jane , Joseph Andrew W. , Douglas Raymond S. , Joseph Shannon S. , Ishii Lisa E.
Published: August 2018

Objective

Measure the attentional distraction of facial deformity related to severe thyroid‐associated orbitopathy using three‐dimensional (3D) images and eye‐tracking technology.

Methods

Observers recruited at an academic tertiary referral center viewed 3D facial images of patients with severe thyroid‐associated orbitopathy (TAO) and controls without TAO. An infrared eye‐tracking monitor recorded their eye movements and fixations in real time. Multivariate Hotelling's analysis, followed by planned posthypothesis testing, was used to compare fixation durations for predefined regions of interest, including the eyes, nose, mouth, central triangle, and remaining face without the central triangle between severe TAO patients and controls.

Results

One hundred sixteen observers (mean age 26.4 years, 51% female) successfully completed the eye‐tracking experiment. The majority of their attention was directed toward the central triangle (eyes, nose, mouth). On multivariate analysis, there were significant differences in the distribution of attention between control and severe TAO faces (T2 = 49.37; F(5,922) = 9.8314, P < 0.0001). On planned posthypothesis testing, observers attended significantly more to the eyes (0.77 seconds, P < 0.0001, 95% confidence interval [CI], 0.51, 1.03 seconds) and less to the nose (−0.42 seconds, P < 0.0001, 95% CI, −0.23, −0.62 seconds) in severe TAO patients. There was no significant difference in time spent on the mouth, the total time spent on the central triangle, or time spent in the remaining face between the two groups.

Conclusion

Severe TAO distracted observer attention toward the eyes compared to control patients. These data lend insight into how TAO may alter observers' perceptions of these patients. Future studies should investigate how these changes in observer gaze patterns may reflect the social perception of TAO patients.

Level of Evidence

NA Laryngoscope, 129:1250–1254, 2019